Autooxidation of Δ17(20)-20-hydroxy derivatives of steroids. Synthesis of 3β-acetoxy-17α-hydroperoxy-16α- methylpregn-5-en-20-one and its reduction to 17α-hydroxy derivative

Article abstract of DOI:10.1134/S1070428011010052

An efficient procedure was proposed for the synthesis of 3β-acetoxy-17α-hydroperoxy-16α-methylpregn-5-en-20-one. Optimal conditions were found for the combined process including 1,4-addition of methylmagnesium bromide at the Δ¹⁶-20-oxo fragment of dehydropregnenolone acetate and autooxidation of resulting bromomagnesium 3β-acetoxy-16α-methylpregna-5,17(20)-dien-20-olate. The subsequent reduction of the 17α-hydroperoxy group and hydrolysis of the 3β-acetoxy group afforded 17α-hydroxy-16α-methyl-substituted dehydropregnenolone acetate and its 3-hydroxy analog in high yield.

Full text of DOI:10.1134/S1070428011010052

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 1, pp. 54–61. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © T.S. Savinova, N.V. Lukashev, L.D. Huy, I.P. Beletskaya, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 1,
pp. 57–64.
Autooxidation of ∆17(20)-20-Hydroxy Derivatives of Steroids.
Synthesis of 3β-Acetoxy-17α-hydroperoxy-16α-methylpregn-5-en-
20-one and Its Reduction to 17α-Hydroxy Derivative
T. S. Savinovaa, N. V. Lukasheva, L. D. Huyb, and I. P. Beletskayaa
a Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: tatiana_savinova@rambler.ru
b Institute of Chemistry, Vietnamese Academy of Science and Technology,
18 Hoang Quoc Viet. Cau Giay, Hanoi, Vietnam
Received December 17, 2009
Abstract—An efficient procedure was proposed for the synthesis of 3β-acetoxy-17α-hydroperoxy-16α-methyl-
pregn-5-en-20-one. Optimal conditions were found for the combined process including 1,4-addition of methyl-
magnesium bromide at the Δ16-20-oxo fragment of dehydropregnenolone acetate and autooxidation of resulting
bromomagnesium 3β-acetoxy-16α-methylpregna-5,17(20)-dien-20-olate. The subsequent reduction of the
17α-hydroperoxy group and hydrolysis of the 3β-acetoxy group afforded 17α-hydroxy-16α-methyl-substituted
dehydropregnenolone acetate and its 3-hydroxy analog in high yield.
DOI: 10.1134/S1070428011010052
Corticosteroids occupy an important place among
synthetic medicines. 16α-Methylcorticoids, e.g., Dexa-
methasone, Mometasone, Flumetasone, and their
derivatives, have found wide application due to their
strong anti-inflammatory and antiallergic activity. Such
corticosteroids can be synthesized from pregnanes
having a Δ16-20-oxo fragment which is necessary for
the introduction of 17α-hydroxy and 16α-methyl
groups. An example is dehydropregnenolone acetate I;
it is an important and most preferred intermediate in
the synthesis of steroid drugs of the pregnane series.
The presence of a Δ16-20-oxo fragment in molecule I
makes it possible to use it for the preparation of
17α-hydroxy-16α-methylpregnanes without additional
modification. Compound I is obtained by cleavage of
diosgenin, i.e., Δ5-steroidal sapogenin [1]. Diosgenin is
isolated on a large scale from renewable vegetable raw
material, rhizomes of wild and cultivated plants be-
longing to the Dioscoreaceae R. Brown family, which
occur mainly in tropical and subtropical regions, in
particular in the Far East (Russia) and South-East Asia.
Promising Dioscoreaceae species are D. membranacea
and D. colletti; they contain 2.3 and 4.4% of diosgenin,
respectively [2].
16α-alkylation. Attachment of a methyl group at the
16α-position of the Δ16-20-oxo fragment in compound
I is usually performed by 1,4-addition of methylmag-
nesium halide in the presence of copper(I) chloride [3].
The subsequent 17α-hydroxylation can be performed
via direct oxidation according to [4] and by the Gal-
lagher–Krichevsky method [5]. Both these procedures
are based on the oxidation of Δ17(20)-20-hydroxy
derivative, which is formed as a result of preliminary
enolization of the C20=O group. In the first version,
enolization occurs in alkaline medium. The resulting
Δ17(20)-20-hydroxy derivative is subjected to oxidation
with molecular oxygen to obtain 17α-hydroperoxide
which is then reduced to 17-hydroxy derivative [6]. In
the second version, enolization is promoted by an or-
ganic acid (as a rule, p-toluenesulfonic acid) in acetic
anhydride with simultaneous acetylation of
Δ17(20)-20-hydroxy intermediate generated in situ. The
subsequent oxidation of the ∆17(20) double bond with
a peroxy acid and mild alkaline hydrolysis of
17α,20-epoxide thus formed gave 17α-hydroxy-20-oxo
compound.
However, acetylation of enolized 20-oxo group in
16α-methyl steroids is difficult to perform. The reac-
tion is slow, and the yield is poor. 16α-Methyl-16,17-
dihydro derivative of I undergoes enolization only
17α-Hydroxy and 16α-methyl groups are generally
introduced in two steps, the first of these being
54

AUTOOXIDATION OF ∆17(20)-20-HYDROXY DERIVATIVES OF STEROIDS.
55
Scheme 1.
Me
Me
Me
Me
O
OMgHlg
Me
CH3MgHlg, CuI
Me
Me
AcO
AcO
I
II
Me
Me
Me
OAc
OAc
Me
O
AcHlg
Peroxy acid
Me
Me
Me
O
Me
AcO
AcO
III
IV
Me
Me
Me
Me
O
O
OH
OH
OH–
Zn, NaI, AcOH
Me
O
Me
Me
Me
HO
HO
V
VI
upon prolonged heating of the reaction mixture in
acetic anhydride with slow removal of acetic acid by
distillation (from 6 [7] to 18 h [8]). The subsequent
epoxidation of the C17=C20 double bond in 16α-meth-
yl-20-enol acetate with peroxy acid required much
longer time than that necessary for the oxidation of
analogous enol acetate having no substituent on C16
[9]. The reaction was not selective: it also involved
other double C=C bonds present in the steroid mole-
cule. Therefore, the C5=C6 bond is protected via trans-
formation into, e.g., 5,6-dichloro derivative [10]. In
some cases, the C5=C6 bond is preliminarily hydro-
genated over palladium catalyst to obtain compounds
of the 5α series [11]. Nevertheless, despite a number of
steps, this procedure was used for a long time for
large-scale manufacture of 17α-hydroxy-16α-methyl-
corticosteroids.
16α-methyl-17α,20-epoxy ester IV, and regeneration
of the C5=C6 double bond in V led to the formation of
17α-hydroxy-16α-methyl derivative VI [13, 14]
(Scheme 1).
There are a few published data on the introduction
of 17α-hydroxy and 16α-methyl groups into
Δ16-20-oxo steroids via reduction of 17α-hydroperoxy
derivatives obtained by autooxidation with molecular
oxygen of halomagnesium 16α-methyl-Δ17(20)-20-olate
[15–17]. However, this rare procedure (unlike those
described above) almost was not used in practice
because of poor yield of 17α-hydroperoxy compounds
and low reproducibility.
In the present article we report on the synthesis of
3β-acetoxy-17α-hydroperoxy-16α-methylpregn-5-en-
20-one (VII) from dehydropregnenolone acetate I,
transformation of VII into 17α-hydroxy derivatives
VIII and VI, and on the effect of the Grignard reaction
conditions on the efficiency of subsequent autooxida-
tion (Scheme 2). The reaction of Δ16-pregnan-20-one
with methylmagnesium bromide is usually carried out
in 9–10-fold amount (with respect to the substrate) of
tetrahydrofuran in the presence of 9.2 wt % of copper
chloride at –15 to 5°C in a stream of an inert gas using
Direct acylation of metal enolates is a modification
of the Gallagher–Krichevsky procedure. It includes
treatment of enolate II with an acylating agent. The
latter may be not only carboxylic acid anhydrides and
chlorides but also heteroelement halides, e.g., trimeth-
ylsilyl chloride [12]. Oxidation of Δ17(20)-20-enol ester
III with an organic peroxy acid, alkaline hydrolysis of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

SAVINOVA et al.
56
Scheme 2.
Me
Me
Me
Me
Me
Me
O
O
OMgBr
Me
OOH
O2
Me
Me
Me
Me
AcO
AcO
AcO
I
II
VII
CH3MgBr
H+
Me
Me
Me
Me
Me
O
O
Me
Me
OMgBr
H
OH
Me
Me
Me
Me
Me
AcO
AcO
AcO
IX
H+
XI
VIII
OH–
OH–
Me
Me
Me
Me
O
H
O
Me
Me
OH
Me
OH
Me
Me
Me
Me
Me
AcO
HO
HO
X
XII
VI
2.5–3 mole of the Grignard compound per mole of
the substrate [14, 17]. Our studies on the conjugate ad-
dition reaction were performed under the same con-
ditions.
ture containing intermediate II on exposure to air
(nitrogen was not passed through the reaction mixture)
resulted in the formation of 10–15% of hydroperoxide
VII. We succeeded in isolating 17-deoxy compound
XI in 90–95% yield only when methanol was slowly
added to the reaction mixture under a strong stream
of nitrogen. Analogous result was obtained using
a 10% aqueous solution of ammonium chloride instead
of methanol.
In order to obtain compound XI which was neces-
sary as reference sample to estimate the purity of the
autooxidation product of compound VII, magnesium
enolate II was subjected to protolysis. It is known that
protolysis of halomagnesium 16α-methyl-Δ17(20)-20-
olate obtained in tetrahydrofuran gives different re-
sults, depending on the conditions. Addition to the re-
action mixture of a dilute mineral acid (sulfuric [15] or
hydrochloric [18]) or methanol [19] leads to protona-
tion of the C17-carbanion with formation of 17-deoxy-
16α-methyl-20-oxo steroids in 75–95% yield. How-
ever, when the same reagents were used in the synthe-
sis of compound XI, the reaction was always accom-
panied by formation of 17α-hydroperoxy derivative VII
as impurity. Addition of methanol to the reaction mix-
Tetrahydrofuran is known to be the most preferable
solvent for 1,4-addition of Grignard compounds to
Δ16-pregnan-20-one derivatives. However, the subse-
quent autooxidation gave 17-hydroperoxy compound
in a yield not exceeding 50% [16, 20]. According to
published data [17], 17α-hydroperoxide can be ob-
tained in up to 86% yield by carrying out autooxida-
tion under heterogeneous conditions, by adding diethyl
ether to the reaction mixture after completion of the
Grignard reaction. We examined the effect of solvent
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

AUTOOXIDATION OF ∆17(20)-20-HYDROXY DERIVATIVES OF STEROIDS.
57
Table 1. Composition (%) of the Grignard reaction and autooxidation products formed in different solvents [TLC: Sorbfil
(Russia), sample amount 10 μg, development with a 5% solution of vanillin in 10% aqueous perchloric acid]
Compound XI (1,4-addition,
Compound VII (1,4-addition,
autooxidation, hydrolysis)
Solvent
Compound X (1,2-addition)
protolysis)
Tetrahydrofuran
Pyridine
–
50
80
80
55
20
–
50
20
20
15
50
70
05
05
–
Acetonitrile
1,4-Dioxane
Diethyl ether
Methylene chloride
Benzene
–
30
30
30
95
95
–
Toluene
–
nature in one-pot synthesis of 17α-hydroperoxy-16α-
methyl derivative VII from compound I with a view to
find optimal conditions ensuring the required selec-
tivity of both 1,4-addition and subsequent autooxida-
tion. As solvents we selected those characterized by
different miscibilities with water (Table 1), and the
autooxidation step was carried out in both homogene-
ous and heterogeneous media. If a water-miscible
solvent was used, a solid separated from the reaction
mixture and was filtered off. When the reaction was
carried out in a water-immiscible solvent, the aqueous
phase was extracted with that solvent, and the products
were analyzed by thin-layer chromatography. The
results are collected in Table 1.
(the reaction occurred at the α,β-unsaturated carbonyl
fragment of the substrate or at the cyano group of the
solvent), a considerable heat evolution was observed,
and double amount of the Grignard compound was
necessary to complete conjugate addition. At 20–22°C
the main process was alkylation of acetonitrile. Thus
we have found that selective alkylation of the
Δ16-20-oxo steroid in acetonitrile is possible at ≤5°.
The use of dioxane as solvent for the conjugate ad-
dition reaction did not ensure acceptable selectivity,
and the reaction mixture contained 30% of 1,2-addition
product X. Presumably, the reason is very poor solu-
bility of copper chloride in that solvent. As in the
above cases, the subsequent autooxidation gave only
15% of compound VII.
As might be expected, the alkylation in tetrahydro-
furan occurred at the C16 atom. However, the subse-
quent autooxidation of bromomagnesium 16α-methyl-
Δ17(20)-20-olate II afforded no more than 50% of
hydroperoxide VII. The use of pyridine which readily
dissolves copper chloride to form coordination com-
pounds [21, 22] improved the yield of the 1,4-addition
product up to 80%, but hydroperoxide VII was formed
in a poor yield (about 20%). Apart from pyridine, cop-
per chloride is readily soluble in acetonitrile (13.4 g of
CuCl in 100 g of the solvent) [23]. On the other hand,
acetonitrile itself is capable of reacting with alkylmag-
nesium halides, so that it is not used as solvent in
Grignard reactions. Our attempts to perform the reac-
tion in acetonitrile gave unexpected results. The reac-
tion at a temperature not exceeding 5°C involved
predominant addition of methylmagnesium bromide at
the Δ16-20-oxo fragment of the initial steroid with
selective formation of 1,4-addition product, but the
subsequent autooxidation gave no more than 20% of
hydroperoxide VII. Raising the temperature to 10°C
sharply reduced the selectivity of the alkylation step
The data in Table 1 show that, on the one hand,
aromatic hydrocarbons, ethers, and methylene chloride
are inappropriate solvents from the viewpoint of selec-
tivity in the conjugate addition of methylmagnesium
bromide; on the other hand, these solvents favor com-
plete autooxidation of the 1,4-addition product (except
for diethyl ether). In the reactions carried out in aro-
matic hydrocarbons, the main process was 1,2-addition
of the Grignard compound, whereas in the reactions in
diethyl ether or methylene chloride the fraction of
compound X in the reaction mixture did not exceed
30%. The subsequent autooxidation of II gave hydro-
peroxide VII. The autooxidation in methylene chloride
was more effective, and the yield of VII reached 70%,
while no compound XI was present. Methylene
chloride has long been used as solvent in Grignard
syntheses [24], but its analogous application in the
chemistry of Δ16-20-oxo steroids was not reported
previously.
Thus our results indicated that the autooxidation
process in heterogeneous medium is more successful,
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SAVINOVA et al.
58
Table 2. Selectivity and yields of 17α-hydroperoxide VII in the autooxidation process
Selectivity for compound VII, %
Yield of VII, mol %
Solventa
a
b
a
b
THF–diethyl ether
THF–CH2Cl2
75
80
75
80
90
90
–
50
85
–
68
–
–
–
THF–ethyl acetate
THF–CCl4
65
65
85
80
–
–
–
–
THF–benzene
90
90
90
90
88
75
40
85
THF–toluene
Pyridine–benzene
Acetonitrile–benzene
–
–
a
Solvent ratio 0.7:1 (by volume).
which is very consistent with published data [17].
Therefore, both versions of the combined process were
compared with a view to optimize conditions for the
synthesis of compound VII. In the first case (method
a), co-solvent (diluent) was added only at the auto-
oxidation step (as in [17]); i.e., a component immis-
cible with water was added to the reaction mixture
after the conjugate addition was complete; in the
second case (method b), the alkylation step was per-
formed in a mixture of solvents ensuring formation of
heterogeneous medium in the subsequent autooxida-
tion process. The selectivity in the formation of com-
pound VII was estimated on the basis of the TLC data.
The results are collected in Table 2.
accompanied by formation of up to 30% of 1,2-ad-
dition product X and 20% of deoxy derivative XI
together with target hydroperoxide VII. The best result
was obtained using mixtures of THF with aromatic
hydrocarbons: the selectivity for hydroperoxy com-
pound VII attained 90%.
The Grignard reaction in acetonitrile–benzene or
pyridine–benzene was characterized by regioselective
alkylation at the C16 atom and fairly complete auto-
oxidation (Table 2). However, in the second case,
evaporation of the solution was accompanied by vigor-
ous decomposition of hydroperoxide VII, so that the
yield of VII did not exceed 40%. It is known that
hydroperoxide in solution readily undergo decomposi-
tion at elevated temperature [25] and that copper salts
are capable of not only catalyzing conjugate addition
of Grignard compounds and initiating autooxidation
(as low concentration of copper salt as ~10–5 M is
sufficient to appreciably accelerate this process) [26]
but also accelerating decomposition of hydroperox-
ides; the rate of decomposition increases in parallel
with the concentration of copper salt [27, 28]. There-
fore, fast removal of the catalyst from solution is nec-
essary, which may be attained by washing. Insofar as
the equilibrium concentration of pyridine in benzene
layer is higher than in aqueous layer [29], removal of
copper ions in such a way may be difficult, which may
be a factor responsible for decomposition of hydroper-
oxide VII upon evaporation.
Diethyl ether and methylene chloride as diluents
ensured comparable results. Addition of these solvents
to the reaction mixture after completion of the
Grignard reaction favored autooxidation. However,
despite high selectivity for compound VII with the use
of methylene chloride (80%, according to the TLC
data), we failed to isolate the product as individual
substance. Compound VII turned out to be very un-
stable in methylene chloride. The IR spectrum of a 1%
solution of VII in CH2Cl2 indicated appreciable de-
composition of this compound in 6 min. After 1 h at
room temperature, compound VII underwent complete
decomposition with formation of a complex mixture of
products. Thus any water-immiscible solvent may be
used as diluent for selective autooxidation (Table 2),
but aromatic hydrocarbons are preferred.
Thus the results of our study led us to conclude that
selective autooxidation requires a heterogeneous
medium consisting of an aqueous layer and organic
layer containing enolate II. Hydrolysis of enolate II is
likely to involve formation of intermediate conjugated
anion XIII. Depending on the hydrolysis conditions,
The suitability of solvent mixtures for the 1,4-ad-
dition of Grignard compound was examined under
analogous conditions. Binary solvent mixtures with
a volume ratio of 0.5:1 to 1:1 were tried. The reaction
in THF–diethyl ether, as in pure diethyl ether, was
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AUTOOXIDATION OF ∆17(20)-20-HYDROXY DERIVATIVES OF STEROIDS.
59
Scheme 3.
Me
Me
Me
Me
Me
Me
OMgBr
Me
O–
O
Me
Me
Me
Me
Me
AcO
AcO
AcO
II
XIII
Me
Me
O
H2O
Me
Me
AcO
XI
Me
Me
Me
Me
O
O
O
O
O–
Me
OH
Me
O2
H2O
Me
Me
AcO
AcO
XIV
VII
protonation of XIII at the C17 atom to give 16α-meth-
yl-17-deoxy derivative XI or autooxidation according
to generally accepted mechanism [30] with formation
of hydroperoxide VII is possible (Scheme 3). The low
yield of the autooxidation product in homogeneous
medium may be rationalized assuming that the rate of
protonation is comparable with the rate of autooxida-
tion. Thus, the solvent nature is an important factor
affecting the selectivity of both conjugate addition of
Grignard compound and subsequent autooxidation.
thiosulfate and potassium or sodium iodide in acetic
acid or aliphatic ketone (e.g., in acetone) can also be
used as reducing agent. Hydroperoxide VII is thus
converted to compound VIII in high yield (90% and
more). Using zinc dust in acetic acid, potassium iodide
in acetone, and sodium thiosulfate in acetone–metha-
nol (1:1) we succeeded in obtaining compound VIII in
95–98% yield. The crude product isolated in the reduc-
tion of VII with sodium thiosulfate contained 2% of
sulfur (according to the elemental analysis data), which
may be regarded as a considerable disadvantage of this
procedure.
The structure of 3β-acetoxy-17α-hydroperoxy-16α-
methylpregn-5-en-20-one (VII) was confirmed by its
elemental composition and spectral data (an analytical
sample was prepared by recrystallization from ethyl
acetate). The IR spectrum of VII recorded from a 1%
solution in methylene chloride contained a strong
absorption band at 3530 cm–1, which is typical of O–H
stretching vibrations in OOH group [31] (the corre-
sponding frequency of OH stretching vibrations in
EXPERIMENTAL
Analysis of compounds and monitoring of chemical
processes by thin-layer chromatography were per-
formed using Sorbfil PTSKh UV-254 plates (Russia)
with hexane–acetone (10:3) and heptane–ethyl ace-
tate–isopropyl alcohol (5:4:1) as eluents; spots were
detected by treatment with a 1% solution of vanillin in
10% aqueous perchloric acid. The optical rotations
[α]D20 were determined on an FEP-02 polarimeter
(USSR) from solutions in chloroform (c = 1). The IR
spectra were recorded on a Perkin–Elmer 599 spec-
trometer. The mass spectra (electron impact, 50 eV)
were obtained on a Varian MAT-112 instrument
1
the spectrum of VIII is 3610 cm–1). In the H NMR
spectrum of VII in CDCl3 we observed a signal at
δ 8.26 ppm, which was assigned to the OOH proton.
17α-Hydroperoxypregnanes can readily be reduced
to the corresponding 17α-hydroxy derivatives by the
action of zinc dust in acetic acid [17, 32] or via
catalytic hydrogenation over Pd/C [17, 33]. Sodium
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 1 2011

SAVINOVA et al.
60
1
(Germany). The H NMR spectra were measured on
a Varian XL-200 spectrometer (USA) at 200 MHz
using CDCl3 as solvent and TMS as internal reference.
water, and dissolved in methanol–methylene chloride
(1:1), and the solution was treated with activated char-
coal and evaporated to dryness under reduced pressure.
The residue was ground with water, and the precipitate
was filtered off, washed on a filter with 1% hydro-
chloric acid and with water until neutral washings, and
dried. Yield 4.56 g (95%), mp 204–206°C; published
data [34]: mp 203–205°C.
17α-Hydroperoxy-16α-methyl-20-oxopregn-5-
en-3β-yl acetate (VII). a. A suspension of 10 g of
compound I and 0.25 g* of copper(I) chloride in
140 ml of THF was cooled to –10 to 0°C, and 60 ml
of a 1.68 N solution of methylmagnesium bromide
(3.6 equiv) in THF was slowly (over a period of
~15 min) added under stirring in a stream of an inert
gas. The mixture was kept for 20 min at that tempera-
ture, and 200 ml of anhydrous benzene was slowly
added, maintaining the temperature below –5°C. The
mixture was stirred for 20 min and poured into 0.5 l of
a 20% solution of ammonium chloride, cooled to 0°C,
under vigorous stirring. The mixture was vigorously
stirred for 20 min at 0–5°C, the organic layer was
separated and washed with a 20% aqueous solution of
ammonium chloride and water, the solvent was re-
moved under reduced pressure at a temperature not
exceeding ≤40°C, the residue was ground with hexane,
and the precipitate was filtered off and washed with
hexane on a filter. Yield 9.64 g (85%), mp 156°C
(decomp.), 169°C (from ethyl acetate; decomp.),
[α]D20 = –35.9°. IR spectrum ν, cm–1: in CH2Cl2: 3530
(OOH); in mineral oil: 3350 (OOH), 1740 (C=O),
b. Potassium iodide, 3.2 g, was added to a suspen-
sion of 8.2 g of compound VII in 160 ml of acetone.
The mixture was stirred for 1 h at room temperature,
a 10% solution of Na2SO3 was added (until the mixture
turned colorless), and 160 ml of water was then added.
The precipitate was filtered off and washed with water.
Yield 7.72 g (98%), mp 205–206°C.
3β,17α-Dihydroxy-16α-methylpregn-5-en-20-one
(VI). Potassium hydroxide, 3.5 g, was added to a sus-
pension of 10 g of compound VIII in 330 ml of
methanol under stirring in a stream of an inert gas. The
mixture was kept for 1 h at room temperature, neutral-
ized with acetic acid, and concentrated under reduced
pressure. The precipitate was filtered off and washed
with water. Yield 7.49 g (84%), mp 242–242.5°C;
published data [34]: mp 245–250°C; [α]D20 = –70° (c =
0.5, pyridine).
1
16α-Methyl-20-oxopregn-5-en-3β-yl acetate
(XI). A suspension of 10 g of compound I and 0.92 g
of copper(I) chloride in 92 ml of THF was cooled to
–10 to 0°C, and 60 ml of a 1.68 N solution of methyl-
magnesium bromide in THF was added under stirring
in a stream of an inert gas. The mixture was kept for
20 min at that temperature, 50 ml of anhydrous metha-
nol was slowly added, maintaining the temperature
below –5°C, and the mixture was stirred for 15 min
and diluted with 200 ml of water. The resulting suspen-
sion was stirred for 2 h at 5–10°C, and the precipitate
was filtered off and washed with aqueous methanol.
Yield 9.9 g (95%), mp 183–185°C (from diethyl
ether); published data [6]: mp 182–184°C.
1685 (C=O), 1240 (C–O). H NMR spectrum, δ, ppm:
0.86 s (3H, 18-CH3), 1.16 s (3H, 19-CH3), 1.32 d (3H,
16-CH3, J = 7.3 Hz), 2.19 s (3H, COCH3), 2.44 s (3H,
21-CH3), 4.70 m (1H, 3-H), 5.50 (1H, 6-H), 8.26 s
(1H, OOH). Mass spectrum: m/z 404 [M]+. Found, %:
C 71.47; H 8.80. C24H36O5. Calculated, %: C 71.25;
H 8.96.
b. A 1.68 N solution of methylmagnesium bromide
in tetrahydrofuran, 60 ml, was added under vigorous
stirring at 0–5°C in a stream of an inert gas to a solu-
tion of 10 g of compound I in a mixture of 140 ml of
THF and 200 ml of benzene containing 0.25 g of cop-
per(I) chloride. After 20 min, the mixture was poured
under vigorous stirring at 0–2°C into 500 ml of
a 20% aqueous solution of ammonium chloride, kept
for 20 min, and then treated as described above in a.
Yield of VII 9.98 g (88%), mp 157.5°C (decomp.).
The authors thank Russian Foundation for Basic
Research and Vietnamese Academy of Sciences and
Technologies (project no. 09-03-90300-V’et_a) for
financial support.
17α-Hydroxy-16α-methyl-20-oxopregn-5-en-3β-
yl acetate (VIII). a. Zinc dust, 2.5 g, was added to
a solution of 5 g of compound VII in 35 ml of glacial
acetic acid. The mixture was stirred for 1 h at room
temperature and poured into 300 ml of water, the
precipitate was filtered off, washed on a filter with
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