CN103183680A - Method for preparing asenapine - Google Patents
Method for preparing asenapine Download PDFInfo
- Publication number
- CN103183680A CN103183680A CN2011104458123A CN201110445812A CN103183680A CN 103183680 A CN103183680 A CN 103183680A CN 2011104458123 A CN2011104458123 A CN 2011104458123A CN 201110445812 A CN201110445812 A CN 201110445812A CN 103183680 A CN103183680 A CN 103183680A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- asenapine
- organic solvent
- react
- 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.)
- Pending
Links
- PLBSIWSIHWRKFT-VOTSOKGWSA-N CC(Oc1c(/C=C/c2cc(Cl)ccc2Cl)cccc1)=O Chemical compound CC(Oc1c(/C=C/c2cc(Cl)ccc2Cl)cccc1)=O PLBSIWSIHWRKFT-VOTSOKGWSA-N 0.000 description 1
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N CN(C[C@@H]12)C[C@@H]1c1cc(Cl)ccc1Oc1c2cccc1 Chemical compound CN(C[C@@H]12)C[C@@H]1c1cc(Cl)ccc1Oc1c2cccc1 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 description 1
- UKIBIRGICXWWEK-HUUCEWRRSA-N CN(C[C@@H]1c(cccc2)c2O)C[C@@H]1c1cc(Cl)ccc1Cl Chemical compound CN(C[C@@H]1c(cccc2)c2O)C[C@@H]1c1cc(Cl)ccc1Cl UKIBIRGICXWWEK-HUUCEWRRSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method for preparing asenapine. The asenapine is prepared by taking inexpensive 2,5-dichlorobenzoic acid as a raw material through esterification, reduction, chlorination, substitution, oxidation, julia, catalysis, Ullmann and other reactions. The process is mild in route and does not involve inversion of cis-trans isomers. The yield of the product is high. By HPLC detection, the purity is no less than 99%. The method is suitable for industrial production.
Description
Technical field
It is flat to the present invention relates to medicine against depressive disorders Arsenal, is specifically related to the flat new preparation method of a kind of Arsenal, and the new midbody compound that is used for this method.
Background technology
Arsenal puts down (asenapine), and chemistry is called trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,36,7]-and oxa-Zhuo [4,5-C] pyrroles also, be a kind ofly to have central nervous system and suppress compound active and that have antihistamine and medmain activity.Research has confirmed that the flat maleate of Arsenal is a kind of antagonist of serotonin, norepinephrine and Dopamine HCL of broad-spectrum high efficacy, has stronger antipsychotic activity, and can be used for the treatment of dysthymia disorders.Have and report that the flat preparation of Arsenal can be used for the clinical treatment of psychosis class disease, therefore extensive synthetic this medicine is essential.
US Patent No. 4145434 discloses the flat general synthetic method of a kind of Arsenal, and its synthetic route is as shown below:
This method at first generates amide compound 3 with substituted phenylacetic acid compound 2 and sulfur oxychloride/N-methyl sarkosine methyl esters reaction, closed loop obtains dione compounds 4 in potassium tert.-butoxide/toluene system subsequently, further obtain alkene acid amides 5 with PPA effect closed loop, in methyl alcohol/MAGNESIUM METAL system, make the two keys of reduction obtain the mixture 6 of suitable/trans lactan then, at last the two is passed through column chromatography for separation, LiAlH
4/ AlCl
3Reduction namely obtains the gentle cis lactam compound 1a of target compound Arsenal.But because cis lactan 1a is dominant in the product, so this route yield is extremely low, the cost height is not suitable for the big production of industry.
Therefore, need need to seek a synthesis technique that new Arsenal is flat at present, that this novel process should have is with low cost, productive rate and purity height, be easy to industrial production and avoid using advantages such as highly toxic solvent or reagent.
Summary of the invention
The new preparation method that provides a kind of Arsenal flat is provided technical problem to be solved by this invention, to overcome above-mentioned defective.The present invention by simple, be easy to industrialized production process, syntheticly obtain highly purified A Senaping, thereby provide certain help for the clinical application research of the flat medicine of current Arsenal.
The present invention with cheaply be easy to get 2, the 5-dichlorobenzoic acid is raw material, through esterification, reduction, chloro, replacement, oxidation, julia reaction, catalysis, ullmann reaction etc., finally makes the flat I of target compound Arsenal.Its operational path is as follows:
The preparation method of flat or its pharmacy acceptable salt of the Arsenal of formula I structure of the present invention specifically may further comprise the steps:
(1) be raw material with 2,5-dichlorobenzoic acid, under acidic conditions with methanol esterification react compound 8;
(2) compound 8 is in organic solvent, through reductive agent reduce compound 9;
(3) compound 9 gets compound 10 through the sulfur oxychloride chloro in organic solvent;
(4) compound 10 is in organic solvent, with compound 11 react compound 12;
(5) compound 12 gets compound 13 through the oxygenant oxidation in organic solvent;
(6) compound 13 under organic solvent, alkaline condition with compound 14 through Julia react compound 15;
(7) compound 15 gets compound 19 with compound 18 under suitable acid catalyst;
(8) compound 19 is catalyzer with the copper powder under organic solvent, alkaline condition, gets target compound Asenapine I through ullmann reaction.
Wherein, among the above-mentioned preparation method, described organic solvent is selected from: THF, methylene dichloride, chloroform, ketones solvent, toluene, benzene etc., the wherein preferred acetone of ketones solvent.
Described acidic conditions such as dilute sulphuric acid or dilute hydrochloric acid, described alkaline condition refer to as one or more solution among salt of wormwood, yellow soda ash, cesium carbonate, the DMAC.
Described reductive agent is lithium chloride and/or POTASSIUM BOROHYDRIDE.
Described oxygenant is metachloroperbenzoic acid or Peracetic Acid, described suitable acid catalyst such as trifluoroacetic acid.
The preparation of described compound 18 comprises: a) compound 16 and methylamine in vexed jar, react compound 17; B) compound 17 gets compound 18 through Mannich reaction.
Advantage of the present invention
(1) be starting raw material with 2,5-dichlorobenzoic acid, be easy to get and low price that per step reaction is popular response, the reaction conditions gentleness makes this technology meet the requirement of pharmaceutical production; (2) and the present invention do not relate to the cis-trans-isomer transposition, simplified technology, be convenient to the operation; (3) total recovery improves greatly, has reduced production cost, and the product purity height, detects purity 〉=99.5% through HPLC.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is described in further detail, but described embodiment does not limit protection scope of the present invention.
Synthesizing of embodiment 1 compound 8
With 50g 2,5-dichlorobenzoic acid (compound 7) is dissolved in the 150ml methyl alcohol, adds dilute sulphuric acid 7ml, refluxed 8 hours, the cooling back adds an amount of sodium carbonate solution to neutral, removes methyl alcohol under reduced pressure, the ethyl acetate extraction product, the saturated sodium-chloride washing, anhydrous sodium sulfate drying is removed siccative, revolve steam oily matter, be compound 8, yield is about 98%, directly drops into the next step.
Synthesizing of embodiment 2 compounds 9
To go up step reaction gained oily matter, namely compound 8 is dissolved among the 200ml THF, adds the 16.3g lithium chloride, adds POTASSIUM BOROHYDRIDE 20.7g more in batches, finishes and refluxes 1 hour.Reaction finishes with the cancellation of 1N hydrochloric acid, the ethyl acetate extraction product, washing, the saturated sodium-chloride washing, anhydrous sodium sulfate drying is removed siccative, revolve steam solid 45.1g, namely compound 9, yield 100%.
Synthesizing of embodiment 3 compounds 10
The above-mentioned 45.1g compound 9 that makes is dissolved in the 300ml methylene dichloride 0 ℃ of following dripping thionyl chloride 23g, insulation reaction 1 hour.Reaction solution is poured frozen water into, layering, and the dichloromethane layer saturated sodium-chloride is washed, anhydrous sodium sulfate drying.Remove siccative, revolve steam 45.8g compound 10, yield 100%.
Synthesizing of embodiment 4 compounds 12
45.8g compound 10 and 48g compound 11 are dissolved in the 628ml acetone, add 40g salt of wormwood, be heated to and refluxed 3 hours, be spin-dried for acetone, add the 1L water dissolution, ethyl acetate extraction water layer, washing organic layer, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Remove siccative, revolve steam 76.8g compound 12, yield 90.2%.
Synthesizing of embodiment 5 compounds 12
45.8g compound 10 and 43g compound 11 are dissolved in the 628ml acetone, add 27g yellow soda ash, be heated to and refluxed 6 hours, be spin-dried for acetone, add the 1L water dissolution, ethyl acetate extraction water layer, washing organic layer, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Remove siccative, revolve steam 70.3g compound 12, yield 82.5%.
Synthesizing of embodiment 6 compounds 13
76.8g compound 12 is dissolved in the 1.5L methylene dichloride, drips the 98g metachloroperbenzoic acid in batches, stirring at room 2 hours, reaction finishes, 10% S-WAT cancellation, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Remove siccative, revolve steam 61.2g compound 13, yield 72.3%.
Synthesizing of embodiment 7 compounds 13
76.8g compound 12 is dissolved in the 1.5L chloroform, adds the 44g Peracetic Acid in batches, stirring at room 3 hours, reaction finishes, 10% S-WAT cancellation, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Remove siccative, revolve steam 58.3g compound 13, yield 68.9%.
Synthesizing of embodiment 8 compounds 15
61.2g compound 13,25g compound 14,70g salt of wormwood, 850ml THF mixing post-heating to refluxing 4 hours, are added shrend after reaction finishes and go out, ethyl acetate extraction water layer, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Remove siccative, revolve steam 38.4g compound 15, yield 73.6%.
Synthesizing of embodiment 9 compounds 15
61.2g compound 13,25g compound 14,167g cesium carbonate, 850ml toluene mixing post-heating to refluxing 2 hours, are added shrend after reaction finishes and go out, layering, methylbenzene extraction water layer, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Remove siccative, revolve steam 35.7g compound 15, yield 68.5%.
Synthesizing of embodiment 10 compounds 17
35g compound 16 and 177g methylamine are mixed, and vexed jar 80 ℃ were reacted 12 hours.Reaction finishes, and tells the upper strata and gets 32.3g compound 17, yield 96.6%.
Synthesizing of embodiment 11 compounds 18
11g methyl alcohol and 27g formaldehyde are placed there-necked flask, be cooled to 0 ℃, drip 32.3g compound 17, temperature dropwises 0～10 ℃ of reaction 2 hours below 10 ℃ in the control, rises to 20 ℃ of reactions 1 hour.Adding 30g salt of wormwood stirred 2 hours.Pour out supernatant liquor, add 3g salt of wormwood and stirred 2 hours, be spin-dried for gained solution, get 41.8g compound 18, yield 94%.
Synthesizing of embodiment 12 compounds 19
20g compound 15 is dissolved in the 150ml toluene, adds the 0.2ml trifluoroacetic acid.Drip 21g compound 18, temperature is about 25 ℃ in the control.Drip off reaction 2 hours.Reaction finishes, and the washing organic layer is spin-dried for solvent, adds the 100ml dissolve with methanol, adds 20% potassium hydroxide 25g again, stirs 1 hour.Drip 1N hydrochloric acid to neutral, filter drying.Get 18g compound 19, yield 86%.
Embodiment 13 target compound Asenapine I's (Asenapine) is synthetic
19g compound 19,8.5g salt of wormwood, 1.3g copper powder, 1g glycine, 57g DMAC are mixed, be warming up to 130 ℃ of reactions 12 hours.Reaction finishes, filters, and ethyl acetate washing solid, the washing organic layer, anhydrous sodium sulfate drying filters, and is spin-dried for.Product is dissolved in 101ml acetone, drips the Hydrogen bromide of 19g 48%, is down to 0 ℃ and stirs 3 hours, filters, and products therefrom is alkalized dichloromethane extraction, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying with sodium hydroxide again.Remove siccative, revolve steam 16.7g target compound Asenapine I, yield 99.1%, HPLC detects purity 〉=99.5%.
1H-NMR(CDCl
3)δ(ppm)2.56(H，s，CH
3)；3.15(H，m)；3.25(H，m)；3.64(H，m)；7.08(H，m，ArH)；7.13(H，m，ArH)；7.18(H，m，ArH)。
Embodiment 14 target compound Asenapine I's (Asenapine) is synthetic
19g compound 19,17g cesium carbonate, 1.3g copper powder, 1g glycine, 37g DMAC are mixed, be warming up to 130 ℃ of reactions 8 hours.Reaction finishes, filters, and ethyl acetate washing solid, the washing organic layer, anhydrous sodium sulfate drying filters, and is spin-dried for.Product is dissolved in 101ml acetone, drips the Hydrogen bromide of 19g 48%, is down to 0 ℃ and stirs 3 hours, filters, and products therefrom is alkalized dichloromethane extraction, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying with sodium hydroxide again.Remove siccative, revolve steam 16.6g, yield 98.5%, HPLC detects purity 〉=99.5%.
1The H-NMR data are with embodiment 13.
Embodiment 15 target compound Asenapine I's (Asenapine) is synthetic
19g compound 19,5.6g yellow soda ash, 1.3g copper powder, 43g DMAC are mixed, be warming up to 130 ℃ of reactions 12 hours.Reaction finishes, filters, and ethyl acetate washing solid, the washing organic layer, anhydrous sodium sulfate drying filters, and is spin-dried for.Product is dissolved in 101ml acetone, drips the Hydrogen bromide of 19g 48%, is down to 0 ℃ and stirs 3 hours, filters, and products therefrom is alkalized chloroform extraction, washing, saturated sodium-chloride washing, anhydrous sodium sulfate drying with sodium hydroxide again.Remove siccative, revolve steam 16.5g target compound Asenapine I, yield 97.9%, HPLC detects purity 〉=99.5%.
Should be noted that at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although with reference to preferred embodiment the present invention is had been described in detail, those of ordinary skill in the art is to be understood that, can make amendment or be equal to replacement the technical scheme of invention, and not breaking away from the spirit and scope of technical solution of the present invention, it all should be encompassed in the claim scope of the present invention.
Claims (9)
1. the method for the Asenapine of preparation formula I structure or its pharmacy acceptable salt is characterized in that, this method is to be that key intermediate prepares as follows and gets with compound 15:
(1) compound 15 generates compound 19 under organic solvent, acid catalyst;
(2) compound 19 is catalyzer with the copper powder under alkaline condition, through ullmann reaction, generates target compound asenapine I.
2. method according to claim 1 is characterized in that, the described organic solvent of step (1) is toluene or benzene, and trifluoroacetic acid is as acid catalyst.
3. method according to claim 1 is characterized in that, step (2) is at salt of wormwood, yellow soda ash or cesium carbonate, and in the DMAC system, is catalyzer with the copper powder, through ullmann reaction, generates target compound asenapine I.
4. according to each described method of claim 1～3, it is characterized in that described key intermediate 15 is to be prepared from as follows with compound 10:
(1.1) compound 10 under organic solvent, alkaline condition with compound 11 react compound 12;
(1.2) compound 12 gets compound 13 through oxidation;
(1.3) compound 13 and compound 14 through Julia react compound 15.
5. method according to claim 4 is characterized in that, in the step (1.1), compound 10 is at ketones solvent, in salt of wormwood, yellow soda ash or the cesium carbonate system with compound 11 react compound 12.
6. method according to claim 4 is characterized in that, in the step (1.2), compound 12 is in methylene dichloride or chloroform system, gets compound 13 through metachloroperbenzoic acid or Peracetic Acid oxidation.
7. method according to claim 4 is characterized in that, in the step (1.3), compound 13 is at salt of wormwood, yellow soda ash or cesium carbonate, in the mixing solutions of THF or toluene, with compound 14 through julia react compound 15.
8. method according to claim 4 is characterized in that, described compound 10 is to be raw material with 2,5-dichlorobenzoic acid, and through esterification, reduction, chloro and get, reaction formula is as follows:
(1.11) compound 7--2,5-dichlorobenzoic acid under acidic conditions with methanol esterification react compound 8;
(1.12) compound 8 is in organic solvent, through reductive agent reduce compound 9;
(1.13) compound 9 gets compound 10 through chloro.
9. method according to claim 8 is characterized in that, in the step (1.12), described organic solvent is THF or toluene, and reductive agent is lithium chloride and/or POTASSIUM BOROHYDRIDE.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104458123A CN103183680A (en) | 2011-12-27 | 2011-12-27 | Method for preparing asenapine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011104458123A CN103183680A (en) | 2011-12-27 | 2011-12-27 | Method for preparing asenapine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103183680A true CN103183680A (en) | 2013-07-03 |
Family
ID=48675157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011104458123A Pending CN103183680A (en) | 2011-12-27 | 2011-12-27 | Method for preparing asenapine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103183680A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484456A (en) * | 2006-07-05 | 2009-07-15 | 欧加农股份有限公司 | Process for the preparation of asenapine and intermediate products used in said process. |
| CN101851242A (en) * | 2010-05-25 | 2010-10-06 | 上海皓元生物医药科技有限公司 | Preparation method of asenapine intermediate |
| CA2801182A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
-
2011
- 2011-12-27 CN CN2011104458123A patent/CN103183680A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484456A (en) * | 2006-07-05 | 2009-07-15 | 欧加农股份有限公司 | Process for the preparation of asenapine and intermediate products used in said process. |
| CN101851242A (en) * | 2010-05-25 | 2010-10-06 | 上海皓元生物医药科技有限公司 | Preparation method of asenapine intermediate |
| CA2801182A1 (en) * | 2010-06-16 | 2011-12-22 | Metabolex, Inc. | Gpr120 receptor agonists and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| SIVARAMAN BALASUBRAMANIAM等，: ""Weinreb Amide Based New Synthetic Equivalents for Convenient Access to Immunosuppressive Agent FTY720 and Analogues"", 《SYNLETT》, vol. 18, 19 October 2007 (2007-10-19), pages 2841 - 2846 * |
| 匡金海等，: ""阿那曲唑合成工艺改进"", 《沈阳药科大学学报》, vol. 25, no. 5, 31 May 2008 (2008-05-31), pages 367 - 369 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
| CN104520275B (en) | For preparation method and the intermediate product of integrase inhibitor | |
| CN104356092B (en) | Preparation method for vortioxetine | |
| CN103980186B (en) | The preparation method of (R)-3-amino piperidine of amido protecting | |
| CN103420855B (en) | Trans-4-amino cyclohexylmethanol hydrochloride and preparation method thereof | |
| CN108218672A (en) | Application of the metal compound/palladium compound catalytic reduction system in de- allyl reaction and deuterated reaction | |
| CN110372608A (en) | A kind of preparation method of antagonists of gonadotropin-releasing hormone | |
| CN113912577B (en) | Rockwell intermediate, rockwell and its derivative, and preparation and application | |
| CN104649857B (en) | Trifluoromethyl-substituted azide, amine and heterocycle compounds and preparing methods thereof | |
| CN101993379B (en) | Preparation method of cinacalcet hydrochloride | |
| CN115490697A (en) | Asymmetric synthesis method of chiral azaspiro [4,5] -decylamine | |
| CN103183680A (en) | Method for preparing asenapine | |
| CN106866538B (en) | A kind of preparation method of Dexmedetomidine and its intermediate | |
| CN105175329A (en) | New synthesis route and method of bedaquiline racemate | |
| CN105348220A (en) | Synthetic method for vortioxetine hydrobromide | |
| CN107235878A (en) | difluoromethyl reagent, its preparation method and application | |
| CN105153083A (en) | Preparation method for polysubstituted furan compound | |
| CN106146457B (en) | 5-chloro-2-acyl chloride thiophene intermediate and preparation method thereof | |
| CN104402849B (en) | The new preparation process of Ta Simeiqiong intermediate | |
| CN108314688B (en) | A kind of synthetic method of sitagliptin | |
| CN104557851A (en) | Preparation method of eliglustat | |
| CN104496930B (en) | A kind of optical purity Aprepitant bulk drug intermediate preparation method | |
| CN106946771B (en) | A kind of preparation method of 3- pyridone class compound | |
| CN101265201B (en) | Method for synthesizing tramadol hydrochloride | |
| CN102827080B (en) | Novel synthetic method of ivabradine and novel intermediate product of ivabradine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 200093 Longchang Road, Shanghai, room 690, No. 119, room Applicant after: Shanghai Huatuo Medicine Sci-Tech Development Co., Ltd. Applicant after: GrowingChem Co., Ltd. Address before: 200093 Longchang Road, Shanghai, room 690, No. 119, room Applicant before: Shanghai Huatuo Medical Science Co., Ltd. Applicant before: GrowingChem Co., Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: SHANGHAI HUATUO MEDICAL SCIENCE CO., LTD. TO: SHANGHAI HUATUO MEDICINE SCI-TECH DEVELOPMENT CO., LTD. |
|
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130703 |
|
| WD01 | Invention patent application deemed withdrawn after publication |