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Патент USA US3080404

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3,080,394
Unite
Patented Mar.- 5, 1963
1
2
3,080,394
their corresponding 19-nor analogs are obtained by the
method illustrated by the following series of reactions:
2-F0RMYL-4-HALG-A2-ANDR0STENES
Albert Bowers, John Edwards, and James C. Orr, all of
Mexico City, Mexico, assignors to Syntex Corporation,
a corporation of Panama
OH
'
No Drawing. Filed Sept. 29, 1961, Ser. No. 141,602
Claims priority, application Mexico Apr. 19, 1961
14 Claims. (Cl. 266-6974)
‘
The present invention relates to certain new cyclo- '
pentanophenanthrene derivatives and to a method for
the preparation thereof.
More particularly, our invention relates to the novel 40:
and 4,8-halo, Ara-methyl and A4-dehydro derivatives of 2
formyl-Az-androsten-1718-01, as well as to their 17u-a1kyl, l5,
alkenyl and:alkynyl substituted derivatives; it also com
prises the preparation of the esters of such compounds
and of their corresponding l9-nor analogs.
Such compounds are powerful anabolic agents which
possess a favorable anabolic-androgenic ratio, stimulate
20
I
,R
irnoono-
the appetite, help to increase the protein metabolism and ~
the deposition of calcium on the bone ‘tissue, and further
.
118"‘
,_
‘exhibit anti-estrogenic EIOtiVitLlOWCI‘ the cholesterol level
in the blood, inhibit the excretion of gonadotrophins by
the pituitary gland and showa depressant action on the
f
/
now
0=-
2
25
'
III-A
.
, \/=
n
CH3
III
n
'
.
CH3
central nervous system.
The 17a-alkeny1 and 17a-alkyny1 compounds further
possess progestational activity.
The novel compounds object of our invention are rep
30
>
resented by the following formulas:
/\
$3,!
...R,
a
i0R1
...R,
R t
fl?
ono35 _
.
one-E:
Q
'
.
A‘
L
CH3
40
034
R‘
one-A
.-'
one i
a
v
H
'
'
at
is
_45
>_
|——1
...R,
Ali
GHQ-A
7
v
R
0
\
.
no
.
50
'In the above formulas R represents hydrogen or methyl, 55
R1 represents hydrogen or an acyl group derived from a
carboxylic acid of 1 to 12 carbon atoms; R2 .represents
hydrogen or a lower aliphatic hydrocarbon group such as
a lower alkyl, alkenyl or alkynyl group such as methyl,
ethyl, propyl, vinyl, ethynyl or propynyl, and X repre
60
sents a halogen atom such as fluorine, chlorine or bro
mine. The wavy line at 0-4 indicates the a or 18 con?gu
ration for the halo. substituent at such position.
The acyl groups'are derived from carboxylic acids of ,
less than 12 carbon atoms, saturated or unsaturated, of 65
straight, branched, cyclic or mixed aliphatic-cyclic chain,
substituted or not with hydroxyl, methoxy, amino, halo
gen or other groups; typical such esters are the acetate,
propionate, butyrate, valerate, hemisuccinate, enanthate,
trimethylacetate, phenoxyacetate, cyclopentylpropionate 70
and B-chloropropionate.
’
The 4a-methy1~17?-hydroxy-Az-androstenes, as well as
.
OHC—,/\
) .
VH1
0313
Ch;
In the above‘ formulas R, R1 and R2 have the same
meaning indicated previously. R4 represents the acyl
group :of a hydrocarbon car-boxylic acid of the type men
tioned' previously.
7
'
The starting compounds 4u—methyl-_androstan-'17B-ol
'3-one or the '19'-nor derivative (I) (which'is-obtained
3,080,394
invention are obtained by the method illustrated by the
from 55,105-estran-17B-ol-3-one by following the method I
described in US. Patent 2,844,602) are respectively con
following series of reactions:
verted into 2-hydroxymethylene-4a-methyl-androstan-17p
1
OH
ol-3-one and 2-hydroxymethylene-4a-methyl-19-nor7an
drostan-l7?-ol-3-one (II) by treatment with ethyl formate 01
in the presence of sodium hydride, in accordance with
the method described by H. J. Ringold et al., J. Am.
Chem. So_c., 81, 427 (1959). By reacting the above 2
hydroxymethylene compounds with an excess of diazo
methane, at room temperature for a prolonged period of 10
time, or with methanol in the presence of perchloric acid,
there are obtained the methoxymethylene compounds
(HI).
By reduction of 2-metlroxymethylene-4ot-methyl-andro
stan-17?-ol-3-one or of the 19-nor derivative with a dou
15'
ble metal hydride, such as sodium borohydride, at room
temperature and in an adequate solvent such as methanol,
‘ dioxane or tetrahydrofurane, for a period of time ?uctuat
ing between 30 minutes and 4 hours, there is obtained
a mixture of 30a and 3/3-hydroxy compounds (III-A),
which is dehydrated by acid ‘treatment, for example with
hydrochloric acid, perchloric acid or sulfuric acid, with
simultaneous transformation of the Z-methoxymethylene
grouping into the respective aldehyde, thus giving rise to
the formation of 2-formyl-4a-methyl-Az-androsten-17?~ol 25
and of the 19-nor derivative (IV). 'By reacting these
compounds with anhydrides or chlorides of acids of 1
to 12 carbon atoms, in pyridine solution, there are ob
tained the respective esters (V).
For obtaining the Hot-substituted compounds, 2-formyl
4ot-methyl-A2-andrcsten-175-01-01‘ the 19-nor derivative
are converted into the respective ethyleneketals (VI),
which on oxidation with chromic acid in pyridine produce
the l7-ketones (VII). By further treatment of these
ketones with an alkyl, alkenyl or alkynyl magnesium
halide, such as methyl, ethyl, propyl, vinyl, ethynyl or
XII
m. .
In the above formulas R and R2 have-the same‘ mean
ing indicated previously; Ac represents the acetyl radical;
X is halogen.
The starting compounds Z-formyl-AZ-androsten-175ml,
or the 17u-alkyl, alkenyl or allcynyi substituted deriva
tives, or the corresponding 19-nor derivatives (X), ob
tained in accordance with the method described in our
copending patent application Serial No. 128,974, ?led
August 3, 1961, is treated with acetic anhydride in the
35 presence of p—toluenesulfonic acid, at room temperature
and for a period of ‘time between 4 and 8 hours, or with
acetic anhydride in the presence .of perchloric acid, at
room temperature for 1 to 2 hours, or by re?uxing with
drolysis ‘of the ethylenedioxy group there are obtained
a mixture of acetic anhydride, acetyl chloride and pyridine
the corresponding l7a4al-kyl, alkenyl or alkynyi deriva
for
1 to 3 hours, to produce the enol acetates at 0-2, with
40
tives of 2-formyl-4a-methyl-A2-androsten-17,6-01 and of
propargyl magnesium bromide, followed by acid hy
simultaneous acetylation of the 17B-hydr-oxyl ‘group, i.e.,
2-formyl-4ot-methyl-A2-l9-nor-androsten-176401 (VII-I).
By reacting these compounds with acid anhydrides or
chlorides of 1 to 12 carbon atoms, in benzene solution
and in the presence of p-toluenesulfonic acid, there are
obtained the respective estens (IX).
Alternatively, the 2-formyl-4a-methyl-17ot-alkyl com
the acetate of 2-acetoxymethylene-ALandrosten-175-01,
, its 17a-aikyl,'alkenyl or alkynyl substituted derivatives,
as well as the corresponding 19-nor derivatives (XI).
45
For introducing a chlorine atom at 0-4, the enol ace- 1
'tates set forth above are treated with N-chlorosuccinimide
in aqueous acetone solution’and in the presence of sodium
acetate and acetic acid, or in dioxane solution and in
pounds may be obtained by treating 2~ethylenedioxymeth~
y1-4u-methyl-A2-androsten-17-one or the 19-nor derivative
the presence of perchloric acid. Alternatively, there may
(VIII) with an alkyl-lithium, followed by acid treatment
50 be employed in this reaction other reagents capable of
to hydrolyze the ketal.
,
'
generating hypochlorous "acid, such as an alkali or alkali
metal hypochlorite or another N-chloroimide or N-chlo
I
The 17a-alkynyl substituted derivatives may also be
obtained by reacting the ketones of Formula VII with
roamide.
sodium or potassium acetylide or with; the sodium or
of 2-formyl-4?-chloro-Az-androsten-175-01, the acetate of
In this manner there are obtained the acetate
potassium salt ofanother alkine, such as propine, fol 55 2-formy1-4B-chloro-A2-l9-nor-androsten-17?-ol, as well as
their Hut-substituted derivatives (XII: X=Cl). By acid
lowed by hydrolysis of the ketal.‘
'
treatment of the above oompounds,preferably with dry
hydrogen chloride in glacial acetic acid solution, or in
acetone solution, there is inverted vthe steric con?guration
formation of 4u-methyl-androstan-17B-ol-3eone into the
3-ethylenedioxy derivative, oxidizing the latter with 60 at 04, thus producing the corresponding 4a-chloro-com
Alternatively, the reaction sequence may be inverted,
i.e., ?rst introducing the substituent at C-17a by trans
chromic acid in pyridine to produce 3-ethylenedioxy-4a
pounds (XIII: X=Cl).
methyl-androstan~17-one, treating this compound with a
Grignard reagent, with an alkyl-lithium or with sodium
cinimide by N-brom-osuccinimide, or employing another
acetylide, and hydrolyzing, the ketal, thus obtaining the
17a-alkyl, 17a-alkenyl and 17u-alkynyl derivatives of 4c:
In a similar manner, substituting the N~chlorosuc
reagent capable of- generating hypobrom'ous acid, there
65 is obtained the acetate of Z-formyl-4[3-bromo-A2~andro
sten-17?-ol and of its 19-nor derivative (XII: X=Br),
which upon treatment with acid produce the 4a-bromo
methyl-androstan-lWS-ol as well as the corresponding 19
nor derivatives; These compounds are then converted
compounds (XIII: X=Br).
into the respective 2~hydroxymethylene and Z-methoxy
The 4-?uoro-2-formyl-A2-androstenes‘are obtained by
methylene derivatives, which on reduction with sodium 70 reacting the enol acetates of formula XI with perchloryl
borohydride followed by acid treatment produce the 17m
fluoride in pyridine, dioxane or dimethylforrnamide solu
alkyl, alkenyl :or alkyny-l derivatives of 2-formyl-4a-meth
yl-Az-androsten-l7l8-ol and of 2-formyl-4a-methyl-A2-19
nor-androsten-??eol;
r
tion, at a temperature between 0° and 20° C.
‘
The novel 4-halo-2-formyl-Az-androstenes object of our
75
Gener
ally the reaction is eifected in a few minutes, although
it is preferred to allow it to proceed for a longer time.
There are thus obtained the acetate of 2-for-myl-4?-?uoro
. 3,080,394
.
'e
5
The following examples serve to illustrate but are not
'Az-‘androsten-??-ol, its 17a-alkyl, alkenyl or alkynyl sub
intended to limit the scope of the present invention:
stituted derivatives, as well as the corresponding 19-nor
derivative (XII: X=IF). Acid treatment of these com
A Example]
‘pounds produces the 4a-?uoro compounds (XIII: X=F).
To a solution of 10 g. of 4a-methyl-androstan-175-01
in 1010 cc. of thiophene free-benzene was added .4 cc.
The 17?-hydroxy compounds are obtained by the 5
method illustrated by the following series of reactions:
of ethyl formate and 3 g. of sodium hydride and the
mixture was stirred for 8 hours under an atmosphere of
nitrogen; at the end of this timethere was collected by
0 Ac
?ltration the resulting sodium salt of the 2-hydroxymeth
ylene derivative together with the excess of hydride; the
precipitate was washed. with benzene and dried under
vacuum. The product was cautiously added to an ice
cold solution of hydrochloric acid, thus affording 2~'hy- ’
droxymethylene-4wmethyl-androstand7,8-01, which was
recrystallized from chloroform-methanol.
To a solution of 10 g. of the above compound in 50
cc. of methanol was added 5 drops of 70% perchloric
XIV
acid and the mixture was stirred ‘at room temperature
for 10 minutes. A precipitate separated immediately,
which was collected by ?ltration, thus yielding TZ-meth- _
oxylrnethylene- 40c - methyl - androstan - 17/3 - o1 - 3 - one,
M.P. 216~l8°
-
C., [a]D+45° (chloroform), )tmax. 27_6
my, log E 4.08.
_
A solution of 4.5 g. of the above methoxymethylene
derivative in 150 cc. of methanol was treated with 2.25 g.
XV
In the above formulas R, R2, Ac and X have the same
meaning set forth previously. The wavy line represents
the a or B con?guration for the 4-halo substituent.v
The acetates of 2-formyl-4/8-halo-AZ-androsten-17B-ols,
of sodium borohydride previously dissolved in 5- cc. of
water and 10 cc. of methanol; the mixture was kept
standing at room temperature for v1 hour, treated with
30 1.5 cc. of concentrated hydrochloric acid (until acid
reaction) and the mixture ‘was kept at room temperature
for 10 minutes further, then poured into water and the
precipitate was collected; crystallization from ethyl acetate .
atforded
2—formyl-4a-methyl-A2~androsten-176-01, 'M.P. Y
196-203“ C.; [06]D+19° (dioxane), Amax. 234 mu, log’
El4.'0‘6.
2-formyl-4/3-halo-19-nor-A2-androsten-17B-ols as ,well as
Example II
their 170L-Sl1'bStltllted derivatives (XII) were converted
A mixture of 1 g. of 2-formyl-4oz-methyl-A2-androsten
into the corresponding ketals (XIV). . By treating these
compounds with lithium aluminum hydridethere was hy 40 17?-ol, 5 cc. of pyridine and 2 cc. of acetic anhydride
drolyzed the acetoxy group at 0-17 and ?nally the formyl , was kept overnight at room temperature, then poured
into water and the precipitate formed was collected, thus
group at C—2 was regenerated by acid treatment, prefer
affording the acetate of_2-t'ormyl-4zit-methyl-Az-androsten~
ably with p-toluenesulfonic acid in acetone, to produce
1711-01. _
the 2-formyl-4?-halo compounds, or also with hydrogen
In the same manner, but using propionic, caproic and
chloride in ethyl acetate or acetic acid, with simultaneous 45
cyclopentylpropionic anhydrides as esterifying agents,
inversion , of the 4-ha1o substituent, thus obtaining
2 - forrnyl - 4oz - halo - A2 - androsten @175 - ol,
there were obtained the prop-ion-a’te, the caproate and
2,- for
the cyclopeutylpropionate of 2~formyl-4a-methyl-A2
my1-4u-halo-19-n0r-A2-androstend7B-ol‘ and their 17a
alkyl, alkenyl and alkynyl substituted derivatives (XV).
By reacting these compounds with anhydrides or
~androsten-l7l8-ol.
chlorides of hydrocarbon carboxylic acids of 1 to 12 car
bon atoms, in accordance with the methods indicated
previously, there are obtained the respective esters.
The A4-dehydro compounds, i.e., 2-f-orrnyl-A2»4-andro
‘A mixture of 5 g. of 2-formyl-4a-methyléAz-androstenl
175-01, 300 cc. of anhydrous benzene, .35 cc. of ethylene
glycol and 1 g. of p-toluenesulfonic acid monohydrate
. was re?uxed for 8 hours, removing the Water formed dur
stadien - 17B - ol, 2 - formyl - A” .- 19 - nor - andro
ing the reaction by means of a water separator; the cooled
solution was washed with 5% sodium carbonate solu
tion and then with water to neutral, dried over anhy
drous sodium sulfate and evaporated to dryness. Chro~
matography of the residue on neutral alumina furnished
stadien-17/3-ol and their 17a-a1kyl, alkenyl or alkynyl
substituted derivatives, are obtained by dehydrobrominat
ing with collidine the 40c and 4p bromo compounds, in
accordance with the following equation:
'
.1
_
~
>
i
so
'
R
oao?
the» ethyleneketal- of 2-formyl-4a-nrethyl-Az-androsten
1716-01.
on!
1;...R,
v
‘Example III
v
a
‘ one-g
>
A solution of 2 g. of the above compound in 20 cc. of
pyridine was treated with 1 g. of chromium trioxide in
40 cc. of pyridine at room temperature for 16 hours. The
mixture was then diluted with ethyl acetate, ?ltered and
the ?ltrate was Washed with‘water to remove the pyridine,
‘
over anhydrous sodium sulfate and the solvent was
65 ' dried
evaporated. Crystallization of the residue from-acetone
' '
hexane afforded the Z-ethyleneketal of 2-f0rn1yl-4e-meth
i,
' 70
wherein R, R1 and R2 have the same meaning set forth
previously._ Alternatively, the .dehydro-bromination may
yl-A2-androsten-17~one.
.
Example IV
A solution of 1 g. of the above ketonein 40 cc. of an
hydrousbenzene free of thiophene was slowly added to
be effected by re?uxing with calcium carbonate in di
methylformamide or dimethylacetamide.
75 5 cc. of a 4 N solution of methyl magnesium ‘bromide in
s,oso,ssa
8
ether and the mixture was re?uxed under anhydrous con
ylene - 40¢ - methyl - 19 - nor - androstan - 17B - ol - 3
ditions for 3 hours, cooled and cautiously poured into
water, acidi?ed with hydrochloric acid and stirred for 3
one and 2-formyl-4wmethyl-A2-19-nor-androsten-17,8-01.
A mixture of 500 mg. of 2-formyl-4a-methyl-A2-19-nor
androsten-1718-ol, 2 cc. of pyridine and 1 cc. of benzoyl
chloride was heated on the steam bath for 1 hour, poured
hours at room temperature; the benzene layer was sepa
rated, the aqueous phase was extracted several times with
ethyl acetate, these extracts were combined with the ben
into water and the precipitate formed was collected by
zene solution and the organic solution was washed to neu
?ltration, thus furnishing the benzoate of 2-formyl-4oc
toluenesulfonic acid was kept at ‘room temperature for
Example VIII
methyl-A2-19-nor-androsten-175-01.
tral, dried over anhydrous sodium sulfate and evaporated
The starting compound, 4a-methyl-19-nor-androstan
to dryness under reduced pressure. Crystallization from
acetone-hexane a?orded 2-formyl-4u,17a-dirnethyl-A2-an 10 17?-ol-3-one was obtained from 5B,l0?-estrane-l7l3-ol-3
one, described by R. Rapalaet al. in J, Am. ‘Chem. Soc.,
drosten-17B-ol.
80, 1008 (1958), by following the method described in
A mixture of 1 g. of the above compound, 40 cc. of
U.S. Patent No. 2,844,602.
acetic acid, 201cc. of acetic anhydride and 1 g. of p
‘16 hours, poured into water, heated for 30 minutes on the 15
steam bath to hydrolyze the excess of reagent and ex
By following the method of Example III, 2 g. of
2-formyl-4u-methyl-A2-19-nor-androsten-17?-ol was con
tracted with ethyl acetate. The organic extract was washed
to neutral, dried and evaporated to dryness. The residue
verted into the corresponding ketal, which was oxidized
with chromium trioxide in pyridine to produce the 2-eth
was dissolved in 50 cc. of 0.5% methanolic potassium
hydroxide solution, kept for 1, hour at room temperature, 20 yleneketal of 2-formyl-4u-methyl-A2-19-nor-androsten~17
one.
diluted with waterv and extracted with ethyl acetate; the
The above‘ compound was treated with methyl mag
extract waswashed to neutral, dried and evaporated to
nesium bromide followed by acid treatment, in accord
dryness. The residue was crystallized from acetone
ance with the method described in Example IV, thus ob~
hexane, thus yielding the acetate of 2-formyl~4a,17a-di
methyl-nz-androsten-17(3-ol.
25
Example V
By following the method of the preceding example, but
taining
2 - formyl - 4a,17a - dimethyl - A2 - 19 - nor - an~
drosten-17?-ol.
Example 1X‘
A solution of 2 g. of the 2-ethyleneketa1 of 2-formyl
4a-methyl-A2-androsten-17-one in 60 cc. of anhydrous
using ethyl magnesium bromide and vinyl'magnesium
bromide instead of methyl magnesium bromide as alkylat
benzene was added under an atmosphere of nitrogen to
ing agents, the 2-ethyleneketal of 2-formyl-4a-rnethyl-A2
a solution of potassium ter-amyloxide previously pre
androsten-l7-one was respectively converted into 2-form
pared from 1.4 g. of potassium and 30 cc. of ter-amyl
alcohol. Into the resulting mixture there was introduced
a slow stream of puri?ed acetylene for 40 hours and the
yl-4a-methyl-l7a-ethyl-Az-androsten-175-01 and 2-formyl
4a-methl-l7a-vinyl~A2-androsten-17,8-01. By subsequent
treatment of these compounds with a mixture of acetic 35 solution was then poured into ice water and extracted ,
acid and acetic anhydride in the presence of p-toluene
with several portions of benzene The combined organic
sulfonic acid, followed by mild alkaline treatment, there
extract was washed to neutral, dried over anhydrous sodi
were obtained the corresponding acetates.
Example VI ‘
um sulfate and evaporated to dryness under vacuum.
The residue was hydrolyzed with p-toluenesulfonic acid in
40 acetone, in accordance with the ‘method of Example VI,‘
A solution of 5 g. of the Z-ethyleneketal of 2-formyl
4oc-methyl-A2-androsten-l7-one in 100 cc. of anhydrous
ether was added dropwise to a solution of propargyl bro~
mide, 1.4 g. of magnesium and 200 cc. of ether. The
mixture was re?uxed under continuous stirring overnight, 45
cooled, poured into 500 cc. of 5% ammonium chloride
solution and the other layer was separated, washed to
neutral with water, dried over anhydrous sodium sulfate
and evaporated to dryness under vacuum. The residue.
thus giving 2-formyl-4a-methyl-l7oc-ethynyl-A2-androsten
17/3-01.
’
'
' A mixture of 500 mg. of the above compound, 25 cc.
of benzene, 2 cc. of, cyclop'entylpropionic anhydride and
250 mg. of p-toluenesulfonic acid was kept at room tem
perature for 48 hours, diluted with water and stirred for
30 minutes to hydrolyze the excess of reagent. The ben
zene layer was separated, washed to neutral, dried over
anhydrous sodium sulfate and evaporated to dryness.
was dissolved in 50 cc. of acetone, treated with 500 mg. 50 The residue was treated with 0.5% methanolic potassium
of p-toluenesulfonic acid and kept overnight at room tem
hydroxide solution, in accordance with the method de
perature; the mixture was then poured into ice water, ex
scribed in Example IV. By crystallization from acetone;
tracted with ethyl acetate and the extract was washed to
ether there’ was obtained the cyclopentylpropionate of
neutral, dried and evaporated to dryness under vacuum.
'2-formyl-4ot-methyl-17ot-ethynyl-A2-androsten-175-01.
By chromatography of the residue there was obtained 55
In the same manner, 1 g. of the ketal of 2-formyl-4u
2-formyl-4oa-methyl-17a-propargyl-M-androsten-l7?~ol.
methyl-Al19-nor-andr0sten-17-one was converted into 2
1 g. of the above compound was dissolved in 20 cc, of
formyl - 4a - methyl - 17a - ethynyl - A2 - 19 - nor - an
benzene, treated with 2 cc. of propionic anhydride and
drosten-lZB-ol, which on esteri?cation with 'caproic anhy
0.5 cc. of p-toluenesulfonic acid and kept overnight at
dride in benzene solutionrand in the presence ofp-toluene
'room temperature. The mixture was then diluted with 60 sulfonic acid produced the caproate of 2-formyl-4a-meth
water, stirred for 30 minutes to hydrolyze the excess of
reagent and the benzene layer was separated, washed with
5% sodium carbonate solution and with water to neutral,
dried over anhydrous sodium sulfate and evaporated to
dryness under vacuum.
yl-17ot-ethynyl-nz-19-nor-androsten-17,8-01.
Example X
A mixture of 5 g. of 2-formyl-A2-androsten-175-01,
The residue was treated with 65 obtained asdescribed in our patent application Serial No.
0.5 %. methanolic potassium hydroxide solution, in accord
128,974, ?led-on August 3, 1961, 50 cc. of aceticanhy
ance with the method described in Example 1V, thus
dride,, 20.5 cc. of acetyl chloride and 225 cc. of pyridine
yielding the propionate of 2-formyl-4u-methyl-17u-pro
was re?uxed for 11/2 hours under an atmosphere of
nitrogen and then the solvents were evaporated under re
70 duced ‘pressure; the residue was dissolved in ethyl acetate,
Example VII
Washed to neutral, dried over anhydrous sodium sulfate
and evaporated until crystallization started. There was
There was repeated the method of Example I, but us
pargyl-Az-androsten-17,8-01.
ing as starting material Zlot-methyl-19-nor-androstan-l7B
ol-3-one, thus affording successively 2-hydroxymethylene
4ea-methyl-19-nor-androstau-17,6-01-3-0ne, Z-methoxymeth
thus obtained the acetate of 2-acetoxymethylene-A3-ans
drosten-17?-ol, M.P. l.13—116° C., [a]D+41° (chloro
75 form); Aniax. 248 mu, log E 4.15.
'
3,080,394
furnished
A solution of 2 g. of the above enol acetate in 40 cc.
of dioxane was cooled to 10° C., treated with 3 cc. of
‘10
2 - formyl-4p-chloro-17a-ethiuyl-A2-androsten
17,8-01.
I
_
‘
‘
c
. The above compound 1was esteri?ed with propionic an
0.5 N perchloric acid and l g. of N-chlorosuccinimide in
was stirred for 2 hours further at room temperature,
hydride in benzene solution and in-the presence of p
toluenesulfonic acid, following the method described in
poured into water and extracted with ethyl acetate. By
crystallization', from acetone-ether there was obtained the
chloro-17a-ethinyl-A2-androsten-17,6-01.
portions and-over‘a period of 30 minutes‘. The mixture
Example VI, to produce the propionate of 2-formyl-4p
-
acetate of 2~formyl-4p-chloro-A2-androsten-1713-01.
Example XIV
Example XI
By ‘following the method described in the preceding
10
example, the acetate of 2-formyl-4?-chloro-A2-androsten
To a solution of 2 g. of the acetate of Z-acetoxymethyl
17,8-01, obtained in Example X, Was converted into the
ene—A3-androsten-l7B-ol in 30 c. of pyridine was intro
duced a stream of perchloryl ?uoride for 5 hours at 0—5°
C.; at the end of this time the mixture was poured into ice
water and extracted with ethyl acetate; the organic ex
tract was washed to neutral, dried over anhydrous so
corresponding ethyleneketal and then saponi?ed with
lithium aluminum hydride to give the ethyleneketal of 2
formyl-ll?-chloro-Az-androsten-17p-ol. A mixture of 500
mg. ‘of this compound and 20 cc. of ethyl acetate saturated
with dry hydrogen chloride was kept standing at room
temperature for 5 hours; at the end of this time it was
washed to neutral, dried over anhydrous sodium sulfate
and evaporated to dryness under vacuum. Under these
conditions there was hydrolyzed the ketal with simultane~
ous inversion of the Zlit-chloro substituent, thus producing
dium sulfate and evaporated to dryness. Crystallization
of the residue from acetone-ether afforded the acetate of
2~formyl-45-fluoro-A2-androsten-176-01.
A solution of 1.5 g. of the above compound in 50 cc.
of acetone was treated with 10 drops of 70% perchloric
acid and the mixture was kept standing overnight at room
?nally Z-formly-4u-chloro-A2-androsten-1718-01.
temperature, then diluted with water and extracted with
The ‘above compound was esteri?ed with 'benzoyl
methylene chloride; the extract was washed with water
‘to neutraLdried and evaporated to dryness. ‘By chroma 25 chloride in pyridine, by following the method of Example
VII, to give the benzoate of 2-f0rmyl-4oz-chloro-A2
tography of the residue there was obtained the acetate of
2-formyl-4a-?uoro-Az-androsten-1-75-01.
_
'
Example XII
androsten-17,B-ol.
Example XV
. '
.
There was repeated the method of Example X, bu
using as starting compounds 2-formyl-l7u-methyl-A2-an-I
2 g. of Z-formyl-17a-methyl-A2-androsten-175-01 was
30 converted into the acetate of 2-acetoxymethylene-17a
methyl-A3-androsten-17?-o1 by treatment with acetic ran
drosten-17p-ol and 2-formyl - 17 cc - methyl-A‘~’-l9-nor-an~
hydride, acetyl chloride and pyridine, in accordance with
the method of Example X.
drosten-l7?-ol, described in our patent application Serial
No. 128,974; there were thus obtained as ?nal products
A solution of 1.5 g. of the above compound in 20 cc.
the acetate of 2-formyl-4l3-chloro-l7a~methyl—A2-andro— 35 of pyridine was cooled to 0-5° C. and a stream of per
sten-17,6-ol and the acetate of 2-formyl-4B-chloro-17a
chloryl ?uoride was introduced into the solution for 5
methyl-A249-nor-androsten-l'Ip-ol.
,
hours; at the end of this time the mixture was poured
Example‘ XIII
2 g. of 2-formyl-l7u-ethinyl~A2-androsten-l7,6—ol was 40
treated with acetic ‘anhydride, acetyl chloride and pyridine,
following the method described in Example X, thusgiving
the acetate of Z-acetoxymethylene-l7a-ethinyl-A3-andro
tion of the residue from acetone-hexane afforded the
acetate of 2-formyl-4p-?uoro-l7oa-methyl-A2-1androsten
1-75-01.
sten-17p-ol, which was converted into the acetate of 2-.
formyl - 4p - chloro - 17cc - ethinyl-Az-androsten-1718-01
treatment with N~chlorosuccinimide.
'
e
by
'
into ice water, extracted with methylene chloride and
the extract was washed to neutral, dried‘ over anhydrous
sodium sulfate and evaporated to dryness. Crystalliza
The above compound was converted into the corre
.45
sponding ethyleneketal, whichwas then saponi?ed with
lithium aluminum hydride to produce the ethyleneketal
A mixture of l g. of the above compound, 60 cc. of
' of 2-formyl-4B-?uoro4l'la-methyLN-androsten-l75-01; the
benzene free of thiophene, 7 cc. of ethyleneglycol and
latter was then hydrolyzed with p-toluenesulfonic acid in
0.2 g. of p-toluenesulfonic acid was re?uxed for 8 hours
acetone, by following the method of Example XIII, thus
using a water separator; at the end of this time the result 50 obtaining ?nally 2-formyl - 4B - ?uoro-l7ot-methyl-A2-an
ing solution was washed with 10% sodium carbonate
v drosten- 175-01. '
‘
.
solution and with Water to neutral, dried over anhydrous
Example VI
sodium sulfate and evaporated to dryness under vacuum.
There was repeated the method of the preceding ex- 1
The residue was crystallized from acetone-ether, thus
affording the ethyleneketal of the acetate of 2-formyl-4B 55 ample, but using as starting compound 2-formyl-17u
vinyl-AZ-androsten-175-01, thus giving rise to the suces
chloro-l7a-ethinyl-A2-androsten-173-01.
'
‘ A solution of 800 mg. of the above compound in 20 cc.
of. anhydrous tetrahydrofuraue was added dropwise to
sive formation of'the acetate of 2eacetoxymethylene-17a4
vinyl-A3-androsten-175-01, the acetate of 2-formyl-4B
400 mg. of lithium aluminum hydride in 40 cc. of tetra
'?uoro-17a-vinyl—A2-androsten-1-75-01, the acetate of 2
drous conditions for 30 minutes. After cooling the excess
of reagent was destroyed by the cautious addition of a few
drops of ethyl acetate, then 20 cc. of saturated aqueous
drosten-l7/3-ol and 2-f0rmyl-4B-?uoro-17oa#vinyl-A2-an
drosten-17/J-ol; by treating the latter with caproic anhy
pressure, thus yielding the ethyleneketal of 2-formyl-4B~>
Example XVII
hydrofurane and the mixture was re?uxed under anhy 60 ethylenedioxymethyl - 4-p-?uoro-l7ot-vinyl-Azeandrosten
176-01, 2-ethylenedioxymethyl-4,8-?uoro-l7a-vinyl-Azsan
dride in benzene solution and in the presence of p¢toluene
sodium sulfate solution was added, followed by anhydrous
sodium sulfate; the solids were removed by ?ltration and 65 sulfonic acid there was obtained the caproate of Z-formyl
4?-?uoro-17a-vinyl-A2-androsten-17,8-01.
the solution was evaporated to dryness under reduced
chloro-17a-ethinyl-A2-androsten-17,8-01.
A mixture of 1g. of the acetate of Z-acetoxyrnethylene
The above crude product was dissolved in 20 cc. of ’
acetone, treated with .50 mg. of p-toluenesulfonic acid and 70 A3-androst'en-17?-ol, 20 cc. of acetone, 400 mg. of anhy
drous sodium acetate and 6.6 cc. of water was cooled to
the mixture Was kept at room temperature for 6-hours;
0-5” C. and then treated with 510 mg. of N-bromosuc
water was then added, the product wasiextracted with
cinimide (1.1 molecular equivalents) and 0.4 cc. of acetic
methylene chloride and the organic extract was washed
acid. The mixture was stirred at 0—5‘’ C. for 30_minutes,
to neutral, dried over anhydrous sodium sulfate and evap
orated to dryness. Crystallization from acetone-hexane 75 diluted with water and the precipitate formed'was col
3,080,394
12
11:
,lected by ?ltration, Washed with water and recrystallized
caproate of 2-formyl-4a-chloro - 17a-vinyl-A2-androsten
from acetone.
17,8-01.
There was thus obtained the acetate of
2-formyl-4b-bromo=A2-androsten-175-01‘, M.P. 179-183”
,C.,’ [ab-32° (chloroform) Amax. 236-238 mp, log E’
4.11.
.
Example XXII
500 mg. of the ethyleneketal of 2-formy1-4/3-chloro-17a- '
ethynyl-M-androsten-U? - 01, intermediate in Example
.
The above compound was converted into the corre
XIII, was dissolved in 15 cc. of ethyl acetate and into
sponding ethyleneketal, saponi?ed with lithium aluminum
the solution there was introduced a slow stream of dry
hydride and ?nally the, ketal was hydrolyzed with p
hydrogen chloride for 1 hour, kept for 5 hours and then
diluted with water; the organic layer was separated,
washed to neutral, dried and evaporated to dryness under
vacuum. Crystallization from acetone-hexane yielded 2
toluenesulfonic acid in acetone, in accordance with the .
method described ‘in Example XlII, to give 2-formyl-4,B—
‘bI'OmO-A2-1aI1ClI'OSlI6I1-17‘3-0l.
Example XVIII
lforrnyl-4a-chloro-17a-ethynyl-A2-androsten-175-01.
In the same manner ,2-formy1-4B-chloro-17a-vinyl
A2-androsten-17/8-ol and- 2-formyl - 4B-?u0ro-17a-vinyl
Example 15 A2-androsten-17/3-ol were respectively converted into 2
2 g. of the acetate of Z-acetoxymethylene-Hoe-methyl
A3-19-nor-androsten-17/3-ol, intermediate in
XII, was treated with N-bromosuccinimide, by following
the method of the preceding example, thus producing the
acetate of 2-formyl-4b-bromo-17a-methyl-19-nor-A2-an
formyl-4a-chloro-17rx-vinyl - A2-androsten-17/3-o1 and 2
formyl-4a-?uoro-17a-vinyl-A2-androsten-175-01.
Example XXIII
drosten-17/3-ol.
To suspension of 500 mg. of the acetate of 2-formyl
To a solution of 1.2 g. of the above compound in 25
cc‘. of ethyl acetate was introduced a slow stream of dry
4,8-chloro-17a-ethynyl-A2-androsten-175-01 in 20 cc. of
acetic acid was introduced a slow stream of dry hydrogen
chloride for 4 hours and then water was added and the
hydrogen chloride for 1 hour, then kept standing over
night at room temperature, treated with water, the organic
layer was separated and washed to neutral, dried over an
hydrous sodium sulfate and evaporated to dryness under
vacuum.
Crystallization of the residue from acetone
precipitate formed was collected. By crystallization from
acetone-ether there was obtained the acetate of 2-formyl
25 4a-chloro-17a-ethynyl-A2-androsten-175-01.
Example XXIV
hexane afforded the acetate of 2-formyl-4a-bromo-17a
methyl-A2-19-nor-androstend7B-ol.
Example XIX
By following the method of Example X, 2 ‘g. of 2
A mixture of 1 g. of the acetate of 2-formyl-4l3-bromo
30 A2-androsten-17/3-o1 in 5 cc. of *y-COllidiIl? was re?uxed
under anhydrous conditions for 30 minutes, then diluted
with ice water and extracted with ethyl acetate; the or
ganic extract was Washed with 5% hydrochloric acid
fOrmyl-AZJ9-nor-androsten~l7?-ol was converted into the
acetate of 2eacetoxymethylene-A3-19-nor-androsten-17B
01, which upon reaction with perchloryl ?uoride followed
by acid treatment, in accordance with the method de
scribed in Example XIV, produced ‘the acetate of 4st
washed alumina, thus giving Z-fOrmyl-AZ,4-androstadien
?uoro-2-formyl-A2-l9-nor-androsten-l7?-ol.
1718-ol-acetate.
solution to remove the collidine and with water to neutral,
dried over ‘anhydrous sodium sulfate and evaporated to
dryness. The residue was chromatographed on 50 g. of
500 mg. of the above compound was hydrolyzed with
‘lithium aluminum hydride, previous protection of the 2 40 lithium aluminum hydride, previous protection of the 2
formyl group by formation of the ethyleneketal, thus giv
formyl group by formation of the ethyleneketal, thus ob
500 mg. of the above compound was hydrolyzed with
ing 2-formyl-A2#Landrostadien-175-01.
taining 2-formyl-4a-?uoro-A2-l9-noraandrosten-17,8-01.
By esterifying this compound with propionic, caproic
By esterifying this compound with propionic, valeric
or undecenoic anhydrides in pyridine solution there were
and cyclopentylpropionic anhydrides there were obtained
45 the respective esters.
obtained the respective esters.
‘
Example XXV
‘By following the method described in Example XVII,
Example XX
By vfollowing the method described in Example X, 5
5 g. of the acetate of Z-acetoxymethylene-Not-methyl
g. of 2-formyl-17a-viny1-A2-androsten-17/3-01 was con
verted into the acetate of Z-acetoxy methylene-17a-viny1 50 A3-androsten-17B-ol, intermediate in Example XII, was
treated with N-bromosuccinimide to form the acetate of
A3-androsten-l7/8-ol.
2-formyl-4B-bromo-17a-methyl5A2-androsten-17,8-01.
The above compound was treated with 1.1 molar equiv
A solution of 3.5 g. of the above compound in 15 cc. of
alents of N-chlorosuccinimide in the presence of sodium
dimethylacetamide
was added to a suspension of 1.75 g.
‘acetate and acetic acid, in accordance with the method
I bf Example XVII, to produce the acetate of 2-formyl 55 of calcium carbonate in 35 cc. of dimethylacetamide,
which had been previously heated to boiling. The result- '
Zip-chloro-17a-vinyl-A2-androsten-17,8-01. By then fo'l-‘ ‘ ing
mixture was re?uxed for 15 minutes with vigorous
lowing the method described in Example XIII, the above
compound was converted into the corresponding ethylene
ketal, which upon treatment with lithium aluminum hy
dride gave the vethyleneketal of 2-formyl-4?-chlorod7a
vinyl-M-androsten-U?-ol. By treatment with p-toluene
sulfonic acid in acetone there was obtained 2-formyl-4?
chloro- 17 a-vinyl-nz-androsten- 1718-01.
Example XXI
In accordance with the method of hydrolysis described
stirring, cooled, poured into dilute hydrochloric acid solu
tion, extracted with methylene chloride and the extract
was washed to neutral, dried and evaporated to dryness.
Crystallization from ether a?orded the acetate of 2
> formyl-17 a-methyl-A2A-androstadien-17,8-01.
The above compound was converted into the corre
sponding ethyleneketal, saponi?ed with lithium aluminum
65
hydride and the ketal was then hydrolyzed by acid treat~
ment, thus giving 2-formyl-17<x-methyl-A2,4~androstadien
175-01.
in Example XIV, 1.75 g. of the ethyleneketal of Z-formyl
By esteri?cation with cyclopentylpropionic anhydride
4I3-chloro-17a-vinyl-A2-androsten-175-01, intermediate in
in benzene solution and in the presence of p-toluenesul
the preceding example, was treated with hydrogen chlo
ride in ethyl acetate to produce 2-formyl-4a-chloro-17a 70 fonic acid, followed by alkaline treatment, in accordance
with the method described in Example VI, there was
vinyl-A2-androsten-l7B-ol.
'
The above compound was esteri?ed with caproic an
hydride in benzene solution and in the presence of p
toluenesulfonic acid, followed by alkaline treatment, in
accordance with the method of Example VI, to give the 75
obtained the cyclopentylpropionate of 2 - formyl-17a
methyl-A254-androstadien-17,8-01.
Example XXVI
In accordance with, the method described in the pre
‘3,080,3941
13
14
vconsisting of hydrogen and methyl; R1 is selected from
ceding example, 750 mg. of the acetate of 2-formyl-4ot
in Example XVIII, was dehydrobrominated with calcium
carbonate in dimethylacetamide, thus giving the acetate
the group consisting of hydrogen and a hydrocarbon car
boxylic acyl group of less than 12 carbon atoms and R2
is selected from the group consisting of hydrogen, lower
of 2-formyl-17a-methyl-A2'4-l9-nor-androstadien-175-01.
alkyl, lower alkenyl and lower alkynyl.
bromo-17u-methyl-A2-l9 - nor-androsten-17B-ol, obtained
' _ .
2. 2-formyl-4?-chloro-A2>andr0sten-17,8-01.
Exam'ple XX VII
.
3. 2-formyl-4B-bromo-A2-androsten-175-01-17 acetate.
4. 2-formyl-4B-chloro:17u-ethynyl-A2-androsten-1713-01.
5. 2-formyl-4/8-?uoro-17a-methy1-A2-androsten-175-01.
5 g. of the acetate of 2-aoetoxymethylene-l7a-ethynyl
A3~androsten-l7?-ol, intermediate in Example XIII, was
treated with N-bromosuccinimide in accordance with the 10
method of Example XVII, thus giving the acetate of 2
6. A compound of the following formula:
formyl-Ll?-bromo-l7u-etl1ynyl-A2-androsten-l75-01.
A mixture of 2.25 g. of the ‘above compound, 40 cc.
of dimethylformamide and 1.15 g. of calcium carbonate
was re?uxed for 30 minutes under anhydrous conditions, 15
poured into aqueous acid solution and extracted with
ethyl acetate; the organic extract was washed to neutral,
fl
one-A
dried and evaporated to dryness. Crystallization from
acetone-ether yielded the acetate of 2-formyl-l7ot-ethynyl
20
Azfi-androstadien-l7?-ol.
In ‘the same manner the acetate of 2-acetoxymethylene
wherein X is selected from the group consisting of chlo
rine, bromine and ?uorine; R is selected from the group
consisting of hydrogen and methyl; R1 is selected from the
l7ot~vinyl-A3~androsten-1718-01, intermediate in Example
XVI, was converted into the acetate of 2-formyl-4/S
bromo-l7a~vinyl-A2-androsten-17,8-ol and then into the
acetate of Z-formyl-l7a-vinyl-Azy‘i-androstadien-1718-01. ,25
Example XX VIII
By following the method described in Example XIII,
l g. of the acetate of 2-formyl-17a-ethynyl-A2’4-andro
stadien-l7/3-ol was converted into the corresponding eth 30
yleneketal, which upon treatment with lithium aluminum
hydride produced the ethyleneketal of 2-formyl-l7u
is selected from the group consisting of hydrogen, lower
alkyl, lower alkenyl and lower alkynyl.
7. Z-formyl-4a-chloro-A2-androsten-175-01.
8. 2-formyl-4a-?uoro-17a-viny1-A2-androsten-175-01.
9. 2-formyl-4u-chloro-l7a-ethynyl-A2-androsten-17,8-01.
10. 2 - formyl- 4a-bromo-17ot-methyl-A2-19-nor-andro
sten-l7?-ol.
11. 2-formyl-4a-chloro-l7oc-vinyl-A2-androsten-175-01.
ethynyl-AZ4-androstadien-l7?-ol; hydrolysis of the latter
with p-toluenesulfonic acid in acetone afforded 2-formyl
17a-ethynyl-A2d-androstadien-1716-01.
group consisting of hydrogen and a hydrocarbon car
boxylic acyl group of less than 12 carbon atoms and R2
35
12. A compound of the following formula:
By esterifying this compound with propionic and ca
proic anhydrides in benzene solution and in the presence
of p-toluenesulfonic acid in accordance with the method
of Example VI, there was obtained the propionate and
the caproate of 2-formyl-17a-ethynyI-AZ-4-androstadien 40
1719-01.
We claim:
1. A compound of the following formula:
ORl
ORl
R
co” ¥
0130-,
45 wherein R is selected from the group consisting of hydro
gen and methyl; R1 is selected from the group consisting
of hydrogen and a hydrocarbon carboxylic acyl group of
less than 12 carbon atoms and R2 is selected from the
OHC '
group consisting of hydrogen, lower alkyl, lower alkenyl
50 and lower alkynyl.
13. 2-formyl-A2A-androstadien-175-01.
14. The 17ot-lower aliphatic hydrocarbon derivative of
2-formyl-A2Y4-androstadien-175-01.
wherein X is selected from the group consisting of chlo
rine, bromine and ?uorine; R is selected from the group
No references cited.
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No° 3,080,394
March 5,, 1963
Albert Bowers et al, I
It is hereby certified that error appears in the above numbered pat
ant requiring correction and that the said Letters Patent should read as
corrected below.
Column 2? lines 15 to
25v formula III A, should appear
as shown below instead of as in the patent:
T
"1
OH
CH3 ;
III A
Signed and sealed this 8th day of October 1963.
ISEAL)
\ttest:
IRNEST W, SWIDER
\ttesting Officer
EDWIN L, REYNOLDS
Acting Commissioner of
Patents
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