2790 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11
Bolli et al.
NMR (CDCl3): δ 7.42-7.22 (m, 9H), 7.17-7.12 (m, 1H), 7.01-
6.93 (m, 5H), 6.79-6.72 (m, 2H), 5.27 (s, 1H), 4.56-4.41 (m,
4H), 3.83 (d, J ) 12.9 Hz, 1H), 3.77 (s, 3H), 3.17 (d, J ) 15.2
Hz, 1H), 2.66-2.56 (m, 2H), 1.62-1.52 (m, 2H), 1.38-1.25 (m,
2H), 0.90 (t, J ) 7.6 Hz, 3H). 13C NMR (CDCl3): δ 166.5, 164.6,
158.9, 143.3, 141.4, 137.9, 136.5, 133.0, 129.76, 129.72, 129.3,
128.8, 128.52, 128.51, 128.28, 128.24, 127.8, 126.9, 126.8,
126.1, 124.2, 114.1, 87.3, 72.6, 71.5, 55.5, 53.1, 45.9, 36.1, 34.2,
22.7, 14.3. MS (ES+) m/z: 561 (M + H). Hydrogenolysis
(method G) of the above R-benzyloxy-â-lactam (5.00 g, 8.92
mmol) afforded the R-hydroxy-â-lactam (4.09 g, 97) as a
7.00-6.95 (m, 2H), 6.65-6.60 (m, 2H), 5.65 (d, J ) 15.2 Hz,
1H), 4.90 (d, J ) 10.0 Hz, 1H), 4.68 (d, J ) 15.2 Hz, 1H), 3.88
(d, J ) 10.0 Hz, 1H), 3.58 (s, 3H). 13C NMR (CDCl3): δ 171.1,
169.1, 158.9, 142.3, 141.3, 140.4, 138.9, 131.7, 130.6, 130.5,
129.6, 129.1, 129.0, 128.9, 128.8, 128.6, 127.8, 127.3, 124.8,
122.9, 114.1, 56.8, 55.4, 49.5. MS (ES+) m/z: 433 (M + H). [2
+ 2]-Cycloaddition reaction (method F) with the above ben-
zodiazepinone (4.40 g, 10.2 mmol) furnished the R-benzyloxy-
â-lactam intermediate (5.84 g, 98%) as a colorless crystalline
1
powder, mp 170-171 °C (diethyl ether). H NMR (CDCl3): δ
7.57-7.21 (m, 15H), 7.04-6.91 (m, 5H), 6.73-6.68 (m, 2H),
5.31 (s, 1H), 4.60-4.46 (m, 4H), 3.87 (d, J ) 13.5 Hz, 1H),
3.72 (s, 3H), 3.32 (d, J ) 15.2 Hz, 1H). 13C NMR (CDCl3): δ
166.6, 164.8, 158.9, 141.7, 141.3, 140.9, 138.7, 136.4, 133.6,
129.9, 129.42, 129.40, 129.0, 128.6, 128.4, 128.3, 127.9, 127.7,
127.5, 127.2, 126.9, 126.1, 125.71, 125.69, 114.1, 87.4, 72.7,
71.6, 55.5, 53.0, 46.0. MS (ES+) m/z: 581 (M + H). The
R-benzyloxy-â-lactam (5.80 g, 9.99 mmol) was subjected to
hydrogenolysis (method G) to furnish the R-hydroxy-â-lactam
derivative (4.78 g, 98%) as a colorless foam. 1H NMR (CDCl3):
δ 7.70 (d, J ) 7.6 Hz, 1H), 7.60-7.28 (m, 11H), 7.02 (d, J )
8.2 Hz, 1H), 6.92-6.84 (m, 2H), 6.70-6.62 (m, 2H), 5.44 (s,
1H), 4.56 (d, J ) 15.2 Hz, 1H), 4.50 (d, J ) 14.1 Hz, 1H), 3.85
(d, J ) 12.9 Hz, 1H), 3.70 (s, 3H), 3.44 (d, J ) 15.2 Hz, 1H),
3.16 (s br, 1H). 13C NMR (CDCl3): δ 168.3, 164.9, 158.9, 142.0,
140.9, 140.5, 138.0, 133.4, 129.9, 129.5, 129.4, 129.1, 128.1,
127.9, 127.6, 127.5, 127.2, 126.0, 114.1, 82.5, 72.1, 55.5, 52.9,
46.0. MS (ES+) m/z: 491 (M + H). The above R-hydroxy-â-
lactam (2.50 g, 5.10 mmol) was reacted with 2-methanesul-
fonyl-4,6-dimethylpyrimidine (method H) to afford the R-
pyrimidinyloxy-â-lactam (2.60 g, 86%) as a colorless crystalline
1
colorless foam. H NMR (CDCl3): δ 7.69 (dd, J ) 1.2, 7.6 Hz,
1H), 7.43 (dt, J d ) 1.2 Hz, J t ) 7.6 Hz, 1H), 7.30 (J d ) 1.2 Hz,
J t ) 7.6 Hz, 1H), 7.29-7.21 (m, 2H), 7.15-7.11 (m, 1H), 7.00-
6.90 (m, 4H), 6.75-6.70 (m, 2H), 5.41 (s, 1H), 4.53 (d, J ) 15.2
Hz, 1H), 4.48 (d, J ) 13.5 Hz, 1H), 3.84 (d, J ) 13.5 Hz, 1H),
3.77 (s, 3H), 3.23 (d, J ) 15.2 Hz, 1H), 2.63-2.56 (m, 2H),
1.63-1.51 (m, 2H), 1.38-1.26 (m, 2H), 0.91 (t, J ) 7.6 Hz, 3H).
13C NMR (CDCl3): δ 168.3, 164.8, 158.9, 144.0, 141.0, 137.3,
133.5, 129.8, 129.5, 129.4, 129.0, 128.9, 128.0, 127.1, 126.5,
126.0, 124.0, 114.1, 82.3, 72.0, 55.5, 53.0, 45.9, 36.0, 34.0, 22.7,
14.3. MS (ES+) m/z: 471 (M + H). Reaction of the above
R-hydroxy-â-lactam (4.08 g, 8.67 mmol) with 2-methanesul-
fonyl-4,6-dimethylpyrimidine (method H) furnished the R-
pyrimidinyloxy-â-lactam (4.24 g, 85%) as a colorless foam after
column chromatography (heptane/ethyl acetate 1:1). 1H NMR
(CDCl3): δ 8.71 (dd, J ) 1.2, 8.2 Hz, 1H), 7.58-7.40 (m, 2H),
7.32 (dt, J d ) 1.2 Hz, J t ) 7.6 Hz, 1H), 6.99-6.70 (m, 2H), two
aromatic H appear as broad signals in the range 7.4-7.1 ppm,
6.64 (s, 1H), 6.52 (s, 1H), 4.52 (d, J ) 13.5 Hz, 1H), 4.47 (d, J
) 15.2 Hz, 1H), 3.92 (d, J ) 13.5 Hz, 1H), 3.76 (s, 3H), 3.10
(d, J ) 15.2 Hz, 1H), 2.38 (s, 6H), the butyl chain appears as
two broad multiplets at 1.4-1.0 and 0.9-0.8 ppm. 13C NMR
(CDCl3): δ 169.2, 164.5, 164.4, 162.7, 158.9, 141.2, 136.6, 134.0,
129.7, 129.6, 129.4, 128.3, 128.0, 127.7, 126.7, 125.9, 124.1,
115.5, 114.1, 83.2, 71.3, 55.5, 52.8, 46.1, 35.9, 34.0, 23.9, 22.5,
14.3. MS (ES+) m/z: 577 (M + H). Hydrolysis of this â-lactam
(150 mg, 0.259 mmol) with LiOH (method K) gave the title
compound rac-79 (145 mg, 94%) as a colorless foam after
chromatography on preparative TLC plates (CH2Cl2/methanol
10:1). 1H NMR (DMSO-d6, 65 °C): δ 7.47 (s br, 1H), 7.32-
7.20 (m, 3H), 7.14-7.06 (m, 2H), 7.02-6.93 (m, 3H), 6.87-
6.79 (m, 4H), 6.01 (s, 1H), 3.82 (d, J ) 15.8 Hz, 1H), 3.72 (s,
3H), 3.48-3.28 (m, 3H), 2.28 (s, 6H), 2.25-2.08 (m, 1H), 1.98-
1.84 (m, 1H), 1.56-1.42 (m, 2H), 1.34-1.22 (m, 2H), 0.88 (t, J
) 7.3 Hz, 3H). 13C NMR (DMSO-d6, 65 °C): δ 170.3, 169.2,
169.1, 164.0, 158.8, 143.9, 143.3, 141.4, 135.4, 130.9, 129.2,
128.6, 128.0, 127.3, 126.7, 125.4, 123.7, 114.8, 114.6, 78.7, 67.3,
55.9, 51.3, 48.9, 36.0, 33.9, 24.0, 22.5, 14.6. MS (ES+) m/z: 595
(M + H). Anal. (C35H38N4O5‚0.4H2O‚0.1SiO2) C, H, N.
r a c-(S*)-[(5S*)-5-Bip h en yl-3-yl-1-(4-m eth oxyben zyl)-2-
oxo-2,3,4,5-tetr ah ydr o-1H-ben zo[e][1,4]diazepin -5-yl]-(4,6-
d im eth ylp yr im id in -2-yloxy)a cetic Acid (r a c-80). 2-Ami-
nobenzonitrile (980 mg, 8.29 mmol) was reacted with 3-bromo-
biphenyl (5.80 g, 24.9 mmol) under Grignard conditions
(method A) to give the benzophenone 52 (2.00 g, 88%) as a
yellow solid. 1H NMR (CDCl3): δ 7.85 (t, J ) 1.8 Hz, 1H), 7.75
(dt, J d ) 7.6 Hz, J t ) 1.8 Hz, 1H), 7.63-7.58 (m, 3H), 7.55-
7.28 (m, 8H), 6.82 (d, J ) 8.2 Hz, 1H), 6.68-6.62 (m, 1H). 13C
NMR (CDCl3): δ 199.0, 150.1, 141.3, 140.7, 140.5, 134.7, 134.5,
130.0, 129.1, 128.8, 128.2, 128.0, 127.9, 127.4, 118.9, 117.7,
116.5. MS (ES+) m/z: 274 (M + H). The benzophenone 52 (4.80
g, 17.6 mmol) was treated with bromoacetyl bromide followed
by ammonia in methanol (method B) to afford the benzodiaz-
epinone 66 (4.28 g, 82%) as an almost colorless crystalline
powder, mp 189-190°C (diethyl ether). 1H NMR (CDCl3): δ
9.46 (s br, 1H), 7.80 (s, 1H), 7.71-7.66 (m, 1H), 7.61-7.56 (m,
2H), 7.54-7.30 (m, 6H), 7.26-7.12 (m, 3H), 4.36 (s, 2H). MS
(ES+) m/z: 313 (M + H). The benzodiazepinone 66 (3.68 g,
11.8 mmol) was reacted with 4-methoxybenzyl chloride (method
D) to furnish the N1 4-methoxybenzylated benzodiazepinone
(4.46 g, 88%) as a colorless crystalline powder, mp 147-148
°C (diethyl ether). 1H NMR (CDCl3): δ 7.69-7.65 (m, 1H),
7.57-7.30 (m, 6H), 7.23-7.20 (m, 1H), 7.15-7.09 (m, 1H),
1
powder, mp 211-213 °C (diethyl ether). H NMR (CDCl3): δ
8.74 (d, J ) 7.6 Hz, 1H), 7.58-7.26 (m, 8H), 7.02-6.84 (m,
5H), 6.72-6.56 (m, 5H), 4.57 (d, J ) 12.9 Hz, 1H), 4.51 (d, J
) 15.2 Hz, 1H), 3.95 (d, J ) 12.9 Hz, 1H), 3.68 (s, 3H), 3.26 (s
br, 1H), 2.37 (s, 6H). 13C NMR (CDCl3): δ 169.4, 164.7, 164.4,
162.9, 158.9, 141.0, 140.9, 137.4, 133.8, 129.8, 129.5, 129.4,
128.8, 128.0, 127.8, 127.5, 127.0, 126.0, 125.7, 125.6, 115.2,
114.1, 83.4, 71.5, 55.4, 52.8, 46.2, 23.9. MS (ES+) m/z: 597 (M
+ H). Hydrolysis of this â-lactam (120 mg, 0.201 mmol) with
LiOH (method K) gave the title compound rac-80 (91 mg, 74%)
as a colorless foam after chromatography on preparative TLC
1
plates (CH2Cl2/methanol 10:1). H NMR (DMSO-d6, 65 °C): δ
7.79 (s br, 1H), 7.63-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.46-
7.39 (m, 3H), 7.34-7.13 (m, 5H), 7.00-6.95 (m, 2H), 6.91-
6.85 (m, 1 H), 6.83-6.77 (m, 3H), 6.05 (s, 1H), 3.88 (d, J )
15.8 Hz, 1H), 3.70 (s, 3H), 3.52 (d, J ) 12.9 Hz, 1H), 3.36 (d,
J ) 12.9 Hz, 1H), 2.27 (s, 6H), one proton as broad signal in
the range 3.6-3.3. 13C NMR (DMSO-d6, 65 °C): δ 170.3, 169.4,
169.2, 164.0, 158.9, 143.94, 143.85, 141.7, 139.7, 135.4, 130.8,
129.3, 128.7, 128.1, 127.8, 127.6, 127.3, 126.9, 125.9, 123.8,
115.0, 114.7, 78.6, 67.3, 55.9, 51.3, 49.0, 24.1. MS (ES+) m/z:
615 (M + H).
r a c-(S*)-[(5S*)-1-(2,6-Dich lor oben zyl)-2-oxo-5-p h en yl-
2,3,4,5-tetr ah ydr o-1H-ben zo[e][1,4]diazepin -5-yl]ph en oxy-
a cetic Acid (r a c-84a ). To a solution of the benzodiazepinone
3552 (2.36 g, 10 mmol) in DMF (30 mL) was added K2CO3 (4.15
g, 30 mmol) and 2,6-dichlorobenzyl chloride (2.40 g, 12 mmol),
and the resulting suspension was stirred at room temperature
for 20 h before it was diluted with water and extracted three
times with ethyl acetate. The organic extracts were washed
with brine, dried over MgSO4, and evaporated. The crude
product was purified by crystallization from a small amount
of ethyl acetate/diethyl ether. The solid material was collected,
washed with cold diethyl ether, and dried under high vacuum
to furnish the 1-(2,6-dichlorobenzyl)-5-phenyl-1,3-dihydrobenzo-
[e][1,4]diazepin-2-one 83 (2.60 g, 66%) as a pale-yellow crystal-
1
line powder, mp 156-158 °C (ethyl acetate/diethyl ether). H
NMR (CDCl3): δ 7.51 (d, J ) 8.2 Hz, 1H), 7.47-7.30 (m, 6H),
7.15-6.99 (m, 5H), 5.84 (d, J ) 15.2 Hz, 1H), 5.09 (d, J ) 14.7
Hz, 1H), 4.83 (d, J ) 10.6 Hz, 1H), 3.83 (d, J ) 10.6 Hz, 1H).
MS (ES+) m/z: 395 (M + H). The benzodiazepinone 83 (150
mg, 0.379 mmol) was then reacted with phenoxyacetic acid
(method E) to give the corresponding â-lactam intermediate