A flow process using microreactors for the preparation of a quinolone derivative as a potent 5HTIB antagonist

QuinolonesThe quinolone derivative shown below is a potent 5HT1B antagonist developed by AstraZeneca. The continuous flow synthesis (the final steps shown below) of this pharmaceutical agent was completed using a combination of flow microreactors, while incorporating polymer-supported reagents and scavengers to aid reaction telescoping and purification [14]. The result is encouraging, as it clearly demonstrates that multi-step sequences can be incorporated into flow chemistry platforms leading to polyfunctional molecules of biological interest. Moreover, we were able to improve on the overall yield via a batch method using the new reactors.

A flow process using microreactors for the preparation of a quinolone derivative as a potent 5HTIB antagonistZ. Qian, I. R. Baxendale, S.V. Ley
Synlett 2010, 505-508

Antimalarial flow synthesis closer to commercialisation

The divergent, multi-step continuous process includes continuous in-line purification

Scientists in Germany have demonstrated the large scale and inexpensive production of a range of antimalarial drugs, using a continuous flow system.

The processes yields several artemisinin-derived APIs that are key components in Artemisinin Combination Therapies

http://www.rsc.org/chemistryworld/2014/09/antimalarial-flow-synthesis-commercialisation-artemisinin

Application of Continuous Flow Micromixing Reactor Technology for Synthesis of Benzimidazole Drugs

Synthesis of pharmaceutically active compounds by employing continuous flow micromixing reactor technology is an interesting research area. In this article we describe the synthesis of benzimidazole core drugs, 

such as lansoprazole (1a), pantaprazole (1b), and rabeprazole (1c) by using a continuous flow micromixing reactor technology. A key feature of the sulfoxidation includes the decreasing the reaction time from 3 h to ∼1 s to minimize the formation of sulfone impurities and improve the yields.

http://pubs.acs.org/doi/abs/10.1021/op300325f?journalCode=oprdfk

Gunupati Sharathchandra Reddy , Narra Santosh Reddy , Kushal Manudhane , Medisetti Venkata Rama Krishna , Kopparapu Janardana Sarma Ramachandra , and Srinivas Gangula *

Center of Excellence in Process Engineering, Research and Development, Integrated Product Development, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, Ranga Reddy District 500072, Andhra Pradesh, India

Org. Process Res. Dev., 2013, 17 (10), pp 1272–1276

DOI: 10.1021/op300325f

http://pubs.acs.org/doi/abs/10.1021/op300325f?journalCode=oprdfk

Continuous Flow Total Synthesis of Rufinamide

Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. 

Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddition reaction. 

Each of the three chemical steps enjoys significant benefits and has several advantages by being conducted in flow. The total average residence time of thesynthesis is approximately 11 min, and rufinamide is obtained in 92% overall yield.

Ping Zhang †, M. Grace Russell ‡, and Timothy F. Jamison *†

† Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

‡ Franciscan University of Steubenville, 1235 University Boulevard, Box 1012, Steubenville, Ohio 43952, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op500166n

http://pubs.acs.org/doi/abs/10.1021/op500166n

http://pubs.acs.org/doi/suppl/10.1021/op500166n/suppl_file/op500166n_si_001.pdf

Fully Continuous Synthesis of Rufinamide (6). A DMSO solution of 2,6-

Difluorobenzyl bromide [1 M] and biphenyl (internal standard) [0.1 M] was loaded in an 

8-mL stainless steel syringe (feed A). A [0.5 M] DMSO solution of sodium azide was 

loaded in a second 8-mL stainless steel syringe (feed B). 

Neat methyl propiolate (feed C) and ammonium hydroxide (~28% ammonia, feed D) were loaded in 2-mL SGE glass syringes, respectively. All the four syringes were pumped with Harvard Apparatus 

syringe pumps. Feed C was pumped at 2.2 µL/min and feed D was pumped at 6.6 

µL/min. The two feeds were mixed and passed through a 40 µL PFA reactor; both mixer 

and reactor were cooled in a ice-water bath.

At the meanwhile, feed A was pumped at 16.5 µL/min and feed B was pumped at 41.3 µL/min and stream upon mixing was passed through a 57 µL PFA reactor at room temperature. The two outlets were jointed with a T-mixer and passed through a 431 µL copper tubing reactor. 

The reactor was heated at 110 ºC and equipped with a 100 psi back-pressure regulator (BPR). The overall residence time for the continuous-flow reaction sequence was 11 minutes. Allowed 44 minutes to stabilize, the reaction was collected for 60 minutes and afforded brown/red solution. Two 

drops of the solution was diluted with methanol to 1 mL, which was then analyzed by 

LCMS to give 98% yield. To the left reaction mixture was added 2V water while stirring 

and the resulting slurry was set for 15 minutes. 

Upon filtration, washing with water, the off-white sticky cake was dried in vacuum oven for 24 hours. The dried off-white solid afforded 215 mg rufinamide (92% yield). NMR in DMSO-d6 was in accordance with 

literature.1

 HRMS (ESI+) for C10H8F2N4ONa [M+Na]: calculated: 261.0558, found: 

261.0559.