Anti-malaria medical raw material benflumetol intermediate 2,7-dichlorofluorene-4-ethylene oxide synthesis process

Abstract

The invention relates to preparation of a key intermediate 2,7-dichlorofluorene-4-ethylene oxide of an anti-malaria medical raw material benflumetol. According to the synthesis process, in a single reaction kettle, 2,7-dichlorofluorene is adopted as a starting raw material, chlorine acetylation is catalyzed through a Lewis acid, metal borohydride reduction is performed, alkalization is performed to obtain an epoxide, and extraction separation, concentration crystallization and methanol or ethanol dispersion washing are performed after completing the reaction to obtain the high purity qualified product. The method has characteristics of simple process and simple operation, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the synthesis of 2,7-dichlorofluorene-4-oxirane, a key intermediate of benzfluorenol, an anti-malarial pharmaceutical raw material, and specifically relates to the synthesis of 2,7-dichlorofluorene-4-oxirane, which is a by-product of coal chemical industry, fluorene. -Dichlorofluorene, obtained by Lewis acid-catalyzed chloroacetylation, then alkalization to epoxide, crystallization from methanol or ethanol. Background technique [0002] 2,7-Dichlorofluorene-4-oxirane is a key intermediate in the synthesis of antimalarial drug lumefantrine. As a new mefloquine drug for the treatment of malaria developed in my country, it is mainly used clinically for a very serious tropical infectious disease. The disease has almost no patients in China, and it is mainly used in Africa, South America, and a few areas of Asia. In Africa, more than 3 million people die from malaria every year, mainly women and children. The characteristi...

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Problems solved by technology

[0005] In a route for the synthesis of benzfluorenol reported by Deng Rongxian of the Academy of Military Medical Sciences, 2,7-dichlorofluorene-4-oxirane was synthesized in four steps using fine fluorene as a raw material, and the main intermediate products were 2,7- Dichlorofluorene, 2,7-dichloro-4-chloroacetyl fluorene and 2,7-dichloro-4-(2-chloroethanol) fluorene, this route is the common route of benzfluorenol manufacturers at home and abroad at present, However, the production process is relatively cumbersome and the production cost is relatively high.

[0006] In a synthesis route of benzfluorenol reported by Dong Liuyu, a graduate student of Wuhan University of Technology in his dissertation, 2,7-dichlorofluorene-4-oxirane was synthesized in four steps using fine fluorene as a raw material, and the main intermediate products were 2,7-dichlorofluorene, 2,7-dichloro-4-bromoacetyl fluorene and 2,7-dichloro-4-(2-bromoethanolyl) fluorene, bromoacetyl bromide, an important raw material for this route, is expensive , although the yield has increased, the overall cost of the synthesized intermediate 2,7-dichlorofluorene-4-oxirane is too high and is not suitable for large-scale industrial production

[0007] The above method has the following shortcomings in the synthesis of benzfluorenol key intermediate-2,7-dichlorofluorene-4-oxirane: (1) Synthetic 2,7-dichlorofluorene with simple chemical raw material o-aminobenzaldehyde -4-Ethylene oxide intermediate, the route is too long, the use of raw and auxiliary materials is too much, the chemical atom economy is not good, and it is not environmentally friendly

(2) The route reported by Deng Rongxian has many shortcomings such as excessive acylation catalyst, not green and environmentally friendly, and complicated process flow.

(3) The route reported by Dong Liuyu is similar to that of Deng Rongxian, but the key acylating agent used is different, and the acylating agent is expensive, which makes the overall cost of 2,7-dichlorofluorene-4-oxirane intermediate too high, while Not suitable for industrial production

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