894 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Wiley et al.
(dd, J ) 2.0, 8.5 Hz, 1H), 7.83 (d, J ) 2.0 Hz, 1H), 7.95 (d, J
) 8.3 Hz, 2H), 9.60 (s, 1H); MS(FD) m/e 326.2. Anal.
(C19H22N2O3) C, H, N.
MgSO4 dried, and concentrated. A portion of the residue (4 g,
9.06 mmol) was dissolved in N,N-dimethylformamide (25 mL).
Benzyl bromide (1.06 g, 6.2 mmol) was added, followed by
K2CO3 (1.6 g, 11.4 mmol). After 3 h, the reaction was
concentrated and the residue was dissolved in ethyl acetate
and washed with saturated aqueous NaHCO3 followed by
brine. The organic layer was MgSO4 dried, filtered and 5 g of
silica gel was added. This mixture was concentrated to a dry
pack, loaded onto a silica gel column and chromatographed
(10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) to
give the title compound as a white solid (3.3 g, 65%): 1H NMR
(300 MHz, DMSO-d6) δ 1.30 (s, 9H), 5.39 (s, 2H), 7.35-7.60
(m, 7H), 7.76 (t, J ) 8.0 Hz, 1H), 7.85-7.95 (m, 4H), 8.08 (d,
J ) 8.0 Hz, 1H), 8.24 (d, J ) Hz, 1H), 8.33 (s, 1H), 8.38 (s,
1H), 10.07 (s, 1H), 10.37 (s, 1H); MS(FD) m/e 531.0. Anal.
(C33H29N3O4) C, H, N.
N1-(3-Cya n ob en zoyl)-N2-(4-isop r op ylb en zoyl)-4-(ter t-
bu tyld im eth ylsilyloxy)-1,2-ben zen ed ia m in e (25). A mix-
ture of compound 12 (5.00 g, 12.6 mmol), 10% Pd/C (2.5 g),
ethanol (160 mL), and tetrahydrofuran (160 mL) was placed
under an atmosphere of hydrogen (balloon) with stirring for
12 h. The mixture was filtered through diatomaceous earth
with hot methanolic washes. The filtrate was concentrated and
chromatographed over silica gel, eluting with a gradient of 20%
to 30% ethyl acetate in hexanes. The fractions containing
compound 16 (contaminated) were combined and concentrated
in vacuo to give 2.72 g of yellow solid (MS(ESI) m/e 367.9).
The solid was dissolved in dichloromethane (45 mL) and
cooled to 0 °C. To this solution was added pyridine (0.65 mL,
8.0 mmol) followed by a solution of 4-isopropylbenzoyl chloride
(10.1 mmol) in dichloromethane (90 mL). The reaction was
allowed to warm to room temperature and stirred for 10 min.
The mixture was diluted with dichloromethane (200 mL) and
washed with saturated aqueous NH4Cl (2 × 50 mL). The
organic layer was separated and dried with MgSO4 filtered,
and concentrated. The residue was chromatographed over
silica gel, eluting with 10% to 20% ethyl acetate in hexanes.
The product containing fractions were combined and concen-
trated to give 3.04 g (83%) of the title compound: 1H NMR
(300 MHz, CDCl3) δ 0.16 (s, 6H), 0.95 (s, 9H), 1.29 (s, 3H),
1.31 (s, 3H), 3.00 (m, 1H), 6.68 (d, J ) 9.0 Hz, 1H), 6.86 (s,
1H), 7.38 (d, J ) 8.1 Hz, 2H), 7.50 (d, J ) 9.0 Hz, 1H), 7.61
(m, 1H), 7.81 (d, J ) 6.3 Hz, 1H), 7.89 (d, J ) 7.1 Hz, 2H),
8.16 (d, J ) 9.3 Hz, 1H), 8.29 (s, 1H), 8.58 (br s, 1H), 9.40 (br
N1,N2-Bis(4-m eth oxyben zoyl)-4-(am in o(h ydr oxyim in o)-
m eth yl)-1,2-ben zen ed ia m in e (34). To a stirring solution of
compound 28 (0.75 g, 1.87 mmol) in ethanol (100 mL) was
added hydroxylamine hydrochloride (0.13 g, 1.87 mmol) fol-
lowed by N,N-diisopropylethylamine (0.3 mL, 1.87 mmol). The
solution was heated to reflux and after 6 h, the solution was
concentrated. The residue was dissolved in ethyl acetate and
washed with brine, then dried with MgSO4 and filtered. The
solution was then allowed to stand and then filtered to give
0.77 g (95%) of a white solid: 1H NMR (300 MHz, DMSO-d6)
δ 3.83 (s, 6H), 5.84 (s, 2H), 7.07 (d, J ) 7.7 Hz, 4H), 7.57 (dd,
J ) 1.8, 8.5 Hz, 1H), 7.67 (d, J ) 8.5 Hz, 1H), 7.9-8.1 (m,
5H), 9.67 (s, 1H), 10.08 (s, 1H), 10.14 (s, 1H); MS(FD) m/e
434.1. Anal. (C23H22N4O5‚1.1H2O) C, H, N.
N1-(3-(Am in oim in om et h yl)b en zoyl)-N2-(4-ter t-b u t yl-
ben zoyl)-1,2-ben zen ed ia m in e Hyd r och lor id e (44). Fol-
lowing the procedure described in the preparation of compound
s, 1H); IR (CHCl3) 2962, 1656, 1610, 1513, 1473, 1295 cm-1
;
MS(FD) m/e 513.1. Anal. (C30H35N3O3Si) C, H, N.
1
N 1-(3-Cya n ob e n zoyl)-N 2-(4-isop r op ylb e n zoyl)-4-h y-
d r oxy-1,2-ben zen ed ia m in e (29). To a mixture of compound
25 (1.57 g, 3.05 mmol) and tetrahydrofuran (30 mL) at 0 °C
was added a 1.0 M solution of tetra-n-butylammonium fluoride
in tetrahydrofuran (3.1 mL, 3.1 mmol). After 1 h, the reaction
was quenched with water (35 mL) and extracted with diethyl
ether (2 × 200 mL). The combined organic layers were dried
with MgSO4, filtered, and concentrated. The residue was
chromatographed over silica gel, eluting with 1:1 ethyl acetate/
hexanes to give the title compound as a solid (1.10 g, 91%):
1H NMR (300 MHz, DMSO-d6) δ 1.15 (s, 3H), 1.17 (s, 3H), 2.90
(m, 1H), 6.63 (d, J ) 9.0 Hz, 1H), 7.34-7.21 (m, 4H), 7.70 (m,
1H), 7.79 (d, J ) 8.1 Hz, 2H), 8.01 (d, J ) 7.2 Hz, 1H), 8.18 (d,
J ) 7.5 Hz, 1H), 8.31 (s, 1H), 9.56 (s, 1H), 9.70 (s, 1H), 10.02
(s, 1H); IR (KBr) 3277, 1629, 1600, 1535, 1478, 1299 cm-1; MS-
(FD) m/e 399.1. Anal. (C24H21N3O3) C, H, N.
4, 44 was prepared from compound 35: 76% yield; H NMR
(300 MHz, DMSO-d6) δ 1.32 (s, 9H), 7.28-7.32 (m, 2H), 7.52
(d, J ) 10.2 Hz, 2H), 7.62-7.67 (m, 1H), 7.67-7.71 (m, 1H),
7.77 (t, J ) 9.3 Hz, 1H), 7.96 (d, J ) 10.2 Hz, 2H), 8.00 (d, J
) 10.8 Hz, 1H), 8.30 (d, J ) 9.3 Hz, 1H), 8.49 (s, 1H), 9.20 (s,
1H), 9.49 (s, 1H), 10.13 (s, 1H), 10.56 (s, 1H); MS(FD) m/e 415;
mp 196-198 °C. Anal. (C25H26N4O2‚1.0HCl‚0.75H2O) C, H, N.
N1-(4-(Am in oim in om et h yl)b en zoyl)-N2-(4-ter t-b u t yl-
ben zoyl)-1,2-ben zen ed ia m in e Hyd r och lor id e (45). Fol-
lowing the procedure described for the synthesis of compound
1
4, 45 was prepared from compound 36: 77% yield; H NMR
(300 MHz, DMSO-d6) δ 1.30 (s, 9H), 7.27-7.33 (m, 2H), 7.53
(d, J ) 8.5 Hz, 2H), 7.62-7.70 (m, 2H), 7.95 (d, J ) 8.5 Hz,
4H), 8.19 (d, J ) 8.3 Hz, 2H), 9.20 (br s, 2H), 9.47 (br s, 2H),
10.19 (s, 1H), 10.42 (s, 1H); MS(FD) m/e 414.9. Anal.
(C25H26N4O2‚1.2HCl‚1.1H2O) C, H, N.
N1-(3-(Am in oim in om eth yl)ben zoyl)-N2-(4-eth xoxyben -
zoyl)-1,2-ben zen ed ia m in e Hyd r och lor id e (46). Following
the procedure described for the preparation of compound 4,
46 was prepared from compound 37: 21% yield; 96% pure by
analytical HPLC, gradient ) 5% to 50% acetonitrile, 1%/min,
N1-(3-Cya n oben zoyl)-N2-(4-isop r op ylben zoyl)-4-ben zyl-
oxyca r bon ylm eth oxy-1,2-ben zen ed ia m in e (30). To a mix-
ture of compound 29 (502 mg, 1.26 mmol), acetone (15 mL),
and potassium carbonate (216 mg, 1.56 mmol) was added
benzyl 2-bromoacetate (0.4 mL, 2.52 mmol). After stirring
overnight, the reaction was concentrated and the residue was
chromatographed (100% dichloromethane to 10% ethyl acetate
in dichloromethane) to give the title compound as a solid (532
mg, 77%): 1H NMR (300 MHz, CDCl3) δ 1.28 (s, 3H), 1.30 (s,
3H), 3.00 (m, 1H), 4.50 (s, 2H), 5.22 (s, 2H), 6.71 (d, J ) 9.3
Hz, 1H), 6.93 (s, 1H), 7.31 (m, 7H), 7.54 (d, J ) 21 Hz, 1H),
7.60 (t, J ) 7.8 Hz, 1H), 7.78 (d, J ) 8.7 Hz, 1H), 7.89 (d, J )
8.1 Hz, 2H), 8.19 (d, J ) 8.1 Hz, 1H), 8.30 (s, 1H), 8.74 (br s,
1H), 9.48 (br s, 1H); IR (CHCl3) 2965, 1759, 1654, 1610, 1514,
1175 cm-1; MS(FD) m/e 547. Anal. (C33H29N3O5) C, H, N.
N1-(3-Cya n oben zoyl)-N2-(4-ter t-bu tylben zoyl)-4-ben zyl-
oxyca r bon yl-1,2-ben zen ed ia m in e (32). To a solution of
compound 26 (5 g, 11 mmol) in tetrahydrofuran (100 mL) was
added methanol (30 mL), followed by a solution of LiOH‚H2O
(1.4 g, 33 mmol) in water (30 mL). After stirring overnight,
more LiOH‚H2O (0.67 g, 16 mmol) in water (5 mL) was added.
After stirring for another 24 h, the pH was adjusted to 3 with
concentrated HCl and the mixture was concentrated in vacuo.
The residue was partitioned between ethyl acetate and water.
The organic layer was washed with 1 N HCl, brine (2×),
1
tR ) 28.35 min; H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J )
7.0 Hz, 3H), 4.07 (q, 2H), 7.01 (d, J ) 7.0 Hz, 2H), 7.20 (m,
2H), 7.60 (m, 2H), 7.65 (t, J ) 7.8 Hz, 1H), 8.00 (m, 3H), 8.29
(d, J ) 7.8 Hz, 1H), 8.54 (s, 1H), 9.33 (s, 2H), 9.54 (s, 2H),
10.14 (s, 1H), 10.72 (s, 1H); MS(FD) m/e 402; mp 163-165 °C.
N1-(3-(Am in oim in om et h yl)b en zoyl)-N2-(4-isop r op yl-
ben zoyl)-1,2-ben zen ed ia m in e Hyd r och lor id e (47). Fol-
lowing the procedure described for the synthesis of compound
1
4, 47 was prepared from compound 38: 63% yield; H NMR
(300 MHz, DMSO-d6) δ 1.20 (d, 6H), 2.95 (sept, 1H), 7.25-
7.35 (m, 2H), 7.40 (d, 2H), 7.60-7.70 (m, 2H), 7.75 (t, 1H),
7.95 (d, 2H), 8.00 (d, 1H), 8.40 (d, 1H), 8.50 (s, 1H), 9.25 (br s,
2H), 9.50 (br s, 2H), 10.15 (s, 1H), 10.60 (s, 1H); MS(FD) m/e
401.1; mp 227-229 °C. Anal. (C24H25N4O2‚HCl‚1.5H2O) C, H,
N.
N1-(3-(Am in oim in om et h yl)b en zoyl)-N2-(4-isop r op yl-
ben zoyl)-4-h yd r oxy-1,2-ben zen ed ia m in e Hyd r och lor id e
(48). Following the procedure described for the preparation
of compound 4, 48 was prepared from compound 39: 62% yield;
1H NMR (300 MHz, DMSO-d6) δ 1.17 (s, 3H), 1.19 (s, 3H), 2.90