Method for producing p-acetamidobenzenesulfonyl chloride based on double-temperature-zone two-stage method of continuous flow reaction

Abstract

The invention relates to a method for producing p-acetamidobenzenesulfonyl chloride by a double-temperature-zone two-stage method based on a continuous flow reaction. The method comprises the following steps: reacting acetanilide with chlorosulfonic acid to generate p-acetamidobenzenesulfonic acid, and reacting p-acetamidobenzenesulfonic acid with chlorosulfonic acid to generate p-acetamidobenzenesulfonyl chloride. The characteristics of efficient mass transfer and heat transfer, controllable reaction time and reaction temperature, continuous production, intrinsic safety and the like of a micro-channel reactor are utilized, a double-temperature-zone micro-channel reactor is used, and a first reaction section adopts a lower temperature, so that generation of a para-sulfonation product is facilitated, and in the second reaction stage, high temperature is adopted, so that sulfonyl chloride is generated. The method solves the problems of low temperature, slow reaction and generation of by-products due to high temperature, safety accidents caused by release of a large amount of reaction heat in the production process are avoided, the stable production is ensured by controlling the reaction time and the reaction temperature, and pollution caused by excessive chlorosulfonic acid used in the batch production process is reduced.

Description

technical field [0001] The present invention relates to a method for realizing the chlorosulfonation of aryl compounds with a dual-temperature zone continuous flow reactor, specifically a highly selective and efficient synthesis of p-acetamidobenzene with acetanilide and chlorosulfonic acid in an inert organic solvent The sulfonyl chloride method. Background technique [0002] Acetamidobenzenesulfonyl chloride is a key intermediate of several sulfonamide drugs as follows: [0003] [0004] The current mainstream production methods all use acetanilide and excess chlorosulfonic acid. Although many documents have reported other methods, such as: CN106866466, CN106810476, CN108640860, CN108640862 all report the synthesis of acetamidobenzenesulfonyl chloride with sulfur trioxide as sulfonating reagent and other sulfonic acid chloride reagents; CN108558712 utilizes chlorine and sulfur dioxide to complete the synthesis of p-acetamidobenzenesulfonyl chloride. Although these me...

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Problems solved by technology

Regardless of the feeding method, there are difficulties in the transfer of heat, especially when chlorosulfonic acid is added to the solid acetanilide system, the temperature control is not good, and the brown oil that is often obtained has more by-products and lower yields.

CN108640859, CN108530324, CN101613308, CN108276346, CN108558713, CN103694151, CN102304070, CN105237446 and "Henan Chemical Industry" 2002, (4) 20-22, and other documents have used the reaction solvent, which has played a positive role in the heat transfer and temperature control of the reaction. , although in some literatures, the amount of chlorosulfonic acid is insufficient or the problem of reaction temperature control causes the yield not to be outstanding, but the use of solvent has greatly improved the control of the reaction and the quality of the product

The traditional tank reactor is not efficient enough to remove the heat of reaction, and large-scale production still requires a long reaction time, which affects production efficiency and leads to an increase in by-products

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