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Патент USA US3079414

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Patented Feb. 26, 1953
prepared by the process illustrated by the following equa
Lawrence H. Knox, Mexico City, Mexico, assignor to
Syntex S.A., Mexico City, Mexico, a corporation of
No Drawing. Filed Apr. 13, 1962, Ser. No. 187,227
Claims priority, application Mexico Jan. 3, 1962
18 Claims. (Cl. 260-3971)
Cl '
The present invention relates to certain new cyclo
pentanophenanthrene derivatives and to a process for the
preparation thereof.
—» 01/ \
3/ ll
(\l/ :'—- R1 ,
\ 'r‘
The new compounds object of the present invention,
which are anabolic agents of reduced androgenic activity
and which show antiestrogenic properties and inhibit the
activity of the pituitary gland, are represented by the
following formulas:
More particularly, the present invention relates to
cyclopropane-(2',3’,2,3)-androstane derivatives.
I :'—- R'
In the above fromulas R, R1 and R2 have the same
meaning set forth previously.
In carrying out the process outlined above, the start
ing compound (I), which is an acylate, preferably the
{ /
acetate of A2—androSten-17?-0l, or a 17cc lower alkyl de
rivative, is treated with an alkali salt of trichloroacetic
I luR:
solvent having a boiling point between 125° and 160°
C., such as for example bis-(2-methoxyethyl)-ether, at
a temperature of approximately 125° C., for a period of
about 2 hours, thus producing the acetate of 1',1'-di
chlorocyclopropane - (2',3';2rx,3a) - androstan -_17[3 - 01
30 acid, preferably with sodium trichloroacetate, in an inert
R200 o-Hof
or its 17oc-l0W6I‘ alkyl derivative (II).
By treating the starting compound (I) with an alkali
salt of monochloro-di?uoro acetic acid, preferably with
sodium monochlorodi?uoro-acetate, under the conditions
40 described
above for the reaction with sodium trichloro
acetate, followed by chromatographic separation, there
are obtained the acetate of 1’,1'-di?uorocyclopropane
(2',3';2a,3a)-androstan-17?-ol and its 2,8, 3?-isomer, or
their 17a-lower alkyl derivatives (IV).
By reacting the starting compound (I) with the diazo
acetate of a lower alkyl, ethyl for example, in the pres
ence of copper, in a solvent inert to the reagent such
as 1,2-dimethoxy-ethane, there is obtained the acetate of
In the above formulas R represents hydrogen or a
1' - carbethoxycyclopropane - (2',3';2oc,3oc) - androstan
hydrocarbon carboxylic acyl group of less than 12 carbon
17,6-01 or its 17a-lower alkyl derivative (III: R2=e1hyl).
atoms; R1 and R2 represent hydrogen or a lower alkyl
The 17B-acylates mentioned above, on saponi?cation
group; the wavy lines indicate that the cyclopropane
by conventional treatment in basic medium, afford the
moiety may be in the 2a, 30: and 2,8, 35 positions.
17,8-alcohols in the free form (II, III, IV: R=H). By
The acyl group derives from hydrocarbon carboxylic
the same reaction there are also hydrolyzed the 1'-car
acids having less than 12 carbon atoms, which may be 55 bethoxy groups (III: R2=ethyl), to furnish the 1’-car
saturated or unsaturated, of straight, branched, cyclic
boxy compounds (III: R2=H).
or mixed aliphatic-cyclic chain, or aromatic, which may
The compounds having a secondary hydroxyl group
be further substituted with functional groups such as
(II, III, IV: R=R1=H) are conventionally acylated in
hydroxyl, alkoxy of up to 5 carbon atoms, acyloxy of
pyridine with an acylating agent, for example with an
up to 12 carbon atoms, nitro, amino or halogen. Typi 60 anhydride derived from ahydrocarbon carboxylic acid
cal such esters are the acetate, propionate, enanthate,
of the type set forth previously, thus giving the 1713
benzo-ate, trimethylacetate, t-butylacetate, phenoxyace
tate, cyclopentylpropionate, aminoacetate and ,B-chloro
The novel compounds of the present invention may be
The compounds having a tertiary hydroxyl group (II,
III, IV: R=H; R1=lower alkyl) are conventionally
acylated in the presence of p-toluenesulfonic acid, with
drostan-17;3_~ol acetate and 17a~methyl-1',1’-diiluorocyclo
propane~( ’,3’;2B,3,6)-androstan-17;8—ol acetate.
Example VII
an" acylating agent such as for example propionic an
hydride, thus giving the corresponding acylates.
The following examples serve to illustrate but are not
intended to limit the scope of the invention:
A suspension of 1 g. of 1’-carbethoxycyclopropane
Example I
2',3';2a,3a)-androstan-17/3-o1 acetate in 60 cc. of meth
anol was treated with a solution of 1 g. of potassium
To a mixture of 1.9 g. of the acetate of Az-androsten
carbonate in 6 cc. of Water and the mixture was re
175-01 (produced from dihydrotestosterone by bromina
fluxed for 1 hour, then cooled and diluted with ice water.
tion with 1 molar equivalent of bromine, reduction of
the Za-bromoketone thus obtained, and treatment of the 10 The precipitate formed was collected by ?ltration and re
crystallized from acetone-hexane, thus affording 1’-car
'resulting bromohydrin with zinc in acetic acid, to pro
duce A2-androsten-17?-ol, which on conventional acety
There were treated in the same manner 1',1’-dichloro
lation affords the desired acetate, as has been described
cyclopropane-(2',3’;2a,3¢x)-androstan-l7;8—ol acetate, 1.’,
in ,copending application Serial No. 128,361 ?led August
1, 1961)‘, 20 cc. of 1,2-dimethoxyethane and 300 mg. 15 1' - di?uorocyclopropane - (2',3';2c¢,3u) - androstan
17,801 acetate and 1’,1’-di?uorocyclopropane-(2',3Z23,
of‘ recently prepared copper powder, at the re?ux tem
3?)-androstan-17?~ol acetate, thus giving respectively,
perature, there was added dropwise and under stirring
1’,1’ - dichlorocyclop-ropane - (2',3';2cz,3a) - androstan
a solution of 3.4 g. of ethyl diazoacetate in 5 cc. of
17 - ol, 1’,1' - di?uorocyclopropane - (2',2’;2ot,3u) - an
1,2-dimethoxyethane, over aperiod of 2 hours, and the
re?uxing was continuedafor 2.5 hours. further. Removal 20 drostan-17?-ol and 1',l’-di?uorocyclopropane-(2',3';25,
of the catalyst. by ‘?ltration, followed by evaporation of
Example VIII
raphy on Florisil yielded 1'-carbethoxycyclopropane~
A mixturevof 1 g. of 1'-carboxycyclopropane-(ZB’;
(2',3’;2e,3a)-androstan-17?-ol acetate, which exhibited
2oc,3oc)-2lI1dI‘OSt£1I1-l7-Ol, 4 cc. of pyridine and 2 cc. of
a melting point of 148-149" 0., [a1]; +24.9° (CHCl3). 25 propionic
anhydride was kept overnight at room tempera
the solvent, a?orded a residue which after chromatog
Example II
ture and then poured into ice water; the precipitate
formed was collected, washed with water, dried and
To a solution of 1.9 g. of the acetate of Az-androstene
crystallized from acetone~hexane, thus yielding the pro
1778=ol in 50 cc. of bis-(2-methoxyethyl)ether heated to
125~130° ‘C. was ‘added 4.4 g. of sodium trichloroacetate 30
in 10 equal portions ‘at 10 minute intervals. The re
actionvmix'ture was cooled, the sodiumchloride formed
was removed by ?ltration and the ?ltrate was evaporated
to dryness under vacuum. The product was ‘adsorbed
on Florisil, and upon elution with-hexane-ether there was
‘obtained a residue which was recrystallized from meth
By the sameprocess there were treated 1’,1'-dichloro~
cyclopropane - (2',35;2a,3u) - androstan - 1713 - o1,
A mixture of 9.5 g. of the acetate of Alandrosten
173-01, 500cc. of bis-(24methoxyethyl)-e-ther and 18.3 g.
'of sodium monochlorodi?uoroacetate was refluxed for 10
minutes,‘ cooledto 50°- (3;, treated vwith 18.3 g. more of 45
and ‘1’,1" - di?uorocyclopropane - (2',3';2?,3;3) - andro
-stan- 175-01 . acetate.
1’,1' - dichlorocyclopropane - (2',3';2C£,30L) - andro
stan-17?-ol, the propiona-te of 1',1'-di?uorocyclopropane
(2’,3';2a,3a)-androstan-17;8~ol and the propionate of 1',1'
point of 163465“ C., ocD+37.Z° (CHC13).
Example III
"cyclopropane- - (2',3';2ot,3a) - androstan - 17/8 - ol acetate
l’,1’ - di?uorocyclopropane - (2',3';2,8,3,8) - andro
stan-l'I?-ol, thus affording, respectively: the propionate
3u)-androstan71-7;8?ol acetate, which showed a melting
“poundswhich after crystallization produced 1’,1’-di?uoro
ditluorocyclopropane - (2’,3';2ct,3a) - androstan - 17B - 01
anol, thus giving 1’,1'-dichloro-cyclopropane-(2’,3';2oe,
‘the sodium salt and the mixture was re?uxed again for
10 ‘minutes. The solution was then ?ltered ‘and the ?ltrate
was evaporated to dryness. The residue was chro
‘matognaphed on Florisil, thus‘furnishing two solid com
pionate of 1Kearboxycyclopropano(2T,3,';2a,3a,):andro
Example IX
The starting compounds of the preceding example were
treated by the process described in that example, except
that the propionic anhydride was substituted by caproic
anhydride, cyclopentylprop-ionic anhydride and benzoyl
chloride, thus obtaining the corresponding caproates, cy
clop-entylpropionates and benzoates.
Example X
A solution of 0.17 g. of potassium hydroxide in 2 cc.
of Walter and 2.5 of methanol was added over a period
of 30 minutes to a boiling solution of 1 g. of 170t-l1'i5tl'lyl
1' - carlbethoxycyclopropane - (2',3';20c,3oc) - androstan
Example IV
175-01 acetate in 30 cc. of methanol, under an atmosphere
The starting compound in this example, namely 17a 55 of nitrogen.
methyl-Az-androsten-1713-01, vwas obtained by oxidizing
The mixture was boiled for 2 hours further, cooled,
Az-androsten-lm-ol to form A2-androsten-17-one, which
upon ‘treatment with methyl magnesium bromide pro
neutralized with acetic acid and concentrated under re
duced pressure.
By the addition of water, followed by crystallization
duced”,17a-rnethy1-A2-androsten-1713-01, which on conven
tional lacetyllaltion with acetic anhydride in the presence 60 of the precipitate from acetone-hexane, there was pro
‘of p-toluenesulfonic acid'yielded the desired‘ 17-acetate.
This acetate was treated by the method described in
_'Example I, thus giving, ?at-methyl-1'-carbethoxycyc1o
propane-(2',3f;2a,3m)-androstan-17;8-ol acetate.
Example V
‘The acetate of 17a-methyl-dz-androsten-173-01 was
treated in accordance with Example ll, thus producing
170: - methyl - 1’,1’ - dichlorocyclopropane - (Z',3';Zo:,
3 0'.) -androsta11- 1718-01 acetate.
Example VI
The acetate of 17a-methyl-A2-androsten-175-01 was
'treated'in accordance with Example III, thus giving 17w
Hot-methyl - 1’ - carboxycyclopropane - (2',3’;
By the same process there
17a - methyl - 1’,1' - dichloropropane - (2',3,;
2a,3a)-androstan-17?-o1 acetate and 17a-methyl-1',1-di
?uorocyclopropane - (2’,3';2a,3a) - androstan - 17,3 - o1
acetate, thus affording respectively 17oz-methyl-1’,1’-di
chlorocyclopropane - (2',3';2a,3 0c) - androstan - 175-01 and
- 17wmethyl - 1',1' - di?uorocyclopropane-(2’,3’;2a,3a) -a.n
Example XI
To a solution of 5 g. of 17a-methyl-1’-carboxycyc1o
~propane-(2',3'; 2m,3a'.)-Et1’1dr0St?I1—17?-Ol in 100 cc. of
anhydrous benzene was added 1 g. of p-toluenesulfonic
75 ‘acid and 10 cc. of propionic anhydride, and the, mixture
was kept standing at room temperature for 24 hours;
after pouring into ice water, the resulting mixture was
stirred in order to hydrolyze the excess of anhydride.
The benzene layer was then separated, washed with 10%
sodium carbonate solution and water, dried and evapo
rated; crystallization of the residue from ether-hexane
7. Not-methyl - 1',1’-difuorocyclopropane~(2',3';
3 a) -androstan-17/3-ol-acetate.
8. A compound of the following formula:
furnished the propionate of 17a-methyl-l'-carboxycyclo
propane-‘( ',3’; 2u,3a)-androstan-17,6-ol.
Example XII
In the same manner there were treated 17u-methy-l-1',
1'-.dichlorocylopropane-(2’,3'; 2a,3a)-androstan - 175-01
and 17u-methyl-1',1'-di?uorocyclopropane<(2',3'; 2oz,3a)~
androstan-lm-ol, thus giving respectively: the propionate
wherein R is selected from the group consisting of hydro
of 17a-methyl-1',l'-dichlorocyclopropane-(2',3'; 205,300
gen and a hydrocarbon carboxylic acyl group of less than
androstan-17?-ol and the propionate of l7on-11'16thYl-l',
12 carbon atoms and R1 is selected from the group con“
1'-di?uorocyclopropane—(2’,3'; 2e,3a)androstan-l7?-ol.
sisting of hydrogen and lower alkyl.
9. 1',1’-dichlorocyclopropane-(2’,3’; 2a,3a)~androstan
Example XIII
The starting compounds of the preceding example were
10. 1',1'-dichlorocyclopropane - (2',3'; 2a,3e)-andro
treated by the process described in that example, except
that the propionic anhydride was substituted by caproic
anhydride, cyclopentylpropionic anhydride and undec
enoic anhydride, thus furnishing the corresponding capro~
ates, cyclopentylpropionates and undecenoates.
I claim:
11. 17u-methyl-1',l'-dichlorocyclopropane - E(2',3';
12. 17u-rnethyl-1’,1' - dichlorocyclopropane~(2',3'
1. A compound of the following formula:
3 a) -androstan-17,6-ol-acetate.
13. A compound of the following formula:
wherein R is selected from the group consisting of hy'dro~
gen and a hydrocarbon carboxylic acyl group of less than
wherein R is selected from the group consisting of hydro
12 carbon atoms and R1 and R2 are members of the
gen and a hydrocarbon carboxylic acyl group of less
than 12 carbon atoms and R1 is selected from the group 40 group consisting of hydrogen ‘and lower alkyl.
14. 1'-carbethoxycyclopropane~(2',3'; 2a,3a) - andro
consisting of hydrogen and lower alkyl.
15. 17a-methyl~1'-carbethoxycyclopropane - (2’,3'; 20c,
3. 1’,1'=di?uorocyclopropane-(2',3’; 2;9,3;9)-androstan
16. 1'-carboxycyclopropanea(2',3';
6. Hot-methyl - 1’,1'-di?uorocyclopropane-(2’,3'; 2a,
2a,3u) - androstan
17. 17a-methyl-1’-carboxycyclopropane-(2'3'; 2a,3a)
18. 17e-methyl-1’-carboxycyclopropane-(2’,3'; 20130:)
androstan-17/3~ol propionate.
5. 1',1'-di?uorocyclopropane-(2',3'; 213,3}3)-androstan
No references cited.
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