SAR of Phenoxyphenylacetic Acid Derivatives
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 907
[R,S]-(4-Ch lor o)p h en yl-[2-cya n o-5-(t h ien -3-yl)m et h -
oxy]p h en oxya cetic Acid 13i. Obtained as a cream solid, mp
158-60 °C (trituration with pentane). 1H NMR (CDCl3): δ 7.55
(d, J ) 8 Hz, 2H), 7.50 (d, J ) 8 Hz, 1H), 7.38 (m, 4H), 7.08 (d,
J ) 3 Hz, 1H), 6.66 (dd, J ) 9, 2 Hz, 1H), 6.44(s, 1H), 5.63 (s,
1H), 5.08 (s, 2H). Anal. (C20H14ClNO4S) C, H, N, S.
2H), 6.60 (dd, J ) 9, 3 Hz, 1H), 6.42 (d, J ) 3 Hz, 1H), 5.97 (s,
2H), 5.84 (s, 1H), 4.91 (s, 2H), 2.50 (s, 3H). Anal. (C24H19NO6)
C, H, N.
[R,S]-[2-Cyan o-5-(th iazol-5-yl)m eth oxy]ph en oxy-(2-m e-
th yl)p h en yla cetic Acid 15c. Obtained as a white solid, mp
1
226-7 °C (recrystallized from ethyl acetate/cyclohexane). H
[R,S]-[5-(Ben zo(1,3)d ioxol-5-yl)m eth oxy-2-cya n o]p h e-
n oxy-(2-tr iflu or om eth yl)p h en yla cetic Acid 14d . Obtained
as a white solid, mp 137-8 °C (flash chromatography with
5% MeOH in CH2Cl2 followed by trituration with diisopropyl
ether/pentane). 1H NMR (CDCl3): δ 7.94 (d, J ) 9 Hz, 1H),
7.72 (d, J ) 9 Hz, 1H), 7.74 (t, J ) 8 Hz, 1H), 7.53 (t, J ) 8
Hz, 1H), 7.48 (d, J ) 9 Hz, 1H), 6.82 (m, 3H), 6.63 (dd, J ) 9,
3 Hz, 1H), 6.52 (d, J ) 3 Hz, 1H), 6.18 (s, 1H), 5.97 (s, 2H),
4.93 (dd, J ) 12, 3 Hz, 2H). Anal. (C24H16F3NO6) C, H, N.
[R,S]-[5-(Ben zo(1,3)d ioxol-5-yl)m eth oxy-2-cya n o]p h e-
n oxy-(2-ch lor o)p h en yla cetic Acid 14e. Obtained as a cream
solid, mp 144-5 °C (flash chromatography with 4:1 pentane/
NMR (DMSO-d6): δ 9.15 (s, 1H), 8.04 (s, 1H), 7.70 (d, J ) 9
Hz, 1H), 7.51 (dd, J ) 9, 2 Hz, 1H), 7.28 (m, 3H), 6.94 (d, J )
3 Hz, 1H), 6.82 (dd, J ) 9, 3 Hz, 1H), 6.26 (s, 1H), 5.49 (s,
2H), 2.46 (s, 3H). IR (KBr) 3433.2 (m), 2219.8 (m), 1732.7 (m),
1609.7 (s) cm-1. Anal. (C20H16N2O4S, H2O) C, H, N.
[R,S]-[2-Cya n o-5-(p yr id -2-yl)m eth oxy]p h en oxy-(2-m e-
th yl)p h en yla cetic Acid 15d . Obtained as a yellow solid, mp
i
1
189-91 °C (recrystallized from PrOH). H NMR (DMSO-d6):
δ 8.60 (d, J ) 5 Hz, 1H), 7.85 (td, J ) 8, 2 Hz, 1H), 7.68 (d, J
) 8 Hz, 1H), 7.52 (t, J ) 8 Hz, 2H), 7.38 (dd, J ) 8, 6 Hz, 1H),
7.27 (m, 3H), 6.97 (d, J ) 3 Hz, 1H), 6.80 (dd, J ) 8, 2 Hz,
1H), 6.25 (s, 1H), 5.26 (dd, J ) 14, 3 Hz, 2H), 2.47 (s, 3H).
Anal. (C22H18N2O4) C, H, N.
1
ethyl acetate). H NMR (CDCl3): δ 7.70 (m, 1H), 7.47 (d, J )
9 Hz, 1H), 7.41 (m, 1H), 7.30 (m, 2H), 6.84 (m, 1H), 6.80 (t, J
) 7 Hz, 2H), 6.60 (dd, J ) 9, 2 Hz, 1H), 6.51 (m, 1H), 6.28 (s,
[R,S]-[2-Cya n o-5-(p yr id -4-yl)m eth oxy]p h en oxy-(2-m e-
th yl)p h en yla cetic Acid 15e. Obtained as a yellow solid, mp
193-4 °C (flash chromatography with a solvent gradient of
1H), 5.98 (s, 2H), 4.92 (dd, J ) 12, 4 Hz, 2H). Anal. (C23H16
ClNO6) C, H, N.
-
1
0-20% MeOH in ethyl acetate). H NMR (DMSO-d6): δ 8.60
[R,S]-[5-(Ben zo(1,3)d ioxol-5-yl)m eth oxy-2-cya n o]p h e-
n oxyp h en yla cetic Acid 14f. Obtained as a cream solid, mp
127-8 °C (flash chromatography with a solvent gradient of
20% to 30% ethyl acetate in pentane). 1H NMR (CDCl3): δ
7.61 (m, 2H), 7.50 (d, J ) 9 Hz, 1H), 7.41 (m, 3H), 6.84 (m,
1H), 6.80 (m, 2H), 6.61 (dd, J ) 9, 3 Hz, 1H), 6.44 (d, J ) 3
(dd, J ) 6, 2 Hz, 2H), 7.69 (d, J ) 8 Hz, 1H), 7.49 (m, 1H),
7.43 (d, J ) 6 Hz, 2H), 7.27 (m, 3H), 6.96 (d, J ) 3 Hz, 1H),
6.88 (dd, J ) 8, 2 Hz, 1H), 6.25 (s, 1H), 5.28 (m, 2H), 2.46 (s,
3H). Anal.(C22H18N2O4) C, H, N.
Gen er a l Meth od C. [R,S]-(5-Ben zyloxy-2-cya n o)p h e-
n oxy-(2-m eth yl)p h en yla cetic Acid 14a . (i) 4-Allyloxy-2-
h yd r oxyben zon itr ile 18b. This was prepared as for 18a and
obtained as a white solid (recrystallization from diisopropyl
Hz, 1H), 5.97 (s, 2H), 5.66 (s, 1H), 4.92 (s, 2H). Anal. (C23H17
NO6, 0.6H2O) C, H, N.
-
Gen er a l Meth od B. [R,S]-[2-Cya n o-5-(th ien -3-yl)-
m eth oxy]p h en oxyfu r a n -3-yla cetic Acid 13j. A solution of
R-hydroxyfuran-3-ylacetic acid23 (0.35 g, 2.46 mmol) in DMSO
(8 mL) was treated with NaH (60% dispersion, 0.20 g, 5.00
mmol) and stirred at room temperature for 5 min. A solution
of 2-fluoro-4-(thien-3-yl)methoxybenzonitrile 22a 18 (0.57 g, 2.45
mmol) in DMSO (2 mL) was then added dropwise. The reaction
mixture was stirred at room temperature for 3h before
quenching with H2O (50 mL) and washing with ethyl acetate
(2 × 50 mL). The aqueous layer was acidified to pH 2 with 1
M HCl and extracted with ethyl acetate (3 × 50 mL). The
organic extracts were dried over MgSO4, filtered, and concen-
trated. Flash column chromatography, eluting with a solvent
gradient of 1:1 pentane/ethyl acetate to ethyl acetate, gave 0.40
g (46%) of 13j as a white solid, mp 100-2 °C. 1H NMR
(CDCl3): δ 7.68 (s, 1H), 7.52 (d, J ) 9 Hz, 1H), 7.45 (m, 1H),
7.37 (dd, J ) 5, 3 Hz, 1H), 7.42 (m, 1H), 7.11 (d, J ) 7 Hz,
1H), 6.66 (dd, J ) 9, 3 Hz, 1H), 6.61 (m, 1H), 6.49 (d, J ) 3
Hz, 1H), 5.69 (s, 1H), 5.08 (s, 2H). Anal. (C18H13NO5S) C, H,
N.
1
ether). H NMR (CDCl3): δ 7.36 (d, J ) 9 Hz, 1H), 6.52 (d, J
) 3 Hz, 1H), 6.44 (dd, J ) 9, 3 Hz, 1H), 6.01 (ddt, J ) 17, 10,
5 Hz, 1H), 5.41 (dd, J ) 17, 2 Hz, 1H), 5.31 (dd, J ) 10, 2 Hz,
1H), 4.52 (dt, J ) 5, 2 Hz, 2H).
(ii) [R,S]-Meth yl (5-Allyloxy-2-cya n o)p h en oxy-(2-m e-
th yl)p h en yla ceta te 24a . This was prepared by alkylation of
18b following the method for 19a and obtained as a white
solid, mp 87-90 °C (trituration with diisopropyl ether). 1H
NMR (CDCl3): δ 7.65 (m, 1H), 7.50 (d, J ) 9 Hz, 1H), 7.28 (m,
2H), 7.23 (m, 1H), 6.56 (dd, J ) 9, 2 Hz, 1H), 6.40 (d, J ) 2
Hz, 1H), 6.00 (ddt, J ) 17, 10, 5 Hz, 1H), 5.86 (s, 1H), 5.90
(dd, J ) 17, 2 Hz, 1H), 5.33 (dd, J ) 10, 2 Hz, 1H), 4.53 (dt, J
) 5, 2 Hz, 2H), 3.75 (s, 3H), 2.51 (s, 3H).
(iii) [R,S]-Meth yl (2-Cya n o-5-h yd r oxy)p h en oxy-(2-m e-
th yl)p h en yla ceta te 23a . A solution of 24a (17.9 g, 53.0 mmol)
in MeOH was treated with DABCO (11.9 g, 106 mmol) and
Wilkinsons catalyst (2.45 g, 2.65 mmol) and stirred at reflux
for 2 h. The reaction mixture was concentrated to a brown oil,
which was dissolved in ethyl acetate (500 mL) and washed
successively with 2 M HCl, H2O, and brine (200 mL each),
dried over MgSO4, filtered, and concentrated. Flash column
chromatography (1:1 ethyl acetate/pentane) then trituration
with pentane gave 9.5 g (60%) of 23a as a white solid, mp 118-
The following compounds were similarly prepared:
[R,S]-[2-Cya n o-5-(th iop h en -3-yl)m eth oxy]p h en oxyfu -
r a n -2-yla cetic Acid 13k . Obtained as a brown solid, mp 85-7
°C (flash column with solvent gradient of 2% to 20% MeOH in
1
1
21 °C. H NMR (CDCl3): δ 7.61 (dd, J ) 8, 2 Hz, 1H), 7.39 (d,
CH2Cl2). H NMR (CDCl3): δ 7.47 (d, J ) 8 Hz, 1H), 7.44 (m,
J ) 9 Hz, 1H), 7.27 (m, 1H), 7.21 (td, J ) 8, 2 Hz, 2H), 6.52
(dd, J ) 8, 2 Hz, 1H), 6.37 (d, J ) 2 Hz, 1H), 5.86 (s, 1H), 3.73
(s, 3H), 2.49 (s, 3H). Anal. (C17H15NO4) C, H, N.
1H), 7.35 (dd, J ) 5, 3 Hz, 1H), 7.32 (m, 1H), 7.11 (dd, J ) 5,
1 Hz, 1H), 6.63 (dd, J ) 9, 3 Hz, 1H), 6.59 (d, J ) 3 Hz, 1H),
6.56 (d, J ) 3 Hz, 1H), 6.38 (m, 1H), 5.73 (s, 1H), 5.06 (s, 2H).
Anal. (C18H13NO5S) C, H, N.
(iv) [R,S]-Met h yl (5-Ben zyloxy-2-cya n o)p h en oxy-(2-
m eth yl)p h en yla ceta te 19b. This was prepared by alkylation
of 23a following the method for 19a and obtained as an off-
white solid, mp 134-6 °C (trituration with pentane/ethyl
[R,S]-[2-Cya n o-5-(p yr id -4-yl)m eth oxy]p h en oxyth ien -3-
yla cetic Acid 13l. Obtained as a white solid, mp 179-80 °C
(recrystallized from ethyl acetate/cyclohexane). 1H NMR
(CDCl3): δ 8.64 (d, J ) 6 Hz, 2H), 7.60 (m, 1H), 7.53 (d, J )
8 Hz, 1H), 7.34 (m, 4H), 6.62 (dd, J ) 8, 2 Hz, 1H), 6.55 (d, J
) 2 Hz, 1H), 5.76 (s, 1H), 5.12 (s, 2H). IR (KBr): 3433.3 (m),
2219.8 (m), 1722.2 (m), 1606.2 (s) cm-1. Anal. (C19H14N2O4S)
C, H, N.
[R,S]-[5-(Ben zo(1,3)d ioxol-5-yl)m eth oxy-2-cya n o]p h e-
n oxy-(2-m eth yl)p h en yla cetic Acid 14c. Obtained as a
white solid, mp 124-5 °C (flash column with solvent gradient
of 1:1 ethyl acetate/pentane to ethyl acetate). 1H NMR
(CDCl3): δ 7.63 (dd, J ) 7, 3 Hz, 1H), 7.49 (d, J ) 9 Hz, 1H),
7.38 (m, 2H), 7.21 (dd, J ) 7, 3 Hz, 1H), 6.84 (s, 1H), 6.80 (m,
1
acetate). H NMR (CDCl3): δ 7.64 (m, 1H), 7.51 (d, J ) 8 Hz,
1H), 7.39 (m, 5H), 7.30 (m, 2H), 7.21 (m, 1H), 6.63 (d, J ) 8
Hz, 1H), 6.46 (s, 1H), 5.83 (s, 1H), 5.06 (s, 2H), 3.72 (s, 3H),
2.49 (s, 3H).
(v) [R,S]-(5-Ben zyloxy-2-cya n o)p h en oxy-(2-m et h yl)-
p h en yla cetic Acid 14a . This was prepared by hydrolysis of
19b following the method for 13a and obtained as a white
solid, mp 128-30 °C (flash chromatography with 5% MeOH
in CH2Cl2 then trituration with diethyl ether/pentane). 1H
NMR (CDCl3): δ 7.63 (dd, J ) 7, 3 Hz, 1H), 7.50 (d, J ) 9 Hz,
1H), 7.34 (m, 5H), 7.28 (m, 2H), 7.22 (td, J ) 6, 2 Hz, 1H),