AU2016102234A4

AU2016102234A4 - Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method

Info

Publication number: AU2016102234A4
Application number: AU2016102234A
Authority: AU
Inventors: ruer liao
Original assignee: Xiamen An Pu Dun Information Technology Co Ltd
Current assignee: Xiamen An Pu Dun Information Technology Co Ltd
Priority date: 2015-12-24
Filing date: 2016-12-23
Publication date: 2017-02-16
Anticipated expiration: 2024-12-23

Abstract

Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method, comprising the following steps: equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel , the reaction vessel was added 300-310ml triethylamine solution, 0.61-0.65mol stannous chloride, controlling the stirring speed 160-190rpm, the temperature of the solution is reduced to 3 - 5 0C, added slowly 0.5-0.65molp -naphthyl methyl ether (2), dropping 0.47 mol propionamide solution (3), controlled drop time in 50-80min, maintaining the reaction 8-9h, the solution temperature increased to 17-19 0C, standing 20-22h, the reaction solution was poured into 1.8L sodium bisulfite solution, controlled the solution temperature at 2--5 0C, steam distillation, until triethylamine completely steamed up, controlling the stirring speed 110-130rpm, allow the solution to cool, solidify oil, suction, washed with saline solution, dehydrated with dehydrating agent, recrystallized in cyclohexane solution, got yellow solid 6-methoxy-2-propionyl naphthalene.

Description

Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method

TECHNICAL FIELD

The present invention relates to naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method.

BACKGROUND ART

Naproxen and ibuprofen are similar in inhibition of prostaglandin synthesis, inhibition of human lymphocyte endonuclease, polymerase and ligase, thereby reducing the DNA and to exert anti-inflammatory effects. The drug's long half-life (13 to 14 hours), excretions slow, especially for patients who have severe morning stiffness. It is with probenecid to extend the half-life and plasma concentration. Same with ibuprofen, can cause a burning sensation in the stomach and gastrointestinal bleeding, ulcers caused by the occurrence of disease was 18%, induced asthma, bullous photosensitivity, optic neuritis, blurred vision, vision loss, edema, hemolytic anemia. After the reduction or withdrawal the side effects can be reduced or disappear. 6-methoxy-2-propionyl naphthalene as naproxen 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 naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method, comprising the following steps: (i) equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel , the reaction vessel was added 300-310ml triethylamine solution, 0.61-0.65mol stannous chloride, controlling the stirring speed 160-190rpm, the temperature of the solution is reduced to 3-5 °C, added slowly 0.5-0.65mol β-naphthyl methyl ether (2), dropping 0.47 mol propionamide solution (3), controlled drop time in 50-80min, maintaining the reaction 8-9h, the solution temperature increased to 17—19 °C, standing 20-22h, the reaction solution was poured into 1.8L sodium bisulfite solution, controlled the solution temperature at 2—5 °C, steam distillation, until triethylamine completely steamed up, controlling the stirring speed 110-130rpm, allow the solution to cool, solidify oil, suction, washed with saline solution, dehydrated with dehydrating agent, recrystallized in cyclohexane solution, got yellow solid 6-methoxy-2-propionyl naphthalene (1); wherein sodium bisulfite solution in step (i) has a mass fraction of 20-25%, saline solution in step (i) is any one of potassium nitrate solution or sodium sulfate solution; dehydrating agent in step (i) is any one of anhydrous calcium sulfate or calcium oxide; cyclohexane solution in step (i) has a mass fraction of 90-95%.

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 reflux condenser, a thermometer and a dropping funnel , the reaction vessel was added 300 ml triethylamine solution, 0.61 mol stannous chloride, controlling the stirring speed 160 rpm, the temperature of the solution is reduced to 3 °C, added slowly 0.5 ηιοΐβ- naphthyl methyl ether (2), dropping 0.47 mol propionamide solution (3), controlled drop time in 50 min, maintaining the reaction 8 h, the solution temperature increased to 17 °C, standing 20 h, the reaction solution was poured into 1.8L sodium bisulfite solution with a mass fraction of 20%, controlled the solution temperature at 2 °C, steam distillation, until triethylamine completely steamed up, controlling the stirring speed 110 rpm, allow the solution to cool, solidify oil, suction, washed with potassium nitrate solution, dehydrated with anhydrous calcium sulfate dehydrating agent, recrystallized in cyclohexane solution with a mass fraction of 90%, got yellow solid 6-methoxy-2-propionyl naphthalene 78.45 g, yield 78%.

Embodiment 2

Equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel , the reaction vessel was added 305 ml triethylamine solution, 0.63mol stannous chloride, controlling the stirring speed 180 rpm, the temperature of the solution is reduced to 4 °C, added slowly 0.6 ηιοΐβ- naphthyl methyl ether (2), dropping 0.47 mol propionamide solution (3), controlled drop time in 70 min, maintaining the reaction 8 h, the solution temperature increased to 18 °C, standing 21 h, the reaction solution was poured into 1.8L sodium bisulfite solution with a mass fraction of 23%, controlled the solution temperature at 3 °C, steam distillation, until triethylamine completely steamed up, controlling the stirring speed 120 rpm, allow the solution to cool, solidify oil, suction, washed with sodium sulfate solution, dehydrated with calcium oxide dehydrating agent, recrystallized in cyclohexane solution with a mass fraction of 91%, got yellow solid 6-methoxy-2-propionyl naphthalene 82.48 g, yield 82% .

Embodiment 3

Equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel , the reaction vessel was added 310 ml triethylamine solution, 0.65mol stannous chloride, controlling the stirring speed 190 rpm, the temperature of the solution is reduced to 5 °C, added slowly 0.65 ιηοΐβ- naphthyl methyl ether (2), dropping 0.47 mol propionamide solution (3), controlled drop time in 80 min, maintaining the reaction 9 h, the solution temperature increased to 19 °C, standing 23 h, the reaction solution was poured into 1.8L sodium bisulfite solution with a mass fraction of 25%, controlled the solution temperature at 5 °C, steam distillation, until triethylamine completely steamed up, controlling the stirring speed 130 rpm, allow the solution to cool, solidify oil, suction, washed with sodium sulfate solution, dehydrated with anhydrous calcium sulfate dehydrating agent, recrystallized in cyclohexane solution with a mass fraction of 92%, got yellow solid 6-methoxy-2-propionyl naphthalene 85.49 g, yield 85%.

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. Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method, comprising the following steps: (i) equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel , the reaction vessel was added 300-310ml triethylamine solution, 0.61-0.65mol stannous chloride, controlling the stirring speed 160-190rpm, the temperature of the solution is reduced to 3 - 5 °C, added slowly 0.5-0.65ηιο1β- naphthyl methyl ether (2), dropping 0.47 mol propionamide solution (3), controlled drop time in 50-80min, maintaining the reaction 8-9h, the solution temperature increased to 17—19 °C, standing 20-22h, the reaction solution was poured into 1.8L sodium bisulfite solution, controlled the solution temperature at 2—5 °C, steam distillation, until triethylamine completely steamed up, controlling the stirring speed 110-130rpm, allow the solution to cool, solidify oil, suction, washed with saline solution, dehydrated with dehydrating agent, recrystallized in cyclohexane solution, got yellow solid 6-methoxy-2-propionyl naphthalene (1); wherein sodium bisulfite solution in step (i) has a mass fraction of 20-25%.

2. Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method according to claim 1 wherein saline solution in step (i) is any one of potassium nitrate solution or sodium sulfate solution.

3. Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method according to claim 1 wherein dehydrating agent in step (i) is any one of anhydrous calcium sulfate or calcium oxide.

4. Naproxen drug intermediates 6-methoxy-2-propionyl naphthalene synthesis method according to claim 1 wherein cyclohexane solution in step (i) has a mass fraction of 90-95%.