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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
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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 occurs to generate 6-hydroxy-3,4-dihydro-2(1H)quinolinone
In this process, the hydrolysis of the alkoxy group is actually redundant, the atom economy is very poor, and the price of the raw material is also high, so it can be replaced by p-aminophenol which is cheaper; in the synthesis process, diethyl ether is needed, and the boiling point of diethyl ether is low. Extremely flammable and anesthetic to the human body; in addition, toxic solvents such as benzene and chloroform need to be used in the synthesis process, which has a certain toxic effect on the health of employees

Method used

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  • Method for synthesizing cilostazol
  • Method for synthesizing cilostazol
  • Method for synthesizing cilostazol

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Embodiment 15

[0025] The preparation of embodiment 15-chloro-N-cyclohexylpentanamide

[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), start stirring, cool to below 5°C, slowly add 77.5g of 5-chlorovaleryl chloride dropwise g (0.5mol), after dropping, react at room temperature for 2h, evaporate the solvent under reduced pressure, extract the residue with chloroform, separate layers, wash the organic phase with 0.1mol / L dilute hydrochloric acid and water successively until neutral, separate layers, water The layer was extracted twice with 50mL*2 chloroform, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the oil was added to 200mL of petroleum ether, stirred at room temperature, white crystals were gradually precipitated, filtered, and dried to obtain 5-chloro-N - Cyclohexylpentanamide 90.6g, yield 83.2%.

Embodiment 25

[0027] The preparation of embodiment 25-chloro-N-cyclohexylpentanamide

[0028] Put 49.6g (0.5mol) of cyclohexylamine into the reaction flask, add 200mL of methyl tetrahydrofuran, 60mL of water, 75.9g of potassium carbonate (0.55mol), start stirring, cool to below 5°C, and slowly add 5-chloropentyl Acyl chloride 77.5g (0.5mol), after dripping, react at room temperature for 2h, separate the layers, wash the organic layer with 0.1mol / L dilute hydrochloric acid and water until neutral, separate the layers, and extract the aqueous layer with 50mL*2 methyl tetrahydrofuran Twice, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure (methyl tetrahydrofuran was applied to the next batch), and the oil was added to 200 mL of petroleum ether, stirred at room temperature, and white crystals were gradually precipitated, filtered, and dried to obtain 5-chloro- N-cyclohexylpentanamide 96.6g, yield 88.7%.

Embodiment 35

[0029] The preparation of embodiment 35-(4-chloro-n-butyl)-1-cyclohexyl tetrazole

[0030] Add 95.8g (0.44mol) of 5-chloro-N-cyclohexylpentanamide to 400mL of toluene, start stirring, cool to below 5°C, slowly add 100.8g (0.48mol) of phosphorus pentachloride in batches, after the drop , kept at room temperature for 2 hours, added 60.7 g (0.53 mol) of azidotrimethylsilane, and reacted at room temperature for 15 hours. After the reaction was completed, 200 mL of water was added, and the layers were separated. The organic phase was washed with 100 mL of water, and then the toluene was evaporated under reduced pressure. Add 400mL of isopropanol, heat up to dissolve, keep warm for 1h, cool down, precipitate needle-like crystals, filter, and dry to obtain 97.4g of 5-(4-chloro-n-butyl)-1-cyclohexanetetrazole. 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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