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Патент USA US3068263

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tlnited dtates patent
3,0h8,253
Patented Dec. ll, 1962
2
1
wherein R2 stands for hydrogen or an alkyl group, R3
is hydrogen or an acyl group, X is hydrogen or halogen,
and Y is hydrogen, hydroxy or keto. Illustrative of the
3,068,253
" “'ETQ-ALL-STERQHDS
Leonard M. Weinstoclr, Highiand li’arir, N31, assignor to
B-WNOL ETHERS
21-esters contemplated above are allcanoates such as ace
lgvlereirdz $0., End, Railway, Nd, a corporation at New
tate, propionate and butyrate, aryl esters such as benzoate
and the sulfobenzoate, esters from dibasic organic acids
ersey
N0 Drawing. Filed Nov. 1%, rant, Ser. No. 79,129
2% Qiaims. (Ci. 2dll~~39'7.45)
Such as the succinate and phthalate, and esters from in
organic acids such as sulfate and phosphate.
This invention is concerned generally with novel 3-enol
According to my invention the novel 3-enol ethyl
ethers of 3~k6lIO-L\.1'4—S't€I0lCl compounds and with proc 10 ethers of the 3-keto-A1-4-pregnadienes are prepared ,by
esses or” preparing the same. More particularly, it re
stirring together a mixture of the 3-keto-AL5-pregnadiene
lates to novel S-enol ethers of A1'4-pregnadiene-l7m21
with ethyl orthoformate in a solvent in the presence of a
strong mineral acid. or an organic sulfonic acid catalyst.
diol-3,20adiones and the Zl-esters thereof, which are po
tent anti-inllammatory agents, and processes for preparing
In a preferred embodiment of my invention, using as
these compounds.
the starting material a 3-keto-A1>5-pregnadiene which has
These novel S-enol ethers of the 3-keto-A1'4-pregna
no hydroxy group at position 11, or which has a hydroxy
dienes (the 3-alkoxy-A1)3t5-pregnatrienes), subject of the
group at position 11 but no hydrogen at position 9
present invention, may he structurally represented as fol
(whereby dehydration to the corresponding Mill-steroid
lows:
cannot occur), the ethyl ether is prepared by stirring the
20 steroid with ethyl orthotormate. a small amount of ab
solute ethanol and a solvent, in the presence of a strong
acid catalyst. For example. a mixture of the 3-keto
A115-pregnadicne, dioxane, ethyl orthoformate. a small
amount of ethanol and sulfuric acid are stirred together
25 at about 25° C. for approximately 3 hours. The acid
is then neutralized with a base such as pyridine.
Water
is added and the oil separating is crystallized to give the
corresponding 3-enol ether. Alternately, the reaction
mixture is extracted with a suitable solvent such as ether.
30 and the extract is dried and evaporated under reduced
pressure. The residue is then chromatographed to ob
tain the corresponding 3-enol ethyl ether.
In a preferred embodiment of my invention, using as
the starting material a 3-ketohll5-pregnadiene which has
wherein R1 stands for an alkyl, cycloalkyl or benzyl
group, R2 stands for hydrogen or an alkyl group, R3 is
hydrogen or an acyl group, X is hydrogen or halogen, Y
is hydrogen, hydroxy or keto and Z is hydrogen, halogen 35 both a hydroxy group at position 11, and a hydrogen at
position 9 (whereby dehydration to the corresponding
or a methyl radical.
Mun-steroid is possible), a mixture of the 3-keto-A1-5
The above de?ned novel 3-enol ethers, produced in
prcgnadiene, absolute ethanol as the only solvent, and
accordance with the present invention, possess high anti
ethyl orthoformate are stirred together in the presence of
in?ammatory activity, considerably greater than that of
a strong acid catalyst. For example, a mixture of the
the parent steroids, and are especially effective for the
steroid, absolute ethanol, ethyl orthoforrnate and 2,4-di
treatment of arthritis and related diseases since thry can
be administered for their cortisone-like action in low
nitrobenzene-sulfonic acid are stirred together at room
dosage thereby minimizing undesired side effects.
temperature until solution takes place. The mixture is
Processes are known for the manufacture of the 3-enol
then stirred for a short time longer, after which time it
ethers of 3-keto-A4-pregnenes, for example, by stirring
45 is neutralized with an organic base, such as pyridine. The
together a mixture of the 3-keto'A4-pregnene and an alkyl
solution is concentrated to about half-volume, water is
added, and the concentration is continued until crystalli
zation of the 3-enol ethyl ether results,
The 3-enol methyl and n-propyl ethers of the 3-keto
orthoformate in a solvent such as dioxane in the presence
of a strong acid. Attempts to apply these methods to
the formation of the B-enol ethers of the 3-kete-A1'4-preg
nadienes, however, are ordinarily unsuccessful due to
the low reactivity of the 3—ketone group in the AL‘Lpreg
nadienes, and in most cases will result only in the recov
dlr‘l-pregnadienes are prepared in the same manner as
the S-enol ethyl ethers, but using methyl orthoformate
or n-propyl-orthoformate in place of ethyl orthoforrnate,
and methanol or n-propanol in place of ethanol. A
ery of unchanged starting material.
slightly longer time is usually required for the formation
of the 3-enol-propyl ethers.
The 3-enol n-butyl, cyclopentyl and cyclohexyi ethers
It has now been found that the 3-enol ethers of the 3
l<.eto-A1'4~pregnadienes, i.e. the 3-alkoxy-A1-3'5-pregna
trienes, can be readily obtained in good yields starting
from the corresponding 3-keto-A1:5-pregnadiene in place
of the 3-keto-A1'4-pregnadiene.
of the 3-keto-A1-4-pregnadienes are prepared by heating a
mixture of the 3-keto-A1‘5-pregnadiene and the correspond
ing alcohol e.g. n-butanol, cyclopentanol or cyclohexanol
with isooctane and an organic sulfonic acid, for example,
p-toluenesulfonic acid, in an apparatus equipped with
means for removing the water from the distillate, and
returning the dry distillate to the reaction mixture. The
In preparing our novel chemical compounds, the start
ing material utilized is the 3-keto-A1,5-pregnadiene which
may be identi?ed by the following structural formula:
acid catalyst is then neutralized with a base such as
65
pyridine, and the liquid is evaporated to dryness in vacuo.
The residue is puri?ed by crystallization, or by chroma
tography, to give the corresponding 3-enol ether.
The 3-enol benzyl ethers of the 3-keto~A1-4-pregnadienes
are prepared by adding the corresponding 3-enol ethyl
70 ether to an anhydrous mixture of benzene, benzyl alcohol
and p-toluene-sulfonic acid. The reaction mixture is then
cooled to room temperature, made alkaline and concen
3,0 cases
3
4
trated to dryness under reduced pressure. The residue is
calcium hydride), 10 m1. of n-propyl orthoformate and
puri?ed by crystallization from methanol containing traces
of pyridine,,or by chromatography, to give the correspond
ing 3-enol-benzyl ether.
0.300 g. of 2,4-dinitrobenzenesulfonic acid are stirred at
room temperature for 1-6 hours. The reaction mixture is
stirred for an additional 15 minutes and 1 ml. of pyridine
is added. The solution is concentrated to half-volume and
10 ml. of water is added. Concentration is continued
until crystallization occurs. About 100 ml. of water is
added and the product is ?ltered, washed well with water,
and dried to give 3-n-propoxy-17a,21-dihydroxy-1,3,5
The above methods are applicable to the preparation
of the novel 3-alkoxy-A1,315-pregnatrienes, subject of the
present invention. However, it has been found, unex
pectedly, that in the case of the 3-alkoxy-A1'35-pregna
trienes which have a substituent in the 6-position of the
steroid molecule, it is also possible to obtain the 3-enol 10 pregnatriene-1l,20~dione 21-acetate.
ethers starting with the more readily available 3-keto
Example 5
Alt‘t-pregnadienes. In a preferred embodiment of our
A mixture of two grams of 17a,21-dihydroxy-l,5-preg
invention the 3-enol ethers of the 6-substituted 3-keto
nadiene-3,l1,20-trione 21-butyrate, 15 ml. of dry dioxane,
Al?-pregnadienes, for example, the 6-halogen and the
6-rnethyl-derivatives, are prepared from the correspond 15 0.2 ml. of absolute ethanol and 2 ml. ethyl orthoformate
is treated with 1.4 ml. of 5% sulfuric acid in dioxane. The
mixture is stirred at room temperature for one-half hour
ing 3-ket0-A1-4-pregnadienes using the procedures de
scribed above, but starting with the 6-substituted-3-keto
AM-pregnadiene instead of the 6-substituted-3-l<eto-A1'5
and then treated with l—2 ml. of pyridine. Twenty~?ve
ml. of water is slowly added and the resulting oil is
scratched and seeded to induce crystallization. The prod
uct is ?ltered and washed with a mixture of 40% dioxane
and water, and dried to give 3-ethoxy-17e,2l-dihydroxy
pregnadiene.
The following examples illustrate methods of carrying
out the present invention but it is to be understood that
these examples are given for purposes of illustration and
1,3,5-pregnatriene-l1,20-dione 21-butyrate.
not of limitation.
Example 1
Example 6
A mixture of two grams of 17a,21-di‘nydroxy-1,5
A mixture of two grams of l7ot,2l-dihydroxy-1,5
pregnadiene-3,20-dione 2l-acetate, 15 ml. of dry dioxane,
pregnadiene-3,l1,20-trione, 15 ml. of dry dioxane, 0.2 ml.
0.2 ml. of absolute ethanol and 2 ml. of ethyl orthoformate
is treated with 1.4 ml. of 5% sulfuric acid in dioxane.
of absolute ethanol and 2 ml. ethyl orthof-ormate is treat:
with 1.4 ml. of 5% sulfuric acid in dioxane. The mix
The mixture is stirred at room temperature for one-half
ture is stirred at room temperature for one-half hour
hour and then treated with 1-2 ml. of pyridine. Twenty 30 and then treated with 1-2 ml. of pyridine. Twenty?ve
?ve ml. of water is slowly added and the resulting oil is
ml. of water is slowly added and the resulting oil is
scratched and seeded to induce crystallization. The prod~
scratched and seeded to induce crystallization. The
not is ?ltered and washed with a mixture of 40% dioxane
product is ?ltered and Washed with a mixture of 40%
and water, and dried to give 3-ethoxy-l7rx,2l-dihydroxy
dioxane and water,- and dried to give 3-ethoxy-17a,21
1,3,5-pregnatriene-20-one 21-acetate.
The 17a,2l-dihydroxy-1,5-pregnadiene-3,20-dione 21»
dihydroxy-1,3,5--pregnatriene-l1,20-dione.
Example 7
acetate used as starting material for this process is pre
pared by dissolving 500 mg. of 6B-bromo-17a,21~dihy—
A mixture of two grams of 9a-?uor0-l7m,21-dihydroxy
droxy-1,4-pregnadiene-3,11,20-trione 21-acetate in 150 ml.
of alcohol and then adding 25 ml. of water and 5 g. of
zinc powder. The suspension is stirred at room tempera
ture for 8 hours, after which time the zinc is ?ltered, and
1,5~pregnadiene-3,l1,20-trione 21-acetate, 15 ml. dry di
oxane, 0.2 ml. of absolute ethanol and 2 ml. ethyl ortho
formate is treated with 1.4 ml. of 5% sulfuric acid in
dioxane. The mixture is stirred at room temperature for
the ?ltrate is concentrated to dryness in vacuo. The re
one-half hour and then treated with 1—2 ml. of pyridine.
Twenty~?ve ml. of Water is stowly added and the result
ing oil is scratched and seeded to induce crystalliza
tion. The product is ?ltered and washed with a mixture
of 40% dioxane and water, and dried to give 3-ethoxy
sulting residue is recrystallized from acetone to yield
170;,2l-dihydroxy-1,5-pregnadiene-3,ZO-dione 21-acetate.
Example 2
A mixture of two grams of 17a,21-dihydroxy-1,5-preg
9o¢~?uoro~17a,2l-dihydroxy-1,3,5 ~ pregnatriene - 11,20-di
nadiene-3,11,20-trione 21-acetate, 15 ml. of dry dioxane,
one 21-acetate.
0.2 ml. of absolute ethanol and 2 ml. of ethyl orthofor 50
Example 8
mate is treated with 1.4 ml. of 5% sulfuric acid in dioxane.
The mixture is stirred at room temperature for one-half
Ten grams of 9a-bromo-17a,21-dihydroxy-1,5-preg
hour and then treated with 1-2 ml. of pyridine. Twenty
nadiene—3,l1,20-trione 21~acetate, 100 ml. of absolute
?ve m1. of water is slowly added and the resulting oil is
ethanol (distilled from calcium hydride), 10 ml. of ethyl
scratched and seeded to induce crystallization. The
orthoformate and 0.300 g. of ,4-dinitrobenzenesulfonic
product is ?ltered and washed with a mixture of 40%
acid are stirred ‘at room temperature until solution is
dioxane and water, and dried to give 3-ethoxy-17u,21
effected. The reaction mixture is stirred for an additional
dihydroxy-1,3,5-pregnatriene-11,20-dione ZI-acetate.
.15 minutes and 1 ml. of pyridine is added. The solution
Example 3
A mixture of two grams of 17a,21-dihydroxy-1,5-preg
nadiene-3,11,20-trione 21-acetate, 15 ml. of dry dioxane,
0.2 ml. of absolute methanol and 2 ml. methyl orthofor
mate is treated with 1.4 ml. of 5% sulfuric acid in dioxane.
The mixture is stirred at room temperature for one-half
hour and then treated with 1-2 ml. of pyridine. Twenty
?ve ml. of water is slowly added and the resulting oil is
scratched and seeded to induce crystallization. The
product is ?ltered and washed with a mixture of 40%
dioxane and water, and dried to give 3-rnethoxy-17a,2l
dihydroxy-1,3,5-pregnatriene-11,20-dione 21-acetate.
Example 4
Ten grams of 17u,2l-dihydroxy-1,5;pregnadiene-3,l1,
20-trione ZI-acetate, 100 ml. of n-propanol (distilled from
15 concentrated to half-volume and 10 ml. of water is
60
added. Concentration is continued until crystallization
occurs. About 100 ml. of water is added and the product
18 ?ltered, Washed well with Water, and dried to give 3
ethoxy - 90c - bromo - 17a,21 - dihydroxy - 1,3,5 - preg
natriene-11,20~dione Zl-acetate.
Example 9
A mixture of two grams of 9ot-chloro-17tz,2l-dihydroxy
1,5*pregnadiene-3,11,20-trione 2l~acetate, 15 ml. of dry
dioxane, 0.2 ml. of absolute ethanol and 2 ml. of ethyl
orthoformate is treated with 1.4 ml. of 5% sulfuric acid
in d1oxane.
The mixture is stirred at room temperature
for one-half hour and then treated with 1-2 ml. of pyri
dine. Twenty-?ve ml. of water is slowly added and the
resulting oil is scratched and seeded to induce crystalliza
tion. The product is ?ltered and Washed With a mixture
soonest’;
5
6
of 40% dioxane and water, and dried to give 3-ethoxy-9a
Example 15
chloro - 17.x,2i - dihydroxy - i,3,5 - pregnatriene - 1l,20
Ten grams of 9a-?uoro-16a-ethyl-17a,21~dihydroxy-1,5
pregnadiene-B,11,20-trione 2l-acetate, 100 ml. of absolute
ethanol (distilled from calcium hydride), 10 m1. of ethyl
dione "ll-acetate.
Example 10
A mixture of two g .us of 9tx-?uoro-lea-methyl
orthoformate and 0.300 g. of 2,4-dinitrobenzenesulfonie
acid are stirred at room temperature until solution is
e?ected. The reaction mixture is stirred for an additional
15 minutes and 1 ml. of pyridine is added. The solution
is concentrated to half-volume and 10 ml. of water is
added. Concentration is continued until crystallization
occurs. About 100 ml. of water is added and the product
is ?ltered, washed well with water, and dried to give 3
17ot,21-dihydroxy-i,5—pregnadieue-3,11,20-trione Zl-uce
tate, 15 ml. or" dry dioxane, 0.2 ml. of absolute ethanol
and 2 ml. ethyl orthoformate is treated with 1.4 ml. of
5% sulfuric acid in dioxane. The mixture is stirred at
room temperature for one-half hour and then treated with
l-Z ml. of pyridine. Twenty-?ve ml. of water is slowly
added and the resulting oil is scratched and seeded to in
duce crystallization. The product is ?ltered and washed
ethoxy - 90¢ - ?uoro-16a-ethyl-17a,2l-dihydroxy-1,3,5-preg
with a mixture of 40% dioxane and water, and dried to
natriene-11,20-dione 21-acetate.
Example 16
give 3~ethoxy-9a-iiuoro-16a - methyl - 17ot,21 - dihydroxy
1,3,5-pregnatriene-11,20-dione ZI-acetate.
A mixture of two grams of 16u-n-butyl-l7ot,2l-dihy
Example 11
A mixture of two grams of 9a-?uoro-16cl-metl1yl-17e
21-dihydroxy-1,5-pregnadiene-3,11,20 - trione 21 - acetate,
20
15 ml. dry dioxane, 0.2 ml. of ‘absolute ethanol and 2
ml. ethyl orthoformate is treated with 1.4 ml. of 5%
sulfuric acid in dioxane. The mixture is stirred at room
temperature for one-half hour and then treated with 1-2
ml. of pyridine. Twenty-?ve ml. of water is slowly added
and the resulting oil is scratched and seeded to induce
crystallization. The product is ?ltered and washed with
a mixture of 40% dioxane and water, and dried to give 3~
droxy-1,5-pregnadiene-3,11,20-trione ZI-acetate, 15 ml. of
dry dioxane, 0.2 m1. of absolute ethanol and 2 ml. ethyl
orthoformate is treated with 1.4 ml. of 5% sulfuric acid
in dioxane. The mixture is stirred at room temperature
for one-half hour and then treated with 1-2 ml. of pyri
dine. Twenty-?ve ml. of water is slowly added and the
resulting oil is scratched and seeded to induce crystalliza
tion. The product is ?ltered and washed with a mixture
of 40% dioxane and water, and dried to give 3-ethoxy
16tt-n-butyl-17a,2l-dihydroxy - 1,3,5 - pregnatriene-l1,20
dione 21-acetate.
Example 17
ethoxy - 9a - fluoro - 16f! - methyl - 17¢,21 - dihydroxy
1,3,5-pregnatriene-11,20-dione 21-acetate.
A mixture of two grams of 16,B-n-butyl-17a,21-dihy
droxy-1,5-pregnadiene-3,11,20-trione ZI-acetate, 15 ml.
dry dioxane, 0.2 ml. of absolute ethanol and 2 ml. ethyl
orthoformate is treated with 1.4 ml. of 5% sulfuric acid
Example 12
'i.‘en grams of 16w.—n1ethyl-17a,21~dihydroxy-1,5-preg~
nadiene-3,11,20-trione 21-acetate,
m1. of absolute
ethanol (distilled from calcium hydride), 10 m1. of ethyl
in dioxane. The mixture is stirred at room temperature
for one-half hour and then treated with 1-2 ml. of pyri
dine. Twenty-?ve ml. of water is slowly added and the
resulting oil is scratched and seeded to induce crystalliza
orthoformate and 0.300 g. of 2,4-dinitrobenzenesulfonic
acid are stirred at room temperature until solution is ef
fected. The reaction mixture is stirred for an additional
tion. The product is ?ltered and washed with a mixture
15 minutes and 1 ml. of pyridine is added. The solution 40 or" 40% dioxane and water, and dried to give B-ethoxy
is concentrated to hall-volume and 10 ml. of water is
1d?-n-butyl-17u,21-dihydroxy ~ 1,3,5 - pregnatriene-11,20
added. Concentration is continued until crystallization
dione 21-acetate.
occurs. About 100 ml. of water is added and the product
Example 18
is ?ltered, washed well with water, and dried to give 3
ethoxy - 16a - meth‘l - 170:,21 » dihydroxy - 1,3,5 ~ preg
ilk Cl
A mixture of two grams of 16c<-methyl-17a,2l-dihy
droxy-l,5-pregnadiene-3,11,20-trione 2l-n-propionate, 15
natriene-l1,20-dione Zl-ac?tate.
ml. of dry dioxane, 0.2 ml. of absolute ethanol and 2
ml. of ethyl orthoformate is treated with 1.4 ml. of 5%
Example 13
A mixture of two grams of l6?-methyl-l7a,21»dihy- ._
sulfuric acid in dioxane. The mixture is stirred at room
temperature for one-half hour and then treated with 1-2
droxy-l,S-pregnadiene-S,l1,20-trione Zl-acetate, 15 mi. of
dry dioxane, 9.2 ml. of absolute ethanol and 2 ml. ethyl
ml. of pyridine. Twenty-?ve ml. of Water is slowly added
pyridine. Twenty-?ve ml. or" water is slowly added and
the resulting oil is scratched and seeded to induce crystal
lization. The product is filtered and washed with a mix
ture of 40% dioxane and water, and dried to give 3
triene-11,20-dione 21-n-propionate.
and the resulting oil is scratched and seeded to induce
orthoformate is treated with 1.4 ml. of 5% sulfuric acid
crystallization. The product is ?ltered and washed with
in dioxane. The mixture is stir-red at room temperature
a mixture of 40% dioxane add water, and dried to give
tor one-half hour and then treated with 1-2 ml. of CH CH 3 - ethoxy ‘- 15a - methyl-17x21-dihydroxy-l,3,S-pregna
natriene-lLZO-dione
ethoxy - 16,8 - methyl2i-acetate.
- 17u,21 - dihydroxy - 1,3,5
60
Example 19
‘Ten grams of l113,l7c¢,21-trihydroxy-1,5-pregnadiene
3,20-dione ZI-acetate, 100 ml. of absolute ethanol (dis
tilled from calcium hydride), 10 ml. of ethyl orthotormate
Example 14
A mixture of two grams of lda-ethyl-lhll-dihy
droxy-l,5—pregnadiene-3,11,20-trione ZI-acetate, 15 ml. oiv
dry dioxane, 0.2 ml. of absolute ethanol and 2 ml. ethyl
orthoformate is treated with 1.4 ml. of 5% sulfuric acid
in dioxane. The mixture is stirred at room temperature
for one—half hour and then treated with 1-2 ml. of
pyridine. Twenty-?ve ml. of Water is slowly added and
the resulting oil is scratched and seeded to induce crystal
lization. The product is ?ltered and washed with a mix~
ture of 40% dioxane and Water, and dried to give 3
ethoxy - 160a - ethyl - 17%21 - dihydroxy - 1,3,5 - preg
natrieue~11,20-dione 21-acetate.
and 0.30 g. of 2,4-dinitrobenzenesultonic acid are stirred
at room temperature until solution is eilected. The reac
tion mixture is stirred for an additional 15 minutes and
1 ml. of pyridine is added. The solution is concentrated
to half-volume and 10 ml. of water is added. Concentra
tion is continued until crystallization occurs. About 100
ml. of water is added and the product is ?ltered, washed
well with water, and dried to give 3-ethoxy-11B,l7a,21
trihydroxy-1,3,5-pregnatriene-20-one ZI-acetate.
Example 20
Ten grams of 9a~?uoro~11B,17a,21-trihydroxy-1,5-preg
nadiene-3,20-dione ill-acetate, 100 ml. of absolute ethanol
(distilled from calcium hydride), 10 ml. of ethyl ortho
3,068,253
8
formats and 0.300 g. of 2,4-dinitrobenzenesulfonic acid
ethanol (distilled from calcium hydride), 10 ml. of ethyl
are stirred at room temperature until solution is effected.
The reaction mixture is stirred for an additional 15 minutes
acid are stirred at room temperature until solution is ef
orthoformate and 0.300 g. of 2,4-dinitrobenzenesulfonic
fected. The reaction mixture is stirred for an additional
15 minutes and 1 ml. of pyridine is added. The solu
tion is concentrated to half-volume and 10 ml. of Water
is added. Concentration is continued until crystalliza
tion occurs. About 100 ml. of water is added and the
and 1 ml. of pyridine is added. The solution is concen
trated to half-volume and 10 ml. of Water is added. Con
centration is continued until crystallization occurs. About
100 ml. or" water is added and the product is ?ltered,
washed well with water, and dried to give 3-ethoxy-9a
iiuoro-l in,l7a,2l-trihydroxy-1,3,5-pregnatriene-20-one 21
product is ?ltered, washed Well with water, and dried to‘
10
acetate.
Example 21
give 3-ethoxy-l6ot-ethyl-l1p’,l7u,21-trihydroxy-l,3,5-preg
natriene-ZO-one 2l-acetate.
Example 26
Ten grams of 9ot-?uoro-l6a-methyl-11B,17a,2l-trihy
droxy~l,5-pregnadiene-3,20-dione 2l-acetate, 100 ml. of
absolute ethanol (distilled from calcium hydride), 10 ml.
Ten grams of 9a-?uoro-16a-ethyl-115,17u,21-trihy
droxy-1,5-pregnadiene-3,ZO-dione ZI-acetate, 100 ml. of
absolute ethanol (distilled from calcium hydride), 10 ml.
of ethyl orthotorrnate and 0.300 g. of 2,4-dinitrobenzene~
of ethyl orthoforrnate and 0.300 g. of 2,4-dinitrobenzene
sulfonic acid are stirred at room temperature until solu‘
tion is elfected. The reaction mixture is stirred for an
sulfonic acid are stirred at room temperature until solu
additional 15 minutes and 1 ml. of pyridine is added. The
tion is effected. The reaction mixture is stirred for an
solution is concentrated to half-volume and 10 ml. of 20 additional 15 minutes and 1 ml. of pyridine is added.
water is added. Concentration is continued until crystal
The solution is concentrated to half-volume and 10 ml.
lization occurs.
About 100 ml. of water is added and
of water is added. Concentration is continued until
crystallization occurs. About 100 ml. of water is added
the product is ?ltered, washed well with water, and dried
to give 3 - ethoxy~9ct-fluo1'o-loa-methyl-ll?,l7o:,2l-trihy
and the product is ?ltered, washed Well with water, and
droxy-l,3,5-pregnatriene-20-one 21-acetate which shows 25 dried to give 3-ethoxy-9ot-?uoro-l6a-ethyl-l1?,17oc,2l-tri
ultraviolet absorption amax.=320, e,u=4310.
hydroxy-l,3,5-pregnatriene-20-one 2l-acetate.
Example 22
.
Example 27
Ten grams of 9a-?uoro-16?-methyl-1 1,8,17u,21-tril1y
Ten grams of 60: - chloro - 9oz - ?uoro - 16a - methyl
droxy-1,5-pregnadiene-3,20-dione Zl-acetate, 100 ml. of 30 11,8,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione 2l~ace~
absolute ethanol (distilled from calcium hydride), 10 ml.
tate, 100 ml. of absolute ethanol (distilled from calcium
of ethyl orthoforrnate and 0.300 g. of 2,4-dinitrobenzene—
sulfonic acid are stirred at room temperature until solu
tion is effected. The reaction mixture is stirred for an
additional 15 minutes and 1 m1. of pyridine is added.
The solution is concentrated to half-volume and 10 ml.
of water is added. Concentration is continued until crys
tallization occurs. About 100 ml. of water is added and
hydride), 10 ml. of ethyl orthoformate and 0.300 g. of
2,4-dinitrobenzenesulfonic acid are stirred at room tem
perature until solution is e?ected. The reaction mixture
is stirred for an additional 15 minutes and 1 ml. of pyr
idine is added. The solution is concentrated to half-vol
ume and 10 ml. of water is added. Concentration is
continued until crystallization occurs. About 100 ml. of
the product is ?ltered, washed with water, and dried to
give 3-ethoxy-9a-?uoro-16/3-methyl-11p,17tx,21-trihydroxy
l,3,5-pregnatriene-20-one 21-acetate.
Example 23
Ten grams of 160L-ll16thyl-11B,17OL,21-i.1‘ll1YdI‘OXY-1,5
pregnadiene-3,20-dione ZI-acetate, 100 ml. of absolute
ethanol (distilled from calcium hydride), 10 ml. of ethyl
orthoformate and 0.300 g. of 2,4-dinitrobenzenesulfonic
acid are stirred at room temperature until solution is ef
fected. The reaction mixture is stirred for an additional
15 minutes and 1 ml. of pyridine is added. The solu
tion is concentrated to half-volume and 10 ml. of water
is added. Concentration is continued until crystallization
occurs. About 100 ml. of water is added and the prod
uct is ?ltered, washed well with water, and dried to give
3-ethoxy-l6a-methyl-l1B,l7ot,2l - trihydroxy - 1,3,5-preg
natriene-ZO-one 21-acetate.
Example 24
40
water is added and the product is ?ltered, washed well
with water, and dried to give 3-ethoxy-6-chloro-9a-?uoro
IGwmCthYl-ll?,170:,21-t1‘ihYClI‘OXY - 1,3,5 - pregnatriene
20-one 2l-acetate.
' starting material in the above example can be prepared
by warming a solution of 2.0 g. of 9OL-?LlOI'O-16OL-II16thy1
Al-‘i-pregnadiene-l1,8,l7a,2l_triol-3,20-dione 2l-acetate in
8 ml. of pyridine and 4 ml. of benzoyl chloride, warmed
at 50° C. for 3 hours.
The solution is then cooled,
poured into 5% aqueous NaHCOs and extracted with
chloroform.
The extracts are washed successively with
water, 5% I-ICl, Water, 5% NaI-ICO3, water, then dried
over anhydrous sodium sulfate and concentrated to an
oily residue. The crude product is adsorbed on 60 g.
of acid-washed alumina and subsequently eluted with
ethyl ether to afford 1.65 g. of the crystalline enol-ben
zoate. After recrystallization from acetone-petroleum
ether, the 904 - fluoro - 16a - methyl - A1315 - pregnatriene
Ten grams of v165-methyl-ll5,l7ot,2l-trihydroxy~l,5- I
3,1lo’,l7u,2l-tetrol-20-one-3-benzoate 2l-acetate has a
pregnadiene-3,20-dione 2l-acetate, 100 ml. of absolute 00 melting point of l61—7° C.;
ethanol (distilled from calcium hydride), 10 ml. of ethyl
orthotormate and 0.300 g. of 2,4-dinitrobenzenesulfonic
acid are stirred at room temperature until solution is
effected. The reaction mixture is stirred for an addition—
21 15 minutes and 1 ml. of pyridine is added. The so
lution is concentrated to half-volume and 10 ml. of wa
ter is added.
lization occurs.
Concentration is continued until crystal
About 100 ml. of water is added and
xgjgo? zzzligétt; 5% 374.; 283 m“; 6% 96; 307 m“; €%
A suspension of 100 mg. of the 9ot-?uoro-l6oz-methyl
A1-3'5-pregnatriene-3Jl5,l7a,21—tetrol-20-one - 3 - benzo
ate-Zl-acetate in 2 ml. of glacial acetic acid is cooled to
about 15° C. prior to the addition of 28 mg. of N-chloro
succinimide and a 5% solution of dry hydrogen chloride
the product is ?ltered, washed well with water, and dried
in 2 ml. of dry tetrahydropyran. The resulting solution
to give 3-ethoxy-l6?-methyl-l1,8,17a,21-trihydroxy-1,3,5
vpregnatriene-ZO-one 2l-acetate.
is stored at 0-5 ‘’ C. for 21/2 hours and then distributed be
tween chloroform and 5% aqueous Nal-ICO3.
The
CHCl3 layer is separated and washed with successive por
tions of Water, 5% NaHSOs, and water.
It is then dried
over MgSO4 and concentrated to a colorless oil which
'pregnadiene-3,20-dione 2l~acetate, 100 ml. of absolute
crystallizes after trituration with ether. Recrystallization
8,068,258
it}
corresponding 3-ethoxy-9a-?uoro-6,16u-dimethyl-115,1706,
from a mixture of acetone and ethyl ether affords crystals
of 6a-chloro-9a » ?uoro ~ 16a - methyl - A1-4 - pregnadiene~
21-trihydroxy-1,3,S-pIegnatriene-ZO-one, the 3-ethoxy-9a
ll?,17oz,21—’l1‘iOl-3,20-dl0t1€ 2l-acetate, M.P. 186—96° C.;
xgglgo? 240 1111;; e % 320
Example 28
?uoro-G,16a-dimethyl-17a,21 - dihydroxy - 1,3,5 - pregna
CI
A mixture of two grams of 6a-b1‘0II10-9oc-?uOrO-16a
methyl-115,l7ot,2ltrihydroxy-1,4-pregnadiene-3,20 - dione
triene-11,20-dione or the 21-acetate thereof.
The starting materials for the above procedures can be
prepared in the following manner:
To a cooled solution of 436 mg. of 6a.,l6u-dimethyl-4
pregnene-l1B,l7c¢,21-triol—3,20-dione 21-acetate in 2.5 cc.
dimethyl formatnide and 2.0 ml. of dry pyridine is added
1.0 ml. of methane sulfonyl chloride, while: maintaining
the temperature ‘below 0° C. The resulting mixture is al~
ZI-acetate, 15 ml. dry dioxane, 0.2 ml. of absolute ethanol
and 2 ml. ethyl orthoformate is treated with 1.4 ml. of
5% sulfuric acid in dioxane. The mixture is stirred at
room temperature for one~half hour and then treated
with 1—2 ml. of pyridine. Twenty~?ve ml. of Water is
slowly added and the resulting oil is scratched and seeded
to induce crystallization. The product is ?ltered and
washed with a mixture of 40% dioxane and water, and
lowed to warm to room temperature, at which point a
precipitate appears; the resulting mixture is then heated
to a temperature of about 70—100° C. for a period of
about 10 minutes. About 15 ml. of water is added slowly
to the reaction mixture, with stirriu g, and the aqueous mix
ture is extracted with ethyl acetate. The combined ethyl
acetate extracts are washed with water, then with dilute
aqueous hydrochloric acid solution, again with water, and
dried to give 3-ethoxy~6-bromo - 90a - ?llOI‘O-l?oc - methyl
11,8,l7a,21-trihydroxy-1,3,5-pregnatriene-20 - one 21-ace
tate.
20 t en with a dilute aqueous sodium bicarbonate solution.
The 60: - ‘bromo-Ehz-?uoro-l6oc-methyl-l1,B,17a,21-trihy
The washed ethyl acetate solution is dried, and the sol
droxy-l,4-pregnadien-e-3,20-dione ZI-acetate used as a
vent is evaporated in vacuo; the residual material is tritu
starting material in the above example can be prepared by
rated with ether, and the crystalline material is recrystal
warming 2. solution of 2.0 g. of 9a-?uoro-16u-methyl-A1'4
lized to
6e:.l6m-dimethyl-4,9(l Dpregnadiene-l’le,
pregnadiene-l1,8,17a,21-trio1,3,20-dione 21-acetate in 8 ml.
2l-diol-3,20'dione 21-acetate. A suspension of 330 mg. of
of pyridine and 4 ml. of benzoyl chloride, warmed at 50°
6ot,16a-dimethyl-3,9(ll)-pregnadiene - l7a,21 - dial-3,20
C. for 3 hours. The solution is then cooled, poured into
dione 21-acetate and 1.8 g. of N-bromo~succinimide in a
5% aqueous NaHCO3 and extracted with chloroform.
mixture of 50 ml. of dioxane and 10 ml. of water is cooled
The extracts are washed successively with Water, 5% H01,
to 10° C. Then with stirring, 10 ml. of cold 1.0 N aque
water, 5% Nai-iCOg, water, then dried over anhydrous so 30 ous perchloric acid is added. The temperature of the re
dium sulfate and concentrated to an oily residue. The
action mixture is allowed to rise to 15° C. and is main
crude product is adsorbed on 60 g. of acid~washed alumina
tained at this point for about two and one-half hours dur
and subsequently eluted with ethyl ether to afford 1.65 g. of
ing which time the solid material slowly dissolves. The
the crystalline enol-benzoate. After recrystallization from
resulting yellow solution is treated with 1.0 ml. of allyl
acetone-petroleum-ether, the 9a-?uoro-l6a-methyl-A1'3'5
35 alcohol to discharge the color and the remaining N-brorno
succinimide, and the resulting solution is evaporated to a
pregnatriene-3,l1?,17o¢,21-tetrol - 20 - one S-benzoate 21
acetate has a nielting point of 161-7" 0;
small volume in vacuo. The concentrated solution is di
luted with water, and the aqueous mixture is extracted
with ethyl acetate. The ethyl acetate extracts are washed,
40 dried and evaporated to dryness, and the residual rraterial
AEEZOH 22.12am; 6% 374; 283 mp; e% '36; 307 mu; 6%
A suspension of 100 mg. of the 9ot-?uoro-16a-methyl
is crystallized from ethyl acetate-ether to give 9a-bromo
A1'3'5-pregnatriene - 3,11/3,17a,21-tetrol-20-one 3-benzoate
21-acetatc in 2 ml. of glacial acetic acid is cooled to about '
15 ° C. prior to the addition of 28 mg. of N-bromosuc
cinimide and a 5% solution of dry hydrogen chloride in
2 m1. of tetrahydropyran. The resulting solution is stored
6ot,16a - dirnethyl - 4 - pregnene - ll?,l7a,2l—i1‘l0l-3,20—
dione Zl-acetate.
A solution of 210 mg. of §a-bromo-6a,16ct-dimethyl-4
, pregnene-l1,8,l7a,2l-triol-3,20-dione 21-acetate and 240
at 0~5° C. for 21/2 hours and then distributed between
of potassium acetate in 10 ml. of absolute ethanol is
heated under re?ux for two hours. The reaction mixture
chloroform and 5% aqueous NaHCO3. The CHCl3
layer is separated and washed with successive portions of
small volume, and diluted with water. The concentrate
water, 5% NaHSO3 and Water. it is then dried over
MgSO, and concentrated to a colorless oil which crystal
, aqueous mixture is extracted with three portions of ethyl
acetate, and the combined ethyl acetate extracts are Washed
lizes after trituration with ether. Recrystallization from
a mixture of acetone and ethyl ether affords crystals of
with water, dried, and evaporated to dryness in vacuo.
The residual material is crystallized from ethyl acetate
6a-bromo-9ix-?uoro - 16“ ~ methyl-AL‘l-pregnadiene-115,
17u,21—'[l‘l0l-3,20-dl0l1€ 21-acetate, M.P. l86—96° C.;
xgi?Pl‘l 240 mu; 6% 320
Example 29
A mixture of two grams of 9ot-?uoro-6a,16u-dimethyl
11,8,17u-2l-trihydroxy-l,4-pregnadiene-3,ZO-dione 21-ace
tate, 15 ml. dry dioxane, 0.2 ml. of absolute ethanol and
2 ml. of ethyl orthoformate is treated with 1.4 ml. of 5%
sulfuric acid in dioxane. The mixture is stirred at room
temperature for one-half hour and then treated with 1-2
ml. of pyridine. Twenty-?ve ml. of water is slowly added
and the resulting oil is scratched and seeded to induce
crystallization. The product is ?ltered and washed With
a mixture of 40% dioxane and water, and dried to give 3
ethOXY-S‘c-z-lluOrO-?a, l?u-dimethyl-l 15,17 01,21 - trihydroxy
1,3,5~pregnatriene-3,20-dione 21-acetate.
In accordance with the above procedure, but using as
starting material the 9et-?uoro-6a,l?a-dimethyl-l118,17“,
2l-trihydroxy-1,4~-pregnadiene-3,20 - dione, the 90c - fluoro
6a,1?a-dirnethyl-17a,21-dihydroxy-1,4 - pregnadiene - 3,
is cooled to room temperature, evaporated in vacuo to a
ether to give 6a,.16ct-dimethyl-9Jl-epoxy-4~pregneue~17a,
, 2l-diol-3,20-dione 21-acetate.
To a solution of 83 mg. of anhydrous hydrogen fluoride
in 4.7 ml. of ice-cold alcohol-free chloroform is added
an ice-cold solution of 416 mg. of 6a,16a—dlmeihyl-9,l1
epoxy-lt-pregnene-17a,2l-diol-3,2{i—dione 21—acetate. The
solution is mixed thoroughly and maintained at 0° C.
for two hours, at the end of which time 13.0 ml. of ice
cold 20% aqueous sodium acetate is added, and the result
ing mixture agitated vigorously. The layers are sepa
rated, and the choloroform layer is washed with Water
until free of acid, dried, and the chloroform evaporated in
vacuo.
The residual material is crystallized from acetone
petroleum ether to give 6a,16u-dimethyl-9u ?uoro-4
pregnene-l1e,17a,2l-triol-3,20~dione 21 - acetate.
Fifty
milligrams of ea,16u-dirnethyl-9a-?uoro-4-pregnene~11B,
70 l7a,2l»triol-3,20-dione 21-acetate is dissolved in a mixture
of 1.0 cc. of benzene and 1.0 cc. of l N methanolic potas
sium hydroxide, and the solution is allowed to stand at
room temperature for a period of about 10 minutes. The
solution is then acidified with acetic acid, the benzene is
11,20-trione or the 21-acetate thereof, there is obtained the 75 evaporated in vacuo, and the residual material is puri?ed
11
by crystallization to give 611,16a-dimethyl-9a-?uoro-4—
pregnene-l1,6,17a,21-triol-3,20-dione.
Way that the isooctane falling from the con-denser before
returning to the flask is separated from the water entrained
by it, by means of a suitable trap supplied with an inner
funnel containing phosphorus pentoxide mixed with a
?lter aid such as Celite (a diatomaceous earth). After
cooling, 1 ml. of pyridine is added to neutralize the p-tolu
To a solution of 100 mg. of 6a,l6cc-Cll11'l8tl1Yl-9u-?u01‘0
4-pregnene-l15,l7a,21-triol-3,20-dione 21-acetate, in 6 ml.
t-butanol, and 0.01 ml. of glacial acetic acid is added '70
mg. of selenium dioxide. The mixture is heated under
reflux in a nitrogen atmosphere for a period of about 60
ene-sulfonic acid and the liquid is completely evaporated
hours. The reaction solution is ?ltered and evaporated in
in vacuo to dryness to give a residue of 3-cyclohexyloxy
17t~.'-2l-dihydroxy-1,3,5-pregnatriene-20-one 21 - acetate.
vacuo. The residual material is dissolved in benzene,
and the benzene solution is washed with an aqueous so 10 l’uri?cation is effected by recrystallization from methanol
dium bicarbonate solution and dried over anhydrous so
containing traces of pyridine or alternately, by chroma
dium sulfate. The benzene solution is stirred with mer
tography over alumina (alkaline) and elution with ether
cury overnight, then centrifuged, and the clear benzene
petroleum ether mixtures.
solution is evaporated in vacuo. The residual material
Example 31
thus obtained is separated, using partition chromatography
on diatomaceous silica (Super-Cel), to give 60¢,160L-dl
A mixture of 5 g. of 17a,2l-dihydroxy-l,S-pregnadiene
methyl-9a-?uoro-1,4-pregnadiene-11o,17ot,21-triol - 3,20
3,20-dione 21-acetate, 550 ml. of isooctane (2,2,4-tri
dione ZI-acetate. This material is hydrolyzed using 1 N
methylpentane), 2.5 ml. of n-butanol and 0.25 g. of p
methanolic potassium hydroxide in benzene as described
toluenesulfonic acid is refluxed for 32 hours employing
above for the hydrolysis of 60c,l6oc-dirh6thYl-9u-?tl01‘O-4 20 an apparatus (such as that described in Organic Syn
pregnene~1 l?,17a,2l-triol-3,20-dione Zl-acetate to give 60c,
thesis, Collective Vol. III (1955), page 382) equipped
16a-dimethyl-9oc-?uoro-1,4-pregnadiene-11;3,17a,21 - triol
in such a Way that the isooctane falling from the con
3,20-dione.
denser before returning to the ?ask is separated from
the water entrained by it, by means of .a suitab‘e trap
A solution of 400 mg. of 6a,16e-dimethy1-9u-?uoro-4
pregnene-l1p‘,17a,21-triol-3,20-dione ZI-acetate in 4 ml.
of pyridine is added to the compelx formed by the addi~
supplied with an inner funnel containing phosphorus
pentoxide mixed with a ?lter aid such as Celite (a diato
tion of 400 mg. of chromium trioxide to a 4 ml. of
maceous earth). After cooling, 1 ml. of pyridine is
added to neutralize the p-toluenesultonic acid and the
and then allowed to stand at room temperature overnight.
liquid is completely evaporated in vacuo to dryness to
The reaction mixture is poured into Water, and the aqueous 30 give a residue of 3-n-butoxy-17u,21-dihydroxy-1,3,5-preg
mixture is extracted with ether and then twice with ethyl
natriene-ZO-one 21-acetate. Puri?cation is e?ected by re
pyridine. The mixture is swirled until thoroughly mixed
acetate. The combined ether and ethyl acetate extracts
are washed with dilute aqueous sulfuric acid at about 0°
crystallization from methanol containing traces of pyri
dine or alternately, by chromatography over alumina
(alkaline) and elution with ether-petroleum ether mix
C., and then with \water until neutral. The organic solvent
layer is then dried, the solvents are evaporated therefrom 35 tures.
in vacuo, and the residual crystalline material is puri?ed
by crystallization to give 61x,16a~dimethyl-9u-?uoro-4
pregnene-17u,21-diol-3,11,20-trione 21-acetate. Fifty mil
ligrams of 6a,16a-dimethyl-9a-?uoro-4-pregnene-170:,21
Example 32
To a mixture of 125 ml. of benzene and 2.1 ml. of
benzyl alcohol is added 30 mgm. of p-toluenesulfonic
diol-3,11,20-trione 21-acetate is dissolved in a mixture of Au acid. A small portion of benzene is distilled from the
1.0 cc. of benzene and 1.0 cc. of 1 N methanolic potas
solution to remove traces of moisture.
sium hydroxide, and the solution is allowed to stand at
room temperature for a period of about 10 minutes. The
ing solution is added 1 g. of 3-ethoxy-17oz,21-dihydroxy
l,3,5-pregnatriene-20-one 2l-acetate. The mixture is
then heated at the boiling point for 30 minutes with slow,
continuous co-distillation of benzene and ethanol. The
solution is then acidi?ed with acetic acid, the benzene is
evaporated in vacuo, and the residual material is puri?ed
by crystallization to give 6ot,16e-dimethyl-9a-?uoro-4
~15 reaction mixture is then cooled to room temperature,
pregnene-17a,21-diol-3,11,20—trione.
To a solution of 100 mg. of 6a,16m-dimethyl-9e-?uoro
4-pregnene-17e,21-diol-3,11,20-trione 21-acetate in 6 ml.
t-butanol, and 0.01 ml. of glacial acetic acid is added 70
mg. of selenium dioxide. The mixture is heated under
reflux in a nitrogen atmosphere for a period of about 60
hours. The reaction solution is ?ltered and evaporated in
vacuo. The residual material is dissolved in benzene,
and the benzene solution is washed with an aqueous so
dium bicarbonate solution and dried over anhydrous so- "
dium sulfate.
To the remain
The benzene solution is stirred with mer
cury overnight, then centrifuged, and the clear benzene
solution is evaporated in vacuo. The residual material
thus obtained is separated using partition chromatography
made alkaline by the addition of a few drops of pyridine,
and concentrated to dryness under reduced pressure to
give a residue of 3-benzyloxy-17a,2l-dihydroxy-1,3,5
pregnatriene-ZO-one ZI-acetate. Puri?cation is etfected
by recrystallization from methanol containing traces of
pyridine. Alternately, the product is purified by chroma
tography over alumina (alkaline) and elution with ether
petroleum ether mixtures.
Example 33
Ten grams of 6?-chloro-9a-?uoro-lGu-methyl-I 15,1705,
21 - trihydroxy - 1,4 - pregnadiene - 3,20 - dione 21 - ace
tate, 100 ml. of absolute ethanol (distilled from calcium
hydride), 10 ml. of ethyl orthoformate and 0.300 g. of
on diatomaceous silica (Super~Cel) to give 6u,l6oc-dl—
2,4-dinitrobenzenesulfonic acid are stirred at room tem
methyl-9u-?uoro-l,4-pregnadiene-17oc,21 - diol - 3,11,20
give 6a,16u-dimethyl—9a-?uoro-1,4-pregnadiene - 17a,21—
perature until solution is effected. The reaction mixture
is stirred for an additional 15 minutes and 1 ml. of pyri
dine is added. The solution is concentrated to half
volume and 10 ml. of water is added. Concentration
is continued until crystallization occurs. About 100 ml.
of water is added and the product is ?ltered, washed Well
dial-3,11,20-trione.
with water, and dried to give 3-ethoxy-6-chloro-9ot-?uoro
trione 2l-acetate. This material is hydrolyzed using 1 N
methanolic potassium hydroxide in benzene as described
hereinabove for the hydrolysis of 606,1605-dll'1'l6thY1-9d
?uoro-4-pregnene-17a,21-dio1-3,l1,20-trione ZI-acetate to
Example 30
A mixture of 5 g. of l7a,2l-dihydroxy-1,5-pregnadiene-3, "
16m - methyl - l1,8,17a,21 - trihydroxy - 1,3,5 - pregna
triene-ZO-one 21-acetate.
The 6,8 - chloro - 9a - ?uoro - 16oz - methyl - 115,17a,
20-dio-ne 21-acetate, 550 ml. of isooctane (2,2,4-trimethyl
21 - trihydroxy - 1,4 - pregnadiene - 3,20 - dione 21
pentane), 2.5 ml. of cyclohexanol and 0.25 g. of p-toluene
acetate used as a starting material in the above example
sulfonic acid is re?uxed for 32 hours employing an ap
is prepared by warming a solution of 2.0 g. of 9a-?uoro
paratus (such as that described in Organic Synthesis, Col
16a - methyl - 1,4 - pregnadiene - 1l,8,17a,21 - triol - 3,
lective Vol. III (1955), page 382) equipped in such a 75 ZO-dione 21-acetate in 8 ml. of pyridine and 4 ml. of
3,068,253
13
id
benzoyl chloride, warmed at 50° C. for 3 hours. The
tracted with 50 ml. of methylene chloride and the
methylene chloride extract is washed two times with 25
cc. of water, dried over magnesium sulfate, evaporated to
dryness and then ?ushed once with 10 ml. of benzene.
solution is then cooled, poured into 5% aqueous
NaHCOa .and extracted with chloroform. The extracts
are washed successively with water, 5% HCl, water, 5%
NaHCO3, Water, and then dried over anhydrous sodium
sulfate and concentrated to an oily residue. The crude
product is adsorbed on 60 g. of acid-washed alumina and
subsequently eluted with ethyl ether to afford 1.65 g. of
The residue is triturated with ether until a smooth sus
pension results and then ?ltered and washed with ether
to give 6,8-bromo-9a-?uoro-loot-methyl-l,4-pregnadiene
11,8,l7et,2l-triol-3,20-dione 2il-acetate, kmax. 243, e% 283.
the crystalline enol-benzoate. After recrystallization
Various changes and modi?cations may be made in
from acetone-petroleum-ether, the 9a-?uoro-16a-methyl 10 carrying out the present invention without departing from
the spirit and scope thereof. Insofar as these changes
and modi?cations are Within the purview of the annexed
1,3,5 ‘ pregnatriene - 3,11,B,l7a,21 - tetrol - 20 - one - 3
benzoate 21~acetate has a melting point of 161-7° C.;
claims, they are to be considered as part of our invention.
xglggm 2212?”; 6% 374; 283 m“; 6% as; 307 mu; e%
I claim:
1. The process which comprises reacting a compound
To a mixture of 5 g. of 9a-?uoro-l6u-methy1-l,3,5
having the following formula:
pregnatriene - 3,11/3,17a,21 - tetrol - 20 - one - 3 - ben
zoate ZI-acetate in 50 ml. of tetrahydrofuran cooled to
0° C., is added 1.69 g. of N chlorosuccinimide and 1.77 g.
of p-toluenesulfonic acid hydrate. The reaction mixture 20
is stirred for one hour at 0° C. and then poured into a
3% potassium carbonate solution. The mixture is ex
tracted with 50 ml. of methylene chloride and the methyl
ene chloride extract is Washed two times with 25 cc. of
water, dried over magnesium sulfate, evaporated to dry 25
ness and then ?ushed once with 10 ml. of benzene. The
residue is triturated with ether until a smooth suspension
results and then ?ltered and washed with ether to give
65 - chloro - 9oz - ?uoro - 160a - methyl - 1,4 - pregna
diene-l1B,l7a,21-triol-3,20-dione 21-acetate.
30
'wherein R2 is a member of the group consisting of hydro
gen and methyl, R3 is a member of the group consisting
Example 34
A mixture of two grams of 6/8-bromo-9u-?uoro-l6u
methyl - 11,8,17a,21 - trihydroxy - 1,4 - pregnadiene - 3,
20-dione 2l-acetate, 15 mi. dry dioxane, 0.2 ml. of abso
lute ethanol and 2 ml. ethyl orthoformate is treated with
1.4 ml. of 5% sulfuric acid in dioxane. The mixture is
of hydrogen and lower hydrocarbon carboxylic acyl, X
is a member of the group consisting of hydrogen and
35 halogen and Y is a member of the group consisting of
stirred at room temperature for one-half hour and then
hydrogen, ,B-hydroxy and keto, With a lower alkyl ortho
formate and an alkanol in the presence of an inert solvent
and acid catalyst to form a compound of the formula:
treated with 1-2 ml. of pyridine. Twenty-?ve ml. of 40
water is slowly added and the resulting oil is scratched
and seeded to induce crystallization. The product is
?ltered and washed With a mixture of 40% dioxane and
Water, and dried to give 3-ethoxy~6-bromo-9a-?uoro-16a
methyl - 11?,17ot,21 - trihydroxy - 1,3,5 - pregnatriene
20-one 2l-acetate.
The 6,8 - bromo - 9a - ?uoro - 16a - methyl - 11,8,17a,
21 - trihydroxy - 1,4 - pregnadiene - 3,20 - dione 2l-ace
tate used as a starting material in the above example is
prepared by warming a solution of 2.0 g. of 9a-?uoro
16a — methyl - 1,4 - pregnadiene - 1l/3,17ix,2l - triol - 3,
20~dione 21-acetate in 8 ml. of pyridine and 4 ml. of
benzoyl chloride, warmed at 50° C. for 3 hours. The
solution is then cooled, poured into 5% aqueous NaHCOs
and extracted With chloroform.
The extracts are Washed
successively with water, 5% HCl, water, 5% NaHCO3,
water, then dried over anhydrous sodium sulfate and
concentrated to an oily residue. The crude product is
adsorbed on 60 g. of acid-washed alumina and subse
quently eluted with ethyl ether to afford 1.65 g. of the 60
crystalline enol-benzoate. After recrystallization from
wherein R1 is a lower alkyl radical and wherein R2, R3,
X and Y have the signi?cance above de?ned.
2. The process which comprises reacting a compound
having the following structure:
cngong
0 =0
acetone~petroleum-ether, the 90c - ?uoro - 16oz - methyl
l,3,5 — pregnatriene - 3,ll,8,l7a,2l -tetro1 - 20 - one - 3
benzoate 21-acetate has a melting point of 161—7° C.;
2242?”; 6% 374; 283 III/.1; c»% 96; 307 11111.; 6%
To a mixture of 5 g. of 9a-?uoro-l6ui-methyl-1,3,5
pregnatriene - 3,1l,6,17ct,21 - tetrol-20-one-3-benzoate
21~
acetate in 50 ml. of tetrahydrofuran cooled to 0° C., is
added 1.69 g. of N bromosuccinimide and 1.77 g. of p
toluenesulfonic acid hydrate. The reaction mixture is
stirred for 5 minutes at 0° C. and then poured into a
3% potassium carbonate solution. The mixture is ex 75
wherein R2 is a member of the group consisting of hydro
gen and methyl, R3 is a member of the group consisting
of hydrogen and lower hydrocarbon carboxylic acyl, X
is a member of the group consisting of hydrogen and
halogen, with an alkyl orthoforrnate and the correspond
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