3030 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Amberg et al.
3-[2-(3,4,5-Tr im et h oxyp h en yl)et h oxy]-2-[(4,6-d im et h -
ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11d ).
Compound 11d was synthesized as described for 11h using
2-(3,4,5-trimethoxyphenyl)ethanol in the first step: 1H NMR
(CDCl3, 200 MHz) δ 7.3-7.1 (10 H, m), 6.7 (1 H, s), 6.35 (2 H,
s), 6.3 (2 H, s), 3.9 (9 H, m), 3.8 (1 H, m), 3.6 (1 H, m), 2.8 (2
H, t), 2.3 (6 H, s); mp 154-155 °C. HRMS calcd, 559.2442;
found, 559.2426 [M + H]+.
ic Acid (12f). Compound 12f was synthesized as described
for 11h using 2-(3-methoxy-4-methoxycarbonylmethoxy-
phenyl)ethanol in step (a). Deprotection of the methyl ester
was carried out during step (b) allowing a trianion during the
last step: 1H NMR (DMSO-d6, 200 MHz) δ 7.3-7.1 (10 H, m),
6.9-6.6 (4 H, m), 6.1 (1 H, s), 4.5 (1 H, s), 4.0 (1 H, m), 3.8 (3
H, s), 3.7 (1 H, m), 2.8 (2 H, t), 2.3 (6 H, s); mp foam. HRMS
calcd, 573.2235; found, 573.2225 [M + H]+.
3-[3-(3,4,5-Tr im eth oxyp h en yl)p r op -(2E)-en oxy]-2-[(4,6-
d im eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid
(11e). Compound 11e was synthesized as described for 11h
using 3-(3,4,5-trimethylphenyl)prop-(2E)-enol in the first
step: 1H NMR (CDCl3, 200 MHz) δ 7.5-7.2 (10 H, m), 6.8 (1
H, m), 6.55 (1H, s), 6.5 (1 H, d), 6.3 (1 H, s), 6.15 (1 H, dt), 4.3
(1 H, dd), 4.1 (1 H, dd), 3.9 (6 H, s), 3.85 (3 H, s), 2.3 (6 H, s);
mass spectra 571 (M + H)+; mp foam.
3-(3,4-Dim eth oxyp h en oxy)-2-[(4,6-d im eth ylp yr im id in -
2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11f). Compound 11f
was synthesized as described for 11h using 3,4-dimethoxy-
phenol in the first step: 1H NMR (CDCl3, 200 MHz) δ 7.75 (2
H, m), 7.4-7.1 (8 H, m), 6.7 (1 H, m), 6.55 (2 H, m), 6.45 (1 H,
dd); 6.2 (1 H, d), 3.8 (3 H, s), 3.6 (3 H, s), 2.3 (6 H, s); mp
115-116 °C. HRMS calcd, 501.2024; found, 501.2029 [M + H]+.
Anal. (C33H34N2O7) C, N; H calcd, 5.6; found, 6.1.
3-(3,4-Dim eth oxyben zyloxy)-2-[(4,6-dim eth ylpyr im idin -
2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11g). Compound
11g was synthesized as described for 11h using 3,4-dimethoxy-
benzyl alcohol in the first step: 1H NMR (CDCl3, 200 MHz) δ
7.5-7.2 (10 H, m), 6.95-6.8 (3 H, m), 6.7 (1 H, s); 6.3 (1 H, s),
4.6 (1 H, d), 4.5 (1 H, d), 3.85 (3 H, s), 3.8 (3 H, s), 2.3 (6 H, s);
mp 125-126 °C. HRMS calcd, 515.2180; found, 515.2159 [M
+ H]+.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12a ). Com-
pound 12a was synthesized as described for 11h using 2-(4-
methoxyphenyl)ethanol in the first step: 1H NMR (DMSO-
d6, 270 MHz) δ 7.4-7.1 (12 H, m), 6.7 (3 H, m), 6.2 (1 H, sbr),
4.0 (1 H, m), 3.7 (3 H, s), 3.65 (1 H, m), 2.8 (2 H, t), 2.3 (6 H,
s); mp foam. HRMS calcd, 499.2231; found, 499.2210 [M + H]+.
3-[2-(4-Ch lor op h en yl)et h oxy]-2-[(4,6-d im et h ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12b). Com-
pound 12b was synthesized as described for 11h using 2-(4-
chlorophenyl)ethanol in the first step: 1H NMR (CDCl3, 200
MHz) δ 7.3-7.0 (14 H, m), 6.7 (1 H, s), 6.3 (1 H, s), 3.75 (1 H,
m), 3.6 (1 H, m), 2.8 (2 H, m), 2.3 (6 H, s); mp 108-110 °C.
HRMS calcd, 503.1736; found, 503.1733 [M + H]+.
3-[2-(4-E t h oxy-3-m e t h oxyp h e n yl)e t h oxy]-2-[(4,6-d i-
m eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid
(12c). Compound 12c was synthesized as described for 11h
using 2-(4-ethoxy-3-methoxyphenyl)ethanol in the first step:
1H NMR (DMSO-d6, 270 MHz) δ 7.4-7.1 (10 H, m), 6.9-6.65
(4 H, m), 6.2 (1 H, s), 4.1-3.9 (3 H, m), 3.7 (3 H, s), 3.6 (1 H,
m), 2.8 (2 H, t), 2.3 (6 H, s), 1.3 (3 H, t); mp 123-125 °C (dec).
Anal. (C32H34N2O6) H, N; C: calcd, 72.2; found, 71.7. HRMS
calcd, 543.2493; found, 543.2494 [M + H]+.
3-(2-P h en ylet h oxy)-2-[(4,6-d im et h ylp yr im id in -2-yl)-
oxy]-3,3-d ip h en ylp r op ion ic Acid (12d ). Compound 12d was
synthesized as described for 11h using 2-phenylethanol in the
first step: 1H NMR (CDCl3, 200 MHz) δ 7.3 (15 H, m), 6.7 (1
H, s), 6.3 (1 H, s), 3.8 (1 H, m), 3.6 (1 H, m), 2.9 (2 H, t), 2.3 (6
H, s); mp 130-133 °C. HRMS calcd, 469.2126; found, 469.2120
[M + H]+.
3-[2-(4-Hyd r oxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12e). Com-
pound 12e was synthesized as described for 11h using 2-(4-
benzyloxyphenyl)ethanol in the first step. Deprotection of the
hydroxy group was carried out as last step via catalytic
hydrogenation (palladium on charcoal in ethyl acetate): 1H
NMR (CDCl3, 270 MHz) δ 7.35-7.15 (10 H, m), 6.9 (2 H, d),
6.7 (1 H, s), 6.6 (2 H, d), 6.3 (1 H, s), 3.75 (1 H, m), 3.6 (1 H,
m), 2.8 (2 H, t), 2.3 (6 H, s); mp 126-127 °C (dec). HRMS calcd,
485.2075; found, 485.2071 [M + H]+.
3-[2-(4-Ca r boxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12g). Com-
pound 12g was synthesized as described for 11h using 2-(4-
carboxyphenyl)ethanol in step (a), allowing a trianion during
the last step: 1H NMR (CDCl3, 200 MHz) δ 7.9 (2 H, d), 7.4 (2
H, d), 7.3-7.1 (10 H, m), 6.6 (1 H, m), 6.2 (1 H, s), 4.2 (1 H,
m), 3.9 (1 H, m), 2.8 (2 H, m), 2.3 (6 H, s); mp foam. HRMS
calcd, 513.2024; found, 513.2005 [M + H]+.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4-m eth oxy-6-m eth -
ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (13a ).
Compound 13a was synthesized as described for 11h using
using 2-(4-methoxyphenyl)ethanol in step (a) and 2-(methyl-
sulfonyl)-4-methoxy-6-methylpyrimidine in step (c): 1H NMR
(DMSO-d6, 270 MHz) δ 7.4-7.1 (12 H, m), 6.8 (2 H, d), 6.4 (1
H, s), 6.1 (1 H, s), 4.0 (1 H, m), 3.8 (3 H, s), 3.7 (3 H, s), 3.65
(1 H, m), 2.8 (2 H, t), 2.2 (3 H, s); mp foam. HRMS calcd,
515.2180; found, 515.2162 [M + H]+.
3-[2-(4-Met h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-5,6-d i-
h ydr ofu r o[2,3-d]pyr im idin -2-yl)oxy]-3,3-bis(4-m eth ylph en -
yl)p r op ion ic Acid (13b). Compound 13b was synthesized as
described for 11h using 2-(4-methoxyphenyl)ethanol and 3,3-
bis-(4-methylphenyl)oxirane-2-carboxylic acid methyl ester19
during step (a) and 2-(methylsulfonyl)-4-methoxy-5,6-dihydro-
furo[2,3-d]pyrimidine in step (c): 1H NMR (DMSO-d6, 200
MHz) δ 7.3-7.0 (10 H, m), 6.8 (2 H, d), 6.0 (1 H, s), 4.6 (2 H,
t), 3.8 (3 H, s), 3.75 (1 H, m), 3.65 (1 H, s), 3.5 (1 H, m), 3.0 (2
H, t), 2.8 (2 H, t), 2.2 (6 H, s); mp foam. HRMS calcd, 571.2442;
found, 571.2462 [M + H]+.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
idin -2-yl)oxy]-3,3-bis-(4-eth ylph en yl)pr opion ic Acid (13c).
Compound 13c was synthesized as described for 11h using
2-(4-methoxyphenyl)ethanol and 3,3-bis-(4-ethylphenyl)oxirane-
2-carboxylic acid methyl ester19 during step (a): 1H NMR
(CDCl3, 200 MHz) δ 7.3-7.0 (10 H, m), 6.8 (2 H, d), 6.6 (1 H,
s), 6.3 (1 H, s), 3.75 (3 H, s), 3.6 (1 H, m), 3.45 (1 H, m), 2.8 (2
H, t), 2.6 (4 H, m), 2.3 (6 H, s), 1.2 (6 H, m); mp 130-133 °C
(dec). HRMS calcd, 555.2857; found, 555.2865 [M + H]+. Anal.
(C34H38N2O5) C, H, N.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4-m eth oxy-6-m eth -
ylp yr im id in -2-yl)oxy]-3,3-b is-(4-et h ylp h en yl)p r op ion ic
Acid (13d ). Compound 13d was synthesized as described for
11h using 2-(4-methoxyphenyl)ethanol and 3,3-bis-(4-ethyl-
phenyl)oxirane-2-carboxylic acid methyl ester during step (a)
and 2-(methylsulfonyl)-4-methoxy-6-methylpyrimidine in step
(c): 1H NMR (CDCl3, 200 MHz) δ 7.3-7.0 (10 H, m), 6.8 (2 H,
d), 6.3 (1 H, s), 6.25 (1 H, s), 3.85 (3 H, s), 3.75 (3 H, s), 3.6 (1
H, m), 3.45 (1 H, m), 2.8 (2 H, t), 2.6 (4 H, m), 2.3 (3 H, s), 1.2
(6 H, m); mp 151-155 °C. HRMS calcd, 571.2806; found,
501.2811 [M + H]+. Anal. (C34H38N2O6) C, H, N.
3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-6-
m eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid
(13e). Compound 13e was synthesized as described for 11h
using 2-(methylsulfonyl)-4-methoxy-6-methylpyrimidine in step
(c): 1H NMR (CDCl3, 200 MHz) δ 7.3 (10 H, m), 6.7 (3 H, m),
6.2 (1 H, s), 6.18 (1 H, s), 3.9 (9 H, m), 3.8 (1 H, m), 3.6 (1 H,
m), 2.8 (2 H, tr), 2.3 (3 H, s); mass spectra 545 (M + H)+; mp
foam.
3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-6-
m eth ylp yr im id in -2-yl)oxy]-3,3-bis-(4-ch lor op h en yl)p r o-
p ion ic Acid (13f). Compound 13f was synthesized as de-
scribed for 11h using 3,3-bis-(4-chlorophenyl)oxirane-2-car-
boxylic acid methyl ester during step (a) and 2-(methylsul-
fonyl)-4-methoxy-6-methylpyrimidine in step (c): 1H NMR
(CDCl3, 200 MHz) δ 7.2 (8 H, m), 6.7 (3 H, m), 6.3 (1 H, s), 6.0
3-[2-(4-Ca r boxym eth oxy-3-m eth oxyp h en yl)eth oxy]-2-
[(4,6-d im eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion -