JPH07188124A - Separation of optically active amine - Google Patents

Abstract

PURPOSE:To obtain an industrially practicable process for the separation of an optically active amine having high affinity to water. CONSTITUTION:The characteristic of this process for the separation of an optically active amine process for the separation of an optically active amine having high affinity to water comprises the treatment of a diastereomer salt composed of an optically active amine having high affinity to water and an optically active carboxylic acid or an optically active sulfonic acid and the transfer of the isolated amine to an alcohol layer. An optically active amine having high affinity to water can be separated in high yield and purity on an industrial scale at a low cost.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a water-affinity diastereomer salt of an optically active amine and an optically active carboxylic acid or an optically active sulfonic acid, which have a high affinity for water and are formed during optical resolution. It relates to a method for isolating highly optically active amines.

Optically active amines having a high affinity for water, such as optically active 1,2-diaminopropane, optically active 1,2-diaminocyclohexane, optically active 2-methylpiperazine, and optically active 3-hydroxypyrrolidine, are intermediates of pharmaceuticals. It is a compound useful as a body or basic resolving agent.

[0003]

2. Description of the Related Art In recent years, the demand for synthetic chiral drugs has been increasing, and optically active amines having high affinity for water, which are used as intermediates, are no exception, and optically active amines having high chemical purity and optical purity are used. Is desired.

However, since relatively low molecular weight optically active amines have many compounds having a high affinity for water and their boiling points are low, it is difficult to separate them from water. For this reason, it is usually marketed as an aqueous solution or salts such as hydrochloride and sulfate.

However, from the viewpoint of utilization, the demand for free amines is great.

Generally, there are various methods for obtaining an optically active amine, such as a preferential crystallization method, a diastereomeric salt resolution method, an asymmetric synthesis method, a method using an enzyme, and a method for separating by chromatography. The method of resolving a diastereomer salt using an acid or an optically active sulfonic acid as a resolving agent is a versatile and convenient means that can be produced on an industrial scale. In this method, after optical resolution, it is essential to desolvate the diastereomeric salt to separate it from the optically active carboxylic acid or optically active sulfonic acid as the resolving agent. It is general to use an alkaline aqueous solution such as caustic soda, an acidic aqueous solution such as sulfuric acid or hydrochloric acid, or an ion exchange resin for the salt-removing operation. With these methods,
It is difficult to isolate an optically active amine having a high affinity for water in high yield, high purity and easily.

Conventionally, as a method for isolating an optically active amine having a high affinity for water from the above-mentioned diastereomeric salt, (1) a high-concentration, large-excess aqueous solution of caustic soda was added to the diastereomeric salt to obtain diethyl ether. A method of extracting with an organic solvent such as ether or benzene (J. Am. Chem. So.
c. , 81 , 290 (1959), Acta Che.
m. Scand. 26 , 3605 (1972)), (2)
A method of distilling after repeating the operation of adding a high-concentration, large-excess aqueous solution of caustic soda to the diastereomer salt to separate the separated amine layer, and removing water in the amine layer with caustic soda (Can. J. Chem. , 54 , 2639
(1976)) and the like are known.

[0008]

[Problems to be Solved by the Invention]
The method of extracting with an organic solvent of (1) requires a large amount of alkali and an organic solvent, and the solvent used is often an organic solvent that is unfavorable for industrial use in terms of toxicity to the human body and recovery rate.
Moreover, the extraction rate is not necessarily high. Further, in the method (2), since the separated amine layer contains a large amount of water,
Alkali metal salt of resolving agent is easily mixed. In addition, it is difficult to remove water because an optically active amine having a relatively low molecular weight and a high affinity for water has a boiling point close to that of water or forms an azeotropic composition with water. Therefore, as a method of removing water in order to obtain a high-purity amine, a method of adding a large amount of alkali such as caustic soda for dehydration is adopted, and since this operation needs to be repeated many times, it is very troublesome. Therefore, the isolation yield is low.

Therefore, there is no known method for isolating an optically active amine having a relatively low molecular weight and a high affinity for water on a commercial scale with a high yield by a simple operation.

[0010]

[Means for Solving the Problems] The inventors of the present invention have developed an optically active amine having a relatively low molecular weight and a high affinity for water with a high purity on an industrial scale by a simple operation from a diastereomeric salt.
As a result of intensive studies aimed at developing a method for isolation with high yield, a diastereomeric salt consisting of an optically active amine and an optically active carboxylic acid or an optically active sulfonic acid having a high affinity for water was added to alcoholic alkali metal water. We have found a method of treating with an oxide to obtain a free amine in the alcohol layer.

That is, in the present invention, a diastereomeric salt consisting of an optically active amine and an optically active carboxylic acid or an optically active sulfonic acid is contacted in the presence of an alcohol and an alkali metal hydroxide to remove an amine free from the alcohol layer. A method for isolating an optically active amine, which is characterized by obtaining the same.

The structure of the present invention will be described in detail below.

The optically active amine forming the diastereomeric salt used in the present invention is not particularly limited, but those having a high affinity for water and close to the boiling point of water can exert the effects of the present invention more effectively. The optically active amines having a high affinity with water are, for example, amines having a relatively small molecular weight, easily soluble in water, and difficult to extract with an organic solvent. Representative amines are lower aliphatic amines, lower aliphatic halogenated amines, lower aliphatic amino alcohols, lower aliphatic aminothiols.

Specifically, for example, sec-butylamine, 2-chloropropylamine, 2-methylazetidine, 3-aminobutyronitrile, monoamines such as 4-amino-3-isoxazolidone, 1,2-diaminopropane. , 2,3-diaminobutane, 1,3-diaminobutane, 1,2-diaminocyclohexane, 3-aminopyrrolidine, 2-methylpiperazine, 2-aminomethylpyrrolidine and other diamines, or 1-amino-2-
Propanol, 2-amino-1-propanol, 2-
Examples thereof include amino alcohols such as amino-1-butanol, 3-amino-2-butanol and 3-hydroxypyrrolidine, and aminothiols such as 1-amino-2-propanethiol.

The optically active carboxylic acid forming a diastereomeric salt is, for example, optically active hydroxy acids represented by tartaric acid, malic acid, lactic acid, mandelic acid, amino acids, or optically active N derived from amino acids.
Well-known as an acylcarboxylic acid, an optically active tartranylic acid which is a derivative from tartaric acid, an O, O′-dialkyltartaric acid, or an optically active substance of a derivative of malic acid, lactic acid, and mandelic acid, and other optical resolving agents D-
Examples thereof include camphoric acid, optically active pantoyl lactone, optically active 2-phenylbutyric acid, and optically active 2-phenylpropionic acid. Also, as the optically active sulfonic acid, 1
Examples thereof include 0-camphorsulfonic acid and 1-phenylethanesulfonic acid.

The alcohol used as the solvent is preferably an alcohol which has a relatively large difference in boiling point from the optically active amine and which hardly dissolves the alkali salt of the optically active carboxylic acid. For example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol or a mixed solvent thereof can be used. In particular, the removal of water is effective when ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol or the like which forms an azeotropic composition with water is used.

Although water may be omitted, the addition of a small amount increases the salt-dissolving speed of the diastereomeric salt of an optically active amine having a high affinity for water. If the amount of water is too much, the alkali salt of the optically active carboxylic acid or the optically active sulfonic acid is easily dissolved in the alcohol solvent, so the content of water is preferably 0 to 80%, preferably 6 to 50% with respect to the alcohol.

Examples of alkali metal hydroxides include lithium hydroxide, sodium hydroxide and potassium hydroxide. The amount used may be equivalent to the diastereomeric salt. If the amount is too large, the amount of distillation residue in the distillation increases and the distillation yield decreases. Further, if it is less than the equivalent, diastereomeric salt which is not unsolvated remains and the isolation yield becomes low. Therefore, 0.9 to 2.5 equivalent, preferably 1.0 to 1 equivalent of diastereomeric salt is used. 1.8 equivalents, more preferably 1.0 to
It may be in the range of 1.5 equivalents.

The temperature at which the diastereomer salt is brought into contact with the alcohol may be any temperature at which the diastereomer salt, the optically active amines having a high affinity for water, and the alkali salt of the resolving agent do not deteriorate, and the type of alcohol used. Depending on
Generally, the temperature is 0 to 150 ° C, preferably 0 to 100 ° C, more preferably 10 to 80 ° C. The reaction time can be appropriately selected depending on other conditions such as reaction temperature and water content,
Generally, it is completed within 20 hours.

The operating procedure is arbitrary. A diastereomeric salt is added all at once or in portions to a hydroalcoholic solution in which an alkali metal hydroxide such as caustic soda is dissolved in hydrous alcohol, and treated at a predetermined temperature and time. Alternatively, a hydroalcoholic solution of an alkali metal hydroxide or an aqueous solution may be added to an alcohol solution or suspension of a diastereomeric salt. Then, a neutralizing salt of an optically active carboxylic acid or an optically active sulfonic acid which is a resolving agent and an alkali metal hydroxide is deposited. By removing the neutralized salt by an operation such as filtration, an alcohol solution of an optically active amine having a high affinity for water can be obtained in the filtrate. By distilling this, optically active amines having a high affinity for high-purity water can be obtained. Furthermore, the filtrate can be recycled.
For example, the amount of the solvent used can be reduced by adding a diastereomeric salt to the filtrate and similarly treating it with an alkali metal hydroxide.

According to this method, the optically active carboxylic acids or optically active sulfonic acids which are resolving agents can be recovered almost quantitatively as an alkali metal salt, which is very economical. Therefore, it can be carried out on an industrial scale.

[0022]

The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

Example 1 19.6 g (0.49 mol) of caustic soda was added to a mixed solution of 470.5 g of ethanol and 35.8 g of water, and dissolved by heating at 50 ° C. While vigorously stirring while maintaining at 50 ° C, 91.6 g (0.245 mol) of (S) -2-methylpiperazine-N-benzenesulfonyl-L-aspartic acid salt was added, and the mixture was stirred at 50 ° C for 5 hours. did. After cooling to room temperature, the precipitated sodium salt of N-benzenesulfonyl-L-aspartic acid was filtered and rinsed with ethanol. The yield was 110.2 g, and the recovery rate of N-benzenesulfonyl-L-aspartic acid sodium salt was 97.6%. On the other hand, 23.8 g of (S) -2-methylpiperazine was dissolved in 547.8 g of the filtrate.

Next, 19.4 g (0.49 mol) of caustic soda was added again to 544.3 g of the above-mentioned demineralization solution, and the mixture was heated and dissolved at 50 ° C. In the same manner as the first time, 91.6 g (0.245 mol) of (S) -2-methylpiperazine.N-benzenesulfonyl-L-aspartic acid salt was desalted. The recovery rate of N-benzenesulfonyl-L-aspartic acid sodium salt was 99.5%, and 48.2 g (0.4
(S) -2-methylpiperazine (81 mol) was contained, and the salt removal rate was 98.2% including the first time. The demineralized filtrate is concentrated and distilled by an evaporator to a boiling point of 152 ° C.
A fraction of 43.4 g was obtained with a yield of 88%.

Example 2 22.9 g (0.573 mol) of caustic soda was added to 35.0% of water.
The solution dissolved in g was added to 145.0 g of isopropanol and mixed. (R, R) -t at 60 ° C. in this mixed solution
68.0 g (0.257 mol) of a salt of rans-1,2-diaminocyclohexane.L-tartaric acid was added in 5 batches, and the mixture was heated with stirring for 6 hours. After cooling to room temperature, the precipitated disodium L-tartrate dihydrate was filtered and rinsed with 17.6 g of isopropanol. Yield 56.4g
And the recovery rate of L-tartaric acid was 95%. The desalted filtrate contained 29.1 g (0.255 mol) of (R, R) -trans-1,2-diaminocyclohexane (dissolving rate 99%). The demineralized filtrate was concentrated and distilled by an evaporator to obtain a distillate having a boiling point of 82 ° C./28 mmHg of 25.
9 g was obtained with a yield of 88%.

Example 3 To a mixed solution of 100.0 g of methanol and 8.0 g of water was added 4.2 g (0.105 mol) of caustic soda, and the mixture was heated and dissolved at 50 ° C. To this mixed solution, 40.6 g (0.100 mol) of a salt of (R) -3-hydroxypyrrolidine / p-toluenesulfonyl-L-phenylalanine was added, and 5
The mixture was stirred at 0 ° C for 7 hours. After cooling to room temperature, the precipitated sodium salt of p-toluenesulfonyl-L-phenylalanine was filtered and rinsed with methanol. The yield of the sodium salt of p-toluenesulfonyl-L-phenylalanine was 33.3 g (98% yield). (R) -3-
The salt removal rate of hydroxypyrrolidine is 99%. The salt-dissolving filtrate is concentrated by an evaporator and distilled to have a boiling point of 93 to 96 ° C./6 m.
A mHg fraction of 7.7 g was obtained with a yield of 89%.

[0027]

【The invention's effect】

(1) According to the present invention, an optically active amine having a high affinity for water is produced from a diastereomeric salt composed of an optically active amine having a high affinity for water and an optically active carboxylic acid in an industrial scale with a high yield and a high yield. It can be isolated with high purity and low cost. (2) According to the present invention, the extraction process from water is unnecessary. (3) According to the present invention, optically active carboxylic acids and optically active sulfonic acids that are resolving agents can be quantitatively recovered as alkali metal salts.

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Claims (2)

[Claims] 1. A method in which a diastereomeric salt of an optically active amine and an optically active carboxylic acid or an optically active sulfonic acid is contacted in the presence of an alcohol and an alkali metal hydroxide to isolate the free amine from the alcohol layer. A method for isolating an optically active amine, which comprises: 2. The method for isolating an optically active amine according to claim 1, wherein the alcohol is an alcohol solution containing 6 to 50% by weight of water.