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Патент USA US3083209

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3,083,199
United States Patent 0 ” ice
Patented Mar. 26, 1963
2
1
tion, thereby causing di?icult problems of separating such
mixtures.
Our invention overcomes the above di?iculties and
provides a process of preparing a A3- or A3-19-nor
3,083,199
M-Sa-STERGIDS AND 3a-HYDRQXY-5a-STEROIDS
AND THE PRE¥ARATEUN THEREOF
Luciano Cagiioti and Gianiranco Cainelli, Milan, Italy,
assignors to Societa Farmaceutici Italia, Milan, Italy, a
corporation of Itaiy
No Drawing. Filed Jan 8, 1962, Ser. No. 165,279
Claims priority, application Italy Jan. 11, 1961
11 Claims. (Ci. 260-23955)
Six-steroid compound unsubstituted in the 3-position and
having no double bonds in other parts of the steroid
molecule wherein the corresponding 3-keto-A4-steroid
compound is treated in solution and under a protective
atmosphere with diborane, and the reaction product is
10
Our invention relates to Soc-steroids and to a process of
preparing such compounds from the corresponding 3
A
B
Our invention includes treating the dehydrated product
of the paragraph just above with diborane and subse
quently with alkaline hydrogen peroxide so as to yield the
keto-A‘i-steroids by a hydroboration reaction. A3502
steroids and 3a-hydroxy-5a-steroids, rings A and B hav
ing the following structural formula:
dehydrated.
15
corresponding 3u-hydroxy or 3u-hydroxy-19-nor-5u
steroid compound.
The treatment with diborane is preferably carried out
on an ethereal solution of the steroid compound. The
process of the invention may be schematized as follows:
20
(1) E2110
(2) dehydrating medium
.—_—_>
where R is a-hydroxy when a double bond is absent in
the 3:4 position, and hydrogen when a double bond is 25
present in the 3:4 position; where R’ is hydrogen or
methyl when a side chain is absent in the 17-position and
methyl when a side chain is present in the 17-position and
I?’ I
' no double bonds are present in other parts of the steroid
molecule, may be prepared according to the invention.
30
The products of the above general formula are useful
both as intermediates for the synthesis of steroid products
the central nervous system, or are hypotensives or are
antifungals.
The products of the invention can be prepared and ad
ministered in a wide variety of pharmaecutical units for
oral and parenteral use, alone or in admixture with a
E2116
All‘,
(2) H 2 0 2 HO—
_
1
:
(II)
hydroxy-Sa-steroids may be prepared) and as physiologi 35
cally active substances. Some or" these products have
tives, corticoids, and natriuretics. Others have activity on
q»
(1)
H
useful in therapy (in particular A3-5-a-steroids, from
which, according to the invention, the corresponding 30;
hormonal activities asanabolics, androgenics, progesta
A
(111)
where R’ has the signi?cance indicated above. A3-5a
steroids and 3a-hydroxy-5a-steroids may be obtained
from the corresponding 3-keto-A4-steroids in good yields
40 (60—90% from I to II and from 11 to III) and With a
simple and reproducible process on an industrial scale.
In greater detail the process of the invention is as follows:
A 3-keto-A4-steroid (I), with no double bonds in the
remainder of the molecule and with other keto groups, if
solid or liquid pharmaceutically acceptable vehicle in
present, blocked by a group which is easily removable
which the compounds may be dissolved, dispersed or sus~ 45
by hydrolysis (preferably a ketalic, hemithioketalic or
pended. Solid compositions may be in the form of tablets,
bismethylenedioxy group) is allowed to react with di
capsules, powders, or pills, while the liquid compositions
may be in the form of solutions, emulsions, suspensions,
borane preferably under nitrogen at atmospheric pres
sure, and at a temperature of from 0° to 100° C., such
syrups or elixirs. They may be administered topically as
as at room temperature, and the reaction product is treated
50
creams, ointments or lotions in the optional admixture
with an organic or inorganic acidic or basic dehydrating
With a therapeutically acceptable carrier or therapeuti
medium, preferably in the Warm.
cally active substances such as antibiotics or germicides.
The resulting A3-5a-steroid (II) can be isolated and
The products of the invention give neither toxic inani
puri?ed
in known manner either by crystallization or by
festations nor undesirable and dangerous collateral effects.
One of the most important products of this steroid 55 chromatographic separation, or it can be directly trans
class is the androsterone, the androgenic properties of
which are well known (A. Butenandt et al.: Z. Angew.
Chem. 44, 1931, p. 905). The literature methods for
preparing A3-5lX‘Stel'OidS from 3-keto-A4-steroids such as
the reduction according to Wolf-Kishner (G. Lardelli et
formed into the 3a-hydroxy-5aasteroid (III) by further
reaction with diborane in an ether, preferably under
nitrogen at atmospheric pressure, and a temperature of
from 0° to 100° C., preferably at room temperature, to
yield a product (III). This product may be puri?ed
according to known isolation and puri?cation procedures.
al.: Helv. Chim. Acta 32, 1949, p. 1817) or the reduc
The hydroboration reaction can be carried out by bub
tion with zinc and acetic acid (J. McKenna et al.: J.
bling
gaseous diborane into a solution of the steroid, by
Chem. Soc. 1959,‘ p. 2502) are both very expensive and
adding a diborane solution into an organic solvent, by
delicate and give low yields (20—40%) of ?nal product,
adding the diborane in the form of a complex or by
owing to the formation of the Sbeta-isomer and/or by 65 forming a diborane complex in situ, for example, by add
products. The literature processes for obtaining 3a
ing lithium and aluminum hydride and boron tri?uoride
hydroxy-5a-steroids from 3-keto-A4-steroids such as the
treatment with non-pyroforic Raney nickel (C. Djerassi
(Ann. Rep. Chem. Soc,-v 1959, pp. 198 et seq). Any
ether such as ethyl ether or propyl ether or tetrahydro~
et al.: J. Am. Chem. Soc. 77, 1955, p. 4925) always 70 furan or the dimethylether of diethyleneglycol ‘and ana~
result in the formation of a mixture of Sa-hydrOXy-Sa
logues thereof can be employed for either hydroboration
steroids and the corresponding stereosiomer in the 3-posi
reaction. In the step from Ito II it is preferable to- use
3,083,199
.
A
3;
diethyleneglycol dimethyl ether, which facilitates the sub
sequent reaction with the dehydrating medium.
Acetic anhydride, acetic acid, propionic acid, p.toluene
for an hour at room temperature and in an atmosphere
of anhydrous nitrogen, and then left to stand'for thirty
'minutes. The reaction mixture was then poured into 30
cc. of 5% methanolic potassium hydroxide; when gas
sulphonic acidv or potassium hydroxide are usually em
ployed as dehydrating media, but acetic anhydride is pre;
ferred since it has been found. to give high yields. Treat
development had ceased 3 cc. of 33 %. hydrogen peroxide
were added. After about half an hour, the mixture was
diluted with water and the whole was extracted with
ether. The ethereal extracts were washed with a solution
ment with acetic anhydride causes the hydrolysis of the
ketalic or hemithioketalic or bismethylenedioxy groups
and the acetylation of hydroxy groups, if. present.
of ferrous sulphate and with water to neutrality, dried
Between the ?rst transformation (1 to II reaction) and 10 over sodium sulphate and evaporated to dryness.
the second ([1 to III reaction) one or more reactions
The residue (545 mg.) was partially crystalline and
may be carried out such as oxidation, esteri?cation, ke
talization or hydrolysis, according to the ?nal product
was further puri?ed chromatographically on an alumina
column. With a 1:1 hexane-benzene mixture it was pos
sought. Thus according to the invention, androsterone
sible to elute 405 mg. of 5a—cholestane-3oc-ol melting at
may be prepared by treating androst-4-ene_-3-,17-dione 15 183—184° C. which, after being‘, twice recrystallized
l7-monoethyleneketal with diborane and subsequently
from dilute aqueous methanol, melts at 185—186° C.;
with acetic anhydride, then by ketalizing in the 17-posi
[a]D22°'=-|—23° (c.=1.06 in chloroform).
tion the obtained 5a-androst-3-ene-17-one, and by allow
EXAMPLE 3
ing the resulting 5ot-androst~3-ene-17-one ethyleneketal
to ‘react with diborane and subsequently with alkaline 20
hydrogen peroxide; and 19-nor-androsterone may be pre
pared by treating 19-nor-androst-4-ene-17beta-ol-3-one
5 04-11 ndr0st-3-En e-1 7-One From- Andr0st-4-Ene-3 ,1 7
Di0ne-17-M0n0ethyIeneketal
with di-borane and subsequently with acetic anhydride,
500 mg. of androst¢4-ene-3,17-dione-17-monoethylene
by hydrolyzing the acetyl group of the 19-nor-5a-androst
ketal (prepared as described in If Amer. Soc., 1953, 75,
3-ene-17beta-ol-acetate obtained, then by oxidizing the 25 p. 4425) ‘dissolved in 20 cc. of diethyleneglycol-dimethyl
17~hydroxy group. to yield 19-nor-5ot-androst-3-ene-17
ether, were treated with a great excess of diborane and
one, which is ?nally ketalized in the 17-position and
then with 10 cc. of acetic anhydride by operating exactly
treated with diborane and alkaline hydrogen peroxide.
in the same conditions and with the same procedure de
According to the present invention the known com
scribed inExample 1 for the cholest-4-ene-3-one.
pounds, 5a-cholest-3-ene (G. Lardelli et al., Helv. Chim. 30
Thus 580 mg. of crude brown colored product were
Acta, 1949, 32, p. 1817), 5u-cholestane-3a-ol (Ruzicka,
obtained.
Helv. Chim. Acta, 1934, 17, p. 1407), '5ot-androst-3-ene
Puri?cation by crystallization from dilute aqueous
17-one J. McKenna et al., J. Chem. Soc. 1959, p. 2502),
methanol or by chromatographic separation on alumina
androsterone (A. Butenandt et 211., Z. Angew. Chem.
and successive elution with benzene yielded Sa-androst
1931, 44, p. 905), 19-nor-andr-osterone (L. Englel et al., 35 3-ene-17-one; melting point 125-126“ C.; [a]D22°=-|-136
J. Biol. Chem, 1958, 231, p. 159), 5ot-pregnane-3a,17<x
(c.=1.08 in chloroform); yield: 62%.
diol-20-one (R. Neher et al., Helv. Chim. Acta, 1958,
41, p. 1667) and the new compounds 19-nor-5ct-and-rost
EXAMPLE 4
3-eneP17beta-ol, 5a~pregn - 3 7 ene - 17beta-ol-20-one, 5a
pregn-3-ene-1lbeta,17a,21-triol-20-one, 50¢ - pregnane-3a, 40
llbeta, 11a, 21-tetrol - 20 - one, 19-nor-5u-androst-3-ene
17beta-ol-acetate, l9-nor-5a-androst-3-ene-17-one, 19-nor
Androsterorte From 5 a-Androst-d-Ene-l 7-One
Ethylerteketal
_ 284 mg. of 5tx-androst-3-ene-17-one-ethyleneketal. (melt
5a-androst-3-ene-17-one '- ethyleneketal, Sm-pregIt-B-ene
ing at '1 15-1 16° C. [a]D22°=-l-‘ 13 ° (c.: 1.53 in chloro
17 tz-ol-20-one-acetate, ' 5 on - pregn-3-ene-17mo1-20-one-eth-'
form). prepared by ketalizing'255 mg. of 5a-androst-3-ene—.
17-one with ethylene glycol’ and p.toluenesulphonic acid
yleneketal,
Son-pregh-B-ene-l lbeta-ol - 17ot,20,20,21 - bis 45
methyleuedioxy, and their derivatives by the process of
the invention, where appropriate, have been prepared.
The following examples‘ are to illustrate but not. to limit
the invention.
in boiling benzene in the usual manner, dissolved in 10
,cc. of tetrahydrofuran were treated with a great excess of
diborane and then oxidized with 30 cc. of alcoholic potas
sium hydroxide and 3 cc. of hydrogen peroxide operating
EXAMPLE 1 '
,5a-Cholest-3-Ene From Cholest—4-Ene-3-One
A solution of 1 g. of cholest-4-ene-3-one in 20 cc. of
diethyleneglycol dimethylether was treated with a great
under the same conditions and in the‘ same manner as
described in Example 2 for 5a-cholest-3-ene. Thus, about
300 mg. of a colorless oil were obtained,- which was dis
solved in 5 cc. of acetic acid and 5 cc. of water and heated
on a water bath for an hour. , Evaporation of the solvent
excess of diborane for an hour at room temperature and 55 under vacuum left a colorless non-crystalline residue
lthen left to stand for another forty minutes. 10' cc. of
weighing about 290 mg.
. '
‘acetic anhydride were added to the solution which was
Recrystallization from a methylene dichlorideheptane
then re?uxed for an hour. All these operations were car
mixture or by chromatographic separation on alumina and
ried out under an atmosphere of anhydrou'swnitrogen. ' 7 subsequent elution with benzene and a'3:'1 benzene-ether
The reaction mixture, of dark brown color was evapo 60 mixture yielded androsterone; melting point 181~182° C.;
rated under vacuum at 80° C., poured into water and
ialnzz°=+97° (c.=1.20 in ethanol); yield: 50%.
extracted with ethyl ether. The ethereal extracts were
washed with 10% sodium hydroxide and with water to
EXAMPLE 5
neutrality and dried over sodium sulphate. Removal of
19-N0r-5m-A ndr0St-3-Ene-l 7Betd-Ol From 19-Nor:
the ethereal solvent’ yielded 1.060 g. of a ‘brown viscous 65
A ndr0'st-4-En e-] 7Beta-0 Z-3-0ne
oil.v By either recrystallization from aqueous’ methanol
or chromatographic, separation on alumina and successive .
3 g. of 19-nor-androst-4-ene-17beta-ol-3-one dissolved
elution with hexane, 5 u-cholest-3-ene was obtained; melt= '
in 50 cc. of diethyleneglycol-dimcthyl-ether were treated
with'a'great excess of diborane and subsequently with 25
70 ccjof acetic anhydride,,operating in exactly the same con
ditions and following the'same procedure as described in
5a-Cholestan-3a-Ol
.
EXAMPLE/2
From 5a-Ch0lest-3-Ene . a»
A solutioniof s03 mgof 5oi-cholest-3-ene in 10 cc. 0t
tetrahydrofuran was treated'with an excess of diborane
Example 1 for cholest-4-ene-3-one.
,
_
About 3.3 ,g. of a crystalline dark-brown colored prod
uct were thus obtained from which by recrystallization or
by chromatographic separation on alumina and subse-'
3,083,199
5
5
EXAMPLE 9
quent recrystallization from dilute aqueous methanol 1.7
g. of product was obtained, which after two further re
5 u-Pregn-3-Ene-1 1 Beta,] 7 0;,21 -Triol-20-One From Pregn
crystallizations from dilute aqueous methanol yielded 19
4 - Ene-l IBeta-Ol-I 7ot-20,20,21-BiSmethylenedioxy-3—One
nor-5m-androst-3-ene-l7beta-ol-acetate; melting point 115
116° C.; [a]D22°=—66.7° (c.=l.93 in chloroform).
By hydrolyzing the l9-nor-5a-androst-3-ene-17beta-ol
Pregn - 4 - ene-llbeta-ol,17a-20,20,2l-bismethylenedi
oxy-3-one (prepared as described in U.S. Patents No..
2,888,456 and No. 2,888, 457) was treated with diborane
and then with acetic anhydride as described in Example 1
acetate with 5% methanolic potassium hydroxide at room
temperature forl4hoursl9-nor-5a-androst-3-ene-l7beta-ol
was obtained; melting point l07—l08° C.; [a.]D22°=27.2°
(c.—_—l.77 in chloroform); quantitative yield.
10
for cholest-4-ene-3-one. By the hydrolysis and saponi?
cation of the resulting product 5a.-pregn-3-e-ne-llbeta,l7a
21-triol-20-one was obtained.
EXAMPLE 6
EXAMPLE 1O
Sa-Pregnane-SuJ1Beta,17a,21-Tetr0l-20-OneI From 5a
19-N0r-A ndrosrerone From 1 9-NOT-5oc-Andl'0St-3-EH6-1 7
One-Ethyleneketal
15
The starting material, l9-nor-5a-androst-3—ene-l7-one
5o¢~pregn - 3 - ene - llbeta - ol - l7a,20,20,2l-bismethyl
ethyleneketal, was prepared .by oxidation of 19-nor-5u
androst-3-ene-l7beta-ol with chromic acid in pyridine at
enedioxy (prepared in known manner from 5a-pregn-3
ene-1lbeta,l7ut,2l-triol-20-one) was reacted with diborane
and then with alcoholic potassium hydroxide 'and hydro—
room temperature in the known manner to l9-nor-5a
androst-3-ene-l7-one; melting point l2l—l22° C.;
Pregn-3-Ene-1 1 -Beta-0l-1 7a,20,20,21 -Bismethylenedioxy
20 ‘gen peroxide under the same conditions, and by the same
procedures as described in Example 2 for 5a-cholest-3
ene and hydrolysis in known manner was transformed
into 5 u-pregnane-3u, 1 lbeta, 17a,2 1-tetrol-20-one.
(c.=l.92 in chloroform), which in turn was ketalized with
ethylene glycol and p.toluenesulphonic acid in boiling 25
benzene by the technique of Example 4 to l9-nor-5a
We claim:
1. A process for preparing Set-steroids, the A and B
rings of said Set-steroids having the formula:
androst-3-ene-l7-one-ethyleneketal.
443 mg. of the crude starting material was dissolved in
15 cc. of tetrahydrofuran and treated for an hour at room
temperature and in the atmosphere of anhydrous nitrogen 30
with excess of diborane and then left to stand for thirty
minutes. The reaction mixture was then slowly poured
into 30 cc. of 5% methanolic potassium hydroxide and
wherein R is a a-hydroxy when a double bond is absent v
when gas development ceased, 3 cc. of 33% hydrogen
peroxide were added. After about half an hour, the mix 35 in the 3:4-position and hydrogen when a double bond is
present in the 3:41position; R’ is selected from the group
ture was diluted with water and the whole was extracted
consisting of hydrogen and methyl when a side chain is
with ethyl ether. The ethereal extracts were washed with
absent from the l7-position and R’ is methyl when a side
a solution of ferrous sulphate and then with water to
chain is present in the l7-position, and double bonds are
neutrality. They were dried over sodium sulphate and
40 absent from other parts of the steroid molecule, which
evaporated to dryness.
comprises treating a 3—keto-A4-steroid free of other double
The residue was dissolved in 5 cc. of acetic acid and in
bonds in the rest of the molecule and free of other un
5 cc. of water, and heated for an hour at 30° C. 420 mg.
protected ketone groups, in etheral solution and under a
of l9-nor-androsterone (melting point 158—l59° C.) were
protective atmosphere with diboran-e and dehydrating the
obtained after the elimination of the solvent under vacuum.
The product recrystallized from heptane melts at 162-— 45 reaction product.
2. A process for preparing a compound selected from
163° C.; [a]D22°=+l05° (c.=1.2 in chloroform).
the group consisting of A3- and A3-l‘9-nor-5u-steroids un—
substituted in the 3-position and lacking double bonds in
other parts of the steroid molecule, which comprises treat
EXAMPLE 7
5 a-Pregn-3-Ene-1 7a—0l-20-0ne From Pregn-4-Ene-1 7a
Ol-3,20-DiOne-ZO—M0noethyleneketal
50
Pregn - 4 _ ene-17a-ol-3,20-dione-20-monoethyleneketal
ing a 3-keto-A4-st-eroid free of other double bonds in the
rest of the molecule and free of other unprotected ketone
groups, in etheral solution and under a protective atmos
phere with diborane ‘and dehydrating the reaction product.
(prepared as described in the U.S. Patent No. 2,648,662)
3. A process for preparing a compound selected from
in solution in ethyleneglycol dimethylether was treated
with diborane and then with acetic anhydride in exactly 55 the group consisting of 3a-hydroxy- ‘and 3oc-l1YdI‘0XY-19
nor-5a-steroids unsubstituted in the 3~position and lack
the same conditions and by the same process as described
ing double bonds in other parts of the steroid molecule,
in Example 1 for the cholest-4-ene-3-one. It was trans
which comprises treating a 3-keto-A4-steroid free of other
formed into 5a-pregn-3-ene-l7a. - ol - 20-one - 17 - acetate
double bonds in the rest of the molecule and free of other
(melting point l82—l84° C.; [Ct]D22°=—|~90, c.=l.2 in
unprotected ketone groups, in etheral solution ‘and under
chloroform; yield 70%) which by hydrolysis in known
a protective atmosphere with diborane, dehydrating the
manner with alkali gave 5a-pregn-3-ene-l7a-ol-20~one.
reaction product, and treating the resulting A3-5a-steroid
in ethanol solution and under a protective atmosphere with
diborane and subsequently with alkaline hydrogen per
EXAMPLE 8
5 a-Pregnane-S 0A,] 7u-Diol-20-One From 5 u-Pregn-3-Ene
1 7a-0l-20-0ne-Ethyleneketal
65
oxide.
'
4. A process for preparing a compound selected from
by ketalization of Sa-pregn-S-ene-l7a-ol-20-one with
ethylene glycol and p.toluenesulphonic acid in boiling
the group consisting of 3a-hydroxy- and 3a-hydroxy-l9
IIOY-Sa-Si?l‘OidS unsubstituted in the 3-position and lack
ing double bonds in other parts of the steroid molecule,
and then with alcoholic potassium hydroxide and hydrogen
peroxide under the same conditions and following the
unprotected ketone groups, in diethyleneglycol dimethyl
same procedure as described in Example 2 for Set-cholest
other solution under a protective with idi-borane, dehydrat
5a - pregn-3-ene-l7u-ol-20-one-ethyleneketal (prepared
benzene in the known manner) was reacted with diborane 70 which comprises treating a 3-keto-A4-steroid free of other
double bonds in the rest of the molecule and free of other
3-ene, and was transformed into 5u-pregnane-3a,l7a-diol
2(l-one.
ing with acetic anhydride, and treating the resulting A3
75 Sa-steroid in tdiethyleneglycol dimethyl ether solution
,
sesame
7'
'
8
under a protective atmosphere with diborane followed by
‘alkaline hydrogen peroxide.
7
5. A process for preparing a compound selected from
the group consisting of 3a-hydroxy- and 3a-hydroxy-l9nor-Su-steroids unsubstituted in the 3-position and free of 5‘
. 5ot-pregn-3-ene-17a-olr20-one.
5uqpregn-3-ene-l7a-ol-20-one acetate.
. 5c¢-pregn-3—ene-17<x-o1-20-one-ethyleneketal.
. 5tx-pregn-3-ene-1llbeta,17a,21-triol-20-one.
10. 5oz - pregn-3-ene-11beta-ol-l7u,20,20,2l-bisrnethyl
double bonds in other parts of the molecule, which vcomenedioxy.
prises treating a compound selected ‘from the group con11. 5e<pregnane-3a,l1beta~17a,2l-tetrol-ZO-one.
sisting of the corresponding A3 and A3-19-nor-5a-steroids
in diethyleneglycol dimethyl ether solution under a proReferences Cited in the ?le of this Pawnt
tective atmosphere with diborane followed by alkaline 10
McKml-m et 91‘; L Chem. Soc. 1959, pages 2502-2509.
hydrogen peroxide.
‘
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