CN104710320A - Method for preparing pregabalin - Google Patents
Method for preparing pregabalin Download PDFInfo
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- CN104710320A CN104710320A CN201510143285.9A CN201510143285A CN104710320A CN 104710320 A CN104710320 A CN 104710320A CN 201510143285 A CN201510143285 A CN 201510143285A CN 104710320 A CN104710320 A CN 104710320A
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- isobutylglutaric
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Abstract
The invention provides a method for preparing pregabalin, which comprises the following steps: mixing (R)-3-isobutylpentadiacid monoamide and drinking water, and stirring uniformly to prepare a mixed solution; dropwisely adding halogen into strong alkali, and stirring to prepare a hypohalous acid salt alkaline solution; dropwisely adding the (R)-3-isobutylpentadiacid monoamide water solution into the hypohalous acid salt alkaline solution at 0-30 DEG C, and keeping the temperature for 1-2 hours; heating to 40-60 DEG C, and keeping the temperature to react for 1-2 hours; slowly and dropwisely adding acid into the system to regulate the pH value at 20-30 DEG C; heating to 50-60 DEG C, cooling to 20-30 DEG C, and measuring the pH value, thereby finishing the acid regulation; and cooling to crystallize, keeping the temperature to crystallize for 2-3 hours, carrying out vacuum filtration, eluting with cold water 2-3 times, and drying to obtain the S-pregabalin. The method has very obvious advantages, can effectively enhance the quality and yield of the product, performs uniform reaction, and has excellent effects on removing partial impurities. The method shortens the reaction time in product, improves the productive capacity, enhances the production efficiency, and greatly lowers the production cost.
Description
Technical field
The invention provides a kind of method being prepared lyrica by pregabalin intermediate (R)-3-isobutylglutaric acid monoamide through Huffman (hoffmann) DeR, belong to field of medicine and chemical technology.
background of invention
Lyrica (Pregabalin), chemistry (3S)-3-amino methyl-5-methylhexanoic acid (3S-3-aminomethy-5-methylhexanoic acid) by name, No. CAS: 148553-50-8; Molecular formula C
8h
17nO
2; Molecular weight: 159.23.It is novel y-aminobutyric acid (GABA) receptor antagonist developed by Pfizer company.Be used for the treatment of the partial seizure of adult patients in July, 2004 first through European Union's approval, commodity are called Lyrica.In June, 2005 goes on the market in the U.S. through FDA Food and Drug Administration (FDA) approval, in March, 2006 increases indication, treatment generalized anxiety disorder and sociability anxiety disorder, within 2009, get permission again to treat Spinal injury, wound, multiple sclerosis, diabetic neuropathy pain and zoster neuralgia, its clinical application is further expanded.
Its structure is as follows:
Current report is prepared lyrica and is mainly contained two classes, and a class is chemosynthesis, and another kind of is enzymatic clarification.And industrialization employing is chemical synthesis more widely, mainly contains: asymmetric catalyst carries out asymmetric reaction, obtain or finally obtain pregabalin; Utilize resolving agent to split and obtain pregabalin through process again; Also be that the more use chiral resolving agent of current industrial applications splits an a certain intermediate below, finally obtain pregabalin, the present invention is exactly improving one's methods for Huffman (hoffmann) DeR in this route.
At present, had many operational paths preparing lyrica, what we adopted is typically is split by 3-amino methyl-5-methylhexanoic acid, the free Huffman (hoffmann) that carries out again degrades and obtain pregabalin, synthetic route is as follows:
Wherein, degraded operation reports that more synthetic route drops in highly basic by (R)-3-isobutylglutaric acid monoamide solid, stir cooling, then slowly drip bromine, advantage of the present invention clearly, can be improved the quality of products and yield effectively, reaction evenly, very good for the effect removing partial impurities, yield is between 87% ~ 92%, and purity can reach more than 99.5%; The reaction times of half can be shortened aborning, enhance production capacities, enhance productivity, production cost is significantly reduced.
Summary of the invention
The object of this invention is to provide a kind of pregabalin intermediate (R)-3-isobutylglutaric acid monoamide prepares lyrica method through hoffman degradation reaction, comprise the following steps:
1) (R)-3-isobutylglutaric acid monoamide is mixed with tap water, stir evenly, be configured to mixing solutions; Halogen is dropped in highly basic, stir, be configured to the basic solution of hypohalite;
2) at 0 ~ 30 DEG C, (R)-3-isobutylglutaric acid monoamide aqueous solution is dropped in hypohalite basic solution, insulation 1 ~ 2h;
3) insulation terminates, and is warming up to 40 ~ 60 DEG C of insulation reaction, insulation 1 ~ 2h; At 20 ~ 30 DEG C, slow acid is dropped in system, regulate pH;
4) after acid adjustment terminates, be warming up to 50 ~ 60 DEG C, then be cooled to 20 ~ 30 DEG C, repetition measurement pH, acid adjustment terminates;
5) cooling crystallization, insulation crystallization 2 ~ 3h, suction filtration, meets cold water drip washing 2 ~ 3 times, dries, obtains pregabalin.
The halogen added in step 1) is selected from: bromine, chlorine water.
In step 1), tap water operating weight is 2 ~ 4 times of (R)-3-isobutylglutaric acid monoamide weight.
1.0 ~ 1.3 times that halogen usage quantity is (R)-3-isobutylglutaric acid monoamide equivalent molar ratio are added in step 1).
The alkali added in step 1) is selected from: sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution; The weight adding alkali is 3.5 ~ 4.5 times of (R)-3-isobutylglutaric acid monoamide weight.
The acid used in step 3) is selected from: hydrochloric acid, sulfuric acid.
In step 3), pH is regulated to refer to that adjust ph is 6.0 ~ 8.0.
In step 4), repetition measurement pH refers to that repetition measurement pH value is 6.0 ~ 8.0.
In step 5), cooling crystallization time controling is at 1.5 ~ 2h.
In step 5), insulation crystallization terminal temperature 0 ~ 10 DEG C.
Embodiment
Below in conjunction with example, the present invention is further elaborated, but these examples do not form any restriction to the present invention.
Example 1:
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 400g30%NaOH solution is added in 1L reaction flask, drips 1.0 equivalent 85g bromines, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of sodium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 74.4g product in 50 ~ 60 DEG C of baking ovens; Yield 87.5%, purity 99.7%.
Example 2
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 400g30%NaOH solution is added in 1L reaction flask, drips 1.1 equivalent 93.5g bromines, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of sodium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 75.3g product in 50 ~ 60 DEG C of baking ovens; Yield 88.6%, purity 99.6%.
Example 3
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 400g30%NaOH solution is added in 1L reaction flask, drips 1.1 equivalent 102g bromines, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of sodium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 76.4g product in 50 ~ 60 DEG C of baking ovens; Yield 89.9%, purity 99.5%.
Example 4
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 400g30%NaOH solution is added in 1L reaction flask, drips 1.3 equivalent 110.5g bromines, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of sodium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 78.2g product in 50 ~ 60 DEG C of baking ovens; Yield 92.0%, purity 99.5%.
Example 5
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 370g30%KOH solution is added in 1L reaction flask, drips 1.0 equivalent 38g chlorine waters, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of potassium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 75.5g product in 50 ~ 60 DEG C of baking ovens; Yield 88.8%, purity 99.8%.
Example 6
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 370g30%KOH solution is added in 1L reaction flask, drips 1.1 equivalent 41.8g chlorine waters, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of potassium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 74.8g product in 50 ~ 60 DEG C of baking ovens; Yield 88.0%, purity 99.7%.
Example 7
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 370g30%KOH solution is added in 1L reaction flask, drips 1.2 equivalent 45.6g chlorine waters, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of potassium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 76.3g product in 50 ~ 60 DEG C of baking ovens; Yield 89.7%, purity 99.6%.
Example 8
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 370g30%KOH solution is added in 1L reaction flask, drips 1.3 equivalent 49.4g chlorine waters, drip and terminate, be cooled to 0 ~ 10 DEG C; Under 0 ~ 10 DEG C of condition, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of potassium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 78.1g product in 50 ~ 60 DEG C of baking ovens; Yield 91.8%, purity 99.5%.
Example 9
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 400g30%NaOH solution is added in 1L reaction flask, drips 1.2 equivalent 102g bromines, drip and terminate, be cooled to 10 ~ 20 DEG C; Under 10 ~ 20 DEG C of conditions, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of sodium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 76.1g product in 50 ~ 60 DEG C of baking ovens; Yield 89.5%, purity 99.6%.
Example 10
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 400g30%NaOH solution is added in 1L reaction flask, drips 1.2 equivalent 102g bromines, drip and terminate, be cooled to 20 ~ 30 DEG C; Under 20 ~ 30 DEG C of conditions, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of sodium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 75.9g product in 50 ~ 60 DEG C of baking ovens; Yield 89.3%, purity 99.5%.
Example 11
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 370g30%KOH solution is added in 1L reaction flask, drips 1.2 equivalent 45.6g chlorine waters, drip and terminate, be cooled to 20 ~ 30 DEG C; Under 20 ~ 30 DEG C of conditions, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of potassium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 76.3g product in 50 ~ 60 DEG C of baking ovens; Yield 89.7%, purity 99.5%.
Example 12
Get (R)-3-isobutylglutaric acid monoamide 100g, with water 300g, mechanical stirring, mixes; 370g30%KOH solution is added in 1L reaction flask, drips 1.2 equivalent 45.6g chlorine waters, drip and terminate, be cooled to 20 ~ 30 DEG C; Under 20 ~ 30 DEG C of conditions, (R)-3-isobutylglutaric acid monoamide aqueous solution is slowly dropped in the basic solution of potassium hypobromite; Drip and terminate, insulation 1 ~ 2h; Be warming up to 40 ~ 60 DEG C, insulation 1 ~ 2h; Insulation terminates, temperature 20 ~ 30 DEG C in the hierarchy of control, and slowly drip refining hydrochloric acid, regulate pH to 6.0 ~ 8.0, acid adjustment is finished, and is warming up to 50 ~ 60 DEG C, then is cooled to 20 ~ 30 DEG C, repetition measurement pH; In 1.5 ~ 2h, slow cooling to 0 ~ 10 DEG C, insulation crystallization 2 ~ 3h; Insulation crystallization is finished, decompress filter, and filter cake meets cold water drip washing 2 ~ 3 times with 10 DEG C; Filter cake is dried and is obtained 76.1g product in 50 ~ 60 DEG C of baking ovens; Yield 89.5%, purity 99.5%.
Claims (10)
1. prepare a method for lyrica, it is characterized in that comprising the following steps:
1) (R)-3-isobutylglutaric acid monoamide is mixed with tap water, stir evenly, be configured to mixing solutions; Halogen is dropped in highly basic, stir, be configured to the basic solution of hypohalite;
2) at 0 ~ 30 DEG C, (R)-3-isobutylglutaric acid monoamide aqueous solution is dropped in hypohalite basic solution, insulation 1 ~ 2h;
3) insulation terminates, and is warming up to the insulation reaction of 40 ~ 60 DEG C, insulation 1 ~ 2h; At 20 ~ 30 DEG C, slow acid is dropped in system, regulate pH;
4) after acid adjustment terminates, be warming up to 50 ~ 60 DEG C, then be cooled to 20 ~ 30 DEG C, repetition measurement pH, acid adjustment terminates;
5) cooling crystallization, insulation crystallization 2 ~ 3h, suction filtration, meets cold water drip washing 2 ~ 3 times, dries, obtains pregabalin.
2. method according to claim 1, is characterized in that the halogen added in aforesaid method step 1) is selected from: bromine, chlorine water.
3. method according to claim 1, is characterized in that in step 1), tap water operating weight is 2 ~ 4 times of (R)-3-isobutylglutaric acid monoamide weight.
4. method according to claim 1, is characterized in that adding 1.0 ~ 1.3 times that halogen usage quantity is (R)-3-isobutylglutaric acid monoamide equivalent molar ratio in step 1).
5. method according to claim 1, is characterized in that the alkali added in step 1) is selected from: sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution; The weight adding alkali is 3.5 ~ 4.5 times of (R)-3-isobutylglutaric acid monoamide weight.
6. method according to claim 1, is characterized in that the acid used in step 3) is selected from: hydrochloric acid, sulfuric acid.
7. method according to claim 1, is characterized in that in step 3), regulates pH to refer to that adjust ph is 6.0 ~ 8.0.
8. method according to claim 1, is characterized in that in step 4), and repetition measurement pH refers to that repetition measurement pH value is 6.0 ~ 8.0.
9. method according to claim 1, is characterized in that in step 5), and cooling crystallization time controling is at 1.5 ~ 2h.
10. method according to claim 1, is characterized in that in step 5), insulation crystallization terminal temperature 0 ~ 10 DEG C.
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| CN201510143285.9A CN104710320A (en) | 2015-03-30 | 2015-03-30 | Method for preparing pregabalin |
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| CN201510143285.9A CN104710320A (en) | 2015-03-30 | 2015-03-30 | Method for preparing pregabalin |
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Cited By (4)
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| CN109761838A (en) * | 2019-02-22 | 2019-05-17 | 浙江华海药业股份有限公司 | A method of preparing pregabalin intermediate and recycling resolving agent |
| CN112062689A (en) * | 2019-06-11 | 2020-12-11 | 太仓市茜泾化工有限公司 | Preparation method of R-3- (carbamoyl) -5-methylhexanoic acid |
| CN113801031A (en) * | 2021-10-26 | 2021-12-17 | 浙江华海药业股份有限公司 | Purification method of pregabalin |
| CN114740101A (en) * | 2022-03-11 | 2022-07-12 | 永信药品工业（昆山）股份有限公司 | Method for detecting impurities in pregabalin pharmaceutical composition |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109761838A (en) * | 2019-02-22 | 2019-05-17 | 浙江华海药业股份有限公司 | A method of preparing pregabalin intermediate and recycling resolving agent |
| CN112062689A (en) * | 2019-06-11 | 2020-12-11 | 太仓市茜泾化工有限公司 | Preparation method of R-3- (carbamoyl) -5-methylhexanoic acid |
| CN113801031A (en) * | 2021-10-26 | 2021-12-17 | 浙江华海药业股份有限公司 | Purification method of pregabalin |
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| CN113801031B (en) * | 2021-10-26 | 2023-12-26 | 浙江华海药业股份有限公司 | Purification method of pregabalin |
| CN114740101A (en) * | 2022-03-11 | 2022-07-12 | 永信药品工业（昆山）股份有限公司 | Method for detecting impurities in pregabalin pharmaceutical composition |
| CN114740101B (en) * | 2022-03-11 | 2023-11-21 | 德全药品(江苏)股份有限公司 | Method for detecting impurities in pregabalin pharmaceutical composition |
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