WO1998032727A1 - Process for producing optically active benzylsuccinic acid and intermediate therefor - Google Patents

Abstract

A process for producing the optically active benzylsuccinic acid represented by formula (III) (wherein the carbon atom indicated by (S) has the S configuration), which is useful as a starting material for the benzylsuccinic acid derivative represented by formula (I) and salts thereof which are useful as a diabetic remedy, from a mixture of corresponding optical isomers through optical resolution using as an optical resolving agent an organic amine selected among (R)-1-(1-naphthyl)ethylamine, (R)-α-methylbenzylamine, (S)-1-phenyl-2-(p-tolyl)ethylamine, and quinine; and salts of the optically active benzylsuccinic acid, useful in the method of optical resolution, with an organic amine selected among (R)-1-(1-naphthyl)ethylamine, (R)-α-methylbenzylamine, (S)-1-phenyl-2-(p-tolyl)ethylamine, and quinine. The optically active benzylsuccinic acid having a high optical purity and a high chemical purity can be efficiently obtained by the method of optical resolution.

Description

 Description Method for producing optically active benzylsuccinic acid and intermediate for producing the same

[Technical field]

 The invention relates to the formula

(The carbon atom with (S) in the formula represents a carbon atom in the S configuration) and a method for producing an optically active benzylsuccinic acid, and an intermediate for the production thereof. More specifically, the present invention provides (R) -1- (1-naphthyl) ethylamine, (R) -methylbenzylamine, (S) _l-phenyl-2- (p) as an optical resolving agent. —Tolyl) Using an organic amine selected from ethylamine and quinine, the formula

Benzyl succinic acid, which is a mixture of (R) -isomer and (S) -isomer represented by the formula, has an excellent hypoglycemic effect and is useful as a therapeutic agent for diabetes.

(HI)

 (Wherein the carbon atom to which (S) is attached has the same meaning as described above), which is useful as a raw material for the production of an optically active benzylsuccinic acid monoamide derivative and a pharmacologically acceptable salt thereof. An optical resolution method for industrially efficiently producing an optically active benzyl succinic acid represented by the formula (I) with high optical purity and high chemical purity, and the above formula

A useful intermediate for the production of an optically active benzylsuccinic acid represented by the formula (I): ^HOOC ^) COOH

(Where the carbon atom with (S) in the formula has the same meaning as described above) and (R) -1- (1-naphthyl) ethylamine, and (R) -a

—Methylbenzylamine, (S) —1-phenyl 2 -— (p-tolyl) ethylamine and a salt with an organic amine selected from quinine.

 [Background technology]

 The optically active benzyl succinic acid monoamide derivative represented by the formula (III), which is useful as a therapeutic agent for diabetes, comprises the optically active benzyl succinic acid represented by the formula (I) or a reactive functional derivative thereof. Imidazole, phenolyldiimidazole, oxalyldiimidazole, thionyldiimidazole, thiocarbonidimidazole, N, N'-disuccinimidyl carbonate, N-hydroxysuccinyl By reacting with imide or N-hydroxy-5-norbornene-2,3-dicarboximide, the general formula

(B in the formula is an imidazolyl group, an N-oxysuccinimide group, or an N-oxy-1-bicyclo [2,2,1] hepta-1-ene-1,3-dicarboximid group. , (S) has the same meaning as above) to obtain a benzylsuccinic acid derivative represented by the formula:

Can be selectively and simply produced by reacting a cyclic amine represented by the formula (1) and then hydrolyzing it (Japanese Patent Application Laid-Open Nos. 6-340622 and 6-340623).

An optically active benzyl ester represented by the formula (III) useful as a therapeutic agent for diabetes _n Hakusan Monoami de derivatives are difficult, low-melting crystalline material is crystallized, for purification on not handle force easily, as a raw material to provide a high optical purity and high chemical purity of the drug substance are required as a medicament It is necessary to produce and use very high quality optically active benzyl succinic acid represented by the above formula (I).

As a method for producing the optically active benzylsuccinic acid represented by the formula (I) used as a starting material in the above production method, a chiral diphosphine complex of a transition metal such as ruthenium is used as an asymmetric hydrogenation catalyst. formula

(E) —Production method by catalytic reduction of itaconic acid derivative (J. Chem. Soc. Perkin Trans. I (1989), pp. 1571-1575; published in Japan Japanese Patent Publication No. Hei 5-170718) is known. However, the method of producing the optically active benzyl succinic acid represented by the above formula (I) by catalytically reducing (E) -itaconic acid derivative using an asymmetric catalyst has the following problem. E) — It is necessary to use geometric isomers, and there are restrictions on the geometric isomerism of the raw materials that can be used. In addition, the obtained optically active substance is still unsatisfactory in optical purity in order to provide an optically active benzylsuccinic acid monoamide derivative represented by the above formula (III) as a pharmaceutical. In order to further improve the optical purity, it is necessary to perform another purification operation after the completion of the catalytic reduction. In addition, the process is complicated, such as the need for treatment under pressure or for a long time using an expensive asymmetric catalyst, and the use of the asymmetric catalyst may cause inactivation or decrease in selectivity. However, problems remain in terms of industrial recovery and reuse.

 [Disclosure of the Invention]

 The formula is a)

Satsu ^ COOH .

 Four

(The carbon atom with (S) in the formula represents a carbon atom in the S configuration.) The present invention relates to a method for producing an optically active benzylsuccinic acid represented by the formula:

 The present invention relates to an optically active benzyl succinic acid of the formula (I) and (R) -1- (1-naphthyl), which is useful as an intermediate for producing the optically active benzyl succinic acid of the formula (I). Ethylamine, (R) — 1-methylbenzylamine, (S) — l-phenyl

—2— (p-tolyl) Ethylamine is a salt with an organic amine selected from quinine.

 The present invention relates to an optically resolving agent for producing the optically active benzylsuccinic acid represented by the formula (I), wherein (R)-(1-methylbenzyl) amine, (S) -1-phenyl-2- (p-) Tolyl) It relates to the use of organic amines selected from ethylamine and quinine.

 The present invention provides an optically active benzyl succinic acid monoamide derivative represented by the above formula (III), which is useful as a therapeutic agent for diabetes. As a method for producing benzyl succinic acid, the present invention provides a novel production method by optical resolution which is different from the production method by catalytic reduction using a conventional asymmetric catalyst.

 That is, the optical resolution method of the present invention uses benzyl succinic acid which is a mixture of the (R) -isomer and the (S) -isomer represented by the formula (II), and uses (R) as an optical resolution agent — 1— (1-naphthyl) ethylamine, (R) — 1-methylbenzylamine, (S) — 1-phenyl-2- (p-tolyl) using an organic amine selected from ethylamine or quinine And dissolving the benzyl succinic acid of the formula (II) in a predetermined solvent to obtain (R) -1- (1-naphthyl) ethylamine, (R) -methylbenzylamine, (S)- After adding an appropriate amount of an organic amine selected from 1-phenyl-1- (p-tolyl) ethylamine or quinine, crystallization is performed by inoculating a diastereomer salt as needed, and, if desired, the obtained diastereomer is obtained. The salt is re-used with the given solvent After crystallizing, this operation is repeated, and then deamination treatment is carried out according to a conventional method to produce the optically active benzylsuccinic acid represented by the above formula (I).

The formula (II) used as a raw material in the optical resolution method of the present invention is represented by the following formula: The benzyl succinic acid to be used is preferably, in consideration of the recovery rate, the content of the (S) -isomer equal to or more than the content of the (R) isomer, If the amount is small, it can be racemized by subjecting it to heat treatment and used as a racemic mixture.

 The amount of the optical resolving agent used in the optical resolving method of the present invention is usually an equimolar amount to the benzylsuccinic acid represented by the formula (II), but the starting material and the optical resolving agent are in a 1: 2 diastereomer. When a monosalt is formed, the amount is twice as much as the benzyl succinic acid represented by the formula (II).

The solvent used in the optical resolution method of the present invention, generally benzyl succinate force represented by raw material der Ru Formula ^(II)? Long as it dissolves, eg if Etano Ichiru, isopropanol Alcohol solvents such as 1 liter can be mentioned. The deamidation treatment in the optical resolution method of the present invention includes an acid treatment using a mineral acid such as hydrochloric acid and sulfuric acid and an alkali treatment using an inorganic base such as sodium hydroxide and potassium hydroxide in a conventional manner. It can be implemented by appropriately combining them.

 The benzyl succinic acid represented by the formula (II) used as a starting material in the optical resolution method can be produced by a method described in a literature or a method similar thereto (J. Am. Chem. So c., Vol. 74, pp 5147-5151 (1952); J. Org. Chem., Vol. 8, pp. 285-289 (1943)). For example, formula (VII)

A racemic mixture obtained by subjecting (E) or (NO) and (Z) -itaconic acid derivatives represented by HOOcJL _COOH to an ordinary hydrogenation operation that is widely used in industry using an ordinary catalyst such as palladium carbon Can be carried out as a raw material. Also, the general formula

(Where R is an alkyl group) and a dialkyl benzylmalonate O 98/32727 g Obtained by reacting with alkyl moacetate in the presence of a base, General formula

 (R in the formula has the same meaning as described above), and then a racemic mixture can be produced by hydrolyzing the tricarboxylic acid ester derivative represented by the formula (1), followed by heat treatment and decarboxylation.

 As described above, the optical resolution method of the present invention, when producing benzyl succinic acid as a raw material, is not subject to any restrictions on the geometrical isomerism of the itaconic acid derivative, which is the source of the production, and is widely used industrially. It can be manufactured by a normal hydrogenation operation, and can be easily manufactured by a separate manufacturing method. Further, the optical resolution method of the present invention is characterized in that the optically active benzyl succinic acid represented by the above formula (I), (R) -1- (1-naphthyl) ethylamine, and (R) -hydroxymethylbenzylamine , (S) —

1 monophenyl-1- (p-tolyl) ethylamine or quinine, which is achieved by a selective salt-forming effect with an organic amine, and is an optically active compound represented by the above formula (I). Select from benzylsuccinic acid and (R) -1- (1-naphthyl) ethylamine, (R) -Hi-methylbenzylamine, (S) -1-phenyl-2- (p-tolyl) ethylamine or quinine The salt with the organic amine is a salt having good crystallinity. The organic amine is added to the solution of the benzyl succinic acid represented by the formula (II) to cause crystallization, and recrystallization is repeated as required. After that, a deamination treatment can be carried out to make the production very simple. The optically active benzylsuccinic acid represented by the formula (I) obtained by performing the optical resolution method of the present invention has high quality.

Further, the filtrate obtained by carrying out the optical resolution method is appropriately deaminated, and then the obtained benzylsuccinic acid is melted at a high temperature for several hours and subjected to a racemization operation. Thus, it can be reused as benzyl succinic acid represented by the formula (II) as a raw material. Thus, in the optical resolution method of the present invention, the benzyl succinic acid of the above formula (II) as a raw material can be effectively used, which is a very useful method. „

[Best Mode for Carrying Out the Invention]

 The content of the present invention will be described in more detail with reference to the following Reference Examples, Examples and Comparative Examples, but the present invention is not limited to these. The melting points of the compounds in the examples and comparative examples are all uncorrected, and the optical purity shows the optical purity of (S) -benzylsuccinic acid. And (S) _benzyl succinic acid dimethyl ester were measured using HPLC (high performance liquid chromatography) under the following conditions.

Column used Chiral cell OD (4.6 y5 X 25 Omm, Daicel Chemical Industries) Elution solvent n-hexane Z isopropanol = 98Z2 (vZv)

Flow rate 1. Om l Z min

Column temperature

Detection wavelength 220 nm

卖 Example 1

 Optical Resolution with (S) -1-1-Phenyl-2- (p-tolyl) ethylamine 2.08 g of benzylsuccinic acid and 2.11 g of (S) -1-phenyl-2- (p-tolyl) ethylamine are heated and dissolved in 50 ml of isopropanol. Then, this solution was inoculated with a diastereomer salt of interest, which was separately prepared, and allowed to stand. The precipitated crystals were collected by filtration to obtain 1.91 g of a diastereomer salt (optical purity: 67.3% e e). 1.91 g of this diastereomer salt was dissolved by heating in 40 ml of isopropanol, and the desired diastereomer monosalt prepared separately was inoculated and allowed to stand. The precipitated crystals were collected by filtration to obtain 1.49 g of a diastereomer salt (optical purity: 90.2% e e). Similarly, recrystallization was performed once using 20 ml of ethanol as a solvent to obtain 0.66 g of a diastereomer salt (recovery rate 31.6%, optical purity 99.2% e e).

Melting point: 152-154 ° C

1 H-NMR (DMS 0- d ₆ ) S ppm:

 2.1-2.25 (m, 2H), 2.22 (s, 3H), 2.4-2.7 (m, 2H), 2.9-3.1 (m, 3H), 4.3-4.4 (m, 1H), 6.9-7.05 (m, 4H ), 7.15-7.4 (m, 10H)

Specific rotation: [H] _D ²⁴ ' ⁵ = + 46.3 ° (c = l.01, methanol) To 500 mg of the obtained diastereomer salt was added 5 ml of a 1N aqueous sodium hydroxide solution and 5 ml of methylene chloride, and the mixture was stirred for 30 minutes. The aqueous layer was separated, washed with 5 ml of methylene chloride, acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to give 235 mg of (S) -benzylsuccinic acid (yield 94.9%, optical purity) 100% ee).

δ Example 2

 (R) Optical resolution with 1- (1-naphthyl) ethylamine

 2.08 g of benzylsuccinic acid and 1.71 g of (R) -1- (1-naphthyl) ethylamine were dissolved in 120 ml of ethanol by heating, and the resulting diastereomer salt, which was separately prepared, was inoculated into the solution and allowed to stand. The precipitated crystals were collected by filtration to obtain 1.17 g of diastereomer 0 salt (optical purity: 86.5% e e). 1.17 g of this diastereomer salt was dissolved by heating in 80 ml of ethanol, and the target diastereomer salt prepared separately was inoculated and allowed to stand. The precipitated crystals were collected by filtration to obtain 0.79 g of a diastereomer salt (recovery rate: 41.4%, optical purity: 99.2% e e).

 Melting point: 163 ~: at I64

5 ¹ H-NMR (DMS 0- d ₆ ) d ppm:

 1.55 (d, J = 6.7Hz, 3H), 2.1-2.25 (m, 2Η), 2.3-2.7 (m, 2Η),

3.00 (dd, J = 13.1, 4.8Hz, 1H), 5.1-5.25 (m, 1H), F.1-7.2

(m, 3H), 7.2-7.3 (m, 2H), 7.55-7.65 (m, 2H), ff 0 (d,

J = 6.8Hz, 1H), 7.92 (d, J = 8.lHz, 1H), 7.99 (d, J = 9.2Hz, 1H), 0 8.19 (d, J = 8.8Hz, 1H)

Specific rotation: [] _D ²⁴ = — 8.5 ° (c = l. 05, methanol)

 Hereinafter, (S) -benzylsuccinic acid was obtained in the same manner as in Example 1 (optical purity 100% e e) o.

 Example 3

δ (R) — optical resolution with methyl benzylamine

2.08 g of benzyl succinic acid and 2.42 g of (R) -methylbenzylamine were dissolved in 80 ml of ethanol while heating, and the resulting diastereomer monosalt separately prepared was inoculated into the solution and allowed to stand. The precipitated crystals were collected by filtration to obtain 2.30 g of a diastereomer salt (optical purity: 41.2% ee). 2.30 g of this diastereomer salt in 60 ml of ethanol _g

And inoculated with a diastereomer salt of interest, which was separately prepared, and allowed to stand. 'The precipitated crystals were collected by filtration to obtain 1.17 g of diastereomer salt (optical purity: 67.0% ee) ₍ Similarly, recrystallization was performed twice using 50 ml and 40 ml of ethanol as a solvent to obtain 0.89 g of diastereomer salt. (Recovery rate 39.6%, optical purity 100% ee, the diastereomer salt is a salt of (S) -benzylsuccinic acid: (R) -methyl benzylamine = 1: 2).

Melting point: 129-131 ° C

^{1 H-NMR (DMSO - d} 6) δ ppm:

 1.35 (d, J = 6.7Hz, 6H), 2.05-2.25 (m, 2H), 2.4-2.6 (m, 2H), 3.03 (dd, J = 12.5, 3.7Hz, 1H), 4.15-4.25 (m, 2H), 7.1-7.45 (m, 15H)

Specific rotation: [] _D ²⁴ = —2.5 ° (c = l.05, methanol)

 Thereafter, (S) -benzylsuccinic acid was obtained in the same manner as in Example 1 (optical purity 100% e e) o.

 m 4

Optical resolution by kinin

 2.08 g of benzylsuccinic acid and 3.24 g of quinine were dissolved in 40 ml of ethanol with heating, and the resulting diastereomer monosalt separately prepared was inoculated into this solution and allowed to stand. The precipitated crystals were collected by filtration to obtain 2.48 g of a diastereomer salt (optical purity: 59.8% e e). 2.48 g of this diastereomer salt was dissolved by heating in 30 ml of ethanol, and after inoculating a separately prepared diastereomer salt of interest, the mixture was allowed to stand. The precipitated crystals were collected by filtration to obtain 1.82 g of a diastereomer salt (optical purity: 80.6% e e). Similarly, recrystallization was performed three times using 30 ml, 20 ml and 30 ml of ethanol as a solvent to obtain 0.66 g of diastereomer salt (recovery rate 24.8%, optical purity 99.4% e e).

Melting point: 177 ~: I 79 ° C

^{1 H-NMR (DMSO - d} 6) δ ppm:

1.45-1.9 (m, 5H), 2.22 (dd, J = 16.4, 4.1Hz, 1H), 2.25-2.4 (m, 2H), 2.55-2.8 (m, 3H), 2.95 (dd, J = 13.3, 5.8 Hz, 1H), 3.05-3.15 (m, 1H), 3.2-3.5 (m, 3H), 3.92 (s, 3H), 4.96 (d, J = 10.4Hz, 1H), 5.03 (d, J = 17.0Hz, 1H), 5.42 (bs, 1H), 5.8-5.95 (m, 2H), 7.15-7.2 (m, 3H), 7.25-7.3 (m , 2H), 7.41 (dd, J = 9.1, 2.7Hz, 1H), 7.55 (d, J = 2.7Hz, 1H), 7.55 (d, J = 4.4Hz, 1H), 7.95 (d, J = 9.1Hz) , 1H), 8.71 (d, J = .7Hz, 1H) Specific rotation: [H] _D ²⁴ = — 1 27.1 ° (c = 1.03, methanol)

 Thereafter, (S) -benzylsuccinic acid was obtained in the same manner as in Example 1 (optical purity 100% e e) o

Comparative Example 1

 (R) Optical resolution by monophenylalaninol

2.08 g of benzylsuccinic acid and 1.51 g of (R) -phenylalaninol were dissolved by heating in 20 ml of ethanol, and the resulting diastereomer salt prepared separately was inoculated into this solution and allowed to stand. The precipitated crystals were collected by filtration to obtain 1.08 g of a diastereomer salt (optical purity: 53.6% ee). 1.08 g of this diastereomer monosalt was dissolved by heating in 10 ml of ethanol, and after inoculating a separately prepared diastereomer salt of interest, the precipitated crystals were collected by filtration to obtain 0.64 g of diastereomer salt (optical purity: 73.7% ee). Similarly, recrystallization was performed three times using 6 ml, 4 ml and 4 ml of ethanol as a solvent to obtain 0.13 g of diastereomer salt (recovery rate 7.1%, optical purity 99.5% ee). _C Melting point: 150 ~ 15 1 ° C

¹ H-NMR (DMSO-d ₆ ) δ ppm:

2.1-2.2 (m, 2H), 2.4-2.65 (m, 2H), 2.78 (d, J = 7.lHz, 2H),

3.01 (dd, J = 13.0, 4.7Hz, 1H), 3.2-3.35 (m, 2H), 3.46 (dd,

J = 11.2, 3.6Hz, 1H), 7.15 -F.4 (m, 10H)

Specific rotation: [H] _D ²⁴ = -10.1 ° (c = 1.02, methanol)

 Thereafter, (S) -benzylsuccinic acid was obtained in the same manner as in Example 1.

Comparative Example 2

 (R) Optical resolution with 1-phenylglycinol

2.08 g of benzylsuccinic acid and 1.37 g of (R) -phenylglycinol were dissolved by heating in 30 ml of ethanol, and this solution was inoculated with a diastereomer salt of interest, which was separately prepared, and allowed to stand. The precipitated crystals were collected by filtration to obtain 1.57 g of a diastereomer salt. (Optical purity 36.396 ee). The Jiasutereoma salt 1.57 g was heated and dissolved in ethanol 20 ml, collected by filtration was left unattended and _{(precipitated} crystals following inoculation with Jiasutereoma salt of interest which is separately prepared to obtain Jiasutereoma salt 0.98 g (ee optical purity 75.6%). Similarly, recrystallization was performed three times using 15 ml, 10 ml and 8 ml of ethanol as a solvent to obtain 0.18 g of diastereomer monosalt (recovery rate 10.2%, optical purity 99.2% ee). _C Melting point: 148 to 1 50 ° C

1 H-NMR (DMSO - d 6) δ ppm:

 2.1-2.2 (m, 2H), 2.3-2.7 (m, 2Η), 2.99 (dd, J = 13.2, 5.0Hz,

1H), 3.5-3.7 (m, 2H), 4.1-4.2 (m, 1H), 7.15-7.5 (m, 10H) Specific rotation: [H] _D ²⁴ = — 28.5 ° (c = l. 09 , Methanol)

 Thereafter, (S) -benzylsuccinic acid was obtained in the same manner as in Example 1.

Reference example

Method for recovering benzylsuccinic acid

 The filtrates of Examples 1 to 4 were distilled off under reduced pressure, and 20 ml of 1N aqueous sodium hydroxide solution and 20 ml of methylene chloride were added to the obtained diastereomer mixture 3.2, followed by stirring. The aqueous layer was separated, neutralized with concentrated hydrochloric acid, and the precipitated benzylsuccinic acid (1.50 g) was melted at 180 ° C for 1 hour.After cooling, 4 ml of a 5N aqueous sodium hydroxide solution was added, and the mixture was heated and returned for 2 hours. Shed. After cooling, the mixture was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to obtain 1.36 g of a racemic mixture.

Claims

Um Claims 1 set C _00H

 (Where the carbon atom with (S) in the formula indicates a carbon atom in the S configuration) and (R) -1- (1-naphthyl) ethylamine, (R) -1- (1-naphthyl) ethylamine and (R)- (1) Formula by subjecting a salt with an organic amine selected from (S) —1-phenyl-2- (p-tolyl) ethylamine and quinine to deamination treatment. ^H COOH

 (Where the carbon atom with (S) in the formula represents a carbon atom in the S configuration). 2. Expression

A mixture of (R) -isomer and (S) -isomer represented by benzyl succinic acid and (R) -1- (1-naphthyl) ethylamine, (R) -methylbenzylamine, (S ) — 1-Phenyl _ 2— (p-tolyl) React with an organic amine selected from ethylamine ^H COOH

(The carbon atom with (S) in the formula indicates a carbon atom in the S configuration.) Benzylsuccinic acid and (R) —1- (1-naphthyl) ethylamine, (R) —— methylbenzylamine, (S) —1-phenyl-1-2- (p-tolyl) ethylamine and quinine By obtaining a salt with an organic amine and subjecting it to a deamination treatment, ^H COOH

 (Where the carbon atom with (S) in the formula represents a carbon atom in the S configuration). 3. Expression ^H COOH

 (Where the carbon atom with (S) in the formula indicates a carbon atom in the S configuration) and (R) — 1— (1-naphthyl) ethylamine, (R) — (1) Methyl benzylamine, (S) — 1-phenyl-2- (p-tolyl) ethyl A salt with an organic amine selected from amines and quinines. 4. Expression

From benzylsuccinic acid, which is a mixture of (R) -isomer and (S) -isomer represented by the formula: ^H COOH

(The carbon atom with (S) in the formula indicates a carbon atom in the S configuration.) ( _R )-! As an optical resolving agent in the process for producing neutral benzylsuccinic acid! One (one naphthyl) ethylamine, (R) one methylbenzylamine, ( _s) — 1—Feneru 2— (p-tolyl) Use of organic amines selected from ethylamine and quinine.