The Suzuki±Miyaura cross-coupling reaction using heterogeneous Pd/C has a homogeneous component. The soluble palladium concentration increases during the reaction reaching a maximum at ca. 90% conversion before falling to < 4 ppm.
A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.
Reaction of pyranoside diol (equatorial) monotriflates with soft, nonbasic nucleophiles is a useful way to make axial heteroatom-substituted and "epimerized" pyranosides, particularly where a fused acetal ring inhibits ring contraction. Among the substrates examined (1,2,3,4,35), only 4 shows a strong tendency to give ring-contracted products. The reaction of 1-3 with more basic nucleophiles (P, t-BuO-) leads to the anhydrosugars 8,25, and 26, respectively. The S N~ reaction of 35 with tetra-n-butylammonium iodide forms the basis for a new synthesis of the Cerny epoxide 32.
An efficient, scalable synthesis of the PDE4 inhibitor, 6-[1methyl-1-(methylsulfonyl)ethyl]-8-(3-{(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl)quinoline benzenesulfonate (10) is described. The synthesis is highly convergent, generating the penultimate 9 by coupling aldehyde 7 and oxadiazole 8 in a Knoevenagel reaction. The process consists of a total of nine chemical steps, five of which comprise the sequence to prepare aldehyde 7 via Skraup reaction, bromination, sulfone formation, methylation and Suzuki-Miyaura cross-coupling, and a two-step sequence for the synthesis of oxadiazole 8 that includes the methylamidoxime and oxadiazole steps. The final two steps are Knoevenagel coupling and salt formation. The process produced the drug candidate 10 in 46% overall yield from 2-bromo-4-methylaniline (1) on multikilogram scale.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.