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Synthetic method of harringtonine intermediate with D-ring

A synthesis method and intermediate technology, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of expensive raw materials, far distances, environmental pollution, etc., and achieve the effect of simple operation

Active Publication Date: 2014-09-17
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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  • Synthetic method of harringtonine intermediate with D-ring
  • Synthetic method of harringtonine intermediate with D-ring
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The following is the synthetic route of 3,4-methylenedioxyphenethylamine to 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone, which can basically be divided into two processes:

[0051] First synthesize N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heptanone from 3,4-methylenedioxyphenethylamine; Synthesis of 3,4-methyleneoxybenzo-3-N-heteroheptanopyrrolidone from nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heptanone.

[0052] First introduce the process of synthesizing N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-heteroheptanone with 3,4-methylenedioxyphenethylamine:

[0053] Step 1: Amino group protection and N-H bond activation: Place a flask containing 1.652g (10mmol) of 3,4-methylenedioxyphenethylamine in 80mL of dichloromethane solution in an ice bath, then add 12mmol of triethylamine , 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 th...

Embodiment 2

[0069] Regarding the acquisition of the raw material "N-methylsulfonyl-3,4-methyleneoxybenzo-3-N-heptanone", refer to the process of Example 1, except that the 3,4-methylene di In the synthesis of oxyphenethylamine "N-p-nitrobenzenesulfonyl-3,4-methyleneoxybenzo-3-N-hepanone", the acylating agent "p-nitrobenzenesulfonyl Acyl chloride" is replaced by "methylbenzenesulfonyl chloride", other processes are similar to Example 1, or slightly adjusted to alkaline conditions or solvents as required, N-methylsulfonyl-3,4-methyleneoxybenzene can be prepared And-3-N-heteroheptanone provides a source of raw materials for the formation of harringtonine D ring intermediates.

[0070] The operation process of synthesizing the D ring intermediate of harringtonine with N-methylsulfonyl-3,4-methyleneoxybenzo-3-N-heptanone is as follows:

[0071] The first step: removal of the amino protecting group: in a reactor containing 10mmol N-methylsulfonyl-3,4-methylenedioxybenzo-3-N-heteroheptanone in ...

Embodiment 3

[0079] The following is the synthetic route of 3,4-methylenedioxyphenethylamine to 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone, which can basically be divided into two processes:

[0080] First synthesize N-tert-butoxyformyl-3,4-methyleneoxybenzo-3-N-heptanone from 3,4-methylenedioxyphenethylamine; then synthesize N-tert-butyl Synthesis of 3,4-methyleneoxybenzo-3-N-heptanopyrrolidone from oxyformyl-3,4-methyleneoxybenzo-3-N-heptanone.

[0081] The following briefly describes the process of synthesizing N-tert-butoxyformyl-3,4-methyleneoxybenzo-3-N-heptanone from 3,4-methylenedioxyphenethylamine:

[0082] Step 1: Amino protection and N-H bond activation: Place a flask containing 1.652g (10mmol) of 3,4-methylenedioxyphenethylamine in 15mL ethanol solution (ethanol as the solvent) in an ice bath, add 10mmol tris Ethylamine 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 add...

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Abstract

The invention relates to an efficient synthetic method of a natural product harringtonine intermediate with D-ring. A raw material of N-acyl-3,4-methoxy methylene benzo-3-N-heterocyclic heptanone is subjected to three steps including deacylation, N-C acylation and carbonyl alpha-site alkylation to complete construction of the D-ring of harringtonine, namely 3,4-methoxy methylene benzo-3-N-heterocyclic heptanone and ketopyrrolidine. Products from each step can be purified by a recrystallization method, and the method has simple operation, total yield reaching 81% 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 a harringtonine intermediate. 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 large amount of it is use...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/147
CPCY02P20/55C07D491/147
Inventor 刘守信杨建华张晓芳张志伟杨毅华冯娟
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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