Epalons: Synthesis of 7-norallopregnanolone

Article abstract of DOI:10.1135/cccc19991471

The title compound 2 was prepared from (20R)-pregn-5-ene-3β,20-diyl 3-acetate 20-benzoate (3) via (20R)-3β-acetoxy-20-benzoyloxy-5-oxo-5,6-secopregnan-6-oic acid (5) and (20R)-3β-acetoxy-20-benzoyloxy-7-nor-5β,6α-pregnane-6,5-carbolac tone (6). An intermediate 7-norpregn-5-ene derivative - (20R)-7-norpregn-5-ene-3β,20-diyl 3-acetate 20-benzoate (7) -was hydrogenated using diimide in statu nascendi. The inversion of configuration at carbon C-3 was carried out via (20R)-7-nor-5α-pregnane-3β,20-diyl 3-tosylate 20-benzoate (12) and (20R)-7-nor-5α-pregnane-3α,20-diyl 20-benzoate 3-formate (13).

Full text of DOI:10.1135/cccc19991471

On Steroids
1471
EPALONS: SYNTHESIS OF 7-NORALLOPREGNANOLONE*
Alexander KASAL
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: kasal@uochb.cas.cz
Received Jun e 24, 1999
Accepted August 18, 1999
Th e title com poun d 2 was prepared from (20R)-pregn -5-en e-3β,20-diyl 3-acetate 20-ben zoate
(3) via (20R)-3β-acetoxy-20-ben zoyloxy-5-oxo-5,6-secopregn an -6-oic acid (5) an d
(20R)-3β-acetoxy-20-ben zoyloxy-7-n or-5β,6α-pregn an e-6,5-carbolacton e (6). An in term ediate
7-n orpregn -5-en e derivative – (20R)-7-n orpregn -5-en e-3β,20-diyl 3-acetate 20-ben zoate (7) –
was h ydrogen ated usin g diim ide in statu nascendi. Th e in version of con figuration at carbon
C-3 was carried out via (20R)-7-n or-5α-pregn an e-3β,20-diyl 3-tosylate 20-ben zoate (12) an d
(20R)-7-n or-5α-pregn an e-3α,20-diyl 20-ben zoate 3-form ate (13).
Key w ord s: Steroids; 7-Norsteroids; Epalon ; 3α,5α-Tetrah ydroprogesteron e; GABAA-Modula-
tor; Mitsun obu reaction ; NMR spectroscopy, 1H.
Neurosteroids th at positively m odulate γ-am in obutyric acid receptors in th e
brain (e.g. 3α-h ydroxy-5α-pregn an -20-on e (1)) in duce an algesia, an aesth e-
sia, an xiolysis an d sleep2. Th ese com poun ds are assum ed to bin d relatively
open receptor sites by oxygen fun ction alities at carbon s 3 an d 20 wh ile th e
flat lipoph ilic m iddle part of th eir m olecule (rin gs B an d C) gets squeezed
in to a n arrow flat h ole with in th e receptor. In our search 3,4 for n ew an a-
COCH3
COCH3
HO
HO
1
2
H
H
logues of com poun d 1, we h ave tried to m odify th e steroid B rin g by m ak-
in g it even flatter wh ich sh ould h ave a better ch an ce of fin din g free space
with in th e receptor. Molecular m odellin g sh ows th at th e volum e of th e B
*
Part CDIII in th e series On Steroids; Part CDII see ref.1
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Kasal:
rin g of th e title com poun d 2 is m uch reduced in com parison with th e par-
en t com poun d 1, th ough som e addition al ch an ges are also in troduced in to
th e m olecule. Th e m olecule of its 7 n or an alogue 2 is sh orter th an th e origi-
n al: e.g. th e distan ce between oxygen atom s in position s 3 an d 20 is sh orter
in com poun d 2 th an in 1. Furth er, th e an gular m eth yl groups in th e form er
com poun d are n o lon ger attach ed to th e skeleton by parallel bon ds as th ey
are in com poun d 1, wh ere th e dih edral an gle C19–C10–C13–C18 is about 7°.
Startin g with (20R)-pregn -5-en e-3β,20-diyl 3-acetate 20-ben zoate (3, see
Sch em e 1), we produced a m ixture of correspon din g 5α,6α- an d 5β,6β-
OBz
OBz
H
H
AcO
AcO
3
4
HO
OH
OBz
OBz
H
H
H
AcO
O
COOH
AcO
5
6
O
O
OBz
OBz
H
H
AcO
AcO
7
9
O
OR2
O
H
R1
RO
H
H
8, R1= β-OAc; R2= Bz
10, R1= β-OH; R2= Bz
11, R1= α-OH; R2= Bz
12, R1= β-OTs; R2= Bz
13, R1= α-OCHO; R2= Bz
14, R1= α-OAcMEM; R2= Bz
15, R1= α-OMEM; R2= H
16, R = MEM
2, R = H
Bz = benzoyl
Ts = tosyl
MEM = CH2OCH2CH2OCH3
SCHEME 1
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On Steroids
1473
epoxides wh ich were cleaved by perch loric acid to a sin gle product –
5α,6β-diol 4. Its oxidation afforded seco acid 5 wh ich on action of ben zoyl
ch loride in pyridin e un derwen t con den sation to a 7-n orsteroid derivative 6.
By pyrolysis of th e β-lacton e 6 th e 7-n orpregn -5-en e derivative 7 was
form ed.
Catalytic h ydrogen ation 5 of 7-n orpregn -5-en e com poun ds leads m ain ly
to 5β-dih ydro derivatives. Th erefore, diim ide reduction 6,7 h ad to be em -
ployed in order to obtain th e target 5α-products. Heatin g of a m ixture of
alken e 7 an d tosylh ydrazin e in 2,4,6-trim eth ylpyridin e yielded th e 5α-
dih ydro product 8 (88%). Wh en a larger-scale experim en t was carried out,
th e yield was lower. Sin ce both com poun ds, 7 an d 8, are of th e sam e po-
larity, the rest of the starting alkene 7 was removed by oxidation8,9 to epoxide 9
an d subsequen t ch rom atograph y.
Partial h ydrolysis of diester 8 was ach ieved selectively by acid-catalyzed
tran sesterification in m eth an ol an d th e 3β-alcoh ol 10 produced was con -
verted10 in to its 3α-isom er 11 eith er via 3β-tosylate 12 by solvolysis or via
3α-form ate 13 by Mitsun obu reaction . Th e 3α-h ydroxy group was protected
by eth erification an d th e (2-m eth oxyeth oxy)m eth oxy derivative 14 was h y-
drolyzed an d oxidized to com poun ds 15 an d 16. On treatm en t with acid,
th e target 7-n orallopregn an olon e (2) was obtain ed in a total yield of 18%
(via 3α-form ate 13) an d 11.7% (via 3β-tosylate 12), respectively.
Iden tity of th e com poun ds prepared was ch ecked by IR an d 1H NMR
spectra. Th e open in g of th e B rin g was m an ifested am on g oth er sign s by th e
ch an ge of m ultiplicity of th e 3α-proton : due to th e loss of rigidity, caused
by th e A/B rin g jun ction , th e 3α-proton lost its axial n ature11 wh ich it re-
1
vealed in all oth er 5α-com poun ds. H NMR of th e β-lacton e 6 h ad a typical
doublet of th e 6α-proton at δ 3.19. All 3β-proton s in th e 7-n or-5α-steroids
prepared gave sign als of an equatorial proton . CD of th e β-lacton e 6 corre-
spon ded to th e ch aracteristics observed earlier12
.
Com poun d 2 was subm itted for biological screen in g (bin din g to GABAA
receptors) wh ose results will be publish ed elsewh ere.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a m icro m eltin g poin t apparatus Boetius (Germ an y) an d
are un corrected. An alytical sam ples were dried over ph osph orus pen toxide at 50 °C/100 Pa.
Optical rotation s were m easured in ch loroform ([α]D values are given in 10–1 deg cm 2 g–1),
IR spectra of ch loroform solution s were recorded on
a Bruker IFS 88 spectrom eter,
waven um bers are given in cm –1. NMR spectra were m easured on FT-NMR spectrom eter
Varian UNITY-200 (at 200 MHz) in CDCl3 with tetram eth ylsilan e as in tern al referen ce.
Ch em ical sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) an d width of m ultiplets
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Kasal:
(W ) in Hz. Un less oth erwise stated, th e data were in terpreted as th e first-order spectra.
Th in -layer ch rom atograph y (TLC) was perform ed on silica gel (ICN Bioch em icals), prepara-
tive TLC (PLC) was carried out on 200 × 200 m m plates coated with an 0.7 m m th ick layer
of th e sam e m aterial. For colum n ch rom atograph y, silica gel 60–120 µm was used. Wh en -
ever aqueous solution s of h ydroch loric acid, potassium h ydrogen carbon ate an d potassium
carbon ate are used, th eir con cen tration is always 5%. Prior to evaporation on a rotary evap-
orator in vacuum (bath tem perature 50 °C), solution s in organ ic solven ts were dried over an -
h ydrous sodium sulfate.
(20R)-5,6β-Dih ydroxy-5α-pregn an e-3β,20-diyl 3-Acetate 20-Ben zoate (4)
A solution of peracetic acid in acetic acid (21%, 40 m l, 110.5 m m ol) was added to a m ixture
of (20R)-pregn -5-en e-3β,20-diyl 3-acetate 20-ben zoate13 (3, 26.0 g, 55.7 m m ol) in ch loroform
(130 m l) an d sodium h ydrogen ph osph ate h eptah ydrate (14.0 g, 52.23 m m ol). Th e m ixture
was stirred at room tem perature for 5 h an d th en it was diluted with ch loroform , wash ed
with water an d th e potassium h ydrogen carbon ate solution an d water. Th e solven t was evap-
orated, th e residue was dissolved in a m ixture of dioxan e an d aceton e (2 : 1, 1 000 m l) an d
treated with aqueous perch loric acid (6%, 100 m l, 59.7 m m ol) at room tem perature. After
4 h , th e solution was con cen trated in vacuum to a quarter of its volum e an d com poun d 4
(24.8 g, 89%) precipitated on addition of brin e (100 m l). An an alytical sam ple crystallized
from m eth an ol at –60 °C; m .p. 123–126 °C, [α]D –40 (c 0.9). IR: 3 621, 3 595, 3 464, 1 049,
963 (OH); 1 709 (C=O); 1 603, 1 451, 1 119 (arom .); 1 263, 1 254, 1 049 (C–O). 1H NMR:
8.05 m , 2 H (H-2′ an d H-6′); 7.60 t, 1 H (J = 7.2, H-4′); 7.49 t, 2 H (J = 7.3, H-3′ an d H-5′);
5.14 m , 2 H (W = 44.0, H-3 an d H-20); 3.54 s, 1 H (W = 16, H-6); 2.02 s, 3 H (CH3CO);
1.26 d, 3 H (J = 6.1, H-21); 1.14 s, 3 H (3 × H-19); 0.68 s, 3 H (3 × H-18). For C30H42O6
(498.7) calculated: 72.26% C, 8.49% H; foun d: 72.19% C, 8.54% H.
(20R)-3β-Acetoxy-20-ben zoyloxy-5-oxo-5,6-secopregn an -6-oic Acid (5)
Jon es reagen t (2.4 m l, 2.63 m m ol) was added to a stirred solution of diol 4 (1.0 g, 2.0 m m ol)
in aceton e (30 m l) with in 1 h at 50 °C. After addition al 1 h at room tem perature, th e excess
of th e oxidizin g agen t was reduced by addition of m eth an ol (6 m l) an d th e solven t was
evaporated at 45 °C in vacuum . Th e dry residue was partition ed between eth er an d water,
com bin ed eth ereal extracts were wash ed with water an d passed th rough a colum n of an h y-
drous sodium sulfate an d silica gel. Eluates were con cen trated in vacuum to give 690 m g
(67%) of n on crystallin e acid 5; [α]D +63 (c 1.0). IR: 3 520 (COOH, m on om er); 2 864, 2 633,
2 561 (COOH, dim er); 1 732, 1 264, 1 252 (AcO); 1 706 (C=O); 1 603, 1 451, 1 277, 964
(ben zoate). 1H NMR: 8.06 d, 2 H (J = 7.7, H-2′ an d H-6′); 7.54 t, 1 H (J = 7.2, H-4′); 7.46 t,
2 H (J = 7.3, H-3′ an d H-5′); 5.39 m , 1 H (W = 23.0, H-3); 5.15 m , 1 H (W = 36, H-20); 3.22 dd,
1 H (J(3α,4α) = 4.3, J(4α,4β) = 18.5, H-4α); 2.01 s, 3 H (CH3CO); 1.26 d, 3 H (J = 6.1,
3 × H-21); 1.01 s, 3 H (3 × H-19); 0.70 s, 3 H (3 × H-18). For C30H40O7 (512.6) calculated:
70.29% C, 7.86% H; foun d: 70.21% C, 7.80% H.
(20R)-3β-Acetoxy-20-ben zoyloxy-7-n or-5β,6α-pregn an e-6,5-carbolacton e (6)
Oxo acid 5 (22.3 g, 43.5 m m ol) was dried by azeotropic distillation with toluen e, dissolved
in pyridin e (80 m l) an d th e solution was cooled to 0 °C. Ben zoyl ch loride (25 m l, 215.0
m m ol) was added an d th e m ixture was allowed to stan d at room tem perature. After 24 h , it
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On Steroids
1475
was poured on to ice (300 m l), th e precipitate was extracted with eth yl acetate (3 × 150 m l)
an d wash ed with a cold solution of sodium h ydroxide (0 °C, 2%) an d water. Th e solven t was
rem oved in vacuum an d ch rom atograph y of th e residue on silica gel (250 g, toluen e) yielded
th e β-lacton e 6 (19.4 g, 90%); [α]D +10 (c 1.2). Circular dich roism : ∆ε227 +0.33, ∆ε243 –0.70
(m eth an ol). IR: 1 819 (β-lacton e); 1 726, 1 254, 1 038 (AcO); 1 709, 1 288, 1 275, 962, 714
(ben zoate); 1 603, 1 315, 1 108, 1 027 (arom .). 1H NMR: 8.05 m , 2 H (H-2′ an d H-6′); 7.60 t,
1 H (J = 7.2, H-4′); 7.49 t, 2 H (J = 7.3, H-3′ an d H-5′); 5.18 m , 1 H (W = 36, H-20); 5.00 m ,
1 H (W = 35, H-3); 3.19 d, 1 H (J(6α,8β) = 13.7, H-7); 2.05 s, 3 H (CH3CO); 1.28 d, 3 H (J =
6.2, 3 × H-21); 0.97 s, 3 H (3 × H-19); 0.70 s, 3 H (3 × H-18). For C30H38O6 (494.6) calculated:
72.85% C, 7.74% H; foun d: 72.76% C, 7.73% H.
(20R)-7-Norpregn -5-en e-3β,20-diyl 3-Acetate 20-Ben zoate (7)
A solution of com poun d 6 (18.4 g, 37.2 m m ol) in toluen e (200 m l) was h eated at reflux
tem perature un der n itrogen for 95 h an d th en th e solven t was evaporated in vacuum . Ch ro-
m atograph y of th e residue on silica gel (250 g, toluen e) gave 13.1 g (78%) of com poun d 7;
m .p. 117–118 °C (m eth an ol), [α]D –73 (c 1.1). IR: 3 072, 3 064, 3 028, 3 012 (C=C–H); 1 727,
1 602, 1 585, 1 279, 961 (ben zoate); 1 708 (C=O); 1 252, 1 027 (acetate); 1 653 (C=C).
1H NMR: 8.05 m , 2 H (H-2′ an d H-6′); 7.60 t, 1 H (J = 7.2, H-4′); 7.49 t, 2 H (J = 7.3, H-3′ an d
H-5′); 5.40 bs, 1 H (W = 10.0, H-6); 5.18 m , 1 H (W = 36, H-20); 4.64 m , 1 H (W = 35, H-3);
2.63 ddd, 1 H (J(4α,4β) = 13.7, J(4α,3α) = 4.9, J(4α,6) = 1.8, H-4α); 2.04 s, 3 H (CH3CO);
0.86 s, 3 H (3 × H-19); 0.64 s, 3 H (3 × H-18). MS, m/z (%): 450 (M+, 0.2), 406 (0.6), 390 (15),
268 (65), 253 (19), 239 (11). For C29H38O4 (450.6) calculated: 77.30% C, 8.50% H; foun d:
77.24% C, 8.47% H.
(20R)-7-Nor-5α-pregn an e-3β,20-diyl 3-Acetate 20-Ben zoate (8)
Method A. A m ixture of alken e 7 (207 m g, 0.46 m m ol) an d tosylh ydrazin e (610 m g, 3.28
m m ol) was h eated in 2,4,6-trim eth ylpyridin e (3.0 m l) at 150 °C. After 3 h , th e solven t was
evaporated, th e residue was dissolved in eth er an d th e eth ereal solution was wash ed succes-
sively with th e solution of h ydroch loric acid, water an d th e solution of potassium carbon ate
an d water. Th e solution was th en dried with an h ydrous sodium sulfate an d th e solven t was
evaporated. Th in layer ch rom atograph y of th e residue (4 PLC plates, ben zen e–eth er 10 : 1)
gave com poun d 8 (182 m g, 88%); m .p. 144–145 °C (m eth an ol), [α]D –37 (c 1.0). IR: 3 092,
3 072, 3 064, 1 603, 1 585, 1 451, 1 120 (arom .); 1 709, 1 285, 972 (ben zoate); 1 709, 1 249,
1 042 (AcO). 1H NMR: 8.04 m , 2 H (W = 16, H-2′ and H-6′); 7.79 m , 1 H (W = 20, H-4′); 7.44 m ,
2 H (W = 20, H-3′ an d H-5′); 5.15 m , 1 H (W = 36, H-20); 4.72 m , 1 H (W = 39, H-3); 2.02 s,
3 H (CH3CO); 1.27 d, 3 H (J = 6.1, H-21); 0.70 s, 3 H (3 × H-19); 0.66 s, 3 H (3 × H-18). For
C
29H40O4 (452.6) calculated: 76.95% C, 8.91% H; foun d: 76.70% C, 9.03% H.
Method B. Alken e 7 (3.09 g, 6.86 m m ol) was treated with tosylh ydrazin e (9.7 g, 52.1
m m ol) in 2,4,6-trim eth ylpyridin e (50 m l) as above. Th e product was dissolved in dich loro-
m eth an e (30 m l) an d treated with 3-ch loroperoxyben zoic acid (0.5 g, 2.9 m m ol) at room
tem perature. After 3 h , th e solution was wash ed with th e potassium carbon ate solution an d
water an d con cen trated in vacuum on a rotary evaporator. Th e solution was applied on a
colum n of silica gel (100 g). A m ixture of ligroin –toluen e (2 : 1) eluted com poun d 8 (2.5 g,
81%) iden tical with th e above described sam ple. Furth er fraction s yielded (20R)-5,6α-ep-
oxy-7-n or-5α-pregn an e-3β,20-diyl 3-acetate 20-ben zoate (9, 0.55 g, 17%); m .p. 204–206 °C
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Kasal:
(m eth an ol), [α]D –52 (c 0.9). 1H NMR: 8.04 m , 2 H (W = 16, H-2′ an d H-6′); 7.55 m , 1 H
(W = 20, H-4′); 7.44 m , 2 H (W = 20, H-3′ an d H-5′); 5.15 m , 1 H (W = 36, H-20); 4.98 m ,
1 H (W = 39, H-3); 3.27 s, 1 H (H-6); 2.03 s, 3 H (CH3CO); 1.27 d, 3 H (J = 6.1, H-21); 0.86 s,
3 H (3 × H-19); 0.64 s, 3 H (3 × H-18). For C29H38O5 (466.6) calculated: 74.65% C, 8.21% H;
foun d: 74.59% C, 8.18% H.
(20R)-3β-Hydroxy-7-n or-5α-pregn an -20-yl Ben zoate (10)
Hydroch loric acid (37%, 1.7 m l) was added to a solution of acetate 8 (1.73 g, 3.82 m m ol) in
ch loroform (8.5 m l) an d m eth an ol (85.0 m l). After 18 h at room tem perature, th e solution
was con cen trated in vacuum to 25 m l an d diluted with brin e (100 m l). Th e precipitate was
filtered off, wash ed with water an d dried. Com poun d 10 (1.51 g, 96%) crystallized from
m eth an ol; m .p. 180–181 °C, [α]D –51 (c 1.1). IR: 3 611, 1 048, 1 009 (OH); 1 706, 1 603,
1 451, 1 285, 1 273, 1 070 (ben zoate). 1H NMR: 8.05 m , 2 H (W = 16, H-2′ an d H-6′); 7.73 m ,
1 H (W = 20, H-4′); 7.44 m , 2 H (W = 20, H-3′ an d H-5′); 5.14 m , 1 H (W = 36, H-20); 3.63 m ,
1 H (W = 39, H-3); 1.27 d, 3 H (J = 6.1, H-21); 0.69 s, 3 H (3 × H-19); 0.66 s, 3 H (3 × H-18).
For C27H38O3 (410.6) calculated: 78.98% C, 9.33% H; foun d: 80.01% C, 9.26% H.
(20R)-3α-Hydroxy-7-n or-5α-pregn an -20-yl Ben zoate (11)
Method A. A solution of tosylate 12 (1.68 g, 3.0 m m ol) in DMF (50 m l) was added to a
stirred suspen sion of sodium n itrite (16.8 g, 247.0 m m ol) in h ot DMF (130 °C, 130 m l). Af-
ter 25 h , th e solution was cooled an d a product was precipitated with a saturated aqueous
solution of am m on ium carbon ate (350 m l). A precipitate was filtered off, wash ed with water
an d purified by ch rom atograph y on a colum n of silica gel (50 g). Toluen e eluted 835 m g
(68%) of com poun d 11; [α]D –28 (c 1.1). IR: 3 615, 1 273, 994 (OH); 1 706, 1 603, 1 452, 1 315,
1 286, 1 120, 1 070, 714 (ben zoate). 1H NMR: 8.06 m , 2 H (W = 16, H-2′ an d H-6′); 7.79 m ,
1 H (W = 20, H-4′); 7.44 m , 2 H (W = 20, H-3′ an d H-5′); 5.15 m , 1 H (W = 32, H-20);
4.10 m , 1 H (W = 16, H-3); 1.27 d, 3 H (J = 6.1, H-21); 0.66 s, 3 H (3 × H-19); 0.63 s, 3 H
(3 × H-18). For C27H38O3 (410.6) calculated: 78.98% C, 9.33% H; foun d: 78.90% C, 9.24% H.
Method B. Form ate 13 (188 m g, 0.43 m ol) was dissolved in boilin g m eth an ol (18 m l) an d
a solution of potassium h ydrogen carbon ate (100 m g, 100.0 m m ol) in water (2 m l) was
added. After 5 m in , th e solven t was evaporated in vacuum an d th e residue was diluted with
water (20 m l). Th e precipitate form ed was extracted with eth er, th e extract was wash ed with
water an d con cen trated in vacuum . Th e product (139 m g, 79%) was iden tical with th e sam -
ple prepared by th e m eth od A.
(20R)-7-Nor-5α-pregn an e-3β,20-diyl 3-Tosylate 20-Ben zoate (12)
4-Meth ylben zen esulfon yl ch loride (8.4 g, 44.1 m m ol) was added to a cold (0 °C) solution of
alcoh ol 10 (1.6 g, 3.9 m m ol) in pyridin e (15 m l). After 56 h stan din g at room tem perature,
th e m ixture was poured on to ice (50 g) an d th e precipitate was extracted with dich loro-
m eth an e. Th e extract was wash ed with th e solution of h ydroch loric acid, water, potassium
h ydrogen carbon ate, water an d con cen trated in vacuum . Th e oily product 12 (1.54 g, 70%)
failed to crystallize from com m on solven ts. IR: 1 706, 1 285, 1 273, 714 (ben zoate); 1 354,
1 175, 931, 579, 557 (SO3); 1 601, 1 452, 1 315, 1 188 (arom .). 1H NMR: 8.04 m , 2 H (W =
16, H-2 an d H-6, ben zoate); 7.79 d, _ H (J = 8.4, H-2 an d H-6, tosylate); 7.55 t, 1 H (J = 7.6,
H-4, ben zoate); 7.46 m , 2 H (W = 20, H-3 an d H-5, ben zoate); 7.32 d, 2 H (J = 8.4, H-3 an d
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H-5, tosylate); 5.13 m , 1 H (W = 36, H-20); 4.44 m , 1 H (W = 39, H-3); 2.45 s, 3 H
(CH3C6H4); 1.26 d, 3 H (J = 6.1, H-21); 0.66 s, 3 H (3 × H-19); 0.63 s, 3 H (3 × H-18). For
C
34H44O5S (564.8) calculated: 72.31% C, 7.85% H, 5.68% S; foun d: 72.32% C, 7.99% H,
5.30% S.
(20R)-7-Nor-5α-pregn an e-3α,20-diyl 20-Ben zoate 3-Form ate (13)
A solution of 3β-alcoh ol 10 (250 m g, 0.61 m m ol) an d triph en ylph osph in e (393 m g, 1.5
m m ol) in toluen e (20 m l) was h eated un til 10 m l of an azeotropic m ixture was distilled off.
Th e m ixture was cooled in an ice bath an d dieth yl azodicarboxylate (261 m g, 1.5 m m ol) was
added un der stirrin g. After 5 m in , 3 drops of form ic acid (98%, 66 m g, 1.43 m m ol) were
added. Th e ice bath was rem oved an d th e m ixture was left aside for 3 h . Th e precipitate
form ed was filtered off an d wash ed with toluen e, th e filtrate was con cen trated in vacuum
an d applied on to a colum n of silica gel. Toluen e eluted form ate 13 (250 m g, 94%); m .p.
178–179 °C (aceton e–h eptan e), [α]D –16 (c 1.1). IR: 1 709, 1 452, 1 285, 1 273, 1 070, 714
(ben zoate); 1 709, 1 206, 1 173 (form ate). 1H NMR: 8.06 m , 3 H (W = 16, overlappin g sign als
of HCOO, H-2′ an d H-6′); 7.79 m , 1 H (W = 20, H-4′); 7.44 m , 2 H (W = 20, H-3′ an d H-5′);
5.23 m , 1 H (W = 15, H-3); 5.15 m , 1 H (W = 36, H-20); 1.27 d, 3 H (J = 6.1, H-21); 0.66 s,
6 H (3 × H-19 an d 3 × H-18). For C28H38O4 (438.6) calculated: 76.68% C, 8.73% H; foun d:
76.96% C, 8.93% H.
(20R)-3α-[(2-Meth oxyeth oxy)m eth oxy]-7-n or-5α-pregn an -20-yl Ben zoate (14)
N,N-Diisopropyleth ylam in e (1 m l, 5.74 m m ol) an d (2-m eth oxyeth oxy)m eth yl ch loride (0.4
m l, 3.50 m m ol) were added to a solution of com poun d 11 (606 m g, 1.48 m m ol) in dich loro-
m eth an e (6 m l). After 3 h , th e m ixture was wash ed with a solution of citric acid (5%,
20 m l), water, th e potassium h ydrogen carbon ate solution , an d water. Th e solven t was con -
cen trated in vacuum yieldin g com poun d 14 (748 m g, 96%); m .p. 80–82 °C (aceton e–
h eptan e), [α]D –10 (c 1.1). IR: 2 824, 1 378, 1 176, 1 106, 1 043 (MEM); 1 705, 1 603, 1 585,
1 491, 1 452, 1 315, 1 285, 1 273, 1 120, 1 070, 1 027, 974, 714 (ben zoate). 1H NMR: 8.06 m ,
2 H (W = 16, H-2′ an d H-6′); 7.55 m , 1 H (W = 20, H-4′); 7.43 m , 2 H (W = 20, H-3′ an d
H-5′); 5.14 m , 1 H (W = 34, H-20); 4.74 s, 2 H (OCH2O), 3.92 t, 1 H (J = 2.7, H-3); 3.70 m
an d 3.56 m , 4 H (W = 19.0, O(CH2)2O); 3.40 s, 3 H (OCH3); 1.27 d, 3 H (J = 6.3, H-21);
0.65 s, 3 H (3 × H-19); 0.64 s, 3 H (3 × H-18). For C31H46O5·0.5 Me2CO (527.8) calculated:
73.97% C, 9.36% H; foun d: 73.10% C, 9.52% H.
(20R)-3α-[(2-Meth oxyeth oxy)m eth oxy]-7-n or-5α-pregn an -20-ol (15)
Ben zoate 14 (331 m g, 0.63 m m ol) was refluxed in a 0.87 M solution of sodium m eth oxide in
m eth an ol (3.5 m l). After 8 h , th e solven t was evaporated in vacuum , th e residue was diluted
with brin e (20 m l) an d th e precipitate form ed was extracted with m eth ylen e dich loride. Th e
extract was wash ed with water an d con cen trated on a rotary evaporator. Th e residue (com -
poun d 15, 248 m g, 95%) failed to crystallize from com m on solven ts; [α]D –22 (c 1.2). IR:
3 610, 3 472 (OH); 2 823, 1 458 (OCH3); 1 184, 1 133, 1 099, 1 043 (C–O). 1H NMR: 4.74 s,
2 H (OCH2O); 3.92 m , 1 H (W = 12.8, H-3); 3.75 m , 1 H (W = 34, H-20); 3.70 m an d 3.56 m
(4 H, W = 19.0 an d 19.0, O(CH2)2O); 3.40 s, 3 H (OCH3); 1.14 d, 3 H (J = 6.3, H-21); 0.74 s,
3 H (3 × H-19); 0.68 s, 3 H (3 × H-18). For C24H42O4 (394.6) calculated: 73.05% C, 10.73% H;
foun d: 72.95% C, 10.78% H.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1478
Kasal:
3α-[(2-Meth oxyeth oxy)m eth oxy]-7-n or-5α-pregn an -20-on e (16)
A solution of 20-h ydroxy derivative 15 (114 m g, 0.29 m m ol) in aceton e (2 m l) was treated
with th e Jon es reagen t (7 drops) at room tem perature. After 5 m in , m eth an ol (1 m l) an d
th en th e potassium h ydrogen carbon ate solution (1 m l) were added before th e solven t was
evaporated. Th e residue was extracted with eth er, th e extract was wash ed with water an d
con cen trated in vacuum . Product 16 (99 m g, 88%) crystallized from m eth an ol at –60 °C;
m .p. 31–33 °C, [α]D +60 (c 1.1). IR: 2 823, 1 101, 1 043 (MEM); 1 697, 1 358 (COCH3).
1H NMR: 4.70 s, 2 H (OCH2O); 3.93 t, 1 H (J = 2.6, H-3); 3.70 m an d 3.57 m , 4 H (W = 17.0
an d 17.0, O(CH2)2O); 3.40 s, 3 H (OCH3); 2.13 s, 3 H (H-21); 0.68 s, 3 H (3 × H-19); 0.60 s,
3 H (3 × H-18). For C24H40O4 (392.6) calculated: 73.43% C, 10.27% H; foun d: 73.36% C,
10.19% H.
3α-Hydroxy-7-n or-5α-pregn an -20-on e (2)
A solution of com poun d 16 (90 m g, 0.23 m m ol) in aqueous tetrah ydrofuran (91%, 5 m l)
was treated with h ydroch loric acid (0.5 m l) at room tem perature. After 24 h , th e solution
was diluted with toluen e (10 m l) an d con cen trated in vacuum to on e h alf of its volum e. Th e
m ixture was partition ed between toluen e an d water, th e organ ic layer was wash ed with wa-
ter, th e solven t was evaporated in vacuum an d th e residue crystallized from aceton e–
h eptan e (49 m g, 70%). PLC of m oth er liquor (1 plate, ben zen e–eth er 3 : 1) afforded an addi-
tion al crop (12 m g; th e overall yield 87%); m .p. 148–149 °C, [α]D +74 (c 0.7). IR: 3 616,
1 000, 984 (OH); 1 696, 1 358 (COCH3). 1H NMR: 4.11 m , 1 H (W = 17, H-3); 2.56 t, 1 H (J =
8.9, H-17); 2.13 s, 3 H (H-21); 0.67 s, 3 H (3 × H-19); 0.61 s, 3 H (3 × H-18). For C20H32O2
(304.5) calculated: 78.90% C, 10.59% H; foun d: 78.86% C, 10.61% H.
Skillful technical assistance was provided by Ms M. Sedláčková. The author is indebted to Dr P.
Fiedler for interpretation of IR spectra measured by Ms K. Matoušková. 1H NMR spectra were mea-
sured by Ms M. Snopková. Elemental analyses were carried out in the Analytical Laboratory (Dr V.
Pechanec, Head). This work was supported by the Ministry of Health of the Czech Republic (grant No.
4668-3).
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Collect. Czech. Chem. Commun. (Vol. 64) (1999)