CN101497607A - Process for synthesizing sunitinib - Google Patents
Process for synthesizing sunitinib Download PDFInfo
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- CN101497607A CN101497607A CNA2008100331901A CN200810033190A CN101497607A CN 101497607 A CN101497607 A CN 101497607A CN A2008100331901 A CNA2008100331901 A CN A2008100331901A CN 200810033190 A CN200810033190 A CN 200810033190A CN 101497607 A CN101497607 A CN 101497607A
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Abstract
The invention discloses a method for synthesizing sunitinib, which comprises the following steps that: tert-butyl acetoacetate and acetylacetic ester are taken as initial raw materials, and tetra-substituted pyrrole is obtained through a nitrosification reduction reaction; then 2,4-dimethyl pyrrole-3-formic acid is obtained through the hydrolysis and is amidated; then an aldehyde group is utilized on position 5 of pyrrole through a Vilsmeier-Hacck reaction; and finally the obtained product and 5-fluorooxindole react to obtain the sunitinib. The method has low cost and simple operation, and is favorable for industrial production.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical compound, relate in particular to a kind of synthetic method of Sutent.
Background technology
Sutent (Sunitinib, SU011248, structural formula I) is a kind of new small molecules tyrosine kinase inhibitor for oral use, has the angiopoietic potential of inhibition and anti-tumour effect.Sutent is the medicine of new research and development, has good bioavailability, but to a certain extent also antagonism can promote angiopoietic tyrosine kinase receptor (RTKs).Sutent also can suppress other some tyrosine kinase receptor family proteins, and these are all relevant with multiple malignant tumour, as small cell lung cancer, gastrointestinal tumor (GISTs), mammary cancer, acute non-lymphoid leukemia etc.Sutent has good effect to treatment neuroendocrine tumour, colorectal carcinoma and mammary cancer in the II clinical trial phase.When being used for the gastrointestinal tumor of kidney and anti-imatinib, Sutent has demonstrated good effect equally.The drugs approved by FDA Sutent can be used for treating kidney and gastrointestinal tumor.
The Sutent of bibliographical information synthetic (US6573293 and J.Med.Chem.2003 the earliest, 1116) mainly be to be raw material with the tert-butyl acetoacetate, obtain quaternary pyrroles through nitrosification zinc powder reduction, sour water is taken off the tert-butyl ester and decarboxylation then, utilize Vilsmeier-Hacck to be reflected at 5 last aldehyde radicals of pyrroles, the ester group of 3 of alkaline hydrolysises is made acid amides with acid then again, and last and 5-fluoro indole reactive ketone obtains Sutent.This method aldehyde radical when doing the acid amides reaction unavoidably will participate in reaction, and because the existence of aldehyde radical makes this reaction very slow, raw material reaction is not intact when synthetic especially in a large number.The reaction scheme of this method is:
On this basis, Pfizer company has developed an other route (US 20060009510 and J.Org.Chem.2003,6447).This method is set out with the butyrolactone of four annulus, synthesize acid amides earlier, nitrosification zinc powder or hydro-reduction obtain quaternary pyrroles then, sour water is taken off the tert-butyl ester and decarboxylation then, utilize Vilsmeier-Hacck be reflected at 5 of the pyrroles go up aldehyde radicals simultaneously and 5-fluoro indole reactive ketone obtain Sutent.Owing to introduce acid amides in advance, making intermediate all is liquid basically, has increased the difficulty of purifying.The reaction scheme of this method is:
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of synthetic method of Sutent.
The synthetic method of Sutent provided by the present invention, its concrete grammar step is:
1. be starting raw material with tert-butyl acetoacetate and acetylacetic ester, obtain quaternary pyrroles by the nitrosification reduction reaction; 2. quaternary pyrroles is hydrolyzed to react and obtains 2,4-dimethyl pyrrole-3-formic acid; 3. 2,4-dimethyl pyrrole-3-formic acid carries out amidation; 4. utilize Vilsmeier-Hacck to be reflected at 5 last aldehyde radicals of pyrroles again; 5. last and 5-fluoro indole reactive ketone obtains Sutent;
Wherein acetylacetic ester is the acetylacetic ester of 1-4 carbon.
Step hydrolysis reaction 2. in two steps, the first step is acidic hydrolysis decarboxylation simultaneously, its used acid is hydrochloric acid, sulfuric acid, formic acid or trifluoracetic acid; Second step was alkaline hydrolysis, and its used alkali is lithium hydroxide, sodium hydroxide or potassium hydroxide.
Step 3. in 2, the amidation of 4-dimethyl pyrrole-3-formic acid is condensation reagent with the carbonyl dimidazoles, solvent uses ethylene dichloride, tetrahydrofuran (THF), 1,2-ethylene dichloride, ethyl acetate or acetonitrile.
Step 4. in 5 of the pyrroles go up with aldehyde radical in the Vilsmeier-Hacck reaction, the preparation of Vilsmeier reagent is pressed classical way and is prepared now-making-now-using.
Step being reflected in the organic solvent 5. carried out, and wherein organic solvent is ethylene dichloride, tetrahydrofuran (THF), 1,2-ethylene dichloride, ethyl acetate or acetonitrile; The alkali that condensation is used is mineral alkali or organic bases, wherein mineral alkali is lithium hydroxide, potassium hydroxide or sodium hydroxide, organic bases is triethylamine, diisopropyl ethyl amine, pyridine, piperidines, Tocosamine, piperidines, Pyrrolidine or 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU), wherein the reaction density scope of alkali in reaction solution is 0.1M-10M.
Its concrete reaction scheme figure is:
Wherein, R is a 1-4 carbon alkyl.
Other not detailed parts are techniques well known, and those skilled in the art in conjunction with specific embodiments, without creative work, can implement the present invention according to foregoing description.
Method of the present invention has following advantage:
1, in the inventive method, because synthetic route has been carried out suitable adjustment, being about to aldehyde radical in the end with before the condensation of 5-fluoro indole ketone receives on the pyrroles, make reaction easier, especially make that amidate action is easier to carry out, the reaction times is short, the yield height, saved the N of half simultaneously, N-diethyl ethylenediamine usage quantity.
2, in the inventive method, the reagent of use substantially all is common reagent, low price, and cost is low.
3, in the inventive method, the intermediate major part is a solid, and very easily crystallization purifying has been simplified purification process greatly.
4. in the inventive method, reaction all is classical reaction, and easy handling is beneficial to suitability for industrialized production.
Embodiment
Following embodiment just is used to illustrate the present invention, and unrestricted the present invention.
Embodiment 1
Add 7.5 liters of acetic acid and tert-butyl acetoacetate 5.0kg in 25 liters of plastic tanks, 0 degree drips the solution that Sodium Nitrite 2.24kg is dissolved in 3.5 premium on currency down, and controlled temperature is no more than 5 degree, drip to finish and to add 3 liters in water, insulation reaction 30 minutes is removed cryostat, slowly temperature reaction, reaction adds 5 liters in water after finishing, carefully be neutralized to nearly neutrality with solid sodium bicarbonate, transfer pH=7-8 with a small amount of 4N sodium hydroxide solution at last, use ethyl acetate extraction, dry, concentrate, get the about 5.6kg of liquid, be directly used in next step reaction.
In 25 liters of plastic tanks, add the product 2.8kg of previous step, 10 liters of methyl aceto acetate 3kg and acetic acid, the mixture that in batches adds 3.4kg zinc powder and 3.4kg sodium-acetate, the control feed rate makes temperature be no more than 85 degree, finish, spend insulation reaction 2 hours 75, after reacting completely, cooling is poured reaction solution in 50 liters of frozen water into, separates out a large amount of solids, suction filtration is with small amount of ethanol washing, oven dry, get the about 3kg of product, be directly used in next step reaction.
Spectroscopic data is as follows:
1H?NMR(500M，CDCl
3)δ：9.25(s，1H)，4.28(q，J＝7.1Hz，2H)，2.53(s，3H)，2.50(s，3H)，1.58(s，9H)，1.35(t，J＝7.1Hz，3H).
In 25 liters of plastic tanks, add the product 3kg of previous step, 10 liters of ethanol drip 5 liters of concentrated hydrochloric acids, finish, heating reflux reaction to raw material disappears, and slowly pours reaction solution into 32 liters of frozen water, has a large amount of solids to separate out, suction filtration, oven dry obtains the about 1.2kg of pink solid, is directly used in next step reaction.Spectroscopic data is as follows:
1HNMR(500M，CDCl
3)δ：8.14(s，1H)，6.35(s，1H)，4.28(m，2H)，2.48(s，3H)，2.24(s，3H)，1.34(t，J＝7.0Hz，3H).
Previous step product 1.2kg, 1 liter in water, 6 liters of methyl alcohol, add potassium hydroxide 2kg, reflux, reaction concentrates methyl alcohol after finishing, the a small amount of dichloromethane extraction of residuum, water concentrated hydrochloric acid pH=1 separates out a large amount of solids, suction filtration, a small amount of cold water washing 2-3 time, 50 degree are dry, get the about 800g of pink solid, are directly used in next step reaction.
Spectroscopic data is as follows:
1H?NMR(400M，DMSO)δ：11.1(s，1H)，7.91(s，1H)，6.37(s，1H)，2.53(s，3H)，2.27(s，3H).
The raw material of 800g previous step is dissolved in 6 liters of tetrahydrofuran (THF)s, add the 1.5kg carbonyl dimidazoles in batches, finish, stirred 30 minutes, drip N, N-diethyl ethylenediamine 800g is dissolved in the solution of 500 milliliters of tetrahydrofuran (THF)s, and reaction concentrates tetrahydrofuran (THF) after finishing, and adds 3 liters in water, use dichloromethane extraction, drying, concentrate the about 1.2kg of dark red liquid, be directly used in next step reaction.
400ml DMF is dissolved in 6 liters of the methylene dichloride, the following dropping of 0 degree 600g oxalyl chloride is dissolved in the solution of 1 liter of methylene dichloride, controlled temperature is no more than 5 degree, there are a large amount of white solids to produce, finish, insulation continues to stir 2 hours, drips the solution that previous step product 1.2kg is dissolved in 1 liter of methylene dichloride, and controlled temperature is no more than 10 degree.Concentrate methylene dichloride after reaction finishes, residuum is dissolved in 3 premium on currency, is neutralized to pH=14 with 10N potassium hydroxide, reflux, cooling, product is separated out, filtration, dry faint yellow solid 1kg, be directly used in next step reaction.
Spectroscopic data is as follows:
1H?NMR(400M，DMSO)δ：11.8(s，1H)，9.54(s，1H)，7.30(t，J＝5.0Hz，1H)，3.25(q，J＝6.5Hz，2H)，2.50(m，6H)，2.37(s，3H)，2.32(s，3H)，0.96(t，J＝7.1Hz，6H).
Previous step product 1kg and 5-fluoro indole ketone 800g, 5 liters of dehydrated alcohols, 100 milliliters of Pyrrolidines, reflux, reaction is chilled to room temperature after finishing, and filters, and uses washing with acetone, the dry about 1.3kg of product that gets, purity is greater than 99%.
Spectroscopic data is as follows:
1H?NMR(500M，DMSO)δ：13.7(s，1H)，10.9(s，1H)，7.75(dd，J＝2.4，9.4Hz，1H)，7.71(s，1H)，7.41(t，J＝5.3Hz，1H)，6.92(m，1H)，6.85(dd，J＝4.5，8.4Hz，1H)，3.28(m，2H)，2.53(m，6H)，2.45(s，3H)，2.43(s，3H)，0.98(t，J＝7.1Hz，6H).
Embodiment 2
Add 1.5 liters of acetic acid and tert-butyl acetoacetate 1.0kg in 5 liters of four-hole bottles, 0 degree drips the solution that Sodium Nitrite 0.5kg is dissolved in 2 premium on currency down, and controlled temperature is no more than 5 degree, drip to finish and to add 1 liter in water, insulation reaction 30 minutes is removed cryostat, slowly temperature reaction, reaction adds 2 liters in water after finishing, carefully be neutralized to nearly neutrality with solid sodium bicarbonate, transfer pH=7-8 with a small amount of 4N sodium hydroxide solution at last, use ethyl acetate extraction, dry, concentrate, get the about 1.2kg of liquid, be directly used in next step reaction.
In 5 liters of four-hole bottles, add the product 1.2kg of previous step, 2 liters of propyl acetoacetate 1kg and acetic acid, the mixture that in batches adds 0.8kg zinc powder and 0.8kg sodium-acetate, the control feed rate makes temperature be no more than 85 degree, finish, spend insulation reaction 2 hours 75, after reacting completely, cooling is poured reaction solution in 10 liters of frozen water into, separates out a large amount of solids, suction filtration is with small amount of ethanol washing, oven dry, get the about 1kg of product, be directly used in next step reaction.
In 5 liters of four-hole bottles, add the product 1kg of previous step, 2 liters of ethanol drip 500 milliliters of concentrated hydrochloric acids, finish, heating reflux reaction to raw material disappears, and slowly pours reaction solution into 2 liters of frozen water, has a large amount of solids to separate out, suction filtration, oven dry obtains the about 300g of pink solid, is directly used in next step reaction.
Previous step product 300g, 200 milliliters in water, 1 liter of methyl alcohol, add potassium hydroxide 200g, reflux, reaction concentrates methyl alcohol after finishing, the a small amount of dichloromethane extraction of residuum, water concentrated hydrochloric acid pH=1 separates out a large amount of solids, suction filtration, a small amount of cold water washing 2-3 time, 50 degree are dry, get the about 250g of pink solid, are directly used in next step reaction.
The raw material of 250g previous step is dissolved in 2 liters of tetrahydrofuran (THF)s, add the 300kg carbonyl dimidazoles in batches, finish, stirred 30 minutes, drip N, N-diethyl ethylenediamine 200g is dissolved in the solution of 100 milliliters of tetrahydrofuran (THF)s, and reaction concentrates tetrahydrofuran (THF) after finishing, and adds 3 liters in water, use dichloromethane extraction, drying, concentrate the about 350g of dark red liquid, be directly used in next step reaction.
80ml DMF is dissolved in 2 liters of the methylene dichloride, the following dropping of 0 degree 60g thionyl chloride is dissolved in the solution of 100 milliliters of methylene dichloride, controlled temperature is no more than 5 degree, there are a large amount of white solids to produce, finish, insulation continues to stir 2 hours, drips the solution that previous step product 350g is dissolved in 300 milliliters of methylene dichloride, and controlled temperature is no more than 10 degree.Concentrate methylene dichloride after reaction finishes, residuum is dissolved in 3 premium on currency, is neutralized to pH=14 with 10N potassium hydroxide, reflux, cooling, product is separated out, filtration, dry faint yellow solid 300g, be directly used in next step reaction.
Previous step product 300g and 5-fluoro indole ketone 150g, 2 liters of dehydrated alcohols, the DBU20 milliliter, reflux, reaction is chilled to room temperature after finishing, and filters, and uses washing with acetone, the dry about 350g of product that gets, purity is greater than 99%.
Embodiment 3
Add 100 liters of acetic acid and tert-butyl acetoacetate 50kg in 250 liters of stills, 0 degree drips the solution that Sodium Nitrite 25kg is dissolved in 35 premium on currency down, and controlled temperature is no more than 5 degree, drip to finish and to add 30 liters in water, insulation reaction 30 minutes is removed cryostat, slowly temperature reaction, reaction adds 50 liters in water after finishing, carefully be neutralized to nearly neutrality with solid sodium bicarbonate, transfer pH=7-8 with a small amount of 4N sodium hydroxide solution at last, use ethyl acetate extraction, dry, concentrate, get the about 56kg of liquid, be directly used in next step reaction.
In 250 liters of stills, add the product 30kg of previous step, 150 liters of methyl acetoacetate 3kg and acetic acid, the mixture that in batches adds 50kg zinc powder and 50kg sodium-acetate, the control feed rate makes temperature be no more than 85 degree, finish, spend insulation reaction 2 hours 75, after reacting completely, cooling is poured reaction solution in 1000 liters of frozen water into, separates out a large amount of solids, suction filtration is with small amount of ethanol washing, oven dry, get the about 30kg of product, be directly used in next step reaction.
In 250 liters of stills, add the product 30kg of previous step, 100 liters of ethanol drip 50 liters of concentrated hydrochloric acids, finish, heating reflux reaction to raw material disappears, and slowly pours reaction solution into 500 liters of frozen water, has a large amount of solids to separate out, suction filtration, oven dry obtains the about 15kg of pink solid, is directly used in next step reaction.
Previous step product 15kg, 10 liters in water, 100 liters of methyl alcohol, add potassium hydroxide 25kg, reflux, reaction concentrates methyl alcohol after finishing, the a small amount of dichloromethane extraction of residuum, water concentrated hydrochloric acid pH=1 separates out a large amount of solids, suction filtration, a small amount of cold water washing 2-3 time, 50 degree are dry, get the about 10kg of pink solid, are directly used in next step reaction.
The raw material of 10kg previous step is dissolved in 100 liters of tetrahydrofuran (THF)s, add the 20kg carbonyl dimidazoles in batches, finish, stirred 30 minutes, drip N, N-diethyl ethylenediamine 10kg is dissolved in the solution of 5 liters of tetrahydrofuran (THF)s, and reaction concentrates tetrahydrofuran (THF) after finishing, and adds 30 liters in water, use dichloromethane extraction, drying, concentrate the about 12kg of dark red liquid, be directly used in next step reaction.
4 liters of DMF are dissolved in 60 liters of the methylene dichloride, the following dropping of 0 degree 6kg oxalyl chloride is dissolved in the solution of 10 liters of methylene dichloride, controlled temperature is no more than 5 degree, there are a large amount of white solids to produce, finish, insulation continues to stir 2 hours, drips the solution that previous step product 12kg is dissolved in 10 liters of methylene dichloride, and controlled temperature is no more than 10 degree.Concentrate methylene dichloride after reaction finishes, residuum is dissolved in 50 premium on currency, is neutralized to pH=14 with 10N potassium hydroxide, reflux, cooling, product is separated out, filtration, dry faint yellow solid 10kg, be directly used in next step reaction.
Previous step product 10kg and 5-fluoro indole ketone 8kg, 100 liters of dehydrated alcohols, the piperidinyl-1 liter, reflux, reaction is chilled to room temperature after finishing, and filters, and uses washing with acetone, the dry about 12kg of product that gets, purity is greater than 99%.
Claims (4)
1, a kind of synthetic method of Sutent is characterized in that this method comprises the steps:
1. be starting raw material with tert-butyl acetoacetate and acetylacetic ester, obtain quaternary pyrroles by the nitrosification reduction reaction; 2. quaternary pyrroles is hydrolyzed to react and obtains 2,4-dimethyl pyrrole-3-formic acid; 3. 2,4-dimethyl pyrrole-3-formic acid carries out amidation; 4. utilize Vilsmeier-Hacck to be reflected at 5 last aldehyde radicals of pyrroles again; 5. last and 5-fluoro indole reactive ketone obtains Sutent;
Wherein acetylacetic ester is the acetylacetic ester of 1-4 carbon.
2, synthetic method according to claim 1 is characterized in that step hydrolysis reaction 2. in two steps, and the first step is acidic hydrolysis decarboxylation simultaneously, and its used acid is hydrochloric acid, sulfuric acid, formic acid or trifluoracetic acid; Second step was alkaline hydrolysis, and its used alkali is lithium hydroxide, sodium hydroxide or potassium hydroxide.
3, synthetic method according to claim 1 is characterized in that during step 3. 2, and the amidation of 4-dimethyl pyrrole-3-formic acid is condensation reagent with the carbonyl dimidazoles, and solvent uses ethylene dichloride, tetrahydrofuran (THF), 1,2-ethylene dichloride, ethyl acetate or acetonitrile.
4, synthetic method according to claim 1 is characterized in that step being reflected in the organic solvent 5. carry out, and wherein organic solvent is ethylene dichloride, tetrahydrofuran (THF), 1,2-ethylene dichloride, ethyl acetate or acetonitrile; The alkali that condensation is used is mineral alkali or organic bases, wherein mineral alkali is lithium hydroxide, potassium hydroxide or sodium hydroxide, organic bases is triethylamine, diisopropyl ethyl amine, pyridine, piperidines, Tocosamine, piperidines, Pyrrolidine or 1.8-diazabicylo 11 are rare-7, and wherein the reaction density scope of alkali in reaction solution is 0.1M-10M.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
| WO2012058780A1 (en) * | 2010-11-01 | 2012-05-10 | Scinopharm (Kunshan) Biochemical Technology Co., Ltd. | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| CN103319392A (en) * | 2013-07-10 | 2013-09-25 | 张家港市华昌药业有限公司 | Preparation method of sunitinib intermediate |
| WO2013140232A1 (en) * | 2012-03-23 | 2013-09-26 | Laurus Labs Private Limited | An improved process for the preparation of sunitinib and its acid addition salts thereof |
| CN112321569A (en) * | 2020-10-12 | 2021-02-05 | 福建南方制药股份有限公司 | Method for controlling impurity difficult to remove in synthesis of anti-tumor drug sunitinib |
Family Cites Families (2)
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| CN101146549A (en) * | 2005-02-18 | 2008-03-19 | 诺华疫苗和诊断公司 | Antiangiogenic agents and aldesleukin |
| CN101033226B (en) * | 2007-04-06 | 2010-05-19 | 复旦大学 | 1-furylmethyl-3-substituted indolin-2-one derivative |
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| WO2012058780A1 (en) * | 2010-11-01 | 2012-05-10 | Scinopharm (Kunshan) Biochemical Technology Co., Ltd. | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| CN103328465A (en) * | 2010-11-01 | 2013-09-25 | 神隆(昆山)生化科技有限公司 | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| JP2013540779A (en) * | 2010-11-01 | 2013-11-07 | サイノファーム （クンシャン） バイオケミカル テクノロジ カンパニー リミテッド | Method for preparing 3-((pyrrol-2-yl) methylene) -2-pyrrolone using 2-silyloxy-pyrrole |
| KR20130141570A (en) * | 2010-11-01 | 2013-12-26 | 시노팜 (쿤샨) 바이오케미컬 테크놀로지 컴퍼니, 리미티드 | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| US8846953B2 (en) | 2010-11-01 | 2014-09-30 | Scinopharm Taiwan, Ltd. | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| KR101696016B1 (en) | 2010-11-01 | 2017-01-13 | 시노팜 (쿤샨) 바이오케미컬 테크놀로지 컴퍼니, 리미티드 | Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles |
| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
| WO2013140232A1 (en) * | 2012-03-23 | 2013-09-26 | Laurus Labs Private Limited | An improved process for the preparation of sunitinib and its acid addition salts thereof |
| US9206163B2 (en) | 2012-03-23 | 2015-12-08 | Laurus Labs Private Ltd. | Process for the preparation of sunitinib and its acid addition salts thereof |
| CN103319392A (en) * | 2013-07-10 | 2013-09-25 | 张家港市华昌药业有限公司 | Preparation method of sunitinib intermediate |
| CN103319392B (en) * | 2013-07-10 | 2015-10-28 | 张家港市华昌药业有限公司 | A kind of preparation method of sutent intermediate |
| CN112321569A (en) * | 2020-10-12 | 2021-02-05 | 福建南方制药股份有限公司 | Method for controlling impurity difficult to remove in synthesis of anti-tumor drug sunitinib |
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Effective date of registration: 20100325 Address after: 200444, No. 868, Chen Cheng Road, No. 2, Shanghai, Baoshan District Applicant after: Parling Shanghai Pharm-technology Co., Ltd. Co-applicant after: Fujian South Pharmaceutical Co., Ltd. Address before: 200444, No. 868, Chen Cheng Road, No. 2, Shanghai, Baoshan District Applicant before: Parling Shanghai Pharm-technology Co., Ltd. |
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Effective date of registration: 20160707 Address after: Mingxi County of Sanming City province Fujian 365200 Xuefeng New Town Road No. 98 Patentee after: Fujian South Pharmaceutical Co., Ltd. Address before: 200444, No. 868, Chen Cheng Road, No. 2, Shanghai, Baoshan District Patentee before: Parling Shanghai Pharm-technology Co., Ltd. Patentee before: Fujian South Pharmaceutical Co., Ltd. |