CN103288736B - A kind of preparation method of eslicarbazepine intermediate - Google Patents
A kind of preparation method of eslicarbazepine intermediate Download PDFInfo
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- CN103288736B CN103288736B CN201310047057.2A CN201310047057A CN103288736B CN 103288736 B CN103288736 B CN 103288736B CN 201310047057 A CN201310047057 A CN 201310047057A CN 103288736 B CN103288736 B CN 103288736B
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- 0 C*1(C)c(cccc2)c2C(*)=Cc2c1cccc2 Chemical compound C*1(C)c(cccc2)c2C(*)=Cc2c1cccc2 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N O=C(OCc1ccccc1)Cl Chemical compound O=C(OCc1ccccc1)Cl HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- VSZGCLXGCOECAY-UHFFFAOYSA-N O=C1c(cccc2)c2Nc2ccccc2C1 Chemical compound O=C1c(cccc2)c2Nc2ccccc2C1 VSZGCLXGCOECAY-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a kind of preparation method of eslicarbazepine intermediate, it is with 5H-dibenzo [B, F] azepine-10 (11H)-one (compound III) is raw material, react with phosgene, trichloromethylchloroformate, triphosgene, chloro-formic ester compounds or chloroformyl sulphinyl chlorine, obtain Compound II per; Compound II per carries out ammonolysis reaction and obtains final product under the existence of ammonia; Present invention process route is shorter, and low in raw material price is simple and quick, and cost is lower, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to chemicals preparation field, be specifically related to a kind of preparation method of eslicarbazepine intermediate.
Background technology
Eslicarbazepine (code name is BIA-2-093), be the exploitation listing of Bial drugmaker of Portugal be mainly used in treat the Newer antiepileptic that pain in epilepsy, affective brain disorders and degeneration and post-ischemic diseases and neural function replace illness, be the prodrug of CBZ class the 3rd generation medicine (S)-(+)-10,11-dihydro-10-hydroxy-5H dibenz/b,f/azepine-5-carboxamide, the active metabolite of OXC.III phase clinical studies show: when eslicarbazepine and other antiepileptic drug combined utilization, effectively can reduce the outbreak frequency of epilepsy partial seizures patient, and security is good, and can patients ' life quality be improved, there are wide market outlook.
10,11-dihydro-10-oxo-5H-dibenzo [b, f] azepine-5-carboxamide (OCBZ) is the important intermediate preparing eslicarbazepine, and its structural formula is shown below:
OCBZ synthesis report is more, mainly contains the 3 class synthetic methods such as iminostilbene method, Carbamzepine method (patent of invention DE2246842), 10-methoxyl group Carbamzepine method (patent of invention US032800).Carbamzepine method and 10-methoxyl group Carbamzepine method also exist cost of material and the problem such as production cost is higher, are unfavorable for suitability for industrialized production.
The present invention is that eslicarbazepine intermediate OCBZ prepared by raw material with 5H-dibenzo [B, F] azepine-10 (11H)-one.Before making the present invention, US Patent No. 20050282797 discloses a kind of synthetic method of OCBZ.Concrete route is as follows:
10-methoxyimino stilbene (compound 1) and hydrochloric acid reaction have been prepared 5H-dibenzo [B by this route, F] azepine-10 (11H)-one (compound 2), then compound 2 and Sulfuryl chloride isocyanate are reacted, obtain compound 3, then obtain final product through hydrolysis.Above-mentioned preparation method uses the toxicant Sulfuryl chloride isocyanate of deep-etching, is unfavorable for suitability for industrialized production.
Patent of invention WO0055138 (A1) discloses a kind of OCBZ preparation method, and concrete scheme is shown below:
This technique iminostilbene carbonyl chloride (compound 1 ') is raw material, with oxynitrides through nitration reaction, prepare compound 2 ', then under iron powder and hydrochloric acid effect, reduction reaction obtains 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (compound 3 '), last and ammonia gas react, prepares OCBZ.Nitration reaction in the method, complicated operation, by product is more, applies hypertoxic corrosives nitrogen tetroxide simultaneously, is unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is, for above problem, to overcome the deficiencies in the prior art, the synthetic method of a kind of eslicarbazepine intermediate OCBZ is provided.Present invention process route is shorter, and low in raw material price is simple and quick, and cost is lower, is applicable to suitability for industrialized production.
Object of the present invention can be reached by following measures:
A preparation method for formula I, it comprises the steps:
A, compound III and phosgene, trichloromethylchloroformate, triphosgene, chloro-formic ester compounds or chloroformyl sulphinyl chlorine react, and obtain Compound II per;
B, Compound II per carry out ammonolysis reaction and obtain Compound I under the existence of ammonia;
Wherein, X is chlorine, substituted alkoxy or substituent phenoxy, and described substituting group is selected from one or more in hydrogen, halogen, phenyl, halogenophenyl, nitrophenyl.
In the present invention, chloro-formic ester compounds is selected from chloroformic acid substituted alkyl ester, chloroformic acid substituted cycloalkyl ester or substituted phenyl chloroformate, and described substituting group is selected from one or more in hydrogen, halogen, phenyl, halogenophenyl, nitrophenyl;
Further, chloro-formic ester compounds is selected from Vinyl chloroformate, propyl chloroformate, phenyl chloroformate, chloroformic acid benzyl ester, methyl-chloroformate, cyclohexyl chloroformate, p-nitrophenyl chloro-formic ester or chloroformic acid-2,2,2-trichloro ethyl ester.
Compound III is 1:(1 ~ 10 with the mol ratio of reacting with phosgene, trichloromethylchloroformate, triphosgene, chloro-formic ester compounds or chloroformyl sulphinyl chlorine).
Further, in step, when compound III is with when reacting with phosgene, trichloromethylchloroformate, triphosgene or chloro-formic ester compounds, alkali can be selected as catalyzer, comprise mineral alkali or organic bases; Described alkali is preferably selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, pyridine, tri-n-butylamine, tri-tert amine, sodium hydrogen, sodium methylate or sodium ethylate or sodium tert-butoxide; The mol ratio of compound III and alkali is 1:(0.1 ~ 10).The temperature of its reaction controls at-20 ~ 100 DEG C; Preferably, compound III be 30 ~ 90 DEG C with the temperature of reaction of phosgene, trichloromethylchloroformate or triphosgene; The temperature of reaction of compound III and chloro-formic ester compounds is 20 ~ 60 DEG C.
Further, in step, when compound III and chloro-formic ester compounds or chloroformyl sulphinyl chlorine react, first compound III and chloro-formic ester compounds or chloroformyl sulphinyl chlorine are reacted, then add chlorination reagent and carry out chlorination reaction; Described chlorination reagent is selected from sulfur oxychloride, chlorine or phosphorus trichloride.The temperature of its reaction controls at-20 ~ 100 DEG C; Preferably, temperature when compound III and chloro-formic ester compounds or chloroformyl sulphinyl chlorine react is 30 ~ 50 DEG C, and the temperature of chlorination reaction is 20 ~ 30 DEG C, and the mol ratio of compound III and chlorination reagent is 1:(1 ~ 20).
Further, in step, compound III and chloro-formic ester compounds react under the catalysis of alkali, obtain Compound II per; Described chloro-formic ester compounds is selected from chloroformic acid substituted alkyl ester, chloroformic acid substituted cycloalkyl ester or substituted phenyl chloroformate, and described substituting group is selected from one or more in halogen, phenyl, halogenophenyl, nitrophenyl.The temperature of its reaction controls at-20 ~ 100 DEG C; Preferably, the temperature that compound III and chloro-formic ester carry out reacting under the catalysis of alkali is 20 to 60 DEG C.
In step, reactant compound III (and alkaline catalysts) first dissolves in organic solvent by compound III and chlorine alkylcarbonic acid ester compound, chloroformyl sulphinyl chlorine or can adopt with the feeding mode that any one compound in phosgene, trichloromethylchloroformate, triphosgene reacts, and the solution then preparing chlorine alkyl carbonate, chloroformyl sulphinyl chlorine or chloro-formic ester is added dropwise to the mode of reaction system.
In stepb, described ammonia is ammoniacal liquor or ammonia; The temperature of reaction controls at-20 ~ 70 DEG C, preferably 20 ~ 70 DEG C.Further, when X in compound ii be substituted alkoxy or substituent phenoxy time, the preparation of compound III can adopt and is dissolved in methyl alcohol or ethanolic soln by compound ii, passes into ammonia or drip ammoniacal liquor to carry out ammonolysis reaction and obtain compound III.The temperature of reaction controls at-20 ~ 70 DEG C.When X in compound ii is chlorine, passes into ammonia by the reaction system of compound ii, be obtained by reacting compound III.
Concrete reaction scheme of the present invention is shown below (wherein R is substituted alkyl or substituted-phenyl):
A kind of concrete technology of the present invention is as follows:
Route is a): select compound III to be raw material, carry out being obtained by reacting compound ii with any one compound with phosgene, trichloromethylchloroformate or triphosgene under the catalysis of alkali ', the temperature of reaction controls at-20 ~ 100 DEG C, and the reaction times is 0.5 ~ 24h; Or be first such as Vinyl chloroformate, propyl chloroformate, phenyl chloroformate, chloroformic acid benzyl ester, methyl-chloroformate, cyclohexyl chloroformate, p-nitrophenyl chloro-formic ester or chloroformic acid-2 by compound III and chloroformyl sulphinyl chlorine and chloro-formic ester compounds, 2, any one compound in 2-trichloro ethyl ester reacts under the catalysis of alkali, then add chlorination reagent and obtain compound ii ', the temperature of reaction controls at-20 ~ 60 DEG C, and the reaction times is 0.5 ~ 48h.Then by compound ii ' reaction system in pass into ammonia, be obtained by reacting chemical compounds I.
Route b): select compound III to be raw material, such as Vinyl chloroformate, propyl chloroformate, phenyl chloroformate, chloroformic acid benzyl ester, methyl-chloroformate, cyclohexyl chloroformate, p-nitrophenyl chloro-formic ester or chloroformic acid-2 with chloro-formic ester compounds, 2, any one compound in 2-trichloro ethyl ester reacts under the effect of alkali, generate compound ii " '; the temperature of reaction controls at-20 ~ 60 DEG C, and the reaction times is 0.5 ~ 24h.Then by compound ii " ' be dissolved in methyl alcohol or ethanolic soln, pass into ammonia or drip ammoniacal liquor and carry out ammonolysis reaction and obtain chemical compounds I; The temperature of reaction controls at-20 ~ 70 DEG C, and the reaction times is 0.5 ~ 48h.
Alkyl in the present invention comprises straight or branched alkyl-alkyl, and as nothing clearly states, the alkyl in the present invention refers to C
1 ~ 6alkyl, preferred C
1 ~ 4alkyl, most preferably C
1 ~ 2alkyl.
Cycloalkyl in the present invention, as without clearly stating, refers to C
3 ~ 8cycloalkyl, preferred C
3 ~ 6cycloalkyl, most preferably C
6cycloalkyl.
Beneficial effect of the present invention:
Technique was compared more in the past, and the processing step that the present invention synthesizes OCBZ is shorter, the low in raw material price selected, and simple and quick, production cost is lower.
Embodiment
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
The preparation of embodiment 1 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (compound ii)
100g5H-dibenzo [B is added successively in 3L there-necked flask, F] azepine-10 (11H)-one (compound III), 800ml toluene, 75g triethylamine, 75g triphosgene (BTC) is dissolved in 200ml toluene, drop in reaction solution, temperature is less than 60 DEG C, add and be heated to 90 DEG C of reaction 4h, TLC detection reaction terminates rear heat filtering, filtrate decompression is spin-dried for, residuum adds 600ml ethyl alcohol recrystallization, cooling, suction filtration, filter cake 50 DEG C of vacuum-drying 6h obtain yellow solid (compound ii) 114.7g, yield 89.7%.
1H NMR(400MHz,CDCl3)δ:3.87(d,1H),4.49(d,1H),7.37-7.46(m,4H),7.55(t,1H),7.63(t,1H),7.70(d,1H),8.15(d,1H).MS(m/z):272。
The preparation of embodiment 2 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (compound ii ')
At room temperature in the solution being dissolved in the compound III 100g of methylene dichloride (600ml), pyridine 38g, drip Vinyl chloroformate 57g gradually, back flow reaction is spent the night, TLC detection reaction terminates, by the solid filtering in system, drip methylene dichloride (400ml) solution of sulfur oxychloride 113g, react 10h under room temperature, TLC monitoring reaction terminates.Be poured in trash ice, be separated organic layer, and extract water layer by methylene dichloride (200ml × 3).Then with saturated sodium bicarbonate and salt water washing organic layer.Steam after anhydrous sodium sulfate drying and desolventize, residuum adds 600ml ethyl alcohol recrystallization, cooling, suction filtration, and filter cake 50 DEG C of vacuum-drying 6h obtain yellow solid (compound ii ') 98g, yield 76.6%.
1H NMR(400MHz,CDCl3)δ:3.87(d,1H),4.49(d,1H),7.37-7.46(m,4H),7.55(t,1H),7.63(t,1H),7.70(d,1H),8.15(d,1H).MS(m/z):272。
The preparation of embodiment 3 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (compound ii ')
Under room temperature under nitrogen protection to be dissolved in methylene dichloride (400ml) compound III 100g solution in drip methylene dichloride (200ml) solution of chloroformyl sulphinyl chlorine 68.9g gradually; temperature rising reflux reaction 3h; TLC detection reaction terminates; chlorine is passed under room temperature; reaction 2h, TLC monitoring reaction terminates.Be poured in frozen water, be separated organic layer, and extract water layer by methylene dichloride (200ml × 3).Then with saturated sodium bicarbonate and salt water washing organic layer.Steam after anhydrous sodium sulfate drying and desolventize, residuum adds 600ml ethyl alcohol recrystallization, cooling, suction filtration, and filter cake 50 DEG C of vacuum-drying 6h obtain yellow solid (compound ii ') 100.1g, yield 78.2%.
1H NMR(400MHz,CDCl3)δ:3.87(d,1H),4.49(d,1H),7.37-7.46(m,4H),7.55(t,1H),7.63(t,1H),7.70(d,1H),8.15(d,1H).MS(m/z):272。
The preparation of embodiment 4 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acid amides benzyl ester (compound ii ")
By the dry DMF(100ml of sodium methylate (18.5g) at-5 ~ 5 DEG C) drip compound III (50g) dry DMF(150ml in solution) solution, after dropwising, 0 ~ 20 DEG C is stirred 1h, then add chloroformic acid benzyl ester (48.8g), react 3h under room temperature, TLC monitoring reaction terminates.Slowly add frozen water 200ml, stir 10min, then add ethyl acetate 150m, stir separatory, separate organic phase, then with saturated sodium bicarbonate and salt water washing organic layer.After anhydrous sodium sulfate drying, concentrating under reduced pressure, residuum adds 300ml re-crystallizing in ethyl acetate, cooling, suction filtration, and filter cake 50 DEG C of vacuum-drying 6h obtain yellow solid (compound ii ") 69.7g, yield 85%.
1H NMR(400MHz,CDCl3)δ:3.88(d,1H),4.49(d,1H),5.10(s,2H),7.34-7.48(m,7H),7.50－7.58(m,4H),7.69(d,1H),8.08(d,1H).MS(m/z):344。
The preparation of embodiment 5 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (chemical compounds I)
100g10 is added successively in 1L round-bottomed flask, 11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (compound ii ') and 800ml methyl alcohol, reaction solution is heated to backflow, pass into ammonia, reaction 3h, TLC detection reaction terminates rear steaming and desolventizes, and adds 1L water and stirs 6h, suction filtration, filter cake 60 DEG C of forced air drying 12h, obtain off-white color solid (chemical compounds I) 92.6g, yield 99.3%.
Recrystallization: 100g3 adds 1.6L Virahol, is heated to backflow, dissolves, adds 320ml water, and backflow 1h, ice-water bath crystallization, suction filtration, 50 DEG C of forced air drying 12h, obtain off-white color solid 80g, yield 80%.
1H NMR(400MHz,CDCl3)δ:3.85(d,J=13.8Hz,1H),4.47(d,J=13.8Hz,1H),5.04(s,2H),7.34-7.43(m,4H),7.51(t,J=4.5Hz,1H),7.60(t,J=4.5Hz,1H),7.68(d,J=7.5Hz,1H),8.11(d,J=7.5Hz,1H).MS(m/z):253。
The preparation of embodiment 6 10,11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (chemical compounds I)
10 are added successively in 500ml round-bottomed flask, 11-dihydro-10-oxo-5H-Dibenzo [B, F] azepine-5-acyl chlorides (compound ii " 35g) and 300ml methyl alcohol, pass into ammonia under room temperature, reaction 4h; TLC detection reaction terminates rear steaming except methyl alcohol; add 500ml water and stir 5h, suction filtration, filter cake 60 DEG C of forced air drying 12h; obtain off-white color solid (chemical compounds I) 24.7g, yield 98.1%.
Recrystallization: 20g3 adds 150ml Virahol, is heated to backflow, dissolves, adds 50ml water, and backflow 1h, ice-water bath crystallization, suction filtration, 50 DEG C of forced air drying 12h, obtain off-white color solid 17g, yield 85%.
1H NMR(400MHz,CDCl3)δ:3.85(d,J=13.8Hz,1H),4.47(d,J=13.8Hz,1H),5.04(s,2H),7.34-7.43(m,4H),7.51(t,J=4.5Hz,1H),7.60(t,J=4.5Hz,1H),7.68(d,J=7.5Hz,1H),8.11(d,J=7.5Hz,1H).MS(m/z):253。
Claims (9)
1. a preparation method for formula I, is characterized in that comprising the steps:
A, compound III and phosgene, trichloromethylchloroformate, triphosgene, chloro-formic ester compounds or chloroformyl sulphinyl chlorine react, and obtain Compound II per; When compound III and phosgene, trichloromethylchloroformate, triphosgene or chloro-formic ester compounds react, select alkali as catalyzer; When compound III and phosgene, trichloromethylchloroformate, triphosgene are reacted, reaction solvent is toluene; When compound III and chloro-formic ester compounds or chloroformyl sulphinyl chlorine react, first compound III and chloro-formic ester compounds or chloroformyl sulphinyl chlorine are reacted, then add chlorination reagent and carry out chlorination reaction; Described chlorination reagent is selected from sulfur oxychloride, chlorine or phosphorus trichloride;
B, Compound II per carry out ammonolysis reaction and obtain Compound I under the existence of ammonia; Described ammonia is ammonia, and reaction solvent is methyl alcohol or ethanol;
Wherein, X is chlorine, substituted alkoxy or substituent phenoxy, and described substituting group is selected from one or more in hydrogen, halogen, phenyl, halogenophenyl, nitrophenyl.
2. method according to claim 1, it is characterized in that described chloro-formic ester compounds is selected from chloroformic acid substituted alkyl ester, chloroformic acid substituted cycloalkyl ester or substituted phenyl chloroformate, described substituting group is selected from one or more in hydrogen, halogen, phenyl, halogenophenyl, nitrophenyl.
3. method according to claim 2, it is characterized in that described chloro-formic ester compounds is selected from Vinyl chloroformate, propyl chloroformate, phenyl chloroformate, chloroformic acid benzyl ester, methyl-chloroformate, cyclohexyl chloroformate, p-nitrophenyl chloro-formic ester or chloroformic acid-2,2,2-trichloro ethyl ester.
4. method according to claim 1, is characterized in that in step, when compound III and phosgene, trichloromethylchloroformate, triphosgene or chloro-formic ester compounds react, selects alkali as catalyzer; Described alkali is selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, pyridine, tri-n-butylamine, tri-tert amine, sodium hydrogen, sodium methylate or sodium ethylate or sodium tert-butoxide; The mol ratio of compound III and alkali is 1:(0.1 ~ 10).
5. method according to claim 4, is characterized in that the temperature of reaction of compound III and phosgene, trichloromethylchloroformate or triphosgene is 30 ~ 100 DEG C; The temperature of reaction of compound III and chloro-formic ester compounds is 20 ~ 60 DEG C.
6. method according to claim 1, it is characterized in that temperature when compound III and chloro-formic ester compounds or chloroformyl sulphinyl chlorine are reacted is 30 ~ 50 DEG C, the temperature of chlorination reaction is 20 ~ 30 DEG C, and the mol ratio of compound III and chlorination reagent is 1:(1 ~ 20).
7. method according to claim 4, is characterized in that in step, and compound III and chloro-formic ester compounds react under the catalysis of alkali, obtain Compound II per; Described chloro-formic ester compounds is selected from chloroformic acid substituted alkyl ester, chloroformic acid substituted cycloalkyl ester or substituted phenyl chloroformate, and described substituting group is selected from one or more in halogen, phenyl, halogenophenyl, nitrophenyl.
8. method according to claim 7, is characterized in that the temperature that compound III and chloro-formic ester compounds carry out reacting under the catalysis of alkali is 20 DEG C to 60 DEG C.
9. method according to claim 1, is characterized in that in step B, and the temperature of ammonolysis reaction controls at-20 ~ 70 DEG C.
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|---|---|---|---|---|
| US4540514A (en) * | 1979-10-30 | 1985-09-10 | Ciba-Geigy Corporation | 5-Cyano- and 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine |
| WO2000055138A1 (en) * | 1999-03-15 | 2000-09-21 | Dsm Fine Chemicals Austria Gmbh | Method of producing oxcarbazepine (=10,11- dihydro- 10- oxo- 5h- dibenz(b,f)- azepine- 5- carboxamide) and its intermediate products |
| CN1944411A (en) * | 2006-11-01 | 2007-04-11 | 浙江工业大学 | Chemically synthetic method for N-chloroformyl imino dibenzyl |
| CN1944410A (en) * | 2006-11-01 | 2007-04-11 | 浙江工业大学 | Chemically synthetic method for N-chloroformyl imino dibenzyl |
| CN101302198A (en) * | 2008-07-03 | 2008-11-12 | 浙江九洲药业股份有限公司 | Chemical synthetic method of azepine derivate |
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- 2013-02-05 CN CN201310047057.2A patent/CN103288736B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4540514A (en) * | 1979-10-30 | 1985-09-10 | Ciba-Geigy Corporation | 5-Cyano- and 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine |
| WO2000055138A1 (en) * | 1999-03-15 | 2000-09-21 | Dsm Fine Chemicals Austria Gmbh | Method of producing oxcarbazepine (=10,11- dihydro- 10- oxo- 5h- dibenz(b,f)- azepine- 5- carboxamide) and its intermediate products |
| CN1944411A (en) * | 2006-11-01 | 2007-04-11 | 浙江工业大学 | Chemically synthetic method for N-chloroformyl imino dibenzyl |
| CN1944410A (en) * | 2006-11-01 | 2007-04-11 | 浙江工业大学 | Chemically synthetic method for N-chloroformyl imino dibenzyl |
| CN101302198A (en) * | 2008-07-03 | 2008-11-12 | 浙江九洲药业股份有限公司 | Chemical synthetic method of azepine derivate |
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Address after: 210046 C3, Jiangsu Huawei medical building, 9 Wei Di Road, Qixia District, Nanjing. Patentee after: Nanjing Huawei Medicine Technology Group Co Ltd Address before: 210012 Huawei science and technology building, 8 Huahua Road, Nanjing, Jiangsu Patentee before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |