JP2917464B2 - Preparation of optically active 1-methyl-3-phenylpropylamine - Google Patents

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 a compound useful as a raw material for the synthesis of pharmaceuticals such as β-blockers, but chemically synthesized 1-methyl-3-phenylpropylamine.
Since 3-phenylpropylamine is an RS, it must be optically resolved to be optically active in order to be used as the raw material for synthesis. As a method for optical resolution of 1-methyl-3-phenylpropylamine, a method using a resolving agent N-benzoylphenylglycine (JP-A-2-53755) is known.

<Problems to be Solved by the Invention> However, the above method has low optical purity and is not at a level that can be industrially practically used. Therefore, the present inventors have intensively studied for the purpose of establishing a practical method for producing optically active 1-methyl-3-phenylpropylamine.

<Means for Solving the Problems> As a result, the above object is to optically resolve (RS) -1-methyl-3-phenylpropylamine via a diastereomer salt using optically active N-formylphenylglycine as a resolving agent. Has been found to be achieved by:

That is, the present invention uses optically active N-formylphenylglycine as a resolving agent to form two diastereomeric salts of the resolving agent and (RS) -1-methyl-3-phenylpropylamine. (RS) -1-methyl-3-phenylpropylamine is optically resolved by utilizing the difference in solubility of diastereomeric salts of (1) to (2), wherein the optically active 1-methyl-3-phenylpropylamine is produced.

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

The resolving agent used in the present invention is N-formylphenylglycine, and any of its D-form and L-form can be used.

In the present invention, (RS) -1-
Methyl-3-phenylpropylamine is (R) -1-
Not only a racemic mixture containing equal amounts of methyl-3-phenylpropylamine and (S) -1-methyl-3-phenylpropylamine, but also a mixture containing one or more optical isomers in equal amounts or more. It is.

Optical resolution of (RS) -1-methyl-3-phenylpropylamine is performed according to the following procedure and conditions.

First, 0.1 to 2.0 mol, preferably 1 mol, of (RS) -1-methyl-3-phenylpropylamine in a solvent.
0.3-1.2 mol, more preferably 0.3-1.0 mol of N-
Contact formyl-D-phenylglycine or N-formyl-L-phenylglycine.

At this time, a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid or an organic acid such as formic acid, acetic acid or propionic acid may be coexisted. Mineral and organic acids used together with resolving agent (RS)
0.1-1.5 mol, preferably 0.2-1.3 mol, more preferably 0.5-1.5 mol, based on -1-methyl-3-propylamine.
1.1 molar amount.

The solvent used herein is one that dissolves 1-methyl-3-phenylpropylamine and N-formylphenylglycine and precipitates a diastereomer salt without chemically changing these compounds in the solution. For example, water, methanol,
A lower alcohol such as ethanol and propanol, an organic solvent such as acetone, ethyl acetate, hexane, chloroform and toluene, or a mixed solvent thereof can be used. Preferred solvents are water and ethanol.

As a method for bringing the resolving agent into contact with (RS) -1-methyl-3-phenylpropylamine, (RS) -1-methyl-3-phenylpropylamine and the resolving agent are separately dissolved and mixed in the solvent described above. Or they may be sequentially dissolved in a solvent. Further, a salt previously prepared from (RS) -1-methyl-3-phenylpropylamine and a resolving agent may be added and dissolved in the solvent.

Next, the solution obtained by the contact is cooled and / or concentrated. Then, a sparingly soluble diastereomer salt crystallizes. The temperature at which the sparingly soluble diastereomer salt is precipitated from the resolving solvent may be within the range of the freezing point to the boiling point of the solvent used, and is appropriately determined according to the purpose. It is.

Crystals of the sparingly soluble diastereomer salt can be easily separated by ordinary solid-liquid separation methods such as filtration and centrifugation.

On the other hand, the remaining mother liquor from which the sparingly soluble diastereomer salt has been separated can be used as it is, or it can be concentrated and / or cooled to precipitate a readily soluble diastereomer salt, which can be separated.

By resolving each diastereomer salt thus obtained by an appropriate method, a resolving agent and (R) -1-methyl-3-phenylpropylamine or (S) -1-methyl-3-phenylpropylamine are separated and collected. can do.

The method of decomposing the diastereomer salt is arbitrary, and for example, a method of treating with an acid or alkali in an aqueous solvent can be applied. That is, for example, when caustic soda is added to a diastereomer salt aqueous solution and extracted with an organic solvent such as toluene, (R) -1-methyl-3-phenylpropylamine or (S) -1-methyl-3-phenylpropylamine is obtained. Since the organic solvent is extracted into the organic solvent layer, the optical activity can be easily increased by distilling the organic solvent after the extraction.
-Methyl-3-phenylpropylamine can be obtained.

<Example> Hereinafter, the present invention will be specifically described with reference to examples.

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

Determination of Optical Purity Prepare a 0.2% water / methanol solution of 1-methyl-3-phenylpropylamine or diastereomer salt,
0.1 ml of acetonitrile solution of 2% triethylamine and 0.4 ml
% 2,3,4,6-tetra-o-acetyl-β-D-glucopyranosyl isothiocyanate (GITC) in 0.1 ml of acetonitrile solution was added and mixed. After reacting at room temperature for 30 minutes, 0.1% diethylamine in acetonitrile solution 0.1
A sample in which excess GITC was decomposed in ml was analyzed under the following HPLC conditions to determine the optical purity of the amine.

HPLC conditions Column: μ-Bondasphere 5μ C ₁₈ -100Å 3.9 × 150m
m Mobile phase: 0.05% H ₃ PO ₄ / methanol = 52/48 1.0 ml / min Column T: 40 ° C. UV: 254 nm Retention time: GITC compound of (R) -1-methyl-3-phenylpropylamine 50.4 min ( S) of 1-methyl-3-phenylpropylamine
GITC compound 53.9 min Example 1 (RS) -1-methyl-3-phenylpropylamine 1
4.9 g and 17.9 g of N-formyl-L-phenylglycine were dissolved in 66.5 g of water by heating at 45 ° C. After cooling with slow stirring, the precipitated crystals were centrifuged at 20 ° C. after 4 hours and rinsed with 5 g of water. The collected crystals were dried to obtain 10.6 g of white (R) -1-methyl-3-phenylpropylamine.N
-Formyl-L-phenylglycine salt was obtained. The resulting diastereomeric salt was recrystallized from 15.0 g of water to give (R) -1
8.3 g of -methyl-3-phenylpropylamine / N-formyl-L-phenylglycine salt was obtained, and 1N-Na
After adding 26 ml of OH, the mixture was extracted twice with 20 ml of toluene. The toluene layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 3.7 g of (R) -1-methyl-3-.
Phenylpropylamine (50% yield vs. (R) -1-methyl-3-phenylpropylamine, optical purity 98.3% ee)
I got

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

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Claims (1)

(57) [Claims] 1. An optically active N-formylphenylglycine is used as a resolving agent, and the resolving agent and (RS) -1-methyl-3 are used.
-Two diastereomeric salts with phenylpropylamine are produced, and (RS) -1-methyl-3-phenylpropylamine is optically resolved by utilizing the difference in solubility between the two diastereomeric salts. Optical activity 1
Production method of methyl-3-phenylpropylamine.