CN101462975A - Preparation of high-purity gabapentin - Google Patents
Preparation of high-purity gabapentin Download PDFInfo
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- CN101462975A CN101462975A CNA2008100418604A CN200810041860A CN101462975A CN 101462975 A CN101462975 A CN 101462975A CN A2008100418604 A CNA2008100418604 A CN A2008100418604A CN 200810041860 A CN200810041860 A CN 200810041860A CN 101462975 A CN101462975 A CN 101462975A
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- gabapentin
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- gahapentin
- oxalate
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Abstract
The invention relates to a method for preparing high purity gabapentin. The method comprises the steps as follows: (1) at the temperature of 0-100 DEG C, gabapentin or gabapentin hydrochloride is dissolved in oxalic acid aqueous solution to be stirred completely; pH is adjusted to 2-4.5 by inorganic alkali; reaction is taken for 10 minutes to 4 hours, wherein, the mol ratio of the gabapentin or the gabapentin hydrochloride and the oxalic acid is 1:0.5 to 1; suction filtration is carried out and a filter mass is pulped by solution of ethanol and water with the volume ratio of 0:1-1:0, filtered and dried to obtain refined gabapentin oxalate; (2) at the temperature of 5 to 65 DEG C, the pH of the refined gabapentin oxalate is adjusted to 7-8 by the inorganic alkali in water soluble alcohol; the reaction is taken for 10 minutes to 4 hours at the temperature and undissolved substance is filtered; after reduced pressure evaporation to dryness of the filtrate, crude gabapentin is obtained; and (3) the crude gabapentin is pulped or recrystallized by alcohol solvent, filtered and dried to form the high purity gabapentin. The preparation method is simple, consumes short time and is easy for industrialization.
Description
Technical field
The invention belongs to the gabapentin preparation field, particularly relate to a kind of preparation method of high-purity gahapentin.
Background technology
Gabapentin, formal name used at school 1-(aminomethyl)-cyclohexyl acetic acid, structural formula is
Be 1977 by American invention, be the main raw material of novel antiepileptic drug and anxiolytic, wherein, the structural formula of Gabapentin hydrochloride is
The structural formula of gabapentin oxalate is
N=1/2 or 1 when n=1/2, is gabapentin half oxalate; When n=1, be the gabapentin oxalate.
Synthetic and a lot of patents of purifying for gabapentin all have report, such as: US4024175, US5068413, US5091567, US5132451, US6054482, US6531509.Wherein back two pieces of patents are particularly related to a kind of method for preparing qualified gabapentin, and the content of major impurity lactamase gabapentin (CDI) is less than 0.5% in the products obtained therefrom, and inorganic anion (particularly chlorion) content is less than 20ppm.Patent US6054482 also mentions, and chloride ion content surpasses 20ppm makes gabapentin change into the impurity lactamase gabapentin easily.
The method that reduces chlorion at present in the document mainly contains: 1) method by ion-exchange obtains the gabapentin aqueous solution, but this method production cycle is long; 2) remove chlorion by the filtering method of ionic membrane, but this method facility investment height; 3) adopt NaOH, KOH or NH
4Arrive iso-electric point with the Gabapentin hydrochloride aqueous solution among the OH etc., separate out the crystalline method, but this method technology is loaded down with trivial details, yield is low; 4) adopt in the organic bases and the method for Gabapentin hydrochloride, but the organic bases price is expensive, industrialization cost height.
At present, the method by gabapentin oxalate intermediate preparation gabapentin does not also have report.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of high-purity gahapentin, this method is simple, cost is low, is easy to suitability for industrialized production.
The preparation method of high-purity gahapentin of the present invention comprises step:
(1) preparation gabapentin oxalate
Under 0～100 ℃, gabapentin or its hydrochloride are dissolved in the oxalic acid aqueous solution, regulate pH to 2～4.5 with mineral alkali, reaction 10min-4h, and wherein, the mol ratio of gabapentin or its hydrochloride and oxalic acid is 1:0.5～1; Suction filtration, filter cake ethanol: water volume ratio is the solution making beating of 0:1～1:0, effectively removes chlorion, filters, and drying gets purified gabapentin oxalate;
(2) by in and the gabapentin oxalate prepare the gabapentin crude product
Under 5～65 ℃, purified gabapentin oxalate in water-soluble alcohol, with mineral alkali regulator solution pH to 7～8, under this temperature, is reacted 10min～4h, the elimination insolubles gets the gabapentin crude product behind the filtrate decompression evaporate to dryness;
(3) refining gabapentin
The gabapentin crude product filters with alcoholic solvent making beating or recrystallization, and drying gets highly purified gabapentin.
Described gabapentin or its hydrochloride are by 1,1-cyclohexyl adipic acid is a raw material, carrying out the Hofmann rearrangement reaction by the method for patent WO0234709 makes, can in the rearrangement reaction solution system, directly add hydrochloric acid, oxalic acid, regulate pH to 2～4.5 with mineral alkali, by directly preparing the gabapentin oxalate without the gabapentin of separating, the mol ratio of hydrochloric acid and gabapentin is 1:1, and the mol ratio of gabapentin or its hydrochloride and oxalic acid is 1:0.5～1.
Mineral alkali in described step (1) or (2) is one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium-acetate, Potassium ethanoate, the ammoniacal liquor etc.
The preferred pH3 of adjusting pH～4 in the described step (1), more preferred pH3.2～3.5, gained gabapentin oxalate precipitation can further be washed, and removes chloride ion content.
Water-soluble alcohol in the described step (2) is methyl alcohol, ethanol or Virahol, and the mass ratio of itself and gabapentin oxalate is 8:1～20:1, regulator solution pH to pH7.1～7.5.
Alcoholic solvent in the described step (3) is methyl alcohol or Virahol or pure water solvent system, and wherein, pure water solvent system preference volume ratio is Virahol-methanol-water of 50:25:6.
Described highly purified gabapentin, its purity 〉=99.5%, content are 100.5%, chloride ion content≤20ppm.
The present invention prepares the gabapentin oxalate by the pH of control reaction system, has reduced the consumption of hydrochloric acid on the one hand, has objectively controlled the content of chlorion; Utilize the low-solubility of gabapentin oxalate in reaction system on the one hand, gabapentin is separated from solution as far as possible; In addition, utilize the low-solubility of potassium oxalate in alcoholic solvent, inorganic oxalate precipitation is come out, gabapentin is stayed in the solution, has effectively controlled the content of inorganic salt in the gabapentin.
Beneficial effect of the present invention:
(1) gabapentin oxalate preparation method is simple, weak point consuming time, and oxalic acid low price, and the technology cost is low;
(2) by directly preparing the gabapentin oxalate, do not need the separation and purification Gabapentin hydrochloride, reduced extraction Gabapentin hydrochloride necessary operations step and solvent;
(3) can remove chlorion effectively by washing gabapentin oxalate; Employing with mineral alkali neutral methods such as potassium hydroxide, can be controlled oxalate content effectively in alcoholic solvent.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1 preparation gabapentin oxalic acid half salt
(1) prepares Gabapentin hydrochloride earlier
1,1-cyclohexyl adipic acid according to a conventional method, through the Hofmann rearrangement reaction, acidifying, preparation Gabapentin hydrochloride (reference: CN1880299 embodiment).
(2) preparation gabapentin oxalic acid half salt
Drop into Gabapentin hydrochloride, 6.1g two oxalic acid hydrates and the 80ml water of 20g oven dry in the 250ml reaction flask, be heated to 30 ℃ molten entirely to solid, after stirring half an hour, begin to drip mass concentration and be 30% aqueous sodium hydroxide solution to pH be 3.52 (pH meter surveys), add 30g sodium-chlor, restir 1 hour, be cooled to-5～0 ℃, again with mass concentration be 30% aqueous sodium hydroxide solution polyphony to pH3.5, add 3ml ethyl acetate and 1ml toluene, keep this temperature to stir 5-6 hour.Suction filtration, filter cake is iced alcohol flushing with 20ml, is 0 ℃ of making beating twice of ethanol of 95% again with the 20ml percent by volume, and each is 1 hour.Filter, 40 ℃ of oven dry of filter cake must about 17g solid.
The adding of NaCl wherein, ethyl acetate and toluene all is to make system polarity generation slight variations, helps improving yield.
Embodiment 2 preparation gabapentin crude products
In and gabapentin oxalic acid half salt
Drop into 15.7g gabapentin oxalic acid half salt (embodiment 1 preparation) and 100ml methyl alcohol in the 250ml reaction flask, be heated to 35 ℃,, finish with 4.97g KOH/50ml methanol solution accent pH to 7.5,35-40 ℃ of reacting by heating 1 hour, repetition measurement pH is 7.5.Reflux is 15 minutes then, suction filtration, filter cake dry 6.86g solid (being mainly potassium oxalate).Add 0.15g gac and 0.15g diatomite in the filtrate, refluxed heat filtering, 35 ℃ of following evaporated under reduced pressure of filtrate again 15 minutes, again with 20ml95% ethanol-5 ℃ making beating 1 hour, suction filtration, 40 ℃ of oven dry, the 10.7g solid, yield is about 88%, it is 40ppm that colorimetry records chloride ion content.
Embodiment 3 preparation high-purity gahapentins
10g gabapentin dissolving crude product is heated to 65-67 ℃ in 25ml (18g) methyl alcohol, under this temperature, slowly add 6ml water, after mixing, adds the Virahol of 50ml (39g) preheating again, slowly is cooled to 0 ℃ then, keeps 4 hours.Filter, filter cake is iced Virahol drip washing with 10ml, and 50 ℃ of vacuum dryings get the 8.5g solid.
Through recording finished product purity 〉=99.5%, content is 100.5%, chloride ion content≤20ppm.
Claims (8)
1. the preparation method of a high-purity gahapentin comprises step:
Under (1) 0～100 ℃, gabapentin or its hydrochloride are dissolved in the oxalic acid aqueous solution, fully stir, and regulate pH to 2～4.5 with mineral alkali, reaction 10min-4h, and wherein, the mol ratio of gabapentin or its hydrochloride and oxalic acid is 1:0.5～1; Suction filtration, filter cake ethanol: water volume ratio is the solution making beating of 0:1～1:0, filters, and drying gets purified gabapentin oxalate;
Under (2) 5～65 ℃, purified gabapentin oxalate in water-soluble alcohol, with mineral alkali regulator solution pH to 7～8, under this temperature, is reacted 10min～4h, the elimination insolubles gets the gabapentin crude product behind the filtrate decompression evaporate to dryness;
(3) the gabapentin crude product filters with alcoholic solvent making beating or recrystallization, and drying gets highly purified gabapentin.
2. the preparation method of high-purity gahapentin according to claim 1, it is characterized in that: the mineral alkali in described step (1) or (2) is one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium-acetate, Potassium ethanoate, the ammoniacal liquor.
3. the preparation method of high-purity gahapentin according to claim 1 is characterized in that: regulate pH to 3～4 in the described step (1).
4. the preparation method of high-purity gahapentin according to claim 3 is characterized in that: regulate pH to 3.2～3.5 in the described step (1).
5. the preparation method of high-purity gahapentin according to claim 1, it is characterized in that: the water-soluble alcohol in the described step (2) is methyl alcohol, ethanol or Virahol, the mass ratio of itself and gabapentin oxalate is 8:1～20:1.
6. the preparation method of high-purity gahapentin according to claim 1 is characterized in that: regulator solution pH to 7.1 in the described step (2)～7.5.
7. the preparation method of high-purity gahapentin according to claim 1, it is characterized in that: the alcoholic solvent in the described step (3) is methyl alcohol or Virahol or pure water solvent system.
8. the preparation method of high-purity gahapentin according to claim 7, it is characterized in that: the pure water solvent system in the described step (3) is that volume ratio is Virahol-methanol-water of 50:25:6.
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| CN2008100418604A CN101462975B (en) | 2008-08-19 | 2008-08-19 | Preparation of high-purity gabapentin |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363598A (en) * | 2011-11-25 | 2012-02-29 | 浙江精进药业有限公司 | Method for preparing high-purity gabapentin |
| CN104230735A (en) * | 2014-08-28 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of gabapentin |
| CN105612145A (en) * | 2013-10-22 | 2016-05-25 | Zach系统股份公司 | Process for preparing gabapentin |
| CN116693410A (en) * | 2023-06-08 | 2023-09-05 | 浙江竹子制药有限公司 | Preparation method of gabapentin with controllable particle size |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3928183A1 (en) * | 1989-08-25 | 1991-02-28 | Goedecke Ag | LACTAM-FREE CYCLIC AMINO ACIDS |
| US6531509B2 (en) * | 2000-06-16 | 2003-03-11 | Teva Pharmaceutical Industries Ltd. | Stable gabapentin containing more than 20 ppm of chlorine ion |
| CN1245379C (en) * | 2003-10-30 | 2006-03-15 | 曹桂东 | Method for preparing gabapentin |
| CN1290822C (en) * | 2005-03-11 | 2006-12-20 | 浙江九洲药业股份有限公司 | Process for preparing gabapentin |
| CN100395230C (en) * | 2005-07-04 | 2008-06-18 | 上海华理生物医药有限公司 | Method for preparing high-purity gahapentin |
-
2008
- 2008-08-19 CN CN2008100418604A patent/CN101462975B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363598A (en) * | 2011-11-25 | 2012-02-29 | 浙江精进药业有限公司 | Method for preparing high-purity gabapentin |
| CN102363598B (en) * | 2011-11-25 | 2014-02-12 | 浙江精进药业有限公司 | Method for preparing high-purity gabapentin |
| CN105612145A (en) * | 2013-10-22 | 2016-05-25 | Zach系统股份公司 | Process for preparing gabapentin |
| CN105612145B (en) * | 2013-10-22 | 2017-11-24 | F.I.S.-菲博利佳意大利合成面料股份公司 | The method for preparing Gabapentin |
| CN104230735A (en) * | 2014-08-28 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of gabapentin |
| CN116693410A (en) * | 2023-06-08 | 2023-09-05 | 浙江竹子制药有限公司 | Preparation method of gabapentin with controllable particle size |
| CN116693410B (en) * | 2023-06-08 | 2024-06-07 | 浙江竹子制药有限公司 | Preparation method of gabapentin with controllable particle size |
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| CN101462975B (en) | 2012-07-25 |
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Address after: 315800 Zhejiang city in Ningbo province Xin Qi Mingzhou West Road No. 501 building two Aquila A1 Patentee after: Ningbo Chemgoo Pharmaceutical Technology Innovation Limited Patentee after: Jiangxi with and medicine company limited-liability company Address before: 315800 Zhejiang city in Ningbo province Xin Qi Mingzhou West Road No. 501 building two Aquila A1 Patentee before: Ningbo Chemgoo Pharmaceutical Technology Innovation Limited Patentee before: Jiangxi Synergy Pharmaceuticals Co., Ltd. |
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