RU2193028C2 - Method of synthesis of derivatives of 2-phenyl-3-naphthylpropionic acid - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to method of synthesis of compound of the formula (III) or its salt:

where R¹ means tert.-butoxycarbonyl, benzyl; R³ means C₁-C₆-alkyl by interaction of compound of the formula (I):

where R¹ has value indicated above and R² means methanesulfonyl group or p-toluenesulfonyl group with compound of the formula (II):

in the presence of a base. Invention relates also to the use of compound of the formula (III) for synthesis of compound of the formula (V):

where R¹ means tertiary butoxycarbonyl-group, benzyl-group; R³ means C₁-C₆-alkyl by means of interaction of compound of the formula (III) with compound of the formula (IV):

Description

 The invention relates to a method for producing intermediate compounds of aromatic amidine derivatives that have an anticoagulant effect based on excellent inhibition of activated coagulation factor X (hereinafter abbreviated as Fxa), and are described in Japanese Patent Application Laid-open (kokai) 5-208946.

(где R¹ представляет защитную группу для атома азота и R³ представляет атом водорода, аралкильную группу или алкильную группу, имеющую 1-6 углеродных атомов);

(где R¹ и R³ имеют такие же значения, как описанные выше); и

(где R¹ и R³ имеют такие же значения, как описанные выше).BACKGROUND OF THE INVENTION
Compounds of the following formulas (V), (Va) and (Vb) and their salts are known as intermediate compounds of aromatic amidine derivatives described in Japanese Patent Application Laid-open (kokai) 5-208946:

(where R ¹ represents a protective group for a nitrogen atom and R ³ represents a hydrogen atom, an aralkyl group or an alkyl group having 1-6 carbon atoms);

(where R ¹ and R ³ have the same meanings as described above); and

(where R ¹ and R ³ have the same meanings as described above).

 The publication also describes methods for preparing the above compounds.

A typical way to obtain these intermediates includes the following steps:
bromination of 7-methyl-2-naphthalenecarbonitrile to form 7-bromomethyl-2-naphthalenecarbonitrile (first step);
the further conversion of 7-bromomethyl-2-naphthalenecarbonitrile to the phosphonium salt and [(7-cyano) -2-naphthyl) methyl] triphenylphosphonium bromide (second stage);
synthesis of ethyl 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-hydroxypyrrolidinyl] oxy] phenyl] -2-oxoacetate using the Mitsunobu reaction between ethyl 2- (4-hydroxyphenyl) -2-oxoacetate and (3R) -1- (tert-butoxycarbonyl) -3-hydroxypyrrolidine (third step);
introduction of the obtained ethyl 2- [4 - [[3S) -1- (tert-butoxycarbonyl) -3-hydroxypyrrolidinyl] oxy] phenyl] -2-oxoacetate and [(7-cyano) -2-naphthyl) methyl] triphenylphosphonium bromide into the Wittig reaction ( fourth stage);
further catalytic hydrogenation to form compounds represented by the formula (V) or (Va) (fifth step); and
dissolving the compounds represented by formula (Va) in ethanol by heating, adding a small amount of sodium hydride to the resulting solution, and crystallizing with stirring the mixture at room temperature to obtain the compounds represented by formula (Vb) (sixth step).

However, the above known method has the following disadvantages:
1) the bromination in the first stage is carried out in carbon tetrachloride, which is supposedly a carcinogen;
2) the product of the first stage, i.e. 7-bromomethyl-2-naphthalenecarbonitrile, causes skin irritation when isolated in the form of crystals;
3) the relatively expensive reagents diethyl azodicarboxylate and 1,8-diazabicyclo [5.4.0] -7-undecene are used;
4) the by-products formed in the third and fourth stages behave like catalytic poisons in the catalytic hydrogenation in the fifth stage and purification by silica gel column chromatography is required to remove the by-products;
5) palladium oxide monohydrate - barium sulfate, which is a catalyst for catalytic hydrogenation, must be prepared directly during use; and
6) the output of the sixth stage is low, in addition, sodium hydride is used, which causes a safety problem.

 In short, the known method is unsatisfactory as an industrial method.

 Thus, it is an object of the present invention to provide an industrially applicable process for the preparation of compounds represented by formulas (V), (Va) and (Vb) and their salts by using safe, inexpensive and readily available starting material (s) and auxiliary material (s) and without a chromatographic purification step on silica gel, as well as the creation of an industrial process for the preparation of intermediate compounds of aromatic amidine derivatives described in Japanese Patent Application Laid-open (kokai) 5-208946.

Disclosure of the invention
Considering the above, serious research has been conducted and has been found
that halogenation in the first stage can be effectively carried out in an alkyl nitrile solvent, which allows the reaction in the next stage without isolating the product;
that the use of a pyrrolidinyloxyphenylacetic acid derivative obtained by condensation of 4-hydroxyphenylacetic acids and sulfonyloxypyrrolidines as a starting material gives a compound represented by formula (V) or (Va), without the need for a phosphonium salt formation reaction and catalytic hydrogenation, and also without the need for an expensive reagent or reagent, which is required at the time of use; and
that adding a base to the diastereomeric mixture of compounds represented by formula (Va) facilitates the formation of compounds represented by formula (Vb). Based on these findings, the present invention was created.

 The present invention is generally represented by reaction schemes I and II (see end of description).

 Thus, in accordance with the present invention, a method for producing a compound represented by formula (III) or (IIIa) or a salt thereof is provided by reacting a compound represented by formula (I) or (Ia) and a compound represented by formula (II) in the presence of grounds.

 The present invention also provides a method for preparing a compound represented by formula (V) (or (Va)) or its salts by reacting a compound represented by formula (III) (or (IIIa)) or a salt thereof and a compound represented by formula ( Iv) in the presence of a base.

 The present invention also provides a process for preparing a compound represented by formula (Vb) by reacting a compound represented by formula (Va) and a base.

(где X² представляет атом галогена), галогенированием соединения, представленного формулой (VII) в алкилнитрильном растворителе.Further, in accordance with the present invention, a method for producing a compound represented by formula (IVa):

(where X ² represents a halogen atom), by halogenation of the compound represented by formula (VII) in an alkyl nitrile solvent.

 Of the compounds shown in the above schemes, some are new compounds that are first obtained in the present invention. Therefore, the present invention also relates to such novel compounds useful as intermediates in the synthesis.

(где R¹ и R³ имеют такие же значения, как описанные выше), и их соли.In addition, in accordance with the present invention proposed compounds represented by formula (III):

(where R ¹ and R ³ have the same meanings as described above), and their salts.

(где R¹ и R³ имеют такие же значения, как описанные выше), и их соли.In accordance with the present invention, there are also provided compounds represented by the formula (IIIa):

(where R ¹ and R ³ have the same meanings as described above), and their salts.

(где R^1c представляет трет-бутоксикарбонильную группу и R^3c представляет атом водорода, аралкильную группу или алкильную группу, имеющую 1-6 углеродных атомов (отличную от этильной группы)), и их соли.In accordance with the present invention, there are provided compounds represented by the formula (Vc):

(where R ^1c represents a tert-butoxycarbonyl group and R ^3c represents a hydrogen atom, an aralkyl group or an alkyl group having 1-6 carbon atoms (other than ethyl group)), and their salts.

(где R^1d представляет бензильную группу и R^3d представляет атом водорода, аралкильную группу или алкильную группу, имеющую 1-6 углеродных атомов), и их соли.Further, in accordance with the present invention, there are provided compounds represented by the formula (Vd):

(where R ^1d represents a benzyl group and R ^3d represents a hydrogen atom, an aralkyl group or an alkyl group having 1-6 carbon atoms), and their salts.

Preferred Embodiment
Further, the present invention is described in more detail. First, substituents of the compounds of the present invention are described.

R ¹ represents a protective group for a nitrogen atom. As a protecting group, commonly used protecting groups may be used. Examples include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a benzyl group, a formyl group, an acetyl group, and a triphenylmethyl group. In the present invention, a tert-butoxycarbonyl group or a benzyl group is preferred.

R ² represents a methanesulfonyl group or a p-toluenesulfonyl group.

An alkyl group having 1-6 carbon atoms represented by R ³ may be straight, branched or cyclic and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, pentyl a group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. An aralkyl group is a group formed by an alkyl group having 1-6 carbon atoms and an aryl group, and examples thereof include a benzyl group and a naphthylmethyl group. The R ³ group in the present invention is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably a methyl group or ethyl group.

X ¹ represents a leaving group. As a leaving group, any such group that is commonly used can be used, and examples thereof include a halogen atom, a methanesulfonyloxy group and a p-toluenesulfonyloxy group. As used in the present invention, examples of a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a bromine atom is preferred.

X ² represents a halogen atom. Examples of a halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a bromine atom is preferred.

 Compounds represented by formula (I) or formula (Ia), compounds represented by formula (II), and compounds represented by formula (VII) used in the present invention are readily available known compounds or compounds that can be easily prepared as described in the literature. ways.

 The compounds represented by formula (I) are known compounds and optically active (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (see Japanese Patent Application Laid-Open (kokai) 2-28180) and Optically Active (3R) The -1- (tert-butoxycarbonyl) -3-p-toluenesulfonyloxypyrrolidine (see WO 9200295) represented by formula (Ia) are also known compounds.

 Of the compounds represented by formula (II), methyl p-hydroxyphenyl acetate and ethyl p-hydroxyphenyl acetate are known. Other p-hydroxyphenylacetic acid alkyl esters can be easily prepared by condensation of the corresponding alcohol and readily available p-hydroxyphenylacetic acid.

 7-Halogenomethyl-2-naphthylylcarbonitrile as an example of a compound of formula (IV) is also a known compound (Japanese Patent Application Laid-open (kokai) 5-20008946 and 7-17937).

 Next, the production method of the present invention is described in more detail.

 (Step A) A process for preparing a compound represented by formula (III) or formula (IIIa), or salts thereof.

 To obtain a compound represented by formula (III) or formula (IIIa), or its salts, a compound represented by formula (I) or formula (Ia) is reacted with a compound represented by formula (II) in the presence of a base and, optionally, a catalyst .

 There is no particular limitation on the solvent used at this stage, as long as it does not adversely affect the reaction. Examples of the solvent include organic solvents such as aprotic polar solvents, ethers, aromatic hydrocarbons and alcohols, mixtures of organic solvents and mixtures of organic solvents and water.

 Examples of aprotic polar solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and acetonitrile. Examples of ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether. Examples of aromatic hydrocarbons include benzene, toluene and xylene. Examples of alcohols include methanol and ethanol. Of these solvents, aprotic polar solvents or aromatic hydrocarbons are preferably used, and more preferably —N, N-dimethylformamide or toluene.

 There is no particular limitation on the base so long as it does not adversely affect the reaction, and a weak or strong base can be used. Examples of the strong base include an alkali metal hydride, such as sodium hydride or lithium hydride; alkaline earth metal hydride, such as calcium hydride; an alkali metal alkoxide such as sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide or potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and an alkali metal carbonate such as sodium carbonate or potassium carbonate. Strong bases are preferred. Particularly preferred is an alkali metal hydride, and more preferred is sodium hydride.

 Examples of the catalyst that is used in the present invention include phase transfer catalysts and molecular sieves. Examples of phase transfer catalysts include quaternary ammonium oleophilic salts such as tetra (n-butyl) ammonium bromide, tetra (n-butyl) ammonium chloride, tetraethylammonium bromide, tetra (n-butyl) ammonium hydrogen sulfide, triethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium bromide, triethylbenzylammonium bromide like 18-crown-6.15-crown-5. Interphase transfer catalysts are preferred. In particular, oleophilic quaternary ammonium salts are preferred, and tetra (n-butyl) ammonium bromide is more preferred. The introduction of catalysts increases the yield of compounds represented by formula (III) or formula (IIIa) or their salts.

There is no particular limitation on the reaction temperature as long as it does not exceed the boiling point of the solvent. The reaction is usually carried out in a temperature range from 0 ^{° C.} to about the boiling point of the solvent used, preferably at 60 ^{° C.} -110 ^° C. The reaction time varies in accordance with the reaction temperature and usually the reaction is carried out for 15 minutes to one day, preferably 4 hours or less.

 (Step B) A process for preparing a compound represented by formula (IV).

 The compound represented by formula (IV) can be obtained in a known manner and is preferably prepared by halogenation of the compound represented by formula (VII) in an alkyl nitrile solvent. In the halogenation process, a radical initiator can be introduced.

There is no particular limitation on the alkyl nitrile solvent as long as it does not adversely affect the reaction, and straight or branched C ₂ -C ₇ alkyl nitriles can be used. Examples of straight or branched C ₂ -C ₇ alkyl nitriles include acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, valeronitrile, hexannitrile and heptannitrile. Of these, unbranched or branched alkyl nitriles having 2-4 carbon atoms, such as acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile, are preferred, and acetonitrile is more preferred.

 There is no particular limitation on the radical initiator as long as it does not adversely affect the reaction, and examples thereof include peroxides, such as dibenzoyl peroxide, or azo compounds, such as azabisisobutyronitrile. Instead of introducing a radical initiator, operations such as irradiation with light or heating can be carried out. Of the various radical initiators, azo compounds are preferred, with 2,2'-azobisisobutyronitrile being particularly preferred.

 Halogenation can be carried out by introducing a halogenating agent. There is no particular limitation on the halogenating agent as long as it does not adversely affect the reaction. Examples thereof include sulfuryl halides and N-haloimides. Of these, N-haloimides are preferred, with N-bromosuccinimide being more preferred.

There is no particular limitation on the reaction temperature as long as it does not exceed the boiling point of the solvent. The reaction is usually carried out at 40 ^o C-120 ^o C, preferably at about 80 ^o C. The reaction time depends on the reaction temperature and usually the reaction is carried out for one hour to one day, preferably 1-4 hours.

 (Step C) A process for preparing a compound represented by formula (V) or formula (Va), or salts thereof.

 To obtain a compound represented by formula (V) or formula (Va), or a salt thereof, a compound represented by formula (III) or formula (IIIa) is reacted with a compound represented by formula (IV) in the presence of a base.

 There is no particular limitation on the solvent used at this stage, as long as it does not adversely affect the reaction. Examples of the solvent include organic solvents such as aprotic polar solvents, ethers, esters, aromatic hydrocarbons and alcohols, mixtures of organic solvents and mixtures of organic solvents and water.

 Examples of aprotic polar solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and acetonitrile. Examples of ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether. Examples of esters include methyl acetate, ethyl acetate, methyl propionate and ethyl propionate. Examples of aromatic hydrocarbons include benzene, toluene and xylene. Examples of alcohols include methanol and ethanol. Mixtures of organic solvents are preferably used. Of these, mixtures of an aprotic polar solvent and an aromatic hydrocarbon are preferred, with a mixture containing N, N-dimethylformamide and toluene being more preferred.

 There is no particular limitation on the base so long as it does not adversely affect the reaction, and a weak or strong base can be used. Examples of the strong base include an alkali metal hydride, such as sodium hydride or lithium hydride; alkaline earth metal hydride, such as calcium hydride; an alkali metal alkoxide such as sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide or potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and an alkali metal carbonate such as sodium carbonate or potassium carbonate. Strong bases are preferred. Particularly preferred is an alkali metal hydride, and more preferred is sodium hydride.

There is no particular limitation on the reaction temperature as long as it does not exceed the boiling point of the solvent, however, the reaction is preferably carried out at a relatively low temperature in order to suppress the side reaction. The reaction is usually carried out in a temperature range from -10 ^{° C.} to room temperature, preferably at 60 ^° -110 ^° C. The reaction time varies according to the reaction temperature and usually the reaction is carried out for one hour to one day, preferably 3-12 hours .

 Derivatives of 2-phenyl-3-naphthyl-propionic acid thus obtained, which are compounds represented by the formula (V) or (Va), are important intermediate compounds of aromatic amidine derivatives described in Japanese Patent Application Laid-open (kokai) 5-208946.

 Steps A and C, steps B and C or steps A, B and C can be carried out continuously. Briefly, the compound represented by formula (III) or formula (IIIa), or its salt, which (s) are obtained in stage A, and the compound represented by formula (IV), or its salt, which (s) are obtained in stage B can be used in the subsequent step C without isolating the compounds in the corresponding steps.

 The following describes an example of the implementation of sequential stages. First, in step A, a compound represented by formula (III) or formula (IIIa) or a salt thereof is obtained by reaction in an aromatic hydrocarbon solvent in the presence of a strong base using an interphase transfer catalyst. Then, in step B, the compound represented by formula (IV) obtained by the reaction in alkyl nitrile is extracted with an aromatic hydrocarbon. Further, the compound represented by formula (III) or formula (IIIa), or its salt and the compound represented by formula (IV), interact with each other, without isolating these compounds, in a solvent mixture containing an aromatic hydrocarbon solvent and an aprotic polar solvent, in the presence of a strong base, and as a result, a compound represented by the formula (V) or the formula (Va) or a salt thereof is obtained.

 Successive steps that do not require an operation such as isolation are preferred in the industrial process. In particular, since the isolated crystals of 7-bromomethyl-2-naphthalenecarbonitrile cause skin irritation, stage B and stage C are preferably performed sequentially.

 (Step D) A method for producing an optically active compound represented by the formula (Vb).

 To obtain a compound represented by formula (Vb) from a compound represented by formula (Va), a compound represented by formula (Va) may be reacted with a base.

 Briefly, a compound represented by formula (Va), which is a mixture of an R-diastereomer and an S-diastereomer, is reacted with a base to give a compound represented by formula (Vb), which is an S-diastereomer.

 In particular, the R-diastereomer is dissolved in a solvent suitable for initiating crystallization of the S-diastereomer and, when dissolved, is reacted with a base to convert the R-diastereomer to the S-diastereomer. The target S-diastereomer is then crystallized using the solubility difference between the R-diastereomer and the S-diastereomer.

 In this case, there is no particular restriction on the solvent until it has an adverse effect on the reaction, and a solvent can be used allowing crystallization of the compounds represented by the formula (Vb). In particular, protic solvents including water and alcohols can be used. These solvents can be used individually or in combination. Protonic solvents can be mixed with aprotic polar solvents, ethers, hydrocarbons, or mixtures thereof.

 Examples of alcohols include methanol and ethanol. Examples of aprotic polar solvents include N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile. Examples of ethers include isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether. Examples of hydrocarbons include benzene, toluene, xylene, n-hexane and n-pentane.

 There is no particular limitation on the basis, as long as it does not adversely affect the reaction. Examples of the strong base include alkali metal alkoxides such as sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide or potassium tert-butoxide; alkali metal amides, such as sodium amides; alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; and alkali metal carbonates such as sodium carbonate or potassium carbonate. Strong bases are preferably used. Of these, alkali metal alkoxides are preferred, with sodium ethoxide being more preferred.

 The amount of base is not limited as long as it does not adversely affect the reaction, and it is preferably 10-30 mol% equivalent to the compound represented by formula (Va).

There is no particular limitation on the reaction temperature as long as it does not exceed the boiling point of the solvent. The reaction is usually carried out in a temperature range from -10 ^{° C.} to room temperature, preferably in a range from 10 ^{° C.} to room temperature. The reaction time varies in accordance with the reaction temperature and usually the reaction is carried out for from 30 minutes to several days, preferably 20 hours or less.

 The optically active derivatives of 2-phenyl-3-naphthalene-propionic acid thus obtained, which are compounds represented by the formula (Vb), are important intermediates of the aromatic amidine derivatives described in this reference material.

 Derivatives of aromatic amidines or their salts can be obtained from compounds represented by the formula (V), (Va) or (Vb) by the method described in Japanese Patent Application Laid-open (kokai) 5-208946.

EXAMPLES
Further, the present invention is described in detail in the examples, which should not be construed as limiting the invention.

Example 1. The method of obtaining (3R) -1-benzyl-3-methanesulfonyloxypyrrolidine
(3R) -1-Benzyl-3-pyrrolidinol (10.0 g, 56 mmol) and triethylamine (6.6 g, 65 mmol) were dissolved in toluene (100 ml) and the resulting solution was cooled to 5 ^° C. In this solution methanesulfonyl chloride (7.1 g, 62 mmol) was added dropwise over 10 minutes at 5 ^° C. After stirring the mixture for 30 minutes, toluene (100 ml) was added, after which the resulting solution was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate (200 ml) and then twice with water (100 ml). After concentrating the obtained organic layer under reduced pressure, the residue was subjected to column chromatography to obtain 9.8 g of the title compound (yield: 68%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
2.19 (1H, m), 2.30 (1H, m), 2.49 (1H, m), 2.76-2.89 (3H, m), 2.99 (3H, s), 3 64 (2H, dd, J = 12.9, 12.9 Hz), 5.20 (1H, m), 7.25-7.35 (5H, m)
Elemental analysis of C ₁₂ H ₁₇ NSO ₃ :
Calculated: C, 56.45; H, 6.71; N, 5.49.

 Found: C, 55.70; H, 6.33; N, 5.48.

FAB MC (m / z): 256 (M ⁺ +1).

Infrared Absorption Spectrum vmax (KBr) cm ^-1 : 3028, 2944, 2804, 1496, 1454, 1356, 1170, 1146, 966.

Rotation angle [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = + 14.0 ^° (c = 1, 0, MeOH).

Example 2. A method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
P-hydroxyphenylacetic acid ethyl ester (39.6 g, 0.22 mol) was dissolved in dimethylformamide (500 ml). A solution of 60% sodium hydride (8.8 g, 0.22 mol) was added to the mixture at room temperature. After forty minutes, (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (53.1 g, 0.2 mol) was added and the mixture was heated for 15 minutes at an internal temperature of 110 ^° C. The resulting mixture was cooled to room temperature. and concentrated by evaporation of the solvent under reduced pressure. To dissolve the residue, ethyl acetate (500 ml) was added to it. The resulting solution was washed 4 times with a 10% aqueous potassium hydroxide solution (100 ml). The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 39.8 g of the title compound (yield: 57%).

Melting point: 39-40 ^o C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.25 (3H, t, J = 6.9 Hz), 1.47 (9H, s), 2.08-2.17 (2H, m), 3.46-3.63 (4H, m) 3.54 (2H, s), 4.14 (2H, kV, J = 6.9 Hz), 4.86 (1H, m), 6.83 (2H, d, J = 8.3 Hz) 7.24 (2H, doublet, J = 8.3 Hz).

Elemental analysis of C ₁₉ H ₂₆ NO ₅ :
Calculated: C, 65.31; H, 7.79; N, 4.01.

 Found: C, 65.20; H, 7.59; N, 3.76.

MS (m / z): 349 (M ⁺ ).

Infrared Absorption Spectrum vmax (KBr) cm ^-1 :
2984, 1736, 1694, 1514, 1482, 1410, 1370, 1168, 1116.

Rotation angle [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = + 22.2 ^° (c = 1.0, CHCl ₃ ).

Example 3. The method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
P-hydroxyphenylacetic acid ethyl ester (39.6 g, 0.22 mol) was dissolved in dimethylformamide (500 ml) and a solution of 60% sodium hydride (8.8 g, 0.22 mol) was added to the mixture at room temperature. After forty minutes, (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (53.1 g, 0.2 mol) was added and the mixture was heated for 15 minutes at an internal temperature of 110 ^° C. The resulting mixture was cooled to room temperature. and concentrated by evaporation of the solvent under reduced pressure. To dissolve the residue, ethyl acetate (500 ml) was added to it and the resulting solution was washed 4 times with 10% aqueous potassium hydroxide solution (100 ml). Analysis by reverse phase chromatography using the product obtained in Example 2 as a standard sample showed that 43.7 g of the title compound was obtained having a purity of 70% (yield: 62%).

Example 4. A method of producing ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
The procedures of Example 3 in dimethyl sulfoxide (25 ml) were repeated, except that p-hydroxyphenylacetic acid ethyl ester (1.8 g, 10 mmol), (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (2) was used. 5 g, 10 mmol) and 60% sodium hydride (440 mg, 10 mmol). Analysis by reverse phase chromatography using the product obtained in example 2 as a standard sample showed that 1.8 g of the title compound were obtained (yield: 52%).

Example 5. A method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
The procedures of Example 3 in dimethylformamide (25 ml) were repeated, except that p-hydroxyphenylacetic acid ethyl ester (1.8 g, 10 mmol), (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (2) was used. 5 g, 10 mmol) and sodium ethoxide (0.7 g, 10 mmol). Analysis by reverse phase chromatography using the product obtained in example 2 as a standard sample showed that 1.7 g of the title compound were obtained (yield: 50%).

Example 6. The method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
The procedures of Example 3 were repeated in dimethylformamide (25 ml), except that p-hydroxyphenylacetic acid ethyl ester (2.0 g, 11 mmol), (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (2) was used. 5 g, 10 mmol) and potassium tert-butoxide (1.2 g, 11 mmol). Analysis by reverse phase chromatography using the product obtained in example 2 as a standard sample showed that 2.0 g of the title compound was obtained (yield: 58%).

Example 7. A method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid
The procedures of Example 3 were repeated in dimethylformamide (68 ml), except that p-hydroxyphenylacetic acid ethyl ester (4.0 g, 22 mmol), (3R) -1- (tert-butoxycarbonyl) -3-p-toluenesulfonyloxypyrrolidine was used (6.8 g, 20 mmol) and 60% sodium hydride (880 mg, 22 mmol). Analysis by reverse phase chromatography using the product obtained in example 2 as a standard sample showed that 4.4 g of the title compound were obtained (yield: 64%).

Example 8. The method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
P-hydroxyphenylacetic acid ethyl ester (1.8 g, 10 mmol) was dissolved in ethanol (25 ml) and sodium ethoxide (0.7 g, 10 mmol) was added to the mixture at room temperature. Forty minutes later, (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (2.5 g, 10 mmol) was added and the mixture was refluxed for 3 hours. The resulting mixture was cooled to room temperature and then concentrated to remove the solvent under reduced pressure. To dissolve the residue, ethyl acetate (30 ml) was added to it and the resulting solution was washed 4 times with 10% aqueous potassium hydroxide solution (20 ml). Analysis by reverse phase chromatography using the product obtained in Example 2 as a standard sample showed that 0.9 g of the title compound was obtained (yield: 25%).

Example 9. The method of producing ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
The procedures of Example 8 were repeated in acetonitrile (26 ml), except that p-hydroxyphenylacetic acid ethyl ester (2.0 g, 11 mmol), (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (2) was used. 5 g, 10 mmol) and 60% sodium hydride (440 mg, 11 mmol). Analysis by reverse phase chromatography using the product obtained in example 2 as a standard sample showed that 2.2 g of the title compound were obtained (yield: 64%).

Example 10. The method of obtaining ethyl ester of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenylacetic acid
P-hydroxyphenylacetic acid ethyl ester (39.6 g, 0.22 mol) was dissolved in toluene (530 ml) and then 60% sodium hydride (8.8 g, 0.22 mol) was added to the mixture at room temperature. After heating the mixture at an internal temperature of 45 ^{° C.} for one hour, (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (53.1 g, 0.2 mol) and tetra-normal butylammonium bromide (19.3 g, 60 mmol). The resulting mixture was heated at an internal temperature of 80 ^o C for 3 hours and then cooled to room temperature. The mixture was washed 3 times with a 10% aqueous potassium hydroxide solution (106 ml). Analysis by reverse phase chromatography using the product obtained in Example 2 as a standard sample showed that 49.0 g of the title compound was obtained having a purity of 79% (yield: 70%).

Example 11. A method of obtaining 7-bromomethyl-2-naphthalenecarbonitrile
To 7-methyl-2-naphthalenecarbonitrile (10.0 g, 60 mmol), 2,2'-azobisisobutyronitrile (982 mg, 6 mmol) and acetonitrile (100 ml) were added at room temperature. N-bromosuccinimide (10.6, 60 mmol) was added to the resulting mixture, and the mixture was heated under reflux for 2 hours. The resulting mixture was cooled to room temperature. For extraction, water (100 ml) and toluene (100 ml) were added to the mixture. The resulting organic layer was washed twice with water (100 ml). After concentrating the organic layer under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 11.4 g of the title compound (yield: 78%). Instrument measurements were consistent with those described in J. Med. Chem., 1991, 3105.

Example 12. A method of obtaining 7-bromomethyl-2-naphthalenecarbonitrile
To 7-methyl-2-naphthalenecarbonitrile (10.0 g, 60 mmol) was added at room temperature 2,2'-azobisisobutyronitrile (982 mg, 6 mmol) and acetonitrile (100 ml). N-bromosuccinimide (10.6 g, 60 mmol) was added to the resulting mixture, and the mixture was refluxed for 2 hours. The resulting mixture was cooled to room temperature. For extraction, water (100 ml) and toluene (100 ml) were added to the mixture. The resulting organic layer was washed twice with water (100 ml). After concentrating the organic layer under reduced pressure, analysis by reverse phase chromatography using the product obtained in Example 11 as a standard sample showed that 12.1 g of the title compound was obtained (yield: 82%).

Example 13. A method of obtaining 7-bromomethyl-2-naphthalenecarbonitrile
To 7-methyl-2-naphthalenecarbonitrile (5.0 g, 30 mmol) was added at room temperature 2,2'-azobisisobutyronitrile (491 mg, 3 mmol) and propionitrile (50 ml). To the resulting mixture was added N-bromosuccinimide (5.3 g, 30 mmol), and the mixture was heated at an internal temperature of 80 ^{° C.} for 4 hours. After that, the experiment was carried out as in Example 12. Analysis by reverse phase chromatography using the product obtained in Example 11 as a standard sample showed that 1.9 g of the title compound were obtained (yield: 82%).

Example 14. The method of obtaining 7-bromomethyl-2-naphthalenecarbonitrile
To 7-methyl-2-naphthalenecarbonitrile (5.0 g, 30 mmol) was added at room temperature 2,2'-azobisisobutyronitrile (491 mg, 3 mmol) and n-butyronitrile (50 ml). To the resulting mixture was added N-bromosuccinimide (5.3 g, 30 mmol) and the mixture was heated at an internal temperature of 80 ^{° C.} for 2 hours. After that, the experiment was carried out as in example 12. Analysis by reverse phase chromatography using the product obtained in example 11 as a standard sample showed that 5.4 g of the title compound 9 were obtained; yield: 74%).

Example 15. The method of obtaining 7-bromomethyl-2-naphthalenecarbonitrile
To 7-methyl-2-naphthalenecarbonitrile (5.0 g, 30 mmol), 2,2'-azobisisobutyronitrile (491 mg, 3 mmol) and isobutyronitrile (50 ml) were added at room temperature. To the resulting mixture was added N-bromosuccinimide (5.3 g, 30 mmol) and the mixture was heated at an internal temperature of 80 ^{° C.} for 2 hours. After that, the experiment was carried out as in example 12. Analysis by reverse phase chromatography using the product obtained in example 11, as
A standard sample showed that 4.3 g of the title compound were obtained (yield: 58%).

Example 16. The method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (1.8 g, 5 mmol) obtained in Example 2 and 7-bromomethyl-2- naphthalenecarbonitrile (1.5 g, 6 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (0.2 g, 5.5 mmol) was added and the mixture was stirred at the same temperature for 2.5 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and washed three times with water (10 ml). After concentrating the obtained organic layer under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 2.37 g of the title compound (yield: 89%). The measurement data of the devices corresponded to the data of reference example 35 described in Japanese Patent Application Laid-open (kokai) 5-208946.

Example 17. The method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (40.0 g, 0.12 mol, 79% purity) obtained in Example 3, and 7-bromomethyl-2-naphthalenecarbonitrile (33.8 g, 0.14 mol) was dissolved in dimethylformamide (340 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (5.0 g, 0.13) was added. mol) and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was diluted with ethyl acetate (680 ml) and washed three times with water (170 ml). Analysis by reverse phase chromatography using the product obtained in Example 16 as a standard sample showed that 54.1 g of the title compound was obtained having a purity of 66% (yield: 92%).

Example 18. The method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (40.0 g, 0.12 mol, 79% purity) obtained in Example 10, and 7-bromomethyl-2-naphthalenecarbonitrile (33.8 g, 0.14 mol) was dissolved in dimethylformamide (400 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (5.0 g, 0.13) was added. mol) and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was diluted with ethyl acetate (800 ml) and washed three times with water (200 ml). Analysis by reverse phase chromatography using the product obtained in Example 16 as a standard sample showed that 53.5 g of the title compound was obtained having a purity of 67% (yield: 91%).

Example 19. A method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 were repeated in dimethylformamide having 0.2% water (10 ml), except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) 3-pyrrolidinyl] hydroxy] phenylacetate was used. acids (1.0 g, 2.8 mmol); 7-bromomethyl-2-naphthalenecarbonitrile (0.7 g, 2.8 mol) 60% sodium hydride (0.1 g, 3.1 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 1.3 g of the title compound were obtained (yield: 90%).

Example 20. A method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 were repeated in a mixture consisting of dimethylformamide (7.5 ml) and toluene (7.5 ml), except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) ethyl ester was used -3-pyrrolidinyl] oxy] phenylacetic acid (1.8 g, 5 mmol), 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) 60% sodium hydride (0.2 g, 5.5 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 2.7 g of the title compound were obtained (yield: 92%).

Example 21. A method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 were repeated in a mixture of triethylene glycol dimethyl ether (9 ml) and toluene (9 ml), except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3 ethyl ester was used -pyrrolidinyl] oxy] phenylacetic acid (1.8 g, 5 mmol), 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) and 60% sodium hydride (0.2 g, 5.5 mmol ) Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 1.8 g of the title compound were obtained (yield: 71%).

Example 22. A method of producing ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] atybk-3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 were repeated in triethylene glycol dimethyl ether (46 ml), except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (3, 5 g, 10 mmol), 7-bromomethyl-2-naphthalenecarbonitrile (3.0 g, 12 mmol) and 60% sodium hydride (0.4 g, 11 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 4.4 g of the title compound were obtained (yield: 86%).

Example 23. The method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 in dimethylformamide (15 ml) were repeated, except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (1.7 g) was used. 5 mmol), 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) and sodium ethoxide (0.4 g, 5.5 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 1.6 g of the title compound were obtained (yield: 65%).

Example 24. A method of obtaining ethyl ester of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 in dimethylformamide (15 ml) were repeated, except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (1.7 g) was used. 5 mmol), 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) and potassium tert-butoxide (0.6 g, 5.5 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 1.0 g of the title compound was obtained (yield: 38%).

Example 25. Method for the production of ethyl 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 in dimethylformamide (10 ml) were repeated, except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (1.0 g) was used. 2.8 mmol), 7-chloromethyl-2-naphthalenecarbonitrile (0.6 g, 2.8 mmol) and sodium hydride (0.1 g, 3.1 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 0.9 g of the title compound was obtained (yield: 61%).

Example 26. Method for the production of ethyl 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl-3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 17 in dimethylformamide (10 ml) were repeated, except that 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (1.0 g) was used. 2.8 mmol), 7-p-toluenesulfonyloxymethyl-2-naphthalenecarbonitrile (0.9 g, 2.8 mmol) and 60% sodium hydride (0.1 g, 3.1 mmol). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 0.9 g of the title compound was obtained (yield: 64%).

Example 27. Method for the production of ethyl 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
P-hydroxyphenylacetic acid ethyl ester (1.4 g, 7.9 mmol) was dissolved in toluene (20 ml), and then 60% sodium hydride (310 mg, 7.9 mmol) was added to the mixture at room temperature. After heating the mixture at an internal temperature of 45 ^{° C.} for one hour, (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (1.9 g, 7.1 mmol) and tetra-normal butylammonium bromide (690 mg, 2, 4 mmol). The resulting mixture was heated at an internal temperature of 80 ^o C for 3 hours and then cooled to room temperature. The mixture was washed 3 times with 10% aqueous potassium hydroxide solution (4 ml). Analysis by reverse phase chromatography using the product obtained in example 2 as a standard sample showed that 1.7 g of 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl ethyl ester were obtained ] hydroxy] phenylacetic acid (yield: 70%).

Without concentrating the resulting organic layer, 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) and dimethylformamide (20 ml) were added, and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (220 mg, 5 5 mmol) and the resulting mixture was stirred at the same temperature for 10 hours. The reaction mixture was washed three times with water (20 ml). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 2.4 g of the title compound were obtained (yield: 92%). The total yield for two stages was 64%.

Example 28. Method for the production of ethyl 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
The procedures of Example 27 were repeated, except that p-hydroxyphenylacetic acid ethyl ester (1.4 g, 7.9 mmol), toluene (20 ml), 60% sodium hydride (310 mg, 7.9 mmol, (3R) -1- (tert-butoxycarbonyl) -3-methanesulfonyloxypyrrolidine (1.9 g, 7.1 mmol) and tetra-normal butylammonium bromide (690 mg, 2.4 mmol). Analysis of the obtained organic layer by reverse phase chromatography using the product obtained in example 2, as a standard sample, showed that 1.7 g of ethyl 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrro was obtained lidinyl] hydroxy] phenylacetic acid (yield: 70%).

 Without concentrating the resulting organic layer, 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) and dimethylformamide (20 ml) were added, followed by 60% sodium hydride (220 mg, 5.5 mmol) and the resulting mixture stirred at room temperature for 8 hours. The reaction mixture was washed three times with water (20 ml). Analysis by reverse phase chromatography using the product obtained in example 16 as a standard sample showed that 2.3 g of the title compound were obtained (yield: 88%). The total yield for the two stages was 61%.

Example 29. Method for the production of ethyl 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
To 7-methyl-2-naphthalenecarbonitrile (6.3 g, 38 mmol) was added at room temperature 2,2'-azobisisobutyronitrile (624 mg, 3.8 mmol) and acetonitrile (65 ml). N-bromosuccinimide (6.8 g, 38 mmol) was added to the resulting mixture, and the mixture was refluxed for 2 hours. The resulting mixture was cooled to room temperature. Water (65 ml) and toluene (65 ml) were added to the mixture for extraction. The resulting organic layer was washed twice with water (65 ml). Analysis by reverse phase chromatography using the product obtained in Example 11 as a standard sample showed that 7.4 g of 7-bromomethyl-2-naphthalenecarbonitrile was obtained (yield: 80%).

Without concentrating this organic layer, 2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (8.7 g, 25 mmol, 79% purity) was added to it. obtained in Example 10 and dimethylformamide (81 ml) and the resulting mixture were cooled to 0 ^° C. Then 60% sodium hydride (1.1 g, 27.5 mmol) was added and the resulting mixture was stirred at the same temperature for 5:00. The resulting solution was diluted with toluene (40 ml) and washed three times with water (80 ml). The resulting organic layer was concentrated under reduced pressure. Analysis of the residue (19.3 g) by reverse phase chromatography using the product obtained in Example 16 as a standard sample showed that 11.7 g of the title compound was obtained (yield: 91%).

Example 30. Method for the preparation of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid methyl ester
2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid methyl ester (1.7 g, 5 mmol and 7-bromomethyl-2-naphthalenecarbonitrile (1.4 g) 5.5 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (0.2 g, 5.5 mmol) was added and the resulting mixture was stirred at the same temperature for 3 hours The resulting mixture was diluted with ethyl acetate (30 ml) and washed three times with water (10 ml). The resulting organic layer was concentrated under reduced pressure and the residue was subjected to column chromium silica gel chromatography to give 2.3 g of the title compound (yield: 93%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.47 (9H, s), 2.14 (2H, m),
3.19 (1H, doublet of doublets, J = 6.9, 13.9 Hz),
3.55 (5H, m), 3.60 (3H, s), 3.90 (1H, w),
4.86 (1H, m), 6.83 (2H, d, J = 8.6 Hz),
7.23 (2H, doublet, J = 8.3 Hz),
7.41 (1H, doublet of doublets, J = 1.5, 8.3 Hz),
7.56 (1H, doublet of doublets, J = 1.5, 8.3 Hz),
7.61 (1H, s), 7.78 (1H, d, J = 8.3 Hz),
7.85 (1H, d, J = 8.3 Hz), 8.13 (1H, s).

Example 31. Method for the preparation of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid isopropyl ester
2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid isopropyl ester (1.8 g, 5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g, 6 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (0.2 g, 5.5 mmol) was added and the resulting mixture was stirred at the same temperature for 3 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and washed three times with water (10 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 2.4 g of the title compound (yield: 92%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.05 (3H, d, J = 6.3 Hz),
1.08 (3H, d, J = 5.6 Hz),
2.14 (2H, m), 3.17 (1H, dd, J = 6.6, 13.7 Hz,
3.55 (5H, m), 3.85 (1H, w), 4.86 (1H, m),
4.90 (1H, m), 6.83 (2H, d, J = 8.6 Hz),
7.23 (2H, br), 7.42 (1H, d, J = 8.3 Hz),
7.55 (1H, doublet of doublets, J = 1.6, 8.6 Hz),
7.62 (1H, s), 7.79 (1H, d, J = 8.6 Hz),
7.84 (1H, d, J = 8.6 Hz), 8.113 (1H, s)
Example 32. Method for the production of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid tert-butyl ester
2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid tert-butyl ester (1.9 g, 5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (1, 5 g, 6 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (0.2 g, 5.5 mmol) was added and the resulting mixture was stirred at the same temperature for 4 hours, followed by stirring at room temperature for 4 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and washed three times with water (10 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 2.1 g of the title compound (yield: 79%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.30 (9H, s), 1.47 (9H, s), 2.13 (2H, m),
3.13 (1H, doublet of doublets, J = 6.6, 13.9 Hz),
3.52 (5H, m), 3.79 (1H, w), 4.87 (1H, m),
6.83 (2H, d, J = 8.6 Hz),
7.21 (2H, d, J = 8.3 Hz),
7.43 (1H, d, J = 7.6 Hz),
7.55 (1H, d, J = 7.6 Hz), 7.62 (1H, s),
7.77 (1H, d, J = 8.6 Hz),
7.86 (1H, d, J = 8.6 Hz), 8.13 (1H, s)
Example 33. Method for the preparation of 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid benzyl ester
2- [4 - [(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenylacetic acid benzyl ester (2.1 g, 5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (1.5 g , 6 mmol) was dissolved in dimethylformamide (15 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (0.2 g, 5.5 mmol) was added and the resulting mixture was stirred at the same temperature for 3 hours . The resulting mixture was diluted with ethyl acetate (30 ml) and washed three times with water (10 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 2.6 g of the title compound (yield: 90%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.47 (9H, s), 2.11 (2H, m), 3.17 (1H, dd),
3.51 (5H, m), 3.93 (1H, w), 4.83 (1H, m),
4.92 (1 H, doublet, J = 13.2 Hz),
5.10 (1H, d, J = 9.9 Hz),
6.83 (2H, d, J = 8.6 Hz),
7.05 - 8.30 (7H, m),
7.39 (1H, d, J = 8.2 Hz),
7.52 (1H, d, J = 9.9 Hz), 7.55 (1H, s),
7.72 (1H, d, J = 8.6 Hz),
7.83 (1H, d, J = 8.6 Hz), 7.99 (1H, s)
Example 34. Method for the preparation of 2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester
P-hydroxyphenylacetic acid ethyl ester (9.1 g, 49.5 mmol) was dissolved in dimethylformamide (120 ml) and 60% sodium hydride (2.0 g, 49.5 mmol) was added to the mixture at room temperature. Forty minutes later, (3R) -1-benzyl-3-methanesulfonyloxypyrrolidine (11.5 g, 45 mmol) was added and the resulting mixture was immediately heated in an oil bath at a temperature of 135 ^° C. After heating at an internal temperature of 110 ^° C. for 15 minutes, the mixture was cooled to room temperature. The mixture was then concentrated to remove the solvent under reduced pressure, and ethyl acetate (120 ml) was added to dissolve the residue. The resulting mixture was washed three times with a 10% aqueous potassium hydroxide solution (24 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 10.9 g of the title compound (yield: 71%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.24 (3H, t, J = 6.9 Hz), 1.98 (1H, m),
2.29 (1H, m), 2.60 (1H, m), 2.74 (2H, m),
2.98 (1H, dd, 6.3, 6.3 Hz), 3.52 (2H, s),
3.67 (2H, dd, 12.9, 12.9 Hz),
4.13 (2H, kB, J = 6.9 Hz), 4.80 (1H, m),
6.78 (2H, d, J = 8.6 Hz),
7.15 (2H, d, J = 8.9 Hz),
7.24-7.35 (5H, m)
Elemental analysis of C ₂₁ H ₂₅ NO ₃ :
Calculated: C, 74.31; H, 7.42; N, 4.13.

 Found: C, 73.82; H, 7.36; N, 4.01.

FAB MC (m / z): 340 (M ⁺ +1).

Infrared Absorption Spectrum vmax (KBr) cm ^-1 :
2984, 2800, 1732, 1614, 1512, 1296, 1244, 1148, 1028.

Rotation angle [α] $\genfrac{}{}{0ex}{}{\text{24}}{\text{D}}$ = + 7.8 ^o (c = l, 0, CHCl ₃ ).

Example 35. Method for the production of ethyl 2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] acetic acid
P-hydroxyphenylacetic acid ethyl ester (9.9 g, 55 mmol) was dissolved in dimethylformamide (120 ml) and 60% sodium hydride (2.2 g, 55 mmol) was added to the mixture at room temperature. After 40 minutes, (3R) -1-benzyl-3-methanesulfonyloxypyrrolidine (12.8 g, 50 mmol) was added and the resulting mixture was immediately heated in an oil bath at a temperature of 135 ^° C. After heating at an internal temperature of 110 ^{° C.} for 15 minutes, the mixture was cooled to room temperature. The mixture was then concentrated to remove the solvent under reduced pressure, and ethyl acetate (120 ml) was added to dissolve the residue. The resulting mixture was washed three times with a 10% aqueous potassium hydroxide solution (24 ml). The obtained organic layer was concentrated under reduced pressure, and analysis of the residue by reverse phase chromatography using the product obtained in Example 34 as a standard sample showed that 12.2 g of the title compound were obtained (yield 72%, purity 82%).

Example 36. Method for the production of ethyl 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (1.0 g, 3 mmol) obtained in Example 34 and 7-bromomethyl-2-naphthalenecarbonitrile (0, 9 g, 3.6 mmol) was dissolved in dimethylformamide (10 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (0.1 g, 3.3 mmol) was added and the mixture was stirred at the same temperature in within 1.5 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and washed three times with water (10 ml). After concentrating the obtained organic layer under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 0.3 g of the title compound (yield: 20%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.10 (3H, t, J = 6.9 Hz), 1.97 (1H, m),
2.28 (1H, m), 2.60 (1H, m), 2.74 (2H, m),
2.97 (1H, m),
3.16 (1H, dd, J = 6.9, 13.5 Hz),
3.54 (1H, dd, J = 8.9, 13.5 Hz),
3.67 (2H, dd, J = 12.9, 12.9 Hz),
3.85 (1H, dd, J = 6.9, 8.6 Hz),
3.99-4.13 (2H, m), 4.79 (1H, m),
6.76 (2H, d, J = 8.6 Hz),
7.20 (2H, d, J = 8.6 Hz), 7.23-7.34 (5H, m),
8.41 (1H, d, J = 8.3 Hz),
7.54 (1H, dd, J = 8.6, 8.6 Hz), 7.60 (1H, s),
7.76 (1H, d, J = 8.6 Hz),
7.85 (1H, d, J = 8.6 Hz), 8.11 (1H, s)
Rotation angle [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = + 3.9 ^o (c = l, 0, CHCl ₃ ).

Example 37. Method for the preparation of 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (500 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml) and the mixture was cooled to -10 ^° C. Then 60% sodium hydride (60 mg, 1.5 mmol) was added and the mixture was stirred at the same temperature for 0.5 hours. Thereafter, 7-bromomethyl-2-naphthalenecarbonitrile (370 mg, 1.5 mmol) was gradually added to the mixture, and the resulting mixture was stirred at the same temperature for 4 hours. The resulting mixture was diluted with ethyl acetate (15 ml) and washed three times with water (5 ml). After concentrating the obtained organic layer under reduced pressure, analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 480 mg of the title compound were obtained (64% yield).

Example 38. Method for the preparation of 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl-3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (0.5 g, 1.5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (440 mg, 1.8 mmol) was dissolved in dimethoxyethane (5 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (66 mg, 1.65 mmol) was added and the mixture was stirred at the same temperature for 5 hours. After this, the procedure of Example 37 was repeated. Analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 158 mg of the title compound was obtained (yield 21%).

Example 39. Method for the preparation of ethyl 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (0.5 g, 1.5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (440 mg, 1, 8 mmol) was dissolved in diethylene glycol dimethyl ether (5 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (66 mg, 1.65 mmol) was added and the mixture was stirred at the same temperature for 5 hours. Thereafter, the procedure of Example 37 was repeated. Analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 555 mg of the title compound was obtained (73% yield).

Example 40. Method for the preparation of 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (0.5 g, 1.5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (440 mg, 1, 8 mmol) was dissolved in triethylene glycol dimethyl ether (5 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (66 mg, 1.65 mmol) was added and the mixture was stirred at the same temperature for 6 hours. After this, the procedure of Example 37 was repeated. Analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 647 mg of the title compound was obtained (85% yield).

Example 41. Method for the preparation of 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (500 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml) and the mixture was cooled to -10 ^° C. Then sodium ethoxide (102 mg, 1.5 mmol) was added and the mixture was stirred at the same temperature for 0.5 hours. After this, 7-bromomethyl-2-naphthalenecarbonitrile (370 mg, 1.5 mmol) was gradually added to the mixture, and the resulting mixture was stirred at the same temperature for 3 hours. Next, the procedures of Example 37 were repeated. Analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 332 mg of the title compound was obtained (44% yield).

Example 42. Method for the preparation of 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (500 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml) and the mixture was cooled to -10 ^° C. Then sodium amide (60 mg, 1.5 mmol) was added and the mixture was stirred at the same temperature for 0.5 hours. Thereafter, 7-bromomethyl-2-naphthalenecarbonitrile (370 mg, 1.5 mmol) was gradually added to the mixture, and the resulting mixture was stirred at the same temperature for 2 hours. Next, the procedures of Example 37 were repeated. Analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 158 mg of the title compound was obtained (yield 21%).

Example 43. Method for the production of ethyl 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (500 mg, 1.5 mmol) and 7-bromomethyl-2-naphthalenecarbonitrile (363 mg, 1.8 mmol) was dissolved in dimethylformamide (5 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (66 mg, 1.65 mmol) was added and the mixture was stirred at the same temperature for 3 hours. After this, the procedure of Example 37 was repeated. Analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 473 mg of the title compound was obtained (yield 62%).

Example 44. Method for the preparation of 2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenylacetic acid ethyl ester (6.4 g, 16 mmol, 82% pure) and 7-bromomethyl-2-naphthalenecarbonitrile (4.7 g, 19.2 mmol) was dissolved in triethylene glycol dimethyl ether (54 ml) and the mixture was cooled to 0 ^° C. Then 60% sodium hydride (704 mg, 17.6 mmol) was added and the mixture was stirred at the same temperature for 8 ocloc'k. The resulting mixture was diluted with ethyl acetate (108 ml) and washed three times with water (216 ml). After concentrating the obtained organic layer under reduced pressure, analysis by reverse phase chromatography using the product obtained in Example 36 as a standard sample showed that 6.4 g of the title compound were obtained (yield 79%).

Example 45. Method for the production of (2S) -2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl-3- (7-cyano-2-naphthyl) propionic ethyl ester acid
2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester (54.1 g, 0 , 11 mol, purity 66%) obtained in Example 17 was heated and dissolved in ethanol (180 ml), and the resulting mixture was cooled to room temperature with stirring, and the crystals precipitated. Then sodium ethoxide (1.1 g, 15.8 mmol) was added, followed by stirring at the same temperature for 30 minutes, after which additional sodium ethoxide (1.1 g, 15.8 mmol) was added, followed by stirring for 18 hours. The crystals were collected by filtration and washed with ethanol (55 ml). HPLC analysis (high performance liquid chromatography) under the conditions of Reference Example 49 described in Japanese Patent Application Laid-Open (kokai) 5-208946 for Japan showed that the crystals had a diastereomeric purity of 94.7%. The crystals were dissolved in ethyl acetate (1228 ml) and washed three times with water (250 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was recrystallized from ethanol (550 ml) to obtain 47.6 g of the title compound (88% yield). The measurement data of the devices corresponded to the data of reference example 49 described in Japanese Patent Application Laid-open (kokai) 5-208946. The diastereomeric purity of the crystals was 99.5%.

Example 46. Method for the production of (2S) -2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) ethyl ester propionic acid
2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester (50.0 g, 0 , 10 mol, purity 67%) obtained in Example 18 was heated and dissolved in ethanol (165 ml), and the resulting solution was cooled to room temperature with stirring with precipitation of crystals. Then sodium ethoxide (1.0 g, 14.6 mol) was added, followed by stirring at the same temperature for 30 minutes, after which additional sodium ethoxide (1.0 g, 14.6 mmol) was added, followed by stirring for 18 hours. The crystals were collected by filtration and washed with ethanol (50 ml). The crystals were found to have a diastereomeric purity of 93.5%. The crystals were dissolved in ethyl acetate (1900 ml) and washed three times with water (240 ml). The organic layer was concentrated under reduced pressure, and the residue was recrystallized from ethanol (500 ml) to obtain 43.8 g of the title compound (88% yield). The diastereomeric purity of the crystals was 99.6%.

Example 47. A method of producing ethyl ester (2S) -2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester (11.3 g, 21 , 9 mmol, purity 61%) obtained in Example 29 was heated and dissolved in ethanol (40 ml), and the resulting solution was cooled to room temperature with stirring with precipitation of crystals. Then sodium ethoxide (235 mg, 3.28 mmol) was added, followed by stirring at the same temperature for 30 minutes, after which additional sodium ethoxide (235 mg, 3.28 mmol) was added, followed by stirring for 18 hours. The crystals were collected by filtration and washed with ethanol (10 ml). The resulting crystals had a diastereomeric purity of 92.8%. The crystals were dissolved in ethyl acetate (250 ml) and washed three times with water (50 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was recrystallized twice from ethanol (120 ml, 100 ml) to give 9.23 g of the title compound (yield 82%). The diastereomeric purity of the crystals was 99.8%.

Example 48. A method of producing ethyl ester (2S) -2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester (1.90 g, 3 , 7 mmol) was heated and dissolved in ethanol (6 ml) and the resulting solution was cooled to room temperature with stirring with precipitation of crystals. Then sodium amide (22 mg, 0.6 mmol) was added, followed by stirring at the same temperature for 30 minutes, after which additional sodium amide (22 mg, 0.6 mmol) was added, followed by stirring for 18 hours. The crystals were collected by filtration to obtain 1.48 g of the title compound (78% yield). The diastereomeric purity of the crystals was 92.3%.

Example 49. A method of producing ethyl ester of (2S) -2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid
2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl-3- (7-cyano-2-naphthyl) propionic acid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (25 ml) and the resulting solution was cooled to room temperature with stirring with precipitation of crystals. Then sodium ethoxide (100 mg, 1.5 mmol) was added, followed by stirring at the same temperature for one hour, after which additional sodium ethoxide (100 mg, 1.5 mmol) was added, followed by stirring for 15 hours. The crystals were collected by filtration to obtain 3.3 g of the title compound (yield 66%). HPLC analysis showed that the obtained crystals had a diastereomeric purity of 82%. The crystals were dissolved in ethyl acetate (75 ml) and washed three times with water (50 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was recrystallized twice from ethanol (31 ml, 23 ml) to obtain 2.1 g of the title compound (yield 43%). The diastereomeric purity of the crystals was 99.1%.

Melting point: 95.0-95.5 ^o C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ:
1.10 (3H, t, J = 6.9 Hz), 1.98 (1 N, m),
2.28 (1H, m), 2.60 (1H, m), 2.74 (2H, m),
2.98 (1H, doublet of doublets, J = 6.9, 8.6 Hz),
3.16 (1H, doublet of doublets, J = 6.9, 13.5 Hz),
3.54 (1H, doublet of doublets, J = 8.6, 13.5 Hz),
3.67 (2H, dd, J = 12.9, 12.9 Hz),
3.85 (1 H, doublet of doublets, J = 6.9, 8.6 Hz),
3.996-4.12 (2H, m), 4.79 (1H, m),
6.76 (2H, d, J = 8.6 Hz),
7.19 (2H, d, J = 8.9 Hz), 7.24-7.35 (5H, m),
7.41 (1H, doublet of doublets, J = 8.3, 8.6 Hz),
7.54 (1H, doublet of doublets, J = 8.3, 8.6 Hz), 7.60 (1H, s),
7.71 (1H, d, J = 8.6 Hz),
7.84 (1H, d, J = 8.6 Hz), 8.11 (1H, s)
Elemental analysis of C ₃₃ H ₃₂ N ₂ O ₄ :
Calculated: C, 78.55; H, 6.39; N, 5, 55.

 Found: C, 78.40; H, 6.48; N, 5.35.

MS (m / z): 504 (M ⁺ ).

Infrared absorption spectrum vmax (KBr) cm ^-1 : 2800, 2232, 1730, 1610, 1512, 1254, 1156, 850.

Rotation angle [α] $\genfrac{}{}{0ex}{}{\text{22}}{\text{D}}$ = + 112.5 ^° (c = 1.0, CHCl ₃ ).

Example 50. Method for the production of (2S) -2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] hydroxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (50 ml), and the resulting solution was cooled to room temperature with stirring with precipitation of crystals. Then sodium ethoxide (100 mg, 1.5 mmol) was added, followed by stirring at the same temperature for one hour, after which additional sodium ethoxide (100 mg, 1.5 mmol) was added, followed by stirring for 15 hours. The crystals were collected by filtration to obtain 2.9 g of the title compound (58% yield). HPLC analysis showed that the obtained crystals had a diastereomeric purity of 84%. The crystals were dissolved in ethyl acetate (66 ml) and washed three times with water (50 ml). The resulting organic layer was concentrated under reduced pressure, and the residue was recrystallized twice from ethanol (14.5 ml, 12 ml) to obtain 2.0 g of the title compound (yield 40%). The diastereomeric purity of the crystals was 93%.

Example 51. Method for the production of (2S) -2- [4 - [[((3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester
2- [4 - [[(3S) -1-benzyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester (5 g, 9.9 mmol) was heated and dissolved in ethanol (15 ml), and the resulting solution was cooled to room temperature with stirring with precipitation of crystals. Then sodium ethoxide (100 mg, 1.5 mmol) was added, followed by stirring at the same temperature for one hour, after which additional sodium ethoxide (100 mg, 1.5 mmol) was added, followed by stirring for 15 hours. The crystals were collected by filtration to obtain 3.9 g of the title compound (yield 77%). HPLC analysis showed that the obtained crystals had a diastereomeric purity of 47%.

Industrial application
In accordance with the present invention, a method for producing derivatives of 2-phenyl-3-naphthylpropionic acid and its optically active compounds, which play an important role as intermediates for the preparation of aromatic amidine derivatives, which have an anticoagulant effect based on excellent inhibitory activity against activated coagulation factor X. The method of the present invention is not only technologically simpler, but also cost-effective. Thus, the method of the present invention is a technologically and economically suitable method for industrial production.

Claims (29)

1. The method of obtaining the compounds of formula III or its salts

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an alkyl group having 1-6 carbon atoms),
characterized in that they carry out the interaction of the compounds represented by formula I

(where R ¹ has the meaning defined above and R ² represents a methanesulfonyl group or a p-toluenesulfonyl group)
with the compound represented by formula II

(where R ³ has the meaning defined above)
in the presence of a base. 2. The method of obtaining according to claim 1, the compounds of formula IIIa or its salts

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an alkyl group having 1-6 carbon atoms),
characterized in that carry out the interaction of the compounds represented by formula Ia

(where R ¹ has the meaning defined above and R ² represents a methanesulfonyl group or a p-toluenesulfonyl group)
with the compound represented by formula II

(where R ³ has the meaning defined above) in the presence of a base.  3. The method according to p. 1 or 2, in which the reaction is carried out in the presence of a catalyst.  4. The method of claim 3, wherein the catalyst is an interphase transfer catalyst.  5. The method according to p. 3 or 4, in which the catalyst is an oleophilic salt of a Quaternary ammonium.  6. The method according to any one of paragraphs. 3-5, in which the catalyst is tetra (n-butyl) ammonium bromide.  7. The method according to any one of paragraphs. 1-6, in which the base is a strong base.  8. The method according to any one of paragraphs. 1-7, in which the base is an alkali metal hydride.  9. The method according to any one of paragraphs. 1-8, in which the base is sodium hydride.  10. The method according to any one of paragraphs. 1-9, in which the reaction is carried out in an aromatic hydrocarbon.  11. The method according to any one of paragraphs. 1-10, in which the reaction is carried out in toluene. 12. The method of obtaining the compounds of formula V or its salts

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an alkyl group having 1-6 carbon atoms)
characterized in that they carry out the interaction of the compounds represented by formula III

(where R ¹ and R ³ have the meanings given above)
with the compound represented by formula IV

(where X ¹ represents a halogen atom, p-toluenesulfonyloxy)
in the presence of a base. 13. The method of obtaining according to claim 12, the compounds of formula Va or its salts

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an alkyl group having 1-6 carbon atoms)
characterized in that it comprises reacting a compound represented by formula IIIa

(where R ¹ and R ³ are as defined above)
with the compound represented by formula IV

(where X ¹ represents a halogen atom, p-toluenesulfonyloxy)
in the presence of a base.  14. The method according to p. 12 or 13, in which the base is a strong base.  15. The method according to any one of paragraphs. 12-14, in which the base is an alkali metal hydride.  16. The method according to any one of paragraphs. 12-15, in which the base is sodium hydride.  17. The method according to any one of paragraphs. 12-16, in which the reaction is carried out in a mixture of an aprotic polar solvent and an aromatic hydrocarbon.  18. The method according to any one of paragraphs. 12-17, in which the reaction is carried out in a mixture of N, N-dimethylformamide and toluene.  19. The method according to any one of paragraphs. 12 or 14-18, in which the compound of formula III is obtained by the method according to any one of paragraphs. 1 or 3-11.  20. The method according to any one of paragraphs. 13-18, in which the compound of formula IIIa is obtained by the method according to any one of paragraphs. 2-11. 21. A method of obtaining a compound represented by formula Vb

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an aralkyl group or an alkyl group having 1-6 carbon atoms)
characterized in that the compound represented by formula Va

(where R ¹ and R ³ have the meanings given above)
dissolved in a proton solvent and reacted with a base.  22. The method according to p. 21, in which the base is an alkali metal alkoxide.  23. The method according to p. 21 or 22, in which the base is sodium ethoxide.  24. The method according to any one of paragraphs. 21-23, in which the reaction is carried out in alcohol.  25. The method according to any one of paragraphs. 21-24, in which the reaction is carried out in ethanol.  26. The method according to any one of paragraphs. 21-25, in which the compound of formula (Va) is obtained by the method according to any one of paragraphs. 13-20.  27. The method of producing according to Claim 21 ethyl 2 (S) -2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano- 2-naphthyl) propionic acid, characterized in that the reaction of ethyl ester 2- [4 - [[(3S) -1- (tert-butoxycarbonyl) -3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano- 2-naphthyl) propionic acid with sodium ethoxide in ethanol. 28. The compound represented by formula III

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an alkyl group having 1-6 carbon atoms)
or its salt. 29. The compound of claim 28, represented by formula IIIa

(where R ¹ represents tert-butoxycarbonyl, benzyl and R ³ represents an alkyl group having 1-6 carbon atoms), or a salt thereof. Priority on points:
09/06/1996, application 8/237013 according to claims. 1-11, 12-20,28,29;
09/06/1996, application 8/237014 in claims. 21-26, 27.

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