CN102199154A - Novel synthesis method for pyrrole derivatives - Google Patents
Novel synthesis method for pyrrole derivatives Download PDFInfo
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- CN102199154A CN102199154A CN2011100248499A CN201110024849A CN102199154A CN 102199154 A CN102199154 A CN 102199154A CN 2011100248499 A CN2011100248499 A CN 2011100248499A CN 201110024849 A CN201110024849 A CN 201110024849A CN 102199154 A CN102199154 A CN 102199154A
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- 150000003233 pyrroles Chemical class 0.000 title abstract description 5
- 238000001308 synthesis method Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000006837 decompression Effects 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- -1 sec.-propyl Chemical group 0.000 claims description 6
- 235000021419 vinegar Nutrition 0.000 claims description 6
- 239000000052 vinegar Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 3
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 abstract 2
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- WENZNTBBHOBISN-UHFFFAOYSA-N pyrrole-1,2-dicarboxylic acid Chemical compound OC(=O)C1=CC=CN1C(O)=O WENZNTBBHOBISN-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- PGTANUNIOXCVLE-UHFFFAOYSA-N CC.[Br] Chemical compound CC.[Br] PGTANUNIOXCVLE-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a novel method for high-efficiency preparation of pyrrole 1,2-dicarboxylic acid and derivatives thereof. Pyrrole derivatives are synthesized from inexpensive and easily available 2-pyrrole carboxylic acid ester compound used as a raw material through bromination, decarboxylation and other unit reactions easy and simple to operate.
Description
Technical field
The present invention relates to organic synthesis fields such as medicine, agricultural chemicals and dyestuff, be mainly the novel method of the adjacent disubstituted derivatives of a kind of efficient production pyrroles.
Background technology
Formula (I)
Suc as formula the chemical structure shown in (I) is a class important intermediate in organic synthesis fields such as medicine, agricultural chemicals and dyestuff, for example at Chemical and Pharmaceutical Bulletin, 1997, vol.45, #10, p.1642-1652 mentioning in, is that formula (I) compound of methyl and the reaction of single fluorobenzene are as NK with R
1Receptor antagonist candidate compound synthetic important method.
Disclosed at present similar compound comprises following compound at least:
Because the special property of electron rich pyrrole ring, make adjacent disubstituted pyrroles compounds especially 2, the synthetic relatively difficulty of 3-disubstituted pyrroles compound, its synthetic method rarely has report at present.
Summary of the invention:
Technical problem to be solved by this invention provides the method for a kind of rational synthesis type (I).
Wherein, the R base is selected from methyl, ethyl, propyl group, sec.-propyl, phenyl, halogenophenyl, haloalkyl phenyl, benzyl.Method of the present invention comprises:
A, starting raw material S1 is carried out the dibrominated after saponification at 2,3, decarboxylation forms intermediate S4;
B, S4 carried out R base replace on N, then by with the metal reagent permutoid reaction, feed CO
2, acidifying obtains S6;
C, adjacent dicarboxylic acid dehydration formation formula (I) compound.
Dibrominated can also two iodate replace the subsequent step unanimity among the above-mentioned reactions steps A.
The reaction conditions of above-mentioned reactions steps A is, S1 is dissolved in for example tetracol phenixin of organic solvent in the presence of the catalytic amount iodine, and the slow carbon tetrachloride solution of dropping liquid bromine at room temperature at room temperature stirs after dripping off then, and decompression steams solvent, obtains S2; S2 is added 20% NaOH solution, in 60～90 ℃ of reaction 2～6h, be acidified to pH 2-3 with 6N HCl then, treat that a large amount of white solids separate out, filtration final vacuum drying obtains S3; S3 is added an amount of monoethanolamine,, finish postcooling, add entry, with organic solvent extracted with diethyl ether for example to room temperature in 100 ℃ of heated and stirred 1-3h; The extraction liquid washing is dry, and concentrating under reduced pressure is directly used in next step reaction;
The reaction conditions of above-mentioned reactions steps B is that S4 solution in 0 ℃, is slowly dropped in the DMF solution of sodium hydride, after stirring 15min, slowly drip BrR, wherein the definition of R base is the same, rises to room temperature reaction 2-4h then, after the end, reaction solution is slowly poured in the frozen water, and with organic solvent extracted with diethyl ether for example, the organic phase washing is dry, concentrating under reduced pressure uses column chromatography purifying and obtains light yellow liquid S5; S5 is dissolved in organic solvent for example among the THF, is cooled to-78 ℃, slowly drip n-BuLi or MAGNESIUM METAL grignard reagent, stir 30min down in-78 ℃, feed CO
2Gas reaction 1-2.5h slowly rises to room temperature then, continues stirring reaction 1-2h.After reaction finishes, reaction solution is slowly poured in the frozen water, being acidified to pH with 2N dilute hydrochloric acid is about 2, and with organic solvent ethyl acetate extraction for example, drying behind the concentrating under reduced pressure, is carried out column chromatography and got the white solid compound s 6;
The reaction conditions of above-mentioned reactions steps C is that with compound s 6 and the dried reflux 3-4h of vinegar, decompression steams vinegar and does, and can get white solid compound formula (I) by purification by silica gel column chromatography then.
The present invention also provides a kind of new intermediate S7, and its structural formula is
Beneficial effect of the present invention is:
One, provide a kind of feasible preparation 2, the synthetic route of 3-pyrroles's acid anhydrides, and can be used for further reaction formation 2,3-disubstituted pyrroles compound;
Two, the yield of each step reaction is higher, more than 74%;
Three, provide a kind of alternative new intermediate S7.
Embodiment:
Content of the present invention is further elaborated by following embodiment, but does not limit the scope of the invention.Embodiment: preparation 1-ethyl-3-(4-fluorobenzoyl)-1H-pyrroles-2-carboxylic acid (1)
With S1 (2.0g, 14.4mmol) and catalytic amount iodine (3mg) place the single port flask of 100ml, adding the 40ml tetracol phenixin dissolves it, at room temperature slow then dropping liquid bromine (4.6g, 28.8mmol) tetracol phenixin (20ml) solution, at room temperature stir 2h after dripping off, decompression steams the solid crude product of solvent, purification by silica gel column chromatography (PE/EtOAc=30/1-20/1) obtains 4.05g compound S 2 then, productive rate 95.0%.
(2.0g 6.7mmol) places the single port flask of 100ml, adds 20% NaOH solution (20ml) with S2, in 85 ℃ of reaction 4h, be acidified to pH 2-3 with 6N HCl then, a large amount of white solids are separated out, filtration final vacuum drying gets 1.78g white solid compound S 3, productive rate 98.3%.
(1g 3.7mmol) places the single port flask of 50ml, adds the 10ml monoethanolamine, in 100 ℃ of heated and stirred 2h, finishes postcooling to room temperature, adds 40ml water, with ether (30ml*3) extraction with S3; Ether extraction liquid is used 2N dilute hydrochloric acid, saturated common salt water washing respectively once, uses anhydrous sodium sulfate drying then, and the S4 solution that is evaporated to 20ml is directly used in next step reaction.
With S4 solution in 0 ℃, slowly drop to sodium hydride (297.5mg, 7.4mmol) DMF (10ml) solution in, after stirring 15min, slow dripping bromine ethane (806.4g, 7.4mmol), rise to room temperature reaction 4h then, after the end, slowly pour into reaction solution in the frozen water, with extracted with diethyl ether (30ml*3), organic phase with the saturated common salt water washing is once used anhydrous sodium sulfate drying, concentrating under reduced pressure then, with silicagel column separation and purification (eluent: PE/EtOAc=40/1-30/1) obtain 696.1mg light yellow liquid S5, productive rate 74.0%.
(696.1mg 2.75mmol) is dissolved in THF (15ml), and solution places the low-temp reaction instrument, is cooled to-78 ℃, and (1.6M 3.6ml), stirs 30min down, feeding CO in-78 ℃ slowly to drip n-BuLi with S5
2Gas reaction 1.5h slowly rises to room temperature then, continues stirring reaction 1h.After reaction finishes, slowly pour into reaction solution in the frozen water, being acidified to pH with 2N dilute hydrochloric acid is about 2, use ethyl acetate extraction, anhydrous sodium sulfate drying, behind the concentrating under reduced pressure, carry out silica gel column chromatography (eluent: PE/EtOAc=5/1-1/1) get 320.2mg white solid compound s 6, productive rate 75.0%.
With compound s 6 (100mg, 0.55mmol) and the dried 50ml single port flask that places of 10ml vinegar, reflux 3-4h, decompression steams vinegar and does, (eluent: PE/EtOAc=10/1-5/1) purifying can get 85.6mg white solid compound S 7, productive rate 95.0% by silica gel column chromatography then.
H-NMR(300MHz，DMSO-d
6)：7.92(d，1H)，6.25(d，1H)，4.36(q，2H)，1.36(t，3H)
(50mg 0.30mmol) is dissolved in the 3ml fluorobenzene to compound S 7, slowly drops to anhydrous AlCl then
3(60mg, 0.45mmol) and the mixture of fluorobenzene (5ml) in, reflux 3-4h, after the end reaction solution is poured in the frozen water, regulating pH with the hydrochloric acid of 6N is about 2, uses ethyl acetate extraction, anhydrous sodium sulfate drying, concentrating under reduced pressure is with silicagel column separation and purification (eluent: PE/EtOAc=10/1-5/1) obtain 62.5mg compound 1, productive rate 79.1%.
The product that makes is tested, and the result is as follows:
1H-NMR(300M，DMSO-d
6)δ12.72(s，1H)，7.80(m，2H)，7.31(m，2H)，7.22(d，1H)，6.28(d，1H)，4.36(q，2H)，1.36(t，3H)。
Claims (9)
1. the method for a synthesis type (I),
Wherein, the R base is selected from methyl, ethyl, propyl group, sec.-propyl, phenyl, halogenophenyl, and haloalkyl phenyl, benzyl is characterized in that described method comprises:
A, starting raw material S1 is carried out the dibrominated after saponification at 2,3, decarboxylation forms intermediate S4;
B, S4 carried out R base replace on N, then by with the metal reagent permutoid reaction, feed CO
2, acidifying obtains S6;
C, adjacent dicarboxylic acid dehydration formation formula (I) compound.
2. method according to claim 1 is characterized in that dibrominated can replace in two iodate among the reactions steps A.
3. method according to claim 1, it is characterized in that among the reactions steps A, S1 is dissolved in for example tetracol phenixin of organic solvent in the presence of the catalytic amount iodine, the slow carbon tetrachloride solution of dropping liquid bromine at room temperature then, at room temperature stir after dripping off, decompression steams solvent, obtains S2.
4. method according to claim 2 is characterized in that S2 is added the NaOH solution of 20 %, in 60 ~ 90 ℃ of reaction 2 ~ 6 h, is acidified to pH 2-3 with 6N HCl then, treats that a large amount of white solids separate out, and filtration final vacuum drying obtains S3.
5. method according to claim 3 is characterized in that S3 is added monoethanolamine, in 100 ℃ of heated and stirred 1-3 h, finishes postcooling to room temperature, adds entry, with organic solvent extracted with diethyl ether for example; The extraction liquid washing is dry, and concentrating under reduced pressure is directly used in next step reaction.
6. method according to claim 1 is characterized in that among the reactions steps B, with S4 solution in 0 ℃, slowly drop in the DMF solution of sodium hydride, stir 15 min after, slowly drip BrR, wherein the definition of R base is with claim 1, rise to room temperature reaction 2-4 h then, after the end, slowly pour into reaction solution in the frozen water, with organic solvent extracted with diethyl ether for example, the organic phase washing is dry, and concentrating under reduced pressure uses column chromatography purifying and obtains light yellow liquid S5.
7. method according to claim 6 is characterized in that S5 is dissolved in organic solvent for example among the THF, is cooled to-78 ℃, slowly drips n-BuLi or MAGNESIUM METAL grignard reagent, stirs 30 min down in-78 ℃, feeds CO
2Gas reaction 1-2.5 h slowly rises to room temperature then, continues stirring reaction 1-2 h; After reaction finishes, reaction solution is slowly poured in the frozen water, being acidified to pH with 2N dilute hydrochloric acid is about 2, and with organic solvent ethyl acetate extraction for example, drying behind the concentrating under reduced pressure, is carried out silica gel column chromatography and got the white solid compound s 6.
8. method according to claim 1 is characterized in that among the reactions steps C, and compound s 6 and vinegar are done reflux 3-4h, and decompression steams vinegar and does, and can get white solid compound formula (I) by column chromatography purification then.
9. intermediate, its structure is
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| CN 201110024849 CN102199154B (en) | 2011-01-24 | 2011-01-24 | Novel synthesis method for pyrrole derivatives |
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| CN 201110024849 CN102199154B (en) | 2011-01-24 | 2011-01-24 | Novel synthesis method for pyrrole derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232461A (en) * | 2013-05-21 | 2013-08-07 | 苏州科捷生物医药有限公司 | Synthesis method of 4-chloroquine anhydride |
| CN104201009A (en) * | 2014-09-03 | 2014-12-10 | 齐鲁工业大学 | Preparation method for nitrogen-containing polymer used for supercapacitor electrode material |
| CN109694343A (en) * | 2018-12-19 | 2019-04-30 | 帕潘纳(北京)科技有限公司 | A kind of heterocyclic carboxylic acid class compound it is decarboxylation method used |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4231785A (en) * | 1979-05-21 | 1980-11-04 | Shell Oil Company | Herbicide antidotes |
-
2011
- 2011-01-24 CN CN 201110024849 patent/CN102199154B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4231785A (en) * | 1979-05-21 | 1980-11-04 | Shell Oil Company | Herbicide antidotes |
Non-Patent Citations (3)
| Title |
|---|
| GRIBBLE, GORDON W.: "Product subclass 14: aryllithium and hetaryllithium compounds", 《SCIENCE OF SYNTHESIS》, no. 8, 31 December 2006 (2006-12-31), pages 357 - 426 * |
| YANBING LIU，ET AL.: "Generation and reactions of 2,3-dilithio-N-methylindole. Synthesis of 2,3-disubstituted indoles", 《TETRAHEDRON LETTERS》, vol. 42, 31 December 2001 (2001-12-31), pages 2949 - 2951, XP004232360, DOI: doi:10.1016/S0040-4039(01)00332-X * |
| YOSHINORI IKEURA, ET AL.: "Potent NK1 Receptor Antagonists: Synthesis and Antagonistic Activity of Various Heterocycles with an N-[3,5-Bis(trifluoromethyl)benzyl]-N-methylcarbamoyl Substituent", 《CHEM. PHARM. BULL.》, vol. 45, no. 10, 31 December 1997 (1997-12-31), pages 1642 - 1652 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103232461A (en) * | 2013-05-21 | 2013-08-07 | 苏州科捷生物医药有限公司 | Synthesis method of 4-chloroquine anhydride |
| CN104201009A (en) * | 2014-09-03 | 2014-12-10 | 齐鲁工业大学 | Preparation method for nitrogen-containing polymer used for supercapacitor electrode material |
| CN104201009B (en) * | 2014-09-03 | 2017-03-01 | 齐鲁工业大学 | A kind of preparation method of the polymer with nitrogen for electrode material for super capacitor |
| CN109694343A (en) * | 2018-12-19 | 2019-04-30 | 帕潘纳(北京)科技有限公司 | A kind of heterocyclic carboxylic acid class compound it is decarboxylation method used |
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Free format text: CORRECT: ADDRESS; FROM: 210042 NANJING, JIANGSU PROVINCE TO: 211800 NANJING, JIANGSU PROVINCE |
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| TR01 | Transfer of patent right |
Effective date of registration: 20150331 Address after: 211800, No. 8, prosperous road, Pukou Economic Development Zone, Jiangsu, Nanjing Patentee after: Nanjing Simcere Dongyuan Pharmaceutical Co., Ltd. Patentee after: Jiangsu Simcere Pharmaceutical Co., Ltd. Address before: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Patentee before: Jiangsu Simcere Pharmaceutical Research Company Limited |
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| CP03 | Change of name, title or address |
Address after: No.99, Huakang Road, Jiangbei new district, Nanjing, Jiangsu Province, 210032 Patentee after: SIMCERE PHARMACEUTICAL Group Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 211800, No. 8, prosperous road, Pukou Economic Development Zone, Jiangsu, Nanjing Patentee before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
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| CP03 | Change of name, title or address |