4796 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Hutchinson et al.
(Na2SO4), and concentrated to give an oil. Column chroma-
tography (silica gel; 5%MeOH in CHCl3 followed by 5% MeOH
in CHCl3 saturated with NH3) gave the title compound as a
viscous oil (8.03 g, 70%). 1H NMR (300 MHz, CDCl3) δ 1.20
(3H, t), 1.8-1.95 (4H, m), 2.5-2.8 (12H, m), 3.39 (2H, m), 3.92
(3H, s), 4.09 (2H, q), 5.01 (1H, bs), 6.34 (1H, d), 6.72 (1H, d),
7.06 (1H, d), 7.59 (1H, dd), 8.07 (1H, d).
water/acetonitrile + 0.1% TFA; gradient) to give (after lyo-
1
philization) 17 as a TFA salt. H NMR (300 MHz, CD3OD) δ
1.86 (2H, m), 1.95 (2H, m), 2.66 (2H, t), 2.81 (2H, t), 2.96 (1H,
m), 3.15 (1H, m), 3.23 (2H, t), 3.35-3.55 (5H, m), 5.23 (1H, t),
6.55 (1H, d), 6.64 (1H, d), 7.44 (1H, d), 7.58 (1H, d), 7.65 (1H,
dd). Exact mass (FAB, M + H) found: 426.2141; C24H29N4O4F
+ H requires 426.2136. Anal. for
C22H27N5O4F‚2.2TFA‚
0.65H2O: Calcd C 46.06; H 4.45; N 10.24. Found: C 46.08; H
4.47; N 10.18.
Step 3. 3(S)-(6-Meth oxypyr idin -2-yl)-3-{2-oxo-[3-(5,6,7,8-
tetr a h yd r o-[1,8]-n a p h th yr id in -2-yl)p r op yl]im id a zolid in -
1-yl}p r op ion ic Acid Eth yl Ester . To a solution of the
diamine from step 2 (8.03 g, 18.2 mmol), DIPEA (9.5 mL, 54.6
mmol), and DMAP (250 mg) in 1,2-dichloroethane (150 mL)
cooled to -20 °C was added p-nitrophenyl chloroformate (3.85
g, 19.1 mmol) in 1,2-dichloroethane (25 mL) dropwise such that
the internal temperature remained below -15 °C. The result-
ing mixture was allowed to warm to 0 °C, stirred for 45 min,
and then heated to reflux for 4 h. After cooling, the solvent
was evaporated in vacuo and the residue taken up in EtOAc
and washed successively with 10% K2CO3 (6 × 150 mL) and
brine. The EtOAc layer was dried (Na2SO4) and concentrated
in vacuo to give an oil. Column chromatography (silica gel;
5% EtOH in CH2Cl2) gave the title compound as an oil (5.28
3(S)-(6-Met h oxyp yr id in -3-yl)-3-{2-oxo-[3-(7-h yd r oxy-
5,6,7,8-tetr a h yd r o-[1,8]-n a p h th yr id in -2-yl)p r op yl]im id a -
zolid in -1-yl}p r op ion ic Acid 15. To a solution of 6 (0.88 g, 2
mmol) in water (20 mL) at room temperature were added 1 N
NaOH (2.0 mL, 2 mmol) and then KMnO4 (0.316, 2 mmol),
and the mixture was stirred for 16 h. After filtration, the
solution was purified by HPLC chromatography (DeltaPak
C-18 column; 0.1% NH4HCO3 (aq) and acetonitrile; gradient
elution). Collection of the second eluting peak followed by
lyophilization afforded 15 as a white solid (1:1 mixture of
1
7-hydroxy epimers). H NMR (600 MHz, CD3OD) δ 1.70 (1H,
m), 1.86 (1H, m), 2.07 (1H, m), 2.12 (1H, m), 2.61 (1H, m),
2.71 (2H, m), 2.75-3.0 (6H, m), 3.17 (1H, q), 3.48 (1H, m), 3.62
(1H, m), 3.90 (3H, s), 4.73 (1H, m), 5.46 (1H, br d), 6.69 (1H,
d), 6.80 (1H, dd), 7.54 (1H, m), 7.67 (1H, dd), 8.09 (1H, d). Mass
spectrum: found 456.1 (M + H)+.
1
g, 62%). H NMR (300 MHz, CDCl3) δ 1.20 (3H, t), 1.8-1.95
(4H, m), 2.52 (2H, dd), 2.68 (1H, dd), 2.9-3.1 (3H, m), 3.15-
3.3 (5H, m), 3.39 (2H, m), 3.92 (3H, s), 4.11 (2H, q), 4.8 (1H,
bs), 5.42 (1H, t), 6.34 (1H, d), 6.72 (1H, d), 7.03 (1H, d), 7.60
(1H, dd), 8.08 (1H, d).
3(S)-(6-Meth oxyp yr id in -3-yl)-3-{2-oxo-[3-(7-oxo-5,6,7,8-
tetr a h yd r o-[1,8]-n a p h th yr id in -2-yl)p r op yl]im id a zolid in -
1-yl}p r op ion ic Acid 14. Following the procedure described
above but collecting the first eluted peak following HPLC
chromatography and lyophilization gave 14 as a white solid.
1H NMR (500 MHz, CD3OD) δ 1.90 (2H, m), 2.57 (2H, m), 2.65
(2H, m), 2.87 (2H, m), 2.93 (3H, m), 3.13 (1H, m), 3.26 (3H,
m), 3.40 (1H, q), 3.89 (3H, s), 5.37 (1H, t), 6.78 (1H, d), 6.82
(1H, d), 7.39 (1H, d), 7.67 (1H, dd), 8.11 (1H, d). Exact mass
(FAB, M + H) found: 454.2066; C23H27N5O5 + H requires
454.2085.
3(S)-(6-Meth oxyp yr id in -3-yl)-3-{2-oxo-3-([1,8]-n a p h th y-
r id in -2-yl)p r op yl]im id a zolid in -1-yl}p r op ion ic Acid 16. To
a solution of 6 (0.44 g, 1 mmol) in pyridine (5 mL) at room
temperature was added CrO3 (0.1 g, 1 mmol), and the mixture
was stirred for 16 h. The mixture was diluted with water (100
mL) and filtered through Celite and the solvent removed in
vacuo. The residue was purified by HPLC chromatography
(DeltaPak C-18 column; 0.1% NH4HCO3 (aq) and MeOH;
gradient elution) to give (after lyophilization) 16 as a pale
yellow solid. 1H NMR (300 MHz, CD3OD) δ 2.12 (2H, m), 2.65-
2.85 (4H, m), 3.03 (2H, t), 3.1-3.4 (4H, m), 3.75 (3H, s), 5.38
(1H, t), 6.75 (1H, d), 7.53 (1H, d), 7.74 (1H,dd), 7.64 (1H, dd),
8.09 (1H, d), 8.22 (1H, d), 8.36 (1H, dd), 8.98 (1H, dd). Mass
spectrum: found 436.0 (M + H)+. Exact mass (FAB, M + H)
found: 436.1978; C23H27N5O5 + H requires 436.1980.
3(S )-(6-Me t h oxyp yr id in -3-yl)-3-{2-oxo-[3-(1N-oxid e -
5,6,7,8-tetr a h yd r o-[1,8]-n a p h th yr id in -2-yl)p r op yl]im id a -
zolid in -1-yl}p r op ion ic Acid 20. Step 1 3(S)-(6-Meth oxy-
pyr idin -3-yl)-3-{2-oxo-[3-(1N-oxide-5,6,7,8-tetr ah ydr o-[1,8]-
n a p h t h yr id in -2-yl)p r op yl]im id a zolid in -1-yl}p r op ion ic
Acid Eth yl Ester 19. To a solution of 18 (1.51 g, 3.2 mmol)
in CH2Cl2 (20 mL) was added m-CPBA (70%; 0.96 g, 3.9 mmol),
and the mixture was stirred at room temperature for 4 h. The
mixture was diluted with CH2Cl2, washed with NaHCO3 (5×)
and brine and dried over Na2SO4. The solvent was removed
and the residue purified by silica gel chromatography (CHCl3/
MeOH 97:3) to afford the N-oxide 19 as a viscous oil. Mass
spectrum: found 484.1 (M + H)+.
Step 2. Com p ou n d 20. To a solution of the ester from step
1 (0.26 g, 0.5 mmol) in MeOH (7.5 mL) was added 1 N NaOH
(1.5 mL, 1.5 mmol), and the mixture was stirred at room
temperature for 16 h. The solvent was removed in vacuo, the
residue dissolved in water (5 mL), and 1 N HCl added (1.5
mL). After extraction with CH2Cl2 (4 × 20 mL), the organic
layers were washed with brine, dried (Na2SO4), and concen-
trated to give 20 as an off-white solid. 1H NMR (300 MHz,
CDCl3) δ 1.7-2.1 (4H, m), 2.7-3.1 (8H, m), 3.21 (1H, m), 3.5
(4H, m), 3.81 (1H, ddd), 3.91 (3H, s), 5.54 (1H, dd), 5.4-5.7
Step 4. Com p ou n d 6. To a solution of the ester from step
3 (3.48 g, 7.4 mmol) in MeOH (50 mL) and water (30 mL) at
room temperature was added 1 N NaOH (22.3 mL, 22.3 mmol)
and the mixture stirred for 16 h. After removal of the solvent
in vacuo, the residue was treated with 1 N HCl (25 mL) and
the solvent removed again. Column chromatography of the
residue (silica gel; EtOAc/EtOH/aq NH4OH/ H2O 20:10:1:1)
gave a gum which was crystallized from water and filtered to
give 6 as a white solid (3.04 g, 93%). 1H NMR (300 MHz, CD3-
OD) δ 1.75-2.1 (4H, m), 2.55-3.1 (8H, m), 3.28 (1H, q), 3.3
(1H, m), 3.4-3.55 (3H, m), 3.63 (1H, q), 3.85 (3H, s), 5.47 (1H,
dd), 6.55 (1H, d), 6.80 (1H, d), 7.48 (1H, d), 7.68 (1H, d), 8.09
(1H, d). Exact mass (FAB, M + H) found: 440.2297; C23H29N5O4
+ H requires 440.2293. Anal. for C23H29N5O4: Calcd C 62.85;
H 6.65; N 15.94. Found: C 62.51; H 6.76; N 16.04.
Compounds 3-5 were prepared using similar procedures
used for the preparation of 6:
3(S)-(Dih yd r oben zofu r a n -6-yl)-3-{2-oxo-[3-(5,6,7,8-tet-
r a h yd r o-[1,8]-n a p h th yr id in -2-yl)p r op yl]im id a zolid in -1-
yl}p r op ion ic Acid 3. 1H NMR (300 MHz, CD3OD) δ 1.93 (4H,
m), 2.67 (2H, t), 2.80 (2H, t), 2.97 (3H, m), 3.14-3.53 (9H, m),
4.53 (1H, t), 5.38 (1H, t), 6.62 (1H, d), 6.72 (1H s), 6.81 (1H,
d), 7.18 (1H, d), 7.55 (1H, d). High res MS (FAB, M + H)
found: 451.2354; C25H30N4O4 + H requires 451.2340.
3(S)-(4-Met h oxy-3-flu or op h en yl)-3-{2-oxo-[3-(5,6,7,8-
tetr a h yd r o-[1,8]-n a p h th yr id in -2-yl)-p r op yl]im id a zolid in -
1
1-yl}p r op ion ic Acid 4. H NMR (300 MHz, CD3OD) δ 1.86
(2H, m), 1.95 (2H, m), 2.66 (2H, t), 2.82 (2H, t), 3.01 (2H, m),
3.05 (1H, q), 3.2-3.2 (7H, m), 3.86 (3H, s), 5.39 (1H, t), 6.63
(1H, d), 7.0-7.2 (3H, m), 7.57 (1H, d). High res MS (FAB, M
+ H) found: 457.2246; C24H29N4O4F + H requires 457.2246.
Anal. for C24H29N4O4F‚1.55TFA‚0.3H2O: Calcd C 50.96; H
4.92; N 8.77. Found: C 50.96; H 4.92; N 8.76.
3(S)-(P yr id in -3-yl)-3-{2-oxo-[3-(5,6,7,8-tetr a h yd r o-[1,8]-
n a p h t h yr id in -2-yl)-p r op yl]im id a zolid in -1-yl}p r op ion ic
Acid 5. 1H NMR (300 MHz, CD3OD) δ 1.93 (3H, m), 2.05 (1H,
m), 2.60 (2H, m), 2.77 (4H, m), 3.01 (2H, m), 3.18 (2H, m),
3.46 (3H, m), 3.63 (2H, m), 5.57 (1H, m), 6.55 (1H, d), 7.46
(2H, m), 7.85 (1H, d), 8.47 (1H, m), 8.54 (1H, m). High res MS
(FAB, M + H) found: 410.2192; C22H27N5O3 + H requires
410.2211.
3(S)-(2(1H)-P yr id on e-5-yl)-3-{2-oxo-[3-(5,6,7,8-tetr a h y-
d r o-[1,8]-n a p h t h yr id in -2-yl)p r op yl]im id a zolid in -1-yl}-
p r op ion ic Acid 17. The acid 6 (100 mg, 0.23 mmol) and
pyridine hydrochloride (300 mg) were placed in a sealed vial
and heated at 125 °C for 2.5 min. The molten mixture was
cooled and purified by reverse phase HPLC (C18 column;