DD210261A5 - PROCESS FOR PREPARING A DIASTEREOMER - Google Patents

Abstract

The invention relates to a process for preparing the diastereomers (+) - di-p-toluoyl-D-tartrate of laevo-l-aethyl-2-aminomethylpyrrolidine, (-) - di-p-toluoyl-L-tartrate of Dextro-l -ethyl-2-aminomethylpyrrolidine, (-) - di-p-toluoyl-L-tartrate of laevo-1-ethyl-2-aminomethylpyrrolidine or (+) - di-p-toluoyl-D-tartrate of dextro-1-ethyl- 2-aminomethylpyrrolidine, which can be used as intermediates for the preparation of pharmaceutically active compounds.

Description

26'i -ISC β

Field of application of the invention

The novel diastereomers prepared by the process of the present invention can be processed as intermediates for the preparation of pharmaceutically active compounds for use in human and veterinary medicine.

Characteristic of the known technical solutions

From GB-PS 1,207,752 it is known that 1-ethyl-2-aminomethylpyrrolidine of the formula

2ä3cRT383 * 119O35

CH., CH

H ₀ NCH ₀ -CH CH ₀

N ₁ /

can be separated into its two optical isomers with the aid of optically active tartaric acid. D (-) - Tartaric acid forms a crystalline tartrate with the levorotatory Arnin, while L (+) - tartaric acid forms a crystalline tartrate with the dextrorotatory Am in. The free amine is then obtained by dissolving the tartrate in water, alkalizing the medium, extracting the amine and distilling it. The method has poor reproducibility in precipitating the crude tartrate and results in low yields (below 40%). Due to the fact that no recrystallization takes place, but rather a series of leaching, insufficient purity of the crude precipitate causes very time-consuming and dubious purification processes. The structure of the crystals in the crude precipitate is of a type that makes the reaction mixture very viscous and difficult to filter.

Object of the invention

The aim of the invention is a new process for the separation of 1-ethyl-2-aminomethylpyrrolidine.

Explanation of the essence of the invention

The object of the invention is a process for the separation of 1-ethyl-2-aminomethylpyrrolidine without the disadvantages of the method in which tartaric acid is used, i. without poor yield and poor optical purity, poor reproducibility, lack of ürnkristaliisierbarkeit and coarse crystals.

The process according to the invention consists in a separation of the optical isomers of 1-ethyl-2-aminomethylpyrrolidone.

lidin by formation of salts with (-) - di-p-toiuoyl-L-tartaric acid or with (+) - di-p-toluoyl-D-tartaric acid.

COOH

EC-Q-CO-

Q-CO

HC-O-CO-

COOH

Di-p-toluoyl-tartaric acid

Four different diastereomers are obtained by the method of the present invention. They have not been described in the literature so far:

(-r) -Di-p-toluoyl-D-tartrate of levo-1-ethyl-2-aminomethylpyrrolidine,

(-) - di-p-toluoyl-L-tartrate of dextro-1-ethyl-2-aminomethylpyrrolidine,

(-) - Di-p-toluoyl-L-tartrate of levo-1-ethyl-2-aminomethyl. pyrrolidine or

( f) Di-p-tolucyl-D-tartrate of dextro-1-ethyl-2-aminomethylpyrrolidine.

The diastereomers can be prepared by direct precipitation or by a two-step process.

A. Direct precipitation means that 3

a crystalline salt is isolated while the other diastereomer remains dissolved in the mother liquor. The levorotatory amine is precipitated with levorotatory (-) - di-p-toluoyl-L-tartaric acid in a solution of water / methanol (preferably 1 to 1.2 volumes / volume) and isolated, while the dextrorotatory amine (with (-) ) -Di-p-toluoyl-L-tartaric acid) remains in the mother liquor.

Similarly, dextrorotatory Amiη is precipitated with dextrorotatory (+) - di-p-toluoyl-D-tartaric acid and isolated, while the levorotatory Arnin (with (+) - di-p-toluoyl-D-tartaric acid) remains in the mother liquor.

B. In the two-step process, the two diastereomers are isolated individually. Clockwise amine is precipitated with dextrorotatory (-) - di-p-toluoyl-L-tartaric acid in a solution of pure methanol and then isolated. The addition of water (ratio of water / methanol 1.0 to 1.5 [volume / volume]) to the methanol mother liquor gives a crystalline salt of levorotatory amine and levorotatory acid.

Similarly, levorotatory amine is precipitated with dextrorotatory (+) - di-p-toluoyl-D-tartaric acid in a solution of pure methanol, and treatment of the methanol mother liquor with water yields a crystalline salt of dextrorotatory amine and dextrorotatory acid.

To obtain the optically active 1-ethyl-2-aminomethylpyrrolidine, the corresponding diastereomer is treated by a conventional method, i. the diastereomer is dissolved in water, the medium is made alkaline, the amine is extracted and distilled.

When using the process according to the invention, the amine (-) - 1-ethyl-2-aminomethylpyrrolidine with a purity of up to 96% and in a yield of 85% with (-) - di-p-toluoyl-L-tartaric acid ( Monohydrate) in a two-step process. Accordingly, (+) - 1-ethyl-2-arninomethylpyrrolidine was prepared to a purity of 90% and in a yield of 85%.

Optical purities can be obtained by crystallization from pure methanol or from a mixture of methanol and water.

embodiments

example 1

? S £ 5iiriyD2_ ZPJL _ ^^^ ίΐΕΊ. ^ Ι ^^ Χ.Ιτί ^ Τ. ^^ ϊΐ. ^. 'Ζ. _ Y 2. ¹ I _ 1 ί 2 IS § ^ i § L ¹ § SZ the 1-Äth νΐ - 2 - aminomethVloVr ^ rol ί d ± ri (airjekceMe th \ oae)

60 g of (-) - di-p-toluoyl-L-we-acid (monohydrate) was dissolved in 3,00 ml of i-methanol in a 1 liter 3-neck round bottom flask equipped with a mechanical stirrer, thermometer and dropping funnel. 18.4 g of racemic 1-ethyl-2-aminomethylpyrrolidine were introduced through the dropping funnel over 15 minutes without the temperature exceeding 30 ° C. The transparent solution was held at 25 ° C for 15 minutes, after which about 300 ml of water was added over about 30 minutes. The addition before. Seed crystals at 20 to 25 ° C initiated the crystallization, which continued at room temperature for 1 hour. Before filtration, the suspension was cooled to 10 ° C and the filtrate was washed with 50 ml of ice-cold water. Yield: 65 1. Purity: 91% (-) - amine.

The preparation of the salt of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine is carried out in the same way as described above, by replacing the iinksdrehenden acid against the dextrorotatory acid. Corresponding yield and purity are obtained.

Example 2 30

in the case of §§§§ {2§22 ^e E} IZ'5i-rYi: Z = I

40 g of (-) - di-p-tciuoyi-L-tartaric acid (monohydrate) were dissolved in 120 ml of methanol in a 250 ml three-neck round bottom flask equipped with. a mechanical stirrer, a thermometer and a dropping funnel. 12.7 g of racemic

-O-Ι l-ethyl-2-aminomethylpyrrolidine were introduced with stirring for 15 minutes through the drip funnel without the temperature exceeding 20 ° C. After the addition of seed crystals and cooling to 5 to 15 ° C, salt of the right-handed

Amine out. After crystallization for 2 hours, 24 g of (-) - di-p-toluoyl-L-tartrate were obtained from dextrorotatory 1-ethyl-2-aminomethylpyrrolidine and washed with 10 ml of ice-cooled methanol. Yield: 90%. Purity: 90% (+) - amine.

100 ml of water was added over 15 minutes to the mother liquor, which was at room temperature. After the addition of seed crystals at room temperature, the salt of the levorotatory amine precipitated. After crystallization for 2 hours (1 hour at 20 ° C and 1 hour at 10 ° C) were obtained 21.9 g of (-) - di-p-toluoyl-L-tartrate of levorotatory l-ethyl-2-aminomethylpyrrolidin and washed with 10 ml ice-cold water. Yield: 86%. Purity: 96% (-) - amine.

When (+) - di-p-toluoyl-D-tartaric acid (mononydrate) was used, the procedure was the same, but the initially isolated salt was (+) - di-p-toluoyl-D-tartrate from left-handed Ethyl-2-aminomethylpyrrolidine, and the second was (-> -) - dip-toluoyl-D-tartrate of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine.

Example 3 y m rista 11 isati ο η _ of_ _ (_-_ ) _H ^ i. ^ P _ ^^ o_ ^ uj ^^^^^ i ^ a_rjtr_a_t_ _Y_q η _ 1 i η ks ^

15.7 g of the title compound (pure hexane: 74% (-) - amine) were dissolved with heating in 3 0 ml of methanol. At room temperature, 30 ml of water was then added to the 3-neck round bottom flask through the dropping funnel. After adding seed crystals, it fell in the headline

given compound and was filtered off at 10 ° C after 2 hours and washed with 5 ml of water. Yield: 82%, purity: 91% (-) - amine.

δ (-) - Di-p-toluoyl-L-tartrate of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine was crystallized in the same manner.

Example 4 10

Recrystallization yon LilL'l? ^: L "LH" lt ° l} i ° Yi "L? ~ ^ LiJl ^ L ^ j- Y ° 51 inks-

15 g of the title compound (purity: 8% (-) - amine) were dissolved in 3 ml of methanol while heating. After the addition of seed crystals at 4 5 to 50 ° C, the title compound dropped out again, and after a crystallization time of 1 hour, it was possible to filter at 10 ° C and washed with 10 ml of ice-cooled methanol. Yield: 30%. Purity: 96% (-) - amine.

(-) - Di-p-toluenyl D-tartrate of right-handed 1-ethyl-2-aminomethylpyrrolidine was recrystallized in the same manner.

Claims (1)

invention claim Process for the preparation of one of the diastereomers (τ) -di-p-toluoyl-D-tartrate of levo-1-ethyl-2-aminomethylpyrrolidine, (-) - di-p-toluoyl-L-tartrate. Of dextro-1-ethyl-2-aminomethylpyrrolidine,. (-) - Di-p-toluoyl-L-tartrate of levo-1-ethyl-2-aminomethylpyrrolidine or (+) - Di-p-toluoyl-D-tartrate of dextro-1-ethyl-2-aminomethylpyrrolidine characterized by dissolving racemic 1-ethyl-2-aminomethylpyrrolidine in aqueous methanol and treating it with (-) - di-p-toluoyl-L-tartaric acid to give (-) - di-p-toluoyl-L-tartrate lävo-l-ethyl-2-aminomethylpyrrolidine and isolated, and (-) - di-p-toluoyl-L-tartrate of dextro-l-ethyl-2-aminomethylpyrrolidine remains in the mother liquor or that racemic l-ethyl 2-aminomethylpyrrolidine is treated with (-) - di-p-toluoyl-L-tartaric acid in methanol to crystallize and isolate (-) - di-p-toluoyl-L-tartrate from dextrc-i-ethyl-2-aminomethylpyrrolidine in which water is added to the methaniline mother liquor to crystallize (-) - di-p-toluoyl-L-tartrate from levo-1-ethyl-2-aminomethylpyrrolidine or by reversing the process for preparing the diastereomers by treating racemic l-Äthyi-2-aminomethylpyrrolidine with [+) - di-p-toluoyl-D-tartaric acid.