A method for recovering pregabalin intermediate 3-isobutylglutaramide

Abstract

The present invention discloses a method for recovering pregabalin intermediate 3-isobutylglutaric acid monoamide, the method comprising the following steps: (1) adding a racemate to be eliminated into an organic solvent, gradually heating up, controlling the temperature and pressure to carry out decompression and water separation; (2) after decompression and water separation, heating up under normal pressure, controlling the temperature to 100-140°C, and carrying out a dehydration cyclization reaction; (3) hydrolyzing the product obtained in step (2) under alkaline conditions to obtain a 3-isobutylglutaric acid monoamide racemate. The present invention has obvious advantages in the current safety, environmental protection, quality improvement and efficiency enhancement, and fierce market competition.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for recovering 3-isobutylglutaramide, an intermediate of pregabalin. Background of the Invention

[0002] Pregabalin (Compound 1) is a new type of γ-aminobutyric acid receptor agonist that can block voltage-dependent calcium channels and reduce the release of neurotransmitters. In 2004, it was approved by the European Medicines Agency for the treatment of peripheral neuropathic pain and partial epileptic seizures in adults, and was later approved in Europe for the treatment of neuropathic pain (peripheral or central) and generalized anxiety disorder. In 2005, it was approved in the United States for the treatment of diabetic peripheral neuropathy and postherpetic neuralgia, partial epileptic seizures. In 2007, it was approved by the US FDA for the treatment of fibromyalgia. With a large market demand, it has become one of the world's best-selling drugs.

[0003]

[0004] At present, there are many documents reporting the synthesis of this compound, and the most widely used is the chemical resolution method using R-phenylethylamine as a resolution agent to chemically resolve and then process to obtain the pregabalin product. 3-isobutylglutaric acid monoamide (compound 4) is an important intermediate in the synthesis process of pregabalin. After being resolved by R-phenylethylamine, a large amount of it remains in the resolution mother liquor (compound 5). The resolution mother liquor is freed to obtain the racemate (i.e., isomer, compound 8), and the racemate is racemized to recover 3-isobutylglutaric acid monoamide.

[0005] The specific process route is as follows.

[0006]

[0007] The methods for recovering 3-isobutylglutaric acid monoamide reported in the prior art are to close the ring of the racemate under high temperature conditions, and then open the ring in the presence of liquid alkali for racemization. There are differences in the acquisition and treatment of the racemate. Patent CN104356016 is to directly distill the split mother liquor without acid treatment and then racemize it. This method has many impurities and needs to be purified multiple times in the later stage, and the product yield is low; CN105152954 is to adjust the acid, filter and dry the mother liquor to obtain the racemate, and then add the material under solvent-free conditions to carry out reduced pressure and high temperature ring closure and liquid alkali ring opening for racemization. The highest yield of the obtained product is about 78.5% (calculated based on the feed of the dry product of the racemate), the yield is low, and the drying step of the racemate is cumbersome, which affects the production capacity, reduces the production efficiency, and increases the production cost; CN105481712 In A, the mother liquor is acidified and filtered to obtain a wet racemate to be fed, and the racemate is subjected to normal pressure and high temperature ring closure, liquid alkali ring opening, etc. for racemization. However, the wet product is directly fed to the high temperature ring closure, and the presence of residual acid water in the racemate promotes the production of side reactions, causing the raw materials to be converted into impurities, resulting in low product purity and low yield. The article does not mention the product quality. After repeated experimental confirmation, the highest yield of the obtained product is about 80.9% (calculated based on the dry racemate fed), the yield is low, and the product quality is poor, with a purity of ≤95.0%. See Comparative Examples 1 to 3 for details.

[0008] Therefore, the present invention seeks a simpler, more economical and safer process for recovering 3-isobutylglutaramide. Summary of the invention

[0009] The purpose of the present invention is to provide a method for 3-isobutylglutaric acid monoamide shown as compound 4, comprising the following steps: 3-isobutylglutaric acid monoamide is resolved by R-phenylethylamine to obtain compound 6 and a resolved mother liquor containing compound 5, the resolved mother liquor is alkalized by adding inorganic alkali water, and then extracted with an organic solvent, the obtained water layer is acidified by adding hydrochloric acid, filtered and separated to obtain a wet product of a racemate containing compound 8, and the wet product of the racemate is treated to obtain recovered 3-isobutylglutaric acid monoamide. The synthesis route is as follows:

[0010]

[0011] The invention is characterized in that the recovery process of the wet racemate to be treated comprises the following steps:

[0012] (1) adding a wet racemate to be distilled to an organic solvent, raising the temperature, and performing decompression and water separation at a temperature of ≤90° C.;

[0013] (2) After the water separation is completed under reduced pressure, the temperature is raised under normal pressure and controlled at 100-140° C. to carry out a dehydration cyclization reaction;

[0014] (3) The product obtained in step (2) is hydrolyzed under alkaline conditions to obtain the racemic 3-isobutylglutaramide.

[0015] The organic solvent in step (1) is selected from: toluene, xylene or n-octane, preferably xylene.

[0016] The volume ratio of the organic solvent in step (1) to the dry weight of the racemate is 0.5:1 to 3:1 L / Kg, preferably 1:1 to 2:1 L / Kg.

[0017] The reduced pressure water separation pressure in step (1) is -0.06 to -0.1 MPa.

[0018] The end point of the decompression water separation in step (1) is that no water is separated.

[0019] The step (3) specifically comprises the following steps:

[0020] (4) After the ring-closure reaction at normal pressure is completed, the temperature is lowered to 20-40°C, water is added, and then ion membrane liquid alkali is added dropwise to adjust the pH to ≥12.0. The reaction is carried out under this temperature condition for 1-3 hours, and then the organic layer is separated;

[0021] (5) adding hydrochloric acid dropwise to the aqueous layer to adjust the pH to 0.5-3.0;

[0022] (6) Extract with ethyl acetate several times, combine the organic layers, control the temperature at 30-50° C., and evaporate 60%-70% of the ethyl acetate under reduced pressure;

[0023] (7) Cooling to 0-15° C. to crystallize, filter, and dry to obtain 3-isobutylglutaric acid monoamide.

[0024] The ratio of the volume of water added in step (4) to the dry weight of the racemate is 1:1 to 3:1 L / Kg.

[0025] The temperature of adding hydrochloric acid in step (5) is 20-40° C.;

[0026] The total volume of ethyl acetate used for extraction in step (6) is in a weight ratio of 1.5:1 to 3:1 L / Kg to the dry weight of the racemate to be extracted, and the number of extractions should be ≥2 times.

[0027] The crystallization time of step (7) is 1.0 to 6.0 hours.

[0028] The present invention has obvious advantages under the current safety, environmental protection, quality improvement and fierce market competition: first, the present invention cancels the drying treatment of the racemate before feeding, reduces the production operation steps, greatly improves the production efficiency and reduces the production cost; secondly, the present invention greatly reduces the occurrence of side reactions during the ring-closing reaction under the condition of high-temperature water by reducing pressure and low-temperature water separation operation, effectively controls the generation of impurities, improves product quality and improves yield, is more conducive to product quality control and reduces production costs. In short, the present invention provides a method for preparing and recovering pregabalin intermediate 3-isobutylglutaric acid monoamide, which is safe, environmentally friendly, simple and convenient, has good product quality and high yield. DETAILED DESCRIPTION

[0029] The features and product performance of the present invention are further described in detail below in conjunction with the embodiments, but the present invention is not limited to the following embodiments.

[0030] Preparation of the racemate:

[0031] Add 3800mL of chloroform, 70g of anhydrous ethanol, and 360g of 3-isobutylglutaric acid monoamide to a 5L reaction bottle in sequence. Heat to 40-60°C, add 180g of R-phenylethylamine dropwise at 40-60°C, and keep warm for 0.5-2h. Cool to 30-45°C, filter, and distill the mother liquor under reduced pressure until no liquid flows out. Add 600g of water, cool to 20-30°C, add alkali to adjust pH ≥ 13.0, extract with chloroform twice, add hydrochloric acid to the water layer to adjust pH to 1-3, and filter to obtain 308g (22% water) of wet product of racemate-1, which is for standby use. Repeat the above steps to obtain 310g (20% water) of wet product of racemate-2, which is for standby use.

[0032] Embodiment 1:

[0033] Add 100.0g of the wet product of racemate-1 to 160mL of xylene, gradually increase the temperature, control the temperature ≤ 90℃, and the pressure -0.08~-0.1MPa to separate the water under reduced pressure until no water is separated; after the reduced pressure separation, increase the temperature, control the temperature at 130~140℃, separate the water under normal pressure (reaction) for 5h; after the normal pressure separation (reaction), cool to 40℃ and add 160mL water; add ion membrane liquid alkali at 30-40°C, adjust the pH to 13.5, keep the reaction at 30-40°C for 3h, and separate the organic layer; add hydrochloric acid to the water layer, control the temperature at 30-40°C, and adjust the pH to 2.0; extract twice with ethyl acetate (100mL+60mL), discard the water layer, and evaporate 100mL of ethyl acetate under reduced pressure; cool to 5-10°C for crystallization for 6h, filter and dry to obtain 70.3g of 3-isobutylglutaric acid monoamide with a yield of 90.1% and a purity of 99.7%.

[0034] Embodiment 2:

[0035] Add 100.0 g of the wet product of the racemate to be distilled into 230 mL of xylene and gradually increase the temperature to control the temperature ≤ 80 ℃, pressure -0.07 ~ -0.09MPa, decompress water until no water is separated; after decompressing water, heat up, control the temperature at 130 ~ 140 ℃, and separate water at normal pressure (reaction) for 2h; after separating water at normal pressure (reaction), cool to 30 ℃ and add 200mL of water; add ion membrane liquid alkali dropwise at 20 ~ 30 ℃, adjust the pH to 12, keep warm for reaction at 20 ~ 30 ℃ for 1h, and separate the organic layer; add hydrochloric acid dropwise to the water layer, control the temperature at 20 ~ 30 ℃, and adjust the pH to 1.0; extract twice with ethyl acetate (150mL + 80mL), discard the water layer, and evaporate 160mL of ethyl acetate under reduced pressure; cool to 10 ~ 15 ℃ for crystallization for 1h, filter and dry to obtain 69.8g of 3-isobutylglutaric acid monoamide with a yield of 89.5% and a purity of 99.8%.

[0036] Embodiment 3:

[0037] 100.0 g of the wet product of racemate-1 to be prepared was added to 80 mL of xylene, and the temperature was gradually raised, and the temperature was controlled to be ≤90°C and the pressure was -0.06 to -0.08 MPa, and the water was separated under reduced pressure until no water was separated; after the water separation under reduced pressure was completed, the temperature was raised, and the temperature was controlled to 130 to 140°C and the water was separated under normal pressure (reaction) for 4 h; after the water separation (reaction) under normal pressure was completed, 100 mL of water was added after the temperature was lowered to 20°C; ion membrane liquid alkali was added dropwise at 20 to 30°C, the pH was adjusted to 13, and the reaction was kept at 20 to 30°C for 2 h, and the organic layer was separated; hydrochloric acid was added dropwise to the water layer, the temperature was controlled to 20 to 30°C, and the pH was adjusted to 3.0; ethyl acetate (120 mL + 70 mL) was extracted twice, the water layer was discarded, and 120 mL of ethyl acetate was evaporated under reduced pressure; the temperature was lowered to 0 to 5°C for crystallization for 2 h, the filter was discarded, and the 3-isobutylglutaric acid monoamide 70.0 g was obtained, with a yield of 89.7% and a purity of 99.8%.

[0038] Embodiment 4:

[0039] Add 100.0g of the wet product of racemate-2 to 160mL of toluene, gradually increase the temperature, control the temperature ≤90℃, and the pressure -0.07~-0.09MPa to separate the water under reduced pressure until no water is separated; after the reduced pressure separation, increase the temperature, control the temperature at 110~120℃ and separate the water under normal pressure (react) for 4h; after the normal pressure separation (reaction), cool to 30℃ and add 180mL water; add ion membrane alkali at 20-30°C, adjust the pH to 13, keep the reaction at 20-30°C for 2h, and separate the organic layer; add hydrochloric acid to the water layer, control the temperature at 20-30°C, and adjust the pH to 1.0; extract twice with ethyl acetate (100mL+60mL), discard the water layer, and evaporate 100mL of ethyl acetate under reduced pressure; cool to 5-10°C for crystallization for 5h, filter and dry to obtain 71.5g of 3-isobutylglutaric acid monoamide with a yield of 89.4% and a purity of 99.8%.

[0040] Embodiment 5:

[0041] Add 100.0g of the wet product of racemate-2 to 230mL of n-octane, gradually increase the temperature, control the temperature ≤80℃, and the pressure -0.06~-0.08MPa to separate the water under reduced pressure until no water is separated; after the reduced pressure separation, increase the temperature, control the temperature at 120~130℃ and separate the water under normal pressure (reaction) for 5h; after the normal pressure separation (reaction), cool to 40℃ and add 160mL of water; add ion membrane liquid alkali at 20~30℃, adjust the pH to 13. Keep the reaction at 20-30°C for 2h, and separate the organic layer; add hydrochloric acid dropwise to the aqueous layer, control the temperature at 20-30°C, and adjust the pH to 0.5; extract twice with ethyl acetate (160mL+80mL), discard the aqueous layer, and evaporate 160mL of ethyl acetate under reduced pressure; cool to 0-5°C for crystallization for 2h, filter, and dry to obtain 72.0g of 3-isobutylglutaric acid monoamide with a yield of 90.0% and a purity of 99.5%.

[0042] Embodiment 6:

[0043] Add 100.0 g of the wet product of racemate-2 to 100 mL of xylene and gradually increase the temperature to control the temperature ≤ 90 ℃, pressure -0.07 ~ -0.09MPa, reduce pressure and separate water until there is no water; after the reduced pressure water separation, heat up, control the temperature at 130 ~ 140 ℃, and separate water (react) at normal pressure for 3h; after the normal pressure water separation (reaction), cool to 30 ℃ and add 100mL of water; 20 ~ 30 ℃, add ion membrane liquid alkali dropwise, adjust the pH to 13.5, keep warm at 20 ~ 30 ℃ for 1h, and separate the organic layer; add hydrochloric acid dropwise to the water layer, control the temperature at 20 ~ 30 ℃, and adjust the pH to 1.0; extract twice with ethyl acetate (120mL + 60mL), discard the water layer, and evaporate 110mL of ethyl acetate under reduced pressure; cool to 0 ~ 5 ℃ for crystallization for 5h, filter and dry to obtain 72.4g of 3-isobutylglutaric acid monoamide with a yield of 90.5% and a purity of 99.6%.

[0044] Comparative Example (reference patent CN105481712 A)

[0045] Preparation of the racemate:

[0046] Add 3800mL of chloroform, 70g of anhydrous ethanol and 360g of 3-isobutylglutaric acid monoamide to a 5L reaction bottle in sequence. Heat to 40-60°C, add 180g of R-phenylethylamine dropwise at 40-60°C, and keep warm for 0.5-2h. Cool to 30-45°C, filter, and vacuum distill the mother liquor until no liquid flows out to obtain 322g of salt. Add 1610g of water, cool to 20-30°C, adjust pH to 2 with concentrated hydrochloric acid, cool to 5°C and keep warm for 1h, filter, use 1000g of water to beat the filter cake for 30min, filter, and obtain 278g of wet product (20% water) of racemate-3 for standby use.

[0047] Comparative Example 1:

[0048] To 930 mL of xylene, add 80.0 g of the wet product of the racemate-3 to be racemized, stir and heat to 120° C., reflux and separate water for 8 h to obtain a reaction mass containing 3-isobutylglutarimide, cool the mass to 30° C., add 1230 g of water and 300 g of potassium carbonate, stir and react for 1 h, stand at 30° C. to separate the layers, adjust the pH of the aqueous layer to 2.0 with concentrated hydrochloric acid at this temperature, extract three times with toluene (500 g*3), combine the organic layers, concentrate, cool to 5° C., keep warm for 1 h, filter and dry to obtain 50.2 g of 3-isobutylglutaramide with a yield of 78.4% and a purity of 94.5%.

[0049] Comparative Example 2:

[0050] To 930 mL of xylene was added 80.0 g of the wet product of the racemate-3 to be racemized, and the mixture was stirred and heated to 130° C. for reflux and water separation reaction for 7 h to obtain a reaction mass containing 3-isobutylglutarimide. The mass was cooled to 30° C., 1230 g of water and 300 g of potassium carbonate were added, and the reaction was stirred for 1 h. The mixture was allowed to stand at 30° C. for stratification, and the pH of the aqueous layer was adjusted to 2.0 with concentrated hydrochloric acid at this temperature. The mixture was extracted 3 times with toluene (500 g*3), and the organic layers were combined and concentrated, cooled to 5° C., and crystallized for 1 h. The mixture was filtered and dried to obtain 51.8 g of 3-isobutylglutaramide with a yield of 80.9% and a purity of 94.7%.

[0051] Comparative Example 3:

[0052] To 1210 mL of xylene, add 80.0 g of the wet product of the racemate-3 to be racemized, stir and heat to 120° C., reflux and separate water for 8 h to obtain a reaction mass containing 3-isobutylglutarimide, cool the material to 30° C., add 1230 g of water and 300 g of potassium carbonate, stir and react for 1 h, stand at 30° C. to separate the layers, adjust the pH of the aqueous layer to 2.0 with concentrated hydrochloric acid at this temperature, extract three times with toluene (500 g*3), combine the organic layers, concentrate, cool to 5° C., keep warm for 1 h, filter and dry to obtain 49.8 g of 3-isobutylglutaramide, with a yield of 77.8% and a purity of 94.5%.

Claims

1. A method for recovering 3-isobutylglutaric acid monoamide shown in compound 4, comprising the following steps: 3-isobutylglutaric acid monoamide was resolved by R-phenylethylamine to obtain compound 6 and a resolution mother liquor containing compound 5. The resolution mother liquor was alkalized by adding inorganic alkali water, and then extracted with an organic solvent. The obtained water layer was acidified by adding hydrochloric acid, and filtered to separate the wet product of the racemate containing compound 8. The wet product of the racemate was treated to obtain the recovered 3-isobutylglutaric acid monoamide. The synthesis route is as follows: The invention is characterized in that the recovery process of the wet racemate to be treated comprises the following steps: (1) adding a wet racemate to be eliminated into an organic solvent, raising the temperature, and controlling the temperature to be ≤90° C. to perform water separation under reduced pressure, wherein the organic solvent is selected from: toluene, xylene or n-octane; (2) After the water separation is completed under reduced pressure, the temperature is raised under normal pressure and controlled at 100-140° C. to carry out a dehydration cyclization reaction; (3) The product obtained in step (2) is hydrolyzed under alkaline conditions to obtain the racemic 3-isobutylglutaramide.

2. The method according to claim 1, characterized in that The organic solvent in step (1) is xylene.

3. The method according to claim 1 or 2, characterized in that The volume ratio of the organic solvent in step (1) to the dry weight ratio of the racemate is 0.5:1 to 3:1 L / Kg.

4. The method according to claim 1 or 2, characterized in that The volume ratio of the organic solvent in step (1) to the dry weight ratio of the racemate is 1:1 to 2:1 L / Kg.

5. The method according to claim 1, characterized in that The water separation pressure in step (1) is -0.06 to -0.1 MPa.

6. The method according to claim 1, characterized in that The end point of the decompression water separation in step (1) is that no water is separated.

7. The method according to claim 1, characterized in that The step (3) specifically comprises the following steps: (4) After the ring-closure reaction at normal pressure is completed, the temperature is lowered to 20-40°C, water is added, and then ion membrane liquid alkali is added dropwise to adjust the pH to ≥12.

0. The reaction is carried out under this temperature condition for 1-3 hours, and then the organic layer is separated; (5) adding hydrochloric acid dropwise to the aqueous layer to adjust the pH to 0.5-3.0; (6) Extract with ethyl acetate several times, combine the organic layers, control the temperature at 30-50° C., and evaporate 60%-70% of the ethyl acetate under reduced pressure; (7) Cooling to 0-15° C. to crystallize, filter, and dry to obtain 3-isobutylglutaric acid monoamide.

8. The method according to claim 7, characterized in that The ratio of the volume of water added in step (4) to the dry weight of the racemate is 1:1 to 3:1 L / Kg.

9. The method according to claim 7, characterized in that The temperature for adding hydrochloric acid in step (5) is 20-40°C.

10. The method according to claim 7, characterized in that The total volume of ethyl acetate used for extraction in step (6) is in a weight ratio of 1.5:1 to 3:1 L / Kg to the dry weight of the racemate to be extracted, and the number of extractions should be ≥2 times.

11. The method according to claim 7, characterized in that The crystallization time of step (7) is 1.0 to 6.0 hours.

Images