Preparation method of 2-methoxy-5-sulfamoylbenzoic acid

A technology of sulfonamidobenzoic acid and methoxybenzenesulfonamide, which is applied in the field of preparation of 2-methoxy-5-sulfonamidobenzoic acid, and can solve problems such as physical and environmental impacts and rare synthetic methods , to achieve the effect of improving selectivity, moderate price, and mild reaction conditions

Active Publication Date: 2020-05-05
苏州诚和医药化学有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] 2-methoxy-5-sulfonamidobenzoic acid is the key intermediate of sulpiride, but its synthesis method is rare, and there are foreign technical materials (Journal of Medicinal Chemistry, 1989, vol. 32, 4, p. 874–880) use 2-hydroxybenzaldehyde as raw material to prepare products through a series of reactions with dimethyl sulfate, potassium permanganate and chlorosulfonic acid, but the raw materials used in this method are dimethyl sulfate and chlorosulfonic acid etc. are highly toxic chemicals, which have a great impact on the human body and the environment

Method used

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  • Preparation method of 2-methoxy-5-sulfamoylbenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] A preparation method of 2-methoxy-5-sulfonamidobenzoic acid, comprising the following steps:

[0024] (1) Add 187 g (1.0 mol) of 4-methoxybenzenesulfonamide, 10.29 g of iron powder, 88 g (1.1 mol) of bromine and 2618 g of methylene chloride into the reactor, and heat up to 60 °C under stirring , reacted at this temperature for 6 h, naturally cooled to room temperature after the reaction was completed, filtered, and the filtrate was evaporated to remove the solvent under normal pressure to obtain 223.44 g of the crude product of 3-bromo-4-methoxybenzenesulfonamide, with a yield of 84.0%;

[0025] (2) Add 266 g (1.0 mol) of 3-bromo-4-methoxybenzenesulfonamide prepared in step (1), 13.3 g of cuprous iodide, and 180 g of cuprous cyanide (2.0 mol) and 2128 g of N,N-dimethylformamide, heated to 120°C under stirring conditions, reacted at this temperature for 12 h, cooled naturally to room temperature after the reaction, filtered, evaporated the filtrate to remove the solvent ...

Embodiment 2

[0033] Other steps are the same as in Example 1, except that the preparation method of 3-bromo-4-methoxybenzenesulfonamide in step (1) is as follows:

[0034] 187 g (1.0 mol) of 4-methoxybenzenesulfonamide, 8.42 g of iron powder, 80 g (1.0 mol) of bromine and 748 g of dichloromethane were added to the reactor, and the temperature was raised to 40 °C under stirring conditions. Reaction at high temperature for 4 h, naturally cooled to room temperature after the reaction, filtered, and the filtrate was evaporated to remove the solvent under normal pressure to obtain 198.97 g of 3-bromo-4-methoxybenzenesulfonamide crude product, the yield was 74.8%, and it was detected by HPLC The content is 99.21%, and the product can be directly used in the next reaction without further purification.

Embodiment 3

[0036]Other steps are the same as in Example 1, except that the preparation method of 3-bromo-4-methoxybenzenesulfonamide in step (1) is as follows:

[0037] Add 187 g (1.0 mol) of 4-methoxybenzenesulfonamide, 9.35 g of iron powder, 84 g (1.05 mol) of bromine and 1683 g of dichloromethane into the reactor, and raise the temperature to 50 °C under stirring conditions. Reaction at high temperature for 5 h, naturally cooled to room temperature after the reaction was completed, filtered, and the filtrate was evaporated to remove the solvent under normal pressure to obtain 206.42 g of 3-bromo-4-methoxybenzenesulfonamide crude product, yield 77.6%, detected by HPLC The content is 99.13%, and the product can be directly used in the next reaction without further purification.

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Abstract

The invention provides a preparation method of 2-methoxy-5-sulfamoylbenzoic acid, comprising the following steps: carrying out bromination reaction on 4-methoxybenzenesulfonamide and bromine under theaction of a reducing agent to obtain 3-bromo-4-methoxybenzenesulfonamide; carrying out substitution reaction on 3-bromo-4-methoxybenzenesulfonamide and cuprous cyanide under the action of a catalystto generate 3-cyano-4-methoxybenzenesulfonamide; carrying out alcoholysis on the 3-cyano-4-methoxybenzenesulfonamide and methanol under the catalysis of an acid to obtain 2-methoxy-5-sulfonamide methyl benzoate; hydrolyzing 2-methoxy-5-sulfonamide methyl benzoate under an alkaline condition, and then acidifying to obtain the 2-methoxy-5-sulfamoylbenzoic acid. The preparation method of the 2-methoxy-5-sulfamoylbenzoic acid is mild in reaction condition, simple in process and equipment, convenient to operate and environmentally friendly.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a preparation method of 2-methoxy-5-sulfonamidobenzoic acid. Background technique [0002] Sulpiride is an antipsychotic drug, a sulfonamide derivative, and a selective antagonist of central dopamine (D2, D3, D4) receptors. It has a good curative effect on symptoms such as apathy, withdrawal, depression, hallucinations, and delusions, but has no obvious sedative and antimanic effects. Also has better antiemetic effect. [0003] 2-methoxy-5-sulfonamidobenzoic acid is the key intermediate of sulpiride, but its synthesis method is rare, and there are foreign technical materials (Journal of Medicinal Chemistry, 1989, vol. 32, 4, p. 874–880) use 2-hydroxybenzaldehyde as raw material to prepare products through a series of reactions with dimethyl sulfate, potassium permanganate and chlorosulfonic acid, but the raw materials used in this method are dimethyl sulfa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/40C07C311/29
CPCC07C303/40C07C311/29
Inventor 陈晓强方欢
Owner 苏州诚和医药化学有限公司
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