Preparation method of dihydropyridine compound

A technology of dihydropyridine and compounds, applied in the chemical and pharmaceutical fields, can solve the problems of volatile, highly toxic and highly flammable acrylonitrile, and achieve the effects of low environmental pollution, low cost and convenient operation

Inactive Publication Date: 2013-08-14
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above technologies all have a common deficiency: even if 2-cyanoethyl is used as a protecting group, the acrylonitrile generated during removal is highly toxic, volatile and highly flammable

Method used

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  • Preparation method of dihydropyridine compound
  • Preparation method of dihydropyridine compound
  • Preparation method of dihydropyridine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Preparation of 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (IV)

[0047]

[0048] tert-butyl 3-aminocrotonate (3) (235mg, 1.5mmol) and methyl 2,3-dichlorobenzylidene acetoacetate (2) (273mg, 1mmol) were added to methanol (20ml) and reacted at 60°C 8 hours, cooled, spin-dried, and separated by column chromatography (ethyl acetate:petroleum ether=1:3) to obtain 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6- Dimethyl-3,5-pyridinedicarboxylic acid-(tert-butyl)methyl ester (1) 298 mg, yield 72.5% (based on 2).

[0049] m / z: 412(M+H); 1 H NMR (CDCl 3 , ppm): δ=7.02-7.37 (m, 3H), 4.78 (s, 1H), 3.77 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.39 (s, 6H).

[0050] 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-(tert-butyl)methyl ester (1) (412mg, 1mmol ) was dissolved in dichloromethane (10ml), added trifluoroacetic acid (1.5mmol), stirred at 20°C for 2.5h, spin-dried the solvent, added ethyl acetate an...

Embodiment 2

[0053] Preparation of 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (IV)

[0054]

[0055]3-Aminocrotonate-(1,1-dimethyl)benzyl ester (5) (26.3g, 0.12mol) and 2,3-dichlorobenzylidene acetoacetate (2) (27.3g, 0.1 mol) was added in isopropanol (300ml), reacted at 80°C for 9 hours, cooled, precipitated crystals, filtered, and dried to obtain 33.3g of product (4), with a yield of 70.3% (based on 2).

[0056] m / z: 474(M+H); 1 H NMR (CDCl 3 , ppm): δ=7.60(m, 1H), 7.38-7.51(m, 5H), 7.02-7.15(t, 3H), 4.78(s, 1H), 3.77(s, 3H), 2.26(s, 6H ), 1.49(s, 6H).

[0057] 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-((1,1-dimethyl)benzyl) Methyl ester (4) (4.74g, 0.01mol) was added to ethyl acetate (50ml), cooled to -10°C, and 1N hydrochloric acid-ethyl acetate solution (0.01mol) was added dropwise under stirring, and the drop was completed, stirred for 1h, filtered , the filter cake was washed with cold eth...

Embodiment 3

[0059] Preparation of 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (IV)

[0060]

[0061] Benzyl 3-aminocrotonate (7) (0.2 g, 1.05 mmol) and methyl 2,3-dichlorobenzylidene acetoacetate (2) (0.2 g, 0.7 mmol) were added to methanol (10 ml), React at 60°C for 3 hours, cool in an ice-water bath, precipitate crystals, filter, wash with a small amount of cold methanol, and dry to obtain 0.27 g of product (6), with a yield of 86.3% (based on 2).

[0062] m / z: 446(M+H); 1 H NMR (CDCl 3 , ppm): δ=7.31(m, 1H), 7.06-7.21(m, 5H), 7.02-7.19(t, 3H), 5.6(s, 1H), 5.52(s, 3H), 5.07-5.14(s , 3H), 2.34(s, 6H).

[0063] 4-(-2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid-(benzyl)methyl ester (6) (446g, 1mol ) into methanol (3L), then 10% by weight of Pa / C (4.46g), react with hydrogen at 30°C for 8 hours, filter off Pd / C, concentrate, precipitate solids, filter, filter the cake with an appropriate amount of cold meth...

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Abstract

The invention discloses a preparation method of a dihydropyridine compound (IV), comprising the following steps: using a compound VII and a compound VIII as initial raw materials and carrying out a cyclization reaction in a solvent to prepare an intermediate IX; and (2) putting the compound IX in a solvent and removing protective groups to prepare the compound IV. The protective groups used in the invention are common, the raw materials are easily available, and poisonous and harmful substances are not generated after the protective groups are removed. In addition, the operation is simple, a reagent used for removing the protective groups is cheap and easily available, the operation is convenient, the post-treatment is simple, costs are low, environmental pollution is little, and the preparation method is suitable for industrial production. The preparation method provided by the invention has advantages of high yield, stable product quality, low cost and simple operation, and is suitable for industrial preparation of a hypotensive drug Cleviprex key intermediate. An equation is shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and pharmacy, and relates 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 (I), developed by the Medicines Company, was approved for marketing by the U.S. 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. [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCY02P20/55
Inventor 李建其郑永勇方干黄道伟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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