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Патент USA US3076832

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United States Patent O??ce
1
3,076,822
Patented Feb. 5, 1963
2
4-methylandrost-4-ene-3,11,17-trione which is an inter
3,076,822
mediate for the preparation of the tlls-hydroxy deriva
tive into which it may be converted by NaBH4 reduc~
tion and MnOz oxidation of the 3-hydroxy group.
4-methyldesoxycorticosterone acetate, which is of value
4-METHYL-l’i-OXWA‘l STEROIDS AND METHODS
FOR PREPARING SAME
David Neville Kirk and Vladimir Petrow, London, Eng
land, assignors to The British Drug Houses Limited,
London, England, a company of Great Britain
N0 Drawing. Filed Nov. 16, 1959, Ser. No. 852,972
Claims priority, application Great Britain Nov. 19, 1958
5 Claims. (Cl. 260-3974)
on account of its effect upon mineral balance.
The method of the invention may be applied to 4-thio
methyl~3-oXo-A4-steroids of the androstane, prcgnane,
cholane, cholestane, ergostane, stigmastanc and spirostane
10 series and their 19-nor and D-horno analogues.
This invention is for improvements in or relating to
In gen~
eral, the following groups do not interfere with the process
of the reaction:
Hydroxy (or esteri?ed hydroxyl) or alkoxy groups, in
organic compounds and has particular reference to a new
method for the preparation of 4-methyl-3-oxo~A4-steroids.
It is an object of the invention to provide a new method
for the preparation of 4-methyl-3-oxo-A4-steroids utilising 15
particular at positions C-6, 11, 12, 14, 16, 17, 20 and 21.
as starting material a 4-organothiomethyl-3-oXo-A4~steroid.
0x0 groups, in particular at positions C—1 1, 12, 17 and 20.
The 4-methyl~3-oxo~n4~steroids are useful on account of
Carboxyl groups (or esteri?ed carboxyl groups), in par
their biological properties, or as intermediates in the prepa
ticular at C-21 and 24.
Alkyl groups containing up to live carbon atoms, in
ration of compounds having valuable biological properties.
Thus, for example, 4-methyltestosterone has a more 20
favourable anabolic/androgenic index than has testos
particular methyl groups at C-1, 2, 6, 7, 11, i4, 16 and
17 and ethyl groups at C—17.
terone, while 4~methylprogesterone, for example, has
Ketal groups, in particular ethylenedioxy or trirnethylcnc
dioxy at positions C-12, 17 and 20, bis-methylenedioxy
According to the present invention there is provided a
at C—17:20:20:21 or substituted methyienedioxy at
progestational activity.
positions such as C—16:17.
method for the preparation of 4~rnethyl-3-oxo-u\4-steroids 25
Fluoro groups, in particular at position C-9.
which comprises reacting a 4-organothiomcthyl-3-oxo
Ethyleriic linkages, in particular endocyclic linkages at
A‘Lsteroid with a reducing agent to achieve reductive
?ssion of the sulphur-containing group.
positions such as 6:7, 7:8, 9:11, 11:12, 14:15, 17:20
and 22:23, and exocyclic linkage in particular such as
The reducing agent is preferably Raney nickel treated
are present in IG-methylene derivatives, also will not
in the manner hereinafter described. Zinc dust/alkali 30
in general interfere with the process of the reaction.
metal hydroxide represents another convenient reducing
agent.
The 4-organothiomethyl~3-oxo~A4-steroids employed as
The invention also provides the following new 4-methyl
starting materials in the present invention are described
3-oXo-A4-steroids:
in our copending application No. 852,971, ?led November
2a:4~dimethyltestosterone, its acetate, propionate, ?~phen 35 16, 1959. They may be prepared by condensing the cor
responding 3-oxoAA4-steroid with formaldehyde or para~
ylpropionate, p-chlorophenoxy acetate, which are of
value on account of their favourable anabolic/andro
formaldehyde and a thiol in the presence of a basic
genie index.
catalyst. It is not essential to isolate the 4-organothio
methyl compounds in crystalline form, as they are gener
416a - dimethyltestosterone, its 17 - acetate, propionate,
?-phenylpropionate, which are of value on account of 40 ally formed in high yield, so that the total product may
be employed for the reaction of the present invention if
their favourable anabolic/androgenic index.
so desired.
17e~acetoxy~4methylprogesterone which is of value on
Desulphurisation of the 4-organothiomethyl starting
account of its progestational activity.
material may be carried out by treating a solution of the
17a-hydroxy-4-methylprogesterone which is of value as an
organothiomethyl compound with Raney nickel of a
intermediate for the preparation of the 17a~acyl deriva
suitable reactivity. The preferred solvent is acetone, but
tives.
l7a-acetoxy-4 : ?wdimethylprogesterone.
4: l6e-dimethylprogesterone which is of value on account
of its progestational activity.
1lp-hydroxy-17a:2U:20:21-bis-methy1enedioxy - 4 - meth
ylpregn-4-en~3-one which is of value as an intermediate
in the preparation of 4-methyl corticoids.
4--methyltestosterone B-phenylpropionate.
4-methyltestosterone phenoxyacetate.
other ketonic solvents such as butan-Z-one or cyclohexa
none may be employed, either alone or diluted with an
inert solvent such as a lower alkanol containing up to 5
50 carbon atoms. The reactivity of the Raney nickel must
?rst be adjusted so as to prevent saturation of the 4:5
ethylenic linkage, which may occur if a highly active
Raney nickel is used. Raney nickel, as ordinarily pre
pared, my be suitably deactivated by preliminary heating
4-methyltestosterone p-chlorophenoxyacetate which are of 55 in the ketonic solvent, preferably acetone, in which'the
desulphurisation is to be effected, preferably in a slow
value on account of their favourable anabolic/andro
stream of nitrogen to facilitate removal of the hydrogen
genic ratios.
gas which is evolved from the nickel. The thiornethyl
4-methyl-17m-caproyloxyprogesterone.
compound is then added to the suspension of deactivated
4-methyl-l7a-acetoxy - 16 - methyleneprogesterone which
are of value on account of their progestational activity. 60 Raney nickel, and heating is continued until desnlp-huri
sation is completed, when the 4-methyl-3-oxo-A4-steroid
may be isolated, for example, by ?ltration to remove the
nickel and evaporation of the ?ltrate.
anabolic/ androgenic index.
When the thiomethyl compound contains a readily oxi
4-methy1-11,8,l7p-dihydroxyandrost-4-en-3-one which is of
value on account of its favourable anabolic/androgenic 65 disable hydroxyl group, such as a 17;‘3-hydroxyl group, it
is advisable to protect this group by formation of a de
index.
rivative such as the acetate or propionate prior to the de
4-methyl-11m,17,8-dihydroxyandrost-4-en-3-one which is an
sulphurisation reaction, in order to avoid partial oxida
intermediate for the preparation of the 11 ?-hydroxy
tion of the hydroxyl group to an oxo group, which may
derivative into which it may be converted by oxidation
70 occur, with concomitant reduction of a part of the ke
to the 3,11,17-trione, NaBH, reduction and MnO;
tonic solvent to the corresponding alcohol, under the cat~
oxidation of the 3~hydroxy group.
4,17nt-dittt6ihYl-9a-?tl0l‘0 - 11 6,1713 - dihydroxyandrost - 4
en~3~one which is of value on account of its favourable
alytic in?uence of Raney nickel. The hydroxyl group
8,078,822
4
may be regenerated after desulphurisation, if desired, by
Example 3
hydrolysis of the ester, for example, with alcoholic alkali.
Alternatively, when esteri?ed products are required, it
thiomethyltestosterone replacing the 4-benzylthiomethyl
The procedure of Example 2 was repeated, 4-ethy1
will be apparent to those skilled in the art that an ester
testosterone.
group may be conveniently introduced into the thiomethyl
compound. The acyl radical of the ester group may, for
example, be derived from a hydrocarbon carboxylic acid
containing up to 10 carbon atoms. Thus, for example,
as before.
Example 4
The procedure of Example 2 was repeated employing
4-butylthiomethyltestosterone. 4-methyltestoster0ne ace
in the preparation of a 4--methyl-testosterone ester a 4
tate was obtained as before.
alkyl or arylthiomethyltestosterone may be converted by
Example 5
The procedure of Example 2 was repeated employing
esteri?cation into the appropriate 4-alkyl or arylthio
methyltestosterone ester, and the latter compound treated
with Raney nickel to give the required 4-methyltestoster
one ester.
4-methyltestosterone acetate was obtained
?-hydroxyethylthiomethyltestosterone. 4-rnethy1testoster
For the preparation of such products as 4
methyltestosterone zinc dust alkali—metal hydroxide
one acetate was obtained as before.
forms a convenient reducing agent.
In applying the reaction to steroidal materials contain
Example 6‘
Testosterone (5.76 g), ethane dithiol (0.92 ml.), form
aldehyde (40% aqueous solution; 3 ml), triethylamine
ing the ketol side-chain, such, for example, as cortisone,
it is generally desirable to prevent the possibility of par
(3 ml.) and ethanol (10 ml.) were heated under rei'lux
ticipation of the ketol side—chain in the process of the 20 for 60 hours, the product was isolated by pouring the
reaction. This is conveniently achieved by ketalisation of
mixture into a 5% aqueous solution of potassium hy
the 20-oxo group or preferably by conversion of the ketol
droxide (200 ml), extracting with chloroform, washing
side-chain into the bismet'nylenedioxy derivative. The
this solution, and evaporating the solvent, as a pale yel
protecting groups may subsequently be removed.
low oil, Am“ 250 mu. Acetylation of this product, fol
Following is a description by way of example of meth
lowed by desulphttrirction as described in Example 2 gave
ods of carrying the invention into effect:
4-methyltestosterone acetate, M.P. 158 to 160° C.
Example I
Example 7
Raney nickel (40 ml. of settled aqueous sludge) was
Tolucne<3z4~dithiol (3.1 ml.) was substituted for
washed by decantation with acetone (3 x 200 ml.), then 30 ethane ditlrinl in Example 6. "the thiomcthylation prod
covered with acetone (200 ml.), and the mixture was
uct was obtained as a granular solid.
heated under re?ux in nitrogen for 1 hour. 4-phenyl
Acetylation and desulphutisation as described in Ex
thiurncthyltestosterone acetate (4.4 g.), dissolved in ace
ample 2 gave 4-rnethyltestosterone acetate, M.P. 158 to
tone (60 ml.), was added to the nickel suspension, and
160° C.
heating was continued for 4 hours. The nickel was then
Example 8
removed by ?ltration, and washed on the ?lter with hot
ethanol (100 ml.) followed by water (50 ml.).
The procedure of Example 1 was repeated employing
Za-methyl-4-phenylthiomethyltestosterone acetate.
The
combined ?ltrates were concentrated under reduced pres
Puri?cation from methanol gave 2a-4-dimcthyltestoster
sure until the product separated in solid form, then the
solids were collected and puri?ed from methanol, giving
4-methyltestosterone acetate, M.P. 158 to 160° C., [11],)“
+l02° (c.,0.2l in chloroform), km“, 249 mu (e=l5,190)
in ethanol.
one acetate in plates, M.P. 188 to 190° G, Am“, 248 mu
(E:14,480) in ethanol, [£11921 +117” (c., 0.24 in chloro
form).
Similarly the following esters were prepared from the
corresponding 2o<~me1hyl-tphenylthiomcthyltestosterone
Sapcni?cation of the foregoing acetate (0.5 g.) by
esters.
heating under reflux for V2 hour with potassium hydrox
ide (0.2 g.) in 80% aqueous methanol (20 m1.), and
puri?cation from aqueous methanol, gave 4-methyltestos
terone, M.P. 172 to 173°’ C., [11:11)” +132° (c., 0.17 in
chloroform).
The following esters of 4-methyltcstosterone were pre
pared in similar manner:
l’ropionste: plates from methanol, Ml’. 136 to 138°
C., [MD24 +1095” (c., 0.42 in chloroform), kmlm
247.5 mu (s:14,340) in ethanol.
?-Phenylpropionate: M.P. 135 to 138° C., [rxhgm
50 +116“ (c., 0.48 in chloroform), Amam 248 mu (sr:l4,900)
in ethanol.
p-Chlorophenoxyacetate: M.P. 133 to 134° C., [111922
+107” (c., 0.46 in chloroform), Am“ 229 mu (5: 15,910),
Propionate, n-butyrate, n-valerate, iso-valerate (penta—
noatc), n'caproate (hexanoate), n-heptylate (heptanoate),
248 mu (£214,020), 278 mu (e:16~40) and 287 mu
n-caprylate (octanoate), n-oenanthate (nonanoate), n 55 (5:1210) in ethanol.
caprate (decanoate), phenylacetate, ?-phenylpropionate,
The foregoing acetate (100 mg.) in 80% aqueous
'y-phenylbutyrate, phenoxyaeetate, p-chlorophenoxyaee
methanol (10 ml.) containing potassium hydroxide (50
tate.
mg.) was heated under reflux for 1/2 hour, diluted to tur
bidity, and the solids which separated on cooling were
Example 2
4-benzylthiomethyltestosterone (2 g.) in anhydrous
pyridine (10 ml.) and acetic anhydride (5 ml.) was
60
puri?ed from acetone/hexane (1:3).
2a:4-dimethyl—
testosterone formed prisms, M.P. 156 to 158° (3., [0:1925
+122° (c., 0.72 in chloroform), Rum, 248.5 mu (e:
14,400) in ethanol.
heated at 50° C. for 2 hours and the mixture was poured
into water. The product was extracted with ether, and
Example 9
the ether extract was washed with water, dilute hydro
65
17a-methyl-4~phenylthiomethyltestosterone
was desul
chloric acid, water, sodium bicarbonate solution and water
phurised according to Example 1, to give 4: 17a-dimethyl~
until neutral, dried over sodium sulphate and evaporated.
testosterone, M.P. 141 to 142° C., [r1152z +85” (c., 0.22
The total acetylation product in acetone (40 ml.), was
in chloroform), 71",“ 249.5 mu (e=l3,230) in ethanol.
added to Raney nickel (20 ml. of sludge) which had
17a-ethyl-4»methyltestostcrone was prepared in a simi
been previously heated with acetone (100 ml.) under 70
lar way.
re?ux in nitrogen for 1 hour. After being heated for
a further 4 hours, the product was isolated as described
in Example 1. Puri?cation from methanol gave 4-methyl
testosterone acetate, M.P. and mixed M.P. 158 to 160° C.,
with the sample prepared in Example 1.
Example 10
_ 4-phenylthiomethylandrost-li-ene-3:17-dione (2.55 g.)
1n acetone (50 ml.) was added to a suspension of Raney
76 nickel (22 ml.) in acetone (100 ml.) which had been
5
8,076,822
6
previously heated under re?ux for 1 hour. The heating
(e=17,620) in ethanol, 7m“, 1669 and 1602 cm.“1 in
carbon tetrachloride.
was then continued for 41/; hours, when the nickel was
removed by ?ltration, and washed with ethanol and
Example 17
water, and the combined ?ltrates were concentrated under
reduced pressure. The separated solids were puri?ed from
The procedure of Example 2 was repeated employing
4 - methylthiomethyltestosterone.
acetone/hexane to give 4-methylandrost-4-ene-3:17-dione
in needles, M.P. 138 to 140° C., [@924 +207“ (c., 0.72
in chloroform), Am,‘- 248.5 mu (e=15,320) in ethanol.
Exam ple 11
4 - methyltestosterone
acetate was obtained as before.
Example 18
The procedure of Example 2 was repeated employing
10 4-n - decylthiomethyltestosterone.
owmethyl - 4 - phcnylthiomethylandrost _ 4 - cue-3:17
4 - methyltestosterone
acetate was obtained as before.
dione was desulphurised as described in Example 10 and
gave 4:6a-dimethylandrost-4-ene-3:l7-dione, which sepa
rated from acetone/hexane (1:2) in prisms, M.P. 176 to
Example 19
The procedure of Example 2 was repeated employing
178° C., Am“ 249 mu (e=15,030) in ethanol.
15 4-n-dodecyltl1iomethyltestosterone. 4-methyltestosterone
Example 12
acetate was obtained as before.
Raney nickel (11 ml. of settled sludge) was washed by
Example 20
decantation with acetone (3 X 100 ml.), then heated with
The
procedure
of
Example
2 was repeated employ
acetone (45 ml.) under re?ux in nitrogen. After 1 hour 20 ing 4-cyclohexylthiomethyltestostero-ne.
4-methyltestos
4-phenylthiomethylprogesterone (l g.) in acetone (25
terone acetate was obtained as before.
ml.) (was added, and heating was continued for 4 hours.
Example 21
The nickel was removed by ?ltration, washed on the
?lter with hot ethanol (50 ml.) and water (30 ml.), and
The procedure of Example 2 was repeated employing
‘the combined ?ltrates were concentrated under reduced
pressure until the product separated as a solid. Puri?ca
4-p - tolylthiomethyltestosterone.
tion from methanol gave 4-methylprogesterone in rods,
M.P. 164 to 166° C., [(211335 +2125“ (c., 0.29 in chloro
form), Am“ 249 mu (£215,320) in ethanol, 7mm 1709,
1671 and 1606 cm?1 in chloroform.
30
Example 22
The procedure of Example 2 was repeated employing
4 - allylthiomethyltestosterone.
Example 23
4-pher1ylthiomethylpregna-4:9(11)-diene - 3:20 - dione
was desulphurised according to Example 12 to give 4
methylpregna—4:9(11)-diene-3.20-dione, which separated
from acetone/hexane (1:10) in needles, M.P. 146 to 149°
The procedure of Example 2 was repeated employing
35 4 - furfurylthiomethyltestosterone.
acetate was obtained as before.
C., Am,“ 249 mu (e=14,8U0) in ethanol, [ixjnm +154°
(c., 0.98 in chloroform).
Example 14
prisms, M.P. 142 to 144° C. or 172 to 175° C., [@1924
4 - methyltcstosterone
Example 24
The procedure of Example 2 was repeated employ
40
ing 4-(naphthalene-2'-thiomethyl)-testosterone.
4~methyltestosterone acetate was obtained as before.
progesterone (250 mg.) with Raney nickel (5 ml.) as
described in Example 12, and puri?cation from acetone/
hexane (1:2) gave 17m<acetoxy~4-meth3lprogesterone in
4 - methyltcstosterone
acetate was obtained as before.
Example 13
Desulphurisation of 17a-acetoxy~4-phenylthiomethyl
4 ~ methyltestosterone
acetate was obtained as before.
Example 25
The procedure of Example 6 was repeated, decane
lzl?-dithiol replacing ethane dithiol.
4~m~ethyltcstos
+80” (c., 0.63 in chloroform), an,“ 248.5 mu (5: 45 terone acetate was obtained as before.
13,720 in ethanol), 'ymm 1736, 1722, 1673 and 1608
Example 26
cm.-1 in carbon disulphide.
The
procedure
of
Example
2 was repeated employing
Saponi?cation of the 17-acetate with 2% methanolic
potassium hydroxide gave 17m-hydroxy-4-methylproges
terone, M.P. 239 to 241° C., [(11921 +99° (c., 0.97 in
chloroform), km“ 250 mu (e=15,540) in ethanol.
Example 15
Desulphurisation of 17a:20:20:21-bismethylenedioxy—
4-phenylthio1nethylpregn-4-ene-3:11~dione (4 g.) with
175 - hydroxy - 4 - phenylthiomethylandrosta - 4:6 - dien
3-one. Puri?cation of the product from (80%) aqueous
methanol gave 17,8-acetoxy-4-inethy1androsta-4:6-dien-3~
one in needles, M.P. 154 to 155° C., [0:113:32 +87‘’ (0.,
0.11 in chloroform), Am“ 289 mu (is: 29,180) in ethanol.
Saponi?cation of the foregoing acetate as in Example
55 1
gave
17s - hydroxy - 4-methylandrosta-4:6-dien-3-one
which separated as prisms from aqueous methanol, M.P.
Raney nickel (40 ml.) as described in Example 1, and
132 to 134° C., Amu- 289.5 mu (e=29,440) in ethanol.
puri?cation from acetone/hexane (1:2) gave 17a:20:20:
21~bismethylenedioxy-4-methylpregna-4-enc-3: 1 l-dione in
Example 27
plates, M.P. 279 to 284° C. [ailn25 +87° (c., 0.63 in 60
The procedure of Example 2 was repeated employ
chloroform), Am“, 248 mu (e=l3,700) in ethanol, 7m,
ing 6a-methyl-4-phenylthiomethyltestosterone. Puri?ca
1706, 1673 and 1601 cm."1 in carbon tetrachloride.
tion of the product from methanol gave 426a~dimethy1~
The foregoing bismethylenedioxy compound (1 g.) in
testosterone acetate, M.P. 155 to 158° C., Am“, 250 mu
60% aqueous formic acid (40 ml.) was heated at 100° C.,
(e=14,73[)) in ethanol. Similarly was prepared 4,6cz-di
for 20 minutes and then poured into water. Puri?cation 65 methyltestosterone propionate, needles from methanol,
of the precipitated solids from acetone/hexane (1:1) gave
M.P. 126 to 128° C., [MD26 +8.5" (c., 0.42 in chloro~
4-methylcortisone, M.P. 229 to 233° C., [(111321 +212°
form) Amm- 250 mu (e:l3,935) in ethanol and 4,6a
(c., 0.10 in chloroform), Am“ 248 mu (e=14,050) in
ethanol.
Example 16
Desulphurisation of 4-phenylthiomethyl-25D-spirost
4-en-3-one as described in Example 1 gave 4-methyl-25D
spirost-4-orie in ?ne needles, M.P. 167 to 170° C.,
[c1925 i0° (c., 0.35 in chloroform), Am“, 251 mu
dimethyltestosterone p-phenylpropionate, M.P. 146 to
148° C., [ch22 +24° (c., 0.38 in chloroform) Am“. 251
70 mu (e=13,5DD) in ethanol.
Saponi?cation of the foregoing acetate as in Example
1 gave 4:6at-diniethyltestosterone, which separated from
acetone/hexane (1:2) in prisms, M.P. 228 to 230° C.,
[@925 +14° (c., 0.22 in chloroform), Am“ 251 mu
75 (e=13,890) in ethanol.
3,076,822
8
7
Example 28
The procedure of Example 2 was repeated, employ
ing 4-phenylthion1ethyl-D-homotcstosterone, when the
product was 4-methyLD-homotestosterone acetate. Su
poni?cation as in Example 1 gave 4~metl1yl-D-homotes
acetone/hexane (1:2) in lea?ets, M.P. 152 to 154“ C.,
M11325 +173“ (c., 0.35 in chloroform), Am“, 249 mu
(e:l6,270) in ethanol.
Example 38
160a: 170a - dimethylmethylenedioxy-4-phenylthiomethyl
progesterone treated according to Example 12 gave 4
tosterone, Am“, 249 mu.
methyl - 160G170: - dimcthyln'lethylenedioxyprogresterone
Example 29
6-methyl-4-phenylthiomethylandrosta-4:6-diene - 3:17
dione was dcsulphurised as described in Example 10, to
which separated from aqueous methanol in needles, MP.
217 to 22!)“ C., Am“, 2485 inn (Er-116,005) in ethanol.
Example 39
give 4:6-dimethylandrosta-4:6~diene-3:17-dionc.
4 - phenylthiomethylpregna - 4: l l-dicne-3 :ZO-dione Was
Example 30
dcsulphurised according to Example 12 and gave 4-mcthyl
pregna-el: 1l-dicne-3 :20‘dione.
phurised according to Example 1, and gave 4-methylcho
Example 40
lest-4-en-3-o-ne which separated from ethanol in prisms,
M.P. 101 to 103° C., [01],;22 +l08° (c., 0.35 in chloro
4~phcnyltniomcthyl-l9-no1'tcstosterone was acetylated
form), Am“ 251 mu (e=15,900) in ethanol.
and desulphurised according to Example 2 to give 4
methyl-Boron-testosterone acetate which separated from
Example 31
20 aqueous methanol in prisms, M1’. 122 to 123° C., [M1324
4-phenylthiomethylstigmasta-4:22-dien-3-onc was de
+51” (c., 0.43 in chloroform), hmm 248 mu (a: 16,230)
sulphurised according to Example 1, and gave 4-methyl
in ethanol.
sligmasta-4:22-ciien-3-one, prisms from ethanol, MP. 83
Saponi?cation as in Example 1 gave 4-rnethyl- l9
to 86° C., [MDJ2 +6l° (c., 0.77 in chloroform), 71mg,‘
nortestostcrone, MP. 156 to 157° C., [@1921 +50° (C.,
252 mu (e=l4,99i)) in ethanol, em“ 3061, 1676 and 25 0.47 in chlorot'orm), >\,,,,,,,_ 250 mu (e11 15,350) in ethanol.
1600 cm."1 in carbon tetrachloride 972 emf] in carbon
Example 41
disulphide.
Example 32
1~methyl~4~ph=3nylthiomethyl - l9 - nortcstosterone was
:tcctyluted and dcsulp'nuriscd according to Example 2 to
4-phcnyl’thiomethylergosta-4:7:22~trien-3-one was dc~
sulphurised according to Example 1 and gave 4>methyi 30 give l:4-dimcthyl-l9-norlcstoslerone acetate.
Saponi?cution as in Example 1 gave 114~dimethyl~
ergosta-4:7z22-trien-3-one prisms from ethanol, MP. 125
19-nortestosterone.
to 127° C., [11],;24 +59 (0.42 in chloroform) km“, 247.5
Example 42
mu (e=18,590) in ethanol 'yma,,_ 1668 and 1603 cm."1
in carbon tetrachloride.
9o: - ?uoro-17e:20:20:21~his-methylenedioxy-4-phenyl
35
thiomethylpregn-4-ene-3:ll-dione was desulphurised ac
Example 33
cording to Example 12 to give 9ca-llu0l‘0~l7<xi29220221
Methyl 3-oxo-4-phenylthiomethylchol-4-en-24-oatc was
hiwnethylenedioxy-4-n1eti'tylprcgn-4-cne-3: 1 l-dione.
desulphurised according to Example 1 and gave methyl-3
Removal of the protecting bis-methylenedioxy group as
oxo-4~methylchol-4-en-24-oate lea?ets from methanol,
in Example 15 gave 9a-?uoro-4-methylcortisone.
MP. 100 to 103° C., [@1533 +80° (c., 0.89 in chloro
Example 43
form) Am“. 250 mu (6:13.980) in ethanol.
4~phcnylthiomethylcholest - 4 - en - 3 - one
was
desul
Example 34
The procedure of Example 2 was repeated employing
7;3-methyl-4-phenylthiomethyltestosterone, when the prod
uct was 4:7?-climcthyltcstosterone acetate.
Saponi?cation as in Example 1 gave 4:7;i-dimethyltes
tosterone.
Example 35
The procedure of Example 14 was repeated employing 50
170: - caproyloxy-ll-phenylthiomethylprogresterone, when
the product was 17a-caproyloxy-4-methylprogesterone,
14a-methyl-17a:20:20:2l-bis-methylenedioxy-4~phenyl~
thiomethylprcgn-4-ene-3:ll-dionc was dcsulphurised ac
cording
to
Example
12
to
give
4:14a-dirnethyl
17mr20: 20:2l~bis-methylenedioxypregn-4-ene-3 : 1 l-dionc.
Removal of the protecting bis-mclhylenedioxy group
as in Example 15 gave 4: ldwrlimethylcortisone.
Example 44
14a-methyl-4-phenylthiomethylcortisome was acetaylated
and desulphuriscd according to Example 2 to give 4214m
dimcthylcortisonc acetate.
Saponiflcation of the foregoing compound (180 mg.)
needles from acetone/hexane (1:6), M.P. 122 to 124°
C., [011D (c., 0.58 in chloroform), hm“. 248.5 mu 55 with potassium bicarbonate (60 mg.) in 80% aqueous
methanol (12 ml.) under re?ux for 20 minutes, gave
(e=14,740) in ethanol. 'ymax_ 1734, 1719, 1669 and 1610
4:l4?—dimcthylcortisone identical with the sample pre
cm.-l in carbon tetrachloride.
pared in Example 43.
The following other Her-esters were prepared in the
Example 45
Propionate, n-butyrate, iso-butyrate, n-valerate, iso 60
207; - hydroxy-4-pheny1thiomethylpregn-4-en-3-one was
valerate.
acetylated and desulphurised according to Example 2 to
Example 36
give ZO?-acetoxy-4-rnethylpregn-4-en-3-one.
Saponi?cation according to Example 1 gave ZOE-hy
The procedure of Example 12 was repeated employing
same way:
174! - acetoxy-6a-methyl-4-phenyltl1iomethylprogestcrone,
when the product was 17a-acetoxy-4:?a-dimethylpro 65
gesterone, M.P. about 137° C., [0111324 +5° (c., 0.25 in
chloroform), Mum 249 (e=12,975) in ethanol.
Saponi?cation of the 17a'acctate with 2% methanolic
droxy-4nmethylpregn-4-en-3-one.
Example 46
21 - hydroxy-4-phenylthiomethylpregna-4:17(20)-dien
3~one was acetylated and desulphurlsed according to Ex
ample 2 to give 21-acetoxy—4'methylpregna-ll:17(20)w
potassium hydroxide gave 17a-hydroxy-4:6oz-dimethyl
70 dicn-S-one.
progresterone.
Saponi?cation according to Example 1 gave ZI-hydroxy
Example 37
1Soc-methyl-4-phenylthiomethylprogresterone was de
sulphurised according to Example 12, when the product
was 4:1?wdimethylprogesterone, which separated from 75
4-‘methylpregna-4:17(20)-dien-3-one.
Example 47
3 - ox0-4-phenylthiomethy1pregua-4: l'i tZUJ-dienQl-oic
8,076,822
10
acid was desulphurised according to Example 10 to give
phenoxyacetyl chloride instead of p-phenylpropionyl chlo
3‘oxo-4-methylpregna-4: 17(20)-dien-21-oic acid.
ride.
4~phenylthiomethyltestosterone phenoxyacctatc was ob
tained, and was converted by desulphurisation into 4
mcthyltestosterone phenoxyacetatc, M.P. 164° C.
Example 5 7
The procedure of Example 55 was repeated employing
Example 48
11,8 _ hydroxy~l7a:20:20:21 - bis - methylenedioxy - 4
phenylthiomethylprcgn-4~cn-3-~one, was desulphurised ac
cording to Example 12 to give 11,6-hydroxy-17m20;20:2]
bis-mathylencdioxy-ll-methylprcgn-4-cn-3-one, which sep
arnted from chloroform/ethanol (1:2) in prisms, M.P.
p-chlorophenoxyacetyl chloride. 4-phenylthiomethyltes
207 to 209° C., Am“ 2505 mu (e=14,220) in ethanol. 10 tosterone p-chlorophenoxyacetate was obtained, and was
Removal of the protecting bis-methylenedioxy group
according to Example 15 gave 11/3:17a:21~trihydroxy-4~
converted by desulphurisation into 4-methyltestosteronc
p-chlorophenoxyacetate, M.P. 169 to 170" C.
methylpregn-4-ene-3:20<dione (4-methylhydrocortisonc)
Example 58
Example 49
15
14a-hydroxy—4-phenylthiomethylprogestcrone was de
11a - hydroxy - 4 - phcnylthiomethyltestosterone, treat
ecl according to the process of Example 12, gave a prod
not which was puri?ed from ethyl acetate, to give 110:
hydroxy-4-mcthyltcstosterone as solvatcd crystals, M.P.
115 to 130° C., with frothing, or M.P. about 180° C.
Example 50
20 after drying at 100° C. in vacuo, [@1021 +66° (C., 0.60
170::20220221 — bis-methylenedioxy-4~phenylthiomethyl
in chloroform) Amu- 250.5 mu (e:l2,900) in ethanol,
pregna-4114dier1e-3:ll-dione was dcsulphurised accord
'ymx, 1658, 1602 cm.-1 in methylene chloride.
sulphurised according to Example 12 to give l4a~hydroxy~
4-methylprogcsteronc.
ing to Example 12 to give 17<x:2():20:Zl-bisanethylene
dioxy-4-methylpregna-4:14-dicne-3z1l-dione.
{emoval of the protecting bis~methylencdioxy-group
according to Example 15 gave 17a:2l~dihydroxy-4
Example 59
25
4-phenylthiornethylondrost~4cue-3,11,17-trione, treated
according to the process of Example 12, gave ‘fl-methyl
androst»4~ene~3,1 1,17-trione as prisms (from acetone/hex
ane 1:4), M.P. 166 to 168° C., [(111320 +307” (c., 0.85
in chloroform), an,“ 247.5 mu (s=l2,670) in ethanol,
methylpregna»4: l4-diene-3:11:20-trione.
Example 51
11,9 - hydroxy - 11:» - methyl - 4 - phenylthiomethyl —
1746, 1711, 1669 and 1606 cm.“1 in carbon tctra~
testosterone was acetylated and desulphurised according 30 7mm
chloride.
to Example 2 to give llB-hydroxy~4:11a-dimethyltcstos—
Example 60
terone17-acetatc.
Saponi?cation according ‘to Example 1 gave lip-hy
11,8 - hydroxy - 4 - phenylthiomethyltestostcrone, treat
droxy-4: 1 1u~dimethyltestosterone
ed according to the process of Example 12, gave 1143
35 hydroxy<4~methyltestosterone, ?akes from methylene
Example 52
chloride/hexane, M.P. about 256° C., 7m“. 3400, 1650,
20:20 ~ ethylencdioxy - 4 - phenylthiomethylpregn - 4 1605 era.-1 in “Nujol,” Amm 251 mu (e=l2,960) in
ethanol.
end-one was desulphurised according to Example 12 to
give 20 : 20-ethylenedioxy-4-methylpregn-4~en~3-onc.
Example 61
40
Example 53
901 < ?uoro - 1113,17,? ~ dihydroxy - 17a - methyl - 4 phenylthiomethylandrost-ll-en—3-one, treatcd according to
11a-hydroxy-4-phenylthiomcthylprogesterone was de
the process of Example 12, gave 9ca-?UOFOJlfLl7fl-(lh
sulphurised by the process of Example 12, and the prod
hydroxy-4,17a-dimethylandrost-4-en-3-one, needles from
uct puri?ed from acetone/hexane and from aqueous
aqueous methanol, M.P. 213 to 216° C., [0:11]“ +111’
methanol (60%) to give 11a-hydroxy-4~methyiprogester
(c., 0.42 in chloroform, Am“ 249 mu (e:16,440) in
one, as ?akes, M.P. 168 to 171° C., lotjnz? +l4>6° (c.,
ethanol.
0.39 in chloroform), Amnx, 250.5 mu (e=12,(]60) in
Example 62
ethanol.
Example 54
50
. 4-phenylthiomethylpregn-4-ene-3,11,20-trione was de
sulphurised by the process of Example 12 and the prod
uct puri?ed from acetone/hexane (1:3) to give 4~methyl
pregn-4-ene-3,11,20-trione as prisms, M.P. 179 to 181°
C., [01],)” +277° (c., 0.50 in chloroform), Amax. 248 mu
(e=13,355) in ethanol, 7mm 1700, 1669, 1601 cm.’1 in
carbon tetrachloride.
Example 55
4~pheny1thiomethyltestosterone (5 g.) in anhydrous
pyridine (50 ml.) at 0° C., was treated dropwise with
?~phcnylpropionyl chloride, then the solution was left to
stand at room temperature for 3 hours, and poured into
saturated sodium hydrogen carbonate solution, shaken
to destroy excess acid chloride, and the product extracted 65
with ether. The ether was washed with water, dilute
sulphuric acid, and water until neutral, dried and evapo~
rated.
4-phcny1thiomethy1testosterone ?-phenylpropio
note was obtained as a crystalline solid.
Desulphurisation of the foregoing compound according 70
to Example 1 gave 4-rnethyltestosterone~B-phenylpropio
nate, needles, M.P. 143 to 145° C.
Example 56
Ethyl 3 < 0x0 ~ 4 - phenylthiomcthylpregna - 4,17(20) -
dien-2l-oate, treated according to the process of Exam
pic 12, gave ethyl 3-oxo-4-methylpregna-4,17(20)-dien~
21-oate, ?akes from aqueous methanol (60%), M.P. 130
to 132° C., [a]D23 +109” (c., 0.14 in chloroform), Am“
225 mu (e=18,670) and 240 to 245 mu (e=17,820) in
ethanol, 'ymax_ 1708, 1665, 1604 cm.-1 in carbon tetra
chloride.
Example 63
160: - hydroxy ~ 4 _ phenylthiomethyltestosterone, treat
ed according to the process of Example 2, gave 16a,17?
discctoxy-4~methylandrost4-en-3-one.
Saponi?cation of the foregoing diacetate with potas
sium hydroxide in aqueous methanol gave l?a-hydroxy
4-1nethyltestosterone.
Example 64
16:1,17a - benzylidencdioxy - 4 - phcnylthiomethylpro -
gesterone, treated according to ‘the process of Example
12, gave 16a,17a-benzylidenedioxy-ll-methylprogesterone.
Example 65
20,20 - ethylenedioxy ~ 17a - hydroxy ~ 4 - (p - tolyl -
thiomethyl)pregn--4-en-3-one, treated according to the
process of Example 12, gave 20,20-ethylenedioxy-17a
The procedure of Example 55 was repeated employing 76 hydroxy-4-methylpregn-4-en-3-onc, needles from methyl
3,076,822
11
12
cording to the process of Example 2, gave 4-methyl
ene chloride/methanol (1:10), M.P. 228 to 230° C.,
[(111321 +77‘’ (c., 0.55 in chloroform), Am“ 250 mu
testosterone acetate, M1’. 158 to 160° C.
(e::l4,530) in ethanol.
The foregoing ethylenedioxy compound was treated
Example 71
with 90% aqueous acetic acid overnight at room tem
Ct
treated according to the process of the process of Exam~
perature, and the product puri?ed from methylene chlo
ride/methanol to give l7a-hydroxy-4-methylprogcstcrone,
MP. 239 to 241° C., [1111,31 +99‘’ (c., 0.97 in chloro
form), Am“ 250 mu ($115,540) in ethanol.
Example 66
ple 2, gave 4-methyltestosterone acetate, MP. 158 to
160° C.
Example 72
10
4-ene-3,20-dione, treated according to the process of Ex
12,
gave
terone acetate.
17a-acetoxy-4-methyl-l6-methylene
We claim:
pregn-4-ene-3,20~dione, flakes from aqueous methanol,
MP. 212 to 214° C., [x1325 —~43° (c., 0.8 in chloro
form), Am“ 249 mu (e=15,490) in ethanol.
1. A method for the preparation of 4-mcthyl-3-oxo-AL
steroids which comprises reacting a 4-organothiomethyl
3-oxo-A4-steroid with a reducing agent selected from the
group consisting of deactivated Haney nickel and zinc in
Example 67
7,7-dimethyl-4-phenylthiornethylcholest-4-en - 3 - one,
4-(13 - ethylthiomethylthiomethyl) - testosterone, treated
according to the process of Example 2, but employing
twice the quantity of Honey nickel, gave 4-methyltestos
l7e-acetoxy-l?-methylene - 4 - phenylthiomethylpregn
ample
47p) ~ mcthoxycarborzylethylthiomethyl) - testosterone,
-
treated according to the process of Example 12, gave
the presence of an alkali base to achieve reductive ?ssion
of the sulphur-containing group.
2. A method as claimed in claim‘ 1 wherein the re
4,7,7-trimethylcholest-at-en-3-one.
ducing agent is Rancy nickel suspended in a ketonic
Example 68
solvent.
3. A method as claimed in claim 2 wherein the Raney
nickel is deactivated by preliminary heating in a ketonic
solvent and the 4-organothiomethyl-3-oxo--A4-steroid is
21-acctoXy-20,ZO-ethylenedioxy - 4 - phenylthiomethyl
prcgn-4-en-3-one, treated according to the process of Ex
ample 12 gave 2l-acetoXy-20.ZO-ethylcnedioxy-rl-methyl
added to the resulting suspension of deactivated Raney
pregn~4-en-3-one, Am”, 249 mu.
nickel.
4. A method as claimed in claim 1 wherein the reduc~
The foregoing compound was treated with potassium
carbonate in 80% aqueous methanol under‘ re?ux for 2 30
ing agent is zinc dust and alkali metal hydroxide.
hours to give 21-hydroxy-20,20~ethylenedioxy-él-methyl
5. 4:6e-dirnethyltestosterone having a melting point of
228—230‘‘ C., [aJDZ5 +l4° (c., 0.22 in chloroform),
pregn-4-en—3-one.
The last compound, in acetone containing 1% of N.
aqueous hydrochloric acid was converted into Zl-hydroxy
4-methylpregn-4-ene-3,20-dione which was converted by
acetylation with acetic anhydride/pyridine (1:1) over
night at room temperature into 2l-acetoxy-‘l-methylpregn
)tmx~ 251 mu (e:l3,890) in ethanol, and acyl esters
thereof, wherein the acyl group is derived from a hydro
carbon carhoxylic acid containing up to 10 carbon atoms.
References Cited in the ?le of this patent
UNITED STATES PATENTS
4-ene-3,20—dione, purified from methanol to give prisms,
M.P. 175 to 176° C., [431L329 +193a (c., 0.20 in chloro
form), Am“ 249 mu (e:15,000) in ethanol; 'ymax, 40
1755, 1730, 1672 and 1611 cm?1 in carbon tetrachloride.
2,753,360
Kaspar ct al ___________ __ July 3, 1956
2,891,075
Sondheimer et a1 _______ __ June 16, 1959
737,773
Great Britain ___________ .. Sept. 28, 1955
Example 69
Zinc dust (60 g.) was washed with dilute hydrochloric
acid (50 ml. concentrated acid +100 ml. freshly boiled
and cooled distilled water) then washed twice with fresh
ly boiled and cooled distilled water (100 ml.) and twice
with acetone (200 1111.). To this zinc was added 4
FOREEGN PATENTS
OTHER REFERENCES
Fieser et 31.: “Natural Products Related to Phenan
threne,” 3rd Edition (1949), page 422.
Feshrnnnn: “Endocrinology,” vol. 57, pages 646—57
phenylthiomethyltestosterone (15 g.) in acetone (100
50 (1955).
ml.), and potassium hydroxide (6 g).
Neher et al.: “Helv. Chim. Acta," vol. 39 (1956),
This mixture was stirred and heated under re?ux for
5 hours, ?ltered and the solids well-washed with acetone.
The acetone ?ltrates were concentrated under reduced
pressure and poured into Water (3 litres). The precip
itated solids were collected and dried, then treated with
pages 2062-88.
Ringold et al.: “Journal of Organic Chemistry," vol.
21 (1956) pages 1333-1335.
Sondheimer et al.: “J.A.C.S.," vol. 79 (1957), pages
acetic anhydride (40 ml.) and pyridine (20 ml.) at 90°
C. for 1.5 hours, and the product precipitated in cold
2906 to 2910.
water and dried. Puri?cation from methanol gave 4
methylwstosterone acetate, MP. 158 to 160° C.
22 (1957), pages 99-100.
Example 70
4-(ti-carboxyethylthiomethyl)-testosterone, treated ac
Ringold et at: “Journal of Organic Chemistry,” vol.
Babcock et 211.:
"Journal of American Chemical
60 Society,” vol. 80 (1958), pages l904-5.
Ringold et 2.1.: "Journal of American Chemical So
ciety,” vol. 81 (1.959), pages 427-9.
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