CN102924290A - Method for synthesizing darapladib intermediate - Google Patents
Method for synthesizing darapladib intermediate Download PDFInfo
- Publication number
- CN102924290A CN102924290A CN2012103586542A CN201210358654A CN102924290A CN 102924290 A CN102924290 A CN 102924290A CN 2012103586542 A CN2012103586542 A CN 2012103586542A CN 201210358654 A CN201210358654 A CN 201210358654A CN 102924290 A CN102924290 A CN 102924290A
- Authority
- CN
- China
- Prior art keywords
- mmol
- diethyl
- darapladib
- trifluoromethyl
- synthetic method
- 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
Abstract
The invention relates to a method for synthesizing darapladib intermediate. The method comprises the following steps: allowing formylphenylboronic acid which serves as a raw material to perform aldimine condensation and hydrogenation reduction reactions with N,N-diethylethylenediamine; performing Suzuki coupling reaction with p-bromobenzotrifluoride by a one-pot method to synthesize N,N-diethyl-N'-(4'-trifluoromethyl-4-biphenyl-methyl)-ethane-1,2-ethanediamine. Compared with an existing method, the method has the advantages of mild condition, simple post-treatment, convenience in operation and high yield, and is applicable to industrial production.
Description
Technical field
The invention belongs to organic and technical field of medicine synthesis, be specifically related to a kind of darapladib intermediate N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) synthetic method of ethane-1,2-diaminoethane.
Background technology
Darapladib is the efficient lipoprotein lipase A of GlaxoSmithKline PLC company exploitation
2(Lp-PLA
2) inhibitor, be the important drugs for the treatment of coronary artery disease (CAD).Darapladib can directly act on atherosclerotic plaque, and can stabilize plaque, significantly suppress the growth of the downright bad core volume of atherosclerotic plaque and prevent plaque rupture, thereby reach treatment CAD purpose.N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane (
I) be the key intermediate of synthetic drugs darapladib.
Ⅰ
darapladib
The whole world has 7,200,000 people to die from coronary artery disease (CAD) every year.Although lipopenicillinase class medicine is used widely in the cardiac, many cardiocerebrovasculaevents events are still continuous.Think at present the Lp-PLA that finds in this and the coronary artery patch
2Level raises relevant, causes blood flow to be obstructed thereby this enzyme level rising can make the plaque rupture possibility increase.Therefore, Lp-PLA
2New treatment target spot, the Lp-PLA such as darapladib have been become at present
2Inhibitor is considered as strong the replenishing of spit of fland class medicine and enjoys favor by people.
The key intermediate of present medicine darapladib
ISynthetic route mainly contain:
4'-trifluoromethyl-the xenyl such as Cardwell-4-formaldehyde and N, the N-diethyl ethylenediamine is raw material, under certain pressure (3.4atm), obtain N through aldimine condensation, hydro-reduction take toluene as solvent, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane.Although the method is simple to operate, 4'-trifluoromethyl-xenyl-4-formaldehyde price is very expensive, and production cost is high.
Mulholland etc. take to formylphenylboronic acid and to 5 bromine benzotrifluoride as raw material through the Suzuki linked reaction; the post separation obtains 4'-trifluoromethyl-xenyl-4-formaldehyde; and then and N; the N-diethyl ethylenediamine is through obtaining N through aldimine condensation, hydro-reduction; N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane.Although the method productive rate is higher, two steps of need finish and the first step need use post to separate, and second step needs certain pressure (3.4atm) through aldimine condensation, hydro-reduction.
Existing synthetic method exists raw material expensive, and complicated operation is unfavorable for the shortcomings such as large-scale production, so we have worked out a kind of mild condition, and aftertreatment is simple, and is easy and simple to handle, and reaction efficiency is high, adapts to the new synthetic method of suitability for industrialized production.
Reference:
1、Robert , L. W.; Yi, S.; Emile, R. M.; Damir, H.; Mark, E. B.; Jun, Li.; Anthony, P.; Robert, S. F.; James, G. B.; Bryan, E. H.; Daniel, J. P.; Jisheng, Y.; Rosanna, C. M.; Christine, L. We.; LeFeng, Z.; Ping, Z.; Michael, H. G.; Max, C. W.; Andrew, Z.;Colin, H. M. Inhibition of lipoprotein associated phospholipase A2 reduces complex coronary atheroscleroticplaque development [J].
Nat Med,
2008,
14(10), 1059-1066.
2、Cardwell, K. S.; Gunnel, W. R.; Stevenage, H.; Carwford, C. F.; Davies, S. H.; Wade, C.E. Novel processes: WO 2011146494 [p], 2011-11-24.
3、Blackie, J. A.; Bloomer, J. C.; Brown, Murray J. B.; Cheng, H. Y.; Hammond, B.; Hickey, D. M. B.; Ife, R. J.; Leach, C. A.; Lewis, V. A.; Macphee, C. H. The Identi cation of Clinical Candidate SB480848: A Potent Inhibitor of Lipoprotein -Associated Phospholipase A2 [J].
Bioorg Med Chem Lett,
2003,
13 (6), 1067 -1070.
4、Abraham, E; Claridge, T. D. W.; Davies, S. G.; Odell, B.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Smith, L. J.; Storr, H. R.; Sweet, M. J.Potent inhibitors of secretory phospholipase A2: Synthesis and inhibitory activities of indolizine and inde -ne derivatives [J].
J. Med. Chem.
1996,
39(19):3636-3658.
5、Mulholland, K. R.; Ross, A. R.; Slsph, G. R.;Smith, G. E.;Novel processes: WO 03016287A2 [p], 2003-02-27.
6、Hendrix, M.; Zimermann, K.; Hirth-Dietrich, C.; Karig, G.; Karthaus D.; Raabe, M.; Weber, O.; Zaiss, S. 3-cycloalkyl-1,2,4-triazin-5(2H)-ones : WO 200 6063812A1 [p], 2006-06-22.
7、Hendrix, M.; Zimmermann K.; Hirth-Dietrich, C.; Karig, G.; Karthaus D.; Raabe, M.; Weber, O.; Zaiss, S. substituted-1,2,4-triazin-5(2H)-ones : DE 10200 -4061009A1.
8、Hendrix, M.; Zimmermann K.; Hirth-Dietrich, C.; Karig, G.; Karthaus D.; Raabe, M.; Weber, O.; Zaiss, S. 3-arylalkyl- substituted and 3-heteroarylkyl substi -tuted-1,2,4-triazin-5(2H)-ones : DE 102004061008A1.
9、Hendrix, M.; Zimmermann K.; Flessner, T.; Hirth-Dietrich, C.; Karig, G.; Raabe, M.; Karthaus D.; Michels M.; Weber, O.; Zaiss, S.; Zumpe, F. 3-benzylthio -1,2,4-triazine-5(2H)-oneaspaf-ahibitors: WO 2006063791A1.
10、Hendrix, M.; Zimmermann K.; Hirth-Dietrich, C.; Karig, G.; Karthaus D.; Raabe, M.; Weber, O.; Zaiss, S.; 3-cycloalkyl-1,2,4-triazine-5(2H)-ones: WO 2006063812A1。
Summary of the invention
Purpose of the present invention with the synthetic method that proposes a kind of darapladib intermediate.
The present invention proposes a kind of synthetic method of darapladib intermediate, and described intermediate is N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane, its synthetic route is as follows:
Ⅰ
Concrete steps are as follows:
In the 50ml round-bottomed flask, add 15~20 mmol to formylphenylboronic acid, 18~27 mmol N; N-diethyl ethylenediamine, 0.18~28 g, 5% Pd/ and 30~40ml solvent; then pass into stirring reaction 1-20h under 1.5~1.8atm hydrogen room temperature; after reaction is finished; in reactor, add 15~20 mmol to 5 bromine benzotrifluoride, 18~31 mmol inorganic salt, 30~40ml water, 0.8~1.1 mmol tetrakis triphenylphosphine palladium stirring and refluxing reaction 10-20h again; separate through the washing post, obtain required product.
Among the present invention, described solvent be toluene or glycol dimethyl ether one or two kind, preferentially select toluene.
Among the present invention, described inorganic salt are salt of wormwood or yellow soda ash, preferentially select salt of wormwood.
Among the present invention, described back flow reaction temperature is 80-120 ℃.
The present invention is with to formylphenylboronic acid and N; the N-diethyl ethylenediamine is initiator, after the effect of ammonification hydro-reduction, again with 5 bromine benzotrifluoride is carried out Suzuki linked reaction single stage method and obtains N; N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane.Compare with existing method, the method has mild condition, and aftertreatment is simple, and is easy and simple to handle, and reaction efficiency is high, adapts to suitability for industrialized production, has significant application value.
Embodiment
Further specify the present invention below by embodiment, but can not limit content of the present invention.
Embodiment 1:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Ⅰ
Under the room temperature with 2.26g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 2.10g in the 30ml dry toluene of 5% palladium carbon 0.22g, passes into hydrogen (1.7atm) until reaction finishes.Nitrogen protection adds 3.38g again to 5 bromine benzotrifluoride and 2.46g salt of wormwood and 30ml water, behind the 1h, adds the 0.88g tetrakis triphenylphosphine palladium, is warmed up to backflow, reacts about 15h.Diatomite filtration, the toluene wash catalyzer, separatory is collected the toluene phase, concentrating under reduced pressure, the post separation obtains the 5.10g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 2:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 2.26g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 2.32g in the 30ml glycol dimethyl ether of 5% palladium carbon 0.18g, passes into hydrogen (1.5atm) until reaction finishes.Nitrogen protection adds 3.38g again to 5 bromine benzotrifluoride and 2.46g salt of wormwood and 30ml water, behind the 1h, adds the 0.88g tetra-triphenylphosphine palladium, is warmed up to backflow, reacts about 14h.Diatomite filtration, the ethyl acetate washing, separatory is collected the ethyl acetate phase, concentrating under reduced pressure, the post separation obtains the 4.99g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 3:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 3.00g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 3.10g in the 40ml dry toluene of 5% palladium carbon 0.26g, passes into hydrogen (1.8atm) until reaction finishes.Nitrogen protection adds 4.50g again to 5 bromine benzotrifluoride and 2.12g yellow soda ash and 40ml water, behind the 1h, adds 1.10 g tetrakis triphenylphosphine palladiums, is warmed up to backflow, reacts about 13h.Diatomite filtration, the toluene wash catalyzer, separatory is collected the toluene phase, concentrating under reduced pressure, the post separation obtains the 6.78g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 4:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 3.00 g 4-formylphenylboronic acids, N, N-diethyl ethylenediamine 2.90 g in the 40ml glycol dimethyl ether of 5% palladium carbon, 0.28 g, pass into hydrogen (1.6atm) until reaction finishes.Nitrogen protection adds 4.5g again to 5 bromine benzotrifluoride and 3.08 g yellow soda ash and 40mL water, behind the 1h, adds 1.02 g tetra-triphenylphosphine palladiums, is warmed up to backflow, reacts about 14 h.Diatomite filtration, the ethyl acetate washing, separatory is collected the ethyl acetate phase, concentrating under reduced pressure, the post separation obtains the 6.60g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 5:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 2.26g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 2.10g in the 30ml dry toluene of 5% palladium carbon 0.22g, passes into hydrogen (1.8atm) until reaction finishes.Nitrogen protection adds 3.38g again to 5 bromine benzotrifluoride and 2.46g yellow soda ash and 30ml water, behind the 1h, adds the 0.99g tetrakis triphenylphosphine palladium, is warmed up to backflow, reacts about 13h.Diatomite filtration, the toluene wash catalyzer, separatory is collected the toluene phase, concentrating under reduced pressure, the post separation obtains the 5.04g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 6:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 2.26g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 2.46g in the 30ml glycol dimethyl ether of 5% palladium carbon 0.20g, passes into hydrogen (1.8atm) until reaction finishes.Nitrogen protection adds 3.38g again to 5 bromine benzotrifluoride and 2.10g yellow soda ash and 30ml water, behind the 1h, adds the 0.95g tetrakis triphenylphosphine palladium, is warmed up to backflow, reacts about 18h.Diatomite filtration, the ethyl acetate washing, separatory is collected the ethyl acetate phase, concentrating under reduced pressure, the post separation obtains the 4.80g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 7:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 3.00g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 3.00g in the 40ml dry toluene of 5% palladium carbon 0.24g, passes into hydrogen (1.7atm) until reaction finishes.Nitrogen protection adds 4.5g again to 5 bromine benzotrifluoride and 3.30g salt of wormwood and 40mL water, after 1 hour, adds 1.24 g tetrakis triphenylphosphine palladiums, is warmed up to backflow, reacts about 12h.Diatomite filtration is used the toluene wash catalyzer, and separatory is collected the toluene phase, concentrating under reduced pressure, and the post separation obtains the 6.88g product.
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Embodiment 8:N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane is synthetic
Under the room temperature with 3.00g 4-formylphenylboronic acid, N, N-diethyl ethylenediamine 2.95g in the 40ml glycol dimethyl ether of 5% palladium carbon 0.27g, passes into hydrogen (1.6atm) until reaction finishes.Nitrogen protection adds 4.5g again to 5 bromine benzotrifluoride and 3.45g salt of wormwood and 40ml water, behind the 1h, adds the 0.99g tetrakis triphenylphosphine palladium, is warmed up to backflow, reacts about 18h.Diatomite filtration, the ethyl acetate washing, separatory is collected the ethyl acetate phase, concentrating under reduced pressure, the post separation obtains the 6.72g product.。
1H-NMR(CDCl
3): 7.69(s,4H),7.43-7.58(dd,4H,
J 1 =8Hz,
J 2 =50.8Hz),3.88(s,2H),2.75-2.76(d,2H,
J=5.6Hz),2.65-2.67(d,2H,
J=5.2Hz),2.56-2.61(dd,4H,
J 1 =6.4Hz,
J 2 =13.6Hz)。
Claims (4)
1. the synthetic method of a darapladib intermediate is characterized in that described intermediate is N, N-diethyl-N'-(4'-trifluoromethyl-4-xenyl-methyl) ethane-1,2-diaminoethane, its synthetic route is as follows:
Ⅰ
Concrete steps are as follows:
In the 50ml round-bottomed flask, add 15~20 mmol to formylphenylboronic acid, 18~27 mmol N; N-diethyl ethylenediamine, 0.18~28 g, 5% Pd/C and 30~40ml solvent; then pass into stirring reaction 1-20h under 1.5~1.8atm hydrogen room temperature; after reaction is finished; in reactor, add 15~20 mmol to 5 bromine benzotrifluoride, 18~31 mmol inorganic salt, 30~40ml water, 0.8~1.1 mmol tetrakis triphenylphosphine palladium stirring and refluxing reaction 10-20h again; separate through the washing post, obtain required product.
2. synthetic method according to claim 1, it is characterized in that described solvent be toluene or glycol dimethyl ether one or two kind.
3. synthetic method according to claim 1 is characterized in that described inorganic salt are salt of wormwood or yellow soda ash.
4. synthetic method according to claim 1 is characterized in that described back flow reaction temperature is 80-120 ℃.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012103586542A CN102924290A (en) | 2012-09-25 | 2012-09-25 | Method for synthesizing darapladib intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012103586542A CN102924290A (en) | 2012-09-25 | 2012-09-25 | Method for synthesizing darapladib intermediate |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102924290A true CN102924290A (en) | 2013-02-13 |
Family
ID=47639253
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2012103586542A Pending CN102924290A (en) | 2012-09-25 | 2012-09-25 | Method for synthesizing darapladib intermediate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102924290A (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003016287A2 (en) * | 2001-08-14 | 2003-02-27 | Smithkline Beecham P.L.C. | Process for preparing 1-(carboxymethyl)- and 1-(aminocarbonyl)- pyrimidin-4-one derivatives |
WO2006063791A1 (en) * | 2004-12-18 | 2006-06-22 | Bayer Healthcare Ag | 3-benzylthio-1,2,4-triazine-5 (2h)-one as paf-ah inhibitors |
-
2012
- 2012-09-25 CN CN2012103586542A patent/CN102924290A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003016287A2 (en) * | 2001-08-14 | 2003-02-27 | Smithkline Beecham P.L.C. | Process for preparing 1-(carboxymethyl)- and 1-(aminocarbonyl)- pyrimidin-4-one derivatives |
WO2006063791A1 (en) * | 2004-12-18 | 2006-06-22 | Bayer Healthcare Ag | 3-benzylthio-1,2,4-triazine-5 (2h)-one as paf-ah inhibitors |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kuan et al. | An efficient Morita–Baylis–Hillman reaction for the synthesis of multifunctional 2-hydroxy-3-nitrobut-3-enoate derivatives | |
CN101624322A (en) | Method for preparing 1, 2-diketone by catalyzing and oxidizing alkynes | |
Laskar et al. | Cellulose as recyclable organocatalyst for ipso-hydroxylation of arylboronic acids | |
CN109456998A (en) | A kind of method of lipase-catalyzed synthesis Dicoumarin Derivatives | |
Xin et al. | Asymmetric Total Synthesis of Norzoanthamine | |
CN107033016B (en) | A kind of synthetic method of 3- amino indanone class compound | |
CN109180625A (en) | A kind of preparation method of seleno flavone compound | |
Zheng et al. | Catalytic Enantioselective 1, 2‐Addition of Terminal 1, 3‐Diynes to Trifluoromethyl Ketones | |
CN106631831B (en) | A kind of preparation method of left-handed Terbutaline | |
Das et al. | Highly Active Bisamino Functionalized Zr (IV)‐UiO‐67 Metal‐Organic Framework for Cascade Catalysis | |
CN106187820B (en) | A kind of preparation method of bambuterol impurity B | |
JP2021001158A (en) | Synthesis method of methylene ether/urushiol/hydroxamic acid derivative having hdac inhibitory activity | |
CN101265271A (en) | Method for synthesizing penem-like pharmaceutical intermediate 4AA | |
CN104829511A (en) | Synthesizing process of Ezetimibe | |
CN104402793A (en) | 3-substituted oxindole derivatives, and synthetic method and application thereof | |
CN103980188B (en) | The synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof | |
CN102924290A (en) | Method for synthesizing darapladib intermediate | |
Khodabakhshi et al. | A Green Strategy to Prepare Warfarin‐like Compounds Catalyzed by Zirconium Oxychloride | |
CN104628630B (en) | Indene derivatives 1-pyridyl-2-bromoindene and synthesis method thereof | |
CN106573874B (en) | The method for manufacturing 2- amino substituted benzoyl aldehyde compounds | |
CN115197232A (en) | Cyclopropane fused oxygen bridge hexacyclic compound and synthesis method thereof | |
CN101182362A (en) | Method for preparing cyclodextrin-phthalocyanine binary combination | |
CN102086191A (en) | 3-methylene indol-2-one derivatives and preparation method thereof | |
TWI287016B (en) | Process for preparing camptothecin | |
CN102584760B (en) | Enantiomorphous-kaurene diterpene and derivative and preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130213 |