The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable conducted a study to elucidate the value of continuous processing, which had been defined as key research area for green engineering. In course defining business case individual cases were collected and evaluated determine specific drivers implement processing find success factors. magnitude timing effects relation principles chemistry investigated.

The development of a continuous flow sulfoxide imidation protocol for pharmaceutically relevant target molecule is described. Sulfoxide key step in the preparation certain ATR kinase inhibitors. Reactions with NaN3 or TMSN3 and concentrated sulfuric acid under literature conditions provided low conversions poor selectivities. In contrast, reactions employing fuming afforded sulfoximine selectivity ∼90% after reaction time only 10–15 min at 50 °C. using as reagent was successfully performed...

AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with chiral morpholine, cyclopropyl sulfoximine, and an azaindole, make it challenging molecule to synthesize on large scale. We describe evolution chemical processes, following manufacture from initial scale-up through multikilos plant During this evolution, we developed biocatalytic process install sulfoxide high enantioselectivity, followed by...

For on-line monitoring of chemical reactions (batch or continuous flow), mass spectrometry (MS) can provide data to (1) determine the fate starting materials and reagents, (2) confirm presence desired product, (3) identify intermediates impurities, (4) steady state conditions point completion, (5) speed up process optimization. Recent developments in small footprint atmospheric pressure ionization portable spectrometers further enable this coupling, as spectrometer be easily positioned with...

A safe and scalable continuous flow strategy for Wolff–Kishner reductions that employs methanol as the solvent has been developed. The use of low-cost hydrazine reducing agent in combination with a caustic base provides an atom-efficient, environmentally friendly method deoxygenation aldehydes ketones to alkanes. Because required harsh corrosive reaction conditions (200 °C, 50 bar), reactor materials such stainless steel, glass, or any type polymer have compatibility problems, rendering this...

A definitive screening design (DSD) combined with reaction profiling was conducted using a flow reactor, in short time frame, for the accurate estimation of kinetic parameters.

A continuous-flow protocol utilizing syngas (CO and H

Abstract A continuous‐flow protocol for Pd‐catalyzed olefin cleavage by using molecular oxygen as the sole oxidant to give carbonyl compounds was explored. The developed flow allowed use of a low catalyst loading (0.1 mol %), and decomposition active prevented through stabilization poly(ethylene glycol)‐400 (PEG‐400), which present cosolvent. Radical scavengers inhibited reaction, indicated involvement free‐radical path in reaction mechanism. applicability demonstrated on several substrates....

The development of a continuous flow ruthenium-catalyzed ester reduction using hydrogen gas is described. assessment green metrics show the protocol substantially more sustainable than commonly employed metal hydride reductions.

The development of a commercial manufacturing process for fulvestrant (the active ingredient in 'Faslodex') is described. Key steps the synthesis are stereoselective 1,6-addition an organocuprate to steroidal dienone followed by copper-mediated aromatisation A-ring. strategy dealing with noncrystalline intermediates outlined. production drug substance acceptable quality critically dependent on limiting formation key impurities. origin these impurities discussed, and measures prevent or control their

Key steps in the synthesis of ZM549865 (a 5-HT receptor antagonist) are palladium-catalysed amination ethyl 8-bromo-6-fluoro-4-oxo-4H-2-chromenecarboxylate and subsequent hydrolysis ester group. The development a simple, robust process capable making multikilogram amounts required intermediate is described. Performing step at 125 °C instead 80 optimising conditions led to an increase overall yield from 44% about 70% as well reducing reaction time days hours. chromone ring was initially...

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTFlow Chemistry and Continuous Processing: More Mainstream than Ever!Kevin P. Cole*Kevin ColeSynthetic Molecule Design Development, Lilly Research Laboratories, Eli Company, Indianapolis, Indiana 46285, United States*Email: [email protected]More by Kevin Colehttps://orcid.org/0000-0002-2333-6557, Jonathan N. JaworskiJonathan JaworskiProcess Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, Massachusetts 02139, StatesMore...

Abstract The spiroketal moiety is an important substructure within many biological natural products. One method to access them via the oxidative cyclisation of a pendant hydroxyl group on pre‐formed pyran. However applications this methodology have been severely limited by requiring use toxic oxidants, such as lead (IV) tetraacetate or mercuric oxide. Herein we report high yielding photochemical route prepare complex spiroketals using approach employing iodine monochloride and sodium acetate...

The development of a continuous-flow sequence for the synthesis an important drug candidate precursor is reported. Abediterol β2-adrenoceptor agonist that has undergone phase IIa clinical trials treatment respiratory disease. A flow developed preparation lipophilic amine tail portion abediterol. comprises phase-transfer-catalyzed liquid/liquid O-alkylation, rhodium-catalyzed hydroformylation, and ruthenium-catalyzed reductive amination. reactions were optimized separately within environments...

In a previous publication (Org. Process Res. Dev. 2010, 14, DOI:10.1021/op100161y) we described the process research and development of manufacturing route for potent SRC kinase inhibitor AZD0530. While was successfully used to manufacture 4.5 kg AZD0530 difumarate, it still relatively long, two Mitsunobu couplings, was, in our opinion, undesirable on larger scale. Herein describe shorter, more practical synthesis difumarate. The new route, which required fewer steps, scaled well produce >80...

Abstract The spiroketal moiety is an important substructure within many biological natural products. One method to access them via the oxidative cyclisation of a pendant hydroxyl group on pre‐formed pyran. However such precursors has hitherto been challenging and requires multistep syntheses frequently with considerable protecting manipulation. Herein we report novel high yielding for preparation hydroxydi‐ hydroxytetra‐hydropyrans, as precursors, utilizing double‐Prins approach.

Abstract On treatment with formamides and POCl 3 , the title compounds produce benzoxazinone structures.