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Preparation of cilostazol

A technology for cilostazol and tetrazolium, which is applied in the field of preparation of raw materials, can solve the problems of increased production cost, large environmental pollution, loss of total yield and the like, and achieves low production cost, little environmental pollution, and sufficient reaction. Effect

Active Publication Date: 2009-05-20
CHONGQING KANGLE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] U.S. Patent No. 4,277,479 uses ethanol as a reaction solvent, 1,8-diazacyclo[5,4,0]undecene-7 (DBU) is a reaction catalyst, and chloroform is an aftertreatment extraction solvent to prepare cilostazol, but the obtained Contain two main impurities in the product, the quality is not good; Disclosed in the follow-up patent WO2006022488 of this patent is removed the method for obtaining high-purity (purity ≥ 99.8%) product by recrystallization to remove above-mentioned two main impurities, but total yield loss serious;
[0005] U.S. Patent No. 6,630,590 uses the mixed solution of toluene and water as the reaction solvent, the mixture of potassium carbonate, tert-butylammonium chloride and ammonium sulfate as the reaction catalyst, and methanol as the recrystallization solvent to prepare cilostazol, but the toxicity of toluene is relatively large. There are safety threats to human health and serious environmental pollution;
[0006] U.S. Patent US2007105898 uses water as the reaction solvent, a mixture of methylpyrrolidone and sodium hydroxide as a reaction catalyst, and a mixture of isopropyl acetate and water as a recrystallization solvent to prepare cilostazol with a purity of 99.53%, but methylpyrrolidone and isopropyl acetate are more expensive, resulting in increased production costs

Method used

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  • Preparation of cilostazol
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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1, the preparation of cilostazol

[0019] According to the theoretical production amount of cilostazol 161.33g, calculate the amount of raw materials; in a 2000mL three-neck round bottom flask, add 106.0g (0.44mol ), 6-hydroxyl-3,4-dihydroquinolone 71.8g (0.44mol), potassium carbonate 33.2g (0.24mol) and potassium hydroxide 13.5g (0.24mol), then add methanol 800mL, and reflux reaction at a temperature of 80°C For 24 hours, monitor the progress of the reaction with thin-layer chromatography (TLC). After the reaction is complete, distill the reaction solution under reduced pressure to remove about 200 mL of methanol, then cool to a temperature of 0°C, and white crystals are precipitated. Filter the filter cake with methanol After washing, it was vacuum-dried at a temperature of 55° C. to obtain 132.30 g of the product cilostazol with a purity of 99.3% and a yield of 82.0%.

Embodiment 2

[0020] The preparation of embodiment 2, cilostazol

[0021] According to the theoretical production amount of cilostazol 161.33g, calculate the amount of raw materials; in a 2000mL three-neck round bottom flask, add 106.0g (0.44mol ), 6-hydroxy-3,4-dihydroquinolone 79.0g (0.484mol), sodium carbonate 35.0g (0.33mol) and sodium hydroxide 9.6g (0.24mol), then add isopropanol 800mL, at a temperature of 82 ℃ Reflux reaction for 24 hours, monitor the progress of the reaction with TLC method, after the reaction is complete, distill the reaction solution under reduced pressure to remove about 200mL of isopropanol, cool to a temperature of 2°C, white crystals are precipitated, filter with suction, filter the cake with isopropanol After washing with alcohol, it was dried in vacuum at 55° C. to obtain 134.00 g of the product cilostazol with a purity of 99.3% and a yield of 83.1%.

Embodiment 3

[0022] Embodiment 3, the preparation of cilostazol

[0023] According to the theoretical production amount of cilostazol 161.33g, calculate the amount of raw materials; in a 2000mL three-neck round bottom flask, add 106.0g (0.44mol ), 6-hydroxy-3,4-dihydroquinolone 86.5g (0.53mol), potassium carbonate 45.0g (0.33mol) and potassium hydroxide 13.5g (0.24mol), then add isopropanol 800mL, at a temperature of 84 ℃ Reflux reaction for 24 hours, monitor the progress of the reaction with TLC method, after the reaction is complete, distill the reaction solution under reduced pressure to remove about 200mL of isopropanol, then cool to 0°C, white crystals are precipitated, filter with suction, filter the cake with isopropanol After washing with alcohol, the product was vacuum-dried at 55° C. to obtain 137.13 g of the product cilostazol with a purity of 99.8% and a yield of 85.0%.

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Abstract

The invention discloses a preparation method of cilostazol. 1-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazolium and 6-hydroxy-3, 4-dihydroquinolone is subjected to substitution reaction with the existence of an inorganic base catalyst and an alcohols solvent to prepare the cilostazol; the preparation method has products with high yield and good quality, avoids the application of toxical reagents and expensive reagents, has little environmental pollution and low production cost, and is suitable for industrialized production.

Description

technical field [0001] The present invention relates to a kind of preparation method of crude drug, particularly a kind of preparation method of cilostazol. Background technique [0002] Cilostazol (cilostazol) is a new drug for the treatment of intermittent claudication developed by Japan's Otsuka Pharmaceutical Company and launched in 1998. It has a significant effect in relieving and improving the symptoms of intermittent claudication and reducing the pain of patients. Widely used clinically. [0003] Cilostazol is mainly prepared by substitution reaction of 1-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazolium and 6-hydroxy-3,4-dihydroquinolone. In existing bibliographical reports, the preparation method that is suitable for industrialized production mainly contains following three kinds, but all there are deficiencies: [0004] U.S. Patent No. 4,277,479 uses ethanol as a reaction solvent, 1,8-diazacyclo[5,4,0]undecene-7 (DBU) is a reaction catalyst, and chloroform is an after...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61P43/00
Inventor 查正华龚大勇王建波张宇生
Owner CHONGQING KANGLE PHARMA
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