Study on efficient dissolution of D-7-ACA using membrane dispersion microreactor

doi:10.11949/0438-1157.20221130

Abstract

Abstract:

3-Decarbamoyl-cefuroxime (DCC), the key intermediate for the synthesis of cefuroxime, is obtained by condensing the 3-deacetyl-7-aminocephalosporanic acid (D-7-ACA) solution with the acid chloride. The dissolution of D-7-ACA in water and methanol using high concentration NaOH solution is the first step. However, the β-lactam ring in D-7-ACA is prone to ring-opening reaction under strong alkaline condition, resulting in low yield. The D-7-ACA dissolution has low concentration and low efficiency in a traditional tank, due to the imprecise pH control and poor micro-mixing. Therefore, a new membrane dispersion microreactor was designed and used to dissolute D-7-ACA. Firstly, the degradation kinetics of D-7-ACA at different concentration, temperature and pH value were investigated. Then the effects of the pH, temperature, and circulation flow rate on the dissolution concentration were investigated carefully. The results showed that the concentration of the D-7-ACA solution is about 76.50 mg/ml, and the target product DCC yield is about 91.90% under the optimal conditions using membrane dispersion microreactor, which were increased by 5.91% and 5.61%, respectively, compared to using traditional reactor. The microreactor provides a good choice for industrially dissolving pH-sensitive drugs.

Key words: dissolution, degradation kinetics, microreactor, 3-deacetyl-7-aminocephalosporanic acid, 3-decarbamoyl-cefuroxime

摘要：

合成头孢呋辛的关键中间体3-去氨甲酰基头孢呋辛（DCC）由3-去乙酰基-7-氨基头孢烷酸（D-7-ACA）溶液与酰氯试剂缩合得到，其中利用高浓度NaOH溶液将D-7-ACA溶解在水和甲醇中是第一步。而D-7-ACA中的β-内酰胺环在强碱性条件下容易发生开环反应，造成收率不高。传统反应釜不能精确控制体系的pH、混合效果差，因此溶解得到的D-7-ACA溶解浓度低。采用一种膜分散微反应器，实现了高效溶解D-7-ACA，并研究了D-7-ACA在不同初始浓度、不同温度和pH条件下的降解动力学。接着详细探讨了pH、温度和循环流速等因素对膜分散微反应器溶解D-7-ACA的影响。结果显示，利用膜分散微反应器在最优条件下得到的D-7-ACA溶解浓度为76.50 mg/ml，DCC收率为91.90%，相比传统搅拌法分别提高了5.91%和5.61%。

关键词: 溶解, 降解动力学, 微反应器, 3-去乙酰基-7-氨基头孢烷酸, 3-去氨甲酰基头孢呋辛

CLC Number:

TQ 465

Yu XIE, Min ZHANG, Weiguo HU, Yujun WANG, Guangsheng LUO. Study on efficient dissolution of D-7-ACA using membrane dispersion microreactor[J]. CIESC Journal, 2023, 74(2): 748-755.

谢煜, 张民, 胡卫国, 王玉军, 骆广生. 利用膜分散微反应器高效溶解D-7-ACA的研究[J]. 化工学报, 2023, 74(2): 748-755.

Figures/Tables 11

Fig.1 The diagram of DCC synthetic route

Fig.2 The degradation reaction of D-7-ACA under alkaline condition

Fig.3 Schematic diagram of experimental devices

Fig.4 D-7-ACA degradation curves at different initial concentrations and temperatures

Fig.5 Dispersed phase flow rate control process and changes of pH

Fig.6 Effect of the reaction temperature on dissolution efficiency and reaction time

Fig.7 Effect of the pH of the microreactor outlet on dissolution efficiency and reaction time

Fig.8 Effect of the circulation flow rate on dissolution efficiency and reaction time

Fig.9 Comparison between the D-7-ACA dissolution efficiency in the microreactor and that in the traditional reactor

Fig.10 Effect of different D-7-ACA solutions on DCC yield

Fig.11 Comparison DCC yield between dissolution in the microreactor and that in the traditional reactor

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