WO2005044780A1 - Aminocarboxylic acid derivative, addition salt thereof, and s1p receptor control agent - Google Patents

Aminocarboxylic acid derivative, addition salt thereof, and s1p receptor control agent

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Publication number
WO2005044780A1
WO2005044780A1 PCT/JP2004/016517 JP2004016517W WO2005044780A1 WO 2005044780 A1 WO2005044780 A1 WO 2005044780A1 JP 2004016517 W JP2004016517 W JP 2004016517W WO 2005044780 A1 WO2005044780 A1 WO 2005044780A1
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WIPO (PCT)
Prior art keywords
formula
general formula
group
acid
reaction
Prior art date
Application number
PCT/JP2004/016517
Other languages
French (fr)
Japanese (ja)
Inventor
Yasushi Kohno
Sayoko Tanioka
Yoshiaki Kikuchi
Miki Kinoshita
Satoru Iwanami
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to JP2005515328A priority Critical patent/JPWO2005044780A1/en
Publication of WO2005044780A1 publication Critical patent/WO2005044780A1/en

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    • C07C317/50—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
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    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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Definitions

  • the present invention relates to an amino carbonate derivative, an addition salt thereof, and a hydrate thereof useful as an S1P (sphingosine-1-phosphate) receptor modulator.
  • S1P 1-phosphate
  • Non-Patent Document 1 Non-Patent Document 1
  • S1P receptors five subtypes of Edg-1, Edg-3, Edg-5, Edg-6 and Edg-8 are known as S1P receptors, and SIP, SIP, SIP, SIP and S1P are each
  • S1P receptor modulators exhibiting agonist activity or antagonist activity at this receptor exhibit efficacy against a wide variety of diseases. It has been done. For example, it has been disclosed in Patent Document 1 that a compound acting on Edg-5 is effective for arteriosclerosis, renal fibrosis, pulmonary fibrosis, and hepatic fibrosis.
  • Patent Document 2 discloses that it is effective as an agent for treating and preventing respiratory diseases such as interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, and irritable pneumonitis.
  • compounds with Edg-1 agonist action are used for obstructive atherosclerosis and obstructive thromboangiitis Venous aneurysm such as, Baja disease, diabetic-urovicular peripheral artery disease, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema disease, arteriosclerosis, hemorrhoids, anal fissure, hemorrhoids, etc.
  • Venous aneurysm such as, Baja disease, diabetic-urovicular peripheral artery disease, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema disease, arteriosclerosis, hemorrhoids, anal fissure, hemorrhoids, etc.
  • Patent Document 3 Dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, heart failure, burns, ulcerative colitis, Crohn's disease, heart transplant, kidney transplant, skin transplant, liver transplant, bone marrow transplant, It is disclosed in Patent Document 3 as being effective as a therapeutic and prophylactic agent for osteoporosis, chronic hepatitis, cirrhosis, chronic renal failure, and glomerulosclerosis. Furthermore, it has been reported that compounds having S1P receptor agonist activity regulate leukocyte migration (Non-patent Document 4, Non-patent Document 5), and a series of derivatives introduced in the aforementioned Non-patent Documents.
  • autoimmune diseases such as rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, I and type II diabetes, Crohn's disease, etc. It is effective for allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, inflammatory diseases such as inflammatory bowel disease and ulcerative colitis (Patent Document 4, It is disclosed in Patent Document 5).
  • Patent Document 4 a phosphate derivative similar to the above (Patent Document 4) and (Patent Document 5) is also disclosed as an S1P receptor antagonist (Patent Document 6).
  • Patent Document 7 a phosphate derivative similar to the above (Patent Document 4) and (Patent Document 5) is also disclosed as an S1P receptor antagonist (Patent Document 6).
  • Patent Document 8 a phosphate derivative similar to the above (Patent Document 4) and (Patent Document 5) is also disclosed as an S1P receptor antagonist (Patent Document 6).
  • Patent Document 7 Patent Document 7
  • Patent Document 8 Patent Document 9
  • Patent Document 10 also disclose S1P receptor modulators.
  • the present inventors have conducted intensive studies with the aim of developing a compound having a modulating effect on S1P receptors involved in various diseases. We focused on acid derivatives and searched for a new type of S1P receptor modulator. Most recently, compounds having both an amino group and a carboxylic acid unit have been disclosed as S1P receptor agonists in (Patent Documents 11), (Patent Documents 12) and (Patent Documents 13). It is characterized by a structure in which a group is incorporated in the linking chain, and has a different structure from the compound of the present application, which is characterized by an ex amino acid, ⁇ amino acid, or ⁇ amino acid structure in which an amino group is introduced on the linking chain. is there.
  • Patent Document 1 WO0198301 pamphlet
  • Patent Document 2 WO03020313 Breadfruit
  • Patent Literature 3 WO02092068 Go broth
  • Patent document 4 pamphlet of WO0218395
  • Patent Document 5 WO02076995 pamphlet
  • Patent Document 6 JP-A-2003-137894
  • Patent Document 7 WO03040097 Breadfruit
  • Patent Document 8 WO02064616 pamphlet
  • Patent Document 9 WO02062389 No.
  • Patent Document 10 WO03051876 pamphlet
  • Patent Document 11 WO03061567 Breadfruit
  • Patent Document 12 WO03062248 pamphlet
  • Patent Document 13 WO03062252 Breadfruit
  • Non-patent literature l Y.Takuma et al., Mol.Cell.Endocrinol, 177, 3 (2001)
  • Non-Patent Document 2 Y.Igarashi, Ann, N.Y.Acad.Sci., 845, 19 (1998)
  • Non-Patent Document 3 H. Okazaki et al., Biochem.Biophs. Res.Commun., 190, 1104 (1993)
  • Non-Patent Document 4 S. Mandala et al., Science, 296, 346 (2002)
  • Non-Patent Document 5 V. Brinkmann et al., J. Biol. Chem., 277, 21453 (2002)
  • the problem to be solved by the present invention is to provide an aminocarboxylic acid derivative which has an excellent regulatory effect on S1P receptors and has few side effects.
  • the present inventors have conducted intensive studies to create a compound having S1P receptor modulatory activity and high safety.
  • the present inventors have found that a novel aminocarboxylic acid derivative having a different structure has a potent S1P receptor regulating action, and completed the present invention.
  • R is a phenyl group which may have a substituent or a carbon atom which may have a substituent 1
  • R is a hydrogen atom, halogen atom, torino, lomethyl group, carbon number 1
  • R is hydrogen atom
  • R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent, and 2 to 4 carbon atoms;
  • R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group
  • X is 0, S, SO, SO
  • n is an integer of 24,
  • aminocarboxylic acid derivative according to 1) which is a compound represented by the formula, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof,
  • the compound represented by the general formula (1) is a compound represented by the general formula (lb)
  • aminocarboxylic acid derivative according to 1) which is a compound represented by the formula, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof,
  • R represents a phenyl group which may have a substituent or a carbon atom which may have a substituent
  • R represents a hydrogen atom, a halogen atom, a torino, a lomethyl group, a lower alkyl group having 14 to 14 carbon atoms or
  • R represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a phenyl group
  • R represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, and a lower alkyl group having 2 to 4 carbon atoms;
  • R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group
  • X represents 0, S, SO, SO, NH or CH
  • n is an integer of 24,
  • a novel aminocarboxylic acid derivative and an addition salt thereof have an excellent S 1P receptor regulating action.
  • Compounds having such S1P receptor modulatory activity include arteriosclerosis, obstructive arteriosclerosis, obstructive thromboangitis, renal fibrosis, hepatic fibrosis, chronic bronchial asthma, diffuse hamartomatous pulmonary angiomyoma.
  • ARDS adult respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • interstitial pneumonia idiopathic interstitial pneumonia, lung cancer, irritable pneumonitis, Bajaja disease, diabetic neurobati peripheral arterial disease , Defeat Blood, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema disease, varicose vein, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, swelling, Drugs for treatment and prevention of ulcerative colitis, Crohn's disease, etc., and drugs for prevention or treatment of rejection such as heart transplant, kidney transplant, skin transplant, liver transplant, bone marrow transplant, rheumatoid arthritis, lupus nephritis, systemic It is useful as a prophylactic or therapeutic agent for erythematosus monolith, Hashimoto's disease, multiple s,
  • compositions represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, Acid addition salts such as citrate and tartrate are mentioned.
  • halogen atom represents a fluorine atom, chlorine atom, bromine atom or iodine atom
  • trino, romethyl group means trifluoromethyl group
  • lower alkyl group having 11 to 10 carbon atoms means, for example, a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc.
  • Hydrocarbons having 1 to 10 carbon atoms.
  • lower alkyl group such as “lower alkyl group having 14 carbon atoms” and “lower alkoxy group having 14 carbon atoms” means, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Linear or branched hydrocarbons having 14 carbon atoms are mentioned.
  • optionally substituted phenyl group refers to a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a trifluoromethyl group, a carbon atom number of 1 to 4 at any position on a benzene ring.
  • a group having an aralkyloxy group, a phenoxy group, a phenethyl group, a styryl group, a phenylethynyl group, and a cyclohexylmethyloxy group which may be substituted by
  • the “aralkyl group” in the “aralkyl group” and the “aralkyl group” is a benzyl group or a diphenyl group.
  • Examples include a methyl group, a phenethyl group and a phenylpropyl group.
  • the "lower aliphatic acetyl group having 115 carbon atoms" is, for example, a straight or branched chain such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, and a vivaloyl group.
  • lower aliphatic acetyl groups having 115 carbon atoms is, for example, a straight or branched chain such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, and a vivaloyl group.
  • lower aliphatic acetyl groups having 115 carbon atoms is, for example, a
  • a lower alkyl group having 1 to 4 carbon atoms which may have a substituent and "an alkyl group having 1 to 10 carbon atoms which may have a substituent” are defined on a branched or straight carbon chain. And those having a hydroxy group, a lower alkoxy group having 14 to 14 carbon atoms, a lower alkylsulfur group having 14 to 14 carbon atoms, a halogen atom, a phenyl group and a phenoxy group.
  • the "lower alkenyl group having 2 to 4 carbon atoms” is, for example, a butyl group, an aryl group, a 1-probeyl group, an isopropyl group, a 1-butyl group, a 2-butenyl group, a 2-methylaryl group, Examples thereof include C2-C4 hydrocarbons having an unsaturated double bond such as a 3-butenyl group.
  • the “lower alkyl group having 2 to 4 carbon atoms” is, for example, an ethyl group, a 1-propyl group, a 2-propyl group, a 1-butyl group, a 2-butyl group, a 3-alkyl group. Examples thereof include C 2-4 hydrocarbons having an unsaturated triple bond such as a butynyl group.
  • Y is (CH 2), and R is carbon
  • Boc represents a t-butoxycarbol group
  • R, R, R, R, R, X and m are as defined above.
  • A represents a chlorine atom, a bromine atom, or an iodine atom
  • R, R, X, and m are as described above.
  • reaction solvent methanol, ethanol, 1,4-dioxane, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), or the like is used as a reaction solvent, and sodium hydride, potassium hydride,
  • the reaction can be carried out in the presence of an inorganic base such as sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate and the like, at a reaction temperature of 0 ° C. and under reflux with heating.
  • the reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. And a reaction temperature of 0 ° C-room temperature.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • a reaction temperature 0 ° C-room temperature.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM
  • the reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
  • the compound represented by the general formula (3) can be produced by hydrolysis and then acid decomposition.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • the temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of
  • the reaction is an alkylborane such as borane (BH) or 9-borabicyclo [3.3.1] nonane (9BBN).
  • alkylborane such as borane (BH) or 9-borabicyclo [3.3.1] nonane (9BBN).
  • NaHH lithium aluminum hydride
  • LiAlH 3 lithium aluminum hydride
  • other metal hydride complexes preferably water
  • LiBH Lithium borohydride
  • the reaction can be carried out at a reaction temperature of o ° C-reflux with heating, preferably at normal temperature, using ethanol, methanol or the like.
  • a reaction temperature of o ° C-reflux with heating preferably at normal temperature, using ethanol, methanol or the like.
  • B represents a halogen atom, a methanesulfo-loxy group, a p-toluenesulfo-loxy group, and R, R, R, Boc, X and m are as described above]
  • the sulfonate is used at 0 ° C-80 ° C with paratoluenesulfonyl chloride or methanesulfonyl chloride in the presence of an organic base such as pyridine and triethylamine using a solvent such as methylene chloride, chloroform and benzene.
  • an organic base such as pyridine and triethylamine
  • a solvent such as methylene chloride, chloroform and benzene.
  • the reaction is carried out at room temperature to synthesize the corresponding sulfonic acid ester.
  • the compound is further reacted with sodium bromide, lithium bromide, sodium iodide, or potassium iodide using THF, acetonitrile, or preferably acetone as a reaction solvent, and heating at room temperature under reflux to produce a halogenated compound. You can do it.
  • Step 2-3 Can be produced by reacting the compound represented by the general formula (6) with NaCN or KCN (Step 2-3).
  • the reaction can be carried out at room temperature and at 100 ° C using THF, DMSO, DMF, or 1,4 dioxane as a solvent, optionally adding water.
  • the compound represented by the general formula (le) can be produced by hydrolyzing the compound represented by the general formula (7) (Step VI).
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • the reaction is carried out at 0 ° C while heating under reflux to hydrolyze the ester moiety, and then in an organic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or in methanol, ethanol,
  • organic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or in methanol, ethanol
  • the reaction is carried out in a mixed solution with an organic solvent such as THF, 1,4-dioxane and ethyl acetate, and the reaction can be carried out at 0 ° C.-normal temperature.
  • the compound represented by the general formula (1e) can also be produced by heating and refluxing the compound (7) in concentrated sulfuric acid or concentrated hydrochloric acid.
  • the reaction can be carried out by a commonly used method for converting an alcohol to an aldehyde.
  • a chromium oxide-pyridinium complex such as pyridinium chromate and pyridinium dichromate can be used.
  • DMSO oxidizers using various metal oxidizing agents such as manganese dioxide and various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC and sulfur trioxide-pyridine complex.
  • the compound represented by the general formula (If) in the synthesis route 3 can be produced by acid-decomposing the compound represented by the general formula (9) (Step 3-3).
  • the reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • the temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
  • the compound can also be produced by hydrolyzing the compound represented by the general formula (9) and then decomposing it with acid.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • the temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of
  • a compound having a lower alkyl group or a benzyl group ie, a compound represented by the general formula (lh):
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol, and THF.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol, and THF.
  • the reaction can be carried out in a solvent such as DMF, ethyl acetate or the like, at normal temperature and 100 ° C under hydrogen pressure at normal pressure and pressure.
  • magnesium can be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
  • the compound represented by the general formula (lh) in the synthesis route 4 can be produced by acid-decomposing the compound represented by the general formula (11) (Step 42).
  • the reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • the temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
  • the reaction is carried out with aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, etc.
  • aqueous sodium hydroxide aqueous potassium hydroxide, aqueous lithium hydroxide, etc.
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO, etc. are used as the reaction solvent at a reaction temperature of 0 ° C. while heating under reflux to hydrolyze the ester portion.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or mixed solutions with organic solvents such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate;
  • organic solvents such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate
  • Y is CH 2 OCH
  • R is the number of carbon atoms.
  • a compound which is a alkyl group or a benzyl group that is, a compound represented by the general formula (lj)
  • the reaction is carried out by using a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent, and using tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as butylammonium and tetrabenzylammonium bromide can be prepared at 0 ° C. to 80 ° C., preferably at room temperature.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent
  • tetrabutylammonium chloride, tetrabutylammonium bromide Quaternary ammonium salts such as butylam
  • the reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent.
  • the temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
  • the compound can also be produced by hydrolyzing the compound represented by the general formula (12) and then decomposing it with acid.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM Using F, DMSO, etc., at a reaction temperature of 0 ° C and heating under reflux to hydrolyze the ester moiety, and then inorganic or organic acids such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, etc.
  • the reaction can be carried out at 0 ° C-normal temperature by acting in a medium or a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate.
  • Y is CH 0 CHCO R and R is a low
  • the reaction can be carried out in the presence of rhodium acetate, using toluene, benzene, chloroform, and preferably methylene chloride as a solvent, at room temperature and under reflux with heating.
  • the compound represented by the general formula (11) can be produced by acid-decomposing the compound represented by the general formula (14) (Step 6-2).
  • the reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • Y is CH 0 CHCO R
  • R is a hydrogen atom
  • the reaction is performed in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide.
  • a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide.
  • the reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
  • reaction can also be produced by hydrolyzing the compound represented by the general formula (14) and then subjecting it to acid decomposition.
  • a base such as an aqueous sodium hydroxide solution, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • the temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of 0 ° C.-normal temperature.
  • an organic solvent such as 1,4-dioxane and ethyl acetate
  • R represents a lower alkoxycarbocarbo having 1 to 4 carbon atoms.
  • reaction methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like is used as a reaction solvent, and sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate, or the like is used.
  • the reaction can be carried out in the presence of an inorganic base at a reaction temperature of 0 ° C to reflux under heating, preferably at 80 ° C to 100 ° C.
  • the compound represented by the general formula (In) in the synthesis route 7 can be produced by acid-decomposing the compound represented by the general formula (16) (Step 7-2).
  • the reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • R is a carboxyl group
  • R is a hydrogen atom
  • Y is
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • the reaction solvent is methanol, ethanol, 1,4-dioxane, DM
  • the reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
  • the compound can also be produced by hydrolyzing the compound represented by the general formula (16) and then subjecting it to acid decomposition.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • the temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of
  • R is a hydroxymethyl group, and R is a group having 1 to 4 carbon atoms.
  • a compound wherein Y is (CH 2), that is, a lower alkyl group or a benzyl group, that is, a compound represented by the general formula (lp)
  • the reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiBH,
  • Metal hydride complex compounds such as LiAlH, preferably lithium aluminum tributoxy hydride (
  • the reaction can be carried out at a reaction temperature of o ° C-heating under reflux, preferably at room temperature, using phenol or the like.
  • the compound represented by the general formula (lp) can be produced by acid-decomposing the compound represented by the general formula (18) (Step 8-2).
  • the reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • R is a hydroxymethyl group
  • R is a hydrogen atom
  • Y is
  • the reaction is carried out with aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, etc.
  • a base methanol, ethanol, 1,4-dioxane, DMF DMSO, or the like is used as a reaction solvent, and the reaction can be carried out at 0 ° C. while heating under reflux.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide.
  • a base such as an aqueous sodium hydroxide solution, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, THF 1, 4 Dioxane, ethyl acetate
  • the reaction can be performed in a mixed solution with any organic solvent and at a reaction temperature of 0 ° C at room temperature.
  • the compound represented by the general formula (lp) can also be synthesized by the following synthesis route.
  • the reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiAlH
  • a metal-hydrogen complex compound such as 3244, preferably LiBH, is used.
  • the reaction can be carried out using oxane, ethanol, methanol, or the like, at a reaction temperature of o ° C under heating to reflux, preferably at room temperature.
  • a general hydroxy-protecting group such as an acetyl group or a benzoyl group is used, or a silyl-type protecting group such as a t-butyldimethylsilyl group or a t-butyldifluorosilyl group is used.
  • a general hydroxy-protecting group such as an acetyl group or a benzoyl group
  • a silyl-type protecting group such as a t-butyldimethylsilyl group or a t-butyldifluorosilyl group is used.
  • the reaction can be carried out at 0 ° C.-room temperature using acetone, DMF, methylene chloride, methylene chloride, ethyl acetate, acetic acid and the like as a reaction solvent.
  • a reaction solvent in the case of the protected acyl-type hydroxy, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like is used as a reaction solvent, and an aqueous solution of sodium hydroxide or potassium hydroxide is used.
  • the reaction can be carried out in the presence of a base such as lithium hydroxide at a reaction temperature of 0 ° C.-normal temperature.
  • THF, DMF, 1,4-dioxane or the like is used as a solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium-dimethyl fluoride is allowed to act at 0 ° C.-room temperature.
  • It can be manufactured by acid decomposition.
  • the reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate.
  • the reaction can be performed at a reaction temperature of 0 ° C-room temperature.
  • the reaction is carried out using potassium permanganate, lead tetraacetate, ruthenium tetroxide, preferably chromium oxide pyridine complex chromium oxide such as pyridinium chromate and pyridinium dichromate as an oxidizing agent.
  • the reaction can be carried out using acetone, DMF, methylene chloride, chloroform, ethyl acetate, acetic acid, etc., at 0 ° C. and room temperature.
  • the compound represented by the general formula (lr) can be produced by acid-decomposing the compound represented by the general formula (20) (Step 10-2).
  • the reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. And a reaction temperature of 0 ° C-room temperature.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • a reaction temperature 0 ° C-room temperature.
  • R is a hydroxymethyl group
  • R is a hydrogen atom
  • Y is
  • the reaction is carried out in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium butoxide, potassium methoxide, potassium ethoxide, potassium butoxide, THF, 1,4-dioxane, Using DMF, benzene, and toluene as reaction solvents, the reaction can be carried out at 0 ° C.-with heating under reflux, preferably at room temperature. In addition, it is preferable to carry out the reaction in a pyridine solvent with paratoluenesulfuric acid lid under reflux with heating, preferably at 80 ° C to 100 ° C.
  • halogenation in the case of halogenation, in the case of halogenation, in the presence of triphenylphosphine and imidazole, methylene chloride, THF, and 1,4-dioxane are used as reaction solvents, and carbon tetrachloride and tetraodor are used at 0 ° C to room temperature. It can be produced by reacting carbon fluoride or iodine.
  • the sulfonic acid ester is prepared by using a solvent such as methylene chloride, chloroform and benzene in the presence of an organic base such as pyridine or triethylamine in the presence of paratoluenesulfonyl chloride or methanesulfonate.
  • the corresponding sulfonic acid ester can be synthesized by reacting with honyl chloride at 0 ° C. to 80 ° C., preferably at room temperature. This compound is further reacted with sodium bromide, lithium bromide, sodium iodide or potassium iodide using THF, acetonitrile, or preferably acetone as a reaction solvent, and heating and refluxing at room temperature to produce a halogenated compound. You can do it.
  • reaction can be carried out at room temperature and 100 ° C using THF, DMSO, DMF, or 1,4 dioxane as a solvent, optionally adding water.
  • the compound represented by the general formula (Is) can be produced by hydrolyzing the compound represented by the general formula (24) (step 11-4).
  • the reaction is carried out in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide in the absence of a solvent or, in some cases, methanol, ethanol, 1,4-dioxane, DMSO, or the like, as a reaction solvent. And the reaction is preferably carried out under heating to reflux.
  • a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide in the absence of a solvent or, in some cases, methanol, ethanol, 1,4-dioxane, DMSO, or the like.
  • R is a lower alkyl group having 1 to 4 carbon atoms or a benzyl group
  • R represents a hydrogen atom or a lower alkyl group having 14 carbon atoms
  • R R R R X represents a hydrogen atom or a lower alkyl group having 14 carbon atoms
  • R is a t-butyldimesylsilyl group, a t-butyldiphenylsilyl group, a methoxymethyl
  • the corresponding silyl chloride can be allowed to act at 0 ° C. and room temperature in the presence of an organic base such as triethylamine, pyridin and diisopropylethylamine using setonitrile, methylene chloride, preferably DMF as a solvent.
  • an organic base such as triethylamine, pyridin and diisopropylethylamine using setonitrile, methylene chloride, preferably DMF as a solvent.
  • an organic base such as triethylamine, pyridine or diisopropylethylamine.
  • the corresponding acid halide or alklyhalide can act.
  • a commonly used method for converting alcohol to aldehyde can be used.
  • a chromium oxide pyridin complex such as pyridinium chromate and pyridinium dichromate, chromium oxide, silver carbonate, manganese dioxide, and the like can be used.
  • DMSO using various metal oxidizing agents or various DMS O activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, and sulfur trioxide-pyridine complex.
  • the compound represented by the general formula (It) can be produced by acid-decomposing the compound represented by the general formula (27) (Step 12-4).
  • R is a methoxymethyl group
  • acetic acid hydrochloric acid, hydrobromic acid, methanesulfonic acid
  • a method which can be carried out by the above-described acid decomposition method is more preferably a method of reacting tetrabutylammonium-dimethyl fluoride, KF, and CsF with THF as a solvent at 0 ° C.-normal temperature, followed by acid decomposition.
  • the compound represented by the general formula (it) can be produced by hydrolyzing the compound represented by the general formula (it).
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • the temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
  • the compound can also be produced by hydrolyzing the compound represented by the general formula (27) and then subjecting it to acid decomposition.
  • the reaction is carried out in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide
  • the temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at
  • R 44 is a lower alkoxymethyl group
  • R is a lower alkyl group or a benzyl group having 14 carbon atoms
  • Y is
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure. It can also be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc.
  • R is a methoxymethyl group, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid,
  • a silyl group it is also possible to carry out the acid decomposition method described above. More preferably, a method is used in which THF is used as a solvent to react with tetrabutylammonium-dimethyl fluoride, KF, and CsF at 0 ° C.-room temperature and then acid decomposition is performed. .
  • the compound represented by the general formula (lv) can also be produced by reducing the compound represented by the general formula (It) (step 13-3).
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol, and THF. , DMF, ethyl acetate, etc., at a normal temperature and 100 ° C. under a hydrogen pressure under normal pressure and pressure. It can also be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol, and THF. , DMF, ethyl acetate, etc.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent.
  • the temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
  • the compound represented by the general formula (lv) can also be produced by hydrolyzing the compound represented by the general formula (29) followed by acid decomposition.
  • R is a t-butyldimethylsilyl group or a t-butyldifluorosilyl group
  • THF is used as a solvent.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous hydroxide solution of lithium, or an aqueous solution of lithium hydroxide.
  • a base such as an aqueous sodium hydroxide solution, an aqueous hydroxide solution of lithium, or an aqueous solution of lithium hydroxide.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in methanol, ethanol, THF 1,4-dioxane, or acetic acid.
  • the reaction can be carried out in a mixed solution with an organic solvent such as ethyl, at a reaction temperature of 0 ° C. at room temperature.
  • R is a lower alkyl group having 14 carbon atoms or a benzyl group
  • Y is
  • the reaction is performed using a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent, and using tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as butylammonium and tetrabenzylammonium bromide can be prepared in a catalytic amount at 0 ° C. to 80 ° C., preferably at room temperature.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent
  • tetrabutylammonium chloride, tetrabutylammonium bromide Quaternary ammonium salts such
  • the compound represented by the general formula (lx) in the synthesis route 14 can be produced by acid-decomposing the compound represented by the general formula (30) (Step 142).
  • R is a methoxymethyl group, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid,
  • a silyl group it is also possible to carry out the acid decomposition method described above. More preferably, a method is used in which THF is used as a solvent to react with tetrabutylammonium-dimethyl fluoride, KF, and CsF at 0 ° C.-room temperature and then acid decomposition is performed. .
  • R represents a hydroxymethyl group
  • R is a hydrogen atom and Y is CH 2 OCH
  • the compound represented by the general formula (1x) can be produced by hydrolyzing the compound represented by the general formula (lx).
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM
  • the reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
  • the compound can also be produced by hydrolyzing the compound represented by the general formula (30) and then subjecting it to acid decomposition.
  • reaction temperature is 0.
  • a base such as an aqueous sodium hydroxide solution, an aqueous hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent, and the reaction temperature is 0.
  • R is carbon number 1
  • the reaction is performed using a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent, using tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as tetrabutylammonium amide and tetrabenzylammonium bromide can be prepared in catalytic amounts at 0 ° C to 80 ° C, preferably at room temperature. it can.
  • the compound represented by the general formula (lz) can be produced by acid-decomposing the compound represented by the general formula (31) (Step 15-2).
  • the reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid
  • organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate.
  • R is a hydrogen atom
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • the reaction can be carried out at a temperature of 0 ° C. while heating under reflux.
  • the compound can also be produced by hydrolyzing the compound represented by the general formula (31) and then decomposing it with acid.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM Using F, DMSO, etc., at a reaction temperature of 0 ° C and heating under reflux to hydrolyze the ester moiety, and then inorganic or organic acids such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, etc.
  • the reaction can be carried out at 0 ° C-normal temperature by acting in a medium or a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate.
  • R is a hydrogen atom
  • Y is (CH)
  • R is a hydrogen atom
  • reaction solvents methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF and the like are used as reaction solvents, and sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate and the like are used.
  • the reaction can be carried out in the presence of an inorganic base at a reaction temperature of 0 ° C to reflux under heating, preferably at 80 ° C to 100 ° C.
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent.
  • the temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
  • potassium hydroxide is allowed to act at 50 ° C. in an ethanol solvent.
  • R represents a lower alkyl group having 14 to 14 carbon atoms
  • R, R, R, R, X, and m are as defined above. Street
  • a general method for converting a carboxyl group into olebamate can be used.
  • DPPA DPPA
  • a benzene or toluene solvent in the presence of a base such as triethylamine, and then added with a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol to continue heating and stirring.
  • a base such as triethylamine
  • a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol
  • the reaction can be carried out under heating and stirring, preferably under heating to reflux, using only lower alcohol as a reaction solvent.
  • the reaction is carried out using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • the temperature is 0 ° C—under reflux with heating, preferably 80. C-1 100.
  • R is a hydrogen atom
  • R is a hydrogen atom
  • the reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiAlH
  • a metal-hydrogen complex compound such as 3244, preferably LiBH, is used.
  • the reaction can be carried out using oxane, ethanol, methanol, or the like, at a reaction temperature of o ° C under heating to reflux, preferably at room temperature.
  • the reaction can be carried out using a commonly used method for converting alcohol to aldehyde.
  • chromium pyridinium complexes such as pyridinium chromate and pyridinium dichromate
  • metal oxidants such as chromium oxide, silver carbonate and manganese dioxide, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, sulfur trioxide-
  • Examples include DMSO oxidation using various DMS O activators such as pyridine complexes.
  • the compound represented by the general formula (1C) can be produced by hydrolyzing the compound represented by the general formula (38) (step 17-4).
  • the reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent, and the reaction temperature.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution
  • methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent
  • R is a hydrogen atom
  • R is a hydrogen atom
  • Y is (CH).
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure.
  • magnesium It can also be produced by operating at o ° c-room temperature in a furnace.
  • the compound represented by the general formula (1D) can be produced by hydrolyzing the compound represented by the general formula (39) (step 18-2).
  • the reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • the temperature is 0 ° C-under heating reflux, preferably
  • the compound can also be produced by reducing the compound represented by the general formula (1C) (Step 18-3).
  • the reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure. It can also be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
  • a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc.
  • R is a hydrogen atom
  • R is a hydrogen atom
  • Y is (CH 2)
  • the reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiBH,
  • Metal hydride complex compounds such as LiAlH, preferably lithium aluminum tributoxy hydride (
  • the reaction can be carried out at a reaction temperature of o ° C-heating under reflux, preferably at room temperature, using phenol or the like.
  • halogenation in the case of halogenation, methyl tetrachloride, THF, and 1,4-dioxane are used as reaction solvents in the presence of triphenylphosphine and imidazole, and carbon tetrachloride and tetraodor are used at 0 ° C to room temperature. It can be produced by reacting carbon fluoride or iodine.
  • the sulfonate is used at 0 ° C-80 ° C with paratoluenesulfonyl chloride or methanesulfonyl chloride in the presence of an organic base such as pyridine and triethylamine using a solvent such as methylene chloride, chloroform and benzene.
  • an organic base such as pyridine and triethylamine
  • a solvent such as methylene chloride, chloroform and benzene.
  • the reaction is carried out at room temperature to synthesize the corresponding sulfonic acid ester.
  • the compound is further reacted with sodium bromide, lithium bromide, sodium iodide, or potassium iodide using THF, acetonitrile, or preferably acetone as a reaction solvent, and heating at room temperature under reflux to produce a halogenated compound. You can do it.
  • reaction can be carried out at room temperature and 100 ° C using THF, DMSO, DMF, or 1,4-dioxane as a solvent, optionally adding water.
  • THF tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • DMF dimethyl sulfoxide
  • 1,4-dioxane 1,4-dioxane
  • the reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • the reaction can be performed at a temperature of 0 ° C with heating under reflux.
  • a general method for converting a carboxyl group into olebamate can be used.
  • DPPA DPPA
  • a benzene or toluene solvent in the presence of a base such as triethylamine, and then added with a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol to continue heating and stirring.
  • a base such as triethylamine
  • a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol
  • the reaction can be carried out under heating and stirring, preferably under heating to reflux, using only lower alcohol as a reaction solvent.
  • the compound represented by the above general formula (1E) in the synthesis route 19 is represented by the above general formula (44) Can be produced by hydrolyzing the compound (Step 19-6).
  • the reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution.
  • the temperature is 0 ° C-under heating reflux, preferably
  • a compound in which X is SO or SO in each of the general formulas is a compound in which the corresponding X is S.
  • reaction was performed using 1,4-dioxane, DMSO, DMF, THF, methylene chloride, chloroform, etc. as the reaction solvent, and using potassium permanganate, metaclo-peroxybenzoic acid, and hydrogen peroxide as the oxidizing agent.
  • the reaction can be carried out at 0 ° C.—with heating under reflux, preferably at room temperature.
  • the target product was obtained as a colorless oily substance in the same manner as in Reference Example 58 using 3-benzyloxyphenol-boric acid and 2-fluoro-4-hydroxybenzaldehyde.
  • the obtained powder was dissolved in DMF (50 mL), potassium carbonate (1.04 g) and benzyl bromide (0.602 mL) were added, and the mixture was stirred at room temperature for 8 hours.
  • the reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain the target substance as a brown oil.

Abstract

An aminocarboxylic acid derivative represented by the general formula (1) (example: 3-amino-6-[4-(3-benzyloxyphenylsulfanyl)-2-chlorophenyl]-3-hydroxymethylhexanoic acid). It is highly effective in controlling a sphingosine-1-phosphoric acid (S1P) receptor.

Description

明 細 書  Specification
アミノカルボン酸誘導体とその付加塩及び S IP受容体調節剤  Aminocarboxylic acid derivatives and their addition salts and SIP receptor modulators
技術分野  Technical field
[0001] 本発明は、 S1P (スフインゴシン- 1-リン酸)受容体調節剤として有用なァミノカルボ ン酸誘導体とその付加塩並びにその水和物に関する。  The present invention relates to an amino carbonate derivative, an addition salt thereof, and a hydrate thereof useful as an S1P (sphingosine-1-phosphate) receptor modulator.
背景技術  Background art
[0002] 1—リン酸 (以下 S1Pと略記）は、スフインゴシン代謝における中間代 謝物にすぎないとみなされていたが、細胞増殖促進作用や細胞運動機能の制御作 用を有することが報告されるに至り、アポトーシス作用、細胞形態調節作用、血管収 縮などの多彩な生理作用を発揮する新しい脂質メディエーターであることが明らかと なってきている (非特許文献 1、非特許文献 2)。この脂質は細胞内セカンドメッセンジ ヤーとしての作用と、細胞間メディエーターとしての二つの作用を併せ持つ力 特に 細胞間メディエーターとして作用に関する研究が活発に行なわれており、細胞膜表 面上に存在する複数の G蛋白質共役型受容体 (Endothelial [0002] 1-phosphate (hereinafter abbreviated as S1P) was considered to be only an intermediate metabolite in sphingosine metabolism, but has been reported to have a cell growth promoting action and a control action on cell motility. As a result, it has been clarified that it is a novel lipid mediator that exerts various physiological actions such as apoptosis action, cell morphology regulation action, and vascular contraction (Non-Patent Documents 1 and 2). This lipid has both the action of an intracellular second messenger and the action of an intercellular mediator. In particular, studies on the action of this lipid as an intercellular mediator have been actively conducted, and multiple lipids existing on the cell membrane surface have been studied. Protein-coupled receptor (Endothelial
ifferentiation Gene, EDG)を介して情報伝達がなされていることが報告されている（ 非特許文献 1、非特許文献 3)。現在 S1P受容体には Edg-1、 Edg-3、 Edg-5、 Edg-6 及び Edg-8の 5つのサブタイプが知られており、各々 SIP、 SIP、 SIP、 SIP、 S1Pとも  It has been reported that information is transmitted via ifferentiation gene (EDG) (Non-Patent Document 1, Non-Patent Document 3). At present, five subtypes of Edg-1, Edg-3, Edg-5, Edg-6 and Edg-8 are known as S1P receptors, and SIP, SIP, SIP, SIP and S1P are each
1 3 2 4 5 呼ばれている。  1 3 2 4 5 is called.
[0003] これら S1P受容体に対する様々な研究から、この受容体へのァゴニスト活性あるい はアンタゴ-スト活性を示す、いわゆる S1P受容体調節剤が多岐にわたる疾患に対 し有効性を発揮する報告がなされるようになった。例えば Edg-5に作用する化合物が 動脈硬化症、腎線維症、肺線維症、肝線維症に有効であることが（特許文献 1)に開 示されている。又、 Edg-1、 Edg-3又は Edg-5へ作用する化合物が、慢性気管支喘息 、びまん性過誤腫性肺脈管筋腫症、成人呼吸促迫症候群 (ARDS)、慢性閉塞性肺 疾患 (COPD)、間質性肺炎、特発性間質性肺炎、肺癌、過敏性肺臓炎などの呼吸 器疾患の治療及び予防剤として有効であることが (特許文献 2)に開示されている。さ らに Edg-1ァゴニスト作用を有する化合物が閉塞性動脈硬化症、閉塞性血栓血管炎 、バージャ一病、糖尿病性-ュロバチ一の末梢動脈疾患、敗血症、血管炎、腎炎、 肺炎、脳梗塞、心筋梗塞症、浮腫性疾患、動脈硬化症、痔核、裂肛、痔ろうなどの静 脈瘤、解離性大動脈瘤、狭心症、 DIC、胸膜炎、うつ血性心不全、多臓器不全、とこ ずれ、火傷、潰瘍性大腸炎、クローン病、心移植、腎移植、皮膚移植、肝移植、骨髄 移植、骨粗しょう、慢性肝炎、肝硬変、慢性腎不全、腎糸球体硬化症の治療及び予 防剤として有効であることが（特許文献 3)に開示されている。さらに、 S1P受容体ァゴ 二スト活性を有する化合物が白血球の遊走を調節することが (非特許文献 4、非特許 文献 5)に報告され、又前述の非特許文献に紹介された一連の誘導体が各種臓器移 植、 GVHDに対する有効性以外に関節リウマチ、ループス腎炎、全身性エリテマトー デス、橋本病、多発性硬化症、重症筋無力症、 I及び Π型糖尿病、クローン病などの 自己免疫疾患、アトピー性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎、アレル ギー性接触皮膚炎などのアレルギー性疾患、炎症性腸疾患、潰瘍性大腸炎などの 炎症性疾患に有効であることが (特許文献 4、特許文献 5)に開示されている。又、上 記 (特許文献 4)ならびに (特許文献 5)に類似したリン酸誘導体が S 1P受容体拮抗薬 として (特許文献 6)にも開示されている。その他、（特許文献 7)、（特許文献 8)、（特 許文献 9)及び (特許文献 10)といった特許文献にも S1P受容体調節剤が開示され ている。 [0003] From various studies on these S1P receptors, there have been reports that so-called S1P receptor modulators exhibiting agonist activity or antagonist activity at this receptor exhibit efficacy against a wide variety of diseases. It has been done. For example, it has been disclosed in Patent Document 1 that a compound acting on Edg-5 is effective for arteriosclerosis, renal fibrosis, pulmonary fibrosis, and hepatic fibrosis. Compounds acting on Edg-1, Edg-3 or Edg-5 may cause chronic bronchial asthma, diffuse hamartomatous pulmonary angiomyomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) Patent Document 2 discloses that it is effective as an agent for treating and preventing respiratory diseases such as interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, and irritable pneumonitis. In addition, compounds with Edg-1 agonist action are used for obstructive atherosclerosis and obstructive thromboangiitis Venous aneurysm such as, Baja disease, diabetic-urovicular peripheral artery disease, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema disease, arteriosclerosis, hemorrhoids, anal fissure, hemorrhoids, etc. , Dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, heart failure, burns, ulcerative colitis, Crohn's disease, heart transplant, kidney transplant, skin transplant, liver transplant, bone marrow transplant, It is disclosed in Patent Document 3 as being effective as a therapeutic and prophylactic agent for osteoporosis, chronic hepatitis, cirrhosis, chronic renal failure, and glomerulosclerosis. Furthermore, it has been reported that compounds having S1P receptor agonist activity regulate leukocyte migration (Non-patent Document 4, Non-patent Document 5), and a series of derivatives introduced in the aforementioned Non-patent Documents. However, besides the efficacy against various organ transplantation and GVHD, autoimmune diseases such as rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, myasthenia gravis, I and type II diabetes, Crohn's disease, etc. It is effective for allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, inflammatory diseases such as inflammatory bowel disease and ulcerative colitis (Patent Document 4, It is disclosed in Patent Document 5). Further, a phosphate derivative similar to the above (Patent Document 4) and (Patent Document 5) is also disclosed as an S1P receptor antagonist (Patent Document 6). In addition, patent documents such as (Patent Document 7), (Patent Document 8), (Patent Document 9) and (Patent Document 10) also disclose S1P receptor modulators.
[0004] 本発明者らは様々な疾患に関与する S1P受容体に対して調節作用を有する化合 物の開発を目的に鋭意研究を行った結果、従来の化合物とは構造を事にするアミノ カルボン酸誘導体に着目し、新しいタイプの S1P受容体調節剤の探索を行った。な お、ごく最近になってァミノ基とカルボン酸ユニットを同時に有する化合物が S1P受 容体ァゴニストとして (特許文献 11)、（特許文献 12)及び (特許文献 13)に開示され たが、これらはアミノ基を連結鎖内に組み込んだ構造を特徴としており、アミノ基を連 結鎖上に導入した ex アミノ酸、 β アミノ酸、又は γ アミノ酸構造を特徴とする本願 の化合物とは構造を異にするものである。  [0004] The present inventors have conducted intensive studies with the aim of developing a compound having a modulating effect on S1P receptors involved in various diseases. We focused on acid derivatives and searched for a new type of S1P receptor modulator. Most recently, compounds having both an amino group and a carboxylic acid unit have been disclosed as S1P receptor agonists in (Patent Documents 11), (Patent Documents 12) and (Patent Documents 13). It is characterized by a structure in which a group is incorporated in the linking chain, and has a different structure from the compound of the present application, which is characterized by an ex amino acid, β amino acid, or γ amino acid structure in which an amino group is introduced on the linking chain. is there.
[0005] 特許文献 1： WO0198301号パンフレット  [0005] Patent Document 1: WO0198301 pamphlet
特許文献 2： WO03020313号パンフレツ卜  Patent Document 2: WO03020313 Breadfruit
特許文献 3： WO02092068吾パンフレツ卜 特許文献 4 :WO0218395号パンフレット Patent Literature 3: WO02092068 Go broth Patent document 4: pamphlet of WO0218395
特許文献 5： WO02076995号パンフレツ卜  Patent Document 5: WO02076995 pamphlet
特許文献 6：特開 2003— 137894号公報  Patent Document 6: JP-A-2003-137894
特許文献 7 :WO03040097号パンフレツ卜  Patent Document 7: WO03040097 Breadfruit
特許文献 8： WO02064616号パンフレット  Patent Document 8: WO02064616 pamphlet
特許文献 9 :WO02062389号パンフレツ卜  Patent Document 9: WO02062389 No.
特許文献 10 :WO03051876号パンフレット  Patent Document 10: WO03051876 pamphlet
特許文献 11 :WO03061567号パンフレツ卜  Patent Document 11: WO03061567 Breadfruit
特許文献 12： WO03062248号パンフレット  Patent Document 12: WO03062248 pamphlet
特許文献 13： WO03062252号パンフレツ卜  Patent Document 13: WO03062252 Breadfruit
非特許文献 l :Y.Takuma et al., Mol. Cell. Endocrinol, 177, 3(2001)  Non-patent literature l: Y.Takuma et al., Mol.Cell.Endocrinol, 177, 3 (2001)
非特許文献 2 : Y. Igarashi, Ann, N.Y. Acad. Sci., 845, 19(1998)  Non-Patent Document 2: Y.Igarashi, Ann, N.Y.Acad.Sci., 845, 19 (1998)
非特許文献 3 : H. Okazaki et al., Biochem. Biophs. Res. Commun., 190, 1104(1993) 非特許文献 4 : S. Mandala et al., Science, 296, 346(2002)  Non-Patent Document 3: H. Okazaki et al., Biochem.Biophs. Res.Commun., 190, 1104 (1993) Non-Patent Document 4: S. Mandala et al., Science, 296, 346 (2002)
非特許文献 5 : V. Brinkmann et al., J. Biol. Chem., 277, 21453(2002)  Non-Patent Document 5: V. Brinkmann et al., J. Biol. Chem., 277, 21453 (2002)
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0006] 本発明が解決しょうとする課題は、 S1P受容体に対し優れた調節作用を有し、かつ 副作用の少ないアミノカルボン酸誘導体を提供することにある。 [0006] The problem to be solved by the present invention is to provide an aminocarboxylic acid derivative which has an excellent regulatory effect on S1P receptors and has few side effects.
課題を解決するための手段  Means for solving the problem
[0007] 本発明者らは、 S1P受容体調節作用を有し、かつ安全性の高い化合物を創製す ベく鋭意研究を重ねた結果、これまでに知られている S1P受容体調節剤とは構造を 異にした新規なアミノカルボン酸誘導体が強力な S1P受容体調節作用を有すること を見出し、本発明を完成した。 [0007] The present inventors have conducted intensive studies to create a compound having S1P receptor modulatory activity and high safety. The present inventors have found that a novel aminocarboxylic acid derivative having a different structure has a potent S1P receptor regulating action, and completed the present invention.
[0008] 即ち、本発明は [0008] That is, the present invention
1) 一般式 (1) [0009] [化 1]
Figure imgf000005_0001
1) General formula (1) [0009] [Formula 1]
Figure imgf000005_0001
[0010] [式中、 Rは置換基を有しても良いフエニル基又は置換基を有しても良い炭素数 1 [Wherein, R is a phenyl group which may have a substituent or a carbon atom which may have a substituent 1
1 一 1 one
10のアルキル基を、 10 alkyl groups,
Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素数 1  R is a hydrogen atom, halogen atom, torino, lomethyl group, carbon number 1
2 一 4の低級アルキル基又 は炭素数 1一 4の低級アルコキシ基を、 Rは水素原子、炭素数 1  2-4 lower alkyl groups or C1-C4 lower alkoxy groups, R is hydrogen atom, C1
3 一 4の低級アルキル 基又はフエニル基を、  (3) a lower alkyl group or a phenyl group,
Rは水素原子、置換基を有しても良い炭素数 1一 4の低級アルキル基、炭素数 2— 4 R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent, and 2 to 4 carbon atoms;
4 Four
の低級アルケニル基、炭素数 2— 4の低級アルキニル基、カルボキシル基、炭素数 1 一 4の低級アルコキシカルボ-ル基、ベンジルォキシカルボ-ル基、 CH OCH CO H  A lower alkenyl group, a lower alkynyl group having 2 to 4 carbon atoms, a carboxyl group, a lower alkoxycarbol group having 14 to 14 carbon atoms, a benzyloxycarbol group, CH OCH CO H
2 2 2 又は CH OCH CO R (Rは炭素数 1  2 2 2 or CH OCH CO R (R is carbon number 1
2 2 2 6 6 一 4の低級アルキル基又はべンジル基)を、 2 2 2 6 6 14 lower alkyl group or benzyl group),
Rは水素原子、炭素数 1一 4の低級アルキル基又はベンジル基を、 R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group,
5  Five
Xは 0、 S、 SO、 SO  X is 0, S, SO, SO
2、 NH又は CHを、  2, NH or CH,
2  2
mは 2 4の整数を、  m is an integer of 24,
Yは CH=CHゝ CH OCH CH は 0 2の整数）又は CH 0CHCO Rを示す]  Y is CH = CH ゝ CH OCH CH is an integer of 0 2) or CH 0CHCO R]
2 2、（ ) n (n  2 2, () n (n
2 2 2 5 で表されることを特徴とするアミノカルボン酸誘導体、その光学異性体及び薬理学的 に許容しうる塩並びにその水和物、  Aminocarboxylic acid derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof,
[0011] 2)前記一般式（1)で表される化合物が、一般式（la) [0011] 2) The compound represented by the general formula (1) is represented by the general formula (la)
[0012] [化 2]
Figure imgf000005_0002
[0012] [Formula 2]
Figure imgf000005_0002
[0013] [式中、 X、 Y、 R、 R及び mは前記定義に同じ]  [Wherein, X, Y, R, R and m are the same as defined above]
2 4  twenty four
で表される化合物であることを特徴とする 1)に記載のアミノカルボン酸誘導体、その 光学異性体及び薬理学的に許容しうる塩並びにその水和物、  The aminocarboxylic acid derivative according to 1), which is a compound represented by the formula, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof,
[0014] 3)前記一般式（la)において Rが塩素原子であることを特徴とする 2)に記載のァミノ [0014] 3) The amino according to 2), wherein R in the general formula (la) is a chlorine atom.
2 カルボン酸誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和 物、 2 Carboxylic acid derivatives, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof,
[0015] 4)前記一般式（1)で表される化合物が、一般式（lb)  4) The compound represented by the general formula (1) is a compound represented by the general formula (lb)
[0016] [化 3] [0016] [Formula 3]
(1 b)(1 b)
Figure imgf000006_0001
Figure imgf000006_0001
[0017] [式中、 pは 5— 10の整数示し、 X、 Y、 R 、 R及び mは前記定義に同じ] [0017] [wherein, p is an integer of 5-10, and X, Y, R, R and m are the same as defined above]
2 4  twenty four
で表される化合物であることを特徴とする 1)に記載のアミノカルボン酸誘導体、その 光学異性体及び薬理学的に許容しうる塩並びにその水和物、  The aminocarboxylic acid derivative according to 1), which is a compound represented by the formula, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof,
[0018] 5)前記一般式（lb)において Rが塩素原子であることを特徴とする 4)に記載のァミノ [0018] 5) The amino according to 4), wherein R in the general formula (lb) is a chlorine atom.
2  2
アルコール誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水和 物。  Alcohol derivatives, optical isomers and pharmacologically acceptable salts thereof, and hydrates thereof.
[0019] 6) 前記一般式（1)で示される化合物が、  6) The compound represented by the general formula (1) is
3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3— ヒドロキシメチルへキサン酸、  3-amino-6- [4- (3-benzyloxyphenylsulfur-)-2-chlorophenol] -3-hydroxymethylhexanoic acid,
3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3— ヒドロキシプロピルへキサン酸、  3-amino-6- [4- (3-benzyloxyphenylsulfur) -2-cyclobutane] -3-hydroxypropylhexanoic acid,
3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3— プロピルへキサン酸、  3-Amino-6- [4— (3-Benzyloxyphenyl-sulfur-yl) -2-cyclobutane] -3-3-Propylhexanoic acid,
3—ァリルー 3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロロフ ェ -ル]へキサン酸、  3-arylu 3-amino-6- [4- (3-benzyloxyphenylsulfur) -2-chlorophenol] hexanoic acid,
3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3— ヒドロキシメチルペンタン酸、  3-amino-5- [4- (3-benzyloxyphenylsulfur-)-2-chlorophenol] -3-hydroxymethylpentanoic acid,
3—ァミノ— 5— [4— (4—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ二ル]— 3— ヒドロキシメチルペンタン酸、  3-amino-5- [4- (4-benzyloxyphenyl-sulfur-yl) -2-chlorophenol] -3-hydroxymethylpentanoic acid,
3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3— ヒドロキシプロピルペンタン酸、 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル） 2 クロ口フエ-ル]— 3— プロピノレペンタン酸、 3-Amino-5- [4- (3-Benzyroxyphenyl-sulfur-yl) -2-chlorophenol] -3-Hydroxypropylpentanoic acid, 3—amino—5— [4— (3-benzyloxyphenol-sulfur-yl) 2-chlorophenol] —3-propinolepentanoic acid,
3—ァリルー 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロロフ ェ -ル]ペンタン酸又は 2—ァミノ— 2 プロピル [4— (3—ベンジルォキシフエ-ルスル ファ -ル) 2—クロロフヱ-ル] 酪酸である 1)に記載のアミノカルボン酸誘導体及び 薬理学的に許容しうる塩並びにその水和物、  3-arylu-3-amino-5- [4- (3-benzyloxyphenyl-sulfur-)-2-chlorophenyl] pentanoic acid or 2-amino-2-propyl [4- (3-benzyloxy-) Rusulfur-) 2-chlorophenyl] butyric acid, the aminocarboxylic acid derivative according to 1), a pharmaceutically acceptable salt thereof and a hydrate thereof,
[0020] 7) 一般式（1)  [0020] 7) General formula (1)
[0021] [化 4]
Figure imgf000007_0001
[0021] [Formula 4]
Figure imgf000007_0001
[0022] [式中、 Rは置換基を有しても良いフエニル基又は置換基を有しても良い炭素数 1 [Wherein, R represents a phenyl group which may have a substituent or a carbon atom which may have a substituent;
1 一 1 one
10のアルキル基を、 10 alkyl groups,
Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素数 1一 4の低級アルキル基又 R represents a hydrogen atom, a halogen atom, a torino, a lomethyl group, a lower alkyl group having 14 to 14 carbon atoms or
2 2
は炭素数 1一 4の低級アルコキシ基を、  Represents a lower alkoxy group having 1 to 4 carbon atoms,
Rは水素原子、炭素数 1一 4の低級アルキル基又はフエ-ル基を、  R represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a phenyl group,
3  Three
Rは水素原子、置換基を有しても良い炭素数 1一 4の低級アルキル基、 2— 4の低級 R represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, and a lower alkyl group having 2 to 4 carbon atoms;
4 Four
ァルケ-ル基、炭素数 2— 4の低級アルキ-ル基、カルボキシル基、炭素数 1一 4の 低級アルコキシカルボ-ル基、ベンジルォキシカルボ-ル基、 CH OCH CO H又は  Alkenyl group, lower alkyl group having 2 to 4 carbon atoms, carboxyl group, lower alkoxycarbol group having 14 to 14 carbon atoms, benzyloxycarbol group, CH OCH COH or
2 2 2 2 2 2
CH OCH CO R (Rは炭素数 1 CH OCH CO R (R is carbon number 1
6 6 一 4の低級アルキル基又はべンジル基)を、  6 6-14 lower alkyl group or benzyl group)
2 2 2  2 2 2
Rは水素原子、炭素数 1一 4の低級アルキル基又はベンジル基を、  R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group,
5  Five
Xは 0、 S、 SO、 SO、 NH又は CHを、  X represents 0, S, SO, SO, NH or CH,
2 2  twenty two
mは 2 4の整数を、  m is an integer of 24,
Yは CH=CHゝ CH OCH、（CH ) n (nは 0 2の整数）又は CH 0CHCO Rを示す]  Y represents CH = CH ゝ CH OCH, (CH) n (n is an integer of 0 2) or CH 0CHCO R]
2 2 2 2 2 5 で表されることを特徴とするアミノカルボン酸誘導体、その光学異性体及び薬理学的 に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とする S1P受 容体調節剤、  An aminocarboxylic acid derivative represented by the formula (2), an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof, comprising at least one of the following: Conditioner,
[0023] 8)前記一般式（1)で示される化合物が、一般式（la) [0024] [化 5]
Figure imgf000008_0001
8) The compound represented by the general formula (1) is a compound represented by the general formula (la) [0024] [Formula 5]
Figure imgf000008_0001
[0025] [式中、 X、 Y、 R、 R及び mは前記定義に同じ]  [Wherein, X, Y, R, R and m are the same as defined above]
2 4  twenty four
で表されるアミノカルボン酸誘導体、その光学異性体及び薬理学的に許容しうる塩 並びにその水和物の少なくとも一種類以上を有効成分とすることを特徴とする 7)に 記載の S1P受容体調節剤、  The S1P receptor according to 7), wherein at least one of an aminocarboxylic acid derivative represented by the formula (I), an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof is used as an active ingredient: Regulator,
[0026] 9)前記一般式（1)で表される化合物が、一般式（lb)  9) The compound represented by the general formula (1) is represented by the general formula (lb)
[0027] [化 6] (1 b) [0027] [Formula 6] (1 b)
Figure imgf000008_0002
Figure imgf000008_0002
[0028] [式中、 pは 6— 10の整数を示し、 X、 Y、 R 及び mは前記定義に同じ]  [Wherein, p represents an integer of 6-10, and X, Y, R and m are as defined above]
2、 R  2, R
4  Four
で表されるアミノカルボン酸誘導体、その光学異性体及び薬理学的に許容しうる塩 並びにその水和物の少なくとも一種類以上を有効成分とすることを特徴とする 7)に 記載の S1P受容体調節剤、  The S1P receptor according to 7), wherein at least one of an aminocarboxylic acid derivative represented by the formula (I), an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof is used as an active ingredient: Regulator,
[0029] 10)上記 1)一 6)のいずれか 1項に記載されたァミノカルボン酸誘導体、その光学異 性体及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効 成分として含有する医薬、 [0029] 10) Effectively use at least one or more of the amino carboxylic acid derivatives, optical isomers, pharmacologically acceptable salts and hydrates thereof described in any one of 1) to 6) above. Medicines contained as ingredients,
に関するものである。  It is about.
発明の効果  The invention's effect
[0030] 上述のように、本発明は、新規なアミノカルボン酸誘導体とその付加塩が優れた S 1P 受容体調節作用を有することを見出したものである。このような S1P受容体調節作用 を有する化合物は、動脈硬化症、閉塞性動脈硬化症、閉塞性血栓血管炎、腎繊維 症、肝繊維症、慢性気管支喘息、びまん性過誤腫性肺脈管筋腫症、成人呼吸促迫 症候群 (ARDS)、慢性閉塞性肺疾患 (COPD)、間質性肺炎、特発性間質性肺炎、 肺癌、過敏性肺臓炎、バージャ一病、糖尿病性ニューロバチ一の末梢動脈疾患、敗 血症、血管炎、腎炎、肺炎、脳梗塞、心筋梗塞症、浮腫性疾患、静脈瘤、解離性大 動脈瘤、狭心症、 DIC、胸膜炎、うつ血性心不全、多臓器不全、とこずれ、火傷、潰 瘍性大腸炎、クローン病などの治療及び予防薬として、又、心移植、腎移植、皮膚移 植、肝移植、骨髄移植などの拒絶反応の予防又は治療薬、関節リウマチ、ループス 腎炎、全身性エリトマト一デス、橋本病、多発性硬化症、重症筋無力症、糖尿病、アト ピー性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎、アレルギー性接触皮膚炎 等の予防又は治療薬として有用である。 As described above, the present invention has found that a novel aminocarboxylic acid derivative and an addition salt thereof have an excellent S 1P receptor regulating action. Compounds having such S1P receptor modulatory activity include arteriosclerosis, obstructive arteriosclerosis, obstructive thromboangitis, renal fibrosis, hepatic fibrosis, chronic bronchial asthma, diffuse hamartomatous pulmonary angiomyoma. Disease, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, irritable pneumonitis, Bajaja disease, diabetic neurobati peripheral arterial disease , Defeat Blood, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema disease, varicose vein, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure, swelling, Drugs for treatment and prevention of ulcerative colitis, Crohn's disease, etc., and drugs for prevention or treatment of rejection such as heart transplant, kidney transplant, skin transplant, liver transplant, bone marrow transplant, rheumatoid arthritis, lupus nephritis, systemic It is useful as a prophylactic or therapeutic agent for erythematosus monolith, Hashimoto's disease, multiple sclerosis, myasthenia gravis, diabetes, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis and the like.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0031] 本発明における上記一般式（1)、一般式（la)及び一般式（lb)は新規ィヒ合物であ る。 [0031] The general formula (1), the general formula (la) and the general formula (lb) in the present invention are novel compounds.
[0032] 本発明における一般式（1)で表される化合物の薬理学的に許容される塩には、塩 酸塩、臭化水素酸塩、酢酸塩、トリフルォロ酢酸塩、メタンスルホン酸塩、クェン酸塩 、酒石酸塩のような酸付加塩が挙げられる。  [0032] Pharmaceutically acceptable salts of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, Acid addition salts such as citrate and tartrate are mentioned.
[0033] 又、本発明の一般式（1)において、「ハロゲン原子」とはフッ素原子、塩素原子、臭 素原子、ヨウ素原子を表し、「トリノ、ロメチル基」とはトリフルォロメチル基、トリクロロメチ ル基を表し、「炭素数 1一 10の低級アルキル基」とは、例えばメチル、ェチル、プロピ ル、イソプロピル、ブチル、 tーブチル、ペンチル、へキシル、ヘプチル、ォクチルなど の直鎖もしくは分岐した炭素数 1一 10の炭化水素が挙げられる。「炭素数 1一 4の低 級アルキル基」、「炭素数 1一 4の低級アルコキシ基」、などの「低級アルキル基」とは 、例えばメチル、ェチル、プロピル、イソプロピル、ブチル、 t ブチルなどの直鎖もしく は分岐した炭素数 1一 4の炭化水素が挙げられる。「置換基を有しても良いフエ-ル 基」とはベンゼン環の任意の位置にフッ素原子、塩素原子、臭素原子、ヨウ素原子な どのハロゲン原子、トリフルォロメチル基、炭素数 1一 4の低級アルキル基、炭素数 1 一 4の低級アルコキシ基、フエ-ル基、ァラルキル基、炭素数 1一 5の低級脂肪族ァ シル基、ヒドロキシ基、ハロゲン原子又は炭素数 1一 4低級アルコキシ基で置換されて いても良いァラルキルォキシ基、フエノキシ基、フエネチル基、スチリル基、フエ-ルェ チニル基、シクロへキシルメチルォキシ基を有するものが挙げられる。又ここでいう「 ァラルキル基」、「ァラルキルォキシ基」の「ァラルキル基」とはべンジル基、ジフエ-ル メチル基、フエネチル基、フエ-ルプロピル基が挙げられる。又、「炭素数 1一 5の低 級脂肪族ァシル基」とは、例えばホルミル基、ァセチル基、プロピオニル基、プチリル 基、イソプチリル基、バレリル基、イソバレリル基、ビバロイル基などの直鎖もしくは分 岐した炭素数 1一 5の低級脂肪族ァシル基が挙げられる。又「置換基を有しても良い 炭素数 1一 4の低級アルキル基」、「置換基を有しても良い炭素数 1一 10のアルキル 基」とは分岐あるいは直鎖状の炭素鎖上にヒドロキシ基、炭素数 1一 4の低級アルコ キシ基、炭素数 1一 4の低級アルキルスルファ-ル基、ハロゲン原子、フエ-ル基、フ エノキシ基を有するものが挙げられる。「炭素数 2— 4の低級アルケニル基」とは例え ばビュル基、ァリル基、 1 プロべ-ル基、イソプロべ-ル基、 1ーブテュル基、 2—ブテ ニル基、 2—メチルァリル基、 3—ブテニル基などの不飽和 2重結合を有する炭素数 2 一 4の炭化水素が挙げられる。「炭素数 2— 4の低級アルキ-ル基」とは例えばェチ- ル基、 1 プロピ-ル基、 2 -プロピ-ル基、 1 プチ-ル基、 2—プチ-ル基、 3 -ブチ ニル基などの不飽和 3重結合を有する炭素数 2— 4の炭化水素が挙げられる。 [0033] In the general formula (1) of the present invention, "halogen atom" represents a fluorine atom, chlorine atom, bromine atom or iodine atom, and "trino, romethyl group" means trifluoromethyl group, Represents a trichloromethyl group, and the term "lower alkyl group having 11 to 10 carbon atoms" means, for example, a straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Hydrocarbons having 1 to 10 carbon atoms. The term "lower alkyl group" such as "lower alkyl group having 14 carbon atoms" and "lower alkoxy group having 14 carbon atoms" means, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Linear or branched hydrocarbons having 14 carbon atoms are mentioned. The “optionally substituted phenyl group” refers to a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a trifluoromethyl group, a carbon atom number of 1 to 4 at any position on a benzene ring. A lower alkyl group having 14 carbon atoms, a lower alkoxy group having 14 carbon atoms, a phenol group, an aralkyl group, a lower aliphatic acyl group having 15 carbon atoms, a hydroxy group, a halogen atom or a lower alkoxy group having 14 carbon atoms And a group having an aralkyloxy group, a phenoxy group, a phenethyl group, a styryl group, a phenylethynyl group, and a cyclohexylmethyloxy group which may be substituted by The “aralkyl group” in the “aralkyl group” and the “aralkyl group” is a benzyl group or a diphenyl group. Examples include a methyl group, a phenethyl group and a phenylpropyl group. The "lower aliphatic acetyl group having 115 carbon atoms" is, for example, a straight or branched chain such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, and a vivaloyl group. And lower aliphatic acetyl groups having 115 carbon atoms. Further, "a lower alkyl group having 1 to 4 carbon atoms which may have a substituent" and "an alkyl group having 1 to 10 carbon atoms which may have a substituent" are defined on a branched or straight carbon chain. And those having a hydroxy group, a lower alkoxy group having 14 to 14 carbon atoms, a lower alkylsulfur group having 14 to 14 carbon atoms, a halogen atom, a phenyl group and a phenoxy group. The "lower alkenyl group having 2 to 4 carbon atoms" is, for example, a butyl group, an aryl group, a 1-probeyl group, an isopropyl group, a 1-butyl group, a 2-butenyl group, a 2-methylaryl group, Examples thereof include C2-C4 hydrocarbons having an unsaturated double bond such as a 3-butenyl group. The “lower alkyl group having 2 to 4 carbon atoms” is, for example, an ethyl group, a 1-propyl group, a 2-propyl group, a 1-butyl group, a 2-butyl group, a 3-alkyl group. Examples thereof include C 2-4 hydrocarbons having an unsaturated triple bond such as a butynyl group.
[0034] 本発明によれば、上記一般式（1)で表される化合物のうち Yが (CH )で、 Rが炭素 According to the present invention, among the compounds represented by the general formula (1), Y is (CH 2), and R is carbon
2 0 5 数 1一 4の低級アルキル基又はべンジル基である化合物、すなわち一般式（ 1 c) [0035] [化 7]  A compound which is a lower alkyl group or a benzyl group represented by the formula (14), that is, a compound represented by the following general formula (1c):
(1 c)(1 c)
Figure imgf000010_0001
Figure imgf000010_0001
[0036] [式中、1^、1^、1^、1^、 及び111は前述の通り]  [0036] [wherein 1 ^, 1 ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 6  1 2 3 6
で表される化合物は、例えば以下に示すような経路により製造することができる。  Can be produced, for example, by the following route.
[0037] <合成経路 1 >  [0037] <Synthetic route 1>
[0038] [化 8]
Figure imgf000010_0002
[0038] [Formula 8]
Figure imgf000010_0002
(2) (3)  (twenty three)
[0039] 合成経路 1で一般式 (3) [0040] [化 9] In the synthetic route 1, the general formula (3) [0040] [Formula 9]
(3)( 3 )
Figure imgf000011_0001
Figure imgf000011_0001
[0041] [式中、 Bocは t ブトキシカルボ-ル基を示し、 R、 R、 R、 R、 R、 X及び mは前述の  [Wherein, Boc represents a t-butoxycarbol group, and R, R, R, R, R, X and m are as defined above.
1 2 3 4 6  1 2 3 4 6
通り]  Street]
で表される化合物は、一般式（2)  The compound represented by the general formula (2)
[0042] [化 10]
Figure imgf000011_0002
[0042] [Formula 10]
Figure imgf000011_0002
[0043] [式中、 Aは塩素原子、臭素原子、ヨウ素原子を示し、 R、 R、 X及び mは前述の通り] [In the formula, A represents a chlorine atom, a bromine atom, or an iodine atom, and R, R, X, and m are as described above.]
1 2  1 2
で表される化合物と一般式 (4)  Compound represented by the general formula (4)
[0044] [化 11] [0044] [Formula 11]
,C02Ft6 , C0 2 Ft 6
BocR3N— (4) BocR 3 N— (4)
R4 R 4
[0045] [式中、 R、R、R及び Bocは前述の通り] [Wherein, R, R, R and Boc are as described above]
3 4 6  3 4 6
で表される化合物を塩基存在下に作用させることによって製造することができる（ェ 程 1—1)。  Can be produced by allowing the compound represented by the formula to act in the presence of a base (step 1-1).
[0046] 反応はメタノール、エタノール、 1, 4 ジォキサン、ジメチルスルホキシド（DMSO) 、 N, N—ジメチルホルムアミド（DMF)、テトラヒドロフラン (THF)などを反応溶媒とし て用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリウムアルコキ シド、炭酸カリウム、炭酸ナトリウムなどの無機塩基の存在下、反応温度としては 0°C 一加熱還流下にて行うことができる。又、 THFを溶媒としてリチウムジイソプリピルアミ ド（LDA)、リチウム 2, 2, 6, 6—テトラメチルピペリジド、リチウムビストリメチルシリルァ ミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミドを塩基とし て用い、場合によってはへキサメチルホスホリルトリアミドゃ N, N, Ν' , Ν，-テトラメチ ルエチレンジァミンをカ卩え、 -78°C—常温下にて行うことができる。 [0047] 合成経路 1で一般式（lc)で表される化合物は、上記一般式（3)で表される化合物 を酸分解することによって製造することができる（工程 1 2)。 In the reaction, methanol, ethanol, 1,4-dioxane, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), or the like is used as a reaction solvent, and sodium hydride, potassium hydride, The reaction can be carried out in the presence of an inorganic base such as sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate and the like, at a reaction temperature of 0 ° C. and under reflux with heating. Further, using THF as a solvent and lithium diisopropylidamide (LDA), lithium 2,2,6,6-tetramethylpiperidide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide and potassium bistrimethylsilylamide as bases In some cases, hexamethylphosphoryltriamide ゃ N, N, Ν ', Ν, -tetramethylethylenediamine is added and the reaction can be carried out at -78 ° C. at room temperature. The compound represented by the general formula (lc) in the synthesis route 1 can be produced by acid-decomposing the compound represented by the general formula (3) (Step 12).
[0048] 反応は、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。 [0048] The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. And a reaction temperature of 0 ° C-room temperature.
[0049] 一般式（1)で表される化合物のうち、 Yが (CH )で、 Rが水素原子である化合物、  [0049] Among the compounds represented by the general formula (1), compounds wherein Y is (CH) and R is a hydrogen atom,
2 0 5  2 0 5
すなわち一般式（Id)  That is, the general formula (Id)
[0050] [化 12]
Figure imgf000012_0001
[0050] [Formula 12]
Figure imgf000012_0001
[0051] [式中、1^、1^、1^、1^、 及び111は前述の通り]  [Wherein 1 ^, 1 ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 4  1 2 3 4
で表される化合物は、上記一般式（lc)で表される化合物を加水分解することによつ て製造することができる。  Can be produced by hydrolyzing the compound represented by the above general formula (lc).
[0052] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM[0052] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM
F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。 The reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
[0053] 又、一般式 (3)で表される化合物を加水分解後、酸分解することによつても製造す ることがでさる。 Further, the compound represented by the general formula (3) can be produced by hydrolysis and then acid decomposition.
[0054] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。  The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of 0 ° C.-normal temperature.
[0055] 一般式（1)で表される化合物のうち Yが (CH )で Rが水素原子である化合物、すな わち一般式 (le) [0055] Compounds represented by the general formula (1) wherein Y is (CH) and R is a hydrogen atom, General formula (le)
[0056] [化 13] [0056]
R  R
ノ X^ ^ ^ノ 2 NHR, ノ X ^ ^ ^ ノ2 NHR,
R1 ¾L (CH2)m R4 (1e) R1 ¾L (CH 2 ) m R 4 ( 1e )
[0057] [式中、 R 、 R 、 R 、 R 、 X及び mは前述の通り] [Wherein, R 1, R 2, R 3, R 2, X and m are as described above]
1 2 3 4  1 2 3 4
で表される化合物は、下記合成経路によって製造することができる。  Can be produced by the following synthetic route.
[0058] <合成経路 2> <Synthetic Route 2>
[0059] [化 14] 0 →
Figure imgf000013_0001
[0059] [Formula 14] 0 →
Figure imgf000013_0001
(7) (1e)  (7) (1e)
[0060] 合成経路 2で一般式（5) [0060] In the synthetic route 2, the general formula (5)
[0061] [化 15] [0061]
R2 NF Boc R 2 NF Boc
OH (5)  OH (5)
(CH2)m 4 (CH 2 ) m 4
[0062] [式中、 R 、 R 、 R 、 R 、 Boc、 X及び mは前述の通り]  [Wherein, R 1, R 2, R 3, R 4, Boc, X and m are as described above]
1 2 3 4  1 2 3 4
で表される化合物は、前記一般式（3)で表される化合物を還元することによって製造 することができる（工程 2— 1)。  Can be produced by reducing the compound represented by the general formula (3) (Step 2-1).
[0063] 反応はボラン（BH )や 9—ボラビシクロ [3.3.1]ノナン（9 BBN)のようなアルキルボラ [0063] The reaction is an alkylborane such as borane (BH) or 9-borabicyclo [3.3.1] nonane (9BBN).
3  Three
ン誘導体、ジイソブチルアルミニウムヒドリド（（iBu) A1H)、水素化ホウ素ナトリウム（  Derivatives, diisobutylaluminum hydride ((iBu) A1H), sodium borohydride (
2  2
NaBH )、水素化アルミニウムリチウム（LiAlH )等の金属水素錯ィ匕合物、好ましくは水  NaHH, lithium aluminum hydride (LiAlH 3) and other metal hydride complexes, preferably water
4 4  4 4
素化ホウ素リチウム（LiBH )を用い、反応溶媒としては THF、 1, 4ージォキサンゃェ  Lithium borohydride (LiBH) was used and the reaction solvent was THF, 1,4-dioxane.
4  Four
タノール、メタノールなどを用い、反応温度は o°c—加熱還流下、好適には常温下に て行うことができる。 [0064] 合成経路 2で一般式 (6) The reaction can be carried out at a reaction temperature of o ° C-reflux with heating, preferably at normal temperature, using ethanol, methanol or the like. In the synthesis route 2, the general formula (6)
[0065] [化 16] R3B0C [0065] R3B0C
1 (CCHH2))m— R4 B ） 1 (C C H H 2) ) m- R 4 B)
[0066] [式中、 Bはハロゲン原子、メタンスルホ-ルォキシ基、 p トルエンスルホ-ルォキシ 基を示し、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [Wherein, B represents a halogen atom, a methanesulfo-loxy group, a p-toluenesulfo-loxy group, and R, R, R, R, Boc, X and m are as described above]
1 2 3 4  1 2 3 4
で表される化合物は上記一般式（5)で表される化合物をハロゲンィ匕する力、メタンス ルホユルクロリドあるいは p—トルエンスルホユルク口リドと作用させることによって製造 することができる（工程 2— 2)。  Can be produced by reacting the compound represented by the above general formula (5) with methanesulfuryl chloride or p-toluenesulfuric acid chloride by a halogenating force (step 2-2).
[0067] 反応はハロゲン化の場合、トリフエ-ルフォスフィン、イミダゾールの存在下、塩化メ チレン、 THF、 1, 4 ジォキサンを反応溶媒として用い、 0°C—常温下にて四塩化炭 素、四臭化炭素あるいはヨウ素等を反応させて製造することができる。又、スルホン酸 エステル体は塩化メチレン、クロ口ホルム、ベンゼンなどの溶媒を用い、ピリジン、トリ ェチルァミン等の有機塩基存在下、パラトルエンスルホニルクロリド、又はメタンスル ホニルクロリドと 0°C— 80°Cにて好ましくは常温下にて反応させ対応するスルホン酸 エステルを合成することができる。さらにこの化合物を、 THF、ァセトニトリル好ましく はアセトンを反応溶媒して用い、常温下力 加熱還流下に臭化ナトリウム、臭化力リウ ム、ヨウ化ナトリウムあるいはヨウ化カリウムを作用させてハロゲン体を製造することも できる。 [0067] In the case of halogenation, in the case of halogenation, in the presence of triphenylphosphine and imidazole, methylene chloride, THF, and 1,4-dioxane are used as reaction solvents, and carbon tetrachloride and tetraodor are used at 0 ° C to room temperature. It can be produced by reacting carbon fluoride or iodine. The sulfonate is used at 0 ° C-80 ° C with paratoluenesulfonyl chloride or methanesulfonyl chloride in the presence of an organic base such as pyridine and triethylamine using a solvent such as methylene chloride, chloroform and benzene. Preferably, the reaction is carried out at room temperature to synthesize the corresponding sulfonic acid ester. The compound is further reacted with sodium bromide, lithium bromide, sodium iodide, or potassium iodide using THF, acetonitrile, or preferably acetone as a reaction solvent, and heating at room temperature under reflux to produce a halogenated compound. You can do it.
[0068] 合成経路 2で一般式 (7)  In the synthetic route 2, the general formula (7)
[0069] [化 17] (7)[0069] [Formula 17] (7)
Figure imgf000014_0001
Figure imgf000014_0001
[0070] [式中、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [Wherein, R, R, R, R, Boc, X and m are as described above]
1 2 3 4  1 2 3 4
で表される化合物は上記一般式 (6)で表されるィ匕合物を NaCN又は KCNと反応させ ること〖こよって製造することができる（工程 2— 3)。 [0071] 反応は THF、 DMSO、 DMF、 1, 4 ジォキサンを溶媒として用い、場合によっては水 を加え、常温一 100°Cにて行うことができる。 Can be produced by reacting the compound represented by the general formula (6) with NaCN or KCN (Step 2-3). [0071] The reaction can be carried out at room temperature and at 100 ° C using THF, DMSO, DMF, or 1,4 dioxane as a solvent, optionally adding water.
[0072] 合成経路 2で一般式（le)で表される化合物は上記一般式（7)で表される化合物を 加水分解することによって製造することができる（工程 VI)。  [0072] In the synthesis route 2, the compound represented by the general formula (le) can be produced by hydrolyzing the compound represented by the general formula (7) (Step VI).
[0073] 反応は、水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液な どの塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 D MF、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水 分解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無 機酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸 ェチルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行う ことができる。  The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The reaction is carried out at 0 ° C while heating under reflux to hydrolyze the ester moiety, and then in an organic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or in methanol, ethanol, The reaction is carried out in a mixed solution with an organic solvent such as THF, 1,4-dioxane and ethyl acetate, and the reaction can be carried out at 0 ° C.-normal temperature.
[0074] あるいは化合物（7)を濃硫酸、濃塩酸中にて加熱還流することによつても一般式（1 e)で表される化合物を製造することができる。  Alternatively, the compound represented by the general formula (1e) can also be produced by heating and refluxing the compound (7) in concentrated sulfuric acid or concentrated hydrochloric acid.
[0075] 一般式（1)で表される化合物のうち Y力 CH=CHで Rが炭素数 1 [0075] Among the compounds represented by the general formula (1), Y force CH = CH and R is 1
5 一 4の低級アルキ ル基又はべンジル基である化合物、すなわち一般式（If)  54 Compounds having 14 lower alkyl groups or benzyl groups, that is, compounds of the general formula (If)
[0076] [化 18]
Figure imgf000015_0001
[0076]
Figure imgf000015_0001
[0077] [式中、 R  [0077] [wherein, R
1、 R  1, R
2、 R  2, R
3、 R  3, R
4、 R  4, R
6、 X及び mは前述の通り]  6, X and m are as described above]
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0078] <合成経路 3 > [0079] [化 19] <Synthetic Route 3> [0079]
(5) 士 Hd (cH2) 3 3 (5) Shi Hd ( cH2 ) 3 3
(9)
Figure imgf000016_0001
'。。 (9)
Figure imgf000016_0001
'. .
Of)  Of)
[0080] 合成経路 3で一般式 (8) [0080] In the synthesis route 3, the general formula (8)
[0081] [化 20] [0081]
-R2 NR,Boc-R 2 NR, Boc
« (8)  «(8)
(CH2)m R4 CHO (CH 2 ) m R 4 CHO
[0082] [式中、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [Wherein, R, R, R, R, Boc, X and m are as described above]
1 2 3 4  1 2 3 4
で表される化合物は前記一般式 (5)で表される化合物を酸ィ匕することによって製造 することができる（工程 3—1)。  Can be produced by subjecting the compound represented by the general formula (5) to acidification (step 3-1).
[0083] 反応は、一般に用いられるアルコールのアルデヒドへの酸ィ匕手法を用いることがで き、例えばクロ口クロム酸ピリジニゥム、ニクロム酸ピリジニゥムなどの酸化クロム—ピリ ジン錯体ゃ酸化クロム、炭酸銀、二酸化マンガン等の金属酸化剤や、塩化ォキザリ ル、無水トリフルォロ酢酸、無水酢酸、 DCC、三酸化硫黄 -ピリジン錯体等の各種 D MSO活性化剤を用いた DMSO酸ィ匕が挙げられる。  [0083] The reaction can be carried out by a commonly used method for converting an alcohol to an aldehyde. For example, a chromium oxide-pyridinium complex such as pyridinium chromate and pyridinium dichromate can be used. Examples include DMSO oxidizers using various metal oxidizing agents such as manganese dioxide and various DMSO activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC and sulfur trioxide-pyridine complex.
[0084] 合成経路 3で一般式 (9)  In the synthetic route 3, the general formula (9)
[0085] [化 21]
Figure imgf000016_0002
[0085] [Formula 21]
Figure imgf000016_0002
[0086] [式中、 R、 R、 R、 R、 R、 Boc、 X及び mは前述の通り]  [0086] [wherein, R, R, R, R, R, Boc, X and m are as described above]
1 2 3 4 6  1 2 3 4 6
で表される化合物は上記一般式 (8)で表される化合物と一般式（10) [0087] [化 22]
Figure imgf000017_0001
The compound represented by the general formula (8) and the compound represented by the general formula (8) [0087]
Figure imgf000017_0001
[0088] [式中、 Rは前述の通り] [Wherein, R is as described above]
6  6
で表される化合物を反応させることによって製造することができる（工程 3— 2)。  (Step 3-2).
[0089] 反応は THF、 DMSO、 1, 4 ジォキサンを溶媒として用い、一般式（10)で表される 化合物を水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、 ナトリウム tーブトキシド、カリウムメトキシド、カリウムエトキシド、カリウム t ブトキシド などの塩基を、 0°C—常温下に作用させた後、一般式 (8)で表される化合物と反応さ せることができる。 [0089] In the reaction, THF, DMSO, and 1,4-dioxane are used as solvents, and the compound represented by the general formula (10) is converted to sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium A base such as methoxide, potassium ethoxide, potassium t-butoxide or the like can be allowed to react with a compound represented by the general formula (8) after acting at 0 ° C.-normal temperature.
[0090] 合成経路 3で一般式（If)で表される化合物は、上記一般式（9)で表される化合物 を酸分解することによって製造することができる（工程 3— 3)。  The compound represented by the general formula (If) in the synthesis route 3 can be produced by acid-decomposing the compound represented by the general formula (9) (Step 3-3).
[0091] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。 [0091] The reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. At a reaction temperature of 0 ° C-normal temperature.
[0092] 一般式（1)で表される化合物のうち、 Yが CH=CHで Rが水素原子である化合物、  [0092] Among the compounds represented by the general formula (1), compounds wherein Y is CH = CH and R is a hydrogen atom,
5  Five
すなわち一般式 (lg)  That is, the general formula (lg)
[0093] [化 23]
Figure imgf000017_0002
[0093] [Formula 23]
Figure imgf000017_0002
[0094] [式中、1 、1 、1 、1 、 及び111は前述の通り] [Wherein 1, 1, 1, 1, 1 and 111 are as described above]
1 2 3 4  1 2 3 4
で表される化合物は、上記一般式（if)で表される化合物を加水分解することによつ て製造することができる。  Can be produced by hydrolyzing a compound represented by the above general formula (if).
[0095] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。 [0096] 又、前記一般式 (9)で表される化合物を加水分解後、酸分解することによつても製 造することができる。 [0095] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C.—the reaction can be carried out under heating to reflux. [0096] Further, the compound can also be produced by hydrolyzing the compound represented by the general formula (9) and then decomposing it with acid.
[0097] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。  [0097] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of 0 ° C.-normal temperature.
[0098] 一般式（1)で表される化合物のうち、 Yが (CH )で、 Rが炭素数 1  [0098] Among the compounds represented by the general formula (1), Y is (CH 2) and R is 1
2 2 5 一 4の低級アルキ ル基又はべンジル基である化合物、すなわち一般式（lh)  A compound having a lower alkyl group or a benzyl group, ie, a compound represented by the general formula (lh):
[0099] [化 24]
Figure imgf000018_0001
[0099] [Formula 24]
Figure imgf000018_0001
[0100] [式中、 R、 R、 R、 R、 R 通り] [0100] [where R, R, R, R, and R]
1 2 3 4 6、 X及び mは前述の  1 2 3 4 6, X and m are
で表される化合物は下記合成経路によって製造することができる。  Can be produced by the following synthetic route.
[0101] <合成経路 4> [0101] <Synthetic route 4>
[0102] [化 25] [0102] [Formula 25]
0)0)
Figure imgf000018_0002
Figure imgf000018_0002
(11) (1 h)  (11) (1 h)
[0103] 合成経路 4で一般式（11) [0103] In the synthesis route 4, the general formula (11)
[0104] [化 26]
Figure imgf000018_0003
[0104] [Formula 26]
Figure imgf000018_0003
[0105] [式中、 R、 R、 R、 R、 R、 Boc、 X及び mは前述の通り]  [Wherein, R, R, R, R, R, Boc, X and m are as described above]
1 2 3 4 6 で表される化合物は前記一般式（9)で表される化合物を還元することによって製造 することができる（工程 4 1)。 1 2 3 4 6 Can be produced by reducing the compound represented by the general formula (9) (Step 41).
[0106] 反応は接触還元触媒であるパラジウム炭素、白金炭素、酸化白金、ロジウム炭素、 ルテニウム炭素等の存在下、好ましくはエチレンジァミンに被毒させた 5%パラジム炭 素を用い、エタノール、メタノール、 THF、 DMF、酢酸ェチル等の溶媒中、常圧一力口 圧下の水素圧下に常温一 100°Cにて行うことができる。又、マグネシウムをメタノール 中にて 0°C—常温下に作用させることによつても製造できる。 The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol, and THF. The reaction can be carried out in a solvent such as DMF, ethyl acetate or the like, at normal temperature and 100 ° C under hydrogen pressure at normal pressure and pressure. Alternatively, magnesium can be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
[0107] 合成経路 4で一般式（lh)で表される化合物は、上記一般式（11)で表される化合 物を酸分解することによって製造することができる（工程 4 2)。 The compound represented by the general formula (lh) in the synthesis route 4 can be produced by acid-decomposing the compound represented by the general formula (11) (Step 42).
[0108] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。 [0108] The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. The reaction can be carried out at a reaction temperature of 0 ° C-normal temperature.
[0109] 一般式（1)で表される化合物のうち、 Yが (CH )で、 Rが水素原子である化合物、  [0109] Among the compounds represented by the general formula (1), compounds wherein Y is (CH) and R is a hydrogen atom,
2 2 5  2 2 5
すなわち一般式（li)  That is, the general formula (li)
[0110] [化 27] [0110] [Formula 27]
(10(Ten
Figure imgf000019_0001
Figure imgf000019_0001
[0111] [式中、尺、！^、1^、1^、 及び111は前述の通り]  [0111] [In the formula, shaku,! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 4  1 2 3 4
で表される化合物は、上記一般式（lh)で表される化合物を酸分解することによって 製造することができる。  Can be produced by acid-decomposing the compound represented by the above general formula (lh).
[0112] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0112] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
[0113] 又、前記一般式（11)で表される化合物を加水分解後、酸分解することによつても 製造することができる。  [0113] Further, it can also be produced by hydrolyzing the compound represented by the general formula (11) and then decomposing it with acid.
[0114] 反応は水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。 [0114] The reaction is carried out with aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, etc. In the presence of a base, methanol, ethanol, 1,4-dioxane, DMF, DMSO, etc. are used as the reaction solvent at a reaction temperature of 0 ° C. while heating under reflux to hydrolyze the ester portion. Act on inorganic or organic acids such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or mixed solutions with organic solvents such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate; The reaction is performed at 0 ° C-room temperature.
[0115] 一般式（1)で表される化合物のうち、 Yが CH OCHで、 Rが炭素数] 、4の低級ァ  [0115] Among the compounds represented by the general formula (1), Y is CH 2 OCH, and R is the number of carbon atoms.
2 2 5  2 2 5
ルキル基又はべンジル基である化合物、すなわち一般式（lj)  A compound which is a alkyl group or a benzyl group, that is, a compound represented by the general formula (lj)
[0116] [化 28]
Figure imgf000020_0001
[0116] [Formula 28]
Figure imgf000020_0001
[0117] [式中、 R、 R、 R、 R、 R、 X及び mは前述の通り]  [0117] [wherein, R, R, R, R, R, X and m are as described above]
1 2 3 4 6  1 2 3 4 6
で表される化合物は、下記合成経路によって製造することができる。  Can be produced by the following synthetic route.
[0118] <合成経路 5 > [0118] <Synthetic pathway 5>
[0119] [化 29] [0119] [Formula 29]
(5)(Five)
Figure imgf000020_0002
Figure imgf000020_0002
(12) dj)  (12) dj)
[0120] 合成経路 5で一般式（12) [0120] In the synthetic route 5, the general formula (12)
[0121] [化 30]
Figure imgf000020_0003
[0121] [Formula 30]
Figure imgf000020_0003
[0122] [式中、 R、 R、 R、 R、 R、 Boc、 X及び mは前述の通り]  [0122] [wherein, R, R, R, R, R, Boc, X and m are as described above]
1 2 3 4 6  1 2 3 4 6
で表される化合物は、前記一般式（5)で表される化合物に一般式（ 13)  Is a compound represented by the general formula (13) in addition to the compound represented by the general formula (5).
ACH CO R (13)  ACH CO R (13)
2 2 6  2 2 6
[式中、 A及び Rは前述の通り] で表される化合物を反応させることによって製造することができる（工程 5— 1)。 [Where A and R are as described above] (Step 5-1).
[0123] 反応は、水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液等 の塩基とベンゼン又はトルエン、キシレンを溶媒として用い、テトラプチルアンモ-ゥ ムクロリド、テトラプチルアンモ-ゥムブロミド、テトラプチルアンモ-ゥムョージド、テト ラベンジルアンモ-ゥムブロミド等の 4級アンモ-ゥム塩をカ卩え、 0°C— 80°C、好ましく は常温下に行うことができる。 The reaction is carried out by using a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent, and using tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as butylammonium and tetrabenzylammonium bromide can be prepared at 0 ° C. to 80 ° C., preferably at room temperature.
[0124] 合成経路 5で一般式（lj)で表される化合物は、上記一般式（12)で表される化合物 を酸分解することによって製造することができる（工程 5— 2)。 [0124] In Synthesis Route 5, the compound represented by the general formula (lj) can be produced by acid-decomposing the compound represented by the general formula (12) (Step 5-2).
[0125] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。 [0125] The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. At a reaction temperature of 0 ° C-normal temperature.
[0126] 一般式（1)で表される化合物のうち、 Yが CH OCHで、 Rが水素原子である化合  [0126] Among the compounds represented by the general formula (1), those in which Y is CH OCH and R is a hydrogen atom
2 2 5  2 2 5
物、すなわち一般式（lk)  Object, that is, general formula (lk)
[0127] [化 31]
Figure imgf000021_0001
[0127] [Formula 31]
Figure imgf000021_0001
[0128] [式中、尺、！^、1^、1^、 及び111は前述の通り] [0128] [In the formula, shaku,! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 4  1 2 3 4
で表される化合物は、上記一般式（lj)で表される化合物を加水分解することによつ て製造することができる。  Can be produced by hydrolyzing the compound represented by the general formula (lj).
[0129] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0129] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent. The temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
[0130] 又、前記一般式（12)で表される化合物を加水分解後、酸分解することによつても 製造することができる。  [0130] Further, the compound can also be produced by hydrolyzing the compound represented by the general formula (12) and then decomposing it with acid.
[0131] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。 [0131] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM Using F, DMSO, etc., at a reaction temperature of 0 ° C and heating under reflux to hydrolyze the ester moiety, and then inorganic or organic acids such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, etc. The reaction can be carried out at 0 ° C-normal temperature by acting in a medium or a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate.
[0132] 一般式（1)で表される化合物のうち、 Yが CH 0CHCO Rで、 Rが炭素数 1一 4の低  [0132] Among the compounds represented by the general formula (1), Y is CH 0 CHCO R and R is a low
2 2 5 5  2 2 5 5
級アルキル基又はべンジル基でィヒ合物、すなわち一般式（11)  Compound with a lower alkyl group or a benzyl group, that is, the general formula (11)
[0133] [化 32]
Figure imgf000022_0001
[0133] [Formula 32]
Figure imgf000022_0001
[0134] [式中、 R、 R、 R、 R、 R、 X及び mは前述の通り] [Wherein, R, R, R, R, R, X and m are as described above]
1 2 3 4 6  1 2 3 4 6
で表される化合物は下記合成経路で製造することができる。  Can be produced by the following synthetic route.
[0135] <合成経路 6 >  [0135] <Synthetic route 6>
[0136] [化 33] [0136] [Formula 33]
(5) (Five)
C02Re
Figure imgf000022_0002
C0 2 Re
Figure imgf000022_0002
[0137] 合成経路 6で一般式（14) [0137] In the synthetic route 6, the general formula (14)
[0138] [化 34] (14)[0138] [Formula 34] (14)
Figure imgf000022_0003
Figure imgf000022_0003
[0139] [式中、 R、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [Wherein, R, R, R, R, R, Boc, X and m are as described above]
1 2 3 4 6  1 2 3 4 6
で表される化合物は前述一般式 (5)で表される化合物と一般式（15) [0140] [化 35] 02R6 The compound represented by the general formula (5) and the compound represented by the general formula (5) [0140] [Formula 35] 0 2 R 6
N （15)  N (15)
C02R6 C0 2 R 6
[0141] [式中、 Rは前述の通り] [0141] [where R is as described above]
6  6
で表される化合物を反応させることによって製造することができる（工程 6— 1)。  Can be produced by reacting the compound represented by the following formula (Step 6-1).
[0142] 反応はロジウムアセテートの存在下、トルエン、ベンゼン、クロ口ホルム、好ましくは 塩化メチレンを溶媒として用い、常温一加熱還流下に行うことができる。 [0142] The reaction can be carried out in the presence of rhodium acetate, using toluene, benzene, chloroform, and preferably methylene chloride as a solvent, at room temperature and under reflux with heating.
[0143] 合成経路 6で一般式（11)で表される化合物は上記一般式（14)で表される化合物 を酸分解することによって製造することができる（工程 6— 2)。 In the synthesis route 6, the compound represented by the general formula (11) can be produced by acid-decomposing the compound represented by the general formula (14) (Step 6-2).
[0144] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。 [0144] The reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. At a reaction temperature of 0 ° C-normal temperature.
[0145] 一般式（1)で表される化合物のうち、 Yが CH 0CHCO R、 Rが水素原子である化  [0145] Among the compounds represented by the general formula (1), Y is CH 0 CHCO R, and R is a hydrogen atom.
2 2 5 5  2 2 5 5
合物、すなわち一般式（lm)  Compound, ie, general formula (lm)
[0146] [化 36] [0146] [Formula 36]
Figure imgf000023_0001
Figure imgf000023_0001
[0147] [式中、尺、！^、1^、1^、 及び111は前述の通り] [0147] [where the formula, shaku,! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 4  1 2 3 4
で表される化合物は上記一般式（lm)で表される化合物を加水分解することによつ て製造することができる。  Can be produced by hydrolyzing the compound represented by the above general formula (lm).
[0148] 反応は水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM[0148] The reaction is performed in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide.
F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。 The reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
[0149] 又、前記一般式（14)で表される化合物を加水分解後、酸分解することによつても 製造することができる。 [0150] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。 [0149] Further, it can also be produced by hydrolyzing the compound represented by the general formula (14) and then subjecting it to acid decomposition. [0150] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of 0 ° C.-normal temperature.
[0151] 一般式（1)で表される化合物のうち、 Rが炭素数 1一 4の低級アルコキシカルボ- [0151] Among the compounds represented by the general formula (1), R represents a lower alkoxycarbocarbo having 1 to 4 carbon atoms.
4 Four
ル基又はべンジルォキシカルボニル基、 Rが炭素数 1  Or benzyloxycarbonyl group, where R is 1 carbon atom
5 一 4の低級アルキル基又はべ ンジル基、 Yが (CH )である化合物、すなわち一般式（In)  54 lower alkyl group or benzyl group, a compound wherein Y is (CH 2), that is, a compound represented by the general formula (In)
2 0  2 0
[0152] [化 37]
Figure imgf000024_0001
[0152] [Formula 37]
Figure imgf000024_0001
[0153] [式中、 R、R、R、R、X及び mは前述の通り]  [Wherein R, R, R, R, X and m are as described above]
1 2 3 6  1 2 3 6
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0154] <合成経路 7>  [0154] <Synthetic pathway 7>
[0155] [化 38]
Figure imgf000024_0002
[0155] [Formula 38]
Figure imgf000024_0002
(16) (1 n)  (16) (1 n)
[0156] 合成経路 7で一般式（16) [0156] In the synthesis route 7, the general formula (16)
[0157] [化 39] [0157] [Formula 39]
R Ί レ co2R (16) R Ί レ co 2 R (16)
(CH2)m CO 2π6 (CH 2 ) m CO 2 π 6
[0158] [式中、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] で表される化合物は前述一般式 ( 2)で表される化合物を一般式（ 17) [Wherein, R, R, R, R, Boc, X and m are as described above] The compound represented by the general formula (17) is a compound represented by the general formula (2)
[0159] [化 40]
Figure imgf000025_0001
[0159] [Formula 40]
Figure imgf000025_0001
[0160] [式中、 R、 R及び Bocは前述の通り] [Wherein, R, R and Boc are as described above]
3 6  3 6
で表される化合物と反応させることによって製造することができる（工程 7— 1)。  (Step 7-1).
[0161] 反応は、メタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFなどを 反応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、カリ ゥムアルコキシド、炭酸カリウム、炭酸ナトリウムなどの無機塩基の存在下、反応温度 としては 0°C—加熱還流下にて、好適には 80°C— 100°Cにて行うことができる。 [0161] In the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like is used as a reaction solvent, and sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate, or the like is used. The reaction can be carried out in the presence of an inorganic base at a reaction temperature of 0 ° C to reflux under heating, preferably at 80 ° C to 100 ° C.
[0162] 合成経路 7で一般式（In)で表される化合物は、上記一般式（16)で表される化合 物を酸分解することによって製造することができる（工程 7— 2)。 The compound represented by the general formula (In) in the synthesis route 7 can be produced by acid-decomposing the compound represented by the general formula (16) (Step 7-2).
[0163] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。 [0163] The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. At a reaction temperature of 0 ° C-normal temperature.
[0164] 一般式（1)で表される化合物のうち、 Rがカルボキシル基、 Rが水素原子、 Yが  [0164] Among the compounds represented by the general formula (1), R is a carboxyl group, R is a hydrogen atom, and Y is
4 5  4 5
(CH )である化合物、すなわち一般式（lo)  (CH 2), that is, a compound represented by the general formula (lo)
2 0  2 0
[0165] [化 41]
Figure imgf000025_0002
[0165] [Formula 41]
Figure imgf000025_0002
[0166] [式中、 R、R、R、X及び mは前述の通り]  [Wherein, R, R, R, X and m are as described above]
1 2 3  one two Three
で表される化合物は上記一般式（In)で表される化合物を加水分解することによって 製造することができる。  Can be produced by hydrolyzing the compound represented by the above general formula (In).
[0167] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。 [0167] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM The reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
[0168] 又、前記一般式（16)で表される化合物を加水分解後、酸分解することによつても 製造することができる。 [0168] The compound can also be produced by hydrolyzing the compound represented by the general formula (16) and then subjecting it to acid decomposition.
[0169] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。  [0169] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent. The temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of 0 ° C.-normal temperature.
[0170] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基、 Rが炭素数 1一 4の  [0170] Among the compounds represented by the general formula (1), R is a hydroxymethyl group, and R is a group having 1 to 4 carbon atoms.
4 5  4 5
低級アルキル基又はべンジル基、 Yが (CH )である化合物、すなわち一般式（lp)  A compound wherein Y is (CH 2), that is, a lower alkyl group or a benzyl group, that is, a compound represented by the general formula (lp)
2 0  2 0
[0171] [化 42]
Figure imgf000026_0001
[0171] [Formula 42]
Figure imgf000026_0001
[0172] [式中、尺、！^、1^、1^、 及び111は前述の通り]  [0172] [In the formula, shaku! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 6  1 2 3 6
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0173] <合成経路 8 >  [0173] <Synthetic route 8>
[0174] [化 43] [0174] [Formula 43]
(16)(16)
Figure imgf000026_0002
Figure imgf000026_0002
[0175] 合成経路 8で一般式（18) [0176] [化 44]
Figure imgf000027_0001
[0175] In the synthesis route 8, the general formula (18) [0176] [Formula 44]
Figure imgf000027_0001
[0177] [式中、1^、1^、1^、1^、 及び111は前述の通り] [0177] [wherein 1 ^, 1 ^, 1 ^, 1 ^, and 111 are as described above]
1 2 3 6  1 2 3 6
で表される化合物は前述一般式（ 16)で表される化合物を還元することによって製造 することができる（工程 8—1)。  Can be produced by reducing the compound represented by the general formula (16) (Step 8-1).
[0178] 反応は BHや 9 BBNのようなアルキルボラン誘導体、（iBu) A1H、 NaBH、 LiBH、  [0178] The reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiBH,
3 2 4 4 3 2 4 4
LiAlH等の金属水素錯化合物、好ましくはトリブトキシ水素化アルミニウムリチウム（Metal hydride complex compounds such as LiAlH, preferably lithium aluminum tributoxy hydride (
4 Four
LiAl(tOBu〇））を用い、反応溶媒としては THF、 1， 4 ジォキサンやエタノール、メタ  LiAl (tOBu〇)) and the reaction solvent is THF, 1,4-dioxane, ethanol,
3  Three
ノールなどを用い、反応温度は o°c—加熱還流下、好適には常温下にて行うことがで きる。  The reaction can be carried out at a reaction temperature of o ° C-heating under reflux, preferably at room temperature, using phenol or the like.
[0179] 合成経路 8で一般式（ lp)で表される化合物は上記一般式（18)で表される化合物 を酸分解することによって製造することができる（工程 8— 2)。  [0179] In the synthesis route 8, the compound represented by the general formula (lp) can be produced by acid-decomposing the compound represented by the general formula (18) (Step 8-2).
[0180] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。 [0180] The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. At a reaction temperature of 0 ° C-normal temperature.
[0181] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基、 Rが水素原子、 Yが  [0181] Among the compounds represented by the general formula (1), R is a hydroxymethyl group, R is a hydrogen atom, and Y is
4 5  4 5
(CH )である化合物、すなわち一般式（lq)  A compound of formula (CH 2), that is, a compound of the general formula (lq)
2 0  2 0
[0182] [化 45] (1q) [0182] [Formula 45] (1q)
Figure imgf000027_0002
Figure imgf000027_0002
[0183] [式中、 R、R、R、X及び mは前述の通り]  [0183] [wherein, R, R, R, X and m are as described above]
1 2 3  one two Three
で表される化合物は上記一般式（lp)で表される化合物を加水分解することによって 製造することができる。  Can be produced by hydrolyzing a compound represented by the above general formula (lp).
[0184] 反応は水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F DMSOなどを用い、反応温度は 0°C 加熱還流下に行うことができる。 [0184] The reaction is carried out with aqueous sodium hydroxide, aqueous potassium hydroxide, aqueous lithium hydroxide, etc. In the presence of a base, methanol, ethanol, 1,4-dioxane, DMF DMSO, or the like is used as a reaction solvent, and the reaction can be carried out at 0 ° C. while heating under reflux.
[0185] 又、前記一般式（18)で表される化合物を加水分解後、酸分解することによつても 製造することができる。 [0185] Further, it can also be produced by hydrolyzing the compound represented by the general formula (18) and then subjecting it to acid decomposition.
[0186] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F DMSOなどを用い、反応温度は 0°C 加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF 1, 4 ジォキサン、酢酸ェ チルな  [0186] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide. After heating at 0 ° C and refluxing to hydrolyze the ester moiety, the residue is dissolved in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, THF 1, 4 Dioxane, ethyl acetate
どの有機溶媒との混合溶液中に作用させ、反応温度は 0°C 常温下に行うことがで きる。  The reaction can be performed in a mixed solution with any organic solvent and at a reaction temperature of 0 ° C at room temperature.
[0187] さらに前記一般式（lp)で表される化合物は下記合成経路によっても合成すること ができる。  [0187] Further, the compound represented by the general formula (lp) can also be synthesized by the following synthesis route.
[0188] <合成経路 9 > [0188] <Synthetic pathway 9>
[0189] [化 46] [0189] [Formula 46]
Figure imgf000028_0001
Figure imgf000028_0001
[0190] 合成経路 9で一般式（19) [0190] In the synthetic route 9, the general formula (19)
[0191] [化 47]
Figure imgf000028_0002
[0191] [Formula 47]
Figure imgf000028_0002
[0192] [式中、 R R R Boc X及び mは前述の通り] [Wherein, R R R Boc X and m are as described above]
1 2 3 で表される化合物は前記一般式（ 16)で表される化合物を還元することによって製造 することができる（工程 9—1)。 one two Three Can be produced by reducing the compound represented by the general formula (16) (Step 9-1).
[0193] 反応は BHや 9 BBNのようなアルキルボラン誘導体、（iBu) A1H、 NaBH、 LiAlH [0193] The reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiAlH
3 2 4 4 等の金属水素錯化合物、好ましくは LiBHを用い、反応溶媒としては THF、 1, 4ージ  A metal-hydrogen complex compound such as 3244, preferably LiBH, is used.
4  Four
ォキサンやエタノール、メタノールなどを用い、反応温度は o°c—加熱還流下、好適 には常温下にて行うことができる。  The reaction can be carried out using oxane, ethanol, methanol, or the like, at a reaction temperature of o ° C under heating to reflux, preferably at room temperature.
[0194] 合成経路 9で一般式（ lp)で表される化合物は上記一般式（ 19)で表される化合物 のヒドロキシ基の一つを保護した後、酸ィ匕反応に付すことによって製造することができ る（工程 9—2)。  [0194] In Synthesis Route 9, the compound represented by the general formula (lp) is produced by protecting one of the hydroxy groups of the compound represented by the general formula (19) and subjecting the compound to an oxidation reaction. (Step 9-2).
[0195] 反応は、まず一般のヒドロキシ基保護基であるァセチル基、ベンゾィル基などのァ シル型保護基や tーブチルジメチルシリル基、 tーブチルジフヱ-ルシリル基などのシリ ル型保護基を用いてヒドロキシ基の一方を保護した後、過マンガン酸カリウム、四酢 酸鉛、四酸化ルテニウム、好ましくはクロ口クロム酸ピリジ-ゥム、ニクロム酸ピリジ-ゥ ムなどの酸ィ匕クロム ピリジン錯体ゃ酸ィ匕クロムを酸化剤として用い、反応溶媒はァセ トン、 DMF、塩化メチレン、クロ口ホルム、酢酸ェチル、酢酸などを用い、 0°C—常温 下に行うことができる。又、引き続くヒドロキシ基の脱保護反応は、ァシル型ヒドロキシ 保護体の場合、メタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFな どを反応溶媒として用い、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リ チウムなどの塩基の存在下、反応温度としては 0°C—常温下にて行うことができる。 又、シリル型ヒドロキシ保護体の場合、 THF、 DMF、 1, 4 ジォキサン等を溶媒とし て用い、フッ化カリウム、フッ化セシウム、テトラプチルアンモ -ゥムフルオリドを 0°C— 常温下に作用させて行う事ができる、その後、酸分解することによって製造することが できる。反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの 無機酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢 酸ェチルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に 行うことができる。  [0195] In the reaction, first, a general hydroxy-protecting group such as an acetyl group or a benzoyl group is used, or a silyl-type protecting group such as a t-butyldimethylsilyl group or a t-butyldifluorosilyl group is used. After protecting one of the hydroxy groups, potassium permanganate, lead tetraacetate, ruthenium tetroxide, preferably pyridinium chromate and pyridinium dichromate, etc. The reaction can be carried out at 0 ° C.-room temperature using acetone, DMF, methylene chloride, methylene chloride, ethyl acetate, acetic acid and the like as a reaction solvent. In the subsequent deprotection reaction of the hydroxy group, in the case of the protected acyl-type hydroxy, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like is used as a reaction solvent, and an aqueous solution of sodium hydroxide or potassium hydroxide is used. The reaction can be carried out in the presence of a base such as lithium hydroxide at a reaction temperature of 0 ° C.-normal temperature. In the case of a protected silyl-type hydroxy compound, THF, DMF, 1,4-dioxane or the like is used as a solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium-dimethyl fluoride is allowed to act at 0 ° C.-room temperature. It can be manufactured by acid decomposition. The reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate. The reaction can be performed at a reaction temperature of 0 ° C-room temperature.
[0196] 一般式（1)で表される化合物のうち、 R、 Rが水素原子、 Yが (CH )である化合物  [0196] Among the compounds represented by the general formula (1), compounds wherein R and R are hydrogen atoms and Y is (CH 2)
4 5 2 0  4 5 2 0
すなわち一般式（lr) [0197] [化 48] That is, the general formula (lr) [0197] [Formula 48]
NHR NHR
ノス ^ノ' z i 3 Nos ^ No 'zi 3
R1 X ¾ ^^L、 *(/ (CΓΓΜ-H2Δ)、m mπ" ' C°2H (1r) R1 X ¾ ^^ L, * (/ (CΓΓΜ-H 2 Δ), m mπ "' C ° 2 H ( 1r )
[0198] [式中、 R 、 R 、 R 、 X及び mは前述の通り] [Wherein R, R, R, X and m are as described above]
1 2 3  one two Three
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0199] <合成経路 10 > [0199] <Synthetic pathway 10>
[0200] [化 49] [0200] [Formula 49]
Figure imgf000030_0001
Figure imgf000030_0001
[0201] 合成経路 10で一般式（21) [0201] In the synthetic route 10, the general formula (21)
[0202] [化 50]
Figure imgf000030_0002
[0202] [Formula 50]
Figure imgf000030_0002
[0203] [式中、 R 、 R 、 R 、 Boc、 X及び mは前述の通り] [0203] [wherein, R 1, R 2, R 3, Boc, X and m are as described above]
1 2 3  one two Three
で表される化合物は合成経路 9で得られる一般式（20)  The compound represented by the general formula (20) obtained by the synthesis route 9
[0204] [化 51]
Figure imgf000030_0003
[0204] [Formula 51]
Figure imgf000030_0003
[0205] [式中、 R 、 R 、 R 、 Boc、 X及び mは前述の通り] [Wherein, R 1, R 2, R 3, Boc, X and m are as described above]
1 2 3  one two Three
で表される化合物を酸ィ匕することによって製造することができる（工程 10— 1)。  Can be produced by acidifying the compound represented by the formula (Step 10-1).
[0206] 反応は過マンガン酸カリウム、四酢酸鉛、四酸化ルテニウム、好ましくはクロ口クロム 酸ピリジ-ゥム、ニクロム酸ピリジ-ゥムなどの酸化クロム ピリジン錯体ゃ酸化クロム を酸化剤として用い、反応溶媒はアセトン、 DMF、塩化メチレン、クロ口ホルム、酢酸 ェチル、酢酸などを用い、 0°C—常温下に行うことができる。 [0207] 合成経路 10で一般式（lr)で表される化合物は上記一般式（20)で表される化合 物を酸分解することによって製造することができる（工程 10— 2)。 [0206] The reaction is carried out using potassium permanganate, lead tetraacetate, ruthenium tetroxide, preferably chromium oxide pyridine complex chromium oxide such as pyridinium chromate and pyridinium dichromate as an oxidizing agent. The reaction can be carried out using acetone, DMF, methylene chloride, chloroform, ethyl acetate, acetic acid, etc., at 0 ° C. and room temperature. [0207] In the synthesis route 10, the compound represented by the general formula (lr) can be produced by acid-decomposing the compound represented by the general formula (20) (Step 10-2).
[0208] 反応は、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。  [0208] The reaction is performed in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. And a reaction temperature of 0 ° C-room temperature.
[0209] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基、 Rが水素原子、 Yが  [0209] Among the compounds represented by the general formula (1), R is a hydroxymethyl group, R is a hydrogen atom, and Y is
4 5  4 5
(CH )である化合物、すなわち一般式（Is)  A compound of the formula (CH 2)
2 1  twenty one
[0210] [化 52]  [0210] [Formula 52]
R1 ¾l H OS) R1 ¾l H OS)
、ハ Cハ02H , Ha C ha 0 2 H
[0211] [式中、 R 、 R 、 R 、 X及び mは前述の通り] [0211] [wherein, R 1, R 2, R 3, X and m are as described above]
1 2 3  one two Three
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0212] く合成経路 11 >  [0212] Synthesis route 11>
[0213] [化 53] 11-3
Figure imgf000031_0001
[0213] [Formula 53] 1 1 - 3
Figure imgf000031_0001
[0214] 合成経路 11で一般式（22) [0215] [化 54] [0214] In synthetic route 11, general formula (22) [0215] [Formula 54]
Figure imgf000032_0001
Figure imgf000032_0001
[0216] [式中、 R、R、R、X及び mは前述の通り] [Wherein, R, R, R, X and m are as described above]
1 2 3  one two Three
で表される化合物は前述一般式（19)で表される化合物を閉環させることによって製 造することができる（工程 11-1)。  Can be produced by ring-closing the compound represented by the general formula (19) (Step 11-1).
[0217] 反応は水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、 ナトリウムブトキシド、カリウムメトキシド、カリウムエトキシド、カリウムブトキシドなどの無 機塩基の存在下、 THF, 1, 4 ジォキサン、 DMF、ベンゼン、トルエンを反応溶媒と して用い、 0°C—加熱還流下、好ましくは常温下に行うことができる。又、ピリジン溶媒 中、パラトルエンスルホユルク口リドと加熱還流下、好ましくは 80°C— 100°Cにて行う ことちでさる。  [0217] The reaction is carried out in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium butoxide, potassium methoxide, potassium ethoxide, potassium butoxide, THF, 1,4-dioxane, Using DMF, benzene, and toluene as reaction solvents, the reaction can be carried out at 0 ° C.-with heating under reflux, preferably at room temperature. In addition, it is preferable to carry out the reaction in a pyridine solvent with paratoluenesulfuric acid lid under reflux with heating, preferably at 80 ° C to 100 ° C.
[0218] 合成経路 11で一般式（23)  [0218] In synthesis route 11, the general formula (23)
[0219] [化 55]  [0219] [Formula 55]
(23)(twenty three)
Figure imgf000032_0002
Figure imgf000032_0002
[0220] [式中、 R、R、R、B、X及び mは前述の通り] [Wherein, R, R, R, B, X and m are as described above]
1 2 3  one two Three
で表される化合物は上記一般式（22)で表される化合物をハロゲンィ匕する力、メタン スルホユルクロリドあるいは p—トルエンスルホユルク口リドと作用させることによって製 造することができる（工程 11-2)。  Can be produced by reacting the compound represented by the general formula (22) with methanesulfuryl chloride or p-toluenesulfuryl chloride by a halogenating force (step 11-). 2).
[0221] 反応はハロゲン化の場合、トリフエ-ルフォスフィン、イミダゾールの存在下、塩化メ チレン、 THF、 1, 4 ジォキサンを反応溶媒として用い、 0°C—常温下にて四塩化炭 素、四臭化炭素あるいはヨウ素等を反応させて製造することができる。又、スルホン酸 エステル体は塩化メチレン、クロ口ホルム、ベンゼンなどの溶媒を用い、ピリジン、トリ ェチルァミン等の有機塩基存在下、パラトルエンスルホニルクロリド、又はメタンスル ホニルクロリドと 0°C— 80°Cにて好ましくは常温下にて反応させ対応するスルホン酸 エステルを合成することができる。さらにこの化合物を、 THF、ァセトニトリル好ましく はアセトンを反応溶媒して用い、常温下力 加熱還流下に臭化ナトリウム、臭化力リウ ム、ヨウ化ナトリウムあるいはヨウ化カリウムを作用させてハロゲン体を製造することも できる。 [0221] In the case of halogenation, in the case of halogenation, in the presence of triphenylphosphine and imidazole, methylene chloride, THF, and 1,4-dioxane are used as reaction solvents, and carbon tetrachloride and tetraodor are used at 0 ° C to room temperature. It can be produced by reacting carbon fluoride or iodine. The sulfonic acid ester is prepared by using a solvent such as methylene chloride, chloroform and benzene in the presence of an organic base such as pyridine or triethylamine in the presence of paratoluenesulfonyl chloride or methanesulfonate. The corresponding sulfonic acid ester can be synthesized by reacting with honyl chloride at 0 ° C. to 80 ° C., preferably at room temperature. This compound is further reacted with sodium bromide, lithium bromide, sodium iodide or potassium iodide using THF, acetonitrile, or preferably acetone as a reaction solvent, and heating and refluxing at room temperature to produce a halogenated compound. You can do it.
[0222] 合成経路 11で一般式（24)  [0222] In the synthetic route 11, the general formula (24)
[0223] [化 56] [0223] [Formula 56]
(24)(twenty four)
Figure imgf000033_0001
Figure imgf000033_0001
[0224] [式中、 R、 R、 R、 X及び mは前述の通り] [0224] [wherein, R, R, R, X and m are as described above]
1 2 3  one two Three
で表される化合物は上記一般式（23)で表されるィ匕合物を NaCN又は KCNと反応させ ること〖こよって製造することができる（工程 11-3)。  Can be produced by reacting the compound of formula (23) with NaCN or KCN (step 11-3).
[0225] 反応は THF、 DMSO、 DMF、 1, 4 ジォキサンを溶媒として用い、場合によっては水 を加え、常温一 100°Cにて行うことができる。 [0225] The reaction can be carried out at room temperature and 100 ° C using THF, DMSO, DMF, or 1,4 dioxane as a solvent, optionally adding water.
[0226] 合成経路 11で一般式（Is)で表される化合物は上記一般式（24)で表される化合 物を加水分解することによって製造することができる（工程 11-4)。 [0226] In the synthetic route 11, the compound represented by the general formula (Is) can be produced by hydrolyzing the compound represented by the general formula (24) (step 11-4).
[0227] 反応は、水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液な どの塩基の存在下、無溶媒又は場合によってはメタノール、エタノール、 1, 4ージォ キサン、 DMSOなどを反応溶媒として用い、反応温度は加熱還流下に行うことが望 ましい。 [0227] The reaction is carried out in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide in the absence of a solvent or, in some cases, methanol, ethanol, 1,4-dioxane, DMSO, or the like, as a reaction solvent. And the reaction is preferably carried out under heating to reflux.
[0228] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基又は低級アルコシキメ  [0228] Among the compounds represented by the general formula (1), R-hydroxymethyl group or lower alkoxymethyl group
4  Four
チル基、 Rが炭素数 1一 4の低級アルキル基又はべンジル基で、 Yが CH=CHである  A butyl group, R is a lower alkyl group having 1 to 4 carbon atoms or a benzyl group, and Y is CH = CH
5  Five
化合物、すなわち一般式（It) [0229] [化 57] Compound, ie, general formula (It) [0229] [Formula 57]
Figure imgf000034_0001
Figure imgf000034_0001
[0230] [式中、 Rは水素原子又は炭素数 1 4の低級アルキル基を示し、 R R R R X [Wherein, R represents a hydrogen atom or a lower alkyl group having 14 carbon atoms, and R R R R X
7 1 2 3 6 及び mは前述の通り]  7 1 2 3 6 and m are as described above]
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0231] <合成経路 12 > [0231] <Synthetic pathway 12>
[0232] [化 58] [0232] [Formula 58]
Figure imgf000034_0002
Figure imgf000034_0002
[0233] 合成経路 12で一般式（25)  [0233] In the synthetic route 12, the general formula (25)
[0234] [化 59] (25)[0234] [Formula 59] (25)
Figure imgf000034_0003
Figure imgf000034_0003
[0235] [式中、 Rは tーブチルジメシルシリル基、 tーブチルジフエ-ルシリル基、メトキシメチル [0235] [wherein, R is a t-butyldimesylsilyl group, a t-butyldiphenylsilyl group, a methoxymethyl
8  8
基、ァセチル基、ベンゾィル基又は炭素数 1 4の低級アルキル基を示し、 R R R  Group, acetyl group, benzoyl group or lower alkyl group having 14 carbon atoms, R R R
1 2 Boc X及び mは前述の通り]  1 2 Boc X and m are as described above]
3  Three
で表される化合物は前記一般式（19)で表される化合物と一般式（28)  The compound represented by the general formula (19) and the compound represented by the general formula (19)
R B (28)  R B (28)
8  8
[式中、 R Bは前述の通り]  [Where R B is as described above]
8  8
で表される化合物と反応させることによって製造することができる（工程 12— 1)。 [0236] 反応は、 Rが tーブチルジメシルシリル基、 tーブチルジフヱ-ルシリル基の場合、ァ(Step 12-1). [0236] In the reaction, when R is a t-butyldimesylsilyl group or a t-butyldifluorosilyl group,
8 8
セトニトリル、塩化メチレン、好ましくは DMFを溶媒として用いトリェチルァミン、ピリジ ン、ジイソプロピルェチルァミン等の有機塩基の存在下、対応するシリルクロリドを 0°C 一常温下に作用させることができる。又、メトキシメチル基、ァセチル基、ベンゾィル 基の場合、 THF、 1, 4 ジォキサン、エーテル、塩化メチレン等を有機溶媒として用 い、トリェチルァミン、ピリジン、ジイソプロピルェチルァミン等の有機塩基の存在下、 0°C—常温下にて対応する酸ノヽライド、又はアルクリハライドを作用させることができる 。さらに低級アルキルキル基の場合は酸ィ匕銀の存在下にァセトニトリルを溶媒として 用い常温下に低級アルキルハライドを作用させるが望ま Uヽ。  The corresponding silyl chloride can be allowed to act at 0 ° C. and room temperature in the presence of an organic base such as triethylamine, pyridin and diisopropylethylamine using setonitrile, methylene chloride, preferably DMF as a solvent. In the case of a methoxymethyl group, an acetyl group or a benzoyl group, THF, 1,4-dioxane, ether, methylene chloride or the like is used as an organic solvent in the presence of an organic base such as triethylamine, pyridine or diisopropylethylamine. At 0 ° C.—normal temperature, the corresponding acid halide or alklyhalide can act. Further, in the case of a lower alkylalkyl group, it is desirable to allow lower alkyl halide to act at room temperature using acetonitrile as a solvent in the presence of silver oxide.
[0237] 合成経路 12で一般式 (26)  [0237] In the synthetic route 12, the general formula (26)
[0238] [化 60]  [0238] [Formula 60]
Figure imgf000035_0001
Figure imgf000035_0001
[0239] [式中、 R [0239] [wherein, R
1、 R 1, R
2、 R  2, R
3、 R  3, R
8、 Boc、 X及び mは前述の通り]  8, Boc, X and m are as described above]
で表される化合物は上記一般式 (25)で表される化合物を酸化することによって製造 することができる（工程 12— 2)。  Can be produced by oxidizing the compound represented by the general formula (25) (Step 12-2).
[0240] 反応は一般に用いられるアルコールのアルデヒドへの酸ィ匕手法を用いることができ 、例えばクロ口クロム酸ピリジニゥム、ニクロム酸ピリジニゥムなどの酸化クロム ピリジ ン錯体や酸化クロム、炭酸銀、二酸化マンガン等の金属酸化剤や、塩化ォキザリル、 無水トリフルォロ酢酸、無水酢酸、 DCC、三酸化硫黄 -ピリジン錯体等の各種 DMS O活性化剤を用いた DMSO酸ィ匕が挙げられる。  [0240] For the reaction, a commonly used method for converting alcohol to aldehyde can be used. For example, a chromium oxide pyridin complex such as pyridinium chromate and pyridinium dichromate, chromium oxide, silver carbonate, manganese dioxide, and the like can be used. DMSO using various metal oxidizing agents or various DMS O activators such as oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, and sulfur trioxide-pyridine complex.
[0241] 合成経路 12で一般式（27) [0242] [化 61] [0241] In the synthetic route 12, the general formula (27) [0242] [Formula 61]
Figure imgf000036_0001
Figure imgf000036_0001
[0243] [式中、 R、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [0243] [wherein, R, R, R, R, R, Boc, X and m are as described above]
1 2 3 6 8  1 2 3 6 8
で表される化合物は前記一般式（26)で表される化合物と前記一般式（10)で表され る化合物を反応させることによって製造することができる（工程 12— 3)。  Can be produced by reacting the compound represented by the general formula (26) with the compound represented by the general formula (10) (step 12-3).
[0244] 反応は THF、 DMSO、 1, 4 ジォキサンを溶媒として用い、一般式（10)で表される 化合物を水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、 ナトリウム tーブトキシド、カリウムメトキシド、カリウムエトキシド、カリウム t ブトキシド などを塩基として用い、 0°C—常温下に作用させた後、一般式 (26)で表される化合 物と反応させることができる。  [0244] In the reaction, THF, DMSO, and 1,4-dioxane were used as solvents, and the compound represented by the general formula (10) was converted to sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, and potassium. Using methoxide, potassium ethoxide, potassium t-butoxide, or the like as a base, it is allowed to react at 0 ° C.-normal temperature, and then reacted with the compound represented by the general formula (26).
[0245] 合成経路 12で一般式（It)で表される化合物は上記一般式（27)で表される化合 物を酸分解することによって製造することができる（工程 12— 4)。  In the synthesis route 12, the compound represented by the general formula (It) can be produced by acid-decomposing the compound represented by the general formula (27) (Step 12-4).
[0246] 反応は Rがメトキシメチル基の場合、酢酸、塩酸、臭化水素酸、メタンスルホン酸、  [0246] When R is a methoxymethyl group, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid,
8  8
トリフルォロ酢酸などの無機酸又は有機酸中、あるいはメタノール、エタノール、 THF 、 1, 4 ジォキサン、酢酸ェチルなどの有機溶媒との混合溶液中に作用させ、反応 温度は 0°C—常温下に行うことができる。又、ァセチル基、ベンゾィル基の場合には、 エタノール、メタノール、 THF, DMSOなどを溶媒として用いて水酸化ナトリウム水溶 液、水酸化カリウム水溶液、水酸化リチウム水溶液を作用させ加水分解後に上述した 酸分解を行なうほうが好ましい。 Rが tーブチルジメチルシリル基、 tーブチルジフエ- Operate in an inorganic or organic acid such as trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate, and perform the reaction at 0 ° C-room temperature. Can be. In the case of an acetyl group or a benzoyl group, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide is used as a solvent with ethanol, methanol, THF, DMSO, or the like, and the above-described acid decomposition is performed after hydrolysis. It is more preferable to perform R is a t-butyldimethylsilyl group, t-butyldiphen-
8 8
ルシリル基の場合も上述の酸分解法にて行うこともできる力 THFを溶媒としてテトラ ブチルアンモ -ゥムフルオリド、 KF、 CsFと 0°C—常温下にて反応させた後に酸分解 する方法がより好ましい。  In the case of a lucilyl group, a method which can be carried out by the above-described acid decomposition method is more preferably a method of reacting tetrabutylammonium-dimethyl fluoride, KF, and CsF with THF as a solvent at 0 ° C.-normal temperature, followed by acid decomposition.
[0247] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基又は炭素数 1 [0247] Among the compounds represented by the general formula (1), R-hydroxymethyl group or carbon number 1
4 一 4の低 級アルコキシメチル基、 Rが水素原子、 Y力 SCH=CHである化合物、すなわち一般式  A compound in which 14 lower alkoxymethyl groups, R is a hydrogen atom, and Y force SCH = CH, that is, a general formula
5  Five
(lu) [0248] [化 62] (lu) [0248] [Formula 62]
Figure imgf000037_0001
Figure imgf000037_0001
[0249] [式中、1^ 111は前述の通り] [0249] [where 1 ^ 111 is as described above]
1、1^ 及び 1, 1 ^ and
2、1^  2, 1 ^
3、1^、  3, 1 ^,
7  7
で表される化合物は、前記一般式（it)で表される化合物を加水分解することによつ て製造することができる。  The compound represented by the general formula (it) can be produced by hydrolyzing the compound represented by the general formula (it).
[0250] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0250] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
[0251] 又、前記一般式 (27)で表される化合物を加水分解後、酸分解することによつても 製造することができる。  Further, the compound can also be produced by hydrolyzing the compound represented by the general formula (27) and then subjecting it to acid decomposition.
[0252] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。  [0252] The reaction is carried out in the presence of a base such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C and the mixture is heated to reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, or THF. It is allowed to act in a mixed solution with an organic solvent such as 1,4-dioxane and ethyl acetate, and the reaction is carried out at a temperature of 0 ° C.-normal temperature.
[0253] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基又は炭素数 1  [0253] Among the compounds represented by the general formula (1), R-hydroxymethyl group or carbon number 1
4 一 4の低 級アルコキシメチル基、 Rが炭素数 1一 4の低級アルキル基又はべンジル基で、 Yが  44 is a lower alkoxymethyl group, R is a lower alkyl group or a benzyl group having 14 carbon atoms, and Y is
5  Five
(CH)である化合物、すなわち一般式（lv)  A compound of formula (CH), that is, a compound of the general formula (lv)
2  2
[0254] [化 63]  [0254] [Formula 63]
Figure imgf000037_0002
Figure imgf000037_0002
[0255] [式中、 R、 R、 R、 R、 R、 X及び mは前述の通り] で表される化合物は下記合成経路によって合成することができる。 [Wherein, R, R, R, R, R, X and m are as described above] Can be synthesized by the following synthesis route.
[0256] <合成経路 13 >  [0256] <Synthetic pathway 13>
[0257] [化 64] [0257] [Formula 64]
(27) (")  (27) (")
Figure imgf000038_0001
Figure imgf000038_0001
[0258] 合成経路 13で一般式（29) [0258] In the synthetic route 13, the general formula (29)
[0259] [化 65] [0259] [Formula 65]
Figure imgf000038_0002
Figure imgf000038_0002
[0260] [式中、 R [0260] [where R
1、 R  1, R
2、 R  2, R
3、 R  3, R
6、 R  6, R
8、 X及び mは前述の通り]  8, X and m are as described above]
で表される化合物は前記一般式（27)で表される化合物を還元することによって製造 することができる（工程 13— 1)。  Can be produced by reducing the compound represented by the general formula (27) (Step 13-1).
[0261] 反応は、接触還元触媒であるパラジウム炭素、白金炭素、酸化白金、ロジウム炭素 、ルテニウム炭素等の存在下、好ましくはエチレンジァミンに被毒させた 5%パラジム 炭素を用い、エタノール、メタノール、 THF、 DMF、酢酸ェチル等の溶媒中、常圧一 加圧下の水素圧下に常温一 100°Cにて行うことができる。又、マグネシウムをメタノー ル中にて 0°C—常温下に作用させることによつても製造できる。  The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure. It can also be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
[0262] 合成経路 13で一般式（lv)で表される化合物は上記一般式（29)で表される化合 物を酸分解することによって製造することができる（工程 13— 2)。  [0262] In Synthesis Route 13, the compound represented by the general formula (lv) can be produced by acid-decomposing the compound represented by the general formula (29) (Step 13-2).
[0263] 反応は Rがメトキシメチル基の場合、酢酸、塩酸、臭化水素酸、メタンスルホン酸、  [0263] When R is a methoxymethyl group, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid,
8  8
トリフルォロ酢酸などの無機酸又は有機酸中、あるいはメタノール、エタノール、 THF 、 1, 4 ジォキサン、酢酸ェチルなどの有機溶媒との混合溶液中に作用させ、反応 温度は 0°C—常温下に行うことができる。又、ァセチル基、ベンゾィル基の場合には、 エタノール、メタノール、 THF, DMSOなどを溶媒として用いて水酸化ナトリウム水溶 液、水酸化カリウム水溶液、水酸化リチウム水溶液を作用させ加水分解後に上述した 酸分解を行うほうが好ましい。 Rが tーブチルジメチルシリル基、 tーブチルジフヱ-ル Operate in an inorganic or organic acid such as trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate, and perform the reaction at 0 ° C-room temperature. Can be. In the case of an acetyl group or a benzoyl group, It is preferable to carry out the above-mentioned acid decomposition after hydrolysis by using an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide using ethanol, methanol, THF, DMSO or the like as a solvent. R is t-butyldimethylsilyl group, t-butyldipropyl
8  8
シリル基の場合も上述の酸分解法にて行うこともできる力 THFを溶媒としてテトラブ チルアンモ -ゥムフルオリド、 KF、 CsFと 0°C—常温下にて反応させた後に酸分解す る方法がより好ましい。  In the case of a silyl group, it is also possible to carry out the acid decomposition method described above. More preferably, a method is used in which THF is used as a solvent to react with tetrabutylammonium-dimethyl fluoride, KF, and CsF at 0 ° C.-room temperature and then acid decomposition is performed. .
[0264] 又上記一般式（lv)で表される化合物は、前記一般式（It)で表される化合物を還 元することによつても製造することができる（工程 13— 3)。  [0264] The compound represented by the general formula (lv) can also be produced by reducing the compound represented by the general formula (It) (step 13-3).
[0265] 反応は、接触還元触媒であるパラジウム炭素、白金炭素、酸化白金、ロジウム炭素 、ルテニウム炭素等の存在下、好ましくはエチレンジァミンに被毒させた 5%パラジム 炭素を用い、エタノール、メタノール、 THF、 DMF、酢酸ェチル等の溶媒中、常圧一 加圧下の水素圧下に常温一 100°Cにて行うことができる。又、マグネシウムをメタノー ル中にて 0°C—常温下に作用させることによつても製造できる。  The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol, and THF. , DMF, ethyl acetate, etc., at a normal temperature and 100 ° C. under a hydrogen pressure under normal pressure and pressure. It can also be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
[0266] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基又は炭素数 1  [0266] Among the compounds represented by the general formula (1), R-hydroxymethyl group or carbon number 1
4 一 4の低 級アルコキシメチル基、 Rが水素原子、 Yが (CH)である化合物、すなわち一般式（1  A compound in which 14 lower alkoxymethyl groups, R is a hydrogen atom, and Y is (CH), that is, a compound represented by the general formula (1
5 2  5 2
w)  w)
[0267] [化 66]  [0267] [Formula 66]
Figure imgf000039_0001
Figure imgf000039_0001
[0268] [式中、1^、1^、1^ び111は前述の通り] [0268] [where 1 ^, 1 ^, 1 ^ and 111 are as described above]
1 2 3、1^、 及  1 2 3, 1 ^, and
7  7
で表される化合物は前記一般式（ lv)で表される化合物を加水分解することによって 製造することができる。  Can be produced by hydrolyzing the compound represented by the general formula (lv).
[0269] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0269] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent. The temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
[0270] 又、一般式（lv)で表される化合物は前記一般式（29)で表される化合物を加水分 解後、酸分解すること〖こよっても製造することができる。 [0271] Rが tーブチルジメチルシリル基、 tーブチルジフヱ-ルシリル基の場合、 THFを溶媒[0270] The compound represented by the general formula (lv) can also be produced by hydrolyzing the compound represented by the general formula (29) followed by acid decomposition. [0271] When R is a t-butyldimethylsilyl group or a t-butyldifluorosilyl group, THF is used as a solvent.
8 8
としてテトラプチルアンモ -ゥムフルオリド、 KF CsFと 0°C 常温下にて反応させた 後に加水分解を行なうことが好ましい。反応は水酸化ナトリウム水溶液、水酸化力リウ ム水溶液、水酸化リチウム水溶液などの塩基の存在下、反応溶媒としてはメタノール 、エタノール、 1, 4 ジォキサン、 DMF DMSOなどを用い、反応温度は 0°C 加熱 還流下に行いエステル部分を加水分解した後、酢酸、塩酸、臭化水素酸、メタンスル ホン酸、トリフルォロ酢酸などの無機酸又は有機酸中、あるいはメタノール、エタノー ル、 THF 1, 4 ジォキサン、酢酸ェチルなどの有機溶媒との混合溶液中に作用さ せ、反応温度は 0°C 常温下に行うことができる。  It is preferable to carry out hydrolysis after reacting with tetrabutylammonium fluoride and KFCsf at 0 ° C. at room temperature. The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous hydroxide solution of lithium, or an aqueous solution of lithium hydroxide. After heating under reflux to hydrolyze the ester moiety, the residue is dissolved in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or in methanol, ethanol, THF 1,4-dioxane, or acetic acid. The reaction can be carried out in a mixed solution with an organic solvent such as ethyl, at a reaction temperature of 0 ° C. at room temperature.
[0272] 一般式（1)で表される化合物のうち、 R力ヒドロキシメチル基又は炭素数 1 4の低 [0272] Among the compounds represented by the general formula (1), R-hydroxymethyl group or a compound having a low carbon number of 14
4  Four
級アルコキシメチル基、 Rが炭素数 1 4の低級アルキル基又はべンジル基で、 Yが  A lower alkoxymethyl group, R is a lower alkyl group having 14 carbon atoms or a benzyl group, and Y is
5  Five
CH OCHである化合物、すなわち一般式（lx)  A compound of the formula CH OCH, ie the general formula (lx)
2 2  twenty two
[0273] [化 67]  [0273] [Formula 67]
(1 x)( 1 x )
Figure imgf000040_0001
Figure imgf000040_0001
[0274] [式中、 R R R R R X及び mは前述の通り] [Wherein, R R R R R X and m are as described above]
1 2 3 6 7  1 2 3 6 7
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0275] <合成経路 14 > [Synthetic Route 14]
[0276] [化 68] [0276] [Formula 68]
Figure imgf000040_0002
Figure imgf000040_0002
[0277] 合成経路 14で一般式（30) [0278] [化 69] [0277] In the synthetic route 14, the general formula (30) [0278] [Formula 69]
Figure imgf000041_0001
Figure imgf000041_0001
[0279] [式中、 R 、 R 、 R 、 R 、 R、 Boc、 X及び mは前述の通り] [Wherein, R 1, R 2, R 3, R 4, R, Boc, X and m are as described above]
1 2 3 6 8  1 2 3 6 8
で表される化合物は前記一般式（ 19)で表される化合物と前記一般式（13)で表され る化合物を反応させることによって製造することができる（工程 14 1)。  Can be produced by reacting the compound represented by the general formula (19) with the compound represented by the general formula (13) (Step 141).
[0280] 反応は、水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液等 の塩基とベンゼン又はトルエン、キシレンを溶媒として用い、テトラプチルアンモ-ゥ ムクロリド、テトラプチルアンモ-ゥムブロミド、テトラプチルアンモ-ゥムョージド、テト ラベンジルアンミニゥムブロミド等の 4級アンモ-ゥム塩を触媒量カ卩え、 0°C— 80°C、 好ましくは常温下に行うことができる。  [0280] The reaction is performed using a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent, and using tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as butylammonium and tetrabenzylammonium bromide can be prepared in a catalytic amount at 0 ° C. to 80 ° C., preferably at room temperature.
[0281] 合成経路 14で一般式（lx)で表される化合物は、上記一般式（30)で表される化合 物を酸分解することによって製造することができる (工程 14 2)。  The compound represented by the general formula (lx) in the synthesis route 14 can be produced by acid-decomposing the compound represented by the general formula (30) (Step 142).
[0282] 反応は Rがメトキシメチル基の場合、酢酸、塩酸、臭化水素酸、メタンスルホン酸、  [0282] When R is a methoxymethyl group, acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid,
8  8
トリフルォロ酢酸などの無機酸又は有機酸中、あるいはメタノール、エタノール、 THF 、 1, 4 ジォキサン、酢酸ェチルなどの有機溶媒との混合溶液中に作用させ、反応 温度は 0°C—常温下に行うことができる。又、ァセチル基、ベンゾィル基の場合には、 エタノール、メタノール、 THF, DMSOなどを溶媒として用いて水酸化ナトリウム水溶 液、水酸化カリウム水溶液、水酸化リチウム水溶液を作用させ加水分解後に上述した 酸分解を行うほうが好ましい。 Rが tーブチルジメチルシリル基、 tーブチルジフヱ-ル  Operate in an inorganic or organic acid such as trifluoroacetic acid, or in a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate, and perform the reaction at 0 ° C-room temperature. Can be. In the case of an acetyl group or a benzoyl group, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide is used as a solvent with ethanol, methanol, THF, DMSO, or the like, and the above-described acid decomposition is performed after hydrolysis. It is preferable to perform R is t-butyldimethylsilyl group, t-butyldipropyl
8  8
シリル基の場合も上述の酸分解法にて行うこともできる力 THFを溶媒としてテトラブ チルアンモ -ゥムフルオリド、 KF、 CsFと 0°C—常温下にて反応させた後に酸分解す る方法がより好ましい。  In the case of a silyl group, it is also possible to carry out the acid decomposition method described above. More preferably, a method is used in which THF is used as a solvent to react with tetrabutylammonium-dimethyl fluoride, KF, and CsF at 0 ° C.-room temperature and then acid decomposition is performed. .
[0283] 一般式（1)で表される化合物のうち、 Rがヒドロキシメチル基、炭素数 1一 4の低級  [0283] Among the compounds represented by the general formula (1), R represents a hydroxymethyl group,
4  Four
アルコキシメチル基、 Rが水素原子、 Yが CH OCHである化合物、すなわち一般式（  A compound wherein an alkoxymethyl group, R is a hydrogen atom and Y is CH 2 OCH,
5 2 2  5 2 2
ly) [0284] [化 70] ly) [0284] [Formula 70]
Figure imgf000042_0001
Figure imgf000042_0001
[0285] [式中、1^ 及び り] [0285] [where, 1 ^ and ri]
1、1^ 1, 1 ^
2、1^  2, 1 ^
3、1^、 111は前述の通  3, 1 ^, 111
7  7
で表される化合物は、上記一般式（lx)で表される化合物を加水分解することによつ て製造することができる。  The compound represented by the general formula (1x) can be produced by hydrolyzing the compound represented by the general formula (lx).
[0286] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1 , 4 ジォキサン、 DM[0286] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM
F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。 The reaction can be carried out using F, DMSO, etc., at a reaction temperature of 0 ° C. while heating under reflux.
[0287] 又、前記一般式 (30)で表される化合物を加水分解後、酸分解することによつても 製造することができる。 [0287] The compound can also be produced by hydrolyzing the compound represented by the general formula (30) and then subjecting it to acid decomposition.
[0288] Rが tーブチルジメチルシリル基、 tーブチルジフエ-ルシリル基の場合のみ、 THFを  [0288] Only when R is a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group, THF
8  8
溶媒としてテトラプチルアンモ -ゥムフルオリド、 KF、 CsFと 0°C—常温下にて反応さ せた後に加水分解させることが好ましい。反応は水酸化ナトリウム水溶液、水酸化力 リウム水溶液、水酸化リチウム水溶液などの塩基の存在下、反応溶媒としてはメタノ ール、エタノール、 1 , 4 ジォキサン、 DMF、 DMSOなどを用い、反応温度は 0°C— 加熱還流下に行いエステル部分を加水分解した後、酢酸、塩酸、臭化水素酸、メタ ンスルホン酸、トリフルォロ酢酸などの無機酸又は有機酸中、あるいはメタノール、ェ タノール、 THF、 1 , 4 ジォキサン、酢酸ェチルなどの有機溶媒との混合溶液中に 作用させ、反応温度は 0°C—常温下に行うことができる。  It is preferable to react with tetrabutylammonium fluoride, KF, and CsF as a solvent at 0 ° C.-room temperature and then hydrolyze. The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent, and the reaction temperature is 0. ° C—Heat under reflux to hydrolyze the ester moiety, and then in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or methanol, ethanol, THF, 1, 4 The compound is allowed to act in a mixed solution with an organic solvent such as dioxane and ethyl acetate, and the reaction can be carried out at a temperature of 0 ° C to room temperature.
[0289] 一般式（1)で表される化合物のうち、 R力 CH OCH CO R 4の低 [0289] Among the compounds represented by the general formula (1), low R-force CH OCH CO R 4
4 2 2 2 5、 Rが炭素数 1  4 2 2 2 5, R is carbon number 1
5 一 級アルキル基又はべンジル基、 Yが CH OCHである化合物、すなわち一般式（lz)  5 Primary alkyl group or benzyl group, a compound wherein Y is CH OCH, that is, a compound represented by the general formula (lz)
2 2 [0290] [ィ匕 71] twenty two [0290] [I-71]
Figure imgf000043_0001
Figure imgf000043_0001
[0291] [式中、 、！^、1 、1^、 及び111は前述の通り] [0291] [where,,! ^, 1, 1 ^, and 111 are as described above]
1 2 3 6  1 2 3 6
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0292] <合成経路 15 >  [0292] <Synthetic pathway 15>
[0293] [化 72] [0293] [Formula 72]
Figure imgf000043_0002
Figure imgf000043_0002
[0294] 合成経路 15で一般式（31)  [0294] In Synthesis Route 15, General Formula (31)
[0295] [化 73] (31)[0295] [Formula 73] (31)
Figure imgf000043_0003
Figure imgf000043_0003
[0296] [式中、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [Wherein, R, R, R, R, Boc, X and m are as described above]
1 2 3 6  1 2 3 6
で表される化合物は、一般式（30— 1)  The compound represented by the general formula (30-1)
[0297] [化 74] (30-1)[0297] [Formula 74] (30-1)
Figure imgf000043_0004
Figure imgf000043_0004
[0298] [式中、 R、 R、 R、 R、 Boc、 X及び mは前述の通り] [Wherein, R, R, R, R, Boc, X and m are as described above]
1 2 3 6  1 2 3 6
で表される化合物と前記一般式（13)で表される化合物を反応させることによって製 造することができる（工程 15—1)。 By reacting a compound represented by the general formula (13) with a compound represented by the general formula (13). (Step 15-1).
[0299] 反応は、水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液等 の塩基とベンゼン又はトルエン、キシレンを溶媒として用い、テトラプチルアンミニゥム クロリド、テトラプチルアンモ-ゥムブロミド、テトラプチルアンミニゥムョ一ジド、テトラべ ンジルアンミニゥムブロミド等の 4級アンモ-ゥム塩を触媒量カ卩え、 0°C— 80°C、好ま しくは常温下に行うことができる。  [0299] The reaction is performed using a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution and benzene, toluene, or xylene as a solvent, using tetrabutylammonium chloride, tetrabutylammonium bromide, Quaternary ammonium salts such as tetrabutylammonium amide and tetrabenzylammonium bromide can be prepared in catalytic amounts at 0 ° C to 80 ° C, preferably at room temperature. it can.
[0300] 合成経路 15で一般式（lz)で表される化合物は、上記一般式（31)で表される化合 物を酸分解させることによって製造することができる（工程 15— 2)。  [0300] In Synthesis Route 15, the compound represented by the general formula (lz) can be produced by acid-decomposing the compound represented by the general formula (31) (Step 15-2).
[0301] 反応は酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機酸 又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェチ ルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこと ができる。  [0301] The reaction is carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, and trifluoroacetic acid, or with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl acetate. At a reaction temperature of 0 ° C-normal temperature.
[0302] 一般式（1)で表される化合物のうち、 R力 CH OCH CO H 、 Yが  [0302] Among the compounds represented by the general formula (1), R force CH OCH CO H and Y
4 2 2 2 、 Rが水素原子  4 2 2 2, R is a hydrogen atom
5  Five
CH OCHである化合物、すなわち一般式（1A)  A compound of the formula CH OCH, that is, a compound of the general formula (1A)
2 2  twenty two
[0303] [化 75]  [0303] [Formula 75]
Figure imgf000044_0001
Figure imgf000044_0001
[0304] [式中、 R [0304] [where R
1、 R  1, R
2、 R  2, R
3、 X及び mは前述の通り]  3, X and m are as described above]
で表される化合物は上記一般式（lz)で表される化合物を加水分解することによって 製造することができる。  Can be produced by hydrolyzing a compound represented by the above general formula (lz).
[0305] 反応は、水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液な どの塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 D MF、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0305] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like as a reaction solvent. The reaction can be carried out at a temperature of 0 ° C. while heating under reflux.
[0306] 又、前記一般式 (31)で表される化合物を加水分解後、酸分解することによつても 製造することができる。  [0306] Further, the compound can also be produced by hydrolyzing the compound represented by the general formula (31) and then decomposing it with acid.
[0307] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行いエステル部分を加水分 解した後、酢酸、塩酸、臭化水素酸、メタンスルホン酸、トリフルォロ酢酸などの無機 酸又は有機酸中、あるいはメタノール、エタノール、 THF、 1, 4 ジォキサン、酢酸ェ チルなどの有機溶媒との混合溶液中に作用させ、反応温度は 0°C—常温下に行うこ とがでさる。 [0307] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DM Using F, DMSO, etc., at a reaction temperature of 0 ° C and heating under reflux to hydrolyze the ester moiety, and then inorganic or organic acids such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, etc. The reaction can be carried out at 0 ° C-normal temperature by acting in a medium or a mixed solution with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate.
[0308] 一般式（1)で表される化合物のうち、 Rが水素原子、 Yが (CH )、 Rが水素原子で  [0308] Among the compounds represented by the general formula (1), R is a hydrogen atom, Y is (CH), and R is a hydrogen atom.
3 2 0 5  3 2 0 5
ある化合物、すなわち一般式（1B)  Certain compounds, ie, general formula (1B)
[0309] [化 76] [0309] [Formula 76]
(1 B)(1 B)
Figure imgf000045_0001
Figure imgf000045_0001
[0310] [式中、 R、R、R、X及び mは前述の通り] [0310] [wherein, R, R, R, X and m are as described above]
1 2 4  1 2 4
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0311] <合成経路 16 >  [0311] <Synthetic route 16>
[0312] [化 77] [0312] [Formula 77]
Figure imgf000045_0002
Figure imgf000045_0002
[0313] 合成経路 16で一般式（32)  [0313] General formula (32) in synthetic route 16
[0314] [化 78] [0314] [Formula 78]
¾ ^ (CCHH2))m C0C 2R0 6 2R6 ) ¾ ^ (CCHH 2 )) m C0 C 2 R 0 6 2R6 )
[0315] [式中、尺、！^、1^、1^、 及び111は前述の通り] [0315] [In the formula, shaku! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 4 6  1 2 4 6
で表される化合物は、前記一般式（2)で表される化合物と一般式（35) [0316] [化 79]
Figure imgf000046_0001
Is a compound represented by the general formula (2) and a compound represented by the general formula (35) [0316] [Formula 79]
Figure imgf000046_0001
[0317] [式中、 R及び Rは前述の通り] [0317] [wherein, R and R are as described above]
4 6  4 6
で表される化合物を塩基存在下に作用させることによって製造することができる（ェ 程 16 - 1)。  Can be produced by allowing the compound represented by the formula to act in the presence of a base (step 16-1).
[0318] 反応はメタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFなどを反 応溶媒として用い、水素化ナトリウム、水素化カリウム、ナトリウムアルコキシド、力リウ ムアルコキシド、炭酸カリウム、炭酸ナトリウムなどの無機塩基の存在下、反応温度と しては 0°C—加熱還流下にて、好適には 80°C— 100°Cにて行うことができる。  [0318] In the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF and the like are used as reaction solvents, and sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, potassium carbonate, sodium carbonate and the like are used. The reaction can be carried out in the presence of an inorganic base at a reaction temperature of 0 ° C to reflux under heating, preferably at 80 ° C to 100 ° C.
[0319] 合成経路 16で一般式（33)  [0319] In synthetic route 16, the general formula (33)
[0320] [化 80]
Figure imgf000046_0002
[0320] [Formula 80]
Figure imgf000046_0002
[0321] [式中、尺、！^、1^、1^、 及び111は前述の通り] [0321] [In the formula, shaku! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 4 6  1 2 4 6
で表される化合物は、前記一般式（32)で表される化合物を加水分解することによつ て製造することができる（工程 16— 2)。  Can be produced by hydrolyzing the compound represented by the general formula (32) (step 16-2).
[0322] 反応は水酸化ナトリウム水溶液、水酸ィ匕カリウム水溶液、水酸化リチウム水溶液など の塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 DM F、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0322] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, and using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent. The temperature is 0 ° C.—the reaction can be carried out under heating to reflux.
、好ましくは水酸ィ匕カリウムをエタノール溶媒中で 50°Cにて作用させる方法が良!、。  Preferably, potassium hydroxide is allowed to act at 50 ° C. in an ethanol solvent.
[0323] 合成経路 16で一般式（34)  [0323] In the synthesis route 16, the general formula (34)
[0324] [化 81]
Figure imgf000046_0003
[0324] [Formula 81]
Figure imgf000046_0003
[0325] [式中、 Rは炭素数 1一 4の低級アルキル基を示し、 R、 R、 R、 R、 X及び mは前述 の通り] [0325] [wherein, R represents a lower alkyl group having 14 to 14 carbon atoms, and R, R, R, R, X, and m are as defined above. Street]
で表される化合物は、上記一般式（33)で表される化合物をクルチウス (Curtius)転 位させることによって製造することができる（工程 16— 3)。  Can be produced by subjecting the compound represented by the above general formula (33) to Curtius rearrangement (step 16-3).
[0326] 反応は、カルボキシル基を力ルバマートに変換する一般的手法を用いることができ 、例えばクロル炭酸ェチルと NaNを用いる方法や、好ましくはジフエ-ルリン酸アジド For the reaction, a general method for converting a carboxyl group into olebamate can be used. For example, a method using ethyl chlorocarbonate and NaN, or preferably a method using azide diphenyl phosphate
3  Three
(DPPA)をトリエチルァミンなどの塩基存在下、ベンゼンやトルエン溶媒中加熱撹拌 した後にメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、 tーブ タノールなどの低級アルコールを加えて加熱撹拌を継続する力、もしくは低級アルコ ールのみを反応溶媒として用い加熱撹拌下、好ましくは加熱還流下に行うことができ る。  (DPPA) is heated and stirred in a benzene or toluene solvent in the presence of a base such as triethylamine, and then added with a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol to continue heating and stirring. Alternatively, the reaction can be carried out under heating and stirring, preferably under heating to reflux, using only lower alcohol as a reaction solvent.
[0327] 合成経路 16で前述一般式（1B)で表される化合物は、上記一般式（34)で表され る化合物を加水分解することによって製造することができる（工程 16— 4)。  [0327] In Synthesis Route 16, the compound represented by the aforementioned general formula (1B) can be produced by hydrolyzing the compound represented by the aforementioned general formula (34) (Step 16-4).
[0328] 反応は、メタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFなどを 反応溶媒として用い、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウ ム水溶液などの塩基の存在下、反応温度としては 0°C—加熱還流下にて、好適には 80。C一 100。Cにて行うこと力 Sできる。  [0328] The reaction is carried out using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution. The temperature is 0 ° C—under reflux with heating, preferably 80. C-1 100. The ability to do in C
[0329] 一般式（1)で表される化合物のうち、 Rが水素原子、 Rが水素原子、 Yが CH=CH  [0329] Among the compounds represented by the general formula (1), R is a hydrogen atom, R is a hydrogen atom, and Y is CH = CH
3 5  3 5
である化合物、すなわち一般式（1C)  A compound of general formula (1C)
[0330] [化 82] [0330] [Formula 82]
Figure imgf000047_0001
Figure imgf000047_0001
[0331] [式中、 R、R [0331] [where R, R
2、R  2, R
1 4、X及び mは前述の通り]  14, X and m are as described above]
で表される化合物は、下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0332] <合成経路 17 > [0333] [化 83] [0332] <Synthetic route 17> [0333] [Formula 83]
Figure imgf000048_0001
Figure imgf000048_0001
[0334] 合成経路 17で一般式（36)  [0334] In Synthesis Route 17, General Formula (36)
[0335] [化 84] [0335] [Formula 84]
R I Ί LNHCO2R9 (36) R I Ί LNHCO 2 R 9 (36)
ヽ OH  ヽ OH
[0336] [式中、尺、！^、1^、1^、 及び111は前述の通り]  [0336] [In the formula, shaku! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 4 9  1 2 4 9
で表される化合物は、前記一般式（34)で表される化合物を還元することによって製 造することができる（工程 17— 1)。  Can be produced by reducing the compound represented by the general formula (34) (Step 17-1).
[0337] 反応は BHや 9 BBNのようなアルキルボラン誘導体、（iBu) A1H、 NaBH、 LiAlH [0337] The reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiAlH
3 2 4 4 等の金属水素錯化合物、好ましくは LiBHを用い、反応溶媒としては THF、 1, 4ージ  A metal-hydrogen complex compound such as 3244, preferably LiBH, is used.
4  Four
ォキサンやエタノール、メタノールなどを用い、反応温度は o°c—加熱還流下、好適 には常温下にて行うことができる。  The reaction can be carried out using oxane, ethanol, methanol, or the like, at a reaction temperature of o ° C under heating to reflux, preferably at room temperature.
[0338] 合成経路 17で一般式（37)  [0338] In the synthetic route 17, the general formula (37)
[0339] [化 85]
Figure imgf000048_0002
[0339] [Formula 85]
Figure imgf000048_0002
[0340] [式中、1^、1^、1^、1^、 及び111は前述の通り] [0340] [wherein 1 ^, 1 ^, 1 ^, 1 ^, and 111 are as described above]
1 2 4 9  1 2 4 9
で表される化合物は、前記一般式（36)で表される化合物を酸ィ匕することによって製 造することができる（工程 17— 2)。  Can be produced by subjecting the compound represented by the general formula (36) to acidification (step 17-2).
[0341] 反応は一般に用いられるアルコールのアルデヒドへの酸ィ匕手法を用いることができ 、例えばクロ口クロム酸ピリジニゥム、ニクロム酸ピリジニゥムなどの酸化クロム ピリジ ン錯体や酸化クロム、炭酸銀、二酸化マンガン等の金属酸化剤や、塩化ォキザリル、 無水トリフルォロ酢酸、無水酢酸、 DCC、三酸化硫黄 -ピリジン錯体等の各種 DMS O活性化剤を用いた DMSO酸ィ匕が挙げられる。 [0341] The reaction can be carried out using a commonly used method for converting alcohol to aldehyde. For example, chromium pyridinium complexes such as pyridinium chromate and pyridinium dichromate, metal oxidants such as chromium oxide, silver carbonate and manganese dioxide, oxalyl chloride, trifluoroacetic anhydride, acetic anhydride, DCC, sulfur trioxide- Examples include DMSO oxidation using various DMS O activators such as pyridine complexes.
[0342] 合成経路 17で一般式（38)  [0342] In the synthesis route 17, the general formula (38)
[0343] [化 86]  [0343] [Formula 86]
Figure imgf000049_0001
Figure imgf000049_0001
[0344] [式中、 R、R、R、R、R、 X及び Mは前述の通り] [0344] [wherein, R, R, R, R, R, X and M are as described above]
1 2 4 6 9  1 2 4 6 9
で表される化合物は、前記一般式（37)で表される化合物と前記一般式（10)で表さ れる化合物を反応させることによって製造することができる（工程 17— 3)。  Can be produced by reacting the compound represented by the general formula (37) with the compound represented by the general formula (10) (step 17-3).
[0345] 反応は THF、 DMSO, 1, 4 ジォキサンを溶媒として用い、一般式（10)で表される 化合物を水素化ナトリウム、水素化カリウム、ナトリウムメトキシド、ナトリウムエトキシド、 ナトリウム tーブトキシド、カリウムメトキシド、カリウムエトキシド、カリウム t ブトキシド などを塩基として用い、 0°C—常温下に作用させた後、一般式 (37)で表される化合 物と反応させることができる。  In the reaction, THF, DMSO, 1,4-dioxane were used as solvents, and the compound represented by the general formula (10) was converted to sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium Using methoxide, potassium ethoxide, potassium t-butoxide, or the like as a base, it is allowed to react at 0 ° C.-normal temperature, and then reacted with the compound represented by the general formula (37).
[0346] 合成経路 17で前記一般式（1C)で表される化合物は、上記一般式（38)で表され る化合物を加水分解することによって製造することができる（工程 17— 4)。  [0346] In the synthesis route 17, the compound represented by the general formula (1C) can be produced by hydrolyzing the compound represented by the general formula (38) (step 17-4).
[0347] 反応は、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液な どの塩基の存在下、反応溶媒としてはメタノール、エタノール、 1, 4 ジォキサン、 D MF、 DMSOなどを用い、反応温度は 0°C—加熱還流下に行うことができる。  [0347] The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution, using methanol, ethanol, 1,4-dioxane, DMF, DMSO, or the like as a reaction solvent, and the reaction temperature. Can be carried out at 0 ° C. with heating under reflux.
[0348] 一般式（1)で表される化合物のうち、 Rが水素原子、 Rが水素原子、 Yが (CH )で  [0348] Among the compounds represented by the general formula (1), R is a hydrogen atom, R is a hydrogen atom, and Y is (CH).
3 5 2 2 ある化合物、すなわち一般式（1D) [0349] [化 87] 3 5 2 2 Certain compounds, that is, general formula (1D) [0349] [Formula 87]
Figure imgf000050_0001
Figure imgf000050_0001
[0350] [式中、 R、R、R、Χ及び mは前述の通り]  [0350] [wherein, R, R, R, Χ, and m are as described above]
1 2 4  1 2 4
で表される化合物は、下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0351] <合成経路 18 >  [0351] <Synthetic pathway 18>
[0352] [化 88] [0352] [Formula 88]
(38) (1 C) (38) (1 C)
18-3 18-3
18-1 18-1
Figure imgf000050_0002
Figure imgf000050_0002
[0353] 合成経路 18で一般式（39) [0353] In the synthetic route 18, the general formula (39)
[0354] [化 89] [0354] [Formula 89]
Figure imgf000050_0003
Figure imgf000050_0003
[0355] [式中、 R、 R、 R、 R、 R、 X及び mは前述の通り] [Wherein, R, R, R, R, R, X and m are as described above]
1 2 4 6 9  1 2 4 6 9
で表される化合物は前記一般式（38)で表される化合物を還元することによって製造 することができる（工程 18— 1)。  Can be produced by reducing the compound represented by the above general formula (38) (Step 18-1).
[0356] 反応は、接触還元触媒であるパラジウム炭素、白金炭素、酸化白金、ロジウム炭素 、ルテニウム炭素等の存在下、好ましくはエチレンジァミンに被毒させた 5%パラジム 炭素を用い、エタノール、メタノール、 THF、 DMF、酢酸ェチル等の溶媒中、常圧一 加圧下の水素圧下に常温一 100°Cにて行うことができる。又、マグネシウムをメタノー ル中にて o°c—常温下に作用させることによつても製造できる。 The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure. In addition, magnesium It can also be produced by operating at o ° c-room temperature in a furnace.
[0357] 合成経路 18で前記一般式（1D)で表される化合物は上記一般式（39)で表される 化合物を加水分解することによって製造することができる（工程 18— 2)。 [0357] In the synthetic route 18, the compound represented by the general formula (1D) can be produced by hydrolyzing the compound represented by the general formula (39) (step 18-2).
[0358] 反応は、メタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFなどを 反応溶媒として用い、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウ ム水溶液などの塩基の存在下、反応温度としては 0°C—加熱還流下にて、好適には[0358] The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution. The temperature is 0 ° C-under heating reflux, preferably
80。C一 100。Cにて行うこと力 Sできる。 80. C-1 100. The ability to do in C
[0359] 又、前記一般式（1C)で表される化合物を還元することによつても製造することがで きる（工程 18— 3)。 [0359] Alternatively, the compound can also be produced by reducing the compound represented by the general formula (1C) (Step 18-3).
[0360] 反応は、接触還元触媒であるパラジウム炭素、白金炭素、酸化白金、ロジウム炭素 、ルテニウム炭素等の存在下、好ましくはエチレンジァミンに被毒させた 5%パラジム 炭素を用い、エタノール、メタノール、 THF、 DMF、酢酸ェチル等の溶媒中、常圧一 加圧下の水素圧下に常温一 100°Cにて行うことができる。又、マグネシウムをメタノー ル中にて 0°C—常温下に作用させることによつても製造できる。  The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon or the like, preferably using 5% palladium carbon poisoned with ethylenediamine, using ethanol, methanol and THF. , DMF, ethyl acetate, etc., at normal temperature and 100 ° C under hydrogen pressure under normal pressure and pressure. It can also be produced by allowing magnesium to act in methanol at 0 ° C.-room temperature.
[0361] 一般式（1)で表される化合物のうち、 Rが水素原子、 Rが水素原子、 Yが (CH )で  [0361] Among the compounds represented by the general formula (1), R is a hydrogen atom, R is a hydrogen atom, and Y is (CH 2)
3 5 2 ある化合物、すなわち一般式（1E)  3 52 2 A certain compound, that is, the general formula (1E)
[0362] [化 90] [0362] [Formula 90]
R1 NH, R1 NH,
(1 E)  (1 E)
、C。2H , C. 2 H
[0363] [式中、 R、R [0363] [wherein, R, R
2、R  2, R
4、X及び mは前述の通り]  4, X and m are as described above]
1  1
で表される化合物は下記合成経路によって合成することができる。  Can be synthesized by the following synthesis route.
[0364] <合成経路 19 > [0365] [化 91] [0364] <Synthetic pathway 19> [0365] [Formula 91]
Figure imgf000052_0001
Figure imgf000052_0001
[0366] 合成経路 19で一般式 (40) [0366] In synthesis route 19, general formula (40)
[0367] [化 92]
Figure imgf000052_0002
[0367] [Formula 92]
Figure imgf000052_0002
[0368」 [式中、1^、1^、1^、1^、 及び [0368] [where 1 ^, 1 ^, 1 ^, 1 ^, and
1 2 4 6 111は前述の通り]  1 2 4 6 111 is as described above]
で表される化合物は前記一般式（32)で表される化合物を還元することによって製造 することができる（工程 19— 1)。  Can be produced by reducing the compound represented by the general formula (32) (Step 19-1).
[0369] 反応は BHや 9 BBNのようなアルキルボラン誘導体、（iBu) A1H、 NaBH、 LiBH、 [0369] The reaction is an alkylborane derivative such as BH or 9BBN, (iBu) A1H, NaBH, LiBH,
3 2 4 4 3 2 4 4
LiAlH等の金属水素錯化合物、好ましくはトリブトキシ水素化アルミニウムリチウム（Metal hydride complex compounds such as LiAlH, preferably lithium aluminum tributoxy hydride (
4 Four
LiAl(t0Bu〇））を用い、反応溶媒としては THF、 1， 4 ジォキサンやエタノール、メタ  LiAl (t0Bu〇)) and the reaction solvent is THF, 1,4-dioxane, ethanol,
3  Three
ノールなどを用い、反応温度は o°c—加熱還流下、好適には常温下にて行うことがで きる。  The reaction can be carried out at a reaction temperature of o ° C-heating under reflux, preferably at room temperature, using phenol or the like.
[0370] 合成経路 19で一般式 (41) [0371] [化 93]
Figure imgf000053_0001
[0370] In synthesis route 19, general formula (41) [0371] [Formula 93]
Figure imgf000053_0001
[0372] [式中、 R、 R、 R、 R、 B、 X及び mは前述の通り] [0372] [wherein, R, R, R, R, B, X and m are as described above]
1 2 4 6  1 2 4 6
で表される化合物は上記一般式 (40)で表される化合物をハロゲンィ匕する力、メタン スルホユルクロリドあるいは p—トルエンスルホユルク口リドと作用させることによって製 造することができる（工程 19— 2)。  Can be produced by reacting the compound represented by the above general formula (40) with methanesulfuryl chloride or p-toluenesulfuryl chloride by a halogenating force (step 19-). 2).
[0373] 反応はハロゲン化の場合、トリフエ-ルフォスフィン、イミダゾールの存在下、塩化メ チレン、 THF、 1, 4 ジォキサンを反応溶媒として用い、 0°C—常温下にて四塩化炭 素、四臭化炭素あるいはヨウ素等を反応させて製造することができる。又、スルホン酸 エステル体は塩化メチレン、クロ口ホルム、ベンゼンなどの溶媒を用い、ピリジン、トリ ェチルァミン等の有機塩基存在下、パラトルエンスルホニルクロリド、又はメタンスル ホニルクロリドと 0°C— 80°Cにて好ましくは常温下にて反応させ対応するスルホン酸 エステルを合成することができる。さらにこの化合物を、 THF、ァセトニトリル好ましく はアセトンを反応溶媒して用い、常温下力 加熱還流下に臭化ナトリウム、臭化力リウ ム、ヨウ化ナトリウムあるいはヨウ化カリウムを作用させてハロゲン体を製造することも できる。 [0373] In the case of halogenation, in the case of halogenation, methyl tetrachloride, THF, and 1,4-dioxane are used as reaction solvents in the presence of triphenylphosphine and imidazole, and carbon tetrachloride and tetraodor are used at 0 ° C to room temperature. It can be produced by reacting carbon fluoride or iodine. The sulfonate is used at 0 ° C-80 ° C with paratoluenesulfonyl chloride or methanesulfonyl chloride in the presence of an organic base such as pyridine and triethylamine using a solvent such as methylene chloride, chloroform and benzene. Preferably, the reaction is carried out at room temperature to synthesize the corresponding sulfonic acid ester. The compound is further reacted with sodium bromide, lithium bromide, sodium iodide, or potassium iodide using THF, acetonitrile, or preferably acetone as a reaction solvent, and heating at room temperature under reflux to produce a halogenated compound. You can do it.
[0374] 合成経路 19で一般式 (42)  [0374] In synthesis route 19, general formula (42)
[0375] [化 94]
Figure imgf000053_0002
[0375] [Formula 94]
Figure imgf000053_0002
[0376] [式中、尺、！^、1^、1^、 及び111は前述の通り] [0376] [In the formula, shaku! ^, 1 ^, 1 ^, and 111 are as described above]
1 2 4 6  1 2 4 6
で表される化合物は、上記一般式 (41)で表されるィ匕合物を NaCN又は KCNと反応さ せることによって製造することができる（工程 19— 3)。  Can be produced by reacting the compound of formula (41) with NaCN or KCN (step 19-3).
[0377] 反応は THF、 DMSO、 DMF、 1, 4 ジォキサンを溶媒として用い、場合によっては水 を加え、常温一 100°Cにて行うことができる。 [0378] 合成経路 19で一般式 (43) [0377] The reaction can be carried out at room temperature and 100 ° C using THF, DMSO, DMF, or 1,4-dioxane as a solvent, optionally adding water. [0378] In the synthetic route 19, the general formula (43)
[0379] [化 95]
Figure imgf000054_0001
[0379] [Formula 95]
Figure imgf000054_0001
[0380] [式中、 R 、 R 、 R 、 X及び mは前述の通り] [Wherein, R, R, R, X and m are as described above]
1 2 4  1 2 4
で表される化合物は上記一般式 (42)で表される化合物を加水分解することによって 製造することができる（ 19 4)。  Can be produced by hydrolyzing the compound represented by the above general formula (42) (194).
[0381] 反応は、メタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFなどを 反応溶媒として用い、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウ ム水溶液などの塩基の存在下、反応温度としては 0°C—加熱還流下にて行うことがで きる。 [0381] The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution. The reaction can be performed at a temperature of 0 ° C with heating under reflux.
[0382] 合成経路 19で一般式 (44)  [0382] In the synthetic route 19, the general formula (44)
[0383] [化 96]
Figure imgf000054_0002
[0383] [Formula 96]
Figure imgf000054_0002
[0384] [式中、 R 、 R 、 R 、 X及び mは前述の通り] [Wherein, R 1, R 2, R 3, X and m are as described above]
1 2 4  1 2 4
で表される化合物は上記一般式 (43)で表される化合物を Curtius転位させることによ つて製造することができる（工程 19— 5)。  Can be produced by subjecting the compound represented by the general formula (43) to Curtius rearrangement (Step 19-5).
[0385] 反応は、カルボキシル基を力ルバマートに変換する一般的手法を用いることができ 、例えばクロル炭酸ェチルと NaNを用いる方法や、好ましくはジフエ-ルリン酸アジド For the reaction, a general method for converting a carboxyl group into olebamate can be used. For example, a method using ethyl chlorocarbonate and NaN, and preferably a diphenyl phosphate azide
3  Three
(DPPA)をトリエチルァミンなどの塩基存在下、ベンゼンやトルエン溶媒中加熱撹拌 した後にメタノール、エタノール、プロパノール、イソプロパノール、ブタノール、 tーブ タノールなどの低級アルコールを加えて加熱撹拌を継続する力、もしくは低級アルコ ールのみを反応溶媒として用い加熱撹拌下、好ましくは加熱還流下に行うことができ る。  (DPPA) is heated and stirred in a benzene or toluene solvent in the presence of a base such as triethylamine, and then added with a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol to continue heating and stirring. Alternatively, the reaction can be carried out under heating and stirring, preferably under heating to reflux, using only lower alcohol as a reaction solvent.
[0386] 合成経路 19で前述一般式（1E)で表される化合物は、上記一般式 (44)で表され る化合物を加水分解することによって製造することができる（工程 19— 6)。 The compound represented by the above general formula (1E) in the synthesis route 19 is represented by the above general formula (44) Can be produced by hydrolyzing the compound (Step 19-6).
[0387] 反応は、メタノール、エタノール、 1, 4 ジォキサン、 DMSO、 DMF、 THFなどを 反応溶媒として用い、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウ ム水溶液などの塩基の存在下、反応温度としては 0°C—加熱還流下にて、好適には[0387] The reaction is performed using methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like as a reaction solvent in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous lithium hydroxide solution. The temperature is 0 ° C-under heating reflux, preferably
80。C一 100。Cにて行うこと力 Sできる。 80. C-1 100. The ability to do in C
[0388] 又、各一般式中の Xが SO、 SOである化合物は、対応する Xが Sである化合物を酸 [0388] Further, a compound in which X is SO or SO in each of the general formulas is a compound in which the corresponding X is S.
2  2
ィ匕すること〖こよっても製造することができる。  It can also be manufactured.
[0389] 反応は 1, 4 ジォキサン、 DMSO、 DMF、 THF、塩化メチレン、クロ口ホルムなど を反応溶媒として用い、酸化剤として過マンガン酸カリウムやメタクロ口過安息香酸、 過酸化水素水を用い、 0°C—加熱還流下にて、好適には常温にて行うことができる。  [0389] The reaction was performed using 1,4-dioxane, DMSO, DMF, THF, methylene chloride, chloroform, etc. as the reaction solvent, and using potassium permanganate, metaclo-peroxybenzoic acid, and hydrogen peroxide as the oxidizing agent. The reaction can be carried out at 0 ° C.—with heating under reflux, preferably at room temperature.
[0390] <実施例 >  [0390] <Example>
次に本発明を具体例によって説明する力 これらの例によって本発明が限定される ものではない。  Next, the power of explaining the present invention by specific examples The present invention is not limited by these examples.
[0391] <参考例 1 > [0391] <Reference Example 1>
2 クロロー 4 [ (3—トリフルォロメチル）フエ-ルスルファ -ル]ベンズアルデヒド [0392] [化 97]
Figure imgf000055_0001
2 Chloro-4 [(3-trifluoromethyl) phenylsulfur] benzaldehyde [0392]
Figure imgf000055_0001
[0393] 2 クロロー 4 フルォロベンズアルデヒド（1.15g)、 3 （トリフルォロメチル）チオフエノ ール（1.33g)の DMF (20mL)溶液に炭酸カリウム（2.76g)をカ卩ぇ 120°Cにて 1時間加 熱撹拌した。反応液を水にあけ酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄 後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムク 口マトグラフィー（へキサン：酢酸ェチル = 10： 1)にて精製した。 目的物（1.96g)を淡 黄色油状物として得た。 [0393] Potassium carbonate (2.76 g) was added to a solution of 2chloro-4 fluorobenzaldehyde (1.15 g) and 3 (trifluoromethyl) thiophenol (1.33 g) in DMF (20 mL) at a temperature of 120 ° C. For 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). The desired product (1.96 g) was obtained as a pale yellow oil.
[0394] <参考例 2— 57 >  [0394] <Reference Example 2—57>
以下、種々のチオフヱノール及びフエノールを用い、上記参考例 1と同様な方法に よって表 1に示すィ匕合物を合成した。 6517 Hereinafter, using various thiophenols and phenols, the conjugates shown in Table 1 were synthesized in the same manner as in Reference Example 1 above. 6517
[0395] [表 1] 表 1
Figure imgf000056_0001
[0395] [Table 1] Table 1
Figure imgf000056_0001
1 R2 R3 R4 X 参考例 R1 2 R3 4 X 1 R2 R3 R4 X Reference example R1 2 R3 4 X
2 a c-CI H CI 0 30 i-PrO c-iPr H CI 02 a c-CI H CI 0 30 i-PrO c-iPr H CI 0
3 t-Bu H H H 0 31 1-PrO c-IPr H H 03 t-Bu H H H 0 31 1-PrO c-IPr H H 0
4 Me H H H O 32 P O H H CI 0 r 4 Me H H H O 32 P O H H CI 0 r
D l-fr O-rrr rl U •Hi n M π J β H H H O 34 PhCH20 H H Br 0D l-fr O-rrr rl UHin M π J β HHHO 34 PhCH 2 0 HH Br 0
7 H H H O 35 PhCH20 H H SMe 07 HHHO 35 PhCH 2 0 HH SMe 0
8 CF, H H H O 36 PhCHjO H H Me 08 CF, H H H O 36 PhCHjO H H Me 0
9 CF, H OMe H 0 37 P CHaO H H B 09 CF, H OMe H 0 37 P CH a OHHB 0
10 CF, H H OMe 0 38 P CH20 c-CI H CI 010 CF, HH OMe 0 38 P CH 2 0 c-CI H CI 0
11 CF, H H OCHaPh 0 39 PhCHj.0 H H CF, 011 CF, H H OCHaPh 0 39 PhCHj.0 H H CF, 0
12 CFa H CFS H 0 40 PhCH20 H H Ph 012 CF a H CF S H 0 40 PhCH 2 0 HH Ph 0
13 CF, H H CF, 0 41 PhCH^ C-PhCH20 H CI 013 CF, HH CF, 0 41 PhCH ^ C-PhCH 2 0 H CI 0
14 CF, c-CF3 H H 0 42 PhCHzO c-PhCH20 H H 014 CF, c-CF 3 HH 0 42 PhCH z O c-PhCH 2 0 HH 0
15 CF, o-CFj H CI 0 43 PhCHjO c-P CH20 H Pr 015 CF, o-CFj H CI 0 43 PhCHjO cP CH 20 H Pr 0
1β CF, b-CI H H 0 44 θΟ c-CF3 H H 01β CF, b-CI HH 0 44 θΟ c-CF 3 HH 0
17 CF, a-CI H H 0 45 MeS H H H 017 CF, a-CI H H 0 45 MeS H H H 0
18 CF, d-CI H H 0 46 PhCHaS H H H 018 CF, d-CI H H 0 46 PhCHaS H H H 0
19 CF, c-MeO H a 0 47 PhCHjS H H a 019 CF, c-MeO H a 0 47 PhCHjS H H a 0
20 Ph(CHj)2 H H 0 48 a c-CI H H s20 Ph (CHj) 2 HH 0 48 a c-CI HH s
21 Ph(CH,)2 H H CF, 0 49 CF3 c-CF3 H a s21 Ph (CH,) 2 HH CF, 0 49 CF 3 c-CF 3 H as
22 Ph(CHj)4 c-CF9 H H 0 50 CF3 C-CF3 H H s22 Ph (CHj) 4 c-CF 9 HH 0 50 CF 3 C-CF 3 HH s
23 o-CFs H CI 0 51 CF3 H H H s23 o-CFs H CI 0 51 CF 3 HHH s
24 Ph(CHa)ac-Ph(CHa)a H H 0 52 CF3 H H CF, s24 Ph (CHa) a c-Ph (CHa) a HH 0 52 CF 3 HH CF, s
2S H CF, 0 53 MeO H H a s2S H CF, 0 53 MeO H H a s
26 H CI 0 54 MeO H H H s26 H CI 0 54 MeO H H H s
27 CF, o-NOa H H 0 55 MeO H H CF, s27 CF, o-NOa H H 0 55 MeO H H CF, s
28 CFS H a H 0 56 PhCHjO H H a 028 CF S H a H 0 56 PhCHjO HH a 0
29 CF, H H O 0 57 PhCH^O H H i-Pr 0 29 CF, H H O 0 57 PhCH ^ O H H i-Pr 0
[0396] <参考例 58 > [0396] <Reference example 58>
2—フルオロー 4一 [ (3—トリフルォロメチル）フエノキシ]ベンズアルデヒド [0397] [化 98]
Figure imgf000057_0001
2-Fluoro-4-[(3-trifluoromethyl) phenoxy] benzaldehyde [0397] [Formula 98]
Figure imgf000057_0001
[0398] 3— (トリフルォロメチル）フエ-ルホウ酸（1.03g)、 2 フルオロー 4—ヒドロキシベンズァ ルデヒド（760mg)を塩化メチレン（20mL)に溶解し撹拌下、酢酸銅 (985mg)、モレキュ ラーシーブス 4A (800mg)、トリエチルァミン（3.76mL)を加えた。 6時間後、さらに 24時 間後酢酸銅を同量追加し、 48時間撹拌後不溶物を濾去し濾液を水にあけ酢酸ェチ ルにて抽出した。水、飽和食塩水の順に洗浄後、無水硫酸マグネシウムにて乾燥し た。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン:酢酸ェ チル = 7 : 1後 2 : 1)にて精製した。 目的物（265mg)を黄色油状物として得た。 [0398] 3- (Trifluoromethyl) phenolic borate (1.03 g) and 2-fluoro-4-hydroxybenzaldehyde (760 mg) were dissolved in methylene chloride (20 mL), and copper acetate (985 mg) and molecular weight were dissolved with stirring. Lacivese 4A (800 mg) and triethylamine (3.76 mL) were added. After 6 hours, further 24 hours later, the same amount of copper acetate was added. After stirring for 48 hours, insolubles were removed by filtration, the filtrate was poured into water and extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 followed by 2: 1). The desired product (265 mg) was obtained as a yellow oil.
[0399] <参考例 59 >  [0399] <Reference example 59>
2 フルオロー 4 [ (3 ベンジルォキシ）フエノキシ]ベンズアルデヒド  2 Fluoro-4 [(3 benzyloxy) phenoxy] benzaldehyde
[0400] [化 99]  [0400] [Formula 99]
Figure imgf000057_0002
Figure imgf000057_0002
[0401] 3—べンジルォキシフエ-ルホウ酸と 2 フルオロー 4ーヒドロキシベンズアルデヒドを用 い参考例 58と同様な方法によって目的物を無色油状物として得た。 [0401] The target product was obtained as a colorless oily substance in the same manner as in Reference Example 58 using 3-benzyloxyphenol-boric acid and 2-fluoro-4-hydroxybenzaldehyde.
[0402] <参考例 60 > [0402] <Reference Example 60>
2' クロロー 4'— [ (3—トリフルォロメチル）フエ-ルスルファ -ル]ケィヒ酸ェチル  2 'Chloro-4' — [(3-Trifluoromethyl) phenylsulfur] ethyl ethyl keichate
[0403] [化 100]
Figure imgf000057_0003
[0403] [100]
Figure imgf000057_0003
[0404] アルゴンガス気流下、 0°Cにてジェチルホスホノ酢酸ェチル（1 .35mL)の THF ( 30mL)溶液に 60%水素化ナトリウム (272mg)を加えて 30分撹拌後、参考例 1の化合 物（1.96g)の THF (15mL)溶液を滴下した。同温にて 2時間撹拌した後、水を加え、 酢酸ェチルにて抽出した。水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて 乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン： 酢酸ェチル = 10 : 1)にて精製した。 目的物（1.72g)を無色油状物として得た。 [0404] Under an argon gas flow, 60% sodium hydride (272mg) was added to a THF (30mL) solution of ethyl phosphonoacetate (1.35mL) at 0 ° C, and the mixture was stirred for 30 minutes, and then the compound of Reference Example 1 was added. (1.96 g) in THF (15 mL) was added dropwise. After stirring at the same temperature for 2 hours, water was added, Extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). The desired product (1.72 g) was obtained as a colorless oil.
[0405] <参考例 61— 118 > [0405] <Reference example 61—118>
参考例 2— 59の化合物を用い上記参考例 60と同様な方法によって表 2に示す化合 物を合成した。  Using the compounds of Reference Examples 2-59, the compounds shown in Table 2 were synthesized in the same manner as in Reference Example 60 above.
[0406] [表 2] 表 2
Figure imgf000058_0001
[0406] [Table 2] Table 2
Figure imgf000058_0001
參考例 R1 R2 R3 R4 X R1 R2 R3 R4 X Reference example R1 R2 R3 R4 X R1 R2 R3 R4 X
61 CI c-CI H CI 0 90 hPrO c-iPr H CI 061 CI c-CI H CI 0 90 hPrO c-iPr H CI 0
62 t-Bu H H H 0 91 t-PrO * c-iPr H H o62 t-Bu H H H 0 91 t-PrO * c-iPr H H o
63 Me H H H 0 92 P O H H Of o63 Me H H H 0 92 P O H H Of o
64 μρΓ c+Pr H CI o 93 i H o64 μρΓ c + Pr H CI o 93 i H o
65 C»H„ u Π u n u n u u or 65 C »H„ u Π ununuuo r
66 H H H 0 95 PhCHaO H H SMe o66 HHH 0 95 PhCH a OHH SMe o
67 CF, H H H o 96 PhCHaO H H Me 067 CF, HHH o 96 PhCH a OHH Me 0
68 CF H O e Ό 9，7 ■J c* o68 CF H O e Ό 9, 7 ■ J c * o
69 CF, H H OMe Q 98 PhCH 0 C-CI H Ci o69 CF, H H OMe Q 98 PhCH 0 C-CI H Ci o
70 CF, rv70 CF, rv
Figure imgf000058_0002
Figure imgf000058_0002
72 CF, H H CPs o 101 PhCHaO c-PhCH20 H a o72 CF, HH CPs o 101 PhCHaO c-PhCH 20 H ao
73 CF, c-CF, H H 0 102 PhCHzO c-PhCHzO H H o73 CF, c-CF, HH 0 102 PhCH z O c-PhCHzO HH o
74 CF, c-CFs H a 0 103 PhCHaO c-PhCH20 H Pr o74 CF, c-CF s H a 0 103 PhCHaO c-PhCH 20 H Pr o
75 CPS -CI H H 0 104 eO C-CF3 H H o75 CP S -CI HH 0 104 eO C-CF 3 HH o
76 CF3 a-CI H H o 105 MeS H H H o76 CF3 a-CI H H o 105 MeS H H H o
77 CF3 d- H H o 106 PhCHaS H H H o77 CF3 d- H H o 106 PhCHaS H H H o
78 CFS c-MeO H CI o 107 PhCHjsS H H CI 078 CF S c-MeO H CI o 107 PhCHjsS HH CI 0
79 H H α o 108 CI c-a H H s79 H H α o 108 CI c-a H H s
80 Ph(CHi)a H H CF3 0 109 CF3 C-CF3 H a s80 Ph (CHi) a HH CF 3 0 109 CF 3 C-CF 3 H as
81 P (CHi)2 H H o 110 CF3 C-CF3 H H s81 P (CHi) 2 HH o 110 CF 3 C-CF 3 HH s
82 Ph(CH2)a c-CF, H CI o 111 CF3 H H H s82 Ph (CH2) a c-CF, H CI o 111 CF 3 HHH s
83 PhtCHaJa c-Ph(CH2)2 H H o 112 CF9 H H CF3 s83 PhtCHaJa c-Ph (CH2) 2 HH o 112 CF 9 HH CF 3 s
84 Ph(CHj)2 c-Ph(CH2)2 H CFa o 113 MeO H H a s 84 Ph (CHj) 2 c- Ph (CH2) 2 H CF a o 113 MeO HH as
85 Ρίι(ΟΗί)2 c-Ph(CHi)a H CI o 114 MeO H H H s85 Ρίι (ΟΗί) 2 c-Ph (CHi) a H CI o 114 MeO HHH s
86 CF3 H H F 0 115 ΜθΟ H H CF3 s86 CF 3 HHF 0 115 ΜθΟ HH CF 3 s
87 PhCH20 H H F 0 116 CF3 C- 02 H H 087 PhCH 2 0 HHF 0 116 CF 3 C- 0 2 HH 0
88 CF, H a H 0 117 PhCHjO H H a 088 CF, H a H 0 117 PhCHjO H H a 0
88 H H PhCH20 H H i-Pr 088 HH PhCH 2 0 HH i-Pr 0
CF CI 0 118 [0407] <参考例 119 > CF CI 0 118 [0407] <Reference Example 119>
4'一（3—ェチルフエノキシ）ケィヒ酸メチル  4 '-(3-Ethylphenoxy) methyl citrate
[0408] [化 101]
Figure imgf000059_0001
[0408] [Formula 101]
Figure imgf000059_0001
[0409] 3 ェチルフエノール（1.13g)、 4' フルォロケィヒ酸メチル（834mg)の DMF (50mL) 溶液に炭酸カリウム（1.92g)を加え 140°Cにて 8時間加熱撹拌した。反応液を水にあ け酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて 乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン： 酢酸ェチル =30： 1)にて精製した。 目的物（540mg)を黄色油状物として得た。 [0409] Potassium carbonate (1.92g) was added to a DMF (50mL) solution of 3ethylphenol (1.13g) and 4'methylfluorokeiate (834mg), and the mixture was heated with stirring at 140 ° C for 8 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1). The desired product (540 mg) was obtained as a yellow oil.
[0410] <参考例 120 >  [0410] <Reference example 120>
4'一（3—イソブチルフエノキシ）ケィヒ酸メチル  Methyl 4 '-(3-isobutylphenoxy) keinate
3 イソブチルフエノール（451mg)、 4' フルォロケィヒ酸メチル（541mg)の DMF ( lOmL)溶液に炭酸カリウム (622mg)をカ卩ぇ 140°Cにて 8時間加熱撹拌した。反応液を 水にあけ酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウ ムにて乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキ サン:酢酸ェチル =30 : 1)にて精製した。 目的物（278mg)を黄色油状物として得た。  Potassium carbonate (622 mg) was heated and stirred at 140 ° C. for 8 hours in a DMF (10 mL) solution of 3 isobutylphenol (451 mg) and 4 ′ methyl fluorokeinate (541 mg). The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1). The desired product (278 mg) was obtained as a yellow oil.
[0411] <参考例 121 >  [0411] <Reference example 121>
4'一 [ (3—フエノキシメチル）フエノキシ]ケィヒ酸ェチル  4'-1-[(3-phenoxymethyl) phenoxy] ethyl ester
[0412] [化 102]
Figure imgf000059_0002
[0412] [Formula 102]
Figure imgf000059_0002
[0413] 参考例 63の化合物（2.82g)を四塩化炭素（50mL)に溶解し、 N プロモコハク酸イミ ド (2.3 lg)を加え光照射下に加熱撹拌した。 24時間後、溶媒を減圧留去し、残渣を 酢酸ェチルにて抽出後、水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムにて乾 燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（へキサン:酢 酸ェチル =6 : 1)にて精製し、 4' [ (3—ブロモメチル）フエノキシ]ケィヒ酸ェチル（1.30 g)を黄色油状物として得た。得られたブロモ体（1.24g)の DMF (25mL)溶液にフエノ ール (380mg)、炭酸カリウム (500mg)をカ卩ぇ 60°Cにて 3時間撹拌した。反応液を水に あけ酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて 乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン： 酢酸ェチル =4 : 1)にて精製した。 目的物（1.30g)を無色油状物として得た。 [0413] The compound of Reference Example 63 (2.82 g) was dissolved in carbon tetrachloride (50 mL), N-bromosuccinic acid imide (2.3 lg) was added, and the mixture was heated with stirring under light irradiation. After 24 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: vinegar). Purification by ethyl acetate = 6: 1) gave ethyl 4 '[(3-bromomethyl) phenoxy] keichate (1.30 g) as a yellow oil. To a solution of the obtained bromo compound (1.24 g) in DMF (25 mL), phenol (380 mg) and potassium carbonate (500 mg) were stirred at 60 ° C for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1). The desired product (1.30 g) was obtained as a colorless oil.
[0414] <参考例 122 >  [0414] <Reference Example 122>
2' クロロー 4'一（3—トリフルォロメチルフエ-ルスルファ -ル）ジヒドロケィヒ酸ェチル 2'Chloro-4 '-(3-trifluoromethylphenylsulfur) diethyl ketyl dihydrokeichate
[0415] [化 103]
Figure imgf000060_0001
[0415] [Formula 103]
Figure imgf000060_0001
[0416] 参考例 60の化合物（1.72g)をエタノール (70mL)に溶解し 0°Cにて撹拌下、塩ィ匕ビ スマス（703mg)を加えた。水素化ホウ素ナトリウム（673mg)を少量ずつ加えた後、同 温にて 1時間、室温にて 3時間撹拌した。反応液に氷水を加え析出する不溶の無機 残渣をセライト濾去し、酢酸ェチルにて抽出した。水、飽和食塩水の順に洗浄後、無 水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、 目的物（1.50g)を無色油状物とし て得た (方法 A)。 [0416] The compound of Reference Example 60 (1.72g) was dissolved in ethanol (70mL), and stirred at 0 ° C, and salted bismuth (703mg) was added. After sodium borohydride (673 mg) was added little by little, the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. Ice water was added to the reaction solution, and the precipitated insoluble inorganic residue was filtered off through celite and extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (1.50 g) as a colorless oil (Method A).
[0417] <参考例 123 >  [0417] <Reference example 123>
4'一（3—ェチルフエノキシ）ジヒドロケィヒ酸メチル  Methyl 4 '-(3-ethylphenoxy) dihydrokeinate
[0418] [化 104]
Figure imgf000060_0002
[0418] [Formula 104]
Figure imgf000060_0002
[0419] 参考例 119の化合物（540mg)をエタノール（20mL)に溶解し、 10% Pd/C (80.0mg) を加え水素気流下、室温にて 3時間撹拌した。触媒を濾去後、減圧濃縮し目的物を 無色油状物として得た (方法 B)。 [0419] The compound of Reference Example 119 (540 mg) was dissolved in ethanol (20 mL), 10% Pd / C (80.0 mg) was added, and the mixture was stirred at room temperature under a hydrogen stream for 3 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain the desired product as a colorless oil (Method B).
[0420] <参考例 124 >  [0420] <Reference example 124>
2' ベンジルォキシー 4' [ (3—トリフルォロメチル）フエノキシ]ジヒドロケィヒ酸ェチル [0421] [化 105]
Figure imgf000061_0001
2 'benzyloxy 4' [(3-trifluoromethyl) phenoxy] ethyl ethyl dihydrokeichate [0421] [Formula 105]
Figure imgf000061_0001
[0422] 参考例 70の化合物（2.29g)を酢酸ェチル（30mL)に溶解し、 5%— Pd/C—エチレン ジアミン錯体 (230mg)を加え水素気流下、室温にて 3.5時間撹拌した。触媒を濾去後 、溶媒を減圧留去し、 目的物 (2.30g)を淡黄色油状物として得た (方法 C)。 [0422] The compound of Reference Example 70 (2.29 g) was dissolved in ethyl acetate (30 mL), 5% -Pd / C-ethylenediamine complex (230 mg) was added, and the mixture was stirred at room temperature for 3.5 hours under a stream of hydrogen. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure to obtain the desired product (2.30 g) as a pale yellow oil (Method C).
[0423] <参考例 125 >  [0423] <Reference example 125>
4'一 [ (3—メチルチオ）フエノキシ]ジヒドロケィヒ酸メチル  4'-Methyl [(3-methylthio) phenoxy] dihydrokeinate
[0424] [化 106]
Figure imgf000061_0002
[0424] [Formula 106]
Figure imgf000061_0002
[0425] アルゴンガス気流下、参考例 105の化合物（4.07g)をメタノール (50mL)に溶解し 10 °Cにて撹拌下に、マグネシウム（l.OOg)を加えた。同温にて 3時間撹拌後、希塩酸を 加え、酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムに て乾燥した。溶媒を減圧留去し、 目的物 (3.70g)を無色油状物として得た (方法 D)。  Under an argon gas stream, the compound of Reference Example 105 (4.07 g) was dissolved in methanol (50 mL), and magnesium (l.OOg) was added at 10 ° C with stirring. After stirring at the same temperature for 3 hours, dilute hydrochloric acid was added, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (3.70 g) as a colorless oil (Method D).
[0426] <参考例 126— 182 >  [0426] <Reference example 126—182>
参考例 61— 69、 71— 104、 106— 116、 117— 118、 120— 121の化合物を用い、上記と 同様な方法によって表 3に示すィ匕合物を合成した。  Using the compounds of Reference Examples 61-69, 71-104, 106-116, 117-118, and 120-121, the compounds shown in Table 3 were synthesized in the same manner as described above.
[0427] [表 3] [0427] [Table 3]
表 3
Figure imgf000062_0001
Table 3
Figure imgf000062_0001
參者例 R1 R2 R3 R4 X 方法 参考例 R1 R2 R3 R4 X 方法 Participant example R1 R2 R3 R4 X method Reference example R1 R2 R3 R4 X method
126 CI c-CI H Ci 0 A 155 i-PrO c-iPr H CI O c126 CI c-CI H Ci 0 A 155 i-PrO c-iPr H CI O c
\ J n リ loo トド ry c-iPr M \ J n Re loo Todo ry c-iPr M
Me o PhO H ：，  Me o PhO H:
129 i-Pr c-l-Pr H a 0 A 158 PhCH20 H H H 0 A129 i-Pr cl-Pr H a 0 A 158 PhCH 2 0 HHH 0 A
130 C^H" H H H 0 B 159 PhCHjO H H Br 0 A130 C ^ H "H H H 0 B 159 PhCHjO H H Br 0 A
131 C7H H H H 0 B 160 PhCHiO H H SMe 0 A131 C7H H H H 0 B 160 PhCHiO H H SMe 0 A
132 CF, H H H 0 B 161 PhCHaO * H H Me 0 A132 CF, H H H 0 B 161 PhCHaO * H H Me 0 A
133 CFS H OMe H 0 B 162 PhCHaO H H Et 0 A133 CF S H OMe H 0 B 162 PhCHaO HH Et 0 A
134 CF, H H OMe 0 B 163 P CHaO c-CI H CI 0 A134 CF, H H OMe 0 B 163 P CHaO c-CI H CI 0 A
135 CF, H H 0 B 164 PhCHjO H H CF3 0 A135 CF, HH 0 B 164 PhCHjO HH CF 30 A
136 CFS H H CFS 0 B 165 PhCHjO H H Ph 0 A136 CF S HH CF S 0 B 165 PhCHjO HH Ph 0 A
137 CF, c-CFs H H 0 B 166 PhCHiO c-PhCHaO H a 0 A137 CF, c-CF s HH 0 B 166 PhCHiO c-PhCHaO H a 0 A
138 CF, c-CF3 H a 0 B 167 PhCHaO c-PhO^O H H 0 A138 CF, c-CF 3 Ha 0 B 167 PhCHaO c-PhO ^ OHH 0 A
139 CF, b-CI H H 0 A 168 PhCHaO c-PhCHaO H 0 A139 CF, b-CI H H 0 A 168 PhCHaO c-PhCHaO H 0 A
140 CF3 a-CI H H 0 A 169 ΜθΟ c-CF3 H H 0 B140 CF3 a-CI HH 0 A 169 ΜθΟ c-CF 3 HH 0 B
141 CF3 d-a H H 0 A 170 PhCHzS H H H 0 A141 CF3 d-a H H 0 A 170 PhCHzS H H H 0 A
CF, c-MeO u μ nι n rCF, c-MeO u μ nι n r
143 Ph(CHj)2 H H a O A 172 ct H H H S D143 Ph (CHj) 2 HH a OA 172 ct HHHSD
144 Ph(CHj)a H H O B 173 CF3 -CF3 H CI s A144 Ph (CHj) a HHOB 173 CF 3 -CF 3 H CI s A
145 0CF3 H H O B 174 CP3 c-Me H H s O145 0CF3 HHOB 174 CP 3 c-Me HH s O
146 c-CFs H a 0 A 175 CF3 H H H s A146 c-CF s H a 0 A 175 CF 3 HHH s A
147 Ph(CH2)2 c-Ph(CHa)2 H H 0 B 176 CF, H H s A147 Ph (CH2) 2 c-Ph (CHa) 2 HH 0 B 176 CF, HH s A
148 c-Ph<CHa)2 H CF, 0 B 177 MeO H H a s A148 c-Ph <CHa) 2 H CF, 0 B 177 MeO HH as A
149 P (CHj)2 c-Ph(CHi)2 H a 0 A 178 MeO H H H s A149 P (CHj) 2 c-Ph (CHi) 2 Ha 0 A 178 MeO HHH s A
150 CF, H H F 0 B 179 MeO H H CF3 s A150 CF, HHF 0 B 179 MeO HH CF 3 s A
151 PhCHjO H H F 0 A 180 l-Bu H H H 0 B151 PhCHjO H H F 0 A 180 l-Bu H H H 0 B
152 PnOCHj H H H 0 A 181 PhCHaO H H Ct 0 A152 PnOCHj H H H 0 A 181 PhCHaO H H Ct 0 A
153 CF, H CI H 0 A 182 PhCHsO H H IPr 0 A153 CF, H CI H 0 A 182 PhCHsO H H IPr 0 A
154 CF, H H O 0 A 154 CF, H H O 0 A
D>Methyl ester  D> Methyl ester
[0428] <参考例 183 > [0428] <Reference Example 183>
4' [3—クロ口— 5— (トリフルォロメチル)フエノキシ]ジヒドロケィヒ酸ェチル  4 '[3-—Mouth— 5— (Trifluoromethyl) phenoxy] diethyl ketyl acid
[0429] [化 107]
Figure imgf000062_0002
[0429] [Formula 107]
Figure imgf000062_0002
[0430] 参考例 116の化合物を用い参考例 124と同様な方法で反応させ、 4' [3 アミノー 5- (トリフルォロメチル)フエノキシ]ジヒドロケィヒ酸ェチルを得た後、この化合物（1.27g) の MeCN (15mL)溶液を、塩化銅（725mg)、 tBuONO (0.51mL)の MeCN (40mL)溶液 に加えた。室温にて 3時間撹拌後、水を加え酢酸ェチルにて抽出し、水洗後無水硫 酸ナトリウムにて乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ へキサン:酢酸ェチル =20 : 1)にて精製後、 目的物（1.10g)を淡黄色油状物として得 た。 [0430] The compound of Reference Example 116 was reacted in the same manner as in Reference Example 124 to give 4 '[3 amino-5- After obtaining (Trifluoromethyl) phenoxy] diethyl keichylate, a solution of this compound (1.27 g) in MeCN (15 mL) was added to a solution of copper chloride (725 mg) and tBuONO (0.51 mL) in MeCN (40 mL). . After stirring at room temperature for 3 hours, water was added, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the desired product (1.10 g) as a pale yellow oil.
[0431] <参考例 184 >  [0431] <Reference example 184>
4' [3—ベンジルォキシー 5— (トリフルォロメチル)フエノキシ]ジヒドロケィヒ酸べンジル [0432] [化 108]  4 '[3-benzyloxy 5- (trifluoromethyl) phenoxy] benzyl dihydrokechate [0432]
Figure imgf000063_0001
Figure imgf000063_0001
[0433] 参考例 169の化合物（840mg)を塩化メチレン (20mL)に溶解し 0°Cにて撹拌下に、 1 mol/L—三臭化ホウ素一塩化メチレン溶液 (3.42mL)を滴下し、その後室温でー晚撹 拌した。反応液に氷水を加え、酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄 後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、 4' (3—トリフルォロメチル —5—ヒドロキシフエノキシ)ジヒドロケィヒ酸 (750mg)を淡褐色粉末として得た。得られ た粉末を DMF (50mL)に溶解し、炭酸カリウム（1.04g)、ベンジルブロミド（0.602mL) を加え室温にて 8時間撹拌した。反応液を氷水にあけ、酢酸ェチルにて抽出し、水、 飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、 目 的物を褐色油状物として得た。 [0433] The compound of Reference Example 169 (840 mg) was dissolved in methylene chloride (20 mL), and a 1 mol / L-boron tribromide monochloride methylene chloride solution (3.42 mL) was added dropwise with stirring at 0 ° C. Thereafter, the mixture was stirred at room temperature. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4 ′ (3-trifluoromethyl-5-hydroxyphenoxy) dihydrokeichic acid (750 mg) as a light brown powder. The obtained powder was dissolved in DMF (50 mL), potassium carbonate (1.04 g) and benzyl bromide (0.602 mL) were added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target substance as a brown oil.
[0434] <参考例 185 >  [0434] <Reference Example 185>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）—2' クロロジヒドロケィヒ酸べンジル [0435] [化 109] 4 '-(3-benzyloxyphenol-sulfur-)-2' benzyl dichlorodihydrocarbylate [0435] [Formula 109]
Figure imgf000064_0001
Figure imgf000064_0001
[0436] 参考例 177の化合物を用い上記参考例 184と同様に行い、 目的物を黄色油状物と して得た。 [0436] The same procedure as in the above reference example 184 was carried out using the compound of reference example 177 to give the desired product as a yellow oil.
[0437] <参考例 186 > [0437] <Reference Example 186>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）ージヒドロケィヒ酸べンジル  Benzyl 4 '-(3-benzyloxyphenol-sulfur-yl) dihydrokeichate
[0438] [化 110]
Figure imgf000064_0002
[0438] [Formula 110]
Figure imgf000064_0002
[0439] 参考例 178の化合物を用い上記参考例 184と同様に行い、 目的物を黄色油状物と して得た。 [0439] The same procedure as in Reference Example 184 was carried out using the compound of Reference Example 178 to give the desired product as a yellow oil.
[0440] <参考例 187 > [0440] <Reference example 187>
4' [3 ベンジルォキシー 5 (トリフルォロメチル)フエノキシ ]—2' クロロジヒドロケィヒ 酸ェチル  4 '[3 benzyloxy 5 (trifluoromethyl) phenoxy] -2' ethyl chlorodihydrokehiate
[0441] [化 111] [0441] [Formula 111]
Figure imgf000064_0003
Figure imgf000064_0003
[0442] 参考例 142の化合物を参考例 184の場合と同様な操作で 2' クロロー 4' (3 トリフル ォロメチルー 5—ヒドロキシフエノキシ）ジヒドロケィヒ酸を得た後、このケィヒ酸（1.47g)を エタノール（lOmL)に溶解し、 0°Cにて撹拌下に塩ィ匕チォ-ル（3mL)を滴下した。同 温にて 2時間撹拌した後、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフ ィー（へキサン:酢酸ェチル = 10 : 1後 6 : 1)にて精製後、 2 クロロー トリフルォ ロメチルー 5—ヒドロキシフエノキシ）ジヒドロケィヒ酸ェチル（1.38g)を無色油状物として 得た。得られたエステルを炭酸カリウム、ベンジルブ口ミドを用い参考例 184の場合と 同様にしてベンジルエーテルィ匕し、 目的物を無色油状物として得た。 [0442] The compound of Reference Example 142 was subjected to the same operation as in Reference Example 184 to obtain 2'chloro-4 '(3 trifluoromethyl-5-hydroxyphenoxy) dihydrocehic acid, and then the keichic acid (1.47 g) was added. It was dissolved in ethanol (10 mL), and salted thiol (3 mL) was added dropwise at 0 ° C with stirring. After stirring for 2 hours at the same temperature, the solvent was removed in vacuo and the residue (hexane: acetic acid Echiru = 10: 1 after 6: 1) silica gel column chromatography after purification by 2-chloro Torifuruo Romechiru 5 —Hydroxyphenoxy) ethyl hydrocarbylate (1.38g) as a colorless oil Obtained. The resulting ester was subjected to benzyl etherification using potassium carbonate and benzylbutamide in the same manner as in Reference Example 184 to give the desired product as a colorless oil.
[0443] <参考例 188 >  [0443] <Reference example 188>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）—2'—トリフルォロメチルジヒドロケィヒ 酸ェチル  4 '-(3-Benzyloxyphenol-sulfur-yl) -2'-ethyl methyl trifluoromethyldihydrocarbylate
[0444] [化 112]
Figure imgf000065_0001
[0444] [Formula 112]
Figure imgf000065_0001
[0445] 参考例 179の化合物を上記参考例 187の場合と同様にして、 目的物を無色油状物 として得た。 The target compound was obtained as a colorless oil in the same manner as in Reference Example 187, using the compound of Reference Example 179.
[0446] <参考例 189 > [0446] <Reference example 189>
4'一 [ (3—ベンジルォキシ）フエ-ルスルファ -ル]—2'—クロロジヒドロシンナミルアル n—ノレ  4'-1-[(3-benzyloxy) phenylsulfur-]-2'-chlorodihydrocinnamyl al n-nore
[0447] [化 113]
Figure imgf000065_0002
[0447] [Formula 113]
Figure imgf000065_0002
[0448] 参考例 185の化合物（7.40g)を THF (lOOmL)に溶解し、 0°Cにて撹拌下、水素化ァ ルミ-ゥムリチウム（500mg)をカ卩えた。 10分後、 20%NaOH水溶液をカ卩え、析出する不 溶の無機残渣をセライト濾去し、酢酸ェチルにて抽出した。水、飽和食塩水の順に洗 浄後、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、 目的物 (6.37g)を無色 油状物として得た。 [0448] The compound of Reference Example 185 (7.40 g) was dissolved in THF (100 mL), and stirred at 0 ° C with potassium aluminum hydride (500 mg). Ten minutes later, a 20% aqueous NaOH solution was removed, and the precipitated insoluble inorganic residue was filtered off through celite and extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product (6.37 g) as a colorless oil.
[0449] <参考例 190— 251 >  [0449] <Reference example 190—251>
参考例 122— 141、 143— 168、 170— 177、 180— 188の化合物を用い、上記参考例 189と同様な方法によって表 4に示すィ匕合物を合成した。  Using the compounds of Reference Examples 122 to 141, 143 to 168, 170 to 177, and 180 to 188, the compounds shown in Table 4 were synthesized in the same manner as in Reference Example 189.
[0450] [表 4] 表 4
Figure imgf000066_0001
[0450] [Table 4] Table 4
Figure imgf000066_0001
参考 1 R2 R3 R4 X 参½例 R1 R2 R3 R4 X Reference 1 R2 R3 R4 X Reference example R1 R2 R3 R4 X
190 CI c-CI H a O 221 i-PrO c-iPr H CI 0190 CI c-CI H a O 221 i-PrO c-iPr H CI 0
191 t-Bu H H H O 222 i-PrO c-iPr H H 0191 t-Bu H H H O 222 i-PrO c-iPr H H 0
192 Me H H H O 223 P O H H CI 0192 Me H H H O 223 P O H H CI 0
193 l-Pr c+Pr H CI O 224 PhCHaO H H H 0193 l-Pr c + Pr H CI O 224 PhCHaO H H H 0
194 H H H O 225 P CH20 H H Br 0194 HHHO 225 P CH 20 HH Br 0
195 C7Hw H H H O PhCH20 H H SMe 0195 C 7 Hw HHHO PhCH 2 0 HH SMe 0
CF3 l CF 3 l
Π U l s n n Me U Π U l s n n Me U
197 CF3 H OMe H 0 228 PhCHzO H H Et 0197 CF 3 H OMe H 0 228 PhCH z OHH Et 0
196 CF t3 U Π 196 CF t 3 U Π
n 230  n 230
200 H H 0 231 PhCH20 H H Ph O200 HH 0 231 PhCH 2 0 HH Ph O
201 CF3 c-CF3 H H O 232 PhCH20 c-PhCHzO H CI 0201 CF 3 c-CF 3 HHO 232 PhCH 2 0 c-PhCH z OH CI 0
202 CF, C-CF3 H a O 233 PhCH20 c-PhCH20 H H 0202 CF, C-CF3 H a O 233 PhCH 2 0 c-PhCH 2 0 HH 0
203 CF3 b-CI H H O 234 PhCHjO c-PhCH20 H i-Pr 0203 CF 3 b-CI HHO 234 PhCHjO c-PhCH 2 0 Hi-Pr 0
204 CF3 a- H H O 235 PhCH20 c-CF3 H H 0204 CF3 a- HHO 235 PhCH 2 0 c-CF 3 HH 0
205 CF3 d-a H H 0 236 PhCHzS H H H 0205 CF3 d-a H H 0 236 PhCHzS H H H 0
206 CF3 c-PhCH20 ri 1 u it 206 CF 3 c-PhCH 2 0 ri 1 u it
Ph(CH H n Π  Ph (CH H n Π
208 Ph(CH H H CF3 0 239 CF3 C-CF3 H CI S208 Ph (CH HH CF 3 0 239 CF 3 C-CF3 H CI S
209 Ph(CH2)j c-CF3 H H O 240 CF3 c-Me H H s209 Ph (CH 2 ) j c-CF 3 HHO 240 CF 3 c-Me HH s
210 Ph(CH2)j c-CF3 H a O 241 CF3 H H H s210 Ph (CH 2 ) j c-CF 3 H a O 241 CF 3 HHH s
211 Ph(CH2)2 o-Ph(CH2)2 H H O 242 CF3 H H CF3 s211 Ph (CH 2 ) 2 o-Ph (CH 2 ) 2 HHO 242 CF 3 HH CF 3 s
212 Ph(CH2)2 o-Ph(CH2)2 H CF3 O 243 eO H H CI s212 Ph (CH 2 ) 2 o-Ph (CH 2 ) 2 H CF 3 O 243 eO HH CI s
213 Ph(CH2)2 o-Ph(CH H CI O 244 PhCHjO H H H s213 Ph (CH 2 ) 2 o-Ph (CH H CI O 244 PhCHjO HHH s
214 CF H H F O 245 PhCH20 H H CF3 s214 CF HHFO 245 PhCH 20 HH CF 3 s
215 PhCH20 H H F O 246 i-Bu H H H 0215 PhCH 2 0 HHFO 246 i-Bu HHH 0
216 CF3 H H a s 247 PhOCHt H H H 0216 CF 3 HH as 247 PhOCHt HHH 0
217 Et H H H 0 24β CF3 c-CI H H 0217 Et HHH 0 24β CF 3 c-CI HH 0
21Θ CF9 H H PhCH20 0 249 eS H H H 021Θ CF 9 HH PhCH 2 0 0 249 eS HHH 0
219 CF, H CI H 0 250 PhC¾0 H H CI 0219 CF, H CI H 0 250 PhC¾0 H H CI 0
220 CFS H H CI 0 251 PhCHaO H H i-Pr 0 <参考例 252 > 220 CF S HH CI 0 251 PhCHaO HH i-Pr 0 <Reference example 252>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）—2'—クロ口- ルョージド [0452] [化 114]
Figure imgf000067_0001
4 '-(3-benzyloxyphenol-sulfur-yl) -2'-clo-rougedo [0452] [Formula 114]
Figure imgf000067_0001
[0453] 参考例 189の化合物（1.38g)を THF (20mL)に溶解し、 0°Cにて撹拌下イミダゾール [0453] The compound of Reference Example 189 (1.38 g) was dissolved in THF (20 mL) and imidazole was stirred at 0 ° C.
(545mg)、トリフエ-ルホスフィン（2.10g)、ヨウ素（2.00g)をカ卩えた。同温にて 2時間、 室温にて 1.5時間撹拌後、イミダゾール（160mg)、トリフエ-ルホスフィン（600mg)、ヨウ 素（500mg)を追加した。そのまま一晩撹拌した後、反応液に水を加えた後、チォ硫酸 ナトリウムを加え、酢酸ェチルにて抽出した。水、飽和食塩水の順に洗浄後、無水硫 酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフ ィー（へキサン:酢酸ェチル =50： 1)にて精製した。 目的物（1.55g)を無色油状物とし て得た。  (545 mg), triphenylphosphine (2.10 g) and iodine (2.00 g) were obtained. After stirring at the same temperature for 2 hours and at room temperature for 1.5 hours, imidazole (160 mg), triphenylphosphine (600 mg) and iodine (500 mg) were added. After stirring as it was overnight, water was added to the reaction solution, sodium thiosulfate was added, and the mixture was extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1). The desired product (1.55 g) was obtained as a colorless oil.
[0454] <参考例 253— 314 > [0454] <Reference example 253—314>
参考例 190— 251の化合物を用い、上記参考例 252と同様な方法によって表 5に示 す化合物を合成した。  Using the compounds of Reference Examples 190-251, the compounds shown in Table 5 were synthesized in the same manner as in Reference Example 252 above.
[0455] [表 5] [0455] [Table 5]
6517 6517
表 5Table 5
Figure imgf000068_0001
Figure imgf000068_0001
参考 w R1 R2 3 R4 X 参考例 1 R2 R3 4 X Reference w R1 R2 3 R4 X Reference example 1 R2 R3 4 X
I Π Π  I Π Π
254 t-B11 H H H o 285 PrO oiPr H H O254 tB 11 HHH o 285 PrO oiPr HHO
255 Me H H H O 286 PhO H H CI O255 Me H H H O 286 PhO H H CI O
256 l-Pr o-i-Pr H CI o 287 PhCH20 H H H O256 l-Pr oi-Pr H CI o 287 PhCH 2 0 HHHO
257 H H H 0 288 PhCH20 H H Br O257 HHH 0 288 PhCH 2 0 HH Br O
258 H H H o 289 PhCH20 H H SMe O258 HHH o 289 PhCH 2 0 HH SMe O
259 CF3 H H H o 290 PhCH20 H H Me O259 CF 3 HHH o 290 PhCH 2 0 HH Me O
260 CF3 H OMe H 0 291 PhCH20 H H Et O260 CF 3 H OMe H 0 291 PhCH 2 0 HH Et O
261 CFS H H OMe o 292 PhCH20 oCI H CI 0261 CF S HH OMe o 292 PhCH 2 0 oCI H CI 0
262 CF3 H CF3 H 0 293 P CH20 H H CF3 0262 CF 3 H CF 3 H 0 293 P CH 2 0 HH CF 30
263 CF, H H CF3 o 294 PhCH20 H H Ph 0263 CF, HH CF 3 o 294 PhCH 2 0 HH Ph 0
264 CF, o-CF3 H H 0 295 PhCH20 c-PhCHjO H CI 0264 CF, o-CF 3 HH 0 295 PhCH 2 0 c-PhCHjO H CI 0
265 CF3 c-CF3 H CI 0 296 PhCH20 c-PhCHjO H H 0265 CF 3 c-CF 3 H CI 0 296 PhCH 2 0 c-PhCHjO HH 0
266 CF3 b-a H H 0 297 PhCH20 c PhCH20 H i-Pr 0266 CF 3 ba HH 0 297 PhCH 2 0 c PhCH 2 0 H i-Pr 0
267 CF3 a-CI H H o 298 PhCH20 c-CF3 H H 0267 CF3 a-CI HH o 298 PhCH 2 0 c-CF 3 HH 0
268 CF3 d-CI H H o 299 PhCH^ H H H 0268 CF3 d-CI H H o 299 PhCH ^ H H H 0
269 CF3 c-PhCH20 H CI o 300 PhCHiS H H CI 0269 CF 3 c-PhCH 2 0 H CI o 300 PhCHiS HH CI 0
270 Ph(CH H H CI 0 301 CI H H H s270 Ph (CH H H CI 0 301 CI H H H s
271 Ph(CH2)2 H H CF3 o 302 CF3 t CF3 H a s271 Ph (CH 2 ) 2 HH CF 3 o 302 CF 3 t CF 3 H as
272 Ph(CH2)2 c-CF3 H H o 303 CF3 c- e H H s272 Ph (CH 2 ) 2 c-CF 3 HH o 303 CF 3 c- e HH s
273 Ph(CH2)2 c-CF3 H a o 304 CF3 H H H s273 Ph (CH 2 ) 2 c-CF 3 H ao 304 CF 3 HHH s
274 c-Ph(CH H H o 305 CF3 H H CF3 s274 c-Ph (CH HH o 305 CF 3 HH CF 3 s
275 o-Ph(CH H CF3 o 306 MeO H H a s275 o-Ph (CH H CF 3 o 306 MeO HH as
276 o-Ph(CH H CI o 307 PhCHzO H H H s276 o-Ph (CH H CI o 307 PhCH z OHHH s
277 CF3 H H 0 308 PhCH20 H H CF3 s277 CF 3 HH 0 308 PhCH 2 0 HH CF 3 s
278 PhCH20 H H F o 309 i-Bu H H H 0278 PhCH 2 0 HHF o 309 i-Bu HHH 0
27S CF3 H H a s 310 PhOCHz H H H 027S CF 3 HH as 310 PhOCHz HHH 0
2B0 Et H H H o 311 CF3 c-CI H H 02B0 Et H H Ho 311 CF3 c-CI H H 0
281 CF3 H H PhCHaO 0 312 MeS H H H 0281 CF 3 HH PhCHaO 0 312 MeS HHH 0
282 CF, H. CI H o 313 PhCH20 H H CI 0282 CF, H. CI Ho 313 PhCH 2 0 HH CI 0
283 CFa H H a o 314 P CH20 H H i-Pr 0 参考例 315 > 283 CF a HH ao 314 P CH 2 0 HH i-Pr 0 Reference example 315>
一（3, 5—ジクロロフエノキシ）ベンジルブロミド [0457] [化 115]
Figure imgf000069_0001
1- (3,5-dichlorophenoxy) benzyl bromide [0457] [Formula 115]
Figure imgf000069_0001
[0458] 3, 5—ジクロロフェノールと 4 フルォロベンズアルデヒドを用い、参考例 1と同様に 反応させ 4一（3, 5—ジクロロフエノキシ)ベンズアルデヒドを得た後、水素化アルミ-ゥ ムリチウムのかわりに水素化ホウ素ナトリウムを用い、参考例 189と同様に反応させ 4 (3, 5—ジクロロフエノキシ）ベンジルアルコールを得た。得られたアルコール（2.03g) 、四臭化炭素（2.75g)の塩化メチレン (30mL)溶液を 0°Cにて撹拌下、トリフ -ルホス フィン (2.17g)を加えた。 0°Cにて 1時間、室温にて 30分撹拌後溶媒を減圧留去した。 残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル =20： 1)にて精製し た。 目的物 (3.12g)を無色油状物として得た。  [0458] A reaction was carried out in the same manner as in Reference Example 1 using 3,5-dichlorophenol and 4 fluorobenzaldehyde to obtain 41- (3,5-dichlorophenoxy) benzaldehyde, and then aluminum-hydride lithium Instead of using sodium borohydride, the reaction was carried out in the same manner as in Reference Example 189 to obtain 4 (3,5-dichlorophenoxy) benzyl alcohol. Trifluorophosphine (2.17 g) was added to a solution of the obtained alcohol (2.03 g) and carbon tetrabromide (2.75 g) in methylene chloride (30 mL) at 0 ° C. while stirring. After stirring at 0 ° C for 1 hour and at room temperature for 30 minutes, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1). The desired product (3.12 g) was obtained as a colorless oil.
[0459] <参考例 316 >  [0459] <Reference example 316>
1 ョードプロピル 4 [ (3 メタンスルフィエル）フエノキシ]ベンゼン  1 eodopropyl 4 [(3 methanesulfiel) phenoxy] benzene
[0460] [化 116]
Figure imgf000069_0002
[0460] [Formula 116]
Figure imgf000069_0002
[0461] 参考例 312の化合物（1.80g)を塩化メチレン（30mL)に溶解し、 0°C撹拌下、 m クロ 口過安息香酸 (770mg)を少量ずつ加えた。同温にて 1時間、室温にて 24時間撹拌後 、反応液に水を加え酢酸ェチルで抽出後、飽和炭酸ナトリウム水溶液、飽和食塩水 の順に洗浄し、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣をシリカゲ ルカラムクロマトグラフィー（へキサン：酢酸ェチル = 2： 1後 1： 2)にて精製した。 目的 物（1.29g)を黄色油状物として得た。 [0461] The compound of Reference Example 312 (1.80 g) was dissolved in methylene chloride (30 mL), and m-chloroperbenzoic acid (770 mg) was added little by little under stirring at 0 ° C. After stirring at the same temperature for 1 hour and at room temperature for 24 hours, water was added to the reaction solution, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, 1: 2). The desired product (1.29 g) was obtained as a yellow oil.
[0462] <参考例 317 >  [0462] <Reference example 317>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）—2'—クロロフエネチルョージド [0463] [化 117]
Figure imgf000070_0001
4 '-(3-benzyloxyphenol-sulfur-yl) -2'-chlorophenethyl roside [0463] [Formula 117]
Figure imgf000070_0001
[0464] <参考例 317-1 > [0464] <Reference Example 317-1>
2'—クロロー 4'一（3—メトキシフエ-ルスルファ -ル）ベンジルシア-ド  2'-Chloro-4 '-(3-methoxyphenylsulfur) benzyl thiazide
[0465] [化 118] t e [0465] [Formula 118] t e
[0466] 参考例 53の化合物を参考例 189と同様に処理しアルコール体を得た後、アルコー ル (5.64g)を塩化メチレン（lOOmL)に溶解し三臭化リン (2.25mL)を滴下した。室温に て 1時間撹拌後氷水を加え、酢酸ェチルで抽出後、水、飽和食塩水の順に洗浄し、 無水硫酸ナトリウムにて乾燥した。溶媒を留去し淡黄色油状物を得た。得られた油状 物、シアン化カリウム（1.56g)の DMSO (25mL)、水（lOmL)溶液を 90°Cにて 5時間撹 拌した。反応液に水を加え酢酸ェチルで抽出後、水、飽和食塩水の順に洗浄し、無 水硫酸ナトリウムにて乾燥した。溶媒を留去し、残渣をシルカゲルカラムクロマトグラフ ィー（へキサン：酢酸ェチル = 10： 1)にて精製した。 目的とするシァノ体 (3.81g)を淡 黄色油状物として得た。  [0466] The compound of Reference Example 53 was treated in the same manner as in Reference Example 189 to obtain an alcohol form. Then, alcohol (5.64 g) was dissolved in methylene chloride (100 mL), and phosphorus tribromide (2.25 mL) was added dropwise. . After stirring at room temperature for 1 hour, ice water was added, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oil. A solution of the obtained oil, a solution of potassium cyanide (1.56 g) in DMSO (25 mL), and water (10 mL) was stirred at 90 ° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). The desired cyano compound (3.81 g) was obtained as a pale yellow oil.
[0467] <参考例 317-2 >  [0467] <Reference example 317-2>
2'—クロロー 4'一（3—メトキシフエ-ルスルファ -ル）フエ-ル酢酸ェチル  2'-Chloro-4 '-(3-methoxyphenylsulfur) phenyl ethyl acetate
[0468] [化 119]
Figure imgf000070_0002
[0468] [Formula 119]
Figure imgf000070_0002
[0469] 上記シァノ体（3.81g)、水酸化カリウム（3.68g)のエタノール（80mL)、水（10mL)溶 液を 6時間加熱還流した。冷後不溶物を濾去し、濾液を希塩酸で中和した。酢酸ェ チルにて抽出後、水、飽和食塩水にて洗浄し無水硫酸ナトリウムにて乾燥した。溶媒 を留去し得られた残渣にエタノール (50mL)、塩ィ匕チォニル (2mL)を加え室温にて 1 時間撹拌後、溶媒を留去した。残渣をシルカゲルカラムクロマトグラフィー（へキサン： 酢酸ェチル = 10： 1)にて精製した。ェチルエステル体 (3.89g)を無色油状物として得 た。 [0469] A solution of the above cyano form (3.81 g), potassium hydroxide (3.68 g) in ethanol (80 mL), and water (10 mL) was heated to reflux for 6 hours. After cooling, insoluble materials were removed by filtration, and the filtrate was neutralized with dilute hydrochloric acid. After extraction with ethyl acetate, the extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and to the resulting residue were added ethanol (50 mL) and thiidion thionyl (2 mL). After stirring for an hour, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). The ethyl ester form (3.89 g) was obtained as a colorless oil.
[0470] <参考例 317-3 >  [0470] <Reference example 317-3>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）—2'—クロロフエネチルョージド 上記ェチルエステルを参考例 187と同様に反応させ 4'一（3—べンジルォキシフエ- ルチオ )—2' クロ口フエ-ル酢酸ェチルを得た後、参考例 189と同様に還元しアルコ 一ル体を得た。ついで、参考例 252と同様に反応させ目的物を無色油状物として得 た。  4 '-(3-Benzyloxyphenylsulfur-yl) -2'-chlorophenethylhodide The above ethyl ester was reacted in the same manner as in Reference Example 187 to give 4'-(3-benzyloxyphenyl-thio) -2 ' After obtaining ethyl ethyl acetate, it was reduced in the same manner as in Reference Example 189 to obtain an alcohol. Then, the reaction was carried out in the same manner as in Reference Example 252 to obtain the desired product as a colorless oil.
[0471] <参考例 318 >  [0471] <Reference example 318>
1— (3—ベンジルォキシフエ-ルスルファ -ル）—3 クロロー 4 ョードブチルベンゼン [0472] [化 120]
Figure imgf000071_0001
1— (3-Benzyloxyphenylsulfur) -3-chloro-4-iodobutylbenzene [0472]
Figure imgf000071_0001
[0473] <参考例 318-1 > [0473] <Reference example 318-1>
4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロロフエネチルアルデヒド  4- (3-benzyloxyphenylsulfur) -2-chlorophenethylaldehyde
[0474] [化 121]
Figure imgf000071_0002
[0474] [Formula 121]
Figure imgf000071_0002
[0475] 参考例 317-3で得られる 4' （3—べンジルォキシフエ-ルスルファ -ル)—2' クロ口 フエ-ル酢酸ェチルをアルカリ加水分解後、 N、 O—ジメチルヒドロキシァミンと縮合さ せアミド体を得た後、参考例 189と同様に還元し目的とするアルデヒド体を黄色油状 物として得た。 [0475] The 4 '(3-benzyloxyphenylsulfur) -2' chloro mouth ethyl acetate obtained in Reference Example 317-3 was alkali-hydrolyzed and then condensed with N, O-dimethylhydroxyamine. After the amide derivative was obtained, it was reduced in the same manner as in Reference Example 189 to obtain the desired aldehyde derivative as a yellow oil.
[0476] <参考例 318-2 >  [0476] <Reference example 318-2>
4一 [ (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]酪酸ェチル [0477] [化 122]
Figure imgf000072_0001
4-([3-Benzyloxyphenyl-sulfur-yl) -2-cyclohexyl] ethyl [0477] [Formula 122]
Figure imgf000072_0001
[0478] 上記 318-1の化合物を参考例 60と同様に反応させた後、参考例 122と同様に不飽 和結合を還元し目的とする酪酸ェチル誘導体を得た。 After reacting the compound of 318-1 in the same manner as in Reference Example 60, the unsaturated bond was reduced in the same manner as in Reference Example 122 to obtain the desired ethyl butylate derivative.
[0479] <参考例 318-3 > [0479] <Reference example 318-3>
1— (3—ベンジルォキシフエ-ルスルファ -ル）—3 クロロー 4 ョードブチルベンゼン 上記 318-2の化合物を参考例 189と同様に反応させアルコール体を得た後、参考例 252と同様に反応させ目的物を無色油状物として得た。  1- (3-Benzyloxyphenol-sulfur) -3-chloro-4-iodobutylbenzene The above compound 318-2 was reacted in the same manner as in Reference Example 189 to obtain an alcohol, and then the same as in Reference Example 252. To give the desired product as a colorless oil.
[0480] <参考例 319 > [0480] <Reference Example 319>
4'一 [ (3—ベンジルォキシ）フエノキシ ]—2'—クロロフエネチルョージド  4'-1-[(3-benzyloxy) phenoxy] -2'-chlorophenethyl chloride
[0481] [化 123]
Figure imgf000072_0002
[0481] [Formula 123]
Figure imgf000072_0002
[0482] 参考例 56の化合物を用い前記参考例 317と同様に反応させ、目的物を黄色油状物 として得た。 [0482] The compound of Reference Example 56 was reacted in the same manner as in Reference Example 317 to obtain the desired product as a yellow oil.
[0483] <参考例 320 > [0483] <Reference example 320>
4一 [ (3—ベンジルォキシ）フエノキシ]—2 クロ口— 1 ョードブチルベンゼン [0484] [化 124]
Figure imgf000072_0003
4-([3-Benzyloxy) phenoxy] —2 Black mouth—1 butyl benzene [0484]
Figure imgf000072_0003
[0485] 参考例 56の化合物を用い、参考例 318と同様に反応させ目的物を淡黄色油状物と して得た。  The compound of Reference Example 56 was reacted in the same manner as in Reference Example 318 to obtain the desired product as a pale yellow oil.
[0486] <参考例 321 > [0486] <Reference Example 321>
4'一べンジルォキシージヒドロシンナミルョージド [0487] [化 125]
Figure imgf000073_0001
4 'benzyloxy dihydrocinnamyl roside [0487] [Formula 125]
Figure imgf000073_0001
[0488] 4'一べンジルォキシジヒドロシンナミルアルコールを用い参考例 252と同様に反応さ せ、 目的物を黄色粉末として得た。 [0488] The desired product was obtained as a yellow powder by reacting with 4'-benzyloxydihydrocinnamyl alcohol in the same manner as in Reference Example 252.
[0489] <参考例 322 > [0489] <Reference example 322>
4'一（3—ベンジルォキシフエ-ルスルファ -ル）—2' クロ口ベンジルブロミド [0490] [化 126]
Figure imgf000073_0002
4 '-(3-Benzyloxyphenyl-sulfur-)-2'clo benzyl bromide
Figure imgf000073_0002
[0491] 2 クロロー 4—フルォロベンズアルデヒドのかわりに 2—クロロー 4 フルォロベンゾ-ト リルを用いて参考例 1と同様に反応させ 2 クロロー 4ー（3—メトキシフエ-ルスルファ- ル)ベンゾニトリルを得た後、参考例 317-2と同様な方法で反応させ加水分解し、引き 続き参考例 187と同様な方法にて、メトキシ基を分解後、エステルイ匕しベンジルエー テル化した後、参考例 189と同様に反応させアルコール体へ変換した。続いて参考 例 315と同様に四臭化炭素を用いて行い目的物を無色油状物として得た。 [0491] 2-Chloro-4-fluorobenzo-tolyl was used in place of 2-chloro-4-fluorobenzaldehyde and reacted in the same manner as in Reference Example 1 to obtain 2-chloro-4- (3-methoxyphenylsulfur) benzonitrile. Then, the reaction was carried out and hydrolyzed in the same manner as in Reference Example 317-2, and then the methoxy group was decomposed, esterified and benzyl etherified in the same manner as in Reference Example 187. And converted to the alcohol form. Subsequently, the reaction was carried out using carbon tetrabromide in the same manner as in Reference Example 315 to obtain the desired product as a colorless oil.
[0492] <参考例 323 >  [0492] <Reference example 323>
3-(4-ベンジルォキシカルボニルァミノフエニル)ジヒドロシンナミルョージド  3- (4-benzyloxycarbonylaminophenyl) dihydrocinnamyl ozide
[0493] [化 127]  [0493] [Formula 127]
Figure imgf000073_0003
Figure imgf000073_0003
[0494] 3- (4-ベンジルォキシカルボ-ルァミノフエ-ル)ジヒドロけい皮酸ェチル (18g)を THF に溶解し、氷冷撹拌下 LiBH (5.99g)及びエタノール (50mL)を加え、同温にて 30分、 [0494] Ethyl 3- (4-benzyloxycarbo-aminophenyl) dihydrocinnamate (18 g) was dissolved in THF, and LiBH (5.99 g) and ethanol (50 mL) were added under ice-cooling and stirring. At 30 minutes,
4  Four
更に常温にて 8時間撹拌した。飽和塩ィ匕アンモ-ゥム水溶液でタエンチ後、酢酸ェチ ルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸ナトリウムにて 乾燥し、溶媒を減圧濃縮し、無色の粉末晶を得た。 The mixture was further stirred at room temperature for 8 hours. The mixture was extracted with a saturated aqueous solution of sodium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After drying, the solvent was concentrated under reduced pressure to obtain colorless powdery crystals.
[0495] これを THFに溶解し、イミダゾール (7.49g)及びトリフエ-ルホスフィン (27.5g)をカ卩えた 。氷冷後、ヨウ素 (27.9g)を加え、同温にて 30分撹拌した。 10%チォ硫酸ナトリウム水 溶液にてタエンチ後、酢酸ェチルにて抽出し、 10%チォ硫酸ナトリウム水溶液、水、 飽和食塩水で順次洗浄した。無水硫酸ナトリウムにて乾燥後、溶媒を減圧留去した。 残さをシリカゲルカラムクロマトグラフィー (へキサン：酢酸ェチル =10 : 1—5 : 1)にて精 製し、 目的物 (17.9g)を無色粉末晶として得た。  [0495] This was dissolved in THF, and imidazole (7.49 g) and triphenylphosphine (27.5 g) were added. After cooling on ice, iodine (27.9 g) was added, and the mixture was stirred at the same temperature for 30 minutes. After washing with a 10% aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate, and washed sequentially with a 10% aqueous sodium thiosulfate solution, water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-5: 1) to give the desired product (17.9 g) as colorless powdery crystals.
[0496] <参考例 324 >  [0496] <Reference example 324>
4' [ (2—トリフルォロメチル）フエノキシ] 2' クロロージヒドロシンナミルョージド  4 '[(2-trifluoromethyl) phenoxy] 2' chlorodihydrocinnamyl ozide
[0497] [化 128]
Figure imgf000074_0001
[0497] [Formula 128]
Figure imgf000074_0001
[0498] 2 トリフルォロメチルフエノールを原料として参考例 1、参考例 60、参考例 124、参考 例 189、参考例 252と同様な操作を順じ実施し、 目的物を無色油状物として得た。  [0498] 2 The same operation as in Reference Example 1, Reference Example 60, Reference Example 124, Reference Example 189, and Reference Example 252 was carried out using trifluoromethylphenol as a raw material, and the target product was obtained as a colorless oil. .
[0499] <参考例 325 >  [0499] <Reference example 325>
4'一 [ (4 トリフルォロメチル）フエノキシ] 2' クロロージヒドロシンナミルョージド  4'-1 [(4 trifluoromethyl) phenoxy] 2 'chlorodihydrocinnamyl ozide
[0500] [化 129]
Figure imgf000074_0002
[0500] [Formula 129]
Figure imgf000074_0002
[0501] 4 トリフルォロメチルフ ノールを原料として参考例 1、参考例 60、参考例 124、参考 例 189、参考例 252と同様な操作を順じ実施し、 目的物を無色油状物として得た。  [0501] 4 Using trifluoromethylphenol as a raw material, the same operation as in Reference Example 1, Reference Example 60, Reference Example 124, Reference Example 189, and Reference Example 252 was carried out in the same order to obtain the desired product as a colorless oil. Was.
[0502] <参考例 326 > [0502] <Reference Example 326>
4— (4—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口べンズアルデヒド [0503] [化 130]
Figure imgf000075_0001
4- (4-Benzyloxyphenol-sulfur-)-2 Benzaldehyde [0503] [Formula 130]
Figure imgf000075_0001
[0504] パラヒドロキシベンゼンチオール（2.12g)を Ν,Ν-ジメチルホルムアミド (40mL)溶液に 溶解し、 2-クロ口- 4-フルォロベンズアルデヒド [0504] Dissolve parahydroxybenzenethiol (2.12 g) in Ν, Ν-dimethylformamide (40 mL) solution and add 2-chloro-4-fluorobenzaldehyde
(2.66g)及び炭酸カリウム (4.64g)をカ卩え、 50°Cにて 2時間攪拌した。さらにベンジルブ ロミド (4.00mL)を加え 50°Cにて 1. 5時間、 70°Cにて 2.5時間攪拌した。反応液に水を 加え酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムに て乾燥した。溶媒を留去しシリカゲルカラムクロマトグラフィー（へキサン  (2.66 g) and potassium carbonate (4.64 g) were stirred and stirred at 50 ° C. for 2 hours. Further, benzyl bromide (4.00 mL) was added, and the mixture was stirred at 50 ° C for 1.5 hours and at 70 ° C for 2.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent is distilled off and silica gel column chromatography (hexane
：酢酸ェチル = 10： 1)にて精製し、 目的物 (5.70g)を無色固体として得た。  : Ethyl acetate = 10: 1) to give the desired product (5.70 g) as a colorless solid.
NMR(400MHz, CDC1 ) δ 5.12(2H, s), 6.96— 7.03(2Η, m),  NMR (400MHz, CDC1) δ 5.12 (2H, s), 6.96-7.03 (2Η, m),
3  Three
7.06 (2Η, m), 7.33-7.50(7H, m), 8.56(1H, d, J=8.6Hz), 10.33(1H, s).  7.06 (2Η, m), 7.33-7.50 (7H, m), 8.56 (1H, d, J = 8.6Hz), 10.33 (1H, s).
[0505] <参考例 327 > [0505] <Reference Example 327>
4— (4—ベンジルォキシフエ-ルスルファ -ル）—2—クロロフエネチルアルデヒド [0506] [化 131]
Figure imgf000075_0002
4- (4-Benzyloxyphenylsulfur) -2-chlorophenethylaldehyde
Figure imgf000075_0002
[0507] 氷冷下、メトキシメチルトリフエ-ルホスホ -ゥムクロリド（8.28g)のテトラヒドロフラン (160mL)溶液に KOt- Bu(2.71g)をカ卩ぇ 1時間攪拌し、上記参考例 326 [0507] Under ice-cooling, KOt-Bu (2.71 g) was stirred in a solution of methoxymethyltriphenylphospho-dimethyl chloride (8.28 g) in tetrahydrofuran (160 mL) for 1 hour, followed by stirring for 1 hour.
(5.70g)を加えて 1時間攪拌した。反応液に水を加え酢酸ェチルにて抽出し、水、飽和 食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去しシリカゲル力 ラムクロマトグラフィー（へキサン  (5.70 g) and stirred for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent is distilled off, and silica gel column chromatography (hexane)
：酢酸ェチル = 6 : 1)にて精製し、ビュルエーテル誘導体 (6.50g, trans: cis = 58： 42の混合物）を淡黄色油状物として得た。このものをテトラヒドロフラン (90mL)に 溶解し、 6mol/L塩酸水溶液 (60mL)を加え 60°Cにて 5時間攪拌した。酢酸ェチルに て抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。反応液 に水をカ卩ぇ溶媒を留去しシリカゲルカラムクロマトグラフィー（へキサン: Ethyl acetate = 6: 1) to give a butyl ether derivative (6.50 g, a mixture of trans: cis = 58:42) as a pale yellow oil. This was dissolved in tetrahydrofuran (90 mL), a 6 mol / L hydrochloric acid aqueous solution (60 mL) was added, and the mixture was stirred at 60 ° C for 5 hours. The mixture was extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. Reaction liquid The solvent is distilled off and the silica gel column chromatography (hexane)
：酢酸ェチル = 9 : 1)にて精製し、 目的物 (4.48g)を無色固体として得た。 : Ethyl acetate = 9: 1) to give the desired product (4.48 g) as a colorless solid.
1H-NMR(400MHz, CDC1 ) δ 3.77(2H, d, J=1.8Hz), 5.09(2H,  1H-NMR (400MHz, CDC1) δ 3.77 (2H, d, J = 1.8Hz), 5.09 (2H,
3  Three
s), 6.97-7.04(3H, m), 7.05— 7.10(1H, m), 7.15(1H, d, J=1.8Hz), 7.32-7.46(7H, m), s), 6.97-7.04 (3H, m), 7.05--7.10 (1H, m), 7.15 (1H, d, J = 1.8Hz), 7.32-7.46 (7H, m),
9.72(1H, t, J=1.8Hz). 9.72 (1H, t, J = 1.8Hz).
[0508] <参考例 328 > [0508] <Reference Example 328>
2 クロロー 4— (3—トリフルォロメチルフエノキシ）フエネチルアルデヒド  2 Chloro-4- (3-trifluoromethylphenoxy) phenethylaldehyde
[0509] [化 132]
Figure imgf000076_0001
[0509] [Formula 132]
Figure imgf000076_0001
[0510] 参考例 29の化合物を用い上記実施例 327と同様に反応させ目的物を無色油状物と して得た。 [0510] The compound of Reference Example 29 was reacted in the same manner as in Example 327 to obtain the desired product as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 3.84(2H, d, J=1.8Hz), 1 H-NMR (400MHz, CDC1) δ 3.84 (2H, d, J = 1.8Hz),
3  Three
6.93(lH,dd,J=2.4, 8.6Hz), 7.11(1H, d, J=2.4Hz), 7.15-7.22(1H, m), 7.22(1H, d, J=8.6Hz), 7.29(1H, s), 7.41(1H, d, J=7.9Hz), 7.49(1H, t, J=7.9Hz), 9.78(1H, t, J=1.8Hz).  6.93 (lH, dd, J = 2.4,8.6Hz), 7.11 (1H, d, J = 2.4Hz), 7.15-7.22 (1H, m), 7.22 (1H, d, J = 8.6Hz), 7.29 (1H , s), 7.41 (1H, d, J = 7.9Hz), 7.49 (1H, t, J = 7.9Hz), 9.78 (1H, t, J = 1.8Hz).
[0511] <参考例 329 >  [0511] <Reference Example 329>
4' [ (4 ベンジルォキシ）フエ-ルスルファ -ル]—2'—クロロフエネチルョージド 4 '[(4 benzyloxy) phenol-sulfur]-2'-chlorophenethyl sulfide
[0512] [化 133]
Figure imgf000076_0002
[0512] [Formula 133]
Figure imgf000076_0002
[0513] 参考例 327の化合物を用い、参考例 189と同様にして還元し、ついで参考例 252と同 様にしてヨウ素化し目的物を淡黄色油状物として得た。  [0513] Using the compound of Reference Example 327, reduction was carried out in the same manner as in Reference Example 189, followed by iodination in the same manner as in Reference Example 252, to obtain the desired product as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 3.18— 3.26(2H, m), 3.28— 3.34(2H,  1H-NMR (400MHz, CDC1) δ 3.18― 3.26 (2H, m), 3.28― 3.34 (2H,
3  Three
m), 5.09(2H, s), 6.96— 7.02(3H, m), 7.09(2H, d, J=7.9Hz), 7.33-7.45(7H, m).  m), 5.09 (2H, s), 6.96- 7.02 (3H, m), 7.09 (2H, d, J = 7.9Hz), 7.33-7.45 (7H, m).
[0514] <参考例 330 > [0514] <Reference example 330>
2' クロロー 4'— [ (3—トリフロォロメチル）フエノキシ]フエネチルョージド [0515] [化 134]
Figure imgf000077_0001
2 'Chloro 4' — [(3-Trifluoromethyl) phenoxy] phenethylhoside [0515] [Formula 134]
Figure imgf000077_0001
[0516] 参考例 328の化合物を用いて上記参考例 329と同様にして目的物を無色油状物と して得た。 [0516] The desired product was obtained as a colorless oil using the compound of Reference Example 328 in the same manner as in Reference Example 329 above.
1H-NMR(400MHz, CDC1 ) δ 3.25— 3.32(2H, m), 3.36— 3.40(2H, 1 H-NMR (400MHz, CDC1) δ 3.25― 3.32 (2H, m), 3.36― 3.40 (2H,
3  Three
m), 6.89(1H, dd, J=2.4,7.9Hz), 7.04(1H, d, J=2.4Hz), 7.17(1H, dd, J=2.4, 7.9Hz), 7.21-7.27(2H, m), 7.39(1H, d, J=7.9Hz), 7.47(1H, t, J=7.9Hz).  m), 6.89 (1H, dd, J = 2.4,7.9Hz), 7.04 (1H, d, J = 2.4Hz), 7.17 (1H, dd, J = 2.4, 7.9Hz), 7.21-7.27 (2H, m ), 7.39 (1H, d, J = 7.9Hz), 7.47 (1H, t, J = 7.9Hz).
[0517] <参考例 331 >  [0517] <Reference Example 331>
4'一 [ (3—ベンジルォキシ）フエ-ルスルファ -ル]—2'—トリフルォロメチルフエネチル ョージド  4'-I-[(3-benzyloxy) phenol-sulfur-]-2'-trifluoromethylphenethyl chloride
[0518] [化 135]
Figure imgf000077_0002
[0518] [Formula 135]
Figure imgf000077_0002
[0519] 4 フルオロー 2 トリフルォロベンズアルデヒドと 3—べンジルォキシベンゼンチォー ルを参考例 1と同様にして反応させた後、得られたィ匕合物を参考例 327ついで参考 例 329と同様な反応を順じ行い目的物を無色油状物として得た。 [0519] After reacting 4-fluoro-2 trifluorobenzaldehyde with 3-benzyloxybenzenethiol in the same manner as in Reference Example 1, the resulting conjugated product was obtained in Reference Example 327 followed by Reference Example 329. The same reaction was performed in order to obtain the desired product as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 3.30(4H, s), 5.03(2H, s),  1H-NMR (400MHz, CDC1) δ 3.30 (4H, s), 5.03 (2H, s),
3  Three
6.90-7.00(3H, m), 7.20-7.42(8H, m), 7.56— 7.59(1H, m).  6.90-7.00 (3H, m), 7.20-7.42 (8H, m), 7.56--7.59 (1H, m).
[0520] [実施例 1] [0520] [Example 1]
2 t ブトキシカルボ-ルァミノ— 5— [2 クロロー 4— (3—トリフルォロメチルフエ-ルス ルファ -ル）フエ-ル ]ー2—エトキシカルボ-ルペンタン酸ェチル [0521] [化 136] 2 t Butoxycarbol-amino-5- [2-Chloro-4- (3-trifluoromethylphenylsulfur-phenyl) phenyl] -2-ethoxycarbolethylpentanoate [0521] [Formula 136]
Figure imgf000078_0001
Figure imgf000078_0001
[0522] アルゴン気流下、 2— t ブトキシカルボ-ルァミノマロン酸ジェチル（1.3mL)の THF [0522] THF of 2-t-butoxycarbol-malaminomalonate getyl (1.3mL) under argon stream
(35mL)、 DMF (4mL)溶液に、室温にてナトリウム t ブトキシド (490mg)をカ卩えた。 80°Cにて 20分撹拌した後室温にもどし、参考例 279 (1.55g)の化合物の THF (5mL) 溶液を滴下した。その後、 5時間加熱還流し、氷水に反応液をあけ酢酸ェチルで抽 出した。水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を減 圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル = 5： 1) にて精製した。 目的物（1.87g)を無色油状物として得た。  (35 mL) and DMF (4 mL) were mixed with sodium t-butoxide (490 mg) at room temperature. After stirring at 80 ° C for 20 minutes, the temperature was returned to room temperature, and a solution of the compound of Reference Example 279 (1.55 g) in THF (5 mL) was added dropwise. Thereafter, the mixture was heated under reflux for 5 hours, the reaction solution was poured into ice water, and extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). The desired product (1.87 g) was obtained as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ .22— 1.36(6H, m), 1.42(9H, s),  1H-NMR (400MHz, CDC1) δ .22― 1.36 (6H, m), 1.42 (9H, s),
3  Three
1.45-1.53(2H, m), 2.37(2H,br), 2.74(2H, t, J=7.8Hz), 4.23(4H, m), 5.94(1H, s), 1.45-1.53 (2H, m), 2.37 (2H, br), 2.74 (2H, t, J = 7.8Hz), 4.23 (4H, m), 5.94 (1H, s),
7.16-7.2K2H, m), 7.36- 7.56(5H, m). 7.16-7.2K2H, m), 7.36- 7.56 (5H, m).
[0523] [実施例 2— 68] [0523] [Example 2—68]
参考例に示した各種ハロゲン誘導体を用い、上記実施例 1と同様な方法によって 表 6と表 7に示す化合物を合成した。  Using the various halogen derivatives shown in Reference Examples, the compounds shown in Tables 6 and 7 were synthesized in the same manner as in Example 1 above.
[0524] [表 6] [0524] [Table 6]
表 6
Figure imgf000079_0001
Table 6
Figure imgf000079_0001
実 例 R1 R2 R3 R4 X n 性状 収率Example R1 R2 R3 R4 X n Property Yield
2 CI c-CI H CI O 3 無色油状 1ft 742 CI c-CI H CI O 3 Colorless oil 1ft 74
3 t-Bu H H H O 3 龥色油状物 643 t-Bu H H H O 3 Blue oil 64
4 CF3 H H H O 3 無色油状 ^9 1004 CF 3 HHHO 3 Colorless oil ^ 9 100
5 CF3 H O e H O 3 鑰色油状物 10O5 CF 3 HO e HO 3 brown oil 10O
6 CF, H H OMe O 3 無色油状物 1006 CF, H H OMe O 3 Colorless oil 100
7 CF3 H CF3 H O 3 無1 e ^状物 1∞7 CF 3 H CF 3 HO 3 None 1 e ^ 1
8 CF3 H H CF3 O 3 饞色油状 928 CF 3 HH CF 3 O 3 Blue oil 92
9 CF3 o-CFz H H o 3 黄色油状 479 CF 3 o-CF z HH o 3 Yellow oil 47
10 CF3 c-CF3 H CI o 3 無色油状 4β9 8910 CF 3 c-CF 3 H CI o 3 Colorless oil 4β9 89
11 CF3 b-CI H H o 3 餹色油状物 9411 CF 3 b-CI HH o 3 Blue oil 94
12 CF, c-PhCH20 H CI o 3 Mr 4Α 9112 CF, c-PhCH 2 0 H CI o 3 Mr 4Α 91
13 Ph(CHj)2 H H CI o 3 餹色油状物 8313 Ph (CHj) 2 HH CI o 3 Yellow oil 83
14 Ph(CH2)2 H H CF3 o 3 無色油状物 9014 Ph (CH 2 ) 2 HH CF 3 o 3 Colorless oil 90
15 Ph(CH2)2 c-CF3 H H o 3 無色油状 40! 9715 Ph (CH 2 ) 2 c-CF 3 HH o 3 Colorless oil 40! 97
16 PhfCH,), c-Ph<CH2)2 H H o 3 9516 PhfCH,), c-Ph <CH 2 ) 2 HH o 3 95
17 Ph(CH2)2 ο-ΡΚ<ΟΗ2)2 H CF3 o 3 無色油 物 10017 Ph (CH 2 ) 2 ο-ΡΚ <ΟΗ 2 ) 2 H CF 3 o 3 Colorless oil 100
18 Ph(CH2)2 c-Ph(CHa H CI o 3 餹色油状物 9618 Ph (CH 2 ) 2 c-Ph (CHa H CI o 3 blue oil 96
19 l-PrO o-iPr H CI o 3 色 i 物 10019 l-PrO o-iPr H CI o 3 colors i object 100
20 PhO H H CI o 3 9220 PhO H H CI o 3 92
21 PhCHzO H H H o 3 無色油状物 9521 PhCH z OHHH o 3 Colorless oil 95
22 PhCH20 H H Br o 3 鶬も油状物 10022 PhCH 2 0 HH Br o 3 Oil 100
23 PhCHzO H H SMe o 3 無 S油状^! -23 PhCH z OHH SMe o 3 No S oil ^!-
24 PhCH20 H H Me o 3 無色油状物 10024 PhCH 2 0 HH Me o 3 Colorless oil 100
25 P CHaO H H Et o 3 齄色油状物 7225 P CH a OHH Et o 3 Blue oil 72
26 PhCHaO H H CI s 2 淡黄色油状物 1∞26 PhCH a OHH CI s 2 pale yellow oil 1∞
27 PhCHaO H H CI s 3 鎢色油状物 1∞27 PhCH a OHH CI s 3 color oil 1
28 PhCHaO H H CI s 4 齄色油状物 100 n n 3 簾 状稱 28 PhCH a OHH CI s 4 Blue oil 100 nn 3
30 CI H H H s 3 無色油状 «1 82 30 CI H H H s 3 colorless oil «1 82
31 CF3 c-CF3 H CI s 3 餹色油状物 6631 CF 3 c-CF 3 H CI s 3 Blue oil 66
32 Et H H H o 3 無色油状 10032 Et H H Ho 3 Colorless oil 100
33 SO e H H H o 3 無 6油状 991 10033 SO e H H H o 3 No 6 Oil 991 100
34 CI ο- H H o 1 齄色油状 MB 5634 CI ο- H H o 1 Blue oil MB 56
35 CF3 H H PhCH20 o 3 1CX)35 CF 3 HH PhCH 2 0 o 3 1CX)
36 PhCH20 H H CI o 3 饞色油状物 Λ0Ο36 PhCH 2 0 HH CI o 3 油 状 colored oil Λ0Ο
37 CF3 H CI H o 3 餹色油状物 10037 CF 3 H CI Ho 3 Blue oil 100
38 CF3 CI 3 餹色油状物 38 CF 3 CI 3 yellow oil
H H o 100 H H o 100
39 PhCH20 H H F . o 3 餹色油状物 10039 PhCH20 H H F .o 3 Blue oil 100
40 •-CI 40 • -CI
CF3 H H o 3 嫵色油状物 100 一は次工程とあわせて表 8-10に示す 7] 表
Figure imgf000080_0001
CF 3 HH o 3 blue oily substance 100 shown in Table 8-10 together with the next step 7] table
Figure imgf000080_0001
R1 R2 R3 R4 X n 性状 収率 （％) R1 R2 R3 R4 X n Property Yield (%)
41 CF3 c- H H 0 3 淡黄色油状物 4141 CF3 c- H H 03 Light yellow oil 41
42 CF3 d-CI H H o 3 淡黄色油状物 7242 CF 3 d-CI HH o 3 pale yellow oil 72
43 P (CH2)2 c-CF3 H CI 0 3 fteft油状^ 9 9343 P (CH 2 ) 2 c-CF 3 H CI 0 3 fteft oil ^ 9 93
44 PhCH20 H H a o 2 無色油状 %9 -44 PhCH 2 0 HH ao 2 Colorless oil% 9-
45 PhCH20 H H CI o 4 無色油状物 -45 PhCH 2 0 HH CI o 4 Colorless oil-
46 CF3 H H F 0 3 無色油状物 ido46 CF 3 HHF 0 3 Colorless oil ido
47 PhCH20 c-PhCH20 H H 0 3 無色油状 -47 PhCH 20 c-PhCH 20 HH 0 3 Colorless oil-
48 PhCH20 c-PhCHjO H a o 3 無色油状物 -48 PhCH 20 c-PhCHjO H ao 3 Colorless oil-
49 PhCH20 c-a H CI 0 3 無色油状物 10049 PhCH 2 0 ca HCI 0 3 Colorless oil 100
50 PhCHzO H H CF3 0 3 無 B油状物 10050 PhCH z OHH CF 3 0 3 None B Oil 100
51 PhCHjO H H Ph 0 3 無 B油状物 -51 PhCHjO H H Ph 0 3 None B Oil-
52 MeS H H H 0 3 色油状物 8352 MeS H H H 0 3-color oil 83
53 n-CsHn H H H o 3 色油 *vC物 8653 n-CsHn H H H o 3-color oil * vC material 86
54 c-C7H15 H H H o 3 色油 物 8854 cC 7 H 15 HHH o 3-color oil 88
55 iPr c-iPrO H H o 3 齄色油状物 9555 iPr c-iPrO H H o 3 Blue oil 95
56 iPr c-iPr H CI o 3 MtB 状物 6656 iPr c-iPr H CI o 3 MtB 66
57 PhCH2S H H H 0 3 kt色油状物 _57 PhCH 2 SHHH 0 3 kt color oil _
58 PhCH2S H H o 3 鵝色油状物 58 PhCH 2 SHH o 3 El oil
59 i-Bu H H H o 3 無4 B^B状物 7659 i-Bu HHH o 3 No 4 B ^ B-like material 76
60 PhOCH2 H H H o 3 無 S油状物 10060 PhOCH 2 HHH o 3 No S oil 100
61 PhCH20 H H i-Pr 0 3 無1 C油状物 61 PhCH 2 0 HH i-Pr 0 3 None 1 C oil
62 CF3 H H H s 3 色 状 1ίο 9062 CF 3 HHH s 3 colors 1ίο 90
63 CF3 H H CF3 s 3 淡黄色油状物 5363 CF 3 HH CF 3 s 3 Light yellow oil 53
64 CF3 c- e H H s 3 簫色油状物 10064 CF 3 c- e HH s 3 Koi oil 100
65 MeO H H a s 3 痛色油 *ΙΛ·1¾Ι 8765 MeO H H a s 3 Paige oil * ΙΛ1¾Ι 87
66 PhCH20 H H H s 3
Figure imgf000080_0002
66 PhCH 2 0 HHH s 3
Figure imgf000080_0002
67 PhCH20 H H CF3 s 3 醣色油状物 10067 PhCH 2 0 HH CF 3 s 3 Blue oil 100
68 PhCH20 H H CI s 1 蠊も油状物 100 68 PhCH 2 0 HH CI s 1
一は次工程とあわせて表 8-10に示す 施例 69]  One is shown in Table 8-10 along with the next process.
— [ (4一ベンジルォキシ）フエ-ル]一 2— t一ブトキシカルボ-ルァミノ— 2—エトキシカ ルポ-ルペンタン酸ェチル — [(4-I-benzyloxy) phenyl] -1-2-t-butoxycarbo-amino- 2-ethoxy Ethyl ethyl pentanate
[0527] [化 137] [0527] [Formula 137]
Figure imgf000081_0001
Figure imgf000081_0001
[0528] 参考例 321の化合物を用い実施例 1と同様に反応させ、目的物を淡黄色油状物とし て得た。 [0528] The same procedures used in Example 1 were carried out except for using the compound of Reference Example 321, to give the desired product as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 1.22(6H, t, J=7.1Hz), 1.42(9H, s),  1H-NMR (400MHz, CDC1) δ 1.22 (6H, t, J = 7.1Hz), 1.42 (9H, s),
3  Three
1.44-1.47(2H, m), 2.31(2H, br s), 2.57(2H, t, J=7.6Hz), 4.11-4.27(4H, m), 5.03(2H, s), 5.92(1H, br s), 6.88(2H, d, J=8.8Hz), 7.06(2H, d, J=8.8Hz),  1.44-1.47 (2H, m), 2.31 (2H, br s), 2.57 (2H, t, J = 7.6Hz), 4.11-4.27 (4H, m), 5.03 (2H, s), 5.92 (1H, br s), 6.88 (2H, d, J = 8.8Hz), 7.06 (2H, d, J = 8.8Hz),
7.29-7.43(5H, m).  7.29-7.43 (5H, m).
[0529] [実施例 70] [0529] [Example 70]
2 t ブトキシカルボ-ルァミノ— 2 エトキシカルボ-ルー 5— [4— (3—イソプロポキシフ エノキシ）フエ-ル]ペンタン酸ェチル  2 t butoxycarbo-lamino-2 ethoxycarbol-5- [4- (3-isopropoxyphenoxy) phenyl] pentane
[0530] [化 138]
Figure imgf000081_0002
[0530] [Formula 138]
Figure imgf000081_0002
[05311 上記実施例 69の化合物を参考例 123と同様に接触還元し、得られたフエノール体（ 850mg)を DMF (20mL)に溶解後、 2 ョードプロパン（0.2mL)、炭酸カリウム（500mg) を加え 60°Cにて 4時間撹拌した。反応液に水を加え酢酸ェチルで抽出後、水、飽和 食塩水の順に洗浄し、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣を シリカゲルカラムクロマトグラフィー（へキサン:酢酸ェチル =4 : 1)にて精製した。 目的 物（760mg)を無色油状物として得た。 [05311] The compound of Example 69 was catalytically reduced in the same manner as in Reference Example 123, and the obtained phenol compound (850 mg) was dissolved in DMF (20 mL), and then 2-propane (0.2 mL) and potassium carbonate (500 mg) were added. The mixture was stirred at 60 ° C for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1). The desired product (760 mg) was obtained as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.23(6H, t, J=7.3Hz), 1.31(6H, d, 1 H-NMR (400MHz, CDC1) δ 1.23 (6H, t, J = 7.3Hz), 1.31 (6H, d,
3  Three
J=5.9Hz), 1.42(9H, s),1.45-1.52(2H, m), 2.34(2H, br), 2.61(2H, t, J=7.8Hz), 4.17-4.27(4H, m), 4.50(1H, heptet, 5.9Hz), 5.94(1H, br s), 6.50— 6.53(2H, m), 6.59— 6.62(1H, m), 6.92(2H, d, J=8.8Hz), 7.10(2H, d, J=8.8Hz), 7.18(1H, t, J=8.8Hz). J = 5.9Hz), 1.42 (9H, s), 1.45-1.52 (2H, m), 2.34 (2H, br), 2.61 (2H, t, J = 7.8Hz), 4.17-4.27 (4H, m), 4.50 (1H, heptet, 5.9Hz), 5.94 (1H, br s), 6.50― 6.53 (2H, m), 6.59-6.62 (1H, m), 6.92 (2H, d, J = 8.8Hz), 7.10 (2H, d, J = 8.8Hz), 7.18 (1H, t, J = 8.8Hz).
[0532] [実施例 71]  [0532] [Example 71]
2 t ブトキシカルボ-ルァミノ— 5— [4— (3、 5—ジクロロフエノキシ）フエ-ル]— 2—ェ トキシカルボ-ルペンタン酸ェチル  2 t Butoxycarbo-lamino—5— [4— (3,5-dichlorophenoxy) phenyl] —2-ethylethoxycarboylpentanoate
[0533] [化 139]
Figure imgf000082_0001
[0533] [Formula 139]
Figure imgf000082_0001
[0534] 前記実施例 69の化合物を参考例 123と同様に接触還元し、得られたフ ノール体（ 1.27g)と 3, 5—ジクロ口フエ-ルホウ酸（1.18g)を塩化メチレン（30mL)に溶解し撹拌 下、酢酸銅 (676mg)、トリェチルァミン (0.86mL)を加えた。 16時間後、さらに 8時間後 酢酸銅を同量追加し、 40時間撹拌後不溶物を濾去し濾液を水にあけ酢酸ェチルに て抽出した。水、飽和食塩水の順に洗浄後、無水硫酸マグネシウムにて乾燥した。 溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン:酢酸ェチル = 20 : 1)にて精製し目的物（333mg)を淡青色油状物として得た。 The compound of Example 69 was catalytically reduced in the same manner as in Reference Example 123, and the obtained phenol form (1.27 g) and 3,5-dichlorophthalic boric acid (1.18 g) were treated with methylene chloride (30 mL). ), And with stirring, copper acetate (676 mg) and triethylamine (0.86 mL) were added. After 16 hours and further 8 hours, the same amount of copper acetate was added. After stirring for 40 hours, insolubles were removed by filtration, the filtrate was poured into water and extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain the desired product (333 mg) as a pale blue oil.
[0535] [実施例 72]  [0535] [Example 72]
2 t ブトキシカルボ-ルァミノ— 2 エトキシカルボ-ルー 5— [4— (3—メタンスルホ-ル フエノキシ）フエ-ル]ペンタン酸ェチル  2 t Butoxycarbo-lamino-2 Ethoxycarbol-5- [4- (3-Methanesulfol phenoxy) phenyl] pentanoate
[0536] [化 140]
Figure imgf000082_0002
[0536] [Formula 140]
Figure imgf000082_0002
[0537] 実施例 33の化合物（l.OOg)を塩化メチレン（30mL)に溶解し、 m クロ口過安息香酸 [0537] The compound of Example 33 (l.OOg) was dissolved in methylene chloride (30 mL), and m-chloroperbenzoic acid was added.
(610mg)を加え室温にて 6時間撹拌した。反応液に水を加え酢酸ェチルで抽出後、 飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄し、無水硫酸ナトリウムにて 乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン： 酢酸ェチル = 1： 1)にて精製した。 目的物（610mg)を無色油状物として得た。 1H-NMR(400MHz, CDC1 ) δ 1.24(6H, t, J=7.3Hz), 1.42(9H, s), (610 mg) was added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The desired product (610 mg) was obtained as a colorless oil. 1H-NMR (400MHz, CDC1) δ 1.24 (6H, t, J = 7.3Hz), 1.42 (9H, s),
3  Three
1.47-1.56(2H, m), 2.34(2H, br), 2.64(2H, t, J=7.8Hz), 3.04(3H, s),  1.47-1.56 (2H, m), 2.34 (2H, br), 2.64 (2H, t, J = 7.8Hz), 3.04 (3H, s),
4.18-4.26(4H, m),5.95(lH, br), 6.95(2H, d, J=8.8Hz), 7.17(2H, t, J=8.8Hz), 7.20-7.30(3H,m), 7.47-7.52(2H, m), 7.62(1H, d, J=8.8Hz).  4.18-4.26 (4H, m), 5.95 (lH, br), 6.95 (2H, d, J = 8.8Hz), 7.17 (2H, t, J = 8.8Hz), 7.20-7.30 (3H, m), 7.47 -7.52 (2H, m), 7.62 (1H, d, J = 8.8Hz).
[0538] [実施例 73] [0538] [Example 73]
2 t ブトキシカルボ-ルァミノ— 2 エトキシカルボ-ルー 5— [4— (3—トリフルォロメチ ルフエ-ルスルフィ -ル） ]フエ-ルペンタン酸ェチル  2 t Butoxycarbo-lamino-2 Ethoxycarbol-5- [4- (3-trifluoromethylsulfuryl)] ethyl phenylpentanoate
[0539] [化 141] [0539] [Formula 141]
Figure imgf000083_0001
Figure imgf000083_0001
[0540] 実施例 62の化合物（1.50g)を塩化メチレン（80mL)に溶解し、 0°C撹拌下、 m クロ口 過安息香酸 (450mg)を少量ずつ加えた。同温にて 1時間、室温にて 2時間撹拌後、 反応液に水を加え酢酸ェチルで抽出後、飽和炭酸水素ナトリウム水溶液、飽和食塩 水の順に洗浄し、無水硫酸ナトリウムにて乾燥した。溶媒を減圧留去し、残渣をシリカ ゲルカラムクロマトグラフィー（へキサン:酢酸ェチル = 1： 1)にて精製した。 目的物（ [0540] The compound of Example 62 (1.50 g) was dissolved in methylene chloride (80 mL), and perbenzoic acid (450 mg) was added little by little under stirring at 0 ° C. After stirring at the same temperature for 1 hour and at room temperature for 2 hours, water was added to the reaction solution, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). Object (
1.10g)を黄色油状物として得た。 1.10 g) was obtained as a yellow oil.
1H-NMR(400MHz, CDC1 ) δ 1.18— 1.21(6H, m), 1.40(9H, s), 1 H-NMR (400MHz, CDC1) δ 1.18― 1.21 (6H, m), 1.40 (9H, s),
3  Three
1.44-1.52(2H, m),  1.44-1.52 (2H, m),
2.30(2H, br), 2.66(2H, t, J=7.3Hz), 4.14-4.22(4H, m), 5.91(1H, br ), 7.27(2H, d,  2.30 (2H, br), 2.66 (2H, t, J = 7.3Hz), 4.14-4.22 (4H, m), 5.91 (1H, br), 7.27 (2H, d,
J=8.3Hz), 7.56(2H, d, J=8.3Hz), 7.59(1H, t, J=8.3Hz), 7.69(1H,  J = 8.3Hz), 7.56 (2H, d, J = 8.3Hz), 7.59 (1H, t, J = 8.3Hz), 7.69 (1H,
d, J=8.3Hz), 7.78(1H, d, J=8.3Hz), 7.95(1H, s).  d, J = 8.3Hz), 7.78 (1H, d, J = 8.3Hz), 7.95 (1H, s).
[0541] [実施例 74] [0541] [Example 74]
2 t ブトキシカルボ-ルァミノ— 5— [4— (3—トリフルォロメチルー 5 メチルフエ-ルス ルフィ-ル）]フエ-ルー 2—エトキシカルボ-ルペンタン酸ェチル [0542] [化 142] 2 t butoxycarbo-amino-5- [4— (3-trifluoromethyl-5-methylphenylsulfyl)] phenyl 2-ethylethoxypentanoate [0542] [Formula 142]
Figure imgf000084_0001
Figure imgf000084_0001
[0543] 実施例 64の化合物を用い、上記実施例 73と同様に行い目的物を無色油状物として 得た。 [0543] The same procedure as in Example 73 above was carried out except for using the compound of Example 64 to give a desired product as a colorless oil.
FABMS : 600 ([M+H]+). FABMS: 600 ([M + H] + ).
1H-NMR(400MHz, CDC1 ) δ 1.18— 1.22(6H, m), 1.41(9H, s),  1H-NMR (400MHz, CDC1) δ 1.18-1.22 (6H, m), 1.41 (9H, s),
3  Three
1.46-1.50(2H, m),2.31(2H, br), 2.45(3H, s), 2.66(2H, t, J=7.3Hz), 4.14-4.22(4H, m), 5.92(1H, br s), 7.27(2H, d, J=7.8Hz), 7.48(1H, s), 7.55(2H, d, J=7.8Hz), 7.62(1H, s), 7.70(1H, s).  1.46-1.50 (2H, m), 2.31 (2H, br), 2.45 (3H, s), 2.66 (2H, t, J = 7.3Hz), 4.14-4.22 (4H, m), 5.92 (1H, br s ), 7.27 (2H, d, J = 7.8Hz), 7.48 (1H, s), 7.55 (2H, d, J = 7.8Hz), 7.62 (1H, s), 7.70 (1H, s).
[0544] [実施例 75] (実施例 9の別途合成）  [Example 75] (Separate synthesis of Example 9)
5— [4一（3、 5—ビストリフルォロメチルフエノキシ）フエ-ル]— 2 t ブトキシカルボ- ルァミノー 2—エトキシカルボ二ルペンタン酸ェチル  5— [4- (3,5-bistrifluoromethylphenoxy) phenyl] —2 t-butoxycarbaluminamine 2-ethoxycarbodiethylpentanoate
[0545] [化 143] [0545] [Formula 143]
Figure imgf000084_0002
Figure imgf000084_0002
[0546] 実施例 69の化合物を参考例 123と同様に接触還元し、得られたフエノール体を 3, 5 ビス（トリフルォロメチル)フエ-ルホウ酸と実施例 71と同様に反応させ目的物を淡黄 色油状物として得た。 The compound of Example 69 was catalytically reduced in the same manner as in Reference Example 123, and the obtained phenol compound was reacted with 3,5 bis (trifluoromethyl) phenol boric acid in the same manner as in Example 71 to give the desired product Was obtained as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 1.24(6H, t, J=7.3Hz), 1.43(9H, s), 1 H-NMR (400MHz, CDC1) δ 1.24 (6H, t, J = 7.3Hz), 1.43 (9H, s),
3  Three
1.47-1.58(4H, m), 2.36(2H, br s), 2.66(2H, t, J=7.3Hz), 4.18- 4.26(4H, m), 5.96(1H, br s), 6.96(2H, d,J=8.3Hz), 7.20(2H, d, J=8.3Hz), 7.36(2H, s), 7.55(1H, s).  1.47-1.58 (4H, m), 2.36 (2H, br s), 2.66 (2H, t, J = 7.3Hz), 4.18- 4.26 (4H, m), 5.96 (1H, br s), 6.96 (2H, d, J = 8.3Hz), 7.20 (2H, d, J = 8.3Hz), 7.36 (2H, s), 7.55 (1H, s).
[0547] [実施例 76及び 77] 2 t ブトキシカルボ-ルァミノ— 2— [2 クロロー 4— (3—トリフルォロメチルフエ-ルス ルファ -ル）フエ-ル]プロピル 1 , 3 プロパンジオール（実施例 76) [0547] [Examples 76 and 77] 2t butoxycarbolamino-2-[[2-chloro-4- (3-trifluoromethylphenylsulfur) phenyl] propyl 1,3 propanediol (Example 76)
[0548] [化 144] [0548] [Formula 144]
Figure imgf000085_0001
Figure imgf000085_0001
[0549] 及び、 2— t ブトキシカルボ-ルァミノ— 5— [2 クロロー 4— (3—トリフルォロメチルフエ ニルスルファ -ル）フエ-ル]ペンタン 1 オール (実施例 77) [0549] and 2-t butoxycarbo-lamino-5- [2-chloro-4- (3-trifluoromethylphenylsulfur) phenyl] pentane 1ol (Example 77)
[0550] [化 145]
Figure imgf000085_0002
[0550] [Formula 145]
Figure imgf000085_0002
[0551] 実施例 1の化合物（1.87g)を THF (30mL)に溶解し、 0°Cにて撹拌下水素化ホウ素 リチウム (675mg)を加えた。常温までに徐々に昇温しながら一晩撹拌した後、反応液 に氷水を加え有機溶媒を減圧留去した。残渣に 10%クェン酸水を加え pH3とした後 、酢酸ェチルにて抽出した。水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて 乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（へキサン： 酢酸ェチル = 1 : 1)にて精製し、ジオール体（1.10g)、モノオール体（0.27g)を各々無 色油状物として得た。 [0551] The compound of Example 1 (1.87g) was dissolved in THF (30mL), and lithium borohydride (675mg) was added at 0 ° C with stirring. After stirring overnight while gradually warming to room temperature, ice water was added to the reaction solution, and the organic solvent was distilled off under reduced pressure. The residue was adjusted to pH 3 by adding 10% aqueous solution of citric acid, and then extracted with ethyl acetate. After washing with water and saturated saline in this order, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a diol form (1.10 g) and a monol form (0.27 g) as colorless oils.
[0552] (実施例 76の化合物）  (Compound of Example 76)
FABMS : 520([M + H]+). FABMS: 520 ([M + H] + ).
1H-NMR(400MHz, CDC1 ) δ 1.43(9Η, s), 1.62— 1.65(4Η, m),  1H-NMR (400MHz, CDC1) δ 1.43 (9Η, s), 1.62-- 1.65 (4Η, m),
3  Three
2.72(2H,br), 3.31(2Η, br), 3.57— 3.62(2Η, m), 3.81— 3.85(2Η, m), 4.93(1Η, s), 7.20-7.27(3H,m), 7.38- 7.55(4H, m).  2.72 (2H, br), 3.31 (2Η, br), 3.57― 3.62 (2Η, m), 3.81― 3.85 (2Η, m), 4.93 (1Η, s), 7.20-7.27 (3H, m), 7.38- 7.55 (4H, m).
[0553] (実施例 77の化合物） (Compound of Example 77)
FABMS :490([M + H]+). FABMS: 490 ([M + H] + ).
1H-NMR(400MHz, CDC1 ) δ 1.44(9H, s), 1.63-1.73(4H, m), 1 H-NMR (400 MHz, CDC1) δ 1.44 (9H, s), 1.63-1.73 (4H, m),
3  Three
2.72-2.78(2H, m), 3.57(1H, br), 3.68-3.70(2H, m), 4.61(1H, br s), 7.20-7.22(2H, m), 7.39-7.55(5H, m). 2.72-2.78 (2H, m), 3.57 (1H, br), 3.68-3.70 (2H, m), 4.61 (1H, br s), 7.20-7.22 (2H, m), 7.39-7.55 (5H, m).
[0554] [実施例 78 184] Example 78 184
実施例 2— 68、 70— 74の化合物を用い。上記実施例 76と同様な方法によって表 8 から表 10に示す化合物を合成した。  The compounds of Examples 2-68 and 70-74 were used. The compounds shown in Tables 8 to 10 were synthesized in the same manner as in Example 76 above.
[0555] [表 8] [0555] [Table 8]
T JP2004/016517 T JP2004 / 016517
表 8Table 8
Figure imgf000087_0001
Figure imgf000087_0001
案 M例 R1 R2 R3 R4 R5 X 性状 収率 (¾) Plan M Example R1 R2 R3 R4 R5 X Property Yield (¾)
O  O
78 CI c-CI H CI CH2OH O 3 無色油状物 7978 CI c-CI H CI CH 2 OH O 3 Colorless oil 79
79 CI c-CI H CI H O 3 餹色油状 Ml 1279 CI c-CI H CI H O 3 Blue oil Ml 12
80 t-Bu H H H CH2OH O 3 無 状 7880 t-Bu HHH CH 2 OH O 3 No change 78
81 t-Bu H H H H O 3 無色油状 1581 t-Bu H H H H O 3 Colorless oil 15
82 CP3 H H H CHaOH O 3 餹色油状物 7482 CP 3 HHH CHaOH O 3 Blue oil 74
63 CF3 H H H H O 3 無色油状物 1763 CF 3 HHHHO 3 Colorless oil 17
84 CF, H O e H CHzOH O ? 色^ 4^ 19 7684 CF, H O e H CHzOH O? Color ^ 4 ^ 19 76
85 CF, H OMe H H O 3 無色油状物 585 CF, H OMe H H O 3 Colorless oil 5
86 CF3 H H ΟΜΘ CH2OH O 3 無色油状物 4586 CF 3 HH ΟΜΘ CH 2 OH O 3 Colorless oil 45
87 CF, H H OMe H O 3 焦色油状 Hi 1787 CF, H H OMe H O 3 Dark oil Hi 17
88 CF, H CF3 H CH2OH O 3 無色 状物 6888 CF, H CF 3 H CH 2 OH O 3 Colorless 68
CFa H CF r- H H O 3 16CF a H CF r- HHO 3 16
90 CF3 H H CH2OH O 3 條色油状 Us 4190 CF 3 HH CH2OH O 3 Multicolor oil Us 41
91 CFa H H CF3 H O 3 22
Figure imgf000087_0002
91 CF a HH CF 3 HO 3 22
Figure imgf000087_0002
CFa H H H q CF a HHH q
CF,  CF,
CF3 n wl u CF 3 n wl u
n n u ft n n u ft
97 CF3 -CI H H H 0 3 無色粉末 2997 CF 3 -CI HHH 0 3 Colorless powder 29
98 CFS c-Ph0H2O H a CHaOH 0 3 無色油状物 6798 CF S c-Ph0H 2 OH a CHaOH 0 3 Colorless oil 67
99 CF, c- hCHsO H o H 0 3 雛色油状物 1299 CF, c- hCHsO H o H 0 3 Chicken oil 12
100 Ph(CHa)a H H CI CH2OH 0 3 饞色油状物 84100 Ph (CHa) a HH CI CH 2 OH 03 Blue oil 84
101 Ph(CH^2 H H a H 0 3 餹色油状物 15101 Ph (CH ^ 2 HH a H 0 3 yellow oil 15
102 Ph(CHa)2 H H CF3 CHaOH 0 3 饞色 物 72102 Ph (CHa) 2 HH CF 3 CHaOH 0 3 Color 72
103 Ph(CH^2 H H CF3 H 0 3 鰊色^ 18103 Ph (CH ^ 2 HH CF 3 H 0 3 Herring color ^ 18
104 Ph(CH£)2 o-CF3 H H CH2OH 0 3 饞色油状 80104 Ph (CH £) 2 o-CF 3 HH CH2OH 0 3 Blue oil 80
105 Ph(CHa)2 o-CFs H H H 0 3 無色油状物 16105 Ph (CHa) 2 o-CF s HHH 0 3 Colorless oil 16
106 Ph(CHa)e C-Ph(CH2)2 H H CH2OH 0 3 齄色油状 71106 Ph (CHa) e C-Ph (CH2) 2 HH CH2OH 0 3 Blue oil 71
107 Ph(CHa>ft o-Ph(CH^2 H H H 0 3 鲡色油状物 11107 Ph (CHa> ft o-Ph (CH ^ 2 HHH 0 3)
106 Ph(CH^2 - h(CH2>2 H CF3 CHaOH 0 3 饞色^ Klto 54106 Ph (CH ^ 2 -h (CH2> 2 H CF 3 CHaOH 0 3 饞 color ^ Klto 54
1∞ oPh(CH2)a H CF3 H 0 3 餹色 1 13 no P (CHJa c-P (CH^2 H CI CH2OH 0 3 痛色油状物 611∞ oPh (CH2) a H CF 3 H 0 3 Yellow 1 13 no P (CHJ a cP (CH ^ 2 H CI CH 2 OH 0 3 Light oil 61
111 Ph(CHa)a o- h(CH2>2 H a H 0 3 齄色油状物 10 111 Ph (CHa) a o- h (CH2> 2 H a H 0 3齄色oil 10
112 l-PrO c-IPr H CI CH2OH 0 3 無色油状物 82112 l-PrO c-IPr H CI CH 2 OH 0 3 Colorless oil 82
113 PrO c-iPr H a H 0 3 焦色油状物 7113 PrO c-iPr H a H 0 3 Dark oil 7
114 PhO H H a CHaOH 0 3 無色油状物 76114 PhO H H a CHaOH 0 3 Colorless oil 76
115 PhO H H a H 0 3 齄色油状物 17115 PhO H H a H 03 Blue oil 17
116 PhCHsO H H H CH2OH 0 3 無色油状物 76116 PhCHsO H H H CH2OH 0 3 Colorless oil 76
117 PhCHaO H H H H 0 3 無色油状 11117 PhCH a OHHHH 0 3 Colorless oil 11
118 PhCHaO H H Br CH2OH 0 3 鳙色油状 » 61118 PhCHaO H H Br CH2OH 0 3 Blue oil »61
11d PhCHsO H H Br H 0 3 饞色油状 1111d PhCHsO H H Br H 03 Yellow oil 11
120 PhCHjO H H oMe CH2OH 0 3 氣色油状 « (3β)120 PhCHjO HH oMe CH 2 OH 03 Bright oil «(3β)
121 PhCHoO H H SMe H 0 3 (10) 121 PhCHoO H H SMe H 0 3 (10)
括 «は at工程からの通算収率も示す  Conclusion «indicates the total yield from the at process
9] T JP2004/016517 9] T JP2004 / 016517
表 9 Table 9
Mi M M v Π 性状 収率 （X Mi M M v Π Property Yield (X
122 PhCHaO H H Me CH2OH O 3 濯&油状 99 7b122 PhCH a OHH Me CH 2 OH O 3 Rinse & oil 99 7b
123 PhCHaO H H Me H O 3
Figure imgf000088_0001
123 PhCH a OHH Me HO 3
Figure imgf000088_0001
124 PhCHaO H H Et CH2OH O 3 餾色油状物 β1124 PhCH a OHH Et CH 2 OH O 3
125 PhCH40 H H Et H O 3 鶴色油状 44H125 PhCH 4 0 HH Et HO 3 Crane oil 44H
126 PhCH20 H H CI CH8OH s 2 餹色粉来 41126 PhCH 20 HH CI CH 8 OH s 2
127 P CHaO H H CI H s 2 酱 c£ inri^ wM*mi127 P CH a OHH CI H s 2 酱 c £ inri ^ wM * mi
126 PhCHaO H H CI CH2OH s 3 鍵 126 PhCH a OHH CI CH 2 OH s 3 key
129 PhCH20 H H CI H s 3 無色油状物 26129 PhCH 2 0 HH CI H s 3 Colorless oil 26
130 PhCHaO H H CI CH2OH s 4 餹色油状物 76130 PhCH a OHH CI CH 2 OH s 4 blue oil 76
131 P CHaO H H CI H s 4 無色油状物 15131 P CH a OHH CI H s 4 Colorless oil 15
132 PhCH20 C-CF3 H H CHsOH 0 3 糠色油状物 63132 PhCH 2 0 C-CF 3 HH CHsOH 0 3 Brown oil 63
133 PhCH,0 C-CF¾ H H H 0 3 , 饞色油状物 10133 PhCH, 0 C-CF ¾ HHH 0 3, blue oil 10
134 CI H H H CH2OH s 3 無色油状物 41134 CI HHH CH 2 OH s 3 Colorless oil 41
135 CI H H H M 0 <5 饞色油状物 31135 CI H H H M 0 <5 Blue oil 31
136 CF3 M 0 0 0 齄色アモルファス 66136 CF 3 M 0 0 0 Blue amorphous 66
137 CF» H CI H 0 c» 3 餹色油状吻 13137 CF »H CI H 0 c» 3 Blue oily snout 13
138 Et n rl M 蘸色油状物 7β138 Et n rl M Blue oil 7β
139 Et H H H H 0 3 鳙色 tt=bM l 13139 Et H H H H 0 3 blue tt = bM l 13
140 SOMe H H H CHaOH 0 3 餹色油状物 67140 SOMe HHH CH a OH 03 Blue oil 67
141 SOMe H H H H 0 3 無色油状《 27141 SOMe H H H H 0 3 Colorless oil << 27
142 CI C-CI H H CHaOH 0 1 無色アモルファス 56142 CI C-CI H H CHaOH 0 1 Colorless amorphous 56
143 CI C-CI H H H 0 1 色 ふ 24143 CI C-CI H H H 0 1 Color F 24
144 CF, H H PhCHaO CH^OH 0 3 餹色油状物 64144 CF, H H PhCHaO CH ^ OH 0 3 Blue oil 64
145 CF8 H H PhCHaO H 0 3 饞色油状 « 5145 CF 8 HH PhCHaO H 0 3 yellow oil «5
146 PhCHaO H H d CH2OH 無色油状 «I 77146 PhCHaO H H d CH2OH colorless oil «I 77
147 PhCH 0 H H CI H 3 147 PhCH 0 H H CI H 3
148 CF H CI H CHaOH 0 3 5β 148 CF H CI H CHaOH 0 3 5β
140 CF* H H CI CHaOH 0 3 68140 CF * H H CI CHaOH 0 3 68
150 PhCH20 H H F CH^OH 0 3 fin csrfiiv m 34150 PhCH 2 0 HHF CH ^ OH 0 3 fin csrfiiv m 34
1S1 a-Q H H CH2OH 0 3 ! / w， c~CI H CH2OH 0 3 鱅色油状 Hi 511S1 a-Q H H CH2OH 0 3! / W, c ~ CI H CH2OH 0 3 Yellow oil Hi 51
153 n 14 r¾^n 饞色油状物 37 n ·> 糠色油状 Hi 46153 n 14 r¾ ^ n blue oil 37 n
158 H l-l CI CH^OH 0 2 ( 9>158 H l-l CI CH ^ OH 0 2 (9>
15β H H "2 饞色油状物 (72)15β H H "2 blue oil (72)
157 CPj M Π c 餹色油状物 63157 CPj M Π c 油 状 oil 63
158 PhCHsO C-PhCH«0 H H CH2OH 0 3 鶄色油状 «1 (45)158 PhCHsO C-PhCH «0 H H CH2OH 0 3 blue oil« 1 (45)
159 PhCHaO c-PhCH,0 H CI CHaOH 0 3 麵色油状物 (17)159 PhCH a O c-PhCH, 0 H CI CHaOH 0 3 blue oil (17)
160 P CHaO c-a H CI CHsOH 0 3 l^fe油状物 61160 P CHaO c-a H CI CHsOH 0 3 l ^ fe oil 61
161 PhCH'O H H CFS CHaOH 0 3 鳙色油 83161 PhCH'O HH CF S CHaOH 0 3 Yellow oil 83
162 PhCHaO H H P CH,OH 0 3 鳔色油状 «I (50)162 PhCHaO H H P CH, OH 0 3 Blue oil «I (50)
163 MeS H H H CHaOH 0 3 色 tfc未 56163 MeS H H H CHaOH 0 3 color tfc not 56
164 IVCQH" H H H CHaQH 0 3 饞 油状物 98164 IVCQH "H H H CHaQH 0 3 油 状 Oil 98
165 C-C7H1S H H H CHaOH 0 3 餹色油状物 90 θβ IPr c-IPrO H H CHaOH 0 3 糠色油状 ito 72165 C-C7H 1S HHH CHaOH 03 Blue oil 90 θβ IPr c-IPrO HH CHaOH 0 3 Brown oil ito 72
1β7 IPr c-tf»r H CI CHaOH 0 3 無色油状 * 331β7 IPr c-tf »r H CI CHaOH 0 3 Colorless oil * 33
1ββ PhCHsS H H H CH2OH 0 3 «κ色油状物 (20) 格 JKttWェ 8か 算 を示す1ββ PhCHsS HHH CH 2 OH 0 3 «κ color oil (20) Rating JKttW
0] 表 1 0 0] Table 10
Hit例 R1 R2 R3 R4 R5 X n 性状 収率 (X) Hit example R1 R2 R3 R4 R5 X n Property Yield (X)
169 PhCH2S H H CI CH2OH 0 q 無色油状 (11) n u u CI-L.OH o 3 無色油状物 92169 PhCH 2 SHH CI CH 2 OH 0 q colorless oil (11) nuu CI-L.OH o 3 colorless oil 92
171 レ H Ul q 無色油状 64 n H LPr o 3 蘸色油状 4ft (62) c 171 H H Ul q Colorless oil 64 n H LPr o 3 Blue oil 4 ft (62) c
ι 7θ 無 末 89 ι 7θ None 89
174 CF3 H H H CH20H so 3 麵 7モ Jレフ ス 71174 CF 3 HHH CH 2 0H so 3 麵 7
175 CFS H H CF3 CHaOH s 3 無色油状 51175 CF S HH CF 3 CHaOH s 3 Colorless oil 51
176 CF3 c-Me H H CH2OH s 3 餹色粉末 81176 CF 3 c-Me HH CH 2 OH s 3 blue powder 81
177 CF, C-Me H H CH2OH so 3 無 末 65177 CF, C-Me HH CH 2 OH so 3 None 65
178 MeO H H a CH2OH s 3 無色油状物 56178 MeO HH a CH 2 OH s 3 colorless oil 56
179 PhCH20 H H H CH20H s 3 無&油状 V) (45)179 PhCH 2 0 HHH CH 2 0H s 3 No & oil V) (45)
180 PhCHaO H H CF3 CH20H s 3 蘸 e油状 i 66180 PhCHaO HH CF 3 CH 2 0H s 3 蘸 e Oil i 66
181 a c-a H H CH20H 0 3 饞色油状 50181 a ca HH CH 2 0H 0 3 yellow oil 50
182 σ c-CI H H H 0 3 色/ A状 M 13182 σ c-CI H H H 0 3 colors / A-shaped M 13
183 MeSO, H H H CH2OH 0 3 無色アモルファス 78183 MeSO, HHH CH 2 OH 0 3 Colorless amorphous 78
184 J-PrO H H H CH20H 0 3 無色油状物 68 184 J-PrO HHH CH 2 0H 0 3 Colorless oil 68
括《は前工程からの通 Φ率を示す  Brackets indicate the Φ rate from the previous process
[0558] [実施例 185] [Example 185]
5- [4— (3—ベンジルォキシフエノキシ）—2 クロ口フエ-ル]— 2 t ブトキシカルボ ニルアミノー 2—メトキシメチルペンタン 1 オール  5- [4- (3-benzyloxyphenoxy) -2-chlorophenol] -2 t-butoxycarbonylamino-2-methoxymethoxypentane 1-ol
[0559] [化 146] [0559] [Formula 146]
Figure imgf000089_0001
Figure imgf000089_0001
[0560] 実施例 146の化合物（720mg)をァセトニトリル（20mL)に溶解し Ag 0 (1.85g)、 Mel (3 The compound of Example 146 (720 mg) was dissolved in acetonitrile (20 mL), and Ag 0 (1.85 g) and Mel (3
2  2
mL)を加え常温にて 7日間撹拌した。セライト濾過後、濾液を濃縮しシリカゲルカラム クロマトグラフィー（へキサン：酢酸ェチル = 3： 1)にて精製し目的物（310mg)を無色 油状物として得た。  mL) and stirred at room temperature for 7 days. After filtration through Celite, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (310 mg) as a colorless oil.
FABMS : 556 ([M+H] .  FABMS: 556 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.43(9H, s), 1.48— 1.81(4H, m), 2.68(2H, t, J=7.8Hz), 3.33(1H, d, J=8.8Hz), 3.36(3H, s), 3.57(1H, d, 8.8Hz), 3.65(2H, d, J=6.8Hz), 5.03(2H, s), 5.10(1H, br s), 6.59— 6.62(2H, m), 6.74(1H, dd, J=8.3Hz, 2.4Hz), 6.84(1H, dd, J=8.3Hz, 2.4Hz), 7.00(1H, d, J=2.4Hz), 7.15(1H, d, J=8.3Hz), 7.23(1H, t, J=8.3Hz), 7.33-7.42(5H, m). 1H-NMR (400MHz, CDC1) δ 1.43 (9H, s), 1.48-1.81 (4H, m), 2.68 (2H, t, J = 7.8Hz), 3.33 (1H, d, J = 8.8Hz), 3.36 (3H, s), 3.57 (1H, d, 8.8Hz), 3.65 (2H, d, J = 6.8 Hz), 5.03 (2H, s), 5.10 (1H, br s), 6.59― 6.62 (2H, m), 6.74 (1H, dd, J = 8.3Hz, 2.4Hz), 6.84 (1H, dd, J = 8.3Hz, 2.4Hz), 7.00 (1H, d, J = 2.4Hz), 7.15 (1H, d, J = 8.3Hz), 7.23 (1H, t, J = 8.3Hz), 7.33-7.42 (5H, m ).
[0561] [実施例 186]  [Example 186]
2- t ブトキシカルボ-ルァミノ— 2—メトキシメチルー 5— [4— (3—トリフルォロメチル フエノキシ）フエ-ル]ペンタン 1 オール  2-t butoxycarbolamino-2-methoxymethyl-5- [4- (3-trifluoromethylphenoxy) phenyl] pentane 1ol
[0562] [化 147]  [0562] [Formula 147]
Figure imgf000090_0001
Figure imgf000090_0001
[0563] 実施例 82の化合物を用い上記実施例 185と同様に反応させ目的物を無色油状物と して得た。 [0563] The same procedures used in Example 185 were carried out except for using the compound of Example 82 to give a desired product as a colorless oil.
FABMS : 484 ([M+H] .  FABMS: 484 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.42(9H, s), 1.48— 1.83(4H, m), 1 H-NMR (400MHz, CDC1) δ 1.42 (9H, s), 1.48-1.83 (4H, m),
3  Three
2.57-2.65(2H, m),3.33(lH, d, J=8.8Hz), 3.37(3H, s), 3.58(1H, d, 8.8Hz),  2.57-2.65 (2H, m), 3.33 (lH, d, J = 8.8Hz), 3.37 (3H, s), 3.58 (1H, d, 8.8Hz),
3.62(2H, br s), 5.07(1H, br s), 6.94(2H, d, J=6.4Hz), 7.10-7.21(4H, m),7.30(lH, d, J=7.8Hz), 7.40(1H, t, J=7.8Hz).  3.62 (2H, br s), 5.07 (1H, br s), 6.94 (2H, d, J = 6.4Hz), 7.10-7.21 (4H, m), 7.30 (lH, d, J = 7.8Hz), 7.40 (1H, t, J = 7.8Hz).
[0564] [実施例 187— 188] [Examples 187-188]
実施例 126と 128の化合物を用い実施例 185と同様に反応させ表 11に示すィ匕合物を 合成した。  Using the compounds of Examples 126 and 128, the reaction was carried out in the same manner as in Example 185, and the conjugates shown in Table 11 were synthesized.
[0565] [表 11] 表 1 1 NHBoc[0565] [Table 11] Table 11 NHBoc
Figure imgf000091_0001
。 H
Figure imgf000091_0001
. H
FABMS FABMS
実施例 n 性状 [M+H]+ Example n Properties [M + H] +
187 2 無色油状物 558  187 2 Colorless oil 558
188 3 無色油状物 572  188 3 Colorless oil 572
[0566] [実施例 189] [Example 189]
2 t ブトキシカルボニルァミノ— 2— [4— (ベンジルォキシカルボ-ルァミノ）フエニル] プロピル 1, 3 プロパンジオール  2 t butoxycarbonylamino-2-[4- (benzyloxycarbo-amino) phenyl] propyl 1,3 propanediol
[0567] [化 148] [0567] [Formula 148]
Figure imgf000091_0002
Figure imgf000091_0002
[0568] 参考例 323の化合物を用い実施例 1と同様にして反応させアミノマロン酸エステル誘 導体を合成後、実施例 76と同様に還元し目的物を無色アモルファスとして得た。  [0568] The compound of Reference Example 323 was reacted in the same manner as in Example 1 to synthesize an aminomalonate derivative, and then reduced in the same manner as in Example 76 to obtain the target product as a colorless amorphous.
[0569] [実施例 190]  [0569] [Example 190]
5 - [3 - [4- (ベンジルォキシカルボ-ルァミノ)フエ-ル]プロピル] - 5 -t -ブトキシカルボ- ルァミノ- 2 , 2 -ジ -t -ブチル- 1,3,2-ジォキサシラン  5- [3- [4- (benzyloxycarbo-lamino) phenyl] propyl] -5-t-butoxycarbo-lamino-2,2-di-t-butyl-l, 3,2-dioxasilane
[0570] [化 149]  [0570] [Formula 149]
Figure imgf000091_0003
Figure imgf000091_0003
[0571] 実施例 189の化合物 (20g)及び 2,6-ルチジン (15.3mL)の DMF(500mL)溶液に、 0°Cに てジ -t-ブチルシリルビストリフルォロメタンスルホネート (15.9mL)の塩化メチレン (lOOmL)溶液をゆっくりと加えた。 0°Cにて 2時間撹拌後、反応液を氷水中に注ぎ、酢 酸ェチルにて抽出した。有機層を希塩酸、水 (2回)、飽和食塩水の順に洗浄後、無水 硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフ ィー (へキサン：酢酸ェチル =7； で精製し、 目的物 (I4.5g)を無色アモルファスとして 得た。 To a solution of the compound of Example 189 (20 g) and 2,6-lutidine (15.3 mL) in DMF (500 mL) at 0 ° C. was added di-t-butylsilylbistrifluoromethanesulfonate (15.9 mL). A methylene chloride (100 mL) solution was added slowly. After stirring at 0 ° C for 2 hours, pour the reaction solution into ice water and add vinegar. Extracted with acid ethyl. The organic layer was washed with diluted hydrochloric acid, water (twice) and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7 ) to obtain the desired product (I4.5 g) as a colorless amorphous.
1H-NMR(400MHz,CDCl ) δ 1.04(9H,s), 1.06(9H,s),  1H-NMR (400MHz, CDCl) δ 1.04 (9H, s), 1.06 (9H, s),
3  Three
1.42(9H,s), 1.53(4H,br s), 2.54(2H,t,J=6.4Hz), 3.88(2H,d,J=11.2Hz),  1.42 (9H, s), 1.53 (4H, br s), 2.54 (2H, t, J = 6.4Hz), 3.88 (2H, d, J = 11.2Hz),
4.21(2H,d,J=11.2Hz), 4.90(lH,br  4.21 (2H, d, J = 11.2Hz), 4.90 (lH, br
s), 5.19(2H,s), 6.59(lH,br s), 7.07(2H,d,J=8.8Hz), 7.26-7.42(7H,m).  s), 5.19 (2H, s), 6.59 (lH, br s), 7.07 (2H, d, J = 8.8Hz), 7.26-7.42 (7H, m).
[0572] [実施例 191] [Example 191]
5 - [3 - (4 -ァミノフエ-ル)プロピル] - 5 - 1 -ブトキシカルボ-ルァミノ- 2 ,2 -ジ -t -ブチル 5- [3- (4-Aminophenyl) propyl] -5-1-butoxycarbolamino-2,2-di-t-butyl
-1,3,2-ジォキサシラン -1,3,2-dioxasilane
[0573] [化 150] [0573] [Formula 150]
Figure imgf000092_0001
Figure imgf000092_0001
[0574] 実施例 190の化合物 (14.5g)のエタノール (200mL)溶液に 10%パラジウム炭素 (1.5g)を 加え、水素ガス気流下 (常圧)、常温で 5時間撹拌した。触媒をセライトを用い濾去し、 濾液を減圧濃縮した。残さをシリカゲルカラムクロマトグラフィー (へキサン：酢酸ェチ ル 5 : 1-3 : 1)で精製し、 目的物 (9.55g)を無色粉末晶として得た。 10% palladium carbon (1.5 g) was added to a solution of the compound of Example 190 (14.5 g) in ethanol (200 mL), and the mixture was stirred at room temperature for 5 hours under a hydrogen gas stream (normal pressure). The catalyst was removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1-3: 1) to give the desired product (9.55 g) as colorless powdery crystals.
NMR(400MHz,CDCl ) δ 1.04(9H,s), 1.06(9H,s),  NMR (400MHz, CDCl) δ 1.04 (9H, s), 1.06 (9H, s),
3  Three
1.43(9H,s), 1.47-1.56(4H,m), 2.46(2H,t,J=7.3Hz), 3.56(2H,br s),  1.43 (9H, s), 1.47-1.56 (4H, m), 2.46 (2H, t, J = 7.3Hz), 3.56 (2H, br s),
3.88(2H,d,J=11.2Hz), 4.22(2H,d,J=11.2Hz), 4.89(lH,br s), 6.62(2H,d,J=8.3Hz), 6.93(2H,d,J=8.3Hz).  3.88 (2H, d, J = 11.2Hz), 4.22 (2H, d, J = 11.2Hz), 4.89 (lH, br s), 6.62 (2H, d, J = 8.3Hz), 6.93 (2H, d, J = 8.3Hz).
[0575] [実施例 192] [Example 192]
5-t-ブトキシカルボ-ルァミノ- 2 ,2 -ジ- 1 -ブチル -5 -[3-[4-(3,5-ジクロロフエ-ルァミノ )フエ-ル]プロピル] - 1,3,2-ジォキサシラン ε'ΐ - ci i ( ェ , ^ 一 / 一 / -ェ ） - z - ^4 ：- 5-t-butoxycarbamino-2,2-di-1-butyl-5- [3- [4- (3,5-dichlorophenamino) phenyl] propyl] -1,3,2-dioxasilane ε'ΐ-ci i (, ^ 1/1 /-)-z-^ 4:-
Figure imgf000093_0001
Figure imgf000093_0001
[I 一 ε6ΐί^¾ϊ第] [8ZS0] '(ω'Ηε)ΐ8·9— 6Ζ·9 '(s J 'HT)
Figure imgf000093_0002
[I-one ε6ΐί ^ ¾ϊfirst] [8ZS0] '(ω'Ηε) ΐ8ΐ996Ζ9' ( s J 'HT)
Figure imgf000093_0002
'(ΖΗΖ·ΐ
Figure imgf000093_0003
'(s'H6)S I '(ΖΗΖ
Figure imgf000093_0003
'(s'H6) SI
'(s'H6)Z0"T '(s'H6)S0"T 9 (OQD^HViOO W -^
Figure imgf000093_0004
、つ it (ΐ： 6= ェ '(s'H6) Z0 "T'(s'H6)S0" T 9 (OQD ^ HViOO W-^
Figure imgf000093_0004
、 つ it (ΐ ： 6 = ェ
[ZZS0] [ZZS0]
Figure imgf000093_0005
Figure imgf000093_0005
[ΐ3ΐ¾] [9 SO] [ΐ3ΐ¾] [9 SO]
36 -プロパンジオール 36 -Propanediol
[0581] [化 152]  [0581] [Formula 152]
Figure imgf000094_0001
Figure imgf000094_0001
[0582] 実施例 202の化合物 (148mg)の THF(2mL)溶液に lmol/L-テトラ- n-ブチルアンモ- ゥムフルオリド THF溶液 (lmL)を加え、常温で 1時間撹拌した。反応液を水に注ぎ、酢 酸ェチルにて抽出した。有機層を水、飽和食塩水の順で洗浄し、無水硫酸ナトリウム で乾燥後、溶媒を減圧留去した。残渣にへキサンを加え固化させた後に濾取し乾燥 した。 目的物を無色粉末として得た。 [0582] To a solution of the compound of Example 202 (148 mg) in THF (2 mL) was added a lmol / L-tetra-n-butylammonium fluoride solution in THF (1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue to solidify, and then filtered and dried. The desired product was obtained as a colorless powder.
1H-NMR(400MHz,CDCl ) δ 1.44(9H, s), 1.58- 1.66(4H, m),  1H-NMR (400MHz, CDCl) δ 1.44 (9H, s), 1.58-1.66 (4H, m),
3  Three
2.58(2H, br s), 3.59(2H, d, J=11.2Hz), 3.83(2H, d, J=11.2Hz), 4.89(1H, s), 2.58 (2H, br s), 3.59 (2H, d, J = 11.2Hz), 3.83 (2H, d, J = 11.2Hz), 4.89 (1H, s),
7.05-7.1K6H, m), 7.29— 7.31(1H, m), 7.42(2H, t, J=7.8Hz), 7.51(2H, d, J=7.8Hz),7.05-7.1K6H, m), 7.29- 7.31 (1H, m), 7.42 (2H, t, J = 7.8Hz), 7.51 (2H, d, J = 7.8Hz),
7.56(2H, d, J=7.8Hz). 7.56 (2H, d, J = 7.8Hz).
[0583] [実施例 213] [0583] [Example 213]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]プロピル 4— ヒドロキシメチルー 2—ォキサゾリジノン  4- [4- (3- (benzyloxyphenyl) sulfur-)-2-cyclophenol] propyl 4-hydroxymethyl-2-oxazolidinone
[0584] [化 153] [0584] [Formula 153]
Figure imgf000094_0002
Figure imgf000094_0002
[0585] 実施例 128の化合物（3.3 0g)を THF (80mL)に溶解し、 0°Cにて 60%水素化ナトリウ ム（600mg)を加え、その後常温にて 24時間撹拌した。反応液に氷水を加え、酢酸ェ チルにて抽出し水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶 媒を留去しシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル = 1： 1後に酢酸 ェチルのみ）にて精製し、 目的物（2.37g)を淡黄色油状物として得た。  The compound of Example 128 (3.30 g) was dissolved in THF (80 mL), 60% sodium hydride (600 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 24 hours. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 followed by only ethyl acetate) to obtain the desired product (2.37 g) as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 1.63— 1.72(4H, m), 2.74(2H, t,  1H-NMR (400MHz, CDC1) δ 1.63-1.72 (4H, m), 2.74 (2H, t,
3 J=6.8Hz), 3.51(lH,d, J=11.2Hz), 3.58(1H, d, J=11.2Hz), 4.09(1H, d, J=8.8Hz),Three J = 6.8Hz), 3.51 (lH, d, J = 11.2Hz), 3.58 (1H, d, J = 11.2Hz), 4.09 (1H, d, J = 8.8Hz),
4.24(1H, d, J=8.8Hz),5.02(2H, s), 5.28(1H, br s), 6.87— 6.90(1H, m), 4.24 (1H, d, J = 8.8Hz), 5.02 (2H, s), 5.28 (1H, br s), 6.87― 6.90 (1H, m),
6.94-7.00(2H, m), 7.09- 7.16(2H, m), 7.22-7.52(7H, m).  6.94-7.00 (2H, m), 7.09-7.16 (2H, m), 7.22-7.52 (7H, m).
[0586] [実施例 214] [0586] [Example 214]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]プロピル 4 ヨウドメチルー 2—ォキサゾリジノン  4— [4— (3-Benzyloxyphenyl-sulfur-)-2-cyclobutane] propyl 4 Iodomethyl-2-oxazolidinone
[0587] [化 154] [0587] [Formula 154]
Figure imgf000095_0001
Figure imgf000095_0001
[0588] 上記実施例 213の化合物（2.37g)のピリジン（30mL)溶液に p トルエンスルホユルク ロリド（1.33g)をカ卩ぇ常温にて 24時間、 60°Cにてさらに 5時間撹拌した。反応液に水を 加え、酢酸ェチルにて抽出後、水、希塩酸、水、飽和食塩水の順に洗浄し無水硫酸 ナトリウムにて乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（へ キサン：酢酸 = 1： 1)にて精製し、スルホン酸エステル体 (2.14g)を無色油状物として 得た。このスルホン酸エステル (2.14g)をアセトン (20mL)に溶解し、ヨウ化ナトリウム（ 2.55g)をカ卩え、 10時間加熱還流した。反応液に水を加え酢酸ェチルにて抽出後、水 、飽和食塩水にて洗浄し無水硫酸ナトリウムにて乾燥した。溶媒を留去し、残渣をシ リカゲルカラムクロマトグラフィー（へキサン：酢酸 = 1： 1)にて精製し目的物（1.47g)を 無色油状物として得た。 To a solution of the compound of Example 213 (2.37 g) in pyridine (30 mL) was stirred p toluenesulfoyl chloride (1.33 g) at room temperature for 24 hours and further at 60 ° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, diluted hydrochloric acid, water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: acetic acid = 1: 1) to obtain a sulfonic ester (2.14 g) as a colorless oil. This sulfonic acid ester (2.14 g) was dissolved in acetone (20 mL), sodium iodide (2.55 g) was added, and the mixture was heated under reflux for 10 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: acetic acid = 1: 1) to obtain the desired product (1.47 g) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.59— 1.65(2H, m), 1.83— 1.89(2H,  1H-NMR (400MHz, CDC1) δ 1.59― 1.65 (2H, m), 1.83― 1.89 (2H,
3  Three
m), 2.75(2H, t, J=7.8Hz), 3.31(2H, s), 4.19(1H, d, J=9.3Hz), 4.21(1H, d,  m), 2.75 (2H, t, J = 7.8Hz), 3.31 (2H, s), 4.19 (1H, d, J = 9.3Hz), 4.21 (1H, d,
J=9.3Hz), 5.02(2H, s), 5.13(lH,br s), 6.88(1H, dd, J=7.8Hz, 2.0Hz),  J = 9.3Hz), 5.02 (2H, s), 5.13 (lH, br s), 6.88 (1H, dd, J = 7.8Hz, 2.0Hz),
6.94-7.00(2H, m), 7.11(1H, d, J=7.8Hz), 7.16(1H, dd, J=7.8Hz, 2.0Hz),  6.94-7.00 (2H, m), 7.11 (1H, d, J = 7.8Hz), 7.16 (1H, dd, J = 7.8Hz, 2.0Hz),
7.22-7.41(7H, m).  7.22-7.41 (7H, m).
[0589] [実施例 215] [Example 215]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]プロピル 4 メチルチオメチルー 2—ォキサゾリジノン 4— [4— (3-Benzyloxyphenol-sulfur) -2-cyclobutane] propyl 4 Methylthiomethyl-2-oxazolidinone
[0590] [化 155] [0590] [Formula 155]
Figure imgf000096_0001
Figure imgf000096_0001
[0591] 上記実施例 214の化合物（1.47§)を丁1^ (3(^し）に溶解し NaSMe (210mg)を力卩ぇ常 温にて 2時間撹拌した。反応液に水を加え酢酸ェチルで抽出後、飽和食塩水にて洗 浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧濃縮し目的物（1.27g)を無色油状 物として得た。 [0591] The compound of Example 214 (1.47 § ) was dissolved in 1 ^^ (3 ^^), NaSMe (210 mg) was stirred at room temperature for 2 hours, water was added to the reaction mixture, and acetic acid was added. After extraction with ethyl acetate, the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the desired product (1.27 g) as a colorless oil.
FABMS : 514 ([M+H]").  FABMS: 514 ([M + H] ").
1H-NMR(400MHz, CDC1 ) δ 1.62-1.77(4H, m), 2.17(3H, s),  1H-NMR (400MHz, CDC1) δ 1.62-1.77 (4H, m), 2.17 (3H, s),
3  Three
2.68(1H, d, J=13.2Hz), 2.74(2H, t, J=7.3Hz), 2.78(1H, d, J=13.2Hz), 4.15(1H, d, 2.68 (1H, d, J = 13.2Hz), 2.74 (2H, t, J = 7.3Hz), 2.78 (1H, d, J = 13.2Hz), 4.15 (1H, d,
J=9.0Hz),4.20(lH, d, J=9.0Hz), 5.03(2H, s), 5.22(1H, br s), 6.87— 6.90(1H, m),J = 9.0Hz), 4.20 (lH, d, J = 9.0Hz), 5.03 (2H, s), 5.22 (1H, br s), 6.87― 6.90 (1H, m),
6.93-6.97(2H, m), 7.10-7.17(2H, m), 7.22-7.41(7H, m). 6.93-6.97 (2H, m), 7.10-7.17 (2H, m), 7.22-7.41 (7H, m).
[0592] [実施例 216] [Example 216]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2— t ブト キシカルボニルアミノー 2—メチルチオメチルペンタン 1 オール  5- [4- (3-benzyloxyphenol-sulfur-yl) -2-cyclobutane]-2-t-butoxycarbonylamino-2-methylthiomethylpentane 1-ol
[0593] [化 156] [0593] [Formula 156]
Figure imgf000096_0002
Figure imgf000096_0002
[0594] 上記実施例 215の化合物（1.27g)をァセトニトリル（20mL)に溶解し、 Boc O (1.09g) The compound of Example 215 (1.27 g) was dissolved in acetonitrile (20 mL), and Boc 2 O 2 (1.09 g)
2 2
、ジメチルァミノピリジン（lOOmg)を加え常温にて 30分撹拌した。反応液を減圧留去し 残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸 =4 : 1)にて精製し N— Boc ォキサゾリジノン体（1.48g)を無色油状物として得た。このものをメタノール (20mL) に溶解し、炭酸セシウム (410mg)を加え常温にて 1晚撹拌した。溶媒を留去し、残渣 を酢酸ェチルに溶解し希塩酸、水にて洗净後、無水硫酸ナトリウムにて乾燥した。溶 媒を留去後、シリカゲルカラムクロマトグラフィー（へキサン:酢酸 = 2 : 1)にて精製し 目的物（1.28g)を無色油状物として得た。 Then, dimethylaminopyridine (100 mg) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: acetic acid = 4: 1) to obtain an N-Boc oxazolidinone compound (1.48 g) as a colorless oil. This was dissolved in methanol (20 mL), cesium carbonate (410 mg) was added, and the mixture was stirred at room temperature for 1 晚. The solvent is distilled off and the residue Was dissolved in ethyl acetate, washed with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: acetic acid = 2: 1) to obtain the desired product (1.28 g) as a colorless oil.
FABMS : 588 ([M+H] .  FABMS: 588 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.43(9H, s), 1.51— 1.66(3H, m),  1H-NMR (400MHz, CDC1) δ 1.43 (9H, s), 1.51-1.66 (3H, m),
3  Three
1.82— 1.85(1H, m),2.15(3H, s), 2.69(2H, t, J=7.3Hz), 2.75(1H, d, J=13.4Hz), 1.82-1.85 (1H, m), 2.15 (3H, s), 2.69 (2H, t, J = 7.3Hz), 2.75 (1H, d, J = 13.4Hz),
2.90(1H, d, J=13.4Hz),3.69-3.70(2H, m), 4.02(1H, br), 4.99(1H, br s), 5.02(2H, s), 6.86— 6.94(3H, m), 7.12-7.17(2H, m), 7.21-7.41(7H, m). 2.90 (1H, d, J = 13.4Hz), 3.69-3.70 (2H, m), 4.02 (1H, br), 4.99 (1H, br s), 5.02 (2H, s), 6.86- 6.94 (3H, m ), 7.12-7.17 (2H, m), 7.21-7.41 (7H, m).
[0595] [実施例 217] [Example 217]
4— [4— (3—ベンジルォキシフエ-ルチオ）— 2—クロ口フエ-ル]プロピル 4—フルォ ロメチルー 2—ォキサゾリジノン  4— [4— (3-Benzyloxyphenol-thio) —2-chlorophenol] propyl 4-fluoromethyl-2-oxazolidinone
[0596] [化 157] [0596] [Formula 157]
Figure imgf000097_0001
Figure imgf000097_0001
[0597] 実施例 213の化合物（600 mg)のァセトニトリル (10 mL)溶液に氷冷下、トリェチル ァミン（0.52mL)及びメタンスルホユルクロリド [0597] To a solution of the compound of Example 213 (600 mg) in acetonitrile (10 mL) was added ice-cooled triethylamine (0.52 mL) and methanesulfoyl chloride.
(0.19mL)をカ卩ぇ 10分間撹拌した。反応液に水を加えた後、酢酸ェチルと飽和食塩 水を用いて分液し、有機層を無水硫酸ナトリウムで乾燥させた後に濃縮し、真空ボン プで乾燥させ、黄色油状の 4  (0.19 mL) was stirred for 10 minutes. After water was added to the reaction solution, liquid separation was performed using ethyl acetate and saturated saline. The organic layer was dried over anhydrous sodium sulfate, concentrated, dried with a vacuum pump, and dried to give a yellow oil.
[4— (3—べンジルォキシフエ-ルチオ）—2—クロ口フエ-ル]プロピル 4 メタンスルホ 二ルォキシメチルー 2—ォキサゾリジノンを得た。得られたメシル体を THF  [4- (3-Benzyloxyphenyl-thio) -2-chlorophenol] propyl 4 methanesulfonyloxymethyl-2-oxazolidinone was obtained. The obtained mesyl form is THF
(6 mL)に溶解させた後、 lmol/Lテトラプチルアンモ -ゥムフロリドの THF溶液 (6.20 mL)を加え、 1時間加熱還流した。反応液を常温にもどした後に濃縮し、残查をシリカ ゲルカラムクロマトグラフィー（へキサン:酢酸ェチル = 1： 1)により精製し、 目的物 (6 mL), and a solution of lmol / L tetrabutylammonium-dumfluoride in THF (6.20 mL) was added, followed by heating under reflux for 1 hour. The reaction solution is returned to room temperature, concentrated, and the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1).
(300 (300
mg)を無色アモルファスとして得た。  mg) as a colorless amorphous.
1H-NMR(400MHz, CDC1 ) δ 1.67-1.70 (4Η, m), 2.75 (2H, t, J=7.0Hz), 4.12 (1H, d, J=9.2Hz), 4.19 (1H, d, J=9.2Hz), 4.32 (2H, d, J=46.4Hz), 1 H-NMR (400MHz, CDC1) δ 1.67-1.70 (4Η, m), 2.75 (2H, t, J = 7.0Hz), 4.12 (1H, d, J = 9.2Hz), 4.19 (1H, d, J = 9.2Hz), 4.32 (2H, d, J = 46.4Hz),
5.02 (2H, s), 5.13 (1H, br), 6.88—6.90 (1H, m), 6.91—6.97 (2H, m), 7.09-7.145.02 (2H, s), 5.13 (1H, br), 6.88—6.90 (1H, m), 6.91—6.97 (2H, m), 7.09-7.14
(2H, m), 7.22-7.26 (1H, m),7.32- 7.39 (6H, m). (2H, m), 7.22-7.26 (1H, m), 7.32 to 7.39 (6H, m).
[0598] [実施例 218] [0598] [Example 218]
5- [4— (3—ベンジルォキシフエ-ルチオ）— 2—クロ口フエ-ル] 2— t ブトキシカル ボ-ルアミノー 2—フルォロメチルペンタン 1 オール  5- [4- (3-benzyloxyphenol-thio) -2-cyclobutane] 2-t-butoxycarbonylamino-2-fluoromethylpentane 1-ol
[0599] [化 158] [0599] [Formula 158]
Figure imgf000098_0001
Figure imgf000098_0001
[0600] 実施例 217の化合物を用い実施例 216と同様に反応させ目的物を無色油状物とし て得た。 [0600] The compound of Example 217 was reacted in the same manner as in Example 216 to give the desired product as a colorless oil.
JH-NMR (400MHz, CDC1 ) δ 1.64-1.77 (4Η, m), 1.47 (9Η, s), J H-NMR (400MHz, CDC1) δ 1.64-1.77 (4Η, m), 1.47 (9Η, s),
3  Three
2.71 (2H, t, J=7.3Hz), 3.68—3.76 (3H, m), 4.43 (1H, dd, J=9.2Hz, J=20.2Hz), 4.55 (1H, dd, J=9.2Hz, J=20.2Hz), 4.81 (1H, br), 5.02 (2H, s), 6.86—6.89 (1H, m), 6.92-6.94 (2H, m), 7.11-7.16 (2H, m), 7.21-7.25 (1H, m), 7.30-7.40 (6H, m).  2.71 (2H, t, J = 7.3Hz), 3.68-3.76 (3H, m), 4.43 (1H, dd, J = 9.2Hz, J = 20.2Hz), 4.55 (1H, dd, J = 9.2Hz, J = 20.2Hz), 4.81 (1H, br), 5.02 (2H, s), 6.86-6.89 (1H, m), 6.92-6.94 (2H, m), 7.11-7.16 (2H, m), 7.21-7.25 ( 1H, m), 7.30-7.40 (6H, m).
[0601] [実施例 219]  [0601] [Example 219]
N フエ-ルー 2— t ブトキシカルボ-ルァミノ— 5— [4— (3—トリフルォロメチルフエノ キシ）フエ-ル]ペンタン酸ェチル  N-Fu-leu 2-t Butoxycarbo-lamino-5- [4- (3- (trifluoromethylphenoxy) phenyl] ethyl] pentanoate
[0602] [化 159]
Figure imgf000098_0002
[0602] [Formula 159]
Figure imgf000098_0002
[0603」 2 フエ-ルァミノマロン酸ジェチル（510mg)の THF (10mL)溶液に Boc 0 (480mg) [0603] 2 Boc 0 (480mg) was added to a solution of getyl phenylaminomalonate (510mg) in THF (10mL).
2 を加え、常温にて 1日撹拌した。この反応液に NaOtBu (190mg)、参考例 259の化合 物（810mg)の THF (2mL)溶液をカ卩ぇ 8時間加熱還流した。反応液を氷水にあけ、酢 酸ェチルにて抽出後、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥した。溶媒を 留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル =6 : 1)に て精製し目的物 (420mg)を無色油状物として得た。 2 was added and stirred at room temperature for 1 day. To this reaction solution, a solution of NaOtBu (190 mg) and the compound of Reference Example 259 (810 mg) in THF (2 mL) was heated under reflux for 8 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 6: 1). Purification gave the desired product (420 mg) as a colorless oil.
FABMS : 558 ([M+H] .  FABMS: 558 ([M + H].
[0604] [実施例 220] [0604] [Example 220]
2 フエニルァミノ— 5— [4— (3—トリフルォロメチルフエノキシ）フエニル]ペンタン オール  2 Phenylamino-5- [4— (3-trifluoromethylphenoxy) phenyl] pentanol
[0605] [化 160]
Figure imgf000099_0001
[0605] [Formula 160]
Figure imgf000099_0001
[0606] 上記実施例 219の化合物を用い実施例 76と同様に反応させ目的物を無色油状物と して得た。 The target compound was obtained as a colorless oil by reacting in the same manner as in Example 76 using the compound of Example 219 described above.
MS(EI) : 415 (〔M]+)  MS (EI): 415 ([M] +)
'H-NMRC^OMHz, CDCl ) δ 1.56— 1.78(4H, m),2.62(2H, t,  'H-NMRC ^ OMHz, CDCl) δ 1.56-- 1.78 (4H, m), 2.62 (2H, t,
3  Three
J=7.8Hz), 3.51— 3.56(2H, m),  J = 7.8Hz), 3.51— 3.56 (2H, m),
3.73- 3.77(lH,m), 6.66(2H,d,J=7.8Hz), 6.73(1H, t, J=7.8Hz), 6.91— 6.95(2H, m)， 7.11-7.2K6H, m), 7.31(1H, d, J=7.8Hz), 7.41(1H, t, J=7.8Hz).  3.73- 3.77 (lH, m), 6.66 (2H, d, J = 7.8Hz), 6.73 (1H, t, J = 7.8Hz), 6.91--6.95 (2H, m), 7.11-7.2K6H, m), 7.31 (1H, d, J = 7.8Hz), 7.41 (1H, t, J = 7.8Hz).
[0607] [実施例 221]  [Example 221]
5- [4— (3—ベンジルォキシフエノキシ） 2 クロ口フエ-ル]— 2—フエ-ルァミノペン タン 1 オール  5- [4— (3-benzyloxyphenoxy) 2 chlorophenol] — 2-phenaminoltantanol
[0608] [化 161]
Figure imgf000099_0002
[0608] [Formula 161]
Figure imgf000099_0002
[0609] [実施例 221- 1] [Example 221-1]
2—ァミノ一 1 ベンゾィルォキシ 5— [4— (3—ベンジルォキシフエノキシ） 2—クロ口 フエ二ノレ]ペンタン [0610] [化 162]
Figure imgf000100_0001
2-Amino 1 Benzoyloxy 5— [4- (3-Benzyloxyphenoxy) 2-cyclopent feninole] pentane [0610] [Formula 162]
Figure imgf000100_0001
[0611] 実施例 147の化合物（500mg)を塩化メチレン（10mL)に溶解しピリジン（0.2mL)、ベ ンゾイルクロリド (0.12mL)を加え、常温にて 1時間撹拌した。反応液に水を加え、酢 酸ェチルにて抽出後、水、飽和食塩水の順に洗浄した。無水硫酸ナトリウムにて乾 燥し溶媒を減圧濃縮後、残渣をメタノール (20mL)に溶解し、 3mol/L塩酸含有酢酸 ェチル（lOmL)を加え常温にて 1時間撹拌した。反応液を濃縮後、飽和炭酸水素ナト リウム水溶液を加え酢酸ェチルで抽出後、無水硫酸ナトリウムで乾燥し目的物（ 670mg)を無色油状物として得た。 [0611] The compound of Example 147 (500 mg) was dissolved in methylene chloride (10 mL), pyridine (0.2 mL) and benzoyl chloride (0.12 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and washed with water and saturated saline in this order. After drying over anhydrous sodium sulfate and concentrating the solvent under reduced pressure, the residue was dissolved in methanol (20 mL), 3 mol / L hydrochloric acid-containing ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate to obtain the desired product (670 mg) as a colorless oil.
[0612] [実施例 221- 2]  [0612] [Example 221-2]
1 ベンゾィルォキシ 5— [4— (3—ベンジルォキシフエノキシ） 2—クロ口フエ-ル]— 2—フエ-ルァミノペンタン  1 Benzoyloxy 5— [4— (3-Benzyloxyphenoxy) 2-cyclobutane] — 2-Fuylaminopentane
[0613] [化 163]
Figure imgf000100_0002
[0613] [Formula 163]
Figure imgf000100_0002
[0614] 上記実施例 221- 1の化合物（670mg)を塩化メチレン（30mL)に溶解し、 Ph Bi(OAc)  [0614] The compound of Example 221-1 (670 mg) was dissolved in methylene chloride (30 mL), and Ph Bi (OAc)
3 2 3 2
(558mg)、酢酸銅（10mg)を加え常温にて 1日撹拌後、溶媒を留去し、シリカゲルカラ ムクロマトグラフィー（へキサン：酢酸ェチル =4： 1)にて精製し、 目的物（560mg)を無 色油状物として得た。 FABMS : (558 mg) and copper acetate (10 mg) were added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired compound (560 mg). ) Was obtained as a colorless oil. FABMS:
592 ([M+H]+). 592 ([M + H] + ).
[0615] [実施例 221- 3] [0615] [Example 221- 3]
5— [4— (3—ベンジルォキシフエノキシ） 2 クロ口フエ-ル]— 2—フエ-ルァミノペン タン 1 オール  5— [4— (3-Benzyloxyphenoxy) 2 chlorinated phenol] —2—Phenylaminopentane 1 All
上記実施例 221-2の化合物（560mg)をエタノール（lOmL)に溶解し、 lmol/L水酸ィ匕 ナトリウム水溶液（5mL)を加え常温にて 1時間撹拌した。水を加え、酢酸ェチルにて 抽出し、飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を濃縮後、残 渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル = 2： 1)にて精製し目 的物（290mg)を無色油状物として得た。 The compound of Example 221-2 (560 mg) was dissolved in ethanol (lOmL), lmol / L aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Add water and add ethyl acetate It was extracted, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the desired product (290 mg) as a colorless oil.
FABMS : 488 ([M+H] .  FABMS: 488 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.57— 1.73(4H, m), 2.70(2H, t,  1H-NMR (400MHz, CDC1) δ 1.57― 1.73 (4H, m), 2.70 (2H, t,
3  Three
J=7.3Hz), 3.53— 3.56(2H, m), 3.74— 3.79(1H, m), 5.02(2H, s), 6.57— 6.75(6H, m), 6.82(1H, dd, J=8.3Hz, 2.4Hz),6.99(lH, d, J=2.4Hz), 7.09(1H, d, J=8.3Hz), 7.17(2H, dd, J=8.3Hz, 7.3Hz), 7.23(1H, t, J=8.3Hz), 7.30-7.42(5H, m).  J = 7.3Hz), 3.53-3.56 (2H, m), 3.74-3.79 (1H, m), 5.02 (2H, s), 6.57-6.75 (6H, m), 6.82 (1H, dd, J = 8.3Hz , 2.4Hz), 6.99 (lH, d, J = 2.4Hz), 7.09 (1H, d, J = 8.3Hz), 7.17 (2H, dd, J = 8.3Hz, 7.3Hz), 7.23 (1H, t, J = 8.3Hz), 7.30-7.42 (5H, m).
[0616] [実施例 222]  [0616] [Example 222]
5- [4— (3—ベンジルォキシフエノキシ） 2 クロ口フエ-ル]— 2— t ブトキシカノレボ ニルァミノペンタン酸メチル  5- [4- (3-Benzyloxyphenoxy) 2-chlorophenol] — 2-t-Methyl butoxycanolevonylaminopentanoate
[0617] [化 164]  [0617] [Formula 164]
Figure imgf000101_0001
Figure imgf000101_0001
[0618] 実施例 147の化合物 (4.20g)を DMF (50mL)に溶解し、ニクロム酸ピリジ-ゥム（[0618] The compound of Example 147 (4.20 g) was dissolved in DMF (50 mL), and pyrididium dichromate (
9.26g)を加え常温にて 17時間撹拌した。反応液に水を加え酢酸ェチルで抽出後、水 、飽和食塩水の順に洗浄し無水硫酸ナトリウムで乾燥した。溶媒を濃縮後、残渣を D MF (50mL)に溶解し、炭酸カリウム（2.00g)、ヨウ化メチル (2mL)をカ卩ぇ常温で 1晚撹 拌した。反応液に水を加え、酢酸ェチルで抽出し、水、飽和食塩水の順に洗浄後、 無水硫酸ナトリウムで乾燥した。溶媒を濃縮後、残渣をシリカゲルカラムクロマトグラフ ィー（へキサン:酢酸ェチル =4 : Dにて精製し目的とするメチルエステル体 (2.67g) を無色油状物として得た。 9.26 g) was added and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After concentration of the solvent, the residue was dissolved in DMF (50 mL), and potassium carbonate (2.00 g) and methyl iodide (2 mL) were stirred at room temperature for 1 min. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: D) to obtain the desired methyl ester (2.67 g) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.44(9H, s), 1.65— 1.88(4H, m),  1H-NMR (400MHz, CDC1) δ 1.44 (9H, s), 1.65― 1.88 (4H, m),
3  Three
2.69-2.71(2H, m), 3.74(3H, s), 4.34(1H, br), 5.00(1H, br), 5.03(2H, s),  2.69-2.71 (2H, m), 3.74 (3H, s), 4.34 (1H, br), 5.00 (1H, br), 5.03 (2H, s),
6.60(1H, ddd, J=8.0Hz, 2.2Hz, 0.7Hz), 6.63(1H, t, J=2.4Hz), 6.75(1H, ddd, J=8.3Hz, 2.4Hz, 0.7Hz), 6.84(1H, dd, J=8.3Hz, 2.4Hz), 7.00(1H, d, J=2.4Hz), 7.13(1H, d, J=8.3Hz), 7.24(1H, t, J=8.0Hz),7.30-7.43(5H, m). [0619] [実施例 223] 6.60 (1H, ddd, J = 8.0Hz, 2.2Hz, 0.7Hz), 6.63 (1H, t, J = 2.4Hz), 6.75 (1H, ddd, J = 8.3Hz, 2.4Hz, 0.7Hz), 6.84 ( 1H, dd, J = 8.3Hz, 2.4Hz), 7.00 (1H, d, J = 2.4Hz), 7.13 (1H, d, J = 8.3Hz), 7.24 (1H, t, J = 8.0Hz), 7.30 -7.43 (5H, m). [0619] [Example 223]
5- [4— (3—ベンジルォキシフエノキシ） 2 クロ口フエ-ル]— 2— t ブトキシカノレボ -ルアミノー 2— tーブチルジフエ-ルシロキシメチルペンタン 1 オール  5- [4- (3-Benzyloxyphenoxy) 2-chlorophenol] — 2-t-butoxycanolevol-amino-2--t-butyldiphenyl-siloxymethylpentane 1-ol
[0620] [化 165] [0620] [Formula 165]
Figure imgf000102_0001
Figure imgf000102_0001
[0621] 実施例 146の化合物（3.25g)を DMF (18mL)に溶解しジイソプロピルェチルァミン（ 10.5mL)、 t-BuPh SiCl (1.73g)をカ卩え、常温にて 8時間撹拌した。反応液に氷水をカロ  [0621] The compound of Example 146 (3.25 g) was dissolved in DMF (18 mL), diisopropylethylamine (10.5 mL) and t-BuPh SiCl (1.73 g) were added, and the mixture was stirred at room temperature for 8 hours. . Add ice water to the reaction solution
2  2
え、酢酸ェチルで抽出後、水、希塩酸、水、飽和食塩水の順に洗浄し、無水硫酸ナト リウムで乾燥した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン The extract was extracted with ethyl acetate, washed with water, diluted hydrochloric acid, water, and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (hexane).
：酢酸ェチル = 7： 1)にて精製し目的物（1.64g)を無色油状物として得た。 : Ethyl acetate = 7: 1) to give the desired product (1.64 g) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.06(9H, s), 1.43(9H, s),  1H-NMR (400MHz, CDC1) δ 1.06 (9H, s), 1.43 (9H, s),
3  Three
1.49-1.82(4H, m), 2.66(2H, t, J=7.8Hz), 3.54(1H, d, J=10.3Hz), 3.65-3.67(2H, m), 3.74(1H, d, J=10.3Hz), 5.03(2H, s), 5.05(1H, br s), 6.59(1H, dd, J=8.3Hz, 2.4Hz), 6.63(1H, t, J=2.4Hz), 6.74(1H, dd, J=8.3Hz, 2.4Hz), 6.82(1H, dd,  1.49-1.82 (4H, m), 2.66 (2H, t, J = 7.8Hz), 3.54 (1H, d, J = 10.3Hz), 3.65-3.67 (2H, m), 3.74 (1H, d, J = 10.3Hz), 5.03 (2H, s), 5.05 (1H, br s), 6.59 (1H, dd, J = 8.3Hz, 2.4Hz), 6.63 (1H, t, J = 2.4Hz), 6.74 (1H, dd, J = 8.3Hz, 2.4Hz), 6.82 (1H, dd,
J=8.3Hz, 2.4Hz), 6.99(1H, d, J=2.4Hz), 7.10(1H, d, J=8.3Hz), 7.23(1H, t,  J = 8.3Hz, 2.4Hz), 6.99 (1H, d, J = 2.4Hz), 7.10 (1H, d, J = 8.3Hz), 7.23 (1H, t,
J=8.3Hz),  J = 8.3Hz),
7.31- 7.45(11H, m), 7.61-7.64(4H, m).  7.31- 7.45 (11H, m), 7.61-7.64 (4H, m).
[0622] [実施例 224] [0622] [Example 224]
5- [4— (3—ベンジルォキシフエノキシ） 2 クロ口フエ-ル]— 2— t ブトキシカノレボ ニルアミノー 2— tーブチルジフエニルシロキシメチルペンタナール  5- [4- (3-Benzyloxyphenoxy) 2 chlorophenol] — 2-t Butoxycanolebonylamino-2- 2-t-butyldiphenylsiloxymethylpentanal
[0623] [化 166] [0623] [Formula 166]
Figure imgf000102_0002
Figure imgf000102_0002
[0624] 上記実施例 223の化合物（940mg)を DMF (10mL)に溶解し、ニクロム酸ピリジ-ゥ ム（800mg)をカ卩ぇ常温にて 48時間撹拌した。反応液に水を加え酢酸ェチルで抽出 後、水、飽和食塩水の順に洗浄し無水硫酸ナトリウムで乾燥した。溶媒を濃縮後、残 渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸ェチル = 3： 1)にて精製し、 目的物（710mg)を無色油状物として得た。 [0624] The compound of Example 223 (940 mg) was dissolved in DMF (10 mL) and pyridi-dichromate was added. (800 mg) was stirred at room temperature for 48 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (710 mg) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.01(9H, s), 1.44(9H, s),  1H-NMR (400MHz, CDC1) δ 1.01 (9H, s), 1.44 (9H, s),
3  Three
1.49-1.73(4H, m), 2.64(2H, br s), 3.84(1H, d, J=10.3Hz), 4.13(1H, d, J=10.3Hz), 5.03(2H, s), 5.43(1H, br s), 6.58(1H, dd, J=8.3Hz, 2.4Hz), 6.62(1H, t,  1.49-1.73 (4H, m), 2.64 (2H, br s), 3.84 (1H, d, J = 10.3Hz), 4.13 (1H, d, J = 10.3Hz), 5.03 (2H, s), 5.43 ( 1H, br s), 6.58 (1H, dd, J = 8.3Hz, 2.4Hz), 6.62 (1H, t,
J=2.4Hz), 6.74(1H, dd, J=8.3Hz, 2.4Hz), 6.82(1H, dd, J=8.3Hz, 2.4Hz), 6.99(1H, d, J=2.4Hz), 7.08(1H, d, J=8.3Hz), 7.23(1H, t, J=8.3Hz), 7.30- 7.43(11H, m), 7.56-7.64(4H,  J = 2.4Hz), 6.74 (1H, dd, J = 8.3Hz, 2.4Hz), 6.82 (1H, dd, J = 8.3Hz, 2.4Hz), 6.99 (1H, d, J = 2.4Hz), 7.08 ( 1H, d, J = 8.3Hz), 7.23 (1H, t, J = 8.3Hz), 7.30- 7.43 (11H, m), 7.56-7.64 (4H,
m), 9.36(1H, s).  m), 9.36 (1H, s).
[0625] [実施例 225]  [0625] [Example 225]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2— t—ブト キシカルボニルァミノペンタナール  5- [4- (3-Benzyloxyphenyl-sulfur-yl) -2-cyclobutane]-2-t-butoxycarbonylaminopentanal
[0626] [化 167]
Figure imgf000103_0001
[0626] [Formula 167]
Figure imgf000103_0001
[0627] - 78°Cにて塩化メチレン（20mL)のォキザリルクロリド（l.OmL)溶液に DMSO (1.7mL )の塩化メチレン（lOmL)混液をカ卩えた後、実施例 129の化合物（5.59g)の塩化メチレ ン（20mL)溶液を滴下した。 15分後トリエチルァミン（7.2mL)をカ卩えた。常温まで 2時 間撹拌し、反応液に水を加え酢酸ェチルで抽出した後に無水硫酸ナトリウムで乾燥 した。溶媒を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（へキサン:酢酸ェチ ル = 3： 1)にて精製し目的物 (4.75g)を淡黄色油状物として得た。 [0627]-A solution of methylene chloride (20 mL) in oxalyl chloride (l.OmL) at 78 ° C was mixed with a mixture of DMSO (1.7 mL) in methylene chloride (lOmL), and the compound of Example 129 ( A solution of 5.59 g) in methylene chloride (20 mL) was added dropwise. After 15 minutes, triethylamine (7.2 mL) was added. The mixture was stirred at room temperature for 2 hours, water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (4.75 g) as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 1.44(9H, s), 1.60-1.74(3H, m),  1H-NMR (400MHz, CDC1) δ 1.44 (9H, s), 1.60-1.74 (3H, m),
3  Three
1.96(1H, br), 2.72-2.77(2H, m), 4.28(1H, br), 5.02(2H, s), 6.87— 6.95(3H, m), 7.10-7.16(2H, m), 7.23(1H, t, J=7.8Hz), 7.28-7.52(5H, m), 9.58(1H, s).  1.96 (1H, br), 2.72-2.77 (2H, m), 4.28 (1H, br), 5.02 (2H, s), 6.87― 6.95 (3H, m), 7.10-7.16 (2H, m), 7.23 ( 1H, t, J = 7.8Hz), 7.28-7.52 (5H, m), 9.58 (1H, s).
[0628] [実施例 226] 5- [4— (3—ベンジルォキシフエ-ルチオ）— 2—クロ口フエ-ル]— 2— t ブトキシカル ボニルアミノー 2— tーブチルジメチルシロキシメチルペンタナール [Example 226] 5- [4- (3-Benzyloxyphenyl-thio) -2-cyclobutane]-2-t-butoxycarbonylamino-2-tert-butyldimethylsiloxymethylpentanal
[0629] [化 168] [0629] [Formula 168]
Figure imgf000104_0001
Figure imgf000104_0001
[0630] 実施例 128の化合物（19.3g)を DMF (200mL)に溶解しトリェチルァミン（12.5mL)、 t-BuMe SiCl (5.12g)をカ卩え、常温にて 8時間撹拌した。反応液に氷水を加え、酢酸[0630] The compound of Example 128 (19.3 g) was dissolved in DMF (200 mL), and triethylamine (12.5 mL) and t-BuMeSiCl (5.12 g) were added. The mixture was stirred at room temperature for 8 hours. Ice water was added to the reaction solution, and acetic acid was added.
2 2
ェチルで抽出後、水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムで乾燥した。溶 媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン:酢酸ェチル = 10 : 1 )にて精製しモノシリル体（18.0g)を無色油状物として得た。得られたモノシリル体を 実施例 225と同様に反応させ目的物を淡黄色油状物として得た。  After extraction with ethyl acetate, the extract was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain a monosilyl compound (18.0 g) as a colorless oil. The obtained monosilyl compound was reacted in the same manner as in Example 225 to obtain the desired product as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 0.02(6H, s), 0.84(9H, s), 1.42(9H,  1H-NMR (400MHz, CDC1) δ 0.02 (6H, s), 0.84 (9H, s), 1.42 (9H,
3  Three
s), 1.55— 1.60(2H, m),1.72-1.78(lH, m), 2.09-2.13(1H, m), 2.67(2H, t, J=7.9Hz), s), 1.55-- 1.60 (2H, m), 1.72-1.78 (lH, m), 2.09-2.13 (1H, m), 2.67 (2H, t, J = 7.9Hz),
3.85(1H, d, J=9.8Hz),4.02(lH, d, J=9.8Hz), 5.02(2H, s), 5.31(1H, br s), 3.85 (1H, d, J = 9.8Hz), 4.02 (lH, d, J = 9.8Hz), 5.02 (2H, s), 5.31 (1H, br s),
6.86— 6.89(1H, m), 6.91— 6.95(2H, m), 7.08(1H, d, J=7.9Hz), 7.13(1H, dd, J=7.9Hz, 6.86— 6.89 (1H, m), 6.91— 6.95 (2H, m), 7.08 (1H, d, J = 7.9Hz), 7.13 (1H, dd, J = 7.9Hz,
1.8Hz), 7.23(1H, t, J=7.9Hz), 7.30- 7.41(6H, m), 9.38(1H, s). 1.8Hz), 7.23 (1H, t, J = 7.9Hz), 7.30- 7.41 (6H, m), 9.38 (1H, s).
FABMS: 670 ([M+H] .  FABMS: 670 ([M + H].
[0631] [実施例 227]  [0631] [Example 227]
7- [4— (3—ベンジルォキシフエ-ルチオ）—2—クロ口フエ-ル] 4 t ブトキシカルボ ニルアミノー 4 tーブチルジメチルシロキシメチルー 2 ヘプテン酸ェチル  7- [4- (3-Benzyloxyphenyl) -2-cyclobutane] 4 t butoxycarbonylamino-4 t-butyldimethylsiloxymethyl-2 ethyl ethyl heptenoate
[0632] [化 169]  [0632] [Formula 169]
Figure imgf000104_0002
Figure imgf000104_0002
[0633] 氷浴中、ジェチルホスホノ酢酸ェチル（246 μ L)の THF (8 mL)溶液に、水素化ナ トリウム（60%) (50.0 mg)を加え約 15分間撹拌した反応液に、上記実施例 226の化合 物 (690 [0633] In an ice bath, sodium hydride (60%) (50.0 mg) was added to a THF (8 mL) solution of ethyl acetyl ethyl phosphonoacetate (246 µL), and the mixture was stirred for about 15 minutes. 226 compound Object (690
mg)の THF (7 mL)溶液を加え、 20分間撹拌した。反応液を酢酸ェチルと飽和食塩 水を用いて分液し、有機層を無水硫酸ナトリウムで乾燥させた後に濃縮し、残查をシ リカゲルカラムクロマトグラフィー（へキサン:酢酸ェチル =4: 1)により精製し、無色油 状の目的物 (733mg)  mg) in THF (7 mL) was added and stirred for 20 minutes. The reaction mixture was separated using ethyl acetate and saturated saline, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1). Purified, colorless oily target (733mg)
を得た。  Got.
1H-NMR(400MHz, CDC1 ) δ 0.02 (3Η, s), 0.0.3 (3H, s), 0.87 1 H-NMR (400MHz, CDC1) δ 0.02 (3Η, s), 0.0.3 (3H, s), 0.87
3  Three
(9H, s), 1.27 (3H, t, J=7.3Hz), 1.41 (9H, s), 1.57-1.63 (2H, m), 1.84-1.90 (2H, m), 2.68 (2H, t, J=7.3Hz), 3.66 (2H, s), 4.18 (2H, q, J=7.3Hz), 4.75 (1H, br), 5.02 (2H, s), 5.82 (1H,  (9H, s), 1.27 (3H, t, J = 7.3Hz), 1.41 (9H, s), 1.57-1.63 (2H, m), 1.84-1.90 (2H, m), 2.68 (2H, t, J = 7.3Hz), 3.66 (2H, s), 4.18 (2H, q, J = 7.3Hz), 4.75 (1H, br), 5.02 (2H, s), 5.82 (1H,
d, J 15.9), 6.88-6.96 (4H, m), 7.09-7.13 (2H, m), 7.21-7.25 (1H, m), 7.30-7.39 d, J 15.9), 6.88-6.96 (4H, m), 7.09-7.13 (2H, m), 7.21-7.25 (1H, m), 7.30-7.39
(6H, m). (6H, m).
[0634] [実施例 228] [Example 228]
7- [4— (3—ベンジルォキシフエ-ルチオ）—2—クロ口フエ-ル] 4 t ブトキシカルボ ニルアミノー 4 tーブチルジメチルシロキシメチルヘプタン酸ェチル  7- [4- (3-Benzyloxyphenyl-thio) -2-cyclobutane] 4 t-butoxycarbonylamino-4 t-butyldimethylsiloxymethylheptanoate
[0635] [化 170] [0635] [Formula 170]
Figure imgf000105_0001
Figure imgf000105_0001
[0636] 上記実施例 227の化合物（733mg)を酢酸ェチル (8 mL)に溶解し、 10%パラジウム 炭素（440 mg)を加え、水素雰囲気下 4日間撹拌した。パラジウム炭素をセライト濾過 し、濾液を濃縮して乾燥させ無色油状の目的物 [0636] The compound of Example 227 (733 mg) was dissolved in ethyl acetate (8 mL), 10% palladium on carbon (440 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 4 days. The palladium carbon is filtered through celite, the filtrate is concentrated and dried to give a colorless oily target substance.
(700 mg)を得た。  (700 mg) was obtained.
1H-NMR(400MHz, CDC1 ) δ 0.3 (6Η, s), 0.87 (9H, s), 1.24 1 H-NMR (400MHz, CDC1) δ 0.3 (6Η, s), 0.87 (9H, s), 1.24
3  Three
(3H, t, J=7.3Hz), 1.41 (9H, s), 1.40-1.58 (2H, m), 1.69-1.74 (2H, m), 1.95-1.99 (2H, m), 2.29 (2H, t, J=8.0Hz), 2.67 (2H, t, J=7.3Hz), 3.55 (2H, s), 4.12 (2H, q, J=7.3Hz), 4.51 (1H, br), 5.02 (2H, s), 6.85— 6.88(1H, m), 6.91—6.95 (2H, m), 7.10-7.18 (2H, m), 7.20-7.24 (1H, m), 7.30-7.40 (6H, m). (3H, t, J = 7.3Hz), 1.41 (9H, s), 1.40-1.58 (2H, m), 1.69-1.74 (2H, m), 1.95-1.99 (2H, m), 2.29 (2H, t , J = 8.0Hz), 2.67 (2H, t, J = 7.3Hz), 3.55 (2H, s), 4.12 (2H, q, J = 7.3Hz), 4.51 (1H, br), 5.02 (2H, s ), 6.85— 6.88 (1H, m), 6.91—6.95 (2H, m), 7.10-7.18 (2H, m), 7.20-7.24 (1H, m), 7.30-7.40 (6H, m).
[0637] [実施例 229] [Example 229]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—メチルペンタン酸ェチル  5- [4- (3-Benzyloxyphenyl-sulfur-)-2-cyclobutane] -2-ethoxycarbol-2-ethyl ethyl methylpentanoate
[0638] [化 171] [0638] [Formula 171]
Figure imgf000106_0001
Figure imgf000106_0001
[0639] 水素化ナトリウム（242mg)を DMF (5mL)に溶解し、ジェチルメチルマロン酸エステ ル（0.956mL)を加え 30分間攪拌した。これに参考例 252の化合物（2.50g)の DMF ( 5mL)溶液を加え 1時間攪拌した。反応液を水で希釈し、酢酸ェチルで抽出後、酢酸 ェチル層を飽和食塩水で洗い、無水硫酸マグネシウムで乾燥後濃縮した。残渣をシ リカゲルカラムクロマトグラフィー（へキサン  [0639] Sodium hydride (242 mg) was dissolved in DMF (5 mL), and getyl methylmalonic acid ester (0.956 mL) was added, followed by stirring for 30 minutes. To this was added a solution of the compound of Reference Example 252 (2.50 g) in DMF (5 mL), and the mixture was stirred for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane).
：酢酸ェチル = 20： 1→ 10： 1)で精製し、 目的物（2.74g)を黄色油状物として得た  : Ethyl acetate = 20: 1 → 10: 1) to give the desired product (2.74g) as a yellow oil
MS(EI) : 540 (〔M]+). MS (EI): 540 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 1.23(6H, t, J=7.3Hz), 1.40(3H, s),  1H-NMR (400MHz, CDC1) δ 1.23 (6H, t, J = 7.3Hz), 1.40 (3H, s),
3  Three
1.52-1.60(2H,m), 1.91— 1.95(2H, m), 2.70(2H, t, J=7.9Hz), 4.16(4H, q, J=7.3Hz), 5.02(2H, s), 6.86— 6.94(3H, m), 7.11-7.14(2H, m), 7.20-7.24(lH, m) ,  1.52-1.60 (2H, m), 1.91― 1.95 (2H, m), 2.70 (2H, t, J = 7.9Hz), 4.16 (4H, q, J = 7.3Hz), 5.02 (2H, s), 6.86 — 6.94 (3H, m), 7.11-7.14 (2H, m), 7.20-7.24 (lH, m),
7.31-7.40(6H, m).  7.31-7.40 (6H, m).
[0640] [実施例 230] [0640] [Example 230]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—ェチルペンタン酸ェチル [0641] [化 172] 5- [4- (3-Benzyloxyphenyl-sulfur-)-2-cyclobutane] -2-ethoxycarbol-2-ethyl ethylpentenoate [0641] [Formula 172]
Figure imgf000107_0001
Figure imgf000107_0001
[0642] ェチルマロン酸ジェチルを用い上記実施例 229と同様に反応させ目的物を黄色油 状物として得た。  [0642] The same reaction as in Example 229 described above was carried out using getyl ethyl malonate to give the desired product as a yellow oil.
MS(EI) : 554 (〔M]+).  MS (EI): 554 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 0.80(3H, t, J=7.3Hz), 1.22(6H, t, 1 H-NMR (400MHz, CDC1) δ 0.80 (3H, t, J = 7.3Hz), 1.22 (6H, t,
3  Three
J=7.3Hz), 1.45-1.53(2H, m), 1.89— 1.97(4H, m), 2.70(2H, t, J=7.3Hz), 4.16(4H, q, J = 7.3Hz), 1.45-1.53 (2H, m), 1.89- 1.97 (4H, m), 2.70 (2H, t, J = 7.3Hz), 4.16 (4H, q,
J=7.3Hz), 5.02(2H, s),6.86— 6.94(3H, m), 7.11— 7.16(2H, m), 7.20-7.24(lH, m) ,J = 7.3Hz), 5.02 (2H, s), 6.86-6.94 (3H, m), 7.11-7.16 (2H, m), 7.20-7.24 (lH, m),
7.31-7.40(6H, m). 7.31-7.40 (6H, m).
[0643] [実施例 231] [0643] [Example 231]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—メチル酪酸ェチル  4— [4— (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] —2-ethoxycarbol 2-ethylethyl butyrate
[0644] [化 173] [0644] [Formula 173]
Figure imgf000107_0002
Figure imgf000107_0002
[0645] 参考例 317の化合物を用い、実施例 229と同様に反応させ目的物を淡黄色油状物 として得た。  [0645] The same procedures used in Example 229 were carried out except for using the compound of Reference Example 317 to give a desired product as a pale yellow oil.
MS(EI) : 526 (〔M]+).  MS (EI): 526 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 1.27(6H, t, J=7.3Hz), 1.52(3H, s), 1 H-NMR (400MHz, CDC1) δ 1.27 (6H, t, J = 7.3Hz), 1.52 (3H, s),
3  Three
2.10-2.14(2H,m), 2.65— 2.69(2H, m), 4.20(4H, q, J=7.3Hz), 5.02(2H, s),  2.10-2.14 (2H, m), 2.65― 2.69 (2H, m), 4.20 (4H, q, J = 7.3Hz), 5.02 (2H, s),
6.86— 6.96(3H, m), 7.15(2H, s), 7.23(1H, t, J=8.0), 7.31— 7.41(6H, m).  6.86— 6.96 (3H, m), 7.15 (2H, s), 7.23 (1H, t, J = 8.0), 7.31— 7.41 (6H, m).
[0646] [実施例 232] [Example 232]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—ェチル酪酸ェチル [0647] [化 174] 4— [4— (3-Benzyloxyphenyl-sulfur-yl) —2-chlorophenol] —2-ethoxycarbol 2-ethylethyl butyrate [0647] [Formula 174]
Figure imgf000108_0001
Figure imgf000108_0001
[0648] 参考例 317の化合物を用い、実施例 230と同様に反応させ目的物を無色油状物とし て得た。 [0648] The same procedures used in Example 230 were carried out except for using the compound of Reference Example 317 to give the desired product as a colorless oil.
MS(EI) : 540 (〔M]+).  MS (EI): 540 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 0.82(3H, t, J=7.3Hz), 1.17(6H, t, 1 H-NMR (400MHz, CDC1) δ 0.82 (3H, t, J = 7.3Hz), 1.17 (6H, t,
3  Three
J=7.3Hz), 1.93(2H, q, J=7.3Hz), 1.98— 2.02(2H, m), 2.45-2.51(2H, m), 4.13(4H, q, J=7.3Hz), 5.10(2H, s),  J = 7.3Hz), 1.93 (2H, q, J = 7.3Hz), 1.98- 2.02 (2H, m), 2.45-2.51 (2H, m), 4.13 (4H, q, J = 7.3Hz), 5.10 ( 2H, s),
6.92-7.0K3H, m), 7.21(1H, dd, J=8.0Hz, 1.9Hz), 7.30- 7.41(8H, m).  6.92-7.0K3H, m), 7.21 (1H, dd, J = 8.0Hz, 1.9Hz), 7.30-7.41 (8H, m).
[0649] [実施例 233] [Example 233]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—メチルペンタン酸  5- [4- (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -2-ethoxycarboxy-2-methylpentanoic acid
[0650] [化 175] [0650] [Formula 175]
Figure imgf000108_0002
Figure imgf000108_0002
[0651] 実施例 229の化合物（2.74g)をエタノール（10mL)に溶解し、水酸化カリウム（330mg )をカ卩ぇ 50°Cで一晩攪拌した。反応液を水で希釈し、 2mol/L塩酸をカ卩えたのち酢酸 ェチルで抽出した。酢酸ェチル層を飽和食塩水で洗い、無水硫酸マグネシウムで乾 燥後濃縮した。残渣をシリカゲルカラムクロマトグラフィー（へキサン [0651] The compound of Example 229 (2.74 g) was dissolved in ethanol (10 mL), and potassium hydroxide (330 mg) was stirred at 50 ° C overnight. The reaction solution was diluted with water, and 2 mol / L hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel column chromatography (hexane
：酢酸ェチル = 10 : 1→2： 1)で精製し、 目的物（2.38g)を黄色油状物として得た。 MS(EI) : 512 (〔M]+).  : Ethyl acetate = 10: 1 → 2: 1) to give the desired product (2.38 g) as a yellow oil. MS (EI): 512 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 1.26(3H, t, J=7.3Hz), 1.47(3H, s),  1H-NMR (400MHz, CDC1) δ 1.26 (3H, t, J = 7.3Hz), 1.47 (3H, s),
3  Three
1.53-1.62(2H,m), 1.92— 2.03(2H, m), 2.71(2H, t, J=7.9Hz), 4.22(2H, q, J=7.3Hz), 5.02(2H, s), 6.87-6.94(3H, m), 7.10-7.14(2H, m), 7.21-7.25(1H, m) ,1.53-1.62 (2H, m), 1.92- 2.03 (2H, m), 2.71 (2H, t, J = 7.9Hz), 4.22 (2H, q, J = 7.3Hz), 5.02 (2H, s), 6.87-6.94 (3H, m), 7.10-7.14 (2H, m), 7.21-7.25 (1H, m),
7.31-7.40(6H, m). 7.31-7.40 (6H, m).
[0652] [実施例 234] [0652] [Example 234]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—ェチルペンタン酸  5- [4- (3-Benzyloxyphenyl-sulfur-)-2-cyclobutane] -2-ethoxycarbol-2-ethylpentanoic acid
[0653] [化 176] [0653] [Formula 176]
Figure imgf000109_0001
Figure imgf000109_0001
[0654] 実施例 230の化合物を用い上記実施例 233と同様に反応させ目的物を黄色油状物 として得た。 [0654] The compound of Example 230 was reacted in the same manner as in the above Example 233 to obtain the desired product as a yellow oil.
MS(EI) : 526 (〔M]+).  MS (EI): 526 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 0.84(3H, t, J=7.3Hz), 1.28(3H, t, 1 H-NMR (400MHz, CDC1) δ 0.84 (3H, t, J = 7.3Hz), 1.28 (3H, t,
3  Three
J=7.3Hz), 1.42-1.59(2H, m), 1.85— 1.95(2H, m), 2.00-2.13(2H, m), 2.66-2.70(2H, m), 4.23-4.3K2H, m), 5.02(2H, s), 6.86— 6.94(3H, m), 7.08— 7.15(2H, m),  J = 7.3Hz), 1.42-1.59 (2H, m), 1.85― 1.95 (2H, m), 2.00-2.13 (2H, m), 2.66-2.70 (2H, m), 4.23-4.3K2H, m), 5.02 (2H, s), 6.86- 6.94 (3H, m), 7.08- 7.15 (2H, m),
7.21-7.25(1H, m) , 7.30- 7.40(6H, m).  7.21-7.25 (1H, m), 7.30-7.40 (6H, m).
[0655] [実施例 235] [0655] [Example 235]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—メチル酪酸  4— [4— (3-benzyloxyphenol-sulfur) -2-cyclobutane] —2-ethoxycarbol 2-methylbutyric acid
[0656] [化 177] [0656] [Formula 177]
Figure imgf000109_0002
Figure imgf000109_0002
[0657] 実施例 231の化合物を用い、実施例 233と同様に反応させ目的物を淡黄色油状物 として得た。  [0657] Using the compound of Example 231, the reaction was carried out in the same manner as in Example 233 to obtain the desired product as a pale yellow oil.
MS(EI) : 499 (〔M]+). 1H-NMR(400MHz, CDC1 ) δ 1.30(3H, t, J=7.3Hz), 1.57(3H, s), MS (EI): 499 ([M] +). 1H-NMR (400MHz, CDC1) δ 1.30 (3H, t, J = 7.3Hz), 1.57 (3H, s),
3  Three
2.11-2.19(2H,m), 2.69(2H, t, J=8.5Hz), 4.24(2H, q, J=7.3Hz), 5.02(2H, s), 6.87-6.96(3H, m), 7.14(2H, s), 7.23(1H, t, J=8.0Hz), 7.31- 7.40(6H, m).  2.11-2.19 (2H, m), 2.69 (2H, t, J = 8.5Hz), 4.24 (2H, q, J = 7.3Hz), 5.02 (2H, s), 6.87-6.96 (3H, m), 7.14 (2H, s), 7.23 (1H, t, J = 8.0Hz), 7.31-7.40 (6H, m).
[0658] [実施例 236]  [Example 236]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—ェチル酪酸  4— [4— (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -2-ethoxycarbol-2-ethylbutyric acid
[0659] [化 178]  [0659] [Formula 178]
Figure imgf000110_0001
Figure imgf000110_0001
[0660] 実施例 232の化合物を用い、実施例 233と同様に反応させ目的物を淡黄色油状物 として得た。 [0660] The same procedures used in Example 233 were carried out except for using the compound of Example 232 to give a desired product as a pale yellow oil.
1H-NMR(400MHz, CDC1 ) δ 0.90(3H, t, J=7.3Hz), 1.33(3H, t, 1 H-NMR (400MHz, CDC1) δ 0.90 (3H, t, J = 7.3Hz), 1.33 (3H, t,
3  Three
J=7.3Hz), 1.94— 1.99(1H, m), 2.05-2.12(1H, m), 2.19— 2.24(2H, m), 2.59— 2.64(2H, m), 4.20-4.3K2H, m), 5.02(2H, s), 6.87— 6.94(3H, m), 7.09-7.14(2H, m), 7.23(1H, t, J=8.0Hz), 7.29-7.40(6H, m).  J = 7.3Hz), 1.94- 1.99 (1H, m), 2.05-2.12 (1H, m), 2.19- 2.24 (2H, m), 2.59- 2.64 (2H, m), 4.20-4.3K2H, m), 5.02 (2H, s), 6.87― 6.94 (3H, m), 7.09-7.14 (2H, m), 7.23 (1H, t, J = 8.0Hz), 7.29-7.40 (6H, m).
[0661] [実施例 237— 239] [0661] [Examples 237-239]
ジェチルプロピルマロン酸エステル、ジェチルブチルマロン酸エステル、ジメチルァリ ルマロン酸エステルを用 V、て実施例 229と同様に反応させた後、実施例 233と同様に して加水分解を行 ヽ表 13に示す化合物を合成した。  After reacting getylpropylmalonate, getylbutylmalonate, and dimethylarylmalonate in the same manner as in Example 229, hydrolysis was carried out in the same manner as in Example 233. The compounds shown were synthesized.
[0662] [表 13] [0662] [Table 13]
Figure imgf000110_0002
Figure imgf000110_0002
MS(EI)  MS (EI)
実施例 R 性状  Example R Properties
M+ M +
237 Pr 黄色油状物 540  237 Pr yellow oil 540
238 Bu 黄色油状物 554  238 Bu Yellow oil 554
239 -CH2CH=CH 黄色油状物 [0663] [実施例 240] 239 -CH 2 CH = CH yellow oil [0663] [Example 240]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—メトキシ カルボニルアミノー 2—メチルペンタン酸ェチル  5- [4- (3-Benzyloxyphenyl-sulfur-yl) -2-cyclobutane]-2-methoxycarbonylamino-2-ethylethylpentanoate
[0664] [化 179] [0664] [Formula 179]
Figure imgf000111_0001
Figure imgf000111_0001
[0665] 実施例 233の化合物（2.38g)をベンゼン（20mL)に溶解し、トリェチルァミン（  The compound of Example 233 (2.38 g) was dissolved in benzene (20 mL), and triethylamine (20 mL) was dissolved in benzene (20 mL).
0.711mL)と DPPA(l.lOmL)をカ卩え、室温で 10分間攪拌後還流させ 1時間 30分間攪 拌した。これにメタノール (3.76mL)を 30分間かけてカ卩え、ー晚攪拌した。反応液を水 で希釈し、酢酸ェチルで抽出後、酢酸ェチル層を飽和食塩水で洗い、無水硫酸マ グネシゥムで乾燥後濃縮した。残渣をシリカゲルカラムクロマトグラフィー（へキサン ：酢酸ェチル = 20： 1  (0.711 mL) and DPPA (1.10 mL) were combined, stirred at room temperature for 10 minutes, refluxed, and stirred for 1 hour and 30 minutes. Methanol (3.76 mL) was added to the mixture over 30 minutes, and the mixture was stirred. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1).
→ 5： 1)で精製し、 目的物 (2.04g)を黄色油状物として得た。  → Purification by 5: 1) afforded the desired product (2.04 g) as a yellow oil.
MS(EI) : 541 (〔M]+).  MS (EI): 541 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 1.24(3H, t, J=7.3Hz), 1 H-NMR (400MHz, CDC1) δ 1.24 (3H, t, J = 7.3Hz),
3  Three
1.36— 1.40(1H, m), 1.54(3H,s), 1.56— 1.65(1H, m), 1.80— 1.87(1H, m), 2.28(1H, m), 2.65-2.69(2H, m), 3.63(3H, s), 4.15- 4.22(2H, m), 5.02(2H, s), 5.61(1H, br s), 6.86— 6.94(3H, m), 7.09- 7.15(2H, m), 7.20-7.24(lH, m) , 7.31- 7.40(6H, m).  1.36— 1.40 (1H, m), 1.54 (3H, s), 1.56— 1.65 (1H, m), 1.80— 1.87 (1H, m), 2.28 (1H, m), 2.65-2.69 (2H, m), 3.63 (3H, s), 4.15- 4.22 (2H, m), 5.02 (2H, s), 5.61 (1H, br s), 6.86―6.94 (3H, m), 7.09-7.15 (2H, m), 7.20 -7.24 (lH, m), 7.31-7.40 (6H, m).
[0666] [実施例 241] [0666] [Example 241]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—ェチル ー2—メトキシカルボニルァミノペンタン酸ェチル [0667] [化 180] 5- [4- (3-Benzyloxyphenyl-sulfur-yl) -2-cycloethyl] -2-ethyl-2-methoxyethylaminoethylpentanoate [0667] [Formula 180]
Figure imgf000112_0001
Figure imgf000112_0001
[0668] 実施例 234の化合物を用い実施例 240と同様に反応させ目的物を黄色油状物とし て得た。 [0668] The same procedures used in Example 240 were carried out except for using the compound of Example 234 to give the desired product as a yellow oil.
MS(EI) : 555 (〔M]+).  MS (EI): 555 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 0.74(3H, t, J=7.3Hz), 1.24(3H, t,  1H-NMR (400MHz, CDC1) δ 0.74 (3H, t, J = 7.3Hz), 1.24 (3H, t,
3  Three
J=7.3Hz), 1.28-1.32(1H, m), 1.57— 1.58(1H, m), 1.70— 1.84(2H, m), 2.34-2.44(2H, m), 2.62-2.72(2H, m), 3.63(3H, s), 4.16- 4.22(2H, m), 5.02(2H, s), 5.78(1H, br s), 6.86— 6.94(3H, m), 7.08- 7.15(2H, m), 7.20-7.24(lH, m) , 7.31- 7.40(6H, m).  J = 7.3Hz), 1.28-1.32 (1H, m), 1.57― 1.58 (1H, m), 1.70― 1.84 (2H, m), 2.34-2.44 (2H, m), 2.62-2.72 (2H, m) , 3.63 (3H, s), 4.16- 4.22 (2H, m), 5.02 (2H, s), 5.78 (1H, br s), 6.86―6.94 (3H, m), 7.08-7.15 (2H, m), 7.20-7.24 (lH, m), 7.31-7.40 (6H, m).
[0669] [実施例 242]  [Example 242]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2 t ブト キシカルボ-ルァミノー 2—メチル酪酸ェチル  4— [4— (3-Benzyloxyphenol-sulfur) -2-butyrocarboxylamine—2 t-butoxycarborumamine 2-ethylethylbutyrate
[0670] [化 181]  [0670] [Formula 181]
Figure imgf000112_0002
Figure imgf000112_0002
[0671] 実施例 235の化合物を用いメタノールのかわりに tーブタノールを使用し、実施例 240 と同様に反応させ目的物を淡黄色油状物として得た。 [0671] The compound of Example 235 was used and the reaction was carried out in the same manner as in Example 240 using t-butanol instead of methanol to obtain the desired product as a pale yellow oil.
FABMS : 569([M+H]+). FABMS: 569 ([M + H] + ).
1H-NMR(400MHz, CDC1 ) δ 1.29(3Η, t, J=7.3Hz), 1.46(9Η, s), 1 H-NMR (400MHz, CDC1) δ 1.29 (3Η, t, J = 7.3Hz), 1.46 (9Η, s),
3  Three
1.58(3Η, s), 2.10(lH,td, J=13.0Hz, 4.9Hz), 2.41(1H, br), 2.53(1H, td, J=13.0Hz, 4.9Hz), 2.67(1H, td,J=13.0Hz, 4.9Hz), 4.19(2H, q, J=7.3), 5.02(2H, s), 5.46(1H, br s), 6.86— 6.94(3H, m), 7.08- 7.15(2H, m), 7.23(1H, t, J=8.0Hz), 7.30— 7.40(6H, m [0672] [実施例 243] 1.58 (3Η, s), 2.10 (lH, td, J = 13.0Hz, 4.9Hz), 2.41 (1H, br), 2.53 (1H, td, J = 13.0Hz, 4.9Hz), 2.67 (1H, td, J = 13.0Hz, 4.9Hz), 4.19 (2H, q, J = 7.3), 5.02 (2H, s), 5.46 (1H, br s), 6.86―6.94 (3H, m), 7.08-7.15 (2H, m), 7.23 (1H, t, J = 8.0Hz), 7.30-7.40 (6H, m [0672] [Example 243]
4— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—ェチル ー2—メトキシカルボ-ルァミノ酪酸ェチル  4— [4— (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -2-ethyl-2-methoxyethylcarboxy-laminobutyrate
[0673] [化 182] [0673] [Formula 182]
Figure imgf000113_0001
Figure imgf000113_0001
[0674] 実施例 236の化合物を用い実施例 240と同様に反応させ目的物を淡黄色油状物と して得た。  [0674] The compound of Example 236 was reacted in the same manner as in Example 240 to obtain the desired product as a pale yellow oil.
MS(EI) : 541 (〔Μ]+).  MS (EI): 541 ([Μ] +).
1H-NMR(400MHz, CDC1 ) δ 0.77(3H, t, J=7.3Hz), 1.30(3H, t, 1 H-NMR (400MHz, CDC1) δ 0.77 (3H, t, J = 7.3Hz), 1.30 (3H, t,
3  Three
J=7.3Hz), 1.75- 1.80(1H, m), 2.05—2.15(1H, m), 2.36— 2.49(2H， m), 2.59- 2.68(2H, m), 3.66(3H, s)， 4.11-4.27(2H, m), 5.02(2H, s), 5.87(1H, br), 6.86— 6.93(3H， m), 7.08-7.14(2H, m)， 7.22(1H, t, J=8.0Hz)， 7.30— 7.40(6H， m).  J = 7.3Hz), 1.75- 1.80 (1H, m), 2.05-2.15 (1H, m), 2.36-2.49 (2H, m), 2.59-2.68 (2H, m), 3.66 (3H, s), 4.11 -4.27 (2H, m), 5.02 (2H, s), 5.87 (1H, br), 6.86- 6.93 (3H, m), 7.08-7.14 (2H, m), 7.22 (1H, t, J = 8.0Hz ), 7.30—7.40 (6H, m).
[0675] [実施例 244— 246]  [Example 244-246]
表 13の化合物を用い実施例 240と同様に反応させ表 14に示す化合物を合成した。  The compounds shown in Table 14 were reacted in the same manner as in Example 240 using the compounds shown in Table 13.
[0676] [表 14]  [0676] [Table 14]
Figure imgf000113_0002
Figure imgf000113_0002
実施例 R R' 性状 MS(EI)  Example R R 'Property MS (EI)
M+  M +
244 Pr Et 無色油状物 569  244 Pr Et colorless oil 569
245 Bu Et 無色油状物  245 Bu Et colorless oil
246 -CH2CH=CH Me 黄 &;田状物 554* 246 -CH 2 CH = CH Me yellow &; rice 554 *
* FABMS  * FABMS
[0677] [実施例 247]  [Example 247]
5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—メトキシ カルボ-ルァミノー 2—メチルペンタン 1 オール 5— [4— (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] —2-methoxy Carbo-Lumimin 2-Methylpentane 1-ol
[0678] [化 183] [0678] [Formula 183]
Figure imgf000114_0001
Figure imgf000114_0001
[0679] 実施例 240の化合物を用い実施例 76と同様に反応させ目的物を無色油状物として 得た。 The compound of Example 240 was reacted in the same manner as in Example 76 to obtain the desired product as a colorless oil.
MS(EI) : 499 (〔M]+).  MS (EI): 499 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 1.18(3H, s), 1.57— 1.84(4H, m), 1 H-NMR (400MHz, CDC1) δ 1.18 (3H, s), 1.57-1.84 (4H, m),
3  Three
2.71(2H, t, J=7.3Hz), 3.59— 3.69(3H, m), 3.63(3H, s), 4.71(1H, br s), 5.02(2H, s), 6.86— 6.94(3H, m), 7.13-7.17(2H, m), 7.21-7.25(1H, m) , 7.30— 7.41(6H, m).  2.71 (2H, t, J = 7.3Hz), 3.59- 3.69 (3H, m), 3.63 (3H, s), 4.71 (1H, br s), 5.02 (2H, s), 6.86- 6.94 (3H, m ), 7.13-7.17 (2H, m), 7.21-7.25 (1H, m), 7.30-7.41 (6H, m).
[0680] [実施例 248及び 249] [Examples 248 and 249]
( + )、及び（一)—5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ ニル ]ー2—メトキシカルボニルアミノー 2—メチルペンタン 1 オール  (+), And (I) -5- [4- (3-benzyloxyphenyl-sulfur-)-2-cyclophenyl] -2-methoxycarbonylamino-2-methylpentane-1ol
上記実施例 247の化合物を高速液体クロマトグラフィー（キラルセル OD,へキサン： イソプロパノール = 70： 30、測定波長： UV 254nm、流速： 3mL/min)で光学分割し た。  The compound of Example 247 was optically resolved by high performance liquid chromatography (chiral cell OD, hexane: isopropanol = 70: 30, measuring wavelength: UV 254 nm, flow rate: 3 mL / min).
[0681] 前溶出部分から [ a ] +15° (C = 1.0,クロ口ホルム）の化合物（実施例 248)を、  [0681] Compound (Example 248) of [a] + 15 ° (C = 1.0, black form) from the pre-eluted portion was
D  D
後溶出部分から [ α ]24·7 -12° (C = 1.0,クロ口ホルム）の化合物（実施例 249)を From the post-eluting part, a compound of [α] 24 · 7 -12 ° (C = 1.0, black form) was obtained (Example 249).
D  D
得た。  Obtained.
[0682] [実施例 250] [0682] [Example 250]
5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2—ェチルー 2—メトキシカルボニルァミノペンタン 1 オール [0683] [化 184] 5— [4— (3-Benzyloxyphenol-sulfur-yl) —2-chlorophenol] —2-ethyl-2-methoxycarbonylaminopentane 1-ol [0683] [Formula 184]
Figure imgf000115_0001
Figure imgf000115_0001
[0684] 実施例 241の化合物を用い実施例 76と同様に反応させ目的物を淡黄色油状物とし て得た。 [0684] The compound of Example 241 was reacted in the same manner as in Example 76 to obtain the desired product as a pale yellow oil.
MS(EI) : 513 (〔M]+).  MS (EI): 513 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 0.83(3H, t, J=7.3Hz), 1 H-NMR (400MHz, CDC1) δ 0.83 (3H, t, J = 7.3Hz),
3  Three
1.51-1.73(6H, m), 2.70 (2H, t, J=7.3Hz), 3.63(3H, s), 3.65-3.70(3H, m),  1.51-1.73 (6H, m), 2.70 (2H, t, J = 7.3Hz), 3.63 (3H, s), 3.65-3.70 (3H, m),
4.63(1H, br s), 5.02(2H, s), 6.86- 6.94(3H,m), 7.12-7.17(2H, m), 7.20-7.24(lH, m) , 7.30-7.40(6H, m).  4.63 (1H, br s), 5.02 (2H, s), 6.86-6.94 (3H, m), 7.12-7.17 (2H, m), 7.20-7.24 (lH, m), 7.30-7.40 (6H, m) .
[0685] [実施例 251及び 252] [0685] [Examples 251 and 252]
( + )及び（一)—5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ- ル ]ー2—ェチルー 2—メトキシカルボニルァミノペンタン 1 オール  (+) And (I) -5- [4- (3-benzyloxyphenyl-sulfur-)-2-chlorophenol] -2-ethyl-2-oxomethoxycarbonylaminopentane 1 all
実施例 250の化合物を高速液体クロマトグラフィー（キラルセル OD,へキサン：イソ プロパノール = 60： 40、測定波長： UV 254nm、流速： 3mL/min)で光学分割した。  The compound of Example 250 was optically resolved by high performance liquid chromatography (Chiral Cell OD, hexane: isopropanol = 60: 40, measurement wavelength: UV 254 nm, flow rate: 3 mL / min).
[0686] 前溶出部分から [ α ]25·6 +14° (C = 1.0,クロ口ホルム）の無色油状物（実施例 251 [0686] Colorless oily substance of [α] 25 · 6 + 14 ° (C = 1.0, black form) from the pre-eluted portion (Example 251)
D  D
)を、  ),
後溶出部分から [ α ]25·7 -15° (C = 1.0,クロ口ホルム）の無色油状物（実施例 252 From the post-eluting part, a colorless oily substance of [α] 25 · 7 -15 ° (C = 1.0, black form) (Example 252)
D  D
)を得た。  ).
[0687] [実施例 253] [Example 253]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2 t ブト キシカルボニルアミノー 2—メチルブタン 1 オール [0688] [化 185] 4— [4— (3-Benzyloxyphenol-sulfur) -2-butoxycarbonyl] —2 t butoxycarbonylamino-2-methylbutane 1ol [0688] [Formula 185]
Figure imgf000116_0001
Figure imgf000116_0001
[0689] 実施例 242の化合物を用い実施例 76と同様に反応させ目的物を無色油状物として 得た。 [0689] The same procedures used in Example 76 were carried out except for using the compound of Example 242 to give a desired product as a colorless oil.
MS(EI) : 527 (〔M]+).  MS (EI): 527 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 1.25(3H, s), 1.44(9H, s), 1.82(1H,  1H-NMR (400MHz, CDC1) δ 1.25 (3H, s), 1.44 (9H, s), 1.82 (1H,
3  Three
td, J=13.0Hz,4.9Hz), 2.06(1H, td, J=13.0Hz, 4.9Hz), 2.65— 2.80(2H, m),  td, J = 13.0Hz, 4.9Hz), 2.06 (1H, td, J = 13.0Hz, 4.9Hz), 2.65― 2.80 (2H, m),
3.66-3.74(2H, m), 4.68(1H, br s), 5.02(2H, s), 6.86— 6.94(3H, m), 7.15(2H, s), 7.23(1H, t, J=8.0Hz),7.32-7.40(6H, m).  3.66-3.74 (2H, m), 4.68 (1H, br s), 5.02 (2H, s), 6.86- 6.94 (3H, m), 7.15 (2H, s), 7.23 (1H, t, J = 8.0Hz ), 7.32-7.40 (6H, m).
[0690] [実施例 254及び 255] [Examples 254 and 255]
( + )及び（一) 4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ- ル ]ー2— t ブトキシカルボニルアミノー 2—メチルブタン 1 オール  (+) And (I) 4- [4- (3-Benzyloxyphenyl-sulfur-)-2-cyclophenol] -2-t Butoxycarbonylamino-2-methylbutane 1ol
実施例 253の化合物を高速液体クロマトグラフィー（キラルパック AD,へキサン：ェ タノール = 85： 15、測定波長： UV 254nm、流速： 3mL/min)で光学分割した。  The compound of Example 253 was optically resolved by high performance liquid chromatography (Chiralpak AD, hexane: ethanol = 85: 15, measurement wavelength: UV 254 nm, flow rate: 3 mL / min).
[0691] 前溶出部分から [ α ]25·3 +4.6° (C = 1.0,クロ口ホルム）の無色油状物（実施例 [0691] Colorless oily substance with [α] 25 · 3 + 4.6 ° (C = 1.0, black form) from the pre-eluted part (Example)
D  D
254)を、  254),
後溶出部分から [ α ]25·6 -2.2° (C = 1.0,クロ口ホルム）の無色油状物（実施例 Colorless oil of [α] 25 · 6 -2.2 ° (C = 1.0, black form) from the post-eluting part (Example
D  D
255)を得た。  255).
[0692] [実施例 256] [0692] [Example 256]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2 ェチル —2—メトキシカルボニルアミノーブタン 1 オール [0693] [化 186] 4- [4- (3-Benzyloxyphenyl-sulfur) -2-cyclobutane]-2-ethyl-2-methoxycarbonylaminobutane 1-ol [0693] [Formula 186]
Figure imgf000117_0001
Figure imgf000117_0001
[0694] 実施例 243の化合物を用い実施例 76と同様に反応させ目的物を無色油状物として 得た。 [0694] The target compound was obtained as a colorless oil by reacting with the compound of Example 243 in the same manner as in Example 76.
MS(EI) : 499 (〔M]+).  MS (EI): 499 ([M] +).
1H-NMR(400MHz, CDC1 ) δ 0.94(3H, t, J=7.3Hz), 1.69(2H, q, 1 H-NMR (400 MHz, CDC1) δ 0.94 (3H, t, J = 7.3 Hz), 1.69 (2H, q,
3  Three
J=7.3Hz), 1.80-1.94(2H, m), 2.62-2.75(2H, m), 3.65(3H, s), 3.77(3H, m), 4.77(1H, br), 5.02(2H, s), 6.86— 6.95(3H, m), 7.16(2H, s), 7.23(1H, t, J=8.0Hz),  J = 7.3Hz), 1.80-1.94 (2H, m), 2.62-2.75 (2H, m), 3.65 (3H, s), 3.77 (3H, m), 4.77 (1H, br), 5.02 (2H, s ), 6.86- 6.95 (3H, m), 7.16 (2H, s), 7.23 (1H, t, J = 8.0Hz),
7.32-7.4K6H, m).  7.32-7.4K6H, m).
[0695] [実施例 257及び 258] [0695] [Examples 257 and 258]
( + )及び（一) 4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ- ル ]ー2—ェチルー 2—メトキシカルボニルアミノーブタン 1 オール  (+) And (I) 4- [4- (3-benzyloxyphenol-sulfur-)-2-cyclophenol] -2-ethyl-2-methoxycarbonylaminobutane 1-ol
実施例 256の化合物を実施例 254及び 255と類似の分取条件にて光学分割した。  The compound of Example 256 was optically resolved under the same preparative conditions as in Examples 254 and 255.
[0696] 前溶出部分から [ α ]25·6 +11. (C = 1.0,クロ口ホルム）の無色油状物（実施例 [0696] Colorless oily substance of [α] 25 · 6 +11. (C = 1.0, black form) from the pre-eluted part (Example
D  D
257)を、  257),
後溶出部分から [ひ]26 1 -9.67° (C = 1.0,クロ口ホルム）の無色油状物（実施例 Colorless oil of [hi] 26 1 -9.67 ° (C = 1.0, black form)
D  D
258)を得た。  258).
[0697] [実施例 259] [0697] [Example 259]
5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2—ブトキシ カルボ-ルァミノー 2—ェチルペンタン 1 オール [0698] [化 187] 5— [4— (3-Benzyloxyphenol-sulfur-) — 2-chlorophenol] —2-butoxycarbo-luminamine 2-ethylpentane 1-ol [0698] [Formula 187]
Figure imgf000118_0001
Figure imgf000118_0001
[0699] 実施例 234の化合物を用い tーブタノールをメタノールのかわりに使用し、実施例 241 と同様に反応させた後、実施例 76と同様に還元し目的物を無色油状物として得た。 MS (EI) : 555 ([M]+). [0699] The compound of Example 234 was used and the reaction was carried out in the same manner as in Example 241, using t-butanol instead of methanol, and then reduced in the same manner as in Example 76 to obtain the desired product as a colorless oil. MS (EI): 555 ([M] + ).
1H-NMR(400MHz, CDC1 ) δ 0.83(3H, t, J=7.3Hz), 1.42(9H, s), 1 H-NMR (400MHz, CDC1) δ 0.83 (3H, t, J = 7.3Hz), 1.42 (9H, s),
3  Three
1.55-1.72(6H,m), 2.70(2H, t, J=6.7Hz), 3.64— 3.66(2H， m), 4.49(1H, br s)，  1.55-1.72 (6H, m), 2.70 (2H, t, J = 6.7Hz), 3.64- 3.66 (2H, m), 4.49 (1H, brs),
5.02(2H, s)， 6.82— 6.95(3H, m), 7.12-7.17(2H, m), 7.20-7.25(lH, m) ,  5.02 (2H, s), 6.82—6.95 (3H, m), 7.12-7.17 (2H, m), 7.20-7.25 (lH, m),
7.30-7.4K6H, m).  7.30-7.4K6H, m).
[0700] [実施例 260— 262] [Example 700—262]
表 14の化合物を用い実施例 76と同様に反応させ表 15に示した化合物を合成した。  The compounds shown in Table 15 were synthesized by reacting with the compounds shown in Table 14 in the same manner as in Example 76.
[0701] [表 15] 表 15 [0701] [Table 15] Table 15
Figure imgf000118_0002
Figure imgf000118_0002
260 Pr 無色油状物 528  260 Pr colorless oil 528
261 Bu 無色油状物  261 Bu colorless oil
262 -CH2CH=CH 無色油状物 526 262 -CH 2 CH = CH colorless oil 526
[0702] [実施例 263] [0702] [Example 263]
2— t一ブトキシカルボニルアミノー 4— [4— (3—ペンジノレオキシフエ-ルスルファ -ル） 一 2—クロ口フエニル ]ー2—メトキシメチルォキシメチルブタンー1一オール [0703] [化 188] 2-t-Butoxycarbonylamino-4- [4- (3-Penzinoleoxyphenylsulfur-yl) -1-2-chlorophenyl] -2-methoxymethyloxymethylbutan-1-ol [0703] [Formula 188]
Figure imgf000119_0001
Figure imgf000119_0001
[0704] 実施例 126の化合物（4.00g)を塩化メチレン（lOOmL)に溶解し、  [0704] The compound of Example 126 (4.00 g) was dissolved in methylene chloride (100 mL),
ルァミン（1.54mL)をカ卩え、 0°Cにてメトキメチルクロリド（710mg)を滴下した。常温まで 1日撹拌後、氷水を反応液に加え酢酸ェチルにて抽出した。無水硫酸ナトリウムにて 乾燥後、溶媒を留去しシリカゲルカラムクロマトグラフィー（へキサン:酢酸ェチル = 2 ： 1)にて精製し目的物 (2.60g)を無色油状物として得た。  Luamine (1.54 mL) was added, and methoxymethyl chloride (710 mg) was added dropwise at 0 ° C. After stirring to room temperature for 1 day, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (2.60 g) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.45(9H, s), 1.90— 2.00(2H, m),  1H-NMR (400MHz, CDC1) δ 1.45 (9H, s), 1.90― 2.00 (2H, m),
3  Three
2.68-2.78(2H, m),3.39(3H, s), 3.54(1H, d, J=9.8Hz), 3.77(2H, d, J=6.1Hz), 3.79(1H, d, J=9.8Hz), 3.99(1H, br), 4.65(2H, s), 5.02(2H, s), 5.20(1H, br s), 6.86-6.94(2H, m), 7.13-7.17(2H, m), 7.22(1H, t, J=8.0Hz), 7.31- 7.40(6H, m).  2.68-2.78 (2H, m), 3.39 (3H, s), 3.54 (1H, d, J = 9.8Hz), 3.77 (2H, d, J = 6.1Hz), 3.79 (1H, d, J = 9.8Hz) ), 3.99 (1H, br), 4.65 (2H, s), 5.02 (2H, s), 5.20 (1H, br s), 6.86-6.94 (2H, m), 7.13-7.17 (2H, m), 7.22 (1H, t, J = 8.0Hz), 7.31-7.40 (6H, m).
[0705] [実施例 264及び 265]  [Examples 264 and 265]
( + )及び (一)—2 t ブトキシカルボ-ルァミノー 4— [4— (3—ベンジルォキシフエ-ル スルファニル）ー2—クロ口フエニル ]ー2—メトキシメチルォキシメチルブタン 1 オール 実施例 263の化合物を高速液体クロマトグラフィー（キラルパック AD-H,へキサン： エタノール = 85： 15、測定波長： UV 254nm、流速： 3mL/min)で光学分割した。  (+) And (I) -2t butoxycarbo-laminol 4- [4- (3-benzyloxyphenylsulfanyl) -2-cyclophenyl] -2-methoxymethyloxymethylbutane 263 compounds were optically resolved by high performance liquid chromatography (Chiralpak AD-H, hexane: ethanol = 85: 15, measurement wavelength: UV 254 nm, flow rate: 3 mL / min).
[0706] 前溶出部分力 無色油状物 (実施例 264)を後溶出部分力 無色油状物（実施例 265)を得た。  A pre-eluting partial strength colorless oil (Example 264) was obtained, and a post-eluting partial strength colorless oil (Example 265) was obtained.
[0707] [実施例 266]  [Example 266]
5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2—ブトキシ カルボニルアミノー 2—メトキシメチルォキシメチルペンタン 1 オール [0708] [化 189] 5— [4 -— (3-Benzyloxyphenol-sulfur) -2-cyclobutane] -2-butoxycarbonylamino-2-methoxymethyloxymethylpentane 1-ol [0708] [Formula 189]
Figure imgf000120_0001
Figure imgf000120_0001
[0709] 実施例 128を用い実施例 263と同様に行い目的物を無色油状物として得た。  [0709] The same procedure as in Example 263 was carried out using Example 128 to obtain the desired product as a colorless oil.
FABMS : 602 ([M+H] .  FABMS: 602 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.43(9H, s), 1.56— 1.68(3H, m), 1 H-NMR (400MHz, CDC1) δ 1.43 (9H, s), 1.56--1.68 (3H, m),
3  Three
1.81- 1.84(1H, m),2.67(2H, t, J=7.8Hz), 3.35(3H, s), 3.46(1H, d, J=9.8Hz), 3.66— 3.68(2H, m), 3.71(1H, d, J=9.8Hz), 4.61(2H, s), 5.02(2H, s), 5.07(1H, br s), 6.87(1H, ddd, J=8.3, 2.5, l.OHz), 6.91— 6.95(3H, m), 7.12-7.16(2H, m), 7.23(1H, t, J=7.8Hz), 7.31— 7.40(6H, m).  1.81- 1.84 (1H, m), 2.67 (2H, t, J = 7.8Hz), 3.35 (3H, s), 3.46 (1H, d, J = 9.8Hz), 3.66― 3.68 (2H, m), 3.71 (1H, d, J = 9.8Hz), 4.61 (2H, s), 5.02 (2H, s), 5.07 (1H, br s), 6.87 (1H, ddd, J = 8.3, 2.5, l.OHz), 6.91-6.95 (3H, m), 7.12-7.16 (2H, m), 7.23 (1H, t, J = 7.8 Hz), 7.31-7.40 (6H, m).
[0710] [実施例 267及び 268] [0710] [Examples 267 and 268]
( + )—5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—プ 口ピル 2 t ブトキシカルボ-ルァミノペンタン— 1 オール及び (一)—5— [4— (3—べ ンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—プロピル 2— t ブトキシ カルボ-ルァミノペンタンー1 オール  (+) —5— [4— (3-Benzyroxyphenol-sulfur-yl) —2-cloth-mouth phyll] —2-p-mouth pill 2 t butoxycarbol-laminopentane—1 all and (1-)-5— [4— (3—benzyloxyphenol-sulfur) —2—chlorophenol] —2-propyl 2-t butoxy carboxy-laminopentane-1 all
[0711] [化 190]  [0711] [Formula 190]
Figure imgf000120_0002
Figure imgf000120_0002
[0712] 実施例 237の化合物を用いて実施例 242と同様に反応させた後、実施例 76と同様 還元した。得られた化合物を高速液体クロマトグラフィー（キラルパック 0D-H, へキサン：エタノール = 97： 3、測定波長： UV 254nm、流速： 3mL/min)で光学分 割した。  [0712] The compound of Example 237 was reacted in the same manner as in Example 242, and then reduced in the same manner as in Example 76. The obtained compound was optically separated by high performance liquid chromatography (Chiral Pack 0D-H, hexane: ethanol = 97: 3, measurement wavelength: UV 254 nm, flow rate: 3 mL / min).
[0713] 前溶出部分から [ a f 1 -10.2° (C = 1.08,クロ口ホルム）の無色油状物を [0713] From the pre-eluted part, a colorless oil at [af 1 -10.2 ° (C = 1.08,
D  D
後溶出部分から [ α ]22·9 +9.48° (C = 1.16,クロ口ホルム）の無色油状物を得た。 FABMS : 570 ([M+H] . A colorless oily substance having [α] 22 · 9 + 9.48 ° (C = 1.16, black form) was obtained from the post-elution portion. FABMS: 570 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 0.90(3H, t, J=7.3Hz), 1.20-1.76(8H,  1H-NMR (400MHz, CDC1) δ 0.90 (3H, t, J = 7.3Hz), 1.20-1.76 (8H,
3  Three
m), 1.42(9H, s), 2.70(2H, t, J=7.3Hz), 3.63— 3.66(2H, m), 4.51(1H, br), 5.02 (2H, s), 6.86— 6.95(3H, m), 7.14-7.15(2H, m), 7.23(1H, d, J=7.8Hz ),  m), 1.42 (9H, s), 2.70 (2H, t, J = 7.3Hz), 3.63− 3.66 (2H, m), 4.51 (1H, br), 5.02 (2H, s), 6.86− 6.95 (3H , m), 7.14-7.15 (2H, m), 7.23 (1H, d, J = 7.8Hz),
7.33-7.4K6H, m).  7.33-7.4K6H, m).
[0714] [実施例 269— 270]  [0714] [Example 269-270]
ジメチルプロパギルマロン酸エステル、ジェチルイソブチルマロン酸エステルを用い て実施例 229と同様に反応させ、表 16に示した化合物を合成した。  The compounds shown in Table 16 were synthesized by reacting in the same manner as in Example 229 using dimethylpropargylmalonate and getylisobutylmalonate.
[0715] [表 16]  [0715] [Table 16]
Figure imgf000121_0001
Figure imgf000121_0001
MS(EI)  MS (EI)
実施例 R R, 性状  Example R R, Properties
M+  M +
269 -CH2CCH Me 無色油状物 536 269 -CH 2 CCH Me colorless oil 536
270 i-Bu Et 無色油状物 583*  270 i-Bu Et colorless oil 583 *
* FABMS[M+H]+ * FABMS [M + H] +
[0716] [実施例 271] [0716] [Example 271]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—ヒドロキ シメチルー 2—プロパルギルペンタン酸メチル  5- [4- (3-Benzyloxyphenyl-sulfur-yl) -2-cyclophenol] -2-hydroxymethyl-2-propargylpentanoate
[0717] [化 191] [0717] [Formula 191]
Figure imgf000121_0002
Figure imgf000121_0002
[0718] 実施例 269の化合物（1.64g)を THF (40mL)に溶解し、氷冷下、 LiAl(OtBu)3H [0718] The compound of Example 269 (1.64 g) was dissolved in THF (40 mL), and LiAl (OtBu) 3H was added under ice-cooling.
(3.88g)を加え撹拌。その後常温までゆるやかに昇温し 2日間撹拌した。再度氷冷し、 希塩酸を加えた後、不溶物を濾去し酢酸ェチルで抽出した。飽和食塩水にて洗浄 後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残渣をシリカゲルカラムクロ マトグラフィー（へキサン：酢酸ェチル = 2： 1)にて精製し、 目的物（1.12g)を無色油状 物として得た。 (3.88 g) and stirred. Thereafter, the temperature was gradually raised to room temperature, and the mixture was stirred for 2 days. After cooling again with ice and adding dilute hydrochloric acid, the insolubles were filtered off and extracted with ethyl acetate. After washing with a saturated saline solution, the solution was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the desired product (1.12 g) as a colorless oil Obtained as a product.
FABMS : 508 ([M+H] .  FABMS: 508 ([M + H].
[0719] [実施例 272] [0719] [Example 272]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—イソブ チルー 2—ヒドロキシメチルペンタン酸ェチル  5- [4- (3-Benzyloxyphenylsulfur) -2-cyclobutane] -2-isobutyl-2-ethyl methyl hydroxypentanoate
[0720] [化 192] [0720] [Formula 192]
Figure imgf000122_0001
Figure imgf000122_0001
[0721] 実施例 270の化合物を用い、上記実施例 271と同様に反応させ目的物を無色油状 物として得た。 [0721] The compound of Example 270 was reacted in the same manner as in Example 271 to give the desired product as a colorless oil.
MS(EI) : 540 [M]+ MS (EI): 540 [M] +
1H-NMR(400MHz, CDC1 ) δ 0.85(3H, d, J=6.7Hz), 0.86(3H, d, 1 H-NMR (400MHz, CDC1) δ 0.85 (3H, d, J = 6.7Hz), 0.86 (3H, d,
3  Three
J=6.7Hz), 1.26(3H, t,J=7.3Hz), 1.45-1.77(7H, m), 2.16(1H, t, J=6.7Hz), 2.68(2H, t, J=7.3Hz), 3.60(1H, dd, J=11.6Hz, 6.7Hz), 3.78(1H, dd, J=11.6Hz, 6.7Hz), 4.11-4.17(2H, m), 5.02 (2H, s), 6.85— 6.94(3H, m), 7.12-7.17(2H, m), 7.22(1H, t, J=7.8Hz ), 7.30-7.40(6H, m).  J = 6.7Hz), 1.26 (3H, t, J = 7.3Hz), 1.45-1.77 (7H, m), 2.16 (1H, t, J = 6.7Hz), 2.68 (2H, t, J = 7.3Hz) , 3.60 (1H, dd, J = 11.6Hz, 6.7Hz), 3.78 (1H, dd, J = 11.6Hz, 6.7Hz), 4.11-4.17 (2H, m), 5.02 (2H, s), 6.85― 6.94 (3H, m), 7.12-7.17 (2H, m), 7.22 (1H, t, J = 7.8Hz), 7.30-7.40 (6H, m).
[0722] [実施例 273]  [0722] [Example 273]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—メトキシ メチルォキシメチルー 2—プロパルギルペンタン酸メチル  5- [4- (3-Benzyloxyphenyl-sulfur-yl) -2-cyclomethyl] -2-methoxymethyloxymethyl-2-propargylpentanoate
[0723] [化 193]  [0723] [Formula 193]
Figure imgf000122_0002
Figure imgf000122_0002
[0724] 実施例 271の化合物（1.12g)をァセトニトリル (30mL)に溶解し、氷冷撹拌下、ジイソ プロピルァミン（0.58mL)、 MOMCl(0.25mL)をカ卩えた。ー晚撹拌し、水を加えた後酢 酸ェチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒 を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（へキサン:酢酸ェチル = 5 : 1) にて精製し、目的物（1.12g)を無色油状物として得た。 [0724] The compound of Example 271 (1.12 g) was dissolved in acetonitrile (30 mL), and diisopropylamine (0.58 mL) and MOMCl (0.25 mL) were added thereto under ice-cooling and stirring. The mixture was stirred, added with water, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. solvent After concentration, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired product (1.12 g) as a colorless oil.
MS(EI) : 552 [M]+ MS (EI): 552 [M] +
1H-NMR(400MHz, CDCl ) δ 1.45— 1.50(1H, m), 1.59— 1.73(3H,  1H-NMR (400MHz, CDCl) δ 1.45― 1.50 (1H, m), 1.59― 1.73 (3H,
3  Three
m), 1.94(1H, t, J=2.4Hz), 2.56— 2.73(4H, m), 3.33(3H, s), 3.57-3.74(5H, m), m), 1.94 (1H, t, J = 2.4Hz), 2.56-2.73 (4H, m), 3.33 (3H, s), 3.57-3.74 (5H, m),
4.59(2H, s), 5.02 (2H, s), 6.85— 6.94(3H, m), 7.10- 7.16(2H, m), 7.22(1H, t,4.59 (2H, s), 5.02 (2H, s), 6.85- 6.94 (3H, m), 7.10- 7.16 (2H, m), 7.22 (1H, t,
J=7.9Hz ), 7.32-7.39(6H, m). J = 7.9Hz), 7.32-7.39 (6H, m).
[0725] [実施例 274] [0725] [Example 274]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—イソブ チルー 2—メトキシメチルォキシメチルペンタン酸ェチル  5- [4- (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -2-isobutyl-2-ethyl methoxymethyloxymethylpentanoate
[0726] [化 194] [0726] [Formula 194]
Figure imgf000123_0001
Figure imgf000123_0001
[0727] 実施例 272の化合物を用い、上記実施例 273と同様に反応させ目的物を黄色油状 物として得た。  [0727] The compound of Example 272 was reacted in the same manner as in the above Example 273 to give the desired product as a yellow oil.
MS(EI) : 584 [M]+ MS (EI): 584 [M] +
1H-NMR(400MHz, CDCl ) δ 0.83(3H, d, J=6.8Hz), 0.85(3H, d, 1 H-NMR (400 MHz, CDCl) δ 0.83 (3H, d, J = 6.8 Hz), 0.85 (3H, d,
3  Three
J=6.8Hz), 1.24(3H, t,J=7.3Hz), 1.45-1.76(7H, m), 2.69(2H, t, J=7.3Hz), 3.32(3H, s), 3.57(1H, d, J=9.8Hz), 3.65(1H, d, J=9.8Hz), 4.08-4.14(2H, m), 4.57(2H, s), 5.02 (2H, s), 6.85— 6.95(3H, m), 7.11- 7.16(2H, m), 7.22(1H, t, J=7.8Hz ), 7.30-7.4K6H, m).  J = 6.8Hz), 1.24 (3H, t, J = 7.3Hz), 1.45-1.76 (7H, m), 2.69 (2H, t, J = 7.3Hz), 3.32 (3H, s), 3.57 (1H, d, J = 9.8Hz), 3.65 (1H, d, J = 9.8Hz), 4.08-4.14 (2H, m), 4.57 (2H, s), 5.02 (2H, s), 6.85-6.95 (3H, m ), 7.11- 7.16 (2H, m), 7.22 (1H, t, J = 7.8Hz), 7.30-7.4K6H, m).
[0728] [実施例 275] [0728] [Example 275]
5- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—メトキシ メチルォキシメチルー 2—プロパルギルペンタン酸 'PP 'Ηΐ)98·9 '(s 'ΗΖ) 10'S '(s 'HS)8S' '(zHS'6=f 'P 'HT)S9"S 6=1" 'P Ήΐ)93·ε '(s '蹄 S'S '(ZHS- =f 'HS)69 '(^ 'HL)W\-LV\ '(zH8"9=f 5- [4- (3-Benzyloxyphenyl-sulfur-yl) -2-cyclobutyryl]-2-methoxymethyloxymethyl-2-propargylpentanoic acid 'PP' Ηΐ) 989 '( s ' ΗΖ) 10'S '(s' HS) 8S ''(zHS'6 = f 'P' HT) S9 "S 6 = 1"'P Ήΐ) 93 · ε' (s 'Hoof S'S' ( Z HS- = f 'HS) 69' (^ 'HL) W \ -LV \' ( z H8 "9 = f
'Ρ Ήε)38 '(zH8"9=f 'P 'HS)S8 9 ( \DQD <zH OO^)H N-HT 'Ρ Ήε) 38' (zH8 "9 = f 'P' HS) S8 9 (\ DQD <z H OO ^) H NH T
· [Η+ ]) 9SS ：  · [Η +]) 9SS:
Figure imgf000124_0001
Figure imgf000124_0001
^-Ζ- Λ(—-^ ^-Z- ( -ェ ^^ べ:^— ε)— ] -9  ^ -Ζ- Λ (—- ^ ^ -Z- (-e ^^ be: ^ — ε) —] -9
Ήϊ)ΖΖΊ '(ΖΗ8·ΐ 'ΡΡ Ήΐ)3 'Ρ Ήΐ)ΐΓΖ '(ω 'HS)S6"9-S8"9 Ήϊ) ΖΖΊ '(ΖΗ8 · ΐ' ΐ Ήΐ) 3 'Ρ Ήΐ) ΐΓΖ' (ω 'HS) S6 "9-S8" 9
'(s 'm
Figure imgf000124_0002
)w '(s 'm f Ήΐ)εζ·ε '(ΖΗ8·6=1" 'Ρ Ήΐ)69·ε '( s ' m
Figure imgf000124_0002
) w '( s ' mf Ήΐ) εζε '(ΖΗ8ΖΗ6 = 1 "' Ρ Ήΐ) 6969ε
'(s Ήε)εε·ε '(ω Ήε)εζ — 89
Figure imgf000124_0003
'(s Ήε) εε · ε' (ω Ήε) εζ — 89
Figure imgf000124_0003
' 'Ηΐ)96·ΐ '(ω 'Η )ΖΖ·ΐ- SS'I 9 ( \DQD <zH 00^)H N-HT '' Ηΐ) 96ΐ ΐ '(ω' Η) ΖΖΖΖΐ- SS'I 9 (\ DQD <z H 00 ^) H NH T
χη] see :(m)S つ;呦^ «^¾¾(s6(n)呦 目 辛恩 瀚缀 χη] see: (m) S 呦; 呦 ^ «^ ¾¾ ( s 6 (n) 呦
[οεζο]
Figure imgf000124_0004
[οεζο]
Figure imgf000124_0004
[36ΐ^ ] [62Z0] 請 OOZdf/ェ:) d 831- J=8.6Hz, 2.4Hz), 6.90— 6.94(2H, m),7.11-7.16(2H, m), 7.22(1H, t, J=7.8Hz ),[36ΐ ^] [62Z0] OOZdf / e :) d 831- J = 8.6Hz, 2.4Hz), 6.90― 6.94 (2H, m), 7.11-7.16 (2H, m), 7.22 (1H, t, J = 7.8Hz),
7.30-7.40(6H, m). 7.30-7.40 (6H, m).
[0734] [実施例 277] [0734] [Example 277]
7- [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] 4ーメトキシ カルボニルアミノー 4ーメトキシメチルォキシメチルー 1 ヘプチン  7- [4 -— (3-Benzyloxyphenylsulfur) -2-cyclobutane] 4-methoxycarbonylamino-4-methoxymethyloxymethyl-1 heptin
[0735] [化 197] [0735] [Formula 197]
Figure imgf000125_0001
Figure imgf000125_0001
[0736] 実施例 275の化合物を用い実施例 240と同様に反応させ、目的物を無色油状物とし て得た。 [0736] The same procedures used in Example 240 were carried out except for using the compound of Example 275, to give the desired product as a colorless oil.
FABMS : 568 ([M+H] .  FABMS: 568 ([M + H].
NMR(400MHz, CDC1 ) δ 1.57— 1.66(2H, m), 1.85— 1.93(1Η,  NMR (400MHz, CDC1) δ 1.57- 1.66 (2H, m), 1.85- 1.93 (1Η,
3  Three
m), 1.99(1H, t, J=2.4Hz), 2.00— 2.05(1H, m), 2.64— 2.75(4H, m), 3.35(3H, s), 3.61(3H, s), 3.62(1H, d, J=9.8Hz), 3.71(1H, d, J=9.8Hz), 4.61(2H, s), 4.92(1H, s), 5.01(2H, s), 6.85— 6.94(3H, m), 7.12-7.17(2H, m), 7.22(1H, t, J=7.9Hz), 7.30-7.40(6H, m).  m), 1.99 (1H, t, J = 2.4Hz), 2.00― 2.05 (1H, m), 2.64― 2.75 (4H, m), 3.35 (3H, s), 3.61 (3H, s), 3.62 (1H , d, J = 9.8Hz), 3.71 (1H, d, J = 9.8Hz), 4.61 (2H, s), 4.92 (1H, s), 5.01 (2H, s), 6.85― 6.94 (3H, m) , 7.12-7.17 (2H, m), 7.22 (1H, t, J = 7.9Hz), 7.30-7.40 (6H, m).
[0737] [実施例 278]  [Example 278]
7— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル] 4ーメトキシ カルボニルアミノー 4ーメトキシメチルォキシメチルー 2 メチルヘプタン  7— [4 -— (3-benzyloxyphenylsulfur) -2-chlorophenol] 4-methoxycarbonylamino-4-methoxymethyloxymethyl-2-methylheptane
[0738] [化 198]  [0738] [Formula 198]
Figure imgf000125_0002
Figure imgf000125_0002
[0739] 実施例 276の化合物を用い実施例 240と同様に反応させ、目的物を黄色油状物とし て得た。  [0739] The compound of Example 276 was reacted in the same manner as in Example 240 to give the desired product as a yellow oil.
MS(EI) : 585 [M]+ 1H-NMR(400MHz, CDC1 ) δ 0.91(3H, d, J=6.8Hz), 0.92(3H, d, MS (EI): 585 [M] + 1H-NMR (400MHz, CDC1) δ 0.91 (3H, d, J = 6.8Hz), 0.92 (3H, d,
3  Three
J=6.8Hz), 1.58-1.82(7H, m), 2.68(2H, t, J=7.3Hz), 3.34(3H, s), 3.56(3H, s), 3.78(1H, d, J=11.0Hz), 3.87(1H, d, J=11.0Hz), 4.59(2H, s), 4.70(1H, s),  J = 6.8Hz), 1.58-1.82 (7H, m), 2.68 (2H, t, J = 7.3Hz), 3.34 (3H, s), 3.56 (3H, s), 3.78 (1H, d, J = 11.0 Hz), 3.87 (1H, d, J = 11.0Hz), 4.59 (2H, s), 4.70 (1H, s),
5.02(2H, s), 6.82-6.94(3H, m), 7.11-7.14(2H, m), 7.17-7.24(1H, m),  5.02 (2H, s), 6.82-6.94 (3H, m), 7.11-7.14 (2H, m), 7.17-7.24 (1H, m),
7.32-7.39(6H, m).  7.32-7.39 (6H, m).
[0740] [実施例 279]  [Example 279]
5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2 tーブトキ シカルボニルアミノー 2—メトキシメチルォキシメチルペンタナール  5- [4- (3- (benzyloxyphenyl) sulfur] -2-cyclobutane] -2 t-butoxycarbonylamino-2-methoxymethyloxymethylpentanal
[0741] [化 199]  [0741] [Formula 199]
Figure imgf000126_0001
Figure imgf000126_0001
[0742] 実施例 266の化合物を用い、実施例 225と同様にして酸化し、目的物を無色油状物 として得た。 Using the compound of Example 266, oxidation was carried out in the same manner as in Example 225 to obtain the desired product as a colorless oil.
FABMS : 600 ([M+H] .  FABMS: 600 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.43(9H, s), 1.54— 1.60(2H, m), 1 H-NMR (400MHz, CDC1) δ 1.43 (9H, s), 1.54-1.60 (2H, m),
3  Three
1.77-1.84(1H, m), 2.00-2.15(1H, m), 2.68(2H, t, J=7.3Hz), 3.30(3H, s), 3.78(1H, d, J=9.8Hz), 3.98(1H, d, J=9.8Hz), 4.57(2H, s), 5.02(2H, s), 5.39(1H, br), 6.86— 6.95(3H, m), 7.07-7.14(2H, m), 7.21-7.39(7H, m), 9.40(1H, s).  1.77-1.84 (1H, m), 2.00-2.15 (1H, m), 2.68 (2H, t, J = 7.3Hz), 3.30 (3H, s), 3.78 (1H, d, J = 9.8Hz), 3.98 (1H, d, J = 9.8Hz), 4.57 (2H, s), 5.02 (2H, s), 5.39 (1H, br), 6.86-6.95 (3H, m), 7.07-7.14 (2H, m), 7.21-7.39 (7H, m), 9.40 (1H, s).
[0743] [実施例 280]  [Example 280]
7— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル] 4 tーブトキ シカルボニルアミノー 4ーメトキシメチルォキシメチルー 3—ヘプテン  7— [4— (3-Benzyloxyphenylsulfur) -2-cyclobutane] 4-t-butoxycarbonylamino-4-methoxymethyloxymethyl-3-heptene
[0744] [化 200]  [0744] [Formula 200]
Figure imgf000126_0002
Figure imgf000126_0002
[0745] EtPh PI (906mg)を THF (20mL)に溶解し、アルゴンガス下、 - 78。Cに冷却し LDA ( 2.20mL)をカロえ 10分撹拌した。いったん 0°Cで 5分撹拌した後再度- 78°Cに冷却し、 上記実施例 279の化合物（l.OOg)の THF (lOmL)溶液を滴下した。- 78°Cにて 1時間 、常温にて 1時間撹拌した後、水を加え酢酸ェチルで抽出後、飽和食塩水で洗浄し 、無水硫酸マグネシウムで乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマト グラフィー（へキサン：酢酸ェチル =4： 1)にて精製し、 目的物（172mg)を黄色油状物 として得た。 [0745] EtPh PI (906 mg) was dissolved in THF (20 mL) and under argon gas -78. Cool to C and LDA ( 2.20 mL) and stirred for 10 minutes. Once stirring at 0 ° C for 5 minutes, the mixture was cooled again to -78 ° C, and a solution of the compound of Example 279 (l.OOg) in THF (lOmL) was added dropwise. After stirring at -78 ° C for 1 hour and at room temperature for 1 hour, water was added, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (172 mg) as a yellow oil.
FABMS : 612 ([M+H] .  FABMS: 612 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.41(9H, s), 1.60— 1.66(2H, m), 1 H-NMR (400MHz, CDC1) δ 1.41 (9H, s), 1.60― 1.66 (2H, m),
3  Three
1.74(3H, dd, J=7.3Hz, 1.8Hz), 1.89— 1.93(2H, m), 2.69(2H, t, J=8.0Hz), 3.34(3H, s), 3.64(1H, d, J=9.2Hz), 3.71(1H, d, J=9.2Hz), 4.60(2H, s), 4.83(1H, br),  1.74 (3H, dd, J = 7.3Hz, 1.8Hz), 1.89― 1.93 (2H, m), 2.69 (2H, t, J = 8.0Hz), 3.34 (3H, s), 3.64 (1H, d, J = 9.2Hz), 3.71 (1H, d, J = 9.2Hz), 4.60 (2H, s), 4.83 (1H, br),
5.02(2H, s), 5.30(1H, br d, J=12.2Hz), 5.54— 5.57(1H, m), 6.86(1H, dd, J=8.0Hz, 2.4Hz), 6.91-6.94(2H, m), 7.11- 7.16(2H, m), 7.22(1H, t, J=7.9Hz), 7.30- 7.41(6H, m).  5.02 (2H, s), 5.30 (1H, br d, J = 12.2Hz), 5.54-5.57 (1H, m), 6.86 (1H, dd, J = 8.0Hz, 2.4Hz), 6.91-6.94 (2H, m), 7.11- 7.16 (2H, m), 7.22 (1H, t, J = 7.9Hz), 7.30- 7.41 (6H, m).
[0746] [実施例 281]  [Example 281]
5- [4— (3—ベンジルォキシフエ-ルスルフィエル）—2—クロ口フエ-ル]— 2 t ブト キシカルボ-ルァミノペンタン 1 オール  5- [4— (3-benzyloxyphenol-sulfiel) —2-chlorophenol] —2 t butoxycarbol-laminopentane 1 all
[0747] [化 201] [0747] [Formula 201]
Figure imgf000127_0001
Figure imgf000127_0001
[0748] 実施例 129の化合物（1.20g)の塩化メチレン (20mL)溶液に、 m-クロ口過安息香酸（ 588mg)を氷冷下にて加え 30分撹拌した。反応液に飽和重曹水を加えたのち溶媒を 減圧留去し、酢酸ェチルで抽出し飽和食塩水で洗い、無水硫酸ナトリウムで乾燥後 濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸ェチル [0748] To a solution of the compound of Example 129 (1.20 g) in methylene chloride (20 mL) was added m-chloroperbenzoic acid (588 mg) under ice-cooling, followed by stirring for 30 minutes. After a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the solvent was distilled off under reduced pressure, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate).
：へキサン = 2： 1)で精製したところ、実施例 281を無色アモルファス（1.04g)及び実 施例 282を無色アモルファス（180mg)として得た。  : Hexane = 2: 1) to give Example 281 as colorless amorphous (1.04 g) and Example 282 as colorless amorphous (180 mg).
FABMS: 544([M+H]+). FABMS: 544 ([M + H] + ).
1H-NMR(400MHz, CDC1 ) δ 1.43(9Η, s), 1.54— 1.69(5Η, m), 2.72-2.78(2H, m), 3.52— 3.57(1H, m), 3.67(2H, d, J=8.5Hz), 4.63(1H, br), 1 H-NMR (400MHz, CDC1) δ 1.43 (9Η, s), 1.54- 1.69 (5Η, m), 2.72-2.78 (2H, m), 3.52― 3.57 (1H, m), 3.67 (2H, d, J = 8.5Hz), 4.63 (1H, br),
5.10(1H, s), 7.05(1H, dd, J=8.6Hz, 2.0Hz), 7.19(1H, d, J=7.9Hz), 7.26- 7.30(2H, m), 7.31-7.42(7H, m), 7.60(1H, d,J=1.2Hz).  5.10 (1H, s), 7.05 (1H, dd, J = 8.6Hz, 2.0Hz), 7.19 (1H, d, J = 7.9Hz), 7.26- 7.30 (2H, m), 7.31-7.42 (7H, m ), 7.60 (1H, d, J = 1.2Hz).
[0749] [実施例 282] [0749] [Example 282]
5- [4— (3—ベンジルォキシフエ-ルスルホ -ル）—2 クロ口フエ-ル]— 2 tーブトキ シカルボ-ルァミノペンタン 1 オール  5- [4- (3-Benzyloxyphenol-sulfol) -2-cyclobutane]-2-t butoxycarbaluminaminopentane 1 all
[0750] [化 202]
Figure imgf000128_0001
[0750] [Formula 202]
Figure imgf000128_0001
[0751] 実施例 281参照。無色アモルファス。 [0751] See Example 281. Colorless amorphous.
FABMS: 560([M+H] .  FABMS: 560 ([M + H].
1H-NMR(400MHz, CDC1 ) δ 1.43(9Η, s), 1.54-1.70(5Η, m),  1H-NMR (400MHz, CDC1) δ 1.43 (9Η, s), 1.54-1.70 (5Η, m),
3  Three
2.73-2.8Κ2Η, m), 3.53— 3.57(1Η, m), 3.67(2Η, d, J=8.5Hz), 4.62(1H, br),  2.73-2.8Κ2Η, m), 3.53― 3.57 (1Η, m), 3.67 (2Η, d, J = 8.5Hz), 4.62 (1H, br),
5.10(1H, s), 7.15-7.18(1H, m), 7.32-7.44(7H, m), 7.52(2H, m, J=6.6Hz, 1.2Hz), 5.10 (1H, s), 7.15-7.18 (1H, m), 7.32-7.44 (7H, m), 7.52 (2H, m, J = 6.6Hz, 1.2Hz),
7.68(1H, dd, J=8.6Hz, 1.8Hz), 7.87(1H, d, J=1.9Hz). 7.68 (1H, dd, J = 8.6Hz, 1.8Hz), 7.87 (1H, d, J = 1.9Hz).
[0752] [実施例 283] [0752] [Example 283]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]プロピル 4 シァノメチルー 2—ォキサゾリジノン  4— [4— (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] propyl 4-cyanomethyl-2-oxazolidinone
[0753] [化 203] [0753] [Formula 203]
Figure imgf000128_0002
Figure imgf000128_0002
[0754] 氷冷下、実施例 213の化合物（610 mg)のァセトニトリル (8 mL)溶液にトリェチルァ ミン（0.35mL)及びメタンスルホユルクロリド  [0754] Under ice cooling, a solution of the compound of Example 213 (610 mg) in acetonitrile (8 mL) was added to triethylamine (0.35 mL) and methanesulfoyl chloride.
(0.13mL)をカ卩ぇ 15分間撹拌した。反応液に水を加えた後、酢酸ェチルと飽和食塩 水を用いて分液し、有機層を無水硫酸ナトリウムで乾燥させた後に濃縮し、黄色油状 の O -メシル体を得た。得られたメシル体を DMF (0.13 mL) was stirred for 15 minutes. After water was added to the reaction solution, liquid separation was performed using ethyl acetate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate and then concentrated to a yellow oil O-mesyl form was obtained. The obtained mesyl form is converted to DMF
(2.5 mL)に溶解させた後、シアンィ匕カリウム（246 mg)をカ卩ぇ 70°Cで 2時間撹拌した。 反応液を常温にもどした後、飽和炭酸水素ナトリゥム水溶液と酢酸ェチルを用 、て分 液し、有機層を無水硫酸ナトリウムで乾燥させた後に濃縮した。残查をシリカゲルカラ ムクロマトグラフィー（へキサン:酢酸ェチル = 1： 1)により精製し、 目的物 (574mg)を無 色アモルファスとして得た。  (2.5 mL), and potassium cyanide (246 mg) was stirred at 70 ° C for 2 hours. After the reaction solution was returned to room temperature, liquid separation was performed using a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product (574 mg) as a colorless amorphous.
1H-NMR(400MHz, CDC1 ) δ 1.63—1.72 (2Η, m), 1.78—1.91 (2H, 1 H-NMR (400MHz, CDC1) δ 1.63-1.72 (2Η, m), 1.78-1.91 (2H,
3  Three
m), 2.67 (2H, s), 2.73(2H, t, J=7.3Hz), 4.21 (2H, d, J=9.5Hz), 5.03 (2H, s), m), 2.67 (2H, s), 2.73 (2H, t, J = 7.3Hz), 4.21 (2H, d, J = 9.5Hz), 5.03 (2H, s),
5.33 (1H, br), 6.89— 6.91(1H, m), 6.95—6.97 (2H, m), 7.09-7.16 (2H, m), 5.33 (1H, br), 6.89—6.91 (1H, m), 6.95—6.97 (2H, m), 7.09-7.16 (2H, m),
7.22-7.25 (1H, m), 7.27-7.42(6H,m).  7.22-7.25 (1H, m), 7.27-7.42 (6H, m).
[0755] [実施例 284] [0755] [Example 284]
5- [4— (3—ベンジルォキシフエノキシ） 2 クロ口フエ-ル]— 2— t ブトキシカノレボ ニルアミノー 2— tーブチルジフエニルシロキシメチルペンタン酸メチル  5- [4- (3-Benzyloxyphenoxy) 2 chlorophenol] — 2-t Butoxycanolebonylamino-2-methyl t-butyldiphenylsiloxymethylpentanoate
[0756] [化 204] [0756] [Formula 204]
Figure imgf000129_0001
Figure imgf000129_0001
[0757] 実施例 224の化合物（780mg)をアセトン (8mL)に溶解し、 0°Cにて撹拌下、ジヨーン ズ試薬（1.5mL)をゆっくりと滴下した。 5時間後、水を加え酢酸ェチルで抽出し水、飽 和食塩水の順で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し残渣を DMF (lOmL)に溶解し、炭酸カリウム（500mg)、ヨウ化メチル（0.5mL)をカ卩ぇ 1晚撹拌 した。反応液に水を加え、酢酸ェチルで抽出し、水、飽和食塩水の順に洗浄後、無 水硫酸ナトリウムで乾燥した。溶媒を濃縮後、残渣をシリカゲルカラムクロマトグラフィ 一（へキサン：酢酸ェチル =4： 1)にて精製し目的物（360mg)を淡褐色油状物として 得た。 [0757] The compound of Example 224 (780 mg) was dissolved in acetone (8 mL), and a dione's reagent (1.5 mL) was slowly added dropwise at 0 ° C with stirring. Five hours later, water was added, extracted with ethyl acetate, washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in DMF (10 mL), and potassium carbonate (500 mg) and methyl iodide (0.5 mL) were stirred in potassium hydroxide (1 mL). Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired product (360 mg) as a pale brown oil.
1H-NMR(400MHz, CDC1 ) δ 0.90(9H, s), 1.44(9H, s), 1 H-NMR (400 MHz, CDC1) δ 0.90 (9H, s), 1.44 (9H, s),
3  Three
1.57-1.66(4H, m), 2.62(2H, br s), 3.73(3H, s), 3.81(1H, d, J=9.8Hz), 4.29(1H, br), 5.03(2H, s), 5.73(1H, br s), 6.58(1H, dd, J=8.3Hz, 2.4Hz), 6.61(1H, t, J=2.4Hz), 6.74(1H, dd, J=8.3Hz, 2.4Hz), 6.81(1H, dd, J=8.3Hz, 2.4Hz), 6.97(1H, d, J=2.4Hz), 7.08(1H, d, J=8.3Hz), 7.22(1H, t, J=8.3Hz), 7.30- 7.46(11H, m), 7.58-7.6K4H, m). 1.57-1.66 (4H, m), 2.62 (2H, br s), 3.73 (3H, s), 3.81 (1H, d, J = 9.8Hz), 4.29 (1H, br), 5.03 (2H, s), 5.73 (1H, br s), 6.58 (1H, dd, J = 8.3Hz, 2.4Hz), 6.61 (1H, t, J = 2.4Hz), 6.74 (1H, dd , J = 8.3Hz, 2.4Hz), 6.81 (1H, dd, J = 8.3Hz, 2.4Hz), 6.97 (1H, d, J = 2.4Hz), 7.08 (1H, d, J = 8.3Hz), 7.22 (1H, t, J = 8.3Hz), 7.30-7.46 (11H, m), 7.58-7.6K4H, m).
[0758] [実施例 285— 289]  [Example 285-289]
参考例 324、 325、 329— 331を用い、実施例 1と同様にして反応させマロン酸エステ ル体を合成後、実施例 76と同様にして還元し、表 17に示す化合物を合成した。  Using Reference Examples 324, 325, and 329-331, the reaction was carried out in the same manner as in Example 1 to synthesize an ester malonate, and then reduced in the same manner as in Example 76 to synthesize the compounds shown in Table 17.
[0759] [表 17] 表 17  [0759] [Table 17] Table 17
NHBOC  NHBOC
'ΟΗ 'ΟΗ
Figure imgf000130_0001
Figure imgf000130_0001
OH  OH
窠施例 Ri R2 X n 性状 窠 Example Ri R 2 X n
285 a-CF3 CI 0 3 無色粉末 504 285 a-CF 3 CI 0 3 Colorless powder 504
286 b-CF3 CI 0 2 無色油状物 490 286 b-CF 3 CI 0 2 Colorless oil 490
287 c-CF3 CI 0 3 無色粉末 504 287 c-CF 3 CI 0 3 Colorless powder 504
288 c-PhCHzO CI S 2 無色油状物 543 288 c-PhCH z O CI S 2 colorless oil 543
289 b-PhCH20 CF3 S 2 無色油状物 578 289 b-PhCH 2 0 CF 3 S 2 Colorless oil 578
[0760] [実施例 290— 298] [Example 290-298]
表 17の化合物及び実施例 76、実施例 126、実施例 130、実施例 136、実施例 149の 化合物を用い、実施例 213と同様に反応させた後、引き続き実施例 283と同様に反応 させ表 18に示す化合物を合成した。  Using the compounds of Table 17 and the compounds of Example 76, Example 126, Example 130, Example 136, and Example 149, the reaction was carried out in the same manner as in Example 213, and then the reaction was carried out in the same manner as in Example 283. The compound shown in 18 was synthesized.
[0761] [表 18] [0761] [Table 18]
表 18
Figure imgf000131_0001
Table 18
Figure imgf000131_0001
S  S
R2 X n FABM 実施例 Ri 性状 R 2 X n FABM Example Ri Properties
[Μ+Η]+ [Μ + Η] +
290 a-CF3 CI 0 3 無色油状物 439 290 a-CF 3 CI 03 Colorless oil 439
291 b-CF3 し I 無色,由 1X Μ15π) 291 b-CF 3し I colorless, free 1X Μ15π)
292 C-CF3 CI o 3 無色油状物 439 292 C-CF 3 CI o 3 Colorless oil 439
293 c-PhCH20 CI s 2 無色油状物 479 293 c-PhCH 2 0 CI s 2 Colorless oil 479
294 b-PhCH20 CF3 s 2 無色油状物 521* 294 b-PhCH 2 0 CF 3 s 2 Colorless oil 521 *
295 b-PhCH20 CI s 2 無色アモルファス 295 b-PhCH 2 0 CI s 2 Colorless amorphous
296 b-PhCH20 CI s 4 無色油状物 296 b-PhCH 20 CIs 4 colorless oil
297 b-CF3 CI 0 3 無色油状物 439 297 b-CF 3 CI 03 Colorless oil 439
298 b,d-bisCF3 CI s 3 淡黄色アモルファス 523 298 b, d-bisCF 3 CI s 3 pale yellow amorphous 523
299 b-CF3 CI s 3 無色油状物 455 299 b-CF 3 CI s 3 Colorless oil 455
[Μ-Η]+ [Μ-Η] +
[0762] [実施例 300] [0762] [Example 300]
4—ヒドロキシメチルー 4一（4ーォクチルフエ-ル）ェチルー 2 ォキサ  4-Hydroxymethyl- 4- (2-octylphenyl) ethyl 2-oxa
[0763] [化 205] [0763] [Formula 205]
Figure imgf000131_0002
Figure imgf000131_0002
[0764] FTY-720 (J. Med. Chem., 43, 2946 (2000)記載）を Boc 0にて Boc化後、実施例 [0764] FTY-720 (described in J. Med. Chem., 43, 2946 (2000)) was converted to Boc at Boc 0, and
2  2
213と同様に反応させ目的物を無色粉末として得た。  The reaction was carried out in the same manner as in 213 to obtain the desired product as colorless powder.
1H-NMR(400MHz, CDC1 ) δ 0.87(3H, t, J=6.7Hz),  1H-NMR (400MHz, CDC1) δ 0.87 (3H, t, J = 6.7Hz),
3  Three
1.24— 1.33(10H, m), 1.54— 1.62(2H m), 1.86— 2.01(2H m)， 2.42(1H, br), 2.56(2H t, J=8.2Hz), 2.65(2H, t J=8.2Hz), 3.57(1H, d, J=11.0Hz), 3.67(1H, d,  1.24-1.33 (10H, m), 1.54-1.62 (2H m), 1.86-2.01 (2H m), 2.42 (1H, br), 2.56 (2H t, J = 8.2Hz), 2.65 (2H, t J = 8.2Hz), 3.57 (1H, d, J = 11.0Hz), 3.67 (1H, d,
J=11.0Hz), 4.15(1H, d, J=9.2Hz), 4.30(1H, d, J=9.2Hz), 5.53(1H, br), 7.08(2H, d, J=8.6Hz), 7.11(2H, d, J=8.6Hz).  J = 11.0Hz), 4.15 (1H, d, J = 9.2Hz), 4.30 (1H, d, J = 9.2Hz), 5.53 (1H, br), 7.08 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 8.6Hz).
[0765] [実施例 301] [Example 301]
4ーシァノメチルー 4 (4一才クチルフエ-ル）ェチルー 2 ォキサゾリジノン [0766] [化 206] 4-cyanomethyl-4 (4-year-old octylphenol) ethyl 2-oxazolidinone [0766] [Formula 206]
Figure imgf000132_0001
Figure imgf000132_0001
[0767] 実施例 300の化合物を用い、実施例 283と同様に反応させ目的物を無色油状物とし て得た。 [0767] Using the compound of Example 300, the reaction was carried out in the same manner as in Example 283 to obtain the desired product as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 0.88(3H， t, J=6.7Hz), 1 H-NMR (400MHz, CDC1) δ 0.88 (3H, t, J = 6.7Hz),
3  Three
1.19— 1.31(10H， m)， 1.53- 1.63(2H, m)， 2.07-2.19(2H, m), 2.57(2H, t, J=8.0Hz), 2.64-2.77(4H, m)， 4.24(1H, d, J=9.6Hz), 4.26(1H, d, J=9.6Hz)， 5.83(1H, br), 7.09(2H, d, J=8.0Hz), 7.13(2H, d, J=8.0Hz).  1.19-1.31 (10H, m), 1.53- 1.63 (2H, m), 2.07-2.19 (2H, m), 2.57 (2H, t, J = 8.0Hz), 2.64-2.77 (4H, m), 4.24 ( 1H, d, J = 9.6Hz), 4.26 (1H, d, J = 9.6Hz), 5.83 (1H, br), 7.09 (2H, d, J = 8.0Hz), 7.13 (2H, d, J = 8.0 Hz).
[0768] [実施例 302— 307]  [Example 302—307]
実施例 76の化合物を実施例 263と同様に反応させメトキシメチルイ匕した後、実施 例 225と同様に酸化、ついで実施例 227と同様に反応させ実施例 306の化合物を得 た。実施例 149の化合物を実施例 226、ついで実施例 227と同様に反応させ実施例 307の化合物を得た。又、実施例 263、実施例 267、実施例 268、及び 267、 268のラセミ 体を用いて実施例 226、ついで実施例 227と同様に反応させ表 19に示したィ匕合物を 合成した。  The compound of Example 76 was reacted and methoxymethylated in the same manner as in Example 263, and then oxidized in the same manner as in Example 225 and then reacted in the same manner as in Example 227 to obtain the compound of Example 306. The compound of Example 149 was reacted in the same manner as in Example 226 and then in Example 227 to obtain the compound of Example 307. Further, using the racemates of Example 263, Example 267, Example 268, and 267, 268, the reaction was carried out in the same manner as in Example 226 and then in Example 227 to synthesize the conjugate shown in Table 19.
[0769] [表 19] 表 19
Figure imgf000132_0002
n FABMS 実施例 Ri R2 X 性状 [0769] [Table 19] Table 19
Figure imgf000132_0002
n Example of FABMS Ri R 2 X
【M+H】+  [M + H] +
302 PhCH20 Pr S 3 無色油状物 302 PhCH 2 0 Pr S 3 Colorless oil
303 (+) PhCH20 Pr S 3 無色油状物 303 (+) PhCH 2 0 Pr S 3 colorless oil
304 (-) PhCH20 Pr S 3 無色油状物 304 (-) PhCH 2 0 Pr S 3 colorless oil
305 PhCH20 CH2OCH2OMe S 2 無色油状物 305 PhCH 2 0 CH 2 OCH 2 OMe S 2 Colorless oil
306 CF3 CH2OCH2OMe S 3 無色油状物 632 306 CF 3 CH 2 OCH 2 OMe S 3 Colorless oil 632
307 CF3 CH2OSi( e)2tBu 0 3 無色油状物 686 [0770] [実施例 308— 310] 307 CF 3 CH 2 OSi (e) 2 tBu 0 3 Colorless oil 686 [Example 308-310]
表 19の実施例化合物 305— 307を用いて、実施例 228と同様に還元し表 20に示す化 合物を合成した。  Using Example Compounds 305 to 307 of Table 19, reduction was carried out in the same manner as in Example 228, and compounds shown in Table 20 were synthesized.
[0771] [表 20] 表 20
Figure imgf000133_0001
実施例 Ri R2 X n FABMS [0771] [Table 20] Table 20
Figure imgf000133_0001
Example Ri R 2 X n FABMS
性状 [M+H]+ Properties [M + H] +
308 PhCH20 CH2OCH2OMe S 2 無色油状物 308 PhCH 2 0 CH 2 OCH 2 OMe S 2 Colorless oil
309 CF3 CH2OCH2OMe S 3 無色油状物 634 309 CF 3 CH 2 OCH 2 OMe S 3 Colorless oil 634
310 CF3 CH2OSi(Me)2tBu 0 3 無色油状物 310 CF 3 CH 2 OSi (Me) 2 tBu 0 3 Colorless oil
[0772] [実施例 311] [Example 311]
5— [4— (3—ベンジルォキシ）フエニルスルファ-ルー 2—クロ口フエ-ル]— 2— tーブトキ シカルボニルアミノー 2—ヒドロキシメチルペンタン酸ェチル  5- [4- (3-Benzyloxy) phenylsulfur-Lu 2-chloromethyl] -2-T-butoxycarbonylamino-2-ethyl methyl hydroxypentanoate
[0773] [化 207] [0773] [Formula 207]
Figure imgf000133_0002
Figure imgf000133_0002
[0774] 実施例 27(1.76g)の THF (lOOmL)溶液に LiAl(OtBu)3H(3.48g)をカ卩ぇ常温にて 5日 間撹拌した。希塩酸を加えた後、酢酸ェチルで抽出し、水、飽和食塩水で洗浄後、 無水硫酸ナトリウムで乾燥した。溶媒を濃縮し、残渣をシリカゲルカラムクロマトグラフ ィー（酢酸ェチル：へキサン = 1： 1)で精製し、 目的物（710mg)を無色油状物として得 た。 A solution of Example 27 (1.76 g) in THF (100 mL) was stirred with LiAl (OtBu) 3 H (3.48 g) at room temperature for 5 days. After adding dilute hydrochloric acid, the mixture was extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product (710 mg) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.25(3H, t, J=7.3Hz), 1.43(9H, s),  1H-NMR (400MHz, CDC1) δ1.25 (3H, t, J = 7.3Hz), 1.43 (9H, s),
3  Three
1.59— 1.63(2H， m), 1.74— 1.82(1H, m), 2.20(1H, br), 2.66-2.71(2H, m), 3.00(1H, br), 3.79(1H, d， J=9.8Hz), 4.11(1H, br), 4.15- 4.28(2H, m), 5.02(2H, s),  1.59-1.63 (2H, m), 1.74-1.82 (1H, m), 2.20 (1H, br), 2.66-2.71 (2H, m), 3.00 (1H, br), 3.79 (1H, d, J = 9.8 Hz), 4.11 (1H, br), 4.15- 4.28 (2H, m), 5.02 (2H, s),
5.55(1H, br), 6.86— 6.95(3H， m), 7.08-7.15(2H, m), 7.23(1H, t， J=7.8Hz), 7.30-7.4K6H, m). 5.55 (1H, br), 6.86- 6.95 (3H, m), 7.08-7.15 (2H, m), 7.23 (1H, t, J = 7.8Hz), 7.30-7.4K6H, m).
[0775] [実施例 312] [Example 312]
4— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 2 tーブトキ シカルボ-ルァミノー 2—ヒドロキシメチル酪酸ェチル  4— [4— (3-benzyloxy) phenyl sulfa-lu 2-chloro-mouth] — 2 t-butoxycarbaluminamine 2-hydroxymethylbutyrate
[0776] [化 208] [0776] [Formula 208]
Figure imgf000134_0001
Figure imgf000134_0001
[0777] 実施例 26の化合物を用い上記実施例 311と同様に反応させ目的物を無色油状物と して得た。  [0777] The compound of Example 26 was reacted in the same manner as in Example 311 to obtain the desired product as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ 1.31(3H, t, J=7.3Hz), 1.47(9H, s), 1 H-NMR (400MHz, CDC1) δ 1.31 (3H, t, J = 7.3Hz), 1.47 (9H, s),
3  Three
2.00-2.07(lH, m), 2.37-2.56(2H, m), 2.64-2.72(1H, m), 2.91(1H, br),  2.00-2.07 (lH, m), 2.37-2.56 (2H, m), 2.64-2.72 (1H, m), 2.91 (1H, br),
3.81— 3.86(1H, m), 4.19- 4.27(1H, m), 4.24(2H, q, J=7.3Hz), 5.02(2H, s), 5.72(1H, br), 6.87-6.89(lH, m), 6.92— 6.94(2H, m), 7.09-7.14(2H, m), 7.21-7.25(1H, m), 3.81-3.86 (1H, m), 4.19-4.27 (1H, m), 4.24 (2H, q, J = 7.3 Hz), 5.02 (2H, s), 5.72 (1H, br), 6.87-6.89 (lH, m), 6.92- 6.94 (2H, m), 7.09-7.14 (2H, m), 7.21-7.25 (1H, m),
7.28-7.4K6H, m). 7.28-7.4K6H, m).
FABMS : 586 ([M+H]")  FABMS: 586 ([M + H] ")
[0778] [実施例 313]  [Example 313]
[5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2 t ブト キシカルボ-ルァミノ]ペンチルォキシ酢酸 t ブチル  [5— [4— (3-benzyloxyphenylsulfur) -2-cyclobutane] —2 t-butoxycarbo-lamino] pentyloxyacetate
[0779] [化 209]
Figure imgf000134_0002
[0779] [Formula 209]
Figure imgf000134_0002
[0780] 実施例 129の化合物（610mg)、 a ブロモ酢酸 t ブチル（0.26mL)、テトラブチルァ ンモ -ゥムクロリド（278mg)、 35%—水酸化ナトリム水溶液（15mL)、トルエン（15mL)の 混液を常温にて激しく撹拌した。 5時間後、酢酸ェチルを加え、有機層を分取し、飽 和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去後、シリカゲル カラムクロマトグラフィー（へキサン：酢酸ェチル = 3： 1)にて精製し、 目的物（555mg) を無色油状物として得た。 [0780] A mixture of the compound of Example 129 (610 mg), t-butyl bromoacetate (0.26 mL), tetrabutylammonium-dimethyl chloride (278 mg), a 35% aqueous solution of sodium hydroxide (15 mL), and toluene (15 mL) was brought to room temperature. And stirred vigorously. Five hours later, ethyl acetate was added, the organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. After distilling off the solvent, silica gel Purification by column chromatography (hexane: ethyl acetate = 3: 1) gave the desired product (555 mg) as a colorless oil.
1H-NMR(400MHz, CDCl ) δ 1.43(9H, s), 1.47(9Η, s),  1H-NMR (400MHz, CDCl) δ 1.43 (9H, s), 1.47 (9Η, s),
3  Three
1.63— 1.68(4Η, m), 2.71-2.74(2Η, m), 3.49- 3.53(1Η, m), 3.57(1Η, dd, J=9.2Hz, 3.7Hz), 3.74(1H, br), 3.95(2H, s),4.95(lH, br), 5.02(2H, s), 6.86(1H, dd,  1.63— 1.68 (4Η, m), 2.71-2.74 (2Η, m), 3.49- 3.53 (1Η, m), 3.57 (1Η, dd, J = 9.2Hz, 3.7Hz), 3.74 (1H, br), 3.95 (2H, s), 4.95 (lH, br), 5.02 (2H, s), 6.86 (1H, dd,
J=8.6Hz, 2.4Hz), 6.91— 6.94(2H, m), 7.14(2H, s), 7.22(1H, t, J=7.8Hz),  J = 8.6Hz, 2.4Hz), 6.91- 6.94 (2H, m), 7.14 (2H, s), 7.22 (1H, t, J = 7.8Hz),
7.30-7.4K6H,  7.30-7.4K6H,
m).  m).
[0781] [実施例 314— 315]  [0781] [Example 314-315]
実施例 247を加水分解後、 Boc化して得られる 5— [4 （ベンジルォキフエ-ルスルフ ァ-ル）—2—クロ口フエ-ル]— 2— t ブトキシカルボ-ルァミノ— 2—メチルペンタン 1— オールと実施例 128の化合物を用い、上記実施例 313と同様に反応させ表 21に示す 化合物を合成した。  Example 247 is hydrolyzed and then converted to Boc to obtain 5- [4 (benzyloxyphenol-sulfur) -2-cyclobutyral] -2-t-butoxycarbol-lamino-2-methylpentane 1-ol Using the compound of Example 128 and the reaction of Example 128, the compounds shown in Table 21 were synthesized.
[0782] [表 21]  [0782] [Table 21]
Figure imgf000135_0001
Figure imgf000135_0001
実施例 R 性状  Example R Properties
314 Me 淡黄色油状物  314 Me pale yellow oil
315 CH2OH 無色油状物 315 CH 2 OH colorless oil
[0783] [実施例 316] [0783] [Example 316]
[5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2 t ブト キシカルボニルァミノ- 2— t ブトキシカルボニルメチルォキシメチル]ペンチルォキシ 酢酸 t—ブチル [0784] [化 210] [5— [4— (3-Benzyloxyphenylsulfur-)-2-cyclobutayl] —2 t-butoxycarbonylamino-2—t-butoxycarbonylmethyloxymethyl] pentyloxy acetic acid t-butyl [0784] [Formula 210]
Figure imgf000136_0001
Figure imgf000136_0001
[0785] 実施例 315の化合物を用い、実施例 313と同様に反応させ目的物を無色油状物とし て得た。 [0785] Using the compound of Example 315, the reaction was carried out in the same manner as in Example 313 to obtain the desired product as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ： 1.41 (9Η, s), 1.46 (18H, s), 1 H-NMR (400 MHz, CDC1) δ: 1.41 (9Η, s), 1.46 (18H, s),
3  Three
1.59-1.68 (2H, m), 1.92—1.96 (2H, m), 2.66-2.70 (2H, m), 3.65—3.72 (4H, m), 3.96 (4H, d, J= 2.4Hz), 5.02 (2H, s), 5.44 (1H, s), 6.84—6.87 (1H, m),  1.59-1.68 (2H, m), 1.92--1.96 (2H, m), 2.66-2.70 (2H, m), 3.65--3.72 (4H, m), 3.96 (4H, d, J = 2.4Hz), 5.02 ( 2H, s), 5.44 (1H, s), 6.84—6.87 (1H, m),
6.90-6.94 (2H, m), 7.15-7.19 (2H, m), 7.21-7.23 (1H, m), 7.30-7.40 (6H, m).  6.90-6.94 (2H, m), 7.15-7.19 (2H, m), 7.21-7.23 (1H, m), 7.30-7.40 (6H, m).
[0786] [実施例 317]  [0786] [Example 317]
2— [5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2 t ブト キシカルボニルァミノペンチルォキシ]マロン酸ジェチル  2— [5— [4— (3-Venzyloxyphenylsulfur) -2-cyclobutane] —2t Butoxycarbonylaminopentyloxy] Jethyl malonate
[0787] [化 211]  [0787] [Formula 211]
Figure imgf000136_0002
Figure imgf000136_0002
[0788] 実施例 129の化合物（530mg)、 2—ジァゾマロン酸ジェチル（500mg)、 Rh (OAc) ( [0788] The compound of Example 129 (530 mg), getyl 2-diazomalonate (500 mg), Rh (OAc) (
2 2 twenty two
50mg)のベンゼン（5mL)溶液を室温にて 20時間撹拌した。シリカゲルカラムクロマト グラフィー（酢酸ェチル：へキサン = 1： 1)にて精製し、 目的物（120mg)を無色油状物 として得た。 A solution of 50 mg) in benzene (5 mL) was stirred at room temperature for 20 hours. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1) gave the desired product (120 mg) as a colorless oil.
1H-NMR(400MHz, CDC1 ) δ： 1.27— 1.32(6H, m), 1.43 (9H, s),  1H-NMR (400MHz, CDC1) δ: 1.27-1.32 (6H, m), 1.43 (9H, s),
3  Three
1.64-1.71 (4H, m), 2.70-2.73 (2H, m), 3.61 (1H, br), 3.67 (1H, dd, J= 9.8Hz, 3.7Hz), 3.80(1H, br), 4.21- 4.33(4H, m), 4.47(1H, s), 4.96(1H, br), 5.02 (2H, s), 6.85-6.97 (3H, m), 7.14(2H, s), 7.24 (1H, t, J=7.8Hz), 7.31-7.40 (6H, m).  1.64-1.71 (4H, m), 2.70-2.73 (2H, m), 3.61 (1H, br), 3.67 (1H, dd, J = 9.8Hz, 3.7Hz), 3.80 (1H, br), 4.21- 4.33 (4H, m), 4.47 (1H, s), 4.96 (1H, br), 5.02 (2H, s), 6.85-6.97 (3H, m), 7.14 (2H, s), 7.24 (1H, t, J = 7.8Hz), 7.31-7.40 (6H, m).
FABMS : 686 ([M+H]  FABMS: 686 ([M + H]
[0789] [実施例 318] 5— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 2—ヒドロキ シメチルー 2—プロピルペンタン酸ェチル [0789] [Example 318] 5- [4- (3-Benzyloxy) phenol-sulfur-ru 2-chloromethyl] -2-hydroxymethyl-2-ethyl propylpentanoate
[0790] [化 212] [0790] [Formula 212]
Figure imgf000137_0001
Figure imgf000137_0001
[0791] アルゴン下、ジェチルプロピルマロネート（0.99)の THF (25mL)及び DMF (3 mL)溶 液に水素化ナトリウム (60%) (192 mg)を加え、 80°Cで 30分間撹拌した後、参考例 252 (1.49g)  [0791] Under argon, sodium hydride (60%) (192 mg) was added to a solution of getylpropyl malonate (0.99) in THF (25 mL) and DMF (3 mL), and the mixture was stirred at 80 ° C for 30 minutes. Later, Reference Example 252 (1.49g)
の THF (5 mL)溶液を加え、更に 80°Cで 2時間撹拌した。反応液を常温にもどし、水 と酢酸ェチルを加えて分液した。有機層を無水硫酸ナトリウムで乾燥させ、濃縮し、 残查をシリカゲルカラムクロマトグラフィー（へキサン  Of THF (5 mL) was added, and the mixture was further stirred at 80 ° C for 2 hours. The reaction solution was returned to room temperature, and water and ethyl acetate were added to carry out liquid separation. The organic layer is dried over anhydrous sodium sulfate, concentrated, and the residue is subjected to silica gel column chromatography (hexane).
I酢酸ェチル =10 I 1)を用いて精製し、無色の油状物質を得た。得られた油状物質 (1.34g)の THF (4 mL)溶液に LiAl(0- tBu) H (800  Purification using I-ethyl acetate = 10 I 1) gave a colorless oil. To a solution of the obtained oil (1.34 g) in THF (4 mL) was added LiAl (0-tBu) H (800
3  Three
mg)と LiAl(0- tBu) H (lmo/L- THF溶液）（11.0 mL)を加えて加熱還流を行い、 2時  mg) and LiAl (0-tBu) H (lmo / L-THF solution) (11.0 mL), and heat under reflux.
3  Three
間後 LiAl(〇- tBu) H (1M- THF溶液）（5.00  After LiAl (〇-tBu) H (1M-THF solution) (5.00
3  Three
mL)を追加し、更に 1時間加熱還流を続けた。反応液を常温にもどした後に水を加え 、セライト濾過をした。濾液を酢酸ェチルと飽和食塩水を用いて分液し、有機層を無 水硫酸ナトリウムで乾燥させ、濃縮した。残查をシリカゲルカラムクロマトグラフィー（へ キサン  mL), and the mixture was further heated to reflux for 1 hour. After the reaction solution was returned to room temperature, water was added, and the mixture was filtered through celite. The filtrate was separated using ethyl acetate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue is subjected to silica gel column chromatography (hexane
I酢酸ェチル =5 I 1)を用いて精製し、無色油状の目的物（969 mg)を得た。  Purification using I-ethyl acetate = 5I1) gave the target compound (969 mg) as a colorless oil.
1H-NMR (400MHz, CDC1 ) δ 0.89 (3Η, t, J=7.3Hz), 1.27 (3H,  1H-NMR (400MHz, CDC1) δ 0.89 (3Η, t, J = 7.3Hz), 1.27 (3H,
3  Three
t, J= 7.3Hz), 1.27-1.30 (2H, m), 1.47-1.72 (6H, m), 2.18 (1H, t, J= 6.1Hz), 2.67 (2H, t, J =8.0Hz), 3.66(2H, t, J= 6.1Hz), 4.14 (2H, q, J =7.3Hz), 5.02  t, J = 7.3Hz), 1.27-1.30 (2H, m), 1.47-1.72 (6H, m), 2.18 (1H, t, J = 6.1Hz), 2.67 (2H, t, J = 8.0Hz), 3.66 (2H, t, J = 6.1Hz), 4.14 (2H, q, J = 7.3Hz), 5.02
(2H, s), 6.86-6.88 (1H, m), 6.91-6.94 (2H, m), 7.11-7.17 (2H, m), 7.20-7.24 (1H, m), 7.30-7.40 (6 H, m).  (2H, s), 6.86-6.88 (1H, m), 6.91-6.94 (2H, m), 7.11-7.17 (2H, m), 7.20-7.24 (1H, m), 7.30-7.40 (6 H, m ).
[0792] [実施例 319— 321] ァリルマロン酸ジメチルと参考例 252又は参考例 317を用い、又プロピルマロン酸ジ ェチルと参考例 317を用いて上記実施例 318と同様に反応させ表 22に示すィ匕合物を 合成した。 [Examples 319-321] Using dimethyl arylmalonate and Reference Example 252 or Reference Example 317, and using diethyl propylmalonate and Reference Example 317 in the same manner as in Example 318 described above, a conjugate shown in Table 22 was synthesized.
[0793] [表 221 表 22
Figure imgf000138_0001
l 実施例 Ri R2 n 性状 [0793] [Table 221 Table 22
Figure imgf000138_0001
l Example Ri R 2 n
319
Figure imgf000138_0002
Me 3 無色油状物 319
Figure imgf000138_0002
Me 3 colorless oil
320 Pr Et 2 無色油状物  320 Pr Et 2 colorless oil
321 -CHsCH-CHg Me 2 無色油状物  321 -CHsCH-CHg Me 2 colorless oil
[0794] [実施例 322] [0794] [Example 322]
5— [4— (3—ベンジルォキシ）フエ-ルスルファ二ルー 2—クロ口フエ-ル]— 2—シァノメ チルー 2—プロピルペンタン酸ェチル  5— [4 -— (3-benzyloxy) phenylsulfanyl 2-cyclomethyl] —2-cyanomethyl-2-ethyl propylpentanoate
[0795] [化 213] [0795] [Formula 213]
Figure imgf000138_0003
Figure imgf000138_0003
[0796] 氷浴中、実施例 318 (969 mg)のァセトニトリル（10 mL)溶液にトリェチルアミン（ In an ice bath, a solution of Example 318 (969 mg) in acetonitrile (10 mL) was added to triethylamine (10 mL).
0.51mL)及びメタンスルホニルクロリド (0.18mL)をカ卩え、 30分間撹拌した。水と酢酸 ェチルを用いて分液し、有機層を無水硫酸ナトリウムで乾燥させ、濃縮し、残查をシリ 力ゲルカラムクロマトグラフィー（へキサン 0.51 mL) and methanesulfonyl chloride (0.18 mL) were stirred and stirred for 30 minutes. The layers are separated using water and ethyl acetate, the organic layer is dried over anhydrous sodium sulfate, concentrated, and the residue is subjected to silica gel column chromatography (hexane).
I酢酸ェチル =3 I 1)を用いて精製し、無色油状のメシル体を得た。得られたメシル 体の DMF(2.5 mL)溶液にシアン化カリウム（358 mg)をカ卩えて 130°Cで 20時間撹拌 した後、水と酢酸ェチルを用いて分液し、有機層を無水硫酸ナトリウムで乾燥させ、 濃縮した。残查をシリカゲルカラムクロマトグラフィー（へキサン I酢酸ェチル =6 I 1)を用いて精製し、無色油状の目的物 (706 mg)を得た。 Purification using I-ethyl acetate = 3 I 1) yielded a colorless oily mesyl. Potassium cyanide (358 mg) was added to a solution of the obtained mesyl compound in DMF (2.5 mL), and the mixture was stirred at 130 ° C for 20 hours. The mixture was separated using water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Dried and concentrated. The residue is subjected to silica gel column chromatography (hexane Purification using I-ethyl acetate = 6 I 1) yielded the desired product (706 mg) as a colorless oil.
1H-NMR (400MHz, CDC1 ) δ 0.92 (3Η, t, J =7.3Hz), 1.05—1.16  1H-NMR (400MHz, CDC1) δ 0.92 (3Η, t, J = 7.3Hz), 1.05-1.16
3  Three
(IH, m), 1.24 (3H, t, J= 7.3Hz), 1.21—1.48 (2H, m), 1.59—1.88 (5H, m), 2.67 (2H, s), 2.70 (2H, t, J =8.0Hz), 4.14 (2H, q, J =7.3Hz), 5.02 (2H, s),  (IH, m), 1.24 (3H, t, J = 7.3Hz), 1.21-1.48 (2H, m), 1.59-1.88 (5H, m), 2.67 (2H, s), 2.70 (2H, t, J = 8.0Hz), 4.14 (2H, q, J = 7.3Hz), 5.02 (2H, s),
6.86-6.89 (IH, m), 6.89— 6.95(2H, m),7.10— 7.16 (2H, m), 7.21-7.25 (IH, m), 7.30-7.41 (6 H, m).  6.86-6.89 (IH, m), 6.89-- 6.95 (2H, m), 7.10-- 7.16 (2H, m), 7.21-7.25 (IH, m), 7.30-7.41 (6 H, m).
[0797] [実施例 323— 325]  [Example 323-325]
表 22に示したィ匕合物を用い、上記実施例 322と同様に反応させ表 23に示すィ匕合物 を合成した。  The same procedure as in Example 322 was used to synthesize a compound shown in Table 23 using the compound shown in Table 22.
[0798] [表 23]  [0798] [Table 23]
Figure imgf000139_0001
Figure imgf000139_0001
実施例 R2 n 性状 Example R 2 n Properties
Me 3 無色油状物  Me 3 colorless oil
Et 2 無色油状物 Et 2 colorless oil
Figure imgf000139_0002
H 2 無色油状物
Figure imgf000139_0002
H 2 colorless oil
[0799] [実施例 326] [Example 326]
5— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 2—シァノメ チルー 2—プロピルペンタン酸  5— [4— (3-Benzyloxy) phenol-sulfur-Lu 2-chloro-mouth] —2-Cyanometyl-2-propylpentanoic acid
[0800] [化 214] [0800] [Formula 214]
Figure imgf000139_0003
Figure imgf000139_0003
[0801] 実施例 322 (623 mg)のエタノール THF (4 / 1) (15 mL)溶液に lmol/L-水酸化カリ ゥム水溶液 (2.46 mL)を加え加熱還流を行った。 2時間後 lmol/L-水酸ィ匕カリウム水 溶液 (3.46 mL)及び THF (5 mL)を追加し、更に 6時間加熱還流を続けた。反応液を常温にもど した後に水をカ卩え、 4mol/い塩酸で PH1とし、酢酸ェチルで抽出した。有機層を無水 硫酸ナトリウムで乾燥させて濃縮し、残查をシリカゲルカラムクロマトグラフィー（へキ サン [0801] To a solution of 322 (623 mg) in ethanol THF (4/1) (15 mL) was added lmol / L aqueous potassium hydroxide solution (2.46 mL), and the mixture was heated under reflux. 2 hours later lmol / L-hydroxydani potassium solution (3.46 mL) and THF (5 mL) were added, and the mixture was further heated at reflux for 6 hours. After the temperature of the reaction solution was returned to room temperature, water was collected, adjusted to PH1 with 4 mol / HCl, and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated, and the residue is subjected to silica gel column chromatography (hexane).
I酢酸ェチル =3 I 1)を用いて精製し、無色油状の目的物 (563 mg)を得た。  Purification using I-ethyl acetate = 3 I 1) afforded the desired product as a colorless oil (563 mg).
1H-NMR (400MHz, CDC1 ) δ 0.94 (3Η, t, J =7.3Hz), 1.15—1.39  1H-NMR (400MHz, CDC1) δ 0.94 (3Η, t, J = 7.3Hz), 1.15-1.39
3  Three
(2H, m), 1.44-1.57 (lH,m), 1.60-1.92 (5H, m), 2.66 (2H, s), 2.71 (2H, t, J= (2H, m), 1.44-1.57 (lH, m), 1.60-1.92 (5H, m), 2.66 (2H, s), 2.71 (2H, t, J =
8.0), 5.01 (2H, s), 6.86-6.88 (1H, m), 6.88—6.94 (2H, m), 7.11-7.17 (2H, m),8.0), 5.01 (2H, s), 6.86-6.88 (1H, m), 6.88—6.94 (2H, m), 7.11-7.17 (2H, m),
7.20-7.24 (1H, m), 7.30-7.41 (6 H, m). 7.20-7.24 (1H, m), 7.30-7.41 (6 H, m).
[0802] [実施例 327— 328] [0802] [Example 327-328]
実施例 323— 324の化合物を用い、上記実施例 326と同様に反応させ表 24に示した 化合物を合成した。  The compounds shown in Table 24 were synthesized by reacting the compounds of Examples 323-324 in the same manner as in Example 326 above.
[0803] [表 24] 表 24
Figure imgf000140_0001
実施例 R 性状 [0803] [Table 24] Table 24
Figure imgf000140_0001
Example R Properties
327 -CHgCH-CHs 3 無色油状物 327 -CHgCH-CHs 3 colorless oil
328 Pr 2 無色油状物  328 Pr 2 colorless oil
[0804] [実施例 329] [0804] [Example 329]
6— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 3—メトキシ カルボニルァミノ— 3—プロピルへキサン二トリル [0805] [化 215] 6— [4— (3-Benzyloxy) phenylsulfur-Lu 2-Clobutyl] —3-Methoxycarbonylamino-3—Propylhexanenitrile [0805] [Formula 215]
Figure imgf000141_0001
Figure imgf000141_0001
[0806] 実施例 326 (583 mg)のベンゼン（8 mL)溶液にアジ化ジフエ-ルホスホリル（275 μ L)及びトリェチルァミン（152 L)を加え 40分間加熱還流を行った。反応液を室温 にもどし、メタノーノレ（1.2 Example 326 Diphenylphosphoryl azide (275 μL) and triethylamine (152 L) were added to a solution of 326 (583 mg) in benzene (8 mL), and the mixture was heated under reflux for 40 minutes. The reaction solution was returned to room temperature, and methanol (1.2
mL)を滴下した後に 2日間加熱還流を続け、 3日目にナトリウムメトキシド (93.5 mg)と メタノール (4 mL)を加え 1時間加熱還流した。酢酸ェチルと飽和食塩水を用いて分 液し、有機層を無水硫酸ナトリウムで乾燥させ、濃縮した。残查をシリカゲルカラムク 口マトグラフィー（へキサン  After dropwise addition of sodium methoxide (93.5 mg) and methanol (4 mL), the mixture was refluxed for 1 hour. The layers were separated using ethyl acetate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography (hexane).
I酢酸ェチル =7 I 1)を用いて精製し、無色油状の目的物（520 mg)を得た。  Purification using I ethyl acetate = 7 I 1) gave the target compound (520 mg) as a colorless oil.
JH-NMR (400MHz, CDC1 ) δ 0.93 (3Η, t, J =7.3Hz),  JH-NMR (400MHz, CDC1) δ 0.93 (3Η, t, J = 7.3Hz),
3  Three
1.19-1.28 (2H, m), 1.50-1.67 (4H,m), 1.70-1.78 (1H, m), 1.91-1.99 (1H, m), 2.71 (2H, t, J=7.3Hz), 2.87 (1H, d, J=17.1Hz), 2.98 (1H, d, J=17.1Hz), 3.63 (3H, s), 4.59 (1H, br), 5.02 (2H, s), 6.87—6.89 (1H, m), 6.92—6.94 (2H, m), 7.11-7.17 (2H, m), 7.21-7.25 (1H, m), 7.32-7.41 (6H, m).  1.19-1.28 (2H, m), 1.50-1.67 (4H, m), 1.70-1.78 (1H, m), 1.91-1.99 (1H, m), 2.71 (2H, t, J = 7.3Hz), 2.87 ( 1H, d, J = 17.1Hz), 2.98 (1H, d, J = 17.1Hz), 3.63 (3H, s), 4.59 (1H, br), 5.02 (2H, s), 6.87--6.89 (1H, m ), 6.92-6.94 (2H, m), 7.11-7.17 (2H, m), 7.21-7.25 (1H, m), 7.32-7.41 (6H, m).
[0807] [実施例 330— 332]  [Examples 330—332]
実施例 325及び表 24の化合物を用い、上記実施例 329と同様に反応させ表 25に示 す化合物を合成した。  Using the compounds of Example 325 and Table 24, the reaction was carried out in the same manner as in Example 329 to synthesize the compounds shown in Table 25.
[0808] [表 25] [0808] [Table 25]
表 25
Figure imgf000142_0001
実施例 R n 性状 Table 25
Figure imgf000142_0001
Example R n Properties
330 3 無色油状物  330 3 Colorless oil
331 2 無色油状物  331 2 Colorless oil
332
Figure imgf000142_0002
2 無色油状物 332
Figure imgf000142_0002
2 Colorless oil
[0809] [実施例 333] [0809] [Example 333]
6— [4— (3 ペンジノレオキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 3—ヒドロキシ プロピル 3—メトキシカルボニルァミノへキサン二トリル  6— [4— (3 Penzinoleoxy) phenylsulfur-Lu 2 chlorophenol] —3-Hydroxypropyl 3-Methoxycarbonylaminohexanenitrile
[0810] [化 216] [0810] [Formula 216]
Figure imgf000142_0003
Figure imgf000142_0003
[0811] 氷冷下、実施例 330 (152 mg)の THF (4 mL)溶液にボラン- THFコンプレックス（1 mol/L-THF溶液）（312 /z L)を滴下し、 1時間撹拌した後、ボラン- THFコンプレックス (lmol/L- THF溶液）（312  [0811] A borane-THF complex (1 mol / L-THF solution) (312 / zL) was added dropwise to a solution of Example 330 (152 mg) in THF (4 mL) under ice cooling, and the mixture was stirred for 1 hour. , Borane-THF complex (lmol / L-THF solution) (312
μ L)を追加、更に 30分後ボラン- THFコンプレックス（lmol/L- THF溶液）（568 μ L) をカロえて 30分間撹拌した。反応液に水（6 mL)をカ卩えた後、 NaBO -4H 0 (196  μL) was added, and 30 minutes later, the borane-THF complex (lmol / L-THF solution) (568 μL) was heated and stirred for 30 minutes. After water (6 mL) was added to the reaction solution, NaBO-4H0 (196
3 2  3 2
mg)を加えて、室温で 15時間撹拌した。反応液を酢酸ェチルで抽出した後、有機層 を無水硫酸ナトリウムで乾燥させ、濃縮し、残查をシリカゲルカラムクロマトグラフィー（ 齚酸ェチル)を用いて精製し、無色油状の目的物（102  mg) and stirred at room temperature for 15 hours. After the reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate) to give a colorless oily product (102).
mg)を待 7こ。  mg) 7
1H-NMR (400MHz, CDC1 ) δ 1.24-1.73 (6Η, m), 1.88-1.98  1H-NMR (400MHz, CDC1) δ 1.24-1.73 (6Η, m), 1.88-1.98
3  Three
(2H, m), 2.71 (2H, t, J=7.3Hz), 2.94 (2H, s), 3.63 (3H, s) 3.63 (2H, m), 4.88 (1H, br), 5.02 (2H, s), 6.88—6.89 (1H, m), 6.92—6.95 (2H， m), 7.11-7.17 (2H, m), 7.21-7.25 (1H, m), 7.33-7.42 (6H, m). (2H, m), 2.71 (2H, t, J = 7.3Hz), 2.94 (2H, s), 3.63 (3H, s) 3.63 (2H, m), 4.88 (1H, br), 5.02 (2H, s ), 6.88—6.89 (1H, m), 6.92—6.95 (2H, m), 7.11-7.17 (2H, m), 7.21-7.25 (1H, m), 7.33-7.42 (6H, m).
[0812] [実施例 334] [0812] [Example 334]
5— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 3—ヒドロキ シプロピル 3—メトキシカルボニルァミノペンタン二トリル  5— [4— (3-Benzyloxy) phenylsulfur-Lu 2 chlorophenol] —3-Hydroxypropyl 3-Methoxycarbonylaminopentane nitrile
[0813] [化 217] [0813] [Formula 217]
Figure imgf000143_0001
Figure imgf000143_0001
[0814] 実施例 332を用いて上記実施例 333と同様に反応させ目的物を無色油状物としてと して得た。  [0814] The same procedure as in Example 333 was carried out using Example 332 to obtain the desired product as a colorless oil.
1H-NMR(400MHz, DMSO-d ) δ 1.49(1H, t, J=4.9Hz), 1.57-1.70(2H,  1H-NMR (400MHz, DMSO-d) δ 1.49 (1H, t, J = 4.9Hz), 1.57-1.70 (2H,
6  6
m), 1.79-1.93(2H,m), 1.98-2.06(1H, m), 2.13— 2.23(1H, m), 2.69(2H, t, J=8.6Hz), 2.97(1H, d, J=17.1Hz), 3.09(1H, d, J=17.1Hz), 3.65(3H, s), 3.71(2H, d,  m), 1.79-1.93 (2H, m), 1.98-2.06 (1H, m), 2.13― 2.23 (1H, m), 2.69 (2H, t, J = 8.6Hz), 2.97 (1H, d, J = 17.1Hz), 3.09 (1H, d, J = 17.1Hz), 3.65 (3H, s), 3.71 (2H, d,
J=5.5Hz), 5.01(1H, br), 5.03(2H, s), 6.88— 6.96(3H, m), 7.12-7.17(2H, m),  J = 5.5Hz), 5.01 (1H, br), 5.03 (2H, s), 6.88- 6.96 (3H, m), 7.12-7.17 (2H, m),
7.22-7.24(lH, m), 7.31-7.42(6H, m).  7.22-7.24 (lH, m), 7.31-7.42 (6H, m).
[0815] [実施例 335]  [0815] [Example 335]
2—アミノー 5— [4— (3—ベンジルォキシフエノキシ) 2 クロ口フエ-ル]— 2—ヒドロキシ メチルペンタン酸、塩酸塩  2-Amino-5- [4- (3-benzyloxyphenoxy) 2-chlorophenol]-2-hydroxymethylpentanoic acid, hydrochloride
[0816] [化 218]  [0816] [Formula 218]
Figure imgf000143_0002
Figure imgf000143_0002
[0817] 実施例 284の化合物（360mg)を THF (5mL)に溶解し、 lmol/L— Bu NF (3mL)をカロ  [0817] The compound of Example 284 (360 mg) was dissolved in THF (5 mL), and lmol / L—BuNF (3 mL) was added to calo.
4  Four
え常温にて 24時間撹拌した。反応液を濃縮後、クェン酸にて酸性とし酢酸ェチルで 抽出後、無水硫酸ナトリウムで乾燥した。溶媒を留去しシリカゲルカラムクロマトグラフ ィー（酢酸ェチル）にて精製しヒドロキシカルボン酸体（lOOmg)を無色アモルファスと して得た。このものをメタノール（5mL)に溶解し、 3mol/L塩酸含有酢酸ェチル（5mL) を加え常温にて 3時間撹拌後濃縮し目的物（90.0mg)を無色アモルファスとして得た The mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated, acidified with citric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the hydroxycarboxylic acid compound (100 mg) as a colorless amorphous. I got it. This was dissolved in methanol (5 mL), 3 mol / L hydrochloric acid-containing ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 3 hours and concentrated to obtain the desired product (90.0 mg) as a colorless amorphous.
FABMS : 456 ([M+H]") FABMS: 456 ([M + H] ")
1H-NMR(400MHz, DMSO— d ) δ 1.44— 1.76(4H, m), 2.63(2Η, br),  1H-NMR (400MHz, DMSO- d) δ 1.44- 1.76 (4H, m), 2.63 (2Η, br),
6  6
3.52(1Η, d, J=11.2Hz),3.73(lH, d, J=11.2Hz), 5.08(2H, s), 6.56(1H, dd, J=7.3Hz, 2.2Hz), 6.66(1H, t, J=2.2Hz), 6.83(1H, dd, J=8.3Hz, 1.7Hz), 6.93(1H, dd,  3.52 (1Η, d, J = 11.2Hz), 3.73 (lH, d, J = 11.2Hz), 5.08 (2H, s), 6.56 (1H, dd, J = 7.3Hz, 2.2Hz), 6.66 (1H, t, J = 2.2Hz), 6.83 (1H, dd, J = 8.3Hz, 1.7Hz), 6.93 (1H, dd,
J=8.3Hz, 2.4Hz), 7.05(1H, d,J=2.4Hz), 7.27-7.43(7H, m), 8.14(3H, br).  J = 8.3Hz, 2.4Hz), 7.05 (1H, d, J = 2.4Hz), 7.27-7.43 (7H, m), 8.14 (3H, br).
[0818] [実施例 336]  [0818] [Example 336]
3—ァミノ— 5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—ヒドロキシメチルペンタン酸  3-Amino-5- [4- (3-Benzyloxyphenol-sulfur) -2-cyclobutane] -3-Hydroxymethylpentanoic acid
[0819] [化 219]  [0819] [Formula 219]
Figure imgf000144_0001
Figure imgf000144_0001
[0820] 実施例 295 (150 mg)に 3mol/L-水酸化ナトリウム水溶液（5 mL)及びエタノール (0.5  [0820] Example 295 (150 mg) was added to a 3 mol / L aqueous sodium hydroxide solution (5 mL) and ethanol (0.5 mL).
mL)を加え、 9時間加熱還流した。反応液を常温にもどした後、水を加え、 4mol/L- 塩酸を用いて PH6— 7にした。析出した結晶を濾取し乾燥させ目的物  mL), and the mixture was heated under reflux for 9 hours. After the reaction solution was returned to room temperature, water was added, and the mixture was adjusted to PH6-7 with 4 mol / L-hydrochloric acid. The precipitated crystals are collected by filtration, dried and dried.
(112 mg,)を無色粉末として得た。  (112 mg,) was obtained as a colorless powder.
1H-NMR(400MHz, DMSO-d ) δ 1.82-1.83 (2Η, m), 2.43 (2H,  1H-NMR (400MHz, DMSO-d) δ 1.82-1.83 (2Η, m), 2.43 (2H,
6  6
s), 2.68-2.73 (2H, m), 3.52—3.53 (2H, m), 5.10 (2H, s), 6.89—6.91 (1H, m), 6.96-7.01 (2H, m), 7.23-7.25 (1H, m), 7.30-7.41 (8H, m).  s), 2.68-2.73 (2H, m), 3.52-3.53 (2H, m), 5.10 (2H, s), 6.89-6.91 (1H, m), 6.96-7.01 (2H, m), 7.23-7.25 ( 1H, m), 7.30-7.41 (8H, m).
HRMS: 472.1375 (+2.6mmu).  HRMS: 472.1375 (+ 2.6mmu).
[0821] [実施例 337] [0821] [Example 337]
3—ァミノ— 5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] - 3—ヒドロキシメチルペンタン酸、塩酸塩 [0822] [化 220] 3-Amino-5- [4- (3-Benzyloxyphenol-sulfur) -2-cyclomethylphenol] -3-Hydroxymethylpentanoic acid, hydrochloride [0822] [Formula 220]
Figure imgf000145_0001
Figure imgf000145_0001
[0823] 上記実施例 336(50.0mg)を水（10mL)に懸濁させ 4mol/L_塩酸（3mL)を加えて激し く撹拌し、酢酸ェチルと飽和食塩水を加えて抽出した。有機層から析出した結晶を濾 取、乾燥後目的物を無色粉末 (38.0mg)として得た。  [0823] The above Example 336 (50.0 mg) was suspended in water (10 mL), 4 mol / L hydrochloric acid (3 mL) was added, the mixture was vigorously stirred, and ethyl acetate and saturated saline were added for extraction. The crystals precipitated from the organic layer were collected by filtration and dried to give the desired product as a colorless powder (38.0 mg).
1H-NMR(400MHz, DMSO-d ) δ 1.85-1.90 (2Η, m), 2.66- 2.74  1H-NMR (400MHz, DMSO-d) δ 1.85-1.90 (2Η, m), 2.66- 2.74
6  6
(4H, m), 3.57 (1H, d, J=11.0Hz), 3.61(1H, d, J=11.0Hz), 5.09 (2H, s), 5.58(1H, br), 6.89-6.91 (1H, m), 6.95—7.00 (2H, m), 7.23-7.41 (9H, m), 8.00 (3H, br). (4H, m), 3.57 (1H, d, J = 11.0Hz), 3.61 (1H, d, J = 11.0Hz), 5.09 (2H, s), 5.58 (1H, br), 6.89-6.91 (1H, m), 6.95-7.00 (2H, m), 7.23-7.41 (9H, m), 8.00 (3H, br).
FABMS : 472 ([M+H] . FABMS: 472 ([M + H].
[0824] [実施例 338] [0824] [Example 338]
3—ァミノ— 6— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—Amino— 6— [4— (3-Benzyloxyphenol-sulfur-yl) —2-Clo-mouth phenol] —
3—ヒドロキシメチルへキサン酸 3-hydroxymethylhexanoic acid
[0825] [化 221] [0825] [Formula 221]
Figure imgf000145_0002
Figure imgf000145_0002
[0826] 実施例 283を用い実施例 336と同様に反応させ目的物を無色粉末として得た。 [0826] Using Example 283, the reaction was carried out in the same manner as in Example 336 to obtain the desired product as a colorless powder.
1H-NMR(400MHz, DMSO-d ) δ 1.50— 1.59(4H, m), 1.94(1Η, d,  1H-NMR (400MHz, DMSO-d) δ 1.50― 1.59 (4H, m), 1.94 (1Η, d,
6  6
J=16.0Hz), 2.03(1H, d, J=16.0Hz), 2.58— 2.62(2H, m), 5.08(2H, s), 6.89— 6.91(1H, m), 6.92-6.99 (2H, m), 7.20-7.22(lH, m), 7.29-7.41(8H, m).  J = 16.0Hz), 2.03 (1H, d, J = 16.0Hz), 2.58-2.62 (2H, m), 5.08 (2H, s), 6.89-6.91 (1H, m), 6.92-6.99 (2H, m ), 7.20-7.22 (lH, m), 7.29-7.41 (8H, m).
FABMS : 486 ([M+H] .  FABMS: 486 ([M + H].
[0827] [実施例 339] [0827] [Example 339]
3—ァミノ— 6— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] - 3—ヒドロキシメチルへキサン酸、塩酸塩 [0828] [化 222] 3-Amino-6- [4- (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -3-Hydroxymethylhexanoic acid, hydrochloride [0828] [Formula 222]
Figure imgf000146_0001
Figure imgf000146_0001
[0829] 実施例 283の化合物（196 mg)〖こ 3mol/L-水酸化ナトリウム水溶液（5 mL)及びエタ ノール（0.5 mL)を加え 8時間加熱還流した。反応液を氷浴中で冷やしながら撹拌さ せ、 4mol/L-塩酸で PH2— 1にした後、酢酸ェチルと水で分液した。有機層を無水硫 酸ナトリウムで乾燥させた後に濃縮し、目的物を淡白色固体 (201 [0829] The compound of Example 283 (196 mg), a 3 mol / L aqueous solution of sodium hydroxide (5 mL) and ethanol (0.5 mL) were added, and the mixture was heated under reflux for 8 hours. The reaction solution was stirred while being cooled in an ice bath, adjusted to PH2-1 with 4 mol / L-hydrochloric acid, and then separated with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and then concentrated.
mg)として得た。  mg).
1H-NMR(400MHz, DMSO— d ) δ 1.58—1.71 (4Η, m), 2.55 (2H, s), 1 H-NMR (400MHz, DMSO- d) δ 1.58-1.71 (4Η, m), 2.55 (2H, s),
6  6
2.65 (2H, t, J= 7.3Hz), 3.46 (1H, d, J=11.0Hz), 3.52 (1H, d, J=11.0Hz), 5.10 (2H s), 5.50 (1H, br), 6.90—6.91 (1H, m), 6.96—7.02 (2H, m), 7.22-7.25 (1H, m), 7.30-7.42 (8H, m), 7.86 (3H, br).  2.65 (2H, t, J = 7.3Hz), 3.46 (1H, d, J = 11.0Hz), 3.52 (1H, d, J = 11.0Hz), 5.10 (2H s), 5.50 (1H, br), 6.90 —6.91 (1H, m), 6.96—7.02 (2H, m), 7.22-7.25 (1H, m), 7.30-7.42 (8H, m), 7.86 (3H, br).
FABMS : 486 ([M+H] .  FABMS: 486 ([M + H].
HRMS: 486.1517(+l.lmmu).  HRMS: 486.1517 (+ l.lmmu).
[0830] [実施例 340] [0830] [Example 340]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (2—トリフルォロメチルフエ-ルォキシ)— 2— クロ口フエ-ル]へキサン酸  3-Amino-3-Hydroxymethyl-6- [4- (2-Trifluoromethylphenoxy) -2-cyclohexyl] hexanoic acid
[0831] [化 223]  [0831] [Formula 223]
Figure imgf000146_0002
Figure imgf000146_0002
[0832] 実施例 290の化合物を用い実施例 336と同様に反応させ目的物を無色粉末として 得た。 [0832] The compound of Example 290 was reacted in the same manner as in Example 336 to obtain the desired product as a colorless powder.
FABMS : 432([M+H]+). FABMS: 432 ([M + H] + ).
1H-NMR(400MHz, DMSO— d ) δ 1.50— 1.62(4H, m), 1.97(1H, d, 1 H-NMR (400 MHz, DMSO-d) δ 1.50- 1.62 (4H, m), 1.97 (1H, d,
6  6
J=15.9Hz), 2.04(1H, d, J=15.9Hz), 2.53— 2.62(2H, m), 3.27-3.34(2H, m), 6.96(1H, dd, J=2.5Hz, 8.6Hz), 7.06- 7.13(2H, m), 7.32-7.37(2H, m), 7.67(1H, t, J=7.3Hz), 7.76-7.82(lH, m). J = 15.9Hz), 2.04 (1H, d, J = 15.9Hz), 2.53-2.62 (2H, m), 3.27-3.34 (2H, m), 6.96 (1H, dd, J = 2.5Hz, 8.6Hz), 7.06- 7.13 (2H, m), 7.32-7.37 (2H, m), 7.67 (1H, t, J = 7.3Hz), 7.76-7.82 (lH, m).
[0833] [実施例 341] [0833] [Example 341]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (2—トリフルォロメチルフエ-ルォキシ )—2- クロロフヱニル]へキサン酸、塩酸塩  3-Amino-3-hydroxymethyl-6- [4- (2-trifluoromethylphenoxy) -2-chlorophenyl] hexanoic acid, hydrochloride
[0834] [化 224]  [0834] [Formula 224]
Figure imgf000147_0001
Figure imgf000147_0001
[0835] 上記実施例 340を用いて実施例 337と同様に反応させ、目的物を無色粉末として得 た。 [0835] The same procedures used in Example 337 were carried out except for using Example 340 to obtain the desired product as a colorless powder.
FABMS : 432([M+H]+)FABMS: 432 ([M + H] + )
— NMR(400MHz, DMSO— d ) δ 1.50-1.74(4H, m), 2.55(2H, d,  — NMR (400MHz, DMSO— d) δ 1.50-1.74 (4H, m), 2.55 (2H, d,
6  6
J=2.4Hz), 2.59-2.70(2H,  J = 2.4Hz), 2.59-2.70 (2H,
m), 3.98-4.36(2H, m), 6.96— 7.00(1H, m), 7.07(1H, d, J=8.0Hz), 7.13(1H, d, H=2.5Hz), 7.14-7.4K2H, m), 7.68(1H, t, J=8.0Hz), 7.80(1H, d, J=8.0Hz),  m), 3.98-4.36 (2H, m), 6.96- 7.00 (1H, m), 7.07 (1H, d, J = 8.0Hz), 7.13 (1H, d, H = 2.5Hz), 7.14-7.4K2H, m), 7.68 (1H, t, J = 8.0Hz), 7.80 (1H, d, J = 8.0Hz),
7.90(3H, br).元素分析値（％)： C H CI F NO .1/2H Oとして  7.90 (3H, br). Elemental analysis value (%): CH CI F NO .1 / 2HO
20 22 2 3 4 2  20 22 2 3 4 2
C H N  C H N
計算値 ： 50.30 4.86 2.93  Calculated value: 50.30 4.86 2.93
実測値 ： 50.20 4.57 2.76  Measured value: 50.20 4.57 2.76
[0836] [実施例 342] [0836] [Example 342]
3—ァミノ— 3—ヒドロキシメチルー 5— [4— (2—トリフルォロメチルフエ-ルォキシ)— 2—ク ロロフエ-ル]ペンタン酸 [0837] [化 225] 3-Amino-3-Hydroxymethyl-5- [4- (2-Trifluoromethylphenoxy) -2-chlorophenyl] pentanoic acid [0837] [Formula 225]
Figure imgf000148_0001
Figure imgf000148_0001
[0838] 実施例 291の化合物を用い実施例 336と同様に反応させ目的物を無色粉末として 得た。 [0838] The same procedures used in Example 336 were carried out except for using the compound of Example 291 to give the desired product as a colorless powder.
FABMS : 417([M+H]+)FABMS: 417 ([M + H] + )
— NMR(400MHz, DMSO— d ) δ 1.70— 1.81(2H, m), 2.08— 2.18(4H,  — NMR (400MHz, DMSO— d) δ 1.70— 1.81 (2H, m), 2.08— 2.18 (4H,
6  6
m), 2.67(2H, t, J=8.6Hz), 3.42(2H, s), 7.03(1H, dd, J=2.4, 7.9Hz), 7.18(1H, d, J=2.4), 7.30(1H, dd, J=2.4Hz, 7.9Hz), 7.33- 7.38(2H, m), 7.51(1H, d, J=7.9Hz), 7.62(1H, d, J=7.9Hz).  m), 2.67 (2H, t, J = 8.6Hz), 3.42 (2H, s), 7.03 (1H, dd, J = 2.4, 7.9Hz), 7.18 (1H, d, J = 2.4), 7.30 (1H , dd, J = 2.4Hz, 7.9Hz), 7.33- 7.38 (2H, m), 7.51 (1H, d, J = 7.9Hz), 7.62 (1H, d, J = 7.9Hz).
[0839] [実施例 343] [0839] [Example 343]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (4—トリフルォロメチルフエ-ルォキシ )—2- クロ口フエ-ル]へキサン酸  3-Amino-3-Hydroxymethyl-6- [4- (4-Trifluoromethylphenyl) -2-cyclohexyl] hexanoic acid
[0840] [化 226]  [0840] [Formula 226]
Figure imgf000148_0002
Figure imgf000148_0002
[0841] 実施例 292の化合物を用い実施例 336と同様に反応させ目的物を無色粉末として 得た。 [0841] The same procedures used in Example 336 were carried out except for using the compound of Example 292 to give a desired product as a colorless powder.
FABMS : 432([M+H]+) FABMS: 432 ([M + H] + )
1H-NMR(400MHz, DMSO— d ) δ 1.52— 1.60(4H, m), 1.97(1H, d, 1 H-NMR (400 MHz, DMSO-d) δ 1.52- 1.60 (4H, m), 1.97 (1H, d,
6  6
J=15.9Hz), 2.06(1H, d, J=15.9Hz), 2.60— 2.68(2H, m), 3.00— 3.50(2H, m), 7.06(1H, dd, J=2.5Hz, 8.6Hz), 7.15(2H, d, J=8.6Hz), 7.23(lH,d, J=2.5Hz), 7.40(1H, d, J=8.6Hz), 7.74(2H, d, J=8.6Hz).  J = 15.9Hz), 2.06 (1H, d, J = 15.9Hz), 2.60― 2.68 (2H, m), 3.00― 3.50 (2H, m), 7.06 (1H, dd, J = 2.5Hz, 8.6Hz) , 7.15 (2H, d, J = 8.6Hz), 7.23 (lH, d, J = 2.5Hz), 7.40 (1H, d, J = 8.6Hz), 7.74 (2H, d, J = 8.6Hz).
[0842] [実施例 344] [0842] [Example 344]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (4—トリフルォロメチルフエ-ルォキシ)— 2—ク ロロフヱニル]へキサン酸、塩酸塩 3-Amino-3-Hydroxymethyl-6- [4- (4-Trifluoromethylphenoxy) -2- Lolophenyl] hexanoic acid, hydrochloride
[0843] [化 227]  [0843] [Formula 227]
Figure imgf000149_0001
Figure imgf000149_0001
[0844] 上記実施例 343の化合物を用い、実施例 337と同様に反応させ目的物を無色ァモ ルファスとして得た。  [0844] Using the compound of Example 343, a reaction was carried out in the same manner as in Example 337, to obtain the desired product as colorless amorphous.
FABMS : 432([M+H]+).FABMS: 432 ([M + H] + ).
— NMR(400MHz, DMSO— d ) δ 1.55-1.75(4H, m), 2.52(2H, s),  — NMR (400MHz, DMSO— d) δ 1.55-1.75 (4H, m), 2.52 (2H, s),
6  6
2.65(2H, t, J=7.9Hz), 3.42- 3.55(2H, m), 7.07(1H, dd, J=.4, 8.6Hz), 7.15(2H, d, 2.65 (2H, t, J = 7.9Hz), 3.42- 3.55 (2H, m), 7.07 (1H, dd, J = .4, 8.6Hz), 7.15 (2H, d,
H=8.6Hz), 7.25(1H, d, H=8.6Hz), 7.39(1H, d, H=7.9Hz), 7.75(2H, d, J=9.2Hz),H = 8.6Hz), 7.25 (1H, d, H = 8.6Hz), 7.39 (1H, d, H = 7.9Hz), 7.75 (2H, d, J = 9.2Hz),
7.76-8.10(3H, br s). 7.76-8.10 (3H, br s).
[0845] <実施例 345 > [0845] <Example 345>
3—ァミノ一 5— [4— (4—ベンジルォキシフエ-ルスルファ -ル） 2—クロ口フエニル] 3-amino-5- [4- (4-benzyloxyphenol-sulfur-) 2-cyclophenyl)
3—ヒドロキシメチルペンタン酸、塩酸塩 3-hydroxymethylpentanoic acid, hydrochloride
[0846] [化 228] [0846] [Formula 228]
Figure imgf000149_0002
Figure imgf000149_0002
[0847] 実施例 293の化合物を用い実施例 339と同様に反応させ、 目的物を無色粉末として 得た。 [0847] The target compound was obtained as a colorless powder by reacting with the compound of Example 293 in the same manner as in Example 339.
FABMS : 471([M+H]+). FABMS: 471 ([M + H] + ).
1H-NMR(400MHz, DMSO-d ) δ 1.75— 1.91(2Η, m), 2.66— 2.88(4Η,  1H-NMR (400MHz, DMSO-d) δ 1.75― 1.91 (2Η, m), 2.66― 2.88 (4Η,
6  6
m), 3.57-3.65(2Η, m),5.12(2H, s), 7.00- 7.15(4Η, m), 7.25-7.45(8Η, m), 8.11(3Η, br s).  m), 3.57-3.65 (2Η, m), 5.12 (2H, s), 7.00-7.15 (4Η, m), 7.25-7.45 (8Η, m), 8.11 (3Η, br s).
[0848] [実施例 346]  [0848] [Example 346]
3—ァミノ— 7— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—ヒドロキシメチルヘプタン酸、塩酸塩 3—Amino—7— [4— (3-Benzyloxyphenol-sulfur) —2—Black mouth 3-hydroxymethylheptanoic acid, hydrochloride
[0849] [化 229] [0849] [Formula 229]
Figure imgf000150_0001
Figure imgf000150_0001
[0850] 実施例 296の化合物を用いて実施例 339と同様に反応させ、目的物を無色ァモル ファスとして得た。  [0850] The compound of Example 296 was reacted in the same manner as in Example 339 to give the desired product as colorless amorphous.
1H-NMR(400MHz, DMSO— d ) δ 1.36—1.40 (2Η, m),  1H-NMR (400MHz, DMSO- d) δ 1.36-1.40 (2Η, m),
6  6
1.48-1.55(2H, m), 1.67-1.71 (2H, m), 2.56(2H, m), 2.64—2.68 (2H, m)3.48 (IH, d, J=11.0Hz), 3.54 (IH, d, J=11.0Hz), 5.10 (2H, s), 5.52 (IH, br), 6.90—6.92 (IH, m), 6.96-7.01 (2H, m), 7.20-7.23 (IH, m), 7.30-7.42 (8H, m), 7.90(3H, br).  1.48-1.55 (2H, m), 1.67-1.71 (2H, m), 2.56 (2H, m), 2.64-2.68 (2H, m) 3.48 (IH, d, J = 11.0Hz), 3.54 (IH, d , J = 11.0Hz), 5.10 (2H, s), 5.52 (IH, br), 6.90-6.92 (IH, m), 6.96-7.01 (2H, m), 7.20-7.23 (IH, m), 7.30- 7.42 (8H, m), 7.90 (3H, br).
HRMS: 500.1647 (- 1.6mmu).  HRMS: 500.1647 (-1.6mmu).
[0851] [実施例 347] [0851] [Example 347]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (3—トリフルォロメチルフエ-ルォキシ)—2— クロ口フエ-ル]へキサン酸  3-Amino-3-Hydroxymethyl-6- [4- (3-Trifluoromethylphenoxy) -2-cyclobutane] hexanoic acid
[0852] [化 230]  [0852] [Formula 230]
Figure imgf000150_0002
Figure imgf000150_0002
[0853] 実施例 297の化合物を用い、実施例 336と同様に反応させ目的物を無色粉末として 得た。 [0853] The same procedures used in Example 336 were carried out except for using the compound of Example 297 to give a desired product as a colorless powder.
1H-NMR(400MHz, DMSO— d ) δ 1.50—1.62 (4Η, m), 1.95(1Η, d, 1 H-NMR (400MHz, DMSO- d) δ 1.50-1.62 (4Η, m), 1.95 (1Η, d,
6  6
J=15.6Hz), 2.04(1H, d, J=15.6Hz), 2.63— 2.66(2H, m), 5.27(1H, br), 7.00—6.03 (IH, m), 7.18-7.19 (IH, m), 7.29-7.30 (IH, m), 7.36-7.39 (2H, m), 7.50— 7.52(1H, m), 7.62-7.64(lH, m).  J = 15.6Hz), 2.04 (1H, d, J = 15.6Hz), 2.63- 2.66 (2H, m), 5.27 (1H, br), 7.00-6.03 (IH, m), 7.18-7.19 (IH, m ), 7.29-7.30 (IH, m), 7.36-7.39 (2H, m), 7.50-7.52 (1H, m), 7.62-7.64 (lH, m).
HRMS: 432.1178 (- 1.2mmu).  HRMS: 432.1178 (-1.2mmu).
FABMS : 432([M+H]+). [0854] [実施例 348] FABMS: 432 ([M + H] + ). [Example 348]
3—アミノー 6— [4— (3、 5—ビストリフルォロメチルフエ-ルスルファ -ル）—2—クロロフ ェ-ル ]ー3—ヒドロキシメチルへキサン酸  3-amino-6- [4- (3,5-bistrifluoromethylphenylsulfur) -2-chlorophenyl] -3-hydroxymethylhexanoic acid
[0855] [化 231] [0855] [Formula 231]
Figure imgf000151_0001
Figure imgf000151_0001
[0856] 実施例 298の化合物を用い、実施例 336と同様に反応させ目的物を無色粉末として 得た。 [0856] The same procedures used in Example 336 were carried out except for using the compound of Example 298 to give a desired product as a colorless powder.
FABMS : 516([M+H]+) FABMS: 516 ([M + H] + )
1H-NMR(400MHz, DMSO-d ) δ 1.54(4Η, brs), 1.93— 2.06(2Η,  1H-NMR (400MHz, DMSO-d) δ 1.54 (4Η, brs), 1.93― 2.06 (2Η,
6  6
m), 2.65-2.67(2Η, m), 3.32(2Η, m), 7.45(2Η, m), 7.64(1Η, d, J=1.2Hz), 7.85(2Η, s), 7.95(1Η, s).  m), 2.65-2.67 (2Η, m), 3.32 (2Η, m), 7.45 (2Η, m), 7.64 (1Η, d, J = 1.2Hz), 7.85 (2Η, s), 7.95 (1Η, s ).
[0857] [実施例 349] [0857] [Example 349]
3—アミノー 6— [4— (3、 5—ビストリフルォロメチルフエ-ルスルファ -ル）—2—クロロフ ェ-ル ]ー3—ヒドロキシメチルへキサン酸、塩酸塩  3-amino-6- [4- (3,5-bistrifluoromethylphenylsulfur) -2-chlorophenyl] -3-hydroxymethylhexanoic acid, hydrochloride
[0858] [化 232] [0858] [Formula 232]
Figure imgf000151_0002
Figure imgf000151_0002
[0859] 上記実施例 348の化合物を実施例 337と同様に反応させ目的物を無色油状物とし て得た。 [0859] The compound of Example 348 was reacted in the same manner as in Example 337 to give the desired product as a colorless oil.
1H-NMR(400MHz, DMSO-d ) δ 1.65— 1.80(4H, m), 2.70— 2.78(2Η,  1H-NMR (400MHz, DMSO-d) δ 1.65― 1.80 (4H, m), 2.70― 2.78 (2Η,
6  6
m), 3.27-3.37(2Η, m),4.21(2H, br s), 7.48(2H, m), 7.66(1H, s), 7.85(2H, s), 8.00(1H, s).  m), 3.27-3.37 (2Η, m), 4.21 (2H, br s), 7.48 (2H, m), 7.66 (1H, s), 7.85 (2H, s), 8.00 (1H, s).
[実施例 350]  [Example 350]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (3—トリフルォロメチルフエ-ルスルファ -ル） —2—クロ口フエ-ル]へキサン酸 3-Amino-3-Hydroxymethyl-6- [4— (3-Trifluoromethylphenylsulfur) —2—Chlorohexyl] hexanoic acid
[0860] [化 233] [0860] [Formula 233]
Figure imgf000152_0001
Figure imgf000152_0001
[0861] 実施例 299(3.00g)を 3mol/L水酸ィ匕ナトリウム (lOmL)水溶液に溶解し、 11時間還流し た。氷冷下、 4mol/L塩酸水溶液で中和して、析出した白色固体をろ取した。これを減 圧乾燥し目的物 [0861] Example 299 (3.00 g) was dissolved in a 3 mol / L aqueous sodium hydroxide solution (lOmL) and refluxed for 11 hours. The mixture was neutralized with a 4 mol / L hydrochloric acid aqueous solution under ice cooling, and the precipitated white solid was collected by filtration. This is dried under reduced pressure and the target product
(1.68g)を無色粉末として得た。  (1.68 g) was obtained as a colorless powder.
FABMS : 448([M+H]+) FABMS: 448 ([M + H] + )
1H-NMR(400MHz, DMSO— d ) δ 1.55(4H, s), 1.94(1H, d,  1H-NMR (400MHz, DMSO-d) δ 1.55 (4H, s), 1.94 (1H, d,
6  6
J=15.9Hz), 2.03(1H, d, J=15.9Hz), 2.64(2H, s), 3.27- 3.34(2H, m), 7.33(1H, dd, J=1.8Hz, 8.0Hz), 7.37-7.40(lH, m), 7.47(1H, d, J=1.8Hz), 7.52— 7.56(1H, m), 7.58-7.67(3H, m).  J = 15.9Hz), 2.03 (1H, d, J = 15.9Hz), 2.64 (2H, s), 3.27- 3.34 (2H, m), 7.33 (1H, dd, J = 1.8Hz, 8.0Hz), 7.37 -7.40 (lH, m), 7.47 (1H, d, J = 1.8Hz), 7.52-7.56 (1H, m), 7.58-7.67 (3H, m).
元素分析値（％) :C H C1F NO S + 2/3 H Oとして  Elemental analysis value (%): CH C1F NO S + 2/3 H O
20 21 3 3 2  20 21 3 3 2
C H N  C H N
計算値 ： 52.23 4.89 3.05  Calculated value: 52.23 4.89 3.05
実測値 ： 52.08 4.46 2.88  Measured value: 52.08 4.46 2.88
[0862] [実施例 351] [0862] [Example 351]
3—ァミノ— 3—ヒドロキシメチルー 6— [4— (3—トリフルォロメチルフエ-ルスルファ -ル） 2—クロロフヱニル]へキサン酸、塩酸塩  3-Amino-3-hydroxymethyl-6- [4- (3-trifluoromethylphenylsulfur) 2-chlorophenyl] hexanoic acid, hydrochloride
[0863] [化 234]
Figure imgf000152_0002
[0863] [Formula 234]
Figure imgf000152_0002
[0864] 上記実施例 （80.0mg)を 3mol/L塩酸 (20mL)水溶液に懸濁させ、酢酸ェチルにて 抽出し、飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去し目的 物（65.8mg)を無色アモルファスとして得た。 [0864] The above example (80.0 mg) was suspended in a 3 mol / L aqueous hydrochloric acid solution (20 mL), extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. Solvent is distilled off (65.8 mg) was obtained as a colorless amorphous.
FABMS : 448([M+H]+) FABMS: 448 ([M + H] + )
1H-NMR(400MHz, DMSO-d ) δ 1.59-1.73(2Η, m), 1.77-1.89(2Η,  1H-NMR (400MHz, DMSO-d) δ 1.59-1.73 (2Η, m), 1.77-1.89 (2Η,
6  6
m), 2.62(1Η, d, J=17.3Hz), 2.67— 2.80(2Η, m), 2.86(1Η, d, J=17.3Hz),  m), 2.62 (1Η, d, J = 17.3Hz), 2.67― 2.80 (2Η, m), 2.86 (1Η, d, J = 17.3Hz),
4.18-4.34(2H, m), 7.35-7.42(lH, m), 7.46(1H, d, J=7.9Hz), 7.51— 7.55(1H, m), 4.18-4.34 (2H, m), 7.35-7.42 (lH, m), 7.46 (1H, d, J = 7.9Hz), 7.51-7.55 (1H, m),
7.57-7.74(4H, m). 7.57-7.74 (4H, m).
[0865] [実施例 352] [0865] [Example 352]
3—アミノー 5—（4一才クチルフエ-ル )ー3—ヒドロキシメチルペンタン酸、塩酸塩  3-amino-5- (4-year-old octylphenol) -3-hydroxymethylpentanoic acid, hydrochloride
[0866] [化 235] [0866] [Formula 235]
Figure imgf000153_0001
Figure imgf000153_0001
[0867] 実施例 301の化合物を用い実施例 339と同様に反応させ目的物を無色粉末として 得た。  [0867] The same procedures used in Example 339 were carried out except for using the compound of Example 301 to give a desired product as a colorless powder.
FABMS : 336([M+H]+) FABMS: 336 ([M + H] + )
HRMS:336.2519(-1.9mmu)  HRMS: 336.2519 (-1.9mmu)
1H-NMR(400MHz, DMSO-d ) δ 0.84(3H, t, J=7.3Hz), 1 H-NMR (400MHz, DMSO-d) δ 0.84 (3H, t, J = 7.3Hz),
6  6
1.23-1.25(10H, m), 1.50- 1.53(2H, m), 1.86— 1.90(2H, m), 2.48- 2.59(4H, m), 2.65(2H, s), 3.54(1H, d, J=11.0Hz), 3.59(1H, d, J=11.0Hz), 5.56(1H, br),  1.23-1.25 (10H, m), 1.50- 1.53 (2H, m), 1.86- 1.90 (2H, m), 2.48- 2.59 (4H, m), 2.65 (2H, s), 3.54 (1H, d, J = 11.0Hz), 3.59 (1H, d, J = 11.0Hz), 5.56 (1H, br),
7.06(2H, d, J=8.6Hz), 7.09(2H, d, J=8.6Hz), 8.05(3H, br).  7.06 (2H, d, J = 8.6Hz), 7.09 (2H, d, J = 8.6Hz), 8.05 (3H, br).
[0868] [実施例 353] [0868] [Example 353]
3—ァミノ— 3—ァリルー 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロロフ ェ：ニ、 ル]へキサン酸、塩酸塩 [0869] [化 236] 3-Amino-3-Arylu 6- [4- (3-Benzyroxyphenol-sulfur-l) -2-chlorophen: di, l] hexanoic acid, hydrochloride [0869] [Formula 236]
Figure imgf000154_0001
Figure imgf000154_0001
[0870] 実施例 330の化合物を用い実施例 339と同様に反応させ目的物を無色粉末として 得た。  [0870] The compound of Example 330 was reacted in the same manner as in Example 339 to obtain the desired product as a colorless powder.
JH-NMR (400MHz, DMSO— d ) δ 1.53—1.71 (4H, m), 2.32-2.42 J H-NMR (400MHz, DMSO- d) δ 1.53-1.71 (4H, m), 2.32-2.42
6  6
(2H, m), 2.54 (2H, s), 2.64 (2H, t, J=7.3Hz), 5.08 (2H, s), 5.13—5.17 (2H, m), (2H, m), 2.54 (2H, s), 2.64 (2H, t, J = 7.3Hz), 5.08 (2H, s), 5.13-5.17 (2H, m),
5.70-5.80 (1H, m), 6.88—6.90 (1H, m), 6.94—7.00 (2H, m), 7.22-7.24 (1H, m),5.70-5.80 (1H, m), 6.88—6.90 (1H, m), 6.94—7.00 (2H, m), 7.22-7.24 (1H, m),
7.29-7.41 (8H, m), 8.05 (3H, br). 7.29-7.41 (8H, m), 8.05 (3H, br).
FABMS： 496 ([M+H]+). FABMS: 496 ([M + H] + ).
HRMS： 496.1698 (- 1.5mmu).  HRMS: 496.1698 (-1.5mmu).
[0871] [実施例 354] [0871] [Example 354]
3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 3 プロピルへキサン酸、塩酸塩  3-Amino-6- [4— (3-Benzyloxyphenol-sulfur-)-2-chlorophenol] —3-Propylhexanoic acid, hydrochloride
[0872] [化 237] [0872] [Formula 237]
Figure imgf000154_0002
Figure imgf000154_0002
[0873] 実施例 329 (520 mg)のジメチルスルホキシド（5 mL)、メタノール (4 mL)溶液に 5 mol/L -水酸ィ匕カリウム水溶液 (8 mL)及び lmol/L-水酸化リチウム水溶液 (2 mL)をカ卩えて 2日間 100°Cで撹拌した。反応液を常温にもどした後に水をカ卩え、 4 mol/L-塩酸を用いて中和した後に酢酸ェチルで抽出した。有機層を無水硫酸ナトリ ゥムで乾燥させ、濃縮し、残查をシリカゲルカラムクロマトグラフィー（酢酸ェチル Iメタノール =4 I 1)を用いて精製した。得られた淡白色アモルファスに 4mol/L-塩酸 を加え、酢酸ェチルで抽出し、淡白色アモルファスの目的物（208 mg)を得た。 [0873] A solution of 5 mol / L-potassium hydroxide aqueous solution (8 mL) and lmol / L-lithium hydroxide aqueous solution (8 mL) in a solution of Example 329 (520 mg) in dimethyl sulfoxide (5 mL) and methanol (4 mL) was added. 2 mL) was stirred at 100 ° C for 2 days. After the temperature of the reaction solution was returned to room temperature, water was removed, neutralized with 4 mol / L-hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified using silica gel column chromatography (ethyl acetate I methanol = 4 I 1). To the obtained pale-white amorphous, 4 mol / L-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. mg).
1H-NMR (400MHz, DMSO— d ) δ 0.83 (3H, t, J =7.3Hz),  1H-NMR (400MHz, DMSO- d) δ 0.83 (3H, t, J = 7.3Hz),
6  6
1.16-1.29 (2H, m), 1.43-1.72 (6H, m), 2.50 (2H, s), 2.65 (2H, t, J=7.3Hz), 5.08 1.16-1.29 (2H, m), 1.43-1.72 (6H, m), 2.50 (2H, s), 2.65 (2H, t, J = 7.3Hz), 5.08
(2H, s), 6.88-6.90 (1H, m), 6.94—7.00 (2H, m), 7.22-7.23 (1H, m), 7.24-7.41(2H, s), 6.88-6.90 (1H, m), 6.94-7.00 (2H, m), 7.22-7.23 (1H, m), 7.24-7.41
(8H, m), 7.94 (3H, br). (8H, m), 7.94 (3H, br).
FABMS： 498 ([M+H]+) FABMS: 498 ([M + H] + )
HRMS： 498.1897 (+2.7mmu.)  HRMS: 498.1897 (+ 2.7mmu.)
[0874] [実施例 355] [Example 355]
3—ァミノ— 6— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] - 3—Amino— 6— [4— (3-Benzyloxyphenyl-sulfur) -2-cyclobutane]
3—ヒドロキシプロピルへキサン酸、塩酸塩 3-hydroxypropylhexanoic acid, hydrochloride
[0875] [化 238] [0875] [Formula 238]
Figure imgf000155_0001
Figure imgf000155_0001
[0876] 実施例 333の化合物を用い実施例 339と同様に反応させ目的物を無色粉末として 得た。 [0876] The target compound was obtained as a colorless powder by reacting with the compound of Example 333 in the same manner as in Example 339.
JH-NMR (400MHz, DMSO- d ) δ 1.32-1.43 (2H, m), 1.51-1.70 J H-NMR (400MHz, DMSO- d) δ 1.32-1.43 (2H, m), 1.51-1.70
6  6
(6H, m), 2.63-2.67 (2H, m), 4.58 (1H, br), 5.09 (2H, s), 6.88—6.90 (1H, m), 6.95-7.00 (2H, m), 7.22-7.25 (1H, m), 7.29-7.41 (8H, m), 7.96 (3H, br).  (6H, m), 2.63-2.67 (2H, m), 4.58 (1H, br), 5.09 (2H, s), 6.88--6.90 (1H, m), 6.95-7.00 (2H, m), 7.22-7.25 (1H, m), 7.29-7.41 (8H, m), 7.96 (3H, br).
FABMS： 514 ([M+H]+). FABMS: 514 ([M + H] + ).
HRMS： 514.1829 (+1.0mmu.).  HRMS: 514.1829 (+ 1.0mmu.).
[0877] [実施例 356] [Example 356]
3—ァミノ— 5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—プロピルペンタン酸、塩酸塩 [0878] [化 239] 3-Amino-5- [4- (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -3-propylpentanoic acid, hydrochloride [0878] [Formula 239]
Figure imgf000156_0001
Figure imgf000156_0001
[0879] 実施例 331の化合物を用い実施例 339と同様に反応させ目的物を無色アモルファス として得た。  [0879] The compound of Example 331 was reacted in the same manner as in Example 339 to give the desired product as a colorless amorphous.
JH-NMR (400MHz, DMSO— d ) δ 0.79— 0.91(1H, m), 0.89(3H, t, J H-NMR (400MHz, DMSO- d) δ 0.79- 0.91 (1H, m), 0.89 (3H, t,
6  6
J=7.3Hz), 1.22-1.40(3H, m), 1.57-1.72(1H, m), 1.77-1.87(1H, m), 2.64-2.72(4H, m), 5.09(2H, s), 6.90— 7.00(3H, m), 7.23-7.40(9H, m), 8.00(3H, br).  J = 7.3Hz), 1.22-1.40 (3H, m), 1.57-1.72 (1H, m), 1.77-1.87 (1H, m), 2.64-2.72 (4H, m), 5.09 (2H, s), 6.90 — 7.00 (3H, m), 7.23-7.40 (9H, m), 8.00 (3H, br).
FABMS： 484 ([M+H]+). FABMS: 484 ([M + H] + ).
HRMS: 484.1736 (+1.8mmu.).  HRMS: 484.1736 (+ 1.8mmu.).
[0880] [実施例 357] [Example 357]
3—ァミノ— 3—ァリル 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口 フエニル]ペンタン酸、塩酸塩  3-Amino-3-Aryl 5- [4- (3-benzyloxyphenylsulfur-)-2-cyclopentylphenyl] pentanoic acid, hydrochloride
[0881] [化 240] [0881] [Formula 240]
Figure imgf000156_0002
Figure imgf000156_0002
[0882] 実施例 332の化合物を用い実施例 339と同様に反応させ目的物を淡黄色ァモルフ ァスとして得た。 [0882] The same procedures used in Example 339 were carried out except for using the compound of Example 332 to give a desired product as a pale yellow amorphous.
JH-NMR (400MHz, DMSO— d ) δ 1.81— 1.86(2H, m), 2.67(2H, d, J H-NMR (400MHz, DMSO- d) δ 1.81- 1.86 (2H, m), 2.67 (2H, d,
6  6
J=19.0Hz), 2.73-2.84(2H, m), 5.10(2H, s), 5.15— 5.25(2H, m), 5.80— 5.90(1H, m), 6.91-7.10(3H, m), 7.23-7.42(9H, m), 8.14(3H, br).  J = 19.0Hz), 2.73-2.84 (2H, m), 5.10 (2H, s), 5.15-5.25 (2H, m), 5.80-5.90 (1H, m), 6.91-7.10 (3H, m), 7.23 -7.42 (9H, m), 8.14 (3H, br).
FABMS： 482 ([M+H]+). FABMS: 482 ([M + H] + ).
HRMS: 482.1541 (— 1.6mmu.). [0883] [実施例 358] HRMS: 482.1541 (— 1.6mmu.). [0883] [Example 358]
3—ァミノ— 5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] - 3—ヒドロキシプロピルペンタン酸、塩酸塩  3-Amino-5- [4- (3-Benzyloxyphenylsulfur) -2-cyclobutane] -3-Hydroxypropylpentanoic acid, hydrochloride
[0884] [化 241] [0884] [Formula 241]
Figure imgf000157_0001
Figure imgf000157_0001
[0885] 実施例 334の化合物を用い実施例 339と同様に反応させ目的物を無色粉末として 得た。  [0885] The compound of Example 334 was reacted in the same manner as in Example 339 to obtain the desired product as a colorless powder.
JH-NMR (400MHz, DMSO— d ) δ 1.46- 1.53(2H, m), J H-NMR (400MHz, DMSO- d) δ 1.46- 1.53 (2H, m),
6  6
1.69-1.9K4H, m), 2.69-2.74(4H, m),3.40-3.41(2H, m), 4.64(1H, br), 5.10(2H, s), 6.91— 6.93(1H, m), 6.97-7.02(2H, m), 7.25-7.42(9H, m), 8.09(3H, br), 12.92(1H, br).  1.69-1.9K4H, m), 2.69-2.74 (4H, m), 3.40-3.41 (2H, m), 4.64 (1H, br), 5.10 (2H, s), 6.91-6.93 (1H, m), 6.97 -7.02 (2H, m), 7.25-7.42 (9H, m), 8.09 (3H, br), 12.92 (1H, br).
FABMS： 500 ([M+H]+). FABMS: 500 ([M + H] + ).
HRMS: 500.1669 (+0.6mmu.).  HRMS: 500.1669 (+ 0.6mmu.).
[0886] [実施例 359] [0886] [Example 359]
4—ァミノ— 7— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル] 4 ーヒドロキシメチルー 2—ヘプテン酸  4-Amino—7— [4— (3-Benzyloxyphenol-sulfur) -2-cyclophenol] 4-hydroxymethyl-2-heptenoic acid
[0887] [化 242] [0887] [Formula 242]
Figure imgf000157_0002
Figure imgf000157_0002
[0888] 実施例 227を実施例 335と同様にして Bu NFにてシリル基を脱保護して得られたアル [0888] In the same manner as in Example 335, Example 227 was used to deprotect the silyl group with Bu NF.
4  Four
コール体（289 mg)のエタノール（3 mL)溶液に lmol/L-水酸化カリウム水溶液（ 0.86mL)をカ卩ぇ 1時間加熱還流した。その後反応液を常温にもどし、水を加え、 4N- 塩酸を反応液が白濁するまでカ卩えた。酢酸ェチルと飽和食塩水を用いて分液し、有 機層を無水硫酸ナトリウムで乾燥させた後に濃縮し、減圧乾燥させ、白色ァモルファ スを得た。このアモルファスに、 10%塩酸含有メタノール（6 A lmol / L-potassium hydroxide aqueous solution (0.86 mL) was heated and refluxed for 1 hour in a solution of the coal (289 mg) in ethanol (3 mL). Thereafter, the reaction solution is returned to room temperature, water is added, and 4N- Hydrochloric acid was added until the reaction solution became cloudy. Liquid separation was performed using ethyl acetate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate, concentrated, and dried under reduced pressure to obtain white amorphous. In this amorphous, methanol containing 10% hydrochloric acid (6
mL)をカ卩え、室温でおよそ 20時間放置した後濃縮し、乾燥させると白色アモルファス が得られた。このものに再び lmol/L-水酸ィ匕カリウム水溶液（1.26 mL)をカ卩ぇ 2時間 加熱還流した。反応液を室温にもどし、水を加え、 PH7になるまで 4mol /い塩酸をカロ え、析出した結晶を濾取して乾燥させ、無色粉末の目的物（135  (mL) was concentrated at room temperature for about 20 hours, concentrated, and dried to obtain a white amorphous substance. To this solution, an lmol / L-potassium hydroxide aqueous solution (1.26 mL) was heated under reflux for 2 hours. The reaction solution is returned to room temperature, water is added, 4 mol / l hydrochloric acid is added until the pH becomes 7, and the precipitated crystals are collected by filtration and dried to give the target compound (135) as a colorless powder.
mg) "^守に。  mg) "^ For protection.
1H-NMR(400MHz, DMSO— d ) δ 1.39—1.59 (4Η, m), 2.61 (2H, t, 1 H-NMR (400MHz, DMSO- d) δ 1.39-1.59 (4Η, m), 2.61 (2H, t,
6  6
J =7.3Hz), 4.81 (1H, br), 5.08 (2H, s), 5.83 (1H, d, J=15.9Hz), 6.75 (1H, d, J=15.9Hz), 6.80-6.90 (1H, m), 6.94—6.99 (2H, m), 7.17-7.20 (1H, m), 7.25-7.40 (8H, m).  J = 7.3Hz), 4.81 (1H, br), 5.08 (2H, s), 5.83 (1H, d, J = 15.9Hz), 6.75 (1H, d, J = 15.9Hz), 6.80-6.90 (1H, m), 6.94-6.99 (2H, m), 7.17-7.20 (1H, m), 7.25-7.40 (8H, m).
HRMS: 489.1496 (— l.Ommu).  HRMS: 489.1496 (— l.Ommu).
[0889] [実施例 360] [0889] [Example 360]
4ーァミノ— 6— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 4-amino-6- [4- (3-benzyloxyphenol-sulfur-)-2-cyclobutane-]
4ーヒドロキシメチルー 2 キセン酸 4-hydroxymethyl-2xenoic acid
[0890] [化 243] [0890] [Formula 243]
Figure imgf000158_0001
Figure imgf000158_0001
[0891] 実施例 305(90 mg)に 10%含有塩酸メタノール (5 mL)を加えてー晚放置した後、濃 縮し、乾燥させて黄色の油状物質を得た。このものに、 lmol/L-水酸ィ匕カリウム水溶 液 (0.41mL)をカ卩え、 2時間加熱還流した。反応液を常温にもどし、 4mol/L-塩酸で PH6— 8とし、析出した結晶を濾取した後、酢酸ェチルとイソプロピルエーテルで洗い 目的物（18 [0891] To 305 (90 mg) was added 10% methanol-hydrochloric acid (5 mL), the mixture was allowed to stand, concentrated, and dried to obtain a yellow oily substance. To this solution was added lmol / L-potassium hydroxide aqueous solution (0.41 mL), and the mixture was heated under reflux for 2 hours. The reaction solution is cooled to room temperature, adjusted to pH 6-8 with 4 mol / L hydrochloric acid, and the precipitated crystals are collected by filtration, washed with ethyl acetate and isopropyl ether, and the desired product (18
mg)を無色粉末として得た。 mg) as a colorless powder.
— NMR(400MHz, DMSO— d ) δ 1.56-1.73 (2Η, m), 2.46-2.54 (1H, m), 2.68-2.76 (2H, m), 4.87 (1H, br), 5.09 (2H, s), 5.95 (1H, d, J=15.9Hz), 6.85-6.90 (2H, m), 6.94.-6.99 (2H, m), 7.20-7.22 (1H, m), 7.29-7.41 (8H, m). — NMR (400MHz, DMSO— d) δ 1.56-1.73 (2Η, m), 2.46-2.54 (1H, m), 2.68-2.76 (2H, m), 4.87 (1H, br), 5.09 (2H, s), 5.95 (1H, d, J = 15.9Hz), 6.85-6.90 (2H, m), 6.94.-6.99 (2H, m), 7.20-7.22 (1H, m), 7.29-7.41 (8H, m).
HRMS: 484.1350 (+0.1mmu).  HRMS: 484.1350 (+ 0.1mmu).
[0892] [実施例 361] [0892] [Example 361]
4ーァミノ— 7— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] - 4-amino-7- [4- (3-benzyloxyphenol-sulfur) -2-cyclobutane]-
4 プロピル 2 ヘプテン酸 4 propyl 2 heptenoic acid
[0893] [化 244] [0893] [Formula 244]
Figure imgf000159_0001
Figure imgf000159_0001
[0894] 実施例 302の化合物を用い上記実施例 360と同様に反応させ目的物を無色粉末と して得た。  [0894] The compound of Example 302 was reacted in the same manner as in Example 360 to obtain the desired product as a colorless powder.
1H-NMR(400MHz, DMSO— d ) δ 0.82(3H, t, J=7.3Hz), 1 H-NMR (400MHz, DMSO-d) δ 0.82 (3H, t, J = 7.3Hz),
6  6
0.82— 1.55(8H, m), 2.63-2.64 (2H, m), 5.09 (2H, s), 5.78 (1H, d, J=15.9Hz), 6.70 0.82-1.55 (8H, m), 2.63-2.64 (2H, m), 5.09 (2H, s), 5.78 (1H, d, J = 15.9Hz), 6.70
(1H, d, J=15.9Hz), 6.89-6.91 (1H, m), 6.95—6.99 (2H, m), 7.00-7.22 (1H, m),(1H, d, J = 15.9Hz), 6.89-6.91 (1H, m), 6.95—6.99 (2H, m), 7.00-7.22 (1H, m),
7.29-7.41 (8H, m). 7.29-7.41 (8H, m).
FABMS : 510 ([M+H]^.  FABMS: 510 ([M + H] ^.
[0895] [実施例 362] [0895] [Example 362]
4ーァミノ— 7— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 4-amino-7- [4- (3-benzyloxyphenol-sulfur-)-2-cyclobutane]-
4ーヒドロキシメチルヘプタン酸 4-hydroxymethylheptanoic acid
[0896] [化 245] [0896] [Formula 245]
Figure imgf000159_0002
Figure imgf000159_0002
[0897] 実施例 228 (149 mg) に 10%—塩酸含有メタノール（6 mL)を加え、室温でおよそ 20 時間放置した後濃縮し、得られた白色アモルファスをエタノール (5 [0897] To 228 mg (149 mg) of methanol containing 10% hydrochloric acid (6 mL) was added at room temperature After standing for a period of time, the mixture was concentrated.
mL)に溶解させ、 lmol/L-水酸ィ匕カリウム水溶液 (0.67mL)をカ卩えて 0.5時間加熱還 流した。反応液を常温にもどし、水を加え、 PH7になるまで 4mol /い塩酸をカ卩えた後、 酢酸ェチルと飽和食塩水を用いて分液した。有機層に析出した結晶を濾取して乾燥 させ、目的物 (42  mL), and an lmol / L-aqueous potassium hydroxide solution (0.67 mL) was added thereto, followed by heating and refluxing for 0.5 hour. The reaction solution was returned to room temperature, water was added, 4 mol / H hydrochloric acid was added until the pH became 7, and then liquid separation was performed using ethyl acetate and saturated saline. The crystals precipitated in the organic layer are collected by filtration and dried to give the desired product (42
mg)を無色粉末として得た。 mg) as a colorless powder.
— NMR(400MHz, DMSO— d ) δ 1.45— 1.54 (4Η, m), 2.15— 2.19  — NMR (400MHz, DMSO— d) δ 1.45— 1.54 (4Η, m), 2.15— 2.19
6  6
(2Η, m), 2.64-2.67 (2H, m), 3.25 (2H, s), 5.10 (2H, s), 6.89—6.91 (1H, m), (2Η, m), 2.64-2.67 (2H, m), 3.25 (2H, s), 5.10 (2H, s), 6.89—6.91 (1H, m),
6.97-7.00(2H, m), 7.21-7.23 (1H, m), 7.30-7.42 (8H, m). 6.97-7.00 (2H, m), 7.21-7.23 (1H, m), 7.30-7.42 (8H, m).
HRMS: 500.1656 (- 0.6mmu).  HRMS: 500.1656 (-0.6mmu).
[0898] [実施例 363] [0898] [Example 363]
4ーァミノ— 6— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 4-amino-6- [4- (3-benzyloxyphenol-sulfur-)-2-cyclobutane-]
4ーヒドロキシメチルへキサン酸 4-hydroxymethylhexanoic acid
[0899] [化 246] [0899] [Formula 246]
Figure imgf000160_0001
Figure imgf000160_0001
[0900] 実施例 308の化合物を用い上記実施例 362と同様に反応させ目的物を無色粉末と して得た。 [0900] The target compound was obtained as a colorless powder by reacting with the compound of Example 308 in the same manner as in Example 362 above.
— NMR(400MHz, DMSO— d ) δ 1.37— 1.38(2Η, m), 1.67— 1.75(3Η,  — NMR (400MHz, DMSO— d) δ 1.37— 1.38 (2Η, m), 1.67— 1.75 (3Η,
6  6
m), 2.28-2.32 (2Η, m), 2.65-2.69 (2Η, m), 5.10 (2H, s), 6.90—6.92 (1H, m), 6.95-7.01 (2H, m), 7.23-7.25 (1H, m), 7.28-7.42 (8H, m).  m), 2.28-2.32 (2Η, m), 2.65-2.69 (2Η, m), 5.10 (2H, s), 6.90--6.92 (1H, m), 6.95-7.01 (2H, m), 7.23-7.25 ( 1H, m), 7.28-7.42 (8H, m).
FABMS : 486 ([M+H] .  FABMS: 486 ([M + H].
[0901] [実施例 364] [0901] [Example 364]
(士 ) 4ーァミノ— 7— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ -ル] 4 プロピルヘプタン酸 [0902] [化 247] (S) 4-amino-7- [4- (3-benzoyloxy-sulfur-)-2-cyclohexyl] 4-propylheptanoic acid [0902] [Formula 247]
Figure imgf000161_0001
Figure imgf000161_0001
[0903] 実施例 302 (135 mg)のエタノール（2 mL)溶液に lmol/L-水酸化カリウム水溶液（ [0903] Example 302 A solution of lmol / L-potassium hydroxide aqueous solution (135 mg) in ethanol (2 mL)
0.64 mL)をカ卩え、 3時間加熱還流した。反応液に水を加え、氷浴中、 4mol/L-塩酸で PH1— 2とした。酢酸ェチルと飽和食塩水を用いて分液し、有機層を無水硫酸ナトリウ ムで乾燥させた後に濃縮し、無色油状物質を得た。この油状物質を酢酸ェチル (7 mL)に溶解させ、 10%パラジウム炭素（100 mg)をカ卩えて水素雰囲気下、 5日間室温 で撹拌した。触媒を濾去した後濾液を濃縮し、無色の油状物質を得た。このものをジ クロロメタン（3 0.64 mL) was heated and refluxed for 3 hours. Water was added to the reaction solution, and the mixture was adjusted to PH1-2 with 4 mol / L-hydrochloric acid in an ice bath. Liquid separation was performed using ethyl acetate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a colorless oily substance. This oily substance was dissolved in ethyl acetate (7 mL), 10% palladium on carbon (100 mg) was added, and the mixture was stirred at room temperature for 5 days under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated to obtain a colorless oily substance. This can be converted to dichloromethane (3
mL)に溶解させ、トリフルォロ酢酸 (2 mL)を加えて室温で 3時間撹拌した。反応液に 水をカ卩えた後、反応液が白濁するまで 4mol/い塩酸を加えていき（PH5— 3)酢酸ェ チルと飽和食塩水で分液した。有機層を無水硫酸ナトリウムで乾燥させた後に濃縮し 、目的物無を無色アモルファス（100  trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 3 hours. After water was added to the reaction solution, 4 mol / l hydrochloric acid was added until the reaction solution became cloudy (PH5-3), and the mixture was separated with ethyl acetate and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated.
mg)として得た。  mg).
1H-NMR(400MHz, DMSO— d ) δ 0.85 (3Η, t, J=7.3Hz), 1 H-NMR (400MHz, DMSO-d) δ 0.85 (3Η, t, J = 7.3Hz),
6  6
1.21- 1.22 (2H, m), 1.42-1.46 (2H, m), 1.52-1.54 (4H, m), 1.73-1.77 (2H, m), 1.21- 1.22 (2H, m), 1.42-1.46 (2H, m), 1.52-1.54 (4H, m), 1.73-1.77 (2H, m),
2.22- 2.26 (2H, m), 2.66 (2H, m), 5.08 (2H, s), 6.88-6.90 (1H, m), 6.92-7.00 (2H, m), 7.21-7.25 (1H, m), 7.26-7.45(8H, m). 2.22- 2.26 (2H, m), 2.66 (2H, m), 5.08 (2H, s), 6.88-6.90 (1H, m), 6.92-7.00 (2H, m), 7.21-7.25 (1H, m), 7.26-7.45 (8H, m).
HRMS: 512.2070 (+4.4mmu).  HRMS: 512.2070 (+ 4.4mmu).
[0904] [実施例 365] [0904] [Example 365]
( + )一 4ーァミノ— 7— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ -ル] 4 プロピルヘプタン酸  (+)-1-Amino—7— [4— (3-Benzyroxyphenol-sulfur-yl) —2-chlorophenol] 4Propylheptanoic acid
実施例 303の化合物を用い、上記実施例 364と同様に反応させ、目的物を無色ァモ 得た。  The same procedures used in Example 364 were carried out except for using the compound of Example 303 to give a desired product as a colorless polymer.
[ a T5 + 0.95° (C = 1.0, MeOH) [0905] [実施例 366] [a T 5 + 0.95 ° (C = 1.0, MeOH) [Example 366]
(一) 4—ァミノ— 7— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ- ル] 4 プロピルヘプタン酸  (1) 4-amino-7- [4- (3-benzyloxyphenylsulfur) -2-chlorophenol] 4-propylheptanoic acid
実施例 304の化合物を用い、上記実施例 364と同様に反応させ、 目的物を無色ァモ ルファスとして得た。  The same procedures used in Example 364 were carried out except for using the compound prepared in Example 304 to give a desired product as colorless ammonium sulfate.
[ α ]25 - 0.78。 (C = 1.0, MeOH) . [Α] 25 - 0.78. (C = 1.0, MeOH).
D  D
[0906] [実施例 367]  [Example 367]
4—アミノー 4—ヒドロキシメチルー 7— [4— (3—トリフルォロメチルフエ-ルスルファ -ル） 4-amino-4-hydroxymethyl-7- [4- (3-trifluoromethylphenylsulfur)
—2—クロ口フエ-ル]ヘプタン酸 —2—Chlorohexyl] heptanoic acid
[0907] [化 248] [0907] [Formula 248]
Figure imgf000162_0001
Figure imgf000162_0001
[0908] 実施例 309 (550mg)を 10%塩酸-メタノール (lOmL)溶液に溶解し、常温にてー晚放 置した。溶媒を留去し、得られた残渣をエタノール（lOmL)溶液に溶解し、 1-mol/L水 酸ィ匕カリウム水溶液 (1.31mL)をカ卩ぇ 3時間還流した。氷冷下、 1-mol/L塩酸水溶液で 中和して酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウム にて乾燥した。シリカゲルカラムクロマトグラフィー（水 Example 309 (550 mg) was dissolved in a 10% hydrochloric acid-methanol (10 mL) solution, and allowed to stand at room temperature. The solvent was distilled off, the obtained residue was dissolved in an ethanol (lOmL) solution, and a 1-mol / L aqueous solution of potassium hydroxide (1.31 mL) was refluxed for 3 hours. Under ice-cooling, the mixture was neutralized with a 1-mol / L hydrochloric acid aqueous solution, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. Silica gel column chromatography (water
：ァセトニトリル = 9 : 1→6 : 1→3 : 1→ 1： 1後にァセトニトリルのみ）で精製し、 目 的物 (72.4mg)を無色アモルファスとして得た。  : Acetonitrile = 9: 1 → 6: 1 → 3: 1 → 1: 1 followed by only acetonitrile) to give the desired product (72.4 mg) as a colorless amorphous.
FABMS : 462([M+H]+)FABMS: 462 ([M + H] + )
— NMR(400MHz, DMSO— d ) δ 1.46-1.62(6H, m), 2.20(2H, t,  — NMR (400MHz, DMSO— d) δ 1.46-1.62 (6H, m), 2.20 (2H, t,
6  6
J=7.3Hz), 2.64-2.68(2H,m), 3.56— 3.62(2H, m), 7.33(1H, dd, J=1.8Hz, 8.0Hz), 7.35-7.42(lH, m), 7.47-7.49(lH, m), 7.52- 7.56(1H, m), 7.58- 7.66(3H, m).  J = 7.3Hz), 2.64-2.68 (2H, m), 3.56― 3.62 (2H, m), 7.33 (1H, dd, J = 1.8Hz, 8.0Hz), 7.35-7.42 (lH, m), 7.47- 7.49 (lH, m), 7.52- 7.56 (1H, m), 7.58- 7.66 (3H, m).
[0909] [実施例 368] [0909] [Example 368]
2—ァミノ— 2—エトキシカルボ-ルー 5— [4— (3、 5 ビストリフルォロメチルフエ-ル）ォ キシフエニル]ペンタン酸ェチル、塩酸塩 -_ (^ ^-Z- ( -ェ ^^ べ:^— ε)— ] - - ^ .-Z 2-Amino-2-ethoxycarbol-5- [4- (3,5-bistrifluoromethylphenyl) oxyphenyl] ethyl ethylpentanoate, hydrochloride -_ (^ ^ -Z- (-e ^^ be: ^ — ε) —]--^ .-Z
•(jq 'm)zvs '(^ ' )WL-6z-L '(ZH8-T 'ΖΗΟ"8=Γ 'PP 'HWL • (jq 'm) zvs'(^') WL-6z-L '( Z H8-T' Ζ ΗΟ "8 = Γ 'PP' HWL
'(ω 'HS)T0"Z-68"9 '( 'HT)T8"S 'H2)80"S '(ω 'HS)SS' —Sr '(ζΗΟ·ΐΐ=ί" '(ω' HS) T0 "Z-68" 9 '(' HT) T8 "S 'H2) 80"S' (ω 'HS) SS' —Sr '( ζ ΗΟ · ΐΐ = ί "
'p Ήΐ)9 ·ε '(ζΗ0·π=ί" 'ρ 'HDSST '(^q 'nz)wz '(s 'HS)SZ'I '(^q 'p Ήΐ) 9 · ε' (ζΗ0 · π = ί "'ρ' HDSST '(^ q' nz) wz '( s ' HS) SZ'I' (^ q
'Hi)es"T '(zHS" =f ^ Ήε)ΖΓΐ 9 ( oswa 'ZH勵 o ) N— HT 'Hi) es "T'(zHS" = f ^ Ήε) ΖΓΐ 9 (oswa 'ZH promote o) N— H T
(+[H+ ])00S： ( + [H +]) 00S:
Figure imgf000163_0001
Figure imgf000163_0001
[0S2^ ] [SI60] /^ェ邈べ^べ ^ 、^ 、 — s [0S2 ^] [SI60] / ^^^^^^^^
-_ ΐ^ ^-Z- ( -ェ ^^ べ:^— ε)— ] -9-/^ .-Z  -_ ΐ ^ ^ -Z- (-e ^^ be: ^ — ε) —] -9-/ ^ .-Z
[69εί^¾ϊ第] [2Ϊ60] •(ω 'HS)99"Z-8S"Z  [69εί ^ ¾ϊdai] [2Ϊ60] • (ω 'HS) 99 "Z-8S" Z
'(s 'HT)S8"Z '(s 'HS)SS'Z
Figure imgf000163_0002
'P 'Η2)3ΓΖ '(s' HT) S8 "Z '(s' HS) SS'Z
Figure imgf000163_0002
'P' Η2) 3ΓΖ
'(zH8"9=f 'b 'HWf WL=i ' 'ΗΖ) 9'Ζ '(ω'Η εΐ — '(ω 'Η 99·ΐ— S9'I '( z H8 "9 = f' b 'HWf WL = i''ΗΖ)9'Ζ'(ω'Η εΐ — '(ω' Η 99 · ΐ— S9'I
'(ΖΗ8·9=1" ' Ή9)0ΖΊ 9 (V-OSViQ 'ΖΗ勵 0 )Η顺— ΗΤ '(ΖΗ8 · 9 = 1 "' Ή9) 0ΖΊ 9 (V-OSViQ 'ΖΗpromotion 0) Η 顺 — Η Τ
。 ェつ;呦^ ^ ¾ 呦 W目 っ 鷇 翻 s .呦 ^^ ¾ 呦 目 目 目 目 s
^ -K^m z^^m ^ ^-%oi^(s ) ^a>6 m^ [π6ο]
Figure imgf000163_0003
^ -K ^ m z ^^ m ^ ^-% oi ^ ( s ) ^ a> 6 m ^ [π6ο]
Figure imgf000163_0003
[6fZ^] [0160] 2—エトキシカルボ二ルペンタン酸ェチル、塩酸塩 [6fZ ^] [0160] 2-Ethylcarboxyethylpentanoate, hydrochloride
[0916] [化 251] [0916] [Formula 251]
Figure imgf000164_0001
Figure imgf000164_0001
[0917] 実施例 27の化合物を用い実施例 368と同様に反応させ目的物を無色アモルファス として得た。  [0917] The compound of Example 27 was reacted in the same manner as in Example 368 to give the desired product as a colorless amorphous.
FABMS : 542([M+H]+). FABMS: 542 ([M + H] + ).
1H-NMR(400MHz, DMSO-d ) δ 1.19(6Η, t, J=6.8Hz),  1H-NMR (400MHz, DMSO-d) δ 1.19 (6Η, t, J = 6.8Hz),
6  6
1.60-1.62(2Η, m), 2.12- 2.16(2Η,  1.60-1.62 (2Η, m), 2.12- 2.16 (2Η,
m), 2.69(2Η, t, J=7.3Hz), 4.23(4H, q, J=6.8Hz), 5.08(2H, s), 6.89— 7.01(3H, m), 7.23(1H, dd, J=6.1Hz, 1.8Hz), 7.29-7.41(8H, m), 9.24(3H, br).  m), 2.69 (2Η, t, J = 7.3Hz), 4.23 (4H, q, J = 6.8Hz), 5.08 (2H, s), 6.89― 7.01 (3H, m), 7.23 (1H, dd, J = 6.1Hz, 1.8Hz), 7.29-7.41 (8H, m), 9.24 (3H, br).
[0918] [実施例 371]  [0918] [Example 371]
2—ァミノ一 5— [4— (3—ベンジルォキシフエ-ルォキシ）一 2—クロ口フエ-ル]ペンタン 酸メチル、塩酸塩  2-amino-5- [4- (3-benzyloxyphen-loxy) -l-chlorophene] methylpentanoate, hydrochloride
[0919] [化 252]  [0919] [Formula 252]
Figure imgf000164_0002
Figure imgf000164_0002
[0920] 実施例 222の化合物を用い実施例 368と同様に反応させ目的物を無色油状物とし て得た。 FABMS : 440([M+H]+). [0920] The compound of Example 222 was reacted in the same manner as in Example 368 to give the desired product as a colorless oil. FABMS: 440 ([M + H] + ).
^-NMRC^OMHz, DMSO-d ) δ 1.60-1.82(4Η, m), 2.67(2Η, t,  ^ -NMRC ^ OMHz, DMSO-d) δ 1.60-1.82 (4Η, m), 2.67 (2Η, t,
6  6
J=7.3Hz), 3.80(3Η, s), 5.08(2Η, s), 6.56(1Η, dd, J=8.0Hz, 1.5Hz), 6.66(1H, d, J=2.2Hz), 6.82(1H, dd, J=8.3Hz, 2.4Hz), 6.94(1H, dd, J=8.3Hz, 2.4Hz), 7.05(1H, t, J=2.4Hz), 7.28-7.43(7H,m), 8.49(3H, br).  J = 7.3Hz), 3.80 (3Η, s), 5.08 (2Η, s), 6.56 (1Η, dd, J = 8.0Hz, 1.5Hz), 6.66 (1H, d, J = 2.2Hz), 6.82 (1H , dd, J = 8.3Hz, 2.4Hz), 6.94 (1H, dd, J = 8.3Hz, 2.4Hz), 7.05 (1H, t, J = 2.4Hz), 7.28-7.43 (7H, m), 8.49 ( 3H, br).
[0921] [実施例 372] [0921] [Example 372]
2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2 プロピノレペンタン酸 2—Amino—5— [4— (3—Benzyroxyfile-Sulfur-L) —2—Black-Mouth-Fer] —2 Propinolepentanoic acid
[0922] [化 253]  [0922] [Formula 253]
Figure imgf000165_0001
Figure imgf000165_0001
[0923] 実施例 244の化合物を用い実施例 336と同様に反応させ目的物を淡黄色粉末とし て得た。  [0923] The compound of Example 244 was reacted in the same manner as in Example 336 to obtain the desired product as a pale yellow powder.
FABMS : 484([M+H]+). FABMS: 484 ([M + H] + ).
1H-NMR(400MHz, DMSO— d ) δ 0.78(3H, t, J=7.3Hz),  1H-NMR (400MHz, DMSO-d) δ 0.78 (3H, t, J = 7.3Hz),
6  6
1.11— 1.33(4H, m), 1.46— 1.88(4H,m), 2.59(2H, br s), 5.08(2H, s), 6.87— 6.99(3H, m), 7.22-7.4K9H, m).  1.11-1.33 (4H, m), 1.46-1.88 (4H, m), 2.59 (2H, br s), 5.08 (2H, s), 6.87-6.99 (3H, m), 7.22-7.4K9H, m).
[0924] [実施例 373] [0924] [Example 373]
2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2 ーヒドロキシメチルペンタン酸  2-Amino-5- [4- (3-benzyloxyphenylsulfur) -2-chlorophenol] -2-hydroxymethylpentanoic acid
[0925] [化 254] [0925] [Formula 254]
Figure imgf000165_0002
Figure imgf000165_0002
[0926] 実施例 369の化合物を用い実施例 336と同様に反応させ目的物を無色粉末として 得た。  [0926] The compound of Example 369 was reacted in the same manner as in Example 336 to obtain the desired product as a colorless powder.
FABMS : 472([M+H]+). FABMS: 472 ([M + H] + ).
1H-NMR(400MHz, DMSO-d ) δ 1.44- 1.69(4Η, m), 2.60(2Η, t,  1H-NMR (400MHz, DMSO-d) δ 1.44- 1.69 (4Η, m), 2.60 (2Η, t,
6  6
J=7.3Hz), 3.43(1Η, d, J=10.4Hz), 3.52(1H, d, J=10.4Hz), 5.05(2H, s), 5.38(1H, br), 6.87-6.99(3H, m), 7.24(1H, dd, J=8.0Hz, 1.8Hz), 7.28-7.41(8H, m).  J = 7.3Hz), 3.43 (1Η, d, J = 10.4Hz), 3.52 (1H, d, J = 10.4Hz), 5.05 (2H, s), 5.38 (1H, br), 6.87-6.99 (3H, m), 7.24 (1H, dd, J = 8.0Hz, 1.8Hz), 7.28-7.41 (8H, m).
[0927] [実施例 374] [0927] [Example 374]
2—アミノー 4— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 2 ーヒドロキシメチル酪酸 2-Amino 4- [4— (3-Benzyroxyphenol-sulfur) -2 -Hydroxymethylbutyric acid
[0928] [化 255]  [0928] [Formula 255]
Figure imgf000166_0001
Figure imgf000166_0001
[0929] 実施例 312の化合物を用い、実施例 362と同様に反応させ目的物を無色粉末として 得た。 FABMS : 458([M+H]+).[0929] The compound of Example 312 was reacted in the same manner as in Example 362 to give the desired product as a colorless powder. FABMS: 458 ([M + H] + ).
- NMR(400MHz, DMSO- d ) δ 1.72- 1.80(1H, m), 1.85- 1.92(1H,  -NMR (400MHz, DMSO- d) δ 1.72- 1.80 (1H, m), 1.85- 1.92 (1H,
6  6
m), 2.53-2.66(1H, m),2.76-2.84(lH, m), 3.54(1H, d, J=11.0Hz), 3.59(1H, d, J=11.0Hz),  m), 2.53-2.66 (1H, m), 2.76-2.84 (lH, m), 3.54 (1H, d, J = 11.0Hz), 3.59 (1H, d, J = 11.0Hz),
5.08(2H, s), 5.37(1H, br), 6.87— 6.89(1H, m), 6.93— 6.98(2H, m), 7.21-7.40(9H, m).  5.08 (2H, s), 5.37 (1H, br), 6.87-6.89 (1H, m), 6.93-6.98 (2H, m), 7.21-7.40 (9H, m).
[0930] [実施例 375]  [0930] [Example 375]
2—ァミノ— 5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—カルボキシペンタン酸  2-Amino-5- [4- (3-Benzyloxyphenyl-sulfur) -2-cyclobutane] -2-carboxypentanoic acid
[0931] [化 256] [0931] [Formula 256]
Figure imgf000166_0002
Figure imgf000166_0002
[0932] 実施例 370の化合物を用い、実施例 336と同様に反応させ目的物を無色粉末として 得た。 [0932] The compound of Example 370 was reacted in the same manner as in Example 336 to give the desired product as a colorless powder.
FABMS : 486([M+H]+). FABMS: 486 ([M + H] + ).
1H-NMR(400MHz, DMSO— d ) δ 1.57(2H, br s), 1.82(2H, br s), 1 H-NMR (400MHz, DMSO-d) δ 1.57 (2H, br s), 1.82 (2H, br s),
6  6
2.63(2H, t, J=7.3Hz), 5.08(2H, s), 6.89— 7.00(3H, m), 7.20(1H, dd, J=8.0Hz, 1.8Hz), 7.27-7.4K8H, m).  2.63 (2H, t, J = 7.3Hz), 5.08 (2H, s), 6.89- 7.00 (3H, m), 7.20 (1H, dd, J = 8.0Hz, 1.8Hz), 7.27-7.4K8H, m) .
[0933] [実施例 376] [2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル] - 2—メチル]ペンチルォキシ酢酸 [0933] [Example 376] [2-Amino-5- [4- (3-benzyloxyphenyl-sulfur-yl) -2-chlorophenol] -2-methyl] pentyloxyacetic acid
[0934] [化 257] [0934] [Formula 257]
Figure imgf000167_0001
Figure imgf000167_0001
[0935] 実施例 314 (492mg)を塩化メチレン（5mL)に溶解し、氷冷下、トリフルォロ酢酸（5mL )を加えた後、常温にもどして 12時間撹拌した。反応液を濃縮後、残渣に水を加え酢 酸ェチルで抽出後、飽和食塩水で洗浄し無水硫酸ナトリウムで乾燥後濃縮した。残 渣をシリカゲルカラムクロマトグラフィー（MeCN:水 = 1： 5→1： 1)で精製し、 目的物 (144mg)を無色粉末として得た。 [0935] Example 314 (492 mg) was dissolved in methylene chloride (5 mL), and trifluoroacetic acid (5 mL) was added under ice-cooling, and the mixture was returned to room temperature and stirred for 12 hours. After concentration of the reaction solution, water was added to the residue, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (MeCN: water = 1: 5 → 1: 1) to give the desired product (144 mg) as a colorless powder.
FABMS : 500 ([M+H] .  FABMS: 500 ([M + H].
1H-NMR(400MHz, DMSO-d +TFA-d) δ 1.16(3Η, s), 1 H-NMR (400MHz, DMSO-d + TFA-d) δ 1.16 (3Η, s),
6  6
1.55- 1.68(4Η, m), 2.68(2Η, t, J=6.7Hz), 3.45(1Η, d, J=9.8Hz), 3.52(1H, d,  1.55- 1.68 (4Η, m), 2.68 (2Η, t, J = 6.7Hz), 3.45 (1Η, d, J = 9.8Hz), 3.52 (1H, d,
J=9.8Hz), 4.11(2H, d, J=2.4Hz), 5.10(2H,s), 6.91(1H, d, J=7.9Hz), 6.96— 6.97(1H, m), 7.01(1H, dd, J=8.6Hz, 2.4Hz), 7.24(1H, dd, J=7.9Hz, 1.8Hz), 7.31-7.42(8H, m).  J = 9.8Hz), 4.11 (2H, d, J = 2.4Hz), 5.10 (2H, s), 6.91 (1H, d, J = 7.9Hz), 6.96-6.97 (1H, m), 7.01 (1H, dd, J = 8.6Hz, 2.4Hz), 7.24 (1H, dd, J = 7.9Hz, 1.8Hz), 7.31-7.42 (8H, m).
元素分析値（％) : C H C1NO S.7/10H Oとして  Elemental analysis value (%): as CH C1NO S.7 / 10HO
27 30 4 2  27 30 4 2
C H N  C H N
計算値 63.26 6.17 2.73  Calculated 63.26 6.17 2.73
実測値 63.16 5.91 2.98  Measured 63.16 5.91 2.98
[0936] [実施例 377] [0936] [Example 377]
[2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—ヒドロキシメチル]ペンチルォキシ酢酸 [0937] [化 258] [2-Amino-5- [4- (3-benzyloxyphenyl-sulfur) -2-cyclobutane] -2-hydroxymethyl] pentyloxyacetic acid [0937] [Formula 258]
Figure imgf000168_0001
Figure imgf000168_0001
[0938] 実施例 315の化合物を用い上記実施例 376と同様に反応させ目的物を無色粉末と して得た。 [0938] The same procedures used in Example 376 were carried out except for using the compound of Example 315 to give the desired product as a colorless powder.
HRMS: 516.1641 (+3.0mmu).  HRMS: 516.1641 (+ 3.0mmu).
JH-NMR (400MHz, DMSO— d ) δ 1.55(4H, m), 2.63 (2H, m), 3.63 J H-NMR (400MHz, DMSO- d) δ 1.55 (4H, m), 2.63 (2H, m), 3.63
6  6
(2H, s), 5.10(2H, s), 6.90—6.92 (1H, m), 6.97— 7.00(2H, m), 7.21-7.24 (1H, m), (2H, s), 5.10 (2H, s), 6.90-6.92 (1H, m), 6.97- 7.00 (2H, m), 7.21-7.24 (1H, m),
7.30-7.42 (8H, m). 7.30-7.42 (8H, m).
[0939] [実施例 378] [0939] [Example 378]
[2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]] ペンチルォキシ酢酸  [2-Amino-5- [4- (3-Benzyroxyphenol-sulfur-yl) -2-chloro-cyclohexyl]] pentyloxyacetic acid
[0940] [化 259]
Figure imgf000168_0002
[0940] [Formula 259]
Figure imgf000168_0002
[0941] 実施例 313ィ匕合物を用い上記実施例 376と同様に反応させ目的物を無色ァモルフ ァスとして得た。 Example 313 The same procedure as in Example 376 was carried out except that the target compound was obtained as a colorless amorphous.
FABMS : 486 ([M+H] .  FABMS: 486 ([M + H].
1H-NMR(400MHz, DMSO-d ) δ 1.56— 1.59(4H, m), 2.63— 2.67(2Η,  1H-NMR (400MHz, DMSO-d) δ 1.56--1.59 (4H, m), 2.63-2.67 (2Η,
6  6
m), 3.29(1Η, br), 3.52— 3.65(2Η, m), 4.05(2Η, s), 5.10(2Η, s), 6.71— 6.81(3Η, m), 7.00-7.35(9Η, m).  m), 3.29 (1Η, br), 3.52― 3.65 (2Η, m), 4.05 (2Η, s), 5.10 (2Η, s), 6.71― 6.81 (3Η, m), 7.00-7.35 (9Η, m) .
[0942] [実施例 379] [Example 379]
[2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 2—メトキシメチルカルボキシ]ペンチルォキシ酢酸 [0943] [化 260] [2-Amino-5- [4- (3-benzyloxyphenyl-sulfur) -2-cyclobutane] -2-methoxymethylcarboxy] pentyloxyacetic acid [0943] [Formula 260]
Figure imgf000169_0001
Figure imgf000169_0001
[0944] 実施例 316の化合物を用い、実施例 376と同様に反応させ目的物を無色粉末として 得た。 HRMS: 574.1631 (- 3.5mmu).  The compound of Example 316 was reacted in the same manner as in Example 376 to obtain the desired product as a colorless powder. HRMS: 574.1631 (-3.5mmu).
1H-NMR(400MHz, DMSO— d ) δ 1.62— 1.64(4H, m), 2.63-2.67(2H,  1H-NMR (400MHz, DMSO- d) δ 1.62- 1.64 (4H, m), 2.63-2.67 (2H,
6  6
m), 3.63 (2H, t, J =7.0Hz), 3.51 (4H, s), 3.88 (4H, s), 5.13 (2H, s), 6.89—6.91 (1H, m), 6.97-7.01 (2H, m), 7.22-7.24 (1H, m), 7.30-7.42 (8H, m).  m), 3.63 (2H, t, J = 7.0Hz), 3.51 (4H, s), 3.88 (4H, s), 5.13 (2H, s), 6.89-6.91 (1H, m), 6.97-7.01 (2H , m), 7.22-7.24 (1H, m), 7.30-7.42 (8H, m).
[0945] [実施例 380]  [0945] [Example 380]
2— [2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル ]ペンチルォキシ]マロン酸ジェチル、塩酸塩  2- [2-Amino-5- [4- (3-Benzyroxyphenyl-sulfur-)-2-cyclobutane] pentyloxy] Jetylmalonate, hydrochloride
[0946] [化 261]  [0946] [Formula 261]
Figure imgf000169_0002
Figure imgf000169_0002
[0947] 実施例 317の化合物を用い実施例 368と同様に反応させ目的物を無色油状物とし て得た。 FABMS : 586 ([M+H]+). The compound of Example 317 was reacted in the same manner as in Example 368 to obtain the desired product as a colorless oil. FABMS: 586 ([M + H] + ).
1H-NMR(400MHz, DMSO— d ) δ 1.18(6H, t, J=6.7Hz), 1.62(4H,  1H-NMR (400MHz, DMSO-d) δ 1.18 (6H, t, J = 6.7Hz), 1.62 (4H,
6  6
br s), 2.67(2H, br s), 3.31(1H, br), 3.45(2H, br), 4.10- 4.17(4H, m),  br s), 2.67 (2H, br s), 3.31 (1H, br), 3.45 (2H, br), 4.10-4.17 (4H, m),
4.75(lH,s), 5.08(2H, s), 6.73— 6.78(1H, m), 6.89— 7.00(2H, m), 7.17-7.43(9H, m), 8.01(3H, br s).  4.75 (lH, s), 5.08 (2H, s), 6.73-6.78 (1H, m), 6.89-7.00 (2H, m), 7.17-7.43 (9H, m), 8.01 (3H, br s).
[0948] [実施例 381] [0948] [Example 381]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]ェチルー 4ーヒ ドロキシメチルー 3—メチルー 2—ォキサゾリジノン [0949] [化 262] 4- [4- (3- (benzyloxyphenyl) sulfur-)-2-cyclobutyryl] ethyl 4-hydroxoxymethyl-3-methyl-2-oxazolidinone [0949] [Formula 262]
Figure imgf000170_0001
Figure imgf000170_0001
[0950] 氷冷下、実施例 295(150mg)の Ν,Ν-ジメチルホルムアミド (10mL)溶液に水素化ナト リウム (12.5mg)を加え、さらによう化メチル (21.4 L)を加え、氷冷下にて 2時間攪拌し た。反応液に飽和塩ィ匕アンモ-ゥム水溶液をカ卩えさらに氷水をカ卩え、酢酸ェチルに て抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を 留去しシリカゲルカラムクロマトグラフィー（和光シリカゲル C-300,  [0950] Under ice cooling, sodium hydride (12.5 mg) was added to a solution of Example 295 (150 mg) in Ν, Ν-dimethylformamide (10 mL), and methyl iodide (21.4 L) was further added. For 2 hours. An aqueous solution of saturated sodium chloride was added to the reaction solution, ice water was further purified, extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (Wako silica gel C-300,
へキサン：酢酸ェチル = 1 : 2)にて精製し、 目的物 (150mg)を無色油状物として得た  Hexane: ethyl acetate = 1: 2) to give the desired product (150 mg) as a colorless oil
NMR(400MHz, CDC1 ) δ 1.91-2.11(2H, m), 2.56-2.78(2H, NMR (400MHz, CDC1) δ 1.91-2.11 (2H, m), 2.56-2.78 (2H,
3  Three
m), 2.69(2H, s), 2.92(3H, s), 4.24(1H, d, J=9.2Hz), 4.40(1H, d, J=9.2Hz), 5.03(2H, s), 6.89— 6.94(1H, m), 6.95— 6.99(2H, m), 7.08— 7.12(1H, m), 7.14— 7.18(1H, m), m), 2.69 (2H, s), 2.92 (3H, s), 4.24 (1H, d, J = 9.2Hz), 4.40 (1H, d, J = 9.2Hz), 5.03 (2H, s), 6.89 6.94 (1H, m), 6.95- 6.99 (2H, m), 7.08- 7.12 (1H, m), 7.14-7.18 (1H, m),
7.24-7.43(7H, m). 7.24-7.43 (7H, m).
[0951] [実施例 382] [0951] [Example 382]
4— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]ェチルー 3— フエ二ルー 4ーヒドロキシメチルー 2—ォキサゾリジノン  4— [4— (3-benzyloxyphenol-sulfur-yl) -2-cyclobutyryl] ethyl 3- 3-phenyl 4-hydroxymethyl-2-oxazolidinone
[0952] [化 263] [0952] [Formula 263]
Figure imgf000170_0002
Figure imgf000170_0002
[0953] 氷冷下、実施例 295(200mg)の塩化メチレン (8mL)溶液に、モリキュラーシーブス (4 A,420mg)をカ卩え、さらにフエ-ルホウ酸 (154mg)、酢酸銅（153mg)及びトリェチルアミ ン（176 L)を加え、常温にて 2日間攪拌した。反応液をセライトろ過して、ろ液を留去 しシリカゲルカラムクロマトグラフィー（和光シリカゲル C-300, へキサン：酢酸ェチル =1： 1のちに 1： 2)にて精製し、 目的物 (96.2mg, 0.173mmol) を無色油状物として得た。 [0953] Under ice-cooling, molecular sieves (4 A, 420 mg) were added to a methylene chloride (8 mL) solution of Example 295 (200 mg), and phenolic boric acid (154 mg) and copper acetate (153 mg) were further added. And triethylamine (176 L) were added, and the mixture was stirred at room temperature for 2 days. The reaction solution was filtered through celite, the filtrate was distilled off, and silica gel column chromatography (Wako silica gel C-300, Hexane: ethyl acetate = 1: 1 followed by 1: 2) to give the desired product (96.2 mg, 0.173 mmol) as a colorless oil.
FABMS : 555([M+H]+). FABMS: 555 ([M + H] + ).
1H-NMR(400MHz, CDC1 ) δ 1.88-2.11(2Η, m), 2.68(2Η, s),  1H-NMR (400MHz, CDC1) δ 1.88-2.11 (2Η, m), 2.68 (2Η, s),
3  Three
2.73-2.93(2Η, m), 4.51(1Η, d, J=9.2Hz), 4.58(1Η, d, J=9.2Hz), 5.02(2H, s), 6.87-7.64(13H, m), 7.74(1H, d, J=7.9Hz), 8.25(3H, d, J=7.9Hz).  2.73-2.93 (2Η, m), 4.51 (1Η, d, J = 9.2Hz), 4.58 (1Η, d, J = 9.2Hz), 5.02 (2H, s), 6.87-7.64 (13H, m), 7.74 (1H, d, J = 7.9Hz), 8.25 (3H, d, J = 7.9Hz).
[0954] [実施例 383]  [0954] [Example 383]
N—メチルー 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口 フエ-ル ]ー3—ヒドロキシメチルペンタン酸、塩酸塩  N-methyl-3-amino-5- [4- (3-benzyloxyphenol-sulfur) -2-cyclophenol] -3-hydroxymethylpentanoic acid, hydrochloride
[0955] [化 264]  [0955] [Formula 264]
Figure imgf000171_0001
Figure imgf000171_0001
[0956] 実施例 381の化合物を実施例 339と同様に反応させ目的物を淡黄色油状物として 得た。 [0956] The compound of Example 381 was reacted in the same manner as in Example 339 to give the desired product as a pale yellow oil.
FABMS : 486([M+H]+). FABMS: 486 ([M + H] + ).
1H-NMR(400MHz, DMSO) δ 1.90(2Η, s), 2.41-2.57(2Η, m), 2.63-2.75(2Η, m), 2.70(3Η, s), 4.30— 4.40(2Η, m), 5.09(2Η, s), 6.87- 7.02(3Η, m), 7.17-7.27(1Η, m), 7.28-7.47(8Η, m).  1H-NMR (400MHz, DMSO) δ 1.90 (2Η, s), 2.41-2.57 (2Η, m), 2.63-2.75 (2Η, m), 2.70 (3Η, s), 4.30-4.40 (2Η, m), 5.09 (2Η, s), 6.87- 7.02 (3Η, m), 7.17-7.27 (1Η, m), 7.28-7.47 (8Η, m).
[0957] [実施例 384] [0957] [Example 384]
Ν—フエ-ルー 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ 口フエ-ル ]ー3—ヒドロキシメチルペンタン酸、塩酸塩 [0958] [化 263] フ -Fu-ru 3-Amino-5- [4- (3-Benzyloxyphenyl-sulfur- yl) -2-chloro phenol] -3-Hydroxymethylpentanoic acid, hydrochloride [0958] [Formula 263]
Figure imgf000172_0001
Figure imgf000172_0001
[0959] 実施例 382の化合物を実施例 339と同様に反応させ目的物を淡黄色油状物として 得た。  [0959] The compound of Example 382 was reacted in the same manner as in Example 339 to obtain the desired product as a pale yellow oil.
FABMS : 548([M+H]+). FABMS: 548 ([M + H] + ).
1H-NMR(400MHz, DMSO) δ 1.91(2Η, s), 2.51-2.62(2Η, m), 2.82(1Η, d, 1 H-NMR (400MHz, DMSO) δ 1.91 (2Η, s), 2.51-2.62 (2Η, m), 2.82 (1Η, d,
J=17.1Hz),  J = 17.1Hz),
2.89(1Η, d, J=17.1Hz), 4.31(1H, d, J=9.2Hz), 4.52(1H, d, J=9.2Hz), 5.08(2H, s), 6.58- 6.64(1H, m), 6.69(2H, d, J=7.9Hz), 6.84— 6.99(3H, m), 7.06— 7.42(11H, m).  2.89 (1Η, d, J = 17.1Hz), 4.31 (1H, d, J = 9.2Hz), 4.52 (1H, d, J = 9.2Hz), 5.08 (2H, s), 6.58- 6.64 (1H, m ), 6.69 (2H, d, J = 7.9Hz), 6.84- 6.99 (3H, m), 7.06-7.42 (11H, m).
[0960] [実施例 385— 386]  [Examples 385-386]
参考例 317の化合物を用いプロピルマロン酸ジェチル、ァリルマロン酸ジメチルを用 い実施例 229と同様に縮合した後、実施例 233と同様に加水分解し、得られたハーフ エステルを実施例 240と同様にして反応させ表 26に示すィ匕合物を得た。  Using the compound of Reference Example 317, condensation was performed in the same manner as in Example 229 using propyl methyl malonate and dimethyl aryl malonate, followed by hydrolysis in the same manner as in Example 233, and the obtained half ester was obtained in the same manner as in Example 240. The reaction was carried out to obtain a compound shown in Table 26.
[0961] [表 26] 表 26
Figure imgf000172_0002
[0961] [Table 26] Table 26
Figure imgf000172_0002
実施例 R R' 性状  Example R R 'Property
385 Pr Et 無色油状物  385 Pr Et colorless oil
386 allyl Me 黄色油状物  386 allyl Me yellow oil
[0962] 実施例 385: 1H-NMR(400MHz, CDC1 ) δ 0.88 (3Η, t, J =7.3Hz), Example 385: 1 H-NMR (400 MHz, CDC1) δ 0.88 (3Η, t, J = 7.3 Hz),
3  Three
1.00-1.05 (1H, m), 1.24—1.36 (1H, m), 1.31 (3H, t, J=7.3Hz), 1.67-1.74 (1H, m), 2.05-2.14 (1H, m), 2.27-2.37 (1H, m), 2.41-2.49 (1H, m), 2.58-2.67 (2H, m), 3.66 (3H, s), 4.20 (2H, m), 5.02 (2H, s), 5.87 (1H, br), 6.86—6.93 (3H, m), 7.11-7.14 (2H, m), 7.20-7.24 (IH, m), 7.29-7.40 (6H, m). 1.00-1.05 (1H, m), 1.24-1.36 (1H, m), 1.31 (3H, t, J = 7.3Hz), 1.67-1.74 (1H, m), 2.05-2.14 (1H, m), 2.27- 2.37 (1H, m), 2.41-2.49 (1H, m), 2.58-2.67 (2H, m), 3.66 (3H, s), 4.20 (2H, m), 5.02 (2H, s), 5.87 (1H, br), 6.86—6.93 (3H, m), 7.11-7.14 (2H, m), 7.20-7.24 (IH, m), 7.29-7.40 (6H, m).
[0963] 実施例 386: 1H-NMR(400MHz, CDC1 ) δ 2.08—2.21 (IH, m), Example 386: 1 H-NMR (400 MHz, CDC1) δ 2.08-2.21 (IH, m),
3  Three
2.48-2.55 (2H, m), 2.60-2.75 (2H, m), 3.10-3.19 (IH, m), 3.70 (3H, s), 3.77 (3H, s), 5.05 (2H, s), 5.09—5.13 (2H, m), 5.59-5.70 (IH, m), 5.83 (IH, br), 6.86-6.96 (3H, m), 7.12-7.18 (2H, m), 7.24-7.25 (IH, m), 7.30-7.40 (6H, m).  2.48-2.55 (2H, m), 2.60-2.75 (2H, m), 3.10-3.19 (IH, m), 3.70 (3H, s), 3.77 (3H, s), 5.05 (2H, s), 5.09— 5.13 (2H, m), 5.59-5.70 (IH, m), 5.83 (IH, br), 6.86-6.96 (3H, m), 7.12-7.18 (2H, m), 7.24-7.25 (IH, m), 7.30-7.40 (6H, m).
[0964] [実施例 387]  [0964] [Example 387]
4— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 2— (3—ヒド ロキシプロピル )ー2—メトキシカルボ-ルァミノ酪酸メチル  4- [4- (3-Benzyloxy) phenylsulfur-Lou 2-Cromouth Phthyl] — 2- (3-Hydroxypropyl) -2-methyl methoxycarbo-laminobutyrate
[0965] [化 264]  [0965] [Formula 264]
Figure imgf000173_0001
Figure imgf000173_0001
[0966] 実施例 386の化合物を用い実施例 333と同様に反応させ目的物を無色油状物とし て得た。  [0966] The target compound was obtained as a colorless oil by reacting with the compound of Example 386 in the same manner as in Example 333.
1H-NMR(400MHz, CDC1 ) δ 1.28—1.36 (IH, m), 1.51—1.62 (IH,  1H-NMR (400MHz, CDC1) δ 1.28-1.36 (IH, m), 1.51-1.62 (IH,
3  Three
m), 1.82-1.90 (IH, m),2.11— 2.17 (IH, m), 2.38—2.49 (2H, m), 2.57-2.70 (2H, m), 3.55-3.63 (2H, m), 3.66 (3H, s), 3.75 (3H, s), 5.02 (2H, s), 5.89 (IH, br), 6.86-6.93 (3H, m), 7.08-7.14 (2H, m), 7.20-7.24 (IH, m), 7.30-7.40 (6H, m).  m), 1.82-1.90 (IH, m), 2.11-2.17 (IH, m), 2.38-2.49 (2H, m), 2.57-2.70 (2H, m), 3.55-3.63 (2H, m), 3.66 ( 3H, s), 3.75 (3H, s), 5.02 (2H, s), 5.89 (IH, br), 6.86-6.93 (3H, m), 7.08-7.14 (2H, m), 7.20-7.24 (IH, m), 7.30-7.40 (6H, m).
[0967] [実施例 388— 390]  [0967] [Example 388-390]
実施例 385— 387の化合物を用い実施例 336と同様に反応させ表 27に示すィ匕合物 を合成した。  Using the compounds of Examples 385 to 387, the reaction was carried out in the same manner as in Example 336, and the conjugates shown in Table 27 were synthesized.
[0968] [表 27] ； ^峯氺％09コ)继缀 (Ί^ ΐ)Η^α¾αΤ¾: ^ ) 丄 O) ^V 39) ^エ； ^邈べ ciム Z60]
Figure imgf000174_0001
[0968] [Table 27] ^^ 氺 ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^
Figure imgf000174_0001
[S92^ ] [SZ60] ^エ邈 -έί / 、^ Hエー [S92 ^] [SZ60] ^ 邈-邈 /, ^ H エ ー
[ / -ェ
Figure imgf000174_0002
[/ -E
Figure imgf000174_0002
[ 60] [60]
•(ω 'Η6) 0VL-0Z-L '(ω 'ΗΖ) 66·9- 6·9 '(ω 'Ηΐ) 06·9- 8·9 '(s 'ΗΖ) 80'S ・ (Ω 'Η6) 0VL-0Z-L' (ω 'ΗΖ) 66 · 9-6.9' (ω 'Ηΐ) 0699-8.9' ( s ' ΗΖ) 80'S
'(ΖΗ6· 'VZ\=[ 'Ρ 'Ηΐ) WZ '(ΖΗ6· 'VZ\=[ 'Ρ 'Ηΐ) 8S '(ω 'HS) 88·ΐ- 8 ·ΐ  '(ΖΗ6 ·' VZ \ = ['Ρ' Ηΐ) WZ '(ΖΗ6 ·' VZ \ = ['Ρ' Ηΐ) 8S '(ω' HS) 88ΐ-8 -ΐ
'(ω 'ΗΪ) zvi- i 9 ( p-os^a ^unoof) ^nn-u^oe [ 60] '(ω' ΗΪ) zvi- i 9 (p-os ^ a ^ unoof) ^ nn-u ^ oe [60]
•(ω 'Η6) 0VL-0Z-L '(ω 'ΗΖ) 66·9- S6'9 '(ω • (ω 'Η6) 0VL-0Z-L' (ω 'ΗΖ) 669-S6'9' (ω
'Ηΐ) 06·9- 88·9 '(ω 'Ηΐ) S8'S- S  'Ηΐ) 069-889' (ω 'Ηΐ) S8'S- S
'(ω Ήζ) sre-eo"s Ήζ) so's '(ζΗε· Ύ£ΐ=ί 'ρ^ 'ΗΪ) OS'Z '(ZHS^ '(ω Ήζ) sre-eo "s Ήζ) so's' (ζΗε · Ύ £ ΐ = ί' ρ ^ 'ΗΪ) OS'Z' (ZHS ^
'VZl=i 'Ρ^ 'Ηΐ) '(ω 'ΗΖ) WZ-WZ Wf VST=f 'Ρ 'Ηΐ) S8"T '(ZHS''VZl = i' Ρ ^ 'Ηΐ)' (ω 'ΗΖ) WZ-WZ Wf VST = f' Ρ 'Ηΐ) S8 "T' (ZHS '
Figure imgf000174_0003
Η Ν-ΗΤ ： es [oz60]
Figure imgf000174_0003
Η Ν-Η Τ: es [ oz60]
•(ω 'Η6) ΖΥΙ-Ζτΐ '(ω Ή2) 00"Z-S6"9 '(ω 'Ηΐ) ΐ6·9— 68·9 • (ω 'Η6) ΖΥΙ-Ζτΐ' (ω Ή2) 00 "Z-S6" 9 '(ω' Ηΐ) ΐ6 · 9—68 · 9
'(s 'Η Ore '(ΖΗ6· 'ZHS 1=1" 'Ρ^ 'Ηΐ) £S'Z '(ΖΗ6· 'S 1=1" 'Ρ 'Ηΐ) 6S  '(s' Η Ore '(ΖΗ6 ·' ZHS 1 = 1 "'Ρ ^' Ηΐ) £ S'Z '(ΖΗ6 ·' S 1 = 1" 'Ρ' Ηΐ) 6S
'(ω 'ΗΖ) 88·ΐ— ·ΐ '(ω 'ΗΖ) 0 ·ΐ-ε3·ΐ '(ω 'Ηΐ) ·ΐ— Γΐ '(ω 'Ηΐ) 9Π— 8ΐ·ΐ '(ω' ΗΖ) 88 · ΐ— · ΐ '(ω' ΗΖ) 0 · ΐ-ε3 · ΐ '(ω' Ηΐ) · ΐ— Γΐ '(ω' Ηΐ) 9Π— 8ΐ · ΐ
Figure imgf000174_0004
Η Ν-ΗΤ： ss M [6960]
Figure imgf000174_0004
Η Ν-Η Τ : ss M [6960]
98fr HOE(zHO) 069 98fr HO E ( z HO) 069
89 |A||B 689  89 | A || B 689
Figure imgf000174_0005
Figure imgf000174_0005
£11 トリウム（lO.Omg)を加え、 80°Cで 20分間攪拌した後、参考例 329の化合物（138 mg)の THF (3mL)溶液をカ卩えた。 2時間後反応液を常温にもどし、 60%水素化ナトリウ ム（34.6mg)を加え 10分間攪拌した後、ァリルプロミド（124 μ L)を加えて攪拌した。 30 分後、反応液に水を加え、酢酸ェチルと飽和食塩水を用いて分液し、有機層を無水 硫酸ナトリウムで乾燥させ、濃縮し、残查をシリカゲルカラムクロマトグラフィー（へキサ ン £ 11 Thorium (100 mg) was added, and the mixture was stirred at 80 ° C for 20 minutes, and then a solution of the compound of Reference Example 329 (138 mg) in THF (3 mL) was added. Two hours later, the reaction solution was returned to room temperature, 60% sodium hydride (34.6 mg) was added, and the mixture was stirred for 10 minutes. Then, arylpromide (124 μL) was added, followed by stirring. After 30 minutes, water was added to the reaction solution, liquid separation was performed using ethyl acetate and saturated saline, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (hexane).
I酢酸ェチル = 10/1)を用いて精製し無色油状の目的物（126 mg)を得た。  Purification using I ethyl acetate (10/1) gave a colorless oily target product (126 mg).
JH-NMR (400MHz, CDC1 ) δ 1.26 (6Η, t, J =7.2Hz), 2.07-2.11  JH-NMR (400MHz, CDC1) δ 1.26 (6Η, t, J = 7.2Hz), 2.07-2.11
3  Three
(2H, m), 2.56-2.60 (2H, m), 2.74 (2H, d, J=7.2Hz), 4.20 (4H, q, J=7.2Hz), 5.08 (2H, m), 2.56-2.60 (2H, m), 2.74 (2H, d, J = 7.2Hz), 4.20 (4H, q, J = 7.2Hz), 5.08
(2H, s), 5.10-5.18 (2H, m), 5.64-5.74 (1H, m), 6.96-7.00 (3H, m), 7.04-7.06(2H, s), 5.10-5.18 (2H, m), 5.64-5.74 (1H, m), 6.96-7.00 (3H, m), 7.04-7.06
(1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m). (1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m).
FABMS : 553([M+H]+) FABMS: 553 ([M + H] + )
[0975] [実施例 392] [0975] [Example 392]
4— [4— (4—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—メチル酪酸ェチル  4— [4 -— (4-benzyloxy) phenylsulfur-l 2-cyclohexyl] — 2-ethoxycarbol 2-ethylethyl butyrate
[0976] [化 266]
Figure imgf000175_0001
[0976] [Formula 266]
Figure imgf000175_0001
[0977] ァリルプロミドの代わりにヨウ化メチルを用い上記実施例 391と同様に反応させ目的 物を無色油状物として得た。 [0977] The reaction was carried out in the same manner as in Example 391 using methyl iodide instead of arylpromide, and the desired product was obtained as a colorless oil.
1H-NMR (400MHz, CDC1 ) δ 1.26 (6Η, t, J =7.2Hz), 1.50 (3H,  1H-NMR (400MHz, CDC1) δ 1.26 (6Η, t, J = 7.2Hz), 1.50 (3H,
3  Three
s), 2.05-2.10 (2H, m), 2.60—2.65 (2H, m), 4.19 (4H, q, J=7.2Hz), 5.08 (2H, s), 6.95-6.99 (3H, m), 7.00-7.09 (1H, m), 7.11-7.12 (1H, m), 7.32-7.44 (7H, m). EIMS： 526 (M  s), 2.05-2.10 (2H, m), 2.60-2.65 (2H, m), 4.19 (4H, q, J = 7.2Hz), 5.08 (2H, s), 6.95-6.99 (3H, m), 7.00 -7.09 (1H, m), 7.11-7.12 (1H, m), 7.32-7.44 (7H, m). EIMS: 526 (M
[0978] [実施例 393] [0978] [Example 393]
4— [4— (4—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 2—エトキシ カルボ-ルー 2—プロピル酪酸ェチル [0979] [化 267]
Figure imgf000176_0001
4- [4- (4-Benzyloxy) phenol-sulfur-Lou 2-Cro-mouth]-2-Ethoxycarbo-Lu 2-ethyl propylbutyrate [0979] [Formula 267]
Figure imgf000176_0001
[0980] ァリルプロミドの代わりにヨウ化プロピルを用い実施例 391と同様に反応させ目的物 を無色油状物として得た。 [0980] The target compound was obtained as a colorless oil by reacting in the same manner as in Example 391 using propyl iodide instead of arylpromide.
JH-NMR (400MHz, CDC1 ) δ 0.95 (3Η, t, J=7.6Hz), 1.19—1.29 J H-NMR (400MHz, CDC1) δ 0.95 (3Η, t, J = 7.6Hz), 1.19-1.29
3  Three
(2H, m), 1.26 (6H, t, J =7.2Hz), 1.92—1.96 (2H, m), 2.08—2.12 (2H, m),  (2H, m), 1.26 (6H, t, J = 7.2Hz), 1.92-1.96 (2H, m), 2.08-2.12 (2H, m),
2.53-2.57 (2H, m), 4.19 (4H, q, J=7.2Hz), 5.08 (2H, s), 6.96-7.00 (3H, m), 2.53-2.57 (2H, m), 4.19 (4H, q, J = 7.2Hz), 5.08 (2H, s), 6.96-7.00 (3H, m),
7.05-7.07 (1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m). 7.05-7.07 (1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m).
EIMS： 554 (M  EIMS: 554 (M
[0981] [実施例 394] [0981] [Example 394]
2—ァリル 4— [4— (4 ベンジルォキシ）フエ-ルスルファ -ル— 2 クロ口フエ-ル]— 2-Aryl 4- [4- (4-benzyloxy) phenol-sulfur- 2-cyclohexyl-]-
2—ヒドロキシメチル酪酸ェチル 2-ethyl methyl butyrate
[0982] [化 268] [0982] [Formula 268]
Figure imgf000176_0002
Figure imgf000176_0002
[0983] 実施例 391の化合物（290 mg)の THF (3 mL)溶液に LiAl(0- tBu) H (666 mg)と  [0983] LiAl (0-tBu) H (666 mg) was added to a solution of the compound of Example 391 (290 mg) in THF (3 mL).
3  Three
LiAl(O-tBu) H (lmol/L- THF溶液）（11.0  LiAl (O-tBu) H (lmol / L-THF solution) (11.0
3  Three
mL)をカ卩えて 3時間加熱還流を続けた。反応液を常温にもどした後に水を加え、セラ イト濾過をした。濾液を酢酸ェチルと飽和食塩水を用いて分液し、有機層を無水硫 酸ナトリウムで乾燥させ、濃縮した。残查をシリカゲルカラムクロマトグラフィー（へキサ ン  mL) and heated under reflux for 3 hours. After the reaction solution was returned to room temperature, water was added, and the mixture was filtered through celite. The filtrate was separated using ethyl acetate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue is subjected to silica gel column chromatography (hexane
I酢酸ェチル =6/1)を用いて精製し、無色油状の目的物（212 mg)を得た。  Purification using I ethyl acetate = 6/1) gave the target compound (212 mg) as a colorless oil.
JH-NMR (400MHz, CDC1 ) δ 1.30 (3Η, t, J= 7.2Hz),  JH-NMR (400MHz, CDC1) δ 1.30 (3Η, t, J = 7.2Hz),
3  Three
1.74-1.88 (2H, m), 2.19 (1H, t, J=6.1Hz), 2.39 (1H, dd, J=14.0Hz, 7.3Hz), 2.52 (1H, dd, J=14.0, 6.7Hz), 2.52-2.72(2H, m), 3.76 (2H, t, J=6.1Hz), 4.19 (2H, q, J=7.2Hz), 5.08 (2H, s), 5.09—5.16 (2H, m), 5.74-5.82 (IH, m), 6.97—6.99 (3H, m), 7.04-7.06 (IH, m), 7.11-7.12 (lH,m), 7.33-7.45 (7H, m). 1.74-1.88 (2H, m), 2.19 (1H, t, J = 6.1Hz), 2.39 (1H, dd, J = 14.0Hz, 7.3Hz), 2.52 (1H, dd, J = 14.0, 6.7Hz), 2.52-2.72 (2H, m), 3.76 (2H, t, J = 6.1Hz), 4.19 (2H, q, J = 7.2Hz), 5.08 (2H, s), 5.09-5.16 (2H, m), 5.74-5.82 (IH, m), 6.97-6.99 (3H, m), 7.04-7.06 (IH, m), 7.11 -7.12 (lH, m), 7.33-7.45 (7H, m).
EIMS： 510 (M  EIMS: 510 (M
[0984] [実施例 395— 396] [0984] [Example 395- 396]
実施例 392、 393の化合物を用い実施例 394と同様に反応させ表 28に示すィ匕合物を 合成した。  Using the compounds of Examples 392 and 393, the reaction was carried out in the same manner as in Example 394, and the conjugates shown in Table 28 were synthesized.
[0985] [表 28] 表 28
Figure imgf000177_0001
[0985] [Table 28] Table 28
Figure imgf000177_0001
EIMS  EIMS
実施例 R 性状  Example R Properties
395 Μθ 無色油状物 484  395 Μθ colorless oil 484
396 Pr 無色油状物 512  396 Pr colorless oil 512
[0986] 実施例 395: 'H-NMR (400MHZ, CDCl ) δ 1.29 (3Η, t, J= 7.2Hz), [0986] Example 395: 'H-NMR (400MHZ, CDCl) δ 1.29 (3Η, t, J = 7.2Hz),
3  Three
1.26 (3H, s), 1.72-1.87 (2H, m), 2.32 (IH, t, J=6.8Hz), 2.62—2.66 (2H, m), 3.58 (IH, dd, J=11.2, 6.8Hz),3.76 (IH, dd, J=11.2, 6.8Hz), 4.19(2H, q, J=7.2Hz), 5.08 (2H, s), 6.96-7.00 (3H, m), 7.05-7.07 (IH, m), 7.11-7.12 (IH, m),  1.26 (3H, s), 1.72-1.87 (2H, m), 2.32 (IH, t, J = 6.8Hz), 2.62-2.66 (2H, m), 3.58 (IH, dd, J = 11.2, 6.8Hz) , 3.76 (IH, dd, J = 11.2, 6.8 Hz), 4.19 (2H, q, J = 7.2 Hz), 5.08 (2H, s), 6.96-7.00 (3H, m), 7.05-7.07 (IH, m ), 7.11-7.12 (IH, m),
7.33-7.45 (7H, m).  7.33-7.45 (7H, m).
[0987] 実施例 396: 'H-NMR (400MHZ, CDCl ) δ 0.92 (3H, t, J= 7.4Hz), [0987] Example 396: 'H-NMR (400MHZ, CDCl) δ 0.92 (3H, t, J = 7.4Hz),
3  Three
1.23-1.36 (2H, m), 1.29 (3H, t, J=7.2Hz), 1.58—1.69 (2H, m), 1.74—1.90 (2H, m), 2.22 (IH, t, J=6.8Hz), 2.57 (IH, dd, J=12.6, 5.2Hz), 2.69 (IH, dd, J=12.6, 5.2Hz), 3.71-3.80 (2H, m), 4.18 (2H, q, J=7.2Hz), 5.08 (2H, s), 6.97—7.00 (3H, m), 7.06-7.08 (IH, m), 7.11-7.12 (IH, m), 7.33-7.44 (7H, m).  1.23-1.36 (2H, m), 1.29 (3H, t, J = 7.2Hz), 1.58--1.69 (2H, m), 1.74--1.90 (2H, m), 2.22 (IH, t, J = 6.8Hz) , 2.57 (IH, dd, J = 12.6, 5.2Hz), 2.69 (IH, dd, J = 12.6, 5.2Hz), 3.71-3.80 (2H, m), 4.18 (2H, q, J = 7.2Hz), 5.08 (2H, s), 6.97-7.00 (3H, m), 7.06-7.08 (IH, m), 7.11-7.12 (IH, m), 7.33-7.44 (7H, m).
[0988] [実施例 397] [0988] [Example 397]
2—ァリルー 4— [4— (4 ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 2 シァノメチル酪酸ェチル [0989] [化 269]
Figure imgf000178_0001
2-arylu 4- [4- (4 benzyloxy) phenylsulfur- 2-chloromethyl-]-2-ethyl ethyl cyanomethylbutyrate [0989] [Formula 269]
Figure imgf000178_0001
[0990] 氷浴中、実施例 394の化合物（205 mg)のジクロロメタン（3 mL)溶液にトリェチルアミ ン（111 L)およびメタンスルホユルクロリド（37.2 L)をカ卩え、 20分間撹拌した。水と 酢酸ェチルを用いて分液し、有機層を無水硫酸ナトリウムで乾燥させ、濃縮し、残查 をシリカゲルカラムクロマトグラフィー（へキサン [0990] In an ice bath, triethylamine (111 L) and methanesulfoyl chloride (37.2 L) were added to a dichloromethane (3 mL) solution of the compound of Example 394 (205 mg), and the mixture was stirred for 20 minutes. Liquid separation was performed using water and ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (hexane).
I酢酸ェチル =5 I 1)を用いて精製し、無色油状のメタンスルホニルエステル体（236 mg)を得た。得られたエステル（236mg)の DMF (1 mL)、 DMSO (l  Purification using I ethyl acetate = 5I 1) gave a colorless oily methanesulfonyl ester (236 mg). DMF (1 mL) of the obtained ester (236 mg), DMSO (l
mL)溶液にシアンィ匕カリウム（104 mg)の水（0.5 mL)溶液を加え、 100°Cで 18時間撹 拌した。水と酢酸ェチルを用いて分液し、有機層を無水硫酸ナトリウムで乾燥させ、 濃縮した。残查をシリカゲルカラムクロマトグラフィー（へキサン  To the solution (mL) was added a solution of potassium cyanide (104 mg) in water (0.5 mL), and the mixture was stirred at 100 ° C for 18 hours. The layers were separated using water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue is subjected to silica gel column chromatography (hexane
I酢酸ェチル =10 I 1)を用いて精製し、無色油状の目的物 (130 mg)を得た。  Purification using I-ethyl acetate = 10 I 1) afforded the desired product (130 mg) as a colorless oil.
JH-NMR (400MHz, CDC1 ) δ 1.30 (3Η, t, J= 7.2Hz), 1.90 (1H, J H-NMR (400MHz, CDC1) δ 1.30 (3Η, t, J = 7.2Hz), 1.90 (1H,
3  Three
td, J=14.0, 5.2Hz), 2.02(1H, td, J=14.0, 5.2Hz), 2.43 (1H, m), 2.51—2.66 (3H, m), 2.73-2.74 (2H, m), 4.18-4.24 (2H, m), 5.08 (2H, s), 5.18—5.26 (2H, m), 5.59-5.67 (1H, m), 6.97—6.99 (3H, m), 7.00-7.07 (1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m).  td, J = 14.0, 5.2Hz), 2.02 (1H, td, J = 14.0, 5.2Hz), 2.43 (1H, m), 2.51-2.66 (3H, m), 2.73-2.74 (2H, m), 4.18 -4.24 (2H, m), 5.08 (2H, s), 5.18-5.26 (2H, m), 5.59-5.67 (1H, m), 6.97-6.99 (3H, m), 7.00-7.07 (1H, m) , 7.11-7.12 (1H, m), 7.33-7.45 (7H, m).
EIMS： 519 (M  EIMS: 519 (M
[0991] [実施例 398— 399]  [0991] [Example 398-399]
実施例 395、 396の化合物を用い上記実施例 397と同様に反応させ表 29に示す化合 物を合成した。  Using the compounds of Examples 395 and 396, the compounds were reacted in the same manner as in Example 397 to synthesize the compounds shown in Table 29.
[0992] [表 29] 表 29
Figure imgf000179_0001
[0992] [Table 29] Table 29
Figure imgf000179_0001
実施例 R EIMS  Example R EIMS
性状  Properties
网 +  Net +
398 Me 無色油状物 493  398 Me colorless oil 493
399 Pr 無色油状物 521  399 Pr colorless oil 521
[0993] 実施例 398 : H— NMR (400MHz, CDC1 ) δ 1.30 (3Η, t, J= 7.2Hz), [0993] Example 398: H-NMR (400MHz, CDC1) δ 1.30 (3Η, t, J = 7.2Hz),
3  Three
1.42 (3H, s), 1.86-1.99(2H, m), 2.56-2.63 (2H, m), 2.66 (1H, d， J=16.8Hz), 2.73 (1H， d, J=16.8Hz), 4.20 (2H, q, J=7.2Hz), 5.08 (2H, s)， 6.97—6.99 (3H， m), 7.04-7.06 (1H， m), 7.10-7.12 (1H， m)， 7.33-7.45 (7H, m).  1.42 (3H, s), 1.86-1.99 (2H, m), 2.56-2.63 (2H, m), 2.66 (1H, d, J = 16.8Hz), 2.73 (1H, d, J = 16.8Hz), 4.20 (2H, q, J = 7.2Hz), 5.08 (2H, s), 6.97-6.99 (3H, m), 7.04-7.06 (1H, m), 7.10-7.12 (1H, m), 7.33-7.45 (7H , m).
[0994] 実施例 399 : NMR (400MHz, CDC1 ) δ： 0.92 (3H, t, J= 7.2Hz), Example 399: NMR (400 MHz, CDC1) δ: 0.92 (3H, t, J = 7.2 Hz),
3  Three
1.13-1.21 (1H， m), 1.27-1.38 (1H, m), 1.29 (3H, t, J=7.2Hz), 1.64-1.93 (3H, m), 1.98-2.06 (1H， m)， 2.47-2.55 (1H, m), 2.61—2.69 (1H, m), 2.75 (1H， d,  1.13-1.21 (1H, m), 1.27-1.38 (1H, m), 1.29 (3H, t, J = 7.2Hz), 1.64-1.93 (3H, m), 1.98-2.06 (1H, m), 2.47- 2.55 (1H, m), 2.61-2.69 (1H, m), 2.75 (1H, d,
J=16.2Hz)， 2.79 (1H， d, J=16.2Hz)， 4.16—4.22 (2H, m)， 5.08 (2H， s)， 6.97—6.99 (3H, m), 7.05-7.07 (1H, m), 7.11—7.12 (1H, m), 7.33-7.45 (7H， m).  J = 16.2Hz), 2.79 (1H, d, J = 16.2Hz), 4.16—4.22 (2H, m), 5.08 (2H, s), 6.97—6.99 (3H, m), 7.05-7.07 (1H, m ), 7.11—7.12 (1H, m), 7.33-7.45 (7H, m).
[0995] [実施例 400]  [0995] [Example 400]
3—ァリルー 5— [4— (4 ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 3 ーメトキシカルボニルァミノペンタン二トリノレ  3-arylu-5- [4- (4-benzyloxy) phenylsulfur- 2-chloromethyl]-3-methoxycarbonylaminoaminopentanetrinole
[0996] [化 270]
Figure imgf000179_0002
[0996] [Formula 270]
Figure imgf000179_0002
[0997] 実施例 397の化合物（128 mg)のエタノール THF (1 / 1) (4 mL)溶液に lmol/L-水 酸化カリウム水溶液 (984 L)を加えて加熱還流を行った。 4時間後、反応液を常温 にもどした後に水を加え、 ½101/ぃ塩酸で PH [0997] To a solution of the compound of Example 397 (128 mg) in ethanol (1/1) (4 mL) was added lmol / L-potassium hydroxide aqueous solution (984 L), and the mixture was heated under reflux. After 4 hours, water was added after the reaction solution is cooled to room temperature, PH in ½1 0 1 / I hydrochloric acid
1とした後酢酸ェチルで抽出した。有機層を無水硫酸ナトリウムで乾燥させて濃縮し 、無色油状のカルボン酸（121 mg)を得た。得られたカルボン酸（121 mg)のベンゼン (2 After setting to 1, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a colorless oily carboxylic acid (121 mg). Benzene of the obtained carboxylic acid (121 mg) (2
mL)溶液にアジ化ジフエ-ルホスホリル（58.7 μ L)およびトリェチルァミン（44.6 μ L) をカロえて 1.5時間加熱還流した後、反応液を常温にもどしてメタノール (2  The reaction solution was heated to reflux for 1.5 hours, and heated to room temperature, and methanol (2 mL) was added to diphenylphosphoryl azide (58.7 μL) and triethylamine (44.6 μL).
mL)を滴下し、再び加熱還流を続けた。 3時間後、ナトリウムメトキシド (26.5 mg)をカロ えて更に 1時間加熱還流した。反応液を常温にもどし、酢酸ェチルで抽出した後、有 機層を無水硫酸ナトリウムで乾燥させ、濃縮し、残查をシリカゲルカラムクロマトグラフ ィー（へキサン  mL) was added dropwise and heating to reflux was continued again. Three hours later, sodium methoxide (26.5 mg) was heated to reflux for an additional hour. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (hexane).
I酢酸ェチル =6 /1)を用いて精製し、無色油状の目的物（120 mg)を得た。 Purification using I ethyl acetate = 6/1) gave the desired product (120 mg) as a colorless oil.
JH-NMR (400MHz, CDC1 ) δ 1.55-1.87 (1Η, m), 2.12-2.18 (1H,  JH-NMR (400MHz, CDC1) δ 1.55-1.87 (1Η, m), 2.12-2.18 (1H,
3  Three
m), 2.48 (1H, dd, J=14.0, J=8.0Hz), 2.60-2.71 (3H, m), 2.89 (1H, d, J=16.8Hz), 3.07 (1H, d, J=16.8Hz), 3.65 (3H, s), 4.75 (1H, br), 5.08 (2H, s), 5.27-5.32 (2H, m), 5.74-5.84 (1H, m), 6.97—6.99 (3H, m), 7.00-7.07 (1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m).  m), 2.48 (1H, dd, J = 14.0, J = 8.0Hz), 2.60-2.71 (3H, m), 2.89 (1H, d, J = 16.8Hz), 3.07 (1H, d, J = 16.8Hz) ), 3.65 (3H, s), 4.75 (1H, br), 5.08 (2H, s), 5.27-5.32 (2H, m), 5.74-5.84 (1H, m), 6.97-6.99 (3H, m), 7.00-7.07 (1H, m), 7.11-7.12 (1H, m), 7.33-7.45 (7H, m).
EIMS： 520 (M  EIMS: 520 (M
[0998] [実施例 401— 402]  [0998] [Example 401-402]
実施例 398、 399の化合物を用い上記実施例 400と同様に反応させ表 30に示すィ匕合 物を得た。  Using the compounds of Examples 398 and 399, the reaction was carried out in the same manner as in Example 400 to obtain a compound shown in Table 30.
[0999] [表 30]  [0999] [Table 30]
表 30
Figure imgf000180_0001
Table 30
Figure imgf000180_0001
EI S  EI S
実施例 R 性状  Example R Properties
【ΜΓ  [ΜΓ
401 Me 無色油状物 494  401 Me colorless oil 494
402 Pr 無色油状物 522  402 Pr colorless oil 522
[1000] 実施例 401：1!"!- NMR (400MHz, CDC1 ) δ 1.48 (3Η, s), 1.75-1.82 [1000] Example 401: 1 ! "!-NMR (400 MHz, CDC1) δ 1.48 (3Η, s), 1.75-1.82
3  Three
(1H, m), 2.17-2.25 (1H, m), 2.61-2.74 (2H, m), 2.81 (1H, d, J=16.8Hz), 3.11 (1H, d, J=16.8Hz), 3.64 (3H,s), 4.79 (1H, br), 5.08 (2H, s), 6.96—6.99 (3H, m),  (1H, m), 2.17-2.25 (1H, m), 2.61-2.74 (2H, m), 2.81 (1H, d, J = 16.8Hz), 3.11 (1H, d, J = 16.8Hz), 3.64 ( 3H, s), 4.79 (1H, br), 5.08 (2H, s), 6.96—6.99 (3H, m),
7.06-7.08 (1H, m), 711-7.12(1H, m), 7.33-7.45 (7H, m). [1001] 実施例 402： 1H-NMR (400MHz, CDC1 ) δ 0.99 (3H, t, J= 7.3Hz), 7.06-7.08 (1H, m), 711-7.12 (1H, m), 7.33-7.45 (7H, m). [1001] Example 402: 1H-NMR (400MHz, CDC1) δ 0.99 (3H, t, J = 7.3Hz),
3  Three
1.24-1.42 (2H, m), 1.62-1.70 (1H, m), 1.76-1.87 (2H, m), 2.10- 2.18(1H, m), 2.61-2.65 (2H, m), 2.87 (lH,d, J=16.8Hz), 3.12 (1H, d, J=16.8Hz), 3.64 (3H, s), 4.68 (1H, br), 5.08 (2H, s), 6.97—6.98 (3H, m), 7.05-7.12 (2H, m), 7.33-7.45 (7H, m).  1.24-1.42 (2H, m), 1.62-1.70 (1H, m), 1.76-1.87 (2H, m), 2.10- 2.18 (1H, m), 2.61-2.65 (2H, m), 2.87 (lH, d , J = 16.8Hz), 3.12 (1H, d, J = 16.8Hz), 3.64 (3H, s), 4.68 (1H, br), 5.08 (2H, s), 6.97-6.98 (3H, m), 7.05 -7.12 (2H, m), 7.33-7.45 (7H, m).
[1002] [実施例 403]  [1002] [Example 403]
5— [4— (4—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 3— (3—ヒド ロキシプロピル)— 3—メトキシカルボニルァミノペンタン二トリル  5- [4- (4-benzyloxy) phenylsulfur-ru 2-chlorophenol] -3- (3-hydroxypropyl) -3-methoxycarbonylaminopentane nitrile
[1003] [化 271]  [1003] [Formula 271]
Figure imgf000181_0001
Figure imgf000181_0001
[1004] 氷浴中、実施例 400の化合物（220 mg)の THF (4 mL)溶液にボラン- THFコンプレツ タス（lmol/L-THF溶液） (844 L)を滴下し、 1時間撹拌した。反応液に水（5 mL)をカ卩えた後、 NaBO -4H 0 (195 mg)を加えて、常温で 1時間撹拌させ、その後  [1004] In an ice bath, borane-THF complex (lmol / L-THF solution) (844 L) was added dropwise to a THF (4 mL) solution of the compound of Example 400 (220 mg), and the mixture was stirred for 1 hour. After water (5 mL) was added to the reaction solution, NaBO-4H0 (195 mg) was added, and the mixture was stirred at room temperature for 1 hour.
3 2  3 2
一晩放置した。反応液を酢酸ェチルで抽出した後、有機層を無水硫酸ナトリウムで 乾燥させ、濃縮し、残查をシリカゲルカラムクロマトグラフィー（へキサン Z酢酸ェチル Left overnight. After the reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (hexane Z ethyl acetate).
= 1/2)を用いて精製し、無色油状の目的物（124 = 1/2) to give the desired product as a colorless oil (124
mg) "^守に。  mg) "^ For protection.
JH-NMR (400MHz, CDC1 ) δ 1.47 (1Η, t, J=4.8Hz), 1.59—1.67 J H-NMR (400MHz, CDC1) δ 1.47 (1Η, t, J = 4.8Hz), 1.59-1.67
3  Three
(2H, m), 1.77-1.89 (2H, m), 1.97-2.03 (1H, m), 2.09-2.17 (1H, m), 2.65 (2H, t, J=8.4Hz), 2.96 (1H, d, J=16.8Hz), 3.06 (1H, d, J=16.8Hz), 3.64 (3H, s)  (2H, m), 1.77-1.89 (2H, m), 1.97-2.03 (1H, m), 2.09-2.17 (1H, m), 2.65 (2H, t, J = 8.4Hz), 2.96 (1H, d , J = 16.8Hz), 3.06 (1H, d, J = 16.8Hz), 3.64 (3H, s)
3.70-3.71 (2H, m), 4.99 (1H, br), 5.08 (2H, s), 6.97-6.99 (3H, m), 7.06-7.12 (2H, m), 7.34-7.45 (7H, m).  3.70-3.71 (2H, m), 4.99 (1H, br), 5.08 (2H, s), 6.97-6.99 (3H, m), 7.06-7.12 (2H, m), 7.34-7.45 (7H, m).
EIMS： 538 (M  EIMS: 538 (M
[1005] [実施例 404] [1005] [Example 404]
3—ァミノ一 5— [4— (4—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]— 3 ーメチルペンタン酸 塩酸塩 [1006] [化 272]
Figure imgf000182_0001
3-amino-5- [4- (4-benzyloxy) phenyl-sulfur-ru 2-chloromethyl] -3-methylpentanoic acid hydrochloride [1006] [Formula 272]
Figure imgf000182_0001
[1007] 実施例 401の化合物（109 mg)のジメチルスルホキシド（2 mL)、メタノーノレ（2 mL)溶 液に 5mol/L -水酸ィ匕カリウム水溶液 (2 mL)および lmol/L水酸化リチウム水溶液（1 mL)をカ卩えて 105°Cで 22時間撹拌した。反応液を常温にもどし、水を加え、撹拌しな 力 4mol/L-塩酸をカ卩えて PH7とし、析出した結晶を濾取して水、酢酸ェチル、イソプ 口ピルエーテルで洗った。この結晶を 4mol/L-塩酸と酢酸ェチルを用いて分液し、有 機層を無水硫酸ナトリウムで乾燥させ、濃縮した。析出した結晶を濾取して乾燥させ 、無色固体の目的物（16 [1007] A solution of the compound of Example 401 (109 mg) in dimethyl sulfoxide (2 mL) and methanol (2 mL) was dissolved in a 5 mol / L aqueous solution of potassium hydroxide (2 mL) and an aqueous solution of lmol / L lithium hydroxide. (1 mL) was added and stirred at 105 ° C for 22 hours. The reaction solution was returned to room temperature, water was added, and the mixture was stirred and stirred at pH 4 with 4 mol / L-hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water, ethyl acetate and isopropyl ether. The crystals were separated using 4 mol / L hydrochloric acid and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The precipitated crystals were collected by filtration and dried to give the target compound as a colorless solid (16
mg; に。  mg;
'H-NMR (400MHZ, DMSO— d ) δ 1.30 (3H, s), 1.71 - 1.80 (2H,  'H-NMR (400MHZ, DMSO- d) δ 1.30 (3H, s), 1.71-1.80 (2H,
6  6
m), 2.41-2.42 (2H, m)， 2.65 (2H, t, J=8.4Hz), 5.13 (2H, s), 7.05-7.12 (4H, m), m), 2.41-2.42 (2H, m), 2.65 (2H, t, J = 8.4Hz), 5.13 (2H, s), 7.05-7.12 (4H, m),
7.24-7.26 (1H, m), 7.32-7.46 (7H, m). 7.24-7.26 (1H, m), 7.32-7.46 (7H, m).
FABMS： 456 ([M+H]+) FABMS: 456 ([M + H] + )
HRMS： 456.1413 (+1.3mmu.).  HRMS: 456.1413 (+ 1.3mmu.).
[1008] [実施例 405— 406] [Examples 405-406]
実施例 402、 403の化合物を用いて上記実施例 404と同様に反応させ表 31に示すィ匕 合物を合成した。  Using the compounds of Examples 402 and 403, the reaction was carried out in the same manner as in Example 404, and the conjugates shown in Table 31 were synthesized.
[1009] [表 31] 表 31
Figure imgf000182_0002
[1009] [Table 31] Table 31
Figure imgf000182_0002
FABMS  FABMS
実施例 R 性状 [M+H]+ Example R Properties [M + H] +
405 Pr 無色粉末 484  405 Pr colorless powder 484
406 (CH2)3OH 無色 TJ}末 500 [1010] 実施例 405： 1H-NMR (400MHz, DMSO— d ) δ 0.88 (3H, t, J=7.3Hz), 406 (CH 2 ) 3 OH colorless TJ} powder 500 [1010] Example 405: 1H-NMR (400MHz, DMSO-d) δ 0.88 (3H, t, J = 7.3Hz),
6  6
1.22-1.36 (2H, m), 1.59-1.66 (2H, m), 1.76-1.80 (2H, m), 2.50-2.66 (4H, m), 5.13 (2H, s), 7.06-7.13 (4H, m), 7.25-7.27 (1H, m), 7.32-7.46 (7H, m), 8.12 (3H, br).  1.22-1.36 (2H, m), 1.59-1.66 (2H, m), 1.76-1.80 (2H, m), 2.50-2.66 (4H, m), 5.13 (2H, s), 7.06-7.13 (4H, m ), 7.25-7.27 (1H, m), 7.32-7.46 (7H, m), 8.12 (3H, br).
HRMS： 454.1750 (+3.6mmu.).  HRMS: 454.1750 (+ 3.6mmu.).
[1011] 実施例 406 : 1H-NMR (400MHz, DMSO- d ) δ 1.41-1.49 (2H, m), [1011] Example 406: 1H-NMR (400MHz, DMSO- d) δ 1.41-1.49 (2H, m),
6  6
1.61-1.75 (4H, m), 2.37-2.42 (2H, m), 2.50-2.65 (2H, m), 3.37-3.40 (2H, m), 1.61-1.75 (4H, m), 2.37-2.42 (2H, m), 2.50-2.65 (2H, m), 3.37-3.40 (2H, m),
5.13 (2H, s), 7.06-7.13 (4H, 5.13 (2H, s), 7.06-7.13 (4H,
m), 7.23-7.26 (1H, m), 7.33-7.46 (7H, m).  m), 7.23-7.26 (1H, m), 7.33-7.46 (7H, m).
HRMS： 500.1704 (+4.2mmu.).  HRMS: 500.1704 (+ 4.2mmu.).
元素分析値（％) :for C H C1NO S HC1 1/3H Oとして  Elemental analysis value (%): for C H C1NO S HC1 1 / 3H O
27 30 4 2  27 30 4 2
C H N  C H N
計算値 ： 59.77 5.88 2.58  Calculated value: 59.77 5.88 2.58
実測値 ： 59.38 5.54 2.53  Measured value: 59.38 5.54 2.53
[1012] [実施例 407] [1012] [Example 407]
2—ァリルー 4— [4— (4 ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 2 ーメトキシカルボ-ルァミノ酪酸ェチル  2-arylu 4- [4- (4 benzyloxy) phenylsulfur- 2-chloromethyl] -ethyl 2-methoxycarbol-laminobutyrate
[1013] [化 273] [1013] [Formula 273]
Figure imgf000183_0001
Figure imgf000183_0001
[1014] 実施例 391の化合物（1.01 g)のエタノール（9 mL)、 THF (5 mL)溶液に lmol/L-水 酸化カリウム水溶液（7.30 mL, 7.30  [1014] A lmol / L-potassium hydroxide aqueous solution (7.30 mL, 7.30 mL) was added to a solution of the compound of Example 391 (1.01 g) in ethanol (9 mL) and THF (5 mL).
mmol)をカ卩えて 3.5時間加熱還流を行った。反応液を常温にもどした後に水を加え、 4mol /い塩酸で PH 1とした後酢酸ヱチルで抽出した。有機層を無水硫酸ナトリウム で乾燥させて濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン Z酢酸ェ チル = 1/1)を用いて精製し無色の油状物質  mmol) and heated under reflux for 3.5 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the mixture was adjusted to pH 1 with 4 mol / hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was purified using silica gel column chromatography (hexane Z ethyl acetate = 1/1) to give a colorless oil.
(669 mg)を得た。このものを実施例 400の場合と同様にクルチウス転位反応を行い、 無色油状の目的物（570 mg)を得た。 (669 mg) was obtained. This was subjected to Curtius rearrangement in the same manner as in Example 400, The target product (570 mg) was obtained as a colorless oil.
1H-NMR (400MHz, CDC1 ) δ 1.28 (3Η, t, J=7.6Hz), 2.06—2.14  1H-NMR (400MHz, CDC1) δ 1.28 (3Η, t, J = 7.6Hz), 2.06-2.14
3  Three
(IH, m), 2.40-2.50 (2H, m), 2.55-2.66 (2H, m), 3.08—3.13 (IH, m), 3.65 (3H, s), 4.16 (2H, m), 5.05—5.08 (2H, m), 5.08 (2H, s), 5.56—5.66 (IH, m), 5.81 (IH, br), 6.96-6.99 (3H, m), 7.02-7.04 (IH, m), 7.10-7.11 (IH, m), 7.33-7.45 (7H, m).  (IH, m), 2.40-2.50 (2H, m), 2.55-2.66 (2H, m), 3.08-3.13 (IH, m), 3.65 (3H, s), 4.16 (2H, m), 5.05-5.08 (2H, m), 5.08 (2H, s), 5.56-5.66 (IH, m), 5.81 (IH, br), 6.96-6.99 (3H, m), 7.02-7.04 (IH, m), 7.10-7.11 (IH, m), 7.33-7.45 (7H, m).
EIMS： 553 (M  EIMS: 553 (M
[1015] [実施例 408] [1015] [Example 408]
2—ァリル 2 アミノー 4— [4— (4 ベンジルォキシ）フエ-ルスルファ-ルー 2—クロロフ ニル]酪酸  2-Aryl 2-amino-4- [4- (4-benzyloxy) phenylsulfur- 2- 2-chlorophenyl] butyric acid
[1016] [化 274] [1016] [Formula 274]
Figure imgf000184_0001
Figure imgf000184_0001
[1017] 実施例 407の化合物（570 mg)のジメチルスルホキシド（3 mL)、メタノール (3 mL)溶 液に 5mol/L -水酸ィ匕カリウム水溶液 (3 mL)および lmol/L水酸化リチウム水溶液（1 mL)をカ卩えて 100°Cで 3日間撹拌した。反応液を常温にもどし、水を加え、撹拌しなが ら 4mol/L_塩酸をカ卩えて PH7とし、析出した結晶を濾取した。結晶を水、酢酸ェチル、 イソプロピルエーテルを用いて洗った後乾燥させて、無色固体の目的物（368 mg) "^守に。  [1017] A solution of the compound of Example 407 (570 mg) in dimethyl sulfoxide (3 mL) and methanol (3 mL) was dissolved in a 5 mol / L-potassium hydroxide aqueous solution (3 mL) and a lmol / L lithium hydroxide aqueous solution. (1 mL) was added and stirred at 100 ° C for 3 days. The reaction solution was returned to room temperature, water was added, and 4 mol / L_hydrochloric acid was added with stirring to obtain PH7, and the precipitated crystals were collected by filtration. The crystals were washed with water, ethyl acetate, and isopropyl ether, and dried to give the target compound (368 mg) as a colorless solid.
JH-NMR (400MHz, DMSO— d ) δ 1.65—1.83 (2H, m), 2.39—2.58 J H-NMR (400MHz, DMSO- d) δ 1.65-1.83 (2H, m), 2.39-2.58
6  6
(3H, m), 2.71-2.79 (IH, m), 5.04—5.13 (2H, m), 5.13 (2H, s), 5.73—5.83 (IH, m), 7.04-7.10 (4H, m), 7.16-7.18 (IH, m), 7.31-7.46 (7H, m).  (3H, m), 2.71-2.79 (IH, m), 5.04-5.13 (2H, m), 5.13 (2H, s), 5.73-5.83 (IH, m), 7.04-7.10 (4H, m), 7.16 -7.18 (IH, m), 7.31-7.46 (7H, m).
FABMS： 468 ([M+H]+). FABMS: 468 ([M + H] + ).
HRMS： 468.1434 (+3.4mmu.).  HRMS: 468.1434 (+ 3.4mmu.).
[1018] [実施例 409] [1018] [Example 409]
4— [4— (4—ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 2 tーブトキ シカルボ-ルァミノー 2—ヒドロキシメチル酪酸ェチル [1019] [化 275]
Figure imgf000185_0001
4— [4 -— (4-benzyloxy) phenylsulfur-Lu 2-chloromethyl] —2 t-butoxycarbaluminamine 2-hydroxymethylbutyrate [1019] [Formula 275]
Figure imgf000185_0001
[1020] 参考例 329の化合物を用い実施例 1と同様に反応させた後、得られたィ匕合物を実 施例 394と同様にして還元し目的物を無色アモルファスとして得た。  [1020] After reacting in the same manner as in Example 1 using the compound of Reference Example 329, the obtained compound was reduced in the same manner as in Example 394 to obtain the desired product as a colorless amorphous.
1H-NMR(400MHz, CDC1 ) δ 1.30 (3Η, t, J=7.2Hz), 1.46 (9H,  1H-NMR (400MHz, CDC1) δ 1.30 (3Η, t, J = 7.2Hz), 1.46 (9H,
3  Three
s), 1.96-2.05 (IH, m), 2.34-2.43 (IH, m), 2.49 (IH, td, J=12.4, 4.9Hz), 2.64 (IH, td, J=12.4, 4.9Hz), 2.92 (IH, br), 3.80—3.84 (IH, m), 4.15—4.19 (IH, m), 4.23 (2H, q, J=7.2Hz), 5.08 (2H. s), 5.69 (IH, br), 6.93—7.03 (4H, m), 7.10-7.11 (IH, m), 7.33-7.45 (7H, m).  s), 1.96-2.05 (IH, m), 2.34-2.43 (IH, m), 2.49 (IH, td, J = 12.4, 4.9Hz), 2.64 (IH, td, J = 12.4, 4.9Hz), 2.92 (IH, br), 3.80-3.84 (IH, m), 4.15-4.19 (IH, m), 4.23 (2H, q, J = 7.2Hz), 5.08 (2H.s), 5.69 (IH, br), 6.93-7.03 (4H, m), 7.10-7.11 (IH, m), 7.33-7.45 (7H, m).
EIMS： 585 (M  EIMS: 585 (M
[1021] [実施例 410]  [1021] [Example 410]
2 アミノー 4— [4— (4 ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ-ル]— 2 ーヒドロキシメチル酪酸  2 Amino-4- [4- (4 benzyloxy) phenylsulfur- 2-cyclohexyl]-2-hydroxymethylbutyric acid
[1022] [化 276]
Figure imgf000185_0002
[1022] [Formula 276]
Figure imgf000185_0002
[1023] 上記実施例 409の化合物を実施例 368と同様に反応させた後、実施例 350と同様 反応させ目的物を無色粉末として得た。 [1023] The compound of Example 409 was reacted in the same manner as in Example 368, and then reacted in the same manner as in Example 350 to obtain the desired product as a colorless powder.
1H-NMR (400MHz, DMSO— d ) δ 1.72 (IH, td, J=13.2, 4.9Hz),  1H-NMR (400MHz, DMSO- d) δ 1.72 (IH, td, J = 13.2, 4.9Hz),
6  6
1.84 (IH, td, J=13.2, 4.9Hz), 2.48—2.58 (IH, m), 2.75 (IH, td, J=12.4, 4.3Hz), 1.84 (IH, td, J = 13.2, 4.9Hz), 2.48-2.58 (IH, m), 2.75 (IH, td, J = 12.4, 4.3Hz),
3.50 (IH, d, J=11.0Hz), 3.57 (IH, d, J=11.0Hz), 5.13 (2H, s), 7.06-7.11 (4H, m), 7.18-7.20 (IH, m), 7.31-7.46 (7H, m). 3.50 (IH, d, J = 11.0Hz), 3.57 (IH, d, J = 11.0Hz), 5.13 (2H, s), 7.06-7.11 (4H, m), 7.18-7.20 (IH, m), 7.31 -7.46 (7H, m).
FABMS： 458 (〔M+H]+).  FABMS: 458 ([M + H] +).
HRMS： 458.1234 (+4.1mmu.).  HRMS: 458.1234 (+ 4.1mmu.).
元素分析値（％)： for C H C1NO S 1/4H Oとして  Elemental analysis (%): as for CH C1NO S 1 / 4HO
24 24 4 2 '(+[Η+ ]) OSZ： 24 24 4 2 '( + [Η +]) OSZ:
•(ω 'ΗΖ) S - εΓΖ '(ω 'Η6) WL-ZZ'L '(ω  • (ω 'ΗΖ) S-εΓΖ' (ω 'Η6) WL-ZZ'L' (ω
'Ηΐ) 0ΓΖ-60"Ζ '(ω 'Η） εθ·Ζ— 96·9 '(ZH0^ <zH6"8=f 'ΡΡ 'Ηΐ) TS 'ΗΖ) 60"3'Ηΐ) 0ΓΖ-60 "Ζ' (ω 'Η) εθ · Ζ— 96 · 9' ( Z H0 ^ <z H6" 8 = f 'ΡΡ' Ηΐ) TS 'ΗΖ) 60 "3
Figure imgf000186_0001
Figure imgf000186_0001
'ρ 'ΗΪ) ετ '(ω 'ΗΪ) ζτ-βιτ
Figure imgf000186_0002
'Ρ 'ΗΪ) βοτ '(ω Ήζ) u'z-m'z 'ρ' ΗΪ) ετ '(ω' ΗΪ) ζτ-βιτ
Figure imgf000186_0002
'Ρ' ΗΪ) βοτ '(ω Ήζ) u'z-m'z
'(ui Ήΐ) 'Z-LVZ '(s Ήε) WZ '(ω 'Ηΐ) - W '(ω Ήε) ZO'S- 88·ΐ '(ui Ήΐ)' Z-LVZ '( s Ήε) WZ' (ω 'Ηΐ)-W' (ω Ήε) ZO'S- 88
'(ω 'Ηΐ) 8 ·ΐ-0 ·ΐ 9 (
Figure imgf000186_0003
Η Ν-ΗΤ： ΐΐ¾ ¾ϊ第 [Ζ20ΐ] '(ω' Ηΐ) 8
Figure imgf000186_0003
Η Ν-Η Τ : ΐΐ¾ ¾ϊ 第 [Ζ20ΐ]
8ε ） ΐ ΐ^: ¾ ^^ (s zvz) oif-^^A^ 8ε) ΐ ΐ ^: ¾ ^^ ( s zvz) oif-^^ A ^
Figure imgf000186_0004
、つ止纖 缀 OS LO S
Figure imgf000186_0004
、 つ STOP Fiber 缀 OS LO S
ri / べエ Ai—J—N- n)
Figure imgf000186_0005
ri / Bee Ai—J—N- n)
Figure imgf000186_0005
W9) (继缀 丄 1/Ιου¾·ΐ)マ ^ ίΗ/·^ :- u
Figure imgf000186_0006
0oSL-、止べ [920ΐ] W9) (继 缀 丄 1 / Ι ου ¾
Figure imgf000186_0006
0 o SL-, stop [920ΐ]
Figure imgf000186_0007
Figure imgf000186_0007
— — ^エ [ -ェ ciE^— / - -ェ {^^ ^ -^- ) -V] -V — — ^ E [-e ciE ^ — /--e {^^ ^-^-) -V] -V
66 ^re zz'Z9 ： M 66 ^ re zz'Z9: M
εο·ε εε-3 ζ^ζ9 ： 軍翥  εο · ε εε-3 ζ ^ ζ9 ： Army 翥
Ν Η ο  Ν Η ο
Ll^9l0/t00Zdr/lDd 981 OSLttO OZ OAV [1028] 実施例 412: ^-NMR (400MHz, CDC1 ) δ 1.70-1.78 (IH, m), Ll ^ 9l0 / t00Zdr / lDd 981 OSLttO OZ OAV [1028] Example 412: ^ -NMR (400MHz, CDC1) δ 1.70-1.78 (IH, m),
3  Three
1.90-2.04 (3H, m), 2.15-2.24 (IH, m), 2.43 (3H, s), 2.46—2.53 (IH, m), 2.71 (IH, d, J=17.1Hz), 2.76-2.82 (2H, m), 3.17-3.23 (IH, m), 3.56 (IH, d,  1.90-2.04 (3H, m), 2.15-2.24 (IH, m), 2.43 (3H, s), 2.46-2.53 (IH, m), 2.71 (IH, d, J = 17.1Hz), 2.76-2.82 ( 2H, m), 3.17-3.23 (IH, m), 3.56 (IH, d,
J=17.1Hz), 3.61-3.67 (IH, m), 4.38 (IH, d, J=9.8Hz), 4.55 (IH, d, J=9.8Hz), 5.07 (2H, s), 5.54 (IH, dd, J=9.2, 3.7Hz), 6.94—6.99 (3H, m), 7.09-7.10 (IH, m), 7.21-7.23 (IH, m), 7.31-7.45 (9H, m), 7.74-7.76 (2H, m).  J = 17.1Hz), 3.61-3.67 (IH, m), 4.38 (IH, d, J = 9.8Hz), 4.55 (IH, d, J = 9.8Hz), 5.07 (2H, s), 5.54 (IH, dd, J = 9.2, 3.7Hz), 6.94-6.99 (3H, m), 7.09-7.10 (IH, m), 7.21-7.23 (IH, m), 7.31-7.45 (9H, m), 7.74-7.76 ( 2H, m).
FABMS： 730 ([M+H]+). FABMS: 730 ([M + H] + ).
[1029] [実施例 413及び 414]  [1029] [Examples 413 and 414]
4— [4— (3—ベンジルォキシ）フエ-ルスルファ-ルー 2—クロ口フエ-ル]ェチルー 4— ヒドロキシメチルー 3— ( 1—トルエンスルホ-ルピロリジン 2 カルボ-ル）—2—ォキサゾ リジノン  4- [4- (3-Benzyloxy) phenylsulfur-ru 2-cyclobutyryl] ethyl- 4-hydroxymethyl-3- (1-toluenesulfol-pyrrolidine 2-carbol) -2-oxazolidinone
[1030] [化 278]  [1030] [Formula 278]
Figure imgf000187_0001
Figure imgf000187_0001
[1031] 実施例 295の化合物を用い上記実施例と同様に反応させ目的物を各々無色ァモ ルファスとして得た。 [1031] The same procedures used in the above Example were carried out except for using the compound of Example 295, to give each of the desired products as colorless ammonium.
前溶出部分実施例 413: 'H-NMR (400MHZ, CDCl ) δ 1.71-1.78 (IH, m),  Pre-elution Part Example 413: 'H-NMR (400MHZ, CDCl) δ 1.71-1.78 (IH, m),
3  Three
1.88-2.10 (3H, m),2.15-2.25 (IH, m), 2.43 (3H, s), 2.51-2.58 (IH, m), 2.63-2.82 (2H, m), 3.10 (IH, d, J=17.1Hz), 3.19-3.25 (IH, m), 3.38 (IH, d, J=17.1Hz), 3.59-3.64  1.88-2.10 (3H, m), 2.15-2.25 (IH, m), 2.43 (3H, s), 2.51-2.58 (IH, m), 2.63-2.82 (2H, m), 3.10 (IH, d, J = 17.1Hz), 3.19-3.25 (IH, m), 3.38 (IH, d, J = 17.1Hz), 3.59-3.64
(IH, m), 4.49 (IH, d, J=9.8Hz), 4.53 (IH, d, J=9.8Hz), 5.03 (2H, s), 5.35 (IH, dd, J=9.1Hz,4.0Hz), 6.90—6.98 (3H, m), 7.07-7.15 (2H, m), 7.25-7.39 (9H, m), 7.73-7.76 (2H,m).  (IH, m), 4.49 (IH, d, J = 9.8Hz), 4.53 (IH, d, J = 9.8Hz), 5.03 (2H, s), 5.35 (IH, dd, J = 9.1Hz, 4.0Hz ), 6.90-6.98 (3H, m), 7.07-7.15 (2H, m), 7.25-7.39 (9H, m), 7.73-7.76 (2H, m).
FABMS： 730 ([M+H]+). FABMS: 730 ([M + H] + ).
後溶出部分実施例 414: 'H-NMR (400MHZ, CDCl ) δ 1.72-1.80 (IH, m),  Post-elution part Example 414: 'H-NMR (400MHZ, CDCl) δ 1.72-1.80 (IH, m),
3  Three
1.91-2.05 (3H, m),2.16-2.24 (IH, m), 2.43 (3H, s), 2.50-2.58 (IH, m), 2.72 (IH, 邈べ^べ ^/^ ^ 、 — ε—[ / 1.91-2.05 (3H, m), 2.16-2.24 (IH, m), 2.43 (3H, s), 2.50-2.58 (IH, m), 2.72 (IH, 邈 ^^^ ^ / ^ ^, — ε— [/
-ェ
Figure imgf000188_0001
— 一 一 ε— (―) -
Figure imgf000188_0001
— One one ε— (―)
[9 ^ 第] [SSOT] zs'z εε-3 9 ： M  [9 ^ No.] [SSOT] zs'z εε-3 9: M
Z6'Z 29"S ΐ8 9 ： ^ΜΊ-ί  Z6'Z 29 "S ΐ89: ^ ΜΊ-ί
Ν Η Ο Ν Η Ο
^Ο HS/ΐ S ONID Η つ (0/0)軍 峯^ ^ Ο HS / ΐ S ONID one Η (0/0) Army Mine ^
(os^a 'ooro =。） 。ss'z+ a LZ [»] (os ^ a 'ooro =.) ss'z + a LZ [»]
。 (Slu os6) 目 ^、 ^雜 ^^m ^ m^^^ s=氺 Z H丄 ¾« 。 氺ェっ ¾難 1 >nffl措
Figure imgf000188_0002
) /— ^ dra es)
Figure imgf000188_0003
. ( Slu os6) eyes ^, ^ Small ^^ m ^ m ^^^ s = 氺 ZH 丄 ¾ «.氺 氺 ¾ Difficulty 1 > nffl measure
Figure imgf000188_0002
) / — ^ D ra es)
Figure imgf000188_0003
[6 s ] [εεοτ] 邈べ^べ ^/^ ^ 、 — ε—[ / ェ crn^— s— / -ェ {^^^ -^- ) -V] - - iJ.-Z- ( + ) [6 s] [εεοτ] 邈 ^^^ ^ / ^ ^, — ε— [/ cr crn ^ — s— /-ェ {^^^-^-) -V]--iJ.-Z- (+ )
[s ^ ¾ϊ第] βεοτ] [s ^ ¾ϊNo.] βεοτ]
'(+[Η+ ]) 0SZ： '( + [Η +]) 0SZ:
"(ω 'ΗΖ) L L-^VL '(ω 'ΗΟΐ) S£'L-IZ'L '(ω 'Ηΐ) ZVL-60'L '(ω Ήε) 6·9- 8·9 '(ζΗ9·ε'ζΗ6·8=ί" 'ΡΡ 'Ηΐ) 9S"S "(ω 'ΗΖ) L L- ^ VL' (ω 'ΗΟΐ) S £'L-IZ'L'(ω' Ηΐ) ZVL-60'L '(ω Ήε) 6.9-8.9' ( ζΗ9 · ε ' ζ · 6 · 8 = ί "' ΡΡ 'Ηΐ) 9S" S
'(s 'ΗΖ) S0"S '(ΖΗ8·6=1" 'Ρ 'Ηΐ) S^ '(ΖΗ9·6=1" 'Ρ 'Ηΐ) Off '(ω 'Ηΐ) 89Τ-09Τ'( s ' ΗΖ) S0 "S '(ΖΗ8 · 6 = 1"' Ρ 'Ηΐ) S ^' (ΖΗ9 · 6 = 1 "'Ρ' Ηΐ) Off '(ω' Ηΐ) 89Τ-09Τ
Figure imgf000188_0004
'Ρ 'Ηΐ) 8ST '(ω 'Ηΐ) ΖΖτ-Σΐτ '(ω 'ΗΖ) 68 — 'Ρ
Figure imgf000188_0004
'Ρ' Ηΐ) 8ST '(ω' Ηΐ) ΖΖτ-Σΐτ '(ω' ΗΖ) 68 — 'Ρ
Ll^9l0/t00Zdr/lDd IQV OSLttO OZ OAV [1036] [化 280]
Figure imgf000189_0001
Ll ^ 9l0 / t00Zdr / lDd IQV OSLttO OZ OAV [1036] [Formula 280]
Figure imgf000189_0001
[1037] 実施例 412の化合物を用い実施例 415と同様に反応させ目的物を無色粉末として 得た。 [1037] The compound of Example 412 was reacted in the same manner as in Example 415 to obtain the desired product as a colorless powder.
元素分析値（％)： for C H C1NO S 1/4H 0として  Elemental analysis value (%): as for CH C1NO S 1 / 4H 0
25 26 4 2  25 26 4 2
C H N  C H N
計算値 ： 63.02 5.60 2.93  Calculated value: 63.02 5.60 2.93
実測値 ： 62.73 5.51 2.86  Measured value: 62.73 5.51 2.86
[1038] [実施例 417] [1038] [Example 417]
(一)一 3—アミノー 4— [4— (3 ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ： ル ]ー3—ヒドロキシメチルペンタン酸  (1) 3-Amino-4- [4- (3-benzyloxy) phenol-sulfur-ru 2
[1039] [化 281] [1039] [Formula 281]
Figure imgf000189_0002
Figure imgf000189_0002
[1040] 実施例 413の化合物を用い実施例 415と同様に反応させ目的物を無色粉末として 得た。 [1040] The compound of Example 413 was reacted in the same manner as in Example 415 to obtain the desired product as a colorless powder.
[ α ] 27 —3.95° (c = 0.300, DMSO) [α] 27 —3.95 ° (c = 0.300, DMSO)
D  D
元素分析値（％) :for C H C1NO S H Oとして  Elemental analysis value (%): for C H C1NO S H O
25 26 4 2  25 26 4 2
C H N  C H N
計算値 ： 61.28 5.75 2.85  Calculated value: 61.28 5.75 2.85
実測値 ： 61.15 5.28 2.77  Measured value: 61.15 5.28 2.77
[1041] [実施例 418] [1041] [Example 418]
( + )一 3 アミノー 4 [4— (3 ベンジルォキシ）フエ-ルスルファ-ルー 2 クロ口フエ -ル ]ー3—ヒドロキシメチルペンタン酸 [1042] [化 282] (+) 1-3 amino-4 [4- (3 benzyloxy) phenylsulfur-ru 2 chlorophenol] -3-hydroxymethylpentanoic [1042] [Formula 282]
Figure imgf000190_0001
Figure imgf000190_0001
[1043] 実施例 414の化合物を用い実施例 415と同様に反応させ目的物を無色粉末として得 た。 [1043] The same procedures used in Example 415 were carried out except for using the compound of Example 414 to give a desired product as a colorless powder.
元素分析値（％)： for C H C1NO S 1/3H 0として  Elemental analysis value (%): as for CH C1NO S 1 / 3H 0
25 26 4 2  25 26 4 2
C H N  C H N
計算値 ： 62.81 5.62 2.93  Calculated value: 62.81 5.62 2.93
実測値 ： 62.77 5.36 2.80  Measured value: 62.77 5.36 2.80
[1044] [実施例 419] [1044] [Example 419]
2 t ブトキシカルボ-ルァミノー 4— [2 クロロー 4— (4ーヒドロキシフエ-ルスルファ- ル）フエ-ル]ェチルー 1, 3 プロパンジオール  2 t-butoxycarbamine 4- [2-chloro-4- (4-hydroxyphenylsulfur) phenyl] ethyl-1,3-propanediol
[1045] [化 283]
Figure imgf000190_0002
[1045] [Formula 283]
Figure imgf000190_0002
[1046] p—ヒドロキシベンゼンチオールを原料として参考例 1と同様に反応させた後、参考 例 327、参考例 329、実施例 実施例 76の実験操作にならい順次反応させ目的物を 無色油状物として得た。 [1046] After reacting in the same manner as in Reference Example 1 using p-hydroxybenzenethiol as a raw material, the reaction was carried out sequentially according to the experimental procedure of Reference Example 327, Reference Example 329, and Example 76 to obtain the target product as a colorless oil. Obtained.
FABMS : 453([M+H]+) FABMS: 453 ([M + H] + )
1H-NMR(400MHz, CDC1 ) δ 1.45(9Η, s), 1.78— 1.85(2Η, m),  1H-NMR (400MHz, CDC1) δ 1.45 (9Η, s), 1.78― 1.85 (2Η, m),
3  Three
2.67-2.71(2Η, m), 3.39(2Η, br), 3.65(2Η, dd, J=11.6, 6.7Hz), 3.89(2H, dd, J=11.6, 6.7Hz), 5.08 (1H, s), 5.40(1H, s), 6.84(2H, d, J=8.6Hz), 6.97(1H, dd, J=1.8, 8.0Hz), 7.08(2H, d, J=8.0Hz), 7.35(2H, d, J=8.0Hz).  2.67-2.71 (2Η, m), 3.39 (2Η, br), 3.65 (2Η, dd, J = 11.6, 6.7Hz), 3.89 (2H, dd, J = 11.6, 6.7Hz), 5.08 (1H, s) , 5.40 (1H, s), 6.84 (2H, d, J = 8.6Hz), 6.97 (1H, dd, J = 1.8, 8.0Hz), 7.08 (2H, d, J = 8.0Hz), 7.35 (2H, d, J = 8.0Hz).
[1047] [実施例 420] [1047] [Example 420]
4— [2 クロロー 4— (4ーヒドロキシフエ-ルスルファ -ル）フエ-ル]ェチルー 4ーヒドロキ シメチルー 2—ォキサゾリジノン 4- [2-chloro-4- (4-hydroxyphenylsulfur) phenyl] ethyl 4-hydroxy Cimethyl-2-oxazolidinone
[1048] [化 284]
Figure imgf000191_0001
[1048] [Formula 284]
Figure imgf000191_0001
[1049] 上記実施例 419の化合物を用い実施例 213と同様に反応させ目的物を無色ァモル ファスとして得た。 [1049] The same procedures used in Example 213 were carried out except for using the compound of Example 419 to give a desired product as colorless amorphous.
FABMS : 380([M+H]+) FABMS: 380 ([M + H] + )
1H-NMR(400MHz, CDC1 ) δ 1.83— 2.00(2Η, m), 2.66-2.77(2Η, 1 H-NMR (400MHz, CDC1) δ 1.83--2.00 (2Η, m), 2.66-2.77 (2Η,
3  Three
m), 3.56-3.70(2Η, m), 4.24(1Η, d, J=8.6Hz), 4.29(1Η, d, J=8.6Hz), 5.01 (1H, s), m), 3.56-3.70 (2Η, m), 4.24 (1Η, d, J = 8.6Hz), 4.29 (1Η, d, J = 8.6Hz), 5.01 (1H, s),
5.10(1H, s), 6.86(2H, d,J=8.6Hz), 6.98(1H, dd, J=1.8, 8.0Hz), 7.06(1H, d, 5.10 (1H, s), 6.86 (2H, d, J = 8.6Hz), 6.98 (1H, dd, J = 1.8, 8.0Hz), 7.06 (1H, d,
J=8.0Hz), 7.11(1H, d, J=1.8Hz), 7.35(2H, d, J=8.0Hz).  J = 8.0Hz), 7.11 (1H, d, J = 1.8Hz), 7.35 (2H, d, J = 8.0Hz).
[1050] [実施例 421] [1050] [Example 421]
4— [2—クロロー 4— (4ーメトキシフエ-ルスルファ -ル）フエ-ル]ェチルー 4ーヒドロキシ メチルー 2—ォキサゾリジノン  4- [2-chloro-4- (4-methoxyphenylsulfur-phenyl) phenyl] ethyl 4-hydroxymethyl-2-oxazolidinone
[1051] [化 285] [1051] [Formula 285]
Figure imgf000191_0002
Figure imgf000191_0002
[1052] 氷冷下にて実施例 420の化合物 (200mg)の Ν,Ν-ジメチルホルムアミド (5mL)溶液に 炭酸カリウム（72.8mg)をカ卩え、さらによう化メタン (36 /z L)を加え、常温にて 1時間、 50 °Cにて 2時間攪拌した。氷冷下にて反応液に水を加え、酢酸ェチルにて抽出し、水、 飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去しシリカゲ ルカラムクロマトグラフィー（和光シリカゲル C-300, 酢酸ェチルのみ）にて精製し、 目的物 (200mg)を無色油状物として得た。  [1052] Under ice-cooling, potassium carbonate (72.8 mg) was added to a solution of the compound of Example 420 (200 mg) in Ν, Ν-dimethylformamide (5 mL), and methane iodide (36 / z L) was further added. In addition, the mixture was stirred at room temperature for 1 hour and at 50 ° C for 2 hours. Water was added to the reaction solution under ice cooling, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Wako silica gel C-300, ethyl acetate only) to obtain the desired product (200 mg) as a colorless oil.
FABMS : 382([M+H]+) FABMS: 382 ([M + H] + )
1H-NMR(400MHz, CDC1 ) δ 1.76— 1.94(2Η, m), 2.66-2.76(2Η, 1 H-NMR (400MHz, CDC1) δ 1.76― 1.94 (2Η, m), 2.66-2.76 (2Η,
3  Three
m), 3.54-3.69(2Η, m), 3.84(3Η, s), 4.22(1Η, d, J=9.2Hz), 4.30(1Η, d, J=9.2Hz), 5.77 (1H, s), 6.92(2H, d,J=8.6Hz), 6.96(1H, dd, J=1.8, 8.0Hz), 7.07(1H, d,m), 3.54-3.69 (2Η, m), 3.84 (3Η, s), 4.22 (1Η, d, J = 9.2Hz), 4.30 (1Η, d, J = 9.2Hz), 5.77 (1H, s), 6.92 (2H, d, J = 8.6Hz), 6.96 (1H, dd, J = 1.8, 8.0Hz), 7.07 (1H, d,
J=8.0Hz), 7.09(1H, d, J=1.8Hz), 7.41(2H, d, J=8.6Hz). J = 8.0Hz), 7.09 (1H, d, J = 1.8Hz), 7.41 (2H, d, J = 8.6Hz).
[1053] [実施例 422— 423] [1053] [Example 422-423]
実施例 420の化合物とシクロへキシルメチルブロミド、またはヨウ化ブタンを用いて実 施例 421と同様に反応させ表 32に示す化合物を合成した。  The compound shown in Table 32 was synthesized by reacting the compound of Example 420 with cyclohexylmethyl bromide or butane iodide in the same manner as in Example 421.
[1054] [表 32] [1054] [Table 32]
表 32
Figure imgf000192_0001
Table 32
Figure imgf000192_0001
FABMS  FABMS
実施例 R 性状 [M+H1+  Example R Properties (M + H1 +
422 無色油状物 476 422 colorless oil 476
Figure imgf000192_0002
Figure imgf000192_0002
423 Bu 燦色油状物 436  423 Bu Bright oil 436
[1055] 実施例 422： 1H-NMR(400MHz, CDC1 ) δ 0.98— 1.38(5H, m), Example 422: 1 H-NMR (400 MHz, CDC1) δ 0.98—1.38 (5H, m),
3  Three
1.70-1.96(8H, m), 2.64-2.74(2H, m), 3.55-3.70(2H, m), 3.77(2H, d, J=6.1Hz), 4.23(1H, d, J=9.2Hz), 4.30(1H, d, J=9.2Hz), 5.22 (1H, s), 6.90(2H, d, J=8.6Hz), 6.96(1H, dd, J=1.8, 8.0Hz), 7.06(1H, d, J=8.0Hz), 7.09(1H, d, J=1.8Hz),  1.70-1.96 (8H, m), 2.64-2.74 (2H, m), 3.55-3.70 (2H, m), 3.77 (2H, d, J = 6.1Hz), 4.23 (1H, d, J = 9.2Hz) , 4.30 (1H, d, J = 9.2Hz), 5.22 (1H, s), 6.90 (2H, d, J = 8.6Hz), 6.96 (1H, dd, J = 1.8, 8.0Hz), 7.06 (1H, d, J = 8.0Hz), 7.09 (1H, d, J = 1.8Hz),
7.40(2H, d, J=8.6Hz).  7.40 (2H, d, J = 8.6Hz).
[1056] 実施例 423： 1H-NMR(400MHz, CDC1 ) δ 0.99(3H, t, J=7.3Hz), Example 423: 1 H-NMR (400 MHz, CDC1) δ 0.99 (3H, t, J = 7.3 Hz),
3  Three
1.43-1.55(2H, m), 1.73- 1.96(4H, m), 2.02(1H, br), 2.64-2.77(2H, m),  1.43-1.55 (2H, m), 1.73- 1.96 (4H, m), 2.02 (1H, br), 2.64-2.77 (2H, m),
3.56-3.71(2H, m), 3.98(2H, t, J=6.7Hz), 4.23(1H, d, J=9.2Hz), 4.30(1H, d, J=9.2Hz), 5.20 (1H, s), 6.91(2H, d, J=8.6Hz), 6.96(1H, dd, J=1.8, 8.0Hz), 7.06(1H, d, J=8.0Hz), 7.09(1H, d, J=1.8Hz), 7.40(2H, d, J=8.6Hz).  3.56-3.71 (2H, m), 3.98 (2H, t, J = 6.7Hz), 4.23 (1H, d, J = 9.2Hz), 4.30 (1H, d, J = 9.2Hz), 5.20 (1H, s ), 6.91 (2H, d, J = 8.6Hz), 6.96 (1H, dd, J = 1.8, 8.0Hz), 7.06 (1H, d, J = 8.0Hz), 7.09 (1H, d, J = 1.8Hz) ), 7.40 (2H, d, J = 8.6Hz).
[1057] [実施例 424] [1057] [Example 424]
4— [2 クロロー 4— (4 フエノキシフエ-ルスルファ -ル）フエ-ル]ェチルー 4ーヒドロ キシメチルー 2—ォキサゾリジノン 4- [2Chloro-4- (4phenoxyphenylsulfur) phenyl] ethyl 4-hydroxymethyl-2-oxazolidinone
mm Κ9οι] mm Κ9οι]
"(ω 'HS)8S"Z-S2"Z  "(ω 'HS) 8S" Z-S2 "Z
'(ω 'Η2)8ΓΖ-60·Ζ '(s 'HI)WTS '(ω 'HS)( ' '(ω 'Η Ζ·ε— 9S'S '(ω 'H2)98"2-^9"2  '(ω' Η2) 8ΓΖ-60 · Ζ '(s' HI) WTS' (ω 'HS) (' '(ω' Η ε · ε—9S'S '(ω' H2) 98 "2- ^ 9" 2
'(ω 'H2)06"T-29"T '(s 'H6)S 'I 9 ( IDOD 'ZH 00^)H N-HT '(ω' H2) 06 "T-29" T '( s ' H6) S 'I 9 (IDOD' ZH 00 ^) H NH T
。 ェつ;呦^ ^雜¾呦  .呦 ^^
^目 ェっ^翁^ 6^^¾？第、 ¾f¾ 一 ^べ べ >^/- / ^H ー d [290Ϊ]
Figure imgf000193_0001
^ Eye ^^^^^^? No., ¾f¾ ^^^> ^ /-/ ^ H ー d [290Ϊ]
Figure imgf000193_0001
[LSZ^ [ΐ90ΐ] /— ;^べ ΰ Ι—ε 'ΐ— ^エ [ / ェ （ / [LSZ ^ [ΐ90ΐ] / —; ^ べ ΰ ε—ε 'ΐ— ^ e [/ e (/
[Zf m [ο9οι][Zf m [ο9οι]
•(ω ' )WL-Z^L '(ω 'H8 Ή6·9 '(s 'HT)6S"S • (ω ') WL-Z ^ L' (ω 'H8 Ή6 · 9' ( s ' HT) 6S "S
'(ΖΗ2·6=Γ 'P ' )Z£-f '(ΖΗ2·6=Γ 'P 'HW '(^ 'HS)U'S— 9S'S '(^ 'WDlVZ-^UZ '( Ζ Η2.6 = Γ' P ') Z £ -f' ( Ζ Η2.6 = · 'P' HW '(^' HS) U'S— 9S'S '(^' WDlVZ- ^ UZ
'( 'HWZ '(ω Ή2)96·ΐ-8 ·ΐ 9 (OQD 'ZH 00^)H N-HT '(' HWZ '(ω Ή2) 96ΐΐ8ΐΐ 9 (OQD' ZH 00 ^) H NH T
° ¾ェ ;呦^ ^雜  ° ¾eh; 呦 ^ ^
¾呦^目 ^$ ^ 翁^^ 6ΐί^¾ϊ第、 ¾f¾邈 ^ / ェ ;呦 ^^Ο)0^ί^¾ϊ第 [630Ϊ]
Figure imgf000193_0002
¾ 呦 ^ eyes ^ $ ^ Okina ^^ 6ΐί ^ ¾ϊNo., ¾f¾ 邈 ^ / 呦; 呦 ^^ Ο) 0 ^ ί ^ ¾ϊNo. [630Ϊ]
Figure imgf000193_0002
[982^ ] [8S0I] [982 ^] [8S0I]
LlS9l0/t00Zd£/∑Jd Z61 08^ 00 OAV [1064] [化 288] LlS9l0 / t00Zd £ / ∑Jd Z61 08 ^ 00 OAV [1064] [Formula 288]
Figure imgf000194_0001
Figure imgf000194_0001
[1065] 上記実施例 425の化合物を用い参考例 315と同様に反応させブロモ体とした後、実 施例 421と同様にしてフエノールと反応させ目的物を無色油状物として得た。 [1065] The compound of Example 425 was reacted in the same manner as in Reference Example 315 to give a bromo form, and then reacted with phenol in the same manner as in Example 421 to obtain the desired product as a colorless oil.
FABMS : 470([M+H]+) FABMS: 470 ([M + H] + )
1H-NMR(400MHz, CDC1 ) δ 1.79— 2.00(2Η, m), 2.13(1Η, br), 1 H-NMR (400MHz, CDC1) δ 1.79― 2.00 (2Η, m), 2.13 (1Η, br),
3  Three
2.70-2.8Κ2Η, m), 3.59-3.72(2Η, m), 4.26(1Η, d, J=8.6Hz), 4.32(1H, d,  2.70-2.8Κ2Η, m), 3.59-3.72 (2Η, m), 4.26 (1Η, d, J = 8.6Hz), 4.32 (1H, d,
J=8.6Hz,), 5.06(2H, s)， 5.34(1H, s), 6.97— 7.01(3H, m), 7.14(2H, s),  J = 8.6Hz,), 5.06 (2H, s), 5.34 (1H, s), 6.97- 7.01 (3H, m), 7.14 (2H, s),
7.28-7.44(7H, m).  7.28-7.44 (7H, m).
[1066] [実施例 427— 432] [Examples 427-432]
実施例 420— 424および 426を用 ヽ実施例 213と同様に反応させた後、弓 Iき続き実施 例 283と同様に反応させ表 33に示す化合物を合成した。  After the reactions of Examples 420-424 and 426 were carried out in the same manner as in Example 213, the compounds shown in Table 33 were synthesized by reacting in the same manner as in Example I.
[1067] [表 33] [1067] [Table 33]
表 33
Figure imgf000194_0002
Table 33
Figure imgf000194_0002
FAB S  FAB S
実施例 R 性状 [M+H]+ Example R Properties [M + H] +
427 MsO 無色粉末  427 MsO colorless powder
428 θΟ 無色油状物 402*  428 θΟ colorless oil 402 *
429 無色油状物  429 colorless oil
CH2 CH 2
430 BuO 無色油状物 444*  430 BuO colorless oil 444 *
431 PhO 無色油状物  431 PhO colorless oil
432 PhOCH2 無色油状物 479 432 PhOCH 2 colorless oil 479
EIMS  EIMS
[1068] 実施例 427:1!"!- NMR(400MHz, CDC1 ) δ 2.01- 2.11(2H， m)， [1068] Example 427: 1 ! "!-NMR (400MHz, CDC1) δ 2.01- 2.11 (2H, m),
3  Three
2.70-2.84(4H, m), 3.18(3H, s), 4.29(1H, d, J=9.2Hz), 4.39(1H, d, J=9.2Hz), 5.55 (1H, s), 7.19(2H, s)， 7.24(2H, s), 7.32- 7.42(3H, m). 2.70-2.84 (4H, m), 3.18 (3H, s), 4.29 (1H, d, J = 9.2Hz), 4.39 (1H, d, J = 9.2Hz), 5.55 (1H, s), 7.19 (2H , s), 7.24 (2H, s), 7.32-7.42 (3H, m).
[e oT][e oT]
' つ 呦 ^^ · コ ε挲^ $ ^ 翁^; 第、 ¾f¾呦^ ^ωεε挲 'Tsu 呦 ^^ · Ko ε 挲 ^ $ ^ Okina ^; No. ¾f¾ 呦 ^ ^ ωεε 挲
•(ω 'HDWL-SZ'L '(s 'HZ)fVL '(ω 'HS)00"Z-96"9 '(s Ήΐ)8Γ3 • (ω 'HDWL-SZ'L' (s 'HZ) fVL' (ω 'HS) 00 "Z-96"9' ( s Ήΐ) 8Γ3
'(s 'H2)Z0"S
Figure imgf000195_0001
'P 'Ηΐ)8 '(ω 'H — ( '( s ' H2) Z0 "S
Figure imgf000195_0001
'P' Ηΐ) 8 '(ω' H — (
'(ω 'Η2)2Γ2-00·29 ( OQD
Figure imgf000195_0002
ΚΖΟΐ] '(ω' Η2) 2Γ2-0029 (OQD
Figure imgf000195_0002
ΚΖΟΐ]
"(ω Ή^)ε^· -^ε· '(ω 'H8)02"Z-S6"9  "(ω Ή ^) ε ^ ·-^ ε · '(ω' H8) 02" Z-S6 "9
'(s 'HT)89"S '(zHS'6=f 'P 'Ηΐ)Ζε· '^ΗΖ'6=ί 'Ρ 'Ηΐ)8 '(ω 'Η — ( '( s ' HT) 89 "S '(zHS'6 = f' P 'Ηΐ) Ηΐε ·' ^ ΗΖ'6 = ί 'Ρ' Ηΐ) 8 '(ω' Η — (
'(ω 'Η2)2Γ2-00·29 ODOD 'ZH 00^)H N-HT： ΐ Zf M β Οΐ] •(zH9"8=f 'P 'HZ)WL '(zH8"T=f 'P 'Ηΐ)60· '(ω' Η2) 2Γ2-00 · 29 ODOD 'ZH 00 ^) H NH T : ΐ Zf M β Οΐ] • ( z H9 "8 = f' P 'HZ) WL' ( z H8" T = f ' P 'Ηΐ) 60
'(ΖΗΟ·8=1" 'P Ήΐ)90"Ζ '(ΖΗ0·8 'ζΗ8·ΐ=ί" 'ΡΡ Ήΐ)Ζ6"9 '(zH9"8=f 'Ρ 'H2)26"9  '(ΖΗΟ · 8 = 1 "' P Ήΐ) 90" Ζ '(ΖΗ0 · 8' ζΗ8 · ΐ = ί "'ΡΡ Ήΐ) Ζ6" 9' (zH9 "8 = f 'Ρ' H2) 26" 9
'(s 'Ηΐ) 0Z"S
Figure imgf000195_0003
'Ρ 'HI)ZS ' '(ΖΗΖ·9=ί" ' 'H2)66"S '(s' Ηΐ) 0Z "S
Figure imgf000195_0003
'Ρ' HI) ZS '' (ΖΗΖ · 9 = ί "'' H2) 66" S
'(ω '(ω 'Η2)ΐΓ2-96·ΐ '(ω 'Η 8·ΐ- '(ω 'HS)WI- 9 ·ΐ '(ω' (ω 'Η2) ΐΓ2-96ΐ ΐ' (ω 'Η 8ΐ'-'(ω' HS) WI- 9
Figure imgf000195_0004
Figure imgf000195_0004
•(ΖΗ9"8=Γ 'Ρ 'HZ)\VL • ( Ζ Η9 "8 = Γ 'Ρ' HZ) \ VL
'(ΖΗ8·ΐ=ί" 'Ρ Ήΐ)60"Ζ
Figure imgf000195_0005
'Ρ Ήΐ)Ζ0"Ζ '(ΖΗ0·8 'ΖΗ8·ΐ=ί" 'ΡΡ Ήΐ)Ζ6"9 '(ΖΗ8 · ΐ = ί "' Ρ Ήΐ) 60" Ζ
Figure imgf000195_0005
'Ρ Ήΐ) Ζ0 "Ζ' (ΖΗ0 · 8 'ΖΗ8 · ΐ = ί"' ΡΡ Ήΐ) Ζ6 "9
'(zH9"8=f 'Ρ 'H2)T6"9 '(s ' )LV '^ΗΖ'6=ί 'Ρ 'Ηΐ)θε· '^ΗΖ'6=ί 'Ρ ' )9Z'f '( z H9 "8 = f' Ρ 'H2) T6"9' ( s ') LV' ^ ΗΖ'6 = ί 'Ρ' Ηΐ) θε ''ΗΖΗΖ'6 = ί 'Ρ') 9Z'f
'(ΖΗΓ9=Γ 'Ρ 'H2)ZZT '(ω 'HW2- 9"2 '(ω 'Η ΐΐ — 86·ΐ '(ω 'Η9)ε6·ΐ— Ζ9·ΐ '( Ζ ΗΓ9 = Γ' Ρ 'H2) ZZT' (ω 'HW2- 9 "2' (ω 'Η ΐΐ — 86 · ΐ' (ω 'Η9) ε6 · ΐ— Ζ9 · ΐ
'(ω 'HS)8S"T-66 9 (OQD ^UnOOfWH-H^eZf M [ΟΖΟΐ] "(zH9"8=f 'Ρ ΉΖ)£Υί '(ζΗ8·ΐ=ί" 'Ρ Ήΐ)0ΓΖ '(zH0"8=f 'Ρ 'HT)Z0"Z '(ΖΗ0·8 'ζΗ8·ΐ=ί" 'ΡΡ 'Ηΐ)86·9 '(zH9"8=f 'Ρ 'H2)S6"9 '(s 'HT)S9"S '(ω' HS) 8S "T-66 9 (OQD ^ UnOOfWH-H ^ eZf M [ΟΖΟΐ]" (zH9 "8 = f 'Ρ ΉΖ) £ Υί' (ζΗ8 · ΐ = ί"'Ρ Ήΐ) 0ΓΖ '(zH0 "8 = f' Ρ 'HT) Z0"Z' (ΖΗ0 · 8 'ζΗ8 · ΐ = ί "' ΡΡ 'Ηΐ) 86 · 9' ( z H9" 8 = f 'Ρ' H2) S6 " 9 '(s' HT) S9 "S
'(ΖΗ2·6=Γ 'Ρ 'Ηΐ)9ε· '(ΖΗ2·6=Γ 'Ρ 'Ηΐ)ΖΖ· '(s 'HS)^8"S '(ω 'Η — ( '( Ζ Η2 · 6 = Γ' Ρ 'Ηΐ) 9ε ·' ( Ζ Η2 · 6 = Γ 'Ρ' Ηΐ) ΖΖ · '( s ' HS) ^ 8 "S '(ω' Η — (
'(ω 'Η 80 - 00 9 (OQD ^UnOOfWH-H^SZf M [6901] Ήε)00·8 '(ω 'Η6)ΐ3· -ΐζ· '(ω' Η 80-00 9 (OQD ^ UnOOfWH-H ^ SZf M [6901] Ήε) 008 '(ω' Η6) ΐ3 -ΐζ
'(ω Ήε)εθ· 06·9 '(s 'Η2)0Γ3 '(¾ 'HZ)WZ-WZ '(ω 'Η ) Ζ8 — 6S'(ω Ήε) εθ · 06 · 9' ( s ' Η2) 0Γ3 '(¾' HZ) WZ-WZ '(ω' Η) Ζ8 — 6S
'(ω 'H2)26"T-8 -T 9 (9Ρ— 'ΖΗ勵 0，) Ν— HT:8S 爾第 [ΐ80ΐ]
Figure imgf000196_0001
'(ω' H2) 26 "T-8 -T 9 ( 9 Ρ— 'ΖΗpromotion 0,) Ν— H T : 8S series [第 80ΐ]
Figure imgf000196_0001
'(ω 'H2)½"T- -T 9 (DaD ^UnOOfWH-H^ LZf M [0801] '(ω' H2) ½ "T- -T 9 (DaD ^ UnOOfWH-H ^ LZf M [0801]
•(jq 'HS)S6"Z '(ΖΗ9·8=ί" 'P 'HZ)\VL • (jq 'HS) S6 "Z' (ΖΗ9 · 8 = ί" 'P' HZ) \ VL
'(ΖΗ9·8=1" 'P ΉΙ)£ΖΊ '(ω
Figure imgf000196_0002
'H2)66"S '(ω "H2)S9"S-2S"S '(ΖΗ9 · 8 = 1 "' P ΉΙ) £ ΖΊ '(ω
Figure imgf000196_0002
'H2) 66 "S'(ω" H2) S9 "S-2S" S
'(ω 'HW2-09"2 '(ω 'H2)S8"T-T8"T '(ω 'Η εΓΐ- 99·ΐ '(ω 'H2)8^"T-8S"T '(ω' HW2-09 "2 '(ω' H2) S8" T-T8 "T '(ω' Η εΓΐ- 99 · ΐ '(ω' H2) 8 ^" T-8S "T
Figure imgf000196_0003
Figure imgf000196_0003
•(ΖΗ9"8=Γ 'Ρ Ή2)ΐ^· '(ΖΗ9·8=1" 'Ρ 'Ηΐ)ΐε· '(ω 'Η 80·Ζ—08·9 '(ω 'HZ)W -ZZ^ • ( Ζ Η9 "8 = Γ 'Ρ Ή2) ΐ ^ ·' (ΖΗ9 · 8 = 1"'Ρ' Ηΐ) ΐε · '(ω' Η 80 · Ζ—08 · 9 '(ω' HZ) W- ZZ ^
'(ΖΗΓ9=Γ 'Ρ 'H2)08"S '(ω 'Η Ή9 '(ω 'Η ΐΟΉ6·ΐ '(ω 'Η9) 98·ΐ— 09·ΐ '( Ζ ΗΓ9 = Γ' Ρ 'H2) 08 "S' (ω 'Η Ή9' (ω 'Η ΐΟΉ6ΐ ΐ' (ω 'Η9) 98ΐ ΐ— 09
'(ω 'Η3)2ε·ΐ-86 9 (DOD 'ZH 00^)H N-HT： SS^p}¾? ^ [8Ζ0ΐ]
Figure imgf000196_0004
'(ω' Η3) 2ε · ΐ-86 9 (DOD 'ZH 00 ^) H NH T : SS ^ p} ¾? ^ [8Ζ0ΐ]
Figure imgf000196_0004
'(s Ήε)8 ·ε '(ω )ο ·ε- ο·ε·ε '(^ 'HS)89 - ο '(^ 'HS) I'S- so'( s Ήε) 8 · ε' (ω) ο · ε- ο · εε '(^' HS) 89-ο '(^' HS) I'S- so
'(ω 'Η ΖΖ·ΐ— ZS'I 9 (9Ρ— OSWa 'ΖΗ勵 0 )Η顺— HT: ; 爾第 [ΖΖΟΐ] •(jq 'HS)S6"Z '(zH9"8=f 'P 'ΗΖ)££Ί '(zH9"8=f 'P 'HT)T2"Z '(ΖΗ0·8 'ζΗ8·ΐ=ί" 'PP 'HT)20"Z '(ζΗ8·ΐ=ί" 'P 'Ηΐ) 66·9 '(zH9"8=f 'Ρ 'H2)S8"9 '(ω 'H S9'S— OS'S '(ω '(ω' Η ΐ · ΐ— ZS'I 9 ( 9 Ρ— OSWa 'ΖΗ promoting 0) Η 顺 — H T :; 爾 [ΖΖΟΐ] • (jq' HS) S6 "Z '(zH9" 8 = f 'P' ΗΖ) ££ Ί '(zH9 "8 = f' P 'HT) T2"Z' (ΖΗ0 · 8 'ζΗ8 · ΐ = ί "' PP 'HT) 20"Z' (ζΗ8 · ΐ = ί "'P' Ηΐ) 66 · 9 '( z H9" 8 = f' Ρ 'H2) S8 "9' (ω 'H S9'S— OS'S' (ω
'HW2-09"2 '(ω Ή2)98·ΐ-8 ·ΐ 9 ( OSWa 'ΖΗ勵 0 )Η顺- ΗΤ : εε 爾第 [9Ζ0ΐ] zHOO d 8efr 'HW2-09 "2' (ω Ή2) 98 · ΐ-8 · ΐ 9 (OSWa 'ΖΗpromotion 0) Η 顺-Τ Τ : εε 爾 [9Ζ0ΐ] zHOO d 8efr
04d  04d
8Efr 乙 S¾ 0"9  8Efr Otsu S¾ 0 "9
sHO.  sHO.
Ό set  Ό set
96£ o  96 £ o
HO est- HO est-
+[H+Wl + [H + Wl
牽  Towing
swa
Figure imgf000196_0005
swa
Figure imgf000196_0005
請 OOZdf/ェ:) d 961- 'Ρ 'Ηΐ)Ζε· '(ζΗζ·6=Γ 'P 'HDSS^ '(ΖΗΖ·9=1" ' 'H2)S6"S '(ω 'HS)U'S— 9S'S OOZdf / e :) d 961- 'Ρ' Ηΐ) Ζε · '( ζ Ηζ · 6 = Γ' P 'HDSS ^' (ΖΗΖ · 9 = 1 "'' H2) S6" S '(ω' HS) U'S— 9S'S
'(zH9"8=f Ήζ)∑-ζ q Ήΐ) ε·ζ '(ω 'HWT-O -T '(ω 'HS)SS'I-
Figure imgf000197_0001
Ήε)96 9 ή αつ' ZH )0 ) WN- Ητ: 第 [9801] '( z H9 "8 = f Ήζ) ∑-ζ q Ήΐ) εζ ζ' (ω 'HWT-O -T' (ω 'HS) SS'I-
Figure imgf000197_0001
Ήε) 96 9 ή α 'ZH) 0) WN- Η τ : No. [9801]
'(ω Ήε) 6·9- 08·9 '(S 'ΗΪ) ere 6=1" 'ρ'Ηΐ)ιε· '(zHs-6=f 'ρ ' ) Z'f '(ω Ήε) 6.9-089' ( S 'ΗΪ) ere 6 = 1 "'ρ'Ηΐ) ιε '( z Hs-6 = f' ρ ') Z'f
'(ΖΗΓ9=Γ 'Ρ 'ΗΖ)Ζ∑τ '(ω 'HS)U'S— 09·ε '(ω 'HS)08 — 0 '(^ 'Η8)00 — S9'I '( Ζ ΗΓ9 = Γ' Ρ 'ΗΖ) Ζ∑τ' (ω 'HS) U'S— 09 · ε' (ω 'HS) 08 — 0' (^ 'Η8) 00 — S9'I
'(ω 'Η3)3ε·ΐ-36 9 ( IDOD 'ZH 00^)H N-HT： T^p}¾? ^ [S80T]'(ω' Η3) 3ε · ΐ-36 9 (IDOD 'ZH 00 ^) H NH T : T ^ p} ¾? ^ [S80T]
•(ζΗ8"ΐ=Γ 'Ρ • ( ζ Η8 "ΐ = Γ 'Ρ
'Ηΐ)ΐε· '(ω 'm)fZ-L-fVL '(ω 'HS)S6'9— ΐ8·9 '(s Ήΐ)ΐε·3 '(ΖΗ9·8=1" 'ρ Ήΐ)οε· 'Ηΐ) ΐε''(ω' m) fZ-L-fVL '(ω' HS) S6'9— ΐ8.9 '( s Ήΐ) ΐε3' (ΖΗ9 · 8 = 1 "'ρ Ήΐ) οε ·
'(ΖΗ9·8=1" 'ρ 'm) Z' '(s Ήε)8 "ε '(ω Ήζ)ζί -8 ws=i ' 'HS)9 "S '(ω  '(ΖΗ9 · 8 = 1 "' ρ 'm) Z' '(s Ήε) 8" ε' (ω Ήζ) ζί -8 ws = i '' HS) 9 "S '(ω
'HI)SrS '(ω 'Η 00 - 08·ΐ 9 (OQD ^UnOOfWH-H^Off M 80ΐ] 'HI) SrS' (ω 'Η 00-08ΐΐ 9 (OQD ^ UnOOfWH-H ^ Off M 80ΐ)
•(ζΗ8"ΐ=Γ• ( ζ Η8 "ΐ = Γ
'Ρ 'H\)ZVL '(s 'm)ZZ-L-fVL '(ZH8"T Ό"8=Γ 'ΡΡ 'Ηΐ)ΐ6·9 '(ZH8"T Ό"8=Γ 'ΡΡ 'Ρ' H \) ZVL '(s' m) ZZ-L-fVL '( Z H8 "T Ό" 8 = Γ' ΡΡ 'Ηΐ) ΐ6.9 · ( Z H8 "T Ό" 8 = Γ' ΡΡ
Ήΐ)2 ·9 '(s Ήΐ)63·9 '(s 'HT)Z9"S 'Ηΐ)ε8· '(zH0"6=f 'Ρ 'Ηΐ)εε· '(zH0"6=f Ήΐ) 2 9 ′ ( s Ήΐ) 639 ′ ( s 'HT) Z9 "S' Ηΐ) ε8 · '( z H0" 6 = f' Ρ 'Ηΐ) εε' ( z H0 "6 = f
'Ρ ' ) Z'f '(ZH0"6=f 'Ρ 'HDO T '(ΖΗ0·6=1" 'Ρ'Ηΐ) 9·ε '(ω 'H2)06"2-28"2 'Ρ') Z'f '( Z H0 "6 = f' Ρ 'HDO T' (ΖΗ0 · 6 = 1"'Ρ'Ηΐ)9ε' (ω 'H2) 06 "2-28" 2
'(ω 'HS) 0 - 68·ΐ 9 ή αつ ' ΖΗ兩 0 )Η顺- 1^:62 爾第 [S80T]  '(ω' HS) 0-68 ・ ΐ 9 ή α '' ΖΗ ΖΗ 0) Η 顺-1 ^: 62 [[S80T]
O d ε O d ε
0"9  0 "9
ZHOo ZHO o
HO HO
WW (葦
Figure imgf000197_0002
WW (Reed
Figure imgf000197_0002
92 ¾ [SS¾ [280Ϊ] /—^^:^ 翁^;? 6ΐ ί^¾ϊ第ェつ; ^！^ 一 ^べ べ:^/^^ ci、 — 請 OOZdf/ェ:) d 961· '(ω 'Ηΐ)Ζ8·9— ΐ8·9 '(s Ήΐ)0ε·3 '^ΗΖ'6=ί 'Ρ 'Ηΐ)8ε· '^ΗΖ'6=ί 'Ρ 'H\)LZ^ 92 ¾ [SS¾ [280Ϊ] / — ^^: ^ Okina ^ ;? 6ΐ ί ^ ¾ϊ¾ϊ; ^! ^ One ^ Be: ^ / ^^ ci, — OOZdf / e :) d 961 · '(ω' Ηΐ) Ζ8 · 9— ΐ8 · 9 '( s Ήΐ) 0ε3' ^ ΗΖ'6 = ί 'Ρ' Ηΐ) 8ε · '^ ΗΖ'6 = ί' Ρ 'H \) LZ ^
'(ΖΗΓ9=Γ 'Ρ 'ΗΖ)Ζ∑τ '(ω ΉΫ)Ζ^Ζ-Οί-Ζ '(ω ΉΖ)\νΖ-^Ζ '(ω 'Η9)88·ΐ— 6S'I '( Ζ ΗΓ9 = Γ' Ρ 'ΗΖ) Ζ∑τ' (ω ΉΫ) Ζ ^ Ζ-Οί-Ζ '(ω ΉΖ) \ νΖ- ^ Ζ' (ω 'Η9) 88 · ΐ— 6S'I
'(ω 'HS) θε·ΐ- ΐΟ·ΐ 9 (OQD ^UnOOfWH-H^dff M Κ60ΐ] '(ω' HS) θεΐ- ΐΟ9 (OQD ^ UnOOfWH-H ^ dff M Κ60Κ)
•(ζΗ8"ΐ=Γ 'ρ Ήΐ)οε· • ( ζ Η8 "ΐ = Γ 'ρ Ήΐ) οε ·
'(ω Ήε)3ΓΖ-εΓΖ '(ω 'HS)86'9- 06·9 '(ΖΗ0·8 'ζΗ8·ΐ=ί" 'ΡΡ 'HT)S6"9 '(s 'HI) 9'S '(ω Ήε) 3ΓΖ-εΓΖ' (ω 'HS) 86'9-06 9' (ΖΗ0 · 8 'ζΗ8 · ΐ = ί "' ΡΡ 'HT) S6"9' ( s ' HI) 9'S
'(ΖΗ2·6=Γ 'Ρ 'Ηΐ)Ζε· '(ΖΗ2·6=Γ 'Ρ 'Ηΐ)8 '(s'HS)6Z'S '(ω 'Η —^ '( Ζ Η2 · 6 = Γ' Ρ 'Ηΐ) Ζε ·' ( Ζ Η2 · 6 = Γ 'Ρ' Ηΐ) 8 '(s'HS) 6Z'S' (ω 'Η — ^
'(ω 'H SrS- 00 9 (OQD ^UnOOfWH-H^Qff M [ΐ60ΐ] "(ω 'ΗΖ) ZYL-WL '(ω Ή3) 82" -2r '(s Ήΐ) 2^-S '(zH6=f 'Ρ 'Ηΐ)6ε· '(ΖΗ6=Γ 'Ρ 'Ηΐ)8 '(s Ήε)3Γε '(ω 'H2) 8"2-8 -2 '(ζΗ8·ΐ=ί" 'Ρ '(ω' H SrS- 00 9 (OQD ^ UnOOfWH-H ^ Qff M [ΐ60ΐ] "(ω 'ΗΖ) ZYL-WL' (ω Ή3) 82" -2r '(s Ήΐ) 2 ^ -S' ( zH6 = f 'Ρ' Ηΐ) 6ε '' ( Ζ Γ6 = Γ 'Ρ' Ηΐ) 8 '( s Ήε) 3Γε' (ω 'H2) 8 "2-8 -2' (ζΗ8 · ΐ = ί"' Ρ
'WDlVZ '(ω 'Η2)8Γ2-ΐΟ·2 9 (OQD ^UnOOfWH-H^fff M [0601]  'WDlVZ' (ω 'Η2) 8Γ2-ΐΟ2 9 (OQD ^ UnOOfWH-H ^ fff M [0601]
OMd OMd
ong  ong
ZHOo ZHO o
OSIftl swa d ii  OSIftl swa d ii
Figure imgf000198_0001
Figure imgf000198_0001
9ε拏 [9S挲] [6801]  9ε [9S 挲] [6801]
Figure imgf000198_0002
Figure imgf000198_0002
•(ω 'HWL-WL '(ω 'H8)02"Z-98"9 '(s 'HI) TS '(ζΗ0·ΐΐ=ί" 'P Ήΐ^ε^ • (ω 'HWL-WL' (ω 'H8) 02 "Z-98"9' ( s ' HI) TS '(ζΗ0 · ΐΐ = ί "' P Ήΐ ^ ε ^
'(ζΗ0·ΐΐ=ί" 'P 'Ηΐ)9 '(ω ΉΖ)ζ∑τ-8 τ '(zH9"8=f 'VHZ)9L-Z '(ω 'HWZ-fVZ '(ζΗ0 · ΐΐ = ί "' P 'Ηΐ) 9' (ω ΉΖ) ζ∑τ-8 τ '( z H9" 8 = f' VHZ) 9L-Z '(ω' HWZ-fVZ
'(ω 'Η 00 - 6Ζ·ΐ 9 (OQD ^UnOOfWH-H^Zff M [ 80ΐ] '(ω' Η 00-6Ζ · ΐ 9 (OQD ^ UnOOfWH-H ^ Zff M [80ΐ]
•(s 'HT)6S"Z '(zH9"8=f ' ΉΙ)£ΖΊ '(s 'HZ) L '(ω 'Η ε6·9— 06·9 '(ZH0"8 '8·ΐ=ί" 'ΡΡ 'Ηΐ) 28"9 '(s 'Ηΐ) IS'S '^ΗΖ'6=ί • (s' HT) 6S "Z '(zH9" 8 = f' ΉΙ) £ ΖΊ '( s ' HZ) L' (ω 'Η ε6.9 · 06 · 9' ( Z H0 "8 '8 = ί "'ΡΡ' Ηΐ) 28" 9 '( s ' Ηΐ) IS'S' ^ ΗΖ'6 = ί
161 6.91— 6.96(2H, m), 7.10-7.18 (2H, m), 7.21-7.31(2H, m). 161 6.91— 6.96 (2H, m), 7.10-7.18 (2H, m), 7.21-7.31 (2H, m).
[1093] 実施例 447 : 1H- NMR(400MHz, CDC1 ) δ 0.97(3H, t, J=7.3Hz), Example 447: 1H-NMR (400 MHz, CDC1) δ 0.97 (3H, t, J = 7.3 Hz),
3  Three
1.42-1.54(2H, m), 1.71— 1.80(2H, m), 2.02-2.13(2H, m), 2.72-2.82(4H, m), 3.94(2H, t, J=6.7Hz), 4.27(lH,d, J=9.2Hz), 4.38(1H, d, J=9.2Hz), 5.35 (1H, s), 6.84— 6.96(3H, m), 7.12-7.17(2H, m), 7.22-7.29(2H, m).  1.42-1.54 (2H, m), 1.71-1.80 (2H, m), 2.02-2.13 (2H, m), 2.72-2.82 (4H, m), 3.94 (2H, t, J = 6.7Hz), 4.27 ( lH, d, J = 9.2Hz), 4.38 (1H, d, J = 9.2Hz), 5.35 (1H, s), 6.84-6.96 (3H, m), 7.12-7.17 (2H, m), 7.22-7.29 (2H, m).
[1094] 実施例 448 : 1H- NMR(400MHz, CDC1 ) δ 2.00-2.12(2H, m), [1094] Example 448: 1H-NMR (400MHz, CDC1) δ 2.00-2.12 (2H, m),
3  Three
2.70-2.82(4H, m), 4.16(1H, d, J=9.2Hz), 4.35(1H, d, J=9.2Hz), 5.62(1H, s), 2.70-2.82 (4H, m), 4.16 (1H, d, J = 9.2Hz), 4.35 (1H, d, J = 9.2Hz), 5.62 (1H, s),
6.84-7.18(8H, m), 7.24-7.39(4H, m). 6.84-7.18 (8H, m), 7.24-7.39 (4H, m).
[1095] [実施例 449] [1095] [Example 449]
4— [2 クロロー 4— (3—トリフルォロメタンスルホ-ルォキシフエ-ルスルファ -ル）フ ェニル]ェチルー 4ーシァノメチルー 2 ォキサゾリジノン  4— [2 Chloro 4— (3-Trifluoromethanesulfo-loxyphenyl-sulfur-phenyl) phenyl] ethyl 4- 4-cyanomethyl-2-oxazolidinone
[1096] [化 289] [1096] [Formula 289]
Figure imgf000199_0001
Figure imgf000199_0001
[1097] 実施例 295の化合物を用い参考例 184にならい三臭化ホウ素にてベンジル基を脱 保護し得られたフエノノール体（llOmg)を塩化メチレン（lOmL)に溶解し、トリェチル ァミン（28mL)、無水硫酸ナトリウムトリフルォロメタンスルホン酸（55mL)を加え、氷冷 下 30分撹拌した。反応液に水を加え酢酸ェチルで抽出し、水、飽和食塩水で洗浄後 、無水硫酸ナトリウムで乾燥した。溶媒を留去し目的物（180mg)を無色油状物として 得た。  [1097] Using the compound of Example 295 and following Reference Example 184, the phenonol compound (llOmg) obtained by deprotection of the benzyl group with boron tribromide was dissolved in methylene chloride (lOmL), and triethylamine (28mL) was obtained. Then, anhydrous sodium sulfate trifluoromethanesulfonic acid (55 mL) was added, and the mixture was stirred under ice cooling for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the desired product (180 mg) as a colorless oil.
FABMS : 521([M+1]+) FABMS: 521 ([M + 1] + )
1H-NMR(400MHz, CDC1 ) δ 2.00-2.18(2Η, m), 2.76— 2.90(4Η,  1H-NMR (400MHz, CDC1) δ 2.00-2.18 (2Η, m), 2.76― 2.90 (4Η,
3  Three
m), 4.32(1Η, d, J=9.2Hz), 4.39(1Η, d, J=9.2Hz), 5.85(1H, s), 7.12- 7.30(5H, m), 7.36-7.43(2H, m).  m), 4.32 (1Η, d, J = 9.2Hz), 4.39 (1Η, d, J = 9.2Hz), 5.85 (1H, s), 7.12- 7.30 (5H, m), 7.36-7.43 (2H, m ).
[1098] [実施例 450] [1098] [Example 450]
4— [2 クロロー 4— (ビフエ-ルー 3—スルファ -ル）フエ-ル]ェチルー 4 シァノメチル 2—ォキサゾリジノン [1099] [化 290] 4— [2 Chloro 4— (Bifu-ru 3-Sulfur-l) phenyl] ethyl 4-cyanomethyl 2-oxazolidinone [1099] [Formula 290]
Figure imgf000200_0001
Figure imgf000200_0001
[1100] 上記実施例 449の化合物を用い実施例 192と同様に反応させ目的物を褐色油状物 として得た。 [1100] The compound of Example 449 was reacted in the same manner as in Example 192 to give the desired product as a brown oil.
FABMS : 449([M+1]+) FABMS: 449 ([M + 1] + )
NMR(400MHz, CDC1 ) δ 2.05-2.10(2Η, m), 2.72-2.80(4Η,  NMR (400MHz, CDC1) δ 2.05-2.10 (2Η, m), 2.72-2.80 (4Η,
3  Three
m), 4.27(1Η, d, J=9.8Hz), 4.37(1Η, d, J=9.8Hz), 5.26(1H, s), 7.07-7.75(12H, m).  m), 4.27 (1Η, d, J = 9.8Hz), 4.37 (1Η, d, J = 9.8Hz), 5.26 (1H, s), 7.07-7.75 (12H, m).
[1101] [実施例 451] [1101] [Example 451]
4— [2—クロロー 4— (3—フエ-ルェチユルフェ-ルスルファ -ル）フエ-ル]ェチルー 4 4— [2-Chloro—4— (3-Fu-Letjyurfer-L-Sulfur-F)
—シァノメチル一 2—ォキサゾリジノン —Cyanomethyl-1-2-oxazolidinone
[1102] [化 291] [1102] [Formula 291]
Figure imgf000200_0002
Figure imgf000200_0002
[1103] 氷冷下にて実施例 449の化合物 (lOOmg)のァセトニトリル (5mL)溶液に、トリェチルアミ ン（ImL)、フエナセチレン（38 μ L)、 Pd(PPh) (32mg)、よう化銅 (15mg)、よう化テトラブ  [1103] To a solution of the compound of Example 449 (100 mg) in acetonitrile (5 mL) under ice cooling was added triethylamine (ImL), phenacetylene (38 μL), Pd (PPh) (32 mg), and copper iodide (15 mg). ), Tetrabu iodide
4  Four
チルアンモ -ゥム（142mg)をカ卩え、ー晚加熱還流した。氷冷下にて反応液に水をカロ え、酢酸ェチルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて 乾燥した。溶媒を留去し、シリカゲルカラムクロマトグラフィー（へキサン  Chillammonium (142 mg) was heated and refluxed with heating. Water was added to the reaction solution under ice cooling, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent is distilled off, and silica gel column chromatography (hexane
：酢酸ェチル = 1 : 1)にて精製し、 目的物 (107mg)を褐色油状物として得た。  : Ethyl acetate = 1: 1) to give the desired product (107 mg) as a brown oil.
FABMS : 473([M+1]+) FABMS: 473 ([M + 1] + )
1H-NMR(400MHz, CDC1 ) δ 2.05-2.15(2Η, m), 2.70— 2.85(4Η,  1H-NMR (400MHz, CDC1) δ 2.05-2.15 (2Η, m), 2.70― 2.85 (4Η,
3  Three
m), 4.28(1Η, d, J=9.8Hz), 4.38(1Η, d, J=9.8Hz), 5.46(1H, s), 7.17(2H, s),  m), 4.28 (1Η, d, J = 9.8Hz), 4.38 (1Η, d, J = 9.8Hz), 5.46 (1H, s), 7.17 (2H, s),
7.30-7.38(6H, m), 7.43-7.57(4H, m). 7.30-7.38 (6H, m), 7.43-7.57 (4H, m).
[1104] [実施例 452] [1104] [Example 452]
4— [2—クロロー 4— (3—スチリルフエ-ルスルファ -ル）フエ-ル]ェチルー 4ーシァノメ チルー 2—ォキサゾリジノン  4- [2-chloro-4- (3-styrylphenol-sulfur-phenyl) phenyl] ethyl-4-cyanomethyl 2-oxoxolidinone
[1105] [化 292]
Figure imgf000201_0001
[1105] [Formula 292]
Figure imgf000201_0001
[1106] 実施例 451の化合物 (107mg)のメタノール (5mL)溶液に、ピリジン（O.lmL)、 5% [1106] To a solution of the compound of Example 451 (107 mg) in methanol (5 mL) was added pyridine (O.lmL), 5%
Pd-BaSO (107mg)をカロえ、水素添加して常温にて 4時間攪拌した。セライトろ過して  Pd-BaSO (107 mg) was caloried, hydrogenated, and stirred at room temperature for 4 hours. Celite filtration
4  Four
、ろ液を留去し、 目的物 (80mg)を褐色油状物として得た。  The filtrate was evaporated to give the desired product (80 mg) as a brown oil.
FABMS : 475([M+1]+) FABMS: 475 ([M + 1] + )
'H-NMRC^OMHz, CDCl ) δ 1.98— 2.20(2Η, m), 2.69— 2.83(4Η,  'H-NMRC ^ OMHz, CDCl) δ 1.98― 2.20 (2Η, m), 2.69― 2.83 (4Η,
3  Three
m), 4.28(1Η, d, J=9.8Hz), 4.38(1Η, d, J=9.8Hz), 5.65 (1H, s), 6.53(1H, d,  m), 4.28 (1Η, d, J = 9.8Hz), 4.38 (1Η, d, J = 9.8Hz), 5.65 (1H, s), 6.53 (1H, d,
J=12Hz), 6.63(1H, d, J=12Hz),7.03-7.55(12H, m).  J = 12Hz), 6.63 (1H, d, J = 12Hz), 7.03-7.55 (12H, m).
[1107] [実施例 453] [1107] [Example 453]
4— [2—クロロー 4— (3—フエネチルフエ-ルスルファ -ル）フエ-ル]ェチルー 4ーシァ ノメチルー 2—ォキサゾリジノン  4- [2-Chloro-4- (3-phenethylphenol-sulfur-phenyl) phenyl] ethyl-4-cyanomethyl-2-oxazolidinone
[1108] [化 293] [1108] [Formula 293]
Figure imgf000201_0002
Figure imgf000201_0002
[1109] 実施例 452の化合物 (lOOmg)の酢酸ェチル (5mL)溶液に、 5%Pd-C (lOOmg)を加え、 水素添加して常温にて 4時間攪拌した。セライトろ過して、ろ液を留去し、シリカゲル カラムクロマトグラフィー（へキサン [1109] To a solution of the compound of Example 452 (100 mg) in ethyl acetate (5 mL) was added 5% Pd-C (100 mg), and the mixture was hydrogenated and stirred at room temperature for 4 hours. The mixture was filtered through Celite, the filtrate was distilled off, and the mixture was subjected to silica gel column chromatography (hexane).
：酢酸ェチル = 2 : 1)にて精製し、 目的物 (80mg)を無色油状物として得た。  : Ethyl acetate = 2: 1) to give the desired product (80 mg) as a colorless oil.
FABMS : 477([M+1]+) 1H-NMR(400MHz, CDC1 ) δ 2.04-2.12(2H, m), 2.76— 2.80(4H, FABMS: 477 ([M + 1] + ) 1H-NMR (400MHz, CDC1) δ 2.04-2.12 (2H, m), 2.76― 2.80 (4H,
3  Three
m), 2.91(4H, s), 4.27(1H, d, J=9.8Hz), 4.37(1H, d, J=9.8Hz), 5.40 (1H, s), m), 2.91 (4H, s), 4.27 (1H, d, J = 9.8Hz), 4.37 (1H, d, J = 9.8Hz), 5.40 (1H, s),
7.06-7.30(12H, m). 7.06-7.30 (12H, m).
[1110] [実施例 454] [1110] [Example 454]
4— {2—クロロー 4— [3— (2 ォキソ—2—フエ-ルァセチル）フエ-ルスルファ -ル]フエ 4— {2—Chloro—4— [3- (2oxo—2—Fe-L-acetyl) phen-Sulfur-Fu
-ル }ェチルー 4 シァノシメチルー 2 ォキサゾリジノン -Le} ethyl-4 cyanosmethyl-2 oxazolidinone
[1111] [化 294] [1111] [Formula 294]
Figure imgf000202_0001
Figure imgf000202_0001
[1112] 実施例 451の化合物 (lOOmg)のジメチルスルホキシド (5mL)溶液に、塩化パラジウム  [1112] A solution of the compound of Example 451 (100 mg) in dimethyl sulfoxide (5 mL) was added to palladium chloride.
(4.0mg)を加え、 120°Cにて 3時間攪拌した。氷冷下にて反応液に水を加え、酢酸ェ チルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。 溶媒を留去し、シリカゲルカラムクロマトグラフィー（へキサン  (4.0 mg) was added, and the mixture was stirred at 120 ° C for 3 hours. Water was added to the reaction solution under ice-cooling, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent is distilled off, and silica gel column chromatography (hexane
：酢酸ェチル = 1 : 1)にて精製し、 目的物 (57mg)を淡黄色油状物として得た。  : Ethyl acetate = 1: 1) to give the desired product (57 mg) as a pale yellow oil.
FABMS : 505([M+1]+) FABMS: 505 ([M + 1] + )
1H-NMR(400MHz, CDC1 ) δ 2.02-2.14(2Η, m), 2.75-2.84(4Η,  1H-NMR (400MHz, CDC1) δ 2.02-2.14 (2Η, m), 2.75-2.84 (4Η,
3  Three
m), 4.29(1Η, d, J=9.8Hz), 4.39(1Η, d, J=9.8Hz), 5.45 (1H, s), 7.16-7.24(2H, m), 7.38(1H, d, J=1.2Hz), 7.44-7.60(4H, m), 7.68(1H, t, J=8.6Hz), 7.82(1H, d, J=8.6Hz), 7.92-7.98(3H, m).  m), 4.29 (1Η, d, J = 9.8Hz), 4.39 (1Η, d, J = 9.8Hz), 5.45 (1H, s), 7.16-7.24 (2H, m), 7.38 (1H, d, J = 1.2Hz), 7.44-7.60 (4H, m), 7.68 (1H, t, J = 8.6Hz), 7.82 (1H, d, J = 8.6Hz), 7.92-7.98 (3H, m).
[1113] [実施例 455] [1113] [Example 455]
4— [4— (3—ァセチルフエ-ルスルファ -ル）—2 クロ口フエ-ル]ェチルー 4—シァノメ チルー 2—ォキサゾリジノン [1114] [化 295] 4— [4— (3-Acetylphenol-sulfur) —2 black mouth] ethyl—4-cyanomethyl-2-oxoxolidinone [1114] [Formula 295]
Figure imgf000203_0001
Figure imgf000203_0001
[1115] Pd(OAc) (llmg, 0.048mmol)の Ν,Ν-ジメチルホルムアミド（2mL)溶液に DPPP( [1115] A solution of Pd (OAc) (llmg, 0.048mmol) in Ν, Ν-dimethylformamide (2mL) was added with DPPP (
2  2
30mg)を加え、常温にて 30分間攪拌した。これに、実施例 449の化合物 (200mg)、ァリ ルブチルエーテル (240mg)、トリェチルァミン（lmL)の Ν,Ν-ジメチルホルムアミド（ 6mL)溶液を加え、 80°Cにて一晩攪拌した。氷冷下にて反応液に水を加え、酢酸ェ チルにて抽出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。 溶媒を留去し、これをテトラヒドロフラン (5mL)に溶解し、 6mol/L塩酸水溶液 (2ml)を 加え、 60°Cにて三時間攪拌した。氷冷下にて反応液に水を加え、酢酸ェチルにて抽 出し、水、飽和食塩水の順に洗浄後、無水硫酸ナトリウムにて乾燥した。溶媒を留去 し、シリカゲルカラムクロマトグラフィー（へキサン  30 mg) and stirred at room temperature for 30 minutes. To this was added a solution of the compound of Example 449 (200 mg), arylbutyl ether (240 mg) and triethylamine (1 mL) in Ν, Ν-dimethylformamide (6 mL), and the mixture was stirred at 80 ° C. overnight. Water was added to the reaction solution under ice-cooling, extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, this was dissolved in tetrahydrofuran (5 mL), a 6 mol / L hydrochloric acid aqueous solution (2 ml) was added, and the mixture was stirred at 60 ° C for 3 hours. Water was added to the reaction solution under ice-cooling, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off, and silica gel column chromatography (hexane
：酢酸ェチル = 1 : 2)にて精製し、 目的物 (140mg)を褐色油状物として得た。  : Ethyl acetate = 1: 2) to give the desired product (140 mg) as a brown oil.
FABMS : 415([M+1]+)FABMS: 415 ([M + 1] + )
— NMR(400MHz, CDC1 ) δ 2.01-2.14(2Η, m), 2.59(3Η, s),  — NMR (400MHz, CDC1) δ 2.01-2.14 (2Η, m), 2.59 (3Η, s),
3  Three
2.72-2.84(4Η, m), 4.29(1Η, d, J=9.8Hz), 4.39(1Η, d, J=9.8Hz), 5.66(1H, s), 2.72-2.84 (4Η, m), 4.29 (1Η, d, J = 9.8Hz), 4.39 (1Η, d, J = 9.8Hz), 5.66 (1H, s),
7.18(2H, s), 7.33(1H, s), 7.44(1H, t, J=8.6Hz), 7.54(1H, d, J=8.6Hz), 7.87(1H, d, J=8.6Hz), 7.95 (1H, s). 7.18 (2H, s), 7.33 (1H, s), 7.44 (1H, t, J = 8.6Hz), 7.54 (1H, d, J = 8.6Hz), 7.87 (1H, d, J = 8.6Hz), 7.95 (1H, s).
[1116] [実施例 456— 466] [1116] [Example 456-466]
実施例 444一 448、 450— 455の化合物を用い実施例 404と同様に反応させ表 37に示 す化合物を合成した。  Example 444 The compounds shown in Table 37 were synthesized by reacting in the same manner as in Example 404 using the compounds of 448 and 450-455.
[1117] [表 37] 表 37
Figure imgf000204_0001
[1117] [Table 37] Table 37
Figure imgf000204_0001
FABMS  FABMS
実施例 R 性状 【M+H】+  Example R Properties [M + H] +
456 OH 熱色アモルファス 382  456 OH thermal color amorphous 382
457 θΟ 無色アモルファス 396  457 θΟ colorless amorphous 396
458 無色アモルファス 478  458 colorless amorphous 478
^"CH2 ^ "CH 2
459 BuO 無色アモルファス 438  459 BuO Colorless amorphous 438
460 PhO 無色アモルファス 458  460 PhO colorless amorphous 458
461 Ph 無 末 442  461 Ph None 442
462 PhCC 無色 wr末 466  462 PhCC colorless wr end 466
463 PhCHCH 色粉朱 468  463 PhCHCH color powder red 468
464 PhCH2CH2 無色粉朱 470 464 PhCH 2 CH 2 colorless powder vermilion 470
465 PhCOCO 無色 末 498  465 PhCOCO colorless powder 498
466 Ac 無 e粉末 408  466 Ac No e-powder 408
[1118] 実施例 456 : iH-NMR OOMHz, DMSO- d ) δ 1.97- 2.01(2Η, m), [1118] Example 456: iH-NMR OOMHz, DMSO- d) δ 1.97- 2.01 (2Η, m),
6  6
2.53-2.77(4Η, m), 3.57— 3.60(2Η, m), 6.71-6.78 (3Η, m), 7.18— 7.40(4Η, s).  2.53-2.77 (4Η, m), 3.57- 3.60 (2Η, m), 6.71-6.78 (3Η, m), 7.18-7.40 (4Η, s).
[1119] 実施例 457 : iH-NMR OOMHz, DMSO- d ) δ 1.85- 1.90(2H, m), [1119] Example 457: iH-NMR OOMHz, DMSO- d) δ 1.85- 1.90 (2H, m),
6  6
2.68-2.80(4H, m), 3.55— 3.63(2H, m), 3.73(3H, s), 6.88— 6.93(3H, m),  2.68-2.80 (4H, m), 3.55--3.63 (2H, m), 3.73 (3H, s), 6.88-6.93 (3H, m),
7.25-7.35(4H, m), 8.00(3H, br).  7.25-7.35 (4H, m), 8.00 (3H, br).
[1120] 実施例 458 : 1H—NMR(400MHz, CDCl ) δ 0.93— 1.30(5H, m), [1120] Example 458: 1H-NMR (400MHz, CDCl) δ 0.93-1.30 (5H, m),
3  Three
1.60-1.88 (8H, m), 2.40— 2.54(2H, m), 3.48- 3.59(2H, m),2.62-2.74(2H, m), 3.75(2H, d, J=6.1Hz), 6.82— 6.93(3H, m), 7.23-7.34(4H, m).  1.60-1.88 (8H, m), 2.40— 2.54 (2H, m), 3.48- 3.59 (2H, m), 2.62-2.74 (2H, m), 3.75 (2H, d, J = 6.1Hz), 6.82— 6.93 (3H, m), 7.23-7.34 (4H, m).
[1121] 実施例 459 : 1H-NMR(400MHz, CDCl ) δ 0.90(3H, t, J=7.3Hz), [1121] Example 459: 1H-NMR (400MHz, CDCl) δ 0.90 (3H, t, J = 7.3Hz),
3  Three
1.35-1.42(2H, m), 1.61-1.70(2H, m), 1.80— 1.90(2H, m), 2.60-2.73(4H, m), 3.56-3.64(2H,, m), 3.94(2H, t,J=6.7Hz), 6.87— 6.93(3H, m), 7.25-7.33(4H, m), 8.04(3H, br).  1.35-1.42 (2H, m), 1.61-1.70 (2H, m), 1.80― 1.90 (2H, m), 2.60-2.73 (4H, m), 3.56-3.64 (2H ,, m), 3.94 (2H, t, J = 6.7Hz), 6.87- 6.93 (3H, m), 7.25-7.33 (4H, m), 8.04 (3H, br).
[1122] 実施例 460 : iH-NMR OOMHz, DMSO- d ) δ 1.80- 1.92(2H, m),  [1122] Example 460: iH-NMR OOMHz, DMSO- d) δ 1.80-1.92 (2H, m),
6  6
2.60-2.78(4H, m), 3.54— 3.62(2H, m), 6.76- 6.83(1H, t, J=1.2Hz), 6.89— 7.08(4H, m), 7.16(1H, t, J=8.6Hz), 7.26-7.40(6H, m), 8.05(3H, br). [1123] 実施例 461 : 1H— NMR(400MHz, DMSO— d ) δ 1.79— 1.98(2H, m), 2.53-2.78(4H, 2.60-2.78 (4H, m), 3.54-3.62 (2H, m), 6.76-6.83 (1H, t, J = 1.2Hz), 6.89-7.08 (4H, m), 7.16 (1H, t, J = 8.6 Hz), 7.26-7.40 (6H, m), 8.05 (3H, br). [1123] Example 461: 1H-NMR (400MHz, DMSO-d) δ 1.79- 1.98 (2H, m), 2.53-2.78 (4H,
6  6
m), 3.50-3.65(2H, m), 7.28-7.52(8H, m), 7.62-7.67(4H, m), 7.99(3H, br).  m), 3.50-3.65 (2H, m), 7.28-7.52 (8H, m), 7.62-7.67 (4H, m), 7.99 (3H, br).
[1124] 実施例 462 : 1H-NMR(400MHz, DMSO- d ) δ 1.84- 1.90(2H, m), [1124] Example 462: 1H-NMR (400MHz, DMSO-d) δ 1.84- 1.90 (2H, m),
6  6
2.57-2.80(4H, m), 3.50— 3.65(2H, m), 7.27-7.79(12H, m), 8.04(3H, br).  2.57-2.80 (4H, m), 3.50- 3.65 (2H, m), 7.27-7.79 (12H, m), 8.04 (3H, br).
[1125] 実施例 463 : 1H-NMR(400MHz, DMSO- d ) δ 1.80- 1.91(2H, m), [1125] Example 463: 1H-NMR (400MHz, DMSO- d) δ 1.80-1.91 (2H, m),
6  6
2.61-2.77(4H, m), 3.53- 3.65(2H, m), 6.60(1H, d, J=12Hz), 6.67(1H, d, J=12Hz), 7.09-7.36(12H, m), 8.00(3H, br).  2.61-2.77 (4H, m), 3.53- 3.65 (2H, m), 6.60 (1H, d, J = 12Hz), 6.67 (1H, d, J = 12Hz), 7.09-7.36 (12H, m), 8.00 (3H, br).
[1126] 実施例 464: iH-NMR OOMHz, DMSO- d ) δ 1.80- 1.91(2H, m), [1126] Example 464: iH-NMR OOMHz, DMSO- d) δ 1.80-1.91 (2H, m),
6  6
2.61- 2.76(4H, m), 2.83- 2.90(4H, m), 3.52— 3.62(2H, m), 7.00-7.34(12H, m), 7.98(3H, br).  2.61- 2.76 (4H, m), 2.83- 2.90 (4H, m), 3.52-3.62 (2H, m), 7.00-7.34 (12H, m), 7.98 (3H, br).
[1127] 実施例 465 : iH-NMR OOMHz, DMSO- d ) δ 1.82- 1.90(2H, m),  [1127] Example 465: iH-NMR OOMHz, DMSO- d) δ 1.82- 1.90 (2H, m),
6  6
2.62- 2.74(4H, m), 3.53— 3.63(2H, m), 7.16-7.45(12H, m), 7.96(3H, br).  2.62- 2.74 (4H, m), 3.53-3.63 (2H, m), 7.16-7.45 (12H, m), 7.96 (3H, br).
[1128] 実施例 466 : iH—NMR OOMHz, DMSO— d ) δ 1.90(3H, s), [1128] Example 466: iH-NMR OOMHz, DMSO-d) δ 1.90 (3H, s),
6  6
2.00-2.08(2H, m), 2.55-2.79(4H, m), 4.38- 4.20(2H, m), 7.31(1H, dd, J=8.6Hz, 1.2Hz), 7.40-7.44(2H, m), 7.53- 7.60(2H, m), 7.86(1H, s), 7.93 (1H, d, J=8.6Hz), 8.63(3H, br).  2.00-2.08 (2H, m), 2.55-2.79 (4H, m), 4.38-4.20 (2H, m), 7.31 (1H, dd, J = 8.6Hz, 1.2Hz), 7.40-7.44 (2H, m) , 7.53- 7.60 (2H, m), 7.86 (1H, s), 7.93 (1H, d, J = 8.6Hz), 8.63 (3H, br).
[1129] [実施例 467]  [1129] [Example 467]
4，一（3—ベンジルォキシフエ-ルァミノ） -2，一クロ口ジヒドロケィヒ酸ェチル 4,1- (3-benzyloxyphenol-amino) -2,1-cycloethyl ether
[1130] [化 296]
Figure imgf000205_0001
[1130] [Formula 296]
Figure imgf000205_0001
[1131] 4'ーァミノ一 2'—クロ口ジヒドロケィヒ酸ェチルと 3—べンジルォキシフエ-ルホウ酸を参 考例 58と同様にして反応させ目的物を褐色油状物として得た。 [1131] 4'-Amino-1 2'-chloroethyl dihydrokeichate and 3-benzyloxyphenol-borate were reacted in the same manner as in Reference Example 58 to give the desired product as a brown oil.
EIMS: 409 (Μ .  EIMS: 409 (Μ.
NMR(400MHz, CDC1 ) δ 1.24(3Η, t, J=7.3Hz), 2.61(2Η, t,  NMR (400MHz, CDC1) δ 1.24 (3Η, t, J = 7.3Hz), 2.61 (2Η, t,
3  Three
J=7.3Hz), 2.99(2H, t,J=7.3Hz), 4.12(2H, q, J=7.3Hz), 5.04(2H, s), 5.66(1H, br s), 6.58— 6.75(3H, m), 7.06— 7.16(2H, m), 7.18(1H, t, J=7.9Hz), 7.27-7.50(6H, m). [1132] [実施例 468] J = 7.3Hz), 2.99 (2H, t, J = 7.3Hz), 4.12 (2H, q, J = 7.3Hz), 5.04 (2H, s), 5.66 (1H, br s), 6.58- 6.75 (3H , m), 7.06— 7.16 (2H, m), 7.18 (1H, t, J = 7.9Hz), 7.27-7.50 (6H, m). [1132] [Example 468]
3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルァミノ）— 2 クロ口フエ-ル]— 3—ヒドロ キシメチルへキサン酸、塩酸塩  3-Amino—6— [4— (3-Benzyloxyphen-lamino) —2-chlorophenol] —3-Hydroxymethylhexanoic acid, hydrochloride
[1133] [化 297] [1133] [Formula 297]
Figure imgf000206_0001
Figure imgf000206_0001
[1134] 実施例 468の化合物を用いて参考例 252、実施例 実施例 76、実施例 213、実施 例 283、実施例 339の実験操作にならい順次反応させ目的物を淡黄色アモルファスと して得た。  [1134] Following the experimental procedures of Reference Example 252, Example Example 76, Example 213, Example 283, and Example 339 using the compound of Example 468, the reaction was carried out sequentially to obtain the target product as a pale yellow amorphous. Was.
FABMS: 469([M+1]+) FABMS: 469 ([M + 1] + )
1H-NMR(400MHz, DMSOd ) δ 1.52-1.72(4Η, m), 2.45-2.59(4Η,  1H-NMR (400MHz, DMSOd) δ 1.52-1.72 (4Η, m), 2.45-2.59 (4Η,
6  6
m), 3.44-3.53(2Η, m), 5.06(2Η, s), 5.50(1Η, br s), 6.52- 6.54(1Η, m),  m), 3.44-3.53 (2Η, m), 5.06 (2Η, s), 5.50 (1Η, br s), 6.52-6.54 (1Η, m),
6.60— 6.63(2Η, m), 6.93(1Η, dd, J=7.9, 2.5Hz), 7.01- 7.02(1H, m), 7.14(1H, t, 6.60— 6.63 (2Η, m), 6.93 (1Η, dd, J = 7.9, 2.5Hz), 7.01-7.02 (1H, m), 7.14 (1H, t,
J=7.9Hz), 7.30-7.44(6H, m), 7.81(3H, br s). J = 7.9Hz), 7.30-7.44 (6H, m), 7.81 (3H, br s).
[1135] [実施例 469] [1135] [Example 469]
(一)—2—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ- ル] 2 -メチルペンタン酸、塩酸塩  (1-)-2-Amino-5- [4- (3-benzyloxyphenylsulfur) -2-chlorophenol] 2-methylpentanoic acid, hydrochloride
[1136] [化 298] [1136] [Formula 298]
Figure imgf000206_0002
Figure imgf000206_0002
[1137] 文献（Synthesis, 1667(2003))にならぃキラルテンプレートを用いて参考例 252の化合 物を反応させた後、ヨウ化メタンを反応させて得られた化合物を加水分解し目的物を 無色粉末として得た。 [1137] According to the literature (Synthesis, 1667 (2003)), the compound of Reference Example 252 was reacted using a chiral template, and then the compound obtained by reacting with methane iodide was hydrolyzed to give the desired product. Obtained as a colorless powder.
[ α ] 28 —3.39° (c = 0.500, DMSO) [α] 28 —3.39 ° (c = 0.500, DMSO)
D D
HRMS : 456.1438 (+3.8 mmu ) 1H-NMR (400 MHz, CDC1 ) 1.17 (3H, s), 1.40 - 1.54 (2H, HRMS: 456.1438 (+3.8 mmu) 1H-NMR (400 MHz, CDC1) 1.17 (3H, s), 1.40-1.54 (2H,
3  Three
m), 1.58 - 1.72 (2H, m ),2.54 - 2.65 (2H, m), 5.07 (2H, s), 6.85 - 6.99 (3H, m), 7.21 - 7.40 (9H, m).  m), 1.58-1.72 (2H, m), 2.54-2.65 (2H, m), 5.07 (2H, s), 6.85-6.99 (3H, m), 7.21-7.40 (9H, m).
[1138] [実施例 470] [1138] [Example 470]
( + )—2—ァミノ— 5— [4— (3—ベンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ- ル] 2 -メチルペンタン酸、塩酸塩  (+) -2-Amino-5- [4- (3-Benzyloxyphenol-sulfur-)-2-cyclopentyl] 2-methylpentanoic acid, hydrochloride
[1139] [化 299]
Figure imgf000207_0001
[1139] [Formula 299]
Figure imgf000207_0001
[1140] 上記実施例 469と逆の順序で試薬を反応させ目的物を無色粉末として得た。 [1140] The reagent was reacted in the reverse order of Example 469 to give the desired product as a colorless powder.
[ α ] 28 +3.01° (c = 0.500, DMSO) [α] 28 + 3.01 ° (c = 0.500, DMSO)
D D
HRMS : 456.1369( -3.1 mmu ) HRMS: 456.1369 (-3.1 mmu)
JH-NMR (400 MHz, CDC1 ) 1.17 (3H, s), 1.40 - 1.54 (2H, J H-NMR (400 MHz, CDC1) 1.17 (3H, s), 1.40-1.54 (2H,
3  Three
m), 1.58 - 1.72 (2H, m ),2.54—2.65 (2H, m), 5.08 (2H, s).， 6.89 - 6.99 (3H, m), 7.22 - 7.40 (9H, m).  m), 1.58-1.72 (2H, m), 2.54-2.65 (2H, m), 5.08 (2H, s)., 6.89-6.99 (3H, m), 7.22-7.40 (9H, m).
[1141] 本発明化合物について、有用性を裏付ける成績を実験例によって示す。 [1141] The results supporting the utility of the compound of the present invention are shown by experimental examples.
<実験例 1 > ヒト S1P (スフインゴシン- 1-リン酸)受容体発現細胞に対する被験化合 物の細胞内カルシウム動員誘導試験  <Experimental Example 1> Induction test of intracellular calcium mobilization of the test compound on cells expressing human S1P (sphingosine-1-phosphate) receptor
10%のゥシ胎児血清、及び 200 g/mLの Geneticinを含む Ham's F-12培地で継代培 養したヒト S1P受容体発現 CHO細胞 (hSIP受容体発現 CHO細胞、あるいは hSIP受  Human S1P receptor-expressing CHO cells (hSIP receptor-expressing CHO cells or hSIP receiving cells) subcultured in Ham's F-12 medium containing 10% fetal bovine serum and 200 g / mL Geneticin.
1 3 容体発現 CHO細胞）を 4 X 104 1 x 3 4 x 10 4
cells/wellで 96穴黒色クリアボトム培養プレート（コースター）に播種し、 37°C、 5%CO  Seed cells / well in a 96-well black clear bottom culture plate (coaster) at 37 ° C, 5% CO
2 条件下で一晩培養した。さらに Ca2+結合性蛍光指示薬として Calcium The cells were cultured overnight under two conditions. Calcium as a Ca 2+ binding fluorescent indicator
Screening Kit試薬（同仁ィ匕学）を添カ卩し、 37°C、 5%CO条件下で 60分間培養した。培  Screening Kit reagent (Dojini-Danigaku) was added, and cultured for 60 minutes at 37 ° C and 5% CO. Culture
2  2
養後、マイクロプレート蛍光分光光度計 (FLEX  After feeding, microplate fluorescence spectrophotometer (FLEX
Station,モレキュラーデバイス）を用いて、励起波長 485nm、検出波長 525nmにおける 蛍光強度を測定した。最終濃度の 10倍の濃度になるよう培地で調製した S1P、あるい は被験化合物（最終 DMSO濃度 0.1%)を蛍光測定開始 18秒後に添加し、 1.5秒毎で 添加後 100秒まで蛍光強度を連続測定した。測定データより最大蛍光強度から最小 蛍光強度を引いた値 (蛍光増加量)を算出し、溶媒を添加したときの蛍光増加量と S1Pを 10— 6Mで作用させたときの蛍光増加量の差を 100%として、被験化合物の蛍光増 加率 (％)を算出した。これを被験化合物の細胞内カルシウム動員誘導作用として、 PRISMソフトウェア（GraphPad)を用いて EC 値を求めた。 EC 値≥10 /z mol/Lについ Station, a molecular device), and measured the fluorescence intensity at an excitation wavelength of 485 nm and a detection wavelength of 525 nm. S1P prepared in culture medium to a concentration 10 times the final concentration, or The test compound (final DMSO concentration 0.1%) was added 18 seconds after the start of fluorescence measurement, and the fluorescence intensity was continuously measured every 1.5 seconds until 100 seconds after the addition. Calculates a value by subtracting the minimum fluorescence intensity from the maximum fluorescence intensity from the measurement data (fluorescence increase), the difference between the fluorescence increase when allowed to act in the fluorescence increase with S1P the 10- 6 M upon addition of a solvent The fluorescence increase rate (%) of the test compound was calculated with the value of 100%. The EC value was determined using PRISM software (GraphPad) as the action of the test compound to induce intracellular calcium mobilization. EC value ≥10 / z mol / L
50 50  50 50
ては一、 10 iu mol/L>EC 値≥ 1 mol/Lについては +、 1 mol/L>EC 値につい For 10 i umol / L> EC value ≥ 1 mol / L, +, 1 mol / L> EC value
50 50  50 50
ては + +と表記し、表 38に示した。  Are shown as ++ and are shown in Table 38.
[1142] [表 38] 表 38 [1142] [Table 38] Table 38
実施例番号 S1 P1 S1 P3 実施例番号 S1 P1 S1 P3  Example number S1 P1 S1 P3 Example number S1 P1 S1 P3
335 + + 358 ++ ++ 335 ++++ 358 ++++
336 ++ ++ 359 +  336 ++++ 359+
337 ++ + 360 ++ +  337 +++ 360 +++
338 ++ 361 +  338 ++ 361 +
339 + 362 + +  339 + 362 + +
343 + 364 +  343 + 364 +
345 + 372 ++ +  345 + 372 ++ +
346 ++ 373 ++  346 ++ 373 ++
351 + 374 ++ +  351 + 374 ++ +
352 ++ ++ 375 ++ +  352 ++ ++ 375 ++ +
353 + 376 + ++  353 + 376 + ++
355 ++ 377 + ++  355 ++ 377 + ++
356 + ++ 379 +  356 +++ 379+
357 ++ ++ 404 ++  357 ++++ 404404 ++
464 ++  464 ++
[1143] 以上の結果から本発明化合物はヒト S1P受容体に作用することが認められた。 [1143] From the above results, it was confirmed that the compound of the present invention acts on human S1P receptor.
[1144] <実験例 2> ヒト S1P受容体発現細胞に対する被験化合物の [1144] <Experimental Example 2> Test compound against human S1P receptor-expressing cells
Extracelluar- Regulatory Kinase (ERK)活性化誘導試験  Extracelluar- Regulatory Kinase (ERK) activation induction test
10%のゥシ胎児血清、及び 200 g/mLの Geneticinを含む Ham's F-12培地で継代培 養したヒト S1P受容体発現 CHO細胞 (hSIP受容体発現 CHO細胞）を 3 X 105 cells/wellで 6穴細胞培養プレート（コースター）に播種し、 37°C、 5%CO条件下でー晚 3 × 10 5 human S1P receptor-expressing CHO cells (hSIP receptor-expressing CHO cells) subcultured in Ham's F-12 medium containing 10% fetal bovine serum and 200 g / mL Geneticin Cells / well are seeded on a 6-well cell culture plate (coaster) and incubated at 37 ° C and 5% CO.
2  2
培養した。翌日、培養プレートから培地を除去し、ゥシ胎児血清を含まない Ham's F-12培地（0.1%の脂肪酸不含ゥシ血清アルブミンを含む）を添カ卩して、 37°C、 5%CO Cultured. On the next day, remove the culture medium from the culture plate, add Ham's F-12 medium containing no fetal serum (containing 0.1% fatty acid-free serum albumin), and add 37 ° C, 5% CO2.
2 条件下で一晩培養した。この培養プレートに最終濃度の 10倍の濃度になるよう Ham's F-12培地 (0.1%の脂肪酸不含ゥシ血清アルブミンを含む)で調製した S1P、あるいは 被験化合物（最終 DMSO濃度 0.1%)を添加し、 37°C、 5%CO条件下で 5分間反応させ  The cells were cultured overnight under two conditions. To this culture plate, add S1P prepared in Ham's F-12 medium (containing 0.1% fatty acid-free serum albumin) or a test compound (final DMSO concentration 0.1%) to a concentration 10 times the final concentration. Reaction at 37 ° C, 5% CO for 5 minutes.
2  2
た。培地を除去し、氷冷した 200 mol/Lの Na VOを含む PBS (リン酸緩衝液）で細胞 It was. Remove the medium and place the cells in ice-cold PBS (phosphate buffer) containing 200 mol / L Na VO.
3 4  3 4
を洗浄した後、 Lysis After washing the Lysis
Buffer (20mmol/L Tris— HC1 pH7.5、 1% Triton X— 100、 lmmol/L EDTA、 lmmol/L EGTA、 0.5mmol/L  Buffer (20mmol / L Tris- HC1 pH7.5, 1% Triton X-100, lmmol / L EDTA, lmmol / L EGTA, 0.5mmol / L
Na VO、 0.1% β -mercaptoethanoU 50mmol/L NaFゝ 5mmol/L Na O P、 lOmmol/L Na VO, 0.1% β-mercaptoethanoU 50 mmol / L NaF ゝ 5 mmol / L Na O P, lOmmol / L
3 4 4 7 3 3 4 4 7 3
C H O Na、 1 mol/L Microcystin LR、 1 X Complete  C H O Na, 1 mol / L Microcystin LR, 1 X Complete
3 7 6  3 7 6
Protease Inhibitor Cocktail (ロシュ））を添カ卩して、氷上で 5分間反応させて細胞を溶 解した。この細胞溶解液を泳動サンプルとして、 SDS-PAGE (ドデシル硫酸ナトリウム- ポリアクリルアミドゲル電気泳動）により蛋白質を分離し、 PVDF膜 (Hybond-P、アマシ ャムバイオサイエンス）に転写した。この膜を 1 ,000倍に希釈した抗リン酸化 ERK (p 42/44  Protease Inhibitor Cocktail (Roche)) was added, and the mixture was reacted on ice for 5 minutes to lyse the cells. Using the cell lysate as an electrophoresis sample, proteins were separated by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and transferred to a PVDF membrane (Hybond-P, Amersham Bioscience). Anti-phosphorylated ERK (p 42/44)
MAPK)モノクローナル抗体（E10、セルシグナリングテクノロジー）と 4°Cでー晚反応さ せた後、 6,000倍に希釈したアルカリホスファターゼ標識抗マウス IgG抗体 (モレキユラ 一プローブ）と室温で 1時間反応させた。 PVDF膜を 20mmol/L  After reacting at 4 ° C with a monoclonal antibody (MAPK) (E10, cell signaling technology), the mixture was reacted with an alkaline phosphatase-labeled anti-mouse IgG antibody (Molecular probe) diluted 6,000-fold for 1 hour at room temperature. PVDF membrane 20mmol / L
Tris- HC1、 150mmol/L NaCl溶液で洗浄した後、アルカリホスファターゼの蛍光基質 である DDAO Phosphate (DyeChrome After washing with Tris-HC1, 150 mmol / L NaCl solution, DDAO Phosphate (DyeChrome
Western Blot Stain Kit,モレキュラープローブ）を用いて蛍光染色し、バリ  Western Blot Stain Kit, molecular probe)
ァブルイメージアナライザー（Typhoon 8600、アマシャムバイオサイエンス）を用いて 検出した。検出したリン酸化 ERKのシグナルは、 ImageQuantソフトウェア（モレキユラ 一ダイナミクス）により定量ィ匕した。溶媒を添加したときのシグナル強度と S1Pを 10 mol/Lで添カ卩したときのシグナル強度の差を 100%とし、被験化合物を添カ卩したときの z強度から ERK活性ィ匕率 (%)を算出して、被験化合物の ERK活性ィ匕誘導作用 を評価した。結果を表 39に示した c Detectable using a portable image analyzer (Typhoon 8600, Amersham Bioscience). The detected phosphorylated ERK signal was quantified using ImageQuant software (Molecular Dynamics). The difference between the signal intensity when the solvent was added and the signal intensity when S1P was added at 10 mol / L was 100%, and the ERK activity ratio (% ) To calculate the ERK activity of the test compound. Was evaluated. The results are shown in Table 39 c
[1145] [表 39] [1145] [Table 39]
Figure imgf000210_0001
Figure imgf000210_0001
[1146] 以上の結果から、本発明化合物はヒト S1P受容体に作用し、 ERKの活性化誘導作 用が認められた。  [1146] From the above results, it was confirmed that the compound of the present invention acts on human S1P receptor and induces ERK activation.
[1147] <実験例 3〉 マウス宿主対移植片拒絶反応に対する被験化合物の抑制作用  [1147] <Experimental Example 3> Inhibitory effect of test compound on mouse host versus graft rejection
トランスプランテーション（Transplantation)、第 55卷、第 3号、第 578- 591頁, 1993年. に記載の方法を参考にして行った。 BALB/c系雄性マウス 7— 9週齢（日本チヤ一ルス 'リバ一）から脾臓を採取した。脾臓は、 RPM卜 1640培地 (シグマ）中に取り出し、スラ イドグラス 2枚ですり潰しセルストレーナ一（70ミクロン、ファルコン）を通過させることに より脾細胞浮遊液にした。この脾細胞浮遊液を遠心して上清を除去した後、塩化アン モ-ゥム-トリス等張緩衝液をカ卩えて赤血球を溶血させた。 RPMI-1640培地で 3回遠 心洗浄した後、 RPMI-1640培地に浮遊した。これに最終濃度が 25 μ gZmLとなるよう にマイトマイシン C (協和醱酵)を加え、 37°C、 5%CO下で 30分間培養した。  Transplantation was performed with reference to the method described in Transplantation, Vol. 55, No. 3, pp. 578-591, 1993. Spleens were collected from BALB / c male mice 7-9 weeks of age (Japan Charles' Riva). The spleen was taken out in RPMT 1640 medium (Sigma), ground with two slide glasses, and passed through a cell strainer (70 micron, Falcon) to obtain a spleen cell suspension. After the supernatant was removed by centrifugation of the spleen cell suspension, an isotonic buffer of ammonium chloride-tris was added to lyse erythrocytes. After centrifugation three times with RPMI-1640 medium, the cells were suspended in RPMI-1640 medium. To this, mitomycin C (Kyowa Hakko) was added to a final concentration of 25 μgZmL, and the cells were cultured at 37 ° C under 5% CO for 30 minutes.
2  2
RPMI-1640培地で 3回遠心洗浄した後、 RPMI-1640培地に 2.5 X 108個 ZmLとなるよ うに浮遊し、これを刺激細胞浮遊液とした。刺激細胞浮遊液 20 μ L· (5 X 106個 Z匹） を、 27G針及びマイクロシリンジ (ハミルトン）を用いて C3HZHeN系雄性マウス 7— 9週 齢（日本クレア）の右後肢足躕部皮下に注射した。正常対照群には、 RPMト 1640培 地のみを注射した。 4日後に、右膝下リンパ節を摘出し、メトラー AT201型電子天秤（ メトラー ·トレド)を用いて重量を測定した。被験化合物は、刺激細胞注射日から 3日後 まで、 1日 1回、計 4回、連日腹腔内投与した。対照群には、被験化合物の調製に用 Vヽたものと同じ組成の溶媒を投与した。結果を表 40に示す。 After washing three times by centrifugation with RPMI-1640 medium, the cells were suspended in RPMI-1640 medium to a volume of 2.5 × 10 8 ZmL, and this was used as a stimulating cell suspension. Using a 27G needle and a microsyringe (Hamilton), apply 20 μL of the stimulated cell suspension (5 × 10 6 Z animals) subcutaneously to the right hind foot and foot of a 7- to 9-week-old (CLEA Japan) male C3HZHeN mouse. Was injected. The normal control group was injected with RPM 1640 medium only. Four days later, the lymph node below the right knee was excised and weighed using a METTLER AT201 electronic balance (Mettler Toledo). The test compound was intraperitoneally administered once a day for a total of four times a day from the day of stimulator cell injection to three days later. The control group received a solvent having the same composition as that used for preparing the test compound. The results are shown in Table 40.
なお、抑制率は下記の計算式を用いて算出した。  The suppression rate was calculated using the following formula.
[1148] [数 1] [ (»性対陳》の右膝下リンパ節重量）一（被験化合物群の右膝下リンパ節重量） ] X 1 00 [1148] [number 1] [Weight of lymph node below right knee of (»Sex vs. Chen) ]- (weight of lymph node below right knee of test compound group) ] X 100
( »性対釅»の右膝下リンパ節 ) _ (正常対照群の右膝下リンパ 15 (»Right knee lymph node of sex vs. 釅) _ (Right knee lymph node of normal control group 15)
[1149] [表 40] 表 40 [1149] [Table 40] Table 40
投与量 抑制率 投与量 抑制率  Dose suppression rate Dose suppression rate
実施例番号 実施例番号  Example number Example number
(mg/kg) (%) (mg/kg) (%)  (mg / kg) (%) (mg / kg) (%)
336 10 83 356 3 63  336 10 83 356 3 63
337 3 73 362 10 48  337 3 73 362 10 48
339 10 76 369 10 67  339 10 76 369 10 67
345 3 71 372 10 58  345 3 71 372 10 58
352 10 72 373 10 51  352 10 72 373 10 51
354 10 61 374 10 82  354 10 61 374 10 82
464 30 67  464 30 67
[1150] 以上の結果から、本発明化合物はマウス宿主対移植片拒絶反応を抑制作用するこ とが明らカ^なつた。 [1150] From the above results, it has been clarified that the compound of the present invention has an inhibitory effect on mouse host versus graft rejection.
産業上の利用可能性  Industrial applicability
[1151] 本発明は、新規なアミノカルボン酸誘導体とその付加塩が優れたスフインゴシン 1 —リン酸 (S1P)受容体調節作用を有することを見出したものである。このような S1P受 容体調節作用を有する化合物は、動脈硬化症、閉塞性動脈硬化症、閉塞性血栓血 管炎、腎繊維症、肝繊維症、慢性気管支喘息、びまん性過誤腫性肺脈管筋腫症、 成人呼吸促迫症候群 (ARDS)、慢性閉塞性肺疾患 (COPD) ,間質性肺炎、特発 性間質性肺炎、肺癌、過敏性肺臓炎、バージャ一病、糖尿病性ニューロバチ一の末 梢動脈疾患、敗血症、血管炎、腎炎、肺炎、脳梗塞、心筋梗塞症、浮腫性疾患、静 脈瘤、解離性大動脈瘤、狭心症、 DIC、胸膜炎、うつ血性心不全、多臓器不全、とこ ずれ、火傷、潰瘍性大腸炎、クローン病などの治療及び予防薬として、又、心移植、 腎移植、皮膚移植、肝移植、骨髄移植などの拒絶反応の予防又は治療薬、関節リウ マチ、ループス腎炎、全身性エリトマト一デス、橋本病、多発性硬化症、重症筋無力 症、糖尿病、アトピー性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎、アレルギ 一性接触皮膚炎等の予防又は治療薬として有用である。  [1151] The present invention has found that a novel aminocarboxylic acid derivative and an addition salt thereof have excellent sphingosine 1-phosphate (S1P) receptor regulating action. Compounds having such S1P receptor-modulating effects include arteriosclerosis, obstructive arteriosclerosis, obstructive thrombosis, renal fibrosis, hepatic fibrosis, chronic bronchial asthma, and diffuse hamartomatous pulmonary vasculature. Myomatosis, adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, idiopathic interstitial pneumonia, lung cancer, irritable pneumonitis, Bajaja disease, peripheral diabetic neurobati Arterial disease, sepsis, vasculitis, nephritis, pneumonia, cerebral infarction, myocardial infarction, edema disease, venous aneurysm, dissecting aortic aneurysm, angina pectoris, DIC, pleurisy, congestive heart failure, multiple organ failure For the treatment and prevention of burns, ulcerative colitis, Crohn's disease, etc., and for the prevention or treatment of rejection such as heart transplant, kidney transplant, skin transplant, liver transplant, bone marrow transplant, rheumatoid arthritis, lupus nephritis , Systemic lupus erythematosus, Hashimoto's disease, multiple sclerosis, Diseases gravis, diabetes, atopic dermatitis, is useful as allergic rhinitis, allergic conjunctivitis, prophylactic or therapeutic agent such as allergic one contact dermatitis.

Claims

請求の範囲 [1] 一般式 (1) Claims [1] General formula (1)
[化 1]  [Chemical 1]
,rH « - . C02R5 (1) , rH «-. C0 2 R 5 (1)
(CH2)m R4 (CH 2 ) m R 4
[式中、 Rは置換基を有しても良いフエニル基又は置換基を有しても良い炭素数 1 [Wherein, R is a phenyl group which may have a substituent or a carbon atom which may have a substituent 1
1 一 1 one
10のアルキル基を、 10 alkyl groups,
Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素数 1  R is a hydrogen atom, halogen atom, torino, lomethyl group, carbon number 1
2 一 4の低級アルキル基又 は炭素数 1一 4の低級アルコキシ基を、  A lower alkyl group having 14 to 14 carbon atoms or a lower alkoxy group having 14 to 14 carbon atoms,
Rは水素原子、炭素数 1一 4の低級アルキル基又はフエ-ル基を、  R represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a phenyl group,
3  Three
Rは水素原子、置換基を有しても良い炭素数 1一 4の低級アルキル基、炭素数 2— 4 R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms which may have a substituent, and 2 to 4 carbon atoms;
4 Four
の低級アルケニル基、炭素数 2— 4の低級アルキニル基、カルボキシル基、炭素数 1 一 4の低級アルコキシカルボ-ル基、ベンジルォキシカルボ-ル基、 CH OCH CO H  A lower alkenyl group, a lower alkynyl group having 2 to 4 carbon atoms, a carboxyl group, a lower alkoxycarbol group having 14 to 14 carbon atoms, a benzyloxycarbol group, CH OCH CO H
2 2 2 又は CH OCH CO R (Rは炭素数 1  2 2 2 or CH OCH CO R (R is carbon number 1
2 2 2 6 6 一 4の低級アルキル基又はべンジル基)を、 2 2 2 6 6 14 lower alkyl group or benzyl group),
Rは水素原子、炭素数 1一 4の低級アルキル基又はベンジル基を、 R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group,
5  Five
Xは 0、 S、 SO、 SO  X is 0, S, SO, SO
2、 NH又は CHを、  2, NH or CH,
2  2
mは 2 4の整数を、  m is an integer of 24,
Yは CH=CH、 CH OCH、 (CH ) 11 (11は0 2の整数）又は(¾ 0CHCO Rを示す]  Y is CH = CH, CH OCH, (CH) 11 (11 is an integer of 0 2) or (¾ represents 0CHCO R)
2 2 2 2 2 5 で表されることを特徴とするアミノカルボン酸誘導体、その光学異性体及び薬理学的 に許容しうる塩並びにその水和物。  An aminocarboxylic acid derivative, an optical isomer, a pharmacologically acceptable salt and a hydrate thereof, characterized by being represented by 2222.
[2] 前記一般式（1)で表される化合物が、一般式（la)  [2] The compound represented by the general formula (1) is a compound represented by the general formula (la)
[化 2]
Figure imgf000212_0001
[Chemical 2]
Figure imgf000212_0001
[式中、 X、 Y、 R 前記定義に同じ]  [Where X, Y, and R are the same as defined above]
2、 R及び mは  2, R and m are
4  Four
で表される化合物であることを特徴とする請求項 1記載のアミノカルボン酸誘導体、そ の光学異性体及び薬理学的に許容しうる塩並びにその水和物。 The aminocarboxylic acid derivative according to claim 1, which is a compound represented by the formula: Optical isomers and pharmacologically acceptable salts thereof and hydrates thereof.
[3] 前記一般式（la)において Rが塩素原子であることを特徴とする請求項 2に記載のァ 3. The method according to claim 2, wherein R in the general formula (la) is a chlorine atom.
2  2
ミノカルボン酸誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水 和物。  Minocarboxylic acid derivatives, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof.
[4] 前記一般式 (1)で表される化合物が、一般式 (lb)  [4] The compound represented by the general formula (1) is represented by the general formula (lb)
[化 3] (1 b) [Formula 3] (1 b)
Figure imgf000213_0001
Figure imgf000213_0001
[式中、 pは 5— 10の整数示し、 X、 Y、 R び mは前記定義に同じ] [Where p is an integer of 5-10, and X, Y, R and m are the same as defined above]
2、 R及  2, R and
4  Four
で表される化合物であることを特徴とする請求項 1に記載のアミノカルボン酸誘導体、 その光学異性体及び薬理学的に許容しうる塩並びにその水和物。  2. The aminocarboxylic acid derivative according to claim 1, which is a compound represented by the formula: ## STR00001 ## and optical isomers and pharmacologically acceptable salts thereof and hydrates thereof.
[5] 前記一般式（lb)において Rが塩素原子であることを特徴とする請求項 4に記載のァ  5. The method according to claim 4, wherein R in the general formula (lb) is a chlorine atom.
2  2
ミノアルコール誘導体、その光学異性体及び薬理学的に許容しうる塩並びにその水 和物。  Mino alcohol derivatives, optical isomers and pharmacologically acceptable salts thereof and hydrates thereof.
[6] 前記一般式 (1)で示される化合物が、  [6] The compound represented by the general formula (1) is
1) 3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—ヒドロキシメチルへキサン酸、  1) 3-amino-6- [4- (3-benzyloxyphenyl-sulfur) -2-cyclophenol] -3-hydroxymethylhexanoic acid,
2) 3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 3—ヒドロキシプロピルへキサン酸、  2) 3-Amino-6- [4- (3-benzyloxyphenylsulfur) -2-cyclophenol] -3-hydroxypropylhexanoic acid,
3) 3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—プロピルへキサン酸、  3) 3-amino-6- [4- (3-benzyloxyphenyl-sulfur-)-2-chlorophenol] -3-propylhexanoic acid,
4) 3—ァリル 3—ァミノ— 6— [4— (3—べンジルォキシフエ-ルスルファ -ル)—2 クロ口 フエ-ル]へキサン酸、  4) 3-aryl 3-amino-6- [4- (3-benzyloxyphenol-sulfur-)-2-chlorophenol] hexanoic acid,
5) 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 3—ヒドロキシメチルペンタン酸、  5) 3-Amino-5- [4- (3-benzyloxyphenol-sulfur) -2-cyclophenol] -3-hydroxymethylpentanoic acid,
6) 3—ァミノ— 5— [4— (4—べンジルォキシフエ-ルスルファ -ル）—2 クロ口フエ-ル]— 3—ヒドロキシメチルペンタン酸、 7) 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—ヒドロキシプロピルペンタン酸、 6) 3-Amino-5- [4- (4-benzyloxyphenol-sulfur) -2-cyclophenol] -3-hydroxymethylpentanoic acid, 7) 3-amino-5- [4- (3-benzyloxyphenylsulfur) -2-cyclophenol] -3-hydroxypropylpentanoic acid,
8) 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル）—2—クロ口フエ-ル]— 3—プロピノレペンタン酸、  8) 3-Amino-5- [4- (3-benzyloxyphenyl-sulfur-yl) -2-chlorophenol] -3-propinolepentanoic acid,
9) 3—ァリル 3—ァミノ— 5— [4— (3—べンジルォキシフエ-ルスルファ -ル)—2 クロ口 フエ-ル]ペンタン酸、又は  9) 3-aryl 3-amino-5- [4- (3-benzyloxyphenyl-sulfur) -2-cyclophthalene] pentanoic acid, or
10) 2—ァミノ— 2—プロピル [4— (3—べンジルォキシフエ-ルスルファ -ル）—2 クロ口 フエニル] -酪酸である請求項 1記載のアミノカルボン酸誘導体及び薬理学的に許容 しうる塩並びにその水和物。  10) The aminocarboxylic acid derivative according to claim 1, which is 2-amino-2-propyl [4- (3-benzyloxyphenylsulfur-)-2-chlorophenyl] -butyric acid, and a pharmaceutically acceptable salt thereof. And hydrates thereof.
[7] 一般式 (1)  [7] General formula (1)
[化 4]
Figure imgf000214_0001
[Formula 4]
Figure imgf000214_0001
[式中、 Rは置換基を有しても良いフエニル基又は置換基を有しても良い炭素数 1 [Wherein, R is a phenyl group which may have a substituent or a carbon atom which may have a substituent 1
1 一 1 one
10のアルキル基を、 10 alkyl groups,
Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素数 1 4の低級アルキル基又 R represents a hydrogen atom, a halogen atom, a torino, a lomethyl group, a lower alkyl group having 14 carbon atoms or
2 一 2 one
は炭素数 1一 4の低級アルコキシ基を、  Represents a lower alkoxy group having 1 to 4 carbon atoms,
Rは水素原子、炭素数 1  R is a hydrogen atom, carbon number 1
3 一 4の低級アルキル基又はフエ-ル基を、  314 lower alkyl group or phenyl group,
Rは水素原子、置換基を有しても良い炭素数 1一 4の低級アルキル基、 2— 4の低級 R represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, and a lower alkyl group having 2 to 4 carbon atoms;
4 Four
ァルケ-ル基、炭素数 2— 4の低級アルキ-ル基、カルボキシル基、炭素数 1一 4の 低級アルコキシカルボ-ル基、ベンジルォキシカルボ-ル基、 CH OCH CO H又は  Alkenyl group, lower alkyl group having 2 to 4 carbon atoms, carboxyl group, lower alkoxycarbol group having 14 to 14 carbon atoms, benzyloxycarbol group, CH OCH COH or
2 2 2 2 2 2
CH OCH CO R (Rは炭素数 1 CH OCH CO R (R is carbon number 1
2 2 2 6 6 一 4の低級アルキル基又はべンジル基)を、 2 2 2 6 6 14 lower alkyl group or benzyl group),
Rは水素原子、炭素数 1一 4の低級アルキル基又はベンジル基を、 R is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a benzyl group,
5  Five
Xは 0、 S、 SO、 SO  X is 0, S, SO, SO
2、 NH又は CHを、  2, NH or CH,
2  2
mは 2 4の整数を、  m is an integer of 24,
Yは CH=CHゝ CH OCH、（CH ) n (nは 0 2の整数）又は CH 0CHCO Rを示す]  Y represents CH = CH ゝ CH OCH, (CH) n (n is an integer of 0 2) or CH 0CHCO R]
2 2 2 2 2 5 で表されることを特徴とするアミノカルボン酸誘導体、その光学異性体及び薬理学的 に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分とする SIP受 容体調節剤。 Aminocarboxylic acid derivative represented by 2 2 2 2 5, its optical isomer and pharmacological property And a pharmaceutically acceptable salt thereof.
[8] 前記一般式 (1)で示される化合物が、一般式 (la)  [8] The compound represented by the general formula (1) is a compound represented by the general formula (la)
[化 5]
Figure imgf000215_0001
[Formula 5]
Figure imgf000215_0001
[式中、 X、 Y、 R [Where X, Y, R
2、 R及び mは前記定義に同じ]  2, R and m are the same as defined above]
4  Four
で表されるアミノカルボン酸誘導体、その光学異性体及び薬理学的に許容しうる塩 並びにその水和物の少なくとも一種類以上を有効成分とすることを特徴とする請求項 Wherein at least one of an aminocarboxylic acid derivative represented by the formula (I), an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof are used as an active ingredient.
7に記載の S1P受容体調節剤。 8. The S1P receptor modulator according to 7.
[9] 前記一般式（1)で表される化合物が、一般式（lb)  [9] The compound represented by the general formula (1) is a compound represented by the general formula (lb)
[化 6]  [Formula 6]
Me(CH2)P M l ¥H γz—' C02H (1 b) Me (CH2) P M l ¥ H γ z — 'C0 2 H (1 b)
(CH2)m R4 (CH 2 ) m R 4
[式中、 pは 6— 10の整数を示し、 X、 Y、 R、 R及び mは前記定義に同じ] [Wherein, p represents an integer of 6-10, and X, Y, R, R and m are as defined above]
2 4  twenty four
で表されるアミノカルボン酸誘導体、その光学異性体及び薬理学的に許容しうる塩 並びにその水和物の少なくとも一種類以上を有効成分とすることを特徴とする請求項 Wherein at least one of an aminocarboxylic acid derivative represented by the formula (I), an optical isomer and a pharmacologically acceptable salt thereof, and a hydrate thereof are used as an active ingredient.
7に記載の S1P受容体調節剤。 8. The S1P receptor modulator according to 7.
[10] 請求項 1一 6のいずれか 1項に記載されたァミノカルボン酸誘導体、その光学異性体 及び薬理学的に許容しうる塩並びにその水和物の少なくとも一種類以上を有効成分 として含有する医薬。  [10] As an active ingredient, it contains at least one or more of the amino carboxylic acid derivative, the optical isomer, the pharmacologically acceptable salt and the hydrate thereof according to any one of claims 116. Medicine.
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