Synthetic method of 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane

A technology for the synthesis of chloromethylpropane, which is applied in the field of synthesis of 1,1-dibromo-2,2-dicyclopropane, can solve the problems of harsh conditions, difficult amplification, low yield, etc., and achieve increased yield, The effect of reducing instantaneous heat generation and high total yield

Active Publication Date: 2020-02-07
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The technical problem to be solved by the present invention is that the existing method for synthesizing 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane has low yield, high cost, and difficult amplification

Method used

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  • Synthetic method of 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane
  • Synthetic method of 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane
  • Synthetic method of 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane

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Embodiment 1

[0037] The synthetic method of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane of the present invention comprises the following steps: 2-amino-2-hydroxymethylpropane-1,3-diol and thionyl chloride Chlorine substitution reaction to obtain (1,3-dichloro-2-(chloromethyl)propan-2-yl) aminosulfone ketone; then hydrolysis by concentrated sulfuric acid aqueous solution to obtain 1,3-dichloro-2-chloromethyl Propan-2-amine sulfate; followed by salt solution under alkaline conditions, and ring closure to obtain 2,2-bis(chloromethyl)aziridine; then react with sodium nitrite to obtain 3-chloro-2-chloro Methylprop-1-ene; Finally, it reacts with tribromomethane under basic conditions to generate 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane. In the present invention, 1,1-dibromo-2,2-bis(chloro Methyl) cyclopropane, the reaction formula that synthetic method involves is as figure 1 shown.

Embodiment 2

[0039] Based on embodiment 1, the specific synthetic method of the present invention is as follows:

[0040] Synthesis of step A, (1,3-dichloro-2-(chloromethyl)propane-2-yl)aminosulfone ketone: 5kg2-amino-2-hydroxymethylpropane-1,3-diol is dissolved in In toluene, add 25 kg of thionyl chloride under temperature control at 20-40 ° C, add 0.653 kg of pyridine after cooling down to 10-15 ° C, react at room temperature for 2 hours, and gradually increase the temperature to 105-110 ° C for 10 hours; after the reaction, 9.18 Toluene solution of kg (1,3-dichloro-2-(chloromethyl)propan-2-yl)aminosulfone, yield 100%.

[0041] Synthesis of step B, 1,3-dichloro-2-chloromethylpropan-2-amine sulfate: 9.18kg (1,3-dichloro-2-(chloromethyl)propane-2- Base) the toluene solution of aminosulfone ketone is controlled at a temperature not exceeding 25°C, and water and concentrated sulfuric acid aqueous solution are added; the temperature is raised to 85-95°C and reacted for 15-22 hours; , the aq...

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Abstract

The invention discloses a synthetic method of 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane. The method comprises the following steps that chlorine substitution reaction happens to 2-amino-2-hydroxylmethylpropane-1,3-diol to obtain (1,3-dichloro-2-(chloromethyl)propane-2-group)amino-sulfone-ketone; the (1,3-dichloro-2-(chloromethyl)propane-2-group)amino-sulfone-ketone is hydrolyzed through a concentrated sulfuric acid aqueous solution to obtain 1,3-dichloro-chloromethylpropyl-2-amine-sulfate; the 1,3-dichloro-chloromethyl-propyl-2-amine-sulfate is subjected to salt dissolution on the alkaline condition, and is subjected to cyclization to form 2,2-dual(chloromethyl)aziridine; reaction happens to 2,2-dual(chloromethyl)aziridine and sodium nitrite to form 3-chloro-2-chloromethyl-propyl-1-alkene; and the 3-chloro-2-chloromethyl-propyl-1-alkene reacts with bromoform on the alkaline condition to generate 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane. The synthetic method of 1,1-dibromo-2,2-dual(chloromethyl)-cyclopropane is simple and can be used for enlarged production.

Description

technical field [0001] The invention relates to an organic synthesis method, in particular to a synthesis method of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane. Background technique [0002] 1,1-Dibromo-2,2-bis(chloromethyl)cyclopropane is the core intermediate of the clinical candidate bicyclo(1.1.1)pentan-1-amine. Due to the shortage of bicyclo(1.1.1)pentan-1-amine due to a large number of purchases on the market, 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane is just a quick synthesis of bicyclo(1.1.1. 1) The core intermediate of pent-1-amine. However, the current schemes for the synthesis of the core fragment 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane have problems such as low yield and difficult amplification. [0003] Lynchand K.M. and DaileyW.P. (referring to J.Org.Chem.1995,60,4666) utilize pentylene glycol as raw material, adopt the route shown in following reaction formula to prepare 1,1-dibromo-2,2-bis( Chloromethyl) cyclopropane. The process step of this ...

Claims

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Application Information

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IPC IPC(8): C07C381/10C07C209/00C07C211/15C07D203/08C07C17/35C07C21/09C07C17/278C07C23/04
CPCC07C17/278C07C17/35C07C209/00C07C381/10C07D203/08C07C2601/02C07C211/15C07C21/09C07C23/04
Inventor 王银哈雷克瑞什南·科拉图尔·纳拉西姆汉·昆奇塔帕达姆拉格海温德·拉奥·莫莎拉赵振宇徐辉郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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