Tetrahydroisoquinolines and tetrahydrobenzazepines were prepared by acid-promoted ring contraction of cyclic ureas, which were themselves formed by ring expansion of indolines and tetrahydroquinolines. The consequent overall one-carbon insertion reaction gives these 6- and 7-membered heterocyclic scaffolds in three steps from readily available precursors. Other ring sizes may be formed by an alternative elimination reaction of bicyclic structures. Scalability of the method was demonstrated by operating it in a flow system.

Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An S N Ar reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer−Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.

At hree-step synthesis of the 2-azabicyclo[3.3.1]nonaner ing system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported. Substrate scope is broad,a llowing the incorporation of aw ider ange of functionalityr elevant to medicinal chemistry.M echanistic studies demonstrate that the processo ccurs by acid-assisted CÀNb ond cleavage followed by b-hydride eliminationt of orm ar eactive diene, demonstratingt hat efficient control of what mightb e considered off-cycle reactionsc an result in productive tandem catalytic processes. This represents as hort and versatile route to the biologically important morphan scaffold.

Work to assess the thermal properties of 2butynoic acid (a precursor to acalabrutinib) has revealed the potential for thermal runaway on heating; testing using accelerated rate calorimetry (ARC) showed exothermic onset from 135 °C, precluding short-path distillation as a means of purification. Recrystallization was shown to be effective as an alternative technique to purify the compound and avoid the distillation procedure.

No abstract