Method for purifying pregabalin

Abstract

The present invention relates to a method for purifying pregabalin, which includes the steps of 1) heating the reaction solution and keeping it at the temperature to remove impurities, and 2) adding an acid to the reaction solution in step 1) to adjust the pH value, precipitating crystals, and drying by centrifugation to obtain high-purity pregabalin. The pregabalin prepared by the purification method of the present invention has a product purity of 99.8% or more, a product yield of 90% or more, the contents of impurities X and Y are both ≦0.05%, and no impurity peak with a relative retention time of 1.3 is detected.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical chemical industry, and particularly to a method for purifying pregabalin. [Background technology]

[0002] Pregabalin is a novel γ-aminobutyric acid (GABA) receptor agonist that can block voltage-dependent calcium channels and reduce neurotransmitter release. It is primarily used clinically for the treatment of peripheral neuralgia and the adjunctive treatment of focal partial epileptic seizures. The prior art discloses many methods for preparing pregabalin. For example, WO2006121557A1 discloses a simple method for preparing pregabalin by subjecting the compound (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid to a Hoffmann rearrangement using a large amount of liquid bromine in the presence of bromine and an alkali metal hydroxide.

[0003] CN101910111B discloses that sodium hypochlorite is used as a substitute for bromine and reacted at a temperature of 50-70°C. Although this reaction condition can reduce the impurity with a relative retention time of 1.3 mentioned in the patent, the reaction temperature mentioned in the patent is too high, resulting in a low reaction yield. At the same time, in some batches of pregabalin prepared by the method of this patent, the impurity with a relative retention time of 1.3 reaches 0.25%, and in a particularly preferred method, the impurity reaches 0.1%, with significant differences in the level of this impurity between different batches.

[0004] CN106748850A discloses a method for preparing pregabalin, which involves reacting (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid with aqueous sodium hypochlorite at low temperature, adding a reducing agent to destroy the sodium hypochlorite, and finally adding a catalyst and introducing hydrogen gas to carry out the reduction reaction. The resulting mixture is filtered, acidified, and filtered again. The wet product is then added to a mixture of isopropanol and water for repurification to obtain pregabalin. This method involves reacting (R)-(-)-3-carbamoylmethyl-5-methylhexanoic acid with aqueous sodium hypochlorite at low temperature, but the reaction is incomplete or the conversion rate is low under these conditions, resulting in an undesirable product yield. This method further involves the addition of a palladium-carbon catalyst to carry out hydrogenation reduction, which can effectively reduce the content of impurities X and Y in pregabalin. However, the addition of a palladium-carbon catalyst makes it easier for the heavy metals in pregabalin products to exceed the standard, and the use of palladium-carbon poses certain safety risks. [ka] [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2006121557A1 [Patent Document 2] CN101910111B [Patent Document 3] CN106748850A Summary of the Invention

[0006] The present invention provides a method for purifying pregabalin, (1) a step of increasing the temperature of the reaction solution and keeping it at that temperature to remove impurities; (2) adding an acid to the reaction solution in step 1) to adjust the pH value, precipitating crystals, and drying them by centrifugation to obtain pregabalin.

[0007] As a preferred technical solution, the reaction solution in step (1) is (a) performing an oxidation reaction between (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and a sodium hypochlorite aqueous solution in a sodium hydroxide aqueous solution to obtain an oxidation reaction solution; (b) adding sodium sulfite to the reaction solution after oxidation in step (a) to quench the sodium hypochlorite, thereby obtaining a reaction solution; It is prepared by a method comprising:

[0008] Preferably, in the step (1), the temperature is increased to 40 to 80°C, more preferably 55 to 70°C.

[0009] Preferably, in the step (1), the incubation time is 1 to 5 hours, more preferably 2 to 3 hours.

[0010] Preferably, in step (2), the acid is hydrochloric acid, sulfuric acid or phosphoric acid, more preferably hydrochloric acid.

[0011] Preferably, in step (2), the pH is adjusted to 5 to 9, more preferably 6 to 8.

[0012] Preferably, in step (a), the mass concentration of the aqueous sodium hydroxide solution is 10% to 40%, more preferably 20% to 25%, and the mass concentration of the aqueous sodium hypochlorite solution is 5% to 14%, more preferably 8% to 12%.

[0013] Preferably, in the step (a), the molar ratio of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, sodium hypochlorite, and sodium hydroxide is 1:(0.8-1.2):(2-5).

[0014] Preferably, in step (a), the aqueous sodium hypochlorite solution is added dropwise to the mixture of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and the aqueous sodium hydroxide solution.

[0015] Preferably, in step (a), the oxidation reaction time is 2 to 20 hours, more preferably 5 to 10 hours, and the oxidation reaction temperature is -20 to 30°C, more preferably -10 to 30°C.

[0016] Preferably, in step (b), the molar ratio of the amount of sodium sulfite added to the amount of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is (0.01 to 0.50):1, more preferably (0.02 to 0.15):1.

[0017] The pregabalin prepared by the method of the present invention has a product purity of 99.8% or more, a product yield of 90% or more, the contents of impurities X and Y are both ≦0.05%, and no impurity peak with a relative retention time of 1.3 is detected.

[0018] Compared with the prior art, the present invention has the following beneficial effects: (1) The preparation method of the present invention avoids the use of palladium carbon and the operation of reduction by hydrogenation, reduces the risk of excessive heavy metals remaining in the product, simplifies the work process, improves production efficiency, shortens the production cycle, and is more favorable for large-scale industrialization.

[0019] (2) The preparation method of the present invention has mild reaction conditions, the entire reaction process is controlled, side reactions caused by self-heating temperature rise are avoided, and the preparation method does not involve conditions such as high temperature, high pressure, catalyst, etc. The impurity content of the product is low, which meets the requirements for pharmaceutical applications.

[0020] (3) In the preparation method of the present invention, by rationally adjusting the dosage ratio of the alkaline solution to the acid, after pregabalin crystals are precipitated, they can be filtered under conditions where the temperature is lowered to room temperature (20 to 30°C), rather than under conditions where the temperature is lowered to -10 to 10°C, which saves a large amount of energy and meets the requirements of energy conservation, emission reduction, and environmental protection. DETAILED DESCRIPTION OF THE INVENTION

[0021] The following examples are given to illustrate the present invention and are not intended to limit the scope of the invention.

[0022] Example 1 66 g of 25% sodium hydroxide solution was added to the reaction flask and cooled to -20°C. 20 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid was added, followed by the slow dropwise addition of 72 g of 10.4% sodium hypochlorite solution. After the dropwise addition was complete, the temperature was slowly raised to 10°C and the reaction was allowed to proceed while maintaining the temperature for 3 hours. The temperature was then continued to rise to 30°C and the reaction was allowed to proceed for 3 hours. 1.0 g of sodium sulfite was added to the reaction solution, which was stirred for 20 minutes. The remaining sodium hypochlorite was quenched, completing the reaction. The reaction solution was then heated to 70°C and maintained at that temperature for 2 hours. The reaction solution was cooled to 45°C, and 25 ml of hydrochloric acid was added dropwise to the reaction flask to adjust the pH to 7.0. The solution was then cooled to room temperature, filtered, and dried to obtain pregabalin in a yield of 91.7%, with a purity of 99.8%, an impurity X content of 0.04%, an impurity Y content of 0.02%, and no impurity peak with a relative retention time of 1.3 was detected.

[0023] Example 2 830 g of 20% sodium hydroxide solution was added to the reaction flask and the temperature was lowered to -15°C. 200 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid was added, followed by the slow dropwise addition of 720 g of 10.4% sodium hypochlorite solution. After the dropwise addition was completed, the temperature was slowly raised to 10°C and the reaction was allowed to proceed while maintaining the temperature for 4 hours. The temperature was then continued to rise to 30°C and the reaction was allowed to proceed for 3 hours. 11.0 g of sodium sulfite was added to the reaction solution and stirred for 20 minutes. The remaining sodium hypochlorite was quenched, and the reaction was completed. The reaction solution was then heated to 65°C and maintained at that temperature for 2.5 hours. The reaction solution was cooled to 40°C, and 265 ml of hydrochloric acid was added dropwise to the reaction flask to adjust the pH to 7.1. The solution was then cooled to room temperature, filtered, and dried to obtain pregabalin in a yield of 92.9%, with a purity of 99.9%, an impurity X content of 0.03%, an impurity Y content of 0.02%, and no impurity peak with a relative retention time of 1.3 was detected.

[0024] Example 3 850 g of 22% sodium hydroxide solution was added to the reaction flask and cooled to -16°C. 200 g of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid was added, followed by the slow dropwise addition of 700 g of 10.6% sodium hypochlorite solution. After the dropwise addition was complete, the temperature was slowly raised to 10°C and the reaction was allowed to proceed while maintaining the temperature for 3 hours. The temperature was then continued to rise to 30°C and the reaction was allowed to proceed for 2 hours. 10.0 g of sodium sulfite was added to the reaction solution, which was stirred for 20 minutes. The remaining sodium hypochlorite was quenched, completing the reaction. The reaction solution was then heated to 60°C and maintained at that temperature for 3 hours. The reaction solution was cooled to 50°C, and 280 ml of hydrochloric acid was added dropwise to the reaction flask to adjust the pH to 7.0. The solution was then cooled to room temperature, filtered, and dried to obtain pregabalin in a yield of 92.3%, with a purity of 99.8%, an impurity X content of 0.04%, an impurity Y content of 0.02%, and no impurity peak with a relative retention time of 1.3 was detected.

[0025] Example 4 420 kg of 20% sodium hydroxide solution was added to the reactor and the temperature was lowered to -18°C. 100 kg of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid was added, followed by the slow dropwise addition of 350 g of 10.4% sodium hypochlorite solution. After the dropwise addition was completed, the temperature was slowly raised to 10°C and the reaction was allowed to proceed while maintaining the temperature for 3 hours. The temperature was then continued to rise to 30°C and the reaction was allowed to proceed for 2 hours. 14 kg of sodium sulfite was added to the reaction solution, which was stirred for 30 minutes. The remaining sodium hypochlorite was quenched, completing the reaction. The reaction solution was then heated to 70°C and maintained at that temperature for 3 hours. The reaction solution was cooled to 50°C, and 140 L of hydrochloric acid was added dropwise to the reaction flask to adjust the pH to 7.0. The temperature was then cooled to room temperature, filtered, and dried to obtain pregabalin. The yield was 93.7%, the purity was 99.9%, the content of impurity X was 0.05%, the content of impurity Y was 0.02%, and no impurity peak with a relative retention time of 1.3 was detected.

Claims

1. (1) increasing the temperature of the reaction solution and maintaining the temperature to remove impurities, the increasing temperature being 40 to 80°C, and the maintaining time being 1 to 5 hours; (2) adding an acid to the reaction solution in step (1) to adjust the pH value, precipitate crystals, and dry them by centrifugation to obtain pregabalin; A method for purifying pregabalin, comprising: The reaction mixture in step (1) is (a) subjecting (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and a sodium hypochlorite aqueous solution to an oxidation reaction reaction in a sodium hydroxide aqueous solution to obtain an oxidation reaction solution; (b) adding sodium sulfite to the oxidation reaction solution in step (a) to quench the sodium hypochlorite, thereby obtaining a reaction solution; 1. A method for purifying pregabalin, wherein the pregabalin is prepared by a method comprising the steps of:

2. The method for purifying pregabalin described in claim 1, characterized in that in step (1), the temperature of the heating is 55 to 70°C.

3. A method for purifying pregabalin as described in claim 1, characterized in that in step (1), the incubation time is 2 to 3 hours.

4. A method for purifying pregabalin as described in claim 1, characterized in that in step (2), the acid is hydrochloric acid, sulfuric acid or phosphoric acid.

5. A method for purifying pregabalin as described in claim 1, characterized in that in step (2), the pH is adjusted to 5 to 9.

6. A method for purifying pregabalin as described in claim 1, characterized in that in step (2), the pH is adjusted to 6 to 8.

7. A method for purifying pregabalin as described in claim 1, characterized in that in step (a), the mass concentration of the sodium hydroxide aqueous solution is 10% to 40%.

8. A method for purifying pregabalin as described in claim 1, characterized in that in step (a), the mass concentration of the sodium hydroxide aqueous solution is 20% to 25%.

9. A method for purifying pregabalin as described in claim 1, characterized in that in step (a), the mass concentration of the sodium hypochlorite aqueous solution is 5% to 14%.

10. A method for purifying pregabalin as described in claim 1, characterized in that in step (a), the mass concentration of the sodium hypochlorite aqueous solution is 8% to 12%.

11. The method for purifying pregabalin according to claim 1, wherein in step (a), the molar ratio of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, sodium hypochlorite, and sodium hydroxide is 1:(0.8-1.2):(2-5).

12. The method for purifying pregabalin according to claim 1, wherein in step (a), the aqueous sodium hypochlorite solution is added dropwise to the mixture of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and the aqueous sodium hydroxide solution.

13. The method for purifying pregabalin according to claim 1, wherein in step (a), the oxidation reaction time is 2 to 20 hours.

14. The method for purifying pregabalin according to claim 1, wherein in step (a), the oxidation reaction time is 5 to 10 hours.

15. The method for purifying pregabalin according to claim 1, wherein in step (a), the temperature of the oxidation reaction is -20 to 30°C.

16. The method for purifying pregabalin according to claim 1, wherein in step (a), the temperature of the oxidation reaction is -10 to 30°C.

17. The method for purifying pregabalin according to claim 1, wherein in step (b), the molar ratio of the amount of sodium sulfite added to (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is (0.01-0.50):

1.

18. The method for purifying pregabalin according to claim 1, wherein in step (b), the molar ratio of the amount of sodium sulfite added to (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid is (0.02-0.15):1.

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