5598 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 17
Shi et al.
5-{3-[2-Chloro-4-(trifluoromethyl)phenoxy]propoxy}-
2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid (33).
The title compound was prepared according to general proce-
1H NMR (500 MHz, CDCl3) δ 7.30 (d, J ) 2.5 Hz, 1H), 7.12
(dd, J ) 9.0, 2.5 Hz, 1H), 7.00 (d, J ) 9.0 Hz, 1H), 6.83 (d, J
) 2.5 Hz, 1H), 6.81 (d, J ) 9.0 Hz, 1H), 6.78 (dd,, J ) 9.0, 2.5
Hz, 1H), 4.36 (t, J ) 6.5 Hz, 2H), 4.14 (t, J ) 6.5 Hz, 2H), 3.56
(d, J ) 16.5 Hz, 1H), 3.33 (d, J ) 16.5 Hz, 1H), 2.32 (m, 1H),
1.09 (d, J ) 7.0 Hz, 3H), 1.02 (d, J ) 7.0 Hz, 3H). MS (ESI,
m/z) 460.1 (M+). Anal. (C21H20ClF3O6) C, H.
1
dure C employing phenol 11c and iodide 20g. H NMR (500
MHz, CD3OD) δ 7.66 (d, J ) 2.0 Hz, 1H), 7.56 (dd, J ) 9.0,
2.0 Hz, 1H), 7.23 (d, J ) 9.0 Hz, 1H), 6.80 (d, J ) 2.5 Hz, 1H),
6.71 (dd, J ) 8.5, 2.5 Hz, 1H), 6.68 (d, J ) 8.5 Hz, 1H), 4.31 (t,
J ) 6.0 Hz, 2H), 4.14 (t, J ) 6.0 Hz, 2H), 3.48 (d, J ) 16.5 Hz,
1H), 3.16 (d, J ) 16.5 Hz, 1H), 2.29-2.24 (m, 2H), 2.08-2.00
(m, 1H), 1.97-1.90 (m, 1H), 0.99 (t, J ) 7.5 Hz, 3H). MS (ESI,
m/z) 445.8 (MH+). Anal. (C21H20ClF3O5) C, H.
5-(3-{2-Chloro-4-[(trifluoromethyl)thio]phenoxy}-
propoxy)-2-ethyl-2,3-dihydro-1-benzofuran-2-carbox-
ylic acid (35). The title compound was prepared according to
general procedure C employing phenol 11c and iodide 20d.
1H NMR (500 MHz, CDCl3) δ 7.68 (d, J ) 2.0 Hz, 1H), 7.58
(dd, J ) 8.0, 2.0 Hz, 1H), 7.18 (d, 8.0 Hz, 1H), 6.79 (d, J ) 1.5
Hz, 1H), 6.70 (dd, J ) 9.0, 1.5 Hz, 1H), 6.67 (d, J ) 9.0 Hz,
1H), 4.29 (t, J ) 6.0 Hz, 2H), 4.13 (t, J ) 6.0 Hz, 2H), 3.47 (d,
J ) 16.5 Hz, 1H), 3.15 (d, J ) 16.5 Hz, 1H), 2.54 (m, 2H), 2.03
(dq, J ) 14.5, 7.5 Hz, 1H), 1.93 (dq, J ) 14.5, 7.5 Hz, 1H),
0.99 (t, J ) 7.5 Hz, 3H). MS (ESI, m/z) 499.1 (MNa+). Anal.
(C21H20ClF3O5S) C, H.
Acknowledgment. We gratefully acknowledge tech-
nical assistance from Neelam Sharma, John Ventre,
Chhabi Biswas, Nancy Hayes, Xiaodong Gan and Marc
Ippolito and large scale synthetic support from Joseph
Leone, Derek Von Langen and Philip Eskola. We also
thank Nancy Tsou and Richard G. Ball for X-ray
crystallographic analysis.
Supporting Information Available: Preparation of an
oxazolinone amide derivation of the R-enantiomer of phenol
11c and its X-ray crystallographic data. This material is
5-{3-[2-Chloro-4-(2,2-dimethylpropyl)phenoxy]pro-
poxy}-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid
(36). The title compound was prepared according to general
procedure C employing phenol 11c (S-isomer) and iodide 20h.
1H NMR (500 MHz, CDCl3) δ 7.11 (d, J ) 1.5 Hz, 1H), 6.98
(dd, J ) 8.0, 1.5 Hz, 1H), 6.95 (d, J ) 8.0 Hz, 1H), 6.79 (d, J
) 2.0 Hz, 1H), 6.70 (dd, J ) 8.5, 2.0 Hz, 1H), 6.67 (d, J ) 8.5
Hz, 1H), 4.17 (t, J ) 6.0 Hz, 2H), 4.12 (t, J ) 6.0 Hz, 2H), 3.48
(d, J ) 16.5 Hz, 1H), 3.15 (d, J ) 16.5 Hz, 1H), 2.20 (m, 2H),
2.02 (dq, J ) 14.5, 7.5 Hz, 1H), 1.93(dq, J ) 14.5, 7.5 Hz, 1H),
0.99 (t, J ) 7.5 Hz, 3H), 0.88 (s, 9H). MS (ESI, m/z) 447.2
(MH+). Anal. (C25H31ClO5) C, H.
(2S)-5-{3-[2-Chloro-4-(2,2,2-trifluoroethyl)phenoxy]pro-
poxy}-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid
(37). The title compound was prepared according to general
procedure C employing phenol 11c (S-isomer) and iodide 20b.
1H NMR (500 MHz, CD3OD) δ 7.35 (d, J ) 2.0 Hz, 1H), 7.21
(dd, J ) 8.5, 2.0 Hz, 1H), 7.06 (d, J ) 8.5 Hz, 1H), 6.80 (d, J
) 2.0 Hz, 1H), 6.70 (dd, J ) 8.5, 2.0 Hz, 1H), 6.68 (d, J ) 8.5
Hz, 1H), 4.22 (t, J ) 6.5 Hz, 2H), 4.14 (t, J ) 6.5 Hz, 2H), 3.48
(d, J ) 16.0 Hz, 1H), 3.48 (q, J ) 11.0 Hz, 2H), 3.16 (d, J )
16.0 Hz, 1H), 2.23 (m, 2H), 2.03 (dq, J ) 14.0, 7.5 Hz, 1H),
1.93 (dq, J ) 14.0, 7.5 Hz, 1H), 0.99 (t, J ) 7.5 Hz, 3H). MS
(ESI, m/z): 481.0 (MNa+). Anal. (C22H22ClF3O5) C, H.
(2S)-5-{3-[2-Chloro-4-(3,3,3-trifluoropropyl)phenoxy]-
propoxy}-2-ethyl-2,3-dihydro-1-benzofuran-2-carbox-
ylic acid (38). The title compound was prepared according to
general procedure C employing phenol 11c (S-isomer) and
iodide 20f. 1H NMR (500 MHz, CD3OD) δ 7.26 (d, J ) 2.5 Hz,
1H), 7.11 (dd, J ) 8.5, 2.5 Hz, 1H), 6.70 (d, J ) 8.5 Hz, 1H),
6.79 (m, 1H), 6.71-6.66 (m, 2H), 4.18 (t, J ) 6.0 Hz, 2H), 4.12
(t, J ) 6.0 Hz, 2H), 3.47 (d, J ) 16.0 Hz, 1H), 3.15 (d, J ) 16.0
Hz, 1H), 2.80-2.77 (m, 2H), 2.47-2.37 (m, 2H), 2.24-2.18 (m,
2H), 2.04 (dq, J ) 14.0, 7.5 Hz, 1H), 1.93 (dq, J ) 14.0, 7.5
Hz, 1H), 0.99 (t, J ) 7.5 Hz, 3H). MS (ESI, m/z): 495.1 (MNa+).
Anal. (C23H24ClF3O5) C, H.
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6-{3-[2-Chloro-4-(trifluoromethoxy)phenoxy]propoxy}-
2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid (40).
The title compound was prepared according to general proce-
1
dure C employing phenol 11e and iodide 20c. H NMR (500
MHz, CD3OD) δ 7.32 (d, J ) 2.0 Hz, 1H), 7.19 (dd, J ) 8.5,
2.0 Hz, 1H), 7.13 (d, J ) 8.5 Hz, 1H), 6.99 (d, J ) 9.0 Hz, 1H),
6.41-6.46 (m, 2H), 4.23 (t, J ) 6.0 Hz, 2H), 4.15 (t, J ) 6.0
Hz, 2H), 3.42 (d, J ) 16.5 Hz, 1H), 3.11 (d, J ) 16.5 Hz, 1H),
2.23 (m, 2H), 2.03 (dq, J ) 14.5, 7.5 Hz, 1H), 1.94 (dq, J )
14.5, 7.5 Hz, 1H), 0.99 (t, J ) 7.5 Hz, 3H). MS (ESI, m/z) 461.2
(MH+). Anal. (C21H20ClF3O6) C, H.
5-{2-[2-Chloro-4-(trifluoromethoxy)phenoxy]ethoxy}-
2-isopropyl-2,3-dihydro-1-benzofuran-2-carboxylic acid
(41). The title compound was prepared according to general
procedure C employing phenol 11f (R-isomer) and iodide 20i.