Method for synthesizing cilostazol

A technology of cilostazol and its synthetic method, which is applied in the field of organic chemical synthesis, can solve the problems of employee health hazards, poor atomic economy, and high raw material prices, and achieve the effects of reduced operational risk, less environmental pollution, and low raw material costs

Active Publication Date: 2015-12-02
ZHEJIANG KINGLYUAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This method has the following disadvantages: in the synthetic process of 5-(4-chlorobutyl)-1-cyclohexyl tetrazole, the toluene solution of azide needs to be used, and as everyone knows, azide is an extremely explosive compound, and toluene As a flammable solvent, the combination of the two is a huge safety hazard; 6-hydroxy-3,4-dihydro-2 (1H) quinolinone uses alkoxy (methyl or ethyl) aniline and 3-chloropropyl The acid chloride first undergoes acylation reaction, then undergoes ring closure reaction, and at the same time, the hydrolysis reaction of the alkoxy group

Method used

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  • Method for synthesizing cilostazol
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  • Method for synthesizing cilostazol

Examples

Experimental program
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Example Embodiment

[0025] Example 15 Preparation of Chloro-N-cyclohexylpentaneamide

[0026] Put 49.6g (0.5mol) of cyclohexylamine into the reaction flask, add 200mL of tetrahydrofuran, 60mL of water, 75.9g of potassium carbonate (0.55mol), turn on the stirring, cool to below 5℃, and slowly add 5-chloropentanoyl chloride 77.5 dropwise g(0.5mol), after dripping, react at room temperature for 2h, evaporate the solvent under reduced pressure, extract the residue with chloroform, separate the layers, wash the organic phase with 0.1mol / L dilute hydrochloric acid and water to neutrality, separate the layers, and water The layers were extracted twice with 50mL*2 chloroform, combined the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added 200mL petroleum ether to the oily substance, stirred at room temperature, white crystals gradually precipitated, filtered and dried to obtain 5-chloro-N -90.6 g of cyclohexyl valeramide, yield 83.2%.

Example Embodiment

[0027] Example 25-Preparation of chloro-N-cyclohexylpentaneamide

[0028] Put 49.6g (0.5mol) of cyclohexylamine into the reaction flask, add 200mL methyltetrahydrofuran, 60mL water, 75.9g potassium carbonate (0.55mol), turn on the stirring, cool to below 5℃, slowly add 5-chloropentane in drops Acid chloride 77.5g (0.5mol), after dripping, react at room temperature for 2h, separate layers, wash the organic layer with 0.1mol / L dilute hydrochloric acid and water until neutral, separate layers, and extract the water layer with 50mL*2 methyltetrahydrofuran Twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure (methyltetrahydrofuran was applied to the next batch). The oily substance was added with 200 mL of petroleum ether and stirred at room temperature. White crystals gradually precipitated, filtered and dried to obtain 5-chloro- N-cyclohexyl pentaneamide 96.6 g, yield 88.7%.

Example Embodiment

[0029] Example 35 Preparation of-(4-chloro-n-butyl)-1-cyclohexanetetrazole

[0030] Add 95.8g (0.44mol) of 5-chloro-N-cyclohexylvaleramide, add 400mL of toluene, turn on the stirring, cool to below 5℃, slowly add 100.8g (0.48mol) of phosphorus pentachloride in batches, after dripping Incubate at room temperature for 2h, add 60.7g (0.53mol) of azidotrimethylsilane, and react at room temperature for 15h. After the reaction is over, add 200mL of water, separate the layers, wash the organic phase with 100mL of water, and then distill off the toluene under reduced pressure. Add 400 mL of isopropanol, heat it to dissolve, keep it warm for 1 hour, cool down, and precipitate needle-like crystals, filter and dry to obtain 97.4 g of 5-(4-chloro-n-butyl)-1-cyclohexyltetrazole. The rate is 91.2%.

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Abstract

The invention discloses a method for synthesizing cilostazol. The method comprises the following steps: cyclohexylamine and 5-chlorovaleryl chloride undergo an acylation reaction to generate 5-chloro-N-cyclohexylpentanamide, and then 5-chloro-N-cyclohexylpentanamide reacts with phosphorus pentachloride and azidotrimethylsilane to generate a tetrazole compound 5-(4-chloro n-butyl)-1-ch cyclohexyl tetrazole; para amino phenol and 3-chloropropionylchloride undergo an acylation reaction to generate 3-chloro-4'-phenol propionamide, and under the effect of aluminum trichloride, 6-hydroxyl-3,4-dihydro-2(1H) quinolinone is generated through cyclization; with methanol serving as a solvent, under the high alkaline conditions of potassium hydroxide, two intermediates undergo a backflow reaction, and cilostazol is generated through butt joint. Raw material costs of the process route are low, the safety risk is low, the environmental pollution is small, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a synthesis method of cilostazol. Background technique [0002] Cilostazol, also known as Cistazol, has a chemical name of 6-[4-(1-cyclohexyl-1H-pentazol-5-yl)butoxy]-3,4-dihydro-2( 1H)-quinolone, the English name is Ciostazol, and its structural formula is as follows: [0003] [0004] Cilostazol was first developed by Japan's Otsuka Co., Ltd. Pharmaceutical Company and was launched in 1988 under the trade name Ciostazol. It was approved to enter China in 1996. Cilostazol (Cilostazol) is a quinoline derivative, a new type of antiplatelet drug, mainly used for the treatment of thrombotic diseases by inhibiting the activity of phosphodiesterase. Cilostazol has attracted more and more people's attention in the prevention of recurrent stroke, prevention and treatment of restenosis after angioplasty, treatment of diabetes combined with lower extremity arteri...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 赵海龙盛金火张晓伟赵斌峰钱志英陈晓红
Owner ZHEJIANG KINGLYUAN PHARMA
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