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. 2021 May 19;12(26):9031-9036.
doi: 10.1039/d1sc01978c. eCollection 2021 Jul 7.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods

Artis Klapars  1 , John Y L Chung  1 , John Limanto  1 , Ralph Calabria  1 , Louis-Charles Campeau  1 , Kevin R Campos  1 , Wenyong Chen  1 , Stephen M Dalby  1 , Tyler A Davis  1 , Daniel A DiRocco  1 , Alan M Hyde  1 , Amude M Kassim  1 , Mona Utne Larsen  1 , Guiquan Liu  2 , Peter E Maligres  1 , Aaron Moment  1 , Feng Peng  1 , Rebecca T Ruck  1 , Michael Shevlin  1 , Bryon L Simmons  1 , Zhiguo Jake Song  1 , Lushi Tan  1 , Timothy J Wright  1 , Susan L Zultanski  1
Affiliations

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods

Artis Klapars et al. Chem Sci. .

Abstract

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Synthetic approaches to uprifosbuvir 1 with the two main challenges highlighted. (a) Me2NH, AcOH, EtOH/MeOH, 80 °C, 1.5 h; (b) Ca(OH)2, water, 70 °C, 24 h, 19% over 2 steps.
Scheme 2
Scheme 2. Decomposition during attempted direct biocatalytic oxidation of uridine 5. (a) General screening conditions: KRED enzyme variants, NAD or NADP cofactor, acetone-water, 30 °C. The reactions were screened using a set of buffers with pH of 6.5–7 (potassium phosphate) and pH of 5–6 (sodium borate).
Scheme 3
Scheme 3. Complexation-driven selective acyl migration/oxidation to access 12. (a) PivCl, pyridine, 0 °C, 16 h; (b) BF3·OEt2, PhMe, 40 °C, 10 h; (c) TEMPO, Bu4NBr, AcOOH, dioctyl sulphide, PhMe, −10 °C to 20 °C, 24 h, 83% from 5.
Scheme 4
Scheme 4. Olefination/hydrochlorination of the ketone 12. (a) TMSCH2MgCl, CPME, 0 °C to rt, 24 h, 91%; (b) (CF3CO)2O, pyridine, DMAP, MeCN, rt, 15 h, then KF, 70 °C, 24 h, 88%; (c) K2CO3, MeOH/THF, 40 °C, 15 h, 94%; (d) FeCl3, PhSiH3, rt, 48 h, 82%.
Scheme 5
Scheme 5. Formation of tertiary chloride 4. (a) BSA, 1 mol% of 37% aq HCl, anisole, 75 °C, 8 h; (b) DBU, MeOH, 60 °C, 10 h, 87% yield from 16; (c) Me2SiCl2, DMF, 1,2-dimethoxyethane (DME), 70 °C, 10 h; (d) FeCl3–6H2O, (Me2SiH)2O, 25 °C, 12 h, 85% from 19.
Scheme 6
Scheme 6. Completion of uprifosbuvir synthesis. (a) TMS-Cl, iPrOH, 70 °C, 12 h; (b) NEt3, iPrOAc, wiped film evaporation, 80%; (c) PhOP(O)Cl2, NEt3, iPrOAc, −20 °C, 2 h, 90%; (d) C6F5OH, NEt3, iPrOAc, −5 °C to 10 °C, 18 h, 76%; (e) 4, 3 mol% 24, 2,6-lutidine, 1,3-dioxolane, −10 °C, 24 h, 88%; (f) 4, tBuMgCl, THF, −5 °C to 5 °C, 15 h, 50%; (g) 4, Me2AlCl, 2,6-lutidine, THF, 35 °C, 16 h, 81%.
Scheme 7
Scheme 7. Summary of uprifosbuvir synthesis. AY = assay yield; IY = isolated yield.
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