AU2016102210A4

AU2016102210A4 - Chlormezanone drug intermediates p-chlorotoluene synthesis method

Info

Publication number: AU2016102210A4
Application number: AU2016102210A
Authority: AU
Inventors: xiangliang peng
Original assignee: Xiamen Lai En Si Te Information Technology Co Ltd
Current assignee: Xiamen Lai En Si Te Information Technology Co Ltd
Priority date: 2015-12-23
Filing date: 2016-12-23
Publication date: 2017-02-16
Anticipated expiration: 2024-12-23

Abstract

Chlormezanone drug intermediates p-chlorotoluene synthesis method, comprising the following steps: equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 500mL potassium chloride solution with a mass fraction of 70%--80%, 1.2mol p-aniline was slowly added, the solution was heated to 70--80'C until it was completely dissolved, the temperature was reduced to 20-25 C, 1.2-1.5mol potassium nitrite was added dropwise in 200ml aqueous solution, controlling the temperature of reaction at 17--20'C, KI test paper measuring the end of reaction; after the addition stirring was continued at 500-700 rpm stirring rate, generating diazonium salt (3), 200ml sodium chloride solution was added a certain amount of ferrous bromide with mass fraction of 40%--60%, the reaction was under the condition of 30-35 C for 4-5h, then the temperature was raised to 70 C for 50-70min, then the temperature of the solution is reduced to 35--40'C, the organic layer was separated, washed with washing solvent and salt solution, filtered, vacuum distillation, collecting fractions of 130--140 C, ultimately got p-chlorotoluene.

Description

Chlormezanone drug intermediates p-chlorotoluene synthesis method

TECHNICAL FIELD

The present invention relates tochlormezanone drug intermediates p-chlorotoluene synthesis method.

BACKGROUND ART

Chlormezanone is a kind of non-prescription drugs for sedative sleep aids; have effects onanxiolytic, sedative, hypnotic and relieving muscle tension, it also play a calming sleeping role on emotional stress, fear, anxiety, irritability for the sleepless. P-chlorotoluene as chlormezanone drug intermediates, its synthesis method is of great economic significance for improving drug synthesis product quality, reducing the by-product content.

SUMMARY OF THE INVENTION

Object of the present invention is to providechlormezanone drug intermediates p-chlorotoluene synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 500mL potassium chloride solution with a mass fraction of 70%--80%, 1.2mol p-aniline was slowly added, the solution was heated to 70—80 °C until it was completely dissolved, the temperature was reduced to 20-25 °C, 1.2-1.5mol potassium nitrite was added dropwise in 200ml aqueous solution, controlling the temperature of reactionat 17—20°C, KI test paper measuring theend of reaction; after the addition stirring was continued at 500-700 rpm stirring rate, generating diazonium salt (3), 200ml sodium chloride solutionwas added a certain amount of ferrous bromidewith mass fraction of 40%—60%,the reaction was under the condition of 30-35 °C for 4-5h, then the temperature was raised to 70 °C for 50-70min, then the temperature of the solution is reduced to 35—40 °C, the organic layer was separated, washed with washing solvent and salt solution, filtered, vacuum distillation, collecting fractions of130— 140°C, ultimately got p-chlorotoluene; wherein, the washing solvent in step (i) is anyone of dichloroethane solution, formic acid solution, ethanol solution, the salt solution for washing in step (i) is any one of magnesium chloride solution, potassium chloride solution, the vacuum distillation in step (i) has a pressure within 1.2-1.3kPa.

Throughout the reaction can be summarized as the following reaction formula:

ω ο) o)

Advantage of the present invention is that: reducing the reaction intermediate links, decreasing the reaction temperature and reaction time, improving the reaction yield.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THEINVENTION

Embodiment 1

Equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 500mL potassium chloride solution with a mass fraction of 70%, 1.2mol p-aniline was slowly added, the solution was heated to 70°C until it was completely dissolved, the temperature was reduced to 25 °C, 1.2mol potassium nitrite was added dropwise in 200ml aqueous solution, controlling the temperature of reaction at 17°C, KI test paper measuring the end of reaction; after the addition stirring was continued at 500 rpm stirring rate, generating diazonium salt (3), 200ml sodium chloride solution was added a certain amount of ferrous bromide with mass fraction of 40%, the reaction was under the condition of 30 °C for 4h, then the temperature was raised to 70 °C for 50min, then the temperature of the solution is reduced to 35 °C, the organic layer was separated, washed with dichloroethane and magnesium chloride solution, filtered, vacuum distillation at 1.2kPa, collecting fractions of 130—140 °C , ultimately got p-chlorotoluenel26.49g, yield 83%.

Embodiment 2

Equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 500mL potassium chloride solution with a mass fraction of 75%, 1.2mol p-aniline was slowly added, the solution was heated to 75 °C until it was completely dissolved, the temperature was reduced to 23 °C, 1.3mol potassium nitrite was added dropwise in 200ml aqueous solution, controlling the temperature of reaction at 18 °C, KI test paper measuring the end of reaction; after the addition stirring was continued at 600 rpm stirring rate, generating diazonium salt (3), 200ml sodium chloride solution was added a certain amount of ferrous bromide with mass fraction of 50%, the reaction was under the condition of 33°C for 4.5h, then the temperature was raised to 70 °C for 60min, then the temperature of the solution is reduced to 38°C, the organic layer was separated, washed with formic acid solutionand potassium chloride solution, filtered, vacuum distillation at 1.25kPa, collecting fractions of 130—140°C, ultimately got p-chlorotoluenel31.06g, yield 86%.

Embodiment 3

Equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 500mL potassium chloride solution with a mass fraction of 80%, 1.2mol p-aniline was slowly added, the solution was heated to 80°C until it was completely dissolved, the temperature was reduced to 20 °C, 1.5mol potassium nitrite was added dropwise in 200ml aqueous solution, controlling the temperature of reaction at 20 °C, KI test paper measuring the end of reaction; after the addition stirring was continued at 700 rpm stirring rate, generating diazonium salt (3), 200ml sodium chloride solution was added a certain amount of ferrous bromide with mass fraction of 60%, the reaction was under the condition of 35°C for 5h, then the temperature was raised to 70 °C for 70min, then the temperature of the solution is reduced to 40 °C, the organic layer was separated, washed with ethanol solution and potassium chloride solution, filtered, vacuum distillation at 1.3kPa, collecting fractions of 130—140 °C, ultimately got p-chlorotoluenel38.68g, yield 91%.

While a number of preferred embodiments have been described, it will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. Chlormezanone drug intermediates p-chlorotoluene synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 500mL potassium chloride solution with a mass fraction of 70%—80%, 1.2mol p-aniline was slowly added, the solution was heated to 70—80°C until it was completely dissolved, the temperature was reduced to 20-25 °C, 1.2-1.5mol potassium nitrite was added dropwise in 200ml aqueous solution, controlling the temperature of reaction at 17—20°C, KI test paper measuring the end of reaction; after the addition stirring was continued at 500-700 rpm stirring rate, generating diazonium salt (3), 200ml sodium chloride solution was added a certain amount of ferrous bromide with mass fraction of 40%—60%, the reaction was under the condition of 30-35 °C for 4-5h, then the temperature was raised to 70 °C for 50-70min, then the temperature of the solution is reduced to 35—40°C, the organic layer was separated, washed with washing solvent and salt solution, filtered, vacuum distillation, collecting fractions of 130—140, ultimately got p-chlorotoluene.

2. Chlormezanone drug intermediates p-chlorotoluene synthesis method according to claim 1 wherein the washing solvent in step (i) is any one of dichloroethane solution, formic acid solution, ethanol solution.

3. Chlormezanone drug intermediates p-chlorotoluene synthesis method according to claim 1 wherein the salt solution for washing in step (i) is any one of magnesium chloride solution, potassium chloride solution.

4. Chlormezanone drug intermediates p-chlorotoluene synthesis method according to claim 1 wherein the vacuum distillation in step (i) has a pressure within 1.2-1.3kPa.