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Патент USA US3088954

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3,088,950
United States Patent 0 " ICC
Patented May 7, 1963
2
1
erably a lower alkyl group such as methyl, ethyl or propyl
or R may represent an aralkyl group such as benzyl. R’
represents a hydroxy group in 5 con?guration or R’ repre
sents a keto group or R’ represents hydrogen. R2 repre
sents a hydroxy group in a con?guration or R2 represents
3,088,950
ZI-FLUORO Z-ALKYL PREGNENE COMPOUNDS
Howard J. Ringoltl and George Rosenkranz, Mexico City,
Mexico, assignors, by mesne assignments, to Syntex
Corporation, a corporation of Panama
No Drawing. Filed Aug. 13, 1957, Ser. No. 677,852
Claims priority, application Mexico Aug. 21, 1956
3 Claims. (Cl. 260-3973)
hydrogen. The novel compounds of the present inven
tion may be prepared by a process exempli?ed by the
following equation:
The present invention relates to cyclopentanophenan 10
threne compounds and to a process for the production
thereof.
More particularly the present invention relates to novel
21-?uoro-2-alkyl and 2-aralkyl derivatives and especially
to 2l-?uoro-2-alkyl and 2-aralkyl derivatives of A‘hpreg 15
pen-3,20-dione which may be substituted with an a-hy
droxyl group at position C-17 and which may also be
O:
R"
\ R’
CH=OH
01120502011:
0
I __Rg
0
i __R 2
omsoici R"
' RV
———-a
Pyridine
substituted with an oxygen function (B-hydroxyl or ke
tone) at position C-ll and to a process for the production
0:
lNaI
20
of these compounds.
The novel hormones of the present invention having a
17a-hydroxy group as for example ZI-?tlOl‘O-Zor-EllkYl or
aralkyl-A‘i-pregnen-17a-ol-3,1 1,20-tri0ne and 21 -?uoro-2e
alkyl or aralkyl-M-pregnen-llB,l7a-diol-3,20-dione are
cortical type hormones having anti-in?ammatory proper
ties. Compounds of this type cause glycogen deposition
in rats. On the other hand, those 2a-methyl-21-?uoro
pregnene derivatives of the present invention without a
hydroxyl group at C-17 are inhibitors of the uterus growth
as shown‘by essays in mice and therefore are anti-estro 30
genic compounds.
In our U.S. application Serial‘ No. 632,014, ?led Janu
ary 2, 1957, now abandoned, there is disclosed the pro
R" I
O:
GHiF
OHzI
i0
1
ResAgF R"
‘
u”
0:
In the above equation R, R’ and R2 represent the same
groups as heretofore set forth.
duction of 2-alkyl and Z-aralkyl derivatives of M-preg
In practicing the process of the present invention the
nene-17a,2l-diol-3,l1,20-trione and of N-pregnene-ll?, 35 Z-alkyl or 2-aralkyl derivative of a A4-pregnene-3,2{)-di~
l‘7d,2l-tl'l0l-3,20-dl0?€. By a method precisely similar
one is dissolved in a mixture of an organic solvent and
to that disclosed in the aforementioned application ex
pyridine. An especially suitable mixture is chloroform
cept starting with compounds without the ll?-hydroxy
pyridine. The solution is then cooled to below room
group or the ll-keto group and without the l'la-hydroxy
temperature as for example 0° C. and'rnethane sulfonyl
group there may also be prepared similar Z-alkyl and 2 40 chloride is added thereto in portions. The reaction mix
aralkyl derivatives of 2a-alkyl or aralkyl-A4-pregnene-21
ture is then kept at a temperature below room tempera
ol-3,20-dione ‘(2a-alkyl or aralkyl desoxycorticosterone),
Za-alkyl or araIkyl-ALpregneneJ701,21-diol-3,2O-dione
ture for a period of time of the order of 14 hours. The
crude methane snlfonate of the Z-alkyl or aralkyl-M
(2a-alkyl or aralkyl Reichstein’s Substance S), 2a-alltyl
pregnene~3,20-dione derivative, obtained from the reac
or aralkyl-A‘Lpregnene-l 1?,21-diol-3,20-dione (2rz-alkyl 45 tion mixture by evaporation to dryness, was then dis
or aralkyl corticosterone), 2a-alkyl or araikyl-M-preg
solved in organic solvent such as acetone and mixed pref
nene-2l-o1-3,11,20-trione (2a-alkyl or aralkyl-ll-dehydro
erably at room temperature (20° C.) with sodium iodide.
corticosterone), etc.
The precipitate formed after pouring the reaction mixture
In accordance with the present invention it has been
into water was the corresponding Za-alkyl or aralkyl-Z'l
discovered that 2ot-alkyl or aralkyl pregnene compounds 50 iodo-A4-pregnene-3,20-dione derivative. The product was
of the character just described upon treatment with meth
collected by ?ltration, dried in a vacuum and then dis
ane sulfonyl chloride in pyridine gave the corresponding
solved in acetonitrile. Thereafter a solution of silver
2l-methane sulfonate which when reacted with sodium
?uoride in water was slowly added thereto. After a short
iodide gave the corresponding 2l-iodo compound. This
time silver iodide started to separate leaving in solution
last intermediate upon reaction with silver ?uoride in
the desired 2l-?uoro-2a-alkyl or aralkyl-M-pregnene-E,
acetonitrile gave the desired ?nal products namely the
ZO-dione derivative. The reaction mixture was then al
2l-?uoro-2-alkyl or aralkyl derivatives of M-prcgnene
3,20-dione. The novel compounds of the present inven
tion may therefore be exempli?ed by the following for
60
mula:
fling
lowed to stand at room temperature for about one day
and then ?ltered. The desired 21-?uoro-2a-alkyl or
aralkyLM-pregnene-3.ZO-dione derivative was then ob
tained from the solution by concentration and crystalliza
tion and puri?ed as by recrystallization from an organic
solvent such as methyl-acetate.
The following speci?c examples serve to illustrate but
are not intended to limit the present invention.
Example I
A solution of 3.4 g. of Za-methyI-M-pregnen-Z1-ol-3,20
dione (2a-methyl-desoxycorticosterone) in 20 cc. of a
In the above formula R represents an alkyl group pref
mixture chloroformpyridine 9:1 was cooled to 0° C. and
mixed with 1.4 g. of methanesulfonyl chloride which was
added in small portions. The reaction mixture was kept
3,088,950
3
4
for 14 hours at 0° C. and then it was washed with dilute
hydro-corticosterone) ; 21-?uoro-2a-methyl-A4-pregnene
hydrochloric acid, water and sodium bicarbonate solu
1 l?,17a-di0l-3,20-di0118 from 2a-methyl-A4~pregnene-1 1,8,
tion and the chloroform was evaporated under vacuum.
17a,2l-trio1-3,20-dione (2a-methyl-hydrocortisone); 21
The residue, consisting of the crude methanesulfonate
?uorO-Za-ethyI-M-pregnene-1 15,17a-diol-3 ,20-dione from
o-f 2a-methyl-desoxycorticosterone was dissolved in 20 cc.
of acetone and treated at room temperature and under
2a-ethyl-A4-pregnene-1 1,B,17u,2 1-triol-3,20-dione (Za-eth
yl-hydrocortisone) ; 21-?uoro-2a-benzyl-A4-pregnene-11B,
17a-diol-3,20-idione from 2a-benzyl-A4-pregnene-ll?,17a,
21-triol-3,20~dione (2a~benzyl-hydrocortisone); 2l-?uoro
stirring with 4 g. of sodium iodide. After decolorizing
the mixture by the addition of sodium thiosulfate solution
the product was precipitated by the addition of water and
the crystalline 2a-methyl-2l-iodo-A4-pregnenc-3,20-dione
ZwmethyI-M-pregmn-1711-01-3,l1,20-tri-one
10
was collected by ?ltration. The crude product was dried
in vacuum, dissolved in 20 cc. of acetonitrile and treated
dropwise with 1.4 g. of silver ?uoride dissolved in 3 cc.
of water. After a short time, silver iodide started to sepa
rate leaving the 2-?uoro-2ot-methyl-A4-pregnene-3,20-dione
in ‘solution. The mixture was kept for 24 hours at room
temperature and ?ltered. Concentration of the ?ltrate
under vacuum gave a crude product which after crystal
lization from methanolacetone yielded the pure 21-?uoro
2a~rnethyl-A4-pregnene-3,20l-dione or 2-?uoro-2a-methyl 20
progesterone.
Example II
By the same method described in Example I, there were
nene-17a,2l-diol-3,1 1,20-trione (Za-benzyl-cortisone).
We claim:
1. 21~?uorO-Za-methyl-A4-pregnen - l7a—ol-3,20-dione.
2. 21-?uoro-2a-methyl-A4-3, 1 1,20-trione.
3. A novel compound of the following formula:
CHgF
:dgm
prepared: 21-?uoro-2a-methyl-A4-pregnen - 17o: - ol-3,20
(2a-rmethy1-“S”); 21-?uoro-2u-ethyl-A4~pregnen-17m-ol-3,
20~dione from 2a-ethyl-A4-pregnene-l7a,2l-diol-3,20-dione
(2a-ethyl-“S”); 21-?uoro-2a-benzyl-A4-pregnen-17u-ol-3,
ZO-dione ‘from 2a—benzyl-A4—pregnene-17¢x,2l-diol-3,20
ethyl-M-pregnen-llB-ol-3,20-dione
from
20: - ethyl-A4
pregnene-l 1,8,21-diol-3,20-dione (2a-ethyl-corticosterone);
21-?uoroP2a-benzyl-Mpregnen-11p-ol-3,20-dione from 2:1
benzyl-M-pregnene-l1B,21-diol-3,20 - dione
(2a - benzyl
corticosterone) ; 2-?uo1ro-2ot-rnethyl-A4-pregnene-3, 1 1,20
trione from 2a-methyl-A4-pregnen-21-ol-3,11,20-trione
(2a-methyl-1 l-dehydro-corticosterone) ; 2 1 -?uoro-2a-eth 40
yl-M-pregnene-SJ1,20-trione from Za-ethyI-Ahpregnen
2l¢ol—3,11,20-trione (Za-ethyl-l 1-dehydro—corticosterone) ;
21-?uoro-2u-benzyl-A4-pregnene-3,11,20-trione from 2:1
benzyl-A4-pregnen-2l-ol-3,11,20-trione (2oc-benzyl-1l-de
20:
20-trione ‘from Za-ethyl-N-pregnene-17a,21-diol-3,11,20
trione (2a-ethyl-cortisone); and 21-?uoro-2a-benzyl-A4
pregnen-17u-ol-3,11,20-trione from Za-benzyl-M-preg
dione from 2a—methyl-A4—pregnene-l7u,21-diol-3,20-dione
dione (2a-benzyl-“S”); 2l-?uoro-2a-methyl-M-pregnen
1113-o1-3,20-dione from 2a-methyl-A4-pregnene-1118,21
diol-3,20-dione (Za-rnethylcorticosterone); 21-?u01'0-2a
from
methyl-M-pregnene-17u,21-tdiol-3 ,1 1,20-trione (Zen-meth
yl-cortisone) ; 21-?uoro-2u-ethyl-A‘i-pregnen-17u-o1-3,1 l,
wherein R is selected from the group consisting of lower
alkyl and aralkyl, and R’ is keto.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,822,318
2,865,953
2,903,449
Kroll et a1 _____________ .._ Feb. 4, 1958
Schneider et a1. ______ __ Dec. 23, 1958
Fried et \al. _________ __ Sept. 8, 1959
OTHER REFERENCES
Hogg et a1.: J.A.C.S. 77, Dec. 5, 1955, pages 6401
402.
Tannhauser et al.: J.A.C.S. 1956, 78, page 2658.
Herz et al.: I.A.C.S. 1956, 78, page 4812.
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