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Synthesis method for antihypertensive agent isradipine and preparation of isradipine

An antihypertensive and drug technology, applied in the field of drug isradipine preparation, can solve the problems of complicated operation, low yield, expensive solvent and the like

Active Publication Date: 2013-01-02
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method has simple operation and high yield, is suitable for industrial production, and solves the problems of complicated operation, expensive solvent and low yield in the production of 4-formylbenzofurazan and isradipine in the existing method

Method used

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  • Synthesis method for antihypertensive agent isradipine and preparation of isradipine
  • Synthesis method for antihypertensive agent isradipine and preparation of isradipine
  • Synthesis method for antihypertensive agent isradipine and preparation of isradipine

Examples

Experimental program
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Effect test

Embodiment 1

[0023] Synthesis of 4-bromomethylbenzofurazan

[0024] 4-Methylbenzofurazan (13.4g, 100mmol) was dissolved in carbon tetrachloride (150ml), then NBS (23.5g, 132mmol) and Bz202 (0.29mol) were added, and the mixture was heated to 80-85°C for reaction, After the reaction was completed, the system was lowered to 40°C, filtered, filtered and washed with chloroform, and the solvent was recovered under reduced pressure to obtain a crude product (25.6 g), which was recrystallized from petroleum ether-ethyl acetate to obtain light yellow needle crystals, 4-bromomethyl Benzofurazan (16.4 g). Yield 77%, mp 94-95°C.

Embodiment 2

[0026] Synthesis of 4-Formylbenzofurazan

[0027] 4-Bromomethylbenzofurazan (21.1 g, 0.1 mol), urotropine (21.0 g, 0.15 mol), acetic acid (80 ml) and water (80 ml) were added to the reaction flask. Heated to reflux under nitrogen protection and stirred for 1 h. Concentrated hydrochloric acid (80ml) was added and stirring was continued for 30min under reflux. After the reaction was completed, it was cooled to room temperature and extracted with ethyl acetate. The organic layers were combined and washed successively with 10% aqueous sodium carbonate solution and saturated brine. After drying with anhydrous sodium sulfate and filtering, the filtrate was evaporated to remove the solvent under reduced pressure to obtain 11.2 g of a light yellow solid, yield 75%, mp 108-109°C.

Embodiment 3

[0029] Synthesis of Methyl 2-(4-Benzofurazamethylene)-3-oxobutanoate

[0030] 4-Formylbenzofurazan (14.8g, 0.1mol) and methyl acetoacetate (11.6g, 0.1mol), stirred at room temperature until the solid was completely dissolved. Cool in an ice bath, stir and add concentrated sulfuric acid (1ml) dropwise below 10°C, continue stirring for 1h after dropping, add water (100ml), stir for 10min, filter, and wash the filter cake with 10% sodium bicarbonate solution until it becomes weakly alkaline, After washing with water to neutral and absolute ethanol, 17.5 g of solid was obtained, with a yield of 71%.

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Abstract

The invention relates to a method for synthesizing an antihypertensive agent containing furazan ring, comprising using 4-methylbenzofurazan as raw material, carrying out bromination and Sommelet reaction to prepare important intermediate 4-benzofurazancarboxaldehyde, carrying out condensation, and carrying out Hantzsch reaction to prepare target compound. The target compound can be directly or indirectly added with pharmaceutically-acceptable excipient in conventional process to prepare into clinically-acceptable dosage forms, such as tablet and capsule, to take better curative action.

Description

1. Technical field [0001] The present invention relates to a synthesis method of an antihypertensive drug containing furazanine, more specifically to a preparation method of drug isradipine; and the prepared target compound is directly or indirectly added to a pharmaceutically acceptable excipient through a conventional process formulations into clinically acceptable dosage forms. 2. Background technology [0002] Isradipine is a novel dihydropyridine calcium channel blocker. Isradipine was developed by the Swiss company Sandoz and was first introduced to the market by the British company Ciba-Geigy in February 1989. Isradipine achieves the purpose of lowering blood pressure by dilating blood vessels, reducing peripheral vascular resistance, increasing coronary blood flow, and improving myocardial oxygen supply. [0003] Isradipine has a strong vasodilator effect, but no heart inhibitory effect, and almost does not cause reflex tachycardia. Clinical and animal experiments...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61P9/12C07D413/04
Inventor 何勇吴宗好陈仕云李甲甲高永好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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