Synthesis of biologically active agents using flow chemistry
Enabling tools and technologies such as flow synthesis devices and approaches, solid-supported reagents, scavengers and computer-led processes has been assisting us in our medicinal chemistry programmes. Here we show some of the flow processes and new methods that we have developed for a number of pharmaceutical compounds.
In this synthesis we used a newly developed, chemically resistant, peristaltic pumping system to pump organometallic reagents (nBuLi), Grignard reagents, and DIBAL-H. We have shown how it can be used in common transformations (metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction) and telescoping of anionic reaction products. This platform allowed truly continuous pumping of these highly reactive substances, over several hours, to generate multigram quantities of products. This work culminated in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.
Meclinertant (SR 48692)
We developed an improved synthesis of the neurotensin antagonist biological probe SR 48692. The preparation includes an number of chemical conversions and strategies involving the use of flow chemistry platforms which helped overcome some of the limiting synthetic transformations in the original chemical route .
We had previously developed a tube-in-tube reactor based on a semipermeable polymer membrane to enable the transfer of gases into liquid flow streams. and here, we demonstrate the scalability and throughput of this reactor when used with ammonia gas. This was made possible by a the inclusion of a titration method to assess parameters including the liquid and gas configuration, reactor temperatures, flow rates, and solvent polarity. These data were then employed in a scaling-up process affording alkyl thioureas which were ultimately used in a telescoped procedure for the preparation of anti-inflammatory agent fanetizole on a multigram scale.
We reported a concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia. This synthesis was conducted using tubular flow coils or cartridges packed with reagents or scavengers to bring about all the steps of the preparation of the API. Furthermore, we devised a simple solution to in-line evaporation and solvent switching during a flow chemistry application.
Synthesis of a δ-Opioid Receptor Agonist
This article describes the design, optimisation and development of a continuous flow synthesis of N,N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl)benzamide, a potent delta-opioid receptor agonist developed by AstraZeneca. With a ReactIR flow cell used as a monitoring device, initiation of the fourth input flow stream was precisely controlled for the dehydration step using the Burgess reagent.
Casein Kinase I Inhibitors
Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing the three principle chemical inputs.
This article describes the continuous flow synthesis of 6-methoxy-8-(4-methyl-1,4-diazepan-1-yl)-N-(4-morpholinophen-yl)-4-oxo-1,4-dihydroquinoline-2-carboxamide, a potent 5HT1B antagonist developed by AstraZeneca. Notably, in this work is the use of Hastelloy flow coils to bring about high temperature reactions commonly achieved using microwave methods.
Tamoxifen: Continuous flow-processing of organometallic reagents using an advanced peristaltic pumping system and the telescoped flow synthesis of (E/Z)-tamoxifen P.R.D. Murray, D.L. Browne, J.C. Pastre, C. Butters, D. Guthrie, S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1192-1208.
Meclinertant (SR 48692): A machine-assisted flow synthesis of SR48692: a probe for the investigation of neurotensin receptor-1 C. Battilocchio, B.J. Deadman, N. Nikbin, M.O. Kitching, I.R. Baxendale, S.V. Ley, Chem. Eur. J. 2013, 19, 7917-7930.
Fanetizole: Scaling-up of continuous flow processes with gases using a tube-in-tube reactor: in-line titrations and fanetizole synthesis with ammonia J. Pastre, D.L. Browne, M. O’Brien and S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1183-1191.
Gleevec: An automated flow-based synthesis of imatinib: the API of gleevec M.D. Hopkin, I.R. Baxendale, S.V. Ley, Chem. Commun. 2010, 46, 2450-2452
Opioid Receptor Antagonist: A continuous flow process using a sequence of microreactors with in-line IR analysis of the preparation of N, N-diethyl-4-(3-fluorophenylpiperidin-4-ylidenemethyl) benzamide as a potent and highly selective gamma-opioid receptor agonist Z. Qian, I.R. Baxendale, S.V. Ley, Chem. Eur. J. 2010, 16, 12342-12348
Casein Kinase Inhibitors: Application of flow chemistry microreactors in the preparation of casein kinase I inhibitors
F. Venturoni, N. Nikbin, S.V. Ley, I.R. Baxendale, Org. Biomol. Chem. 2010, 8, 1798-1806
5HT1B Antagonist: A flow process using microreactors for the preparation of a quinolone derivative as a potent 5HTIB antagonist Z. Qian, I. R. Baxendale, S.V. Ley, Synlett, 2010, 505-508