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1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate and preparation method thereof

A technology of methyl formate and bipyridine, which is applied in the field of discovery through Scifinder database retrieval, achieves the effects of high yield, reduced production cost, and easy preparation

Active Publication Date: 2013-06-12
SHANDONG INST FOR FOOD & DRUG CONTROL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the impurity control of milrinone in the prior art, only impurity A is controlled, and there are no relevant reports, control standards and reference substances for other possible impurities

Method used

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  • 1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate and preparation method thereof
  • 1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate and preparation method thereof
  • 1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate and preparation method thereof

Examples

Experimental program
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Embodiment

[0039] Mix milrinone (0.5g, 2.37mmol) with 10ml of methanol to obtain a white solid suspension, place it in a 50ml single-necked bottle, slowly add 10-12ml of 98% concentrated sulfuric acid dropwise under stirring conditions, and release a large amount of heat. , the white solid dissolved, and the solution was colorless and transparent. Continue the reflux reaction at 90~100°C for 12~14 hours, cool to room temperature, pour the reaction solution into 30ml of ice water, add 150ml of acetone, precipitate the solid, filter, filter The cake was washed with methanol to obtain 0.56 g of a white product, which was the sulfate salt of the target compound, which was dissolved in water to obtain the target compound.

[0040] Yield: 81.2%.

[0041] The resulting compound was 1 Confirmed by HNMR and MS, HPLC. 1 H-NMR (DMSO-d 6 ) δ: 12.61 (s, 1H, CO-N H ), 8.91 (d, J = 6.6 Hz, 2H, Ar- H ), 8.19 (s, 1H, Ar- H ), 8.10 (d, J = 6.6 Hz, 2H, Ar- H ), 3.77 (s, 3H, C H 3 ), 3.42 (s, 3...

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Abstract

The invention relates to the technical field of medicine milrinone and in particular relates to a compound 1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate. The preparation method of the 1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate comprises the following steps of: mixing the milrinone with methanol to obtain turbid liquid; dropwise adding 98% concentrated sulfuric acid to the turbid liquid under the stirring condition until the turbid liquid is colorless and transparent; carrying out reflux reaction for 12-14 hours at 90 DEG C to 100 DEG C to obtain reaction liquid; and cooling the reaction liquid to the room temperature, pouring the cooled reaction liquid to ice water, adding acetone to the mixture to separate out solid, filtering the mixture, washing the filter cake by methanol to obtain a white product. According to the preparation method disclosed by the invention, milrinone used as a raw material and methanol used as reaction agent have reflux reaction at 90-100 DEG C under the catalysis of sulphuric acid; the reaction liquid is treated in the ice way after the reaction is completed, and therefore no new impurities are introduced, and the follow-up separation work is convenient; the acetone is used as crystallization solvent and the solvent residue in the product is easy to remove; the purity can reach 99.5%, and so the 1,6-dihydro-2-methyl-6-oxygen-(3,4'-dipyridine)-5-methyl formate can be used as a working comparison product.

Description

technical field [0001] The invention relates to the technical field of the drug milrinone, in particular to the compound 1,6-dihydro-2-methyl-6-oxo-(3,4'-bipyridine)-5-methyl carboxylate, and to a preparation method thereof . Background technique [0002] Milrinone is a phosphodiesterase inhibitor and a congener of amrinone. Its mechanism of action is the same as that of amrinone. It is suitable for short-term treatment of patients with severe heart failure who are ineffective to digitalis, diuretics, and vasodilators. The product was researched and developed by Sterling-Winthrop Company, and it went on sale in 1990. The currently marketed milrinone preparation in China is milrinone injection, while abroad it is milrinone lactate injection. At present, many literatures at home and abroad only report the impurity A of milrinone, while there are few research reports on other impurities of milrinone. Through the study and investigation of the stability of milrinone and mil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/79C07D213/803
Inventor 徐玉文张桂芳李军李涛王国金
Owner SHANDONG INST FOR FOOD & DRUG CONTROL