CN102363598A - Method for preparing high-purity gabapentin - Google Patents
Method for preparing high-purity gabapentin Download PDFInfo
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Abstract
The invention discloses a method for preparing high-purity gabapentin, which comprises the following steps: 1) subjecting 2-aza-spiro[4,5]-3-decanone to reflux acidolysis in strong acid or aqueous solution of strong acid under pressure and obtaining gabapentin strong acid salt and acidolysis mother solution; 2) recycling the obtained acidolysis mother solution for preparing gabapentin strong acid salt; 3) repeating the step 2); 4) obtaining gabapentin strong acid salt obtained by the two steps and preparing coarse gabapentin; and 5) dissolving the coarse gabapentin in aqueous solution of lower alcohol, distilling under reduced pressure and recrystallizing. The high-purity gabapentin can be obtained by using the method, and the method has the characteristics of high yield, low cost and the like.
Description
Technical field
The present invention relates to a kind of preparation technology's method of high-purity gahapentin, i.e. preparation technology's method of 1-(methylamino-) Cyclohexaneacetic acid belongs to the technical field of medication preparation.
Background technology
Gabapentin (Gabapentin); Trade(brand)name Neurotin; Chemical name 1-(methylamino-) Cyclohexaneacetic acid, (GABA) is similar for its molecular structure and γ-An Jidingsuan, the earliest by U.S. Warner-Lambert company successful development; Went on the market as a kind of epilepsy ancillary drug in Britain first in 1993, and go on the market in the U.S. in next year acquisition FDA (Food and Drug Adminstration) (FDA) approval.Find in clinical study that subsequently gabapentin also has significant curative effect to multiple chronic pain; Have simultaneously without hepatic metabolism; Reasons such as untoward reaction is little, and conformability is good, the treatment neurogenic pain is used it in FDA approval in 2002; But up to now, relevant its epilepsy and analgesic activity really cutter system also still imperfectly understand.Since its listing, world's total sales volume is soaring continuously, and account for anti-insane medicine market than large portion, still have the trend of rising.Gabapentin compound patent expires, and many countries have carried out the value research to this product, and the bulk drug demand in the whole world is high, has the wide development prospect.
At present, the synthetic process of gabapentin is more, mainly contains following several kinds:
1, patent WO2006090208 prepares the gabapentin hydrobromate with the Hydrogen bromide acidolysis, and water and acetone are made solvent; Diethylamine transfers pH value to neutral, and cooling is filtered and separated out the gabapentin bullion; Methanol aqueous solution refluxes and dissolves clearly, adds Virahol and separates out the gabapentin elaboration.This compound method will be used more Hydrogen bromide and organic bases, and the spent acid of generation is more, and cost is higher, and yield and purity are all not high.With organic basess such as dicyclohexylamine, N-ethyl-Diisopropylamine and triethylamines, not only cost an arm and a leg among patent US2004063997, patent EP1468985, the patent US2008207945, be unfavorable for industrial production, also produce more waste water.
2, patent US5693845, WO2007129286,1-cyanocyclohexanoic base acetonitrile are in toluene, alcoholic solution, and dry hydrogen chloride compressive reaction, and removed excessive solvent and gas is transferred the PH washing, steam desolventize 1-cyanic acid-cyclohexyl acetic acid ethyl ester.1-cyanic acid-cyclohexyl acetic acid ethyl ester reacting by heating under alkaline condition, through the raney ni catalysis hydrogenation, glacial acetic acid transfers PH to neutral, separates out the gabapentin bullion, gets the gabapentin elaboration through methyl alcohol, water, Virahol recrystallization.At first, this method is raw materials used to be difficult to obtain, and existing market does not have the technical grade sale, can increase cost virtually; Secondly, the waste gas of generation must absorb by a large amount of alkali lye, and step is more, and yield is obviously lower.
3, patent WO0234709 adopts 1, and 1-cyclohexyl-oxalic acid monoamide is a raw material; Through Hofmann degradation, transfer different PH, use n-butanol extraction; Merge n-butanol layer, cross ion exchange resin, with 28% ammoniacal liquor wash-out; Solvent evaporated prepares the gabapentin elaboration with methyl alcohol, water, Virahol recrystallization.Be easy to generate a large amount of impurity in this process degradation system, the operating process of no intermediate purification, its purity does not reach requirement; The process of crossing ion exchange resin in the patent is complicated bothersome, is unfavorable for large-scale industrialization production.Patent WO2005092837 makes improvements, but still needs labor soda acid and purity not high.
4, patent US2003009055, starting raw material is a pimelinketone, under the alkaline condition, refluxes several hours in the normal hexane, obtains the cyclohexyl acetonitrile.Cyclohexyl acetonitrile and Nitromethane 99Min. are under alkaline condition, and reacting by heating number hour obtains 1-nitre methyl-cyclohexyl base acetonitrile.The carbon reduction of product process palladium, alkaline condition refluxed, the Raney's nickel hydrogenating reduction, the strong acid condition refluxed, the water layer evaporate to dryness adds the crust hydrochloride with acetone making beating preparation, and after ion exchange resin, cost is very high, complex operation.
5, patent US2007287861, with 1,1-cyclohexyl-oxalic acid monoamide is a raw material, through Hofmann degradation, transfers pH value, preparation 2-azepine-spiral shell [4,5]-3-decanone refluxes.The too high meeting of temperature causes that foreign matter content is high in the reaction process, finally can influence the purity of finished product; 2-azepine-spiral shell [4,5]-3-decanone and strong acid mol ratio are by 2～15: 1 acidolysis prepares Gabapentin hydrochloride, and the acidolysis mother liquor neutralizes with alkali lye, and the alkaline condition refluxed reclaims 2-azepine-spiral shell [4,5]-3-decanone, strong acid, highly basic large usage quantity; Gabapentin hydrochloride prepares the process that bullion does not have the organic solvent purifying, and purity is high not enough; It is 73.4% (with respect to 2-azepine-spiral shell [4,5]-3-decanone) that 2-azepine-spiral shell [4,5]-3-decanone prepares gabapentin elaboration total recovery, and purity is 99.8% (HPLC), and yield and purity all await further raising.
Summary of the invention
The technical problem that the present invention will solve provides the preparation method of the high-purity gahapentin that a kind of purity is high, yield is high, cost is low.
In order to solve the problems of the technologies described above, the present invention provides a kind of preparation method of high-purity gahapentin, may further comprise the steps:
1), 2-azepine-spiral shell [4,5]-3-decanone is forced into 0.1～5MPa backflow acidolysis 1～8 hour in strong acid or strong acid aqueous solution, in ice-water bath, stirred then 2～4 hours; Suction filtration gets gabapentin strong acid salt and acidolysis mother liquor respectively;
The mol ratio of 2-azepine-spiral shell [4,5]-3-decanone and strong acid is 1: 1～20;
2), the acidolysis mother liquor is used to apply mechanically preparation gabapentin strong acid salt:
After in the acidolysis mother liquor of above-mentioned steps gained, adding strong acid, be forced into 0.1～5MPa backflow acidolysis 1～8 hour, in ice-water bath, continue then to stir 2～4 hours with 2-azepine-spiral shell [4,5]-3-decanone; Suction filtration gets gabapentin strong acid salt and acidolysis mother liquor once more respectively;
The ratio of the molar weight sum of strong acid is 1: 1～20 in the molar weight of 2-azepine-spiral shell [4,5]-3-decanone and molar weight and the acidolysis mother liquor of adding strong acid;
That is, in the acidolysis mother liquor of above-mentioned steps gained, add strong acid after, the ratio of the molar weight of the integral molar quantity of the strong acid of gained and 2-azepine-spiral shell [4,5]-3-decanone is 1～20: 1;
3), repeat above-mentioned steps 2) 1～5 time, perhaps repeat above-mentioned steps 2 always) be lower than at 18% o'clock until the mass content of strong acid in the acidolysis mother liquor of measuring gained, just get into following step 4); (that is, no longer applying mechanically this acidolysis mother liquor);
4), merge the above-mentioned institute gabapentin strong acid salt of gained in steps, prepare the gabapentin bullion, carry out following steps successively:
A, in the gabapentin strong acid salt, add purified water, make the dissolving of gabapentin strong acid salt thereby be warming up to 30～70 ℃; The mass ratio of said gabapentin strong acid salt and water is 1: 0.5～2.5;
B, add gac,, thereby realize that decolouring handles in 30～70 ℃ of insulated and stirred 0.2～1h as discoloring agent; The mass ratio of said discoloring agent and gabapentin strong acid salt is 1%～8%;
C, suction filtration add organic solvent in the filtrating of gained, extremely neutral with adjusting PH with base earlier, in ice-water bath, stir insulation 2～4h then;
D, the neutralization reaction gains of step C gained are carried out suction filtration,, obtain the gabapentin bullion with organic solvent drip washing filter cake;
5), the gabapentin bullion is dissolved in the aqueous solution of lower alcohol,, obtain gabapentin through removing (mixed solvent of a spot of lower alcohol and water, that is, the aqueous solution of lower alcohol) and recrystallization under reduced pressure.
Improvement as the preparation method of high-purity gahapentin of the present invention: strong acid is inorganic acid or organic acid.Inorganic acid is: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or sulfuric acid; Organic acid is: trichoroacetic acid(TCA), trifluoroacetic acid, methylsulfonic acid or Phenylsulfonic acid.
Further improvement as the preparation method of high-purity gahapentin of the present invention: step 1) and step 2) in: the mol ratio of 2-azepine-spiral shell [4,5]-3-decanone and water is 1: 0.1～40.
Further improvement as the preparation method of high-purity gahapentin of the present invention: in the C step of step 4): the alkali of regulating pH is mineral alkali or organic bases.Mineral alkali is sodium hydroxide, Pottasium Hydroxide, yellow soda ash or salt of wormwood; Organic bases is sodium methylate, potassium methylate, triethylamine or diethylamine.
Further improvement as the preparation method of high-purity gahapentin of the present invention: the C step of step 4) and the organic solvent in the D step are ester class organic solvent or arene organic solvent.Ester class organic solvent is ethyl formate, ETHYLE ACETATE, propyl acetate or butylacetate etc.; The arene organic solvent is benzene, toluene or YLENE.
Further improvement as the preparation method of high-purity gahapentin of the present invention: the lower alcohol in the step 5) is at least a in methyl alcohol, ethanol, propyl alcohol and the Virahol.
Further improvement as the preparation method of high-purity gahapentin of the present invention: in the step 5): recrystallization temperature is 30～80 ℃ (preferred 60～78 ℃); The mass ratio of gabapentin bullion and water is 1: 0.1～5, with the mass ratio of lower alcohol is: 1: 1～20.
In step 5) of the present invention, the gabapentin bullion is put into the aqueous solution of lower alcohol, be warming up to 30～70 ℃ (preferred 35～45 ℃), thereby the gabapentin bullion can be dissolved in the aqueous solution of lower alcohol; When removing under reduced pressure, the decompression pressure-controlling 0～-0.5MPa, temperature is controlled at 35～65 ℃ (preferred 40～50 ℃).
The present invention is a raw material with commercial 2-azepine-spiral shell [4,5]-3-decanone, and its operational path such as Fig. 1 are said; Among Fig. 1:
(I): 2-azepine-spiral shell [4,5]-3-decanone
(II): 1-(methylamino-) Cyclohexaneacetic acid hydrochloride;
(III): 1-(methylamino-) Cyclohexaneacetic acid (gabapentin)
Among the preparation method in the present invention, preferred following data:
1, said step 1) and step 2) in: the mol ratio preferred 1: 3～9 of 2-azepine-spiral shell [4,5]-3-decanone and strong acid,, the preferred 0.5～1.5MPa of pressure, preferred 2～4 hours of reaction times;
2, in the A step of step 4): the mass ratio of gabapentin strong acid salt and water preferred 1: 1.2～1.8, preferred 40～50 ℃ of the temperature of intensification;
3, in the step 5): the mass ratio of gabapentin bullion and water preferred 1: 0.5～2.5; The mass ratio of gabapentin bullion and lower alcohol preferred 1: 1～8;
4, step 1), step 2) and step 3) in the preferred hydrochloric acid of strong acid;
5, being used in the C step of step 4) regulated the preferred sodium hydroxide of alkali of pH value;
6, the C step of step 4) and the preferred butylacetate of organic solvent in the D step;
7, the preferred Virahol of the lower alcohol in the step 5), preferred 60～78 ℃ of recrystallization temperature.
Synthesis technique of the present invention has following advantage:
1), the pressurization acidolysis prepare Gabapentin hydrochloride, simple to operate, weak point consuming time has improved reaction yield, the technology cost is lower, the hydrochloride purity of preparation is higher;
2), the strong acid consumption is few, reduced the discharging of trade effluent, the water yield is less in the system, yield also improves thereupon, the science environmental protection;
3), applying mechanically of acidolysis mother liquor can utilize the material in spent acid and the mother liquor once again, reduced the discharging of waste water, turns waste into wealth, and improved the total recovery of reaction, reduced production cost;
4), Gabapentin hydrochloride prepares in the gabapentin bullion process, adds a small amount of organic solvent dexterously, reduces purification step, improves bullion purity and yield, reached the effect of preparation high-purity gahapentin.
5), for the method for informing in the background technology 5; The topmost advantage of the present invention is: pressurization has reduced the consumption of strong acid; Apply mechanically the acidolysis mother liquor, and in preparation bullion process, add organic solvent and carry out purifying, total recovery can rise (for the total recovery of method 5) more than 5%; Prepared elaboration purity is up to more than 99.9%, and single impurity is less than 0.05%.
Therefore, adopt the gabapentin purity of the present invention's preparation high, yield is high, cost is low, easy and simple to handle, be convenient to commercial scale prodn, technological design rationally, science, safety and environmental protection.
Description of drawings
Do further explain below in conjunction with the accompanying drawing specific embodiments of the invention.
Fig. 1 is that the present invention is the process route chart of raw material with 2-azepine-spiral shell [4,5]-3-decanone.
Embodiment
In following examples, there is not the % that specifies to be quality %.
Embodiment 1: a kind of preparation method of high-purity gahapentin, carry out following steps successively:
1), the preparation of Gabapentin hydrochloride:
In the 500ml autoclave, add 2-azepine-spiral shell [4,5]-3-decanone 40g, water 40g, refining hydrochloric acid 100g (refining hydrochloric acid is that mass concentration is 36% aqueous hydrochloric acid), the capping system is forced into 0.8MPa, is warming up to backflow.Room temperature (with tap water processings of lowering the temperature) is slowly reduced in reaction behind the 3h, and ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃ of stirring 3h; Suction filtration obtains the wet article 59.9g of Gabapentin hydrochloride (surveying moisture content 211%, yield 87.2%); 45 ℃ of oven-dried weight 49.8g, purity 98.4% (HPLC); Get acidolysis mother liquor 109.0g, this acidolysis mother liquor is through titration (promptly adopting volumetry to survey the mass content of hydrochloric acid), and the mass content of its hydrochloric acid is 22.6%.
2), the applying mechanically of acidolysis mother liquor ():
In the 500ml autoclave, add 2-azepine-spiral shell [4,5]-3-decanone 40g, above-mentioned steps 1) the acidolysis mother liquor 109.0g of gained, add refining hydrochloric acid 32.5g, the capping system is forced into 0.8MPa, is warming up to backflow.Slowly reduce to room temperature behind the reaction 3h, ice-water bath continues to be cooled to 0～4 ℃, and in 0～4 ℃ of stirring 3h, suction filtration obtains the wet article 68.8g of Gabapentin hydrochloride (surveying moisture content 20.3%, yield 1011%), 45 ℃ of oven-dried weight 57.0g, purity 98.9% (HPLC); Get acidolysis mother liquor 103.3g, the hydrochloric acid mass content is 23.2% in this acidolysis mother liquor.
3), the applying mechanically of acidolysis mother liquor (two):
In the 500ml autoclave, add 2-azepine-spiral shell [4,5]-3-decanone 40g, above-mentioned steps 2) the acidolysis mother liquor 103.3g of gained, add refining hydrochloric acid 32.7g, add water 4g.The capping system is forced into 0.8MPa, is warming up to backflow.Slowly reduce to room temperature behind the reaction 3h, ice-water bath continues to be cooled to 0～4 ℃, and in 0～4 ℃ of stirring 3h, suction filtration obtains the wet article 65.6g of Gabapentin hydrochloride (surveying moisture content 20.0%, yield 96.3%), 45 ℃ of oven-dried weight 55.8g, purity 98.7% (HPLC); Get acidolysis mother liquor 102.5g, the hydrochloric acid mass content is 23.7%.
Three step acidolysis, total recovery average near 95%.
4): the preparation of gabapentin bullion:
With above-mentioned steps 1)～Gabapentin hydrochloride of step 3) gained merges, amount to the Gabapentin hydrochloride of 162.6g.The 50g Gabapentin hydrochloride of getting wherein carries out following operation successively:
A), in 250ml four-hole reaction flask, add Gabapentin hydrochloride 50g, purified water 75g is warming up to 42 ℃, stirs Gabapentin hydrochloride is dissolved fully.
B), add 1g gac (as discoloring agent) decolouring, 42 ℃ of insulated and stirred 30 minutes;
C), suction filtration while hot, must filtrate and filter cake;
Available a small amount of (3～5ml) the purified water cleaning of filter cake (mainly containing gac, the water-fast particle of solid, trace iron ion etc.); The purpose of cleaning is in order to wash the material on the gac to come, and the cleaning of this filter cake also can be ignored and do not carry out.
D), add the 20g butylacetate, using mass concentration is that 35% sodium hydroxide solution transfers pH value to neutral, slowly reduces to room temperature, and ice-water bath continues to be cooled to 0～4 ℃, stirs 3h in 0～4 ℃ the filtrating of gained;
E), above-mentioned neutralization reaction gains are carried out suction filtration, with (3～5ml) ice (0～5 ℃) butylacetate drip washing filter cakes obtain gabapentin bullion weight in wet base 40.1g (surveying moisture content 8.6%, yield 93.6%), purity 99.7% (HPLC) on a small quantity; The filtrating standing demix is told organic phase butylacetate layer, and distillation back recovery set is used for this step.
5), the preparation of gabapentin elaboration
In 250ml four-hole reaction flask, add 40.1g gabapentin bullion, purified water 100g, Virahol 50g is warming up to 40 ℃; Insulated and stirred 30 minutes, decompression (about 0.1MPa) boils off about 50g solvent (mixture of Virahol and water) (for example to be 40～45 ℃) below 45 ℃, adds the 50g Virahol, and decompression below 45 ℃ boils off about 50g solvent again; Add the 200g Virahol, be warming up to 65 ℃, insulated and stirred 30 minutes; Slowly be cooled to room temperature, ice bath continues to be cooled to 0～4 ℃, stirs 3h in 0～4 ℃; Suction filtration is with (3～5ml) ice Virahol drip washing filter cakes obtain gabapentin elaboration weight in wet base 34.1g on a small quantity; 45 ℃ of oven-dried weight 33.4g, yield 92.7%, purity 99.9% (HPLC).
Warp all coincide with standard substance with the contrast of USS article, the liquid phase RT of product and ir spectra.Thereby the proof gains really are gabapentin.
In the foregoing description 1,
Use 2-azepine-spiral shell [4,5]-3-decanone 120g altogether, refining hydrochloric acid 165.2g can get gabapentin bullion 130.41g (surveying moisture content 8.6%), the final gabapentin elaboration 108.62g (always receiving 81%, purity 99.9%) that gets, and single impurity is less than 0.05%.
Comparative Examples 1, according to the method for patent US2007287861, use 2-azepine-spiral shell [4,5]-3-decanone 120g; Need refining hydrochloric acid 720g; Can get gabapentin bullion 103.7g (moisture content is disregarded), the final gabapentin elaboration 98.5g (total recovery 73.5%, purity 99.8%) that gets.
Step 1), the step 2 of Comparative Examples 2, cancellation the foregoing description 1) and step 3) in be forced into 0.8MPa, that is, change under normal pressure and carrying out.All the other are with embodiment 1.The final gabapentin elaboration 99.8g (total recovery 74%, purity 99.9%) that gets.
The preparation method of embodiment 2, a kind of high-purity gahapentin, carry out following steps successively:
1), the preparation of Gabapentin hydrochloride
In the 500ml autoclave, add 2-azepine-spiral shell [4,5]-3-decanone 40g, refining hydrochloric acid 140g, the capping system is forced into 0.5MPa, is warming up to backflow.Slowly reduce to room temperature behind the reaction 4h, ice-water bath continues to be cooled to 0～4 ℃, and in 0～4 ℃ of stirring 3h, suction filtration obtains the wet article 55.8g of Gabapentin hydrochloride (surveying moisture content 19.1%, yield 83.3%), 45 ℃ of oven-dried weight 47.8g, purity 98.0% (HPLC); Get acidolysis mother liquor 117.1g, salt acidometric titration content is 33.5% in this acidolysis mother liquor.
2), the applying mechanically of acidolysis mother liquor ():
In the 500ml autoclave, add 2-azepine-spiral shell [4,5]-3-decanone 40g, above-mentioned steps 1) the acidolysis mother liquor 117.1g of gained, add refining hydrochloric acid 32.5g, the capping system is forced into 0.5MPa, is warming up to backflow.Slowly reduce to room temperature behind the reaction 4h, ice-water bath continues to be cooled to 0～4 ℃, and in 0～4 ℃ of stirring 3h, suction filtration obtains the wet article 69.7g of Gabapentin hydrochloride (surveying moisture content 20.1%, yield 102.7%), 45 ℃ of oven-dried weight 58.0g, purity 98.6% (HPLC); Get acidolysis mother liquor 112.7g, salt acidometric titration content is 32.7% in this acidolysis mother liquor.
3), the applying mechanically of acidolysis mother liquor (two):
In the 500ml autoclave, add 2-azepine-spiral shell [4,5]-3-decanone 40g, above-mentioned steps 2) the acidolysis mother liquor 112.7g of gained, add refining hydrochloric acid 39.0g, the capping system is forced into 0.5MPa, is warming up to backflow.Slowly reduce to room temperature behind the reaction 4h, ice-water bath continues to be cooled to 0～4 ℃, and in 0～4 ℃ of stirring 3h, suction filtration obtains the wet article 62.5g of Gabapentin hydrochloride (surveying moisture content 19.9%, yield 92.1%), 45 ℃ of oven-dried weight 52.6g, purity 98.2% (HPLC); Get acidolysis mother liquor 121.3g, salt acidometric titration content is 31.1%.
Three step acidolysis, total recovery average 92.7%.
4), the preparation of gabapentin bullion
With above-mentioned steps 1)～Gabapentin hydrochloride of step 3) gained merges, amount to the Gabapentin hydrochloride of 158.4g.The 50g Gabapentin hydrochloride of getting wherein carries out following operation successively:
Repeat steps A among the embodiment 1)～C);
D), add 20g toluene, using mass concentration is that 35% sodium hydroxide solution transfers pH value to neutral, slowly reduces to room temperature, and ice-water bath continues to be cooled to 0～4 ℃, stirs 3h in 0～4 ℃ the filtrating of gained;
E), above-mentioned neutralization reaction gains are carried out suction filtration, with (3～5ml) ice toluene drip washing filter cakes obtain gabapentin bullion weight in wet base 40.4g (surveying moisture content 10.2%, yield 92.6%), purity 99.6% (HPLC) on a small quantity; The filtrating standing demix is told the organic phase toluene layer, and distillation back recovery set is used for this step.
5), the preparation of gabapentin elaboration
Repeat step 5) among the embodiment 1: obtain elaboration weight in wet base 34.4g, 45 ℃ of oven-dried weight 33.6g, purity 99.9% (HPLC).
In the foregoing description 2,
Use 2-azepine-spiral shell [4,5]-3-decanone 120g altogether, refining hydrochloric acid 211.5g; Can get gabapentin bullion 128.0g (surveying moisture content 10.2%); The final gabapentin elaboration 106.4g (total recovery 79.4%, purity 99.9%) that gets, single impurity is less than 0.05%.
The preparation method of embodiment 3, a kind of high-purity gahapentin is with step 1), step 2) and step 3) in pressure make 1.5MPa into; All the other are with embodiment 1.
Use 2-azepine-spiral shell [4,5]-3-decanone 120g altogether, refining hydrochloric acid 165.2g can get gabapentin bullion 127.8g (surveying moisture content 9.3%), the final gabapentin elaboration 105.0g (total recovery 78.3%, purity 99.9%) that gets, and single impurity is less than 0.05%.
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (10)
1. the preparation method of high-purity gahapentin is characterized in that may further comprise the steps:
1), 2-azepine-spiral shell [4,5]-3-decanone is forced into 0.1～5MPa backflow acidolysis 1～8 hour in strong acid or strong acid aqueous solution, in ice-water bath, stirred then 2～4 hours; Suction filtration gets gabapentin strong acid salt and acidolysis mother liquor respectively;
The mol ratio of said 2-azepine-spiral shell [4,5]-3-decanone and strong acid is 1: 1～20;
2), said acidolysis mother liquor is used to apply mechanically preparation gabapentin strong acid salt:
After in the acidolysis mother liquor of above-mentioned steps gained, adding strong acid, be forced into 0.1～5MPa backflow acidolysis 1～8 hour, in ice-water bath, stirred then 2～4 hours with 2-azepine-spiral shell [4,5]-3-decanone; Suction filtration gets gabapentin strong acid salt and acidolysis mother liquor once more respectively;
The ratio of the molar weight sum of strong acid is 1: 1～20 in the molar weight of 2-azepine-spiral shell [4,5]-3-decanone and molar weight and the acidolysis mother liquor of adding strong acid;
3), repeat above-mentioned steps 2) 1～5 time, perhaps repeat above-mentioned steps 2 always) be lower than at 18% o'clock until the mass content of strong acid in the acidolysis mother liquor of measuring gained, just get into following step 4);
4), merge the above-mentioned institute gabapentin strong acid salt of gained in steps, prepare the gabapentin bullion, carry out following steps successively:
A, in the gabapentin strong acid salt, add purified water, make the dissolving of gabapentin strong acid salt thereby be warming up to 30～70 ℃; The mass ratio of said gabapentin strong acid salt and water is 1: 0.5～2.5;
B, add gac,, thereby realize that decolouring handles in 30～70 ℃ of insulated and stirred 0.2～1h as discoloring agent; The mass ratio of said discoloring agent and gabapentin strong acid salt is 1%～8%;
C, suction filtration add organic solvent in the filtrating of gained, extremely neutral with adjusting PH with base earlier, in ice-water bath, stir insulation 2～4h then;
D, the neutralization reaction gains of step C gained are carried out suction filtration,, obtain the gabapentin bullion with organic solvent drip washing filter cake;
5), the gabapentin bullion is dissolved in the aqueous solution of lower alcohol,, obtain gabapentin through removing under reduced pressure and recrystallization.
2. the preparation method of high-purity gahapentin according to claim 1, it is characterized in that: said strong acid is inorganic acid or organic acid.
3. the preparation method of high-purity gahapentin according to claim 2 is characterized in that:
Said inorganic acid is: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or sulfuric acid;
Said organic acid is: trichoroacetic acid(TCA), trifluoroacetic acid, methylsulfonic acid or Phenylsulfonic acid.
4. the preparation method of high-purity gahapentin according to claim 3 is characterized in that: said step 1) and step 2) in: the mol ratio of 2-azepine-spiral shell [4,5]-3-decanone and water is 1: 0.1～40.
5. according to the preparation method of claim 3 or 4 described high-purity gahapentins, it is characterized in that: in the C step of said step 4): the alkali of said adjusting pH is mineral alkali or organic bases.
6. the preparation method of high-purity gahapentin according to claim 5, it is characterized in that: said mineral alkali is sodium hydroxide, Pottasium Hydroxide, yellow soda ash or salt of wormwood; Said organic bases is sodium methylate, potassium methylate, triethylamine or diethylamine.
7. the preparation method of high-purity gahapentin according to claim 6, it is characterized in that: the C step of said step 4) and the organic solvent in the D step are ester class organic solvent or arene organic solvent.
8. the preparation method of high-purity gahapentin according to claim 7, it is characterized in that: said ester class organic solvent is ethyl formate, ETHYLE ACETATE, propyl acetate or butylacetate etc.; Said arene organic solvent is benzene, toluene or YLENE.
9. the preparation method of high-purity gahapentin according to claim 8 is characterized in that: the lower alcohol in the said step 5) is at least a in methyl alcohol, ethanol, propyl alcohol and the Virahol.
10. the preparation method of high-purity gahapentin according to claim 9, it is characterized in that: in the said step 5): recrystallization temperature is 30～80 ℃; The mass ratio of gabapentin bullion and water is 1: 0.1～5, with the mass ratio of lower alcohol is: 1: 1～20.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230735A (en) * | 2014-08-28 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of gabapentin |
| CN105061242A (en) * | 2015-08-18 | 2015-11-18 | 太仓运通生物化工有限公司 | Gabapentin purification method |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998028255A1 (en) * | 1996-12-24 | 1998-07-02 | Teva Pharmaceutical Industries Ltd. | Preparation of gabapentin |
| WO2000001660A1 (en) * | 1998-07-03 | 2000-01-13 | Zambon Group S.P.A. | Process for the preparation of gabapentin |
| US6790986B1 (en) * | 2003-04-18 | 2004-09-14 | Farchemia S.R.L. | Process for the preparation of gabapentin free from inorganic acids anions |
| CN1539815A (en) * | 2003-10-30 | 2004-10-27 | 曹桂东 | Method for preparing gabapentin |
| US20050187295A1 (en) * | 2004-02-19 | 2005-08-25 | Surendra Kalyan | Processes for the preparation of gabapentin |
| CN1683322A (en) * | 2005-03-11 | 2005-10-19 | 浙江九洲药业股份有限公司 | Process for preparing gabapentin |
| CN1727329A (en) * | 2004-07-28 | 2006-02-01 | 长春吉大天元化学技术股份有限公司 | New method for synthesizing Gabapentin hydrochloride |
| CN1891684A (en) * | 2005-07-04 | 2007-01-10 | 上海华理生物医药有限公司 | Method for preparing high-purity gahapentin |
| CN1896050A (en) * | 2006-06-12 | 2007-01-17 | 浙江手心医药化学品有限公司 | Production of gabapendin |
| CN101462975A (en) * | 2008-08-19 | 2009-06-24 | 宁波经济技术开发区九胜创新医药工艺开发有限公司 | Preparation of high-purity gabapentin |
-
2011
- 2011-11-25 CN CN201110379862.6A patent/CN102363598B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998028255A1 (en) * | 1996-12-24 | 1998-07-02 | Teva Pharmaceutical Industries Ltd. | Preparation of gabapentin |
| WO2000001660A1 (en) * | 1998-07-03 | 2000-01-13 | Zambon Group S.P.A. | Process for the preparation of gabapentin |
| US6790986B1 (en) * | 2003-04-18 | 2004-09-14 | Farchemia S.R.L. | Process for the preparation of gabapentin free from inorganic acids anions |
| CN1539815A (en) * | 2003-10-30 | 2004-10-27 | 曹桂东 | Method for preparing gabapentin |
| US20050187295A1 (en) * | 2004-02-19 | 2005-08-25 | Surendra Kalyan | Processes for the preparation of gabapentin |
| CN1727329A (en) * | 2004-07-28 | 2006-02-01 | 长春吉大天元化学技术股份有限公司 | New method for synthesizing Gabapentin hydrochloride |
| CN1683322A (en) * | 2005-03-11 | 2005-10-19 | 浙江九洲药业股份有限公司 | Process for preparing gabapentin |
| CN1891684A (en) * | 2005-07-04 | 2007-01-10 | 上海华理生物医药有限公司 | Method for preparing high-purity gahapentin |
| CN1896050A (en) * | 2006-06-12 | 2007-01-17 | 浙江手心医药化学品有限公司 | Production of gabapendin |
| CN101462975A (en) * | 2008-08-19 | 2009-06-24 | 宁波经济技术开发区九胜创新医药工艺开发有限公司 | Preparation of high-purity gabapentin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230735A (en) * | 2014-08-28 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of gabapentin |
| CN105061242A (en) * | 2015-08-18 | 2015-11-18 | 太仓运通生物化工有限公司 | Gabapentin purification method |
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Denomination of invention: Preparation of high-purity gabapentin Effective date of registration: 20160824 Granted publication date: 20140212 Pledgee: Industrial Commercial Bank of China Ltd Taizhou Huangyan branch Pledgor: Zhejiang Excel Pharmaceutical Co., Ltd. Registration number: 2016330000059 |
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