WO2003101944A1

WO2003101944A1 - Process for producing compound having biphenyl group substituted with lower alkylthio group

Info

Publication number: WO2003101944A1
Application number: PCT/JP2003/006659
Authority: WO
Inventors: Akira Okuyama; Yoshiyuki Masui; Yoji Kitaura
Original assignee: Shionogi & Co., Ltd.
Priority date: 2002-05-30
Filing date: 2003-05-28
Publication date: 2003-12-11
Also published as: AU2003241826A1

Abstract

A process for producing a compound of the general formula (IV) or a salt or solvate thereof, characterized in that a compound of the general formula (V) or a salt or solvate thereof is subjected to reaction for conversion to an alkylthio: (V) (IV) wherein R1 is a substituted or unsubstituted lower alkyl, and X2 is a halogen.

Description

Description Method for producing compound having biphenyl group substituted by lower alkylthio group

The present invention relates to a simple and economical method for producing a compound having a biphenyl group substituted with a lower alkylthio group. Background art

Matrix metaoral protease is an enzyme that contains zinc in the enzyme and degrades extracellular matrix (collagen, gelatin, fibronectin, etc.) as a substrate. This enzyme is thought to be involved in various pathologies such as osteoarthritis, tumor metastasis or invasion, congestive heart failure, nephritis, and retinopathy.

In recent years, many MMP inhibitors having various structures have been reported. In particular, it has been reported that sulfonamide derivatives having a biphenyl group have excellent activity (Patent Documents 1 and 2 and Non-Patent Documents 1 to 3).

Non-Patent Document 2 reports the following two methods for synthesizing a sulfonamide derivative having a biphenyl group.

Method A

Br- -S. ₂ CI +

B method

-so ₂ ci X S0 ₂ -N COO e

Hc COO e

In each case, the ester of the amino acid is reacted with the sulfonyl chloride. If the final product is a carboxylic acid, a further deprotection (hydrolysis) step is required. Becomes In the case of industrialization, including the steps of protection and deprotection not only increases the number of steps but lowers the yield, but also includes impurities that cannot be removed in the final deprotection reaction There is also. Therefore, a method of directly reacting a sulfonyl chloride with a carboxylic acid without ester protection of an amino acid, as in Patent Document 3, has been reported. However, there is no description of the solubility of the biphenyl compound or precipitation in the reaction system.

Β S0 ₂ CI ₊ H ₂ N

As a method for introducing a lower alkylthio group into an aromatic ring, the following method is known in which a halogenated benzene derivative is reacted with an alkyl mercaptan in the presence of a base. (Patent Documents 4 and 5) However, there is no description applicable to biphenyl compounds. On the other hand, biphenyl derivatives substituted with lower alkylthio groups are useful as MMMM inhibitors, and their industrial synthesis is desired.

R R

/ = <MeSH + NaOHaq. / = <

《/>-CI → / SMe

^ n-Bu ₄ NBr

R = CN, C (= 0) e

(Patent Document 1)

International Publication No. 97/2 7 1 7 4 Pamphlet

(Patent Document 2)

U.S. Pat.No. 5,756,545

(Patent Document 3)

International Publication No. 0 1/7 9 2 0 1 Pamphlet

(Patent Document 4)

Japanese Patent Application Laid-Open No. 08-134 051

(Patent Document 5)

Japanese Patent Application Laid-Open No. Hei 8—1 4 3 5 3 4 (Non-Patent Document 1)

Yoshinori Tamura et al., Journal of Medicinal Chemistry (J. Med. Chem.) 1998, Vol. 41, p. 640-649

(Non-Patent Document 2)

Patrick M. O'Brien et. Al., J. Med. Chem., 2000, Vol. 43, No. 2, p. 156-166 '(Non-Patent Document 3)

Stanislaw Pikul et. Al. Journal of Medicinal Chemistry (J. Med. Chem.) 2001, Vol. 44, No. 16, p. 2499-2502 Disclosure of the Invention

It is desired to develop a simple and economical method for producing a compound having a biphenyl group substituted with a lower alkylthio group.

In view of the above points, the present inventors have conducted intensive studies and, as a result, have found a simple and economical method for producing a compound having a biphenyl group substituted with a lower alkylthio group.

That is, the present invention provides 1) a general formula (V):

. ,, / ^OH

x-one, '

(V)

Wherein X ² is a halogen, a salt thereof or a solvate thereof is subjected to an alkylthioation reaction, wherein the compound is represented by the following general formula (IV):

(Wherein, R ¹ is lower alkyl which may be substituted), a salt thereof, or a solvate thereof. For further details, please refer to the following 2) to 6)

2) General formula (IV):

Wherein R ¹ has the same meaning as 1), a salt thereof, or a solvate thereof, which is subjected to a halogenation reaction, wherein the compound represented by the general formula (II):

(Wherein, R ¹ has the same meaning as in 1); X ¹ is a halogen), a salt thereof, or a solvate thereof.

3) General formula (II):

(Wherein, R ¹ has the same meaning as 1); X ¹ has the same meaning as 2)), a salt thereof, or a solvate thereof, and a general formula (III): H ₂ N or ² (-I )

COOH

Wherein R ² is lower alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, heteroaryl which may be substituted, or heteroarylalkyl which may be substituted. A compound represented by the formula, a salt thereof, or a solvate thereof, which is subjected to an amidation reaction;

(Wherein, R ¹ has the same meaning as 1); R ² has the same meaning as described above). 2) The process according to 2), which comprises the step of manufacturing a compound represented by the formula:

4) Alkyl thiolation reaction agrees with KSR ¹ (where R ¹ is 1) as reaction reagent The production method according to any one of 1) to 3), wherein

5) In the alkylthiolation reaction, alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, alkyl esters, alkyl phosphites, nitrates, acetates, and tetras The method according to any one of 1) to 4), wherein an alkylating agent selected from the group consisting of alkylammonium salts is added.

Further, as the alkylating agent, an alkylating agent selected from the group consisting of alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, and tetraalkylammonium salts is preferable.

In particular, an alkylating agent selected from the group consisting of alkyl halides, dialkyl carbonates, alkyl sulfonates, and dialkyl sulfates and tetraalkylammonium salts is preferred.

6) The production method according to any one of 1) to 5), wherein R ¹ is methyl and X ² is bromine. 7) General formula (II):

(Wherein, R ¹ has the same meaning as 1); X ¹ has the same meaning as 2)), a salt thereof, or a solvate thereof, and a general formula (III):

H ₂ N COOH

Wherein R ² has the same meaning as 3), a salt thereof, or a solvate thereof, which is subjected to an amidation reaction, wherein the compound represented by the general formula (I):

(Wherein, R ¹ has the same meaning as 1); R ² has the same meaning as 3)), a salt thereof, or a solvate thereof. 8) General formula (IV)

(Wherein R ¹ has the same meaning as 1); X ¹ has the same meaning as 2)), a salt thereof, or a solvate thereof.

Where the general formula (IV): (, v)

(Wherein R ¹ has the same meaning as 1), a salt thereof, or a solvate thereof. Particularly, a compound wherein R ¹ is methyl, a salt thereof, or a solvate thereof is preferred. This compound is an important intermediate in the synthesis of pharmaceuticals containing biphenylsulfonamide.

Furthermore, the general formula (II):

(Wherein, R ¹ has the same meaning as 1); X ¹ has the same meaning as 2)) (however, when R ¹ is methyl, X ¹ is not chlorine), a salt thereof, or a solvent thereof. Japanese foods are also new. Particularly, a compound in which R ¹ is methyl, a salt thereof, or a solvate thereof is preferable. Also preferred are compounds wherein X ¹ is chlorine, salts thereof, or solvates thereof. This compound is an important intermediate for synthesizing pharmaceuticals containing biphenylsulfonamide.

9) General formula (V): '

(Wherein is the same as in 1)), a process for producing a compound thereof, a salt thereof, or a solvate thereof.

10) General formula (VI):

Where R ¹ is 1); R ³ and: ³ ′ are simultaneously a hydrogen atom or a lower alkyl, or a ring containing R ³ and R ³ ′ together containing an adjacent oxygen atom. Or a salt thereof, or a solvate thereof, and a compound represented by the general formula (VII):

(In the formula, X ³ is halogen or 1 S 0 ₃ R ⁴ (wherein, R ⁴ is lower alkyl or halo lower alkyl)), a salt thereof, or a solvate thereof in the presence of a catalyst. By subjecting it to a one-carbon bond reaction, the general formula (IV):

(In the formula, R ^ il), a process for producing a compound thereof, a salt thereof, or a solvate thereof.

1 1) General formula (V I I I):

(VIII)

Wherein the compound represented by the formula, a salt thereof or a solvate thereof is subjected to an alkylation reaction, characterized by the general formula (IV):

(Wherein R 11) is a compound represented by the formula: or a salt thereof, or a solvate thereof.

1 2) General formula (IX):

Wherein the compound represented by the formula (wherein, R 1) is subjected to a sulfonation reaction, wherein the compound is represented by the following general formula (IV):

13) The method according to any one of 1) to 5) and 7) to 12), wherein R ¹ is methyl.

14) R ² is hydrogen, optionally substituted lower alkyl (substituent is hydroxy, lower alkyloxy, lower alkylthio, carboxy, or carbamoyl), benzyl, or indole-3-ylmethyl The production method according to any one of 3) to 13).

1 5) R ² is hydrogen, methyl, isopropyl, Lee Sopuchiru, sec- heptyl, Cal Pamoirumechiru force Rubamoiruechiru, 2 Mechiruchioechiru, human Dorokishimechi Le, carboxymethyl, Karubokishechiru, phenyl, benzyl or Lee down de, 14. The production method according to 14), wherein the methyl is 3-ylmethyl.

16) The production method according to any one of 2) to 15), wherein X ¹ is chlorine. In the present specification, "halogen" means fluorine, chlorine, bromine, and iodine. Preferably, chlorine and bromine are used.

Examples of the "halogen" in X ^1, arbitrariness preferred chlorine.

As the “halogen” for X ² , chlorine or bromine is preferred. In particular, bromine is preferred.

In the present specification, the term `` lower alkyl '' used alone or in combination with other terms includes a linear or branched monovalent hydrocarbon group having 1 to 8 carbon atoms. . For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. Preferably, a C1-C6 alkyl is mentioned. Even more preferred are C 1 -C 3 alkyl.

As the “lower alkyl” for R ^1, methyl, ethyl, n-propyl, isopropyl, n-butyl, isoptyl, sec-butyl, tert-butyl and the like are preferable. Further, methyl and ethyl are preferred. Methyl is most preferred.

As the “lower alkyl” for R ^2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl, sec-butyl, tert-butyl and the like are preferable. Methyl, ethyl, isopropyl, isoptyl, sec-butyl are even more preferred.

As the “lower alkyl” for R ³ and R ³ ′, methyl, ethyl, n-propyl, isopropyl and the like are preferable. Further, methyl is preferred.

As the “lower alkyl” for R ^4, methyl, ethyl and the like are preferable. Further, methyl is preferred.

In the present specification, the term “aryl” used alone or in combination with other terms includes a simple or condensed cyclic aromatic hydrocarbon. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like can be mentioned.

Phenyl as "Ariru" in R ^2, 1 - naphthyl, 2-naphthyl, etc. Is mentioned. Phenyl is preferred.

In the present specification, the “aralkyl” is the above “lower alkyl” substituted by one or more “aryl”, and these may be substituted at all possible positions. For example, benzyl, phenylethyl (eg, 2-phenylethyl), phenylpropyl (eg, 3-phenylpropyl), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl), anthrylmethyl (eg, , 9-anthrylmethyl, etc.).

As the “aralkyl” for R ^2, benzyl, phenylethyl, naphthylmethyl and the like are preferable. Further, benzyl is preferred. In the present specification, the term `` heteroaryl j '' used alone or in combination with other terms is an arbitrarily selected 5 to 6 containing one or more oxygen, sulfur or nitrogen atoms in the ring. Membered aromatic rings, which may be fused with cycloalkyl, aryl, non-aromatic heterocycle, or other heteroaryl, which may be fused at all possible positions. , Pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (for example, 2-furyl, 3-furyl), chenyl (for example, 2- phenyl, 3-) Chenyl), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-virazolyl), isothiazolyl (eg, 3-isothiazolyl), isokiki Zolyl (eg, 3-isoxazolyl), oxazolyl (eg, 2-oxazolyl), thiazolyl (eg, 2-thiazolyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), virazinyl ( For example, 2-pyrazinyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl), tetrazolyl (eg, 1H-tetrazolyl), oxazidazolyl (eg, 1,3,4-thoxadiazolyl), thiadiazolyl (eg, 1,3,4-thiadiazolyl), indridinyl (eg, 2-indolinidinyl, 6-indridinyl), isoindolinyl (eg, 2 —Isoin drill), in Drills (eg, 1-indrill, 2—indrill, 3—indrill), indazolyl (eg, 3—indazolyl), purinyl (eg, 8—purinyl), quinolizinyl (For example, 2-quinolinyl), isoquinolyl (for example, 3-isoquinolyl), quinolyl (for example, 2-quinolinyl, 5-quinolinyl), furazinyl (for example, 1-phthalazinyl) ), Naphthyridinyl (eg, 2-naphthyridinyl), quinoxalinyl (eg, 2-quinoxalinyl), quinazolinyl (eg, 2-quinazolinyl), cinnolinyl (eg, 3-cinnolinyl), pteridinyl (eg, , 2-pteridinyl), L-rubazolyl (eg, 2—Luvazolyl, 3—Luvazolyl), phenanthridinyl (eg For example, 2 — phenanthridinyl, 3 — phenanthridinyl), acridinyl (eg, 1-acrylidinyl, 2 — acrilinidyl), dibenzofuranyl (eg, 1-dibenzofuranyl, 2 — Dibenzofuranyl), benzoimidazolyl (for example, 2-benzoisomidazolyl), benzoisoxazolyl (for example, 3-benzoisoxazolyl), benzoxoxazolyl (for example, 2-benzozoxazolyl), benzozo Oxadiazolyl (eg, 4-benzoxodiazolyl), benzothithiazolyl (eg, 3-benzoisothiazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzofuryl (eg, 3-pentozofryl) , Penzochenyl (eg, 2-benzozoenyl), benzotriazolyl (eg For example, 1-benzotriazolyl) and the like.

Is a "Heteroariru" in R ^2, arbitrariness pyridyl, thienyl, off Lil, I down drill, I imidazolyl, etc. are preferred.

In the present specification, the “heteroarylalkyl” refers to a “lower alkyl” wherein one or two or more of the above “heteroaryl” are substituted at any position of the “lower alkyl”, and these are substituted at all possible positions. sell. For example, thiazolylmethyl (for example, 4-triazolylmethyl), thiazolylethyl (for example, 5-thiazolyl-2-ethyl), benzothiazolylmethyl (for example, (benzothiazol-2-yl) methyl), and indolylmethyl (Eg, (indole-3-yl) methyl), imidazolylmethyl (eg, 4-imidazolylmethyl), benzothiazolylmethyl (eg, 2-benzothiazolylmethyl), indazolylmethyl (for example, 1-indazolylmethyl), benzotriazolylmethyl (for example, 1-benzotriazolylmethyl), benzoquinolylmethyl (for example, 2-benzoquinolylmethyl) ), Benzoymidazolylmethyl (for example, 2-benzylazomidazolylmethyl), pyridylmethyl (for example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl) and the like.

As the “heteroarylalkyl” for R ² , indolylmethyl (for example, indole-3-ylmethyl), imidazolylmethyl (for example, imidazole-5-ylmethyl) and the like are preferable. In the present specification, the term “halo lower alkyl” used alone or in combination with other terms refers to the aforementioned “lower alkyl” substituted at 1 to 8, preferably 1 to 5 positions by the “halogen”. "Is included. For example, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl and the like can be mentioned. Preferable is trifluoromethyl.

In the present specification, examples of the substituent in the “optionally substituted lower alkyl” include cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), hydroxy, lower alkyloxy (eg, methoxy) , Ethoxy, t-butoxy), mercapto, lower alkylthio (eg, methylthio, ethylthio), halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-yl) Butoxycarbonyl), halo-lower alkyl, halo-lower alkyloxy (eg, trifluoromethyloxy), amino optionally substituted with lower alkyl (eg, amino, methylamino, dimethylamino, ethylamino, getylamino) , Methylethylamino), rubambamoyl, formyl, acyl (eg, acetyl, benzoyl), acyloxy (eg, acetyloxy, benzoyloxy), non-aromatic heterocycle Groups (eg, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl), aryloxy (eg, phenyloxy), aralkyloxy (eg, benzyloxy), lower alkylsulfonyl (eg, methanesulfonyl) Guanidino, azo group, peridode and the like. These may be substituted one or more times in all possible positions.

As the “optionally substituted lower alkyl” for R ¹ , unsubstituted lower alkyl is preferable.

As the substituent for the “optionally substituted lower alkyl” for R ² , preferred are a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a carboxyl group and a carpamoyl group.

Substituents in “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted aralkyl”, and “optionally substituted heteroarylalkyl” include: Optionally substituted lower alkyl, cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), lower alkenyl (eg, vinyl, propenyl, butenyl), lower alkynyl (ethynyl, propynyl), Droxy, lower alkyloxy (for example, methoxy, ethoxy, t-butoxy), mercapto, lower alkylthio (for example, methylthio, ethylthio), halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl (for example, , Methoxyl Nil, ethoxycarbonyl, t-butoxycarbonyl), halo-lower alkyl, halo-lower alkyloxy (eg, trifluoromethyloxy), amino optionally substituted by lower alkyl (eg, amino) Amino, methylamino, dimethylamino, ethylamino, getylamino, methylethylamino), levavamoyl, formyl, acyl (for example, acetyl, benzoyl), acyloxy (for example, acetyloxy, benzoyloxy), aryl, heteroaryl Non-aromatic heterocycles (eg, pyrrolidyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrobiranyl), aralkyl, aryloxy (eg, phenyloxy), ara Examples thereof include ruquiloxy (for example, benzyloxy), lower alkylsulfonyl (for example, methanesulfonyl), guanidino, azo group, and ureide. These may substitute one or more at all possible positions.

Substituents for “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted aralkyl”, and “optionally substituted heteroarylalkyl” for R ² As a preference, hydroxy or halogen is preferred. In addition, "unsubstituted aryl", "unsubstituted heteroaryl", "unsubstituted aralkyl", and "unsubstituted heteroarylalkyl" are also preferred. a reaction using a "is KSR ^1, including the case, and used to generate the KSR ¹ in the reaction system if, both used directly as a reagent KSR ^1. In the case where KSR ¹ is generated and used in the reaction system, R ¹ SH (for example, methyl mercaptan gas (methane thiol)) is introduced in the presence of potassium hydroxide to cause a reaction in the reaction system. In some cases, KSR ¹ is generated.

In the present specification, the term “alkylating agent” means a reagent used for a reaction for introducing an alkyl group into an organic compound. Examples include alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, alkyl phosphates, alkyl phosphites, nitrates, acetates, and tetraalkyl ammonium salts.

Examples of alkyl nodogenides include methyl iodide, methyl bromide, methyl chloride, chloroiodide, chlorobromide, chlorochloride, propyl iodide, propyl bromide, propyl chloride, isopropyl iodide, and bromide. Isopropyl, isopropyl chloride, butyl iodide, butyl bromo, butyl butyl, S-butyl iodide, S-butyl bromo, S-butyl butyl, S-butyl butyl, t-butyl iodide, t-butyl bromo, t-chloride Butyl and the like. Dialkyl carbonate includes dimethyl carbonate, getyl carbonate, dipropyl carbonate, and diisocarbonate Propyl, dibutyl carbonate, di-S-butyl carbonate, t-butyl carbonate and the like. Examples of the alkyl sulfinate include methyl sulfinate, ethyl sulfinate, propyl sulfinate, isopropyl sulfinate, butyl sulfinate and the like. Examples of the alkyl sulfonate include alkyl triflate (methyl triflate, ethyl triflate, propyl triflate, isopropyl triflate, butytriflate, etc.), alkyl tosylate (methyl tosylate, ethyl tosylate) , Propyl tosylate, isopropyl tosylate, butyl tosylate, etc.), alkyl mesylate (methyl mesylate, ethyl mesylate, propyl mesylate, isopropyl mesylate, butyl mesylate, etc.), alkyl brosylate (methyl prosylate, ethyl brosylate, etc.) Propyl brosylate, isopropyl brosylate, butyl brosylate), alkylbenzenesulfonate (methylbenzenesulfonate, ethylbenzenesulfonate, propyl Benzenesulfonate, isopropylbenzenesulfonate, butylbenzenesulfonate, etc.). Examples of the dialkyl sulfate include dimethyl sulfate, getyl sulfate, dipropyl sulfate, diisopropyl sulphate, dibutyl sulphate, s-butyl sulphate and t-butyl sulphate. Examples of alkyl phosphates include trialkyl phosphate (such as trimethyl phosphate and triethyl phosphate), dialkyl phosphate (such as dimethyl phosphate and getyl phosphate), and phosphoric acid. Monoalkyl (monomethyl phosphate, monoethyl phosphate, etc.). Examples of the alkyl phosphite include trialkyl phosphite (trimethyl phosphite, triethyl phosphite, etc.), dialkyl phosphite (dimethyl phosphite, getyl phosphite, etc.) ), Monoalkyl phosphite (monomethyl phosphite, monoethyl phosphite, etc.). Examples of the nitrate include trifluoromethyl nitrate. Examples of the acetate include trifluoromethyl acetate. The tetraalkylammonium salts include phenyltrimethylammonium chloride, phenyltrimethylammonium bromide, phenyltrimethylammonium iodide, and phenyltrimethylammonium iodide. And the like. Preferably, alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates (alkyl triflates, alkyl tosylates, alkyl mesylates, alkyl esters, alkyl benzene sulfonates, etc.), dialkyl sulfates And tetraalkylammonium salts. More preferred are alkyl halide, dialkyl carbonate, alkyl sulfonate (alkyl tosylate, alkyl mesylate, etc.), dialkyl sulfate, tetraalkyl ammonium salt and the like. Particularly preferred are methyl iodide, methyl bromide, chloro iodide, dimethyl bromobromide, dimethyl carbonate, ethyl methyl tosylate carbonate, ethyl tosylate, methyl mesylate, dimethyl ethyl mesylate sulfate, dimethyl sulphate sulfate, and methylammonium chloride. Is mentioned. As used herein, the term "catalyst" is used in a chemical reaction system in a relatively small amount to change the reaction rate, start the reaction, or select a reaction without changing the result. Means a compound which is allowed to proceed. Examples include palladium compounds, rhodium compounds, platinum compounds, copper compounds, and ruthenium compounds. Palladium compounds are preferred. In the present specification, the ring represented by “R ³ and R ³ ′ may be combined with each other to form a ring containing an adjacent oxygen atom” includes the following 璟.

BEST MODE FOR CARRYING OUT THE INVENTION

When referring to a “compound”, the compound is not limited to a particular isomer but includes all possible isomers (eg, optical isomers) and racemates. Further, a pharmaceutically acceptable salt or a solvate thereof is also included. When the "salt" of the compound used in the present invention is referred to, an alkali metal (lithium, sodium, potassium, cesium, etc.), an alkaline earth metal (magnesium, calcium, norium, etc.), ammonium, etc. , Salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.), and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid). These salts can be formed by a commonly used method.

The “solvate” of the compound used in the present invention includes, for example, solvates with organic solvents, hydrates and the like. When forming a hydrate, it may be coordinated with any number of water molecules.

(I ")

9th step

(Wherein, A + and:. B + it it independently of one ^{another, Na +, K +, L} i +, C s + NH 4 + , etc. ^{^{^{cations; R 1 R 2, R 3}}} , R 3 ', X ¹ , X ² and X ³ are as defined above.

(First step) This step is a step of sulfonating a biphenyl halogen derivative (X) as a starting material.

In a solvent such as chloroform, dichloromethane, hexane, heptane, and toluene, or a mixed solvent thereof, 1 to 10 equivalents, preferably 1.5 to 5 equivalents of the sulfonating agent is added to compound (X). After reacting at 0 ° C to 80 ° C, preferably 5 ° C to 50 ° C for 0.5 to 10 hours, preferably for 1 hour to 5 hours, the usual post-treatment is performed. Thus, compound (V) can be obtained.

Examples of the sulfonating agent include sulfuric acid, fuming sulfuric acid, and black sulfuric acid. Black sulfuric acid is preferred.

(2nd step)

In this step, the starting material, biphenylsulfonic acid (V), is converted to a salt (Va).

Examples of the salt include a lithium salt, a sodium salt, a potassium salt, a cesium salt, an ammonium salt and the like. Potassium salts are preferred.

Compound (V) is dissolved in a solvent such as water, methanol or ethanol, and a base is added. The reaction mixture is allowed to react at 0 ° C to 100 ° C, preferably 5 ° C to 50 ° C, for 0.5 hours to 24 hours, preferably for 0.5 hours to 5 hours. The compound (V a) can be obtained by performing the following post-treatment.

As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, rubidium hydroxide, ammonia, lithium carbonate, lithium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, Carbon dioxide lime, hydrogen carbonate lime, rubidium carbonate, rubidium hydrogen carbonate, cesium carbonate, cesium hydrogen carbonate, and the like. Hydroxylated and hydroxylated rims are preferred. In addition, a hydroxylating reamer is preferred.

(3rd step)

In this step, a salt (Va) of a biphenyl halogen derivative as a starting material is alkylthioated to obtain a compound (IVa). In the present specification, the alkylthioation reaction mainly includes the third step, but the second step, the third step, the third step, the fourth step, the second step, the third step ">> the fourth step, and the compound The step of directly synthesizing compound (IV) from (V) is also included.

In a solvent such as N-methylpyrrolidine, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, or a mixed solvent of these solvents and water, compound (Va) and 1 To 30 equivalents, preferably 1.5 equivalents to 10 equivalents of an alkali metal salt of a lower alkyl thiol at 5 CTC to 200 ° C, preferably 70 ° C to 150 ° C. The compound (IVa) can be obtained by reacting for 5 to 20 hours, preferably for 3 hours to 10 hours, and performing a usual post-treatment. '' As the raw material compound (Va), a lithium salt, a sodium salt, or a potassium salt is preferable. In particular, potassium salts are preferred.

Also, instead of directly using an alkyl thiol metal salt of an alkyl thiol, an alkyl thiol generated in a reaction system from a base such as sodium hydroxide or potassium hydroxide and a lower alkyl thiol is used. Alkali metal salts can also be used.

On the other hand, if an alkylating agent is added to the reaction system, the yield is improved, which is preferable. Examples of the alkylating agent include an alkyl halide, a dialkyl carbonate, an alkyl sulfonate, and a dialkyl sulfate.

In particular, it is preferable to use a potassium salt of an alkyl thiol generated in a reaction system by introducing an alkyl thiol into dimethyl sulfoxide of potassium hydroxide. More preferred is the addition of dialkyl carbonate.

Under the conditions of the alkylthioation in the water reaction described in Patent Documents 4 and 5, the reaction conversion is extremely low due to the poor solubility inherent in the biphenylsulfonate derivative. In addition, when the alkylthioation reagent is used in an equal amount or in a small excess in the polar solvent system, the reaction conversion is low, and unreacted raw materials remain in the target product. If the raw material remains, it is difficult to separate the raw material halide and the product alkylthio compound, and they are mixed in the final product, which is a serious problem in the case of pharmaceuticals. On the other hand, if the alkylthioation reagent is used in excess in a polar solvent, the reaction speeds up and the conversion of the reaction increases. However, the alkylthioating agent attacks the alkyl group adjacent to the sulfur in the product, and a disulfide compound of biphenylthiol / biphenyl, which is a dealkylated product, is produced as a by-product, resulting in a low yield.

Therefore, in order to solve these problems, first, by devising the metal species of the alkylthiometal in a polar solvent, the generation method and the usage method, a high conversion rate was realized, and then the by-product dealkylation side reaction was performed. The re-alkylation of the product allows for an increase in yield and content.

(4th step)

This step is a step of obtaining the compound (IV) by treating the compound (IVa) with an acid.

N-Methylpyrrolidinone-water mixed solvent, ethyl acetate-water mixed solvent, isopropyl acetate pill-water mixed solvent, isoptyl acetate-water mixed solvent, normal butyl acetate-water mixed solvent, etc. Mixed solvent of ton-water, mixed solvent of acetonitrile-water, mixed solvent of tetrahydrofuran-water, mixed solvent of dimethylformamide-water, mixed solvent of dimethylacetamide-water, mixed solvent of dimethylsulfoxide By adding an acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, phosphoric acid, nitric acid or the like in a solvent or a solvent such as a mixed solvent of dichloromethane and water, the solution is made acidic, and the compound ( IV) can be obtained. Seed crystals are added as necessary, and N-methylpyrrolidinone-ice mixed solvent, acetone-water mixed solvent, acetonitrile-water mixed solvent, methanol-water mixed solvent, ethyl acetate, ethyl acetate-hexane mixed solvent The compound (IV) can be obtained as crystals from a solvent such as a solvent, a mixed solvent of tetrahydrofuran-water, a mixed solvent of dimethylformamide and water, a mixed solvent of dimethylacetamide-water, and a mixed solvent of dimethylsulfoxide water. .

As the solvent, a mixed solvent of N-methylpyrrolidinone-water and acetate-water is preferable. The mixing ratio is preferably N-methylpyrrolidinone: water = 1: 0: 1 to 1: 5 or acetone: water = 1: 10: 1 to 1: 5. More preferably, the ratio is from 4: 1 to 1: 2. (Fifth step)

This step is a step of converting a sulfonic acid (IV) as a starting material into a sulfonyl halide compound (II) with a halogenating agent. In the present specification, the halogenation reaction means this step and the tenth step.

Compound (IV) in a solvent such as toluene, N, N-dimethylformamide, N-methylpyrrolidinone or a mixed solvent thereof in an amount of 0.9 to 30 equivalents, preferably 1.0 to 10 equivalents. Is reacted at 0 ° C. to 200 ° C., preferably 30 ° C. to 100 ° C., for 0.5 to 20 hours, preferably 0.5 to 3 hours. The compound (I) can be obtained by performing the post-treatment performed.

The reaction can be carried out without solvent.

Examples of the halogenating agent include thionyl chloride, sulfuryl chloride, oxychlorinated phosphorus, pentachloride linole, linyl trichloride, thionyl bromide, sulfuryl bromide, oxybromide, pentabromide, Examples include phosphorus tribromide, chlorine, and bromine. Thionyl chloride or oxychlorinated chloride are preferred.

(Step 6)

This step is a step of capping using a sulfonyl compound (II) and a compound (III) as starting materials by using the Schotten-Bamann method. In the present specification, the amidation reaction means this step.

Water-acetone mixed solvent, water-1,4-dioxane mixed solvent, water-tetrahydrofuran mixed solvent, water dimethoxane mixed solvent, water-acetonitrile mixed solvent, _water-mexanol mixed solvent Water-alcohol mixed solvent such as water-ethanol mixed solvent, water-propanol mixed solvent, water-isopropanol mixed solvent, water-butanol mixed solvent, water-isobutanol mixed solvent, water-sec-butanol mixed solvent, N, N —Dimethylformamide, N, N—Dimethylacetamide, dimethylsulfoxide, etc. in a solvent such as 0.9 to 2 equivalents, preferably 1.0 to 1.2 equivalents of compound (III). (II) in the presence of 2 to 10 equivalents, preferably 2 to 3 equivalents of a base at —20 ° C. to 30 ° C., preferably—5 ° C. to 10 ° C. for 1 to 20 hours , The compound (I) can be obtained by reacting the mixture for 1 hour to 3 hours, preferably, and performing a usual post-treatment.

As the solvent, a mixed solvent of acetate and water is preferable. As a mixing ratio, acetone: water = 5: 1 to 1: 5 is preferable. Further, 2: 1 to 1: 2 is preferred.

Examples of the base include sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, cesium carbonate, cesium hydrogencarbonate, lithium carbonate, lithium hydrogencarbonate, rubidium carbonate, rubidium hydrogencarbonate, and water. Inorganic bases such as lithium oxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, and ammonium carbonate; and alkali bases such as triethylamine, triptylamine, and diisoprovirethylamine. 3ammin and the like are exemplified. Sodium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, triethylamine and the like are preferred.

In addition, comparing the step of directly reacting the carboxylic acid of the amino acid portion without protection as in this step with the reaction of protecting with the ester as in the prior art, the step of deprotection becomes unnecessary, and the total Yields also increase and costs can be reduced.

Further, the sulfonamide derivative having a biphenyl skeleton produced in this step has very poor solubility. When the reaction is carried out directly without protecting the carboxylic acid moiety as in this step, there is an advantage that the solubility is easily isolated. However, in the reaction of deprotecting (hydrolyzing) a compound protected as an ester in the same manner as described above, a large amount of solvent and heating are required due to the poor solubility. Increasing the amount of solvent has a significant effect on yield and cost in the case of industrial production. In addition, since a large amount of waste liquid is generated, the impact on the environment is great. In addition, by heating, a part of the asymmetric carbon in the amino acid portion undergoes racemization. Even if a trace amount of optical isomers is produced, it can pose serious problems in developing pharmaceuticals.

This solubility is not described in the prior art and is a unique property of the biphenylsulfonamide derivative having a lower alkylthio group. Therefore, the present reaction in which the carboxylic acid in the amino acid portion is directly protected and reacted with the sulfonyl compound This is a very useful reaction.

(Step 7)

This step is a step of coupling an arylpoic acid derivative (VI) and an aryl halide (VII) as starting materials to synthesize a biphenyl compound. In the present specification, the carbon-carbon bond reaction means this step.

In the presence of from 0.001 to 0.5 equivalents, preferably from 0.02 to 0.1 equivalents of the catalyst, 0.8 to 5 equivalents of biphenyl halide (VII) in a solvent. The equivalent, preferably 1 to 1.5 equivalents, of the arylopulonic acid derivative (VI) and the basic substance at 30 ° C to 200, preferably 50. The compound (IVa) can be obtained by reacting at C to 100 ° C for 1 hour to 30 hours, preferably 1.5 hours to 5 hours, and performing a usual post-treatment. .

Examples of the solvent include solvents such as benzene, toluene, N, N-dimethylformamide, dimethoxetane, tetrahydrofuran, dioxane, methanol, and ethanol, or a mixed solvent of these solvents and water. Particularly, dioxane, a mixed solvent of dimethoxetane-ethanol and a mixed solvent of dimethoxetane-ethanol-water are preferred.

Catalysts include palladium black, palladium monocarbon, palladium chloride (11), palladium (II) bisbenzonitrile, palladium (II) bisacetonitrile, palladium bromide, (11), iodide Palladium (11), palladium oxide (II), palladium sulfide (II), palladium acetate (II), palladium propionate (II), palladium sulfate (II), palladium hydroxide (II), palladium cyanide ( II), palladium trifluoroacetate (11), bistriphenylphosphine palladium chloride (II), and tetrakis (triphenylphosphine) palladium (0). Tetrakis (triphenylphosphine) palladium (0) and bistriphenylphosphine palladium chloride (I) are preferred.

Examples of the basic substance include sodium hydroxide, sodium methoxide, and hydroxylated water. , Ammonia, lithium hydroxide, cesium hydroxide, rubidium hydroxide, norium hydroxide, lithium methoxide, potassium methoxide, cesium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, Cesium ethoxide, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, rubidium carbonate, rubidium bicarbonate, cesium carbonate, cesium bicarbonate, etc. Can be Sodium carbonate is preferred. Preferred is a reaction condition in which the solvent is a mixture of dimethoxetane-ethanol or a mixture of dimethoxetane-ethanol and ethanol, the catalyst is tetrax (triphenylphosphine) palladium (0), and the basic substance is sodium carbonate. .

(8th process)

This step is a step for lower alkylation of a biphenyl thiol compound (VIII) as a starting material. In the present specification, the alkylation reaction means this step.

Solvents such as N-methylpyrrolidine, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dioxane, dimethoxetane, or a mixed solvent of these solvents and water Medium, compound (VIII) and 1 to 20 equivalents, preferably 1 to 5 equivalents of an alkylating agent such as a lower alkyl halide, dialkyl carbonate, dialkyl sulfate, etc., at 120 ° C. to 100 ° C. The compound (IVa) is reacted by reacting at 0 ° C to 50 ° C for 0.5 to 20 hours, preferably for 1 hour to 5 hours, and performing a usual post-treatment. Obtainable.

(9th step)

In this step, the starting material biphenyl compound (IX) is sulfonated to obtain biphenylsulfonic acid (IV).

Compound (IX) and 0.9 to 30 equivalents, preferably 1.0 to 10 equivalents, of a sulfonating agent in a solvent such as chloroform, methylene chloride, hexane, and heptane at 0 ° The compound (IV) is reacted at a temperature of C to 100 ° C., preferably 0 ° C. to ° C. for 0.5 to 10 hours, preferably 1 hour to 5 hours, and subjected to a usual post-treatment to give the compound (IV). Obtainable. Sulfonating agents include sulfuric acid, fuming sulfuric acid, and sulfuric acid. Black sulfuric acid is preferred.

(Step 10)

This step is a step of converting the sulfonate (IVa) to a sulfonyl halide compound (II) by a halogenating agent. In the present specification, the halogenation reaction means this step and the fifth step. The reaction can be carried out under the same conditions as in the fifth step. Example

In the examples, the following abbreviations are used.

M e: Methyl

D ME: Jim Tokishetan

DMF: N, N-dimethylformamide

D M S 0: Dimethyl sulfoxide

E t O H: ethanol

P h: Fanil

THF: Tetrahydrofuran Example 1 Preparation of Compound (1)

18 1

Dissolve the compound (18) (120 g, 0.51 mol) in chloroform (600 mL) and add sulfuric acid (72.0 g, 0.62 mol). Was. This solution was stirred at room temperature for 1.5 hours. The precipitated crystals were filtered and washed with a black hole form. After drying, 144.52 g of compound (1) was obtained (yield: 90%).

IR (KB r) 1 12 9, 8 13 cm- ¹ ;

¹ H-N MR (DM SO-d ₆₎ ppm) δ 7.6 1-7.70 (m, 8 H). Example 2 Preparation of compound (lb)

20 g (0.064 mol) of the lb compound (1) was dissolved in water (40 mL), and 8.33 g (0.13 mol) of a hydration power was added. This solution was stirred at room temperature for 1.5 hours. The precipitated crystals were filtered and washed with water. Drying yielded 20.83 g (93% yield) of compound (lb).

IR (KBr) 1 12 9, 8 13 cm- ¹ ;

^{1 H - N MR (DMSO -} d 6, pm) δ 7 6 1 -.. 7 7 Preparation of 0 (m, 8 H) · Example 3 Compound (2 a)

2 g (6.4 mm o 1) of N-methylpyrrolidinone was dissolved in 40 mL of N-methylpyrrolidinone, and sodium thiomethoxide (1.lg (16 mmol)) was dissolved. In addition, it was heated to 115 ° C. After stirring at 115 ° C for 8 hours, the mixture was cooled to room temperature. The precipitated crystals were filtered and washed with N-methylpyrrolidinone and water. After drying, 1.4 g (yield 74%) of compound (2a) was obtained.

1 R (KBr) 1 1 8 9, 8 1 2 cm- ¹ ;

¹ H-NMR (DMSO-d _6> ppm) δ 2.5 3 (s, 3H), 7.37 (m _;

2H), 7.64-7.67 (m, 6H). Example 4 Preparation of Compound (2a)

2a

Sodium hydroxide . .8 g (20 mmo1) was suspended in N-methylpyrrolidinone (12.5 mL), and dissolved by adding 2.5 mL of water. After introducing methylmer butane gas into this solution, a part was distilled off under reduced pressure. To this solution, 2 g (6.4 mm 01) of the compound (1) was added, and the mixture was heated to 115 ° C. After stirring at 115 ° C for 4 hours, the mixture was cooled to room temperature. The precipitated crystals were filtered and washed with N-methylpyrrolidinone and water. After drying, 1.4 g (yield 74%) of compound (2a) was obtained.

1 R (KBr) 1 1 8 9, 8 1 2 cm- ¹

¹ H-N MR (DMS 0-d _6; pm) δ 2.5 3 (s, 3H), 7.37 (m,

2 H), 7.64-7.67 (m, 6 H).

0.886 g (22 mmo1) of sodium hydroxide was suspended in N-methylpyrrolidinone (13 mL), and dissolved by adding 2.5 mL of water. After introducing methyl mercaptan gas into this solution, a part was distilled off under reduced pressure. To this solution was added 1.0 g (3.6 mm 01) of the compound (1), and the mixture was heated to 120 ° C. After stirring at 120 ° C for 5 hours, the mixture was cooled to room temperature. To this reaction solution was added 0.6 mL (1 lmmo1) of methane, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were filtered and washed with N-methylpyrrolidinone and water. After drying, 0.88 g (yield 91%) of compound (2a) was obtained. 1 R (KBr) 1 189, 8 1 2 cm-

¹ H-NMR (DMSO-d6 _; ppm) 6 2.53 (s, 3H), 7.37 (m

2H), 7.64-7.67 (m, 6H). Example 6 Preparation of Compound (2b)

1.3 g (23 mmo1) of potassium hydroxide was suspended in N-methylpyrrolidinone (12.5 mL), and dissolved by adding 1.5 mL of water. After introducing methylmer gas into this solution, a part was distilled off under reduced pressure. To this solution, 2.5 g (8 mmo 1) of the compound (1) was added, and the mixture was heated to 115 ° C. After stirring at 115 ° C for 4 hours, the mixture was cooled to room temperature. The precipitated crystals were filtered and washed with N-methylpyrrolidinone and water. After drying, 2.0 g (yield 77%) of compound (2b) was obtained.

IR (KBr) 1 1 8 6, 8 1 2 cm- ¹ Example 7 Preparation of compound (2a)

4.64 g (71.1 mmol) of potassium hydroxide was suspended in dimethyl sulfoxide (50 mL), and methyl mercaptan gas was introduced into the solution. 5 g (14.2 mm 01) of the compound (1b) was added to this solution, and the mixture was heated to 115 ° C. After stirring at 115 ° C for 6 hours, the mixture was cooled to 80 ° C, 7.8 mL (92.6 mL) of dimethyl carbonate was added, and then ice (50 mL) and 48% hydroxylation were added. 7.2 g of sodium water (86.4 mmol) Was added and stirred at the same temperature for 1 hour. The reaction solution was cooled to 5 ° C. and stirred at the same temperature for 30 minutes, and the precipitated crystals were filtered and washed with water. After drying, 4.12 g (yield 96%) of compound (2a) was obtained.

1 R (KBr) 1 1 8 9, 8 1 2 cm- ¹

¹ H-NMR (DMSO-d ₆ ipm) δ 2.53 (s, 3H), 7.37 (m _;

2 H), 7.64-7.67 (m, 6 H).

Example 8 Preparation of compound (2)

2a 2 Suspend 10 g (0.033 mol) of compound (2a) in a mixed solvent of 200 mL of acetate and 200 mL of water, and heat to 60 to 70 ° C did. After adding 35.17 g (0.050 m 01) of 35% hydrochloric acid, the mixture was stirred at the same temperature for 30 minutes, and concentrated under reduced pressure to distill off acetate. The precipitated crystals were filtered and washed with water. After drying, 9.27 g of compound (2) was obtained (yield: 100%).

IR (KBr) 3 4 4 8, 1 1 8 9, 8 1 2 cm- ¹ ;

¹ H-NMR (DMSO-d _6; ppm) δ 2.51 (s, 3H), 7.32 — 7.37 (m, 2H), 7.58-7.68 ( m, 6H).

Example 9 Preparation of compound (2a)

3 4 2a

60 g (0.233 mol) of compound (4) and 40 g (0.24 mol) of compound (3) mo 1) was suspended in a mixed solvent of 40 mL of DME and 100 mL of ethanol. An aqueous solution obtained by dissolving 75 g of sodium carbonate in 300 mL of water was added thereto, and after purging with nitrogen, 9.6 g (0.008 mo1) of tetraxtriphenylphosphine palladium was added. In addition, the mixture was stirred at about 80 for 4 hours. After the reaction, 300 mL of water was added, and the precipitate was collected by filtration and washed with water, acetate and THF. The crude crystals containing carbonate were suspended in 600 mL of water and neutralized with hydrochloric acid. The crystals were filtered and dried to obtain 57.5 g of compound (2a) (yield 86%).

1 R (KBr) 1 1 8 9, 8 1 2 cm- ¹

¹ H-NMR (DMSO-d ₆₎ ppm) δ 2.53 (s, 3H), 7.37 (m,

2H), 7.64-7.67 (m, 6H). Example 10 Preparation of Compound (2b)

5 e 2b

53 mg (0.2 mmo1) of compound (5) was suspended in 0.27 mL of N-methylpyrrolidinone, and 83 mg (0.6 mm01) of potassium carbonate and 57 mg of iodomethane were suspended. (0.4 mm o 1). After stirring at room temperature for 3 hours, the reaction solution was filtered and washed with water. After drying, 48 _mg (yield 75%) of compound (2b) was obtained.

IR (KB r) 1 1 8 6, 8 1 2 cm- ¹ . Example 1 Preparation of compound (2)

Suspend 1.0 g (5.0 mm 01) of compound (6) in 5 mL of black hole form. 7557 mg (6.5 mmol) of lolosulfuric acid was added. After stirring at room temperature for 4 hours, the precipitated crystals were filtered and washed with a filter. Dry the compound (2) with 4 1

0 mg (29% yield) was obtained.

1 R (KBr) 3 4 4 8, 1 1 8 9, 8 1 2 cm- ¹

¹ H-NMR (DMSO-d _{6 j} ppm) δ 2.51 (s, 3H), 7.32 — 7.37 (m, 2H), 7.58-7.68 ( Example 12 Preparation of compound (2)

2a Me 2

40 g (0.13 mol) of the compound (2a) was suspended in a mixed solvent of 140 mL of N-methylpyrrolidinone and 60 mL of water, and heated to 115 ° C. did. After adding 13.8 g (0.13 mol) of 35% hydrochloric acid, 30.8 mL of N-methylpyrrolidinone and 132 mL of water were added and dissolved. After stirring at 115 ° C for 10 minutes, the mixture was cooled to about 5 ° C. The precipitated crystals were filtered and washed with water. Drying yielded 33 g of compound (2) (91% yield).

IR (KBr) 3 4 4 8, 1 1 8 9, 8 1 2 cm- ¹ ;

¹ H-NMR (DMSO-d _6; ppm) δ 2.51 (s, 3 layers), 7.3 2 — 7.37 (m, 2 layers), 7.58-7.68 ( Example 13 Preparation of compound (2)

Compound (2b) (0.42 g, 0.0013 mol) was suspended in a mixed solvent of N-methylpyrrolidinone (2 mL) and water (2 mL), and heated to 115 ° C. After 0.14 g (0.013mo1) of 35% hydrochloric acid was added, 3 mL of N-methylpyrrolidinone and 1 mL of water were added and dissolved. After stirring at 115 ° C for 10 minutes, the mixture was cooled to about 5 ° C. The precipitated crystals were filtered and washed with water. After drying, 0.35 g (yield: 91%) of compound (2) was obtained.

IR (KBr) 3448, 1189, 812cm- ¹ ;

¹ H-NMR (DMSO-d _6; pm) δ 2.51 (s, trilayer), 7.32-7.37 (m, 2H), 7.58-7.68 ( m, 6 H). Example 14 Preparation of Compound (2c)

2 2c

5 g (16 mmo 1) of the compound (2) was dissolved in 10 mL of water, and 5.2 g (24 mm 01) of a 11% aqueous solution of lithium hydroxide was added. After stirring at room temperature for 1 hour, the precipitated crystals were filtered and washed with water. After drying, 4.0 g (yield: 78.4%) of compound (2c) was obtained.

IR (KBr) 1 189, 812 cm— ¹ . Example 15 Preparation of Compound (2a)

2 2a

Dissolve 2.0 g (6.4 mm o 1) of compound (2) in 4 mL of water and add 48% 0.8 g (9.6 mmol) of an aqueous sodium chloride solution was added. After stirring at room temperature for 1 hour, the precipitated crystals were filtered and washed with water. After drying, 1.7 g (yield 89.5%) of compound (2a) was obtained.

IR (KBr) 1189, 812 cm- Example 16 Preparation of Compound (2b)

2 2b

2.0 g (6.4 mmol) of the compound (2) was dissolved in 4 mL of water, and 1.0 g (9.6 mm 01) of a 53% aqueous hydroxide solution was added. After stirring at room temperature for 1 hour, the precipitated crystals were filtered and washed with water. After drying, 1.6 g (yield: 72.7%) of compound (2b) was obtained.

IR (KBr) 1 1 8 6, 8 1 2 cm ¹ Example 1 7 Preparation of compound (2d)

2 2d

Compound (2) was dissolved in 2.0 g (6.4 mmO 1) and 2 mL of water, and 3.1 g (9.5 mm 01) of cesium carbonate was added. After stirring at room temperature for 1 hour, the precipitated crystals were filtered and washed with water. After drying, 2.0 g (yield: 71.4%) of compound (2d) was obtained.

IR (KBr) 1 19 2, 8 12 cm— ¹ . Example 18 Preparation of Compound (7)

2 7

To 1.4 g (5 mmo1) of 1.4 g (5 mmo1), 0.73 mL (10 mmo1) of thionyl chloride and 4.2 mL of toluene were added, and DMF0.05 was added thereto. g (0.65 mmo

1) was added and the mixture was heated to about 70 ° C. and stirred for about 2 hours. After the reaction, the mixture was concentrated, hexane was added, and the mixture was filtered. The crystals were filtered and washed with hexane. After drying, 1.3 g (yield 87%) of compound (7) was obtained.

IR (KBr) 1588, 1368, 1169, 811cm- ¹ ;

¹ H-NMR (DMS 0-d _6; m) δ 2.51 (s, 3Η), 7.35 (d:

J = 8.4 Hz, 2 H), 7.6 1-7.70 (m, 6 H). Example 19 Preparation of Compound (7)

To 0.1 g (0.5 mm o 1) of 0.12 g (0.5 mm o 1), 0.33 ml (45 mm o 1) of thionyl chloride was added, and DMF 0.01 ml ( After adding 0.013 mmo 1), the mixture was heated to about 0 ° C. and stirred for about 90 minutes. After the reaction, the mixture was concentrated, hexane was added, and the mixture was filtered. The crystals were filtered and washed with hexane. Drying yielded 0.13 g (yield 87%) of compound (7).

IR (KBr) 1588, 1368, 1169, 811cm- ¹ ;

1 H-NMR (DMS 0-d ₆ , pm) δ 2.51 (s, triad), 7.35 (d _; J = 8.4 Hz, diad), 7.6 1-7 7 0 (m, 6 H). Example 20 Preparation of Compound (7)

0.2 g (0.71 mmol) of the compound (2) was suspended in Ν, Ν-dimethylformamide (1 mL), and 0.25 g (2.1 mmol) of thionyl chloride was suspended in the suspension. added. The suspension was heated to 40 ° C and heated at the same temperature for 1 hour. The reaction solution was ice-cooled, cold water (1 mL) was added, and the mixture was stirred for 30 minutes. The precipitated crystals were filtered and washed with water. After drying, 0.118 g (yield 84%) of compound (7) was obtained.

IR (KB r) 1 5 8 8, 1 3 6 8, 1 1 6 9, 8 1 1 cm 1;

¹ H-N MR (DMSO-d ₆₎ ppm) 6 2 .5 1 (s, 3 H), 7.35 (d _;

J = 8.4 Hz, 2H), 7.6 1-7.7 (m, 6H).

2a 7

To 0.95 g (1.7 mm o 1) of 0.92 g (1.7 mm o 1), 0.98 g (8 mmol) of thionyl chloride and 3 mL of toluene were added, and DMF 0.048 g (0.66 mmo 1) was added, and the mixture was heated to about 70 ° C. and stirred for about 1 hour. After the reaction, 6 mL of toluene and 3 mL of ice were added, and the desired product was extracted into an organic layer. Concentrate and crystallize from ethanol, filter the crystals and wash with ethanol. Drying yielded 0.35 g (yield 71%) of compound (7).

IR (KBr) 1588, 1368, 1169, 811cm- ¹ ;

¹ H-N MR (DMSO-d ₆ , pm) δ 2.5 1 (s, 3 3), 7.35 (d; J = 8.4 Hz, 2 H), 7.6 1 -7.70 (m, 6 H) Example 22 Preparation of Compound (7)

2 7

30.0 g (107 mmol) of the compound (2) was suspended in toluene (90 mL), and 32.8 g (23.9 mmol) of oxylin chloride was added. . The suspension was heated to 80 ° C and stirred at the same temperature for 30 minutes. Next, 5.30 g (53.5 mmol) of N-methylpyrrolidinone was added, and the mixture was stirred at the same temperature for 4 hours. The obtained solution was ice-cooled, and toluene (90 mL) and cold water (9 OmL) were added thereto to carry out liquid separation. The upper layer was washed with water (9 O mL) and concentrated under reduced pressure to obtain a concentrated solution. The concentrated solution was heated to 55 ° C, n-heptane (60 mL) was added at the same temperature, then cooled to 5 ° C and stirred at the same temperature for 30 minutes. The precipitated crystals were filtered and washed with cold n-heptane. Drying yielded 29.1 g (yield 91%) of compound (7).

IR (KBr) 1588, 1368, 1169, 811cm- ¹ ;

1 H-NMR (DMSO-d ₆ , ppm) δ 2.51 (s, 3 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.6 1 — 7. 70 (m, 6 H) Example 23 Preparation of Compound (7)

0.2 g (0.71 mmol) of the compound (2) was suspended in N-methylpyrrolidinone (1 mL), and 0.44 g (2.9 mmol) of oxylin chloride was added. . 8 this suspension The mixture was heated to 0 ° C and stirred at the same temperature for 2 hours. The reaction solution was ice-cooled, cold water (2 mL) was added, and the mixture was stirred for 30 minutes. The precipitated crystals were filtered and washed with water. After drying, 0.19 g of the compound (7) was obtained (yield: 83%).

IR (KBr) 1588, 1368, 1169, 811cm- ¹ ;

¹ H-NMR (DMSO-d ₆₎ pm) δ 2.51 (s, 3H), 7.35 (d;

J = 8.4 Hz, 2 H), 7.6 1 — 7.70 (m, 6 H). Example 24 Preparation of Compound (7)

7

4.64 g (71.1 mmol) of lithium hydroxide was suspended in dimethyl sulfoxide (50 mL), and methylmer gas was introduced into the solution. 5 g (14.2 mm 01) of the compound (1b) was added to this solution, and the mixture was heated to 115 ° C. After stirring at 115 ° C for 6 hours, the mixture was cooled to 80 ° C, 7.8 mL (92.6 mL) of dimethyl carbonate was added, and water (50 mL) and 48% hydroxylated water were added. 7.2 g (86.4 mmol) of sodium water was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was cooled to 5 ° C. and stirred at the same temperature for 30 minutes, and the precipitated crystals were filtered and washed with water. Drying gave 4.12 g of the sulfonate. A portion (3.00 g) of the obtained sulfonate was suspended in toluene (9.0 mL), and 3.28 g (21.4 mmol) of oxylin chloride was added. The suspension was heated to 80 ° C and stirred at the same temperature for 30 minutes. Next, 0.53 g (0.54 mmol) of N-methylpyrrolidinone was added, and the mixture was stirred at the same temperature for 4 hours. The obtained solution was ice-cooled, and toluene (9 mL) and cold water (9 mL) were added thereto to carry out liquid separation. The upper layer was washed with water (9 mL) and concentrated under reduced pressure to obtain a concentrated solution. The concentrated solution was heated to 55 ° C, n-heptane (6 mL) was added at the same temperature, then cooled to 5 and stirred at the same temperature for 30 minutes. The precipitated crystals were filtered and washed with cold n-heptane. Dry the compound 2.91 g (yield 87%) of (7) was obtained.

IR (KBr) 1588, 1368, 1169, 811cm- ¹ ;

¹ H-NMR (DMS O— d ₆ , p pm) δ 2.5 1 (s, 3 H), 7.35 (d

J = 8.4 Hz, 2 H), 7.6 1-770 (m, 6 H). Example 25 Preparation of Compound (I-1)

1-1

To 18 mg (0.24 mmo1) of glycine (8), add 64 mg (0.6 mmo1) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetone, and bring the mixture to about 0 ° C. Cooled. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 55 mg of the compound (1-1) was obtained (yield: 82%).

IR (KB r) 3448, 3285, 1735, 1335, 1 160, 809 cm ^-1 ; ¹ H-NMR (DMS O-d ₆ , p pm) δ 2.50 (s, 3 H), 3.5 9 (d, J = 6.0 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.4 Hz, 2H), 7.83 (m, 4H), 8.08 (d, J = 6.0 Hz, 1H), 12.47 (brs, 1H). Preparation of compound (I-la) To COONa

To 18 mg (0.24 mmo1) of glycine (8), add 64 mg (0.6 mmo1) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetone, and add approximately 0 mL. Cooled to ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. The crystals were filtered and washed with water. Drying yielded 63.5 mg of compound (I-la) (88% yield).

I R (K B r) 3 4 4 8, 1 6 1, 1 3 1 4, 1 1 6 3, 8 1 0 cm —

Example 2 Preparation of 7 compound (I-1S)

I-2S

To 1 mg (0.24 mmo 1) of L-alanine (9S), 64 mg (0.6 mmo 1) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetone were added. And cooled to about 0 ° C. To this solution, add 60 mg (0.2 mmo 1) of the compound (7), and add

The mixture was stirred at 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 58 mg (yield: 82%) of compound (I-2S) was obtained.

1 R (KBr) 3 4 4 8, 3 3 1, 1, 1 7 4 5, 1 3 2 4, 1 1 6 4, 8 1 0 cm ^-1

¹ H-NMR (DMSO-d _{6 j} ppm) 6 1.18 (d, J = 7.2 Hz, 3H), 2.53 (s, 3H), 3.80 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.8 1-7.88 (m, 4H), 7.70 (d, J = 8. 4Hz, 2H), 8.18 (d, J = 7.5Hz, 1H), 12.60 (brs, 1H). Example 28 Compound (I-2a) Preparation of

I-2a

L-alanine (9S) 2 1 mg (0.24 mmo1) to sodium carbonate 64 mg (0.6 mmol), water 0.6 mL and acetone 0.6 mL And cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. The crystals were filtered and washed with water. Drying yielded 68 mg (92% yield) of compound (I-2a).

IR (KB r) 3 4 4 8, 1 5 9 6, 1 3 1 6, 1 1 7 3, 8 0 8 cm-Example 29 Preparation of 9 Compound (I-I 2R)

I-2R

D-alanine (9R) 21 mg (0.24 mmo 1) plus sodium carbonate 64 mg (0.6 mmol), water 0.6 mL and acetone 0.6 mL And cooled to about 0 ° C. To this solution, add 60 mg (0.2 mmo 1) of the compound (7), and add

The mixture was stirred at 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 56 mg (yield: 80%) of the compound (I-R) was obtained.

1 R (KBr) 3 4 4 8, 3 3 1 1, 1 7 4 5, 1 3 4 4, 1 16 4, 8 10 cm ~ ^Α ;

^{1 H - NMR... (} DMS 0 - d e, pm) δ 1 1 8 (. D, J = 7 2 H z, 3 H), 2 5 3 (s, 3 H), 3 8 0 (m , 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.81—7.88 (m, 4H), 7.70 (d, J = 8 4Hz, 2H), 8.18 (d, J = 7.5Hz, 1H), 12.60 (brs, 1H). Example 30 Compound (1-3S) Preparation of

I-3S L-aspartic acid (10S) (32 mg, 0.24 mmol), sodium carbonate (102 mg, 0.96 mmol), water (0.6 mL) and acetone (0.1 mL) were added. 6 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 71 mg of the compound (13S) (89% yield).

IR (KB r) 3 2 9 7, 1 7 3 1, 1 3 3 2, 1 1 6 0, 8 1 0 cm - 1; 1 H - N MR (DMSO - d 6; ppm). Δ 2 4 5 (dd, J = 6.9, 16.5Hz, 1H), 2.53 (s, 3H), 2.63 (dd, J = 6.9, 16.5Hz, 1H), 4.10 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2 H), 7.80-7.89 (m, 4H), 8.24 (brs, 1H), 12.2.62 (brs, 2H) .Example 31 Compound (I 3 Preparation of a)

I-3a

32 mg (0.24 mmo 1) of L-aspartic acid (10 S), 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of ice and 0.6 mL of acetone mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. The crystals were filtered and washed with water. Drying yielded 15 mg of the compound (A3a) (17% yield).

IR (KBr) 3 4 4 8, 1 5 9 6, 1 1 8 9, 8 1 2 cm- ¹ Example 3 Preparation of compound (1-3R)

I-3R

To 32 mg (0.24 mmo 1) of D-aspartic acid (10 R) was added 102 mg (0.96 mmol) of sodium carbonate, 0.6 mL of water and 0.1 mL of acetone. 6 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 68 mg (yield 85%) of compound (I-3R) was obtained.

IR (KB r) 3 2 9 7, 1 7 3 1, 1 3 3 2, 1 1 6 0, 8 1 0 cm - 1;. 1 H - NMR (DMSO - d 6> ppm) 6 2 4 5 ( dd, J = 6.9, 16, 5Hz, 1H), 2.53 (s, 3H), 2.63 (dd, J = 6.9, 16.5Hz, 1H), 4.10 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2 H), 7.80-7.89 (m, 4H), 8.24 (brs, 1H), 12.2.62 (brs, 2H). Example 33 Compound (I— 4 Preparation of S)

I-4S

35 mg (0.24 mmo 1) of L-glutamic acid (11S) to 0.2 mg of sodium carbonate (0.96 mmol), 0.6 mL of water and 0 mL of acetate Add 6 mL Then, it was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmo 1) of the compound (7) was added, and the mixture was stirred at about 0 ° C. for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 63 mg of the compound (I-4S) (77% yield).

1 R (KBr) 3 2 8 7, 1 7 2 0, 1 3 3 3, 1 16 1, 8 1 0 cm- ¹ ;

¹ H-NMR (DMSO-d ₆₎ ppm) δ 1.69 (m, 1 H), 1.86 (m, 1 H), 2.22 (t, J = 7.2 Hz, 2H), 2.53 (s, 3H), 3.81 (m, 1H), 7.35-7.41 (m, 2H), 7.67—7.7 3 (m,

2H), 7.78-7.87 (m, 4H), 8.19 (d, J = 8.1 Hz, 1H), 12.2.42 (brs, 2H) Example 3 Preparation of Compound (I-14a)

I-4a

35 mg (0.24 mmo 1) of L-glutamic acid (11S), 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0. 6 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmο1) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. The crystals were filtered and washed with water. Drying yielded 48 mg of the compound (I-4a) (55% yield).

IR (KBr) 3 3 7 3, 1 594, 13 17, 1 166, 808 cm-Example 35 Preparation of 5 Compounds (I-14R)

I-4R

D To 35 mg (0.24 mmo 1) of nitric acid (11 R) was added 102 mg (0.96 mmol) of sodium carbonate, 0.6 mL of water, and acetate. 0.6 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmo 1) of the compound (7) was added, and the mixture was stirred at about 0 ° C. for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 63 mg (yield 77%) of compound (I-4R).

1 R (KB r) 3 2 8 7, 1 7 2 0, 1 3 3 3, 1 1 6 1, 8 1 0 cm- ¹ ;

¹ H-NMR (DMSO-d ₆₎ ppm) δ 1.69 (m, 1 H), 1.86 (m: 1 H), 2.22 (t, J = 7.2 Hz, 2H), 2.53 (s, 3H), 3.81 (m, 1H), 7.35-7.41 (m, 2H), 7.67-7.7 3 (m,

2 H), 7.78-7.87 (m, 4 H), 8.19 (d, J = 8.1 Hz, 1 H), 12.2.4 2 (brs, 2 H) Example 3 Preparation of 6 Compound (1-5S)

I-5S

L-leucine (2S) 32 2 mg (0.24 mmo1) to sodium carbonate 64 mg (0.6 mmol), 0.6 mL of water and 0.6 mL of acetone were added, and the mixture was cooled to about 0 ° C. To this solution was added 60 mg (0.2 mmo 1) of compound (7),

The mixture was stirred at 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 63 mg of the compound (I-5S) (80% yield).

1 R (KBr) 3 4 4 8, 3 3 2 1, 1 7 4 9, 1 3 2 5, 1 16 6, 8 10 cm ^-1 ;

¹ H-NMR (DMSO-d ₆ jpm) 60.7 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.3 Hz, 3H) , 1.40 — 1.42 (m, 2H), 1.59 (m, 1H), 2.53 (s, 3H), 3.67-3.72 (m , 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.79-7. 87 (m, 4H), 8.19 (d, J = 9.0 Hz, 1H), 12.276 (brs, 1H). Example 37 Compound (I-a Preparation of

I-5a

L One bit isine (12 S) 32 mg (0.24 mmo 1) to 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetate And cooled to about 0 ° C. To this solution, add 60 mg (0.2 mmo 1) of the compound (7), and add

The mixture was stirred at 0 ° C for about 3 hours. The crystals were filtered and washed with water. Drying yielded 61 mg of compound (I-5a) (74% yield).

1 R (KBr) 3 4 4 8, 1 5 9 0, 1 3 1 4, 1 1 6 4, 8 10 cm- ¹ . Example 3 Preparation of 8 compound (I-5b)

I-5b

32 mg (0.24 mmo 1) of potassium carbonate (83 mg, 0.6 mmo 1), 0.6 mL of water and 0.6 mL of acetate are added to 32 mg (0.24 mmo 1) In addition, it was cooled to about 0 ° C. To this solution, add 60 mg (0.2 mmo1) of the compound (7), and add

The mixture was stirred at 0 ° C for about 3 hours. The crystals were filtered and washed with water. Drying yielded 69 mg of (I-5b) (80% yield).

1 R (KBr) 342 3, 159 2, 1 314, 1172, 807 cm- ¹ . Example 39 Preparation of compound (1-5R)

I-5R

D—Mouth isine (12R) 32 mg (0.24 mmo 1) to sodium carbonate 64 mg (0.6 mmo l), water 0.6 mL and acetone 0.6 mL In addition, it was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Dry As a result, (I-5R) (yield 78%) was obtained.

I R (KBr) 3 4 4 8, 3 3 2 1 1 7 4 9 3 2 5, 1 1 6 6, 8 1 0 cm

¹ H-NMR (DMSO-ds _; ppm) δ 0.7 (d J = 6.3 Hz, 3 H), 0.81 (d, J = 6.3 Hz 3 H 1.4 0-1.42 (m, 2H), 1.59 (m1H), 2.53 (s, 3H), 3.67-3.72 (m1H), 7 3 8 (d J = 8.4 Hz 2 H), 7.70 (d J = 8.7 Hz, 2 H), 7.79-7.87 (m, 4 H), 8.19 (d, J = 9.0 Hz 1 H), 12.76 (brs 1 H) Example 40 Preparation of Compound (I-6S)

I-6S

L-phenylalanine (13S) 40 mg (0.24 mmo 1) to sodium carbonate 64 mg (0.6 mmo 1), water 0.6 mL and acetate After adding 0.6 mL, the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mMol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 70 mg (yield 82%) of compound (I-6S) was obtained.

IR (KBr) 3 4 4 8, 3 3 1 3, 1 7 4 9, 1 3 2 4, 1 16 4, 8 10 cm ^-1 ;

¹ H-NMR (DMSO-d _{6 j} ppm) δ 2.53 (s, 3 H), 2.73 (dd, J = 9.3, 13.8 Hz, 1 H), 2. 9 5 (dd, J = 5.7, 13.8 Hz, 1H) 3.90 (m, 1H), 7.00-7.22 (m, 5H), 7.38 (d, J = 8.4 Hz, 2 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.64—7.72 (m, 4H), 8.32 (d, J = 9.0 Hz, 1H), 12.73 (brs, lH). Example 4 Preparation of Compound (-6a)

I-6a

40 mg (0.24 mmo 1) of L-phenylalanine (13 S) and 64 mg (0.6 mmo 1) of sodium carbonate, 0.6 mL of water and 0. Added 6 mL and cooled to about 0 ° C. To this solution, 60 mg (0.2 mmo 1) of the compound (7) was added, and the mixture was stirred at about 0 ° C. for about 3 hours. The crystals were filtered and washed with water. After drying, 71 mg (yield: 79%) of compound (I-6a) was obtained.

IR (KBr) 3448,1595,1303,1157,808cm—Example 42 Preparation of compound (1-6R)

I-6R

D-phenylalanine (13R) 40 mg (0.24 mmo 1) to sodium carbonate 64 mg (0.6 mmo 1), ice 0.6 mL and acetone 0.6 mL Add Then, it was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 71 mg (yield 83%) of the compound (I-16R) was obtained.

IR (KBr) 344 8, 3 3 1 3, 1 7 4 9, 1 3 2 4, 1 1 6 4, 8 10 cm ^-1 ;

¹ H-NMR (DMS O— d _6> ppm) δ 2.53 (s, 3H), 2.73 (dd, J = 9.3, 13.8Hz, 1H), 2 . 9 5 (dd, J = 5.7, 13.8 Hz, 1 H), 3.90 (m, 1 H), 7.08—7.22 (m, 5 H), 7.38 (d, J = 8.4Hz, 2H), 7.59 (d, J = 8.4Hz, 2H), 7.64-7.72 (m, 4H), 8.32 (d, J = 9.0Hz, 1H), 12.73 (brs, lH). Example 4 Preparation of compound (7S)

I-7S

To 25 mg (0.24 mmo 1) of L-serine (14S), 64 mg (0.6 mmo 1) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetone were added. And cooled to about 0 ° C. To this solution, 60 mg (0.2 mmo 1) of the compound (7) was added, and the mixture was stirred at about 0 ° C. for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 56 mg of (I-S) (76% yield).

IR (KBr) 35 48,3447,32 94,17 28,13 24,11 16 1,8 ¹⁰ cm- ¹ ;

¹ H-NMR (DMS O-d _6; ppm) δ 2.53 (s, 3 H), 3.47- 3.58 (m, 2H), 3.79 (m, 1H), 5.20 (brs, 1H),

7.38 (d, J = 8.1 Hz, 2H), 7.7 1 (d, J = 8.1 Hz, 2

H), 7.85 (s, 4H), 8.06 (d, J = 8, 4Hz, 1H), 12.50 (brs, 1H) Example 4 4 compounds Preparation of (7a)

I-7a

To 25 mg (0.24 mmo 1) of L-serine (14 S) was added 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of ice and 0.6 mL of acetone. In addition, it was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. The crystals were filtered and washed with water. After drying, 72 mg (yield: 92%) of compound (I-7a) was obtained.

IR (KBr) 354 8, 3 4 4 8, 1 5 9 3, 1 2 9 3, 1 1 5 5 8 10 cm ^-1 . Example 45 Preparation of compound (I- 17 R)

I-7R 25 mg (0.24 mmo 1) of D-Serine (14 R), 64 mg (0.6 mmo 1) of sodium carbonate, 0.6 mL of water and 6 m of acetone L was added and cooled to about 0 ° C. To this solution was added 60 mg (0.2 mmo 1) of compound (7),

The mixture was stirred at 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 58 mg of compound (I-7R) (79% yield).

1 R (KBr) 3 5 4 8, 3 4 4 7, 3 2 9 4, 1 7 2 8, 1 3 2 4, 1 16 1, 8 1 0 cm- ¹ ;

¹ H-NMR (DMSO-d ₆ ppm) 6 2.53 (s, 3H), 3.47-3.58 (m, 2H3.79 (m, 1H), 5. 20 (brs, 1H), 7.38 (d, J = 8.1Hz2H), 7.71 (d, J = 8.1Hz, 2H), 7.85 (s, 4H), 8.06 (d, J = 8.4 Hz, 1 H), 12.50 (brs 1H).

Example 4 Preparation of 6 compound (1-8S)

I-8S

29 mg (0.24 mmo1) of L-threonine (15S), 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0.6 m of acetone L was added and cooled to about 0 ° C. To this solution was added 60 mg (0.2 mmo 1) of the compound (7), and

The mixture was stirred at 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. Drying yielded 55 mg of the compound (18S) (yield: 72%).

1 R (KBr) 3 5 8 9, 3 4 4 8, 3 3 1 8 1 7 5 2, 1 3 2 1, 1 1 6 8, 8 10 cm- ¹ ; ¹ H-N MR (DMSO-d ₆₎ ppm) δ 1.04 (d, J = 6.0 Hz,

3 H), 2.5 3 (s, 3 H), 3.6 9-4.08 (m, 3 H), 7.3 3-7.39 (m, 2 H), 7.5 9-7.74 (m, 4H), 7.84 (m, 1H) 14.50 (brs, 1H). Example 4 Preparation of Compound (I-8a)

I-8a

29 mg (0.24 mmo 1) of L-threonine (15 S), 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetate And cooled to about 0 ° C. To this solution, add 60 mg (0.2 mmo 1) of the compound (7), and add

The mixture was stirred at 0 ° C for about 3 hours. The crystals were filtered and washed with water. After drying, 62 mg (yield 77%) of compound (I-8a) was obtained.

1 R (KBr) 3589, 3432, 1596, 1304, 1162, 810 cm ^-1 . Example 4 Preparation of 8 Compound (I-18R)

D-threonine (15R) 29 mg (0.24 mmo1) plus sodium carbonate 64 mg (0.6 mmo1), water 0.6 mL and acetate 0.6 Add mL and add

Cooled to 0 ° C. To this solution was added 60 mg (0.2 mmo 1) of the compound (7). The mixture was stirred at about 0 ° C. for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 55 mg (yield: 73%) of the compound (I-8R) was obtained.

1 R (KBr) 3589, 3448, 3318, 1752, 1321, 1168, 810 cm- ¹ ;

¹ H-NMR (D MS 0-d _6; ppm) δ 1.04 (d, J = 6.0 Hz, 3 H), 2.53 (s, 3 H), 3.69— 4.08 (m, 3H), 7.33—7.39 (m, 2H), 7.59—7.74 (m, 4H), 7.84 (m, 1 H): 14.50 (brs, 1H). Example 49 Preparation of Compound (I-19S)

I-9S L-tributofan (16S) 49 mg (0.24 mmo 1) to 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetone And cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 79 mg (yield 84%) of compound (I-9S) was obtained.

IR (KBr) 3 39 3, 3 3 13 3, 1 7 4 6, 1 3 2 2, 1 1 6 3, 8 10 cm- ¹ ;

¹ H-NMR (DMS O-d _6> pm) δ 2.53 (s, 3Η), 2.87 (dd, J = 7.5, 14.1 Hz, 1H), 3 0 8 (dd, J = 5.7, 14.1 Hz, 1 H), 3.89-3.97 (m, 1 H), 6.87-7.09 (m , 3 H), 7.24 (d, J = 8.1 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.37-7. 40 (m, 2 H), 7.58-7.66 (m, 7 H), 8.30 (d, J = 8.4 Hz, 1 H), 10.8. brs, 1H), 12.74 (brs, 1H).

Example 50 Preparation of Compound (9a)

I-9a

To 49 mg (0.24 mmo1) of L-tributofan (16 S) was added 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of ice and 0.1 mL of acetone. 6 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. The crystals were filtered and washed with water. Dry and compound 86 mg (yield 88%) of the product (I-9a) was obtained.

I R (KBr) 3 4 3 7, 1 5 9 5, 1 3 5 5, 6 1, 8 10 cm 'Example 5 Preparation of compound (I-9R)

D—Tributofan (16R) 49 mg (0.24 mmo 1) with 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0.6 mL of acetone In addition, it was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 79 mg (yield 85%) of the compound (I-19R) was obtained.

IR (KBr) 3 39 3, 3 31 3, 17 46, 13 22, 1 16 3, 8 10 cm ^-1 ;

¹ H-NMR (DMS O- d ₆₎ ppm) δ 2.53 (s, 3H), 2.87 (dd, J = 7.5, 14.1Hz, 1H), 3 .08 (dd, J = 5.7, 14.1 Hz, 1H), 3.89-3.97 (m, 1H), 6.87-7.09 (m , 3H), 7.24 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 7.8Hz, 1H), 7.37-7. 4 0 (m, 2 H), 7.58-7.66 (m, 7 H), 8.30 (d, J = 8.4 Hz, 1 H), 10.8.0 ( (rs, 1H) _; 1 2.74 (brs, 1H). Example 5 Preparation of Compound (I-10S)

I-10S

28 mg (0.24 mmo 1) of L-linoline (17 S), 64 mg (0.6 mmol) of sodium carbonate, 0.6 mL of water and 0.6 of acetate mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 59 mg (yield 78%) of compound (I-10S) was obtained.

R (KBr) 3393, 3333, 1747, 1332, 1164, 810 cm ^-1 ;

¹ H-NMR (DMSO-d ₆₎ ppm) δ 0.84 (d, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H) , 1.94-2.01 (m, 1H), 2.56 (s, 3H), 3.58 (dd, J = 6.3, 9.3Hz, 1H) , 7.41 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.86-7.87 (m , 3H), 8.09 (d, J = 9.0 Hz, 2H), 12.65 (brs, lH). Example 53 Preparation of Compound (I—10S)

I-10S 1.27 g (10.8 mmol) of L-valin (17 S) was added to 2.89 g (20.9 mmol) of potassium carbonate, 22.9 mL of water and acetate 34.3 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 2.5 g (8.4 mmol) of compound (7) was added, and the mixture was stirred at about 0 ° C for about 4 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 3.0 g (yield 94%) of the compound (I-10S) was obtained.

IR (KBr) 33 39,33 33,17 47,13 23,11 64,8 ¹⁰ cm- ¹ ;

¹ H-NMR (DMS O-d _6; pm) δ 0.84 (d, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H ), 1.94-2.01 (m, 1H), 2.56 (s, 3H), 3.58 (dd, J = 6.3, 9.3Hz, 1H) _; 7.41 (d, J = 8.4Hz, 2H), 7.73 (d, J = 8.7Hz, 2H), 7.86-7.87 (m , 3H), 8.09 (d, J = 9.0Hz, 2H), 12.65 (rs, 1H). Example 54 Preparation of Compound (I-10a)

I-10a

To 28 mg (0.24 mmo 1) of L-parin (17 S) was added 64 mg (0.6 mmo 1) of sodium carbonate, 0.6 mL of water, and 0.6 mL of acetone. And cooled to about 0 ° C. To this solution was added 60 mg (0.2 mmo 1) of the compound (7), and the mixture was stirred at about 0 ° C. for about 3 hours. The crystals were filtered and washed with water. After drying, 76 mg (yield 94%) of the compound (I-10a) was obtained. R (KB r) 3 4 4 8, 1 5 9 4 3 2 2 1 6 8, 8 9 cm 1

Example 5 Preparation of 5 Compound (0R)

I-10R D Barine (17 R) 28 mg (0.24 mmo 1) plus sodium carbonate 64 mg (0.6 mmo 1), water 0.6 mL and acetate 0.6 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 60 mg (0.2 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 3 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 59 mg (yield 78%) of the compound (110R) was obtained.

IR (KBr) 3393, 3333, 1747, 1332, 1164, 810 cm— ¹ ;

¹ H-N MR (DMS 0-d _6; pm) δ 0.84 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3 H), 1.94-2.01 (m, 1H), 2.56 (s, 3H), 3.58 (dd, J = 6.3, 9.3Hz, 1 H): 7.41 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.86-7.87 (m, 3H), 8.09 (d, J = 9.0 Hz, 2H), 12.65 (brs, lH). Example 56 Preparation of Compound (0R)

I-10R

D-parin (17 R) 1.27 g (10.8 mmol) to potassium carbonate 2.89 g (20.9 mmol), water 22.9 mL and acetone 34.3 mL was added, and the mixture was cooled to about 0 ° C. To this solution, 2.5 g (8.4 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C for about 4 hours. After neutralization with hydrochloric acid, the crystals were filtered and washed with water. After drying, 3.0 g (yield: 94%) of the compound (I-10R) was obtained.

IR (KBr) 3339,3333,1747,1323,1164,810cm ^-1 ;

¹ H-NMR (DMSO—d ₆ , ppm) δ 0.84 (d, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H) , 1.94-2.01 (m, 1H), 2.56 (s, 3H), 3.58 (dd, J = 6.3, 9.3Hz, 1H) , 7.41 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.86-7.87 (m , 3H), 8.09 (d, J = 9.0 Hz, 2H), 12.65 (brs, lH). Example 57 Preparation of Compound (I—10R)

I-10R

D-barine (17 R) 1.27 g (7.4 mmo 1) plus potassium carbonate 2.32 g (16.8 mmo 1), 15 mL water and 15 acetone mL was added and cooled to about 0 ° C. To this solution, 2.0 g (6.7 mmol) of the compound (7) was added, and the mixture was stirred at about 0 ° C. for about 4 hours, and then allowed to stand at room temperature for 16 hours. After neutralization with hydrochloric acid, the crystals were filtered off and washed with ice. After drying, 2.25 g (yield 89%) of compound (I-10R) was obtained.

I R (KBr) 3 3 9 3, 3 3 3 3, 1 7 4 7, 1 3 2 3, 1 1 6 4, 8 1 0 cm-1

1 H-NMR (DMS O-d ₆₎ pm) δ 0.84 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H ), 1.94-2.01 (m, 1H), 2.56 (s, 3H), 3.58 (dd, J = 6.3, 9.3Hz, 1H) 7.41 (d, J = 8.4Hz, 2H), 7.73 (d, J = 8.7Hz, 2H), 7.86-7.87 (m, 3 H), 8.09 (d, J = 9.0 Hz, 2 H), 12.65 (brs, 1 H). Industrial applicability

According to this production method, a compound having a biphenyl group substituted with a lower alkylthio group can be produced simply and economically.

Claims

The scope of the claims

1. General formula (V)

(Wherein, R ¹ is lower alkyl which may be substituted), a salt thereof, or a solvate thereof.

2. General formula (IV):

(Wherein, R ¹ has the same meaning as in claim 1), a salt thereof or a solvate thereof, which is subjected to a halogenation reaction.

^R1 (ii)

(Wherein, R ¹ has the same meaning as in claim ¹ ; X ¹ is halogen). The method according to claim 1, which comprises a step of producing a compound represented by the formula: Production method.

3. General formula (II):

(Wherein, R ¹ has the same meaning as in claim ¹ ; X ¹ has the same meaning as in claim 2), a salt thereof, or a solvate thereof, and a general formula (III): I ² (, „)

H ₂ N COOH

(Wherein R ² is lower alkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, heteroaryl which may be substituted, or heteroaryl which may be substituted. Wherein the compound represented by the formula (I) is subjected to an amidation reaction, or a salt thereof, or a solvate thereof.

( ^|)

(Wherein, R ¹ has the same meaning as in claim ¹ ; R ² has the same meaning as described above). A compound, a salt thereof, or a solvate thereof, the method comprising: The manufacturing method according to paragraph 2.

4. The method according to any ^one of claims 1 to 3, wherein the alkylthiolation reaction is a reaction using KSR ¹ (wherein R ¹ has the same meaning as in claim 1) as a reaction reagent. Manufacturing method described in.

5. The alkylthiolation reaction, wherein an alkylating agent selected from the group consisting of alkyl halides, dialkyl carbonates, alkyl sulfinates, alkyl sulfonates, dialkyl sulfates, and tetraalkylammonium salts is added. Item 5. The production method according to any one of Items 1 to 4.

6. R ¹ is methyl, A process according to any one of X ² ranges the items 1 to 5 of Claims bromine.