A kind of preparation method of dihydropyridine compound

A technology of dihydropyridine and compound, applied in the field of chemical pharmacy, can solve the problems of unfavorable environmental protection, low yield of deprotection step, large waste solvent processing capacity, etc., and achieves the effects of convenient operation, low cost and stable product quality

Active Publication Date: 2021-05-11
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the disadvantages of this method are also very obvious. In the hydrolysis process, a large amount of acid and alkali alcohol solutions are used, and the amount of waste solvent to be treated is large, which is not conducive to environmental protection, and the yield of the deprotection step is not high.

Method used

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  • A kind of preparation method of dihydropyridine compound
  • A kind of preparation method of dihydropyridine compound
  • A kind of preparation method of dihydropyridine compound

Examples

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preparation example Construction

[0028] A method for preparing dihydropyridine compounds, the method uses compound II raw materials to carry out demethylation reaction in methanesulfonic acid to prepare dihydropyridine compound I;

[0029]

[0030] The reaction formula is as follows:

[0031]

[0032] Preferably, the reaction temperature is 60-80°C, and the reaction time is 3-4h.

[0033] Preferably, the reaction temperature is 80° C., and the reaction time is 3 hours.

[0034] Preferably, the weight ratio of methanesulfonic acid to compound II is 1-4:1.

[0035] Preferably, the weight ratio of methanesulfonic acid to compound II is 2:1.

[0036] Preferably, the method further includes the steps of cooling, filtering, washing and drying after the demethylation reaction.

[0037] Preferably, the temperature is lowered to 5-10° C. after the demethylation reaction.

[0038] Preferably, the washing is with cold methanesulfonic acid washing.

Embodiment 1

[0041] The preparation of 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (I), its reaction formula as follows:

[0042]

[0043] Methyl 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (II) (500g, 1.35mol) was added to methane In sulfonic acid (1000g), heat to the reaction temperature of 80°C under stirring, and stir at this temperature for 3h, then cool the reaction to 5-10°C, filter, wash the filter cake with a small amount of cold methanesulfonic acid, and dry to obtain the product ( 1) 476.2g, yield 99%.

[0044] mp.187~188℃; m / z: 356(M+H); 1 H NMR (DMSO, ppm): δ=11.57(s, 1H), 8.75(s, 1H), 7.25-7.36(m, 3H), 5.33(s, 1H), 3.51(s, 3H), 2.25(s , 3H), 2.22(s, 3H).

Embodiment 2

[0046] This example is basically the same as Example 1, except that in this example, the reaction temperature is 60° C., and the reaction time is 4 hours.

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Abstract

The invention relates to a method for preparing dihydropyridine compounds. In the method, compound II is used as a raw material to carry out demethylation reaction in methanesulfonic acid to prepare dihydropyridine compound I. Compared with the prior art, the raw materials of the deprotection reagent used in the present invention are easy to obtain, the reaction and post-treatment are simple and convenient, the environmental pollution is small, and it is suitable for industrial production; the present invention has high yield, stable product quality, low cost, simple operation, and is suitable for reducing Industrial preparation of key intermediates of clevidipine butyrate for pressing.

Description

technical field [0001] The invention relates to the technical field of chemical industry and pharmacy, in particular to a preparation method of dihydropyridine compounds. Background technique [0002] Clevidipine butyrate, the chemical name is 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Acid methyl (butyryloxymethyl) ester (compound 1), developed by the Medicines Company, was approved for marketing by the US FDA on August 1, 2008. This product has a quick onset of action and quick elimination of effects. It can precisely control blood pressure with incremental doses, and does not accumulate in the body, with little toxic and side effects. It is the first antihypertensive drug for intravenous injection in foreign countries in the past ten years. It is suitable for the treatment of high blood pressure when oral preparations are not applicable or desired. It is also used in the treatment of acute blood pressure elevation after cardiac surgery. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 方亚辉姚凌燕
Owner SHANGHAI INST OF TECH
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