Preparation method of manidipine hydrochloride

A technology of manidipine hydrochloride and ethyl acetoacetate, which is applied in the field of preparation of manidipine hydrochloride, can solve the problems of low recovery rate, complex preparation method of manidipine hydrochloride, low product purity, etc., and achieve low cost, The effect of mild reaction conditions and high purity

Inactive Publication Date: 2017-11-10
JIANGXI YONGTONG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Existing manidipine hydrochloride preparation method is complex, the recovery rate is low, and the product purity is low

Method used

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  • Preparation method of manidipine hydrochloride
  • Preparation method of manidipine hydrochloride
  • Preparation method of manidipine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1) Synthesis of N-(2-hydroxyethyl)piperazine

[0036]Add 194g of piperazine (MNDP-0) and 400ml of water into the reaction flask, cool in an ice bath to 15-20°C, add 26.5g of ethylene oxide, stir and react at 30-35°C for 2 hours, then slowly heat to Temperature 108-110°C, stop the reaction when 360ml of water is distilled, cool to 10°C, filter to remove unreacted piperazine after standing still, distill the filtrate under reduced pressure, collect fractions at 125-127°C / 1.6kPa to obtain off-white viscous oil 1-Benzhydryl-4-(2-hydroxyethyl)piperazine 48.4g (namely MNDP-1), yield 81.7%, such as figure 2 shown.

[0037] 2) Synthesis of 1-benzhydryl-4-(2-hydroxyethyl)piperazine

[0038] Add 48.4g of MNDP-1, 51.5g of anhydrous potassium carbonate powder and 500ml of DMF into the reaction flask, add 91.4g of benzhydryl bromide in 3 batches under stirring, stir at room temperature for 3.5 hours, transfer to 1000ml of water, and extract with ether. The ether phase was washed...

Embodiment 2

[0044] A preparation method of manidipine hydrochloride, comprising the following steps:

[0045] (1) Synthesis of N-(2-hydroxyethyl)piperazine, piperazine and water were added to the reaction flask, cooled to 18°C ​​in an ice bath, added ethylene oxide, stirred and reacted at 32°C for 2 hours, then slowly Heat to a temperature of 109°C, stop the reaction when 90% of water is distilled, cool to 10°C, filter to remove unreacted piperazine after standing still, distill the filtrate under reduced pressure, collect when the temperature is 126°C and the pressure is 1.6kPa The fraction of N-(2-hydroxyethyl)piperazine is obtained as gray-white viscous oil, such as figure 2 shown;

[0046] (2) Synthesis of 1-benzhydryl-4-(2-hydroxyethyl) piperazine, N-(2-hydroxyethyl) piperazine, anhydrous potassium carbonate powder and DMF are added in the reaction flask, stirred Add benzhydryl bromide in 3 batches, stir at room temperature for 3.5 hours, add water, extract with ether, wash the et...

Embodiment 3

[0054] A preparation method of manidipine hydrochloride, comprising the following steps:

[0055] (1) Synthesis of N-(2-hydroxyethyl)piperazine, piperazine and water were added to the reaction flask, cooled to 18°C ​​in an ice bath, added ethylene oxide, stirred and reacted at 32°C for 2 hours, then slowly Heat to a temperature of 108°C, stop the reaction when 90% of water is distilled, cool to 10°C, filter to remove unreacted piperazine after standing still, distill the filtrate under reduced pressure, collect when the temperature is 125°C and the pressure is 1.6kPa The fraction of N-(2-hydroxyethyl)piperazine is obtained as gray-white viscous oil, such as figure 2 shown;

[0056] (2) Synthesis of 1-benzhydryl-4-(2-hydroxyethyl) piperazine, N-(2-hydroxyethyl) piperazine, anhydrous potassium carbonate powder and DMF are added in the reaction flask, stirred Add benzhydryl bromide in 3 batches, stir at room temperature for 3.5 hours, add water, extract with ether, wash the et...

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Abstract

The invention discloses a preparation method of manidipine hydrochloride and belongs to the technical field of medicine preparation. Piperazine serving as a starting raw material is used for synthesis of N-(2-hydroxyethyl)piperazine, then 1-diphenylmethyl-4-(2-hydroxyethyl)piperazine is synthesized, and 2-(4-diphenylmethyl-1-piperazinyl)ethyl acetoacetic ester is synthesized; 2-(4-diphenylmethyl-1-piperazinyl)ethyl acetoacetic ester, m-nitrobenzaldehyde and methyl 3-aminocrotonate are dissolved in isopropanol, the mixture is subjected to heating reflux, a solvent is removed through steaming, residues are dissolved in trichloromethane, the mixture is dried with anhydrous sodium sulfate and filtered, a solvent of the filtrate is recovered under reduced pressure, residues are mixed with methanol to be completely dissolved, hydrogen chloride is introduced in an ice bath, the solvent is removed through steaming, residues are mixed with methanol, activated carbon is added for decoloration, filtering is performed, filtrate is cooled, and manidipine hydrochloride is obtained. The preparation method of manidipine hydrochloride is simple in process, the yield is high, the cost is low, and the product purity is high.

Description

technical field [0001] The invention relates to a preparation method of manidipine hydrochloride, which belongs to the technical field of medicine preparation. Background technique [0002] Manidipine hydrochloride, Chinese alias: 1,4-dihydro-2,6-dimethyl-4-m-nitrophenyl-3,5-pyridinedicarboxylate methyl ester-2-(4-dibenzyl 1-piperazinyl) ethyl ester hydrochloride, the English name is MANIDIPINE DIHYDROCHLORIDE, CAS number: 89226-75-5, molecular formula: C 35 h 39 ClN 4 o 6 , molecular weight: 647.1604 [0003] It is antihypertensive, yellow or light yellow crystalline powder, melting point: 174-182°C, single impurity: ≤0.5%, total impurity: ≤1.0%, loss on drying: ≤6.0%, sulfate residue ≤0.1%, Heavy metals: ≤0.001%. [0004] The existing manidipine hydrochloride preparation method is complicated, the recovery rate is low, and the product purity is low. Contents of the invention [0005] In view of this, the invention provides a preparation method of manidipine hydroc...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 刘忠春
Owner JIANGXI YONGTONG TECH
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