2318 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
Carter et al.
solution. The extracts were dried and then evaporated, giving an
oil which was triturated with diethyl ether giving an off-white solid
(305 mg, 33%). H NMR (DMSO-d6): δ 4.25 (s, 1H) 7.17-7.66
(m, 9H) 10.65 (brs, 1H).
N-(2-Oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-
yl)isobutyramide (19) Method F. A solution of 5a (100 mg, 0.398
mmol) and diisopropyl ethylamine (62 mg, 1.2 equiv) in 9:1 DCM:
DMF (2 mL) was treated with isobutyryl chloride (0.041 mL, 1
equiv). The mixture was stirred at room temperature for 18 h and
was then partitioned between water and DCM. The solvent was
evaporated and the residue purified on a silica gel SPE cartridge.
Gradient elution with 5% EtOAc/petrol to neat EtOAc gave the
title compound as a colorless solid (35 mg, 27%). MS: found [M
+ H]+ )322. 1H NMR (DMSO-d6): δ 1.03 (d, 6H, J ) 7.58 Hz),
2.72 (septet, 1H, J ) 1.89 Hz), 5.23 (d, 1H, J ) 8.21 Hz), 7.20-
7.68 (m, 9H), 8.90 (d, 1H, J ) 8.21 Hz), 10.77 (brs, 1H). Anal.
(C19H19N3O2‚0.55H2O) C, H, N.
1
3-Amino-1-methyl-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-
2-one (5p). To a cold (0 °C) stirred solution of 5a (325 mg, 1.295
mmol) in dry DMF (20 mL) was added sodium hydride (60% in
oil, 52 mg, 1 equiv). The mixture was stirred for 30 min and then
methyl iodide (2 M in TBME, 0.65 mL, 1 equiv) was added. The
mixture was then allowed to warm slowly to room temperature
and was stirred for 18 h. This mixture was then partitioned between
ammonium chloride solution and DCM. The dried organic layer
was evaporated and the residue chromatographed on silica gel.
Gradient elution with DCM:EtOH:NH3 400:8:1 to 200:8:1 gave a
2-Methoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-
diazepin-3-yl)benzamide (25). This material was prepared as
described in method F except that 2-methoxybenzoyl chloride
(0.059 mL) was used. The title compound was a colorless solid
1
pale brown gum (213 mg, 41%). H NMR (CDCl3): δ 3.39 (s,
3H), 5.23 (s, 1H), 7.13 (dt, 1H, J ) 1.26, 6.95 Hz), 7.24-7.39 (m,
6H), 7.46-7.58 (m, 4H).
1
(69 mg, 46%). MS: found [M + H]+ ) 386. H NMR (DMSO-
4-Oxy-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-2-one (12).
m-Chloroperbenzoic acid (50-55%, 11 g, 1 equiv) in DCM (75
mL) was treated dropwise, with stirring, with a solution of 5-phenyl-
1,3-dihydrobenzo[e][1,4]diazepin-2-one (11) (7.5 g, 31.78 mmol)
in DCM (380 mL) over 1 h. Stirring was maintained for 18 h, and
then ammonium hydroxide (25%) was added until pH 8 was
reached. The precipitate that formed was then collected by filtration,
washed with DCM and water, and then dried, giving the title
compound as a pale yellow solid (9.4 g, >100%). This material
was then used without further purification or characterization in
the preparation of 13.
Acetic Acid 2-Oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-
diazepin-3-yl Ester (13). A suspension of 12 (9.3 g) in acetic
anhydride (90 mL) was heated to 70 °C for 3 h, producing a clear
solution. The mixture was cooled and the solvent evaporated. The
orange oil produced was dissolved in hot EtOH and then stored at
4 °C overnight. The colorless solid was then collected by filtra-
tion and dried (5.26 g, 56%). A further 5 g of crude material
was obtained from evaporation of the mother liquor. 1H NMR
(DMSO-d6): δ 2.1 (3H, s), 5.58 (1H, s), 7.13-7.60 (m, 9H), 10.89
(s, 1H).
d6): δ 4.05 (s, 3H), 5.44 (d, 1H, J ) 7.58 Hz), 7.11 (t, 1H),
7.24-7.70 (m, 11H), 7.97 (dd, 1H, J ) 7.58, 1.89 Hz), 9.50 (d,
1H, J ) 6.95 Hz), 10.97 (s, 1H). 13C NMR (DMSO-d6): δ 56.75,
68.36, 112.91, 121.05, 121.28, 122.01, 123.80, 126.92, 128.70,
129.77, 130.79, 130.92, 131.59, 132.50, 133.33, 133.86, 138.56,
138.95, 158.11, 164.37, 167.10, 167.99. Anal. (C23H19N3O3‚0.3H2O)
C, H, N.
2-Ethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-
diazepin-3-yl)benzamide (29) Method G. 5a (40 mg, 0.159 mmol),
2-ethoxybenzoic acid (40 mg, 1.5 equiv), O-benzotriazol-1-yl-
N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg, 2
equiv), and triethylamine (0.07 mL, 3 equiv) in dry DMF (1 mL)
was stirred at room temperature for 1 h. Water (10 mL) was then
added and stirring continued for 10 min. The colorless precipitate
was collected by filtration and then partitioned between dichlo-
romethane and water. The dried organic phase was evaporated and
the residue purified on a silica gel SPE cartridge. Elution with ethyl
acetate:petrol 1:1 gave the title compound as a colorless solid (46
1
mg, 72%). H NMR (DMSO-d6): δ 1.56 (t, 3H, J ) 6.95 Hz),
4.31 (q, 2H, J ) 6.95 Hz), 5.43 (d, 1H, J ) 6.95 Hz), 7.07-7.70
(m, 12H), 8.03 (dd, 1H, J ) 1.89, 8.21 Hz), 9.75 (d, 1H, J ) 6.95
Hz), 11.03 (s, 1H). Anal. (C24H21N3O3‚0.15H2O) C, H, N.
2-Morpholin-4-ylmethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-
benzo[e][1,4]diazepin-3-yl)benzamide (37). A mixture of 2-formyl-
benzoic acid (500 mg, 3.33 mmol) and morpholine (0.29 mL, 1
equiv) in dry THF (10 mL) and acetic acid (1 mL) was treated
with sodium (triacetoxy)borohydride (1.4 g, 2 equiv). The mixture
was stirred for 18 h and was then partitioned between DCM and
pH 7.4 buffer. Evaporation of the extracts gave very little material,
so the aqueous layer was evaporated and the residue stirred in DCM/
MeOH. Filtration of the insoluble inorganic material and evapora-
tion gave a colorless gum (impure); 88 mg of this material and 50
mg (0.198 mmol) of 5a were reacted together as described in
Method G. The title compound was isolated as a colorless solid
(47 mg, 52%). 1H NMR (DMSO-d6): δ 2.48-2.60 (m, 4H), 3.48-
3.62 (m, 4H), 3.69 (d, 1H, J ) 12.00 Hz), 3.92 (d, 1H, J ) 12.00
Hz), 5.47 (d, 1H, J ) 7.58 Hz), 7.26-7.42 (m, 3H), 7.44-7.56
(m, 8H), 7.65-7.77 (m, 2H), 10.94 (s, 1H), 11.66 (d, 1H, J ) 7.58
Hz). Anal. (C27H26N4O3‚0.79H2O) C, H, N.
3-Hydroxy-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-2-
one (14). A mixture of 13 (10.2 g) in MeOH (100 mL) and 4 M
NaOH (60 mL) was stirred for 2 h. Water (400 mL) was then added,
and the mixture was acidified to pH 3 with acetic acid and then
extracted with DCM. The solvent was evaporated and the residue
chromatographed on silica gel. Elution with DCM followed by
gradient elution with DCM:EtOH:NH3 800:8:1 to 50:8:1 gave the
1
title compound as a pale yellow solid (900 mg, 10%). H NMR
(DMSO-d6): δ 4.58 (1H, d, J ) 8.2 Hz), 6.14 (d, 1H, J ) 8.8 Hz),
7.03-7.43 (9H, m), 10.58 (1H, s).
3-Methylamino-5-phenyl-1,3-dihydrobenzo[e][1,4]diazepin-2-
one (16). A stirred solution of 14 (100 mg, 0.39 mmol) in dry THF
(10 mL) containing triethylamine (0.08 mL) was treated with
methanesulfonyl chloride (0.046 mL). The mixture was stirred for
30 min, and then methylamine (2M in THF, 1 mL, 5 equiv) was
added. After 18 h the mixture was partitioned between aqueous
K2CO3 and DCM. The solvent was evaporated and the residue
purified on a silica gel SPE cartridge. Elution with DCM:EtOH:
NH3 200:8:1 gave the title compound as a pale yellow solid (55
Furan-2-carboxylic Acid (2-Oxo-5-phenyl-2,3-dihydro-1H-
benzo[e][1,4]diazepin-3-yl)amide (38). This material was prepared
as described in method F except that furan-2-carbonyl chloride
(0.039 mL) was used. The title compound was a colorless solid
1
mg, 53%). H NMR (DMSO-d6): δ 2.62 (3H, s), 4.17 (s, 1H),
7.09-7.64 (m, 9H), 8.88 (s, 1H).
N-(2-Oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-
yl)acetamide (18). A solution of 5a (300 mg, 1.19 mmol) in
pyridine (5 mL) was treated with acetic anhydride (183 mg). The
mixture was stirred at room temperature for 1.5 h and was then
evaporated. The residue was partitioned between water and di-
chloromethane. The dried extract was evaporated and the resi-
due triturated with petroleum ether, giving a colorless solid (231
mg, 66%). MS: found [M - H]- ) 292. NMR (DMSO-d6): δ
1.99 (s, 3H), 5.25 (d, 1H, J ) 8.21 Hz), 7.21-7.66 (m, 9H), 9.06
(d, 1H, J ) 8.21 Hz), 10.81 (s, 1H). Anal. (C17H15N3O2‚0.42H2O)
C, H, N.
1
(17 mg, 31%). LC-MS: tR ) 4.53 min, found ES+ ) 346. H
NMR (DMSO-d6): δ 5.42 (d, 1H, J ) 8.21 Hz), 6.68 (m, 1H),
7.24-7.70 (m, 10H), 7.90 (m, 1H), 9.02 (d, 1H, J ) 8.21 Hz),
10.95 (s, 1H). Anal. (C20H15N3O3‚0.37H2O) C, H, N.
1-(2-Fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo-
[e][1,4]diazepin-3-yl)urea (42) Method H. A mixture of 5a (30
mg, 0.12 mmol) and triethylamine (0.05 mL) in dry THF (4 mL)
was treated with 1-fluoro-2-isocyanatobenzene (0.011 mL) and was
left to stir at room temperature for 24 h. The mixture was then
partitioned between water and DCM. The dried organic layer was