JP3312459B2 - Method for isolating optically active amines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a water-soluble diastereomeric salt of an optically active amine and an optically active carboxylic acid or an optically active sulfonic acid formed during optical resolution. The present invention relates to a method for isolating a high optically active amine.

[0002] optically active 1,2-diaminopropane, optically active 2-methylpiperazine, high optical active amines affinity to water, such as optically active 3-hydroxypyrrolidine is an intermediate of pharmaceuticals or, as the basic resolving agent It is a useful compound.

[0003]

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

However, optically active amines having relatively low molecular weight have many compounds having a high affinity for water and have a low boiling point, so that it is difficult to separate them from water. For this reason, they are usually commercially available as aqueous solutions or salts such as hydrochlorides and sulfates.

However, in consideration of utilization, there is a great demand for free amines.

In general, optically active amines are obtained in a wide variety of ways, such as preferential crystallization, diastereomeric salt resolution, asymmetric synthesis, use of enzymes, and separation by chromatography. The method of resolving diastereomeric salts using an acid or an optically active sulfonic acid as a resolving agent is a means that is versatile, simple, and can be produced on an industrial scale. In this method, after the optical resolution, it is essential that the diastereomer salt is dissolved and separated from the optically active carboxylic acid or optically active sulfonic acid as the resolving agent. It is common 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 desalting operation. With these methods,
It is difficult to easily isolate an optically active amine having high affinity for water with high yield and high purity.

Heretofore, as a method for isolating an optically active amine having a high affinity for water from the diastereomer salt as described above, (1) adding a highly concentrated aqueous solution of caustic soda to a diastereomer salt to diethyl ether Extraction 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 adding a high-concentration, large excess aqueous solution of caustic soda to a diastereomer salt, separating the separated amine layer, repeating the operation of removing the water in the amine layer with caustic soda or the like, followed by distillation (Can. J. Chem. , 54 , 2639
(1976)).

[0008]

SUMMARY OF THE INVENTION
The method of extracting with an organic solvent of (1) requires a large amount of an alkali and an organic solvent, and the solvent used is often an organic solvent that is disadvantageous for industrial use in terms of toxicity to the human body and recovery rate,
Moreover, the extraction rate is not always high. In the method (2), since the separated amine layer contains a large amount of water,
The alkali metal salt of the resolving agent is easily mixed. In addition, an optically active amine having a relatively low molecular weight and high affinity for water has a boiling point close to that of water or forms an azeotropic composition with water, so that it is difficult to remove water. Therefore, as a method of removing water in order to obtain high-purity amine, a method of adding a large amount of alkali such as caustic soda and dehydrating is adopted, and it is necessary to repeat this operation many times, which is very troublesome. And the isolation yield is low.

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

[0010]

Means for Solving the Problems The present inventors have prepared an optically active amine having a relatively low molecular weight and a high affinity for water on a commercial scale with a high purity by a simple operation from a diastereomer salt.
As a result of intensive studies for the purpose of developing a method for isolating with high yield, a diastereomer salt composed of an optically active amine having high affinity for water and an optically active carboxylic acid or an optically active sulfonic acid was converted to an alcoholic alkali metal water. We have found a way to obtain a free amine in the alcohol layer by treatment with an oxide.

That is, the present invention relates to an optically active amine (optical
Alcohol <br/> Le solution and alkali metal hydroxides, including academic active 1,2 excluding diaminocyclohexane) and diastereomer salt comprising an optically active carboxylic acid or an optically active acid 6-50% by weight of water Contact in the presence of
This is a method for isolating an optically active amine, which comprises obtaining a free amine from an alcohol layer.

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

The optically active amine (optically active 1,2-diaminocyclo) which forms the diastereomer salt used in the present invention.
(Excluding hexane) 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. The optically active amines having a high affinity for water are, for example, amines having a relatively small molecular weight, being easily soluble in water, and being difficult to extract with an organic solvent. Representative amines are lower aliphatic amines, lower aliphatic halogenated amines, lower aliphatic amino alcohols, and lower aliphatic amino thiols.

Specifically, for example, monoamines such as sec-butylamine, 2-chloropropylamine, 2-methylazetidine, 3-aminobutyronitrile, 4-amino-3-isoxazolidone, and 1,2-diaminopropane 2,3-diaminobutane, 1,3-diaminobutane , 3 -aminopyrrolidine, 2-methylpiperazine,
Diamines such as 2-aminomethylpyrrolidine, or 1-amino-2-propanol, 2-amino-1-propanol, 2-amino-1-butanol, 3-amino-2-butanol, 3-hydroxypyrrolidine and the like And aminothiols such as amino alcohols and 1-amino-2-propanethiol.

Examples of the optically active carboxylic acid which forms a diastereomer salt include optically active hydroxy acids, amino acids, and optically active N derivatives derived from amino acids, such as tartaric acid, malic acid, lactic acid, and mandelic acid.
-Well-known as optically active isomers of acylcarboxylic acids, derivatives of tartaric acid, optically active tartranilic acids, O, O'-dialkyltartaric acids, or derivatives of malic acid, lactic acid, and mandelic acid; and other optical resolving agents D-
Examples include camphoric acid, optically active pantoyl lactone, optically active 2-phenylbutyric acid, and optically active 2-phenylpropionic acid. The optically active sulfonic acid is 1
0-camphorsulfonic acid, 1-phenylethanesulfonic acid and the like can be mentioned.

The alcohol used as the solvent is preferably an alcohol having a relatively large difference in boiling point from the optically active amine and hardly dissolving 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 use of ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, or the like, which forms an azeotropic composition with water, effectively removes water.

Here, an alcohol containing 6 to 50% by weight of water is used.
Use a solution of the By doing so, the salt dissolution rate of the diastereomer salt of the optically active amine having a high affinity for water is increased. Since the water is too large, alkali salts of optically active carboxylic acids or optically active acid becomes soluble in an alcohol solvent, the water content is to alcohol 6-5
It must be 0%.

Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide and potassium hydroxide. The used amount may be equivalent to the diastereomer salt. If it is too large, the amount of the residue in the distillation increases, and the distillation yield decreases. If the amount is less than the equivalent, a diastereomer salt which is not desolvated remains, and the isolation yield becomes low. Therefore, 0.9 to 2.5 equivalents, preferably 1.0 to 2.5 equivalents per equivalent of the diastereomer salt. 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, optically active amines having a high affinity for water, and the alkali salt of the resolving agent do not deteriorate. Depending on
Generally, the temperature is 0 to 150 ° C, preferably 0 to 100 ° C, and 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 operation procedure is optional. A diastereomer salt is added at once or in portions to a hydroalcoholic solution obtained by dissolving an alkali metal hydroxide such as caustic soda in hydrous alcohol, and treated at a predetermined temperature and time. Alternatively, an aqueous alcohol solution or an aqueous solution of an alkali metal hydroxide may be added to an alcohol solution or suspension of a diastereomer salt. Then, a neutralized salt of an optically active carboxylic acid or an optically active sulfonic acid as a resolving agent and an alkali metal hydroxide is precipitated. If the neutralized salt is removed by an operation such as filtration, an alcohol solution of an optically active amine having a high affinity for water is obtained in the filtrate. By distilling this, optically active amines having high affinity for high-purity water can be obtained. Further, the filtrate can be recycled.
For example, the amount of the solvent can be reduced by adding a diastereomer salt to the filtrate and treating the filtrate with an alkali metal hydroxide in the same manner.

According to this method, an optically active carboxylic acid or an optically active sulfonic acid as a resolving agent can be almost quantitatively recovered as an alkali metal salt, which is very economical. Therefore, it can be implemented on an industrial scale.

[0022]

EXAMPLES 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. 91.6 g (0.245 mol) of a salt of (S) -2-methylpiperazine / N-benzenesulfonyl-L-aspartic acid was added while stirring vigorously while maintaining the temperature at 50 ° C., followed by stirring 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 of sodium N-benzenesulfonyl-L-aspartate was 97.6%. On the other hand, (S) -2-methylpiperazine was subjected to 23.8 g of salt in 547.8 g of the filtrate.

Next, 19.6 g (0.49 mol) of caustic soda was added again to 544.3 g of the above-mentioned salt solution, and the mixture was heated and dissolved at 50 ° C. 91.6 g (0.245 mol) of the salt of (S) -2-methylpiperazine / N-benzenesulfonyl-L-aspartic acid was deionized in the same manner as the first time. The recovery of N-benzenesulfonyl-L-aspartate sodium salt was 99.5%, and 48.2 g (0.4
81 mol) of (S) -2-methylpiperazine, and the salt removal rate was 98.2% in total with the first time. The desalted filtrate is concentrated by an evaporator and distilled to a boiling point of 152 ° C.
Was obtained in a yield of 88%.

Example 2 4.2 g (0.105 mol) of caustic soda was added to a mixed solution of 100.0 g of methanol and 8.0 g of water, and dissolved by heating at 50 ° C. 40.6 g (0.100 mol) of a salt of (R) -3-hydroxypyrrolidine / p-toluenesulfonyl-L-phenylalanine was added to this mixed solution,
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. 33.3 g (98% yield) of a sodium salt of p-toluenesulfonyl-L-phenylalanine was obtained. (R) -3-
Hydroxypyrrolidine has a salt removal rate of 99%. The desalted filtrate is concentrated by an evaporator and distilled to have a boiling point of 93 to 96 ° C / 6m.
7.7 g of a fraction of mHg were obtained with a yield of 89%.

[0027]

(1) According to the present invention, an optically active amine having a high affinity for water is obtained from a diastereomer salt comprising an optically active amine having a high affinity for water and an optically active carboxylic acid or an optically active sulfonic acid. Can be isolated on an industrial scale with high yield, high purity and low cost. (2) According to the present invention, an extraction step from water is not required. (3) According to the present invention, optically active carboxylic acids and optically active sulfonic acids as resolving agents can be quantitatively recovered as alkali metal salts.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI C07D 241/04 C07D 241/04 (56) References JP-A-3-271269 (JP, A) JP-A-4-128270 (JP) JP-A-7-188122 (JP, A) JP-A-7-188097 (JP, A) JP-A-3-279375 (JP, A) JP-A-60-231632 (JP, A) (58) Surveyed field (Int.Cl. ⁷ , DB name) C07C 211/36 C07C 209/88 C07C 211/11 C07D 207/12 C07D 241/04 C07B 57/00 360

Claims (1)

(57) [Claims] 1. An optically active amine (optically active 1,2-dia
A diastereomeric salt consisting of an optically active carboxylic acid or an optically active sulfonic acid ) and an alcohol solution containing 6 to 50% by weight of water in the presence of an alkali metal hydroxide. A method for isolating an optically active amine, comprising isolating a free amine.