EA027373B1 - Method for separating racemic 3-carboxy-4-phenylpyrrolydine-2-one using 3-(s)-benzoyloxyquinuclidine - Google Patents

Abstract

A novel method for obtaining 3-carboxy-4-(R)-phenylpyrrolidine-2-one from 3-carboxy-4-(R,S)-phenylpyrrolidine-2-one in which the racemic mixture is separated using 3-(S)-benzoyloxyquinuclidine.

Description

This invention generally relates to intermediates for the manufacture of medicaments, in particular to a new process for the preparation of 3-carboxy-4- (K) -phenylpyrrolidin-2-one.

State of the art

From decarboxylation of 3-carboxy-4- (K) -phenylpyrrolidin-2-one, one can obtain the known 4- (K) -phenylpyrrolidin-2-one (δνηΐΗοδίδ. (1991), 1023-1026), an important starting material for the synthesis of I -carbamoylmethyl-4- (K) -phenylpyrrolidin-2-one, which is known as the active enantiomer of the central nervous system of the active drug Carfedon (\ UO 2007104780).

Separation of racemic 3-carboxy-4-phenylpyrrolidin-2-one by fractional crystallization of the cinchonidine salt of 3-carboxy-4- (K) -phenylpyrrolidin-2-one is described in the literature (Po1.

1. SNST .. 53 (1979), 435-446). However, this method is not applicable on an industrial scale due to the large number of flammable solvents used, and also because it is very labor intensive and expensive and also has a low and unstable yield.

The enzymatic synthesis of this optically active substance (LY13635 (2006)) is also known, but this method also has several disadvantages, such as high cost, and is not applicable for high volume production.

Considering that the limitations of the known methods mentioned cannot be ignored, there is a need to develop a new convenient process that is well suited for the scale of industrial production and has a significant positive economic effect.

Description of the invention

The inventors unexpectedly found that 3-carboxy-4- (K) -phenylpyrrolidin-2-one forms a highly crystalline salt with 3- (§) -benzoyloxyquinquidine, the use of which for the separation of enantiomers was not previously known. Mentioned 3- (§) -benzoyloxyquinuclidine can be obtained by separating the commercially available 3- (K, §) -benzoyloxyquinuclidine (ΙΝΝ: VetoeIDte), or by benzoylation of a commercially available 3- (§) -hydroxyquinuclidine, as described for the preparation of racemate (ΒίοΓ §. & MED. Sz. Ley., 14, 3781-3784).

In accordance with this invention, a new highly crystalline salt of 3-carboxy-4- (K) phenylpyrrolidin-2-one with 3- (§) -benzoyloxyquinuclidine can be easily obtained by a method well suited for industrial scaling. The high-purity salt of 3-carboxy-4- (K) phenylpyrrolidin-2-one with 3- (§) benzoyloxyquinuclidine can be obtained in high yield by the reaction of racemic 3-carboxy-4- (K, §) -phenylpyrrolidin-2-one with 3- (§) -benzoyloxyquinuclidine in the presence of a solvent, followed by recrystallization of the resulting product.

In a preferred embodiment of the invention, the solvent for this reaction and recrystallization is selected from the group consisting of water, methanol, propanol-1, propanol-2 and acetonitrile. In a most preferred embodiment of the invention, the reaction of 3-carboxy-4- (K, §) -phenyl-pyrrolidin-2-one with 3- (§) -benzoyloxy-quinuclidine is carried out in ethanol, and the recrystallization of the salt of 3-carboxy-4- (K) -phenyl-pyrrolidine- 2-one with 3- (§) -benzoyloxyquinuclidine is carried out from water.

3-Carboxy-4- (K) -phenylpyrrolidin-2-one can be obtained from said salt by protonating it with a suitable mineral acid in an aqueous solution, preferably using hydrochloric acid. 3-Carboxy-4- (K) -phenylpyrrolidin-2-one, which crystallizes from solution, can be used further without further purification, but can also be recrystallized from water.

Thus, the present invention describes a new simple method for producing 3-carboxy-4- (K) phenylpyrrolidin-2-one from a racemate, using a new resolving agent, in a solvent suitable for industrial use.

The invention is illustrated by the following non-limiting examples.

Examples

The following examples cannot be construed as limiting the invention and are used for demonstration purposes only.

Example 1. The salt of 3-carboxy-4- (K) -phenylpyrrolidin-2-one with 3- (§) -benzoyloxyquinuclidine.

3-Carboxy-4- (K, §) -phenylpyrrolidin-2-one (210 g) was suspended in ethanol (570 ml). The suspension was heated to approximately 60 ° C and a solution of 3- (§) -benzoyloxyquinuclidine (240 g) in ethanol (240 ml) was added with stirring. The reaction mixture was stirred at the indicated temperature for approximately 20 minutes and then allowed to cool to room temperature. The crystallized precipitate was filtered and washed with ethanol (300 ml). The resulting salt was dried, then dissolved in hot water (750 ml), filtered and allowed to crystallize at room temperature for 2 hours. The crystalline precipitate was filtered, washed with water (200 ml) and dried. The yield was 160 g of a white crystalline salt. | α] [.) ²⁰ (methanol, c = 2) = -55.7 °; melting point 170-172 ° C (decomposition); C ₂₅ H ₂ ^ ₂ O ₅ , Th. %: C 68.79; H, 6.47; N, 6.42; Found%: C, 68.94; H, 6.46; N, 6.42.

Example 2. The salt of 3-carboxy-4- (K) -phenylpyrrolidin-2-one with 3- (§) -benzoyloxyquinuclidine.

3-Carboxy-4- (K, §) -phenylpyrrolidin-2-one (210 g) was suspended in acetonitrile (520 ml). Suspension was heated to approximately 60 ° C and a solution of 3- (8) benzoyloxyquinuclidine (240 g) in acetonitrile (320 ml) was added with stirring. The reaction mixture was stirred at the indicated temperature for approximately 20 minutes and then allowed to cool to room temperature. The crystallized precipitate was filtered and washed with acetonitrile (170 ml). The resulting salt was dried, then dissolved in hot water (750 ml), filtered and allowed to crystallize at room temperature for 2 hours. The crystalline precipitate was filtered, washed with water (200 ml) and dried. The yield was 152 g of a white crystalline salt. [α] _ο ²⁰ (methanol, s = 2) = -56.2 °; melting point 170-172 ° C (decomposition).

Example 3. 3-Carboxy-4- (K) -phenylpyrrolidin-2-one.

The 3-carboxy-4- (K) -phenylpyrrolidin-2-one salt with 3- (8) -benzoyloxyquinuclidine (160 g) was dissolved in water (700 ml) at 65 ° C, and concentrated HC1 (40 ml) was added dropwise to pH values <3. The precipitation of white crystals of 3-carboxy-4- (K) -phenylpyrrolidin-2-one was observed. The reaction mixture was cooled to room temperature. After 2 hours at room temperature, the precipitate was filtered off, washed with water (200 ml) at room temperature and dried in vacuo. 3-Carboxy-4 (K) -phenylpyrrolidin-2-one (70 g) was obtained as a white crystalline solid (yield from the racemate 34.3%), melting point 136.5 ° C, [α] _ο ²⁰ (methanol , c = 2) = -138.6 °.

Claims (7)

1. The salt of 3-carboxy-4- (K) -phenylpyrrolidin-2-one with 3- (8) -benzoyloxyquinuclidine (I) 2. The method of obtaining 3-carboxy-4- (K) -phenylpyrrolidin-2-one, characterized in that 3-carboxy-4- (K, 8) -phenylpyrrolidin-2-one reacts with 3- (8) -benzoyloxyquinuclidine in a solvent, followed by isolation of the obtained salt I, its purification and treatment with mineral acid. 3. The method according to claim 2, in which the solvent is selected from the group comprising water, methanol, ethanol, propanol-1, propanol-2, acetonitrile and mixtures thereof. 4. The method according to claim 2, in which the solvent is ethanol. 5. The method according to claim 2, in which the solvent is acetonitrile. 6. The method according to claim 2, in which the purification of salt I is carried out by crystallization from water. 7. The method according to claim 2, in which the mineral acid is hydrochloric acid.