AU2018100525A4

AU2018100525A4 - Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method

Info

Publication number: AU2018100525A4
Application number: AU2018100525A
Authority: AU
Inventors: Fei Peng
Original assignee: Chengdu Qie Si Te Technology Co Ltd
Current assignee: Chengdu Qie Si Te Technology Co Ltd
Priority date: 2017-06-16
Filing date: 2018-04-24
Publication date: 2018-06-21
Anticipated expiration: 2026-04-24
Also published as: CN108238996A; IES20180117A2; GB201709977D0

Abstract

Abstract The present invention discloses drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method, comprises the following steps:. 5 2-methyl-4-hydroxy-3,6-dimethylol toluene, 2,4-pentanedione solution were added to the reaction vessel, controlled the stirring speed, increase the solution temperature, added the gadolinium oxide in batches; washed with sodium sulfate solution for several times, washed with 2-methyl-2,4-pentanediol solution for several times, washed with 3-methylfuran solution for several times, adjusted the pH with the oxalic 10 acid solution, recrystallized in the 3-methyl-2-butanone solution, dehydrated with dehydration, got the finished product of p-carboxybenzenesulfonic amide.

Description

The present invention discloses drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method, comprises the following steps:.

2-methyl-4-hydroxy-3,6-dimethylol toluene, 2,4-pentanedione solution were added to the reaction vessel, controlled the stirring speed, increase the solution temperature, added the gadolinium oxide in batches; washed with sodium sulfate solution for several times, washed with 2-methyl-2,4-pentanediol solution for several times, washed with 3-methylfuran solution for several times, adjusted the pH with the oxalic acid solution, recrystallized in the 3-methyl-2-butanone solution, dehydrated with dehydration, got the finished product of p-carboxybenzenesulfonic amide.

2018100525 24 Apr 2018

Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method

FIELD OF THE INVENTION

The present invention relates to a method for preparing a pharmaceutical intermediate which belongs to the field of organic synthesis, more particularly, relates to drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method.

GENERAL BACKGROUND

P-carboxybenzenesulfonic amide is mainly used as an organic synthesis intermediate and for pharmaceutical synthesis. However, most of the existing synthetic methods are using the method that p-toluenesulfonamide reacts with potassium permanganate. This method of production requires potassium permanganate as reactant, due to the toxicity of potassium permanganate, and it’s corrosive, irritating properties cause human burns, the reactant attribute to high-risk chemicals, and the synthesis is complicated and the final yield is not very high. Therefore, it is necessary to propose a new synthetic method.

SUMMARY

Based on the technical problems of the background technology, the purpose of the present invention is to provide drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method, comprises the following steps:

A: 2-methyl-4-hydroxy-3,6-dimethylol toluene, 2,4-pentanedione solution were added to the reaction vessel, controlled the stirring speed at 150-180 rpm, increase the solution temperature to 40-50 °C, added the gadolinium oxide in batches;

B: increased the temperature of the solution to 70-78°C, reacted for 90-110 min, reduced the temperature of the solution to 10-16°C, washed with sodium sulfate solution for several times, washed with 2-methyl-2,4-pentanediol solution for several times, washed with 3-methylfuran solution for several times, adjusted the pH to 3-3.5 with the oxalic acid solution, recrystallized in the 3-methyl-2-butanone solution,

2018100525 24Apr2018 dehydrated with dehydration, got the finished product of p-carboxybenzenesulfonic amide.

Preferably, the 2,4-pentanedione solution has a mass fraction of 60-70%. Preferably, the mass fraction of the sodium sulfate solution is 35-40%.

Preferably, the 2-methyl-2,4-pentaned io 1 solution has a mass fraction of 75-80%. Preferably, the 3-methylfurau solution has a mass fraction of 80-86%.

Preferably, the mass fraction of oxalic acid solution is 30-35%.

Preferably, the mass fraction of 3-methyl-2-butanone solution is 85-92%. Preferably, the dehydrating agent is any one of anhydrous calcium sulfate and anhydrous calcium chloride.

Throughout the reaction process can be the following reaction formula:

Compared with the synthetic method disclosed in the background ail, the invention provides drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method, it is unnecessary to use potassium permanganate as reactant, avoiding the corrosiveness and irritation of the reactants and reduce the high-risk of chemicals, reducing intermediate Jinks reaction, decreasing the reaction time and improving the reaction yield, at the same time, the present invention provides a new synthetic route which has laid a good foundation for further enhancing the yield of the reaction.

DESCRIPTION OF THE DRAWINGS

Figure I is the ^HCNMR analysis spectrum of finished product p-carboxybenzenesulfonic amide.

Figure 2 is the atomic position marker map of finished product p -carbo xybenzene s u Ifon ic a m ide.

2018100525 24 Apr 2018

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples with reference to specific embodiments of the present invention are further illustrated:

Embodiment 1

Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method, comprises the following steps:

A: 2mol 2-methyl-4-hydroxy-3,6-dimethylol toluene, 3mol 2,4-pentanedione solution with a mass fraction of 60% were added to the reaction vessel, controlled the stirring speed at 150 rpm, increase the solution temperature to 40 °C, added 2 mol gadolinium oxide in 3 times;

B: increased the temperature of the solution to 70 °C, reacted for 90 min, reduced the temperature of the solution to 10°C, washed with sodium sulfate solution with a mass fraction of 35% for 3 times, washed with 2-methyl-2,4-pentanediol solution with a mass fraction of 75% for 5 times, washed with 3-methylfuran solution with a mass fraction of 80%for 6 times, adjusted the pH to 3 with the oxalic acid solution with a mass fraction of 30%, recrystallized in the 3-methyl-2-butanone solution with a mass fraction of 85%, dehydrated with anhydrous calcium sulfate dehydration, got the finished product of p-carboxybenzenesulfonic amide 357.78g, yield of 89%.

Embodiment 2

A: 2mol 2-methyl-4-hydroxy-3,6-dimethylol toluene, 3.5mol 2,4-pentanedione solution with a mass fraction of 60% were added to the reaction vessel, controlled the stirring speed at 160 rpm, increase the solution temperature to 45 °C, added 2.5 mol gadolinium oxide in 4 times;

B: increased the temperature of the solution to 73 °C, reacted for 100 min, reduced the temperature of the solution to 13 °C, washed with sodium sulfate solution with a mass fraction of 37% for 4 times, washed with 2-methyl-2,4-pentanediol solution with

2018100525 24 Apr 2018 a mass fraction of 77% for 6 times, washed with 3-methylfuran solution with a mass fraction of 83% for 7 times, adjusted the pH to 3.2 with the oxalic acid solution with a mass fraction of 32%, recrystallized in the 3-methyl-2-butanone solution with a mass fraction of 87%, dehydrated with anhydrous calcium chloride dehydration, got the finished product of p-carboxybenzenesulfonic amide 369.84g, yield of 92%.

Embodiment 3

A: 2mol 2-methyl-4-hydroxy-3,6-dimethylol toluene, 4mol 2,4-pentanedione solution with a mass fraction of 70% were added to the reaction vessel, controlled the stirring speed at 180 rpm, increase the solution temperature to 50 °C, added 3 mol gadolinium oxide in 6 times;

B: increased the temperature of the solution to 78°C, reacted for 110 min, reduced the temperature of the solution to 16 °C, washed with sodium sulfate solution with a mass fraction of 40% for 5 times, washed with 2-methyl-2,4-pentanediol solution with a mass fraction of 80% for 7 times, washed with 3-methylfuran solution with a mass fraction of 86%for 86 times, adjusted the pH to 3.5 with the oxalic acid solution with a mass fraction of 35%, recrystallized in the 3-methyl-2-butanone solution with a mass fraction of 92%, dehydrated with anhydrous calcium sulfate dehydration, got the finished product of p-carboxybenzenesulfonic amide 377.86g, yield of 94%.

Nuclear magnetic analysis of finished product p-carboxybenzenesulfonic amide, the ¹³CNMR analysis spectrum is shown in figure 1, the atomic position marker map of the p-carboxybenzenesulfonic amide is shown in figure 2, the analysis of data is shown in Table 1:

2018100525 24 Apr 2018

Table 1 Analysis data

Chemical	Peak area	Atomic
shift	integration	number
166.20	200	1
147.65	249	2
133.60	172	3
129.81	974	4
125.83	1000	5

The embodiments of the present invention are merely preferred embodiments of the present invention, but the range of the present invention is not limited this, and any person who is familiar with those skilled in the arts, within the technical range of the present invention. It is intended that the technical solution and its inventive concept be replaced or modified equivalently with reference to the range of the invention.

2018100525 24 Apr 2018

Claims

Claims

1. Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method, comprises the following steps:

A:
2-methyl-4-hydroxy-3,6-dimethylol toluene, 2,4-pentanedione solution were 5 added to the reaction vessel, controlled the stirring speed at 150-180 rpm, increase the solution temperature to 40-50 °C, added the gadolinium oxide in batches;

B: increased the temperature of the solution to 70-78°C, reacted for 90-110 min, reduced the temperature of the solution to 10-16°C, washed with sodium sulfate solution for several times, washed with 2-methyl-2,4-pentanediol solution for several

10 times, washed with 3-methylfuran solution for several times, adjusted the pH to 3-3.5 with the oxalic acid solution, recrystallized in the 3-methyl-2-butanone solution, dehydrated with dehydration, got the finished product of p-carboxybenzenesulfonic amide.

15 2. Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method according to claim 1 wherein the 2,4-pentanedione solution has a mass fraction of 60-70%.
3. Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis

20 method according to claim 1 wherein the mass fraction of the sodium sulfate solution is 35-40%.
4. Drug synthesis intermediates p-carboxybenzenesulfonic amide synthesis method according to claim 1 wherein the 2-methyl-2,4-pentanediol solution has a

25 mass fraction of 75-80%.

1/1

2018100525 24 Apr 2018 ppm

Figure 1

Figure 2