close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3080408

код для вставки
B?b??gg
United gtates I '? atent
Patented Mar. 5, 1963
2
1
drosten compounds by a method illustrated by the fol
3,080,3%
lowing equation:
_
2~HALOMETHYL-M-ANDROSTENES AND
'
DERIVATIVES THEREGF
Albert Bowers, John Edwards, and .iarnes C. Orr, allot
' Mexico City, Mexico, assignors to Syntax 8A., Mexico
City, Mexico, a corporation of Mexico
No Drawing. Filed Apr. 13, 1962, Ser. No. 187,222
'
18 Claims. (Cl. zeta-397.4)
The present invention relates to certain new cyclopen 10
tanophenantrene derivatives and to the method for mak
ing the same.
More particularly it relates to the novel 2-halomethyl
Az-androstenes, which may be further substituted at
C-l7zx by an alkyl, alkenyl or alkynyl group as well as 15
to the 19-nor derivatives and the esters thereof.
The present invention relates also to a new method for
making Za-halomethyl-androstan and l9-nor-androstan
l7?-ol-3-one derivatives, which have been described in
R
our copending application Serial No. 107,039, ?led on 20
May 2, 1961.
The novel compounds object of our invention are
potent anabolic agents with a favorable anabolic-andro
FHiC-I
o
:
OR2
(IV) I
?R
R
.XlHzC /\
i
i
I
Is”
(III)
In the above formula R, R1 and R2 have the same
genic ratio, lower the blood cholesterol level, relieve pre
menstrual tension and exhibit anti-estrogenic and anti 25 meaning as heretofore set forth; X1 represents chlorine
gonadotrophio activities. The 17a-alkenyl and alkynyl
or
bromine.
_
,
In practicing the process set forth above Z-hydroxy
compounds are also progestational agents.
The novel compounds of the invention are represented
methyl-M-androsten-175-01, 2 - hydroxymethyl-19-nor-A2
by the following formula:
androsten-17?-ol, the esters thereof or the corresponding
30
170t-SllbSlltl1ted derivatives (I) is treated with thionyl
chloride in benzene solution. The reaction is effected at
room temperature, for a period of time in the order of
OR2
5 minutes to 1 hour, thus producing the 3B-chloro-2
methylene derivatives (II: X1=chlorine) which upon
35 heating with lithium chloride in dimethylformamide, for
a period of time of 18 to 24 hours at 90° C. give rise
to the corresponding 2-chloromethyl-Az-androstenes and
19-nor-androstenes (III: X1=chlorine). In a similar
manner, but using thionyl bromide and lithium bromide
40 instead of the corresponding chlorides, there are pro
In thev above formula R represents hydrogen or meth
duced SB-bromo-Z-methylene and 2-,brornomethyl-A2-an
yl, R1 represents hydrogen or a lower alkyl, alkenyl or
drostenes and 19-nor-androstenes (II and III: X1=bro
alkynyl group containing up to 8 carbon atoms; X rep
mine).
'
_
resents chlorine, bromine or ?uorine and R2 represents
In order to obtain the 2‘?uoromethyl-nz-androstenes
hydrogen or a hydrocarbon carboxylic acyl radical of 45 object of the present invention, a‘ Z-hydroxymethyl de~
less than 12 carbon atoms.
rivative of Ag-androsten-1718-01-l9p-nor-Az-androsten-17B
The acyl group is derived from hydrocarbon carboxylic
ol, the corresponding 17ot-alkyl, alkenyl or alkynyl de
acids containing less- than 12 carbon atoms which may
rivatives or esters thereof is reacted with anhydrous hy
be saturated or unsaturated, of straight, branched, cyclic
drogen ?uoride in mixture with methylene chloride
or cyclic-aliphatic chain, aromatic and may be substi 50 tetrahydrofuran, at low temperature, preferably between
tuted by functional groups such as hydroXy, alkoxy con
-—70° and‘ 0° C. for a period of time in the order of 15
taining up to 5 carbon atoms, acyloxy containing up to 12
to 24 hours preferably for 18 hours, thus producing the
carbon‘ atoms, nitro, amino or halogen. Typical ester
2-?uorornethyl-Az-androsten compounds (IV).
groups are the acetate, propionate, enanthate, benzoate,
Alternatively, the esters of the 2-halomethyl-A2-andro
trirnethylacetate, t-butylacetate, phenoxyacetate, cyclo 55 stenes object of the present invention may be obtained by
pentylpropionate, aminoacetate and ?-chloropropionate.
In our copending patent application Serial No. 146,455,
conventional esteri?cation of the free compounds (III
and IV: R2.=H), that is, by treatment with acid anhy
?led on- October 20, 1961, there is described the method
drides or chlorides of less than 12 carbon atoms in pyri
for producing 2-hydroxymethyl-A2-androsten-1713-01, the '
dine solution-‘for the 17-unsubstituted 2-halomethyl
17OC-Sllb5tltllt8d derivatives and the corresponding l9-nor
compounds by reducing 2-formyl-A2-androstenes and 2
formyl-AF-19-nor-androstenesYwith sodium borohydride‘.
The novel 2-halomethyl-dz-compounds of the present
invention are obtained from the Z-hydroXymethyl-AZ-an
androstenes and l9-nor-androstenes or With acid anhy
drldes in benzene solution and in the presence of p
toluenesulfonic acid for the 170C-Zi1kyl, alkenyl' and al
kynyl derivatives.
The new method for producing 2a-halomethyl 17a
‘3,080,398
substituted androstan derivatives is illustrated by the fol
lowing sequence of reactions:
9R’
"-33
‘RR’
"-113
in
R i
Xroo
I
.
n
XHzC
/
——'
(V)
E
01
“
;
(VI)
H0
In the above formulas R, R2 and X have the same
on:
on
i __R3
I --R3 15 or lower alkyl.
R
n
Xmo-
Kano--
l
/
(VIII)
In practicing the process outlined above, a 2-halomethyl
derivative of A2-androsten-17B-ol, which may be further
substituted at C-17u by a lower alkyl group, or the cor
responding 19-nor derivatives (IX), is treated with a cur
20 rent of diborane in a solvent such as tetrahydroi‘uran.
,_
0:
meaning as heretofore set forth; R4 represents hydrogen
no“
,
(v11)
In the above formulas R, R2 and X have the same
meaning as previously set forth; R3 represents a lower
alkyl or alkynyl group.
In practicing the process set forth above, a Z-halomethyl
derivative of A2-androsten-17B-ol, which is further sub
Upon subsequent reaction with aqueous alkali and hy
drogen peroxide there is formed the 3u-hydroxy-2/3-halo
methyl derivative (X) which is converted into the 3-keto
compound (XI) upon reaction with chormium trioxide
in acetic acid or acetone solution.
stituted at C-17ct by an alkyl or alkynyl group, or the
The inversion of the steric con?guration of the halo
methyl substituent at C-2 is effected by acid treatment,
acid in acetone solution or with chromic acid in acetic
intended to limit the scope of the present invention.
preferably using anhydrous hydrogen chloride in chloro
corresponding 19-nor-derivatives (V), is treated with 1.1
molor equivalents of a peracid, preferably monoperph 30 form solution, thus producing 2ot-halomethyl androstan
17?-ol-3-one, 2ot-halomethyl-l7a-alkyl androstan-l75-ol
thalic or perbenzoic acid, to give the corresponding 2,8
3-one and the corresponding l9-nor compounds and esters
halomethyl-2a,3a-oxido compounds (Vi). Upon treat
(XII).
ment of these epoxides with lithium aluminum hydride
The novel compounds represented by Formulas VIII
in tetrahydrofuran solution at re?ux temperature and for
a prolonged period of time, preferably during 18 hours, 35 and XII are potent anabolic agents having a favorable
anabolic-androgenic ratio; exhibit anti-estrogenic and
the epoxide ring is opened, thus producing the Zea-halo
anti-gonadotrophic activities; relieve premenstrual ten
methyl-3a-hydroxy derivatives (VII), with concomitant
sion, lower the blood cholesterol and have anti-?brilla
saponi?cation at C-17, when an ester has been used as
tory properties.
‘the starting material.
Oxidation of the above compounds with 8 N chromic 40 The following examples serve to illustrate but are not
acid produce the corresponding 3-ketone (‘Villz R2=hy
PREPARATION 1
To a solution of 5 g. of Z-hydroxymethyl-Not-methyl
methyl 17ot-alkyl and l7a-alkynyl-androstan-175-01-3 45 A2-androsten-l7?-ol in 100 cc. of anhydrous benzene
there were added 1 g. of p-toluenesulfonic acid and 15
one and the esters of 2a-halomethyl~17a-alkyl and 17a
cc. of acetic anhydride and the mixture was allowed to
alkynyl-19-nor-androstan-l7r3-ol-3-one (VII: R2=acyl).
stand for 24 hours at room temperature, poured into ice
By partial hydrogenation of the 2-halornethyl-17a
and Water, and the resulting mixture stirred to effect
allrynyl compounds (VH1: R3=alkynyl) using 2% pal
ladium on calcium carbonate as catalyst and in pyridine 50 hydrolysis of the excess anhydride. The benzene layer
was separated and washed with 10% sodium carbonate
solution there are obtained the 2ot-halornethyl-17a-alkenyl ,
solution and water. Drying, evaporation and crystalliza
derivatives.
drogen), which are then esteri?ed by the methods herein
above set forth, thus producing the esters of Zea-halo
Thus for example, starting from Z-chloromethyl-lh
ethynyl-dg-androsten-l75-01 acetate there are obtained
tion of the residue from ether-hexane produced Z-acetoxy
methyl-17a-rnethyl-A2-androsten-17,6-ol-acetate.
successively 2,8-chloromethyl-2a,3ot-oXido-l7a-ethynyl-an
A mixture of 2 g. of the above compound and 20 cc.
drostan-17B-ol acetate, 2ot-chloromethyl-17ot-ethynyl-an
2a-chlorornethyl-l7a-ethynyl-andro
stan-17,6-ol-3-oue and Za-chlommethyl-l7a-vinyl-andro
stan-l7?-ol-3-one.
of a 1% potassium hydroxide solution was stirred for 1
hour at 0° C.; it was then poured into water and the
chloromethyl, Za-bromomethyl and 2a-fluoromethyl-an
PREPARATION 2
formed precipitate collected by ?ltration, thus giving 2
hydroxymethyl - 17a - methyl - A2 - androsten - 17,8 - ol
In another aspect of the present invention the 20: 60 acetate.
drostan-l7?-ol-3-one, the 17a-alkyl substituted derivatives
and the corresponding 19-nor compounds are obtained
by the method illustrated by the following equation:
By the same method of Preparation 1, Z-hydroxy
methyl-17a~methy1-19-nor-A2—androsten-17,8-01, 2-hydroxy
methyl-l7a-ethyl-Az-androsten-175-01, 2-hydroxymethyl~
17ct-vinyl-A2—19-norandrosten-l7B-ol, 2 - hydroxymethyl
l7a-ethinyl-A2-androsten-17,8 - 01 and 2 - hydroxymethylv
l7a-ethinyl-A2-19-nor-androsten-17/3-ol were converted
into the corresponding 17-acetates, namely 2-hydroxy
70 methyl-l7a-rnethyl-19-nor-A2-androsten-17,3-01-acetate, 2
hydroxy-methyl-l7a-ethyl-Az-androsten-17/3-ol-acetate, 2
hydroxy-methyl-17a-vinyl-A2-19-nor-androsten-17/3-ol ace
tate, 2-hydroxymethyl-17u-ethinyl-A2-androsten - 1713 - ol
acetate and 2-hydroxymethyl-l7ot-ethinylal9-nor-Az-an
75 drosten-17?-ol acetate.
3,080,398
5
Example I
vented into the 2-chloromethyl-Az-androsten derivatives
.
(I11).
A solution of 2.5 g. of 2-hydroxymethyl-A2-androsten
175-01 in 250 cc. of dry benzene thiofene free was treated
with 2.5 cc. of freshly distilled thionyl chloride and the
reaction mixture was kept at room temperature during
I
2-hydroxymethyl-
1 hour. It was then diluted with water and the organic
layer washed well with 5% sodium carbonate solution
chloro-19-nor-
androstan17?-ol-
2-hydroxymethyl-
l7a-methyl-A2orated to dryness under vacuo. The residue was ?ltered
through a column of 100 g. of acetic acid washed alumina 10 androsten-H?-ol.
2-hydroxymethylusing 500 ‘cc. of benzene-hexane 1:1 as solvent. The
17a-vmyl-Ncrystalline fractions were combined and recrystallized
androsten-U?-ol-
caproate.
2-hydroxymethyl17a-ethiny1-A2-
from methanol, thus affording 1 g. of 3?-chloro-2-methyl
ene-androstan-17B-ol.
'
A mixture of the above compound (1 g.), 1 g. of
2-mcthylene-3B-
19-n0r-A2-
androsten-17?-olacetate.
and water, dried over anhydrous sodium sulfate and evap
II
androsten-WB-ol.
acetate.
2-methylene-35Gh10l‘O-17a-
ir;gtl11yl-androstan
-0 .
2-methylene-3B-
ehlor0-17aviuyl-androstan17/3-ol-eapr0ate.
2-methylene-3?011lOI‘0-17ixethinyl-androstan
III
2eh1oromethyl-19
nor-A?-androsten
17B-0l-acetate.
2-chl0r0methyl-17a
methyl-N-androsten
1718-01.
2-ehloromethyl-17a
viuyl-Aa-androsten
1713-01-capr0ate.
2-chloromethyl-l7a
ethinyl-Az-androsten
176-01.
'
175-01.
lithium chloride and 100 cc. of dimethyl formamide Was
heated on the steam bath for 18 hours. Water was added
Example V
By following the method of Example II, 5 g. of 2
and the formed precipitate collected by ?ltration, thus
giving the crude 2-chloromethyl-A2-androsten-175-01
which was puri?ed by recrystallization from methanol 20 hydroxymethyl-17a-methyl-A2-androsten-17,8-ol were con
water.
verted into 2-fluoromethyl - 17a - methyl-Az-androsten
A mixture of 1 g. of the latter compound, 4 cc. of pyr
idine and 2 cc. of acetic anhydride was kept at room
175-01.
temperature overnight. It was then poured into water,
and the formed precipitate collected by ?ltration, thus
producing the acetate of 2-chloromethyl-Az-androsten
of anhydrous benzene there were added 200 mg. of p
toiuenesulfonic acid and 2 cc. of acetic anhydride and
the mixture was allowed to stand for 24 hours at room
1713-01.
temperature, poured into ice and water, and the resulting
hydrogen fluoride and 144 g. of tetrahydrofuran pre
viously cooled to —70° C. in a Dry Ice-acetone bath.
evaporation and crystallization of the residue from
ether-hexane produced the acetate of 2-fluoromethyl-17u
The mixture was kept standing at —-10° C. for 18 hours.
It was then carefully poured into water and the excess
methyl-Alandrosten-175-01.
To a solution of 1 g. of the latter compound in 20 cc.
A solution of 2 g. of 2-hydroxy-methyl-A2-androsten
mixture stirred to e?'ect hydrolysis of the excess anhy
1713-01 in 80 cc. of methylene chloride was cooled to
dride. The benzene layer was separated and washed
30
--70° C. and added to a mixture of 8 g. of anhydrous
with 10% sodium carbonate solution and water. Drying,
Example VI
of hydrogen ?uoride decomposed by adding 50 g. of
,
In accordance with the esteri?cation method of th
sodium carbonate. The product was then extracted with
methylene chloride and the organic extract washed to
neutral, dried over anhydrous sodium sulfate and evap
orated to dryness under reduced pressure. The crude
preceding example 2 - chloromethyl - 17a - methyl-A2
.androsten-lm-ol was converted into the corresponding
product was dissolved in 100 cc. of hexane-benzene (1:1) 40
and ?ltered rapidly through a column of 50 g. of acetic
acid washed alumina. The crystalline fractions were
acetate.
.
In a similar manner, but using capro‘ic and propionic
anhydride as esterifying agents, there were produced
caproate and the propionate of Z-chloromethyl-lh
methyvl-dg-androsten-175-01.
combined and recrystallized from methanol, thus giving
0.7 g. of 2-?uoromethyl-A2-androsten-17B-ol.
Example VIZ
In accordance with the method described in Example
A solution of 1 g. of the latter compound in 4 cc. of
pyridine was treated with 2 cc. of benzoyl chloride and
then heated on the steam bath for 1 hour. The mixture
was then poured into ice water and the formed precipitate
III, 1 g. of 2-hydroxymethyl-17a-vinyl-A2-androsten-1718
01 Was reacted with thionyl‘ bromide, thus a?ording 3f}
collected, washed with water and dried. Recrystallization
bromo-2-methylene-17ot-vinyl=androstan - 175-01. Upon
from methylene chloride-hexane a?orded the benzoate of 50 treatment of the ‘above compound with lithium bromide
2-?uoromethyl-A2-androsten-1713-01.
in dimethyl formamide there was produced 2-bromo
methyl-17a-Vinyl-A2-androsten-1716-01.
Example III
250 mg. oi the latter compound were esteri?ed with
A solution of 5 g. of 2-hydroxymethyl-M-androsten
propi-onic anhydride in benzene solution and in the pres
17,8-01- in 500 cc. of dry benzene, thiophene free was 55 ence of p-toluenesulfonic acid; by following ‘the method
treated with 5 cc. of freshly distilled thionyl bromide
of the preceding example, thus producing the propionate
and the mixture kept at room temperature for 1 hour. It
‘ of, Z-bromomethyl-17a-vinyl-A2-androsten-1713-01.
was then washed with water, 5% sodium carbonate solu
' 'tion and water to neutral, dried and evaporated to dryness
under vacuo. The residue was dissolved in 1 1t. of 60
benzene-hexane 1:1 and ?ltered through a column of
200 g. of acetic acid washed alumina thus producing 318
Example VIII
A slow stream of dibonane was passed through ‘a so
lution of 10 g. of Z-chlorornethyl - 17a-metl1yl-A’2
=androsten-17/8-ol acetate in 150 cc, of tetrahydrofuran
' bromo~2-rnethylene-androstan-175-01. .
for 1 hour.
A mixture of 1 g. of the above compound 1 g. of
(After 20- minutes the solution became
lithium bromide and 100 cc. of dimethyl-formamide was 65 warm and then the temperature slowly sub-sided.) The
excess of diborane was decomposed by careful addition
heated on the steam bath for 18 hours. It was then
of Water. Then 1 it. of water was added and the. formed
poured into water and the formed precipitate collected
precipitate was ?ltered, washed ‘and dried, thus giving
by ?ltration. Recrystallization from methanol gave the
pure 2-brornomethyl-A2-androsten-17[3-ol.
Example IV
By following the method of Example I the compounds
listed below under I were treated with thionyl chloride
in benzene solution to give the corresponding 3B-chloro
. 9.6 g. of the organoboron- compound.
70
This material was dissolved in 200 cc. of tetrahydro
furan and treated with 9 g. of sodium hydroxide previ
ously dissolved in 25 cc. of water, and 45 cc. of 35%
. hydrogen peroxide, stirring and. keeping the temperature
around 15° C. The mixture was stirred ‘for 2 hours,
Z-methylene compounds (II), which in turn were con 75 after this time, the precipitatedv product was ?ltered,
3,080,898
d
400 mg. of pre-hydrogenated 2% palladium calcium car
bonate catalyst.
When 1.1 molar equivalent of hydrogen had been ab
sorbed, the reaction was stopped, the catalyst separated
by ?ltration through celite, washed with ethyl acetate and
washed ‘and dried, thus producing 25-chloromethyl-17a
methyl androstane-3u,17B-diol-17-acetate.
A solution of 2 g. of the above compound in 50 cc.
of acetone was cooled to 0° C. and treated under an
‘atmosphere of nitrogen and with stirring, with a solu
tion of 8 N chrornic acid (prepared by mixing 26 g. of
the combined solutions evaporated to dryness in vacuo,
yielding the crude vinyl derivative. This crude product
chromium trioxide with 23 cc, of concentrated sulfuric
was dissolved in ethyl acetate, the organic solution washed
acid and diluting with water to 100 cc.), until the color
with dilute hydrochloric acid and Water to neutral, dried
of the reagent persisted in the mixture. It was stirred
for 5 minutes further at 0~5° C. and diluted with water. 10 and evaporated to dryness. Recrystallization from ace
tone gave Za-?uoromethyl-lh-vinyl-19-nor-androstan
The precipitate was collected, washed with water and
dried under vacuum, thus affording a crude product
17/3-ol-3-one.
The above compound was esteri?ed with acetic, propi
which upon recrystallization from acetone-hexane gave
onic and undecenoic anhydride in benzene solution and
ZB-chloromethyl - 17cc - methyl-androstan-l7?-ol-3-one
acetate.
A solution of 1 g. of the preceding compound in 50 cc.
of dry chloroform was treated with 1 cc. of dry chloro
form saturated with hydrogen chloride. After 3 hours at
15 in the presence of p-toluenesulfonic acid, thus producing
the corresponding esters.
Example XII
Examples I and IX were repeated but using 2-hydroxy
room temperature the reaction mixture was washed with
5% sodium bicarbonate solution and water to neutral, 20 methyl-17e-ethyl-A2-androsten-17?-ol acetate as starting
material. There were thus obtained successively 2-meth—
dried over anhydrous sodium sulfate and evaporated to
dryness under reduced pressure. The crude product after
crystallization from ether-pentane a?orded 0.4 g. of 2a
ylene - 3,8 - chloro - 17a - ethyl - androstan - 17,8 - ol
chloromethyl-l7a-methyl-androstan-l7?-ol-3-one acetate.
1713-01 acetate, 2,8-chloromethyl-2e,3a-oxido-17a-ethyl
androstan-17/8-ol acetate, 2ot-chloromethyl-l7u-ethyl-an
Example 1X
By following the method of Example II, 5 g. of 2-hy
droxymethyl-lh-ethinyl-19-nor-A2-androsten-1713-01 was
converted into Z-?uoromethyl-17e-ethinyl-19-nor-A2-an
dr0sten-175-ol. Esteri?cation of the above compound with
acetic anhydride in benzene solution and in the presence
of p-toluenesulfonic acid gave the corresponding acetate.
A solution of 2.5 g. of 2-?uoromethyl-l7u-ethinyl-19
nor-Az-androsten-17,8-ol-acetate in 100 cc. of chloroform
was cooled to 0° C. and mixed with 1.4 g. (1.1 molar
equivalents) of monoperphthalic acid in ether solution.
The mixture was kept at room temperature for 20 hours,
diluted with Water, the organic layer was separated,
acetate,
25
2 - chloromethyl - 17a - ethyl - A2 - androsten
drostane-3a,17p-diol,
Za-chloromethyl-l7a-cthyl-andro
stan-17?-ol-3-one and 2a-chloromethyl-l7a-ethyl-andro
stan-l7?-ol-3-one propionate.
Example XIII
5 g. of 2-chloromethyl-Az-androsten-175-01 were con
verted into the corresponding benzoate by treatment with
benzoyl chloride in pyridine solution.
The above benzoate was then subjected to the reactions
35 described in Example VIII, thus producing Z?-chloro
methyl-androstane-f'm,175-diol - 17 - benzoate, Z?-chloro
methyl-androstan-17?-ol-3-one benzoate and Z-oc-ChlOIO
methyl-androstan-l7?-ol-3-one benzoate.
In a similar manner, starting with 2-bromomethyl-A2
washed with aqueous sodium bicarbonate solution and
then with water to neutral, dried over anhydrous sodium 40 androsten-N?-ol there were obtained successively 2-bro
momethyl - A2 - androsten - 1713 - ol-benzoate,
sulfate and evaporated to dryness. Crystallization from
acetone-hexane gave 2,8-?uoromethyl-2a,3a-oxido-17a
ethinyl-lQ-nor-androstan-17(3-01 acetate.
Z?-bromo
'methyl-androstane-3ot,17,8-diol 17-benzoate, 2,8-bromo
methyl-androstan-17/8-ol-3-one benzoate and 2a-bromo
methyl-androstan-17,6-01-3-one benzoate.
Example XIV
A solution of 1 g. of the preceding epoxide in 50 cc.
of tetrahydrofuran was added over a 30 minute period
to a stirred suspension of 1 g. of lithium aluminum hydride
In accordance with the method of Example III, 2 g. of
in 50 cc. of anhydrous tetrahydrofuran. The mixture
2 - hydroxymethyl - l7ot-ethinyl-androstan-17?-ol acetate
was re?uxed for 18 hours, then cooled and cautiously
were treated with thionyl-bromide, to give 3,8-bromo-2
treated with 5 cc. of ethyl acetate and 2 cc. of water.
Solid sodium sulfate was added, the inorganic material 50 methylene-17a-ethinyl-androstan-1713-01 acetate, which
upon reaction with lithium bromide in dimethyl-forma
?ltered off and thoroughly washed with hot ethyl acetate,
mide gave Z-bromethyl-l7a-ethinyl-A2-androsten-1713-01
the combined organic solutions upon evaporation yielded
a crude material, which was puri?ed by crystallization
from acetone-hexane thus giving 2a-?uoromethyl-l7u
ethinyl-19-nor-androstan-3a,l7,8-diol.
Upon oxidation of the above diol with 8 N chromic
acid in acetone solution, in accordance with the method
of Example VIIl there was obtained 2a-?uoromethyl-17ot—
ethinyl-l9-nor-androstan-17,8-ol-3-one which was esteri
acetate.
The latter compound was then converted into 2oz-b1'0m0
55
methyl-l7a-ethinyl-androstan-175-01-3-0116, by following
the method of Example IX.
'
Example XV
2 g. of 2-chloromethyl-17a-ethinyl-A2-androsten-1713-01
?ed with propionic anhydride in benzene solution and in 60 acetate were oxidized with monoperphthalic acid, in ac
cordance with the method of Example IX, and the result
the presence of p-toluenesulfonic acid, to give the corre
ing epoxide re?uxed for 18 hours with lithium aluminum
sponding propionate.
Example X
By following the methods of Examples II and VIII,
the acetate of 2-hydroxymethyl-l9-nor-A2-androsten-17?
01 was converted successively into 2-?uoromethyl-A2-l9
hydride thus giving 2a-chloromethyl-17a-ethiny1-andro
stane-Zia,17?-diol.
A solution of 250 mg. of chromic acid in 5 cc. of 80%
acetic acid was added dropwise to a stirred solution of 1 g.
of 2u-chloromethyl-l7ct-ethinyl-androstan-3a,l7?-diol in
nor-androsten-17?-ol-acetate, 2,8-fluoromethyl-l9-nor~an
75 cc. of glacial acetic acid, while the temperature was
maintained around 20° C. After 2 hours at room tem
drostane-Sor,l7?-diol-l7-acetate and 2a-fluoromethyl-l9
70 perature, the mixture was poured into ice water and the
nor-androstan-17,8-ol-3-0ne-acetate.
formed precipitate collected, washed with water and re
Example XI
crystallized trom methanol, thus giving 2a-chloromethyl
A solution of 1 g. of 2u-?uoromethyl-17a-ethinyl-19
nor-androstan-17,6-ol-3-one,in 40 cc. of pyridine was hy
17d-ethinyl-androstan-17B-ol-3-one.
The above compound was esteri?ed with acetic and
drogenated at 25 ° C. and 570 mm. in the presence of 75 cyclopentylpropionic anhydride in benzene solution and
3,080,398
10
7. Z-?uoromethyl-17a-ethynyl-A2-androsten-175-01.
in the presence of p-toluenesulfonic acid, to give the ace
tate and the cyclopentylpropionate of 2m-chloromethyl
8. The acetate of Z-?uoromethyl-17a-methy1-A2-andro
17a-ethinyl-androstan-17B-ol-3-one.
sten-17?-ol.
9. 2oz - fluoromethyl - 17oz - ethynyl - 19 - nor - an
Example XVI
By following the method of Example XI, Zwbromo
drostan-17?-ol-3-one.
methyl-17a-ethinyl-androstan-17B-ol-3-one and Zea-chloro
drostan-l7?-ol-3-one.
methyl - 17a-ethinyl-androstan-17/3-ol-3~one
10. 2a - ?uoromethyl - 17a - vinyl - 19 - nor - an
cyclopentyl
11. 2a - chloromethyl - 17a - ethynyl - androstan - 175
propionate were converted respectively into 2a~bromo
methyl-l7a-vinyl-androstan-17/8-ol-3-one and 2a-chloro
methyl-17a-viny1-androstan-17?-ol-3-one cyclopentylpro
pionate.
ol-3-onc.
10
12. 2a - chloromethyl - 17oz - vinyl - androstan - 17B
01-3~one-cyclopenty1propionate.
13. 2a - bromornethyl - 17a - ethynyl - androstan - 1718
ol-3-one.
Example X VZI
14. The method ‘for the production of Za-halomethyl
In accordance with the methods of Examples II and 1 5 17-substituted androstanes which comprises treating the
VIII, 5 g. of 2-hydroxymethy1-17a-methyl-19-nor-A2-an
corresponding 2-ha1omethyl-A2-compound with a peracid,
drosten-17?-ol acetate were converted successively into
reacting the 2a,3a-epoxide thus formed with lithium alu
2-fluoromethyl-17a-methyl - 19 - nor-Az-androsten-??-ol
minum hydride in a suitable solvent to give the 2a-halo
acetate ZB-?uoro-methyl-17a-methyl-l9-nor-androstan-3a,
methyl-3a-hydroxy compound, and oxidizing with chro
17?-diol-17-acetate,
Z?-?uoromethyl-17u-methyl~19 - nor 2 0 mium trioxide to form the corresponding 3-keto com
pound.
androstan 17?-ol-3-one acetate and Za-?HOI‘OmGthYI-I'Ya
methyl-19-nor-androstan-17/3-ol-3-one-acetate.
15. The method for the production of a compound se
lected from the group consisting of 2oc-halomethyl-an
We claim:
1. A compound of the following formula:
drostan-l7p-ol-3-one compounds and the corresponding
2 5 17a-al‘kyl derivatives, which comprises treating 'a corre
sponding 2-hal0methy1-A2-androstan-17,8-01 with diborane,
followed by hydrogen peroxide-alkaline treatment, to give
the corresponding 2?-halomethyl-3a-hydroxy compound,
oxidizing to the 3-keto and thereafter treating with acid
3 0 to form the corresponding 2a-halomethyl-androstan-175
XHQ l
0l-3-one derivative.
16. The method of claim 15 wherein the 2a-halomethyl
derivative is the chloromethyl derivative, the peracid is
the monoperphthalic acid, the suitable solvent for the re
l
I
wherein X is selected from the group consisting of chlo
rine, bromine and ?uorine, R is selected from the group 3 5 duction is tetrahydrofuran.
17 . The method of claim 15 wherein the 2a-halomethyl
consisting of hydrogen and methyl; R1 is selected from
derivative is the bromomethyl derivative, the peracid is
the group consisting of hydrogen, lower alkyl, lower a1
the monoperphthalic acid, the suitable solvent for the re~
kenyl and lower alkynyl radicals and R2 is selected from
duction is tetrahydrofuran.
the group consisting of hydrogen and a hydrocarbon car
boxylic radical of less than 12 carbon atoms.
40
5. 2-chloromethyl-19-nor-A2-androsten-175-01, acetate.
6. 2-chloromethyl-17a-methy1-M-androsten-1713-01.
18. The method of claim 15 wherein the 2a-halomethyl
derivative is the ?uoromethyl derivative, the peracid is
‘the monoperphthalic acid, the suitable solvent for the re
duction is tetrahydrofuran.
2. 2-chloromethyl-A2-androsten-175-01.
3. 2-bromornethyl-A2-androsten-175-01.
4. 2-?uoromethyl-A2-androsten-175-01.
5
No references cited.
Документ
Категория
Без категории
Просмотров
0
Размер файла
720 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа