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Патент USA US3062852

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f,
‘i
3,652,846
p
Patented Nov. 6, 1962
2
dihydroxylated steroids, such as
3,062,846
16a,17a-dihydroxyprogesterone,
(LOWER ALKOXYWIETHYL ETHER DERIVATIVES
1 111,2l-dihydroxyprogesterone,
1 1a,17a-dihydroxyprogesterone,
0F STEROIDS AND PROCESS THEREFOR
Josef Fried, Princeton, N.J., assignor to Olin Mathieson
Chemical Corporation, New York, N.Y., a corporation 5 corticosterone,
9a-halocorticosterone (e.g., 9a-?uorocorticosterone),
of Virginia
cortisone,
No Drawing. Filed Apr. 28, 1961, Ser. No. 106,178
9a-halocortisone,
12 Ciaims. (Cl. 260-3914)
prednisone,
This invention relates to the synthesis of steroids, and 10 9a-haloprednisone (e.g., 9a-?uoroprednisone),
has for its object the provision of a new class of steroids
6u-halo-16a,17a-dihydroxyprogesterone (e.g., 6a-?uoro
and the provision of a new process by which they are
16a,17a-dihydroxyprogesterone),
made.
It has been found that when a steroid having an un—
12u-halocortisone,
hindered primary or secondary hydroxyl group is reacted 15
with a lower alkyl acetal of formaldehyde and formalde
trihydroxylated and tetrahydroxylated steroids, such as
hyde (or a source of formaldehyde) in the presence of
hydrocortisone,
a strong acid catalyst, a (lower alkoxy)methyl ether
9a-halohydrocortisones (e.g., 9a-?uorohydrocortisone
derivative is formed. By a steroid having an unhindered
and 9a-chlorohydrocortisone)prednisolone,
hydroxyl group is meant a steroid containing a hydroxyl 20 9oa-haloprednisolones (e.g., 9u-?uoroprednisolone and
group at one or more of the following positions: la,
9a-chloroprednisolone),
15, 2a, 2,8, 3a, 35, 40a, 4,8, 60:, 6,8, 70:, 75, 110:, 12a, 12a,
150a, 15,8, 1604, 16/3, 18 or 19. In addition, such steroids
include ‘those of the androstane series containing a 1700
or 175 hydroxyl group and those of the pregnane series 25
containing a 20a, 20;? or 21 hydroxyl group.
‘If more than one unhindered hydroxyl group is pres
ent in the steroid reactant and a poly-alkoxyrnethyl ether
M-pregnene-l lor,17a,21-t1'lOl-3,20-d101'16,
9u-halo-16a-methylprednisolones (e.g., dexamethasone),
12a—halohydrocortisones (e.g., 12a-?uorohydrocortisone
and 12a-chlorohydrocortisone),
12a-haloprednisolone (e.g., 12a-?uoroprednisolone,
‘ -6oc,12u-prednisolone),
16a-hydroxyhydrocortisone,
16a-hydroxycortisone,
16a-hydr0xyprednisolone,
l6ot-hydroxyprednisone,
9a-halo-16a-hydroxyhydrocortisones (i.e., 9a-?uoro-16a
hydroxyhydrocortisone, 9a-chloro-l6a-hydroxyhydro
is formed, and assuming the hydroxyl groups involved
display a difference in reactivity, the compound may be
selectively hydrolyzed by treatment with an acid, such
as a dilute mineral acid (e.g., aqueous sulfuric acid), or
an organic acid (e.g., oxalic acid) to yield a less etheri
?ed product.
Although the process of this invention may be utilized
with any steroid containing an unhindered hydroxyl
cortisone, 9u-bromo~16u-hydroxyhydrocortisone and
9a-iod0-16a-hydroxyhydrocortisone) ,
9a-halo-16a-hydroxycortisones,
9a-halo-l6a-hydroxyprednisolone (e.g., triarncinolone),
9u-halo-16a-hydroxyprednisones,
12ot-halo-16a-hydroxyhydrocortisones (e.g., 12oz-?1101‘0~
16a-hydroxyhydrocortisone),
group, the preferred steroid reactants are those of the
pregnane series, particularly those of the general formula
12a-halo-16a-hydroxycortisones (e.g., 12oc-Ch101‘O-16uc
hydroxycortisone) ,
12a-halo-16a~hydroxyprednisolones (e.g., 12a-?uoro
16a-hydroxyprednisolone),
12a-halo~l6ot-hydroxyprednisones,
6u-methyl-16a-hydroxycortisone,
6a-methyl-16a-hydroxyprednisolone,
6m-methyl-l6u-hydroxyprednisone,
Zea-methyl-16a-hydroxyhydrocortisone,
Za-methyl-16a-hydroxycortis0ne,
Z-methyl-16a-hydroxyprednisolone,
wherein the 1,2; 4,5; 5,6; and 6,7 positions are saturated
or double-bonded; R is hydrogen, R’ is a-hydroxy,
a-acyloxy, ?-hydroxy, or ?-aeyloxy or together R and R’
is keto; R" is hydrogen, R'” is u-hydroxy, a-acyloxy or
18~hydroxy, or together R" and R’” is keto; the X’s are
the same or different and represent hydrogen, halogen,
or lower alkyl, at least one X being hydrogen; Y is hy
drogen, hydroxy or acyloxy; Y’ is hydrogen or methyl;
Y" is hydrogen, halogon or methyl; Z is hydrogen or
hydroxy; and Z’ is hydrogen, halogen, hydroxy, acyloxy,
or methyl.
Examples of such steroids of the pregnane series in
clude:
monohydroxylated steroids, such as
Z-metyl- 1 6u-hydroxyprednisone,
2a,6<x-dimethyl-16a-hydroxyhydrocortisone,
2a,6a-dimethyl-16u-hydroxycortisone,
9a-halo-2-rnethy1-16a-hydroxy prednisolones (e.g.,
60
Z-methyltriamcinolone),
9u-halo-6a-methyl-16a-hydroxyhydrocortisones (e.g.,
9a-?uoro-6a-rnethyl-16u-hydroxyhydrocortisone),
9u-halo-6u-methyl-16a-hydroxyprednisolones (e.g.,
6a-methyl triamcinolone) ,
16a-hydroxy-6-dehydrocortisone,
16a-hydroxy-6-dehydrohydrocortisone,
16u-hydroxy-6-dehydroprednisolone,
9a-halo-16a-hydroxy-6-dehydroprednisolones,
1 la-hydroxyprogesterone,
1 15, 16a, I7a-trihydroxyprogesterone,
pregnenolone,
ZI-hydroxyprogesterone,
12a-hydroxyprogesterone,
15 a-hydroxyprogesterone A4-pregnene-20?-ol-3-one,
1 l-keto-l 6a,17a-dihydroxyprogesterone,
60a and G?-hydroxyprogesterone and l9-hydroxy
progesterone;
1113,16a,17a-trihydroxy-l-dehydroprogesterone,
1 l-keto-l 6oz, 17¢x-dihydroxy-1-dehydroprogesterone,
9a-halo-1 13,16rx,17a-trihydroxyprogesterones (e.g.,
9a-chloro-1118,16a,17a-trihydroxyprogesterone and
9OL-?L1OIO-1 118, 16a,17a-trihydroxyprogesterone) ,
3,062,846
4
3
In addition the process of this invention is applicable
9a-halo-16a,17a-dihydroxy-l l-keto-progesterones (e. g.,
in treating steroids of the androstane series, particularly
9d'?uOl'O-16BC,17d-dlhydI'OXy-1 l-keto-progesterone) ,
those of the general formula
9a-halo-l 15,16a,l7a-trihydroxy-l~dehydroprogesterones
(e.g., 9a-?l10rO-l 1 5, 1 611,17 a-trihydroxy-l-dehydro
progesterone),
12a-halo-115,16a,17a-trihydroxyprogesterones (e. g.,
X A
II
B
I
I
12a-?uoro-ll5,16a,l7a-trihydroxyprogesterone),
12a-halo-l 15,16a, l7a-trihydroxy-l-dehydroprogesterones
( e. g., llu-?uoro-l15,l6n,l7ot-trihydroxy-l-dehydro
progesterone),
10
21-halo-115,16a,17a-trihydroxyprogesterones (e. g.,
Zl-?uoro-l15,160‘,17a-trihydroxyprogesterone),
2l-halo-l 15,16a,l7a~trihydroxy-l-dehydroprogesterones,
9a,21-dihal0-115,1605,l7u-trihydroxyprogesterones (e.g.,
90:,21-di?l101'0-1 15, l 6a,17a-trihydroxyprogesterone) ,
15
9m,21-dihalo-6a-methy1-115,16u,l7a-trihydroxy-1
dehydroprogesterones,
are as hereinbefore de?ned, and A is hydrogen or lower
alkyl, B is hydroxyl or acyloxy, or together A and B
16a-hydroxy-l2a-(lower alkyl) -hydrocortisones (e.g.,
l6a-hydroxy-12a-methyl-hydrocortisone) ,
16a-hydroxy-12a-(lower alkyl) -cortisones (e.g.,
20 is keto.
Examples of such steroids of the androstane
series include: monohydroxylated steroids, such as testos
terone 9a-?uoro-ll-ketotestosterone l2ot-?uoro-1l-keto
16a-hydroxy-12a-methylcortisone) ,
16a-hydroxy-9u-(lower alkyl)-hydrocortisones (e.g.,
testosterone, l6ot-?uorotestosterone, lla-hydroxyandros
16whydroxy-9u-methylhydrocortisone ) ,
l6m-hYdl'OXY-90t-(1OWCI‘ alkyl)cortisones (e.g.,
16u-hydroxy-9a-methyl-cortisone) ,
tenedione, etiocholanolone, androsterone and l9-nor
25 testosterone; dihydroxylated steroids, such as 9a-?uoro
115 - hydroxy - testosterone - 16a - hydroxy - testosterone,
16a-hYCl1'OXY-12ot-(IOWCI' alkyl ) prednisolone ( e. g.,
15u-hydroxy - testosterone - lloc - hydroxy - 17a _ methyl
16a-hydroxy-l Za-methylprednisolone) ,
testosterone, and 19-hydroxy-testosterone; and trihydrox
ylated steroids.
16a-hydroxy-[ l2oc-( lower alkyl) prednisones,
16a-hydroxy-9a-(lower alkyl) prednisolones (e.g.,
'16u-hydroxy-9a-methylprednisolone) ,
30
16a-hydroxy] -9 a-( lower alkyl ) predniscnes,
12a-( lower alkyl)-115,1611,l7a-trihydroxyprogesterones
(e.g., 12a-methyl-115,16a,17a-trihydroxyprogesterone),
9a-(l0wer alkyl)-115,16u,l7a-trihydroxyprogesterones
(e.g., 9u-methyl-115,16a,17a[trihydroxyprogesterone),
12m-(1OW€1‘ alkyl)-11-keto-16a,17a]-dihydroxy
of formaldehyde which may be used can be mentioned
35 methylal, ethylal, and the butylalcetal of formaldehyde.
The reaction is conducted in the presence of a strong
acid catalyst. Suitable acids include perchloric acid and
progesterones,
12a-(lower alkyl)-A4l6-pregnadiene-115,16a,17a-trio1
p-toluenesulfonic acid.
The alkoxymethyl ethers formed, which represent new
40 compounds of this invention, are useful as intermediates
in the synthesis of steroids. Thus, the process of this
3,20-diones,
9a-( lower alkyl)-A4,6-pregnadiene-115,16a,17a-triol
invention affords a method for protecting otherwise re
active alcoholic groups during future chemical opera
tions on other parts of the molecule utilizing either neu
tral or alkaline reagents. As such, the products of this
invention represent useful intermediates in steroidal syn—
3,20-diones,
12a-(lower alkyl)-A1'4-pregnadiene-1l5,16a,17a-triol
3,20-diones,
9a~( lower alkyl)-A1'4-pregnadiene-115,16a,17a-triol
3,20-di0nes,
12a-( lower alkyl) -A1-4-pregnadiene-16a, l7a-diol
3,11,20-triones,
9oc-( lower alkyl)-A1,4-pregnadiene-16a,l7a-diol-3,11,20
theses. In addition, those compounds which are alkoxy
methyl ether derivatives of physiologically active steroids,
contrary to what would be expected, retain their activity
50
triones,
3,20-diones,
12vt-(lower alkyl)-A1-416-pregnatriene-115,16a,17a-triol~
The following examples illustrate the invention (all
temperatures being in eentigrade):
3,20-diones,
IZa-(lower alkyl)-A4-pregnene-1la,l6a,17a,21-tetrol
3 ,20-diones (e.g., 12a-methyl-A4-pregnene-11a,16a,
EXAMPLE 1
17a,21-tetrol-3,ZO-dione) ,
17a,21-tetrol-3,20-dione) ,
12ot-(lower a1ky1)-A1'4-pregnadiene-1 1a,16a, 1711,21
tetrol-3,20-diones,
Qua-(lower alkyl)-A1'4-pregnadiene-11a,16a,17a,21-tetr01
3,20-diones,
12a-(lower alkyl)-A4-pregnene-11a,16a,l7¢z-triol-3 ,20
diones,
9ot-(lower alkyl)-A4-pregnene-11u,16a,17a-triol-3,20
diones,
12ot-(lower alkyl) -A114-pregnadiene—1 1m,16OL,17tZ-t1‘l0l—
-3,20-diones,
9a-(l0wer alky1)-A1-4-pregnadiene-l 1oz,16a,17:x-tri01
3,20-diones
and hence can be used for the same purpose as the
parent compound. Thus, alkoxymethyl other derivatives
of glucocorticoids, such as triamcinolone and hydro
cortisone, possess glucocorticoid activity and ‘may be
used in the treatment of rheumatoid arthritis.
9a-(lower alkyl)-A1-4-6-pregnatriene-1l5,16a,17a-diol
9oz-( lower alkyl)-A4-pregnene-l1m,16a,17o:,2l-tetrol
3,20-diones (e.g., 9u-rnethyl-A4-pregnene-1 111,1611,
The formaldehyde used in the reaction can be sup
plied as such (e.g., as gaseous formaldehyde) or pre
pared in situ from a polymerized form of formaldehyde,
such as trioxane. Among the suitable lower alkyl acetals
9a-(lower alkyl)-1 1-k8t0-16ot,l70t-dll'1yd1'OXy
progesterones,
wherein the 1,2; 4,5; and 6,7-positions are saturated or
double-bonded, and R, R’, R”, R'”, X, Y’, Y”, and Z’
‘
3-Meth0xymethyIene-A5-Pregnene-35-Ol-20-Orze
(it)
To a suspension of 1 g. of pregnenolone in 50 ml. of
methylal and 20 g. of trioxane is added with stirring .5
ml. of 70% perchloric acid. The suspension clears within
1/2 minute and the reaction is allowed to proceed for 20
minutes. Six ml. of 1 N sodium hydroxide is then added
" and after dilution with water the methylal and trioxane
are removed in vacuo. The residual suspension is ex
tracted with chloroform, the chloroform extract washed
with water, dried over sodium sulfate and evaporated to
dryness in vacuo. The residue (about 1.18 g.) upon re
70 crystallization from a small amount of acetone and
mostly hexane furnishes the pure methoxymethylene de~
rivative of pregnenolone possessing the following prop
erties: MP. about 102-104“; [a]D +19° (c., 1.32 chlf.);
and Ila-esters thereof, particularly esters with hydro
A1322‘ No OH band, 5.87, 6.02 (weak) I115
carbon carboxylic acids having less than ten carbon atoms, 75
3,062,846
5
6
Analysis.—Calcd. for Casi-13603 (360.52): C, 76.62;
H, 10.07; OCH3, 8.65. Found: C, 76.54; H, 9.97;
OCH3, 8.95.
EXAMPLE 7
I6a,21-Bis-(Methoxymethylene) and 16a-M0n0-(Meth
oxymethylene) Derivatives of Triamcinolone
EXAMPLE 2
1 1 -Meth0xymethylene-1 1 a-Hydroxyprogesterone
To a solution of 600 mg. of triamcinolone in 30 ml. of
methylal and 24 g. of trioxane is added with stirring
.3 ml. of 70% perchloric acid. The reaction is allowed
to proceed at room temperature for 22 hours, after which
To a suspension of 1 g. of llu-hydroxyprogesterone in
50 ml. of methylal and 20 g. of trioxane is added with
stirring at room temperature .5 ml. of 70% perchloric
time it is neutralized rapidly by the addition of sodium
acid. The solution clears within 3 minutes and the re 10 bicarbonate solution. Water is added, the mixture ?ltered
action is allowed to proceed for a total of 30 minutes.
and the methylal and trioxane removed in vacuo. The
Eight ml. of 1 N sodium hydroxide is added and the
solution diluted with water. Evaporation in vacuo to
resulting crystalline precipitate about (400 mg.) is ?ltered
and after recrystallization from 95% alcohol furnishes
the pure bis-(methoxymethylene) derivative of triarn
remove methylal and trioxane leaves an aqueous suspen
sion, which is extracted with chloroform, the chloroform 15 cinolone possessing the following properties: M.P. about
washed with water, dried over sodium sulfate and evapo
rated to dryness in vacuo. The residual material is taken
up in 5 ml. of benzene and 5 ml. of hexane and chromat
ographed on 20 g. of acid-washed alumina. Benzene
2l8—219°; [81D +34“ (0., 1.1chlf.);
ANuiol
mm 2.92, 5.81, 6.0, 6.14 and 622p,
Analysis.—Ca-lcd. for C25H35OSF (482.53): C, 62.22;
hexane 1:1 (1000 ml.) and benzene (500 m1.) elutes 20 H, 7.31; F, 4.02; OCH3, 12.87. Found: C, 62.05; H,
7.58; F, 4.14; OCH3, 14.67.
crystalline material, which after one recrystallization
Chromatography of 100 mg. of this material on 2 g.
from acetone-hexane melts sharply at about 138-139“.
of silicagel from a solution containing 4 ml. of chloro
The material has the following properties: [04]]; +169°
form and 16 m1. of benzene furnishes on elution with
(c., 1.37 chlf.);
chloroform-benzene (1:4) pure material-melting at about
M153, 241 mu (e=16,000); A231?‘ N0 OH band, 5.91, 6.02,
224—225°.
and 622p. .
Analysis.-—Calcd. for Cal-13404 (374.50): C, 73.76;
H, 9.15; OCH3, 8.28. Found: C, 73.50; H, 9.40; OCH3,
over sodium sulfate and evaporation of the solvent in
vacuo about 370 mg. of material which after crystalliza
tion from 95% ethanol melts at about 188—200°. To
10.29.
EXAMPLE 3
achieve complete puri?cation this material is dissolved
1 7-Meth oxymethylene-Testosterone
Following the procedure of Example 2 but substituting
in 4 ml. of chloroform and 8 ml. of benzene and chromat
ographed on 7 g. of silicagel. Elution with mixtures of
1 g. of testosterone for the 1lot-hydrox'yprogesterone, 17
methoxymethylene-testosterone is obtained.
'
Extraction of the aqueous mother liquors With chloro
form furnishes after drying of the chloroform extract
chloroform, benzene and 100% cholroform eluted about
43 mg. of material, which is discarded. This is followed
by the 16-mono-methoxymethylene derivative of triam
cinolone when the elution is continued with chloroform
1
EXAMPLE 4
21 -Meth0xymethylen e-Qa-Fluorocortisol
containing 5% of acetone. The 16-mono-rnethoxymeth
To a suspension of 200 mg. of 9a-?uorocortisol in 10 40 ylene derivative of triamcinolone obtained from 900‘ ml.
ml. of methylal and 8 g. of trioxane is added with stirring
of this eluant after three crystallizations from acetone
.1 ml. of 70% perchloric acid. The reaction is allowed
hexane has the following properties: M.P. about 220
to proceed at room temperature for 22 hours after which
time dilute sodium bicarbonate and water is added. The
methylal and trioxane are removed in vacuo and the resi
due extracted with chloroform. The chloroform extract
is washed with water, dried over sodium sulfate and
evaporated to dryness in vacuo. The residue is taken
up in 4 ml. of chloroform and 2 ml. of benzene and
chromatographed on 4.2 g. of acid-washed alumina.
223°; [111323 +42“ (c., .52 chlf.);
am“ 2.95, 5.88, 6.02, 6.18, and 6.23,.
Analysis.—Calcd. for C23H31O7F (438.48): C, 63.00;
max.
H, 7.13. Found: C, 63.40; H, 7.39.
EXAMPLE 8
l6a-Mono-Methoxymethylene Derivative of
Triamcinolone
Elution with chloroform-benzene 2:1 (250 ml.) elutes
about 96 mg. of crystalline material, which on recrystal
30 mg. of 16,21-bis-(methoxymethylene) triamcinolone
lization ?rst from acetone-hexane and then from 95%
in 10 m1. of methanol and .34 ml. of 14% aqueous sul
ethanol furnishes pure 21-methoxymethylene-9a-?uoro
furic acid is heated at re?ux for 2 hours, the mixtures
cortisol possessing ‘the following properties: M.P. about 55 neutralized
with dilute sodium bicarbonate, the methanol
288-294"; [@1323 +43° (c., .65 chlf.);
A113; 238
(e=15,700); A222‘ 2.91, 5.82, 6.0 and (811.)
6.15.11.
Analysis.—Calcd. for C23H33O6F (424.49): C, 65.06;
H, 7.83. Found: C, 64.92; H, 7.50.
_
removed in vacuo and the residual suspension extracted
with chloroform. The residue (about 20 mg.) after
crystallization from acetone-hexane melts at about 219
222° ‘and possesses an infrared spectrum identical with
60 that of 16-methoxymethylenetriamcinolone obtained in
Example 7.
EXAMPLE 5
EXAMPLE 9
21~Méth0xymethylene-Cortisol
2] ~A'cetate of 16~Meth0xymethylenetriamciizolone
Following the procedure of Example 4 but substituting 65
A solution of 33 mg. of 16-methoxymethylenetriam
200 mg. of cortisol for the 90t-?LlOI‘OCOI'tiSOl, 21-methoxy
cinolone in 1 ml. of pyridine and .5 ml. of acetic anhy
methylene-cortisol is obtained.
dride is allowed to stand at room temperature for 18
EXAMPLE 6
hours. After removal of the reagents in vacuo the
residual material is crystallized from ‘acetone-hexane.
21 -Methoxymethylene-M-Pregnene-I 7a,21
70 After two crystallizations the material has the following
Diol-3,20-Dione
properties: M.P. about 178—180°; [(111323 +32° (c., 1.02
Following the procedure of Example 4 but substituting
200 mg. of A‘t-pregnene-17og21-diol-3,20-dione for the 9m
chlf.);
?uorocortisol, 21-methoxymethylene-M-pregnene-170:,21
A313; 239 mu (e=16,500); A231?‘ 2.92, 5.71, 5.79, 6.01, 6.18,
diol-3,20-dione is obtained.
.
75
and 6.23/1.
'
3,062,846
-
o
O
7
ample 11 and following the Procedure of the example,
Analysis.-—Calcd. for C25H33O8F (480.51): C, 62.48;
the corresponding 16,2l-bis-butoxymethylene) derivative
H, 6.92. Found: C, 61.66; H, 7.34.
is obtained.
EXAMPLE 10
This invention may be variously otherwise embodied
16,21-Bis-(Methoxymethylene) 9a-Flu0r0-16a-Hydroxy
within the scope of the appended claims.
Prednisone
What is claimed is:
1. (Lower alkoxy)methyl ether of a steroid of the
A solution of 50 mg. of 16,21-bis-(methoxymethylene)
triamcinolone in 1 ml. of pyridine is added to a suspen
sion of 50 mg. of chromium trioxide in 1 ml. of pyridine.
The resulting mixture is allowed to remain at room tem
general formula
10
perature for 20 hours, after which time water and chloro
form is added. The chloroform solution is Washed With
water to remove excess pyridine, dried over sodium sul
fate and evaporated to dryness in vacuo. The amorphous
residue is dissolved in 15 ml. of benzene and chroma
tographed on a column of 900 mg. of acid-Washed alu~
mina. Elution with 10% chloroform in benzene fur
nishes material, which after recrystallization from ace
tone-hexane melts at about 139-140";
20
A331?‘ 3.03, 5.80, 6.01, 6.17 and 6.23;;
wherein the 1,2; 4,5; 5,6; and 6,7 positions are saturated
or double-bonded; R is hydrogen, R’ is ,B-hydroxy and
together R and R’ is keto; R" is hydrogen, R’” is selected
from the group consisting of a-hydroxy, wacyloxy and
B-hydroxy, and together R" and R’ is keto; the X’s are
each selected from the group consisting of hydrogen, halo
gen and lower alkyl, at least one X being hydrogen; Y
is selected from the group consisting of hydrogen, hy
droxy and acyloxy; Y’ is selected from the group con
sisting ‘of hydrogen and methyl; Y" is selected from the
group consisting of hydrogen, halogen and methyl; Z
is selected from the group consisting of hydrogen and
hydroxy; and Z’ is selected ‘from the group consisting of
Analysis.—-Ca1cd. for C25H33O8F (480.51); C, 62.48;
H, 6.92. Found: C, 62.44; H, 6.98.
EXAMPLE 11
16,21-Bis-(Methoxymethylene)-16a-Hydr0xy-9a
F luorocortisol
To a stirred suspension of 200 mg. of 16u-hydroxy-9a
?uorocortisol in 10 ml. of methylal and 8 g. of trioxane
is added at room temperature .1 ml. of 70% perchloric
acid.
After 20 hours at room temperature all material
has dissolved ‘and the reaction mixture is neutralized by
the addition of sodium bicarbonate solution. Water is
added and the methylal and trioxane removed in vacuo.
The resulting crystals are ?ltered, the aqueous mother
liquor is extracted with chloroform and the chloroform
extract taken to dryness in vacuo. The combined crystals
and material ‘from the chloroform extract (about 293
mg.) is dissolved in 2 ml. of chloroform and 8 ml. of
benzene and chromatographed on 6 g. of si‘ricagel
hydrogen, hydroxy, and methyl.
2. A process for preparing a (lower alkoxy)methyl
ether of a steroid of the androstane and pregnane series
having an unhindered hydroxyl group, which comprises
reacting said steroid with a lower alkyl acetal of form
aldehyde and formaldehyde in the presence of a strong
acid catalyst selected from the group consisting of per
chloric acid and p-toluenesulfonic acid.
3. The process of claim 2 wherein the formaldehyde
is prepared in situ by the reaction of a polymer of form
aldehyde with said strong acid.
4. A process for preparing a methoxymethyl ether of
Chloroform-benzene 1:4 (‘200 ml.) elutes approximately
25 mg. of material which is discarded. The bulk of the
material is eluted with chloroform-benzene 4:1 (800 ml.)
and with chloroform (150 ml.). Recrystallization of
this material from acetone furnishes the pure bis-(meth
a steroid of the androstane and pregnane series having
oxymethylene)-l6u-hydroxy-9a - ?uorocortisol possessing
the following properties: M.P. about 213°; [@1323 +7l0°
(0., .43 chlf.);
an unhindered hydroxyl group, which comprises reacting
said steroid with methylal and trioxane in the presence
X113 239 mg (er-15,500), in,“ 2.92, 5.84, 5.99 and 6.15#
ing of perchloric acid and p-toluenesulfonic acid.
of a strong acid catalyst selected from the group consist
5. A process for preparing a 16,21-di-(lower alkoxy)
methyl ether of a steroid of the pregnane series having
hydroxyl groups in at least the 1611-, 17w and 2l-positions,
which comprises reacting said steroid with a lower alkyl
acetal of formaldehyde and formaldehyde in the presence
of a strong acid catalyst selected from the group consist
Analysis.-—C~alcd. for (1251-1370813 (484.54): C, 61.96;
H, 7.69. Found: C, 61.82; H, 7.18.
Similarly, by following the procedure of Example 11,
but substituting an equivalent amount of the following
steroids for the 16whydroxy-9tx-fluorocortisol, the indi
cated product is formed:
Steroid Reaetant
?a-Fluorotriamcinolone __________ .._
Product: l?éa‘l-lliis?nethoxy
e v
?a-lt‘luorotriamcinolone.
ing of perchloric acid and p-toluenesulfonic acid.
6. The process of claim 5 wherein the formaldehyde is
prepared in situ by the reaction of a polymer of formal
60
dehyde with said strong acid.
7. The process of claim 5 wherein the di(lower alkoxy)
l?a-?ydroxycortisol _____________ __
16a-Hydroxyprednis010ne.
(id-Methyl-1?a-hydroxycortisoL.___ ?a-Methyl-ltiwhydroxyeortisol.
16wllyrlroxyprednisolone ________ __
EXAMPLE 12
16,2] -Bis-(Etlioxymethylene)-16ot-Hydr0xy-9a
Fluorocortisol
Following the procedure of Example 11 but substitut 70
mg an equivalent amount of ethylal for the methylal,
16,21 - bis - (ethoxymethylene)
- 16a - hydroxy - 9a
?uorocortisol is obtained.
Similarly, by substituting an equivalent amount of the
dibutylacetal of formaldehyde for the methylal in Ex 75
methyl ether is then hydrolyzed to a mono-ether com
pound by treatment with a mineral acid.
8. A compound. of the formula
CHzO CH2OCHs
0:0
3,062,846
9
1Q
9. A compound of the formula.
11. A compound of the formula
CH3
<E=o
--—0H
nofl: Tocmoom
5
10
0113001120
]
O:
12. A compound of the formula
10. A compound of the formula
CHRO CHQOCHB
15
OHQOCMQ
‘
2o
47:0
I——-0H
HOW/\Q
/
F
No references cited.
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