JP2712669B2 - Preparation of optically active 1,2-propanediamine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for producing optically active 1,2-propanediamine.

<Prior Art> Optically active 1,2-propanediamine is a compound useful as a raw material for synthesizing pharmaceuticals such as anticancer drugs, but chemically synthesized 1,2-propanediamine is an RS compound, In order to make it a synthetic raw material, it must be optically resolved to make it optically active. As a method for optical resolution of 1,2-propanediamine, a method using tartaric acid (J. Am. Chem. Soc.
81 290-294 (1959)).

<Problems to be Solved by the Invention> However, the above-described method is very complicated, such as ten reprecipitations, has a low yield, and is not at an industrially practical level. Therefore, the present inventors have made intensive studies for the purpose of establishing a practical production method of optically active 1,2-propanediamine.

<Means for Solving the Problems> As a result, it was found that the above object was achieved by resolving (RS) -1,2-propanediamine using optically active dibenzoyltartaric acid as a resolving agent.

That is, the present invention is a method for producing optically active 1,2-propanediamine, comprising optically resolving (RS) -1,2-propanediamine using optically active dibenzoyltartaric acid as a resolving agent.

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

The resolving agent used in the present invention is optically active dibenzoyltartaric acid, and any of its D-form and L-form can be used.

In the present invention, (RS) -1,2 used as a raw material
-Propanediamine is not only a racemic mixture containing (R) -1,2-propanediamine and (S) -1,2-propanediamine in equal amounts, but also one of the optical isomers in equal amounts or more. And mixtures containing the same.

Optical resolution of (RS) -1,2-propanediamine is performed according to the following procedure and conditions.

First, in a solvent, 0.1 to 2.0 mol, preferably 0.3 to 1.0 mol, of dibenzoyl-D-tartaric acid or dibenzoyl-L- per 1 mol of (RS) -1,2-propanediamine.
Contact tartaric acid. At this time, a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like, or an organic acid such as acetic acid may coexist. The coexistence amount is 0.4 to 1.2 mol, preferably 0.5 to 1.0 mol, in total with the resolving agent.

The solvent used here may be any solvent that dissolves 1,2-propanediamine and dibenzoyltartaric acid and does not chemically change these compounds in the solution, and precipitates diastereomeric salts. For example, a proton solvent such as water, ethanol, propanol, acetone, and acetonitrile, or a mixed solvent thereof can be used. The preferred solvent is water.

As a method for bringing the resolving agent into contact with (RS) -1,2-propanediamine, (RS) -1,2-
The propanediamine and the resolving agent may be separately dissolved and mixed, or they may be sequentially dissolved in a solvent. Further, a salt prepared in advance from (RS) -1,2-propanediamine 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 appropriately determined depending on the purpose as long as it is within the range from the freezing point to the boiling point of the solvent used. is there.

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 separating each diastereomer salt thus obtained by an appropriate method, the resolving agent and (R) -1,2-propanediamine or (S) -1,2-propanediamine can be separated and collected. .

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, sodium hydroxide is added as a decomposing agent to a diastereomer salt aqueous solution to remove the sodium salt of a separating agent that precipitates, and the solution is concentrated and distilled, or the diastereomer salt is added to a sulfuric acid or hydrochloric acid aqueous solution. After successive additions and separation of the insoluble resolving agent or extraction of the resolving agent with an organic solvent such as ethyl acetate, the solution is made alkaline by adding sodium hydroxide and concentrated and distilled easily. R) -1,2-propanediamine or (S) -1,2-propanediamine can be obtained. If the solution is concentrated and crystallized as it is, sulfates and hydrochlorides of (R) -1,2-propanediamine or (S) -1,2-propanediamine are obtained. Alternatively, an optically active 1,2-propanediamine can be obtained by positively separating a cation exchange resin or an anion exchange resin from a resolving agent and concentrating it by distillation or reverse osmosis.

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

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

Optical purity: 0.1 ml of a 0.6% aqueous solution of 1,2-propanediamine or 3.5 g of a diastereomer salt in 0.1 ml of a 2% tetramethylethylenediamine in acetonitrile and 0.4% 2,3,4,6-tetra-O-acetyl- β-D-glucopyranosyl isothiocyanate (hereinafter abbreviated as GITC) in acetonitrile
0.1 ml was added and mixed. After reacting for 15 minutes at room temperature, a sample obtained by decomposing unreacted GITC with 0.1 ml of 0.3% diethylamine in acetonitrile was analyzed by high performance liquid chromatography (GPLC) under the following conditions, and the optical purity of the amine (% ee ).

HPLC conditions _{Column: μ-Bondasphere 5μC 18 -100Å 3.9} × 150mm mobile phase: 0.05% H ₃ PO ₄ / acetonitrile = 65/35 1.0ml / min Column T: 35 ℃ U V: 254nm Retention time: (S) -1 , 2-propanediamine derivative 13.3 min (R) -1,2-propanediamine derivative 15.5 min Example 1 5.0 g of (RS) -1,2-propanediamine and 24.2 g of dibenzoyl-L-tartaric acid monohydrate were dissolved in water. The mixture was dissolved in 100 ml by heating at 60 ° C. The mixture was cooled with slow stirring, and after 8 hours, the precipitated crystals were separated at 22 ° C. and dried to obtain 12.8 g of white (R) -1,2-propanediamine.dibenzoyl-L-tartrate.
The yield based on the amount of (R) -1,2-propanediamine used was 88%. The optical purity was 92.5% ee.

Example 2 2.0 g of (RS) -1,2-propanediamine and 4.8 g of dibenzoyl-D-tartaric acid monohydrate in 27 ml of 1N hydrochloric acid and 2 ml of water
Was heated and dissolved at 70 ° C. Cool while stirring slowly,
After 6 hours, the precipitated crystals are separated at 25 ° C and dried to obtain 4.3 g of white (S) -1,2-propanediamine-dibenzoyl-D.
-A tartrate is obtained. The yield based on the amount of (S) -1,2-propanediamine used was 73%, and the optical purity was 44% ee.
Met.

Example 3 2.0 g of (RS) -1,2-propanediamine, 4.8 g of dibenzoyl-D-tartaric acid monohydrate and 1.6 g of acetic acid were dissolved in 25 ml of water by heating at 60 ° C. Cool for 6 hours with gentle stirring, 25
Stirred at C overnight. The precipitated crystals were separated and dried to obtain 4.0 g of white (S) -1,2-propanediamine-dibenzoyl-
D-tartrate was obtained. The yield based on the amount of (S) -1,2-propanediamine used was 68%, and the optical purity was 77%.
was ee.

Example 4 2.0 g of (RS) -1,2-propanediamine, 4.8 g of dibenzoyl-D-tartaric acid monohydrate and 1.3 g of 95% sulfuric acid were added to 25 ml of water 70 times.
It melted by heating at ° C. The mixture was cooled for 6 hours while stirring slowly, and stirred at 25 ° C. overnight. Separate the precipitated crystals and dry 4.
1 g of white (S) -1,2-propanediamine dibenzoyl-D-tartrate was obtained. The yield was 70% based on the amount of (S) -1,2-propanediamine used, and the optical purity was 90% ee.

Example 5 (S) -1,2-propanediamine having an optical purity of 91% ee
106.9 g of dibenzoyl-D-tartrate was added to 250 ml of water, and 7
After stirring at 0 ° C for 1 hour, the mixture was cooled, and after 5 hours, dried at 30 ° C separately and dried to obtain 94.4 g of (S) -1,2-propanediamine.
Dibenzoyl-D-tartrate was obtained. This salt was added to 205 ml of 9% aqueous hydrochloric acid over 3 hours. After stirring for 1 hour after the addition was completed, dibenzoyl-D-tartaric acid was washed with water. 50% aqueous sodium hydroxide solution 56
After adding g to make it alkaline, the mixture is distilled under normal pressure and
15.3 g of a 118 留 fraction were obtained. The (S) -1,2-propanediamine obtained contained 15% water (yield 80
%). The optical purity was 98% ee.

Example 6 (S) -1,2-propanediamine having an optical purity of 98% ee
29.4 g of dibenzoyl-D-tartaric acid in 6% hydrochloric acid aqueous solution 100
ml was added in portions over 2 hours. After the addition, the mixture was stirred for 1 hour, and then dibenzoyl-DP-tartaric acid was washed with water.
Combine the solution and washing solution together to a concentration of 8.7 g, and add 30 ml of ethanol
And cooled to 5 ° C. Separately dry the precipitated crystals and 8.6 g
Of (S) -1,2-propanediamine dihydrochloride in a yield of 87
%. The optical purity was 99% ee.

Example 7 (S) -1,2-propanediamine having an optical purity of 99% ee
Dibenzoyl-D-tartrate (45.9 g) was added to an 8.5% aqueous sulfuric acid solution (15).
0 ml was added in portions over 2 hours. After stirring for 1 hour after the addition was completed, dibenzoyl-D-tartaric acid was washed with water. Concentrate the solution and washing solution together to 15 g, and add ethanol 3
0 ml was added and stirred for 1 hour at room temperature. The precipitated crystals were dried separately to obtain 16.6 g of (S) -1,2-propanediamine sulfate in a yield of 91%. The optical purity was 99% ee.

Example 8 1.0 g of (RS) -1,2-propanediamine and 4.83 g of dibenzoyl-D-tartaric acid monohydrate in 17 ml of water and acetonitrile 2
The mixture was heated and dissolved in a mixed solvent with 5 ml at 50 ° C. The mixture was cooled with slow stirring, and stirred at 22 ° C. overnight after 5 hours. The precipitated crystals were separated, washed with water and dried to obtain 1.99 g of white (S) -1,2.
-Propanediamine dibenzoyl-D-tartrate was obtained. The yield based on the amount of (S) -1,2-propanediamine used was 68%, and the optical purity was 90% ee.

Example 9 1.0 g of (RS) -1,2-propanediamine and 4.83 g of dibenzoyl-D-tartaric acid monohydrate were dissolved by heating at 50 ° C. in a mixed solvent of 10 ml of water and 30 ml of acetone. After cooling with slow stirring, the mixture was stirred at 22 ° C. overnight after 5 hours. The precipitated crystals were separated, washed with water and dried to obtain 2.37 g of white (S) -1,2-propanediamine dibenzoyl-D-tartrate. The yield based on the amount of (S) -1.2-propanediamine used was 8
It was 1% and the optical purity was 91% ee.

Example 10 1.0 g of (RS) -1,2-propanediamine and 4.83 g of dibenzoyl-D-tartaric acid monohydrate were mixed with 6 ml of water and 2-propanol.
The mixture was heated and dissolved in a mixed solvent with 10 ml at 60 ° C. After cooling with slow stirring, the mixture was stirred at 22 ° C. overnight after 5 hours. The precipitated crystals are separated, washed with water and dried to give 2.66 g of white (S) -1,2-
Propanediamine dibenzoyl-D-tartrate was obtained. The yield based on the amount of (S) -1,2-propanediamine used was 91%, and the optical purity was 90% ee.

Comparative Example 1 (RS) -1,2-propanediamine 5.0 g and D-tartaric acid 10.
1 g was dissolved in 10 ml of water by heating at 60 ° C. The mixture was cooled with slow stirring, but no crystals were precipitated even after stirring at room temperature for 2 days.

<Effects of the Invention> Thus, according to the present invention, (RS) -1,2-propanediamine can be optically resolved with a very simple method in good yield and high optical purity. The optically active dibenzoyltartaric acid as a resolving agent can be easily recovered by treating a diastereomer salt with an acid or alkali, and the recovered optically active dibenzoyltartaric acid can be reused.

Claims (1)

(57) [Claims] 1. A process for producing optically active 1,2-propanediamine, comprising optically resolving (RS) -1,2-propanediamine using optically active dibenzoyltartaric acid as a resolving agent.