Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
K540a
9~6
Steroidal[16a,17-b]1,4-dioxanes and steroidal[l6~,17-h]-
1,4-dioxins have been prepared and found to have useful anti-
inflammatory activity. The steroids encompassed by this
invention are the 3,20-diketo pregnenes having an ll~-hydroxy
group or an ll-keto group and having fused on the 16- and
17-positions a 1,4-dioxane ring or a 1,4-dioxin riny.
F,xemplary of the ~teroids of the above description are
steroids having the structural formula
H2Z -
I C=0 _
~ ~ o /~
1 . o : .
Q
In formula I, and throughout the specification, the symbols
~'~ are as defined below. ::
.
Z can be hydrogen, hydroxyl, acyloxy or halogen; :~
Y can be hydrogen and Y' can be hydroxyl or together Y
and Y' can be -0;
X can be hydrogen or halogen;
P can be hydrogen, methyl or chLoro;
: Q can be hydrogen, methyl or fluoro;
, :
:`' ' ' ~
. ., . ~ ~ , . . ~ . .
~S~9~6 K540a
l l4 l5
Al can be -CH-CH2-, -C=CH-, -C = C-, R2O-CH-CH2-,
-C-CH2- or R3C-O-cH CH2 ;
Rl can be hydrogen, alkyl or aryl;
R2 can be hydrogen, alkyl or arylalkyl;
R3 can be alkyl, cycloalkyl or aryl; and
R4 and R5 can be the same or different and can be
alkyl or aryl.
Steroids having the formula
CH2 Z
II C=O
__ - OH
p___
O ':
Q
are useful as intermediates in the preparation of the
steroidal[l6a,l7-h]l~4-dioxanes and steroidal[16~,17-b]-
1,4-dioxins of formula I. In formula II, and throughout
the specification, the symbol A2 can be l-C~ C - CH2,
-C-R6, -CH-OH, -CH-O-S-CH3, ~CH(O-R7~2, or -CH2-O ~
. .:
The symbol R6, as used throughout the ~pecification, can be
alkyl or aryl. The symbol R7, as used throughout the Sp2Ci-
fica*ion, can be alkyl or arylalkyl.
' .
,
.
K54Oa
Steroids having the formula
CH2 z
IIa C=O
Y' I
--OH
O-C~
:
are also useful as intermediates in the preparation of the
novel steroids of formula I. In formula IIa, and throughout
the specification, the symbol A3 can be l(o alkyl) or
-C-R4.
The dotted lines in the 1,2- and the 6,7-positions of
the steroids of this invention represent the optional presence
of double bonds.
, . .
The term "pregnene", as used throughout the specifi-
cation, refers to pregnanes having ethylenic unsaturation in
one or more positions. Exemplary of pregnànes specifically
contemplated are ~4-pregnenes, ~1'4-pregnadienes, ~4'6-pregna-
dienes, and ~l'4'6-pregnatrienes. The ~4-pregnenes and the
Ql'4-pregnadienes are prefexred.
The expression "1,4-dioxane ring", as used throughout
the speciication, refers to unsubstituted and substituted
,
1,4-dioxane xings. Exemplary substitueOts are alkyI, ar31-
alkyl, aryl, alkoxy, arylalkoxy, alkyl-C-O~, cycloalkyl-C-O-,
arylalkyl-C-O-, ar/l-C-O- and oxo gr~up~.
.
1 30
., . ' '
. i .
K54Oa
~L~5~ 6~
Th~ expression "1,4-dioxin ring", as used throughout
the specification, refers to unsubstituted and substituted
1,4-dioxin rings. Exemplary substituents are alkyl, aryl-
alkyl, and aryl groups.
The term "alkyl", as used throughout the specifica-
tion, refers to both branched and straight chain alkyl
groups having 1 to 8 carhon atoms. Alkyl groups of :L to 4
carbon atoms are preferred, and methyl is the most pre~erred.
The term "cycloalkyl", as used throughout the speci-
~0 fication, refers to cycloalkyl groups having 3 to 6 carbon
; atoms.
The term "aryl", as used throughout the specification,
refers to phenyl or phenyl substituted with one or more
halogen, alkyl, and alkoxy groups. Phenyl and monosubstituted
phenyl are the preferred aryl groups.
The term "halogen", as used throughout the specifi-
cation, refers to fluorine, chlorine, bromine, and iodine.
The term "alkoxy", as used throughout the specifica-
tion, refers to groups having the structure alkyl-O- wherein
alkyl is as defined above. Alkoxy groups having 1 to ~
carbon atoms are preerred, and methoxy is the most preferred.
The term "acyloxy", as used throughout the specifi-
cation, refers to groups wherein the acyl portion is a
physiologically acceptable acid residue derived from an
organic or inorganic acid. Exemplary monocarboxylic acids
are those having the formula R-COOH wherein R is alkyl,
cycloalkyl, arylalkyl or aryl; e.g., acetic propionic,
valeric, cyclohexanecarboxylic, phenylacetic, ben~oic, and
toluic acids. Exemplary polycarboxylic acids are malonic,
_4
.,
. ....... .
. , . , ~,. ..
K540a
~S~96~
succinic, glutaric,adipic, pimelic, and phthalic acids.
Exemplary inorganic acid are sulfuric, nitricj and phos-
phori~ ~cids.
'
The s~eroids of formula I are physiologically active
substances which possess glucocorticoid and anti-inflamma-
tory activity and hence can be used in lieu of known gluco-
corticoids in the treatment of rheumatoid arthritis, for
which purpose they can be administered in the same~manner
as hydrocortisone, for example, the dosage being adjusted
for the relative potency of the particular steroid. In
addition, the steroids of this invention can be used topically
in lieu of known glucocorticoids in the treatment of skin
conditions such as dermatitis, psoriasis, sunhurn, neuro-
dermatitis, eczema, and anogenital pruritus.
., .
When given orally, the compounds of this invention
1 may be used in a daily dosage range of O.l to 20n milli-
¦ grams per 70 kilograms, preferably 0.3 to 100 milligrams
per 70 kilograms. If administered topically, the compounds
of this invention may be used in the range of 0.01 to 5.0~
by weight, pre~erably 0.05 to 2.0% by weight, in a conven-
, tional cream or lotion. The topical mode of administration
,. . : i8 preferred.
,~ '; - Cycloborate-esters of 16~,17-dihydroxy steroids having
,, ~
he formula
~. .
, 30
'
. .
: '. : . ' ~ "''' ': ' '' ~ . . . '
iios~6i6, K540a
. IH2Z
C--O
IIIyl I
Y~ / B-OH
P---^r
. , o~
Q
are one of the starting materials for the prepara~ion of
the steroids of formula I. The cycloborate esters of
formula III are known; see, for examp}e, United States patent
2,831,003, issued April 15, 1958. They can be prepared by
reacting the corresponding 16a,17-dihydroxy steroid with
boric acid anhydride in an organia solvent at re~lux tem- :
perature. .
Exemplary cycloborate ester starting materials of :~
formula III are
1 11~,16a,17,21-tetrahydroxypregn-4-ene-3,20-dione,
l . 16,17-cycloborate,
~ 9-~luoro-11~,16a,17,21-tetrahydroxypregn-4-ene-3,20-
dione, 16,17-cyclohorate,
I 6~,9-difluoro-11~,16a,17,21-tetrahydroxypregn-4-ene-
:~ 3,20-dione, 16,17~cycloborate,
,16a,17,21-tetxahydroxy-6~-methylpregn-4-ene-3,20-
dione, 16,17-cycloborate, - ~ ~
21-chloro~ ,16~,17-trihydroxypregn-4-ene-3,20-dione, ;;
16~,17~-cycloborate, :~
I ~ 21-chloro-9-fluoro~ ,lS~,17-trihydroxypregn-4-ene-
j 3,20~dione, 16,17-cycloborate, :
. ' 3 0
..1: .
: -6
K54Oa
- ~OS~66
~ 21-chloro-6~,9-difluoro-11~,16~,17-trihydroxypregn-
: 4-ene-3,20-dione, 16,17-cycloborate,
21-chloro-6~-fluoro-11~,16~,17-trihydroxyprec3n-4-ene-
3,20-dione, 16,17-cycloborate,
21-chloro-11~,16a,17-trihydroxy-6~-methylpregn-4-ene-
; 3,20-dione, 16,17-cycloborate,
11~,16a,17,21-tetrahydroxypregna-1,4-diene-3,20-d.ione,
16,17-cycloborate,
9-fluoro-11~,16~,17,21-tetrahydroxypregna-1,4-diene-
3,20-dione, 16,17-cycloborate,
6~,9-difluoro-11~,16~,17,21-tetrahydroxypregna~l,A-
diene-3,20-dione, 16,17-cycloborate~
6a-fluoro~ ,16a,17,21-tetrahydroxypregna-1,4-diene-
3,20-dione, 16,17-cycloborate,
11~,16a,17,21-tetrahydroxy-6~-methylpregna-1,4-diene-
3,20-dione, 16,17-cycloborate,
21-chloro-11~,16~,17-trihydroxypregna-1,4-diene-3,20-
dione, 16,17-cycloborate,
21-chloro-9-fluoro-11~,16~,17-trihydroxypregna-1,4-
diene-3,20-dione, 16,17-cycloborate,
21-chloro-6a,9-difluoro-11~,16~,17-trihydroxypregna-
1,4-diene-3,20-dione, 16,17-cycloborate,
; 21-chloro-6a-fluoro-11~,16a,17-trihydroxypregna-1,4-
diene-3,20-dione, 16,17-cycloboratej
21 chloro~ ,16a,17-trihydroxy-6a-methylpregna-1,4-
diene-3,20-dione, 16~17 cycloboratq,
2-chloro-11~,16a,17,21tetrahydroxypregna-1,4-diene-
3,20-dione, 16,17-cycloborate,
.
. . . ~ .
: . . .
K540a
lOSO9b;B
2-chloro-9-fluoro~ /16a,17,21-tetrahydroxypregna-
1,4-diene-3,20-dione, 16,17-cycloborate,
9-fluoro-11~,16~,17,21-tetrahydroxypregna-1,4,6-
triene-3,20-dione, 16,17-cycloborate.
Diazoalkenes having the formula
IV C~2=C ~CHN~
are also used as starting materials for the preparation of
Rl OH
theOsteroids of fOrmula I wherein Al is -C=CH- ' --CH-CH2-,
R3-C-O-CH-CH2-' -C-cH2-' or CH CH . In formula IV,
those diazoalkenes wherein Rl is hydrogen or alkyl are known;
see, for example, the Journal of the American Chemical
Society, 91, 711 (1969). The preparation of the diazoalkene
of formula IV wherein Rl is aryl ~e.g., 2-phenyl-3-diazo-1-
propene) is described in the examples of this s~ecification.
Reaction of a cycloborate ester of formula III with a
diazoalkene of formula IV yields a steroid having the formula
, ' .
V 1 2Z
C=O
y _ ~ ,,J~ O~I
p_ ~ b-CH2-C=C!12
Q -
.:
The reaction can be conducted in an organic solvent, prefer-
ably a lower alkanol such as methanol, at a temperature of
about -10C ~o +40C for about 30 minutes to 4 hours,
;, :
-8-
K540a
~ 5~9G,~i
preferably at 0C to 20C for 30 minutes to 1 hour. The
steroid and the diazoalkene are reacted in at least a 1:4
molar ratio.
The steroid of formula V can be reacted with m-chloro-
perbenzoic acid to yield a steroid having the formula
CH2 Z
VI C=O
~ -OH
l O-CH2-- C CH2
1'0 p__~ 3/ \0/
o
Q
The reaction can be conducted in an organic solvent, prefer-
ably a halogenated hydrocarbon such as dichloromethane, at
a temperature of from about 0C to 40C for about l.hour to
96 hours, preferably at room temperature for about 2hours
; to 72 hours. The steroid of formula V and the m-chloroper-
benzoic acid are reacted in approximately a 1:1 molar ratio.
Reaction of a steroid of formula VI when Rl is alkyl
or aryl with a strong oxidizing agent such as periodic acid,
yields a steroid having the formula
1~2z
C--O
p ~ /~ CN2--C--R6
Q
30`
_9_ :
K540a
~563~
Reaction of a steroid of formula VI when Rl is hydrogen with
a strong oxidizing agent yields a cyclic lactol (formula VIII)
which is in equilibrium with the corresponding aldehyde
(formula VIIIa), i.e.,
CH~2
I H2 C=O
p _ ~ ~ ~ 2 p ~ -CH2-
Q
Q ~
VIII VIIIa
These oxidation reactions can be conducted in an organic
~ solvent such as tetrahydrofuran mixed with water at a
; temperature of about 0C to 40C, for about 1 hour to 8
hours, preferably at room temperature for 2 hours to 4 hours.
The steroids of formula VII or VIII can be r~acted in
a slurry or solution of an organic acid catalyst such as
~-toluenesulfonic acid in an organic solvent such as benzene
! to yield steroidal 2',3'-dihydroE16a,17-b]1,4-dioxins having
the ormula
CH Z
C=O
IX - Y ~ _ O-C-R
. I O-CH
~, p~
.~ ' ~
Q
1 0--
K540a
~1~5~66
The reaction can be conducted under reflux conditions in
an inert atmosphere for about 2 hours to 48 hours, prefer-
ably 4 hours to 24 hours.
Reaction of a steroid oO formula VIII with an an-
hydride having the formula (R3C~2O yields a steroidal
[16~,17-b]1,4-dioxane having the formula
CE~ Z
X C=O
~o ~ o_f~l
P f ~ --CH2
. .
Q
The reaction can be conduc~ed in an organic solvent such as
pyridine at a temperature of about 0C to 40C for about 3n
minutes to 4 hours, preferably at room temperature for 1
hour to 2 hours.
Oxidation of a steroid of formula VIII with Fetizon's
reagent ~An~ew. Chem. Internat. Edit., 8, 444 (1969)) yields
a steroid having the formula
CH2Z
XI y~ ¦ O - C~
0 ~
Q
.
- . :
K54Oa
~05~966
The reaction can be conducted in an organic solvent such
as benzene, toluene, etc. at a temperature of about 80C
to 110C for about 2 hours to 48 hours, preferably at re-
flux temperature for about 24 hours.
Reaction of a steroid of formula VII or VIII with
sodium borohydride yields a steroid having the formula
CH Z
: XII I 2
y~ C=o .:
rO y _ ~ -OH
o,~/~ Rl
Q :
The reaction can be carried out in an organic solvent, prefer-
ably a lower alkanol such as methanol at a temperature of
from about -10C to 20C for about 10 to 60 minutes, prefer-
ably at about 0C for 10 minutes to 30 minutes.
A 16~-hydroxyethoxy steroid of formula XII can be re-
acted with a methanesulfonyl halide ~methanesulfonyl chloride
is preferred) to yield a steroid having the formula
IH2Z
XIII y~ C=O
O-CH2-CR-O-S-Ci33
Q
` ~ - .
' , .
-12-
.
K540a
9~ .
The reaction can be carried out in an organic solvent such
as pyridine, in an inert atmosphere, at a tempera~ure of
about -10C to 40C for 30 minutes to 4 hours, pre~erably
at about 0C for 1 hour to 2 hours.
- Reaction of a steroid of formula XIII with sodium
bicarbonate in a dipolar aprotic solvent such as dimethyl-
sulfoxide yields a steroidal[l6a,17-b]1,4-dioxane having
the formula
CH2 Z R
XIV Y' I
---~0 - CH
y _ _ ~ ~ O--CH2
O'~ ~
Q
The reaction can be conducted at a temperature of from about
60C to 130C for about 1 hour to 24 hours, preferably at
about 110C ~or 2 hours to 4 hours.
Steroidal[16a,170b]1,4-dioxanes of formula I wherein
Al Os R20-CH-CH2- ~ R3 C~0-CH-C~2-~ -CH=CH-, -CH2-CH2- or
-~-CH2~ can be prepared ~rom the cycloborate esters of
16a,17-dihydroxy steroids of formula III and diazoethers
having the formula
XV ~R7-0)2CHCHN~ .
The diazoethers of formula XV are known; seé, for exampIe,
Chem. Ber. 100, 1491 (1967).
Reaction of a cycloborate ester of formula III with
a diazoether o~ formula XV yields a steroid having the
~ormula
: .
-13-
.
: ! ~
K540a
~S~g66
CH 2
XVI I 2
y~ C=O
y ~ ~ OH O-R
p ~ 2 1 ~ :
Q ~.
The reaction can be conducted in an organic solvent, prefer-
ably a lower alkanol such as methanol, at a temperature of
from about -10C to 40C until nitrogen evolution ceases.
The preferred reaction temperature is from 0C to 20C. :
The steroid of formula XVI can be reacted with an
organic acid such as ~-toluenesulfonic acid in an organic
solvent such as benzene to yield a steroidal~l6~,17-b]l/4-
dioxane having the formula
H2 Z
XVII I C=O ~ O-R7 ~-
. 20 ~ ~ -CH2
P~
,. ..
The ~eaction can be carried out at a temperature of about
60C to 140C for about 1 hour to 24 hours, preferably 80C
to 1.10C for 2 hours to 4 hours.
Reaction o a steroid of formula XVI with a mineral
acid, e.g., hydrochloric acid, yields a steroidalrl6~,17-b]-
1,4-dioxane of formula VIII. The reaction can be carried
., ~ .
-14~ ~
K54~a
~S~ .
out in an organic solvent such as tetrahydrofuran at a
temperature of from about 0C to 100C for about 1 hour to
24 hours, preferably 40C to 60C for 2 hours to 8 h~urs.
A steroid of formula VIII can be used to obtain a
steroid of formula IX (wherein Rl is hydrogen), ~ steroid
of formula X, a steroid of formula XI and a steroid of
formula XIV (wherein Rl is hydro~en) follo~ing the proce-
dures set forth above.
Steroidal[16~,1?-b]1,4-dioxanes of formula I wherein
Al is -CH2-CH2- can also be prepared from the ~yclo~orate
esters of 16~,17-dihydroxy sterolds o formula III and 2-
(tetrahydropyran-2-yloxy)-1-diazoethane, the preparation of
wl~ich is set forth in the examples below.
Reaction of a cycloborate ester of formula III with
2-(tetrahydropyran-2-yloxy)-1-diazoethane yields a steroid
having the formula
CH Z
XVIII I 2
C=O
Y'
y~ OH
p ~ ~J ~ O-CH2-CH2-
'' O~J : .
.
~ ~ Q
The reaction can be carried out in organic solvent, prefer-
ably a lower alkanol such as methanol, at a temperature of
from about -10C to 40~C, preferably 0C to 20C. The re-
action is continued until nitrogen evolution ceases.
3~
;
.~ '
'
,,
K54Oa
1a~5C 1966
A steroid of formula XVIII may be cleaved with an
acid to yield a steroid of formula XII (wherein Rl is
hydrogen). The cleavage reaction can be conducted in water
at a temperature of from about 0C to 40C, preferably at
room temperature, for about l hour to 24 hours, preferably
2 hours to 8 hours. Both organic and inorganic acids can
be used in this reaction. The preparation of a steroid of
formula I wherein Al is -CH2-CH2- from a steroid of formula
XII is set forth above. R4 l5
A s~eroid of formula I wherein A1 is -C- C- can be
prepared from the cycloborate esters of 16~,17-dihydroxy
steroids of formula III and diazoethers having the formula
I4
XIX (alkyl-0)2CCIN2
R5
Reaction of a cycloborate ester of formula III with
a diazoether of formula XIX yields a steroid having the
formula CIH2z
C=O
Y' _OH
2Q XX y__ ~ ~ O-alkyl
O-CH- C - 4
Q
The reaction can be conducted in an organic solvent, prefer-
j ably a lower alkanol such as methanol, at a temperature of
from about -10C to 40C until nitrogen evolution ceases.
The preferred reaction temperature is from 0C to 20C.
.i ,
- 30
,.:
-16-
'' .
,, , .. . , .. ~ - - . ~ , , , , ., , ~ ............ . .
K54Oa
~5~
Reaction of a steroid of formula XX with a mineral
acid, e.g. hydrochloric acid, yields a steroid having the
structure
Cl 1~2
XXIyl C-=O
y~
~ p _ _ ~ ~ O-CH-C-R
.
1~ Q
The reaction can be carried out in an organic solvent such
as tetrahydrofuran at a temperature of from about 0C to
100C for about 1 hour to 24 hours, preferably 40C to 60C
for 2 hours to 8 hours.
, .,
A steroid of formula XXI can be reacted with a slurry
or solution of an organic acid such as ~-toluenesulfonic
acid in an organic solvent such as benzene to yield a steroid
having the formula
CH2 Z
~ XXII~, C=o
~ ~ - O- C- R4
p ~l~ ~ ~ , O- C - R5
O~J
Q
.
The reaction can be conducted under reflux conditions in
an inert atmosphere for about 2 hours to 48 hours, prefer-
ably 4 hours to 24 hours.
-17-
K540a
~L~5~96~
Those steroids of formula I containing ethylenic
unsaturation in the 6,7-position can be prepared as described
above with the additional step of selectively introducing a
carbon-carbon double bond in the 6,7-position of either a
steroid starting material of formula III or a steroid product
of formula VIII, IX, X, XI, XIV, XVII, or ~II without effecting
other functional groups of the steroid. Exemplary of the
oxidizing agents which meet the above requirements is 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone when used in the
presence of an acid. About one molar equivalent of the
oxidizing agent is used per molar equivalent of steroid.
The oxidation reac~ion can be conducted in an organic sol-
vent such as benzene, toluene, dioxane, etc.; dioxane is
preferred. The reaction can be carried out for about 1 hour
to 96 hours at a temperature of about 50C to 150C, prefer-
ably for about 4 to 24 hours at about 70C to 130C. Alternately
a borate containing unsaturation in the 6,7-position can be
prepared from the corresponding, kno~n 6,7-unsaturated 16,17-
diols and boric anhydride.
Additional methods for the preparation of the com-
pounds of this invention will be readily apparent to a person
of ordinary ~kill in the steroid art. For example, those
steroids of this invention having a halogen in the 21-
- ~ position can be prepared from the correspondin~ 21-hydroxy
steroid by reacting the later with an alkyl or aryl sul- -
fonyl halide ~e~.g.; methanesulfonyl chloride or ~-toluene-
.
sulfonyl chlorlde), in the presence of an organic base
such as pyridine, to yield a 21-alkyl ~or aryl) sulfonyl-
; oxy steroid. The 21-alkyl (or laryl) sulfonyloxy
18-
;: ~
',
,; ~ ., . : ~ . . . .
K54Oa
~S~9~6
steroid intermediate can be reacted with alkali metal halide
(e.g., potassium fluoride, lithium chloride, lithium bromide,
sodium iodide, etc.) to yield the corresponding 21-halo
steroid.
- It will also be readily apparent to the practitioner
of this invention that because of the stability of the
dioxane and dioxin ring structures, functional groups repre-
sented by the various symbols used in fomrula I can be added
to the steroid nucleus after the addition of the dioxane or
~ dicxin ring
Using procedures well known to those of ordinary skill
in the steroid art it is also possible to prepare 21-acyloxy
steroids of this invention from the corresponding 21-hydroxy
steroids. Other variations will be apparent to the practitioner
of this invention.
Steroids of formula I wherein P and Q are hydrogen are
preferred.
Steroids of formula I wherein X is halogen are pre-
' ferred, and those wherein X is fluorine are most preferred.
Steroids of formula I wherein Y is hydrogen and Y' is
hydroxyl are preferred. Rl
Steroids of formula I wherein Al is -CH2-CH2-, -C=CH-,
O CH CH - -C-CH2-, or R3C-O-C~H CH2 p
. OSteroids oO formula I wherein Z is hydrogen, hydroxyl,
alkyl-C-O-, aryl-C-O- or halogen are preferred.
The ollowing examples are ~pecific embodiments of
this invention.
`
~0 :
' ' '
.
--1 9--
:
,, , , . . . . . .. : . ., :. . :
K5~oa
~S0gl66
Example 1
9-Fluoro-5~ ,21-trihydroxypregn-4-eno[16~,17-b]-
[1,4]dioxane-3,20-dione, 21-acetate
A. 16~-Al~yloxy-9-fluoro-11~,17,21-tr hydroxypregn-4-
ene-3,20-dione
6.6 g of 9-fluoro-11~,16a,17,21-tetrahydroxypregn-4-
ene-3,20-dione,16,17-cycloborate i~ added to a solution of
vinyl dia~omethane in 1:1 methanol-ether at 0C. After
stirring for 1 hour, the solvellt is evaporated and the
residue di~olved in chloroorm and chromatographed on a
150-g silica gel column. Elution with 5~ ethyl acetate in
chloroforln gives 1.04 g of TLC ~thin layer chromatography)
pure material. Two recrystallizations from acetone-hexane
give 0.5 g oE 16a-allyloxy-9-fluoro-11~,17,21-trihydroxy-
pregn-4-ene-3,20-dione, melting point 199-201C.
iY~ ta c d for C24H33F06: C, 66.04; H, 7.62; F, 4.35.
Found: C, 65.82; H, 7.83; F, 4.24.
B. 16~-Allyloxy-9 fluoro~ ,17,21-trihydroxypre~n-4-
__ _
el~e-3,~0-dione, 21-acetate
~ solution of 2.5 g of 16a-allyloxy-9-fluoro-11~,17,
21-trihydroxypregn-4-ene-3,20-dione in 25 ml of pyridine
is stirred or 2 hours with 2.5 ml of acetic anhydride and
the so3vent i9 then removed ln vacuo. A solution of the
resïdue ln chloro~orm is washed with sta~ hydrochloric acid,
water, 10~ sodium bicarbonate solution, water, and dried.
~oivent removal in acuo give~ an oil which crystallizes
.. . .
from acetone-hexane to yield 2.5 g o 16~-allyloxy-9-
fluoro-~ ,17,21-trihydroxypregn-4-ene-3,20-dione, 21-
aceta1:e, ~eltin~ point 189-191C.
.. . .
-20-
.
;~
K5~0 a
~5~g~6
C. 9-Fluoro-11~,17,21-trihydroxy-16~-(oxiranyl-methox~)-
pregn-4-ene-3,20-dione, 21-acetate
A solution of 6.44 g of 9-fluoro-16a-allyloxy-11~,17,
21-trihydroxypregn-4-ene-3,20-dione, 2!1-acetate in 15G ml
of dichloromethane i5 stirred with 2.88 g of m-chloroper-
benzoic acid for 19 hours at room temperature. The re-
sulting solution is washed with a mixture of 10~ potassium
carbonate solution and 10% sodium sulfite solution, dried,
and evaporated in vacuo. The residue is dissolved in di-
chloromethane and chromatographed on a 125 g - silica gel
column. Elution with chloroform and a chloroform-ethyl
acetate mix~ure gives 3.5 g of unreacted starting material
in ~racti~ns (100 ml) 25-37 and 1.7 g (25.6%) of TLC pure
product in ~ractions 49-61.
The 1.7 g is recrystallized from acetone-hexane to
~iv~ 991 mg o material having a melting point of 191-192.5C.
A 500 mg portion of this material is recrystallized from the
same solvent to give 430 ~g of 9-fluoro-11~,17,21-trihyd~roxy-
16a-toxiranyl~lnethoxy)pregn-4-ene-3~2o-dione~ 21-aceta-te,
melting ~oint 191-192.5C.
Anal~. Calc d for C26H35FO8: C, 63.15; H, 7.13; F, 3.84.
Found: C, 63.17; H, 6.84; F, 3.64.
- D. 9-Fluoro-5'~ 21-trihydroxypregn-4-eno[16~,17-b3-
[l!~ldioxane-3,20-dione, 21-acetate
A ~olution of 20.1 g of crude 9-fluoro~ ,17,21-
trihydroxy-16~-~oxiranyl-methoxy)pregn-~l-ene 3,20-dione,
21-acetat~ in 300 ml of tetrahydroEuran is stirred ~ith a
solution of 30 g of-periodic acid in 75 ml o~ t~ater or
~
' ' : ; .
.. . . . . . . .
K54Oa
~5~66
~, 6 3/4 hours. The solution is diluted with water and ex-
tracted with chloroform. The chloroform extract was washed
with 5~ sodi~n bicarbonate solution, dried, and evaporated
in vacuo to give 18.2 g of crude productO This material is
dissolved in 60 ml of dichloromethane and chromatographed
~n a 450 g -silica gel column. Fractions of 250 ml are
collected as the column is eluted with 3 liters of dichloro-
methane, 3 liters of chloroform, and then 3 liters of 19:1
chloroform-ethyl acetate. Fractions 17-21 are combined and
evaporated in vacuo to give 4.4 g of 9-fluoro-160~-allyloxy-
11~,17,21-trihydroxypregn-4-ene-3,2-diIIe, 21-acetate.
Fractions 23-31 are combined and evaporated in vacuo
to give 8.1 g of slightly impure (53.2% based on recovered
material) 9-Eluoro-5'~;,11~,21 trihydroxypregn-4-eno[160~,-
17-b] ~1,4]dioxane-3,20-dione, 21-acetate. A portion of
this material is recrystallized from acetone~hexane and
then from acetonitrile to give the analytical sample,
melting point 205-20~C.
Anal-Calc'd forC2SH33F8 C~ 62~10; ~ 7-50; ~ 3-93-
Found: C, 62.22; H, 7.28; F, 3.690
." ' , .
.
Example 2
9-Fluoro-2',3l-dihydro~ ,21-dihydrcxy-5'-methyl-;;
. , pregn-4-eno[16c~,17-b] [1,41dioxin-3,20-dione, 21-acetate
A. 9-Fluoro-113,17,21-trihvdroxv-160~ 2-methyl-2-pr
penyl)oxylpregn-~-ene-3,20-dione ~
~ solution of 2-methyl-3-diazo-1-propene in 2SO m:l of
ether ~prepared from 0.2 mole of N-~Z-methyl-2~propenyl)-
ethyl carbama-te by the method o~ J. L. Br~wbAker and H. ~lar t,
- ~
.
22-
,
', : :
: , j . , : .
.. . : . ~ . . . .
K54Oa
~ISi096g~i
O J. Am. Chem. Soc., 91, 711 tl969)) is d~luted with
300 ml of methanol and cooled to ~C. A total of 6.5 g
of 9-fluoro~ ,16~,1t,~1-tetrahydroxypregn-4-ene-
3,20-dione, 16,17-cycloborate is added in portions ~ntil
the initial red color fad2s and nitrogen evolution ceases.
~he solvent is evaporated ln vacuo and the residue dis-
solved in chloroform and chromatographed on a 100 g - silica
gel column. Elution with chloroform and chloroform-ethyl
; acetate gives TLC homogeneous material which crystallizes
10 - from acetone-hexane to give 3.73 g of 9-fluoro-11~,17,21-
trihydroxy-16~-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20
dione, melting point 213-215C, softening at 198-200C.
Anal. Calc'd for C25H35F06: C, 66.64; H, 7-83; F~ 4-22-
Found: C, 66.41; H, 8.03, F, 4.16.
. 9-Fluoro-11~,17,21-trihydroxy-16~-[(2-methyl-2-pro-
penyl)oYv]pregn-4-ene-3,20-dione, 21-acetate
A solution of 3 g of 9-fluoro-llg,17,21-trihydro.cy-
16a-~(2-methyl-2-propenyl)oxy~pregn-4-ene-3,20-dione in
25 ml of pyridine is stirred for 2 hours with 4 ml of acetic
anhydride. l'he solvent is removed ln vacuo and the residue
i~ dissolved in chloroform, washed with 5~ hydrochloric
acid solution, water, 5% ~sodium bicarbon2te solution, and
dried. Solvent removal in vacuo gives a solid which is
recryst~llized from acetone-hexane to give 2.82 g of material
having a melting point o~ 230-231C. Recrystallization of
0.6 g oE this m~terial from acetone-heYane gives 481 mg oE
9-fluoro~ ,17,21-trihydroxy-16~-[(2-m~thyl-2-propenyl)-
oxy]pregn-~-~ne-3,20-dione, 21-ncetate, melting point
230-232~C.
.' : ,
~ ~ -23-
,
K54Oa
~s~g~ .
Anal. Calc'd for C H F07: C, 65.84; H, 7.57; F, 3.86.
- 27 37
Found: C, 65.89; H, 7.56; F, 4.06.
C. 9-Fluoro~ ,17,21-trihydroxy-16a-~(2-methyl-
oxiranyl)methoxy] pre~n-4-ene-3,20-dione, 21-acetate
~ slurry of 1.0 g of 9-fluoro-11~,17,21-trihydroxy-
16a-[(2-methyl-2-propenyl)Oxy~pregn-4-ene-3~20-diOne, 21-
acetate in 50 ml of dichloromethane is stirred with 500 mg
of m-chloroperbenzoic acid at room temperature for 210
minutes. The resulting solution is washed with a mixture
of 10~ sodium carbonate solution and 10% sodium sulfite
solution, dried, and evaporated to give 1.04 g of oil which
solidifie~. Recrystallization from acetone~hexane gives
793 mg of material, melting point 221-224C and 160 mg of
material, melting point 219-224C. Recrystallization of
a mixture of 390 mg of crop 1 and 160 mg oE crop 2 from
acetone-hexane gives 298 mg of 9-fluoro-11~,17,21-tri~
hydroxy-16a-[~2-methyl-oxiranyl)methOxy]pregn-4-ene
3,20-dioner 21-acetate, melting point 223-227~C.
~na~l- Calc d for C27H37F08: C, 63.76; H, 7.33; F, 3~74.
Found: C, 63.96; H, 7.10; F, 3~g3.
The nmr spectrum of this material indicates it is a
mixture of epimers ~ca. 2:1 ratio) at the quaternary
- ~ epoxide carbon atom.
. .
:
` 3
' ' :
-24-
! . , , . .. . :
'' : ~ ` ' ;. .. ' . ' :
1050966 K540a
. D 9-Fluoro~ ,17,21-trihydroxy-16a-(2-oxopropoxy)
: pregn-4-ene-3,20-dione, 21-acetate
A solution of 1.54 g of 9-fluoro-11~,17,21-tri-
hydroxy-16~-[(2-methyl-oxir~nyl)methoxy]pregn-4-ene-3,20-
dione, ~l-acetate in 50 ml of tetrahydrofuran is stirred
for 270 minutes with a solution of 2.6 g of periodic acid
in 20 ml of water. The solution is poured into water and
extracted wit:h chloroform. The chloroform solution is
~ washed with 10% sodium bicarbonate solution, dried, and
evaporated in vacuo to give an oily residue. This is
dissolved ill chloroform and chromatographed on a 40-silica
gel column. Elution with chloroform gives 400 mg of
slightly .imuure ~roduct follo~ed by 990 mg of TLC homo-
geneous solid. The 990 mg is recrystallized twice ~rom
acetone-h~xane to give 328 mg of 9-fluoro-11~,17,21-tri~
hydroxy-1~-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-
acetate, meltlng point 203-208C.
Anal- C~c'd for C26H35F8 C, 63-15; H~ 7-13; F~ 3-84-
Found: C, 63.01; H, 7.04; F, 4.08.
E. 9-Fluoro-2',3'-dihydro-11~,21-dihyclrox~-5'-methyl-
pre~ ~4-eno[16~,17-b_[1,4]dioxin-3,20-dione, 21-
; acet.ate
- .
A .sl.urry of 100 mg of ~-toluenesulfonic acid in 250
. .
ml of ben~ene is refluxed wit~ a Dean-Stark tran. The first
50 ml of l~enzene-water azeotro~e is discarded and Linde
t~pe 4A molecular sieves are added to the trap. AEter 30
~ minutes ~ reflux, the solution is cooled and 1.0 g of
.-: 9-fluoro lL,B,17,21-trihydroxy-16a-(2-oxopropoxy)precJn~4-
ene-3,2n dione, 21-acetate is added. The resultin~ slurry
-
~5-
.
.. . . ., :
- . .
x54oa
66
is refluxed for 5 hours under nitrogen, cooled, diluted
with chloroform, washed with 5% sodium bicarbonate solu-
tion, water, dried and evaporated. The crude residue is
dissolved in a small amount of chloroform and chroma-
~ographed on a 20 g - silica gel column. Elution with
chloroform gives 805 mg of material wh:ich is recrystallized
from acetone-hexane to give 501 mg of 9-fluoro-2',3'-di-
hydro-11~,21-dihydroxy-5'-methylpregn-4-eno[16~,17-b][1,4]-
dioxin-3,20-dione, 21-acetate, melting point 233-235C,
dec.
Anal. Calc'd for C26H33FO7: C, 65.53; H, 6.98; F, 3.99.
Pound: C, 65.78; H, 6.84; F, ~.14.
: ' ~
9-Fluoro-2',3'-dihydro-11~,21-dihydroxy-5'-methyl-
pregn-4 eno[16~,17-b][1!4~dioxin-3,20-dione
A solution of 886 mg of 9-fluoro-2',3'-dihydro-11~,
21-dihydroxy-5'-methylDregn-4-eno[16a,17-b][l,~ldioxin-
3,20-dione, 21-acetate (prepared as described in Exam~le
2) in 270 ml of methanol is cooled to 0C and 27 ml of
10~ potassium carbonate solution is added. After 15
minutes, 27 ml of acetic acid is added and the mixture
is diluted with water and extracted with chlorofor~ to
give 775 mg of TLC pure 9-fluoro-2',3'-dihydro-11~,21-
dihydroxy-5'-methylpregn-~-eno[16,17-b][1,4]dioxin-
3,20 dione.
::
::
.
- 30 ~
.
-2~
-
105iO966 K540 a
O Exam~le 4
9-Fluoro-2',3'-dihydro-11~,21-d:LhydrQxy-5'-pllen~l-
pregn-4-eno[16~,17-b][1,4]dioxin=3,20-dione, 21-
acetate
.
A r 9-Fluoro-llg,17,21-trihydrox~-16~-[(2-phenyl-2-
pro~enyl)ox~]~regn-4-ene 3,20-dLone, 21-acetate
a~ N-(2-phenyl-2-propenyl)phthalImide
~ mixture of 60 g-of potassium phthalimide
and 66.4 g of -bromomethyl styrene (prepared by
the met-hod of S. F. Reed, Jr., J. Org. Chem., 30, 3258
(1965)) in 150 ml of dimeth~lformamide is refluxed for 2
hours, cooled, and diluted with 400 ml of water. The re-
sulting solid is filtered and dried in vacuo to give 83.4 g
of N-(2-phenyl-2-propenyl)phthalimide. A small sample that
is recrystallized from acetone-hexane has a melting point
of 118-121C.
b) N-(2-phenyl-2-propenyl)ethyl carbamate
A solution of 83 g of N-(2-phenyl-2-~ropenyl)
phthalimide and 30 g of 99% hydrazine-hydrate is refluxed
for 270 minutes and cooled. The slurry is treated with
125 ml of conc. hydrochloric acid and filtered. The
solid is washed with fo~r 100 ml portions of water and
the filtrate is evaporated in vacuo to a volume of 300 ml.
.
Thls solution is cooled and ~ixed with a solution of~60 g
of sodil~m hydroxide in 250 ml o, cold ~ater. The re-
sultin~ solution is extracted wlth four 200 ml ~ortions o~
ether and the ether solution is dried and eva~orated in
~ vacuo to give 30.7 g of oil. The oil is dissolvecl in
~ -27-
K540a
~051D966
250 ml of e~her, cooled to 0C, and 33 g of ethyl chloro-
formate is addedO A solution of 12 g of sodium hydroxide
in 30 ml of water is added simultaneously with the second
half of the ethyl chloroformate solution. After 1 hour
at 10C, the ether layer is washed w:ith 5% hydrochloric
acid, dried, and evaporated in vacuo to give 41.7 g of
oil. Trituration with hexane and fi:Ltration gave 33 g
of N-(2-phenyl-2-propenyl)ethyl carhamate, melting point ~;
41-42.5C.
~) N-Nitroso-N~(2-phenyl-2-propenyl)ethyl
carbamate
A solution of 21 ml (29.4 g) of nitrosyl chloride
in 60 ml of pyridine (prepared at -25C) is added over a
period of 15 minutes to a solution o 57 g of N-(2-phenyl-
2-propenyl)çthyl carbamate in 400 ml of pyridine at -5C.
The solution is stirred for 15 minutes and poured into 4
i liters of cold water. The oil which separates is e~tracted
, .
into ether ~three 6Q0 ~1 portions) and the ether ex~ract is
washed successively with 1 liter of 10% hydrochloric acid,
water, 1 liter of 5% sodium bicarbonate solution, and
dried. Solvent removal gives 63 g of red oil that shows
only minor .impurities on T~C.
d) 2-Phenyl-3-diazo-1-pro~ene-
A solution of 63 g of N-nitroso-N-(2-phenyl-2-
propenyl)ethyl carba.~ate in 300 ml of ether is add~d to
300 ml of 3M sodium methoxide in methanol at -1 to -2C
over a period o~ 30 minutes. Tho solution is stirred for
a further hour and then poure~ into 2 liters ~ ice water
.` : ` ,
~2~-
: .
.: .
~0$09~6 KS40 a
and 100 ml each of ether and pentane. The organic layer
is separated and kept at 0C while the aqueous layer is
~ extracted with 300 ml of ether. The combined organic
layer is washed with t~Jo 1 liter portions of ice water,
dried for 10 minutes at 0C over NaOH pellets, and Eiltered
to give 700 ml of red solution.
e) ?-Fluoro~ ,17,21-trih~droxy-16~-~t2-~henyl-2-
~ro~nylJoxy]preyn-4-ene-3,20-dione
The solution of 2-phenyl-3-diazo-1-propene prepared as
described above is diluted with 150 ml of cold methanol and
stirred well at 0C as 13 g of 9-fluoro-11~,16~,17,21-
tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is
added in portions. The slurry is stirred for 1 hour at
0C and filtered to give 9.6 g of the title compound. The
filtrate is stirred at room temperature for 1 hour with 4 g
of the cycloborate and the resulting solution is cooled to
0C and filtered to ~ive 4.2 g of the tltle co~pound. The
filtrate is evaporated in vacuo and the residue is dis-
solved in 400 ml of 3:1 ether-methanol and cooled to -10C
to give a ~urther 3.0 g of material. A small sample re-
crystallized from acetone hexane has a melting point of
161-163.5C.
'
'
, :
' ' ' ~ ' ':
30 ~ ~
. ; . . . .
~ ~ -29- ~
.; .
.
K540 a
S~9~6
O B. 9-Fluoro~ ,17!21-trihydroxy-16~-[(2-phenyl-2-
propenyl)oxy] pre~n-4 -ene-3, ? 0-dione, 21-acetate
- A solution of 3.0 g of 9-fluoro~ ,17,21-tri-
hydroxy-l~a-[(2-phenyl-2-propenyl)oxy]pregn-4-ene-3~2o-
dione in 30 ml of pyridine is allowed to stand with 3 ml
of acetic anhydride for 2 hours at room tem~erature. The
solvent is removed in vacuo and the residue is dissolved
in chloroform, washed with 5% hydrochloric acid, water,
5% sodium bicarbonate solution, and driedO Solvent re-
moval gives an oil that crystallizes rom acetone-hexane
to give 2.3 g of material. Recrystallization of 600 mg
from acetone-hexane gives 510 mg of 9-fluoro-11~,17,21-
trihydroxv-16a-[(2-phenyl-2-propenyl)oxy]pregn-4-ene-
3,20-dione, 21-acetate, melting point 169-171C
Anal Calc d for C32~39FO7: C, 69.29; H, 7.09; F, 3.42.
Found: C, 69.13; H, 7.11; F, 3.26.
~ .
C. 9-Fluoro-11~,17,21-trihydroxy-16d-E(2-phenyl- ;
. .
oxiranyl)methoxy]pregn-4-ene-3,20-dione,_21-
`
_cetate
A solution of 555mg of 9-fluoro-11~,17,21-trihydroxy-
16a-[~2-phenyl-2-propenyl)oxylpregn-4-ene-3,20-dione, 21-
acetate ln 25 ml of dichlo~romethane lS stirred for 330~
minutes with 200 mg of m-chloroperbenzoic acid. The solu-
,
tion is ~shed with 50 ml each of 5~ sodium sulfite solu-
tion and 5~ potassium carbonate solution. The dichloro-
methane solution is dried and evaporated to giv~ 58~ mg of
`` product. Recrystallizatlon from acetone-hexane gives~360
mg of 9-Eluoro-11~,17,21-trih~droxy-16a-[(2-phenyl-oxira nyl
30 ~ methoxy]pregn-4-ene-3,20-dione, 21-a~cetate.~ ~
.
~ ; -30- -
.. . . ~ .. , . , , ; -
:, :
`` :
X540a
l~S(~9~6
D. 9-Fluoro~ ,17,21-trih~droxy-16a-(2-phenyl-2
oxoethoxy)~reqn-4-ene-3,20-dione, 21-acetate
.
A solution of 2.4 g of 9-fluoro-11~,17,21-tri-
hydroxy-16a-1(2-phenyl-oxiranyl)methoxy~2regn-4-ene-3,20-
- dione, 21-acetate in 75 ml of tetrahydrofuran is stirred
with a solut:ion of 5 g of periodic acid in 20 ml of water
for 270 mimlte~. The resulting slurry is diluted with
150 ml of watex and the solid is filtered and dried ln
vacuo to givo 1.79 g of crude product. This material is
L0 chromatographed on a 40 g-silica gel column. Elution
with chloroform gives 1.6 g of TLC pure solicl that is re-
crystallized rom acetone-hexane to give 1.42 g of 9~fluoro
11~,17,21-trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn--4~ene-
3,20-dione, 21-ace~atet melting point 228-230C.
Anal- C~alcd for C31H37F8 C~ 66-89; H~ 6-70; F~ 3-41-
~ ~ Found: C, 67.07; H, 6.69; F, 3.~5.
E. 9-Fluoro-2',3'-dihydro~ ,21-dihydroxy-5'-phenvl- -
~ecln-4-eno[16a,17-b][1,4]dioxin-3,20-dione,
2a . 21-a~etate
A ~lurr~ of 150 mg of ~-toluenesulfonic acid in
~ 300 ml of benzene i6 refluxed with a Dean-Stark trap.
; The firsl: 50 ml o~ distillate is discarded, Linde 4A
mole~ular sieves added, and the solution is refluxed for
30 minutes. The solution is cooled, 1.25 g of 9-fluoro- -
,17,21-trihydroxy-16a-(2-phenyl-2-oxoethoxy)pregn-4- -
ene-3,20-dione, 21-acetate added, and the solution re
fluxed for 5 hours under nitrogen. The resulting solu-
,
tion i~ cooled, washed with 5~ sodium bicarbonate solution,
. .
: '
..
-31-
~.. ...
.
.. .
K540 a
~S~g~6
dried, and evaporated in vacuo. The residue i5 chromato-
graphed on a 20 g-silica gel column. Elution with 1:1
hexane-chloroform gives 825 mg of crude product. This
material is plate chromatographed on three 20 x 20 cm-2mm
silica gel plates. After 2 developments with 1:1 chloro-
form-ethyL acetate the major W -active band is excised and
eluted with chloroform to give TLC pure material. Re-
cry~tallization from benzene gives 380 mg, of 9-fluoro-
2',3'-dihydro~ ,21-dihydroxy-5'-phenylpregn-4-eno-
1. ' ' , ! .
[16a,17-bl~1,4]dioxin-3,20-dione, 21-acetate, melting
point 145-147C.
Anal. Calcd for C31~35F07: C, 69.13; H, 6.55; F, 3.53.
Foundi C, 68;.90; H, 6.73; F, 3.58.
Ex ple 5
9-~luoro-2~3'-dihydro~ 21-dihydroxypr_gn-4-
eno[l6a,17-b][1,4]dioxin-3,20-dione, 21-acetate
A slurry of 100 mg of ~-toluenesulfonic acid in 250
ml of benzene is distilled to a volume of 200 ml and 1.0
of 9-fluoro-s~ 2l-trihydroxypregn-4-eno[l6a,l7-b]-
Cl, 4]dioxane-3,20-dione, 21-acetate (prepared as described
in Example 1) is added. The resulting solution is re-
fluxed with a Dean~Stark trap filled with 4A molecular
- sieves for 24 hours under nitrogen. The solution is ccoled,
diluted with chloroform, washed with 5% sodium bicarbonate
1~ ~olution, and dried. The residue obtained on solvent re-
moval in vacuo is chromatographed on a 20 g - silica gel
':
column. Elution with 1:1 dichloromethane-chloroform gives
~1 ,
~ 30
:, ,
' ~ .
. j .
~ -32-
.
;
, . , . ~ .... .
K540 a
~6~5~6~
510 mg of pure compound. Recrystallization from aceto~e-
hexane gives 325 mq of TLC Pure solid, in two crops. The
mother liquor is purified by preparative thin layer chroma-
o~raphy on a ~n x 20 cm - 2 mm silica gel plate. After
three developments with 9:1 chloroform-ethyl acetate, the
major UV-active band is excised and eluted wi-th chloroform-
methanol. The residue obtained on solvent removal is
crystallized fxom acetone-hexane to give 96 mg of pure
material~ This is combined with the 325 my obtained above
lQ and recrystallized from acetone-hexane to give 312 mg o
9-fluoro-2',3'-dihydro~ ,21-dihydroxypregn-4-eno[16a,17-b]-
[1,4]dioxir.-3,20-dione, 21-acetate, melking point 231-240C,
dec.
Anal. Calc d for C25H31FO7: C, 64.92; H, 6.76; F, 4~11.
Found: C, 64.64; H, 6.54; F, 3O90.
. ' ~ .
: :
~E~
9-Fluor_-2',3'-dihydro-11~,21-dihydroxy~re~n-4-eno-
[16~,17-b~[1,4]dioxin-3,20-dlone
A solution of 700 mg of 9-fluoro-2',3'-dihydro~
21-dihydroxypregn~4-eno[1~,17-b][1,4}dioxin-3,20-dione,
21-acetate (prepared as described in Example 5) in 75 ml ~-
of methanol is cooled to O~C and 7 ml of 10% potassium
carbonate solution is added. After lS minutes, 20 ml of
20~ aqueous acetic acid is added and the resulting solld
is fil-tered and dried in vacuo to give 310 mg of 9-fluoro-
2',3~-dihydro-11~,21-dihydroxypregn-4-eno[16~,17-~][1,4]-
dio.Yin-3,20-dione, melting point 255-258QC, dec.
33-
:,
~ . . . . . . : . : . :
K540 a
51:)~6~
21-Chloro-9-fluoro-2',3'-dih~dro~ -hyd ~
methylpregna-1,4-dieno[16a,17-b][1,4]dloxin-3,20-
dione
:
A. 21-Chloro-9-fluorc-11~!16a!17-_rihyd~y~3l~DL~ L~
diene-3t20-dione, 16,17-cycloborate
. . .............. . .
A solution o~ 15.0 g of 21-chloro-9-fluoro~ ,16~,17-
txihydroxypregna-1,4-diene-3,20-dione and 60 g of boric
oxide in 750 ml of methanol is xe~luxed for l hou:e, cooled
1~ to 30C and diluted with 1.5 liters of water. Th,~ re-
sulting solid is filtered and dried Ln vacuo to give 13.85
g of 21-chloro-9-fluoro~ ,16~,17-trihydrox~pregna-1,4-
diene-3,20-dione, 16,17-cycloborate.
. , ,
B~ 21-Chloro-9-fluoro-11~,17-dihydroxy-16a-~(2 methyl-
. 2-propenyl)oxy]~regna-1,4-diene-3,20-dione
. - A solutlon of 2-methyl-3-diazp-1-propene in 150 ml
of ether (prepared from 0.1 mole of N-(2-methyl-2-propenyl~-
ethyl carbamate by the method of J. L~ Brewbaker and H. Har~,
J. Am. Chem., Soc., 91, 711 ~1969)) is diluted with S0 ml
o~ methanol and cooled to 0C. A total o 7 g o$ 21-chloro-
9-fluoro~ ,16~,17~trihydroxypregna-1,4-diene-3,20-dione,
16,17-cycloborate is adde~ in portions un~il ni~rogen
evolution ceases. The solvent is removed in vacuo and the
residue is dissolved ln chloroform and chromatographed on
an 80 g -silica gel column. Elution with chloroform gives
TLC pure material which cxystallizes from acetone-hexane
to give 5.4 g of 2l-chloro~9-fluoro~ 7-dihydroxy-l6a
: [(2-methyl-2~propenyl)oxy]pregna-1,4-diene-3,20-dione,
. 30 : : .
'
~34- .
,, " , . . . ~ .
. .. K540 a
~ 5~66
O melting point 238-240Co
Anal. Calc'd for C25H32ClFO5: C, 64.30; H, 6.91;
Cl, 7.59; F, 4.06.
Found: C, 64.53; Hl 7.04; Cl, 7.74; F, 4.27.
C. 21-Ch~oro-9-fluoro~ ,17-dihydroxy-16~-[(2-_1ethy~
oxiranyl)methox~pre~na-1,4-diene-3,20-dione
. .
A solution of 3.0 g of 21-chloro-9-fluoro~ ,17-
dihydroxy~l6a-[~2-methyl-2-propenyl)oxy]pregna-1,4-diene-
3,20-dione in 100 ml of dichloromethane is stirred with .
: 1.4 g of m-chloroperbenzoic acid for 210 minutes. The
solution :i.s washed with a mixture of 10~ pota.ssium carbonate
.~olution and 10~ sodium sulfite solution! dried, and evapor-
ated in vacuo to give an oil which solidiEies on standing~ :
Recrysta.LL;.zation from acetone-hexane gives 1.94 g as a
~irst crop, and 820 mg as a second crop. Recrystalli-
i zation of 600 mg of crop 1 from acetone-hexane gives 460
- mg of 21-chloro-9-fluoro-113,17-dihydroxy-16~-[(2-methyl-
oxiranyl)methoxy]pregna-1,4-diene-3,20-dione, mel-ting ~.
point 193-236C~
AnaL.. Calc'd for C25H32ClFO6: C, 62.16; H, 6.68; . .
Cl, 7.34; F, 3.93.~
Found: C, 62.19, ~, 6.67i Cl, 7.52; F, 4.07.
,
-(~he nmr spectrum of this material~indicates that
it is ca. a 1:1 mixture of epimers at the quaternary
: :~ .oxirane carbon~2tom.~ - :
30.
. ~ ~35-
' ~ ' '
K54Oa
D. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-(2-oxo-
propoxy)pre~na-1,4-diene-3,20-dione
A solution of 2.16 g of 21-chloro-9-fluoro-11~,17-
dihydroxy-16~-[(2-methyloxiranyl)meth~xy~pregna-1,4-diene-
3,20-dione in 50 ml of tetrahydrofuran is stirred with a
solution of 5 g of periodic acid in 10 ml of water for
180 minutes. The solution is diluted with water and ex-
tracted with chloroform. The chloroform solution is dried
and evaporated in vacuo and the residue is dissolved in
chloroform and chromatographed on a 50 g-silica gel column.
Elution with chloroform and collection of 50 ml fractions
gives 1.81 g of TLC pure solid in fractions 9-17. Recrystal-
lization from acetone-hexane gives 1.15 g of irst crop
material and O.SO g in crops 2 and 3. Recrystallization from
acetone-hexane of 600 mg of the first crop gives 490 mg of
21-chloro-9-fluoro-11~,17-dihydroxy-16~-(2-oxopropoxy)pregna-
1,4-diene-3,20-dione, melting point 226-227C.
Anal. Calc'd for C24H30ClF06: C~ 61.51; H, 6.45;
Cl, 7.56; F, 4.05.
Found: C, 61.69; H, 6.35; Cl, 7.53; F, 3.94.
.
E. 21-Chloro-9-fluoro-2',3'-dihydro-ll~~hydroxv-S~-
methy~lpre~na-1,4-dieno~16~,17-b]~1,4]dioxin-3,20-
dione
. :
A slurry of 100 mg of ~-toluenesulfonic acid in 250
ml of benzene is refluxed with a Dean-Stark trap. The
first 50 ml of benzene-water azeotrope is discarded and
Linde type 4A molecular sieves are added to the trap.
AEter 30 minutes at reflux, the solution is cooled and
-36- -
'
!
K54Oa
- ~5~66 :
980 mg of 21-chloro-9-fluoro-llB,17-dihydroxy 16a-(2-
oxopropoxy)pregna-1,4-diene-3,20-dione:is added. The
resulting ~lurry is refluxed for 25 hours under nitrogen,
cooled, and filtered to give 720 mg of solid. The filtrate
is diluted with chloroform, washed wi.th 5% sodium bicar-
bonate solution, water, dxied, and evaporated to give 210
mg of material identical by T~C to the 720 mg of solid. ~:
These materials are combined, slur~ied with 50 ml of
~ineral oil, diluted with chloroform, a~d chromatographed
10 on a 100 ~ -.5ilica gel column. Elution with chloroform
gives 850 mg of material which is recrystallized from :
acetone to give 487 mg o 21-chloro-9-1uoro-2',3'-di-
hydro~ -hydroxy-5'-methylpregna-1,4-dieno[16a,17~b]
11,4~dioxin-3,20 dione, melting point 259-260C.
. -
Anal. Calc'd for C24H2805~Cl: C, 63.92; H, 6.26;
Cl, 7.86; F, 4.19.
Found: C, 63.80; H, 6,49; Cl, 8~07; F, 4.13.
Example 8
5'~-Ethoxy-9-fluoro-llB,21-dihydroxypre~n-4-eno-
~16a,17-b][1,4]dioxane-3,20-dione
A. 16a-~2,2-Diethoxyethoxy)-9-fluoro~ ,17,21-tri-
hydro_y~egn-l-ene ~
A solution of 2,2-di~thoxy-1-diazoethane ~prepared : :
, : .
from 0.0935 mole of N-2,2~diethoxyethyl~:urea by the method
of W. Kirmss and M. Buschhoff, Chem. Ber.~100, 1491 (1967))
~in 3QO ml of 3:~ ether-pentane is diluted~with 100 ml of
., .
methanol and cooled to 0C. A total of 5.5 g of 9~1uoro-
30 . llR,16~,17,21-tetrahydroxypregn-4-ene-3~20~dione,
.
~37- :-
,: .
:'
K54Oa
~0~i~1966
16,17-cycloborate is added in portions until ni~rogen
evolution ceases. The solvent is removed ln vacuo and
the residue is recrystallized from mlethanol to give 3.4
g of slightly impure material. This is dissolved in chloro-
form and chromatographed on an 80 g - silica gel column.
Elution with chloroform gives 2.95 g of material which
is recrystallized from acetone-hexane to give 2.6 g of
16a-(2,2'-diethoxyethoxy)-9 fluoro~ ,17,21-trihydroxy-
pregn-4-ene-3,2~-dione, melting point 208-210C.
~nal.Calc'd for C27H41F8 C~ 63-26; H~ 8-07; F~ 3-71-
Found: C, 63.03; H, 7.86; F, 3.79.
.
B. 5'~-Ethoxy-9-fluoro~ 21 dihydroxypregn-4-eno~
[lfia,17-b]tl,4]dioxane-3,2Q-dione
' A slurry o 100 mg of ~-toluenesul~onic acid in 250
; ml of benzene is refluxed with a Dean-Stark trap. The
first 50 ml of benzene-water azeotrope is discarded and
Linde type 4A molecular sieves are added to the trap.
After 30 minutes at reflux, the solution is cooled and
2 g of 16a-(2,2-diethoxyethoxy)-9-fluoro~ ,17,21-tri-
hydroxypregn-4-ene-3,20-dione is added. The'resulting
slurry is refluxed for 2 hours under nitrQgen, cooled,
diluted with chloroform, washed with 5% sodium bicarbonate
solution, water, dried and evaporated. The crude residue
' (2.25 g) is dissolved in'chloroform and chromatographed on
a 100 g - silica gel column.~ Elution ~ith chloroform and
4:1 c1lloroform-ethyl a~etate givea a total of 1.33 c~ o~
TLC pure material. Two recrystallizations from acetone-
' hexane (the last with charcoal) give 57'0 mg of 5'~-ethoxy-
9-fluoro-11~,21-dih~droxypregn-4-eno[16~,17-b][1,4]-
-3~-
.
.
. , ,: .' ' . . .. . '' ' . ~
Ki40a
.~S~
:
dioxane-3,20-dione, melting point 248-250C, dec.
Anal. Calc d for C25H33FO7: C, 64.64; H, 7-16; F, 4-10-
Found C, 64.75; H, 7.02; F, 3.95.
,
Example 9
5'~-Meth
[l6a~l7--b]~l~4ldioxane-3~2o~dione
A. 16a-(2,2-Dime xyethoxy)-9-fluoro~ ,17,21-tri-
~ oxypregn-4-ene-3,20-dione
A solution of 2,2-dimathoxy-1-diazoethane in 100 ml
of 6:4 pentane-ether (prepared by the method of W. Rirmse
and M. Busahhof, Chem. Ber., 100, 1491 ~19671utllized for
the diethoxy analog) i9 diluted with 50 ml of methanol and
cooled to 0C. A total of 2 g of 9-fluoro-11~,16~,17,21-
- tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate i~
adde~. After nitrogen evolution ceases the solvent is
removed in vacuo and the residue is dissolved in chloro-
form and chromatographed on an alumina column ~neutral,
~ activity III~. Elution-with chloroorm gives 485 mg of
slightly impure material and t~en 1.27 g o~ TLC pure com~ ;
pound. Recrystallization o the 485 mg from acetone-
; hexane yives 175 ~g of TLC homogeneous solid which i5
combined with the 1.27 g ~nd recrystallized from acetcne~
hexane to give 1.09 g of 16~-(2,2 - dimethoxyethoxyj-g-
~luoro~ ,17,21-trihydroxypregn-4-ene-3,20-dione, melting
point 192-194C.
. . ~na Ccllc d for C25H37F08: C, 61.96; H, 7.70; F, 3.94~
Found: C, 62.21; H, 7.79, F, 3.85.
:-
., ~ :. .
,
' 30
'. ~
:, , ,. : , ,.. : .
K54Oa
50 9 66
B. 5~ Methoxy-9-fluoro-llB~2l-dih~gea~oæ ern-~ -ern-
~16a,17-b] ~1,4] dioxane-3 ! 20-dione
Following the procedure of Example 8B, but sub-
s~itutir.~ 16a- (2, 2-dimethoxyethoxy)~9-fluoro~ ,17,21-
trihydroxypregn-4-ene-3,20-dione for the 2,2-diethoxy-
ethoxy steroid, the title compound i~; obtainedO
~,
eno~l6a~l7-bl[l~4]dioxane-3~2o-dione
A. ~ F.thoxy-9-fluoro-llg,21-dihydroxypregn-4-eno-
[l6a~l7-b]ll~4]dioxane-3~2o-dione~ 21-mesylate
. .
A s~lut~on of 950 mg of 5'~-ethoxy-9-fluoro-11~,21-
dihydroxy~regn-4-eno~16a,.l7-b] [1,4~dioxane-3,20-dione
(prepareci as described in Example 8~ in 10 ml of pyridine
is stirred at 0C wi~h 3 ml of methanesulfonyl chlori~e
for lSO minutes. Ice is added and the mixture poured into
cold, dilute hydrochloric acid and extracted with chloro-
form. The chloroform solution is dried and evaporated in
vacuo to give 1.0 g of crude mesylate.
B. 21-Chloro-S'~ethoxy-9-~luoro~ hydroxypregn-4-
enoll6~,17-b][1,4]dioxane-3,20-dione~
solution of 1 g of 5'~-ethoxy-9-fluoro~ ,21-di-
hyaroxyp~ ec3n-4-enoll6~,17-b311,4]dioxane-3,20-dione, 21-
mesylate in 100 ml of dimethylformamide is reflux2d with
4 g of lithium ch~oride for 30 minutes, cooled, and poured
into ic~-water. The resultin~ solid is filtered, washed
well with water, and ~ried in vacilo to give 782 mg o~ ~
.
~4~-
:
lOS0966 KS40a
product. This material is dissolved in chloroEorm and
chromatographed on a 20 g - silica gel column. Elution
wi~h chloroform gives 715 mg of TLC pure solid. Re- -
crystallization from acetone-hexane gives 600 mg of 21-
chloro-5'~-ethoxy-9~fluoro~ -hydroxypregn-4-eno[16a,~
17-b]l1,41dioxane-3,20-dione, melting point 235-237C,
dec.
A~l~ Calc'd for C25H34ClF06: C, 61.91; H, 7.07;
. Cl, 7.31: F, 3.92.
Found: C, 61.75j d, 7.27; Cl, 7.24 ~, 3.85.
"', ' "''' ,-
. ', ' - .
, .
' ' ' ' ' :'
.1 ~'' .
;3 : ~
.` , . .. . .
.
! ~ :
. :, ~ :
, -41-
' .
. ~ ,
'
... ,.... .. ' . ~ - . . '
I ~5~
~5~9~6
- Example 11
..
9-Fluoro-5~,11g,21-trihydroxypregn-4-eno~l6a,17-b]-
~1,4~dioxane-3,20-dione
- A solution of 1.6 g of 16a-(2,2--diethoxyethoxy)-9-
fluoro 11~,17,21-trihydroxypregn-4-ene-3,20-dione (pre-
pared as described in Example 8A) in ;200 ml of tetra-
hydrofuran is refluxed with 20 ml of lM hydrochloric acid
for 3 hours. The solution is cooled, evaporated in vacuo
to one third the original volume, and diluted with water.
The resulting solid is filtered and dried in vacuo to
give 800 mg of product. Re,crystallization from methanol
gives 350 mg of 9-fluoro-5'~ ,21-trihydroxypregn-4-eno-
~16a,17-b]~1,4]dioxane-3,20-dione, melting point 260-26~C,
dec.
Anal. Calc'd for C23H31FO7: C, 63.00; H, 7.13; F, 4.33.
Found: C, 62.96; H, 7.07; F, 4.48.
.
Example 12
9-Fluoro-5'~ ,21-trihydroxypr~n-4-eno~16~,17-b]-
[1,4]dioxane-3,20-dione, 5',21-diacetate
.
To a solution of 1.3 g of 9-fluoro 5'~ ,21-tri-
hydroxypregn-4-eno[16~,17-b]tl,4]dioxane-3,20-dione (pre-
pared as described in Example 11) in 10 ml of; pyridine is
, ~ . ~
added 5 ml of acetic anhydride. The solution is kept at
.
room temperature for 4 hours. The solvent is removed in
vacuo and the residue dissolved in chloroform, washed with
dilute hydrochloric acld~ and dried. The solvent is se-~
` moved in vacuo and the residue dissolved in chloroform and
chromatographed on a silica gel column. Elution with
~chloroform gives 730 mg of impure compound and 506 mg of
-420
` . ' ~; :
K540 a
~5(~9~;6
TLC pure material. The 730 mg of impure material is dis-
solved in chloroform and plate-chromatographed on two
20 x 20 cm - 2 mm silica gel plates. After three develop-
ments with 1:1 chloro~orm-ethyl acetate, the UV-active
band of lowest R~ is excised and eluted with chloroform.
The chloroform is removed in vacuo and the residue combined
with the 506 mg of pure material and recrystallized from
acetone-hexane to give 530 mg of 9-fluoro-5'~ ,21-tri-
hydroxypregn-4 eno[l6a,17-b][1,4]dioxane-3,20-dione,
5',21-diacetate, melting point 195-197C.
Anal. Calc'd ~or C25H35FOg C, 62.42; H, 6.21; F, 3.66.
Found: C, 62.37; H, 6.44; F, 3.61.
Exam~e 13
9-Fluoro-5'~ ! 21-trihydroxypre~n-4-eno[16a,17-b]-
El, 4]dioxane-3,20-dione, 5'-valerate, 21-acetate
~ .
A solution of 9-fluoro-5'~ ,21-trihydroxypregn-4-
eno[16~,17-bl[1,4]d oxane-3,20-dione, 21-acetate (prep~red
as described in Example 1) in pyridine is stirxed with
zo excess valeric anhydride for 2 hours. The solvent is re-
moved in VACUO and the residue dissolved in chloro~orm
The chloro~orm solution is washed with 5~ hydrochloric
acid, waterr 5~ sodium bicarbonate, and dried. Solvent
removal yields 9-fluoro-~ ,21-trihydroxypre~n-4-
eno~l6~,17-b][1,4]dioxane-3,20-dione, 5'-valerate, 21-
acetate.
-43-
~54Oa
~5~3~66
O
21-Chloro-9-fluoro-5'~ dihydroxypre~na-1,4-
- dieno[l6,17-b]~1,4]dioxane-3,20-dione
A. 21-Chloro-16~ (2,2-diethoxyethoxy)-9-fluoro~ ,17-
dihydroxypregna-1,4-diene-3,20-dione
A solution of 2,2-diethoxy-1-diazoethane (prepared
from 0.0935 mole of N-2,2-diethoxyethyl urea by the method
of WO Xirmse and Mo Buschhoff, Chem. Ber., 100, 1491 ~1967))
in 300 ml of 3:2 ether-pentane is diluted with 100 ml of
methanol and cooled to 0C. A total of 2.5 g of 21-chloro-
9-fluoro~ ,16~,17-trihydroxypregna-1,4-diene-3,20-dione,
16,17-cycloborate is added in portions until nitrogen
evolution ceases. The solvent is removed ln vacuo and the
residue is dissolved in chloroform and chromatographed on
an 80 g - silica gel column. Elution with chloroform
gives 2.16 g of TLC pure material that is recrystallized
from acetone-hexane to give 1.75 g of 21-chloro-16~-(2,2-
diethoxyethoxy)-9-fluoro-11~,17-dihydroxypregna-1,4-
diene-3j20-dione, melting point 200-202C.
20Anal. Calc'd for C27H38ClFO7: C, 61.30; H, 7.2~;
Cl, 6.70: F, 3.59.
Found: C, 61.55; H, 7.24;
Cl, 6.68; F, 3.47.
,, .
-
Bo ?l-Chloro-~ fluoro-5'~,11g-dihydrox~pre~na-1_4-
dieno[l6~,17-b]11,41dioxane-3,20-d7One
A solutioll of 1.6 g of 2l-chloro-l6~-!2~2~diet
ethoxy)-9-1uoro-11~,17-dihydroxypregna-1,4-~iene-3,20-
dione in 200 ml of tetrahydroEuran is re~luxed with 20 ml
39
.
-44-
~, ~
.: . - :
- . . . . - . ~ . : . . ,. ., . ,,, . ~ . - ~ ,
X540 a
.:
1~3SO966
of lN hydrochloric acid for 5 1/2 hours~ The solvent is
removed in vacuo and the residue is diluted with water,
.. ex~racted with chloroform, and the chloroform solution is
wa~h~d witll 5~ sodium bic~rb~nate solution, water, dried,
and evaporated. The residue is dissolved in chloroform
and chromatographed on a 60 g - silica gel column. Elution
with a mixture of 3:2 chloroform:ethyl acetate gives 1.29 g
of pure material which is recrystallized from acetonitrile
to give 940 mg of 21-chloro-9-fluoro-5'~ dihydroxy-
pregna-l~4-dienotl6a~l7-b]~l~4]dioxane-3~2o-dione~ melting
point 242-245C, dec.
Anal- Calc'd for C23H286ClF C, 60.72~ H~ 6-20;
. Cl, 7.79; F, 4.:L8.
Found: C, 60.52; H, 5.97; Cl, 7.86; F, 4.03.
: .
Example 15
21-Chloro-9-fluoro- ~ 13-dihydroxy~regna-1,4-
dieno~l6u,17-b~[1,4]dioxane-3,20-dione,~5'-acetate
To a solution of 887 mg of 21-chloro-9-fluoro-5'~,
11~-dihydroxypregna-1,4-dieno[16~,17-bl~1,4]dioxane-3,20-
~ dione (prepared as described in Example 14) in 5 ml of
: pyridine is added 2 ml of acetic anhydride. The solution
is kept at ambient temperature for 4 hours. The solvent
: is removed in~vacuo and the residue~is dissolved in
chloroform, washed with ~ilute hydrochloric:acid, and
. dried. The solvent is removed in vacuo and~the residue
~- is dissolved in chloroform and chromatographed on a silica
gel column. Elution wlth chloroform gives 748 mg of~
material. Recrystallization from~acetone-hexane gives
-~
~ 45 ~ ~ ~
~540a
5~966
' !
505 mg of slightly impure material. A second recrystalli-
zation fxom ~ethanol gives 420 mg of TLC pure 21-chloro-
.. 9-fluoro-5'~ -dihydroxypregna-1,4-d~ienoE16,17-b]~1,4]-
dioxane-3,20-dione, 5'-acetate, melting point 242-244C,
decr
Anal. Calc a for C25H307F~l C~ 58041; H~ 6-39;
Cl, 7.50; F, 4.02.
Found- C, 58.23; H, 6.23; Cl, 7.40; F, 4.08.
Example 16
21 Chloro-9-fluoro-2',3'-dihydro~ -hydroxypregna-
. 1,4-dienotl6~,17-blEl,4]dioxin-3,20 dione
A slurry of 300 mg o~ ~-toluenesulfonic acid in 1.1
liters of benzene is refluxed with a Dean-Stark trap. The
first 100 ml of distillate is discarded, Linde 4A molecular
sieves are added to the tra~ and the solllt.;.~n. i.q r~fluxed
for 30 minutes. The solution is cooled, 2.0 g of 21-chloro-
9-fluoro-5'~ -dihydroxypresna-1,4-dieno[16~,17-b][1,4]-
dioxane-3,20-dione (prepared as described in Example 14)
is added, and the resulting slurry is refLuxed for 36 hours
under nitrogen. The slurry is cool~d and the benzene is
removed in vacuo. The residue is dissolved in chloroform
and the chloroform solution washed with 5%~sodium bicar-
bonate solution, water, dried, and evaporated in vacuo. :
The residue is dissolved .in chloroform and chromatographed .
on a 50 g - silica gel column. Elution with chloroform
gives 985 mg of sQlid which is recrystallized from acetone- .~
. hexal~e to give 528 mg of 21-chloro-9-~luoro-2',3'-dihydro- :
113-hydroxypregna-1,4-dienoE16~.,17-b~[1,4]dioxin-3,20-~ ~ ~
; . . . :
- 30 dione, melting point 248-2 0C,:dec.
~ .: -
.
~ ~ 4~
~ .. . .. . . . . . .. . ........ .
~osos6~ K54 0 a
Anal. Calc dfor C23H26ClF05: C, 63.23; H, 6.00;
Cl, 8.12; F, 4.35.
Found: C, 62.95; H, 5.88; Cll 8.24; F, 4.22.
~ , " ' .
9-Fluoro-llB~2l-dihydroxypregn-4-eno[l5a~l7-b~[l~4
dioxane-3,5',20-trione, 21-acetate
, .
A solution of 1.2 g of 9-fluoro-5'~ ,2L-tri-
hydroxypregn-4-eno[16a,17-b] E 1,4]dioxane-3,20 dione, 21-
!0 acetate (prepared as described in Example 1) in 250 ml of
toluene is slurried with Z2 g of Fetizon's reagent tV.
Balogh, M. Fetizon and M. Golfier, Angew. Chem. Internat.
Edit., 8, 444 (1969)) and distilled to a volume of 200 ml.
The resulting slurry is refluxed under nitrogen for 12 1/2
hours, cooled, filtered, and the resulting solid is washed
well with chloroform. The filtrate and washings are com
.
bin~d, evaporated ~n vacuo, and the r~sidue chromatographed
on ~ 40 ~ - silica gel co:Lumn. Elution with chloroform
g~ves 270 mg of oil which crystallizes from aceton~-hexane
to give 181 mg of TLC pure solid. This is combined with
151 mg of identical material, obtained from repeating this
reaction on a 1 g scale, and recrystallized from acetone-
. . .
~;~ hexane to give 275 mg of 9-fluoro~ ,21-dihydroxypregn-
4-eno[1~,17-b][1,4]dioxane-3,~', 20-trione, 21-acetate, ~ ~-
ne1ting point 217.5-220Ct dec.
A~ Calc'd for C2s~l31F8
~ ~ ~ Found:r~ 62.61; H, 6.53; F~ 3.73. :
'` ' . ' ::
, 30 ;: ~ :
.~
:
47~
X54Oa
:IOS~966
xam~
9-Fluoro-llB,21-dihydroxypregn-4-eno[16a,17-b]-
~1,4]dioxane-3,20-dione, 21-acetate
A. 9-Fluoro~ ,17, 2i-trihydroxy-l6a-[2-(tetr-ahvdr
pyran-2-yloxy)ethoxy]pre~n-4-ene-3,20-dione
a) Tetrahydropyran-2-yloxy~acetonitrile
This material is prepared by the method of J. Davoll
and D. H. Laney, ~ Chem. Soc. 2129 (1956~ and has a boil-
inq point of 78-79C at 2 ~m.
,:
- b) 2-(Tetrahydropyran-2-yloxy)Qthylamine
A solution of 35 g o tetrahydropyran-2-yloxy aceto-
nitrile in 100 ml of ether is added dropwise to a slurry
of 10 g of lithium aluminum hydride in 300 ml of ether
and 100 m~ of tetrahydrofuran. The slurry is refluxed
for 210 minutes, cooled, and 25 ml of sat. potassium
carb~nate solution is added at;a rate that maintalns
gentle reflux. After 90 minutes the sIurry is filtered
and the solid is washed with ether. The filtrate is
evaporated in vacuo and distilled to give 33.6 g of 2-(tetra- -~
hydropyran-2-yloxy)_thylamine, boiling point 41.5-46C at
0.5-0.8 mm.
. ~ '
c~ 2-lTetrahydropvran-2-ylo~y)ethyl]urea
A mixture of 33.2~g of 2-(tetrahydropyran-2-yloxy~
ethylamin~ SO g of lce, and a ~solution oE~35 g of
~- potassium isocyanate in~80 ml of~water is~stirred well as
4;.6 m- of SN~hydrochloric acid~ ~cooled to~ -40C) is added
in bne portkA ~bc Fosu~ ting~solution s reEIu~ed for~
~OS096~ K54 oa
.
90 minutes, cooled, and extracted with four 150 ml por-
tions of chloroform. The chloroform extract is dried
and evaporated in vacuo to give 39.6 g of oil.
d) I~-Nl so~ 2-(tetrahydropyran-2-yloxy)
ethyl)urea
A solution of 39.6 g of N-12-(tetrahydropyran-2-
yloxy)urea in 400 ml of ether and 100 ml of methylene
chloride is slurried with 50 g of sodium acetate and
cooled to -10C with mechanical stirring. A solution of
30 g of nitrogen dioxide in 100 ml of ether is added over
a 30 minute period, the slurry is stirred a-t -10C for 20
minutes and then filtered. The filtrate is washed with
saturated sodium bicarbonate solution, dried, and evapor-
ated to give 41.8 g of yellow oil.
.,, ' .
e) 2-(Tetrahydropyran-2-yloxy)-1-diazoethane
A solution of 41.8 g of N-nitroso-N-[2-(tetrahydro-
pyran-2-yloxy)ethylJurea in 200 ml of ether and 100 ml of
pentane i5 added to 450 ml of lN sodium hydroxide solu-
tion at 1-4~C over a 25 minute period. The solution is
~ stirred for an additional 30 minutes and the layers are
i separated. The organic layer is dried over sodium hydroxide
pellets at 0C for 5 minutes, and then filtered.
,
.
-49-
K54Oa
~S~g66
f) 9-Fluoro~ ,17,21-trihydroxy-16~-[2-(tetra-
hydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione
A solution of 2-(tetrahydropyran-2-yloxy)-1-diazo-
ethane ~prepared from 0.21 mole of precursor) in 400 ml
o~ 3:1 ether-pentane is diluted with 100 ml of cold methanol
and stirred well as 5.0 g of 9-fluoro~ ,16a,17,21-
tetrahydroxypregn-4-ene-3,20~dione, 16,17-cycloborate is
added in portions. When nitrogen evolution ceases, the
slurry is filtered to give 0.4 g of recovered borate. The
filtrate is evaporated ln vacuo to give an oil that is
dissolved in chloroform and chromatographed on a 150 g -
silica gel column. Elution with 1:1 chloroform-ethyl :
acetate gives 4.0 g o~ TLC pure product. A small sample
of similar material is recrystallized from acetone-hexane to . :
give 9-fluoro-11~,17,21-trihydroxy-16~-12-(tetrahydro-
.
.j pyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione, melting point
196-200C. ;~
- . B. 9-Fluoro-11~,17,21-trihydroxy-16a-~2-(tetrahy~
.
; 20 pyran-2-yloxy)ethox~]pregn-4-ene-3,20-dione, 21-
. ~ ... .
acetate
A solution of 4.0 ~ of 9-fluoro~ ,17,21-trihydroxy-
16a-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20~
dione in SO ml of pyridine is allowed to stand with 5 ml :::
of acetic anhydride for 3 hours. The :solvents are re-
. moved in vacuo and the residue is dissolved in chloroform
-l and washed with 5% hydrochloric acid, water, and 5%
. - . .
sodium:bicarbonate solutionO Drying and solvent removal
gives 4~4 g of crude product. Crystallizatlon of a
-'! : .
3 0 ~ ' :
50~
: :~
,
:
K54Oa
~05096G
similar sample from acetone-hexane gives 9-fluoro-11~,17,~
21-trihydroxy-16a-~2-(tetrahydropyran-2-yloxy)ethoxy]-
pregn-4-ene-3,20-dione, 21-acetate, melting point 150-152C.
C. 9-Fluoro-11~,17,21-~rihydroxy-16c~-(2-hydroxyethoxy)-
~regn-4-ene-3,20-dione, 21-acetate
.,
Method A
A solution of 4.4 g of 9-fluoro-11~,17,21-~rihydroxy-
}6a-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-
lo dione, 21-acetate in 60 ml each of acetic acid and water
is stirred for 4 hours and the bulk of the solvent removed
ln vacuo. The residue is dissolved in chloroform and
washed with 5~ sodium bicarbonate solution. Drying and
solvent removal gives an oil whlch crystallizes from acetone- :~
hexane to give 2.4 g of 9-fluoro-ll~l7~2l-trihydroxy-l6a- .
(2-hydroxyethoxy)pregn-4-ene 3,20-dione, 21-acetate, melt- : :
ing pc~int 162-165C. ~ :
,
Method B
A solution of 1.98 g of 9-fluoro-5'~ ,21-tri-
hydroxypregn-4-eno-[16a,17-h] [1,4]dioxane-3,20-dione, 21-
acetate (prepared as described in Example 1) in 100 ml of
methanol is cooled ~o 0C and 148 mg of sodlum boro
~iydride is added. After g minutes the solution is poured
into a mixture of ice and 5% hydrochloric acid and ex-
.
tracted with chloroform to give 1.78 g of oil. This
material is chromatographed on a SO~ g~- silica gel column.
Elution with 19:1 chloroform-ethyl~ acetate gi~es 0.45 g
of pure 9-fluoro~ 7~2l-trihydroxy-l6o~-t2-hydroxyethoxy)
pregn-4-ene-3,20-dione, 21-acetate`and a total of 0.35~ g
of impure material.
. . : ~ :
~51- I ~
:
: , . . .
K540 a
~0~
D. 9-Fluoro-16~-(2-mesyloxyethoxy)~ 7~2l-tri
hydroxypregn-4-ene-3,20-dione, 21-acetate
A solution of 0.80 g of 9-fluoro-16~-(2-hydroxy-
ethoxy)-11~,17,21-trihydroxypregn-4-ene-3,20-dione, 21-
acetate in 10 ml of pyridine is stirred with 0.5 ml of
methanesulfonyl chloride for 90 minutes at 0C under
nitrogen. The solution is poured into cold 5% hydrochloric
acid and extracted with chloroform. The chloroform extract
is dried and evaporated to give an oil which is chromato-
graphed on a 20 g - silica gel column. Elution with
chloroform gives 521 mg of TLC pure 9-fluoro-16~-(2-
mesyloxyethoxy)-11~,17,21-trihydroxypregn-4-ene-3,20-dione,
21-acetate.
E. 9-Fluoro-llg,21-dihydroxypre~n-4-eno[16~,17-~[1,4]-
dioxane-3,20-dione, 21-acetate
. . _ .
A solution of 521 mg of 9-fluoro-16~-(2-mesyloxy-
ethoxy)~ ,17,21-trihydroxypregn-4-ene-3,20-dione, 21-
; acetate in 40 ml of dimethylsulfoxide is stirred at 110C
under nitrogen for 2 hours with 600 mg of sodium bicarbonate
(dried at 110C ln vacuo). The solution is cooled, poured
into 5% hydrochloric acid and extracted with chloroform.
The chloroform extract is washed twice with 2~ hydrochloric -
acid, dried, and evaporated in vacuo to give 421 mg of oil.
.,.,j .
This material is chromatographed on a 20 g - silica gel
column. Elution with chloroform gives 331 mg of TLC pure
material which solidifies. Recrystallization from acetone- -
hexane gives 215 mg o 9-fluoro-11~,21 dihydroxypregn-4-
eno[l6~,17-b][1,4]dioxane-3,20-dione, 21-acetate, melting
polng 275-280C, dec.
~, .. .
-52-
. . .; : , . .
. : ~. . . . . . . . . .
K540 a
Anal. Calc'd for C25H33FO7 C~ 64-64; H~ 7-16; F~ 4-09-
E~ound: C, 64.59; H, 7.21; F, 3.98.
Example 19
21-Chloro-9-fluoro-5'~ -dihydroxypreqn-4-eno-
` [16~,17-b][1,4~dioxane-3,20-dione
A. 16~-~llyloxy-9-fluoro-11~l17,21-trill~droxypreqn-
4-ene-3,20-dione, 21-methanesulfonate
.. . .. ... . .. .. . . .. . _ _
i A solution of 1.0 g of 16~-allyloxy-9-fluoro-11~,
17,21-trihydroxypregn-4-ene-3,20-dione (prepared as de-
scribed in Example lA) in 15 ml of pyridine is stirred at
0C under nitrogen for 150 minutes with Q.35 ml of methane-
sulforlyl chloride. The resulting solution is poured into
cooled 5~ hydrochloric acid and extracted with chloroform.
The chloroform solution is washed with water, dried, and
evaporated ln vacuo to give 1.05 g of residue.
'
B. 16~-Allyloxy-21-chloro-9-fluoro-llB,17-dihvdrox~-
pregn-4-ene-3,20-clione
A solution of 1.05 of 16~-allyloxy-9--fluoro-11~,~
17,21-trihydroxypregn-q-ene-3,20-dione, 21-methanesulonate
in 65 ml of dimethylformamide is refluxed for 1 hour under
nitrogen with 1.05 g of lithium chloride. The solution is
cooled, diluted with 400 ml of water and filtered. The
solid is dissolved in chloroform, washed with 5% hydro-
chloric acid, water, dried, and evaporated in vacuo to
~ give 800 mg of residue. This material is dissolved in
- chloroform and chromatographed on an 18 g - silica gel
column. Elution Wi.th chloroform gives 600 mg of TLC pure
~ 30
.
-53-
.
~540 a
3i66
material. Two recrystalli2ations from acetone-hexane give
500 mg of 16~-allyloxy-21-chloro 9-fluoro-11~,17-di-
hydroxypregn-4-ene-3,20-dione, melting point 224-225C.
Anal. Calc'd for C24H32ClFO5: C, 63.36; H, 7.09;
Cl, 7.79; F, 4.18.
Found: C, 63.53; H, 6.97; Cl, 7.50; F, 4.14.
C. 21-Chloro-9-fluoro~ ,17-dihydrox~-16~-(oxiranyl-
methoxy)pregn-4-ene-3,20-dione
.,
Following the procedure of Example lC, but sub-
stituting 16a-allyloxy-21-chlorQ-9-fluoro llB,17-dihydroxy-
pregn-4-ene-3,20-dione for 9-fluoro-16a-allyloxy-11~,17,21-
trihydroxypregn-4-ene-3,20-dione, 21-acetate, the title com~
pound is obtained.
D. 21-Chloro-9-fluoro-5'~ -dihydroxypr~n-4-eno-
116~,1?-b}[1,4]dioxane-3,20-dione
Following the procedure of Example lD, but sub-
~-~ stituting 21-chloro-9-fluoro-11~,17-dihydroxy-16~-(oxiranyl-
methoxy)pregn-4-ene-3,20-dione for 9-fluoro~ ,17,21-tri-
hydroxy-16~-(oxiranyl~methoxy)pregn-4-ene-3,20-dione,
21-~cetate, the title compo~nd is obtained.
~ ,.....
,
-54-
K540 a
Example 20
21-Chloro-9-fluoro-2',3'-dihydro-11~-hydroxy-5'-
phenylpreyna-1,4-dieno116~,17~b]~1,4]dioxin-
' 3,20-dione
A. 21-Chloro-9-fluoro~ ,17-dih~droxy-16~-[(2-phenyl-
2-propenyl)oxy]pregna-1,4-diene-3,20-dione
A solution of 2-phenyl-3-diazo-1-propene (pxepared
from 28.5 g of N-(2-phenyl-2-propenyl~ethyl carbamate,
prepared as described in Example 4) in 700 ml of ether
and 50 ml of pentane is diluted with 150 ml of methanol
at 0C and 10 g of 21-chloro-9-fluoro-11~,16a,17 tri-
hydroxypregna-1,4-diene-3,20-dione, 16,17~cycloborate is
added in portions. After nitrogen evolution ceases the
solvents are removed ln vacuo and the residue is re-
crystallized from methanol to give 6.1 g of 21-chloro-9-
fluoro-llR~l7-dihydroxy-l6a~[(2-phenyl-2-propenyl)oxy3
pregna-1,4-diene-3,20-dione, melting point 212-214C.
Anal. Calc'd. for C30H34 5 C, 68.11; H, 6.48;
Cl, 6.70; ~, 3.59.
Found: C, 68.37; H, 6.75; Cl, 6.92; F, 3.49.
B. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-[(2-phenyl-
oxiranyl)methoxyJpregna~1,4-diene-3,~0-dione
A solution of 4.0 g of 21-chloro-9-fluoro~ ,17- -
dihydroxy-16a-[(2-phenyl-2-propenyl~oxy]pregna-1,4-diene-
3,20-dione in 100 ml of dichloromethane is stirred with
1.6 g of m-chloroperben~oic acid for 1 hour at room
-temperature. The resulting solution is washed with a
mixture of 100 ml each of 5~ sodium sulfite solution and
-55-
.i ,:
., , .:
'
X540a
1~S6)966
5~ sodium bicarbonate solution, dried, and evaporated 1n
vacuo to give 4.8 g of crude 21-chloro-9-fluoro-11~,17-
dihydroxy-16a-~(2-phenyloxiranyl)methoxy]pregna-1,4-
diene-3,20-dione.
C. 21-Chloro-9-fluoro-11~,17-dihy~ (2-oxo-2-
phenylethoxy)pregna-1,4-diene-3,20-dione
A solution of 4.8 g of 21-chloro-9-fluoro-11~,17-
dihydroxy-16~-[(2-phenyloxiranyl)methoxy]pregna-1,4-
diene-3,20-dione in 150 ml of tetrahydrofuran is stirred
with a solution of 10 g of periodic acid in 40 ml of
water for 4 hours. The resultiny slurry is diluted with
1 liter of water and Eiltered. The solid is dried ln
vacuo and recrystallized from methanol-chloroEorm to give
2.4 g of 21-chloro-9-fluoro-11~,17-dihydroxy-16a-(2-oxo
2-phenylethoxy)pregna-1,4-diene-3,20-dione, melting
point 266-268C, dec.
Anal. Calc'd. for C29H32ClFO6: C, 65.59; H, 6.08; Cl, 6.68;
F, 3.58.
Foond: C, 65.28 H, 6.38; Cl, 6.62; F, 3.i7.
.
. I .
3 0
.` .
-56-
., ~
.
,
K540 a
66
D. 21-Chloro-9-fluoro-2',3'-dihydro-11~-hydroxy-5'-
phenylpregna-1,4-dieno[16a,17-b][1,4]_-dioxin-
3,20-dione
A slurry of 150 mg of p-toluenesulfonic acid in 750
ml of benzene is refluxed with a Dean-Stark trap. The
first 150 ml of benzene-water azeotrope is discarded and
Linde type 4A molecular sieves are added to the trap.
After 30 minutes at reflux, the solution is cooled and
1.0 g of 21-chloro-9-fluoro~ , 17-dihydroxy-16a-(2-oxo-
2-phenylethoxy~pregna-1,4-diene-3,20-dione is added. The
resulting slurry is refluxed for 6 hours under nitrogen,
cooled, washed with 5% sodium bicarbonate solution, water,
dried and evaporated ln vacuo -to yive 955 mg of crude
product. This material is dissolved in chloroform and
chromatographed on a 40-g silica gel column. Elution with
chloroform gives TLC pure material which fails to crystallize
and is rechromatographed on a 20-g silica gel column.
Elution with 3:1 chloroform-hexane gives 525 mg of solid.
Recrystall~æation from ethyl acetate-hexane gives 443 mg
of 21-chloro-9-fluoro-2',3'-dihydro-11~-hydroxy-5'-
phenylpregna-1,4-dieno[16~,17-b][1,4]dioxin-3,20-dione,
melting point 195-197C.
Anal. Calcd. for C2gH30ClFO5:
C, 67.89; H, 5.90; Cl, 6.91; F, 3.71.
Found: C, 68.02; H, 5.84; Cl, 6.70; F, 3.59.
-57-
,
K540 a
Example 21
21-Chloro-9-fluoro-11~-hydroxypregna-1,4-dieno-
- 116~,17-b][1,4]dioxane-3,20-dione
A. 21-Chloro-9-fluoro-11~,17-dihydroxy-16a-[2-(tetra-
hydropyran-2-yloxy)ethoxy]pregna-1,4-diene-3,20-
dione
A solution of 2-(tetrahydropyran-2-yloxy)-l~diazo-
ethane (prepared from 0.21 mole of N-[2-(tetrahydropyran-
2-yloxy)ethyl~urea as described in Example 18) in 400 ml
of 3:1 ether-pentane is diluted with 100 ml each of ether
and methanol at 0C and stirred vigorously while 5.0 g
of 21-chloro 9-fluoro-11~,16~,17-trihydroxypregna-],4-
diene-3,20-dione, 16,17-cycloborate is added. After
nitrogen evolution ceases the solvents are removed }n
vacuo and the residue dissolved in chloroform and chroma-
tographed on a 100 g-silica gél column. Elution with
chloroform give 3.6 g of solid. Recrystallization from
acetone-hexane gives 3.26 g of 21-chloro-9-fluoro~ ,17-
s dihydroxy-16~-[2-(tetrahydropyran-2-yloxy)ethoxy]pregna-
1,4-diene-3,20-dione, melting point 168-170C.
B. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-(2-hydroxy-
ethoxy)pregna-1,4-diene-3,20-dione
A solution of 4.2 g of 21-chloro-9-fluoro-llg,17-
dihydroxy-16-[2-tetrahydropyran-2-yloxy)e~hoxylpregna-
, 1,4-diene-3,20-dione in 150 ml of acetic acid and 75 ml
of water is stirred at room temperature for 6 hours,
diluted with 1.5 liter of cold water, and the resulting
solid ~iltered and dried in vacuo to give 2.63 g.
.
` -58
`
. . , , ': : , : , .,
K54 0 a
~\5û9~6 . `
, -
Recrystallization from acetone-nexane gives 2.03 g of
21-chloro-9-fluoro-11~,17-dihydroxy-16~-(2-hydroxy-
ethoxy)pre~na-1,4-diene-3~20-dione, melting point 226-
228C, dec.
Anal. Calcd. for C23H30ClFO6:
C, 60.46; H, 6.62; Cl, 7.76; F, 4.1~.
Found: C, 60.26; H, 6.49; Cl, 7.88, F~ 4.26.
' .
C. 21-Chloro-9-fluoro-11~,17-dihydroxy-16
.. i .
mesyloxyetho~y)pre~na-1,4-diene-3,20~-dione
A . A sol~tion of 1.5 g of 21-chloro-9-fluoro-llB,17-
`; dihydroxy-16a-(2-hydroxyethoxy)pregna-1,4-diene~3,20-
dione in 25 ml of pyridine is cooled to 0C and 0.6 ml o
methanesulronyl chloride is added. After 2 hours the
mixture is poured into cold dilute hydrochloric acid and
extracted with chloroform. The chloroform solution is
driea and evaporated in vacuo to 2.0 g of crude mesylate.
.
Do 21-Chloro-9-fluoro-~ hydroxypregna-l~4-dien
~16,17-b][1,4]dioxane-3,20-dione
A solution of 2.0 g of 21-chloro-9-fluoro-11~,17-
dihydroxy-16~-~2-mesyloxyethoxy)pregna-1,4-diene-3,20-
dione in 100 ml of dimethylsulfoxide is stirred at 110C
.
under nitrogen with 2.0 g of sodium bicarbonate (dried
. ~
? at 110C }n vacuo). After 1 hour the slurry is cooled,
., .
poured into 2 liters of 2.5% hydrochloric acid, and 2X-
~racted with chloroform. The chloroform solution is
, -:
washed twice with dilute hydrochloric acid, dried, and
evaporated in vacuo to give 1.4 g of crude product.
- ~ .
. . . : .
'-59-
. .
.
K540a
~5~6i6
This material is dissolved in chloroform and chromato-
graphed on a 100 g-silica gel column. Elution with
chloroform gives 880 mg of material wh~ch crystallizes
from methanol-chloroform to give 405 mg of 2~-chloro-9-
fluoro-ll~-hydroxypregna-1,4-dieno[16a,17-b][1,4]dioxane-
3,20-dione, mel-ting point 320-321C, dec.
Anal. Calcd for C H ClFO :
23 28 5
C, 62.g4; H, 6.43; Cl, 8.08; F, 4.33.
Found: C, 62.73; H, 6.20; Cl, 8.27; F, 4.27.
Example 22
_~,21-Dih~droxyer ~n -1,4-dieno[16~,17-b][l,~]-
dioxane-3,20~dione, 21-acetate
-
A. 16~-[2-(Tetrahydrop~ran-2-yloxy)ethoxy~ ,17,21-
trihydroxypregna-1,4-diene-3,20-dione
A solution of 2~(tetrahydropyran-2-yl)oxy-1-diazo-
ethane ~prepared from 69.1 g of N-[2-(tetrahydropyran-2-yl-
oxy)ethyl]urea by the procedure described in Example 18)
; in 600 ml of 3:1 ether-pentane is stirred with 200 ml
each of ether and methanol at O~C. 14 g of 11~,16~,17,
21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cyclo-
borate is added in portions. After nitrogen evolu-tion
ceases the solvents are removed in vacuo and the residue
is dissolved in chloroform and chromatographed on a
150 g-silica gel column. Eiution with chloroform and
then 1:1 chloroform-ethyl acetate gives 4.0 g of TLC
pure 16~-[2-(tetrahydropyran-2~yloxy~ethoxy]~ ,17,21-
trihydroxypregna-1,4-diene-3,20-dione.
'.
-60
K540a
B. 16~-[2-(Tetrahydropyran-2-yloxy)ethoxyl~11~,17,21-
trihydroxypregna~ -diene-3,20-dione, 21-acetate
A solution of 3.75 g of 16a-[2-tetrahydropyran-2-
yloxy)ethoxy]-11~,17,21-trihydroxypregna-1,4-diene-3,20-
dione in 15 ml of pyridine and 5 ml of acetic anhydride
is kept at room temperature for 4 hours and the solvents
are then evaporated in vacuo. The residue is dissolved
in chloroform and washed with dilute hydrochloric acid,
; water, dilute sodium bicarbonate solution, and dried.
Solvent removal gives 4.9 g of crude 16~-~2-(tetrahydro~
pyran-2-yloxy)ethoxy]-11~,17,21-trihydroxypregna-1,4-
diene-3,20~dione, 21-acetate.
C. 16~-(2-Hydroxyethoxy)~llR,17,21-trihydroxypreqna-
1,4-diene-3,20-dione, 21-acetate
A solution of 4.9 g of crude 16a-~2-~tetrahydro-
pyran-2-yloxy)ethoxyl-11~,17,21-trihydroxypregna-1,4-
diene-3,20-dione, 21-acetate in 60 ml each of acetic acid
and water is stirred for 6 hours at room temperature.
. .
The solvents are removed ln vacuo and the residue is
dissolved in chloroform and washed with 5~ sodium bi-
carbonate solution and dried. Solvent removal gives
3.9 g of product which is combined with 750 mg of product
from a different batch and chromatographed on a 90 g-silica
gel column. Elution with chloroform and then 1:1 chloro-
form-ethyl acetate gives 3.7 g of material which crystallizes
from acetone-hexane to give 3.17 of 16~-(2-hydroxyethoxy)-
,17,21-trihydroxypregna-1,4~diene-3~20-dione, 21-
acetate~ melting point 138-140C.
-61-
.
,. - ~.. ~: . .
1050966 KS40a
. .
D. 16~-(2-Mesyloxyethoxy)~ ,17,21-trihydroxypregna~
1,4-diene-3,20-dione, 21-acetate
A solution of 3.0 g of 16a-(2-hydroxyethoxy)~
17,21-trihydroxypregna-1,4-diene-3,20-dione, 21 acetate
in 15 ml of pyridine is stirred with 0.75 ml of methane
sulfonyl chloride at 0C for 150 minutes. The mixture is
poured into 1.5 liter of cold lN hydrochlorie acid,
stirred for a short time, and filtered. The resulting
solid is dissolved in chloroform, washed with water,
dried, and evaporated in vacuo to give 4.0 g of crude
16a-(2-mesyloxyethoxy~ ,17,21-trihydroxypregna-1,4-
diene-3,20 dione, 21-acetate
.
. ~ , .
E. 11~,21-Dihydroxypre~na-1,4-dieno[16~,17-b][1,4
dioxane-3,20-dione, 21-acetate
A solution of 4.0 g of crude 16~-~2-mesyloxy- -
~j ethoxy)-11~,17,21 ~rihydroxypregna-1,4-diene-3,20-dione,
.
21-aeetate in 200 ml of dimethylsulfoxide is stirred at
110C under nitrogen, with 4.0 g of sodium bicarbonate
, ~ ' 'I . .
for 2 hours. The slurry is cooled, poured into 2 liters
. . ~ . ~. .
of cold 2.5% hydrochloric acid, and extracted with
c~loroform ~three 250 ml portions). The chloroform
solution is washed with two 1 liter portions of 2.5
.
hydroohlorie aeid, dried, and evaporated in vacuo. The
.::
residue i5 dissolved in chloroform and chromatographed on
a 66 g-silica gel eolumn. Elution with chloroform gives
2.4 g of material which erystallizes from acetone-hexane
to give 1.55 g of 11~,21-dihydroxypregna-1,9-dienoll6a,~
- ~ 17 b][l,4]dioxane-3,20-dione, 21-~cetate, melting point
280-282C.
' .
Z -62- ~
., .
.
i.... . . ,, , ,.. , . ... . ~ . . . .~:
; : : ..... .. :.... : .. :: :, . . .: . :. . , , , : ..
105~966 K540a
Examples_23-25
Following the proc~dure of Example 1, but substituting
the steroid listed in column I for 9-fluoro~ ,16~,17,21-
tetrahydroxypregn-4-ene-3 t 20-dione, 16,17-cycloborate, -the
steroid listed in column II is obtained.
'
3~
-63-
X54 0 a
~15~966
~`I Q ~),~ .IJ
Q. `` I aJ I ~L)
X
X
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Examples 26-28
Following the procedure of Example 15, but sub~
stituting the acid anhydrid~ listed in column I for acetic
' anhydride, the steroid listed in col.umn II is obtained.
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Examples 29-32
.
Following the procedure of Example 20, but sub-
stituting the steroid listed in column I for 21-chloro-9-
fluoro~ ,16~,17-trihydroxypregna-1,4-diene-3,20-dione,
16,17-cycloborate, the steroid listed in column II is
obtained
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Examples 33-35
Following the procedure of Example 22, but sub-
stituting the acid anhydride listed in column I for acetic
anhydride, the steroid listed in col~mn II is obtained.
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O Example 36
.
21-Chloro-5'-(4-chlorophen~1)-9--fluoro-~',3'-
- dihydro~ -hydroxypregna-1,4-dieno[16~,17-b]-
- [1,4]dioxin-3,20-dione
Following the procedure of Example 20, but sub-
stituting 2-~4-chlorophenyl)-3-diazo-1--propene for 2-
; phenyl-3-diazo-1-propene, yields 21-chloro-5'-(4-chloro-
phenyl)-9-fluoro-2',3'-dihydro-11~-hydroxypregna-1,4-
dienotl6~,17-b][1,4]dioxin-3,20-dione, melting point
212-214C, dec., softening at 200C.
Example 37
21-Chloro-5'-(1,1-dimeth~lethyl)-9-fluoro-2',3'-- :
dihydro-llB-h~droxypregna-l~4--dieno~l6~l7-~]
11,4]dioxin-3,20-dlone :~
Following the procedure of Example 7, but sub- :
stituting 2-(1,1-dimethylethyl)-3-diazo-1-propene fcr 2- ~ .
methyl-3-diazo-1-propene, yields 21-chloro-5'-(1,1-dimethyl-
ethyl)-9-fluoro-2',3'-dihydro-11~-hydroxypregna-1,4-dieno-
[16~,17-~]~1,4]dioxin-3,20-dione, melting point 240-242C,
dec.
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o ~
9-Fluoro~ ,21-dihydroxy-5'~-methylpre~n-4-eno-
[16a,17-b][1,4~dioxane-3,20-dione, 21-acetate
Ao 9-Fluoro-11~,17,21-trihydroxy-16a-(2~-hydroxypro-
~oxy)pregn-4-ene-3,20-dione, 21-acetate
A solution of 1.0 g of 9-fluoro-11~, 17,21-trihydroxy-
16~-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate (pre-
pared as described in Example 2D) in 80 ml of methanol is
cooled to 0C and 80 mg of sodium borohydride is added. After
10 minutes the solution is poured into chloroform and ex-
tracted with dilute hydrochloric acid. The chloroform solu-
tion is dried and evaporated in vacuo to give the crude
product. Chromatography on a 30 g-silica gel column, eluting
with 9:1 chloroform-ethyl acetate, yields 730 mg of the title
compound.
B. 9-Fluoro~ ,17,21-trihydroxy-16a-(2~-mesyloxy-
propoxy)pre~n-4-ene-3,20-dione, 21-acetate
A solution of 7Q0 mg of 9-fluoro-11~,17,21-tri-
hydroxy-16a-(2~-hydroxypropoxy)pregn-4-ene-3,~0-dione, 21-
acetate in lQ ml of pyridine is cooled to 0C and 0.4 ml of
methanesulfonyl chloride is added. After 4 hours the mixture
i~ extracted, dried and evaporated to give the title compound.
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.
C. 9-Fluoro~ ,21-dihvdroxv-S~-methvl~regn-4-eno-
[16a,17-b][1,4~dioxane-3,20-dione, 21-acetate
A solution of 750 mg of 9-fluoro~ ,17,21-trihydroxy-
16~ (2~-mesyloxypropoxy)pregn-4-ene-3,20-dione, 21-acetate
in 50 ml of dimethylsulfoxide is stirred at llO~C under
nitrogen with 1.0 g of sodium bicarbonate. After ~ hours
the reaction mixture is extracted, dried and evaporated to
yield the title compoundO
-
9-Fluoro-11~,21-dihvdroxv-5'~-~henvl~recn-4-eno-
~16,17-bl~1,4]dioxane-3,20-dione, 21-acetate
A. 9-Fluoro-11~,17,21-trihydroxy-16~-(2-phenyl-?-
hydroxyethoxy)pre~n-4-ene-3~2o-dione~ 21-acetate
A solution of 1~0 g of 9-fluoro-11~,17,21-trihydroxy-
16~(2-phenyl-2-oxoethoxy)pregn-4-ene-3,20-dione, 21-acetate
;; (prepared as described in Example 4D) in 80 ml of methanol
is cooled to.0C ànd 80 mg of sodium borohydride is added.
.
After 10 minutes, the solution is poured into chloroform
; 20 and extracted with dilute hydrochloric acid. The chloroform
solution is dried and evaporated ln vacuo to yield the title
compound.
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Bo 9-Fluoro~ ,17,~1-trihydroxy-l6a-(2-mesyloxy-2
enylethoxy)pre~n-4-ene-3,20-dione, 21-acetate
~ A solution of 700 mg of 9-fluoro~ ,17,21-trihydrox~-
16a- (2-phenyl-2 hydroxyethoxy)pregn-4-ene-3,20~dione, 21-
acetate in 10 ml of pyridine is cooled to 0C and 0.4 ml of
methanesulfonyl chloride is added. After 4 hours the mixture
is extracted, dried and evaporated to give the title compound.
C. 9-Fluoro-llB,21-dihydroxy-s~-phenylpreqn-4-en
[16~,1 -b][1,4~dioxane-3,20-dione, 21-acetate
A solution of 750 mg of 9-fluoro-116,17,21-trihydroxy~
16a-(2-mesyloxy~2-phenylethoxy)pregn-4-ene-3,20--dione, 21-
a¢etate in 50 ml of dimethylsulfoxide is stirred at 110C
under nitrogen with 1.0 g of sodium bicarbonate. After 2
hours the reaction mixture is extracted, dried and evapor-
ated to yield the title compound.
Ex ~
21-Chloro-9-fluoro-11~-hydroxy-5'-methyl-4'-phenyl-
preqna-1,4- dieno[16~,17-b][1,4]dioxin-3,20-dione
_
A. 21-Chloro-9-fluoro-11~,17-dihydroxy-16~-[(3-oxo-3
henylprop-2-yl)oxy]pregna-1,4-diene-3,20-dione~
,
- a. N-[2-~3-oxo-3-phenyl~opyl)~phthalimide
; A solution of 58 g of ~-bromopropiophenone and 50 g
of potassium phthalimide in 200 ml~of dimethylformamide is
refluxed for 2 hours under nitrogen, cooled, and poured into
500 ml of water. The resulting mlxture is extracted with
ether, and khe ether solution is drled and evaporated in vacuo.
A solu ion of the residue in 200 ml of ether gives the title
~ .
3G compound as a solid.
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K540a
5iO966
I b. 2-[1-(N-phthalimidoeth~1)]-2-phenyldioxolane
.~
A solution of 49.9 g of ~-[2-(3-oxo-3-phenylpropyl)]
phthalimide in 500 ml of toluene is refluxed for a total of
13 days with S g of ~-toluenesulfonic acid and 150 ml of
ethylene glycol. The solution is cooled, diluted with
chloroform, and washed with dilute sodium bicarbonate solu-
tion. The chloroform solution is dried and evaporated to
give, on trituration with ether, 51.5 g of the title com-
pound, melting point 127 130C.
I0
c 2~ Aminoethyl)-2-phenyldioxolane
A solution of 51.5 g of 2-[1-(N-phthalimidoethyl)]-
2-phenyldioxolane in 500 ml of méthanol is refluxed for 6
hours with 5.76 g of hydrazine. The slurry is cooled t f il-
tered and the solid washed well with methanol. The filtrate
is evaporated in vacuo, and the residue triturated ~ith di-
chloromethane and filtered. The filtrate is distilled in
vacuo to give 28.25 g of the title compound, boiling point -
`1 97-100C at 1.1 mm Hg.
d. 2-Phenyl-2-(1-~ethox~ca~bonylamlnoethyl)-
dioxolan_ ~
A solution of 2-~1-aminoethyl)-2-phenyldioxolane
(20 mmoles), triethyl amine (24 mmoles), and ethyl chloro- ; -
.
ormate (22 mmol~s) in L00 ml of dichloromethane is stirred
at 0C for 2 hours, washed wi~h water, dried, and evapor-
"
aeed to give the title compound. ~ ~
.
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.
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e. 2-Phenyl-2~ diazoeth~)dioxolane
Following the procedure of Example 4A (parts c and
d), hut substituting 2-phenyl-2-~1-ethoxycarbonylamino-
ethyl)dioxolane for N-(2-phenyl-2-propenyl)ethyl carhamate,
the title compound is obtained.
f. 21-Chloro-9-fluoro-11~,17 ~ ~-[(3
oxo~ henylprop-2-yl)oxy]~regna-1,4-diene-
3,20-dione
A solution of 2-phenyl-2-(1-diazoethyl)dioxolane in
3:2 ether-pentane is diluted with methanol and cooled to 0C.
21-Chloro-9-fluoro-11~,16~,17-trihydroxypregna-1,4-diene-
3,20-dione, 16,17-cycloborate is added in portions until
nitrogen evolution ceases. The solvent is removed ln vacuo.
The residue is purified and dissolved in tetrahydro-
furan. The solution i9 refluxed with hydrochloric acid. The
solvent is removed ln vacuo and the residue is diluted with
water, extracted with chloroform, and the chloroform solution
is washed with 5% sodium hicarbonate solution, water, dried,
and evaporated to yield the title compound.
.
~; . . ':
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. ... , . .. . . . , . , ~. . .. . . . .
K540a
66
B. 21-Chloro-9-fluoro~ hydroxy-5'-me h
phenylpregna-1,4-dieno[16~,17-b][1,4]dioxin-
-- v . . _
3,20-dione
A slurry of 150 mg of ~-toluenesulfonic acid in
750 ml of benzene is refluxed with a Dean-Stark trap. The
first 150 ml of benzene-water azeotrope is discarded and
~inde type 4A molecular sieves are added to the trap. After
30 minutes at reflux, the solution is cooled and 1.0 g of
21-chloro-9-fluoro-11~,17-dihydroxy-16~-[(3-oxo-3-phenyl-
io prop-2-yl)oxy]pregna-1,4-diene-3,20-dione is added. The
mixture is refluxed for 6 hours under nitrogen, cooled,
washed with 5~ sodium bicarbonate solution, water, dried
and evaporated ln vacuo to yield the title compound.
.,~ .
., - .. . .
.
i 30 ~
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