Inhibitors of Hepatitus C Virus
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 10 2497
7.59 (m, 2 H), 7.71-7.74 (m, 2 H), 7.99-8.00 (m, 1 H); LCMS
m/z 447.1 (M + H)+.
spectrometry data. They are grateful for the assistance
of Dr. Bruce Belanger and Mrs. Ferdous Gheyas in the
development of the KD determination process, and of Dr.
Bryan Marten in the modeling of linked compounds.
They also thank Dr. Patricia Weber for her continued
support of the project.
Com p ou n d 17. Argon was bubbled into a solution of 16
(3.0 g, 6.73 mmol) in EtOH (125 mL) for approximately 1 h. It
was then cooled to 0 °C and 10% Pd/C was added portionwise
(3 × 1 g) followed by dropwise addition of 1,4-cyclohexadiene
(6.3 mL, 67.3 mmol). The reaction mixture was warmed to
room temperature over 30 min and heated to 45 °C over 2 h.
TLC indicated completion of reaction. The reaction mixture
was cooled to room temperature, filtered through a pad of
Celite, and concentrated. Purification by flash chromatography
(Biotage flash system using 40M silica cartridge) using 5/95
to 20/80 EtOAc/dichloromethane provided 17 (1.2 g, 50% yield).
LCMS m/z 357.1 (M + H)+.
Com p ou n d 18. To a cold (0 °C) solution of 17 (1.0 g, 2.81
mmol, 1.0 equiv) in THF/MeCN (9 mL/1.3 mL) were added
4-nitrophenyl chloroformate (623 mg, 3.09 mmol, 1.1 equiv)
and pyridine (dropwise, 0.25 mL, 3.09 mmol, 1.1 equiv). The
reaction temperature was maintained between 0 and 5 °C for
30 min, and the mixture was slowly warmed to room temper-
ature over 2 h. At this time, the reaction mixture was diluted
with EtOAc (30 mL), washed with water (25 mL) and brine
(25 mL), dried (MgSO4), and concentrated. Purification by flash
chromatography (Biotage flash system using 40M silica car-
tridge) using 0/100 to 20/80 EtOAc/dichloromethane afforded
1.04 g of the 4-nitrophenyl carbonate derivative.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
18 and 19. This material is available free of charge via the
Internet at http://pubs.acs.org.
Refer en ces
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To a 0 °C solution of the activated carbonate (500 mg, 0.95
mmol, 1.0 equiv) in DMF (4 mL) was added a solution of HCl
salt of diiodotyrosine tert-butyl ester (500 mg, 0.95 mmol, 1.0
equiv) and triethylamine (0.15 mL, 1.05 mmol, 1.1 equiv) in
DMF (4 mL + 2 mL). Finally a few crystals of imidazole were
added and the reaction mixture was warmed to room temper-
ature overnight. The reaction mixture was diluted with EtOAc,
washed with 10% citric acid and brine, dried (Na2SO4), and
concentrated. The crude material was purified by flash chro-
matography (Biotage flash system using 40M silica cartridge)
with 3/97 to 25/75 EtOAc/dichloromethane to provide com-
1
pound 18 (165 mg, 20% yield). H NMR δ 1.26 (s, 9 H), 1.43
(s, 9H), 2.13 (m, 2 H), 2.94 (d, J ) 5.6 Hz, 2 H), 4.08-4.10 (m,
2 H), 4.24-4.30 (m, 2 H), 4.42 (q, 1 H), 5.22 (d, 1 H), 5.68 (s,
1 H), 6.89-6.91 (m, 2 H), 7.32-7.34 (m, 1 H), 7.46 (s, 2 H),
7.51-7.60 (m, 2 H), 7.72-7.74 (m, 2 H), 7.99-8.01 (m, 1 H);
13C NMR δ 28.0, 28.5, 29.3, 36.8, 55.4, 62.2, 65.1, 82.5, 83.0,
83.5, 114.6, 127.9, 129.7, 130.4, 131.0, 131.4, 132.3, 132.4,
132.7, 140.5, 141.7, 153.1, 156.0, 163.2, 165.8, 170.5, 196.0;
HRMS (FAB) m/z calcd for C35H40I2NO9 872.0793 (M + H)+,
found 872.0794.
Com p ou n d 19. The di-tert-butyl ester 18 (50 mg, 0.057
mmol) was treated with dichloromethane/TFA (1 mL each) at
room temperature for 2 h and then concentrated. To the
residue was added AcOH (1 mL) and concentrated. This
procedure was repeated with heptane (2×) to remove all the
volatiles. The required product 19 was obtained in quantitative
yield as a white solid. 1H NMR (CD3OD) δ 2.00-2.15 (m, 2
H), 2.77 (dd, 1H), 3.02-3.10 (m, 1H), 4.1-4.35 (m, 5H), 6.96
(d, 2H), 7.35 (d, 1H), 7.60-7.71 (m, 6H), 8.10 (d, 1H); 13C NMR
(CD3OD) δ 29.1, 35.5, 55.6, 61.6, 64.9, 84.1, 114.4, 127.6, 129.6,
130.3, 130.5, 132.0, 132.4, 133.7, 140.4, 154.6, 157.4, 163.6,
168.0, 173.9, 195.0; HRMS (FAB) m/z calcd for C27H24I2NO9
759.9541 (M + H)+, found 759.9553.
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Ack n ow led gm en t. The authors thank Dr. Hugh
Eaton for assistance in automating the processing and
analysis of NMR data, Mr. Ashwin Ranchod for small-
molecule library construction, and Mr. Richard Ingram
and Dr. Bruce Malcolm for the determination of the
inhibition data. They also thank Dr. Lata Ramanathan,
Mrs. Michelle Wendel, and Dr. J ennifer Gesell for
assistance in the growth and purification of the protein.
They thank the following people for providing analytical
support: Dr. Charles McNemar for N-terminal sequenc-
ing; Dr. Yan-Hui Liu and Mrs. Shi-Hong Wang for mass