Communication pubs.acs.org/OPRD
A Simple Scale-up Strategy for Organolithium Chemistry in Flow Mode: From Feasibility to Kilogram Quantities Andreas Hafner, Paolo Filipponi, Lorenzo Piccioni, Mark Meisenbach, Berthold Schenkel, Francesco Venturoni, and Joerg Sedelmeier* Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland S Supporting Information *
alities (e.g., nitriles), and (4) the limited stability of aryl lithium intermediates over extended reaction times often observed with increasing batch sizes.4 Continuous manufacturing (CM) can address these issues as it allows for a superior control of the reaction conditions compared to batch mode due to the enhanced control of process parameters like mixing, residence time, temperature, concentration profile, and stoichiometry.5 Previously, we reported the development of a CM platform which uses standardized reaction conditions dedicated to the reaction sequence of Hal/Li exchange and a consecutive electrophilic quench allowing for the rapid assessment, evaluation, investigation, and demonstration of a chemical and technical feasibility of a flow process (Scheme 1).6 As a showcase, the usefulness of this setup was demonstrated by the synthesis of various boronic acids in high purity on multigramscale within ≤1 s total residence time.
ABSTRACT: A platform for conducting organolithium chemistry in continuous flow mode, covering the scales from medicinal chemistry to later phase process development, is described. The use of this flow setup, which mimics the concept of f lash chemistry on scale, has been demonstrated by the exemplary, large-scale preparation of (4-fluoro-2-(trifluoromethyl)phenyl)boronic acid following a reaction sequence of halogen/lithium exchange, borylation, and semibatch workup. Furthermore, the key factors and corresponding practical assessments required for the streamlined and seamless scale-up from lab environment to higher productivity are highlighted. KEYWORDS: continuous manufacturing, organolithium chemistry, aryl boronic acids, scale-up concept
1. INTRODUCTION The timelines in the pharmaceutical industry for process development and the supply of drug product for clinical trials are often challenging tasks. The product demand from initial few kilograms in early phases may rapidly rise to hundreds of kilograms in late phase projects.1 To fulfill the ambitious delivery timelines for intermediates and drug products and to ensure consistent yields and purities, the time for redevelopment of a chemical process during scale-up must be minimal, and the process must be robust and reliable. Scale-up operations, commonly performed in traditional batch vessels, are often not straightforward and unexpected issues arise. Common phenomena might include change in product yield or purity, which could be a result of varying mixing efficiency, changing of batch vessels geometry, differing heating/cooling capacity of a reactor or deviating holding/dosing times, among others.1a The widespread application of arylboronic acids in modern organic synthesis originates from their role as a reaction partner in transition metal catalyzed cross coupling reactions.2 The most attractive and cost-effective method for their preparation on a large scale proceeds via an aryl lithium moiety and consecutive quench with a trialkyl borate at low temperature followed by an acidic aqueous hydrolysis.3 Execution of this general methodology in conventional batch mode bears certain drawbacks, such as (1) the need for cryogenic conditions which appears challenging and costly on scale, (2) the potential hotspots formation generating undesired byproducts, (3) the incompatibility with certain pendant electrophilic function© 2016 American Chemical Society
Scheme 1. Previously Reported Flow Setup for the Continuous Flow Synthesis of Boronic Acids on a Laboratory Scale
Although this setup already provides a throughput of about 1 g/min, which is sufficient for medicinal chemistry application or early development phases in pharmaceutical industry, greater productivity is necessary for later development phases (∼multikilograms/days). Therefore, it is of paramount importance to have an appropriate concept in place allowing for a seamless scale-up of an early to a late development setup capable of delivering multikilograms per day. Therefore, in contrast to previously reported impressive work on the synthesis and use of boronic acids under flow conditions,7 we herein focused on a technically simple and Received: August 24, 2016 Published: September 27, 2016 1833
DOI: 10.1021/acs.oprd.6b00281 Org. Process Res. Dev. 2016, 20, 1833−1837
Organic Process Research & Development
Communication
Scheme 2. Metalation/Borylation Sequence for the Synthesis of Boronic Acid 2a Starting from Aryl Bromide 1a
straightforward scale-up concept based on our previously developed metalation platform (Scheme 1) enabling for the practical and efficient synthesis of aryl boronic acids in continuous flow mode within one second.
solubility of all reaction partners and intermediates at the applied concentrations. (B) The reaction in flow mode (JT = −30 °C) is superior to batch mode (JT = −78 °C) as the desired product was obtained in higher yield and higher purity. (C) The metalation step as well as the borylation step is very fast (limited by mixing), and full conversion can be achieved in 0.5 s per step. (D) As the residence time of both steps is very short (
