CN1245379C - Method for preparing gabapentin - Google Patents
Method for preparing gabapentin Download PDFInfo
- Publication number
- CN1245379C CN1245379C CN 200310108375 CN200310108375A CN1245379C CN 1245379 C CN1245379 C CN 1245379C CN 200310108375 CN200310108375 CN 200310108375 CN 200310108375 A CN200310108375 A CN 200310108375A CN 1245379 C CN1245379 C CN 1245379C
- Authority
- CN
- China
- Prior art keywords
- gabapentin
- heating
- cooled
- add
- room temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a technological method for preparing gabapentin from gabapentin hydrochloride. The present invention comprises the following steps: gabapentin hydrochloride is dissolved in ion exchange water, is neutralized by KHCO3, K2 CO3, NaHCO3 or Na2CO3 until the pH value reaches 7.14 to 8, stirred, heater in a water bath mode (the temperature material is controlled below 60DEG C), decompressed and concentrated to form solid completely; after an organic solvent capable of generating azeotropy with water is added to the solid, the solid is decompressed and steamed, and an anhyrous organic solvent capable of dissolving gabapentin is added so as to dissolve the gabapentin by heating; the gabapentin solution is cooled to room temperature and filtered; the filtrate is evaporated to dryness, dissolved in anhydrous alcohol by heating, back flowed and crystallized by cooling to obtain the crude gabapentin product; the crude gabapentin product is dissolved in anhydrous alcohol by heating, cooled to room temperature and filtered; the filtrate is concentrated, cooled, crystallized, filtered and washed by a small amount of anhydrous alcohol to obtain the gabapentin. The present invention has the characteristics of reasonable technological design, convenient operation, short periodicity, little equipment investment, low cost, easy industrial production, etc.
Description
Technical field
The present invention relates to a kind of method for making of gabapentin, belong to chemical industry synthetic technical field, especially relate to a kind of improvement such as processing method that prepare gabapentin with Gabapentin hydrochloride.
Background technology
Gabapentin, formal name used at school 1-(aminomethyl) Cyclohexaneacetic acid, invented by the American in 1977, be the main raw material of novel antiepileptic drug and anxiolytic, be used for show effect epileptic's the assisting therapy of generalization then of the epileptic of the limitation outbreak that conventional antiepileptic drug can not Satisfactory Control maybe can not tolerate and limitation.Find again that in the recent period gabapentin has following new purposes: a. to feeling sick effectively that chemotherapy caused; B. it is effective to treat the neuropathic pain syndromes; C. U.S. food and FAD (FDA) permission is used for the treatment of postherpetic neuralgia.Prior art mainly is to prepare the gabapentin aqueous solution by Gabapentin hydrochloride, and its method mainly contains: a. removes hydrochloric acid by ion exchange resin and obtains the gabapentin aqueous solution, and its production cycle of this method is longer, is unfavorable for suitability for industrialized production; B. use NaOH, KOH or NH
4Any aqueous solution neutralizes to add to cling to spray and decides the iso-electric point 7.14 of hydrochloride to gabapentin among the OH, gets the gabapentin aqueous solution by ionic membrane filtering salt again, and its equipment requirements of this method is very high; C. utilize dicyclohexylamine and HCl bonding force strong, the HCl in the Gabapentin hydrochloride aqueous solution is seized, form the dicyclohexylamine precipitation, filter, obtain the gabapentin aqueous solution, its raw material dicyclohexylamine of this method costs an arm and a leg, and it is uneconomical to be used for industrial production.Then, three kinds of methods all are the moisture in the evaporate to dryness gabapentin aqueous solution, obtain the gabapentin crude product, re-refine finished product, their yield is between 72～82%, its yield is lower.
Summary of the invention
The present invention solves: prior art prepares the method for gabapentin with Gabapentin hydrochloride, exists or the production cycle is long or equipment requirements is high or expensive raw material price and yield are low etc. technical problem; A kind of technological design is reasonable, easy and simple to handle, with short production cycle, facility investment is few, cost is low thereby provide, and yield is higher relatively, is easy to the preparation method of the gabapentin of suitability for industrialized production.
Above-mentioned technical problem of the present invention is mainly solved by following technical proposals: it is water-soluble clear earlier Gabapentin hydrochloride to be added ion-exchange, uses KHCO
3, K
2CO
3, NaHCO
3Or Na
2CO
3Any is neutralized to PH7.14～8, stir, heating in water bath, temperature of charge is controlled at below 60 ℃, is evaporated to whole one-tenth solids, add again can with water generates azeotropic organic solvent such as methyl alcohol or ethanol (carboxylic acid series is except amine series), decompression is heavily steamed, add anhydrous organic solvent such as methyl alcohol or ethanol (carboxylic acid series is except the amine series) heating for dissolving that to dissolve gabapentin then, be cooled to room temperature, filter, the filtrate evaporate to dryness is (when in the filtrate during moisture content less, filtrate directly can be concentrated, crystallisation by cooling filters, dry gabapentin), then add the alcohols heating for dissolving, reflux, crystallisation by cooling gets the gabapentin crude product; The gabapentin crude product is added anhydrous alcohols heating for dissolving, be cooled to room temperature, filter, filtrate concentrates cooling, and crystallization is filtered, and washes with a small amount of anhydrous alcohols, gets gabapentin.In order to obtain more highly purified gabapentin, the gabapentin of gained can be carried out recrystallization.
As preferably, the described KHCO that uses
3, K
2CO
3, NaHCO
3Or Na
2CO
3Be preferably 7.2～7.5 with endpoint pH in any.
As preferably, described heating in water bath, temperature of charge are preferably 30～50 ℃.
The present invention also can adopt NaOH, KOH or NH
4In any of OH and the hydrochloric acid in the Gabapentin hydrochloride, but in must control and the pH value of terminal point be 7.14.KHCO wherein
3, K
2CO
3, NaHCO
3Or Na
2CO
3Be weakly alkaline, can not react with gabapentin, thus in and terminal point pH value a wider range, thereby in making and the operation of the HCl in the Gabapentin hydrochloride easier, be easy to suitability for industrialized production.Wherein filtration step can be removed most of salt.Wherein can refer to that mainly alcohol is serial, ketone is serial, ether is serial and methyl chloride is serial with water generates azeotropic organic solvent, the anhydrous organic solvent that wherein can dissolve gabapentin mainly refers to benzene series row, pure series and ketone series.Wherein remove by filter salt by crystallization, avoided prior art by ion-exchange-resin process desalt the acid problem the problem includes: production cycle is long or by ionic membrane filtering salt problem the problem includes: production unit has high input etc. problem.
Therefore, the present invention has that technological design is reasonable, easy and simple to handle, with short production cycle, facility investment is few, cost is low and be easy to characteristics such as suitability for industrialized production.Wherein adopt KHCO
3, K
2CO
3, NaHCO
3Or Na
2CO
3In and the hydrochloric acid in the Gabapentin hydrochloride because KHCO
3, K
2CO
3, NaHCO
3Or Na
2CO
3Be weakly alkaline, can not react with gabapentin, thus neutralization back pH value a wider range, thus the operation with HCl is easier in making, is easy to suitability for industrialized production.Remove by filter salt by crystallization, avoided prior art by ion-exchange-resin process desalt the acid problem the problem includes: production cycle is long or by ionic membrane filtering salt problem the problem includes: production unit has high input etc. problem.
Embodiment
Below by embodiment, and in conjunction with the accompanying drawings, technical scheme of the present invention is further described in detail.
Embodiment 1: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds KHCO
3, stirred about 30 minutes, do not produce to there being bubble, KHCO is surveyed in the solution clarification
3Between the pH value to 7.2 of neutralization solution～7.5, directly use heating in water bath, temperature of charge is controlled at below 50 ℃, is evaporated to whole one-tenth solids, then, add small amount of methanol, decompression is heavily steamed, and eliminates moisture as far as possible, add the 120ml anhydrous methanol, be heated to backflow, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate is reclaimed methyl alcohol, to being solid entirely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling, filter, wash with ethanol, dry crude product 16.2g; Crude product adds dehydrated alcohol, is heated to backflow, and dissolving is cooled to room temperature fully, filters, and filtrate decompression concentrates, and cooling is filtered, and washes with ethanol, dry gabapentin 15.5g, HPLC analyzes content 98.55%, 165～166 ℃ of fusing points, yield are 96.09%.
Embodiment 2: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds K
2CO
3, stirred about 30 minutes, do not produce to there being bubble, K is surveyed in the solution clarification
2CO
3Between the pH value to 7.2 of neutralization solution～7.5, directly use heating in water bath, temperature of charge is controlled at below 50 ℃, be evaporated to whole one-tenth solids, then, add small amount of methanol, decompression is heavily steamed, and eliminates moisture as far as possible, adds the 120ml anhydrous methanol, be heated to backflow, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate is reclaimed methyl alcohol, is solid entirely extremely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling filters, wash with ethanol, dry crude product 16.1g, crude product adds dehydrated alcohol, be heated to backflow, dissolving is cooled to room temperature fully, filter, filtrate decompression concentrates, cooling, filter, wash with ethanol, dry gabapentin 15.45g, HPLC analyzes content 98.37%, 165～166 ℃ of fusing points, yield are 95.78%.
Embodiment 3: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds NaHCO
3, stirred about 30 minutes, do not produce to there being bubble, NaHCO is surveyed in the solution clarification
3Between the pH value to 7.2 of neutralization solution～7.5, directly use heating in water bath, temperature of charge is controlled at below 50 ℃, be evaporated to whole one-tenth solids, then, add small amount of ethanol, decompression is heavily steamed, and eliminates moisture as far as possible, adds the 120ml anhydrous methanol, be heated to backflow, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate is reclaimed methyl alcohol, is solid entirely extremely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling filters, wash with ethanol, dry crude product 16.2g, crude product adds dehydrated alcohol, be heated to backflow, dissolving is cooled to room temperature fully, filter, filtrate decompression concentrates, cooling, filter, wash with ethanol, dry gabapentin 15.4g, HPLC analyzes content 98.32%, 165～166 ℃ of fusing points, yield are 95.47%.
Embodiment 4: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds Na
2CO
3, stirred about 30 minutes, do not produce to there being bubble, Na is surveyed in the solution clarification
2CO
3Between the pH value to 7.2 of neutralization solution～7.5, directly use heating in water bath, temperature of charge is controlled at below 60 ℃, be evaporated to whole one-tenth solids, then, add small amount of ethanol, decompression is heavily steamed, and eliminates moisture as far as possible, adds the 120ml anhydrous methanol, be heated to backflow, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate is reclaimed methyl alcohol, is solid entirely extremely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling filters, wash with ethanol, dry crude product 16.3g, crude product adds dehydrated alcohol, be heated to backflow, dissolving is cooled to room temperature fully, filter, filtrate decompression concentrates, cooling, filter, wash with ethanol, dry gabapentin 15.4g, HPLC analyzes content 98.21%, 165～166 ℃ of fusing points, yield are 95.47%.
Embodiment 5: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds KHCO
3, stirred about 30 minutes, do not produce to there being bubble, KHCO is surveyed in the solution clarification
3Between the pH value to 7.2 of neutralization solution～7.5, directly use heating in water bath, temperature of charge is controlled at below 50 ℃, be evaporated to whole one-tenth solids, then, add small amount of toluene, decompression is heavily steamed, and eliminates moisture as far as possible, adds the 150ml dehydrated alcohol, be heated to backflow,, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate concentrates recovery part ethanol, to being solid entirely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling, filter, wash with ethanol, dry crude product 16.2g, crude product adds dehydrated alcohol, is heated to backflow, and dissolving fully, be cooled to room temperature, filter, filtrate decompression concentrates, cooling is filtered, and washes with ethanol, dry gabapentin 15.6g, HPLC analyzes content 98.51%, and 165～166 ℃ of fusing points, yield are 96.71%.
Embodiment 6: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds KHCO
3, stirred about 30 minutes, do not produce to there being bubble, KHCO is surveyed in the solution clarification
3Between the pH value to 7.2 of neutralization solution～7.5, directly use heating in water bath, temperature of charge is controlled at below 50 ℃, be evaporated to whole one-tenth solids, then, add small amount of toluene, decompression is heavily steamed, and eliminates moisture as far as possible, adds the 100ml anhydrous propanone, be heated to backflow,, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate concentrates recovery part ethanol, to being solid entirely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling filters, and washes with ethanol, dry crude product 16.1g, crude product adds dehydrated alcohol, is heated to backflow, dissolving is cooled to room temperature fully, filters, filtrate decompression concentrates, and cooling is filtered, wash with ethanol, dry gabapentin 15.5g, HPLC analyzes content 98.50%, 165～166 ℃ of fusing points, yield are 96.09%.
Embodiment 7: get Gabapentin hydrochloride 20g, it is molten clear to add ion exchanged water 50g, adds KHCO
3, stirred about 30 minutes, do not produce to there being bubble, KHCO is surveyed in the solution clarification
3Between the pH value to 7.5 of neutralization solution～8.0, directly use heating in water bath, temperature of charge is controlled at below 50 ℃, be evaporated to whole one-tenth solids, then, add small amount of acetone, decompression is heavily steamed, and eliminates moisture as far as possible, adds 50ml ether and 100ml ethanol, be heated to backflow,, be incubated 20 minutes, be cooled to room temperature, remove by filter most salt, filtrate is reclaimed methyl alcohol, to being solid entirely, add dehydrated alcohol and be heated to backflow, crystallisation by cooling, filter, wash with ethanol, dry crude product 16.1g, crude product adds dehydrated alcohol, is heated to backflow, and dissolving fully, be cooled to room temperature, filter, filtrate decompression concentrates, cooling is filtered, and washes with ethanol, dry gabapentin 15.4g, HPLC analyzes content 98.32%, and 165～166 ℃ of fusing points, yield are 95.47%.
In order to obtain more highly purified gabapentin, the gabapentin of gained can be carried out recrystallization: get above-mentioned gabapentin 10g,, carry out recrystallization with anhydrous methanol 80ml and Virahol 40ml heating for dissolving, can get 9.8g content greater than 99.5% gabapentin, 166 ℃-167 ℃ of fusing points.
Claims (3)
1. the method for making of a gabapentin is characterized in that its preparation process is as follows:
(1) to add ion-exchange water-soluble clear for Gabapentin hydrochloride, uses KHCO
3, K
2CO
3, NaHCO
3Or Na
2CO
3Any is neutralized to PH7.14～8, stirs, and heating in water bath, temperature of charge are controlled at below 60 ℃, are evaporated to whole one-tenth solids;
(2) add organic solvent methanol or ethanol, decompression is heavily steamed;
(3) add anhydrous organic solvent methyl alcohol or ethanol, heating for dissolving is cooled to room temperature, filters the filtrate evaporate to dryness;
(4) add the alcohols heating for dissolving, reflux, crystallisation by cooling gets the gabapentin crude product;
(5) the gabapentin crude product is added anhydrous alcohols heating for dissolving, be cooled to room temperature, filter, filtrate concentrates cooling, and crystallization is filtered, and washes with a small amount of anhydrous alcohols, gets gabapentin.
2. the method for making of gabapentin according to claim 1 is characterized in that the described KHCO of using
3, K
2CO
3, NaHCO
3Or Na
2CO
3PH value after any neutralization is 7.2～7.5.
3. the method for making of gabapentin according to claim 1 is characterized in that described temperature of charge is 30～50 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310108375 CN1245379C (en) | 2003-10-30 | 2003-10-30 | Method for preparing gabapentin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310108375 CN1245379C (en) | 2003-10-30 | 2003-10-30 | Method for preparing gabapentin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1539815A CN1539815A (en) | 2004-10-27 |
| CN1245379C true CN1245379C (en) | 2006-03-15 |
Family
ID=34334634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200310108375 Expired - Fee Related CN1245379C (en) | 2003-10-30 | 2003-10-30 | Method for preparing gabapentin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1245379C (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN100398513C (en) * | 2006-06-12 | 2008-07-02 | 浙江手心医药化学品有限公司 | Production of gabapendin |
| CN101462975B (en) * | 2008-08-19 | 2012-07-25 | 宁波九胜创新医药科技有限公司 | Preparation of 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 |
| US9320725B2 (en) * | 2012-05-18 | 2016-04-26 | Gruenenthal Gmbh | Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and a gabapentinoid |
| US20130310385A1 (en) | 2012-05-18 | 2013-11-21 | Gruenenthal Gmbh | Pharmaceutical Composition Comprising (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine and Antidepressants |
| US9345689B2 (en) | 2012-05-18 | 2016-05-24 | Gruenenthal Gmbh | Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N, N-dimethyl-4-phenyl-4,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and an anticonvulsant |
| CN107235850B (en) * | 2017-05-31 | 2019-07-26 | 浙江工业大学 | The method for directly synthesizing Gabapentin using 1- cyanocyclohexanoic guanidine-acetic acid |
-
2003
- 2003-10-30 CN CN 200310108375 patent/CN1245379C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1539815A (en) | 2004-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5814946B2 (en) | Method for producing succinic acid | |
| JP2018048114A (en) | Circulation method for producing taurine | |
| JP2021172652A (en) | Method and system for preparing high-purity taurine and salts | |
| CN109134287B (en) | Purification method of byproduct sodium chloride in betaine or betaine hydrochloride production | |
| CN104003830A (en) | Method for separating amino acid and iminodicarboxylic acid from aqueous solution of alkali metal salt of amino acid | |
| CN1245379C (en) | Method for preparing gabapentin | |
| CN116535338B (en) | Potassium salt recycling process in production process of D, L-methionine | |
| CN103265443B (en) | Industrial production method of high-purity iminodiacetic acid | |
| CN111393281A (en) | Environment-friendly clean production method of high-purity glycolic acid | |
| CN109970543B (en) | Method for recycling acyclovir condensation by-product and solvent | |
| CN100395230C (en) | Method for preparing high-purity gahapentin | |
| MXPA03004775A (en) | A process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid. | |
| CN1290822C (en) | Process for preparing gabapentin | |
| CN110642765A (en) | Synthesis method of D-p-methylsulfonyl phenyl serine ethyl ester | |
| CN113861056A (en) | Synthetic method of hydrophilic micromolecule amino acid | |
| JPS60217897A (en) | Method for separating and purifying lactic acid | |
| EP1727784B1 (en) | Improved process for preparation of gabapentin | |
| CN111620774A (en) | Production method for preparing high-purity solid malonic acid from calcium malonate | |
| CN115894553B (en) | Method for separating and purifying glufosinate | |
| CN112811647B (en) | Method for treating waste liquid in DL-methionine production | |
| CN110615749A (en) | Method for treating waste liquid from production of N-acetylcysteine | |
| KR101395558B1 (en) | Refining method of quinolinic acid | |
| CN117165960B (en) | Method for purifying crude ammonium fluoride | |
| JP2003212829A (en) | Method for purifying glycine | |
| JP2017137243A (en) | Manufacturing method of 2-nitro-4-methylsulfonyl benzoate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Quzhou Weirong Pharmaceutical & Chemical Co., Ltd. Assignor: Cao Guidong Contract fulfillment period: 2008.1.15 to 2013.1.14 contract change Contract record no.: 2009330000518 Denomination of invention: Method for preparing gabapentin Granted publication date: 20060315 License type: Exclusive license Record date: 2009.3.23 |
|
| LIC | Patent licence contract for exploitation submitted for record |
Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.1.15 TO 2013.1.14; CHANGE OF CONTRACT Name of requester: QUZHOU WEIRONG PHARMACEUTICAL + CHEMICAL CO., LTD. Effective date: 20090323 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20060315 Termination date: 20151030 |
|
| EXPY | Termination of patent right or utility model |