微反应器内药物连续流制备的研究进展

doi:10.11949/0438-1157.20231416

摘要/Abstract

摘要：

由于微反应器的特征尺寸较小，其比表面积大，混合效率高，热质传递效率快，可精确调控反应过程。相比于传统的釜式反应器，在微反应器内开展药物的单步/多步合成，具有高选择性、高效率、本质安全等优势。综述了近年来在三种常用的微反应器包括毛细管微反应器、板式微反应器和微填充床反应器以及其他新型微反应器中进行药物及其中间体连续流合成的研究进展。从均相和非均相反应进行分析，总结了不同类型微反应器的优势。最后，对药物连续流合成的发展方向进行了展望。

关键词: 微反应器, 药物, 过程强化, 动力学, 连续流合成

Abstract:

Due to small characteristic size of microreactors, it has a large specific surface area, high mixing efficiency, fast heat and mass transfer efficiency, and can accurately control the reaction process. Compared with the traditional synthesis in batch, the single/multi-step synthesis of drugs in microreactors can achieve the advantages of high selectivity, high efficiency and intrinsic process safety. This article reviews the recent research progress in continuous flow synthesis of drugs and their intermediates in three commonly used microreactors, including capillary microreactors, plate microreactors and micropacked bed reactors, as well as other new microreactors. The advantages of different types of microreactors are summarized from the perspective of homogeneous and heterogeneous reactions. Finally, the development directions of continuous-flow synthesis of drugs in the future are prospected.

Key words: microreactors, pharmaceuticals, process intensification, kinetics, continuous-flow manufacturing

中图分类号:

TQ052

薛潇, 商敏静, 苏远海. 微反应器内药物连续流制备的研究进展[J]. 化工学报, DOI: 10.11949/0438-1157.20231416.

Xiao XUE, Minjing SHANG, Yuanhai SU. Advances on continuous-flow synthesis of drugs in microreactors[J]. CIESC Journal, DOI: 10.11949/0438-1157.20231416.

图/表 18

图1 用于治疗HIV-1的整合酶抑制剂注:(a) 多替拉韦 (b)卡替拉韦 (c)比克替拉韦

Fig.1 Integrase inhibitors for the treatment of HIV-1

图2 圆形截面弯管内的迪恩涡流

Fig.2 Dean vortices in the curved tube of circular cross-section

图3 毛细管微反应器中API前体3的对映选择性合成

Fig.3 Enantioselective synthesis of API precursors 3 in capillary microreactor

图4 在级联微反应器系统中DTG-4经两步法合成DTG-6的装置图

Fig.4 Experimental setup for two-step synthesis of DTG-6 from DTG-4 in the cascade microreactor system

图5 DTG-7脱甲基反应的装置图

Fig.5 Experimental setup for DTG-7 demethylation

图6 DTG-7脱甲基反应的操作窗口

Fig.6 The operating window of DTG-7 demethylation

图7 连续流合成叠氮5

Fig.7 Continuous-flow synthesis of azide 5

图8 连续流合成间二硝基苯

Fig.8 Continuous-flow synthesis of m-dinitrobenzene

图9 不同材质的微流控芯片：（a）硅玻璃，（b）陶瓷，（c）不锈钢，（d）玻璃

Fig.9 Microfluidic chips of different materials

图10 (a) 内置三角形障碍物的板式微反应器[60]；（b）三种不同通道（线形、双蛇型、蛇形）的板式微反应器[61]；（c）光学显微镜下分裂重组（SAR）微反应器[51]

Fig.10 (a) Chip-type microreactor embedding triangular obstacles[60]; (b) chip-type microreactors with three different channels (linear-like, double-snake-like, snake-like)[61]; (c) splitting and recombining (SAR) microreactor under the optical microscope[51]

图11 （a）传统的地西泮合成路线[63]；（b）板式微反应器中产生固体[64]；（c）地西泮的连续流合成装置图[64]

Fig.11 (a) Traditional synthesis route of diazepam[63]; (b) generation of solids in chip-type microreactor[64]; (c) experimental setup for the continuous-flow synthesis of diazepam[64]

图12 板式微反应器中连续流合成埃索美拉唑

Fig.12 Continuous-flow synthesis of esomeprazole in chip-type microreactor

图13 板式微反应器中的苄氧化反应

Fig.13 Benzyl carbonylation in chip-type microreactor

图14 微填充床反应器中合成厄洛替尼中间体15

Fig.14 Synthesis of erlotinib intermediate 15 in micropacked-bed reactor

图15 （a）H-Cube Pro微填充床反应器，（b）FlowCAT微填充床反应器

Fig.15 (a) Micropacked-bed reactor of H-Cube Pro, (b) micropacked-bed reactor of FlowCAT

表1 H-Cube微填充床反应器内加氢反应的结果

Table 1 Results for hydrogenation reaction in micropacked-bed reactor of H-Cube

产物	产率/%
5-氨基吲哚	96
2-萘胺	85
7-氨基吲哚	98
4-氨基苯酚	96
4-哌嗪基苯胺	98

图16 微填充床反应器中连续流氢化反应的装置图

Fig.16 Experimental setup for continuous-flow hydrogenation in micropacked-bed reactor

图17（a） 叠层催化膜微反应器，（b）气-液-固微型流化床反应器，（c）薄膜微反应器

Fig.17 (a) Stacked catalytic membrane microreactor, (b) gas-liquid-solid mini-fluidized bed, (c) thin film microreactor

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