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Process for synthesizing lacidipine of antihypertensive drugs

A technology of lacidipine and its compounds, which is applied in the field of synthetic technology of antihypertensive drug lacidipine, can solve problems such as low yield, long route, and no practical production significance, and achieve high yield, low cost, and easy separation Effect

Inactive Publication Date: 2005-03-16
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This method has a long route and extremely low yield, and the products of each step need to be separated by high vacuum distillation and column chromatography. This method has no practical production significance

Method used

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  • Process for synthesizing lacidipine of antihypertensive drugs
  • Process for synthesizing lacidipine of antihypertensive drugs
  • Process for synthesizing lacidipine of antihypertensive drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] In a 500ml round bottom flask, add 13.4g (0.1mol) of o-phthalaldehyde, 100ml of ethyl acetate, 23.2g (0.2mol) of ethyl aminocrotonate, cool in an ice-water bath, and add 50ml of glacial acetic acid dropwise with stirring. After reacting at 0-5°C for 4 hours, add 250ml of ethyl acetate and 50ml of water, separate the water layer, wash the organic layer with 2×50ml of water, wash once with 50ml of saturated NaCl aqueous solution, and wash with anhydrous NaCl. 2 SO 4 Dry and concentrate to obtain a brown oil, which was placed in the refrigerator; the next day, crystals were precipitated, filtered, and washed with a small amount of cold ethyl acetate to obtain compound (IV), 17.85 g of yellow crystals, m.p.177-179°C, yield 50%. 1 H-NMR (CDCl 3 , 60MHz) ppm: 1.18 (6H, triplet); 2.3 (6H, singlet); 4.0 (4H, quartet); 5.8 (1H, singlet); 6.25 (1H, singlet); 7.17.9 ( 4H, multiplet).

Embodiment 2

[0049] In a 250ml round bottom flask, add 3.57g (0.01mol) of compound (IV), 5.24g (0.02mol) of phosphate (III) (R = ethyl), 150ml of absolute ethanol, and cool with ice water at 0-5°C , add dropwise 20ml ethanol solution containing 0.02mol sodium ethoxide under stirring, finish adding in 30 minutes, then react at room temperature for 5 hours, stop stirring, evaporate about 100ml ethanol under reduced pressure, add 100ml water, precipitate yellow solid, filter, use Ethyl acetate was recrystallized to obtain 3.64 g of the product lacidipine as yellow-white crystals, m.p 175-177°C, and the yield was 80%. 1 H NMR (CDCl 3 , 90M Hz) ppm: 1.1 (6H, triplet); 1.5 (9H, singlet); 2.3 (6H, singlet); 4.0 (4H, multiplet); 5.4 (1H, singlet); 6.3 (1H, J=13 Hz, doublet); 6.5 (1H, singlet); 7.1-7.6 (4H, multiplet); 8.5 (1H, J=13Hz, doublet).

Embodiment 3

[0051] In a 100ml round-bottomed flask, add 39g of tert-butyl bromoacetate, dropwise add 35g of triethyl phosphite at 110°C, finish adding in 1 hour, then react for 3 hours, stop; distill under reduced pressure to obtain compound (III) (R =ethyl) 45.0g, b.p 122~124°C / 3mm Hg, yield 83%. 1 HNMR (CDCl 3, 300 MHz) ppm: 1.3 (6H, triplet); 1.4 (9H, singlet); 2.85 (2H, doublet); 4.15 (4H, quartet).

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PUM

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Abstract

The invention discloses a novel process for synthesizing lacidipine of antihypertensive drugs which comprises the steps of, (a) subjecting ortho-xylenediol aldehyde (I) to reaction with beta-amido crotonic acid ethyl ester (II) in protonic or non-protonic solvent at the presence of organic acid catalyst, so as to obtain compound (IV), (2) reacting compound (IV) with phosphoric ester (III) in protonic or nonprotonic solvent at the presence of alkali.

Description

technical field [0001] The present invention relates to antihypertensive drug lacidipine (Lacidipine, chemical name: (E)-4-{2-[3-(1,1-dimethylethoxy)-3-oxo-1-propene Base]-phenyl}-1,4-dihydro-2,6-dimethyl-3,5-diethyl pyridinedicarboxylate) new synthesis process. Background technique [0002] DE 3529997, US 4801599 and CN85107087 disclose several methods for synthesizing this compound, two of which are relevant to the present invention. [0003] The characteristic of a kind of method is to be raw material with o-phthalaldehyde (I), ethyl aminocrotonate (II), triphenylphosphine Ylide, by connecting the branch on the benzene ring first, then form the method for dihydropyridine ring To synthesize lacidipine; the total yield of this route is 5.4%. [0004] The route is as follows: [0005] [0006] The disadvantage of this method is that the raw materials are expensive, the yield is low, and the two-step reaction products need to be separated by column chromatography, which...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P9/12C07D211/90C07F9/40
Inventor 黄河清李中军王安邦蔡孟深
Owner PEKING UNIV
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