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Synthesis method for preparing antihypertensive medicine having benzofuroxan ring

An anti-hypertensive, synthetic method technology, applied in drug combination, organic chemistry, cardiovascular system diseases, etc., can solve the problems of large environmental pollution of chromium ions, cumbersome operation and post-processing, and high price

Active Publication Date: 2011-12-21
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Similar to the above method, the difference is that it is different from the use of oxidants. As a commonly used oxidant, PCC has the advantage of mild conditions, but the reaction conditions require anhydrous, acid-resistant equipment, and chromium ions are relatively polluted to the environment.
[0021] Therefore, there is an urgent need to solve the related problems in the above-mentioned technologies. The present invention also provides a method for preparing darodipine and its important intermediate 4-formylbenzofurazan efficiently and simply, avoiding the use of expensive reagents, operations and Post-processing cumbersome method

Method used

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  • Synthesis method for preparing antihypertensive medicine having benzofuroxan ring
  • Synthesis method for preparing antihypertensive medicine having benzofuroxan ring
  • Synthesis method for preparing antihypertensive medicine having benzofuroxan ring

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Synthesis of 4-bromomethylbenzofurazan

[0029] 4-Methylbenzofurazan (13.4g, 100mmol) was dissolved in carbon tetrachloride (150ml), then NBS (23.5g, 132mmol) and Bz 2 o 2 (0.29g, 1.2mmol), the mixture was heated to 80-85°C for reaction, the reaction was completed, the system dropped to 40°C, filtered, filtered and washed with chloroform, and the solvent was recovered under reduced pressure to obtain a crude product (25.6g), petroleum ether-acetic acid Ethyl ester was recrystallized to obtain light yellow needle crystals, 4-bromomethylbenzophenazine (15.3g). Yield 77.6%, mp 94-95°C.

Embodiment 2

[0031] 4-Formylbenzofurazan

[0032] 4-Bromomethylbenzofurazan (19.7 g, 0.1 mol), DMSO 15 ml, and sodium bicarbonate (10 g, 0.12 mol) were added to the reaction flask. Heated to 100-150°C under nitrogen protection. After the reaction was completed, it was cooled to room temperature, extracted with water and ethyl acetate. The organic layers were combined and washed with saturated brine. Dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain 10.6 g of light yellow solid, yield 71.6%, mp 108-109°C.

Embodiment 3

[0034] Synthesis of Darrodipine

[0035] Add 4-formylbenzofurazan (14.8g, 0.1mol), ethyl acetoacetate (28g, 0.2mol), ammonium carbonate (15.8g, 0.2mol) in the 500mL three-neck round bottom flask, under stirring at 70 ℃ reaction, TLC tracking. After the reaction was finished, 200ml of water was added, and the reaction mixture was extracted 3 times with 200mL of ethyl acetate, the organic layers were combined, washed with water, dried, and the solvent was recovered under reduced pressure, cooled and crystallized, and recrystallized to obtain 29.5g of yellow solid darodipine, the yield 79.5%, mp 153-154°C. 1 H-NMR (CDCl 3 400MHz) δ: 7.61(m, 1H, Ar-H), 7.29(m, 2H, Ar-H), 5.98(s, 1H, N-H), 5.49(s, 1H, Ar-CH), 4.04(q, J=7.2Hz, 4H, COOCH 2 ), 2.32(s, 6H, 2×CH 3 ), 1.13(t, J=7.2Hz, 6H, COOCH 2 CH 3 ).

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Abstract

The invention relates to a synthesis method for preparing an antihypertensive medicine having a benzofuroxan ring. In the method, 4-methylbenzofuroxan is used as a raw material, the 2,1,3-benzoxadiazole-4-aldehyde serving as an important intermediate is prepared by bromination and oxidation reactions, and the 2,1,3-benzoxadiazole-4-aldehyde and acetoacetic ester undergo a Hantzsch reaction to form the target compound. Compared with other processes, the method has the characteristics of mild reaction conditions, simple and efficient operation, high yield and the like and has a certain industrial production prospect.

Description

1. Technical field [0001] The invention relates to a synthesis method of an antihypertensive drug containing furazanine, in particular to a preparation method of drug darodipine. 2. Background technology [0002] Darodipine (darodipine) is a potent dihydropyridine calcium antagonist, has a good antihypertensive effect, and is effective for stable angina pectoris. The half-life is as long as 11h. In addition to the obvious antihypertensive and anti-anginal effects clinically, it also has a bronchodilator effect on asthmatic patients and can prevent bronchospasm. Darrodipine has a better effect than nifedipine. It is used in patients with mild and moderate essential hypertension. It can reduce supine and standard arterial blood pressure without adverse effects on heart rate. [0003] Darrodipine (Darodipine), nicardipine and nifendipine in 10 -6 In the low concentration (5.5mM) and high concentration (22mM) of glucose, it inhibited the release of insulin from rat islets. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/04A61P9/12
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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