CN106146365B - A kind of preparation method of Tiopronin and its Zn complex - Google Patents
A kind of preparation method of Tiopronin and its Zn complex Download PDFInfo
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- CN106146365B CN106146365B CN201610447530.XA CN201610447530A CN106146365B CN 106146365 B CN106146365 B CN 106146365B CN 201610447530 A CN201610447530 A CN 201610447530A CN 106146365 B CN106146365 B CN 106146365B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/12—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by reactions not involving the formation of mercapto groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/08—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols by replacement of hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/06—Zinc compounds
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Abstract
The invention discloses the preparation method of a kind of Tiopronin and its Zn complex, belong to the medical compounds technical field for improving urgency/chronic liver disease.Technical scheme of the present invention main points are：
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical fields, and in particular to the preparation of a kind of Tiopronin and its Zn complex
Method.
Background technology
Tiopronin and Tiopronin zinc are all metabolism improving antidotes, and molecular formula is respectively：C5H9NO3S and
C5H8NO3SZn.2H2O, molecular weight are respectively：163.2 and 260.9, structural formula difference is as follows：
It is mainly used for the Hepatic function improvement of urgency/chronic liver disease.Foreign countries, which are used for a long time, to be confirmed：Tiopronin can be comprehensive, bright
Aobvious improvement virus hepatitis, the liver function index of alcoholic liver injury and related symptom, it is curative for effect, securely and reliably.General sieve of sulphur
The carboxyl contained in peaceful structure shows stronger acidity, larger to blood vessel irritation, therefore existing preparation is mostly to be formulated as
Neutrality is applied to clinic.If the freeze-dried powder clinically used at present is general sieve of sulphur for being packed into 0.1g or 0.2g in every 1 cillin bottle
Rather, and it is equipped with dedicated sodium bicarbonate aqueous solution, when Clinical practice, which is again dissolved Tiopronin with sodium bicarbonate aqueous solution, to be neutralized,
Production, packaging and use are cumbersome in this way.In addition, we have discovered that, Tiopronin is neutralized in water phase by acidity
It is easily decomposed in neutral process and generates a large amount of by-products, product purity is made to decline, to influence the medicinal safety of the product and have
Effect uses.In addition, the sulfydryl contained in Tiopronin structure, property is very unstable, and oxidation reaction easily occurs, and is unfavorable for drug
Storage, impacts the safety of clinical application.The secondary work of larger poison is generated after many document report Clinical practice Tiopronins
With, may in N-process easily decompose and the unstability of sulfydryl it is related.
Currently, the domestic preparation method about Tiopronin is mainly the following：1, it is that starting is former with alpha-mercapto propionic acid
Material is made acyl chlorides through benzyl protection, then target compound is made with glycine condensation deprotection base, and wherein deprotection base is wanted
It is reacted with the sodium in liquid nitrogen at -55 DEG C, yield 30%, the route reaction condition is harsh, it is difficult to industrialize；2, with alpha-brominated
Propiono glycine is condensed with the compound (such as thiobenzoate) containing potential sulfydryl, and then ammonolysis obtains target compound, yield
Up to 52%, raw material domestic supply needed for the route is seldom, and prepares difficult, and toxicity is big；3, using propionic acid as starting material, first
It is acylated with phosphorus trichloride, then alpha-chloro propionyl chloride is made through chlorination, substitution reaction in logical chlorine, is condensed with glycine, then two sulphur
Change thiylation group, Tiopronin finally is made by reduction, it is anti-that which generally carries out curing using sodium disulfide
It answers, the easy moisture absorption of sodium disulfide is extremely unstable, and smell is very heavy.
Bioinorganic chemistry studies have shown that zinc is the essential trace elements of the human body, be the constituent of a variety of enzymes and swash
The factor living, it is not only involved in the synthesis and degradation of carbohydrate, lipid, protein and nucleic acid, promotes the metabolism of tissue, be conducive to
The regeneration and reparation of epithelial tissue, and as the ingredient of copper-zinc superoxide dismutase (CuZn-SOD), participate in superoxides
Elimination, have defense function to cell.The content of the Zn in serum of chronic hepatitis patient reduces, and it is slow to take the treatment of Tiopronin zinc
Property hepatitis, alcoholic liver injury can play the synergistic effect of Tiopronin and zinc, play better therapeutic effect.In order to reduce sulphur
The production cost of Pu Luoning zinc, it is necessary to a kind of easy to operate, low in raw material price of design and the repetition of process route experimental result
The preparation method of the preferable Tiopronin zinc of property.
Invention content
The technical problem to be solved by the present invention is to provide a kind of easy to operate, low in raw material price, process route experiment knots
Fruit repeatability is preferable and can significantly reduce the Tiopronin of production cost and its preparation method of Zn complex.
The present invention adopts the following technical scheme that a kind of preparation method of Tiopronin is special to solve above-mentioned technical problem
Sign be the specific steps are：
Step (1) generates 2- by propionic acid under bromide phosphine and bromine effect under conditions of heating and illumination are carried out at the same time
Bromo-propionic acid；
Step (2), 2 bromopropionic acid is under potassium methoxide or sodium methoxide effect, and halogen is hydrolyzed to hydroxyl, while companion in ether
With carboxyl at salt, 2 hydroxy propanoic acid sylvite or 2 hydroxy propanoic acid sodium salt are finally obtained；
Under lawesson reagent effect, being reacted in toluene makes for step (3), 2 hydroxy propanoic acid sylvite or 2 hydroxy propanoic acid sodium salt
Hydroxyl is converted into sulfydryl, and finally acidification obtains 2 mercaptopropionic acid or 2 hydroxy propanoic acid sylvite or 2 hydroxy propanoic acid sodium salt in first
Under base sulfonic acid chloride and thioacetic acid potassium synergistic effect, being reacted in toluene makes hydroxyl be converted into sulfydryl, and finally acidification obtains 2- mercaptos
Base propionic acid；
Step (4), 2 mercaptopropionic acid make carboxyl become acyl chlorides to obtain 2- mercaptopropionyls under phosphorus chloride and concentrated sulfuric acid effect
Chlorine；
Tiopronin is obtained by the reaction with amion acetic acid in step (5), 2- mercaptopropionyls chlorine.
Further preferably, the detailed process of step (1) is：In the reaction equipped with blender, reflux condensing tube and thermometer
150g propionic acid and 3g bromide phosphines are sequentially added in container, is placed under high-pressure sodium lamp after being heated to 60 DEG C, and 360g bromines, side is added dropwise
It heats side and carries out illumination reaction, low-boiling-point substance, which is evaporated off, after reaction 6h obtains flaxen 2 bromopropionic acid.
Further preferably, the detailed process of step (2) is：Sequentially add in the reaction vessel 300g 2 bromopropionic acids and
1000mL ether is added dropwise 1000mL dissolved with the methanol solution of 280g potassium methoxides in 0 DEG C, is heated to after dripping under nitrogen protection
Reflux steams ether after reacting 4h, and crystallisation by cooling is placed at 0 DEG C, and suction filtration obtains solid 2 hydroxy propanoic acid sylvite.
Further preferably, the detailed process of step (3) is：110g 2 hydroxy propanoic acid sylvite is added in the reaction vessel
Into 2000mL toluene, 400g lawesson reagents are added, are heated to 80 DEG C of reaction 12h, concentration of reaction solution, then concentrate is poured into
In ice water, the pH value that solution is adjusted with dilute hydrochloric acid is 4, is extracted with ethyl acetate to obtain 2 mercaptopropionic acid；Or in reaction vessel
It is middle that 110g 2 hydroxy propanoic acid sylvite is added in 2000mL toluene, 120g methylsufonyl chlorides are added, 80 DEG C of reactions are heated to
120g thioacetic acid potassiums are added in 2h, continue to react 6h at 80 DEG C, after reaction concentration of reaction solution, then concentrate is poured into ice
In water, the pH value that solution is adjusted with dilute hydrochloric acid is 4, is extracted with ethyl acetate to obtain 2 mercaptopropionic acid.
Further preferably, the detailed process of step (4) is：106g 2 mercaptopropionic acids are added in the reaction vessel, in 40 DEG C
The concentrated sulfuric acid of 65g phosphorus chloride and 20g mass concentrations 98% is added dropwise, the fraction that 115-120 DEG C of collection is distilled after reaction 2h obtains liquid
Body 2- mercaptopropionyl chlorine.
Further preferably, the detailed process of step (5) is：90g glycine is added in the reaction vessel, and 400mL is added
The finely ground natrium carbonicum calcinatums of 64g are added portionwise in water stirring and dissolving, and 150g 2- mercaptopropionyl chlorine is added dropwise after being cooled to 0 DEG C, are added dropwise
Sodium carbonate liquor is added after complete makes reaction solution keep alkalescent, and the reaction was continued 5h, it is 2 to be acidified to pH value with dilute hydrochloric acid, uses second
Vacuum distillation obtains Tiopronin after acetoacetic ester extraction.
The preparation method of Tiopronin zinc of the present invention, it is characterised in that：By Tiopronin and mercapto-protective agent second
Edetate disodium and soluble zinc salt are under ammonium hydroxide effect, in autoclave under 60 DEG C, 0.3MPa pressure conditions
It is reacted, precipitating reagent acetone is added after reaction by Precipitation, filtering, dry, obtained Tiopronin zinc.
Further preferably, the soluble zinc salt is zinc chloride, zinc sulfate, zinc nitrate or zinc acetate.
Further preferably, the specific building-up process of the Tiopronin zinc is：28g zinc chloride and 30mL ammonium hydroxide are placed in
In autoclave, 150mL is added and analyzes pure methanol, is stirred to dissolve, sequentially adds 32.0g Tiopronins, 130mL analyses
Pure methanol and 0.5g mercapto-protective agent disodium ethylene diamine tetraacetates, nitrogen is then passed through into autoclave, its pressure is made to reach
To 0.3MPa, 5h is reacted under conditions of 60 DEG C, filters, filters out insoluble matter, filtrate is put into ultrasound reactor, adds in 0 DEG C
Enter 100mL precipitating reagent acetone, voluntarily coagulating sedimentation, suction filtration, filter cake are dried to obtain target production in 60 DEG C under 80KHz ultrasonications
Object Tiopronin zinc, target product is detected through sulfate ion finds that sulfate radical-free ion exists.
Reaction equation in the preparation method of Tiopronin zinc of the present invention is：
It replaces chlorine to prepare halogenated compound by using bromine in the experimentation of the present invention, is passed through using liquid ratio
Gas has measured and easy to use；Become 2 hydroxy propanoic acid sylvite by 2 bromopropionic acid, then passes through lawesson reagent or methyl sulphur
Hydroxyl is become sulfydryl by acyl chlorides and thioacetic acid potassium, is avoided the carbonyl on carboxyl and is easy to be changed to the risk of carbon sulphur double bond,
And lawesson reagent or methylsufonyl chloride and thioacetic acid potassium are compared with sodium disulfide, and it is not only easy to use, but also it is not easy the moisture absorption,
Sharp aroma is smaller, it is often more important that two thio reaction high incomes of single thio ratio, by-product is few, can obtain pure intermediate 2-
Mercaptopropionic acid.
Specific implementation mode
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on the above of the present invention belong to this hair
Bright range.
Embodiment 1
Propionic acid 150g (2mol) is added in the there-necked flask equipped with blender, reflux condensing tube and thermometer, is then added
Bromide phosphine 3g is placed into after being heated to 60 DEG C under high-pressure sodium lamp, and bromine 360g (2.25mol) is slowly added dropwise, and is carried out in heating
Illumination reaction is evaporated off low-boiling-point substance after reacting 6h, obtains flaxen 2 bromopropionic acid 310g.
Embodiment 2
2 bromopropionic acid 300g (2mol) is added in reaction bulb, adds 1000mL ether, under nitrogen protection, 0 DEG C of item
Under part, the methanol solution 1000mL dissolved with potassium methoxide 280g (4mol) is slowly added dropwise, is slowly heated to flow back after dripping, reacts
Ether is steamed after 4h, crystallisation by cooling is placed at 0 DEG C, and suction filtration obtains solid 2 hydroxy propanoic acid sylvite 180g.
Embodiment 3
2 bromopropionic acid 300g (2mol) is added in reaction bulb, adds 1000mL ether, under nitrogen protection, 0 DEG C of item
Under part, the methanol solution 1000mL dissolved with sodium methoxide 216g (4mol) is slowly added dropwise, is slowly heated to flow back after dripping, reacts
Ether is steamed after 4h, crystallisation by cooling is placed at 0 DEG C, and suction filtration obtains solid 2 hydroxy propanoic acid sodium salt 149g.
Embodiment 4
In reaction bulb, 2 hydroxy propanoic acid sylvite 110g is added in 2000mL toluene, lawesson reagent 400g is added,
After being heated to 80 DEG C of reaction 12h, concentration of reaction solution, then concentrate is poured into ice water, the pH value that solution is adjusted with dilute hydrochloric acid is
4, it is extracted with ethyl acetate to obtain 2 mercaptopropionic acid 95g.
Embodiment 5
In reaction bulb, 2 hydroxy propanoic acid sylvite 110g is added in 2000mL toluene, methylsufonyl chloride is added
Thioacetic acid potassium 120g is added after being heated to 80 DEG C of reaction 2h in 120g, and continuation reacts 6h under the conditions of 80 DEG C, after reaction
Concentration of reaction solution, then concentrate is poured into ice water, it is 4 to adjust solution ph with dilute hydrochloric acid, is extracted with ethyl acetate to obtain 2-
Mercaptopropionic acid 90g.
Embodiment 6
In 1000mL round-bottomed flasks be added 2 mercaptopropionic acid 106g, be slowly added dropwise under the conditions of 40 DEG C phosphorus chloride 65g and
The fraction of 115-120 DEG C of distillation collection obtains liquid 2- mercaptopropionyl chlorine after the concentrated sulfuric acid 20g that mass concentration is 98%, reaction 2h
80g。
Embodiment 7
Glycine 90g is added in more mouthfuls of reaction bulbs, adds water 400mL stirring and dissolvings, is gradually added into finely ground Carbon Dioxide
After being cooled to 0 DEG C, 2- mercaptopropionyl chlorine 150g are slowly added dropwise, a certain amount of sodium carbonate liquor is added after dripping to be made in sodium 64g
Reaction solution keeps alkalescent, and the reaction was continued 5h, it is 2 to be acidified to pH value with dilute hydrochloric acid, after being extracted with ethyl acetate, is evaporated under reduced pressure to
To Tiopronin 190g.
Embodiment 8
It weighs zinc chloride 28g (0.20mol) and ammonium hydroxide 30mL is placed in autoclave, be added and analyze pure methanol 150mL,
It is stirred to dissolve, weighs Tiopronin 32.0g (0.20mol) and be added thereto, add the pure methanol 130mL of analysis and sulfhydryl protected
Agent disodium ethylene diamine tetraacetate 0.5g；It is passed through nitrogen into autoclave, its pressure is made to reach 0.3MPa, under the conditions of 60 DEG C
React 5h；It filtering, filters out insoluble matter, filtrate is put into ultrasound reactor, and precipitating reagent acetone 100mL is added in 0 DEG C,
Voluntarily coagulating sedimentation, suction filtration, filter cake obtain Tiopronin zinc 47g, yield 90%, product in 60 DEG C of dryings under 80KHz ultrasonications
Find exist without chlorion through chloride test.
Embodiment above describes the basic principles and main features and advantage of the present invention, and the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (6)
1. a kind of preparation method of Tiopronin, it is characterised in that the specific steps are：
Step（1）, by propionic acid under phosphonium bromide and bromine effect, 2- bromines third are generated under conditions of heating and illumination are carried out at the same time
Acid；
Step（2）, for 2 bromopropionic acid under potassium methoxide or sodium methoxide effect, bromo base is hydrolyzed to hydroxyl in ether, while adjoint
Carboxyl finally obtains 2 hydroxy propanoic acid sylvite or 2 hydroxy propanoic acid sodium salt at salt；
Step（3）, under lawesson reagent effect, being reacted in toluene makes hydroxyl for 2 hydroxy propanoic acid sylvite or 2 hydroxy propanoic acid sodium salt
It is converted into sulfydryl, finally acidification obtains 2 mercaptopropionic acid or 2 hydroxy propanoic acid sylvite or 2 hydroxy propanoic acid sodium salt in methyl sulphur
Under acyl chlorides and thioacetic acid potassium synergistic effect, being reacted in toluene makes hydroxyl be converted into sulfydryl, and finally acidification obtains 2- sulfydryls third
Acid；
Step（4）, 2 mercaptopropionic acid makes carboxyl become acyl chlorides to obtain 2- mercaptopropionyl chlorine under phosphorus chloride and concentrated sulfuric acid effect；
Step（5）, Tiopronin is obtained by the reaction in 2- mercaptopropionyls chlorine and amion acetic acid.
2. the preparation method of Tiopronin according to claim 1, it is characterised in that step（1）Detailed process be：
150g propionic acid and 3g phosphonium bromides are sequentially added in reaction vessel equipped with blender, reflux condensing tube and thermometer, are heated to 60
It is placed under high-pressure sodium lamp after DEG C, 360g bromines is added dropwise, illumination reaction is carried out in heating, low-boiling-point substance, which is evaporated off, after reaction 6h obtains
Flaxen 2 bromopropionic acid.
3. the preparation method of Tiopronin according to claim 1, it is characterised in that step（2）Detailed process be：
300g 2 bromopropionic acids and 1000mL ether are sequentially added in reaction vessel, under nitrogen protection in 0 DEG C be added dropwise 1000mL dissolved with
The methanol solution of 280g potassium methoxides is heated to flowing back after dripping, and ether is steamed after reacting 4h, and crystallisation by cooling is placed at 0 DEG C, takes out
Filter obtains solid 2 hydroxy propanoic acid sylvite.
4. the preparation method of Tiopronin according to claim 1, it is characterised in that step（3）Detailed process be：
110g 2 hydroxy propanoic acid sylvite is added in 2000mL toluene in reaction vessel, 400g lawesson reagents is added, is heated to 80
DEG C reaction 12h, concentration of reaction solution, then concentrate is poured into ice water, the pH value that solution is adjusted with dilute hydrochloric acid is 4, with acetic acid second
2 mercaptopropionic acid is obtained by extraction in ester；Or 110g 2 hydroxy propanoic acid sylvite is added in 2000mL toluene in the reaction vessel,
120g methylsufonyl chlorides are added, 80 DEG C of reaction 2h is heated to, 120g thioacetic acid potassiums is added, continue to react 6h at 80 DEG C, instead
Concentration of reaction solution after answering, then concentrate is poured into ice water, the pH value that solution is adjusted with dilute hydrochloric acid is 4, uses ethyl acetate
2 mercaptopropionic acid is obtained by extraction.
5. the preparation method of Tiopronin according to claim 1, it is characterised in that step（4）Detailed process be：
106g 2 mercaptopropionic acids are added in reaction vessel, the concentrated sulfuric acid of 65g phosphorus chloride and 20g mass concentrations 98% are added dropwise in 40 DEG C, instead
The fraction that distillation after 2h collects 115-120 DEG C is answered to obtain liquid 2- mercaptopropionyl chlorine.
6. the preparation method of Tiopronin according to claim 1, it is characterised in that step（5）Detailed process be：
90g glycine is added in reaction vessel, and 400mL water stirring and dissolvings are added, the finely ground natrium carbonicum calcinatums of 64g are added portionwise, it is cold
But to dropwise addition 150g 2- mercaptopropionyl chlorine after 0 DEG C, sodium carbonate liquor is added after dripping makes reaction solution keep alkalescent, after
Continuous reaction 5h, it is 2 to be acidified to pH value with dilute hydrochloric acid, is evaporated under reduced pressure after being extracted with ethyl acetate and obtains Tiopronin.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101205206A (en) * | 2006-12-22 | 2008-06-25 | 常州市第四制药厂有限公司 | Potassium tiopronin as well as preparation and uses thereof |
| CN102898339A (en) * | 2012-10-29 | 2013-01-30 | 苏州二叶制药有限公司 | Method for preparing tiopronin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2009196951A (en) * | 2008-02-25 | 2009-09-03 | Kazumichi Izaki | Method for producing alkyl hydrosulfide compound or derivative thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101205206A (en) * | 2006-12-22 | 2008-06-25 | 常州市第四制药厂有限公司 | Potassium tiopronin as well as preparation and uses thereof |
| CN102898339A (en) * | 2012-10-29 | 2013-01-30 | 苏州二叶制药有限公司 | Method for preparing tiopronin |
Non-Patent Citations (5)
| Title |
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| 硫普罗宁的合成;苏春轩等;《化学与生物工程》;20071231;第24卷(第4期);47-48 * |
| 硫普罗宁的合成工艺改进;王东阳等;《中国药物化学杂志》;19940930;第4卷(第3期);198-201 * |
| 硫普罗宁的合成工艺研究;杨静华等;《中国药师》;20051231;第8卷(第8期);631-633 * |
| 硫普罗宁的合成工艺研究;王哲等;《当代化工》;20080630;第37卷(第3期);241-242 * |
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|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
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| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
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Effective date of registration: 20210513 Address after: 224200 No.15, Weiba Road, Dongtai City, Yancheng City, Jiangsu Province Patentee after: JIANGSU SHENLONG PHARMACEUTICAL Co.,Ltd. Address before: 453007 No. 46 East Road, Makino District, Henan, Xinxiang Patentee before: HENAN NORMAL University |