CN104418783A - Preparation method of ezetimibe SSS isomer - Google Patents
Preparation method of ezetimibe SSS isomer Download PDFInfo
- Publication number
- CN104418783A CN104418783A CN201310383419.5A CN201310383419A CN104418783A CN 104418783 A CN104418783 A CN 104418783A CN 201310383419 A CN201310383419 A CN 201310383419A CN 104418783 A CN104418783 A CN 104418783A
- Authority
- CN
- China
- Prior art keywords
- ezetimibe
- preparation
- sss
- isomer
- reaction
- 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.)
- Granted
Links
- 0 O[C@@](CC*([C@@](c(cc1)ccc1O)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F Chemical compound O[C@@](CC*([C@@](c(cc1)ccc1O)N1c(cc2)ccc2F)C1=O)c(cc1)ccc1F 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of an ezetimibe SSS isomer. Specifically, the preparation method is used for producing the ezetimibe SSS cis-isomer by use of an RSS intermediate as a starting raw material and by virtue of Mitsunobu reaction and deprotection. The preparation method of the ezetimibe SSS isomer is simple in process steps, and the obtained product is good in yield and high in purity.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to a kind of preparation method of Ezetimibe isomer.
Background technology
Ezetimibe (ezetimibe) is the novel anticholesteremic agent of a class.As a kind of selectivity cholesterol absorption inhibitor, it mainly blocks the exogenous absorption features of cholesterol.It suppresses the absorption of enteron aisle inner cholesterol by acting on cholesterol transporter.In October, 2002 by FDA approval listing, commodity are called Ai Zeting (Zetia).Nomenclature of drug benefit suitable pure (EZETROL) in Discussion on Chinese Listed.
Schering Corp discloses a kind of method of chiral synthesize Ezetimibe in the compound patent CN1050830C that on September 14th, 1994 applies for; A kind of method of chiral synthesize Ezetimibe of improvement is disclosed in the patent CN1130342C of application on December 6th, 1999.Hao Sen medicine company stock company discloses a kind of method of chiral synthesize Ezetimibe of improvement in the patent CN102850390A that on July 1st, 2011 applies for, wherein described all the elements is incorporated in the middle of the present invention at this.The method that CN102850390A records first by using borine chiral reduction to obtain chiral alcohol intermediate under (R)-Me-CBS catalysis; then mix with N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine; trimethyl silicon based protection on simultaneously under the effect of organic silylating agent, then add TiCl by one kettle way
4carry out Mannich reaction and obtain hydroxyl by the intermediate of trimethyl silicon based protection; then under the acting in conjunction of organic silylating agent BSA and tetrabutyl ammonium fluoride, cyclization obtains the intermediate of beta-lactam structure, removes silica-based protection, palladium charcoal debenzylation protective material obtains Ezetimibe finally by acidic conditions.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of Ezetimibe SSS isomer.The method comprises the steps:
A. formula (II) compound and p-nitrobenzoic acid or derivatives thereof react through Mitsunobu in reaction solvent, obtain intermediate formula (III) compound;
B. intermediate formula (III) compound obtains target compound after palladium carbon reduction Deprotection.
Preferably, the reaction solvent of described step a is triphenylphosphine and tetrahydrofuran (THF).
Preferably, the temperature of described Mitsunobu reaction is-10 DEG C to-30 DEG C, preferably-15 DEG C to-25 DEG C.
Preferably, described step a also needs the tetrahydrofuran solution adding diisopropyl azodiformate.
Preferably, the reaction environment of described step b Deprotection is for add Pd/C and ammonium formiate in organic solvent.Preferably, described organic solvent is one or more in methyl alcohol, ethanol, Virahol, the trimethyl carbinol, particular methanol.
Preferably, the temperature of reaction of described step b is 20 DEG C-40 DEG C, preferably 25 DEG C to 35 DEG C.
Preferably, described p-nitrobenzoic acid or derivatives thereof is p-nitrobenzoic acid.
Preparation method's processing step of the present invention is simple, and can obtain the SSS Ezetimibe cis-isomeride without No. CAS, and products obtained therefrom yield is high, and purity is good.
Accompanying drawing explanation
Fig. 1 is (SSS)-Ezetimibe
1h-NMR composes;
Fig. 2 is (SSS)-Ezetimibe
1h-NMR heavy water exchange spectrum;
Fig. 3 is the displacement spectrogram of fragrant district hydrogen atom in (SSS)-Ezetimibe;
Fig. 4 is the partial enlargement collection of illustrative plates of Fig. 1.
Embodiment
In order to further illustrate the present invention, below in conjunction with specific embodiment, the present invention is made an explanation, but these embodiments are not intended to limit protection scope of the present invention.
Contriver is incorporated herein all the elements disclosed in patent CN102850390A, for the preparation of reference during this patent Raw.
According to conventional Chiral Synthesis, prepare compound 1, i.e. the enantiomer of patent CN102850390A compound of formula III.Prepare compound 3 according to the similar approach disclosed by patent CN102850390A, the result through liquid phase test shows: in the crude product 3, the content of 4 is 5% ~ 20%.We use the method for column chromatography to carry out separation and concentration to 4 in the crude product of 3, can obtain the compound 4 of purity >95%.
The similar approach that compound 4 discloses according to patent CN102850390A prepares compound 5, then deprotection obtains formula of the present invention (II) compound.
The preparation of embodiment 1:SSS intermediate (formula (III) compound)
By raw material RSS crude intermediate (formula (II) compound) (0.8g, 1.6mmol), p-nitrobenzoic acid (0.54g, 3.2mmol), triphenylphosphine (0.86g, 3.2mmol), tetrahydrofuran (THF) (10ml) joins in reaction flask, under agitation be cooled to-15 DEG C ~-25 DEG C, drip containing diisopropyl azodiformate (DIAD) (1.30g, tetrahydrofuran solution (5ml) 6.4mmol), insulation reaction 30min at-10 DEG C ~ 10 DEG C, show raw material to TLC and disappear (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.8).Add methyl tertiary butyl ether (80ml), wash 3 times with saturated sodium bicarbonate solution (50ml), saturated nacl aqueous solution (50ml) is washed once, and reaction solution drying is concentrated into dry, obtains the p-nitrobenzoic acid ester of SSS intermediate.Methyl alcohol (10ml), tetrahydrofuran (THF) (10ml) is added in above-mentioned oily matter, add salt of wormwood (2.1g, 15mmol), reaction solution is in 10 ~ 20 DEG C of stirring reaction 1h, TLC shows raw material and substantially disappears (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.2).Add methylene dichloride (100ml), water (150ml), stir separatory, organic phase saturated sodium bicarbonate solution (100ml) is washed once, and saturated brine (100ml) is washed once, anhydrous sodium sulfate drying, filters, and concentrates to obtain 2.3g yellow oil crude product.Column chromatography roughing out, collects qualified component, obtains pale yellow oil SSS intermediate 1.5g, and detect through HPLC, product purity is 97%.
The preparation of comparative example 1:SSS intermediate (formula (III) compound)
By raw material RSS crude intermediate (0.5g, 1mmol), Chlorodracylic acid (0.32g, 2mmol), triphenylphosphine (0.52g, 2mmol), anhydrous diethyl ether (10ml) joins in reaction flask, is under agitation cooled to-10 DEG C ~-30 DEG C, drips containing diisopropyl azodiformate (DIAD) (0.81g, diethyl ether solution (5ml) 4mmol), insulation reaction 30min at-10 DEG C ~ 10 DEG C, shows raw material to TLC and disappears (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.8).Add ether (80ml), wash 3 times with saturated sodium bicarbonate solution (50ml), saturated nacl aqueous solution (50ml) is washed once, and reaction solution drying is concentrated into dry, obtains the Chlorodracylic acid ester of SSS intermediate.In above-mentioned oily matter, add methyl alcohol (10ml), salt of wormwood (1.4g, 10mmol), reaction solution shows raw material in 10 ~ 30 DEG C of stirring reaction 1h, TLC and substantially disappears (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.2).Add methylene dichloride (100ml), water (100ml), stir separatory, organic phase saturated sodium bicarbonate solution (100ml) is washed once, and saturated brine (100ml) is washed once, anhydrous sodium sulfate drying, filters, and concentrates to obtain 1.2g yellow oil crude product.Column chromatography roughing out, collects qualified component, obtains pale yellow oil SSS intermediate 0.6g, and detect through HPLC, product purity is 61%.
The preparation of comparative example 2:SSS intermediate (formula (III) compound)
By raw material RSS intermediate 3 crude product (0.5g, 1mmol), p-nitrobenzoic acid (0.32g, 2mmol), triphenylphosphine (0.52g, 2mmol), methylene dichloride (10ml) joins in reaction flask, under agitation be cooled to 0 DEG C ~-10 DEG C, drip containing diisopropyl azodiformate (DIAD) (0.81g, dichloromethane solution (5ml) 4mmol), insulation reaction 30min at-10 DEG C ~ 20 DEG C, show raw material to TLC and substantially disappear (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.8).Add methylene dichloride (100ml), wash 3 times with saturated sodium bicarbonate solution (50ml), saturated nacl aqueous solution (50ml) is washed once, and reaction solution drying is concentrated into dry, obtains the p-nitrobenzoic acid ester of SSS intermediate.In above-mentioned oily matter, add methyl alcohol (10ml), salt of wormwood (1.4g, 10mmol), reaction solution shows raw material in 10 ~ 30 DEG C of stirring reaction 1h, TLC and substantially disappears (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.2).Add methylene dichloride (100ml), water (100ml), stir separatory, organic phase saturated sodium bicarbonate solution (100ml) is washed once, and saturated brine (100ml) is washed once, anhydrous sodium sulfate drying, filters, and concentrates to obtain 1.3g yellow oil crude product.Column chromatography roughing out, collects qualified component, obtains pale yellow oil SSS intermediate 0.3g, and detect through HPLC, product purity is 54%.
The preparation of comparative example 3:SSS intermediate (formula (III) compound)
By raw material RSS crude intermediate (0.5g, 1mmol), p-nitrobenzoic acid (0.32g, 2mmol), triphenylphosphine (0.52g, 2mmol), ethyl acetate (10ml) joins in reaction flask, under agitation be cooled to-10 DEG C ~-30 DEG C, drip containing diisopropyl azodiformate (DIAD) (0.81g, ethyl acetate solution (5ml) 4mmol), insulation reaction 30min at-10 DEG C ~ 20 DEG C, show raw material to TLC and substantially disappear (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.8).Add methylene dichloride (100ml), wash 3 times with saturated sodium bicarbonate solution (50ml), saturated nacl aqueous solution (50ml) is washed once, and reaction solution drying is concentrated into dry, obtains the p-nitrobenzoic acid ester of SSS intermediate.In above-mentioned oily matter, add methyl alcohol (10ml), salt of wormwood (1.4g, 10mmol), reaction solution shows raw material in 10 ~ 30 DEG C of stirring reaction 1h, TLC and substantially disappears (developping agent is ethyl acetate: normal hexane=1:3, Rf=0.2).Add methylene dichloride (100ml), water (100ml), stir separatory, organic phase saturated sodium bicarbonate solution (100ml) is washed once, and saturated brine (100ml) is washed once, anhydrous sodium sulfate drying, filters, and concentrates to obtain 1.3g yellow oil crude product.Column chromatography roughing out, collects qualified component, obtains yellow oil SSS intermediate 0.7g, and detect through HPLC, product purity is 74%.
Embodiment 2:(SSS) preparation of-Ezetimibe (formula (I) compound)
Be dissolved in by SSS intermediate (0.7g, 1.4mmol) in methyl alcohol (50ml), adding Pd/C(water content is 1%) (1.8g), ammonium formiate (1g, 15.8mmol), at 30 DEG C, stirring reaction 1h, TLC detect to react completely (normal heptane: ethyl acetate=1:1, Rf=0.3); Suction filtration, removing palladium carbon, filtrate is concentrated into dry, adds ethyl acetate (80ml), water (80ml), stirs, separatory; Organic phase saturated brine (50ml) washes 1 time, separatory, anhydrous Na
2sO
4dry; Organic phase is filtered, and concentrates to obtain (SSS)-Ezetimibe oily matter crude product (0.6g).Prepare plate to be separated, obtain SSS finished product 220mg(HPLC:98.979%; Remarks: TLC shows, and moving phase is normal heptane: during ethyl acetate=1:2, can divide the impure point having a Rf=0.28).In conjunction with the Fig. 1 to Fig. 4 in Figure of description, wherein the proton nmr spectra of sample is shown in Fig. 1, and heavy water exchange spectrum is shown in Fig. 2 (nuclear magnetic resonance analyser: be designated as TMS in Bruker AV400MHz NMR(); Measure solvent: DMSO-d
6).Relevant data and parsing are in table 1.
The hydrogen nuclear magnetic resonance modal data of table 1. sample and ownership
Note: sample contains a small amount of residual solvent and impurity, is got rid of during parsing.
Resolve:
1h-NMR spectrum provides 10 kind of proton peaks, and corresponding to 21 protons, heavy water has 2 protons to disappear after exchanging, this conforms to the number of Labile protons with torpescence in SSS-isomer structure.Wherein:
(1) respectively there is one group of multiplet at δ 0.97-1.00 and 1.30-1.35ppm place, are equivalent to 1 proton respectively, belong to 8 methene protons.Due to neighbour chiral centre, 2 proton shift values of same methylene radical are different.
(2) there are two groups of multiplets at δ 1.46-1.57ppm place, is equivalent to 2 protons, belongs to 9 methene protons.Due to neighbour chiral centre, 2 proton shift values of same methylene radical are different.
(3) there is one group of quartet at δ 3.56-3.62ppm place, is equivalent to 1 proton, belongs to 1 proton of 10 precedence methyl.
(4) there is one group of triplet at δ 4.25ppm place, is equivalent to 1 proton, belongs to 1 proton of 7 precedence methyl.
(5) there is one group of broad peak at δ 5.10ppm place, is equivalent to 1 proton, disappears, belong to and 1 of 7 hydroxyls be connected Labile protons after heavy water exchanges.
(6) there is one group of doublet at δ 5.24-5.26ppm place, is equivalent to 1 proton, belongs to 1 proton of 12 precedence methyl.
(7) there is one group of doublet at δ 6.73-6.75ppm place, is equivalent to 2 protons, belongs to each 1 proton of 15 and 17 aryl respectively.
(8) there is one group of multiplet at δ 7.01-7.23ppm place, is equivalent to 10 protons, belongs to each 1 proton of 2,6,5,3,14,18,20,24,21,23 aryl respectively.
(9) there is one group of broad peak at δ 9.52ppm place, is equivalent to 1 proton, disappears after heavy water exchanges,
Belong to 1 Labile protons of the hydroxyl be connected with 16 carbon.
As from the foregoing, in conjunction with reaction process and the sample hydrogen modal data of controlled syntheses of the present invention, can confirm that products obtained therefrom is Ezetimibe SSS isomer.
Claims (8)
1. a preparation method for Ezetimibe SSS isomer as shown in the formula (I), it comprises the steps:
A. formula (II) compound and p-nitrobenzoic acid or derivatives thereof react through Mitsunobu in reaction solvent, obtain intermediate formula (III) compound;
B. intermediate formula (III) compound obtains target compound after palladium carbon reduction Deprotection.
2. the preparation method of Ezetimibe SSS isomer as claimed in claim 1, it is characterized in that, the reaction solvent of described step a is triphenylphosphine and tetrahydrofuran (THF).
3. the preparation method of Ezetimibe SSS isomer as claimed in claim 1, is characterized in that, the temperature of described Mitsunobu reaction is-10 DEG C to-30 DEG C, preferably-15 DEG C to-25 DEG C.
4. the preparation method of Ezetimibe SSS isomer as claimed in claim 2, it is characterized in that, described step a also needs the tetrahydrofuran solution adding diisopropyl azodiformate.
5. the preparation method of Ezetimibe SSS isomer as claimed in claim 1, it is characterized in that, the reaction environment of described step b Deprotection for add Pd/C and ammonium formiate in organic reagent.
6. the preparation method of Ezetimibe SSS isomer as claimed in claim 5, is characterized in that, described organic reagent is one or more in methyl alcohol, ethanol, Virahol, the trimethyl carbinol, particular methanol.
7. the preparation method of Ezetimibe SSS isomer as claimed in claim 5, it is characterized in that, the temperature of reaction of described step b is 20 DEG C to 40 DEG C, preferably 25 DEG C to 35 DEG C.
8. the preparation method of Ezetimibe SSS isomer as claimed in claim 1, it is characterized in that, described p-nitrobenzoic acid or derivatives thereof is p-nitrobenzoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310383419.5A CN104418783B (en) | 2013-08-28 | 2013-08-28 | Preparation method of ezetimibe SSS isomer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310383419.5A CN104418783B (en) | 2013-08-28 | 2013-08-28 | Preparation method of ezetimibe SSS isomer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104418783A true CN104418783A (en) | 2015-03-18 |
| CN104418783B CN104418783B (en) | 2020-08-07 |
Family
ID=52968990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310383419.5A Active CN104418783B (en) | 2013-08-28 | 2013-08-28 | Preparation method of ezetimibe SSS isomer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104418783B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008091818A1 (en) * | 2007-01-25 | 2008-07-31 | Allergan, Inc. | Substituted arylcyclopentenes as therapeutic agents |
| CN102112430A (en) * | 2008-07-30 | 2011-06-29 | 力奇制药公司 | Process for synthesis of ezetimibe and intermediates useful therefor |
| CN102850390A (en) * | 2011-07-01 | 2013-01-02 | 江苏豪森药业股份有限公司 | Intermediate of ezetimibe and its preparation method |
-
2013
- 2013-08-28 CN CN201310383419.5A patent/CN104418783B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008091818A1 (en) * | 2007-01-25 | 2008-07-31 | Allergan, Inc. | Substituted arylcyclopentenes as therapeutic agents |
| CN102112430A (en) * | 2008-07-30 | 2011-06-29 | 力奇制药公司 | Process for synthesis of ezetimibe and intermediates useful therefor |
| CN102850390A (en) * | 2011-07-01 | 2013-01-02 | 江苏豪森药业股份有限公司 | Intermediate of ezetimibe and its preparation method |
Non-Patent Citations (3)
| Title |
|---|
| MARCIN SNIEZEK，等: "Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor", 《J. ORG. CHEM.》 * |
| 徐显秀: "依泽替米贝异构体和1，5-自由基转移法合成氮杂螺环的研究", 《中国博士学位论文全文数据库（电子期刊）》 * |
| 蔡金刚: "依折麦布的合成研究", 《中国硕士学位论文全文数据库（电子期刊）》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104418783B (en) | 2020-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108440553B (en) | Method for asymmetrically synthesizing optical-purity glabridin by ruthenium compound catalysis | |
| CN111170855A (en) | Compound and method for synthesizing 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid by using same | |
| CN102757431B (en) | A kind of novel method of synthesizing sitagliptin | |
| CN102140086A (en) | Method for synthesizing vitamin C crude product by adopting L-gulonic acid | |
| CN102643194B (en) | Preparation method of posaconazole intermediate | |
| US8912345B2 (en) | Method for preparing optically pure (−)-clausenamide compound | |
| CN106220624B (en) | The method for preparing Eliquis N-1 forms | |
| JP6692408B2 (en) | Dimer impurities of apixaban and method for removing the same | |
| CN112430208A (en) | Preparation method of PF-06651600 intermediate | |
| CN102344431B (en) | Method for preparing nebivolol hydrochloride | |
| CN103709039B (en) | Method for synthesizing methyl (ethyl) gallate through catalysis of Cu-mordenite | |
| CN104058990B (en) | A kind of aliskiren or the method for separating and analyzing of its salt | |
| CN104418783A (en) | Preparation method of ezetimibe SSS isomer | |
| CN115108937A (en) | Synthesis method of alpha-azidoketone containing three-level stereocenter | |
| CN107629107B (en) | Synthetic method of ulipristal acetate | |
| CN113461643A (en) | Synthesis method of 4-methylbenzenesulfonic acid [ (3-fluoro-oxetan-3-yl) methyl ] ester | |
| CN108997297B (en) | Preparation method of nebivolol intermediate, intermediate for preparing nebivolol intermediate and preparation method of nebivolol intermediate | |
| CN102260236B (en) | Preparation method of coumarin compounds | |
| CN111196777A (en) | Synthetic preparation of brivaracetam | |
| CN109438543A (en) | A kind of preparation method of high-purity fluticasone furoate | |
| CN107827916A (en) | A kind of (R)（The methyl of 1 amino 3）The synthetic method of the boric acid pinane diol ester of butyl 1 | |
| CN114790161B (en) | Synthesis method of 4-methoxycarbonylethyl-3-methyl-2-pyrrolal and intermediate thereof | |
| CN100556906C (en) | A kind of preparation method of proteinase inhibitor important intermediate | |
| CN101314574B (en) | Process for synthesizing acylations enamine | |
| CN117185886A (en) | Preparation method of plant diene compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| CB02 | Change of applicant information |
Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL Co.,Ltd. |
|
| COR | Change of bibliographic data | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| CB02 | Change of applicant information |
Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
|
| COR | Change of bibliographic data | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160324 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |