Method for synthesis of betamipron in continuous-flow microreactor

A technology of betamipron and microreactor, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as low purification yield and complicated operation, and achieve simplified purification operation and increased yield , the effect of reducing the content

Active Publication Date: 2014-02-19
ZHEJIANG UNIV
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  • Abstract
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  • Claims
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Problems solved by technology

The benzoic acid produced by the hydrolysis of benzoyl chloride is the main by-product during the reaction process. Most of the benzoic acid is removed by washing with benzene, and then high-purity betamipron can be obtained through multiple recrystallizations. Highly toxic benzene is used in the purification process. As a solvent, the operation is complicated and the purification yield is low

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  • Method for synthesis of betamipron in continuous-flow microreactor

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Embodiment 1

[0025] Example 1 Microfluidic Synthesis of Betamipron (I)

[0026] 0.01 mol alanine, 0.01 mol sodium hydroxide and 0.022 mol sodium bicarbonate were dissolved in 13.5 ml water to obtain solution A and 1.16 ml benzoyl chloride, respectively at a flow rate of V A = 24 ul / min and V B = 2.06 ul / min is simultaneously propelled by pump A and pump B to inject into the mixer and then enter the reactor for reaction. The diameter of the reactor microtube is 0.7 mm, the length of the tube is 1 m, and the temperature of the water bath is 0 o C, the solution of the collected betamipron sodium salt was acidified to pH=2 with concentrated hydrochloric acid, the betamipron solid was collected by filtration, washed with water and dried, and vacuum-dried to constant weight to obtain 1.82 g, with an HPLC purity of 95%. The rate is 90% (according to alanine).

[0027] 1 H NMR (CD 3 OD, ppm): δ 2.65 (t, J = 6.9 Hz, 2H), 3.62 (t, J = 6.9 Hz, 2H), 7.40-7.50 (3H), 7.79 (m, 2H). 13 C NMR (...

Embodiment 2

[0029] 0.01 mol alanine, 0.01 mol sodium hydroxide and 0.022 mol sodium bicarbonate were dissolved in 13.5 ml water to obtain solution A and 1.16 ml benzoyl chloride, respectively at a flow rate of V A = 4 ul / min and V B = 0.35 ul / min is simultaneously propelled by pump A and pump B to inject into the mixer and enter the reactor for reaction. The diameter of the microtube of the reactor is 0.7 mm, the length of the tube is 1 m, and the temperature of the water bath is -5 o C, the solution of the collected betamipron sodium salt was acidified to pH=2 with concentrated hydrochloric acid, the betamipron solid was collected by filtration, washed with water and dried, and vacuum-dried to constant weight to obtain 1.66 g, with an HPLC purity of 86%. The rate is 74% (according to alanine).

Embodiment 3

[0031] 0.01 mol alanine, 0.01 mol sodium hydroxide and 0.022 mol sodium bicarbonate were dissolved in 13.5 ml water to obtain solution A and 1.16 ml benzoyl chloride, respectively at a flow rate of V A = 28ul / min and V B = 2.41ul / min is simultaneously propelled by pump A and pump B to inject into the mixer and enter the reactor for reaction. The diameter of the microtube of the reactor is 0.7 mm, the length of the tube is 1 m, and the temperature of the water bath is 0 o C, the solution of the collected betamipron sodium salt was acidified to pH=2 with concentrated hydrochloric acid, the betamipron solid was collected by filtration, washed with water and dried, and vacuum-dried to constant weight to obtain 1.78 g, with an HPLC purity of 92%. The rate is 85% (according to alanine).

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Abstract

The invention discloses a method for synthesis of betamipron in a continuous-flow microreactor. The method comprises the following steps: 1) injecting an aqueous solution containing 0.5-1 M of a mixture of beta-alanine, sodium hydroxide and sodium bicarbonate into a micro mixer through a connecting pipe at a flow rate of 4-48 [mu]l/min, at the same time, injecting benzoyl chloride into the micro mixer through a same-diameter connecting pipe at a flow rate of 0.35-4.14 [mu]l/min, mixing, then allowing the mixed solution to go into the micro-tube reactor for reaction, and thus obtaining a betamipron sodium salt solution, wherein the water bath temperature of the microreactor is -5 DEG C to 5 DEG C, the micro-tube diameter of the micro-tube reactor is 0.3-1.5 mm, and the tube length is 1-3 m; 2) acidizing the betamipron sodium salt solution by concentrated hydrochloric acid until the pH is 2, precipitating out a betamipron solid, filtering, washing, and drying to obtain the betamipron. The betamipron is synthesized in the continuous-flow microreactor; through precise control of mixing of the raw materials and strengthening condensation reaction conditions, the main reaction speed is accelerated, and generation of a benzoyl chloride hydrolysis side reaction is reduced, so that the content of benzoic acid in the crude product is reduced, the purification operation is simplified, and the betamipron yield is improved.

Description

technical field [0001] The invention relates to a method for synthesizing betamipron, in particular to a method for synthesizing betamipron in a continuous flow microreactor. Background technique [0002] Betamipron (Betamipron) also known as " N -Benzoyl-β-alanine" is a compound that is often used in combination with the antibiotic panipenem at a ratio of 1:1. Panipenem-betamiron is a carbapenem antibiotic drug, It has attracted widespread attention due to its wide antibacterial spectrum, strong antibacterial activity, low toxicity and drug resistance. It has become an effective antibacterial drug for the treatment of severe nosocomial infections, multidrug-resistant bacterial infections, and mixed infections. Important position [1]. Betamipron can competitively inhibit the secretion of panipenem to the renal tubules, thereby reducing the concentration of panipenem in the renal cortex and weakening the nephrotoxicity of panipenem. [0003] The synthesis method reported in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/83C07C231/02
Inventor 雷鸣李伟张宏
Owner ZHEJIANG UNIV
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