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Патент USA US3080400

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"ice
3,080,390‘
Patented Mar. 5, 1953
2
3,080,390
A2'5-PREGNADlEN-20-0NE DERIVATIVES
John A. Zderic, Palo Alto, Calif., and Albert Bowers, ?tto
Halpern, and Belig Berlioz, Mexico City, Mexico, as
signors, by mesne assignments, to Syntex Corporation,
CH5
I
a corporation of Panama
No Drawing. Filed .Ian. 31,1962, Ser. No. 170,272
13 Claims. (Cl. 260-3973)
- The present invention relates to novel cyclopentano~
phenanthrene derivatives and to a process for the produc
tion thereof.
g.
10
_
More particularly the present invention relates to novel
A2'5-pregnadien-20-one derivatives.
In the above formulas R and R’ have the same meaning
The novel compounds of the present invention are rep
resented by the following formula:
as previously described.
15
'
In practicing the process just outlined, the starting A5
pregnen-3?-ol-20-one derivative (1) is treated with an or.
OH:
ganic peracid, preferably monoperphthalic acid, to give the
corresponding 5a,6uc-OXld0 pregnan-3?-ol-20-one deriva
tive (II). The latter compound is treated with a lower
20
hydrocarbon sulfonic acid chloride, preferably tosyl chlo
ride, in a tertiary amine such as pyridine, thus alfording
the respective 3l8-tosylate (III) which upon dehydrotosyla
tion with a suitable agent, such as lithium carbonate in di
2,5
methylformamide at re?ux temperature for a period of
time of the order of 31/2 hours, yields the corresponding
In the above formula R represents hydrogen or methyl
and R’ represents hydrogen, hydroxyl or an acyloxy group
latter, upon treatment with sodium iodide, sodium ‘acetate
,derived from hydrocarbon carboxylic acids containing less
and zinc dust in acetic acid, yields the respective Abs-pre
than 12 carbon atoms which may be saturated or unsatu
gnadien-20-one derivative (V).
chain, aromatic and may be substituted by functional
groups such as hydroxy, alkoxy containing up to 5 carbon
(atoms, acyloxy containing up to 12 carbon atoms, nitro,
The following speci?c examples, serve to illustrate, but
are not intended to limit the scope of the present inven
tion:
PREPARATION 1
5a,6ot-oxido-A2-pregnen - 20 - one compound (IV). . The
rated, of straight, branched, cyclic or cyclic-aliphatic 30
amino or halogen. Typical ester groups are the acetate, 35
propionate, enanthate, benzoate, trimethylacetate, t-butyl
acetate, phenoxyacetate, cyclopentylpropionate, aminoace
I
g
A mixture of 6.6 g. of 19-nor-pregnenolone prepared in
{accordance with the copending patent application of
Zderic et al. Serial No. 164,626, ?led January 5, 1962, 2.7
g. of p-toluenesulfonic acid and 300 cc. of acetate anhy
are progesta-tional agents With oral activity. They are use 40 'dride was submitted to a slow distillation; during 5 hours.
The residue was cooled and poured into iced water. The
'ful oral contraceptives and exhibit anti—estrogenic and
product was then extracted with ether, the extract washed
anti-gonadotrophic activities. In addition they lower the
successively with an aqueous solution of sodium carbonate
cholesterol levels in blood, serum, and the adrenal.
and water to neutral, dried and evaporated to dryness.
The novel compounds of the present invention are pre
The residue consisted of 318,20-diacetoxy-19-nor¢A5-1'l(2°)
pared by the process illustrated as follows:
45
t-ate, and ?-chloropropionate.
The novel compounds represented by the above formula
pregnadiene which was utilized in the following step ‘with:
out puri?cation.
4
6 g. of this crude diacetoxy compound were treated with
480 cc. of a 1.2 molar solution of perbenzoic acid in ben
zene (2.2 molar equivalents) at room temperature and in
the dark, for 20 hours. Water was then added, the organic
layer separated, washed with an aqueous solution of so—
dium bicarbonate, then with water, dried with anhydrous
sodium sulfate and evaporated to dryness. The residue
55 consisted of the crude 3?,20?—diacetoxy-5a,6a; 170:,2011
bisoxido-19-nor-pregnane.
'
This crude oxide compound was treated with 500 cc.'of
a 1% methanolic solution .of potassium hydroxide at room
temperature for 1 hour, the mixture was neutralized by
addition of acetic acid, concentrated to small volume-un
der reduced pressure, the product was precipitated by ad
dition of ice water, ?ltered off, washed with water, dried
and recrystallized from acetone-methanol, thus yielding
5a,6a-oxicto-19-nor-pregnane-3?,17a-diol-20-one.
'
To 5 g. of the foregoing oxide in 80 cc. of glacial
acetic acid, there was added a mixture of 6 g. of sodium
0
iodide, 1.6 g. of sodium acetate, 320 mg. of zinc and 2
drops of water. While cooling in an ice bath and stir
ring, there were added to the resulting mixture, 800 mg.
70 of zinc dust in small portions. The stirring was con
tinued for 6 hours and the temperature allowed to at
tain 25° C.
'
8,080,390
3
The reaction mixture was ?ltered and the ?ltrate di
luted with ice water, alkalized with sodium bicarbonate
I
and extracted with ethyl acetate. The extract was washed
to neutral, dried over anhydrous sodium sulfate and evap
ltl-nor-pregnenolone ______________ __
orated to dryness.
17a-hydroxy-prcgnenolone _______ __
Crystallization from acetone-hexane
yielded 19-nor-A5-pregnene-3B,l7a-diol-20aone.
II
17a-hydroxy-lQ-nor-pregnenolone.__
l’la-acotoxy-N-pregnen-3B-ol-20
PREPARATION 2
To a solution of 5 g. of the known l7a-hydroxy
pregnenolone in 100 cc. of anhydrous benzene there were
added 1 g. of p-toluenesulfonic acid and 10 cc. of acetic
anhydride and the mixturewas allowed to stand for 24
hours at room temperature, poured into ice and water,
and the resulting mixture stirred to effect hydrolysis 15
of the excess anhydride. The benzene layer Was sep
arated and washed with 10% sodium carbonate solution
and water. Drying, evaporation and crystallization of
the residue from _ether~hexane produced 3 p,l7ot-diacetoxy—
17ZI-laec'etoxy-lQ-nor-N-prcgnen-3d
ol-20-one.
17a-propionoxy-N-pregnen-BB-ol
-one.
17a-propi0noxy-19—nor-A5-pregnen
01~20-0ne.
l7a-caproxy-A5-pregnen-3B-ol-20one.
17a-caproxy-19-nor-preguen-B?-ol20-one.
nor-preguan-35-ol-20-one.
5a,6a—oxido-17a-caprcry-pregnan
35-ol-20-one.
5a,Ga-oxido-17a-caproxy-19-n0r
pregnan-3?-ol-20-oue.
Example II '
A solution of 5 g. of 5a,6a-oxido-pregnan-3B-oI-ZO-one
in 25 cc. of pyridine was cooled to 0° C. Under stir
A5-pregnen-2O-one.
Following the same procedure, the hereinbe-fore de
ring there was added 1.3 g. of tosyl chloride, the mixture
was kept for 16 hours at 0° C., diluted with 100 cc. of
scribed 19-nor-A5-pregnene-3B,1,7a-diol-20-one (Um-hy
droxy-19-nor-pregnenolone) was transformed into 35,171:
chloroform, washed with dilute hydrochloric acid, water,
aqueous sodium bicarbonate solution and again with
Upon treatment of 17u-hydroxy-pregnenolone and 17a 25 water,
dried over anhydrous sodium sulfate and then
hydroxy-19-nor-pregnenolone by the above described pro
evaporated ‘to dryness under reduced pressure. Thus
cedure, except that acetic anhydride was substituted by
there was obtained the crude 3,8-tosylate of the starting
propionic anhydride and caproic anhydride, there were
vdiacetoxy-l9-110réNY-pregnen-20~one.
compound. The total crude tosylatev in 50 cc. of cold
correspondingly obtained:
3B,171x-dipropionoxy-M-pregnen-ZO-one,
3 ,8,17a-d-ipropi0n0xy-19-nor-A5-pregnen-2O-one,
35,l7a-dicaproxy-A5-pregnen-2O-one and
3 B,17a-dicaproxy-l9-nor-A5-pregnen-20-one.
PREPARATION 3
dimethylformamide was added over 15 minutes to a sus
30 pension of 5 g. of ?nely divided lithium carbonate in 25
cc. of re?uxing dimethylformamide. The mixture was
re?uxed for 31/2v ‘hours further, cooled and ?ltered. The
?ltrate was diluted with water and extracted with ethyl
acetate. The extract was washed with dilute hydro
35 chloric acid, water, aqueous sodium bicarbonate solution
and water, then dried over anhydrous sodium sulfate and
evaporated to dryness. Recrystallization of the residue
2 g. of 3,8,17qt-diacetoxy-A5-pregnen-2O-one dissolved
in 50 cc. of methanol and treated with 5 cc. of a 4%
gave 5a,6a-oxido-A2-pregnen-20-one.
'
’
'
aqueous solution of potassium hydroxide; the reaction 40 The starting compounds under I upon treatment by
the preceding method, afforded ?rst’ the corresponding
mixture was stirred for 1 hour under an atmosphere of
3,8-tosylates and thereafter the products under H. Y'
'
nitrogen at 0° (3.; the mixture was neutralized with acetic
acid and the methanol distilled under reduced pressure.
The residue was triturated with water and the solid col
lected, washed with water, dried and recrystallized from
ethyl acetate-methanol, thus producing 17u-acetoxy-A5
I
II
45
pregnen-3,8—o1-20,-one.
When applying the above procedure to
.3 ,3, 17tx—diacetoxy-1 9-nor-A5-pregnen-2 O-one,
3 5, 17a-dipropionoxy-A5-pregnen-20-one,
60
3 ?,17a-dipropionoxy-19-nor-A5-pregnen-2O-one,
313,17a-d-icaproxy-M-pregnen-ZO-one and
35,717wdicaproxy-19-nor-A5-pregnen-20-one,
there were respectively obtained:
55
ljaaacetoxy-19-nor-A5-pregnen-3B-ol-20-one,
l7a-propiotnoxy-A5epregnen-3,B-ol-20-one,
17or-propionoxy-19-nor-A5-pregncn-3?-ol-20—one,
17a-caproxy-M-pregnen-S?-ol-ZO-one and
17u-caproxy-l9-nor-A5-pregnen-3?-ol-20-one.
Example I
Example III
60
To 5 g. of 5a,6u-oxido-A2~pregnen-20-one in 80 cc. of
glacial acetic acid, there was added a mixture of 6 g.
of sodium iodide, 1.6 g. of sodium acetate, 320 mg. of
zinc and 2 drops of Water. While cooling in an ice bath
A solution of 2.5 g. of pregnenolone in 100 cc. of
chloroform was cooled to 0° C. and mixed with 1.1 65 and stirring, there were added to the resulting mixture,
800 mg. of zinc dust in small portions. The stirring
molar equivalents of monoperphthalic acid in ether solu
'was continued for 6 hours and the temperature allowed to
tion. The mixture was kept at room temperature for 20
attain 25° C.
hours, diluted with water, the organic layer was separated,
The reaction mixture was ?ltered and the ?ltrate di
washed with aqueous sodium bicarbonate solution and
then with water to neutral, dried over anhydrous sodium 70 luted with ice water, alkalized with sodium bicarbonate
and extracted with ethyl acetate. The extract was washed
sulfate and evaporated to dryness. ‘Crystallization from
to neutral, dried over anhydrous sodium sulfate and
acetone-hexane gave 5ot,6a-oxido-pregnan-3?-ol-20-one.
The starting com-pounds under I were treated following
evaporated to dryness.
Crystallization from acetone
hexane yielded A215-pregnadien-2O-one.
the above procedure, thus a?ording the corresponding
When applying the above procedure to the starting
products underII.
75
3,080,390
5
drogen and methyl and R’ is selected from the group con
sisting of hydrogen, hydroxyl and a hydrocarbon car
boxylic acyloxy group of less than 12 carbon atoms.
2. A2-5-pregnadien-20-one.
II
5a-Ga-oxido-19-nor-A2-pregnen-20
pregnen-ZO-one.
5a,Ga-orido—17a-caproxy-19-nor
A2-pregnen-20~one.
6
wherein R is selected from the group consisting of hy
compounds under I, there were obtained the correspond
ing products under II.
3. 19-nor-A2'?-pregnadien-ZO-one.
4. 17a-hydroxy-A2'5-pregnadien-2O-one.
5. 17a-hydroxy-19~nor-AZ?-pregnadien-ZO-one.
6. 17u-acetoxy-Az,5-pregnadien-20-one.
7. 17a-acetoxy-19-nor-A2'5-pregnadien-20-one.
8. 17u-propionoxy-A215-pregnadien-20-one.
9. 17a-propionoxy-19-n0r-A2'5-pregnadien-20-one.
10. 17wcaproxy-Az-5-pregnadien-20-one.
11. 17a-caproxy-19-nor-A2?-pregnadien-ZO-onc.
19-nor-A2-5-pregnadien-2O-one.
17a-hydroxy-Az?-pregnadlen
-one.
17a-hydroxy-19-n0nA2li-preg
nadien-20-one.
17a-acetoxy-A2IE-pregnadien-ZO
10
one.
17a-acetoxy-19-n0r-A2J-pregnadien
20-0ne.
17a-propionoxy-A2-!-pregnadien
20-one.
17a-propi0n0xy-19-nor-A2'5
pregnadien-20-one.
12. The hydrocarbon carboxylic acid esters of less than
17a-caproxy~A2-5-pregnadten-20
15 12 carbon atoms of 17a-hydroxy-AZ-5-pregnadien-20-one.
one.
13. The hydrocarbon carboxylic acid esters of less
than 12 carbon atoms of 17a-hydroxy-l9-nor-Azt5-preg
na dien-ZO-one.
' 17a-caproxy-19-nor-A2-5
pregnadien-20-one.
We claim:
1. A compound of the following formula:
1]
20
N0 references cited.
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