2216 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 13
Ukita et al.
Meth yl 2-(4-Am in op h en yl)-1,2-d ih yd r o-4-[(4-h yd r oxy-
3,5-d im eth oxy)p h en yl]-1-oxo-7-(2-p yr id ylm eth oxy)-3-iso-
qu in olin eca r boxyla t e (41). A mixture of 36a (1.92 g, 3.0
mmol), concentrated HCl (30 mL), and dioxane (30 mL) was
heated under reflux overnight. The reaction mixture was
neutralized with 2 N aqueous NaOH and extracted with
AcOEt. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by silica gel chromatography (CHCl3/acetone )
2:1) gave 41 (920 mg, 55%), mp 202-205 °C. 1H NMR
(CDCl3): δ 3.26 (s, 3H), 3.87 (s, 6H), 5.39 (s, 2H), 6.60 (s, 2H),
6.74 (d, 2H, J ) 8.6 Hz), 7.14 (d, 2H, J ) 8.6 Hz), 7.25-7.45
(m, 3H), 7.52-7.64 (m, 1H), 7.80 (m, 1H), 8.03 (m, 1H), 8.48-
8.70 (m, 1H). MS (EIMS): m/z 554 (M+ + 1, base).
7-Ben zyloxy-2-[(4-ter t-bu toxyca r bon yla m in o)p h en yl]-
1,2-d ih yd r o-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-3-isoqu in o-
lin eca r boxylic Acid (42). A mixture of 11e (1.5 g, 3.12
mmol), Boc-p-phenylenediamine (780 mg, 3.74 mmol), i-Pr2-
NEt (1.3 mL, 7.49 mmol), and DMI (10 mL) was heated at
100 °C overnight. The mixture was diluted with AcOEt and
washed with aqueous saturated citric acid. The organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The crystallization of the residue from
i-Pr2O gave 42 (1.51 g, 74%), mp 151-153 °C dec. 1H NMR
(DMSO-d6): δ 1.49 (s, 9H), 3.72 (s, 3H), 3.74 (s, 6H), 5.26 (s,
2H), 6.66 (s, 2H), 7.17-7.62 (m, 11H), 7.80 (d, 1H, J ) 2.6
Hz), 9.57 (s, 1H), 13.28 (br s, 1H). IR (KBr): 3258, 1723, 1645,
1235, 1159 cm-1. MS (ESI): m/z 653 (M+ + 1).
yl)-3-isoqu in olin eca r boxa m id e (47). 47 was prepared from
42 and dimethylamine as described for 45. Yield 76%; mp 171-
1
172 °C. H NMR (CDCl3): δ 1.52 (s, 9H), 2.42 (s, 3H), 2.74 (s,
3H), 3.83 (s, 3H), 3.84 (s, 3H), 3.91 (s, 3H), 5.20 (s, 2H), 6.54
(d, 1H, J ) 1.8 Hz), 6.62 (s, 1H), 6.77 (d, 1H, J ) 1.8 Hz),
7.05-7.54 (m, 10H), 7.70 (d, 1H, J ) 8.0 Hz), 8.02 (d, 1H, J )
2.6 Hz). IR (KBr): 3484, 1725, 1646, 1497, 1238 cm-1. MS
(SIMS): m/z 680 (M+ + 1, base), 624, 579, 532, 91.
Eth yl 2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d i-
h yd r o-7-h yd r oxy-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-3-iso-
qu in olin eca r boxyla te (48). 48 was prepared from 43 as
described for 34a . Yield 90%; mp 222-223 °C dec. 1H NMR
(CDCl3): δ 0.78 (t, 3H, J ) 7.1 Hz), 1.53 (s, 9H), 3.70 (q, 2H,
J ) 7.1 Hz), 3.83 (s, 6H), 3.90 (s, 3H), 6.60 (s, 2H), 6.62 (s,
1H), 7.12-7.42 (m, 4H), 7.42-7.60 (m, 2H), 8.42 (d, 1H, J )
2.5 Hz). IR (KBr): 3357, 1729, 1647, 1505, 1232 cm-1. MS
(SIMS): m/z 591 (M+ + 1, base), 535.
Meth oxym eth yl 2-[(4-ter t-Bu toxyca r bon yla m in o)p h en -
yl]-1,2-d ih yd r o-7-h yd r oxy-1-oxo-4-(3,4,5-t r im e t h oxy-
p h en yl)-3-isoqu in olin eca r boxyla te (49). 49 was prepared
from 44 as described for 34a . Yield 89%; powder. 1H NMR
(DMSO-d6): δ 1.49 (s, 9H), 2.90 (s, 3H), 3.70 (s, 3H), 3.74 (s,
6H), 4.74 (s, 2H), 6.64 (s, 2H), 7.15-7.32 (m, 4H), 7.54 (d, 2H,
J ) 8.8 Hz), 7.66 (s, 1H), 9.57 (s, 1H), 10.29 (s, 1H). IR (KBr):
3319, 1732, 1648, 1506, 1161 cm-1. MS (SIMS): m/z 607 (M+
+ 1, base), 551, 489.
2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d ih yd r o-
7-h yd r oxy-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-3-isoqu in o-
lin eca r boxa m id e (50). 50 was prepared from 45 as described
E t h yl 7-Ben zyloxy-2-[(4-ter t-b u t oxyca r bon yla m in o)-
p h en yl]-1,2-d ih yd r o-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-3-
isoqu in olin eca r boxyla te (43). 43 was prepared from 11e
and Boc-p-phenylenediamine as described for 25a , using EtI
1
for 34a . Yield 83%; mp >250 °C. H NMR (DMSO-d6): δ 1.49
(s, 9H), 3.71 (s, 3H), 3.74 (s, 6H), 6.67 (s, 2H), 7.08-7.31 (m,
5H), 7.49 (d, 2H, J ) 8.8 Hz), 7.63 (d, 1H, J ) 2.4 Hz), 7.72 (s,
1H), 9.52 (s, 1H), 10.10 (s, 1H). IR (KBr): 3384, 1675, 1644,
1239 cm-1. MS (SIMS): m/z 562 (M+ + 1, base), 506, 489.
2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d ih yd r o-
7-h yd r oxy-N-m eth yl-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-3-
isoqu in olin eca r boxa m id e (51). 51 was prepared from 46
as described for 34a . Yield 97%; mp 223-225 °C dec. 1H NMR
(DMSO-d6): δ 1.49 (s, 9H), 2.12 (d, 3H, J ) 4.6 Hz), 3.71 (s,
3H), 3.73 (s, 6H), 6.64 (s, 2H), 7.11-7.25 (m, 4H), 7.49 (d, 2H,
J ) 8.8 Hz), 7.63 (s, 1H), 8.21 (q, 1H, J ) 4.6 Hz), 9.52 (s, 1H),
10.13 (s, 1H). IR (KBr): 3355, 1643, 1239 cm-1. MS (SIMS):
m/z 576 (M+ + 1), 520 (base), 489.
1
instead of MeI. Yield 61%; mp 183-185 °C. H NMR (CDCl3):
δ 0.79 (t, 3H, J ) 7.1 Hz), 1.53 (s, 9H), 3.71 (q, 2H, J ) 7.1
Hz), 3.83 (s, 6H), 3.90 (s, 3H), 5.20 (s, 2H), 6.60 (s, 3H), 7.26-
7.57 (m, 11H), 8.02 (d, 1H, J ) 1.6 Hz). IR (KBr): 1732, 1668,
1161 cm-1. MS (ESI): m/z 681 (M+ + 1).
Met h oxym et h yl
7-Ben zyloxy-2-[(4-ter t-b u t oxyca r -
bon yla m in o)p h en yl]-1,2-d ih yd r o-1-oxo-4-(3,4,5-tr im eth -
oxyp h en yl)-3-isoqu in olin eca r boxyla te (44). 44 was pre-
pared from 11e and Boc-p-phenylenediamine as described for
25a , using chloromethyl methyl ether instead of MeI. Yield
1
62%; mp 151-154 °C. H NMR (CDCl3): δ 1.52 (s, 9H), 2.99
(s, 3H), 3.84 (s, 6), 3.89 (s, 3H), 4.77 (s, 2H), 5.21 (s, 2H), 6.63
(s, 3H), 7.32-7.58 (m, 11H), 8.03 (d, 1H, J ) 1.7 Hz). IR
(KBr): 1722, 1668, 1516, 1162 cm-1. MS (SIMS): m/z 697 (M+
+ 1), 641, 91 (base).
2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d ih yd r o-
7-h ydr oxy-N,N-dim eth yl-1-oxo-4-(3,4,5-tr im eth oxyph en yl)-
3-isoqu in olin eca r boxa m id e (52). 52 was prepared from 47
as described for 34a . Yield 81%; mp 217-220 °C dec. 1H NMR
(DMSO-d6): 1.49 (s, 9H),2.28 (s, 3H), 2.74 (s, 3H), 3.71 (s, 6H),
3.76 (s, 3H), 6.59 (m, 1H), 6.65 (m, 1H), 7.10-7.32 (m, 4H),
7.40-7.70 (m, 3H), 9.54 (s, 1H), 10.14 (s, 1H). IR (KBr): 3361,
1640 cm-1. MS (SIMS): m/z 590 (M+ + 1, base), 534, 489.
Eth yl 2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d i-
h yd r o-1-oxo-7-(2-p yr id ylm et h oxy)-4-(3,4,5-t r im et h oxy-
p h en yl)-3-isoqu in olin eca r boxyla te (53). 53 was prepared
from 48 as described for 35a . Yield 86%; mp 210-212 °C dec.
1H NMR (CDCl3): δ 0.78 (t, 3H, J ) 7.1 Hz), 1.52 (s, 9H), 3.71
(q, 2H, J ) 7.1 Hz), 3.84 (s, 6H), 3.90 (s, 3H), 5.35 (s, 2H),
6.60 (s, 2H), 6.62 (s, 1H), 7.21-7.62 (m, 8H), 7.76 (dt, 1H, J )
7.7, 1.7 Hz), 8.03 (s, 1H), 8.63 (d, 1H, J ) 4.2 Hz). IR (KBr):
3329, 2975, 1727, 1667 cm-1. MS (SIMS): m/z 682 (M+ + 1,
base), 628, 534.
2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d ih yd r o-
1-oxo-7-(2-p yr id ylm eth oxy)-4-(3,4,5-tr im eth oxyp h en yl)-
3-isoqu in olin eca r boxa m id e (55). 55 was prepared from 50
as described for 35a . Yield 63%; mp 236-238 °C dec. 1H NMR
(DMSO-d6): δ 1.49 (s, 9H), 3.72 (s, 3H), 3.74 (s, 6H), 5.32 (s,
2H), 6.69 (s, 2H), 7.15-7.52 (m, 9H), 7.69-7.82 (m, 2H), 7.84
(dt, 1H, J ) 7.7, 1.8 Hz), 8.59 (d, 1H, J ) 4.1 Hz), 9.53 (s, 1H).
IR (KBr): 1680, 1650, 1508, 1238 cm-1. MS (SIMS): m/z 653
(M+ + 1, base), 597.
7-Ben zyloxy-2-[(4-ter t-bu toxyca r bon yla m in o)p h en yl]-
1,2-d ih yd r o-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-3-isoqu in o-
lin eca r boxa m id e (45). To a mixture of 42 (500 mg, 0.77
mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDCI‚HCl) (176 mg, 0.92 mmol), and 1-hydroxyben-
zotriazole hydrate (HOBt‚H2O) (129 mmol, 0.84 mmol) in DMF
(5 mL) was added 28% aqueous NH3 (0.5 mL), and the mixture
was stirred at room temperature for 3 h. The mixture was
poured into H2O and extracted with AcOEt. The organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The crystallization of the residue from
1
AcOEt gave 45 (373 mg, 75%), mp 242-246 °C dec. H NMR
(DMSO-d6): δ 1.49 (s, 9H), 3.72 (s, 3H), 3.74 (s, 6H), 5.25 (s,
2H), 6.69 (s, 2H), 7.15-7.58 (m, 12H), 7.75 (s, 1H), 7.79 (d,
1H, J ) 2.7 Hz), 9.52 (s, 1H). IR (KBr): 3438, 1646, 1500, 1237
cm-1. MS (SIMS): m/z 652 (M+ + 1), 596, 91 (base).
7-Ben zyloxy-2-[(4-ter t-bu toxyca r bon yla m in o)p h en yl]-
1,2-d ih yd r o-N-m eth yl-1-oxo-4-(3,4,5-tr im eth oxyp h en yl)-
3-isoqu in olin eca r boxa m id e (46). 46 was prepared from 42
and methylamine as described for 45. Yield 76%; mp 206-
1
208 °C. H NMR (CDCl3): δ 1.52 (s, 9H), 2.34 (d, 3H, J ) 3.5
Hz), 3.84 (s, 6H), 3.91 (s, 3H), 5.19 (s, 2H), 5.35 (q, 1H, J )
3.5 Hz), 6.62 (s, 3H), 7.12-7.53 (m, 11H), 8.01 (d, 1H, J ) 2.5
Hz). IR (KBr): 3484, 1647, 1238 cm-1. MS (SIMS): m/z 666
(M+ + 1), 610, 518, 91 (base).
2-[(4-ter t-Bu toxyca r bon yla m in o)p h en yl]-1,2-d ih yd r o-
N-m et h yl-1-oxo-7-(2-p yr id ylm et h oxy)-4-(3,4,5-t r im et h -
oxyp h en yl)-3-isoqu in olin eca r boxa m id e (56). 56 was pre-
pared from 51 as described for 35a . Yield 89%; mp 203-206
7-Ben zyloxy-2-[(4-ter t-bu toxyca r bon yla m in o)p h en yl]-
1,2-dih ydr o-N,N-dim eth yl-1-oxo-4-(3,4,5-tr im eth oxyph en -