CN104557576A - Method for preparing high-purity pregabalin - Google Patents
Method for preparing high-purity pregabalin Download PDFInfo
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- CN104557576A CN104557576A CN201410791988.8A CN201410791988A CN104557576A CN 104557576 A CN104557576 A CN 104557576A CN 201410791988 A CN201410791988 A CN 201410791988A CN 104557576 A CN104557576 A CN 104557576A
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- lyrica
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Abstract
The invention provides a method for preparing high-purity pregabalin. The method comprises the following steps: adding purified water, heating, dissolving, adding acid for extracting, regulating the pH value of the solution, adding an alcohol solvent and a seed crystal, cooling, crystallizing, thereby obtaining the pregabalin product. According to the technical method, the effect of removing impurities in pregabalin is obvious, the method is high in yield, high in purity and convenient to operate and is suitable for industrial production, and special equipment is not needed.
Description
Technical field
The present invention relates to a kind of preparation method of high purity lyrica, be particularly useful for making the lyrica product that purity is high, isomer is few, belong to chemical pharmacy field.
Technical background
Lyrica (Pregabalin) is novel γ-aminobutyric acid (GABA) receptor antagonist researched and developed by Pfizer, chemical name be (3S)-3-aminomethyl-5-methylhexanoic acid (as shown in the formula), commodity are called Lyrica.In July, 2004, the partial seizure of primary treatment adult patients, obtained FDA Food and Drug Administration (FDA) approval listing in June, 2005 by European Union's approval listing.In March, 2006 increases indication, treatment generalized anxiety disorder and sociability anxiety disorder, within 2009, gets permission again to treat spinal cord injury, wound, multiple sclerosis, diabetic neuropathy pain and zoster neuralgia.In clinical application, lyrica has the advantages such as dosage is low, curative effect is strong, toxic side effect is few, has become one of global best-selling medicine, and within 2013, global marketing volume breaks through 4,500,000,000 U.S. dollars.
Up to the present, the preparation method of existing a large amount of document and patent report lyrica, with lyrica prepared by these methods, although quality standard (pregabalin lactan≤0.15 % of Europe and American Pharmacopeia can be met, unknown single assorted≤0.10 %, impurity summation≤1.0 %, R-lyrica≤0.15 %), but do not reach specification of quality (pregabalin lactan≤0.05 % of high purity lyrica, unknown single assorted≤0.05 %, impurity summation≤0.5 %, R-lyrica≤0.05 %).Therefore, develop high purity lyrica preparation method and become the key point improving its quality.We have developed a kind of preparation method of high purity lyrica here, not only yield is high, purity good for the lyrica product utilizing the method to prepare, and simple to operate, is easy to the large production of commercialization.
Summary of the invention
The object of the invention is the effective especially process for purification of exploitation one, for the preparation of high purity lyrica, be applicable to industrialized production.
The object of the invention is to realize by following technical solution:
Lyrica crude product to be purified is joined in the aqueous solution, heats up clearly molten; Then be 5.0 ~ 6.0 by acid-conditioning solution pH value, then use organic solvent extracting aqueous, the aqueous phase adjusting PH with base value after extraction is 6.0 ~ 7.5; Then in this solution, add alcohol solution and lyrica crystal seed, slow cooling crystallization, suction filtration, drying obtain high purity lyrica product.
Lyrica crude product described in the method and the mass ratio of the aqueous solution are 1:4 ~ 1:20, and preferred proportion is 1:8 ~ 1:12.
Aforesaid method acid used is hydrochloric acid, sulfuric acid or nitric acid, preferred hydrochloric acid.
Described organic solvent is ester or ether solvent, and esters solvent is selected from methyl acetate, ethyl acetate, isopropyl acetate, butylacetate or ethyl formate, ethyl acetate; Ether solvent is selected from ether, isopropyl ether, tetrahydrofuran (THF), methyl-propyl ether or methyl tertiary butyl ether, preferable methyl tertbutyl ether; Described consumption of organic solvent is 5 ~ 15% of volume of water consumption.
Alkali used is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus, preferred sodium carbonate and salt of wormwood.
Alcoholic solvent used is methyl alcohol, ethanol, Virahol or propyl carbinol, preferred Virahol, and described alcoholic solvent consumption is 20 ~ 50% of volume of water consumption.
Lyrica Seed charge is 1 ~ 3% of lyrica crude product quality.
Described recrystallization temperature is-5 ~ 40 DEG C, and preferable temperature is 10 ~ 30 DEG C.
Selectivity drying temperature is 30 ~ 80 DEG C, and preferred temperature is 40 ~ 60 DEG C.
The invention provides preferred technical scheme as follows:
In reaction flask, add lyrica crude product and the aqueous solution, heat up clearly molten.Be 5.0 ~ 6.0 by the pH value of acid (example hydrochloric acid) regulator solution, then use the organic solvent (as ethyl acetate, methyl tertiary butyl ether) of 5 ~ 15% volumes extract, by the aqueous phase after extracting with alkali (as K
2cO
3or Na
2cO
3) pH value of polyphony solution, add the Virahol of 20 ~ 50% and the crystal seed of 1 ~ 3%, near slow cooling to 10 DEG C, separate out off-white color crystal, suction filtration, drying under reduced pressure, obtains lyrica product.
Lyrica tool prepared by present method has the following advantages:
1, quality is good, yield is high, is applicable to the preparation of high purity lyrica;
2, easy to operate, aftertreatment simple, be applicable to industrial amplification production;
3, preparation condition is gentle, and agents useful for same is cheap and easy to get.
Embodiment
The present invention is further described in conjunction with the embodiments.Following examples just illustrate the present invention, and not limit the present invention by any way.
Embodiment 1
20 g lyrica crude products, 80 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then adjust the pH value of solution to be 5.0 with HCl, then extract with 12 ml ethyl acetate solutions, the aqueous solution after extraction adds Na
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 40 ml Virahols and 0.2 g lyrica crystal seed, stirs a moment, is cooled to 10 DEG C, separate out white crystal, filter, vacuum-drying at 30 DEG C, yield 88 %, purity is 99.95 %, mp:180 ~ 182 DEG C.
Embodiment 2
20 g lyrica crude products, 160 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then adjust the pH value of solution to be 5.0 with HCl, then extract with 20 ml ethyl acetate solutions, the aqueous solution after extraction adds K
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 48 ml Virahols and 0.4 g lyrica crystal seed, stirs a moment, is cooled to 20 DEG C, separate out white crystal, filter, vacuum-drying at 40 DEG C, yield 90 %, purity is 99.98 %, mp:180 ~ 182 DEG C.
Embodiment 3
20 g lyrica crude products, 240 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then H is used
2sO
4the pH value adjusting solution is 5.5, then extracts with 24 ml t-butyl methyl ether solution, and the aqueous solution after extraction adds Na
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 96 ml Virahols and 0.6 g lyrica crystal seed, stirs a moment, is cooled to 30 DEG C, separate out white crystal, filter, vacuum-drying at 60 DEG C, yield 86 %, purity is 99.96 %, mp:180 ~ 182 DEG C.
Embodiment 4
20 g lyrica crude products, 400 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then H is used
2sO
4the pH value adjusting solution is 5.5, then extracts with 20 ml t-butyl methyl ether solution, and the aqueous solution after extraction adds Na
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 80 ml Virahols and 0.3 g lyrica crystal seed, stirs a moment, is cooled to 40 DEG C, separate out white crystal, filter, vacuum-drying at 80 DEG C, yield 91 %, purity is 99.97 %, mp:180 ~ 182 DEG C.
Embodiment 5
20 g lyrica crude products, 80 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then HNO is used
3the pH value adjusting solution is 5.5, then extracts with 12 ml ethyl acetate solutions, and the aqueous solution after extraction adds K
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 40 ml Virahols and 0.5 g lyrica crystal seed, stirs a moment, is cooled to-5 DEG C, separate out white crystal, filter, vacuum-drying at 60 DEG C, yield 87 %, purity is 99.98 %, mp:180 ~ 182 DEG C.
Embodiment 6
20 g lyrica crude products, 160 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then HNO is used
3the pH value adjusting solution is 6.0, then extracts with 20 ml t-butyl methyl ether solution, and the aqueous solution after extraction adds K
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 48 ml Virahols and 0.2 g lyrica crystal seed, stirs a moment, is cooled to 0 DEG C, separate out white crystal, filter, vacuum-drying at 30 DEG C, yield 89 %, purity is 99.95 %, mp:180 ~ 182 DEG C.
Embodiment 7
20 g lyrica crude products, 240 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then adjust the pH value of solution to be 6.0 with HCl, then extract with 24 ml ethyl acetate solutions, the aqueous solution after extraction adds Na
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 96 ml Virahols and 0.4 g lyrica crystal seed, stirs a moment, is cooled to 10 DEG C, separate out white crystal, filter, vacuum-drying at 40 DEG C, yield 86 %, purity is 99.97 %, mp:180 ~ 182 DEG C.
Embodiment 8
20 g lyrica crude products, 400 g water are joined together in reaction flask, heating up, it is clearly molten to stir.Then adjust the pH value of solution to be 5.0 with HCl, then extract with 20 ml t-butyl methyl ether solution, the aqueous solution after extraction adds K
2cO
3the pH value of regulator solution is 6.5, in the aqueous solution, then slowly add 80 ml Virahols and 0.6 g lyrica crystal seed, stirs a moment, is cooled to 15 DEG C, separate out white crystal, filter, vacuum-drying at 80 DEG C, yield 90 %, purity is 99.96 %, mp:180 ~ 182 DEG C.
quality versus's situation before and after table 1. lyrica is refining
| Batch | Purity | Lactan | Unknown single assorted | Impurity summation | R-lyrica |
| Crude product | 98.50 % | 0.19 % | 0.38 % | 1.50 % | 0.27 % |
| Embodiment 1 | 99.95 % | 0.01 % | 0.02 % | 0.05 % | 0.04 % |
| Embodiment 2 | 99.98 % | ND | 0.02 % | 0.02 % | 0.03 % |
| Embodiment 3 | 99.96 % | 0.01 % | 0.03 % | 0.04 % | 0.02 % |
| Embodiment 4 | 99.97 % | ND | 0.03 % | 0.03 % | 0.03 % |
| Embodiment 5 | 99.98 % | 0.01 % | 0.01 % | 0.02 % | 0.01 % |
| Embodiment 6 | 99.95 % | 0.02 % | 0.03 % | 0.05 % | 0.03 % |
| Embodiment 7 | 99.97 % | ND | 0.01 % | 0.03 % | 0.01 % |
| Embodiment 8 | 99.96 % | 0.01 % | 0.03 % | 0.04 % | 0.02 % |
In sum, the preparation of high purity lyrica of the present invention has technique simply, and the features such as easy to operate, yield is high, and application prospect is wide, are adapted to suitability for industrialized production.
Claims (9)
1. a preparation method for high purity lyrica, is characterized in that: join in the aqueous solution by lyrica crude product to be purified, heat up clearly molten; Then be 5.0 ~ 6.0 by acid-conditioning solution pH value, then use organic solvent extracting aqueous, the aqueous phase adjusting PH with base value after extraction is 6.0 ~ 7.5; Then in this solution, add alcohol solution and lyrica crystal seed, slow cooling crystallization, suction filtration, drying obtain high purity lyrica product.
2. high purity lyrica preparation method according to claim 1, is characterized in that: the mass ratio of lyrica crude product and the aqueous solution is 1:4 ~ 1:20, and preferred proportion is 1:8 ~ 1:12.
3. high purity lyrica preparation method according to claim 1, is characterized in that: described acid is hydrochloric acid, sulfuric acid or nitric acid, preferred hydrochloric acid.
4. high purity lyrica preparation method according to claim 1, it is characterized in that: described organic solvent is ester or ether solvent, esters solvent is selected from methyl acetate, ethyl acetate, isopropyl acetate, butylacetate or ethyl formate, ethyl acetate; Ether solvent is selected from ether, isopropyl ether, tetrahydrofuran (THF), methyl-propyl ether or methyl tertiary butyl ether, preferable methyl tertbutyl ether; Described consumption of organic solvent is 5 ~ 15% of volume of water consumption.
5. high purity lyrica preparation method according to claim 1, is characterized in that: alkali used is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, salt of wormwood or saleratus, preferred sodium carbonate and salt of wormwood.
6. high purity lyrica preparation method according to claim 1, it is characterized in that: alcoholic solvent used is methyl alcohol, ethanol, Virahol or propyl carbinol, preferred Virahol, described alcoholic solvent consumption is 20% ~ 50% of volume of water consumption.
7. high purity lyrica preparation method according to claim 1, is characterized in that: lyrica Seed charge is 1 ~ 3% of lyrica crude product quality.
8. high purity lyrica preparation method according to claim 1, it is characterized in that: described recrystallization temperature is-5 ~ 40 DEG C, preferable temperature is 10 ~ 30 DEG C.
9. high purity lyrica preparation method according to claim 1, it is characterized in that: selectivity drying temperature is 30 ~ 80 DEG C, preferred temperature is 40 ~ 60 DEG C.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109678737A (en) * | 2019-02-18 | 2019-04-26 | 常州制药厂有限公司 | A kind of preparation method of Pregabalin |
| CN113717069A (en) * | 2021-09-29 | 2021-11-30 | 浙江华海药业股份有限公司 | Crystallization method of pregabalin |
| CN113801031A (en) * | 2021-10-26 | 2021-12-17 | 浙江华海药业股份有限公司 | Purification method of pregabalin |
| CN113804805A (en) * | 2021-10-08 | 2021-12-17 | 浙江华海药业股份有限公司 | Pregabalin intermediate impurity compound II and preparation method thereof |
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| CN113717069A (en) * | 2021-09-29 | 2021-11-30 | 浙江华海药业股份有限公司 | Crystallization method of pregabalin |
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| CN113804805B (en) * | 2021-10-08 | 2023-04-07 | 浙江华海药业股份有限公司 | Pregabalin intermediate impurity compound II and preparation method thereof |
| 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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