AU2018100367A4

AU2018100367A4 - Fluconazole drugs intermediates 2,4-dinitrobenzoic acid synthesis method

Info

Publication number: AU2018100367A4
Application number: AU2018100367A
Authority: AU
Inventors: xiangliang peng
Original assignee: Chengdu Zhong Heng Hua Tie Technology Co Ltd
Current assignee: Chengdu Zhong Heng Hua Tie Technology Co Ltd
Priority date: 2017-03-26
Filing date: 2018-03-25
Publication date: 2018-05-17
Anticipated expiration: 2026-03-25
Also published as: GB201705522D0; CN108623466A

Abstract

Abstract Fluconazole drugs intermediates 2,4-dinitrobenzoic acid synthesis method, comprises the following steps: 2 mol 2-amino-4-nitro-6-hydroxybutylbenzene and 4-5 5 mol 2- (methoxymethoxy) ethanol solution were added to the reaction vessel, controlled the stirring speed at 90-120 rpm, raised the temperature of the solution to 40-50 C, added 3-4 mol trimethyl antimony by 3-5 times, the adding time was controlled in 70-80 min, continued to react 2-3 h, precipitated the solid, filtrated, washed with potassium bromide solution, washed with diphenyl ether solution, 10 washed with 2,3-dimethylaniline solution, reduced the temperature of the solution to 3-6 'C, precipitated the crystals again, dehydrated with dehydration, got the finished product 2,4-dinitrobenzoic acid.

Description

FIELD OF THE INVENTION

The present invention relates to fluconazole drugs intermediates 5 2,4-dinitrobenzoic acid synthesis method.

GENERAL BACKGROUND

2,4-dinitrobenzoic acid is mainly used as organic synthesis intermediates, it can be used for the synthesis of antifungal agents fluconazole. However, most of the existing synthetic methods are using potassium permanganate 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 fluconazole drugs intermediates

2,4-dinitrobenzoic acid synthesis method, comprises the following steps:

(i) 2 mol 2-amino-4-nitro-6-hydroxybutylbenzene and 4-5 mol 2(methoxymethoxy) ethanol solution were added to the reaction vessel, controlled the stirring speed at 90-120 rpm, raised the temperature of the solution to 40-50Ό, added 3-4 mol trimethyl antimony by 3-5 times, the adding time was controlled in 70-80 min, continued to react 2-3 h, precipitated the solid, filtrated, washed with potassium bromide solution, washed with diphenyl ether solution, washed with

2.3- dimethylaniline solution, reduced the temperature of the solution to 3-6 °C , precipitated the crystals again, dehydrated with dehydration, got the finished product

2.4- dinitrobenzoic acid; wherein, the mass fraction of the 2- (methoxymethoxy) ethanol solution in step (i) is 80-87%, the mass fraction of the potassium bromide solution described in step (i) is 15-20%, the mass fraction of the diphenyl ether solution in step (i) is 75 to 80%, the mass fraction of the 2,3-xylene solution described in step (i) is 85 to 90%, and the dehydrating agent described in step (i) is any one of anhydrous

2018100367 25 Mar 2018 chlorine calcium and phosphorus pentoxide.

Throughout the reaction process can be the following reaction formula:

nh₂ + CJIinO-i + CjH^Sb

no₂

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 10 invention are further illustrated:

fluconazole drugs intermediates 2,4-dinitrobenzoic acid synthesis method.

Embodiment 1 mol 2-amino-4-nitro-6-hydroxybutylbenzene and 4 mol 2- (methoxymethoxy) ethanol with a mass fraction of 80% were added to the reaction vessel to control the stirring rate at 90 rpm, the temperature of the solution was increased to 40 °C, and 3 mol trimethyl antimony was added in 3 times, the reaction time was controlled at 70 min and the reaction was continued for 2 h, the solid was precipitated and filtered, washed with potassium bromide solution with mass fraction of 15%, washed with the diphenyl ether solution with mass fraction of 75%, washed with the 2,3-dimethylaniline solution with a mass fraction of 85%, reduced the temperature of the solution to 3 °C , precipitated crystals again, dehydrated with anhydrous calcium chloride dehydration, got the finished product 2,4,5-dinitrobenzoic acid 385.84 g, yield of 91%.

Embodiment 2 mol 2-amino-4-nitro-6-hydroxybutylbenzene and 4.5 mol 2- (methoxymethoxy)

2018100367 25 Mar 2018 ethanol with a mass fraction of 83% were added to the reaction vessel to control the stirring rate at 110 rpm, the temperature of the solution was increased to 45 °C, and 3.5 mol trimethyl antimony was added in 4 times, the reaction time was controlled at 75 min and the reaction was continued for 2.5 h, the solid was precipitated and filtered, washed with potassium bromide solution with mass fraction of 18%, washed with the diphenyl ether solution with mass fraction of 78%, washed with the

2,3-dimethylaniline solution with a mass fraction of 87%, reduced the temperature of the solution to 4°C, precipitated crystals again, dehydrated with phosphorus pentoxide, got the finished product 2,4,5-dinitrobenzoic acid 394.32 g, yield of 93%.

Embodiment 3 mol 2-amino-4-nitro-6-hydroxybutylbenzene and 5 mol 2- (methoxymethoxy) ethanol with a mass fraction of 87% were added to the reaction vessel to control the stirring rate at 120 rpm, the temperature of the solution was increased to 50 °C, and 4 mol trimethyl antimony was added in 5 times, the reaction time was controlled at 80 min and the reaction was continued for 3 h, the solid was precipitated and filtered, washed with potassium bromide solution with mass fraction of 20%, washed with the diphenyl ether solution with mass fraction of 80%, washed with the

2,3-dimethylaniline solution with a mass fraction of 90%, reduced the temperature of the solution to 6°C, precipitated crystals again, dehydrated with anhydrous calcium chloride dehydration, got the finished product 2,4,5-dinitrobenzoic acid 411.28 g, yield of 97%.

2018100367 25 Mar 2018

Claims

1. Fluconazole drugs intermediates 2,4-dinitrobenzoic acid synthesis method, comprises the following steps:

(i) 2 mol 2-amino-4-nitro-6-hydroxybutylbenzene and 4-5 mol 25 (methoxymethoxy) ethanol solution were added to the reaction vessel, controlled the stirring speed at 90-120 rpm, raised the temperature of the solution to 40-50°C, added 3-4 mol trimethyl antimony by 3-5 times, the adding time was controlled in 70-80 min, continued to react 2-3 h, precipitated the solid, filtrated, washed with potassium bromide solution, washed with diphenyl ether solution, washed with

10 2,3-dimethylaniline solution, reduced the temperature of the solution to 3-6 °C, precipitated the crystals again, dehydrated with dehydration, got the finished product

2. Fluconazole drugs intermediates 2,4-dinitrobenzoic acid synthesis method according to claim 1 wherein the mass fraction of the 2,3-xylene solution described in step (i) is 85 to 90%.

2,4-dinitrobenzoic acid; wherein, the mass fraction of the 2- (methoxymethoxy) ethanol solution in step (i) is 80-87%, the mass fraction of the potassium bromide solution described in step (i) is 15-20%, the mass fraction of the diphenyl ether

15 solution in step (i) is 75 to 80%.

3. Fluconazole drugs intermediates 2,4-dinitrobenzoic acid synthesis method according to claim 1 wherein the dehydrating agent described in step (i) is any one of anhydrous chlorine calcium and phosphorus pentoxide.