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Synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate

A technology of phenylaminosulfonyl and methyl benzoate, applied in the field of synthesis of 4-chloro-2-methyl benzoate, can solve the problems of high price, low product yield, long reaction steps and the like, and achieves safety Good, easy to obtain raw materials, simplified operation effect

Active Publication Date: 2016-04-20
山东诚汇双达药业有限公司
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Problems solved by technology

[0003] Methyl 4-chloro-2-(N-methyl-N-phenylsulfamoyl)benzoate is an important intermediate in the synthesis of tianuptine, and there is little research on its synthesis process
[0006] Route 1 uses few sources of main raw materials and is expensive. Although the reaction steps of this route are short, its applicability is poor; it is mainly reflected in the fact that chlorine gas is used in the reaction, and the safety in production is poor, and it is necessary to absorb tail gas with lye; Route 2 The reaction steps are longer and the use of potassium permanganate is not conducive to environmental protection, and the resulting product yield is low and unsatisfactory

Method used

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  • Synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate
  • Synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate
  • Synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate

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preparation example Construction

[0029] A kind of synthetic method of 4-chloro-2-(N-methyl-N-phenylsulfamoyl) benzoic acid methyl ester, comprises the steps: take 4-chloro-2-aminobenzoic acid as raw material, through esterification After the reaction, diazotization and Sandmeyer reaction were used to obtain methyl 4-chloro-2-sulfonic acid chlorobenzoate, and then condensed with N-methylaniline to obtain 4-chloro-2-(N-methyl-N- phenylsulfamoyl)benzoate methyl ester.

[0030] Its chemical reaction equation is as follows:

[0031]

Embodiment 1

[0033] In 400 grams of methanol, add 100 grams (0.58 mol) of 4-chloro-2-aminobenzoic acid, cool down in an ice-water bath, and slowly add 125 grams (1.05 mol) of thionyl chloride dropwise below 20°C, then dropwise add After completion, slowly raise the temperature to reflux, and after 12 hours of reflux reaction, concentrate under reduced pressure at 30~40°C and concentrate to dryness. Cool down to 0-5°C in an ice-water bath, without further treatment, add 300 grams of concentrated hydrochloric acid directly, add 150 grams (0.65 mol) of 30% sodium nitrite solution dropwise at 0-5°C, and continue at 0-5°C React at 5°C for 1 hour, then add 8.5 grams (0.05mol) of copper chloride, and add 120 grams of saturated sulfur dioxide in acetic acid solution dropwise at 5-10°C, and continue to react at 5-10°C for 1 hour after the dropwise addition is completed. After the reaction, add 500 g of dichloromethane and 200 g of water, stir for 15 minutes and then separate into layers, remove the...

Embodiment 2

[0035] In 400 grams of methanol, add 100 grams (0.58 mol) of 4-chloro-2-aminobenzoic acid, cool down in an ice-water bath, and slowly add 120 grams (1.00 mol) of thionyl chloride dropwise below 20°C, then dropwise add After completion, slowly raise the temperature to reflux, and after 10 hours of reflux reaction, concentrate under reduced pressure at 30~40°C and concentrate to dryness. Cool down to 0-5°C in an ice-water bath, without further treatment, add 300 grams of concentrated hydrochloric acid directly, add 150 grams (0.65 mol) of 30% sodium nitrite solution dropwise at 0-5°C, and continue at 0-5°C React at 5°C for 1 hour, then add 8.5 grams (0.05mol) of copper chloride, and add 120 grams of saturated sulfur dioxide in acetic acid solution dropwise at 5-10°C, and continue to react at 5-10°C for 1 hour after the dropwise addition is completed. After the reaction, add 500 g of dichloromethane and 200 g of water, stir for 15 minutes and then separate into layers, remove the...

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Abstract

The invention provides a synthetic method of 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate. The technical scheme is that 4-chloro-2-aminobenzoic acid is taken as a raw material and has an esterification reaction, a product is subjected to diazotization and the Sandmeyer reaction, methyl 4-chloro-2-(chlorosulfonyl)benzoate is prepared and subjected to condensation with N-methylaniline, and 4-chloro-2-(N-methyl-N-phenyl sulfamoyl) methyl benzoate is obtained. The synthetic method has the advantages of conciseness, high efficiency, mild conditions, no need of purification of an intermediate and simple operation, the total yield of three steps of reactions is as high as 65%, and the method is quite suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medical chemical synthesis, and in particular relates to a synthetic method of methyl 4-chloro-2-(N-methyl-N-phenylsulfamoyl)benzoate. Background technique [0002] Methyl 4-chloro-2-(N-methyl-N-phenylsulfamoyl)benzoate is one of the important intermediates of antidepressant Tianeptine. Thienuptine was developed by Servier International, France, and its trade name is Tatinol. It is a 5-hydroxytryptamine (5-HT) reuptake accelerator and is suitable for various depressions and anxiety symptoms related to depression. , and less adverse reactions, almost no adverse effects on the cardiovascular system, no damage to blood, liver, kidney function, and no sedative effect. [0003] Methyl 4-chloro-2-(N-methyl-N-phenylsulfamoyl)benzoate is an important intermediate in the synthesis of tianuptine, and there is little research on its synthesis process. At present, there are mainly 2 synthetic routes to the compound...

Claims

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Application Information

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IPC IPC(8): C07C303/38C07C311/21
CPCC07C227/18C07C303/02C07C303/38C07C311/21C07C309/89C07C229/56
Inventor 李跃东宋希军刘志文赵坤张智慧
Owner 山东诚汇双达药业有限公司
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