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Патент USA US3049566

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3,®49,55?
Patented Aug. 14, 1962
2
3,049,556
lMPRGVED PROCESS FGR THE PRODUCTIGN OF
FLUORO HYDROXY STEROIDS
Ralph F. Hirschmann, Scotch Plains, N..I., assignor to
Merck & Co., Inc, Rahway, N.J., a corporation of
New Jersey
No Drawing. Filed Nov. 12, 1958, Ser. No. 773,173
3 Claims. (Cl. 260—397.45)
It is indeed surprising and unexpected to ?nd that this
?uorination reaction can be carried out in the mixture
of hydrogen ?uoride and tetrahydrofuran without the ad
dition of any other solvent. I have found that this mix
ture has the desirable property of being a suitable sol
vent for the oxido steroids and makes it unnecessary to
utilize additional solvents. Further, the method of the
present invention can be utilized to convert oxido steroid
alcohols to the corresponding ?uoro-hydroxy steroid alco
This invention relates to an improved process for the 10 hols, thus avoiding the necessity of ?rst converting the
conversion of oxido steroids to the corresponding ?uoro
alcohol to an ester and then subjecting this ester to ?uori
hydroxy steroids.
The ?uoro steroids such as Qa-?HOI'OhYdI'OCOI‘tiSOHG
acetate and 9a-?uoro-16u-hydroxyprednisolone are valu
able anti-in?ammatory agents currently being used ther
apeutically. The introduction of the ?uoro substituent in
such compounds is usually accomplished by reacting the
corresponding 96,11,3-oxido-2l-acyl0xy compound with
nation. Accordingly, my process has the additional ad
vantage of avoiding the esteri?cation and hydrolysis steps
usually required when other ?uorination methods are em
ployed in order to convert the oxido steroid alcohols to
the corresponding ?uoro-hydroxy steroid alcohols.
The improved procedure of the present invention is
carried out by adding the oxido steroid, as a solid or in
the form of a suspension in tetrahydrofuran, to a hydro
aqueous or anhydrous hydrogen ?uoride in the presence of
a solvent for the resulting 9(1-?llOI'O-l1l3-hYdI‘OXY com 20 gen ?uoride-tetrahydrofuran mixture and allowing the
pound. For example, solvents such as methylene chloride,
reaction to continue at low temperature for su?icient time
chloroform, mixtures of ‘chloroform and tetrahydrofuran
and mixtures of acetic and propionic acids have been
used for this purpose. Upon completion of the reaction,
the desired product is recovered by washing the reaction
mixture with aqueous alkali, separating the solvent solu
tion, and ?nally evaporating the solvent.
to complete the formation of the desired ?uoro-hydroxy
steroid. In carrying out this method of preparing the
?uoro-hydroxy steroids, it is found that maximum yields
of the desired product are obtained when the reaction is
carried out at temperatures below about 10° C., although
temperatures up to about 20° C. can also be employed.
The use of solvents for the recovery and separation of
The process is conveniently effected by cooling the reac
the ?uoro steroids has a number of disadvantages. In
tion solutions to a lower temperature of the order of
the ?rst place the recovery of the desired product is com 30 about —50° to —60° C. and then allowing the reaction
plicated by the steps of extracting the aqueous layer, wash
mixture to warm up to between about 0° and 10° C.,
ing and drying the solvent layer, and ?nally evaporating
the solvent. Further, these procedures require large vol
for suiiicient time to ‘complete the formation of the de
umes of solvents since the ?uoro steroids are not very
sired ?uoro-hydroxy steroid.
and’ maintaining the reaction mixture at this temperature
soluble in the solvents. Also, the use of solvents requires 35
The hydrogen ?uoride-tetrahydrofuran reagent em
additional equipment for carrying out the extraction and
ployed in the process of the present invention is prepared
washing steps and for recovering such solvents. In addi
by mixing anhydrous hydrogen ?uoride with tetrahydro
tion, this method is not suitable for the ?uorination of
furan. The ratio of hydrogen ?uoride to tetrahydrofuran
steroid alcohols such as 20-keto-21-hydroxy pregnanes
should be in excess of about 1 mol of hydrogen ?uoride
and unsaturated pregnanes since these alcohols are even 40 per mol of tetrahydrofuran since at ratios below this the
more insoluble than the corresponding esters and require
reaction is very slow and poor yields of the desired ?uoro
large volumes of solvents. Accordingly, such alcohols are
steroids are obtained. In general, I prefer to use a hy
usually ?rst converted to a suitable ester such as the 21
dro gen ?uoride-tetrahydrofuran reagent wherein the molar
acetate, and this ester is then converted to the correspond
‘ratio of hydrogen ?uoride to tetrahydrofuran is within
ing ?uorohydroxy steroid. When the desired ?nal prod 45 the range of about 3 to 8. At such concentrations the
uct is the free alcohol, it is then necessary to hydrolyze
reaction is rapid and maximum yields of the desired prod
the ?uoro ester to produce the desired product. Further,
ucts are obtained under optimum conditions. I ?nd the
the reaction of the steroid ester with hydrogen ?uoride
use of a reagent consisting of about 2 parts by weight of
sometimes results in partial cleavage of the ester, and a
hydrogen ?uoride and 1 part by weight of tetrahydrofuran
mixture of the ester and the free alcohol is obtained
(molar ratio about 7 to 7.5 to be especially useful in my
which must be esteri?ed or hydrolyzed depending upon
process since this reagent permits the use of minimum
the form of the product desired. The prior art methods
amounts of the solvent.
for preparing the ?uoro steroids are therefore unsatis
After completion of the ?uorination reaction, the mix
factory in several respects and improved methods for the
ture is quenched ‘by the addition of aqueous alkali. In
preparation of these ?uorinated steroids have been sought. 55 order to avoid the formation of undesirable by-products,
It is an object of this invention to provide an im
it is preferred to carry out this quenching of the reaction
proved method for the conversion of oxido steroids to the
at temperatures below about 10° C. Any alkali can be
corresponding ?uoro-hydroxy steroids whereby the de
employed for this purpose, although I prefer to use an
sired product can be readily recovered in high yields. An
aqueous alkali such as an alkali metal carbonate, for
other object is to provide a method whereby the oxido 60 example, sodium or potassium carbonate for this pur
steroid alcohols can be directly converted to the corre
sponding ?uoro-hydroxy steroid alcohols. Still another
pose. The amount of alkali used should be su?icient to
neutralize the excess hydrogen ?uoride and render the
object of my invention is to provide‘an improved process
reaction mixture slightly alkaline. When an alkali metal
whereby the use of large amounts of solvents is avoided
carbonate is used, I prefer to use an amount equivalent
and the product can be recovered in crystalline form by
to one mol for each mol of hydrogen ?uoride to be neu
?ltration. Other objects will be apparent from the de 65 tralized.
tailed description of my invention hereafter provided.
The addition of the aqueous alkali to the ?uorination
In accordance with this invention, these desiderata are
reaction mixture results in the precipitation of the ?uoro
achieved by adding the oxido steroid to a hydrogen ?uo
hydroxy steroid from the reaction mixture. Usually this
ride-tetrahydrofuran mixture at low temperatures, quench
occurs in the form of a gum or ‘oil which contains tetra
70
ing the resulting reaction mixture with aqueous alkali,
hydrofuran. This tetrahydrofuran is then removed by
and recovering the precipitated ?uoro-hydroxy steroid by
warming the reaction mixture under reduced pressure
?ltration.
whereupon the solvent is quickly removed and the pre—
3,049,556
5
6
mixture of hydrogen ?uoride and tetrahydrofuran 2:1 by
EXAMPLE 9
weight was then added at —60° C. The solution was
placed in an ice bath and allowed to remain at 0° C. for
2'hours. The solution was then cooled to ---60° C. and
9oz-Flu0ro-l 15,115,] 7u,21-Tetrahydroxy-I,4-Pregnadiene
3,20-Di0ne
added dropwise to a mixture consisting of 2.96 gms. of 5
When the procedure is Example 1 is repeated using
potassium carbonate, 3 ml. of water and 34 gms. of ice.
95,1 1/8-oxido-16,17a,2l-trihydroxy-1,4-pregnadiene - 3,20
The resulting slurry was concentrated in vacuo to essen
dione as the starting material, 9a-?ll01‘O-11,B,16,17a,21
tetrahydroxy-1,4-pregnadiene-3,20-dione is obtained.
tially no tetrahydrofuran, cooled and ?ltered. The prod
uct was washed neutral with Water and dried in vacuo to
The 95,11B-oxido-17a,2l~dihydroxy- 16a -methyl - 1,4
200 mgs. The cooled product was chromatographed on 10 pregnadiene and its acetate used as the starting materials
Florisil. The 15% and 20% acetone in normal hexane
in Examples 1 and 2 can be prepared in accordance with
fractions were combined and triturated with ethyl acetate
procedures described in the copending application of Arth,
to yield pure 6a,16a-dimethyl-9a-£?uoro prednisolone,
M.P. 229-231“ C.
Johnston and Sarett, Serial No. 642,655, ?led February
27, 1957, and in my copending application Serial No.
U.V. max. 2390 EG=375.
15 742,993, tiled June 19, 1958.
EXAMPLE 4
1 119,21 -Dihydr0xy-12a-Fluoro-ll-Pregnene-3,20-Di0ne
3a-hydroxy-l6-pregnene-11,20-dione-3—acetate is re
acted with methyl magnesium iodide in the presence of
When the procedure described in Example 1 is followed
cuprous chloride thereby forming 16a-methy1-3a-hydroxy
using 115,12B-oxido-21-hydroxy-4-pregnene-3,ZO-dione as
the starting material, 11,6,21-dihydroxy—12a-?uoro-4-preg
These processes are as
follows:
20 pregnane-LLZO-dione B-acetate, which is reacted with
aqueous methanolic hydrochloric acid to form ‘16u-methyl
nene-3,20-dione is obtained.
3a-hydroxy-pregnane-11,20-dione. The latter compound,
The 115,12B-oxido-21-hydroxy-4-pregnene - 3,20 - dione
which is a potent anesthetic, is reacted with acetic anhy
dride in the presence of p-toluene sulfonic acid catalyst to
Using the experimental conditions described in United 25 form a mixture of enol acetate containing 16a-methyl
used as the starting material in this example can be pre
pared as follows:
3a,20-dihydroxy-17,20-pregnene~1l-one 3,20 - diacetate;
States Patent 2,628,966, IZa-bromo-Z1-hydroxy-4-preg
nene-3,11,20-trione is reacted with excess semi-carbazide
to form the 3,20-bissemicarbazone; ‘this compound is re
acted with lithium boronhydride in tetrahydrofuran to
this mixture, after chromatographic puri?cation over acid
form 11 5-21-dihydroxy-12u-bromo-4-pregnene-3,20~dione 30
methyl-17a,20-epoxy - 30:,20 - dihydroxy-pregnane-l l-one
washed alumina to remove any unchanged starting mate
rial, is reacted with perbenzoic acid and the resulting 16a
3,20-bissemicarbazone; reaction of this compound with a
pyruvic acid a?ords 11,8,21-dihydroxy-12a-bromo-4-preg
pregnane-11,20-dione. The latter compound is reacted
with bromine in chloroform to form 21-brorno-16u-meth
yl-3a,17a-dihydr0xy-pregnane-11,20-dione which is re
acted with sodium iodide in acetone to produce 21-iodo
nene-3,20-dione; and treatment of this compound with a
base yields 11B,12/3-oxido-21-hydroxy-4-pregnene-3,20
dione.
This latter compound can then be acetylated by reaction
with acetic anhydride to form the 21-acetate derivative
when this compound is treated with the hydrogen-?uoride
tetrahydrofuran reagent as described above, 115,21-dihy
droxy-12u-?uoro-4-pregnene-3,20-dione-2l-acetate is ob
tained.
3,20-diacetate is hydrolyzed with methanolic potassium
bicarbonate to produce 16a-methyl-3a,17a~dihydroxy
16a-methyl-3 a, 1 7a-dihydroxy-pregnane-1 1,20-dione which
is converted Without isolation to 16a-methyl-3a,-l7u,2l
trihydroxy-pregnane-l1,20-dione ZI-acetate by reaction
40
with anhydrous potassium acetate; this compound is re
acted with chromium trioxide in pyridine to form 160:
methyl - 170:,21 - dihydroxy-pregnane-3,11,20-trione 21
EXAMPLE 5
acetate.
9u-Fluor0-1Z 5,1 7oz,21-Trihydroxy-1 6B-Methyl-],4~
The 16a - methyl - 16a,21 - dihydroxy - preg -
nane - 3,11,20 - trione 21 - acetate is reacted with bromine
Pregnadiene-3,2 0-D ione
in glacial acetic acid-chloroform to produce 4-bromo
When the procedure of Example 1 is repeated using
'
16oz - methyl - 170:,21 - dihydroxy - pregnane - 3,11,20 -
trione, which is then reacted with semicarbazide to form
95,1118-oxido-17a,21-dihydroxy-165-methyl - 1,4 - pregna
diene-3,20-dione as the starting material, 9oc-?ll01'0
160: - methyl - 1711,21 - dihydroxy - 4 - pregnene - 3,11,
115,17a,2l-trihydroxy-1613-methyl-1,4-pregnadiene - 3,20
20 - trione 3,20 - bissemicarbazone 21 - acetate.
dione is obtained.
50
EXAMPLE 6
When the procedure ‘of Example 1 is repeated using
the starting material, 9a-?uoro-11,8,17a,21-trihydroxy-4
' diene compound by contacting it with the dehydrogenating
activity of microorganisms of the class Schizomycetes, for
example, Bacillus sphaericus (ATCC 245) or Nocardia
pregnene-3,20-dione is obtained.
EXAMPLE 7
izsteroides (ATCC 9970). The 16a-methy1~11}9,17a,21
trihydroxy-l,4-pregnadiene-3,20-dione so obtained is then
60 reacted with acetic anhydride in the presence of pyridine
9a-Fluor0-l1?J 7a-Dihydroxy-2l -Acetoxy-1,4
Pregnadiene-3,20-Dione
to produce the corresponding 16u~methyl-l1?,17u,21~tri
When the procedure of Example 1 is repeated using
hydroxy-1,4-pregnadiene-3,20-dione-2l-acetate. These re
9,8,1l?-oxido-l7a-hydroxy-2l-acetoxy - 1,4 - pregnadiene
actions are more fully described in Serial No. 642,655.
3,20-dione as the starting material, 9oc-?I1OI'O-1l/5,l7ot-di
hydroxy-21-acetoxy - 1,4 - pregnadiene ~ 3,20 - dione is ob
tained.
»
hydride to form lda-methyl-l1,8,17a,21-trihydroxy-4-preg
nene-3,20-dione 3,20Jbissemicarbazone which is hydro
lyzed under acid conditions to form 16u-methyl-11?,17a,
21-trihydroxy-4-pregnene-3,20-dione. This latter com
pound is then converted to the corresponding 1,4-pregna
9oz-Flll0r0-l1}3,1 70:,21-Trihydroxy-4-Pregnene-3,20-Di0ne
913,1l?-oxido-17a,21-dihydroxy-4-pregnene-3,20 - dione as
This
3,20 - lbissemicarbazone is reacted with sodium boro
The 1 1i9,'17a,21-trihydroxy—l 6u-methyl-1,4-pregnadiene
65 3,20-dione-21-acetate is reacted with a dehydrating agent
such as methane-sulfonyl chloride to produce 16ix-methyl
EXAMPLE 8
170:,21-dihydroxy - 1,4,9(1:1) - pregnatriene-3,20-dione-21
9a-Flu0ro-1 113,115,] 7a-Trihydr0xy-21 -Acetoxy-I,4
acetate. Upon adding aqueous perchloric acid to a sus
’
'
Pregnadiene-3,20-Dione
’ When the procedure of Example 1 is repeated using
9,8,1118-oxid0-16,l7u-dihydroxy-21 - acetoxy - 1,4 - pregna
diene-3,20-dione as the starting material, 9a-?l1OI‘0-1l/3,15,
17a-trihydroxy~21-acetoxy~1,4-pregnadiene-3,20 - dione is
obtained.
pension of this compound and N-bromosuccinamide in
.
70
acetone, the bromohydrin, 9a-bromo-11p,17a,21-trihy
droxy-1,4-pregnadiene-3,20-dione-2l-acetate, is obtained.
Reaction of the latter compound with sodium methoxide
in a mixture of tetrahydrofuran and methanol affords a
mixture of 9,9,lll?-oxido-l6aamethyl-17a,2l-dihydroxy
75 1,4-pregnadiene-3,20-dione and the 21-acetate derivative
3,049,556
8
7''
l
4-pregnadiene-3,20-dione'employed as the starting material‘
which upon acetylation with acetic anhydride is converted
in Example 4 can be prepared as follows:
to the 21-acetate derivative. Hydrolysis of the acetate
with sodium methoxide in ‘methanol affords the free alco
These 6,16 - dimethyl - 11-oxygenated~1,4-pregnadiene
17u,2l-diol-3,20-dione compounds are prepared by re5
hol 9§,115-oxido-16a-methyl - 170:,21 - dihydroxy - 1,4 -
acting 16oz - methyl-4-pregnene-17u,21-diol-3,11,20-trione
pregnadiene-3,20-dione.
with formaldehyde under acidic conditions to form 17¢,
The 9,8,11-5-oxido 17u,~21-dihydroxy-IG?-methyl-l,4
20,20,21 - bismethylenedioxy-16a-methyl-4-pregnene-3J1
dione which is reacted with ethylene glycol in the presence
Example 6 can be prepared as follows:
of an acidic catalyst to produce 3-ethylenedioxy-17a,20,20,
To a solution of 3a-acetoxy-l6-pregnene-11,20-dione
in a mixture of tetrahydrofuran and ethyl ether is added 10 21 - bismethylenedioxy - 16oz - methyl-5-pregnene-11-one.;
pregnadiene-3,20-dione used as the starting material in
The latter compound is reacted with perbenzoic acid, per-‘
phthalic acid and the like, thereby forming 3-ethyl- '
diazomethane to produce 3u-acetoxy-16a,17a-methylene
azopregnane-lLZO-dione (M.P. 186-190" C.) which pre
cipitated from solution. Heating this compound at about
enedioxy - 17a,20,20,21-bismethylenedioxy-5,6-epoxy-16a
180° C. in vacuo produces 3oc-acetoxy-l6-methyl-16-preg--v
methyl-pregnane-l l-one which is then reacted with formic
ide in methanol solution for 18 hours at room temperature
and 17a,20,20,21-bismethylenedioxy-16u-methyl-5-formyl
nene-1’1,20-dioner (M.P., l65¢l~l67° C.) which upon reaction 15 acid to produce a mixture of 17a,20,20,21-bismethylene
dioxy - 16a-methyl-6-formyloxy-pregnane-5-ol-3,1l-dione
with hydrogen peroxide in the presence of sodium hydrox
oxy-pregnane-6-ol-3,1l-dione, which mixture, upon reac
a?ords l6a,17a-epoxy-3a-hydroxy-16?-methyl-pregnane
tion with an aqueous valkalihydroxide solution, is con-‘
treated with perchloric acid in aqueous dioxane at 25—30° 20 verted to 17u,20,20,2l-bismethylenedioxy-16u-methyl-al
lopregnane-3,6,11-trione. The last-named compound is
C. for 65 hours and the resulting reaction mixture is di
reacted with’ butanone dioxolane to produce 3-ethylene
luted with water a mixture of 3a,l7a-dihydroxy-l6~meth
11,20-dione (M.P. 178—180° C.). When this compound is
dioxy - 17oc,20,20,21 - bismethylenedioxy-léa-methyl-allo
yl - ‘15 - pregnene - 11,20-dione and 3a,17a-dihydrOXY-16
methylene-11,20-pregnane dione (M.P. 158-167° C.) is
precipitated and recovered by ?ltration. Reduction of this
pregnane-6,11-dione which is reacted with a methyl Grig
nard reagent to form S-ethylenedioxy-17a,20,20,2l-bis
25
methylenedioxy - 60:,16u - dimethyl-allopregnane-6/8-ol-11
mixture with hydrogen in methanol in the presence of pal~
ladium-calcium carbonate catalyst affords a mixture of
one. This 3-ethylenedioxy-17a,20,20,2l-bismethylenedi
oxy-6u,16a-dimethyl-allopregnane-65-01-1l-one is reacted
3a,17a - dihydroxy-l6m-methyl-pregnane-11,20-dione and
with a dehydrating agent such as thionyl chloride in pyri
ing at 150° C. VBromination of this mixture with bromine 30 dine to form the corresponding 3-ethylenedioxy-17a,20,20,
. 3a,17a-dihydroxy-16?-methylpregnane-11,20-dione sinter
21 - bismethylenedioxy-6,16a-dimethyl-5-pregnene-1l-one,
in chloroform at 40-45 ° C. affords a mixture of 2l-bromo-.
304,170: - dihydroxyd6a-methylpregnane~11,20-dione and
which, upon reaction with p-toluene sulfonic acid mono-'
hydrate in acetone is converted to 17a,20,20,21-bismethyl
2l-bromo-3m,17a-dihydroxy-16B - methylpreguane-1l,20- .
enedioxy-6a,16m-dimethyl-4-pregnene~3,1l-dione; the lat
dione which upon reaction with potassium acetate and
potassium iodide in acetone produces a mixture of
ter compound is reacted with an aqueous organic acid hy
drolyzing agent to form 6a,16u-di1'n6thYl-4-PI'6guenE-17m,
3a,17oc,2l-trihydroxy-lG?-methyl - preguane - 11,20-dione
ZI-acetate and 3a,17a,2-l-trihydroxy - 16a - methylpreg
21-diol-3,11,20-trione which can be reacted with an acylat-y.
ing agent to form the corresponding 2l-acylate. A1terna-,
nane-l1,20-dione-21-acetate. To a solution of this mix
tively, the 3 - ethylene-dioxy-1'lu,20,20,21=bismethylene
ture is aqueous 't-butanol at 10—15° C; is added N-bromo
succiuimide to produce a mixture of 17a,21-dihydroxy 40 dioxy-6,16u-dimethyl-5-pregnene-11—one, above-mention
ed, can be reacted with lithium aluminum hydride thereby
reducing the 1 l-keto substituent to an 11 ?-hydroxy radical
16a-methylpregnane-3,11,20-trione-2l-acetate and 17a,21
dihydroxy-l6?~methylpregnane-3,111,20-trione - 21 - ace
to produce 3-ethylenedioxy-17a,20,20,21-bismethylene
dioxy-6,I6a-dimethyLS-pregnene-I118-01 which is convert
ed, by reaction with p-toluenesulfonic acid monohydrate in
acetone, rto 17a,20,20,2l-bismethylenedioxy-6a,16a-di
methyl-4-pregnene-11?-ol-3-one; the latter compound is
tate which on chromatography on neutral alumina elution
with chloroform-benzene (1:1) and ‘benzene yields 17a,
21 - dihydroxy-l6B-methylpregnane-3;l1,20-trione-21-ace
45
tate'(M.P.. 210—213°.C.). Reaction of this compound
with bromine in a mixture of acetic acid and chloroform
reacted with an aqueous organic acid hydrolyzing agent‘
alfords the corresponding 4dbromo compound (M.P. 165-,
170° C. dec.) which is converted by reaction with semi
carbazide to the 3-semicarbazone of 17¢,2'1-dihydroxy
thereby forming 6a,16m-dimethyl-4-pregnene-1118,17a,2l
triol-3,20-dione which can be reacted with an acylating
‘ agent thereby forming the corresponding 21-acylate deriva
1613 - methyl-4-pregnene-3,11,20~trione-21-acetate. Treat
tive.‘
ment of this compound with a mixture of acetic acid and
The 611,160“ dimethyl _- 11B,17a,21-trihydroxy-4
pyruvic acid gives l7a,2l-dihydroxyd6,8-methyl-4-preg
pregnene-3,20-dione-2l-acylate is then converted to the
heme-3,11,20-trione-21-acetate (M.P. 226—232° C.). Con
corresponding 1,4-pregnadiene compound by reaction with
version of this compound to the disemicarbazone, reduc 55 selenium, dioxide. This process is fully described in the
tion of the disemicarbazone with sodium borohydride, and
pending patent application of Glen E. Arth, Roger B.
cleavage of the reduction product aifords 1‘1?,17a,21-tri
Beyler, and Lewis H. Sarett, Serial No. 683,923, now
hydroxy-l65-methyl-4-pregnene-3,20-dione.' Acetylation
Patent No. 3,004,994, ?led September 16, 1957.
of this product with acetic anhydride in the presence of
The 605,160; - dimethyl - 11B,17a,21-trihydroxy-4-preg
pyridine gives the 21-acetoxy compound which is con 60 nene-3,20-dione-2l-acylate is then converted to 95,1118
verted to the corresponding 1,4-pregnadiene compound by
oxido-17¢,21-dihydroxy-6a,IGa-dimethyHA-Pregnadiene
reacting it with selenium dioxide in t-butyl alcohol under
3,20-dione following the procedures described above for
reflux for 48 hours, These reactionsare described in de-'
the corresponding 16a-methy1 compound.
tail in the pending application of David Taub, Norman L.
.Various changes and modi?cations may be made in
Wendler and Harry L. Slates, Serial No. 722,390, ?led 65 carrying out the present invention without departing from.
March 19, 1958.
the spirit and scope thereof. Insofar as these changes and
The 1113,17a,21-trihydroxy-16B-methyl-1,4-pregnadiene
modi?cations are within the . purview of the annexed‘
3,20-dione-21-acetate is then converted to 9,6,116-oxido
claims, they are to be considered as'part of my invention.
170:,21 - dihydroxy-16?~methyl~1,4-pregnadiene53,20-dione
What is claimed is:
'
1. In a process for preparing a compound selected from
' the'group consisting of 9a-?uoro-11?,17u,21-trihydroxy
following the procedures described above for the cor 70
responding 16a-methyl compound. These procedures are
described in the copending application of Norman L.
Wendler and David Taub, Serial No. 742,992, ?led June
19, 1958.
.
.
.
'l
20-keto-p1'egnanes by reacting the corresponding oxido
steroid selected from the group consisting of 95,11B-oxido
The 95,1l?-oxido-17a,21-dihydroxy-6a,16u-dimethy1-1, 775 and 11?,12,3-oxido steroids with hydrogen ?uoride, the‘;
3,049,556
improvement which comprises reacting said oxido steroid
with a reagent consisting essentially of a mixture of hydro
gen ?uoride and tetrahydrofuran wherein the ratio of
hydrogen ?uoride to tetrahydrofuran is in excess of 1:1,
maintaining said oxido steroid in contact with said mixture
at a temperature of from about —60° C. to 20° C.,
quenching {the resulting reaction mixture with aqueous
alkali thereby precipitating the ?uorohydroxy steroid,
evaporating the tetrahydrofuran, ‘and recovering the pre
cipitated ?uorohydroxy steroid.
2. The process of claim 1, wherein the steroid starting 10
material is 9,6,1118-oxido - 16a-methyl-17a,2l-dihydroxy
1,4-pregnadiene-3,20-dione.
10
3. The process of claim 1 wherein the steroid starting
material is 913,1l?-oxido-17a,21-dihydroxy-4-pregnene-3,
20-dione.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,813,109
2,831,001
Colton et a1 ___________ __ Nov. 12, 1957
Agnello et ‘a1. ____- ____ __ Apr. 15, 1958
2,838,501
Campbell et a1 ______ .__'.__..June10, 1958
2,876,219
Cambell et a1. ________ __ Mar. 3, 1959
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