New process for synthesis of asenapine

A new process and compound technology, applied in the field of arsenic, can solve the problems of low total reaction yield, difficult monitoring of the reaction process, difficult to obtain, etc. Effect

Active Publication Date: 2011-11-02
安庆润科生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The main problems of this process are: (1) The total yield of the reaction is not high; (2) There are multiple steps in the reaction, for example, in the preparation process of trimethylamine-N-oxi...

Method used

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  • New process for synthesis of asenapine
  • New process for synthesis of asenapine
  • New process for synthesis of asenapine

Examples

Experimental program
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Embodiment 1

[0037] Embodiment 1: the preparation of compound 11

[0038] Reflux 68g of o-bromobenzaldehyde, 200ml of nitromethane and 40g of ammonium acetate in 50ml of glacial acetic acid for 2 hours. After the reaction, add 1300ml of water to the system, stir well and filter, and the obtained yellow crude product is dissolved in ethanol Recrystallized to obtain 78 g of 2-bromo-β-nitrostyrene, namely compound 11, with a yield of 87.2%.

Embodiment 2

[0039] Embodiment 2: the preparation of compound 13

[0040] Dissolve 38.6g of dry isopropanol in 150ml of dry tetrahydrofuran (THF), cool the system to below -60 degrees Celsius, and add 192ml of n-butyl lithium in n-hexane dropwise while stirring. After stirring the reaction for 30 minutes, a solution of 94.5 g of methyl 2-methoxy-5-chlorophenylacetate in 300 ml of dry THF was added dropwise. After stirring for a further 15 minutes, a solution of 64.4 g of 2-methoxy-β-nitrostyrene (11) in 600 ml of dry THF was added dropwise with stirring, keeping the temperature below 50°C. Stir the reaction for 30 minutes after the addition, add a small amount of water to quench the reaction, evaporate most of the THF under reduced pressure, add an appropriate amount of 6N hydrochloric acid solution to the residue to acidify the solution, extract with dichloromethane two to three times, combine the organic layers, and add saturated salt Washed with water, dried over anhydrous magnesium su...

Embodiment 3

[0041] Embodiment 3: the preparation of compound 14

[0042] Dissolve the oily compound 13 obtained in the previous step reaction in 1000ml of ethanol, add 10g of 10% Pd / C, hydrogenation reaction overnight, filter to remove the catalyst after the reaction, concentrate the filtrate under reduced pressure, add an appropriate amount of diethyl ether to obtain off-white solid, ethanol Recrystallization gave 103 g of the refined product of amide compound 14 (a mixture of cis and trans isomers), and the two-step yield was 76.4%.

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Abstract

The invention discloses a process for synthesis of asenapine. The asenapine is prepared through adopting a compound (18) as a key intermediate and carrying out the following steps that: 1.1, the compound 18 is subjected to a Ullmann reaction under a alkaline condition through adopting copper powder as a catalyst to generate a ether (19); 1.2, the ether (19) is subjected to a carbonyl reduction to obtain the target compound of the asenapine (1). The process has the following advantages that: cheap and available 2-bromobenzaldehyde is adopted as an initial raw material and is subjected to acondensation, a addition, a reductive amination and a intramolecular cyclization reaction, a aminomethylation, a open loop transposition and then loop closing, a demethylation and a Ullmann loop closing reaction to synthesize of the asenapine (1); cis-trans-isomer is subjected to a delicate transposition to obtain a trans-product, such that the process is simplified and easy to be operated; the raw material is easy to be obtained and has cheap price; each reaction is a normal reaction, and reaction conditions are mild; a total yield is substantially improved; production cost is reduced; a purity of the product is more than 99% through a detection by HPLC.

Description

technical field [0001] The present invention relates to arsenalpine for the preparation of antipsychotic drugs, i.e. trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6 ,7]-oxazolo[4,5-C]pyrrole preparation method, and the intermediates involved. Background technique [0002] Asenapine, trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxazepine The maleate salt of [4,5-C]pyrrole is a compound with central nervous system depressant activity and antihistamine and antiserotonin activity. Studies have confirmed that arsenapine maleate is a broad-spectrum and highly effective antagonist of 5-hydroxytryptamine, norepinephrine and dopamine, has strong antipsychotic activity, and can be used to treat depression. It has been reported that the preparation of arsenalpine is used for the clinical treatment of psychiatric diseases, so large-scale synthesis of the drug is necessary. [0003] At present, the synthesis method of arsenalpine has been reported i...

Claims

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Application Information

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IPC IPC(8): C07D491/044
Inventor 肖锋楼旭初张淑彦龚明明
Owner 安庆润科生物医药科技有限公司
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