CN101723955B - Method for preparing olanzapine - Google Patents
Method for preparing olanzapine Download PDFInfo
- Publication number
- CN101723955B CN101723955B CN2008101725718A CN200810172571A CN101723955B CN 101723955 B CN101723955 B CN 101723955B CN 2008101725718 A CN2008101725718 A CN 2008101725718A CN 200810172571 A CN200810172571 A CN 200810172571A CN 101723955 B CN101723955 B CN 101723955B
- Authority
- CN
- China
- Prior art keywords
- amino
- thiotolene
- cyanic acid
- organic solvent
- olanzapine
- 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.)
- Active
Links
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZKNARUVAUOSLGV-UHFFFAOYSA-N N1N=CC=CC=C1.C1=CC=CC=C1 Chemical compound N1N=CC=CC=C1.C1=CC=CC=C1 ZKNARUVAUOSLGV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical group Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011968 lewis acid catalyst Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RSEACRIWQRAVPE-UHFFFAOYSA-N Cc1cc(C#N)c(Nc(cccc2)c2N)[s]1 Chemical compound Cc1cc(C#N)c(Nc(cccc2)c2N)[s]1 RSEACRIWQRAVPE-UHFFFAOYSA-N 0.000 description 1
- NPXUFPFFHANGDL-UHFFFAOYSA-N Cc1cc(C#N)c(Nc(cccc2)c2[N+]([O-])=O)[s]1 Chemical compound Cc1cc(C#N)c(Nc(cccc2)c2[N+]([O-])=O)[s]1 NPXUFPFFHANGDL-UHFFFAOYSA-N 0.000 description 1
- YEHIIKLKSBNZDR-UHFFFAOYSA-N Cl.N1N=CC=CC=C1.C1=CC=CC=C1 Chemical compound Cl.N1N=CC=CC=C1.C1=CC=CC=C1 YEHIIKLKSBNZDR-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 229940039925 zyprexa Drugs 0.000 description 1
Abstract
The invention relates to a synthetic route for preparing olanzapine by using o-fluoro-nitrobenzene as a raw material. In the method, the o-fluoro-nitrobenzene is used as a starting material to prepare the olanzapine by steps of coupling, reduction and ring closing.
Description
Technical field:
The present invention relates to the o-fluoronitrobenzene is the synthetic route of feedstock production olanzapine (olanzapine).
Background technology:
Olanzapine (olanzapine) has another name called Zyprexa; It is the development of U.S. Lilly company; In October, 1996, clinical trial showed that it has better therapeutic and the outer spinoff of cone still less than antipsychotics such as haloperidol at the schizoid atypical antipsychotic of a kind of treatment of U.S.'s listing.Chemical name 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzene diazepine, its molecular formula is:
The common synthetic route of olanzapine has following several kinds:
(1) disclosed the method that two kinds of different steps prepare olanzapine among the EP04544436A1.
First method be with 4-amino-10H-thiophene [2,3-b] [1,5] benzene diazepine hydrochloride and N methyl piperazine at organic solvent such as toluene, N, dinethylformamide etc., 100-150 ℃ of reaction generates olanzapine.This reaction yield is low, has only 50% left and right sides yield, and needs in the preparation of compd A to use like SnCl
2, SnCl
4Deng poisonous reagent.
Second method be with methyl-2-(2-oil of mirbane amino)-5-thiotolene-3-methyl-formiate under titanium tetrachloride catalysis and N methyl piperazine prepared in reaction olanzapine.In this preparation method, complicated operation, temperature of reaction is high when closing ring, and reaction is violent, and the separation and purification trouble, needs behind column chromatography, to use the acetonitrile recrystallization more earlier according to EP04544436, prepares the olanzapine single step reaction at last and only is lower than 60% productive rate.
(2) WO041000847 and CN1420117A have disclosed and have a kind ofly prepared the method for olanzapine from 4-amino-2-methyl-10H-thiophene [2,3-b] [1,5] benzene diazepine two-step approach of setting out.
This compound method productive rate is low, and final product is of low quality.
Summary of the invention:
It is the method for raw material high-efficient simple preparing olanzapine that the problem that the present invention will solve provides with the o-fluoronitrobenzene, comprises with the o-fluoronitrobenzene being starting raw material, through coupling, reduction, Guan Huansan step preparation olanzapine I.
In a kind of embodiment of route of the present invention; A kind of method for preparing olanzapine is provided, and this method comprises: in the presence of lewis acid catalyst, in the organic solvent; 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II and N methyl piperazine reaction, preparing olanzapine I.
In a preferred embodiment of the invention, preferred described lewis acid catalyst is aluminum chloride or zinc chloride.
In a preferred embodiment of the invention, preferred described organic solvent is toluene, acetonitrile, N, dinethylformamide, DMSO 99.8MIN. etc.
Preferred 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II and N methyl piperazine be 1:1-1:6 in molar ratio, more preferably 1:2.5-1:5, preferable reaction temperature 40-200 ℃.
In further embodiment of the present invention; Wherein said 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II is under solutions of weak acidity; In organic solvent or mixed solvent, through obtaining with iron powder reducing 2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III.
Solutions of weak acidity is produced by strong acid weak base salt, and said strong acid weak base salt is selected from ammonium chloride or ammonium sulfate.
In further preferred embodiment, 2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III (synthesized reference USP5229382) wherein.With the mol ratio of iron powder be 1:0.5～1:6, be recommended as 1:3～1:5, temperature of reaction is 25-120 ℃, the reaction times is 1～20 hour.The mol ratio of 2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III and strong acid weak base salt is 1:0.2～1:3.
Preferred said organic solvent is selected from N, dinethylformamide, DMSO 99.8MIN., toluene, benzene, C
1-C
10The alcohol of straight or branched, like methyl alcohol, ethanol, Virahol etc.Preferred described mixed solvent comprises the mixture of above-mentioned organic solvent or the mixture of above-mentioned organic solvent and water formation.
2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III obtains through o-fluoronitrobenzene and the coupling under alkali such as salt of wormwood effect of 2-amino-3-cyanic acid-5-thiotolene.
In above-mentioned preparation method, formula II compound is novel compound, therefore, relates to formula II compound in another aspect of this invention, further relates to the application of formula II compound in the preparation olanzapine.
Embodiment:
The present invention will be helped to understand through following embodiment, but content of the present invention can not be limited.
Embodiment one
2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III's is synthetic:
With o-fluoronitrobenzene 65mL, DMSO 99.8MIN. 375mL, 2-amino-3-cyanic acid-5-thiotolene 75g and salt of wormwood 225g add in the 1L there-necked flask, are heated to 60-70 ℃ of reaction 4-7 hour, react completely to 2-amino-3-cyanic acid-5-thiotolene.Cool to room temperature is poured in the 3L frozen water, and dichloromethane extraction three times merges organic phase, organic phase with anhydrous magnesium sulfate drying after, filter, concentrate, ethyl alcohol recrystallization obtains 104g yellow solid III (yield: 74.3%).
1H?NMR(400MHz，CDCl
3)δ9.62(s，1H)，8.24(d，J＝8.6Hz，1H)，7.52(dd，J＝8.4Hz，1H)，7.20(d，J＝8.4Hz，1H)，6.97(dd，J＝7.3Hz，1H)，6.78(s，1H)，2.47(s，3H)；
13C?NMR(100MHz，CDCl
3)：148.9，141.2，136.2，136.1，134.1，126.6，123.9，119.9，116.1，113.7，104.6，15.6；MS：258(M
+)；IR(film，cm
-1)：3304，2921，2361，2225，1611，1502；UV：218nm。
Embodiment two
2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II's is synthetic:
104g2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III is dissolved in 450mLN, in the mixed solvent of dinethylformamide and 100mL water, adds 30g ammonium chloride and 66g iron powder, be warmed up to 60-80 ℃ of reaction 6-9 hour; Treat that raw material total overall reaction postcooling to envrionment temperature, filters, filtrating is poured in the 2.5L cold water; Separate out light grey deposition, filter, washing; The solid oven dry, the absolute ethyl alcohol recrystallization obtains 64.8g crystal II (yield: 68.9%).
1H?NMR(400MHz，CDCl
3)δ7.21(d，J＝7.8Hz，1H)，7.09(dd，J＝7.6Hz，1H)，6.77-6.84(m，2H)，6.46(s，1H)，6.16(s，1H)，3.81(s，2H)，2.27(s，3H)；
13C?NMR(100MHz，CDCl
3)：161.9，141.4，127.9，127.7，124.9，122.3，119.5，116.9，116.2，86.8，15.0；MS：229(M
+-1)；IR(film，cm
-1)：3383，3300，3206，3041，2361，2205，1540；UV：308，217.8nm。
Embodiment three
Synthesizing of 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzene diazepine (I):
24.5g2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II and 40mL N methyl piperazine are dissolved in the mixed solvent of 60mL DMSO 99.8MIN. and 60mL toluene, add the 1.6g Zinc Chloride Anhydrous, reflux 14-16 hour intact to the raw material II total overall reaction.Be cooled to envrionment temperature, pour in the 400mL water, separate out light grey deposition, filter, washing, oven dry, solid obtains 26.5g pale yellow crystals I with the acetonitrile recrystallization, and (yield: 79%), purity is greater than 99%.
1H?NMR(400MHz，CDCl
3)δ7.02(d，J＝7.8Hz，1H)，6.97(dd，J＝7.5Hz，1H)，6.88(dd，J＝1.6，7.6Hz，1H)，6.60(d，J＝7.7Hz，1H)，6.30(s，1H)，4.97(s，`H)，3.54(t，J＝4Hz，4H)，2.50(t，J＝4.9Hz，4H)，2.35(s，3H)，2.31(s，3H)；
13C?NMR(100MHz，CDCl
3)：157.6，151.7，142.5，141.0，129.1，128.2，124.7，123.7，123.0，119.7，118.9，55.1，46.8，46，2，15.5；MS:313(M
++1)；IR(film，cm
-1):3247，3180，2969，2923，2843，2803，2361，1592；UV:270.2，226.4，204.4nm。
Claims (8)
1. method for preparing olanzapine, this method comprises: in the presence of the zinc chloride catalyzer, in organic solvent, make the reaction of 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II and N methyl piperazine, preparing olanzapine I
2. according to the process of claim 1 wherein that described organic solvent is toluene, acetonitrile, N, dinethylformamide or DMSO 99.8MIN..
3. according to the process of claim 1 wherein that the mol ratio of 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II and N methyl piperazine is 1: 1-1: 6, temperature of reaction 40-200 ℃.
4. according to the process of claim 1 wherein that the mol ratio of 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II and N methyl piperazine is 1: 2.5-1: 5.
5. according to the method for claim 1; Wherein said 2-(2-amino phenyl amino)-3-cyanic acid-5-thiotolene II is under solutions of weak acidity; In the mixture of organic solvent or organic solvent and water, obtain with iron powder reducing 2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III
6. according to the method for claim 5, wherein the mol ratio of 2-(2-oil of mirbane is amino)-3-cyanic acid-5-thiotolene III and iron powder is 1: 0.5～1: 6.
7. according to the method for claim 5, wherein said organic solvent is selected from N, dinethylformamide, DMSO 99.8MIN., toluene, benzene or C
1-C
10The alcohol of straight or branched.
8. according to the method for claim 5, wherein said solutions of weak acidity is that ammonium chloride or ammonium sulfate produce.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101725718A CN101723955B (en) | 2008-10-30 | 2008-10-30 | Method for preparing olanzapine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008101725718A CN101723955B (en) | 2008-10-30 | 2008-10-30 | Method for preparing olanzapine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101723955A CN101723955A (en) | 2010-06-09 |
| CN101723955B true CN101723955B (en) | 2012-05-30 |
Family
ID=42445573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008101725718A Active CN101723955B (en) | 2008-10-30 | 2008-10-30 | Method for preparing olanzapine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101723955B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225941B (en) * | 2011-06-01 | 2013-11-27 | 宁波人健医药化工有限公司 | Preparation method of antipsychotic drug olanzapine |
| CN102250116B (en) * | 2011-07-12 | 2013-11-27 | 江西富祥药业股份有限公司 | Preparation method of olanzapine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150948A (en) * | 1995-11-20 | 1997-06-04 | 沈阳药科大学 | Preparation method of 6,7-dimethoxy-2,4-(1H,3H)-quinazoline diketon |
-
2008
- 2008-10-30 CN CN2008101725718A patent/CN101723955B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150948A (en) * | 1995-11-20 | 1997-06-04 | 沈阳药科大学 | Preparation method of 6,7-dimethoxy-2,4-(1H,3H)-quinazoline diketon |
Non-Patent Citations (2)
| Title |
|---|
| 方频等.奥氮平合成新工艺研究.《浙江工业大学学报》.2008,第36卷(第1期),16-19. * |
| 杨先金等.奥氮平的合成工艺改进.《中国新药杂志》.2007,第16卷(第22期),1891-1892. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101723955A (en) | 2010-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106146379B (en) | A kind of synthetic method of Oxiracetam | |
| JPH0395144A (en) | Production of aminophenol derivative | |
| Zhang et al. | An efficient synthesis of 4-substituted pyrazolyl-3, 4-dihydropyrimidin-2 (1H)-(thio) ones catalyzed by Mg (ClO4) 2 under ultrasound irradiation | |
| WO2015054960A1 (en) | Gout drug lesinurad preparation method, and lesinurad intermediate | |
| CN105801572B (en) | A kind of preparation method of razaxaban | |
| WO2017080414A1 (en) | Method for preparing silodosin intermediate | |
| AU2018366342A1 (en) | Method for preparing Baricitinib | |
| CN102336704A (en) | Method for preparing Roflumilast | |
| CN101723955B (en) | Method for preparing olanzapine | |
| CN103509037B (en) | A kind of clopidogrel and the preparation method of intermediate thereof | |
| CN103864773B (en) | Razaxaban and its preparation method of intermediate | |
| CN104529734A (en) | Preparation method and preparation intermediate of fingolimod hydrochloride | |
| WO2016037588A2 (en) | New intermediate for synthesis of anti-aids drug enhancer cobicistat | |
| CN101723954B (en) | Technique for preparing olanzapine | |
| CN106957237B (en) | A method of synthesis bromfenac sodium | |
| WO2016066116A1 (en) | Preparation method of apremilast and intermediate thereof | |
| CN104876883A (en) | Synthetic method for intermediate of suvorexant as anti-insomnia medicament | |
| CN106749235A (en) | The preparation method of poly-substituted quinoline and azole derivatives | |
| CN104557877A (en) | Avanafil intermediate as well as preparation method and application thereof | |
| CN102491992A (en) | Method for preparing carbapenem type antibiotic key intermediate 4-BMA | |
| CN112479993A (en) | Synthetic method applied to KRAS inhibitor drug heterocyclic intermediate | |
| CN107382867B (en) | 4-isothiocyanato pyrazolones | |
| CN105348197A (en) | Preparation method of lorcaserin hydrochloride | |
| CN105418436B (en) | A kind of preparation method of melitracen hydrochloride | |
| JPH03188060A (en) | Benzylselenobenzamides obtained erom anilines and benzylamines and its preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of olanzapine Effective date of registration: 20201226 Granted publication date: 20120530 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210425 Granted publication date: 20120530 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of olanzapine Effective date of registration: 20210729 Granted publication date: 20120530 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000982 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230130 Granted publication date: 20120530 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000982 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of olanzapine Effective date of registration: 20230228 Granted publication date: 20120530 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2023330000447 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |