CN103254202A - Preparation method of asenapine - Google Patents
Preparation method of asenapine Download PDFInfo
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- CN103254202A CN103254202A CN2013101840577A CN201310184057A CN103254202A CN 103254202 A CN103254202 A CN 103254202A CN 2013101840577 A CN2013101840577 A CN 2013101840577A CN 201310184057 A CN201310184057 A CN 201310184057A CN 103254202 A CN103254202 A CN 103254202A
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- asenapine
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- sainaping
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Abstract
The invention discloses a preparation method of asenapine. According to the preparation method, the asenapine (III) is prepared from a compound I with formula 1 or a compound II with formula 2 under a vitride solution reduction condition. The method is high in yield and low in production cost due to the fact that vitride is much cheaper than borane; and moreover, vitride is safer and simpler to operate compared with the reagent used in the prior art, so that the asenapine is applicable to in-scale production.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, say it is the preparation method who can be used as schizophrenia medicine A Sainaping (Asenapine) definitely.
Background technology
A Sainaping (Asenapine), commodity are called Saphris, and by Organon BioSciences research and development, Schering Plough company produces.On August 14th, 2009, FDA ratified the emergency treatment that this medicine is used for grownup's schizophrenia, manic disorder or mixes outbreak with the two-way affective disorder of I type.
The English chemical name of A Sainaping is: trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7] oxepino[4,5-c] pyrrole; The Chinese chemical name: trans-5-chloro-2,3,3a, 12b-tetrahydrochysene-2-methyl isophthalic acid H-dibenzo [2,3:6,7] oxa-Zhuo is [4,5-c] pyrroles also; Molecular formula: C17H16ClNO; Relative molecular weight: 285.77; CAS registration number: 65576-45-6.A Sainaping since coming out, a lot of patents and bibliographical information have been arranged both at home and abroad its preparation method.But major part all is to be that starting raw material obtains the A Sainaping III through reduction with chemical compounds I or II, obtains the A Sainaping maleate with toxilic acid salify in ethanolic soln again, shown in one:
Wherein, the reductive condition of employing is mainly two kinds: a kind of is to adopt tetrahydrochysene lithium aluminium, and the aluminum chloride system is reduced and obtained the A Sainaping III, obtain the A Sainaping maleate with the toxilic acid salify again, as: US20060229352, WO2006106136, US20090209608 etc.; Another kind method is to adopt borane complex (borine dimethyl sulphide or borine tetrahydrofuran (THF)) reduction to obtain the A Sainaping III, obtains the A Sainaping maleate with the toxilic acid salify again, as CN101851242.These two kinds of reaction systems all need adopt anhydrous system, and reaction conditions requires harsh relatively, and operation is relatively more dangerous.Tetrahydrochysene lithium aluminium and borane complex are inflammable and explosive chemical, meet damp atmosphere or water generation vigorous reaction, easily cause burning or blast.Tetrahydrochysene lithium aluminium or borine that industrial a large amount of use is valuable, danger is big, cost is high.
Summary of the invention
In order to solve above-mentioned shortcoming, the invention provides a kind of preparation method of novelty, utilize red aluminium (two (2-methoxyethoxy) sodium aluminates of dihydro) to substitute tetrahydrochysene lithium aluminium or borine, chemical compounds I shown in the formula one or II are obtained compound III (A Sainaping) under red aluminum solutions reductive condition, synthetic reaction formula suc as formula two or formula three shown in, the concrete practice is: adopt structure suc as formula two or formula three shown in be raw material with chemical compounds I or II, be solvent with toluene, obtain III (A Sainaping) under the condition of red aluminium reducing, the method for recycling bibliographical information and toxilic acid salify obtain the A Sainaping maleate.
Because red aluminum solutions all will be stablized than lithium aluminum hydride or borine in moisture and air, its thermostability is also higher, can spontaneous combustion, solvability is good, is easy to dispose, and has high reducing activity, be the surrogate of the safety of lithium aluminum hydride or borine, reduced the danger of operation, greatly reduce cost, simplify the risk of post-processing operation, shortened the production cycle.
Experiment confirm provided by the present invention suc as formula two or formula three shown in the method for preparing the compound III through chemical compounds I or II yield height not only; and because red aluminium is cheaply a lot of than borine; so production cost is low; simultaneously because the borine severe toxicity is explosive; red aluminium is then much safe; so method operation provided by the invention is simpler, is suitable for large-scale production.
Embodiment
Embodiment one: in the synthetic route shown in two, wherein be raw material with the chemical compounds I, the preparation of compound III: in the 500mL there-necked flask, add 30g compound compound I, with 300mL toluene it is dissolved, drip 70% red aluminum solutions 144g under the room temperature.Reaction mixture is warming up to 40 ℃ to 50 ℃ reactions 3 hours under constantly stirring.The ice-water bath cooling drips 100mL methyl alcohol cancellation reaction down, adds the sodium hydroxide solution of 100mL water and 200mL10%, stirs a moment.Tell organic phase, water 100mL dichloromethane extraction.Merge organic phase, drying, concentrating under reduced pressure reclaims solvent, gets 26g compound III, yield 71%.
Embodiment two: in the synthetic route shown in three, be raw material with the compound ii wherein, in the 500mL there-necked flask, add 30g compound compound I, with 300mL toluene it is dissolved, drip 70% red aluminum solutions 144g under the room temperature.Reaction mixture is warming up to 40 ℃ to 50 ℃ reactions 3 hours under constantly stirring.The ice-water bath cooling drips 100mL methyl alcohol cancellation reaction down, adds the sodium hydroxide solution of 100mL water and 200mL10%, stirs a moment.Tell organic phase, water 100mL dichloromethane extraction.Merge organic phase, drying, concentrating under reduced pressure reclaims solvent, gets 25.5g compound III, yield 69%.
Claims (2)
1. suc as formula the preparation method of compound III in 1, it is characterized in that chemical compounds I is obtained the compound III under red aluminum solutions reductive condition,
2. suc as formula the preparation method of compound III in 2,, it is characterized in that compound ii is obtained the compound III under red aluminum solutions reductive condition,
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101840577A CN103254202A (en) | 2013-05-19 | 2013-05-19 | Preparation method of asenapine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013101840577A CN103254202A (en) | 2013-05-19 | 2013-05-19 | Preparation method of asenapine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103254202A true CN103254202A (en) | 2013-08-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN2013101840577A Pending CN103254202A (en) | 2013-05-19 | 2013-05-19 | Preparation method of asenapine |
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| CN (1) | CN103254202A (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 |
|---|---|---|---|---|
| CN101175741A (en) * | 2005-04-07 | 2008-05-07 | 欧加农股份有限公司 | Intermediate compounds for the prepation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-C]pyrrole |
| 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 |
| CN103254201A (en) * | 2012-02-21 | 2013-08-21 | 四川科伦药物研究有限公司 | Preparation method of asenapine |
-
2013
- 2013-05-19 CN CN2013101840577A patent/CN103254202A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101175741A (en) * | 2005-04-07 | 2008-05-07 | 欧加农股份有限公司 | Intermediate compounds for the prepation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-C]pyrrole |
| 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 |
| CN103254201A (en) * | 2012-02-21 | 2013-08-21 | 四川科伦药物研究有限公司 | Preparation method of asenapine |
Non-Patent Citations (1)
| Title |
|---|
| 张思晨 等: "新型高效还原剂红铝", 《精细与专用化学品》 * |
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 |
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Application publication date: 20130821 |