JPS59231065A - Novel propionic acid derivative salt and optical resolution of propionic acid derivative - Google Patents

Abstract

NEW MATERIAL:The salt of the propionic acid derivative of formula I (Ar is lower alkoxy-substituted phenyl) and alpha-phenylethylamine. USE:A synthetic intermediate of pharmaceuticals. For example, it is useful as a synthetic intermediate of a vasodilator, diltiazem hydrochloride. PREPARATION:The compound of formula I (threo-type) is prepared by reacting 2-aminothiophenol with the glycidic acid ester of formula II (R<3> is eater residue) in a solvent at 100-140 deg.C, and hydrolyzing the reaction product. The optical resolution of the propionic acid derivative can be carried out reacting the racernic compound of the propionic acid derivative of formula I with an optically active alpha-phenylethylamine to obtain the corresponding salt, and separeting and collecting the produced hardly soluble salt and the easily soluble salt from each other taking advantage of the solubility difference of the optically active salts.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel salt of a propionic acid derivative represented by the general formula (wherein Ar represents a lower alkyl group substituted with a lower alkoxy group) and a method for optical resolution of the propionic acid derivative [I]. .

The above compound [I] is a compound useful as an intermediate for the synthesis of pharmaceutical compounds, and is an important compound, for example, as an intermediate for the synthesis of diltiazem hydrochloride, a coronary vasodilator.

Conventionally, the method for optically resolving this compound is to use ephedrine [Pharmaceutical Journal Vol. 93.

No. 6, 729-732 (1973)), but the separation yield by this method was low (about 34%) and could not be called a sufficiently advantageous method industrially.

In view of this situation, the present inventors have conducted intensive research to find a more industrially advantageous dividing method.

The propionic acid derivative represented by the general formula (1) forms a diastereomeric salt with optically active α-phenylethylamine, and if this diastereomeric salt is used, it is possible to form a compound based on the excellent properties of the salt. It has been found that optical resolution can be carried out with industrial advantage.

That is, according to the present invention, the optically active form of the propionic acid derivative [I] is produced by reacting the racemic form of the propionic acid derivative C1) with the optically active α-phenylethylamine to form the corresponding salt. It can be produced by utilizing the solubility difference between the optically active salts of the species and further eliminating the optically active amine from the obtained optically active salt.

In the present invention, the phenyl group substituted with a lower alkoxy group represented by Ar in compound [1] which is the agent to be split includes a phenyl group substituted with a methoxy group or an ethoxy group. In addition, since this compound [1] has two asymmetric carbon atoms at the 2- and 3-positions, it has two stereoisomers: the threo-type and the erythro-type. In the present invention, the threo-type is particularly used. is preferred.

The amount of optically active α-phenylethylamine used as a resolving agent varies slightly depending on the optical purity of the resolving agent. It is preferable to use 1 to 1.2 equivalents.

As a solvent, water, a hydrophilic organic solvent such as methanol, ethanol, or acetone, a mixed solvent of water and these hydrophilic organic solvents, or a hydrophobic organic solvent such as benzene or ethyl acetate are used. In this case, due to the large solubility difference between the two diastereomeric salts produced and the small solubility of the poorly soluble diastereomeric salt,
It is industrially and economically advantageous to use water.

The salt-forming reaction can be carried out, for example, by stirring the racemic propionic acid derivative (1) and optically active phenylethylamine in the above-mentioned solvent at room temperature or under heating. Here d
-When using α-phenylethylamine, the compound [1]
The fence with the 6 bodies is also l! When using one unit, the compound (1
) together with l becomes a sparingly soluble salt and precipitates out. In order to precipitate the sparingly soluble salts among the diastereomers produced, in addition to cooling the reaction solution, concentration, changing the solvent composition, formation, etc. (or a combination thereof) can be employed.

In order to separate and obtain the precipitated sparingly soluble diastereomer salt, a conventional solid-liquid separation method such as filtration can be employed.

The optical purity of the hardly soluble diastereomeric salt thus obtained is usually 95% or more, and if it is necessary to further increase the optical purity, an optically pure diastereomeric salt can be easily obtained by recrystallization. I can do it.

The obtained slightly soluble diastereomeric salt can be decomposed to obtain the optically active form of compound (1) using conventional methods. For example, the diastereomeric salt may be heated and dissolved in water, and a mineral acid such as hydrochloric acid may be added thereto to precipitate crystals.

On the other hand, in order to obtain the optically active compound [I] from the easily soluble diastereomer salt contained in the mother liquor from which the poorly soluble diastereomer salt has been separated, a mineral acid such as hydrochloric acid is added to the mother liquor. All you have to do is remove the crystals that precipitate.

The optically active α-phenylethylamine used as a resolving agent was obtained by making the 0 solution obtained by taking the optically active form of compound [I] with an alkali such as sodium hydroxide or potassium hydroxide, and then adding a solution of benzene, ethyl acetate, ether, etc. After extraction with hydrophobic organic solvents.

By distilling off the solvent, it can be quantitatively recovered and reused.

2. Compound (1) of the present invention can be produced by the method described in Japanese Patent Publication No. 45-9383. That is, 2-aminothiophenol and a glycidic acid ester represented by the general formula (wherein, Ar has the same meaning as above and + R8 represents an ester residue) are mixed in a solvent with a concentration of 100 to 14
React at 0°C, then hydrolyze 11. Just do it.

According to this method, compound [I) is obtained in the threo form.

Next, the present invention will be specifically explained using examples.

Example 1 2-hydroxy-3-(2'-aminophenylthio)-
Racemic form of 3-phenylpropionic acid (threo form)6.
389 and d-α-phenylethylamine 2.5El
After heating and dissolving the mixture in 100 rnl of water, the mixture was stirred at room temperature for 5 hours. The precipitated crystals were separated and recrystallized from 60 ml of water to obtain 3.952 ml of a salt of an optically pure threo-type compound and d-α-phenylethylamine.

m, p, 157-158°C [α)” = +376° (C = 0.511.ethanol)
Almost similar results were obtained even when ethanol and 50% ethanol aqueous solution were used as the solvent.

Example 2 The optically pure salt obtained in Example 1 was heated and dissolved in 180 mL of water, and 8.9 ml of 1N aqueous hydrochloric acid solution was added thereto, followed by cooling. The precipitated crystals were separated, washed with water, and dried to obtain 2.687 optically pure threo-type compound [I]. Yield 84% m, p, 138-139°C [α] o-ki 346° (C = 0.355. ethanol)
On the other hand, 8.5 ml of 1N aqueous hydrochloric acid solution was added to the mother liquor from which six d-α-phenylethylamine salts of compound [1] were collected.
Seven crystals were collected, washed with water, and dried to obtain 2.405' of a threo-type compound CD.

[α)”=-306° (C=0.360.ethanol)
l〕

Claims (1)

[Claims] 1) A salt of a propionic acid derivative represented by the general formula) and α-phenylethylamine. 2) The compound according to claim 1, which is a salt of a threo-type propionic acid derivative and optically active α-phenylethylamine. 3) The compound according to claim 1 or 2, which is a salt of a threo-type optically active propionic acid derivative and optically active α-phenylethylamine. 4) Racemic form of propionic acid derivative represented by the general formula (Ar represents a phenyl group substituted with a lower alkoxy group) and optical activity α
- After reacting with phenylethylamine to form the corresponding salt, the sparingly soluble salt and easily soluble salt are separated and collected by utilizing the solubility difference between the two optically active salts produced. Characteristic manufacturing method. 5) Racemic form of propionic acid derivative represented by the general formula (where Ar represents a phenyl group substituted with a lower alkoxy group) and optical activity α
- After reacting with phenylethylamine to form the corresponding salt, one of the optically active propionic acid derivatives, optically active α- After separating and collecting phenylethylamine salt. A method for producing an optically active propionic acid derivative 0), which comprises further eliminating optically active α-phenylethylamine from the obtained optically active salt.