Advances on continuous-flow synthesis of drugs in microreactors

doi:10.11949/0438-1157.20231416

Abstract

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, drug, process intensification, kinetics, continuous-flow synthesis

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

CLC Number:

TQ 052

Xiao XUE, Minjing SHANG, Yuanhai SU. Advances on continuous-flow synthesis of drugs in microreactors[J]. CIESC Journal, 2024, 75(4): 1439-1454.

薛潇, 商敏静, 苏远海. 微反应器内药物连续流合成的研究进展[J]. 化工学报, 2024, 75(4): 1439-1454.

Figures/Tables 18

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

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

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

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

Fig.5 Experimental setup for DTG-7 demethylation

Fig.6 The operating window of DTG-7 demethylation

Fig.7 Continuous-flow synthesis of azide 5

Fig.8 Continuous-flow synthesis of m-dinitrobenzene

Fig.9 Microfluidic chips of different materials

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]

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]

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

Fig.13 Benzyl carbonylation in chip-type microreactor

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

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

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

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

Fig.17 (a) Stacked catalytic membrane microreactor; (b) Gas-liquid-solid mini-fluidized bed; (c) Thin film microreactor

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