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The synthetic method of harringtonine C ring intermediate

A technology of harringtonine and intermediates, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of expensive raw materials, environmental pollution, long routes and the like, and achieves the effect of simple operation

Active Publication Date: 2018-10-19
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are more than ten synthetic methods of harringtonine reported in the literature, but these routes are either too long, or the raw materials are too expensive, or cause serious environmental pollution due to the low yield and high consumption, which are far from practical application.

Method used

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  • The synthetic method of harringtonine C ring intermediate
  • The synthetic method of harringtonine C ring intermediate
  • The synthetic method of harringtonine C ring intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Preparation of N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone from 3,4-methylenedioxyphenethylamine

[0041] The first step: amino protection and N-H bond activation: put the flask containing 1.652g (10mmol) 3,4-methylenedioxyphenethylamine in 80mL dichloromethane solution in an ice bath, and then add triethylamine 12mmol to provide an alkaline environment. While stirring, 20 mmol of p-nitrobenzenesulfonyl chloride was slowly added dropwise. After 0.5 h, the ice bath was removed, and the reaction was continued for 4 h at room temperature, and the reaction was stopped. The reaction solution was washed twice with water and once with saturated sodium chloride, and then dried over anhydrous sodium sulfate. Filtration, rotary evaporation to recover the solvent, add petroleum ether to the remaining red oily liquid, after the crystallization is complete, recrystallize to obtain a light yellow solid product N-p-nitrobenzenesulfonyl-3,4-methylenedioxyphenet...

Embodiment 2

[0048] Preparation of N-trifluoromethylsulfonyl-3,4-methyleneoxybenzo-3-N-hepanone from 3,4-methylenedioxyphenethylamine

[0049] Step 1: Amino protection and N-H bond activation: Place a flask containing 1.652g (10mmol) of 3,4-methylenedioxyphenethylamine in 80mL of chloroform solution in an ice bath, then add diisopropylethylamine Amine 11mmol to provide an alkaline environment. While stirring, 18 mmol of trifluorosulfonic anhydride was slowly added dropwise. After 1 h, the ice bath was removed, and the reaction was continued for 3 h at room temperature, and the reaction was stopped. The reaction solution was washed with water three times and saturated sodium chloride once, and dried over anhydrous sodium sulfate. Filtration, rotary evaporation to recover the solvent, adding hexane to the remaining oily liquid to crystallize, after the crystallization is complete, recrystallize to obtain the light yellow solid product N-trifluoromethylsulfonyl-3,4-methylenedioxyphenethylam...

Embodiment 3

[0059] Preparation of N-tert-butoxycarbonyl-3,4-methyleneoxybenzo-3-N-heptanone from 3,4-methylenedioxyphenethylamine

[0060] The first step: amino protection and N-H bond activation: put the flask containing 1.652g (10mmol) 3,4-methylenedioxyphenethylamine in 15mL ethanol solution (ethanol as solvent) in an ice bath, add 10mmol Triethylamine and 3 mmol DBU (1,8-diazacyclo[5,4,0]undecene-7) to provide a basic environment. While stirring, 20 mmol of di-tert-butyl carbonate anhydride was slowly added dropwise to the system, and the ice bath was removed 0.5 h after the dropwise addition, and the reaction was continued for 5 h at room temperature. After the reaction was completed, it was concentrated, and 150 mL of ethyl acetate was added to the residue, washed once with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. Filtrate with suction, concentrate the filtrate, and recrystallize from ethyl acetate-petroleum ether to obtain N-tert-buto...

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Abstract

The invention relates to an artificial synthetic method of a harringtonine C-ring intermediate. According to the method, 3,4-methylenedioxyphenethylamine (compound I) as a raw material is subjected to acylation in alkaline conditions to obtain N-acylated-3,4-methylenedioxyphenethylamine (compound II), which is then reacts with halogenated acetic acid or halogenated acetic acid derivative to generate N-acylated-3,4-methylenedioxyphenethylamine acetic acid (compound III); and the compound (III) is catalyzed by Lewis acid to generate intramolecular Friedel-crafts acylation reaction to obtain N-acyl-3,4-metheneoxybenzo-3-N-cycloheptanone, namely C ring of harringtonine. In the preparation process, products of each step are purified by washing and recrystallization; and the method has simple operation, total yield of 87.4%, and good industrial prospect.

Description

technical field [0001] The invention relates to a method for synthesizing a drug intermediate, in particular to a method for synthesizing an intermediate containing a C ring of harringtonine. Background technique [0002] Horringtonine is a kind of alkaloid extracted from the plant of the genus Spicera, which has good anticancer activity and is mainly used clinically for the treatment of acute myeloid leukemia, acute monocytic leukemia, promyelocytic leukemia, and promyelocytic leukemia. Cell leukemia, chronic myelogenous leukemia and polycythemia vera and other diseases, also have a certain therapeutic effect on lymphoma. [0003] At present, the harringtonine drugs used clinically are all extracted from plants, because the harringtonine plant resources are limited, the growth cycle is long, and the content of ester alkaloids with anticancer activity in plants is extremely low (per 100g The total alkaloid content in the cloverleaf branches and leaves is only 0.39%). If a l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/056
CPCC07D491/056
Inventor 刘守信张晓芳张志伟杨毅华杨建华
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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