JPS6033380B2 - Production method of optically active amino alcohol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing optically active amino alcohols.

More specifically, the present invention relates to a method for producing an optically active amino alcohol, which is characterized by reacting pendylmagnesium chloride, which is an optically active Q amino acid.

The optically active amino alcohol obtained by the method of the present invention is an important substance as an industrial chemical.

For example, it is useful as an optical resolution agent or an aid for asymmetric synthesis, and is also expected to have various physiological activities. As a prior art method, there is a method in which penzylmagnesium halide is reacted with the active Q amino acid ester or its hydrochloride.

(Pharmaceutical Journal 48 46 (1928), Chem. Mr. R.
62 287 (see 193) According to this method, various optically active amino alcohols can be obtained by changing the optically active Q amino acid ester.

However, the above method requires a pre-step for producing an optically active Q-amino acid ester from an optically active Q-amino acid, and is not industrially advantageous.

In order to produce a series of optically active amino alcohols having a pendyl group as a substituent introduced from a Grignard reagent, the present inventors have intensively investigated a novel method in which the optical activity is determined by directly acting pendylmagnesium chlorhalide on an amino acid. As a result, it was unexpectedly discovered that the reaction proceeded smoothly and the desired optically active amino alcohol was obtained in good yield.The present invention was completed after further studies. That is, the present invention has the general formula:
* represents an asymmetric carbon.

The method is characterized in that an optically active Q amino acid represented by (R is an alkyl, aralkyl, or aryl group) is reacted with a Grignard reagent such as penzylmagnesium chlorhalide. This is a method for producing an optically active amino alcohol represented by the general formula (0) (N ratio) C (CH2C6 ratio) m) (wherein * and R have the same meanings as above).

The alkyl group in the substituent R of the optically active Q amino acid of general formula (1), which is a raw material of the present invention, also includes a cycloalkyl group and a cycloalkylalkyl group.

Examples of R include the following. That is, C, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se-butyl, etc.
4 alkyl group, C5-6 cycloalkyl group such as cyclohexyl, C6-7 cycloalkylalkyl group such as cyclohexylmethyl, aralkyl group such as benzyl,
Examples include aryl groups such as phenyl.

Specific examples of the optically active Q amino acid of the present invention include the following compounds.

That is, alanine, valine, leucine, isoleucine, phenylalanine, phenylglycine, and the like. The Grignard reagent is penzylmagnesium chlorhalide.

As the optically active amino alcohol of the general formula (b) obtained by the present invention, the following compounds can be specifically exemplified.

That is, 2-amino-1,1-dibenzyl-1-propanol 2-amino-1,1-dibenzyl-3-methyl-1-butanol 2-amino-1,1-dibenzyl-3-methyl-1-bentanol 2-amino-1,1-dibenzyl-4-methyl-1-pentanol /-l 2-amino-1,1-dibenzyl-3-phenyl-1-pro/gnol, 2-amino-1,1-dibenzyl-2-phenyl-ethanol, and the like.

Next, the reaction conditions will be described.

This reaction is usually carried out in a solvent.

As the solvent, a solvent commonly used in Grignard reactions is used.

That is, single or mixed solvent systems of ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethylcellosolve, and diglyme, and hydrocarbons such as hexane, heptane, cyclohexane, benzene, and toluene may be added to the above solvents. can.

The reaction temperature can be from 20°C to the boiling point of the solvent used. The molar ratio of the Grignard reagent used in the reaction to the amino acid must be at least 4 times the molar amount, and is 4 to 10 times the molar ratio.
Used between twice the molar range. It is preferable to use the Q amino acid after pulverizing it in order to increase the dissolution rate.

The reaction time depends on the reaction temperature, but is usually between 5 and 2 hours. The optically active amino alcohol obtained here is usually obtained in the form of a crystal by hydrolyzing the reaction mixture and then using a suitable isolation method.

Purification methods include extraction with stannic acid, recrystallization, or column chromatography. The present invention will be explained in more detail with reference to Examples below, but the present invention is of course not limited to these. Reference Example Preparation of penzylmagnesium chloride 24.3 pieces of magnesium (1 polyatomic) and 300 g of tetrahydrofuran were placed in a 500 x 4 flask, and while keeping the temperature at -5 to 0°C under a nitrogen stream, benzyl chloride 126 Penzylmagnesium chloride was prepared by adding 0.5 mol (1 mol) dropwise to the solution over 7 hours and then stirring at 0° C. for 1 hour.

A gas chromatograph analysis of toluene, which is produced by decomposition with water, revealed that it was pendylmagnesium. The yield of lido was 80%. (Benzyl chloride standard) Example
1 11.87 g of L-alanine pulverized (0
．． 133 mol) was added thereto, and the mixture was heated under reflux for 7 hours.

The reaction mixture was hydrolyzed by dropping it into a solution of 83 parts of concentrated hydrochloric acid and 300 parts of water.

After adjusting the - of the aqueous layer to 7.5 to 8.0 with IN-alkali, remove the aqueous layer and concentrate the organic layer to have a residual weight of 5.
3.59 was obtained. This residue was dissolved in 200% of toluene and mixed with 135% of IN-hydrochloric acid and 135% of methanol, and the amino alcohol hydrochloride was extracted into the water-methanol layer. The water-methanol layer was neutralized by adding IN-sodium hydroxide 13-molecular weight, the amino alcohol was extracted with 200 mcm of toluene, the solvent was distilled off, and the 2-amino-1
- 17.4 tons of 1-dibenzyl-1-propanol were obtained. (Yield 51%) The physical properties of the sample recrystallized from isopropanol-n-hexane were m. P. It was 80.200 [Q]D +30.20 (C=1, CHC13).

Example 2 L-leucine 17.43 (0) instead of L-alanine
．． The reaction was carried out in the same manner as in Example 1 using 133 mol).

The reaction mixture was hydrolyzed with hydrochloric acid, and the organic layer was concentrated to obtain a residue of 61.7 mm. This residue was dissolved in 200 parts of n-heptane and extracted with 135 parts of IN-hydrochloric acid and 135 parts of methanol, and the water-methanol layer was extracted with 1 part of IN-sodium hydroxide.
Neutralize with 35% of toluene, extract with 100% of toluene, and distill off the solvent to obtain 2-amino-1,1-dibenzyl-4-methyl-
21.39 (yield 54%) of 1-pentanol was obtained. The physical properties of the sample recrystallized from n-beptane were m. n. 90
．． 400 [Q].

It was 110.20 (C=1, CHC13). Example 3 L-phenylalanine instead of L-alanine 21.9
A reaction was carried out in the same manner as in Example 1 using 0.133 mol of 2-amino-1,1-dibenzyl-3-phenyl-1-propanol (yield: 52%). %) was obtained.

n-Hef. The physical properties of the sample recrystallized from tan are m. P
．． 14500 [Q]D +59.2o (C=1, CHC
13).

Claims (1)

[Claims] 1. Optical activity represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. An optically active amino alcohol manufacturing method characterized by the action of benzylmagnesium chloride on an α-amino acid and is represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein * and R have the same meanings as above) .