Daring the Challenge and Thinking Big: The Value of Early Process R&D.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block.

The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog.

1. The metabolism of the endothelin receptor antagonist macitentan has been characterized in bile duct-cannulated rats and dogs. 2.

Industrial applications of the Diels-Alder reaction.

The Diels-Alder reaction is one of the most popular transformations for organic chemists to generate molecular complexity efficiently. Surprisingly, little is known about its industrial application for the synthesis of pharmacologically active ingredients, agrochemicals, and flavors and fragrances. This Review highlights selected examples, with a focus on large-scale applications (>1 kg) from a process research and development perspective.

A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate.

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.

A versatile protocol for Stille-Migita cross coupling reactions.

The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact.

Reversal of facial selectivity in complex Diels-Alder reactions.

A complex Diels-Alder reaction between a semi-cyclic diene with allylic silyloxy substituents and a bromo enone presented an unusual diastereoselectivity: attack of the diene occured on its more hindered face, and this reversal of selectivity was shown to be induced by the presence of a bromo substituent in the dienophile.

Enyne versus diene RCM in the synthesis of cyclopentene derivatives toward the A ring of FR182877.

The A ring of FR182877, exemplified by ent-4-b,c, has been synthesized, involving an enyne RCM as the key step. A systematic comparison of enyne vs diene RCM for the formation of cyclopentene derivatives showed that the latter metathesis proceeds much more easily even for this ring size.