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The method for the intermediate of separation and purification high-purity umeclidinium bromide

A separation and purification, high boiling point technology, applied in the direction of organic chemistry, can solve the problems of no cheap, efficient, high-quality separation and purification methods, increase the risk of hydrolysis of ester groups, and removal of difficult impurities, etc., to achieve clear appearance and stable content , High stability effect

Active Publication Date: 2021-05-18
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First of all, the solution or gas of hydrogen chloride has to be used in this scheme. No matter which scheme needs to face operational difficulties, at the same time, some impurities will also form salt during the process of salt formation, and it is difficult to remove such impurities in subsequent crystallization.
Moreover, the yield of this method is generally relatively low, and alkaline hydrolysis is also required in the subsequent use process, which increases the risk of ester group hydrolysis
[0013] In summary, 1-(2-chloroethyl)piperidine-4-carboxylate and quinuclidine-4-carboxylate currently have no cheap, efficient, high-quality separation and purification methods

Method used

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  • The method for the intermediate of separation and purification high-purity umeclidinium bromide
  • The method for the intermediate of separation and purification high-purity umeclidinium bromide
  • The method for the intermediate of separation and purification high-purity umeclidinium bromide

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Preparation of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate

[0056] Add 12 kg of ethyl 4-piperidinecarboxylate and dichloromethane in sequence in the reaction kettle, stir evenly, heat to the material temperature between 40-45°C, slowly feed ethylene oxide, control the internal temperature not to exceed 45°C, and react 5-7 hours, sampling in the control. After confirming that the reaction is complete, lower the temperature to 35°C, add triethylamine, and add thionyl chloride dropwise. After the dropwise addition is complete, keep warm and continue to react for 1-2 hours, and take samples for control. After confirming that the reaction is complete, add aqueous sodium carbonate solution dropwise, stir and stand still for phase separation, collect the organic phase, and distill under reduced pressure until no obvious liquid distills off to obtain the crude product of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate. Add 1.5 kg of β-(3,5-di-tert-butyl-4-hydroxyphenyl) n...

Embodiment 2

[0062] Preparation of 1-(2-chloroethyl)-4-piperidinecarboxylic acid methyl ester

[0063] Add 20 kg of methyl 4-piperidinecarboxylate and toluene in sequence in the reaction kettle, stir evenly, heat to the temperature of the material between 55°C and 65°C, slowly feed ethylene oxide, control the internal temperature not to exceed 65°C, and react for 5 -7 hours, sampling in the control. After confirming that the reaction is complete, lower the temperature to 45°C and add thionyl chloride dropwise. After the dropwise addition is complete, keep warm and continue the reaction for 1-2 hours, and take samples for control. After confirming that the reaction is complete, add aqueous sodium carbonate solution dropwise, stir and stand still for phase separation, collect the organic phase, and distill under reduced pressure until no obvious liquid distills off to obtain the crude product of methyl 1-(2-chloroethyl)-4-piperidinecarboxylate. Add 4 kg of dilauryl thiodipropionate and stir...

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Abstract

The invention discloses a method for synthesizing umeclidinium bromide intermediates 1-(2-chloroethyl)piperidine-4-carboxylate and quinuclidine-4-carboxylate. In this method, the crude products of intermediate 1-(2-chloroethyl) piperidine-4-formate and quinuclidine-4-carboxylate are purified by molecular distillation or vacuum distillation to obtain high-purity pharmaceutical intermediates. The purification cost can be effectively reduced and the yield can be increased by means of molecular distillation or vacuum rectification, and the product purity can be as high as 99% or more. The synthesis method of the present invention is adopted to prepare 1-(2-chloroethyl)piperidine-4-carboxylate and quinuclidine-4-carboxylate, the process route is short, the scale-up production is easy, and the yield is high. The invention has the characteristics of novel process, high yield, low cost, high product purity and the like.

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to a novel method for separating and purifying high-purity umeclidinium bromide intermediates. Background technique [0002] Umeclidinium bromide is a long-acting muscarinic receptor antagonist (LAMA), a new chemical entity of the me-better class, which can be used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). The structure of umeclidinium bromide is shown below: [0003] [0004] 1-(2-Chloroethyl)piperidine-4-carboxylate and quinuclidine-4-carboxylate are important intermediates of umeclidinium bromide, which have a broad market demand. [0005] [0006] Previously, in order to overcome the long reaction route, low reactivity, low conversion rate and many reaction by-products in the synthesis of 1-(2-chloroethyl)-4-piperidine carboxylate and quinuclidine-4-carboxylate And other shortcomings, designed and developed a new process route using 4-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/62C07D471/08
CPCC07D211/62C07D471/08
Inventor 吴桂宝周章涛叶伟平费安杰黎达生
Owner RAFFLES PHAMRMATECH CO LTD