Development and Manufacture of a Curtius Rearrangement Using Continuous Flow towards the Large-Scale Manufacture of AZD7648

Abstract

Flow chemistry has been more frequently used in the development and manufacture of pharmaceuticals due to the progression of equipment and the availability of manufacturing facilities. This important tool for manufacture enables chemistries which were previously inefficient, hazardous, or not viable on scale in batch. Described herein is how continuous flow has been used to overcome issues with respect to the handling of hazardous materials in batch. The manufacturing step described is a Curtius reaction using diphenylphosphoryl azide (DPPA) as the azide precursor in the formation of a purinone at high temperatures with inline infrared monitoring.

Continuous Flow Chemistry with Solids: A Review

“…A continuous Curtius rearrangement toward the synthesis of compound AZD7648 was reported by scientists at AstraZe-neca. 79 Precipitation of the cyclized product from the reaction solution was observed upon exiting the reactor which ultimately caused clogging in the system. The issue of clogging was circumvented by maintaining the temperature of the outlet stream above 70 °C, preventing solid formation and ensuring collection of a completely homogeneous solution at the end of reaction on multi kilo scale.…”

Pilot-Scale Operation and Characterization of an Organolithium-Mediated Coupling Reaction in Flow to Form a Ketone Intermediate on the Route to Nemtabrutinib

“…While chemical reactions performed in batch remain the workhorse for organic synthesis in the pharmaceutical industry, flow reactions are becoming increasingly prevalent, as they can enable chemical transformations that are inaccessible or difficult to scale in batch mode. − Flow chemistry can mitigate some of the challenges with using reactive, water-sensitive reagents such as organolithium, alkoxide, and Grignard , reagents. Exothermic reactions involving highly reactive reagents can often be more easily controlled in tubular reactors compared to batch reactors, primarily due to more efficient heat transfer and more consistent stoichiometry during reagent addition in flow reactors .…”

Unified and green oxidation of amides and aldehydes for the Hofmann and Curtius rearrangements

“…The Hofmann and Curtius rearrangements [1][2][3] have found wide applications in organic synthesis because they offer a convenient and reliable way to convert carboxylic acid derivatives (amides and acyl azides) into synthetically valuable amines or protected amines (carbamates and ureas) through a common isocyanate intermediate as a result of formal insertion of nitrogen into C-C bond (Scheme 1a). Notably, both the Hofmann and Curtius rearrangements have been used for (continuous flow) industrial production of pharmaceutically relevant amines/carbamates: 4 (a) the Hofmann rearrangement using (diacetoxyiodo)benzene as the oxidant has been applied to the industrial degradation (100 kg quantities) of asparagine derivatives; 5 (b) a continuous flow Hofmann rearrangement using trichloroisocyanuric acid (TCCA) has been developed for the massive production of highly medicinally valuable 2-benzoxazolinone (23 g h −1 ) from inexpensive salicylamide; 6 and (c) a continuous flow Curtius rearrangement 4,7,8 typically using diphenylphosphoryl azide (DPPA) 9,10 as an activating reagent for carboxylic acids has been rigorously studied for the largescale preparation of the medicine-relevant carbamate intermediates including the carbamate (5.97-kg scale) of AZD7648 (a selective inhibitor of DNA-dependent protein kinase for anticancer treatment) 11 and p-methoxybenzyl carbamate (0.8 kg h −1 , 40 kg scale) for the synthesis of a CCR1 antagonist. 12 An in situ generation of the unstable rearrangement substrates, N-halo amides and acyl azides, is generally conducive to the overall efficiency of both the Hofmann and Curtius rearrangements, which can be readily achieved by the halogenation of primary amides and the azidation of carboxylic acid derivatives (i.e., acid chloride), respectively.…”