CN103772402A - Novel refining method of asenapine maleate crude product - Google Patents
Novel refining method of asenapine maleate crude product Download PDFInfo
- Publication number
- CN103772402A CN103772402A CN201410006192.7A CN201410006192A CN103772402A CN 103772402 A CN103772402 A CN 103772402A CN 201410006192 A CN201410006192 A CN 201410006192A CN 103772402 A CN103772402 A CN 103772402A
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- CN
- China
- Prior art keywords
- crude product
- acetone
- asenapine
- ethyl acetate
- asenapine maleate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Abstract
The invention belongs to the field of pharmaceutical chemistry, and relates to a refining method of an asenapine maleate crude product, which is simple and easy to implement and suitable for industrialization. The salt can be used for emergency treatment of mixed episode of adult schizophrenia, mania or I-type bipolar affective disorder.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the process for purification of asenapine maleate crude product.
Background technology
Asenapine (English name asenapine, trade(brand)name SAPHRIS), chemistry is called trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] also [4,5-c] pyrroles of oxa-Zhuo, it is a kind of CNS-of having inhibitor activity and has antihistamine and the compound of medmain activity (referring to US patent: US4145434A).Its structural formula is as follows:
Asenapine is developed to its maleate.The maleate (being called Org5222) of asenapine is a kind of norepinephrine, serotonin and dopamine antagonist of broad-spectrum high efficacy, and its potential antipsychotic activity can mix for the two-way affective disorder of grownup's schizophrenia, manic disorder or I type the emergency treatment of outbreak.This product is researched and developed by Arganon BioSciences company, and Schering Plough company produces, in Nikkei U.S. FDA approval listing Augusts 13 in 2009.At present, the maleate of asenapine is the important topic of clinical study, and it necessitates on a large scale.
Summary of the invention
Starting point of the present invention is: provide a kind of with low cost, and safety and environmental protection, process for purification easy and simple to handle, obtains highly purified target compound, makes this compound meet pharmaceutical quality requirement through refining.
The preparation of asenapine maleate (2) is by the hot ethanolic soln that is dissolved in of asenapine (1), then excessive a little toxilic acid is added in reaction system, for further refining, asenapine maleate (2) crystallization in Virahol obtaining obtains white solid.
In the alcohol-water mixed system that it is 9:1 by asenapine maleate in volume ratio that CN1861604B describes, in crystallization, the product of not only having purified, has also obtained the iris type of wishing; In WO2012123325A1, in the time of preparation crystalline form T, use the mixture of ketone (acetone, methyl ethyl ketone and methyl butyl ketone) and alkane (pentane, hexane, hexanaphthene, methylcyclohexane or heptane etc.) as the solvent of recrystallization; In WO2012150538A1 by asenapine free alkali first with phosphoric acid salify, then separate the maleate that salt preparation needs, reached the object of purifying.The invention reside in asenapine maleate is attempted respectively with ethyl acetate, acetonitrile, acetone, ethanol, alcohol-water, acetone-isopropyl ether, acetone-hexanaphthene, ethyl acetate-methyl tertiary butyl ether, ethyl acetate-acetone, Virahol, isopropanol-water, n-propyl alcohol, methanol-water etc. as solvent recrystallization, check the refining situation of all kinds of SOLVENTS to impurity by HPLC, obtaining the recrystallization solvent that refining effect is good and yield is high is ethyl acetate-acetone (volume ratio is 1:2) mixed solvent, and solid-to-liquid ratio is 1:6.
concrete embodiment
Following embodiment is to describe in detail the present invention, but should not be construed as limiting the invention.
Embodiment mono-: the preparation of asenapine maleate
Asenapine free alkali compound (1) 5g and toxilic acid 2.2 g are dissolved in 25 mL dehydrated alcohols, are heated to reflux, and stirring reaction 2h.Then reactant is chilled to room temperature, decompression steams etoh solvent, obtains faint yellow dope.Adding therein the Virahol reflux of 15 mL again, be cooled to stirring at room temperature crystallization 1h, there is white opacity in system, more each crystallization 1h in bathing respectively at ice-water bath and cryosel, takes advantage of cold decompress filter, obtains white solid with cold isopropanol washing leaching cake.Put into 40 ℃ of thermostatic drying chambers 3.68g that dries to constant weight to obtain, yield 52.3%.
That formulates according to my company declares clinical quality standard, detects through high performance liquid chromatography (HPLC), and it is 0.85% that maximum is singly mixed, and always assorted 2.2%.
Embodiment bis-: ethyl acetate is the recrystallizing and refining of solvent to asenapine maleate crude product
The asenapine maleate (3.6g) preparing according to the method for describing in embodiment mono-is dissolved in reflux in 75 mL ethyl acetate, be cooled to stirring at room temperature crystallization 1h, there is white opacity in system, each crystallization 1h in bathing respectively at ice-water bath and cryosel again, take advantage of cold decompress filter, obtain white solid with a small amount of cold ethyl acetate washing leaching cake.Put into 40 ℃ of thermostatic drying chambers, 2.5 g that dry to constant weight to obtain, yield 70%.
That formulates according to my company declares clinical quality standard, detects through high performance liquid chromatography (HPLC), and it is 0.08% that maximum is singly mixed, and always assorted 0.5%.
Embodiment tri-: the recrystallizing and refining of ethyl acetate-acetone mixed solvent to asenapine maleate crude product
The asenapine maleate (3.0g) preparing according to the method for describing in embodiment mono-is dissolved in the middle reflux of mixing solutions (volume ratio of ethyl acetate and acetone is 1:2) of 18 mL ethyl acetate and acetone, be cooled to stirring at room temperature crystallization 1h, there is white opacity in system, each crystallization 1h in bathing respectively at ice-water bath and cryosel again, takes advantage of cold decompress filter and obtains white solid.Put into 40 ℃ of thermostatic drying chambers 2.0g that dries to constant weight to obtain, yield 67%.
That formulates according to my company declares clinical quality standard, detects through high performance liquid chromatography (HPLC), and it is 0.03% that maximum is singly mixed, and always assorted 0.2%.
Claims (3)
1. a process for purification for asenapine maleate crude product, is characterized in that using following solvent: ethyl acetate, acetonitrile, acetone, ethanol, acetone-isopropyl ether, acetone-hexanaphthene, ethyl acetate-methyl tertiary butyl ether, ethyl acetate-acetone, alcohol-water carry out recrystallization to asenapine toxilic acid crude product.
2. according to claim 1, asenapine maleate crude product recrystallization solvent, is characterized in that optimum solvent used is ethyl acetate-acetone mixed system.
3. according to the refining solvent of the asenapine maleate crude product described in claim 1,2, the solid-to-liquid ratio that it is characterized in that asenapine toxilic acid crude product and solvent is 1:6, and the volume ratio of ethyl acetate and acetone is 1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410006192.7A CN103772402A (en) | 2014-01-07 | 2014-01-07 | Novel refining method of asenapine maleate crude product |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410006192.7A CN103772402A (en) | 2014-01-07 | 2014-01-07 | Novel refining method of asenapine maleate crude product |
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| Publication Number | Publication Date |
|---|---|
| CN103772402A true CN103772402A (en) | 2014-05-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410006192.7A Pending CN103772402A (en) | 2014-01-07 | 2014-01-07 | Novel refining method of asenapine maleate crude product |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| 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 (6)
| 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. |
| WO2012066565A2 (en) * | 2010-11-16 | 2012-05-24 | Cadila Healthcare Limited | Asenapine maleate amorphous and crystalline form and process for preparation thereof |
| WO2012123325A1 (en) * | 2011-03-11 | 2012-09-20 | Medichem S.A. | NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID |
| WO2013024492A2 (en) * | 2011-07-01 | 2013-02-21 | Megafine Pharma (P) Ltd. | A process for the preparation of asenapine and novel salts thereof |
| CN102952144A (en) * | 2011-08-29 | 2013-03-06 | 上海华拓医药科技发展股份有限公司 | Crystal forms of asenapine maleate, and preparation method and medical composition thereof |
| CN103254201A (en) * | 2012-02-21 | 2013-08-21 | 四川科伦药物研究有限公司 | Preparation method of asenapine |
-
2014
- 2014-01-07 CN CN201410006192.7A patent/CN103772402A/en active Pending
Patent Citations (6)
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| 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. |
| WO2012066565A2 (en) * | 2010-11-16 | 2012-05-24 | Cadila Healthcare Limited | Asenapine maleate amorphous and crystalline form and process for preparation thereof |
| WO2012123325A1 (en) * | 2011-03-11 | 2012-09-20 | Medichem S.A. | NEW CRYSTAL FORMS OF THE SALT OF TRANS-5-CHLORO-2-METHYL-2,3,3A,12b-TETRAHYDRO-1H-DIBENZO[2,3:6,7]OXEPINO[4,5-c]PYRROLE WITH MALEIC ACID |
| WO2013024492A2 (en) * | 2011-07-01 | 2013-02-21 | Megafine Pharma (P) Ltd. | A process for the preparation of asenapine and novel salts thereof |
| CN102952144A (en) * | 2011-08-29 | 2013-03-06 | 上海华拓医药科技发展股份有限公司 | Crystal forms of asenapine maleate, and preparation method and medical composition thereof |
| 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)
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| 张晓影，等: "抗精神病药阿塞那平的合成", 《化学试剂》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10898449B2 (en) | 2016-12-20 | 2021-01-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| US10980753B2 (en) | 2016-12-20 | 2021-04-20 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| 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: 20140507 |