IES87019B2

IES87019B2 - Pyranzinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method

Info

Publication number: IES87019B2
Application number: IES20180104A
Authority: IE
Inventors: Peng Xiangliang
Original assignee: Chengdu Zhong Heng Hua Tie Tech Co Ltd
Priority date: 2018-04-03
Filing date: 2018-04-03
Publication date: 2019-06-12
Also published as: IES20180104A2

Abstract

Pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method, comprises the following steps: 2 mol 5-methyl-8-bromo-1,4-dinaphthalene, 3-4 mol 4-carboxybenzoic acid, 30 g selenium dioxide were added to the reaction vessel, controlling the stirring speed at 90-120 rpm, stirring for 80-90min, standing for 2-3 h, absorbing the supernatant, adding potassium bromide solution to wash the lower material, controlling the stirring speed at 70-90rpm, raising the solution temperature to 60-70 °C , filter, merging the supernatant and filtrate, vacuum distillation, collecting fractions of 70-80°C, adding oxalic acid solution, adjusting the pH of the solution to 3-4, reducing the temperature to 5-10°C, crystals precipitated, filtration, filter cake washed with isopentane solution, washed with isobutyl propionate solution, dehydrated with dehydration, to obtain the product p-diazabenzene-2,3-dicarboxylic acid.

Description

Pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method FIELD OF THE INVENTION The present invention relates to pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method.

GENERAL BACKGROUND P-diazabenzene-2,3-dicarboxylic acid is an intermediate for the anti-tuberculosis drug pyrazinamide, however, most of the existing synthetic methods are using benzopyrazine as reactants, it is complicated and the final yield is not very high. Therefore, it is necessary to propose a new synthetic method for further improving the quality and yield of the product and reducing the byproduct content, it has important economic significance.

SUMMARY The purpose of the present invention is to provide pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method, comprises the following steps: (i) 2 mol 5-methyl-8-bromo-l,4-dinaphthalene, 3-4 mol 4-carboxybenzoic acid, 30 g selenium dioxide were added to the reaction vessel, controlling the stirring speed at 90-120 rpm, stirring for 80-90min, standing for 2-3 h, absorbing the supernatant, adding potassium bromide solution to wash the lower material, controlling the stirring speed at 70-90rpm, raising the solution temperature to 60-70°C, filter, merging the supernatant and filtrate, vacuum distillation, collecting fractions of 70-80°C, adding oxalic acid solution, adjusting the pH of the solution to 3-4, reducing the temperature to 5-10°C, crystals precipitated, filtration, filter cake washed with isopentane solution, washed with isobutyl propionate solution, dehydrated with dehydration, to obtain the product p-diazabenzene-2,3-dicarboxylic acid; wherein, the mass fraction of the potassium bromide solution described in step (i) is 10-15%, the mass fraction of oxalic acid solution in step (i) is 20-27%, the mass fraction of isopentane solution m step (i) is 50 to 55%, and the mass fraction of isobutyl propionate solution in step (i) is 60 to 68%, and the dehydrating agent described in step (i) is any one of anhydrous sodium sulfate and anhydrous potassium carbonate.

Throughout the reaction process can be the following reaction formula: SeO, - N. ,COOH Advantage of the present invention is that: reducing intermediate links reaction, decreasing the reaction time and improving the reaction yield.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The following examples with reference to specific embodiments of the present invention are further illustrated: pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method.

Embodiment 1 moles 5-methyl-8-bromo-1,4-dinaphthalene, 3 mol 4-carboxybenzoic acid and 30 g selenium dioxide were added to the reaction vessel, controlling the stirring speed at 90 rpm, stirring for 80min, standing for 2 h, absorbing the supernatant, adding potassium bromide solution with a mass fraction of 10% to wash the lower material, controlling the stirring speed at 70rpm, the temperature of the solution was raised to 60 C , filter, merging the supernatant and filtrate, vacuum distillation, collecting fractions of 70 °C, adding oxalic acid solution with a mass fraction of 20%, adjusting the solution pH to 3, reducing the temperature to 5°C, crystals precipitated, filter, the filter cake washed with isopentane solution with a mass fraction of 50%, washed with isobutyl propionate solution with a mass fraction 60% and dehydrated with anhydrous sodium sulfate dehydrating agent to obtain p-diazabenzene-2,3-dicarboxylic acid 292.32 g,yield of 87%.

Embodiment 2 mol 5-methyl-8-bromo-l,4-dinaphthalene, 3.5 mol 4-carboxybenzoic acid and 30 g selenium dioxide were added to the reaction vessel, controlling the stirring speed at 110 rpm, stirring for 85min, standing for 2.5 h, absorbing the supernatant, adding potassium bromide solution with a mass fraction of 12% to wash the lower material, controlling the stirring speed at 80rpm, the temperature of the solution was raised to 65 C , filter, merging the supernatant and filtrate, vacuum distillation, collecting fractions of 75’C, adding oxalic acid solution with a mass fraction of 23%, adjusting the solution pH to 3.5, reducing the temperature to 7“C, crystals precipitated, filter, the filter cake washed with isopentane solution with a mass fraction of 52%, washed with isobutyl propionate solution with a mass fraction 63% and dehydrated with anhydrous potassium carbonate dehydrating agent to obtain p-diazabenzene-2,3-dicarboxylic acid 305.76g, the yield of 91%.

Embodiment 3 mol 5-methyl-8-bromo-l,4-dinaphthalene, 4 mol 4-carboxybenzoic acid and 30 g selenium dioxide were added to the reaction vessel, controlling the stirring speed at 120 rpm, stirring for 90min, standing for 3 h, absorbing the supernatant, adding potassium bromide solution with a mass fraction of 15% to wash the lower material, controlling the stirring speed at 80rpm, the temperature of the solution was raised to 70 C , filter, merging the supernatant and filtrate, vacuum distillation, collecting fractions of 80”C, adding oxalic acid solution with a mass fraction of 27%, adjusting the solution pH to 4, reducing the temperature to 10°C, crystals precipitated, filter, the filter cake washed with isopentane solution with a mass fraction of 55%, washed with isobutyl propionate solution with a mass fraction 68% and dehydrated with anhydrous sodium sulfate dehydrating agent to obtain p-diazabenzene-2,3-dicarboxylic acid 3 12.48g, the yield of 93%.

Claims

1. Pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid synthesis method, comprises the following steps: (i) 2 mol 5-methyl-8-bromo-l,4-dinaphthalene, 3-4 mol 4-carboxybenzoic acid, 30 g selenium dioxide were added to the reaction vessel, controlling the stirring speed at 90-120 rpm, stirring for 80-90min, standing for 2-3 h, absorbing the supernatant, adding potassium bromide solution to wash the lower material, controlling the stirring speed at 70-90rpm, raising the solution temperature to 60-70°C, fdter, merging the supernatant and filtrate, vacuum distillation, collecting fractions of 70-80”C, adding oxalic acid solution, adjusting the pH of the solution to 3-4, reducing the temperature to 5-10‘‘C, crystals precipitated, filtration, filter cake washed with isopentane solution, washed with isobutyl propionate solution, dehydrated with dehydration, to obtain the product p-diazabenzene-2,3-dicarboxylic acid; wherein, the mass fraction of the potassium bromide solution described in step (i) is 10-15%, the mass fraction of oxalic acid solution in step (i) is 20-27%, the mass fraction of isopentane solution in step (i) is 50 to 55%.

2. Pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid according to claim 1 wherein the mass fraction of isobutyl propionate solution in step (i) is 60 to 68%.

3. Pyrazinamide drug intermediates p-diazabenzene-2,3-dicarboxylic acid according to claim 1 wherein the dehydrating agent described in step (i) is any one of anhydrous sodium sulfate and anhydrous potassium carbonate.