CN100361964C - Gabapentin hydrochloride and its intermediate preparation method - Google Patents
Gabapentin hydrochloride and its intermediate preparation method Download PDFInfo
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- CN100361964C CN100361964C CNB2005100404824A CN200510040482A CN100361964C CN 100361964 C CN100361964 C CN 100361964C CN B2005100404824 A CNB2005100404824 A CN B2005100404824A CN 200510040482 A CN200510040482 A CN 200510040482A CN 100361964 C CN100361964 C CN 100361964C
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Abstract
The present invention relates to a method for preparing hydrochloric acid gabapentin and an intermediate compound thereof, which comprises the following step: 1, 1-cyclohexanediacctic acid reacts with urea to generate a gabapentin intermediate compound 3, 3-penta methene glutarimide. The present invention has the advantages of easy obtainment of the reaction raw materials, low cost, simple operation, and easy program control, and is favorable to mass industrial production.
Description
Technical field
The invention belongs to antiepileptic drug gabapentin and intermediates preparation thereof.
Background technology
The document that relates to the gabapentin synthetic method in the prior art is a lot, as U.S.Pat.Nos.5, and 132,451,5,095,148,5,068,413, include the intermediate that contains cyanogen in these patented methods, its hydrogenation is needed special, strict condition, thereby do not fit into industrialized production.
In the U.S. Patent application 20040063997, " with the mixture and 1 of diacetyl oxide and ammonium acetate, the reaction of 1-cyclohexanediacetic acid.Reactive material is heated to 160-170 ℃, 8 hours.Remove the acetic acid that generates in the dereaction with distillation method.Be cooled to 90-110 ℃, add entry and sec-butyl alcohol.Then, further be cooled to room temperature, transfer to ph with 30% ammoniacal liquor and be about 9, filter 3,3-pentamethylene glutaramide.3,3-pentamethylene glutaramide and water and 30%NaOH solution, be heated to together 50～80 ℃ about 2 hours, until dissolving 3 fully, 3-pentamethylene glutaramide.To dissolve after product and pour (be made up of NaClO15% and NaOH30%, the maintenance temperature is between 0-30 ℃) in the NaOH/NaClO mixture into.Room temperature is poured this liquid in 32% hydrochloric acid into after leaving standstill about 3 hours again.Excessive chlorine decomposes by handling with aqueous solution of sodium bisulfite, stirs some hrs in 40-60. ℃ then.Be cooled to again about 0 ℃, cross filter solid, and, obtain Gabapentin hydrochloride with the ethyl acetate washing.”
The mixture and 1 of U.S. Patent application 20040063997 usefulness diacetyl oxides and ammonium acetate, the reaction of 1-cyclohexanediacetic acid, long reaction time not only, and a large amount of acetic acid of generation in the reaction process, therefore have to increase with the step of distillation method except that the acetic acid that generates in the dereaction, and distill and to cool off through two steps, and need add the ammoniacal liquor neutralization again.Add entry and sec-butyl alcohol after the cooling for the first time, further be cooled to room temperature then, transfer to ph with 30% ammoniacal liquor and be about 9.In addition, this U. S. application is in obtaining the step of Gabapentin hydrochloride, and with 3,3-pentamethylene glutaramide dissolving after product is poured in the NaOH/NaClO mixture, and room temperature is poured this liquid in 32% hydrochloric acid into after leaving standstill about 3 hours again.Produce excessive chlorine in this step, with aqueous solution of sodium bisulfite excessive chlorine is decomposed again, then in 40-60 ℃ of stirring some hrs, to remove chlorine.
Summary of the invention
The technical problem to be solved in the present invention is a kind of gabapentin of research and development and intermediates preparation thereof, makes every effort to raw material and is easy to get, and is with low cost, simple to operate, and program is easy to control, more helps industrial and large-scale and produces use.Gabapentin intermediate 3 among the preparation method of 3-pentamethyleneglutarimide, by screening reaction raw materials or reagent, does not generate a large amount of acetic acid, to reduce follow-up distillation acetic acid, secondary cooling and to add ammoniacal liquor neutral step.In gabapentin and one step of hydrochloric acid salify,, reduce the generation of excess chlorine by improving control manipulation as far as possible.
A kind of preparation method of gabapentin is characterized in that comprising the steps: a) 1, and 1-cyclohexanediacetic acid and urea reaction generate 3, the 3-pentamethyleneglutarimide; B) with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution that potassium hydroxide and/or sodium hydroxide joins, and adds aqueous sodium hypochlorite solution earlier, adds potassium hydroxide and/or aqueous sodium hydroxide solution again; Be neutralized to pH1-2 with hydrochloric acid then, obtain gabapentin.
More preferably in the gabapentin hydrochloride preparing process, step a) get by weight 20: 3～20 parts 1,1-cyclohexanediacetic acid and urea reaction, temperature of reaction is 140～200 ℃, the reaction times is 1-3 hour; 3 of generation, the 3-pentamethyleneglutarimide can be used C
1-C
5Straight or branched alcohol and water mixing solutions recrystallization;
More preferably in the gabapentin hydrochloride preparing process, get by weight 20: 6～12 parts 1,1-cyclohexanediacetic acid and urea reaction, temperature of reaction is 150～180 ℃, the reaction times is 2 hours; 3, the C that 3-pentamethyleneglutarimide recrystallization is used
1-C
5Straight or branched alcohol be selected from methyl alcohol, ethanol, Virahol, C
1-C
5The ratio of straight or branched alcohol and water be 1-2: 2-1 by volume;
In the preferred gabapentin hydrochloride preparing process, 1,1-cyclohexanediacetic acid and urea are counted 20: 10 parts by weight, temperature of reaction is 150 ℃, reacts after 2 hours, is cooled to room temperature, directly add 1: 1 by volume solution of second alcohol and water, reflux is used activated carbon decolorizing, filtered while hot, the filtrate cooling, filter dry purified 3, the 3-pentamethyleneglutarimide of getting.
The preparation method of described gabapentin, wherein step b) is with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 15-25% potassium hydroxide or sodium hydroxide, and 3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide counts 18 by weight: 5-25 part; Room temperature was placed after 20～30 hours, joined among the chlorine bleach liquor who is cooled to 0～5 ℃ in advance, under 0 ℃ of condition, added 35-45% potassium hydroxide or aqueous sodium hydroxide solution again.Preferably with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 20% potassium hydroxide or sodium hydroxide, and 3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide counts 18 by weight: 10-15 part; Room temperature was placed after 22～26 hours, joined in the aqueous sodium hypochlorite solution of the 5-15% that is cooled to 0 ℃ in advance, stirred 10-20 minute, under 0 ℃ of condition, added 40% potassium hydroxide or aqueous sodium hydroxide solution again, stirred 25-40 minute.More preferably be with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 20% potassium hydroxide or sodium hydroxide, and 3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide is counted 18: 11 parts by weight; Room temperature was placed after 24 hours, be cooled to 0 ℃, join among the chlorine bleach liquor of the 8-12% that is cooled to 0 ℃ in advance, stirred 15 minutes, under 0 ℃ of condition, after adding 40% potassium hydroxide or aqueous sodium hydroxide solution again, stir after 30 minutes, be warming up to 30-80 ℃, stirred 1-5 hour, be neutralized to pH1-2 with 30-40% hydrochloric acid then, filter, drying obtains gabapentin.Preferred method is with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 20% potassium hydroxide or sodium hydroxide, room temperature was placed after 24 hours, be cooled to 0 ℃, join among 10% the chlorine bleach liquor who is cooled to 0 ℃ in advance, stirred 15 minutes, under 0 ℃ of condition, add 40% potassium hydroxide or aqueous sodium hydroxide solution again after, stir after 30 minutes, be warming up to 45～50 ℃, stirred 2 hours, and be neutralized to pH1-2 with 36～38% hydrochloric acid then, filter, drying obtains gabapentin, available Virahol recrystallization.
A kind of gabapentin intermediate 3 of the present invention, the preparation method of 3-pentamethyleneglutarimide comprises the steps: 1,1-cyclohexanediacetic acid and urea reaction generate 3, the 3-pentamethyleneglutarimide.This method preferably will get by weight 20: 3～20 parts 1,1-cyclohexanediacetic acid and urea reaction, temperature of reaction is 150～180 ℃, the reaction times is 2 hours.
Be detailed description below to preparation method of the present invention.
One, 3, the preparation of 3-pentamethyleneglutarimide:
With 20: 3 by weight～20 parts (being preferably 20: 6～12 parts) 1,1-cyclohexanediacetic acid and urea mix, and are heated to 140～200 ℃, better temperature of reaction is 150-180 ℃, is preferably in about 150 ℃; Reaction times 1-3 hour, be preferably in about 2h.Be chilled to room temperature after the reaction, the water that generates in the elimination reaction, dry reaction product 3,3-pentamethyleneglutarimide.If desired with 3, the 3-pentamethyleneglutarimide is made with extra care, and when being chilled to room temperature after the reaction, adds the C of 1500ml
1-C
5Straight or branched alcohol, water (preferably 1: 1 by volume) mixed solution, C herein
1-C
5Straight or branched alcohol can be selected from methyl alcohol, ethanol, Virahol, preferred alcohol; Reflux 30 minutes, activated carbon decolorizing, filtered while hot, filtrate cooling is filtered, and is dry 3, the 3-pentamethyleneglutarimide.Herein 3,3-pentamethyleneglutarimide treating process is similar to conventional recrystallization method.C
1-C
5The total amount of straight or branched alcohol and water is 3,5～10 times of 3-pentamethyleneglutarimide amount, preferred 7.5 times (weight ratios).
Two, the preparation of gabapentin
With 3, the 3-pentamethyleneglutarimide is dissolved in 15～25% (preferred 20%) solution that potassium hydroxide and/or sodium hydroxide is mixed with.3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide counts 18 by weight: 5-25 part, and preferred 18: 10～15 parts, 3,3-pentamethyleneglutarimide and potassium hydroxide more preferably weight ratio are 18: 11 parts.Room temperature is placed, and is preferably in 30 ℃ and places about one day, and the time has been lacked reaction not exclusively, has grown as the time and has both reacted excessive, loses time again.Cooling joins among 940ml 10% chlorine bleach liquor who is cooled to 0 ℃ in advance at 0～5 ℃ (0-30 ℃ all can, best 0～5 ℃), stirred 15 minutes, KOH (basic solution gets final product, and mineral alkali is better, and KOH, NaOH are best) the solution 300ml of dropping 40% under same temperature, continue to stir 30 minutes, be warming up to 45～50 ℃ (30-80 ℃ all can, this is best) again, preferred 2 hours of churning time (1-5 hour all can), cooling is neutralized to pH1～2 with concentrated hydrochloric acid.Concentrated hydrochloric acid generally is meant the hydrochloric acid of 30%-40%, and concentration is big more, and its water content is few more, because the product gabapentin behind the hcl acidifying is soluble in water, the hydrochloric acid that concentration is too low can reduce owing to the moisture more yield that makes.If do not consider the height of yield, concentration of hydrochloric acid can hang down harmless a bit, preferred 36～38% hydrochloric acid.Filter, drying is with Virahol (alcohols, this is best) crystallization, yield 65%.
Three, preparation gabapentin
Operate routinely gabapentin by deacidite, as D
301, change gabapentin into.Gabapentin of the present invention and intermediates preparation thereof, prepare gabapentin intermediate 3 with urea as reaction reagent, the 3-pentamethyleneglutarimide does not generate a large amount of acetic acid, thereby reduces follow-up distillation acetic acid, secondary cooling and add ammoniacal liquor neutral step.In gabapentin and one step of hydrochloric acid salify, regulate and control to pH1-2, reduced the generation of excess chlorine, simplified subsequent treatment process.In a word, preparation method's raw material of the present invention is easy to get, and is with low cost, simple to operate, and program is easy to control, more helps industrial and large-scale and produces use.
Embodiment
Embodiment one
With 200g 1, the urea of 1-cyclohexanediacetic acid and 120g mixes, and is heated to 150 ℃, reaction 2h.Be chilled to room temperature slightly, need not filter, directly add ethanol, the water (1: 1) of 1500ml, reflux 30 minutes, activated carbon decolorizing, filtered while hot, the filtrate cooling is filtered, and drying gets 3, the 3-pentamethyleneglutarimide.Yield 95%, mp:168-172 ℃.
With 3 of 180g, the 3-pentamethyleneglutarimide is dissolved in the potassium hydroxide of 110g and 20% solution that water is mixed with, can not heat during dissolving, room temperature was placed 24 hours, cool off 0 ℃, join among 940ml 10% chlorine bleach liquor who is cooled to 0 ℃ in advance, stirred 15 minutes, the KOH solution 300ml of dropping 40% under same temperature, continue to stir 30 minutes, be warming up to 45 ℃ again, stir 2h, cooling is neutralized to pH2 with 38% hydrochloric acid.Filter, drying is used the Virahol crystallization, promptly gets gabapentin.Yield 85%, mp:117-118 ℃.
Technology changes the ion exchange resin of gabapentin by the D301 model into gabapentin (embodiment 1 of reference: US4024175 (1977.5)) routinely.
Embodiment two
With 200g 1, the urea of 1-cyclohexanediacetic acid and 30g mixes, and is heated to 180 ℃, and reaction 3h is chilled to room temperature slightly, the methyl alcohol, the water (1: 1) that add 1500ml, reflux 30 minutes, activated carbon decolorizing, filtered while hot, filtrate cooling, filter, drying gets 3, the 3-pentamethyleneglutarimide.
With 3 of 180g, the 3-pentamethyleneglutarimide is dissolved in 25% solution that the potassium hydroxide of 50g is mixed with, and room temperature was placed 30 hours, was cooled to 5 ℃, join among 940ml 8% chlorine bleach liquor who is cooled to 0 ℃ in advance, stirred 10 minutes, the KOH solution 420ml of Dropwise 35 % under same temperature continues to stir 40 minutes, be warming up to 70 ℃ again, stir 3h, cooling is neutralized to pH1 with 36% hydrochloric acid.Filter, drying is used the Virahol crystallization, promptly gets gabapentin.Yield 70%, mp:117-118 ℃.
Embodiment three
With 200g 1, the urea of 1-cyclohexanediacetic acid and 60g mixes, and is heated to 140 ℃, reaction 3h is chilled to room temperature slightly, adds ethanol, water (2: the 1) mixing solutions of 1500ml, reflux 30 minutes, activated carbon decolorizing, filtered while hot, filtrate cooling, filter, drying gets 3, the 3-pentamethyleneglutarimide.
With 3 of 180g, the 3-pentamethyleneglutarimide is dissolved in 20% solution that the sodium hydroxide of 250g is mixed with, and room temperature was placed 26 hours, cooling, join among 940ml 12% chlorine bleach liquor who is cooled to 0 ℃ in advance at 5 ℃, stirred 20 minutes, and under same temperature, dripped 30% sodium hydroxide solution 420ml, continue to stir 40 minutes, be warming up to 45 ℃ again, stir 3h, cooling is neutralized to pH1 with 40% hydrochloric acid.Filter, drying is used the Virahol crystallization, promptly gets gabapentin.Yield 80%, mp:117-118 ℃.
Embodiment four
With 200g 1, the urea of 1-cyclohexanediacetic acid and 200g mixes, and is heated to 200 ℃, reaction 1h is chilled to room temperature slightly, adds ethanol, water (1: the 2) mixing solutions of 1500ml, reflux 30 minutes, activated carbon decolorizing, filtered while hot, filtrate cooling, filter, drying gets 3, the 3-pentamethyleneglutarimide.
With 3 of 180g, the 3-pentamethyleneglutarimide is dissolved in 15% solution that the potassium hydroxide of 100g is mixed with, and room temperature was placed 20 hours, cooling, join among 940ml 15% chlorine bleach liquor who is cooled to 0 ℃ in advance at 5 ℃, stirred 15 minutes, and under same temperature, dripped 45% KOH solution 420ml, continue to stir 40 minutes, be warming up to 50 ℃ again, stir 3h, cooling is neutralized to pH2 with 30% hydrochloric acid.Filter, drying is used the Virahol crystallization, promptly gets gabapentin.Yield 88%, mp:117-118 ℃.
Embodiment five
With 200g 1, the urea of 1-cyclohexanediacetic acid and 100g mixes, and is heated to 150 ℃, reaction 2h.Be chilled to room temperature, the water that generates in the filtering reaction, dry reaction product 3,3-pentamethyleneglutarimide.Make with extra care 3 routinely, the 3-pentamethyleneglutarimide is removed excessive urea.
With 3 of 180g, the 3-pentamethyleneglutarimide is dissolved in 20% solution that the potassium hydroxide of 150g is mixed with.Room temperature was placed 24 hours, cooled off 0 ℃, joined among 940ml 10% chlorine bleach liquor who is cooled to 0 ℃ in advance, stirred 15 minutes, the KOH solution 300ml of dropping 40% under same temperature continues to stir 30 minutes, is warming up to 45 ℃ again, stir 2h, cooling is neutralized to pH2 with 38% hydrochloric acid.Filter, drying is used the Virahol crystallization, promptly gets gabapentin.Yield 84%, mp:117-118 ℃.
Claims (10)
1. the preparation method of a gabapentin is characterized in that comprising the steps: that a) with 1,1-cyclohexanediacetic acid and urea reaction generate 3, the 3-pentamethyleneglutarimide; B) with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution that potassium hydroxide and/or sodium hydroxide joins, and adds aqueous sodium hypochlorite solution earlier, adds potassium hydroxide and/or aqueous sodium hydroxide solution again; Be neutralized to pH1-2 with hydrochloric acid then, obtain gabapentin.
2. the preparation method of claim 1 gabapentin, wherein step a) get by weight 20: 3～20 parts 1,1-cyclohexanediacetic acid and urea reaction, temperature of reaction is 140～200 ℃, the reaction times is 1-3 hour; 3 of generation, 3-pentamethyleneglutarimide C
1-C
5Straight or branched alcohol and water mixing solutions recrystallization.
3. the preparation method of claim 2 gabapentin, wherein get by weight 20: 6～12 parts 1,1-cyclohexanediacetic acid and urea reaction, temperature of reaction is 150～180 ℃, the reaction times is 2 hours; 3, the C that 3-pentamethyleneglutarimide recrystallization is used
1-C
5Straight or branched alcohol be selected from methyl alcohol, ethanol, Virahol, C
1-C
5The ratio of straight or branched alcohol and water be 1-2: 2-1 by volume.
4. the preparation method of claim 3 gabapentin, wherein 1,1-cyclohexanediacetic acid and urea are counted 20: 10 parts by weight, temperature of reaction is 150 ℃, reacts after 2 hours. be cooled to room temperature, directly add 1: 1 by volume solution of second alcohol and water, reflux is used activated carbon decolorizing, filtered while hot, the filtrate cooling, filter dry purified 3, the 3-pentamethyleneglutarimide of getting.
5. the preparation method of claim 1 gabapentin, wherein step b) is with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 15-25% potassium hydroxide or sodium hydroxide, 3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide counts 18 by weight: 5-25 part; Room temperature was placed after 20～30 hours, joined among the chlorine bleach liquor who is cooled to 0～5 ℃ in advance, under 0 ℃ of condition, added 35-45% potassium hydroxide or aqueous sodium hydroxide solution again.
6. the preparation method of claim 5 gabapentin, wherein with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 20% potassium hydroxide or sodium hydroxide, and 3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide counts 18 by weight: 10-15 part; Room temperature was placed after 22～26 hours, joined in the aqueous sodium hypochlorite solution of the 5-15% that is cooled to 0 ℃ in advance, stirred 10-20 minute, under 0 ℃ of condition, added 40% potassium hydroxide or aqueous sodium hydroxide solution again, stirred 25-40 minute.
7. the preparation method of claim 6 gabapentin, wherein with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 20% potassium hydroxide or sodium hydroxide, and 3, the ratio of 3-pentamethyleneglutarimide and potassium hydroxide or sodium hydroxide is counted 18: 11 parts by weight; Room temperature was placed after 24 hours, be cooled to 0 ℃, join among the chlorine bleach liquor of the 8-12% that is cooled to 0 ℃ in advance, stirred 15 minutes, under 0 ℃ of condition, after adding 40% potassium hydroxide or aqueous sodium hydroxide solution again, stir after 30 minutes, be warming up to 30-80 ℃, stirred 1-5 hour, be neutralized to pH1-2 with 30-40% hydrochloric acid then, filter, drying obtains gabapentin.
8. the preparation method of claim 7 gabapentin, wherein with 3, the 3-pentamethyleneglutarimide is dissolved in the aqueous solution of 20% potassium hydroxide or sodium hydroxide, room temperature was placed after 24 hours, be cooled to 0 ℃, join among 10% the chlorine bleach liquor who is cooled to 0 ℃ in advance, stirred 15 minutes, under 0 ℃ of condition, after adding 40% potassium hydroxide or aqueous sodium hydroxide solution again, stir after 30 minutes, be warming up to 45～50 ℃, stirred 2 hours, be neutralized to pH1-2 with 36～38% hydrochloric acid then, filter, drying obtains gabapentin, uses the Virahol recrystallization.
9. gabapentin intermediate 3, the preparation method of 3-pentamethyleneglutarimide is characterized in that comprising the steps: with 1,1-cyclohexanediacetic acid and urea reaction generate 3, the 3-pentamethyleneglutarimide.
10. claim 9 gabapentin intermediate 3, the preparation method of 3-pentamethyleneglutarimide, get by weight 20: 3～20 parts 1,1-cyclohexanediacetic acid and urea reaction, temperature of reaction is 150～180 ℃, the reaction times is 2 hours.
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| CN103450080B (en) * | 2012-05-31 | 2015-08-12 | 盐城拜克化学工业有限公司 | A kind of preparation method of 3,3-pentamethylene glutarimide |
| CN102690207B (en) * | 2012-05-31 | 2014-03-26 | 湖北楚阳科技股份有限公司 | Gabapentin synthesizing method |
| CN104230735A (en) * | 2014-08-28 | 2014-12-24 | 太仓运通生物化工有限公司 | Preparation method of gabapentin |
| CN104478802A (en) * | 2014-11-26 | 2015-04-01 | 太仓运通生物化工有限公司 | Process for synthesizing 3,3-pentamethylene glutarimide |
| CN104402796A (en) * | 2014-11-26 | 2015-03-11 | 太仓运通生物化工有限公司 | Preparation method for 3,3-amylidene butyrolactam |
| CN105061241A (en) * | 2015-08-18 | 2015-11-18 | 太仓运通生物化工有限公司 | Gabapentin preparation method |
| CN111116345A (en) * | 2019-12-30 | 2020-05-08 | 上海华理生物医药股份有限公司 | Novel method for preparing Mirogabalin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6054482A (en) * | 1989-08-25 | 2000-04-25 | Godecke Aktiengesellschaft | Lactam-free amino acids |
| US6846950B2 (en) * | 2002-10-01 | 2005-01-25 | Erregierre S.P.A. | Process for synthesis of 1-(aminomethyl)cyclohexane acetic acid hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6054482A (en) * | 1989-08-25 | 2000-04-25 | Godecke Aktiengesellschaft | Lactam-free amino acids |
| US6846950B2 (en) * | 2002-10-01 | 2005-01-25 | Erregierre S.P.A. | Process for synthesis of 1-(aminomethyl)cyclohexane acetic acid hydrochloride |
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Address after: 221007 No. 18 Yang Shan Road, Xuzhou Economic Development Zone, Jiangsu, China Patentee after: Jiangsu Nhwa Pharmaceutical Co., Ltd. Address before: 221007 Zhongshan North Road, Jiangsu, No. 289, Patentee before: Jiangsu Nhwa Pharmaceutical Co., Ltd. |