A Synthesis of a Spirocyclic Macrocyclic Protease Inhibitor for the Treatment of Hepatitis C

Abstract

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.

New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors

“…In marked contrast, when reduction of diarylketone (5c) corresponding to dapagliflozin (3b) was examined, the reaction gave a dimer 7c (Table 3, entry 2). 8 For reduction of 5c, another protocol using InCl 3 /Al/BF 3 • OEt 2 9 was tested to furnish the desired diarylmethane 1c in 56% yield (Scheme 3).…”

“…For reduction of 5c , another protocol using InCl 3 /Al/BF 3 ·OEt 2 9 was tested to furnish the desired diarylmethane 1c in 56% yield ( Scheme 3 ).…”

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

“…The process route for the synthesis of the P2* moiety of 214 was conducted analogously to the discoveryr oute, but with the introduction an alternative methodt oi nstall the acetyl moiety that relied upon aP d-catalyzed coupling of the bromide with 2-(vinyloxy)ethan-1-ol in the presence of Cs 2 CO 3 (Scheme 26). [83] Macrocycle 224 was prepared in an overall yield of 90 %f rom diene 206 in at wo-step process involving Boc protection of the hydroxyproline and amide moieties followed by aR CM reactionc atalyzed by 0.5 mol %o fZ han catalyst 1B (243). Global deprotection of the three Boc groups of 224 was followed by installation of the isobutyryl carbamate moiety and conversion of the alcohol into ketone 225,w hich was accomplished by aP arikh-Doering oxidation in 98 %y ield over the three steps.…”

“…The process route for the synthesis of the P2* moiety of 214 was conducted analogously to the discovery route, but with the introduction an alternative method to install the acetyl moiety that relied upon a Pd‐catalyzed coupling of the bromide with 2‐(vinyloxy)ethan‐1‐ol in the presence of Cs 2 CO 3 (Scheme ) . Macrocycle 224 was prepared in an overall yield of 90 % from diene 206 in a two‐step process involving Boc protection of the hydroxyproline and amide moieties followed by a RCM reaction catalyzed by 0.5 mol % of Zhan catalyst 1B ( 243 ).…”

Bio- and Chemocatalysis for the Synthesis of Late Stage SAR-Enabling Intermediates for ROMK Inhibitors and MK-7145 for the Treatment of Hypertension and Heart Failure

“…In order to transform the phenol 12 to the desired bromoketone 3 , a sequence of phenol activation, regioselective Heck reaction with n -butyl vinyl ether, and treatment of the resultant vinyl ether with NBS was designed (Scheme ). We prepared a series of aryl sulfonates in an effort to assess the regioselectivity of the subsequent Heck reaction.…”