5586 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17
O’Meara et al.
(130 mg, 17% yield) as a colorless gum. 1H NMR (DMSO-d6) δ
10.25 (s, 1H), 7.70 (d, J ) 2.1 Hz, 1H), 7.66 (dd, J ) 8.4, 2.1
Hz, 1H), 6.86 (d, J ) 8.4 Hz, 1H), 3.77 (s, 3H), 2.56 (q, J ) 7.5
Hz, 2H), 1.13 (t, J ) 7.5 Hz, 3H); MS (m/z) 178.9 (M - H)-.
Hz, 1H), 7.91 (d, J ) 2.4 Hz, 1H), 7.66 (d, J ) 8.0 Hz, 1H),
7.50-7.46 (m, 2H), 6.65 (d, J ) 8.2 Hz, 1H), 6.53 (d, J ) 8.0
Hz, 1H), 4.03-3.90 (bm, 4H), 3.72 (s, 3H), 3.21 (bs, 3H), 2.92
(t, J ) 6.2 Hz, 2H), 1.95 (s, 3H), 1.11 (t, J ) 7.2 Hz, 3H); 13C
NMR (DMSO-d6) δ 174.1, 169.9, 166.3, 159.2, 158.0, 157.0,
151.7, 150.7, 141.2, 135.4, 131.6, 129.5, 128.1, 124.0, 123.6,
120.4, 109.5, 106.0, 67.5, 53.3, 40.1, 36.7, 31.1, 16.1, 13.5; MS
(m/z) 463.2 (MH+); HRMS calcd for C25H26N4O5 (MH+) 462.1903,
found 462.1894. Compound 22 (48 mg, 50% yield) elutes
Ethyl (4-Hydroxy-3-methylphenyl)acetate (18). Acid 17
(1.0 g, 5.6 mmol) was dissolved in CH2Cl2 (50 mL), oxalyl
chloride (0.73 mL, 8.3 mmol) was added followed by DMF (0.1
mL), and the reaction mixture was stirred for 90 min. EtOH
(15 mL) was added, and the mixture was stirred for 1 h at
room temperature. The reaction was concentrated in vacuo,
and the resulting residue was dissolved in EtOAc, washed with
H2O, dried over MgSO4, filtered, and concentrated in vacuo
to give ethyl (4-methoxy-3-methylphenyl)acetate. This ester
was dissolved in CH2Cl2 (50 mL), BBr3 (7.2 mL of a 1.0 M
solution in CH2Cl2, 7.2 mmol) was added dropwise over 5 min,
and then, the mixture was stirred for 3 h at room temperature.
EtOH (5 mL) was added, and the reaction mixture was stirred
for an additional 30 min. The reaction mixture was concen-
trated in vacuo, taken into EtOAc, washed with H2O, dried
over MgSO4, filtered, and concentrated in vacuo. The product
was purified (FCC; 30% EtOAc/hexane) to give compound 18
1
second and as a white solid. H NMR (DMSO-d6) δ 8.47 (d, J
) 2.3 Hz, 1H), 8.12 (d, J ) 2.3 Hz, 1H), 8.11 (t, J ) 5.3 Hz,
1H), 7.66-7.64 (m, 2H), 7.08 (dd, J ) 8.6, 3.5 Hz, 1H), 6.80
(d, J ) 9.0 Hz, 1H), 4.18 (t, J ) 6.3 Hz, 2H), 4.04 (bm, 2H),
3.47 (s, 3H), 3.11 (t, J ) 6.3 Hz, 2H), 2.11 (s, 3H), 1.24 (t, J )
7.02 Hz, 3H); 13C NMR (DMSO-d6) δ 175.1, 170.1, 166.4, 158.9,
157.4, 152.4, 151.4, 141.6, 137.8, 132.1, 131.9, 130.4, 128.9,
128.5, 124.0, 109.8, 105.4, 67.7, 40.7, 37.3, 31.3, 16.3, 13.5; MS
(m/z) 451.2 (MH+); HRMS calcd for C24H24N4O4F, (MH+)
451.1782, found 451.1800.
4-[2-(11-Ethyl-5-methyl-6-oxo-6,11-dihydro-5H-dipyrido-
[2,3-e:3′,2′-b][1,4]diazepin-8-yl)ethoxy]-1-naphthoic Acid
(24). 1H NMR (DMSO-d6) δ 12.58 (bs, 1H), 8.92 (d, J ) 8.5
Hz, 1H), 8.43 (d, J ) 2.3 Hz, 1H), 8.12-8.09 (m, 3H), 8.05 (d,
J ) 2.3 Hz, 1H), 7.75 (dd, J ) 8.0, 1.6 Hz, 1H), 7.54 (t, J ) 8.0
Hz, 1H), 7.42 (t, J ) 8.0 Hz, 1H), 7.17 (dd, J ) 8.0, 4.7 Hz,
1H), 6.97 (d, J ) 8.5 Hz, 1H), 4.35 (t, J ) 6.3 Hz, 2H), 3.99
(bm, 2H), 3.36 (s, 3H), 3.15 (t, J ) 6.3 Hz, 2H), 1.10 (t, J ) 7.0
Hz, 3H); MS (m/z) 469.2 (MH+); HRMS calcd for C27H25N4O4
(MH+) 469.1876, found 469.1886.
5-[2-(11-Ethyl-5-methyl-6-oxo-6,11-dihydro-5H-dipyrido-
[2,3-e:3′,2′-b][1,4]diazepin-8-yl)ethoxy]-1-naphthoic Acid
(25). 1H NMR (DMSO-d6) δ 13.25 (bs, 1H), 8.67 (d, J ) 2.2
Hz, 1H), 8.52 (d, J ) 8.8 Hz, 1H), 8.50 (d, J ) 8.6 Hz, 1H),
8.37 (dd, J ) 4.7, 1.3 Hz, 1H), 8.29 (d, J ) 2.2 Hz, 1H), 8.27
(d, J ) 7.4 Hz, 1H), 8.02 (dd, J ) 8.0, 1.3 Hz, 1H), 7.69-7.65
(m, 2H), 7.43 (dd, J ) 8.0, 4.7 Hz, 1H), 7.22 (dd, J ) 7.7 Hz,
1H), 4.53 (t, J ) 6.1 Hz, 2H), 4.25-4.12 (bm, 2H), 3.61 (s, 3H),
3.37 (t, J ) 6.1 Hz, 2H), 1.35 (t, J ) 7.0 Hz, 3H); 13C NMR
(DMSO-d6) δ 168.9, 166.4, 157.7, 154.1, 153.9, 151.2, 144.2,
141.2, 131.8, 131.6, 131.2, 130.0, 129.4, 127.8, 127.7, 126.1,
125.3, 124.2, 120.3, 117.7, 105.7, 68.2, 40.44, 36.81, 31.0, 13.5;
MS (m/z) 469.2 (MH+); HRMS calcd for C27H25N4O4 (MH+)
469.1876, found 469.1887.
6-[2-(11-Ethyl-5-methyl-6-oxo-6,11-dihydro-5H-dipyrido-
[2,3-e:3′,2′-b][1,4]diazepin-8-yl)ethoxy]-1-naphthoic Acid
(26). 1H NMR (DMSO-d6) δ 13.05 (bs, 1H), 8.78 (d, J ) 9.4
Hz, 1H), 8.47 (d, J ) 2.2 Hz, 1H), 8.23 (dd, J ) 4.7, 1.6 Hz,
1H), 8.09 (d, J ) 2.2 Hz, 1 H), 8.02 (d, J ) 8.2 Hz, 1H), 7.99
(d, J ) 5 Hz, 1H), 7.87 (dd, J ) 8.0, 1.6 Hz, 1H), 7.54 (t, J )
7.6 Hz, 1H), 7.46 (d, J ) 2.5 Hz, 1H), 7.30-7.27 (m, 2H), 4.33
(t, J ) 6.4 Hz, 2H), 4.11-4.05 (bm, 2H), 3.46 (s, 3 H), 3.15 (t,
J ) 6.4 Hz, 2H), 1.21 (t, J ) 7.0 Hz, 3H); 13C NMR (DMSO-d6)
δ 168.7, 166.4, 157.7, 156.0, 154.1, 151.2, 144.1, 141.1, 135.1,
131.8, 131.2, 129.1, 127.6, 127.5, 127.1, 126.1, 125.4, 120.0,
107.6, 67.6, 40.44, 36.8, 30.9, 13.5; MS (m/z) 469.2 (MH+);
HRMS calcd for C27H25N4O4 (MH+) 469.1876, found 469.1875.
1
(802 mg, 74% yield) as a white solid. H NMR (DMSO-d6) δ
9.19 (s, 1H), 6.92 (s, 1H), 6.84 (dd, J ) 8.2, 2.0 Hz, 1H), 6.69
(d, J ) 8.2 Hz, 1H), 4.04 (q, J ) 7.0 Hz, 2H), 3.46 (s, 2H), 2.08
(s, 3H), 1.16 (t, J ) 7.0 Hz, 3H); MS (m/z) 192.9 (M - H)-.
Ethyl 3-(4-Hydroxy-3-methylphenyl)propanoate (20).
Triethyl phosphonoacetate (2.6 mL, 13.3 mmol) was dissolved
in THF (50 mL) and cooled to -78 °C. n-BuLi (9.6 mL of a 1.4
M solution in hexane, 13.4 mmol) was added dropwise over 5
min, and the resulting solution was stirred for 30 min at -78
°C. Aldehyde 19 (2.0 g, 13.3 mmol) was dissolved in THF (10
mL) and added dropwise via syringe pump over 1 h. After the
addition was complete, the reaction mixture was stirred at -78
°C for 45 min and then warmed to 0 °C for 90 min. The reaction
mixture was carefully concentrated in vacuo and diluted with
Et2O and H2O. The aqueous phase was extracted twice with
Et2O; the combined organics were washed twice with H2O and
brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified (FCC; 10% EtOAc/hexane) to give
ethyl (2E)-3-(4-methoxy-3-methylphenyl)acrylate (2.6 g, 89%)
as a yellow oil. The R,â-unsaturated ester (1.0 g, 4.5 mmol)
was dissolved in EtOH (20 mL) and degassed under vacuum
for 10 min. 10% Pd/C (0.1 g) was added, and the resulting
mixture was stirred under an H2 atmosphere for 18 h. The
mixture was filtered through Celite and concentrated in vacuo
to give the reduced compound (0.96 g, 95%) as a pale yellow
oil. This compound (350 mg, 1.58 mmol) was dissolved in CH2-
Cl2 (15 mL) and cooled to 0 °C. BBr3 (4 mL of a 1.0 M solution
in CH2Cl2, 4 mmol) was added dropwise over 5 min. The
mixture was stirred at 0 °C for 4 h. The reaction was quenched
by the addition of EtOH (0.5 mL) and stirred for 30 min. The
resulting solution was diluted with EtOAc, washed with H2O
and brine, dried over MgSO4, filtered, and concentrated in
vacuo to give compound 20 (175 mg, 54%) as a yellow solid.
1H NMR (DMSO-d6) δ 9.03 (s, 1H), 6.88 (s, 1H), 6.80 (dd, J )
8.0, 1.7 Hz, 1H), 6.65 (d, J ) 8.0 Hz, 1H), 4.02 (q, J ) 7.0 Hz,
2H), 2.69 (t, J ) 7.7 Hz, 2H), 2.55 (m, 2H), 2.06 (s, 3H), 1.15
(t, J ) 7.0 Hz, 3H); MS (m/z) 207.0 (M - H)-.
6-[2-(11-Ethyl-5-methyl-6-oxo-6,11-dihydro-5H-dipyrido-
[2,3-e:3′,2′-b][1,4]diazepin-8-yl)ethoxy]-2-naphthoic Acid
1
(27). H NMR (DMSO-d6) δ 12.84 (bs, 1H), 8.56 (s, 1H), 8.51
4-[2-(11-Ethyl-2-fluoro-5-methyl-6-oxo-6,11-dihydro-
5H-dipyrido[2,3-e:3′,2′-b][1,4]diazepin-8-yl)ethoxy]-3-me-
thylbenzoic Acid (22) and 4-[2-(11-Ethyl-2-methoxy-5-
methyl-6-oxo-6,11-dihydro-5H-dipyrido[2,3-e:3′,2′-b]-
[1,4]diazepin-8-yl)ethoxy]-3-methylbenzoic Acid (23). Com-
pound 21 (100 mg, 0.215 mmol) was dissolved in 25% MeOH
in THF (6 mL), 1.0 M LiOH (1.0 mL, 1.0 mmol) was added,
and the reaction mixture was stirred for 24 h at room
temperature. The reaction mixture was diluted with H2O and
washed with Et2O. The aqueous phase was acidified with 1.0
N HCl and extracted with EtOAc. The combined organics were
dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified (FCC; 50% EtOAc/hexane contain-
ing 1% AcOH). Compound 23 (25 mg, 25%) elutes from the
column first as a white solid upon concentration of the
(d, J ) 2.3 Hz, 1H), 8.27 (dd, J ) 4.5, 1.4 Hz, 1H), 8.13 (d, J
) 2.3 Hz, 1H), 8.05 (d, J ) 9.0 Hz, 1H), 7.97 (dd, J ) 6.0, 1.4
Hz, 1H), 7.92-7.88 (m, 2H), 7.48 (d, J ) 2.1 Hz, 1H), 7.33 (dd,
J ) 13.9, 9.2 Hz, 1H), 7.27 (dd, J ) 9.0, 2.3 Hz, 1H), 4.38 (t,
J ) 6.6 Hz, 2H), 4.15-4.05 (bm, 2H), 3.49 (s, 3H), 3.18 (t, J )
6.6 Hz, 2H), 1.24 (t, J ) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ
167.5, 166.3, 158.0, 157.7, 154.0, 151.2, 144.1, 141.1, 136.7,
131.8, 131.2, 130.9, 130.3, 129.1, 127.5, 126.9, 125.7, 120.3,
119.5, 106.8, 67.8, 40.4, 36.8, 30.8, 13.5; MS (m/z) 469.2 (MH+);
HRMS calcd for C27H24N4O4 (M) 468.1799, found 468.1797.
4-[2-(11-Ethyl-5-methyl-6-oxo-6,11-dihydro-5H-dipyrido-
[2,3-e:3′,2′-b][1,4]diazepin-8-yl)ethoxy]benzoic Acid (28).
1H NMR (DMSO-d6) δ 8.32 (d, J ) 2.3 Hz, 1H), 8.13 (dd, J )
4.7, 1.6 Hz, 1H), 8.12 (d, J ) 1.4 Hz, 1H), 7.76 (dd, J ) 8.0,
1.4 Hz, 1H), 7.65 (d, J ) 8.7 Hz, 2H), 7.19 (dd, J ) 8.0, 4.7 Hz,
1
appropriate fractions. H NMR (DMSO-d6) δ 8.26 (d, J ) 2.4