2730 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9
Ahmad et al.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-
methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxy-
hept-6-enoate (1b). A solution of lithium bis(trimethylsilyl)amide
(1 M in THF, 146 mL, 146 mmol) was added dropwise at -60 °C
to a stirred solution of 1-methyl-1H-1,2,4-triazol-5-amine50 (14.3
g, 145.9 mmol) and compound 5 (33 g, 60.2 mmol) in 300 mL of
DMF. The reaction mixture was stirred at -60 °C for 30 min
followed by the addition of methyl iodide (68 g, 479 mmol). The
mixture was allowed to come to RT, stirred for 30 min, and
partitioned between ethyl acetate and saturated sodium bicarbonate
solution. The organic layer was dried (MgSO4) and concentrated,
and the residue was subjected to flash chromatography (silica gel/
hexanes-ethyl acetate 100:0 to 50:50 gradient) to afford tert-butyl
2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-
methyl-1H-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)vinyl)-2,2-di-
methyl-1,3-dioxan-4-yl)acetate (7b) as a pale gummy solid (25 g,
72%): 1H NMR (400 MHz, CDCl3) δ 7.86 (1 H, s), 7.56 (2 H, dd,
J ) 9.07, 5.54 Hz), 7.05 (2 H, t, J ) 8.81 Hz), 6.47 (1 H, dd, J )
16.12, 1.01 Hz), 5.40 (1 H, dd, J ) 16.37, 5.79 Hz), 4.40 (1 H, dd,
J ) 10.58, 5.54 Hz), 3.67 (3 H, s), 4.27 (1 H, m), 3.29 (1 H, m),
3.58 (3 H, s), 2.44 (1 H, dd, J ) 15.11, 6.55 Hz), 2.29 (1 H, dd,
J ) 15.36, 6.30 Hz), 1.48 (3 H, s), 1.50 (2 H, m), 1.46 (9 H, s),
1.39 (3 H, s), 1.14 (6 H, t, J ) 6.55 Hz); MS (ESI) m/z 581 (M +
H)+; analytical HPLC (system D) tR ) 4.59 min.
Compound 7b was dissolved in THF (75 mL) and treated with
6 N HCl (22 mL). After 15 min, the reaction mixture was made
basic by the addition of 6 N NaOH (30 mL) followed by the
addition of methanol (5 mL). The mixture was stirred at RT for 15
min and concentrated, and the residue was subjected to reversed-
phase chromatography (C18/water-MeOH 100:0 to 50:50 gradient)
to afford the title compound as a white solid (11.1 g, 36% yield
from the sulfone 5): 1H NMR (500 MHz, CD3OD) δ 7.91 (1 H, s),
7.61 (2 H, dd, J ) 8.3, 5.5 Hz), 7.14 (2 H, t, J ) 8.8 Hz), 6.54 (1
H, d, J ) 16.5 Hz), 5.48 (1 H, dd, J ) 16.2, 6.3 Hz), 4.26-4.39
(1 H, m), 3.83-3.97 (1 H, m), 3.67 (3 H, s), 3.53 (3 H, s),
3.34-3.49 (1 H, m), 2.17-2.37 (2 H, m), 1.56-1.70 (1 H, m),
1.39-1.54 (1 H, m), 1.16 (3 H, s), 1.15 (3 H, s); MS (ESI) m/z
525 (M + H)+. Anal. (C24H28FN6NaO4 ·1.59H2O) C, H, N.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(1-methyl-
1H-1,2,4-triazol-5-ylamino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-
enoate (1a). This compound was prepared in a manner similar to
that described for the synthesis of compound 1b except that the
step involving alkylation with MeI was omitted. 1H NMR (500
MHz, CD3OD) δ 7.84 (s, 1 H), 7.61 (dd, J ) 8.6, 5.5 Hz, 2 H),
7.14 (t, J ) 8.9 Hz, 2 H), 6.54 (d, J ) 15.9 Hz, 1 H), 5.48 (dd, J
) 16.2, 6.4 Hz, 1 H), 4.32 (q, J ) 6.7 Hz, 1 H), 3.87-3.95 (m, 1
H), 3.38-3.48 (m, 1 H), 3.76 (s, 3 H), 2.23 (dd, 1 H), 2.31 (dd, 1
H), 1.58-1.68 (m, 1 H), 1.43-1.51 (m, 1 H), 1.20 (d, J ) 6.7 Hz,
6 H); MS (ESI) m/z 471 (M + H)+; analytical HPLC (system B)
tR ) 1.17 min.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-(1-
methyl-1H-1,2,4-triazol-5-yl)methylsulfonamido)pyrimidin-5-yl)-
3,5-dihydroxyhept-6-enoate (1c). This compound was prepared in
a manner similar to that described for the synthesis of compound
1b except that MeI was substituted with methanesulfonyl chloride.
1H NMR (400 MHz, CD3OD) δ 8.04 (1 H, s), 7.67 (2 H, dd, J )
8.3, 5.5 Hz), 7.16 (2 H, t, J ) 9.0 Hz), 6.60 (1 H, d, J ) 17.0 Hz),
5.60 (1 H, dd, J ) 16.2, 6.0 Hz), 4.40-4.25 (1 H, m), 3.90 (4 H,
br s), 3.75 (3 H, s), 3.55-3.47 (1 H, m), 2.34 (1 H, dd, J ) 15.5,
4.9 Hz), 2.25 (1 H, dd, J ) 15.5, 7.9 Hz), 1.70-1.64 (1 H, m),
1.58-1.50 (1 H, m), 1.22 (3 H, d, J ) 1.58 Hz), 1.20 (3 H, d, J )
1.58 Hz); MS (ESI) m/z 549 (M + H)+; analytical HPLC (system
B) tR ) 1.38 min.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(5-phenyl-
1,2,4-thiadiazol-3-ylamino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-
enoate (8a). This compound was prepared from compound 5 and
5-phenyl-1,2,4-thiadiazol-3-amine as described for compound 1a. 1H
NMR (400 MHz, CD3OD) δ 8.04 (2 H, dd, J ) 8.1, 1.5 Hz), 7.77 (2
H, dd, J ) 9.1, 5.5 Hz), 7.53-7.60 (3 H, m), 7.18 (2 H, t, J ) 8.8
Hz), 6.62 (1 H, dd, J ) 16.1, 1.0 Hz), 5.54 (1 H, dd, J ) 16.1, 6.0
Hz), 4.36 (1 H, q, J ) 6.0 Hz), 3.91-3.98 (1 H, m), 3.43-3.57 (1 H,
m), 2.34 (1 H, dd, J ) 19.6, 4.5 Hz), 2.25 (1 H, dd, J ) 15.1, 7.6 Hz),
1.61-1.71 (1 H, m), 1.47-1.55 (1 H, m), 1.32 (6 H, d, J ) 6.5 Hz);
MS (ESI) m/z 550 (M + H)+; analytical HPLC (system B) tR ) 1.71
min.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(isoxazol-
3-ylamino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (9a). This
compound was prepared from compound 5 and isoxazol-3-amine as
described for compound 1a. 1H NMR (400 MHz, CD3OD) δ 8.46 (1
H, d, J ) 1.5 Hz), 7.67 (2 H, dd, J ) 9.1, 5.5 Hz), 7.26 (1 H, d, J )
1.5 Hz), 7.17 (2 H, t, J ) 8.8 Hz), 6.56 (1 H, dd, J ) 16.1, 1.0 Hz),
5.49 (1 H, dd, J ) 16.1, 6.5 Hz), 4.33 (1 H, q, J ) 6.5 Hz), 3.79-4.12
(1 H, m), 3.34-3.65 (1 H, m), 2.32 (3 H, dd, J ) 15.1, 4.5 Hz), 2.24
(1 H, dd, J ) 15.1, 8.1 Hz), 1.57-1.70 (1 H, m), 1.40-1.53 (1 H,
m), 1.29 (6 H, d, J ) 6.5 Hz); MS (ESI) m/z 457 (M + H)+; analytical
HPLC (system A) tR ) 3.33 min, (system B) tR ) 1.52 min.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(isoxazol-
3-yl(methyl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (9b).
This compound was prepared from compound 5 and isoxazol-3-amine
as described for compound 1b. 1H NMR (400 MHz, D2O) δ 8.30 (1
H, d, J ) 2.0 Hz), 7.43 (2 H, dd, J ) 8.6, 5.5 Hz), 7.09 (2 H, t, J )
8.8 Hz), 6.99 (1 H, d, J ) 2.0 Hz), 6.51 (1 H, d, J ) 15.6 Hz), 5.34
(1 H, dd, J ) 16.1, 7.1 Hz), 4.22 (1 H, q, J ) 6.5 Hz), 3.58-4.07 (1
H, m), 3.47 (3 H, s), 3.24-3.38 (1 H, m), 2.05-2.28 (2 H, m),
1.42-1.64 (1 H, m), 1.24-1.47 (1 H, m), 1.14 (3 H, d, J ) 6.5 Hz),
1.15 (3 H, d, J ) 7.1 Hz); MS (ESI) m/z 471 (M + H)+; analytical
HPLC (system A) tR ) 3.80 min, (system B) tR ) 1.88 min.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-(isox-
azol-3-yl)methylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-
enoate (9c). This compound was prepared from compound 5 and
isoxazol-3-amine as described for compound 1c. 1H NMR (400
MHz, CD3OD) δ 8.67 (1 H, d, J ) 1.5 Hz), 7.57 (2 H, dd, J ) 8.8,
5.3 Hz), 7.03-7.11 (2 H, m), 6.68 (1 H, d, J ) 2.0 Hz), 6.52 (1 H,
d, J ) 16.1 Hz), 5.52 (1 H, dd, J ) 16.1, 6.0 Hz), 4.07-4.33 (1 H,
m), 3.75-3.90 (1 H, m), 3.60 (3 H, s), 3.23-3.46 (1 H, m),
1.93-2.36 (2 H, m), 1.48-1.67 (1 H, m), 1.38-1.47 (1 H, m),
1.12 (6 H, d, J ) 7.1 Hz); MS (ESI) m/z 535 (M + H)+; analytical
HPLC (system A) tR ) 3.11 min, (system B) tR ) 0.95 min. Anal.
(C24H26FN4NaO7S·2.1H2O) C, H, N, F, Na, S.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(1-methyl-
1H-pyrazol-5-ylamino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-
enoate (10a). This compound was prepared from compound 5 and
1
1-methyl-1H-pyrazol-5-amine as described for compound 1a. H
NMR (400 MHz, CD3OD) δ 7.62 (2 H, dd, J ) 9.1, 5.5 Hz), 7.38
(1 H, d, J ) 2.0 Hz), 7.15 (2 H, t, J ) 8.8 Hz), 6.54 (1 H, dd, J )
16.1, 1.5 Hz), 6.39 (1 H, d, J ) 2.0 Hz), 5.46 (1 H, dd, J ) 16.1,
6.0 Hz), 4.31 (1 H, q, J ) 6.4 Hz), 3.81-4.13 (1 H, m), 3.76 (3 H,
s), 3.34-3.54 (1 H, m), 2.31 (1 H, dd, J ) 15.1, 5.0 Hz), 2.22 (1
H, dd, J ) 15.1, 8.1 Hz), 1.57-1.71 (1 H, m), 1.32-1.56 (1 H,
m), 1.23 (6 H, d, J ) 6.5 Hz); MS (ESI) m/z 470 (M + H)+;
analytical HPLC (system A) tR ) 3.21 min, (system B) tR ) 1.44
min.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-
methyl-1H-pyrazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-
6-enoate (10b). This compound was prepared from compound 5
and 1-methyl-1H-pyrazol-5-amine as described for compound 1b.
1H NMR (400 MHz, CD3OD) δ 7.59 (2 H, dd, J ) 8.6, 5.5 Hz),
7.47 (1 H, d, J ) 2.0 Hz), 7.12 (2 H, t, J ) 8.8 Hz), 6.52 (1 H, d,
J ) 16.1 Hz), 6.16 (1 H, d, J ) 2.0 Hz), 5.44 (1 H, dd, J ) 16.1,
6.6 Hz), 4.30 (1 H, q, J ) 6.4 Hz), 3.87-3.93 (1 H, m), 3.63 (3 H,
s), 3.48 (3 H, s), 3.34-3.43 (1 H, m), 2.18-2.34 (2 H, m),
1.57-1.67 (1 H, m), 1.42-1.51 (1 H, m), 1.14 (6 H, d, J ) 6.6
Hz); MS (ESI) m/z 484 (M + H)+; analytical HPLC (system A) tR
) 3.65 min, (system B) tR ) 1.67 min. Anal. (C25H29FN5NaO4 ·
1.0H2O) C, H, N, F, Na.
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-(1-
methyl-1H-pyrazol-5-yl)methylsulfonamido)pyrimidin-5-yl)-3,5-di-
hydroxyhept-6-enoate (10c). This compound was prepared from
compound 5 and 1-methyl-1H-pyrazol-5-amine as described for
compound 1c. 1H NMR (400 MHz, CD3OD) δ 7.66 (2 H, dd, J )
8.7, 5.4 Hz), 7.53 (1 H, d, J ) 2.0 Hz), 7.16 (2 H, t, J ) 8.8 Hz),
6.59 (1 H, d, J ) 16.2 Hz), 6.36 (1 H, d, J ) 2.0 Hz), 5.60 (1 H,