CN103113408A - Novel method for preparing fosfomycin phenylethylamine - Google Patents
Novel method for preparing fosfomycin phenylethylamine Download PDFInfo
- Publication number
- CN103113408A CN103113408A CN2012105270351A CN201210527035A CN103113408A CN 103113408 A CN103113408 A CN 103113408A CN 2012105270351 A CN2012105270351 A CN 2012105270351A CN 201210527035 A CN201210527035 A CN 201210527035A CN 103113408 A CN103113408 A CN 103113408A
- Authority
- CN
- China
- Prior art keywords
- phosphonomycin
- phenylethylamine
- fosfomycin
- novel method
- dextrorotation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 18
- ODALAXKSIBESFV-PXRNWTNJSA-N [(2r,3s)-3-methyloxiran-2-yl]phosphonic acid;(1r)-1-phenylethanamine Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O.C[C@@H](N)C1=CC=CC=C1 ODALAXKSIBESFV-PXRNWTNJSA-N 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 6
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 101100059652 Mus musculus Cetn1 gene Proteins 0.000 claims description 8
- 101100059655 Mus musculus Cetn2 gene Proteins 0.000 claims description 8
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 150000007925 phenylethylamine derivatives Chemical class 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000006735 epoxidation reaction Methods 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 208000012839 conversion disease Diseases 0.000 claims description 2
- 235000021050 feed intake Nutrition 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008367 deionised water Substances 0.000 claims 1
- 229910021641 deionized water Inorganic materials 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims 1
- 229960000308 fosfomycin Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XWCIXXXLOAAWPU-IHWYPQMZSA-N [(z)-prop-1-enyl]phosphonic acid Chemical compound C\C=C/P(O)(O)=O XWCIXXXLOAAWPU-IHWYPQMZSA-N 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 229910052698 phosphorus Inorganic materials 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- -1 Amine salt Chemical class 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 1
- 206010011844 Dacryocystitis Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010056254 Intrauterine infection Diseases 0.000 description 1
- 241001263448 Mycetozoa Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 206010061512 Serratia infection Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000008025 hordeolum Diseases 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Abstract
The invention discloses a novel method for preparing fosfomycin phenylethylamine, which comprises the following steps: by using cis-propenylphosphonic acid as a raw material, carrying out oxidation and cyclization under the actions of a catalyst and an oxidizer, carrying out dynamic resolution under specific solvent conditions to precipitate levo-fosfomycin, adding a certain amount of dextro-phenylethylamine, reacting, and refining to obtain the levo-fosfomycin dextro-phenylethylamine. The preparation method has the advantages of low reaction cost, fewer steps, fewer byproducts and low environmental pollution, and is suitable for industrial mass production and prepration.
Description
Technical field
The present invention relates to a kind of novel method for preparing the phosphonomycin fosfomycin phenylethylamine calt, the present invention proposes easier a, synthetic method cheaply, belong to the field of chemical synthesis.
Background technology
Phosphonomycin is a kind of wide spectrum, low toxicity, is difficult for sensitization, is difficult for producing resistance, has synergistic a kind of antibiotic with most of antibiotic, all responsive to staphylococcus, intestinal bacteria, meningococcus, gonococcus, Corynebacterium diphtheriae, Serratia, Bacillus proteus, Pseudomonas aeruginosa, dysentery bacterium and Hp etc., but the anti-bacteria cell walls is synthetic, the sterilant of a kind of nursery stage, all inhibited to most of suis, Pseudomonas aeruginosa, Proteus mirabilis and part pneumobacillus and the negative mycetozoan of indoles.Phosphonomycin is applicable to urinary tract, respiratory tract, digestive tube, gynaecology, skin soft tissue and other site infections and septicemia.Oral administration can be treated intestinal tract infections, urinary tract infections, Serratia infection, Helicobacter pylori infection and blepharitis, hordeolum, otitis media, nasal sinusitis, dacryocystitis etc.; Intravenous injection can be treated the gynaecopathias such as respiratory tract infection, urinary tract infection, septicemia and pelvic inflammatory disease, appendagitis, intra-uterine infection, and range of application is very extensive.
It is to extract from the actinomycetes nutrient solution that phosphonomycin begins, and is all produced by the synthetic method at present.
Various phosphonomycin salt are usually transformed by phosphonomycin dextrorotation phenylethylamine salt and generate, and the route of synthesis of phosphonomycin dextrorotation phenylethylamine salt is as follows:
In following formula, effective body (A) is phosphonomycin dextrorotation phenylethylamine salt, the left-handed benzene second of invalid body (B) dextrorotation phosphonomycin
Amine salt, both respectively account for half.
Fosfomycin phenylethylamine calt splits the prior art of preparation:
Domestic patent or some english literatures are described: adopt the induced crystallization method, add left salt as crystal seed in the solution of racemic modification, it is separated out, reach whereby the separation purpose.
Detailed process is as follows: with 330 kilograms of the mixed salts (the right amine of left phosphorus and the left amine salt of right phosphorus) that obtain after epoxidation, 0.25 kilogram of right amine crystal seed of left phosphorus and 400 liters of dehydrated alcohol heating for dissolving stir and are cooled to 20 and spend to 1.65 kilograms of the right amine of the left phosphorus of crystallization.Add again 1.65 kilograms of mixed salts after filtration, add the left amine salt crystal seed of right phosphorus, after separating out the left amine salt of right phosphorus.Repeating above operation 60 times to mother liquor can not be used again, merges each time fractionation and obtains approximately 100 kilograms of fosfomycin phenylethylamine calts, and the fractionation rate is 60%, is 132 degree with fusing point after ethyl alcohol recrystallization.
Shortcoming: in splitting operation, need to repeat tens of crystallizations and obtain fosfomycin phenylethylamine calt, the one, lose time, the 2nd, whole fractionation rate is not high, and it is large that cost becomes.The left amine salt of the right phosphorus of ineffective treatment compound accounts for the composition of half simultaneously, does not add to utilize to have caused the wasting of resources.
The present invention be directed to above-mentioned present situation, provide that a kind of raw material is cheap and easy to get, toxicity is little, reactions steps is few, side reaction is few, and the three wastes are few, is fit to this method for splitting of industrialized production, the method is take water as primary solvent, adds appropriate dimethyl sulfoxide (DMSO), avoids the pollution in traditional method for splitting.This resolution process is easy and simple to handle simultaneously, and raw material is easy to get, mild condition, and product purity is high, steady quality.
Summary of the invention
The object of the invention is to provide a kind of novel method for splitting with preparation phosphonomycin dextrorotation phenylethylamine, is used for the synthetic of Fosmicin sodium salt, the needs of producing to satisfy medicinal industry department.The present invention does not adopt common induced crystallization method, and adopts the Dynamic Kinetic Resolution method.We find under study for action, and when phosphonomycin racemic modification spontaneous crystallization slowly in solution that reaction generates, phosphonomycin is preferentially separated out, and the racemic modification in mother liquor has asymmetric Transformation Phenomenon.Also having a kind of is in the patent of invention of one piece of fosfomycin trometamol as previous in this institute, to utilize outside chiral reagent effect, and its isomer balance is moved, and obtains the ee value and be 90% phosphonomycin, and this is no longer described.
Concrete steps are described as follows:
(1) preparation compound (+,-)-
1: under the catalysis of catalyzer, by oxygenant to the cis-propene phosphoric acid asymmetric Epoxidation.Whole oxidising process is used the HPLC(nh 2 column) the monitoring reaction conversion ratio.
(2) dynamic resolution: under the specific solvent condition, phosphonomycin is separated out.
(3) preparation of phosphonomycin dextrorotation phenylethylamine: the phosphonomycin that step (2) is obtained and dextrorotation phenylethylamine feed intake after reaction according to a certain percentage, separate out the phosphonomycin dextrorotation phenylethylamine salt that obtains making with extra care in ethanol.
Embodiment
The below sets forth the present invention with example:
1. compound
1Synthetic:
Get 1.2g(10mmol) cis-propene phosphoric acid and dehydrated alcohol (5 milliliters) be added in 50 milliliters of three-necked bottles, stirs entirely molten.Dropping is by 0.5g Na
2WO
4With the solution of water-soluble 5 milliliters of 0.13g EDTA-2Na, then add 30% hydrogen peroxide 1.7g(15mmol), be heated to 40 degree entirely molten, reaction 1h.High performance liquid phase monitoring reaction.Cooling filtering insolubles, after the ethanol steaming is removed, the DL phosphonomycin that adds ethyl acetate extraction to generate, anhydrous sodium sulfate drying filters, the concentrated colorless oil (1.3g, yield 94%) that obtains.
2. dynamic resolution
8 milliliters of deionized waters are added in reaction flask with 2 milliliters of dimethyl sulfoxide (DMSO), open stirring, the DL phosphonomycin of upper step product 1.3 grams drops into wherein, is warmed up to 40 degree insulation 15 minutes, cools to 5 degree, vapor away most of solvent, phosphonomycin is separated out from this solution, leaches fast, and the vacuum Air drying obtains clear crystal 0.6g, split productive rate and reach 91%, ee value 98%.Mother liquor finds that by surveying specific optical rotation the dextrorotation phosphonomycin has the part configuration conversion, collects pending.
3. the preparation of phosphonomycin dextrorotation phenylethylamine
Under nitrogen protection; phosphonomycin (0.6g) is dropped in the dehydrated alcohol reaction flask that is equipped with 5 milliliters; after slowly squeezing into wherein with syringe the dextrorotation phenylethylamine of 0.53g; kept room temperature reaction 3 hours; leach and obtain white solid phosphonomycin dextrorotation phenylethylamine salt (1.05g, yield 93%).
Claims (4)
1. novel method for preparing the phosphonomycin fosfomycin phenylethylamine calt is characterized in that the operation steps of the method is as follows:
(1) preparation compound (+,-)-
1: under the catalysis of catalyzer, by oxygenant to the cis-propene phosphoric acid asymmetric Epoxidation,
Whole oxidising process is used the HPLC(nh 2 column) the monitoring reaction conversion ratio;
(2) dynamic resolution: under the specific solvent condition, phosphonomycin is separated out;
(3) preparation of phosphonomycin dextrorotation phenylethylamine: the phosphonomycin that step (2) is obtained and dextrorotation phenylethylamine feed intake after reaction according to a certain percentage, separate out the phosphonomycin dextrorotation phenylethylamine salt that obtains making with extra care in ethanol.
2. prepare as described in claim 1 the novel method of phosphonomycin fosfomycin phenylethylamine calt, it is characterized in that, the catalyzer described in step (1) is sodium wolframate, and oxygenant is hydrogen peroxide.
3. prepare as described in claim 1 the novel method of phosphonomycin fosfomycin phenylethylamine calt, it is characterized in that, the specific solvent described in step (2) is the mixed solvent of deionized water and dimethyl sulfoxide (DMSO), this both volume ratio be 4:1.
4. prepare as described in claim 1 the novel method of phosphonomycin fosfomycin phenylethylamine calt, it is characterized in that, the certain proportion described in step (3) is that the mol ratio of phosphonomycin and dextrorotation phenylethylamine is 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210527035.1A CN103113408B (en) | 2012-12-10 | 2012-12-10 | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210527035.1A CN103113408B (en) | 2012-12-10 | 2012-12-10 | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt |
Publications (2)
| Publication Number | Publication Date |
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| CN103113408A true CN103113408A (en) | 2013-05-22 |
| CN103113408B CN103113408B (en) | 2015-11-18 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382752A (en) * | 2017-07-12 | 2017-11-24 | 杭州科兴生物化工有限公司 | A kind of method for reclaiming the right amine of raw material for making d biotins |
| CN112409410A (en) * | 2020-12-09 | 2021-02-26 | 商河探荣新技术开发中心 | Application of silver catalyst in preparation of antibacterial intermediate |
| CN112442084A (en) * | 2020-12-03 | 2021-03-05 | 商河探荣新技术开发中心 | Preparation method of antibacterial drug intermediate |
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| CN101723979A (en) * | 2009-12-08 | 2010-06-09 | 张庆武 | Refining method of R-(+)-alpha-phenethylammonium.IR.2S-(-)-cis-1,2-Epoxypropyl phosphonate |
| CN101759719A (en) * | 2010-01-18 | 2010-06-30 | 张庆武 | Method for synthesizing fosfomycin phenylethylamine calt |
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| CN102807586A (en) * | 2012-08-31 | 2012-12-05 | 东北制药（沈阳）科技发展有限公司 | Preparation method of fosfomycin amine salt |
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2012
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107382752A (en) * | 2017-07-12 | 2017-11-24 | 杭州科兴生物化工有限公司 | A kind of method for reclaiming the right amine of raw material for making d biotins |
| CN107382752B (en) * | 2017-07-12 | 2021-03-30 | 杭州科兴生物化工有限公司 | Method for recovering raw material dextroamine for preparing d-biotin |
| CN112442084A (en) * | 2020-12-03 | 2021-03-05 | 商河探荣新技术开发中心 | Preparation method of antibacterial drug intermediate |
| CN112442084B (en) * | 2020-12-03 | 2022-09-09 | 国药集团致君（深圳）制药有限公司 | Preparation method of antibacterial drug intermediate |
| CN112409410A (en) * | 2020-12-09 | 2021-02-26 | 商河探荣新技术开发中心 | Application of silver catalyst in preparation of antibacterial intermediate |
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| Publication number | Publication date |
|---|---|
| CN103113408B (en) | 2015-11-18 |
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Address after: 238251 Anhui Province, Ma'anshan city and county of Wujiang fine chemical base Anhui cinorch Pharmaceutical Chemical Co. Ltd. Applicant after: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Applicant after: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. Applicant after: NNAJING FARMASINO PHARMACEUTICAL SCIENCE & TECHNOLOGY Co.,Ltd. Address before: 238251 Anhui Province, Ma'anshan city and county of Wujiang fine chemical base Anhui cinorch Pharmaceutical Chemical Co. Ltd. Applicant before: FarmaSino Pharmaceuticals (Anhui) Co.,Ltd. Applicant before: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. Applicant before: NNAJING FARMASINO PHARMACEUTICAL SCIENCE & TECHNOLOGY Co.,Ltd. |
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Free format text: CORRECT: APPLICANT; FROM: ANHUI SAINUO PHARMACEUTICAL CHEMICALS CO., LTD. TO: ANHUI SAINUO PHARMACEUTICAL CO., LTD. |
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Effective date of registration: 20160715 Address after: 238251 Anhui Ma'anshan county and Wujiang fine chemical base Patentee after: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee after: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. Address before: 238251 Anhui Province, Ma'anshan city and county of Wujiang fine chemical base Anhui cinorch Pharmaceutical Chemical Co. Ltd. Patentee before: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee before: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. Patentee before: NNAJING FARMASINO PHARMACEUTICAL SCIENCE & TECHNOLOGY Co.,Ltd. |
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Address after: 238251 Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee after: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee after: Jiangsu Kaiyuan Pharmaceutical Co.,Ltd. Address before: 238251 Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee before: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee before: FARMASINO PHARMACEUTICALS (JIANGSU) CO.,LTD. |
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Effective date of registration: 20220114 Address after: 210033 9th floor, F6 building, No.9, Weidi Road, Qixia District, Nanjing City, Jiangsu Province Patentee after: SKYRUN PHARMA Co.,Ltd. Address before: 238251 Wujiang fine chemical base, he County, Ma'anshan City, Anhui Province Patentee before: FARMASINO PHARMACEUTICAL (ANHUI) CO.,LTD. Patentee before: Jiangsu Kaiyuan Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20240304 Address after: 234000, No. 368 Jinjiang Fifth Road, Economic Development Zone, Suzhou City, Anhui Province Patentee after: Kaiyuan Pharmaceutical (Anhui) Co.,Ltd. Country or region after: China Address before: 210033 9th floor, F6 building, No.9, Weidi Road, Qixia District, Nanjing City, Jiangsu Province Patentee before: SKYRUN PHARMA Co.,Ltd. Country or region before: China |