JPH021429A - Production of optically active 1-methyl-3-phenylpropylamine - Google Patents

Abstract

PURPOSE:To simply subject (RS)-1-methyl-3-phenylpropylamine to optical resolution through a diastereomer salt in high optical purity and good yield using optically active di-toluoyl tartaric acid or dibenzoyl tartaric acid as a resolution agent. CONSTITUTION:(RS)-1-methyl-3-phenylpropylamine is optically resolved by using an optically active ditoluoyl tartaric acid or dibenzoyl tartaric acid as a resolution agent and producing two kind of diastereomers of the above-mentioned resolution agent and (RS)-1-methyl-3-phenylpropylamine and then utilizing the difference of solubility of the resultant diastereomers to provide the optically active 1-methyl-3-phenylpropylamine useful as a raw material for medicine such as beta-blocker in extremely simple method, good yield and high optical purity. Furthermore, the above-mentioned resolution agent can be readily recovered and reused by treating the above-mentioned diastereomer salts with an acid or alkali.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing optically active 1-methyl-3-phenylpropylamine.

<Prior art> Optically active 1-methyl-3-phenylpropylamine is
It is a compound useful as a raw material for the synthesis of pharmaceuticals such as β-blockers, but chemically synthesized 1-methyl-3-
Since phenylpropylamine is in the R3 form, it must be optically resolved to make it optically active in order to be used as the synthetic raw material.As a method for optically resolving 1-methyl-3-phenylpropylamine, cis-camphoric anhydride is used as a resolving agent. (Aust, J. Chell.

l and (3) 665-670 (1981)), (2
R,3R)-2,3-diacetoxysuccinic anhydride method (Aust, J. Chem, 32,
(2) 2625-2629 (1979)) is known.

<Problems to be Solved by the Invention> However, both of the above methods involve optical resolution by reacting 1-methyl-3-phenylpropylamine with a resolving agent to form an amide. It is not industrially practical because it requires an amidolysis reaction.
Furthermore, both methods have low yields and low optical purity, and are not at a level that can be put to practical use industrially. Therefore, the present inventors conducted extensive studies with the aim of establishing a practical method for producing optically active 1-methyl-3-7enylpropylamine.

As a result, the above purpose can be achieved by using di-toluoyl tartaric acid or di-
It has been found that this can be achieved by optically resolving (RS)-1-methyl-3-phenylpropylamine via a diastereomer salt using benzoyltartaric acid as a resolving agent.

That is, the present invention uses optically active di-toluoyltartaric acid or di-benzoyltartaric acid as a resolving agent, and produces two types of diastereomeric salts of the resolving agent and (RS)-1-methyl-3-phenyl-10-bylamine. Using the solubility difference between the two diastereomeric salts, (RS)-1
- A method for producing optically active 1-methyl-3-phenylpropylamine, which is characterized by optically resolving methyl-3-phenylpropylamine.

Hereinafter, the configuration of the present invention will be explained in detail.

The resolving agent used in the present invention is di-m-toluoyltartaric acid,
It is a tartaric acid derivative selected from di-m-toluoyltartaric acid or di-benzoyltartaric acid such as di-o-toluoyltartaric acid and di-m-toluoyltartaric acid, and both the D-form and L-form thereof can be used.

In the present invention, (RS)-1- used as a raw material
Methyl-3-phenylpropylamine is (R)-1-
Not only a racemic mixture containing methyl-3-7enylpropylamine and (S)-1-methyl-3-phenylpropylamine in equal positions, but also a racemic mixture containing one of the optical isomers in equal proportions.
It also includes mixtures of the above.

Optical resolution of (RS)-1-methyl-3-phenyl-10-bylamine is carried out under the following procedure and conditions.

First, in a solvent, 0.1 to 2.0 mol, preferably 0.5 to 1.0 mol of D-tartaric acid derivative or L- Contact with tartaric acid derivative.

The solvent used here is one that dissolves 1-methyl-3-7enyl 10-pyramine and the tartaric acid derivative, does not chemically alter these compounds in solution, and allows diastereomeric salts to precipitate. For example, water, lower alcohols such as methanol, ethanol, and 10-panol, acetone, or a mixed solvent thereof can be used. Preferred solvents are water and lower alcohols.

The method of bringing the resolving agent into contact with (RS)-1-methyl-3-phenylpropylamine includes dissolving (RS)-1-methyl-3-phenyl-10-bylamine and the resolving agent separately in the above-mentioned solvent. They may be mixed, or they may be sequentially dissolved in a solvent. Furthermore, a salt prepared in advance from (RS)-1-methyl-3-phenyl-10-bylamine and a resolving agent may be added and dissolved in the solvent.

Next, the solution obtained by contacting is cooled and/or concentrated. Then, a sparingly soluble diastereomeric salt crystallizes out.゛The temperature at which the poorly soluble diastereomeric salt is precipitated from the splitting solvent may be within the range from the freezing point to the boiling point of the solvent used, and is determined as appropriate depending on the purpose, but is usually between θ°C and 80°C. The range is sufficient.

Crystals of poorly soluble diastereomeric salts can be easily separated by conventional solid-liquid separation methods such as filtration and centrifugation.

On the other hand, the remaining mother liquor from which the poorly soluble diastereomeric salts have been separated can be used as is or by concentrating and/or cooling to precipitate easily soluble diastereomeric salts, which can then be separated.

By separating each diastereomer salt obtained in this way by an appropriate method, the resolving agent and (R)-1-methyl-
3-7enyl-10-bylamine or (S)-1-methyl-3-phenylpropylamine can be separated and collected.

Any method can be used to decompose the diastereomeric salt, and for example, a method of treating with an acid or an alkali in an aqueous solvent can be applied. That is, for example, when ammonia is added to an aqueous diastereomeric salt solution and this is extracted with an organic solvent such as chloroform, (R)-1-methyl-3-phenylpropylamine or (S)-1-methyl-3phenylpropylamine is produced. is extracted into the organic solvent layer, so by distilling off the organic solvent after extraction, optical activity 1 can be easily reduced.
-Methyl-3-phenylpropylamine can be obtained.

<Example> Hereinafter, the present invention will be specifically explained with reference to Examples.

Example 1 (RS)-1-methyl-3-phenyl 10viramine 2
．． 98 g and 3.8 fl of D-di-p-toluoyltartaric acid
zr was heated and dissolved in 1,100 ml of water at 50°C. After 6 hours, the precipitated crystals were dried at room temperature to obtain 2.29 g of white (R)-1-methyl-3-phenylpropylamine D-di-p-toluoyl tartrate. Obtained. (R)-1-methyl-3- used
The yield based on the amount of phenylpropylamine was 67%. The total amount of the obtained crystals was dissolved in 9 ml of water, and 28
Add 2011% ammonia water, 11% chloroform
Extracted 3 times with 0ml. The chloroform layer was washed with 10 ml of saturated sodium sulfate water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give (R)-1 of 0.95+r.
-Methyl-3=phenylpropylamine (95% yield vs. salt, optical purity 70% e, e,) was obtained.

Measurement of optical purity Prepare 8 solutions (0.2% water/alcohol) of 1-methyl-3-phenyl 10-bylamine or diastereomeric salt, and add 0.1 ml of 2% triethylamine solution in acetonitrile.
l and 0.4% GITC (2°3.4.6-tetra-
D-Acetyl-β-D-Glucopyrano
After adding acetonitrile solution of syl 1sothiocyanate) and reacting at room temperature for 30 minutes without mixing, excess GITC was decomposed with 0.3% diethylamine acetonitrile solution.The sample was subjected to the following HPLC conditions. The e, e, and % of the amine were determined.

HPLC conditions Column: μmBondasphere 5μ C+a -100 large 3.9X150 crucian carp Mobile phase: 0.05% H3PO4/methanol - Column T: 40°C Retention time: (R)-1-methyl-3-phenylpropylamine 47.3n+1n (S )-1-Methyl-3-phenylpropylamine 513+++in Examples 2 to 9 Table 1 shows the results of crystallization experiments conducted in the same manner as in Example 1 by changing the solvent and resolving agent.

<Effects of the Invention> Thus, according to the present invention, (RS)-1 methyl-3-
Phenylpropylamine can be optically resolved with high yield and high optical purity using an extremely simple method. Further, the optically active tartaric acid derivative of the resolving agent can be easily recovered by treating the diastereomeric salt with an acid or alkali, and the recovered optically active tartaric acid derivative can be reused.

Claims (1)

[Claims] Using optically active di-toluoyl tartaric acid or di-benzoyl tartaric acid as a resolving agent, two types of diastereomer salts of the resolving agent and (RS)-1-methyl-3-phenylpropylamine are produced, and the two types of It is characterized by optically resolving (RS)-1-methyl-3-phenylpropylamine using the solubility difference between diastereomeric salts.
A method for producing optically active 1-methyl-3-phenylpropylamine.