HU208670B - Process for separating and clean ing 1-methyl-2-pyrrolidinyl ethanol enenthiomers - Google Patents

Abstract

1-methyl-2-pyrrolidinyl-ethanol enantiomers are sepd. and purified by application of (-)-di:p-toluyl-tartaric acid. Diastereomers are isolated from the reaction mixt. to and the diastereomer salts are decomposed. Enantiomers are extracted and are obtd. following prior concn.

Description

The present invention relates to a process for the separation and purification of 1-methyl-2-pyrrolidinyl ethanol enantiomers.

Optically active 1-methyl-2-pyrrolidinyl ethanol enantiomers are intermediates between various pharmacologically active molecules. Preparation of the racemic compound from the enantiomers is known [J. Chem. Soc. 92, 2976 (1970)], since they were acylated with (+) - N-benzoylcis-2-aminocyclohexanecarboxylic acid chloride and the diastereomeric esters were separated by fractional crystallization. The resulting esters were hydrolyzed to the enantiomers. Although this process is suitable for the separation of enantiomers, the resolving agent is virtually inaccessible. A further problem is that the acid chloride used as the resolving agent is difficult to store and the conditions of acylation and hydrolysis complicate the process.

It has now been found that a solution of the racemic compound in a solvent, preferably i-propyl alcohol, forms well-crystalline salts of (-) - di-p-toluyl tartaric acid which is liberated from the solution so that the base (-) - contains an excess of its enantiomer. It has been found that the acid salt of the (-) - enantiomer is predominantly precipitated when the molar ratio of the racemic compound to the resolving agent is 1: 1, but also when the ratio of the resolving agent is less than 1. Alternatively, less than the equivalent, preferably 0.5 mole, of the resolving agent may be used per mole of the racemic compound with 0.5 mole of hydrochloric acid dissolved in alcohol or water. The resulting crystalline crystalline diastereomeric salt is liberated by addition of an aqueous base, preferably ammonium hydroxide, and your solvent, e.g. extract the crude (-) enantiomer with dichloromethane, which remains after evaporation of the solvent. The crude (+) - enantiomer is obtained from the evaporation residue of the mother liquor after filtration of the diastereomeric salt in the same manner as the other enantiomer. The optical purity of the enantiomers thus obtained is increased by repeatedly resolving the crude enantiomers separately, as described for the resolution of the racemic compound. The purification of the (-) - enantiomer may also be accomplished by partially recrystallizing the diastereomeric salt mixture resulting from the resolution of the racemic compound and, after filtering out the less soluble salt, liberating and separating the optically active base as described above.

Unexpectedly, purification of the crude (+) enantiomer by re-resolution showed that the crystalline excellent diastereomeric salt still contained an excess of the (-) - enantiomer, but a much higher optical purity base from the parent crude (+) - enantiomer. we can separate. The following examples illustrate the process.

Example 7

44.3 g (0.343 mol) of racemic base are dissolved in 45 cm ³ of isopropyl alcohol, and with cooling 14.2 cm ³ (0.171 moles) of cc. hydrochloric acid is added dropwise. To the solution thus obtained, 68.8 g (0.170 mol) of (-) - di-p-toluyl tartaric acid, dissolved in 228 cm ^{3 of} i-propyl alcohol, is added and a solution is formed. This solution was allowed to cool at room temperature and the crystallization occurred at ca. After starting at 50 ° C, the resulting dense mixture was allowed to stand for 1 hour with external ice-water cooling. The precipitated diastereomeric salt is decanted, washed with 2 x 20 cm ^{3 of} i-propyl alcohol, and the wet salt is then washed with 300 cm ^{3 of} i-propyl alcohol for ca. Boil for 5 minutes, then leave to stand and cool as before. The precipitated salt was filtered to give a wet weight of 76.7 g. The salt 70 cm ³ cc. aqueous ammonium hydroxide was added and the solution was extracted with dichloromethane ( ³ x 100 cm ³ ). The combined organic solutions were dried and evaporated. The crude (-) enantiomer was 13.7 g (61.9%). [α] ^2θ · = -42.2 ° (c = 1, methanol). I-propyl alcohol mother liquors were combined and concentrated, to the residue 70 cm ³ cc. aqueous ammonium hydroxide was added. The solution was extracted with dichloromethane ( ³ x 100 cm ³ ). The combined organic solutions were dried and evaporated, and the residue was evaporated in vacuo (50 ° C, 2.7 Pa). The crude (+) - enantiomer was 29.0 g. [α] ²⁰ = + 29.0 ° (c = 1, methanol).

Example 2

62.5 g (0.484 mol) of crude (+) - enantiomer ([α] ^2θ + 27.1 °) are dissolved in 80 cm ^{3 of} i-propyl alcohol and then

15.2 cm ³ (0.184 mol) cc. hydrochloric acid was added dropwise while cooling. Then, 108.2 g (0.268 mole) of (-) - di-p-toluyl-borlősav 300 cm ³ of isopropyl alcohol was added. Crystallization was carried out as in Example 1 and the mixture was allowed to stand at a temperature below 5 ° C for 16 hours.

The crystalline precipitated diastereomeric salt was filtered, washed with 2 x 20 cm ^{3 of} i-propyl alcohol, and weighed 87.0 g. The salt thus obtained was 100 cm ³ cc. it was quenched by the addition of ammonium hydroxide and the solution was extracted with dichloromethane (4 x 100 cm ³ ). The combined organic solutions were dried and evaporated. The weight of the rest of the regenerated base was 22.0 g, [α] ^2θ = -12.3 ° (c = 1, methanol). Can be used for re-partitioning. I-propyl alcohol mother liquor was concentrated, the residue 50 cm ³ cc. ammonium hydroxide was added and the mixture was extracted with dichloromethane (4 x 100 cm ³ ). The combined organic solutions were dried and evaporated and the residue was evaporated in vacuo (50 ° C, 2.7 Pa) to give the (+) - enantiomer: 33.0 g [α] ^2θ = + 51.2 ° (c = 1). , methanol).

Example 3

56.6 g (0.376 mol) of the (-) enantiomer ([α] ²⁰ → -47.2 °) are dissolved in 70 cm ^{3 of} i-propyl alcohol and 13.2 cm ³ (0.159 mol) cc. hydrochloric acid was added under cooling and 91.0 g (0.226 mol) of (-) - di-p-toluoyl tartaric acid dissolved in 250 cm ^{3 of} i-propyl alcohol were added. The

After crystallization from Example 1, the precipitated diastereomeric salt was decanted, washed with 2 x 25 cm ^{3 of} i-propyl alcohol to give a wet weight of 120.0 g. The diastereomeric salt was prepared as in Example 2. The (-) - enantiomer of the salt had a mass of 21.8 g [α] ^2θ = -73.0 °, (c = 1, methanol). The base recovered from the mother liquor can be used again for resolution, weighing 24.0 g. [α] ²⁰ D = -27.0 ° (c = 1, methanol).

Claims (5)

PATENT CLAIMS A process for separating the enantiomers of 1-methyl-2-pyrrolidinyl ethanol by diastereomeric salt formation, characterized in that the (-) - di-p-toluyl tartaric acid salt is formed from a racemic compound in a solvent and the salt mixture containing an excess of (-) enantiomer crystallizes out. isolated by filtration, quenched with aqueous base, the crude (-) - enantiomer extracted with water immiscible solvent and the combined solvent was evaporated, the mother liquor of the diastereomeric salt was evaporated, the residue was quenched with ), the crude enantiomers are purified by resolution in the same manner as the enantiomers of the racemic compound. 2. The process of claim 1 wherein the solvent is i-propyl alcohol and the acid salt of (-) - di-p-toluoyl tartaric acid is filtered off. 3. The process according to claim 1 or 2, wherein the racemic base is equivalent to 5 (or less) (-) - di-p-toluyl tartaric acid is used and the molar amount of the resolving agent is then added by the addition of hydrochloric acid. 4. Process according to any one of claims 1 to 3, characterized in that the crystalline dia10 stereoisomeric salt is purified by recrystallization. 5. Process according to any one of claims 1 to 3, characterized in that upon purification of the crude (-) - enantiomer, the purified enantiomer is separated from the crystalline excellent diastereomeric salt, and when the crude (+) - enan15 isomer is resolved from the mother liquor of the diastereomeric salt.