JP2001131157A - Method for producing optically active 2-methylpiperazine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing optically 2-methylpiperazine having a highly optically active purity by optically resolving (±)-2-methylpiperazine. SOLUTION: This method for producing optically active 2-methylpiperazine, comprising a process for reacting 1 mole of (±)-2-methylpiperazine with 1 mole of an optically active tartaric acid selected from L-tartaric acid and D-tartaric acid to produce the 2-methylpiperazine.monotartarate as two kinds of the diastereomers and then utilizing the difference between the dissolution degrees of the diastereomers to deposit and separate one of the diastereomers, thus dissolving two kinds of the diastereomers in the crystals and the mother liquor, respectively, a process for further reacting with at least 1 mole of the same optically active tartaric acid to produce the 2-methylpiperazine.ditartarate as two kinds of the diastereomers and then utilizing the difference between the dissolution degrees of the diastereomers to deposit and separate one of the diastereomers, thus dissolving the two diastereomers in the crystals and the mother liquor, respectively, and so on.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing optically active 2-methylpiperazine, and more particularly, to optically resolving (±) -2-methylpiperazine using optically active tartaric acid. The present invention relates to an optical resolution method for piperazine. According to the method of the present invention, optically active 2-methylpiperazine having extremely high optical purity useful as a raw material for synthesizing pharmaceuticals or agricultural chemicals can be obtained.

[0002]

2. Description of the Related Art An optically active 2-methylpiperazine is produced by a process for synthesizing 2-methylpiperazine and producing (±) 2-methylpiperazine.
And an optical resolution step of 2-methylpiperazine. (±)
As a method for optical resolution of -2-methylpiperazine, a method using optically active tartaric acid is disclosed in the following documents and the like. 1) In a mixed solvent, 1 mol of an optically active tartaric acid is reacted per 1 mol of (±) -2-methylpiperazine to form 2-methylpiperazine monotartrate as two diastereomers, Method of optical resolution using the difference in solubility in mixed solvents (T. Miyamoto et.
al, J. Med. Chem., 33 , 1645, 1990), 2) 2-methylpiperazine by reacting 2 mol of optically active tartaric acid per mol of (±) -2-methylpiperazine in a mixed solvent. A method of producing bitartrate as two kinds of diastereomers and performing optical resolution by utilizing a difference in solubility in a mixed solvent (Japanese Patent Application Laid-Open No. 1-149775); 3) (±) -2 in water 2 moles of optically active tartaric acid per 1 mole of methylpiperazine are reacted to form 2-methylpiperazine ditartrate as two diastereomers, and the optical resolution is obtained by utilizing the difference in solubility in a mixed solvent thereof. (JP-A-3-279375).

[0003]

In any of the above-mentioned methods, the first 2-methylpiperazine mono- or di-tartrate diastereomer separated and separated is freed to obtain the first 2-methylpiperazine. And concentrating the mother liquor from which the first diastereomer was separated to precipitate or free the second diastereoisomer of 2-methylpiperazine mono- or ditartrate, freeing 2-methylpiperazine. It has gained. Therefore,
If one diastereomer is carefully precipitated, the first 2-methylpiperazine having a considerably higher optical purity can be obtained, but the second 2-methylpiperazine is not dissolved in the mother liquor in the first diastereomer. Since the second diastereomer is freed by precipitating or not precipitating while containing a considerable amount of, the optical purity is low. In any case, in order to obtain an optically active 2-methylpiperazine having a high optical purity exceeding 98% ee, recrystallization is required to be repeated several times at a diastereomer stage.

An object of the present invention is to provide an industrial method for producing optically active 2-methylpiperazine having high optical purity using (±) -2-methylpiperazine as a starting material.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above object, and as a result, (±) -2
-Two diastereomers of 2-methylpiperazine monotartrate, which are produced by reacting either L-form (natural type) or D-form (unnatural type) tartaric acid with -methylpiperazine to water The solubility difference is larger than expected, and one diastereomer can be preferentially precipitated with high purity. Therefore, by reacting tartaric acid in two stages, purification by recrystallization at the diastereomer stage Omitted, it was found that both enantiomers of (S) -and (R) -2-methylpiperazine having extremely high optical purity could be obtained, and the present invention was completed.

The present invention relates to (a) reacting one mole of any optically active tartaric acid selected from L-tartaric acid and D-tartaric acid per mole of (±) -2-methylpiperazine in water, -2 methylpiperazine monotartrate
One diastereomer is produced as a diastereomer, and one of them is precipitated and separated by filtration by utilizing the difference in solubility of the two diastereomers formed in water. (B) at least one mole of the same optically active tartaric acid as used in step (a) per mole of 2-methylpiperazine monotartrate in the mother liquor separated in step (a) To give 2-methylpiperazine ditartrate in 2
One diastereomer is produced as a diastereomer, and one of them is precipitated and separated by filtration by utilizing the difference in solubility of the two diastereomers formed in water. (C) diastereomers of 2-methylpiperazine monotartrate precipitated and separated in step (a) and (b) diastereomers of 2-methylpiperazine / dartrate precipitated and separated in step (b) A method for producing optically active 2-methylpiperazine, which comprises the step of liberating each of the mer.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the starting material (±) -2-methylpiperazine is usually a racemic compound obtained by a general synthesis method, but is not limited to a racemic compound. One of the optically active substances may be contained in an amount equal to or more than that of its enantiomer.

The optically active tartaric acid may be either L-tartaric acid or D-tartaric acid, but one selected from them is used. When L-tartaric acid is used, in the step (a), (R) -2-methylpiperazine mono-L-tartrate precipitates as a diastereomer having a lower solubility in water, and in the step (b), the (S) − 2-Methylpiperazine di-L-tartrate precipitates as a diastereomer.
On the other hand, when D-tartaric acid is used, in step (a),
(S) -2-methylpiperazine mono-D-tartrate precipitates as a diastereomer having a lower solubility in water, and in step (b), (R) -2-methylpiperazine di-D-tartrate is diastereomeric. It precipitates as a mer.

In the method of the present invention, first, in step (a), D-methyl per mole of (±) -2-methylpiperazine is
1 mol of an optically active tartaric acid selected from the isomer and the L-isomer is dissolved, mixed and reacted to form 2-methylpiperazine monotartrate as two diastereomers,
One diastereomer is preferentially precipitated by utilizing the difference in solubility in water, separated by filtration, and the two diastereomers are separated into a precipitated crystal and a mother liquor.

The reaction can be carried out at room temperature, for example, by dissolving a mixture of (±) -2-methylpiperazine and optically active tartaric acid in water as a solvent. Precipitation of the diastereomer can be carried out at a temperature in the range of about 0 to 40 ° C., but it is preferable that the diastereomer is precipitated at around room temperature for simplicity of operation. The reaction time is not particularly limited, and is generally about 1 to 72 hours, preferably about 3 to 24 hours, from the reaction to the precipitation.

The amount of water used in the reaction varies depending on the reaction temperature and the precipitation operating temperature, and the concentration of at least one of the two diastereomers formed at the reaction temperature is saturated even at the precipitation temperature at which the other predetermined amount is precipitated. It is the range that does not reach the solubility. For example, when the reaction is carried out at room temperature or higher and the precipitation is resolved at room temperature, the amount of water is 5 to 10 ml, preferably about 5 ml, per 1 g of the raw material (±) -2-methylpiperazine. When an excess of water is used, the reaction solution needs to be cooled or concentrated more than necessary to precipitate one diastereomer. If the amount of water is too small, undesired diastereomers reach the saturation concentration and precipitate, so that purification by recrystallization is required to achieve the desired optical density.

Next, in the step (b), the same mother liquor as that selected in the step (a) is added to the mother liquor separated in the step (a) per mole of 2-methylpiperazine monotartrate present in the mother liquor. One mole or more of optically active tartaric acid is mixed and dissolved and reacted to form 2-methylpiperazine ditartrate as two types of diastereomers, and one diastereomer is preferentially utilized by utilizing the difference in solubility in water. And separated by filtration, and the two diastereomers are separated into a crystal and a mother liquor.

The amount of the optically active tartaric acid used is at least 1 mol, preferably 1 mol to the starting material (±) per mol of 2-methylpiperazine monotartrate present in the mother liquor.
The range is 2 moles per mole of -2-methylpiperazine. The reaction conditions and the crystal precipitation conditions in the step (b) are as described above.
Same as step (a).

In the step (c), each of the 2-methylpiperazine monotartrate diastereomer and the 2-methylpiperazine ditartrate diastereomer precipitated and separated in the steps (a) and (b) is dissolved in water-soluble. By neutralization with a base described above to release optically active 2-methylpiperazine. As a base for making the diastereomer free, an inorganic base such as sodium hydroxide or potassium hydroxide is preferably used.

Further, the optical activity 2 released in the neutralization reaction solution
-Extraction of methylpiperazine with an organic solvent such as benzene and toluene, followed by distilling off the solvent under normal pressure or reduced pressure, has a high optical purity of 98% ee or more.
(S) -2-Methylpiperazine and (R) -2-methylpiperazine are obtained.

[0016]

The present invention will be described in more detail with reference to Examples and Comparative Examples. Optical activity 2 in Examples and Comparative Examples
-The optical purity of methyl piperazine is as follows: Solution A: 29 mg (0.29 mmol) of 2-methylpiperazine / 25 ml of acetonitrile, Solution B: 40 mg (0.10 mmol) of GITC / 5 m of acetonitrile
l (GITC is 2,3,4,6-tetra-O-acetyl-β
-D-glucopyranosyl isothiocyanate) was prepared, and 0.86 ml (0.01 mmol) of solution A was added to 0.48 ml (0.4 mm) of solution B.
Was added and the mixture was allowed to stand at room temperature for 10 minutes, after which 2 μl of the resulting reaction solution was measured by HPLC analysis. HPLC analysis conditions Column: TSK-gel ODS-80TM (φ4.6 × 250 mm) Column temperature: 30 ° C. Mobile phase: methanol: 0.05 M sodium dihydrogen phosphate = 25: 75 Flow rate: 0.7 ml / min Detection: UV254nm

Example 1 40.0 g of (±) -2-methylpiperazine in 200 ml of water
(0.40 mol) and 60.0 g (0.40 mol) of D-tartaric acid
Was added and stirred at room temperature to dissolve, and the mixture was further stirred for 6 hours. The precipitated crystals were collected by filtration and washed with 100 ml of water.
Drying under reduced pressure at a temperature of 4 ° C. gave 44.8 g (90%) of white crystals of (S) -2-methylpiperazine mono-D-tartrate. 40.0 g (0.27 mo) of D-tartaric acid was added to the mother liquor after filtering the crystals.
After l) was further added and dissolved, the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure at 80 ° C. to obtain 58.2 g (73%) of white crystals of (R) -2-methylpiperazine di-D-tartrate.

[0018] (S) -2-methylpiperazine mono D- tartrate 20.0 g (0.80 mol) was added 40ml water and potassium hydroxide 40.0g of (0.71 mol) was stirred for 5 min, (S) - 2-Methylpiperazine was released. Liberation
(S) -2-Methylpiperazine was extracted with 40 ml of toluene, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.6 g (70%) of (S) -2-methylpiperazine. The optical purity was 98.5% ee.

[0019] 113 ml of water and 113 g (2.02 mol) of potassium hydroxide were added to 56.7 g (0.14 mol) of (R) -2-methylpiperazine di-D-tartrate, and the mixture was stirred for 5 minutes.
(R) -2-Methylpiperazine was released. Free (R) −
After extracting 2-methylpiperazine with 120 ml of toluene and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
10.7 g (75%) of (R) -2-methylpiperazine were obtained. This had an optical purity of 99.6% ee.

Example 2 40.0 g of (±) -2-methylpiperazine in 200 ml of water
(0.40 mol) and 60.0 g (0.40 mol) of L-tartaric acid
Was added and the mixture was stirred and dissolved at room temperature, and further stirred for 5 hours. The precipitated crystals were collected by filtration, washed with 100 ml of water, and dried under reduced pressure at 80 ° C to obtain 48.8 g (88%) of white crystals of (R) -2-methylpiperazine mono-L-tartrate. 40.0 g (0.27 mol) of L-tartaric acid was further added to and dissolved in the mother liquor after filtering the crystals, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to obtain white crystals of (S) -2-methylpiperazine di-L-tartrate 5
7.7 g (72%) were obtained.

[0021] (R)-2-methyl piperazine mono L- tartrate 35.0 g (0.14 mol) was added water 70ml and potassium hydroxide 70.0g of (1.25 mol) was stirred for 5 minutes, (R) - 2-Methylpiperazine was released. Liberation
(R) -2-methylpiperazine was extracted with 70 ml of toluene, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 10.0 g (71%) of (R) -2-methylpiperazine. Its optical purity was 98.9% ee.

To 50.0 g (0.13 mol) of (S) -2-methylpiperazine di-D-tartrate, 100 ml of water and 100 g (1.79 mol) of potassium hydroxide were added, and the mixture was stirred for 5 minutes.
(S) -2-Methylpiperazine was released. Free (S) −
After extracting 2-methylpiperazine with 100 ml of toluene and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
9.4 g (75%) of (S) -2-methylpiperazine were obtained.
The optical purity was 98.8% ee.

Comparative Example 1 25.0 g of (±) -2-methylpiperazine in 200 ml of water
(0.25 mol) and 75.0 g (0.50 mol) of L-tartaric acid
Was stirred and dissolved at room temperature, and further stirred for 24 hours. The precipitated crystals of (R) -2-methylpiperazine.di-L-tartrate were collected by filtration and neutralized with an aqueous sodium hydroxide solution. The oil separated into the neutralized solution was extracted with benzene, and the benzene layer was washed with an aqueous sodium hydroxide solution.
After drying over anhydrous sodium sulfate, the solvent was distilled off and (R)
7.13 g (57%) of 2-methylpiperazine were obtained. Its optical purity was 91.0% ee.

The mother liquor from which the crystals of (R) -2-methylpiperazine di-L-tartrate were separated by filtration was concentrated to 1/2 and the precipitated crystals were separated by filtration and the filtrate was concentrated to dryness. The obtained residue was neutralized with an aqueous sodium hydroxide solution, the separated oily substance was extracted with benzene, and the benzene layer was washed with sodium hydroxide. After drying over anhydrous sodium sulfate, the solvent was distilled off and 6.63 g of ( S) -2-methylpiperazine (53% ).
%). The optical purity was even lower at 71.0% ee.

[0025]

As shown in the above examples, the optically active 2-methylpiperazine obtained by the method of the present invention is:
As in the present invention, the optical purity is much higher than the optically active 2-methylpiperazine obtained by the conventional method using water as a solvent. Furthermore, the amount of optically active tartaric acid used in the method of the present invention is smaller than that of the conventional method.

The present invention provides a method for producing (±) -2-methylpiperazine by optical resolution, which can obtain optically active 2-methylpiperazine having extremely high optical purity in a high yield without special purification. It has a significant industrial significance.

Claims (1)

[Claims] (1) (a) (±) -2-methylpiperazine 1
One mole of any optically active tartaric acid selected from L-tartaric acid and D-tartaric acid per mole was reacted in water to form 2-methylpiperazine monotartrate as two diastereomers and formed. (B) using the difference in solubility of two diastereomers in water to precipitate one of the diastereomers, separating them by filtration, and separating the two diastereomers into crystals and a mother liquor, At least one mole of the same optically active tartaric acid as used in step (a) is further reacted per mole of 2-methylpiperazine monotartrate in the mother liquor separated in step a) to give 2-methylpiperazine. Bitartrate is produced as two kinds of diastereomers, and one of them is precipitated and separated by filtration using the difference in solubility of the two kinds of diastereomers formed in water. (C) separating the two diastereomers in the crystal and the mother liquor from each other; (c) diastereomers of 2-methylpiperazine monotartrate precipitated and separated in step (a) and (b) A method of freeing each of the separated and separated diastereomers of 2-methylpiperazine / dartrate salt from optically active 2-methylpiperazine.