Journal of Medicinal Chemistry
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three times with brine, dried over MgSO4, and concentrated in vacuo.
Purification of the residue by flash chromatography on silica gel (5−
25% EtOAc in hexanes) gave 33 (5.87 g, 14.17 mmol, 94% yield) as a
white solid. LCMS (method formate): retention time 1.01 min, [M +
H]+ = 414, 416 (1 Br). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (d, J
= 16.2 Hz, 1H), 7.45−7.65 (m, 2H) 7.03 (t, J = 8.0 Hz, 1H), 6.46 (d, J
= 16.2 Hz, 1H), 5.15−5.37 (m, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.01 (t, J
= 4.8 Hz, 2H), 3.57 (d, J = 5.1 Hz, 2H), 1.47 (s, 9H), 1.35 (t, J = 7.1
Hz, 3H).
chromatography on silica gel (0−80% EtOAc in hexanes) gave tert-
butyl 9-cyano-5-(2-ethoxy-2-oxoethyl)-2,3-dihydrobenzo[f ][1,4]-
oxazepine-4(5H)-carboxylate (56.1 g, 92%) as pale yellow solid.
LCMS (method formate): retention time 1.32 min, [M + H]+ = 361.
1H NMR (250 MHz, DMSO-d6) δ ppm 7.60−7.66 (m, 1H), 7.52−
7.57 (m, 1H), 7.18−7.27 (m, 1H), 5.65 (s, 1H), 5.53−5.63 (m, 1H),
4.42−4.54 (m, 1H), 4.10 (m, 2H), 3.85−3.99 (m, 1H), 3.61−3.75 (m,
1H), 2.93−3.16 (m, 2H), 1.40 (s, 9H), 1.18 (t, J = 7.1 Hz, 3H). This
material (59 g, 164 mmol) was dissolved in EtOH (200 mL) by
heating to 60 °C, and the cooled solution (room temperature) was
then diluted with Et2O (900 mL). Lithium borohydride (2 M in THF,
246 mL, 491 mmol) was added under nitrogen, and the solution was
stirred for 2 h at room temperature, giving a thick suspension. The
mixture was treated slowly with MeOH (20 mL) and then added very
cautiously to vigorously stirred water (300 mL). The mixture was
extracted with EtOAc (200 mL). The organic phase was dried over
MgSO4 and concentrated in vacuo to give 77 (50.2 g, 96%), which was
used in the next step without further purification. LCMS (method
tert-Butyl 9-Bromo-5-(2-ethoxy-2-oxoethyl)-2,3-
dihydrobenzo[f ][1,4]oxazepine-4(5H)-carboxylate (76). A sol-
ution of ethyl (2E)-3-(3-bromo-2-{[2-({[(1,1-dimethylethyl)oxy]-
carbonyl}amino)ethyl]oxy}phenyl)-2-propenoate, 75 (58.1 g, 140
mmol), in CH2Cl2 (150 mL) at room temperature was treated with
CF3COOH (108 mL, 1.4 mol), and the resulting mixture was stirred
for 14 h at this temperature and then was concentrated in vacuo. The
residue was suspended in water (300 mL), and the mixture was
basified with a 2 N NaOH aqueous solution to pH 10. The aqueous
phase was then extracted with EtOAc (2 × 200 mL). The combined
organic phases were dried over MgSO4 and concentrated in vacuo to
give (E)-ethyl 3-(2-(2-aminoethoxy)-3-bromophenyl)acrylate (48.2 g,
153 mmol, 109% yield) as a white solid, which was carried through as
is to the next step without purification. LCMS (method formate):
retention time 0.61 min, [M + H]+ = 314, 316 (1 Br). 1H NMR (400
MHz, CDCl3) δ ppm 7.96 (d, J = 16.2 Hz, 1H), 7.59 (dd, J = 8.0, 1.4
Hz, 1H), 7.51 (dd, J = 7.8, 1.3 Hz, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.46
(d, J = 16.2 Hz, 1H), 6.28 (br s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.10−
4.19 (m, 2H), 3.40 (t, J = 4.9 Hz, 2H), 1.29−1.33 (t, J = 7.1 Hz, 3H).
A solution of this material (48.4 g, 137 mmol) in THF (200 mL) at
room temperature was treated with DBU (25 mL, 166 mmol), and the
resulting mixture was stirred at 60 °C for 16 h and then cooled to
room temperature and concentrated in vacuo. The residue was
dissolved in EtOAc (300 mL), and the organic phase was washed with
water (2 × 300 mL) and then brine (100 mL), dried over MgSO4, and
concentrated in vacuo to give ethyl (9-bromo-2,3,4,5-tetrahydro-1,4-
benzoxazepin-5-yl)acetate (41.9 g, 97%) as a pale yellow oil, which was
used in the next step without further purification. LCMS (method
1
formate): retention time 0.92 min, [M + H]+ = 318. H NMR (400
MHz, CDCl3) δ ppm 7.36−7.61 (m, 2H), 7.13 (t, J = 7.7 Hz, 1H),
5.55 (d, J = 5.6 Hz, 1H), 4.53 (dd, J = 12.6, 2.3 Hz, 2H), 4.08−4.36
(m, 1H), 3.81−4.01 (m, 1H), 3.45−3.70 (m, 3H), 2.27 (m, 1H),
1.96−2.16 (m, 1H), 1.46 (br s, 9H).
(E)-tert-Butyl 9-Cyano-5-(4-ethoxy-4-oxobut-2-en-1-yl)-2,3-
dihydrobenzo[f ][1,4]oxazepine-4(5H)-carboxylate (79). A sol-
ution of 1,1-dimethylethyl 9-cyano-5-(2-hydroxyethyl)-2,3-dihydro-
1,4-benzoxazepine-4(5H)-carboxylate, 77 (36 g, 102 mmol), in
CH2Cl2 (300 mL) at 0 °C was treated with DMSO (35 mL) and
DIPEA (62.2 mL, 356 mmol). In a separate flask, pyridine sulfur
trioxide (32.4 g, 204 mmol) and pyridine (16.46 mL, 204 mmol) were
mixed in DMSO (35 mL) for 10 min, and the mixture was added to
the mixture of alcohol, base, and DMSO at 0 °C. The resulting mixture
was stirred for 2 h at this temperature, until the alcohol was fully
converted to the corresponding aldehyde. Ethyl 2-
(triphenylphosphoranylidene)acetate (46.1 g, 132 mmol) was then
added, and the resulting mixture was stirred at room temperature for
18 h. The mixture was diluted with CH2Cl2 (500 mL), washed
successively with water (1 L), 10% citric acid in water (1 L), and water
(1 L), and then dried over MgSO4 and concentrated in vacuo to a pale
yellow gum. Purification of the residue by flash chromatography on
silica gel (0−30% EtOAc in hexanes) gave 79 (37.1 g, 94%) as pale
yellow solid. LCMS (method formate): retention time 1.20 min, [M +
1
formate): retention time 0.59 min, [M + H]+ = 314, 316 (1 Br). H
NMR (400 MHz, CDCl3) δ ppm 7.46 (dd, J = 8.1, 1.5 Hz, 1H), 7.10
(dd, J = 7.6, 1.3 Hz, 1H), 6.81−6.97 (m, 1H), 4.50 (dd, J,=,9.3, 5.8 Hz,
1H), 4.08−4.25 (m, 3H), 4.00 (ddd, J = 12.3, 7.5, 2.5 Hz, 1H), 3.44
(ddd, J = 14.7, 7.5, 2.5 Hz, 1H), 3.16 (ddd, J = 14.8, 5.8, 2.4 Hz, 1H),
3.07 (dd, J = 15.7, 9.3 Hz, 1H), 2.80 (dd, J = 15.5, 5.7 Hz, 1H), 1.75
(br s, 1H), 1.15−1.34 (m, 3H). A solution of this material (41.9 g, 133
mmol) and Et3N (22.31 mL, 160 mmol) in CH2Cl2 (600 mL) was
treated at room temperature with di-tert-butyl dicarbonate (34.1 mL,
147 mmol), and the resulting mixture was stirred for 18 h at room
temperature. The organic phase was successively washed with water
(400 mL), a 0.5 N HCl aqueous solution (300 mL), and brine (300
mL), dried over MgSO4, and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel (0−30% EtOAc in
hexanes) gave 76 (50.7 g, 92%) as a white solid. LCMS (method
1
H]+ = 387. H NMR (400 MHz, CDCl3) δ ppm 7.31−7.63 (m, 2H),
7.13 (t, J = 7.1 Hz, 1H), 6.72−6.86 (m, 1H), 5.89 (d, J = 15.7 Hz, 1H),
5.32 (m, 1H), 4.55 (d, J = 12.4 Hz, 1H), 4.08−4.33 (m, 4H), 3.84 (m,
1H), 3.57 (d, J = 11.6 Hz, 1H), 2.96−3.15 (m, 1H), 2.59−2.76 (m,
1H), 1.44 (s, 9H), 1.29 (t, J = 6.6 Hz, 3H).
tert-Butyl 5-(4-Ethoxy-4-oxobutyl)-9-(N′-hydroxycarbamimi-
doyl)-2,3-dihydrobenzo[f ][1,4]oxazepine-4(5H)-carboxylate
(80). Ethylenediamine (20 mL, 296 mmol) was added to a suspension
of Pd/C (10% w/w, 50% wet, 10 g, 9.40 mmol) in EtOH (40 mL)
under nitrogen, and the mixture was stirred for 16 h and then filtered,
and the solid washed with EtOH (40 mL) and MTBE (40 mL).
Compound 79 (92 g, 238 mmol) was dissolved in THF (400 mL) and
was treated with activated charcoal (Norit, SC123792) for 1 h; then
the solution was filtered through a filter cup and added to the solid
palladium catalyst (10 g) under nitrogen. The vessel was purged, and
the solution was hydrogenated at atmospheric pressure for 18 h. The
expected hydrogen uptake was not achieved (only 800 mL consumed
compared with expected approximately 6 L). The suspension was
filtered under nitrogen and then added to fresh catalyst (8 g, prepared
as above), giving very rapid hydrogen uptake. After 2 h, the mixture
was filtered under nitrogen, and the filter pad was washed with EtOAc.
The combined filtrates were evaporated in vacuo to give tert-butyl 9-
cyano-5-(4-ethoxy-4-oxobutyl)-2,3-dihydrobenzo[f ][1,4]oxazepine-
4(5H)-carboxylate (92.5 g, 238 mmol, 100%) as a colorless oil, which
crystallized on standing to a colorless crystalline solid. LCMS (method
1
formate): retention time 1.32 min, [M + H]+ = 414, 416 (1 Br). H
NMR (400 MHz, DMSO-d6) δ ppm 7.52 (dd, J = 8.0, 1.6 Hz, 1H),
7.22 (dd, J = 7.6, 1.5 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 5.52 (s, 1H),
4.36 (d, J = 9.9 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.98−4.04 (m, 1H),
3.73 (s, 1H), 3.63−3.68 (m, 1H), 3.10 (d, J = 8.1 Hz, 1H), 2.91−2.98
(m, 1H), 1.40 (s, 9H), 1.15−1.19 (m, 3H).
tert-Butyl 9-Cyano-5-(2-hydroxyethyl)-2,3-dihydrobenzo[f ]-
[1,4]oxazepine-4(5H)-carboxylate (77). 1,1-Dimethylethyl 9-
bromo-5-[2-(ethyloxy)-2-oxoethyl]-2,3-dihydro-1,4-benzoxazepine-
4(5H)-carboxylate, 76 (70 g, 169 mmol), and Zn(CN)2 (23.80 g, 203
mmol) were suspended in DMF (400 mL), and the resulting mixture
was placed under vacuum for 5 min, then the flask was flushed with
nitrogen. Pd(PPh3)4 (19.52 g, 16.90 mmol) was added, and the
resulting mixture was stirred at 96 °C for 16 h under nitrogen and then
was cooled to room temperature. The mixture was diluted with EtOAc
(1 L) and filtered through Celite. The filtrate was washed with water
(2 × 1 L) and brine (500 mL), dried over MgSO4, and concentrated in
vacuo to give a yellow oil. Purification of the residue by flash
1
formate): retention time 1.20 min, [M + H]+ = 389. H NMR (250
MHz, DMSO-d6) δ ppm 7.57 (m, 2H), 7.11−7.31 (m, 1H), 5.14 (t, J
= 7.7 Hz, 1H), 4.49 (d, J = 12.3 Hz, 1H), 4.00−4.22 (m, 2H), 3.87 (t, J
P
dx.doi.org/10.1021/jm5010336 | J. Med. Chem. XXXX, XXX, XXX−XXX