AG13736 (Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under investigation as an oncology drug, is currently manufactured via a three-step process that utilizes two palladium-mediated cross-couplings. Historically, removal of residual heavy metals from the active pharmaceutical ingredient has been a persistent issue. The development of a much improved process for palladium removal and a useful screening technique developed to rapidly identify the most efficient reagents for this purpose are outlined. The performance of the new endgame process in pilot-plant scale-up is also discussed.
The
manufacturing process of axitinib (1) involves
two Pd-catalyzed coupling reactions, a Migita coupling and a Heck
reaction. Optimization of both of these pivotal bond-formation steps
is discussed as well as the approach to control impurities in axitinib.
Essential to the control strategy was the optimization of the Heck
reaction to minimize formation of impurities, in addition to the development
of an efficient isolation of crude axitinib to purge impurities.
The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.
An electrochemical method has been developed for a mediated oxidation of primary alcohols to carboxylic acids. The method is compatible with a variety of alcohols bearing nitrogen-containing heterocycles in undivided batch and flow modes. The use of a heterogeneous NiOOH electron−proton transfer mediator avoids the need for homogeneous catalysts that contribute to more unit operations during downstream purging and increased process mass intensity. To demonstrate the applicability of this method for continuous processing, a single-pass flow electrochemical oxidation of nicotinyl alcohol to nicotinic acid is demonstrated with a 77% isolated yield. The NiOOH-coated anodes show no reduction in catalysis efficiency over 12 h, and minimal Ni metal leaching (22.3 μg per liter) is observed.
Anhydrous tert-butyl
hydroperoxide (TBHP) is a
powerful oxidizing agent in many chemical transformations. Despite
the versatility in organic reactions, the use of anhydrous TBHP has
been greatly limited because of safety concerns over its shipping,
handling, and storage, particularly on production scale. Herein we
describe a membrane pervaporation method that allows the production
of the anhydrous TBHP solution in continuous manner. The system consists
of membrane modules in series that are made of perfluorinated polymer
with very high gas permeability, allowing it to remove water efficiently.
The pervaporation skid has been successfully implemented in production
by continuously generating anhydrous 1.5 M TBHP solution in nonane
at a rate of up to 100 mL·min–1 for more than
96 h, achieving the target of 0.15 wt % water. An integrated flow
oxidation of a γ-butyrolactam substrate provides an efficient
and diastereoselective synthesis of a key lactam intermediate for
the preparation of a drug candidate targeting interleukin-1 receptor
associated kinase 4 for the treatment of inflammation and oncology
diseases.
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