CN102363598B - Method for preparing high-purity gabapentin - Google Patents
Method for preparing high-purity gabapentin Download PDFInfo
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- CN102363598B CN102363598B CN201110379862.6A CN201110379862A CN102363598B CN 102363598 B CN102363598 B CN 102363598B CN 201110379862 A CN201110379862 A CN 201110379862A CN 102363598 B CN102363598 B CN 102363598B
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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 process of preparing of high-purity gahapentin, the process of preparing of 1-(methylamino-) Cyclohexaneacetic acid, belongs to technical field prepared by medicine.
Background technology
Gabapentin (Gabapentin), trade(brand)name Neurotin, chemical name 1-(methylamino-) Cyclohexaneacetic acid, (GABA) is similar for its molecular structure and γ-aminobutyric acid, by U.S. Warner-Lambert company, researched and developed successfully the earliest, within 1993, in Britain, as a kind of anti-epileptic ancillary drug, go on the market first, and go on the market in the U.S. in next year acquisition FDA (Food and Drug Adminstration) (FDA) approval.In clinical study, find that subsequently gabapentin also has significant curative effect to multiple chronic pain, have without hepatic metabolism simultaneously, untoward reaction is little, the reasons such as conformability is good, treatment neurogenic pain is used it in FDA approval in 2002, but up to now, the precise mechanism of relevant its anti-epileptic and analgesic activity also still imperfectly understands.Since its listing, world's total sales volume is soaring continuously, and account for anti-insane medicine market compared with large portion, still there is 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 wide DEVELOPMENT PROSPECT.
At present, the synthetic process of gabapentin is more, mainly contains following several:
1, patent WO2006090208, prepares gabapentin hydrobromate with Hydrogen bromide acidolysis, and water and acetone are made solvent, diethylamine adjusts pH value to neutral, cooling, filters and separates out gabapentin crude product, methanol aqueous solution refluxes molten clear, adds Virahol to separate out gabapentin fine work.This synthetic method will be with 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 expensive in patent US2004063997, patent EP1468985, patent US2008207945, be unfavorable for industrial production, also produce more waste water.
2, patent US5693845, WO2007129286,1-cyanocyclohexanoic base acetonitrile is in toluene, alcoholic solution, and dry hydrogen chloride compressive reaction, and removed excessive solvent and gas, adjusts PH washing, steams and desolventizes to obtain 1-cyano group-cyclohexyl acetic acid ethyl ester.1-cyano group-cyclohexyl acetic acid ethyl ester reacting by heating under alkaline condition, by raney ni catalysis hydrogenation, glacial acetic acid adjusts PH to neutral, separates out gabapentin crude product, through methyl alcohol, water, Virahol recrystallization, obtains gabapentin fine work.First, the method is raw materials used to be difficult to obtain, and existing market is sold without technical grade, virtually can increase cost; Secondly, the waste gas of generation is alkali liquor absorptions in a large number, and step is more, and yield is obviously lower.
3, patent WO0234709, adopt 1,1-cyclohexyl-oxalic acid monoamide is raw material, through Hofmann degradation, adjusts different PH, with n-butanol extraction, merge n-butanol layer, cross ion exchange resin, with 28% ammoniacal liquor wash-out, solvent evaporated, prepares gabapentin fine work with methyl alcohol, water, Virahol recrystallization.In this process degradation system, easily produce a large amount of impurity, without the operating process of intermediate purification, its purity does not reach requirement; The process complexity of crossing ion exchange resin in patent is bothersome, is unfavorable for large-scale industrialization production.Patent WO2005092837 makes improvements, but still need to expend a large amount of soda acids and purity is not high.
4, patent US2003009055, starting raw material is pimelinketone, under alkaline condition, in normal hexane, refluxes a few hours, obtains cyclohexyl acetonitrile.Cyclohexyl acetonitrile and Nitromethane 99Min., under alkaline condition, reacting by heating a few hours, obtain 1-nitre methyl-cyclohexyl base acetonitrile.Product is through refluxing under the reduction of palladium carbon, alkaline condition, and Raney's nickel hydrogenating reduction, refluxes under strong acid condition, and water layer evaporate to dryness adds bar hydrochloride with acetone making beating preparation, and after ion exchange resin, cost is very high, complex operation.
5, patent US2007287861, for raw material, through Hofmann degradation, adjusts pH value with 1,1-cyclohexyl-oxalic acid monoamide, and preparation 2-aza-spiro [4,5]-3-decanone refluxes.In reaction process, excess Temperature can cause that foreign matter content is high, finally can affect the purity of finished product; 2-aza-spiro [4,5]-3-decanone and strong acid mol ratio are by 2～15: Gabapentin hydrochloride is prepared in 1 acidolysis, and acidolysis mother liquor neutralizes with alkali lye, and alkaline condition flows back to next time receives 2-aza-spiro [4,5]-3-decanone, strong acid, highly basic large usage quantity; Gabapentin hydrochloride is prepared the process that crude product does not have organic solvent purifying, and purity is high not enough; It is 73.4% (with respect to 2-aza-spiro [4,5]-3-decanone) that 2-aza-spiro [4,5]-3-decanone is prepared gabapentin fine work total recovery, and purity is 99.8% (HPLC), and yield and purity all await further raising.
Summary of the invention
The technical problem to be solved in the present invention is to provide 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 invention provides a kind of preparation method of high-purity gahapentin, comprise the following steps:
1), 2-aza-spiro [4,5]-3-decanone is forced into 0.1～5MPa backflow acidolysis 1～8 hour in strong acid or strong acid aqueous solution, then in ice-water bath, stir 2～4 hours; Suction filtration, obtains respectively gabapentin strong acid salt and acidolysis mother liquor;
The mol ratio of 2-aza-spiro [4,5]-3-decanone and strong acid is 1: 1～20;
2), acidolysis mother liquor be used for applying mechanically prepare gabapentin strong acid salt:
In the acidolysis mother liquor of above-mentioned steps gained, add after strong acid, be forced into 0.1～5MPa backflow acidolysis 1～8 hour with 2-aza-spiro [4,5]-3-decanone, then in ice-water bath, continue to stir 2～4 hours; Suction filtration, obtains respectively gabapentin strong acid salt and acidolysis mother liquor again;
The molar weight of 2-aza-spiro [4,5]-3-decanone is 1: 1～20 with the ratio of adding the molar weight sum of strong acid in the molar weight of strong acid and acidolysis mother liquor;
That is, in the acidolysis mother liquor of above-mentioned steps gained, add after strong acid, the ratio of the molar weight of the integral molar quantity of the strong acid of gained and 2-aza-spiro [4,5]-3-decanone is 1～20: 1;
3), repeat above-mentioned steps 2) 1～5 time, or repeat above-mentioned steps 2 always) until after measured in the acidolysis mother liquor of gained the mass content of strong acid lower than 18% time, just enter following step 4); (that is, no longer applying mechanically this acidolysis mother liquor);
4), merge above-mentioned the gabapentin strong acid salt of gained in steps, prepare gabapentin crude product, carry out successively following steps:
A, in gabapentin strong acid salt, add purified water, thereby be warming up to 30～70 ℃, gabapentin strong acid salt is dissolved; The mass ratio of described gabapentin strong acid salt and water is 1: 0.5～2.5;
B, add the gac as discoloring agent, in 30～70 ℃ of insulated and stirred 0.2～1h, thereby realize decolouring, process; The mass ratio of described discoloring agent and gabapentin strong acid salt is 1%～8%;
C, suction filtration add organic solvent in the filtrate of gained, first extremely neutral with adjusting PH with base, then in ice-water bath, stir insulation 2～4h;
D, the neutralization reaction gains of step C gained are carried out to suction filtration, with organic solvent drip washing filter cake, obtain gabapentin crude product;
5), gabapentin crude product is dissolved in the aqueous solution of lower alcohol, (a small amount of lower alcohol and the mixed solvent of water, that is, the aqueous solution of lower alcohol) and recrystallization, obtain gabapentin through removing 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-aza-spiro [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 C step step 4): regulating the alkali of pH is mineral alkali or organic bases.Mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate 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: C step step 4) and the organic solvent in D step are ester class organic solvent or arene organic solvent.Ester class organic solvent is ethyl formate, ethyl acetate, propyl acetate or butylacetate etc.; Arene organic solvent is benzene, toluene or dimethylbenzene.
Further improvement as the preparation method of high-purity gahapentin of the present invention: the lower alcohol step 5) is at least one in methyl alcohol, ethanol, propyl alcohol and Virahol.
Further improvement as the preparation method of high-purity gahapentin of the present invention: step 5): recrystallization temperature is 30～80 ℃ (preferably 60～78 ℃); The mass ratio of gabapentin crude product and water is 1: 0.1～5, is: 1: 1～20 with the mass ratio of lower alcohol.
In step 5 of the present invention) in, gabapentin crude product is put into the aqueous solution of lower alcohol, be warming up to 30～70 ℃ (preferably 35～45 ℃), thereby gabapentin crude product can be dissolved in the aqueous solution of lower alcohol; When removing under reduced pressure, decompression pressure-controlling is at 0～-0.5MPa, and temperature is controlled at 35～65 ℃ (preferably 40～50 ℃).
The present invention is with commercial 2-aza-spiro [4,5]-3-decanone for raw material, and its operational path as described in Figure 1; In Fig. 1:
(I): 2-aza-spiro [4,5]-3-decanone
(II): 1-(methylamino-) Cyclohexaneacetic acid hydrochloride;
(III): 1-(methylamino-) Cyclohexaneacetic acid (gabapentin)
In preparation method in the present invention, preferred following data:
1, described step 1) and step 2) in: the mol ratio preferably 1: 3～9 of 2-aza-spiro [4,5]-3-decanone and strong acid,, pressure is 0.5～1.5MPa preferably, preferably 2～4 hours reaction times;
2, in A step step 4): the mass ratio of gabapentin strong acid salt and water preferably 1: 1.2～1.8, preferably 40～50 ℃ of the temperature of intensification;
3, step 5): the mass ratio of gabapentin crude product and water preferably 1: 0.5～2.5; The mass ratio of gabapentin crude product and lower alcohol preferably 1: 1～8;
4, step 1), step 2) and step 3) in the preferred hydrochloric acid of strong acid;
5, in C step step 4) for regulating the preferred sodium hydroxide of alkali of pH value;
6, C step step 4) and the preferred butylacetate of organic solvent in D step;
7, the preferred Virahol of lower alcohol step 5), preferably 60～78 ℃ of recrystallization temperatures.
Synthesis technique of the present invention, tool has the following advantages:
1), pressurization acidolysis prepare Gabapentin hydrochloride, simple to operate, consuming time short, improved reaction yield, process costs is lower, the hydrochloride purity of preparation is higher;
2), strong acid consumption is few, reduced the discharge of trade effluent, in system, the water yield is less, yield also improves thereupon, science environmental protection;
3), applying mechanically of acidolysis mother liquor can utilize once again to the material in spent acid and mother liquor, reduced the discharge of waste water, turns waste into wealth, and improved the total recovery of reaction, reduced production cost;
4), Gabapentin hydrochloride prepared in gabapentin crude product process, adds dexterously a small amount of organic solvent, reduces purification step, improves crude product purity and yield, reached the effect of preparing high-purity gahapentin.
5), for the method 5 of informing in background technology, the topmost advantage of the present invention is: pressurization has reduced the consumption of strong acid, apply mechanically acidolysis mother liquor, and in preparing crude product process, add organic solvent to carry out purifying, total recovery can rise more than 5% (for the total recovery of method 5), prepared fine work purity is up to more than 99.9%, and single impurity is less than 0.05%.
Therefore, the gabapentin purity that adopts the present invention to prepare is high, yield is high, cost is low, easy and simple to handle, be convenient to commercial scale production, technological design rationally, science, safety and environmental protection.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in further detail.
Fig. 1 is the present invention with the process route chart that 2-aza-spiro [4,5]-3-decanone is raw material.
Embodiment
In following examples, do not have the % of special instruction to be quality %.
Embodiment 1: a kind of preparation method of high-purity gahapentin, carries out following steps successively:
1), the preparation of Gabapentin hydrochloride:
In 500ml autoclave, add 2-aza-spiro [4,5]-3-decanone 40g, water 40g, refining hydrochloric acid 100g (refining hydrochloric acid is that mass concentration is 36% aqueous hydrochloric acid), capping system, is forced into 0.8MPa, is warming up to backflow.Room temperature (with the tap water processing of lowering the temperature) is slowly down in reaction after 3h, ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stir 3h, suction filtration, obtain Gabapentin hydrochloride wet product 59.9g and (survey moisture content 211%, yield 87.2%), 45 ℃ of oven-dried weight 49.8g, purity 98.4% (HPLC); Obtain acidolysis mother liquor 109.0g, this acidolysis mother liquor is through titration (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 500ml autoclave, add 2-aza-spiro [4,5]-3-decanone 40g, above-mentioned steps 1) the acidolysis mother liquor 109.0g of gained, add refining hydrochloric acid 32.5g, capping system, is forced into 0.8MPa, is warming up to backflow.After reaction 3h, be slowly down to room temperature, ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h, suction filtration, obtains Gabapentin hydrochloride wet product 68.8g (surveying moisture content 20.3%, yield 1011%), 45 ℃ of oven-dried weight 57.0g, purity 98.9% (HPLC); Obtain acidolysis mother liquor 103.3g, in this acidolysis mother liquor, hydrochloric acid mass content is 23.2%.
3), the applying mechanically of acidolysis mother liquor (two):
In 500ml autoclave, add 2-aza-spiro [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.Capping system, is forced into 0.8MPa, is warming up to backflow.After reaction 3h, be slowly down to room temperature, ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h, suction filtration, obtains Gabapentin hydrochloride wet product 65.6g (surveying moisture content 20.0%, yield 96.3%), 45 ℃ of oven-dried weight 55.8g, purity 98.7% (HPLC); Obtain acidolysis mother liquor 102.5g, hydrochloric acid mass content is 23.7%.
Three step acidolysis, total recovery average nearly 95%.
4): the preparation of gabapentin crude product:
By above-mentioned steps 1)～step 3) Gabapentin hydrochloride of gained merges, and amounts to obtain 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 completely.
B), add 1g gac (as discoloring agent) decolouring, 42 ℃ of insulated and stirred 30 minutes;
C), suction filtration while hot, obtain filtrate and filter cake;
Available a small amount of (3～5ml) purified water of filter cake (mainly containing gac, the water-fast particle of solid, trace iron ion etc.) is cleaned; The object of cleaning is that the cleaning of this filter cake also can be ignored and not carry out for the material on gac is washed.
D), the filtrate of gained, add 20g butylacetate, the sodium hydroxide solution that is 35% by mass concentration adjusts pH value to neutral, is slowly down to room temperature, and ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h;
E), above-mentioned neutralization reaction gains are carried out to suction filtration, with a small amount of (3～5ml) ice (0～5 ℃) butylacetate drip washing filter cake, obtain gabapentin crude product weight in wet base 40.1g (surveying moisture content 8.6%, yield 93.6%), purity 99.7% (HPLC); Filtrate stratification, separates organic phase butylacetate layer, and after distillation, recovery is in this step.
5), the preparation of gabapentin fine work
In 250ml four-hole reaction flask, add 40.1g gabapentin crude product, purified water 100g, Virahol 50g, be warming up to 40 ℃, insulated and stirred 30 minutes, 45 ℃ of following (being for example 40～45 ℃) decompressions (0.1MPa left and right) boil off about 50g solvent (mixture of Virahol and water), add 50g Virahol, 45 ℃ of following decompressions boil off about 50g solvent again, add 200g Virahol, be warming up to 65 ℃, insulated and stirred 30 minutes, slow cooling is to room temperature, ice bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stir 3h, suction filtration, with a small amount of (3～5ml) ice Virahol drip washing filter cake, obtain gabapentin fine work weight in wet base 34.1g, 45 ℃ of oven-dried weight 33.4g, yield 92.7%, purity 99.9% (HPLC).
Through contrasting with USS product, the liquid phase retention time of product and infrared spectra all coincide with standard substance.Thereby proof gains are really gabapentin.
In above-described embodiment 1,
Use altogether 2-aza-spiro [4,5]-3-decanone 120g, refining hydrochloric acid 165.2g, can obtain gabapentin crude product 130.41g (surveying moisture content 8.6%), the final gabapentin fine work 108.62g (always receiving 81%, purity 99.9%) that obtains, single impurity is less than 0.05%.
Comparative example 1, according to the method for patent US2007287861, use 2-aza-spiro [4,5]-3-decanone 120g, need to refine hydrochloric acid 720g, can obtain gabapentin crude product 103.7g (moisture content is disregarded), the final gabapentin fine work 98.5g (total recovery 73.5%, purity 99.8%) that obtains.
Comparative example 2, the step 1 of above-described embodiment 1 cancelled), step 2) 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 fine work 99.8g (total recovery 74%, purity 99.9%) that obtains.
The preparation method of embodiment 2, a kind of high-purity gahapentin, carries out following steps successively:
1), the preparation of Gabapentin hydrochloride
In 500ml autoclave, add 2-aza-spiro [4,5]-3-decanone 40g, refining hydrochloric acid 140g, capping system, is forced into 0.5MPa, is warming up to backflow.After reaction 4h, be slowly down to room temperature, ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h, suction filtration, obtains Gabapentin hydrochloride wet product 55.8g (surveying moisture content 19.1%, yield 83.3%), 45 ℃ of oven-dried weight 47.8g, purity 98.0% (HPLC); Obtain acidolysis mother liquor 117.1g, in this acidolysis mother liquor, salt acidometric titration content is 33.5%.
2), the applying mechanically of acidolysis mother liquor ():
In 500ml autoclave, add 2-aza-spiro [4,5]-3-decanone 40g, above-mentioned steps 1) the acidolysis mother liquor 117.1g of gained, add refining hydrochloric acid 32.5g, capping system, is forced into 0.5MPa, is warming up to backflow.After reaction 4h, be slowly down to room temperature, ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h, suction filtration, obtains Gabapentin hydrochloride wet product 69.7g (surveying moisture content 20.1%, yield 102.7%), 45 ℃ of oven-dried weight 58.0g, purity 98.6% (HPLC); Obtain acidolysis mother liquor 112.7g, in this acidolysis mother liquor, salt acidometric titration content is 32.7%.
3), the applying mechanically of acidolysis mother liquor (two):
In 500ml autoclave, add 2-aza-spiro [4,5]-3-decanone 40g, above-mentioned steps 2) the acidolysis mother liquor 112.7g of gained, add refining hydrochloric acid 39.0g, capping system, is forced into 0.5MPa, is warming up to backflow.After reaction 4h, be slowly down to room temperature, ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h, suction filtration, obtains Gabapentin hydrochloride wet product 62.5g (surveying moisture content 19.9%, yield 92.1%), 45 ℃ of oven-dried weight 52.6g, purity 98.2% (HPLC); Obtain 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 crude product
By above-mentioned steps 1)～step 3) Gabapentin hydrochloride of gained merges, and amounts to obtain the Gabapentin hydrochloride of 158.4g.The 50g Gabapentin hydrochloride of getting wherein carries out following operation successively:
Repeat steps A in embodiment 1)～C);
D), the filtrate of gained, add 20g toluene, the sodium hydroxide solution that is 35% by mass concentration adjusts pH value to neutral, is slowly down to room temperature, and ice-water bath continues to be cooled to 0～4 ℃, in 0～4 ℃, stirs 3h;
E), above-mentioned neutralization reaction gains are carried out to suction filtration, with a small amount of (3～5ml) ice toluene drip washing filter cake, obtain gabapentin crude product weight in wet base 40.4g (surveying moisture content 10.2%, yield 92.6%), purity 99.6% (HPLC); Filtrate stratification, separates organic phase toluene layer, and after distillation, recovery is in this step.
5), the preparation of gabapentin fine work
Repeat step 5 in embodiment 1): obtain fine work weight in wet base 34.4g, 45 ℃ of oven-dried weight 33.6g, purity 99.9% (HPLC).
In above-described embodiment 2,
Use altogether 2-aza-spiro [4,5]-3-decanone 120g, refining hydrochloric acid 211.5g, can obtain gabapentin crude product 128.0g (surveying moisture content 10.2%), the final gabapentin fine work 106.4g (total recovery 79.4%, purity 99.9%) that obtains, single impurity is less than 0.05%.
The preparation method of embodiment 3, a kind of high-purity gahapentin, by step 1), step 2) and step 3) in pressure make 1.5MPa into; All the other are with embodiment 1.
Use altogether 2-aza-spiro [4,5]-3-decanone 120g, refining hydrochloric acid 165.2g, can obtain gabapentin crude product 127.8g (surveying moisture content 9.3%), the final gabapentin fine work 105.0g (total recovery 78.3%, purity 99.9%) that obtains, single impurity is less than 0.05%.
Finally, it is also to be noted that, what more than enumerate is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (7)
1. the preparation method of gabapentin, is characterized in that comprising the following steps:
1), 2-aza-spiro [4,5]-3-decanone is forced into 0.5～1.5MPa backflow acidolysis 2 ~ 4 hours in strong acid or strong acid aqueous solution, then in ice-water bath, stir 2 ~ 4 hours; Suction filtration, obtains respectively gabapentin strong acid salt and acidolysis mother liquor;
The mol ratio of described 2-aza-spiro [4,5]-3-decanone and strong acid is 1:3 ~ 9;
2), described acidolysis mother liquor be used for applying mechanically prepare gabapentin strong acid salt:
In the acidolysis mother liquor of above-mentioned steps gained, add after strong acid, be forced into 0.5～1.5MPa backflow acidolysis 2 ~ 4 hours with 2-aza-spiro [4,5]-3-decanone, then in ice-water bath, stir 2 ~ 4 hours; Suction filtration, obtains respectively gabapentin strong acid salt and acidolysis mother liquor again;
The molar weight of 2-aza-spiro [4,5]-3-decanone is 1:1 ~ 20 with the ratio of adding the molar weight sum of strong acid in the molar weight of strong acid and acidolysis mother liquor;
3), repeat above-mentioned steps 2) 1 ~ 5 time, or repeat above-mentioned steps 2 always) until after measured in the acidolysis mother liquor of gained the mass content of strong acid lower than 18% time, just enter following step 4);
Above-mentioned steps 1) strong acid described in ~ step 3) is inorganic acid or organic acid;
Described inorganic acid is: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or sulfuric acid;
Described organic acid is: trichoroacetic acid(TCA), trifluoroacetic acid, methylsulfonic acid or Phenylsulfonic acid;
4), merge above-mentioned the gabapentin strong acid salt of gained in steps, prepare gabapentin crude product, carry out successively following steps:
A, in gabapentin strong acid salt, add purified water, thereby be warming up to 30 ~ 70 ℃, gabapentin strong acid salt is dissolved; The mass ratio of described gabapentin strong acid salt and water is 1:0.5 ~ 2.5;
B, add the gac as discoloring agent, in 30 ~ 70 ℃ of insulated and stirred 0.2 ~ 1h, thereby realize decolouring, process; The mass ratio of described discoloring agent and gabapentin strong acid salt is 1% ~ 8%;
C, suction filtration add organic solvent in the filtrate of gained, first extremely neutral with adjusting PH with base, then in ice-water bath, stir insulation 2 ~ 4h;
D, the neutralization reaction gains of step C gained are carried out to suction filtration, with organic solvent drip washing filter cake, obtain gabapentin crude product;
5), gabapentin crude product is dissolved in the aqueous solution of lower alcohol, through removing under reduced pressure and recrystallization, obtain gabapentin; Described lower alcohol is at least one in methyl alcohol, ethanol, propyl alcohol and Virahol;
Purity >=99.9% of described gabapentin.
2. the preparation method of gabapentin according to claim 1, is characterized in that: described step 1) and step 2) in: the mol ratio of 2-aza-spiro [4,5]-3-decanone and water is 1:0.1 ~ 40.
3. the preparation method of gabapentin according to claim 2, is characterized in that: in the C step of described step 4): the alkali of described adjusting pH is mineral alkali or organic bases.
4. the preparation method of gabapentin according to claim 3, is characterized in that: described mineral alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood; Described organic bases is sodium methylate, potassium methylate, triethylamine or diethylamine.
5. the preparation method of gabapentin according to claim 4, is characterized in that: the C step of described step 4) and the organic solvent in D step are ester class organic solvent or arene organic solvent.
6. the preparation method of gabapentin according to claim 5, is characterized in that: described ester class organic solvent is ethyl formate, ethyl acetate, propyl acetate or butylacetate; Described arene organic solvent is benzene, toluene or dimethylbenzene.
7. the preparation method of gabapentin according to claim 6, is characterized in that: in described step 5): recrystallization temperature is 30 ~ 80 ℃; The mass ratio of gabapentin crude product and water is 1:0.1 ~ 5, is: 1:1 ~ 20 with the mass ratio of lower alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110379862.6A CN102363598B (en) | 2011-11-25 | 2011-11-25 | Method for preparing high-purity gabapentin |
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| 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 (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL119890A (en) * | 1996-12-24 | 2002-03-10 | Teva Pharma | Gabapentin form iii and preparation of gabapentin form ii |
| ITMI981535A1 (en) * | 1998-07-03 | 2000-01-03 | Zambon Spa | PROCESS FOR THE PREPARATION OF GABAPENTINA |
-
2011
- 2011-11-25 CN CN201110379862.6A patent/CN102363598B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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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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