JPH10101629A - Production of optically active butyric acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for effectively producing an optically active butyric acid derivative useful as an intermediate, etc., for a medicine such as an agent for inhibiting platelet coagulation in high optical purity and high yield by treating a specific racemic butyric acid derivative with a specified optically active phenylethylamine derivative as a resolution agent in a specific condition. SOLUTION: The objective optically active butyric acid derivative having R-configuration or S-configuration of formula III is obtained by separating a racemic butyric acid derivative of formula I (Z is a protective group of an amino group) by using an optically active phenylethylamine derivative of formula II [X is nitro, a halogen or an alkyl; (n) is 0-5] having R-configuration or S-configuration as a resolution agent in 0.4-0.9mol based on 1mol racemic butyric acid derivative in the method for producing the optically active butyric acid derivative. Further, the racemic butyric acid derivative of formula I is preferably recovered by racemizing the needless optically active butyric acid derivative of formula III having the R-configuration or the S-configuration in the presence of a salt or an acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the formula [III]

[0002]

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The present invention relates to an industrially useful method for producing an optically active butyric acid derivative represented by the formula (wherein Z represents a hydrogen atom or an amino group-protecting group). The optically active butyric acid derivative represented by the formula [II] has, for example, an excellent inhibitory effect on platelet aggregation, and is expected to have therapeutic usefulness in the formula [IV]

[0004]

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An optically active compound (WO 96)
/ 15117) is useful as an intermediate in the synthesis.

[0006]

2. Description of the Related Art An optically active butyric acid derivative represented by the formula [III] is synthesized by asymmetric synthesis (Japanese Patent Laid-Open No. 3-163).
No. 050), but it is not suitable for industrial production because it requires a high-pressure and expensive catalyst. Further, an optically active butyric acid derivative, a similar compound of the formula [III] (in the formula [III], ZN
A method of performing optical resolution of a compound having a H portion of Br is described in the literature (Journal of Medicinal Chemistry, Vol. 39, 2
97, 1996). However, in this method, an equal amount of an optical resolving agent is used, and purification is repeated in order to obtain a target product having a high optical purity, so that the yield is poor and also unsuitable for industrial production.

[0007]

The prior art is high pressure,
An expensive catalyst was used or the yield was poor, and it was not suitable for producing an optically active butyric acid derivative represented by the formula [III] on an industrial scale. An object of the present invention is to produce an optically active butyric acid derivative represented by the formula [III] by a method useful for industrial production.

[0008]

The present invention provides a compound of the formula [I]

[0009]

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(Wherein Z has the same meaning as described above), and a racemic butyric acid derivative represented by the formula [II]

[0011]

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Wherein X is a nitro group, a halogen atom or an alkyl group, n is 0 or an integer of 1 to 5, provided that when n is 2 or more, X may be different good.)
The optically active phenylethylamine derivative having the R-configuration or the S-configuration represented by the following formula is used as a resolving agent, and the corresponding resolving agent is used in an amount of 0.4 to 0.9 mol per mol of the racemic butyric acid derivative.
1 is a method for producing an optically active butyric acid derivative having an R-configuration or an S-configuration represented by the formula [III].

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the formula [III] has the following formula:

[0014]

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Although it may exist in the form of either the R-form or the S-form shown by the formula, when used as an intermediate of the final useful compound of the formula [IV], the former R-form is preferred. The compound of the formula [II] used as the optical resolving agent has the following formula

[0016]

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In the case where the R-form of the formula [III] is obtained as a resolving salt, the latter S-form is used. The solvent used for the optical resolution of the racemic butyric acid derivative is not particularly limited as long as it is inert to the reaction, but an alcohol solvent, acetonitrile, dioxane, DMF, acetone, etc., or a mixed solvent of those solvents is used. Can be used. Among them, alcoholic solvents are preferable, and C1 to C4 are particularly preferable.
Is preferred.

The amount of the resolving agent used at the time of optical resolution is
In order to obtain a butyric acid derivative having high optical purity, 0.4 to 0.9 mol per 1 mol of the compound represented by the formula [I],
Preferably, 0.48 to 0.52 mol is used. From the racemic butyric acid derivative represented by the formula [I], the reaction of the R- or S-form optically active butyric acid derivative with the phenylethylamine salt is carried out by adding the racemic butyric acid derivative and R or S
After addition of phenylethylamine, the temperature is raised until both are dissolved and stirred at that temperature for a few minutes to a few hours. Thereafter, the mixture is cooled, and if necessary, a phenylethylamine of an optically active butyric acid derivative is inoculated. After sufficiently stirring, the precipitated phenylethylamine salt of the optically active butyric acid derivative is separated by filtration. The crystals of the obtained salt are usually 90% e.g. e. Having the above optical purity, the optical purity can be further increased by means such as recrystallization.

The salt of the optically active substance thus obtained is
As a salt or as a free form with a base such as sodium hydroxide or sodium carbonate, the compound is reacted with hydrazine according to a known method, if necessary, in the presence of an acid to obtain a compound of the formula [V]

[0020]

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(Wherein, Z represents the same meaning as described above). At this time, the recovered optically active phenylethylamine can be used again as a resolving agent. The above-mentioned optically active butyric acid derivative is separated, and phenylethylamine is separated from the filtrate containing an unnecessary excess of the optically active butyric acid derivative and racemized, whereby the racemic butyric acid derivative represented by the formula [I] is recovered. be able to.

When the racemization is carried out with a base, the filtrate is, if necessary, replaced with a solvent which is immiscible with water. The solvent used here is not particularly limited as long as it is inert to the reaction and does not freely mix with water, and examples thereof include toluene and ethyl acetate. Here, if the filtrate is a solvent that does not mix with water, this step is unnecessary. Add a basic aqueous solution such as sodium hydroxide and sodium carbonate to the substituted solvent,
Perform liquid separation. From the organic layer, optically active phenylethylamine is recovered, which can again be used as a resolving agent.

The aqueous layer is subjected to racemization by stirring it at 50 ° C. under reflux for several minutes to several hours. After cooling, the aqueous layer is adjusted to a pH at which the butyric acid derivative becomes a free form. The racemic butyric acid derivative can be extracted from this aqueous solution with a solvent capable of extracting the butyric acid derivative, for example, ethyl acetate.
Extraction can be performed and recovered. When the racemization is carried out with an acid, if necessary, the filtrate is not mixed with water, and is replaced with a solvent capable of extracting a butyric acid derivative, for example, ethyl acetate.
Here, if the filtrate is a solvent that does not mix with water and can extract the butyric acid derivative, this step is unnecessary.

An acidic aqueous solution such as hydrochloric acid is added to the substituted solvent to carry out liquid separation. From the aqueous layer, an optically active phenylethylamine salt is recovered, which can be used again as a resolving agent after being freed. The organic layer is racemized by substituting with water, adding an acid if necessary, and stirring the mixture at 50 ° C. to reflux for several minutes to several hours. After cooling, the aqueous layer is adjusted to a pH at which the butyric acid derivative becomes a free form. The racemic butyric acid derivative can be extracted and recovered from this aqueous solution with a solvent capable of extracting the butyric acid derivative, for example, ethyl acetate.

The formula [II] recovered by these methods
Can be again divided into optically active butyric acid derivatives by the above-mentioned optical resolution method.
Hereinafter, the present invention will be described in detail with reference to examples.

[0026]

【Example】

Example 1 (Optical Resolution) Racemic 4- (4-aminophenyl) -3-methyl-
2.08 g of 4-oxybutyric acid and 0.64 g of S-phenylethylamine were added to 20 ml of 1-propyl alcohol, and then the temperature was raised to 85 ° C. to dissolve completely. Then, after stirring at 85 ° C. for 10 minutes, the mixture was slowly cooled to 70 ° C. After stirring at 70-75 ° C for 30 minutes, 5 ° C
, Stirred at that temperature for 30 minutes, and filtered. The obtained crystals were washed with 10 ml of 1-propyl alcohol and mixed with the filtrate. The obtained crystals are dried and R-4-
1.17 g of (4-aminophenyl) -3-methyl-4-oxybutyric acid / S-phenylethylamine salt was obtained (optical purity: 98.4% ee). Further, S-4- (4-aminophenyl) -3-methyl- in the obtained filtrate was used.
The optical purity of 4-oxybutyric acid is 55.1% e. e.
And R-4- (4-aminophenyl) -3-methyl-4-oxybutyric acid.S obtained as a crystal by calculation
The yield of -phenylethylamine salt was determined to be 35.9%.

Comparative Example (Optical Resolution; Using Equal Amount of Resolving Agent) Racemic 4- (4-aminophenyl) -3-methyl-
1.05 g of 4-oxybutyric acid and 0.60 g of S-phenylethylamine were added to 15 ml of 1-propyl alcohol, and then the temperature was raised to 90 ° C. to dissolve completely. Then, after stirring at 85 ° C. for 10 minutes, the mixture was slowly cooled to 5 ° C., stirred at that temperature for 30 minutes, and filtered.
The obtained crystals were washed with 10 ml of i-propyl alcohol and mixed with the filtrate. The obtained crystals are dried and R-4- (4
1.30 g of (aminophenyl) -3-methyl-4-oxybutyric acid / S-phenylethylamine salt was obtained (optical purity: 7.5% ee). In addition, S in the obtained filtrate was
The optical purity of 4- (4-aminophenyl) -3-methyl-4-oxybutyric acid is 28.4% e. e. The yield of R-4- (4-aminophenyl) -3-methyl-4-oxybutyric acid / S-phenylethylamine salt obtained as a crystal was calculated to be 79.1%.

Example 2 (Recovery of racemization) The filtrate 60.94 obtained by the same method as in Example 1
g (The optical purity of the contained S-4- (4-aminophenyl) -3-methyl-4-oxybutyric acid is 47.9%
e. e. (Concentration: 6.65 wt%) and replaced with 30 ml of toluene. Add 50 ml of water and add 28%
The pH of the aqueous layer was adjusted to 12.3 with an aqueous NaOH solution. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with 30 ml of toluene.
The aqueous layer was directly heated and refluxed for 2 hours. After cooling the aqueous solution to room temperature, the pH was adjusted to 3 with 6N HCl. This aqueous solution was extracted twice with 30 ml of ethyl acetate, and saturated aqueous sodium chloride was added.
After washing with 0 ml, it was dried over anhydrous magnesium sulfate. After filtering off the anhydrous magnesium sulfate, the ethyl acetate was concentrated and toluene was added to precipitate crystals. The precipitated crystals were separated by filtration and dried to obtain racemic 4-aminophenyl-3.
3.72 g of -methyl-4-oxybutyric acid were obtained. (Purity 97.8wt%)

[0029]

Industrial Applicability The present invention provides an excellent platelet aggregation inhibitor (W
Optically active 4-aminophenyl-3-methyl-4-oxybutyric acid, which is useful as an intermediate for pharmaceuticals such as O96 / 15117 /), can be provided by an industrially advantageous method. Furthermore, the production method of the present invention is an industrially advantageous method because an optically active resolving agent can be recovered by a simple method, and unnecessary optically active substances can be efficiently racemized and reused.

Claims (2)

[Claims] 1. A compound of the formula [I] (Wherein, Z represents a hydrogen atom or an amino-protecting group)
The racemic butyric acid derivative represented by the formula [II] (In the formula, X is a nitro group, a halogen atom or an alkyl group, n is 0 or an integer of 1 to 5, provided that when n is 2 or more, Xs may be different. ), Wherein an optically active phenylethylamine derivative of R-configuration or S-configuration represented by the formula (1) is used as a resolving agent, and the corresponding resolving agent is used in an amount of 0.4 to 0.9 mol per 1 mol of the racemic butyric acid derivative. Formula [III] (Wherein, Z has the same meaning as described above). A process for producing an optically active butyric acid derivative having an R-configuration or an S-configuration represented by the formula: 2. A compound of the formula [III] which is split according to claim 1 and has an undesired R- or S-configuration. Wherein Z represents the same meaning as described above, wherein the optically active butyric acid derivative is racemized in the presence of a salt or an acid. (Wherein, Z has the same meaning as described above).