AU2016102203A4

AU2016102203A4 - Clofibrate drug intermediates p-chlorophenol synthesis method

Info

Publication number: AU2016102203A4
Application number: AU2016102203A
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

Clofibrate drug intermediates p-chlorophenol synthesis method, comprising the following steps: equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 700mL sodium chloride solution with a mass fraction of 60%-70%,2mol p-aminophenol was slowly added, stirred at a low rate until completely dissolved, the temperature of the solution was reduced to 8-12C, dripping 1.5-2mol potassium hydrogen sulfate in 200ml water, maintaining the temperature at 15-20C during the process, KI test paper measuring the end of the reaction, generating diazonium salt (3); the diazonium salt (3) generating in the step (i) was added to a 200mL concentrated potassium chloride solution containing 1.5mol chromous bromide, warmed to 120--130C, refluxed 30-40min, the solution is reduced to a temperature of 30--35C, the oil was separated and the aqueous layer extracted with a solvent, the solvent combined with the oil layer was distilled under reduced pressure to recover the solvent, collecting fractions of 110--125C, ultimately got p-chlorophenol.

Description

Clofibrate drug intermediates p-chlorophenol synthesis method

TECHNICAL FIELD

The present invention relates to clofibrate drug intermediates p-chlorophenol synthesis method.

BACKGROUND ART

Clofibrate can reduce platelet adhesion; it can reduce platelet sensitivity to ADP and epinephrine and inhibit ADP-induced platelet aggregation. It also extended the lifetime of platelets. It has the nature of the ester, has generated hydroxamic potassium with hydroxylamine hydrochloride in alkaline conditions, after acidification twice, adding an aqueous solution of ferric chloride to form hydroxamic acid iron, present purple.With lipid-lowering effect, it is applied to hypertriglyceridemia, hypercholesterolemia and mixed hyperlipidemia. P-chlorophenol as clofibrate 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 provide clofibrate drug intermediates p-chlorophenol synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 700mL sodium chloride solutionwith a mass fraction of 60% -70%, 2mol p-aminophenol was slowly added, stirred at a low rate until completely dissolved, the temperature of the solution was reduced to 8—12°C, dripping 1.5-2mol potassium hydrogen sulfate in 200ml water, maintain the temperature at 15-20°C during the process, KI test paper measuring the end of the reaction, generating diazonium salt (3); (ii) the diazonium salt (3) generating in the step (i) was added to a 200mL concentrated potassium chloride solution, containing 1.5mol chromous bromide, warmed to 120—130°C, refluxed 30-40min, the solution is reduced to a temperature of 30-35 °C, the oil was separated and the aqueous layer extracted with a solvent, the solvent combined with the oil layer was distilled under reduced pressure to recover the solvent, collecting fractions of 110—125 °C, ultimately got p-chlorophenol; wherein, p-aminophenol added slowly in step (i) and it’s adding speed was 0.5-0.8mol per hour, the stirring speed of low speed agitation in step (i) is the 300-500rpm, extraction for the aqueous layer in step (ii), the solvent used is any one of ethanol, methyl ether, dichloromethane; vacuum distillation for recovering solvent in step (ii), has a pressure of 1.2-1.3kPa.

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

a) 0) (i)

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 700mL sodium chloride solution with a mass fraction of 60%, 2mol p-aminophenol was slowly added, stirred at a low rate until completely dissolved, the temperature of the solution was reduced to 8°C, dripping 1.5mol potassium hydrogen sulfate in 200ml water, maintaining the temperature at 15°C during the process, KI test paper measuring the end of the reaction, generating diazonium salt (3); the diazonium salt (3) was added to a 200mL concentrated potassium chloride solution containing 1.5mol chromous bromide, warmed to 120°C, refluxed 30min, the solution is reduced to a temperature of 30°C, the oil was separated and the aqueous layer extracted with ethanol solvent, the solvent combined with the oil layer was distilled under reduced pressure 1.2kPa to recover the solvent, collecting fractions of 110—125°C, ultimately got p-chlorophenol 190.92g, yield 74%.

Embodiment 2

Equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 700mL sodium chloride solution with a mass fraction of 65%, 2mol p-aminophenol was slowly added, stirred at a low rate until completely dissolved, the temperature of the solution was reduced to 10°C, dripping 1.8mol potassium hydrogen sulfate in 200ml water, maintaining the temperature at 18°C during the process, KI test paper measuring the end of the reaction, generating diazonium salt (3); the diazonium salt (3) was added to a 200mL concentrated potassium chloride solution containing 1.5mol chromous bromide, warmed to 125°C, refluxed 35min, the solution is reduced to a temperature of 33°C, the oil was separated and the aqueous layer extracted with methyl ether solvent, the solvent combined with the oil layer was distilled under reduced pressure 1.3kPa to recover the solvent, collecting fractions of 110—125°C, ultimately got p-chlorophenol 201.24g, yield 78%.

Embodiment 3

Equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 700mL sodium chloride solution with a mass fraction of 70%, 2mol p-aminophenol was slowly added, stirred at a low rate until completely dissolved, the temperature of the solution was reduced to 12°C, dripping 2mol potassium hydrogen sulfate in 200ml water, maintaining the temperature at 20°C during the process, KI test paper measuring the end of the reaction, generating diazonium salt (3); the diazonium salt (3) generating in the step (i) was added to a 200mL concentrated potassium chloride solution containing 1.5mol chromous bromide, warmed to 130°C, refluxed for 40min, the solution is reduced to a temperature of 35°C, the oil was separated and the aqueous layer extracted with dichloromethane solvent, the solvent combined with the oil layer was distilled under reduced pressure 1.2kPa to recover the solvent, collecting fractions of 110—125°C, ultimately got p-chlorophenol 214.14g, yield 83%.

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

Claims

1. Clofibrate drug intermediates p-chlorophenol synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer, a dropping funnel, a reaction vessel was added 700mL sodium chloride solution with a mass fraction of 60% -70%, 2mol p-aminophenol was slowly added, stirred at a low rate until completely dissolved, the temperature of the solution was reduced to 8—12°C, dripping 1.5-2mol potassium hydrogen sulfate in 200ml water, maintaining the temperature at 15-20°C, during the process, KI test paper measuring the end of the reaction, generating diazonium salt (3); (ii) the diazonium salt (3) generating in the step (i) was added to a 200mL concentrated potassium chloride solution containing 1.5mol chromous bromide, warmed to 120—130°C, refluxed for 30-40min, the solution is reduced to a temperature of 30-35°C, the oil was separated and the aqueous layer extracted with a solvent, the solvent combined with the oil layer was distilled under reduced pressure to recover the solvent, collecting fractions of 110—125°C, ultimately got p-chlorophenol; wherein, p-aminophenol added slowly in step (i) and it’s adding speed was 0.5-0.8mol per hour.

2. Clofibrate drug intermediates p-chlorophenol synthesis method according to claim 1 wherein the stirring speed of low speed agitation in step (i) is the 300-500rpm.

3. Clofibrate drug intermediates p-chlorophenol synthesis method according to claim 1 wherein extraction for the aqueous layer in step (ii), the solvent used is any one of ethanol, methyl ether, dichloromethane.

4. Clofibrate drug intermediates p-chlorophenol synthesis method according to claim 1 wherein vacuum distillation for recovering solvent in step (ii) has a pressure of 1.2-1.3kPa.