Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions, 1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, 2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and finally 3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. A regioselective synthesis of an N-Boc-1-mesyl pyrazole fragment was achieved via a base promoted mesyl group isomerisation to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multi-kilogram deliveries, and improved the overall diastereoselectivity and efficiency of the route.

Inline IR has been applied to evaluate the scale-up of processes that potentially generate hazardous diborane, hydrazoic acid, methyl chloride, or acetylene in the headspace of reactors. In addition, a new, simplified approach to calibrate the online IR analyzer for the measurement of hydrazoic acid in the gas phase has been described.

Medical students across the USA have increasingly made the medical institution a place for speculating racially just futures. From die-ins in Fall 2014 to silent protests in response to racially motivated police brutality, medical schools have responded to the public health crisis that is racial injustice in the USA. Reading science fiction may benefit healthcare practitioners who are already invested in imagining a more just, healthier futurity. Fiction that rewrites the future in ways that undermine contemporary power regimes has been termed 'visionary fiction'. In this paper, the authors introduce 'visionary medicine' as a tool for teaching medical students to imagine and produce futures that preserve health and racial justice for all. This essay establishes the connections between racial justice, medicine and speculative fiction by examining medicine's racially unjust past practices, and the intersections of racial justice and traditional science and speculative fiction. It then examines speculative fiction author Octavia Butler's short story 'Bloodchild' as a text that can introduce students of the medical humanities to a liberatory imagining of health and embodiment, one that does not reify and reinscribe boundaries of difference, but reimagines the nature of Self and Other, power and collaboration, agency and justice.

No abstract

The area between the Colorado Plateau on the north, New Mexico and Chihuahua to the east, and southern and Baja California to the southwest has undergone a complicated thermal and tectonic history climaxing in medial Cretaceous time and manifested in a sequence of events which continue to the present time, independent of plate boundary transform faulting. This sustained sequence of events was initiated by subduction‐related magmatic emplacement, largely between 120 and 50 Ma, beginning in the west and sweeping eastward across the region. The emplacement of these rocks generated a large isostatic welt which began to elevate in late medial Cretaceous time in the west central portion of the area and spread outward until in Oligocene time the west coast of southern California was emergent almost to the continental escarpment. Both erosional and tectonic unloading accompanied elevation, with the axis of the welt achieving its maximum elevation in earliest Cenozoic time when north central Sonora may have had elevations of the order of 5000 m. Body forces caused the welt to relax laterally, producing thrust and nappe structures which were westward vergent in the west and eastward vergent in the east. To the east these structures are included in what is called the Larimide Orogeny; to the west they include such features as the Santa Rosa mylonite belt and related structures. As with the magmatic emplacement, the gravitational spreading began in the west. During the Eocene, additional rebound in response to deep erosion and tectonic unroofing began to expose midcrustal rocks within the core area of the welt, and subhorizontal detachment began along the brittle‐ductile boundary. During Oligocene and early Miocene time, renewed isostatic uplift resulted from rising magma, and continued erosional and tectonic denudation spawned both brittle and ductile extension, hydrothermal alteration, and mineral deposition. From mid‐Miocene to the present time the central portion of the area has subsided, while the marginal mountain ranges have elevated.

No abstract

No abstract

No abstract