N-(2-Benzoylphenyl)-L-tyrosine PPARγ Agonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5049
poured into saturated NaHCO3, and the product was extracted
with EtOAc. The combined organic layers were dried (Na2-
SO4), filtered, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography using
hexanes/EtOAc (1:1) as eluent to give 542 mg (39% overall) of
the title compound: 1H NMR (CDCl3, 400 MHz) δ 8.86 (d, 1
H, J ) 7.2), 7.79 (d, 2 H, J ) 7.6), 7.62-7.25 (m, 10 H), 7.14
(d, 2 H, J ) 8.4), 6.76 (d, 2 H, J ) 8.4), 6.64 (d, 1 H, J ) 8.8),
6.58 (t, 1 H, J ) 7.6), 4.40 (dd, 1 H, J ) 7.2, 6.0), 4.11 (t, 2 H,
J ) 7.2), 3.69 (s, 3 H), 3.20 (dd, 1 H, J ) 14.0, 5.6), 3.12 (dd,
1 H, J ) 14.0, 7.2), 2.98 (t, 2 H, J ) 6.0), 2.19 (s, 3 H); low-
resolution MS (ES) m/e 560 (MH+); TLC (EtOAc/hexanes (2:
1)) Rf ) 0.29. Anal. (C35H33N3O4‚1.3H2O) C, H, N.
2(S )-((2-Be n zoylp h e n yl)a m in o)-3-{4-[2-(5-m e t h yl-2-
p yr id in -4-yloxa zol-4-yl)et h oxy]p h en yl}p r op ion ic Acid
Meth yl Ester . Prepared from 3 and 2-(5-methyl-2-pyridin-
4-yloxazol-4-yl)ethanol according to general procedure A.
Purification by silica gel flash chromatography using EtOAc/
hexane (1:1 to 9:1) provided the title compound in 51% yield:
1H NMR (CDCl3, 300 MHz) δ 8.83 (d, 1 H, J ) 7.4), 8.63 (m,
2 H), 7.74 (m, 2 H), 7.60 (m, 2 H), 7.53 (m, 2 H), 7.45 (m, 1 H),
7.27 (m, 1 H), 7.10 (m, 2 H), 6.75 (m, 2 H), 6.55 (m, 2 H), 4.31
(m, 1 H), 4.13 (t, 2 H, J ) 6.6), 3.63 (s, 3 H), 3.09 (m, 2 H),
2.90 (t, 2 H, J ) 6.5), 2.32 (s, 3 H); low-resolution MS (ES)
m/e 562 (MH+).
1 H), 7.16 (d, 2 H, J ) 8.5), 6.81 (d, 2 H, J ) 8.5), 6.63 (d, 1 H,
J ) 8.3), 6.58 (dd, 1 H, J ) 7.5, 7.5), 4.38 (m, 1 H), 4.13 (t, 2
H, J ) 7.0), 3.69 (s, 3 H), 3.26 (t, 2 H, J ) 6.3), 3.19 (dd, 1 H,
J ) 5.9, 13.8), 3.11 (dd, 1 H, J ) 7.4, 13.8), 2.90 (t, 2 H, J )
7.0), 2.39 (t, 2 H, J ) 6.5), 2.22 (m, 8 H), 1.76 (m, 2 H); low-
resolution MS (FAB) m/e 602 (MH+), 601 (M+).
2(S)-((2-Ben zoylp h en yl)a m in o)-3-(4-{2-[5-m eth yl-2-(4-
m e t h y lp ip e r a zin -1-y l)t h ia zo l-4-y l]e t h o x y }p h e n y l)-
p r op ion ic Acid Meth yl Ester . Prepared from 3 and 2-[5-
methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethanol according
to general procedure C. Purification by silica gel flash column
chromatography using EtOAc/MeOH (10:1) with 1% am-
monium hydroxide as eluent afforded 3.06 g of the title
compound as a yellow oil. Approximately 130 mg of the
material was dissolved in Et2O, and the pH was adjusted to
1.0 by the addition of a 1.0 M solution of HCl in Et2O. The
resulting yellow precipitate was filtered and dried under
vacuum to afford 100 mg of the HCl salt: 1H NMR (MeOH-
d4, 400 MHz) δ 7.57 (m, 3 H), 7.50 (m, 2 H), 7.41 (m, 2 H),
7.09 (d, 2 H, J ) 8.5), 6.77 (m, 3 H), 6.61 (dd, 1 H, J ) 7.5,
7.5), 4.62 (t, 1 H, J ) 5.7), 4.19 (t, 2 H, J ) 5.8), 3.73 (s, 3 H),
3.30 (m, 4 H), 3.20 (dd, 1 H, J ) 5.3, 13.9), 3.11 (dd, 1 H, J )
6.2, 13.9), 3.04 (t, 2 H, J ) 5.8), 2.97 (s, 3 H), 2.26 (s, 3 H);
low-resolution MS (FAB) m/e 599 (MH+); RP-HPLC (Dynamax
C-8, 25 cm × 4.1 mm; 30-80% CH3CN in H2O with 0.1% TFA
buffer; 30 min; 1 mL/min) tR ) 17.79 min.
Gen er a l P r oced u r e D for th e Sa p on ifica tion of th e
Meth yl Ester (Sch em e 1). 2(S)-((2-Ben zoylph en yl)am in o)-
3-{4-[2-(5-m et h yl-2-p h en ylt h ia zol-4-yl)et h oxy]p h en yl}-
p r op ion ic Acid (4). To a solution of 350 mg (0.61 mmol) of
2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenylthi-
azol-4-yl)ethoxy]phenyl}propionic acid methyl ester in 5.6 mL
of THF and 1.9 mL of H2O at 0 °C was added 0.91 mL (0.91
mmol) of 1.0 N LiOH. The reaction was immediately warmed
to 25 °C, stirred 2.5 h, and poured into EtOAc. The solution
was acidified with 0.1 N HCl, and the product was extracted
with EtOAc. The combined organic layers were concentrated
in vacuo, and the residue was dissolved in CHCl3, filtered, and
concentrated in vacuo. Trituration with Et2O/hexanes pro-
vided 283 mg (83%) of title compound as a yellow solid: 1H
NMR (DMSO-d6, 400 MHz) δ 8.62 (d, 1 H, J ) 8.0), 7.82 (dd,
2 H, J ) 6.0, <1.0), 7.60-7.36 (m, 9 H), 7.33 (d, 1 H, J ) 8.0),
7.09 (d, 2 H, J ) 8.8), 6.80 (t, 3 H, J ) 8.4), 6.58 (t, 1 H, J )
7.6), 4.50 (dd, 1 H, J ) 7.2, 6.0), 4.19 (t, 2 H, J ) 6.8), 3.18-
2.94 (m, 4 H), 2.37 (s, 3 H); low-resolution MS (ES) m/e 586
(MNa+), 563 (M+); RP-HPLC (C-18, 4.6 mm × 25 cm; 30-80%
CH3CN in H2O with 0.1% TFA; 30 min; 1 mL/min) tR ) 28.9
min (t0 ) 3 min). Anal. (C34H30N2O4S‚0.3H2O) C, H, N, S.
2(S)-((2-Ben zoylp h en yl)a m in o)-3-{4-[2-(5-m eth yl-2-p y-
r id in -4-yloxa zol-4-yl)eth oxy]p h en yl}p r op ion ic Acid (16).
Prepared from 2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-meth-
yl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid meth-
yl ester according to general procedure D. Purification by silica
gel chromatography using MeOH/CH2Cl2 (1:9) as eluent
provided the title compound in 96% yield: 1H NMR (DMSO-
d6, 400 MHz) δ 8.75 (d, 1 H, J ) 7.0), 8.68 (m, 2 H), 7.76 (m,
2 H), 7.52 (m, 1 H), 7.46 (m, 4 H), 7.28 (m, 2 H), 7.08 (m, 2 H),
6.73 (m, 3 H), 6.45 (m, 1 H), 4.22 (bm, 1 H), 4.07 (bm, 2 H),
3.17 (m, 1 H), 2.96 (m, 1 H), 2.86 (m, 2 H), 2.31 (s, 3 H); RP-
HPLC (50-100% CH3CN in water with 0.1% TFA buffer; 25
min) tR ) 7.58 min; chiral HPLC (Daicel chiralcel OD-H, 4.6
× 250 mL, 5 mm; 25% ethanol/hexane with 0.1% TFA; 1 mL/
min; 30 min) tR ) 9.45 min, 96% ee; low-resolution MS (ES)
m/e 548 (MH+); high-resolution MS (EI) m/e 548.2194 (MH+),
C33H29N3O5 requires 548.2185.
2(S)-((2-Ben zoylp h en yl)a m in o)-3-(4-{2-[5-m eth yl-2-(4-
m e t h y lp ip e r a zin -1-y l)t h ia zo l-4-y l]e t h o x y }p h e n y l)-
p r op ion ic Acid Hyd r och lor id e (24). Prepared from 2(S)-
((2-ben zoylph en yl)a m in o)-3-(4-{2-[5-m et h yl-2-(4-m et h yl-
piperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid methyl
ester according to general procedure D. Acidification of the
reaction with 1 equiv of acetic acid and concentration in vacuo
provided a residue. The residue was purified by silica gel
chromatography using MeOH/EtOAc (gradient of 2:3 to 3:2 to
Gen er a l P r oced u r e B for th e Mitsu n obu Rea ction
(Sch em e 1). 2(S)-((2-Ben zoylp h en yl)a m in o)-3-{4-[2-(5-
m e t h y l-1-p h e n y l-1H -p y r a z o l-3-y l)e t h o x y ]p h e n y l}-
p r op ion ic Acid Meth yl Ester . Prepared from 3 and 2-(5-
methyl-3-phenylpyrazol-1-yl)ethanol according to general
procedure A. After stirring for 15 h, the solvent was removed
in vacuo. The residue was stirred vigorously for 1 h in 2:1
diethyl ether/1 N LiOH biphasic solution to effect selective
removal of residual 3. Workup as in general procedure A and
purification with hexane/EtOAc (4:1 to 2:1) as eluent afforded
the title compound as a yellow solid: 1H NMR (CDCl3, 400
MHz) δ 8.91 (d, 1 H, J ) 7.4), 7.60 (d, 2 H, J ) 8.3), 7.45 (m,
6 H), 7.34 (m, 1 H), 7.19 (d, 2 H, J ) 8.6), 6.87 (d, 2 H, J )
8.6), 6.63 (d, 1 H, J ) 8.5), 6.57 (dd, 1 H, J ) 7.5, 7.5), 4.38
(dd, 1 H, J ) 7.2, 13.3), 4.22 (t, 2 H, J ) 7.1), 3.70 (s, 3 H),
3.20 (dd, 1 H, J ) 6.0, 13.7), 3.12 (m, 3 H), 2.31 (s, 3 H); low-
resolution MS (FAB) m/e 561 (MH+), 560 (M+). Anal. (C35
33N3O4) C, H, N.
2(S)-((2-Ben zoylp h en yl)a m in o)-3-{4-[2-(5-m eth yl-2-(4-
-
H
flu or op h en yl)oxa zol-4-yl)eth oxy]p h en yl}p r op ion ic Acid
Meth yl Ester . Prepared from 3 and 2-[2-(4-fluorophenyl)-5-
methyloxazol-4-yl]ethanol according to general procedure B.
Purification with hexane/EtOAc (4:1 to 2:1) as eluent afforded
the title compound in 48% yield as a yellow solid: 1H NMR
(CDCl3, 400 MHz) δ 8.89 (d, 1 H, J ) 7.3), 7.95 (m, 2 H), 7.58
(d, 2 H) 7.44 (m, 4 H), 7.34 (m, 1 H), 7.17 (d, 2 H, J ) 8.6),
7.10 (dd, 2 H, J ) 8.7, 8.7), 6.82 (d, 2 H, J ) 8.6), 6.62 (d, 1 H,
J ) 8.5), 6.57 (dd, 1 H, J ) 7.5, 7.5), 4.36 (dd, 1 H, J ) 7.2,
13.3), 4.19 (t, 2 H, J ) 6.5), 3.69 (s, 3 H), 3.19 (dd, 1 H, J )
5.8, 13.7), 3.11 (dd, 1 H, J ) 7.4, 13.7), 2.93 (t, 2 H, J ) 6.5),
2.34 (s, 3 H); low-resolution MS (FAB) m/e 580 (MH+), 579
(M+). Anal. (C35H31FN2O5) C, H, N.
Gen er a l P r oced u r e C for th e Mitsu n obu Rea ction
(Sch em e 1). 2(S)-((2-Ben zoylp h en yl)a m in o)-3-(4-{2-[2-
[(3-(d im eth yla m in o)p r op yl)a m in o]-5-m eth ylth ia zol-4-yl]-
eth oxy}p h en yl)p r op ion ic Acid Meth yl Ester . A suspen-
sion of 715 mg (2.73 mmol, 1.10 equiv) of triphenylphosphine,
929 mg (2.48 mmol) of 3, and 600 mg (2.48 mmol) of 2-[2-[(3-
(dimethylamino)propyl)amino]-5-methylthiazol-4-yl]ethanol in
25 mL of dry toluene was heated to 95 °C for 15 min to effect
dissolution of 3. To this solution was added 452 mg (2.60
mmol, 1.05 equiv) of diethyl azodicarboxylate dropwise over 5
min. The reaction was then allowed to cool to room temper-
ature and stir for 16 h. The toluene was removed in vacuo,
and the residue was purified by silica gel flash column
chromatography using EtOAc/MeOH (1:1) with 1% ammonium
hydroxide as eluent to afford 770 mg (52% yield) of the title
compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.89
(d, 1 H, J ) 7.3), 7.60 (d, 2 H, J ) 7.0), 7.48 (m, 3 H), 7.33 (m,