Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor

Abstract

The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol. The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at >8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.

Development of a Scalable Chiral Synthesis of MK-3281, an Inhibitor of the Hepatitis C Virus NS5B Polymerase

“…Our studies were a useful starting point for the development of a process route to the compound, which has been object of a recent publication. 13 Preparation of 15 A suspension of CaCl 2 (49.9 g, 450 mmol) in dry THF (400 mL) was cooled to 0°C, and NaBH 4 (34.0 g, 900 mmol) was added under stirring. To the resulting suspension, a solution of Boc-Ser(TBDMS)OMe (100 g, 300 mmol) in dry EtOH (400 mL) was added dropwise over the course of 2 h. Stirring was then continued over night.…”

Synthesis of α‐Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases

“…The azido analogue 29 (Scheme 5) was prepared in a4 0% yield directly from bisamidate 22 by its treatment with diphenoxyphosphoryl azide (DPPA) [34] under Mitsunobu reaction conditions. [35] To study the inhibitory potential of novel halo-ANT-ANPs directly on ACT and EF enzymes,t he selected analogues 18 and 19 were converted into their diphosphate derivatives( halo-ANT-ANPpp), that is, analogues of natural NTPs. Because the standardm orpholidate methodology for the NTPs synthesis [36] failed,amethod using 1,1'-carbonyldiimidazole( CDI) was used instead.…”

Non‐natural Acetogenin Analogues as Potent Trypanosoma brucei Inhibitors

“…With the alcohols in hand, both diastereomers could be independently converted to the azide by Mitsunobu reaction (diphenylphosphoryl azide (DPPA), diisopropyl azodicarboxylate (DIAD), N,N-diisopropylethylamine, triphenylphosphine) of alcohols 8 a and 9 a to give 11 a and 12. [12] The enantiomeric syn azide (13) could be accessed in an analogous manner from (R)-epoxyoctane. [11] For the alkyne subunits, syn-8 a and anti-9 a alcohols were oxidized under Swern conditions to afford aldehydes 14 a and 15 a in excellent yields, and subsequent exposure of 14 a to Ohira-Bestmann homologation [13] gave exclusively syn-16 a in 72 % yield.…”