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Preparation method of 1-cyclopropylcarbonylpiperazine hydrochloride

A technology of cyclopropamoylpiperazine and hydrochloride, which is applied in the field of preparation of 1-cyclopropamoylpiperazine hydrochloride, can solve the problems of low yield and low purity, and achieve high product yield, The effect of high purity and mild reaction conditions

Pending Publication Date: 2020-05-08
GUANGZHOU BIO CURRENT BIOLOGICAL TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 1) WO 2008047082 discloses using acetic acid as a solvent to react piperidine and cyclopropanoyl chloride to prepare 1-cyclopropanoylpiperazine hydrochloride. After the reaction, crystallize with toluene. This method can only obtain low-purity The product, the piperazine impurity content is greater than 1%, and the yield is not high;

Method used

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  • Preparation method of 1-cyclopropylcarbonylpiperazine hydrochloride
  • Preparation method of 1-cyclopropylcarbonylpiperazine hydrochloride

Examples

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Effect test

Embodiment 1

[0036] A preparation method of 1-cyclopropanoylpiperazine hydrochloride includes the following steps:

[0037] 1) Add 68g of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester to 170mL of anhydrous dichloromethane, stir and cool to 0℃, and then add 140g of trifluoroacetic acid dropwise under nitrogen protection. After the dropwise addition is completed, the temperature is raised to 25°C and stirred for 3h, the gas phase monitoring raw material has reacted, and concentrated under reduced pressure to an oily substance to obtain 1-cyclopropanoylpiperazine;

[0038] 2) Add 1-cyclopropanoylpiperazine to 102mL of absolute ethanol, stir and cool to 0°C, and then add 25.2g of cyclopropanoyl chloride dropwise with stirring under the protection of nitrogen. After the addition, the temperature is raised to 25°C and added Seed crystals, continue to stir for 1h, then add 51mL of methyl tert-butyl ether dropwise, cool to 0℃, stir for 1h and then filter, the filtered solid is r...

Embodiment 2

[0040] A preparation method of 1-cyclopropanoylpiperazine hydrochloride includes the following steps:

[0041] 1) Add 120g of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester to 330mL of anhydrous dichloromethane, stir and cool down to 5℃, then add 242g of trifluoroacetic acid dropwise under nitrogen protection while stirring After the dropwise addition is completed, the temperature is raised to 25°C and stirred for 3h, the gas phase monitoring raw material has reacted, and concentrated under reduced pressure to an oily substance to obtain 1-cyclopropanoylpiperazine;

[0042] 2) Add 1-cyclopropanoylpiperazine to 180mL of absolute ethanol, stir and cool to 5°C, then add 46g of cyclopropanoyl chloride dropwise with stirring under the protection of nitrogen. After the addition, heat to 25°C, add crystal Plant, continue to stir for 1h, then add 90mL of methyl tert-butyl ether dropwise, cool to 0℃, stir for 1h and then filter, the filtered solid is rinsed with methy...

Embodiment 3

[0044] A preparation method of 1-cyclopropanoylpiperazine hydrochloride includes the following steps:

[0045] 1) Add 150g of 4-(cyclopropanecarbonyl)piperazine-1-carboxylic acid tert-butyl ester into 250mL of anhydrous dichloromethane, stir and cool to 5℃, and then add 270g of trifluoroacetic acid dropwise under nitrogen protection. After the dropwise addition, the temperature was raised to 25°C and stirred for 5 hours. After the reaction of the gas phase monitoring raw material was completed, it was concentrated under reduced pressure to an oily substance to obtain 1-cyclopropanoylpiperazine;

[0046] 2) Add 1-cyclopropanoylpiperazine to 190mL of absolute ethanol, stir and cool down to 5°C, then add 56g of cyclopropanoyl chloride dropwise with stirring under the protection of nitrogen. After the addition, the temperature is raised to 25°C, and the crystal is added. After stirring for 1 hour, add 90 mL of isopropyl ether dropwise, cool to 0°C, stir for 1 hour, filter, and rinse th...

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Abstract

The invention discloses a preparation method of 1-cyclopropylcarbonylpiperazine hydrochloride. The preparation method comprises the following steps: removing a tert-butyloxycarbonyl protecting group in tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate by trifluoroacetic acid, and carrying out a salt forming reaction on the obtained material and acyl chloride to obtain the 1-cyclopropylcarbonylpiperazine hydrochloride. The preparation method of the 1-cyclopropylcarbonylpiperazine hydrochloride has the advantages of easily available raw materials, simple process, mild reaction conditions, environmental protection, economical property, high yield and high purity of the product, and suitableness for industrial production.

Description

Technical field [0001] The invention relates to a method for preparing 1-cyclopropylpiperazine hydrochloride. Background technique [0002] Olaparib, chemical name 1-(cyclopropanoyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2- Fluorobenzoyl]piperazine, a PARP inhibitor, can act on BRCA1 or BRCA2 mutations. Olaparib has been used to treat BRCA-mutated tumors, such as ovarian cancer, breast cancer, and prostate cancer. In addition, olaparib inhibits ATM (ataxia telangiectasia mutant gene) defective tumor cells with selectivity and can be used as a potential agent for the treatment of ATM-mutated lymphomas. [0003] 1-Cyclopropanoylpiperazine is an important raw material for the synthesis of olaparib, but 1-cyclopropanoylpiperazine is liquid, which is not convenient for storage and transportation, so 1-cyclopropanoylpiperazine hydrochloride in solid state Salt has more advantages. Currently, the preparation methods of 1-cyclopropylpiperazine hydrochloride include the follow...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/182
CPCC07D295/182Y02P20/55
Inventor 王勇李永鹏谭颂德
Owner GUANGZHOU BIO CURRENT BIOLOGICAL TECH LTD