334 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Yanagisawa et al.
filtered off through a Celite pad. The organic phase was
separated, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (MeOH/
CH2Cl2, 1:15) to give crystalline 39 which was washed with
IPE: yield 1.47 g (82%); mp 113 °C (EtOAc-IPE); NMR
(CDCl3) 0.99 (3H, t, J ) 7.5 Hz), 1.24 (9H, s), 1.31 (3H, t, J )
7 Hz), 1.80 (2H, sx, J ) 7.5 Hz), 2.69 (2H, t, J ) 7.5 Hz), 3.63
(1H, br s), 4.27 (2H, q, J ) 7 Hz), 4.88 (2H, s), 5.61 (2H, s),
7.00 (2H, d, J ) 8 Hz), 7.27 (2H, d, J ) 8 Hz), 7.27 (1H, d,d,
J ) 1, 7 Hz), 7.39 (1H, d,t, J ) 1, 7.5 Hz), 7.48 (1H, d,t, J ) 1,
7.5 Hz), 7.77 (1H, d,d, J ) 1, 7.5 Hz); IR (KBr) 3234, 1706,
1698 cm-1. Anal. (C28H34N2O5) C,H,N.
to give the following fractions. Faster moving fraction 45:
yield 3.55 g (66%); mp 123-124.5 °C (IPE); NMR (CDCl3) 0.96
(3H, t, J ) 8 Hz), 1.26 (9H, s), 1.43 (3H, t, J ) 7 Hz), 1.73 (2H,
sx, J ) 8 Hz), 2.67 (2H, t, J ) 8 Hz), 3.73 (1H, t, J ) 6.5 Hz),
4.44 (2H, q, J ) 7 Hz), 4.72 (2H, d, J ) 6.5 Hz), 5.26 (2H, s),
6.97 (2H, d, J ) 8.5 Hz), 7.26-7.31 (3H, m), 7.42 (1H, t, J )
7 Hz), 7.49 (1H, t, J ) 7 Hz), 7.78 (1H, d, J ) 6.5 Hz); IR
(KBr) 3310, 1715 cm-1. Anal. (C28H34N2O5) C,H,N.
Slower moving fraction 39 was obtained as a mixture of 39
and 45: yield 0.45 g (10%).
Similarly, 22a was reduced with LiAlH(OBut)3 to give 46
and 40. 46: 79%; mp 162-164 °C (color), 174-177 °C (melt).
Anal. (C43H40N6O3) C,H,N. 40: 8.3% (as a mixture of 22a and
40).
Similarly, 40 and 51 were prepared from 22a and 45. 40:
69%; mp 134-136 °C (EtOAc). Anal. (C43H40N6O3) C,H,N.
51: 77%; mp 176-177 °C. Anal. (C26H32N2O4) H,N; C: calcd,
71.53; found, 71.12.
Eth yl 1-[[2′-(ter t-Bu toxycar bon yl)biph en yl-4-yl]m eth yl]-
4-m eth yl-2-p r op ylim id a zole-5-ca r boxyla te (53a ). To a
solution of 39 (479 mg, 1.00 mmol) and Et3N (0.35 mL, 2.52
mmol) in CH2Cl2 (6 mL) was added ClCOCO2Et (165 mg, 1.21
mmol) under ice cooling and N2. After stirring at room
temperature for 0.5 h, the reaction mixture was diluted with
EtOAc and washed with aqueous NaHCO3. The organic phase
was dried over MgSO4 and concentrated in vacuo to give the
4-ethoxyglyoxylyl ester of 39 as a syrup (590 mg, quantita-
tive): NMR (CDCl3) 0.98 (3H, t, J ) 7.5 Hz), 1.23 (9H, s), 1.29
(3H, t, J ) 7.5 Hz), 1.36 (3H, t, J ) 7 Hz), 1.78 (2H, sx, J )
7.5 Hz), 2.67 (2H, t, J ) 7.5 Hz), 4.27 (2H, q, J ) 7 Hz), 4.35
(2H, q, J ) 7.5 Hz), 5.53 (2H, s), 5.62 (2H, s), 7.02 (2H, d, J )
8 Hz), 7.25-7.29 (3H, m), 7.39 (1H, t, J ) 7.5 Hz), 7.48 (1H,
t, J ) 7.5 Hz), 7.77 (1H, d, J ) 7.5 Hz).
Eth yl 1-[(2′-Ca r boxybip h en yl-4-yl)m eth yl]-4-(h yd r oxy-
m eth yl)-2-p r op ylim id a zole-5-ca r boxyla te (41). By the
same procedure as described in the preparation of 23a , 39 (0.84
g, 1.76 mmol) was treated with 4 N HCl in dioxane (10 mL) to
give 41 (0.69 g, 93%): mp 224-226 °C (EtOH); NMR (DMSO-
d6) 0.89 (3H, t, J ) 7.5 Hz), 1.22 (3H, t, J ) 7.5 Hz), 1.64 (2H,
sx, J ) 7.5 Hz), 2.62 (2H, t, J ) 7.5 Hz), 4.19 (2H, q, J ) 7.5
Hz), 4.60 (2H, d, J ) 5 Hz), 4.75 (1H, t, J ) 5 Hz), 5.58 (2H,
s), 7.01 (2H, d, J ) 8.5 Hz), 7.29 (2H, d, J ) 8.5 Hz), 7.34 (1H,
d, J ) 7.5 Hz), 7.44 (1H, t, J ) 7.5 Hz), 7.55 (1H, t, J ) 7.5
Hz), 7.71 (1H, d, J ) 7.5 Hz), 12.74 (1H, s); IR (KBr) 3410,
2452, 1701 cm-1. Anal. (C24H26N2O5) C,H,N.
Similarly, 47 and 52 were prepared. 47: quantitative; mp
215 °C (soften), 230 °C (melt) (EtOH). Anal. (C24H26N2O5)
C,H,N. 52: obtained as HCl salt; quantitative; mp 200 °C
(color), 217 °C (melt). Anal. (C22H24N2O4‚HCl‚1/3H2O) C,H,
Cl,N.
To a solution of the above ester (544 mg, 0.92 mmol) in
toluene (10 mL) were added Bu3SnH (600 mg, 2.06 mmol) and
2,2′-azobis(isobutyronitrile) (20 mg, 0.12 mmol), and the
mixture was refluxed for 1.5 h under N2. The reaction solution
was concentrated in vacuo. The residue was purified by flash
column chromatography (EtOAc/hexane, 1:1) to give 53a as a
syrup (282 mg, 61%): NMR (CDCl3) 0.97 (3H, t, J ) 7.5 Hz),
1.22 (9H, s), 1.31 (3H, t, J ) 7.5 Hz), 1.76 (2H, sx, J ) 7.5
Hz), 2.52 (3H, s), 2.63 (2H, t, J ) 7.5 Hz), 4.24 (2H, q, J ) 7.5
Hz), 5.58 (2H, s), 6.99 (2H, d, J ) 8 Hz), 7.25 (2H, d, J ) 8
Hz), 7.28 (1H, d, J ) 8 Hz), 7.38 (1H, t, J ) 8 Hz), 7.47 (1H,
Eth yl 4-(Hyd r oxym eth yl)-2-p r op yl-1-[(2′-1H-tetr a zol-
5-ylb ip h en yl-4-yl)m et h yl]im id a zole-5-ca r b oxyla t e (42).
By the same procedure as described in the preparation of 24a ,
40 (700 mg, 1.02 mmol) was treated with 25% aqueous AcOH
to give crystalline 42 (293 mg, 64%): mp 160-162 °C (EtOAc-
IPE); NMR (DMSO-d6) 0.87 (3H, t, J ) 7.5 Hz), 1.20 (3H, t, J
) 7 Hz), 1.59 (2H, sx, J ) 7.5 Hz), 2.57 (2H, t, J ) 7.5 Hz),
4.17 (2H, q, J ) 7 Hz), 4.58 (2H, s), 4.74 (1H, br s), 5.53 (2H,
s), 6.92 (2H, d, J ) 8 Hz), 7.05 (2H, d, J ) 8 Hz), 7.51-7.58
t, J ) 8 Hz), 7.76 (1H, d, J ) 8 Hz); IR (liquid film) 1703 cm-1
Anal. (C28H34N2O4) C,H,N.
.
(2H, m), 7.63-7.69 (2H, m); IR (KBr) 1710 cm-1
(C24H26N6O3) C,H,N.
.
Anal.
Similarly, 53b and 54a ,b were prepared from 27c, 40, and
29c, respectively. 53b: 45%; syrup. Anal. (C29H36N2O4)
C,H,N. 54a : 87%; mp 178.5-179 °C dec (MeCN-EtOAc).
Anal. (C43H40N6O2) C,H,N. 54b: 52%; mp 139-141 °C (IPE-
hexane). Anal. (C44H42N6O2) C,H,N.
Eth yl 1-[(2′-Ca r boxybip h en yl-4-yl)m eth yl]-4-m eth yl-2-
p r op ylim id a zole-5-ca r boxyla te (55a ). By the same proce-
dure as described in the preparation of 23a , 53a (1.30 g, 2.80
mmol) was treated with 4 N HCl in dioxane to give 55a (1.02
g, 89%): mp 186-188 °C (EtOH-EtOAc); NMR (DMSO-d6)
0.87 (3H, t, J ) 7.5 Hz), 1.21 (3H, t, J ) 7 Hz), 1.62 (2H, sx,
J ) 7.5 Hz), 2.39 (3H, s), 2.58 (2H, t, J ) 7.5 Hz), 4.18 (2H, q,
J ) 7 Hz), 5.56 (2H, s), 6.99 (2H, d, J ) 8 Hz), 7.28 (2H, d, J
) 8 Hz), 7.34 (1H, d,d, J ) 1, 7.5 Hz), 7.44 (1H, d,t, J ) 1, 7.5
Hz), 7.55 (1H, d,t, J ) 1, 7.5 Hz), 7.71 (1H, d,d, J ) 1, 7.5 Hz),
12.75 (1H, br s); IR (KBr) 2438, 1704 cm-1. Anal. (C24H26N2O4)
C,H,N.
Similarly, 48 was prepared. 48: quantitative; mp 128 °C
(soften). Anal. (C24H26N6O3) C,H,N.
1-[(2′-Car boxybiph en yl-4-yl)m eth yl]-4-(h ydr oxym eth yl)-
2-p r op ylim id a zole-5-ca r boxylic Acid (43). By the same
procedure as described in the preparation of 25a , 41 (584 mg,
1.38 mmol) was hydrolyzed with LiOH‚H2O (232 mg, 5.54
mmol) to give 43 (520 mg, 96%): mp 216-218 °C dec (MeOH);
NMR (DMSO-d6) 0.88 (3H, t, J ) 7.5 Hz), 1.62 (2H, sx, J )
7.5 Hz), 2.57 (2H, t, J ) 7.5 Hz), 4.62 (2H, s), 5.64 (2H, s),
7.04 (2H, d, J ) 8 Hz), 7.29 (2H, d, J ) 8 Hz), 7.35 (1H, d, J
) 7.5 Hz), 7.44 (1H, t, J ) 7.5 Hz), 7.55 (1H, d,t, J ) 1, 7.5
Hz), 7.70 (1H, d, J ) 7.5 Hz); IR (KBr) 2610, 2499, 1717, 1634,
1599 cm-1. Anal. (C22H22N2O5) C,H,N.
Similarly, 44, 49, and 50 were obtained by hydrolysis of 42,
47, and 48, respectively. 44: 95%; mp 223-224 °C dec (EtOH).
Anal. (C22H22N6O3) C,H,N. 49: quantitative; mp 210-212 °C
dec (EtOH). Anal. (C22H22N2O5‚1/2C2H5OH) C,H,N. 50: quan-
titative; mp >270 °C. Anal. (C22H22N6O3) C,H,N.
Eth yl 1-[[2′-(ter t-Bu toxycar bon yl)biph en yl-4-yl]m eth yl]-
5-(h ydr oxym eth yl)-2-p r op ylim id a zole-4-ca r boxyla te (45).
A mixture of 21a (5.87 g, 11.3 mmol) and LiAlH(OBut)3 (5.73
g, 22.6 mmol) in THF (59 mL) was stirred at room temperature
for 5 days. During the above reaction period, two portions of
additional LiAl(OBut)3 (1.43 g × 2, 11.3 mmol) were added to
the reaction mixture, respectively, on the second and third
days. MeOH (10 mL) was added under ice cooling, and the
mixture was stirred for 10 min. The solvent was removed by
distillation in vacuo, and the residue was dissolved in EtOAc
and H2O. After removal of the precipitates by filtration
through a Celite pad, the organic phase was separated, dried
over Na2SO4, and concentrated in vacuo. The residue was
subjected to flash column chromatography (EtOAc/CH2Cl2, 1:1)
Similarly, 55b was prepared. 55b: 89%; mp 181-182 °C
(EtOAc). Anal. (C25H28N2O4) C,H,N.
Eth yl 4-Meth yl-2-p r op yl-1-[(2′-1H-tetr a zol-5-ylbip h en -
yl-4-yl)m eth yl]im idazole-5-car boxylate (56a). By the same
procedure as described in the preparation of 24a , 54a (1.15 g,
1.71 mmol) was treated with 25% aqueous AcOH to give 56a
(710 mg, 96%): mp 179.5-180.5 °C (EtOAc); NMR (CDCl3)
0.84 (3H, t, J ) 7.5 Hz), 1.18 (3H, t, J ) 7.5 Hz), 1.54 (2H, sx,
J ) 7.5 Hz), 1.93 (3H, s), 2.18 (2H, t, J ) 7.5 Hz), 4.14 (2H, q,
J ) 7.5 Hz), 5.40 (2H, s), 6.70 (2H, d, J ) 8 Hz), 7.03 (2H, d,
J ) 8 Hz), 7.44 (1H, d,d, J ) 1.5, 7.5 Hz), 7.52-7.62 (2H, m),
7.87 (1H, d,d, J ) 1.5, 7.5 Hz); IR (KBr) 1705 cm-1
(C24H26N6O2) C,H,N.
. Anal.
Similarly, 56b was prepared. 56b: 95%; mp 182-183 °C
(EtOAc-Et2O). Anal. (C25H28N6O2) C,H,N.
1-[(2′-Ca r b oxyb ip h en yl-4-yl)m et h yl]-4-m et h yl-2-p r o-
p ylim id a zole-5-ca r b oxylic Acid (57a ). By a procedure