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A. Casimiro-Garcia et al. / Bioorg. Med. Chem. 17 (2009) 7113–7125
1H), 2.61 (t, J = 7.3 Hz, 2H), 2.51 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 2.24
(s, 3H), 1.98 (qn, J = 7.6 Hz, 2H); CIMS m/z 459.3 (M+1).
5.1.8. (R)-3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-pyrazol-1-yl-propionic acid (17f)
This compound was obtained from the above purification. Acid
17f was obtained as a pale yellow solid (4.17 g): ½a D25
¼ þ61:0
ꢃ
5.1.5.3. Step 3: 2-(3-Methyl-isoxazol-5-yl)-3-{4-[3-(5-methyl-2-
phenyl-oxazol-4-yl)-propyl]-phenyl}-propionic acid (17c). This
compound was prepared from ester 16c following Method III.
The purification was carried out by chromatography on silica gel
eluting with methanol in chloroform (0–5%). Acid 17c was ob-
tained as an off-white solid in 85% yield: mp 133–135 °C; 1H
NMR (CDCl3, 400 MHz) d 7.98–7.95 (m, 2H), 7.42–7.39 (m, 3H),
7.07 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.01 (s, 1H), 4.11
(t, J = 8.1 Hz, 1H), 3.30 (dd, J = 13.9, 8.5 Hz, 1H), 3.18 (dd, J = 13.9,
7.1 Hz, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.48 (t, J = 7.6 Hz, 2H), 2.26 (s,
3H), 2.24 (s, 3H), 1.90 (qn, J = 7.6 Hz, 2H); CIMS m/z 431.2 (M+1).
Anal. Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51. Found: C,
72.32; H, 6.28; N, 6.41.
(c = 1.22, THF); mp 124–127 °C; 1H NMR and MS were identical
to racemate. Enantiomer purity: 98.35%, retention time = 8.12 min.
5.1.9. 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-
2-1,2,4-triazol-1-yl-propionic acid (17g)
5.1.9.1. Step 1: Ethyl 3-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-
yl)propanoate (15g). General method IV. A solution of diisopropyl
amine (1.0 mL, 7.089 mmol) in dry diethyl ether (10 mL) was cooled
to ꢀ20 °C under a nitrogen atmosphere. A solution of n-BuLi in hex-
anes (1.6 M, 4.8 mL, 7.734 mmol) was added. Mixture stirred for
20 min. A solution of ethyl 2-1,2,4-triazol-1-yl acetate (1.0 g,
6.445 mmol) in diethyl ether (10 mL) was added and this was fol-
lowed by the addition of a solution of 4-bromobenzyl bromide
(1.61 g, 6.445 mmol) in diethyl ether (20 mL). The mixture was stir-
red at ꢀ20 °C for 4 h, then allowed to reach room temperature and
stirred overnight. Mixture was quenched with water and the phases
were separated. Aqueous phase was acidified with 10% HCl and ex-
tracted with ethyl acetate (3 ꢁ 35 mL). The combined organic ex-
tracts were washed with water, brine, dried over MgSO4, filtered,
and the solvent removed. Purification by flash chromatography on
silica gel eluting with ethyl acetate in hexanes (0–45%) gave bromide
15g as a thick oil (0.447 g, 21%): 1H NMR (CDCl3, 400 MHz) d 8.10 (s,
1H), 7.98 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.16
(dd, J = 8.1, 6.7 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.46 (d, J = 7.6 Hz, 2H),
1.23 (t, J = 7.1 Hz, 3H); CIMS m/z 324 (M)+.
5.1.6. 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-
2-pyrazol-1-yl-propionic acid (17d)
5.1.6.1. Step 1: Ethyl 3-(4-bromophenyl)-2-(1H-pyrazol-1-yl)pro-
panoate (15d). Prepared from pyrazol-1-yl acetic acid ethyl ester
(10.0 g, 64.86 mmol) following general method I. Bromide 15d
was obtained as a clear, thick oil (9.73 g, 46%): 1H NMR (CDCl3,
400 MHz) d 7.53 (d, J = 1.7 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.33 (d,
J = 8.5 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.05 (dd, J = 8.8, 6.6 Hz, 1H),
4.18 (dd, J = 14.2, 7.1 Hz, 2H), 3.49–3.39 (m, 2H), 1.20 (t, J = 7.1 Hz,
3H); CIMS m/z 323 (M)+.
5.1.6.2. Step 2: 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-pyrazol-1-yl-propionic acid ethyl ester (16d). Pre-
pared from bromide 15d (0.760 g, 2.351 mmol) by the general
method II. Purification by column chromatography afforded 16d
(0.735 g, 70%): 1H NMR (CDCl3, 400 MHz) d 7.98–7.95 (m, 2H),
7.52 (d, J = 1.5 Hz, 1H), 7.44–7.38 (m, 4H), 7.05 (d, J = 8.0 Hz, 2H),
6.94 (d, J = 8.0 Hz, 2H), 6.22 (t, J = 2.1 Hz, 1H), 5.11 (t, J = 7.7 Hz,
1H), 4.16 (q, J = 7.1 Hz, 2H), 3.43 (d, J = 7.8 Hz, 2H), 2.60 (t,
J = 7.6 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 1.95 (qn,
J = 7.8 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H); CIMS m/z 444 (M+1).
5.1.9.2. Step 2: 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-1,2,4-triazol-1-yl-propionic acid ethyl ester (16g). Pre-
pared from bromide 15g (0.440 g, 1.357 mmol) following general
method II. Ester 16g was obtained as a thick oil (0.492 g, 82%): 1H
NMR (CDCl3, 400 MHz) d 8.09–8.07 (m, 2H), 8.00 (s, 1H), 7.94 (s,
1H), 7.48–7.41 (m, 3H), 7.06 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz,
2H), 5.17 (dd, J = 8.0, 6.6 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.43 (d,
J = 7.3 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 2.53 (t, J = 7.3 Hz, 2H), 2.28
(s, 3H), 1.99 (qn, J = 7.8 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); CIMS m/z
445 (M+1).
5.1.6.3. Step 3: 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-pyrazol-1-yl-propionic acid (17d). Prepared from es-
ter 16d (0.735 g, 1.657 mmol) by the general method III. Acid
17d was obtained as a yellowish solid (0.602 g, 87%): mp 75–
5.1.9.3. Step 3: 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-1,2,4-triazol-1-yl-propionic acid (17g). Prepared from
ester 16g (0.492 g, 1.106 mmol) following general method III. Acid
17g was obtained as a white solid (0.33 g, 72%): mp 169–171 °C;
1H NMR (CDCl3, 400 MHz) d 8.16 (s, 1H), 8.02-7.99 (m, 2H), 7.98
(s, 1H), 7.45–7.40 (m, 3H), 7.01 (d, J = 8.0 Hz, 2H), 6.87 (d,
J = 8.0 Hz, 2H), 5.24 (t, J = 7.1 Hz, 1H), 3.42 (d, J = 7.1 Hz, 2H), 2.57
(t, J = 7.6 Hz, 2H), 2.52 (t, J = 7.6 Hz, 1H), 3.42 (d, J = 7.1 Hz, 2H),
2.57 (t, J = 7.6 Hz, 2H), 2.51 (t, J = 7.6 Hz, 2H), 2.28 (s, 3H), 1.93
(qn, J = 7.6 Hz, 2H); CIMS m/z 417 (M+1). Anal. Calcd for
C24H24N4O3ꢂ0.2H2O: C, 68.62; H, 5.85; N, 13.34. Found: C, 68.51;
H, 5.85; N, 13.26.
77 °C; 1H NMR (CDCl3, 400 MHz)
d 7.96 (m, 2H), 7.61 (d,
J = 2.0 Hz, 1H), 7.40 (m, 3H), 7.09 (d, J = 2.0 Hz, 1H), 7.02 (d,
J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.19 (t, J = 2.2 Hz, 1H),
5.02 (dd, J = 10.0, 4.6 Hz, 1H), 3.42 (dd, J = 13.9, 4.6 Hz, 1H), 3.27
(dd, J = 13.9, 10.0 Hz, 1H), 2.59 (t, J = 7.6 Hz, 2H), 2.47 (t,
J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.93 (m, 2H); CIMS m/z 416 (M+1).
Anal. Calcd for C25H25N3O3ꢂ0.4H2O: C, 71.04; H, 6.15; N, 9.94.
Found: C, 70.76; H, 6.08; N, 9.91.
5.1.7. (S)-3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-pyrazol-1-yl-propionic acid (17e)
5.1.10. 3-{4-[3-(5-Methyl-2-phenyl-oxazol-4-yl)-propyl]-
phenyl}-2-1,2,3-triazol-1-yl-propionic acid (17h)
The enantiomers of acid 17d (10.1 g) were separated by pre-
parative chiral HPLC: chiralpak AD column, 4.6 ꢁ 250 mm; mobile
phase A: 75% hexanes with 0.1% trifluoroacetic acid; mobile phase
B; 25% ethanol; flow rate: 1 mL/min; detection at 280 nm. Com-
pound 17e was obtained as a pale yellowish solid (4.06 g): mp
5.1.10.1. Step 1: Ethyl 2-(1H-1,2,3-triazol-1-yl)acetate (14h). Pre-
pared following the procedure described by Kume et al.43 Following
this procedure, starting from 1H-1,2,3-triazole (18.17 g, 0.263 mol),
the N-1 alkylated product 14h was obtained as a liquid (26.45 g,
65%) after purification by column chromatography on silica gel elut-
ing with ethyl acetate in hexanes (0 to 55%): 1H NMR (CDCl3,
400 MHz) d 7.75 (d, J = 1.0 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H), 5.19 (s,
2H), 4.25 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H); CIMS m/z 156
(M+1).
115–117 °C; ½a 2D5
ꢃ
¼ ꢀ57:0 (c 1.47, THF); 1H NMR and MS were
identical to racemate. Enantiomer purity: 98.1%, retention
time = 6.48 min. Anal. Calcd for C25H25N3O3ꢂ0.29CHCl3: C, 67.48;
H, 5.66; N, 9.34. Found: C, 67.09; H, 5.63; N, 9.19.