AU2016102284A4 - Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method - Google Patents
Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method Download PDFInfo
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- AU2016102284A4 AU2016102284A4 AU2016102284A AU2016102284A AU2016102284A4 AU 2016102284 A4 AU2016102284 A4 AU 2016102284A4 AU 2016102284 A AU2016102284 A AU 2016102284A AU 2016102284 A AU2016102284 A AU 2016102284A AU 2016102284 A4 AU2016102284 A4 AU 2016102284A4
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- ethyl ester
- acid ethyl
- malonic acid
- propafenone
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Abstract
Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method, comprising the following steps: equipped with a stirrer, a thermometer and a dropping funnel, the reaction vessel was added 4.6mol malonate terephthalate (2), 0.13 mol cuprous chloride, 13.6 mol sodium sulfite solution, 310ml nitromethane, controlling the agitation speed 130-160rpm, the solution temperature was raised to 60-65 0C, added 5.1-5.3mol benzylamine solution (3), after addition keeping reaction for 30-35h, the precipitated solid was filtered, the filter cake was washed with salt solution, washed with cyclohexane solution, vacuum distillation, collecting fractions of 90--95 0C, and recrystallized from acetonitrile solution , got crystalline benzyl malonic acid ethyl ester .
Description
Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method
TECHNICAL FIELD
The present invention relates to propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method.
BACKGROUND ART
Propafenone drug is sodium channel blockers, it has rapid antiarrhythmic effect. It has direct cell membrane stability, can reduce cardiac conduction fibers before and myocardial action potential maximum rate of rise of phase 0, so that conduction slowing, action potential duration and effective refractory period extended for a block or bypass and reverse conduction. It can improve cardiac excitability threshold, reducing the excitability of myocardial cells spontaneously, blocking the reentry path, eliminating reentry. There are slight inhibition of myocardial contractility and procaine and similar, suitable for oral premature ventricular contractions and paroxysmal supraventricular tachycardia. Benzyl malonic acid ethyl ester as propafenone 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 propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer and a dropping funnel, the reaction vessel was added 4.6mol malonate terephthalate (2), 0.13 mol cuprous chloride, 13.6 mol sodium sulfite solution, 310ml nitromethane, controlling the agitation speed 130-160rpm, the solution temperature was raised to 60—65 °C, added 5.1-5.3mol benzylamine solution (3), after addition keeping reaction for 30-35h, the precipitated solid was filtered, the filter cake was washed with salt solution, washed with cyclohexane solution, vacuum distillation, collecting fractions of 90—95 °C, and recrystallized from acetonitrile solution , got crystalline benzyl malonic acid ethyl ester (1); wherein sodium sulfite solution in step (i) has a mass fraction of 85-90%, salt solution in step (i) is any one of potassium nitrate solution or sodium bromide solution; cyclohexane solution in step (i) has a mass fraction of 80-85%, vacuum distillation in step (i) has a pressure of 0.95-0.98kPa, acetonitrile 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 thermometer and a dropping funnel, the reaction vessel was added 4.6mol malonate terephthalate (2), 0.13 mol cuprous chloride, 13.6 mol sodium sulfite solution with a mass fraction of 85%, 310ml nitromethane, controlling the agitation speed 130 rpm, the solution temperature was raised to 60 °C, added 5.1 mol benzylamine solution (3), after addition keeping reaction for 30 h, the precipitated solid was filtered, the filter cake was washed with potassium nitrate solution, washed with cyclohexane solution with a mass fraction of 80%, vacuum distillation with a pressure of 0.95 kPa, collecting fractions of 90—95 °C, and recrystallized from acetonitrile solution with a mass fraction of 90%, got crystalline benzyl malonic acid ethyl ester 874 g, yield 76%.
Embodiment 2
Equipped with a stirrer, a thermometer and a dropping funnel, the reaction vessel was added 4.6mol malonate terephthalate (2), 0.13 mol cuprous chloride, 13.6 mol sodium sulfite solution with a mass fraction of 87%, 310ml nitromethane, controlling the agitation speed 140 rpm, the solution temperature was raised to 62 °C, added 5.2 mol benzylamine solution (3), after addition keeping reaction for 32 h, the precipitated solid was filtered, the filter cake was washed with sodium bromide solution, washed with cyclohexane solution with a mass fraction of 82%, vacuum distillation with a pressure of 0.97 kPa, collecting fractions of 90—95 °C, and recrystallized from acetonitrile solution with a mass fraction of 92%, got crystalline benzyl malonic acid ethyl ester 931.5 g, yield 81%.
Embodiment 3
Equipped with a stirrer, a thermometer and a dropping funnel, the reaction vessel was added 4.6mol malonate terephthalate (2), 0.13 mol cuprous chloride, 13.6 mol sodium sulfite solution with a mass fraction of 85%, 310ml nitromethane, controlling the agitation speed 160 rpm, the solution temperature was raised to 65 °C, added 5.3 mol benzylamine solution (3), after addition keeping reaction for 35 h, the precipitated solid was filtered, the filter cake was washed with potassium nitrate solution, washed with cyclohexane solution with a mass fraction of 80%, vacuum distillation with a pressure of 0.98 kPa, collecting fractions of 90—95 °C, and recrystallized from acetonitrile solution with a mass fraction of 95%, got crystalline benzyl malonic acid ethyl ester 954.5 g, yield 83%.
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 (4)
1. Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method, comprising the following steps: (i) equipped with a stirrer, a thermometer and a dropping funnel, the reaction vessel was added 4.6mol malonate terephthalate (2), 0.13 mol cuprous chloride, 13.6 mol sodium sulfite solution, 310ml nitromethane, controlling the agitation speed 130-160rpm, the solution temperature was raised to 60—65 °C, added 5.1-5.3mol benzylamine solution (3), after addition keeping reaction for 30-35h, the precipitated solid was filtered, the filter cake was washed with salt solution, washed with cyclohexane solution, vacuum distillation, collecting fractions of 90—95 °C, and recrystallized from acetonitrile solution , got crystalline benzyl malonic acid ethyl ester (1); wherein sodium sulfite solution in step (i) has a mass fraction of 85-90%, salt solution in step (i) is any one of potassium nitrate solution or sodium bromide solution.
2. Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method according to claim 1 wherein cyclohexane solution in step (i) has a mass fraction of 80-85%.
3. Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method according to claim 1 wherein vacuum distillation in step (i) has a pressure of 0.95-0.98kPa.
4. Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method according to claim 1 wherein acetonitrile solution in step (i) has a mass fraction of 90-95%.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015109925676 | 2015-12-25 | ||
| CN201510992567.6A CN105601513A (en) | 2015-12-25 | 2015-12-25 | Synthesis method of propafenone drug intermediate benzyl malonic acid diethyl ester |
| CN201610827802.9A CN106518673A (en) | 2015-12-25 | 2016-09-18 | Synthesis method of propafenone drug intermediate benzylmalonic acid diethyl ester |
| CN2016108278029 | 2016-09-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2016102284A4 true AU2016102284A4 (en) | 2017-02-23 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2016102284A Ceased AU2016102284A4 (en) | 2015-12-25 | 2016-12-24 | Propafenone drug intermediates benzyl malonic acid ethyl ester synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU2016102284A4 (en) |
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2016
- 2016-12-24 AU AU2016102284A patent/AU2016102284A4/en not_active Ceased
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| FGI | Letters patent sealed or granted (innovation patent) | ||
| MK22 | Patent ceased section 143a(d), or expired - non payment of renewal fee or expiry |