JPWO2009072581A1 - Lactam compound or salt thereof and PPAR activator - Google Patents

Abstract

Provided is a compound having a lactam skeleton useful as a PPAR activator or a salt thereof. A lactam compound represented by formula (1) or a salt thereof. [Wherein, R1 represents a halogen, a hydrocarbon group, a carboxyl group, etc., Z1 represents an arene ring or a heterocycle, Z3 represents an alicyclic or aromatic hydrocarbon ring, and Z2 contains a 5- to 6-membered nitrogen atom. X1 represents a C, O, S or N atom, a group —N—C (═O) — or a group —C (═O) —N—, and R2 has a hydrogen atom or a substituent. R3 and R4 each represents a single bond or a divalent aliphatic hydrocarbon group, at least one is an aliphatic hydrocarbon group, and X2 and X3 are a single bond, O or An S atom, an imino group, etc., A1 represents a single bond or a phenylene group which may have a substituent, Y1 represents a hydrogen atom, a halogen atom, a carboxyl group or the like, a is 0 to 5, b Are 0-2 and c is an integer of 1-3]

Description

  The present invention relates to a lactam compound or a salt thereof (such as a pharmacologically acceptable salt) useful as a peroxisome proliferator-activated receptor (PPAR) agonist (activator), a compound having a lactam skeleton, or a pharmacological thereof A composition (such as a pharmaceutical composition) containing an acceptable salt, a PPAR activator, fatty acid, lipid or sugar abnormalities and various diseases caused by excessive intake compared to metabolism (eg, arteriosclerosis, cerebral infarction) , Stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistant diabetes, obesity, etc.).

  Peroxisome proliferators-activated receptor (PPAR) is a nuclear transcription factor that belongs to the nuclear receptor superfamily and regulates transcription in a ligand-dependent manner. In mammals, three subtypes (isoforms) of PPARα, PPARγ, and PPARδ are known, and various studies have been conducted so far.

  PPARα is mainly expressed in tissues that metabolize fatty acids such as liver, myocardium, and small intestine crypts, and regulates fatty acid metabolism. PPARγ is highly expressed in adipose tissues, and differentiation of adipocytes, lipoprotein lipase and CD36 It has been clarified that the fatty acid uptake is promoted by inducing and the like, and has a function of storing as neutral fat. PPARδ is a transcription receptor (regulatory factor) that is not expressed in tissue specificity at the site of expression, is universally expressed in almost all organs, and is involved in fatty acid metabolism. With regard to fatty acid metabolism, PPARδ is significantly induced in the regulation of fatty acid metabolism such as fatty acid uptake, transport, oxidation, and uncoupling protein of skeletal muscle and myocardium, and differentiation from monocytes to macrophages. It is known to be involved in lipid metabolism.

  Thus, PPAR controls various factors related to lipid and carbohydrate metabolism at the gene level. PPAR is also classified as an RXR (retinoic acid X receptor) heterodimeric receptor, forming a heterodimer with RXR, a nuclear receptor for retinoids, and a peroxisome proliferator response sequence (PPRE) of DNA. Combines with and performs its function.

Therefore, by binding a ligand to PPAR, it activates PPAR (or heterodimer) to promote binding with PPRE, or inhibits binding of PPAR (or heterodimer) to PPRE to target It becomes possible to regulate gene transcription. The ligands that bind to PPAR include endogenous ligands and non-endogenous ligands (exogenous ligands), but for endogenous ligands, long-chain fatty acids act as ligands for all subtypes of PPAR, and ligands for PPARα as eicosanoids, a ligand as 15-deoxy - [delta ^{12, 14} of PPARy ^- although prostaglandin is known, still often elucidated portion not for more information. For exogenous ligands, PPARα ligands (activators) are fibrate hyperlipidemia drugs, phenoxyacetic acids and phenylpropionic acids, PPARγ ligands (activators) are thiazolidinedione (TZD) diabetes drugs (Pioglitazone, rosiglitazone, etc.), non-TZD PPARγ activators (TAK-559 (Takeda Pharmaceutical Co., Ltd.), RG12525 (Aventis), etc.) and the like are known.

  In particular, among PPARδ, PPARδ is delayed in research on its physiological function compared to PPARα and γ, and in recent years, the pharmacology of PPARδ receptor (substance (or activator) having an activating action) has been delayed. Knowledge about activity and pharmaceutical use is being obtained.

  For example, regarding PPAR activator (agonist), WO97 / 28149 (patent document 1) increases the plasma HDL (high density lipoprotein) amount, and is effective in the treatment and prevention of atherosclerotic coronary arteriosclerosis. In addition, there is an effect in the treatment or prevention of atherosclerotic coronary sclerosis when used in combination with an HMG-CoA reductase inhibitor. WO99 / 28115 (Patent Document 2) discloses a therapeutic drug for diabetes and It is useful as an anti-obesity drug, WO99 / 4815 (patent document 3) has a serum cholesterol lowering action and LDL (low density lipoprotein) -cholesterol lowering action, WO01 / 603 (patent document 4). Includes HDL-cholesterol raising action, fibrinogen lowering action, triglyceride lowering action and insulin level lowering action Dyslipidemia, syndrome X (including metabolic syndrome), heart failure, hypercholesterolemia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity And the like, and WO03 / 8967 (Patent Document 5) show a heat production enhancing action, a mitochondrial uncoupling respiratory enhancing action, a fatty acid β oxidation enhancing action, etc., and an antidiabetic agent, It is disclosed that it is useful as an anti-obesity agent or visceral fat accumulation reducing agent and visceral fat accumulation inhibitor. Furthermore, in Patent Document 4 and Proc. Natl. Acad. Sci., USA, vol. 100, p15924-15929, 2003 (Non-patent Document 1), GW501516 (chemical name: known as a selective PPARδ agonist) is known. 2- {2-methyl-4-[({4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazol-5-yl} methyl) thio] phenoxy} acetic acid) The effect of improving obesity and insulin resistance is observed in fat diet-induced obese animals, the improvement of diabetes is observed in genetically obese animals by the action of lowering plasma glucose and blood insulin levels, and WO06 / 1092 (Patent Document 6) discloses that GW501516 is useful as a glucose-dependent insulin secretagogue that responds to hyperglycemia. The structural formula of GW501516 is represented by the following formula.

  From the above points, PPARδ activators are various diseases caused by or affected by abnormal metabolism of fatty acid or sugar and / or imbalance with metabolism due to excessive intake of fatty acid or sugar, such as obesity, insulin resistance It is expected as a prophylactic and / or therapeutic drug for hyperlipidemia, arteriosclerotic diseases (such as atherosclerotic diseases), and metabolic syndrome.

  In WO96 / 30014 (Patent Document 7), as a compound having a farnesyl-protein transferase inhibitory action, and in WO04 / 89897 (Patent Document 8), as a compound having a 5-HT2C activating action, Furthermore, WO05 / 113501 (Patent Document 9) discloses isoindol-1-one derivatives as compounds useful as neuropathic pain control agents, respectively. However, these prior literatures disclose nothing about the binding properties of isoindol-1-one derivatives to PPAR, subtypes of PPAR that can be bound, and the like.

  WO 04/63155 (Patent Document 10) discloses a fused heterocyclic derivative as a PPAR modulator, but does not disclose a compound having a lactam skeleton. Moreover, although the measuring method of PPAR (delta) activation is described, the physiological activity with respect to PPAR (delta) of the said condensed heterocyclic derivative is not disclosed specifically.

In addition, WO05 / 54176 (Patent Document 11) discloses a diphenyl ether compound as a PPAR agonist. In the examples, 2- {4- [3- (5-chloro-1-oxo-1,3) is disclosed. -Dihydro-isoindol-2-ylmethyl) -5-fluoro-phenoxy] -2-methyl-phenoxy} -2-methyl-propionic acid and 2- {4- [3-fluoro-5- (1-oxo-1) , 3-Dihydro-isoindol-2-ylmethyl) -phenoxy] -2-methyl-phenoxy} -2-methyl-propionic acid is described. However, Patent Document 11 also does not disclose the binding characteristics of the above compounds to PPAR, the subtypes of PPAR that can be bound, and the like.
International Publication No. WO 97/28149 International Publication No. WO 97/28115 International Publication No. WO99 / 4815 International publication WO01 / 603 International Publication WO 03/8967 International Publication WO 06/1092 International Publication WO96 / 30014 International Publication No. WO04 / 89897 International Publication WO05 / 113501 International Publication No. WO04 / 63155 International Publication No. WO05 / 54176 Tanaka et al., Proc. Natl. Acad. Sci., USA, vol. 100, p15924-15929, 2003

  Accordingly, an object of the present invention is to provide a novel lactam compound or a salt thereof useful as a PPAR activator (PPARα activator, PPARδ activator, etc.) and a method for producing the same.

  Another object of the present invention is to provide a PPAR activator (agonist) and a pharmaceutical composition capable of effectively activating PPAR (PPARα, PPARδ, etc.).

  Still another object of the present invention includes a lactam compound or a salt thereof and a method for producing the lactam compound or a salt thereof that have a regulated metabolism in the body and can selectively bind to PPAR (PPARα, PPARδ, etc.), and the lactam compound or a salt thereof. It is to provide a pharmaceutical composition and a PPAR activator.

  Another object of the present invention is to provide a preventive and / or therapeutic agent capable of effectively preventing or treating various diseases caused or affected by abnormal metabolism of fatty acids, lipids or sugars and / or excessive intake compared to metabolism. There is to do.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that a compound having a benzopyrrolidone skeleton selectively binds to PPAR (PPARα, PPARβ and / or PPARδ) to improve PPAR activity. As a result, the present invention has been completed.

  That is, the lactam compound of the present invention or a salt thereof is a lactam compound or a salt thereof condensed with a hydrocarbon ring represented by the following formula (1).

[In the formula, R ¹ represents a halogen atom, a hydrocarbon group which may have a substituent, a group —C (═O) —O—R ^5a (wherein R ^5a has a hydrogen atom or a substituent, An optionally substituted acyl group, a carbamoyl group or an N-substituted carbamoyl group, —O—R ^5a (wherein R ^5a is as defined above), —S—R ^5a (wherein R ^5a is the same as above), an amino group or an N-substituted amino group, a sulfonic acid group —SO ₃ H or a sulfonic acid ester group, a sulfonamide group or an N-substituted sulfonamide group, a sulfinic acid group -SO 2 _H or sulfinic acid ester groups, sulfinic acid amide or N- substituted sulfinic acid amide group, a sulfenic acid -SOH or sulfenic acid ester group, a sulfenyl amido group, N- substituted sulfenyl amide group Heterocyclic group, a nitro group, a cyano group or an isocyanate group,
The coefficient a represents an integer of 0 to 5,
Ring Z ¹ represents an arene ring or a hetero ring,
Ring Z ³ represents an alicyclic hydrocarbon ring or an aromatic hydrocarbon ring,
Ring Z ² is a nitrogen-containing 5-6 membered ring having an amido bond as a constituent unit of a ring,
X ¹ represents a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, a group —N—C (═O) — or a group —C (═O) —N—,
R ² represents a hydrogen atom or an alkyl group which may have a substituent, depending on the valence v of X ¹ ;
The coefficient b represents an integer of 0 to 2, depending on the valence v of the X ¹ ,
R ³ and R ⁴ are the same or different and represent a single bond or a divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent, and at least one of R ³ and R ⁴ is A divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent,
X ² and X ³ are the same or different and each represents a single bond, an oxygen atom, a sulfur atom, an imino group, a substituted imino group, or an amide group —NH—C (═O) — or —C (═O) —NH—. Show
A ¹ represents a single bond or a phenylene group which may have a substituent,
Y ¹ represents a hydrogen atom, a halogen atom, a group —C (═O) —O—R ^5a (wherein R ^5a is the same as above), an optionally substituted acyl group, a carbamoyl group, or N— Substituted carbamoyl group, amino group or N-substituted amino group, sulfonic acid group —SO ₃ H or sulfonic acid ester group, sulfinic acid group —SO ₂ H or sulfinic acid ester group, sulfonamide group or N-substituted sulfonamide group, Represents a nitro group or a cyano group,
The coefficient c represents an integer of 1 to 3 depending on the valence v of X ¹ ,
Valence v = b + c + 1,
When A ¹ is a single bond, at least one of X ² and X ³ is a single bond].

Ring Z ¹ may be a C _6-14 arene ring, and ring Z ³ may be an arene ring. Further, each of the ring Z ¹ and the ring Z ³ may be a benzene ring. Further, the ring Z ² may be a nitrogen-containing 5-6 membered ring having an amido bond as a constituent unit of a ring. R ¹ represents a halogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a carboxyl group, or a substituent. An alkoxycarbonyl group which may have, an alkylcarbonyl group which may have a substituent, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an N-acylcarbamoyl group, an N, N- Diacylcarbamoyl group, hydroxyl group, mercapto group, optionally substituted alkoxy group, optionally substituted cycloalkyloxy group, optionally substituted aryloxy group, substituted An alkylthio group which may have a group, a cycloalkylthio group which may have a substituent, an arylthio group which may have a substituent, An amino group, an N-alkylamino group, an N, N-dialkylamino group, an N-acylamino group, an N, N-diacylamino group, a sulfonic acid group, an optionally substituted alkylsulfonyl group, and a substituent. Arylsulfonyl group, sulfonamide group, N-alkylsulfonamide group, N, N-dialkylsulfonamide group, N-arylsulfonamide group, sulfinic acid group, alkylsulfinyl group, arylsulfinyl group, sulfinyl which may have Amido group, N-alkylsulfinylamide group, N, N-dialkylsulfinylamide group, N-arylsulfinylamide group, sulfenyl group, alkylsulfenyl group, arylsulfenyl group, sulfenic acid group, alkylsulfenyl group, aryl Sulfenyl group, sulfenylamide , N- alkylsulfenyl amide group, N- aryl sulfenyl amide group may be a nitro group, or a cyano group. The coefficient a may be an integer from 0 to 3.

The ring Z ² may be a nitrogen atom-containing 5-membered ring having an amide bond as a structural unit of the ring.

X ¹ represents a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, a group —N—C (═O) —, or a group —C (═O) —N—, and when X ¹ is a carbon atom, The coefficient b is 2, when X ¹ is an oxygen atom or a sulfur atom, the coefficient b is 0, and when X ¹ is a nitrogen atom, R ² may have a hydrogen atom or a substituent. Represents an alkyl group, the coefficient b is 1, and when X ¹ is a group —N—C (═O) — or a group —C (═O) —N—, R ² represents a hydrogen atom or a substituent. In addition to indicating an alkyl group that may be present, the coefficient b may be 1. The nitrogen atom of the group —N—C (═O) — or group —C (═O) —N— represented by X ¹ may have a hydrogen atom or substituent represented by R ^2. A good alkyl group is substituted. R ³ and R ⁴ are the same or different and each represents a single bond or a linear or branched divalent saturated or unsaturated aliphatic hydrocarbon group having 1 to 20 carbon atoms. It may be.

X ² and ^{X 3} are the same or different, a single bond, an oxygen atom, a sulfur atom, an imino group, substituted imino group, or an amide group -C (= O) may be -NH-. A ¹ represents a single bond, a divalent aromatic hydrocarbon ring group which may have a substituent, or at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom. Examples thereof include a divalent 5- or 6-membered heterocyclic group which may be contained as a constituent atom and may have a substituent.

Y ¹ represents a hydrogen atom, a halogen atom, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a carbamoyl group, an N-alkylcarbamoyl group, N, N -Dialkylcarbamoyl group, N-acylcarbamoyl group, N, N-diacylcarbamoyl group, N- (alkylsulfonyl) carbamoyl group, N, N-di (alkylsulfonyl) carbamoyl group, amino group, N-alkylamino group, N , N-dialkylamino group, N-acylamino group, N, N-diacylamino group, sulfonic acid group, sulfonic acid alkyl ester group, sulfinic acid group, sulfinic acid alkyl ester group, or cyano group, The coefficient c may be 1.

  The lactam compound of the formula (1) or a salt thereof is represented by the following formula (3)

[Wherein X ⁵ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), —X ^1a (—R ^2a ) _b1 —H (wherein X ^1a is a carbon atom, oxygen atom, sulfur An atom or a nitrogen atom, R ^2a represents a hydrogen atom or an optionally substituted alkyl group, and the coefficient b1 is an integer of 0 to 2 depending on the valence v1 of X ^1a ), a carboxyl group , An alkoxycarbonyl group, a halocarbonyl group or a group -SL (wherein L represents a leaving group). R ¹ , Z ^{1 to} Z ³ , and the coefficient a are the same as described above. ]
And a lactam compound represented by the following formula (4):
^{X 6 -R 3 -X 2 -A 1} -X 3 -R 4 -Y 1 (4)
[Wherein X ⁶ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), or —X ^1b (—R ^2b ) _b2 —H (wherein X ^1b is a carbon atom, oxygen atom, A sulfur atom or a nitrogen atom, R ^2b represents a hydrogen atom or an optionally substituted alkyl group, and the coefficient b2 is 0 or 1 depending on the valence v2 of X ^1b ), a carboxyl group, An alkoxycarbonyl group or a halocarbonyl group, and when X ⁵ is an alkylsulfonyloxy group optionally having a halogen atom or a substituent, X ⁶ is —X ^1b (—R ^2b ) _b2 —H; , when said ^{X 5} is _{^{-X 1a (-R 2a) b1 -H}} , X 6 is a halogen atom, an optionally substituted alkyl sulfonyloxy group, a carboxyl group, an alkoxycarbonyl Or a halocarbonyl group, when ^{X 5} is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, ^{X 6} is -N ^(-R 2a) -H, when ^{X 5} is a group -S-L , X ⁶ is a halogen atom or an alkylsulfonyloxy group which may have a substituent. R ³ , R ⁴ , X ² , X ³ , Y ¹ and A ¹ are the same as above]
It can manufacture by making the compound or its salt represented by these react.

  The lactam compound represented by the formula (1) or a salt thereof is represented by the following formula (10):

[Wherein, X ¹⁰ represents a halogen atom, an alkylsulfonyloxy group which may have a substituent, —X ^3a —H (wherein X ^3a represents an oxygen atom, a sulfur atom, an imino group or a substituted imino group) ), A carboxyl group, an alkoxycarbonyl group or a halocarbonyl group. R ^{1 to} R ³ , Z ^{1 to} Z ³ , X ¹ , X ² , A ¹ and coefficients a to c are the same as described above. ]
Or a salt thereof and the following formula (8)

[Wherein X ¹¹ represents a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), —X ^3a —H (wherein X ^3a represents an oxygen atom, sulfur atom, imino group or substituted imino group) ), A carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and when X ¹⁰ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, X ¹¹ is a group —X ^3a —H. , X ¹⁰ is a group -X ^3a -H, X ¹¹ is a halogen atom, an optionally substituted alkylsulfonyloxy group, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and X ¹⁰ is When it is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ¹¹ is an amino group or an N-monosubstituted amino group. R ⁴ and Y ¹ are the same as above. ]
It can also manufacture by making the compound or its salt represented by these react.

  In the present invention, a PPAR activity comprising as an active ingredient a lactam compound represented by the above formula (1), a compound having a lactam skeleton represented by the following formula (I), or a pharmacologically acceptable salt thereof. Agents are also included. The PPAR activator may be an activator for activating at least one selected from PPARα, PPARγ, and PPARδ. The compound having a lactam skeleton represented by the formula (I) only needs to have the lactam skeleton, and may be variously modified.

(Wherein R ¹ , Z ^{1 to} Z ³ and coefficient a are the same as above)
The pharmaceutical composition of the present invention includes a lactam compound represented by the formula (1), a compound having a lactam skeleton represented by the formula (I) or a pharmacologically acceptable salt thereof, and a carrier. Containing. The preventive or therapeutic agent of the present invention comprises (i) diseases caused by abnormal metabolism of fatty acids, lipids (including fats and oils, phospholipids) or sugars, and / or (ii) compared with metabolism of fatty acids, lipids or sugars. , A preventive or therapeutic agent for diseases caused by excessive intake of fatty acids, lipids or sugars, and a lactam compound represented by the formula (1) or a compound having a lactam skeleton represented by the formula (I) And a pharmacologically acceptable salt thereof as an active ingredient. The disease is selected from the group consisting of arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistant diabetes and obesity Is mentioned.

  In the present invention, a novel lactam compound or a salt thereof useful as a PPAR activator can be easily and efficiently obtained. In addition, since the PPAR activator is composed of a specific lactam compound or a salt thereof, it can be selectively bound to PPAR to effectively activate PPAR. Furthermore, the lactam compound or a salt thereof can be used as a pharmaceutical composition in combination with a carrier or the like. In addition, the lactam compound or a salt thereof is adjusted in metabolism in the body and can selectively bind to PPAR. In addition, since the prophylactic and / or therapeutic agent of the present invention uses a specific lactam compound or a salt thereof, abnormal metabolism of fatty acids, lipids (including fats and oils, phospholipids) or sugars and / or excessive intake compared to metabolism, etc. Various diseases caused by or affected by can be effectively prevented or treated.

Detailed Description of the Invention

(Lactam compound or salt thereof)
The lactam compound in the present invention has a lactam skeleton (lactam skeleton condensed with a hydrocarbon ring) represented by the following formula (I).

[Wherein R ¹ represents a halogen atom, an optionally substituted hydrocarbon group, a group —C (═O) —O—R ^5a (wherein R ^5a has a hydrogen atom or a substituent, An optionally substituted acyl group, a carbamoyl group or an N-substituted carbamoyl group, —O—R ^5e (wherein R ^5e is a hydrogen atom or a substituent) -S-R ^5e (wherein R ^5e is as defined above), an amino group or an N-substituted amino group, a sulfonic acid group -SO ₃ H or a sulfonic acid Ester group, sulfonamide group or N-substituted sulfonamide group, sulfinic acid group —SO ₂ H or sulfinic acid ester group, sulfinic acid amide group or N-substituted sulfinic acid amide group, sulfenic acid group —SOH or sulfenic acid ester group , Sulphe Ruamido group, N- substituted sulfenyl amido group, a heterocyclic group, a nitro group, a cyano group or an isocyanate group,
The coefficient a represents an integer of 0 to 5,
Ring Z ¹ represents an arene ring or a hetero ring,
Ring Z ³ represents an alicyclic hydrocarbon ring or an aromatic hydrocarbon ring,
Ring Z ² represents a nitrogen atom-containing 5- or 6-membered ring having an amido bond as a constituent unit of a ring]
Such a lactam compound may be variously modified and includes, for example, a compound represented by the following formula (Ia).

(In the formula, R ⁷ represents a halogen atom, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, a carboxyl group, an alkoxycarbonyl group, an amino group, a nitro group, a sulfo group or an organic group, and f represents the number of substitutions of R ⁷ . And is an integer greater than or equal to ^1. R ¹ , Z ^{1 to} Z ³ and coefficient a are the same as above)
Examples of the halogen atom represented by R ⁷ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkoxy group include alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy group (C _1-10 alkoxy group, preferably C _1-6 alkoxy group). Examples of the alkylthio group include an alkylthio group corresponding to the alkoxy group. Examples of the alkoxycarbonyl group include alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl group (C _1-10 alkoxy-carbonyl group, preferably C _{1 -6} alkoxycarbonyl group and the like). Examples of the organic group represented by R ⁷ include a chain or cyclic hydrocarbon group which may have a substituent, a chain or cyclic heteroatom-containing group which may have a substituent, and a cyano group. And isocyanate groups.

  Examples of the substituent of the chain-like or cyclic hydrocarbon group and the chain-like or cyclic heteroatom-containing group (first substituent) include, for example, a halogen atom, a hydrocarbon group (an alkyl group such as a methyl group or an ethyl group, cyclohexyl) A cycloalkyl group such as a group, an aryl group such as a phenyl group, a bisaryl group such as a biphenylyl group or a phenylmethylphenyl group), a group having a carboxyl group or a carbonyl group (an acyl group such as an acetyl group or a benzoyl group; an acetoacetyl group) ), Ester bond-containing groups (for example, alkoxycarbonyl groups such as methoxycarbonyl group, bromomethoxycarbonyl group, trifluoromethoxycarbonyl group, ethoxycarbonyl group, hydroxyethylcarbonyl group; cyclohexyloxycarbonyl group, bromocyclohexyl group) Shi A cycloalkyloxycarbonyl group such as an oxycarbonyl group; an aryloxycarbonyl group such as a phenoxycarbonyl group and a methylphenoxycarbonyl group; an alkoxy-carbonylalkyl group and the like; an amide bond-containing group (carbamoyl group, N-monosubstituted or N-2 Substituted carbamoyl group, N-mono or N, N-diacylamino group, etc., hydroxyl group, mercapto group, ether bond-containing group (alkoxy group such as methoxy group, bromomethoxy group, trifluoromethoxy group, ethoxy group; cyclohexyloxy) Group, cycloalkyloxy group such as hydroxycyclohexyloxy group; aryloxy group such as phenoxy group and tolyloxy group), thioether bond-containing group (for example, thioether bond corresponding to the ether bond-containing group) ), Amino group, N-monosubstituted or N, N-disubstituted amino group (for example, alkylamino group such as methylamino group, dimethylamino group and aminoethylamino group; cycloalkylamino group such as cyclohexylamino group; phenyl Arylamino groups such as amino groups), groups having sulfonyl groups (alkylsulfonyl groups (such as methylsulfonyl groups) substituted sulfonyl groups, sulfamoyl groups, substituted sulfamoyl groups (such as methylsulfamoyl groups) )), A heterocyclic group (containing at least one hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom (for example, 1 to 3, preferably 1 or 2) as a ring-constituting atom. Group, etc.). Each of the chain-like or cyclic hydrocarbon group and the chain-like or cyclic heteroatom-containing group may have one or a plurality of these substituents (first substituents), and has a plurality of substituents. The type of the substituent may be the same or different.

  Moreover, these substituents (1st substituent) may have a substituent (2nd substituent) further according to the kind. Examples of such second substituent include a halogen atom, the exemplified hydrocarbon group, carboxyl group, the group having the exemplified carbonyl group, the exemplified ester bond-containing group, the exemplified amide group bond-containing group, Hydroxyl group, mercapto group, the above exemplified ether or thioether bond-containing group, amino group, the above exemplified N-monosubstituted or N, N-disubstituted amino group, the group having the above exemplified sulfonyl group, the above exemplified heterocyclic ring Groups and the like. The number of these second substituents is not particularly limited, and may be one or more. In the case of being plural, the type of the second substituent may be the same or different.

F indicating the number of R ⁷ is not particularly limited, and is, for example, an integer of 1 to 6, preferably an integer of 1 to 4, more preferably an integer of 1 to ³ , depending on the type of ring Z ^3. However, it is usually 1 or 2 in many cases.

  Among such lactam compounds (I), for example, a lactam compound condensed with a hydrocarbon ring represented by the following formula (1) or a salt thereof is a novel compound.

[Wherein X ¹ represents a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, a group —N—C (═O) —, or a group —C (═O) —N—,
R ² represents a hydrogen atom or an alkyl group which may have a substituent, depending on the valence v of X ¹ ;
The coefficient b represents an integer of 0 to 2, depending on the valence v of the X ¹ ,
R ³ and R ⁴ are the same or different and represent a single bond or a divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent, and at least one of R ³ and R ⁴ is A divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent,
X ² and X ³ are the same or different and each represents a single bond, an oxygen atom, a sulfur atom, an imino group, a substituted imino group, or an amide group —NH—C (═O) — or —C (═O) —NH—. Show
A ¹ represents a single bond or a phenylene group which may have a substituent,
Y ¹ represents a hydrogen atom, a halogen atom, a group —C (═O) —O—R ^5a (wherein R ^5a represents a hydrogen atom or a hydrocarbon group which may have a substituent), and a substituent. Acyl group, carbamoyl group or N-substituted carbamoyl group, amino group or N-substituted amino group, sulfonic acid group —SO ₃ H or sulfonic acid ester group, sulfinic acid group —SO ₂ H or sulfinic acid which may have An ester group, a sulfonamide group or an N-substituted sulfonamide group, a nitro group, or a cyano group;
The coefficient c represents an integer of 1 to 3 depending on the valence v of X ¹ ,
Valence v = b + c + 1,
When A ¹ is a single bond, at least one of ^{X 2} and ^{X 3} is a single ^bond, R ^1, Z ¹ ~Z ³ and coefficient a have the same meanings).

In the formula (1) (or (I) or (Ia)), the arene corresponding to the arene ring represented by the ring Z ¹ includes C _6-20 arenes such as benzene, naphthalene, phenanthrene, anthracene, bisaryl ( Biphenyl; bis C _6-20 aryl (thio) ether such as diphenyl ether and diphenyl thioether; bis C _6-20 aryl-C _1-4 alkane such as diphenylmethane and 2,2-diphenylpropane) and the like. The arene ring preferably has at least a benzene ring, and is a condensed ring of a benzene ring and a hydrocarbon ring or a heterocyclic ring [for example, a benzene ring such as indene, biphenylene, fluorene, acenaphthylene, and a 4- to 20-membered monocycle. A condensed ring with a formula or polycyclic hydrocarbon ring; a benzene ring such as benzofuran, chromene, indole, quinoline and the like, and a 4- to 20-membered monocyclic or polycyclic heterocycle (the hetero atom forming the ring is an oxygen atom , A heterocyclic ring containing a sulfur atom and / or a nitrogen atom, etc.). Among the above arene rings, C _6-14 arene rings such as a benzene ring and a naphthalene ring (C _6-10 arene ring etc.) are preferable, and a benzene ring is particularly preferable.

Examples of the heterocycle represented by the ring Z ¹ include a heterocycle having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a constituent atom of the ring (for example, a 4- to 10-membered heterocycle). Can be mentioned. Examples of the heterocycle include an oxygen atom-containing heterocycle [for example, tetrahydrofuran, dioxolane, dioxane, dioxene, furan, pyran, benzofuran, chromene, xanthene, alkylenedioxybenzene (1,2-methylenedioxybenzene, etc.) and the like. Hydrocarbon rings (such as C _6-10 arene rings such as benzene rings) which may be condensed, such as heterocycles containing oxygen atoms, preferably 5- to 8-membered oxygen atoms], sulfur atom-containing heterocycles [ For example, a 4-10 membered (preferably 5-8 membered) sulfur atom that may be condensed with a hydrocarbon ring (such as a C _6-10 arene ring such as a benzene ring) such as dithiolane, thiophene, dithiaphthalene, or thianthrene. -Containing heterocycles], nitrogen atom-containing heterocycles [eg, pyrrolidine, piperidine, pyrazo Monocyclic or polycyclic 4- to 16-membered (preferably monocyclic or bicyclic) such as gin, pyrazoline, pyrroline, pyrazolone, piperazine, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, pyrimidazole, naphthyridine Or a tricyclic 5- to 12-membered) nitrogen atom-containing heterocycle; hydrocarbon rings such as indoline, isoindoline, isoindole, quinoline, and phthalazine (C _6-10 arene ring such as benzene ring) are condensed 4-10-membered (preferably 5- to 8-membered nitrogen-containing heterocycle, etc.)], heterocycles having a plurality of heteroatoms [3-oxothiolane, hydrocarbon rings such as phenoxathiin (C such as benzene ring, etc.) _6-10 4-10 membered (good with arene ring) is fused or unprotected oxygen atom and a sulfur atom Properly 5-8 membered) heterocycle; with morpholine, isoxazole, hydrocarbon ring (C _6-10 arene ring) is optionally fused oxygen atom and a nitrogen atom such as a benzene ring, such as a furazane 4-10 Member (preferably 5 to 8 member) heterocycle; a hydrocarbon atom such as thiadiazine, thiazole, thiadiazole, isothiazole, phenothiazole and the like, and a sulfur atom which may be condensed (such as C _6-10 arene ring such as benzene ring) And a 4- to 10-membered (preferably 5- to 8-membered) heterocyclic ring having a nitrogen atom; an oxygen atom such as oxathiazine, a 5- to 10-membered (preferably 6- to 8-membered heterocyclic ring having a sulfur atom and a nitrogen atom, etc.] Is mentioned. Of these heterocycles, a 4- to 10-membered heterocycle having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a constituent atom of the ring is preferred.

Particularly preferred Z ¹ is a benzene ring.

In the formula (1) (or (I) or (Ia)), the 5- to 6-membered nitrogen atom-containing ring represented by the ring Z ² is the formula (1) (or (I) or (Ia)). May have an amide bond as a constituent unit of the ring Z ² and can be represented by the following formula.

(In the formula, coefficient d is 0 or 1, coefficient e is 0 or 1, coefficient e is 0 when coefficient d is 1, and coefficient e is 0 or 1 when coefficient d is 0. In addition, the ring Z ¹ and the ring Z ³ in the above formulas (1), (I) and (Ia) are omitted)
Such ring ^{Z 2} is specifically represented by the following formula (Z2-1), which is one lactam ring having an unsaturated bond represented by (Z2-2) and (Z2-3).

(In the formula, ring Z ¹ and ring Z ³ in the above formulas (1), (I) and (Ia) are omitted)
Ring Z ² is preferably a nitrogen atom-containing 5-membered ring having an amide bond as a ring constituent unit, and particularly preferably a pyrrolidone ring represented by the above formula (Z2-1). Ring Z ² may have a substituent if necessary.

In the formula (1) (or (I) or (Ia)), examples of the alicyclic hydrocarbon ring represented by the ring Z ³ include a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, a cyclooctene ring, a cyclononene ring, and a cyclodecene ring. Cycloalkene rings such as rings (eg, C _5-12 cycloalkene rings); cycloalkadiene rings such as cyclohexadiene ring, cyclooctadiene ring, cyclodecadiene ring (eg, C _6-12 alkadiene ring), etc. In addition to the monocyclic alicyclic hydrocarbon ring, 4,5,6,7-tetrahydro-1-H-cyclopentacyclohexene ring, 4,5,6,7,8,9-hexahydro-1H-cyclopenta cyclooctene, 1,2-cyclopenta-1 ', 3'-diethyl Roh polycyclic unsaturated alicyclic hydrocarbon ring such as cyclooctene (e.g., C _{8 20} polycyclic unsaturated alicyclic hydrocarbon ring), and the like.

In the formula (1) (or (I) or (Ia)), examples of the aromatic hydrocarbon ring represented by the ring Z ³ include the same arene rings as those exemplified in the item of the ring Z ¹ . Ring Z ³ is preferably a C _6-14 arene ring (such as a C _6-10 arene ring) such as a benzene ring or a naphthalene ring, and more preferably a benzene ring.

Of the rings Z ³ , an aromatic hydrocarbon ring is particularly preferable. Ring Z ¹ and ring Z ³ may be different types of arene rings, but may be the same arene ring. Ring Z ³ may have a substituent if necessary.

In the formula (1), a lactam compound in which both of the rings Z ¹ and Z ³ are benzene rings and the ring Z ² is a pyrrolidone ring represented by the above formula (Z2-1) is represented by the following formula (1a). Can be represented.

(Wherein R ^{1 to} R ⁴ , X ^{1 to} X ³ , Y ¹ , A ¹ , and coefficients a to c are the same as above)
In the formulas (1) and (1a) (or formulas (I) and (Ia)), examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The hydrocarbon group represented by R ¹ includes an aliphatic hydrocarbon group [saturated or unsaturated aliphatic hydrocarbon group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s- Linear or branched alkyl group such as butyl, t-butyl, hexyl, octyl, decyl, dodecyl group (C _1-20 alkyl group, preferably C _1-10 alkyl group); vinyl, 1-propenyl, Linear or branched alkenyl groups such as allyl, isopropenyl, butenyl, pentenyl, hexenyl groups (C _2-20 alkenyl groups, preferably C _2-10 alkenyl groups); alkadienyls such as 1,3-butadienyl groups Group (C _3-20 alkadienyl group, preferably C _4-10 alkadienyl group); ethynyl, propynyl, hexynyl, octynyl group, etc. Any linear or branched alkynyl group (C _2-20 alkynyl group, preferably C _3-10 alkynyl group); aliphatic carbonization with double and triple bonds such as 2-pentene-4-ynyl group A hydrogen group (such as an aliphatic hydrocarbon group having 4 to 20 carbon atoms (preferably 5 to 10 carbon atoms)), an alicyclic hydrocarbon group [an alicyclic hydrocarbon to which an aromatic hydrocarbon ring may be condensed. Groups (saturated or unsaturated alicyclic hydrocarbon groups), for example, cycloalkyl groups such as cyclohexyl and cyclooctyl groups (C _4-10 cycloalkyl groups, preferably C _5-8 cycloalkyl groups, etc.); cyclohexenyl, cycloalkenyl group (C _4-10 cycloalkenyl group, such as preferably a C _5-8 cycloalkenyl group), such as cyclooctenyl group; cyclohexadienyl group What cycloalkadienyl groups _{(C 5-10} cycloalkadienyl group, preferably such as _{C 6-8} cycloalkadienyl group); norbornyl, 5-norbornene-2-yl, norpinyl, such as 3-pinanyl group not A polycyclic alicyclic hydrocarbon group which may have a saturated bond (such as a polycyclic alicyclic hydrocarbon group having 8 to 20 carbon atoms (preferably 10 to 16 carbon atoms)); 2-indenyl, 1- Alicyclic hydrocarbon group (C _4-10 alicyclic hydrocarbon group, preferably C _5-8 aliphatic group) condensed with an aromatic hydrocarbon ring such as acenaphthenyl group (C _6-10 arene ring such as benzene ring). etc. alicyclic hydrocarbon group)], an aromatic hydrocarbon group [phenyl, naphthyl, anthryl, aryl group _{(C 6-20} aryl group such as phenanthryl group, etc. preferably _{C 6-14} aryl group); 5, , 7,8-tetrahydro-2-naphthyl _{(C 4-10} alicyclic hydrocarbon rings such as cyclohexane ring, and preferably a _{C 5-8} cycloalkyl or cycloalkenyl group) alicyclic hydrocarbon ring such groups Condensed aryl groups (such as C _6-20 aryl groups); bisaryl groups such as biphenylyl groups (such as bisC _6-10 aryl groups)] and the like.

-C group represented by ^{R 1 (= O) -O-} R 5a, in ^{-O-R 5a} and ^{-S-R 5a,} examples of the hydrocarbon group represented by ^{R 5a,} is represented by ^{R 1} Examples of the hydrocarbon group are the same as those exemplified in the section of the hydrocarbon group. Among the hydrocarbon groups R ^5a , aliphatic hydrocarbon groups (C _1-10 alkyl group, C _2-10 alkenyl group, etc.), monocyclic alicyclic hydrocarbon groups (C _5-8 cycloalkyl group, etc.) An aromatic hydrocarbon group (an aryl group such as a phenyl group) is preferred.

An acyl group optionally having a substituent represented by R ¹ , an N-substituted carbamoyl group, an N-substituted amino group, an N-substituted sulfonamido group, an N-substituted sulfinic acid amide group, an N-substituted sulfenyl In the amide group, examples of the substituent include a chain or cyclic hydrocarbon group and a chain or cyclic heteroatom-containing group substituent exemplified in the above R ⁷ section (first substituent and second substituent), etc. Can be illustrated.

Examples of the acyl group include aliphatic acyl groups such as alkylcarbonyl groups and alkenylcarbonyl groups (for example, C _1-6 alkyl-carbonyl groups such as acetyl groups (preferably C _1-4 alkyl-carbonyl groups)), Alicyclic acyl groups such as cycloalkylcarbonyl groups (C _5-10 cycloalkyl-carbonyl groups such as cyclohexylcarbonyl groups), aromatic acyl groups (C _6-14 aryl-carbonyl groups such as benzoyl groups), etc. Can be mentioned. As the substituent of the acyl group, a halogen atom, a hydroxyl group, a mercapto group, a linear or branched C _1-4 alkoxy group, a linear or branched C _1-4 alkylthio group, a linear or branched group Linear halo _C1-4 alkoxy group, linear or branched _C1-4 haloalkylthio group, carboxyl group, linear or branched _C1-4 alkoxy-carbonyl group, linear or branched chain Illustrative examples include a C _1-4 alkoxy-carbonyl-C _1-4 alkyl group. The carbamoyl group having a substituent may be either an N-monosubstituted carbamoyl group or an N, N-disubstituted carbamoyl group. For example, an N-alkylcarbamoyl group (C _1-10 such as an N-alkylcarbamoyl group). Alkyl-carbamoyl group), N, N-dialkylcarbamoyl group (N, N-diC _1-10 alkyl-carbamoyl group such as N, N-dimethylcarbamoyl group), N-acylcarbamoyl group (N-acetylcarbamoyl group) N- (C _1-6 alkyl-carbonyl) carbamoyl group, etc.), N, N-diacylcarbamoyl group (N, N-di (C _1-6 alkyl-carbonyl) carbamoyl, such as N, N-diacetylcarbamoyl group) Group, etc.). The N-substituted amino group may be either an N-monosubstituted amino group or an N, N-disubstituted amino group. For example, an N-alkylamino group (N-methylamino, N-ethylamino, N- (C _1-10 alkylamino group such as (hydroxyethyl) amino group), N, N-dialkylamino group (N, N-dimethylamino, N, N-diethylamino, N, N-di (hydroxyethyl) amino group) Di-C _1-10 alkylamino group such as N-acylamino group (N- (C _1-6 alkyl-carbonyl) amino group such as N-acetylamino group), N, N-diacylamino group (N N, N-di (C _1-6 alkyl-carbonyl) amino group such as N, diacetylamino group). Examples of the N-substituted sulfonamido group include N-alkylsulfonamido groups (C _1-10 alkyl-sulfonic acid amide groups such as N-methylsulfonic acid amide group and N-ethylsulfonic acid amide group (N—C _1-10 Alkyl sulfamoyl groups)), N, N-dialkylsulfonamide groups (N, N-dimethylsulfonic acid amide groups, N, N-diethylsulfonic acid amide groups, etc. di-C _1-10 alkyl-sulfonic acid amide groups) And N-arylsulfonamide groups (N—C _6-10 aryl-sulfonic acid amide groups such as N-phenylsulfonic acid amide group) and the like. Examples of the N-substituted sulfinic acid amide group include N-alkylsulfinylamide groups (C _1-10 alkyl-sulfinylamide groups such as N-methylsulfinylamide group and N-ethylsulfinylamide group), N, N-dialkylsulfinyl groups. Amide groups (such as di-C _1-10 alkyl-sulfinylamide groups such as N, N-dimethylsulfinylamide group and N, N-diethylsulfinylamide group), N-arylsulfinylamide groups (such as N-phenylsulfinylamide group) N—C _6-10 aryl-sulfinylamide group and the like). Examples of the N-substituted sulfenyl amide group include an N-alkyl sulfenyl amide group (N—C _1-10 alkyl sulfenyl amide group such as N-methyl sulfenyl amide group) and an N-aryl sulfenyl amide group (N -N-C _6-10 arylsulfenylamide group such as -phenylsulfenylamide group).

Examples of the sulfonic acid ester group represented by R ¹ include an alkylsulfonyl group (eg, a C _1-10 alkylsulfonyl group such as a methylsulfonyl group) which may have a substituent (such as the above-described second substituent). ), An arylsulfonyl group (such as a C _6-10 arylsulfonyl group such as a phenylsulfonyl group or a tolylsulfonyl group) which may have a substituent (such as the second substituent illustrated above), and the like. As the sulfinic acid ester group, an alkylsulfinyl group (such as a C _1-10 alkylsulfinyl group such as a methylsulfinyl group) which may have a substituent (such as the second substituent illustrated above), an arylsulfinyl group (such as And C _6-10 arylsulfinyl groups such as phenylsulfinyl group and tolylsulfinyl group). The sulfenic acid ester group includes an alkyl sulfenyl group (C _1-10 alkyl sulfenyl group such as methyl sulfenyl group) and an aryl sulfenyl group (C _6-10 aryl sulfenyl group such as phenyl sulfenyl group). Etc.).

Examples of the heterocyclic group represented by R ¹ include, for example, at least one (for example, 1 to 3, preferably 1 or 2) heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in a ring structure. The heterocyclic group contained as an atom is mentioned. The heterocyclic group may be a saturated or unsaturated heterocyclic group, and may be any of a non-aromatic group and an aromatic heterocyclic group. The unsaturated bond in the heterocyclic group may be a carbon-carbon double bond or a triple bond, or may be a nitrogen-carbon double bond. Examples of such a heterocyclic group include oxygen atom-containing heterocyclic groups [for example, hydrocarbon rings such as tetrahydrofuranyl, dioxolanyl, dioxanyl, dioxenyl, furanyl, pyranyl, benzofuranyl, chromenyl, xanthenyl, etc. (C _6-10 such as benzene ring). 4-10-membered (preferably 5-8-membered) oxygen atom-containing heterocyclic group etc.] which may be condensed), sulfur atom-containing heterocyclic group [for example, thienyl, dithiolanyl, thiophenyl, dithianaphthyl, thianthrenyl 4-10 membered (preferably 5-8 membered) sulfur atom-containing heterocyclic group, etc., which may be condensed with a hydrocarbon ring such as a C _6-10 arene ring such as a benzene ring], a nitrogen atom-containing hetero Ring groups [eg pyrrolidinyl, piperidinyl, pyrazolidinyl, pyrazolinyl Monocyclic or polycyclic 4 to 16 members (preferably monocyclic, bicyclic or tricyclic) such as pyrrolinyl, pyrazolonyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrimidazolyl, naphthyridinyl 5-12 member) heterocyclic group containing nitrogen atom; hydrocarbon ring such as indolinyl, isoindolinyl, isoindolyl, quinolinyl, phthalazinyl (C _6-10 arene ring such as benzene ring) may be condensed 4-10 Member (preferably 5 to 8 membered) nitrogen atom-containing heterocyclic group, etc.], heterocyclic groups having a plurality of heteroatoms [hydrocarbon rings such as oxothiolanyl, phenoxathiinyl (C _6-10 arenes such as benzene ring) 4 to 4 having an oxygen atom and a sulfur atom that may be condensed) 0-membered (preferably 5-8 membered) heterocyclic group; a morpholinyl, isoxazolyl, a hydrocarbon ring fused which may be oxygen atoms and nitrogen atoms (C _6-10 arene ring such as benzene ring), such as furazanyl 4 to 10-membered (preferably 5 to 8-membered) heterocyclic group; sulfur which may be condensed with a hydrocarbon ring such as thiadiazinyl, thiazolyl, isothiazolyl, phenothiazolyl and the like (C _6-10 arene ring such as benzene ring) 4- to 10-membered (preferably 5- to 8-membered) heterocyclic group having an atom and a nitrogen atom; 5- to 10-membered (preferably 6- to 8-membered) heterocyclic ring having an oxygen atom such as oxathiazinyl, a sulfur atom and a nitrogen atom Group, etc.]. In addition, a carbon atom may be sufficient as the bond of a heterocyclic group, and a nitrogen atom may be sufficient in the heterocyclic group which has a nitrogen atom.

The hydrocarbon group and heterocyclic group represented by R ¹ and the hydrocarbon group represented by R ^5a may have a substituent (first substituent). Such a substituent (first substituent) can be appropriately selected according to the type of R ¹ or R ^5a , for example, a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), hydrocarbon A group [the aliphatic, alicyclic or aromatic hydrocarbon group exemplified in the section of the hydrocarbon group represented by R ¹ (preferably the alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl group exemplified above), etc. ], A carbonyl group (such as a carbonyl group of an oxopyrrolidinyl group), an acyl group [for example, an aliphatic acyl group (saturated or unsaturated aliphatic acyl group such as acetyl, propionyl, butyryl, valeryl, pivaloyl, lauroyl group, etc.) alkylcarbonyl group _{(C 1-20} alkyl - group, preferably a _{C 1-10} alkyl - carbonyl group); acrylo Le, methacryloyl, crotonoyl, alkenylcarbonyl groups such as an oleyl group (C _2-20 alkenyl - carbonyl group, preferably a C _2-10 alkenyl - carbonyl group), etc.); alicyclic acyl group (saturated or unsaturated alicyclic An acyl group, for example, a cycloalkylcarbonyl group such as a cyclohexylcarbonyl group (C _4-10 cycloalkyl-carbonyl group, preferably a C _5-8 cycloalkyl-carbonyl group); a cycloalkenylcarbonyl group such as a cyclohexenylcarbonyl group ( C _4-10 cycloalkenyl-carbonyl group, preferably C _5-8 cycloalkenyl-carbonyl group etc.); aromatic acyl group (benzoyl, naphthoyl group and other arylcarbonyl groups (C _6-20 aryl-carbonyl group, etc.) preferably _{C 6-1} Aryl - carbonyl group), etc.], an ester bond-containing group containing a carboxyl group ^{[-C (= O) -O-} R 5a ( ^wherein said ^{R 5a} same) {e.g., a carboxyl group, methoxycarbonyl, ethoxycarbonyl , An alkoxycarbonyl group such as propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, hexyloxycarbonyl group (C _1-20 alkoxy-carbonyl group, preferably C _1-10 alkoxycarbonyl group); An alkenyloxycarbonyl group such as a loxycarbonyl group (C _2-20 alkenyloxy-carbonyl group, preferably a C _2-10 alkenyloxy-carbonyl group); a cycloalkyloxycarbonyl group such as a cyclohexyloxycarbonyl group (C _{A 4-10} cycloalkyloxy-carbonyl group, preferably a C _5-8 cycloalkyloxy-carbonyl group, etc .; a cycloalkenyloxycarbonyl group such as a cyclohexenyloxycarbonyl group (C _4-10 cycloalkenyloxy-carbonyl group, preferably Is a C _5-8 cycloalkenyloxy-carbonyl group); an aryloxycarbonyl group such as a phenoxycarbonyl group (C _6-20 aryloxy-carbonyl group, preferably a C _6-10 aryloxy-carbonyl group, etc.)}; acetoxy, Cyclohexylcarbonyloxy, acyloxy group corresponding to the above exemplified acyl group such as benzoyloxy group, etc.], amide bond-containing group [for example, carbamoyl group, N-substituted (N-monosubstituted or N, N-disubstituted) exemplified above ) Carbamoy Group, carbazoyl group, ureido group, N-substituted ureido group (N-monosubstituted, N, N-disubstituted or N, N, N-trisubstituted ureido group), allophanoyl group, N-substituted allophanoyl group (N- Mono-substituted, N, N-disubstituted, or N, N, N-trisubstituted allophanoyl groups), semicarbazide groups, N-substituted semicarbazide groups (N-monosubstituted, N, N-disubstituted, N, N, N- Trisubstituted or N, N, N, N-tetrasubstituted semicarbazide group), carbazono group, substituted carbazono group (N-monosubstituted, N, N-disubstituted or N, N, N-trisubstituted carbazono group), acylamino group, etc.], an ether bond-containing group ^{-O-R 5a} containing hydroxyl groups [e.g., hydroxyl group; methoxy, ethoxy, n- propoxy, i- propoxy, n- butoxy, s- butoxy, t-butoxy, Biniruo Exemplified above alkoxy groups corresponding to the alkyl groups, such as groups (C _1-20 alkoxy group, preferably such as C _1-10 alkoxy group); vinyloxy alkenyloxy group corresponding to an alkenyl group exemplified above, such group; wherein A cycloalkyl or cycloalkenyloxy group corresponding to the exemplified cycloalkyl or cycloalkenyl group; an aryloxy group corresponding to the above exemplified aryl group, etc.], a thioether bond-containing group containing a mercapto group —S—R ^5a (eg, mercapto Group; a thioether bond-containing group corresponding to the ether bond-containing group, etc.), an amino group or the above-exemplified N-substituted amino group, sulfonamide group or N-substituted sulfonamide group, sulfinic acid group —SO ₂ H or sulfinic acid Ester group, sulfinic acid amide group or N-substituted sulfi Acid amide group, a sulfenic acid -SOH or sulfenic acid ester group, a sulfenyl amido group, N- substituted sulfenyl amido group, a nitro group, a cyano group and an isocyanate group, can be exemplified.

The hydrocarbon group and heterocyclic group represented by R ¹ and R ^5a may have one or more of these substituents (first substituents), and have a plurality of first substituents. In this case, the kind may be either the same kind or a different kind.

Moreover, the said substituent (1st substituent) may have a substituent (2nd substituent) further according to the kind. Examples of such a second substituent include various substituents exemplified in the section of the first substituent, that is, a halogen atom, a hydrocarbon group, an acyl group, an ester bond-containing group (including a carboxyl group), an amide A bond-containing group, an ether bond-containing group, a thioether bond-containing group, an amino group or the above-exemplified N-substituted amino group, a sulfonamide group or an N-substituted sulfonamide group, a sulfinic acid group-SO ₂ H or a sulfinic acid ester group, Examples include sulfinic acid amide groups or N-substituted sulfinic acid amide groups, sulfenic acid groups or sulfenic acid ester groups, sulfenyl amide groups, N-substituted sulfenyl amide groups, nitro groups, cyano groups, and isocyanate groups. The number of these second substituents is not particularly limited, and may be one or more. In the case of being plural, the type of the second substituent may be the same or different.

When the hydrocarbon group represented by R ¹ and R ^5a is a saturated or unsaturated aliphatic hydrocarbon group, the substituent of these hydrocarbon groups is a halogen atom, —C (═O) —O—R. ^5a (wherein R ^5a is the same as above), an optionally substituted acyl group, an optionally substituted carbamoyl group, an ether or thioether bond-containing group, an amino group or an N-substituted group Amino group, sulfonic acid group, sulfonic acid ester group, sulfonamide group, sulfinic acid group —SO ₂ H or sulfinic acid ester group, sulfinic acid amide group or N-substituted sulfinic acid amide group, sulfenic acid group —SOH or sulfenic acid At least one selected from an ester group, a sulfenylamide group, an N-substituted sulfenylamide group, a heterocyclic group, a nitro group, a cyano group, and an isocyanate group There may be.

When the hydrocarbon group represented by R ¹ and R ^5a is a saturated or unsaturated alicyclic hydrocarbon group or an aromatic hydrocarbon group, the substituent of these hydrocarbon groups is a halogen atom, an alkyl group, Haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, acylalkyl group, aminoalkyl group, N-alkylaminoalkyl group, —C (═O) —O—R ^5a (wherein R ^5a is the same as above), substitution An acyl group which may have a group, a carbamoyl group which may have a substituent, an ether or thioether bond-containing group, an amino group or an N-substituted amino group, a sulfonic acid group, a sulfonic acid ester group, a sulfonamide group, sulfinic acid group -SO ₂ H or sulfinic acid ester groups, sulfinic acid amide or N- substituted sulfinic acid amide group, sulfenic acid group -SO It may be at least one selected from H or sulfenic acid ester group, sulfenylamide group, N-substituted sulfenylamide group, heterocyclic group, nitro group, cyano group and isocyanate group.

Among R ¹ , a halogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, a carboxyl group, and a substituent An alkoxycarbonyl group which may have a substituent, an alkylcarbonyl group which may have a substituent, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an N-acylcarbamoyl group, an N, N A diacylcarbamoyl group, a hydroxyl group, a mercapto group, an alkoxy group which may have a substituent, a cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, An optionally substituted alkylthio group, an optionally substituted cycloalkylthio group, an optionally substituted arylthio group Group, amino group, N-alkylamino group, N, N-dialkylamino group, N-acylamino group, N, N-diacylamino group, sulfonic acid group, optionally substituted alkylsulfonyl group, substituted Arylsulfonyl group which may have a group, sulfonamido group (sulfamoyl group), N-alkylsulfonamido group (N-alkylsulfamoyl group), N, N-dialkylsulfonamido group, N-arylsulfonamido Group, sulfinic acid group, alkylsulfinyl group, arylsulfinyl group, sulfinylamide group, N-alkylsulfinylamide group, N, N-dialkylsulfinylamide group, N-arylsulfinylamide group, sulfenic acid group, alkylsulfenyl group, Arylsulfenyl group, sulfenylamide group, N- Ruki Rusuru phenylamide group, N- aryl sulfenyl amido group, a nitro group, or cyano group is preferable.

Among the above R ¹ (and its substituents (ie, the first substituent, the combination of the first and second substituents)), a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) At least selected from a halogen atom (a fluorine atom, a chlorine atom, etc.), a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group A linear or branched C _1-4 alkyl group which may have one kind of substituent (for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoro mono- to pentahalo _{C 1-4} alkyl group (preferably mono- to tetrahalo _{C 1-4} alkyl group such as ethyl, especially tri or pentahalo _{C 1-3,} such as trihalomethyl Alkyl group), etc.); carboxyl group; a halogen atom, a hydroxyl group, a linear or branched _{C 1-4} alkoxy group, a linear or branched halo _{C 1-4} alkoxy group, a carboxy _{-C 1- 4} alkyl group and a linear or branched C _1-4 alkoxy - carbonyl -C _1-4 at least one of substituents may be straight-chain selected from an alkyl group or a branched C _{1 -4} alkoxy-carbonyl group; halogen atom, hydroxyl group, mercapto group, linear or branched C _1-4 alkoxy group, linear or branched C _1-4 alkylthio group, linear or branched chain Jo halo C _1-4 alkoxy group, a linear or branched C _1-4 haloalkylthio group, a carboxyl group, a linear or branched C _1-4 alkoxy - carbonyl group and linear or branched Chain C _1-4 alkoxy - carbonyl -C _1-4 at least one may have a substituent group linear or branched C _1-4 alkyl selected from alkyl groups - carbonyl group; a carbamoyl group N—C _1-4 alkylcarbamoyl group, N, N-diC _1-4 alkylcarbamoyl group, N—C _1-4 alkylcarbonyl-carbamoyl group, N, N-diC _1-4 alkylcarbonyl-carbamoyl group; Hydroxyl group; mercapto group; at least one substituent selected from a halogen atom, hydroxyl group, linear or branched C _1-4 alkoxy group and linear or branched halo C _1-4 alkoxy group; the have they may be straight-chain or branched-chain _{C 1-4} alkoxy group (e.g., difluoromethoxy, trifluoromethoxy, 2,2,2 Ruoroetokishi, mono- to pentahalo C _1-4 alkoxy group (preferably mono- to tetrahalo C _1-4 alkoxy groups, especially such as tri to pentahalo C _1-3 alkoxy group such as trihalomethoxy) such as perfluoro ethoxy, etc.); a halogen atom A linear group optionally having at least one substituent selected from a hydroxyl group, a linear or branched C _1-4 alkoxy group, and a linear or branched halo C _1-4 alkoxy group Or branched C _1-4 alkylthio groups (for example, mono to pentahalo C _1-4 alkylthio groups such as trifluoromethylthio, 2,2,2-trifluoroethylthio, perfluoroethylthio (preferably mono to tetrahalo) C _1-4 birds through pentahalo C, such as an alkylthio group, especially trihalomethyl thio _-3, etc. alkylthio group), etc.); an amino group; _{N-C 1-4} alkylamino group, N, _{N-di-C 1-4} alkylamino group, _{N-C 1-4} alkyl-carbonyl - amino group, N, N _-DiC1-4 alkylcarbonyl-amino group; _C1-4 alkylsulfonyl group; Sulfonamide group (sulfamoyl group); N- _C1-4 alkylsulfonamido group (N- _C1-4 alkylsulfamoyl group) ) Or a nitro group is preferred.

In the formulas (I), (Ia), (1), and (1a), the coefficient a indicating the number of R ¹ can be appropriately selected according to the type of the ring Z ¹ , for example, an integer of 0 to 4, preferably 0. It may be an integer of -3, more preferably an integer of 0-2, especially 1 or 2. Incidentally, the substitution position of R ¹ is not particularly limited, can be selected according to the kind of ring Z ^1, for example, when ring Z ¹ is a benzene ring, the position of the substituents R ¹ are, o- position, It may be m-position or p-position, and is usually m-position or p-position (particularly p-position). When ring Z ¹ is a benzene ring and a is 1 or more, the substitution position of R ¹ may be any of positions 2 to 6, and is preferably at least m-position and / or p-position (particularly at least p-position). When a plurality of substituents R ¹ are substituted on the benzene ring Z ¹ , the positions of the substituents R ¹ are usually p-position, o-position and / or m-position. In the p-position of the benzene ring Z ¹ , a halogen atom or a halogen-containing group (haloalkyl group, haloalkoxy group, haloalkylthio group, etc.), alkyl group, alkoxy group, alkylthio group, carboxyl group, alkoxycarbonyl group, etc. The substituent may be substituted.

In the formulas (1) and (1a), X ¹ represents a carbon atom, a hetero atom (oxygen atom, sulfur atom or nitrogen atom), a group —N—C (═O) —, or a group —C (═O). -N-, preferably a carbon atom, oxygen atom or sulfur atom. The nitrogen atom of the group —N—C (═O) — or group —C (═O) —N— represented by X ¹ may have a hydrogen atom or substituent represented by R ^2. A good alkyl group is substituted.

In the formula (1) and the formula (1a), the substitution position of X ¹ is usually on a constituent atom of the ring Z ³ such as a benzene ring. In the formula (1a), the substitution position of X ¹ is The benzopyrrolidone skeleton in which the benzene ring is condensed to the pyrrolidone ring may be at the 4th to 7th position, preferably the 4th, 5th or 7th position, and more preferably the 4th position.

Examples of the alkyl group represented by R ² include the alkyl groups exemplified above, for example, a C _1-20 alkyl group, preferably a C _1-10 alkyl group, and more preferably a C _1-6 alkyl group (eg, C _{1 1- 4} alkyl group). The alkyl group may be linear or branched. Examples of the substituent of the alkyl group include the substituents exemplified in the section of the first substituent of the hydrocarbon group represented by R ¹ and R ^5a , for example, a halogen atom, an aliphatic carbon having an unsaturated bond. Esters containing hydrogen groups (alkenyl groups, alkynyl groups, alkadienyl groups, etc.), alicyclic hydrocarbon groups (cycloalkyl groups, cycloalkenyl groups, etc.), aromatic hydrocarbon groups (aryl groups, etc.), acyl groups, carboxyl groups Bond-containing group, amide bond-containing group, ether bond-containing group containing hydroxyl group, thioether bond-containing group containing mercapto group, amino group or N-substituted amino group, sulfonamide group or N-substituted sulfonamide group, sulfinic acid group Or sulfinic acid ester group, sulfinic acid amide group or N-substituted sulfinic acid amide group, sulfenic acid group or sulfinic acid group E phosphate ester group, sulfenyl amido group, N- substituted sulfenyl amido group, a nitro group, a cyano group and an isocyanate group, can be exemplified. The alkyl group may have one or more of these substituents. When it has a plurality of substituents, the kind thereof may be the same or different.

R ² is preferably at least one selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group.

The coefficient b indicating the number of R ² is an integer of 0 to 2 according to the valence v of X ¹ . The coefficient b is 2 when X ¹ is a carbon atom, and the coefficient b is ¹ when X ¹ is a nitrogen atom. When X ¹ is an oxygen atom or a sulfur atom, the coefficient b is 0. The coefficient b is 0 when the X ¹ is an oxygen atom or a sulfur atom. When X ¹ is a carbon atom, R ² is preferably a hydrogen atom or an alkyl group (for example, C 1) optionally having a substituent (such as at least one substituent selected from a halogen atom and a hydroxyl group). _1-4 alkyl group, etc.). When X ¹ is a nitrogen atom, R ² is preferably a hydrogen atom or an alkyl group (for example, C ₁ ) optionally having a substituent (such as at least one substituent selected from a halogen atom and a hydroxyl group). _-4 alkyl group and the like, and the coefficient b is 1. When X ¹ is a group N—C (═O) —, R ² may preferably have a hydrogen atom or a substituent (such as at least one substituent selected from a halogen atom and a hydroxyl group). An alkyl group (for example, a C _1-4 alkyl group and the like) is shown, and the coefficient b is 1.

In the formulas (1) and (1a), R ³ and R ⁴ are the same or different and are a single bond or a divalent saturated or unsaturated aliphatic hydrocarbon group (straight chain) which may have a substituent. A divalent saturated or unsaturated aliphatic hydrocarbon group having about 1 to 20 carbon atoms in the form of a branched or branched chain, and at least one of R ³ and R ⁴ may have a substituent. A saturated saturated or unsaturated aliphatic hydrocarbon group.

Examples of the divalent saturated or unsaturated aliphatic hydrocarbon group represented by R ³ and R ⁴ include alkylene or alkylidene group, alkenylene group, alkynylene group [either linear or branched chain such as ethynylene or propynylene group] An alkynylene group (C _2-20 alkynylene group, preferably C _3-10 alkynylene group, etc.)] or a dienylene group [linear or branched chain such as butadiene diyl group] may be used. An alkadiene diyl group (C _3-20 alkadienylene group, preferably C _4-10 alkadienylene group etc.) and the like. Of these hydrocarbon groups, an alkylene or alkylidene group, an alkenylene group, and the like are preferable.

Examples of the alkylene or alkylidene group include methylene, ethylene, propylene, ethylethylene, trimethylene, dimethylmethylene (isopropylidene), 1,4-butylene, 1,2-butylene, hexamethylene, 1,8-octylene, 1,10. -C _1-20 alkylene or alkylidene group such as decylene group can be exemplified, preferably C _1-16 alkylene or alkylidene group, more preferably C _1-12 alkylene or alkylidene group (for example, C _1-10 alkylene or alkylidene group) ). The alkylene or alkylidene group may be linear or branched.

Examples of the alkenylene group include C _2-20 alkenylene groups such as vinylidene, propenylene, butenylene (2-butenylene, etc.), 2-pentenylene, 4-propyl-2-pentenylene, 2-hexenylene, 3-hexenylene group, Preferably a _C2-12 alkenylene group, More preferably, a _C2-10 alkenylene group (for example, _C2-6 alkenylene group etc.) etc. are mentioned. The alkenylene group may be linear or branched.

Examples of the substituent that the divalent hydrocarbon group represented by R ³ and R ⁴ may have are exemplified in the section of the first substituent of the hydrocarbon group represented by R ¹ and R ^5a . Examples thereof include a halogen atom, alkynyl group, alkadienyl group, alicyclic hydrocarbon group (cycloalkyl group, cycloalkenyl group etc.), aromatic hydrocarbon group (aryl group etc.), acyl group, carboxyl group An ester bond-containing group containing, an amide bond-containing group, an ether bond-containing group containing a hydroxyl group, a thioether bond-containing group containing a mercapto group, an amino group, an N-substituted amino group, a sulfonamide group or an N-substituted sulfonamide group, Sulfinic acid group —SO ₂ H or sulfinic acid ester group, sulfinic acid amide group or N-substituted sulfinic acid amide group, sulfenic acid group —SOH or sulfenic acid Examples include an enoic acid ester group, a sulfenylamide group, an N-substituted sulfenylamide group, a nitro group, a cyano group, and an isocyanate group. The divalent hydrocarbon group represented by R ³ and R ⁴ may have one or more of these substituents. When it has a plurality of substituents, the kind thereof may be the same or different.

In the formulas (1) and (1a), when X ¹ is a group —N—C (═O) —, R ³ is the hydrocarbon group.

Among R ³ and R ⁴ , particularly selected from a single bond; or a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group A linear or branched C1-C10 divalent saturated or unsaturated aliphatic hydrocarbon group which may have at least one kind of substituent is preferable.

In the formulas (1) and (1a), examples of the substituent of the substituted imino group represented by X ² and X ³ include a hydrocarbon group and an acyl group exemplified in the section of the substituent of the hydrocarbon group. Can be illustrated. Of the substituted imino group, an alkylimino group (methylimino, ethylimino, propylimino, isopropyl imino, n- butylimino, t-like C _1-10 alkylimino group such butylimino group), haloalkyl imino group (fluoromethyl imino, Mono to trifluoro C _1-10 alkylimino groups such as difluoromethylimino, trifluoromethylimino and fluoroethylimino groups, and mono to trichloro C _1-10 alkyls corresponding to the mono to trifluoroC _1-10 alkylimino groups imino groups, such as mono- or tribromo _{C 1-10} alkylimino group and mono- to triiodo _{C 1-10} alkylimino group), or hydroxyalkyl imino group (such as hydroxy _{C 1-10} alkylimino group corresponding to the alkylimino Etc.).

In the formulas (1) and (1a), when X ² is an amide group (or amide bond), R ³ is the above divalent saturated or unsaturated aliphatic hydrocarbon group, and X ³ is an amide group. In certain instances, R ⁴ is the above divalent saturated or unsaturated aliphatic hydrocarbon group. X ² and X ³ are preferably a single bond, an oxygen atom, a sulfur atom, an imino group or a substituted imino group (for example, a linear or branched C _1-4 alkyl group, a hydroxy linear or branched chain) C _1-4 alkyl group, linear or branched C _1-4 alkyl group having a halogen atom, or substituted imino group having a linear or branched C _1-4 alkylcarbonyl group as a substituent) Or an amide group —C (═O) —NH—.

In the formulas (1) and (1a), the phenylene group represented by A ¹ may be any of 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene.

The phenylene group represented by A ¹ may have a substituent (first substituent). Examples of such a substituent include the substituents exemplified in the section of the first substituent of the hydrocarbon group represented by R ¹ and R ^5a . For example, a halogen atom, an aliphatic hydrocarbon group ( Alkyl group, alkenyl group, alkynyl group, alkadienyl group, etc.), alicyclic hydrocarbon group (cycloalkyl group, cycloalkenyl group etc.), aromatic hydrocarbon group (aryl group etc.), ester containing acyl group, carboxyl group Bond-containing group, amide bond-containing group, ether bond-containing group including hydroxyl group (hydroxyl group, alkoxy group, etc.), thioether bond-containing group including mercapto group, amino group or N-substituted amino group, sulfonamide group or N- Substituted sulfonamide group, sulfinic acid group or sulfinic acid ester group, sulfinic acid amide group or N-substituted sulfinic acid amino acid Group, sulfenic acid group or sulfenic acid ester group, a sulfenyl amido group, N- substituted sulfenyl amido group, a nitro group, a cyano group and an isocyanate group, it can be exemplified.

The phenylene group represented by A ¹ may have one or more of these substituents (first substituents), and when it has a plurality of first substituents, the type thereof may be the same or different. Any of these may be used.

Further, the substituent (first substituent) of A ¹ may further have a substituent (second substituent) depending on the type thereof. Examples of such a second substituent include the various substituents exemplified in the section of the first substituent. The number of these second substituents is not particularly limited, and may be one or more. In the case of being plural, the type of the second substituent may be the same or different.

Further, among the first substituent in A ¹ or the combination of the first and second substituents (that is, the substituent of the phenylene group), a halogen atom; a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a straight chain or branched halo C _1-4 at least one of substituents may be straight-chain or branched-chain C _1-4 alkyl group selected from alkoxy groups; Carboxyl group; halogen atom, hydroxyl group, linear or branched C _1-4 alkoxy group, linear or branched halo C _1-4 alkoxy group, carboxy-C _1-4 alkyl group and linear or branched-chain C _1-4 alkoxy - carbonyl -C _1-4 alkyl selected at least one of substituents may be straight-chain from the group or a branched-chain C _1-4 alkoxy - carbonyl group Carbamoyl group; N—C _1-4 alkylcarbamoyl group, N, N-diC _1-4 alkylcarbamoyl group, N—C _1-4 alkylcarbonyl-carbamoyl group, N, N-diC _1-4 alkylcarbonyl; A carbamoyl group; a hydroxyl group; a mercapto group; at least one selected from a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group A linear or branched C _1-4 alkoxy group which may have a substituent of: a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched chain A linear or branched C _1-4 alkylthio group optionally having at least one substituent selected from a halo C _1-4 alkoxy group; an amino group; N— C _1-4 alkylamino group, N, N-diC _1-4 alkylamino group, N—C _1-4 alkylcarbonyl-amino group, N, N-diC _1-4 alkylcarbonyl-amino group; and nitro It is preferably at least one selected from the group. In many cases, the substituent of the phenylene group A ¹ is a halogen atom, an alkyl group, a haloalkyl group, or the like.

In the formulas (1) and (1a), when A ¹ is a single bond, at least one of X ² and X ³ may be a single bond, and both may be a single bond.

In the formulas (1) and (1a), Y ¹ , a halogen atom, a group —C (═O) —O—R ^5a (wherein R ^5a is the same as described above), and may have a substituent. acyl group, a carbamoyl group or N- substituted carbamoyl group, an amino group or N- substituted amino group, a sulfonic acid group -SO 3 _H or sulfonic acid ester group, a sulfonamido group or N- substituted sulfonamide group, said R ¹ The atom or group similar to each atom and group illustrated by the term of said is mentioned.

Among the above Y ¹ , a hydrogen atom, a halogen atom, a carboxyl group, a substituent (for example, a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group, a linear or branched halo C _{1 -4} alkoxy group, carboxy- _C1-4 alkyl group, and linear or branched _C1-4 alkoxy-carbonyl- _C1-4 alkyl group. An alkoxycarbonyl group (such as a linear or branched C _1-4 alkoxy-carbonyl group), a substituent (for example, a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group, and An alkylcarbonyl group (C _1-4 alkyl-) which may have at least one substituent selected from a linear or branched halo C _1-4 alkoxy group and the like. Carbonyl group etc.), carbamoyl group, N-alkylcarbamoyl group (N—C _1-4 alkylcarbamoyl group etc.), N, N-dialkylcarbamoyl group (N, N-diC _1-4 alkylcarbamoyl group etc.), N - acylcarbamoyl group _{(N-C 1-4} alkyl-carbonyl - such as carbamoyl group), N, N-diacylate carbamoyl group (N, _{N-di-C 1-4} alkylcarbonyl - carbamoyl group, etc.), N- (alkylsulfonyl) Carbamoyl group (such as N- ( _C1-4 alkylsulfonyl) carbamoyl group), N, N-di (alkylsulfonyl) carbamoyl group (such as N, N-di ( _C1-4 alkylsulfonyl) carbamoyl group), amino group N-alkylamino group (such as N- _C1-4 alkylamino group), N, N-dialkylamino group (N, such as N- di _{C 1-4} alkylamino group), N- acylamino group _{(N-C 1-4} alkyl-carbonyl - such as an amino group), N, N- diacylamino group (N, N- di _{C 1 -4} alkylcarbonyl-amino groups), sulfonic acid groups, sulfonic acid alkyl ester groups (such as sulfonic acid _C1-4 alkyl ester groups), sulfinic acid groups, or sulfinic acid alkyl ester groups (such as sulfinic acid methyl ester groups). Sulfinic acid C _1-4 alkyl ester group, etc.) or cyano group is preferred.

In the formulas (1) and (1a), the coefficient c indicating the number of groups —R ³ —X ² —A ¹ —X ³ —R ⁴ —Y ¹ is ^{1 to 3} depending on the valence v of X ¹ . It is an integer of 3, preferably 1 or 2, and more preferably 1. The coefficient c is 1 when X ¹ is an oxygen atom or a sulfur atom, and the coefficient c is 1 or 2 when X ¹ is a nitrogen atom. The coefficient c is preferably 1. Note that the valence of X ¹ is v = b + c + 1.

  The lactam compound having high PPAR (such as PPARδ) agonist activity may be the following compound in the formulas (1) and (1a).

Ring Z ¹ : benzene ring R ¹ : halogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, alkylthio group, haloalkylthio group, carboxyl group, alkoxycarbonyl group, alkylcarbonyl group, carbamoyl group, N-alkylcarbamoyl group or N-alkylcarbonyl-carbamoyl group (particularly halogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, alkylthio group, haloalkylthio group, carboxyl group, alkoxycarbonyl group, or alkylcarbonyl) Base)
Coefficient a: integer from 0 to 2 (especially 1 or 2)
Ring Z ² : Pyrrolidone ring Ring Z ³ : Benzene ring X ¹ : Carbon atom, oxygen atom, or sulfur atom R ² : Hydrogen atom or alkyl group Coefficient b: 2 when X ¹ is a carbon atom, X ¹ is an oxygen atom Or 0 when sulfur atom
R ³ and R ⁴ : single bond, alkylene group or alkenylene group (provided that at least one of R ³ and R ⁴ is an alkylene group or alkenylene group)
X ² and X ³ : single bond, oxygen atom, sulfur atom, amide group —NH—C (═O) — or —C (═O) —NH—
A ¹ : a single bond, or a phenylene group optionally having a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, or a haloalkylthio group (provided that when A ¹ is a single bond, X ² and X ^At least one of ³ is a single bond)
Y ¹ : group —C (═O) —O—R ^5a (R ^5a is a hydrogen atom or an alkyl group), carbamoyl group, N-alkylcarbamoyl group, N-alkylcarbonyl-carbamoyl group, N- (alkylsulfonyl) carbamoyl group, a sulfonic acid group _-SO 3 H, sulfonic acid ester group _-SO 3 ^{R 5b (R} 5b represents an alkyl group), a sulfinic acid group -SO ₂ H or sulfinic acid ester group _-SO 2 ^{R 5b (R} 5b represents an alkyl group ) (Especially the group —C (═O) —O—R ^5a (R ^5a is a hydrogen atom or an alkyl group), a carbamoyl group, an N- (alkylsulfonyl) carbamoyl group, a sulfonic acid group —SO ₃ H or a sulfonic acid ester. group _-SO 3 ^{R 5b (R} 5b represents an alkyl group))
Coefficient c: 1.

  The compound having higher PPAR (such as PPARδ) agonist activity may be the following compound.

R ¹ : halogen atom, haloalkyl group, haloalkoxy group, haloalkylthio group, alkyl group, alkoxy group, alkylthio group, carboxyl group, alkoxycarbonyl group, alkylcarbonyl group (particularly halogen atom, haloalkyl group, haloalkoxy group, halo) Alkylthio group)
X ¹ : carbon atom, sulfur atom, oxygen atom (particularly carbon atom or sulfur atom)
A ¹ : An optionally substituted phenylene group (in particular, one or more substituents selected from a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, and a haloalkylthio group) Phenylene group which may have).

Formula (1) or a partial structure of _{^{(1a) -X I (R 2}} ) b -R 3 -X 2 -A 1 -X 3 -R 4 relates -Y ^1, each ^{R 3, X 2, A 1} , The bonding mode of X ³ and R ⁴ (not including a single bond) is not particularly limited, but usually X ² does not bind to X ³ , and X ² is Y via at least A ¹ and / or R ^{4. In} many cases, X ³ is bonded to Y ¹ , and X ³ is often bonded to Y ¹ via R ⁴ . Bonding mode of the partial structure ^{-R 3 -X 2 -A 1 -X 3} -R 4 -Y 1 may be, for example, as follows.

_{^{-X I (R 2) b -R}} 3 -X 2 -A 1 -X 3 -R 4 -Y 1 (a-1)
_{^{-X I (R 2) b -R}} 3 -X 2 -A 1 -R 4 -Y 1 (a-2)
_{^{-X I (R 2) b -R}} 3 -X 2 -A 1 -Y 1 (a-3)
_{^{-X I (R 2) b -R}} 3 -X 2 -R 4 -Y 1 (a-4)
_{^{-X I (R 2) b -R}} 3 -X 2 -Y 1 (a-5)
_{^{-X I (R 2) b -R}} 3 -A 1 -X 3 -R 4 -Y 1 (a-6)
_{^{-X I (R 2) b -R}} 3 -A 1 -R 4 -Y 1 (a-7)
_{^{-X I (R 2) b -R}} 3 -X 3 -R 4 -Y 1 (a-8)
_{^{-X I (R 2) b -R}} 3 -Y 1 (a-9)
_{^{-X I (R 2) b -X}} 2 -A 1 -X 3 -R 4 -Y 1 (a-10)
(Wherein ^XI is a carbon atom)
_{^{-X I (R 2) b -X}} 2 -A 1 -R 4 -Y 1 (a-11)
(Wherein ^XI is a carbon atom)
_{^{-X I (R 2) b -A}} 1 -X 3 -R 4 -Y 1 (a-12)
_{^{-X I (R 2) b -X}} 3 -R 4 -Y 1 (a-13)
(Wherein ^XI is a carbon atom)
_{^{-X I (R 2) b -R}} 4 -Y 1 (a-14).

  Of the compounds of the formula (1a), for example, compounds represented by the following formulas (1a-1) to (1a-11) are preferable.

[Wherein, R ^2a represents a hydrogen atom or an alkyl group, and R ^3a and R ^4a are the same or different and may be a divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent (for example, , C _1-10 alkylene group or C _2-10 alkenylene group), X ^1c represents a carbon atom, oxygen atom, sulfur atom or nitrogen atom (for example, a carbon atom, oxygen atom or sulfur atom), and d3 represents When X ^1c is a carbon atom, the coefficient d3 is 2, when X ^1c is an oxygen atom or a sulfur atom, the coefficient d3 is 0, and when X ^1c is a nitrogen atom, The coefficient d3 is 1, X ^2a and X ^3b are the same or different and represent an oxygen atom, a sulfur atom, an imino group or a substituted imino group (for example, an oxygen atom or a sulfur atom), and A ^1b has a substituent. Phenyle you may have Represents a group, Y ^1a represents an alkyl group which may have a hydrogen atom or a substituent, Y ^1b represents an alkyl sulfonyl group may have a substituent. Y ^1c represents a group —C (═O) —O—R ^5a (wherein R ^5a is the same as above), a carbamoyl group, an N-substituted carbamoyl group or a cyano group. R ¹ and coefficient a are the same as above]
Examples of the alkyl group represented by R ^2a include the alkyl groups exemplified in the section of R ² , preferably a C _1-6 alkyl group, and more preferably a C _1-4 alkyl group. The alkyl group may be linear or branched.

The divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent represented by R ^3a and R ^4a has the substituents exemplified in the above R ³ and R ⁴ terms. Examples thereof may include divalent saturated or unsaturated aliphatic hydrocarbon groups.

Examples of the substituted imino group represented by X ^2a and X ^3b include the substituted imino groups exemplified in the section of X ² and X ³ .

Examples of the phenylene group optionally having a substituent represented by A ^1b include the groups exemplified in the above section A ¹ .

Examples of the alkyl group which may have a substituent represented by Y ^1a include an alkyl group which may have the substituent exemplified in the aforementioned Y ¹ section. Examples of the alkylsulfonyl group represented by Y ^1b include the sulfinic acid alkyl ester groups exemplified in the section of Y ¹ .

  The lactam compound as described above in the present invention may form a salt with an acid or a base. Acids that can form salts with lactam compounds include organic acids [organic carboxylic acids (eg, alkane carboxylic acids such as acetic acid, propionic acid, butyric acid; alkene carboxylic acids such as (meth) acrylic acid; tartaric acid, citric acid, lactic acid] Hydroxycarboxylic acids such as gluconic acid, malic acid, succinic acid, salicylic acid, phenolphthaline, and tannic acid; haloalkanecarboxylic acids such as trichloroacetic acid and trifluoroacetic acid; Divalent carboxylic acids; organic sulfonic acids (alkane sulfonic acids such as methane sulfonic acid, arene sulfonic acids such as benzene sulfonic acid, toluene sulfonic acid, diphenyl disulfonic acid; amino acids such as aspartic acid), inorganic acids (for example, hydrochloric acid, odor Halogen acids such as hydrofluoric acid; sulfuric acid, nitric acid, lithium The salt of the lactam compound and the acid may be a mixed acid salt (for example, hydrochloric acid-sulfate, etc.) The base capable of forming a salt with the lactam compound is an organic base (amine). For example, mono- to trialkylamines such as methylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, diisopropylethylamine; alkanolamines such as ethanolamine; alkylene polyamines such as ethylenediamine and diethylenetriamine), inorganic bases [water Metal hydroxides such as sodium oxide, potassium hydroxide, calcium hydroxide, iron hydroxide, aluminum hydroxide (alkali metal or alkaline earth metal hydroxide, etc.); sodium carbonate, sodium hydrogen carbonate, potassium carbonate, rubidi carbonate And alkali metal carbonates such as cesium carbonate, ammonia, etc.] The lactam compound may form a salt with one of these bases or may form a salt with two or more bases. May be.

  The lactam compound or a salt thereof may be a solvate (such as an organic solvate such as a hydrate or an organic solvent such as ethanol) or an anhydride. In addition, the lactam compound or a salt thereof may be a prodrug or an active metabolite that is modified in the functional group of the compound or the salt and exhibits an activity in vivo. The lactam compound or a salt thereof includes a tautomer, an optically active form having an asymmetric carbon atom ((R) form, (S) form, diastereomer, etc.), a racemate, or a mixture thereof. .

(Method for producing lactam compound)
(A) Reaction of Carboxylic Acid Ester Compound with Aminoarene Compound The lactam compound having a lactam skeleton (lactam skeleton condensed with a hydrocarbon ring) represented by the formula (I) or a salt thereof may be a conventional reaction or a conventional one. You may manufacture by combining these methods suitably. The lactam compound is, for example, a compound having a carboxylic acid ester skeleton represented by the following formula (II) or a salt thereof (for example, a salt with an acid or a base exemplified in the paragraph of the lactam compound), You may produce | generate by carrying out the cyclization reaction with the aminoarene compound represented by following formula (2), and forming a lactam ring frame | skeleton.

(Wherein R ⁶ represents an alkyl group, X ⁴ represents a halogen atom, and R ¹ , Z ¹ , Z ³ , coefficients a, d and e are the same as above)
Examples of the alkyl group represented by R ⁶ include C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl groups. The alkyl group is preferably a C _1-4 alkyl group, more preferably a C _1-2 alkyl group.

Examples of the halogen atom represented by X ⁴ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Of these halogen atoms, a chlorine atom, a bromine atom and an iodine atom (particularly a bromine atom) are preferred.

The lactam ring formed by the cyclization reaction corresponds to the ring Z ² in the lactam skeleton of the formula (I).

  In the cyclization reaction, the ratio (molar ratio) between the compound having a carboxylic acid ester skeleton represented by the formula (II) or a salt thereof and the aminoarene compound represented by the formula (2) is, for example, It can be selected from the range of about 0.3 / 1 to 2/1, preferably 0.5 / 1 to 1.5 / 1, more preferably about 0.7 / 1 to 1.2 / 1. .

  The cyclization reaction may be performed in the absence of a solvent, but is usually performed in the presence of a solvent in many cases. Examples of the reaction solvent include solvents inert to the reaction, for example, amides such as N, N-dimethylformamide (DMF) and N, N-dimethylacetamide (DMAA); 1,4-dioxane, tetrahydrofuran (THF). Ethers such as methanol and ethanol; nitriles such as acetonitrile and benzonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); hydrocarbons such as cyclohexane, benzene and toluene; N-methylpyrrolidone (NMP) ) And the like. These solvents can be used alone or in combination of two or more.

  The reaction can be carried out at a temperature lower than the reflux temperature of the raw material and / or reaction solvent depending on the type of the raw material and / or reaction solvent. The reaction temperature may be, for example, room temperature (about 20 to 30 ° C.) to 300 ° C., preferably 40 to 200 ° C., more preferably about 50 to 180 ° C. Moreover, you may perform reaction, changing temperature as needed. For example, the reaction temperature may be gradually increased or decreased, and the temperature may be increased or decreased in multiple stages. Moreover, you may repeat the raise and fall of reaction temperature. For example, after reacting at a low temperature (for example, a temperature of about 35 to 100 ° C., preferably about 40 to 80 ° C.), the temperature is raised to a high temperature (for example, a temperature of about 120 to 250 ° C., preferably about 130 to 200 ° C.). Further reaction may be performed.

  The reaction time varies depending on the type of raw material and / or solvent, and is not particularly limited. For example, the reaction time is appropriately within the range of 0.5 to 48 hours, preferably 1 to 24 hours, more preferably 2 to 12 hours. You can choose.

  The cyclization reaction may be performed in the air, or may be performed in a circulation or atmosphere of an inert gas (such as helium gas, nitrogen gas, or argon gas). The reaction may be performed under normal pressure, reduced pressure, or increased pressure.

  The cyclization reaction may be performed in the presence of a catalyst, for example, a base catalyst (the organic bases and inorganic bases exemplified above) as necessary.

  The obtained lactam compound or a salt thereof may be further subjected to acid treatment or base treatment, if necessary. Examples of the acid usable for the acid treatment include the organic acids and inorganic acids exemplified above, and examples of the base usable for the base treatment include the organic base and inorganic base exemplified above.

  The obtained lactam compound or a salt thereof, or a lactam compound or a salt thereof after acid treatment or base treatment is subjected to a conventional separation or purification (or isolation) method, for example, filtration, phase transfer, salting out, distillation, if necessary. May be separated or purified by solvent removal, precipitation (eg, precipitation by forming a salt, etc.), crystallization, recrystallization, decantation, extraction, drying, washing, chromatography, and combinations thereof. . Further, the lactam compound or a salt thereof may be subjected to other reactions without being subjected to separation or purification treatment.

(B) Method for producing lactam compound of formula (1) or a salt thereof Among the lactam compounds or salts thereof in the present invention, the lactam compound represented by formula (1) or a salt thereof is, for example, a halide or a sulfonate compound. Reaction with a compound having a nucleophilic group such as a hydroxyl group, a mercapto group, an amino group or an imino group, or a coupling reaction between a halide and a compound having an unsaturated bond, a halide or a sulfonate compound, and a mercapto It can also be produced by utilizing a coupling reaction with a compound having a group or an amide (or imide) bond forming reaction between a carboxyl or halocarbonyl group and an amino group or imino group.

  (B-1) The lactam compound of formula (1) or a salt thereof is, for example, a lactam compound (precursor) represented by the following formula (3) or a salt thereof, and a compound represented by the following formula (4) or You may manufacture by making the salt react and utilizing a nucleophilic substitution reaction, a coupling reaction, or an amide bond formation reaction.

[Wherein X ⁵ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), —X ^1a (—R ^2a ) _b1 —H (wherein X ^1a is a carbon atom, oxygen atom, sulfur An atom or a nitrogen atom, R ^2a represents a hydrogen atom or an optionally substituted alkyl group, and the coefficient b1 is an integer of 0 to 2 depending on the valence v1 of X ^1a ), a carboxyl group , An alkoxycarbonyl group, a halocarbonyl group or a group -SL (wherein L represents a leaving group). R ¹ , Z ^{1 to} Z ³ , and the coefficient a are the same as described above. ]
^{X 6 -R 3 -X 2 -A 1} -X 3 -R 4 -Y 1 (4)
[Wherein X ⁶ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), or —X ^1b (—R ^2b ) _b2 —H (wherein X ^1b is a carbon atom, oxygen atom, A sulfur atom or a nitrogen atom, R ^2b represents a hydrogen atom or an optionally substituted alkyl group, and the coefficient b2 is 0 or 1 depending on the valence v2 of X ^1b ), a carboxyl group, An alkoxycarbonyl group or a halocarbonyl group, and when X ⁵ is an alkylsulfonyloxy group optionally having a halogen atom or a substituent, X ⁶ is —X ^1b (—R ^2b ) _b2 —H; , when said ^{X 5} is _{^{-X 1a (-R 2a) b1 -H}} , X 6 is a halogen atom, an optionally substituted alkyl sulfonyloxy group, a carboxyl group, an alkoxycarbonyl Or a halocarbonyl group, when ^{X 5} is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, ^{X 6} is -N ^(-R 2a) -H, when ^{X 5} is a group -S-L , X ⁶ is a halogen atom or an alkylsulfonyloxy group which may have a substituent. R ³ , R ⁴ , X ² , X ³ , Y ¹ and A ¹ are the same as above. ]
(I) In the formula (1), X ¹ corresponds to X ^1a and X ^1b and represents a carbon atom, oxygen atom, sulfur atom or nitrogen atom, and R ² corresponds to R ^2a and R ^2b . And a hydrogen atom or an alkyl group which may have a substituent, the coefficient d corresponds to the coefficients d1 and d2, and is an integer of 0 to 2 depending on the valence v of X ¹ , X ¹ valence v corresponds to the valence of v1 and v2 of ^{X 1a} and ^{X 1b.}

Examples of the halogen atom represented by X ⁵ and X ⁶ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom or a bromine atom is preferred. X ⁵ and as good alkylsulfonyloxy group which may have a substituent represented by X ^6, methanesulfonyloxy group (CH 3 _SO 3 _-), fluoro methanesulfonyloxy group, trifluoromethanesulfonyloxy group, ethane Examples include a C _1-6 alkylsulfonyloxy group which may have a substituent such as a halogen atom such as a sulfonyloxy group, and in particular, a C _1-4 alkylsulfonyloxy group or a halo C _1-4 alkylsulfonyloxy group. Etc. are preferable. Examples of the halocarbonyl group represented by X ⁵ and X ⁶ include a chlorocarbonyl group and a bromocarbonyl group. In the group -S-L represented by X ^5, examples of the leaving group L, a known leaving group, for example, alkyl groups such as t- butyl group, 2- (2-ethylhexyloxycarbonyl) ethyl group In addition to an alkoxycarbonylalkyl group, the leaving group described in Org. Lett., 24, 4587 (2004) or a reference in this document can be used.

In the coupling reaction, X ⁵ is a halogen atom, an optionally substituted alkylsulfonyloxy group, X ⁶ is HC (—R ^2b ) —, and R ³ and X You may use the compound whose bond between ⁶ is a carbon-carbon double bond.

  In the above reaction, the ratio (molar ratio) between the compound (3) or a salt thereof and the compound (4) or a salt thereof can be selected from a range of about 0.3 / 1 to 3/1, for example, preferably 0. It may be about 0.5 / 1 to 2.5 / 1, more preferably about 0.7 / 1 to 2/1 (for example, 0.8 / 1 to 1.5 mol).

  The reaction of the compound (3) or a salt thereof and the compound (4) or a salt thereof can be performed in the presence of a base or a coupling catalyst, if necessary. As the base, the organic bases and inorganic bases exemplified above can be used. Preferred bases include, for example, inorganic bases such as alkali metal carbonates (such as potassium carbonate and cesium carbonate), and trialkylamines such as triethylamine and diisopropylethylamine. Even if the ratio of a base is about 0.2-5 mol with respect to 1 mol of compounds (2) or its salt, Preferably it is 0.3-4 mol, More preferably, it is about 0.5-3 mol. Good.

  In addition, as the coupling catalyst, for example, an organic base (trialkylamine such as triethylamine or diisopropylethylamine) may be used, and the organic base and a metal compound [for example, a platinum group metal such as Ni, Pd, or Pt. Compounds (for example, inorganic acid salts such as oxides, hydroxides, carbonates, complexes (for example, tris (dibenzylideneacetone) dipalladium (0)) and the like) and / or phosphine catalysts (for example, 4, A catalyst system using 5-bis (diphenylphosphino) -9,9-dimethylxanthene or the like may be used. The proportion of the organic base is, for example, about 0.2 to 5 mol, preferably about 0.3 to 4 mol, and more preferably about 0.5 to 3 mol, relative to 1 mol of the compound (2) or a salt thereof. Also good. The ratio of the metal compound was about 0.001 to 2 mol, preferably 0.005 to 1 mol, and more preferably about 0.01 to 0.5 mol with respect to 1 mol of the compound (3) or a salt thereof. May be. The ratio of the phosphine catalyst is about 0.001 to 2 mol, preferably about 0.005 to 1 mol, more preferably about 0.01 to 0.7 mol, relative to 1 mol of the compound (3) or a salt thereof. It may be.

  The above reaction may be performed in the absence of a solvent, but is usually performed in the presence of a solvent in many cases. Examples of such a reaction solvent include the reaction solvents exemplified in the section of the cyclization reaction (a). The reaction solvents can be used alone or in combination of two or more.

  The reaction can be carried out at a temperature lower than the reflux temperature of the raw material and / or reaction solvent depending on the type of the raw material and / or reaction solvent. The reaction temperature may be, for example, −20 ° C. to 300 ° C., preferably 0 to 200 ° C., more preferably about 10 to 180 ° C., or the reflux temperature of the raw materials and / or reaction solvent. Moreover, you may perform reaction, changing temperature as needed. For example, the reaction temperature may be gradually increased or decreased, and the temperature may be increased or decreased in multiple stages. Moreover, you may repeat the raise and fall of reaction temperature. For example, you may make it react at room temperature (about 20-30 degreeC), after making it react at the temperature of about 40-250 degreeC (preferably 40-150 degreeC).

  The reaction time varies depending on the type of raw material and / or solvent and is not particularly limited. For example, the reaction time is 0.1 hour to 1 week, preferably 0.5 hour to 6 days, and more preferably 1 hour to 5 days. It can be appropriately selected from a range of about (eg, 2 hours to 3 days).

  The reaction between the compound (3) or a salt thereof and the compound (4) or a salt thereof may be carried out in the air, and is carried out under the flow or atmosphere of an inert gas (helium gas, nitrogen gas, argon gas, etc.). May be. The reaction may be performed under normal pressure, reduced pressure, or increased pressure.

  If necessary, the reaction product obtained by the above reaction may be further subjected to acid treatment or base treatment. Examples of the acid that can be used for the acid treatment include at least one selected from the organic acids and inorganic acids exemplified above. Examples of the base that can be used for the base treatment include at least one selected from the organic bases and inorganic bases exemplified above.

In addition, various substituents in the compound represented by the formula (1) (for example, R ¹ , R ² , Y ¹ and the like, substituents of these groups, R ³ , R ⁴ , X ² , X ³ , A ¹ or the like) may be produced by carrying out the above reaction using a raw material having these substituents, but may produce a compound (1) or a salt thereof. Furthermore, it is subjected to other conventional reactions (various reactions such as esterification, amidation, nitration, reduction, oxidation, hydrogenation, etc.) to introduce a desired substituent, whereby the compound of formula (1) Or you may produce | generate the salt. For example, in the presence of an esterification catalyst such as an acid (for example, an organic acid or an inorganic acid exemplified above, preferably an inorganic acid such as hydrochloric acid, etc.), an alcohol in the presence of a compound having a carboxyl group at R ¹ , Y ¹ or the like (For example, it may be converted to an alkoxycarbonyl group by reacting with C _1-4 alcohol such as methanol or ethanol). In addition, if necessary, a compound having an alkoxycarbonyl group in R ¹ , Y ¹ or the like is converted into an acid (the organic acid and / or inorganic acid exemplified above) or a base (the organic base and / or inorganic base exemplified above, particularly water). It may be converted to a carboxyl group by treatment with an inorganic base such as sodium oxide). In addition, a compound having an acyl group in R ¹ , Y ¹ or the like is reduced with a reducing agent (for example, hydrogen; a hydrogen source such as tetrafluoroborates (alkali metal salts) such as sodium tetrafluoroborate) and a catalyst (if necessary) Reduction (catalytic hydrogen reduction) using a reduction catalyst such as palladium carbon), the carbonyl group in the acyl group may be converted to a hydroxyl group, and a compound having a nitro group in R ¹ , Y ¹ or the like is reduced. Reduction may be performed using an agent (such as the reducing agent exemplified above) to convert the nitro group to an amino group. Further, a —C═C— bond such as R ³ and / or R ⁴ may be converted to a —CH—CH— bond by hydrogenation using a reducing agent (such as the reducing agent exemplified above).

  The obtained compound (1) or a salt thereof may be separated or purified by the conventional separation or purification (or isolation) method exemplified in the item (a), if necessary. You may use for another reaction, without giving.

  (Ii) The compound (3) or a salt thereof can be obtained by utilizing the cyclization reaction of (a). More specifically, by using a carboxylic acid ester represented by the following formula (5) or a salt thereof as the compound having a carboxylic acid ester skeleton of the formula (II) or a salt thereof, the compound (3) or a salt thereof (For example, a salt with an acid or a base exemplified in the section of the lactam compound) can be produced.

(Wherein R ⁶ , X ⁵ , X ⁴ , Z ³ , coefficients d and e are the same as above)
(Iii) The compound having a carboxylic acid ester skeleton of the formula (II) or a salt thereof may be a commercially available product, and is produced by utilizing a conventional method (for example, halogenation, esterification, etc.). Also good. For example, (a) a compound having a skeleton represented by the following formula (IIa) or a salt thereof is converted into a dicarboxylic acid having a halogen atom such as a halogen acid imide (bromosuccinimide) in the presence of a peroxide (such as benzoyl peroxide). (B) an alcohol compound having a skeleton represented by the following formula (IIb) or a salt thereof, if necessary, in the presence of a dehydrating agent (sulfuric acid, zinc chloride, etc.). It may be obtained by reacting with hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.). And (c) a compound having a carboxylate skeleton of the formula (II) or a salt thereof by reacting the alcohol compound or a salt thereof with a halogenated phosphorus compound (phosphorus pentachloride, phosphorus tribromide, etc.). (D) by reacting the alcohol compound or a salt thereof with a thionyl halide (such as thionyl chloride) in the presence of a tertiary amine (such as pyridine or dimethylaniline). A compound having a carboxylic acid ester skeleton of the formula (II) or a salt thereof may be generated. In addition, (e) the compound represented by the following formula (IIc) or a salt thereof and a metal halide (such as an alkali metal halide such as potassium bromide) are reacted to have the carboxylic acid ester skeleton of the formula (II). A compound or a salt thereof can also be produced.

(Wherein R ⁶ , Z ³ , coefficients d and e are the same as above)
Moreover, a commercial item may be used for the carboxylic acid ester compound or its salt represented by the said Formula (5), and it obtains with the manufacturing method of the compound or its salt which has the carboxylic acid ester frame | skeleton of the said Formula (II). You can also.

In the carboxylic acid ester compound represented by the formula (5) or a salt thereof, the group X ⁵ is —X ^1d (—R ^2a ) _d1 —H (wherein X ^1d is an oxygen atom, a sulfur atom or a nitrogen atom) are ^shown, if ^{R 2a} and coefficient d1 is the same) to the, in the production of carboxylic acid ester compound represented by the formula (5) is a group ^-X 1d in the raw material ^(-R _{2a) d1} - H is a protecting group [alkyl group (C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl group, preferably C _1-4 alkyl group); acyl group (acetyl group etc. C _1-6 alkyl - group, preferably a _{C 1-4} alkyl - carbonyl group); an alkoxycarbonyl group (methoxycarbonyl, _{C 1-6} a, such as an ethoxycarbonyl group Kokishi - carbonyl group, preferably a C _1-4 alkoxy - may be reacted with protected with carbonyl groups), etc.].

  Further, the protecting group may be deprotected with an acid (such as the organic acid and / or inorganic acid exemplified above) or a base (such as the organic base and / or inorganic base exemplified above) at an appropriate stage.

Of the compounds represented by the formula (3) or salts thereof, the compound or salt thereof in which X ⁵ is a mercapto group is derived from the compound of formula (5) or a salt thereof in which X ⁵ is a hydroxyl group. You can also For example, a compound of formula (5) wherein X ⁵ is a hydroxyl group or a salt thereof is treated with alkanesulfonic acid or an anhydride thereof (eg, methanesulfonic acid, trifluoromethanesulfonic acid or an anhydride thereof) Group is converted to an alkylsulfonyloxy group, and this alkylsulfonyloxy compound or a salt thereof is reacted with a thiol HS-L having a leaving group (wherein L is the same as described above) (coupling reaction) It may be synthesized by utilizing a leaving group elimination reaction. In the reaction of the alkylsulfonyloxy compound or a salt thereof and thiol, the coupling catalyst may be used.

The elimination reaction may be performed in the presence of an alkali metal alkoxide. As the alkali metal alkoxide, alkali metal C _1-6 alkoxide such as sodium methoxide, sodium ethoxide, potassium ethoxide, preferably alkali metal C _1-4 alkoxide can be used. The elimination reaction may be carried out in the absence of a solvent, but usually a solvent (the reaction solvent exemplified in the above cyclization reaction of (a) or a mixed solvent thereof, particularly methanol, ethanol, etc. In many cases, the reaction is performed in the presence of an alkanol (C _1-6 alkanol, preferably C _1-4 alkanol, etc.).

  (Iv) As a compound or its salt represented by the said Formula (4), a commercial item may be used and what was synthesize | combined using the conventional method may be used. Compound (4) is similar to, for example, compounds (6), (7) and (8) having a unit constituting compound (4) in the nucleophilic substitution reaction, coupling reaction and / or amide bond forming reaction described above. Can be obtained by utilizing the reaction of

[Wherein, X ⁷ represents a hydrogen atom, a halogen atom, or —X ^1b (—R ^2b ) _b2 —H (wherein X ^1b , R ^2b and coefficient b2 are the same as above), and X ⁸ and X ⁹ Represents a halogen atom, an optionally substituted alkylsulfonyloxy group, —X ^2a —H (wherein X ^2a is the same as above), a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, ^{When 8} is a halogen atom or an optionally substituted alkylsulfonyloxy group, X ⁹ is a group —X ^2a —H, and when X ⁸ is a group —X ^2a —H, X ⁹ is halogen atom, an optionally substituted alkyl sulfonyloxy group, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ⁸ is a carboxyl group, an alkoxycarbonyl group or When a halocarbonyl group, X ⁹ is an amino group or N- mono-substituted amino group. X ¹⁰ and X ¹¹ are each a halogen atom, an alkylsulfonyloxy group which may have a substituent, —X ^3a —H (wherein X ^3a represents an oxygen atom, a sulfur atom, an imino group or a substituted imino group) ), A carboxyl group, an alkoxycarbonyl group or a halocarbonyl group. When X ¹⁰ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, X ¹¹ is a group —X ^3a —H, and when X ¹⁰ is a group —X ^3a —H, X ¹¹ Is a halogen atom, an optionally substituted alkylsulfonyloxy group, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and when X ¹⁰ is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ¹¹ Is an amino group or an N-monosubstituted amino group. R ³ , R ⁴ , X ² , X ³ , A ¹ and Y ¹ are the same as above]
Examples of the halogen atom represented by X ^{7 to} X ¹¹ include the halogen atoms exemplified in the above sections X ⁵ and X ⁶ . As the alkylsulfonyloxy group which may have a substituent represented by X ^{8 to} X ¹¹ , an alkylsulfonyloxy group which may have a substituent exemplified in the aforementioned X ⁵ and X ⁶ terms Can be mentioned. Examples of the substituted imino group represented by X ^3a include the substituted imino groups exemplified in the aforementioned X ³ section. Examples of the halocarbonyl group represented by X ^{8 to} X ¹¹ include a chlorocarbonyl group and a bromocarbonyl group. The N- mono-substituted amino group represented by X ^11, include N- mono-substituted amino group corresponding to the ^-X 3a -H.

In addition, after making the compound represented by the said Formula (6), the compound represented by Formula (7), or its salt react, the product obtained and the compound represented by the said Formula (8), or its salt And the product obtained by reacting the compound represented by the formula (7) or a salt thereof with the compound represented by the formula (8) or a salt thereof, and the above formula (6) You may make it react with the compound represented by these. As the reaction conditions, the conditions exemplified in the items (b-1) and (i) can be used. Further, instead of the reaction product obtained by reaction of a compound represented by the formula the compound represented by the formula (6) (7), a commercially available X ⁷ -R ³ -X ² -A ¹ A compound represented by —X ¹⁰ (wherein R ³ , X ² , X ⁷ , X ¹⁰ and A ¹ are the same as described above) or a salt thereof may be used.

  Among the compounds represented by the above formula (4) or salts thereof, the compounds represented by the following formula (4a) or salts thereof are represented by the compounds represented by the above formula (6) and the following formula (9). It may be obtained by reacting the represented compound or a salt thereof.

[Wherein X ¹² is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), -X ^2a -H (wherein X ^2a is the same as above), a carboxyl group, an alkoxycarbonyl group or a halocarbonyl. When X ⁸ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, X ¹² is a group —X ^2a —H, and X ⁸ is a group —X ^2a —H. X ¹² is a halogen atom, an alkylsulfonyloxy group optionally having a substituent, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and X ⁸ is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group. When X ¹² is an amino group or an N-substituted amino group. R ³ , R ⁴ , X ² , X ⁶ , X ⁷ , X ⁸ and Y ¹ are the same as above]
Examples of the halogen atom represented by X ¹² include the halogen atoms exemplified in the above-mentioned X ⁵ and X ⁶ terms. As good alkylsulfonyloxy group which may have a substituent represented by X ^12, exemplified in the paragraph may have a substituent group alkylsulfonyloxy group of the X ⁵ and X ⁶ may be mentioned. The halocarbonyl group represented by X ^12, chlorocarbonyl group, and bromo carbonyl group. The N- mono-substituted amino group represented by X ^12, include N- mono-substituted amino group corresponding to the ^-X 2a -H. As the reaction conditions, the conditions exemplified in the items (b-1) and (i) can be used.

  Of the compound represented by the above formula (4) or a salt thereof, the compound represented by the following formula (4b) or a salt thereof is represented by the compound represented by the following formula (6a) and the formula (8). It may be obtained by reacting a compound or a salt thereof. As the reaction conditions, the conditions exemplified in the items (b-1) and (i) can be used.

(In the formula, R ³ , R ⁴ , X ³ , X ⁷ , X ⁸ , X ¹¹ , A ¹ and Y ¹ are the same as above. X ⁸ may be a halogen atom or an alkylsulfonyloxy which may have a substituent. When X ¹¹ is a group —X ^2a —H, and when X ⁸ is a group —X ^2a —H, X ¹¹ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), When it is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and X ⁸ is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ¹¹ is an amino group or an N-monosubstituted amino group.)
In the compound obtained by the above reaction, the compound of formula (4), (4a) or (4b) or a salt thereof, wherein X ⁶ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, A compound in which the group X ⁷ is a hydroxyl group, a mercapto group, an amino group or an imino group can be obtained by further treatment with an alkanesulfonyl halide (C _1-4 alkanesulfonyl halide such as methanesulfonyl chloride). In addition, when X ⁷ is a hydrogen atom, the compound of formula (4) or (4b) or a salt thereof in which X ⁶ is a halogen atom can be obtained by halogenating this group X ⁷ .

  As the reaction conditions, the conditions exemplified in the items (b-1) and (i) can be used.

In addition, among the compounds (4), a compound represented by HSR ^3a -Y ¹ (wherein R ^3a and Y ¹ are the same as above) is, for example, X ⁷ -R ^3a -Y ^1. (Wherein R ^3a , X ⁷ and Y ¹ are the same as above), a thiolate salt and / or a thionate salt [R ⁸ —C (═O) SM or R ⁸ -C (= S) OM (wherein R ⁸ represents a C _1-4 alkyl group such as methyl or ethyl group, and M represents a monovalent metal atom), for example, a thiol carboxylic acid such as potassium thioacetate R ⁸ —C (═O) —S—R ^3a —Y ¹ (wherein R ^3a , R ⁸ and Y ¹ are the same as above) are generated by reaction with an alkali metal salt of Organic bases and / or inorganic bases exemplified above, preferably potassium carbonate, cesium carbonate, etc. Can be obtained by treating the alkali metal carbonate, etc.).

(V) In the lactam compound of the above formula (1) or a salt thereof, the group —R ³ —X ² —A ¹ —X ³ —R ⁴ —Y ¹ is a group —R ^3a —C (═O) —. A compound or a salt thereof is obtained which is NH—R ^4a —Y ^1c or —R ^3a —C (═O) —NH—Y ^1b (wherein R ^3a , R ^4a , Y ^1c and Y ^1b are the same as above). In this case, a compound having the group —R ^3a —C (═O) —NH—R ^4a —Y ^1c or —R ^3a —C (═O) —NH—Y ^1b or a salt thereof may be used as a raw material. , by reacting the compound or salt thereof having a ^-R 3a ^-COOH, and Y ^1c -R 4a -NH ₂ or ^Y 1b -NH _2, the group ^{-R 3a -C (= O) -NH} -R ^4a -Y ^1c or ^-R 3a -C (= O) may also be formed ^{-NH-Y 1b.}

  (B-2) The lactam compound of the formula (1) or a salt thereof is, for example, a compound represented by the following formula (10) or a salt thereof and a compound represented by the following formula (8) or a salt thereof. By reacting with the reaction (step (I)), the nucleophilic substitution reaction, the coupling reaction or the amide bond forming reaction can be used for the production.

(Wherein R ^{1 to} R ⁴ , Z ^{1 to} Z ³ , X ^{1 to} X ³ , X ¹⁰ , X ¹¹ , A ¹ , Y ¹ and coefficients a to c are the same as above. X ¹⁰ is a halogen atom or a substitution When it is an alkylsulfonyloxy group which may have a group, X ¹¹ is a group -X ^3a -H, and when X ¹⁰ is a group -X ^3a -H, X ¹¹ is a halogen atom or a substituent. which may have an alkyl sulfonyloxy group, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, when X ¹⁰ is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ¹¹ is an amino group or N- mono- A substituted amino group.)
(I) The reaction conditions of the nucleophilic substitution reaction, coupling reaction, and amide bond formation reaction in the reaction step (I) can be the conditions exemplified in the section (b-1) (i).

  In the reaction step (I), the ratio (molar ratio) between the compound (10) or a salt thereof and the compound (8) or a salt thereof can be selected from a range of about 0.3 / 1 to 2/1, for example. Preferably, it may be about 0.5 / 1 to 1.5 / 1, more preferably about 0.7 / 1 to 1.2 / 1.

  (Ii) As the compound represented by the above formula (10) or a salt thereof, a commercially available product may be used, or a compound synthesized using a conventional method may be used. Compound (10) or a salt thereof, for example, as represented by the following formula, compounds (3), (6a) and (7) having units constituting this compound or a salt thereof are converted into the nucleophilic substitution reaction, It can be obtained by utilizing a reaction similar to the coupling reaction and / or the amide bond forming reaction.

[Wherein, R ^{1 to} R ⁴ , Z ^{1 to} Z ³ , X ¹ , X ² , X ⁵ , X ⁶ , X ⁸ , X ⁹ , X ¹⁰ , A ¹ and the coefficients a to c are the same as described above. When X ⁵ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, X ⁶ is —X ^1b (—R ^2b ) _b2 —H (wherein R ^2b , X ^1b and when the coefficient b2 is the same), in the ^{X 5} is _{^{-X 1a (-R 2a) b1 -H}} ( ^wherein, R ^{2a, X 1a} and coefficient b1 are the same) to the, ^{X 6} is a halogen atom, When an optionally substituted alkylsulfonyloxy group, carboxyl group, alkoxycarbonyl group or halocarbonyl group, and X ⁵ is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ⁶ is —N ( -R ^2a) -H ^{(wherein, R 2a} is the same) to said, when ^{X 5} is a group -S-L, ^{X 6} is a halogen atom, which may have a substituent alkylsulfonyl Oki A group. When X ⁸ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, X ⁹ is a group —X ^2a —H, and when X ⁸ is a group —X ^2a —H, X ⁹ Is a halogen atom, an optionally substituted alkylsulfonyloxy group, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and when X ⁸ is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ⁹ Is an amino group or an N-monosubstituted amino group. ]
In addition, after making the compound represented by the said Formula (3), the compound represented by Formula (6a), or its salt react, the product obtained, and the compound represented by the said Formula (7), or its salt The compound obtained by reacting the compound represented by the formula (6a) or a salt thereof with the compound represented by the formula (7) or a salt thereof, and the above formula (3) You may make it react with the compound represented by these. As the reaction conditions, the conditions exemplified in the items (b-1) and (i) can be used. In place of the compound or a reaction product obtained by reacting a salt thereof represented by the formula (6a) represented by or a salt thereof, with a compound formula (7), a commercially available X ⁶ -R ³ -X ² A compound represented by -A ¹ -X ¹⁰ (wherein R ³ , X ² , X ⁶ , X ¹⁰ and A ¹ are the same as described above) or a salt thereof may be used. As the reaction conditions for each reaction, the conditions exemplified in the items (b-1) and (i) can be used.

(PPAR activator and pharmaceutical composition)
The compound having a lactam skeleton represented by the formula (I) or a salt thereof has a high binding property to PPAR (PPARα, PPARγ and / or PPARδ), and is useful as a PPAR activator.

  The PPAR activator of the present invention may contain at least a compound having a lactam skeleton represented by the formula (I) or a pharmacologically acceptable salt thereof, and a compound having the lactam skeleton or a pharmacology thereof. It may be composed of a salt that is acceptable as a salt. The PPAR activator usually contains the compound having the lactam skeleton or a pharmacologically acceptable salt thereof as an active ingredient. The PPAR activator of the present invention is a pharmaceutical comprising a combination of the compound having a lactam skeleton or a pharmacologically acceptable salt thereof and a carrier (such as a pharmacologically or physiologically acceptable carrier). You may comprise with a composition (or formulation).

  The pharmaceutical composition of the present invention can be composed of a compound having a lactam skeleton represented by the above formula (I) or a pharmacologically acceptable salt thereof and a carrier.

  The compound having a lactam skeleton represented by the formula (I) constituting the PPAR activator and the pharmaceutical composition is at least one selected from the compounds represented by the formulas (1) and (1a). A lactam compound or the like is preferable. The compound having a lactam skeleton (particularly the compounds represented by the formulas (1) and (1a)) or a pharmacologically acceptable salt thereof is active at least one selected from PPARα, PPARγ and PPARδ. And preferably has high activity against PPARα and / or PPARδ (particularly PPARδ).

  In the pharmaceutical composition constituting the PPAR activator and the pharmaceutical composition of the present invention, the carrier is appropriately selected according to the form (ie, dosage form), dosage form, use, etc. of the pharmaceutical composition (or formulation). Is done. The dosage form is not particularly limited, and is a solid preparation (powder, powder, granule (granule, fine granule, etc.), pill, pill, tablet, capsule, dry syrup, suppository, etc., semi-solid preparation (cream) Agents, ointments, gels, gummi, etc.), liquids (solutions, suspensions, emulsions, syrups, elixirs, lotions, injections, etc.). Also included are sprays such as the powders and / or liquids, aerosols and the like. The capsule may be a liquid-filled capsule or a capsule filled with a solid agent such as a granule. The preparation may be a lyophilized preparation. Furthermore, the preparation may be a preparation with controlled drug release rate (sustained release preparation, immediate release preparation). In aerosols used as inhalants and the like, the aerosol generation method is not particularly limited. For example, the same sealed container is filled with a pharmaceutically active ingredient and a propellant such as chlorofluorocarbon and sprayed. Alternatively, it may be a method in the form of a nebulizer or an atomizer using a compressed gas such as carbon dioxide or nitrogen filled in a separate container from the active pharmaceutical ingredient. Furthermore, the preparation may be an oral administration preparation or a parenteral administration preparation (nasal drops, inhalants, transdermal preparations, etc.). Furthermore, the preparation may be a topical preparation (solutions such as injections (aqueous injections, non-aqueous injections, etc.), suspensions, ointments, patches, cataplasms, etc.). The preparation of the present invention is often a solid preparation (especially an orally administered preparation).

  Examples of the carrier include, in addition to the pharmacopoeia, (1) Pharmaceutical Additive Handbook, Maruzen Co., Ltd., (1989), (2) “Pharmaceutical Additives Dictionary 2000” (Pharmaceutical Daily Report, published in March 2002), (3) “Pharmaceutical Additives Dictionary 2005” (Pharmaceutical Daily Report, published in May 2005), (4) Pharmacy, Revised 5th Edition, Nanedo (1997), and (5) Pharmaceutical Additives Standard 2003 Among the components (for example, excipients, binders, disintegrants, lubricants, coating agents, etc.) listed in (Pharmaceutical Daily, August 2003), depending on the route of administration and formulation application, as appropriate You can choose. For example, as a carrier for a solid preparation, at least one carrier selected from excipients, binders and disintegrants is often used, and additives such as lipids may be used.

  Examples of the excipient include sugars such as lactose, sucrose, glucose, sucrose, mannitol, sorbitol or sugar alcohols; starch such as corn starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose); Examples thereof include silicon oxides such as acids and synthetic aluminum silicates or silicates. Binders include soluble starch such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as agar, gum arabic, dextrin, sodium alginate, tragacanth gum, xanthan gum, hyaluronic acid, sodium chondroitin sulfate; polyvinylpyrrolidone, polyvinyl alcohol, carboxy Synthetic polymers such as vinyl polymer, polyacrylic acid polymer, polylactic acid, and polyethylene glycol; and cellulose ethers such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. . Examples of disintegrants include calcium carbonate, carboxymethylcellulose or a salt thereof (carmellose, carmellose sodium, carmellose calcium, croscarmose sodium, etc.), cross-linked polyvinyl pyrrolidone (polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone (crospovidone), croscopovidone, etc. ), Low-substituted hydroxypropylcellulose and the like. These carriers can be used alone or in combination of two or more.

  Examples of the coating agent include saccharides, cellulose derivatives such as ethyl cellulose and hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, Eudragit (meta Acrylic acid / acrylic acid copolymer). The coating agent may be an enteric component such as cellulose phthalate, hydroxypropylmethylcellulose phthalate, or methyl methacrylate- (meth) acrylic acid copolymer, and a polymer containing a basic component such as dialkylaminoalkyl (meth) acrylate ( Gastric soluble components composed of Eudragit etc.). The preparation may also be a capsule containing these enteric components and gastric components in the skin.

  Among oil carriers, oily carriers include animal and vegetable oils (vegetable oils such as jojoba oil, olive oil, palm oil, and cottonseed oil; animal oils such as squalane) and mineral oils (liquid paraffin, silicone oil, etc.) Etc. can be exemplified. Examples of the aqueous carrier include water (purified or aseptic water, distilled water for injection, etc.), physiological saline, Ringer's solution, glucose solution, water-soluble organic solvents [lower aliphatic alcohols such as ethanol and isopropanol; (poly) alkylene glycols ( Ethylene glycol, diethylene glycol, polyethylene glycol and the like); glycerin and the like], dimethylisosorbide, dimethylacetamide and the like. The semi-solid carrier may be selected from the solid pharmaceutical carrier and / or the liquid carrier. Furthermore, the carrier of the semi-solid preparation may contain a lipid.

Examples of lipids include waxes (beeswax, carnauba wax, lanolin, paraffin, petrolatum, etc.), long chain fatty acid esters (saturated or unsaturated fatty acid alkyl esters, fatty acids and polyhydric alcohols [poly C _2-4 alkylene glycol, glycerin or Polyglycerin, etc.) and esters (glycerides, etc.)], hardened oils, higher alcohols (saturated fatty alcohols such as stearyl alcohol, unsaturated aliphatic alcohols such as oleyl alcohol), higher fatty acids (linoleic acid, linolenic acid, Stearic acid, oleic acid and the like), metal soaps (for example, fatty acid metal salts such as sodium coconut oil fatty acid and calcium stearate) and the like.

  In the preparation, known additives can be appropriately used depending on the administration route and dosage form. Examples of such additives include lubricants (for example, talc, magnesium stearate, polyethylene glycol 6000), disintegration aids, antioxidants or antioxidants, and emulsifiers (for example, nonionic surfactants). Surfactants), dispersants, suspending agents, solubilizers, solubilizers, thickeners (water-soluble polymers such as carboxyvinyl polymer, polyvinyl alcohol, carrageenan, gelatin; cellulose such as carboxymethylcellulose) Ethers), pH adjusters or buffers (citric acid-sodium citrate buffer, etc.), stabilizers, preservatives or preservatives (parabens, such as methylparaben and butylparaben), bactericides or antibacterial agents (benzoic acid) Benzoic acids such as sodium acid), antistatic agents, flavoring agents or masking agents (for example, Etc. Taste agents), coloring agents (such as dyes and pigments such as red iron oxide), such as flavoring agents, or perfumes (fragrances), fresheners, defoamers, isotonic agents, soothing agents. These additives can be used alone or in combination of two or more.

  For example, in an injection, a solubilizer, a solubilizer, a suspending agent, a buffer, a stabilizer, a preservative and the like are usually used as the additive. In addition, in the powder injection for use by dissolving or suspending at the time of administration, conventional additives used in powder injection can be used.

  In addition, in topical administration agents such as inhalants and transdermal absorption agents, dissolution aids, stabilizers, buffers, suspending agents, emulsifiers, preservatives and the like are usually used as the above additives. .

  In addition to the compound having the lactam skeleton or a pharmacologically acceptable salt thereof, if necessary, one or more other substances that do not adversely affect the effects for the purpose of enhancing the action, reducing the dose, reducing side effects, etc. These drugs may be used in combination. The drugs that can be used in combination may be small molecules (for example, small molecule drugs), polypeptides, antibodies, vaccines, and the like. For example, “diabetes treatment drugs”, “diabetes complication treatment drugs”, “anti-obesity” Drugs, hypertension drugs, hyperlipidemia drugs, diuretics, antithrombotic drugs, Alzheimer's disease drugs, antidepressants, antianginal drugs, “Antiarrhythmic agents”, “vasodilators”, “anti-inflammatory agents”, “antitumor agents” and the like can be mentioned.

  The PPAR activator and the pharmaceutical composition of the present invention are each a compound having a lactam skeleton represented by the above formula (I) or a pharmacologically acceptable salt thereof, a carrier component, and an additive if necessary. Can be prepared by a conventional formulation method, for example, a production method described in the 15th revision Japanese Pharmacopoeia or a method according to this production method.

  The PPAR activator and pharmaceutical composition of the present invention are highly safe and are human and non-human animals, usually mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys). Etc.), especially for humans.

  The dosage of the PPAR activator and the pharmaceutical composition of the present invention includes the subject to be administered, age, weight, sex and condition (general condition, medical condition, presence / absence of complications, etc.), administration time, dosage form, administration It can be appropriately selected depending on the method or the like. Similarly, the administration method can be selected in consideration of these requirements.

(Preventive and / or therapeutic agent)
The compound having the lactam skeleton (such as at least one selected from the compounds represented by the formulas (1) and (1a)) or a pharmacologically acceptable salt thereof has a specific binding property to PPAR. And PPAR can be effectively activated, so that metabolism of fatty acids, lipids (including fats and oils, phospholipids) and / or sugars can be promoted. Therefore, the compound having the lactam skeleton or a pharmacologically acceptable salt thereof (or the PPAR activator or the pharmaceutical composition) is (i) a disease caused by abnormal metabolism of fatty acid, lipid or sugar, and / Or (ii) It is more effective as a preventive or therapeutic agent for diseases caused by excessive intake of fatty acids, lipids or sugars compared to fatty acid, lipids or sugars. In addition, such a preventive or therapeutic agent normally contains the compound having the lactam skeleton or a pharmacologically acceptable salt thereof as an active ingredient.

  Examples of the diseases (i) and (ii) include arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistance Examples include diseases selected from the group consisting of diabetes and obesity.

  In the PPAR activator, pharmaceutical composition, preventive and / or therapeutic agent, the dose of the compound having a lactam skeleton or a pharmacologically acceptable salt thereof to a human is usually 0.01 to 1 per day. It can be selected from a range of about 1000 mg, preferably about 0.1 to 750 mg, more preferably about 0.1 to 500 mg (for example, 0.1 to 300 mg). The PPAR activator, pharmaceutical composition, prophylactic and / or therapeutic agent can be administered once or multiple times (about 2 to 6 times) per day.

  The novel lactam compound of the present invention or a salt thereof (such as a pharmacologically acceptable salt) and a compound having a lactam skeleton or a salt thereof (such as a pharmacologically acceptable salt) are PPAR (PPARα, PPARγ and / or It has a high binding property to PPARδ) and can activate PPAR, so that it is useful as a PPAR activator (such as a PPARα activator, a PPARγ activator and / or a PPARδ activator). is there. Therefore, the compound or a pharmacologically acceptable salt thereof is various diseases (for example, arteriosclerosis) caused by abnormal intake of fatty acids, lipids (including fats and oils, phospholipids) or sugar and excessive intake compared to metabolism. , Cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes that may be insulin resistant, obesity, etc.) . That is, the compound or pharmacologically acceptable salt thereof is useful as a pharmaceutical composition in combination with a carrier.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Synthesis Example 1 ( Synthesis of 4-hydroxy-2-phenylisoindoline-1-one)
(I) 3-Acetoxy-2-methylbenzoic acid (5.18 g, 26.70 mmol) was stirred in a hydrochloric acid-methanol solution (hydrochloric acid concentration 5-10%, 30 mL) for 3 days. The solvent was distilled off from the reaction mixture, and the obtained oily substance was dried to obtain methyl 3-hydroxy-2-methylbenzoate in a stoichiometric amount (yield 4.42 g).
mp 77-78 ° C
¹ H NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.89 (3H, s), 5.02 (1H, br), 6.93 (1H, dd, J = 1.0 Hz, 8.2 Hz), 7.11 (1H, app-dt, J = 0.7 Hz, 7.9 Hz), 7.42 (1H, dd, J = 1.0 Hz, 7.9 Hz).

(Ii) To a solution of methyl 3-hydroxy-2-methylbenzoate (4.40 g, 26.50 mmol) in acetone (30 mL), potassium carbonate (3.72 g, 26.90 mmol) and methyl iodide (3.70 mL, 39.9 mmol) was added, and the mixture was heated to reflux at 60 to 70 ° C. overnight. After allowing to cool, the reaction mixture was filtered, the filtrate was concentrated, and the oily residue was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The obtained mixture was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was dried to obtain oily methyl 3-methoxy-2-methylbenzoate (yield 4.53 g, yield 95%).
¹ H NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.84 (3H, s), 3.88 (3H, s), 6.98 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.19 (1H, app-t, J = 7.9 Hz), 7.39 (1H, dd, J = 1.0 Hz, 7.9 Hz).

(Iii) To a solution of methyl 3-methoxy-2-methylbenzoate (2.52 g, 14.00 mmol) in carbon tetrachloride (50 mL), N-bromosuccinimide (2.57 g, 21.80 mmol) and benzoyl peroxide (Water content 25% by weight, 30 mg) was added and heated to reflux for 3 hours. After standing to cool, the insoluble material was filtered off, and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dried to obtain methyl 2-bromomethyl-3-methoxybenzoate (yield 3.57 g, yield 98%).
mp 108-110 ° C
¹ H NMR (CDCl ₃ ) δ: 3.93 (3H, s), 3.93 (3H, s), 5.06 (2H, s), 7.06 (1H, dd, J = 1.0 Hz, 8.2 Hz), 7.34 (1H, app-t, J = 7.9 Hz), 7.52 (1H, dd, J = 1.0 Hz, 7.9 Hz).

(Iv) Methyl 2-bromomethyl-3-methoxybenzoate (259 mg, 1.00 mmol) and aniline (100 mg, 1.07 mmol) were stirred in dimethylformamide (2 mL) at 60 ° C. for 1 hour, then at 150 ° C. for 1 hour. Stir for half an hour. The solvent was distilled off, and the resulting residue was purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) to give 4-methoxy-2-phenylisoindoline-1-one (yield 223 mg). , Yield 93%).
mp 158-159 ° C
¹ H NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.80 (2H, s), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.17 ( 1H, tt, J = 1.3 Hz, 7.6 Hz), 7.39-7.50 (3H, m), 7.52 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.86 -7.91 (2H, m).

(V) 4-methoxy-2-phenylisoindoline-1-one (1.20 g, 5.02 mmol) and hydrobromic acid (hydrogen bromide concentration 47 wt%, 3.9 mL) in acetic acid (15 mL) Heated to reflux for 2 days. After standing to cool, it was diluted with dichloromethane, and the precipitate was collected by filtration, washed with water and dichloromethane, and dried to give 4-hydroxy-2-phenylisoindoline-1-one (yield 1.06 g, yield 94%). Crystal was obtained.
mp 260-262 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.89 (2H, s), 7.05 (1H, dd, J = 0.7 Hz, 7.9 Hz), 7.17 (1H, tt, J = 1) .3 Hz, 7.6 Hz), 7.23 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.36 (1H, app-t, J = 7.6 Hz), 7.40-7. 47 (2H, m), 7.88-7.93 (2H, m), 10.24 (1H, br).

Synthesis Example 2 ( Synthesis of 2- (4-carboxyphenyl) -4-hydroxyisoindoline-1-one)
The same operation as in Synthesis Example 1 except that ethyl 4-aminobenzoate (1.16 g, 7.02 mmol) was used in place of aniline in the step (iv) of Synthesis Example 1 and the reaction scale was increased to 7 times. To give 2- (4-ethoxycarbonylphenyl) -4-methoxyisoindoline-1-one, and 2- (4-carboxyphenyl) -4-hydroxyisoindoline-1 from this compound (1.86 g) -One was synthesized (yield 1.55 g, yield 96%).
mp> 310 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.94 (2H, s), 7.08 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.26 (1H, dd, J = 1) 0.0 Hz, 7.6 Hz), 7.38 (1H, app-t, J = 7.6 Hz), 7.98-8.08 (4H, m), 10 vicinity (1H, br), 13 vicinity (1H , Br).

Synthesis Example 3 ( Synthesis of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one)
(I) A solution of 3-acetoxy-2-methylbenzoic acid (9.92 g, 51.1 mmol) in dimethylformamide (105 mL) and potassium carbonate (7.77 g, 56.2 mmol) and methyl iodide (3.82 mL, 61 3 mmol) and stirred at room temperature for 40 minutes. After the reaction, water was added and extracted with diisopropyl ether. The solvent was distilled off, and the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 4/1 (v / v)) to give an oily methyl 3-acetoxy-2-methylbenzoate (yield 8. 65 g, 81% yield).
¹ H NMR (CDCl ₃ ) δ: 2.35 (3H, s), 2.39 (3H, s), 3.89 (3H, s), 7.17 (1H, dd, J = 1.6 Hz, 7.9 Hz), 7.26 (1 H, t, J = 7.9 Hz), 7.77 (1 H, dd, J = 1.6 Hz, 7.9 Hz).

(Ii) (Synthesis of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindolin-1-one)
To a solution of methyl 3-acetoxy-2-methylbenzoate (5.38 mg, 25.9 mmol) in carbon tetrachloride (100 mL), N-bromosuccinimide (4.60 mg, 25.9 mmol) and benzoyl peroxide (water content) 25 wt%, 313 mg) was added, and the mixture was heated to reflux for 1 hour. After standing to cool, insoluble matter was filtered off and the solvent was removed to obtain methyl 3-acetoxy-2-bromomethylbenzoate. A solution of this compound (540 mg, 1.88 mmol) and 1-amino-4- (trifluoromethyl) benzene (303 mg, 1.88 mmol) in dimethylformamide (8 mL) was stirred at 60 ° C. for 2 hours and then at 150 ° C. for 2 hours. did. After allowing to cool, potassium carbonate (260 mg, 1.88 mmol) and methanol (10 mL) were added, and the mixture was stirred at room temperature for 15 hours. After neutralizing with 1N (mol / L) hydrochloric acid, water was added, and the resulting crystals were dried to give 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (yield 409 mg, yield). 74%) of crystals were obtained.
mp 246-249 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.95 (2H, s), 7.07-7.10 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.25-7.28 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.35-7.41 (1H, t, J = 7.6 Hz), 7.78-7.82 (2H, d, J = 8 .6 Hz), 8.14-8.17 (2H, d, J = 8.6 Hz), 10.31 (1 H, s).

Synthesis Example 4 ( Synthesis of 4 -hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one)
In Step (ii) of Synthesis Example 3, methyl 4-aminobenzoate (3.91 mg, 25.9 mmol) is used instead of 1-amino-4- (trifluoromethyl) benzene, and the reaction scale is changed as appropriate. Except for the above, the same operation as in Synthesis Example 3 was carried out to synthesize 4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 5.26 mg, yield 72%).
mp 287-289 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.94 (2H, s), 7.08 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7. 26 (1 H, dd, J = 0.7 Hz, 7.6 Hz), 7.38 (1 H, t, J = 7.6 Hz), 7.99-8.12 (4 H, m), 10.30 (1 H , S).

Synthesis Example 5 ( Synthesis of 2- (4-fluorophenyl) -4-hydroxyisoindoline-1-one)
Synthesis was performed in the same manner as in Synthesis Example 3 except that 4-fluoroaniline (267 mg, 2.40 mmol) was used instead of 1-amino-4- (trifluoromethyl) benzene and the reaction scale was appropriately changed. The same operation as in Example 3 was performed to synthesize 2- (4-fluorophenyl) -4-hydroxyisoindoline-1-one (yield 112 mg, yield 23%).
mp 226-228 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.88 (2H, s), 7.51 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.21-7.39 (4H, m ), 7.90-7.95 (2H, m), 10.30 (1H, br).

Synthesis Example 6 ( Synthesis of 2- (4-chlorophenyl) -4-hydroxyisoindoline-1-one)
Synthesis was performed except that 4-chloroaniline (306 mg, 2.40 mmol) was used instead of 1-amino-4- (trifluoromethyl) benzene and the reaction scale was changed as appropriate in the step (ii) of Synthesis Example 3. The same operation as in Example 3 was performed to synthesize 2- (4-chlorophenyl) -4-hydroxyisoindoline-1-one (yield 443 mg, yield 85%).
mp 265-267 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.88 (2H, s), 7.06 (1H, dd, J = 0.8 Hz, 7.8 Hz), 7.23 (1H, d, J = 7) .8 Hz), 7.36 (1H, t, J = 7.8 Hz), 7.49 (2H, app-dt, J = 3.0 Hz, 10.0 Hz), 7.95 (2H, app-dt, J = 3.0 Hz, 10.0 Hz), 10.31 (1H, br).

Synthesis Example 7 ( Synthesis of 2- (4-bromophenyl) -4-hydroxyisoindoline-1-one)
Synthesis was performed except that 4-bromoaniline (413 mg, 2.40 mmol) was used instead of 1-amino-4- (trifluoromethyl) benzene and the reaction scale was appropriately changed in the step (ii) of Synthesis Example 3. The same operation as in Example 3 was performed to synthesize 2- (4-bromophenyl) -4-hydroxyisoindoline-1-one (yield 543 mg, yield 89%).
mp 262-264 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.87 (2H, s), 7.05 (1H, d, J = 7.8 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.35 (1H, t, J = 7.8 Hz), 7.61 (2H, d, J = 8.9 Hz), 7.91 (2H, d, J = 8.9 Hz).

Synthesis Example 8 ( Synthesis of 4-hydroxy-2- (4-iodophenyl) isoindoline-1-one)
Synthesis was performed except that 4-iodoaniline (526 mg, 2.40 mmol) was used instead of 1-amino-4- (trifluoromethyl) benzene and the reaction scale was appropriately changed in the step (ii) of Synthesis Example 3. The same operation as in Example 3 was performed to synthesize 4-hydroxy-2- (4-iodophenyl) isoindoline-1-one (yield 340 mg, yield 48%).
mp 249-252 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.87 (2H, s), 7.04-7.07 (1H, d, J = 7.6 Hz), 7.22-7.25 (1H, d , J = 7.6 Hz), 7.33-7.39 (1H, t, J = 7.6 Hz), 7.61 (4H, s), 10.28 (1H, s).

Synthesis Example 9 ( Synthesis of 2- (2,4-dichlorophenyl) -4-hydroxyisoindoline-1-one)
In Step (ii) of Synthesis Example 3, 2,4-dichloroaniline (648 mg, 4.00 mmol) was used in place of 1-amino-4- (trifluoromethyl) benzene, and the reaction scale was appropriately changed. In the same manner as in Synthesis Example 3, 2- (2,4-dichlorophenyl) -4-hydroxyisoindoline-1-one was synthesized (yield 528 mg, yield 47%).
mp 255-257 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.71 (2H, s), 7.08 (1H, dd, J = 0.8 Hz, 7.8 Hz), 7.24 (1H, dd, J = 0) .8 Hz, 7.8 Hz), 7.39 (1 H, t, J = 7.8 Hz), 7.57 (1 H, dd, J = 2.2 Hz, 8.6 Hz), 7.67 (1 H, d, J = 8.6 Hz), 7.83 (1H, d, J = 2.2 Hz).

Synthesis Example 10 ( Synthesis of 4-hydroxy-2- (3-methylphenyl) isoindoline-1-one)
Synthesis was performed in the same manner as in Synthesis Example 3 except that 3-methylaniline (429 mg, 4.00 mmol) was used instead of 1-amino-4- (trifluoromethyl) benzene and the reaction scale was appropriately changed. The same operation as in Example 3 was performed to synthesize 4-hydroxy-2- (3-methylphenyl) isoindoline-1-one (yield 159 mg, yield 17%).
mp 231-232 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.35 (3H, s), 4.86 (2H, s), 6.98-7.00 (1H, m), 7.05 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.22 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.28-7.38 (2H, m), 7.72-7.75. (2H, m), 10.25 (1H, br).

Synthesis Example 11 ( Synthesis of 4-hydroxy-2- (4-methylphenyl) isoindoline-1-one)
Synthesis was performed except that 4-methylaniline (429 mg, 4.00 mmol) was used instead of 1-amino-4- (trifluoromethyl) benzene in the step (ii) of Synthesis Example 3 and the reaction scale was changed as appropriate. The same operation as in Example 3 was performed to synthesize 4-hydroxy-2- (4-methylphenyl) isoindoline-1-one (yield 560 mg, yield 59%).
mp 254-256 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.25 (3H, s), 4.85 (2H, s), 7.04 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7. 20-7.25 (3H, m), 7.35 (1H, t, J = 7.8 Hz), 7.78 (2H, d, J = 8.6 Hz), 10.25 (1H, br).

Synthesis Example 12 ( Synthesis of 2- (4-bromo-3-methylphenyl) -4-hydroxyisoindoline-1-one)
Methyl 3-acetoxy-2-methylbenzoate (1.06 g, 3.71 mmol) and 4-bromo-3-methylaniline (689 mg, 3.71 mmol) obtained in the same manner as in step (i) of Synthesis Example 3 Were dissolved in dimethylformamide (15 mL) and the solution was stirred at 60 ° C. for 2 hours and then at 150 ° C. for 15 hours. After allowing to cool, water was added to the reaction mixture, the resulting crystals were recrystallized from dimethylformamide, and the crystals were collected by filtration. Crystals obtained by cooling the remaining filtrate to 0 ° C. were filtered off, and water was added to the filtrate to produce crystals. The crystals obtained from this filtrate and the crystals obtained by the above recrystallization were combined to prepare a methanol (15 mL) solution. To this solution was added potassium carbonate (512 mg, 3.71 mmol), and 1 mL at room temperature was added. Stir for hours. After neutralizing with 1N (mol / L) hydrochloric acid, water was added, and the resulting crystals were recrystallized from dimethylformamide to give 2- (4-bromo-3-methylphenyl) -4-hydroxyisoindoline-1-one. (Yield 521 mg, 44% yield) of crystals were obtained.
mp 314-317 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 4.87 (2H, s), 7.06 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7. 23 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.61 (1H, d, J = 8.6 Hz), 7.80 (1H, dd, J = 2.6 Hz, 8.6 Hz), 7.87 (1H, d, J = 2.6 Hz), 10.27 (1H, s).

Synthesis Example 13 ( Synthesis of 4-hydroxy-2- (3,4-dimethylphenyl) isoindoline-1-one)
To a carbon tetrachloride (10 mL) solution of methyl 3-acetoxy-2-methylbenzoate (833 mg, 4.00 mmol) synthesized in the same manner as in Step (i) of Synthesis Example 3, N-bromosuccinimide (712 mg, 4 0.000 mmol) and benzoyl peroxide (water content 25 wt% concentration, 50 mg) were added, and the mixture was heated to reflux for 1 hour. After allowing to cool, it was washed with water and the solvent was distilled off to obtain methyl 3-acetoxy-2-bromomethylbenzoate.

A solution of this compound and 3,4-dimethylaniline (485 mg, 4.00 mmol) in dimethylformamide (10 mL) was stirred at 60 ° C. for 2 hours and then at 120 ° C. for 1 hour. After allowing to cool, potassium carbonate (553 mg, 4.00 mmol) and methanol (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Further, water was added and neutralized with concentrated hydrochloric acid. The precipitate was collected by filtration and recrystallized using dimethylformamide and methanol to give 4-hydroxy-2- (3,4-dimethylphenyl) isoindoline-1- On (yield 590 mg, 58% yield) crystals were obtained. Further, recrystallization from the mother liquor gave 4-hydroxy-2- (3,4-dimethylphenyl) isoindoline-1-one (yield 137 mg, yield 14%). The total yield was 72%.
mp 287-289 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 2.26 (3H, s), 4.83 (2H, s), 7.36 (1H, dd, J = 1. 1 Hz, 7.8 Hz), 7.15-7.22 (2 H, m), 7.35 (1 H, t, J = 7.6 Hz), 7.62-7.65 (2 H, m), 10. 21 (1H, s).

Synthesis Example 14 ( Synthesis of 4-hydroxy-2- (3-isopropylphenyl) isoindoline-1-one)
A solution of methyl 3-acetoxy-2-bromomethylbenzoate and 3-isopropylaniline (540 mg, 4.00 mmol) obtained in the same manner as in Synthesis Example 13 in dimethylformamide (10 mL) was stirred at 60 ° C. for 2 hours, then 110 Stir for 1 hour at ° C. After allowing to cool, 3-isopropylaniline (270 mg, 2.00 mmol) was further added to the reaction mixture, and the mixture was stirred at 120 ° C. for 2.5 hours. After allowing to cool, potassium carbonate (553 mg, 4.00 mmol) and methanol (10 mL) were added to the resulting reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Further, water was added, neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration and recrystallized repeatedly with methanol to give 4-hydroxy-2- (3-isopropylphenyl) isoindoline-1-one (yield 278 mg). , Yield 26%). Furthermore, recrystallization was performed from the mother liquor to obtain crystals of 4-hydroxy-2- (3-isopropylphenyl) isoindoline-1-one (yield 211 mg, yield 20%). The total yield was 46%.
mp 194-195 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.98 (1H, quin, 7.0 Hz), 4.88 (2H, s), 7. 03-7.07 (2H, m), 7.20-7.23 (1H, m), 7.31-7.38 (2H, m), 7.70-7.74 (1H, m), 7.80 (1H, t, J = 2.1 Hz), 10.26 (1H, br).

Synthesis Example 15 ( Synthesis of 4-hydroxy-2- (4-isopropylphenyl) isoindoline-1-one)
A solution of methyl 3-acetoxy-2-bromomethylbenzoate and 4-isopropylaniline (547 mg, 4.00 mmol) obtained in the same manner as in Synthesis Example 13 in dimethylformamide (10 mL) was stirred at 60 ° C. for 2 hours, and then 100 Stir overnight at ° C. After allowing to cool, potassium carbonate (553 mg, 4.00 mmol) and methanol (10 mL) were added to the reaction mixture, and the mixture was heated to reflux for 1 hour. Further, water was added, neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried to 4-hydroxy-2- (4-isopropylphenyl) isoindoline-1-one (yield 561 mg, yield 52%). Crystal was obtained.
mp 255-257 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.22 (6H, d, J = 6.8 Hz), 2.90 (1H, quin, J = 6.8 Hz), 4.85 (2H, s), 7.04 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.21 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.27-7.38 (3H, m) 7.80 (2H, app-dt, J = 2.2 Hz, 9.2 Hz), 10.25 (1H, br).

Synthesis Example 16 ( Synthesis of 2- (3-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one)
Dimethylformamide of methyl 3-acetoxy-2-bromomethylbenzoate (530 mg, 1.85 mmol) and 1-amino-3- (trifluoromethyl) benzene (297 mg, 1.85 mmol) obtained in the same manner as in Synthesis Example 13. (8 mL) The solution was stirred at 60 ° C. for 2 hours and then at 150 ° C. for 2 hours. After allowing to cool, potassium carbonate (255 mg, 1.85 mmol) and methanol (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was neutralized with 1N (mol / L) hydrochloric acid, water was added, and the precipitated crystals were dried to give 2- (3-trifluoromethylphenyl) -4-hydroxyisoindoline-1- On (yield 392 mg, 72% yield) crystals were obtained.
mp 243-245 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.97 (2H, s), 7.08 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.26 (1H, dd, J = 0) .7 Hz, 7.6 Hz), 7.38 (1 H, t, J = 7.6 Hz), 7.52 (1 H, dd, J = 1.0 Hz, 7.9 Hz), 7.68 (1 H, t, J = 7.9 Hz), 8.11 (1H, ddd, J = 1.0 Hz, 1.6 Hz, 7.9 Hz), 8.43 (1 H, s), 10.30 (1 H, s).

Synthesis Example 17 ( Synthesis of 2- (4-acetylphenyl) -4-hydroxyisoindoline-1-one)
To a carbon tetrachloride (15 mL) solution of methyl 3-acetoxy-2-methylbenzoate (1.04 g, 5.00 mmol) synthesized in the same manner as in Step (i) of Synthesis Example 3, N-bromosuccinimide (890 mg) was added. , 5.00 mmol) and benzoyl peroxide (water content 25 wt%, 61 mg) were added and heated to reflux for 1 hour. After allowing to cool, the organic layer was washed with water and the solvent was distilled off to obtain methyl 3-acetoxy-2-bromomethylbenzoate.

A solution of this compound and p-aminoacetophenone (676 mg, 5.00 mmol) in dimethylformamide (15 mL) was stirred at 60 ° C. for 1.5 hours, and then stirred at 150 ° C. for 2 hours. After allowing to cool, potassium carbonate (691 mg, 5.00 mmol) and methanol (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. The resulting mixture was neutralized with 1N (mol / L) hydrochloric acid, water was added, and the obtained crystals were dried to give 2- (4-acetylphenyl) -4-hydroxyisoindoline-1- On (yield 1.01 g, yield 76%) crystals were obtained.
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.58 (3H, s), 4.95 (2H, s), 7.08 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7. 26 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.38 (1H, t, J = 7.6 Hz), 8.00-8.11 (4H, m), 10.36 (1H , Brs).

Synthesis Example 18 ( Synthesis of 4-hydroxy-2- [4- (1-hydroxyethyl) phenyl] isoindoline-1-one)
To a suspension of 2- (4-acetylphenyl) -4-hydroxyisoindoline-1-one (588 mg, 2.20 mmol) obtained in Synthesis Example 17 in methanol (10 mL), sodium borohydride (1.25 g) was added. , 33.0 mmol) was gradually added to carry out the reaction. After the reaction, 1N (mol / L) hydrochloric acid is added to the reaction mixture to make it acidic, and the precipitated crystals are collected by filtration and dried to give 4-hydroxy-2- [4- (1-hydroxyethyl) phenyl] isoindoline. Crystals of -1-one (yield 544 mg, yield 92%) were obtained.
mp 168-171 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.33 (3H, d, J = 6.6 Hz), 4.68-4.77 (1H, m), 4.86 (2H, s), 5. 14 (1H, d, J = 4.0 Hz), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.22 (1H, dd, J = 1.0 Hz, 7.6 Hz) 7.36 (1H, t, J = 7.6 Hz), 7.37-7.41 (2H, m), 7.80-7.85 (2H, m), 10.22 (1H, brs) .

Synthesis Example 19 ( Synthesis of 2- (4-trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one)
A solution of methyl 3-acetoxy-2-bromomethylbenzoate and 4-trifluoromethoxyaniline (726 mg, 4.00 mmol) obtained in the same manner as in Synthesis Example 13 in dimethylformamide (10 mL) was stirred at 150 ° C. for 3 hours, After allowing to cool, potassium carbonate (553 mg, 4.00 mmol) and methanol (10 mL) were added, and the mixture was stirred overnight. Further, water was added, neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried to give 2- (4-trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one (yield 627 mg, yield 51). %) Crystals.
mp 233-234 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.91 (2H, s), 7.06 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.23 (1H, dd, J = 1) .1 Hz, 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.43-7.48 (2H, m), 8.03 (2H, app-dt, J = 2. 4Hz, 9.2Hz).

Synthesis Example 20 ( Synthesis of 4-hydroxy-2- (4-methoxyphenyl) isoindoline-1-one)
A solution of methyl 3-acetoxy-2-bromomethylbenzoate and 4-methoxyaniline (547 mg, 4.00 mmol) obtained in the same manner as in Synthesis Example 13 in dimethylformamide (10 mL) was stirred at 60 ° C. for 2 hours, then 120 The mixture was stirred overnight at 150 ° C., and further stirred at 150 ° C. for 1 hour. After allowing to cool, potassium carbonate (553 mg, 4.00 mmol) and methanol (10 mL) were added to the reaction mixture, and the mixture was heated to reflux for 1 hour. Further, water was added, neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried to 4-hydroxy-2- (4-methoxyphenyl) isoindoline-1-one (yield 505 mg, yield 49%) Crystal was obtained.
mp 258-261 ° C
¹ H NMR (CDCl ₃ ) δ: 3.77 (3H, s), 4.82 (2H, s), 7.00 (2H, app-dt, J = 2.4 Hz, 9.2 Hz), 7. 02-7.05 (1H, m), 7.20 (1H, dd, J = 0.8 Hz, 7.6 Hz), 7.34 (1 H, t, J = 7.6 Hz), 7.78 (2H , App-dt, J = 2.4 Hz, 9.2 Hz).

Synthesis Example 21 ( Synthesis of 2- (4-carbamoylphenyl) -4-hydroxyisoindoline-1-one)
To a solution of methyl 3-acetoxy-2-methylbenzoate (1.04 g, 5.00 mmol) synthesized in the same manner as in Step (i) of Synthesis Example 3 in carbon tetrachloride (15 mL), N-bromosuccinimide (890 mg) was added. , 5.00 mmol) and benzoyl peroxide (water content 25% by weight, 80 mg) were added and heated to reflux for 1 hour. After standing to cool, insoluble matters were filtered off, and the solvent was distilled off from the filtrate to obtain methyl 3-acetoxy-2-bromomethylbenzoate.

A solution of this compound and p-aminobenzamide (681 mg, 5.00 mmol) in dimethylformamide (15 mL) was stirred at 60 ° C. for 1.5 hours, and then stirred at 150 ° C. for 2 hours. After allowing to cool, potassium carbonate (691 mg, 5.00 mmol) and methanol (15 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. The obtained mixture was neutralized with 1N (mol / L) hydrochloric acid, water was added, and the precipitated crystals were filtered off and dried to give 2- (4-carbamoylphenyl) -4-hydroxyiso Crystals of indoline-1-one (yield 556 mg, yield 41%) were obtained.
mp 294-296 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.93 (2H, s), 7.07 (1H, d, J = 7.6 Hz), 7.25 (1H, d, J = 7.6 Hz), 7.32 (1H, brs), 7.37 (1H, t, J = 7.6 Hz), 7.93-8.02 (5H, m), 10.29 (1H, brs).

Synthesis Example 22 ( Synthesis of 4-hydroxy-2- (4-nitrophenyl) isoindoline-1-one)
To a solution of methyl 3-acetoxy-2-methylbenzoate (1.25 g, 6.00 mmol) synthesized in the same manner as in step (i) of Synthesis Example 3 in carbon tetrachloride (15 mL), N-bromosuccinimide (1 0.07 g, 6.00 mmol) and benzoyl peroxide (water content 25% by weight, 75 mg) were added and heated to reflux for 1 hour. After allowing to cool, it was washed with water and the solvent was distilled off to obtain methyl 3-acetoxy-2-bromomethylbenzoate.

A solution of this compound and 4-nitroaniline (829 mg, 6.00 mmol) in dimethylformamide (10 mL) was stirred at 150 ° C. for 1 hour. After allowing to cool, potassium carbonate (829 mg, 6.00 mmol) and methanol (15 mL) were added to the reaction mixture, and the mixture was stirred for 1 hour. Further, water was added, neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration and dried to give 4-hydroxy-2- (4-nitrophenyl) isoindoline-1-one (yield 1.31 g, yield). 81%) of crystals were obtained.
mp 282-284 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.99 (2H, s), 7.10 (1H, d, J = 7.6 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.39 (1H, t, J = 7.6 Hz), 8.18-8.24 (2H, m), 8.30-8.35 (2H, m).

Synthesis Example 23 ( Synthesis of 2- (4-ethoxycarbonylphenyl) -5-methoxyisoindoline-1-one)
(I) 4-Methoxy-2-methylbenzoic acid (4.98 g, 30.00 mmol) was added to a hydrochloric acid-methanol solution (hydrochloric acid concentration 5-10%, 50 mL), and the mixture was heated to reflux overnight. The solvent was distilled off, and the mixture was made weak alkaline with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off and dried to obtain oily methyl 4-methoxy-2-methylbenzoate (yield 5.23 g, yield 97%).
¹ H NMR (CDCl ₃ ) δ: 2.60 (3H, s), 3.83 (3H, s), 3.86 (3H, s), 6.72-6.76 (2H, m), 7 .91-7.95 (1H, m).

(Ii) Synthesis of 2- (4-ethoxycarbonylphenyl) -5-methoxyisoindoline-1-one To a solution of methyl 4-methoxy-2-methylbenzoate (1.80 g, 10.0 mmol) in benzene (100 mL) N-bromosuccinimide (2.14 g, 10.0 mmol) and benzoyl peroxide (water content 25% by weight, 20 mg) were added, and the mixture was heated to reflux for 2 hours. The reaction solution was washed with water, and the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain methyl 4-acetoxy-2-bromomethylbenzoate.

To this compound, ethyl 4-aminobenzoate (1.65 g, 10.0 mmol) and dimethylformamide (30 mL) were added, and the mixture was heated and stirred at 60 ° C. for 45 minutes, and further heated and stirred at 150 ° C. for 1.5 hours. After allowing to cool, the precipitate was collected by filtration and dried to give 2- (4-ethoxycarbonylphenyl) -5-methoxyisoindoline-1-one (yield 1.65 g, yield 53%) as colorless needles. Obtained.
mp 216-217 ° C
¹ H NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.3 Hz), 3.92 (3H, s), 4.38 (2H, q, J = 7.3 Hz), 4. 85 (2H, s), 7.00-7.01 (1H, m), 7.02-7.06 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.84-7.87 (1H, d, J = 8.4 Hz), 7.95-8.00 (2H, m), 8.08-8.13 (2H, m).

Synthesis Example 24 ( Synthesis of 2- (4-carboxyphenyl) -5-hydroxyisoindoline-1-one)
2- (4-Ethoxycarbonylphenyl) -5-methoxyisoindoline-1-one (667 mg, 2.10 mmol) obtained in Synthesis Example 23 was converted to hydrobromic acid (hydrogen bromide concentration 47 wt%, 30 mL). And acetic acid (10 mL), and the mixture was heated to reflux for 5 days. After allowing to cool, water was added to the reaction mixture, the precipitate was collected by filtration, washed with water, and dried to give 2- (4-carboxyphenyl) -5-hydroxyisoindoline-1-one (yield 549 mg, 95% yield). ) White solid was obtained.
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.96 (2H, s), 6.91-6.94 (1H, dd, J = 1.6 Hz, 8.1 Hz), 6.98 (1H, s ), 7.61-7.64 (1H, d, J = 8.1 Hz), 7.96-8.03 (4H, m), 10.40 (1H, s), 12.75 (1H, s) ).

Synthesis Example 25 ( Synthesis of 5-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one)
2- (4-Carboxyphenyl) -5-hydroxyisoindoline-1-one (2.30 g, 8.50 mmol) obtained in Synthesis Example 24 was added to a hydrochloric acid-methanol solution (hydrochloric acid concentration 5 to 10%, 50 mL). Added and heated to reflux overnight. Furthermore, hydrochloric acid-methanol solution (hydrochloric acid concentration 5-10%, 50 mL) was added, and the mixture was heated to reflux overnight. After allowing to cool, the precipitate was collected by filtration, washed with methanol, recrystallized from dimethylformamide, and dried to give 5-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 1.80 g). , Yield 75%).
mp 282-284 ° C / DMF
¹ H NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.96 (2H, s), 6.90-6.99 (2H, m), 7.61-7.64 ( 1H, app-d, J = 8.6 Hz), 7.98-8.03 (4H, m), 10.45 (1H, br).

Synthesis Example 26 ( Synthesis of 2- (4-ethoxycarbonylphenyl) -6-methoxyisoindoline-1-one)
(I) To a suspension of ethyl propiolate (9.68 g, 98.7 mmol) and aluminum chloride (13.16 g, 98.7 mmol) in dichloromethane (500 mL), 2-methylfuran (8.10 g, 98.7 mmol) Of dichloromethane (100 mL) was added dropwise over 30 minutes. After stirring at room temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off, and the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)), recrystallized with chloroform and hexane, and 5-hydroxy-2-methyl. Crystals of ethyl benzoate (yield 5.83 g, yield 33%) were obtained.
mp 62-64 ° C
¹ H NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.3 Hz), 2.51 (3H, s), 4.35 (2H, q, J = 7.3 Hz), 4. 91 (1H, brs), 6.89 (1H, dd, J = 2.6 Hz, 8.2 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 2.6 Hz).

(Ii) To a suspension of ethyl 5-hydroxy-2-methylbenzoate (5.81 g, 32.2 mmol) in acetone (40 mL), potassium carbonate (4.46 g, 32.2 mmol) and methyl iodide (6. 86 g, 48.4 mmol) was added, and the mixture was heated to reflux at 70 ° C. overnight. After the reaction, the mixture was acidified with 1N (mol / L) hydrochloric acid and extracted with ethyl acetate. The solvent was distilled off, and the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)) to give an oily ethyl 5-methoxy-2-methylbenzoate (yield 5. 17 g, 83% yield).
¹ H NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.3 Hz), 2.51 (3H, s), 3.82 (3H, s), 4.35 (2H, q, J = 7.3 Hz), 6.95 (1H, dd, J = 3.0 Hz, 8.2 Hz), 7.14 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 3.0 Hz).

  (Iii) To a suspension of ethyl 5-methoxy-2-methylbenzoate (1.94 g, 10.0 mmol) in carbon tetrachloride (40 mL), N-bromosuccinimide (1.78 g, 10.0 mmol) and Benzoyl oxide (water content 25% by weight, 73 mg) was added, and the mixture was heated to reflux for 1.5 hours. After allowing to cool, insoluble matters were filtered off, and the solvent was distilled off to obtain ethyl 2-bromomethyl-5-methoxybenzoate.

A solution of this compound and ethyl 4-aminobenzoate (1.65 g, 10.0 mmol) in dimethylformamide (40 mL) was stirred at 60 ° C. for 1 hour, and further stirred at 150 ° C. for 1.5 hours. After allowing to cool, the obtained crystal was washed with ethanol to obtain 2- (4-ethoxycarbonylphenyl) -6-methoxyisoindoline-1-one (yield 1.99 g, yield 64%).
mp 196-198 ° C
¹ H NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.3 Hz), 3.90 (3H, s), 4.38 (2H, q, J = 7.3 Hz), 4. 84 (2H, s), 7.18 (1H, dd, J = 2.6 Hz, 8.2 Hz), 7.40 (1H, d, J = 2.6 Hz), 7.42 (1H, d, J = 8.2 Hz), 7.96-8.01 (2H, m), 8.08-8.13 (2H, m).

Synthesis Example 27 ( Synthesis of 2- (4-carboxyphenyl) -6-hydroxyisoindoline-1-one)
2- (4-Ethoxycarbonylphenyl) -6-methoxyisoindoline-1-one (1.88 g, 6.03 mmol) obtained in Synthesis Example 26 was added to acetic acid (30 mL) and hydrobromic acid (hydrogen bromide). Suspended in a concentration of 47% by weight, 24 mL) and heated to reflux for 10 days. After allowing to cool, the resulting crystals were collected by filtration. Recrystallization from dimethylformamide gave crystals of 2- (4-carboxyphenyl) -6-hydroxyisoindoline-1-one (yield 1.40 g, yield 86%).
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.95 (2H, s), 7.08-7.11 (2H, m), 7.46-7.49 (1H, m), 7.95- 8.06 (4H, m), 9.92 (1H, s), 12.82 (1H, s).

Synthesis Example 28 ( Synthesis of 6-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one)
2- (4-Carboxyphenyl) -6-hydroxyisoindoline-1-one (1.08 g, 4.00 mmol) obtained in Synthesis Example 27 was added to hydrochloric acid-methanol solution (hydrochloric acid concentration 5-10%, 40 mL). And the mixture was stirred with heating at 50 ° C. for 3 days. Then, hydrochloric acid-methanol solution (hydrochloric acid concentration 5-10%, 40 mL) was added, and the mixture was further heated under reflux for 4 days. After allowing to cool, the resulting crystals were collected by filtration and recrystallized from dimethylformamide to give 6-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 976 mg, 86% yield) as crystals. Obtained.
mp 268-271 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.95 (2H, s), 7.08-7.13 (2H, m), 7.46-7.49 ( 1H, m), 7.9-8.09 (4H, m), 9.93 (1H, s).

Synthesis Example 29 ( Synthesis of 7-methoxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one)
To a solution of ethyl 2-methoxy-6-methylbenzoate (1.94 g, 10.0 mmol) in carbon tetrachloride (40 mL), N-bromosuccinimide (1.96 g, 11.0 mmol) and benzoyl peroxide (containing water) 25 wt%, 180 mg) was added, and the mixture was heated to reflux for 5 and a half hours. After standing to cool, insoluble matters were filtered off, and the solvent was distilled off from the filtrate to obtain ethyl 6-bromomethyl-2-methoxybenzoate.

A solution of this compound and methyl 4-aminobenzoate (1.51 g, 10.0 mmol) in dimethylformamide (25 mL) was stirred at 60 ° C. for 1.5 hours, and then stirred at 150 ° C. for 2 hours. After allowing to cool, water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 30/1 (v / v)) and 7-methoxy-2- (4-methoxycarbonylphenyl). ) Crystals of isoindoline-1-one (yield 845 mg, yield 28%) were obtained.
mp 222-224 ° C
¹ H NMR (CDCl ₃ ) δ: 3.91 (3H, s), 4.01 (3H, s), 4.83 (2H, s), 6.94 (1H, d, J = 7.9 Hz) 7.08 (1H, d, J = 7.9 Hz), 7.55 (1H, t, J = 7.9 Hz), 7.96-8.10 (4H, m).

Synthesis Example 30 ( Synthesis of 2- (4-carboxyphenyl) -7-hydroxyisoindolin-1-one)
7-Methoxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (794 mg, 2.95 mmol) obtained in Synthesis Example 29 was mixed with acetic acid (10 mL) and hydrobromic acid (hydrogen bromide concentration 47 (Weight%, 10 mL) and heated to reflux for 7 days. After allowing to cool, the resulting crystals were collected by filtration and recrystallized from dimethylformamide to obtain 2- (4-carboxyphenyl) -7-hydroxyisoindoline-1-one (yield 550 mg, 70% yield). It was.
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.97 (2H, s), 6.87 (1H, d, J = 7.9 Hz), 7.04 (1H, d, J = 7.9 Hz), 7.47 (1H, t, J = 7.9 Hz), 7.99 (4H, m), 9.98 (1H, s), 12.80 (1H, br).

Synthesis Example 31 ( Synthesis of 7-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one)
2- (4-Carboxyphenyl) -7-hydroxyisoindoline-1-one (515 mg, 1.91 mmol) obtained in Synthesis Example 30 was suspended in a hydrochloric acid-methanol solution (hydrochloric acid concentration 5-10%, 40 mL). Turbid and heated to reflux for 4 days. After allowing to cool, the resulting crystals were collected by filtration to give 7-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 440 mg, 81% yield).
mp 190-192 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.98 (2H, s), 6.87 (1H, d, J = 7.9 Hz), 7.04 (1H, d, J = 7.9 Hz), 7.47 (1H, t, J = 7.9 Hz), 7.98-8.06 (4H, m), 9.99 (1H, s).

Synthesis Example 32 ( Synthesis of ethyl 3- (2-hydroxyethylthio) propionate)
To a solution of 2-bromoethanol (3.75 g, 30.0 mmol) in acetonitrile (35 mL) was added potassium carbonate (4.98 g, 36.0 mmol) and ethyl 3-mercaptopropionate (4.56 mL, 36.0 mmol). And stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give oily 3- (2-hydroxyethylthio). ) Ethyl propionate (yield 3.15 g, yield 59%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.37 (1H, brs), 2.61 (2H, t, J = 6.9 Hz), 2. 75 (2H, t, J = 5.9 Hz), 2.79-2.85 (2H, m), 3.75 (2H, brs), 4.17 (2H, q, J = 7.3 Hz).

Synthesis Example 33 ( Synthesis of 5-amino-2- (4-ethoxycarbonylphenyl) isoindoline-1-one)
(I) Synthesis of methyl 2-methyl-4-nitrobenzoate A solution of 2-methyl-4-nitrobenzoic acid (5.00 g, 27.6 mmol) in 10 wt% hydrochloric acid-methanol (50 mL) was heated to reflux for 20 hours. . After allowing to cool, the resulting crystals were collected by filtration and dried to obtain stoichiometrically (yield 5.39 g) of methyl 2-methyl-4-nitrobenzoate.
mp 78-80 ° C
_{^{1 H NMR (CDCl 3) δ}} : 2.69 (3H, s), 3.95 (3H, s), 8.01-8.12 (3H, m).

(Ii) Synthesis of 2- (4-ethoxycarbonylphenyl) -5-nitroisoindoline-1-one Methyl 2-methyl-4-nitrobenzoate (1.95 g, 10.0 mmol) was suspended in benzene (40 mL). To this suspension, N-bromosuccinimide (1.78 g, 10.0 mmol) and an aqueous benzoyl peroxide solution (75 wt% concentration, 73 mg) were added, and the mixture was heated to reflux for 8 hours. After standing to cool, insoluble matters were filtered off, and the solvent was distilled off from the filtrate to obtain methyl 2-bromomethyl-4-nitrobenzoate.

A solution of this compound and ethyl 4-benzoate (1.65 g, 10.0 mmol) in dimethylformamide (40 mL) was stirred at 60 ° C. for 50 minutes, and further stirred at 150 ° C. for 2 hours. After allowing to cool, the precipitated crystals were washed with ethanol to give 2- (4-ethoxycarbonylphenyl) -5-nitroisoindoline-1-one (yield 1.71 g, yield 52%).
mp 252-254 ° C
¹ H NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.3 Hz), 4.40 (2H, q, J = 7.3 Hz), 5.03 (2H, s), 7. 96-8.01 (2H, m), 8.09-8.17 (3H, m), 8.40-8.43 (2H, m).

(Iii) Synthesis of 5-amino-2- (4-ethoxycarbonylphenyl) isoindoline-1-one 2- (4-ethoxycarbonylphenyl) -5-nitroisoindoline-1-one (1.65 g, 5. (05 mmol) was suspended in ethanol (30 mL), activated carbon-palladium (50 mg) was added to the suspension, and the mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite, and the residue obtained by considering the solvent from the filtrate was dissolved in dimethylformamide and crystallized by adding water. The obtained crystals were purified by flash column chromatography (solvent dichloromethane / methanol / dimethylformamide = 10/1/1 (v / v / v)) to give 5-amino-2- (4-ethoxycarbonylphenyl) isoindoline. -1-one (yield 932 mg, yield 62%) was obtained.
mp 262-265 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32 (3H, t, J = 7.3 Hz), 4.30 (2H, q, J = 7.3 Hz), 4.86 (2H, s), 6.07 (2H, brs), 6.63-6.67 (2H, m), 7.40-7.46 (1H, m), 7.94-8.04 (4H, m).

Synthesis Example 34 ( Synthesis of 6-amino-2- (4-ethoxycarbonylphenyl) isoindoline-1-one)
(I) Synthesis of methyl 2-methyl-5-nitrobenzoate 2-Methyl-5-nitrobenzoic acid (1.00 g, 5.52 mmol) was suspended in hydrochloric acid-methanol (30 mL). Stir at 50 ° C. for 18 hours. After the solvent was distilled off, extraction was performed with ethyl acetate, and the organic layer was washed with saturated sodium hydrogen carbonate and dried to obtain crystals of methyl 2-methyl-5-nitrobenzoate (yield 814 mg, yield 76%). It was.
mp69-71 ° C
¹ H NMR (CDCl ₃ ) δ: 2.73 (3H, s), 3.96 (3H, s), 7.43-7.46 (1H, d, J = 8.6 Hz), 8.23- 8.27 (1H, dd, J = 2.6 Hz, 8.6 Hz), 8.78-8.79 (1H, d, J = 2.6 Hz).

(Ii) Synthesis of 2- (4-ethoxycarbonylphenyl) -6-nitroisoindoline-1-one To a solution of methyl 2-methyl-5-nitrobenzoate (765 mg, 3.92 mmol) in dichloroethane (12 mL), N -Bromosuccinimide (698 mg, 3.92 mmol) and aqueous benzoyl peroxide (15 mg) were added. The mixture was refluxed for 4 hours and then washed with water. The solvent was distilled off from the organic layer, and then dried at room temperature for a while to obtain methyl 2-bromomethyl-5-nitrobenzoate.

The obtained compound was dissolved in dimethylacetamide (8 mL), and a solution of ethyl 4-aminobenzoate (619 mg, 3.74 mmol) in dimethylformamide (5 mL) was added dropwise. The mixture was stirred at room temperature for 14 and a half hours and further stirred at 120 ° C. for 3 days. After allowing to cool, the resulting crystals were filtered and dried to give 2- (4-ethoxycarbonylphenyl) -6-nitroisoindoline-1-one (yield 460 mg, yield 36%).
mp 257-259 ° C
¹ H NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.3 Hz), 4.40 (2H, q, J = 7.3 Hz), 5.04 (2H, s), 7. 75 (1H, d, J = 8.2 Hz), 7.96-8.01 (2H, m), 8.12-8.17 (2H, m), 8.52 (1H, dd, J = 2) .6 Hz, 8.2 Hz), 8.78 (1H, d, J = 2.6 Hz).

(Iii) Synthesis of 6-amino-2- (4-ethoxycarbonylphenyl) isoindoline-1-one 2- (4-Ethoxycarbonylphenyl) -6-nitroisoindoline-1-one (216 mg, 0.66 mmol) Methanol (10 mL) and activated carbon-palladium (16 mg) were added to the mixture, and the mixture was stirred overnight under a hydrogen atmosphere. After filtering the reaction mixture through celite, the residue obtained by distilling off the solvent from the filtrate was dissolved in dimethylformamide, water was added, and the precipitated crystals were filtered to give 6-amino-2- ( 4-Ethoxycarbonylphenyl) isoindoline-1-one (yield 136 mg, yield 69%) was obtained.
mp 255-258 ° C
¹ H NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.3 Hz), 3.90 (2H, brs), 4.38 (2H, q, J = 7.3 Hz), 4. 80 (2H, s), 6.93 (1H, dd, J = 2.0 Hz, 7.9 Hz), 7.18 (1H, d, J = 2.0 Hz), 7.28-7.31 (1H , M), 7.95-8.00 (2H, m), 8.07-8.12 (2H, m).

Example 1 (Synthesis of 4-ethoxycarbonylmethoxy-2-phenylisoindolin-1-one)
To a suspension of 4-hydroxy-2-phenylisoindolin-1-one (451 mg, 2.00 mmol) obtained in Synthesis Example 1 in acetonitrile (10 mL), cesium carbonate (847 mg, 2.40 mmol) and ethyl bromoacetate were added. (401 mg, 2.40 mmol) was added and the suspension was stirred at room temperature for 2 days. Ethyl bromoacetate (106 mg, 0.63 mmol) and acetonitrile (2 mL) were added, and the mixture was further stirred overnight. Water was added to the obtained mixture, and extraction treatment was performed three times using dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off from the obtained solution, the obtained residue was subjected to a recrystallization treatment using acetonitrile, and the obtained crystal was dried to give 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1- On (yield 515 mg, 83% yield) crystals were obtained.
mp 150-152 ° C / CH ₃ CN
¹ H NMR (DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7.3 Hz), 4.19 (2H, q, J = 7.3 Hz), 4.97 (2H, s), 4.99 (2H, s), 7.15-7.21 (1H, m), 7.21 (1H, dd, J = 0.7 Hz, 7.9 Hz), 7.40 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.40-7.46 (2H, m), 7.50 (1H, app-t, J = 7.6 Hz), 7.90-7.95 (2H, m).

Example 2 (Synthesis of 4-carboxymethoxy-2-phenylisoindoline-1-one)
4-Ethoxycarbonylmethoxy-2-phenylisoindoline-1-one (311 mg, 1.00 mmol) obtained in Example 1 was mixed with aqueous sodium hydroxide (2N (mol / L), 2 mL) and ethanol (2 mL). The mixture was suspended in a mixed solution and heated to reflux for 1 hour. The reaction solution was acidified with 1N (mol / L) hydrochloric acid, the precipitate was filtered off, washed with water, and dried to give 4-carboxymethoxy-2-phenylisoindoline-1-one (yield 276 mg, 97% yield). Crystal was obtained.
mp 200-202 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.88 (2H, s), 4.96 (2H, s), 7.15-7.21 (2H, m), 7.37-7.52 ( 4H, m), 7.91-7.96 (2H, m).

Example 3 Synthesis of 4-ethoxycarbonylmethoxy-2- (4-ethoxycarbonylmethoxycarbonylphenyl) isoindoline-1-one
Example 1 was used except that 2- (4-carboxyphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 2 was used instead of 4-hydroxy-2-phenylisoindoline-1-one. In the same manner, 4-ethoxycarbonylmethoxy-2- (4-ethoxycarbonylmethoxycarbonylphenyl) isoindoline-1-one (yield 129 mg) was obtained.
mp 204-207 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.22 (3H, t, J = 7.3 Hz), 1.23 (3H, t, J = 7.3 Hz), 4.18 (2H, q, J = 7.3 Hz), 4.19 (2H, q, J = 7.3 Hz), 4.91 (2H, s), 5.00 (2H, s), 5.04 (2H, s), 7. 25 (1H, dd, J = 0.7 Hz, 7.9 Hz), 7.44 (1H, d, J = 6.9 Hz), 7.52 (1H, t, J = 7.6 Hz), 8.03 -8.08 (2H, m), 8.13-8.19 (2H, m).

Example 4 Synthesis of 4-carboxymethoxy-2- (4-carboxyphenyl) isoindoline-1-one
Instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one, 4-ethoxycarbonylmethoxy-2- (4-ethoxycarbonylmethoxycarbonylphenyl) isoindoline-1-one obtained in Example 3 was used. The same operation as in Example 2 was carried out except that it was used, and crystals of 4-carboxymethoxy-2- (4-carboxyphenyl) isoindoline-1-one (yield 289 mg, yield 88%) were obtained.
mp> 310 ° C. (dec.)
¹ H NMR (DMSO-d ₆ ) δ: 4.89 (2H, s), 5.01 (2H, s), 7.22 (1H, d, J = 7.3 Hz), 7.41 (1H, d, J = 6.9 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.97-8.02 (2H, m), 8.07-8.12 (2H, m), 13 (1H, br).

Example 5 (Synthesis of 4-[(3-ethoxycarbonylpropyl) oxy] -2-phenylisoindoline-1-one)
4-Hydroxy-2-phenylisoindoline-1-one (225 mg, 1.00 mmol) obtained in Synthesis Example 1 was suspended in acetonitrile (5 mL), and cesium carbonate (529 mg) was added to the resulting suspension. , 1.50 mmol) and ethyl 4-bromobutanoate (293 mg, 1.50 mmol) were added and the suspension was stirred at room temperature overnight. Furthermore, it stirred at 50 degreeC for 5 hours. After standing to cool, water was added and extraction was performed 3 times with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-[(3-ethoxycarbonylpropyl) oxy]- Crystals of 2-phenylisoindoline-1-one (yield 292 mg, yield 86%) were obtained.
mp 72-73 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.19 (2H, quin, J = 6.6), 2.55 (2H, t, J = 7) .3 Hz), 4.16 (2 H, t, J = 6.3 Hz), 4.16 (2 H, q, J = 7.3 Hz), 4.79 (2 H, s), 7.04 (1 H, dd) , J = 1.0 Hz, 7.9 Hz), 7.18 (1H, dt, J = 1.0 Hz, 7.6 Hz), 7.39-7.53 (4H, m), 7.87-7. 92 (2H, m).

Example 6 (Synthesis of 4-[(3-carboxypropyl) oxy] -2-phenylisoindolin-1-one)
Instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one, 4-[(3-ethoxycarbonylpropyl) oxy] -2-phenylisoindoline-1-one obtained in Example 5 is used. The same operation as in Example 2 was performed, except that 4-[(3-carboxypropyl) oxy] -2-phenylisoindoline-1-one (yield 207 mg, yield 98%) was obtained.
mp 207-210 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.96-2.05 (2H, m), 2.45 (2H, t, J = 6.9 Hz), 4.17 (2H, t, J = 6) .3 Hz), 4.93 (2 H, s), 7.18 (1 H, td, J = 1.0 Hz, 7.6 Hz), 7.26 (1 H, d, J = 7.6 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.39-7.46 (2H, m), 7.50 (1H, t, J = 7.6 Hz), 7.91-7.96 (2H, m).

Example 7 (Synthesis of 4-[(3-ethoxycarbonylpropyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one)
Instead of 4-hydroxy-2-phenylisoindoline-1-one, 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 3 was used, and cesium carbonate was used. Instead of using potassium carbonate, the same operation as in Example 5 was performed, and 4-[(3-ethoxycarbonylpropyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 789 mg). Yield 97%).
mp 104.5-105.5 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.20 (2H, quin, J = 7.3 Hz), 2.56 (2H, t, J = 7) .3 Hz), 4.13-4.21 (4H, m), 4.81 (2H, s), 7.68 (1H, dd, J = 1.1 Hz, 8.1 Hz), 7.46 (1H) , T, J = 8.1 Hz), 7.52 (1H, dd, J = 1.1 Hz, 8.1 Hz), 7.67 (2H, d, J = 8.9 Hz), 8.59 (2H, d, J = 8.9 Hz).

Example 8 (Synthesis of 4-[(3-carboxypropyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one)
Instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one, 4-[(3-ethoxycarbonylpropyl) oxy] -2- (4-trifluoromethylphenyl) iso The same operation as in Example 2 was performed except that indoline-1-one was used, and 4-[(3-carboxypropyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield) 633 mg, yield 97%) of crystals were obtained.
mp 207-208 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.01 (2H, quin, J = 6.2 Hz), 2.47 (2H, t, J = 6.2 Hz), 4.19 (2H, t, J = 6.2 Hz), 5.00 (2 H, s), 7.30 (1 H, d, J = 7.8 Hz), 7.39 (1 H, d, J = 7.8 Hz), 7.52 (1 H , T, 7.8 Hz), 7.79 (2H, d, 8.9 Hz), 8.19 (2H, d, J = 8.9 Hz).

Example 9 (Synthesis of 4-[(3-ethoxycarbonylpropyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one)
Example 5 except that 4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Synthesis Example 4 was used instead of 4-hydroxy-2-phenylisoindoline-1-one The crystals of 4-[(3-ethoxycarbonylpropyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 375 mg, yield 94%) were obtained.
mp 127-130 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.20 (2H, quin, J = 6.6), 2.56 (2H, t, J = 7) .3 Hz), 3.93 (3 H, s), 4.17 (2 H, t, J = 6.3 Hz), 4.17 (2 H, q, J = 7.3 Hz), 4.82 (2 H, s) ), 7.06 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.52 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.9-8.13 (4H, m).

Example 10 Synthesis of 2- (4-carboxyphenyl) -4-[(3-carboxypropyl) oxy] isoindoline-1-one
4-[(3-Ethoxycarbonylpropyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline obtained in Example 9 instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one Except for using -1-one, the same operation as in Example 2 was performed to give 2- (4-carboxyphenyl) -4-[(3-carboxypropyl) oxy] isoindoline-1-one (yield 265 mg, yield). 97%) of crystals were obtained.
mp 281-283 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.01 (2H, quin, J = 6.6), 2.44-2.52 (2H, m), 4.18 (2H, t, J = 6) .3 Hz), 4.99 (2 H, s), 7.29 (1 H, d, J = 8.2 Hz), 7.38 (1 H, d, J = 7.3 Hz), 7.51 (1 H, t , J = 7.6 Hz), 7.96-8.12 (4H, m), 12.5 (1H, br).

Example 11 Synthesis of 4-[(5-ethoxycarbonylpentyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
4-Hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in Synthesis Example 4 was suspended in dimethylformamide (6 mL), and the resulting suspension was obtained. To the solution were added potassium carbonate (152 mg, 1.10 mmol) and ethyl 6-bromohexanoate (245 mg, 1.10 mmol), and the mixture was stirred at 70 ° C. overnight. After allowing to cool, water was added to the reaction mixture, and the resulting crystals were recrystallized from dichloromethane and hexane to give 4-[(5-ethoxycarbonylpentyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline- Crystals of 1-one (yield 331 mg, 78% yield) were obtained.
mp 107-109 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.49-1.65 (2H, m), 1.75 (2H, quin, J = 7.3 Hz) ), 1.89 (2H, quin, J = 6.6 Hz), 2.37 (2H, t, J = 7.3 Hz), 3.93 (3H, s), 4.11 (2H, t, J = 6.6 Hz), 4.14 (2H, q, J = 7.3 Hz), 4.83 (2H, s), 7.05 (1H, d, J = 7.3 Hz), 7.42-7 .52 (2H, m), 8.02-8.12 (4H, m).

Example 12 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2-phenylisoindoline-1-one
4-Hydroxy-2-phenylisoindoline-1-one (225 mg, 1.00 mmol) obtained in Synthesis Example 1 was suspended in acetonitrile (5 mL), and cesium carbonate (529 mg) was added to the resulting suspension. , 1.50 mmol) and ethyl 7-bromoheptanoate (356 mg, 1.50 mmol) were added and the suspension was stirred at room temperature overnight. Furthermore, it stirred at 50 degreeC overnight. After standing to cool, water was added and extraction was performed 3 times with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-[(6-ethoxycarbonylhexyl) oxy]- Acicular crystals of 2-phenylisoindoline-1-one (yield 344 mg, yield 90%) were obtained.
mp 56 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.37-1.56 (4H, m), 1.63-1.74 (2H, m), 1.80-1.91 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 4.09 (2H, t, J = 6.6 Hz), 4.13 (2H, q , J = 7.3 Hz), 4.80 (2H, s), 7.02 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.17 (1H, dt, J = 1.0 Hz, 7.6 Hz), 7.39-7.52 (4H, m), 7.87-7.92 (2H, m).

Example 13 Synthesis of 4-[(6-carboxyhexyl) oxy] -2-phenylisoindoline-1-one
Instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one, 4-[(6-ethoxycarbonylhexyl) oxy] -2-phenylisoindoline-1-one obtained in Example 12 is used. Except for the above, the same operation as in Example 2 was performed to obtain a gum-like substance. The gum-like substance was dissolved in a small amount of acetic acid, ethyl acetate was added, and the mixture was allowed to stand at -25 ° C or lower. The precipitate was filtered off, washed with a small amount of ethyl acetate and dried to give crystals of 4-[(6-carboxyhexyl) oxy] -2-phenylisoindoline-1-one (yield 135 mg, 56% yield). Got.
mp 120-123 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.29-1.60 (6H, m), 1.72-1.82 (2H, m), 2.22 (2H, t, J = 7.3 Hz) ), 4.14 (2H, t, J = 6.6 Hz), 4.92 (2H, s), 7.17 (1H, t, J = 7.6 Hz), 7.26 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 7.3 Hz), 7.39-7.46 (2H, m), 7.49 (1H, t, J = 7.9 Hz), 7 .93 (2H, d, J = 7.6 Hz), 12 (1H, br).

Example 14 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-fluorophenyl) isoindolin-1-one
Instead of 4-hydroxy-2-phenylisoindoline-1-one obtained in Synthesis Example 1, 2- (4-fluorophenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 5 was used. , Except that potassium carbonate was used instead of cesium carbonate, the same operation as in Example 12 was performed, and 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-fluorophenyl) isoindoline-1 was quantitatively determined. -One (yield 152 mg) of crystals was obtained.
mp 84-86 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.39-1.52 (4H, m), 1.69 (2H, quin, J = 7.3 Hz) ), 1.85 (2H, quin, J = 7.3 Hz), 2.33 (2H, t, J = 7.3 Hz), 4.07-4.17 (4H, m), 4.77 (2H) , S), 7.03 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.07-7.15 (2H, m), 7.44 (1H, t, J = 7.8 Hz) 7.49 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.81-7.89 (2H, m).

Example 15 (Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-fluorophenyl) isoindoline-1-one)
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-fluorophenyl) isoindoline- obtained in Example 14 instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one The same operation as in Example 2 was carried out except that 1-one was used, and 4-[(6-carboxyhexyl) oxy] -2- (4-fluorophenyl) isoindoline-1-one (yield 60 mg, yield) 71%) crystals were obtained.
mp 115-117 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.31-1.59 (6H, m), 1.71-1.82 (2H, m), 2.21 (2H, d, J = 7.3 Hz) ), 4.14 (2H, d, J = 6.5 Hz), 4.93 (2H, s), 7.24-7.30 (3H, m), 7.34 (1H, d, J = 7) .6 Hz), 7.49 (1 H, t, J = 7.6 Hz), 7.92-7.97 (2 H, m).

Example 16 Synthesis of 2- (4-chlorophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] indoline-1-one
Instead of 4-hydroxy-2-phenylisoindoline-1-one obtained in Synthesis Example 1, 2- (4-chlorophenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 6 was used, The same operation as in Example 12 was carried out except that potassium carbonate was used instead of cesium carbonate, and 2- (4-chlorophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (yield 396 mg) , Yield 62%).
mp 92-94 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.28-1.47 (4H, m), 1.64-1.74 (2H, m), 1.80-1.90 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 4.97-4.17 (4H, m), 4.77 (2H, s), 7.03 (1H, dd, J = 1.4 Hz, 8.1 Hz), 7.37-7.51 (4H, m), 7.85-7.93 (2H, m).

Example 17 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-chlorophenyl) isoindoline-1-one
Instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one, 2- (4-chlorophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1 obtained in Example 16 The same operation as in Example 2 was carried out except that -one was used, and quantitatively analyzed for 4-[(6-carboxyhexyl) oxy] -2- (4-chlorophenyl) isoindoline-1-one (yield 192 mg). Crystals were obtained.
mp 107-108 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.31-1.60 (6H, m), 1.72-1.82 (2H, m), 2.22 (2H, d, J = 7.3 Hz) ), 4.14 (2H, d, J = 6.2 Hz), 4.93 (2H, s), 7.27 (1H, d, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.45-7.50 (3H, m), 7.98 (2H, app-dt, J = 2.2 Hz, 8.9 Hz), 12.03 (1H, br).

Example 18 Synthesis of 2- (4-bromophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one
Instead of 4-hydroxy-2-phenylisoindoline-1-one obtained in Synthesis Example 1, 2- (4-bromophenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 7 was used. Used, except that potassium carbonate was used instead of cesium carbonate, and the same operation as in Example 12 was performed to give 2- (4-bromophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one Crystals (yield 388 mg, yield 56%) were obtained.
mp 90-91 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.39-1.52 (4H, m), 1.63-1.74 (2H, m), 1.80-1.90 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 4.07-4.17 (4H, m), 4.77 (2H, s), 7.03 (1H, dd, J = 7.6 Hz), 7.44 (1H, t, J = 7.6 Hz), 7.49 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7 .53 (2H, app-dt, J = 3.0 Hz, 8.9 Hz), 7.83 (2H, app-dt, J = 3.0 Hz, 8.9 Hz).

Example 19 Synthesis of 2- (4-bromophenyl) -4-[(6-carboxyhexyl) oxy] isoindoline-1-one
Instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one, 2- (4-bromophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline obtained in Example 18 The same operation as in Example 2 was carried out except that 1-one was used, and 2- (4-bromophenyl) -4-[(6-carboxyhexyl) oxy] isoindoline-1-one (yield 185 mg, yield) 98%) of crystals were obtained.
mp 115-117 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.31-1.59 (6H, m), 1.72-1.82 (2H, m), 2.22 (2H, t, J = 7.3 Hz) ), 4.14 (2H, t, J = 6.2 Hz), 4.92 (2H, s), 7.27 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.50 (1 H, t, J = 7.8 Hz), 7.60 (2 H, d, J = 8.9 Hz), 7.93 (2 H, d, J = 8.9 Hz) .

Example 20 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-iodophenyl) isoindoline-1-one
Instead of 4-hydroxy-2-phenylisoindoline-1-one obtained in Synthesis Example 1, 4-hydroxy-2- (4-iodophenyl) isoindoline-1-one obtained in Synthesis Example 8 was used. In the same manner as in Example 12 except that potassium carbonate was used instead of cesium carbonate, 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-iodophenyl) isoindoline-1-one ( A crystal having a yield of 181 mg and a yield of 42% was obtained.
mp 83-84 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.39-1.50 (4H, m), 1.68 (2H, quin, J = 7.0 Hz) ), 1.80-1.90 (2H, m), 2.33 (2H, t, J = 7.0 Hz), 4.07-4.17 (4H, m), 4.56 (2H, s) ), 7.03 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.44 (1H, t, J = 7.6 Hz), 7.49 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.72 (4H, s).

Example 21 (Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-iodophenyl) isoindoline-1-one)
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-iodophenyl) isoindoline- obtained in Example 20 instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one The same operation as in Example 2 was carried out except that 1-one was used, and 4-[(6-carboxyhexyl) oxy] -2- (4-iodophenyl) isoindoline-1-one (yield 30 mg, yield) 35%) crystals were obtained.
mp 117-119 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.59 (6H, m), 1.72-1.82 (2H, m), 2.21 (2H, t, J = 7.3 Hz) ), 4.14 (2H, t, J = 6.2 Hz), 4.91 (2H, s), 7.27 (1H, d, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.49 (1 H, t, 7.8 Hz), 7.73-7.81 (4 H, m), 12.10 (1 H, br).

Example 22 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (2,4-dichlorophenyl) isoindoline-1-one
Instead of 4-hydroxy-2-phenylisoindoline-1-one obtained in Synthesis Example 1, 2- (2,4-dichlorophenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 9 was used. Used in the same manner as in Example 12 except that potassium carbonate is used instead of cesium carbonate, and oily 4-[(6-ethoxycarbonylhexyl) oxy] -2- (2,4-dichlorophenyl) isoindoline- 1-one (yield 440 mg, 98% yield) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 1.40-1.50 (4H, m), 1.63-1.71 (2H, m), 1.77-1.85 (2H, m), 2.31 (2H, t, J = 7.0 Hz), 4.08 (2H, t, J = 6.2 Hz), 4.11 (2H, q , J = 7.3 Hz), 4.72 (2H, s), 7.05 (1H, d, J = 7.6 Hz), 7.35 (2H, s), 7.46 (1H, t, J = 7.6 Hz), 7.51-7.54 (2H, m).

Example 23 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (2,4-dichlorophenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (2,4-dichlorophenyl) isoindoline obtained in Example 22 instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one Except that -1-one was used, the same operation as in Example 2 was performed, and 4-[(6-carboxyhexyl) oxy] -2- (2,4-dichlorophenyl) isoindoline-1-one (yield 295 mg, A yield of 87%) was obtained.
mp 132-134 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.29-1.57 (6H, m), 1.69-1.79 (2H, m), 2.20 (2H, t, J = 7.3 Hz) ), 4.13 (2H, t, J = 6.2 Hz), 4.76 (2H, s), 7.29 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.52 (1 H, t, J = 7.8 Hz), 7.56 (1 H, dd, J = 2.2 Hz, 8.6 Hz), 7.66 (1 H, d, J = 8.6 Hz), 7.82 (1 H, d, J = 2.2 Hz), 12.01 (1 H, br).

Example 24 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3-methylphenyl) isoindolin-1-one
Instead of 4-hydroxy-2-phenylisoindoline-1-one obtained in Synthesis Example 1, 4-hydroxy-2- (3-methylphenyl) isoindoline-1-one obtained in Synthesis Example 10 was used. In the same manner as in Example 12 except that potassium carbonate was used instead of cesium carbonate, 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3-methylphenyl) isoindoline-1-one ( Crystals with a yield of 132 mg and a yield of 69% were obtained.
mp 79-80 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.42-1.49 (4H, m), 1.69 (2H, quin, J = 7.3 Hz) ), 1.86 (2H, quin, J = 6.2 Hz), 2.33 (2H, t, J = 7.3 Hz), 2.42 (3H, s), 4.09 (2H, t, J = 6.2 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.79 (2H, s), 6.99-7.04 (2H, m), 7.31 (1H, t) , J = 7.6 Hz), 7.43 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.66-7.69 ( 1H, m), 7.74 (1H, s).

Example 25 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (3-methylphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (3-methylphenyl) isoindoline- obtained in Example 24 instead of 4-ethoxycarbonylmethoxy-2-phenylisoindoline-1-one The same operation as in Example 2 was performed except that 1-one was used, and quantitatively 4-[(6-carboxyhexyl) oxy] -2- (3-methylphenyl) isoindoline-1-one (yield 89 mg) ) Crystals were obtained.
mp 136-138 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.60 (6H, m), 1.72-1.82 (2H, m), 2.23 (2H, t, J = 7.3 Hz) ), 2.35 (3H, s), 4.14 (2H, t, J = 6.2 Hz), 4.91 (2H, s), 6.99 (1H, d, J = 7.6 Hz), 7.25-7.35 (3H, m), 7.49 (1H, t, J = 7.6 Hz), 7.72-7.79 (2H, m), 11.97 (1H, s).

Example 26 (Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methylphenyl) isoindoline-1-one)
To a solution of 4-hydroxy-2- (4-methylphenyl) isoindoline-1-one (359 mg, 1.50 mmol) obtained in Synthesis Example 11 in dimethylformamide (5 mL), potassium carbonate (218 mg, 1.58 mmol) And ethyl 7-bromoheptanoate (374 mg, 1.58 mmol) were added, and the mixture was stirred at 70 ° C. for 2.5 hours. After standing to cool, water was added and extraction was performed 3 times with dichloromethane. The organic layer is washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent is further distilled off and dried to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methylphenyl) iso Crystals of indoline-1-one (yield 529 mg, yield 81%) were obtained.
mp 90-91 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.36 to 1.55 (4H, m), 1.68 (2H, quin, J = 7.6 Hz) ), 1.85 (2H, quin, J = 6.2 Hz), 2.33 (2H, t, J = 7.6 Hz), 2.36 (3H, s), 4.09 (2H, t, J = 6.2 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.77 (2H, s), 7.01 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7 .21-7.24 (2H, m), 7.42 (1H, t, J = 7.6 Hz), 7.49 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.74- 7.79 (2H, m).

Example 27 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-methylphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-methylphenyl) isoindoline-1-one (338 mg, 0.77 mmol) obtained in Example 26 was added to an aqueous sodium hydroxide solution (6. (0 mL, 6.00 mmol) and ethanol (6 mL) were added, and the mixture was stirred at 70 ° C. for 1.5 hours. Water was added to the reaction mixture, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Then, the obtained residue was precipitated using water, acetone and methanol, and 4-[(6-carboxyhexyl) Crystals of oxy] -2- (4-methylphenyl) isoindolin-1-one (yield 252 mg, yield 88%) were obtained.
mp 136-138 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.59 (6H, m), 1.72-1.82 (2H, m), 2.22 (2H, t, J = 7.3 Hz) ), 2.31 (3H, s), 4.14 (2H, t, J = 6.2 Hz), 4.89 (2H, s), 7.21-7.27 (3H, m), 7. 33 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J = 7.6 Hz), 8.10 (2H, d, J = 8.1 Hz), 11.97 (1H, s ).

Example 28 Synthesis of 2- (4-bromo-3-methylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one
To a solution of 2- (4-bromo-3-methylphenyl) -4-hydroxyisoindoline-1-one (398 mg, 1.25 mmol) obtained in Synthesis Example 12 in dimethylformamide (8 mL), potassium carbonate (190 mg, 1.38 mmol) and ethyl 7-bromoheptanoate (326 mg, 1.38 mmol) were added, and the mixture was stirred overnight at room temperature, and further stirred at 50 ° C. for 4 hours. Water was added to the reaction mixture, and the precipitate was purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) to give 2- (4-bromo-3-methylphenyl) -4- [ Crystals of (6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (yield 465 mg, yield 78%) were obtained.
mp 82-83 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.37-1.56 (4H, m), 1.69 (2H, quin, J = 7.6 Hz) ), 1.86 (2H, quin, J = 6.6 Hz), 2.33 (2H, t, J = 7.6 Hz), 2.45 (3H, s), 4.09 (2H, t, J = 6.6 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.76 (2H, s), 7.03 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7 41-7.63 (4H, m), 7.84 (1H, d, J = 2.3 Hz).

Example 29 Synthesis of 2- (4-bromo-3-methylphenyl) -4-[(6-carboxyhexyl) oxy] isoindolin-1-one
2- (4-Bromo-3-methylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (179 mg, 0.38 mmol) obtained in Example 28 was added to sodium hydroxide. It added to the mixed solution of aqueous solution (7 mL, 0.38 mmol) and ethanol (10 mL), and it heated and refluxed for 1 hour. After allowing to cool, hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration and dried to give 2- (4-bromo-3-methylphenyl) -4-[(6-carboxyhexyl) oxy] isoindoline-1. -On (yield 140 mg, 83% yield) crystals were obtained.
mp 123-125 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.28-1.59 (6H, m), 1.77 (2H, quin, J = 6.6 Hz), 2.21 (2H, t, J = 7) .3 Hz), 2.39 (3 H, s), 4.14 (2 H, t, J = 6.6 Hz), 4.91 (2 H, s), 7.27 (1 H, d, J = 7.6 Hz) ), 7.34 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J 7.6 Hz), 7.60 (1H, d, J = 8.9 Hz), 7.83 (1H) , Dd, J = 2.6 Hz, 8.9 Hz), 7.88 (1H, d, J = 2.6 Hz).

Example 30 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3,4-dimethylphenyl) isoindolin-1-one
To a solution of 4-hydroxy-2- (3,4-dimethylphenyl) isoindoline-1-one (290 mg, 1.10 mmol) obtained in Synthesis Example 13 in dimethylformamide (5 mL), potassium carbonate (159 mg, 1. 20 mmol) and ethyl 7-bromoheptanoate (273 mg, 1.20 mmol) were added, and the mixture was stirred at 70 ° C. overnight. After allowing to cool, water was added, and the precipitate was collected by filtration and recrystallized with ethanol and water to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3,4-dimethylphenyl) isoindoline-1. Colorless needle-like crystals of -one (yield 438 mg, yield 97%) were obtained.
mp 84-85 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.38-1.50 (4H, m), 1.68 (2H, quin, J = 7.6 Hz) ), 1.85 (2H, quin, J = 7.6 Hz), 2.27-2.35 (8H, m), 4.06-4.16 (4H, m), 4.76 (2H, s) ), 7.01 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.17 (1H, d, J = 8.1 Hz), 7.42 (1H, t, J = 7.6 Hz) 7.49 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.57 (1H, dd, J = 1.9 Hz, 8.1 Hz), 7.68 (1H, d, J = 1) .9 Hz).

Example 31 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (3,4-dimethylphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (3,4-dimethylphenyl) isoindoline-1-one (260 mg, 0.63 mmol) obtained in Example 30 was added to an aqueous sodium hydroxide solution ( 0.5 mL, 1.00 mmol) and a mixed solution of ethanol (10 mL) and stirred overnight at room temperature. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was further neutralized with concentrated hydrochloric acid. The precipitate was collected by filtration and dried to give 4-[(6-carboxyhexyl) oxy] -2- (3 , 4-Dimethylphenyl) isoindoline-1-one (yield 227 mg, yield 98%) was obtained.
mp 121-122 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.59 (6H, m), 1.72-1.82 (2H, m), 2.22 (3H, s), 2.26 ( 3H, s), 4.14 (2H, t, J = 6.2 Hz), 4.87 (2H, s), 7.17 (1H, d, J = 7.8 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.32 (1H, d, J = 7.0 Hz), 7.48 (1H, d, J = 7.8 Hz), 7.66-7.70 (2H, m) ), 11.97 (1H, br).

Example 32 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3-isopropylphenyl) isoindoline-1-one
To a solution of 4-hydroxy-2- (3-isopropylphenyl) isoindoline-1-one (267 mg, 1.00 mmol) obtained in Synthesis Example 14 in dimethylformamide (5 mL), potassium carbonate (145 mg, 1.10 mmol) And ethyl 7-bromoheptanoate (249 mg, 1.10 mmol) were added, and the mixture was stirred at 70 ° C. for 2 hours. After allowing to cool, water was added to the reaction mixture, and extraction was performed three times using dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/0 to 5/1 (v / v)) to give oily 4-[(6-ethoxy Carbonylhexyl) oxy] -2- (3-isopropylphenyl) isoindoline-1-one (yield 377 mg, yield 88%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.30 (6H, d, J = 6.8 Hz), 1.43-1.50 (4H, m ), 1.63-1.74 (2H, m), 1.81-1.91 (2H, m), 2.33 (2H, t, J = 7.0 Hz), 2.97 (1H, quin) , J = 6.8 Hz), 4.10 (2H, t, J = 6.8 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.80 (2H, s), 7.03 (1H, dd, 0.8 Hz, 7.8 Hz), 7.06 (1H, d, J = 7.6 Hz), 7.35 (1H, t, J = 7.8 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.50 (1H, dd, J = 0.8 Hz, 7.6 Hz), 7.63 (1H, ddd, J = 0.8 Hz, 1.9 Hz, 7.8 Hz) , 7. 4 (1H, t, J = 1.9Hz).

Example 33 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (3-isopropylphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (3-isopropylphenyl) isoindoline-1-one (228 mg, 0.54 mmol) obtained in Example 32 was added to an aqueous sodium hydroxide solution (0. 5 mL, 1.00 mmol) and a mixed solution of ethanol (10 mL) and stirred at room temperature for 3 hours. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was further neutralized with concentrated hydrochloric acid. The precipitate was collected by filtration, dried and 4-[(6-carboxyhexyl) oxy] -2- (3 Crystals of -isopropylphenyl) isoindoline-1-one (yield 218 mg, stoichiometric amount) were obtained.
mp 110-111 ° C
¹ HNMR (DMSO-d ₆ ) δ: 1.24 (6H, d, J = 7.0 Hz), 1.32-1.60 (6H, m), 1.73-1.83 (2H, m) , 2.22 (2H, t, 7.2 Hz), 2.94 (1H, quin, J = 7.0 Hz), 4.15 (2H, t, J = 6.2 Hz), 4.93 (2H, s), 7.07 (1H, d, J = 7.6 Hz), 7.25-7.36 (3H, m), 7.50 (1H, t, J = 7.6 Hz), 7.70- 7.74 (1H, m), 7.82 (1H, s), 12.04 (1H, br).

Example 34 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-isopropylphenyl) isoindoline-1-one
To a solution of 4-hydroxy-2- (4-isopropylphenyl) isoindoline-1-one (401 mg, 1.50 mmol) obtained in Synthesis Example 15 in dimethylformamide (4 mL) was added potassium carbonate (218 mg, 1.58 mmol). And ethyl 7-bromoheptanoate (374 mg, 1.58 mmol) were added, and the mixture was stirred at 80 ° C. for 2.5 hours. After allowing to cool, water was added to the reaction mixture, and extraction was performed three times using dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give oily 4-[(6-ethoxycarbonylhexyl) oxy ] -2- (4-isopropylphenyl) isoindoline-1-one (yield 728 mg, stoichiometric amount) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.27 (6H, d, J = 7.0 Hz), 1.36 to 1.58 (4H, m ), 1.62-174 (2H, m), 1.80-1.90 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 2.92 (1H, quin, J = 7.0 Hz), 4.09 (2H, t, J = 6.2 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.78 (2H, s), 7.01 (1H) , Dd, J = 1.1 Hz, 7.6 Hz), 7.29 (2H, app-dt, J = 1.9 Hz, 8.4 Hz), 7.43 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.79 (2H, app-dt, J = 1.9 Hz, 8.4 Hz).

Example 35 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3-trifluoromethylphenyl) isoindolin-1-one
To a solution of 4-hydroxy-2- (3- (trifluoromethyl) phenyl) isoindoline-1-one (205 mg, 0.70 mmol) obtained in Synthesis Example 16 in dimethylformamide (6 mL), potassium carbonate (102 mg, 0.74 mmol) and ethyl 7-bromoheptanoate (174 mg, 0.74 mmol) were added, and the mixture was stirred at 70 ° C. for 5 hours. After allowing to cool, water was added to the reaction mixture, and the precipitate was recrystallized from diethyl ether to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (3-trifluoromethylphenyl) isoindoline-1-one. Crystals (yield 282 mg, yield 90%) were obtained.
mp 97-99 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.37-1.60 (4H, m), 1.69 (2H, quin, J = 7.6 Hz) ), 1.87 (2H, quin, J = 6.6 Hz), 2.33 (2H, t, J = 7.6 Hz), 4.11 (2H, t, J = 6.6 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.82 (2H, s), 7.06 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.41-7.57 (4H, m), 8.15-8.21 (2H, m).

Example 36 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (3-trifluoromethylphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (3-trifluoromethylphenyl) isoindoline-1-one (126 mg, 0.28 mmol) obtained in Example 35 was added to an aqueous sodium hydroxide solution ( 2 mL, 0.56 mmol) and ethanol (4 mL) were added and heated to reflux for 40 minutes. After allowing to cool, ethanol was distilled off from the reaction mixture, 1N (mol / L) hydrochloric acid was added, and the precipitate was collected by filtration. This precipitate was recrystallized from dimethylformamide and dried to give 4-[(6-carboxyhexyl) oxy] -2- (3-trifluoromethylphenyl) isoindoline-1-one (yield 99 mg, yield). 84%) of crystals were obtained.
mp 121-123 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.60 (6H, m), 1.78 (2H, quin, J = 6.6 Hz), 2.22 (2H, t, J = 7) .3 Hz), 4.15 (2 H, t, J = 6.6 Hz), 5.02 (2 H, s), 7.30 (1 H, d, J = 7.3 Hz), 7.37 (1 H, d , J = 7.3 Hz), 7.48-7.54 (2H, m), 7.67 (1H, t, J = 7.9 Hz), 8.13 (1H, dt, J = 1.0 Hz, 7.9 Hz), 8.46 (1H, s), 12.01 (1H, brs).

Example 37 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-trifluoromethylphenyl) isoindolin-1-one
To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (205 mg, 0.70 mmol) obtained in Synthesis Example 3 in dimethylformamide (5 mL), potassium carbonate (102 mg,. 74 mmol) and ethyl 7-bromoheptanoate (174 mg, 0.74 mmol) were added, and the mixture was stirred at 70 ° C. for 3.5 hours. After allowing to cool, water was added to the reaction mixture, and the precipitate was dried to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 278 mg). , Yield 88%).
mp 91-92 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.37-1.59 (4H, m), 1.69 (2H, quin, J = 7.6 Hz) ), 1.87 (2H, quin, J = 6.6 Hz), 2.33 (2H, t, J = 7.6 Hz), 4.10 (2H, t, J = 6.6 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.82 (2H, s), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, d, J = 8.9 Hz), 8.07 (2H, d, J = 8) .9 Hz).

Example 38 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (135 mg, 0.30 mmol) obtained in Example 37 was added to an aqueous sodium hydroxide solution ( 3 mL, 0.60 mmol) and ethanol (5 mL) were added and heated to reflux for 40 minutes. After allowing to cool, ethanol was distilled off from the reaction mixture, 1N (mol / L) hydrochloric acid was added, and the precipitate was collected by filtration and dried to give 4-[(6-carboxyhexyl) oxy] -2- ( Crystals of 4-trifluoromethylphenyl) isoindoline-1-one (yield 122 mg, yield 97%) were obtained.
mp 155-157 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.60 (6H, m), 1.72-1.83 (2H, m), 2.23 (2H, t, J = 7.3 Hz) ), 4.15 (2H, t, J = 6.3 Hz), 5.00 (2H, s), 7.30 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.38 (1H , Dd, J = 0.7 Hz, 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.79 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 12.01 (1H, brs).

Example 39 Synthesis of 2- (4-trifluoromethylphenyl) -4-[(6-methanesulfonylcarbamoylhexyl) oxy] isoindoline-1-one
A suspension of 4-[(6-carboxyhexyl) oxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (211 mg, 0.50 mmol) obtained in Example 38 in dichloromethane (16 mL). N, N′-carbonyldiimidazole (486 mg, 3.00 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (304 mg, 2.00 mmol) and methanesulfonylamide (285 mg, 3 .00 mmol) was gradually added, and the mixture was stirred at room temperature for 8 days. The obtained crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 30/1 (v / v)) to give 2- (4-trifluoromethylphenyl) -4-[(6-methanesulfonylcarbamoylhexyl). Crystals of oxy] isoindoline-1-one (70 mg yield, 28% yield) were obtained.
mp 159-161 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.22-1.50 (4H, m), 1.57 (2H, quin, J = 7.3 Hz), 1.78 (2H, quin, J = 6) .6 Hz), 2.29 (2H, t, J = 7.3 Hz), 3.21 (3H, s), 4.14 (2H, t, J = 6.6 Hz), 4.97 (2H, s) ), 7.29 (1H, dd, J = 1.6 Hz, 7.9 Hz), 7.37 (1H, dd, J = 1.6 Hz, 7.9 Hz), 7.50 (1H, t, J = 7.9 Hz), 7.78 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 11.66 (1H, br).

Example 40 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- [4- (1-hydroxyethyl) phenyl] isoindoline-1-one
To a solution of 4-hydroxy-2- [4- (1-hydroxyethyl) phenyl] isoindoline-1-one (323 mg, 1.20 mmol) obtained in Synthesis Example 18 in dimethylformamide (7 mL) was added potassium carbonate (174 mg). , 1.26 mmol) and ethyl 7-bromoheptanoate (299 mg, 1.26 mmol) were added, and the mixture was stirred at 70 ° C. for 4 hours. After allowing to cool, water was added to the reaction mixture, acidified with 1N (mol / L) hydrochloric acid, extracted with dichloromethane, and then flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)). The product was purified by The obtained oily compound was dissolved in diisopropyl ether, washed with water, and the solvent was distilled off to remove oily 4-[(6-ethoxycarbonylhexyl) oxy] -2- [4- (1-hydroxyethyl) phenyl]. Isoindoline-1-one (yield 391 mg, 77% yield) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.36 to 1.58 (4H, m), 1.52 (3H, d, J = 6.6 Hz) ), 1.68 (2H, quin, J = 7.3 Hz), 1.85 (2H, quin, J = 6.6 Hz), 2.33 (2H, t, J = 7.3 Hz), 4.06 -4.17 (4H, m), 4.79 (2H, s), 4.89-4.96 (1H, m), 7.02 (1H, dd, J = 1.0 Hz, 7.6 Hz) 7.43 (1H, t, J = 7.6 Hz), 7.42-7.45 (2H, m), 7.50 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7. 85-7.90 (2H, m).

Example 41 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- [4- (1-hydroxyethyl) phenyl] isoindolin-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- [4- (1-hydroxyethyl) phenyl] isoindoline-1-one (255 mg, 0.60 mmol) obtained in Example 40 was added to ethanol ( To a suspension suspended in 3 mL) and water (3 mL), 2N (mol / L) aqueous sodium hydroxide solution (0.6 mL, 1.20 mmol) was added and heated to reflux for 50 minutes. In the heated state, 1N (mol / L) hydrochloric acid was added to acidify, and the organic solvent was distilled off. The remaining solution was extracted with dichloromethane, and the organic solvent was distilled off from the obtained organic layer. The residue was recrystallized with ethanol and diisopropyl ether to give 4-[(6-carboxyhexyl) oxy] -2- [4- (1-hydroxyethyl) phenyl] isoindoline-1-one (yield 152 mg, yield 64). %) Crystals.
mp 127-128 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (1H, s), 1.39-1.59 (4H, m), 1.51 (3H, d, J = 6.6 Hz), 1.71 ( 2H, quin, J = 7.6 Hz), 1.86 (2H, quin, J = 6.3 Hz), 2.40 (2H, t, J = 7.6 Hz), 4.09 (2H, t, J = 6.3 Hz), 4.78 (2 H, s), 4.92 (1 H, q, J = 6.6 Hz), 7.02 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7 .43 (1H, t, J = 7.6 Hz), 7.41-7.46 (2H, m), 7.50 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.84- 7.90 (2H, m).

Example 42 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one
To a solution of 2- (4-trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one (597 mg, 1.93 mmol) obtained in Synthesis Example 19 in dimethylformamide (5 mL), potassium carbonate (320 mg, 2. 32 mmol) and ethyl 7-bromoheptanoate (320 mg, 2.32 mmol) were added and stirred at 70 ° C. overnight. After allowing to cool, water was added to the reaction mixture, and the precipitate was collected by filtration. The precipitate was recrystallized with a mixed solvent of dimethylformamide, methanol, and water to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (yield). 847 mg, 94% yield) of crystals were obtained.
mp 80.5-81.5 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.39-1.51 (4H, m), 1.69 (2H, quin, J = 7.3 Hz) ), 1.81-1.91 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 4.10 (2H, t, J = 6.2 Hz), 4.13 (2H , Q, J = 7.3 Hz), 4.79 (2H, s), 7.41 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.26-7.30 (2H, m) 7.45 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.92-7.98 (2H, m).

Example 43 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (500 mg, 1.07 mmol) obtained in Example 42 was added to an aqueous sodium hydroxide solution ( (6.0 mL, 12.00 mmol) and ethanol (6 mL) were added, and the mixture was stirred at 70 ° C. for 1.5 hours. After allowing to cool, water was added to the reaction mixture, neutralized with concentrated hydrochloric acid, the precipitate was collected by filtration and dried to give 4-[(6-carboxyhexyl) oxy] -2- (4-trifluoromethoxy). Crystals of phenyl) isoindoline-1-one (yield 471 mg, stoichiometric amount) were obtained.
mp 117.5-118.5 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.42 (6H, m), 1.72-1.82 (2H, m), 2.22 (2H, t, J = 7.3 Hz) ), 4.15 (2H, t, J = 6.5 Hz), 4.96 (2H, s), 7.28 (1H, d, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.51 (1H, t, J = 7.6 Hz), 8.04-8.09 (2H, m), 11 .93 (1H, br).

Example 44 Synthesis of 2- (4-trifluoromethoxyphenyl) -4-[(6-methanesulfonylcarbamoylhexyl) oxy] isoindoline-1-one
To a solution of 4-[(6-carboxyhexyl) oxy] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (219 mg, 0.50 mmol) obtained in Example 43 in dichloromethane (5 mL), Triethylamine (61 mg, 0.60 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg, 0.60 mmol), 4-dimethylaminopyridine (6 mg, 0.05 mmol), and methanesulfonic acid Amide (57 mg, 0.60 mmol) was added and stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane, purified by flash column chromatography (solvent dichloromethane / methanol = 10/1 (v / v)), and 2- (4-trifluoromethoxyphenyl) -4- [ Crystals of (6-methanesulfonylcarbamoylhexyl) oxy] isoindoline-1-one (yield 159 mg, yield 62%) were obtained.
mp 138-140 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.29-1.60 (6H, m), 1.71-1.81 (2H, m), 2.27 (2H, t, J = 7.3 Hz) ), 3.19 (3H, s), 4.13 (2H, t, J = 6.2 Hz), 4.94 (2H, s), 7.26 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.42 (2H, d, J = 9.2 Hz), 7.49 (1H, t, J = 7.8 Hz), 8.05 (2H) , D, J = 9.2 Hz), 11.6 (1H, br).

Example 45 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxyphenyl) isoindoline-1-one
To a solution of 4-hydroxy-2- (4-methoxyphenyl) isoindoline-1-one (383 mg, 1.50 mmol) obtained in Synthesis Example 20 in dimethylformamide (4 mL), potassium carbonate (218 mg, 1.58 mmol) And ethyl 7-bromoheptanoate (374 mg, 1.58 mmol) were added, and the mixture was stirred at 80 ° C. for 2.5 hours. After allowing to cool, water and methanol are added to the reaction mixture, and the precipitate is collected by filtration, washed, and dried to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxyphenyl) iso Crystals of indoline-1-one (yield 389 mg, yield 63%) were obtained. Furthermore, water was added to the mother liquor after the precipitate was filtered, and the precipitate was collected by filtration, washed, and dried to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxyphenyl). ) Crystals of isoindoline-1-one (yield 117 mg, yield 19%) were obtained. The total yield was 82%.
mp 85.5-86.5 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.42-1.49 (4H, m), 1.63-1.74 (2H, m), 1.80-1.90 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 3.84 (3H, s), 4.09 (2H, t, J = 7.3 Hz) ), 4.12 (2H, q, J = 7.3 Hz), 4.75 (2H, s), 6.96 (2H, app-dt, J = 2.2 Hz, 9.2 Hz), 7.01 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.43 (1H, t, J = 7.6 Hz), 7.49 (1H, dd, J = 1.1 Hz, 7.6 Hz), 7.77 (2H, app-dt, J = 2.2 Hz, 9.2 Hz).

Example 46 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
To a suspension of 4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in Synthesis Example 4 in acetonitrile (5 mL), cesium carbonate (529 mg, 1. 50 mmol) and ethyl 7-bromoheptanoate (356 mg, 1.50 mmol) were added and stirred at room temperature overnight, then at 50 ° C. overnight. After allowing to cool, water was added to the reaction mixture, and extraction was performed 3 times with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- ( Crystals of 4-methoxycarbonylphenyl) isoindoline-1-one (yield 420 mg, yield 96%) were obtained.
mp 95-97 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.37-1.59 (4H, m), 1.69 (2H, quin, J = 7.3 Hz) ), 1.81-1.81 (2H, m), 2.33 (2H, t, J = 7.3 Hz), 3.92 (3H, s), 4.07-4.19 (4H, m ), 4.82 (2H, s), 7.04 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.44 (1H, t, J = 7.6 Hz), 7.50 (1H) , Dd, J = 1.3 Hz, 7.6 Hz), 8.00-8.12 (4H, m).

Example 47 Synthesis of 4-[(6-carboxyhexyl) oxy] -2- (4-carboxyphenyl) isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (343 mg, 0.78 mmol) obtained in Example 46 was added to an aqueous sodium hydroxide solution (2N (Mol / L), 2 mL) and ethanol (2 mL) were suspended in the solution and heated to reflux for 1 hour. After allowing to cool, the reaction mixture was acidified with 1N (mol / L) hydrochloric acid, the precipitate was filtered off, washed with water, and dried to give 4-[(6-carboxyhexyl) oxy] -2- (4- Crystals of carboxyphenyl) isoindoline-1-one (yield 294 mg, yield 95%) were obtained.
mp 209-210 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.30-1.60 (6H, m), 1.73-1.83 (2H, m), 2.23 (2H, t, J = 7.3 Hz) ), 4.14 (2H, t, J = 6.3 Hz), 4.98 (2H, s), 7.29 (1H, d, J = 7.9 Hz), 7.37 (1H, d, J = 7.3 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.96-8.12 (4H, m), 12.40 (1H, br).

Example 48 Synthesis of 2- (4-acetylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one
To a suspension of (2- (4-acetylphenyl) -4-hydroxyisoindoline-1-one (321 mg, 1.20 mmol) obtained in Synthesis Example 17 in dimethylformamide (7 mL), potassium carbonate (174 mg, 1 .26 mmol) and ethyl 7-bromoheptanoate (299 mg, 1.26 mmol) and stirred for 3 hours at 70 ° C. After standing to cool, water was added to the reaction mixture, and the precipitate was subjected to flash column chromatography (solvent dichloromethane / Ethanol = 30/1 (v / v)) and purified by 2- (4-acetylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (yield 470 mg, 92% yield) ) Crystals were obtained.
mp 116-117 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.37-1.57 (4H, m), 1.69 (2H, quin, J = 7.3 Hz) ), 1.86 (2H, quin, J = 6.6 Hz), 2.33 (2H, t, J = 7.3 Hz), 2.61 (3H, s), 4.10 (2H, t, J = 6.6 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.83 (2H, s), 7.05 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7 .45 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.01-8.08 (4H, m).

Example 49 Synthesis of 2- (4-acetylphenyl) -4-[(6-carboxyhexyl) oxy] isoindoline-1-one
2- (4-acetylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (212 mg, 0.50 mmol) obtained in Example 48 was added to ethanol (3 mL) and water ( 2N (mol / L) sodium hydroxide aqueous solution (0.5 mL, 1.00 mmol) was added to the suspension suspended in 1 mL), and the mixture was heated to reflux for 40 minutes. In the heated state, 1N (mol / L) hydrochloric acid was added to the reaction mixture to make it acidic, and after cooling, the organic solvent was distilled off. The precipitated crystals were collected by filtration and dried to obtain crystals of 2- (4-acetylphenyl) -4-[(6-carboxyhexyl) oxy] isoindoline-1-one (yield 186 mg, yield 94%). It was.
mp 168-170 ° C
¹ H NMR (CDCl ₃ ) δ: 1.43-1.62 (4H, m), 1.72 (2H, quin, J = 7.3 Hz), 1.88 (2H, quin, J = 6.6 Hz) ), 2.41 (2H, t, J = 7.3 Hz), 2.61 (3H, s), 4.11 (2H, t, J = 6.6 Hz), 4.83 (2H, s), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7. 6 Hz), 8.01-8.08 (4H, m).

Example 50 Synthesis of 2- (4-carbamoylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindolin-1-one
To a suspension of 2- (4-carbamoylphenyl) -4-hydroxyisoindoline-1-one (268 mg, 1.00 mmol) obtained in Synthesis Example 21 in dimethylformamide (7 mL), potassium carbonate (145 mg, 1. 05 mmol) and ethyl 7-bromoheptanoate (249 mg, 1.05 mmol) were added, and the mixture was stirred at 70 ° C. for 2 hours. After allowing to cool, water was added to the reaction mixture, and crystals of 2- (4-carbamoylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (yield 372 mg, yield 88%) were obtained. Obtained.
mp 203-205 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.16 (3H, t, J = 7.3 Hz), 1.32-1.62 (6H, m), 1.78 (2H, quin, J = 7) .3 Hz), 2.30 (2H, t, J = 7.3 Hz), 4.03 (2H, q, J = 7.3 Hz), 4.15 (2H, t, J = 6.3 Hz), 4 .97 (2H, s), 7.28 (1 H, d, J = 7.6 Hz), 7.31-7.33 (1 H, brs), 7.36 (1 H, d, J = 7.6 Hz) 7.51 (1H, t, J = 7.6 Hz), 7.92-8.05 (5H, m).

Example 51 Synthesis of 2- (4-carbamoylphenyl) -4-[(6-carboxyhexyl) oxy] isoindolin-1-one
2- (4-Carbamoylphenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one (212 mg, 0.50 mmol) obtained in Example 50 was added to 1,4-dioxane (5 mL). ) And 2N (mol / L) aqueous sodium hydroxide solution (0.5 mL, 1.00 mmol) were added to the suspension suspended in water (2 mL), and the mixture was stirred at room temperature for 4 and a half hours. After the reaction, the reaction mixture was neutralized with 1N (mol / L) hydrochloric acid, and the obtained crystals were collected by filtration and dried to give 2- (4-carbamoylphenyl) -4-[(6-carboxyhexyl) oxy] isoindoline- Crystals of 1-one (yield 190 mg, yield 96%) were obtained.
mp 219-221 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.32-1.60 (6H, m), 1.78 (2H, quin, J = 6.3 Hz), 2.23 (2H, t, J = 7) .3 Hz), 4.15 (2 H, t, J = 6.3 Hz), 4.97 (2 H, s), 7.29 (1 H, d, J = 7.9 Hz), 7.31 (1 H, brs) ), 7.36 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.9 Hz), 7.92-8.05 (5H, m), 12.01 (1H , Br).

Example 52 Synthesis of 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-nitrophenyl) isoindoline-1-one
To a solution of 4-hydroxy-2- (4-nitrophenyl) isoindoline-1-one (811 mg, 3.00 mmol) obtained in Synthesis Example 22 in dimethylformamide (8 mL), potassium carbonate (435 mg, 3.15 mmol) And ethyl 7-bromoheptanoate (747 mg, 3.15 mmol) were added, and the mixture was stirred at 80 ° C. for 2.5 hours. After allowing to cool, water was added to the reaction mixture, and the precipitate was collected by filtration. This precipitate was recrystallized with a mixed solvent of dimethylformamide and methanol to give 4-[(6-ethoxycarbonylhexyl) oxy] -2- (4-nitrophenyl) isoindoline-1-one (yield 1.10 g, yield). 86%) of crystals were obtained.
mp 137-139 ° C
¹ H NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.3 Hz), 1.32-1.63 (6H, m), 1.73-1.83 (2H, m), 2.31 (2H, t, J = 7.3 Hz), 4.04 (2H, q, J = 7.3 Hz), 4.16 (2H, t, J = 6.2 Hz), 5.03 (2H , S), 7.32 (1H, d, J = 7.6 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.53 (1H, t, J = 7.6 Hz), 8 .22-8.34 (4H, m).

Example 53 Synthesis of 2- (4-aminophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one
4-[(6-Ethoxycarbonylhexyl) oxy] -2- (4-nitrophenyl) isoindoline-1-one (300 mg, 0.70 mmol) obtained in Example 52 was added to methanol (30 mL) and dichloromethane ( 50 mL), and activated carbon-palladium (Pd supported amount: 10 wt%, 30 mg) was added to the mixed solution, followed by stirring for 2 and a half hours in a hydrogen atmosphere. After filtration, dichloromethane was distilled off from the filtrate, water was added, the precipitate was collected by filtration, and 2- (4-aminophenyl) -4-[(6-ethoxycarbonylhexyl) oxy] isoindoline-1-one. Crystals (yield 238 mg, yield 85%) were obtained.
mp 134-136 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.16 (3H, t, J = 7.3 Hz), 1.34-1.59 (6H, m), 1.16-1.78 (2H, m ), 2.30 (2H, t, J = 7.3 Hz), 4.03 (2H, q, 7.3 Hz), 4.12 (2H, t, J = 6.5 Hz), 4.78 (2H) , S), 5.06 (2H, s), 6.60 (2H, d, J = 8.4 Hz), 7.21 (1H, d, J = 7.6 Hz), 7.29 (1H, d , J = 7.6 Hz), 7.43-7.50 (3H, m).

Example 54 Synthesis of 5-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
To a solution of 5-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in Synthesis Example 25 in dimethylformamide (5 mL) was added potassium carbonate (166 mg, 1.20 mmol). ) And ethyl 7-bromoheptanoate (284 mg, 1.20 mmol) were added, and the mixture was stirred at 70 ° C. for 1 hour. After allowing to cool, water was added to the reaction mixture, and the precipitate was collected by filtration. By washing the precipitate with methanol, 5-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 419 mg, yield 95%) was obtained. Obtained.
mp 175-178 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.17 (3H, t, J = 7.3 Hz), 1.34-1.44 (4H, m), 1.50-1.58 (2H, m ), 1.73-1.78 (2H, m), 2.30 (2H, t, J = 7.3 Hz), 3.85 (3H, s), 4.00-4.11 (4H, m) ), 5.01 (2H, s), 7.06-7.10 (1H, dd, J = 2.2 Hz, 8.6 Hz), 7.20-7.21 (1H, d, J = 2. 2 Hz), 7.69-7.72 (1 H, d, J = 8.6 Hz), 7.99-8.08 (4 H, m).

Example 55 Synthesis of 6-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindolin-1-one
To a solution of 6-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in Synthesis Example 28 in dimethylformamide (6 mL), potassium carbonate (152 mg, 1.10 mmol). ) And ethyl 7-bromoheptanoate (261 mg, 1.10 mmol) were added, and the mixture was stirred at 70 ° C. for 5 hours. Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)). Recrystallization from dichloromethane and hexane gave crystals of 6-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (303 mg, 69% yield). .
mp 147-149 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.38-1.52 (4H, m), 1.68 (2H, quin, J = 7.3 Hz) ), 1.83 (2H, quin, J = 6.9 Hz), 2.32 (2H, t, J = 7.3 Hz), 3.92 (3H, s), 4.04 (2H, t, J = 6.9 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.84 (2H, s), 7.17 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7 .37 (1H, d, J = 2.3 Hz), 7.41 (1H, d, J = 8.2 Hz), 7.97-8.12 (4H, m).

Example 56 Synthesis of 7-[(6-ethoxycarbonylhexyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
To a solution of 7-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in Synthesis Example 31 in dimethylformamide (7 mL) was added potassium carbonate (180 mg, 1.30 mmol). ) And ethyl 7-bromoheptanoate (308 mg, 1.30 mmol), and stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 50/1 (v / v)) to give 7-[(6-ethoxycarbonylhexyl) oxy] -2- ( Crystals of 4-methoxycarbonylphenyl) isoindoline-1-one (yield 308 mg, yield 70%) were obtained.
mp 117-119 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.36-1.48 (2H, m), 1.51-1.61 (2H, m), 1.68 (2H, quin, J = 7.6 Hz), 1.94 (2H, quin, J = 6.6 Hz), 2.31 (2H, t, J = 7.6 Hz), 3.91 (3H , S), 4.12 (2H, q, J = 7.3 Hz), 4.14 (2H, t, J = 6.6 Hz), 4.81 (2H, s), 6.91 (1H, d) , J = 7.6 Hz), 7.05 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.95-8.09 (4H, m) .

Example 57 Synthesis of 4-[(7-ethoxycarbonylheptyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
(I) Potassium carbonate (276 mg, 2.00 mmol) and ethyl iodide (343 mg, 2.20 mmol) were added to a suspension of 8-bromooctanoic acid (446 mg, 2.00 mmol) in dimethylformamide (8 mL) at room temperature. And stirred overnight. After the reaction, 1N (mol / L) hydrochloric acid and water were added, and the mixture was extracted twice with diethyl ether. The solvent was distilled off from the obtained ether layer to obtain a desired mixture containing ethyl 8-bromooctanoate.

(Ii) 4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained by the same method as in Synthesis Example 4 was suspended in dimethylformamide (6 mL). A mixture containing potassium carbonate (152 mg, 1.10 mmol) and ethyl 8-bromooctanoate prepared in the above step (i) was added to this suspension, and the mixture was stirred at 70 ° C. for 6 hours. Water was added to the reaction mixture, and the obtained crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) to give 4-[(7-ethoxycarbonylheptyl) oxy] -2- Crystals of (4-methoxycarbonylphenyl) isoindoline-1-one (yield 130 mg, yield 29%) were obtained.
mp 101-103 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.32-1.55 (6H, m), 1.66 (2H, quin, J = 7.6 Hz) ), 1.85 (2H, quin, J = 6.6 Hz), 2.31 (2H, t, J = 7.6 Hz), 3.92 (3H, s), 4.09 (2H, t, J = 6.6 Hz), 4.12 (2H, q, J = 7.3 Hz), 4.82 (2H, s), 7.05 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7 .45 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.00-8.12 (4H, m).

Example 58 Synthesis of 4-[(8-ethoxycarbonyloctyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
4-Hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained by the same method as in Synthesis Example 4 was suspended in dimethylformamide (6 mL). To the suspension were added potassium carbonate (145 mg, 1.05 mmol) and ethyl 9-bromononanoate (278 mg, 1.05 mmol), and the mixture was stirred at 70 ° C. for 5 hours. Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)), recrystallized from diisopropyl ether, and 4-[(8-ethoxycarbonyl Crystals of octyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 320 mg, yield 68%) were obtained.
mp 97-99 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.32-1.53 (8H, m), 1.64 (2H, quin, J = 7.6 Hz) ), 1.85 (2H, quin, J = 6.6 Hz), 2.30 (2H, t, J = 7.6 Hz), 3.93 (3H, s), 4.10 (2H, t, J = 6.6 Hz), 4.12 (2H, q, J = 7.3 Hz), 4.83 (2H, s), 7.05 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7 .45 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.00-8.13 (4H, m).

Example 59 Synthesis of 4-[(10-ethoxycarbonyldecyl) oxy] -2- (4-methoxycarbonylphenyl) isoindolin-1-one
4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained by the same method as in Synthesis Example 4 was suspended in dimethylformamide (6 mL). To the suspension were added potassium carbonate (145 mg, 1.05 mmol) and ethyl 11-bromoundecanoate (308 mg, 1.05 mmol), and the mixture was stirred at 70 ° C. for 5 hours. Water was added to the reaction mixture, and the obtained crystals were recrystallized from diisopropyl ether to give 4-[(10-ethoxycarbonyldecyl) oxy] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 398 mg). , Yield 80%).
mp 95-97 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.31-1.65 (14H, m), 1.85 (2H, quin, J = 6.6 Hz) ), 2.29 (2H, t, J = 7.6 Hz), 3.93 (3H, s), 4.10 (2H, t, J = 6.6 Hz), 4.12 (2H, q, J = 7.3 Hz), 4.83 (2 H, s), 7.06 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.45 (1 H, t, J = 7.6 Hz), 7 .51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.00-8.13 (4H, m).

Example 60 Synthesis of 4-({2-[(2-ethoxycarbonylethyl) thio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one
Ethyl 3- (2-hydroxyethylthio) propionate (357 mg, 2.00 mmol) obtained in Synthesis Example 32 was dissolved in dichloromethane (7 mL), and this solution was triethylamine (364 mg, 3.60 mmol) under ice cooling. ) And methanesulfonyl chloride (412 mg, 3.60 mmol) were added and stirred at room temperature overnight. Aqueous sodium hydrogen carbonate solution was added, extraction was performed with dichloromethane, and the solvent was distilled off from the obtained organic layer to obtain ethyl 3- (2-chloroethylthio) propionate.

2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (293 mg, 1.00 mmol) obtained by the same method as in Synthesis Example 3 was dissolved in dimethylformamide (8 mL). To the solution were added potassium carbonate (152 mg, 1.10 mmol) and ethyl 3- (2-chloroethylthio) propionate, and the mixture was stirred at 70 ° C. for 3 days. Water was added to the reaction mixture, and the obtained crystals were purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-({2-[(2-ethoxycarbonyl Crystals of ethyl) thio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 276 mg, 61% yield) were obtained.
mp 79-81 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.67 (2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7) .6 Hz), 3.00 (2H, t, J = 6.6 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.32 (2H, t, J = 6.6 Hz), 4 .84 (2H, s), 7.06 (1H, d, J = 7.6 Hz), 7.46 (1H, d, J = 7.6 Hz), 7.53 (1H, t, J = 7. 6 Hz), 7.67 (2H, d, J = 8.9 Hz), 8.09 (2H, d, J = 8.9 Hz).

Example 61 Synthesis of 4-({2-[(2-carboxyethyl) thio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({2-[(2-Ethoxycarbonylethyl) thio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 60 (159 mg, 0.35 mmol) ) Was suspended in ethanol (3 mL) and water (3 mL), 2N (mol / L) aqueous sodium hydroxide solution (0.35 mL, 0.70 mmol) was added to this suspension, and the mixture was heated to reflux for 30 minutes. . After standing to cool, the insoluble material was filtered off, and the filtrate was neutralized with 1N (mol / L) hydrochloric acid. The obtained crystals were purified by flash column chromatography ((solvent dichloromethane / methanol = 20/1 (v / v)) to give 4-({2-[(2-carboxyethyl) thio] ethyl} oxy) -2. Crystals of-(4-trifluoromethylphenyl) isoindoline-1-one (yield 30 mg, yield 20%) were obtained.
mp 142-144 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.58 (2H, t, J = 7.3 Hz), 2.86 (2H, t, J = 7.3 Hz), 2.97 (2H, t, J = 6.3 Hz), 4.33 (2H, t, J = 6.3 Hz), 4.97 (2H, s), 7.32 (1H, d, J = 7.6 Hz), 7.40 (1H) , D, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.78 (2H, d, J = 8.9 Hz), 8.17 (2H, d, J = 8.9 Hz), 12.32 (1H, br).

Example 62 Synthesis of 4-([2- (4-Ethoxycarbonylmethoxy-3-methylphenylthio) ethyl] oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 4-hydroxy-3-methylphenyl thiocyanate Under ice-cooling, suspension of o-cresol (5.41 g, 0.05 mol) and sodium thiocyanate (12.97 g, 0.16 mmol) in methanol (35 mL) A solution of sodium bromide (5.15 g, 0.05 mol) and bromine (2.65 mL, 0.05 mol) in methanol (50 mL) was added dropwise to the solution. After stirring at 0 ° C. for 3 hours, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture. After extraction with dichloromethane four times, the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give 4-hydroxy-3-methylphenyl thiocyanate (yield 6.79 g, A yield of 82%) was obtained.
mp 70-72 ° C
¹ H NMR (CDCl ₃ ) δ: 2.25 (3H, s), 5.32 (1H, brs), 6.78-6.82 (1H, d, J = 8.2 Hz), 7.26- 7.30 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.34-7.35 (1H, m).

(Ii) Synthesis of 4-mercapto-2-methylphenol 4-Hydroxy-3-methylphenyl thiocyanate (826 mg, 5.00 mmol), zinc (826 mg), and 2,6-di, obtained in the above step (i) To a suspension of -t-butyl-4-methylphenol (80 mg) in methanol (25 mL), several drops of concentrated hydrochloric acid were added at 0 ° C. Then, further zinc (1.24 g) was added little by little, and the mixture was heated to reflux overnight. The mixture was filtered through celite, and the solvent was distilled off. Water was added to the residue, and the mixture was extracted twice with ethyl acetate, and then purified by flash column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give 4-mercapto-2-methylphenol ( Yield 182 mg, yield 26%).
mp 34-36 ° C
¹ H NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.32 (1H, s), 4.60 (1H, s), 6.65-6.68 (1H, d, J = 7.9 Hz), 7.04-7.08 (1H, dd, J = 2.3 Hz, 7.9 Hz), 7.11-7.12 (1 H, m).

(Iii) Synthesis of 4- (2-chloroethyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one 2- (4-trifluoromethylphenyl)-obtained in the same manner as in Synthesis Example 3 4-hydroxyisoindoline-1-one (2.93 g, 10.0 mmol) was dissolved in dimethylformamide (30 mL), and 1-bromo-2-chloroethane (2.15 g, 15.0 mmol) and carbonic acid were added to this solution. Potassium (1.38 g, 10.0 mmol) was added and stirred overnight. Furthermore, 1-bromo-2-chloroethane (2.86 g, 20.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added, and the mixture was stirred at 50 ° C. overnight. Water was added to the reaction mixture, and the precipitate was collected by filtration and recrystallized from dimethylformamide to give 4- (2-chloroethyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 3.45 g). Yield 97%).
mp 154-156 ° C
¹ H NMR (CDCl ₃ ) δ: 3.89 (2H, t, 5.9 Hz), 4.40 (2H, t, 5.9 Hz), 4.87 (2H, s), 7.07 (1H, dd, J = 0.5 Hz, 7.6 Hz), 7.48 (1 h, t, J = 7.6 Hz), 7.57 (1H, dd, J = 0.5 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.4 Hz), 8.07 (2H, d, J = 8.4 Hz)
(Iv) Synthesis of 4- (2- (4-ethoxycarbonylmethoxy-3-methylphenylthio) ethyl) oxy-2- (4-trifluoromethylphenyl) isoindolin-1-one Obtained in the above step (ii) 4-mercapto-2-methylphenol (285 mg, 0.80 mmol) and cesium carbonate (323 mg, 1.00 mmol) were mixed with a mixed solvent of acetonitrile (2 mL) and dimethylformamide (1 mL). 4- (2-Chloroethyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one (140 mg, 1.00 mmol) obtained in the above step (iii) was added and stirred at room temperature for 4 days. Furthermore, ethyl bromoacetate (165 mg, 1.00 mmol), cesium carbonate (323 mg, 1.00 mmol) and dimethylformamide (1 mL) were added, and the mixture was stirred at 50 ° C. for 30 minutes. Ethanol and water were added to the reaction mixture, and the precipitate was collected by filtration and recrystallized twice using a mixed solvent of ethanol, dimethylformamide and water, and 4-([2- (4-ethoxycarbonylmethoxy- Crystals of 3-methylphenylthio) ethyl] oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 170 mg, yield 39%) were obtained.
mp 103-105 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.19 (3H, t, J = 7.3 Hz), 2.14 (3H, s), 3.26-3.38 (2H, m), 4. 14 (2H, q, J = 7.3 Hz), 4.33 (2H, t, J = 6.5 Hz), 4.73 (2H, s), 4.77 (2H, s), 6.81 ( 1H, d, J = 7.8 Hz), 7.23-7.28 (3H, m), 7.39 (1H, d, J = 7.8 Hz), 7.50 (1H, t, J = 7) .8 Hz), 7.79 (2H, d, J = 8.4 Hz), 8.11 (2H, d, J = 8.4 Hz).

Example 63 Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenylthio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
3,3-Dihydrodiphenyl disulfide (250 mg, 1.00 mmol) and zinc dust (250 mg) were suspended in methanol (10 mL), concentrated hydrochloric acid (1 mL) was added to the suspension, and the mixture was heated to reflux for 20 minutes. After filtration, the solvent was distilled off from the filtrate, water was added to the residue, and extraction was performed 3 times with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3-mercaptophenol.

To this dimethylformamide (3 mL) solution of 3-mercaptophenol, 4- (2-chloroethyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in step (iii) of Example 62 was added. (356 mg, 1.00 mmol) and cesium carbonate (489 mg, 1.50 mmol) were added, and the mixture was stirred at 50 ° C. for 3 days. Furthermore, ethyl bromoacetate (334 mg, 2.00 mmol) and cesium carbonate (489 mg, 1.50 mmol) were added, and the mixture was stirred at 50 ° C. overnight. Water and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and extraction was performed three times with dichloromethane. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)), and re-purified with a mixed solvent of n-hexane and ethyl acetate. Crystallization gave 4-({2- [3- (ethoxycarbonylmethoxy) phenylthio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 210 mg, 40% yield). Got.
mp 114-116 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 3.37 (2H, t, J = 6.5 Hz), 4.23 (2H, q, J = 7) .3 Hz), 4.32 (2H, t, J = 6.5 Hz), 4.59 (2H, s), 4.68 (2H, s), 6.72-6.76 (1H, m), 6.9-7.05 (3H, m), 7.20-7.23 (1H, d, J = 7.6 Hz), 7.41-7.47 (1H, t, J = 7.6 Hz) 7.51-7.53 (1H, d, J = 7.6 Hz), 7.66-7.69 (2H, d, J = 7.6 Hz), 8.01-8.04 (2H, d , J = 8.4 Hz).

Example 64 Synthesis of 4-({2- [3- (carboxymethoxy) phenylthio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) phenylthio] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 63 (150 mg, 0.28 mmol) ) Was mixed with aqueous sodium hydroxide solution (1.0 mL, 2.00 mmol) and ethanol (3 mL) and stirred at 50 ° C. for 3 hours. Water was added to the reaction mixture, neutralized with concentrated hydrochloric acid, the precipitate was collected by filtration, and 4-({2- [3- (carboxymethoxy) phenylthio] ethyl} oxy) -2- (4-trifluoromethylphenyl). ) Crystals of isoindoline-1-one (yield 132 mg, yield 93%) were obtained.
mp 149-151 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.46 (2H, t, J = 6.2 Hz), 4.38 (2H, t, J = 6.2 Hz), 4.67 (2H, s), 4.78 (2H, s), 6.78 (1H, dd, J = 2.2 Hz, 7.8 Hz), 6.97 (1H, t, J = 2.2 Hz), 7.00 (1H, d , J = 7.8 Hz), 7.22-7.32 (2H, m), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz) 7.81 (2H, d, J = 8.4 Hz), 8.12 (2H, d, J = 8.4 Hz), 13.04 (1H, br).

Example 65 (Synthesis of 4-([3- (2-ethoxycarbonylethylthio) propyl] oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
(I) Synthesis of 4- (3-chloropropyl) oxy-2- (4-trifluoromethylphenyl) isoindoline-1-one 2- (4-trifluoromethylphenyl) obtained in the same manner as in Synthesis Example 3. ) -4-Hydroxyisoindoline-1-one (586 mg, 2.00 mmol) was dissolved in dimethylformamide (1.5 mL) and 1-bromo-3-chloropropane (346 mg, 2.20 mmol) and carbonic acid were dissolved in this solution. Potassium (304 mg, 2.00 mmol) was added and stirred overnight. Furthermore, 1-bromo-3-chloropropane (173 mg, 1.10 mmol) was added and stirred overnight. Water was added to the reaction mixture, the precipitate was collected by filtration, recrystallized from water and dimethylformamide, and 4- (3-chloropropyl) oxy-2- (4-trifluoromethylphenyl) isoindoline-1-one ( A crystal having a yield of 600 mg and a yield of 81% was obtained.
mp 123-125 ° C
¹ H NMR (CDCl ₃ ) δ: 2.33 (2H, quin, J = 5.9 Hz), 3.79 (2H, t, J = 5.9 Hz), 4.29 (2H, t, J = 5) .9 Hz), 4.82 (2 H, s), 7.11 (1 H, dd, J = 1.4 Hz, 7.6 Hz), 7.48 (1 H, t, J = 7.6 Hz), 7.54 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.1 Hz), 8.06 (2H, d, J = 8.1 Hz).

(Ii) Synthesis of 4-([3- (2-ethoxycarbonylethylthio) propyl] oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one 4 obtained in the above step (i) -(3-Chloropropyl) oxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (296 mg, 0.80 mmol) was dissolved in dimethylformamide (5 mL) and potassium carbonate (155 mg) was dissolved in this solution. , 1.12 mmol) and ethyl 3-mercaptopropionate (182 mg, 1.36 mmol), stirred at 50 ° C. for 1 hour and then at room temperature overnight. Water was added to the reaction mixture, extracted with dichloromethane, purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), and oily 4-([3- (2-ethoxy Carbonylethylthio) propyl] oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 119 mg, yield 32%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 2.15 (2H, m), 2.60-2.65 (2H, m), 2.78 ( 2H, t, J = 7.3 Hz), 2.81-2.86 (2H, m), 4.15 (2H, q, J = 7.3 Hz), 4.21 (2H, t, J = 5) .9 Hz), 4.80 (2 H, s), 7.07 (1 H, dd, = 1.3 Hz, 7.6 Hz), 7.45 (1 H, t, J = 7.6 Hz), 7.50 ( 1H, dd, = 1.3 Hz, 7.6 Hz), 7.66 (2H, dd, = 0.7 Hz, 9.2 Hz), 8.05 (2H, dd, = 0.7 Hz, 9.2 Hz).

Example 66 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one)
(I) Synthesis of (4-methylphenoxy) ethyl acetate To a solution of p-cresol (1.08 g, 10.0 mmol) in dimethylformamide (20 mL), potassium carbonate (1.45 g, 10.5 mmol) and ethyl bromoacetate ( 1.75 g, 10.5 mmol) was added, and the mixture was stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The solvent was distilled off from the organic layer, and the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 4/1 (v / v)) to give ethyl (4-methylphenoxy) acetate (yield 1.63 g). Yield 84%).
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.28 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4. 59 (2H, s), 6.78-6.83 (2H, m), 7.05-7.11 (2H, m).

(Ii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindolin-1-one obtained in the above step (i) (4 -Methylphenoxy) ethyl acetate (233 mg, 1.20 mmol) was dissolved in carbon tetrachloride (5 mL) and N-bromosuccinimide (214 mg, 1.20 mmol) and benzoyl peroxide (water content 25 wt. %, 15 mg) was added and heated to reflux for 30 minutes. After allowing to cool, it was washed with water, and the solvent was distilled off from the organic layer to obtain ethyl (4-bromomethylphenoxy) acetate.

To a solution of 4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (142 mg, 0.50 mmol) obtained in the same manner as in Synthesis Example 4 in dimethylformamide (5 mL), potassium carbonate (69 mg, 0.50 mmol) and (4-bromomethylphenoxy) ethyl acetate were added, and the mixture was stirred at 70 ° C. for 3 hours. After allowing to cool, water was added to the reaction mixture, the mixture was cooled to 0 ° C., and the precipitated crystals were collected by filtration. The crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) and 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-methoxy Crystals of carbonylphenyl) isoindoline-1-one (yield 79 mg, yield 33%) were obtained.
mp 166-168 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 3.91 (3H, s), 4.28 (2H, q, J = 7.3 Hz), 4. 65 (2H, s), 4.81 (2H, s), 5.11 (2H, s), 6.93-6.98 (2H, m), 7.12 (1H, dd, J = 1. 0 Hz, 7.6 Hz), 7.35-7.41 (2 H, m), 7.44 (1 H, t, J = 7.6 Hz), 7.52 (1 H, dd, J = 1.0 Hz, 7 .6 Hz), 7.97-8.10 (4H, m).

Example 67 (4-({Synthesis of [3- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one}
(I) Synthesis of 4-[(3-hydroxyphenyl) methyl] oxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one Carbon tetrachloride of m-tolyl acetate (1.50 g, 10.0 mmol) To the (40 mL) solution, N-bromosuccinimide (1.78 g, 10.0 mmol) and benzoyl peroxide (water content 25% by weight, 152 mg) were added, and the mixture was heated to reflux for 1.5 hours. After cooling, the reaction mixture was washed with water, and the solvent was distilled off from the organic layer to obtain 1-acetoxy-3-bromomethylbenzene.

4-Hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in the same manner as in Synthesis Example 4 was dissolved in dimethylformamide (8 mL). Potassium (138 mg, 1.00 mmol) and 1-acetoxy-3-bromomethylbenzene (687 mg, 3.00 mmol) were added, and the mixture was stirred at 70 ° C. for 1.5 hours. After allowing to cool, methanol (10 mL) and potassium carbonate (138 mg, 1.00 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 1N (mol / L) hydrochloric acid, water was added, and the obtained crystals were recrystallized from dimethylformamide to give 4-[(3-hydroxyphenyl) methoxy] -2- (4-methoxy Crystals of carbonylphenyl) isoindoline-1-one (yield 215 mg, yield 55%) were obtained.
mp 222-224 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 5.04 (2H, s), 5.22 (2H, s), 6.73 (1H, ddd, J = 1. 0 Hz, 2.3 Hz, 7.6 Hz), 6.89-6.90 (1 H, m), 6.93 (1 H, d, J = 7.6 Hz), 7.20 (1 H, t, J = 7) .6 Hz), 7.34-7.41 (2 H, m), 7.51 (1 H, t, J = 7.6 Hz), 7.98-8.16 (4 H, m), 9.50 (1 H) , S).

(Ii) Synthesis of 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one 4- (obtained in the above step (i)) [(3-Hydroxyphenyl) methyl] oxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (156 mg, 0.40 mmol) was dissolved in dimethylformamide (6 mL), and potassium carbonate ( 58 mg, 0.42 mmol) and ethyl bromoacetate (70 mg, 0.42 mmol) were added, and the mixture was stirred at 70 ° C. for 1.5 hours. After allowing to cool, water was added to the reaction mixture, and the obtained crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) to give 4-({[3- (ethoxycarbonylmethoxy ) Phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 168 mg, 88% yield).
mp 170-172 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 3.91 (3H, s), 4.25 (2H, q, J = 7.3 Hz), 4. 64 (2H, s), 4.82 (2H, s), 5.15 (2H, s), 6.88 (1H, ddd, J = 1.0 Hz, 2.6 Hz, 8.2 Hz), 7. 04-7.10 (3H, m), 7.33 (1H, t, J = 7.6 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.98-8.10 (4H, m).

Example 68 Synthesis of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (i) [3- ( Synthesis of 2-hydroxyethyl) phenoxy] ethyl acetate To a solution of 3-hydroxyphenethyl alcohol (1.00 g, 7.24 mmol) in acetonitrile (15 mL) was added potassium carbonate (1.10 g, 7.96 mmol) and ethyl bromoacetate (1 The reaction mixture was added with water, extracted with ethyl acetate, and then flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v). )) And oily ethyl [3- (2-hydroxyethyl) phenoxy] acetate (yield 1.55 g). 95% yield).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.48 (1H, brs), 2.84 (2H, t, J = 6.6 Hz), 3. 82-3.87 (2H, m), 4.27 (2H, q, J = 7.3 Hz), 4.61 (2H, s), 6.76 (1H, ddd, J = 1.0 Hz, 2 .3 Hz, 7.9 Hz), 6.80 (1 H, t, J = 2.3 Hz), 6.86 (1 H, dt, J = 1.0 Hz, 7.9 Hz), 7.23 (1 H, t, J = 7.9 Hz).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one [3- (2-hydroxyethyl) phenoxy] ethyl acetate (449 mg, 2.00 mmol) obtained in (1) was dissolved in dichloromethane (10 mL), and triethylamine (263 mg, 2.60 mmol) and methanesulfonyl chloride were dissolved in this solution. (298 mg, 2.60 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off from the obtained organic layer to obtain [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate.

2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (440 mg, 1.50 mmol) obtained in the same manner as in Synthesis Example 3 was dissolved in dimethylformamide (10 mL). Were added potassium carbonate (228 mg, 1.65 mmol) and [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate, and the mixture was stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the obtained crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 50/1 (v / v)) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl. ] Ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 626 mg, 84% yield) was obtained.
mp 118-119 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 3.13 (2H, t, J = 6.6 Hz), 4.23 (2H, q, J = 7) .3Hz), 4.31 (2H, t, J = 6.6 Hz), 4.62 (2H, s), 4.75 (2H, s), 6.77 (1H, ddd, J = 1.0 Hz) , 2.6 Hz, 8.2 Hz), 6.91-6.94 (2H, m), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.22-7.28 ( 1H, m), 7.44 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, d, J = 8) .6 Hz), 8.06 (2H, d, J = 8.6 Hz).

Example 69 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 68 ((250 mg,. 50 mmol) is suspended in a mixed solution of ethanol (3 mL) and water (3 mL), and 2N (mol / L) aqueous sodium hydroxide solution (0.5 mL, 1.00 mmol) is added to this suspension for 1 hour. The insoluble matter was removed by filtration, the solvent was distilled off from the filtrate, the residue was neutralized with 1N (mol / L) hydrochloric acid, and the resulting crystals were recrystallized from diisopropyl ether to give 4- ( Crystals of {2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 163 mg, yield 69%) were obtained.
mp 142-145 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4.62 (2H, s), 4.94 (2H, s), 6.76 (1H, dt, J = 1.0 Hz, 8.2 Hz), 6.93-6.95 (2H, m), 7.22 (1H, t, J = 8.2 Hz), 7.33 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.9 Hz) 7.79 (2H, d, J = 8.6 Hz), 8.17 (2H, d, J = 8.6 Hz).

Example 70 Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one)
(I) Synthesis of [4- (2-hydroxyethyl) phenoxy] ethyl acetate To a solution of 4-hydroxyphenethyl alcohol (2.76 g, 20.0 mmol) in acetonitrile (40 mL), potassium carbonate (3.04 g, 22.0 mmol). ) And ethyl bromoacetate (3.67 g, 22.0 mmol) were added, and the mixture was heated to reflux for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and then purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to obtain [4- (2-hydroxyethyl) phenoxy. Crystals of ethyl acetate (yield 4.06 g, yield 91%) were obtained.
mp 58-60 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.35 to 1.39 (1H, m), 2.81 (2H, t, J = 6.6 Hz) ), 3.79-3.86 (2H, m), 4.27 (2H, q, J = 7.3 Hz), 4.60 (2H, s), 6.86 (2H, d, J = 8) .6 Hz), 7.15 (2H, d, J = 8.6 Hz).

(Ii) Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one The above step (i) under ice-cooling To a solution of [4- (2-hydroxyethyl) phenoxy] ethyl acetate (449 mg, 2.00 mmol) obtained in 1) in dichloromethane (10 mL), triethylamine (263 mg, 2.60 mmol) and methanesulfonyl chloride (298 mg, 2.60 mmol) were added. ) And stirred at 0 ° C. for 50 minutes. Water was added to the reaction mixture, extraction was performed with dichloromethane, and the solvent was distilled off from the obtained organic layer to obtain [4- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate.

(4-Hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in the same manner as in Synthesis Example 4 was suspended in dimethylformamide (7 mL). Potassium carbonate (152 mg, 1.10 mmol) and [4- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate were added to the suspension, and the mixture was stirred for 3 hours and a half at 70 ° C. Water was added to the reaction mixture, and the mixture was added at 0 ° C. And the precipitated crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 30/1 (v / v)) to give 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy ) -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 460 mg, 94% yield) To obtain a crystal.
mp 145-147 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 3.09 (2H, t, J = 6.9 Hz), 3.91 (3H, s), 4. 25 (2H, q, J = 7.3 Hz), 4.26 (2H, t, J = 6.9 Hz), 4.60 (2H, s), 4.70 (2H, s), 6.86- 6.91 (2H, m), 7.02 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.19-7.24 (2 H, m), 7.41 (1 H, t, J = 7.6 Hz), 7.48 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.95-8.10 (4 H, m).

Example 71 Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindolin-1-one)
[3- (2-Hydroxyethyl) phenoxy] ethyl acetate (561 mg, 2.50 mmol) obtained in step (i) of Example 68 was dissolved in dichloromethane (10 mL), and this solution was added to triethylamine under ice cooling. (329 mg, 3.25 mmol) and methanesulfonyl chloride (372 mg, 3.25 mmol) were added, and the mixture was stirred at 0 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off from the obtained organic layer to obtain [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate.

4-Hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (283 mg, 1.00 mmol) obtained in the same manner as in Synthesis Example 4 was suspended in dimethylformamide (7 mL). To the suspension were added potassium carbonate (152 mg, 1.10 mmol) and [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate, and the mixture was stirred at 70 ° C. for 5 hours. Water was added to the reaction mixture, the mixture was cooled to 0 ° C., and the precipitated crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 30/1 (v / v)) to give 4-({2- [3- ( Crystals of ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 358 mg, yield 73%) were obtained.
mp 143-145 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 3.10 (2H, t, J = 6.6 Hz), 3.90 (3H, s), 4. 23 (2H, q, J = 7.3 Hz), 4.26 (2H, t, J = 6.6 Hz), 4.62 (2H, s), 4.64 (2H, s), 6.77 ( 1H, ddd, J = 1.0 Hz, 2.3 Hz, 8.2 Hz), 6.91-6.93 (2H, m), 6.98 (1H, dd, J = 1.0 Hz, 7.6 Hz) 7.22-7.28 (1 H, m), 7.37 (1 H, t, J = 7.6 Hz), 7.44 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7. 94-8.06 (4H, m).

Example 72 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one (171 mg, 0.35 mmol) obtained in Example 71 Was suspended in a solution of ethanol (3 mL) and water (3 mL), 2N (mol / L) sodium hydroxide aqueous solution (3 mL, 1.05 mmol) was added to the suspension, and the mixture was heated to reflux for 30 minutes. After standing to cool, the insoluble material was filtered off, and the filtrate was neutralized with 1N (mol / L) hydrochloric acid. The precipitated crystals were collected by filtration to give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one (yield 154 mg, yield). 98%) of crystals were obtained.
mp 228-230 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4.93 (2H, s), 6.78 (1H, ddd, J = 0.7 Hz, 2.6 Hz, 8.2 Hz), 6.95-6.97 (2 H, m), 7.24 (1H) , T, J = 7.9 Hz), 7.32-7.39 (2H, m), 7.51 (1H, t, J = 7.9 Hz), 7.97-8.10 (4H, m) .

Example 73 Synthesis of (4-({2- [3-((1E) -2-ethoxycarbonylethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one )
(I) Synthesis of (2E) -3- [3- (2-hydroxyethyl) phenyl] ethyl acrylate To a solution of 3-bromophenethyl alcohol (704 mg, 3.50 mmol) in dimethylformamide (10 mL), triethylamine (390 mg, 3.85 mmol), tris (dibenzylideneacetone) dipalladium (0) (80 mg, 0.09 mmol), tri-o-tolylphosphine (107 mg, 0.35 mmol) and ethyl acrylate (613 mg, 6.13 mmol) were added. , And stirred at 110 ° C. for 2 hours. After allowing to cool, the reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with a mixed solvent of n-hexane / ethyl acetate = 3/1 (v / v). Purification by flash column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) and ethyl (2E) -3- [3- (2-hydroxyethyl) phenyl] acrylate (yield 486 mg, Yield 63%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.3 Hz), 1.45 (1H, t, J = 5.6 Hz), 2.89 (2H, t, J = 6) .6 Hz), 3.85-3.92 (2H, m), 4.26 (2H, q, J = 7.3 Hz), 6.44 (1H, d, J = 16.2 Hz), 7.24 −7.42 (4H, m), 7.67 (1H, d, J = 16.2 Hz).

(Ii) Synthesis of 4-({2- [3-((1E) -2-ethoxycarbonylethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Ethyl (2E) -3- [3- (2-hydroxyethyl) phenyl] acrylate (463 mg, 2.10 mmol) obtained in step (i) was dissolved in dichloromethane (15 mL), and this was cooled under ice-cooling. Triethylamine (276 mg, 2.73 mmol) and methanesulfonyl chloride (313 mg, 2.73 mmol) were added to the solution, and the mixture was stirred at 0 ° C. for 1 hour. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with an aqueous sodium hydrogen carbonate solution to obtain ethyl (2E) -3- [3- (2-methanesulfonyloxyethyl) phenyl] acrylate.

2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (557 mg, 1.90 mmol) obtained by the same manner as in Synthesis Example 3 using this compound and potassium carbonate (275 mg, 1.99 mmol). ) In dimethylformamide (10 mL) and stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 100/1 (v / v)) to give 4-({2- [3-((1E) -2- Crystals of ethoxycarbonylethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 688 mg, yield 73%) were obtained.
mp 169-171 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 3.18 (2H, t, J = 6.6 Hz), 4.26 (2H, q, J = 7) .3 Hz), 4.33 (2 H, t, J = 6.6 Hz), 4.71 (2 H, s), 6.47 (1 H, d, J = 15.8 Hz), 7.06 (1 H, dd) , J = 1.0 Hz, 7.6 Hz), 7.31 (1H, dt, J = 1.6 Hz, 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.42− 7.53 (4H, m), 7.67 (2H, d, J = 8.9 Hz), 7.71 (1H, d, J = 15.8 Hz), 8.02 (2H, d, J = 8) .9 Hz).

Example 74 Synthesis of 4-({2- [3-((1E) -2-carboxyethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [3-((1E) -2-Ethoxycarbonylethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1- obtained in Example 73 On (198 mg, 0.40 mmol) was suspended in a mixed solution of ethanol (3 mL) and water (1 mL). ) Was added, and the mixture was stirred at 50 ° C. for 2 hours and further heated to reflux for 1 and a half hours. The solvent was distilled off from the reaction mixture and acidified with 1N (mol / L) hydrochloric acid. The precipitate was collected by filtration to give 4-({2- [3-((1E) -2-carboxyethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1- On (yield 177 mg, 95% yield) crystals were obtained.
mp 207-210 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.13 (2H, t, J = 6.6 Hz), 4.38 (2H, t, J = 6.6 Hz), 4.89 (2H, s), 6.59 (1H, d, J = 16.2 Hz), 7.33-7.44 (4H, m), 7.48-7.57 (2H, m), 7.62 (1H, d, J = 16.2 Hz), 7.75 (1H, s), 7.79 (2H, d, J = 8.9 Hz), 8.14 (2H, d, J = 8.9 Hz), 12.47 (1H) , Br).

Example 75 Synthesis of (4-({2- [3- (2-ethoxycarbonylethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in Example 73 4-({2- [3-((1E) -2-ethoxycarbonylethenyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (248 mg, 0 .50 mmol), dichloromethane (5 mL) and ethanol (15 mL) in a mixed solution, activated carbon-palladium (20 mg) was added and stirred for 4 and a half hours in a hydrogen atmosphere, the reaction mixture was filtered, and the solvent was distilled off from the filtrate. 4-({2- [3- (2-ethoxycarbonylethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) Isoindolin-1-one (yield 223 mg, 90% yield) of crystals.
mp 110-112 ° C
¹ H NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.3 Hz), 2.62 (2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7) .6 Hz), 3.13 (2H, t, J = 6.9 Hz), 4.10 (2H, q, J = 7.3 Hz), 4.31 (2H, t, J = 6.9 Hz), 4 .77 (2H, s), 7.04-7.15 (4H, m), 7.24-7.29 (1H, m), 7.45 (1H, t, J = 7.6 Hz), 7 .51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.9 Hz), 8.05 (2H, d, J = 8.9 Hz).

Example 76 Synthesis of 4-({2- [3- (2-carboxyethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-({2- [3- (2-Ethoxycarbonylethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 75 (174 mg, 0 .35 mmol) is suspended in a mixed solution of ethanol (3 mL) and water (1 mL), and 2N (mol / L) aqueous sodium hydroxide solution (0.35 mL, 0.70 mmol) is added to the suspension. Heated to reflux for hours. The solvent was distilled off and acidified with 1N (mol / L) hydrochloric acid. The precipitate was collected by filtration to give 4-({2- [3- (2-carboxyethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 119 mg, A crystal having a yield of 72%) was obtained.
mp 154-157 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.53 (2H, t, J = 7.9 Hz), 2.82 (2H, t, J = 7.9 Hz), 3.06 (2H, t, J = 6.6 Hz), 4.33 (2H, t, J = 6.6 Hz), 4.91 (2H, s), 7.09 (1H, d, J = 6.9 Hz), 7.15-7 .26 (3H, m), 7.31 (1H, d, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J = 7. 6 Hz), 7.78 (2H, d, J = 8.9 Hz), 8.16 (2H, d, J = 8.9 Hz).

Example 77 Synthesis of 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
(I) Synthesis of ethyl 1,3-phenylenediacetate A solution of 1,3-phenylenediacetic acid (971 mg, 5.00 mmol) in a hydrobromic acid-ethanol solution (hydrobromic acid concentration 10-20%, 30 mL) The suspension was heated to reflux for 40 minutes. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off from the organic layer to obtain oily ethyl 1,3-phenylenediacetate (yield 1.19 g, yield 95%).
¹ H NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.3 Hz), 3.60 (4H, s), 4.15 (4H, q, J = 7.3 Hz), 7. 17-7.31 (4H, m).

(Ii) Synthesis of [3- (ethoxycarbonylmethyl) phenyl] acetic acid To a solution of ethyl 1,3-phenylenediacetate (2.43 g, 9.69 mmol) obtained in the above step (i) in ethanol (8 mL), A solution of potassium hydroxide (544 mg, 9.69 mmol) in ethanol (8 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, water was added to the residue and washed with ether. 1N (mol / L) hydrochloric acid was added to the obtained aqueous layer to make it acidic. Extraction with ethyl acetate was performed, and the solvent was distilled off to obtain oily [3- (ethoxycarbonylmethyl) phenyl] acetic acid (yield 1.13 g, yield 53%).
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 3.60 (2H, s), 3.64 (2H, s), 4.14 (2H, q, J = 7.3 Hz), 7.18-7.32 (4H, m).

(Iii) Synthesis of 3- (ethoxycarbonylmethyl) phenethyl alcohol [3- (ethoxycarbonylmethyl) phenyl] acetic acid (1.13 g, 5.08 mmol) obtained in the above step (ii) was added to tetrahydrofuran (25 mL). After dissolution, borane / tetrahydrofuran complex (6.4 mL, 6.60 mmol) was added dropwise to the solution. After stirring at room temperature for 2 hours, water was added to the reaction mixture, which was further acidified with concentrated hydrochloric acid. Extraction with ethyl acetate and purification by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) gave oily 3- (ethoxycarbonylmethyl) phenethyl alcohol (yield 791 mg, yield 75). %).
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.49 (1H, t, J = 5.6 Hz), 2.86 (2H, t, J = 6) .6 Hz), 3.60 (2H, s), 3.82-3.89 (2H, m), 4.15 (2H, q, J = 7.3 Hz), 7.12-7.30 (4H) , M).

(Iv) 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
3- (Ethoxycarbonylmethyl) phenethyl alcohol (417 mg, 2.00 mmol) obtained in the above step (iii) was dissolved in dichloromethane (10 mL), and triethylamine (263 mg, 2.60 mmol) was added to this solution under ice cooling. And methanesulfonyl chloride (298 mg, 2.60 mmol) were added, and the mixture was stirred at 0 ° C. for 1 hour. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with brine to obtain [3- (2-methanesulfonyloxyethyl) phenyl] ethyl acetate.

2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (586 mg, 2.00 mmol) was prepared by synthesizing this compound and potassium carbonate (276 mg, 2.00 mmol) in the same manner as in Synthesis Example 3. In dimethylformamide (10 mL) and stirred at 70 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. Purification by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) and further purification by flash column chromatography (solvent dichloromethane / ethanol = 50/1 (v / v)) Crystals of 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 569 mg, yield 59%) were obtained. It was.
mp 85-87 ° C
¹ H NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.3 Hz), 3.15 (2H, t, J = 6.6 Hz), 3.61 (2H, s), 4. 10 (2H, q, J = 7.3 Hz), 4.33 (2H, t, J = 6.6 Hz), 4.78 (2H, s), 7.06 (1H, dd, J = 1.0 Hz) , 7.6 Hz), 7.15-7.33 (4 H, m), 7.44 (1 H, t, J = 7.6 Hz), 7.51 (1 H, dd, J = 1.0 Hz, 7. 6 Hz), 7.67 (2H, d, J = 8.6 Hz), 8.07 (2H, d, J = 8.6 Hz).

Example 78 Synthesis of 4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({2- [3- (Ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (193 mg, 0.40 mmol) obtained in Example 77. ) Is suspended in a mixed solvent of ethanol (3 mL) and water (1 mL), 2N (mol / L) aqueous sodium hydroxide solution (0.4 mL, 0.80 mmol) is added to the suspension, and the mixture is heated for 30 minutes. Refluxed. The solvent was distilled off from the reaction mixture, and the residue was acidified with 1N (mol / L) hydrochloric acid. The precipitate was collected by filtration to give 4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 163 mg, yield). Crystal with a rate of 89%).
mp 183-186 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.09 (2H, t, J = 6.6 Hz), 3.57 (2H, s), 4.36 (2H, t, J = 6.6 Hz), 4.93 (2H, s), 7.13 (1H, dt, J = 2.0 Hz, 6.6 Hz), 7.23-7.31 (3H, m), 7.34 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 6.6 Hz), 7.51 (1H, t, J = 7.9 Hz), 7.79 (2H, d, J = 8.6 Hz) 8.17 (2H, d, J = 8.6 Hz), 12.32 (1H, br).

Example 79 Synthesis of 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-methoxycarbonylphenyl) isoindoline-1-one
(I) Synthesis of 4-trifluoromethanesulfonyloxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one 4-hydroxy-2- (4-methoxycarbonylphenyl) obtained in the same manner as in Synthesis Example 4. Isoindoline-1-one (1.13 g, 4.00 mmol) was suspended in dichloromethane (20 mL), and this suspension was mixed with pyridine (1.58 g, 20.0 mmol) and trifluoromethanesulfonic acid under ice cooling. Anhydride (2.60 g, 9.20 mmol) was added and stirred at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the obtained crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 50/1 (v / v)) to give 4-trifluoromethanesulfonyloxy-2- (4-methoxycarbonylphenyl). ) Crystals of isoindoline-1-one (yield 1.54 g, yield 93%) were obtained.
mp 171-172 ° C
¹ H NMR (CDCl ₃ ) δ: 3.94 (3H, s), 5.02 (2H, s), 7.54 (1H, d, J = 7.6 Hz), 7.66 (1H, t, J = 7.6 Hz), 7.95-8.00 (2H, m), 7.99 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.11-8.16 (2H, m) ).

(Ii) Synthesis of 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-methoxycarbonylphenyl) isoindoline-1-one 4-Trifluoro obtained in the above step (i) L-methanesulfonyloxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one (831 mg, 2.00 mmol) and diisopropylethylamine (517 mg, 4.00 mmol) were dissolved in 1,4-dioxane (15 mL), To this solution was added tris (dibenzylideneacetone) dipalladium (0) (46 mg, 0.05 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (58 mg, 0.10 mmol) and 3-mercapto. 2-ethylhexyl propionate (480 mg, 2.20 m mol) and heated to reflux for 3 hours. After allowing to cool, the reaction mixture was filtered through celite. The solvent was distilled off from the filtrate, and the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-{[2- (2-ethylhexyloxycarbonyl). Crystals of ethyl] thio} -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 959 mg, yield 99%) were obtained.
mp 81-83 ° C
¹ H NMR (CDCl ₃ ) δ: 0.88 (6H, t, J = 7.3 Hz), 1.26-1.39 (8H, m), 1.54-1.59 (1H, m), 2.68 (2H, t, J = 7.3 Hz), 3.28 (2H, t, J = 7.3 Hz), 3.93 (3H, s), 4.01 (2H, dd, J = 1) .0 Hz, 5.6 Hz), 4.84 (2 H, s), 7.51 (1 H, t, J = 7.6 Hz), 7.60 (1 H, dd, J = 1.0 Hz, 7.6 Hz) 7.80 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.99-8.14 (4H, m).

Example 80 Synthesis of 4-[(5-ethoxycarbonylpentyl) thio] -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of 4-trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one 2- (4-trifluoromethylphenyl) -4 obtained in the same manner as in Synthesis Example 3. -Hydroxyisoindoline-1-one (1.47 g, 5.00 mmol) was suspended in dichloromethane (25 mL), and this suspension was added with pyridine (1.98 g, 25.0 mmol) and trifluoromethane under ice cooling. Sulfonic anhydride (3.24 g, 11.5 mmol) was added and stirred at 0 ° C. for 1 hour. Water was added to the reaction mixture, extracted with dichloromethane, and the solvent was distilled off. The residue was recrystallized with ethyl acetate, and the precipitated crystals were dried to give 4-trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 1.71 g, yield 80). %) Crystals.
mp 165-167 ° C
¹ H NMR (CDCl ₃ ) δ: 5.02 (2H, s), 7.55 (1H, d, J = 7.6 Hz), 7.67 (1H, t, J = 7.6 Hz), 7. 71 (2H, d, J = 8.9 Hz), 8.00 (1H, d, J = 7.6 Hz), 8.02 (2H, d, J = 8.9 Hz).

(Ii) Synthesis of 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (obtained in the above step (i)) Trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (668 mg, 1.57 mmol) and diisopropylethylamine (406 mg, 3.14 mmol) are dissolved in 1,4-dioxane (15 mL). In this solution, tris (dibenzylideneacetone) dipalladium (0) (36 mg, 0.04 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (45 mg, 0.08 mmol) and 3 -2-ethylhexyl mercaptopropionate (377 mg, 1.73 mm ol) and heated to reflux for 2.5 hours. After allowing to cool, the reaction mixture was filtered through celite. The solvent was removed from the filtrate, and the residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), and 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] Crystals of thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 740 mg, yield 95%) were obtained.
mp 66-68 ° C
¹ H NMR (CDCl ₃ ) δ: 0.88 (6H, t, J = 7.3 Hz), 1.26 to 1.40 (8H, m), 1.56 (1H, sep, J = 5.9 Hz) ), 2.68 (2H, t, J = 7.3 Hz), 3.28 (2H, t, J = 7.3 Hz), 4.01 (2H, dd, J = 1.0 Hz, 5.9 Hz) , 4.81 (2H, s), 7.51 (1H, t, J = 7.6 Hz), 7.59 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, d, J = 8.6 Hz), 7.78 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

(Iii) Synthesis of 4-[(5-ethoxycarbonylpentyl) thio] -2- (4-trifluoromethylphenyl) isoindoline-1-one 4-{[2- (2-ethylhexyloxy) obtained above Carbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (346 mg, 0.70 mmol) was dissolved in ethanol (7 mL) and sodium ethoxide (477 mg, 7.00 mmol) was added slowly. After stirring at room temperature for 3.5 hours, the mixture was neutralized with 1N (mol / L) hydrochloric acid, and the precipitate was collected by filtration to give 2- (4-trifluoromethylphenyl) -4-mercaptoisoindoline-1-one. Obtained.

The 2- (4-trifluoromethylphenyl) -4-mercaptoisoindoline-1-one was dissolved in dimethylformamide (7 mL), and potassium carbonate (106 mg, 0.77 mmol) and ethyl 6-bromohexanoate were added to the solution. (172 mg, 0.77 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, extracted with dichloromethane, purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), and 4-[(5-ethoxycarbonylpentyl) thio]. Crystals of 2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 197 mg, yield 62%) were obtained.
mp 93-94 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.44 to 1.57 (2H, m), 1.61-1.77 (4H, m), 2.31 (2H, t, J = 7.3 Hz), 3.03 (2H, t, J = 7.3 Hz), 4.12 (2H, q, J = 7.3 Hz), 4.79 (2H , S), 7.45-7.54 (2H, m), 7.67 (2H, d, J = 8.6 Hz), 7.73 (1H, dd, J = 2.3 Hz, 6.3 Hz) , 8.06 (2H, d, J = 8.6 Hz).

Example 81 Synthesis of 4-[(6-ethoxycarbonylhexyl) thio] -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of methyl 2-methyl-3-nitrobenzoate To a solution of 2-methyl-3-nitrobenzoic acid (8.15 g, 45.0 mmol) in dimethylformamide (60 mL) was added potassium carbonate (6.91 g, 50 0.0 mmol) and methyl iodide (7.81 g, 55.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was recrystallized with a mixed solvent of n-hexane and ethyl acetate and dried to give methyl 2-methyl-3-nitrobenzoate (yield 6.38 g, yield 73%). Crystals were obtained.
mp 65-67 ° C
¹ H NMR (CDCl ₃ ) δ: 2.63 (3H, s), 3.94 (3H, s), 7.39 (1H, t, J = 8.1 Hz), 7.85 (1H, dd, J = 1.4 Hz, 8.1 Hz), 7.9 (1H, dd, J = 1.4 Hz, 8.1 Hz).

(Ii) Synthesis of methyl 3-amino-2-methylbenzoate Methyl 2-methyl-3-nitrobenzoate (2.73 g, 18.0 mmol), methanol (100 mL) and acetic acid obtained in step (i) above Activated carbon-palladium (300 mg, palladium loading 10 wt%) was added to a mixed solution of ethyl (100 mL), and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated and dried to obtain stoichiometrically oily methyl 3-amino-2-methylbenzoate (yield 3.01 g).
¹ H NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.72 (2H, br), 3.88 (3H, s), 6.81 (1H, dd, J = 0.9 Hz, 7.8 Hz), 7.02-7.08 (1 H, m), 7.21 (1 H, dd, J = 0.9 Hz, 7.8 Hz).

(Iii) Synthesis of methyl 3-bromo-2-methylbenzoate Methyl 3-amino-2-methylbenzoate (826 mg, 5.00 mmol) obtained in the above step (ii) was added to hydrobromic acid (1. 5 mL, hydrogen bromide concentration 47 wt%, hydrogen bromide amount 12.5 mmol) and water (5 mL) were added, and the resulting suspension was a solution of sodium nitrite (350 mg, 5.00 mmol) in water (1 mL). And stirred for 15 minutes. The reaction mixture was mixed at 70 ° C. with hydrobromic acid (0.4 mL, hydrogen bromide concentration 47 wt%, hydrogen bromide amount 3.00 mmol) and copper (I) bromide (395 mg, 2.75 mmol). In addition to the solution, the mixture was further stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and purified by flash column chromatography (solvent n-hexane / ethyl acetate = 20/1 (v / v)) to give an oily methyl 3-bromo-2-methylbenzoate (yield). 922 mg, 81% yield).
¹ H NMR (CDCl ₃ ) δ: 2.63 (3H, s), 3.90 (3H, s), 7.06-7.12 (1H, m), 7.64-7.74 (2H, m).

(Iv) Synthesis of 4-bromo-2- (4-trifluoromethylphenyl) isoindoline-1-one Methyl 3-bromo-2-methylbenzoate (824 mg, 3.60 mmol) obtained in the above step (iii) ) In carbon tetrachloride (10 mL) was added N-bromosuccinimide (641 mg, 3.60 mmol) and benzoyl peroxide (water content 25 wt%, 50 mg), and the mixture was heated to reflux for 5 hours. After allowing to cool, the reaction mixture was filtered, and the solvent was distilled off from the filtrate to obtain methyl 3-bromo-2-bromomethylbenzoate.

This compound and 4-trifluoromethylaniline (644 mg, 4.00 mmol) were dissolved in dimethylformamide (5 mL), and this solution was stirred at 60 ° C. for 1 hour, and further stirred at 150 ° C. for 1.5 hours. After allowing to cool, water and methanol were added to the reaction mixture, and the precipitate was collected by filtration and dried to give 4-bromo-2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 1.15 g). , Yield 90%).
mp 164-166 ° C
¹ H NMR (CDCl ₃ ) δ: 4.82 (2H, s), 7.45 (1H, t, J = 7.8 Hz), 7.70 (2H, d, J = 8.4 Hz), 7. 76 (1H, dd, J = 0.5 Hz, 7.8 Hz), 7.90 (1H, d, J = 7.8 Hz), 8.05 (2H, d, J = 8.4 Hz).

(V) Synthesis of ethyl 7- (acetylthio) heptanoate To a solution of ethyl 7-bromoheptanoate (1.19 g, 5.00 mmol) in ethanol (20 mL) was added potassium thioacetate (685 mg, 6.00 mmol) at room temperature. And stirred overnight. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. Purification by flash column chromatography (solvent n-hexane / ethyl acetate = 6/1 (v / v)) gave an oily ethyl 7- (acetylthio) heptanoate (yield 1.14 g, yield 98%). .
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.30-1.44 (4H, m), 1.52-1.67 (4H, m), 2.29 (2H, t, J = 7.6 Hz), 2.32 (3H, s), 2.86 (2H, t, J = 7.3 Hz), 4.12 (2H, q, J = 7) .3 Hz).

(Vi) Synthesis of ethyl 7-mercaptoheptanoate To a solution of ethyl 7- (acetylthio) heptanoate (465 mg, 2.00 mmol) obtained in the above step (v) in ethanol (20 mL), potassium carbonate (304 mg, 2. 20 mmol) was added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, purified by flash column chromatography (solvent n-hexane / ethyl acetate = 6/1 (v / v)), and oily ethyl 7-mercaptoheptanoate (yield 311 mg). Yield 82%).
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.29-1.49 (5H, m), 1.56-1.69 (4H, m), 2.29 (2H, t, J = 7.6 Hz), 2.52 (2H, q, J = 7.6 Hz), 4.12 (2H, q, J = 7.3 Hz).

(Vii) Synthesis of 4-[(6-ethoxycarbonylhexyl) thio] -2- (4-trifluoromethylphenyl) isoindoline-1-one 4-bromo-2- () obtained in the above step (iv) 4-trifluoromethylphenyl) isoindoline-1-one ((356 mg, 1.00 mmol), ethyl 7-mercaptoheptanoate obtained in the above step (vi), and diisopropylethylamine (259 mg, 2.00 mmol), Dissolve in 1,4-dioxane (12 mL) and add tris (dibenzylideneacetone) dipalladium (0) (23 mg, 0.025 mmol) and 4,5-bis (diphenylphosphino) -9,9-dimethyl to this solution. Xanthene (29 mg, 0.05 mmol) was added and the mixture was heated to reflux for 1 hour. The mixture was filtered through Celite, and the solvent was distilled off from the filtrate, and recrystallized with ethyl acetate and diisopropyl ether to give 4-[(6-ethoxycarbonylhexyl) thio] -2- (4-trifluoromethylphenyl) isoindoline. Crystals of -1-one (yield 396 mg, yield 85%) were obtained.
mp 122-124 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 1.30-1.55 (4H, m), 1.58-1.76 (4H, m), 2.30 (2H, t, J = 7.3 Hz), 3.03 (2H, t, J = 7.3 Hz), 4.11 (2H, q, J = 7.3 Hz), 4.80 (2H , S), 7.46-7.54 (2H, m), 7.67-7.70 (2H, m), 7.75 (1H, dd, J = 2.3 Hz, 6.3 Hz), 8 .05-8.08 (2H, m).

Example 82 Synthesis of 4-[(6-carboxyhexyl) thio] -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-[(6-Ethoxycarbonylhexyl) thio] -2- (4-trifluoromethylphenyl) isoindoline-1-one (163 mg, 0.35 mmol) obtained in Example 81 was added with acetic acid (3 mL) and The mixture was suspended in a mixed solution of hydrobromic acid (hydrogen bromide concentration 47 wt%, 1 mL) and stirred at 80 ° C. overnight. After allowing to cool, the precipitated crystals were collected by filtration and purified by flash column chromatography (solvent dichloromethane / methanol = 30/1 (v / v)) to give 4-[(6-carboxyhexyl) thio] -2- ( Crystals of 4-trifluoromethylphenyl) isoindoline-1-one (yield 102 mg, 67% yield) were obtained.
mp 125-127 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.25 to 1.57 (6H, m), 1.65 (2H, quin, J = 7.3 Hz), 2.18 (2H, t, J = 7) .3 Hz), 3.08 (2 H, t, J = 7.3 Hz), 4.96 (2 H, s), 7.54 (1 H, t, J = 7.6 Hz), 7.63-7.69. (2H, m), 7.75 (2H, d, J = 8.6 Hz), 8.15 (2H, d, J = 8.6 Hz).

Example 83 Synthesis of 4-[(6-ethoxycarbonylhexyl) thio] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
4-{[2- (2-Ethylhexyloxycarbonyl) ethyl] thio} -2- (4-methoxycarbonylphenyl) isoindoline-1-one (330 mg, 0.68 mmol) obtained in Example 79 was added to ethanol. (10 mL) and sodium ethoxide (558 mg, 4.08 mmol) was gradually added to the suspension at 0 ° C. After stirring at room temperature for 4 hours, the mixture was neutralized with 1N (mol / L) hydrochloric acid, and the resulting crystals were filtered to obtain 2- (4-methoxycarbonylphenyl) -4-mercaptoisoindoline-1-one. .

To a solution of this compound (188 mg, 0.63 mmol) in dimethylformamide (5 mL) was added potassium carbonate (87 mg, 0.63 mmol) and ethyl 7-bromoheptanoate (149 mg, 0.63 mmol), and the mixture was stirred at room temperature for 40 minutes. . Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 50/1 (v / v)), and further flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) and purified by 4-[(6-ethoxycarbonylhexyl) thio] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 87 mg, 28%) Crystal was obtained.
mp 103-105 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 1.30-1.76 (8H, m), 2.29 (2H, t, J = 7.3 Hz) ), 3.02 (2H, t, J = 7.3 Hz), 3.93 (3H, s), 4.11 (2H, q, J = 7.3 Hz), 4.80 (2H, s), 7.45-7.54 (2H, m), 7.74 (1 H, dd, J = 2.3 Hz, 6.3 Hz), 7.99-8.13 (4 H, m).

Example 84 (Synthesis of 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of [3- (hydroxymethyl) phenoxy] ethyl acetate To a suspension of m-hydroxybenzyl alcohol (1.86 g, 15.0 mmol) in acetonitrile (30 mL) was added potassium carbonate (2.28 g, 16.5 mmol). ) And ethyl bromoacetate (2.76 g, 16.5 mmol) were added and heated to reflux for 3 hours. Water was added to the reaction mixture, extracted with ethyl acetate, purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)), and oily [3- (hydroxymethyl) phenoxy] Ethyl acetate (yield 2.02 g, yield 64%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.59 (1H, brs), 4.27 (2H, q, J = 7.3 Hz), 4. 63 (2H, s), 4.67 (2H, brs), 6.84 (1H, dd, J = 2.3 Hz, 7.9 Hz), 6.94 (1H, t, J = 2.3 Hz), 6.98 (1H, dt, J = 1.0 Hz, 7.9 Hz), 7.27 (1H, t, J = 7.9 Hz).

(Ii) Synthesis of [3- (chloromethyl) phenoxy] ethyl acetate [3- (hydroxymethyl) phenoxy] ethyl acetate (273 mg, 1.30 mmol) obtained in the above step (i) was dissolved in dichloromethane (7 mL). Under ice cooling, triethylamine (171 mg, 1.69 mmol) and methanesulfonyl chloride (194 mg, 1.69 mmol) were added to the solution, and the mixture was stirred at 0 ° C. for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off from the obtained organic layer to obtain [3- (chloromethyl) phenoxy] ethyl acetate.

(Iii) Synthesis of 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 80, steps (i) and ( 4-{[2- (2-Ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (494 mg, 1.00 mmol) obtained as in ii) Was dissolved in ethanol (5 mL), sodium ethoxide (681 mg, 10.0 mmol) was gradually added to this solution, and the mixture was stirred at room temperature for 1 hour. 1N (mol / L) hydrochloric acid was added to the reaction mixture to make it acidic, and water was further added to obtain crystals of 2- (4-trifluoromethylphenyl) -4-mercaptoisoindoline-1-one.

To this dimethylformamide (7 mL) solution of 2- (4-trifluoromethylphenyl) -4-mercaptoisoindoline-1-one was obtained in potassium carbonate (138 mg, 1.00 mmol) and the above step (ii) [ 3- (Chloromethyl) phenoxy] ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent dichloromethane / ethanol = 50/1 (v / v)), and further flash column chromatography (solvent n-hexane / ethyl acetate = 2 / 1 (v / v)) and 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 214 mg, (43% yield) of crystals were obtained.
mp 116-118 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 4.10 (2H, s), 4.23 (2H, q, J = 7.3 Hz), 4. 51 (2H, s), 4.55 (2H, s), 6.74 (1H, ddd, J = 0.7 Hz, 2.0 Hz, 7.9 Hz), 6.78 (1H, dd, J = 2) 0.0 Hz, 7.9 Hz), 6.84 (1 H, t, J = 2.0 Hz), 7.16 (1 H, t, J = 7.9 Hz), 7.48 (1 H, t, J = 7. 6 Hz), 7.58 (1 H, dd, J = 1.3 Hz, 7.6 Hz), 7.66 (2 H, d, J = 8.6 Hz), 7.80 (1 H, dd, J = 1.3 Hz) , 7.6 Hz), 7.98 (2H, d, J = 8.6 Hz).

Example 85 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate [3- (2-hydroxyethyl) phenoxy] obtained in the same manner as in step (i) of Example 68 under ice-cooling. Ethyl acetate (292 mg, 1.30 mmol) was dissolved in dichloromethane (7 mL), triethylamine (171 mg, 1.69 mmol) and methanesulfonyl chloride (194 mg, 1.69 mmol) were added to this solution, and the mixture was stirred at 0 ° C. for 40 minutes. did. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off from the obtained organic layer to obtain [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate.

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one Step (i) of Example 80 And 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (494 mg, 1. 00 mmol) was dissolved in ethanol (7 mL), sodium ethoxide (1.09 g, 16.0 mmol) was gradually added to the solution, and the mixture was stirred at room temperature for 2 hours. 1N (mol / L) hydrochloric acid was added to the reaction mixture to make it acidic, and water was further added to obtain 2- (4-trifluoromethylphenyl) -4-mercaptoisoindoline-1-one crystals.

To a solution of 2- (4-trifluoromethylphenyl) -4-mercaptoisoindoline-1-one in dimethylformamide (7 mL), potassium carbonate (152 mg, 1.10 mmol) and obtained in the above step (i) [3 -(2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the resulting crystals were purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), recrystallized from dimethylformamide, and 4-({2- Crystals of [3- (ethoxycarbonylmethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 161 mg, yield 31%) were obtained.
mp 119-121 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.95 (2H, t, J = 7.6 Hz), 3.29 (2H, t, J = 7) .6 Hz), 4.25 (2H, q, J = 7.3 Hz), 4.58 (2H, s), 4.75 (2H, s), 6.73 (1H, dd, J = 2.6 Hz) , 7.9 Hz), 6.78-6.87 (2 H, m), 7.21 (1 H, t, J = 7.9 Hz), 7.50 (1 H, t, J = 7.6 Hz), 7 .56 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.68 (2H, d, J = 9.2 Hz), 7.77 (1H, dd, J = 1.3 Hz, 7.6 Hz) ), 8.05 (2H, d, J = 9.2 Hz).

Example 86 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (74 mg, 0.14 mmol) obtained in Example 85. Is suspended in a mixed solution of acetic acid (2 mL) and hydrobromic acid (2 mL, hydrogen bromide concentration 47% by weight), and the suspension is stirred at 50 ° C. for 30 minutes and further at 80 ° C. for 5 minutes. Stir. After allowing to cool, water was added to the reaction mixture, and 4-({2- [3- (carboxymethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 64 mg). Yield 91%).
mp 168-170 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.90 (2H, t, J = 7.6 Hz), 3.39 (2H, t, J = 7.6 Hz), 4.64 (2H, s), 4.95 (2H, s), 6.74 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.86-6.87 (2H, m), 7.19 (1H, t, J = 8.2 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz), 7.75 (1H, d, J = 7.6 Hz) 7.80 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 12.96 (1H, br).

Example 87 (Synthesis of 4-({3- [3- (carboxymethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 3- (3-methoxyphenyl) propan-1-ol To a solution of 3- (3-methoxyphenyl) propionic acid (901 mg, 5.00 mmol) in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran complex (5. 4 mL, 6.50 mmol) was added dropwise. After stirring at room temperature for 2 hours, methanol was added, insolubles were filtered off, the solvent was distilled off, and the resulting crystals were washed with ether to give oily 3- (3-methoxyphenyl) propan-1-ol. (Yield 556 mg, 67% yield) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.47 (1H, brs), 1.84-1.95 (2H, m), 2.69 (2H, t, J = 7.6 Hz), 3.68 ( 2H, t, J = 6.6 Hz), 3.80 (3H, s), 6.72-6.81 (3H, m), 7.20 (1H, dt, J = 1.6 Hz, 7.3 Hz) ).

(Ii) Synthesis of 3- (3-bromopropyl) phenol 3- (3-methoxyphenyl) propan-1-ol (539 mg, 3.24 mmol) obtained in the above step (i) was dissolved in acetic acid (2 mL). Then, hydrobromic acid (hydrogen bromide concentration 47 wt%, 2 mL) was added to this solution, and the mixture was stirred at 80 ° C. overnight. After the solvent was distilled off, potassium carbonate (896 mg, 6.48 mmol) and methanol (3 mL) were added, and the mixture was further stirred overnight at room temperature. Water was added to the reaction mixture, extracted with dichloromethane, purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), and oily 3- (3-bromopropyl) phenol ( Yield 253 mg, yield 36%).
¹ H NMR (CDCl ₃ ) δ: 2.10-2.20 (2H, m), 2.73 (2H, t, J = 7.3 Hz), 3.39 (2H, t, J = 6.6 Hz) ), 4.76 (1H, s), 6.66-6.69 (2H, m), 6.77 (1H, d, J = 7.6 Hz), 7.13-7.19 (1H, m) ).

(Iii) Synthesis of [3- (3-bromopropyl) phenoxy] ethyl acetate To a solution of 3- (3-bromopropyl) phenol (232 mg, 1.08 mmol) obtained in the above step (ii) in acetonitrile (5 mL) , Potassium carbonate (232 mg, 1.68 mmol) and ethyl bromoacetate (280 mg, 1.68 mmol) were added, and the mixture was heated to reflux for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give oily [3- (3-bromopropyl) Phenoxy] ethyl acetate (yield 234 mg, yield 72%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.15 (2H, quin, J = 6.9 Hz), 2.75 (2H, t, J = 7) .3 Hz), 3.38 (2 H, t, J = 6.6 Hz), 4.28 (2 H, q, J = 7.3 Hz), 4.61 (2 H, s), 6.74 (1 H, dd) , J = 2.3 Hz, 7.9 Hz), 6.77 (1H, t, J = 2.3 Hz), 6.84 (1H, d, J = 7.9 Hz), 7.21 (1H, t, J = 7.9 Hz).

(Iv) Synthesis of 4-({3- [3- (carboxymethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one Step (i) of Example 80 above And 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (222 mg, 0. 45 mmol) was dissolved in ethanol (5 mL), and an ethanol solution of sodium ethoxide (sodium ethoxide concentration 21 wt%, 0.30 mL, 0.81 mmol) was added dropwise to this solution while cooling in a water bath. Stir for 70 minutes. To this mixture was added a solution of [3- (3-bromopropyl) phenoxy] ethyl acetate (137 mg, 0.45 mmol) obtained in step (iii) in ethanol (3 mL), and the mixture was stirred overnight at room temperature. After the reaction, the precipitated crystals were collected by filtration and dissolved in water. 1N (mol / L) hydrochloric acid was added, and the precipitated crystals were purified by flash column chromatography (solvent dichloromethane / methanol = 10/1 (v / v)) to give 4-({3- [3- (carboxymethoxy)). Phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 67 mg, yield 30%) was obtained.
mp 134-137 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.90 (2H, quin, J = 7.3 Hz), 2.68 (2H, t, J = 7.3 Hz), 3.11 (2H, t, J = 7.3 Hz), 4.01 (2H, s), 5.00 (2H, s), 6.59 (1H, dd, J = 2.3 Hz, 7.9 Hz), 6.64-6.68 (2H, m), 7.09 (1H, t, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.63-7.67 (2H, m), 7 .80 (2H, d, J = 8.6 Hz), 8.20 (2H, d, J = 8.6 Hz).

Example 88 Synthesis of 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one
3- (Ethoxycarbonylmethyl) phenethyl alcohol (250 mg, 1.20 mmol) synthesized in the same manner as in steps (i) to (iii) of Example 77 was dissolved in dichloromethane (5 mL), and this solution was cooled with ice. Were added triethylamine (158 mg, 1.56 mmol) and methanesulfonyl chloride (179 mg, 1.56 mmol), and the mixture was stirred at 0 ° C. for 1 hour. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was distilled off from the obtained organic layer to obtain [3- (2-methanesulfonyloxyethyl) phenyl] ethyl acetate.

  On the other hand, 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) iso obtained in the same manner as in steps (i) and (ii) of Example 80. Indoline-1-one (494 mg, 1.00 mmol) was dissolved in ethanol (7 mL), and this solution was cooled with a water bath, while ethanol solution of sodium ethoxide (0.30 mL, sodium ethoxide concentration 21 wt%, Sodium ethoxide amount 0.81 mmol) was added dropwise and stirred at room temperature for 50 minutes.

To the obtained reaction mixture, an ethanol solution of [3- (2-methanesulfonyloxyethyl) phenyl] ethyl acetate was added and stirred overnight at room temperature. Water was added to the reaction mixture, and the precipitated crystals were dissolved in dichloromethane. The solvent was distilled off from the organic layer, and hexane was added to the obtained oily substance for crystallization, and 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} thio) -2- (4-tri Crystals of fluoromethylphenyl) isoindoline-1-one (yield 261 mg, yield 52%) were obtained.
mp 88-90 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 2.97 (2H, t, J = 7.6 Hz), 3.29 (2H, t, J = 7) .6 Hz), 3.57 (2H, s), 4.12 (2H, q, J = 7.3 Hz), 4.75 (2H, s), 7.08-7.16 (3H, m), 7.23-7.29 (1H, m), 7.50 (1H, t, J = 7.6 Hz), 7.56 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.77 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

Example 89 (Synthesis of 4-({2- [3- (carboxymethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (100 mg, 0.20 mmol) obtained in Example 88. Is suspended in a mixed solvent of ethanol (3 mL) and water (1 mL), 2N (mol / L) aqueous sodium hydroxide solution (0.2 mL, 0.40 mmol) is added to the suspension, and the mixture is heated for 1 hour. Refluxed. The solvent was distilled off from the reaction mixture, and the residue was acidified with 1N (mol / L) hydrochloric acid. The precipitate was collected by filtration to give 4-({2- [3- (carboxymethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 91 mg, yield). 97%) of crystals were obtained.
mp 172-174 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.92 (2H, t, J = 7.3 Hz), 3.39 (2H, t, J = 7.3 Hz), 3.51 (2H, s), 4.95 (2H, s), 7.09-7.17 (3H, m), 7.24 (1H, t, J = 7.6 Hz), 7.58 (1H, t, J = 7.6 Hz) ), 7.67 (1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 12.32 (1H, br).

Example 90 Synthesis of 4-{[(2E) -4- (methoxycarbonylmethoxy) butenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of methyl ((2E) -4-bromo-2-butenyloxy) acetate A solution of methyl glycolate (3.60 g, 40.0 mmol) in tetrahydrofuran (140 mL) at 0 ° C. with sodium hydride (1.60 g). , 40.0 mmol) was added and stirred for 10 minutes. At the same temperature, trans-1,4-dibromo-2-butene (17.1 g, 80.0 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the solvent was distilled off from the organic layer. The residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)) to give methyl ((2E) -4-bromo-2-butenyloxy) acetate (yield 3.36 g). Yield 38%).
¹ H NMR (CDCl ₃ ) δ: 3.77 (3H, s), 3.96 (2H, d, J = 7.3 Hz), 4.09-4.13 (4H, m), 5.81- 6.04 (2H, m).

(Ii) Synthesis of 4-{[(2E) -4- (methoxycarbonylmethoxy) butenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one Step (i) of Example 80 and 4-{[2- (2-Ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (494 mg, 1.00 mmol) synthesized in the same manner as (ii) Is dissolved in methanol (7 mL), and an ethanol solution of sodium ethoxide (389 mg, sodium ethoxide concentration 21 wt%, sodium ethoxide amount 1.20 mmol) is added dropwise to this solution while cooling in a water bath. Stir for 50 minutes.

A methanol solution of ((2E) -4-bromo-2-butenyloxy) methyl acetate (268 mg, 1.20 mmol) obtained in the above step (i) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N (mol / L) hydrochloric acid and water was added. The obtained crystals were purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give 4-{[(2E) -4- (methoxycarbonylmethoxy) butenyl] thio}. Crystals of 2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 389 mg, yield 86%) were obtained.
mp 112-114 ° C
¹ H NMR (CDCl ₃ ) δ: 3.64 (2H, d, J = 6.9 Hz), 3.69 (3H, s), 3.91 (2H, s), 3.99 (2H, d, J = 4.9 Hz), 4.83 (2H, s), 5.57-5.89 (2H, m), 7.50 (1H, t, J = 7.6 Hz), 7.57 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.79 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.06 (2H, d, J = 8.6 Hz).

Example 91 Synthesis of 4-{[(2E) -4- (carboxymethoxy) butenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-{[(2E) -4- (methoxycarbonylmethoxy) butenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (90 mg, 0.20 mmol) obtained in Example 90 Is suspended in a mixed solvent of methanol (3 mL) and water (1 mL), 2N (mol / L) aqueous sodium hydroxide solution (0.1 mL, 0.20 mmol) is added to the suspension, and 5 ° C. is added. Stir for hours. The solvent was distilled off from the reaction mixture and acidified with 1N (mol / L) hydrochloric acid. By filtering the precipitate, 4-{[(2E) -4- (carboxymethoxy) butenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 84 mg, yield) 96%) crystals were obtained.
mp 89-91 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.81 (2H, d, J = 5.6 Hz), 3.84 (2H, s), 3.92 (2H, d, J = 4.3 Hz), 5.00 (2H, s), 5.65-5.82 (2H, m), 7.55 (1H, t, J = 7.6 Hz), 7.67 (1H, d, J = 7.6 Hz) ), 7.71 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 12.60. (1H, br).

Example 92 Synthesis of 4- (6-ethoxycarbonylhexylamino) -2- (4-methoxycarbonylphenyl) isoindoline-1-one
(I) Synthesis of methyl 2-methyl-3-nitrobenzoate To a solution of 2-methyl-3-nitrobenzoic acid (8.15 g, 45.00 mmol) in dimethylformamide (60 mL) was added potassium carbonate (6.91 g, 50 0.0000 mmol) and methyl iodide (7.81 g, 55.00 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, extracted three times with diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was recrystallized with a mixed solvent of n-hexane and ethyl acetate and dried to give methyl 2-methyl-3-nitrobenzoate (yield 6.38 g, yield 73%). Crystals were obtained.
mp 65-67 ° C
¹ H NMR (CDCl ₃ ) δ: 2.63 (3H, s), 3.94 (3H, s), 7.39 (1H, t, J = 8.1 Hz), 7.85 (1H, dd, J = 1.4 Hz, 8.1 Hz), 7.9 (1H, dd, J = 1.4 Hz, 8.1 Hz).

(Ii) Synthesis of 2- (4-methoxycarbonylphenyl) -4-nitroisoindoline-1-one Methyl 2-methyl-3-nitrobenzoate (4.88 g, 25.0 mmol) in carbon tetrachloride (60 mL) To the solution, N-bromosuccinimide (4.45 g, 25.0 mmol) and an aqueous benzoyl peroxide solution (water content 25 wt%, 300 mg) were added, and the mixture was heated to reflux for 7 hours. After allowing to cool, the reaction mixture was washed with water, and the solvent was distilled off to obtain methyl 2-bromomethyl-3-nitrobenzoate.

A solution of methyl 2-bromomethyl-3-nitrobenzoate and methyl 4-aminobenzoate (3.78 g, 25.0 mmol) in dimethylformamide (45 mL) was stirred at 60 ° C. for 30 minutes and further at 150 ° C. for 1 hour. . After allowing to cool, water was added to the reaction mixture, and the precipitate was collected by filtration and dried to give 2- (4-methoxycarbonylphenyl) -4-nitroisoindoline-1-one (yield 6.14 g, yield 77%). Crystal was obtained.
mp 255-257 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.87 (3H, s), 5.51 (2H, s), 7.88 (1H, t, J = 8.1 Hz), 8.04-8. 18 (4H, m), 8.27 (1H, dd, J = 1.1 Hz, 7.6 Hz), 8.52 (1H, dd, 1.1 Hz, 7.6 Hz).

(Iii) Synthesis of 4-amino-2- (4-methoxycarbonylphenyl) isoindoline-1-one 2- (4-methoxycarbonylphenyl) -4-nitroisoindoline-1-one (5.69 g, 18. 2 mmol) was added to methanol (200 mL) and ethyl acetate (100 mL), 10% palladium carbon (500 mg) was added to the resulting solution, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The precipitate was dissolved with dimethyl sulfoxide, filtered, and water was added to the filtrate. The precipitate was collected by filtration, washed with water and dried to give 4-amino-2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 4.80 g, yield 93%).
mp 233-236 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.85 (3H, s), 4.81 (2H, s), 5.59 (2H, s), 6.85 (1H, d, J = 7. 6 Hz), 6.98 (1 H, d, J = 7.6 Hz), 7.23 (1 H, t, J = 7.6 Hz), 8.04 (4 H, s).

(Iv) Synthesis of 4- (6-ethoxycarbonylhexylamino) -2- (4-methoxycarbonylphenyl) isoindoline-1-one 4-amino-2- (4-methoxycarbonylphenyl) isoindoline-1-one To a solution of (564 mg, 2.00 mmol) in dimethylformamide (5 mL) was added ethyl 7-bromoheptanoate (498 mg, 2.10 mmol), and the mixture was stirred at 120 ° C. for 30 minutes and further at 150 ° C. for 7 hours and a half. After allowing to cool, the reaction mixture was diluted with water, extracted three times with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to flash column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)) and (solvent dichloromethane / methanol = 100/1 to 60/1 (v / v)) and recrystallized with a mixed solvent of n-hexane and ethyl acetate to give 4- (6-ethoxycarbonylhexylamino) -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 138 mg). , Yield 16%).
mp 115-116 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.38-1.45 (2H, m), 1.65-1.74 (2H, m ), 2.33 (2H, t, J = 7.3 Hz), 3.25 (2H, br), 3.54 (1H, br), 3.92 (3H, s), 4.13 (2H, q, J = 7.3 Hz), 6.83 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.30 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.39 (1H, t, J = 7.8 Hz), 8.03 (2H, dt, J = 2.2 Hz, 9.2 Hz), 8.10 (2H, dt, J = 2.2 Hz, 9.2 Hz).

Example 93 Synthesis of 4- (7-methoxycarbonylheptanoylamino) -2- (4-methoxycarbonylphenyl) isoindoline-1-one
To a solution of 4-amino-2- (4-methoxycarbonylphenyl) isoindoline-1-one (564 mg, 2.00 mmol) in dimethylformamide (5 mL) was added methyl 8-chloro-8-oxooctanoate (434 mg, 2. 10 mmol) was added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the precipitate was filtered off. Recrystallization was performed using dimethylformamide and methanol to obtain 4- (7-methoxycarbonylheptanoylamino) -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 540 mg, yield 60%).
mp 156-158 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.41-1.53 (4H, m), 1.62-1.86 (4H, m), 2.35 (2H, t, J = 7.3 Hz) ), 2.47 (2H, t, J = 7.6 Hz), 3.68 (3H, s), 3.92 (3H, s), 4.91 (2H, s), 7.35 (1H, br), 7.50 (1H, t, J = 7.8 Hz), 7.59 (1H, dd, J = 1.1 Hz, 7.8 Hz), 7.79 (1H, dd, J = 1.1 Hz) , 7.8 Hz), 8.00 (2H, dt, J = 1.9 Hz, 8.9 Hz), 8.09 (2H, dt, J = 1.9 Hz, 8.9 Hz).

Example 94 Synthesis of 4- [N- (7-methoxycarbonylheptanoyl) -N-methylamino] -2- (4-methoxycarbonylphenyl) isoindoline-1-one
(I) Synthesis of 4-methylamino-2- (4-methoxycarbonylphenyl) isoindoline-1-one 4-amino-2- (4-methoxycarbonylphenyl) isoindoline-1-one (847 mg, 3.00 mmol) ) In dimethylformamide (20 mL) was added methyl iodide (468 mg, 3.30 mmol), potassium carbonate (456 mg, 3.30 mmol), and water, and the precipitate was collected by filtration. Water was added to the obtained filtrate, and the precipitate was collected by filtration. The obtained precipitates were combined, recrystallized with a mixed solvent of dimethylformamide and methanol, and 4-methylamino-2- (4-methoxycarbonylphenyl) isoindolin-1-one (yield 308 mg, yield 35%). Crystals were obtained.
mp 277-279 ° C
¹ H NMR (DMSO-d ₆ , 80 ° C.) δ: 2.85 (3H, d, J = 5.4 Hz), 3.85 (3H, s), 4.81 (2H, s), 5.66 (1H, br), 6.77 (1H, d, J = 7.6 Hz), 7.01 (1H, dd, J = 0.5 Hz, 7.6 Hz), 7.34 (1H, d, J = 7.6 Hz), 8.02 (4H, s).

(Ii) Synthesis of 4- [N- (7-methoxycarbonylheptanoyl) -N-methylamino] -2- (4-methoxycarbonylphenyl) isoindoline-1-one 4-Methylamino-2- (4- To a solution of methoxycarbonylphenyl) isoindoline-1-one (296 mg, 1.00 mmol) in dimethylformamide (30 mL) was added methyl 8-chloro-8-oxooctanoate (413 mg, 3.30 mmol) and stirred for 4 hours. . Water was added to the reaction mixture, the solution was made alkaline by adding potassium carbonate, and extracted three times with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give 4- [N- ( 7-methoxycarbonylheptanoyl) -N-methylamino] -2- (4-methoxycarbonylphenyl) isoindoline-1-one (yield 377 mg, 81% yield) was obtained.
mp 139-141 ° C
¹ H NMR (DMSO-d ₆ , 80 ° C.) δ: 1.20 (4H, br), 1.48-1.50 (4H, m), 2.11 (2H, br), 2.22 (2H , T, J = 7.3 Hz), 3.25 (3H, s), 3.56 (3H, s), 3.87 (3H, s), 4.99 (2H, s), 7.58- 7.67 (2H, m), 7.80 (1H, d, J = 6.8 Hz), 8.00-8.12 (4H, m).

Example 95 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of ethyl (3-bromomethylphenyl) acetate N-bromosuccinimide (1.78 g, 10.0 mmol) was added to a carbon tetrachloride (25 mL) solution of ethyl m-tolyl acetate (1.78 g, 10.0 mmol). ) And benzoyl peroxide (water content 25% by weight, 40 mg) were added and heated to reflux for 4 hours. After standing to cool, insolubles were removed and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give oily (3-bromomethylphenyl) ethyl acetate (yield 1 0.03 g, 40% yield).
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 3.61 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4. 48 (2H, s), 7.20-7.38 (4H, m).

(Ii) Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in the same manner as in Synthesis Example 3. To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (293 mg, 1.00 mmol) in dimethylformamide (7 mL), potassium carbonate (138 mg, 1.00 mmol) and the above (i) (3-Bromomethylphenyl) acetate obtained in step (309 mg, 1.20 mmol) was added, and the mixture was stirred at 50 ° C. for 1.5 hours. Water was added and the resulting residue was extracted with dichloromethane. Purification by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) gave 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4- Crystals of trifluoromethylphenyl) isoindoline-1-one (yield 327 mg, yield 70%) were obtained.
mp 117-119 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 3.66 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4. 85 (2H, s), 5.19 (2H, s), 7.13 (1H, d, J = 7.6 Hz), 7.22-7.42 (4H, m), 7.46 (1H, t, J = 7.6 Hz), 7.54 (1H, d, J = 7.6 Hz), 7.66 (2H, d, J = 8.9 Hz), 8.05 (2H, d, J = 8) .9 Hz).

Example 96 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (117 mg, 0.25 mmol) obtained in Example 95 A 2N aqueous sodium hydroxide solution (0.25 mL, 0.50 mmol) was added to a suspension of ethanol (5 mL) and water (1 mL), and the mixture was heated to reflux for 50 minutes. The solvent was distilled off and acidified with 1N hydrochloric acid. The resulting crystals were collected by filtration, and 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 107 mg, yield 97%). ) Crystals were obtained.
mp 182-184 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 5.05 (2H, s), 5.28 (2H, s), 7.25 (1H, dt, J = 1. 6 Hz, 7.3 Hz), 7.34-7.44 (5 H, m), 7.52 (1 H, t, J = 7.6 Hz), 7.78 (2 H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 12.41 (1H, brs).

Example 97 Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (494 mg, 1.00 mmol) in methanol (7 mL), a 21% sodium ethoxide ethanol solution (389 mg, 1.20 mmol) was added dropwise at a water temperature, and the mixture was stirred at room temperature for 50 minutes. A methanol solution of ethyl (3-bromomethylphenyl) acetate (309 mg, 1.20 mmol) obtained in Example 95 (i) was added, and the mixture was stirred at room temperature for 3 hours. Water was added and the resulting crystals were dried.

The dried crystals were dissolved in dichloromethane (3 mL) and ethanol (7 mL), 21% sodium ethoxide ethanol solution (324 mg, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. Water was added, and the obtained crystals were purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl. } Thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 220 mg, yield 45%) was obtained.
mp 106-108 ° C
¹ H NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.3 Hz), 3.53 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 4. 12 (2H, s), 4.50 (2H, s), 7.06 (1H, dt, J = 1.6 Hz, 7.3 Hz), 7.10-7.15 (2H, m), 7. 21 (1H, t, J = 7.3 Hz), 7.48 (1H, t, J = 7.6 Hz), 7.60 (1H, d, J = 7.6 Hz), 7.65 (2H, d) , J = 8.9 Hz), 7.79 (1H, d, J = 7.6 Hz), 7.97 (2H, d, J = 8.9 Hz).

Example 98 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (146 mg, 0.30 mmol) obtained in Example 97 To a suspension of ethanol (5 mL) and water (1 mL) was added 2N aqueous sodium hydroxide solution (0.3 mL, 0.60 mmol), and the mixture was heated to reflux for 40 minutes. The solvent was distilled off, and the solution was acidified by adding 1N hydrochloric acid while being heated to 50 ° C. The resulting crystals were collected by filtration, and 4-({[3- (carboxymethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 133 mg, yield 97%). ) Crystals were obtained.
mp 206-208 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.53 (2H, s), 4.34 (2H, s), 4.88 (2H, s), 7.11-7.28 (4H, m) 7.53 (1H, t, J = 7.6 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.72 (1H, d, J = 7.6 Hz), 7.79 ( 2H, d, J = 8.9 Hz), 8.15 (2H, d, J = 8.9 Hz), 12.33 (1H, br).

Example 99 Synthesis of 4- [4- (methoxycarbonylmethyloxy) butoxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of methyl [(2E) -4-bromo-2-butenyloxy] acetate A solution of methyl glycolate (3.60 g, 40.0 mmol) in tetrahydrofuran (140 mL) at 0 ° C. with sodium hydride (1.60 g). , 40.0 mmol) was added and stirred for 10 minutes. At the same temperature, trans-1,4-dibromo-2-butene (17.1 g, 80.0 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added, extracted with ethyl acetate, and the solvent was distilled off. The residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)) to give oily methyl [(2E) -4-bromo-2-butenyloxy] acetate (yield 3.36 g). Yield 38%).
¹ H NMR (CDCl ₃ ) δ: 3.77 (3H, s), 3.96 (2H, d, J = 7.3 Hz), 4.09-4.13 (4H, m), 5.81- 6.04 (2H, m).

(Ii) Synthesis of 4-{[(2E) -4- (methoxycarbonylmethyloxy) butenyl] oxy} -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in the same manner as in Synthesis Example 3. To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (151 mg, 0.52 mmol) obtained in dimethylformamide (5 mL), potassium carbonate (71 mg, 0.52 mmol) and the above ( Methyl [(2E) -4-bromo-2-butenyloxy] acetate (115 mg, 0.52 mmol) obtained in i) was added and stirred at 70 ° C. for 4 hours. Water was added, and the obtained crystals were purified by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give 4-{[(2E) -4- (methoxycarbonylmethyloxy). ) Butenyl] oxy} -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 144 mg, 64% yield) was obtained.
mp 128-130 ° C
¹ H NMR (CDCl ₃ ) δ: 3.77 (3H, s), 4.14 (2H, s), 4.16-4.19 (2H, m), 4.68-4.70 (2H, m), 4.84 (2H, s), 5.95-6.10 (2H, m), 7.06 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.46 (1H, t, J = 7.6 Hz), 7.53 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 8.06 (2H, d) , J = 8.6 Hz).

(Iii) Synthesis of 4- [4- (methoxycarbonylmethyloxy) butoxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one 4-{[(obtained in Example 99 (ii) 2E) -4- (methoxycarbonylmethyloxy) butenyl] oxy} -2- (4-trifluoromethylphenyl) isoindoline-1-one (566 mg, 1.30 mmol) in dichloromethane (5 mL), methanol (10 mL) 10% activated carbon-palladium (37 mg) was added to the suspension, and the mixture was stirred for 1 hour in a hydrogen atmosphere. After filtration, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent dichloromethane / methanol = 50/1 (v / v)) to give 4- [4- (methoxycarbonylmethyloxy) butoxy] -2- (4 Crystals of -trifluoromethylphenyl) isoindoline-1-one (yield 448 mg, yield 79%) were obtained.
mp 77-79 ° C
¹ H NMR (CDCl ₃ ) δ: 1.80-2.04 (4H, m), 3.64 (2H, t, J = 6.3 Hz), 3.76 (3H, s), 4.12 ( 2H, s), 4.16 (2H, t, J = 6.3 Hz), 4.82 (2H, s), 7.07 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7. 46 (1H, t, J = 7.6 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.67 (2H, d, J = 8.9 Hz), 8.07 (2H, d , J = 8.9 Hz).

Example 100 Synthesis of 4- [4- (carboxymethyloxy) butoxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one
4- [4- (methoxycarbonylmethyloxy) butoxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (131 mg, 0.30 mmol) methanol (5 mL) obtained in Example 99, A 2N aqueous sodium hydroxide solution (0.15 mL, 0.30 mmol) was added to a water (1 mL) suspension, and the mixture was stirred at 50 ° C. for 1 hour. The solvent was distilled off and acidified with 1N hydrochloric acid. The resulting crystals were collected by filtration to give 4- [4- (carboxymethyloxy) butoxy] -2- (4-trifluoromethylphenyl) isoindoline-1-one (121 mg, 95% yield). It was.
mp 107-108 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.67-1.91 (4H, m), 3.53 (2H, t, J = 6.3 Hz), 4.01 (2H, s), 4. 19 (2H, t, J = 6.3 Hz), 5.00 (2H, s), 7.31 (1H, d, J = 7.9 Hz), 7.38 (1H, d, J = 7.9 Hz) ), 7.52 (1H, t, J = 7.9 Hz), 7.78 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 12.64. (1H, br).

Example 101 Synthesis of (4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one (i) (4-hydroxymethylphenoxy ) Synthesis of ethyl acetate To a suspension of 4-hydroxybenzyl alcohol (1.24 g, 10.0 mmol) in acetonitrile (20 mL), potassium carbonate (1.52 g, 11.0 mmol) and ethyl bromoacetate (1.84 g, 11. The reaction mixture was left to cool, then added with water and extracted with ethyl acetate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / V)) to obtain an oily ethyl acetate (4-hydroxymethylphenoxy) acetate (yield 1.73 g, yield 82%). It was.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.61 (1H, t, J = 5.6 Hz), 4.27 (2H, q, J = 7) 3 Hz), 4.62-4.63 (4H, m), 6.87-6.93 (2H, m), 7.27-7.32 (2H, m).

(Ii) 4 - obtained in ({[4- (ethoxycarbonyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindolin -1-under ice cooling on, the (i) Triethylamine (210 mg, 2.08 mmol) and methanesulfonyl chloride (238 mg, 2.08 mmol) were added to a solution of the obtained ethyl (4-hydroxymethylphenoxy) acetate (336 mg, 1.60 mmol) in dichloromethane (10 mL). Stir for hours. Aqueous sodium hydrogen carbonate solution was added and extracted with dichloromethane. The solvent was distilled off from the obtained organic layer to obtain ethyl (4-chloromethylphenoxy) acetate.

4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (642 mg, 1.30 mmol) in ethanol (7 mL), a 21% sodium ethoxide ethanol solution (463 mg, 1.43 mmol) was added dropwise at a water temperature, and the mixture was stirred at room temperature for 40 minutes. (4-Chloromethylphenoxy) ethyl acetate was added, and the mixture was stirred overnight at room temperature. Water was added, and the obtained crystals were purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)), recrystallized with ethanol, and 4-({[4- ( Crystals of ethoxycarbonylmethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 352 mg, yield 54%) were obtained.
mp 134-136 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 4.10 (2H, s), 4.23 (2H, q, J = 7.3 Hz), 4. 50 (2H, s), 4.52 (2H, s), 6.77-6.83 (2H, m), 7.10-7.16 (2H, m), 7.48 (1H, t, J = 7.6 Hz), 7.57 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.79 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.97 (2H, d, J = 8.6 Hz).

Example 102 (Synthesis of 4-({[4- (carboxymethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one (150 mg, 0.30 mmol) obtained in Example 101 To a suspension of ethanol (3 mL) and water (1 mL) was added 2N aqueous sodium hydroxide solution (0.30 mL, 0.60 mmol), and the mixture was stirred at 50 ° C. for 3 hours and then at 60 ° C. for 1 hour. At the same temperature, 1N hydrochloric acid was added to make it acidic. The resulting crystals were collected by filtration, and 4-({[4- (carboxymethoxy) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 113 mg, yield 80%). ) Crystals were obtained.
mp 240-243 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.11 (2H, s), 4.30 (2H, s), 4.91 (2H, s), 6.73 (2H, d, J = 8. 6 Hz), 7.23 (2 H, d, J = 8.6 Hz), 7.53 (1 H, t, J = 7.6 Hz), 7.64 (1 H, d, J = 7.6 Hz), 7. 71 (1H, d, J = 7.6 Hz), 7.79 (2H, d, J = 8.6 Hz), 8.15 (2H, d, J = 8.6 Hz).

Example 103 Synthesis of 4-({3- [3- (ethoxycarbonylmethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (987 mg, 2.00 mmol) in ethanol (15 mL), a 21% sodium ethoxide ethanol solution (746 μL, 2.0 mmol) was added dropwise at a water temperature, and the mixture was stirred at room temperature for 1.5 hours. [3- (3-Bromopropyl) phenoxy] ethyl acetate (723 mg, 2.40 mmol) obtained in step (iii) of Example 87 was added, and the mixture was stirred at room temperature for 6 and a half hours. Water was added, and after refrigeration overnight, the obtained crystals were recrystallized with a mixed solvent of ethanol and water to give 4-({3- [3- (ethoxycarbonylmethoxy) phenyl] propyl} thio) -2- (4- Crystals of trifluoromethylphenyl) isoindoline-1-one (yield 237 mg, yield 22%) were obtained. Further, recrystallization from the mother liquor gave 4-({3- [3- (ethoxycarbonylmethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 225 mg, A yield of 21%) was obtained.
mp 89-90 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.01 (2H, quin, J = 7.3 Hz), 2.76 (2H, t, J = 7) .3 Hz), 3.01 (2H, t, J = 7.3 Hz), 4.26 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 4.79 (2H, s) ), 6.69-6.82 (3H, m), 7.20 (1H, t, J = 7.8 Hz), 7.47-7.49 (2H, m), 7.69 (2H, d) , J = 8.3 Hz), 7.74-7.77 (1H, m), 8.06 (2H, d, J = 8.3 Hz).

Example 104 Synthesis of 4-({3- [3- (ethoxycarbonylmethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one
To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (440 mg, 1.50 mmol) obtained in the same manner as in Synthesis Example 3 in dimethylformamide (2 mL), potassium carbonate (452 mg) , 1.80 mmol) and [3- (3-bromopropyl) phenoxy] ethyl acetate (249 mg, 1.80 mmol) obtained in step (iii) of Example 87 were added and stirred at 70 ° C. for 5 hours. After allowing to cool, water was added and extraction was performed 3 times with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give 4-({3- [3- (ethoxycarbonylmethoxy ) Phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 605 mg, 79% yield) was obtained.
mp 98-100 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.14-2.24 (2H, m), 2.83 (2H, t, J = 7.6 Hz) ), 4.11 (2H, t, J = 6.2 Hz), 4.25 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 4.78 (2H, s), 6.71-6.75 (1H, m), 6.83-6.87 (2H, m), 7.00-7.03 (1H, m), 7.21 (1H, d, J = 7) .6 Hz), 7.44 (1 H, t, J = 7.6 Hz), 7.50-7.52 (1 H, m), 7.68 (2 H, d, J = 8.4 Hz), 8.07 (2H, d, J = 8.4 Hz).

Example 105 Synthesis of 4-({3- [3- (carboxymethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-({3- [3- (Ethoxycarbonylmethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (268 mg, 0.52 mmol) obtained in Example 104. ) In aqueous sodium hydroxide (1.0 mL, 2.00 mmol) and ethanol (5 mL) at 70 ° C. for 1 hour. After adding water and neutralizing with concentrated hydrochloric acid, the precipitate was collected by filtration, washed with water and dried to give 4-({3- [3- (carboxymethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethyl). Crystals of phenyl) isoindoline-1-one (yield 246 mg, yield 97%) were obtained.
mp 83-87 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.13-2.34 (2H, m), 2.83 (2H, t, J = 7.6 Hz), 4.11 (2H, t, J = 6) .2 Hz), 4.62 (2 H, s), 4.77 (2 H, s), 6.74-6.81 (2 H, m), 6.89 (1 H, d, J = 8.1 Hz), 7.00-7.02 (1H, m), 7.21-7.26 (1H, m), 7.43 (1H, t, J = 7.6 Hz), 7.49-7.52 (1H M), 7.67 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.4 Hz).

Example 106 (4 - ({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one Synthesis of (i) [3- ( Synthesis of 2-hydroxyethyl) phenylthio] ethyl acetate Tris (dibenzylideneacetone) in 1,4-dioxane (20 mL) solution of 3-bromophenethyl alcohol (402 mg, 2.00 mmol) and diisopropylethylamine (517 mg, 4.00 mmol) Add dipalladium (0) (46 mg, 0.05 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (58 mg, 0.10 mmol), ethyl mercaptoacetate (264 mg, 2.20 mmol) Heated to reflux for 1 hour, left to cool, The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 to 1/1 (v / v)), and [3- (2-hydroxyethyl) phenylthio] A yellow oil of ethyl acetate (Yield 323 mg, Yield 67%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.3 Hz), 2.84 (2H, t, J = 6.5 Hz), 3.63 (2H, s), 3. 85 (2H, t, J = 6.5 Hz), 4.17 (2H, q, J = 7.3 Hz), 7.09 (1H, dt, J = 2.2 Hz, 6.8 Hz), 7.21 -7.28 (2H, m).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Triethylamine (121 mg, 1.20 mmol) and methanesulfonyl chloride (137 mg, 1.20 mmol) were added to a solution of ethyl [3- (2-hydroxyethyl) phenylthio] acetate (240 mg, 1.00 mmol) obtained in 1 above in dichloromethane (3 mL). And stirred at 0 ° C. for 15 minutes. After diluting with water, an aqueous sodium hydrogen carbonate solution is added. After extraction with dichloromethane, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)). , Ethyl 3- (2-methanesulfonyloxyethyl) phenylthioacetate was obtained.

To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (293 mg, 1.00 mmol) obtained in the same manner as in Synthesis Example 3 in dimethylformamide (3 mL), potassium carbonate (166 mg, 1.20 mmol) and ethyl 3- (2-methanesulfonyloxyethyl) phenylthioacetate were added and stirred at 70 ° C. for 30 minutes. After adding water and extracting with dichloromethane, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give 4-({2- [ Crystals of 3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 277 mg, yield 54%) were obtained.
mp 127-129 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.08 (3H, t, J = 7.3 Hz), 3.08 (2H, t, J = 6.8 Hz), 3.89 (2H, s), 4.02 (2H, q, J = 7.3 Hz), 4.36 (2H, t, J = 6.8 Hz), 4.92 (2H, s), 7.20-7.40 (6H, m ), 7.51 (1H, t, J = 7.6 Hz), 7.80 (2H, d, J = 8.9 Hz), 8.17 (2H, d, J = 8.9 Hz).

Example 107 Synthesis of 4-({2- [3- (carboxymethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (150 mg, 0.29 mmol) obtained in Example 106. ) Was stirred in aqueous sodium hydroxide (0.3 mL, 0.60 mmol) and ethanol (5 mL) at 50 ° C. for 1 hour. Water was added and neutralized with concentrated hydrochloric acid, and the precipitate was collected by filtration. Recrystallized with a mixed solvent of dimethylformamide, ethanol and water, and 4-({2- [3- (carboxymethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Crystals (yield 95 mg, 67% yield) were obtained.
mp 180-182 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.8 Hz), 3.82 (2H, s), 4.36 (2H, t, J = 6.8 Hz), 4.94 (2H, s), 7.18-7.40 (6H, m), 7.51 (1H, t, J = 7.6 Hz), 7.80 (2H, d, J = 8.9 Hz) ), 8.18 (2H, d, J = 8.9 Hz), 12.78 (1H, br).

Example 108 (Synthesis of 2- (4-trifluoromethylphenyl) -4-({2- [3- (methanesulfonylcarbamoylmethoxy) phenyl] ethyl} oxy) isoindoline-1-one)
4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 69 (198 mg, 0.42 mmol) In dichloromethane (4 mL), triethylamine (64 mg, 0.63 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (121 mg, 0.63 mmol), 4-dimethylaminopyridine (5. 0 mg, 0.04 mmol) and methanesulfonamide (60 mg, 0.63 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent dichloromethane / ethanol = 20/1 (v / v)) to give 2- (4-trifluoromethylphenyl) -4-({2- [3 Crystals of-(methanesulfonylcarbamoylmethoxy) phenyl] ethyl} oxy) isoindoline-1-one (yield 107 mg, 47%) were obtained.
mp 214-216 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.08 (2H, t, J = 6.8 Hz), 3.22 (3H, s), 4.36 (2H, t, J = 6.8 Hz), 4.69 (2H, s), 4.93 (2H, s), 6.76-6.80 (1H, m), 6.97-6.99 (2H, m), 7.25 (1H, t, J = 7.6 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.39 (1H, d, J = 7.8 Hz), 7.51 (1H, t, J = 7) .8 Hz), 7.80 (2H, d, J = 9.2 Hz), 8.15 (2H, d, J = 9.2 Hz).

Example 109 (2- (4-trifluoromethylphenyl) -4-({2- [3- (methanesulfonylcarbamoylmethyl) phenyl] ethyl} oxy) isoindoline-1-one)
4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 78 (99 mg, 0.22 mmol) Of triethylamine (44 mg, 0.43 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (83 mg, 0.43 mmol), 4-dimethylaminopyridine (2. 6 mg, 0.02 mmol) and methanesulfonamide (41 mg, 0.43 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent dichloromethane / ethanol = 20/1 (v / v)) to give 2- (4-trifluoromethylphenyl) -4-({2- [3 Crystals of-(methanesulfonylcarbamoylmethyl) phenyl] ethyl} oxy) isoindoline-1-one (54 mg, 47% yield) were obtained.
mp 171-173 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.10 (2H, t, J = 6.6 Hz), 3.17 (3H, s), 3.61 (2H, s), 4.37 (2H, t, J = 6.6 Hz), 4.94 (2H, s), 7.12-7.15 (1H, m), 7.28-7.40 (5H, m), 7.51 (1H, t, J = 7.9 Hz), 7.79 (2H, d, J = 8.9 Hz), 8.17 (2H, d, J = 8.9 Hz), 11.93 (1H, s).

Example 110 Synthesis of 4-({2- [4- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
(I) Synthesis of diethyl 1,4-phenylenediacetic acid A suspension of 1,4-phenylenediacetic acid (5.83 g, 30.0 mmol) in hydrobromic acid-ethanol (60 mL) was heated to reflux for 1.5 hours. After allowing to cool, water was added and extracted with dichloromethane. The solvent was distilled off to obtain a stoichiometric crystal of diethyl 1,4-phenylenediacetate (7.51 g).
mp 57-59 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.3 Hz), 3.59 (4H, s), 4.14 (4H, q, J = 7.3 Hz), 7. 24 (4H, s).

(Ii) Synthesis of [4- (ethoxycarbonylmethyl) phenyl] acetic acid To a solution of diethyl 1,4-phenylenediacetate (7.51 g, 30.0 mmol) in ethanol (24 mL) was added potassium hydroxide (1.68 g, 30. 0 mmol) in ethanol (24 mL) was added dropwise and stirred at room temperature for 2 hours. The solvent was distilled off to remove insoluble matters. Water was added, washed with diethyl ether, and concentrated hydrochloric acid was added to the resulting aqueous layer to make it acidic. Extraction with ethyl acetate was performed, and the solvent was distilled off to obtain crystals of [4- (ethoxycarbonylmethyl) phenyl] acetic acid (yield 2.28 g, yield 34%).
mp 68-70 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 3.59 (2H, s), 3.64 (2H, s), 4.14 (2H, q, J = 7.3 Hz), 7.25 (4H, s).

(Iii) Synthesis of 4- (ethoxycarbonylmethyl) phenethyl alcohol To a solution of [4- (ethoxycarbonylmethyl) phenyl] acetic acid (2.28 g, 10.26 mmol) in tetrahydrofuran (50 mL) was added borane-tetrahydrofuran complex (12.0 mL, 12.31 mmol) was added dropwise and stirred at room temperature for 3 hours. Water was added and acidified with concentrated hydrochloric acid. Extraction with ethyl acetate and purification by flash column chromatography (solvent n-hexane / ethyl acetate = 1/2 (v / v)) gave oily 4- (ethoxycarbonylmethyl) phenethyl alcohol (yield 1.68 g, yield). 79%).
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 1.44 (1H, t, J = 6.3 Hz), 2.85 (2H, t, J = 6) .3 Hz), 3.59 (2H, s), 3.85 (2H, q, J = 6.3 Hz), 4.15 (2H, q, J = 7.3 Hz), 7.17-7.26. (4H, m).

(Iv) Synthesis of 4-({2- [4- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one (iii) under ice-cooling Triethylamine (935 mg, 9.24 mmol) and methanesulfonyl chloride (1.06 g, 9.24 mmol) were added to a solution of 4- (ethoxycarbonylmethyl) phenethyl alcohol (1.60 g, 7.70 mmol) obtained in 1) in dichloromethane (30 mL). And stirred at 0 ° C. for 1 hour. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, and then the solvent was distilled off. Ethyl 4- (methanesulfonyloxyethyl) phenylacetate (yield 2.16 g, yield 98%) Got.

To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (352 mg, 1.20 mmol) obtained in the same manner as in Synthesis Example 3 in dimethylformamide (6 mL), potassium carbonate (182 mg , 1.32 mmol) and ethyl 4- (methanesulfonyloxyethyl) phenylacetate (378 mg, 1.32 mmol) were added, and the mixture was stirred at 70 ° C. overnight. After allowing to cool, water was added, and the obtained crystals were purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-({2- [4- (ethoxy Crystals of carbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 357 mg, yield 62%) were obtained.
mp 94-96 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 3.15 (2H, t, J = 6.9 Hz), 3.60 (2H, s), 4. 13 (2H, q, J = 7.3 Hz), 4.31 (2H, t, J = 6.9 Hz), 4.74 (2H, s), 7.05 (1H, d, J = 7.6 Hz) ), 7.26-7.27 (4H, m), 7.44 (1H, t, J = 7.6 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.68 (2H) , D, J = 8.9 Hz), 8.04 (2H, d, J = 8.9 Hz).

Example 111 Synthesis of 4-({2- [4- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [4- (Ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (193 mg, 0.40 mmol) obtained in Example 110. ) Was added to a suspension of ethanol (5 mL) and water (2 mL), 2N aqueous sodium hydroxide solution (0.40 mL, 0.80 mmol) was added, and the mixture was heated to reflux for 1 hour. After allowing to cool, the solvent was distilled off, 1N hydrochloric acid was added, and the resulting crystals were collected by filtration to give 4-({2- [4- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoro). Crystals of methylphenyl) isoindoline-1-one (yield 179 mg, yield 98%) were obtained.
mp 156-158 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.08 (2H, t, J = 6.9 Hz), 3.52 (2H, s), 4.36 (2H, t, J = 6.9 Hz), 4.94 (2H, s), 7.21 (2H, d, J = 7.9 Hz), 7.29-7.40 (4H, m), 7.51 (1H, t, J = 7.6 Hz) ), 7.80 (2H, d, J = 8.6 Hz), 8.16 (2H, d, J = 8.6 Hz), 12.27 (1H, br).

Example 112 Synthesis of 4-({2- [4- (ethoxycarbonylmethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
Under ice-cooling, triethylamine (935 mg, 9.24 mmol) and methanesulfonyl were added to a solution of 4- (ethoxycarbonylmethyl) phenethyl alcohol (1.60 g, 7.70 mmol) obtained in Example 110 (iii) in dichloromethane (30 mL). Chloride (1.06 g, 9.24 mmol) was added and stirred at 0 ° C. for 1 hour. An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with water, and then the solvent was distilled off. Ethyl 4- (methanesulfonyloxyethyl) phenylacetate (yield 2.16 g, yield 98%) Got.

4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (592 mg, 1.20 mmol) in ethanol (7 mL), a 21% sodium ethoxide ethanol solution (389 mg, 1.20 mmol) was added dropwise at a water temperature, and the mixture was stirred at room temperature for 1 hour. 4- (Methanesulfonyloxyethyl) phenyl acetate ethyl acetate (412 mg, 1.44 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added, and the obtained crystals were purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-({2- [4- (ethoxycarbonylmethyl) phenyl]. ] Ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 436 mg, yield 73%) was obtained.
mp 119-120 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 2.93-2.99 (2H, m), 3.25-3.31 (2H, m), 3.57 (2H, s), 4.14 (2H, q, J = 7.3 Hz), 4.74 (2H, s), 7.13-7.24 (4H, m), 7.47- 7.52 (1H, m), 7.55 (1H, dd, J = 1.6 Hz, 7.9 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.76 (1H, dd) , J = 1.6 Hz, 6.9 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 113 Synthesis of 4-({2- [4- (carboxymethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({2- [4- (Ethoxycarbonylmethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (200 mg, 0.40 mmol) obtained in Example 112. ) Was added to a suspension of ethanol (5 mL) and water (2 mL), 2N aqueous sodium hydroxide solution (0.40 mL, 0.80 mmol) was added, and the mixture was heated to reflux for 1 hour. At the same temperature, 1N hydrochloric acid is added to acidify, and the resulting crystals are collected by filtration to give 4-({2- [4- (carboxymethyl) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl). Crystals of isoindoline-1-one (yield 182 mg, yield 96%) were obtained.
mp 152-154 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.91 (2H, t, J = 7.6 Hz), 3.39 (2H, t, J = 7.6 Hz), 3.52 (2H, s), 4.95 (2H, s), 7.16-7.24 (4H, m), 7.57 (1H, t, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz) ), 7.75 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 8.17 (2H, d, J = 8.6 Hz), 12.29 (1H, s).

Example 114 Synthesis of (4-({[4- (ethoxycarbonylmethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one (i) (4-Bromomethylphenyl ) Synthesis of ethyl acetate N-bromosuccinimide (1.78 g, 10.0 mmol) and benzoyl peroxide (water content 25) were added to a solution of ethyl p-tolylacetate (1.78 g, 10.0 mmol) in carbon tetrachloride (25 mL). (Weight%, 62 mg) was added, and the mixture was heated to reflux for 2 hours, allowed to cool, then insolubles were removed, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 4/1 (v / v)), Crystals of ethyl (4-bromomethylphenyl) acetate (yield 1.02 g, yield 39%) were obtained.
mp 34-36 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 3.60 (2H, s), 4.15 (2H, q, J = 7.3 Hz), 4. 48 (2H, s), 7.24-7.28 (2H, m), 7.33-7.38 (2H, m).

(Ii) Synthesis of 4-({[4- (ethoxycarbonylmethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindolin-1-one Example 80, steps (i) and ( 4-{[2- (2-Ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one (592 mg, 1.20 mmol) obtained as in ii) 21% sodium ethoxide ethanol solution (448 mg, 1.20 mmol) was added dropwise to an ethanol (10 mL) solution at a water temperature, and the mixture was stirred at room temperature for 1 hour. A methanol solution of ethyl (4-bromomethylphenyl) acetate (401 mg, 1.56 mmol) obtained in (i) above was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added, and the obtained crystals were purified by flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give 4-({[4- (ethoxycarbonylmethyl) phenyl] methyl. } Thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 324 mg, yield 56%) was obtained.
mp 150-152 ° C
¹ H NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.3 Hz), 3.52 (2H, s), 4.08 (2H, q, J = 7.3 Hz), 4. 13 (2H, s), 4.52 (2H, s), 7.14-7.21 (4H, m), 7.48 (1H, t, J = 7.6 Hz), 7.58 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.79 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.96 (2H, d, J = 8.6 Hz).

Example 115 (Synthesis of 4-({[4- (carboxymethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (ethoxycarbonylmethyl) phenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (194 mg, 0.40 mmol) obtained in Example 114 To a suspension of ethanol (3 mL) and water (1 mL) was added 2N aqueous sodium hydroxide solution (0.20 mL, 0.40 mmol), and the mixture was heated to reflux at 50 ° C. for 2 hours and then for 1 hour. The solvent was distilled off, 1N hydrochloric acid was added at 70 ° C. to make it acidic, and the resulting crystals were collected by filtration to give 4-({[4- (carboxymethyl) phenyl] methyl} thio) -2- (4-trifluoro. Crystals of methylphenyl) isoindoline-1-one (yield 170 mg, yield 93%) were obtained.
mp 143-145 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.51 (2H, s), 4.36 (2H, s), 4.92 (2H, s), 7.19 (2H, d, J = 8. 2 Hz), 7.33 (2 H, d, J = 8.2 Hz), 7.53 (1 H, t, J = 7.6 Hz), 7.65 (1 H, d, J = 7.6 Hz), 7. 72 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.9 Hz), 8.15 (2H, d, J = 8.9 Hz), 12.27 (1H, br) ).

Example 116 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-difluoromethoxyphenyl) isoindoline-1-one)
(I) Synthesis of 2- (4-difluoromethoxyphenyl) -4-hydroxyisoindoline-1-one Methyl 3-acetoxy-2-methylbenzoate (1.04 g) obtained in step (i) of Synthesis Example 3 , 5.0 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (890 mg, 5.0 mmol) and benzoyl peroxide (12 mg), and the mixture was heated to reflux for 2 hours. After standing to cool, insoluble matters were filtered off, and the solvent was distilled off to obtain methyl 3-acetoxy-2-bromomethylbenzoate.

A solution of methyl 3-acetoxy-2-bromomethylbenzoate and 4-difluoromethoxyaniline (622 μL, 5.0 mmol) in N, N-dimethylformamide (10 mL) at 60 ° C. for 1 hour and then at 150 ° C. for 1.25 hours. did. After allowing to cool, potassium carbonate (691 mg, 5.0 mmol) and methanol (10 mL) were added, and the mixture was stirred overnight at room temperature. After neutralizing with 1N hydrochloric acid, water was added, and the resulting crystals were dried to give 2- (4-difluoromethoxyphenyl) -4-hydroxyisoindoline-1-one (yield 1.17 g, yield 80.6). %) Crystals.
mp 243-245 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.88 (2H, s), 7.22 (1H, t, J = 73.4 Hz), 7.06 (1H, d, J = 8.1 Hz), 7.25-7.39 (4H, m), 7.95 (2H, d, J = 8.9 Hz), 10.25 (1H, s).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-difluoromethoxyphenyl) isoindolin-1-one Step of Example 68 under ice cooling Triethylamine (818 μL, 5.9 mmol) and methanesulfonyl chloride (460 μL) were added to a solution of ethyl [3- (2-hydroxyethyl) phenoxy] acetate (1.0 g, 4.5 mmol) obtained in (i) in dichloromethane (20 mL). , 5.9 mmol) and stirred at 0 ° C. for 1.5 hours. Aqueous sodium hydrogen carbonate solution was added, extraction was performed with dichloromethane, and the solvent was distilled off from the obtained organic layer to obtain [3- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate.

To a solution of 2- (4-difluoromethoxyphenyl) -4-hydroxyisoindoline-1-one (1.19 g, 4.1 mmol) in N, N-dimethylformamide (25 mL) and potassium carbonate (622 mg, 4.5 mmol) [3- (2-Methanesulfonyloxyethyl) phenoxy] ethyl acetate was added, and the mixture was stirred at 70 ° C. overnight. After the reaction, the solvent was concentrated, 2N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Flash column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) was followed by recrystallization with ethanol, and 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl } Oxy) -2- (4-difluoromethoxyphenyl) isoindoline-1-one (yield 300 mg, yield 14.7%) was obtained.
mp 120-123 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.17 (3H, t, J = 7.3 Hz), 3.06 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.3 Hz), 4.36 (2H, t, J = 6.5 Hz), 4.76 (2H, s), 4.86 (2H, s), 6.76-7.37 (9H, m) ), 7.50 (1H, t, J = 7.6 Hz), 7.95 (2H, d, J = 9.2 Hz).

Example 117 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-difluoromethoxyphenyl) isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-difluoromethoxyphenyl) isoindoline-1-one (100 mg, 0.2 mmol) obtained in Example 116 2N aqueous sodium hydroxide solution (5 mL) was added to a suspension of ethanol (5 mL) and water (3 mL), and the mixture was stirred at 70 ° C. for 6 hours. Insolubles were filtered off, the solvent was distilled off, and neutralized with 1N hydrochloric acid. The obtained crystals were recrystallized from ethanol and stoichiometrically 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-difluoromethoxyphenyl) isoindoline-1- On (98 mg) crystals were obtained.
mp 152-155 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.5 Hz), 4.35 (2H, t, J = 6.5 Hz), 4.67 (2H, s), 4.88 (2H, s), 6.77-7.38 (9H, m), 7.50 (1H, t, J = 8.0 Hz), 7.96 (2H, d, J = 8.9 Hz) ), 12.96 (1H, br).

Example 118 Synthesis of 4-((E) -2-ethoxycarbonylethenyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one
To a solution of 4-bromo-2- (4-trifluoromethylphenyl) isoindoline-1-one (356 mg, 1.00 mmol) obtained in step (vi) of Example 81 in dimethylformamide (5 mL) was triethylamine (121 mg). , 1.10 mmol), tris (dibenzylideneacetone) dipalladium (0) (23 mg, 0.025 mmol), tri-o-tolylphosphine (30 mg, 0.10 mmol), ethyl acrylate (190 μL, 1.75 mmol). In addition, the mixture was stirred at 110 ° C. for 1 hour. After allowing to cool, the mixture was filtered through celite, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by flash column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)) to give 4-((E) -2-ethoxycarbonylethenyl. ) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 255 mg, 68% yield) was obtained.
mp 147-150 ° C
¹ H NMR (CDCl ₃ ) δ: 1.38 (3H, t, J = 7.3 Hz), 4.33 (2H, q, J = 7.3 Hz), 5.02 (2H, s), 6. 51 (1H, d, J = 16.2 Hz), 7.59 (1 H, t, J = 7.8 Hz), 7.71 (2H, d, J = 8.4 Hz), 7.79 (1H, d , J = 16.2 Hz), 7.83 (1H, d, J = 7.8 Hz), 7.97 (1H, dd, J = 1.1 Hz, 7.8 Hz), 8.08 (2H, d, J = 8.4 Hz).

Example 119 (Synthesis of 4- (2-ethoxycarbonylethyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-((E) -2-ethoxycarbonylethenyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one (700 mg, 1.86 mmol) obtained in Example 118 was added to ethanol (50 mL). And ethyl acetate (50 mL), 10% activated carbon-palladium (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 3.5 hours. After filtration, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)) to give 4- (2-ethoxycarbonylethyl)- A white solid of 2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 540 mg, 77% yield) was obtained.
mp 76-78 ° C
¹ H NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.3 Hz), 2.74 (2H, t, J = 7.3 Hz), 3.05 (2H, t, J = 7) .3 Hz), 4.13 (2H, q, J = 7.3 Hz), 4.91 (2H, s), 7.43-7.52 (2H, m), 7.69 (2H, d, J = 8.6 Hz), 7.80 (1H, dd, J = 2.0 Hz, 6.9 Hz), 8.07 (2H, d, J = 8.6 Hz).

Example 120 Synthesis of (4- [3- (4-Ethoxycarbonylmethoxy-3-methylphenylthio) propyl] -2- (4-trifluoromethylphenyl) isoindolin-1-one (i) 4- (3 Synthesis of -hydroxypropyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (2-ethoxycarbonylethyl) -2- (4-trifluoromethylphenyl) obtained in Example 119 Isoindoline-1-one (500 mg, 1.32 mmol) was mixed with dehydrated methanol (5 mL) and dehydrated dichloromethane (5 mL), and to this mixture was added lithium borohydride (662 mg, 30.39 mmol) over 4 hours. The mixture was diluted with water, neutralized with concentrated hydrochloric acid, and the resulting solid was collected by filtration. Purified by chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) and 4- (3-hydroxypropyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one ( A white solid having a yield of 316 mg and a yield of 71% was obtained.
mp 157-160 ° C
¹ H NMR (CDCl ₃ ) δ: 1.36 (1H, t, J = 4.9 Hz), 1.93-2.03 (2H, m), 2.86 (2H, t, J = 7.8 Hz) ), 3.73 (2H, q, J = 5.1 Hz), 4.88 (2H, S), 7.45-7.52 (2H, m), 7.68 (2H, d, J = 8) 0.9 Hz), 7.79 (1H, dd, J = 2.7 Hz, 6.2 Hz), 8.06 (2H, d, J = 8.9 Hz).

(Ii) Synthesis of 4- (3-bromopropyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (3-hydroxypropyl) -2 obtained in the step (i) above To a solution of-(4-trifluoromethylphenyl) isoindoline-1-one (350 mg, 1.04 mmol) in tetrahydrofuran (10 mL) under ice cooling, carbon tetrabromide (519 mg, 1.57 mmol) and triphenylphosphine ( 412 mg, 1.57 mmol) was added and stirred for 1 hour. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give 4- (3-bromopropyl) -2- (4 -Trifluoromethylphenyl) isoindoline-1-one (yield 258 mg, 62% yield) was obtained.
mp 107-108 ° C
¹ H NMR (CDCl ₃ ) δ: 2.22-2.32 (2H, m), 2.93 (2H, t, J = 7.3 Hz), 3.47 (2H, t, J = 6.2 Hz) ), 7.45-7.50 (2H, m), 7.69 (2H, d, J = 8.6 Hz), 7.82 (1H, dd, J = 1.9 Hz, 7.0 Hz), 8 .06 (2H, d, J = 8.6 Hz).

(Iii) Synthesis of 4- [3- (4-ethoxycarbonylmethoxy-3-methylphenylthio) propyl] -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in the step (ii) above. The obtained 4- (3-bromopropyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one (251 mg, 0.63 mmol) in acetonitrile (5 mL) was obtained in Example 62 (ii). 4-Mercapto-2-methylphenol (210 mg, 1.50 mmol) and cesium carbonate (489 mg, 1.50 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution were added ethyl bromoacetate (418 mg, 2.50 mmol) and cesium carbonate (882 mg, 2.50 mmol), and the mixture was stirred at 50 ° C. overnight. Water was added and extracted three times with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)) to give 4- [3- (4-ethoxycarbonylmethoxy-3 -Methylphenylthio) propyl] -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 243 mg, 71% yield) was obtained.
mp 105-106 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 1.93-2.05 (2H, m), 2.24 (3H, s), 2.84- 2.91 (4H, m), 4.25 (2H, q, J = 7.3 Hz), 4.58 (2H, s), 4.78 (2H, s), 6.60 (1H, d, J = 8.6 Hz), 7.13-7.19 (2H, m), 7.41 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.47 (1H, t, J = 7) .6 Hz), 7.69 (2H, d, J = 8.6 Hz), 7.79 (1H, dd, J = 1.4 Hz, 7.6 Hz), 8.03 (2H, d, J = 8. 6 Hz).

Example 121 Synthesis of 4- [3- (4-carboxymethoxy-3-methylphenylthio) propyl] -2- (4-trifluoromethylphenyl) isoindolin-1-one
4- [3- (4-Ethoxycarbonylmethoxy-3-methylphenylthio) propyl] -2- (4-trifluoromethylphenyl) isoindoline-1-one (178 mg, 0.33 mmol) obtained in Example 120 ) In ethanol (3 mL) was added 2N aqueous sodium hydroxide solution (2 mL, 2.0 mmol) and stirred at room temperature for 1 hour. Ethanol was distilled off, water was added and neutralized with concentrated hydrochloric acid. The obtained crystals were collected by filtration, and 4- [3- (4-carboxymethoxy-3-methylphenylthio) propyl] -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 142 mg, yield). 84%) of crystals were obtained.
mp 123-124 ° C
¹ H NMR (CDCl ₃ ) δ: 1.94-2.04 (2H, m), 2.22 (3H, s), 2.83-2.91 (4H, m), 4.62 (2H, s), 4.76 (2H, s), 6.61 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 2.2 Hz, 8.9 Hz), 7.19 ( 1H, d, J = 1.4 Hz), 7.40 (1H, dd, J = 1.4 Hz, 7.6 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.68 (2H , D, J = 8.6 Hz), 7.78 (1H, dd, J = 1.4 Hz, 7.3 Hz), 8.01 (2H, d, J = 8.6 Hz).

Example 122 Synthesis of 4-({3- [3- (cyanomethyl) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of ethyl (E) -3- [3- (cyanomethyl) phenyl] acrylate To a solution of 3-bromobenzyl cyanide (1.96 g, 10.0 mmol) in dimethylformamide (10 mL), triethylamine (1.11 g) , 11.0 mmol), tris (dibenzylideneacetone) dipalladium (0) (458 mg, 0.50 mmol), tri-o-tolylphosphine (304 mg, 1.00 mmol), ethyl acrylate (2.18 mL, 20.0 mmol) ) And stirred at 110 ° C. for 3 hours. After standing to cool, water was added and the mixture was filtered through celite. The mixture was extracted with n-hexane / ethyl acetate = 1/1 and purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to obtain (E) -3- [3- ( Crystals of ethyl cyanomethyl) phenyl] acrylate (yield 1.94 g, yield 90%) were obtained.
mp 68-70 ° C
¹ H NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.3 Hz), 3.78 (2H, s), 4.27 (2H, q, J = 7.3 Hz), 6. 47 (1H, d, J = 16.2 Hz), 7.33-7.51 (4H, m), 7.66 (1 H, d, J = 16.2 Hz).

(Ii) Synthesis of ethyl 3- [3- (cyanomethyl) phenyl] propionate (E) -3- [3- (cyanomethyl) phenyl] ethyl acrylate (1.61 g, 7.50 mmol) in dichloromethane (4 mL), Activated carbon-palladium (100 mg) was added to an ethanol (20 mL) solution, and the mixture was stirred under a hydrogen atmosphere for 6 hours. Filtration and evaporation of the solvent gave oily ethyl 3- [3- (cyanomethyl) phenyl] propionate (yield 1.49 g, 91% yield).
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 2.62 (2H, t, J = 7.6 Hz), 2.96 (2H, t, J = 7) .6 Hz), 3.72 (2H, s), 4.13 (2H, q, J = 7.3 Hz), 7.16-7.33 (4H, m).

(Iii) Synthesis of [3- (3-hydroxypropyl) phenyl] acetonitrile Sodium 3-borohydride in a solution of ethyl 3- [3- (cyanomethyl) phenyl] propionate (1.48 g, 6.81 mmol) in ethanol (15 mL) (1.03 g, 27.2 mmol) was added and stirred for 2 days. Water was added, ethanol was distilled off, and concentrated hydrochloric acid was added to make it acidic. Extraction with ethyl acetate and purification by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) gave oily [3- (3-hydroxypropyl) phenyl] acetonitrile (yield 848 mg, Yield 71%).
¹ H NMR (CDCl ₃ ) δ: 1.31 (1H, t, J = 5.3 Hz), 1.84 to 1.94 (2H, m), 2.73 (2H, t, J = 7.6 Hz) ), 3.65-3.71 (2H, m), 3.73 (2H, s), 7.14-7.33 (4H, m).

(Iv) Synthesis of 4-({3- [3- (cyanomethyl) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in (iii) above under ice cooling. Triethylamine (158 mg, 1.56 mmol) and methanesulfonyl chloride (179 mg, 1.56 mmol) were added to a solution of [3- (3-hydroxypropyl) phenyl] acetonitrile (210 mg, 1.20 mmol) in dichloromethane (7 mL). Stir at 0 ° C. for 20 minutes. Aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The solvent was distilled off from the obtained organic layer to obtain [3- (3-methanesulfonyloxypropyl) phenyl] acetonitrile.

4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (494 mg, 1.00 mmol) in ethanol (7 mL), a 21% sodium ethoxide ethanol solution (356 mg, 1.10 mmol) was added dropwise at water temperature, and the mixture was stirred at room temperature for 50 minutes. [3- (3-Methanesulfonyloxypropyl) phenyl] acetonitrile was added and stirred at room temperature overnight. Water was added, and the obtained crystals were purified by silica gel column chromatography (solvent dichloromethane / ethanol = 50/1 (v / v)) to give 4-({3- [3- (cyanomethyl) phenyl] propyl} thio) Crystals of 2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 373 mg, yield 80%) were obtained.
mp 102-104 ° C
¹ H NMR (CDCl ₃ ) δ: 2.02 (2H, quin, J = 7.3 Hz), 2.80 (2H, t, J = 7.3 Hz), 3.02 (2H, t, J = 7) 3 Hz), 3.72 (2H, s), 4.80 (2H, s), 7.13-7.16 (3H, m), 7.26-7.33 (1H, m), 7. 46-7.52 (2H, m), 7.68 (2H, d, J = 8.6 Hz), 7.72-7.79 (1H, m), 8.06 (2H, d, J = 8) .6 Hz).

Example 123 Synthesis of 4-({3- [3- (carboxymethyl) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({3- [3- (cyanomethyl) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (140 mg, 0.30 mmol) obtained in Example 122 A solution of acetic acid (5 mL) and 47% hydrobromic acid (2 mL) was stirred at 70 ° C. overnight. 47% hydrobromic acid (2 mL) was added, and the mixture was further stirred at 70 ° C. overnight. After allowing to cool, water was added and filtered, and the residue was dissolved in dichloromethane. The organic layer was washed with water and purified by silica gel column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)) to give 4-({3- [3- (carboxymethyl) phenyl] propyl} thio) -2. Crystals of-(4-trifluoromethylphenyl) isoindoline-1-one (yield 98 mg, 67%) were obtained.
mp 130-132 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.91 (2H, quin, J = 7.3 Hz), 2.73 (2H, t, J = 7.3 Hz), 3.11 (2H, t, J = 7.3 Hz), 3.52 (2H, s), 4.98 (2H, s), 7.05-7.09 (3H, m), 7.22 (1 H, t, J = 7.6 Hz) ), 7.51-7.57 (1H, m), 7.63-7.66 (2H, m), 7.80 (2H, d, J = 8.6 Hz), 8.18 (2H, d) , J = 8.6 Hz), 12.30 (1H, brs).

Example 124 Synthesis of 4-({3- [4- (ethoxycarbonylmethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of [4- (3-hydroxypropyl) phenoxy] ethyl acetate To a solution of 3- (4-hydroxyphenyl) -1-propanol (1.00 g, 6.57 mmol) in acetonitrile (15 mL) was added potassium carbonate (999 mg). 7.23 mmol) and ethyl bromoacetate (1.21 g, 7.23 mmol) were added, and the mixture was heated to reflux for 3 hours. Add water, extract with ethyl acetate, purify by flash column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)), oily [4- (3-hydroxypropyl) phenoxy] acetic acid Ethyl (yield 1.42 g, yield 91%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.80-1.91 (2H, m), 2.65 (2H, t, J = 7.6 Hz) ), 3.66 (2H, t, J = 6.6 Hz), 4.27 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 6.81-6.86 (2H) , M), 7.09-7.14 (2H, m).

(Ii) Synthesis of 4-({3- [4- (ethoxycarbonylmethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Under ice-cooling, Synthesis Example 3 and 2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (119 mg, 0.50 mmol) obtained in the same manner, [4- (3-hydroxypropyl) obtained in (i) above. ) Phenoxy] Ethyl acetate (147 mg, 0.50 mmol), Triphenylphosphine (170 mg, 0.65 mmol) in toluene (3 mL) suspension in azodicarboxylate diethyltoluene solution (0.27 mL, 0.60 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. The solvent was distilled off, and ethyl acetate (2 mL) and hexane (3 mL) were added. The insoluble material was filtered off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), dried and 4-({3- [4- (ethoxycarbonylmethoxy). ) Phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (221 mg, 86% yield) was obtained.
mp 80-82 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.11-2.21 (2H, m), 2.80 (2H, t, J = 7.6 Hz) ), 4.11 (2H, t, J = 6.3 Hz), 4.27 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 4.78 (2H, s), 6.83-6.89 (2H, m), 7.02 (1H, d, J = 7.6 Hz), 7.12-7.17 (2H, m), 7.41-7.52 (2H M), 7.68 (2H, d, J = 8.9 Hz), 8.06 (2H, d, J = 8.9 Hz).

Example 125 Synthesis of 4-({3- [4- (carboxymethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({3- [4- (Ethoxycarbonylmethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (128 mg, 0.25 mmol) obtained in Example 124. ) Was added to a suspension of ethanol (5 mL) and water (1 mL), and 2N aqueous sodium hydroxide solution (0.25 mL, 0.50 mmol) was added, and the mixture was heated to reflux for 40 minutes. The solvent was distilled off, 1N hydrochloric acid was added to make it acidic, and the resulting crystals were collected by filtration to give 4-({3- [4- (carboxymethoxy) phenyl] propyl} oxy) -2- (4-trifluoromethyl). Crystals of phenyl) isoindoline-1-one (yield 117 mg, yield 96%) were obtained.
mp 151-153 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.01-2.11 (2H, m), 2.75 (2H, t, J = 6.9 Hz), 4.14 (2H, t, J = 6) 3 Hz), 4.62 (2H, s), 5.00 (2H, s), 6.81-6.86 (2H, m), 7.15-7.20 (2H, m), 7. 27 (1 H, dd, J = 0.7 Hz, 7.9 Hz), 7.38 (1 H, dd, J = 0.7 Hz, 7.9 Hz), 7.51 (1 H, t, J = 7.9 Hz) 7.80 (2H, d, J = 8.6 Hz), 8.20 (2H, d, J = 8.6 Hz), 12.94 (1H, brs).

Example 126 Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) -4-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 3-methoxy-4-methylbenzoic acid To a solution of methyl 3-methoxy-4-methylbenzoate (1.80 g, 10.0 mmol) in methanol (12 mL) and water (3 mL), 2N aqueous sodium hydroxide solution (6.0 mL, 12.0 mmol) was added, and the mixture was heated to reflux for 1 hour. The solvent was distilled off, and concentrated hydrochloric acid was added to make it acidic. The resulting crystals were collected by filtration and dried to obtain crystals of 3-methoxy-4-methylbenzoic acid (yield 1.42 g, yield 86%). .
mp 159-161 ° C
¹ H NMR (CDCl ₃ ) δ: 2.29 (3H, s), 3.90 (3H, s), 7.22 (1H, d, J = 7.6 Hz), 7.53 (1H, d, J = 1.3 Hz), 7.64 (1H, dd, J = 1.3 Hz, 7.6 Hz).

(Ii) Synthesis of (3-methoxy-4-methylphenyl) methanol A solution of 3-methoxy-4-methylbenzoic acid (1.41 g, 8.47 mmol) in tetrahydrofuran (20 mL) under ice-cooling borane-tetrahydrofuran complex ( 9.86 mL, 10.16 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 hours and a half. Methanol was added, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give oily (3-methoxy-4-methylphenyl) methanol ( Yield 1.24 g, 97% yield).
¹ H NMR (CDCl ₃ ) δ: 1.64 (1H, t, J = 5.9 Hz), 2.21 (3H, s), 3.84 (3H, s), 4.65 (2H, d, J = 5.9 Hz), 6.83 (1 H, d, J = 7.6 Hz), 6.86 (1 H, s), 7.11 (1 H, d, J = 7.6 Hz).

(Iii) Synthesis of (3-methoxy-4-methylphenyl) acetonitrile (3-methoxy-4-methylphenyl) methanol (913 mg, 6.00 mmol), acetone cyanohydrin (1.22 mL, 12.0 mmol) under ice cooling To a solution of triphenylphosphine (2.05 g, 7.80 mmol) in toluene (30 mL) was added dropwise a solution of diethyl azodicarboxylate (3.27 mL, 7.20 mmol) at 0 ° C. for 1 hour and then at room temperature for 2 hours. Half stirred. The solvent was distilled off, and ethyl acetate (6 mL) and hexane (9 mL) were added. Insoluble matter was filtered off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 3/1 (v / v)), dried and oily (3-methoxy-4-methylphenyl) acetonitrile. (Yield 680 mg, yield 70%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.72 (2H, s), 3.84 (3H, s), 6.76 (1H, s), 6.79 (1H , D, J = 7.6 Hz), 7.11 (1H, d, J = 7.6 Hz).

(Iv) Synthesis of (3-hydroxy-4-methylphenyl) acetic acid (3-methoxy-4-methylphenyl) acetonitrile (882 mg, 5.47 mmol) in acetic acid (3 mL) and 47% hydrobromic acid (2 mL) Was stirred at 70 ° C. for 3.5 hours. Thereafter, 47% hydrobromic acid (22 mL) and acetic acid (3 mL) were gradually added, and the mixture was stirred at 70 ° C. for 4 days. After cooling, water is added, extracted with dichloromethane, purified by silica gel column chromatography (solvent dichloromethane / ethanol = 10/1 (v / v)), dried and (3-hydroxy-4-methylphenyl) acetic acid. Crystals (yield 755 mg, yield 83%) were obtained.
mp 108-110 ° C
¹ H NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.56 (2H, s), 6.71 (1H, s), 6.75 (1H, d, J = 7.6 Hz) 7.07 (1H, d, J = 7.6 Hz).

(V) Synthesis of 5- (2-hydroxyethyl) -2-methylphenol Borane tetrahydrofuran was added to a solution of (3-hydroxy-4-methylphenyl) acetic acid (731 mg, 4.40 mmol) in tetrahydrofuran (10 mL) under ice-cooling. The complex (5.1 mL, 5.28 mmol) was added dropwise, and the mixture was stirred at room temperature for 9 hours. Borane-tetrahydrofuran complex (2.6 mL, 2.64 mmol) was added, and the mixture was stirred overnight at room temperature. Methanol was added, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)) to give oily 5- (2-hydroxyethyl) -2-methyl. Phenol (yield 623 mg, yield 93%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.63 (1H, brs), 2.22 (3H, s), 2.79 (2H, t, J = 6.3 Hz), 3.84 (2H, t, J = 6.3 Hz), 5.07 (1H, s), 6.71 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.05 (1H, d, J = 7.6 Hz).

(Vi) Synthesis of [5- (2-hydroxyethyl) -2-methylphenoxy] ethyl acetate To a solution of 5- (2-hydroxyethyl) -2-methylphenol (609 mg, 4.00 mmol) in acetonitrile (12 mL), Potassium carbonate (608 mg, 4.40 mmol) and ethyl bromoacetate (735 mg, 4.40 mmol) were added, and the mixture was heated to reflux for 6 hours. After allowing to cool, water was added, the mixture was extracted with ethyl acetate, purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)), dried and [5- (2-hydroxy Ethyl) -2-methylphenoxy] ethyl acetate (yield 776 mg, yield 81%) was obtained.
mp 67-69 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.39 (1H, t, J = 6.3 Hz), 2.26 (3H, s), 2. 81 (2H, t, J = 6.3 Hz), 3.82 (2H, q, J = 6.3 Hz), 4.27 (2H, q, J = 7.3 Hz), 4.64 (2H, s ), 6.58 (1H, d, J = 1.6 Hz), 6.77 (1H, dd, J = 1.6 Hz, 7.6 Hz), 7.10 (1H, d, J = 7.6 Hz) .

(Vii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) -4-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one under ice-cooling, 2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (235 mg, 0.80 mmol) obtained in the same manner as in Synthesis Example 3, obtained in the above (vi) [5- ( 2-Hydroxyethyl) -2-methylphenoxy] ethyl acetate (191 mg, 0.80 mmol), triphenylphosphine (273 mg, 1.04 mmol) in toluene (5 mL) suspension in diethyl azodicarboxylate toluene solution (0.44 mL) , 0.96 mmol) was added dropwise and stirred at 0 ° C. for 30 minutes and then at room temperature overnight. The solvent was distilled off, and ethyl acetate (6 mL) and hexane (9 mL) were added. The insoluble material was filtered off, and the residue was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), dried and 4-({2- [3- (ethoxycarbonylmethoxy). ) -4-Methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 325 mg, yield 79%) was obtained.
mp 120-122 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.27 (3H, s), 3.09 (2H, t, J = 6.9 Hz), 4. 22 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 6.9 Hz), 4.64 (2H, s), 4.74 (2H, s), 6.65 ( 1H, d, J = 1.0 Hz), 6.84 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.05 (1H, d, J = 7.6 Hz), 7.12 (1H , D, J = 7.6 Hz), 7.42-7.53 (2H, m), 7.68 (2H, d, J = 8.9 Hz), 8.06 (2H, d, J = 8. 9 Hz).

Example 127 Synthesis of 4-({2- [3- (carboxymethoxy) -4-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) -4-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (154 mg) obtained in Example 126. , 0.30 mmol) in ethanol (5 mL) and water (1 mL) was added 2N aqueous sodium hydroxide solution (0.3 mL, 0.60 mmol), and the mixture was heated to reflux for 80 minutes. The solvent was distilled off, 1N hydrochloric acid was added to acidify, and the resulting crystals were collected by filtration and dried to give 4-({2- [3- (carboxymethoxy) -4-methylphenyl] ethyl} oxy) -2. Crystals of-(4-trifluoromethylphenyl) isoindoline-1-one (yield 142 mg, yield 98%) were obtained.
mp 169-171 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.15 (3H, s), 3.03 (2H, t, J = 6.6 Hz), 4.33 (2H, t, J = 6.6 Hz), 4.72 (2H, s), 4.93 (2H, s), 6.84-6.87 (2H, m), 7.09 (1H, d, J = 7.6 Hz), 7.33 ( 1H, d, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.79 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 12.97 (1 H, brs).

Example 128 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) -4-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
Under ice-cooling, triethylamine (158 mg, 1) was added to a solution of [5- (2-hydroxyethyl) -2-methylphenoxy] ethyl acetate (286 mg, 1.20 mmol) obtained in Example 126 (vi) in dichloromethane (7 mL). .56 mmol) and methanesulfonyl chloride (179 mg, 1.56 mmol) were added, and the mixture was stirred at 0 ° C. for 20 minutes. Aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The solvent was distilled off from the obtained organic layer to obtain [5- (2-methanesulfonyloxyethyl) -2-methylphenoxy] ethyl acetate.

4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (494 mg, 1.00 mmol) in ethanol (7 mL), a 21% sodium ethoxide ethanol solution (324 mg, 1.00 mmol) was added dropwise at a water temperature, and the mixture was stirred at room temperature for 1 hour. [5- (2-Methanesulfonyloxyethyl) -2-methylphenoxy] ethyl acetate was added, and the mixture was stirred overnight at room temperature. Water was added and the obtained crystals were recrystallized from dichloromethane and ethanol to give 4-({2- [3- (ethoxycarbonylmethoxy) -4-methylphenyl] ethyl} thio) -2- (4-trifluoromethyl). Crystals of phenyl) isoindoline-1-one (yield 232 mg, yield 44%) were obtained.
mp 152-154 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 2.92 (2H, t, J = 7.6 Hz), 3. 26 (2H, t, J = 7.6 Hz), 4.24 (2H, q, J = 7.3 Hz), 4.60 (2H, s), 4.73 (2H, s), 6.53 ( 1H, d, J = 1.3 Hz), 6.72 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.07 (1H, d, J = 7.6 Hz), 7.48-7 .57 (2H, m), 7.68 (2H, d, J = 8.9 Hz), 7.77 (1H, dd, J = 1.3 Hz, 6.9 Hz), 8.05 (2H, d, J = 8.9 Hz).

Example 129 (Synthesis of 4-({2- [3- (carboxymethoxy) -4-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) -4-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 128 (106 mg , 0.20 mmol) in ethanol (10 mL) and water (5 mL) was added 2N aqueous sodium hydroxide solution (0.2 mL, 0.40 mmol), and the mixture was heated to reflux for 1 hour. The solvent was distilled off, 1N hydrochloric acid was added to make it acidic, and the resulting crystals were collected by filtration and dried to give 4-({2- [3- (carboxymethoxy) -4-methylphenyl] ethyl} thio) -2. Crystals of-(4-trifluoromethylphenyl) isoindoline-1-one (yield 99 mg, yield 98%) were obtained.
mp 185-187 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.13 (3H, s), 2.88 (2H, t, J = 7.6 Hz), 3.34 (2H, t, J = 7.6 Hz), 4.60 (2H, s), 4.90 (2H, s), 6.72-6.75 (2H, m), 7.01 (1H, d, J = 7.6 Hz), 7.55 ( 1H, t, J = 7.6 Hz), 7.66 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.71 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7 .76 (2H, d, J = 8.9 Hz), 8.14 (2H, d, J = 8.9 Hz).

Example 130 Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
Under ice-cooling, triethylamine (541 μL, 3.9 mmol) and chloride were added to a solution of [4- (2-hydroxyethyl) phenoxy] ethyl acetate (673 mg, 3.0 mmol) synthesized in Example 70 (i) in dichloromethane (10 mL). Methanesulfonyl (304 μL, 3.9 mmol) was added, and the mixture was stirred at 0 ° C. for 1.5 hours. Aqueous sodium hydrogen carbonate solution was added, extraction was performed with dichloromethane, and the solvent was distilled off from the obtained organic layer to obtain [4- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate.

  4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 Sodium ethoxide (1.1 mL, 2.8 mmol) was gradually added to a solution of 1-one (1.2 g, 2.5 mmol) in ethanol (25 mL) in a water bath and stirred for 1 hour.

A solution of [4- (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate in ethanol (10 mL) was added, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was concentrated, 2N hydrochloric acid was added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was flushed. Column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)), followed by recrystallization from ethanol, 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} Thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 434 mg, yield 33.7%) was obtained.
mp 140-144 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.92 (2H, t, J = 7.3 Hz), 3.26 (2H, t, J = 7.0 Hz), 4.26 (2H, q, J = 7.0 Hz), 4.58 (2H, s), 4.73 (2H, s), 6.83-6.86 (2H, m) ), 7.09-7.12 (2H, m), 7.50-7.54 (2H, m), 7.67-7.78 (3H, m), 8.04 (2H, d, J) = 8.4 Hz).

Example 131 Synthesis of 4-({2- [4- (carboxymethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({2- [4- (Ethoxycarbonylmethoxy) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 130 (100 mg, 0.19 mmol) ) In ethanol (5 mL) and water (1 mL) was added 2N aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at 70 ° C. for 6 hours. After acidifying with 1N hydrochloric acid, the resulting crystals were collected by filtration, recrystallized with ethanol, and 4-({2- [4- (carboxymethoxy) phenyl] ethyl} thio) -2- (4-trifluoro). Crystals of methylphenyl) isoindoline-1-one (yield 30 mg, yield 32%) were obtained.
mp 104-108 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.93 (2H, t, J = 7.3 Hz), 3.27 (2H, t, J = 7.6 Hz), 4.63 (2H, s), 4.72 (2H, s), 6.84 (2H, d, J = 8.9 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.47-7.56 (2H, m ), 7.67-7.78 (3H, m), 8.04 (2H, d, J = 8.6 Hz).

Example 132 Synthesis of 4-({3- [4- (ethoxycarbonylmethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
Under ice cooling, triethylamine (651 μL, 4.7 mmol) was added to a solution of ethyl [4- (3-hydroxypropyl) phenoxy] ethyl acetate (858 mg, 3.6 mmol) synthesized in Step (i) of Example 124 in dichloromethane (15 mL). And methanesulfonyl chloride (366 μL, 4.7 mmol) were added, and the mixture was stirred at 0 ° C. for 1.5 hours. Aqueous sodium hydrogen carbonate solution was added, extraction was performed with dichloromethane, and the solvent was distilled off from the obtained organic layer to obtain [4- (3-methanesulfonyloxypropyl) phenoxy] ethyl acetate.

  4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (1.48 g, 3.0 mmol) in ethanol (50 mL), sodium ethoxide (1.2 mL, 3.3 mmol) was gradually added in a water bath and stirred for 1 hour.

A solution of [4- (3-methanesulfonyloxypropyl) phenoxy] ethyl acetate in ethanol (10 mL) was added, and the mixture was stirred overnight at room temperature. After the reaction, the solvent was concentrated, 2N hydrochloric acid was added, extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was flushed. Column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) followed by recrystallization from ethanol, 4-({3- [4- (ethoxycarbonylmethoxy) phenyl] propyl} Thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 221 mg, yield 13.9%) was obtained.
mp 90-94 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.20 (3H, t, J = 7.0 Hz), 1.82-1.92 (2H, m), 2.68 (2H, t, J = 7) .3 Hz), 3.09 (2H, t, J = 7.3 Hz), 4.15 (2H, q, J = 6.8 Hz), 4.71 (2H, s), 4.98 (2H, s) ), 6.83 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.55-7.82 (5H, m), 8.18 (2H) , D, J = 8.6 Hz).

Example 133 Synthesis of 4-({3- [4- (carboxymethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-({3- [4- (Ethoxycarbonylmethoxy) phenyl] propyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (160 mg, 0.3 mmol) obtained in Example 132 ) In ethanol (2 mL) was added 2N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 70 ° C. for 6 hours. After acidifying with 1N hydrochloric acid, the resulting crystals were collected by filtration, recrystallized with ethanol, and 4-({3- [4- (carboxymethoxy) phenyl] propyl} thio) -2- (4-trifluoro). Crystals of methylphenyl) isoindoline-1-one (yield 72 mg, yield 76%) were obtained.
mp 236-239 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.83-1.93 (2H, m), 2.67 (2H, t, J = 7.3 Hz), 3.09 (2H, t, J = 7) .0Hz), 4.56 (2H, s), 4.97 (2H, s), 6.80 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz) ), 7.54-7.65 (3H, m), 8.00 (2H, d, J = 8.9 Hz), 8.09 (2H, d, J = 8.9 Hz).

Example 134 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Ethyl (4-formyl-2-methylphenoxy) acetate A solution of 4-hydroxy-3-methylbenzaldehyde (884 mg, 6.49 mmol) in acetonitrile (25 mL) was added potassium carbonate (987 mg, 7.14 mmol) and bromoacetic acid. Ethyl (1.30 g, 7.79 mmol) was added and heated to reflux for 1 hour. After allowing to cool, water was added, extracted with ethyl acetate, purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)), dried and oily (4-formyl- 2-Methylphenoxy) ethyl acetate (yield 1.37 g, yield 95%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.35 (3H, s), 4.28 (2H, q, J = 7.3 Hz), 4. 73 (2H, s), 6.79 (1H, d, J = 8.6 Hz), 7.67-7.71 (2H, m), 9.87 (1H, s).

(Ii) Synthesis of ethyl 2- [4- (hydroxymethyl) -2-methylphenoxy] acetate A solution of ethyl (4-formyl-2-methylphenoxy) acetate (646 mg, 2.88 mmol) in tetrahydrofuran (10 mL) was cooled with ice. Underneath, borane-tetrahydrofuran complex (2.8 mL, 2.88 mmol) was added dropwise and stirred at 0 ° C. for 2 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off to obtain oily ethyl 2- [4- (hydroxymethyl) -2-methylphenoxy] acetate (yield 639 mg, yield 99%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.52-1.56 (1H, m), 2.30 (3H, s), 4.26 ( 2H, q, J = 7.3 Hz), 4.59 (2H, d, J = 4.6 Hz), 4.64 (2H, s), 6.69 (1H, d, J = 8.2 Hz), 7.12 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.18 (1H, d, J = 2.0 Hz).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis example under ice-cooling 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (293 mg, 1.00 mmol), 2- [4- (hydroxymethyl) -2-methylphenoxy obtained in the same manner as in Example 3 To a suspension of ethyl acetate (247 mg, 1.10 mmol) and triphenylphosphine (341 mg, 1.30 mmol) in toluene (7 mL) was added dropwise a solution of diethyl azodicarboxylate in toluene (0.55 mL, 1.20 mmol). Stir at <RTIgt; 30 C </ RTI> for 30 minutes and then at room temperature overnight. The solvent was distilled off, and ethyl acetate (6 mL) and hexane (9 mL) were added. The insoluble material was filtered off and purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 1/1 (v / v)), and further silica gel column chromatography (solvent dichloromethane / ethanol = 40/1 (v / V)). After drying, 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 145 mg, 29% yield) ) Crystals were obtained.
mp 147-149 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 2.33 (3H, s), 4.28 (2H, q, J = 7.3 Hz), 4. 67 (2H, s), 4.82 (2H, s), 5.09 (2H, s), 6.73 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 8.2 Hz), 7.21 (1 H, dd, J = 2.0 Hz, 8.2 Hz), 7.26 (1 H, m), 7.44-7.55 (2 H, m), 7.66 ( 2H, d, J = 8.9 Hz), 8.05 (2H, d, J = 8.9 Hz).

Example 135 Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 134 (100 mg, 0 .20 mmol) in ethanol (5 mL) and water (3 mL) suspension was added 2N aqueous sodium hydroxide solution (0.2 mL, 0.40 mmol) and heated to reflux for 30 minutes. After the solvent was distilled off, the residue was acidified with 1N hydrochloric acid, and the resulting crystals were collected by filtration and dried to give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4 Crystals of -trifluoromethylphenyl) isoindoline-1-one (94 mg) were obtained stoichiometrically.
mp 178-180 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.68 (2H, s), 5.00 (2H, s), 5.16 (2H, s), 6.83 (1H, d, J = 7.9 Hz), 7.28-7.31 (2H, m), 7.38-7.41 (2H, m), 7.52 (1H, t, J = 7. 3 Hz), 7.77 (2H, d, J = 8.9 Hz), 8.19 (2H, d, J = 8.9 Hz).

Example 136 Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
Under ice cooling, triethylamine (158 mg, 1) was added to a solution of ethyl 2- [4- (hydroxymethyl) -2-methylphenoxy] acetate (269 mg, 1.20 mmol) obtained in Example 134 (ii) in dichloromethane (7 mL). .56 mmol) and methanesulfonyl chloride (179 mg, 1.56 mmol) were added, and the mixture was stirred at 0 ° C. for 25 minutes. Aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The solvent was distilled off from the obtained organic layer to obtain ethyl (4-chloromethyl-2-methylphenoxy) acetate.

4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 To a solution of 1-one (494 mg, 1.00 mmol) in ethanol (7 mL), a 21% sodium ethoxide ethanol solution (324 mg, 1.00 mmol) was added dropwise at a water temperature, and the mixture was stirred at room temperature for 50 minutes. (4-Chloromethyl-2-methylphenoxy) ethyl acetate was added, and the mixture was stirred overnight at room temperature. Water was added, the mixture was extracted with dichloromethane, purified by silica gel column chromatography (solvent dichloromethane / ethanol = 40/1 (v / v)), and further silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 ( v / v)) and purified by 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 201 mg, yield 39%) of crystals were obtained.
mp 123-125 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 4.07 (2H, s), 4.22 (2H, q, J = 7.3 Hz), 4.48 (2H, s), 4.50 (2H, s), 6.55 (1H, d, J = 8.6 Hz), 6.91 (1H, dd, J = 2.3 Hz, 8.6 Hz), 7.03 (1 H, d, J = 2.3 Hz), 7.49 (1 H, t, J = 7.6 Hz), 7.59 (1 H, d, J = 7) .6 Hz), 7.67 (2H, d, J = 8.9 Hz), 7.79 (1H, d, J = 7.6 Hz), 7.96 (2H, d, J = 8.9 Hz).

Example 137 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 136 (103 mg, 0 .20 mmol) in ethanol (5 mL) and water (3 mL) was added 2N aqueous sodium hydroxide (0.2 mL, 0.40 mmol), and the mixture was heated to reflux for 1 hour. After the solvent was distilled off, the residue was acidified with 1N hydrochloric acid, and the resulting crystals were collected by filtration and dried to give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} thio) -2- (4 Crystals of -trifluoromethylphenyl) isoindoline-1-one (yield 76 mg, yield 78%) were obtained.
mp 173-175 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.14 (3H, s), 4.27 (2H, s), 4.62 (2H, s), 4.87 (2H, s), 6.74 (1H, d, J = 9.2 Hz), 7.11-7.14 (2H, m), 7.55 (1H, t, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz), 7.72 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 8.15 (2H, d, J = 8.6 Hz).

Example 138 (Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 1-methoxy-4- (2-methoxyvinyl) -2-methylbenzene Suspension of (methoxymethyl) triphenylphosphonium chloride (13.71 g, 40.0 mmol) in tetrahydrofuran (100 mL) under ice-cooling To the solution was added dropwise bis (trimethylsilyl) amido sodium tetrahydrofuran solution (40 mL, 40.0 mmol), and the mixture was stirred at 0 ° C. for 20 minutes. 4-Methoxy-3-methylbenzaldehyde (6.01 g, 40.0 mmol) was added dropwise, stirred at 0 ° C. for 20 minutes, and stirred at room temperature for 6 hours. Water was added, extracted with ethyl acetate, and the solvent was distilled off. The precipitated crystals were separated by filtration, and the filtrate was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 10/1 (v / v)) to give oily 1-methoxy-4- (2-methoxy Vinyl) -2-methylbenzene (yield 6.25 g, yield 88%) was obtained.
E-isomer: ¹ H NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.66 (3H, s), 3.81 (3H, s), 5.76 (1H, d, J = 12.9 Hz), 6.72-6.77 (1H, m), 6.92 (1 H, d, J = 12.9 Hz), 7.00-7.03 (1 H, m), 7.36- 7.40 (1H, m)
Z-isomer: ¹ H NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.75 (3H, s), 3.81 (3H, s), 5.14 (1H, d, J = 6.9 Hz), 6.03 (1H, d, J = 6.9 Hz), 6.72-6.77 (1H, m), 7.00-7.03 (1H, m), 7.36- 7.40 (1H, m).

(Ii) Synthesis of 1-methoxy-4- (2-methoxyethyl) -2-methylbenzene Methanol of 1-methoxy-4- (2-methoxyvinyl) -2-methylbenzene (6.23 g, 35.0 mmol) Activated carbon-palladium (222 mg) was added to the (100 mL) solution, and the mixture was stirred overnight under a hydrogen atmosphere. After filtration and evaporation of the solvent, extraction with dichloromethane gave oily 1-methoxy-4- (2-methoxyethyl) -2-methylbenzene (yield 6.03 g, yield 96%).
¹ H NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.80 (2H, t, J = 7.3 Hz), 3.35 (3H, s), 3.56 (2H, t, J = 7.3 Hz), 3.80 (3H, s), 6.75 (1H, d, J = 7.9 Hz), 6.99-7.03 (2H, m).

(Iii) Synthesis of 4- (2-bromoethyl) -2-methylphenol 1-methoxy-4- (2-methoxyethyl) -2-methylbenzene (507 mg, 2.81 mmol) in acetic acid (3 mL) and 47% odor The hydrofluoric acid (5 mL) solution was stirred at 80 ° C. overnight, and further stirred at 100 ° C. for 1.5 hours. After allowing to cool, water was added, extracted with dichloromethane, purified by silica gel column chromatography (solvent dichloromethane / ethanol = 30/1 (v / v)), and 4- (2-bromoethyl) -2-methylphenol (yield). 356 mg, 59% yield) were obtained.
mp 62-64 ° C
¹ H NMR (CDCl ₃ ) δ: 2.24 (3H, s), 3.06 (2H, t, J = 7.6 Hz), 3.52 (2H, t, J = 7.6 Hz), 4. 66 (1H, s), 6.72 (1H, d, J = 7.9 Hz), 6.92 (1H, dd, J = 2.0 Hz, 7.9 Hz), 6.96 (1H, d, J = 2.0 Hz).

(Iv) Synthesis of [4- (2-bromoethyl) -2-methylphenoxy] ethyl acetate To a solution of 4- (2-bromoethyl) -2-methylphenol (860 mg, 4.00 mmol) in acetonitrile (20 mL) was added potassium carbonate. (553 mg, 4.00 mmol) and ethyl bromoacetate (2.00 g, 12.00 mmol) were added, and the mixture was stirred at 70 ° C. for 9 hours. After allowing to cool, water was added, the mixture was extracted with ethyl acetate, purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 5/1 (v / v)), dried and oily [4- (2 -Bromoethyl) -2-methylphenoxy] ethyl acetate (yield 716 mg, yield 59%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.28 (3H, s), 3.07 (2H, t, J = 7.6 Hz), 3. 52 (2H, t, J = 7.6 Hz), 4.26 (2H, q, J = 7.3 Hz), 4.62 (2H, s), 6.64 (1H, d, J = 8.2 Hz) ), 6.94-7.00 (2H, m).

(V) Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis Example 3 and To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (293 mg, 1.00 mmol) obtained in the same manner in dimethylformamide (7 mL), potassium carbonate (138 mg, 1.00 mmol) was added. ) And [4- (2-bromoethyl) -2-methylphenoxy] ethyl acetate (301 mg, 1.00 mmol) obtained in (iv) above were added, and the mixture was stirred at 70 ° C. for 4 hours. After allowing to cool, water was added, extracted with dichloromethane, and purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)). After recrystallization from ethanol, the solution was collected by filtration and dried to give 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) iso Crystals of indoline-1-one (yield 80 mg, yield 16%) were obtained.
mp 106-107 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.30 (3H, s), 3.07 (2H, t, J = 6.9 Hz), 4. 25 (2H, q, J = 7.3 Hz), 4.27 (2H, t, J = 6.9 Hz), 4.62 (2H, s), 4.74 (2H, s), 6.67 ( 1H, d, J = 8.2 Hz), 7.02-7.10 (3H, m), 7.45 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1) 0.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 139 (Synthesis of 4-({2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [4- (Ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (51 mg) obtained in Example 138 , 0.10 mmol) to a suspension of ethanol (4 mL) and water (2 mL) was added 2N aqueous sodium hydroxide solution (0.1 mL, 0.20 mmol) and heated to reflux for 30 minutes. After the solvent was distilled off, the residue was acidified with 1N hydrochloric acid, and the resulting crystals were collected by filtration and dried to give 4-({2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} oxy) -2- Crystals of (4-trifluoromethylphenyl) isoindoline-1-one (yield 31 mg, yield 64%) were obtained.
mp 168-170 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.19 (3H, s), 3.00 (2H, t, J = 6.6 Hz), 4.31 (2H, t, J = 6.6 Hz), 4.65 (2H, s), 4.94 (2H, s), 6.76 (1H, d, J = 8.2 Hz), 7.12 (1H, d, J = 8.2 Hz), 7. 15 (1H, s), 7.34 (1H, d, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz) ), 7.80 (2H, d, J = 8.6 Hz), 8.17 (2H, d, J = 8.6 Hz).

Example 140 Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2- (4-trifluoromethylphenyl) -4-{[2- (4-hydroxy-3-methylphenyl) ethyl] thio} isoindoline-1-one Step (i) of Example 80 And 4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in the same manner as in (ii) and Example 138 ( 2- (4-Trifluoromethylphenyl) -4-{[2- (4-hydroxy) was obtained in the same manner as in Example 84 using 4- (2-bromoethyl) -2-methylphenol obtained in iii). -3-Methylphenyl) ethyl] thio} isoindoline-1-one was obtained.
mp 174-176 ° C
¹ H NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.88 (2H, t, J = 7.6 Hz), 3.25 (2H, t, J = 7.6 Hz), 4. 73 (2H, s), 4.75 (1H, s), 6.70 (1H, d, J = 7.9 Hz), 6.87-6.92 (2H, m), 7.50 (1H, t, J = 7.3 Hz), 7.56 (1H, dd, J = 1.0 Hz, 7.3 Hz), 7.68 (2H, d, J = 8.9 Hz), 7.77 (1H, dd) , J = 1.0 Hz, 7.3 Hz), 8.04 (2H, d, J = 8.9 Hz).

(Ii) Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (i) Of 2- (4-trifluoromethylphenyl) -4-{[2- (4-hydroxy-3-methylphenyl) ethyl] thio} isoindoline-1-one (381 mg, 0.86 mmol) obtained in To a formamide (7 mL) solution were added potassium carbonate (131 mg, 0.95 mmol) and ethyl bromoacetate (172 mg, 1.03 mmol), and the mixture was stirred at 70 ° C. for 7 hours. Water was added, and the obtained crystals were recrystallized from ethanol and dried to give 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoro). Crystals of methylphenyl) isoindoline-1-one (240 mg, 53%) were obtained.
mp 126-128 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.25 (3H, s), 2.88 (2H, t, J = 7.6 Hz), 3. 25 (2H, t, J = 7.6 Hz), 4.25 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 4.73 (2H, s), 6.61 ( 1H, d, J = 8.2 Hz), 6.92 (1H, dd, J = 2.0 Hz, 8.2 Hz), 6.96 (1H, s), 7.50 (1H, t, J = 7) .6 Hz), 7.56 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.69 (2H, d, J = 8.9 Hz), 7.77 (1H, dd, J = 1. 3 Hz, 7.6 Hz), 8.04 (2H, d, J = 8.9 Hz).

Example 141 Synthesis of 4-({2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 140 was carried out. Operate analogously to Example 69 to give 4-({2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 183-185 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.14 (3H, s), 2.83 (2H, t, J = 7.3 Hz), 3.35 (2H, t, J = 7.3 Hz), 4.64 (2H, s), 4.93 (2H, s), 6.71 (1H, d, J = 7.9 Hz), 7.01-7.04 (2H, m), 7.57 ( 1H, t, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz), 7.74 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 12.99 (1H, brs).

Example 142 (4-({2- [4- (1-ethoxycarbonyl-1-methylethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1- ON synthesis)
2- (4-Trifluoromethylphenyl) -4-{[2- (4-hydroxy-3-methylphenyl) ethyl] thio} isoindoline-1-one obtained in Example 140 (i) (383 mg, To a solution of 0.86 mmol) in dimethylformamide (7 mL) were added potassium carbonate (131 mg, 0.95 mmol) and ethyl 2-bromoisobutyrate (185 mg, 0.95 mmol), and the mixture was stirred at 70 ° C. overnight. Further, potassium carbonate (262 mg, 1.90 mmol) and ethyl 2-bromoisobutyrate (370 mg, 1.90 mmol) were added, and the mixture was stirred at 70 ° C. for 4 days. Water was added, and the resulting crystals were purified by silica gel column chromatography, recrystallized with ethanol, and dried to give 4-({2- [4- (1-ethoxycarbonyl-1-methylethoxy) -3- Crystals of methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one (47 mg, 10%) were obtained.
mp 112-114 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 1.55 (3H, s), 1.57 (3H, s), 2.19 (3H, s) , 2.86 (2H, t, J = 7.6 Hz), 3.24 (2H, t, J = 7.6 Hz), 4.23 (2H, q, J = 7.3 Hz), 4.74 ( 2H, s), 6.59 (1H, d, J = 8.6 Hz), 6.86 (1H, dd, J = 2.0 Hz, 8.6 Hz), 6.95 (1H, d, J = 2) .0 Hz), 7.50 (1H, t, J = 7.3 Hz), 7.56 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.69 (2H, d, J = 8. 6 Hz), 7.77 (1H, dd, J = 1.3 Hz, 7.3 Hz), 8.05 (2H, d, J = 8.6 Hz).

Example 143 (4-({2- [4- (1-carboxy-1-methylethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis)
(4-({2- [4- (1-Ethoxycarbonyl-1-methylethoxy) -3-methylphenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) iso] obtained in Example 142 Indoline-1-one was operated in the same manner as in Example 69 to give 4-({2- [4- (1-carboxy-1-methylethoxy) -3-methylphenyl] ethyl} thio) -2- (4- Trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 150-152 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.47 (6H, s), 2.10 (3H, s), 2.82 (2H, t, J = 7.6 Hz), 3.33-3. 38 (2H, m), 4.94 (2H, s), 6.60 (1H, d, J = 8.6 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.04 ( 1H, s), 7.57 (1H, t, J = 7.6 Hz), 7.66 (1H, d, J = 7.6 Hz), 7.74 (1H, d, J = 7.6 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.17 (2H, d, J = 8.6 Hz), 13.00 (1H, br).

Example 144 Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindolin-1-one
(I) Synthesis of 2- (4-trifluoromethylphenyl) -4-[(E) -2- (4-methoxyphenyl) ethenyl] isoindoline-1-one 4 obtained in Example 80 (i) -Trimethylamine (789 mg, 7.80 mmol), tris () was added to a solution of trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (2.55 g, 6.00 mmol) in dimethylformamide (30 mL). Dibenzylideneacetone) dipalladium (0) (275 mg, 0.30 mmol), tri-o-tolylphosphine (365 mg, 1.20 mmol), 4-vinylanisole (1.41 g, 10.5 mmol) were added, and 110 ° C. Stir for 4 hours. Water was added and the resulting crystals were collected by filtration and dissolved in dichloromethane. After filtration through celite, recrystallization from ethyl acetate and 2- (4-trifluoromethylphenyl) -4-[(E) -2- (4-methoxyphenyl) ethenyl] isoindoline-1-one (1. 55 g, 63%) of crystals.
mp 191-193 ° C
¹ H NMR (CDCl ₃ ) δ: 3.86 (3H, s), 5.00 (2H, s), 6.92-6.97 (2H, m), 7.01 (1H, d, J = 16.2 Hz), 7.16 (1 H, d, J = 16.2 Hz), 7.49-7.57 (3 H, m), 7.70 (2 H, d, J = 8.9 Hz), 7. 82 (2H, d, J = 7.6 Hz), 8.09 (2H, d, J = 8.9 Hz).

(Ii) Synthesis of 2- (4-trifluoromethylphenyl) -4-[(E) -2- (4-hydroxyphenyl) ethenyl] isoindoline-1-one Obtained in (i) above under ice-cooling. 2- (4-trifluoromethylphenyl) -4-[(E) -2- (4-methoxyphenyl) ethenyl] isoindoline-1-one (1.02 g, 2.50 mmol) in dichloromethane (30 mL) To the suspension was added boron tribromide dichloromethane solution (2.75 ml, 2.75 mmol), and the mixture was stirred overnight at room temperature. Further, boron tribromide dichloromethane solution (1.25 ml, 1.25 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The precipitated crystals were collected by filtration and dried to give 2- (4-trifluoromethylphenyl) -4-{(E) -2- (4-hydroxyphenyl) ethenyl} isoindoline-1-one (988 mg, quant) crystals were obtained.
mp 178-181 ° C
¹ H NMR (DMSO-d ₆ ) δ: 5.26 (2H, s), 6.83 (2H, d, J = 8.2 Hz), 7.19 (1H, d, J = 16.5 Hz), 7.35 (1H, d, J = 16.5 Hz), 7.54-7.59 (3H, m), 7.68 (1 H, d, J = 7.6 Hz), 7.84 (2H, d , J = 8.9 Hz), 8.00 (1H, d, J = 7.6 Hz), 8.27 (2H, d, J = 8.9 Hz), 9.71 (1H, s).

(Iii) Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in (ii) above 2- (4-trifluoromethylphenyl) -4-{(E) -2- (4-hydroxyphenyl) ethenyl} isoindoline-1-one (988 mg, 2.50 mmol) in dimethylformamide (12 mL) , Potassium carbonate (415 mg, 3.00 mmol) and ethyl bromoacetate (501 mg, 3.00 mmol) were added, and the mixture was stirred at 70 ° C. overnight. Furthermore, potassium carbonate (138 mg, 1.00 mmol) and ethyl bromoacetate (167 mg, 1.00 mmol) were added, and the mixture was stirred at 70 ° C. overnight. Water was added, and the obtained crystals were recrystallized from dichloromethane and ethanol, dried, and dried to 4-{(E) -2- [4- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethyl). Crystals of phenyl) isoindoline-1-one (501 mg, 42%) were obtained.
mp 202-204 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 4.30 (2H, q, J = 7.3 Hz), 4.67 (2H, s), 4. 99 (2H, s), 6.96 (2H, d, J = 8.6 Hz), 7.02 (1H, d, J = 16.2 Hz), 7.16 (1H, d, J = 16.2 Hz) ), 7.50-7.57 (3H, m), 7.70 (2H, d, J = 8.9 Hz), 7.82 (1H, d, J = 7.6 Hz), 7.83 (1H) , D, J = 7.6 Hz), 8.09 (2H, d, J = 8.9 Hz).

Example 145 (Synthesis of 4-{(E) -2- [4- (carboxymethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-{(E) -2- [4- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 144 was The same operation was performed to obtain 4-{(E) -2- [4- (carboxymethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 256-258 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.73 (2H, s), 5.26 (2H, s), 6.99 (2H, d, J = 8.2 Hz), 7.27 (1H, d, J = 16.5 Hz), 7.39 (1H, d, J = 16.5 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.66-7.71 (3H, m ), 7.83 (2H, d, J = 8.9 Hz), 8.01 (1H, d, J = 7.6 Hz), 8.27 (2H, d, J = 8.9 Hz).

Example 146 (Synthesis of 4-{(E) -2- [3- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2- (4-trifluoromethylphenyl) -4-[(E) -2- (3-methoxyphenyl) ethenyl] isoindoline-1-one 4 obtained in Example 80 (i) 2-Trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one and 3-vinylanisole were operated in the same manner as in Example 144 (i) to give 2- (4-trifluoromethylphenyl) -4-[(E) -2- (3-methoxyphenyl) ethenyl] isoindoline-1-one was obtained.
mp 190-192 ° C
¹ H NMR (CDCl ₃ ) δ: 3.88 (3H, s), 5.00 (2H, s), 6.90 (1H, dd, J = 2.3 Hz, 7.9 Hz), 7.10 ( 1H, t, J = 2.3 Hz), 7.15-7.19 (3H, m), 7.34 (1H, t, J = 7.9 Hz), 7.56 (1H, t, J = 7 .6 Hz), 7.70 (2H, d, J = 8.9 Hz), 7.85 (2H, dd, J = 2.0 Hz, 7.6 Hz), 8.09 (2H, d, J = 8. 9 Hz).

(Ii) Synthesis of 2- (4-trifluoromethylphenyl) -4-[(E) -2- (3-hydroxyphenyl) ethenyl] isoindoline-1-one 2- (obtained in (i) above 4-Trifluoromethylphenyl) -4-[(E) -2- (3-methoxyphenyl) ethenyl] isoindoline-1-one was treated in the same manner as in Example 144 (ii) to give 2- (4-tri Fluoromethylphenyl) -4-[(E) -2- (3-hydroxyphenyl) ethenyl] isoindoline-1-one was obtained.
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 5.29 (2H, s), 6.76 (1H, dt, J = 1.0 Hz, 7.6 Hz), 7.12-7.26 (3H, m ), 7.35 (2H, s), 7.59 (1H, t, J = 7.6 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.84 (2H, d, J = 8.9 Hz), 8.05 (1H, d, J = 7.6 Hz), 8.28 (2H, d, J = 8.9 Hz), 9.48 (1H, br).

(Iii) Synthesis of 4-{(E) -2- [3- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in (ii) above 2- (4-trifluoromethylphenyl) -4-[(E) -2- (3-hydroxyphenyl) ethenyl] isoindoline-1-one was prepared in the same manner as in Example 144 (iii), and 4- {(E) -2- [3- (Ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 178-180 ° C
¹ H NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.3 Hz), 4.31 (2H, q, J = 7.3 Hz), 4.69 (2H, s), 5. 00 (2H, s), 6.84-6.88 (1H, m), 7.15 (2H, s), 7.18-7.21 (2H, m), 7.34 (1H, t, J = 8.2 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.71 (2H, d, J = 8.9 Hz), 7.84 (1H, d, J = 7.6 Hz) ), 7.85 (1H, d, J = 7.6 Hz), 8.10 (2H, d, J = 8.9 Hz).

Example 147 (Synthesis of 4-{(E) -2- [3- (carboxymethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-{(E) -2- [3- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 146 The same operation was performed to obtain 4-{(E) -2- [3- (carboxymethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 194-196 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.74 (2H, s), 5.29 (2H, s), 6.87-6.93 (1H, m), 7.31-7.36 ( 3H, m), 7.42 (2H, s), 7.60 (1H, t, J = 7.6 Hz), 7.74 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7. 84 (2H, d, J = 8.6 Hz), 8.04 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.28 (2H, d, J = 8.6 Hz), 13.12 (1H, br).

Example 148 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of [4- (hydroxymethyl) -2-methoxyphenoxy] ethyl acetate To a solution of vanillyl alcohol (771 mg, 5.00 mmol) in acetonitrile (25 mL), cesium carbonate (1.79 g, 5.50 mmol) and Ethyl bromoacetate (919 mg, 5.50 mmol) was added and stirred overnight at room temperature. After adding water and extracting with ethyl acetate, the solvent was distilled off to obtain oily ethyl [4- (hydroxymethyl) -2-methoxyphenoxy] acetate (1.20 g, quant).
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 1.67 (1H, t, J = 5.6 Hz), 3.90 (3H, s), 4. 26 (2H, q, J = 7.3 Hz), 4.63 (2H, d, J = 5.6 Hz), 4.68 (2H, s), 6.80 (1H, d, J = 8.2 Hz) ), 6.86 (1H, dd, J = 1.6 Hz, 8.2 Hz), 6.96 (1H, d, J = 1.6 Hz).

(Ii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis example under ice-cooling 2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (586 mg, 2.00 mmol) obtained in 3 above, [4- (hydroxymethyl) -2-methoxyphenoxy obtained above To a suspension of ethyl acetate (481 mg, 2.00 mmol) and triphenylphosphine (682 mg, 2.60 mmol) in toluene (15 mL) was added dropwise a solution of diethyl azodicarboxylate in toluene (1.1 mL, 2.40 mmol). Stir at 15 ° C. for 15 minutes and then at room temperature overnight. The solvent was distilled off, the residue was purified by silica gel column chromatography, recrystallized with dichloromethane and ethanol, and dried to give 4-({[4- (ethoxycarbonylmethoxy) -3-methoxyphenyl] methyl} oxy) -2. Crystals of-(4-trifluoromethylphenyl) isoindoline-1-one (210 mg, 20%) were obtained.
mp 162-164 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 3.92 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4. 72 (2H, s), 4.83 (2H, s), 5.12 (2H, s), 6.85 (1H, d, J = 8.2 Hz), 6.96-6.99 (2H, m), 7.15 (1H, d, J = 7.6 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.55 (1H, d, J = 7.6 Hz), 7. 67 (2H, d, J = 8.9 Hz), 8.05 (2H, d, J = 8.9 Hz).

Example 149 (Synthesis of 4-({[4- (carboxymethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 148 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 164-166 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.81 (3H, s), 4.67 (2H, s), 5.03 (2H, s), 5.20 (2H, s), 6.87 (1H, d, J = 8.2 Hz), 7.04 (1H, d, J = 8.2 Hz), 7.15 (1H, s), 7.39-7.42 (2H, m), 7 .53 (1H, t, J = 7.6 Hz), 7.78 (2H, d, J = 8.6 Hz), 8.20 (2H, d, J = 8.6 Hz), 13.04 (1H, br).

Example 150 (Synthesis of 4-({[3-chloro-4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of ethyl (2-chloro-4-formylphenoxy) acetate To a solution of 3-chloro-4-hydroxybenzaldehyde (783 mg, 5.00 mmol) in acetonitrile (25 mL) was added cesium carbonate (1.79 g, 5.50 mmol). ) And ethyl bromoacetate (919 mg, 5.50 mmol) were added, and the mixture was stirred at room temperature for 7 hours. After adding water and extracting with ethyl acetate, the solvent was distilled off to obtain oily ethyl (2-chloro-4-formylphenoxy) acetate (1.22 g, quant).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 4.29 (2H, q, J = 7.3 Hz), 4.81 (2H, s), 6. 92 (1H, d, J = 8.6 Hz), 7.75 (1H, dd, J = 2.0 Hz, 8.6 Hz), 7.95 (1H, d, J = 2.0 Hz), 9.87 (1H, s).

(Ii) Synthesis of ethyl [2-chloro-4- (hydroxymethyl) phenoxy] ethyl acetate The ethyl (2-chloro-4-formylphenoxy) ethyl acetate (1.21 g, 4.98 mmol) obtained in (i) above was used. Borane-tetrahydrofuran complex (4.8 mL, 4.98 mmol) was added dropwise to a tetrahydrofuran (25 mL) solution under ice-cooling, and the mixture was stirred at 0 ° C. for 5 and a half hours. After adding water and extracting with ethyl acetate, the solvent was distilled off to obtain oily ethyl [2-chloro-4- (hydroxymethyl) phenoxy] acetate (1.22 g, quant).
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 1.77 (1H, brs), 4.27 (2H, q, J = 7.3 Hz), 4. 61 (2H, s), 4.70 (2H, s), 6.83 (1H, d, J = 8.2 Hz), 7.19 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.41 (1H, d, J = 2.3 Hz).

(Iii) Synthesis of 4-({[3-chloro-4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Triethylamine (237 mg, 2.34 mmol) and methanesulfonyl chloride (268 mg, 2.34 mmol) were added to a solution of the obtained [2-chloro-4- (hydroxymethyl) phenoxy] ethyl acetate (440 mg, 1.80 mmol) in dichloromethane (10 mL). ) And stirred overnight at room temperature. Aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The solvent was distilled off from the obtained organic layer to obtain [2-chloro-4- (chloromethyl) phenoxy] ethyl acetate.

To a solution of 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (440 mg, 1.50 mmol) obtained in Synthesis Example 3 in dimethylformamide (10 mL), potassium carbonate (228 mg, 1. 65 mmol) and the prepared [2-chloro-4- (chloromethyl) phenoxy] ethyl acetate were added and stirred at 70 ° C. overnight. Water was added, and the resulting crystals were recrystallized from dichloromethane and ethanol, dried and then 4-({[3-chloro-4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoro Crystals of methylphenyl) isoindoline-1-one (488 mg, 63%) were obtained.
mp 170-172 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 4.29 (2H, q, J = 7.3 Hz), 4.74 (2H, s), 4. 84 (2H, s), 5.10 (2H, s), 6.88 (1H, d, J = 8.6 Hz), 7.12 (1H, d, J = 7.9 Hz), 7.22- 7.30 (1H, m), 7.45-7.57 (3H, m), 7.67 (2H, d, J = 8.9 Hz), 8.06 (2H, d, J = 8.9 Hz) ).

Example 151 Synthesis of 4-({[4- (carboxymethoxy) -3-chlorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[3-Chloro-4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 150 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -3-chlorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 180-183 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.82 (2H, s), 5.04 (2H, s), 5.22 (2H, s), 7.05 (1H, d, J = 8. 6 Hz), 7.39 (1 H, d, J = 7.6 Hz), 7.41 (1 H, d, J = 7.6 Hz), 7.45 (1 H, dd, J = 2.0 Hz, 8.6 Hz) ), 7.53 (1H, t, J = 7.6 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.77 (2H, d, J = 8.9 Hz), 8.20 (2H, d, J = 8.9 Hz), 13.29 (1H, br).

Example 152 Synthesis of 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-{[2- (2-ethylhexyloxycarbonyl) ethyl] thio} -2- (4-trifluoromethylphenyl) isoindoline- obtained in the same manner as in steps (i) and (ii) of Example 80 21% sodium ethoxide ethanol solution (233 mg, 0.72 mmol) was added dropwise to a solution of 1-one (320 mg, 0.65 mmol) in ethanol (20 mL) while cooling with water, and the mixture was stirred at room temperature for 50 minutes. A methanol solution of ethyl 3- (2-methanesulfonyloxyethyl) phenylthioacetate (350 mg, 1.10 mmol) obtained in Example 106 (ii) was added, and the mixture was stirred at room temperature overnight. Acidify with 1N hydrochloric acid and add water. The obtained crystals were purified by flash column chromatography, and 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one Crystals (164 mg, 48%) were obtained.
mp 121-122 ° C
¹ H NMR (DMSO) δ: 1.11 (3H, t, J = 7.3 Hz), 2.90 (2H, t, J = 7.8 Hz), 3.40 (2H, t, J = 7. 3 Hz), 3.86 (2H, s), 4.05 (2H, q, J = 7.0 Hz), 4.95 (2H, s), 7.11-7.28 (4H, m), 7 .55-7.82 (5H, m), 8.18 (2H, d, J = 8.9 Hz).

Example 153 (Synthesis of 4-({2- [3- (carboxymethylthio) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 152 was used in the same manner as in Example 69. To give 4-({2- [3- (carboxymethylthio) phenyl] ethyl} thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 152-153 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.90 (2H, t, J = 7.6 Hz), 3.39 (2H, t, J = 7.0 Hz), 3.79 (2H, s), 4.95 (2H, s), 7.09-7.27 (4H, m), 7.55-7.82 (5H, m), 8.18 (2H, d, J = 8.4 Hz), 12.76 (1H, br).

Example 154 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-fluorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of ethyl (2-fluoro-4-formylphenoxy) acetate To a solution of 3-fluoro-4-hydroxybenzaldehyde (701 mg, 5.00 mmol) in acetonitrile (25 mL) was added cesium carbonate (1.79 g, 5.50 mmol). ) And ethyl bromoacetate (919 mg, 5.50 mmol) were added, and the mixture was stirred overnight at room temperature. After adding water and extracting with ethyl acetate, the solvent was distilled off to obtain oily ethyl (2-fluoro-4-formylphenoxy) acetate (1.16 g, quant).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 4.29 (2H, q, J = 7.3 Hz), 4.79 (2H, s), 6. 97-7.03 (1H, m), 7.61-7.67 (2H, m), 9.88 (1 H, d, J = 2.0 Hz).

(Ii) Synthesis of ethyl [2-fluoro-4- (hydroxymethyl) phenoxy] ethyl acetate The ethyl (2-fluoro-4-formylphenoxy) ethyl acetate (1.14 g, 5.00 mmol) obtained in (i) above was used. Borane-tetrahydrofuran complex (5.1 mL, 5.00 mmol) was added dropwise to a tetrahydrofuran (20 mL) solution under ice cooling, and the mixture was stirred at 0 ° C. for 2.5 hours. Methanol was added and the solvent was distilled off, followed by extraction with ethyl acetate to obtain oily ethyl [2-fluoro-4- (hydroxymethyl) phenoxy] acetate (1.02 g, 90%).
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 1.69 (1H, t, J = 5.9 Hz), 4.27 (2H, q, J = 7) .3 Hz), 4.63 (2H, d, J = 5.9 Hz), 4.69 (2H, s), 6.91 (1H, t, J = 8.2 Hz), 7.04 (1H, d) , J = 8.2 Hz), 7.14 (1H, dd, J = 2.0 Hz, 11.9 Hz).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-fluorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in Synthesis Example 3. 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one, ethyl [2-fluoro-4- (hydroxymethyl) phenoxy] acetate obtained in (ii) above was used in Example 150. Operate in the same manner as in iii) to obtain 4-({[4- (ethoxycarbonylmethoxy) -3-fluorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. .
mp 135-136 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 4.28 (2H, q, J = 7.3 Hz), 4.72 (2H, s), 4. 84 (2H, s), 5.11 (2H, s), 6.96 (1H, t, J = 8.2 Hz), 7.09-7.15 (2H, m), 7.23 (1H, dd, J = 2.0 Hz, 11.5 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.55 (1H, d, J = 7.6 Hz), 7.67 (2H, d , J = 8.9 Hz), 8.06 (2H, d, J = 8.9 Hz).

Example 155 (Synthesis of 4-({[4- (carboxymethoxy) -3-fluorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-fluorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 154 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -3-fluorophenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 208-210 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.80 (2H, s), 5.05 (2H, s), 5.23 (2H, s), 7.10 (1H, t, J = 8. 6 Hz), 7.28 (1 H, d, J = 8.2 Hz), 7.37-7.46 (3 H, m), 7.53 (1 H, t, J = 7.9 Hz), 7.78 ( 2H, d, J = 8.9 Hz), 8.20 (2H, d, J = 8.9 Hz), 13.17 (1H, br).

Example 156 (Synthesis of 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 3 and [3- (chloromethyl) phenoxy] ethyl acetate obtained in Example 84 (ii) were used. In the same manner as in Example 138 (v), 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained. .
mp 144-146 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 4.26 (2H, q, J = 7.3 Hz), 4.65 (2H, s), 4. 86 (2H, s), 5.18 (2H, s), 6.87-6.91 (1H, m), 7.05-7.09 (2H, m), 7.12 (1H, dd, J = 1.0 Hz, 8.2 Hz), 7.35 (1H, t, J = 8.2 Hz), 7.46 (1H, t, J = 7.6 Hz), 7.54 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, d, J = 8.6 Hz), 8.07 (2H, d, J = 8.6 Hz).

Example 157 (Synthesis of 4-({[3- (carboxymethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 156 was operated in the same manner as in Example 69. 4-({[3- (carboxymethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 184-186 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.68 (2H, s), 5.06 (2H, s), 5.27 (2H, s), 6.88 (1H, dd, J = 3. 0 Hz, 8.2 Hz), 7.09 (1H, d, J = 2.0 Hz), 7.12 (1H, d, J = 8.2 Hz), 7.30-7.42 (3H, m), 7.53 (1H, d, J = 7.6 Hz), 7.79 (2H, d, J = 8.9 Hz), 8.21 (2H, d, J = 8.9 Hz).

Example 158 (Synthesis of 4- {2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-{(E) -2- [3- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 146 (301 mg,. To a suspension of 63 mmol) in dichloromethane (12 mL) and ethanol (10 mL) was added activated carbon-palladium (33 mg), and the mixture was stirred under a hydrogen atmosphere for 6 hours. After filtering through Celite and distilling off the solvent, crystallization was performed with ethanol and isopropyl ether, and 4- {2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) iso Crystals of indoline-1-one (263 mg, 87%) were obtained.
mp 101-102 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.99 (4H, t, J = 3.3 Hz), 4.24 (2H, q, J = 7) .3 Hz), 4.41 (2H, s), 4.56 (2H, s), 6.68-6.75 (3H, m), 7.17 (1 H, t, J = 7.6 Hz), 7.42-7.51 (2H, m), 7.66 (2H, d, J = 8.6 Hz), 7.78 (1H, dd, J = 1.6 Hz, 6.9 Hz), 7.97 (2H, d, J = 8.6 Hz).

Example 159 (Synthesis of 4- {2- [3- (carboxymethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4- {2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 158 was operated in the same manner as in Example 69. 4- {2- [3- (carboxymethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 113-116 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.90-3.05 (4H, m), 4.62 (2H, s), 5.01 (2H, s), 6.72 (1H, ddd, J = 1.0 Hz, 2.6 Hz, 7.9 Hz), 6.85 (1 H, d, J = 7.9 Hz), 6.88-6.90 (1 H, m), 7.18 (1 H, t , J = 7.9 Hz), 7.49 (1H, t, J = 7.3 Hz), 7.56 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.66 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.20 (2H, d, J = 8.6 Hz).

Example 160 Synthesis of 4- {2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-{(E) -2- [4- (ethoxycarbonylmethoxy) phenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 144 was The same operation was performed to obtain 4- {2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 116-117 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.96 (4H, t, J = 3.3 Hz), 4.23 (2H, q, J = 7) 3 Hz), 4.42 (2H, s), 4.52 (2H, s), 6.79-6.84 (2H, m), 699-7.04 (2H, m), 7. 42 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.47 (1H, t, J = 7.3 Hz), 7.66 (2H, d, J = 8.9 Hz), 7.78 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.95 (2H, d, J = 8.9 Hz).

Example 161 Synthesis of 4- {2- [4- (carboxymethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one
4- {2- [4- (Ethoxycarbonylmethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 160 was operated in the same manner as in Example 69. 4- {2- [4- (carboxymethoxy) phenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 202-203 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.87-3.02 (4H, m), 4.61 (2H, s), 5.01 (2H, s), 6.84 (2H, d, J = 8.2 Hz), 7.20 (2H, d, J = 8.2 Hz), 7.46-7.55 (2H, m), 7.66 (1H, d, J = 6.9 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 12.99 (1H, br).

Example 162 Synthesis of 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2-phenylisoindoline-1-one)
(I) Synthesis of 2- [4- (hydroxymethyl) phenoxy] ethyl acetate To a solution of 4- (hydroxymethyl) phenol (3.72 g, 30.0 mmol) in acetonitrile (37 mL), ethyl bromoacetate (5.51 g, 33.0 mmol) and cesium carbonate (10.37 g, 33.0 mmol) were added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, and ethyl 2- [4- (hydroxymethyl) phenoxy] acetate (3.13 g, 50%) oil was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, dt, J = 1.0, 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.63 (2H, s ), 4.64 (2H, s), 6.84-6.96 (2H, m), 7.25-7.35 (2H, m).

(Ii) Synthesis of ethyl 2- [4- (bromomethyl) phenoxy] acetate ethyl 2- [4- (hydroxymethyl) phenoxy] acetate (1.50 g, 7.14 mmol) obtained in (i) above (20 mL) To the solution, N-bromosuccinimide (1.52 g, 8.56 mmol) and triphenylphosphine (2.25 g, 8.56 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain an oily substance of ethyl 2- [4- (bromomethyl) phenoxy] acetate (555 mg, 29%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.49 (2H, s), 4. 62 (2H, s), 6.84-6.95 (2H, m), 7.27-7.35 (2H, m).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2-phenylisoindoline-1-one 4-hydroxy-2-phenylisoindoline- obtained in Synthesis Example 1 1-one and 2- [4- (bromomethyl) phenoxy] ethyl acetate obtained in (ii) above were treated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) phenyl ] Methyl} oxy) -2-phenylisoindoline-1-one was obtained.
mp 89-91 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 4.29 (2H, q, J = 7.1 Hz), 4.65 (2H, s), 4. 81 (2H, s), 5.12 (2H, s), 6.96 (2H, d, J = 8.7 Hz), 7.10-7.20 (2H, m), 7.55-7. 30 (6H, m), 7.90 (2H, d, J = 8.7 Hz).

Example 163 (Synthesis of 4-({[4- (carboxymethoxy) phenyl] methyl} oxy) -2-phenylisoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2-phenylisoindoline-1-one obtained in Example 162 was operated in the same manner as in Example 69, and 4-({[ 4- (Carboxymethoxy) phenyl] methyl} oxy) -2-phenylisoindoline-1-one was obtained.
mp 204-206 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.69 (2H, s), 4.96 (2H, s), 5.21 (2H, s), 6.94 (2H, d, J = 8. 4 Hz), 7.12-7.20 (1 H, m), 7.34-7.54 (7 H, m), 7.94 (2 H, d, J = 8.4 Hz).

Example 164 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 3 and 2- [4- (bromomethyl) phenoxy] ethyl acetate obtained in Example 162 (ii) Was operated in the same manner as in Example 138 (v) to obtain 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 131-133 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 4.29 (2H, q, J = 7.1 Hz), 4.65 (2H, s), 4. 82 (2H, s), 5.13 (2H, s), 6.96 (2H, d, J = 8.96 Hz), 7.12-7.57 (5H, m), 7.67 (2H, d, J = 8.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

Example 165 (Synthesis of 4-({[4- (carboxymethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 164 was operated in the same manner as in Example 69. 4-({[4- (carboxymethoxy) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 210-226 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.53 (2H, s), 5.01 (2H, s), 5.20 (2H, s), 6.91 (2H, d, J = 8. 6 Hz), 7.37-7.56 (5 H, m), 7.77 (2 H, d, J = 8.9 Hz), 8.20 (2 H, d, J = 8.6 Hz).

Example 166 (Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 4-ethoxycarbonylmethoxy-3-methyl-vinylbenzene Under ice-cooling, sodium hydride (144 mg, 144 mg, 3.60 mmol) was added, and the mixture was stirred at room temperature for 35 minutes. Then, ethyl (4-formyl-2-methylphenoxy) acetate (667 mg, 3.00 mmol) obtained in Example 134 (i) was added, and the mixture was overnight at room temperature. Stir. Further, potassium t-butoxide (667 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added, and the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain oily 4-ethoxycarbonylmethoxy-3-methyl-vinylbenzene (140 mg, 21%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4. 64 (2H, s), 5.12 (1H, d, J = 10.9 Hz), 5.60 (1H, d, J = 17.5 Hz), 6.57-6.68 (2H, m), 7.16 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.24 (1H, d, J = 2.0 Hz).

(Ii) Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one 4-trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in (i), 4-ethoxycarbonylmethoxy-3-methyl-vinyl obtained in (i) above Benzene was operated analogously to Example 144 (i) and 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) Isoindoline-1-one was obtained.
mp 176-177 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 4. 69 (2H, s), 5.00 (2H, s), 6.73 (1H, d, J = 8.6 Hz), 7.00 (1H, d, J = 16.2 Hz), 7.13 ( 1H, d, J = 16.2 Hz), 7.32 (1 H, dd, J = 2.0 Hz, 8.6 Hz), 7.42 (1 H, d, J = 2.0 Hz), 7.54 (1H , T, J = 7.6 Hz), 7.70 (2H, d, J = 8.9 Hz), 7.81 (1H, d, J = 7.6 Hz), 7.82 (1H, d, J = 7.6 Hz), 8.10 (2H, d, J = 8.9 Hz).

Example 167 Synthesis of 4-{(E) -2- [4- (carboxymethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 166 By operating in the same manner as in Example 69, 4-{(E) -2- [4- (carboxymethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one Got.
mp 239-241 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 4.75 (2H, s), 5.26 (2H, s), 6.88 (1H, d, J = 8. 6 Hz), 7.24 (1 H, d, J = 16.5 Hz), 7.35 (1 H, d, J = 16.5 Hz), 7.47 (1 H, dd, J = 2.0 Hz, 8.6 Hz) ), 7.54-7.60 (2H, m), 7.69 (1H, d, J = 7.9 Hz), 7.84 (2H, d, J = 8.9 Hz), 8.00 (1H) , D, J = 7.9 Hz), 8.28 (2H, d, J = 8.9 Hz).

Example 168 (Synthesis of 4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 166 In the same manner as in Example 158, 4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained. .
mp 107-109 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.26 (3H, s), 2.87-3.01 (4H, m), 4.22 ( 2H, q, J = 7.3 Hz), 4.41 (2H, s), 4.52 (2H, s), 6.57 (1H, d, J = 8.2 Hz), 6.80 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.95 (1H, d, J = 2.3 Hz), 7.43 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.48 (1H, t, J = 7.3 Hz), 7.66 (2H, d, J = 8.9 Hz), 7.78 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.94 ( 2H, d, J = 8.9 Hz).

Example 169 (Synthesis of 4- {2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindolin-1-one)
4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 168 was The same operation was performed to obtain 4- {2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 177-180 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.17 (3H, s), 2.83-3.01 (4H, m), 4.62 (2H, s), 5.01 (2H, s) 6.73 (1H, d, J = 8.2 Hz), 7.03 (1H, d, J = 8.2 Hz), 7.08 (1H, s), 7.49 (1H, t, J = 7.3 Hz), 7.55 (1H, d, J = 7.3 Hz), 7.66 (1H, d, J = 7.3 Hz), 7.81 (2H, d, J = 8.9 Hz), 8.19 (2H, d, J = 8.9 Hz), 12.98 (1H, br).

Example 170 Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2-phenylisoindolin-1-one)
(I) Synthesis of ethyl 2- [4- (bromomethyl) -2-methylphenoxy] acetate Ethyl 2- [4- (hydroxymethyl) -2-methylphenoxy] acetate (1) obtained in Example 134 (ii) N-bromosuccinimide (2.31 g, 12.97 mmol) and triphenylphosphine (3.40 g, 12.97 mmol) were added to a solution of .94 g, 8.64 mmol) in methylene chloride (30 mL) at room temperature. For 3.5 hours. After completion of the reaction, methanol (3 mL) was added and stirred at room temperature for 20 minutes. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform and purified by silica gel column chromatography to obtain crystals of 2- [4- (bromomethyl) -2-methylphenoxy] ethyl acetate (1.78 g, 72%).
mp 44-49 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.28 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4. 47 (2H, s), 4.64 (2H, s), 6.64 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 2.3, 8.2 Hz), 7.21 (1H, d, J = 2.3 Hz).

(Ii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2-phenylisoindoline-1-one 4-hydroxy-2-obtained in Synthesis Example 1 Phenylisoindoline-1-one and ethyl 2- [4- (bromomethyl) -2-methylphenoxy] acetate obtained in (i) above were operated in the same manner as in Example 138 (v), and 4-({[ 4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2-phenylisoindoline-1-one was obtained.
mp 102-105 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 2.33 (3H, s), 4.28 (2H, q, J = 7.1 Hz), 4. 67 (2H, s), 4.81 (2H, s), 5.09 (2H, s), 6.73 (1H, d, J = 8.2 Hz), 7.08-7.55 (8H, m), 7.89 (2H, t, J = 7.6 Hz).

Example 171 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-trifluoromethylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
(I) Synthesis of 4-hydroxy-3- (trifluoromethyl) benzaldehyde 2-trifluorophenol (5.00 g, 30.84 mmol) to trifluoroacetic acid (50 mL) and hexamethylenetetramine (8.65 g, 61.69 mmol) ) And stirred at 65 ° C. for 22 hours. After cooling, trifluoroacetic acid was distilled off under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with diethyl ether. The diethyl ether extract was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in chloroform, purified by silica gel column chromatography, and then washed with chloroform-hexane to obtain 4-hydroxy-3- (trifluoromethyl) benzaldehyde (405 mg, 21%) crystals. .
mp 154-160 ° C
¹ H NMR (CDCl ₃ ) δ: 7.11 (1H, d, J = 8.6 Hz), 7.99 (1H, dd, J = 2.0, 8.6 Hz), 8.09 (1H, d , J = 2.0 Hz), 9.93 (1H, s).

(Ii) Synthesis of ethyl 2- [4-formyl-2- (trifluoromethyl) phenoxy] acetate 4-hydroxy-3- (trifluoromethyl) benzaldehyde (600 mg, 3.16 mmol) obtained in (i) above To an acetonitrile (6 mL) solution were added ethyl bromoacetate (632 mg, 3.79 mmol) and cesium carbonate (1.23 g, 3.79 mmol), and the mixture was stirred at room temperature for 14.5 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain crystals of 2- [4-formyl-2- (trifluoromethyl) phenoxy] ethyl acetate (838 mg, 96%).
mp 75-82 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz), 4.84 (2H, s), 6. 99 (1H, d, J = 8.4 Hz), 8.03 (1H, dd, J = 1.8, 8.4 Hz), 8.16 (1H, d, J = 1.8 Hz), 9.95 (1H, s).

(Iii) Synthesis of 2- [4- (hydroxymethyl) -2- (trifluoromethyl) phenoxy] ethyl acetate 2- [4-formyl-2- (trifluoromethyl) phenoxy] obtained in (ii) above To a solution of ethyl acetate (815 mg, 2.95 mmol) in ethanol (16 mL) was added sodium borohydride (134 mg, 3.54 mmol) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. An oily product of ethyl 2- [4- (hydroxymethyl) -2- (trifluoromethyl) phenoxy] acetate (723 mg, 88%) Got.
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.68 (2H, s), 4. 73 (2H, s), 6.87 (1H, d, J = 8.4 Hz), 7.48 (1H, dd, J = 2.0, 8.4 Hz), 7.62 (1H, d, J = 2.0 Hz).

(Iv) Synthesis of ethyl 2- [4- (bromomethyl) -2- (trifluoromethyl) phenoxy] acetate 2- [4- (hydroxymethyl) -2- (trifluoromethyl) obtained in (iii) above To a solution of ethyl phenoxy] ethyl acetate (650 mg, 2.34 mmol) in methylene chloride (10 mL), N-bromosuccinimide (624 mg, 3.50 mmol) and triphenylphosphine (918 mg, 3.50 mmol) were added under ice-cooling. For 2 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain crystals of ethyl 2- [4- (bromomethyl) -2- (trifluoromethyl) phenoxy] acetate (632 mg, 79%).
mp 61-69 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.2 Hz), 4.27 (2H, q, J = 7.2 Hz), 4.48 (2H, s), 4. 73 (2H, s), 6.84 (1H, d, J = 8.5 Hz), 7.50 (1H, dd, J = 2.2, 8.5 Hz), 7.63 (1H, d, J = 2.2 Hz).

(V) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-trifluoromethylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one In Synthesis Example 3 The obtained 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one and 2- [4- (bromomethyl) -2- (trifluoromethyl) phenoxy] obtained in (iv) above Ethyl acetate was operated as in Example 138 (v) and 4-({[4- (ethoxycarbonylmethoxy) -3-trifluoromethylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl). Isoindoline-1-one was obtained.
mp 160-164 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 4.28 (2H, q, J = 7.1 Hz), 4.77 (2H, s), 4. 83 (2H, s), 5.15 (2H, s), 6.93 (1H, d, J = 8.6 Hz), 7.13 (1H, d, J = 7.5 Hz), 7.49 ( 1H, t, J = 7.5 Hz), 7.57 (2H, d, J = 6.9 Hz), 7.64-7.72 (3H, m), 8.06 (2H, d, J = 8) .9Hz)
Example 172 (Synthesis of 4-({[4- (carboxymethoxy) -3-trifluoromethylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-trifluoromethylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 171 was carried out. Operate analogously to Example 69 to obtain 4-({[4- (carboxymethoxy) -3-trifluoromethylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 126-132 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.88 (2H, s), 5.03 (2H, s), 5.29 (2H, s), 7.17 (1H, d, J = 8. 6 Hz), 7.41 (2H, d, J = 7.3 Hz), 7.55 (1H, t, J = 7.9 Hz), 7.78 (4H, d, J = 10.9 Hz), 8. 19 (2H, d, J = 8.6 Hz).

Example 173 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
2- (4-Methylphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 11, 2- [4- (hydroxymethyl) -2-methylphenoxy obtained in Example 134 (ii) Ethyl acetate was operated in the same manner as in Example 150 (iii) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline- 1-one was obtained.
mp 226-228 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 2.33 (3H, s), 2.35 (3H, s), 4.28 (2H, q, J = 7.3 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.08 (2H, s), 6.72 (1 H, d, J = 8.2 Hz), 7 .11 (1H, d, J = 8.2 Hz), 7.19-7.26 (4H, m), 7.44 (1H, t, J = 7.6 Hz), 7.52 (1H, d, J = 7.6 Hz), 7.73-7.78 (2H, m).

Example 174 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
Synthesis of 4- (4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methylphenyl) isoindolin-1-one obtained in Example 173 In the same manner as in Example 69, 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1-one was obtained.
mp 192-195 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 2.30 (3H, s), 4.70 (2H, s), 4.91 (2H, s), 5.15 (2H, s), 6.83 (1H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.2 Hz), 7.27-7.36 (4H, m), 7 .49 (1H, t, J = 7.6 Hz), 7.81 (2H, d, J = 8.2 Hz), 13.11 (1H, br).

Example 175 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
2- (4-Trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 19 and 2- [4- (hydroxymethyl) -2-yne obtained in Example 134 (ii) Methylphenoxy] ethyl acetate was operated in the same manner as in Example 150 (iii) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl). ) Isoindoline-1-one was obtained.
mp 132-134 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 2.33 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4. 67 (2H, s), 4.78 (2H, s), 5.08 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 7.13 (1H, d, J = 7.6 Hz), 7.21 (1 H, dd, J = 2.3 Hz, 8.2 Hz), 7.25-7.28 (3 H, m), 7.45 (1 H, t, J = 7.6 Hz) ), 7.52 (1H, d, J = 7.6 Hz), 7.90-7.95 (2H, m).

Example 176 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4- (4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 175 was used. In the same manner as in Example 69, 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindolin-1-one was obtained. .
mp 153-154 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.72 (2H, s), 4.97 (2H, s), 5.16 (2H, s), 6.83 (1H, d, J = 7.9 Hz), 7.27-7.31 (2H, m), 7.36-7.44 (4H, m), 7.48-7.54 (1H, m) 8.04-8.10 (2H, m), 13.07 (1H, br).

Example 177 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2-methylisophthalic acid To a suspension of 2,6-dicyanotoluene (2.84 g, 20.0 mmol) in ethylene glycol (20 mL) was added 14N aqueous sodium hydroxide solution (7 mL, 0.10 mol), Stir at 150 ° C. overnight. Concentrated hydrochloric acid was added, and the resulting crystals were collected by filtration and dried to obtain crystals of 2-methylisophthalic acid (3.61 g, quant).
mp 239-241 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.58 (3H, s), 7.35 (1H, t, J = 7.9 Hz), 7.80 (2H, d, J = 7.9 Hz), 13.14 (2H, brs).

(Ii) Synthesis of dimethyl 2-methylisophthalate A suspension of 2-methylisophthalic acid (3.59 g, 19.9 mmol) obtained in (i) above in hydrochloric acid-methanol (40 mL) was heated to reflux overnight. Aqueous sodium hydrogen carbonate solution was added, and the resulting crystals were collected by filtration and dried to obtain crystals of dimethyl 2-methylisophthalate (3.61 g, 87%).
mp 54-55 ° C
¹ H NMR (CDCl ₃ ) δ: 2.69 (3H, s), 3.91 (6H, s), 7.29 (1H, t, J = 7.9 Hz), 7.87 (2H, d, J = 7.9 Hz).

(Iii) Synthesis of 4-methoxycarbonyl-2- (4-trifluoromethylphenyl) isoindoline-1-one of dimethyl 2-methylisophthalate (1.67 g, 8.00 mmol) obtained in (ii) above Bromosuccinimide (1.42 g, 8.00 mmol) and benzoyl peroxide (75% in Water, 143 mg) were added to a carbon tetrachloride (25 mL) solution, and the mixture was heated to reflux for 8 hours. After standing to cool, m insoluble matter was filtered off, and the solvent was distilled off to obtain dimethyl 2-bromomethylisophthalate.

A solution of dimethyl 2-bromomethylisophthalate and 1-amino-4- (trifluoromethyl) benzene (1.29 g, 8.00 mmol) in dimethylformamide (25 mL) is stirred at 60 ° C. for 2 hours and 120 ° C. for 1.5 hours. did. After allowing to cool, the obtained crystals were collected by filtration and dried to give 4-methoxycarbonyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (1.84 g, 69%). .
mp 195-196 ° C
¹ H NMR (CDCl ₃ ) δ: 4.02 (3H, s), 5.22 (2H, s), 7.65 (1H, t, J = 7.6 Hz), 7.70 (2H, d, J = 8.9 Hz), 8.10 (2H, d, J = 8.9 Hz), 8.14 (1H, d, J = 7.6 Hz), 8.28 (1H, d, J = 7.6 Hz) ).

(Iv) Synthesis of 4-carboxy-2- (4-trifluoromethylphenyl) isoindoline-1-one 4-methoxycarbonyl-2- (4-trifluoromethylphenyl) isoindoline obtained in (iii) above To a suspension of -1-one (671 mg, 2.00 mmol) in methanol (10 mL) and water (2 mL) was added 2N aqueous sodium hydroxide solution (1.5 mL, 3.00 mmol), and the mixture was heated to reflux for 70 minutes. 1N Hydrochloric acid was added, and the resulting crystals were collected by filtration and dried to give 4-carboxy-2- (4-trifluoromethylphenyl) isoindoline-1-one (604 mg, 94%).
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 5.32 (2H, s), 7.72 (1H, t, J = 7.6 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.07 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.17 (2H, d, J = 8.9 Hz), 8.23 (1H, dd, J = 1.0 Hz, 7. 6 Hz), 13.60 (1H, br).

(V) Synthesis of 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one 4-carboxy-2- (4-trifluoromethylphenyl) isoindoline obtained in (iv) above Borane-tetrahydrofuran complex (2.16 mL, 2.14 mmol) was added dropwise to a solution of -1-one (574 mg, 1.79 mmol) in tetrahydrofuran (35 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 45 minutes and at room temperature overnight. . Further, borane-tetrahydrofuran complex (0.90 mL, 0.90 mmol) was added, and the mixture was stirred at room temperature for 4 hours and a half. Methanol was added and the solvent was distilled off. Water was added, and the mixture was extracted with dichloromethane to obtain crystals of 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (520 mg, 95%).
mp 148-149 ° C
¹ H NMR (CDCl ₃ ) δ: 1.98 (1H, t, J = 5.6 Hz), 4.90 (2H, d, J = 5.6 Hz), 4.97 (2H, s), 7. 48 (1H, t, J = 7.3 Hz), 7.53 (1H, dd, J = 1.0 Hz, 7.3 Hz), 7.68 (2H, d, J = 8.9 Hz), 7.85 (1H, dd, J = 1.0 Hz, 7.3 Hz), 8.05 (2H, d, J = 8.9 Hz).

(Vi) Synthesis of 4-chloromethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one 4-hydroxymethyl-2- (4-trifluoromethylphenyl) iso obtained in (v) above Triethylamine (204 mg, 2.02 mmol) and methanesulfonyl chloride (231 mg, 2.02 mmol) were added to a solution of indoline-1-one (517 mg, 1.68 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature. Further, triethylamine (204 mg, 2.02 mmol) and methanesulfonyl chloride (231 mg, 2.02 mmol) were added, and the mixture was stirred overnight at room temperature. Aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, and washed with saturated brine. The solvent was distilled off to obtain crystals of 4-chloromethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (536 mg, 98%).
mp 170-172 ° C
¹ H NMR (CDCl ₃ ) δ: 4.73 (2H, s), 5.01 (2H, s), 7.54 (1H, t, J = 7.6 Hz), 7.61 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.70 (2H, d, J = 8.9 Hz), 7.93 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.07 (2H , D, J = 8.9 Hz).

(Vii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained by (vi) above To a solution of 4-chloromethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (293 mg, 0.90 mmol) obtained in acetonitrile (20 mL) with cesium carbonate (293 mg, 0.90 mmol) and Example 62 4-Mercapto-2-methylphenol (175 mg, 1.25 mmol) obtained in (ii) was added and stirred at room temperature for 1 hour. Thereafter, cesium carbonate (586 mg, 1.80 mmol) and ethyl bromoacetate (301 mg, 1.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added, and the obtained crystals were purified by silica gel column chromatography to obtain 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethylphenyl). Crystals of isoindoline-1-one (225 mg, 48%) were obtained.
mp 120-122 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 4.03 (2H, s), 4.23 (2H, q, J = 7.3 Hz), 4.53 (2H, s), 4.67 (2H, s), 6.54 (1H, d, J = 8.2 Hz), 7.02 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.11 (1 H, d, J = 2.0 Hz), 7.27 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.40 (1 H, t , J = 7.6 Hz), 7.68 (2H, d, J = 8.9 Hz), 7.81 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.99 (2H, d, J = 8.9 Hz).

Example 178 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 177 was To give 4-({[4- (carboxymethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 173-174 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.11 (3H, s), 4.27 (2H, s), 4.61 (2H, s), 4.94 (2H, s), 6.75 (1H, d, J = 8.2 Hz), 7.13-7.17 (2H, m), 7.43-7.49 (2H, m), 7.67-7.70 (1H, m) 7.81 (2H, d, J = 8.9 Hz), 8.13 (2H, d, J = 8.9 Hz), 13.04 (1H, br).

Example 179 (Synthesis of 4-{[4- (ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 4- (4-hydroxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one 4-trifluoromethanesulfonyloxy-2-obtained in Example 80 (i) Tris (dibenzylideneacetone) dipalladium in a solution of (4-trifluoromethylphenyl) isoindoline-1-one (638 mg, 1.50 mmol) and diisopropylethylamine (388 mg, 3.00 mmol) in 1,4-dioxane (10 mL) (0) (37 mg, 0.04 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (43 mg, 0.08 mmol), 4-hydroxythiophenol (208 mg, 1.65 mmol) were added. , Heated to reflux overnight. Further, tris (dibenzylideneacetone) dipalladium (0) (37 mg, 0.04 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (43 mg, 0.08 mmol), 4-hydroxythio Phenol (95 mg, 0.75 mmol) was added and heated to reflux for 3 hours. The mixture was filtered through celite, and water was added to the filtrate. The obtained crystals were purified by silica gel column chromatography to obtain crystals of 4- (4-hydroxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one (143 mg, 24%). .
mp 196-200 ° C
¹ H NMR (DMSO-d ₆ ) δ: 5.00 (2H, s), 6.85-6.90 (2H, m), 7.19 (1H, dd, J = 1.0 Hz, 7.6 Hz) ), 7.39-7.45 (2H, m), 7.48 (1H, t, J = 7.6 Hz), 7.64 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7 .81 (2H, d, J = 8.9 Hz), 8.17 (2H, d, J = 8.9 Hz), 9.97 (1H, s).

(Ii) Synthesis of 4-{[4- (ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (4-hydroxyphenyl) thio-2- ( To a solution of 4-trifluoromethylphenyl) isoindoline-1-one (143 mg, 0.36 mmol) in dimethylformamide (7 mL) was added potassium carbonate (54 mg, 0.39 mmol) and ethyl bromoacetate (65 mg, 0.39 mmol). , And stirred at 70 ° C. for 1.5 hours. Water was added, and the obtained crystals were purified by silica gel column chromatography to give 4-{[4- (ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one ( 129 mg, 74%) of crystals.
mp 146-147 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 4.27 (2H, q, J = 7.3 Hz), 4.64 (2H, s), 4. 72 (2H, s), 6.91-6.96 (2H, m), 7.32 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.38-7.45 (3H, m ), 7.68 (2H, d, J = 8.9 Hz), 7.77 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.01 (2H, d, J = 8.9 Hz) .

Example 180 Synthesis of 4-{[4- (carboxymethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one
The 4-{[4- (ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 179 was operated in the same manner as in Example 69, and 4 -{[4- (Carboxymethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 197-198 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.74 (2H, s), 5.01 (2H, s), 7.02 (2H, d, J = 8.2 Hz), 7.29 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.51 (2H, d, J = 8.2 Hz), 7.69 (1H, d, J = 7) .6 Hz), 7.82 (2H, d, J = 8.9 Hz), 8.17 (2H, d, J = 8.9 Hz), 13.12 (1H, br).

Example 181 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 3-hydroxy-2-methylbenzoic acid To a solution of 3-acetoxy-2-methylbenzoic acid (10 g, 51.5 mmol) in methanol (100 mL) was added 1N aqueous sodium hydroxide solution (62 mL, 62 mmol), Stir at room temperature for 30 minutes. The reaction solution was concentrated to about ½ volume under reduced pressure, 1N hydrochloric acid (62 mL, 62 mmol) was added, and the solvent was distilled off under reduced pressure. Chloroform-methanol was added to the resulting residue, dried over magnesium sulfate, and then the solvent was distilled off to obtain 3-hydroxy-2-methylbenzoic acid (7.73 g, 99%) crystals.
mp 146-147 ° C
¹ H NMR (CDCl ₃ ) δ: 2.51 (3H, s), 6.95 (1H, d, J = 7.7 Hz), 7.05 (1H, t, J = 7.7 Hz), 7. 18 (1H, d, J = 7.7 Hz), 9.59 (1H, s), 12.68 (1H, br).

(Ii) Synthesis of 3-methoxy-2-methylbenzoic acid methyl ester To a solution of 3-hydroxy-2-methylbenzoic acid (7.67 g, 50.4 mmol) obtained in (i) above in dimethylformamide (80 mL). Potassium carbonate (15.33 g, 111.0 mmol) and methyl iodide (15.75 g, 111.0 mmol) were added, and the mixture was stirred at 60 ° C. for 23 hours. The reaction solution was evaporated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The chloroform extract was dried over magnesium sulfate, and the solvent was distilled off to obtain an oily product of 3-methoxy-2-methylbenzoic acid methyl ester (8.25 g, 91%).
¹ H NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.85 (3H, s), 3.89 (3H, s), 6.98 (1H, dd, J = 1.0, 8.1 Hz), 7.20 (1H, t, J = 8.1 Hz), 7.40 (1H, dd, J = 1.0, 8.1 Hz).

(Iii) Synthesis of 2- (2-chloro-4-trifluoromethylphenyl) -4-methoxyisoindoline-1-one 3-methoxy-2-methylbenzoic acid methyl ester (0) obtained in (ii) above 0.5 g, 2.77 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (0.494 g, 2.77 mmol) and benzoyl peroxide (0.025 g), and the mixture was heated to reflux for 1 hour. The reaction solution was cooled, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. 2-Chloro-4-trifluoromethylaniline (0.542 g, 2.77 mmol) and dimethylformamide (10 mL) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 1.5 hours and 120 ° C. for 20 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, washed with diethyl ether-hexane, and 2- (2-chloro-4-trifluoromethylphenyl) -4- Crystals of methoxyisoindoline-1-one (355 mg, 37%) were obtained.
mp 162-165 ° C
¹ H NMR (CDCl ₃ ) δ: 3.94 (3H, s), 4.79 (2H, s), 7.10 (1H, dd, J = 1.3, 7.6 Hz), 7.47− 7.67 (4H, m), 7.80 (1H, m)
(Iv) Synthesis of 2- (2-chloro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one 2- (2-chloro-4-trifluoromethylphenyl) obtained in (iii) above ) -4-Methoxyisoindoline-1-one (0.33 g, 0.97 mmol) in methylene chloride (6 mL) with 1 mol / L boron tribromide methylene chloride solution (2.12 mL, 2.12 mmol) in ice It added under cooling and stirred at room temperature for 8 hours. The reaction mixture was evaporated under reduced pressure, and ice water was added to the residue. The precipitated crystals were collected by filtration, washed with water and dried to obtain crystals of 2- (2-chloro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (305 mg, 96%).
mp 241-247 ° C
¹ H NMR (CDCl ₃ ) δ: 4.83 (2H, s), 7.01 (1H, d, J = 7.3 Hz), 7.42 (1H, t, J = 7.7 Hz), 7. 55-7.67 (3H, s), 7.79-7.82 (1H, m).

(V) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one iv) 2- (2-chloro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in Example 170 (i) and 2- [4- (bromomethyl)- 2-Methylphenoxy] ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-chloro- 4-Trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 126-127 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.31 (3H, s), 4.26 (2H, q, J = 7.1 Hz), 4. 65 (2H, s), 4.80 (2H, s), 5.09 (2H, s), 6.70 (1H, d, J = 8.2 Hz), 7.14-7.25 (3H, m), 7.48 (1H, t, J = 7.7 Hz), 7.54-7.65 (3H, m), 7.79 (1H, s)
Example 182 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 181 Was prepared in the same manner as in Example 69, and 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1 -Obtained ON.
mp 188-189 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 4.71 (2H, s), 4.87 (2H, s), 5.17 (2H, s), 6.82 (1H, d, J = 8.6 Hz), 7.2-3.30 (2H, m), 7.37-7.44 (2H, m), 7.55 (1H, t, J = 7. 6 Hz), 7.88 (2H, s), 8.08 (2H, s), 12.99 (1H, br).

Example 183 (Synthesis of 7-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2- (4-trifluoromethylphenyl) -7-methoxyisoindoline-1-one Carbon tetrachloride of 2-methoxy-6-methylbenzoic acid methyl ester (3.71 g, 19.12 mmol) ( 50 mL) solution was added N-bromosuccinimide (3.40 g, 19.12 mmol) and benzoyl peroxide (1.50 g), and the mixture was heated to reflux for 4.5 hours. The reaction solution was cooled, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue were added 4-trifluoromethylaniline (3.08 g, 19.12 mmol) and dimethylformamide (50 mL), and the mixture was stirred at 60 ° C. for 1.5 hours and 120 ° C. for 17 hours. The reaction mixture was evaporated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was washed with diethyl ether to give 2- (4-trifluoromethylphenyl) -7-methoxyisoindoline- Crystals of 1-one (1.70 g, 29%) were obtained.
mp 173-178 ° C
¹ H NMR (CDCl ₃ ) δ: 4.02 (3H, s), 4.83 (2H, s), 6.95 (1H, d, J = 8.2 Hz), 7.09 (1H, d, J = 8.2 Hz), 7.56 (1H, t, J = 8.2 Hz), 7.66 (2H, d, J = 8.7 Hz), 8.02 (2H, d, J = 8.7 Hz) ).

(Ii) Synthesis of 2- (4-trifluoromethylphenyl) -7-hydroxyisoindoline-1-one 2- (4-trifluoromethylphenyl) -7-methoxyisoindoline- obtained in (i) above To a solution of 1-one (922 mg, 3.00 mmol) in methylene chloride (20 mL) was added 1 mol / L boron tribromide methylene chloride solution (3.3 mL, 3.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was evaporated under reduced pressure, and ice water was added to the residue. The precipitated crystals were collected by filtration, washed with water and dried to give 2- (4-trifluoromethylphenyl) -7-hydroxyisoindoline-1-one (870 mg, 99%).
mp 172-174 ° C
¹ H NMR (CDCl ₃ ) δ: 4.89 (2H, s), 6.93 (1H, d, J = 7.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 7. 50 (1H, t, J = 7.8 Hz), 7.69 (2H, d, J = 8.7 Hz), 7.97 (2H, d, J = 8.7 Hz), 8.66 (1H, s) ).
(Iii) Synthesis of 7-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one 2- (obtained in (ii) above) (4-Trifluoromethylphenyl) -7-hydroxyisoindoline-1-one and ethyl (3-bromomethylphenyl) acetate obtained in Example 95 (i) were operated in the same manner as in Example 138 (v). , 7-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 99-106 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 3.63 (2H, s), 4.14 (2H, q, J = 7.1 Hz), 4. 83 (2H, s), 5.32 (2H, s), 6.94 (1H, d, J = 7.9 Hz), 7.08 (1H, d, J = 6.9 Hz), 7.21- 7.52 (5H, m), 7.66 (2H, d, J = 8.7 Hz), 8.03 (2H, d, J = 8.7 Hz).

Example 184 (Synthesis of 7-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 7-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 183 was operated in the same manner as in Example 69. 7-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 188-192 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.60 (2H, s), 5.01 (2H, s), 5.28 (2H, s), 7.21 (3H, q, J = 8. 0 Hz), 7.34-7.50 (3 H, m), 7.62 (1 H, t, J = 8.7 Hz), 7.79 (2 H, d, J = 8.7 Hz), 8.12 ( 2H, d, J = 8.7 Hz), 12.35 (1H, br).

Example 185 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2-phenylisoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2-phenylisoindolin-1-one obtained in Example 170 was operated in the same manner as in Example 69, and 4 -({[4- (Carboxymethoxy) -3-methylphenyl] methyl} oxy) -2-phenylisoindoline-1-one was obtained.
mp 131-132 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.71 (2H, s), 4.95 (2H, s), 5.17 (2H, s), 6.83 (1H, d, J = 7.9 Hz), 7.17 (1H, d, J = 6.8 Hz), 7.27-7.54 (7H, m), 7.94 (2H, d, J = 8.6 Hz).

Example 186 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
To a suspension of 2- (4-methylphenyl) -4-hydroxyisoindoline-1-one (239 mg, 1.00 mmol) obtained in Synthesis Example 11 in acetonitrile (7 mL), cesium carbonate (358 mg, 1.10 mmol) And ethyl (3-bromomethylphenyl) acetate (283 mg, 1.10 mmol) obtained in Example 95 (i) was added and stirred at room temperature for 2.5 hours. Water was added, the mixture was extracted with ethyl acetate, purified by silica gel column chromatography, and 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1- On (270 mg, 65%) crystals were obtained.
mp 106-107 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 3.65 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4.81 (2H, s), 5.18 (2H, s), 7.10 (1H, d, J = 8.2 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.26-7.31 (1 H, m), 7.34-7.46 (4 H, m), 7.53 (1 H, d, J = 7.6 Hz), 7.76 ( 2H, d, J = 8.6 Hz).

Example 187 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 186 was operated in the same manner as in Example 69, 4-({[4- (Carboxymethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 193-194 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 3.61 (2H, s), 4.94 (2H, s), 5.27 (2H, s), 7.21 -7.26 (3H, m), 7.33-7.43 (5H, m), 7.50 (1H, t, J = 7.6 Hz), 7.81 (2H, d, J = 8. 2 Hz), 12.38 (1 H, s).

Example 188 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
To a suspension of 2- (4-trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one (309 mg, 1.00 mmol) obtained in Synthesis Example 19 in acetonitrile (7 mL), cesium carbonate (358 mg, 1. 10 mmol) and (3-bromomethylphenyl) ethyl acetate (283 mg, 1.10 mmol) obtained in Example 95 (i) were added, and the mixture was stirred at room temperature for 2.5 hours. Water was added, extracted with ethyl acetate, purified by silica gel column chromatography, and 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline- Crystals of 1-one (324 mg, 67%) were obtained.
mp 98-101 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 3.66 (2H, s), 4.16 (2H, q, J = 7.3 Hz), 4. 82 (2H, s), 5.19 (2H, s), 7.13 (1H, d, J = 7.6 Hz), 7.25-7.39 (6H, m), 7.46 (1H, t, J = 7.6 Hz), 7.54 (1H, d, J = 7.6 Hz), 7.91-7.96 (2H, m).

Example 189 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 188 was operated in the same manner as in Example 69. 4-({[4- (carboxymethoxy) -3-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 188-189 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 5.01 (2H, s), 5.28 (2H, s), 7.25 (1H, dt, J = 1. 6 Hz, 7.3 Hz), 7.34-7.45 (7 H, m), 7.52 (1 H, t, J = 7.6 Hz), 8.04-8.10 (2 H, m), 12. 37 (1H, s).

Example 190 Synthesis of 4-({2- [5- (ethoxycarbonylmethoxy) -2-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 5-methoxy-2-methylbenzoic acid To a solution of ethyl 5-methoxy-2-methylbenzoate (2.16 g, 11.11 mmol) in ethanol (10 mL) and water (2 mL), 2N aqueous sodium hydroxide solution (11.1 mL, 22.22 mmol) was added and heated to reflux for 1 hour. The solvent was distilled off, 1N hydrochloric acid was added, and the resulting crystals were collected by filtration and dried to obtain crystals of 5-methoxy-2-methylbenzoic acid (1.79 g, 97%).
mp 148-149 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.43 (3H, s), 3.76 (3H, s), 7.03 (1H, dd, J = 3.0 Hz, 8.2 Hz), 7. 21 (1H, d, J = 8.2 Hz), 7.33 (1H, d, J = 3.0 Hz), 12.88 (1H, s).

(Ii) Synthesis of (5-methoxy-2-methylphenyl) methanol Borane was added to a solution of 5-methoxy-2-methylbenzoic acid (1.76 g, 10.6 mmol) obtained in (i) above in tetrahydrofuran (40 mL). -Tetrahydrofuran complex (21.4 mL, 21.2 mmol) was added dropwise and stirred at room temperature for 1 hour. Methanol was added and the solvent was distilled off. Water was added, and the mixture was extracted with ethyl acetate to obtain oily (5-methoxy-2-methylphenyl) methanol (1.60 g, quant.).
¹ H NMR (CDCl ₃ ) δ: 1.57 (1H, t, J = 5.6 Hz), 2.27 (3H, s), 3.80 (3H, s), 4.67 (2H, d, J = 5.6 Hz), 6.75 (1H, dd, J = 3.0 Hz, 8.2 Hz), 6.96 (1H, d, J = 3.0 Hz), 7.08 (1H, d, J = 8.2 Hz).

(Iii) Synthesis of (5-methoxy-2-methylphenyl) acetonitrile (5-methoxy-2-methylphenyl) methanol (1.59 g, 10.41 mmol) obtained in the above (ii) under acetone cooling, acetone To a suspension of cyanohydrin (2.12 g, 20.83 mmol) and triphenylphosphine (3.55 g, 13.54 mmol) in toluene (50 mL) was added dropwise a solution of diethyl azodicarboxylate in toluene (5.68 mL, 12.50 mmol). The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 6 hours. The solvent was distilled off, and ethyl acetate (60 mL) and hexane (90 mL) were added. The insoluble material was filtered off and purified by silica gel column chromatography to obtain crystals of (5-methoxy-2-methylphenyl) acetonitrile (1.24 g, 74%).
mp 44-46 ° C
¹ H NMR (CDCl ₃ ) δ: 2.26 (3H, s), 3.63 (2H, s), 3.80 (3H, s), 6.79 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.92 (1H, d, J = 2.6 Hz), 7.11 (1H, d, J = 8.2 Hz).

(Iv) Synthesis of ethyl (5-hydroxy-2-methylphenyl) acetate (5-methoxy-2-methylphenyl) acetonitrile (1.19 g, 7.37 mmol) obtained in (iii) above (7 mL) And a 47% hydrobromic acid (7 mL) solution were stirred at 80 ° C. for 2 days. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent dichloromethane / ethanol = 10/1 (v / v)), and oily ethyl (5-hydroxy-2-methylphenyl) acetate (1.23 g, 86% )
¹ H NMR (DMSO-d ₆ ) δ: 1.18 (3H, t, J = 7.3 Hz), 2.09 (3H, s), 3.54 (2H, s), 4.07 (2H, q, J = 7.3 Hz), 6.55 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.60 (1H, d, J = 2.6 Hz), 6.94 (1H, d) , J = 8.2 Hz), 9.12 (1H, s).

(V) Synthesis of 3- (2-hydroxyethyl) -4-methylphenol Obtained in (iv) above in a suspension of lithium aluminum hydride (235 mg, 6.20 mmol) in tetrahydrofuran (30 mL) under ice-cooling. A tetrahydrofuran solution of ethyl (5-hydroxy-2-methylphenyl) acetate (1.20 g, 6.20 mmol) was added, and the mixture was stirred at room temperature for 7 hours. Methanol and water were added, and the mixture was filtered through celite and purified by silica gel column chromatography to obtain 3- (2-hydroxyethyl) -4-methylphenol (333 mg, 35%) crystals.
mp 74-76 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.14 (3H, s), 2.63 (2H, t, J = 7.3 Hz), 3.49-3.56 (2H, m), 4. 64 (1H, t, J = 5.3 Hz), 6.48 (1H, dd, J = 1.6 Hz, 7.9 Hz), 6.56 (1H, d, J = 1.6 Hz), 6.89 (1H, d, J = 7.9 Hz), 8.98 (1H, s).

(Vi) Synthesis of [3- (2-hydroxyethyl) -4-methylphenoxy] ethyl acetate 3- (2-hydroxyethyl) -4-methylphenol (304 mg, 2.00 mmol) obtained in (v) above Of cesium carbonate (717 mg, 2.20 mmol) and ethyl bromoacetate (367 mg, 2.20 mmol) were added to an acetonitrile (10 mL) solution, and the mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain oily [3- (2-hydroxyethyl) -4-methylphenoxy] ethyl acetate (455 mg, 95%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.43 (1H, t, J = 5.9 Hz), 2.26 (3H, s), 2. 85 (2H, t, J = 6.6 Hz), 3.80-3.86 (2H, m), 4.27 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 6.68 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.78 (1H, d, J = 2.6 Hz), 7.08 (1H, d, J = 8.2 Hz).

(Vii) Synthesis of 4-({2- [5- (ethoxycarbonylmethoxy) -2-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one In Synthesis Example 3 The obtained 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one and ethyl [3- (2-hydroxyethyl) -4-methylphenoxy] acetate obtained in (vi) above were used. And was operated in the same manner as in Example 148 (ii), and 4-({2- [5- (ethoxycarbonylmethoxy) -2-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) iso Crystals of indolin-1-one were obtained.
mp 149-150 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 2.32 (3H, s), 3.13 (2H, t, J = 6.9 Hz), 4. 22 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 6.9 Hz), 4.59 (2H, s), 4.78 (2H, s), 6.69 ( 1H, dd, J = 3.0 Hz, 8.2 Hz), 6.90 (1H, d, J = 3.0 Hz), 7.05 (1H, d, J = 7.6 Hz), 7.11 (1H , D, J = 8.2 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.52 (1H, d, J = 7.6 Hz), 7.68 (2H, d, J = 9.2 Hz), 8.07 (2H, d, J = 9.2 Hz).

Example 191 (Synthesis of 4-({2- [5- (carboxymethoxy) -2-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({2- [5- (ethoxycarbonylmethoxy) -2-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 190 was carried out. Operate analogously to Example 69 to give 4-({2- [5- (carboxymethoxy) -2-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 212-213 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 3.06 (2H, t, J = 6.6 Hz), 4.33 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 4.94 (2H, s), 6.69 (1H, dd, J = 2.6 Hz, 8.6 Hz), 6.91 (1H, d, J = 2.6 Hz) ), 7.09 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.51 (1H, t, J = 7.6 Hz), 7.80 (2H, d, J = 8.9 Hz), 8.16 (2H, d, J = 8.9 Hz), 12.97 (1H, br) .

Example 192 Synthesis of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindolin-1-one (I) Synthesis of 4-chloro-N- (4-nitrophenyl) butanamide In a solution of 4-nitroaniline (5.00 g, 36.20 mmol) and pyridine (5.73 g, 72.40 mmol) in tetrahydrofuran (100 mL), 4 -Chlorobutyryl chloride (6.12 g, 43.44 mmol) was added dropwise and the mixture was stirred at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. Washed and dried over anhydrous magnesium sulfate, distilled off solvent, purified by silica gel column chromatography, And chloroform and diisopropyl ether crystallized and dried to give 4-chloro -N- (4- nitrophenyl) butanamide (8.38 g, 95%) as a form of crystal.
mp 108-110 ° C
¹ H NMR (CDCl ₃ ) δ: 2.18-2.27 (2H, m), 2.65 (2H, t, J = 6.9 Hz), 3.68 (2H, t, J = 5.9 Hz) ), 7.60 (1H, brs), 7.69-7.74 (2H, m), 8.19-8.25 (2H, m).

(Ii) Synthesis of 1- (4-nitrophenyl) pyrrolidin-2-one 4-Dichloro-N- (4-nitrophenyl) butanamide (8.31 g, 34.23 mmol) obtained in (i) above Sodium hydride (oiliness 60%, 1.51 g, 37.62 mmol) was added to a formamide (200 mL) solution, and the mixture was stirred at room temperature for 11 hours. A saturated aqueous sodium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and dried to obtain 1- (4-nitrophenyl) pyrrolidin-2-one (7.39 g, quantitative) crystals.
mp 132-135 ° C
¹ H NMR (CDCl ₃ ) δ: 2.18-2.29 (2H, m), 2.68 (2H, t, J = 8.2 Hz), 3.94 (2H, t, J = 6.9 Hz) ), 7.82-7.87 (2H, m), 8.22-8.27 (2H, m).

(Iii) Synthesis of 1- (4-aminophenyl) pyrrolidin-2-one 1- (4-nitrophenyl) pyrrolidin-2-one (7.20 g, 34.85 mmol) of methanol obtained in (ii) above (100 mL) To the solution was added activated carbon-palladium (300 mg, 10% by weight of palladium supported), and the mixture was stirred at room temperature for 5 hours. After filtration of the reaction mixture, the filtrate was concentrated and dried to give 1- (4-aminophenyl) pyrrolidin-2-one (5.70 g, 94%) crystals.
mp 131-134 ° C
¹ H NMR (CDCl ₃ ) δ: 2.07-2.19 (2H, m), 2.57 (2H, t, J = 7.6 Hz), 3.63 (2H, br), 3.80 ( 2H, t, J = 6.9 Hz), 6.65-6.71 (2H, m), 7.31-7.37 (2H, m).

(Iv) Synthesis of 4-hydroxy-2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindoline-1-one In step (ii) of Synthesis Example 3, 1-amino-4- (tri Synthesis example, except that 1- (4-aminophenyl) pyrrolidin-2-one (881 mg, 5.00 mmol) obtained in (iii) above was used instead of fluoromethyl) benzene, and the reaction scale was appropriately changed. In the same manner as in Example 3, 4-hydroxy-2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindolin-1-one (yield 897 mg, yield 58%) was synthesized.
mp 308-310 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.02-2.13 (2H, m), 2.47-2.53 (2H, m), 3.85 (2H, t, J = 6.9 Hz) 4.87 (2H, s), 7.05 (1H, dd, J = 0.7 Hz, 7.9 Hz), 7.22 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7. 36 (1H, t, J = 7.9 Hz), 7.68-7.74 (2H, m), 7.87-7.93 (2H, m), 10 (1H, br).

(V) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindoline-1-one 4-Hydroxy-2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindolin-1-one obtained in (iv) and [3- (2 -Hydroxyethyl) phenoxy] ethyl acetate was operated in the same manner as in Example 68 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2- Oxopyrrolidin-1-yl) phenyl] isoindoline-1-one was obtained.
mp 122-124 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.13-2.24 (2H, m), 2.63 (2H, t, J = 7.6 Hz) ), 3.89 (2H, t, J = 7.3 Hz), 4.25 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 6.9 Hz), 4.62. (2H, s), 4.73 (2H, s), 6.77 (1H, ddd, J = 1.0 Hz, 2.6 Hz, 8.2 Hz), 6.90-6.95 (2H, m) 7.02 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.26 (1H, t, J = 7.3 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.65-7.71 (2H, m), 7.87-7.92 (2H, m).

Example 193 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindoline-1- obtained in Example 192 The ON is operated as in Example 69 and 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [4- (2-oxopyrrolidin-1-yl) phenyl] isoindoline. -1-one was obtained.
mp 218-220 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.02-2.13 (2H, m), 2.47-2.53 (2H, m), 3.05 (2H, t, J = 6.9 Hz) ), 3.85 (2H, t, J = 6.9 Hz), 4.34 (2H, t, J = 6.9 Hz), 4.60 (2H, s), 4.85 (2H, s), 6.74-6.78 (1H, m), 6.92-6.95 (2H, m), 7.22 (1H, t, J = 7.9 Hz), 7.29-7.35 (2H M), 7.49 (1H, t, J = 7.6 Hz), 7.67-7.32 (2H, m), 7.88-7.94 (2H, m).

Example 194 Synthesis of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one (i) 4-hydroxy-2- Synthesis of (4-methylthiophenyl) isoindoline-1-one In Step (ii) of Synthesis Example 3, instead of 1-amino-4- (trifluoromethyl) benzene, 4-methylthioaniline (1.39 g, 10 Except that the reaction scale was appropriately changed, and 4-hydroxy-2- (4-methylthiophenyl) isoindoline-1-one (yield 1.51 g, yield) was obtained. 56%) was synthesized.
mp 259-260 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.49 (3H, s), 4.86 (2H, s), 7.05 (2H, dd, J = 0.7 Hz, 7.9 Hz), 7.22 (2H, dd, J = 0.7 Hz, 7.6 Hz), 7.32-7.38 (3H, m), 7.84-7.90 (2H, m), 10 (1H, br).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one 4- (obtained in (i) above) Hydroxy-2- (4-methylthiophenyl) isoindoline-1-one and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) were used in the same manner as in Example 68 (ii). By operation, 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one was obtained.
mp 131-132 ° C
¹ HNMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.50 (3H, s), 3.12 (2H, t, J = 6.9 Hz), 4.24 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 6.9 Hz), 4.62 (2H, s), 4.71 (2H, s), 6.77 (1H , Ddd, J = 1.0 Hz, 2.3 Hz, 8.2 Hz), 6.91-6.94 (2H, m), 7.02 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.22-7.28 (1H, m), 7.31-7.36 (2H, m), 7.42 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.80-7.86 (2H, m).

Example 195 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one obtained in Example 194 was operated in the same manner as in Example 69. 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one was obtained.
mp 198.5-200 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.49 (3H, s), 3.06 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4 .66 (2H, s), 4.85 (2H, s), 6.77 (1H, ddd, J = 1.0 Hz, 2.3 Hz, 8.2 Hz), 6.93-6.96 (2H, m), 7.23 (1H, t, J = 7.9 Hz), 7.29-7.37 (4H, m), 7.49 (1H, t, J = 7.6 Hz), 7.85- 7.90 (2H, m).

Example 196 Synthesis of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methanesulfonylphenyl) isoindoline-1-one 4 obtained in Example 194 -({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiophenyl) isoindoline-1-one (400 mg, 0.84 mmol) in chloroform (14 mL) was added m- Chloroperbenzoic acid (content: about 70%, 622 mg, 2.52 mmol) was added and stirred overnight at room temperature, saturated aqueous sodium carbonate solution was added, and the organic layer was separated. After washing with an aqueous sodium solution and drying over anhydrous magnesium sulfate, the solvent was distilled off and a silica gel column chromatography was performed. To give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methanesulfonylphenyl) isoindoline-1-one (300 mg, 70%). It was.
mp 163-165 ° C
¹ HNMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 3.08 (3H, s), 3.14 (2H, t, J = 6.6 Hz), 4.24 (2H, q, J = 7.3 Hz), 4.32 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 4.77 (2H, s), 6.77 (1H , Ddd, J = 1.0 Hz, 2.3 Hz, 8.2 Hz), 6.91-6.95 (2H, m), 7.07 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.23-7.29 (1H, m), 7.46 (1H, t, J = 7.9 Hz), 7.52 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.96 -8.02 (2H, m), 8.13-8.18 (2H, m).

Example 197 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methanesulfonylphenyl) isoindolin-1-one)
4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methanesulfonylphenyl) isoindoline-1-one obtained in Example 196 was treated in the same manner as in Example 69. Operation gave 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methanesulfonylphenyl) isoindoline-1-one.
mp 162-164 ° C
¹ HNMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.6 Hz), 3.22 (3H, s), 4.36 (2H, t, J = 6.6 Hz), 4 .66 (2H, s), 4.95 (2H, s), 6.78 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.94-6.96 (2H, m), 7 .24 (1H, t, J = 7.9 Hz), 7.34-7.41 (2H, m), 7.52 (1H, t, J = 7.6 Hz), 7.97 (2H, app- d, J = 8.9 Hz), 8.21 (2H, app-d, J = 8.9 Hz).

Example 198 Synthesis of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one Obtained in the same manner as in Synthesis Example 11. 2- (4-methylphenyl) -4-hydroxyisoindoline-1-one and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) were used in Example 148 (ii). To give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one.
mp 115-116 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 3.12 (2H, t, J = 6.9 Hz), 4. 24 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 6.9 Hz), 4.62 (2H, s), 4.73 (2H, s), 6.77 ( 1H, ddd, J = 1.0 Hz, 2.6 Hz, 7.9 Hz), 6.90-6.94 (2H, m), 7.02 (1H, dd, J = 1.0 Hz, 7.9 Hz) , 7.21-7.28 (3H, m), 7.42 (1H, t, J = 7.9 Hz), 7.50 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7. 73-7.78 (2H, m).

Example 199 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 198 was operated in the same manner as in Example 69. 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one was obtained.
mp 193-195 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 3.06 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6.6 Hz), 4.66 (2H, s), 4.83 (2H, s), 6.77 (1H, dt, J = 1.3 Hz, 8.2 Hz), 6.94-6.96 (2H, m), 7.20-7.23 (1H, m), 7.23 (2H, d, J = 8.2 Hz), 7.30 (1H, d, J = 7.9 Hz), 7.34 (1H, d , J = 7.9 Hz), 7.48 (1H, t, J = 7.9 Hz), 7.79 (2H, d, J = 8.2 Hz), 12.98 (1H, br).

Example 200 (Synthesis of 7-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
2- (4-Trifluoromethylphenyl) -7-hydroxyisoindoline-1-one obtained in Example 183 (ii) and 2- [4- (bromomethyl)-obtained in Example 170 (i) 2-Methylphenoxy] ethyl acetate was operated in the same manner as in Example 138 (v) to give 7-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoro Methylphenyl) isoindoline-1-one was obtained.
mp 156-158 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.30 (3H, s), 4.26 (2H, q, J = 7.1 Hz), 4. 63 (2H, s), 4.82 (2H, s), 5.24 (2H, s), 6.71 (1H, d, J = 8.4 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.07 (1 H, d, J = 7.7 Hz), 7.24-7.30 (2 H, m), 7.49 (1 H, t, J = 7.7 Hz), 7. 66 (2H, d, J = 8.6 Hz), 8.03 (2H, d, J = 8.6 Hz).

Example 201 (Synthesis of 7-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 7-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 200 was prepared in Example 69. To give 7-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 129-132 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.71 (2H, s), 4.50 (2H, s), 5.17 (2H, s), 6.85 (1H, d, J = 8.9 Hz), 7.14-7.21 (2H, m), 7.28-7.33 (2H, m), 7.61 (1H, t, J = 7. 9 Hz), 7.78 (2H, d, J = 8.7 Hz), 8.11 (2H, d, J = 8.7 Hz).

Example 202 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindolin-1-one)
(I) Synthesis of 2- (3-fluoro-4-trifluoromethylphenyl) -4-methoxyisoindoline-1-one 3-methoxy-2-methylbenzoic acid methyl ester obtained in Example 181 (ii) (1.0 g, 5.55 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (0.988 g, 5.55 mmol) and benzoyl peroxide (0.050 g), and the mixture was heated to reflux for 2 hours. The reaction solution was cooled, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue were added 3-fluoro-4-trifluoromethylaniline (0.994 g, 5.55 mmol) and dimethylformamide (20 mL), and the mixture was stirred at 60 ° C. for 2 hours and 120 ° C. for 15 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, washed with diethyl ether-hexane, and 2- (3-fluoro-4-trifluoromethylphenyl) -4- Crystals of methoxyisoindoline-1-one (1.11 g, 62%) were obtained.
mp 213-214 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.94 (3H, s), 5.01 (2H, s), 7.34 (1H, d, J = 8.5 Hz), 7.41 (1H, d, J = 7.7 Hz), 7.56 (1H, t, J = 7.7 Hz), 7.83 (1H, t, J = 8.5 Hz), 7.98 (1H, d, J = 8) .5 Hz), 8.15 (1H, d, J = 14.1 Hz).

(Ii) Synthesis of 2- (3-fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one 2- (3-fluoro-4-trifluoromethylphenyl) obtained in (i) above ) -4-Methoxyisoindoline-1-one (0.80 g, 2.46 mmol) in methylene chloride (32 mL) in a 1 mol / L boron tribromide methylene chloride solution (4.90 mL, 4.90 mmol) Was added under ice cooling and stirred at 0 ° C. for 1 hour. The reaction mixture was evaporated under reduced pressure, and ice water was added to the residue. The precipitated crystals were collected by filtration, washed with water and dried to obtain crystals of 2- (3-fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (763 mg, quant.).
mp 243-256 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.96 (2H, s), 7.10 (1H, d, J = 8.5 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.39 (1H, t, J = 7.6 Hz), 7.84 (1H, t, J = 8.5 Hz), 7.92 (1H, d, J = 8.5 Hz), 8.15 (1H , Dd, J = 2.3, 12.7 Hz), 10.25 (1H, s).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindolin-1-one 2- (3-Fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in ii) and 2- [4- (bromomethyl)-obtained in Example 170 (i) 2-Methylphenoxy] ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro- 4-Trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 147-149 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 2.34 (3H, s), 4.28 (2H, q, J = 7.1 Hz), 4. 68 (2H, s), 4.79 (2H, s), 5.09 (2H, s), 6.73 (1H, d, J = 8.2 Hz), 7.16 (1H, dd, J = 1.0, 7.6 Hz), 7.18-7.30 (2H, m), 7.44-7.71 (4H, m), 8.03 (1 H, d, J = 12.8 Hz).

Example 203 Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindolin-1-one)
4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Synthesis Example 4 and 2- [4- (bromomethyl) -2-methylphenoxy obtained in Example 170 (i) Ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline. -1-one was obtained.
mp 149-151 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 2.34 (3H, s), 3.92 (3H, s), 4.28 (2H, q, J = 7.1 Hz), 4.67 (2H, s), 4.83 (2H, s), 5.09 (2H, s), 6.73 (1H, d, J = 8.2 Hz), 7 .14 (1H, d, J = 7.3 Hz), 7.19-7.27 (2H, m), 7.42-7.55 (2H, m), 8.02 (2H, d, J = 9.2 Hz), 8.09 (2H, d, J = 9.2 Hz).

Example 204 Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Example 203 was The same operation was performed to obtain 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one.
mp 196-200 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.67 (2H, s), 4.99 (2H, s), 5.16 (2H, s), 6.82 (1H, d, J = 8.9 Hz), 7.25-7.36 (4H, m), 7.48-7.55 (1H, m), 7.97 (2H, d, J = 8. 9 Hz), 8.10 (2H, d, J = 8.9 Hz).

Example 205 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- (3-fluoro-4-methylphenyl) isoindoline-1-one In step (ii) of Synthesis Example 3, 1-amino-4- (trifluoromethyl) benzene Instead, using 3-fluoro-4-methylaniline (0.902 g, 7.20 mmol) and changing the reaction scale as appropriate, the same procedure as in Synthesis Example 3 was carried out to give 4-hydroxy-2- (3 -Fluoro-4-methylphenyl) isoindoline-1-one (0.902 g, 7.20 mmol) (yield 1.27 g, 68% yield) was synthesized.
mp 272-282 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.23 (3H, s), 4.87 (2H, s), 7.06 (1H, d, J = 8.1 Hz), 7.23 (1H, d, J = 7.3 Hz), 7.28-7.40 (2H, m), 7.57 (1H, dd, J = 2.3, 8.1 Hz), 7.85 (1H, dd, J = 2.3, 12.7 Hz), 10.25 (1H, s).

(Ii) Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one obtained in (i) above 4-hydroxy-2- (3-fluoro-4-methylphenyl) isoindoline-1-one and ethyl (3-bromomethylphenyl) acetate obtained in Example 95 (i) were combined with Example 138 (v). The same operation was performed to obtain 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one.
mp 108-110 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 2.27 (3H, s), 3.66 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 4.79 (2H, s), 5.18 (2H, s), 7.09-7.55 (9H, m), 7.74 (1H, dd, J = 2. 1,12.0 Hz).

Example 206 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one)
4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one obtained in Example 205 was used in the same manner as in Example 69. To give 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one.
mp 214-217 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.23 (3H, s), 3.61 (2H, s), 4.97 (2H, s), 5.28 (2H, s), 7.23 −7.54 (8H, m), 7.62 (1H, dd, J = 2.2, 8.4 Hz), 7.88 (1H, dd, J = 2.2, 12.5 Hz), 12. 37 (1H, br).

Example 207 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one)
4-Hydroxy-2- (3-fluoro-4-methylphenyl) isoindoline-1-one obtained in Example 205 (i) and 2- [4- (bromomethyl) obtained in Example 170 (i) ) -2-methylphenoxy] ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3- Fluoro-4-methylphenyl) isoindoline-1-one was obtained.
mp 123-124 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 2.26 (3H, s), 2.33 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 4.67 (2H, s), 4.75 (2H, s), 5.08 (2H, s), 6.73 (1H, d, J = 8.1 Hz), 7 .12 (1H, dd, J = 1.0, 8.1 Hz), 7.15-7.27 (3H, m), 7.40-7.54 (3H, m), 7.74 (1H, dd, J = 2.3, 12.2 Hz).

Example 208 Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one obtained in Example 207 was carried out. Operate analogously to Example 69 to give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-methylphenyl) isoindoline-1-one. It was.
mp 187-189 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (6H, s), 4.70 (2H, s), 4.93 (2H, s), 5.16 (2H, s), 6.83 (1H, d, J = 8.2 Hz), 7.25-7.39 (5H, m), 7.50 (1H, t, J = 7.7 Hz), 7.62 (1H, dd, J = 2.1, 8.2 Hz), 7.87 (1H, dd, J = 2.1, 12.7 Hz).

Example 209 (Synthesis of 4-({[3- (ethoxycarbonylmethoxy) -5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 4-({[3-methoxymethoxy-5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in the same manner as in Synthesis Example 3. 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one and 1-bromomethyl-3-methoxymethoxy-5-methylbenzene synthesized according to International Publication No. WO2006 / 126514 were prepared in Example 138 (v ) To give 4-({[3-methoxymethoxy-5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 163-164 ° C
¹ HNMR (CDCl ₃ ) δ: 2.37 (3H, s), 3.48 (3H, s), 4.85 (2H, s), 5.13 (2H, s), 5.18 (2H, s), 6.87-6.94 (3H, m), 7.12 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.53 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, app-d, J = 8.6 Hz), 8.05 (2H, app-d, J = 8. 6 Hz).

(Ii) Synthesis of 4-{[(3-hydroxy-5-methylphenyl) methyl] oxy} -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (obtained in (i) above) ({[3-methoxymethoxy-5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (739 mg, 1.61 mmol) in acetic acid (20 mL) and ethanol (20 mL The mixture was dissolved by heating, hydrochloric acid (0.25 g) was added, and the mixture was stirred at 95 ° C. for 45 minutes. After concentration, the residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and dried to give 4-{[(3-hydroxy-5-methylphenyl) methyl] oxy} -2- (4-trifluoromethylphenyl) isoindoline-1-one (666 mg, 100%) Got.
mp 225-227 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.24 (3H, s), 5.03 (2H, s), 5.17 (2H, s), 6.56-6.74 (3H, m), 7.32-7.41 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.78 (2H, app-d, J = 8.6 Hz), 8.19 (2H , App-d, J = 8.6 Hz), 9.37 (1H, s).

(Iii) 4-({[3- (ethoxycarbonylmethoxy) -5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in (ii) above 4-{[(3-Hydroxy-5-methylphenyl) methyl] oxy} -2- (4-trifluoromethylphenyl) isoindoline-1-one was operated in the same manner as in Example 140 (ii), and 4- Crystals of ({[3- (ethoxycarbonylmethoxy) -5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one (307 mg, 85%) were obtained.
mp 152-154 ° C
¹ HNMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4.63 (2H, s), 4.85 (2H, s), 5.13 (2H, s), 6.71-6.88 (3H, m), 7.11 (1H, dd, J = 0.7 Hz) , 7.9 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.54 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, app-d, J = 8.6 Hz), 8.07 (2H, app-d, J = 8.6 Hz).

Example 210 (Synthesis of 4-({[3- (carboxymethoxy) -5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[3- (Ethoxycarbonylmethoxy) -5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 209 was To give 4-({[3- (carboxymethoxy) -5-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 203-205 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 4.67 (2H, s), 5.05 (2H, s), 5.22 (2H, s), 6.72- 6.93 (3H, m), 7.35-7.42 (2H, m), 7.52 (1H, t, J = 7.6 Hz), 7.78 (2H, app-d, J = 8) .9 Hz), 8.20 (2H, app-d, J = 8.6 Hz).

Example 211 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of (3-methoxymethoxy-5-methylphenyl) acetic acid (3-methoxymethoxy-5-methylphenyl) acetonitrile (1.78 g, 9.3 mmol) synthesized in accordance with International Publication No. WO2006 / 126514 (1.78 g, 9.3 mmol) 20 mL) solution was added potassium hydroxide (2.68, 47.8 mmol) in water (10 mL), and the mixture was heated to reflux for 6 hours. After concentration, the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and dried to give (3-methoxymethoxy-5-methylphenyl) acetic acid (1.92 g, 98%).
mp 81-82 ° C
¹ H NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.47 (3H, s), 3.58 (2H, s), 5.15 (2H, s), 6.75-6 .78 (3H, m).

(Ii) Synthesis of 1- (2-hydroxyethyl) -3-methoxymethoxy-5-methylbenzene (3-methoxymethoxy-5-methylphenyl) acetic acid (1.88 g, 9. 0 mmol) in tetrahydrofuran (18 mL) was added dropwise borane / tetrahydrofuran complex (1M, 11.6 mL, 11.6 mmol), and the mixture was stirred at room temperature for 2 hours. After diluting with diethyl ether and adding methanol, the organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Purification by silica gel column chromatography gave oily 1- (2-hydroxyethyl) -3-methoxymethoxy-5-methylbenzene (1.56 g, 89%).
¹ H NMR (CDCl ₃ ) δ: 1.49 (1H, br), 2.31 (3H, s), 2.80 (2H, t, J = 6.6 Hz), 3.48 (3H, s) 3.84 (2H, t, J = 6.3 Hz), 5.15 (2H, s), 6.70-6.74 (3H, m).

(Iii) Synthesis of 3- (2-hydroxyethyl) -5-methylphenol 1- (2-hydroxyethyl) -3-methoxymethoxy-5-methylbenzene (1.52 g, 7) obtained in (ii) above .8 mmol) in methanol (30 mL) was added hydrochloric acid (0.20 g) and heated to reflux for 1 hour. Dilute with ethyl acetate, wash the organic layer with water and saturated aqueous sodium chloride, and dry over anhydrous magnesium sulfate to give oily 3- (2-hydroxyethyl) -5-methylphenol (1.13 g, 96%). It was.
¹ H NMR (CDCl ₃ ) δ: 2.03 (1H, br), 2.26 (3H, s), 2.75 (2H, t, J = 6.3 Hz), 3.83 (2H, t, J = 6.3 Hz), 6.06 (1H, br), 6.49-6.58 (3H, m).

(Iv) Synthesis of [3- (2-hydroxyethyl) -5-methylphenoxy] ethyl acetate 3- (2-hydroxyethyl) -5-methylphenol obtained in (iii) above (1.11 g, 7. To a solution of 3 mmol) in acetonitrile (25 mL) were added cesium carbonate (2.85 g, 8.8 mmol) and ethyl bromoacetate (1.46 g, 8.8 mmol), and the mixture was stirred at room temperature for 4 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily [3- (2-hydroxyethyl) -5-methylphenoxy] ethyl acetate (1.43 g, 82%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.46 (1H, br), 2.31 (3H, d, J = 1.0 Hz), 2. 79 (2H, t, J = 6.6 Hz), 2.83 (2H, br), 4.27 (2H, q, J = 7.3 Hz), 4.60 (2H, s), 6.60 ( 2H, br), 6.69 (1H, m).

(V) 4-({2- [3- (ethoxycarbonylmethoxy) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Synthesis Example 3 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (440 mg, 1.5 mmol), [3- (2-hydroxyethyl) -5-methyl obtained in (iv) above Phenoxy] ethyl acetate (357 mg, 1.5 mmol) was used in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) -5-methylphenyl] ethyl} oxy) Crystals of -2- (4-trifluoromethylphenyl) isoindoline-1-one (638 mg, 83%) were obtained.
mp 106-107 ° C
¹ HNMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 2.32 (3H, s), 3.08 (2H, t, J = 6.6 Hz), 4.23 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 6.6 Hz), 4.60 (2H, s), 4.76 (2H, s), 6.60-6 .74 (3H, m), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.44 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, app-d, J = 8.6 Hz), 8.06 (2H, app-d, J = 8.2 Hz).

Example 212 Synthesis of 4-({2- [3- (carboxymethoxy) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one
4-({2- [3- (Ethoxycarbonylmethoxy) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 211 was carried out Operate analogously to Example 69 to obtain 4-({2- [3- (carboxymethoxy) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 172-174 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 3.02 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6.6 Hz), 4 .65 (2H, s), 4.94 (2H, s), 6.61-6.78 (3H, m), 7.33-7.40 (2H, m), 7.51 (1H, t , J = 7.6 Hz), 7.80 (2H, app-d, J = 8.9 Hz), 8.17 (2H, app-d, J = 8.6 Hz).

Example 213 Synthesis of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-sulfamoylphenyl) isoindoline-1-one (i) 4-hydroxy- Synthesis of 2- (4-sulfamoylphenyl) isoindoline-1-one In Step (ii) of Synthesis Example 3, 4-sulfamoylaniline was used instead of 1-amino-4- (trifluoromethyl) benzene. (861 mg, 5.00 mmol) was used, except that the reaction scale was appropriately changed, and the same operation as in Synthesis Example 3 was carried out to give 4-hydroxy-2- (4-sulfamoylphenyl) isoindoline-1-one ( Yield 1.05 g, yield 69%) was synthesized.
mp 292-295 ° C
¹ HNMR (DMSO-d ₆ ) δ: 4.94 (2H, s), 7.08 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.25-7.41 (4H, m) 7.84-7.89 (2H, m), 8.08-8.14 (2H, m), 10.34 (1H, br).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-sulfamoylphenyl) isoindolin-1-one obtained in (i) above. 4-hydroxy-2- (4-sulfamoylphenyl) isoindoline-1-one and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) were used in Example 68 (ii). ) To give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-sulfamoylphenyl) isoindoline-1-one.
mp 199-201 ° C
¹ HNMR (DMSO-d ₆ ) δ: 1.17 (3H, t, J = 7.3 Hz), 3.08 (2H, t, J = 6.6 Hz), 4.12 (2H, q, J = 7.3 Hz), 4.37 (2H, t, J = 6.6 Hz), 4.77 (2H, s), 4.92 (2H, s), 6.77-6.82 (1H, m) , 6.96-6.99 (2H, m), 7.25 (1 H, t, J = 7.6 Hz), 7.33-7.40 (4H, m), 7.52 (1 H, t, J = 7.6 Hz), 7.84-7.89 (2H, m), 8.09-8.15 (2H, m).

Example 214 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-sulfamoylphenyl) isoindolin-1-one
4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-sulfamoylphenyl) isoindoline-1-one obtained in Example 213 was used in the same manner as in Example 69. To give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-sulfamoylphenyl) isoindolin-1-one.
mp 217-229 ° C
¹ HNMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.6 Hz), 4.36 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4 .94 (2H, s), 6.78 (1H, dd, J = 1.6 Hz, 7.6 Hz), 6.95-6.97 (2H, m), 7.24 (1H, t, J = 7.9 Hz), 7.33-7.40 (4 H, m), 7.51 (1 H, t, J = 7.6 Hz), 7.84-7.89 (2 H, m), 8.10 − 8.15 (2H, m).

Example 215 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [3,4- (methylenedioxy) phenyl] isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- (3,4-methylenedioxyphenyl) isoindoline-1-one In step (ii) of Synthesis Example 3, 1-amino-4- (trifluoromethyl) benzene was converted to Instead, 3,4-methylenedioxyaniline (411 mg, 3.00 mmol) was used, and the reaction scale was changed as appropriate, and the same operation as in Synthesis Example 3 was carried out to give 4-hydroxy-2- (3,4 -Methylenedioxyphenyl) isoindoline-1-one (yield 293 mg, yield 36%) was synthesized.
mp 270-274 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.82 (2H, s), 6.04 (2H, s), 6.97 (1H, d, J = 8.6 Hz), 7.04 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.21 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.25 (1H, dd, J = 2.0 Hz, 8.6 Hz) 7.35 (1H, t, J = 7.6 Hz), 7.59 (1H, d, J = 2.0 Hz), 10.19 (1H, s).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [3,4- (methylenedioxy) phenyl] isoindoline-1-one (i) 4-hydroxy-2- (3,4-methylenedioxyphenyl) isoindoline-1-one obtained in 1) and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) Was prepared in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [3,4- (methylenedioxy) phenyl] isoindoline. -1-one was obtained.
mp 136-138 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 3.12 (2H, t, J = 6.6 Hz), 4.25 (2H, q, J = 7) .3 Hz), 4.30 (2H, t, J = 6.6 Hz), 4.62 (2H, s), 4.69 (2H, s), 5.99 (2H, s), 6.77 ( 1H, ddd, J = 1.0 Hz, 2.3 Hz, 8.2 Hz), 6.85 (1H, d, J = 8.2 Hz), 6.90-6.95 (2H, m), 7.02 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.15 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.25 (1H, t, J = 8.2 Hz), 7.42 (1H, t, J = 7.6 Hz), 7.49 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.57 (1H, d, J = 2.3 Hz).

Example 216 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [3,4- (methylenedioxy) phenyl] isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [3,4- (methylenedioxy) phenyl] isoindoline-1-one obtained in Example 215 was carried out. Operate analogously to Example 69 to give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [3,4- (methylenedioxy) phenyl] isoindoline-1-one. It was.
mp 192-193 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4.82 (2H, s), 6.05 (2H, s), 6.76-6.79 (1H, m), 6.94-6.99 (3H, m), 7.20-7. 35 (4H, m), 7.49 (1H, t, J = 7.6 Hz), 7.61 (1H, t, J = 2.0 Hz), 12.96 (1H, br).

Example 217 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
2- (4-Trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one obtained in the same manner as in Synthesis Example 19 and [3- (2-hydroxyethyl) obtained in Example 68 (i) Phenoxy] ethyl acetate was operated as in Example 148 (ii) and 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline. -1-one was obtained.
mp 106-107 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 3.12 (2H, t, J = 6.6 Hz), 4.24 (2H, q, J = 7) .3Hz), 4.31 (2H, t, J = 6.6 Hz), 4.62 (2H, s), 4.73 (2H, s), 6.77 (1H, dd, J = 2.3 Hz) , 7.6 Hz), 6.91-6.94 (2 H, m), 7.04 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.23-7.30 (3 H, m) 7.44 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.91-7.97 (2H, m).

Example 218 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 217 was used in the same manner as in Example 69. To give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 161-162 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.6 Hz), 4.36 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4.90 (2H, s), 6.78 (1H, dd, J = 2.3 Hz, 7.9 Hz), 6.95-6.97 (2H, m), 7.24 (1H, t, J = 7.9 Hz), 7.33 (1H, d, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.45 (2H, d, J = 9.2 Hz) 7.51 (1H, t, J = 7.6 Hz), 8.02-8.08 (2H, m), 12.97 (1H, s).

Example 219 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-phenoxyphenyl) isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- (4-phenoxyphenyl) isoindoline-1-one In the step (ii) of Synthesis Example 3, instead of 1-amino-4- (trifluoromethyl) benzene, 4 4-Hydroxy-2- (4-phenoxyphenyl) isoindoline-1-one was prepared in the same manner as in Synthesis Example 3, except that phenoxyaniline (926 mg, 5.00 mmol) was used and the reaction scale was appropriately changed. (Yield 890 mg, 56% yield) was synthesized.
mp 254-257 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.88 (2H, s), 7.01-7.17 (6H, m), 7.24 (1H, d, J = 7.6 Hz), 7. 34-7.43 (3H, m), 7.89-7.95 (2H, m), 10.23 (1H, s).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-phenoxyphenyl) isoindoline-1-one)
4-hydroxy-2- (4-phenoxyphenyl) isoindoline-1-one obtained in (i) above and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) To give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-phenoxyphenyl) isoindoline-1-one. It was.
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 3.12 (2H, t, J = 6.6 Hz), 4.23 (2H, q, J = 7) .3 Hz), 4.31 (2 H, t, J = 6.6 Hz), 4.62 (2 H, s), 4.74 (2 H, s), 6.77 (1 H, ddd, J = 1.3 Hz) , 2.3 Hz, 7.9 Hz), 6.91-6.95 (2H, m), 7.01-7.14 (6H, m), 7.22-7.28 (1H, m), 7 .31-7.39 (2H, m), 7.43 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.81- 7.87 (2H, m).

Example 220 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-phenoxyphenyl) isoindolin-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-phenoxyphenyl) isoindoline-1-one obtained in Example 219 was operated in the same manner as in Example 69. 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-phenoxyphenyl) isoindoline-1-one was obtained.
mp 192-193 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4.87 (2H, s), 6.77 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.94-6.96 (2H, m), 7.02-7.05 (2H M), 7.09-7.16 (3H, m), 7.23 (1H, t, J = 8.2 Hz), 7.30-7.43 (4H, m), 7.50 (1H) , T, J = 7.6 Hz), 7.90-7.96 (2H, m), 12.97 (1H, brs).

Example 221 Synthesis of 4-{[3- (ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of 4- (3-methoxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one 4-trifluoromethanesulfonyloxy-2- obtained in Example 80 (i) Tris (dibenzylideneacetone) dipalladium in a solution of (4-trifluoromethylphenyl) isoindoline-1-one (851 mg, 2.00 mmol) and diisopropylethylamine (517 mg, 4.00 mmol) in 1,4-dioxane (12 mL) (0) (46 mg, 0.05 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (58 mg, 0.10 mmol), 3-methoxybenzenethiol (336 mg, 2.40 mmol) were added. Heated to reflux for 3 hours. Water was added and the precipitated oil was filtered through celite and purified by silica gel column chromatography to give 4- (3-methoxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one (831 mg). , Quant.).
mp 93-96 ° C
¹ H NMR (CDCl ₃ ) δ: 3.77 (3H, s), 4.74 (2H, s), 6.81-6.86 (2H, m), 6.89 (1H, ddd, J = 1.0 Hz, 1.6 Hz, 7.6 Hz), 7.22-7.28 (1 H, m), 7.50 (1 H, t, J = 7.6 Hz), 7.57 (1 H, dd, J = 1.3 Hz, 7.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 7.87 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8.00 (2H, d, J = 8.6 Hz).

(Ii) Synthesis of 4- (3-hydroxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (3-methoxyphenyl obtained in (i) above under ice-cooling ) To a solution of thio-2- (4-trifluoromethylphenyl) isoindoline-1-one (810 mg, 1.95 mmol) in dichloromethane (15 mL), boron tribromide in dichloromethane (2.14 ml, 2.14 mmol) And stirred at room temperature overnight. Further, boron tribromide dichloromethane solution (0.98 ml, 0.98 mmol) was added and stirred overnight at room temperature. Neutralized with triethylamine, added with water, extracted with dichloromethane, purified by silica gel column chromatography, 4- (3-hydroxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one Crystals (402 mg, 51%) were obtained.
mp 174-177 ° C
¹ H NMR (DMSO-d ₆ ) δ: 5.00 (2H, s), 6.71-6.75 (2H, m), 6.84 (1H, dd, J = 1.0 Hz, 7.9 Hz) ), 7.21 (1H, t, J = 7.9 Hz), 7.55 (1H, dd, J = 1.6 Hz, 7.6 Hz), 7.60 (1H, t, J = 7.6 Hz) , 7.78-7.82 (3H, m), 8.15 (2H, d, J = 8.6 Hz), 9.71 (1H, s).

(Iii) Synthesis of 4-{[3- (ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (3- Hydroxyphenyl) thio-2- (4-trifluoromethylphenyl) isoindoline-1-one was treated in the same manner as in Example 179 (ii) to give 4-{[3- (ethoxycarbonylmethoxy) phenyl] thio}- 2- (4-Trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 142-143 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 4.22 (2H, q, J = 7.3 Hz), 4.58 (2H, s), 4. 71 (2H, s), 6.80 (1 H, ddd, J = 1.0 Hz, 2.6 Hz, 7.9 Hz), 6.85-6.87 (1 H, m), 6.94 (1 H, ddd) , J = 1.0 Hz, 1.6 Hz, 7.9 Hz), 7.25 (1 H, t, J = 7.9 Hz), 7.52 (1 H, t, J = 7.6 Hz), 7.60 ( 1H, dd, J = 1.3 Hz, 7.6 Hz), 7.67 (2H, d, J = 8.6 Hz), 7.89 (1H, dd, J = 1.3 Hz, 7.6 Hz), 8 .00 (2H, d, J = 8.6 Hz).

Example 222 Synthesis of 4-{[3- (carboxymethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one
4-{[3- (Ethoxycarbonylmethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 221 was operated in the same manner as in Example 69, and 4 -{[3- (Carboxymethoxy) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 175-176 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.67 (2H, s), 4.99 (2H, s), 6.87-6.93 (2H, m), 6.97 (1H, ddd, J = 1.0 Hz, 1.6 Hz, 7.6 Hz), 7.31 (1H, t, J = 7.9 Hz), 7.56-7.63 (2H, m), 7.78-7.84 (3H, m), 8.16 (2H, d, J = 8.6 Hz), 13.11 (1H, br).

Example 223 Synthesis of 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one
(I) Synthesis of ethyl (2-methyl-4-thiocyanatophenoxy) acetate. Org. Chem. 68, 9116 (2003), 2-methyl-4-thiocyanatophenol (330 mg, 2.00 mmol) in acetonitrile (10 mL) was added to cesium carbonate (782 mg, 2.40 mmol) and ethyl bromoacetate (401 mg, 2 .40 mmol) was added and stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate to give oily (2-methyl-4-thiocyanatophenoxy) ethyl acetate (463 mg, 92%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.30 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4. 67 (2H, s), 6.71 (1H, d, J = 8.2 Hz), 7.33-7.38 (2H, m).

(Ii) Synthesis of (4-mercapto-2-methylphenoxy) ethyl acetate Ethanol (10 mL) of ethyl (2-methyl-4-thiocyanatophenoxy) acetate (460 mg, 1.83 mmol) obtained in (i) above. ) Zinc (310 mg), 2,6-di-t-butyl-4-methylphenol (33 mg) and concentrated hydrochloric acid (1 mL) were added to the solution, and the mixture was heated to reflux overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain oily (4-mercapto-2-methylphenoxy) ethyl acetate (343 mg, 83%).
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 3.30 (1H, s), 4.25 (2H, q, J = 7.3 Hz), 4.60 (2H, s), 6.59 (1H, d, J = 8.2 Hz), 7.09 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.14 (1H, d, J = 2.3 Hz).

(Iii) Synthesis of 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in Example 80 (i) 4-trifluoromethanesulfonyloxy-2- (4-trifluoromethylphenyl) isoindoline-1-one and (4-mercapto-2-methylphenoxy) ethyl acetate obtained in (ii) above were used in Example 179 ( The same operation as i) was performed to obtain 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 149-150 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4. 67 (2H, s), 4.73 (2H, s), 6.70 (1H, d, J = 8.2 Hz), 7.24-7.32 (3H, m), 7.41 (1H, t, J = 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.02 (2H, d) , J = 8.6 Hz).

Example 224 (Synthesis of 4-{[4- (carboxymethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-{[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 223 was treated in the same manner as in Example 69. The operation yielded 4-{[4- (carboxymethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 205-206 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 4.76 (2H, s), 5.01 (2H, s), 6.92 (1H, d, J = 7. 9 Hz), 7.26 (1 H, dd, J = 1.0 Hz, 7.9 Hz), 7.36-7.41 (2 H, m), 7.50 (1 H, t, J = 7.6 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.82 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz), 13.09 (1H , Br).

Example 225 (Synthesis of 4-({[3- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of methyl (3-hydroxyphenyl) acetate A solution of 3-hydroxyphenylacetic acid (761 mg, 5.00 mmol) in hydrochloric acid-methanol (20 mL) was heated to reflux overnight. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily methyl (3-hydroxyphenyl) acetate (787 mg, 95%).
¹ H NMR (CDCl ₃ ) δ: 3.58 (2H, s), 3.70 (3H, s), 5.40 (1H, s), 6.72-6.78 (2H, m), 6 .83 (1H, d, J = 7.6 Hz), 7.18 (1H, t, J = 7.6 Hz).

(Ii) Synthesis of 4-({[3- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Obtained in Example 177 (v) Similar to Example 148 (ii) using 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one and methyl (3-hydroxyphenyl) acetate obtained in (i) above. By operation, crystals of 4-({[3- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one were obtained.
mp 125-126 ° C
¹ H NMR (CDCl ₃ ) δ: 3.63 (2H, s), 3.70 (3H, s), 4.98 (2H, s), 5.24 (2H, s), 6.90-6 .97 (3H, m), 7.29 (1H, t, J = 7.9 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.64 (1H, dd, J = 1. 0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.93 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

Example 226 (Synthesis of 4-({[3- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[3- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 225 was operated in the same manner as in Example 69. 4-({[3- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 171-172 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.56 (2H, s), 5.19 (2H, s), 5.31 (2H, s), 6.89 (1H, d, J = 7. 6 Hz), 6.98-7.02 (2 H, m), 7.27 (1 H, t, J = 7.6 Hz), 7.61 (1 H, t, J = 7.6 Hz), 7.79- 7.84 (4H, m), 8.18 (2H, d, J = 8.6 Hz), 12.34 (1H, s).

Example 227 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of ethyl (4-acetyl-2-methylphenoxy) acetate A solution of 4-hydroxy-3-methylacetophenone (1.50 g, 10.0 mmol) in acetonitrile (25 mL) was added with cesium carbonate (3.58 g, 11. 0 mmol) and ethyl bromoacetate (1.84 g, 11.0 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate, and then purified by silica gel column chromatography to obtain oily (4-acetyl-2-methylphenoxy) ethyl acetate (2.25 g, 95%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.33 (3H, s), 2.55 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4.71 (2H, s), 6.71 (1H, d, J = 8.2 Hz), 7.76-7.80 (2H, m).

(Ii) Synthesis of ethyl (4-acetoxy-2-methylphenoxy) acetate A solution of ethyl (4-acetyl-2-methylphenoxy) acetate (709 mg, 3.00 mmol) obtained in (i) above in dichloromethane (10 mL) P-toluenesulfonic acid monohydrate (5.7 mg, 0.03 mmol) and m-chloroperbenzoic acid (1.10 g, 4.80 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 days. Sodium sulfite was added and stirred at room temperature for 20 minutes, and then sodium carbonate was further added and stirred at room temperature for 10 minutes. The organic layer was washed with sodium carbonate and brine and dried to give oily ethyl (4-acetoxy-2-methylphenoxy) acetate (653 mg, 86%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.27 (3H, s), 2.28 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4.61 (2H, s), 6.69 (1H, d, J = 8.6 Hz), 6.82-6.89 (2H, m).

(Iii) Synthesis of ethyl (4-hydroxy-2-methylphenoxy) acetate (4-acetoxy-2-methylphenoxy) ethyl acetate (638 mg, 2.53 mmol) obtained in (ii) above in ethanol (7 mL) To the mixture was added 20% sodium ethoxide ethanol solution (86 mg, 0.25 mmol), and the mixture was stirred at room temperature for 1 day. After the solvent was distilled off, ethyl acetate was added and filtered, and the filtrate was washed with aqueous sodium hydrogen carbonate solution and brine. The solvent was distilled off, and the obtained crystals were recrystallized from ethyl acetate and hexane to obtain crystals of (4-hydroxy-2-methylphenoxy) ethyl acetate (438 mg, 82%).
mp 84-85 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4. 57 (2H, s), 4.72 (1H, s), 6.55-6.67 (3H, m).

(Iv) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 177 (v) Using 4-hydroxymethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in 1 above and (4-hydroxy-2-methylphenoxy) ethyl acetate obtained in (iii) above Operating in analogy to Example 148 (ii), 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Crystal was obtained.
mp 130-131 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.30 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4. 60 (2H, s), 4.97 (2H, s), 5.18 (2H, s), 6.67-6.76 (2H, m), 6.84 (1H, d, J = 2. 3 Hz), 7.55 (1 H, t, J = 7.6 Hz), 7.62 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2 H, d, J = 8.9 Hz) ), 7.92 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.04 (2H, d, J = 8.9 Hz).

Example 228 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 227 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 188-189 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.19 (3H, s), 4.63 (2H, s), 5.17 (2H, s), 5.25 (2H, s), 6.78 (1H, d, J = 8.6 Hz), 6.86 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.96 (1H, d, J = 2.3 Hz), 7.60 ( 1H, t, J = 7.6 Hz), 7.76-7.84 (4H, m), 8.18 (2H, d, J = 8.6 Hz), 12.92 (1H, br).

Example 229 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -2-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 1-bromo-4- (tert-butyldimethylsilyloxy) -2-methylbenzene To a solution of 4-bromo-3-methylphenol (935 mg, 5.00 mmol) in dichloromethane (25 mL) was added imidazole (681 mg, 10.00 mmol) and t-butyldimethylsilyl chloride (1.13 g, 7.50 mmol) were added and stirred overnight at room temperature. Water was added, extracted with dichloromethane, and purified by silica gel column chromatography to obtain oily 1-bromo-4- (tert-butyldimethylsilyloxy) -2-methylbenzene (1.45 g, 96%).
¹ H NMR (CDCl ₃ ) δ: 0.18 (6H, s), 0.97 (9H, s), 2.32 (3H, s), 6.54 (1H, ddd, J = 0.7 Hz, 3.0 Hz, 8.6 Hz), 6.72 (1H, dd, J = 0.7 Hz, 3.0 Hz), 7.33 (1H, d, J = 8.6 Hz).

(Ii) Synthesis of 4- (tert-butyldimethylsilyloxy) -2-methylbenzaldehyde 1-bromo-4- (tert-butyldimethylsilyloxy) -2-methyl obtained in (i) above under ice-cooling To a solution of benzene (603 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was added s-butyllithium (1.85 mL, 2.00 mmol), and the mixture was stirred at 0 ° C. for 20 minutes. Dimethylformamide was added, and the mixture was stirred at 0 ° C. for 20 minutes and at room temperature for 3 hours. Water was added, the mixture was extracted with ethyl acetate, and purified by silica gel column chromatography to obtain oily 4- (tert-butyldimethylsilyloxy) -2-methylbenzaldehyde (58 mg, 12%).
¹ H NMR (CDCl ₃ ) δ: 0.25 (6H, s), 0.99 (9H, s), 2.62 (3H, s), 6.69 (1H, d, J = 2.3 Hz) 6.78 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.70 (1H, d, J = 8.2 Hz), 10.12 (1H, s).

(Iii) Synthesis of 4-hydroxy-2-methylbenzaldehyde To a solution of 4- (tert-butyldimethylsilyloxy) -2-methylbenzaldehyde (47 mg, 0.19 mmol) obtained in (ii) above in tetrahydrofuran (7 mL) Tetrabutylammonium fluoride (0.21 mL, 0.21 mmol) was added and stirred at room temperature for 40 minutes. Water was added and the mixture was extracted with ethyl acetate to obtain oily 4-hydroxy-2-methylbenzaldehyde (26 mg, quant.).
¹ H NMR (CDCl ₃ ) δ: 2.59 (3H, s), 6.83 (1H, d, J = 2.3 Hz), 6.91 (1H, dd, J = 2.3 Hz, 8.6 Hz) ), 7.67 (1H, d, J = 8.6 Hz), 10.06 (1H, s).

(Iv) Synthesis of 4-ethoxycarbonylmethoxy-2-methylbenzaldehyde To a solution of 4-hydroxy-2-methylbenzaldehyde (26 mg, 0.19 mmol) obtained above in acetonitrile (5 mL), cesium carbonate (67 mg, 0.21 mmol) ) And ethyl bromoacetate (34 mg, 0.21 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate to obtain oily 4-ethoxycarbonylmethoxy-2-methylbenzaldehyde (38 mg, 91%).
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 2.65 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 4. 69 (2H, s), 6.77 (1H, d, J = 2.3 Hz), 6.83 (1H, dd, J = 2.3 Hz, 8.6 Hz), 7.77 (1H, d, J = 8.6 Hz), 10.13 (1 H, s).

(V) Synthesis of ethyl (4-hydroxymethyl-3-methylphenoxy) acetate A solution of 4-ethoxycarbonylmethoxy-2-methylbenzaldehyde (158 mg, 0.71 mmol) obtained above in tetrahydrofuran (10 mL) was cooled with ice. Was added dropwise borane-tetrahydrofuran complex (0.72 mL, 0.71 mmol), and the mixture was stirred at 0 ° C. for 1 hour. Methanol was added and the solvent was distilled off. Water was added, and the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain oily (4-hydroxymethyl-3-methylphenoxy) ethyl acetate (85 mg, 53%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.56 (1H, brs), 2.35 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4.61 (2H, s), 4.63 (2H, s), 6.71 (1H, dd, J = 2.6 Hz, 8.6 Hz), 6.77 (1H, d, J = 2.6 Hz), 7.24 (1H, d, J = 8.6 Hz).

(Vi) 4-({[4- (Ethoxycarbonylmethoxy) -2-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one 2 obtained in Synthesis Example 3 -(4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one, (4-hydroxymethyl-3-methylphenoxy) ethyl acetate obtained in (v) above was used in the same manner as in Example 150 (iii). To give 4-({[4- (ethoxycarbonylmethoxy) -2-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 127-129 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 2.38 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 4. 65 (2H, s), 4.79 (2H, s), 5.10 (2H, s), 6.76 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.85 (1H, d, J = 2.6 Hz), 7.19 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.49 (1H, t , J = 7.6 Hz), 7.55 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.66 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 230 Synthesis of 4-({[4- (carboxymethoxy) -2-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -2-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 229 was used in Example 69. To give 4-({[4- (carboxymethoxy) -2-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 162-163 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.35 (3H, s), 4.69 (2H, s), 4.99 (2H, s), 5.19 (2H, s), 6.75 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.84 (1H, d, J = 2.6 Hz), 7.38-7.42 (2H, m), 7.46 (1H, d, J = 7.9 Hz), 7.55 (1H, t, J = 7.9 Hz), 7.76 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8) .6 Hz), 13.01 (1H, brs).

Example 231 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindolin-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 202 Was prepared in the same manner as in Example 69, and 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1 -Obtained ON.
mp 168-170 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 4.71 (2H, s), 5.01 (2H, s), 5.17 (2H, s), 6.84 (1H, d, J = 7.8 Hz), 7.26-7.33 (2H, m), 7.38-7.44 (2H, m), 7.54 (1H, t, J = 7. 8 Hz), 7.80 (1 H, d, J = 8.6 Hz), 8.00 (1 H, d, J = 8.6 Hz), 8.17 (1 H, d, J = 14.5 Hz).

Example 232 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one)
(I) Synthesis of 2- (2-fluoro-4-methylphenyl) -4-methoxyisoindoline-1-one 3-methoxy-2-methylbenzoic acid methyl ester (1) obtained in Example 181 (ii) 0.5 g, 8.32 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (1.48 g, 8.32 mmol) and benzoyl peroxide (0.080 g), and the mixture was heated to reflux for 2 hours. The reaction solution was cooled, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. 2-Fluoro-4-methylaniline (1.04 g, 8.32 mmol) and dimethylformamide (30 mL) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 2 hours and 150 ° C. for 19 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether-hexane to obtain crystals of 2- (2-fluoro-4-methylphenyl) -4-methoxyisoindoline-1-one (1.27 g, 56%).
mp 154-159 ° C
¹ H NMR (CDCl ₃ ) δ: 2.38 (3H, s), 3.93 (3H, s), 4.77 (2H, s), 6.98-7.18 (3H, m), 7 .43-7.51 (2H, m), 7.55 (1H, dd, J = 1.0, 7.6 Hz).

(Ii) Synthesis of 2- (2-fluoro-4-methylphenyl) -4-hydroxyisoindolin-1-one 2- (2-fluoro-4-methylphenyl) -4- obtained in (i) above A suspension of methoxyisoindoline-1-one (1.20 g, 4.42 mmol) in methylene chloride (48 mL) was charged with a 1 mol / L boron tribromide methylene chloride solution (8.80 mL, 8.80 mmol) under ice cooling. The mixture was further stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether to obtain crystals of 2- (2-fluoro-4-methylphenyl) -4-hydroxyisoindoline-1-one (943 mg, 83%).
mp 232-238 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.36 (3H, s), 4.75 (2H, s), 7.04-7.13 (2H, m), 7.17-7.25 ( 2H, m), 7.38 (1H, t, J = 7.6 Hz), 7.52 (1H, t, J = 8.1 Hz), 10.19 (1H, s).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one (ii) 2- (2-Fluoro-4-methylphenyl) -4-hydroxyisoindoline-1-one obtained in 1) and 2- [4- (bromomethyl) -2-methylphenoxy obtained in Example 170 (i) Ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl). ) Isoindoline-1-one was obtained.
mp 92-100 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.31 (3H, s), 2.37 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4.65 (2H, s), 4.78 (2H, s), 5.08 (2H, s), 6.71 (1 H, d, J = 8.2 Hz), 6 97-7.05 (2H, m), 7.12 (1H, d, J = 7.7 Hz), 7.15-7.25 (2H, m), 7.44 (2H, t, J = 7.7 Hz), 7.55 (1H, d, J = 7.3 Hz).

Example 233 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one obtained in Example 232 was carried out. Operate analogously to Example 69 to give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one. It was.
mp 173-174 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 2.35 (3H, s), 4.70 (2H, s), 4.82 (2H, s), 5.16 (2H, s), 6.82 (1H, d, J = 8.0 Hz), 7.07-7.30 (4H, m), 7.34-7.39 (2H, m), 7.52 (2H, t, J = 8.0 Hz).

Example 234 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one)
2- (2-Chloro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one synthesized in Example 181 (iv) and (3-bromomethylphenyl) obtained in Example 95 (i) ) Ethyl acetate was operated as in Example 138 (v) to give 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) iso Indoline-1-one was obtained.
mp 93-98 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 3.63 (2H, s), 4.14 (2H, q, J = 7.1 Hz), 4. 83 (2H, s), 5.19 (2H, s), 7.15 (1H, d, J = 7.7 Hz), 7.26-7.37 (4H, m), 7.48 (1H, d, J = 7.7 Hz), 7.55-7.66 (3H, m), 7.80 (1H, s).

Example 235 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 234 was used in Example 69. To give 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (2-chloro-4-trifluoromethylphenyl) isoindoline-1-one.
mp 163-166 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.59 (2H, s), 4.91 (2H, s), 5.28 (2H, s), 7.20-7.43 (6H, m) 7.52-759 (1H, m), 7.89 (2H, s), 8.09 (1H, s), 12.34 (1H, br).

Example 236 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one)
2- (2-Fluoro-4-methylphenyl) -4-hydroxyisoindoline-1-one synthesized in Example 232 (ii) and (3-bromomethylphenyl) acetic acid obtained in Example 95 (i) Ethyl was operated as in Example 138 (v) and 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1- Got on.
mp 69-72 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 2.38 (3H, s), 3.64 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4.81 (2H, s), 5.18 (2H, s), 6.98-7.05 (2H, m), 7.11 (1H, d, J = 7. 9 Hz), 7.25-7.30 (2H, m), 7.34-7.38 (2H, m), 7.45 (2H, dt, J = 2.1, 8.2 Hz), 7. 56 (1H, d, J = 7.6 Hz).

Example 237 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
2- (3-Fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one synthesized in Example 202 (ii) and [3- (2- Hydroxyethyl) phenoxy] ethyl acetate was operated in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (3-fluoro-4- Trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 114-115 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.13 (2H, t, J = 6.8 Hz), 4.23 (2H, q, J = 7) .1 Hz), 4.32 (2H, t, J = 6.8 Hz), 4.63 (2H, s), 4.73 (2H, s), 6.74-6.80 (1H, m), 6.90-6.95 (2H, m), 7.07 (1H, dd, J = 1.1 Hz, 7.7 Hz), 7.22-7.30 (1H, m), 7.42-7 .53 (2H, m), 7.63 (1H, t, J = 8.2 Hz), 7.74 (1H, d, J = 11.0 Hz), 8.02 (1H, d, J = 1.11. 0 Hz).

Example 238 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 237 was carried out Operate analogously to Example 69 to give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 171-172 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.8 Hz), 4.36 (2H, t, J = 6.8 Hz), 4.66 (2H, s), 4.95 (2H, s), 6.78 (1H, dd, J = 2.1, 7.7 Hz), 6.93-6.98 (2H, m), 7.23 (1H, t, J = 7.9 Hz), 7.38 (2H, dd, J = 7.7, 9.7 Hz), 7.52 (1H, t, J = 7.9 Hz), 7.83 (1H, t, J = 8.7 Hz), 7.94 (1H, d, J = 9.7 Hz), 8.18 (1H, d, J = 14.1 Hz).

Example 239 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (6-trifluoromethylpyridin-3-yl) isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- [6- (trifluoromethyl) pyridin-3-yl] isoindoline-1-one In step (ii) of Synthesis Example 3, 1-amino-4- (trifluoro Instead of methyl) benzene, 6- (trifluoromethyl) -3-pyridinamine (811 mg, 5.00 mmol) was used, and the reaction scale was changed appropriately. Hydroxy-2- [6- (trifluoromethyl) pyridin-3-yl] isoindoline-1-one (yield 901 mg, 61% yield) was synthesized.
mp 276-278 ° C
¹ HNMR (DMSO-d ₆ ) δ: 5.02 (2H, s), 7.11 (1H, dd, J = 1.0 Hz, 7.9 Hz), 7.29 (1H, dd, J = 1. 0 Hz, 7.6 Hz), 7.40 (1 H, t, J = 7.6 Hz), 7.99 (1 H, t, J = 8.6 Hz), 8.65 (1 H, dd, J = 2.6 Hz) , 8.6 Hz), 9.27 (1H, d, J = 2.6 Hz), 10.42 (1H, br).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [6- (trifluoromethyl) pyridin-3-yl] isoindoline-1-one 4-hydroxy-2- [6- (trifluoromethyl) pyridin-3-yl] isoindolin-1-one obtained in i) and [3- (2-hydroxy) obtained in Example 68 (i) Ethyl) phenoxy] ethyl acetate was operated as in Example 68 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [6- (trifluoromethyl). Pyridin-3-yl] isoindoline-1-one was obtained.
mp 139-141 ° C
¹ HNMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3 Hz), 3.14 (2H, t, J = 6.6 Hz), 4.23 (2H, q, J = 7. 3 Hz), 4.33 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 4.78 (2H, s), 6.77 (1H, ddd, J = 1.0 Hz, 2.6 Hz, 8.2 Hz), 6.91-6.94 (2 H, m), 7.08 (1 H, dd, J = 1.3 Hz, 7.3 Hz), 7.26 (1 H, t, J = 7.9 Hz), 7.46 (1 H, t, J = 7.6 Hz), 7.52 (1 H, dd, J = 1.6 Hz, 7.6 Hz), 7.74 (1 H, d, J = 8.6 Hz), 8.71 (1 H, ddd, J = 1.0 Hz, 2.6 Hz, 8.9 Hz), 9.11 (1 H, d, J = 2.6 Hz).

Example 240 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [6- (trifluoromethyl) pyridin-3-yl] isoindoline-1-one)
4-({2- [3- (Ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [6- (trifluoromethyl) pyridin-3-yl] isoindoline-1-one obtained in Example 239 Was prepared in the same manner as in Example 69, and 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [6- (trifluoromethyl) pyridin-3-yl] isoindoline-1 -Obtained ON.
mp 183-184 ° C
¹ HNMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.6 Hz), 4.36 (2H, t, J = 6.6 Hz), 4.61 (2H, s), 5 .01 (2H, s), 6.74-6.78 (1H, m), 6.93-6.96 (2H, m), 7.23 (1H, t, J = 7.9 Hz), 7 .35-7.42 (2H, m), 7.53 (1H, t, J = 7.6 Hz), 7.98 (1H, d, J = 8.6 Hz), 8.63 (1H, dd, J = 2.6 Hz, 8.9 Hz), 9.34 (1H, d, J = 2.6 Hz).

Example 241 (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2-[(5-trifluoromethyl) -1,3,4-thiadiazolyl-2-yl] isoindoline Synthesis of -1-one)
(I) Synthesis of 4-hydroxy-2- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] isoindolin-1-one In the step (ii) of Synthesis Example 3, Instead of amino-4- (trifluoromethyl) benzene, 5- (trifluoromethyl) -1,3,4-thiadiazol-2-amine (846 mg, 5.00 mmol) was used and the reaction scale was changed appropriately. Was operated in the same manner as in Synthesis Example 3, and 4-hydroxy-2- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] isoindoline-1-one (yield 184 mg, yield). 12%) was synthesized.
mp 255-268 ° C
_{^{1 H NMR (DMSO-d 6}} ) δ: 5.14 (2H, s), 7.19-7.21 (1H, m), 7.40-7.50 (2H, m), 10.51 ( 1H, br).

(Ii) 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] isoindoline- 1-one 4-hydroxy-2- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] isoindoline-1-one obtained in (ii) above and Example 68 (i The ethyl [3- (2-hydroxyethyl) phenoxy] acetate obtained in) was treated in the same manner as in Example 68 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy ) -2- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] isoindoline-1-one was obtained.
mp 124-126 ° C
¹ HNMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 3.14 (2H, t, J = 6.6 Hz), 4.26 (2H, q, J = 7. 3 Hz), 4.33 (2H, t, J = 6.6 Hz), 4.64 (2H, s), 5.15 (2H, s), 6.78 (1H, ddd, J = 0.7 Hz, 2.6 Hz, 8.2 Hz), 6.89 (1 H, t, J = 1.6 Hz), 6.93-6.97 (1 H, m), 7.15 (1 H, dd, J = 1.0 Hz) , 7.9 Hz), 7.27 (1 H, t, J = 7.9 Hz), 7.51 (1 H, t, J = 7.9 Hz), 7.57 (1 H, dd, J = 1.0 Hz, 7.6 Hz).

Example 242 Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiazol-2-yl) isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- (4-methyl-2-thiazolyl) isoindoline-1-one In step (ii) of Synthesis Example 3, instead of 1-amino-4- (trifluoromethyl) benzene Then, except that 2-amino-4-methylthiazole (343 mg, 3.00 mmol) was used and the reaction scale was appropriately changed, the same operation as in Synthesis Example 3 was performed, and 4-hydroxy-2- (4-methyl- 2-thiazolyl) isoindoline-1-one (yield 125 mg, 17% yield) was synthesized.
mp 199-200 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 4.99 (2H, s), 6.91-6.92 (1H, m), 7.10-7.15 ( 1H, m), 7.27-7.32 (1H, m), 7.38-7.44 (1H, m), 10.28 (1H, br).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiazol-2-yl) isoindoline-1-one Obtained by (i) above 4-hydroxy-2- (4-methyl-2-thiazolyl) isoindoline-1-one obtained and ethyl [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) 68 (ii) and 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiazol-2-yl) isoindoline-1-one Obtained.
mp 199-200 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.43 (3H, s), 3.12 (2H, t, J = 6.9 Hz), 4. 26 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 6.9 Hz), 4.63 (2H, s), 5.06 (2H, s), 6.61 ( 1H, s), 6.78 (1H, dd, J = 2.3 Hz, 7.9 Hz), 6.89 (1H, t, J = 2.3 Hz), 6.95 (1H, d, J = 7) .9 Hz), 7.06 (1H, d, J = 7.6 Hz), 7.23-7.29 (1H, m), 7.45 (1H, t, J = 7.6 Hz), 7.53 (1H, d, J = 7.6 Hz).

Example 243 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methylthiazol-2-yl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methylthiazol-2-yl) isoindoline-1-one obtained in Example 242 was obtained in Example 69. To give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-methylthiazol-2-yl) isoindoline-1-one.
mp 222-223 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 3.08 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4.97 (2H, s), 6.76-6.80 (1H, m), 6.92-6.97 (3H, m), 7.24 (1H, t, J = 7.9 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.41 (1H, d, J = 7.6 Hz), 7.53 (1H, t, J = 7) .6 Hz).

Example 244 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (3-thienyl) phenyl] isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- [4- (3-thienyl) phenyl] isoindolin-1-one In the step (ii) of Synthesis Example 3, 1-amino-4- (trifluoromethyl) benzene was converted to Instead, 4-hydroxy-3- [4- (4-thienyl) aniline (526 mg, 3.00 mmol) was used in the same manner as in Synthesis Example 3 except that the reaction scale was appropriately changed. 3-thienyl) phenyl] isoindoline-1-one (125 mg, 17% yield) was synthesized.
mp> 300 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.92 (2H, s), 7.07 (1H, d, J = 7.6 Hz), 7.25 (1H, d, J = 7.6 Hz), 7.37 (1H, t, J = 7.6 Hz), 7.59 (1H, dd, J = 1.3 Hz, 4.9 Hz), 7.65 (1H, dd, J = 2.6 Hz, 4. 9 Hz), 7.80 (2H, d, J = 8.6 Hz), 7.87 (1H, dd, J = 1.3 Hz, 2.6 Hz), 7.97 (2H, d, J = 8.6 Hz) ), 10.25 (1H, s).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (3-thienyl) phenyl] isoindoline-1-one Obtained by (i) above 4-hydroxy-2- [4- (3-thienyl) phenyl] isoindoline-1-one obtained and ethyl [3- (2-hydroxyethyl) phenoxy] acetate obtained in Example 68 (i) Operating as in Example 148 (ii), 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (3-thienyl) phenyl] isoindoline-1-one Got.
mp 165-167 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 3.14 (2H, t, J = 6.6 Hz), 4.24 (2H, q, J = 7) .3 Hz), 4.32 (2H, t, J = 6.6 Hz), 4.63 (2H, s), 4.77 (2H, s), 6.76-6.80 (1 H, m), 6.92-6.95 (2H, m), 7.03 (1H, d, J = 7.9 Hz), 7.23-7.29 (1H, m), 7.38-7.46 (4H M), 7.52 (1H, d, J = 7.3 Hz), 7.63-7.69 (2H, m), 7.92-7.97 (2H, m).

Example 245 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [4- (3-thienyl) phenyl] isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (3-thienyl) phenyl] isoindoline-1-one obtained in Example 244 was prepared in Example 69. To give 4-({[4- (carboxymethoxy) -3-methoxyphenyl] methyl} oxy) -2- [4- (3-thienyl) phenyl] isoindoline-1-one.
mp 213-215 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.08 (2H, t, J = 6.6 Hz), 4.36 (2H, t, J = 6.6 Hz), 4.68 (2H, s), 4.91 (2H, s), 6.77-6.81 (1H, m), 6.95-6.98 (2H, m), 7.24 (1H, t, J = 7.9 Hz), 7.32 (1H, d, J = 7.9 Hz), 7.37 (1H, d, J = 7.9 Hz), 7.51 (1H, t, J = 7.9 Hz), 7.58-7 .61 (1H, m), 7.64-7.67 (1H, m), 7.80 (2H, d, J = 8.6 Hz), 7.87-7.88 (1H, m), 7 97 (2H, d, J = 8.6 Hz), 12.98 (1H, br).

Example 246 of (4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2,2,2-trifluoroethoxy) phenyl] isoindoline-1-one Synthesis)
(I) Synthesis of 4-hydroxy-2- [4- (2,2,2-trifluoroethoxyphenyl)] isoindolin-1-one In the step (ii) of Synthesis Example 3, 1-amino-4- ( The same operation as in Synthesis Example 3 was performed except that 4- (2,2,2-trifluoroethoxy) aniline (573 mg, 3.00 mmol) was used instead of (trifluoromethyl) benzene and the reaction scale was changed as appropriate. 4-hydroxy-2- [4- (2,2,2-trifluoroethoxyphenyl)] isoindoline-1-one (yield 333 mg, yield 34%) was synthesized.
mp 209-211 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.78 (2H, q, J = 8.9 Hz), 4.86 (2H, s), 7.05 (1H, d, J = 7.6 Hz), 7.14 (2H, d, J = 8.9 Hz), 7.23 (1H, d, J = 7.6 Hz), 7.36 (1H, t, J = 7.6 Hz), 7.85 (2H , D, J = 8.9 Hz), 10.21 (1H, s).

(Ii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2,2,2-trifluoroethoxy) phenyl] isoindoline-1-one The above (i) and the obtained 4-hydroxy-2- [4- (2,2,2-trifluoroethoxyphenyl)] isoindolin-1-one and the [3- (2-Hydroxyethyl) phenoxy] ethyl acetate was operated in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- ( 2,2,2-trifluoroethoxy) phenyl] isoindoline-1-one was obtained.
mp 132-133 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.3 Hz), 3.12 (2H, t, J = 6.6 Hz), 4.24 (2H, q, J = 7) .3 Hz), 4.30 (2H, t, J = 6.6 Hz), 4.38 (2H, q, J = 8.2 Hz), 4.62 (2H, s), 4.71 (2H, s) ), 6.75-6.79 (1H, m), 6.91-6.94 (2H, m), 699-7.04 (3H, m), 7.25 (1H, t, J = 7.9 Hz), 7.43 (1H, t, J = 7.6 Hz), 7.50 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.80-7.86 (2H, m).

Example 247 Synthesis of (4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [4- (2,2,2-trifluoroethoxy) phenyl] isoindoline-1-one )
4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4- (2,2,2-trifluoroethoxy) phenyl] isoindoline-1 obtained in Example 246 The -one is operated as in Example 69 and 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- [4- (2,2,2-trifluoroethoxy) phenyl] Isoindoline-1-one was obtained.
mp 217-219 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4.67 (2H, s), 4.78 (2H, q, J = 8.9 Hz), 4.84 (2H, s), 6.78 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.94-6.96 (2H, m), 7.11-7.17 (2H, m), 7.23 (1H, t, J = 8.2 Hz), 7.30 (1H, d, J = 7.9 Hz), 7 .35 (1H, d, J = 7.9 Hz), 7.49 (1H, t, J = 7.9 Hz), 7.83-7.89 (2H, m), 13.02 (1H, br) .

Example 248 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -2-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of (4-formyl-3-methoxyphenoxy) ethyl acetate To a suspension of 4-hydroxy-2-methoxybenzaldehyde (1.13 g, 7.45 mmol) in acetonitrile (25 mL) was added cesium carbonate (2.67 g, 8.20 mmol) and ethyl bromoacetate (1.37 g, 8.20 mmol) were added and stirred overnight at room temperature. Further, cesium carbonate (728 mg, 2.24 mmol) and ethyl bromoacetate (373 mg, 2.24 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate to give oily (4-formyl-3-methoxyphenoxy) ethyl acetate (1.77 g, quant.).
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 3.90 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 4. 69 (2H, s), 6.48 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.55 (1H, d, J = 2.3 Hz), 7.81 (1H, d, J = 8.6 Hz), 10.30 (1 H, s).

(Ii) Synthesis of ethyl (4-hydroxymethyl-3-methoxyphenoxy) acetate (4-formyl-3-methoxyphenoxy) ethyl acetate (1.87 g, 7.86 mmol) obtained in the above step (i) Borane-tetrahydrofuran complex (7.90 mL, 7.86 mmol) was added dropwise to the (30 mL) solution under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. Methanol was added and the solvent was distilled off, followed by purification by silica gel column chromatography to obtain crystals of (4-hydroxymethyl-3-methoxyphenoxy) ethyl acetate (1.23 g, 65%).
mp 49-52 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 3.84 (3H, s), 4.28 (2H, q, J = 7.3 Hz), 4. 61 (4H, s), 6.38 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.57 (1H, d, J = 2.6 Hz), 7.16 (1H, d, J = 8.2 Hz).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -2-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one In the same manner as in Synthesis Example 3. 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in the above and (4-hydroxymethyl-3-methoxyphenoxy) ethyl acetate obtained in the above step (ii) were used in Examples. The same operation as in 148 (ii) was performed to obtain 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- [4-trifluoromethylphenyl] isoindoline-1-one. .
mp 134-137 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.3 Hz), 3.84 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 4. 64 (2H, s), 4.80 (2H, s), 5.14 (2H, s), 6.44 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.61 (1H, d, J = 2.3 Hz), 7.17 (1H, d, J = 7.6 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.45 (1H, t, J = 7) .6 Hz), 7.51 (1H, d, J = 7.6 Hz), 7.65 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 249 (Synthesis of 4-({[4- (carboxymethoxy) -2-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -2-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 248 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -2-methoxyphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 152-154 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.82 (3H, s), 4.72 (2H, s), 4.97 (2H, s), 5.15 (2H, s), 6.51 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.66 (1H, d, J = 2.3 Hz), 7.37-7.41 (3H, m), 7.53 (1H, t, J = 7.3 Hz), 7.76 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz), 13.04 (1H, br).

Example 250 Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) -4-fluorophenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of (4-fluoro-3-methoxyphenyl) methanol A solution of 4-fluoro-3-methoxybenzaldehyde (1.54 g, 10.0 mmol) in tetrahydrofuran (30 mL) under ice-cooling with borane-tetrahydrofuran complex (11 0.1 mL, 11.0 mmol) was added dropwise and stirred overnight at room temperature. Methanol was added and the solvent was distilled off to obtain crystals of (4-fluoro-3-methoxyphenyl) methanol (1.56 g, quant.).
mp 47-50 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.82 (3H, s), 4.45 (2H, s), 5.22 (1H, s), 6.83 to 6.88 (1H, m) 7.08-7.16 (2H, m).

(Ii) Synthesis of (4-fluoro-3-methoxyphenyl) acetonitrile (4-Fluoro-3-methoxyphenyl) methanol (1.56 g, 10.0 mmol) obtained in (i) above, and acetone under ice-cooling To a suspension of cyanohydrin (1.89 g, 20.0 mmol) and triphenylphosphine (3.41 g, 13.0 mmol) in toluene (40 mL) was added dropwise azodicarboxylate diethyltoluene solution (5.45 mL, 12.0 mmol). The mixture was stirred at 0 ° C. for 45 minutes and at room temperature overnight. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily (4-fluoro-3-methoxyphenyl) acetonitrile (1.11 g, 67%) crystals.
¹ H NMR (CDCl ₃ ) δ: 3.72 (2H, s), 3.91 (3H, s), 6.81-6.87 (1H, m), 6.92 (1H, dd, J = 2.0 Hz, 7.9 Hz), 7.04-7.11 (1H, m).

(Iii) Synthesis of methyl (4-fluoro-3-hydroxyphenyl) acetate (4-Fluoro-3-methoxyphenyl) acetonitrile (1.07 g, 6.48 mmol) obtained in (ii) above in acetic acid (5 mL) And a 47% hydrobromic acid (5 mL) solution were stirred at 80 ° C. for 4 days. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily methyl (4-fluoro-3-hydroxyphenyl) acetate (867 mg, 73%).
¹ H NMR (CDCl ₃ ) δ: 3.55 (2H, s), 3.70 (3H, s), 5.17 (1H, s), 6.73-6.78 (1H, m), 6 .94 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.98-7.05 (1H, m).

(Iv) Synthesis of (4-fluoro-3-hydroxyphenyl) acetic acid Methyl (4-fluoro-3-hydroxyphenyl) acetate (848 mg, 4.60 mmol) obtained in (iii) above (1,4-dioxane ( 2N aqueous sodium hydroxide solution (6.90 mL, 13.81 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 hours. Water and 1N hydrochloric acid were added, and the mixture was extracted with ethyl acetate to obtain oily (4-fluoro-3-hydroxyphenyl) acetic acid (644 mg, 82%).
¹ H NMR (DMSO-d ₆ ) δ: 3.78 (2H, s), 6.94-6.99 (1 H, m), 7.17 (1 H, dd, J = 2.3 Hz, 8.6 Hz) ), 7.32-7.39 (1H, m), 10.09 (1H, s), 12.58 (1H, br).

(V) Synthesis of 2-fluoro-5- (2-hydroxyethyl) phenol (4-Fluoro-3-hydroxyphenyl) acetic acid ((628 mg, 3.69 mmol) obtained in the above (iv) in tetrahydrofuran (10 mL) Under ice-cooling, borane-tetrahydrofuran complex (4.47 mL, 4.43 mmol) was added dropwise to the solution and stirred overnight at room temperature, methanol was added, the solvent was evaporated, and oily 2-fluoro-5- (2- Hydroxyethyl) phenol (558 mg, 97%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 2.80 (2H, t, J = 6.3 Hz), 3.84 (2H, t, J = 6.3 Hz), 6.68-6.73 (1H, m ), 6.88 (1H, dd, J = 2.3 Hz, 8.6 Hz), 6.97-7.04 (1H, m).

(Vi) Synthesis of [2-fluoro-5- (2-hydroxyethyl) phenoxy] ethyl acetate 2-fluoro-5- (2-hydroxyethyl) phenol (558 mg, 3.57 mmol) obtained in (v) above Of cesium carbonate (1.28 g, 3.93 mmol) and ethyl bromoacetate (656 mg, 3.93 mmol) were added to an acetonitrile (15 mL) solution, and the mixture was stirred at room temperature for 1.5 hours. Water was added, and the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain oily ethyl [2-fluoro-5- (2-hydroxyethyl) phenoxy] acetate (499 mg, 58%).
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.80 (2H, t, J = 6.6 Hz), 3.83 (2H, t, J = 6) .6 Hz), 4.27 (2H, q, J = 7.3 Hz), 4.69 (2H, s), 6.79-6.85 (2H, m), 6.98-7.07 (1H) , M).

(Vii) Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) -4-fluorophenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis Example 3 and 2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in the same manner and [2-fluoro-5- (2-hydroxyethyl) phenoxy obtained in the above step (vi) Ethyl acetate was operated in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) -4-fluorophenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl). ) Isoindoline-1-one was obtained.
mp 140-142 ° C
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.3 Hz), 3.10 (2H, t, J = 6.6 Hz), 4.20 (2H, q, J = 7) .3 Hz), 4.29 (2H, t, J = 6.6 Hz), 4.70 (2H, s), 4.78 (2H, s), 6.86-6.92 (1H, m), 6.94 (1H, dd, J = 2.0 Hz, 7.9 Hz), 7.02-7.10 (2H, m), 7.45 (1H, t, J = 7.6 Hz), 7.52 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 8.07 (2H, d, J = 8.6 Hz).

Example 251 (4 - ({2- [3- (carboxymethyl) -4-fluorophenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one Synthesis of)
Obtained in Example 250 4 - ({2- [3- (ethoxycarbonyl) -4-fluorophenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one exemplary example 69 and the same procedure as, 4 - ({2- [3- (carboxymethyl) -4-fluorophenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1 to obtain an oN It was.
mp 188-189 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.6 Hz), 4.34 (2H, t, J = 6.6 Hz), 4.80 (2H, s), 4.95 (2H, s), 6.92-6.97 (1H, m), 7.11-7.20 (2H, m), 7.33 (1H, d, J = 7.6Hz), 7.39 (1H, d, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.79 (2H, d, J = 8.6 Hz), 8.18 (2H , D, J = 8.6 Hz), 13.11 (1H, br).

Example 252 (4-({[4- (1-Ethoxycarbonyl-1-methylethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one Synthesis)
(I) Synthesis of ethyl 2- (4-formyl-2-methylphenoxy) -2-methylpropionate To a solution of 4-hydroxy-3-methylbenzaldehyde (978 mg, 7.18 mmol) in dimethylformamide (10 mL), 2- Ethyl bromo-2-methylpropionate (1.68 g, 8.62 mmol) and cesium carbonate (2.81 g, 8.62 mmol) were added, and the mixture was stirred at 60 ° C. for 18.5 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain oily ethyl 2- (4-formyl-2-methylphenoxy) -2-methylpropionate (936 mg, 52%).
¹ H NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1 Hz), 1.68 (6H, s), 2.29 (3H, s), 4.23 (2H, q, J = 7.1 Hz), 6.67 (1H, d, J = 8.5 Hz), 7.59 (1H, dd, J = 2.1, 8.5 Hz), 7.70 (1H, d, J = 2.1 Hz), 9.85 (1H, s).

(Ii) Synthesis of ethyl 2- [4- (hydroxymethyl) -2-methylphenoxy] -2-methylpropionate Ethyl 2- (4-formyl-2-methylphenoxy) propionate obtained in (i) above To a solution of (978 mg, 7.18 mmol) in tetrahydrofuran (15 mL), 0.99 M borane / tetrahydrofuran complex (5.44 mL, 5.39 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. Methanol was gradually added to the reaction solution with stirring, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain an oily substance of ethyl 2- [4- (hydroxymethyl) -2-methylphenoxy] -2-methylpropionate (773 mg, 85%).
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.59 (6H, s), 2.24 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.58 (2H, d, J = 5.9 Hz), 6.64 (1H, d, J = 8.4 Hz), 7.04 (1H, dd, J = 2.2) , 8.4 Hz), 7.16 (1H, d, J = 2.2 Hz).

(Iii) Synthesis of ethyl 2- [4- (bromomethyl) -2-methylphenoxy] -2-methylpropionate 2- [4- (hydroxymethyl) -2-methylphenoxy]-obtained in (ii) above To a solution of ethyl 2-methylpropionate (722 mg, 2.86 mmol) in methylene chloride (15 mL), N-bromosuccinimide (764 mg, 4.29 mmol) and triphenylphosphine (1.13 mg, 4.29 mmol) were ice-cooled. Under addition, it stirred at room temperature for 2 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain an oily substance of ethyl 2- [4- (bromomethyl) -2-methylphenoxy] -2-methylpropionate (300 mg, 33%).
¹ H NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.1 Hz), 1.60 (6H, s), 2.22 (3H, s), 4.23 (2H, q, J = 7.1 Hz), 4.45 (2H, s), 6.58 (1H, d, J = 8.5 Hz), 7.07 (1H, dd, J = 2.4, 8.5 Hz), 7.18 (1H, d, J = 2.4 Hz).

(Iv) Synthesis of 4-({[4- (1-ethoxycarbonyl-1-methylethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one 2- (4-Trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in the same manner as in Synthesis Example 3, and 2- [4- (bromomethyl) -2-one obtained in (iii) above. Ethyl methylphenoxy] -2-methylpropionate was operated in the same manner as in Example 138 (v) to give 4-({[4- (1-ethoxycarbonyl-1-methylethoxy) -3-methylphenyl] methyl} oxy. ) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 110-113 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.62 (6H, s), 2.27 (3H, s), 4.25 (2H, q, J = 7.1 Hz), 4.83 (2H, s), 5.08 (2H, s), 6.68 (1H, d, J = 8.2 Hz), 7.1-7.16 (2H, m), 7.22-7.25 (1H, m), 7.46 (1H, t, J = 7.6 Hz), 7.51-7.55 (1H, m), 7.67 (2H, d, J = 8.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

Example 253 Synthesis of (4-({[4- (1-carboxy-1-methylethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one )
4-({[4- (1-Ethoxycarbonyl-1-methylethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1 obtained in Example 252 The -one is operated as in Example 69 and 4-({[4- (1-carboxy-1-methylethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylphenyl) Isoindoline-1-one was obtained.
mp 175-178 ° C
¹ H NMR (DMSO-d ₆ ) δ: 1.53 (6H, s), 2.18 (3H, s), 5.02 (2H, s), 5.16 (2H, s), 6.71 (1H, d, J = 8.2 Hz), 7.27 (1H, d, J = 8.2 Hz), 7.32 (1H, s), 7.40 (2H, d, J = 7.7 Hz) 7.53 (1H, t, J = 7.7 Hz), 7.77 (2H, d, J = 8.7 Hz), 8.20 (2H, d, J = 8.7 Hz).

Example 254 (Synthesis of 4-{[3- (methoxycarbonylmethyl) phenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
3-Aminophenylacetic acid was added to a solution of 4-carboxy-2- (4-trifluoromethylphenyl) isoindolin-1-one (711 mg, 2.21 mmol) obtained in Example 177 (iv) in methylene chloride (10 mL). Methyl (439 mg, 2.66 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (510 mg, 2.66 mmol), 1-hydroxybenzotriazole monohydrate (359 mg, 2.66 mmol) and diisopropylethyl Ether (686 mg, 5.30 mmol) was added and stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with hexane: ethyl acetate = 1: 1, and 4-{[3- (methoxycarbonylmethyl) phenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one (244 mg, 24%) of crystals were obtained.
mp 195-197 ° C
¹ H NMR (CDCl ₃ ) δ: 3.64 (3H, s), 3.71 (2H, s), 5.37 (2H, s), 7.05 (1H, d, J = 7.3 Hz) , 7.34 (1H, t, J = 7.9 Hz), 7.66-7.80 (5H, m), 8.03 (1H, d, J = 7.6 Hz), 8.19 (2H, d, J = 8.9 Hz), 8.30 (1H, d, J = 7.6 Hz), 10.52 (1H, s).

Example 255 (Synthesis of 4-{[3- (carboxymethyl) phenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-{[3- (methoxycarbonylmethyl) phenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 254 was operated in the same manner as in Example 69, and 4 -{[3- (Carboxymethyl) phenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 284-289 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.59 (2H, s), 5.37 (2H, s), 7.04 (1H, d, J = 7.3 Hz), 7.33 (1H, t, J = 7.6 Hz), 7.68 (1H, d, J = 7.9 Hz), 7.73-7.80 (4H, m), 8.03 (1H, d, J = 7.6 Hz) ), 8.19 (2H, d, J = 8.6 Hz), 8.30 (1H, d, H = 7.6 Hz), 10.51 (1H, s), 12.37 (1H, br).

Example 256 (Synthesis of 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
Using 2- (4-trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 19 and 3- (ethoxycarbonylmethyl) phenethyl alcohol obtained in Example 77 (iii) Operating in analogy to Example 148 (ii), the 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one An oily material was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.3 Hz), 3.15 (2H, t, J = 6.6 Hz), 3.61 (2H, s), 4. 11 (2H, q, J = 7.3 Hz), 4.32 (2H, t, J = 6.6 Hz), 4.75 (2H, s), 7.05 (1H, dd, J = 1.0 Hz) , 7.6 Hz), 7.15-7.21 (2H, m), 7.26-7.33 (4H, m), 7.44 (1 H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.92-7.98 (2H, m).

Example 257 (Synthesis of 4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 256 was used in the same manner as in Example 69. To give 4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 182-183 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.08 (2H, t, J = 6.6 Hz), 3.56 (2H, s), 4.35 (2H, t, J = 6.6 Hz), 4.90 (2H, s), 7.12-7.14 (1H, m), 7.23-7.28 (3H, m), 7.31-7.38 (2H, m), 7. 43-7.53 (3H, m), 8.03-8.09 (2H, m), 12.31 (1H, br).

Example 258 (Synthesis of 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
Example using 4-hydroxy-2- (4-methylphenyl) isoindoline-1-one obtained in Synthesis Example 11 and 3- (ethoxycarbonylmethyl) phenethyl alcohol obtained in Example 77 (iii) The oily substance of 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one was obtained by operating in the same manner as in 148 (ii). It was.
¹ H NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 3.14 (2H, t, J = 6.6 Hz), 3. 61 (2H, s), 4.12 (2H, q, J = 7.3 Hz), 4.31 (2H, t, J = 6.6 Hz), 4.73 (2H, s), 7.02 ( 1H, dd, J = 0.7 Hz, 7.6 Hz), 7.16-7.33 (6H, m), 7.42 (1H, t, J = 7.6 Hz), 7.50 (1H, dd) , J = 0.7 Hz, 7.6 Hz), 7.73-7.79 (2H, m).

Example 259 (Synthesis of 4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethyl) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 258 was operated in the same manner as in Example 69. 4-({2- [3- (carboxymethyl) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one was obtained.
mp 156-159 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 3.08 (2H, t, J = 6.6 Hz), 3.56 (2H, s), 4.34 (2H, t, J = 6.6 Hz), 4.83 (2H, s), 7.13 (1H, dt, J = 2.0 Hz, 6.3 Hz), 7.22-7.31 (6H, m), 7.34 (1H, d, J = 7.6 Hz), 7.48 (1H, t, J = 7.6 Hz), 7.77-7.82 (2H, m), 12.33 (1H, br) ).

Example 260 Synthesis of 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindolin-1-one)
2- (4-Trifluoromethoxyphenyl) -4-hydroxyisoindoline-1-one obtained in Synthesis Example 19 and [3- (2-hydroxyethyl) phenylthio] acetic acid obtained in Example 106 (i) The same procedure as in Example 148 (ii) was performed using ethyl, and 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline- 1-one crystals were obtained.
mp 92-94 ° C
¹ H NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.3 Hz), 3.12 (2H, t, J = 6.6 Hz), 3.64 (2H, s), 4. 13 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 6.6 Hz), 4.73 (2H, s), 7.04 (1H, dd, J = 1.0 Hz) , 7.6 Hz), 7.13-7.17 (1H, m), 7.24-7.33 (4H, m), 7.38-7.39 (1H, m), 7.44 (1H) , T, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.92-7.98 (2H, m).

Example 261 (Synthesis of 4-({2- [3- (carboxymethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 260 was used in the same manner as in Example 69. To give 4-({2- [3- (carboxymethylthio) phenyl] ethyl} oxy) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 167-168 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.6 Hz), 3.83 (2H, s), 4.35 (2H, t, J = 6.6 Hz), 4.90 (2H, s), 7.19-7.22 (2H, m), 7.26-7.39 (4H, m), 7.44-7.54 (3H, m), 8. 03-8.10 (2H, m), 12.77 (1H, s).

Example 262 (Synthesis of 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
4-hydroxy-2- (4-methylphenyl) isoindoline-1-one obtained in Synthesis Example 11 and ethyl [3- (2-hydroxyethyl) phenylthio] acetate obtained in Example 106 (i) Of 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one. Crystals were obtained.
mp 90-91 ° C
¹ H NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 3.12 (2H, t, J = 6.6 Hz), 3. 64 (2H, s), 4.13 (2H, q, J = 7.3 Hz), 4.29 (2H, t, J = 6.6 Hz), 4.72 (2H, s), 7.01 ( 1H, d, J = 7.9 Hz), 7.15 (1H, dt, J = 2.0 Hz, 6.3 Hz), 7.22-7.32 (4H, m), 7.38-7.45 (2H, m), 7.50 (1H, d, J = 7.6 Hz), 7.74-7.79 (2H, m).

Example 263 (Synthesis of 4-({2- [3- (carboxymethylthio) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethylthio) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 262 was operated in the same manner as in Example 69. 4-({2- [3- (carboxymethylthio) phenyl] ethyl} oxy) -2- (4-methylphenyl) isoindoline-1-one was obtained.
mp 175-176 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 3.07 (2H, t, J = 6.6 Hz), 3.82 (2H, s), 4.34 (2H, t, J = 6.6 Hz), 4.83 (2H, s), 7.18-7.23 (3H, m), 7.26-7.36 (5H, m), 7.49 (1H, t, J = 7.6 Hz), 7.78-7.83 (2H, m), 12.77 (1H, s).

Example 264 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
(I) Synthesis of 4-methoxycarbonyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one Dimethyl 2-methylisophthalate obtained in Example 177 (ii) (5.00 g, 8.00 mmol) ) To a carbon tetrachloride (75 mL) solution was added bromosuccinimide (4.27 g, 24.01 mmol) and benzoyl peroxide (75% in Water, 400 mg), and the mixture was heated to reflux for 2 hours. After standing to cool, insolubles were filtered off and the solvent was distilled off to obtain dimethyl 2-bromomethylisophthalate.

A solution of dimethyl 2-bromomethylisophthalate and 1-amino-4- (trifluoromethoxy) benzene (4.25 g, 24.01 mmol) in dimethylformamide (75 mL) at 60 ° C. for 1 hour and a half and at 120 ° C. for 1 hour Half stirred. After standing to cool, the reaction solution was diluted with methanol and then with water. The obtained crystals were collected by filtration, washed with water, and dried to give 4-methoxycarbonyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (7.17 g, 85%).
mp 156-165 ° C
¹ H NMR (CDCl ₃ ) δ: 4.01 (3H, s), 5.19 (2H, s), 7.30 (2H, d, J = 9.1 Hz), 7.64 (1H, t, J = 7.5 Hz), 7.98 (2H, d, J = 9.1 Hz), 8.13 (1H, dd, J = 0.8, 7.5 Hz), 8.27 (1H, dd, J = 0.8, 7.5 Hz).

(Ii) Synthesis of 4-carboxy-2- (4-trifluoromethoxyphenyl) isoindoline-1-one 4-methoxycarbonyl-2- (4-trifluoromethoxyphenyl) isoindoline obtained in (i) above To a solution of -1-one (7.11 g, 20.23 mmol) in dioxane (50 mL) was added 2N aqueous sodium hydroxide solution (15.2 mL, 30.4 mmol), and the mixture was stirred at room temperature for 17 hours. 1N hydrochloric acid (30.4 mL) was added to the reaction solution, diluted with ice water, and the resulting crystals were collected by filtration. The obtained crystals were washed with water and dried to give 4-carboxy-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (6.63 g, 97%).
mp 233-242 ° C
¹ H NMR (DMSO-d ₆ ) δ: 5.28 (2H, s), 7.48 (2H, d, J = 9.2 Hz), 7.71 (1H, t, J = 7.6 Hz), 8.00-8.10 (3H, m), 8.22 (1H, d, J = 7.6 Hz), 13.57 (1H, br).

(Iii) Synthesis of 4-hydroxymethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one 4-carboxy-2- (4-trifluoromethoxy) obtained in (ii) above To a solution of (phenyl) isoindoline-1-one (4.00 g, 11.86 mmol) in tetrahydrofuran (250 mL) was added dropwise borane-tetrahydrofuran complex (38.8 mL, 41.13 mmol) under ice-cooling. Stir for 17.5 hours at room temperature. Methanol was added to the reaction solution under ice-cooling, and the solvent was distilled off. Water was added to the residue and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether-hexane to obtain crystals of 4-hydroxymethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (3.32 g, 87%).
mp 120-123 ° C
¹ H NMR (CDCl ₃ ) δ: 2.05 (1H, t, J = 5.2 Hz), 4.88 (2H, d, J = 5.2 Hz), 4.92 (2H, s), 7. 25-7.32 (3H, m), 7.42-7.53 (2H, m), 7.83 (1H, dd, J = 1.5, 7.1 Hz), 7.88-7.96 (2H, m).

(Iv) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in (iii) above 4-hydroxymethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained and ethyl (4-hydroxy-2-methylphenoxy) ethyl acetate obtained in Example 227 (iii) Operating in analogy to Example 148 (ii), 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one Crystal was obtained.
mp 113-114 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 2.30 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4. 59 (2H, s), 4.94 (2H, s), 5.16 (2H, s), 6.68 (1H, d, J = 8.9 Hz), 6.74 (1H, dd, J = 3.0 Hz, 8.9 Hz), 6.84 (1 H, d, J = 3.0 Hz), 7.26-7.30 (2 H, m), 7.54 (1 H, t, J = 7.6 Hz) ), 7.60 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.89-7.95 (3H, m).

Example 265 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 264 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 193-195 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.18 (3H, s), 4.62 (2H, s), 5.13 (2H, s), 5.23 (2H, s), 6.77 (1H, d, J = 8.9 Hz), 6.85 (1H, dd, J = 3.0 Hz, 8.9 Hz), 6.94 (1H, d, J = 3.0 Hz), 7.47 ( 2H, d, J = 8.2 Hz), 7.58 (1H, t, J = 7.6 Hz), 7.74-7.78 (2H, m), 8.02-8.08 (2H, m ), 12.92 (1H, br).

Example 266 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
(I) Synthesis of 4-bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one 4-hydroxymethyl-2- (4-trimethyl) obtained in Example 264 (iii) under ice cooling To a solution of fluoromethoxyphenyl) isoindoline-1-one (1.29 g, 4.00 mmol) in dichloromethane (24 mL), triphenylphosphine (1.57 g, 6.00 mmol), N-bromosuccinimide (1.07 g, 6. 00 mmol) was added, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 50 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 4-bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (1.48 g, 96%) crystals.
mp 134-135 ° C
¹ H NMR (CDCl ₃ ) δ: 4.58 (2H, s), 4.93 (2H, s), 7.28-7.31 (2H, m), 7.51 (1H, t, J = 7.6 Hz), 7.58 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.88 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.91-7.97. (2H, m).

(Ii) Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in (i) above. 4-Bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (309 mg, 0.80 mmol) and (4-mercapto-2-methylphenoxy) acetic acid obtained in Example 223 (ii) Cesium carbonate (261 mg, 0.80 mmol) was added to a solution of ethyl (181 mg, 0.80 mmol) in acetonitrile (12 mL), and the mixture was stirred overnight at room temperature. Water was added, and the resulting crystals were recrystallized from ethanol and dichloromethane, dried, and 4-({[4- (carboxymethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethoxy). Crystals of (phenyl) isoindoline-1-one (319 mg, 75%) were obtained.
mp 128-130 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.21 (3H, s), 4.02 (2H, s), 4.24 (2H, q, J = 7.3 Hz), 4.54 (2H, s), 4.64 (2H, s), 6.54 (1H, d, J = 8.2 Hz), 7.01 (1H, ddd, J = 0.7Hz, 2.3Hz, 8.2Hz), 7.10 (1H, dd, J = 0.7Hz, 2.3Hz), 7.24-7.30 (3H, m), 7.40 (1H , T, J = 7.6 Hz), 7.80 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.84-7.90 (2H, m).

Example 267 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
The 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 266 was prepared in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] thio} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 168-171 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.11 (3H, s), 4.25 (2H, s), 4.62 (2H, s), 4.91 (2H, s), 6.75 (1H, d, J = 8.2 Hz), 7.13-7.17 (2H, m), 7.42-7.49 (4H, m), 7.64-7.70 (1H, m) , 7.98-8.04 (2H, m), 13.13 (1H, br).

Example 268 (Synthesis of 4-([4- (ethoxycarbonylmethyl) phenyl] thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of methyl (4-mercaptophenyl) acetate A solution of 4-mercaptophenylacetic acid (505 mg, 3.00 mmol) in hydrochloric acid-methanol (20 mL) was heated to reflux overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain oily methyl (4-mercaptophenyl) acetate (487 mg, 89%).
¹ H NMR (CDCl ₃ ) δ: 3.43 (1H, s), 3.57 (2H, s), 3.69 (3H, s), 7.13-7.17 (2H, m), 7 .22-7.26 (2H, m).

(Ii) 4-{[4- (methoxycarbonylmethyl) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one 4-trifluoromethanesulfonyl obtained in Example 80 (i) Oxy-2- (4-trifluoromethylphenyl) isoindoline-1-one and methyl (4-mercaptophenyl) acetate obtained in (i) above were operated in the same manner as in Example 179 (i), and 4- {[4- (Methoxycarbonylmethyl) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindolin-1-one was obtained.
mp 143-144 ° C
¹ H NMR (CDCl ₃ ) δ: 3.63 (2H, s), 3.69 (3H, s), 4.72 (2H, s), 7.25-7.33 (4H, m), 7 .46-7.55 (2H, m), 7.67 (2H, d, J = 8.9 Hz), 7.86 (1H, dd, J = 1.3 Hz, 6.9 Hz), 8.00 ( 2H, d, J = 8.9 Hz).

Example 269 (Synthesis of 4-([4- (carboxymethyl) phenyl] thio) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-{[4- (methoxycarbonylmethyl) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 268 was operated in the same manner as in Example 69, and 4 -{[4- (Carboxymethyl) phenyl] thio} -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 200-201 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.60 (2H, s), 5.00 (2H, s), 7.29-7.34 (2H, m), 7.39-7.44 ( 2H, m), 7.49 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.57 (1H, t, J = 7.6 Hz), 7.76-7.82 (3H, m ), 8.15 (2H, d, J = 8.6 Hz), 12.40 (1H, brs).

Example 270 (Synthesis of 4-({[4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one 4-hydroxymethyl-2- (4-trifluoromethylphenyl) obtained in Example 177 (v) To a solution of isoindoline-1-one (2.00 g, 6.51 mmol) in methylene chloride (30 mL) was added N-bromosuccinimide (1.74 g, 9.76 mmol) and triphenylphosphine (2.56 g, 9.76 mmol). ) Was added under ice cooling, followed by stirring at room temperature for 2.5 hours. After completion of the reaction, methanol (2 mL) was added and stirred at room temperature for 20 minutes. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain crystals of 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (2.00 g, 83%).
mp 162-163 ° C
¹ H NMR (CDCl ₃ ) δ: 4.60 (2H, s), 4.97 (2H, s), 7.53 (2H, d, J = 9.1 Hz), 7.61 (1H, dd, J = 1.2, 7.5 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.91 (1H, dd, J = 1.2, 7.5 Hz), 8.07 (2H , D, J = 8.7 Hz).

(Ii) Synthesis of 4-({[4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one 4- (obtained in (i) above) Operate as in Example 266 (ii) using bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one and methyl 4-hydroxyphenylacetate to give 4-({[4- (methoxycarbonyl Crystals of methyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one were obtained.
mp 120-123 ° C
¹ H NMR (CDCl ₃ ) δ: 3.59 (2H, s), 3.70 (3H, s), 4.96 (2H, s), 5.23 (2H, s), 6.94-6 .99 (2H, m), 7.22-7.27 (2H, m), 7.55 (1H, t, J = 7.6 Hz), 7.63 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.67 (2H, d, J = 8.9 Hz), 7.92 (1H, dd, J = 0.7 Hz, 7.6 Hz), 8.03 (2H, d, J = 8) .9 Hz).
Example 271 (Synthesis of 4-({[4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 270 was treated in the same manner as in Example 69. 4-({[4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 181-182 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.50 (2H, s), 5.18 (2H, s), 5.31 (2H, s), 7.02-7.08 (2H, m) , 7.18-7.23 (2H, m), 7.60 (1H, t, J = 7.6 Hz), 7.77-7.84 (4H, m), 8.18 (2H, d, J = 8.6 Hz), 12.27 (1H, br).

Example 272 (Synthesis of 4-({[4- (ethoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of (4-methoxy-3-methylphenyl) acetonitrile Under ice-cooling, (4-methoxy-3-methylphenyl) methanol (761 mg, 5.00 mmol), acetone cyanohydrin (946 mg, 10.0 mmol), A solution of phenylphosphine (1.70 g, 6.50 mmol) in toluene (25 mL) was added dropwise with a solution of diethyl azodicarboxylate in toluene (2.73 mL, 6.00 mmol), and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature overnight. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily (4-methoxy-3-methylphenyl) acetonitrile (411 mg, 51%).
¹ H NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.65 (2H, s), 3.83 (3H, s), 6.80 (1H, d, J = 8.2 Hz) 7.08-7.13 (2H, m).

(Ii) Synthesis of methyl (4-hydroxy-3-methylphenyl) acetate (4-methoxy-3-methylphenyl) acetonitrile (392 mg, 2.43 mmol) obtained in (i) above and acetic acid (7 mL) and 47 A solution of% hydrobromic acid (7 mL) was stirred at 80 ° C. for 2 days. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily methyl (4-hydroxy-3-methylphenyl) acetate (237 mg, 54%).
¹ H NMR (CDCl ₃ ) δ: 2.23 (3H, s), 3.53 (2H, s), 3.69 (3H, s), 4.80 (1H, s), 6.70 (1H , D, J = 8.2 Hz), 6.97 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.03 (1H, d, J = 2.0 Hz).

(Iii) Synthesis of 4-({[4- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 270 (i) Using 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in 1 above and methyl (4-hydroxy-3-methylphenyl) acetate obtained in (ii) above Of 266 (ii) and 4-({[4- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one. Crystals were obtained.
mp 166-167 ° C
¹ H NMR (CDCl ₃ ) δ: 2.29 (3H, s), 3.56 (2H, s), 3.70 (3H, s), 4.98 (2H, s), 5.23 (2H , S), 6.88 (1H, d, J = 8.2 Hz), 7.08-7.12 (2H, m), 7.56 (1H, t, J = 7.6 Hz), 7.64 -7.70 (3H, m), 7.93 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.03 (2H, d, J = 8.6 Hz).

Example 273 (Synthesis of 4-({[4- (carboxymethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 272 was used in Example 69. To give 4-({[4- (carboxymethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 208-209 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.23 (3H, s), 3.46 (2H, s), 5.18 (2H, s), 5.31 (2H, s), 7.01 −7.08 (3H, m), 7.61 (1H, t, J = 7.6 Hz), 7.78-7.84 (4H, m), 8.18 (2H, d, J = 8. 9 Hz), 12.23 (1 H, s).

Example 274 (Synthesis of 4-({[4- (methoxycarbonylmethyl) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of (4-methoxy-2-methylphenyl) methanol A solution of 4-methoxy-2-methylbenzoic acid (831 mg, 5.00 mmol) in tetrahydrofuran (25 mL) was added to a borane-tetrahydrofuran complex (4.72 mL, 5. 00 mmol) was added dropwise and stirred at room temperature for 5 hours. Methanol was added and the solvent was distilled off. Water was added, and the mixture was extracted with ethyl acetate to obtain oily (4-methoxy-2-methylphenyl) methanol (761 mg, quant.).
¹ H NMR (CDCl ₃ ) δ: 2.37 (3H, s), 3.80 (3H, s), 4.64 (2H, s), 6.70-6.80 (2H, m), 7 .22-7.26 (1H, m).

(Ii) Synthesis of (4-methoxy-2-methylphenyl) acetonitrile Under ice-cooling, (4-methoxy-2-methylphenyl) methanol (727 mg, 4.78 mmol) obtained in (i) above, acetone cyanohydrin ( 903 mg, 9.55 mmol) and triphenylphosphine (1.63 g, 6.21 mmol) in toluene (25 mL) were added dropwise with a solution of diethyl azodicarboxylate in toluene (2.61 mL, 5.73 mmol) at 0 ° C. for 30 minutes. And stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain oily (4-methoxy-2-methylphenyl) acetonitrile (730 mg, 95%).
¹ H NMR (CDCl ₃ ) δ: 2.32 (3H, s), 3.60 (2H, s), 3.80 (3H, s), 6.73-6.76 (2H, m), 7 .21-7.26 (1H, m).

(Iii) Synthesis of methyl (4-hydroxy-2-methylphenyl) acetate (4-methoxy-2-methylphenyl) acetonitrile (690 mg, 4.28 mmol) obtained in (ii) above with acetic acid (10 mL) and 47 A solution of% hydrobromic acid (10 mL) was stirred at 80 ° C. for 6 days. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily methyl (4-hydroxy-2-methylphenyl) acetate (149 mg, 19%).
¹ H NMR (CDCl ₃ ) δ: 2.24 (3H, s), 3.57 (2H, s), 3.69 (3H, s), 5.17 (1H, br), 6.59 (1H , Dd, J = 2.6 Hz, 8.2 Hz), 6.63 (1H, d, J = 2.6 Hz), 7.03 (1H, d, J = 8.2 Hz).

(Iv) Synthesis of 4-({[4- (methoxycarbonylmethyl) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 270 (i) Using 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in 1 above and methyl (4-hydroxy-2-methylphenyl) acetate obtained in (iv) above Of 266 (ii) and 4-({[4- (methoxycarbonylmethyl) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one. Crystals were obtained.
mp 131-132 ° C
¹ H NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.60 (2H, s), 3.70 (3H, s), 4.98 (2H, s), 5.21 (2H) , S), 6.80 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.85 (1H, d, J = 2.6 Hz), 7.15 (1H, d, J = 8. 2 Hz), 7.56 (1 H, t, J = 7.6 Hz), 7.63 (1 H, dd, J = 0.7 Hz, 7.6 Hz), 7.68 (2 H, d, J = 8.9 Hz) ), 7.92 (1H, dd, J = 0.7 Hz, 7.6 Hz), 8.04 (2H, d, J = 8.9 Hz).

Example 275 (Synthesis of 4-({[4- (carboxymethyl) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[4- (methoxycarbonylmethyl) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 274 was To give 4-({[4- (carboxymethyl) -3-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 197-199 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 3.52 (2H, s), 5.16 (2H, s), 5.29 (2H, s), 6.87 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.94 (1H, d, J = 2.6 Hz), 7.12 (1H, d, J = 8.2 Hz), 7.59 ( 1H, t, J = 7.6 Hz), 7.77-7.83 (4H, m), 8.17 (2H, d, J = 8.9 Hz), 12.26 (1H, brs).

Example 276 (Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of [4- (2-hydroxyethyl) phenoxy] ethyl acetate The 4-hydroxyphenethyl alcohol was operated in the same manner as in Example 68 (i), and [4- (2-hydroxyethyl) phenoxy] ethyl acetate was prepared. Synthesized.
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.3 Hz), 1.40-1.45 (1H, m), 2.81 (2H, t, J = 6.6 Hz) ), 3.79-3.85 (2H, m), 4.27 (2H, q, J = 7.3 Hz), 4.60 (2H, s), 6.84-6.89 (2H, m) ), 7.12-7.18 (2H, m).

(Ii) Synthesis of 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one 2 obtained in Synthesis Example 3 Example 148 (ii) using-(4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one and [4- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in (i) above To give 4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 131-132 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 3.10 (2H, t, J = 6.9 Hz), 4.26 (2H, q, J = 7) .3 Hz), 4.28 (2H, t, J = 6.9 Hz), 4.60 (2H, s), 4.73 (2H, s), 6.86-6.92 (2H, m), 7.05 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.19-7.24 (2H, m), 7.44 (1H, t, J = 7.6), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz).

Example 277 (Synthesis of 4-({2- [4- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindolin-1-one)
4-({2- [4- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 276 (ii) The same operation as in 69 was performed to obtain 4-({2- [4- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 169.5-170.5 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.04 (2H, t, J = 6.9 Hz), 4.32 (2H, t, J = 6.9 Hz), 4.63 (2H, s), 4.94 (2H, s), 6.84-6.90 (2H, m), 7.26-7.31 (2H, m), 7.34 (1H, d, J = 8.2 Hz), 7.38 (1H, d, J =, 6.9 Hz), 7.51 (1H, t, J = 7.6), 7.80 (2H, d, J = 8.9 Hz), 8.17 ( 2H, d, J = 8.6 Hz).

Example 278 (Synthesis of 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
To a solution of methyl (3-hydroxy-5-methylphenyl) acetate (149 mg, 0.83 mmol) synthesized in accordance with International Publication No. WO2006 / 126514 in dimethylformamide (6 mL) was added potassium carbonate (124 mg, 0.90 mmol) and Example 270 ( 4-Bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one (278 mg, 0.75 mmol) obtained by the same method as in i) was added, and the mixture was stirred at 70 ° C. for 7 hours. Water was added and the crystals obtained by filtration were purified by silica gel column chromatography to give 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethyl). Crystals of phenyl) isoindoline-1-one (182 mg, 52%) were obtained.
mp 164.5-166 ° C
¹ H NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.69 (3H, s), 4.97 (2H, s), 5.21 (2H, s), 6.74-6 .77 (3H, m), 7.55 (1H, t, J = 7.6 Hz), 7.63 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.66-7.71 ( 2H, m), 7.92 (1H, dd, J = 1.0 Hz, 7.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

Example 279 (Synthesis of 4-({[3- (carboxymethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 278 was obtained in Example 69. To give 4-({[3- (carboxymethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 171-172 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.28 (3H, s), 3.50 (2H, s), 5.17 (2H, s), 5.28 (2H, s), 6.71 (1H, s), 6.82 (2H, s), 7.60 (1H, t, J = 7.6 Hz), 7.78-7.84 (4H, m), 8.18 (2H, d , J = 8.6 Hz).

Example 280 (Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one)
(I) Synthesis of 4-bromo-2- (4-methylphenyl) isoindoline-1-one Using 4-methylaniline and operating in the same manner as in Example 81 (iv), 4-bromo-2- (4 -Methylphenyl) isoindoline-1-one was synthesized.
mp 144-146 ° C
¹ HNMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 4.93 (2H, s), 7.25 (2H, d, J = 8.2 Hz), 7.52 (1H, t , J = 7.9 Hz), 7.77-7.82 (3H, m), 7.89 (1H, dd, J = 1.0 Hz, 7.9 Hz).

(Ii) Synthesis of 4- (methoxymethoxy) -3-methylbenzaldehyde To a solution of 4-hydroxy-3-methylbenzaldehyde (1.0 g, 7.34 mmol) in acetone (20 mL), potassium carbonate (1.32 g, 9. 55 mmol) and chloromethyl methyl ether (0.71 g, 8.81 mmol) were added and heated to reflux. Potassium carbonate (1.32 g, 9.55 mmol) and chloromethyl methyl ether (0.71 g, 8.81 mmol) were each added twice as appropriate, and the mixture was heated to reflux for a total of 8 hours. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography, and dried to give oily 4- (methoxymethoxy) -3-methylbenzaldehyde (1.15 g, 87%).
¹ HNMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.50 (3H, s), 5.29 (2H, s), 7.16 (1H, d, J = 7.9 Hz), 7.66-7.71 (2H, m), 9.87 (1H, s).

(Iii) Synthesis of 1- (methoxymethoxy) -2-methyl-4-vinylbenzene Under ice cooling, sodium hydride was added to a suspension of methyltriphenylphosphonium bromide (4.42 g, 12.4 mmol) in tetrahydrofuran (22 mL). (Oil 60%, 0.49 mg, 12.4 mmol) was added and stirred at room temperature for 1 hour, and then 4- (methoxymethoxy) -3-methylbenzaldehyde (1.11 g, 6. 18 mmol) in THF (30 mL) was added and stirred at room temperature for 2.5 hours. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily 1- (methoxymethoxy) -2-methyl-4-vinylbenzene (872 mg, 79%).
¹ HNMR (CDCl ₃ ) δ: 2.25 (3H, s), 3.48 (3H, s), 5.12 (1H, dd, J = 1.0 Hz, 10.9 Hz), 5.20 (2H , S), 5.61 (1H, dd, J = 1.0 Hz, 17.5 Hz), 6.63 (1H, dd, J = 10.9 Hz, 17.5 Hz), 6.99 (1H, d, J = 8.6 Hz), 7.16-7.23 (2H, m).

(Iv) Synthesis of 4-{(E) -2- [4- (methoxymethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one obtained in (i) above 4-bromo-2- (4-methylphenyl) isoindoline-1-one (302 mg, 1.00 mmol) obtained, 1- (methoxymethoxy) -2-methyl-4-vinyl obtained in (iii) above Benzene (197 mg, 1.11 mmol), triethylamine (0.4 mL), palladium acetate (4.45 mg, 0.02 mmol), tri-o-tolylphosphine (24.4 mg, 0.08 mmol) in acetonitrile (2 mL). Heated to reflux overnight. Dimethylformamide (1 mL) was added and stirred at 120 ° C. overnight. Palladium acetate (11.4 mg, 0.05 mmol) and tri-o-tolylphosphine (61.4 mg, 0.20 mmol) were added and stirred overnight at 120 ° C. Water was added and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, water, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography, and 4-{(E) -2- [4- (methoxymethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline- Crystals of 1-one (223 mg, 56%) were obtained.
mp 123-131 ° C
¹ H NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.37 (3H, s), 3.51 (3H, s), 4.94 (2H, s), 5.24 (2H , S), 6.99 (1H, d, J = 16.2 Hz), 7.07 (1H, d, J = 8.2 Hz), 7.11 (1H, d, J = 16.2 Hz), 7 .23-7.27 (2H, m), 7.33 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.38-7.39 (1H, m), 7.51 (1H, t, J = 7.6 Hz), 7.75-7.82 (4H, m).

(V) Synthesis of 4-[(E) -2- (4-hydroxy-3-methylphenyl) ethenyl] -2- (4-methylphenyl) isoindoline-1-one 4 obtained in (iv) above -{(E) -2- [4- (methoxymethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one (203 mg, 0.51 mmol) in acetic acid (5 mL) Then, ethanol (5 mL) was added and dissolved, 5 drops of hydrochloric acid was added, and the mixture was stirred at 90 ° C. for 4.5 hours. After adding water, the precipitate is filtered off, washed with water and dried to give 4-[(E) -2- (4-hydroxy-3-methylphenyl) ethenyl] -2- (4-methylphenyl) iso. Indoline-1-one (131 mg, 72%) was obtained.
mp 252-256 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.18 (3H, s), 2.33 (3H, s), 5.15 (2H, s), 6.82 (1H, d, J = 8. 2 Hz), 7.14 (1 H, d, J = 16.5 Hz), 7.25-7.28 (2 H, m), 7.28 (1 H, d, J = 16.2 Hz), 7.36 ( 1H, dd, J = 2.0 Hz, 8.2 Hz), 7.47-7.47 (1 H, m), 7.53 (1 H, t, J = 7.6 Hz), 7.62 (1 H, dd) , J = 1.0 Hz, 7.6 Hz), 7.88-7.94 (3H, m), 9.61 (1H, br).

(Vi) Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one In the above (v) The obtained 4-[(E) -2- (4-hydroxy-3-methylphenyl) ethenyl] -2- (4-methylphenyl) isoindoline-1-one was operated in the same manner as in Example 140 (ii). 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one (144 mg, 98%) Got.
mp 152-154 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 2.35 (3H, s), 2.37 (3H, s), 4.28 (2H, q, J = 7.3 Hz), 4.68 (2H, s), 4.94 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 6.99 (1H, d, J = 16.2 Hz), 7.10 (1 H, d, J = 16.2 Hz), 7.23-7.27 (2 H, m), 7.31 (1 H, dd, J = 2.3 Hz, 8.2 Hz) ), 7.40-7.41 (1H, m), 7.51 (1H, t, J = 7.6 Hz), 7.75-7.82 (4H, m).

Example 281 (Synthesis of 4-{(E) -2- [4- (carboxymethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one)
4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one obtained in Example 280 The same operation as in 69 was performed to obtain 4-{(E) -2- [4- (carboxymethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one.
mp 244-246 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 2.33 (3H, s), 4.75 (2H, s), 5.16 (2H, s), 6.87 (1H, d, J = 8.6 Hz), 7.22 (1H, d, J = 16.5 Hz), 7.25-7.29 (2H, m), 7.32 (1H, d, J = 16.5 Hz), 7.46 (1 H, dd, J = 2.0 Hz, 8.6 Hz), 7.54 (1 H, t, J = 7.6 Hz), 7.57-7.58 (1 H, m ), 7.64 (1H, dd, J = 0.7 Hz, 7.6 Hz), 7.88-7.93 (2H, m), 7.95 (1H, d, J = 7.3 Hz).

Example 282 (Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
(I) Synthesis of 4-bromo-2- (4-trifluoromethoxyphenyl) isoindoline-1-one Using 4-trifluoromethoxyaniline and operating in the same manner as in Example 81 (iv), 4-bromo- 2- (4-Trifluoromethylphenyl) isoindoline-1-one was synthesized.
mp 151-155 ° C
¹ H NMR (CDCl ₃ ) δ: 4.77 (2H, s), 7.26-7.33 (2H, m), 7.43 (1H, t, J = 7.6 Hz), 7.74 ( 1H, dd, J = 1.0 Hz, 7.9 Hz), 7.88 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.89-7.95 (2H, m).

(Ii) Synthesis of 4-{(E) -2- [4- (methoxymethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (i) 4-Bromo-2- (4-trifluoromethoxyphenyl) isoindoline-1-one (372 mg, 1.00 mmol) obtained in 1), 1- (methoxymethoxy) -2 obtained in Example 280 (iii) -Methyl-4-vinylbenzene (202 mg, 1.11 mmol), triethylamine (0.4 mL), tris (dibenzylideneacetone) dipalladium (0) (46.2 mg, 0.05 mmol), tri-o-tolylphosphine ( 62.0 mg, 0.20 mmol) was stirred in acetonitrile (2 mL) and dimethylformamide (1 mL) at 85 ° C. overnight. did. Water was added and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, water, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent CH ₂ Cl ₂ / EtOH = 50/1) to give 4-{(E) -2- [4- (methoxymethoxy) -3-methylphenyl] ethenyl. } -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (271 mg, 58%) was obtained.
mp 141-145 ° C
¹ H NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.51 (3H, s), 4.97 (2H, s), 5.25 (2H, s), 6.99 (1H , D, J = 16.2 Hz), 7.08 (1H, d, J = 7.3 Hz), 7.12 (1H, d, J = 16.2 Hz), 7.26-7.35 (2H, m), 7.39-7.39 (1H, m), 7.53 (1H, t, J = 7.6 Hz), 7.78-7.89 (2H, m), 7.90-8. 00 (3H, m).

(Iii) Synthesis of 4-[(E) -2- (4-hydroxy-3-methylphenyl) ethenyl] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in (ii) above 4-{(E) -2- [4- (methoxymethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (255 mg, 0.54 mmol) Acetic acid (7 mL) and ethanol (10 mL) were added and dissolved, 7 drops of hydrochloric acid was added, and the mixture was stirred at 60 ° C. for 7 hr. After adding water, the precipitate was filtered off, washed with water and dried to give 4-[(E) -2- (4-hydroxy-3-methylphenyl) ethenyl] -2- (4-trifluoromethoxyphenyl). ) Isoindoline-1-one (218 mg, 94%) was obtained.
mp 228-231 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.34 (3H, s), 5.22 (2H, s), 6.82 (1H, d, J = 8.2 Hz), 7.14 (1H, d, J = 16.5 Hz), 7.29 (1H, d, J = 16.5 Hz), 7.36 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.47-7.51. (3H, m), 7.55 (1H, t, J = 7.6 Hz), 7.65 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.95 (1H, d, J = 7.3 Hz), 8.12-8.18 (2H, m).

(Iv) Synthesis of 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (iii) 4-[(E) -2- (4-hydroxy-3-methylphenyl) ethenyl] -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 140 (ii) 4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one (194 mg) , 78%) crystals were obtained.
mp 154-155 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.3 Hz), 2.36 (3H, s), 4.29 (2H, q, J = 7.3 Hz), 4. 69 (2H, s), 4.96 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 6.99 (1H, d, J = 16.5 Hz), 7.11 ( 1H, d, J = 16.2 Hz), 7.26-7.33 (3H, m), 7.40-7.41 (1H, m), 7.53 (1H, t, J = 7.6 Hz) ), 7.78-7.83 (2H, m), 7.93-7.99 (2H, m).

Example 283 (Synthesis of 4-{(E) -2- [4- (carboxymethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 282 was used. The same operation as in Example 69 was carried out, and 4-{(E) -2- [4- (carboxymethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one Got.
mp 213-215 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 4.75 (2H, s), 5.23 (2H, s), 6.88 (1H, d, J = 8. 6 Hz), 7.23 (1H, d, J = 16.5 Hz), 7.33 (1 H, d, J = 16.5 Hz), 7.44-7.59 (5 H, m), 7.66- 7.69 (1H, m), 7.79 (1 H, d, J = 6.9 Hz), 8.12-8.18 (2H, m).

Example 284 (Synthesis of 4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-methylphenyl) isoindoline-1-one)
4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-methylphenyl) isoindoline-1-one obtained in Example 280 In the same manner as in 158, 4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-methylphenyl) isoindoline-1-one was obtained.
mp 135-137 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.27 (3H, s), 2.35 (3H, s), 2.85-2.99 ( 4H, m), 4.24 (2H, q, J = 7.3 Hz), 4.43 (2H, s), 4.54 (2H, s), 6.58 (1H, d, J = 8. 2 Hz), 6.81 (1H, dd, J = 2.3 Hz, 8.2 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.20-7.23 (2H, m), 7.38 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.45 (1H, t, J = 7.6 Hz), 7.63-7.68 (2H, m), 7.76 (1H, dd, J = 1.0 Hz, 7.6 Hz).

Example 285 (Synthesis of 4- {2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} -2- (4-methylphenyl) isoindoline-1-one)
4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-methylphenyl) isoindoline-1-one obtained in Example 284 was treated in the same manner as in Example 69. The operation yielded 4- {2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} -2- (4-methylphenyl) isoindoline-1-one.
mp 210-212 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.17 (3H, s), 2.31 (3H, s), 2.82-2.99 (4H, m), 4.60 (2H, s) , 4.88 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 7.00 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.07-7. 07 (1H, m), 7.24 (2H, d, J = 8.2 Hz), 7.46 (1H, t, J = 7.3 Hz), 7.51 (1H, dd, J = 1.6 Hz) , 7.3 Hz), 7.60 (1 H, dd, J = 1.6 Hz, 6.9 Hz), 7.78-7.83 (2 H, m)
Example 286 (Synthesis of 4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-{(E) -2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethenyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 282 In the same manner as in Example 158, 4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one was obtained. .
mp 106-107 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 2.26 (3H, s), 2.86-2.99 (4H, m), 4.23 ( 2H, q, J = 7.3 Hz), 4.39 (2H, s), 4.53 (2H, s), 6.57 (1H, d, J = 8.2 Hz), 6.80 (1H, dd, J = 2.0 Hz, 8.2 Hz), 6.94 (1H, d, J = 1.6 Hz), 7.23-7.30 (2H, m), 7.41 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.77 (1H, dd, J = 1.3 Hz, 7.3 Hz), 7.79-7. 85 (2H, m).

Example 287 (Synthesis of 4- {2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4- {2- [4- (ethoxycarbonylmethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethoxyphenyl) isoindolin-1-one obtained in Example 286 was The same operation was performed to obtain 4- {2- [4- (carboxymethoxy) -3-methylphenyl] ethyl} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 166-168 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.17 (3H, s), 2.82-3.00 (4H, m), 4.58 (2H, s), 4.97 (2H, s) 6.72 (1H, d, J = 8.2 Hz), 7.02 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.07-7.07 (1H, m), 7. 44-7.51 (3H, m), 7.53 (1H, dd, J = 1.6 Hz, 7.6 Hz), 7.64 (1H, dd, J = 1.3 Hz, 7.3 Hz), 8 .04-8.10 (2H, m).

Example 288 (Synthesis of 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-methylphenyl) isoindoline-1-one)
4-Bromo-2- (4-methylphenyl) isoindoline-1-one obtained in Example 280 (i) and (4-mercapto-2-methylphenoxy) acetic acid obtained in Example 223 (ii) Ethyl was operated as in Example 179 (i) to give 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-methylphenyl) isoindoline-1-one. It was.
mp 123.5-124.5 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.28 (3H, s), 2.36 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4.66 (2H, s), 4.70 (2H, s), 6.69 (1H, d, J = 8.2 Hz), 7.19-7.29 (5H, m), 7.39 (1H, t, J = 7.6 Hz), 7.69-7.76 (3H, m).

Example 289 (Synthesis of 4-{[4- (carboxymethoxy) -3-methylphenyl] thio} -2- (4-methylphenyl) isoindoline-1-one)
4-{[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-methylphenyl) isoindoline-1-one obtained in Example 288 was operated in the same manner as in Example 69. 4-{[4- (carboxymethoxy) -3-methylphenyl] thio} -2- (4-methylphenyl) isoindoline-1-one was obtained.
mp 213.5-215.5 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.19 (3H, s), 2.31 (3H, s), 4.70 (2H, s), 4.89 (2H, s), 6.89 (1H, d, J = 8.2 Hz), 7.21-7.26 (3H, m), 7.35 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.38-7. 39 (1H, m), 7.47 (1H, t, J = 7.6 Hz), 7.61 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.76-7.81 (2H , M).

Example 290 (Synthesis of 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-Bromo-2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 282 (i) and (4-mercapto-2-methylphenoxy) obtained in Example 223 (ii) ) Ethyl acetate was operated as in Example 179 (i) and 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethoxyphenyl) isoindoline-1 -Obtained ON.
mp 163.5-164.5 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.28 (3H, s), 4.27 (2H, q, J = 7.3 Hz), 4. 67 (2H, s), 4.70 (2H, s), 6.70 (1H, d, J = 8.2 Hz), 7.23-7.31 (5H, m), 7.41 (1H, t, J = 7.6 Hz), 7.75 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.86-7.92 (2H, m).

Example 291 (Synthesis of 4-{[4- (carboxymethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-{[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 290 was treated in the same manner as in Example 69. The operation yielded 4-{[4- (carboxymethoxy) -3-methylphenyl] thio} -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 199-200 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 4.76 (2H, s), 4.97 (2H, s), 6.92 (1H, d, J = 8. 6 Hz), 7.25 (1 H, dd, J = 1.0 Hz, 7.6 Hz), 7.35-7.52 (5 H, m), 7.65 (1 H, dd, J = 1.0 Hz, 7 .6 Hz), 8.03-8.08 (2H, m).

Example 292 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one)
Example 138 was prepared by using 4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Synthesis Example 4 and ethyl (3-bromomethylphenyl) acetate obtained in Example 95 (i). The same operation as in (v) was performed to obtain 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one.
mp 123-128 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 3.66 (2H, s), 3.92 (3H, s), 4.16 (2H, q, J = 7.2 Hz), 4.86 (2H, s), 5.19 (2H, s), 7.13 (1H, d, J = 7.2 Hz), 7.25-7.56 (6H, m), 8.02 (2H, d, J = 8.9 Hz), 8.10 (2H, d, J = 8.9 Hz).

Example 293 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Example 292 was operated in the same manner as in Example 69. 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one.
mp 277-283 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 5.04 (2H, s), 5.28 (2H, s), 7.25 (1H, d, J = 7. 4 Hz), 7.33-7.46 (5 H, m), 7.51 (1 H, d, J = 7.4 Hz), 7.98 (2 H, d, J = 8.7 Hz), 8.10 ( 2H, d, J = 8.7 Hz).

Example 294 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one)
4-hydroxy-2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Synthesis Example 4 and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in Example 68 (i) Was used in the same manner as in Example 148 (ii), and 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1- On crystals were obtained.
mp 116-121 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.14 (2H, t, J = 6.8 Hz), 3.93 (3H, s), 4. 24 (2H, q, J = 7.1 Hz), 4.32 (2H, t, J = 6.8 Hz), 4.63 (2H, s), 4.78 (2H, s), 6.74- 6.80 (1H, m), 6.91-6.96 (2H, m), 7.05 (1H, d, J = 7.7 Hz), 7.23-7.30 (1H, m), 7.44 (1H, t, J = 7.7 Hz), 7.51 (1H, d, J = 7.7 Hz), 8.02 (2H, d, J = 9.2 Hz), 8.11 (2H , D, J = 9.1 Hz).

Example 295 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one)
4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-methoxycarbonylphenyl) isoindoline-1-one obtained in Example 294 was prepared in the same manner as in Example 69. The operation yielded 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-carboxyphenyl) isoindoline-1-one.
mp 223-228 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.7 Hz), 4.36 (2H, t, J = 6.7 Hz), 4.67 (2H, s), 4.93 (2H, s), 6.78 (1H, dd, J = 1.6 Hz, 8.2 Hz), 6.94-6.98 (2H, m), 7.24 (1H, t, J = 7.7 Hz), 7.36 (2H, dd, J = 7.9, 11.7 Hz), 7.51 (1H, t, J = 7.7 Hz), 8.00 (2H, d, J = 9.2 Hz), 8.08 (2H, d, J = 9.2 Hz).

Example 296 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one)
4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one obtained in Example 236 was used in the same manner as in Example 69. To give 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-methylphenyl) isoindoline-1-one.
mp 137-138 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.36 (3H, s), 3.59 (2H, s), 4.86 (2H, s), 5.27 (2H, s), 7.10 (1H, d, J = 8.2 Hz), 7.15-7.26 (2H, m), 7.30-7.41 (5H, m), 7.52 (2H, t, J = 7. 9 Hz), 12.33 (1 H, s).

Example 297 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2- (2-fluoro-4-trifluoromethylphenyl) -4-methoxyisoindolin-1-one 3-methoxy-2-methylbenzoic acid methyl ester obtained in Example 181 (ii) N-bromosuccinimide (1.99 g, 11.17 mmol) and benzoyl peroxide (0.10 g) were added to a carbon tetrachloride (40 mL) solution of (2.01 g, 11.17 mmol), and the mixture was heated to reflux for 2 hours. The reaction solution was cooled, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. 2-Fluoro-4-trifluoromethylaniline (2.00 g, 11.17 mmol) and dimethylformamide (40 mL) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 1 hour and 120 ° C. for 19 hours. The solvent of the reaction solution was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were collected by filtration, washed with water, dried and then washed with diethyl ether to give 2- (2-fluoro-4-trifluoromethylphenyl) -4-methoxyisoindoline-1-one (2.25 mg). 62%) of crystals.
mp 132-137 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.93 (3H, s), 4.96 (2H, s), 7.33 (1H, d, J = 8.4 Hz), 7.41 (1H, dJ = 7.8 Hz), 7.57 (1H, t, J = 7.8 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.89 (1H, d, J = 10.9 Hz) ), 7.9 (1H, t, J = 7.8 Hz).

(Ii) Synthesis of 2- (2-fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one 2- (2-fluoro-4-trifluoromethylphenyl) obtained in (i) above ) 4-Methoxyisoindoline-1-one (2.00 g, 6.15 mmol) in methylene chloride (40 mL) suspension in 1 mol / L boron tribromide in methylene chloride (12.3 mL, 12.3 mmol) Was added under ice cooling and stirred at room temperature for 3.5 hours. The reaction mixture was evaporated under reduced pressure, and ice water was added to the residue. The precipitated crystals were collected by filtration, washed with water and dried to obtain crystals of 2- (2-fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one (1.85 g, 97%). It was.
mp 186-213 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.91 (2H, s), 7.10 (1H, dd, J = 1.0, 8.2 Hz), 7.28 (1H, d, J = 7) .7 Hz), 7.40 (1 H, t, J = 7.7 Hz), 7.72 (1 H, d, J = 8.2 Hz), 7.88 (1 H, d, J = 11.2 Hz), 8 0.00 (1H, t, J = 7.7 Hz), 10.28 (1 H, s).

(Iii) Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one 2- (2-Fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in ii) and 2- [4- (bromomethyl)-obtained in Example 170 (i) 2-Methylphenoxy] ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro- 4-Trifluoromethylphenyl) isoindoline-1-one was obtained.
mp 110-111 ° C
¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.32 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4. 65 (2H, s), 4.88 (2H, s), 5.09 (2H, s), 6.71 (1H, d, J = 8.2 Hz), 7.13-7.30 (3H, m), 7.43-7.53 (3H, m), 7.56 (1H, d, J = 6.9 Hz), 7.90 (1H, t, J = 8.4 Hz).

Example 298 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindolin-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 297 Was prepared in the same manner as in Example 69, and 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1 -Obtained ON.
mp 157-160 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.20 (3H, s), 4.67 (2H, s), 4.97 (2H, s), 5.17 (2H, s), 6.81 (1H, d, J = 7.9 Hz), 7.23-7.30 (2H, m), 7.40 (2H, d, J = 7.9 Hz), 7.54 (1H, t, J = 7.9 Hz), 7.70 (1 H, d, J = 8.9 Hz), 7.87 (1 H, d, J = 10.9 Hz), 7.99 (1 H, t, J = 7.9 Hz).

Example 299 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
2- (2-Fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in Example 297 (ii) and (3-bromomethyl obtained in Example 95 (i) Phenyl) ethyl acetate was operated as in Example 138 (v) and 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) Isoindoline-1-one was obtained.
mp 76-78 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 3.64 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 4. 91 (2H, s), 5.19 (2H, s), 7.14 (1H, d, J = 8.2 Hz), 7.23-7.40 (4H, m), 7.44-7. 54 (3H, m), 7.57 (1H, t, J = 7.3 Hz), 7.91 (1H, t, J = 8.1 Hz).

Example 300 Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
4-({[3- (Ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 299 was obtained in Example 69. To give 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one.
mp 161-166 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.60 (2H, s), 5.00 (2H, s), 5.28 (2H, s), 7.20-7.26 (1H, m) , 7.31-7.44 (5H, m), 7.55 (1H, t, J = 7.7 Hz), 7.72 (1H, d, J = 8.2 Hz), 7.89 (1H, d, J = 9.2 Hz), 8.00 (1H, t, J = 7.7 Hz), 12.35 (1H, s).

Example 301 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
2- (2-Fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one obtained in Example 297 (ii) and step (i) of Example 68 [3- (2-Hydroxyethyl) phenoxy] ethyl acetate was operated in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (2-fluoro -4-Trifluoromethylphenyl) isoindoline-1-one was obtained.
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.11 (2H, t, J = 6.8 Hz), 4.24 (2H, q, J = 7) .1 Hz), 4.30 (2H, t, J = 6.8 Hz), 4.61 (2H, s), 4.82 (2H, s), 6.76 (1H, dd, J = 2.3). , 8.0 Hz), 6.80-6.90 (2 H, m), 7.06 (1 H, d, J = 6.9 Hz), 7.25 (1 H, t, J = 8.0 Hz), 7 .42-7.56 (4H, m), 7.90 (1H, t, J = 8.0 Hz).

Example 302 Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 301 was carried out. Operate analogously to Example 69 to give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (2-fluoro-4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 148-149 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.05 (2H, t, J = 6.8 Hz), 4.36 (2H, t, J = 6.8 Hz), 4.65 (2H, s), 4.89 (2H, s), 6.74-6.79 (1H, m), 6.90-6.96 (2H, m), 7.22 (1H, t, J = 7.8 Hz), 7.38 (2H, dd, J = 7.8, 10.2 Hz), 7.54 (1H, t, J = 7.8 Hz), 7.72 (1H, d, J = 8.6 Hz), 7 .88 (1H, t, J = 11.2 Hz), 7.99 (1H, d, J = 7.8 Hz), 12.96 (1H, br).

Example 303 Synthesis of 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindolin-1-one
(I) Synthesis of tert-butyl 4-hydroxy-3-methylphenylcarbamate To a solution of 4-amino-2-methylphenol (2.00 g, 16.24 mmol) in acetonitrile (20 mL) was added di-tert-butyl dicarbonate (4 .25 g, 19.49 mmol) and triethylamine (2.47 g, 24.36 mmol) were added under ice cooling, followed by stirring at 0 ° C. for 1 hour and then at room temperature for 19.5 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain an oily product of tert-butyl 4-hydroxy-3-methylphenylcarbamate (1.16 g, 32%). .
¹ H NMR (CDCl ₃ ) δ: 1.51 (9H, s), 2.20 (3H, s), 6.41 (1H, br), 6.99 (1H, d, J = 8.6 Hz) 7.10 (1H, dd, J = 2.4, 8.6 Hz), 7.31 (1H, d, J = 2.4 Hz).

(Ii) Synthesis of ethyl 2- (4-amino-2-methylphenoxy) acetate tert-butyl 4-hydroxy-3-methylphenylcarbamate (1.09 g, 4.87 mmol) obtained in (i) above (20 mL) To the solution were added ethyl bromoacetate (1.46 mg, 8.77 mmol) and cesium carbonate (1.90 g, 5.84 mmol), and the mixture was stirred at room temperature for 14.5 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. Methylene chloride (10 mL) and trifluoroacetic acid (1.5 mL) were added to the obtained oil (643 mg) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain crystals of 2- (4-amino-2-methylphenoxy) ethyl acetate (459 mg, 45%).
mp 117-122 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1 Hz), 2.22 (3H, s), 3.93 (2H, s), 4.25 (2H, q, J = 7.1 Hz), 6.60-6.72 (3H, m).

(Iii) Synthesis of 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one In Example 254, 3-aminophenyl The same procedure as in Example 254 was performed except that the reaction scale was appropriately changed using ethyl 2- (4-amino-2-methylphenoxy) acetate obtained in (ii) above instead of methyl acetate, 4-{[4- (ethoxycarbonylmethoxy) -3-methylphenyl] carbamoyl} -2- (4-trifluoromethylphenyl) isoindoline-1-one (yield 194 mg, 61% yield) was synthesized.
mp 185-186 ° C
¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.1 Hz), 2.19 (3H, s), 3.92 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 5.27 (2H, s), 6.49-6.57 (2H, m), 6.99 (1H, d, J = 8.4 Hz), 7.63-7. 77 (3H, m), 8.08 (2H, t, J = 8.4 Hz), 8.21 (1H, dd, J = 1.1, 7.7 Hz), 8.48 (1H, dd, J = 1.1, 7.7 Hz).

Example 304 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
2- (3-Fluoro-4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one synthesized in Example 202 (ii) and (3-bromomethylphenyl) obtained in Example 95 (i) ) Ethyl acetate was treated as in Example 138 (v) and 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) iso Indoline-1-one was obtained.
mp 129-131 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 3.66 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 4. 82 (2H, s), 5.19 (2H, s), 7.16 (1H, d, J = 7.9 Hz), 7.25-7.73 (8H, m), 8.03 (1H, d, J = 13.2 Hz).

Example 305 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 304 was converted to Example 69. To give 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (3-fluoro-4-trifluoromethylphenyl) isoindoline-1-one.
mp 183-187 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.62 (2H, s), 5.05 (2H, s), 5.29 (2H, s), 7.26 (1H, d, J = 7. 3 Hz), 7.34-7.45 (5 H, m), 7.54 (1 H, dd, J = 6.8, 8.7 Hz), 7.82 (1 H, t, J = 8.7 Hz), 8.00 (1H, d, J = 8.7 Hz), 8.17 (1H, d, J = 13.5 Hz).

Example 306 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one)
(I) Synthesis of 4-hydroxy-2- (4-trifluoromethylthiophenyl) isoindoline-1-one In Step (ii) of Synthesis Example 3, instead of 1-amino-4- (trifluoromethyl) benzene , 4-trifluoromethylthioaniline (2.00 g, 10.4 mmol) was used and the same procedure as in Synthesis Example 3 was performed except that the reaction scale was changed as appropriate. 4-hydroxy-2- (4-trifluoromethylthio Phenyl) isoindoline-1-one (yield 2.98 g, 89% yield) was synthesized.
mp 229-247 ° C
¹ H NMR (DMSO-d ₆ ) δ: 4.94 (2H, s), 7.08 (1H, d, J = 7.7 Hz), 7.26 (1H, d, J = 7.7 Hz), 7.38 (1H, t, J = 7.7 Hz), 7.78 (2H, d, J = 8.6 Hz), 8.11 (2H, d, J = 8.6 Hz), 10.31 (1H , S).

(Ii) Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindolin-1-one 4- (obtained in (i) above) Hydroxy-2- (4-trifluoromethylthiophenyl) isoindoline-1-one and ethyl (3-bromomethylphenyl) acetate obtained in Example 95 (i) were operated in the same manner as in Example 138 (v). 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one.
mp 122-123 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 3.66 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 4. 84 (2H, s), 5.19 (2H, s), 7.14 (1H, d, J = 7.9 Hz), 7.22-7.56 (6H, m), 7.70 (2H, d, J = 8.7 Hz), 8.01 (2H, d, J = 8.7 Hz).

Example 307 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one obtained in Example 306 was operated in the same manner as in Example 69. 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one was obtained.
mp 184-186 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 5.04 (2H, s), 5.29 (2H, s), 7.25 (1H, d, J = 7. 6 Hz), 7.33-7.46 (5 H, m), 7.53 (1 H, t, J = 7.6 Hz), 7.77 (2 H, d, J = 8.6 Hz), 8.15 ( 2H, d, J = 8.6 Hz).

Example 308 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one)
4-Hydroxy-2- (4-trifluoromethylthiophenyl) isoindoline-1-one obtained in Example 306 (i) and 2- [4- (bromomethyl)-obtained in Example 170 (i) 2-Methylphenoxy] ethyl acetate was operated in the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoro Methylthiophenyl) isoindoline-1-one was obtained.
mp 163-164 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 2.33 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 4. 67 (2H, s), 4.81 (2H, s), 5.09 (2H, s), 6.73 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 8.1 Hz), 7.18-7.30 (2H, m), 7.42-7.55 (2H, m), 7.69 (2H, d, J = 8.9 Hz), 8.00 ( 2H, d, J = 8.9 Hz).

Example 309 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindolin-1-one obtained in Example 308 was obtained in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one.
mp 152-155 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 4.72 (2H, s), 5.00 (2H, s), 5.17 (2H, s), 6.84 (1H, d, J = 7.8 Hz), 7.26-7.33 (2H, m), 7.39 (2H, d, J = 8.2 Hz), 7.52 (1H, t, J = 7.8 Hz), 7.76 (2H, d, J = 8.7 Hz), 8.15 (2H, d, J = 8.7 Hz).

Example 310 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one)
4-Hydroxy-2- (4-trifluoromethylthiophenyl) isoindoline-1-one obtained in Example 306 (i) and [3- (2-Hydroxy) obtained in step (i) of Example 68. Ethyl) phenoxy] ethyl acetate was operated in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylthiophenyl) Isoindoline-1-one was obtained.
mp 119-122 ° C
¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.13 (2H, t, J = 6.7 Hz), 4.24 (2H, q, J = 7) .1 Hz), 4.32 (2H, t, J = 6.7 Hz), 4.62 (2H, s), 4.75 (2H, s), 6.77 (1H, dd, J = 2.3). , 7.9 Hz), 7.05 (1H, dd, J = 1.0, 6.6 Hz), 7.23-7.30 (3H, m), 7.40-7.53 (2H, m) , 7.71 (2H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.6 Hz).

Example 311 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one)
4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one obtained in Example 310 was used in the same manner as in Example 69. To give 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one.
mp 152-155 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.07 (2H, t, J = 6.7 Hz), 4.36 (2H, t, J = 6.7 Hz), 4.67 (2H, s), 4.93 (2H, s), 6.78 (1H, dd, J = 2.8, 8.1 Hz), 6.88-6.97 (2H, m), 7.24 (1H, t, J = 7.8 Hz), 7.36 (2H, dd, J = 7.8, 11.2 Hz), 7.51 (1H, t, J = 7.8 Hz), 7.78 (2H, d, J = 8.7 Hz), 8.12 (2H, d, J = 8.6 Hz).

Example 312 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one)
4-hydroxy-2- (4-iodophenyl) isoindoline-1-one synthesized in Synthesis Example 8 and ethyl (3-bromomethylphenyl) acetate obtained in Example 95 (i) were used in Example 138 (v ) To give 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one.
mp 103-105 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.2 Hz), 3.66 (2H, s), 4.16 (2H, q, J = 7.2 Hz), 4. 79 (2H, s), 5.18 (2H, s), 7.12 (1H, d, J = 6.9 Hz), 7.27-7.55 (6H, m), 7.70 (4H, s).

Example 313 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one obtained in Example 312 was operated in the same manner as in Example 69, 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-iodophenyl) isoindolin-1-one was obtained.
mp 187-190 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 4.97 (2H, s), 5.27 (2H, s), 7.25 (1H, d, J = 7. 6 Hz), 7.33-7.48 (5 H, m), 7.51 (1 H, t, J = 7.6 Hz), 7.75 (2 H, d, J = 8.7 Hz), 7.80 ( 2H, d, J = 8.7 Hz).

Example 314 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-iodophenyl) isoindoline-1-one)
4-Hydroxy-2- (4-iodophenyl) isoindoline-1-one synthesized in Synthesis Example 8 and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in step (i) of Example 68 Was prepared in the same manner as in Example 148 (ii), and 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-trifluoromethylthiophenyl) isoindoline-1-one Got.
mp 149-150 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 3.12 (2H, t, J = 6.6 Hz), 4.24 (2H, q, J = 7) .1 Hz), 4.30 (2H, t, J = 6.6 Hz), 4.62 (2H, s), 4.70 (2H, s), 6.74-6.79 (1 H, m), 6.90-6.95 (2H, m), 7.03 (1H, d, J = 6.6 Hz), 7.22-7.28 (1H, m), 7.43 (1H, t, J = 7.6 Hz), 7.49 (1H, dd, J = 2.0 Hz, 7.6 Hz), 7.71 (4H, s).

Example 315 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-iodophenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-iodophenyl) isoindoline-1-one obtained in Example 314 was operated in the same manner as in Example 69. 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-iodophenyl) isoindoline-1-one was obtained.
mp 234-237 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.5 Hz), 4.35 (2H, t, J = 6.5 Hz), 4.67 (2H, s), 4.85 (2H, s), 6.78 (1H, d, J = 8.6 Hz), 6.92-6.97 (2H, m), 7.23 (1H, t, J = 8.0 Hz) ), 7.33 (2H, dd, J = 8.0, 9.9 Hz), 7.50 (1H, t, J = 8.0 Hz), 7.77 (4H, s).

Example 316 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one)
4-hydroxy-2- (4-iodophenyl) isoindoline-1-one synthesized in Synthesis Example 8 and 2- [4- (bromomethyl) -2-methylphenoxy] acetic acid obtained in Example 170 (i) Ethyl was operated as in Example 138 (v) and 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1- Got on.
mp 137-140 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 2.33 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4. 67 (2H, s), 4.76 (2H, s), 5.08 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.18-7.30 (2 H, m), 7.44 (1 H, t, J = 7.8 Hz), 7.48-7.53 (1 H, m), 7.70 ( 4H, s).

Example 317 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one obtained in Example 316 was used in the same manner as in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-iodophenyl) isoindoline-1-one.
mp 195-197 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.71 (2H, s), 4.93 (2H, s), 5.16 (2H, s), 6.83 (1H, d, J = 8.2 Hz), 7.25-7.32 (2H, m), 7.36 (2H, dd, J = 2.8, 7.7 Hz), 7.50 (1H, t, J = 7.7 Hz), 7.74 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7 Hz).

Example 318 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-bromophenyl) isoindoline-1-one)
4-hydroxy-2- (4-bromophenyl) isoindoline-1-one synthesized in Synthesis Example 7 and 2- [4- (bromomethyl) -2-methylphenoxy] acetic acid obtained in Example 170 (i) Ethyl was operated as in Example 138 (v) and 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-bromophenyl) isoindoline-1- Got on.
mp 140-142 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 2.33 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 4. 67 (2H, s), 4.77 (2H, s), 5.08 (2H, s), 6.73 (1H, d, J = 8.2 Hz), 7.10-7.25 (4H, m), 7.45 (1H, t, J = 7.6 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.80 (2H, d, J = 8.7 Hz).

Example 319 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-bromophenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-bromophenyl) isoindoline-1-one obtained in Example 318 was used in the same manner as in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-bromophenyl) isoindoline-1-one.
mp 186-189 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 4.72 (2H, s), 4.95 (2H, s), 5.16 (2H, s), 6.84 (1H, d, J = 7.8 Hz), 7.25-7.40 (4H, m), 7.51 (1H, t, J = 7.8 Hz), 7.59 (2H, d, J = 8.9 Hz), 7.94 (2H, d, J = 8.2 Hz).

Example 320 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one)
2- (4-Chlorophenyl) -4-hydroxyisoindoline-1-one synthesized in Synthesis Example 6 and ethyl 2- [4- (bromomethyl) -2-methylphenoxy] acetate obtained in Example 170 (i) In the same manner as in Example 138 (v) to give 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one. Obtained.
mp 135-138 ° C
¹ H NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 2.33 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 4. 67 (2H, s), 4.77 (2H, s), 5.08 (2H, s), 6.72 (1H, d, J = 8.2 Hz), 7.13 (1H, d, J = 7.3 Hz), 7.18-7.25 (1 H, m), 7.34-7.54 (5 H, m), 7.85 (2 H, d, J = 8.9 Hz).

Example 321 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one)
4-({[4- (Ethoxycarbonylmethoxy) -3-methylphenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one obtained in Example 320 was prepared in the same manner as in Example 69. Operation yielded 4-({[4- (carboxymethoxy) -3-methylphenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one.
mp 121-124 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 4.72 (2H, s), 4.96 (2H, s), 5.16 (2H, s), 6.84 (1H, d, J = 7.9 Hz), 7.26-7.40 (4H, m), 7.44-7.54 (3H, m), 7.99 (2H, d, J = 8. 9 Hz).

Example 322 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one)
The 2- (4-chlorophenyl) -4-hydroxyisoindoline-1-one synthesized in Synthesis Example 6 and the ethyl (3-bromomethylphenyl) acetate obtained in Example 95 (i) were used in Example 138 (v). To give 4-({[3- (ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one.
mp 85-91 ° C
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.1 Hz), 3.66 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 4. 80 (2H, s), 5.18 (2H, s), 7.12 (1H, d, J = 7.9 Hz), 7.25-7.55 (8H, m), 7.83-7. 90 (2H, m).

Example 323 (Synthesis of 4-({[3- (carboxymethyl) phenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one)
4-({[3- (Ethoxycarbonylmethyl) phenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one obtained in Example 322 was operated in the same manner as in Example 69, and 4 -({[3- (Carboxymethyl) phenyl] methyl} oxy) -2- (4-chlorophenyl) isoindoline-1-one was obtained.
mp 179-182 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 4.99 (2H, s), 5.28 (2H, s), 7.25 (1H, d, J = 7. 3 Hz), 7.33-7.44 (4H, m), 7.45-7.55 (4H, m), 7.99 (2H, d, J = 8.9 Hz).

Example 324 (Synthesis of 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-bromophenyl) isoindoline-1-one)
2- (4-Bromophenyl) -4-hydroxyisoindoline-1-one synthesized in Synthesis Example 7 and [3- (2-hydroxyethyl) phenoxy] ethyl acetate obtained in step (i) of Example 68 To give 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-bromophenyl) isoindoline-1-one as in Example 148 (ii). It was.
mp 126-133 ° C
¹ H NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 3.13 (2H, t, J = 6.8 Hz), 4.24 (2H, q, J = 7) .3 Hz), 4.31 (2H, t, J = 6.8 Hz), 4.62 (2H, s), 4.71 (2H, s), 6.74-6.79 (1 H, m), 6.90-6.95 (2H, m), 7.04 (1H, d, J = 6.9 Hz), 7.22-7.29 (1H, m), 7.40-7.56 (4H , M), 7.79-7.85 (2H, m).

Example 325 (Synthesis of 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-bromophenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethoxy) phenyl] ethyl} oxy) -2- (4-bromophenyl) isoindoline-1-one obtained in Example 314 was treated in the same manner as in Example 69. 4-({2- [3- (carboxymethoxy) phenyl] ethyl} oxy) -2- (4-bromophenyl) isoindoline-1-one was obtained.
mp 199-209 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.06 (2H, t, J = 6.6 Hz), 4.35 (2H, t, J = 6.6 Hz), 4.66 (2H, s), 4.87 (2H, s), 6.78 (1H, d, J = 8.0 Hz), 6.93-6.97 (2H, m), 7.23 (1H, t, J = 8.0 Hz) ), 7.34 (2H, dd, J = 8.0, 10.6 Hz), 7.50 (1H, t, J = 8.0 Hz), 7.62 (2H, d, J = 8.7 Hz) 7.92 (2H, d, J = 8.9 Hz).

Example 326 (Synthesis of 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
Synthesized with 4-bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 266 (i) according to International Publication No. WO2006 / 126514 (3-hydroxy-5-methylphenyl) Using methyl acetate in the same manner as in Example 266 (ii), 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) Crystals of isoindoline-1-one were obtained.
mp 138-140 ° C
¹ H NMR (CDCl ₃ ) δ: 2.34 (3H, d, J = 0.7 Hz), 3.58 (2H, s), 3.69 (3H, s), 4.94 (2H, s) , 5.21 (2H, s), 6.73-6.76 (3H, m), 7.26-7.32 (2H, m), 7.55 (1H, t, J = 7.6 Hz) 7.62 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.90-7.96 (3H, m).

Example 327 (Synthesis of 4-({[3- (carboxymethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
The 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindolin-1-one obtained in Example 326 was obtained in Example 69. To give 4-({[3- (carboxymethyl) -5-methylphenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 194-196 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 3.49 (2H, s), 5.13 (2H, s), 5.27 (2H, s), 6.70 (1H, s), 6.82 (2H, s), 7.45-7.49 (2H, m), 7.59 (1H, t, J = 7.6 Hz), 7.76-7.80. (2H, m), 8.03-8.09 (2H, m).

Example 328 (Synthesis of 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
(I) Synthesis of 4-methoxycarbonyl-2- (4-methylphenyl) isoindoline-1-one dimethyl 2-methylisophthalate (2.00 g, 9.61 mmol) obtained in Example 177 (ii) Bromosuccinimide (1.71 g, 9.61 mmol) and benzoyl peroxide (75% in Water, 150 mg) were added to a carbon tetrachloride (30 mL) solution, and the mixture was heated to reflux for 3.5 hours. After standing to cool, insolubles were filtered off and the solvent was distilled off to obtain dimethyl 2-bromomethylisophthalate.

A solution of dimethyl 2-bromomethylisophthalate and 1-amino-4-methylbenzene (1.03 g, 9.61 mmol) in dimethylformamide (30 mL) was stirred at 60 ° C. for 3 hours and 120 ° C. for 2 hours. After allowing to cool, the reaction solution was diluted with methanol and then with water. The obtained crystals were collected by filtration, washed with water, and dried to give 4-methoxycarbonyl-2- (4-methylphenyl) isoindoline-1-one (2.14 g, 79%).
mp 155-163 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 3.95 (3H, s), 5.22 (2H, s), 7.27 (2H, d, J = 8. 6 Hz), 7.72 (1 H, t, J = 7.7 Hz), 7.81 (2 H, d, J = 8.6 Hz), 8.05 (1 H, dd, J = 1.0, 7.7 Hz) ), 8.22 (1H, dd, J = 1.0, 7.7 Hz).

(Ii) Synthesis of 4-carboxy-2- (4-methylphenyl) isoindoline-1-one 4-methoxycarbonyl-2- (4-methylphenyl) isoindoline-1-one obtained in (i) above A 2N aqueous sodium hydroxide solution (5.3 mL, 10.6 mmol) was added to a solution of (2.00 g, 7.11 mmol) in dioxane (20 mL), and the mixture was stirred at room temperature for 17 hours and half. 1N Hydrochloric acid (5.3 mL) was added to the reaction mixture, diluted with ice water, and the resulting crystals were collected by filtration. The obtained crystals were washed with water and dried to give 4-carboxy-2- (4-methylphenyl) isoindoline-1-one (1.84 g, 97%).
mp 262-270 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.32 (3H, s), 5.22 (2H, s), 7.27 (2H, d, J = 8.6 Hz), 7.72 (1H, t, J = 7.7 Hz), 7.81 (2H, d, J = 8.6 Hz), 8.05 (1H, dd, J = 1.0 Hz, 7.7 Hz), 8.22 (1H, dd) , J = 1.0 Hz, 7.7 Hz)
(Iii) Synthesis of 4-hydroxymethyl-2- (4-methylphenyl) isoindoline-1-one 4-carboxy-2- (4-methylphenyl) isoindoline-1-one obtained in (ii) above Borane-tetrahydrofuran complex (6.9 mL, 7.30 mmol) was added dropwise to a tetrahydrofuran (100 mL) solution of (1.30 g, 4.86 mmol) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 25.5 hours. did. Methanol was added to the reaction solution under ice-cooling, and the solvent was distilled off. Water was added to the residue and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was washed with diethyl ether-hexane to obtain crystals of 4-hydroxymethyl-2- (4-methylphenyl) isoindoline-1-one (1.01 g, 82%).
mp 186-191 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 4.69 (2H, d, J = 5.5 Hz), 5.00 (2H, s), 5.39 (1H, t, J = 5.5 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.52 (1H, t, J = 7.4 Hz), 7.64 (2H, t, J = 7) .4 Hz), 7.80 (2H, d, J = 8.4 Hz).

(Iv) Synthesis of 4-bromomethyl-2- (4-methylphenyl) isoindoline-1-one 4-hydroxymethyl-2- (4-methylphenyl) isoindoline obtained in (iv) above under ice-cooling Triphenylphosphine (1.50 g, 5.70 mmol) and N-bromosuccinimide (1.01 g, 5.70 mmol) were added to a suspension of -1-one (963 mg, 3.80 mmol) in dichloromethane (40 mL). Stir at 30 ° C. for 30 minutes and room temperature for 2 hours. Water was added, extracted with dichloromethane, and purified by silica gel column chromatography to obtain crystals of 4-bromomethyl-2- (4-methylphenyl) isoindoline-1-one (650 mg, 54%).
mp 185-186 ° C
¹ H NMR (CDCl ₃ ) δ: 2.37 (3H, s), 4.58 (2H, s), 4.91 (2H, s), 7.23-7.26 (2H, m), 7 .50 (1H, t, J = 7.6 Hz), 7.56 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.73-7.78 (2H, m), 7.88 ( 1H, dd, J = 1.3 Hz, 7.6 Hz).
(V) Synthesis of 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one obtained in (iv) above. Example 266 (ii) using 4-bromomethyl-2- (4-methylphenyl) isoindoline-1-one and methyl (3-hydroxy-5-methylphenyl) acetate synthesized according to International Publication No. WO2006 / 126514 The same operation was performed to obtain crystals of 4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one.
mp 133-135 ° C
¹ H NMR (CDCl ₃ ) δ: 2.33 (3H, s), 2.36 (3H, s), 3.58 (2H, s), 3.69 (3H, s), 4.92 (2H , S), 5.19 (2H, s), 6.74-6.75 (3H, m), 7.21-7.25 (2H, m), 7.52 (1H, t, J = 7) .6 Hz), 7.60 (1 H, dd, J = 1.3 Hz, 7.6 Hz), 7.72-7.77 (2 H, m) 7.90 (1 H, dd, J = 1.3 Hz, 7 .6 Hz).

Example 329 (Synthesis of 4-({[3- (carboxymethyl) -5-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
4-({[3- (methoxycarbonylmethyl) -5-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 328 was used in the same manner as in Example 69. To give 4-({[3- (carboxymethyl) -5-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one.
mp 191-193 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.27 (3H, s), 2.31 (3H, s), 3.50 (2H, s), 5.07 (2H, s), 5.27 (2H, s), 6.70 (1H, s), 6.81 (2H, s), 7.25 (2H, d, J = 8.6 Hz), 7.55-7.60 (1H, m ), 7.33-7.76 (2H, m), 7.78-7.83 (2H, m).

Example 330 (Synthesis of 4-({2- [3- (ethoxycarbonylmethyl) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 1,3-bis (bromomethyl) -5-methylbenzene To a solution of mesitylene (21.98 g, 182 mmol) in carbon tetrachloride (200 mL), N-bromosuccinimide (61.55 g, 346 mmol) and 2, 2′-Azobisisobutyronitrile (896 mg) was added and heated under reflux for 2 hours. After standing to cool, insoluble matter was filtered off and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain crystals of 1,3-bis (bromomethyl) -5-methylbenzene (20.36 g, 40%).
mp 59-68 ° C
¹ H NMR (CDCl ₃ ) δ: 2.34 (3H, d, J = 0.7 Hz), 4.44 (4H, s), 7.14 (2H, br), 7.22 (1H, br) .

(Ii) Synthesis of 1,3-bis (cyanomethyl) -5-methylbenzene 1,3-bis (bromomethyl) -5-methylbenzene (14.18 g, 51.0 mmol) dimethyl obtained in (i) above Sodium cyanide (5.02 g, 102.0 mmol) was added to the sulfoxide (170 mL) solution, and the mixture was stirred at room temperature for 1.5 hours. Water was added and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 1,3-bis (cyanomethyl) -5-methylbenzene (1.93 g, 22%).
mp 74-79 ° C
_{^{1 H NMR (CDCl 3) δ}} : 2.38 (3H, s), 3.73 (4H, s), 7.08 (1H, s), 7.13 (2H, s).

(Iii) Synthesis of 5-methyl-1,3-phenylenediacetic acid The 1,3-bis (cyanomethyl) -5-methylbenzene (1.90 g, 11.1 mmol) obtained in (ii) above was added to ethanol ( 25 mL) and an aqueous solution (25 mL) of potassium hydroxide (3.80 g) were added and heated to reflux for 6 hours. After cooling, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was dried to obtain crystals of 5-methyl-1,3-phenylenediacetic acid (2.01 g, 87%).
mp 174-178 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 3.49 (4H, s), 6.93 (1H, s), 6.95 (2H, s), 12.29 (2H, br).

(Iv) Synthesis of diethyl 5-methyl-1,3-phenylenediacetate DMF (20 mL) of 5-methyl-1,3-phenylenediacetic acid (1.99 g, 9.53 mmol) obtained in (iii) above To the solution, potassium carbonate (2.90 g, 20.98 mmol) and ethyl iodide (3.27 g, 20.98 mmol) were added and stirred overnight. Furthermore, potassium carbonate (2.90 g, 20.98 mmol) and ethyl iodide (3.27 g, 20.98 mmol) were added and stirred at 50 ° C. overnight. After cooling, water was added and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain oily diethyl 5-methyl-1,3-phenylenediacetate (1.85 g, 73%).
¹ H NMR (CDCl ₃ ) δ: 1.25 (6H, t, J = 7.3), 2.32 (3H, s), 3.56 (4H, s), 4.15 (4H, q, J = 7.3 Hz), 7.00 (3H, s).

(V) Synthesis of ethyl [3- (2-hydroxyethyl) -5-methylphenyl] acetate diethyl 5-methyl-1,3-phenylenediacetate (1.82 g, 6.87 mmol) obtained in (iv) above ) In ethanol (5 mL) was added ethanolic potassium hydroxide (0.5 M, 13.7 mL, 6.85 mmol) and stirred for 4 hours. The reaction mixture was concentrated to about half volume, water was added, and the mixture was washed with diethyl ether. The water tank layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate to obtain a mixture (1.10 g) of ethyl (3-carboxymethyl-5-methylphenyl) acetate. Under ice cooling, borane-tetrahydrofuran complex (1M, 10 mL, 10 mmol) was added dropwise to a solution of the obtained mixture in THF (50 mL), and the mixture was stirred overnight at room temperature. Water was added and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain oily ethyl [3- (2-hydroxyethyl) -5-methylphenyl] acetate (0.40 g, 26%).
¹ H NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3), 1.48 (1H, t, J = 5.9), 2.32 (3H, s), 2. 82 (2H, t, J = 6.6 Hz), 3.56 (2H, s), 3.85 (2H, q, J = 6.3 Hz), 4.15 (2H, q, J = 7.3 Hz) ), 6.95 (2H, s), 6.97 (1H, s).

(Vi) Synthesis of 4-({2- [3- (ethoxycarbonylmethyl) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one In Synthesis Example 3 The obtained 2- (4-trifluoromethylphenyl) -4-hydroxyisoindoline-1-one and the ethyl [3- (2-hydroxyethyl) -5-methylphenyl] acetate obtained in (v) above were used. And was operated in the same manner as in Example 148 (ii) to give 4-({2- [3- (ethoxycarbonylmethoxy) -6-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) iso Crystals of indolin-1-one were obtained.
mp 92-95 ° C
¹ H NMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.3), 2.34 (3H, s), 3.11 (2H, t, J = 6.6 Hz), 3. 57 (2H, s), 4.10 (2H, q, J = 7.3 Hz), 4.31 (2H, t, J = 6.6 Hz), 4.78 (2H, s), 7.00- 7.07 (4H, m), 7.45 (1H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 1.0 Hz, 7.6 Hz), 7.67 (2H, d) , J = 8.6 Hz), 8.08 (2H, d, J = 8.6 Hz).

Example 331 (Synthesis of 4-({2- [3- (carboxymethyl) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({2- [3- (ethoxycarbonylmethyl) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 330 was run. Operate analogously to Example 69 to give 4-({2- [3- (carboxymethyl) -5-methylphenyl] ethyl} oxy) -2- (4-trifluoromethylphenyl) isoindoline-1-one. It was.
mp 201-203 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.28 (3H, s), 3.04 (2H, t, J = 6.6 Hz), 3.51 (2H, s), 4.34 (2H, t, J = 6.6 Hz), 4.93 (2H, s), 6.94 (1H, s), 7.06 (2H, s), 7.33-7.40 (2H, m), 7 .51 (1H, t, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 8.18 (2H, d, J = 8.6 Hz).

Example 332 (Synthesis of 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
4-Bromomethyl-2- (4-methylphenyl) isoindoline-1-one obtained in Example 328 (iv) and (4-hydroxy-2-methylphenoxy) acetic acid obtained in Example 227 (iii) The same procedure as in Example 266 (ii) was performed using ethyl, and 4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline- 1-one crystals were obtained.
mp 115-116 ° C
¹ H NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 2.35 (3H, s), 4.26 (2H, q, J = 7.3 Hz), 4.59 (2H, s), 4.90 (2H, s), 5.14 (2H, s), 6.67 (1H, d, J = 8.9 Hz), 6 .73 (1H, dd, J = 2.6 Hz, 8.9 Hz), 6.83 (1H, d, J = 2.6 Hz), 7.21-7.24 (2H, m), 7.51 ( 1H, t, J = 7.6 Hz), 7.57 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.71-7.76 (2H, m), 7.89 (1H, dd) , J = 1.3 Hz, 7.6 Hz).

Example 333 (Synthesis of 4-({[4- (carboxymethoxy) -3-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
4-({[4- (ethoxycarbonylmethoxy) -3-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 332 was used in the same manner as in Example 69. To give 4-({[4- (carboxymethoxy) -3-methylphenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one.
mp 198-200 ° C
¹ H NMR (CDCl ₃ ) δ: 2.18 (3H, s), 2.32 (3H, s), 4.62 (2H, s), 5.06 (2H, s), 5.23 (2H , S), 6.77 (1H, d, J = 8.9 Hz), 6.84 (1H, dd, J = 3.0 Hz, 8.9 Hz), 6.94 (1H, d, J = 3. 0 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.72 (1H, d, J = 7.6 Hz), 7. 73 (1H, d, J = 7.6 Hz), 7.80 (2H, d, J = 8.6 Hz), 12.92 (1H, brs).

Example 334 (Synthesis of 4-({[3- (ethoxycarbonylmethyl) -4-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-Bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 270 (i) and (5-hydroxy-2-methylphenyl) obtained in Example 190 (iv) ) Using ethyl acetate in the same manner as in Example 266 (ii), 4-({[3- (ethoxycarbonylmethyl) -4-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) ) Crystals of isoindoline-1-one were obtained.
mp 181-182 ° C
¹ H NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 2.26 (3H, s), 3.61 (2H, s), 4.15 (2H, q, J = 7.3 Hz), 4.98 (2H, s), 5.22 (2H, s), 6.83 (1H, dd, J = 2.6 Hz, 8.2 Hz), 6.90 (1H, d, J = 2.6 Hz), 7.13 (1H, d, J = 8.2 Hz), 7.55 (1H, t, J = 7.6 Hz), 7.64 (1H, d, J = 7) .6 Hz), 7.68 (2H, d, J = 8.9 Hz), 7.92 (1H, d, J = 7.6 Hz), 8.05 (2H, d, J = 8.9 Hz).

Example 335 (Synthesis of 4-({[3- (carboxymethyl) -4-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[3- (ethoxycarbonylmethyl) -4-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 334 was obtained in Example 69. To give 4-({[3- (carboxymethyl) -4-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 178-180 ° C
¹ H NMR (CDCl ₃ ) δ: 2.16 (3H, s), 3.57 (2H, s), 5.17 (2H, s), 5.28 (2H, s), 6.90 (1H , Dd, J = 2.6 Hz, 8.2 Hz), 6.97 (1H, d, J = 2.6 Hz), 7.11 (1H, d, J = 8.2 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.77-7.84 (4H, m), 8.18 (2H, d, J = 8.6 Hz), 12.37 (1H, br).

Example 336 (Synthesis of 4-({[5- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of methyl (3-hydroxy-4-methylphenyl) acetate (3-methoxy-4-methylphenyl) acetonitrile (645 mg, 4.00 mmol) synthesized in Example 126 (iii) with acetic acid (10 mL) A 47% hydrobromic acid (7 mL) solution was stirred at 80 ° C. for 3 days. The solvent was distilled off, methanol was added to the residue, and the mixture was stirred for 1 hour. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily methyl (3-hydroxy-4-methylphenyl) acetate (570 mg, 79%).
¹ H NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.55 (2H, s), 3.69 (3H, s), 4.98 (1H, s), 6.72-6 .76 (2H, m), 7.06 (1H, d, J = 7.3 Hz).

(Ii) Synthesis of 4-({[5- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 270 (i) Using 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in 1 above and methyl (3-hydroxy-4-methylphenyl) acetate obtained in (i) above Of 266 (ii) and 4-({[5- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one. Crystals were obtained.
mp 174-176 ° C
¹ H NMR (CDCl ₃ ) δ: 2.27 (3H, s), 3.62 (2H, s), 3.69 (3H, s), 4.99 (2H, s), 5.24 (2H , S), 6.85 (1H, dd, J = 1.3 Hz, 7.6 Hz), 6.91 (1H, d, J = 1.3 Hz), 7.15 (1H, d, J = 7. 6 Hz), 7.57 (1 H, t, J = 7.6 Hz), 7.67-7.70 (3 H, m), 7.93 (1 H, d, J = 7.6 Hz), 8.05 ( 2H, d, J = 8.9 Hz).

Example 337 (Synthesis of 4-({[5- (carboxymethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[5- (methoxycarbonylmethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in Example 336 was obtained in Example 69. To give 4-({[5- (carboxymethyl) -2-methylphenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 244-248 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.21 (3H, s), 3.54 (2H, s), 5.19 (2H, s), 5.29 (2H, s), 6.79 (1H, d, J = 7.6 Hz), 7.04 (1H, s), 7.12 (1H, d, J = 7.6 Hz), 7.62 (1H, t, J = 7.6 Hz) , 7.79-7.85 (4H, m), 8.18 (2H, d, J = 8.9 Hz), 12.35 (1H, br).

Example 338 (Synthesis of 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2-methoxymethoxy-4-methyl-1-chlorobenzene To a solution of 2-chloro-5-methylphenol (7.17 g, 50.3 mmol) in tetrahydrofuran (60 mL) was added diisopropylethylamine (13.1 mL, 75.75 g). 2 mmol) and chloromethyl methyl ether (5.1 mL, 67.1 mmol) were added, and the mixture was heated to reflux overnight. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily 2-methoxymethoxy-4-methyl-1-chlorobenzene (8.62 g, 92%).

¹ H NMR (CDCl ₃ ) δ: 2.32 (3H, s), 3.53 (3H, s), 5.23 (2H, s), 6.75-6.79 (1H, m), 6 .99 (1H, d, J = 1.6 Hz), 7.23 (1H, d, J = 8.2 Hz).

(Ii) Synthesis of 4-bromomethyl-2-methoxymethoxy-1-chlorobenzene Carbon tetrachloride of 2-methoxymethoxy-4-methyl-1-chlorobenzene (8.55 g, 45.8 mmol) obtained in (i) above (70 mL) N-bromosuccinimide (6.77 g, 42.1 mmol) and 2,2′-azobisisobutyronitrile (226 mg) were added to the solution, and the mixture was heated to reflux for 1 hour. After standing to cool, insoluble matter was filtered off and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain oily 4-bromomethyl-2-methoxymethoxy-1-chlorobenzene (9.40 g, 77%).
¹ H NMR (CDCl ₃ ) δ: 3.53 (3H, s), 4.44 (2H, s), 5.26 (2H, s), 6.99 (1H, dd, J = 2.0 Hz, 7.9 Hz), 7.21 (1H, d, J = 2.0 Hz), 7.33 (1H, d, J = 8.2 Hz).

(Iii) Synthesis of (4-chloro-3-methoxymethoxyphenyl) acetonitrile 4-Bromomethyl-2-methoxymethoxy-1-chlorobenzene (8.54 g, 32.2 mmol) obtained in (ii) above (dimethylsulfoxide) 110 mL) solution was added sodium cyanide (1.90 g, 38.8 mmol) and stirred at room temperature for 7 hours. Water was added and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain oily (4-chloro-3-methoxymethoxyphenyl) acetonitrile (4.82 g, 71%).
¹ H NMR (CDCl ₃ ) δ: 3.53 (3H, s), 3.72 (2H, s), 5.26 (2H, s), 6.93-6.97 (1H, m), 7 .13 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.2 Hz).

(Iv) Synthesis of methyl (4-chloro-3-hydroxyphenyl) acetate (4-Chloro-3-methoxymethoxyphenyl) acetonitrile (2.76 g, 13.0 mmol) obtained in (iii) above was added to ethanol (20 mL). ) And an aqueous solution (20 mL) of potassium hydroxide (3.72 g) were added and heated to reflux for 5 hours. After cooling, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was dried to obtain crystals of (4-chloro-3-methoxymethoxyphenyl) acetic acid (3.03 g).

Concentrated sulfuric acid (1 mL) was added to a methanol (60 mL) solution of (4-chloro-3-methoxymethoxyphenyl) acetic acid obtained above, and the mixture was heated to reflux overnight. After concentration, the residue was dissolved in ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain oily methyl (4-chloro-3-hydroxyphenyl) acetate (2.40 g, 92%).
¹ H NMR (CDCl ₃ ) δ: 3.57 (2H, s), 3.70 (3H, s), 5.61 (1H, s), 6.79 (1H, dd, J = 2.0 Hz, 8.2 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.26 (1H, d, J = 7.9 Hz).

(V) Synthesis of 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 270 (i) Using 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in 1 above and methyl (4-chloro-3-hydroxyphenyl) acetate obtained in (iv) above Of 266 (ii) and 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one. Crystals were obtained.
mp 183-184 ° C
¹ H NMR (CDCl ₃ ) δ: 3.62 (2H, s), 3.70 (3H, s), 5.14 (2H, s), 5.34 (2H, s), 6.89 (1H , Dd, J = 2.0 Hz, 7.9 Hz), 7.02 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.56 (1H, t, J = 7.6 Hz), 7.63 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.93 (1H, dd) , J = 1.3 Hz, 7.6 Hz), 8.06-8.10 (2H, m).

Example 339 (Synthesis of 4-({[2-chloro-5- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
The 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 338 was To give 4-({[2-chloro-5- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 232-240 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.60 (2H, s), 5.23 (2H, s), 5.40 (2H, s), 6.92 (1H, dd, J = 1. 6 Hz, 8.2 Hz), 7.28 (1 H, d, J = 1.6 Hz), 7.41 (1 H, d, J = 8.2 Hz), 7.63 (1 H, t, J = 7.6 Hz) ), 7.81-7.85 (4H, m), 8.17 (2H, d, J = 8.6 Hz).

Example 340 (Synthesis of 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-Bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 266 (i) and (4-chloro-3-hydroxyphenyl) obtained in Example 338 (iv) ) Using methyl acetate in the same manner as in Example 266 (ii), 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) ) Crystals of isoindoline-1-one were obtained.
mp 158-160 ° C
¹ H NMR (CDCl ₃ ) δ: 3.62 (2H, s), 3.70 (3H, s), 5.10 (2H, s), 5.33 (2H, s), 6.89 (1H , Dd, J = 1.6 Hz, 8.2 Hz), 7.14 (1H, d, J = 1.6 Hz), 7.26-7.32 (2H, m), 7.38 (1H, d, J = 8.2 Hz), 7.55 (1H, t, J = 7.6 Hz), 7.62 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.93 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.94-7.99 (2H, m).

Example 341 Synthesis of 4-({[2-chloro-5- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindolin-1-one)
The 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindolin-1-one obtained in Example 340 was To give 4-({[2-chloro-5- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 231-238 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.61 (2H, s), 5.20 (2H, s), 5.39 (2H, s), 6.92 (1H, dd, J = 1. 6 Hz, 8.2 Hz), 7.27 (1 H, d, J = 1.6 Hz), 7.41 (1 H, d, J = 7.9 Hz), 7.47-7.51 (2 H, m), 7.62 (1H, t, J = 7.6 Hz), 7.79-7.83 (2H, m), 8.02-8.08 (2H, m).

Example 342 (Synthesis of 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
4-Bromomethyl-2- (4-methylphenyl) isoindoline-1-one obtained in Example 328 (iv) and (4-chloro-3-hydroxyphenyl) acetic acid obtained in Example 338 (iv) Using methyl as in Example 266 (ii), 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline- 1-one crystals were obtained.
mp 159-162 ° C
¹ H NMR (CDCl ₃ ) δ: 2.36 (3H, s), 3.61 (2H, s), 3.70 (3H, s), 5.06 (2H, s), 5.31 (2H , S), 6.87 (1H, dd, J = 2.0 Hz, 7.9 Hz), 7.00 (1H, d, J = 2.0 Hz), 7.23 (2H, d, J = 7. 9 Hz), 7.36 (1 H, d, J = 7.9 Hz), 7.53 (1 H, t, J = 7.6 Hz), 7.60 (1 H, dd, J = 1.3 Hz, 7.6 Hz) ), 7.76-7.81 (2H, m), 7.91 (1H, dd, J = 1.3 Hz, 7.6 Hz).

Example 343 (Synthesis of 4-({[2-chloro-5- (carboxymethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
The 4-({[2-chloro-5- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 342 was used in the same manner as in Example 69. To give 4-({[2-chloro-5- (carboxymethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one.
mp 121-123 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 3.61 (2H, s), 5.14 (2H, s), 5.39 (2H, s), 6.91 (1H, dd, J = 1.6 Hz, 8.2 Hz), 7.26 (2H, d, J = 7.9 Hz), 7.27 (1H, d, J = 1.6 Hz), 7.41 ( 1H, d, J = 8.2 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.73-7.83 (4H, m).

Example 344 (Synthesis of 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
(I) Synthesis of 2-methoxymethoxy-5-methyl-1-chlorobenzene To a solution of 2-chloro-4-methylphenol (7.17 g, 50.3 mmol) in tetrahydrofuran (60 mL) was added diisopropylethylamine (13.1 mL, 75.75 g). 2 mmol) and chloromethyl methyl ether (5.1 mL, 67.1 mmol) were added, and the mixture was heated to reflux overnight. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain oily 2-methoxymethoxy-5-methyl-1-chlorobenzene (8.90 g, 95%).
¹ H NMR (CDCl ₃ ) δ: 2.27 (3H, s), 3.52 (3H, s), 5.21 (2H, s), 6.97-7.01 (1H, m), 7 .61 (1H, d, J = 8.6 Hz), 7.19 (1H, d, J = 2.0 Hz).

(Ii) Synthesis of 5-bromomethyl-2-methoxymethoxy-1-chlorobenzene Carbon tetrachloride of 2-methoxymethoxy-5-methyl-1-chlorobenzene (8.82 g, 47.2 mmol) obtained in (i) above (70 mL) To the solution was added N-bromosuccinimide (7.57 g, 42.5 mmol) and 2,2′-azobisisobutyronitrile (233 mg), and the mixture was heated to reflux for 1 hour. After standing to cool, insoluble matter was filtered off and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain oily 5-bromomethyl-2-methoxymethoxy-1-chlorobenzene (10.01 g, 80%).
¹ H NMR (CDCl ₃ ) δ: 3.51 (3H, s), 4.43 (2H, s), 5.25 (2H, s), 7.14 (1H, d, J = 8.6 Hz) , 7.23 (1H, d, J = 8.6 Hz), 7.42 (1H, d, J = 2.0 Hz).

(Iii) Synthesis of (3-chloro-4-methoxymethoxyphenyl) acetonitrile 5-bromomethyl-2-methoxymethoxy-1-chlorobenzene (9.89 g, 37.3 mmol) dimethylsulfoxide obtained in (ii) above ( 125 mL) solution was added sodium cyanide (1.83 g, 37.3 mmol) and stirred at room temperature for 1.5 hours. Water was added and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (solvent n-hexane / ethyl acetate = 2/1 (v / v)) to give oily (3-chloro-4-methoxymethoxyphenyl) Acetonitrile (3.17 g, 40%) was obtained.
¹ H NMR (CDCl ₃ ) δ: 3.52 (3H, s), 3.69 (2H, s), 5.26 (2H, s), 7.17-7.18 (2H, m), 7 .35-7.36 (1H, m).

(Iv) Synthesis of methyl (3-chloro-4-hydroxyphenyl) acetate (3-Chloro-4-methoxymethoxyphenyl) acetonitrile (3.11 g, 14.7 mmol) obtained in (iii) above was added to ethanol (25 mL). ) And potassium hydroxide (4.17 g) in water (25 mL) were added and heated to reflux overnight. After cooling, the mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was dried to obtain crystals of (3-chloro-4-methoxymethoxyphenyl) acetic acid (4.82 g).

Concentrated sulfuric acid (1 mL) was added to a methanol (60 mL) solution of (3-chloro-4-methoxymethoxyphenyl) acetic acid obtained above, and the mixture was heated to reflux for 4 hours. After concentration, the residue was dissolved in ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain oily methyl (3-chloro-4-hydroxyphenyl) acetate (2.16 g, 73%).
¹ H NMR (CDCl ₃ ) δ: 3.54 (2H, s), 3.70 (3H, s), 5.58 (1H, s), 6.96 (1H, d, J = 8.2 Hz) 7.85 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.26 (1H, d, J = 2.0 Hz).

(V) Synthesis of 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one Example 270 (i) Using 4-bromomethyl-2- (4-trifluoromethylphenyl) isoindoline-1-one obtained in 1 above and methyl (3-chloro-4-hydroxyphenyl) acetate obtained in (iv) above Of 266 (ii) and 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one. Crystals were obtained.
mp 164-166 ° C
¹ H NMR (CDCl ₃ ) δ: 3.58 (2H, s), 3.71 (3H, s), 5.12 (2H, s), 5.32 (2H, s), 6.99 (1H , D, J = 8.2 Hz), 7.17 (1H, dd, J = 2.3 Hz, 8.2 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.55 (1H, t, J = 7.6 Hz), 7.61 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.68 (2H, d, J = 8.6 Hz), 7.93 (1H, dd) , J = 1.3 Hz, 7.3 Hz), 8.08 (2H, d, J = 8.2 Hz).

Example 345 (Synthesis of 4-({[2-chloro-4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one)
4-({[2-Chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindolin-1-one obtained in Example 344 was obtained in Example 69. To give 4-({[2-chloro-4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethylphenyl) isoindoline-1-one.
mp 194-197 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.55 (2H, s), 5.23 (2H, s), 5.43 (2H, s), 7.22 (1H, dd, J = 2. 0 Hz, 8.6 Hz), 7.27 (1 H, d, J = 8.6 Hz), 7.39 (1 H, d, J = 2.0 Hz), 7.62 (1 H, t, J = 7.6 Hz) ), 7.80-7.86 (4H, m), 8.17 (2H, d, J = 8.6 Hz).

Example 346 (Synthesis of 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
4-Bromomethyl-2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 266 (i) and (3-chloro-4-hydroxyphenyl) obtained in Example 344 (iv) ) Using methyl acetate in the same manner as in Example 266 (ii), 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) ) Crystals of isoindoline-1-one were obtained.
mp 158-160 ° C
¹ H NMR (CDCl ₃ ) δ: 3.57 (2H, s), 3.71 (3H, s), 5.08 (2H, s), 5.31 (2H, s), 6.99 (1H , D, J = 8.6 Hz), 7.16 (1H, dd, J = 2.0 Hz, 8.6 Hz), 7.26-7.30 (2H, m), 7.37 (1H, d, J = 2.0 Hz), 7.54 (1H, t, J = 7.6 Hz), 7.60 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.90-7.99 (3H) , M).

Example 347 (Synthesis of 4-({[2-chloro-4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one)
The 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one obtained in Example 346 was obtained in Example 69. To give 4-({[2-chloro-4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-trifluoromethoxyphenyl) isoindoline-1-one.
mp 191-193 ° C
¹ H NMR (DMSO-d ₆ ) δ: 3.55 (2H, s), 5.19 (2H, s), 5.41 (2H, s), 7.21 (1H, dd, J = 2. 0 Hz, 8.2 Hz), 7.27 (1 H, d, J = 8.6 Hz), 7.39 (1 H, d, J = 2.0 Hz), 7.47-7.51 (2 H, m), 7.61 (1H, t, J = 7.6 Hz), 7.80 (2H, d, J = 7.3 Hz), 8.01-8.07 (2H, m).

Example 348 (Synthesis of 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
4-Bromomethyl-2- (4-methylphenyl) isoindoline-1-one obtained in Example 328 (iv) and (3-chloro-4-hydroxyphenyl) acetic acid obtained in Example 344 (iv) Using methyl as in Example 266 (ii), 4-({[2-chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline- 1-one crystals were obtained.
mp 164-167 ° C
¹ H NMR (CDCl ₃ ) δ: 2.36 (3H, s), 3.56 (2H, s), 3.70 (3H, s), 5.04 (2H, s), 5.29 (2H , S), 6.98 (1H, d, J = 8.2 Hz), 7.15 (1H, dd, J = 2.0 Hz, 8.2 Hz), 7.21-7.25 (2H, m) , 7.36 (1H, d, J = 2.0 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.58 (1H, dd, J = 1.3 Hz, 7.6 Hz), 7.75-7.80 (2H, m), 7.90 (1H, dd, J = 1.3 Hz, 7.3 Hz).

Example 349 (Synthesis of 4-({[2-chloro-4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one)
4-({[2-Chloro-4- (methoxycarbonylmethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one obtained in Example 348 was used in the same manner as in Example 69. To give 4-({[2-chloro-4- (carboxymethyl) phenyl] oxy} methyl) -2- (4-methylphenyl) isoindoline-1-one.
mp 196-199 ° C
¹ H NMR (DMSO-d ₆ ) δ: 2.31 (3H, s), 3.54 (2H, s), 5.13 (2H, s), 5.41 (2H, s), 7.21 (1H, dd, J = 1.6 Hz, 8.6 Hz), 7.26 (1H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.38 ( 1H, d, J = 1.6 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.75-7.82 (4H, m).

Test Example 1 (PPAR screening method: measurement of PPARα, PPARγ or PPARδ agonist activity)
Twenty-four hours before transfection, 0.6 × 10 ⁶ cells of CHO cells were seeded on 100 mm plates. TransIT LT-1 (transfection reagent, manufactured by Miras) was added to RPMI 1640 (medium, manufactured by IWAKI), mixed using a vortex mixer, and allowed to stand. This solution is mixed with a receptor plasmid pBIND-hPPARα (or γ or δ) that expresses a fusion protein of a DNA binding domain of the transcription factor Gal4 of yeast and a PPARα (or γ or δ) ligand binding domain and a reporter plasmid pG5-Luc. After standing, the whole amount was added to a 100 mm plate. After 24 hours, cells were harvested and seeded in 96 well plates. Next, 1% by weight of a dimethyl sulfoxide (DMSO) solution was added to the test substance prepared to give the final concentration for measurement, and luciferase activity was measured 24 hours after the addition of the drug. A solution (test substance concentration 1% by weight) dissolved in was added, and luciferase activity was measured 24 hours after the addition of the drug.

  The luciferase activity of the test substance non-administered group was set to 1, and the induction ratio was calculated based on the luciferase activity when the control drug and each test substance were added. Further, the induction ratio of the control drug was set to 1 (reference), and the induction ratio when the test substance was added at different concentrations was calculated. Tables 1 to 18 show the results of evaluating the relative value of the induction ratio of the control drug as a percentage. In the table, NT is untested.

  Table 19 shows the reference drugs for PPARα, PPARγ, and PPARδ, and the concentration added as a reference. In Table 1, fenofibric acid is a carboxylic acid form of fenofibrate.

  In addition, the compound of the Example which showed the PPAR (alpha) activity stronger than fenofibric acid addition of 100 micromol is as follows about the addition density | concentration of each test substance.

Test substance 100 μg / mL:
Examples 15, 21, 78 and 80
Test substance 30 μg / mL:
Examples 17, 60, 61, 85, 91, 99, 104, 116, 118, 132 and 135
Test substance 10 μg / mL:
Examples 19, 68, 82, 87 and 105
Test substance 3 μg / mL:
Examples 39, 44, 103 and 123.

  Moreover, the compound of the Example which showed the PPARγ activity stronger than the addition of 10 μM triglitazone is as follows with respect to the addition concentration of each test substance.

Test substance 30 μg / mL:
Examples 85, 88, 116 and 132
Test substance 10 μg / mL:
Examples 86, 87, 89, 103, 104, 105, 107 and 129
Test substance 3 μg / mL:
Example 123.

  GW501516 The compound of the Example which showed PPAR (delta) activity stronger than 100 nM addition is a compound which showed the numerical value of 100% or more in Table 1-Table 18.

Formulation Example 1 (tablet)
Tablets were obtained according to the known methods described in the General Formulation of JP XIV for the following prescription.

Formulation example in one tablet:
50 mg of the compound of Example 103
Crystalline cellulose 100mg
Lactose 20mg
Corn starch 28mg
Magnesium stearate 2mg
Total amount 200mg
Formulation Example 2 (Capsule)
Capsules were obtained in accordance with known methods described in the General Rules for Preparations of JP XIV for the following formulations.

Formulation example in one capsule:
Example 123 Compound 50mg
Lactose 100mg
Corn starch 28mg
Magnesium stearate 2mg
Total amount 200mg
Formulation Example 3 (granule and tablet)
Hydroxypropyl methylcellulose 2910 aqueous solution (HPMC, solid content 13 parts by weight) was added to a mixture of 30 parts by weight of the compound of Example 177, 20 parts by weight of lactose, and 50 parts by weight of crystalline cellulose, kneaded, extruded, granulated, and adjusted. Granulated, dried and sieved to obtain granules. To 100 parts by weight of the obtained granules, 65 parts by weight of crystalline cellulose and 2 parts by weight of magnesium stearate were added, mixed, and tableted to obtain tablets having the following composition.

Compound of Example 177 30 mg
Lactose 20mg
Hydroxypropyl methylcellulose 2910 13mg
Crystalline cellulose 115mg
Crospopidone 20mg
Magnesium stearate 2mg
Total amount 207mg
Formulation Example 4 (granule and tablet)
Granules and tablets were obtained in the same manner as in Formulation Example 3, except that the compound of Example 253 was used instead of the compound of Example 177.

Claims (16)

A lactam compound represented by the following formula (1) or a salt thereof.

[In the formula, R ¹ represents a halogen atom, a hydrocarbon group which may have a substituent, a group —C (═O) —O—R ^5a (wherein R ^5a has a hydrogen atom or a substituent, An optionally substituted acyl group, a carbamoyl group or an N-substituted carbamoyl group, —O—R ^5a (wherein R ^5a is as defined above), —S—R ^5a (wherein R ^5a is the same as above), an amino group or an N-substituted amino group, a sulfonic acid group —SO ₃ H or a sulfonic acid ester group, a sulfonamide group or an N-substituted sulfonamide group, a sulfinic acid group -SO 2 _H or sulfinic acid ester groups, sulfinic acid amide or N- substituted sulfinic acid amide group, a sulfenic acid -SOH or sulfenic acid ester group, a sulfenyl amido group, N- substituted sulfenyl amide group Heterocyclic group, a nitro group, a cyano group or an isocyanate group,
The coefficient a represents an integer of 0 to 5,
Ring Z ¹ represents an arene ring or a hetero ring,
Ring Z ³ represents an alicyclic hydrocarbon ring or an aromatic hydrocarbon ring,
Ring Z ² is a nitrogen-containing 5-6 membered ring having an amido bond as a constituent unit of a ring,
X ¹ represents a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, a group —N—C (═O) —, or a group —C (═O) —N—,
R ² represents a hydrogen atom or an alkyl group which may have a substituent, depending on the valence v of X ¹ ;
The coefficient b represents an integer of 0 to 2, depending on the valence v of the X ¹ ,
R ³ and R ⁴ are the same or different and represent a single bond or a divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent, and at least one of R ³ and R ⁴ is A divalent saturated or unsaturated aliphatic hydrocarbon group which may have a substituent,
X ² and X ³ are the same or different and each represents a single bond, an oxygen atom, a sulfur atom, an imino group, a substituted imino group, or an amide group —NH—C (═O) — or —C (═O) —NH—. Show
A ¹ represents a single bond or a phenylene group which may have a substituent,
Y ¹ represents a hydrogen atom, a halogen atom, a group —C (═O) —O—R ^5a (wherein R ^5a is the same as above), an optionally substituted acyl group, a carbamoyl group, or N— Substituted carbamoyl group, amino group or N-substituted amino group, sulfonic acid group —SO ₃ H or sulfonic acid ester group, sulfinic acid group —SO ₂ H or sulfinic acid ester group, sulfonamide group or N-substituted sulfonamide group, Represents a nitro group or a cyano group,
The coefficient c represents an integer of 1 to 3 depending on the valence v of X ¹ ,
Valence v = b + c + 1,
When A ¹ is a single bond, at least one of X ² and X ³ is a single bond]. In the formula (1), the ring Z ¹ is a C _6-14 arene ring, or a 4-10 membered heterocycle having at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as a constituent atom of the ring. The lactam compound or a salt thereof according to claim 1, wherein ring Z ³ is a C _6-14 arene ring. ^{3. The} ring according to claim ¹ , wherein in formula (1), ring Z ¹ and ring Z ³ each represent a benzene ring, and ring Z ² is a nitrogen atom-containing 5- to 6-membered ring having an amide bond as a structural unit of the ring. A lactam compound or a salt thereof. The lactam compound represented by the formula (1) is represented by the following formula (1a)

In the formula (1a),
R ¹ represents a halogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, a carboxyl group, or a substituent. An alkoxycarbonyl group which may have, an alkylcarbonyl group which may have a substituent, a carbamoyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an N-acylcarbamoyl group, an N, N- Diacylcarbamoyl group, hydroxyl group, mercapto group, optionally substituted alkoxy group, optionally substituted cycloalkyloxy group, optionally substituted aryloxy group, substituted An alkylthio group which may have a group, a cycloalkylthio group which may have a substituent, an arylthio group which may have a substituent, An amino group, an N-alkylamino group, an N, N-dialkylamino group, an N-acylamino group, an N, N-diacylamino group, a sulfonic acid group, an optionally substituted alkylsulfonyl group, and a substituent. Arylsulfonyl group, sulfonamide group, N-alkylsulfonamide group, N, N-dialkylsulfonamide group, N-arylsulfonamide group, sulfinic acid group, alkylsulfinyl group, arylsulfinyl group, sulfinyl which may have Amide group, N-alkylsulfinylamide group, N, N-dialkylsulfinylamide group, N-arylsulfinylamide group, sulfenic acid group, alkylsulfenyl group, arylsulfenyl group, sulfenylamide group, N-alkylsulfenyl group Amido group, N-arylsulfenyl De group, a nitro group, or a cyano group,
The coefficient a represents an integer of 0 to 3,
X ¹ represents a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, a group —N—C (═O) — or a group —C (═O) —N—,
R ² represents a hydrogen atom or an alkyl group which may have a substituent, depending on the valence v of X ¹ ;
The coefficient b represents an integer of 0 to 2, depending on the valence v of the X ¹ ,
When X ¹ is an oxygen atom or a sulfur atom, the coefficient b is 0. When X ¹ is a nitrogen atom, R ² represents a hydrogen atom or an optionally substituted alkyl group, and a coefficient. b is 1, and when X ¹ is a group —N—C (═O) — or a group —C (═O) —N—, R ² is a hydrogen atom or an alkyl which may have a substituent. And the coefficient b is 1,
R ³ and R ⁴ are the same or different and each represents a single bond or a linear or branched divalent saturated or unsaturated aliphatic hydrocarbon group having 1 to 20 carbon atoms. And
X ² and X ³ are the same or different and each represents a single bond, an oxygen atom, a sulfur atom, an imino group, a substituted imino group, or an amide group —C (═O) —NH—,
Y ¹ represents a hydrogen atom, a halogen atom, a carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted alkylcarbonyl group, a carbamoyl group, an N-alkylcarbamoyl group, N, N -Dialkylcarbamoyl group, N-acylcarbamoyl group, N, N-diacylcarbamoyl group, N- (alkylsulfonyl) carbamoyl group, N, N-di (alkylsulfonyl) carbamoyl group, amino group, N-alkylamino group, N , N-dialkylamino group, N-acylamino group, N, N-diacylamino group, sulfonic acid group, sulfonic acid alkyl ester group, sulfinic acid group, sulfinic acid alkyl ester group, or cyano group,
The lactam compound or a salt thereof according to any one of claims 1 to 3, wherein the coefficient c is 1. R ¹ is at least one substituent selected from a halogen atom; a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group A linear or branched C _1-4 alkyl group which may have a carboxyl group; a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group, a linear or branched chain Having at least one substituent selected from a linear halo C _1-4 alkoxy group, a carboxy-C _1-4 alkyl group, and a linear or branched C _1-4 alkoxy-carbonyl-C _1-4 alkyl group and it may be linear or branched C _1-4 alkoxy - carbonyl group; a halogen atom, a hydroxyl group, a mercapto group, a linear or branched C _1-4 alkoxy group, a linear addition It branched C _1-4 alkylthio group, a linear or branched halo C _1-4 alkoxy group, a linear or branched C _1-4 haloalkylthio group, a carboxyl group, linear or branched Linear or optionally having at least one substituent selected from a C _1-4 alkoxy-carbonyl group and a linear or branched C _1-4 alkoxy-carbonyl-C _1-4 alkyl group; Branched C _1-4 alkyl-carbonyl group; carbamoyl group; N—C _1-4 alkylcarbamoyl group, N, N-diC _1-4 alkylcarbamoyl group, N—C _1-4 alkylcarbonyl-carbamoyl group, N, N-diC _1-4 alkylcarbonyl-carbamoyl group; hydroxyl group; mercapto group; halogen atom, hydroxyl group, linear or branched C _1-4 alkoxy group And a linear or branched C _1-4 alkoxy group which may have at least one substituent selected from a linear or branched halo C _1-4 alkoxy group; a halogen atom, a hydroxyl group A linear or branched group optionally having at least one substituent selected from a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group Chain C _1-4 alkylthio group; amino group; N—C _1-4 alkylamino group, N, N-diC _1-4 alkylamino group, N—C _1-4 alkylcarbonyl-amino group, N, N -Di-C _1-4 alkylcarbonyl-amino group; or nitro group,
The coefficient a is an integer from 0 to 2,
Ring Z ² is a nitrogen-containing 5-membered ring having an amido bond as a constituent unit of a ring,
X ¹ is a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom. When X ¹ is a carbon atom, the coefficient b is 2, and when X ¹ is an oxygen atom or a sulfur atom, the coefficient b is 0. And when X ¹ is a nitrogen atom, R ² represents a hydrogen atom or a C _1-4 alkyl group which may have at least one substituent selected from a halogen atom and a hydroxyl group, and a coefficient b is 1,
R ³ and R ⁴ are the same or different and are a single bond; or a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group A linear or branched divalent saturated or unsaturated aliphatic hydrocarbon group having 1 to 10 carbon atoms which may have at least one substituent selected from
X ² and X ³ are the same or different and are a single bond; oxygen atom; sulfur atom; imino group; linear or branched C _1-4 alkyl group, hydroxy linear or branched C _1-4 alkyl Group, a linear or branched C _1-4 alkyl group having a halogen atom, or a substituted imino group having a linear or branched C _1-4 alkylcarbonyl group as a substituent; or an amide group -C ( = O) -NH-
Y ¹ is a hydrogen atom; halogen atom; carboxyl group; halogen atom, hydroxyl group, linear or branched C _1-4 alkoxy group, linear or branched halo C _1-4 alkoxy group, carboxy-C _A linear or branched chain optionally having at least one substituent selected from a _1-4 alkyl group and a linear or branched C _1-4 alkoxy-carbonyl-C _1-4 alkyl group C _1-4 alkoxy-carbonyl group; at least one selected from a halogen atom, a hydroxyl group, a linear or branched C _1-4 alkoxy group and a linear or branched halo C _1-4 alkoxy group optionally substituted _{C 1-4} alkyl - carbonyl group; a carbamoyl group; _{N-C 1-4} alkylcarbamoyl group, N, _{N-di-C 1-4} alkylcarbamoyl , _{N-C 1-4} alkylcarbonyl - carbamoyl group, N, _{N-di-C 1-4} alkylcarbonyl - carbamoyl group, _{N-(C 1-4} alkyl) carbamoyl group, N, N-di _{(C 1- 4} alkylsulfonyl) carbamoyl group; amino group; N—C _1-4 alkylamino group, N, N-diC _1-4 alkylamino group, N—C _1-4 alkylcarbonyl-amino group, N, N-di C _1-4 alkylcarbonyl-amino group, sulfonic acid group; sulfonic acid C _1-4 alkyl ester group; sulfinic acid group; sulfinic acid C _1-4 alkyl ester group, or cyano group,
The lactam compound or a salt thereof according to any one of claims 1 to 4, wherein the coefficient c is 1. The compound of the formula (1) is a compound represented by the formula (1a), and in this formula (1a), the substitution position of X ¹ is the 4-position of the benzopyrrolidone skeleton in which the benzene ring is condensed to the pyrrolidone ring, The lactam compound or a salt thereof according to any one of claims 1 to 5, wherein when the coefficient a is 1 or more, the substitution position of R ¹ is at least the m-position and / or the p-position. Following formula (3)

[Wherein X ⁵ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), —X ^1a (—R ^2a ) _b1 —H (wherein X ^1a is a carbon atom, oxygen atom, sulfur An atom or a nitrogen atom, R ^2a represents a hydrogen atom or an optionally substituted alkyl group, and the coefficient b1 is an integer of 0 to 2 depending on the valence v1 of X ^1a ), a carboxyl group , An alkoxycarbonyl group, a halocarbonyl group or a group -SL (wherein L represents a leaving group). R ¹ , Z ^{1 to} Z ³ , and the coefficient a are the same as described in claim 1. ]
And a lactam compound represented by the following formula (4):
^{X 6 -R 3 -X 2 -A 1} -X 3 -R 4 -Y 1 (4)
[Wherein X ⁶ is a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), or —X ^1b (—R ^2b ) _b2 —H (wherein X ^1b is a carbon atom, oxygen atom, A sulfur atom or a nitrogen atom, R ^2b represents a hydrogen atom or an optionally substituted alkyl group, and the coefficient b2 is 0 or 1 depending on the valence v2 of X ^1b ), a carboxyl group, An alkoxycarbonyl group or a halocarbonyl group, and when X ⁵ is an alkylsulfonyloxy group optionally having a halogen atom or a substituent, X ⁶ is —X ^1b (—R ^2b ) _b2 —H; , when said ^{X 5} is _{^{-X 1a (-R 2a) b1 -H}} , X 6 is a halogen atom, an optionally substituted alkyl sulfonyloxy group, a carboxyl group, an alkoxycarbonyl Or a halocarbonyl group, when ^{X 5} is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, ^{X 6} is -N ^(-R 2a) -H, when ^{X 5} is a group -S-L , X ⁶ is a halogen atom or an alkylsulfonyloxy group which may have a substituent. R ³ , R ⁴ , X ² , X ³ , Y ¹ and A ¹ are the same as described in claim 1]
The method of manufacturing the lactam compound or its salt of Claim 1 by making the compound or its salt represented by these react. Following formula (10)

[Wherein, X ¹⁰ represents a halogen atom, an alkylsulfonyloxy group which may have a substituent, —X ^3a —H (wherein X ^3a represents an oxygen atom, a sulfur atom, an imino group or a substituted imino group) ), A carboxyl group, an alkoxycarbonyl group or a halocarbonyl group. R ^{1 to} R ³ , Z ^{1 to} Z ³ , X ¹ , X ² , A ¹ and coefficients a to c are the same as described above. ]
Or a salt thereof and the following formula (8)

[Wherein X ¹¹ represents a halogen atom, an alkylsulfonyloxy group optionally having substituent (s), —X ^3a —H (wherein X ^3a represents an oxygen atom, sulfur atom, imino group or substituted imino group) ), A carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and when X ¹⁰ is a halogen atom or an alkylsulfonyloxy group which may have a substituent, X ¹¹ is a group —X ^3a —H. , X ¹⁰ is a group -X ^3a -H, X ¹¹ is a halogen atom, an optionally substituted alkylsulfonyloxy group, a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, and X ¹⁰ is When it is a carboxyl group, an alkoxycarbonyl group or a halocarbonyl group, X ¹¹ is an amino group or an N-monosubstituted amino group. R ⁴ and Y ¹ are the same as described in claim 1. ]
The method of manufacturing the lactam compound or its salt of Claim 1 by making the compound or its salt represented by these react.   A PPAR activator comprising the lactam compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient. Formula (I)

(Wherein R ¹ , Z ^{1 to} Z ^3, and coefficient a are the same as described in claim 1)
A PPAR activator comprising, as an active ingredient, a compound having a lactam skeleton represented by the formula: or a pharmacologically acceptable salt thereof.   The PPAR activator according to claim 9 or 10, which is an activator for activating at least one selected from PPARα, PPARγ and PPARδ.   A pharmaceutical composition comprising the lactam compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof and a carrier. Formula (I)

(Wherein R ¹ , Z ^{1 to} Z ^3, and coefficient a are the same as described in claim 1)
A pharmaceutical composition comprising a compound having a lactam skeleton represented by the formula (1) or a pharmacologically acceptable salt thereof and a carrier.   Prevention or treatment of diseases caused by abnormal metabolism of fatty acids, lipids or sugars and / or (ii) diseases caused by excessive intake of fatty acids, lipids or sugars compared to metabolism of fatty acids, lipids or sugars A preventive or therapeutic agent comprising the lactam compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient. Prevention or treatment of (i) diseases caused by abnormal metabolism of fatty acids, lipids or sugars and / or (ii) diseases caused by excessive intake of fatty acids, lipids or sugars compared to metabolism of fatty acids, lipids or sugars An agent having the following formula (I)

(Wherein R ¹ , Z ^{1 to} Z ^3, and coefficient a are the same as described in claim 1)
Or a pharmacologically acceptable salt thereof having a lactam skeleton represented by the formula:   The disease is a disease selected from the group consisting of arteriosclerosis, cerebral infarction, stroke, dilated cardiomyopathy, hypertension, hyperlipidemia, hypoHDLemia, metabolic syndrome, diabetes, insulin resistant diabetes and obesity The preventive or therapeutic agent according to claim 14 or 15.