JPH04308556A - Method for racemizing optically active benzyl alcohol derivative - Google Patents

Abstract

PURPOSE:To readily racemize the (+)-isomer in optically active alpha-[(t-butylamino) methyl]-2-chloro-4-hydroxybenzyl alcohol and obtain the (-)-isomer by treating the aforementioned (+)-isomer with an acid such as hydrochloric acid. CONSTITUTION:The (+)-isomer which has hardly any uses in optically active alpha-[(t-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol expressed by the formula or a mixture containing the (+)-isomer in a high proportion is preferably heated with hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, p-toluenesufonic acid, etc., to produce the racemic modification thereof. The (-)-isomer is then separated from the resultant racemic modification by optical resolution and used as a metratonic agent or a urinary bladder relaxant.

Description

[Detailed description of the invention]

0001

[Field of Industrial Application] The present invention relates to a method for racemizing optically active benzyl alcohol derivatives, and more specifically, to
The following formula (I)

The present invention relates to a method for producing a racemate of optically active α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol represented by the following formula with an acid.

0002

BACKGROUND OF THE INVENTION A method for racemizing optically active benzyl alcohol derivatives according to the present invention has not been known so far.

0003

[Problems to be Solved by the Invention] The present inventors have previously discovered a novel (-)-α-[(tert
-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol and its salts, and their use as uterine relaxants and bladder relaxants.

[0004] In producing the compound represented by formula (I), its racemic form is optically resolved.

[0005] This separation method separates (-)-isomer and (+)-isomer.
This is a method of obtaining the (-)-isomer by optical resolution from a racemate containing isomers at a ratio of 1:1, and the (+)- isomer is recovered from the mother liquor after obtaining the desired (-)-isomer. Isomers or mixtures with a high proportion of (+)-isomers had to be discarded without being reused.

[0006] It is possible to racemize the conventionally discarded (+)-isomer or a mixture with a high proportion of (+)-isomer to obtain a racemate and reuse it as a manufacturing raw material. (-
)-isomers can be obtained efficiently, which has great industrial value.

[0007]

[Means for Solving the Problem] As a result of intensive research in view of the above-mentioned circumstances, the present inventors have discovered that the optically active α-[(tert-butylamino)methyl]-
The present invention was completed based on the discovery that the racemization reaction progresses by treating 2-chloro-4-hydroxybenzyl alcohol with an acid.

Examples of acids used in the production method of the present invention include hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and p-toluenesulfonic acid.
These acids can be used in the reaction as a hydrous alcohol solution such as propanol or isopropanol, and these acids can be used as optically active α-[(tert-butylamino)methyl]-2-chloro-4- It is preferable to use 2 or more equivalents per 1 equivalent of hydroxybenzyl alcohol.

[0009] The reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent, but since this racemization reaction requires a long time at room temperature, it is preferable to heat the reaction.

0010

[Examples] The present invention will be explained below with reference to Examples.
The invention is not limited to the specific details of these examples.

Example 1 α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol L-tartrate ((+)-isomer: (-)-isomer= 9:
After dissolving 2.02 g of the mixture of 1) in 20 ml of 2N hydrochloric acid,
The mixture was stirred at 75°C for 6 hours. After cooling the reaction solution, it was made alkaline with potassium carbonate, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and dried to obtain 1.05 g of colorless crystals of (±)-α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol. This crystal was determined by HPLC as (+)-isomer: (-)-isomer = 1:
It was confirmed that it was a mixture of 1. <HPLC measurement conditions> Wavelength: 220 nm Column: Ovomucoid ULTRON ES-OV
M mobile phase: pH 6.5 0.02M phosphoric acid Buf
fer.MeOH (21:4) This crystal was converted into a hydrochloride salt according to a conventional method, and recrystallized from a mixture of isopropanol and isopropyl ether to give a melting point of 17.
Colorless prism crystals having a temperature of 8 to 179°C were obtained.

Example 2 α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol L-tartrate (by HPLC (+)-isomer: (-)-isomer= 9:
After dissolving 4.00 g of the mixture of 1) in 20 ml of 2N hydrochloric acid,
The mixture was stirred at 75°C for 6 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 2.11 g of colorless crystals of (±)-α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol. This crystal was confirmed by HPLC (measurement conditions were the same as in Example 1) to be a mixture of (+)-isomer: (-)-isomer = 1:1. This crystal was converted into a hydrochloride salt according to a conventional method, and recrystallized from a mixture of isopropanol and isopropyl ether to obtain colorless prism crystals. This product had the same melting point and IR as that obtained in Example 1.

Example 3 (+)-α-[(tert-butylamino)methyl]-
2-chloro-4-hydroxybenzyl alcohol L-
After dissolving 2.00 g of tartrate in 20 ml of 2N hydrochloric acid, 75
The mixture was stirred at ℃ for 4 hours. Thereafter, in the same manner as in Example 1, (±)-α-[(tert-butylamino)methyl]-
1.03 g of colorless crystals of 2-chloro-4-hydroxybenzyl alcohol were obtained. This crystal was confirmed by HPLC (measurement conditions were the same as in Example 1) to be a mixture of (+)-isomer: (-)-isomer = 1:1. This crystal was converted into a hydrochloride salt according to a conventional method, and recrystallized from a mixture of isopropanol and isopropyl ether to obtain colorless prism crystals. This product had the same melting point and IR as that obtained in Example 1.

Reference Example 1 (-)-α-[(tert-butylamino)methyl]-
2-chloro-4-hydroxybenzyl alcohol L-
After dissolving 2.00 g of tartrate in 20 ml of 2N hydrochloric acid, 75
The mixture was stirred at ℃ for 4 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain (±)-α-[(tert-butylamino)methyl]
1.06 g of colorless crystals of -2-chloro-4-hydroxybenzyl alcohol were obtained. This crystal was confirmed by HPLC (measurement conditions were the same as in Example 1) to be a mixture of (+)-isomer: (-)-isomer = 1:1. This crystal was converted into a hydrochloride salt according to a conventional method, and recrystallized from a mixture of isopropanol and isopropyl ether to obtain colorless prism crystals. This product has the same melting point and IR as that obtained in Example 1.
matched.

[0015]

Effects of the Invention According to the method of the present invention, (-)-α-[(tert
-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol can be obtained efficiently.

Claims (1)

[Claims] 1. A method for producing a racemate of optically active α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol, which comprises treating the same with an acid.