118 Journal of Medicinal Chemistry, 2011, Vol. 54, No. 1
Gillerman and Fischer
(CD3OD, 300 MHz) δ: 8.01-7.23 (m, 5H, Bn), 4.45 (s, 2H, CH2)
ppm. 13C NMR δ: 177.1 (C-2), 166.0 (C-5), 148.6 (C-4), 139.7
(C-6), 137.1, 128.7, 127.7 (Bz), 34.6 (SCH2) ppm. MS TOF ESþ:
262 (M-Hþ). HRMS, calcd for C14H7N5OS 261.0684 (MHþ),
found 261.0652.
2-(Benzylthio)pyrimidine-4,5,6-triamine (37). 2-Benzylthio-
5-nitrosopyrimidine-4,6-diamine, 36 (2.079 g, 7.96 mmol), dis-
solved in EtOH (50 mL) was hydrogenated at atmospheric
pressure, for 6 h, at RT, over PtO2 catalyst. The reaction mixture
was filtered through a bed of Celite. The filtrate was concen-
trated and dried to give product as green oil, in a quantitative
yield. 1H NMR (CD3OD, 300 MHz) δ: 7.49-7.1 (m, 5H, Bn),
4.31 (s, 2H, CH2) ppm. 13C NMR δ: 162.0 (C-2), 155.4 (C-4,
C-6), 137.1-127.6 (Bz), 108.9 (C-5) ppm. HRMS: calcd for
C11H13N5S 247.0892 (MHþ), found 247.0862.
5-(Benzylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (39).
2-Benzylthiopyrimidine-4,5,6-triamine, 37 (14.7 mmol), was dis-
solved in 30% HCl and a solution of sodium nitrite (1.65 g,
23.9 mmol, 1.6 equiv) in water (20 mL) was added dropwise. A
green solid precipitated during the addition of sodium nitrite. The
suspension was stirred for 3 h at 0 °C. The reaction mixture was
extracted with ethyl acetate. Organic phase was dried over
MgSO4, filtered, and the volatiles were evaporated. The product
was obtained as a green solid in a 55% yield (2.09 g). 1H NMR
(CD3OD, 300 MHz) δ: 7.8-7.3 (m, 5H, Bn), 4.43 (t, 2H, SCH2)
ppm. 13C NMR δ: 171.0 (C-2), 159.9 (C-4), 156.1 (C-6), 137.1,
128.7, 127.7 (Bn), 122.9 (C-5), 34.7 (SCH2) ppm. MS TOF ESþ:
259 (M-Hþ). HRMS: calcd for C14H6N6S (Mþ) 258.0688, found
258.0695.
1H, H50), 4.64 (dd, J = 13, 5.4 Hz, 1H, H500), 4.52 (s, 2H,
SCH2) ppm. 13C NMR δ: 171.66 (C-2), 166.16, 165.15, 165.03
(CO), 154.81 (C-6), 150.10 (C-4), 137.00 (C-5), 133.78, 133.58,
129.87, 129.77, 129.36, 129.04, 128.71, 128.55, 128.46, 128.37,
127.18, 122.97 (Bz), 87.77 (C-10), 80.35 (C-40), 74.33 (C-2þ0),
771.81 (C-40), 63.62 (C-50), 35.72 (SCH2) ppm. MS TOF ES :
703 (MHþ). HRMS calcd for C37H30N6O7S 702.1885, found
702.1897.
(2R,3R,4R,5R)-2-(7-Amino-5-(hexylthio)-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-3-yl)-5-(benzoyloxymethyl)tetrahydrofuran-
3,4-diyl Dibenzoate (42). A solution of 5-(hexylthio)-3H-
[1,2,3]triazolo[4,5-d]pyrimidin-7-amine, 40 (813.6 mg, 3.23 mmol),
and (NH4)2SO4 (catalytic amount) in freshly distilled HMDS
(38 mL) was stirred under reflux for 1 h under nitrogen atmo-
sphere. The solution was cooled down to room temperature
and evaporated under high vacuum. A solution of 1-O-acetyl-
20,30,50-tri-O-benzoyl-β-D-ribofuranose (1.6 g, 3.17 mmol,
0.98 equiv) in freshly distilled 1,2-DCE (10 mL) was added to
the oily residue of the silylated base, followed by a solution of
trimethylsilyl triflate (1.37 mL, 7.6 mmol, 2.3 equiv) in 1,2-DCE
(10 mL). The mixture was heated under reflux for 2 h, at which
time TLC indicated a complete consumption of the sugar. The
reaction mixture was diluted with methylene chloride and
washed with saturated NaHCO3 solution and brine. The or-
ganic phase was dried with MgSO4, filtered, concentrated, and
flash chromatographed on silica gel column using 99:1 CHCl3:
MeOH. Product was obtained in a 36% yield (798.2 mg).
1H NMR (CDCl3, 600 MHz) δ: 7.99-7.97 (m, 3H, Bz), 7.57-
7.53 (m, 6H, Bz) 7.39-7.36 (m, 6H, Bz), 6.72 (d, J = 3 Hz, 1H,
H10), 6.53 (dd, 1H, J = 5, 3 Hz, H20), 6.38 (dd, J = 7, 5 Hz, 1H,
H30), 4.9 (ddd, J = 7, 5, 4.5 Hz, 1H, H40), 4.79 (dd, J = 12,
5 Hz,1H, H50), 4.64 (dd, J = 12, 4.5 Hz, 1H, H500), 3.22 (m, 2H,
SCH2), 1.72 (m, 2H, SCH2CH2), 1.41 (m, 2H, SCH2CH2CH2),
1.3 (m, 2H, SCH2CH2CH2CH2), 1.2 (m, 2H, CH2CH3), 0.82
(t, J = 7 Hz, 3H, CH3) ppm. 13C NMR δ: 171.99 (C-2), 166.13,
165.10, 164.97 (CO), 154.41 (C-6), 151.5 (C-4), 133.79, 133.61,
133.24, 129.93, 129.87, 129.82, 128.60, 128.51, 128.42 (Bz), 88.11
(C-10), 80.44 (C-40), 74.3 (C-20), 71.71 (C-40), 63.60 (C-50), 31.42
(SCH2), 31.34 (SCH2CH2CH2CH2), 28.79 (SCH2CH2), 28.52
(SCH2CH2CH2), 22.64 (CH2CH3), 13.34 (CH3) ppm. MS
(FABþ) 697 (MHþ). HRMS calcd for C36H36N6O7S 696.2385
(Mþ), found 696.2366.
5-(Hexylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine (40).
2-(Hexylthio)pyrimidine-4,5,6-triamine, 3876 (9.73 mmol), was
dissolved in 30% HCl and a solution of sodium nitrite (1.08 g,
15.7 mmol, 1.6 equiv) in water (5 mL) was added dropwise.
A green solid was precipitated during the addition of sodium
nitrite. The suspension was stirred for 3 h at 0 °C. The reaction
mixture was extracted with ethyl acetate (5 times), organic phase
was dried over MgSO4, and the volatiles were evaporated. The
product was obtained as a green solid in a 73% yield (1.8 g).
1H NMR (CD3OD, 600 MHz) δ: 2.93 (m, 2H, SCH2), 1.456
(m, 2H, SCH2CH2), 1.9 (m, 2H, SCH2CH2CH2), 1.04 (m, 4H,
SCH2CH2CH2CH2CH2), 0.65 (t, J = 7 Hz, 3H, CH3) ppm. 13
C
NMR δ: 165.39 (C-2), 160.63 (C-6), 155.66 (C-4), 122.89 (C-5),
31.76 (SCH2), 31.3 (SCH2CH2), 29.93 (SCH2CH2CH2), 29.58
(SCH2CH2CH2CH2), 22.85 (SCH2CH2CH2CH2CH2), 14.24
(CH3) ppm. MS TOF ESþ: 253 (MHþ). HRMS: calcd for
C10H13N6S (Mþ) 253.1202, found 253.1210.
(2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(7-chloro-5-(hexylthio)-
3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3,4-diyl
Dibenzoate (44). BTEA-NO2 (2.023 g, 8.5 mmol) was dis-
76
solved in dry CH2Cl2 (17 mL) and added dropwise (1 drop/2 s)
to the cold (0 °C), stirred solution of AcCl (765 μL, 0.85 g,
10.8 mmol) in CH2Cl2 (8.5 mL). A cold solution of nucleoside 42
(1.2 g, 1.7 mmol) in dried CH2Cl2 (17 mL) was then added
dropwise to the cooled, stirred AcCl/BTEA-NO2/CH2Cl2 solu-
tion. After 4 h, TLC (9:1 CH3Cl:MeOH) indicated completion
of the reaction. Then the cold reaction mixture was added drop-
wise to mixture of CH2Cl2 (200 mL) and saturated NaHCO3
(200 mL). The aqueous phase was extracted (CH2Cl2, 2 ꢀ
100 mL), and the combined organic phase was dried (MgSO4)
and filtered. The volatiles were evaporated, and the residue was
separated on a MPLC system using a silica gel column (40 þ
M column) and the following gradient scheme: 2 column
volumes (CV) of 98:2 (A) CH2Cl2 (B) MeOH, 8 CV of a gradient
from 98:2 to 80:20 of A:B and 2 CV of 80:20 A:B at a flow rate of
40 mL/min. The product was obtained in a 59% yield (720 mg,
1 mmol). 1H NMR (CDCl3, 300 MHz) δ: 8.03-8.00 (m, 3H, Bz),
7.60-7.58 (m, 6H, Bz) 7.46-7.3 (m, 6H, Bz), 6.8 (d, J = 2.6 Hz,
1H, H10), 6.60 (dd, J = 5.5, 2.6 Hz 1H, H20), 6.39 (dd, J = 6.8,
5.5 Hz, 1H, H30), 5.10 (ddd, J = 6.8, 5, 4 Hz, 1H, H40), 4.82 (dd,
J = 12, 4 Hz, 1H, H50), 4.71 (dd, J = 12, 5 Hz, 1H, H500), 3.31
(s, 2H, SCH2), 1.82-1.77 (m, 2H, SCH2CH2), 1.35-1.30
(m, 6H), 0.9 (m, 3H, CH3) ppm. 13C NMR (200 MHz) δ:
173.17 (C-2), 166.04, 165.10, 165.00 (CO), 153.40 (C-6), 150.70
(C-4), 133.87, 133.68, 133.26, 129.85, 129.73, 129.34, 128.59,
(2R,3R,4R,5R)-2-(7-Amino-5-(benzylthio)-3H-[1,2,3]triazolo-
[4,5-d]pyrimidin-3-yl)-5-(benzoyloxymethyl)tetrahydrofuran-3,4-diyl
Dibenzoate (41). A solution of 5-(benzylthio)-3H-[1,2,3]-
triazolo[4,5-d]pyrimidin-7-amine, 39 (530 mg, 2.05 mmol), and
(NH4)2SO4 (catalytic amount) in freshly distilled HMDS (16 mL)
was stirred under reflux for 2 h under argon atmosphere. The
solution have been cooled down to room temperature and
evaporated under high vacuum. A solution of 1-O-acetyl-
20,30,50-tri-O-benzoyl-β-D-ribofuranose (1.04 g, 2.05 mmol,
0.98 equiv) in freshly distilled 1,2-DCE (10 mL) was added
to the oily residue of the silylated base, followed by a solu-
tion of trimethylsilyl triflate (3 mL, 16.6 mmol, 2.3 equiv) in
1,2-DCE (10 mL). The mixture was heated under reflux for
2 h. TLC (9:1 CHCl3:MeOH) indicated that no starting
material was left. The reaction mixture was diluted with
methylene chloride and washed with saturated NaHCO3
solution and brine. The organic phase was dried with MgSO4,
filtered, concentrated, and flash chromatographed on silica
gel column using 99.7:0.3 CHCl3:MeOH. Product was ob-
tained in a 23% yield (333.4 mg). 1H NMR (CDCl3, 300 MHz)
δ: 8.15-7.97 (m, 3H, Bz), 7.6 (m, 5H, Bn), 7.43 (m, 6H, Bz)
7.39-7.36 (m, 6H, Bz), 6.81 (d, J = 2.7 Hz, 1H, H10), 6.6 (dd,
J = 5.4, 2.7 Hz, 1H, H20), 6.43 (dd, J = 6.6, 5.4 Hz,1H, H30),
4.97 (ddd, J = 6.6, 5.4, 4 Hz, 1H, H40), 4.81 (dd, J = 13, 4 Hz,