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A kind of preparation method of asenapine

A technology of asenapine maleate and tetrahydrofuran, applied in the field of organic synthesis, can solve problems such as easy combustion or explosion, potential safety hazards, and violent reactions

Active Publication Date: 2016-04-13
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The shortcoming of this route is that aluminum lithium tetrahydrogen has strict requirements on anhydrous environment, violent reaction, easy to burn or explode in the reaction process, and has potential safety hazards, so it cannot be used in large quantities in industrial production, which limits the development of asenapine. mass production

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  • A kind of preparation method of asenapine

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Embodiment 1

[0021] Example 1 Trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa And [4,5-C]pyrrol-1-one (compound 1) to prepare asenapine

[0022] 0℃, under nitrogen protection and stirring, add 11.2g (83.8mmol) of AlCl 3 , Put into dry 240mL tetrahydrofuran, drip 70% red aluminum toluene solution and tetrahydrofuran mixed solution, of which the red aluminum toluene solution and tetrahydrofuran were 52mL and 60ml; after the dripping, add trans-5- Chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa[4,5-C]pyrrol-1-one (compound 1,20g, 66.8mmol) dissolved in 160mL of tetrahydrofuran, after the dripping, heat and stir for 30min, warm up to 66℃, stir for 5h, use petroleum ether: ethyl acetate=1: 2 as the developing solvent, TLC (GF254 ) The detection of the raw material point disappeared; cooling to room temperature, adding 300 mL of ethyl acetate to the reaction solution, stirring for 30 minutes, and then adding dropwise 250 mL of 1 mol / L sodium hydroxide solution to ...

Embodiment 2

[0025] Example two trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa And [4,5-C]pyrrol-1-one (compound 3) to prepare asenapine

[0026] 0℃, under nitrogen protection and stirring, the AlCl 3 (8.2g, 61.7mmol) into 240mL of dry tetrahydrofuran, add dropwise a mixed solution of 70% red aluminum toluene solution (38.3mL, 133.6mmol) and tetrahydrofuran (50mL), control the rate of dropping to make the temperature below 5℃, After the dripping, add trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa[ 4,5-C]pyrrol-1-one (compound 1, 20g, 66.8mmol) in tetrahydrofuran (160mL), after the dripping, keep stirring for 30min, warm to 66℃, stir and react for 5h, use petroleum ether: acetic acid Ethyl is the developing solvent, and the volume ratio of petroleum ether: ethyl acetate is 1:2, the raw material point detected by TLC (GF254) disappears, cool to room temperature, add 300 mL ethyl acetate to the reaction solution, stir for 30 min, and then add to the ...

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Abstract

The invention relates to a preparation method of a psychotropic medicine asenapine. The method comprises a step that asenapine is prepared through a reaction of a raw material trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-monobenzo[2,3:6,7]oxepino[4,5-C]pyrrole-1-one or trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-C]pyrrole-1-one under the action of a reducing agent sodium bisaluminumhydride or a composite reducing agent composed of sodium bisaluminumhydride and other regents. The method has the advantages of mild and controllable reaction technology, low production cost, good product yield, realization of the large scale application in the industrial production, and good enforcement values and social and economic benefits.

Description

Technical field [0001] The invention relates to a method for preparing a psychotropic drug asenapine. It belongs to the field of organic synthesis. Background technique [0002] Asenapine, the chemical name is trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa And [4,5-c]pyrrole has CNS-inhibitor activity, antihistamine and anti-serotonin activities, and its maleate is clinically used. Asenapine maleate can be made into pharmaceutical preparations for sublingual or oral administration (see International Application Patent WO / 23600), which is clinically suitable for adults with schizophrenia, mania or mixed with type I bipolar disorder For emergency treatment of mental illnesses, the trade name is Saphris. The extensive clinical research and application of Asenapine maleate necessitates the large-scale synthesis of the drug. [0003] A large number of studies on the synthesis of asenapine have been conducted at home and abroad. Patent US4145434, EP1710241 and d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/044
Inventor 卢建勋朱晓丹童元峰郭培良王朝阳吴松
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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