Method for synthesizing methyl 4-chloroacetoacetate or ethyl 4-chloroacetoacetate

Abstract

The invention discloses a method for synthesizing methyl 4-chloroacetoacetate or ethyl 4-chloroacetoacetate. The synthesis steps are as following: adding a first part of a solvent into a chlorinationkettle, cooling, adding a second part of a solvent and diketene mixed solution, and cooling; introducing chlorine in sections, adjusting the introduction flow rate of chlorine in each section, and after introduction of chlorine is finished, dropwise adding methanol or ethanol, and carrying out esterification reaction; after the esterification reaction is finished, desolventizing and rectifying thereaction liquid to obtain a finished product of methyl 4-chloroacetoacetate or ethyl 4-chloroacetoacetate; in the chlorination reaction process, the traditional constant-flow chlorine introduction mode is changed and is replaced by a segmented introduction and variable-flow-rate mode; compared with the traditional process, multiple times of production experience groping verification confirms thatthe chlorine addition mode of segmented introduction and variable flow rate has the advantages that few chlorine-containing by-products are generated in the synthesis process, the environmental pollution is reduced, and the yield and content of the prepared product are higher.

Description

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing methyl 4-chloroacetoacetate or ethyl 4-chloroacetoacetate. Background technique

[0002] Methyl 4-chloroacetoacetate or ethyl 4-chloroacetoacetate is an important pharmaceutical intermediate, which is used to synthesize drugs such as oxiracetam and dolutegravir. Among them, oxiracetam belongs to the treatment of cerebrovascular diseases, and dolutegravir is a new anti-AIDS drug. Therefore, methyl 4-chloroacetoacetate has broad market prospects as a pharmaceutical intermediate.

[0003] At present, the main conventional production method of methyl 4-chloroacetoacetate or ethyl 4-chloroacetoacetate in industrial production is: batch production, first dissolving diketene in a solvent, and cooling it to -30°C ~ -10°C , start stirring, feed a certain amount of chlorine gas into the reactor at a certain flow rate, keep it warm at -30°C to -10°C for...