CN1245379C

CN1245379C - Method for preparing gabapentin

Info

Publication number: CN1245379C
Application number: CN 200310108375
Authority: CN
Inventors: 曹桂东
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-10-30
Filing date: 2003-10-30
Publication date: 2006-03-15
Anticipated expiration: 2023-10-30
Also published as: CN1539815A

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

The method for making of gabapentin

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

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 ℃.