5068 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Cobb et al.
LiOH (3:1:1, 5 mL) was stirred under N2 for 16 h. Water (10
mL) was added, and the organic solvents were removed by
rotary evaporation. The residual aqueous solution was washed
with EtOAc (10 mL). The aqueous solution was acidified to
pH 1 with 2.0 M HCl and extracted with EtOAc (50 mL). This
extract was washed with brine (10 mL), dried over Na2SO4,
and concentrated to a white solid. Recrystallization of this
material from MeOH provided 60 (44.6 mg, 59%) as a white
solid: mp 214-217 °C; 1H NMR (CDCl3, 400 MHz) δ 12.85
(bs, 1 H), 12.65 (bs, 1 H), 8.13 (d, 1 H, J ) 7.7), 7.90 (d, 2 H,
J ) 7.9), 7.77 (d, 1 H, J ) 7.8), 7.49-7.47 (m, 3 H), 7.32 (t, 3
H, J ) 7.9), 7.11 (d, 2 H, J ) 8.4), 6.82 (d, 2 H, J ) 8.4), 6.65
(d, 1 H, J ) 8.5), 6.57 (t, 1 H, J ) 7.5), 4.36 (q, 1 H, J ) 6.3),
4.15 (t, 2 H, J ) 6.5), 3.08 (dd, 1 H, J ) 5.3, 13.8), 2.98 (dd, 1
H, J ) 6.6, 13.6), 2.89 (t, 2 H, J ) 6.5), 2.33 (s, 3 H); MS (ES)
m/e 487.2 (MH)+. Anal. (C28H26N2O6) C, H, N.
1.0 M LiOH (3:1:1, 15 mL) was stirred under N2 for 2 h. A
solution of 0.4 M HCl (25 mL) was added, and the mixture
was then extracted with EtOAc (150 mL). This extract was
washed with brine (25 mL), dried over Na2SO4, and concen-
trated to a white solid. This material was flash chromato-
graphed on silica gel with EtOAc (containing 0.1% HOAc) to
produce 63 (450 mg, 80%) as a white solid: mp 140-141 °C
(EtOAc); 1H NMR (DMSO-d6, 400 MHz) δ 12.95 (bs, 1 H),
7.94-7.88 (m, 3 H), 7.77 (d, 1 H, J ) 8.0), 7.49-7.45 (m, 3 H),
7.35 (t, 1 H, J ) 7.9), 7.08 (d, 2 H, J ) 8.5), 6.82 (d, 1 H, J )
8.6), 6.69 (d, 1 H, J ) 8.6), 6.59 (t, 1 H, J ) 7.5), 4.42-4.38
(m, 1 H), 4.15 (t, 2 H, J ) 6.7), 3.75 (s, 3 H), 3.09 (dd, 1 H, J
) 5.3, 13.9), 2.96 (dd, 1 H, J ) 6.1, 14.0), 2.89 (t, 2 H, J )
6.6), 2.32 (s, 3 H); MS (ES+) m/e 501 (MH)+; TLC (EtOAc) Rf
) 0.51; chiral chromatography (Chiralcel OD-H, 4.6 × 250 mm;
EtOH/hexane (3:7) and 0.1% TFA; 0.7 mL/min) tR ) 7.8 min
(major enantiomer), 7.2 min (minor enantiomer); 88% ee; [R]D
) -9.8°, R ) -0.109°, c ) 1.11 (CH2Cl2) (not corrected for ee).
Anal. (C29H28N2O6) C, H, N.
(S)-2-(1-Ca r b oxy-2-{4-[2-(5-m et h yl-2-p h en yloxa zol-4-
yl)eth oxy]p h en yl}eth yla m in o)ben zoic Acid Eth yl Ester
(64). A solution of 0.97 g (1.94 mmol) of 21 in THF (40 mL)
and EtOH (10 mL) was treated with 1 M LiOH (10 mL). The
reaction was stirred for 30 h. Water (50 mL) and 1 N HCl (5
mL) were added. The reaction was extracted with EtOAc (3
× 100 mL). The combined organics were washed with brine
(100 mL), dried over MgSO4, filtered, and concentrated. The
residue was suspended in toluene (3 × 40 mL) and concen-
trated to afford 900 mg (1.85 mmol, 95%) of the diacid (S)-60
as an off-white solid.
A suspension of 0.432 g (0.889 mmol) of (S)-60 in methanol
(15 mL) was treated with concentrated HCl (1 mL) and heated
to 70 °C. The solution was stirred for 4 h and then concen-
trated and the residue purified by flash chromatography
(EtOAc with 0.1% AcOH) to afford 0.166 g (0.332 mmol, 37%)
of 2(S)-(1-(methoxycarbonyl)-2-{4-[2-(5-methyl-2-phenyloxazol-
4-yl)ethoxy]phenyl}ethylamino)benzoic acid as a yellow foam:
1H NMR (CDCl3, 400 MHz) δ 8.00 (m, 2 H), 7.95 (d, 1 H, J )
6.3), 7.44 (m, 3 H), 7.33 (t, 1 H, J ) 6.8), 7.08 (d, 2 H, J ) 8.6),
6.83 (d, 2 H, J ) 8.7), 6.64 (d, 1 H, J ) 7.5), 6.53 (t, 1 H, J )
8.4), 4.34 (m, 1 H), 4.23 (t, 2 H, J ) 6.7), 3.69 (s, 3 H), 3.13
(ddd, 2 H, J ) 5.6, 8.1, 8.1), 2.36 (s, 3 H); MS m/e 501 (MH)+.
A solution of 0.059 g (0.118 mmol) of the above (S)-(1-
(methoxycarbonyl)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
phenyl}ethylamino)benzoic acid in DMF (2 mL) was treated
with 0.018 g (0.130 mmol) of K2CO3 and 0.037 g (0.236 mmol)
of ethyl iodide. The solution was stirred at room temperature
for 16 h, diluted with EtOAc (25 mL), washed with water (3 ×
30 mL) and brine (30 mL), dried over MgSO4, filtered, and
concentrated to afford 0.053 g (0.100 mmol, 85%) of 64 methyl
ester as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.19 (d, 1
H, J ) 8.7), 8.00 (m, 2 H), 7.91 (d, 1 H, J ) 8.0), 7.43 (bd, 3
H), 7.30 (t, 1 H, J ) 7.0), 7.11 (d, 2 H, J ) 8.6), 6.81 (d, 2h, J
) 8.5), 6.61 (d, 1 H, J ) 7.6), 6.53 (t, 1 H, J ) 8.4), 4.41 (m, 3
H), 4.23 (t, 2 H, J ) 6.5 Hz), 3.65 (s, 3 H), 3.16 (ddd, 2 H, J )
5.8, 7.9, 7.9), 2.99 (t, 2 H, J ) 6.5), 2.37 (s, 3 H), 1.35 (t, 3 H,
J ) 7.1); MS m/e 529 (MH)+.
2-(1-Ca r b oxy-2-{4-[2-(5-m et h yl-2-p h en yloxa zol-4-yl)-
eth oxy]p h en yl}eth yla m in o)ben zoic Acid Meth yl Am id e
(61). To a solution of 60 methyl ester (49.5 mg, 100 µmol),
HOBt (6.7 mg, 49 µmol), triethylamine (41.3 µL, 300 µmol),
and methylamine (12.8 µL (40% solution in water), 150 µmol)
in CH2Cl2 was added 1-ethyl-3-(3-dimethylaminopropyl)car-
bodiimide (22.7 mg, 120 µmol). The resulting solution was
stirred for 16 h under N2 and then diluted with EtOAc (50
mL) and washed with 20 mL each of 0.5 M HCl (2×), saturated
NH4Cl, water, and 2.0 M NaHCO2 (2×). This solution was
dried over MgSO2 and concentrated to a yellow oil which was
flash chromatographed on silica gel (10 g) with EtOAc/hexane
(1:1) to afford 33.8 mg (67%) of 61 methyl ester as a colorless
oil: MS (ES+) m/e 514 (MH+); TLC (hexane/EtOAc (1:1)) Rf )
0.31. A solution of this material in THF/EtOH/1.0 M LiOH
(3:1:1, 5 mL) was stirred under N2 for 16 h. The resulting
mixture was diluted with EtOAc (25 mL) and washed with
1.0 M HCl (10 mL) and brine (10 mL). The organic solution
was dried over MgSO4 and concentrated to afford 61 (33.4 mg,
100%) as a white solid after trituration with ether: mp 85-
1
90 °C; H NMR (DMSO-d6, 400 MHz) δ 12.71 (s, 1 H), 8.24-
8.20 (m, 2 H), 7.90-7.88 (m, 2 H), 7.49-7.45 (m, 4 H), 7.21 (t,
1 H, J ) 7.2), 7.10 (d, 2 H, J ) 8.5), 6.82 (d, 2 H, J ) 8.6),
6.60-6.53 (m, 2 H), 4.23-4.22 (m, 1 H), 4.15 (t, 2 H, J ) 6.5),
3.02 (dd, 1 H, J ) 5.6, 13.8), 2.92-2.87 (m, 3 H), 2.69 (d, 3 H,
J ) 4.5), 2.33 (s, 3 H); MS (ES+) m/e 500 (MH)+; high-resolution
MS (FAB+) m/e (MH+) calcd for C29H29N3O5 500.2185, found
500.2184. Anal. (C29H29N3O5‚0.75Et2O) C, H, N.
(S)-(1-(Met h oxyca r b on yl)-2-{4-[2-(5-m et h yl-2-p h en yl-
oxa zol-4-yl)et h oxy]p h en yl}et h yla m in o)b en zoic
Acid
Meth yl Ester (21). A solution of 15 (664 mg, 1.75 mmol) and
methyl cyclohexanone-2-carboxylate (300 mg, 1.92 mmol) in
toluene (50 mL) was refluxed for 16 h under N2 into a Dean-
Stark trap (oil bath temperature of 130 °C). The toluene was
then removed by rotary evaporation and replaced with anisole
(50 mL). To this solution was added 10% palladium on carbon
(250 mg), and the resulting suspension was heated to 190 °C
and stirred for 6 h under N2. After cooling to room temper-
ature the catalyst was removed by filtration through a pad of
Celite (5 g) with an EtOAc wash (200 mL). The filtrate was
concentrated to a brown oil which was flash chromatographed
on silica gel (100 g) with hexane/EtOAc (4:1) to provide 21 (590
mg, 66%) as a white solid: mp 102-103 °C (ether/hexane);
1H NMR (CDCl3, 400 MHz) δ 8.17 (d, 1 H, J ) 7.3), 7.98-7.96
(m, 2 H), 7.89 (d, 1 H, J ) 8.1), 7.45-7.39 (m, 3 H), 7.30 (t, 1
H, J ) 7.8), 7.12 (d, 2 H, J ) 8.6), 6.82 (d, 2 H, J ) 8.5), 6.61
(t, 1 H, J ) 7.6), 6.54 (d, 1 H, J ) 8.6), 4.32 (q, 1 H, J ) 6.9),
4.21 (t, 2 H, J ) 6.8), 3.85 (s, 3 H), 3.66 (s, 3 H), 3.16 (dd, 1 H,
J ) 6.1, 14.0), 3.08 (dd, 1 H, J ) 7.1, 13.9), 2.96 (t, 2 H, J )
6.4), 2.36 (s, 3 H); MS (ES+) m/e 515 (MH)+; TLC (hexane/
EtOAc (2:1)) Rf ) 0.60; chiral chromatography (Chiralcel OD-
H, 4.6 × 250 mm; EtOH/hexane (3:7); 0.7 mL/min) tR ) 11.5
min (major enantiomer), 13.9 min (minor enantiomer); 99%
ee; [R]D ) -37.1°, R ) -0.412°, c ) 1.1 (CH2Cl2). Anal.
(C30H30N2O6) C, H, N.
To a solution of 0.082 g (0.154 mmol) of 64 methyl ester in
THF (1 mL) was added 1 M LiOH (1 mL). The reaction was
stirred for 2 h and then the pH adjusted to 3.5 with 1 N HCl.
The reaction was extracted with EtOAc (3 × 25 mL). The
combined organics were washed with water (2 × 15 mL) and
brine (mL), dried over MgSO4, filtered, and concentrated to
afford 0.087 g (0.165 mmol, 61%) of 64 as an off-white solid:
1H NMR (CDCl3, 400 MHz) δ 8.19 (bd, 1 H), 7.88 (bd, 2 H),
7.38-7.30 (m, 3 H), 7.26 (t, 2 H, J ) 7), 7.10 (d, 2 H, J ) 8.5),
6.72 (d, 2 H, J ) 8.5), 6.60 (t, 1 H, J ) 7.6), 6.52 (d, 1 H, J )
8.3), 4.25 (q, 3 H, J ) 7.1), 4.10 (t, 2 H, J ) 7), 3.19 (ddd, 2 H,
J ) 5.6, 7.0, 7.0), 2.88 (t, 2 H, J ) 6.5), 2.30 (s, 3 H), 1.30 (t,
3 H, J ) 7.2); MS m/e 513 (M - H)-; chiral chromatography
(Chiralcel OD-H, 4.6 × 250 mm; iPrOH/hexane (1:9) and 0.1%
TFA; 1.0 mL/min) tR ) 19.2 min (major enantiomer), 24.6 min
(minor enantiomer); 90% ee. Anal. (C30H30N2O6‚0.5H2O) C,
H, N.
(S)-2-(1-Ca r b oxy-2-{4-[2-(5-m et h yl-2-p h en yloxa zol-4-
yl)eth oxy]p h en yl}eth yla m in o)ben zoic Acid Meth yl Es-
ter (63). A solution of 21 (582 mg, 1.13 mmol) in THF/EtOH/