close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3056823

код для вставки
United States Patent 0
.
3,056,808
Patented Oct. 2, 1962
2
1
tract and the bones and internal organs due to bacterial or
viral infections, contact-dermatitis and allergic reactions,
3,056,808
156-FLUQRINATED CORTICGSTEROIDS
Donald E. Ayer, Portage Township, Kalamazoo County,
Mich., assignor to The Upjohn Company, Kalamazoo,
and rheumatoid arthritis.
The novel compounds of the invention having the For
mula I also possess progestational activity and affect the
Mich., a corporation of Delaware
No Drawing. Filed Oct. 9, 1961, Ser. No. 143,557
10 Claims. (Cl. 260—397.3)1
secretion of gonadotropins and thus regulate ovulation
and endometrial and placental development and, par
ticularly when used in conjunction with estrogens, for ex
This invention’ r/elates to novel steroid compounds and
ample, ethinylestradiol, and with androgens, for example,
processes for their preparation and is more particularly
Halotestin (9oZ-?uoro-1lB-hydroxy-17m - methyltestoster
concerned with novel ISQ-?uorinated corticosteroids and
one), reduce fertility, and constitute effective therapy for
with processes for their preparation.
The novel compounds of the invention can be represent
ed by the following formula:
'dysmenorrhea, amenorrhea, endometriosis, threatened
abortion and related gynecological disorders in humans
and valuable domestic animals.
15
The novel compounds of Formula I above also possess
central nervous system depressant activity which makes
them useful as sedatives and general anesthetics in mam
mals, particularly in humans and animals. For example,
they can be used as sedatives and anesthetics in the labora
20 tory manipulation of experimental animals such as mice
and ‘rats.
x’ '
The novel compounds of Formula I can be prepared
and administered in a wide variety of oral or parenteral
dosage forms singly, or in admixture with other active
0..
i
Y
25 compounds. They can be associated with a pharmaceuti
cal carrier which can be solid material or a liquid in
(I)
which the compound is dissolved, dispersed, or suspend
ed. The solid compositions can take the form of tablets,
wherein the dotted line between carbon atoms 1 and 2
indicates that these carbon atoms are joined by a single or
double bond, and wherein R is selected from the class
powders, capsules, pills, or the like, preferably in unit
dosage forms for simple administration or precise dosages.
The liquid compositions can take the form of solutions,
consisting of hydrogen, hydroxy, and acyloxy, R’ rep
resents hydroxy and, when R represents hydrogen, R’ also
emulsions, suspensions, syrups or elixirs.
represents a group selected from the class consisting of
The novel compounds of the invention can for the most
hydrogen and acyloxy, X is selected from the class con
part be prepared according to the following reaction
sisting‘ of hydrogen and ?uorine, Y is selected from the
classfconsisting of hydrogen, ?uorine and methyl, and Z 35 scheme.
is selected from the class consisting of ?-hydroxymethyl
REACTION SCHEME A
ene and carbonyl, and wherein the acyl of the acyloxy
17a-_hydmxy derivatives
group in each instance is that of an organic carboxylic
and Al-analogues
acid preferably a hydrocarbon carboxylic acid contain
ing from 1 to 12 carbon atoms, inclusive.
40
I
The organic carboxylic acids, from which the acylates
of the invention are derived, include saturated and un
CH3
saturated aliphatic acids and aromatic acids such as acetic,
propionic, butyric, isobutyric, tert.-butylacetic, valeric, iso
valeric, caproic, caprylic, decanoic, dodecanoic acrylic,
crotonic, hexynoic, heptynoic, octynoic, cyclobutanecar
boxylic, cyclopentanecarboxylic, cyclopentenecarboxylic,
cyelohexanecarboxylic, dimethylcyclohexanecarboxylic,
benzoic, toluic, naphthoic, ethylbenzoic, phenylacetic,
naphthaleneacetic, phenylvaleric, cinnamic, phenylpropio
lic, phenylpropionic, succinic, cyclopentylpropionic, a,a'
45
=0
O=/\
.X
0_
.X
»‘
-OH
I’
/\
50
r
.
O:
dimethylsuccinic, ,8,/i-dimethylglutaric acids, and the like.
The novel compounds of the invention having the For
mula I above possess valuable physiological activity. Il
lustratively, the novel compounds of the Formula I
possess glucocorticoid, mineralocorticoid and anti-in?am~
matory activity. The anti-in?ammatory activity of the
compounds of the invention is markely greater than that of
the corresponding known compounds which lack the 155
?uoro group. In addition, the compounds of the inven
tion possess the advantage that they exhibit much less
sodium-retaining activity than the corresponding com
pounds which lack the ISB-?uoro group‘. Accordingly,
the compounds having the Formula I above can be ad
ministered to mammals and birds, particularly to humans
and valuable domestic animals, for the treatment of vari
ous in?ammatory conditions of the skin, eyes, respiratory
CH3
=0
O:
2"
(II)
55
3'?
(III)
i
COzAlk
0 0mm
ta
60
°—
‘15H
°—
IX
[X
65 A/
°= 3/
\o
‘
Y
(v)
i!
av)
3,056,808
A,
above, A represents an alkylene radical containing from
2 to 6 carbon atoms, inclusive, wherein the attaching
CHzO R"
oxygen to carbon bonds are separated by a chain of at
least 2 and not more than 3 carbon atoms, and Alk is an
C HzOAc
H
:0
alkyl radical containing from 1 to 8 carbon atoms, inclu
sive, such as methyl, ethyl, propyl, butyl, amyl, hexyl,
heptyl, and octyl, and isomeric forms thereof.
The 21-deoxy-17-hydroxy compounds of the invention
having the Formula I wherein R=H and R’=hydroxy
or acyloxy can also be prepared from the corresponding
17a,2l-dihydroxy compounds according to the follow
ing Reaction Scheme B:
REACTION SCHEME B
CHzOH
15
CHzOR’”
=0
IW011
/
T451
2A1
L ,X
F
'
/
x’
F
/
———->
0_
25
0:
a
(VIIA)
a
1
l
0_
s’;
(XV)
i’
(IX)
CH3
011,012"
|é=0
""OH
I
Z/\
[(X
' -—-—-—F
30
.
(VIII)
if
=0
/\ ""OH
4|3=0
----OH
3
—F
if
ir
C H21
:0
CHZOAO
HO_/\
lI‘ [Br
(XVI)
1,
/\
, ix l1,
(fig
(XVIIl)
Y
(XVII)
In the above formulae, X, Y, and Z have the signi?cance
hereinbefore de?ned and R’” represents an aryl or alkyl
sulfonyl radical, preferably that of a ‘hydrocarbon sul
(X)
fonic acid containing from one to twelve carbon atoms,
(llHzOAc
inclusive, for example, methanesulfonic acid, ethanesul
fonic acid, benzenesulfonic acid, p-toluenesulfonic acid
CHzOAc
and the like.
o=o
The process of the invention shown diagrammatically
in Reaction Scheme A is carried out in the following man
ner:
A 15u-hydroXy-1l-ketoprogesterone having the Formula
II is subjected to ?uorination by treatment with a ?uori
nating agent having the formula:
55
wherein R1 and R2 taken individually represent lower alkyl
and R1 and R2 taken together with the attached nitrogen
atom rep-resent the residue of a heterocyclic radical con
taining from 5 to 7 ring atoms, inclusive, X1 is selected
from the class consisting of chlorine and fluorine, and
X2 is selected from the class consisting of chlorine, ?uo
rine, and tri?uo-romethyl in an inert organic solvent,
and advantageously in the presence of an acid catalyst,
whereby replacement of the lS-hydroxy by ?uorine takes
place accompanied by inversion to yield the corresponding
15 ?-?uoro-l l-ketoprogesterone (HI) .
The term “lower-alkyl” employed above in de?ning the
In the above formulae X and Y have the signi?cance
hereinbefore de?ned, Ac represents the acyl radical of an
organic carboxylic acid, preferably a hydrocarbon car
boxylic acid containing from 1 to 12 carbon atoms, in
clusive, R” is selected from the class consisting of hy
?uorinating agent means an alkyl radical containing from
1 to 8 carbon atoms, inclusive, such as methyl, ethyl,
propyl, butyl, amyl, hexyl, heptyl, octyl and isomeric
forms thereof.
The term “heterocyclic radical containing from 5 to
7 ring atoms, inclusive” is inclusive of pyrrolidino, 2
drogen and Ac,‘ wherein Ac has the signi?cance de?ned 75 methyl - pyrrolidino, 2,2 - dimethylpyrrolidino, and like
3,056,808 '
5
alkylpyrrolidino groups, 4-methylpiperazino, 2,4-dimethyl
piperazino and like 4-alkylpiperazino groups, morpholino,
piperidino, Z-methylpiperidino, 3-methylpiperidino, and
like alkylpiperidino groups, hexarnethyleneimino, homo
morpholino, and the like.
Examples, of ?uorinating agents which can be used in
the above process are N-(2-chloro-1,l,2-tri?uoroethyl)di
5
excess of the stoichiometric quantity based on the steroid
(II). Preferably the ?uorinating agent is present in an
excess of the order of about 1.1 to 10 moles per mole of
starting steroid (II).
The desired lS?-?uoro-ll-oxoprogesterone (III) so
produced can be isolated from the reaction mixture and
puri?ed by conventional procedures, for example, by
ethylamine, N-(1,1,2,2-tetra?uoroethyl)diethylamine, N
(2-chloro-1,1,2-tri?uoroethyl)dimethylamine, N- (2-chlo
solvent extraction of the reaction product followed by
?uoroethyl)dioctylamine, N-(Z-chloro - 1,1,2 - tri?uoro
can be converted to the corresponding llB-hydroxy com
pounds using procedures known in the art. vFor exam
ple, the ll-oxo compounds are converted to the corre
removal of the solvent and recrystallization and/or
ro-l , 1 ,Z-tri?uoroethyl) dipropylamine, N-(2-chloro-l,1,2 10 chromatography of the resulting product.
The 15,8-?uoro-1l-oxoprogesterone (III) so obtained
tri?uoroethyl)diisobutylamine, N-(2 - chloro-l,1,2 - tri
ethyl)-methylethylamine, N-(1,l,2,2 - tetra?uoroethyl)di
isopropylamine, N-(12,2-dichloro-1,1-di?uoroethyl)dieth
ylamine, N-(1,1,2,3,3,3 - hexa?uoropropyl)diethylamine,
and the like. The preferred ?uorinating agent for use
in the above ?uorination process is N-(2-chloro-l,1,2-tri
?uoroethyl) diethylamine.
sponding 3,20-bisketal derivatives, for example by re
action with an alkylene glycol such as ethylene glycol,
the 11-oxo-3,20-bisketal so obtained is reduced using, for
example, lithium aluminum hydride to give the corre
The term “inert organic solvent” means any organic
solvent which does not react with the ?uorinating agent
sponding 11?-hydroxy-3,20-bisketal and the latter is then
hydrolyzed to give the desired 1518-?uoro-11p-hydroxy
and in which the steroid starting material is appreciably
progesterone.
soluble such as aromatic and aliphatic hydrocarbons,
halogenated hydrocarbons, esters, ketones, ethers and ter
tiary alcohols. Examples of such solvents are benzene,
toluene, chlorobenzene, pentanes, hexanes, cyclohexane,
ethyl acetate, butyl acetate, acetone, methyl ethyl ketone,
tetrahydrofuran, ethyl ether, t-butyl alcohol, t-amyl al
cohol, and the like. Advantageously, the inert organic
solvent employed in the above ?uorination process is a
The compound (III) or the IS?-?uoro-l l?-hydroxy
progesterones obtained as described above can then be
subjected to l7ot-hydroxylation by, for example, a micro
organism of the genus Tr-ichothecium using procedures
such as that described in U.S. Patent 2,925,366 to obtain
the desired 15,8-?uoro-1l-oxo-Nut-hydroxyprogesterones
and 15f3-?uoro-l1,8,17u-dihydroxyprogesterones.
The ISB-?uoro-ll-oxoprogesterone (III), the 15p
?uoro-1Iii-hydroxyprogesterones, the 15B-?uoro-11-oxo
halogenated aliphatic hydrocarbon such as methylene 3O
17a-hydroxyprogesterones, or the 15/3-?uor0-ll;8,17a-di
chloride, chloroform, carbon tetrachloride, ethylene di
chloride, ethylidene chloride, propylene chloride, tri
methylene chloride, and the like. The solvent which is
particularly preferred is methylene chloride.
Advantageously, but not necessarily, the process of the
invention is carried out in the presence of an acid cata
lyst. The acid catalysts which are employed for this
purpose are proton-forming acids such as the hydrogen
halides, phosphoric acid, sulfuric acid, and the like or
Lewis acids (see Fieser and Fieser, “Organic Chemistry,”
third edition, page 138, Reinhold, 1956) such as boron tri
?uoride, boron trichloride, aluminum tri?uoride, arsenic
tri?uoride, phosphorus penta?uoride, titanium tetra?uo
hydroxyprogesterones obtained as described above can
then be dehydrogenated using procedures known in the
art to obtain the corresponding Al-analogues. The l-de
hydrogenation can be effected microbiologically using a
l-dehydrogenation microorganism, for example, of the
genus Septomyxa using procedures such as that described
in U.S. Patent 2,897,218, or can be e?ected chemically,
for example, by treatment with selenium dioxide using
procedures such as that described by Meystre et al.,
I-Ielv. vChim. Acta, 39, 734 (1956), or that described in
British patent speci?cation No. 864,414.
In the next stage of the process of Reaction Scheme
A, the 15y6-?uoro-ll-oxoprogesterone (III) is converted
ride, and the like. The preferred acids are the hydrogen
halides, particularly hydrogen ?uoride. In the case of hy 45 to the Favorskii ester (IV) using conventional procedures.
For example, the compound (III) is reacted with more
drogen ?uoride, the acid can be added to the reaction mix
than 2 molar equivalents each of sodium methoxide and
ture or can be generated in situ, for example, by addition
an alkyl oxalate to produce the 2,21-digloxalate; the latter
of the requisite quantity of water or an aliphatic alcohol
is tribrominated with bromine followed by rearrangement
such as methanol, ethanol, and the like, to produce the
desired quantity of hydrogen ?uoride by reaction with 50 with sodium methoxide in methanol to produce the cor
responding 2-br0mo-3,1=l-dioxo - 155 - ?uoro - 4,17(20)
the ?uorinating agent as ‘follows:
[cis]-pregnadien-2l-oic acid alkyl ester; and removing the
bromine from the latter compound by treatment with re
ducing agents such as zinc and acetic acid, chromous
55 chloride, and the like, to produce the Favorskii ester
(IV). Alternatively the bromine can be removed by
treatment with sodium iodide in acetone followed by
wherein R1, R2, X1, X2 have the signi?cance hereinbefore
reaction with the aforementioned reducing agents or col
described and R3 represents hydrogen or lower-alkyl.
lidine. The procedure employed in the above series of
In general the acid catalyst is present in the reaction
mixture in catalytic quantities only, i.e. of the order of 60 reactions is advantageously that described in U.S. Patent
2,790,814. The Favorskii ester (IV) is then converted to
about 0.1 to about 25 percent of the starting hydroxy
steroid on a mole equivalent basis.
The ?uorination of the 15a-hydroxy-1l-oxoprogesterone
the corresponding 3-ketal (V) using, for example, the
procedure described in U.S. Patents 2,707,184 or 2,758,
993. Ethylene glycol is the preferred ketalizing agent but
(II) is carried out conveniently by bringing together the
steroid (II), the ?uorinating agent, and the acid catalyst 65 other glycols suitable for use include propylene-1,2-gly
col, 2,2-dimethylpropylene-1,3-glycol and like lower al
in the presence of the inert organic solvent. The re
kylene glycols.
action is preferably carried out at a temperature Within
The 3-ketal (V) so obtained is reduced to the 3-ketal
the range of about 0° C. up to the boiling point of the
of the corresponding 3-oxo~lSB-?uoro-A“:"QM-pregna
reaction mixture. The reaction time employed to com
plete the ?uorination varies according to the reaction 70 diene-llB,2l-di0l (VI). The reduction is effected using
conventional procedures, for example, by treatment with
temperature and is generally of the order of one to
lithium aluminum hydride in the presence of .an inert sol—
eighteen hours at temperatures of about 0° C. to about
vent such as ether, tetrahydrofuran, and the like using
25° C. Shorter reaction times can be employed at higher
procedures such as that described in U.S. Patent 2,695,
reaction temperatures.
Advantageously the ?uorinating agent is employed in 75 906.
3,056,808
7
8
Acylation of the 21-hydroxy group of the compound
(VI), for example, by reaction of the latter compound
biological or chemical means as hereinbefore described
with the appropriate acid halide or acid .anhydride in the
to yield the corresponding l-dehydro compounds (XIV).
presence of a tertiary base such as pyridine, followed by
deketalization for example, by hydrolysis with mineral
acid, of the ZI-acylate of (VI) so obtained and oxidative
biological processes any 211-acyl group present in the start
hydroxylation of the 3-oxo-lSB-?uoro-A‘L"QM-pregna
diene-llp’,21-diol Zl-acylate so obtained, yields the cor
responding IS?-?uoro-I1p’,17a,2l-trihydroxy-pregn-4-ene
can be subjected to l-dehydrogenation using either micro
Where the l-dehydrogenation is carried out by micro
ing materials will generally be eliminated during the re
action. The 21-free alcohols (XIV; R”=H) can be
acylated by reaction with‘the appropriate acid halide or
acid .anhydride using procedures described above to ob
3,20-dione 2l- acylate (VII). The oxidative hydroxyla 10 tain the corresponding 2l-acylates (XIV: R”=Ac).
tion is carried out by conventional procedures, for exam
The 21-deoxy-17a-hydroxy compounds of the invention
ple, by treatment with osmium tetroxide and an oxidizing
agent, for example, hydrogen peroxide or N-methylmor
pholine oxide peroxide using procedures such as that de
(1; R=H; R1=hydroxy or acyloxy) can also be prepared
using the sequence of reactions shown in Reaction Scheme
B as follows: The compounds (VII), (VIIA), (VIII),
scribed in US. Patents 2,769,823, 2,769,824, and 2,769, 15 (XII), (XIII), or (XIV), [represented generically as
825.
compound (XV) in Reaction Scheme B] are hydrolyzed,
The ZI-acylates (VII) can then be hydrolyzed to the
where necessary, to the corresponding free 2l-alcohols
corresponding free 21-alcohols, i.e. to the corresponding
and the latter are reacted with an organic sulfonyl halide
15/3 - ?uoro - 11?,17oc,2l trihydroxypregn-4-ene - 3,20
such as methanesulfonyl chloride, toluenesulfonyl chlo
dione by hydrolysis using conventional procedures, for 20 ride, toluenesulfonyl bromide, benzenesulfonyl chloride,
example, by treatment with a base such as sodium bi
carbonate in solution in a lower alkanol such as methanol.
The 2l-acylates (VII) can also be oxidized, for ex
naphthalenesulfonyl chloride, and the like, in the pres
ample, by treatment with oxidizing agents such as chro
The 21-sulfonate esters (XVI) so obtained are con
ence of a tertiary base such as pyridine, to obtain the
corresponding 21»sulfonate esters (XVI).
mic acid, sodium dichromate, and the like whereby the 25 verted to the corresponding 2l-iodo compounds (XVII)
ll?-hydroxy group is oxidized and the corresponding 11
by reaction with an alkali metal iodide, such as sodium
oxo compound (VIIA) is obtained.
iodide, potassium iodide, and the like, in the presence of
The latter com
pounds can be hydrolyzed to the corresponding free 21
a suitable solvent, for example an alkanone such as ace
hydroxy compounds using the procedure outlined above.
tone, methyl ethyl ketone, and the like.
The compounds (VII) or (VIIA) or the correspond 30
ing free 21-hydroxy compounds can, if desired, be sub
jected to l-dehydrogenation using either microbiological
or chemical means as described above, to yield the cor
The 21-iodo compounds (XVII) are reacted with a re
ducing agent such as hydrogen iodide in acetic acid, zinc
and acetic acid, chromous chloride, and the like, whereby
the corresponding 21-deoxy compounds (XVIII) are ob
tained. Where the group Z in the 21-deoxy compound
responding l-dehydro compounds (VIII). Where the 1
dehydrogenation is carried out using microbiological 35 (XVIII) represents hydroxyl, said compound can be con
means a 2l~acylate in the starting compound (VII) 0r
(VIIA) will generally be removed during the ‘dehydro
genation. The resulting free 21-hydroxy compound
(VIII; R”=H) can be .acylated, if desired, by reaction
verted to the corresponding 11~oxo compound by reac
tion with an oxidizing agent such as chromic acid, sodium
dichromate, N-bromoacetamide, N-bomosuccinimide, and
the like, using conditions hereinbefore described.
with the appropriate acid halide or acid anhydride using 40
The 2l-deoxy compounds (XVIII) can be converted to
the procedures described above.
the corresponding 17-acylates by reaction with the appro
The 15?-fluoro-115317092l~trihydroxy-pregn-4-ene-3,20
priate acid anhydride in the presence of an acid catalyst
such as p-toluenesulfonic acid or a basic catalyst such as
dione 21-acylates (VII) wherein the radical X represents
hydrogen can then be treated by conventional procedures,
calcium carbonate. The 15a-hydroxy-1l-oxoproges
terones (II) which are employed as starting materials
for example, those described in US. Patent 2,838,499,
for the introduction of a 9oc-?l10r0 group. Thus the com
in the process of the invention can be prepared from the
corresponding ll-oxoprogesterones by subjecting the lat
pounds (VII; X=H) can be subjected to 9,11-dehydra
tion using conventional procedures, for example, treat
ter to the action of a 15a-hydroxylating microorganism
such as Penicillium- urticae using the procedures set
ment with an N-haloamide such as N-bromoacetamide
followed by treatment with sulfur dioxide, to yield the 50 forth in the following preparations.
corresponding A961) compound (IX).
_
The following preparations and examples are illustra
tive of the process and products of the present invention,
The compound (IX) so obtained is then converted to
the corresponding 9a-halo-llp-hydroxy-compound (X)
by the addition of the appropriate hypohalous acid, i.e.
hypochlorous, hypoiodous acid, or hypobromous acid for
example by treatment with the appropriate N-haloaceta
mide or like N-haloamide. The 9zx-halo-ll?-hydroxy
compound (X) so obtained is converted to the corre
sponding 9;3,11;3-epoxy compound (XI) by reaction with
a mild base such as potassium acetate.
The epoxide (XI) is reacted with hydrogen ?uoride
or a hydrogen ?uoride releasing agent, to produce the cor
responding 9oc,15B-di?uoro-1 1B,17a,21-trihydroxypregn-4
but are not to be construed as limiting.
PREPARATION 1
15a-Hydr0xy-11 -Ox0pr0gester0ne
A medium was prepared of 10 g. of Cerelose (dextrose),
20 g. of corn steep liquor and 1 liter of water and ad
justed to a pH between 5.5 and 6. A 12 liter portion of
this sterilized medium was inoculated with spores of
Penicillium urticae ATCC 10120 and incubated for a
period of 24 hours at a temperature of 26° C. using a
rate of aeration and stirring such that the oxygen uptake
was 13 millimoles per hour per liter [estimated accord
ene-3,20-dione 21-acylate (XII). The latter compound
can be deacylated, if desired, using procedures herein 65 ing to the method of Cooper et al., Ind. Eng. Chem. 36,
before described for the hydrolysis of 21-acylates, to ob
504 ( 1944)]. To this medium containing a 24-hour
tain the corresponding free 21-hydroxy compounds.
growth of Penicillium‘ urticae was added 2 g. of 11-oxo
The 9a,15,6<di?u0ro-11,8,l7u,21-trihydroxypregn-4-ene
progesterone, dissolved in 100 ml. of acetone. The mix
3,20-dione-21-acylates (XII) can be oxidized using chro
ture so obtained was incubated for a further 24 hours
mic acid, sodium dichromate and like oxidizing agentsrto 70 under the same temperature and aeration conditions be
obtain the corresponding 9a,15?-di?uoro-17a,21-dihy
fore being harvested and clari?ed. The mycelium was
droxy-pregn-4-ene-3,1l20-dione 21-acy1ates (XIII). The
Washed twice with a roughly equal volume of acetone and
was then extracted twice with an equal volume of meth
free 21-hydroxy compounds using the procedures de
ylene chloride. The acetone and methylene chloride ex
scribed above. Both the compounds (X11 and XIII) 75 tracts were added to the beer ?ltrate and the combined
latter compounds can be hydrolyzed to the corresponding
3,056,808
9
10
The column was eluted with 4 l. of mixed hexanes (Skelly
extracts and beer ?ltrate were extracted successively with
solve B) containing 12.5% by volume of acetone. The
two one-half by volume portions of methylene chloride
and then with two one-fourth by volume portions of meth
?rst 4 l. of eluate was evaporated to dryness to yield 1.98
g. of pregna-4,14-diene-3,11,20-trione in the form of a
crystalline solid having a melting point of 193 to 196° C.
The next 3 l. of eluate was evaporated to give 1.59 g. of
a mixture containing 2 parts of l5?-?uoropregn-4-ene-3,
ylene chloride. The methylene chloride extracts were
combined and washed with aqueous sodium bicarbonate
solution and then with Water. The Washed extracts were
dried over anhydrous sodium sulfate and ?ltered. The
11,20-trione, 1 part of pregna-4,14-diene-3,11,20-trione,
?ltrate was evaporated to dryness and the residue was
and 1 part of the l5-chloro?uoroacetate of 15a-hydroxy
chromatographed on a column of magnesium silicate
(Florisil). The column was eluted with Skelysolve B 10 pregn-4-ene-3,11,20-trione. The column was then eluted
with Skellysolve B containing increased proportions of
containing increasing proportions of acetone and those
acetone up to 30% by volume. The next 4.5 l. of eluate
fractions which, on the basis of infrared analysis, were
was evaporated to obtain 2.28 g. of 15/3-?uoropregn-4
shown to contain the desired product were combined and
ene-3,11,20-trione in the form of a crystalline solid hav
evaporated to dryness. The residue was recrystallized
twice from a mixture of acetone and ether and then once 15 ing a melting point of 157 to 159° C. Later fractions of
eluate yielded a further 1.7 g. of impure lSB-?uoropregn
from a mixture of acetone and Skellysolve B. There was
4-ene-3,11,20-trione which was combined with the earlier
thus obtained 15a-hydroxy-1l-oxoprogesterone in the
impure fraction and rechromatographed under similar sol
form of a crystalline solid having a melting point of 227
vent conditions to obtain an additional 1.9 g. of product
to 229° C.; [1111320 +257° (ethanol).
PREPARATION 2
20
(total yield of l5?-?uoropregn-4-ene-3,11,20-trione=
42%). An analytical sample of 15?~?uoro—pregn-4-ene
15a-Hydr0xy ~6a-Methyl-1 1 -Ox0pr0gester0ne
3,11,20-trione having a melting point of 159 to 161° C.
Using the procedure described in Preparation 1, but re
was obtained by recrystallization from a mixture of ace
placing ll-oxoprogesterone by 6a-methyl-11-oxopro
tone and Skellysolve B. The ultraviolet spectrum of this
PREPARATION 3
15a-Hydr0xy ~6oc-Flu0r0-1 1 -Ox0progesterone
5.48. Found: C, 73.42; H, 7.64; F, 5.20.
Using the above procedure, but replacing ISa-hYdI‘OXY
compound (in ethanol) exhibited a maximum at 237.5
gesterone (US. 2,968,655), there is obtained 15a-hy 25 millimicrons (E=l4,300).
dr0xy-6ct-methyl-l l-oxoprogesterone.
Analysis.—Calcd. for C21H27O3'F: C, 72.80; H, 7.86; F,
Using the procedure described in Preparation 1, but
30 l1 _ oxoprogesterone by 15a-hydroxy-6u-methyl-1l-oxo
progesterone, 15a - hydroxy - 6a - ?uoro-ll-oxoproges
terone, 150a - hydroxy - 60¢,9u - di?uoro-ll-oxoproges
terone, 15a - hydroxy - 90c - ?uoro-ll-oxoprogesterone,
replacing ll-oxoprogesterone by 6m-?uoro-11-oxopro
gesterone (U.S. 2,838,501), there is obtained 15a-hy
droxy-6ot-?uoro-1 l-oxoprogesterone.
PREPARATION 4
15a-Hydroxy-6a,9a ~Di?u0r0-1 1 -Ox0 progesterone
Using the procedure described in Preparation 1, but
or 15a - hydroxy - 60c - methyl—9a-?uoro-1l-oxoproges
35 lterone, there are obtained 15,8 - ?uoro - 6a - methyl-11
oxoprogesterone, 611,155 - di?uoro-ll-oxoprogesterone,
6u,9u,155 - tri?uoro - 11 - oxoprogesterone, 9a,15B-di~
?uoro-ll-oxoprogesterone, and 60: - methyl - 90t,15[8-dl—
?uoro-l l-oxoprogesterone, respectively.
replacing ll-oxoprogesterone by 6a,9o¢-di?u0ro-ll-oxo
progesterone (US. 2,838,501), there is obtained l5oc-hy 40
EXAMPLE 2
droxy-6a,9a-di?uoro-1 l-oxoprogesterone.
PREPARATION 5
1 5 u-Hydroxy -9u-Flu0r0-1 1 -0x0progesterone
15,6~Flu*oro—1 1?-Hydroxypregn-4-iEne—3,20-Dione
A mixture of 1 g. of 156-?uoropregn-4-ene-3J1,20-tri
one, 0.06 g. of p-toluenesulfonic acid, 5 ml. of ethylene
Using the procedure described in Preparation 1, but 45 glycol, and 100 ml. of benzene is stirred and heated under
replacing 11 - oxoprogesterone by 9oc-?ll0I‘O-11-OXOPI‘O
re?ux.
gesterone [3‘. Fried et al., J. Am. Chem. Soc., 77, 1068
(1955)], there is obtained 15a-hydroxy-9w?uoro-11-oxo~
progesterone.
in a water trap. When the elimination of water is com
The water formed in the reaction is collected
plete, the reaction mixture is cooled, washed with aqueous
sodium bicarbonate solution, and then with water, and
PREPARATION 6
50 dried over anhydrous sodium sulfate. The dried solution
is ?ltered, the ?ltrate is evaporated to dryness, and the
15a-Hydr0xy-6a -Methyl-9a-Flu0r0-1 1 -Ox0progesterone
residue is recrystallized from ethyl acetate.
Using the procedure described in Preparation 1, but
A slurry of 1 g. of the 3,20-bisethylene ketal of 15,8
replacing ll-oxoprogesterone by 6a-rnethyl-9u-?uoro-1l
?uoropregn-4-ene-3,11,20-trione so obtained in 20 ml. of
oxoprogesterone (US. 2,968,655), there is obtained 150c 55 benzene is added to a slurry of 0.35 g. of lithium alumi
hydroxy-6a-methyl-9a-?uoro-1 l-oxoprogesterone.
EXAMPLE 1
15,8-Flu0r0pregn-4-Ene-3,1 1 ,2 0- Trione
A solution of 10 g. (0.029 mole) of 15a-hydroxy-11
oxoprogesterone in 300 ml. of methylene chloride was
cooled to 5° C. with exclusion of moisture and 9 ml.
(10.7 g.; 0.0564 mole) of N-(2-chloro-1,1,2-tri?uoro
ethyl) diethylamine was added. The resulting mixture
num hydride in 100 ml. of anhydrous ether at such a rate
as to cause gentle re?uxing. When the addition is com
plete, the reaction mixture is heated under re?ux to com
plete the reaction and is then cooled and hydrolyzed with
The organic layer is separated, washed with wa
60 Water.
ter, and dried over anhydrous sodium sulfate. The dried
solution is ?ltered, the ?ltrate is evaporated to dryness,
and the residue is recrystallized from ethyl acetate.
A mixture of 0.5 g. of the 3,20-bisethylene ketal of 15,8
was allowed to stand for 4.5 hours at 5° C. before ice 65 ?uoro - 11;? - hydroxypregn - 4-ene-3,20-dione so obtained,
water was added. The organic layer was separated,
20 ml. of acetone and 5 ml. of 3 N hydrochloric acid is
washed successively with water, aqueous sodium bicar
heated under re?ux for several hours before being diluted
with water. The solid which separates is isolated by ?l
hydrous magnesium sulfate. The dried solution was ?l
tration and dried. There is thus obtained 15,8-?uoro-11B
tered and the ?ltrate was distilled initially at atmospheric 70 hydroxypregn-4-ene-3,20-dione in the form of a crystal
pressure to remove solvent and ?nally at 90° C. under a
line solid.
bonate solution, and water before being dried over an
pressure of 1 mm. of mercury to remove residual N,N
diethylchloro?uoroacetamide. The oily distillation resi
Using the above procedure, but replacing 15,8-f1uoro
pregn - 4 - ene - 3,11,20-trione by 15,8-?uoro-6a-methyl
due was dissolved in methylene chloride and chromato
pregn - 4-ene-3,11,20-trione, 6a,15?-di?uoropregn-4-ene
graphed on a column of magnesium silicate (Florisil). 75 3,11,20 - trione, 6a,9u,15p-tri?uoropregn-4-ene-3,11,20
1 1.
1.2
trione, 9a,15?~di?uoropregn-4-ene-3,11,20-trione, or 9a,
of t-butyl alcohol at 60° C. was added 3.8 ml. (4.08 g.,
155 - di?uoro-6a-methylpregn-4-ene-3,11,20-trione, there
0.028 mole) of ethyl oxalate followed by 3.9 g. (0.0175
are obtained 15,8 - ?uoro - 11/3 - hydnoxy-6a-methylpregn
4 - ene _ 3,20-dione, 6orl5l3-di?uoro-l1?-hydroxypregn-4
ene - 3,20 - dione, 6a,9a,15t3 - tri?uoro-llB-hydroxy
mole) of 24.3% methanolic sodium methoxide. The re
sulting mixture was stirred for 45 minutes after the addi
tion was complete and was then cooled and neutralized
by the addition of 1 ml. of acetic acid and 0.85 g. of
sodium acetate in 25 ml. of methanol. The neutral mix
pregn - 4 - ene - 3,20-dione, 9a,15,8-di?uoro-1lB-hydroxy
pregn - 4 - ene - 3,20-dione, and 9u,l5?-di?uoro-11,B-hy
droxy-6u-methylpregn-4-ene,3,20-dione, respectively.
ture was cooled to 0° C. and a solution of 3.36 g. (0.021
mole) of bromine in 10 ml. of methanol at minus 30° C.
EXAMPLE 3
1 SB-Fluoropregna-l ,4 -D iene-3,1 1 ,ZO-Trione
A mixture of 0.5 g. of l5B-?uoropregn-4-ene-3,l1,20
trione, 50 m1. of t-butyl alcohol, 0.5 ml. ‘of acetic acid and
0.2 g. of selenium dioxide is heated under re?ux for 48
10 was added dropwise thereto over a period of 5 minutes.
To the mixture so obtained was added 8.55 g. (0.0385
mole) of a 24.3% methanolic solution of sodium meth
oxide over a short period keeping the temperature below
15° C. The resulting mixture was warmed to 25° C. and
hrs. At the end of this time an additional quantity of 0.2 15 stirred for 1 hour, after which 3 ml. of acetic acid and
g. of selenium dioxide is added and the heating is con
2.4 g. of zinc dust was added and the mixture was stirred
tinued for approximately 20 hrs. The resulting mixture
is then ?ltered and the ?ltrate is evaporated to dryness.
The residue is dissolved in ethyl acetate and the solution
for a further 30 minutes. The reaction mixture was then
?ltered through diatomaceous earth (Celite) and the ?l
trate was evaporated to a small volume. The residue was
so obtained is washed successively with cold aqueous 20 dissolved in methylene chloride and washed successively
sodium bicarbonate solution, aqueous ammonium poly
sul?de solution, aqueous ammonium hydroxide solution,
with water, aqueous sodium bicarbonate solution, and
water. The washed solution was evaporated to dryness
and the residue was dissolved in methylene chloride and
chromatographed on a column of magnesium silicate
(Florisil). The column was eluted with Skellysolve B
water, dilute hydrochloric acid, and water. The washed
solution is evaporated to dryness and the residue is dis
solved in methylene chloride and chromatographed on a
magnesium silicate (Florisil) column. The column is
containing 12.5% by volume of acetone and those frac
tions which were found by paper chromatographic anal
portions of acetone and those fractions which, on the basis
ysis to contain the desired material were combined and
of infrared analysis, are shown to contain the desired 15,8
evaporated to dryness. The residue (1.52 g.) was re
?uoropregna-l,4-diene-3,1l,20~trione are combined and 30 crystallized from a mixture of acetone and Skellysolve B.
evaporated to dryness. The residue is recrystallized from
There was thus obtained 0.58 g. of methyl 3,11-oxo-15p
aqueous acetone. There is thus obtained 15,8-?uoropreg
?uoro-4,17(20)-[cis]-pregnadiene-21-oate in the form of
a crystalline solid having a melting point of 220 to 222°
na-1,4-diene-3,l1,20-trione in the form of a crystalline
solid.
C. The ultra-violet spectrum of the compound (ethanol
eluted with methylene chloride containing increasing pro
Using the procedure described above, but replacing
35 solution)
15 B~?uoropregn-4-ene-3,1 1,20-trione by
15?-?uoro-6a-methyl-l l-oxoprogesterone,
exhibited a maximum at 231 millimicrons
ISB-?uoro-l lB-hydroxy-6ot-methylpregn-4-ene-3,20
(E=23,200). The infrared spectrum of the compound
(mineral oil mull) exhibited maxima at 1720, 1700, 1675,
1660, and 1620 reciprocal centimeters.
Analysis.—Calcd. for C22H27O4FI C, 70.56‘; H, 7.27; F,
5.07. Found: C, 70.15; H, 7.38; F, 5.09.
Using the above procedure, but replacing lS?-?uoro
pregn-4-ene-3,11,20-trione as starting material by
15 B-?uoro-6a-methyl-1 l-oxoprogesterone,
dione,
601,15 ,B-difluoro-l l B-hydroxypregn-4-ene-3,20Ldione,
6a,9a,15B-triflUOrO-1 1?-hydroxypregn-4-ene-3 ,20-dione,
6u-methyl—9<x,15,8-difluoro-l l-oxoprogesterone,
9a,l5,6-di?uoro-1 l-oxoprogesterone,
40
6a-methyl-9a, 15 B-di?uoro-l l-oxoprogesterone,
15/8-fluoro-1 l B-hydroxypregn-4-ene3,20-dione,
604,153-(11111101‘0-11-OXOPI‘Og6St?I‘OI16,
6a,90<,15?-’[r1?llOI‘O-1 l-oxoprogesterone, or
there are obtained
methyl 3,11-dioxo-15[3-?uoro-6u-methyl-4,17(20)
there are obtained
[cis] -pregnadiene-21-oate,
methyl 3,11-dioxo-6a,15?-di?uoro-4,17(20)-[cis]
15 B-?uoro-6a-methylpregna-1,4-diene-3,1 1,20-trione,
60¢,15 ?-di?uoropregna-1,4-diene-3,1 1,20-trione,
methyl 3,1l-dioxo-6ot,9a,15,6-tri?uoro-4,17(20)-[cis]
pregnadiene-Zl-oate,
9zx,l5,6-di?uoropregna-1,4-diene-3,l 1,20-trione,
9oz,15,8-di?uoro-6a-methylpregna-1,4-diene-3,l1,20
pregnadiene-Zl-oate,
methyl 3,1 l-dlOXO-9OL, 15 ,8-di?uoro-4,17 ( 20) - [cis] 55
[cis] -pregnadiene-21-oate,
ISB-?uoro-l 1?-hydroxypregna-1,4-diene-3,20>dione,
respectively.
15 B-?uoro-l 1 ,8-hydroxy-6a-methylpregna-1,4-diene
3,20-dione,
60:,15?-di?1101'0-1 lB-hydroxypregna-l ,4-diene-3,20'
dione,
60
3 ,ZO-Dione 21 Acetate
65
EXAMPLE 4
Methyl 3,11-Di0x0~15,B-Flu0r0-4,1 7(20) - [Cis] -
Pregnadien-ZI -Oate
To a stirred, nitrogen-purged solution of 2.42 g. (0.007
EXAMPLE 5
1516-Flu0r0-1 15,1 70¢,21~Trihydroxypregn-4-Ene
6a,9a,15,8-tri?uoro-1 1 ,B-hydroxypregna-1,4-diene-3 ,20
dione,
respectively.
pregnadiene-Zl-oate, and
methyl 3,11-dioxo-6u-methyl-9ot,15,B-difluoro-4,17(20)-’
trione,
A mixture of 2.59 g. of methyl 3,11-dioxo-155-fluoro
4,17(20)-[cis]-pregnadien-21-oate, 150 mg. of p-toluene
sulfonic acid monohydrate, and 5 ml. of ethylene glycol
in 120 ml. of benzene was heated under re?ux with stirring
and azeotropic distillation of water until no further water
was eliminated from the reaction mixture. The reaction
70 mixture was then cooled to about 40° C., 0.4 ml. of
pyridine was added and the mixture was cooled to room
temperature. The benzene layer was separated, washed
with water and ‘dried over anhydrous magnesium sulfate.
The dried solution was ?ltered and the ?ltrate was
mole) of l55-?uoropregn-4'ene-3J1,20-trione in 50 ml. 75 evaporated to dryness.
The residue was recrystallized
3,056,808
13
14
On drying under high vacuum at 115° C., there is ob
tained the anhydrous material.
from a mixture of ethyl acetate and Skellysolve B. There
was thus obtained the 3-ethylene ketal of methyl 3,11
Using the procedure described above, but replacing
dioxo-l5B-fluoro-4,17(20)-[cis]-pregnadien-Zl-oate in the
methyl 3, 1 1-dioxo-15?-?uoro-4, 17( 20) - [cis] ~pregnadien
form of a crystalline solid having a melting point of 203
to 205° C.
21-oate by methyl 3,11-dioxo-15/3-?uoro-6u-methyl-4,17
ture was ?ltered and the ?lter cake was washed with ethyl
acetate. The ?ltrate was evaporated to dryness under
pregn-4-ene-3,20-dione 21-acetate, 6a,15/3-di?uoro-11,B,
17a,21-trihydroxypregn-4-ene-3,20-dione 21-acetate, 6a,
(20)-[cis]-pregnadien-21~oate, methyl 3,l1-diOXO-6o¢,15?~
A solution of 3 g. of the above 3-ethylene ketal in 30
di?uoro-4,17(20)-[cis]-pregnadien-21-oate, methyl 3,11
ml. of benzene was added to a mixture of 1 g. of lithium
dioxo - 6a,90c,15? - trifluoro-4,17( 20)-[cis1-pregnadien-21
aluminum hydride and 75 ml. of ether which had pre
oate, methyl 3,11-dioxo-9a,15?-difluoro-4,17(20)-[cis]
viously been stirred for 2 hr. at room temperature. The
resulting mixture was stirred for 1 hr. at room tempera 10 pregnadien-Zl-oate, or methyl 3,11-dioxo-6a-methyl-9a,
15B-di?uoro-4,17(20)-[cis] -pregnadiene-21-oate, there are
ture before the excess hydride was decomposed by the
obtained 15 ,8 - ?uoro-6ot-methyl - 11/3,17a,21 - trihydroxy
addition of- ethyl acetate and water. The reaction mix
reduced pressure. The residue (ll-ethylene ketal of 115, 15
9a,15/3-tri?uoro - 11,8,17a,21 - trihydroxypregn-4-ene-3,20
21 - dihydroxy - 15,6‘ - ?uoro-4,17(20)-[cis]-pregnadien-3
dione 21-acetate, > 9a,15/3-di?uoro-11?,17o¢,21-trihydroxy
pregn-4-ene-3,20-dione 21-acetate, and 6a—methyl-9ot,15/8
difluoro-l1,8,17u,21-trihydroxypregn-4-ene-3,20-dione 21~
acetate, respectively.
one) was dissolved in 4 ml. of pyridine and 8 ml. of
acetic anhydride and was allowed to stand at room tem
perature for 18 hr. The resulting mixture was decom
posed by pouring onto ice and water and the solid which
separated was isolated by ?ltration and washed with water.
EXAMPLE 6
IS?-Fluoro-l 1 5,1 704,21-Trihydr0xypregn-4-Ene
3,20-Di0ne
The washed solid (3-ethylene ketal of 11,8,21-dihy
droxy - 15B - ?uoro - 4,17(20)-[cis]-pregnadien-El-one 21
A mixture of 1 g. of ISB-?uoro-l1B,17a,21-trihydroxy
acetate) was dissolved in a mixture of 100 m1. of acetone
and 10 ml. of 5% sulfuric acid and allowed to stand for 25 pregn-4-ene-3,20-dione 21-acetate, 1 g. of potassium bi
20 hrs. at room temperature before adding 40 m1. of 4%
carbonate, 100 ml. of methanol and 15 ml. of Water is
purged with nitrogen and maintained at room tempera
sodium bicarbonate solution and evaporating the resulting
ture for several hours with stirring. The solution so ob
mixture to a small volume. The residue was extracted
The methylene chloride ex
tained is neutralized ‘by the addition of acetic acid and
tract was washed with aqueous sodium bicarbonate solu
30 then distilled under reduced pressure to remove the
with methylene chloride.
tion and water before being evaporated to dryness. The
methanol. The residue is extracted with methylene
chloride and the extract is dried over anhydrous sodium
residue was dissolved in methylene chloride and
chromatographed on a column of magnesium silicate
sulfate. The dried solution is ?ltered and the ?ltrate is
evaporated to dryness. There is thus obtained ISB-?uoro
(Florisil). The column was eluted with Skellysolve B
containing 12.5% by volume of acetone. Those fractions 35 11B,1711,21-trihydroxypregn-4-ene-3,20-dione.
Using the above procedure 15?-?uoro-6oc-methyl-115,
of the eluate which were found by paper chromatographic
analysis to contain the desired product were combined
17a,21-trihydroxypregn-4-ene-3,20-dione, 6a,15[3-di?uoro—
and evaporated to dryness. There was thus obtained
115,170:,21-trihydroxypregn-4-ene-3,20-dione, 6a,9oc,l5}3
l15,21~dihydroxy-l5B-?uoro-4,17(20) - [cis] - pregnadi
tri?uoro - 11B,17oz,21 - trihydroxypregn-4-ene-3,20 - dione,
40 9u,15,6-di?uoro - 11B,l70c,21 - trihydroxypregn-4-ene-3,20
en-3-one 2l-acetate in the form of a crystalline solid.
dione, and 6a-methyl-9a,ISB-di?uoro-11(3,17u,21-trihy
A mixture of 1.93 g. of the latter compound, 106 ml.
droxypregn-4-ene-3,20-dione were obtained by hydrolysis
of t-butyl alcohol, 0.6 ml. of pyridine, 12 mg. of osmium
tetroxide and 6 ml. (2.75 mol. eq.) of N-methylmor
of the corresponding 21-acetates.
pholine oxide hydroperoxide in t-butanol was allowed to
stand at room temperature under a nitrogen atmosphere 45
for 21 hr.
To the resulting mixture was then added a
EXAMPLE 7
1 5?-Fluoro-l 1 [1,] 704,21 -Trihydr0xypregn-4-Ene
solution of 0.25 g. of sodium hydrosul?te in 50 ml. of
'
3,20-Dione 21 -Pr0pi0nate
water and the mixture was stirred for 30 minutes before
A
solution
of
1 g. of 15,8-?uoro-11,8,17a,21-trihydroxy
being evaporated to a small volume. The residue was
extracted with ethyl acetate and the extract was washed 50 pregn-4-ene-3,20-dione in 10 ml. of pyridine and 10 ml.
of propionic anhydride is allowed to stand for several
hours
at room temperature before being poured into
tion, and water. The washed extract was dried over an
water. The solid which separates is isolated by ?ltration,
hydrous magnesium sulfate and ?ltered. The ?ltrate was
washed with water and recrystallized from aqueous
evaporated to dryness and the residue was dissolved in
methylene chloride and chromatographed on a column of 55 methanol. There is thus obtained 15?-?uoro-11/8,17u,21
trihydroxypregn-4-ene-3,20-dione 21-propionate in the
magnesium silicate (Florisil). The column was eluted
form of a crystalline solid.
with Skellysolve B containing increasing portions of ace
In like manner, but replacing propionic anhydride by
tone and those fractions which were found by paper
successively with Water, aqueous sodium bicarbonate solu
chromatographic analysis to contain the desired product
the appropriate hydrocarbon carboxylic acid anhydride,
was recrystallized from aqueous methanol.
There was
?uoro - 1118,17a,21-trihydroxypregn-4-ene-3,20-dione such
thus obtained 0.63 g. of 15B-?uoro-11?,17a,21-trihydroxy
pregn-4-ene-3,20-dione 21-acetate in the form of a crystal
line solid having a melting point-of 206 to 208° C. with
cycl-opentylpropionate, 21-hemisuccinate, 21-glutarate, 21
?ue-dimethylglutarate, 21-benzoate, 21-phenylacetate, and
were combined and evaporated to dryness. The residue 60 or acid halide, there are prepared other 21-esters of 15,5‘
decomposition.
as the 21-trimethylacetate, 21-butyrate, 21-hexanoate, 21,8
65 the like.
In like manner by reacting any of the compounds named
An analytical sample having a melting point of 210 to
211° C., with decomposition, was obtained by further
in the paragraph following Example 6 with the appropri
recrystallization from aqueous methanol. The ultra
violet spectrum of this compound (ethanol solution) ex
corresponding 21~acylate.
hibited a maximum at 241 millimicrons.
The infrared 70
spectrum of this compound (mineral oil mull) exhibited
maxima at 3580, 3360, 1730, 1715, 1662, 1630, 1620
(sh.), 1595, 1265, and 1245 reciprocal centimeters.
Analysis.—Calcd. for C23H31FO6.%H2O: C, 64.96; H
75
7.44; F, 4.45. Found: C, 64.54; H, 7.68; F, 4.41.
ate acid anhydride or acid halide there is obtained the
EXAMPLE 8
15B-Flu0ro-1 70¢,21-Dihydr0xypregn-4-Ene
3,11,20-Tri0ne ZJ-Acetate
A solution containing 0.1 g. of 15?-?uoro-11p,17a,21
3,056,808
15
l6
trihydroxypregn-4-ene-3,20-di0ne 2l-acetate, 1 ml. of ace
tic acid, 20 mg. of chromic anhydride and 1 drop of water
21-acetate, 6oz - methyl - 90¢,155 - di?uoro - 11B,17a,21
trihy-droxy - 1,4 - pregnadiene - 3,210 - dione 2l-acetate,
and 6a - methyl - 904,155 - di?uoro - 17a,21 - dihydroxy
is shaken and allowed to stand for several hours at room
temperature. Thereafter the solution is poured into water
and the solid which separates is isolated by ?ltration,
Washed with Water, and dried. There is thus obtained
ly. The aforementioned compounds can be converted to
155 - ?uoro - 17a,21-dihydroxypregn-4-ene-3,l1,20-trione
procedure described in Example 6. The free 2l-alcohols
1,4 - pregnadiene - 3,11,20 - tr-ione 2l-acetate, respective
the corresponding free 2l-hydroxy compounds using the
21-acetate.
so obtained can be converted to the corresponding 21
Using the above procedure, but replacing 155-?uoro
115,17u,21 - trihydroxypregn - 4 - ene - 3,20 - dione 21
acetate by l55-?uoro-6a-methyl-1l5,17a,2l-trihydroxy
acylates by reaction with the appropriate acid anhydride
10 or acid halide using the procedure described in Example 7.
EXAMPLE 10
pregn - 4 - ene - 3,20 - dione 21 -acetate, 6a,155 - di?uoro
115,17u,21
- trihydroxypregn - 4 - ene - 3,20 - dione,
21 - acetate, 60:,9a155 - tri?uoro - 11/3,17cc,21 - tri
hydroxypregn - 4 - ene - 3,20 - dione 21 - acetate, 90¢,l55
155-Flubro-1 7a,21-Dihya‘r0xy-95,1 15-0xid0pregn
15
di?uoro-115,l7ot,21 - trihydroxypregn - 4 - ene - 3,20
4-Ene-3,2 O-Dione 21 -Acetate
To a solution of 0.7 g. of 155-?uoro-115,17u,21-trihy
dione v2l-acetate, or 6u-methyl-9a,l55-di?uoro-115,17u,
droxypregn - 4 - ene - 3,20 - dione ZI-acetate in 15 ml.
21 - tr-ihydroxypregn - 4 - ene - 3,20 - dione 2l-acetate,
of pyridine was added 0.38 g. of N-bromoacetamide.
The mixture was stirred under an atmosphere of nitrogen
20 for 20 minutes at 25° C. and then cooled to 10° C. Sul
there are obtained 155 - ?uoro - 60c - methyl - 170:,21
dihydroxypregn - 4 - ene - 3,11,20 - trione 21 - acetate,
fur dioxide was passed over the surface of the cooled
solution for 15 minutes after which the reaction mixture
was diluted with ice water. The solid which separated
Was isolated by ?ltration, washed with Water and dried.
60c, 155 - di?uoro - 17oc,2l - dihydroxypregn - 4 - ene - 3,
11,20 - trione 21 - acetate, 6ot,9u,155 - tri?uoro - 17a,21
.dihydroxypregn - 4 - ene - 3,11,20 - trione ZI-acetate, 9a,
155 - di?uoro - 1704,21-dlhYClI'OXYPI‘BgH - 4 - ene - 3,11,20
trione 21 - acetate, and 6ot-methyl-9a,l55-di?uoro-l7ec,21
25
dihydroxypregn - 4 - ene - 3,11,20 - trione .21-a-cetate, re—
spectively.
was dissolved in a mixture of 10 ml. of methylene chlo
ride and 18 ml. of t-butyl alcohol. To this solution was
added 0.16 ml. of 70% perchloric acid in 1.25 ml. of
water, and 0.25 ‘g. of N-bromoacetamide in 2.5 ml. of t
butyl alcohol. The mixture was stirred for 15 minutes
at 25 to 30° C. and 0.25 g. of sodium white in 2.5 ml.
The 21-acetates obtained as described above can be
converted to the corresponding free 21-hydroxy com~
pounds using the procedure described in Example 6. The
free 21-hydroxy compounds can be converted to other
2l-acylates by reaction with the appropriate acid anhy
dride or acid halide using the procedure described in
Example 7.
EXAMPLE 9
The 155 - ?uoro - 170:,21 - dihydroxy - 4,9(11) - preg
nadiene - 3,20 - dione 21-acetate (0.53 g.) so obtained
of water was added. The resulting solution was con
centrated under reduced pressure and the residue was
35 diluted with ice water. The solid which separated was
isolated by ?ltration, washed with water and dried.
155-Flu0r0-115J 70;,21-Trihydr0xy-1,4-Pregnadiene
The 904 - tbromo - 155 - ?uoro - 115,17a,21 - trihy
3,20-Dione 21 Acetate
droxypregn - 4 - ene - 3,20 - dione 21-acetate (0.55 g.)
so obtained was dissolved in 15 ml. of acetone and heated
Using the procedure described in Example 3, but re
under re?ux with 0.6 -g. of potassium acetate for 24 hrs.
The resulting mixture was evaporated to dryness and the
placing 155 - ?uoropregn - 4 - ene - 3,11,20 -trione by
155 - ?uoro - 115,17a,2l -trihydroxypregn - 4 - ene - 3,20~
residue was shaken with a mixture of water and methylene
dione 21-acetate, there is obtained 155 - ?uoro - 115,17oc,
chloride. The methylene chloride layer was separated,
washed with water, and dried over anhydrous magnesium
21 - trihydroxy - 1,4 -
pregnadiene - 3,20 - dione 21
acetate.
sulfate. The dried solution was ?ltered and the ?ltrate
was evaporated to dryness. The residue (0.486 g.) Was
dissolved in methylene chloride and chromatographed on
a column of magnesium silicate (Florisil). The column
Similarly, using the procedure described in Example
3 but replacing 155 - ?uoropregn - 4 - ene - 3,11,20 - tri
one by 155 - ?uoro - 17oc,2l - dihydroxypregn - 4 - ene
was eluted with Skellysolve B containing 12.5% by
3,11,20 - trione 2l-acetate, 155 - ?uoro - 6a -methy-l ~ 11b,
17a,21 - trihydroxypregn - 4 - ene - 3,20 - dione 21-ace
50 volume of acetone and those fractions which, on the basis
of paper chromatographic analysis, were shown to con
tain the desired product, were combined and evaporated
to dryness. There Was thus obtained 0.359 g. of 155
tate, 155 - ?uoro - 60¢ - methyl - 1711,21 - dihydroxypregn
4 - ene - 3,11,20‘ - trione 21-acetate, 60:,155 - di?uoro - 115,
1711,21 - trihydroxypregn - 4 - ene - 3,20 - dione 21-ace
tate, 60:,155 - di?uoro - 17oc,21 - dihydroxypregn - 4 - ene
3,1l,20 - trione 21-acetate, 6a,9a,155 - tri?uoro - 115,17a,
fiuoro - 1711,21 - dihydroxy - 95,115 - oxidopregn - 4 - ene
55 3,20 - dione 21-acetate in the form of a crystalline solid
having am-elting point of 205 to 207° C.
21 - trihydroxypregn - 4 - ene - 3,20 - dione 21-acetate,
>
Using the above procedure, but replacing l55-?uoro
6a,9a,155 - tri?uoro - 170;,21 - dihydroxypregn - 4 - ene
3,11,20 - trione 21-acetate, 90:,155 - di?uoro - 1711,21
ll5,l7a,21 - trihydroxypregn - 4 - ene - 3,20 - dione 2l
dihydroxy-pregn - 4 - ene - 3,11,210 - trione 2l-acetate, 6a
methyl - 90¢,155 - di?uoro - 115,17u,21 - trihydroxypregn
4 - ene - 3,20 - dione 21-acetate‘, or 61 - methyl - 9a,155
acetate by the 2l-acetates or other 21-acylates of 155
60
?uoro - 6oz - methyl - 115,17a,21 - trihydroxypregn - 4~
ene - 3,20 - dione or 6a,155 - di?uoro - l15,17a,21 - tri
di?uoro - 17oz,21 - dihydroxypregn - 4 - ene - 3,11,20
hydroxypregn - 4 - ene - 3,20 - dione, there are obtained
trione ZI-acetate there are obtained 155 - ?uoro - 170:,21
the corresponding 2l-acylates of 155 - ?uoro - 6a - meth
dihydroxy - 1,4 - pregnadiene - 3,11,20 - trione 2l-acetate,
155 - ?uoro - 6a - methyl - 1l5,l7u,21 - trihydroxy - 1,4
yl - 1711,21 - dihydroxy - 95,115 - oxidopregn - 4 - ene
65 3,20 - dione, and 609,155 - di?uoro - 17a,2l - dihydroxy
pregnadiene - 3,20 - dione 21-acetate, 155 - ?uoro - 6a
methyl - 170:,21 - dihydroxy - 1,4 - pregnadiene - 3,11,20
95,l15 - oxidopregn - 4 - ene - 3,20‘ - dione, respectively.
trione 21-acetate, 6a,155 - di?uoro - 11,6,170L,21 - trihy
droxy - 1,4 - pregnadiene - 3,20 - dione 2l-acetate, 60¢,155
EXAMPLE 11
di?uoro - 17oc,21 - dihydroxy - 1,4 - pregnadiene - 3,11,20
trione 21-acetate, 60c, 9a,155 - tri?uoro - 115,l7<x,21 - tri
hydroxy - 1,4 - pregnadiene - 3,20 - dione 21-acetate, 6oz,
9a,155 - tri?uoro - 170:,21 - dihydroxy - 1,4 - pregna
diene - 3,11,20 - trione 21 - acetate, 911,155 - di?uoro
17OL,Z1 - dihydroxy - 1,4 - pregnadiene - 3,11,20 - trione
70
A solution of 0.35 g. of 155-?uoro-17a,2l-dihydroxy
95,115—oxipregn-4-ene-3,20-dione 21-acetate in 3.5 m1. of
methylene chloride was cooled to ——70° C. and added to
75 a mixture of 3 g. of anhydrous hydrogen ?uoride and
3,056,808
17
537ml. of tetrahydrofuran at —-20° C. The mixture was
allowed to stand for 16 hours at -20° C. and then for 4
hrs. at +5° C. before being poured into a stirred ice-cold
solution of 21.6 g. of sodium bicarbonate in 100 ml. of
water. The resulting mixture was extracted with ethyl
acetate and the organic extract was washed with water,
Using the procedure described in Example 7, but re
placing 155 - ?uoro - 1l5,17u,21-trihydroxypregn-4-ene 3,
20-dione by 9a,155-di?uoro-115,17a,21-trihydroxy-1,4
dried over anhydrous magnesium sulfate, and ?ltered. The
pregnadiene-3,20-dione, there is obtained 9a,l55-di?uo'ro
?ltrate was evaporated to dryness and the residue was re
crystallized twice from a mixture of acetone and Skelly
solve B. There was thus obtained 110 mg. of 90¢,155-di 10
?uoro - 11,3,l7oc,21 - trihyroxypregn-4-ene-3,20-dione
21
acetate in the form of a crystalline solid having a melting
point of 213 to 214° C., with decomposition. The ultra—
violet spectrum of this compound (in ethanol solution) ex
15
hibitedra maximum at 238 millimicrons.
Analysis.——-Calcd. for C23H30F2O6: C. 62,71; H, 6.87;
F, 8.63. Found: C, 63.02; H, 6.85; F, 8.12.
Using the above procedure, but replacing 155-?uoro
17a,2l-dihydroxy-95,115-oxidopregn-4-ene-3,ZO-dione 21
115,l7a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-pro
pionate.
Similarly, by reacting 9a,155-di?uoro-115,17a,21-tri
hydroxy-l,4-pregnadiene-3,20-dione with the appropriate
acid anhydride or acid halide in the presence of pyridine
there are obtained the corresponding 2l-acylate's such as
the 21-benzoate, 21-isobutyrate, 2l-valerate, 21-hexano
ate, 21-trimethylacetate, 21-5-cyclopentylpropionate, 21
hemisuccinate, 21-glutarate, and the like.
EXAMPLE 15
acetate by the 21-acetates or other 21-acylates of 155 20 9a,15,B-Dl'?u0r0-1 15,1 7 04,21 -Trihydroxy-1,4-Pregnadiene
3 ,2 0-D ione 21 -Methanesulfonate
?uoro - 6a - methyl-171131-dihydroxy-95,115-oxidopregn
4-ene-3,20-dione or 6a,155-di?uoro-l7a,2l-dihydroxy-95,
A solution of 1 g. of 9a,155-di?uoro-115,17a,21~trihy
115-oxidopregn-4-ene-3,20-dione, there are obtained the
droxy-l,4-pregnadiene-3,20-dione in 7 ml. of pyridine is
corresponding 21-acylates of 9a,155-di?uoro-6a-methyl
cooled to 0° C. and treated with 0.3 ml. of methanesul
115,17a,21-trihydroxypregn-4-ene-3,20-dione and 60:,911, 25 fonyl chloride. ‘The resulting mixture is allowed to stand
155-tri?uoro-115,17a,21-trihydroxypregn-4-ene - 3,20-di
at 0° C. to 5° C. for several hours and is then diluted
one, respectively.
with water and extracted three times with methylene
EXAMPLE 12
chloride. The methylene chloride extracts are combined,
washed with an excess of dilute hydrochloric acid, then
30 with aqueous sodium bicarbonate solution, and ?nally
3,20-Di0ne 21-Acetate
with water. The washed solution is dried over anhydrous
A mixture of 300 mg. of 9a,155-di?uoro-115,17u,21-tri
sodium sulfate and ?ltered. The ?ltrate is evaporated to
hydroxypregn-4-ene-3,20-dione 2l-acetate, 40 ml. of t
dryness. There is thus obtained the 2l-methanesulfonate
butyl alcohol, 0.4 ml. of acetic acid, and 150 mg. of
of 90¢,155 - di?uoro - 115,17 11,21-trihydroxy-1,4-pregnadi
selenium dioxide was heated under re?ux for 44 hrs. An 35
ene-3,20-dione.
additional 150 mg. of selenium dioxide was then added
Using the above procedure, but replacing 9a,155-diflu
and the mixture was heated for an additional 19 hrs.
oro-l
15,17oc,21-trihydroxy-1,4-pregnadiene-3,20-dione by
The mixture was ?ltered and the ?ltrate was evaporated to
9a,155-di?uoro-115,17u,21-trihydroxypregn-4-ene-3-20~
dryness. The residue was dissolved in ethyl acetate and
the solution so obtained was washed successively with 40
dione,
155-?u0ro-115,17a,21-trihydroxypregn-4-ene-3,20-dione,
cold aqueous sodium bicarbonate solution, aqueous am
9oz,155-Di?uor0-115,1 7a,21-Trihydr0xy-1,4-Pregnadie‘ne
155-?uoro-1 15,17a,21-trihydroxy-1,4-pregnadiene-3 ,20
monium polysul?de solution, dilute ammonium hydroxide
solution, water, dilute hydrochloric acid, and water. The
dione,
Washed solution was dried over anhydrous magnesium sul
fate and ?ltered. The ?ltrate was evaporated to dryness 45
and the residue was dissolved in methylene chloride con
taining 5 by volume of acetone and chromatographed on a
column of 100 g. of magnesium silicate (Florisil). The
column was eluted with 1.5 l. of methylene chloride con
155-?uoro-6u-methyl-115,17a,21-trihydroxy-1,4
pregnadiene-3,20-dione,
60:,155-(11111101'0-1 15,17¢,21-trihydroxypregn-4-ene-3 ,20
dione,
6a,l55-di?uoro-115,17a,21-trihydroxy-1,4
taining 7.5% by volume of acetone followed by 750 ml.
of methylene chloride containing 12.5% of acetone. The
eluate obtained was evaporated to dryness and the residue
pregnadiene-3,20-dione,
60¢,9oc, 1 55-tri?uoro-115,17a,21-trihydroxypregn-4-ene
3,20-dione,
(200 mg. was recrystallized twice from a mixture of ace
tone and Skellysolve B. There was thus obtained 60 mg.
ene-3,20-dione 21 acetate in the form of a crystalline solid
6u,9a,155-tri?uoro-115,17a,21-trihydroxy-1,4
pregnadiene-3 ,20-dione,
6a-methyl-9u,155-di?uoro-115,17a,21-trihydroxypregn
having a melting point of 232 to 233° C., with decomposi
tion. The ultraviolet spectrum of the compound (in
6a-methyl-9ot,155-difluoro-115,17a,21-trihydroxy-1,4
of 90;,155 - di?uoro - 115,17a,2l-trihydroxy-1,4-pregnadi
ethanol solution) exhibited a maximum at 238 milli
microns (e=16,000). The infrared spectrum of the com
pound (mineral oil mull) exhibited maxima at 3560,
3470, 3330, 1750, 1740, 1710, 1665, 1625, 1608, 1230,
and 1215 reciprocal centimeters.
_
_
55
4-ene-3,20-dione, or
pregnadiene-3 ,ZO-dione
60 there are produced the 21-methanesulfonates of these
compounds.
EXAMPLE 16
_
Analysis.—Calcd. for C23H28F2O5: C, 63.00; H, 6.44;
F, 8.67. Found: C, 63.26; H, 6.24; F, 8.62.
EXAMPLE 13
65
To a solution of 1 g. of ‘90:,155-di?1101’0-11B,17oz,21
9u,155-Di?uoro-115,1701,21-Irihydroxy-1,4-Pregnadiene
trihydroxy-1,4-pregnadiene-3,20-dione 21-methanesulfo
3,20-Di0ne
nate in 15 ml. of acetone is added a solution of 1 g. Of
Using the procedure described in Example 6, but re 70 sodium' iodide in 10 ml, of acetone. The mixture so
placing
155 - ?uoro - 115,17a,21 - trihydroxypregn-4-ene
3,20-dione 21-acetate by 9u,155-di?uoro-115,17a,21-tri
hydroxy-1,4-pregnadiene-3,20-dione 21-acetate, there is
obtained is heated under re?ux for a short period and
is then concentrated under reduced pressure to about one
third volume. Ice water is added to the concentrate and
the solid which separates is isolated by ?ltration, washed
obtained 9u,155-di?uoro-l15,-17m,2letrihydroxy-lA-preg
with water ‘and dried. There is thus obtained ‘90:,155
75
nadiene-3,20-dione.
3,056,808
2t)
"1%
Using‘the above procedure, but‘ using as starting
material
di?uoro —'11[3,17cc - dihydroxy - 21 - iodo-1,4-pregnadiene
3,20-dione.
.
Using the above procedure, but using as starting
materials the ZI-methanesulfonates of
9a,155-di?u0ro-1 15,17a-dihydroxy-21-iodopregn-4-ene
'
3 ,ZO-dione,
9a,155-di?uoro-115,17a,2l-trihydroXypregn-4-ene-3 ,20
dione,
155-?uoro—115,1701,21-trihydroxypregn-4-ene-3 ,ZO-dione,
15 5-?uoro-1 15,17c-dihydroxy-21~iodopregn-4-ene- *
3 ,20-dione,
155-?uoro-1 l5,17a-dihydroxy-21-iodo-1,4-pregnadiene
7 1S 5-?uoro—1 l 5,17a,21-trihydroxy-1,4-pregnadiene-3,20
3 ,20-dione,
dione,
155-?uoro-6a-methyl-1 15, 1711,21-trihydroXypregn-4-ene3,20-dione,
15,8-?uOrO-6oz-II161IhYl-l 15,17a-dihydroxy-2l-iodopregn
10
4-ene-3 ,20-dione,
155-?uoro~6a-methyl-115,17a-dihydroxy-21-iodo-1,4
155-?uoro-6a-rnethyl-115,17a,21-trihydroXy-1,4-pregna
pregnadiene-3 ,ZO-dione,
60¢,155-di?t10fO-1 15,17a-dihydroxy-21-iodopregn-4-ene
diene-3 ,ZO-dione,
6a,155-difluoro-ll5,1704,2l-trihydroxypregn-4-ene-3 ,20
3,20-dione,
dione,
60:,155-Cll?UOIO-1 15,17a-dihydroXy-21-iodo-1,4-pregna
15
60:,15/3-di?l101‘0-1 15,1704,2l-trihydroxy-l,4-pregnadiene
diene-3,20-dione,
3 ,ZO-dione,
60:,911,155-tri?uoro-l15,17oz-dihydroXy-21-iodopregn-4
3 ,ZO-dione,
6a,9a,155-tri?uoro-115,17m-dihydroxy-21-iodo-1,4-preg
601,911, 155-tri?uoro-1 l5,170:,2l-trihydr0Xypregu-4-ene
ene-3 ,20-dione,
6a,9a,155-tri?uoro-1l5,17<x,2l-trihydroxy-lA-pregna
diene-3,20-dione,
6u-methyl-9u,155-di?uoro-115,17a,21-trihydroxypregn
nadiene-3,20-dione,
pregn-4-ene-3,20-dione, or
6oc-methyl-9oc, 15 5-di?uoro-1 15,17a-dihydroxy-21-iodo
1,4-pregnadiene-3 ,20-dione,
4-ene-3,20-dione, or
. 6a-methyl-9a,155-di?uoro-115,l7a,21-trihydroXy-1,4
pregnadiene-3,20-dione
there are obtained
there are produced
‘9oz, 155-di?uoro-1 15,17a-dihydroxypregn-4-ene-3,20
dione,
155-?uoro-1 15,17a-dihydroXypregn-4-ene-3 ,20-dione,
90:,15B-di?110I0-1 15,17a-dihydroxy-21-iodopregn-4-ene
3 ,20-dione,
155~?uoro-115,17a,dihydroxy-21-iodopregn-4-ene-3,20dione,
30 155-?uoro-1l5,17a-dihydroxy-1,4-pregnadiene-3,20
dione,
155-?uoro-115,17u-dihydroxy-21-iodo-1,4-pregnadiene
l55-?uoro-6ot-methy1-1 15,17oc-dihydroxypregn-4-ene
3,20-dione,
3 ,20-dione,
’ 155-?uoro-6a-methyl-115,17a-dihydroxy-21-iodopregn
4-ene-3 ,ZO-dione,
7 155-?uoro-6a-methyl-1 15,17a-dihydroxy-2l-iodo-1,4
6oz,155-di?uoro—115,17a-dihydroxypregn-4-ene~3,20~
pregn adiene-3 ,ZO-dione,
dione,
‘60¢,15/3-di?l101‘0-1 15,17a-dihydroxy-1,4-pregnadiene-3,20
40 dione,
60:,15B-di?LlOIO-11B,I'I'a-dihYdI‘OXY-Z1-l0dO-p1‘6g1‘b-4-6I1e
3,20-dione,
6u,155-di?uoro-115,17a-dihydroxy-21-iodo-1,4-pregna, diene-3 ,20-dione,
6a,9a,155-tri?uoro-115,17a-dihydroxy-21-iodopregn-4
cue-3 ,ZO-dione,
6u,9a, 15 5-tri?u oro-l 15, 17oL-dlhyd1'OXY-21-iOdO-1,4-
pregnadiene-3 ,ZO-dione,
6a-methyl-9a,155-di?uoro-115,17a-dihydroxy-21-iodo
pregn-4-ene-3,20-dione, or
6a-methyl-9a,155-difluoro-115,17m-dihydroxy-21-iodo
‘
6a-rnethyl-9a,155-di?uoro-1'15,17u-dihydroxy-1,4-preg
nadiene-3,20-dione,
respectively.
50
1,4-pregnadiene-3,ZO-dione,
respectively.
dione,
601,9“, 155-tri?uoro-1 15,17u-dihydroxy-1,4-pregnadiene
;
3,20-dione,
'
6a-methyl-9a, 155-di?uoro-1 15,17a-dihydroxypregn-4
45 cue-3,20-dione, and
EXAMPLE 18
,
EXAMPLE 17
9a,155-Di?u0r0-115,1 7u-Dihydroxy-1,4-Pregnadiene
9oc,I55-Di?u0r0-]15,I7ot-Dihydr0xy-1,4-Pregnadiene
3,11,20-Tri0ne
3,20-Dione
55 Using the procedure described in Example 8, but re
placing 155-?uoro-115,17a,21-trihydroxypregn-4-ene-3,20
A slurry of 150 mg. of 9a,155-di?uoro-115,17a-dihy
droxy-Z1-iodo-1,4-pregnadiene-3,20-dione and 150 mg. of
tdione 2l-acetate by 9a,155-di?uoro-1l5,17u-dihydroxy
'1,4-pregnadiene-3,20-dione, there is obtained 90:,155-di
sodium iodide in 5 ml. of acetic acid is stirred for 45
minutes before a solution of 250 mg. of sodium thiosul
,?uoro-17a-hydroxy-1,4-pregnadiene-3, 1 1,20-trione.
of magnesium silicate (Florisil). The column is eluted
155-?uoro-6a-methyl-1 15,17a-dihydroxy-1,4-pregnadiene
fate pentahydrate in 10 ml. of Water is added thereto. 60 Similarly
When the iodine color has disappeared the mixture is
‘9m,155-di?uoro-115,17a-dihydroxypregn-4-ene-3,20
diluted with water and extracted with methylene chloride.
dione,
The methylene chloride extract is Washed with water and
V155-?uoro-115,17a-dihydroxypregn-4-ene-3
,ZO-dione,
then with aqueous sodium bicarbonate solution before
’155-?uoro-1
15,17a-dihydroxy-1,4-pregnadiene-3,20
being dried over anhydrous sodium sulfate. The dried 65 dione,
solution is ?ltered and the ?ltrate is evaporated to small
15 5-?uoro-6 a-methyl-l 15,17u-dihydroxypregn-4-ene-3 ,20
.volume. The residue is chromatographed on a column
dione,
with Skellysolve B containing increasing proportions of
3,20-dione,
‘acetone and those fractions which, on the basis of paper 70 60:, 1 55-di?uoro-1 15,17u-dihydroxypregn-4-ene-3,20-' '
chromatographic analysis, are shown to contain the de
dione,
,
sired product are combined and evaporated to dryness.
604,15/3-Cli?1101‘O-1 15,17a-dihydroxy-1,4-pregnadiene-3,20
There is thus obtained 9a,155-di?uoro-l l5,17a-dihydroxy
1,;1:§regnadiene-3,20-dione in the form of a crystalline
so 1 .
dione,
60;,901, 1 55-tri?uoro-1 15,17a-dihydIoxypregn-4-ene-3,20
dione,
v
3,056,808
22
I claim:
1. A ISp-?uoro compound having the formula
cum
I =0
_.._R!
A1
z
are oxidized to the corresponding 11-oxo compounds.
EXAMPLE 19
{x
I’
F
10
To 1a solution of 1 g. of 9a,15)3-di?\10rO-11B,17a-di
hydroxy-l,4-pregnadiene-3,20’di0ne in 15 ml. of acetic
acid is added 4 ml. of acetic anhydride. The mixture is 15
purged with nitrogen and cooled whilst 0.4 g. of p
toluene-sulfonic acid is added. The reaction mixture is
allowed to stand for several hours and then poured into
ice water. The solid which separates is isolated by ?ltra
tion, washed with Water, and recrystallized from aque 20
ous methanol. There is thus obtained 9a,15/3-di?u01‘0
wherein the bond between carbon atoms 1 ‘and 2 is se
lected from the class consisting of single and double bonds,
R is selected from the class consisting of hydrogen, hy
droxy, and acyloxy, R’ represents hydroxy and, when R
represents hydrogen, R’ ‘additionally represents a group
selected from the class consisting of hydrogen and
acyloxy, X is selected from the class consisting of hy
115,170‘ - dihydroxy - 1,4 - pregnadiene - 3,20 - dione .17
drogen and ?uorine, Y is selected from the class con
acetate in the form of a crystalline solid.
sisting of hydrogen, ?uorine, and methyl, 'and Z is se
Using the above procedure but replacing acetic an
lected from the class consisting of B-hydroxymethylene and
hydride by the appropriate acid anhydride there are ob 25 carbonyl, and wherein the acyl of the acyloxy group in
tained other 17-acylates of 9a,l5?-di?uoro-1l?,l7a~dihy
each instance is that of a hydrocarbon carboxylic acid con
droxy-1,4-pregnadiene-3,20-dione.
taining from 1 to 12 carbon atoms, inclusive.
Similarly, using the above procedure but replacing
2. l5B-?uoropregn-4-ene-3,11,20-trione.
90:,156 - di?uoro - 115,17a - dihydroxy-lA-pregnadiene
3. 15;8-?uoro-11B,17a,21 - trihydroxypregn-4-ene-3,20
3,20-dione by 90¢,l5? — di?uoro-l1[3,l7u- dihydroxypregn 30 dione.
4-ene-3,20-dione, 15,8 - ?uoro - 1l?,17a-dihydroxypregn-4
4. 15B - ?uoro-11,3,l7a,21-trihydroxypregn-4-ene-3,20
dione 21-acetate.
5. 15B - ?uoro-11,8,170:,2l-trihydroxy-lA-pregnadriene
ene-3,20-dione, 15B - ?uoro - 115,17u - dihydroxy-1,4
pregnadiene-3,20-dione, 15p - ?uoro-6a-methyl - 11}9,17a
dihydroxypregn-4-ene-3,ZO-dione, 15,8 - ?uoro-6a-methyl
1113,17“ - dihydroxy-l,4-pregnadiene-3,ZO-dione, 60:,1518 35
di?uoro-ll?,l7u-dihydroxypregn - 4 - ene - 3,20 - dione,
6a,15;3-di?uoro-11;8,l7a-dihydroxy - 1,4 - pregnadiene
3,20-dione.
6. 155 - ?uoro-1118,17a,21-trihydroxy-1,4-pregnadiene
' 3,20-dione ZI-acetate.
7. 911,153 - di?uoro-l 1p,17u,21-trihydroxypregn-4-ene
3,20-dione, 6a,9a,15/8-tri?uoro-l 15, l7a-dihydroxypregn-4—
ene-3,20-dione, 6a,9a,15? - tri?uoro-l1;8,17a-dihydroxy
1,4-pregnadiene - 3,20 - dione, ‘6a-methyl-9oz,ISB-di?uoro
11,3,l7a-dihydroxypregn-4-ene-3,20 - dione, 6a-methyl
‘8. 9a,15,6 - di?uoro-l1B,17u,21-trihydroxypregn-4-ene
40 3,20-dione 2l-acetate.
9. 90:,155 - di?uoro-l1B,17a,21-trihydroxy-1,4-pregnadi
9a,1518-di?uoro - 115,17“ - dihydroxy-l,4-pregnadiene
3,20-dione or the corresponding ll-oxo derivatives of the
‘above-named compounds there are obtained the corre
sponding 17-acetates and like 17-acylates of the above 45
compounds.
3,20-dione.
ene-3,20-dione.
10. 9u,15[3 - di?uoro - 11?,17u,21
pregn»adiene-3,20-dione 21-acetate.
- trihydroxy - 1,4
No references cited.
Документ
Категория
Без категории
Просмотров
0
Размер файла
1 657 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа