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Method of preparing 1,4-dihydrogen pyridine derivatives

A technology of dihydropyridines and derivatives, applied in 1 field, can solve problems such as troublesome post-processing, serious environmental pollution, affecting product yield and quality, and achieve the effects of good product quality, high catalytic activity, and maintaining yield

Inactive Publication Date: 2009-08-19
武汉同源药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The environmental pollution caused by its reaction conditions is serious, and post-processing is troublesome, which affects product yield and quality

Method used

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  • Method of preparing 1,4-dihydrogen pyridine derivatives
  • Method of preparing 1,4-dihydrogen pyridine derivatives

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Experimental program
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Embodiment 1

[0016] Embodiment one: 4-(3 / Preparation of -nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxymethoxyethyl ester isopropyl ester (compound 1)

[0017] Add 5g (14.5mmol) 4-(3 / -nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxyisopropyl-5 carboxylic acid, 1.32g (1.37ml, 17mmol,) ethylene glycol monomethyl ether, After 0.75g of D001 type cation exchange resin and 50ml of cyclohexane, heat to reflux and react until no water is carried out in the condenser tube. Cool, filter, recover the solvent, precipitate pale yellow crystals, filter and dry to obtain the crude product and recrystallize from isopropyl ether, filter, wash the crystals with isopropanol / water mixture, and suck dry. Dry under vacuum at 40°C. 4.7 g of light yellow crystalline powder (Compound 1) was obtained with a yield of 78%, a melting point of 124.5-126.5°C, a content of 99.1% as determined by HPLC, and an impurity content of 0.43%.

Embodiment 2

[0018] Embodiment two: 4-(3 / Preparation of -nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxymethoxyethyl ester isopropyl ester (compound 1)

[0019] Preparation of AlCl 3 -D001 type ion exchange resin: Soak D001 type cation exchange resin with 2mol / HCl for 24 hours, drain the acid solution, wash with distilled water until neutral, drain the water, dry at 60°C and place in a desiccator for later use. 20g of the above resin and 2g of anhydrous FeCl 3 Ethanol solution, refluxed for 8 hours, naturally cooled to room temperature, filtered, washed 3 times with distilled water, then washed 2 times with acetone, dried under vacuum at 60°C to obtain AlCl 3 -D001 type ion exchange resin, ready for use.

[0020] Add 5g (14.5mmol) 4-(3 / -nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxyisopropyl-5 carboxylic acid, 1.32g (1.37ml, 17mmol,) ethylene glycol monomethyl ether, 0.5 g of AlCl prepared above 3 After -D001 type cation exchange resin and 50ml hexanaphthene,...

Embodiment 3

[0021] Embodiment three: 4-(2 / Preparation of -nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxymethyl-2-oxopropyl ester (compound 2)

[0022] 6.6g (20mmol) 4-(2 / -Nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxymethyl-5-carboxylic acid, 0.55g 717 type anion exchange resin and 50ml DMF were stirred and mixed, then added 2.75g (23mmol) Acetyl methyl nitrate was reacted at 65°C for 4 hours, filtered, cooled, and pale yellow crystals were precipitated, filtered, and dried to obtain a crude product, which was recrystallized in 3:7 ethanol water, filtered, and crystallized with cooled ethanol / Water (3:7 V / V, volume ratio) mixture was washed and drained. Dry under vacuum at 40°C. 7.1 g of light yellow crystalline powder (compound 2) was obtained with a yield of 91.5%, a melting point of 149.3-152.6°C, a content of 98.7% as determined by HPLC, and an impurity content of 0.98%.

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Abstract

The invention relates to a method for preparing 1, 4-dihydropyridine derivatives. In the presence of a resin catalyst, a compound of formula II and a compound of formula III are reacted for 1 to 36 hours at a temperature between 0 and 150 DEG C to obtain the 1, 4-dihydropyridine derivatives represented by formula I, wherein R1 is hydrogen; C1-5 is alkyl and the like; R2 is phenyl or substituted phenyl; R3 is C1-5 alkyl or C1-5 alkanoyl and the like; and X is halogen, nitryl, cyano, sulfonic alkyl or hydroxyl. The catalyst used by the method has high catalytic activity, reaction conditions are mild and separation of product is easy; the method has no environment pollution, no erosion to equipment, and simple post treatment; the catalyst can be repeatedly used and regenerated, the reaction is easy to control, and good yield can be maintained; and the prepared product has good quality, and the method is suitable for mass production, in particular for large-scale production and preparation of raw material drugs or medicine.

Description

technical field [0001] The invention relates to a preparation method of 1,4-dihydropyridine derivatives. Background technique [0002] 1,4-Dihydropyridine compounds are a class of high-efficiency calcium channel blockers developed successively since the 1970s, and are widely used in the treatment of angina pectoris, supraventricular arrhythmia, hypertension and peripheral vascular diseases. In the past ten years, in the research on new derivatives of 1,4-dihydropyridine, on the premise of improving its efficacy, more attention has been paid to the expansion of efficacy, the development of its long-term effect, and the improvement of bioavailability; the new Action characteristics, reduce damage to target organs; study changes in drug routes, adapt to the use of various patients, make them short-acting, and be used for emergency critical care or blood pressure control during surgery, etc., and continuously expand the clinical application of this type of compound ((a) Anonymo...

Claims

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Application Information

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IPC IPC(8): C07D211/90B01J31/08A61P9/10A61P9/06A61P9/12A61P9/00
Inventor 林徐星吴云飞杨振东
Owner 武汉同源药业有限公司
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