HU189751B - Process for producing diastereomeres of 2-amino-methyl-pyrrolidine produced with di-p-toluyl-tartaric acid - 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

The present t.i. The subject of the invention is 2- (an) inomylethyl) -1-ethyl-pi ^. yin for the preparation of a new diastereomer.

Diastereomers are useful intermediates for the preparation of pharmaceutically active compounds.

No. 1,207,752. s. It is known from the British patent that 2 - (aminoethyl / l-ethylpyrrolidine) represented by formula I can be resolved with two optical isomers by optically active tartaric acid. AD (- / tartaric acid forms crystalline tartrate with the reductive amine and L (+)). tartaric acid forms crystalline tartrate with the digestive amine The free amine is then obtained by dissolving the tartrate in water, frustrating the medium, extracting it and distilling it. The method is poorly reproducible by precipitating the crude tartrate and low (40%). Due to the fact that not the recrystallization is carried out but instead a series of washes, the unsatisfactory purity of the crude product requires very purposeful and doubtful purification processes. The structure of the crystals in the crude product is such that it is very viscous and difficult to filter.

The object of the present invention is to provide a method for the resolution of 2- (aminomethyl) -1-ethylpyrrolidine which does not have the disadvantages of a method using tartaric acid which results in poor yield and poor optical purity, recrystallization and imperfect crystallization.

The essence of the method of the present invention is the resolution of the optical isomers of 2-minomethyl) -1-ethylpyrrolidine with (-) - di- (p-toluoyl) -L-tartaric acid or (+) - di-β-toluoyl / tartaric acid. (di- (p-toluQuL) tartaric acid can be represented by formula II)

The present ϊ, .τιίΑ? According to the method of the girl, four different diastereomers are obtained. These have not yet been reported in the literature. Diastereomers include:

levo-2- (aminomethyl) -1-ethylpyrrolidine ( ⁺ ) - di- (p-toluoyl) -D-tartrate, dextro-2- (aminomethyl) -1-ethylpyrrolidine (>) - toluoyl L-tartrate, levo-2- (aminomethyl) -1-ethylpyrrolidine (-) - di (p-ololoyl) -L-tartrate and dexthio-1-aminomethyl-1-ethyl- pyrrolidine (η 3 -3- (p-toluoyl) -D-tartrate.

Diastereomers may be prepared by direct separation or by a two step process.

A) Direct separation indicates that one diastereomer is crystallized as a crystalline salt, while the other diastereomer remains dissolved in the mother liquor. The leftover rotor amine is separated from the leftover (-) di (p-toluoyl) L-tartaric acid in aqueous methanolic solution (preferred ratio is 1-1.2% v / v) and the right handed rotary amine [(-) - di- ( p-taluoyl) -L-tartaric acid] remains in the mother liquor.

Similarly, the right-handing amine is isolated by right-handing (+) di- (p-toluoyl) -U-tartaric acid and is isolated while the left-handing amine is fused with the mother liquor in the presence of f (+> di- (p-toluoyl) -U-tartaric acid).

B) In the two-step process, the two diastereomers are separated individually. The right-rotator amine is separated with the left-rotator (-) di- (p-toluoyl) -L-tartaric acid in a solution in pure methanol and then isolated. Addition of water to the methanolic mother liquor [water: methanol ratio 1.0-1.5% (v / v)] gives the crystalline salt of the dopant amine and the dopant acid.

Similarly, the quaternary amine is precipitated in a solution of pure methanol in pure methanol with right-rotating (*) di- (p-toluoyl) -D-tartaric acid and mixed with water to give crystalline salts of right-rotating amine and right-rotating acid.

To obtain optically active 2- (aninomethyl) ethyl ethylpyrrolidine, the corresponding diastereomer is worked up by conventional means, i.e., the diastereomer is dissolved in water, made alkaline, the amine is extracted and distilled.

Using the process of the invention, (- / 2- (amino4-methyl) 1-ethylpyrrolidine is prepared in 96% purity and 85% yield with (-) - di- (p-toluoyl) -L-tartaric acid (monohydrate) in a two step process. Similarly, (+) 2- (aminomethyl) 1-ethylpinnolidine is prepared in 90% purity and 85% yield.

Optical purification can be accomplished by recrystallization from pure methanol or a mixture of methanol and water.

The following examples illustrate the invention and the best embodiments thereof, without limiting the scope of the invention in any way.

Example 1

Preparation of the (-) di- (p-toluoyl) -L-tartrate of (-) di- (p-toluoyl) -L-tartaric acid monohydrate (2-aminomethyl) 1-ethylpyrralidine In 300 ml of methanol, in a 1-liter three-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel, 18.4 g of racemic acid is added from the dropping funnel over 15 minutes.

2- (aminomethyl) -1-ethylpinnolidine so that the temperature does not rise above 30 ° C. The temperature of the clear solution was maintained at 25 ° C for 15 minutes, and then about 300 ml of water was added over 30 minutes. At the addition of seed crystals, crystallization begins at 20-25 ° C and continues for 1 hour at room temperature. Before filtration, the slurry was cooled to 10 ° C and the filtrate was washed with 50 ml of ice-cold water. Yield: 65%. Purity; 91% (- / amine, m.p. 162-163 ° C).

The preparation of the 2-aminomethyl-1-ethylpinalidine salt of the jobinic acid is prepared in a similar manner to that described above, but with the use of the right-hand acid instead of the left-hand acid. Similar yields and purity are obtained. 162-163 ° C.

Example 2

Right Rotator & Rotator 2- (Amino Methyl)

- Preparation of (-) di- (p-taloyl) L-tartrate of 1-ethylpyrralidine (two-step process)

In a 250 ml three-necked round-bottom flask equipped with a mechanical stirrer, a thermometer and a dropping funnel, 40 g of (-> di- (p-toluoyl) L. tartaric acid monohydrate were dissolved in 120 ml of methanol. 12.7 g of racemic 2- (amino- methyl) -T-ethylpyrrolidine was added over 15 minutes so that the temperature did not rise above 20 ° C. After addition of seed crystals and cooling to 5-15 ° C,

189,751 right-handed amine salts precipitate. After two hours of crystallization and washing with ice-cold methanol (10 ml), 24 g of the dextrorotatory 2- (aminomethyl) -1-ethylpyrrolidine (-) - di- (p-tduoyl) -L-tartrate are obtained. Yield 90%. Purity = 90% (*) - amine. 162-163 ° C.

Water (100 ml) was added to the mother liquor at room temperature over 15 minutes. After addition of inoculum bottles, the salt of the rotating amine is precipitated at room temperature. After two hours of crystallization (1 hour at 20 ° C and 1 hour at 10 ° C) and washing with 10 ml of ice-cold water, 21 g of the rotary 2- (aminomethyl) -1-ethylpyrrolidine (_} Di- (p-toluoyl) -L-tartrate was obtained. Yield: 86%. Purity = 96% (-) - amine. m.p. 162-163 ° C.

When (*) - di- (p-toluoyl) -D-tartaric acid monohydrate is used, the procedure is similar, but the first isolated salt is left-turning, 2- (aminomethyl) -1-ethylpyrrolidine (+) - di- (p) -toluoyl) -Ū-tartrate (m.p. 162-163 ° C), and the second salt is a refluxing 2-aminomethyl-1-ethylpyrrolidine O-di- (p-toluoyl) -D-tartrate. 162-163 'C.

Example 3

Recrystallization of left-turning 2- (aminomethyl) -1-ethylpyrrolidine (-) - di- (p-toluoyl) -L-tartrate from methanol / water

15.7 g of the title compound (purity > 74% (-) - amine) are dissolved in 30 ml of methanol with heating. Water (30 ml) was then added to the three-necked round bottom flask from the dropping funnel at room temperature. After addition of seed crystals, the title compound precipitated and after standing for 2 hours at 10 ° C was filtered and washed with 5 ml of water. Yield: 82%. Purity = 91% (-) - amine. 162-163 ° C.

The (-) - di- (p-toluoyl) -L-tartrate of the right-turning 2- (aminomethyl) -1-ethylpyrrolidine is recrystallized in a similar manner. 162-163 ° C.

Example 4

Recrystallization of Dopartrate 2- (aminomethyl) -1-ethylpyrrolidine (*) - di- (p-toluoyl) - D-tartrate from methanol to give the title compound (purity · 85% (-> -amine)) with heating After addition of seed crystals at 45-50 ° C, the title compound precipitated again and after 1 hour crystallization, it was filtered off and washed with 10 ml of ice-cold methanol, yield 80%, purity 96% (- m.p. 162-163 ° C.

The (-) -di- (p-toluoyl) -D-tartrate of the right-rotating 2- (aminomethyl) -1-ethylpyrrolidine is crystallized in a similar manner. 162-163 ° C.

Claims (2)

Patent Claim Point Procedure for diastereomer 2Q levo-1- (aminoethyl) -1-ethylpyrralidine (*) - di- (p-toluoyl) -D-tarrate, dextro-2- (aminomethyl) -1-ethylpyrrolidine (- ) -di- (p-toluoyl) -L-tartrate, leo-2- (aminomethyl) -1-ethylpyridine (-} di - (p-toluoyl) -L-tartrate, or 25 for the preparation of dextro-2- (aminomethyl) -1-ethylpyrrolidine (*) - di- (p-toluoyl) -D-tartrate, characterized in that the racemic 2- (aminomethyl) -1-ethyl- Pyrralidine is dissolved in aqueous methanol and (-) - di- (p-toluoyl) -L-tartaric acid is added and levo-2- (aminomethyl) -1-ethylpyrrolidine is added. 30 (-} di- (p-toluoyl) -L-tartrate crystallizes out which is isolated and the dextro-2- (aminomethyl) -1-ethylpyrrolidine (-j-di-1-t-toluoyl) -L- or the racemic 2- (aminomethyl) -1-ethylpyrrolidine (-} di- (p-toluoyl) -L-tartaric acid in methanol) and the dextro-2- (aminomethyl) - The (-) - di- (p-toluoyl) L-tartrate of 1-ethylpyrrolidine crystallizes out and is added to the methanolic mother liquor with levo-2- (aminomethylB-1-ethylpyrrolidine (-) - di). - (p-toludyl) -L-tartrate crystallizes, or the process for the preparation of diastereomers is reversed The reaction was carried out in 40 sequences by reaction of racemic 2- (aminomethyl) -1-ethylpinnolidine with (+> di- (p-toluyl) -D-tartaric acid).