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Scheme 1: Flow synthesis of fluoxetine (46).
PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry,and , Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134
One of the early published examples of industry-based research on multi-step flow synthesis of a pharmaceutical was reported in 2011 by scientists from Eli Lilly/UK and detailed the synthesis of fluoxetine 46, the API of Prozac. In this account each step was performed and optimised individually in flow, with analysis and purification being accomplished off-line. The synthesis commences with the reduction of the advanced intermediate ketone 47 using a solution of pre-chilled borane–THF complex (48) to yield alcohol 49 (Scheme 1).
Conversion of the pendant chloride into iodide 51 was attempted via Finckelstein conditions, however, even when utilising phase-transfer conditions in order to maintain a homogeneous flow regime the outcome was not satisfactory giving only low conversions. Alternatively direct amination of chloride 49 utilising high temperature flow conditions (140 °C) allowed the direct preparation of amine 50 in excellent yield.
Flow processing using a short residence time (10 min) at the elevated temperature allowed for a good throughput; in addition, the handling of the volatile methylamine within the confines of the flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up.
The final arylation of 50 was intended to be performed as a SNAr reaction, however, insufficient deprotonation of the alcohol 50 under flow conditions (NaHMDS or BEMP instead of using a suspension of NaH as used in batch) required a modification to the planned approach. To this end a Mitsunobu protocol based on the orchestrated mixing of four reagent streams (50, 54 and reagents 52 and 53) was developed and successfully applied to deliver fluoxetine (46) in high yield.
Overall, this study is a good example detailing the intricacies faced when translating an initial batch synthesis into a sequence of flow steps for which several adaptations regarding choice of reagents and reaction conditions are mandatory in order to succeed.
Dr Marcus Baumann
Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.
Prof. Ian R. Baxendale
(email at email@example.com)
My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.
My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.
For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/
- Ahmed-Omer, B.; Sanderson, A. J. Org. Biomol. Chem. 2011, 9, 3854–3862. doi:10.1039/C0OB00906G
Preparation of fluoxetine by multiple flow processing steps*Corresponding authorsaEli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UKOrg. Biomol. Chem., 2011,9, 3854-3862
Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
1 The general method set-up of flow process used for the synthesis of (±)- fluoxetine.
Scheme 1 Synthesis of (±)-fluoxetine in flow: (i) BH3·THF, r.t., 5 min (77%); (ii) NaI, toluene: water, 100 °C, 20 min (43%); (iii); MeNH2 (aq), …
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