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Патент USA US3080410

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3,080,400‘
United States Patent 0 ”
Patented Mar. 5, 1963
2
3.
The process set forth above is. illustratedvby the follow
ing series of reactions:
3,080,400
Z-HYDROXYME I‘HYL ANDROSTANES
Albert Bowers, John Edwards, and James C. Orr, all of
OH
OH
l_....R5
Mexico City, Mexico, assignors, by mesne assignments,
lung
to Syntax Corporation, a corporation of Panama
No Drawing. Filed Aug. 3, 1961, Ser. No. 128,972
Claims priority, application Mexico Mar. 20, 1961
21 Claims. (Cl. 260-3975)
The present invention relates to certain new cyclopen
tanophenanthrene derivatives and to a method for the 10
preparation of the same.
More particularly, our invention relates to the novel 20c
n
R
OHC—|/\
b.
Home" ii
(I)
H
}'I
i
(In
and Z?-hydroxymethyl, alkoxymethyl, aralkoxymethyl and
acyloxymethyl derivatives of androstan-17?-ol, which may
further possess a l7a-alkyl, alkenyl or alkynyl group; it 15
also comprises the preparation of the esters of such com
0R1
/\ ""R’
pounds and the corresponding l9-nor-derivatives.
RI l
Such compounds are powerful anabolic agents having a
favorable anabolic-androgenic ratio, they help to increase
the protein metabolism and the deposition of calcium on 20
R4OHnC--
l p
/
i
I (In)
the bone tissue; they further show anti-estrogenic activity,
lower the cholesterol level in the blood and inhibit the
secretion of gonadotropins by the pituitary gland.
The l7a-alkenyl and l7a-alkynyl compounds further
It
In the above formulas R and R1 have the same meaning
exhibit progestational activity.
expressed previously; R‘1 represents an acyl group of less
The novel compounds object of our invention are repre
than 12 carbon atoms and R5 represents hydrogen or
sented by the following formula:
alkyl.
OBl
fl
In practice, a solution of a 2-formyl-A2-androsten-17B
30 ol (I:R=Me), prepared as described in our copending
patent application Serial No. 128,974, in ether, dioxane
or a mixture of both solvents, is reduced with an alkali
metal, preferably lithium, in liquid ammonia, under an
hydrous conditions, followed immediately by the destruc
35 tion of the complex formed with a proton donor such as
methanol; there is thus produced in good yield the cor
responding 2a-hy-droxymethyl compound (II:R=Me).
In the above formula, R represents hydrogen or methyl;
R1 represents hydrogen or an acyl group derived from
Esteri?cation of such compounds with anhydrides or chlo
rides derived from carboxylic acids of 1 to 12 carbon
a carboxylic acid of 1 to 12 carbon atoms; R2 represents 40 atoms in pyridine or benzene solution produces the 2,17
hydrogen, a lower alkyl, alkenyl or alkynyl group such as
diesters (III: R=Me, R5=hydrogen) or 2~monoesters
methyl, ethyl, propyl, vinyl, ethynyl or propynyl; R3 rep
(III: R=Me, R5=alkyl). The C-2 monoesters may be
resents hydrogen, a lower alkyl group of 1 to 8 carbon
esteri?ed at C-l7 with the same or with a different acid
atoms, a lower aralkyl group of up to 8 carbon atoms or
anhydride or chloride, in benzene solution and in the
an acyl group derived from a carboxylic acid of 1 to 12
presence of p-toluenesulfonic acid.
carbon atoms. The wavy line at C-2 indicates the a 45
The C-17 monoesters are obtained by selective saponi
or B con?guration for the substituent at such position.
?cation of the 2-acyloxymethyl group of the 2,17-diesters.
The acyl groups referred to above, derive from a car
The 2u-hydroxymethyl and acyloxymethyl androstanes
boxylic acid of less than 12 carbon atoms, saturated or un
having a l7a-alkenyl or alkynyl group are obtained by the
saturated, of straight, branched, cyclic or mixed cyclic
method illustrated by the following series of reactions:
aliphatic chain, substituted or not with hydroxy, lower al 50
koxy such as methoxy, amino, halogen or other groups;
typical such esters are the acetate, propionate, butyrate,
valerate, hemisuccinate, enanthate, caproate, benzoate,
undecenoate, trimethylacetate, phenoxyacetate, cyclopent
ylpropionate and ?-chloropropionate.
In our copending patent application Serial No. 128,974,
?led of even date, there is described the preparation of 2
AOOHQO"
Reid mid
AcOHzC-—
/
—)
formyl-Alandrostenes starting from 2-alkoxymethylene
derivatives of dihydroallotestosterone, of 19-nor-dihydro
allotestosterone as well as of their 17a-alkenyl, alkynyl or 60
1'1
(IV)
it
(v)
alkyl substituted derivatives, which upon reduction with a
double metal hydride produce the corresponding 3-hy
droxy compounds; on further treatment with acid, the
latter give rise to the formation of the 2-formyl-A2-an
drostenes and l9-nor-androstenes.
65
The novel compounds object of the present invention
possessing a Z-hydroxymethyl group in the tit-con?guration
and further having a l7a-alkyl group, are obtained by re
R4OH2C..
duction with an alkali metal in liquid ammonia of the
2-formyl-17e-hydroxy-A2-androstenes and of their 19-nor 70
analogs; by esteri?cation of such compounds there are
obtained the corresponding mono- and di-esters.
OR1
OH
‘guru
R
Horne--
l--—R°
R
/
,____
1’;
(VII)
it
(W)
8,080,400
4
3
- In the above formulas, R, R1 and R4 have the same
meaning set forth above; R6 represents a lower alkenyl or
alkynyl group and Ac represents the acetyl group.
‘ In practicing the process outlined above, 2a-hydroxy
0 R1
L....R2
methyl-androstan-IZB-ol (II: R=Me, R5=hydrogen) is
selectively acetylated at C-2 with approximately 1 molar
equivalent of .acetic anhydride in pyridine solution and
R Pl I
at low temperature, preferably between ‘0° and 5° C.,
to
produce
2a-acetoXymethyl-androstan-175-01
(IV:
momo
R-rr-Me); oxidation of the latter with chromic acid in 10
acetone or acetic acid produces Za-acetoxymethyl-andro
stan-l7-one (V: R=Me). By treatment of the latter
a
(XIV)
compound with sodium or potassium acetylide, or with
the sodium or potassium salt of another lower alkyne,
In the above .formulas, R, R1, R2 and R4 have the
there are obtained the Za-hydroxymethyl-Hot-alkynyl 15 same meaning set forth previously; Ac represents the
compounds (VI: R=Me, R6=alkynyl), which upon
catalytic hydrogenation in the presence of a palladium
acetyl radical.
In practicing the process outlined above, 2-hydroxy
catalyst, preferably palladium on calcium carbonate, and
in pyridine solution, produce the corresponding 170c
methyl-M-androsten-17,8-ol or its corresponding 19-nor
derivative (VIII), is obtained by reducing with sodium
alkenyl derivatives (VI: R=Me, Rbalkenyl).
20 borohydride Z-fOrmyl-AZ-androsten-175-01 and 2-forn1yl
Alternatively, the 17a-alkenyl and alkynyl compounds
19-nor-A2-androsten-175-01 as described in our patent
maybe obtained by treating 2a-acetoxymethyl-androstan
application Serial No. 128,974, ?led of even date. By
17-one (V: R=Me) with an alkenyl or alkynyl mag
hydrogenation of such compounds in the presence of a
nesium bromide, with simultaneous saponi?cation of the
acetoxymethyl group.
palladium catalyst, such as palladium on charcoal, pal
The mono- and di-esters of these compounds (VII) are
obtained in accordance with the methods of esteri?cation
bonate, with the uptake of one molar equivalent of hy
drogen, there are obtained 2i8-hydroxymethybandrostan?
ladium on barium sulfate or palladium on calcium car
described previously for the 17u-alkyl derivatives.
175-01 and ZQ-hydroxymethyl-l9-noraandrostan-175-01
In the same manner, the processes which we have just
(IX). Suitable solvents for this hydrogenation are the
‘described are applied to the 2-formyl-19-nor-A2-andro 30 aliphatic alcohols such as methanol, ethanol or pro~
stenes, thus producing 2a-hydroxymethyl-19-nor-andro
stan-17/3-ol, the corresponding l7a-alkyl, alkenyl and
panol; ethyl acetate, dioxane, tetrahydrofuran, etc.
Modi?cations in the reaction temperature, pressure and
catalyst used do not vary considerably the course of the
reaction.
alkynyl derivatives as well as the mono- and di-esters of
such compounds.
The novel compounds possessing a Zp-hydwxymethyl
35
or 2,8-acyloxymethyl group are obtained by the process
illustrated by the following series of reactions:
By esteri?cation of the Ze-hydrOXymethyI-androstanes
by conventional methods with anhydrides or chlorides of
carboxylic acids of the type set forth above, there are
obtained the 2,17-diesters (X), which by selective hy
(‘3H
l
R
?H
l
EOHaC-
R
II
drolysis of the acyloxymethyl group at C~2 afford the
40 l7-monoesters.
By treatment of 2/3-hydroxymethyl-androstan-l7;3~0l
or its 19-nor-derivative with approximately 1 molar equiv
alent of acetic anhydride in pyridine solution and at room
vtemperature, preferably between 0° and 5° 0, there are
HOHzC
' \J
ft
45
(vm)
r'r
/
(RH
AcOHzC-
R
dation with an 8N solution of chromic acid, in acetone
solution, or with 1.1 equivalents of chromic acid in acetic
(IX)
l
acid, furnish the l7-ketones (XII).
50 . _ For preparing the 17u-alkyl, alkenyl or alkynyl deriva
tives (XIII), 2B-acetoxymethyl-androstan-l7-one or its
19-nor derivative is treated with an organometallic halide,
ORl
R‘OHzC-
RI
‘obtained 2B-acetoxymethyl-androstan-17/3-01 and ZB-ace
toxymethyl-l9-nor-androstan-17,6-01 (XI) which by oxi
at the re?ux temperature for 2 to 5 hours or overnight
at room temperature. Adequate solvents for this reac
55 tion are the aromatic hydrocarbons, such as benzene,
toluene or xylene, or other organic solvents inert to this
reaction such as ether or tetrahydrofuran. In this man
ner the l7-keto group is converted into the l7?-hydroxy
15
(XI)
17a-alkyl, 17,8-hydroxy-17a-alkenyl or l7l8-hydroxy-l7a
60
alkynyl groupings, according to the Grignard reagent em
ployed for the reaction, simultaneously, the Z?-acetoxy
methyl group is hydrolyzed to produce the 17oL-sllb
stituted Z?-hydroxymethyl-l7l9-hydroxyaandrostanes. For
example, by reacting Z?-acetoxymethyl-androstan-17-one
with methyl~magnesium bromide, there is obtained 2/3~
hydroxymethyl-l7u-methyl-androstan-1713-01.
AOOHzC
By esteri?cation of the Not-substituted 2?-hydroxy
methyl-androstanes and 19-nor-androstanes, by conven
tional methods, there are obtained the C-2 monoesters,
which on treatment with the same or a different acid
anhydride or chloride in benzene solution and in the
presence of p-toluenesulfonic acid, produce the diesters.
; The selective hydrolysis of the 2,6-acy1oxymethyl group
produces the 177II1OI1O€SI€I'S.
Alternatively,'the l7d-Valky1 substituted compounds'may
6
Example 11
By following the method of the preceding example,
but using 2-formyl-19-nor-A2-androsten-1713-01 as starting
be obtained by treating the 17-ketones (XII) with an
alkyl-lithium.
The 17a-alkynyl substituted compounds. are also ob
tained by treating 2/3-acetoxymethyl-androstan-17-one or
material, there was obtained 2a-hydroxymethyl-19-n0r
androstan-17B-ol and its corresponding diacetate.
its l9-nor derivative with sodium or potassium acetylide
or with the sodium or potassium salt of another alkine.
Example III
By partial hydrogenation of the 2/3-hyroxymethy1-17a
alkynyl-17-?-hydroxyandrostanes and 19-nor-androstanes,
A solution of 5 g. of 2-hydroxymethyl-androstan-1718-01
in‘ 20 cc. of pyridine was cooled at 0° C., treated with 1.8
on calcium carbonate, and using an amine as solvent, 10 g. of: acetic anhydride (1.1 equivalents) and allowed to re
preferably pyridine, there are obtained the 2,8-hydroxy
act at 0° C., for 24 hours; it was then poured into water,
methyl-l7a-alkenyl-17?-hydroxy-androstanes and 19-nor
extracted with ethyl acetate and the extract was washed to
audrostanes.
neutral, dried and evaporated to dryness. The residue
The novel 20: and ZB-alkoxy and 2a- and ZB-aralkoxy
was chromatographed on washed alumina, thus affording
in the presence of a palladium catalyst such as palladium
compounds object of our invention are obtained by the 15
method illustrated by the following equation:
2a-acetoxy-methyl-androstan-175-01.
A stirred solution of 3 g. of the above compound in
60 cc. of acetone was treated with 5 cc. of an 8 N solu
tion of chromic acid (prepared in 23% sulfuric acid) and
the mixture was kept at room temperature for 10 minutes.
20 At the end of this time the mixture was poured into water
and the precipitate formed was collected, thus giving 2o¢~
acetoxymethyl-androstan-17-one.
A solution of 2 g. of the above ketone in 60 cc. of
anhydrous benzene was added under an atmosphere of
25 nitrogen to a solution of potassium t-amyloxide, prepared
In the above formulas, ‘R, R1 and R2 have the same
meaning set forth previously; R’7 represents a lower alkyl
previously from 1.4 g. of potassium and 30 cc. of t-amyl
alcohol. A slow stream of puri?ed acetylene was intro
duced into the resulting solution for 40 hours and the
solution was then poured into ice water and extracted with
or aralkyl group; the wavy line indicates the a or is con 30 several portions of benzene.
?guration for the substituent at C—2.
-In practicing the process outlined above, a 17-ester of
Z-hydroxymethyl-androstan-1713-01, which may further
possess a substituent at C-17cl. of the type set forth
previously, or the corresponding 19-nor derivatives (XV),
is reacted at room temperature with an excess of an ether
solution of a diazoalkane, such as diazomethane or
diazoethane, and in the presence of a catalyst, such as
boron tri?uoride or aluminum chloride, and there are
The combined extract was
washed‘ to neutral, the organic layer was dried over an
hydrous sodium sulfate and evaporated to dryness under
vacuum.
The residue was chromatographed on 50 times
its weight of washed alumina and the crystalline fractions
were recrystallized from acetone-hexane, thus furnishing
Zu-hydroxyrnethyl-l7a-ethynyl-androstan-l7-5-01.
A mixture of 500 mg. of the above compound, 2 cc. of
pyridine and 1 cc. of acetic anhydride was heated on the
steam bath for 1 hour, poured into water and the precipi
produced the Z-methoxymethyl or 2-ethoxymethyl deriva 40 tate formed was collected. There was thus obtained 2a
tives (XVI: R7=Me, Et; R1=acyl). Saponi?cation of
these compounds by conventional methods affords the free
ethers.
Alternatively, the etheri?cation may be effected by re
acting at the re?ux temperature the 2-hydroxymethyl
compounds of Formula XV with an alkyl or aralkyl halide,
preferably with an alkyl or aralkyl iodide, in an organic
solvent such as acetone and in the presence of a base
such. as potassium carbonate, or by treatment with an
alkyl sulfate in acetone solution and in the presence of a
base, preferably potassium hydroxide, at room tempera
ture.
The following examples serve to illustrate but are not
intended to limit the scope of the invention:
Example I
A solution of 5 g. of 2-formyl-A2-androsten-1713-01 in
100 cc. of a mixture of dioxane and ether (1:1) was slow
ly added to a stirred solution of 1.5 g. of lithium metal in
lacetoxymethyl-l7a~ethynyl-androstan-17,8-01.
In the same manner 2a-hydroxymehyl-17-nor-andro
stan-17?-ol was converted into 2a-acetoxymethyl-19-nor
androstan-17?-ol, 2a-acetoxymethyl-19-r10r-andro-stan-17
one, Za-hydroxymethyl-17a-ethynyl-1-9=nor-androstan-17/3
01 and ?nally into Za-acetoxymethyl-17a-ethynyl-19-nor
androstan-UB-ol.
_
Example IV
In accordance with the method of reduction described
in Example I, .there was treated 5 g. of 2-formyl-17a
rnethyl-Az-and-rosten-17/3-01 and 5 g. of 2-formyl-17a
methyl-l9-nor-A2-androsten-1713-01 with lithium in liquid
ammonia to produce 2a-hydrroxymethyl-17or-methyl-an~
drostan-17/3-ol and its corresponding 1'9-nor analog.
From a solution of 1 g. of Za-hydrOXymethyl-I7a-meth~
yl-androstan-17?-ol in 130 cc. of benzene free of thio
phene there was distilled approximately 30 cc. in order to
remove moisture; there was then added 0.52 cc. of py
750 cc. of liquid ammonia. At the end of the addition 60 ridine and 1.5 cc. of undecenoyl chloride and the mixture
was re?uxed for 1 hour [and evaporated to dryness; the
there was added dropwise 10 cc. of methanol until the
residue was chromatographed on 30 g. of washed alumina,
blue color of the solution was discharged. The ammonia
was evaporated, water was added to the residue and the
product was extracted with ether; the organic extract was
washed to neutral, dried over anhydrous sodium sulfate
thusv yielding 2a-undecenoyloxymethyl-17a-methyl-an
drostan-17?-ol.
Example V
and evaporated to dryness. Chromatography of the resi
A solution of 500 mg. of 2a-hydroxymethyl-androstan~
due on 250 g. of washed alumina, followed by recrystal
lization of the solid fractions from acetone-hexane afford
175-01 in 2 cc. of pyridine was treated with 1 cc. of caproic
anhydride and the mixture was kept overnight at room
ed 2a-hydroxymethyl-androstan-1719-01.
temperature, then poured into water and the precipitate
A mixture of 1 g. of the above compound, 4 cc. of 70 formed was collected, thus giving the caproa-te of 2-cap
ronoxymethyl-androstan-175-01.
pyridine and 2 cc. of acetic anhydride was heated on the
steam bath for 1 hour, then poured into water and the
precipitate formed was collected, washed with water to
By the same methods, but using propionic, valeric and
cyclopentyl-propionic anhydrides as esterifying agents
neutral and dried. Crystallization from acetone-hexane
there were obtained the corresponding diesters of 2a-hy
yielded 2a-acetoxymethyl-androstan-1713-01 acetate.
droxymethylaandrostan-17,8-01.
3,080,400
Example VI
pyridine and 5 cc. of propionic anhydride was allowed
A mixture of 1 g. of 2a-hydroxymethyl-17a-methyl-an
drostan-IZB-ol, 50 cc. of benzene, 2 cc. of acetic anhy
to react at room temperature overnight and then poured
into water. The precipitate formed was collected by
dride and 500 mg. of p-toluenesulfonic acid was kept at
room temperature for 48 hours, then diluted with water
and the benzene layer was separated, washed with 5%
?ltration to give the propionate of 2,8-propionoxymethyl
androstan -17?-ol.
By the same method of esteri?cation, but using acetic
anhydride and caproic anhydride as esterifying agents
sodium carbonate solution and water, dried over an
there were obtained the acetate of Z?-acetoxymethyl
hydrous sodium sulfate and evaporated to dryness under
androstan-17?-ol and the caproate of Z?-capronoxymeth
reduced pressure. By chromatography of the residue fol
lowed by crystallization of the solid fractions from ace 10 yl-androstan-17B-ol.
'
Example X
tone-ether there was obtained the acetate of 2a-acetoxy
A solution of 15 g. of 2/8-hydroxymethyl-androstan
methyl-17a-methyl-androstan-175-01.
1713-01 in 60 cc. of pyridine was cooled to 0° C. and
In the same manner, but using propionic, caproic, un
- treated with 5.5 ‘g. of acetic anhydride (1.1 equivalents).
decenoic and cyclopentylpropionic anhydrides as esterify
The mixture was allowed to react at 0° C. for 18 hours,
ing agents (of the latter two anhydrides, twice the amount
then poured into water and extracted with ethyl acetate.
was employed), there were obtained the propionate of 2a
propionoxymethyl-17a-methyl-androstan-1718-01, the cap
roate of 2ot-capronoxymethyl-17a-methyl-androstan-1715’
ol, the undecenoate of 2a-undecenoyloxymethyl-andro
stan-17B-ol and the cyclopentylpropionate of Zen-cyclo
pentylpropionoxymethyl-androstan-173-01.
Example VII
A solution of 750 mg. of 2a-hydroxymethyl-17a-ethy
The extract was washed to neutral, dried, evaporated to
dryness and the residue was chromatographed on washed
alumina, thus producing 213-acetoxymethyl-androstan
175-01. A stirred solution of 10 g. of the above com
pound in 100 cc. of acetic acid was treated dropwise with
a solution of 2.5 g. of chromic acid in 25 cc. of 80%
acetic acid at a temperature between 15 and 20° C.
The mixture was kept standing at room temperature for
ny1-androstan-17?-ol in 20 cc. of pyridine was hydroge 25 1 hour, poured into ice cold salt solution and the precipi~
nated at room temperature and atmospheric pressure us
tate formed was collected by ?ltration and washed with
ing 0.2 g. of 5% palladium on calcium carbonate catalyst
(which had been previously reduced). After the uptake
Water to neutral, thus yielding Z?-acetoxyrnethyl-andros
tan-17-one, which was puri?ed by crystallization from
chloroform-methanol.
of 1 molar equivalent of hydrogen the catalyst was re
moved by ?ltration and the ?ltrate was evaporated to 30'
A solution of 5 g. of 2,8-acetoxymethyl-androstan-17
dryness under vacuum. The residue was dissolved in
one in 100 cc. of anhydrous benzenefree of thiophene
ethyl acetate, washed with hydrochloric acid to complete
ly remove the pyridine and ?nally with water to neutral,
dried and concentrated to a small volume.
Crystalliza
tion from ethyl acetate-hexane atforded 2a-hydroxymeth
yl-17a-vinyl-androstan-175-01.
was added little by little to 25 cc. of a 4N solution of
methyl magnesium bromide in ether and the mixture was
re?uxed under anhydrous conditions for 3 hours; after
cooling, the mixture was cautiously poured into water,
acidi?ed with hydrochloric acid and the benzene layer
A mixture of 1 g. of 2ot-hydroxymethyl-17a-vinyl-an
drostan-17p-ol, 10 cc. of pyridine and 1 cc. of acetyl chlo
ride was kept at room temperature for 36 hours and then
was separated. The aqueous phase was extracted sev
eral times with ethyl acetate and the extract was corn
lbelow 60° C. By crystallization of the residue from
methylene chloride-hexane there was obtained 2a-acetoxy
fate and evaporated to dryness under reduced pressure.
Crystallization of the residue from acetone-hexane af
bined with the benzene solution. The organic solution
the solvent was removed under vacuum at a temperature 40 was washed to neutral, dried over anhydrous sodium sul
methyl-17a-vinyl-androstan-1718-01.
forded 2/3-hydroxymethyl-17a-methyl-androstan-175-01.
‘ By the same method, but using 2a-hydroxymethy1-17a
A mixture of 2.5 g. of the above compound, 100 cc.
were successively obtained Za-hydroxymethyl-l7a-vinyl
p-toluenesulfonic acid was kept at room temperature for
ethynyl-19-nor-androstan-l7?-ol as starting material there 45 of acetic acid, 50 cc. of acetic anhydride and 2.5 g. of
19-nor-androstan-17p-ol and 2a-acetoxymethyl-17a-vinyl
19-nor-androstan-17p-ol.
18 hours, then poured into water, heated for 30 minutes
on the steam bath to hydrolyze the excess of reagent and
the precipitate formed was collected by ?ltration, and
Example VIII
1 g. of the acetate of 2e-acetoxymethyl-17a-methyl-an
drostan-17/3-ol was dissolved in 50 cc. of a 1% solution
50 washed with water to neutral, thus producing the acetate
of 2,8-acetoxyrnethyl-17a-methyl-androstan-1718-01.
By selective saponi?cation by treatment with 1%
methanolic potassium hydroxide solution in accordance
of potassium hydroxide in methanol and the mixture was
kept at room temperature for 4 hours, then neutralized
with the method of Example VIII, there was obtained the
with a few drops of acetic acid, concentrated to a small 55 17-acetate of 2,8-hydroxymethyl-17a-methyl-androstan
volume and diluted with water. The precipitate formed
1713-01.
was collected, washed, dried and crystallized from ace
Example XI
tone-ether, thus furnishing the 17-acetate of 2a-hydroxy
methyl-17a-methyl-androstan-17?-ol.
'
By the same method the dicaproate, the dipropionate
and the dicyclopentylpropionate of 17a-methyl-androstan
17;.8-01, obtained in Example VI, were converted into the
corresponding 17-monoesters.
Example IX
A solution of 20 g. of Z-hydroxymethyl-M-androsten
A solution of 5 g. of Z?-acetoxymethyl-androstan-17
one in 100 cc. of anhydrous ether was added dropwise
to a solution of propargyl magnesium bromide (prepared
from 6.8 g. of propargyl bromide, 1.4 g. of magnesium
and 200 cc. of ether). The mixture was re?uxed with
stirring for 5 hours, cooled and poured into 500 cc. of
5% ammonium chloride solution; the ether layer was
separated, washed with water to neutral, dried over an
hydrous sodium sulfate and evaporated to dryness under
‘1718-01 in 400 cc. of ethyl acetate was hydrogenated at
vacuum. Crystallization of the residue from methanol
room temperature and atmospheric pressure in the pres
furnished 2,8-hydroxymethyl - 17oz - propargyl-androstan
ence of 2 g. of 5% palladium on charcoal catalyst which
had been previously reduced. After the uptake of 1 molar 70 175-01.
1 g. of the above compound was dissolved in 20 cc.
equivalent of hydrogen the catalyst was removed by ?ltra
of benzene and treated with 2 cc. of propionic anhydride
tion through celite and the ?ltrate was evaporated to dry
and 0.5 g. of p-toluenesulfonic acid. The mixture was kept
ness. Chystallization of the residue from methylene chlo
overnight at room temperature, then diluted with water
ride-hexane afforded ZB-hydroxymethyl-androstan-17,8-01.
A mixture of 1 g. of the above compound, 5 cc. of is and stirred for 30 minutes to hydrolyze the excess of re
3,080,400
10
agent; the benzene layer was separated and washed with
5% sodium carbonate solution and ?nally with water
to neutral, dried over anhydrous sodium sulfate and
evaporated to dryness under vacuum. Chromatography
of the residue on washed alumina followed by crystal
lization of the solid fractions from acetone-hexane af
obtained Z?-acetoxymethyl - l9 - nor - androstan - 17-,8 - 01,
forded the propionate of ZB-propionoxymethyl-l7a-pro
nor-androstan-l75-ol.
which on oxidation with chromic acid in acetic acid
a?orded 2/8-acetoxymethyl-l9-nor-androstan-17-one.
5 g. of the above compound was treated with methyl
magnesium bromide in accordance with the method of
Example X, thus giving 2,8-hydroxymethyl-17/3-methyl-l9
In the same manner, but using ethyl, vinyl and ethynyl
pargyl-androstan-lmeol.
magnesium bromide as alkylating agents, there were ob
Example XII
A solution of 2 g. of 2IS-acetoxymethyl-androstan-l7 10
one in 60 cc. of anhydrous benzene was added under an
tained, respectively: 2?-hydroxymethyl-l7a-ethyl-l9-nor
andr0stan-1718-o1, 2?~hydroxyrnethyl-l7a - vinyl - l9 - nor
androstan-l7?-ol and 2/3-hydroxymethyl-l7a-ethynyl-19
nor-androstan-UB-ol.
atmosphere of nitrogen to a solution of potassium amyl
oxide previously prepared from 1.4 g. of potassium in
30 cc. of amyl alcohol. A slow stream of puri?ed acetyl
Example XVI
A solution of l g. of the caproate of 2a-hydroxymethyl~
ene was then introduced into the resulting solution for 15
l7a-methyl-androstan-l7?-ol, obtained in accordance with
40 hours and the solution was then poured into ice water
Example VIII, in 100 cc. of ether was cooled to 0-5° C.
and extracted with several portions of benzene. The
and treated with an ether solution of diazomethane (pre
combined extract was washed to neutral, the organic
pared from 5v g. of nitrosomethylurea) and 3 drops of
layer was dried over anhydrous sodium sulfate and evapo
rated to dryness under vacuum. The residue was chro 20 recently distilled borontri?uoride etherate. The mixture
was kept at room temperature for 1 hour, treated with
matographed on 50 times its weight of washed alumina
a few drops of acetic acid to destroy the excess of diazo
and the solid fractions were recrystallized from acetone
methane and evaporated to dryness, thus giving the
hexane, thus yielding Z?-hydroxymethyl - 17oz - ethynyl
caproate of 2a-methoxymethyl-l7a-methyl-androstan-17B
androstan-17pl-ol.
A mixture of 500 mg. of the above compound, 2 cc. 25 ol.
5
A solution of 500 mg. of the above compound in 50 cc.
of methanol was treated with a solution of 500 mg. of
potassium hydroxide in 1 cc. of water and the mixture
precipitate formed was collected, thus giving 2?-acetoxy—
was kept overnight at room temperature; it was then
methyl-l7a-ethynyl-androstan-17,8-01.
30 neutralized with acetic acid, concentrated to a small vol
Example XIII
ume and diluted with water until complete precipitation
A solution of 2 g. of 2/3-hydroxymethyl-l7u-ethynyl
of the product, which was collected and crystallized from
androstan-l7B-ol in 50 cc. of pyridine was hydrogenated
methylene chloride-hexane, thus furnishing 2et-methoxy
at room temperature and atmospheric pressure in the
methyl-17a-methyl-androstan-176-01.
presence of 0.6 g. of 5% palladium on calcium carbonate 35
Example XVII
of pyridine and 1 cc. of acetic anhydride was heated for
1 hour on the steam bath and poured into water. The
(which had been previously reduced). After the uptake
A mixture of 2 g. of ZB-hydroxymethyl-l7a-vinyl-l9
nor-androstan-l7?-ol, 100 cc. of anhydrous acetone, 10
cc. of methyl iodide and 2v g. of anhydrous potassium
ness under vacuum. The residue was dissolved in ethyl
acetate, washed with hydrochloric acid to remove all of 40 carbonate was re?uxed for 48 hours under anhydrous
of 1 molar equivalent of hydrogen the catalyst was re
moved by ?ltration and the ?ltrate was evaporated to dry
conditions.
the pyridine and ?nally with water to neutral, dried and
concentrated to a small volume.
At the end of this time the mixture was
poured into water, extracted with ethyl acetate and the
Crystallization from
organic extract was washed with water, dried over an
ethyl acetate-hexane furnished 2,8-hydroxymethyl-l7a
hydrous sodium sulfate and evaporated to dryness under
The residue was puri?ed by chromatography on
tic anhydride in pyridine gave Z?-acetoxymethyl-17a-vinyl 4:5 vacuum.
washed alumina, thus giving 2/3-methoxymethyl-l7a-vinyl
vinyl-androstan-l7/3-ol. Subsequent acetylation with ace
androstan-l7?-ol.
l9-nor-androstan-17?-ol.
benzene, 2 cc. of cyclopentylpropionic anhydride and 250
pound with propionic anhydride in benzene solution and
A mixture of 500 mg. of the above compound, 25 cc. of
By esteri?cation of this com
in the presence of p-toluenesulfonic acid there was ob
mg. of p-toluenesulfonic acid was kept standing at room
temperature for 48 hours and then diluted with water and 50 tained the propionate of ZB-methoxymethyl-l7a-vinyl-19
nor-androstan-l7?-o-l.
stirred for 30 minutes to hydrolyze the excess of reagent;
Example XVIII
the benzene layer was separated, washed to neutral, dried
By following the method of the preceding example, but
over anhydrous sodium sulfate and evaporated to dry
using ethyl, propyl or benzyl iodide instead of methyl
ness. Crystallization from acetone-ether afforded the
cyclopentylpropionate of Z?-acetoxy-methyl-l7tx-vinyl
55 iodide,
andro-stan-l7B-ol.
Example XIV
By following the method of hydrogenation described
in the preceding example, 500 mg. of the propionate of 2/3
propionoxymethyl-17a-propargyl-androstan - 17B - 01 was 60
converted into the propionate of 2B—propionoxyrnethyl
l7a-propenyl-androstan-175-01.
Example XV
A suspension of 10 g. of Z-hydroxymethyl-l9-nor-A2
androsten-l75-ol in 100 cc. of methanol was added to a 65
the acetate of Z?-hydroxymethyl-l7a-methyl
androstan-l7B-ol, obtained by the method of Example X,
was converted into Z?-ethoxymethyl-l7rx-methyl-andro
stan-l7?-ol acetate, ZB-propoxymethyl-17a-methyl-andro
stan-l7B-ol acetate and 2,8-benzyloxymethyl-l7a-methyl
androstan-l7B-ol acetate. By subsequent saponi?cation of
these compounds, in accordance with the method of Ex
ample XVI, there were obtained the respective free com
pounds.
Example XIX
A mixture of 1 g. of the acetate of ZB-acetoxymethyl
androstan-l7?-ol and 50 cc. of 1% potassium hydroxide
suspension of 10% palladium on calcium carbonate which
solution was kept standing at 0° C. for 2 hours; it was
had been previously reduced and the mixture was hy
then neutralized with a few drops of acetic acid, poured
drogenated at room temperature and atmospheric pres
into water and extracted with ethyl acetate; the organic
sure until the equivalent of 1 mol of hydrogen had been
absorbed. The catalyst was removed by ?ltration and 70 extract was washed to neutral, dried and evaporated to
dryness under vacuum. Chromatography of the residue
the ?ltrate was evaporated until crystallization started,
thus aifording ZB-hydroxymethyl-l9-nor-androstan-l7B-ol.
afforded the l7-acetate of Z?-hydroxymethyl-androstan
175-01.
The above compound was treated with 1.1 molar equiv
500 mg. of the above compound was treated with an
alents of acetic anhydride in pyridine, at 0° C., in accord
ance with the method of Example X. There was thus 75 excess of diazomethane, in the presence of borontri?uo
3,080,400
12
11
ride, folowing the method of Example XVI, to produce
wherein R is selected from the group consisting of hy
the acetate of Z?-methoxymethyl-androstan-17,8-01.
drogen and methyl; R1 is selected from the group con
. A solution of 300 mg. of the above compound in 501
cc. of methanol was re?uxed for 1 hour with 159 mg.
sisting of hydrogen and a hydrocarbon carboxylic acyl
of potassium hydroxide, cooled, poured into water and
the group consisting of hydrogen, lower alkyl, lower
group of less than 12 carbon atoms; R2 is selected from
the precipitate'formed Was collected and washed to neu
alkenyl and lower alkynyl and R3 is selected from the
tral, thus giving Zti-methoxymethyl-androstan-175-01. .
Example XX
group consisting of an alkyl group containing from 1
to 8 carbon atoms, and aralkyl group containing up to
8 carbon atoms and a hydrocarbon carboxylic acyl group
' A solution of} 250 mg. of the above ether in 1 cc. of 10 of less than 12 carbon atoms.
pyridine was treated with 0.5 cc. of benzoyl chloride '
2. The 2-lower alkoxymethyl-androstan~17,8:01.
and heated on the steam bath for 1 hour; the mixture
was then cooled, poured into water and the precipitate
formed was collected and recrystallized from chloroform
3. 2a-methoxymethyl-androstan-1713-01.
4. Z?-ethoxymethyl-androstan-1718-01.
methanol, thus furnishing the benzoate of 2,8-methoxy 15
l6. The cyclopentylpropionate of 2a-methoxymethyl
5. 2a-methoxy-methyl-l7e-rnethy1-androstan-‘175-01.
methyl-androstan-Np-ol.
17a-ethynyl-androstan-1713-01.
7. The caproate of 2u-methoxymethyl-17a-methyl~
Example XXI
vandrostan-17i3-ol.
There was repeated the preceding example, but using
8. The hydrocarbon carboxylic acid esters of less than
the acetate of 2a-acetoxymethyl-l9-nor-androstan-l7? 20 12 carbon atoms of 2~hydroxymethyl-androstan-l7,8-01.
01 as starting material, thus obtaining successively the
179. The propionate of 2a-propionoxymethyl-androstan
acetate of 2a-hydroxymethyl- l9-nor-androstan-17?-ol,
the acetate of Zu-methoXymethyl-I9-nor-androstan-17B,
.i710.1'1‘he caproate of 2oe-capronoxymethyl-androstan
o1, 2a-methoxymethyl-19-nor-androstan-17/3-ol and the
benzoate of 2a-methoxymethyl-l9-nor-androstan-1713-ol.
Example XXII
11. 2a-acetoxymethyl-17u-ethynyl-androstan-175-01.
’ 12. A compound ‘of the following formula:
A solution of 500 mg. of the acetate of ZB-hydroxy
methyl-l7a-methyl-androstan-175-01 in 75 cc. of ether
was treated with an excess of an ether solution of di
azoethane in the presence of 10 mg. of aluminum chloride
30
as catalyst and the mixture was allowed to react at room
temperature ?or 1 hour; the excess of reagent was de
stroyed with a few drops of acetic acid and the mixture
was evaporated to dryness, thus giving the acetate of 35
2?-ethoxymethyl-l7ot - methyl-androstan-Up-ol, identical
with the one obtained in Example XVIII.
HOHzCMN
TF1
i
Example XXIII
By following the method of esteri?cation described in 40
Example VI, of 2 g. of 2a-acetoxymethyl-l7a-ethylny1-an
H
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
cyclopentylpropionate of 2a-acetoxyrnethyl-l7a-ethynyl 45 of less than 12 carbon atoms; and R2 is selected from
the group consisting of hydrogen, lower alkyl, lower al
androstan-17?-ol.
kenyl and lower alkynyl.
The above compound was selectively sapom'?ed at
13. 2-hydroxymethyl-androstan-175-01.
C—2, in accordance with the method of Example VIII,
f14. Z-hydroxymethyl-l9-nor-androstan-17?-ol.
and the resulting 2ot-hydroxymethyl compound was
l5. Z-hydroxymethyl-l7ot-ethynyl-androstan-1718-01.
treated with methyl iodide in acetone and in the presence 50
drostan -17,6-ol, obtained in Example VI, was treated with
cyclopentylpropionic anhydride in benzene solution and
in the presence of p-toluenesulfonic acid, thus giving the
cedure described in Example XVII; there was thus ?nally
16. Z-hydroxyrnethyl-17u-methyl-androstan-1713-01.
17. Z-hydroxymethyl-l7u-vinyl-androstan-17?-ol.
obtained the cyclopentylpropionate of 2a-methoxymethyl
1 l8. Z-hydroxymethyl-l7ot-methyl - 19 - nor - androstan
of anhydrous potassium carbonate, by following the pro
17u-ethynyl-androstan-17,3-01.
We claim:
7,B'ol.
“
55
1. A compound of the following formula:
1 19. Z-hydroxymethyl-l7a-ethynyl - l9 - nor - audrostan
76-01.
20. A process for preparing a ZOL-hydroXymethyI-an
drostan-17?-ol comprising reducing a 2-forn1yl-A2-andro
sten-17?-ol with an alkali metal in liquid ammonia.
21. A process for preparing a Zp-hydroXymethyI-an
. n15”
drostan-17/3-ol comprising hydrogenating a 2-hydroxy
methyl-Az-androsten-lm-ol in the presence of a palladium
3.301120 MN
catalyst.
65
No references cited.
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