New process for synthesis of asenapine

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...

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-oxide, the reaction process is difficult to monitor and other shortcomings

But because the starting material compound 7 in this method is difficult to obtain, so this reaction is also difficult to industrialization

Images