82 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Upasani et al.
and 22. The crude compound was purified by column chro-
matography on silica gel. Elution with hexane:acetone mix-
ture (4:1) gave the product as a colorless solid, which was found
to be identical to 18 (TLC Rf, mp, NMR).
(toluene:acetone, 95:5); mp 208-210 °C; 1H NMR (CDCl3) δ
7.35 (d, 2H, J ) 7.4 Hz), 7.11 (d, 2H, J ) 7.4 Hz), 2.52 (m,
1H), 2.35 (s, 3H), 2.12 (s, 3H), 0.98 (s, 3H), 0.60 (s, 3H). Anal.
(C30H40O2) C, H.
3â-[(3,4-Dim eth oxyph en yl)eth yn yl]-3r-h ydr oxy-5â-pr eg-
n a n -20-on e (19). This compound was prepared in 45% yield
in a manner analogous to the preparation of 10 starting from
2,2-dibromo-1-(3,4-dimethoxyphenyl)ethene23 (obtained by the
Wittig reaction of 3,4-dimethoxybenzaldehyde with carbon
tetrabromide in the presence of triphenylphosphine) and 2.
The crude compound was purified by column chromatography
on silica gel. Elution with toluene:acetone mixture (96:4) gave
a phenylacetylene compound, which was not characterized.
Further elution with the same solvent yielded 3R-[(3′,4′-
dimethoxyphenyl)ethynyl]-3â-hydroxy-5â-pregnan-20-one (11%)
as a first fraction and 3â-[(3′,4′-dimethoxyphenyl)ethynyl]-3R-
hydroxy-5â-pregnan-20-one as a second fraction (45%): TLC
Rf 0.18 (hexane:acetone, 4:1); mp 82-88 °C; IR 2929, 2867,
2361, 1697 cm-1; 1H NMR (CDCl3) δ 7.05 (dd, 1H, J ) 1.8 and
8.3 Hz), 6.91 (d, 1H, J ) 1.8 Hz), 6.78 (d, 1H, J ) 8.3 Hz),
3.89 (s, 6H), 2.52 (m, 1H), 2.12 (s, 3H), 0.99 (s, 3H), 0.61 (s,
3H). Anal. (C31H42O4) C, H.
3â-[(4-Am in op h en yl)eth yn yl]-3r-h yd r oxy-5â-p r egn a n -
20-on e (26). This compound was prepared in 60% yield in a
manner analogous to the preparation of 23 starting from
4-iodoaniline and 22. The crude compound was purified by
column chromatography on silica gel. Elution with hexane:
acetone mixture (4:1) gave 26 as a pale yellow solid: TLC Rf
0.22 (hexane:acetone, 95:5); mp 203-207 °C dec; IR 3441, 3352,
1
2923, 2859, 2345, 1686 cm-1; H NMR (CDCl3) δ 7.25 (d, 2H,
J ) 8.4 Hz), 6.58 (d, 2H, J ) 8.4 Hz), 3.80 (bs, 2H), 2.52 (m,
1H), 2.11 (s, 3H), 0.97 (s, 3H), 0.60 (s, 3H). Anal. (C29H39
NO2) C, H, N.
-
3r-Hyd r oxy-3â-[[4-(t r iflu or om et h yl)p h en yl]et h yn yl]-
5â-p r egn a n -20-on e (27). This compound was prepared in
31% yield in a manner analogous to the preparation of 23
starting from 4-(trifluoromethyl)iodobenzene and 22. The
crude compound was purified by column chromatography on
silica gel. Elution with toluene:acetone mixture (95:5) gave
27 as a colorless solid: TLC Rf 0.23 (toluene:acetone, 95:5);
3r-Hydr oxy-3â-[[3,4-(m eth ylen edioxy)ph en yl]eth yn yl]-
5â-p r egn a n -20-on e (20). Meth od A. This compound was
prepared in 65% yield in a manner analogous to the prepara-
tion of 10 starting from 2,2-dibromo-1-[3′,4′-(methylenedioxy)-
phenyl]ethene (obtained by the Wittig reaction of 3,4-(meth-
ylenedioxy)benzaldehyde with carbon tetrabromide in the
presence of triphenylphosphine) and 2. The crude compound
was purified by column chromatography on silica gel (toluene:
acetone, 95:5): TLC Rf 0.43 (hexane:acetone, 7:3); mp 188-
mp 201-203 °C; IR 2922, 2863, 2358, 1688, 1312 cm-1 1H
;
NMR (CDCl3) δ 7.58 (d, 2H, J ) 7 Hz), 7.52 (d, 2H, J ) 7 Hz),
2.52 (m, 1H), 2.12 (s, 3H), 0.99 (s, 3H), 0.61 (s, 3H). Anal.
(C30H37F3O2) C, H, F.
3â-[(4-Acetylp h en yl)eth yn yl]-3r-h yd r oxy-5â-p r egn a n -
20-on e (28). This compound was prepared in 51% yield in a
manner analogous to the preparation of 23 starting from
4-iodoacetophenone and 22. The crude compound was purified
by column chromatography on silica gel. Elution with hexane:
acetone mixture (7:3) gave 28 as a colorless solid: TLC Rf 0.40
(toluene:acetone, 9:1); mp 192-194 °C; IR 2935, 2858, 2360,
1700, 1683 cm-1; 1H NMR (CDCl3) δ 7.91 (d, 2H, J ) 8.1 Hz),
7.51 (d, 2H, J ) 8.1 Hz), 2.60 (s, 3H), 2.52 (m, 1H), 2.12 (s,
3H), 0.99 (s, 3H), 0.61 (s, 3H). Anal. (C31H40O3) C, H.
3â-[(4-Car beth oxyph en yl)eth yn yl]-3r-h ydr oxy-5â-pr eg-
n a n -20-on e (29). This compound was prepared in 68% yield
in a manner analogous to the preparation of 23 starting from
4-iodobenzoic acid ethyl ester and 22. The crude compound
was purified by column chromatography on silica gel. Elution
with hexane:acetone mixture (4:1) gave 29 as a colorless
solid: TLC Rf 0.31 (hexane:acetone, 4:1); mp 164-166 °C; IR
1
191 °C; IR 2929, 2868, 2361, 1697 cm-1; H NMR (CDCl3) δ
6.98 (d, 1H, J ) 7.95 Hz), 6.88 (s, 1H), 6.73 (d, 1H, J ) 7.95
Hz), 5.97 (s, 2H), 2.52 (m, 1H), 2.12 (s, 3H), 0.98 (s, 3H), 0.60
(s, 3H). Anal. (C30H38O4) C, H.
Meth od B. Alternatively, this compound was prepared in
30% yield in a manner analogous to the preparation of 23 (see
below) by the Pd-catalyzed coupling reaction of 4-bromo-1,2-
(methylenedioxy)benzene and 22. The crude compound was
purified by column chromatography on silica gel. Elution with
hexane:acetone mixture (7:3) gave the product as a colorless
solid, which was found to be identical to 20 (TLC Rf, mp,
NMR).
1
2922, 2871, 2347, 1717, 1700 cm-1; H NMR (CDCl3) δ 8.01
3â-(2-Hyd r oxyp h en yleth yn yl)-3r-h yd r oxy-5â-p r egn a n -
20-on e (23).A solution of 2-iodophenol (96 mg, 0.44 mmol) and
3â-ethynyl-3R-hydroxy-5â-pregnan-20-one (227, 150 mg, 0.44
mmol) in dry degassed triethylamine (0.5 mL) was stirred
under argon at room temperature. Bis(triphenylphosphine)-
palladium chloride (5 mg) and CuI (5 mg) were added, and
the mixture was stirred at this temperature for 45 min. CH2-
Cl2 (5 mL) was added, and the stirring was continued for
another hour. The TLC showed 100% conversion of the
starting material; hence, the solvent was removed and the
residue was purified by chromatography on silica gel. Elution
with hexane:EtOAc (4:1) gave 23 (40 mg) as a colorless solid;
TLC Rf 0.34 (toluene:acetone, 95:5); mp 210-212 °C; IR 3427,
(d, 2H, J ) 8.1 Hz), 7.49 (d, 2H, J ) 8.1 Hz), 4.39 (m, 2H),
2.52 (m, 1H), 2.12 (s, 3H), 1.42 (m, 3H), 0.99 (s, 3H), 0.61 (s,
3H). Anal. (C32H42O4) C, H.
3â-[(4-F or m ylp h en yl)eth yn yl]-3r-h yd r oxy-5â-p r egn a n -
20-on e (30). This compound was prepared in 25% yield in a
manner analogous to the preparation of 23 starting from
4-bromobenzaldehyde and 22. Triethylamine was replaced
with diethylamine. The crude compound was purified by
column chromatography on silica gel. Elution with hexane:
acetone mixture (7:3) gave 30 as a colorless solid: TLC Rf 0.18
(hexane:acetone, 4:1); mp 212-215 °C; IR 2922, 2858, 2347,
1694, 1684 cm-1 1H NMR (CDCl3) δ 10.01 (s, 1H), 7.91 (d,
;
1
2929, 2868, 2359, 1697 cm-1; H NMR (CDCl3) δ 7.58 (d, 1H,
2H, J ) 8.1 Hz), 7.58 (d, 2H, J ) 8.1 Hz), 2.52 (m, 1H), 2.12
(s, 3H), 1.00 (s, 3H), 0.62 (s, 3H). Anal. (C30H38O3) C, H.
3â-[(3-Acetylp h en yl)eth yn yl]-3r-h yd r oxy-5â-p r egn a n -
20-on e (31). This compound was prepared in 58% yield in a
manner analogous to the preparation of 23 starting from
3-iodoacetophenone and 22. The crude compound was purified
by column chromatography on silica gel. Elution with hexane:
acetone mixture (4:1) gave 31 as a colorless solid: TLC Rf 0.22
(hexane:acetone, 4:1); mp 195-197 °C; IR 2927, 2859, 2361,
1699, 1684 cm-1; 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.91 (d, 1H,
J ) 7.7 Hz), 7.62 (d, 1H, J ) 7.9 Hz), 7.42 (dd, 1H, J ) 7.7
and 7.9 Hz), 2.62 (s, 3H), 2.54 (m, 1H), 2.12 (s, 3H), 0.99 (s,
3H), 0.61 (s, 3H). Anal. (C31H40O3) C, H.
J ) 7.5 Hz), 7.59 (d, 1H, J ) 8 Hz), 7.26 (m, 2H), 6.68 (s, 1H),
2.57 (m, 1H), 2.13 (s, 3H), 0.87 (s, 3H), 0.61 (s, 3H). Anal.
(C29H38O3) C, H.
3â-[(3-Hydr oxyph en yl)eth yn yl]-3r-h ydr oxy-5â-pr egn an -
20-on e (24). This compound was prepared in 25% yield in a
manner analogous to the preparation of 23 starting from
3-iodophenol and 22. The crude compound was purified by
column chromatography on silica gel. Elution with hexane:
acetone mixture (4:1) gave 24 as a colorless solid: TLC Rf 0.31
(toluene:acetone, 85:15); mp 208-213 °C; IR 3500, 2928, 2358,
1677 cm-1; 1H NMR (MeOH-d4) δ 7.15 (m, 1H), 6.70-6.95 (m,
3H), 2.68 (m, 1H), 2.16 (s, 3H), 1.05 (s, 3H), 0.65 (s, 3H). Anal.
(C29H38O3) C, H.
3r-Hyd r oxy-3â-[(4-m eth ylp h en yl)eth yn yl]-5â-p r egn a n -
20-on e (25). This compound was prepared in 46% yield in a
manner analogous to the preparation of 23 starting from
4-iodotoluene and 22. The crude compound was purified by
column chromatography on silica gel. Elution with hexane:
acetone mixture (7:3) gave 25 as a colorless solid: TLC Rf 0.25
3â-[[4-(N,N-Dieth ylca r ba m oyl)p h en yl]eth yn yl]-3r-h y-
d r oxy-5â-p r egn a n -20-on e (32). This compound was pre-
pared in 12% yield in a manner analogous to the preparation
of 23 starting from 4-iodo-N,N-diethylbenzamide and 22. The
crude compound was purified by column chromatography on
silica gel. Elution with hexane:acetone mixture (3:1) gave 32
as a colorless solid: TLC Rf 0.22 (hexane:acetone, 3:1); mp