Practical Large‐Scale Synthesis of the Hepatitis C Virus Protease Inhibitor BI 201335

Abstract

A concise synthetic route for large‐scale manufacture of the hepatitis C virus (HCV) protease inhibitor BI 201335 has been developed. A convergent synthetic design was achieved by using three advanced intermediates: a densely functionalized thiazole‐quinoline, a hydroxyproline‐containing dipeptide acid, and an optically pure vinylcyclopropane. Only three subsequent synthetic steps were then required for the final assembly of this complex target. The first step is a critical CO bond formation to join the heterocycle and the peptidic portion of the molecule, which was done by using a newly‐designed heterocyclic sulfone. The second step uses an inexpensive peptide coupling of the aminocyclopropane and ester saponification, then recrystallization completes the route. This economical and practical process is suitable for large scale production of BI 201335, requires no protecting groups or chromatography, and every isolated intermediate is a crystalline solid.

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

“…Isobutyl chloroformate (IBCF) is a fairly common coupling reagent for large-scale amide bond formations. ,,,, This reagent is widely available in bulk quantities and inexpensive. Compared to ethyl chloroformate, the isobutyl reagent is less toxic, and its mixed anhydride shows greater selectivity in the reaction of the amine (due to the greater steric demand of isobutyl vs ethyl).…”

Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

“…Prior experience from our laboratories 15 has shown that the reaction between a carbanion and a sulfonylpyridine is an efficient method for construction of pyridine derivatives; this guided our investigations toward the coupling of 4a with 5c . To our delight, the reaction occurred smoothly in the presence of NaHMDS at room temperature in high yield after 2 h, allowing facile access to the key intermediates 3a–b in a straightforward and economical fashion.…”

Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing

“…In contrast, pivaloyl chloride (PivCl, entry 8) displayed no exothermic activity up to 400 °C. Chloroformates are also common peptide couple agents that historically have been popular choices among industrial chemists . Both ethyl chloroformate (entry 9) and isobutyl chloroformate (entry 10) have relatively low onset temperatures of decomposition at 136 and 113 °C, respectively.…”