CN101318928B - Process for the separation of 2-hydroxymethyl-3, 5-dimethyl-4-methoxy pyridine - Google Patents
Process for the separation of 2-hydroxymethyl-3, 5-dimethyl-4-methoxy pyridine Download PDFInfo
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- CN101318928B CN101318928B CN2008100631569A CN200810063156A CN101318928B CN 101318928 B CN101318928 B CN 101318928B CN 2008100631569 A CN2008100631569 A CN 2008100631569A CN 200810063156 A CN200810063156 A CN 200810063156A CN 101318928 B CN101318928 B CN 101318928B
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- 238000000034 method Methods 0.000 title claims abstract description 17
- PSEPRWKZZJWRCB-UHFFFAOYSA-N (4-methoxy-3,5-dimethylpyridin-2-yl)methanol Chemical compound COC1=C(C)C=NC(CO)=C1C PSEPRWKZZJWRCB-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000000926 separation method Methods 0.000 title claims abstract description 9
- 239000007788 liquid Substances 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000004821 distillation Methods 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000006200 vaporizer Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000012452 mother liquor Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 150000001555 benzenes Chemical class 0.000 claims description 6
- 239000010409 thin film Substances 0.000 claims description 6
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 abstract description 3
- 229960000381 omeprazole Drugs 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 229920000642 polymer Polymers 0.000 abstract 2
- 150000003222 pyridines Chemical class 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 abstract 1
- 239000010413 mother solution Substances 0.000 abstract 1
- 238000009835 boiling Methods 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- GFYHSKONPJXCDE-UHFFFAOYSA-N 2,3,5-trimethylpyridine Chemical compound CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000000199 molecular distillation Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 238000003822 preparative gas chromatography Methods 0.000 description 2
- LCJDHJOUOJSJGS-UHFFFAOYSA-N 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridin-1-ium;chloride Chemical compound Cl.COC1=C(C)C=NC(CCl)=C1C LCJDHJOUOJSJGS-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000009774 resonance method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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- Pyridine Compounds (AREA)
Abstract
The invention relates to a method for separating an intermediate of omeprazole, namely 2-hydroxymethyl-3, 5-dimethyl-4-methoxy pyridine. The method comprises the following steps of: distilling and removing high polymer impurities from a 2-hydroxymethyl-3, 5-dimethyl-4-methoxy pyridine mother solution containing pyridine derivative, high polymer and other impurities by an evaporator, and then separating and removing the pyridine derivative impurities from the mixed solution through a rectifying tower to separate a product. The product obtained by the method has the advantages of high purity, simple and convenient separation method, manufacturing cost reduction, environmental pollution reduction and suitability for industrial production.
Description
(1) technical field:
The present invention relates generally to and separate purification 2-methylol-3, the method for 5-dimethyl-4-methoxypyridine from methyl pyridine mixture.
(2) background technology:
2-methylol-3,5-dimethyl-4-methoxypyridine are the key intermediates of omeprazole, and omeprazole is the proton pump inhibitor that is used for the treatment of digestive tract ulcer.Because 2-methylol-3 in 5-dimethyl-4-methoxypyridine building-up process, produces 2,3, the 5-trimethylpyridine, 2,3,5-trimethylammonium-4-methoxypyridine, 2-aldehyde methyl-4-methoxyl group-3,5-lutidine, 2,3, impurity such as 5-trimethylammonium-4-pyridone and superpolymer, impurity causes 2-methylol-3,5-dimethyl-4-methoxypyridine solubleness increases, and is can't crystallization complete, obviously influences yield, increase production cost, it is more to separate out crystal impurity, refining difficulty.
(3) summary of the invention:
Task of the present invention is to overcome the weak point that relies on crystallization process fully, provide a kind of simple to operate, cycle short, be easy to control and separation 2-methylol-3 that yield is high the method for 5-dimethyl-4-methoxypyridine.
The present inventor is through discovering, be mixed with the omeprazole intermediate 2-methylol-3 of impurity behind the crystallization, 5-dimethyl-4-methoxypyridine mother liquor, remove superpolymer with the vaporizer distillation earlier, again with the feed liquid rectifying that distills out, thereby rectifying is easy to operate and control, isolated product, purity height.
The superpolymer impurity main component that the present invention relates to is the dimerization or the trimerizing compound of pyridine derivate.Its boiling point is than 2-methylol-3, the boiling point height of 5-dimethyl-4-methoxypyridine, and proportion is about about 10% in mother liquor.
The pyridine derivate impurity that the present invention relates to is mainly 2,3,5-trimethylpyridine, 2,3,5-trimethylammonium-4-methoxypyridine, 2-aldehyde methyl-4-methoxyl group-3,5-lutidine, 2,3,5-trimethylammonium-4-pyridone, and 2-methylol-3, the boiling point of 5-dimethyl-4-methoxypyridine is than the boiling point height of above-mentioned pyridine derivate impurity, 2-methylol-3, the boiling point of 5-dimethyl-4-methoxypyridine are 138～140 ℃ (10mmHg).
The said separation method of the present invention comprises the steps:
(1) will contain 2-methylol-3, the crystallization mother liquor of 5-dimethyl-4-methoxypyridine distills with vaporizer, distillation condition in the vaporizer: 150～250 ℃ of temperature, vacuum tightness≤20mmHg, collect overhead product, be and contain 2-methylol-3, the mixing solutions of 5-dimethyl-4-methoxypyridine; When the overhead product of collecting accounts for 90% left and right sides of the preceding total mother liquor of distillation, stop distillation, because the boiling point height of superpolymer is stayed in the vaporizer, account for 10% of the preceding total mother liquor of distillation, promptly removed superpolymer;
What (2) step (1) is obtained contains 2-methylol-3, the mixing solutions of 5-dimethyl-4-methoxypyridine separates by rectifying tower, tower bed material liquid temp is controlled in 100～180 ℃ of scopes, vacuum tightness≤20mmHg, according to tower top temperature, collect each component, when rectifying to 120～135 ℃ of tower top temperatures, vacuum tightness≤20mmHg stops rectifying, and tower bed material liquid is cooled to 60-70 ℃, adding organic solvent in the last feed liquid at the bottom of the tower, equal volume unit's ratio of tower bed material liquid and added organic solvent, promptly L/L is 1: 0.5～2;
(3) liquid cooling of tower bed material frozen be cooled to 0 ± 10 ℃, separate out crystallization, filter, dry below 50 ℃, target product 2-methylol-3,5-dimethyl-4-methoxypyridine, purity 〉=98.0%, filtrated stock is recyclable to be applied mechanically.
The described vaporizer of step (1) is scrapper thin film evaporator or molecular still, and described vaporizer distillation optimum condition is: 180～220 ℃ of temperature, vacuum tightness≤10mmHg.
The described rectifying tower of step (2) is selected from packing tower, or bubble-plate column, or valve tray column, and optimum condition is at the bottom of the described rectifying Tata: 130～150 ℃ of temperature, vacuum tightness≤10mmHg.
The rectifying tower that the present invention relates to, theoretical plate number are 20-40, and preferred stage number is 35-40, in rectifying, can adopt gas-chromatography to follow the tracks of, and determine the terminal point that different fractions are collected.
In the step (2), according to the boiling point of each component of pyridine derivate, during in tower top temperature≤80 ℃, that collects is mainly 2,3,5-trimethylpyridine product; When temperature is 80 ℃～125 ℃, be mainly 2,3,5-trimethylpyridine, 2,3,5-trimethylammonium-4-methoxypyridine, 2-aldehyde methyl-4-methoxyl group-3,5-lutidine, 2,3,5-trimethylammonium-4-pyridone.
In the step (2), added organic solvent is a kind of in the benzene derivative, acetone of alkyl alcohol, benzene, the C7～C10 of C1～C4 at the bottom of the tower; The alkyl alcohol of C1～C4 comprises methyl alcohol, ethanol, and propyl alcohol, Virahol, butanols etc., the benzene derivative of C7～C10 comprises toluene, ethylbenzene, dimethylbenzene etc.; Optimum condition is: preferred Virahol of organic solvent or toluene, the add-on of organic solvent are 1 times～1.5 times of last material liquid volume (L/L) at the bottom of the tower;
In the step (3), the preferred temperature of tower bed material liquid cooling freezing cooling is 0 ± 5 ℃.
Product nucleus magnetic resonance conclusive evidence of the present invention: fractional crystallization product of the present invention is analyzed with magnetic nuclear resonance method, detect affirmation through BRUKER AVANCE DMX500 nuclear magnetic resonance analyser, 2-methylol-3,5-dimethyl-4-methoxypyridine nuclear magnetic resonance map (seeing figure one) is consistent with standard diagram;
Product purity of the present invention is analyzed: with vapor-phase chromatography to fractional crystallization product 2-methylol-3 of the present invention, 5-dimethyl-4-methoxypyridine is analyzed, operating process and experiment condition are by " the described method of Chinese pharmacopoeia appendix VE vapor-phase chromatography is carried out product purity 〉=98.0%.
Product 2-methylol-3 of the present invention, the ebulliometry of 5-dimethyl-4-methoxypyridine detects according to GB616-88 chemical reagent ebulliometry universal method.
Separate 2-methylol-3 with the inventive method, 5-dimethyl-4-methoxypyridine is simple to operate, can improve yield, reduces production costs, and reduces environmental pollution, is suitable for technology production.
(4) accompanying drawing:
Figure one is a 2-methylol-3, the nuclear magnetic spectrum of 5-dimethyl-4-methoxypyridine
(5) specific embodiments:
The present invention can be further understood by embodiment, but content of the present invention can not be limited.
Embodiment 1:
Adopt molecular distillation method to separate purification 2-methylol-3, the method for 5-dimethyl-4-methoxypyridine, high boiling point superpolymer proportion is about 10%, comprises the steps:
(1) molecular distillation is removed high boiling point superpolymer impurity: in the molecular distillation system, control oil bath Heating temperature is 150～250 ℃, vacuum tightness≤20mmHg, slowly add 500ml through crystallizing and separating contain 2-methylol-3,5-dimethyl-4-methoxypyridine mother liquor, adding speed is 10ml/min, needed add in 50 minutes approximately, collect gaseous condensate, about 450ml stops distillation.
(2) pyridine derivate impurity is removed in rectifying: in the distillation system of 500ml there-necked flask and φ 20mm * 800mm filled column, add the liquid 450ml that easily boils that molecular distillation goes out, rectification under vacuum separates, 100-180 ℃ of control oil bath temperature, vacuum tightness≤20mmHg, collect the cut below 80 ℃, about 50ml is mainly 2 after testing, 3, the 5-trimethylpyridine is collected 80～125 ℃ cut, about 210ml, be mainly 2 after testing, 3,5-trimethylammonium-4-methoxypyridine, 2-aldehyde methyl-4-methoxyl group-3, the 5-lutidine, 2,3,5-trimethylammonium-4-pyridone; Decompression steam to gas phase temperature be 120～130 ℃, about 150 ℃ of feed temperature stops rectifying, and feed liquid in the flask is cooled to 60～70 ℃, the about 190ml of last solution, adding 200ml Virahol; Illustrate: the add-on of this organic solvent Virahol can be any volume milliliter number in 0.5～2.0 times of last solution, the organic solvent Virahol also can be substituted by following: the alkyl alcohol of any C1～C4, or the benzene derivative of any C7～C 10, or acetone;
(3) 2-methylol-3, the crystallization purifying of 5-dimethyl-4-methoxypyridine: with the above-mentioned last solution that is added with organic solvent, frozen cooling to 0 ± 10 ℃, suction filtration; Use a small amount of washed with isopropyl alcohol solid then, dry under 50 ℃ again, get 2-methylol-3,5-dimethyl-4-methoxypyridine, light brown solid 143g, GC purity 99.4%, 139 ℃ of boiling points (10mmHg).
Embodiment 2:
Adopt scraper plate thin film distillation method to separate purification 2-methylol-3, the method for 5-dimethyl-4-methoxypyridine, high boiling point superpolymer proportion is about 10%, comprises the steps:
(1) high boiling point superpolymer impurity is removed in the scraper plate thin film distillation: at 2m
2In the scraper plate thin film distillation system, 180～220 ℃ of control oil bath temperatures, vacuum tightness≤10mmHg, 150 rev/mins of scraper plate rotating speeds slowly add the centrifugalled 2-methylol-3 that contains, 5-dimethyl-4-methoxypyridine mother liquor 1000kg with 200kg/h speed, about 5h adds, collection steams liquid, and about 900kg stops distillation;
(2) pyridine derivate impurity is removed in rectifying: in the distillation system of the stainless steel mesh rectifying tower of the stainless head tower still of 1000L and tower diameter φ 300 * 6000mm, add the 900kg that steams in the scraper plate thin film distillation system and contain 2-methylol-3,5-dimethyl-4-methoxypyridine solution, 130～150 ℃ of control tower bed material liquid temps, vacuum tightness≤10mmHg collects the cut 96kg of tower top temperature≤80 ℃, be 2 after testing, 3, the 5-trimethylpyridine is collected the cut 425kg of 80～125 ℃ of tower top temperatures, main 2,3,5-trimethylammonium-4-methoxypyridine, 2-aldehyde methyl-4-methoxyl group-3, the 5-lutidine, 2,3,5-trimethylammonium-4-pyridone; Underpressure distillation to tower top temperature is 125～135 ℃, and tower bed material liquid temp is 150 ℃, stops rectifying, and tower bed material liquid is cooled to 65 ℃, and last solution is 380L at the bottom of the tower, adds 400L toluene; Illustrate: the add-on of this organic solvent toluene can be the last solution of Yi Tadi 1 times～1.5 times of meters any volume rise number, organic solvent also can be a benzene, acetone, the perhaps benzene derivative of any C7～C10;
(3) 2-methylol-3, the crystallization purifying of 5-dimethyl-4-methoxypyridine: last feed liquid at the bottom of the above-mentioned tower that is added with toluene is cooled to 0 ℃, centrifugation, add the small amount of toluene rinsing, dry under 50 ℃, get light brown solid 317kg, GC purity: 99.3%, 139 ℃ of boiling points (10mmHg).
Claims (5)
1. one kind is separated 2-methylol-3, and the method for 5-dimethyl-4-methoxypyridine is characterized in that:
(1) will contain 2-methylol-3, the crystallization mother liquor of 5-dimethyl-4-methoxypyridine is removed superpolymer with the vaporizer distillation, obtains containing 2-methylol-3, the mixing solutions of 5-dimethyl-4-methoxypyridine; Distillation condition in vaporizer: 150～250 ℃ of temperature, vacuum tightness≤20mmHg;
(2) mixing solutions that step (1) is obtained separates by rectifying tower, tower bed material liquid temp keeps 100～180 ℃, vacuum tightness≤20mmHg according to tower top temperature, collects each component, rectifying is to 120～135 ℃ of tower top temperatures, vacuum tightness≤20mmHg stops rectifying, and tower bed material liquid temp is reduced to 60-70 ℃, adding organic solvent in the last feed liquid at the bottom of the tower, tower bed material liquid is 1: 0.5～2 with equal volume unit's ratio of added organic solvent;
The organic solvent of described adding is a kind of in the benzene derivative, benzene, acetone of alkyl alcohol, the C7～C10 of C1～C4, and wherein the alkyl alcohol of C1～C4 is a methyl alcohol, or ethanol, or propyl alcohol, or Virahol, or butanols; The benzene derivative of C7～C10 is a toluene, or ethylbenzene, or dimethylbenzene;
(3) tower bed material liquid is cooled to 0 ± 10 ℃, separates out crystallization, filter,, get 2-methylol-3,5-dimethyl-4-methoxypyridine dry below 50 ℃.
2. separation method according to claim 1 is characterized in that: temperature is 180～220 ℃ in the vaporizer described in the step (1), vacuum tightness≤10mmHg.
3. separation method according to claim 1 and 2 is characterized in that described vaporizer is a scrapper thin film evaporator, or molecular still.
4. separation method according to claim 1 is characterized in that: the last feed liquid of step (2) Zhong Tadi compares 1: 1～1.5 with the equal volume unit of added organic solvent.
5. separation method according to claim 1 is characterized in that: the liquid cooling of tower bed material is frozen and is cooled to 0 ± 5 ℃ in the step (3).
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| Application Number | Priority Date | Filing Date | Title |
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| CN2008100631569A CN101318928B (en) | 2008-07-15 | 2008-07-15 | Process for the separation of 2-hydroxymethyl-3, 5-dimethyl-4-methoxy pyridine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100631569A CN101318928B (en) | 2008-07-15 | 2008-07-15 | Process for the separation of 2-hydroxymethyl-3, 5-dimethyl-4-methoxy pyridine |
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| Publication Number | Publication Date |
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| CN101318928A CN101318928A (en) | 2008-12-10 |
| CN101318928B true CN101318928B (en) | 2011-01-19 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817492A (en) * | 2015-05-22 | 2015-08-05 | 抚州三和医药化工有限公司 | Separation purification method of lansoprazole intermediate 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225904B (en) * | 2011-04-22 | 2013-11-27 | 天津美科泰化工科技有限公司 | Recovering and refining apparatus and separation method of dimethyl sulfoxide (DMSO) |
| CN113461601B (en) * | 2021-06-24 | 2022-12-27 | 上海星可高纯溶剂有限公司 | Treatment method of 3-methylpyridine waste liquid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817492A (en) * | 2015-05-22 | 2015-08-05 | 抚州三和医药化工有限公司 | Separation purification method of lansoprazole intermediate 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine |
| CN104817492B (en) * | 2015-05-22 | 2018-05-18 | 抚州三和医药化工有限公司 | Lansoprazole intermediate 2- methylol -3- methyl -4- (2,2,2- trifluoro ethoxies）The isolation and purification method of pyridine |
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Address after: 322002 Zhejiang city in Yiwu Province, the temple town of Shuangfeng Road No. 15 Co-patentee after: ESTEVE HUAYI PHARMACEUTICAL Co.,Ltd. Patentee after: ZHEJIANGHUAYI PHARMACEUTICAL Co.,Ltd. Address before: 322002 Yi Nan Industrial Zone, Yiwu, Zhejiang Co-patentee before: ESTEVE HUAYI PHARMACEUTICAL Co.,Ltd. Patentee before: Zhejiang Huayi Pharmaceutical Co.,Ltd. |
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