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Патент USA US3071588

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aired tat
Patented Jan. 1, 1953
pared by the process illustrated by the following equa
Pierre (Irahhé, Mexico (Iity, Mexico, assignor, by mesne 5
assignments, to Syntex Corporation, a corporation of
No Drawing. Filed .lnly 19, 1961, Ser. No. 125,106
19 Qlaims. (ill. 260-2395)
The present invention relates to novel cyclopentano
phenanthrene compounds and to a process for the pro
duction thereof.
More particularly the present invention relates to novel
androstane-lG?,17,8-dicarboxylic acid imide derivatives
and to novel intermediates for the production thereof.
The novel compounds of the present invention which
are anti-epileptic and central nervous system depressant
agents and which also exhibit anti-ovulatory activity, are
represented by the following formulas:
mm\I toz/ @x
In the above formulas Z represents a double bond for
a saturated linkage between C—4 and C——5; Y represents
a double bond or a saturated linkage between C-5 and
0-6; X represent the group
in the doling-positions, wherein R1 may be hydrogen, 55
a lower alkyl, di(lower alkyl) amino, lower alkyl, aryl
or aralkyl group, each containing up to 8 carbon atoms;
R represents hydrogen or a hydrocarbon carboxylic acyl
group of less than 12 carbon atoms.
The acyl group is derived from hydrocarbon carboxylic
acids containing less than 12 carbon atoms which may be
saturated or unsaturated, of straight, branched, cyclic or
cyclic-aliphatic chain, aromatic and may be substituted
by ‘functional groups such as hydroxy, alkoxy containing 65
up to 5 carbon atoms, aeyioxy containing up to 12 carbon
atoms, nitro, amino or halogen. Typical ester groups are
the acetate, propionate, enanthate, benzoate, trimethyl
acetate, t-butylacetate, phenoxyacetate, cyclopentylpropi
onate, aminoacetate and ?-chloropropionate.
The novel compounds of the present invention are pre
= __
In the above formulas R1 has the same meaning as
hereinabove set forth; Ac represents an acyl group, prefer
ably the acetyl group.
In practicing the process outlined above the starting
compound (I) 1‘6a-cyano-A5-pregnen-3,8-ol-20-one 3-ace
tate [1. Romo, Tetrahedron 3, 37 (1958)], is hydrolyzed
in a basic medium, such as methanolic potassium hy
droxide, affording A5-17a-pregnen-3?-ol-20-one-lGB-car
concentrated solution poured into water. The formed pre
cipitate was ?ltered off, washed with water and dried in
vacuo. Recrystallization from acetone-hexane afforded
A5-androsten-3/8-ol-l6/3,17,8-dicarboxylic acid. M.P. 312
314° C.; [oc]D —63° (pyridine).
Example II
By reversing the steps described in the preceding Ex
ample, 5 g. of 16u-cyano-A5-pregnen-3?-ol-ZO-one 3-ace
boxylic acid (II). This compound is treated with an
alkali metal hypohalogenite such as sodium hypobromite 10 tate was ?rst hydrolyzed with 4% methanolic potassium
hydroxide as described in Example I to afford A5-17oc
at a lower temperature, approximately 0° C., for a period
pregnen-B/i-ol-ZO-one-16/3-carboxylic acid, identical with
of time of the order of 2 hours, thus giving A5-androsten
an authentic specimen.
3,6-01-165,17,3-dicarboxylic acid (III). Upon re?ux of
Upon further treatment with sodium hydroxide and
this compound with acetic anhydride there is obtained the
anhydride of A5-androsten-3?-ol-16B,'17,B-dicarboxylic acid 15 bromine as described in Example I and working up the
product as set forth in that example, there was afforded
3-acetate (IV).
A5-androsten-3B-ol-165,17,8-dicarboxylic acid. M.P. 307
Alternatively the starting compound (I) is treated with
309° 0., identical with the above obtained diacid.
an alkali metal hypohalogenite, such as sodium hypo
brornite, at a low temperature, approximately 0° C., for
Example III
a period of time of the order of 2 hours, thus furnishing 20
‘l6a-cyano-A5-androsten-3,B-ol-l7?-carboxylic acid 3-ace
tate (IX). Hydrolysis of this compound in a basic me
dium such as methanolic potassium hydroxide, affords the
The foregoing compound, A5-androsten-3?-ol-16?,17,9
dicarboxylic acid was re?uxed for 10 minutes with 60 cc.
of acetic anhydride. 'Ihe acetic anhydride was then
evaporated under vacuum and the residue recrystallized
above obtained A5-androsten-3B-ol-11613,17?-dicarboxylic
25 from methylene-chloride-hexane affording the anhydride
acid (III).
of the A5-androsten-3/8-ol-16p,17,8-dicarboxylic acid 3
The anhydride of A5-andr0sten-3/8-o1-1618,17?-dicarbox
acetate. M.P. 171-175° C.; [1x113 —83° (CHCl3).
ylic acid 3-acetate compound (IV) is treated with a pri
mary amine, as for example, methylamine, ethylamine,
Example IV
propylamine, aniline, benzylamine or ammonia, thus giv
ing the corresponding A5-androsten-3?-ol-l6p,17,8#dicar 30
boxylic acid imide 3-acetate derivative (V) which upon
saponi?cation in a mild alkaline medium, such as potas
sium carbonate solution, affords the corresponding free
3,8-alcohol (VI). This free alcohol is oxidized under
2 g. of this last anhydride was treated with a solution
of 2 g. of propylamine in methylene chloride. The reac
tion mixture was allowed to-stand at room temperature
overnight. The solvent was then evaporated and the resi
due recrystallized from acetone-hexane affording N
Oppenauer conditions to the corresponding A4-androsten 35 propyl-A5-androsten-3/8-ol-16,8,17,8-dicar-boxylic acid imide
3-one-16?,17?-dicarboxylic acid amide derivative (VII)
Example V
which is hydrogenated to the ‘respective saturated 3-ketone
androstane (VIII).
2 g. of the anhydride of A5-androsten-3)3—ol-l6?,17;8-di
The A5-313-alcoho1 derivative (VI) is hydrogenated to
the corresponding androstan-3l3-ol-li6?,17?-dicarboxylic
acid amide derivative.
The above obtained compounds containing a free sec
ondary hydroxyl group at C-3 are conventionally acylated
in pyridine with a hydrocarbon carboxylic acid anhydride
or chloride containing up to 12 carbon atoms of the type 45
mentioned previously to furnish the corresponding 35
acyloxy derivative.
The following speci?c examples serve to illustrate but
are not intended to limit the scope of the present inven
Example I
carboxylic acid 3-acetate was treated following the tech
nique described in Example IV except that propylamine
was substituted by N,N-diethylamino-ethylamine, giving
N - (N',N' - diethylaminoethyl)-A5-androsten-3?-ol-16B,
17,6-dicarboxylic acid imide 3-acetate.
Example VI
2 g. of the anhydride of A5-androsten-3B-ol-16?,17,8
dicarboxylic acid 3-acetate was treated following the
technique described in Example IV except that‘ propyl—
amine was substituted by aniline affording N-phenyl-A5
androsten-3?-ol-165,175-dicarboxylic acid imide 3-acetate.
Example VII
2 g. of the anhydride of A5-androsten~3?-ol-16/8,17?
5 g. of 16a-cyano-A5-pregnen-3,8-ol-2O-one 3-acetate
[1. Romo, Tetrahedron 3, 37 (1958)], were dissolved in
dicarboxylic acid 3-acetate were treated with 50 cc. of
200 cc. of dioxane. A solution, prepared by dissolving 55 a saturated solution of ammonia in anhydrous ethanol.
7 g. of sodium hydroxide in 60 cc. of water and 40 cc.
The reaction mixture was kept in a closed vessel at room
temperature for 24 hours. It was then evaporated to dry
' mine, was added to the steroid solution, the operation
ness and the residue recrystallized from acetone thus
being conducted at —5° C. The resulting mixture was
affording A5 - androsten-3?-ol-l6?,l7?-dicarboxylic acid
stirred for 2 hours, maintaining the temperature under
imide 3-acetate.
of dioxane and further adding dropwise 3.2 cc. of bro
5° C.
It was then treated with 50 cc. of a saturated
solution of sodium sul?te in water, re?uxed for 15 min
utes, acidi?ed with concentrated hydrochloric acid, satur
ated with sodium chloride and extracted with ethyl ace
Example VIII
1.5 g. of A5-androsten-3?-ol-16/3,17/3-dicarboxylic acid
imide 3-acetate in 50 cc. of methanol were treated with
tate. The extract was washed with water, dried over an 65 0.5 g. of potassium carbonate in 2.5 cc. of water. The
hydrous sodium sulfate and evaporated to dryness thus
16a-cyano - A5 - androsten-B’?-ol-17,8-carboxylic
acid B-acetate. M.P. 259—261° C.; [04]]; -62° (pyri
dine). By alkaline hydrolysis the 3?-alcohol was ob
tained: M.P. 271—274°; [oc]D —-71° (pyridine).
The foregoing compound was re?uxed for 10 hours
with 250‘ cc. of 4% methanolic potassium hydroxide
solution and then neutralized with acetic acid. Part of
the solvent was removed under reduced pressure and the 75
mixture was re?uxed for 30 minutes, then poured into ice
water and the precipitate collected, washed with water
and dried, thus producing a crude product which upon
recrystallization from acetone-hexane afforded A5-andro
sten-3B-ol-16p,17B-dicarboxylic acid imide.
When applying this selective saponi?cation to N-pro
pyl-M-androsten-SB-ol-16/3,17/8-dicarboxylic acid imide
3~acetate, N-(N’,N'-diethylaminoethyl)-A5-androsten-3B
o1-16;8,l7?-dicarboxylic acid imide B-acetate, N-phenyl~
A5-androsten-3?-ol-1613,1713-dicarboxylic acid imide 3-ace
dried. Recrystallization from acetone-hexane afforded A5
tate, there were respectively obtained A5-androsten-3?-ol
androsten-3l3-ol-l 65,17,8-dicarboxylic acid imide 3-propi
165,175-dicarboxylic acid imide, N-propyl-M-androsten
35-01-16?,17/3-dicarboxylic acid imide, N-(N’,N'-diethyl
aminoethyl)-A5~androsten-3,8-ol‘165,17?-dicarboxylic acid
imide and N-phenyl-A5-androsten-318-01-16,8,l7?-dicarb0x
Following the above technique were treated the starting
materials listed below, with the acylating agent indicated,
furnishing the corresponding products hereinafter set
ylic acid imide.
Example IX
A solution of 1 g. of A5-androsten-3/3-ol-16,8,17?-di 10
carboxylic acid imide in 80 cc. of toluene and 20 cc. of
cyclohexanone was dried by distilling oif 10‘ cc. of the
Starting compound
Acylating agent
solvent. A solution of 1 g. of aluminum isopropoxide in
A?-androsten-ii?-olcaproic anhydride___ 3-caproate of A5
7 cc. of anhydrous toluene was then added and the mix
ture was re?uxed for 45 minutes.
acid imide.
4 cc. of acetic acid were added and the solvents re
Do ________________ l_ cyclopentylpropl3-cyclopentylpropio
onic anhydn'de.
nate of AE-andro
moved by steam distillation. The product was extracted
several times with ethyl acetate and the organic extracts
washed with 1% hydrochloric acid solution, water, 10%
sodium carbonate solution and water until neutral, dried 20
over anhydrous sodium sulfate and evaporated to dryness.
Crystallization from methanol afforded A4-androsten-3
one-165,17/3-dicarboxylic acid imide.
Upon oxidation by the same technique of N-propyl-A5
androsten~3?-ol-16,8,175-dicarboxylic acid imide, N-(N',
3-propionate of N
dicarboxylic acid
N- (N ’ N’-diethy1ami-
carboxylic acid imide, N-phenyl-A5-androsten-318-01-l6B,
17B-dicarboxylic acid imide, there were correspondingly
formed A4-androsten-3-one-l6p,17B-dicarboxylic acid im
dicarb oxylic acid
androstan-3B-o1-16?,17?dicarboxylic acid
35 imide.
caproic anhydride..- 3-caproate of N
ide, N-propyl-A4-androsten-3-one-16p},175 - dicarboxylic 30 N- (N’,N’-dicthy1a1ninoethyD-N-androacid imide, N-(N',N'-diethylaminoethyl)-A4-androsten~3
sten-3B-ol-16?,17§one-165,17l3-dicarboxylic acid imide and N-phenyl-M- an
dicarboxylic acid.
A solution of 800 mg. of A4-androsten-3-one-163,175
dicarboxylic acid imide in 40 cc. of ethyl acetate was
dicarboxylic acid
boxylic acid imide.
Do ________________ __ propionic anhy-
N’-diethylaminoethyl)-A5 - androsten - 3p3~o1-16B,17B - di
drosten-3-one-163,17,8-dicarboxylic acid imide.
Example X
dicarboxylic acid
benzoyl ch1oride_____ B-bcnzoate of N
dicarboxylic acid
onic anhydride.
nate of N-(N’ , N’
acid imide.
propionic anhydride.
3-pr0pionate of an
onic anhydrid e.
nate oi androstan
acid imide.
D0 ________________ ..
shaken with 50 mg. of 5% palladium-charcoal catalyst in
a hydrogen atmosphere, until 1 mol. of gas was consumed.
N- (N ’,N'-diethylam1~
The catalyst was ?ltered off and the ?ltrate evaporated to 40 noethyD-androstan
dryness. Recrystallization from methanol-benzene af
boxylic acid imide.
forded androstan-3-one-16,8,17,8-dicarboxylic acid imide.
Following the same technique were hydrogenated N-pro
boxylic acid imide.
caproic anhydride.__ S-caproate of N
dicarboxylic acid
im e.
Do ________________ __
pyl-A4-androsten-3-one-163,17,8-dicarboxylic acid imide,
beuzoyl chloride .... -.
S-benzoate of N
(N’ ,N’-diethylami
N-(N’,N’-diethylaminoethyl)-A4-androsten-3 - one - 16,8,
17?-dicarboxy1ic acid imide, N-phenyl-A4—androsten-3-or1e
dicarboxylic acid
16,8,17B-dicarboxylic acid imide giving respectively an
N -phenyl-androstan
drostan-3-one-166,17?-dicarboxylic acid imide, N-propyl
androstan-3-one-16,8,17?-dicarboxylic acid imide, N-(N',
propionic anhy
dride .
boxylic acid imide.
N’-diethylaminoethyl)-androstan-3 - one - 165,17}? - dicar
Do ________________ __
benzoyl chloride"..
boxylic acid imide and N-phenyl-androstan-3one-16p},
17?-dicarboxylic acid imide.
3-propionate of N
boxylic acid imide.
3-benzoate of N
boxylic acid imide.
Example X1
800 mg. of A5-androsten-3/3-ol-16,8,17,3-dicarboxylic
acid imide were hydrogenated following the technique de
Example XIII
By substituting in the method of Example IV the pro
pylamine by other alkylamines such as methylamine,
scribed in Example X, giving androsten-350L165,17,6-di
carboxylic acid imide.
When applying this procedure to N-propyl-As-androsten
3,8-01-16/5’,17,6-dicarboxylic acid imide, N-(N',N’-diethyl—
aminoethyl)-A5-androsten-3B-ol-16,8,17,5-dicarboxylic acid
ethylamine or heptylamine, there was obtained the corre
sponding N-methyl, N-ethyl, and N-heptyl derivatives of
acid imide, there were correspondingly formed androstan
A5-androsten-3/S-ol~16,8,17,8-dicarboxylic acid imide 3~
acetate which upon selective saponi?cation by the method
described in Example VIII were transformed into the
3/3-o1-16l3,17B-dicarboxylic acid imide, N-propyl-andro
stan-3?-ol-16?,l7,B-dicarboxylic acid imide, N-(N’,N’-di
corresponding free 3,3-alcohols.
By following the technique described in Example ‘IX
ethylarninoethyl)-androstan - 3?-ol-16[3,l7[3 » dicarboxylic
the thus :formed 3B~alcohols were oxidized to the cor~
acid imide and N-phenyl-androstan-3,8-01-165,17,B-dicar
boxylic acid imide.
Example XII
responding 3-ketones, namely the N-methyl, N-ethyl and
N-hepty-l derivatives of A4~androstene-3-one-16?,173-di
imide, N-phenyl-A5-androsten-31301-165,175-dicarboxylic
carboxylic acid imide.
500 mg. of A5-androsten-3?-ol-16,8,17,8-dicarboxylic
acid imide in 5 cc. of pyridine were treated with 1 cc. of
propionic anhydride. The reaction mixture was left over
Example XIV
By substituting in Example VI the aniline by benzyl
amine or phenethylamine, there were obtained the corre
night at room temperature, then poured into ice water, the
formed precipitate ?ltered 0E, washed with water and 75 sponding N-benzyl and N-phenethyl derivatives.
between C—5 and C—6; R is selected from the group con
I claim:
1. A compound selected from the group consisting of
the following formula:
sisting of hydrogen and a hydrocarbon carboxylic acyl
group of ‘less than 12 carbon atoms and R1 is selected
from the group consisting of hydrogen, alkyl, dialky‘l
aminoalkyl, avryl and aralkyl radicals each containing up
to 8 carbon atoms.
8. Androstan-3/8-ol-1618,17p-dicarboxylic acid imide.
9. Nwpropylaandrostan-fi,B-ol-1616,l7?-dicarboxylic acid
11. The 3-acetate of A5-androsten-3l3-ol-165,17B-dicar
boxy-lie acid imide.
12. The 3-propionate of N-propyl-A5-androsten-3?-ol
wherein Z is selected ‘from the group consisting of a
double bond between 0-4 and C~5 and a saturated link 15 16,8,17?-dicarboxylic acid imide.
13. The 3-caproate of N-(N',N’-diethy1aminoethyl)-A5
age between 0-4 and C-5 and R1 is selected from the
group ‘consisting of hydrogen, alkyl, dialkylaminoalkyl,
aryl and aralkyl radicals each containing up to 8 car
bon atoms.
2. Meandrosten-B-one-l65,1713-dicarboxylic acid imide. 20
l7?-dicarboxylic acid imide.
l6. A5-androsten-3B-ol-1613,l7?-dicarboxylic acid.
17. The acetate of A5-androsten-35-ol-16B,17,8-dicar
N-(NQN’aiiethylaminoethyl)-A4-androsten - 3 - one
165,17B-dicarboxylic acid imide.
androsten-S‘?-ol-IQB,l7?—dicarboxylic acid imide.
14. The S-propionate of N-pheny1-androstan-3 5-01-1653
17,8-dicarboxylic acid imide.
15. The B-benzoate of N-phenyl-androstan-3?-ol-16/3,
4. N-phenyl-A4-androsten-3one-16,3,175 - dicarboxylic
acid imide.
b‘oxylic acid anhydride.
18. A process for the production of androstan-l6?,17,8
5. Androstan-3-one-16,B,17B-dicarboxylic acid imide. 25
dicarboxyllic acid imide derivatives which comprises treat
6. Nqpropyl-androstan-3-one-165,17B-dicarboxylic acid
ing the corresponding 16ot-cyano-pregnan-20-one com
pound with an alkali metal hypohalogenite, hydrolyzing
7. A compound selected from the group consisting of
the 1éa-cyano-androstan-l6,6-carboxylic acid thus formed
the following ?ormula:
30 in a basic medium, re?uxing the obtained dicarboxylic
acid with an acid anhydride and treating the formed
steroid anhydride with a primary amine selected from the
group consisting of alkylamine, dialkylaminoalkylamine,
arylamine and aralkyyamine each containing up to 8 car
35 bon atoms and ammonia.
119. The process of claim 18 wherein the alkali metal
hypohalogenite is sodium hypobromite, the basic medium
is dilute methanolic potassium hydroxide, the anhydride
is acetic anhydride and the amine is propylamine.
wherein Y is selected from the group consisting of a 40
double bond between 0-5 and C-6 and a single bond
No reference cited.
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