Method for producing 4,4-difluoro cyclohexyl formic ether by using counter cyclohexanone formic ether through fluorination

Abstract

The invention discloses a method for producing 4,4-difluoro cyclohexyl formic ether by using counter cyclohexanone formic ether through fluorination, which belongs to the technical field of chemical industry. The method comprises the steps of (1) respectively putting the counter cyclohexanone formic ether, sulfur tetrafluoride and hydrogen fluoride in a pressure kettle, starting blending, enabling the reaction temperature in the pressure kettle to be controlled at 0-80 DEG C, and enabling response time to be 0.5-24.0h; (2) opening an outlet valve of the pressure kettle, enabling surplus gas to be led in alkali liquid, and enabling the gas to be absorbed by the alkali liquid; (3) opening the pressure kettle, enabling reaction liquid to be poured in ice water, starting blending simultaneously, stewing and layering after completing pouring to separate an oil layer; and (4) adjusting the separated oil layer to be neutral by using the alkali liquid, stewing to remove a water layer, adding a desiccating agent to the oil layer, and filtering the desiccating agent to obtain the 4,4-difluoro cyclohexyl formic ether. The method synthesizes target products through a one-step reaction, and is simple in reaction, few in steps, few in secondary products, apt to obtain products with high purity through distillation, high in total recovery, good in safety and favorable for scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical industry, and particularly relates to a method for producing 4,4-difluorocyclohexyl formate by using p-cyclohexanone formate as a raw material through sulfur tetrafluoride fluorination. Background technique [0002] 4,4-difluorocyclohexyl carboxylate can be hydrolyzed to obtain 4,4-difluorocyclohexyl carboxylic acid, which is the raw material for the production of anti-HIV drug Maraviro. At present, there are few reports on the synthesis method of 4,4-difluorocyclohexyl carboxylate in China. The published methods for producing 4,4-difluorocyclohexyl carboxylate include: [0003] (1) The World Intellectual Property Organization, WO2008 / 132128 A2 discloses that p-cyclohexanone formate is used as a raw material to synthesize p-bis(trifluoroacetoxy)cyclohexane formate with trifluoroacetic anhydride, and then React with hydrogen fluoride to synthesize 4,4-difluorocyclohexyl carboxylate. The disadvan...

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Problems solved by technology

The disadvantages of this method are: a) the reaction time of the first step in this method is too long, it takes 45~166 hours, and there are still raw materials that do not react, and the residual amount of raw materials reaches 17%~3.2%; b) after the second step reaction, 4,4-difluorocyclohexyl carboxylate is not easy to separate;

[0004] (2) The Chinese invention patent ZL 02804233.6 and the European patent EP 1364938 applied by Asahi Glass Co., Ltd. disclosed that p-cyclohexanone carboxylate was used as a raw material, and the five Phosphorus chloride reacts to obtain ethyl 4,4-dichlorocyclohexyl carboxylate, and then reacts with hydrogen fluoride to obtain ethyl 4,4-difluorocyclohexyl carboxylate. The disadvantage of this method is: a) The first step produces a by-product monochlorocyclocyclic Ethyl hexene carboxylate, the by-product ratio reaches 2 / 3, so after the second step of fluorination, the overall yield is very low; b) The boiling point of the by-product fluoroolefins is close to that of the target product, so it is difficult to separate and difficult Obtain high-purity 4,4-difluorocyclohexyl carboxylate target product;

[0005] (3) Journal of Tetrahedron 46 (2005) 5005-5007 disclosed that p-cyclohexanone formate and DAST [diethylamine sulfur trifluoride, (C 2H5) 2NSF3] reaction to prepare the target product, the disadvantage is that DAST is easy to explode when heated, Safety issues are not conducive to large-scale production, and at the same time generate a by-product of monofluorocyclohexyl carboxylate that is difficult to separate

[0007] (1) The overall yield is low: the residual amount of raw materials in the prior art is relatively high, or the amount of by-products is relatively large, resulting in the target product 4,4-difluoro The overall yield of cyclohexyl carboxylate is low, wastes raw material, and production efficiency is low;

[0008] (2) Difficulty in separation: Since the boiling point of the by-product produced by the reaction is close to that of the target product 4,4-difluorocyclohexylcarboxylate, it is difficult to separate , unable to obtain high-purity 4,4-difluorocyclohexyl carboxylate;

[0009] (3) Poor safety: DAST is easy to explode when heated, and has poor safety issues, which is not conducive to large-scale production

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