AU2016102310A4 - Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester synthesis method - Google Patents
Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester synthesis method Download PDFInfo
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Abstract
Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 methyl 2 oxo benzoic acid methyl ester synthesis method , comprising the following steps: equipped with a stirrer, thermometer and reflux condenser, the reaction vessel was added 0.13mol 3-methoxy-4,5-dihydroxybenzoic acid methyl ester(2), 300ml nitromethane solution, 0.16-0.19mol diamino methane solution (3), 500ml propionitrile solution, controlling the stirring speed 130-180rpm, the solution temperature is raised to 65-70 C, continued the reaction for 5-7 h, added 300ml sodium sulfite solution, the reaction was refluxed for 4-6h, cooled, added 200ml sodium chloride solution, the organic layer was separated, the aqueous layer was washed with ethylenediamine solution, the combined organic layer was washed with salt solution, washed with cyclohexanone solution, dehydrated with dehydrating agent, recrystallized in the p-xylene solution, got crystals of 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester.
Description
Biphenyldicarboxylate drug intermediates 3 - methoxy - 4,5 - methyl 2 oxo benzoic acid methyl ester synthesis method
TECHNICAL FIELD
The present invention relates to biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester synthesis method.
BACKGROUND ART
Biphenyldicarboxylate is for the treatment of viral hepatitis and drug-induced liver injury which is caused by elevated transaminase commonly used drugs. In past it can protect the liver cells to increase the liver's detoxification function of the pharmacological effects. Especially its role in reducing enzyme, the effect is obvious for low toxicity, side effects. Purpose: anti-hepatitis drugs for chronic persistent hepatitis; chronic active hepatitis: fatty liver disease. Biphenyldicarboxylate outstanding advantage is reducing enzyme effect rapid, and convenient, rare adverse reactions. But experience shows that long-term clinical applications, DDB major decrease ALT, and it has no significant effects on other liver enzymes, at least inconsistent effects on ALT. 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester as biphenyldicarboxylate 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 biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester synthesis method , comprising the following steps: (i) equipped with a stirrer, thermometer and reflux condenser, the reaction vessel was added 0.13mol 3-methoxy-4,5-dihydroxybenzoic acid methyl ester(2), 300ml nitromethane solution, 0.16-0.19mol diamino methane solution (3), 500ml propionitrile solution, controlling the stirring speed 130-180rpm, the solution temperature is raised to 65—70 °C, continued the reaction for 5-7 h, added 300ml sodium sulfite solution, the reaction was refluxed for 4-6h, cooled, added 200ml sodium chloride solution, the organic layer was separated, the aqueous layer was washed with ethylenediamine solution, the combined organic layer was washed with salt solution, washed with cyclohexanone solution, dehydrated with dehydrating agent, recrystallized in the p-xylene solution, got crystals of 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester (1); wherein, nitromethane solution in step (i) has a mass fraction of 30-36%; diamino methane solution in step (i) has a mass fraction of 60-66%; propionitrile solution in step (i) has a mass fraction of 50-56%, sodium sulfite solution in step (i) has a mass fraction of 35-40%, ethylenediamine solution in step (i) has a mass fraction of 70-75%; salt solution in step (i) is any one of ammonium bromide solution or sodium iodide solution; cyclohexanone solution in step (i) has a mass fraction of 75-80%, dehydrating agent in step (i) is any one of anhydrous calcium sulfate or anhydrous potassium carbonate; p-xylene in step (i) has a mass fraction of 90-98%.
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, thermometer and reflux condenser, the reaction vessel was added 0.13mol 3-methoxy-4,5-dihydroxybenzoic acid methyl ester(2) , 300ml nitromethane solution with a mass fraction of 30%, 0.16mol diamino methane solution (3) with a mass fraction of 60%, 500ml propionitrile solution with a mass fraction of 50%, controlling the stirring speed 130 rpm, the solution temperature is raised to 65 °C, continued the reaction for 5 h, added 300ml sodium sulfite solution with a mass fraction of 35%, the reaction was refluxed for 4h, cooled, added 200ml sodium chloride solution, the organic layer was separated, the aqueous layer was washed with ethylenediamine solution with a mass fraction of 70%, the combined organic layer was washed with ammonium bromide solution, washed with cyclohexanone solution with a mass fraction of 75%, dehydrated with anhydrous calcium sulfate dehydrating agent, recrystallized in the p-xylene solution with a mass fraction of 90%, got crystals of 3-methoxy-4, 5-methyl 2 oxo benzoic acid methyl ester 21.57 g, yield 79%.
Embodiment 2
Equipped with a stirrer, thermometer and reflux condenser, the reaction vessel was added 0.13mol 3-methoxy-4,5-dihydroxybenzoic acid methyl ester(2) , 300ml nitromethane solution with a mass fraction of 33%, 0.17mol diamino methane solution (3) with a mass fraction of 62%, 500ml propionitrile solution with a mass fraction of 53%, controlling the stirring speed 160 rpm, the solution temperature is raised to 67 °C, continued the reaction for 6 h, added 300ml sodium sulfite solution with a mass fraction of 37%, the reaction was refluxed for 5h, cooled, added 200ml sodium chloride solution, the organic layer was separated, the aqueous layer was washed with ethylenediamine solution with a mass fraction of 72%, the combined organic layer was washed with ammonium bromide solution, washed with cyclohexanone solution with a mass fraction of 77%, dehydrated with anhydrous calcium sulfate dehydrating agent, recrystallized in the p-xylene solution with a mass fraction of 92%, got crystals of 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester 22.39 g, yield 82%.
Embodiment 3
Equipped with a stirrer, thermometer and reflux condenser, the reaction vessel was added 0.13mol 3-methoxy-4,5-dihydroxybenzoic acid methyl ester(2) , 300ml nitromethane solution with a mass fraction of 36%, 0.17mol diamino methane solution (3) with a mass fraction of 66%, 500ml propionitrile solution with a mass fraction of 56%, controlling the stirring speed 180 rpm, the solution temperature is raised to 70°C, continued the reaction for 6 h, added 300ml sodium sulfite solution with a mass fraction of 37%, the reaction was refluxed for 5h, cooled, added 200ml sodium chloride solution, the organic layer was separated, the aqueous layer was washed with ethylenediamine solution with a mass fraction of 75%, the combined organic layer was washed with ammonium bromide solution, washed with cyclohexanone solution with a mass fraction of 80 %, dehydrated with anhydrous calcium sulfate dehydrating agent, recrystallized in the p-xylene solution with a mass fraction of 92%, got crystals of 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester 22.39 g, yield 82%.
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. Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester synthesis method , comprising the following steps: (i) equipped with a stirrer, thermometer and reflux condenser, the reaction vessel was added 0.13mol 3-methoxy-4,5-dihydroxybenzoic acid methyl ester(2), 300ml nitromethane solution, 0.16-0.19mol diamino methane solution (3), 500ml propionitrile solution, controlling the stirring speed 130-180rpm, the solution temperature is raised to 65—70 °C, continued the reaction for 5-7 h, added 300ml sodium sulfite solution, the reaction was refluxed for 4-6h, cooled, added 200ml sodium chloride solution, the organic layer was separated, the aqueous layer was washed with ethylenediamine solution, the combined organic layer was washed with salt solution, washed with cyclohexanone solution, dehydrated with dehydrating agent, recrystallized in the p-xylene solution, got crystals of 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester (1); wherein, nitromethane solution in step (i) has a mass fraction of 30-36%; diamino methane solution in step (i) has a mass fraction of 60-66%; propionitrile solution in step (i) has a mass fraction of 50-56%, sodium sulfite solution in step (i) has a mass fraction of 35-40%; ethylenediamine solution in step (i) has a mass fraction of 70-75%; salt solution in step (i) is any one of ammonium bromide solution or sodium iodide solution.
2. Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 -methyl 2 oxo benzoic acid methyl ester synthesis method according to claim 1 wherein cyclohexanone solution in step (i) has a mass fraction of 75-80%.
3. Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 -methyl 2 oxo benzoic acid methyl ester synthesis method according to claim 1 wherein dehydrating agent in step (i) is any one of anhydrous calcium sulfate or anhydrous potassium carbonate.
4. Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 -methyl 2 oxo benzoic acid methyl ester synthesis method according to claim 1 wherein p-xylene in step (i) has a mass fraction of 90-98%.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015109992632 | 2015-12-25 | ||
| CN201510999263.2A CN105669636A (en) | 2015-12-25 | 2015-12-25 | Synthetic method for bifendate medicine intermediate 3-methoxy-4,5-methylenedioxymethyl benzoate |
| CN201610830897X | 2016-09-19 | ||
| CN201610830897.XA CN106432174A (en) | 2015-12-25 | 2016-09-19 | Synthetic method of bifendate drug intermediate 3-methoxy-4,5-methylenedioxy methyl benzoate |
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| Publication Number | Publication Date |
|---|---|
| AU2016102310A4 true AU2016102310A4 (en) | 2017-02-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| AU2016102310A Ceased AU2016102310A4 (en) | 2015-12-25 | 2016-12-24 | Biphenyldicarboxylate drug intermediates 3 - methoxy - 4, 5 - methyl 2 oxo benzoic acid methyl ester synthesis method |
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| AU (1) | AU2016102310A4 (en) |
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2016
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