JP2005247773A - Method for producing 2-pyridylalanine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for selectively producing an optically active 2-pyridylalanine in high yield. <P>SOLUTION: A 2-substituted amino-3-(2-pyridyl)acrylic acid derivative is reduced by asymmetric reduction with a complex of a transition metal and an optically active ligand and the produced optically active 2-pyridylalanine derivative is hydrolyzed to obtain the optically active pyridylalanine. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing optically active 2-pyridylalanine useful as a raw material for enzyme inhibitors such as NO synthesis inhibitors.

  Enzyme inhibitors such as NO synthesis inhibitors are attracting attention as improving agents for cardiovascular diseases such as hypertension, heart disease and diabetes, and amide compounds (N-imidazolylmethylcarboxamide) which are one of such enzyme inhibitors Is also known to use an optically active 2-pyridylalanine derivative as a raw material (see, for example, Patent Document 1), and in order to produce such an inhibitor industrially advantageously, the optical activity that is a starting material thereof is used. The superiority or inferiority of the production method of 2-pyridylalanine has a great influence.

Regarding the method for producing such an optically active 2-pyridylalanine or D, L-isomer, 1) D-2-L-pyridylmethylhydantoin is biologically converted in the presence of microbial cells, and D-2-pyridyl is obtained. A method for obtaining alanine (for example, see Patent Document 2) 2) Synthesis of D, L-pyridylalanine from chloromethylpyridine and diethyl acetamidomalonate, N-acetylation, and hydrolysis of only the L-form with acylase A method for obtaining L-pyridylalanine and D-acetylpyridylalanine (for example, see Non-Patent Document 1), 3) In the presence of L-phenylalanine ammonia lyase, pyridylacrylic acid and ammonia are reacted to obtain 2-pyridylalanine. 4) 2-formylamino-3- (, for example, as a method for producing a D, L-isomer (see, for example, Patent Document 3). A method is known in which 2-pyridyl) propenoic acid alkyl ester is reduced with palladium carbon and then hydrolyzed to obtain D, L-2-pyridylalanine (see, for example, Patent Document 4).
WO01 / 02387 JP-A-3-19696 Japanese Patent No. 3121688 JP 2003-221382 A Pept. Chem. 1994, 469 (1995).

  However, in the method 1), a large amount of biocatalyst is required and the reaction time is very long. In the method 2), since it is reacted with diethyl acetamidomalonate, the D, L-form (racemic form) is used. However, since the L-form is further acetylated and only the L-form is hydrolyzed with amylase in order to obtain an L-form from this, the process is long and the yield is only 50% or less. Since it is a reaction, the substrate concentration in the reaction solution cannot be increased and the efficiency is poor. Also, in the method 4), only the racemic body can be synthesized because the acrylic acid derivative is reduced with palladium carbon. In order to obtain an optically active substance, it is necessary to perform an operation such as optical resolution. Any of these methods is disadvantageous for industrial implementation, and optically active 2-pyridylalanine is more efficiently used. It is where the method of granulation is desired.

  Therefore, as a result of intensive studies in view of the above-described present situation, the present inventors have found that a 2-substituted amino-3- (2-pyridyl) acrylic acid derivative is asymmetric using a complex of a transition metal and an optically active ligand. It was found that optically active 2-pyridylalanine derivative obtained by reduction was selectively hydrolyzed to obtain optically active 2-pyridylalanine, and the present invention was completed.

（式中、Ｒ^１は水素原子、メチル基又はｔｅｒｔ−ブチル基のいずれかを示す。） In the present invention, the optically active ligand is an optically active phosphine, the optically active phosphine is a compound represented by the following general formula (1) or (2), and the transition metal is rhodium. Are preferred embodiments of the present invention.

(In the formula, R ¹ represents a hydrogen atom, a methyl group or a tert-butyl group.)

  According to the production method of the present invention, optically active 2-pyridylalanine useful as a raw material for enzyme inhibitors such as NO synthesis inhibitors can be produced selectively and in high yield.

（式中、Ｒ^２は水素原子、低級アルキル基、低級アルキル基もしくは低級アルコキシ基で置換されていてもよいフェニル基を示し、Ｒ^３は水素原子、低級アルキル基、低級アルキル基もしくは低級アルコキシ基で置換されていてもよいフェニル基、または低級アルキル基もしくは低級アルコキシ基で置換されていてもよいベンジル基を示す） The present invention will be described in detail.
In the present invention, first, a 2-substituted amino-3- (2-pyridyl) acrylic acid derivative is asymmetrically reduced using a complex of a transition metal and an optically active ligand. The amino-3- (2-pyridyl) acrylic acid derivative is represented by the following general formula (3) and is synthesized from 2-pyridylaldehyde and isocyanoacetic acid ester as disclosed in JP-A-2003-221382. Or a method of synthesis using 2-pyridylaldehyde and N-substituted glycine as disclosed in Anales de Quimica, Series C: Quimica Organic Bioquimica (1985), 81, 56.

(In the formula, R ² represents a hydrogen atom, a lower alkyl group, a lower alkyl group or a phenyl group which may be substituted with a lower alkoxy group, and R ³ represents a hydrogen atom, a lower alkyl group, a lower alkyl group or a lower alkoxy group. A phenyl group which may be substituted with a benzyl group which may be substituted with a lower alkyl group or a lower alkoxy group)

  Specific examples of the derivatives include methyl 2-formylamino-3- (2-pyridyl) propenoate, ethyl 2-formylamino-3- (2-pyridyl) propenoate, 2-formylamino-3- (2- N-propyl pyridyl) propenoate, 2-acetamino-3- (2-pyridyl) propenoic acid, methyl 2-acetamino-3- (2-pyridyl) propenoate, 2-benzoylamino-3- (2-pyridyl) propene And acid, methyl 2-benzoylamino-3- (2-pyridyl) propenoate, and the like.

  The complex includes a transition metal complex and an optically active ligand. Examples of the transition metal complex include transition metal complexes such as rhodium, ruthenium, and iridium. A rhodium complex represented by the following general formula (4) is preferably used.

[RhX (diene)] ₂ (4)
(In the formula, X is a chlorine atom, bromine atom or iodine atom, and diene is cyclooctadiene or norbornadiene)

（式中、Ｒ^１は水素原子、メチル基又はｔｅｒｔ−ブチル基のいずれかを示す。） Examples of the optically active ligand include optically active ligands such as BINAP, tol-BINAP, BIPHEMP, DIOP, and CHIRAPHOS. Among them, the optically active ligand is an optically active phosphine. It is preferable to use a compound represented by the following general formula (1) or (2) as a complex consisting of the above-mentioned transition metal complex and such a ligand. TON (Turn over number) It is preferable at such points.

(In the formula, R ¹ represents a hydrogen atom, a methyl group or a tert-butyl group.)

（式中、＊印は光学活性であることを示し、Ｒ^２、Ｒ^３は上記一般式（５）と同様である。） When the above-mentioned acrylic acid derivative is asymmetrically reduced using a complex of a transition metal and an optically active ligand, the autoclave is a raw material such as a 2-substituted amino-3- (2-pyridyl) acrylic acid derivative. 150 to 150 times (by weight) of solvent (alcohols such as methanol and ethanol, ethers such as diethyl ether and THF, ketones such as acetone, aromatic hydrocarbons such as benzene and toluene, dichloromethane, etc.) Alternatively, a solution in which the acrylic acid derivative is dissolved in the above solvent is charged, and the reaction may be started by adding 0.0001 to 0.02 mol of the above complex to 1 mol of the acrylic acid derivative. This reaction is carried out at a hydrogen pressure of 0.1 to 10 MPa and a temperature of 20 to 150 ° C. for 3 to 48 hours, whereby the following general formula (5) It is possible to obtain an optical active 2-pyridyl-alanine derivative shown. In the above, a solution in which such an acrylic acid derivative and a complex are mixed may be charged into an autoclave, or a solvent may be charged after charging the acrylic derivative and the complex into the autoclave.

(In the formula, * indicates optical activity, and R ² and R ³ are the same as those in the general formula (5).)

  The optically active 2-pyridylalanine derivative thus obtained is then hydrolyzed with a mineral acid such as hydrochloric acid in an aqueous solution according to a conventional method to obtain the desired optically active 2-pyridylalanine. . Thereafter, it is appropriately purified by conventional means such as concentration, distillation, recrystallization and the like, if necessary.

（式中、＊印は光学活性であることを示す） Thus, the objective optically active 2-pyridylalanine represented by the following general formula (6) is obtained.

(In the formula, * indicates optical activity)

  Hereinafter, the present invention will be described in detail with reference to examples. “%” Is based on weight. The yield was determined by liquid chromatography analysis.

Reference example 1
[Synthesis of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate]
Dissolve 5.31 g (0.05 mol) of 2-pyridylaldehyde and 5.66 g (0.05 mol) of isocyanoacetic acid ethyl ester in 150 ml of methylene chloride, add 0.26 g (0.003 mol) of triethylamine and add 25 The reaction was carried out at 0 ° C. for 10 hours. After completion of the reaction, washing was performed twice with 100 ml of water, the dichloromethane layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 6.50 g (yield 59%) of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate.

Example 1
Under a nitrogen atmosphere, 30 ml of toluene was added to 25 mg (0.05 mmol) (cod: cyclooctadiene) [RhCl (cod)] ₂ and 70 mg (0.12 mmol) of (R) -BINAP, followed by stirring at 25 ° C. for 30 minutes. A catalyst solution was prepared.
Next, in a 100 ml autoclave purged with nitrogen after adding the above catalyst solution to 2.2 g (10 mmol) of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate synthesized in Reference Example 1 above. The reaction solution was reacted at a hydrogen pressure of 7 MPa and 100 ° C. for 8 hours, the solvent of the resulting reaction solution was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate = 4 / 6), 2.1 g of ethyl (S) -2-formylamino-3- (2-pyridyl) propionate was obtained. The yield at this time was 95%, and the optical purity was 99.5% ee. The optical purity was measured using high performance liquid chromatography (manufactured by Daicel Corporation: CHIRACEL AD).

  Next, 50 ml of 6N hydrochloric acid was added to 310 mg (1.4 mmol) of ethyl (S) -2-formylamino-3- (2-pyridyl) propionate, and the mixture was heated to reflux for 5 hours. After cooling, the solvent was removed under reduced pressure. The residue was subjected to ion exchange chromatography ("Diaion SK-1B", eluent 10% aqueous ammonia) to obtain 200 mg of (S) -2-pyridylalanine. The yield at this time was 86%. The optical purity was 99.5% ee, and no decrease in optical purity due to hydrolysis was observed. The optical purity was measured by using high performance liquid chromatography (“Sumichiral OA-5000” manufactured by Sumika Chemical Analysis Co., Ltd.).

Example 2
Under a nitrogen atmosphere, [RhCl (cod)] ₂ 25 mg (0.05 mmol), (R) -BINAP 70 mg (0.12 mmol) and Z-2-formylamino-3- (2-pyridyl) synthesized in Reference Example 1 above. ) After charging 2.2 g (10 mmol) of ethyl propenoate into a 100 ml autoclave and substituting with nitrogen, 30 ml of toluene was added and stirred at 25 ° C. for 30 minutes. The reaction mixture was allowed to react for a period of time, the solvent of the resulting reaction solution was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and ethyl (S) -2-formylamino-3- (2-pyridyl) propionate was added in 2. 1 g was obtained. The yield at this time was 95%, and the optical purity was 99.0% ee.

  Next, the above ethyl (S) -2-formylamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1 to obtain (S) -2-pyridylalanine in a yield of 86%. . The optical purity at this time was 99.0% ee.

Example 3
In Example 1, except that methyl Z-2-formylamino-3- (2-pyridyl) propenoate was used instead of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate The same operation as in Example 1 was performed to obtain methyl (S) -2-formylamino-3- (2-pyridyl) propionate. The yield at this time was 93%, and the optical purity was 97.5% ee.

  Subsequently, the above methyl (S) -2-formylamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1 to obtain (S) -2-pyridylalanine in a yield of 86%. It was. The optical purity at this time was 97.5% ee.

Example 4
In Example 1, instead of using ethyl Z-2-formylamino-3- (2-pyridyl) propenoate, n-propyl Z-2-formylamino-3- (2-pyridyl) propenoate was used. Were the same as in Example 1 to obtain n-propyl (S) -2-formylamino-3- (2-pyridyl) propionate. The yield at this time was 94%, and the optical purity was 98.0% ee.

  Subsequently, n-propyl (S) -2-formylamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1 to obtain 86% yield of (S) -2-pyridylalanine. Got in. The optical purity at this time was 98.0% ee.

Example 5
Example 1 is the same as Example 1 except that methyl Z-2-acetamino-3- (2-pyridyl) propenoate was used instead of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate. The same operation was performed to obtain methyl (S) -2-acetamino-3- (2-pyridyl) -propionate. The yield at this time was 93%, and the optical purity was 96.0% ee.

  Subsequently, the above methyl (S) -2-acetamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1 to obtain (S) -2-pyridylalanine in a yield of 86%. . The optical purity at this time was 96.0% ee.

Example 6
Example 1 is the same as Example 1 except that Z-2-benzylamino-3- (2-pyridyl) propenoic acid was used instead of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate. The same operation was performed to obtain (S) -2-benzylamino-3- (2-pyridyl) propionic acid in a yield of 90%. The optical purity at this time was 97.0% ee.

  Next, the above Z-2-benzylamino-3- (2-pyridyl) propionic acid was hydrolyzed in the same manner as in Example 1 to obtain (S) -2-pyridylalanine in a yield of 86%. The optical purity at this time was 97.0% ee.

Example 7
The same operation as in Example 1 was performed except that (S) -BINAP was used instead of (R) -BINAP in Example 1, and (R) -2-formylamino-3- (2-pyridyl) propion was obtained. Ethyl acid was obtained. The yield at this time was 95%, and the optical purity was 99.2% ee.

Next, the above (R) -2-formylamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1 to obtain (S) -2-pyridylalanine in a yield of 86%. It was. The optical purity at this time was 99.2% ee.

Example 8
In Example 1, (R) -2-formylamino-3- (2-pyridyl) propion was carried out in the same manner as in Example 1, except that (R) -BIPEMP was used instead of (R) -BINAP. Ethyl acid was obtained. The yield at this time was 94%, and the optical purity was 98.0% ee.

Next, the above (R) -2-formylamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1 to obtain (S) -2-pyridylalanine in a yield of 86%. It was. The optical purity at this time was 98.0% ee.

Comparative Example 1
6.6 g of ethyl Z-2-formylamino-3- (2-pyridyl) propenoate synthesized in Reference Example 1 was dissolved in 50 ml of methanol, charged into an autoclave, and further 10% palladium carbon (50% water-containing product) was added. 1.5 g was added, and the reaction was carried out at a hydrogen pressure of 0.5 MPa and 25 ° C. for 6 hours. After completion of the reaction, the reaction solution was filtered to remove the catalyst and concentrated to obtain 4.8 g of ethyl 2-formylamino-3- (2-pyridyl) propionate. The yield at this time was 72.1%, and the obtained compound was a racemate.

  Subsequently, the above-mentioned ethyl 2-formylamino-3- (2-pyridyl) propionate was hydrolyzed in the same manner as in Example 1, and 2-pyridylalanine was obtained in a yield of 86%, but only the racemic body was obtained. And optically active 2-pyridylalanine could not be obtained.

  The optically active 2-pyridylalanine obtained by the method of the present invention is useful as a raw material for enzyme inhibitors such as NO synthesis inhibitors.

Claims (4)

  Hydrolysis of an optically active 2-pyridylalanine derivative obtained by asymmetric reduction of a 2-substituted amino- (2-pyridyl) acrylic acid derivative with a complex of a transition metal and an optically active ligand. A method for producing 2-pyridylalanine, which is characterized.   The method for producing 2-pyridylalanine according to claim 1, wherein the optically active ligand is an optically active phosphine. The method for producing 2-pyridylalanine according to claim 2, wherein the optically active phosphine is a compound represented by the following general formula (1) or (2).

(In the formula, R ¹ represents a hydrogen atom, a methyl group or a tert-butyl group.)   The method for producing 2-pyridylalanine according to any one of claims 1 to 3, wherein the transition metal is rhodium.