CN101851242B - Preparation method of asenapine intermediate - Google Patents
Preparation method of asenapine intermediate Download PDFInfo
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- CN101851242B CN101851242B CN 201010181602 CN201010181602A CN101851242B CN 101851242 B CN101851242 B CN 101851242B CN 201010181602 CN201010181602 CN 201010181602 CN 201010181602 A CN201010181602 A CN 201010181602A CN 101851242 B CN101851242 B CN 101851242B
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- VOTGBXTUIFUDJK-UHFFFAOYSA-N CN(CC(C1c2ccccc2Oc(cc2)ccc2Cl)=O)C1=O Chemical compound CN(CC(C1c2ccccc2Oc(cc2)ccc2Cl)=O)C1=O VOTGBXTUIFUDJK-UHFFFAOYSA-N 0.000 description 1
- UEFINICFHHBHJQ-UHFFFAOYSA-N CN(CC1=C2c3ccccc3Oc(cc3)c1cc3Cl)C2=O Chemical compound CN(CC1=C2c3ccccc3Oc(cc3)c1cc3Cl)C2=O UEFINICFHHBHJQ-UHFFFAOYSA-N 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a novel preparation method of an asenapine intermediate, comprising the following steps of: carrying out cyclization in protonic acid including trifloromethanesulfonic acid by taking 3-(2-(4- chlorophenoxyl)-phenyl-4-hydroxyl-1-methyl-1H-pyrrole-2(5H)-ketone (compound 1) or 3-(5-chlorine-2-phenoxyl phenyl)-1-methyl-1H-pyrrole-2(4H)-ketone (compound 4) as a raw material to generate key intermediate compounds 2 and 4 of asenapine; and carrying out reduction reaction to obtain asenapine. The invention has the advantages of novel process route, high reaction yield and low production cost, and has greater application value and social economic effect.
Description
Technical field
The present invention relates to a kind of chemical synthesis process, particularly can be used as the novel preparation method of intermediate of the asenapine (Asenapine) of schizophrenia medicine; Belong to the organic synthesis field.
Technical background
Asenapine (Asenapine) commodity are called Saphris, and by Organon BioSciences research and development, ScheringPlough 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 asenapine: (3aR, 12bR)-rel-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-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-Zhuo is [4,5-c] pyrroles also; Molecular formula: C17H16ClNO; Relative molecular mass: 285.77; The CAS registration number: the 65576-45-6. asenapine since coming out, a lot of patents and bibliographical information have been arranged both at home and abroad its preparation method.WO2006106136, WO2007046554, US20090209608, WO2008078482 have reported with starting raw material 1 and 5 and have obtained intermediate 2 and 5 respectively through the ring-closure reaction in polyphosphoric acid that reduction obtains asenapine through intermediate 3 and 6 respectively then.The route See Figure:
When adopting above-mentioned route to synthesize final product asenapine (compound 7), exist the reaction yield that obtains compound 2 or 5 low, the impurity difficulty is removed, the problem that waste water is many.
Summary of the invention:
In view of this,, the invention provides a kind of preparation method of novelty, reduce the generation of impurity, improve the preparation yield of compound 2 and 5, and significantly reduce the amount of waste water in order to solve the aforesaid drawbacks.
1. the present invention prepares the preparation method of asenapine intermediate 2 and 5, it is characterized in that may further comprise the steps:
(1), the preparation method of compound 2, wherein make compound 1)
Cyclization in strong acid generates compound 2
(2), the preparation method of compound 5, wherein make compound 4)
Cyclization in strong acid generates compound 5
2. according to the described preparation method of claim 1, it is characterized in that described protonic acid is trifluoromethanesulfonic acid, methylsulphonic acid, p-methyl benzenesulfonic acid, perchloric acid, Tetrafluoroboric acid, four (phenyl-pentafluoride base) boric acid, the vitriol oil, wherein trifluoromethanesulfonic acid most preferably.
3. according to the described preparation method of claim 1-3, the temperature that it is characterized in that described ring-closure reaction is a room temperature-200 ℃, and wherein preferred temperature is about 110 degree.
Operational path novelty of the present invention, processing condition are reasonable, and are simple to operate, the reaction yield height, production cost is low, and the three wastes are few, have bigger implementary value and economic results in society.
The invention will be further described with by way of example more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
The specific embodiment mode:
Embodiment 15-chloro-2, and 3-dihydro-2-methyl isophthalic acid H-dibenzo [2,3:6,7] Evil English in heptan are the preparation of [4,5-c] pyrroles-1-ketone (compound 2) also
3-(2-(4-chlorophenoxy)-phenyl)-4-hydroxyl-1-methyl isophthalic acid H-pyrroles-2 (5H)-ketone (compound 1) 232g is added 5 liters of four-hole reaction flasks, and 2 liters of trifluoromethanesulfonic acids of disposable adding are warming up to 110 ℃ of reaction 10-15h.
Reaction removes most of trifluoromethanesulfonic acid under reduced pressure after finishing, and the cooling raffinate in the impouring frozen water, has a large amount of solids to separate out to room temperature, filters.Solid obtains product 135g, yield 71%, purity＞96%. with acetone and water recrystallization
HNMR data (DMSO-d6 solvent)
3.10(d，J＝2.5Hz)，4.70(d，2H，J＝4.2Hz)，7.2-7.6(m，6H)，8.1(s，1H)
Embodiment 211-chloro-2, and 3-dihydro-2-methyl isophthalic acid H-dibenzo [2,3:6,7] Evil English in heptan are the preparation of [4,5-c] pyrroles-1-ketone (compound 5) also
3-(5-chloro-2-Phenoxyphenyl)-1-methyl isophthalic acid H-pyrroles-2 (4H)-ketone (compound 4) 232g is added 5 liters of four-hole reaction flasks, and 2 liters of trifluoromethanesulfonic acids of disposable adding are warming up to 110 ℃ of reaction 10-15h.Reaction removes most of trifluoromethanesulfonic acid under reduced pressure after finishing, and the cooling raffinate in the impouring frozen water, has a large amount of solids to separate out to room temperature, filters.Solid obtains product 145g, yield 76%, purity＞95%. with acetone and water recrystallization
The preparation of embodiment 3 asenapines
With compound 2 or 5,, can obtain highly purified asenapine (trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-Zhuo is [4,5-c] pyrroles also) by the method for WO2006/106136.
Comparative example 15-chloro-2, [2,3:6,7] Evil English in heptan be the preparation (polyphosphoric acid method) of [4,5-c] pyrroles-1-ketone (compound 2) also for 3-dihydro-2-methyl isophthalic acid H-dibenzo
3-(5-chloro-2-Phenoxyphenyl)-1-methyl isophthalic acid H-pyrroles-2 (4H)-ketone (compound 1) 232g is added 5 liters of four-hole reaction flasks, add polyphosphoric acid 1L, be warming up to 150 ℃ of reaction 15h.Reaction is not over yet, and adds Vanadium Pentoxide in FLAKES, is warmed up to 160 ℃, and after reaction finished, cooling solution to 50 degree in the impouring frozen water, had a large amount of solids to separate out, and filters.Solid obtains product 110g, yield 50%, purity 75%. with acetone and water recrystallization
Claims (3)
1. prepare the preparation method of asenapine intermediate 2 and 5, it is characterized in that may further comprise the steps:
(1), the preparation method of compound 2, wherein make compound 1)
Cyclization in trifluoromethanesulfonic acid generates compound 2
(2), the preparation method of compound 5, wherein make compound 4)
Cyclization in trifluoromethanesulfonic acid generates compound 5
2. preparation method according to claim 1, the temperature that it is characterized in that described ring-closure reaction are room temperature to 200 ℃.
3. preparation method according to claim 2, the preferred temperature that it is characterized in that described ring-closure reaction is 110 ℃.
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| CN101851242B true CN101851242B (en) | 2013-07-24 |
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Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2468751B1 (en) * | 2010-12-24 | 2016-03-16 | Medichem, S.A. | Processes for the preparation of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole |
| CN103183680A (en) * | 2011-12-27 | 2013-07-03 | 上海华拓医药科技发展股份有限公司 | Method for preparing asenapine |
| CN103254202A (en) * | 2013-05-19 | 2013-08-21 | 甘肃皓天化学科技有限公司 | Preparation method of asenapine |
| CN103351393B (en) * | 2013-07-03 | 2016-04-06 | 华裕(无锡)制药有限公司 | For the preparation of the reductive agent of Asenapine and the preparation method of Asenapine |
| CN103772401A (en) * | 2014-01-07 | 2014-05-07 | 万特制药(海南)有限公司 | New refining method of 11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrryl-1-one |
| CN104098580B (en) * | 2014-07-22 | 2016-04-13 | 成都百裕科技制药有限公司 | A kind of preparation method of asenapine key intermediate |
| CN104297366A (en) * | 2014-09-24 | 2015-01-21 | 万特制药(海南)有限公司 | Liquid phase analysis method of maleic acid asenapine and impurities thereof |
| PL3338768T3 (en) | 2016-12-20 | 2020-05-18 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| CA3047354A1 (en) | 2016-12-20 | 2018-06-28 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| CA3067938A1 (en) | 2017-06-26 | 2019-01-03 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| CA3101420A1 (en) | 2018-06-20 | 2019-12-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
Citations (4)
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|---|---|---|---|---|
| WO2007046554A1 (en) * | 2005-10-21 | 2007-04-26 | Sumitomo Chemical Company, Limited | Process for production of dibenzoxepinopyrrole compound, intermediate for production of the compound, and process for production of the intermediate |
| 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 |
| US20090209608A1 (en) * | 2007-08-29 | 2009-08-20 | Protia, Llc | Deuterium-enriched asenapine |
| CN101563312A (en) * | 2006-12-22 | 2009-10-21 | 住友化学株式会社 | Process for producing intermediate of asenapine synthesis |
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- 2010-05-25 CN CN 201010181602 patent/CN101851242B/en active Active
Patent Citations (4)
| 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 |
| WO2007046554A1 (en) * | 2005-10-21 | 2007-04-26 | Sumitomo Chemical Company, Limited | Process for production of dibenzoxepinopyrrole compound, intermediate for production of the compound, and process for production of the intermediate |
| CN101563312A (en) * | 2006-12-22 | 2009-10-21 | 住友化学株式会社 | Process for producing intermediate of asenapine synthesis |
| US20090209608A1 (en) * | 2007-08-29 | 2009-08-20 | Protia, Llc | Deuterium-enriched asenapine |
Non-Patent Citations (1)
| Title |
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| Vader, J. et, al.THE SYNTHESIS OF RADIOLABELLED ORG 5222 AND ITS MAIN METABOLITE ORG 30526.《journal of labelled compounds and radiopharmaceuticals》.1994,第34卷(第9期),845-869. * |
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Address after: 3 / F, building 8, No.15 and 16, Lane 1999, zhangheng Road, China (Shanghai) pilot Free Trade Zone, Shanghai, 201203 Patentee after: MEDCHEMEXPRESS CHINA Co.,Ltd. Address before: 201203 Shanghai city Pudong New Area Cailun Road No. 2 No. 601 720 Patentee before: MEDCHEMEXPRESS CHINA Co.,Ltd. |