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Preparing method of cilostazol

A technology of cilostazol and tetrazole, which is applied in the field of preparation of raw materials, can solve the problems of poor atom economy, redundancy, and difficulty in removal, and achieve the effects of reduced synthesis steps, less environmental pollution, and easy operation

Active Publication Date: 2019-05-21
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this process, the hydrolysis of the alkoxy group is actually redundant, the atom economy is very poor, and the raw material price is also high
The synthesis process requires the use of highly corrosive aluminum trichloride, and the post-treatment produces a large amount of hydrogen chloride gas and waste acid, which is not conducive to environmental protection and employee health, and has high anti-corrosion requirements for equipment.
In this process, the potential genotoxic impurity compound 5-(4-chlorobutyl)-1-cyclohexyltetrazole can be produced into cilostazol only through one-step reaction, which is difficult to complete the reaction and is difficult to remove in cilostazol , the residue of genotoxic impurity in cilostazol has a greater safety risk

Method used

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  • Preparing method of cilostazol
  • Preparing method of cilostazol
  • Preparing method of cilostazol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of compound 1

[0047]

[0048] 1. In a 250ml three-neck round bottom flask, add 21.8g (0.1mol) of p-nitro-3-bromophenol, 8g (0.2mol) of sodium hydroxide, 1-cyclohexyl-5-(4-chlorobutyl) - 48.5 g (0.2 mol) of 1H-tetrazolium and 150 ml of n-butanol. Reflux for 8 hours, TLC detects that the reaction is complete, cool the reaction solution to room temperature, add water and ethyl acetate, separate the organic phase, wash with water and saturated brine, dry and concentrate under reduced pressure, the obtained residue is recrystallized with ethanol, and the precipitate is collected by filtration , and dried to obtain compound 138.1g with a purity of over 98% and a yield of 90%.

[0049] 2. In a 250ml three-neck round bottom flask, add 21.8g (0.1mol) of p-nitro-3-bromophenol, 34.5g (0.25mol) of potassium carbonate, 4g (0.1mol) of sodium hydroxide, 1-cyclohexyl- 48.5 g (0.2 mol) of 5-(4-chlorobutyl)-1H-tetrazolium and 150 ml of n-butanol. Ref...

Embodiment 2

[0052] Embodiment 2: the preparation of compound 2

[0053]

[0054] 1. In a 500ml three-necked round bottom flask, add 142.3g (0.1mol) of the compound, 28g (0.5mol) of reduced iron powder, 8.0g (0.15mol) of ammonium chloride, 200ml of methanol and 40ml of water, and raise the temperature to 45°C. Add 12 g (0.2 mol) of glacial acetic acid, and after the dropwise addition, heat up to reflux for 5 h. After the reaction was completed, it was cooled to room temperature, filtered, concentrated, dissolved in ethyl acetate, washed with water until neutral, dried, and concentrated to obtain compound 237.7g with a purity of over 98% and a yield of 96%.

Embodiment 3

[0055] Embodiment 3: the preparation of compound 3

[0056]

[0057] 1. In a 500ml three-neck round bottom flask, add 200ml of dichloromethane, add 239.3g (0.1mol) of the compound, 12.1g (0.12mol) of triethylamine, stir to cool down, and add 9.9g of acryloyl chloride dropwise at 0°C (0.11mol) (diluted with dichloromethane), stirred for 3 hours. TLC detection, after the reaction was completed, poured into water, the organic layer was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated saline, dried and filtered, and concentrated under reduced pressure to obtain 43.3g of compound 3 with a purity of more than 98% and a yield of 97%. .

[0058] 2. In a 500ml three-necked round-bottomed flask, use 200ml of dichloromethane as a solvent, add 39.3g (0.1mol) of compound 2, 27.6g (0.2mol) of potassium carbonate, stir to cool down, and add acryloyl chloride dropwise at 0°C 9.9 g (0.11 mol) (diluted with dichloromethane), stirred for 3 hours. TLC detecti...

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Abstract

The invention discloses a preparing method of cilostazol. According to the preparing method, p-nitro-3-bromophenol and 1-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole serves as raw materials, and a reaction is carried out under the function of inorganic base to obtain a compound 1; the compound 1 is reduced to obtain a compound 2; the compound 2 reacts with allyl acyl chloride in the presence of an acid-binding agent to obtain a compound 3; the compound 3 is subjected to cyclization under the catalysis of a catalyst to obtain the cilostazol. According to the preparing method, the side chain 1-cyclohexyl-5-(4-chlorobutyl)-1H-tetrazole serves as a protecting group of a phenolic hydroxyl group, the synthesis step of the cilostazol is reduced, the cost is reduced, and the yield is increased; meanwhile, the use of strongly-corrosive aluminum trichloride is avoided, the reaction is milder, the operation is easy, the pollution to the environment is small, the preparing method is suitable for industrial production, and the health of operating personnel is also better guaranteed. In the meanwhile, the risk that latent gene toxic impurities which are hard to remove in the product are left in theproduct is reduced.

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, 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 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 arterial occlu...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D257/04
CPCY02P20/55
Inventor 叶天健陈鑫刘永江韩立鹏鄢光毅
Owner ZHEJIANG YONGNING PHARMA