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Патент USA US3077494

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3,577,434
Elite States PatentO?tice
Patented Feb. 12, 1953
2
1
treatment vgive rise to the formation of the 2-formyl-A2
- ‘androstenes and l9-nor-androstenes.
3,077,484
The 211 and ZB-formyl derivatives of androstan-UB-ol
2~FORMYL ANDRQSTANES AND PROQESS
TEERBFOR
Aihcrt Bowers, .iohn Edwards, and James C. on, all of
and 19-nor-androstan-17/3-ol, as well as of their l7ot-alkyl,
'alk‘e‘nyl'and alkynyl substituted derivatives, ‘are obtained
Mexico tCity, Mexico, assignors, by mesue assignments,
by oxidation of an ‘ester of 20a or ‘2,8-hydroxymethy1
androstan-17?-ol or of their 19-n0r derivatives, with
to Syntax Corporation, a corporation of Panama
No Brewing. Filed Aug. '3, 1961, her. No. 128,971
Claims priority, application Mexico Apr. 12, 1961
23 Claims. (Cl. 260-39714)
chromic acid in pyridine, at low temperature, preferably
between 0'’ and 5° C., and for a period of time between
10 6 and 10 hours. By oxidation of 20: and Z?-hydroxy
methyl-l7ct-alkyl, alkenyl or alkynl androstan-17?-ol, of
The present invention relates to certain new ‘cyclopen
the‘ corresponding 19-nor compoundsor of an ester of
the same, “there are obtained the 20; and ZB-fcrmyl deriva
tanophenanthrene derivatives and to a‘ method for-‘the
preparation thereof.
‘
v
tives of 17a-alkyl, l7a-alkenyl and 17‘a-alknyl andro
More particularly,‘ our invention ‘relates ‘to the novel
2-formyl derivatives of androstan-l'iB-ol, which may ‘fur 15 s'tan-17/3-ol, the corresponding 19-nor derivatives and the
esters of-the same.
ther possess a lower 17e-alky1,‘alkenylor‘alkynyl‘group;
Where the starting compound contains an ester group,
it also comprises the-‘preparation ‘of‘thei'esters of such
compounds and of the corresponding 19'-nor'derivatives.
this could bersaponi?ed by well known methods. The
17B-hydroxy-2e and 2,8-formyl-androstan‘es may be ester
These novel compounds are powerful anabolic agents
having a favorable anabolic-androgenic ratio; they help 20 i?ed with anhydrides or chlorides of acids‘of 1 to 12 car
bon atoms, in pyridine solution for the C-17ot unsubsti
to increase the protein metabolism and the deposition of
tuted compounds, or in benzene solution and in the pres
calcium on the bone tissue; they further exhibit anti-estro~
genic activity, lower the cholesterol level in the blood and
ence of p-toluenesulfonic acid for the 17u-alkyl, alkenyl
and alkynyl substituted derivatives.
inhibit the secretion of gonadotrophins by the ‘pituitary
25
. gland.
'TheWZu‘and ZB-formyl derivatives of androstan~17f3~ol
and of 17otialkyl-audrostan-175-01, as well as of the corre
The 17a-alkenyl and 17 u-alkyny-l compounds further
posses progestational activity.
sponding 19-nor compounds may also be obtained through
the method illustrated by the following series of reactions:
The novel compounds of ‘the present invention are rep
resented by the following formula:
30
Cd
Ht~l_/\
‘[0
R
OH
OH
‘ L~-R4
Lug,
/ .
Hit
'0
n
/
E
H
35
i
I
in the above formula R represents hydrogen or methyl, 40
R1 represents hydrogen or an acyl group derived from a
OH
carboxylic acid of 1 to 12 carbon atoms; R2 represents
hydrogen or a lower alkyl, alkenyl or alkynyl group such
i __R4
as methyl, ethyl, propyl, vinyl, ethynyl or propynyl. The
‘wavy line at (3-2 indicates the 0: or B con?guration for the 45
Ho-Q
(R ’\R‘
substituent at such position.
The acyl groups referred to above derive from carbox
ylic acids of less than 12 carbon atoms, saturated or un
saturated, of straight, branched, cyclic or mixed aliphatic
cyclic chain, substituted or not with hydroxyl, methoxy, 50
amino, halogen or other groups; typical such esters are
the acetate, propionate, butyrate, valerate, hemisuccinate,
enanthate, caproate, benzoate, undecenoate, trimethylace
Vtate, phenoxyacetate, cyclopentylpropionate and ?-chloro~
propionate.
V The novel compounds object of our invention are ob
E
/
III
In ‘the above formulas R represents hydrogen or methyl
‘ and Rt represents hydrogen or a lower alkyl group.
‘By catalytic hydrogenation of 2-formyl-A2-androsten
17,8-01, 2-forrnyl-19-nor-A2-androsten-17,8-01‘or one of
their 17a-alkyl substituted derivatives (1), until the ab
55 sorption of 1 molar equivalent of hydrogen, there are
‘obtained the ZB-formyl-androstanes as well as the corre
sponding l9-nor-compounds (11). This hydrogenation
tained ‘by oxidation of the 2a and ZB-hydroxymethyl
is carried out in the presence of a palladium catalyst,
androstanes and l9~nor-androstanes, or by hydrogenation
such as 5%> palladium on charcoal, 10% palladium on
of the 2-formyl-A2-androstenes and 19-nor-androstenes.
In our copending patent application Serial No. 128,972, 60 ‘barium sulfate, 10% palladium on calcium carbonate, etc.
Suitable solvents for this reaction are ethyl acetate, eth
'?led on August 3, 1961, there is described the prepara
anol, methanol, tetrahydrofuran and dioxane.
tion of 2a and 2,8-hydroXymethyl-androstanes and their
By‘ alkaline treatment of the above compounds, using
17a-allryl, alkenyl and alkynyl substituted derivatives, as
‘well as the corresponding l9-nor derivatives.
vfor example a dilute solution of ‘sodium methoxide in
of Z-forrnyl-?-androstenes starting from Z-alkoxymeth
2a-forrnyl compounds (III). Thus, for example, by hy
drogenation of 2-forrnyl-A2-androsten-175-01 in ethyl ace~
In our copending patent application Serial No. 128,974, 65 methanol, 0.5% ethanolic potassium hydroxide, potas
sium t-butoxide in t-butanol, etc., there are obtained the
?led on August 3, 1961, there is described the preparation
ylene derivatives of dihydroallotestosterone and 19-nor
,dihydroallotestosterone, as well as from their l7a-alkyl,
tate solution and in the presence of 5% palladium on
reduction with a double metal hydride produce the corre
which is converted into the 2ot-isomer‘by treatment with
alkenyl and alkynyl substituted derivatives, which upon 70 charcoal, there is obtained Z?-formyl-‘androstan-l718-01,
sponding Z-hydioxy compounds; the latter, upon acid
sodium methoxide.
3,077,484
2a - formyl - androstan ~ 17,9 - 01 and
4
2c: - formyl~
By
1.9-nor-androstan-l7p-ol may also be obtained by re
esteri?cation
of
20a - formyl - 17a - ethynyl
l9-nor-androstan,l7,8-ol with propionic anhydride in ben~
preferably 2-methoxymethylene-dihydroaliotestosterone,
ducing a 2-lower alkoxymethylene-dihydroallotestosterone,
zene solution and in the presence or" p-toluenesulfonic
(IV) and its 19-nor derivative with lithium aluminum hy
and 2 - methoxymethylene - l9 - nor - androstan - 17;? ~ 01
the corresponding propionate.
Example HI
(V). By hydrolysis of these compounds with perchloric
acid in ether for a prolonged period of time, preferably
ample I, the hydroxymethyl compounds mentioned below
acid, followed by alkaline treatment, there was obtained
dride, thus giving 2-methoxymethylene-androstan-l7?-ol
By following the method of oxidation described in Ex
for 16 to 24 hours, there are obtained Za-furmyl-an 10 in column I were converted into the corresponding 2
formyl derivatives (column I1).
drostan - 17/8 - 01 and 20a - formyl - l9 - nor - androstan
1718-01 (VI). The method described above is represented
by the following series of reactions:
on
00H, 12
i
I
0
on
‘2,9-formy1-17a-methyl-19-n0r
0on3 R
—~
17~acetate of 2B-hydroxymeth
yl-l7a-methyl~androstan-17B
HO:
|
.
15
.
of
25 - formyl - 17a
methyl-androstan-UB-ol.
androstan-l'i'?
i
Iv
androstan-l 75-01.
acetate
Example IV
V
A solution of 2.5 g. of Z-formyl-M-androsten-l7?~ol in
25 50 cc. of ethyl acetate was hydrogenated at room tem
perature and atmospheric pressure in the presence of
500 mg. of 5% palladium on charcoal catalyst which
had been previously reduced. After the uptake of 1
molar equivalent of hydrogen the catalyst was removed
by ?ltration through celite and the ?ltrate was evaporated
to dryness. Crystallization of the residue from methylene
CE
H0-—
9
R
/
chloride-hexane afforded 2?-formyl-androstan-17/3-01.
A mixture of 1 g. of the above compound, 5 cc. of pyri
dine and 2 cc. of benzoyl chloride was allowed to react
'
VI
35 overnight at room temperature, poured into water and the
In the above formulas R has the same meaning set forth
previously.
The following examples serve to illustrate but are not
intended to limit the scope of the invention:
40
Example I
precipitate formed was collected, thus giving the benzoate
of 2B-formyl-androstan-17?-ol.
Example V
A mixture of 1 g. of 2,8-formyl-androstan-1718-01 and
25 cc. of a 0.5% solution of sodium methoxide was kept
for 5 hours at room temperature and then poured into
A solution of 2 g. of 2tt-hydroxymethyl—l7a-methyl
water. The precipitate formed was collected by ?ltra
androstan 4716-01 in 20 cc. of pyridine was treated with
tion and crystallized from methylene chloride-hexane,
1 g. of chromic acid in 10 cc. of pyridine and the mix
ture was kept at 0° C. for 10 hours, then diluted with 45 thus furnishing Za-fOrmyI-androstan-l7?-ol.
A mixture of 500 mg. of the above compound, 2 cc.
ethyl acetate and ?ltered through celite; the ?ltrate was
of pyridine and 1 cc. of acetic anhydride was heated
washed with hydrochloric acid solution, with 5% sodium
on the steam bath for 1 hour and poured into water;
carbonate solution and with water to neutral, dried over
anhydrous sodium sulfate and evaporated to dryness
under vacuum.
Crystallization of the residue from ace
tone-ether yielded 2ot-formyl-17a-methyl-androstan-175
01.
A mixture of 1 g. of 2a-formyl-17u-methyl-androstan
17B-ol, 25 cc. of benzene, 2 cc. of acetic anhydride and
500‘ mg. of p-toluenesulfonic acid was kept at room tem
the precipitate formed was collected, thus giving the
acetate of ZOt-fOI‘mYl-EIIIdI‘OStHII-I7?-Ol.
By the same method, but using caproic anhydride and
undecenoic anhydride as esterifying agents there were
obtained the caproate and the undecenoate of 2a-formyl
androstan-17?-ol.
Example Vl
perature for 48 hours and then diluted with water; the
benzene layer was separated, successively washed with
By following the method of hydrogenation described
neutral, dried and evaporated to dryness under vacuum.
175-01 in 25 cc. of tetrahydrofuran was hydrogenated in
in Example IV, 2 g. of 2~formyl-17a-methyl-19-nor-A2
5% sodium carbonate solution and Water, dried over an
androsten-17B-ol was converted into 2?-formyl-l7a
hydrous sodium sulfate and evaporated to dryness under
methyl-19-nor-androstan-175-01, identical with the one
60
reduced pressure. The residue was dissolved in 50 cc.
obtained in Example 111.
of 0.5% methanolic potassium hydroxide solution, kept
Example VII
for 1 hour at room temperature, treated with water and
extracted with ethyl acetate; the extract was washed to
A solution of 1 g. of 2-formyl-17a-ethyl-A2-androsten
By chromatography of the residue followed by crystalliza~ 65 the presence of 150 mg. of 10% palladium on barium
tion of the solid fractions from acetone-ether there was
sulfate, until the uptake of one molar equivalent of hy
obtained the acetate of 2a-formyl-17a-methy1-androstan
drogen. The catalyst was removed by ?ltration through
1713-01.
celite and the ?ltrate was evaporated to dryness. By
Example II
70 crystallization from acetone-hexane there was obtained
By following the method of oxidation described in the
2?-formyl-l7a~ethyl-androstan-l73-01.
preceding example, 20: and ZB-hydroxymethyl-17e-ethy
300 mg. of the above compound was treated with
nyl-19-nor-androstan~175-01 were respectively converted
sodium rnethoxide in methanol, in accordance with the
into Zwformyl-17a-ethynyl—19-nor-androstan-l7?-ol and
method described in Example V, thus giving Za-formyl
2l3-forn1yl-l7oc-ethynyl-l9-nor-androstan-l7B-ol.
75 l7a-ethyl-androstan-l75-01.
amuse
5
6
4. 2/3-formyl-androstan-175-01.
Example VIII
There was repeated the preceding Example, but using
as starting compound 2-formyl-l9-nor-A2-androsten-l7?
01, thus obtaining Z/B-formyl-19-nor-androstan-17B-ol and
2a-forrnyl-l9-nor-androstan-l7B-ol. Esteri?cation of the
17,8-01.
latter compound with propionic anhydride in pyridine
produced the propionate of Za-formyl-19-nor-androstan
175-01.
9. 2-formyl-17a-ethyl-androstan-175-01.
l7;8-ol.
5. 2<z-formyl-l7ot~methyl-androstan-175-01.
6. ZB-fermyl-17a-methyl-androstan-l7/3-ol.
7. The acetate of 2a-formyl-l7a-methyl-androstan
8. The acetate of ZB-formyl-17a-methyi-androstan
l . Z-formyl-l7a-vinyl-androstan-17,6-01.
. 2-formyl-l7a-ethynyl-androstan-175-01.
Example IX
.
.
.
.
A solution of 2 g. of 2~methoxymethylene-androstan
l7?-ol-3-one (obtained by esteri-?cation of Z-hydroxy
methylene-dihydroallotestosterone with diazomethane) in
50 cc. of tetrahydrofuran was cautiously added to 1 g.
Za-formyl-17ot-ethynyl-androstan-l713-01.
Z-formyi-l7or-propargyl-androstan-175-01.
Za-formyh19-nor-androstan-l76-ol.
2,8-formyl-l9-nor-androstan-l7?-ol.
16. The propionate of 2a~formyl~l9-nor-androstan
of lithium aluminum hydride in 100 cc. of anhydrous 15
ether and the resulting mixture was re?uxed for 16 hours.
The mixture was cooled, the excess of anhydride was
17,8-ol.
l7. 2-formyl-l7a-rnethyl-l9-nor-androstan-l7?-oi.
destroyed by the addition of methanol and after acidify
ing with dilute hydrochloric acid the organic layer was
19. 25-formyl-l7a-ethynyl-nor-androstan-175-01.
18. Za-forrnyl- l7 a-ethynyl- 1 9-nor-androstan-l 7(3-oi.
separated, Washed to neutral, dried over anhydrous so 20
dium sulfate and evaporated to dryness. By crystalliza
20. A process for preparing a compound of the fol
lowing formula:
tion of the residue from acetone-hexane there Was ob
tained 2-methoxymethylene-androstan-175-01.
To a solution of 500 mg. of the above compound in
50 cc. of ether was added 5 drops of 70% perchloric 25
acid and the mixture was kept overnight at room tem
perature, then washed with water to neutral, dried over
(1?
R
11-0 M
Cling
anhydrous sodium sulfate and evaporated until the prod
uct crystallized.
There was thus obtained Za-formyl
l
androstan-17B-ol, identical with the compound obtained 30
in Example V.
wherein R is selected from the group consisting of hy
In the same manner 2-methoxymethylene-19-nor-di
drogen and methyl; R1 is selected from the group con
hydroallotestosterone was converted into 2a-formyl-l9
sisting of hydrogen and a hydrocarbon carboxylic acyl
nor-androstan-17e-o1, identical with that obtained in Ex
group of less than 12 carbon atoms; and R2 is selected
ample VIII. Esteri?cation with undecenoic anhydride 35 from
the group consisting of hydrogen, lower alkyl, lower
in pyridine afforded the undecenoate of 2a-formyl-19
alkenyl and lower alkynyl comprising oxidizing with
nor-androstan-l7?-ol.
chromic acid a compound of the following formula:
Example X
A solution of 2 g. of the propionate of 2?-propionoxy~ 40
|
methyl-17a-propargyl-androstan-17,8-01, obtained as de
scribed in our patent application Serial No. 128,972,
?led on August 3, 1961, in 100 cc. of methanol was
treated with 10 cc. of a 2% solution of potassium h '
droxide in methanol and the mixture was kept at 0° C. 45
for 2 hours, then neutralized with acetic acid and con
centrated to a small volume under vacuum.
Water was
added until complete precipitation of the product which
was collected and crystallized from acetone-ether, thus giv
wherein R, R1 and R2 have the same meaning de?ned
above at a low temperature.
ing the 17-pr0pionate of 2/3-hydroxymethyl-17a-propa1'gyl
21. A process for preparing a compound selected from
the group consisting of Z?-formyl-androstan-175-01, 2,8
androstan-17?-ol.
The above compound was oxidized with chromic acid
in pyridine, in accordance with the method described in
Example I, to produce the propionate of 2f3-formyl-17a
propargyl-androstan-17,8-01.
forrnyl-l9-nor-androstan-1718-01,
2,8 - formyl - l7u-lower
alkyl-androstan-U?-ol and 2e-formyl-l7oc-lower alkyl~19
55
nor-androstan-U?-ol comprising hydrogenating the cor
responding 2-formyl-A2-androsten-175-01 compound in
We claim:
the presence of a. palladium catalyst until one molar
1. A compound of the following formula:
equivalent of hydrogen is absorbed.
N5”
22. A process for preparing a compound selected from
the group consisting of 2a-formyl-androstan-l'I?-ol, 2a
60 -formyl-l9-nor-androstan-l718-01, Za-fOrniyl - 17cc - lower
alkyl-androstan-U?-ol and 2a-formyl-17e-lower alkyd-19
nor-androstan-U?-ol comprising reacting the correspond
ing 2l3-formyl derivative with an alkali metal lower alkox
ide.
65
23. A process for preparing a 2a-formyl-androstan-l7e
ol derivative comprising reducing a 2-lower alkoxymethyl
enedihydroallotestosterone with lithium aluminum hy
wherein R is selected from the group consisting of hy
dride and hydrolyzing the thus formed 2-lower alkoxy
drogen and methyl; R1 is selected from the group con
methylene-androstan-175-01 with acid for a prolonged
sisting of hydrogen and a hydrocarbon carboxylic acyl 70 period of time.
group of less than 12 carbon atoms; and R2 is selected
from the group consisting of hydrogen, lower alkyl, lower
alkenyl and lower alkynyl.
2. 2a-formyl-androstan-l713-01.
,3. The acetate of 2a-formyl-androstan-1713-01.
References Cited in the ?le of this patent
UNITED STATES PATENTS
75
2,883,401
Babccck et a1. ________ __ Apr. 21, 1959
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