A kind of safe preparation method of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine

A technology of methyl and pyrazole, applied in the field of safe preparation of 1-piperazine, can solve problems affecting product yield and purity, potential safety hazards, strong explosiveness, etc., and achieve avoidance of unsafe reagents, high safety, The effect of mild conditions

Active Publication Date: 2020-11-24
ZHEJIANG SCI-TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The substance is highly explosive, and industrial production has great safety hazards; commercial sodium hydride wraps about 40% of paraffin oil, which is difficult to remove during post-treatment after the reaction, which affects the yield and purity of the product

Method used

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  • A kind of safe preparation method of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine
  • A kind of safe preparation method of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine
  • A kind of safe preparation method of 1-(3-methyl-1-phenyl-1h-pyrazol-5-yl)piperazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043]1) Add 3.5g (0.028mol) N-acetylpiperazine and 20mL toluene to a 50mL single-mouth bottle equipped with a water separator, stir and heat to reflux, after the water removal is completed, cool to room temperature, add 20mL DMF, 4g anhydrous Potassium carbonate, 5.5g (0.025mol) raw materials, heat up and distill toluene out at the same time, react at a temperature of 130°C for 6h, after the reaction, cool to room temperature, filter, rinse the filter cake (5mL*2) with DMF, concentrate the filtrate, and the residue Add water and 1,2-dichloroethane for extraction, and concentrate to obtain an oil.

[0044] 2) Add the oil obtained in the previous step and 20 mL of n-butanol to a 50 mL single-mouth bottle, stir evenly, add 5 mL of hydrochloric acid dropwise, and heat up to reflux for 3 hours. After the reaction, cool to room temperature, add 20 mL of water and stir thoroughly, ethyl acetate Wash the water layer (10mL*2), separate the water layer, adjust the pH of the water layer...

Embodiment 2

[0046] 1) Add 5.3g (0.028mol) N-benzoylpiperazine and 20mL toluene to a 50mL single-mouth bottle equipped with a water separator, stir and heat to reflux, after the water removal is completed, cool to room temperature, add 20mL DMF, 4g Anhydrous potassium carbonate, 5.5g (0.025mol) raw materials, heat up and distill toluene out at the same time, react at a temperature of 130°C for 6h, after the reaction is completed, cool to room temperature, filter, rinse the filter cake (5mL*2) with DMF, concentrate the filtrate, The residue was extracted with water and 1,2-dichloroethane, and concentrated to obtain an oil.

[0047] 2) Add the oil obtained in the previous step and 20 mL of n-butanol to a 50 mL single-mouth bottle, stir evenly, add 5 mL of hydrochloric acid dropwise, and heat up to reflux for 3 hours. After the reaction, cool to room temperature, add 20 mL of water and stir thoroughly, ethyl acetate Wash the water layer (10mL*2), separate the water layer, adjust the pH of the...

Embodiment 3

[0049] 1) Add 3.5g (0.028mol) N-acetylpiperazine and 20mL toluene to a 50mL single-mouth bottle equipped with a water separator, stir and heat to reflux, after the water removal is completed, cool to room temperature, add 20mL DMSO, 4g anhydrous Potassium carbonate, 5.5g (0.025mol) raw materials, heat up and distill toluene out at the same time, react at a temperature of 130°C for 6h, after the reaction, cool to room temperature, filter, rinse the filter cake (5mL*2) with DMSO, concentrate the filtrate, and the residue Add water and 1,2-dichloroethane for extraction, and concentrate to obtain an oil.

[0050] 2) Add the oil obtained in the previous step and 20 mL of n-butanol to a 50 mL single-mouth bottle, stir evenly, add 5 mL of hydrochloric acid dropwise, and heat up to reflux for 3 hours. After the reaction, cool to room temperature, add 20 mL of water and stir thoroughly, ethyl acetate Wash the water layer (10mL*2), separate the water layer, adjust the pH of the water la...

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Abstract

The invention relates to the field of medicine synthesis, and discloses a safe preparation method for 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine. The method disclosed by the invention comprises the steps: allowing 5-chloro-3-methyl-1-phenylpyrazol-4-formaldehyde to react with N-acylpiperazine under conditions of inorganic alkali such as anhydrous potassium carbonotate and anhydrous sodium carbonotate, to obtain an intermediate product with a higher yield; and allowing the intermediate product to react in the hydrochloric acid solution of n-butyl alcohol, to simutaneously remove formacyl and acyl protection group of piperazine, thereby obtaining a target product. The method has the advantages of mild conditions, higher yield, simple post-treatment, avoidance of unsafe reagents, and good industrial production prospect.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a safe preparation method of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine. Background technique [0002] 1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazine is an important intermediate in the synthesis of tiagliptin. Tiagliptin, also known as Terryliptin, trade name Tenelia, chemical name 3-[[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole- 5-yl)-1-piperazinyl]-2-pyrrolidinyl]formyl]thiazolidine, white crystalline powder, CAS registration number: 760937-92-6, relative molecular weight: 426.58, molecular formula C22H30N6OS, structural formula as shown below : [0003] [0004] Developed by Tanabe Mitsubishi Pharmaceutical Company, it was first launched in Japan in September 2012. This product is dipeptidyl peptidase-IV (DPP-4) inhibitor, used for the treatment of type II diabetes. This product hinders the degradation of glucagon-like peptide-1 (GLP-1) by inhibiting the activity of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/38
CPCC07D231/38
Inventor 朱锦桃赵飞孟静李杨
Owner ZHEJIANG SCI-TECH UNIV
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