JP2616211B2 - 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-mentioned method is very complicated in operation such as ten reprecipitations, has a low yield, and is not at a level that can be industrially practically used. Thus, the present inventors have proposed an optically active 1,2-
The aim of this study was to establish a practical method for producing propanediamine.

<Means for Solving the Problems> As a result, the above object was achieved by using (RS) -1,2-(-) as optically active Np-toluenesulfonylaspartic acid, N-benzenesulfonylaspartic acid or N-benzoylglutamic acid as a resolving agent. It has been found that this can be achieved by splitting propanediamine.

That is, the present invention is characterized by optically resolving (RS) -1,2-propanediamine using optically active Np-toluenesulfonylaspartic acid, N-benzenesulfonylaspartic acid or N-benzoylglutamic acid as a resolving agent. This is a method for producing optically active 1,2-propanediamine.

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

The resolving agent used in the present invention is optically active Np-toluenesulfonylaspartic acid, N-benzenesulfonylaspartic acid or N-benzoylglutamic acid,
Both the D-form and the 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, 0.1 to 2.0 mol, preferably 0.3 to 1.0 mol, of Np-toluenesulfonyl-D-aspartic acid or Np-toluene is used in a solvent in an amount of 0.1 to 2.0 mol, preferably 0.3 to 1.0 mol, per 1 mol of (RS) -1,2-propanediamine. Contacting sulfonyl-L-aspartic acid, N-benzenesulfonyl-D-aspartic acid or N-benzenesulfonyl-L-aspartic acid or N-benzoyl-D-glutamic acid or N-benzoyl-L-glutamic acid. At this time, a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid or an organic acid such as acetic acid may be coexisted. The amount of the mineral acid or organic acid to be used is 0.1 to 1.5 mol, preferably 0.3 to 1.0 mol, per 1 mol of (RS) -1,2-propanediamine together with the resolving agent.

As the solvent used here, 1,2-propanediamine and Np-toluenesulfonyl aspartic acid, N-
Any compound may be used as long as it dissolves benzenesulfonyl aspartic acid or N-benzoylglutamic acid and does not chemically alter the compound in the solution, and precipitates diastereomeric salts.
Proton solvents such as water, ethanol, propanol, acetone, and acetonitrile, or mixed solvents thereof can be used. Preferred solvents are water and ethanol.

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 within the range of the freezing point to the boiling point of the solvent used, and is appropriately determined depending on 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, it is possible to separate and collect the resolving agent and (R) -1,2-propanediamine or (S) -1,2-propanediamine. it can.

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 methoxide or sodium ethoxide is added as a resolving agent to a diastereomer salt solution of ethylene glycol monobutyl ether or ethylene glycol monopentyl ether or a solution or suspension thereof, and the sodium salt of the resolving agent that precipitates is removed. By distilling, or adding diastereomeric salts to sulfuric acid or hydrochloric acid aqueous solution successively, and separating out the separating agent that separates out, or extracting the separating agent with an organic solvent such as n-butanol or ethyl acetate. After that, the solution is made alkaline by adding sodium hydroxide and concentrated (R) -1,2,
-Propanediamine or (S) -1,2-propanediamine can be obtained. If the solution is concentrated and crystallized as it is, (R) -1,2-propanediamine or (S)
Sulfate and hydrochloride of 1,2-propanediamine are obtained. Alternatively, the optically active 1,2-propanediamine can be obtained also by separating from the resolving agent using a cation exchange resin or an anion exchange resin, and performing concentration distillation or reverse osmosis membrane.

<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 mg of a diastereomer salt was mixed with 0.1 ml of a 2% tetramethylethylenediamine solution in acetonitrile and 0.4% 2,3,4,6-tetra-O-acetyl- 0.1 ml of an acetonitrile solution of β-D-glucopyranosyl isothiocyanate (hereinafter abbreviated as GITC) was added and mixed. After reacting for 15 minutes at room temperature, 0.1 ml of 0.3% diethylamine in acetonitrile
The sample obtained by decomposing the unreacted GITC was analyzed by high performance liquid chromatography (HPLC) under the following conditions to determine the optical purity (% ee) of the amine.

HPLC conditions Column: μ-Bondasphere 5μC ₁₈ -100Å3.9 × 1.50mm Mobile phase: 0.05% H ₃ PO ₄ / acetonitrile = 65/35 1.0ml / mi
n Column T: 35 ° C UV: 254 nm Retention time: GITC compound of (S) -1,2-propanediamine 1
3.3 min GITC compound of (R) -1,2-propanediamine 15.5 min Example 1 3.7 g of (RS) -1,2-propanediamine and 14.4 g of Np-toluenesulfonyl-L-aspartic acid in 70 ml of water
Was heated and dissolved at 70 ° C. Cool while stirring slowly,
After 8 hours, the precipitated crystals were separated at 25 ° C. and dried to obtain 7.5 g of white (S) -1,2-propanediamine.Np-toluenesulfonyl-L-aspartate. Used (S)
The yield based on the amount of -1,2-propanediamine was 83%. The optical purity was 92.9% ee. 6% sulfuric acid aqueous solution 45
Add the above diastereomer salt to 100 ml, and add ethyl acetate 100 m
l to convert Np-toluenesulfonyl-aspartic acid to 2
After extraction twice, the aqueous layer was concentrated to 7 g, and 20 ml of methanol was added to obtain 3.1 g of (S) -1,2-propanediamine sulfate. The optical purity was 93.0% ee.

Example 2 3.7 g of (RS) -1,2-propanediamine and 12.6 g of N-benzoyl-L-glutamic acid were dissolved by heating at 70 ° C. in 250 ml of ethanol and 20 ml of water. After cooling for 6 hours, the precipitated crystals were separated at 25 ° C. and dried to obtain 4.5 g of white (R) -1,2-propanediamine.N-benzoyl-L-glutamate. This crystal is ethanol
Recrystallization from 50 ml and 5 ml of water gave 3.6 g of (R) -1,2-propanediamine.N-benzoyl-L-glutamate. The yield based on the amount of (R) -1,2-propanediamine used was 44%, and the optical purity was 89% ee.

Example 3 7.4 g of (RS) -1,2-propanediamine and 16.4 g of N-benzenesulfonyl-L-aspartic acid were added to 41.6 g of water in 65 g of water.
The mixture was heated and dissolved at ℃, and 4.1 g of 95% sulfuric acid was added dropwise. The mixture was cooled to 24 ° C. over 4 hours with stirring, centrifuged, and the crystals were rinsed with 6 g of water. Drying yielded 12.6 g of white (S) -1,2-propanediamine.N-benzenesulfonyl-L-aspartate. The crystals were recrystallized with 37.8 g of water,
9.4 g of (S) -1,2-propanediamine.N-benzenesulfonyl-L-aspartate was obtained. The yield based on the amount of (S) -1,2-propanediamine used was 54.
The optical purity was 2% and the optical purity was 98% ee.

<Effect of the Invention> Thus, according to the present invention, (RS) -1,2-propanediamine can be optically resolved with a very simple method and with high yield and high optical purity. In addition, the optically active Np-toluenesulfonyl aspartic acid, N-benzenesulfonyl aspartic acid or N-benzoylglutamic acid of the resolving agent can be easily recovered by treating the diastereomer salt with an acid or alkali, and further recovered. Optically active Np-toluenesulfonyl aspartic acid, N-
Benzenesulfonyl aspartic acid or N-benzoylglutamic acid can be reused.

Claims (1)

(57) [Claims] 1. An optically active Np-toluenesulfonylaspartic acid, N-benzenesulfonylaspartic acid or N-benzoylglutamic acid as a resolving agent (RS)
1. A process for producing optically active 1,2-propanediamine, comprising optically resolving 1,2-propanediamine.