1676 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Anderson et al.
1.06 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.35-2.78 (m, 6H), 3.25-
3.47 (m, 2H), 3.52-3.70 (m, 1H), 3.78-3.95 (m, 2H); IR (KBr)
3447, 1704 cm-1. Anal. (C28H45NO4) C, H, N.
δ 0.60 (s, 3H, CH3), 0.85 (s, 3H, CH3), 1.15 (d, 3H, J ∼ 7, CH3),
2.13 (s, 3H, CH3), 2.45-2.78 (m, 5H), 3.30-3.80 (m, 3H), 3.80-
3.95 (m, 2H); IR (KBr) 3470, 1700 cm-1. Anal. (C26H43NO3)
C, H, N.
(2â,3r,5r)-3-Hyd r oxy-2-[(2S)-2-p r op yl-4-m or p h olin yl]-
p r egn a n e-11,20-d ion e (14):25d crystallized from methanol
(3%); mp 107-110 °C; [R]D +131.6° (c 0.4); 1H NMR (CDCl3) δ
0.57 (s, 3H, CH3), 0.90 (t, 3H, J ∼ 7, CH3), 1.05 (s, 3H, CH3),
2.10 (s, 3H, CH3), 3.30-3.65 (m, 3H), 3.75-3.95 (m, 2H); IR
(2â,3r,5r)-2-[(2R)-2-E t h yl-4-m or p h olin yl]-3-h yd r oxy-
p r egn a n -20-on e (26):25c crystallized from acetone (13%); mp
1
190-192 °C; [R]D +151.8° (c 0.9); H NMR (CDCl3) δ 0.62 (s,
3H, CH3), 0.85 (s, 3H, CH3), 0.95 (t, 3H, J ∼ 7, CH3), 2.12 (s,
(KBr) 3464, 1702 cm-1
N.
. Anal. (C28H45NO4‚0.4MeOH) C, H,
3H, CH3), 2.42-2.75 (m, 5H), 3.23-3.75 (m, 3H), 3.80-3.97
(m, 2H); IR (CH2Cl2) 3600, 3470, 1699 cm-1. Anal. (C27H45
NO3) C, H, N.
-
(2â,3r,5r)-3-Hyd r oxy-2-[(2R)-2-(p h en ylm eth yl)-4-m or -
p h olin yl]p r egn a n e-11,20-d ion e (15):25e crystallized from
(2â,3r,5r)-2-[(2S)-2-Eth yl-4-m or ph olin yl]-3-h ydr oxypr eg-
1
ether (11%); mp 170-171.5 °C; [R]D +91.6° (c 0.6); H NMR
n a n -20-on e (27):25c crystallized from acetone (8%); mp 120.5-
1
(CDCl3) δ 0.57 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.11 (s, 3H, CH3),
3.32 (br s, 1H, OH), 7.10-7.35 (m, 5H); IR (KBr) 3532, 1703
cm-1. Anal. (C32H45NO4) C, H, N.
122 °C; [R]D +156.6° (c 0.6); H NMR (CDCl3) δ 0.60 (s, 3H,
CH3), 0.85 (s, 3H, CH3), 0.94 (t, 3H, J ∼ 7, CH3), 2.12 (s, 3H,
CH3), 2.45-2.75 (m, 5H), 3.30-3.70 (m, 3H), 3.78-3.95 (m,
2H); IR (CH2Cl2) 3600, 3432, 1699 cm-1. Anal. (C27H45NO3)
C, H, N.
(2â,3r,5r)-3-Hyd r oxy-2-[(2S)-2-(p h en ylm eth yl)-4-m or -
p h olin yl]p r egn a n e-11,20-d ion e (16):25e crystallized from
methanol (18%); mp 160-161.5 °C; [R]D +159° (c 0.6); 1H NMR
(CDCl3) δ 0.57 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.11 (s, 3H, CH3),
3.34 (br s, 1H, OH), 7.12-7.35 (m, 5H); IR (KBr) 3507, 1705,
1695 cm-1. Anal. (C32H45NO4) C, H, N.
(2â,3r,5r)-3-Hyd r oxy-2-(2,2-d im et h yl-4-m or p h olin yl)-
p r egn a n -20-on e (28):25a crystallized from methanol (41%); mp
1
183-186 °C; [R]D +153.0° (c 0.7); H NMR (CDCl3) δ 0.61 (s,
3H, CH3), 0.87 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.26 (s, 3H,
(2â,3r,5r)-3-Hyd r oxy-2-[(2R)-2-(1-m eth yleth yl)-4-m or -
p h olin yl]p r egn a n e-11,20-d ion e (17):25f crystallized from
diethyl ether/heptane (34%); mp 149-153 °C; [R]D +121.4° (c
CH3), 2.12 (s, 3H, CH3), 3.28 (br s, 1H, OH), 3.65-3.80 (m,
2H), 3.80-3.95 (m, 1H); IR (KBr) 3519, 1702 cm-1
. Anal.
(C27H45NO3) C, H, N.
1
0.5); H NMR (CDCl3) δ 0.57 (s, 3H, CH3), 0.95 (br t, 6H, J ∼
(2â,3r,5r)-3-H yd r oxy-2-(4-t h iom or p h olin yl)p r egn a n -
20-on e (29): crystallized from acetone/petroleum ether (15%);
mp 198-199 °C; [R]D +166.1° (c 0.5); 1H NMR (CDCl3) δ 0.61
(s, 3H, CH3), 0.82 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.84-3.07
(m, 2H), 3.63 (br s, 1H, OH), 3.75-3.90 (m, 1H); IR (KBr) 3495,
1705 cm-1. Anal. (C25H41NO2S) C, H, N; S, calcd 7.64; found
8.07.
Conversion of this free base to the methanesulfonate (1:1)
salt in methanol gave, after removal of the solvent under
reduced pressure and precipitation from dry diethyl ether, an
7, 2 × CH3), 1.07 (s, 3H, CH3), 2.11 (s, 3H, CH3), 3.05-3.18
(m, 1H), 3.34 (br s, 1H, OH), 3.50-3.70 (m, 1H), 3.80-3.97
(m, 2H); IR (KBr) 3451, 1702 cm-1. Anal. (C28H45NO4) C, H,
N.
(2â,3r,5r)-3-Hyd r oxy-2-{(2R)-2-[(1S)-1-m eth ylp r op yl]-
4-m or p h olin yl}p r egn a n e-11,20-d ion e (18):25g crystallized
from diethyl ether/heptane (51%); mp 131-135 °C; [R]D
1
+118.8° (c 0.6); H NMR (CDCl3) δ 0.57 (s, 3H, CH3), 0.85-
0.97 (m, 6H), 1.07 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.40-2.75
(m, 7H), 3.20-3.28 (m, 1H), 3.37 (br s, 1H, OH), 3.55-3.65
analytically pure sample: [R]D +116.4° (c 0.7). Anal. (C26H45
NO5S2‚0.7H2O) C, H, N, S.
-
(m, 1H), 3.83-3.92 (m, 2H); IR (KBr) 3490, 1703, 1700 cm-1
Anal. (C29H47NO4) C, H, N.
.
(2â,3r,5r)-3-Hyd r oxy-2-(4-th iom or p h olin yl)p r egn a n e-
11,20-d ion e (30): crystallized from methanol (34%); mp
216.5-218 °C; [R]D +156.1° (c 0.8); 1H NMR (CDCl3) δ 0.57 (s,
3H, CH3), 1.01 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.88-3.06 (m,
2H), 3.68 (br s, 1H, OH), 3.75-3.92 (m, 1H); IR (KBr) 3470,
1693 cm-1. Anal. (C25H39NO3S) C, H, N, S.
(2â,3r,5r)-3-H yd r oxy-2-(2,2-d im et h yl-4-t h iom or p h o-
lin yl)p r egn a n -20-on e (31):25l crystallized from methanol
(22%); mp 184-185 °C; [R]D -96.2° (c 0.9); 1H NMR (CDCl3) δ
0.59 (s, 3H, CH3), 0.82 (s, 3H, CH3), 1.34 (s, 6H, CH3), 2.12 (s,
3H, CH3), 3.65 (br s, 1H, OH), 3.73-3.92 (m, 1H); IR (KBr)
3454, 1700 cm-1. Anal. (C27H45NO2S) C, H, N, S.
(2â,3r,5r)-2-(2,2-Dieth yl-4-m or ph olin yl)-3-h ydr oxypr eg-
n a n e-11,20-d ion e (20):25h crystallized from diethyl ether
(52%); mp 178-180 °C; [R]D +123.8° (c 0.6); 1H NMR (CDCl3)
δ 0.57 (s, 3H, CH3), 0.75-0.90 (m, 6H), 1.06 (s, 3H, CH3), 2.10
(s, 3H, CH3), 3.28 (br s, 1H, OH), 3.60-3.80 (m, 2H), 3.80-
3.93 (m, 1H); IR (KBr) 3547, 1695 cm-1. Anal. (C29H47NO4)
C, H, N.
(2â,3r,5r)-2-(2,2-Dibu tyl-4-m or ph olin yl)-3-h ydr oxypr eg-
n a n e-11,20-d ion e (21):25i crystallized from diethyl ether
(28%); mp 159.5-162.5 °C; [R]D +109.2° (c 0.5); 1H NMR
(CDCl3) δ 0.57 (s, 3H, CH3), 0.80-1.00 (m, 6H), 1.06 (s, 3H,
CH3), 2.11 (s, 3H, CH3), 3.33 (br s, 1H, OH), 3.57-3.80 (m,
2H), 3.80-3.93 (m, 1H); IR (KBr) 3485, 1703, 1687 cm-1. Anal.
(C33H55NO4) C, H, N.
(2â,3r,5r)-3-H yd r oxy-2-(2,2-d im et h yl-4-t h iom or p h o-
lin yl)p r egn a n e-11,20-d ion e (32):25l crystallized from metha-
nol/dichloromethane (19%); mp 201.5-203 °C; [R]D +149.7° (c
1
(2â,3r,5r)-3-Hyd r oxy-2-(2,2-d ip h en yl-4-m or p h olin yl)-
p r egn a n e-11,20-d ion e (22):25j crystallized from methanol
(11%); mp 248-250 °C; [R]D +166.2° (c 0.7); 1H NMR (CDCl3)
δ 0.55 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.90-
3.30 (m, 2H), 3.35 (br s, 1H, OH), 3.55-3.75 (m, 1H), 3.75-
0.6); H NMR (CDCl3) δ 0.57 (s, 3H, CH3), 1.01 (s, 3H, CH3),
1.32 (s, 3H, CH3), 1.33 (s, 3H, CH3), 2.11 (s, 3H, CH3), 3.67 (br
s, 1H, OH), 3.76-3.93 (m, 1H); IR (KBr) 3486, 1698 cm-1. Anal.
(C27H43NO3S) C, H, N, S.
(2â,3r,5r)-3-Hyd r oxy-2-(2,2,6,6-tetr a m eth yl-4-th iom or -
p h olin yl)p r egn a n e-11,20-d ion e (33):25m crystallized from
ethanol (15%); mp 151-153 °C; [R]D +142.5° (c 1.0); 1H NMR
(CDCl3) δ 0.58 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.32 (s, 6H, CH3),
1.36 (s, 6H, 2 × CH3), 2.11 (s, 3H, CH3), 2.18-2.31 (m, 1H),
2.38-2.51 (m, 3H), 2.65-2.78 (m, 5H), 3.67 (br s, 1H, OH),
3.95 (m, 2H), 7.15-7.45 (m, 10H); IR (KBr) 3490, 1694 cm-1
Anal. (C37H47NO4) C, H, N.
.
(2â,3r,5r)-3-H yd r oxy-2-(2,2,6,6-t e t r a m e t h yl-4-m or -
p h olin yl)p r egn a n e-11,20-d ion e (23):25k crystallized from
acetone/hexane (6%); mp 212-215 °C; [R]D +126.8° (c 0.5); 1H
NMR (CDCl3) δ 0.58 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.22 (s,
3H, CH3), 1.25 (s, 3H, CH3), 2.11 (s, 3H, CH3), 3.48 (br s, 1H,
3.83-3.94 (m, 1H); IR (KBr) 3470, 1705 cm-1. Anal. (C29H47
NO3S) C, H, N, S.
-
OH), 3.80-3.97 (m, 1H); IR (KBr) 3556, 1701 cm-1
(C29H47NO4) C, H, N.
. Anal.
(2â,3r,5r)-3,21-Dih yd r oxy-2-(4-m or p h olin yl)p r egn a n -
20-on e (34). To a stirred suspension of (2â,3R,5R)-21-(acetyl-
oxy)-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (35) (10.0 g,
21.7 mmol) in methanol (100 mL), under nitrogen, was added
a saturated solution of potassium carbonate in methanol (100
mL, 0.2 M). After 20 min the reaction mixture was poured
into aqueous sodium chloride (2 L). The precipitated solid was
filtered off and dissolved in dichloromethane, and the solution
was dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the solid residue was
chromatographed on silica gel (gradient elution, dichlo-
romethane/diethyl ether/methanol).
(2â,3r,5r)-3-Hyd r oxy-2-[(2R)-2-m eth yl-4-m or p h olin yl]-
p r egn a n -20-on e (24):25c crystallized from ethanol (13%); mp
1
196-198 °C; [R]D +151.5° (c 0.8); H NMR (CDCl3) δ 0.60 (s,
3H, CH3), 0.84 (s, 3H, CH3), 1.14 (d, 3H, J ∼ 7, CH3), 2.12 (s,
3H, CH3), 2.42-2.75 (m, 5H), 3.40-3.75 (m, 3H), 3.80-3.95
(m, 2H); IR (KBr) 3470, 1693 cm-1. Anal. (C26H43NO3) C, H,
N.
(2â,3r,5r)-3-Hyd r oxy-2-[(2S)-2-m eth yl-4-m or p h olin yl]-
p r egn a n -20-on e (25):25c crystallized from diethyl ether/hex-
ane (3%); mp 163-167 °C; [R]D +160° (c 1.0); 1H NMR (CDCl3)