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Патент USA US3071592

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?nited grates Patent
lice
3-,WL582
Patented Jan. 1, I963
1
2
vention may be produced by the process illustrated as fol
lows:
3,071,582
DERIVATIVES 0F 3p-HALO - 17oz - (CARBOXYETH
YL)"A5'ANDRQSTEN“175‘0L'LACTONE AND 3(3
l7p-OL-LACTONE
O=(|3——-
HALO-I7a(CARB®XYVINYL) - A5 - ANDRGSTEN
O=C——-—
0y
John A. Zderic, Palo Alto, (Iali?, and ()tto Halpern and
.Iose Iriarte, Mexico City, Mexico, assignors, by mesne
assignments, to Syntex Corporation, a corporation of
Panama
R
No Drawing. Filed .Iau. 17, 1962, Ser. No. 166,951
20 Claims. (Cl. 260-—239.57)
The present invention relates to novel cyclopenta
(I
R. i
/
(111)
,
no
nophenanthrene derivatives and to a process for the pro
duction thereof.
(IV)
no
i
it :
X
More particularly the present invention relates to de_ 15
rivatives of 3?-halo-17a-(carboxyethyl)-A5-androsten~l7[3
ol-lactone and SIB-halo-17a-(carboxyvinyl)-A5-androsten
17?-ol-lactone.
O=C—
The novel compounds of the present invention which
I
are diuretic compounds showing anabolic, anti-estrogenic 20
and anti-gonadotrophic activities are represented by the
following formulas:
0
R
O=
1 J
l
/\
R. I
/
25
(VI)
Y-——
—
,
(v)
HO
X
a
In the above formulas R, X and Y have the same mean
ing as heretofore set forth.
In practicing the process just outlined, the starting com
pound which is a 17a-(2'-carboxyethyl)-A5-androstene
X
35
In the above formulas R represents hydrogen or methyl;
X represents ?uorine or chlorine, Y represents fluorine,
chlorine or bromine; and Z may be a double bond or a
saturated linkage.
The novel C—6~unsubstituted compounds of the pres
ent invention are prepared by the process exempli?ed by
the following equation:
35,1713-diol-1actone derivative (III) is treated with phenyl
iodoso di?uoride or dichloride to give the respective 50c,
6a-di?uoro or dichloro l7a-(2’-carboxyethyl) -androstane
36,1713-diol lactone (IV) which upon dehydrohalogena
tion with a suitable agent such as calcium carbonate in
dimethyl formamide, yields the corresponding 6-halo-17c
(2’-carboxyethyl)-A5-androstene-3B,17a-diol-1actone (V).
The latter compound upon halogenation of the 3p-hy
droxyl with a suitable agent such as hydrogen ?uoride,
phosphorus pentachloride or phosphorus pentabromide,
45 yields the respective 3,8-?uoro, chloro or brorno-6-halo
17a- (2'-carboxyethyl ) -A5-androsten-17?-ol-lactone (VI) .
The following speci?c examples serve to illustrate, but
are not intended to limit the scope of the present inven
tion:
PREPARATION 1
50
A solution of 5 g. of 17a-(2'-carboxyethyl)-l9-nor—
A4-androsten-17,B-ol-3~one lactone (Celia et al., J. Org.
Chem. 24, 743 (1959)), in 50 cc. of acetic anhydride
and 50 cc. of acetyl chloride was boiled for 4 hours under
In the above formulas R, Y and Z have the same mean~ 55 an atmosphere of nitrogen. The reaction mixture was
then distilled almost to dryness, cooled, diluted with ether
ing as previously set forth. In practicing the process out
and the organic extract washed with water, then with 5%
lined above, the starting compound which is a I7CL-(ZI
sodium bicarbonate solution and ?nally with water. There
carboxyethyl or carboxyvinyl)-A5~androstene-3?,17?-dio1
was thus obtained 3-acetoxy-l7a-(2'-carboxyethyl)-l9
lactone derivative (I), is treated with a halogenating agent
such as phosphorus pentabromide, phosphorus penta 60 nor-A315-androstadien-l7/3~ol lactone.
Following the same procedure, 17a-(2'-carboxyvinyl)
chloride or hydrogen ?uoride in a solvent inert to the
reagent, thus a?'ording the respective 3B-halo derivative
19-nor-A4-androsten-17?-ol-3-one lactone was treated
(Cella et al. v. supra) thus yielding 3-acetoXy-l7a—(2'
(II).
The novel C-6-substituted compounds of the present in
carboxyvinyl)-19-nor-A3Y5-anclrostadien-17p-ol lactone.
3,071,582
ll
3
phenyl iodoso dichloride and 100 cc. of chloroform was
A solution of 4 g. of 3-acetoxy-l7a-(2’-carboxyethyl)
19-nor-A3'5-androstadien-175-01 lactone in a mixture of
re?uxed until the crystals of the reagent disappeared. The
100 cc. of 95% ethanol and 35 cc. of tetrahydrofuran was
solvents were removed and the residue recrystallized from
cooled at 10° C. and added dropwise, with occasional
stirring over a 1 hour period, to a cold solution of 4 g.
of sodium borohydride in 50 cc. of 80% ethanol, the
reaction temperature not being allowed to exceed 5° C.
After completion of addition, the solution was kept at
0-5” C. for 2 hours further; then 200 cc. of 10% sodi
urn hydroxide was added and the solution boiled for 15 10
chloroform-ethyl acetate thus yielding 5 oc,6oc-dlChlOf0
170a - (2’ - carboxyethyl) - androstane - 35,175-diol lac
tone.
Following the same technique there was treated 170442’
carboxyethyl) - 19 - nor - A5 - androstene - 35,175 - diol
lactone thus affording 50:,6oc-(11Chl01‘0-17cc-(2'-Ca1'b0Xy
ethyl) ~19-nor-androstane-35,175-diol lactone.
minutes. Most of the solvent was removed in vacuo, the
Example IV
residue acidi?ed with 20% hydrochloric acid and the
crystalline precipitate collected and washed. Recrystal
2
(2'-'carboxyethyl)-19-nor-A5-androstene-35,175-diol
g.
of
5a,6ot - dichloro - 17a - (2’ - carboxyethyl)
androstane-35,175-diol lactone in 40 cc. of cold dimethyl
forrnamide was added over 15 minutes to a suspension of
lization of the crude material from acetone furnished 17a
lac
5 g. of ?nely divided calcium carbonate in 15 cc. of re
tone.
?uxing dimethylforma-mide. The mixture was refluxed
for 30 minutes further, cooled and ?ltered. The ?ltrate
By the above procedure there was treated 3-acetoxy
17u-(2'-c'arboxyvinyl)-l9-110r-A315-androstadien - 175 - ol
was diluted with water and extracted with ethyl acetate.
The extract was washed with dilute hydrochloric acid,
water, aqueous sodium bicarbonate solution and water,
then dried over anhydrous sodium sulfate and evaporated
lactone to give 17a-(2’-carboxyvinyl)-19-nor-A5-andros
tene-35,l75-diol lactone.
Example I
to dryness. Silica gel chromatography and recrystalliza
tion afforded 6-chloro-17a-(2’-carboxyethyl)-A5-andro
To a solution of 5 g. of l7u-(2'-carboxyethyl)-A5
androstene-35,l75-diol lactone (Cella et al. v. supra) in
1010 cc. of benzene were added 5 g. of phosphorus penta
chloride and the resulting mixture was re?uxed for 1
hour in the absence of moisture. it was then cooled,
poured into water; the benzene layer was washed with
Water several times, dried over anhydrous sodium sulfate
stene-35,175-diol lactone.
ethyl) - 19 - nor - A5 - androstene - 35,175 -diol
A5-androstene-35,175-diol lactone.
Example V
from acetone-hexane yielded 35-chloro-l7ot-(2’-carboxy
ethyl)-A5-androsten-175-ol lactone.
17cc - (2’ - carboxyethyl) -' A5 -androstene - 35,175- dial
In accordance with the foregoing technique there were
lactone, 17oz - (2' -carboxyethy1) - 19 - nor - A5 -andro
stene-35,l75-diol lactone were treated following the pro
17a. - (2' - carboxyethyl) - 19 - nor - A5 - andro
stene - 35,175 - diol
lactone,
lactone
was converted to 6-chloro17ot-(2’-carboxyethyl)-l9-nor
and evaporated to dryness. Crystallization of the residue 30
treated:
.
By the same procedure 5u,6e-dichloro-17a-(2’-carboxy
17a - (2’ - carboxyvinyl)
35
cedure described in Example III, except that phenyl
19-nor-A5-androstene-35,175-diol lactone and 17OC-(2'-Ca1'
iodoso dichloride was substituted by phenyl iodoso di
tboxyvinyl) - A5 - androsten - 35,175 - diol lactone (Cella
fluoride thus giving respectively: 5a,6e-ditiuoro-l7a-(2’
et al. v. supra) yielding correspondingly: 35-chloro-17a
carboxyethyl) - androstane - 35,175 - diol
(2' - carboxyethyl) - l9 - nor - A5 - androsten - 175 - ol
5a,6a - di?uoro - 171x - (2’ - carboxyethyl) - 19 - nor
lactone, 35 - chloro - 17a - (2’ - carboxyvinyl) - 19 - nor
'A5 - androsten - 175 - ol
lactone,
and
40
35 - chloro - 170c
(2'-carboxyvinyl)-A5-androsten-175-ol lactone.
Example I]
In a polyethylene ?ask, adapted with magnetic stirrer,
there was dissolved 2.8 g. of 17ot-‘(2'-carboxyethyl)A5
androstene-35,175~diol lactone in 30 cc. of methylene
chloride, the solution was cooled to 0° C. and a solution
of 12 g. of anhydrous hydrogen ?uoride in 20 cc. of tetra
hydrofuran cooled in a Dry-Ice acetone bath (-—70° C.)
was added over a period of 20 minutes with constant stir
ring. The mixture was stirred at a temperature lower
than 10° C. for 6 additional hours, then neutralized by
cautiously adding a 5% aqueous sodium bicarbonate so
lution and transferred to a separatory funnel.
The or
ganic layer was washed with water, dried over anhydrous
sodium sulfate and concentrated until formation of an
abundant precipitate. The mixture was cooled, the pre
cipitate ?ltered and redissolved in hot ethyl acetate, the
soluble material was ?ltered oli and the ?ltrate cooled
whereby there crystallized 35-?uoro-17u-(2’-carboxy
ethyl)-A5-androsten-175-ol lactone.
There were treated according to the above procedure:
lactone
and
androstane-35,175-diol lactone.
Example V1
The two preceding compounds were treated, following
the procedure described in Example IV yielding‘ corre
spondingly: 6 - ?uoro - 17a - (2’ -carboxyethyl) - A5
androstene - 35,175 - diol lactone, and 6 - ?uoro - 17cc
‘(2' - carboxyethyl) - 19 - nor - A5 - androstene - 3 5,175
diol lactone.
’
Example VII
6 - chloro - 170a - (2' - carboxyethyl) - A5 - androstene
35,175 - diol
boxyethyl)
lactone,
lactone,
6 - chloro - 17m - (2' - car
- 19 - nor - A5 - androstene ~ 35,175, - diol
6 - ?uoro - 17a’. - (2’ - carboxyethyl) ~ 19 - nor
A5 - androstene - 35,175 - diol
lactone,
and
6 - ?uoro
17a-(2’-carboxyethy1) - A5 - androstene - 35,175 - diol lac
tone were treated following the procedure described in
Example I, affording respectively: 35-6-dichloro-17a~(2’
carboxyethyl) - A5 - androsten - 175 - ol
lactone,
35,6-.
idichloro - 17oz - (2' - carboxyethyl) - 19 - nor - A5 - an
drosten
175 - ol lactone,
35 - chloro - 6 - ‘?uoro- 17m
,(2' - carboxyethyl) - 19 -nor - A5 - androsten - 175 - o1
lactone and 35 - chloro - 6 - ?uoro - 170a - (2' - carboxy
ethyl)-A5-androsten—l75-ol lactone.
.
170: - (2’ - carboxyethyl) - 19 - nor - A5 - androstene - 35,
I 175 ~ diol
lactone,
17oz - (2' - carboxyvinyl) - 19 - nor
A5-androstene-35,175-diol 'lactone, and 17w(2’-carboxy
vinyl)-A5-androstene-35,175-diol lactone thus giving re
spectively: 35-?uoro-17ot-(2'-carboxyethyl)-19-nor-/_\5-an
drosten-175-ol lactone, 35-fluoro-17a-(2'-carboxyvinyl)
Example VIII
6 - chloro - 17oz - (2’ -carboxyethyl) - A5 - androstene
35,175 - diol lactone, 6 - chloro - 170a - ,(2’ - carboxy
ethyl) - 19 - nor - A5 - androstene -_35,l75 - diol lactone,
6 - ?uoro - 17a - (2’ -carboxyethyl) - 19 -nor - A5 - an
19-nor-A5-androsten-175-o1 lactone, and 35~?uoro-17a 70 drostene-35,175-diol lactone, and 6-‘fluoro-l7a-(2lcar
(2’-carboxyvinyl)-A5-androsten-175-ol lactone.
boxyethyl) - A5 - androstene ~ 35,175 - diol lactone were
treated by the technique delineatedin Example 11, thus
Example III
producing correspondingly: 35-?uoro-6-chloro-17a-(2'
A mixture of 2.5 g. of 17o¢-(2'-earboxyethyl)-A5-an
drosten-35,175-diol lactone, 1.05 mol. equivalents cf 75
carboxyethyl) - A5 - androsten - 175 - ol
lactone,
35
?uoro - 6 - chloro 17a - (2' -carboxyethy1) - 19 -nor - A5
3,071,582
5
androsten - 175 - ol
6
lactone,
313,6 -di?uoro - 17a-(2'
3. 35,6-dichloro - 17a - (Z’carboxyethyl)-19-nor-A5-an
drosten-17?-ol-lactone.
carboxyethyl) - 19 - nor - A5 - androsten - 17,8 - o1 lactone
and
35,6 - di?uoro - 17cc - (2' -carboxyethyl) - A5 - an
4. 313-chloro-6—?uoro - 170a ' (ZHcarboxyethyl)-19-nor
drosten-17?-ol lactone.
A5-a11drosten-17,8-ol-lactone.
Example IX
In accordance with Example I, except that phosphorus
pentachloride was substituted by phosphorus pentabro
rnide, there were treated: 17a-(2’-carboXyethyl)-A5-an
6. 3j3-?uoro-6-chloro - 170a - (2'carboxyethy1) - Aian
drosten-17?-ol-lactone.
7. 3/3-?‘uoro-6-chloro - 17cc - (2'carboxyethy1)-19-rnor
drostene-3B,17/3-diol lactone, 17u-(2’-carboxyethyl)-19
nor-A5-androstene-3B,17,8-diol lactone, 17zx-(2'-C8IbOXy
A5-androsten-17,8-ol-lactone.
vinyl)-l9~nor-A5-androstene-3{3,17,8-diol lactone, and 170c
(2’-carboxyvinyl)-A5-androstene-3,8,17?-dio1 lactone thus
drosten-17?-io1-lact0ne.
giving respectively: 3,8-brorno—l7u-(2’-carboxyethyl)-A5
androsten-17?-ol lactone, 3?~bromo-17a-(2’carboxyeth
yl)-l9-nor-A5-androsten-17,8-01 lactone, 3?~broino-l7a
'8. 3/8,6-difiuoro-17a-(2’carboxyethyl) - 19 - nor-A5-an
9. 3,6,6~di?uor0—17a-(Z'carboxyethyl - A5 - androsten
17‘8-ol-1actone.
15
‘
10. 3?-bromo-6-?uoro-l7a-(2'—carboxyethyl) - A5 - an
drosten-17,8-iol—lactone.
(2'-carboxyviny1-19-nor-A5-androsten-176-01 lactone, and
11.’ A ‘compound of the following formula:
3?-bromo - 17a - (2'-carboxyvinyl)-A5-androsten-17?-ol
lactone.
Example X
6-Cl1lOI‘O-l7oc-(2' - carboxyethyl) -r A5 - androstene-3l3,
17,6-diol lactone, 6-ch1oro-17ot-(2'-carboxyethyl)~19-nor
A5-androstene-3?,17(3-diol laotone, 6-?uoro-17u-(2'car
boxyethyl)q19-nor-A5-androstene-3B,17?-diol lactone, and
6~?uoro-17a-(2’-carboxyethyl) - A5 - androstene—3/3,17B
25
diol lactone were treated following the technique de~
scribed in the foregoing example, yielding respectively:
3,8-bromo-6-ch10r0-17a-(2'-carboxyethyl)
- A5 - ‘andro
Y
sten-17B~ol lactone, 3?<bromo—6-chloro-17a-(2'carboxy
ethyl)-19-nor-A5-androsten~17,8-01 lactone, 3,8-brorno-6
?uoro~17ct-(2'—carboXyethyl)-19-nor - A5 - androsten-17?
o1 lactone, ‘and 3/3‘bromo-6-?uor0-17a-(2'-carboxyethy1)
A5-androsten-17/3-o1 'lactone.
We claim:
1. A compound of the following formula:
wherein R is selected from (the group consisting of hydro
gen and methyl; Y is selected from the group consisting of
?uorine, chlorine and bromine; and Z is selected from the
35 group consisting of a double bond and a saturated linkage.
12. 3,8-chloro-17a-(2'-carboxyethyl) - A5 - androsten
17,8-o1-lactone.
0=c——
13. 3,B—?uoro-17a-(2’ - carboxyethyl) - A5 - androsten
0
17B-o1-lactone.
l
\/
40
14. 3,8-brorno-17a-(2' - carboxyethyl) - A5 - androsten~
17,8-o1-lactone.
15. 3,8-?uoro-17a~(2’-carboxyethy1 - 9 - nor-M-andro
sten-17?-ol-lactone.
R
16. 3,8-chloro-17a-(2’ - carboxyethyl) - 19 - nor-Aman
45
drosten-17B-o1-lactone.
17. 3?-?uoro-17rx-(2’ - canboxyvinyl) - A5 - androsten
Y
17/9-o1-lactone.
X
18. 3?-chloro-l7a-(2' - carboxyvinyl) - A5 - androsten
17B-o1-lactone.
wherein R is selected from the group consisting of hydro
19. 3,8-?uoro-17a-(2'~carboxyvinyl) gen and methyl; Y is selected from the group consisting 50
drosten-17;3~ol-lactone.
of ?uorine, chlorine and bromine and X is selected from
20. 3,B-chloro-17a-(2' - carboxyvinyl)
the group consisting of ?uorine and chlorine.
2. 36,6-dichl0ro - 17a - (2'-carboxyethyl) - A5 - andro
sten-17,8-ol-lact0ne.
drosten-l7?-ol-lact0ne.
No references cited.
19 - nor - As-an
- 19 - nor-A5-an
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