JPH023627A - Production of optically active 1-methyl-3-phenylpropylamine - Google Patents

Abstract

PURPOSE:To easily obtain the subject compound useful as a synthetic raw material for pharmaceuticals in high yield and optical purity by the optical resolution of (RS)-1-metyl-3-phenyl-propylamine with optically active N- acylmethione as a resolution agent. CONSTITUTION:The objective compound useful as a synthetic raw material for pharmaceuticals such as beta-blocker is produced by contacting 1mol of (RS)-1- methyl-3-phenylpropylamine with 0.1-2.0mol of optically active N-acrylmethionine of formula (R is phenyl or CH3) as a resolution agent in a solvent (e.g., water) to effect the optical resolution, cooling and/or concentrating the obtained solution to crystallize a hardly soluble diastereomer salt usually at 0-80 deg.C and easily separating the objective compound using conventional solid-liquid separation process. The compound of formula used as the resolution agent can be easily recovered by treating the diastereomer salt with an acid and an alkali and the recovered optically active N-acylmethionine can be reused.

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 optical resolution of 1-methyl-3-7enylprobylamine, a method using cis-camphoric anhydride (Aust, J., Chen+, 34, (3)
665-670 1981), <2R,3R)-2,3
- Method using diacetoxysuccinic anhydride (Aust
, J. Chen, , 32, (2) 2625-
2629 (1979)) is known.

<Problems to be Solved by the Invention> However, both of the above methods have low yields and low optical purity, and are not at a level that is industrially practical. We conducted extensive research with the aim of establishing a practical method for producing methyl-3-phenyl-10-pyramine.

As a result, the above object is achieved by using an optically active N-acylmethionine represented by (wherein R represents a phenyl group or a methyl group) as a resolving agent, (R,5)-1 -Methyl-3-phenylpropylamine.

That is, the present invention provides (R3)-1-methyl-3-phenylpropylene using an optically active N-acylmethionine represented by the following general formula (wherein R represents a phenyl group or a methyl group) as a resolving agent. This is a method for producing optically active 1-methyl-3-phenylpropylamine, which is characterized by optically resolving 1-methyl-3-phenylpropylamine.

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

The resolving agent used in the present invention is an optically active N-acylmethionine represented by the following general formula (where R represents a phenyl group or a methyl group), and both its D and L forms can be used. I can do it.

In the present invention, (R3)-1- used as a raw material
Methyl-3-phenylpropylamine is (R)-1-
Not only a racemic mixture containing methyl-3-phenylpropylamine and (S)-1-methyl-3-phenylpropylamine, but also one of the optical isomers, etc.
It also includes mixtures of the above.

Optical resolution of (R3)-1-methyl-3-phenylpropylamine 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-N-acylmethionine or Contact L-N-acylmethionine.

The solvent used here is one that dissolves 1-methyl-3-phenylpropylamine and N-acylmethionine, does not chemically alter these compounds in solution, and precipitates diastereomeric salts. For example, water, lower alcohols such as methanol, ethanol, propatool, acetone, or a mixed solvent thereof can be used.

Preferred solvents are water and lower alcohols, with water being most preferably used.

(R3)-1-Methyl-3-7enyl-10-bylamine is brought into contact with the resolving agent by dissolving (R3)-1-methyl-3-phenylpropylamine and the resolving agent separately in the above-mentioned solvent. Alternatively, they may be sequentially dissolved in a solvent, or a salt prepared in advance from (R3)-1-methyl-3-phenylpropylamine and a resolving agent may be added and dissolved in the solvent. You may.

Next, the solution obtained by contacting is cooled and/or concentrated. Then, a poorly soluble diastereomeric salt ((
R)-1-methyl-3-phenylpropylamine・<
D) -N-acylmethionine salt or (S)-1-methyl-3-phenylpropylamine (L)-N-acylmethionine salt) crystallizes. 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 in the range of 0°C to 80°C. It is enough.

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 salt has been separated is used as it is, or by concentrating and/or cooling the easily soluble diastereomeric salt ((R)-1-methyl-3
-Phenylpropylamine (L)-N-acylmethionine salt or (S)-1-methyl-3-phenylpropylamine (D)-N-acylmethionine salt) can also be precipitated and separated.

By separating each diastereomer salt obtained in this way by an appropriate method, the resolving agent and (R)-1-methyl-
3-phenylpropylamine 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-3-phenylpropylamine is produced. Since it is extracted into the organic solvent phase,
Optically active 1-methyl-3-phenylpropylamine can be easily obtained by distilling off the organic solvent after extraction.

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

In addition, in the examples, the optical purity is measured as follows.

Optical purity: Prepare a 0.2% water/alcohol solution of 1-methyl-3-phenylpropylamine or diastereomeric salt,
0.1 m of 2% triethylamine in acetonitrile
l and 0.4% GITC (2°3.4,6.tetra-
0-acetyl-β-D-glucopyrano
0.1 ool of an acetonitrile solution of syl 1ssthiocyanate) was added and mixed. 30
After reacting at room temperature for several minutes, excess GITC was decomposed with a 0.3% diethylamine acetonitrile solution, and the sample was analyzed under the following HPLC conditions to determine amine e and e%.

HPLC condition column: μmBondasphere 5u (, +8
-100 people 3.9X150m + Mobile phase: 0.05%H
3PO4/methanol; 53/47 1.1ml/m
in Column T: 40°C Retention time: (R)-1-methyl-3-phenyl 10 pylamine 47.8 nin (S)-1-methyl-3-phenylpropylamine 51.3 nun Example 1 (R3)-1- Methyl-3-phenylpropylamine 4
．． 48 g and 5.73 g of (D)-acetylmethionine were dissolved in 40 ml of water by heating at 53°C. Cool while stirring slowly, and after 4 hours at 29°C, precipitate crystals are separated from P and dried to give 3.65 g of white (R)-1-methyl-3-phenyl 10-pyramine (D)=N-acetylmethionine. Got salt. The yield was 71% based on the amount of (R)-1-methyl-3-7enylprobylamine used. The entire amount of the obtained crystals was dissolved in 9 ml of water, 2.2 ml of 28% aqueous ammonia was added, and the mixture was extracted three times with 10 ml of chloroform. The chloroform layer was washed with 10 ml of saturated sodium sulfate water, dried over anhydrous sodium sulfate, the solvent was distilled off, and 1.56 g of (R)-1-methyl-
3-phenylpropylamine (95% yield vs. salt, optical purity 76% e, e,) was obtained.

Example 2 3.1 g of (,R3)-1-methyl-3-phenylpropylamine and 5.07 g of (D)-N-benzoylmethionine
g was dissolved in water by heating at 60°C to 50°C. Cool while stirring slowly, and after 4 hours, separate the precipitated crystals at 15°C in a furnace.
When dried, 1.99 g of white (R)-1-methyl-3-
Phenylpropylamine/(D)-N-benzoylmethionine salt was obtained. The yield was 49% based on the (R)-1-methyl-3-phenylpropylamine used.

Treated as in Example 1, 0.7 g of (R)-1-methyl-3-phenylprobylamine (yield 95% vs. salt,
An optical purity of 65% e, e,) was obtained.

<Effect of the invention> Thus, according to the present invention, (R3)-1-methyl-3
- Phenylglopylamine can be optically resolved in a very simple manner with good yield and high optical purity. Also,
The optically active N-acylmethionine of the resolving agent can be easily recovered by treating the diastereomeric salt with an acid or alkali, and the recovered optically active N-acylmethionine can be reused.

Claims (1)

[Claims] The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(I
) (In the formula, R represents a phenyl group or a methyl group.) (RS)-1-Methyl-3-phenylpropylamine is optically resolved using an optically active N-acylmethionine represented by the following as a resolving agent. A method for producing optically active 1-methyl-3-phenylpropylamine.