HU212667B - Process for optical resolution of metamphetamine - Google Patents

Abstract

The present invention relates to a novel process for the preparation of the enantiomers of the known N-methyl-3-phenylisopropylamine of the formula (I), wherein the racemic N-methyl-β-phenylisopropylamine base is less than an O.O. β-toluyl-R, R-tartaric acid resolving agent (a) is reacted in a solvent medium consisting of one or two liquid phases to produce the L-enantiomer, the L-enantiomer is recovered in the form of a poorly soluble salt with the resolving agent, and the L-enantiomer is liberated from the resulting salt; or b) reacting and recovering from the reaction mixture by distillation of the D-enantiomer and then liberating the L-enantiomer from the residue by alkaline treatment. The L-enantiomer of the compound of formula (I) is the intermediate of JumexR and the D-enantiomer is a chiral reagent for organic synthesis. CH3 (η) - ch2-chnchch3 (I.) HU 212 667 B Scope of the description: 4 pages (including 1 sheet)

Description

The present invention relates to the preparation of optically pure enantiomers of N-methyl-p-phenylisopropylamine (methamphetamine).

LN-methyl-β-phenylisopropylamine (methamphetamine) is an intermediate of Jumex ^R (a key ΜΑΟ-β selective inhibitor in dopamine degradation) and the Denantiomer is a chiral reagent for other syntheses. The L-enantiomer is prepared from the racemic compound by resolution. The resolution was performed with d-tartaric acid in an organic solvent (Tetrahedron 25 2979 (1969)) and in an aqueous medium (Hungarian Patent No. 169,845). In both cases, the acid tartrate of the L-isomer precipitates. A common disadvantage of the above processes is that they cannot further increase the production and optical purity of the L and D enantiomers.

It has now surprisingly been found that O.O'-di-p-toluoyl-RR-tartaric acid is suitable for the preparation of optically pure methamphetamine enantiomers by the addition of less than one molar equivalent of the racemic N-methylphenylisopropylamine base. Reacting the O'di-p-toluyl-RR-tartaric acid resolving agent by reacting it in a solvent medium consisting of one or two liquid phases to form the L-enantiomer, recovering the L-enantiomer in the form of an insoluble salt thereof with a resolving agent, and liberating the free base; or the D-enantiomer is prepared by reaction with or without a solvent and the enantiomer is obtained as a base by distillation from the reaction mixture. and the L-enantiomer is liberated from the residue by alkaline treatment.

Preferably, the racemic base is reacted with a quarter or a half molar equivalent of the resolving agent in the presence or absence of hydrochloric acid. in a single-phase solvent, or in the absence of hydrochloric acid, in an immiscible two-solvent phase.

In such cases, the neutral and acid salts of L-methamphetamine with O, O'-di-ptoluyl-R.R. tartaric acid are crystallized from the reaction mixture.

Unexpectedly, it has been found that 0.0'di-p-toluyl tartaric acid is capable of performing the resolution not only by the conventional method of selective crystallization of diastereomeric salts, but also by partial distillation.

Preferably, the racemic methamphetamine is deposited on the O, O'-di-ptoluyl-R, R,-tartaric acid, preferably in a 1: 4 molar ratio, and then subjected to distillation, preferably vacuum distillation. Distillation yields D-methamphetamine almost quantitatively, while the enantiomeric mixture enriched in the L-enantiomer and the neutral salt of the resolving agent remain.

Alternatively, the base and the resolving agent may be reacted beforehand in a solvent, which is then removed by evaporation and the resulting mixture is distilled from a free portion of the methamphetamine base. Thus, if the enantiomeric mixture enriched in L-methamphetamine is to be separated from the reaction mixture, fractional crystallization is used, and if the enriched mixture in the D-enantiomer is distilled. In the former case, the mother liquor is processed to yield a mixture containing an excess of the L-enantiomer in the decomposition of the D-residue and in the latter.

By repeating or sequentially applying either of the two solutions, one can obtain methamphetamine enantiomers of any optical purity. For example, re-distillation or recrystallization of the resulting distillate according to the examples provided gives optically pure methamphetamine enantiomers.

The process is illustrated by the following examples, without limiting our claims.

Examples

Example 1

Dissolve 3.0 g (0.02 mol) of racemic methamphetamine in 6 cm ^{3 of} methanol, add 1.9 g (0.005 mol) of (-) O, O'-di-p-toluyl-R, R-tartaric acid in 4 cm ^{3 of} methanol. solution. The reaction mixture was stirred at room temperature for one hour. and kept at 5 ° C for two hours. The precipitated salt is filtered off and dried under an infrared lamp. The resulting salt (2.4 g) was dissolved in a mixture of 5.5 cm ^{3 of} 2M NaOH and 15 cm ^{3 of} water, extracted with ³ x 20 cm ^{3 of} chloroform, and the combined organic phases were dried and evaporated. The residue is a colorless oil.

Yield: 1.1 g of L-methamphetamine.

[α] D = -14.9 ° (c: 1, N HCl). Optical purity: 92.0%.

The filtrate is concentrated to dryness in the mother liquor and processed in the same way as the salt. The residue is a colorless oil. Yield: 1.7 g of D-methamphetamine.

[α] D = + 8.0 ° (c: 1.N HCl). Optical purity: 49.4%.

Example 2

Dissolve 3.0 g (0.02 mol) of racemic methamphetamine in 6 cm ^{3 of} methanol and add a solution of 3.9 g (0.01 mol) of (-) - O.O'-dip-toluyl-R, R-tartaric acid in 4 cm ^{3 of} methanol. The reaction mixture was stirred at room temperature for 1 hour and then held at 5 ° C for 2 hours. The precipitated salt is filtered off and dried under an infrared lamp. The resulting salt was dissolved in 3.6 g of 3x20 cm extracted with chloroform ³ NaOH 20 cm ³ ΙΜ V. The combined organic phases are dried and evaporated. The residue is a colorless oil.

Yield: 1.5 g of L-methamphetamine.

[[alpha]] D = -11.5 [deg.] (c: 1, N HCl). Optical purity: 71.0%.

The filtrate mother liquor is evaporated to dryness and processed in the same way as the salt. The residue is a colorless oil. Yield: 1.2 g D-methamphetamine.

[α] D 20 = + 11.6 ° (c: 1, N HCl). Optical purity: 71.6%.

Example 3

3.0 g (0.02 mol) of racemic methamphetamine are dissolved in 4 cm ^{3 of} methanol and 0.84 cm ³ (0.01 mol) of ccHCl are added under cooling, followed by 1.9 g (0.005 mol) of (-) - A solution of O, O'-di-p-toluoyl tartaric acid in 4 cm ^{3 of} methanol was added. The mixture was heated at 5 ° C for 1 hour. The precipitated salt is born and dried under an infrared lamp. 2.2 g of salt were obtained

It was dissolved in a mixture of 5.5 cm ^{3 of} 2M NaOH and 20 cm ^{3 of} water and extracted with 3 x 20 cm ^{3 of} chloroform. The combined organic phases are dried and evaporated. The residue is a colorless oil. Yield: 1.0 g of L-methamphetamine.

[.alpha.] D @ 20 = -13.0 DEG (c: 1, NHCl). Optical purity: 80.3%.

HU 212 667 Β

The filtrate mother liquor is evaporated to dryness and processed in the same way as the salt. The residue is a colorless oil. Yield: 1.8 g of D-methamphetamine.

[.alpha.] D @ 20 = + 6.7 DEG (c: 1, N HCl). Optical purity: 41.4%.

Example 4

3.0 g (0.02 mol) of racemic methamphetamine are dissolved in a mixture of 6 cm ^{3 of} dichloroethane and 3 cm ^{3 of} water and 1.9 g (0.005 mol) of (-) - O, O'-di-p-toluyl tartaric acid are added. cm ³ dissolved in dichloroethane. The mixture was stirred at room temperature for one hour and then held at 5 ° C for two hours. The precipitated salt is born and dried under an infrared lamp. The resulting salt (2.6 g) was dissolved in a mixture of 5.5 cm ^{3 of} 2M NaOH and 20 cm ^{3 of} water and extracted with ³ x 20 cm ^{3 of} chloroform. The residue is a colorless oil.

Yield: 1.1 g of L-methamphetamine.

[α] D = -15.5 ° (c: 1, N HCl). Optical purity: 95.7%.

The two-phase filtrate mother liquor was separated, the dichloroethane portion evaporated to dryness and worked up in the same manner as the salt. The residue is a colorless oil.

Yield: 1.6 g D-methamphetamine.

[α] D = +10.1 '(c: 1, n HCl). Optical purity: 62.3%.

Example 5

3.9 g (0.01 mol) of (-) - O.O'-di-p-toluoyl tartaric acid are layered with 3.0 g (0.02 mol) of racemic methamphetamine. After standing for half an hour, the mixture was subjected to vacuum distillation. P = 2.5 Pa. Head temperature: 37 ° C. The distillate is a colorless oil.

Yield: 0.7 g D-methamphetamine.

[α] D = + 12.9 ° (c: 1, N HCl). Optical purity: 79.6%.

Example 6

To 1.9 g (0.005 mole) of (-) - O.O'-di-p-toluoyl tartaric acid was added 3.0 g (0.02 mole) of racemic methamphetamine and after standing for one hour the mixture was heated to 37 DEG C. under P = 2.5 P vacuum. at room temperature. The distillate is a colorless oil.

Yield: 1.2 g D-methamphetamine.

[.alpha.] D @ 20 = + 11.1 DEG (c: 1, N / HCl). Optical purity: 68.5%.

Example 7

A solution of 3.0 g of racemic methamphetamine and 1.9 g (0.005 mol) of (-) - O-O-di-p-toluyl tartaric acid in 20 cm ^{3 of} methanol. Evaporate the solvent and then P =

Distill at a pressure of 2.5 P at a head temperature of 37 ° C. The distillate is a colorless oil.

Yield: 1.4 g D-methamphetamine [α] D = + 10.6 ° (c: 1, N HCl). Optical purity: 65.4%.

Example 8

The distillation residue from Example 7 was dissolved in 20 cm ³ of NaOH, extracted with ³ x 10 cm ^{3 of} chloroform, and the combined organic phases were dried and evaporated. The residue is a colorless oil.

Yield: 1.5 g of L-methamphetamine.

[α] D = -9.8 ° (c: 1, N HCl). Optical purity: 60.5%.

Example 9

2.7 g of the distillation residue obtained in Example 7 were recrystallized from 6 cm ^{3 of} methanol. The precipitated salt is filtered off and dried under an infrared lamp. The resulting 1.6 g salt was dissolved in 20 cm ³ of NaOH, extracted with ³ x 10 cm ^{3 of} chloroform, and the combined organic phases were dried and evaporated. The residue is a colorless oil.

Yield: 0.7 g L-methamphetamine.

[.alpha.] D @ 20 = -15.3 DEG (c: 1, NHCl). Optical purity: 94.4%.

Example 10

1.1 g (0.0033 mol) of (-) - O, O'-di-p-toluyl tartaric acid

1.5 g of D-methamphetamine having an optical purity of 79.6% are layered. After standing for half an hour, P is distilled under vacuum at P = 2.5 ° C at 37 ° C. The distillate is a colorless oil.

Yield: 1.1 g D-methamphetamine.

[α] D = + 15.7 ° (c: 1, N HCl). Optical purity: 96.9%.

Claims (3)

PATENT CLAIMS A process for the preparation of the enantiomers of N-methyl-p-phenylisopropylamine of formula I wherein the racemic N-methyl-P-phenylisopropylamine base is less than one molar equivalent of (-) - O, O'- di-p-toluyl-RR-tartaric acid with resol a) reacting the L-enantiomer in a solvent medium consisting of one or two liquid phases, recovering the L-enantiomer in the form of a poorly soluble salt of the resolving agent, and liberating the resulting L-enantiomer; b) reacting and recovering the D-enantiomer from the reaction mixture by distillation. the L-enantiomer is then liberated from the residue by alkaline treatment. Process (a) according to claim 1, characterized in that the racemic amine base is reacted with the resolving agent in a homogeneous organic solvent. Process b) according to claim 1, characterized in that vacuum distillation is used.