close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3062856

код для вставки
United States Patent v O
1
3,062,843
Patented Nov. 6, 19§2
‘C3 .
1
1
..
2
.
ent invention is illustrated in’ part by the following equa4
3,062,843
C-Z-CARBOXYLIC ACL’D AND C-Z-HYDROXY
METHYL DEREVATIVES OF THE ANDRO
STANE SERIES
tion:
‘
~>
-
-
'
Y
'
>
,
Lawrence H. Knox, Mexico City, Mexico, assignor, by
mesne assignments, to Syntex Corporation, a corpora
tion of Panama
'
_
No Drawing. Filed Jan. 4, 1961, Ser. No. 80,527
Claims priority, application Mexico Jan. 6, 1960 '
31 Claims. ‘(Cl. 260—397.1)
10
The present invention relates to novel cyclopentano
phenanthrene compounds and to a method for the pro
duction thereof.‘
.
More particularly the present invention relates to.C-2
carboxylic acid and C-Z-hydroxymethyl derivatives of the
androstane series and more speci?cally of androstanes
havin'g keto or hydroxyl groupsatC-3 and 017, which
may also contain an alkyl group at _C-l7a,.to 19-nor-de
rivatives thereof as well as esters thereof.
The novel compounds of the present invention which 20
are valuable anabolic agents having a favorable anabolic
androgenic ratio and which exhibit anti-estrogenic ac,
tivity, in?uence the secretion of the gonadotrophic
hormone of the pituitary gland and lower the cholesterol
‘level are represented by the following formulas:
R
onion»
Ho~w
ORI
m5
,
:
o
R
R3O—(JJ-~/\
210mb.:
V
IIIa: R3=
hydrogen
.
I.
I
CHQORL~
.
'
RZONW
onto RL
.
alkyi
on,
,
‘ R
R3O——O—(I?
.
2
IIII): R9=
‘
Rlolwv
VI
I
‘
0R1
_R
I
1
~
IVa: R3:
.
hydrogen
IVb: R3=
alkyl
In the, above formulas, R ‘represents hydrogen or
methyl, R’ and R3 represent hydrogen or an alkyl radical
In the above formulas R, R2 and R3 havethe same
containing 1 to 5 carbon atoms, such as methyl, ethyl,
meaning as previously set forth.
v 1
propyl, R2 and R4 vrepresenthydrogen or the acyl radical 50 In practicing the process outlined abovethe starting
of a hydrocarbon carboxylic acid oflless than 12 carbon
compound p2a-hydroxyrnethyl-dihydroallotestosterone or
atoms which may be saturated or unsaturated, of straight,
2a-hydroxymethyl-19anoridihydroallotestosterone (I) pre
branched, cyclic or cyclic-aliphatic chain and may be sub
pared by hydrogenation of the corresponding Z-hydroxy
stituted with functional groups such ashydroxy, acyloxy,
methylene derivative as more fully described in copend
alkoxy, amino, nitro or halogen. Typical ester groups 55 ing application Serial No. 80,528, ?led January 4, 1961-,
are the acetate, propicnate, butyrate, caproate, hemisuc
now ‘Patent No; 3,000,912, ‘is’ subjected to oxidation,
cinate, benzoate, aminoacetate, cyclopentylpropionate,
trimethylacetate and ?-chloropropionate. I
‘
‘
_
_
The novel compounds of "the present invention are
preferably in acetone solution at low temperature with a
solution of 8 N chromic acid’prepared 'in dilute sulfuric
acid. Alternatively the chromic oxide-pyridine. complex
prepared by reducing a 2whydroxymethybdihydroallo 60 may be employed‘ as the oxidizing agent ‘to form 2a;
testosterone to form a 2whydroxymethyl-androstane-3,17
carboxy-androstane-3,17-dione or 2u-carboXy-l9-nor-an;
diol or by oxidizing a 2a-hydroxymethyl-di-hydroallotes
tosterone to form 2-carboXy-androstane—3,17-dione or a
Za-carboxy-androstaned7;8<ol-3-one which may then be
subjected to reduction to produce the 3 ,l7-diol.
The preparation of the novel compounds ‘of the'presi
>drostane-3>,l7-dione. (11a). The latter can then-be 'est'er'i'7
?ed by reaction with a diazoalkane such as diaz'omethane,
diazoethane orxother diazoalkanes containing up 'to ‘5.
carbon atoms to form the carboalkoxy'derivative (lib).
Upon treatment of thefZd-carboxy (Ilq) ora ;_2aécarb'ol
3,062,848
corresponding 30;,17/3 and 35,17/3-diols (111a and H111).
Conventional esteri?cation of the latter products with hy
drocarbon carboxylic acid anhydrides of the type men
tioned previously results in the formation of the corre
sponding 3,17-diesters (IVa and IVb).
kyl- dihydroallotestosterone or the 17,8 - ester thereof
The treatment of 2a-hydroxymethyl-dihydroallotestos
(VIIIa). The ester group at C~l7?, if present, can be
saponi?ed to afford the free alcohol (R2=hydrogen)
terone or la-hydroxymethyl-19-nor-dihydroallotestos
terone (I) with lithium aluminum hydride leads to the
which can be esteri?ed with another hydrocarbon car
formation of the corresponding 2a-hydroxymethylandro
stan-3,17?-diol (V) with the SIB-isomer as the main prod
uct.
boxylic acid anhydride or chloride of the type mentioned
previously. The Za-CBI‘bOXY compounds can then be es
Conventional esteri?cation of the latter with the
teri?ed as ‘by reaction with a diazoalkane to form the car
hydrocarbon carboxylic acids described hereinabove
boalkoxy derivative (VIIIb).
affords the triesters (VI).
In another aspect of the present invention the novel
Upon treatment of the 2a-carboxy (VIIIa) or Za-car
boalkoxy compound (VIIIb) with sodium borohydride
compounds may be prepared in part by the following
equation:
1%
Alternatively there may be employed the chromic oxide
pyridine complex as the oxidizing agent to form the 211
carboxy derivative (VIIIa). Thus a l7-ester of Zoe-hy
droxyrnethyl-dihydroallotestosterone or the l7u-alkyl de
rivative of 2a-hydrornethyl dihydroallotestosterone or the
ester thereof (VII) affords the corresponding 17-ester of
2wcarboxy-dihydroallotestosterone or 2a-carboxy-17a-al
alkoxy (IIb) compound with a reducing agent such as
sodium borohydride, there is formed a mixture of the
as described previously, there is formed a mixture of the
corresponding 30: and 3/3 hydroxy compounds (IX and
20 IXb).
Upon conventional esteri?cation of the 3,17-diols (IXa
or IXb: R2=hydrogen) with hydrocarbon carboxylic
acid anhydrides of the type described previously, there is
formed the corresponding C-3,l7-diesters (X) when R’ is
hydrogen or the C-3 monoesters when R’ is alkyl. For
formation of the diesters of C-3,17-diols when R’ is alkyl,
the esteri?cation is effected in the presence of an acid cat
alyst such as p-toluenesulfonic acid and an inert solvent
such as benzene. Esteri?cation of the C-3 hydroxy group
of the 175-esters (IXa or IXb: R2=acyl) may be effected
by conventional methods with the same or different acylat
ing agent to afford the C-3,17-diesters (X) having the
same or different ester groups.
The treatment of 2a-hydroxymethyl~dihydroallotestos~
35 terone, the l7a-alkyl derivative or the esters thereof, as
well as the corresponding 19-nor compounds (VII) with
lithium aluminum hydride forms the corresponding 3-hy
droxy compound with the EMS-form as the main product
(XI). Conventional esteri?cation with hydrocarbon car
boxylic acid anhydrides as described previously results in
esteri?cation of the primary and secondary hydroxyl
groups. Esteri?cation of a tertiary hydroxyl group at
C-17,8 is effected in the presence of an acid catalyst as
described above. Thus there can be produced diesters
(XII: R5=hydrogeng R'=alkyl) which may be further
esteri?ed with the same or different acylating agent to
yield triesters (XII: R4 and R5=acyl). The latter com
pounds can also be formed upon conventional esteri?ca’
tion of the 17/3-esters (XI: R5=acyl) with same or dif
ferent acylating agent utilized in the formation of the
C-17? ester group.
Alternatively the 2a~hydroxymethyl-androstame-3B,17B
diol or the l7a-alkyl derivative thereof (XI) may be ob
tained by treating 2-hydroxymethylene-dihydroallotestos
terone or Z-hydroxymethylene-l7a-lower 'alkyl-dihydro
allotestosterone with lithium aluminum hydride in the
same manner as set forth previously.
There may also vbe produced the valuable anabolic
agents, 2a-lower alkoxymethyl-androstane-3,17?-diols or
the 17a-lower alkyl derivatives thereof by reacting 2a
In the above formulas R, R’, R2, R3 and R4 have the 60 lower alkoxvmethyl dihydroallotestosterone or Zen-lower
same meaning as previously set forth. R5 represents the
alkoxymethyl-lh-lower alkyl-dihydroallotestosterone, de
acyl group of a hydrocarbon carboxylic acid of the type
scribed in copending application Serial No. 80,528, ?led
mentioned previously when R’ is hydrogen and represents
January 4, 1961, now Patent No. 3,000,912, with lithium
hydrogen or the acyl group of a hydrocarbon carboxylic
acid when R’ is alkyl.
In practicing the process outlined above, the starting
compound, the 17a-ester of 2ot-hydroxymethyl-dihydroal
lotestosterone or of 19-nor-dihydroallotestosterone or the
17u-alkyl derivative of the free compound or of the 175
ester (VII) prepared by hydrogenation of the correspond 70
ing Lhydroxymethylene compound as set forth in co
pending application Serial No. 80,528, ?led January 4,
aluminum hydride.
The following examples serve to illustrate but are not
intended to limit the scope of the invention:
Example I
1 g. of 2a-hydroxymethyl-androstan-17?-ol-3-one dis
solved in 25 cc. of acetone was cooled to 0° C.; the air
in the container was substituted by nitrogen and there
was added a solution of 8 N chromic acid, at 0° C., under
1961, now Patent No. 3,000,912, is subjected to oxida
an atmosphere of nitrogen, with stirring and until the red
tion preferably in acetone solution at low temperature
with 8 N chromic acid prepared in dilute sulfuric acid. 75 dish color'of chromium trioxide persisted. (The solution
8,062,843
6
vof 8 N chromic acid had been prepared by dissolving 26.7
Example VIII
g. of chromium trioxide in 23 cc. of concentrated sulfuric
acid, diluting with water to 100 cc.). The mixture was
stirred at 0° C. for approximately 10 minutes more, then
poured into ice water; the solid was ?ltered, washed with
2 g. of 2a-hydroxymethyl-17a-acetoxy-androstan-3-one
was dissolved in 50 cc. of acetone; the solution was cooled
to 0° C., and the air in the container was substituted by
nitrogen. Then there was added little by little a solu
tion of 8 N chromic acid prepared from 26.7 g. of chro
water, dried and recrystallized from acetone. Thus there
was obtained the 3,17-diketo-androstan-2a-carboxylic
mium trioxide and diluted sulfuric acid little by little and
with stirring at 0° C. under an atmosphere of nitrogen,
until the reddish color of chromium trioxide persisted;
acid, M.P. 172-175 ° C.
Example 11
To a solution of 3.2 g. (0.01 mol) of 3,17-diketo-an
10 it was then stirred under the same conditions for some
minutes further and ?nally poured into ice water. The
drostan-2wcarboxylic acid in 75 cc. of methanol was
solid was ?ltered, washed with water, dried and recrys
tallized from acetone. Thus there was obtained 3-keto
added dropwise with stirring in 30 minutes a solution of
0.20 g. (0.005 mol) of sodium borohydride in a mixture
of 30 cc. of methanol and 0.6 cc. of water. After 1 hour,
l7,d-acetoxy'androstane-Za-carboxylic acid.
Example IX
Exactly as described in Example VIII, the 2a-hydroxy
tated in cold water, the product collected on a ?lter,
methyl derivatives of 17B-propionoxy-androStan-3-one, of
washed to neutrality, dried and crystallized from meth
anol, affording pure 3,8,17B-dihydroxy-androStane-Za-car 20 17,B-capronoxy~androstan-3-one_ and of l7/3-cyclopentyl
propionoxy-androstan-3-one were'oxidized to a?ord the
boxylic acid.
.
2a-carboxylic derivatives of the aforementioned steroids.
Example III
Example‘ 7X
According to the method of Example I, 1 g. of 3,17
diketo-androstane-2a-carboxylic acid was prepared and
Exactly as described ingExample VIII, there were oxi
dized the‘la-hydroxymethyl derivatives of '17a-methyl
treated in ether with 60 cc. of an ether solution of diazo
methane, prepared from 1.6 g. of nitrosomethylurea. The
androstan-l7?-ol-3-one, of" l7a-ethyl-androstan-1713-01-3
the mixture containing the isomeric 30:,17/3 and 3B,l7/3~
dihydroxy-androstane-Za-carboxylic acids was precipi
one, as Well as the 1'7-es'ters of said compounds, more spe
solution‘of diazomethane was ‘added with stirring and
ci?cally‘ the acetates, propionates, caproates and cyclo
within a few minutes. It was kept for 15 minutes at
pentylpropionates. Thus there were obtained the 17a
room temperature, acidi?ed by addition of acetic acid and
the liquid was evaporated at reduced pressure. The resi 30 methyl 3-keto-17B-hydroxyeandrostane-Za-carboxylic and
the 17:1 - ethyl-3-keto-j1‘LB-hydroxy-androstane-Za-carbox
due was puri?ed by recrystallization from acetone-hexane
ylic acids as well as the 17-acetate, 17-propionate, 17
to afford the methyl ester of 3,l7-diketo-androstane-2a
carboxylic acid.
caproate and l7-cyclopentylpropionate of said acids.
Example IV
Following the method of the foregoing example but
employingvdiazoethane instead of diazomethane, there
was obtained the ethyl ester of 3,17-diketo-androstane
,2-carboxylic acid.
Example V
Example X1
35
.
To a solution-of 3.5 g. (0.01 mol) of l7a-methyl-3
vketo - 17p - hydroxy - androstane- 20c ~ carboxylic acid
prepared in accordance with the method described in the
preceding example, in 75 cc. of methanol, was added
40 dropwise with stirring in 30 minutes a solution of 0.10
g. (0.0025 mol) of sodium borohydride in a mixture of
1 g. of 2a-hydroxymethyl-19-nor-androstan-1713-01-3
15 cc. of methanol and 0.3 cc. of water.
After one
one dissolved in 25 cc. of acetone was cooled to 0° C.;
hour, the mixture was precipitated in cold water, ?ltered,
under an atmosphere of nitrogen, with stirring and until
the reddish color of. chromium trioxide persisted. (The
solution of 8 N chromic acid had been prepared by dis~
acid and of 17a-methylandrostane-3?,l7?-diol-2-carbox
ylic acid was puri?ed by crystallization from methanol.
the air in the container was substituted by nitrogen and 45 washed to neutrality and dried. The crude mixture of
'17.. - methylandrostane - 3a,17;8 - diol - 2oz - carboxylic
there was added a solution of 8 N chromic acid, at 0° C.,
The Bil-isomer was-separated by chromatography.
solving 26.7 g. of chromium trioxide in 23 cc. of con 50
centrated sulfuric acid, diluting with water to 100 cc.)
The'mixture was stirred at 0° C. for vapproximately 10
' Example X11
1 g. of 3-keto-l7?-acetoxy-androstane - 2a - carboxylic
acid of Example VIII dissolved in 10 cc. of ether was
‘minutes more, then poured into ice water; the solid was
treated
with 6 cc. of an ether solution. of diazomethane,
?ltered, washed with water, dried and recrystallized from
acetone. Thus there was obtained the 3,17-diketo-19-nor 55 prepared from 1.6 g. of nitrosomethylurea,‘ adding the
solution of diazomethane ~witlrstirring and in the course
androstane-2a-carboxylic acid.
Example VI
v‘According to the method of Example V, 1 g. of 3,17
diketo-l9-nor-androstane-2a-carboxylic acid was prepared
and treated in 10 cc. ‘of ether with 60 cc. of an ether solu
of apfew minutes...lt was keptfor ‘15 minutes at room
‘temperature, then acidi?ed by addition of acetic acid
and the ether was evaporated at reduced pressure.
The
residue was puri?ed by recrystallization from acetone
hexane to afford the methyl ester. of 3-keto-l7l3-acetoxy
androstane-2a-carboxylic acid, identical with the ?nal com
pound of Example VIII.
somethylurea. The solution of diazomethane was added
with stirring and within a few minutes. It was kept for
Example XIII]v
15 minutes at room temperature, acidi?ed by addition of 65
Following
the
method
of Example XII, but employ
acetic acid and the liquid was evaporated at reduced pres
ing diazoethane instead of diazomethane, there was ob
sure. The residue was puri?ed by recrystallization from
tained the ethyl ester of 3~keto-l7/3-acetoxy-androstane
acetone-hexane to afford the methyl ester of 3,17-diketo
2a-carboxylic acid.
h "
-
tion of diazomethane, prepared from 1.6 g. of nitro
dl9-nor-androstane-2wcarboxylic acid.
70
Example VII
l g. of S-keto-17B-acetoxy-androstane-Zd-carboxylit
Following the method of ‘the foregoing example but
acid, obtained by following the method of Example VIII,
employing diazoethane instead of diazor'nethane, there
was treated overnight with 50 cc. of a 1% methanolic
solution of potassiumhydroxide. ‘ Then it was acidi?ed
was'obtained‘the ethyl ester of 3,l7idiketo-l9-nor-androé
stane-Za-carboxylid acid.
>
75 by addition of vacetic acid,_ concentrated to' small volume
I
v
I
I
Example‘XlV
V
_
3,062,843
uct was extracted with ethyl acetate.
The resi
due was puri?ed by recrystallization from acetone hexane
to afford the methyl ester of 3-keto-17?-acetoxy-l9-n0r
androstane-h-carboxylic acid.
Example XX
Following to the method of Example XIX, but em
The extract was
washed with water, dried over anhydrous sodium sulfate
and evaporated to dryness.
8
the ether was evaporated at reduced pressure.
at reduced pressure, then poured into water and the prod
By recrystallization of the
residue there was obtained the 3-keto-l7?-hydroxy-an
drostane-2a-carboxylic acid.
The foregoing compound was treated with diazometh
ane, following the method described in Example XII;
there was obtained the methyl ester of 3-keto-l7p-hy
ploying diazoethane instead of diazomethane, there was
obtained the ethyl ester of 3-keto-17/3-acetoxy-19-nor
androstane-2a-carboxylic acid.
Example XXI
droxy-androstane-2a-carboxylic acid.
1 g. of the foregoing compound was dissolved in 5
cc. of pyridine, 2 cc. of propionic auhydride added, the
l g. of 3-keto-17?-acetoxy-19-noreandrostane-2u-car
boxylic acid, obtained by following the method of Ex
mixture was left at room temperature overnight, then
poured into water; the precipitate was ?ltered, washed with
dilute hydrochloric acid and ?nally with water, dried
and recrystallized from acetone to give the methyl ester
ample XVI, was treated overnight with 50 cc. of a 1%
.iethanolic solution of potassium hydroxide.
Then it
was acidified by addition of acetic acid, concentrated to a
small volume at reduced pressure, then poured into water
and ‘the product was extracted with ethyl acetate. The
extract was washed with water, dried over anhydrous
of 3 - keto - 17o - propionoxy - androstane - 2a - carbox
ylic acid.
Example XV
By reaction with diazomethane, described in Example
XII, there were prepared the methyl esters of l7a~methyl
sodium sulfate and evaporated to dryness. By recrystal
lization of the residue there was obtained the 3-keto-l7?
3 - keto - 17o - acetoxy - androstane - 2a - carboxylic
hydroxy-19-nor-androstane-2a-carboxylic acid.
acid, 17a - methyl - 3 - keto - 175 - propionoxy - an
The foregoing compound was treated with diazometh
ane, following the method described in Example XIX;
drostane - 2o: - carboxylic acid, 170: - methyl - 3 - keto
17oz - hydroxy - androstane - 20c - carboxylic acid, 17a
there was obtained the methyl ester of 3-keto-175-hy
ethyl - 3 - keto - 17,8 - hydroxy - androstane - 2a - carbox
droxy-19-nor-androstane-2a-carboxylic acid.
1 g. of the foregoing compound was dissolved in 5 cc.
of pyridine, 2 cc. of propionic acid was added, the mix
l7B-propionoxy-androstane-2-carboxylic acid.
30 ture was left at room temperature overnight, then poured
into water; the precipitate was ?ltered, washed with dilute
Example XVI
hydrochloric acid and ?nally with water, dried and re‘
2 g. of 2a-hydroxymethy1-l7;3-acetoxy~19-nor-andro
crystallized from acetone to give the methyl ester of 3
ylic acid, 170: - ethyl - 3 - keto - 17B - acetoxy - andro
stane - 2a - carboxylic acid and 17a - ethyl - 3 - keto
stan-S-one was dissolved in 50 cc. of acetone; the so
keto - 175 - propionoxy-l9-nor-androstane-2a-carboxylic
lution was cooled to 0° C., and the air in the container
was substituted by nitrogen. Then there was added
little by little a solution of 8 N chromic acid, prepared
from 26.7 g. of chromium trioxide and diluted sulfuric
acid, little by little and with stirring at 0° C., under an
acid.
Example XXII
By reaction with diazomethane, described in Example
XIX, there were prepared from the respective acids, the
methyl esters of l7a-methyl-3-keto-17f3-hydroxy-l9-nor
atmosphere of nitrogen, until the reddish color of chro 40 androstane-Z-carboxylic acid, 17a-methyl-3-keto-l7p-ace
mium trioxide persisted; then it was stirred under the
toxy-19-noiwandrostane-Z-carboxylic acid, 17a-methyl-3
same conditions for 10 minutes further and ?nally poured
keto - 17,6 - propionoxy-l9-nor-androstane-Z-carboxylic
into ice water. The solid was ?ltered, washed with
acid, l'le-ethyl - 3 - keto-17?-hydroxy-l9-nor-androstane
water, dried and recrystallized from acetone. Thus there
2-carboxylic
acid, 17a-ethyl-3-ketoa17B-acetoxy-l9-nor
was obtained 3~keto-175-acetoxy-19-nor-androstane-2u
androstane-2-carboxylic acid, and 17a-ethyl-l7B-propion
carboxylic acid.
45
Example XVII
Exactly as described in Example XVI, the 2-hydroxy
A solution of 1.0 g. of 2a-hydroxymethyldihydroallo
methyl derivatives of 17j8-propionoxy-l9-nor-androstan
testosterone in 200 cc. of dry ether was added in 15 min
3-one, of 175-capronoxy-19-nor-androstan-3-one and of
utes with stirring to a suspension of 1 g. of lithium
aluminum hydride in 150 cc. of dry ether. Stirring was
continued for 1.5 hours and the product isolated in the
usual manner. Two recrystallizations from methanol af
17B-cyclopentyl propionoxy-l9-nor-androstan-3-one were
oxidized to afford the Za-carbdxyl derivatives of the above
mentioned steroids.
Example XVIII
55
Exactly as described in Example XVI there were oxi
dized the 2iz-hydroxymethyl derivatives of l7a-methyl
19-nor-androstan-17,3-ol-3-one, of 17a-ethyl-l9-nor-andro
stan-17?-ol-3-one, as well as the 17-esters of said com
pounds, more speci?cally the acetates, propionates,
caproates and cyclopentylpropionates. Thus there were
obtained the 17u-methyl-3-keto-17p-hydroxy-l9-nor-an
drostane-2a-carboxylic and the 17¢z-ethyl-3-keto-l7;3-hy
droxy-l9-nor~androStane-Zu-carbOXylic acids as well as
the l7-acetate, 17-propionate, l7-caproate and 17-cyclo
pentylpropionate of said acids.
Example XIX
1 g. of 3-keto-17,8-acetoxy-l9-nor-androstaue-2a-carbox
ylic acid of Example XVI dissolved in 10 cc. of ether was
treated with 6 cc. of an ether solution of diazomethane,
prepared from 1.6 g. of nitrosomethylurea, adding the
solution of diazomethane with stirring and in the course
of a few minutes.
It was kept for 15 minutes at room
oxy-19-nor-androstane-2-carboxylic acid.
Example XXIII
forded pure 2a-hydroxymethyl-androstane-3,8,17,3-diol,
M.P. 245—246° C., [ah (CI-K313) +45.9.
Pyridine-acetic anhydride acetylation of the latter com
pound afforded the triacetate, M.P. 162-163" C., [a]D
(CI-{(313) —23.5.
Example XXIV
A solution of 5.0 g. of 2a-hydroxymethyl-l7a-methyl
dihydroallotestosterone in 150 cc. of dry tetrahydrofuran
was added dropwise with stirring in 30 minutes to a sus
pension of 5.0 g. of lithium aluminum hydride in 300 cc.
of tetrahydrofuran. Stirring was continued for 1 hour
and the product isolated in the usual manner had M.P.
275~277° C. Upon recrystallization from methanol there
was atforded 2a-hydroxymethyl-17a-methyl-androstane
3?,l7B-diol, M.P. 280~282° C.
Example XXV
By substituting in the method of Example XXIII, 2a
hydroxymethyl - 19 - nor-dihydroallotestosterone there
was obtained 2a-hydro-xymethyl - 19 - nor-androstane
temperature, then acidi?ed by addition of acetic acid and 75 3,3,17,3-diol as the main product.
3,082,843
9
10
Example XXXII
Example XXVI ‘
By substituting in the method of Example XXIV, 2a
An etheral solution of 1 g. of 3?,17/3-dihydroxy-andro
stane-Za-carboxylic acid was treated with an ether solu
tion of diazomethane in accordance with the method of
hydroxymethyl - 17oz - me.hyl-19-nor-dihydroallotestos
terone there was a?‘orded, as the main product, 2a-hy
droxymethyl - 17oz - methyl-19-nor-androstane-3B,17e
Example II, and the resulting methyl ether was acetylated
diol.
with acetic anhydride in pyridine solution in a conven
'
tional manner, to aiford ?nally the 3-methyl ester of 31?,
. Example XX VII
17?-diacetoxy androstane-‘2a-carboxylic acid.
' A solution of 1 g. of 2a-hydroxymethyl-17ot-methyl
androstane - 3B - l7?-diol, obtained as described in Ex
‘In a similar manner, 17a-methy1 androstane 313,175
10 diol-2a-carboxylic acid was converted into its correspond
ample XXIV in 4 cc. of pyridine was treated with 4 cc. of
ing methyl ester and then into the 3-methyl ester of 3B
acetic anhydride'and the mixture kept at room tempera
acetoxy-lh-mcthyl androstan-17,8-o1-2u-carboxylic acid.
ture overnight; it was then poured into water, heated on
I claim:
..
~. .
the steam bath for 30 minutes, and the precipitate col
1. A compound'of the following formula:
'
lected by ?ltration. Crystallization from acetone-ether 15
gave the pure 2a-acetoxymethy1-17a-methyl-androstane—
3?-17/3-diol-3-acetate.
In a similar manner, 2ot-hydroxymethyl-l7a-methy1-19
nor-androstane-3/8,17,8-diol was converted into Za-ace
toxymethyl - 17oz - methyl-19-nor-androstane-3B-17B-diol
3Hacetate.
Example XXVIII
Following the method of the preceding example, ‘but
using propionic, caproic and cyclopentylpropionic anhy
25 wherein R is selected from the group consisting of hydro
drides as esterifying agents, there were produced the cor
gen and methyl and R3 is selected from the group consist
responding 2,3 diesters of 2a-hydroxy-methyl-17u-methyl
ing of hydrogen and lower alkyl. .
androstane-3B-l7?-diol, namely 2u-propionoxymethyl
.
2. 3,17-diketo-androstane-2u-carboxylic acid.
l7a-methyi-androstane - 3B - 17?-diol 3-propionate, 2a
3. Methyl - ’3,17-diketo-19-nor-androstane-Za-carboxyl
capronoxymethyl - 17a - methyl-androstane-3/8-17,6-diol _
ate.
1'
~
3-caproate and 2a-cyclopentylpropionoxymethyl - 17a
4. Ethyl 3,17-diketo-androstane-2a-carboxylate.
methyl-androstane - 313 - l'l?-diol 3-cyclopentylpropionate.
5. A compound of‘the following ‘formula:
' Example XXIX
A solution of 1 g. of r2-hydr0xymethylene \dihydroallo
testosterone in 50 cc. of anhydrous tetrahydrofuran was
OR2
35
slowly added to a stirred suspension of 500 mg. of lithium
aluminum hydride in 50 cc. of dry ether, with cooling.
The mixture was then stirred for 3 hours at room tempera
ture, the excess of hydride was decomposed by the addi 40'
tion of a few drops of ethyl acetate and saturated sodium
sulfate solution was added, followed by anhydrous sodi
um sulfate. The solids were removed by ?ltration and the
wherein R is selected from the group consisting of hydro~
solution was evaporated to dryness. Chromatography of
gen and methyl, R’ and R3 are eachselected from the
I
the residue ‘gave 2a-hydroxymethyl-androstaneéS?-17p
45 group consisting of hydrogen and lower alkyl and R3 is
diol, identical with that obtained in Example XXIII.
Upon treatment of the above compound with propionic
anhydride in pyridine solution there was obtained the
corresponding tripropionate.
Example XXX
selected from the group consisting of hydrogen and the
acyl radical of a hydrocarbon carboxylic acid of less than
.12 carbon atoms.
50
droallotestosterone was reduced with lithium aluminum
-
1y
-
‘
-
>=
9. The l7-hydrocarbon carboxylic acid esters of less
55 than 12 carbon atoms of 3-ket0-17l3-hydroxy-androstane
2ot-carboxylic acid.
androstane-3,8,l7B-diol identical with the compound ob
tained in Example XXIV.
10. The 17-hydrocarbon carboxylic acid esters of less
than 12 carbon atoms of 3-keto-l7?-hydroxy-19-nor-an
A mixture of 1 g. of the above compound, 100 cc. of
anhydrous benzene, 10 cc. of acetic anhydride and 400
perature for 24 hours and diluted with water; the organic
layer was separated, washed with water, 5% sodium
carbonate solution and again with water to neutral, dried
over anhydrous sodium sulfate and evaporated. Re
crystallization of the residue from acetone-hexane aiford
-
8. 17a-lower alkyl-3-keto-17/8-hydroxy-androstane-Za
carboxylic acid.
ceding -example, 2-hydroxymethylene-l7a-methyl dihy
mg. of p-toluenesulfonic acid was stirred at room tem
'
7. 3 - keto - 17,8-hydroxy-19-nor-androstane~2a-carbox
ylicacid.
In accordance with the reduction method of the pre
hydride thus producing Za-hydroxymethyl-17ot-methyl
'
6. 3-keto-17?-hydroxy-androstane-2ot-carboxylic acid. -
drostane-Za-carboxylic acid.
60
11. The lower alkyl esters of 3-keto-17p-hydroxy-an
drostane-Za-carboxylic acid.
12. The lower alkyl esters of the 17-hydrocarbon car~
boxylic acid esters of less than 12 carbon atoms of 3
keto-17,8-hydroxy-androstane-Za-carboxylic acid.
13. The 17-hydrocarbon carboxylic acid esters of less
ed the triester, i.e. 2ot-acetoxymethyl-17a-methyl andro
than 12 carbon atoms of l7a-lower alkyl-3-keto-17B-hy
stane-3/3,17?-diol 3,17 diacetate.
droxy-androstane-Za-carboxylic acid.
14. The lower alkylesters of 17OL-1OWCI' alkyl-3-keto
Example XXXI
17?-hydroxy-androstane-2u-carboxylic acid.
'
By following the esteri?cation method of the preceding 70
15. The lower alkyl esters of the l7-hydrocarbon car
example, but using cyclopentyl propionic anhydride in
boxylic acid esters of less than 12 carbon atoms of 17cc
stead of acetic anhydride 500 mg. of Za-acetoxymethyl
lower 'alkyl-3-ket0-17?-hydroxy-androstane-2a-carboxylic
17a - methyl - androstane-3/8-l7?-diol-3-acetate was con
acid.
verted into 2a-acetoxymethyl-17ot-methyl-androstane 3p,
17?-diol 3-acetate-17-cyclopentylpropionate.
16. The lower alkyl esters of the 17-hydrocarbon car?
75 boxylic acid esters of less than 12 carbon atoms of 17a
3,062,843
ll
12
27. The hydrocarbon carboxylic acid esters of less than
12 carbon atoms of Za-hydroxymethyl-17a-lower alkyl
lower alkyl 3-keto-17/3-hydroxy-l-9-nor-androstane-2a-car
boxylic acid.
androstane-3?,17,B-diol.
17. A compound of the following formula:
28. A process for preparing 3,l7-diketo-androstane-2a
carboxylic acid comprising oxidizing 2a-hydroxymethyl
OR2
dihydroallotestosterone with chromic acid.
29. A process for preparing 3,17-diketo-l9-nor-andro
StaHG-ZOL-CBIbOXYIiC acid comprising oxidizing 2a-hydroxy
0
methyl-19-nor-dihydroallotestosterone with chromic acid.
30. A process for producing a compound of the follow
ing formula:
Rio-ll"
OR2
wherein R is selected from the group consisting of hy
drogen and methyl, R’ and R3 are each selected from the
group consisting of hydrogen and lower alkyl and R2 and
R4 are selected from the group consisting of hydrogen
and the acyl radical of a hydrocarbon carboxylic acid of
less than 12 carbon atoms.
18. 318,175-dihydroxy-androstane-2a-carboxylic acid.
19. 35,1718 -dihydroxy-17a-lower alkyl-androstane-2a
carboxylic acid.
wherein R is selected from the group consisting of hy~
drogen and methyl, R’ and R3 are each selected from
20. The hydrocarbon carboxylic acid esters of less
than 12 carbon atoms of 3,3,17?-dihydroxy-androstane
the group consisting of hydrogen and lower alkyl and R2
is selected from the group consisting of hydrogen and
the acyl radical of a hydrocarbon carboxylic acid of less
than 12 carbon atoms, comprising oxidizing with chromic
acid a compound of the following formula:
2a-carboxylic acid.
21. The hydrocarbon carboxylic acid esters of less than
12 carbon atoms of 3B,17?-dihydroxy-17a-lower alkyl
androstane‘2a-carboxylic acid.
22. A compound of the following formula:
OR’!
30
B
01120114
0:
wherein R is selected from the group consisting of hydro
gen and methyl; R' is selected from the group consisting
of hydrogen and lower alkyl and R2 and R4 are selected
from the group consisting of hydrogen and the acyl
radical of a hydrocarbon carboxylic acid of less than
12 carbon atoms.
7
23. 2a-hydroxymethyl-androstane-SB,17,8-diol.
25. 2a - hydroxymethyl-l7a-methyl~androstane-3?,17/3
diol.
26. The hydrocarbon carboxylic acid esters of less than 50
12 carbon atoms of 2a-hydroxymethyl-androstane-3p,17B
diol.
wherein R and R’ have the same meaning as previously
set ‘forth and R5 is selected from the group consisting of
hydrogen and a hydrocarbon carboxylic acyl group of
less than 12 carbon atoms when R’ is lower alkyl and
R5 is a hydrocarbon carboxylic acyl group of less than
12 carbon atoms and R’ is hydrogen.
31. The triacetate of 2a-hydroxymethyl-androstane
3,6,17?-diol.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,853,501
2,883,401
Hoehn et a1 ___________ __ Sept. 23, 1958
Babcock et al7 ________ _- Apr. 21, 1959
Документ
Категория
Без категории
Просмотров
0
Размер файла
823 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа