AU2016102177A4

AU2016102177A4 - Loxoprofen sodium pharmaceutical intermediates 2-chloro-1-p-tolyl-1-propanone synthesis method

Info

Publication number: AU2016102177A4
Application number: AU2016102177A
Authority: AU
Inventors: donghong chu
Original assignee: Xiamen An Pu Dun Information Technology Co Ltd
Current assignee: Xiamen An Pu Dun Information Technology Co Ltd
Priority date: 2015-12-22
Filing date: 2016-12-22
Publication date: 2017-02-16
Anticipated expiration: 2024-12-22

Abstract

Loxoprofen sodium pharmaceutical intermediates 2-chloro-1-p-tolyl-1-propanone synthesis method comprises the following steps: equipped with a stiffer, a thermometer , a reflux condenser and a dropping funnel, the reaction vessel was added stannous chloride 2.4-2.43mol, 1.2 L toluene solution, the temperature of the solution is reduced to 2- 5 C, added 2.1 mol 2-chloride propionamide solution, dropwise time control for 3-4h, maintaining the stirring speed 180-210rpm, sustained 9-10h, the reaction solution was poured into 2L sodium chloride solution, the solution temperature is reduced to 2--4 C separated the organic layer, the aqueous layer was extracted 3-6 times with toluene solution, and the combined organic layer was successively washed with sodium carbonate solution, saline solution, distilled under reduced pressure to recover the solvent to got oil, the temperature of the solution is reduced to 12 - 15 C, solid precipitation, added cyclohexane solution, maintaining the stirring speed 200-230rpm, filtration, dehydration with dehydrating agent, got white solid2-chloro- 1 -p-tolyl- 1 -propanone.

Description

Loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method

TECHNICAL FIELD

The present invention relates to loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method.

BACKGROUND ART

The mechanism of loxoprofen sodium drug is by inhibition of prostaglandin synthesis; its role point is cyclooxygenase. Oral mucosal irritation is to the unchanged weak state, it is absorbed from the digestive tract, thereafter rapidly converted into a strong inhibition of prostaglandin biosynthesis effect, active metabolite trans-OH form (SRS ligand) play a role. It features mainly reflected in: more (clinical effect), faster (30 minutes of oral peak plasma concentration that is reached), safer (less side effects). 2-chloro-l-p-tolyl-l-propanone as loxoprofen sodium 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 loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer , a reflux condenser and a dropping funnel, the reaction vessel was added stannous chloride 2.4-2.43mol, 1.2 L toluene solution, the temperature of the solution is reduced to 2 - 5 °C, added 2.1 mol 2-chloride propionamide solution, drop wise time control for 3-4h, maintaining the stirring speed 180-210rpm, sustained 9-10h, the reaction solution was poured into 2L sodium chloride solution, the solution temperature is reduced to 2—4 °C separated the organic layer, the aqueous layer was extracted 3-6 times with toluene solution, and the combined organic layer was successively washed with sodium carbonate solution, saline solution, distilled under reduced pressure to recover the solvent to got oil, the temperature of the solution is reduced to 12 - 15 °C, solid precipitation, added cyclohexane solution, maintaining the stirring speed 200-230rpm, filtration, dehydration with dehydrating agent, got white solid2-chloro-1 -p-tolyl-1 -propanone; wherein the sodium chloride solution in step (i) has a mass fraction of 15-25%;saline solution in step (i) is any one of sodium sulfate solution or potassium bromide solution; distillation under reduced pressure in step (i) has a pressure of 1.7-1.8 kPa; cyclohexane solution in step (i) has a mass fraction of 95-98%; dehydrating agent in step (i) is any one of activated alumina or anhydrous magnesium sulfate.

The throughout reaction process can be summarized using the following reaction formula:

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

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

Embodiment 1

Equipped with a stirrer, a thermometer , a reflux condenser and a dropping funnel, the reaction vessel was added stannous chloride 2.4mol, 1.2 L toluene solution, the temperature of the solution is reduced to 2 °C, added 2.1 mol 2-chloride propionamide solution, dropwise time control for 3 h, maintaining the stirring speed 180 rpm, sustained 9 h, the reaction solution was poured into 2L sodium chloride solution with a mass fraction of 15%, the solution temperature is reduced to 2 °C separated the organic layer, the aqueous layer was extracted 3 times with toluene solution, and the combined organic layer was successively washed with sodium carbonate solution with a mass fraction of 35%, sodium sulfate solution, distilled under reduced pressure which has a pressure of 1.7 kPa to recover the solvent to got oil, the temperature of the solution is reduced to 12 - 15 °C, solid precipitation, added cyclohexane solution with a mass fraction of 95%, maintaining the stirring speed 200 rpm, filtration, dehydration with activated alumina dehydrating agent, got white solid2-chloro-l-p-tolyl-l-propanone 318.97g, yield 83%.

Embodiment 2

Equipped with a stirrer, a thermometer , a reflux condenser and a dropping funnel, the reaction vessel was added stannous chloride 2.41mol, 1.2 L toluene solution, the temperature of the solution is reduced to 3 °C, added 2.1 mol 2-chloride propionamide solution, dropwise time control for 3 h, maintaining the stirring speed 200 rpm, sustained 9 h, the reaction solution was poured into 2L sodium chloride solution with a mass fraction of 20 %, the solution temperature is reduced to 3 °C separated the organic layer, the aqueous layer was extracted 5 times with toluene solution, and the combined organic layer was successively washed with sodium carbonate solution with a mass fraction of 38%, sodium sulfate solution, distilled under reduced pressure which has a pressure of 1.7 kPa to recover the solvent to got oil, the temperature of the solution is reduced to 12 - 15 °C, solid precipitation, added cyclohexane solution with a mass fraction of 95%, maintaining the stirring speed 220 rpm, filtration, dehydration with anhydrous magnesium sulfate dehydrating agent, got white solid 2-chloro-l-p-tolyl-l-propanone330.50 g, yield 86%.

Embodiment 3

Equipped with a stirrer, a thermometer , a reflux condenser and a dropping funnel, the reaction vessel was added stannous chloride 2.43mol, 1.2 L toluene solution, the temperature of the solution is reduced to 5 °C, added 2.1 mol 2-chloride propionamide solution, dropwise time control for 10 h, maintaining the stirring speed 210 rpm, sustained 9 h, the reaction solution was poured into 2L sodium chloride solution with a mass fraction of 25 %, the solution temperature is reduced to 4 °C separated the organic layer, the aqueous layer was extracted 6 times with toluene solution, and the combined organic layer was successively washed with sodium carbonate solution with a mass fraction of 40%, sodium sulfate solution, distilled under reduced pressure which has a pressure of 1.8 kPa to recover the solvent to got oil, the temperature of the solution is reduced to 12 - 15 °C, solid precipitation, added cyclohexane solution with a mass fraction of 98%, maintaining the stirring speed 230 rpm, filtration, dehydration with activated alumina dehydrating agent, got white solid 2-chloro-l-p-tolyl-l-propanone349.71 g, 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. Loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer , a reflux condenser and a dropping funnel, the reaction vessel was added stannous chloride 2.4-2.43mol, 1.2 L toluene solution, the temperature of the solution is reduced to 2 - 5 °C, added 2.1 mol 2-chloride propionamide solution, drop wise time control for 3-4h, maintaining the stirring speed 180-210rpm, sustained 9-10h, the reaction solution was poured into 2L sodium chloride solution, the solution temperature is reduced to 2—4 °C separated the organic layer, the aqueous layer was extracted 3-6 times with toluene solution, and the combined organic layer was successively washed with sodium carbonate solution, saline solution, distilled under reduced pressure to recover the solvent to got oil, the temperature of the solution is reduced to 12 - 15 °C, solid precipitation, added cyclohexane solution, maintaining the stirring speed 200-230rpm, filtration, dehydration with dehydrating agent, got white solid2-chloro-l-p-tolyl-l-propanone; wherein the sodium chloride solution in step (i) has a mass fraction of 15-25%; saline solution in step (i) is any one of sodium sulfate solution or potassium bromide solution.

2. Loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method according to claim 1 wherein distillation under reduced pressure in step (i) has a pressure of 1.7-1.8 kPa.

3. Loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method according to claim 1 wherein cyclohexane solution in step (i) has a mass fraction of 95-98%.

4. Loxoprofen sodium pharmaceutical intermediates 2-chloro-l-p-tolyl-l-propanone synthesis method according to claim 1 wherein dehydrating agent in step (i) is any one of activated alumina or anhydrous magnesium sulfate.