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Preparation method of asenapine

A technology of tetrahydrofuran and red aluminum, applied in the direction of organic chemistry, can solve the problems of potential safety hazards, restrictions on the large-scale production of asenapine, and the inability to use it in large quantities.

Active Publication Date: 2013-08-21
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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  • Preparation method of asenapine

Examples

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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 The method for preparing asenapine from [4,5-C]pyrrol-1-one (compound 1)

[0022] 0°C, under nitrogen protection and stirring, 11.2g (83.8mmol) of AlCl 3 , put into dry 240mL tetrahydrofuran, add dropwise a mixed solution of 70% red aluminum toluene solution and tetrahydrofuran, wherein the red aluminum toluene solution and tetrahydrofuran are 52mL and 60ml respectively; after the dropwise addition, 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 dropwise addition, keep stirring for 30min, heat up to 66°C, stir for 5h, use petroleum ether: ethyl acetate = 1:2 as the developer, TLC (GF254 ) to detect the disappearance of the raw material point; cool to room temperature, add 300 mL of ethyl acetate to the reaction solution, stir for 30 min, then add 250 mL of 1 mol / L sodi...

Embodiment 2

[0025] Example 2 Trans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxa The method for preparing asenapine from [4,5-C]pyrrol-1-one (compound 3)

[0026] 0°C, under nitrogen protection and stirring, the AlCl 3(8.2g, 61.7mmol) was dropped into 240mL dry tetrahydrofuran, and a mixed solution of 70% red aluminum toluene solution (38.3mL, 133.6mmol) and tetrahydrofuran (50mL) was added dropwise, and the rate of addition was controlled so that the temperature was lower than 5°C. After the dropwise addition, 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 dropwise addition, keep stirring for 30min, heat up to 66°C, stir and react for 5h, add petroleum ether: acetic acid Ethyl is used as a developer, and the volume ratio of petroleum ether: ethyl acetate is 1:2. TLC (GF254) detects that the raw material point disappears. After cooling to room temperature, 300 m...

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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 activity, 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 applicable to adults with schizophrenia, mania or mixed episodes with type I bipolar disorder The emergency treatment of mental illness, etc., the trade name is Saphris. The extensive clinical research and application of asenapine maleate necessitates the large-scale synthesis of the drug. [0003] A lot of research has been done on the synthesis of asenapine at home and abroad. Patents US4145434, EP1710241...

Claims

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Application Information

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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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