CN101220011A - Midbody for producing sodium bisulfite andrographolide and production method thereof - Google Patents
Midbody for producing sodium bisulfite andrographolide and production method thereof Download PDFInfo
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- CN101220011A CN101220011A CNA2008100521200A CN200810052120A CN101220011A CN 101220011 A CN101220011 A CN 101220011A CN A2008100521200 A CNA2008100521200 A CN A2008100521200A CN 200810052120 A CN200810052120 A CN 200810052120A CN 101220011 A CN101220011 A CN 101220011A
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- sodium bisulfite
- natrii bisulfis
- intermediates preparation
- acid
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- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 title claims abstract description 22
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 title claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 title abstract description 6
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title abstract 6
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 title abstract 6
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 239000000543 intermediate Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000002347 injection Methods 0.000 abstract description 5
- 239000007924 injection Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 201000008197 Laryngitis Diseases 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 206010001093 acute tonsillitis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an intermediate for producing andrographolide sodium bisulfite and a preparation method thereof; wherein, the intermediate for producing andrographolide sodium bisulfite is defined as: 2-(6-hydroxide radical-5-(hydroxymethyl)-5, 8a-dimethyl-2-yliden decalin-1-radical)-1-(2-oxy-2, and a 5-dihydrofuran-3-radical) ethylsulfonic acid. The method for producing andrographolide sodium bisulfite of the invention further reacts to synthesize the andrographolide sodium bisulfite with high purity and a content of more than 99.8 percent; thereby completely meeting the raw material medication requirements of producing Lianbizhi injection; in addition, the method for producing andrographolide sodium bisulfite of the invention has no pollution to the environment.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of intermediate and preparation method who produces rographolidum Natrii Bisulfis specifically.
Background technology
Rographolidum Natrii Bisulfis is the bulk drug of Lian Bizhi injection, and the Lian Bizhi injection is widely used in bacterial dysentery, pneumonia, acute tonsillitis, parotitis, laryngitis and upper respiratory tract infection clinically.
The rographolidum Natrii Bisulfis that obtains with traditional rographolidum Natrii Bisulfis synthetic method, mostly be to adopt chloroform extraction impurity, this method mainly exists two deficiencies, the one, unstable product quality, the foreign matter content height is difficult to reach the requirement of injection stage bulk drug; The 2nd, a large amount of in operation chloroforms that use easily cause environmental pollution.
Therefore, be badly in need of a kind of constant product quality, the foreign matter content trace can reach the requirement of injection stage bulk drug; And the production method of not using the production rographolidum Natrii Bisulfis of the organic solvent that environment is polluted in operation.
When the research novel method, we have obtained a new intermediate.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of intermediate of producing rographolidum Natrii Bisulfis is provided.
Second purpose of the present invention provides a kind of intermediates preparation of producing rographolidum Natrii Bisulfis.
Technical scheme of the present invention is summarized as follows:
A kind of intermediate of producing rographolidum Natrii Bisulfis has following structure:
With its called after: 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid.
A kind of preparation method who produces the intermediate (2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid) of rographolidum Natrii Bisulfis comprises the steps:
(1) concentration expressed in percentage by weight that the rographolide of 350 weight parts is dissolved in 2100～4890 weight parts is in 50%～100% the aqueous ethanolic solution or methanol aqueous solution;
(2) sodium bisulfite with the 100-200 weight part is dissolved in the water of 700～1000 weight parts;
(3) solution that step (2) is made joined in the solution that step (1) makes, in 40～95 ℃ of reactions 0.5～6 hour;
(4) at vacuum tightness＞0.03MPa, temperature is steamed ethanol or methyl alcohol to the greatest extent for 20～85 ℃;
(5) be cooled to 0～30 ℃, left standstill 1～12 hour, add the activated carbon filtration of 1～8 weight part;
(6) adding is equivalent to 0.7～1.5 times of normal mineral acid of sodium bisulfite in filtrate, is cooled to-5 ℃～20 ℃, separates out crystal.
The weight part of described aqueous ethanolic solution is 2947, and described concentration expressed in percentage by weight is 95%.
The weight part of described sodium bisulfite is 114.
Temperature of reaction is 60～70 ℃ in the described step (3), and the described reaction times is 2 hours.
Vacuum tightness＞the 0.07MPa of described step (4).
The weight part of described gac is 2.
The add-on of described mineral acid and sodium bisulfite equivalent.
Described mineral acid is hydrochloric acid or sulfuric acid or nitric acid or phosphoric acid.
By a kind of intermediate (2-(6-hydroxyl-5-(methylol)-5 that produces rographolidum Natrii Bisulfis of synthetic of the present invention, 8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid) further rographolidum Natrii Bisulfis is synthesized in reaction, its purity height, its content reaches the raw material medication requirement of production LIANBIZHI ZHUSHEYE fully more than 99.8%.A kind of intermediates preparation of producing rographolidum Natrii Bisulfis of the present invention does not pollute environment.
Description of drawings
Fig. 1 is 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid
1The H-NMR collection of illustrative plates;
Fig. 2 is 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid uv-spectrogram;
Fig. 3 is 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid infared spectrum;
Fig. 4 is 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid mass spectrum.
Embodiment
The present invention is further illustrated below in conjunction with specific embodiment.
A kind of intermediates preparation of producing rographolidum Natrii Bisulfis comprises the steps:
(1) concentration expressed in percentage by weight that the rographolide of 350 weight parts is dissolved in 2947 weight parts is in 95% the aqueous ethanolic solution;
(2) sodium bisulfite with 114 weight parts is dissolved in the water of 800 weight parts;
(3) solution that step (2) is made joined in the solution that step (1) makes, in 60～70 ℃ of reactions 2 hours;
(4) at vacuum tightness＞0.07MPa, temperature is steamed ethanol to the greatest extent for 50 ℃;
(5) be cooled to 25 ℃, left standstill 2 hours, add the activated carbon filtration of 2 weight parts;
(6) hydrochloric acid of adding and sodium bisulfite equivalent in filtrate, be cooled to 5 ℃, separate out crystal, by analysis, this compound is a new compound, the compound of called after: 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid.(above-mentioned weight can be chosen gram, also can choose kilogram.)
2-(6-hydroxy-5-(hydroxymethyl)-5，8a-dimethyl-2-methylenedecahydronaphthalen-1-yl)-1-(2-oxo-2，5-dihydrofuran-3-yl)ethanesulfonic?acid
The compounds of this invention
1The H-NMR collection of illustrative plates is seen Fig. 1.
1H-NMR(D
2O，500MHz，25℃，TMS)δ：7.75(s，1H，4-H(furan))，4.96(q，2H，5-H(furan))，4.88(s，1H，2-CH2(decahydronaphthalen))，4.65(s，2H，4-CH2OH(decahydronaphthalen))，3.95(d，1H，2-CH2(decahydronaphthalen)，3.87(d，1H，2-H)，3.31-3.37(m，2H，6-H，1-H(decahydronaphthalen))，2.30(d，1H，3-H(decahydronaphthalen))，2.20(t，1H，7-H(decahydronaphthalen))，2.03(t，1H，8-H(decahydronaphthalen))，1.66-1.79(m，5a-H，7-H，4-H，3-H(decahydronaphthalen)，1-H)，1.37(d，1H，4-H(decahydronaphthalen))，1.11-1.35(m，1H，8-H(decahydronaphthalen))，1.10(m，1H，5a-H)，1.08(s，3H，4-CH3(decahydronaphthalen))，0.6(s，3H，8a-CH3(decahydronaphthalen)).
The uv-spectrogram of The compounds of this invention is seen Fig. 2.
Carbonyl in the structure (C=O) produces a peak with carbon-carbon double bond (C=C) conjugation about 225.
The infared spectrum of The compounds of this invention is seen Fig. 3.
IR(KBr)v：3379(-OH)，2955(-CH
3)，2859(-CH2)，1735(-C＝O)，1639(-C＝C)，1047(-S＝O).
The mass spectrum of The compounds of this invention is seen Fig. 4.
MS(ESI，m/z)：413(C
20H
29O
7S
+)
A kind of intermediates preparation of producing rographolidum Natrii Bisulfis comprises the steps:
(1) concentration expressed in percentage by weights that the rographolides of 350 grams are dissolved in 2100 grams are in 100% the methyl alcohol;
(2) sodium bisulfite with 100 grams is dissolved in the water of 700 grams;
(3) solution that step (2) is made joined in the solution that step (1) makes, in 40～50 ℃ of reactions 6 hours;
(4) at vacuum tightness＞0.03MPa, temperature is steamed methyl alcohol to the greatest extent for 85 ℃;
(5) be cooled to 0 ℃, left standstill 1 hour, add the activated carbon filtration of 1 gram;
(6) adding is equivalent to 0.7 times of normal sulfuric acid of sodium bisulfite in filtrate, is cooled to-5 ℃, separates out crystal.
A kind of intermediates preparation of producing rographolidum Natrii Bisulfis comprises the steps:
(1) 350 rographolides that restrain being dissolved in 4890 concentration expressed in percentage by weights that restrain is in 50% methanol aqueous solution;
(2) sodium bisulfite with 200 grams is dissolved in the water of 1000 grams;
(3) solution that step (2) is made joined in the solution that step (1) makes, in 85～95 ℃ of reactions 0.5 hour;
(4) at vacuum tightness＞0.07MPa, temperature is steamed methyl alcohol to the greatest extent for 20 ℃;
(5) be cooled to 30 ℃, left standstill 12 hours, add the activated carbon filtration of 8 grams;
(6) adding is equivalent to 1.5 times of normal nitric acid of sodium bisulfite in filtrate, is cooled to 20 ℃, separates out crystal.
A kind of intermediates preparation of producing rographolidum Natrii Bisulfis comprises the steps:
(1) concentration expressed in percentage by weights that the rographolides of 350 grams are dissolved in 3000 grams are in 85% the aqueous ethanolic solution;
(2) sodium bisulfite with 150 grams is dissolved in the water of 800 grams;
(3) solution that step (2) is made joined in the solution that step (1) makes, in 70～80 ℃ of reactions 3 hours;
(4) at vacuum tightness＞0.04MPa, temperature is steamed ethanol to the greatest extent for 60 ℃;
(5) be cooled to 10 ℃, left standstill 6 hours, add the activated carbon filtration of 5 grams;
(6) adding is equivalent to 1.2 times of normal phosphoric acid of sodium bisulfite in filtrate, is cooled to 10 ℃, separates out crystal.
Claims (9)
1. intermediate of producing rographolidum Natrii Bisulfis is characterized in that having following structure:
Called after: 2-(6-hydroxyl-5-(methylol)-5,8a-dimethyl-2-methene base perhydronaphthalene-1-yl)-1-(2-oxygen-2,5-dihydrofuran-3-yl) ethylsulfonic acid.
2. an intermediates preparation of producing rographolidum Natrii Bisulfis is characterized in that comprising the steps:
(1) concentration expressed in percentage by weight that the rographolide of 350 weight parts is dissolved in 2100～4890 weight parts is in 50%～100% the aqueous ethanolic solution or methanol aqueous solution;
(2) sodium bisulfite with the 100-200 weight part is dissolved in the water of 700～1000 weight parts;
(3) solution that step (2) is made joined in the solution that step (1) makes, in 40～95 ℃ of reactions 0.5～6 hour;
(4) at vacuum tightness＞0.03MPa, temperature is steamed ethanol or methyl alcohol to the greatest extent for 20～85 ℃;
(5) be cooled to 0～30 ℃, left standstill 1～12 hour, add the activated carbon filtration of 1～8 weight part;
(6) adding is equivalent to 0.7～1.5 times of normal mineral acid of sodium bisulfite in filtrate, is cooled to-5 ℃～20 ℃, separates out crystal.
3. according to the described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis of claim 2, the weight part that it is characterized in that described aqueous ethanolic solution is 2947, and described concentration expressed in percentage by weight is 95%.
4. according to the described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis of claim 2, the weight part that it is characterized in that described sodium bisulfite is 114.
5. according to the described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis of claim 2, it is characterized in that temperature of reaction is 60～70 ℃ in the described step (3), the described reaction times is 2 hours.
6. according to the described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis of claim 2, it is characterized in that the vacuum tightness＞0.07MPa of described step (4).
7. according to the described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis of claim 2, the weight part that it is characterized in that described gac is 2.
8. according to the described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis of claim 2, it is characterized in that the add-on and the sodium bisulfite equivalent of described mineral acid.
9. according to claim 2 or 8 described a kind of intermediates preparation of producing rographolidum Natrii Bisulfis, it is characterized in that described mineral acid is hydrochloric acid or sulfuric acid or nitric acid or phosphoric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810052120A CN100595197C (en) | 2008-01-18 | 2008-01-18 | Midbody for producing sodium bisulfite andrographolide and production method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810052120A CN100595197C (en) | 2008-01-18 | 2008-01-18 | Midbody for producing sodium bisulfite andrographolide and production method thereof |
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| Publication Number | Publication Date |
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| CN101220011A true CN101220011A (en) | 2008-07-16 |
| CN100595197C CN100595197C (en) | 2010-03-24 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119254A (en) * | 2013-04-24 | 2014-10-29 | 江西青峰药业有限公司 | 7-Dehydro-andrographolide-17-sulfonic acid-16-carboxylic acid or its salt, and preparation method and medicine preparation uses thereof |
| CN109010108A (en) * | 2018-08-31 | 2018-12-18 | 广州中医药大学(广州中医药研究院) | The application of the anti-skin photoage of Andrographolidi Natrii Bisulfis and suncream |
| CN111635383A (en) * | 2020-07-07 | 2020-09-08 | 郑州大学 | Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate and preparation method thereof |
| CN113861141A (en) * | 2020-06-30 | 2021-12-31 | 江西青峰药业有限公司 | Preparation method of andrographolide sulfonate for controlling anaphylactic reaction of Chinese medicinal injection |
-
2008
- 2008-01-18 CN CN200810052120A patent/CN100595197C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119254A (en) * | 2013-04-24 | 2014-10-29 | 江西青峰药业有限公司 | 7-Dehydro-andrographolide-17-sulfonic acid-16-carboxylic acid or its salt, and preparation method and medicine preparation uses thereof |
| CN104119254B (en) * | 2013-04-24 | 2015-09-09 | 江西青峰药业有限公司 | 7-dehydrogenation-rographolide-17-sulfonic acid-16-carboxylic acid or its salt, preparation method and prepare pharmaceutical use |
| CN109010108A (en) * | 2018-08-31 | 2018-12-18 | 广州中医药大学(广州中医药研究院) | The application of the anti-skin photoage of Andrographolidi Natrii Bisulfis and suncream |
| CN113861141A (en) * | 2020-06-30 | 2021-12-31 | 江西青峰药业有限公司 | Preparation method of andrographolide sulfonate for controlling anaphylactic reaction of Chinese medicinal injection |
| CN113861141B (en) * | 2020-06-30 | 2024-03-19 | 江西青峰药业有限公司 | Preparation method of andrographolide sulfonate for controlling anaphylactic reaction of traditional Chinese medicine injection |
| CN111635383A (en) * | 2020-07-07 | 2020-09-08 | 郑州大学 | Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate and preparation method thereof |
| CN111635383B (en) * | 2020-07-07 | 2023-01-24 | 郑州大学 | Single crystal of 14-dehydroxy-13-dehydroandrographolide-12-calcium sulfonate acetone solvate and preparation method thereof |
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| CN100595197C (en) | 2010-03-24 |
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Effective date of registration: 20101123 Address after: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee after: ZHEJIANG JIUXU PHARMACEUTICAL Co.,Ltd. Address before: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Co-patentee before: ZHEJIANG JIUXU PHARMACEUTICAL Co.,Ltd. Patentee before: Li Hong |
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Owner name: JIANGSU JIUXU PHARMACEUTICAL CO., LTD. Effective date: 20150717 Owner name: LI HONG Free format text: FORMER OWNER: ZHEJIANG JIUXU PHARMACEUTICAL CO., LTD. Effective date: 20150717 |
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| C41 | Transfer of patent application or patent right or utility model | ||
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Effective date of registration: 20150717 Address after: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee after: Li Hong Patentee after: JIANGSU JIUXU PHARMACEUTICAL Co.,Ltd. Address before: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee before: ZHEJIANG JIUXU PHARMACEUTICAL Co.,Ltd. |
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Address after: 221200 No. 998, Jiuxu Avenue, Suining Economic Development Zone, Xuzhou City, Jiangsu Province Patentee after: Li Hong Patentee after: JIANGSU JIUXU PHARMACEUTICAL Co.,Ltd. Address before: 321016 Zhejiang city of Jinhua province Xian No. 398 North Street Patentee before: Li Hong Patentee before: JIANGSU JIUXU PHARMACEUTICAL Co.,Ltd. |
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
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Granted publication date: 20100324 |