A kind of continuous preparation method of tert-butyl 6-cyano-5-hydroxyl-3-oxohexanoate

Abstract

The invention relates to a continuous preparing method for 6-cyano-5-hydroxyl-3-oxohexanoate tert-butyl ester. The preparing method comprises the following steps that firstly, tert-butyl ester and strong alkali are consecutively added into a first reactor for a reaction, and a first reaction solution is obtained; secondly, the first reaction solution and 4-cyano-3-hydrosybutyric acid ethyl ester are consecutively added into a second reactor for a reaction, and a second reaction solution is obtained; thirdly, the second reaction solution and mineral acid are consecutively added into a third reactor for a reaction, a third reaction solution is obtained, the pH value of the third reaction solution is made to range from 2 to 3 by controlling the adding amount of mineral acid, the third reaction solution is subjected to layered extraction and desolvation, and then the 6-cyano-5-hydroxyl-3-oxohexanoate tert-butyl ester product is obtained. The preparing method has the advantages of being mild in reaction condition, high in yield, high in reaction efficiency, small in energy consumption, safe and environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis application, and in particular relates to a continuous preparation method of tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate. Background technique [0002] Atorvastatin is a novel inhibitor of HMG-CoA reductase, which can effectively reduce blood lipids. Because it has the advantages of high efficiency and low toxicity and side effects, it is favored by people and has broad application market prospects. And tert-butyl 6-cyano-5-hydroxyl-3-oxohexanoate (abbreviated as ATS-6, CAS No.: 125988-01-4) is an important core intermediate of atorvastatin, so the ATS- The improvement of the synthesis of 6 plays a very important role in the research of the preparation method of atorvastatin. [0003] The simplified chemical structure of ATS-6 is: [0004] [0005] The prior art has the following four types of methods to synthesize ATS-6: [0006] The first type of method: represented by CN1046737...

AI Technical Summary

Problems solved by technology

[0020] This process is mature and reliable, but has the following disadvantages: (1) the high-risk compounds related to lithium are operated in batch kettles, which causes the safety of the process to be difficult to control, and the industrialization cost is very high; (2) in the preparation of lithium diisopropylamide When reacting with α-tert-butyl lithium acetate, the reaction temperature is required to be between -70 and -50°C. Such a low temperature needs to be cooled with liquid nitrogen.

Due to the extremely low temperature of the gasified nitrogen during the cooling and use of liquid nitrogen, it is difficult to recycle, resulting in a very low utilization efficiency of the cold capacity of the raw material, and a large consumption of liquid nitrogen during use, resulting in high energy consumption. In addition, during use, liquid nitrogen accounts for more than 10% of the cost of ATS-6, resulting in high production costs

(3) The above steps are all strong exothermic reactions at low temperatures, which are difficult to control in batch operations, resulting in many side reactions. The yield of ATS-6 calculated with the important raw material 4-cyano-3-hydroxybutyrate ethyl ester The rate generally does not exceed 70%

A large amount of organic impurities constitute wastewater containing complex pollution factors, resulting in a substantial increase in the recovery and separation of the subsequent product ATS-6 and the treatment of the three wastes

(4) The above steps of reaction all adopt intermittent operation, the reaction time is long, and the operation efficiency is low

This patent realizes the continuous production of ATS-6 for the first time, but the reaction temperature adopted is too high, resulting in obviously bad reaction effect. 1 The yield of ATS-6 determined by HNMR analysis is only 72%, which is basically the same as that of traditional batch operation. Except for the obvious improvement of operation safety and operation efficiency, there is no obvious improvement in other aspects

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