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Патент USA US3053844

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United States Patent 0 '“
C@
35,053,834
vPatented Sept. 11,v 1962
1
3,053,834
ZI-PHOSPHATES 0F STEROID ACETALS
.
_
AND KETALS
Josef Fried, Princeton, N.J., assignor to Olin Mathieson
Chemical Corporation, New York, N.Y., a corporation
of Virginia
No Drawing. Filed Jan, 26, 1961, Ser. No. 85,002
13 Claims. (Cl. 260—239.55)
This invention relates to, and has for its object the 10
provisions of, a method of preparing physiologically active
steroids, and to the physiologically active steroids pro
duced thereby.
, The steroids of this invention are 21-phosphates of the
hydrolyzed with water in the presence of the same
1‘6u,17a-acetal and ketal denivatives of 16u,17a-dihydroxy 15 is
tertiary
base to obtain a compound of Formula I.
steroids and ketones or aldehydes and to the alkali metal
desired, treatment with an alkali metal compound, e.g.
salts thereof. More particularly, the steroids of this
an alkali metal hydroxide such as sodium hydroxide, potas-'
invention have the general formula
sium hydroxide or the like, an alkali metal carbonate such
20 as sodium carbonate, potassium carbonate or the like,
yields the alkali metal salt of the 2l-phosphate. Both the
mono- and di-alkali metal salts are contemplated.
In Formulas II and III above, the symbols have the,
same meaning assigned in Formula I.
25
The compounds of Formula II are prepared by inter
acting a steroid reactant of the general formula
(IV)
30
wherein the 1,2-position is saturated or double-bonded; 35
R is hydrogen, R’ is ?-hydroxy or together R and R’ is
keto; X is hydrogen, halogen (i.e. ?uoro, chloro, bromo
or iodo), or lower alkyl; X’ is hydrogen or lower alkyl;
at least one of the symbols X and X’ being hydrogen;
{5,
wherein the 1,2-position -is saturated or double-bonded;
Y is hydrogen or methyl; Y’ is halogen (preferably 40 R, R’, X, X’, Y and Y’ are as hereinbefore de?ned; and
Z’ is hydroxy, with an aldehyde or ketone of the formula:
?uoro); and P and Q are hydrogen, lower alkyl, halo
lower alkyl, monocyclic cycloalkyl, monocyclic aryl,
monocyclic aryl lower alkyl, monocyclic heterocyclic or
monocyclic heterocyclic lower alkyl; or together with the
carbon atom to which they are joined P and Q is cyclo
alkyl or monocyclic heterocyclic. Not more than one
of the symbols P and Q represents hydrogen in a given
compound. Particularly preferred are those compounds
wherein the 1,2-position is double-bonded, R is hydrogen
and R’ is ,B-hydroxy or together R and R’ are keto,
X is halogen (optimally ?uoro), Y is hydrogen and P
and Q each is lower alkyl.
The compounds of this invention are prepared by re
acting a steroid of the formula
wherein P and Q are as hereinbefore de?ned, and re
covering the resultant acetal or ketal derivative. The
reaction is preferably carried about by treating a suspen
sion or solution of the steroid in the aldehyde or ketone
with or without an inert organic solvent (e.g. dioxane)
with an acid catalyst (e.g. perchloric acid, p-toluenesul
fonic acid and hydrochloric acid), neutralizing the acid
and recovering the acetal or ketal derivative formed.
Among the suitable starting steroids utilizable for the
65 production of compounds of Formula II and conversion to
compounds of Formula I in the process of this invention
may be mentiioned, 6a-halo-16ot-hydroxyhydrocortisone
(e.g. 6a-?uoro-16u-hydroxyhydrocortisone), 6a-halo-16a
hydroxycortisone, 6a-halo-16a-hydroXy-prednisolone, 6a
halo-l6a-hydroxyprednisone, 6a,9a-dihalo-l6u-hydroxy
hydrocortisone (e.g. 6a,9a-di?uoro-l6a-hydroxyhydrocor
tisone), 60¢,9a-dih2110-16oz-hyd1'OXyC0I‘tiS01'1e, 6a,9a-dihalo
16oz - hydroxyprednisolone (e.g. 60:,91: - di?uoro-16a-hy
droxyprednisolone) , 60¢,9oc-dih?l0-1 6a-hydroxyprednisone,
Zea-methyl - 6a - ?uoro - 16a, - hydroxyhydrocortisone, 2oz
methyl-6m-?uoro - 16a - hydroxyhydrocortisone, Got-halo
9ot-(lower alkyl)-16a-hydroxyhydrocortisone (e.g. 6a
?uoro-9a-methyl - 16a - hydroxyhydrocortisone) , 6a-halo
9a - (lower alkyl) - 16cc - hydroxycortisone, 6a - halo - 90c
(lower alkyl) - 160a - hydroxyprednisolone, 6a - halo - 90:
with phosphorous oxychloride in the presence of a tertiary 70
(lower alkyl)-l6a-hydroxyprednisone, 6u,9a-dihalo-12u
base such as pyridine, triethylamine etc. The resulting
chloride intermediate of the formula
(lower alkyl)~16ot-hydroxyhydrocortisone (e.g. 6a,9a-di
3,053,834
3
4
.
fluoro-l2a-methyl-16u-hydroxyhydrocortisone), 6a,9u-di
treatment of dermatoses, ‘for which purpose they can be
halo-l2a-(lower alkyl)-l6a-hydroxycortisone, 60¢,9a-di
administered in the same manner as hydrocortisone
hal0-l2a-(lower alkyl)-16a-hydroxyprednisolone (e.g. 6a
phosphate, for example, the dosage being adjusted for
chloro-9a-?uoro-l2a-methyl - 16a - hydroxyprednisolone),
the relative potency of the particular steroid. They are
particularly advantageous in those cases where a stable,
water soluble preparation is desired.
The following examples are illustrative of the inven
and 6a,9a-dihalo-l2a-(lower alkyl)-l6a-hydroxypredni
sone.
Particularly preferred steroid reactants are those where
tion (all temperatures being in Centigrade):
in the 1,2-position is either saturated or double-bonded,
R is hydrogen and R’ is ?-hydroxy or together R and R’
EXAMPLE 1
‘are keto; X is hydrogen, chlorine or ?uorine; Y is hydro 10
gen; and Y’ is tluoro.
16a,17a-Is0pr0pylidene 6 a~Fluorotriamcinolone 21 -Phos—
In those cases where the starting steroid reactants are
new compounds, they can be prepared from the corre
phate (16u,17tx ~ Isopropylidene - 6:1,9a - Di?uoro - A13
Pregrmdiene-I 1 [3,] 6a,] 7 0:,21 -Tetr0l-3,20—Di0ne 21 -Ph0S
sponding 16-desoxy derivative by subjecting the latter to
the oxygenating action of a microorganism such as 15
phate)
To a suspension of 500 mg. of ou-?uorotriamcinolone
in 75 ml. of acetone is added 0.05 ml. of 72% perchloric
acid and the mixture agitated at room temperature for
Streptomyces roseochromogenus in accordance with the
method described in the US. application of Josef Fried
et al., Serial No. 739,943, ?led June 4, 1958, now Patent
three hours. During this period the crystals gradually
No. 2,855,343.
dissolve and the clear solution is neutralized with dilute
Suitable aldehyde and 'ketone reactants include alde
bicarbonate and the acetone removed in vacuo. The re
hydes such as paraldehyde, propanal, chloral hydrate,
sulting crystalline suspension is ?ltered and the crystals
tri?uoroacetaldehyde hemiacetal, hepta?uorobutanal ethyl
washed with water. The dried material is recrystallized
hemiacetal and hexanal; di(lower alkyl) ketones, such
from 95% alcohol to give the pure 6a-?uorotriamcinolone
as acetone, diethyl ketone, dibutylketone, methylethylke
tone, and methyl isobutylketone; mono and dicycloalkyl 25 16a,17lx-£1Cet0nld6.
To a solution of .08 ml. of redistilled phosphorus oxy
ketones, such as cyclohexyl methyl ketone and dicyclo
chloride in 2 ml. of pyridine is added at —23° with stir
propyl ketone; cycloalkanones, such as cyclobutanone,
ring a solution of 200 mg. of 6a-?uorotriamcinolone
cyclopentanone, cyclohexanone, suberone, and cyclodec
acetonide in 3 ml. of anhydrous pyridine. The addition
anone; monocyclic aromatic aldehydes such as benzal
dehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde
30 is complete within 10 seconds and the temperature rises
and p-?uorobenzaldehyde), lower alkoxy benzaldehydes
to —l0°. The reaction is allowed to proceed for an ad
(e.g. o-anisaldehyde), di(lower alkoxy)benzaldehydes
ditional three minutes. To the dichloride thus formed,
.16 ml. of water is added at a rate so that the reaction
(e.g. veratraldehyde), hydroxybenzaldehydes (e.g. sali
temperature does not exceed ~10". The mixture is then
cylaldehyde), dihydroxy-benzaldehydes (e.g. resorcylal
dehyde), lower alkyl benzaldehydes (e.g. m-tolnaldehyde 35 allowed to remain at room temperature for 12 minutes
and the pyridine is removed in vacuo without applying
and p-ethylbenzaldehyde), di(lower alkyl)benzaldehydes
(e.g. o,p-dimethylbenzaldehyde), nitrobenzaldehydes,
acylaminobenzaldehydes (e.g. N-acetylanthranilaldehyde),
and cyanobenzaldehydes; monocyclic aromatic lower al
kanals, such as phenylacetaldehyde, u-phenyl-propion 40
aldehyde, ?-phenylpropionaldehyde, 'y-phenylbutyralde
external heat. The resulting thick syrup is taken up in
chloroform and the 6a-?uorotriamcinolone l6a,17a
acetonide 21-phosphate is extracted several times with wa
ter.
The aqueous solution of the phosphate is carefully neu
tralized with potassium carbonate solution to pH 7 and ly
hyde, and aromatically substituted halo, lower alkoxy,
ophilized. The resulting white powder (515 mg.) is taken
hydroxy, lower alkyl, nitro, acylamido ‘and cyano de
up in methanol and the resulting suspension is centrifuged.
rivatives thereof; rnonocyclic heterocyclic aldehydes, such
as picolinaldehydes, furfural, thiophene carbonals, and 45 The supernatant is separated and concentrated in vacuo,
taken up again in methanol and the process of centrifuga
halo, lower alkoxy, hydroxy, lower alkyl, nitro, and
tion, separation and evaporation of the supernatant is re
cyano derivatives thereof; rnonocyclic heterocyclic lower
peated until the material obtained by evaporation of the
alkanals; monocyclic aromatic lower ‘alkyl ketones, such
supernatant is completely soluble in methanol. Addition
as acetophenone, propiophenone, butyrophenone, valero
of ether to a methanol solution of this material results
phenone, isocarprophenone, halophenyl lower alkyl ke
in crystals of the dipotassium salt of ?a-?uorotriam
tones (e.g. p-chloroacetophenone and p-chloropropio
cinolone 16a,17a-acetonide 2l-phosphate. On drying at
phenone), (lower alkoxy) phenyl lower alkyl ketones
(e.g. p-anisyl methyl ketone), di(lower alkoxy)phenyl
lower ‘alkyl ketones, hydroxyphenyl lower alkyl ketones,
dihydroxyphenyl lower alkyl ketones (e.g. resacetophe
none), (lower alkyl)phenyl lower alkyl ketones (e.g.
methyl p-tolyl ketone), di(lower alkyl)phenyl lower alkyl
ketones (o,p-xylyl methyl ketone), nitrophenyl lower
alkyl ketones (e.g. p-nitroacetophenone), acylamido
phenyl lower alkyl ketones (e.g. acetylanilines), and
cyanophenyl lower alkyl ketones; benzophenone, and
mono or his substituted halo-lower alkoxy, hydroxy,
137° this material loses 11.17% of its weight.
k231i“ 2.80—3.0 (broad), 5.83, 6.02 and 6.14;;
H,AnaL-Cal’d
4.80; K, 12.85;
for P,C24H29O9K2S2P
5.09. Found: C, 45.81; C,H, 5.25;
K, 11.28; P, 5.03.
EXAMPLE 2
1601,] 7a-(2 ’-Butylidene) -6a-Flu0r0triamcinolone
21 -Phosphate
lower alkyl, nitro, acylamido and cyano derivatives there
To a suspension of 100 mg. of 6a-?uorotriamcinolone
of; monocyclic aromatic lower alkanones, such as 1
phenyl-3-butanone and 1-phenyl-4-pentanone, and aro 65 in 15 ml. of methyl ethyl ketone is added 0.05 ml. of
72% perchloric acid, and the mixture stirred at room
matically substituted derivatives thereof; rnonocyclic heter
temperature for two hours. The resulting solution is
ocyclic ketones, such as Z-acetylfuran, 2-benzoylfuran, and
neutralized with sodium bicarbonate solution and after
Z-acetyI-thiophene; rnonocyclic heterocyclic lower al
addition of water the methyl ethyl ketone is evaporated
kanones; and rnonocyclic heterocyclic ketones, such as
70 in vacuo. The resulting crystals are filtered, washed with
alloxan.
1 All of the compounds of this invention are physiologi
water and dried in vacuo. Recrystallization from acetone
cally active substances which possess glucocorticoid and
hexane gives the pure isobutylidene derivative.
The isobutylidene derivative is treated with phosphorus
anti-inflammatory activity and hence can be used in lieu
oxychloride, water and potassium carbonate according to
of known glucocorticoids such as hydrocortisone and cor
tisone in the treatment of rheumatoid arthritis, and in the 75 the procedure described in Example 1 to obtain the di
3,053,834
5
chloride, 16a,17a-(2'-butylidene)-6a-?uorotriamcinolone
from acetone-hexane gives the pure isopr'opylidene dc?
21-phosphate and dipotassium salt, respectively.
rivative.
6
The isopropylidene derivative is treated with phospho
rus oxychloride and processed according to Example 1
EXAMPLE 3
16u,17a~(4’-Methyl-2’-Pentylidene) -6u
Fluorotriam cinolone 21-Ph0sphate
to obtain the corresponding dichloride, 21-phosphate and
dipotassium salt.
Reaction of 6a,9a-di?uoro-A4-pregnene-16a,17a,21-tri
ol-3,11,20-trione with acetone gives the corresponding
To a suspension of 100 mg. of 6u-?uorotriamcinolone
in 15 ml. of methyl isobutyl ketone is added 0.05 ml. of
ll-keto derivative and treatment of the product with
The mixture is stirred at room
temperature for 6 hours and the resulting solution ex 10 phosphorus oxychloride with subsequent processing as in
Example 1 yields the corresponding dichloride, 21-phos
tracted with dilute sodium bicarbonate solution, washed
phate and dipotassium salt, respectively.
with water, the organic phase dried over sodium sulfate
and the solvent evaporated in vacuo. Recrystallization
EXAMPLE 8
72% perchloric acid.
of the resulting crystals from acetone-hexane gives the
15
pure isohexylidene derivative.
The isohexylidene derivative is treated with phosphorus
oxychloride and processed as in Example 1 to obtain the
dichloride, 16a,17a-(4’-methyl-2’-pentylidene)-6<x-?uoro
160a,] 7 a-Cyclohexylidene-o a-Fluoro-l 6oc
Hydroxyhydrocortisone 21-Phosphate '
To a suspension of 100 mg. of 6a-?uoro-l6a-hydroxy
hydrocortisone in 15 ml. of cyclohexanone is added 0.05
triamcinolone 21-phosphate and dipotassium salt, respec
ml. of 72% perchloric acid. The mixture is treated as in
20 Example 3 and results in the formation of the cyclohex
tively.
ylidene derivative of 6a-?uoro-16a-hydroxyhydrocorti
EXAMPLE 4
sone.
16a,17a-Cyclohexylidene-6a-Fluorotriamcinolone
If 6oc-flll01'0-16oc-hYd1‘OXYCOI‘?SOIl6 is substituted for the
6a-?uoro-l6a-hydroxyhydrocortisone in the procedure of
21 -Ph0sphate
A suspension of 200 mg. of 6a-?uorotriamcinolone in 25 this example, ‘164x,17a-cyclhexylidene-6a-?uoro-16a-hy
15 ml. of redistilled cyclohexanone is treated for two hours
droxycortisone is obtained.
as described in Example 3, and the product is then treated
Treatment of each of the above products as in Ex
with phosphorus oxychloride and processed as in Example
ample 1 yields the corresponding dichloride, 21-phosphate
1 to obtain the dichloride, 16a,l7a-cyclohexylidene-6a
and dipotassium salt, respectively.
?uorotriamcinolone 21-phosphate and dipotassium salt, re 30
EXAMPLE 9
spectively. Neutralization of the ZI-phosphate with so
16a,]7ot-Is0pr0pylidene-6a-Flu0r0-16a
dium carbonate instead of potassium carbonate gives the
Hydroxyprednisolone 21 -Phosphate
disodium salt.
EXAMPLE 5
1600,] 7a- (3 '-Pentylidene ) -6a-Fluorotriamcinolone
21 -Ph osphate
35
Treatment of 6a-?uoro-16a-hydroxyprednisolone with
‘acetone in the presence of perchloric acid according to
the procedure of Example 1 results in the formation of
16a,17a-isopropylidene
A suspension of 200 mg. of 6a-?uorotriamcinolone in
6ot-?ll01‘0-l6oc-hYdI‘OXYPI‘CdDiSO
lone and further treatment with phosphorus oxychloride
scribed in Example 3 and the product is treated with 40 as in the same example yields the 21-phosphate.
phosphorus oxychloride and processed as in Example 1
EXAMPLE 10
30 ml. of diethyl ketone is treated for four hours as de~
to obtain the dichloride, 16a,17u-(3’-pentylidene) ~6oc-?ll0
rotriamcinolone 21-phosphate ‘and dipotassium salt, re
spectively.
EXAMPLE 6
16u,17a-Ethylidene-6u-Flu0r0triamcinol0ne
1 604,1 7oc-Is0propylidene-6a-Fluoro-9a-Methyl-1 6a
Hydroxyprednisolone 21-Ph0sphate
4.5 (A) PREPARATION OF 5a,Ga-OXIDO-Qa-METHYLHYDRO
CORTISONE 3,20‘-ETHYLENE KETAL
To a solution of 750 mg. of 9u-methylhydrocortisone
21 -Ph0sphate
3,20-bis-ethylene ketal in 50 ml. of chloroform is added
To a suspension of 200 mg. of 6a-?uorotriamcinolone
at 0° 7.5 ml. of 0.28 N perbenzoic acid. After 18 hours
in 15 ml. of freshly distilled paraldehyde is added 0.05 50 at 4° the mixture is washed successively with sodium
ml. of 72% perchloric acid and the mixture agitated for
iodide, sodium bicarbonate, dilute sodium sul?te and wa
v3.5 hours at room temperature. The resulting solution
ter, the chloroform solution dried and the solvent re
is extracted with dilute bicarbonate and water, dried, and
moved in vacuo. The residual 5a,6u-epoxide is recrys
the excess paraldehyde removed in vacuo. The residual
tallized from acetone-hexane.
'
material represents 16a,17ot-ethylidene-6a-?uorotriamcino
lone.
55
(B) PREPARATION
OF
G?-FLUORO-Qa-METHYLPREG
_ NANE-5a,11?,17a,21~TETROL—3,20-DIONE 3,20-BIS-ETH
Substitution of 6u,9u-di?uoro-A1-4-pregnadiene-16a,17a
YLENE KETAL
21-triol-3,l1,20-trione for 6a-?uorotriamcinolone in the
To ‘a solution of 500 mg. of 5a,6m-epoxy¥9a-methyl-,
procedures of Examples 1 through 6, yields the corre
sponding ll-keto derivatives. Treatment of the product 60 hydrocortisone 3,20-bisethylene ketal in 60 ml. of dry
benzene and 15 ml. of absolute ether is added 1 ml. of
in each instance with phosphorus oxychloride and process,
freshly redistilled boron tri?uoride etherate and the solu
ing according to Example 1 yields in each instance the
corresponding dichloride, 2l-phosphate and dipotassium
salt.
EXAMPLE 7
tion allowed to remain at room temperature for three
hours. After thorough washing with water the organic
65 phase is dried over sodium sulfate and the solvents re
moved in vacuo.
Recrystallization from acetone-hexane
gives the pure ?uorohydrin.
(C) PREPARATION OF 6a-FLUOR-0-9a-METHYLHYDRO
A suspension of 200 mg. of 6a,9a-di?uoro-A4-pregnene
To a solution of 500 mg. of v6?-?uoro-9ot-meth'ylpreg
11,3,160c,17oc,21-’[6tI‘Ol-3,2O—dl0118 in 30 ml. of acetone is 70
stirred at room temperature with 100 mg. of p-toluene
nane - 5oz - 1l?,l7oc,21 - tetrol - 3,20 - dione 3,20 - bis
sulfonic acid monohydrate for 18 hours. The clear so
ethylene ketal in 25 ml. of glacial acetic acid is added
lution is neutralized with sodium bicarbonate solution
3 m1. of concentrated hydrochloric acid, and the result
and the acetone evaporated in vacuo. The resulting crys
ing solution allowed to remain at room temperature for
tals are ?ltered and dried in vacuo. Recrystallization 75 18 hours. The mixture is diluted with water and chloro
I
CORTISONE
1
3,053,834‘
8
7
isopropylidene-M9a-di?uoro - 12oz - methyl-l6whydroxy
form, the chloroform solution washed with water, dilute
prednisolone.
sodium bicarbonate and again with water, dried over so
dium sulfate and the solvent evaporated in vacuo. The
Reaction of this isopropylidene derivative with phos
phorus oxychloride and further processing as in Example
resulting 6a-?uoro-9a-methylhydrocortisone is recrystal
1 but using sodium carbonate instead of potassium car
lized from acetone-hexane.
bonate yields the corresponding dichloride, 2l-phosphate
and sodium salt, respectively.
(D) PREPARATION OF Ga-FLUORO-Qa-METHYL-l?a
HYDROXYHYDROCORTISONE'
EXAMPLE 13
6a-?uoro-9a-methylhydrocortisone is fermented with
Streptomyces roseochromogenus (Waksman No. 3689)
following the procedure in application Serial No. 739,943.
The resultant 6a-?uoro-9a-methyl-l6a-hydroxyhydrocor
10
16a,l7a-Chl0ral Derivative of 6a-Fluorolriamcinolone
21 -Pl10sphate
A suspension of 500 mg. of ?a-?uorotriamcinolone and
tisone is extracted from the ?ltered broth with methyl
4 gm. of chloral hydrate in 20 ml. of dioxane is agitated
isobutyl ketone and recovered from the latter solvent by
concentration and ?ltration of the resulting crystalline 15 at room temperature for 24 hours. The mixture is ?l
tered, neutralized with aqueous sodium bicarbonate and
material.
extracted with chloroform. The chloroform-dioxane
(E) PREPARATION OF Ba-FLUORO-QwMETHYL-l?n
phase is dried over sodium sulfate, the solvent removed
HYDROXYPREDNISOLONE
in vacuo and the residual chloral derivative crystallized
6a-?uoro-9a-methyl-16a-hydroxyhydrocortisone is de
from methanol.
hydrogenated in a concentration of 200 mg./ml. with
The chloral derivative is treated with phosphorus oxy
Nocara‘ia aurantia following the procedure in the applica
chloride and further processed as in Example 1 to obtain
the corresponding dichloride, 21-phosphate and dipotas
tion of Kroll et 211., Serial No. 660,748, ?led May 22,
1957, thereby yielding 6a-?uoro-9'a-methyl-l6a-hydroxy
prednisolone.
sium salt, respectively.
EXAMPLE 14
> (F) PREPARATION OF 16a,17a-ISOPROPYLIDENE-6a
FLUORO-Qa-METHYL~1Ga-HYDROXYPREDNISOLONE
Following the procedure of Example 1, but substituting
500 mg. of 6u-?uoro~9a-methyl-l6u-hydroxyprednisolone
for the 6a-?uorotriamcinolone in that example, there is
obtained 16a,l7a - isopropylidene - 6m - ?uoro - 9m - meth
yl~16a-hydroxyprednisolone.
Treatment of the isopropylidene derivative with phos
phorus oxychloride and further processing as in Exam
ple 1, yields the corresponding dichloride, 2l-phosphate
and dipotassium salt, respectively.
EXAMPLE ll
Following the procedure of Example 1 but replacing
the 75 ml. of acetone used in that example by a mixture
of 10 ml. of dioxane and 10 ml. of 1,1,1-trifluoroacetone
there is obtained the tri?uoroisopropylidene derivative.
Further treatment with phosphorus oxychloride, water
and potassium carbonate yields the corresponding dichlo
ride, 2l-phosphate and potassium salt, respectively.
EXAMPLE 15
Acetophenune Derivative of 6ot-Flu0r0triamcin0l0ne
21-Ph0sphate
To a suspension of 4 g. of 6a-?uorotriamcinolone in
(A) PREPARATION OF‘ 9a-FLUORO-l2a-METHYLHYDRO
CORTISONE 3,20~BIS~ETHYLENE KETAL
A mixture of 2 g. of 9a-?uoro-12a-methylhydrocorti
some, 40 mg. of p-toluenesulfonic acid, 32 m1. of ethyl
ene glycol and 60 ml. of benzene is heated at re?ux with
a Dean-Stark separator for six hours. After cooling, the
mixture is neutralized with dilute sodium bicarbonate, the
layers separated and the aqueous phase extracted with
100 ml. of ‘freshly redistilled acetophenone is added 1.0
ml. of 72% perchloric acid and the mixture stirred at
room temperature for two hours, during which period all
the 6a-?uorotriamcinolone has dissolved. The solution
is neutralized by the addition of 8 ml. of 1.1 N NaOH
and of su?icient aqueous bicarbonate to render it neu
tral.
Water and chloroform is then added and the
chloroform-acetophenone layer concentrated in high vac
uum. The residue is recrystallized from acetone-hexane
chloroform. The combined benzene and chloroform 50 and the crystals Washed well with hexane to remove ad
phases are washed with water, dried over sodium sulfate
hering acetophenone.
and the solvents evaporated in vacuo. The residual di
This acetophenone derivative is reacted with phos
ketal is recrystallized from acetone.
phorus oxychloride and further processed as in Example
(B) PREPARATION OF 16a,17a—ISOPROPYLIDENE-6d,9a—
DIFLUORO - 12a -METHYL-16a-HYDROXYHYDROCORTI
'
1 to obtain the corresponding dichloride, 21-phosphate
and dipotassium salt.
SONE
EXAMPLE 16
Following the procedures in steps a, b, c, d, and f of
Example 10, but substituting 800 mg. of got-?UOl'O-IZDL
p-Nitroacetophenone Derivative of 6a-Flu0r0triamcino
methylhydrocortisone 3,20-bis-ethylene ketal for the 90: 60
lone ZI-Phosphate
methylhydrocortisone 3,20-bis-ethylene ketal in step a,
To a suspension of 200 mg. of 6a-?uorotriamcinolone
there is obtained 16m,17ot-isopropylidene-6a,9u-di?uoro
in a mixture of 7 ml. of dioxane and 4 grams of p-nitro
l2m-methyl-16u-hydroxyhydrocortisone.
acetophenone is added 0.05 ml. of 72% perchloric acid
Reaction of this isopropylidene derivative with phos
and the mixture stirred at room temperature for 31/2
phorus oxychloride and further processing as in Example
hours. The mixture is then neutralized with dilute so
1 yields the corresponding dichloride, 21-phosphate and
dipotassium salt, respectively.
EXAMPLE 12
160a,]7a-Is0pr0pyIidene-6u,9u-Di?u0r0-12a-Methyl-l 6 oc
Hydrvxyprednisolone 21 -Ph0sphate
Following the procedures in steps e and f of Example
10, but substituting 60¢,9OL-dl?ll0l'O-1zot-n'lethyl-l60t-hY
droxyhydrocortisone for the 6a-?uoro-9a-methyl-l6a-hy
droxyhydrocortisone in step e, there is obtained 160:,17ot
dium bicarbonate solution and the dioxane and excess
p-nitroacetophenone removed by vacuum steam distilla
tion. The residual aqueous suspension is extracted with
chloroform, the chloroform layer washed with water,
dried over sodium sulfate and the solvent removed in
vacuo. The remaining derivative is puri?ed by recrys~
tallization from, acetone-hexane.
The product is reacted with phosphorus oxychloride
and further treated as in Example 1 to obtain the corre
sponding dichloride, 21-phosphate and dipotassium salt.
9
.
v
.
.
.
10
.
l
.
.
.
This invention may be variously otherwise embodied
within the scope of the appended claims.
11?,16u,1 7m,21-Tetrol-3,20-Dione 21 -Ph0sphate
A suspension of 200 mg. of 6a,9a-di?uoro-A4-pregnene
11,3,1611,17a,2l-tetrol-3,20-dione in 30 ml. of acetophe
,
t'ained the dicyclopropyl derivative of 6a-?uorotriamcin-j
olone, then the 21-phosphate.
EXAMPLE 17
Acetophenone Derivative 0 f 6a,9a-Di?uoro-M-Pregnene
5
What is claimed is:
'
1. A compound selected from the group consisting of
steroids of the general formula
none is stirred at room temperature with 100 mg. of p
toluene-sulfonic acid monohydrate for 18 hours. The
clear solution is neutralized with sodium bicarbonate so—
lution and the acetone evaporated in vacuo. The result
ing crystals are ?ltered and dried in vacuo. Recrystalli
zation from acetone-hexane gives the pure acetophenone
derivative.
Reaction of 6u,9a-di?uoro-A‘i-pregnene-16oz,17a,21triol—
3,11,20-trione with acetophenone gives the corresponding
ll-keto derivative.
Treatment of each of the above products with phos
phorus oxychloride and further treating as in Example 1
yields the corresponding dichloride, 21~phosphate and di
potassium salt, respectively.
iv,
EXAMPLE 18
the 1,2-dehydro derivatives and the alkali metal salts
thereof, wherein R is hydrogen, R’ is B-hydroxy and to~
Benzaldehyde Derivative of 6m-Flu0ro-16a-Hydr0xyhy
dracortisone 21-Phosphwte
To a suspension of 100‘ mg. of 6a-?uoro-l6a-hydroxy
hydrocortisone in 15 ml. of benzaldehyde is added 0.05
ml. of 72% perchloric acid. The mixture is treated as
in Example 15 and results in the formation of the benzal
dehyde derivative of oa-?uoroh16a.-hydroxyhydrocorti
sone.
If 6a-?uoro-16a-hydroxycortisone is substituted for
the 6ot-?uoro—16a-hydroxyhydrocortisone in the procedure
25
gether R and R’ are keto; X is selected from the group
consisting of hydrogen, halogen and lower alkyl; X’ is
selected from the group consisting of hydrogen and lower
alkyl, at least one of the symbols X and X’ being hydro
gen; Y is selected \?rom the group consisting of hydrogen
and methyl; Y’ is halogen; and P and Q are selected
30 from the group consisting of hydrogen, lower alkyl, halo
lower alkyl, monocyclic cycloalkyl, monocyclic aryl,
monocyclic aryl lower alkyl, monocyclic heterocyclic, and
of this example the benzaldehyde derivative of 6a-?uoro
16a-hydroxycortisone is obtained.
monocyclic heterocyclic lower alkyl, at least one of said
P and Q representing other than hydrogen; and together
Treatment of each of the above benzaldehyde deriva '35 with the carbon atom to which they are joined P and
tives with phosphorus oxychloride and ‘further treatment
as in Example 1 yields the corresponding dichloride, 21
phosphate and dipotassium salt, respectively.
EXAMPLE 19
Furfural Derivatives of 6a-Flu0r0-16a-Hydr0xyprednis0
Q are selected from the group consisting of cycloalkyl
and monocyclic heterocyclic.
2. l6ot,l7a-lower alkylidene-6a,9u-dihalo-16a-hydroxy
4O hydrocortisone ZI-phosphat'e.
3. 16a,17a-lower alkylidene-6a,9a-dihalo-16a-hydroxy
lone 21-Ph0sphate
Treatment of 6a-?uoro-l6a-hydroxyprednisolone with
prednisolone 21-phosphate.
4. 16u,17a~halo-1ower alkylidene-6u,9a-dihalo-16u-hy
droxyprednisolone 21-phosp'hate.
furfural in the presence of perchloric acid according to 45 5. 16u,l7a-lower alkylidene-6a-halotriamcinolone 21
phosphate.
the procedure of Example 15 results in the formation of
6. 16m,17a-isopropylidene-6a-?uorotriamcinolone 21
the furfural derivative of 6ot-?uoro-16u-hydroxyprednis
phosphate.
olone.
7. 16a,17a-isopropylidene-6a-?uorotriamcinolone 21
The furfural derivative, when treated with phosphorus
oxychloride and further processed as in Example 1, yields 50 phosphate potassium salt.
the corresponding dichloride, 21-phosphate and dipotas
sium salt.
EXAMPLE 20
16a,17a-All0xan Derivative of 6u-Flu0r0triamcin0l0ne
21-Phosphate
8. 16ot,17u—10W61' alkylidene-6a-halo-16a-hydroxypred
nisolone 21-phosphate.
9. 16u,17a-1ower alkylidene-6a,9u-dihalo-lZoe-(lower
alkyl) -16u-hydroxyhydroc0rtisone ZI-phosphate.
10. A compound selected from the group consisting of
steroids of the general formula
A suspension of 0.5 gm. 6a-?uorotriamcinolone and
2.5 gm. of alloxan in 20 ml. of dioxane and 0.15 ml.
of 72% perchloric acid is agitated at room temperature
for 24 hours. The mixture is neutralized with aqueous 60
sodium bicarbonate solution and after the addition of
20 ml. of water extracted with chloroform. The chloro
form extract is dried over sodium sulfate and evaporated
to dryness in vacuo. The residual alloxan derivative
is recrystallized from 95% alcohol.
65
The alloxan derivative, when treated with phosphorus
oxychloride and processed as in Example 1, yields the
corresponding dichloride, 21-phosphat‘e and dipotassium
salt.
EXAMPLE 21
Dicyclopropyl Ketone Derivative of 6a-Flu0rotriamcin0
lane 21 -Ph0sphate
Following the procedure of Example 14 but replacing
the tri?uoroacetone by dicyclopropyl ketone, there is ob 75
and the 1,2-dehydro derivatives thereof, wherein R is
hydrogen, R’ is p-hydroxy and together R and R’ are
keto; X is selected vfrom the group consisting of hydro
gen, halogen and lower alkyl; X’ is selected from the
group consisting of hydrogen and lower alkyl, at least
3,053,834;
12
one of the symbols X and X’ being hydrogen; Y is se
lected from the group consisting of hydrogen and methyl;
Y’ is halogen; and P and Q are selected from the group
consisting of- hydrogen, lower alkyl, halo-lower alkyl,
12. 16m,17a-isopropylidene-6u-?uorotriamcinolone 21
dichlorophosphate.
‘ 13. 16a,17a-is0propy1idene-6a-?uoro - 16oz - hydroxy
prednisolone 21-phosphate.
monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl
lower alkyl, monocyclic heterocyclic, and monocyclic
References Cited in the ?le of this patent
heterocyclic lower alkyl, at least one of said P and Q
UNITED STATES PATENTS
representing other than hydrogen; and together with
2,183,589
the carbon atom to which they are joined P and Q are
selected from the group consisting of cycloalkyl and 10 ‘2,779,775
monocyclic heterocyclic.
11. 16u,17a-1ower alkylidene-6a-halotriamcinolone 21
dichlorophosphate.
2,932,657
2,966,486
2,990,401
Reichstein et al ________ __ Dec. 19, 1939
Sarett ________________ __ Jan. 29, 1957
Christensen et al _______ __ Apr. 12, 1960
Smith et al. __________ __ Dec. 27, 1960
Bernstein et a1 _________ __ June 27, 1961
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