Preparation method of lorcaserin hydrochloride

Abstract

The invention provides a preparation method of lorcaserin hydrochloride, namely (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. The method comprises the following steps: taking p-chlorophenyl acetate as raw material, performing aminolysis with isopropanol amine, then performing chlorination, reduction and Friedel-Crafts alkylation, further splitting by L-tartaric acid, and performing salt formation to get the lorcaserin hydrochloride. The invention provides the preparation method of the lorcaserin hydrochloride. The method has the advantages of low cost, simplicity in operation and higher product purity; according to the process disclosed by the invention, the continuous operation can be performed, and the production cycle is greatly reduced; meanwhile a reagent is low in price and easy to obtain, the operation is simple, and the post-treatment is simple and convenient, so that the preparation method is a brand new and economic synthesis method which can realize industrial production.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a preparation method of lorcaserin hydrochloride, a weight-loss drug. Background technique [0002] Lorcaserin hydrochloride formula (I), English name Lorcaserin, chemical name (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine Zhuo hydrochloride, used in obese patients, was developed by American Ainina Pharmaceutical Company in 2005. On June 27, 2012, it was first approved by the US Food and Drug Administration for marketing in the United States. Its specific target is 5 -HT2C has a strong effect on appetite control, but has no effect on 5-HTM or 5-HT2B receptors, so it has fewer side effects than previous weight-loss drugs. At the same time, lorcaserin is effective in weight loss At the same time, it can also improve heart rate, blood pressure and low-density lipoprotein cholesterol levels. [0003] [0004] The currently reported synthetic route has the following m...

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Problems solved by technology

[0011] In the published document WO2005003096, the synthesis method of route 1 is reported, using p-chlorophenethylamine as the starting material, reacting with 2-chloropropionyl chloride, then undergoing Friedel-Crafts alkylation, and reductive resolution to obtain lorcaserin , although there are only four steps in this route, the starting material p-chlorophenethylamine has little market demand and is an unconventional chemical raw material, so the price is expensive

[0012] US20090143576 uses the method of route 2 to synthesize lorcaserin, using the relatively easy-to-obtain p-chlorophenylethanol as the starting material, bromination, substitution, K-alkylation, and resolution to obtain the product. This route is very dangerous to use Phosphorus tribromide, large industrial pollution, post-treatment produces a large amount of hydrogen bromide, and at the same time, it is easy to produce multi-substituted products during substitution, and the reaction requirements are harsh

[0013] Along with the research on lorcaserin, some literatures have reported the synthesis method of Route 3, using the more readily available p-chlorophenylacetic acid as the starting material, condensing with isopropanolamine, and then reducing the amide, chlorination, Fu Ke alkylation, resolution to obtain the product, but in the process of synthesizing 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide formula (V), the condensation reagent is expensive, greatly improving Production costs, or the difficulty of product purification after the application of cheap condensing agents, WO2008070111 improved the condensation reaction, using boric acid and phenylboronic acid to catalyze the condensation, which greatly reduced the reaction cost, but the reaction required a long time of water separation to complete , the reaction requires high water content, and the production cycle is long

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