Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor Synthesis of Natural Org

A. J. DELMONTE* ET AL. (BRISTOL-MEYERS SQUIBB COMPANY, NEW BRUNSWICK, USA) Category The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor Synthesis of Natural Org. Process Res. Dev. 2018, 22, 1393–1408. Products and Potential Drugs Synthesis of Beclabuvir Key words

beclabuvir N2 OMe asymmetric Ph O cyclopropanation O Ph3P=CH2 O (1.05 equiv) OMe C (ca. 1.0 equiv) arylation OMe MeO OMe H THF, 25 °C, 3 h Rh2(S-DOSP)4 Heck reaction Al O chromatography Br (0.002 equiv) Br 2 3 Ph Br 55% (372 mol scale) heptane, r.t., 2 h rhodium B 94% (93 mol scale) A D mp not reported palladium 83% ee

1. O3/CH2Cl2, –60 °C 2. NaBH4 (3.3 equiv) MeOH, –10 °C, 2 h O Ph NH2 1. TMSCl (3.0 equiv) O 3. LiOH (4.0 equiv) E EtOH, 64 °C, 5.5 h Ph NH2 THF–MeOH–H2O EtO OMe HO OMe 2. TsCl (1.0 equiv) 4. E (0.96 equiv) DABCO (1.38 equiv) 2-PrOH–H O, 75–25 °C OTs OH 2 Br PhMe, 0–20 °C Br 56.5% (64.6 mol scale) G 56.8 mol scale F mp not reported 99.6% ee O O O H S N O Me2N N H EtO 1. Pd(OAc)2 (0.05 equiv) OMe Cy3P•HBF4 (0.1 equiv) O O O KHCO3 (4.0 equiv) H (1.06 equiv) DMAc–PhMe, 125 °C S N Br Me2N N NaHMDS (1.9 equiv) H 2. KOH (2.9 equiv), THF–DMF, 60 °C; DMAc–H2O, 40 °C cryst ex 2-PrOH–heptane 3. aq HCl to pH 1–3 47% from G 4. KOEt in EtOH to pH 7.0–8.0 I 85% (64.8 mol scale) mp not reported

N • HCl Me N O • 2 HCl KO O Me N • 0.5 DMAc NH O O O O K (1.22 equiv) O O S N S N Me2N N EDCI (1.23 equiv) Me2N N H H OMe HATU (1.22 equiv) OMe DIPEA (3.2 equiv) MeCN, 5–20 °C, 16 h then HCl (1.04 equiv) Beclabuvir hydrochloride J 89.5% (3.32 mol scale) mp not reported mp not reported

Significance: Beclabuvir (Ximency®, BMS-791325) Comment: Key steps in the large-scale synthesis This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. is a non-nucleoside, nonstructural protein 5B (NS5B) depicted include (1) the rhodium-catalyzed asym- RNA polymerase inhibitor that was approved in Ja- metric cyclopropanation of styrene C (94% yield, pan for use in combination with Asunaprevir and 83% ee) and (2) the construction of the seven- Daclatasvir for the treatment of hepatitis C virus in- membered ring by an intramolecular Heck reac- fection. tion. Beclabuvir was prepared in twelve linear steps with five isolations in 8% overall yield.

SYNFACTS Contributors: Philip Kocienski Synfacts 02012019, 15(01), 0003 Published online: 14.12.20181861-19581861-194X