The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

Abstract

The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process.

Keywords: continuous processing; flow synthesis; in-line analysis; manufacture; pharmaceuticals; scalability.

Figure 1

Pharmaceutical structures targeted in early flow syntheses.

Scheme 1

Flow synthesis of 6-hydroxybuspirone (9). Inserted photograph reprinted with permission from [45]. Copyright 2008 American Chemical Society.

Figure 2

Configuration of a baffled reactor tube (left) and its schematic working principle (right).

Scheme 2

McQuade’s flow synthesis of ibuprofen (16).

Scheme 3

Jamison’s flow synthesis of ibuprofen sodium salt (17).

Scheme 4

Flow synthesis of imatinib (23).

Scheme 5

Flow synthesis of the potent 5HT1B antagonist 28.

Scheme 6

Flow synthesis of a selective δ-opioid receptor agonist 33.

Scheme 7

Flow synthesis of a casein kinase I inhibitor library (38).

Scheme 8

Flow synthesis of fluoxetine (46).

Scheme 9

Flow synthesis of artemisinin (55).

Scheme 10

Telescoped flow synthesis of artemisinin (55) and derivatives (62–64).

Scheme 11

Flow approach towards AZD6906 (65).

Scheme 12

Pilot scale flow synthesis of key intermediate 73.

Scheme 13

Semi-flow synthesis of vildagliptine (77).

Scheme 14

Pilot scale asymmetric flow hydrogenation towards 83. Inserted photograph reprinted with permission from [75]. Copyright 2012 American Chemical Society.

Figure 3

Schematic representation of the ‘tube-in-tube’ reactor.

Scheme 15

Flow synthesis of fanetizole (87) via tube-in-tube system.

Scheme 16

Flow synthesis of diphenhydramine^.HCl (92).

Scheme 17

Flow synthesis of rufinamide (95).

Scheme 18

Large scale flow synthesis of rufinamide precursor 102.

Scheme 19

First stage in the flow synthesis of meclinertant (103).

Scheme 20

Completion of the flow synthesis of meclinertant (103).

Scheme 21

Flow synthesis of olanzapine (121) utilising inductive heating techniques.

Scheme 22

Flow synthesis of amitriptyline·HCl (127).

Scheme 23

Flow synthesis of E/Z-tamoxifen (132) using peristaltic pumping modules.

Figure 4

Container sized portable mini factory (photograph credit: INVITE GmbH, Leverkusen Germany).

Scheme 24

Flow synthesis of imidazo[1,2-a]pyridines 136 linked to frontal affinity chromatography (FAC).

Figure 5

Structures of zolpidem (142) and alpidem (143).

Scheme 25

Synthesis and screening loops in the discovery of new Abl kinase inhibitors.

Figure 6

Schotten–Baumann approach towards LY573636^.Na (147).

Scheme 26

Pilot scale flow synthesis of LY2886721 (146).

Scheme 27

Continuous flow manufacture of alikiren hemifumarate 152.