JP3266603B2 - Method for producing 3- (7-amidino-2-naphthyl) -2-phenylpropionic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an intermediate for producing an aromatic amidine derivative having an anticoagulant effect based on an excellent activated blood coagulation factor X inhibitory effect (JP-A-5-208946) and its production. About the method.

[0002]

2. Description of the Related Art The general formula (3)

[0003]

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In the formula, R ¹ represents a hydrogen atom or an alkyl group. R ² is a hydrogen atom, an alkyl group, a formyl group, an alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl group, an alkanoimidoyl group, a benzimidoyl group, a carboxyl group, an alkoxycarbonyl group, or a carboxyalkyl group , An alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino group, an alkanoylaminoalkyl group, an aralkyl group or an aralkyloxycarbonyl group. The compound represented by｝ and a salt thereof are known as intermediates of the aromatic amidine derivative described in JP-A-5-208946. Further, the manufacturing method described in the publication is also known. The production method means a compound represented by the general formula (1)
It is called a nitrile form (1). ) Or a salt thereof is reacted with ethanol in the presence of an acid, and the resulting compound represented by the general formula (4) or a salt thereof is reacted with ammonia to give a compound represented by the general formula (3) , Amidine derivative (3)) or a salt thereof.

[0005]

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In the reaction scheme, R ¹ and R ² are the same as described above. Et represents an ethyl group. However, in the above-described production method, when R ² is a substituent that can be cleaved by an acid (such as an alkoxycarbonyl group such as a tertiary-butoxycarbonyl group), it causes a by-product. In addition, since the epimerization partially proceeds to lower the optical purity, the reaction is kept at a low temperature in order to suppress the epimerization.
As a result, it takes more than one week to synthesize the amidine compound (3) or its salt from the nitrile compound (1) or its salt. Furthermore, it cannot be said that it is suitable for large-scale production, for example, a large amount of hydrogen chloride gas and ammonia gas must be used.

[0007]

The inventors of the present invention have conducted intensive studies, and as a result, have found an industrial production method that can be produced on a large scale in a short period of time with a good yield without lowering the optical purity. The present invention has been completed.

The production method of the present invention comprises the following reaction scheme -I
And the reaction scheme -II.

[0009]

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[0010]

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{Reaction Scheme-I and Reaction Scheme-II
In the formula, R ³ represents a hydrogen atom, an alkyl group or an alkanoyl group, and R ¹ and R ² are the same as described above. ｝ That is, the method of the present invention comprises reacting a nitrile compound (1) or a salt thereof or a compound represented by the general formula (I) (hereinafter, referred to as a nitrile compound (I)) or a salt thereof with a hydroxylamine, The obtained compound represented by the general formula (2) (hereinafter, referred to as amidoxime compound (2)) or a salt thereof, or a compound represented by the general formula (II) (hereinafter, referred to as amidoxime compound (II)) or The present invention relates to a method for producing an amidine derivative (3) or a salt thereof or a compound represented by the general formula (III) (hereinafter, referred to as an amidine derivative (III)) or a salt thereof by reducing the salt. .

The present invention also relates to the amidoxime compound (2) or a salt thereof, and the amidoxime compound (II) or a salt thereof, which are useful as production intermediates.

Further, the present invention provides a method for deprotecting an amidine compound (3) or a salt thereof obtained as described above to obtain 3- (7-
Amidino-2-naphthyl) -2- [4-[[(3S)-
3-pyrrolidinyl] oxy] phenyl] propionic acid
An alkyl ester or a salt thereof is obtained, and this is reacted with an alkylacetimidate or a salt thereof to give 2- [4-
Obtaining [[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid alkyl ester or a salt thereof, and then hydrolyzing it. Features 2
The present invention relates to a method for producing-[4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof.

Further, the present invention provides a method for deprotecting the amidine compound (III) or its salt obtained as described above (2S).
-3- (7-Amidino-2-naphthyl) -2- [4-
[[(3S) -3-pyrrolidinyl] oxy] phenyl]
Propionic acid alkyl ester or a salt thereof is obtained, and is reacted with alkylacetimidate or a salt thereof to give (2S) -2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy]. Phenyl] -3-
(2S) -2- [4-[[(3S)-(7-amidino-2-naphthyl) propionic acid alkyl ester or a salt thereof, which is then hydrolyzed.
-1-acetimidoyl-3-pyrrolidinyl] oxy]
Phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. First, the substituents of the compound according to the present invention will be described.

R ¹ represents a hydrogen atom or an alkyl group. Examples of the alkyl group include a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert group -Butyl group, pentyl group, hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like. In the present invention, R ¹ is preferably an alkyl group, and particularly preferably a methyl group or an ethyl group.

R ² is a hydrogen atom, an alkyl group, a formyl group, an alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a formimidoyl group, an alkanoimidoyl group, a benzimidoyl group, a carboxyl group, an alkoxycarbonyl group, It means a carboxyalkyl group, an alkylcarbonylalkyl group, an aminoalkyl group, an alkanoylamino group, an alkanoylaminoalkyl group, an aralkyl group, an aralkyloxycarbonyl group and an alkanoyl group. Examples of the alkyl group include the same as those described above for R ¹ .
Examples of the alkanoyl group include a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group. Specific examples include an acetyl group and a propionyl group.

Examples of the monoalkylcarbamoyl group include groups in which one hydrogen atom of a carbamoyl group is substituted by a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. Specific examples include a monomethylcarbamoyl group, a monoethylcarbamoyl group, and a monoisopropylcarbamoyl group.

Examples of the dialkylcarbamoyl group include groups in which two hydrogen atoms of a carbamoyl group have been substituted with the same or different linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms. Specific examples include a dimethylcarbamoyl group, a diethylcarbamoyl group, and an ethylmethylcarbamoyl group.

The alkanoimidoyl group means a group consisting of an alkyl group and a —C (＝ NH) — group.
A group represented by (（NH) —C _1-6 alkyl; Specific examples include an acetimidoyl group.

The alkoxycarbonyl group includes a linear, branched or cyclic C1-C6 alkoxyl group and a carbonyl group. Specific examples include a methoxycarbonyl group, an ethoxycarbonyl group, and a tertiary butoxycarbonyl group.

Examples of the carboxyalkyl group include a group consisting of a carboxyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. In particular,
Examples include a carboxymethyl group and a carboxyethyl group.

As the alkylcarbonylalkyl group,
Examples thereof include a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group, and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Specific examples include a methylcarbonylmethyl group, a methylcarbonylethyl group, and an ethylcarbonylmethyl group.

Examples of the aminoalkyl group include a group consisting of an amino group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Specific examples include an aminomethyl group, an aminoethyl group, an aminopropyl group and the like.

Examples of the alkanoylamino group include a group consisting of the above-mentioned alkanoyl group and imino group. Specific examples include a formylamino group, an acetylamino group and a propionylamino group.

As the alkanoylaminoalkyl group,
Examples include the above-described alkanoylamino group and a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms. Specific examples include a formylaminomethyl group, an acetylaminomethyl group, and a propionylaminoethyl group.

Examples of the aralkyl group include an aryl group such as a phenyl group and a naphthyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Specific examples include a benzyl group, a phenethyl group, a triphenylmethyl group, a naphthylmethyl group and the like.

The aralkyloxycarbonyl group includes
A group consisting of the above-mentioned aralkyl group and oxycarbonyl group is exemplified. Specific examples include a benzyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group.

In the present invention, R ² is a hydrogen atom,
Alkanoyl group, alkoxycarbonyl group, alkanoimidoyl group, aralkyl group, aralkyloxycarbonyl group is preferable, and among them, hydrogen atom, acetyl group, tertiary butoxycarbonyl group, acetimidoyl group, benzyl group, and benzyloxycarbonyl group are preferable. .

R ³ represents a hydrogen atom, an alkyl group or an alkanoyl group, and examples of the alkyl group and the alkanoyl group include the same as those described above for R ¹ .
In the present invention, R ³ is preferably a hydrogen atom.

Hereinafter, the production method of the present invention will be described. (Step A) Method for producing amidoxime (2) or a salt thereof or amidoxime (II) or a salt thereof

The amidoxime compound (2) or a salt thereof or the amidoxime compound (II) or a salt thereof can be produced, for example, by a nitrile compound (1) or a salt thereof produced by the method disclosed in JP-A-5-208946. It can be produced by reacting a hydroxylamine with the compound (I) or a salt thereof. The hydroxylamines used in the present invention, for example, hydroxylamine and its salts, O- methylhydroxylamine, can be exemplified O- alkyl hydroxylamine and its salts such as O- ethyl hydroxylamine of the general formula NH ₂ OR ³ ｛wherein, R ³ is the same as above. ｝
And salts thereof. When these hydroxylamines are used in the reaction, the properties of the hydroxylamines themselves (for example, liquid, solid, gas) may be used, or when the properties are liquid, a mixture with an appropriate solvent may be used. When the properties are solid, a solution dissolved in an appropriate solvent may be used.

In the present invention, the hydroxylamines are preferably hydroxylamine and salts thereof.
Specific examples include hydroxylamine, hydroxylammonium hydrochloride and hydroxylammonium sulfate. In the reaction, a hydroxylamine aqueous solution and a solution in which hydroxylammonium hydrochloride and / or hydroxylammonium sulfate are dissolved in an aqueous sodium hydroxide solution are more preferable.

The reaction of the nitrile derivative (1) or a salt thereof or the nitrile derivative (I) or a salt thereof with a hydroxylamine is preferably carried out in a solvent. Examples of the solvent include alcohols having 1 to 6 carbon atoms such as methanol, ethanol, propanol and butanol; ethers such as tetrahydrofuran and diisopropyl ether; aprotic polar solvents such as dimethylformamide and dimethylsulfoxide; ketones such as acetone and water. These solvents may be used alone or in combination of two or more.

In the present invention, an alcohol having 1 to 6 carbon atoms and a mixed solvent containing an alcohol having 1 to 6 carbon atoms are preferable, and among them, ethanol and a mixed solvent containing ethanol are preferable.

The amount of the solvent used is as follows: the nitrile compound (1)
Alternatively, the amount may be 2 to 50 mL, preferably 5 to 15 mL, per 1 g of the salt or nitrile (I) or a salt thereof. The reaction is usually carried out at a temperature from 0 ° C. to the boiling point of the solvent for 0.1 to 48 hours, and preferably refluxed for 1 to 6 hours.

The resulting amidoxime compound (2) or amidoxime compound (II) can be isolated by crystallization of the reaction solution by cooling or the like. It is also possible to crystallize the amidoxime compound (2) or amidoxime compound (II) from the reaction solution. Examples of the salt include mineral salts such as hydrochloride and sulfate, and organic sulfonic acid salts such as methanesulfonic acid salt and p-toluenesulfonic acid.

If necessary, the reaction solution was treated with ethyl acetate, chloroform, dichloromethane, dichloroethane,
The solution extracted with an extraction solvent such as toluene or butanol to extract the amidoxime compound (2) or the amidoxime compound (II) may be directly used in the next step.

(Step B) Method for producing amidine derivative (3) or a salt thereof or amidine derivative (III) or a salt thereof Amidine derivative (3) or a salt thereof or amidine derivative (II)
I) or a salt thereof can be produced by reducing the amidoxime compound (2) or a salt thereof or the amidoxime compound (II) or a salt thereof. Specifically, the reduction of the amidoxime compound (2) or a salt thereof, or the amidoxime compound (II) or a salt thereof is performed by a hydrogenation reaction using a metal catalyst, a metal reduction using a metal such as zinc, iron, or titanium.

Examples of the metal catalyst in the hydrogenation reaction using a metal catalyst include a nickel catalyst, a palladium catalyst, a platinum catalyst, a rhodium catalyst and the like. The nickel-based catalyst means a nickel compound and a compound in which the compound is supported on carbon, barium sulfate, diatomaceous earth, and the like, and the same applies to other metals such as palladium, platinum, and rhodium.

In the present invention, a palladium catalyst is preferred. Examples of the palladium-based catalyst include palladium black, palladium-barium sulfate using barium sulfate as a support, and palladium-carbon. Among them, palladium-carbon is preferred. The amount of the metal catalyst to be used may be appropriately examined. For example, in the case of 10% palladium-carbon, 0.1% of the amidoxime compound (2) or its salt or 1 g of the amidoxime compound (II) or its salt is used.
001 to 0.5 g may be used.

In the hydrogenation reaction using a metal catalyst, examples of the hydrogen source include hydrogen gas, isopropanol, silanes, formic acid and formate.
Among them, formic acid is preferred. The used amount of the hydrogen source may be any equivalent or more. For example, when the hydrogen source is formic acid, 2 to 10
An equivalent amount may be used.

The reaction is preferably carried out in a solvent. Examples of the solvent include those having 1 to 6 carbon atoms such as chloroform, dichloromethane, dichloroethane, toluene, methanol, ethanol, propanol, isopropanol and butanol.
Alcohols, ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran, esters such as ethyl acetate and ethyl formate, N, N
-Dimethylformamide, dimethylsulfoxide, water and the like.
A mixed solvent of more than one kind may be used. In the present invention, alcohols and esters having 1 to 6 carbon atoms are preferable, and among them, ethanol and ethyl acetate are preferable.

The amount of the solvent used may be 2 to 25 mL per 1 g of the amidoxime compound (2) or a salt thereof or the amidoxime compound (II) or a salt thereof, and may be 2 to 15 mL.
mL is preferred. The reaction may be carried out at a temperature from 0 ° C. to the boiling point of the solvent used, preferably 5 to 30 ° C., for 0.1 to 24 hours, and preferably for 0.5 to 5 hours.

The metal reduction with a metal such as zinc, iron or titanium is carried out in the presence of an acid such as hydrochloric acid or sulfuric acid or a salt such as ammonium chloride using a metal in an equivalent amount or more. The metal reduction is preferably performed in a solvent. Examples of the solvent include alcohols having 1 to 6 carbon atoms such as methanol, ethanol, propanol, isopropanol and butanol, N, N-dimethylformamide, dimethylsulfoxide and water. These solvents can be used alone or as a mixture of two or more. In the present invention, alcohols having 1 to 6 carbon atoms are preferable, and methanol and ethanol are particularly preferable.

The solvent may be used in an amount of 2 to 50 mL per 1 g of the amidoxime compound (2) or a salt thereof, or 1 g of the amidoxime compound (II) or a salt thereof.
mL is preferred. The metal reduction is carried out at a temperature from 0 ° C. to the boiling point of the solvent used, preferably at reflux temperature, for 0.1 to 24 hours.
It may be performed for an hour, and preferably for 2 to 8 hours. At the time of metal reduction, a proton source is preferably present in the reaction system. Examples of the proton source include mineral acids and salts thereof such as hydrochloric acid and sulfuric acid and nitric acid, and organic acids and salts thereof such as formic acid and acetic acid. Hydrochlorides such as ammonium hydrochloride are preferred.

After the reduction, the reaction solution is extracted with an extraction solvent such as ethyl acetate, chloroform, dichloromethane, dichloroethane, toluene, or butanol, if necessary, and then subjected to a treatment for removing unnecessary acids or salts by washing with water or the like. Thus, it can be used in the next step.

The amidine compound (3) or the amidine compound (III) can be crystallized and purified from the reaction solution or the solution subjected to the above treatment as a salt of the amidine compound (3) or the amidine compound (III). It is. Examples of the salt include mineral salts such as hydrochloride, hydrobromide, hydroiodide, boron tetrafluoride, perchlorate, nitrate, and sulfate, methanesulfonate, and 2-hydroxyethane. Organic sulfonates such as sulfonate, p-toluenesulfonate, benzenesulfonate, and formate, acetate, propionate, butyrate, pivalonate, oxalate, malonate, succinate Salts, glutarates, adipates, tartrates, maleates, malates, mandelates, carboxylate salts such as benzoates and the like can be mentioned. Methanesulfonate, acetate, fumarate, maleate, succinate,
Mandelates and benzoates are preferred, and maleates are particularly preferred.

When R ³ represents a hydrogen atom, the amidoxime compound (2) or the amidoxime compound (II)
May be reduced after O-acylation with an acylating agent. O-acylation is preferred because it facilitates reduction. As a reduction method, the amidoxime compound (2) or the amidoxime compound (II) may be subjected to acylation and then reduced, or may be reduced in the presence of an acylating agent in the reaction system. Preferably, reduction in the presence of an acylating agent in the reaction system is simple and convenient.

Examples of the acylating agent include acid anhydrides such as acetic anhydride, benzoic anhydride, maleic anhydride, and phthalic anhydride; mixed acid anhydrides prepared from different carboxylic acids or from carboxylic acids and acid anhydrides; And acid chlorides such as chloride and acetyl chloride. Specific examples of mixed acid anhydrides include those prepared from formic acid and acetic anhydride. In the present invention, the acylating agent is preferably an acid anhydride or a mixed acid anhydride.

These are used in an equivalent amount or more based on the amidoxime compound (2) or amidoxime compound (II). In the present invention, it is preferable to use equivalent amounts of acetic anhydride and a mixed acid anhydride prepared from formic acid and acetic anhydride.

In order to convert the substituent (R ² ) at the nitrogen atom of the pyrrolidinyl group in the amidine derivative (3) or a salt thereof or the amidine derivative (III) or a salt thereof into a hydrogen atom, R ² must be tertiary butoxycarbonyl. An alkoxycarbonyl group such as a benzyl group, an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, an alkanoyl group such as an acetyl group, that is, an amidine derivative which is a protecting group for a nitrogen atom in a pyrrolidine ring [(3) or (III)] or a salt thereof may be deprotected. Specifically, TW Green, PGM Wuts, “P
rotective GroupsinOrganic Synthesis. 2nd Edition ”
And the like.
For example, in the case of an alkoxycarbonyl group, it proceeds easily by reaction with an acid. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid and p-toluenesulfonic acid. The acid may be used in an equivalent amount to a large excess. The reaction is preferably performed in a solvent, and examples of the solvent include ethanol, ethyl acetate, toluene, and N, N-dimethylformamide. These solvents may be used alone or as a mixed solvent of two or more kinds. . The reaction is carried out at a temperature from -10C to the boiling point of the solvent for 5 minutes to 10 hours.

For example, when hydrochloric acid is used as the acid, the amidine compound (3) or a salt thereof or the amidine compound (II)
I) or 1 g of a salt thereof may be reacted with 1 to 10 mL of an ethanol solution containing 30% by weight of hydrogen chloride at room temperature or lower for 5 minutes to 2 hours. When sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid is used as the acid, it is sufficient to use 1 to 5 equivalents and reflux with ethanol for 1 to 5 hours.

The compound in which the substituent (R ² ) at the nitrogen atom of the pyrrolidinyl group in the amidine derivative (3) represents a hydrogen atom can be represented by the following general formula (3 ′).

[0055]

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In the formula, R ¹ is the same as described above. A compound in which the substituent (R ² ) at the nitrogen atom of the pyrrolidinyl group in the amidine compound (III) represents a hydrogen atom can be represented by the following general formula (III ′).

[0057]

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In the formula, R ¹ is the same as described above. ｝

The compounds produced in the above reaction can be isolated and purified as salts of these compounds after the reaction or concentration. As salts, hydrochloride, hydrobromide,
Mineral salts such as hydroiodide, tetrafluoroboronate, perchlorate, nitrate and sulfate, methanesulfonate, 2-hydroxyethanesulfonate, p-toluenesulfonate, benzenesulfone Organic sulfonates and formates such as acid salts, acetate, propionate, butyrate, pivalonate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate And carboxylate such as malate, mandelate and benzoate.

The compounds and / or salts thereof in the present invention include solvates of the compounds and solvates of the salts of the compounds. Examples of the solvent include water, an alcohol having 1 to 6 carbon atoms, and the like.

By reacting the thus obtained amidine compound [(3 ') or (III')] or a salt thereof with an alkylacetimidate or a salt thereof, a nitrogen atom on the pyrrolidine ring of the compound or acetimide is obtained. Compound substituted with an yl group, 2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3-
(7-Amidino-2-naphthyl) propionic acid alkyl ester (acetimidoyl form) or a salt thereof is obtained, which is further hydrolyzed to give 2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid or a salt thereof is obtained. Here, the acetimidylation reaction is carried out, for example, by adding an alkylacetimidate or a salt thereof to an amidine compound (3 ′) or a salt thereof in a suitable solvent, using triethylamine, sodium hydroxide,
The reaction is carried out in the presence of a base such as potassium hydroxide. The hydrolysis of the obtained acetimidoyl compound or a salt thereof is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as p-toluenesulfonic acid by -2.
It is carried out under the condition of 0 ° C. to reflux temperature. These acetimidylation reaction and hydrolysis are described in JP-A-5-20894.
No. 6 is described.

[0062]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the invention thereto.

Embodiment 1 (2S) -3- [7-amino (hydroxyimino) methyl-2-naphthyl] -2-
[4-[[(3S) -1-tert-butoxycarbonyl-
3-pyrrolidinyl] oxy] phenyl] propionic acid
Ethyl ester 32.83 g of hydroxylammonium sulfate at room temperature
Was dissolved in 76 mL of 5N aqueous sodium hydroxide solution. This solution was poured into 520 mL of ethanol with stirring. At room temperature, (2S) -2- [4-
[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-
2-naphthyl) propionic acid ethyl ester 51.4
6 g were suspended, and this was heated and stirred and refluxed for 2 hours. TL
After confirming the completion of the reaction with C (chloroform: acetone = 3: 1) and allowing to cool, the precipitated inorganic salt was removed by filtration, and the filtrate was stirred and crystallized at room temperature overnight. Water 52
After adding 0 mL and further stirring at room temperature for 3 hours, the crystals were collected by suction filtration. After air-drying the crystals for one day,
Drying under reduced pressure for an hour gave 53.14 g of the title compound as colorless crystals.

¹ H-NMR (DMSO-d ⁶ , ref.
MS = 0.00 ppm) δ: 1.00 (3H, t, J =
7 Hz), 1.38 (9H, d, J = 5 Hz), 1.9
To 2.2 (2H, m), 3.1 to 3.6 (6H, m),
3.9 to 4.1 (3H, m), 4.95 (1H, m),
5.91 (2H, br), 6.89 (2H, d, J = 8
Hz), 7.29 (2H, d, J = 8 Hz), 7.39
(1H, d, J = 9 Hz), 7.67 (1H, s),
7.7 to 7.9 (3H, m), 8.09 (1H, s),
9.76 (1H, br). FAB-MS: 548 (M +
1), 532

Embodiment 2 FIG. (2S) -3- (7-amidino-2-naphthyl) -2- [4-[[(3S) -1-tert
-Butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] propionic acid ethyl ester maleate (2S) -3- [7-amino (hydroxyimino) methyl-2-naphthyl] -2- [4-[[(3S) -1-te
rt-butoxycarbonyl-3-pyrrolidinyl] oxy]
Phenyl] propionic acid ethyl ester 5.476 g
Then, 0.548 g of 10% palladium-carbon was suspended in 50 mL of ethanol, and 0.95 mL of acetic anhydride and 1.90 mL of formic acid were added with stirring at room temperature. After stirring at room temperature for 2 hours to confirm the completion of the reaction, palladium-carbon was removed by filtration.
After the filtrate was concentrated under reduced pressure, ethyl acetate 10% was added to the residue.
0 mL and 1.161 g of maleic acid were added.
The mixture was heated and stirred at 10 ° C. for 10 minutes. After cooling, the precipitated crystals were collected by filtration and dried under reduced pressure at 50 ° C to give the title compound 5.168.
g was obtained.

¹ H-NMR (DMSO-d ⁶ , ref. T
MS = 0.00 ppm) δ: 1.00 (3H, t, J =
7 Hz), 1.39 (9H, d, J = 6 Hz), 1.9
To 2.2 (2H, m), 3.1 to 3.6 (6H, m),
3.9-4.2 (3H, m), 4.95 (1H, m),
6.02 (2H, s), 6.89 (2H, d, J = 9H)
z), 7.29 (2H, d, J = 9 Hz), 7.62
(1H, dd, J = 8, 1 Hz), 7.74 (1H, d
d, J = 8, 1 Hz), 7.85 (1H, s), 7.9
6 (1H, d, J = 8 Hz), 8.08 (1H, d, J
= 8 Hz), 8.34 (1H, s), 8.96, 9.4
0 (each 2H, br).

Embodiment 3 FIG. (2S) -3- (7-amidino-2-naphthyl) -2- [4-[[(3S) -3-pyrrolidinyl] oxy] phenyl] propionic acid ethyl ester dihydrochloride Hydroxylammonium sulfate at room temperature 64 g was dissolved in 3.8 mL of 5N aqueous sodium hydroxide solution. The solution was poured into 52 mL of ethanol with stirring. At room temperature, (2S) -2- [4-[[((3
5.15 g of S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-2-naphthyl) propionic acid ethyl ester were suspended, and the suspension was heated and stirred and refluxed for 4 hours. . After confirming the completion of the reaction by TLC (chloroform: acetone = 3: 1), the mixture was allowed to cool, and then concentrated under reduced pressure. Acetic acid ethyl ester 5 in the residue
0 mL and 50 mL of water were added and dissolved. The ethyl acetate phase was separated and washed with 50 mL of water.
S) -3- [7-Amino (hydroxyimino) methyl-
2-naphthyl] -2- [4-[[(3S) -1-tert-
A solution of ethyl butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] propionate in ethyl acetate was obtained. 10% palladium-carbon 0.5
48 g were suspended and stirred at 15 ° C. with 0.95 acetic anhydride.
mL and 1.90 mL of formic acid were added. After stirring at 15 ° C. for 2 hours to confirm the completion of the reaction, 27 mL of 30% hydrochloric acid-ethanol was added, and the mixture was further stirred at the same temperature for 30 minutes.
The completion of the reaction was confirmed by HPLC, and the solvent was concentrated under reduced pressure to about half the volume. After adding 27 mL of ethanol to the concentrated solution for dilution,
Palladium-carbon was removed by filtration. The filtrate was concentrated under reduced pressure, 50 mL of water was added to the residue, and the mixture was dissolved at room temperature. The resulting solution was mixed with a mixture of water and acetonitrile as an eluting solvent to form a porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer; Purification by column chromatography in -20), a small amount of dilute hydrochloric acid was added to the portion containing the target compound, and the residue was dried under reduced pressure to obtain 4.62 g of the title compound.
(2S) -3- (7-amidino-2-naphthyl) -2- [4-[[(3S) -3-pyrrolidinyl] oxy] phenyl] propionic acid ethyl ester dihydrochloride thus obtained is This was consistent with that synthesized by the method described in Example 34 of JP-A-5-208946.

Reference Example 1. (2S) -2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid dihydrochloride (2S) having an optical purity of 99.7% by the method described in Examples 34, 40 and 46 of JP-A-5-208946.
-2- [4-[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] -3-
From (123.1 g of (7-cyano-2-naphthyl) propionic acid ethyl ester, (2S) -2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
103.6 g of propionic acid dihydrochloride were obtained. This is referred to as HP described in Example 46 of JP-A-5-208946.
When the optical purity was measured under LC conditions, it was 94.8% d.
e.

Embodiment 4 FIG. (2S) -2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid dihydrochloride (2S) -3- (7-amidino-2-naphthyl) -2- [4-[[(3S) -3 synthesized by the method of Example 3.
-Pyrrolidinyl] oxy] phenyl] propionic acid ethyl ester dihydrochloride from 4.60 g
By the method described in Examples 40 and 46 of 8946, 4.35 g of the title compound was obtained. This is disclosed in
Optical purity was measured under the conditions of HPLC described in Example 46 of 08946 to find that it was 99.1% de. Further, the obtained title compound was obtained by the method described in JP-A-5-2089.
By performing the same treatment as in Example 52 in JP-B-46, (2S) -2- [4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3.
-(7-Amidino-2-naphthyl) propion hydrochloride pentahydrate was obtained.

In the following reaction formula,

[0071]

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In the formula, Et represents an ethyl group. Boc represents a tertiary butoxycarbonyl group. 、 By the method disclosed in JP-A-5-208946, (2S) -2- [4-
[[(3S) -1-tert-butoxycarbonyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-cyano-
From (2-naphthyl) propionic acid ethyl ester, (2S) -2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
When the dihydrochloride of propionic acid is derived, the optical purity is 9
Even when the compound represented by the formula (Ia) having 9.7% de was used, the optical purity of the obtained compound represented by the formula (IIIa) was 94.8% de (see Reference Example 1.). ).

On the other hand, represented by the following reaction formula:

[0074]

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Wherein, Et and Boc are the same as above.場合 When the compound represented by the formula (IIIa) is synthesized by the production method of the present invention, the compound represented by the formula (Ia) having an optical purity of 99.7% de
The optical purity of the salt of the compound represented by the formula (IIIa) obtained from the compound represented by the formula was 99.1% de, and high optical purity was maintained (see Example 4.). That is,
In the production method of the present invention, almost no epimerization was observed.

[0076]

According to the production method of the present invention, Japanese Patent Application Laid-Open
The intermediate of the aromatic amidine derivative described in JP-A-208946 can be industrially produced without reducing the optical purity, and is useful.

Claims (6)

(57) [Claims] 1. A compound of the general formula (2) Wherein R ¹ represents a hydrogen atom or an alkyl group; R ² represents an alkanoyl group, an alkoxycarbonyl group, an aralkyl group or an aralkyloxycarbonyl group; R ³ represents a hydrogen atom, an alkyl group or an alkanoyl group. The compound represented by the general formula (3) is reduced by reducing the compound or a salt thereof. 中 In the formula, R ¹ and R ² are the same as described above. And a salt thereof, which is deprotected to give 3- (7-amidino-2-naphthyl) -2- [4-[[(3S) -3-
Pyrrolidinyl] oxy] phenyl] propionic acid alkyl ester or a salt thereof is obtained, and is reacted with alkylacetimidate or a salt thereof to give 2- [4-
Obtaining [[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid alkyl ester or a salt thereof, and then hydrolyzing it. Features 2
A method for producing-[4-[[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof. 2. A compound of the general formula (1) 中 In the formula, R ¹ and R ² are the same as those in claim 1. ｝
A compound represented by the general formula (2): 中 In the formula, R ¹ , R ² and R ³ are the same as those in claim 1. And a salt thereof, which is reduced to form a compound represented by the general formula (3): Wherein R ¹ and R ² are the same as those in claim 1. ｝
Or a salt thereof, which is deprotected to give 3- (7-amidino-2-naphthyl) -2- [4-
[[(3S) -3-pyrrolidinyl] oxy] phenyl]
Propionic acid alkyl ester or a salt thereof is obtained, and is reacted with alkylacetimidate or a salt thereof to give 2- [4-[[(3S) -1-acetimidoyl-3].
2- [4-[[(3S-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid alkyl ester or a salt thereof, which is then hydrolyzed. ) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3-
A method for producing (7-amidino-2-naphthyl) propionic acid or a salt thereof. 3. A compound of the general formula (II) 中 In the formula, R ¹ , R ² and R ³ are the same as those in claim 1. The compound represented by｝ or a salt thereof is reduced to obtain a compound represented by the general formula (III): Wherein R ¹ and R ² are the same as those in claim 1. ｝
And a salt thereof, which is deprotected to give (2S) -3- (7-amidino-2-naphthyl) -2-
[4-[[(3S) -3-Pyrrolidinyl] oxy] phenyl] propionic acid alkyl ester or a salt thereof is obtained, and this is reacted with alkylacetimidate or a salt thereof to give (2S) -2- [4- [ [(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl]
-3- (7-Amidino-2-naphthyl) propionic acid
(2S) -2- [4-characterized in that an alkyl ester or a salt thereof is obtained and then hydrolyzed.
A process for producing [[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof. 4. (2S) -2- [4-[[(3S) -1
-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof is (2S) -2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
The production method according to claim 3, which is propionic acid hydrochloride pentahydrate. 5. A compound of the general formula (I) Wherein R ¹ and R ² are the same as those in claim 1. ｝
And a salt thereof is reacted with a hydroxylamine to form a compound represented by the general formula (II): 中 In the formula, R ¹ , R ² and R ³ are the same as those in claim 1. And a salt thereof, which is reduced to form a compound represented by the general formula (III): Wherein R ¹ and R ² are the same as those in claim 1. ｝
And a salt thereof, which is deprotected to give (2S) -3- (7-amidino-2-naphthyl) -2-
[4-[[(3S) -3-Pyrrolidinyl] oxy] phenyl] propionic acid alkyl ester or a salt thereof is obtained, and this is reacted with alkylacetimidate or a salt thereof to give (2S) -2- [4- [ [(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl]
-3- (7-Amidino-2-naphthyl) propionic acid
(2S) -2- [4-characterized in that an alkyl ester or a salt thereof is obtained and then hydrolyzed.
A process for producing [[(3S) -1-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof. 6. (2S) -2- [4-[[(3S) -1
-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid or a salt thereof is (2S) -2- [4-[[(3
S) -1-Acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2-naphthyl)
The production method according to claim 5, which is propionic acid hydrochloride pentahydrate.