CN102702114B - Method for preparing nitro orotic acid - Google Patents
Method for preparing nitro orotic acid Download PDFInfo
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- CN102702114B CN102702114B CN201210173667.2A CN201210173667A CN102702114B CN 102702114 B CN102702114 B CN 102702114B CN 201210173667 A CN201210173667 A CN 201210173667A CN 102702114 B CN102702114 B CN 102702114B
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- methyl uracil
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- 238000000034 method Methods 0.000 title claims abstract description 20
- PXQPEWDEAKTCGB-UHFFFAOYSA-N vitamin B13 Natural products OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title abstract description 6
- -1 nitro orotic acid Chemical compound 0.000 title abstract description 5
- 229960005010 orotic acid Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 7
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims abstract description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 3
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical compound CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 claims description 33
- OPGJGRWULGFTOS-UHFFFAOYSA-N 5-nitro-2,4-dioxo-1h-pyrimidine-6-carboxylic acid Chemical compound OC(=O)C=1NC(=O)NC(=O)C=1[N+]([O-])=O OPGJGRWULGFTOS-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 20
- 229910017604 nitric acid Inorganic materials 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- LIVYMRJSNFHYEN-UHFFFAOYSA-N 6-methyl-5-nitro-1h-pyrimidine-2,4-dione Chemical compound CC=1NC(=O)NC(=O)C=1[N+]([O-])=O LIVYMRJSNFHYEN-UHFFFAOYSA-N 0.000 claims description 14
- 238000006396 nitration reaction Methods 0.000 claims description 13
- 230000001590 oxidative effect Effects 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 238000010792 warming Methods 0.000 description 8
- 238000004064 recycling Methods 0.000 description 7
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 3
- 229960002768 dipyridamole Drugs 0.000 description 3
- 238000002715 modification method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- NOHUXXDTQJPXSB-UHFFFAOYSA-N 2-acetyloxybenzoic acid;2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O.C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 NOHUXXDTQJPXSB-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 229940003558 aggrenox Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing nitro orotic acid, and belongs to the field of chemical synthesis. According to the method, the conventional method for preparing the nitro orotic acid is improved. The method is characterized in that the nitro orotic acid (III) is obtained by performing nitratlon reaction of 6-methyl urea pyrimidine (I) and subsequent oxidation reaction of 5-nitryl-6-methyl urea pyrimidine (II) at the temperature of between 50 and 80 DEG C in the presence of a specific organic solvent and a catalyst, wherein the organic solvent is selected from at least one of chloroform, dichloroethane, dichloromethane, n-pentane, normal hexane or normal heptane; and the catalyst is acid, and preferably is concentrated sulfuric acid. By the method, the reaction can be performed stably at the temperature of between 50 and 80 DEG C, so that risk of a production process is reduced greatly, and the method has the great advantage in the aspect of safety. In addition, the product is high in purity, so that the purification coat is reduced, and the yield of the process is improved.
Description
Technical field
The present invention relates to a kind of preparation method of compound, particularly a kind of method of preparing nitroorotic acid.Belong to the field of chemical synthesis.
Background technology
Nitroorotic acid is the key intermediate of synthetic Dipyridamole, and Dipyridamole is the precursor of synthetic Persantin and Aggrenox.
Several method of preparing nitroorotic acid known in the state of the art:
Nitroorotic acid can be prepared by the nitration reaction of vitamin B13, the report at initial stage (M.Bachstez, Ber.dtsch.chem.Ges.63,1930,1000 and H.Biltz, Ann 456,1924, and 165) show that this reaction yield is lower, although the Luo Erfu of Boehringer Ingelheim company etc. (CN 101812023) are optimized this reaction, reaction yield has been brought up to 90%, but because raw materials cost is higher, this method is not in industrial extensive use at present.
F.G.Fshcher etc. (Ann.572,1951,217) have reported by 4-methyl-2-deracil and have prepared nitroorotic acid sylvite as starting raw material, and yield is about 50-55%.
Nitroorotic acid also can be by the oxidizing reaction preparation (R.Behrend of the nitration reaction of 6-methyl uracil and follow-up 5-nitro-6-methyl uracil, Ann.251,1889,238 and H.Biltz, Ann.413,1916,110 and Takehiko, US5389641,24), this is the commercial run of current scale operation nitroorotic acid.
This commercial run becomes 5-nitro-6-methyl uracil because nitric acid and 6-methyl uracil are first nitrated, slowly be warming up to again 110 ℃ of 5-nitro-6-methyl uracils and carry out oxidizing reaction, in reaction process, emit a large amount of heats, if can not control well temperature, reaction system has the danger of heavy explosion.
Summary of the invention
The object of the invention is to overcome the current problem that nitroorotic acid produces of preparing on a large scale, proposed a kind of modification method of preparing nitroorotic acid, thereby improved, adopt the method to carry out the security of scale operation.
The preparation method of a kind of nitroorotic acid of the present invention, is characterized in that the oxidizing reaction of nitration reaction by 6-methyl uracil (I) and follow-up 5-nitro-6-methyl uracil (II) obtains nitroorotic acid (III),
Described nitration reaction is at the temperature of 50-80 ℃, under specific organic solvent and catalyzer exist, with concentrated nitric acid (nitrosonitric acid) by 6-methyl uracil (I) nitrated be 5-nitro-6-methyl uracil (II);
Described oxidizing reaction is at the temperature of 50-80 ℃, under specific organic solvent and catalyzer existence, 5-nitro-6-methyl uracil (II) is oxidized to nitroorotic acid (III);
Wherein, described organic solvent be selected from chloroform, ethylene dichloride, methylene dichloride, Skellysolve A, normal hexane or normal heptane wherein at least one;
Wherein, described catalyzer is a kind of acid.
Wherein, the object of the existence of this specific solvent be by the condensing reflux of this solvent and time remove the heat that reaction is put, thereby the danger of avoiding reaction system to blast.
In the present invention, preferred, the nitration reaction of described 6-methyl uracil and follow-up oxidizing reaction are carried out in same system simultaneously.
In the present invention, preferred, the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction are to carry out at the temperature of 55 ℃.
In the present invention, preferred, in the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction, concentrated nitric acid is dropwise to join in the mixture that contains 6-methyl uracil and specific organic solvent and catalyzer, after dropwising, and return stirring 30-60 hour at the temperature of 50-80 ℃, after having reacted, stop heating, in system, add water, keep system temperature to be no more than 35 ℃, layering, water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, dry, obtain product.
In the present invention, preferred, the mol ratio of 6-methyl uracil and concentrated nitric acid is 1: 5-14, the mol ratio of preferred 6-methyl uracil and concentrated nitric acid is 1: 12.
In the present invention, preferred, described catalyzer is the vitriol oil.
Preferably, the mol ratio of the vitriol oil and nitrosonitric acid is 1: 3 to 1: 40, and more preferably, the ratio of the vitriol oil and concentrated nitric acid is 1: 7.7.
In the present invention, preferred, the mol ratio of 6-methyl uracil and the vitriol oil is 1: 0.3-3.
In the present invention, preferred, 6-methyl uracil and specific organic solvent and mol ratio be 1: 1-30, preferred, the mol ratio of 6-methyl uracil and organic solvent is 1: 17.7.
Adopt modification method of the present invention to solve the associated problem in current large-scale production process.
The most important thing is, the invention solves the risk that reaction system bumping even explodes, this is due to the present invention, to have changed the existence of the vitriol oil and specific organic solvent in the feed way of 6-methyl uracil and nitric acid in 6-methyl uracil nitration reaction and follow-up oxidizing reaction and reaction system, this reaction can steadily be carried out at the temperature of 50-80 ℃, greatly reduce the danger in production technique, aspect security, there is very large advantage.
The productive rate of product (75-85%) is close with prior art, but purity is very high, has reduced purifying cost, has improved the earning rate of this technique.
In addition present method is after reaction completes, and nitroorotic acid can be separated with free acid form, thereby has avoided extra treatment step.
Embodiment
Below in conjunction with specific embodiment, further describe the present invention, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these modifications and replacement all fall within the scope of protection of the present invention.
The preparation of embodiment 1 nitroorotic acid
By 1.8kg(18.18mol) vitriol oil (98%) and 17kg (142.9mol) chloroform mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 50 ℃.Control temperature at 50-55 ℃, to this mixture, splash into the concentrated nitric acid (98%) of 9kg (140mol), after dropwising, return stirring 30 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 1.96kg(84.1%);
Purity: 97.6%(HPLC).
The preparation of embodiment 2 nitroorotic acids
By 1.8kg(18.18mol) vitriol oil (98%) and 17kg (142.9mol) chloroform mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 50 ℃.Control temperature at 50-55 ℃, to this mixture, splash into the concentrated nitric acid (98%) of 4.5kg (70mol), after dropwising, return stirring 30 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 1.31kg(56%);
Purity: 97.0%(HPLC).
The preparation of embodiment 3 nitroorotic acids
By 1.8kg(18.18mol) vitriol oil (98%) and 17kg (142.9mol) chloroform mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 50 ℃.Control temperature at 50-55 ℃, to this mixture, splash into the concentrated nitric acid (98%) of 10.5kg (163mol), after dropwising, return stirring 30 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 1.86kg(80.1%);
Purity: 97.7%(HPLC).
The preparation of embodiment 4 nitroorotic acids
By 0.36kg(3.636mol) vitriol oil (98%) and 17kg (142.9mol) chloroform mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 50 ℃.Control temperature at 50-55 ℃, to this mixture, splash into the concentrated nitric acid (98%) of 9kg (140mol), after dropwising, return stirring 56 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, chloroform layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 1.77kg(76.2%);
Purity: 96.3%(HPLC).
The preparation of embodiment 5 nitroorotic acids
By 0.347kg(3.50mol) vitriol oil (98%) and 12.6kg (174mol) Skellysolve A mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 50 ℃.Control temperature at 50-55 ℃, to this mixture, splash into the concentrated nitric acid (98%) of 9kg (140mol), after dropwising, return stirring 30 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, Skellysolve A layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 1.93kg(83.2%);
Purity: 97.3%(HPLC).
The preparation of embodiment 6 nitroorotic acids
By 1.8kg(18.18mol) vitriol oil (98%) and 14.2kg (143.5mol) ethylene dichloride mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 70 ℃.Control temperature at 65-75 ℃, to this mixture, splash into 9kg (140mol) concentrated nitric acid (98%), after dropwising, return stirring 30 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, ethylene dichloride layer can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 1.97kg(85%);
Purity: 98%(HPLC).
The preparation of embodiment 7 nitroorotic acids
By 1.8kg(18.18mol) vitriol oil (98%) and 14.3kg (166mol) normal hexane mix and blend, then disposable 1.5kg (11.6mol) the 6-methyl uracil that adds, is warming up to 65 ℃.Control temperature at 65-70 ℃, to this mixture, splash into 9kg (140mol) concentrated nitric acid (98%), after dropwising, return stirring 30 hours (HPLC detects to reacting completely) at this temperature.
After having reacted, stop heating, in system, add 3kg water, keep system temperature to be no more than 35 ℃, layering, the mixed layer of normal hexane can directly carry out recycling.
Water layer is cooled to 1-5 ℃, and suction filtration after this temperature keeps 3 hours is dry, obtains product.
Output: 2.01kg(86%);
Purity: 96.5%(HPLC).
Claims (6)
1. a preparation method for nitroorotic acid, is characterized in that the oxidizing reaction of nitration reaction by 6-methyl uracil (I) and follow-up 5-nitro-6-methyl uracil (II) obtains nitroorotic acid (III),
Described nitration reaction is at the temperature of 50-80 ℃, under specific organic solvent and the vitriol oil exist, with concentrated nitric acid by 6-methyl uracil (I) nitrated be 5-nitro-6-methyl uracil (II); Wherein, the mol ratio of 6-methyl uracil and concentrated nitric acid is 1:5-14, and the mol ratio of 6-methyl uracil and the vitriol oil is 1:0.3-3, and the mol ratio of the vitriol oil and concentrated nitric acid is 1:3 to 1:40;
Described oxidizing reaction is at the temperature of 50-80 ℃, under specific organic solvent and catalyzer existence, 5-nitro-6-methyl uracil (II) is oxidized to nitroorotic acid (III);
Wherein, the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction are carried out in same system simultaneously, in the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction, concentrated nitric acid is dropwise to join in the mixture that contains 6-methyl uracil and specific organic solvent and catalyzer, after dropwising, return stirring 30-60 hour at the temperature of 50-80 ℃, after having reacted, stop heating, in system, add water, keep system temperature to be no more than 35 ℃, layering, water layer is cooled to 1-5 ℃, suction filtration after this temperature keeps 3 hours, dry, obtain product,
Wherein, described organic solvent be selected from chloroform, ethylene dichloride, methylene dichloride, Skellysolve A, normal hexane or normal heptane wherein at least one.
2. in accordance with the method for claim 1, it is characterized in that the nitration reaction of 6-methyl uracil and follow-up oxidizing reaction are to carry out at the temperature of 55 ℃.
3. the mol ratio that in accordance with the method for claim 1, it is characterized in that 6-methyl uracil and concentrated nitric acid is 1:12.
4. the mol ratio that in accordance with the method for claim 1, it is characterized in that the vitriol oil and concentrated nitric acid is 1:7.7.
5. the mol ratio that in accordance with the method for claim 1, it is characterized in that 6-methyl uracil and organic solvent is 1:1-30.
6. the mol ratio that in accordance with the method for claim 5, it is characterized in that 6-methyl uracil and organic solvent is 1:17.7.
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| CN201210173667.2A CN102702114B (en) | 2012-05-28 | 2012-05-28 | Method for preparing nitro orotic acid |
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| CH592636A5 (en) * | 1975-01-13 | 1977-10-31 | Lonza Ag | |
| DD126811B1 (en) * | 1976-07-29 | 1980-12-24 | Herbert Goldner | Method for producing 5-nitrouracilcarboxylic acid (4) |
| FR2589153B1 (en) * | 1985-10-25 | 1988-09-23 | Recordati Chem Pharm | PROCESS FOR THE MANUFACTURE OF 5-AMINOOROTIC ACID |
| US4741818A (en) * | 1985-12-12 | 1988-05-03 | Learonal, Inc. | Alkaline baths and methods for electrodeposition of palladium and palladium alloys |
| EP0445239A4 (en) * | 1989-06-21 | 1992-03-25 | The Catholic University Of America | Anti-malarial composition and method of use |
| RO104719B1 (en) * | 1989-08-09 | 1994-09-30 | Medicamente De | Production method of 5- |
| TW274551B (en) * | 1991-04-16 | 1996-04-21 | Takeda Pharm Industry Co Ltd | |
| CN101812023A (en) * | 2009-02-23 | 2010-08-25 | 勃林格殷格翰国际贸易(上海)有限公司 | Novel method for preparing nitroorotic acid |
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Inventor after: Bao Rusheng Inventor after: Jiang Fuguo Inventor after: Dai Weie Inventor after: Zhao Chenliang Inventor after: Li Jin Inventor after: Xu Jianyong Inventor before: Jiang Fuguo Inventor before: Dai Weie Inventor before: Zhao Chenliang Inventor before: Li Jin Inventor before: Xu Jianyong |
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Address after: 226407 20 beach four road, Rudong Economic Development Zone, Rudong, Nantong, Jiangsu Patentee after: Nantong Hisun Chemical Co. Ltd. Address before: No. 4, Haibin Road, Rudong County Coastal Economic Development Zone, Nantong, Jiangsu Patentee before: Haizheng Chemical Nantong Co., Ltd. |
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| CP03 | Change of name, title or address | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 226407 20 beach four road, Rudong Economic Development Zone, Rudong, Nantong, Jiangsu Patentee after: Shunyi Nantong Chemical Co., Ltd Address before: 226407 20 beach four road, Rudong Economic Development Zone, Rudong, Nantong, Jiangsu Patentee before: Nantong Hisun Chemical Co. Ltd. |
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| CP01 | Change in the name or title of a patent holder | ||
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 226407 20 beach four road, Rudong Economic Development Zone, Rudong, Nantong, Jiangsu Patentee after: Shunyi Nantong Chemical Co., Ltd Address before: 20 Haibin 4th Road, coastal economic development zone, Rudong County, Nantong City, Jiangsu Province, Taizhou City, Zhejiang Province Patentee before: Shunyi Nantong Chemical Co., Ltd |