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Патент USA US3072650

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United States Patent ()?ice‘
1
3,072,640
Patented Jan. 8, 1963
2
~ ing the 16u,l7u-acetal or ketal, together with a tetrahy
3,072,640
dropyranyl group at carbon-21, as shown is compound 8
16 - OXYGENA'I‘ED - 4 - PREGNENO - [3,2-c]
of Flow Sheet B.
PYRAZOLES AND PROCESS OF PRE
-
The 1l-oxygenated-16u,1711,21-trihydroxy-4-pregnene
PARING THEM
Ralph F. Hirschmann, Scotch Plains, and Arthur A. 5 3,20-‘dione (or the A'tl?-analogs thereof) used as starting
materials for the compounds shown in Flow Sheet A are
Patchett, Metuchen, N.J., assignors to Merck & Co.,
prepared from the known 1l-oxygenated-lhJl-dihy
Inc., Rahway, N.J., a corporation of New Jersey
droxy-4-pregnene-3,20-diones as indicated on the Flow
No Drawing. Filed Mar. 5, 1962, Ser. No. 177,169
Sheet for Starting Materials, in column 6, lines 1-40.
26 Claims. (Cl. 260--239.5)
Among-the compounds which may be used as starting
10
This invention is concerned generally with novel
materials are the following:
steroids and with processes of preparing the same. More
1 15,16“,17a,21-tetrahydroxy-4-pregnene-3,ZO-dione,
particularly it relates to novel l15,1604,17a-trihydroxy-20
oxo - 4 - pregneno-
and
4,6-pregnadieno-[3,2-c]pyrazole
compounds and to the 16m,l7a-acetals and ketals of these 15
[3,2-c]pyrazo1es.
The novel compounds which form the subject of the
6a-chloro-1 1,6,16a,l7a,21-tetrahydroxy-4-pregnene-3,20
dione;
'
6u-?uoro-l l?,16a,l7a,21-tetrahydroxy-4-pregnene-3,20
dione;
6a~methyl-1 1,8,1601,1704,21-tetrahydroxy-4-pregnene-3,20
present invention have structural Formulas A ‘and B.
dione;
6a-chloro-9a-?uoro-1 113,16a,17a,21-tetrahydroxy-4
pregnene-3,20-dione;
25
6a,9a-di?uoro-1 1,9,16a,17a,2l-tetrahydroxy-4-pregnene
3,20-dione; and
'
6u-methyl-9a-?uoro-l 1,8-16u,17a,21-tetrahydroxy-4
pregnene-3 ,20-dione.
Detailed procedures for preparing speci?c starting mate
rials included in Flow Sheet B, starting from known in
30 termiates are included in columns 28—30.
wherein the dotted line between carbons 6 and 7 indicates
that a double bond may be present in this position, and
wherein R’ refers to hydrogen, ?uoro-hydroxy, acyloxy,
the ‘dihydrogen phosphate, and the alkali metal salts of
the dihydrogen phosphate, R is hydrogen acyl, alkyl,
Upon treatment of an ll-oxygenated 16a,17u,2l-trihy
droxy-4-pregnene-3,20-dione (or a A4'6~analog thereof),
having a protected side chain, with an alkyl formate and
sodium hydride in an inert atmosphere there is formed
the corresponding 2-hydroxymethylene derivative which
may be mixed with the formate esters thereof. The 2
aralkyl, cycloalkyl, aryl, a heterocyclic nucleus or sub
hydroxymethylene-derivative is designated on Flow Sheet
stituted derivatives thereof, X refers to hydrogen or ?uoro,
A as compound 2 and on Flow Sheet B as compound 11.
and Y refers to hydrogen, methyl, ?uoro or chloro groups.
In a preferred embodiment of our invention, the steroid
The 16a,l7a-acetals and ketals of the above compounds 40 is dissolved in a solvent such as benzene or pyridine and
which are also indcluded in the present invention have
the resulting solution is cooled to room.temperature and
the following structures:
treated with ethyl formate. The air in the system is re
placed with nitrogen, sodium hydride or alkoxide is added
and the mixture is stirred at room temperature for several
hours.
The 2-hydroxymethylene compound and/or its derived
formates reacts with hydrazine in an inert atmosphere to
form the corresponding [3,2-clpyrazole.
Upon treatment of the Z-hydroxymethylene-compound
with a lower alkanol in the presence of an acidic reagent
such as p-toluenesulfonic acid the corresponding 2-alkoxy
methylene-compound is formed. When the hydroxymeth
ylene compound containing variable amounts of the
alkoxymethylene derivative is reacted with a monosuh
wherein the dotted line between carbons 6 and 7, and R, 55 stituted hydrazine, the following N-substituted [3,2-cl
pyrazole derivatives are formed,
R’, X and Y have the meaning a-bove de?ned and where
in P and Q are each selected from the group consisting of
hydrogen, alkyl and aryl, and together with the carbon to
which they are joined, P and Q are cycloalkyl.
The above de?ned [3,2-c]pyrazole-steroids possess high 60
anti-in?ammatory activity and are especially etfective for
the treatment of arthritis and related diseases since they
can ‘be administered for their cortisone-like action in low
dosage thereby minimizing undesirable side effects.
In preparing our novel chemical compounds, the start 65
ing material utilized is an l1oxygenated-16a,l7a,21~tri
hydroxy-4~pregnene-3,2‘0-dione, or a MIG-analog thereof,
which has a protected cortical side chain. The side chain
wherein X, Y and R have the signi?cance above de?ned.
of the steroid may be protected with an ethylenedioxy
' The above compounds are shown on Flow Sheet A as
group at carbon-20, as shown in compound 1 of Flow 70 compounds 3A and 3B, and on Flow Sheet B as com
Sheet A. The side chain may also be protected by form
pounds 12A and 12B. The mixture of products may be
3,072,640
4
stituted [3,2-clpyrazoles.
the ketal shown in all the ?ow sheets is the l6a,17oz-l50
propylidenedioxy-derivative which is obtained with ace
tone. However, it is understood that other acetal and
ketal derivatives may be substituted in these examples.
The 16a,17a-acetonide group may be removed by heat‘
ing for a short time with 60% formic acid.
mixtures may be obtained when starting with the 2-hy
pionic anhydride; or a polybasic anhydride such a 19,153
separated by chromatography.
The N-substituted
[3,2-c] pyrazoles having structure A are designated as the
l’-substituted-[3,2-c]pyrazoles and the N-substituted com
pounds having structure B are designated as the 2’-sub
Upon treatment of a 2~hydroxymethylene-compound
The N-suhstituted-l15,21-dihydroxy-16a,17a-isopropyl
directly with a monosubstituted arylhydrazine, without
idenedioxy-20-oxo-4-pregneno-(or
4,6-pregnadieno)[3,2~
the intermediate formation of the 2-alkoxymethylene
c]pyrazole (compound 6 of Flow Sheet A) is converted
derivative, one isomer is generally formed in preponderant
into the 21-acy1oxyderivative by treating with one equiva
amounts, whereas when reacting the 2-alkoxymethylene 10 lent of an acylating agent, e.g. a lower hydrocarbon car
compound with a monosubstituted arylhydrazine, signi?
boxylic acid acylating agent such as benzoic anhydride,
cant amounts of both isomers are obtained. When these
tertiary butyl acetyl chloride; 21 lower alkanoic anhydride
reactions take place with monosubstituted-alkylhydrazines,
or lower alkanoyl halide such as acetic anhydride, pro
droxymethylene-steroid as well as with the Z-alkoxymeth
ylene-steroid. A mixture of isomers may also result from
the reaction of a monosubstituted-hydrazine with a 2-hy
dimethyl-glutaric anhydride, succinic anhydride and the
like, in the presence of an organic base such as pyridine.
The N-unsubstitutedd15,21-dihydroxy-16a,17a-isopro
droxymethylene-compound which possibly contains var
pylidenedioxy - 20-oxo-4-pregneno-(or 4,6-pregnadieno)
iable amounts of the Z-alkoxymethylene-compound due
to the operating procedures employed, for example, due 20 [3,2-c1pyrazole is converted into the 21-acyl derivative
‘by reacting with 2 equivalents of the acylating agent to
to recrystallization in the presence of a trace of alcohol
form the N-acyl-2l-acetate and then heating the latter
a solution of the 2-hydroxymethylene-compound from
compound with aqueous acetic acid, whereupon the N-acyl
which acid has not been completely removed.
group is selectively removed.
Any formate ester groups present in the resulting
The products of our invention include, among others,
[3,2-c]pyrazo1e may be removed by treating with sodium 25
the following:
methoxide in methanol at room temperature for about
10 minutes.
115,16u,17a,21-tetrahydroxy-20-oxo-4-pregneno-[3 ,2-c]
Among the monosubstituted hydrazines which may be
pyrazole;
used for the process of our invention are: alkylhydrazines,
such as methylhydrazine, ethylhydrazine, propylhydra
30
zines, butylhydrazines, ?-hydroxyethylhydrazine; cyclo
om-chloro-l1p,16a,171:,21-tetrahydroxy-20-oxo-4-preg
neno [3 ,2~c] pyrazole;
alkylhydrazines; monosubstituted-hydrazines which may
be derived from any aromatic or heterocyclic ring nucleus
including phenylhydrazine and the substituted phenylhy
116,1611,17a,21-tetrahydroxy-6a-methyl-20-oxo-4-preg
drazines, such as 0-, m-, and p-halophenylhydrazines, o-, 35
m-, and p-tolyhydrazines, 0-, m-, and p-alkoxyphenyl
9a-?uoro-1 1p, 160:,17 11,21-tetrahydroxy»20-oxo-4-preg
hydrazines, o-, m-, and p-nitrophenylhydrazines, l-hydra
neno- [ 3,2-c] pyrazole;
neno- [3,2-c]pyrazole;
zinonaphthalene; 2-hydrazinopyridine, 3-hydrazinopyri
dine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide, and
2-hydrazinopyrimidine; aralkylhydrazines, such as benzyl
40
hydrazine and phenylethylenehydrazine.
6u,9a-difiuoro-11B,16a,17a,21-tetrahydroxy-20-oxo-4
pregneno-[3,2-c] pyrazole;
There are thus produced the corresponding N-sub
stituted'[3,2-clpyrazoles including: N—alkyl such as N
methyl-, N-ethyl-, N-butyl, N-propyl-, N-(?-hydroxyeth
yl)-; N-cycloalkyl-; N-substituted derivatives which may 45
be derived from any aromatic or heterocyclic nucleus, in
2'-acyl—, 1'- and 2'-alkyl-, the 1'- and 2'-cycloalky1-, the 1’
and 2'-aralkyl and the 1’- and 2'-substituted derivatives
cluding N-phenyl~ and the N-substituted-phenyl deriva
tives such as o-, m-, and p-halophenyl; o-, m-, and p
tolyl-; o-, m-, and p-alkoxyphenyl-, o-, m-, and p
nitrophenyl-; N-(1"-naphthyl)-, N-(2"-pyridyl)-, N-(3"
pyridyl)-, N-(4"-pyridyl)-, N-(4"-pyridyloxide)-, N-(2"
which may be derived from any aromatic or heterocyclic
50 nucleus of all the above named compounds, as well as
their 16a,17a-acetals and ketals, and their 21-acylates.
This invention also includes the M's-analogs of all of
pyrimidyl)-; N-aralkyl-, such as N-benzyl- and N-phenyl
ethenyl-4-pregneno- or 4,6-pregnadieno-[3,2-clpyrazo1es.
An 11—keto-group is reduced to the ll?-hydroxy-group
using sodium borohydride. The ZO-ethylenedioxy-group
This invention also includes the 16a,l7a-acetals and
ketals of the foregoing compounds, as well as the 1'- and
the foregoing compounds.
In order to convert the 21-hydroxy group of an N
55
is removed by heating the steroid, dissolved in a solvent
substituted 11/3,21-dihydroxy-16a,17a-isopropylidenedioxy
20-oxo-40-pregneno-(or 4,6-pregnadieno) [3,2-c]pyrazole
(compounds 13 and 18 of Flow Sheet C) into the corre
such as methanol, with aqueous sulfuric acid.
sponding 21-desoxy-derivative (compound 22), the,21
The dihydroxy-steroid is converted into the 160:,17a
acetal or ketal by treating with a carbonyl reactant of
hydroxy compound is ?rst reacted with methane sulfonyl
the general formula:
chloride in a non-aqueous base .to form the 21~mesylate
wherein P and Q are each selected from the group con
sisting of hydrogen, alkyl, and aryl, and together with
the carbon to which they are joined, P and Q are cyclo
alkyl. For example, a suspension of the free ll?,16oz,l7ot,
(compound 19). The 21-mesylate is heated with an
alkali iodide to form the 21-iodo-steroid (compound 21),
which is then reacted with an alkali metal bisul?te to
form the 21-desoxy~derivative (compound 22).
65
In order to convert the 21-hydroxy group of an N-un
substituted-11B,21-dihydroxy-16a,17a-isopropylidenedioxy
2O - oxo-4-pregneno-(or 4,6-pregnadieno) [3,2-c1pyrazole
(compounds 6 and 13 of Flow Sheet C) into the 21
21-tetrol in a ketone or aldehyde is treated with a trace
desoxy
derivative, the 21-hydroxy group is ?rst converted
of perchloric acid and stirred at room temperature until 70
into
the
21-tetrahydropyranyl other (compounds 7 and
solution is complete. The ketones and aldehydes which
12).
This
is accomplished by treating the steroid with ‘
are suitable for this purpose include acetaldehyde, meth
dihydropyran in the presence of an acidic reagent such
yl ethyl ketone, cyclohex‘anone, and acetophenone.
In a preferred embodiment of our invention acetone
is used. For purposes of greater simplicity in the formulas
as concentrated hydrochloric acid.
The steroid is then '
reacted with acetic anhydride in a non-aqueous base to
3,072,640
6
form the N-acetyl-derivative (compound 17). The 21
tetrahydropyranyl ether group of compound 17 is then
removed by treating a methanol solution of the steroid
FLOW SHEET OF STARTING MATERIALS
up,“
with a p-toluenesulfonic acid. The -N-acetyl-2l-hydroxy
01
20 - oxo-4-pregneno-(or 4,6-pregnadieno) [3,2-c]pyrazole
0
(compound 18) is then converted into the corresponding
HO
2l-desoxy-derivative (compound 22) by the procedure
described above for the N-substituted pyrazole. The N
acetyl group of compound 22 is ?nally removed by treat
ment of the steroid with sodium methoxide in methanol.
The 21-desoxy-c0mpounds of our invention include the
‘"“OH
[:0
following:
0
Y
B
H 2OAc
01
o
E0
0
Y
o
This invention also includes the 16a,17a-acetals and
ketals of the foregoing compounds, as well as the 1’- and
_2'-acyl-, the 1' and 2’-alkyl, the l'- and 2’-cyc1oalkyl-,
the 1'- and 2'-aralkyl-derivatives and the 1'- and 2'-sub
stituted derivatives whcih may be derived from any aro
matic or heterocyclic nucleus of all of the above named
compounds, as well as their 16a,17a-acetals and ketals.
This invention also includes the MIG-analogs of all of the
foregoing compounds.
The 21-?uoro-derivatives of all of the above named
compounds are obtained by heating the corresponding 21
mesylate with an alkali metal ?uoride, preferably in a 40
solvent such vas dimethylformamide.
The ZI-dihydrogen phosphate esters are prepared by
the reaction of the corresponding 2l-iodo compound with
wherein X is a member of the group consisting of hydro
gen, and ?uoro, Y is a member of the group consisting
a mixture of silver phosphate and phosphoric acid. Both
the mono and dialkali metal salts may 'be obtained by
neutralization of the dihydrogen phosphate ester with an
_ of methyl, ?uoro and chloro and R is a member of the
alkali metal hydroxide.
group consisting of alkyl, cycloalkyl, aryl, aralkyl, and
a heterocyclic nucleus, or substituted derivatives thereof.
Treatment with additional
amounts of alkali methoxide will convert an N-acyl (R
acyl) into the free amine (R=H) dialkali metal salt 50
from which the dihydrogen phosphate can be obtained by
contacting with ‘an ion exchange resin.
FLOW SHEET A
TH 7OAc
-----OH
The [3,2-c]pyrazolo compounds described in the fore
going structures form salts such as the hydrochloride,
sulfate, chlorate, perchlorate, picrate and trichloroace
tate, on treatment with the corresponding acid.
A further embodiment of our invention comprises
novel pharmaceutical compositions containing the novel
[3,2-c1pyrazolo compounds of the pregnane series, ex
empli?ed in the foregoing structures.
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
not of limitation.
75
3,072,640
5
10
wherein X is a member of the group consisting of hydro
gen and ?uoro, Y is a member of the group consisting
of methyl, ?uoro and chloro and R is a member of the
group consisting of hydrogen, alkyl, cycloalkyl, aralkyl,
30
s (R=H)
‘3 <R=H>
aryl, and a heterocyclic nucleus or substituted derivatives
thereof.
FLOW SHEET B
wherein the linkage indicated by the broken line between
carbon atoms 6 and 7 indicates that a double bond may
be present in this position, and wherein X is a member of
the group consisting of hydrogen and ?uoro, Y is a mem
ber of the group consisting of methyl, ?uoro and chloro,
and R is a member of the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, aralkyl, and a heterocyclic nucleus,
or substituted derivatives thereof.
3,072,640
9
10
wherein the linkage indicated by the broken line between
FLOW SHEET 6
carbon atoms 6 and 7 indicates that a double bond may
be present in this position, and wherein X is a member
fi-ipn
of the group consisting of hydrogen and ?uoro, and Y is
a member of the group consisting of methyl, ?uoro and
cu =0
chloro.
.
Example]
A suspension of 610 mg. of 20-ethylenedioxy-6a,9a
di?uoro-16a,17a,21-trihydroxy-4-pregnene-3-1 l-dione 21
acetate in 50 ml. of dry benzene is stirred in a nitrogen
atmosphere with 1 ml. of ethyl formate and 450 mg. of
a suspension of about 54% sodium hydride in mineral
oil at room temperature for 19 hours.
Then an addi
tional 1 ml. of ethyl formate and 350 mg. of sodium
hydride is added. After two hours, the reaction mixture
is chilled in an ice bath and acidi?ed with an excess of
an aqueous solution of sodium dihydrogen phosphate.
The layers are separated and the aqueous phase is ex
tracted with ether, with ethyl acetate and with methylene
chloride. The combined organic layers are extracted
with sodium bicarbonate ,to remove impurities. The
product is then extracted into a 2% aqueous solution of
sodium hydroxide. Acidi?cation of the alkaline extracts
with dilute hydrochloric acid gives a product which is
taken up in methylene chloride. The solution is ?ltered
and evaporated to dryness to give 20-ethylenedioxy-6u,
9a - di?uoro-16a,17¢,21-trihydroxy-2-hydroxymethylene
4-pregnene-3,11-dione, and/or formate esters thereof.
Example 2
A 25 mg. aliquot of 20-ethylenedioxy-6u,9u-di?uoro
16a,l7ot,2l - trihydroxy - 2 - hydroxymethylene - 4 - preg
nene-3,ll-dione, and/or the formate esters thereof, is dis
solved in 0.6 ml. 06 ethanol. An 0.032 ml. aliquot of a
reagent, prepared by dissolving 0.48 ml. of hydrazine
hydrate in- 0.9-6 ml. of ethanol, is added and the mix
ture is re?uxed under nitrogen for 45 minutes. The
volatiles are removed in vacuo and the residue is ex
tracted with hot methylene chloride. The methylene
chloride is ?ltered to remove insolubles and taken to dry
ness. It is redissolved in 3 ml. of methanol and 0.5 ml.
of sodium methoxide in methanol and left under nitro
gen for 10 minutes. The alkoxide is neutralized with
acetic acid and the mixture is diluted with ethyl acetate
and washed with water. Removal of the dried solvent
leaves 2O-ethylenedioxy-'6a,:9a-di?uoro416a,17a,2l-rtrihy
idroxy-l l-oxo-4-pregneno- [ 3,2-c] pyrazole.
Example 3
To a solution of 0.5 millimole of 20-et-hylene~dioxy
60:,90: - di?uoro - :1'6a,17a,2l - trihydroxy - 2 - hydroxy
methylene~4-pregnene-3,\1l-dione, .and/or the formate
25
esters thereof, in about 3 ml. of absolute ethanol is added
0.6 millimole of sodium acetate and then 0.6 millimole
of methylhydrazine sulfate. The mixture is re?uxed un
der nitrogen for 40 minutes and then ?ltered hot. The
?ltrate is taken to dryness, water is added, and the prod
uct is removed by filtration. It is redissolved in 30 ml.
65 of methanol and 5 ml. of sodium methoxide in methanol
and left under nitrogen for 10 minutes. The alkoxide
is neutralized with acetic acid and the mixture is diluted
with ethyl acetate and washed with water. Removal of
70 the dried solvent leaves N-methyl-Z0-ethylenedioxy-6u,
9a - di?uoro - 1‘61Z,170t,21 - trihydroxy - 11 - oxo - 4 -
pregneno- [3,2-c] pyrazoles.
A mixture of the -1'-methyl- and 2’-methyl-2‘0-ethyl
enedioxy - 6a,9m - di?uoro - 16d,17d,2l1 - trihydroxy -
75 11-oxo-4-pregneno-[3,2-c]pyrazo1e is prepared by the
.
3,072,640
11
12
route: A mixture of 1 gram of 20-ethylenedioxy-6a,9a
following route: A mixture of 1 gram of 20-ethylenedi
Cli?ll0r0-16a,17a,2l — trihydroxy-2 - hydroxymethylene-4
oxy - 611,90: - di?uoro - 16cc,170t,21 - trihydroxy - 2 - hy
pregnene-3,1l dione, and its derived formates, 200 ml.
of methanol, and 200 mg. of p-toluenesulfonic acid is
droxy-methy1ene-4-pregnene-3,1l-dione, and/or the for
mate esters thereof, 200 m1. of methanol, and 200 mg. of
p-toluenesulfonic acid is allowed to stand at room tem
perature for two hours. The reaction mixture is then
diluted with water and extracted with ethyl acetate. The
ethyl acetate extract is washed two times with 2 N aque
ous sodium hydroxide solution and then with water. The
ethyl acetate extract is then dried and concentrated in
vacuo to give the desired 20-ethylenedioxy-6a,9a-di?uoro
allowed to stand at room temperature for two hours.
The reaction mixture is then diluted with water and ex
tracted with ethyl acetate. The ethyl acetate extract is
washed two times with 2 N aqueous sodium hydroxide
solution and then with water. The ethyl acetate extract
is then dried and concentrated in vacuo. The 20- ethyl
€l'ledlOXy-6ot,9ot-dl?llOI'O - l6oc,l7ot,21 - trihydroxy-2-meth
oxymethylene~4-pregnene-3,ll-dione is obtained by chro
1‘6u,~17ct,21 - trihydroxy - 2 - methoxymethylene - 4 -
matography on acid-washed alumina and elution with
etherzchloroform mixtures.
A mixture of 500 mg. of the above 2-meth0xy-methyl
15
cue-steroid,
100 ml. of ethanol, and 1 ml. of phenyl
hydrazine is heated under nitrogen until dissolved, and
pregnene-3,1\1-dione.
A mixture of 500 mg. of the above Z-methoxymethyl
cue-derivative, 100 ml. of ethanol, and 1 ml. of methyl
hydrazine is heated under nitrogen until dissolved, and
then allowed to stand under nitrogen at- room tempera
ture over night. The reaction mixture is then diluted
with ethyl acetate, Washed two times with 2 N sulfuric
then allowed to stand under nitrogen at room tempera
ture over night. The reaction mixture is then diluted
with ethyl acetate, washed two times with 2 N sulfuric
acid, two times with 2.5 N sodium hydroxide, and then
two times with water. The ethyl acetate extract is then
dried, concentrated, and chromatographed on Florisil1
or silica gel to yield the l’-phenyl- and 2'-phenyl-20
acid, two times with 2.5 N sodium hydroxide, and then
two times with water. The ethyl acetate extract is then
dried, concentrated, and chromatographed on Florisil or
silica gel to yield the l’-methyl- and the 2’-methyl-20
ethylenedioxy - 601,90: - di?uoro - 16oz,l7oz,21 - trihy
droxy-l l-oxo'4-pregneno- [3 ,2-c]pyrazole.
25 ethylenedioxy-6119a - di?uoro - 16a,l7a,21-trihydroxy
1 1-oxo-4-pregneno- [ 3,2-c] pyrazole.
In accordance with the above procedures, but starting
with the 2-hydroxymethylene-derivative which is obtained
The 20 - ethylenedioxy-611,9a-di?uoro-d6a,-17a,2i1-trihy
droxy-N-methyl-l 1-oxo-4-pregneno- [ 3,2-c] pyrazoles may
also be prepared by the following procedure: A solution
of about 0.47 millimole of 20-ethylenedioxy~6a,9a-di
from each of the starting materials which are listed in
30 column 2, there are obtained the corresponding l’
phenyl- and 2’-phenyl-derivatives.
?uoro - 1612,170521 - trihydroxy - l'l - oxo - pregneno -
In accordance with the above procedures, but using
[3,2-c]pyrazole in 10 ml. of benzene is treated with 30
other substituted hydrazines such as cyclohexylhydrazine,
38 mg. of about 51% sodium hydride (in oil suspen
p-tolylhydrazine, p-chlorophcnylhydrazine, p-methoxy
sion). After the addition of 2-3 ml. of dimethylform 35 phenylhydrazine, or benzylhydrazine in place of phenyl
amide (dried over calcium hydride) and 5 ml. of methyl
hydrazine, there are obtained the corresponding 1’- and
iodide the mixture is stirred at room temperature over
night. The product is ?ltered, washed with methylene
2’—cyclohexyl-, 1'- and 2'-p-tolyl-, 1'- and 2'-(p-chloro
phenyl)-, l'- and 2’-(p-methoxyphenyl)-, and 1'- and
chloride, and the ?ltrate and washings are taken to dry
ness. The residue is treated with water and the prod 40
uct is ?ltered to give N-methyl-ZO-ethylenedioxy-6a,9a
trihydroxy-1l-oxo-4-pregneno-[3,2-c]pyrazoles.
di?uoro - 1‘6oc,17ot,21 - trihydroxy - 11 - oxo - 4 - preg
neno-[3,2-c]pyrazole.
In accordance with the above procedures, by using
other alkylating agents in place of methyl iodide, there
are obtained the corresponding N-alkyl-20-ethylenedioxy
2’-benzyl-20-ethylenedioxy - 611,90: - di?UOI'0-16ot,l7a,2l
Example 5
A 111.5 mg. sample of 20-ethy1enedioxy-6a,9a- di
45 ?l101'0-16a,17a,2l - trihydroxy-2 - hydroxymethylene-4
pregnene-3,ll-dione, and/or the formate esters thereof,
is suspended in 2.5 ml. of ethanol and treated with 24.5
6u,9u - di?uoro - 1\6ot,17oc,2l - trihydroxy - 11 - 0x0 - 4 mg. of sodium acetate, followed by the addition of 48.5
pregneno-[3,2-c]pyrazole.
'
mg. of p-?uorophenylhydrazine hydrochloride. The air
50
In accordance with all of the above procedures but
in the system is replaced with nitrogen and the mixture
starting with the Z-hydroxymethylene derivatives of the
is quickly brought to re?ux temperature. After re?ux
compounds listed in column 2, there are obtained the
corresponding 1'-methyl- and 2’-methyl derivatives.
Example 4
ing for one hour the mixture is taken to dryness. The
residue is dissolved in ether, the ether layer is treated
55 three times with 2.5 N hydrochloric acid, then three
times with 2.5 N sodium hydroxide and ?nally With
water.
The ether layer is dried over magnesium sul
A mixture of 90 mg. of 20-ethylenedioxy-6a,9a-di?u
fate, ?ltered and concentrated to dryness in vacuo. It
oro - 16a,17a,21 - trihydroxy - 2 - hydroxymethylene -4 pregnene-3,vll-dione, and its derived formates, and 0.028 60 is redissolved in 12 ml. of methanol and 2.0 ml. of 1.33
N sodium methoxide in methanol and left under nitro
ml. of phenylhydrazine is re?uxed under nitrogen in 1.2
gen for 10 minutes. The alkoxide is neutralized with
ml. of absolute ethanol for about 50 minutes. The re- ,
acetic acid and the mixture is diluted with ethyl acetate
action mixture is taken to dryness. Water is added and
and washed with water. Removal of the dried solvent
the product is ?ltered to give an amorphous solid. It
~leaves
2’-(p-?uorophenyl) -20 - ethylenedioxy-6a,9a-di
65
is redissolved in 8 ml. of methanol and 2 ml. of 1 M so
?uoro-l6a,17a,2l - trihydroxy-ll - oxo-4-pregneno-[3,2
dium methoxide in methanol and left under nitrogen for
c]pyrazole.
10 minutes. The alkoxide is neutralized with acetic
A mixture of l'-(p-?uorophenyl)- and 2'-(p-?uoro
acid and the mixture is diluted with ethyl acetate and
phenyl)20-ethylenedioxy-6a,9a-di?uoro - 16a,l7iz,2l-tri
washed with water. Removal of the dried solvent leaves 70
hydroxy-l1-oxo-4-pregneno - [3,2-c1pyrazole is prepared
2' - phenyl - 20 - ethylenedioxy - 160:,90: - di?uoro - 16a,
l7a,2l-trihydroxy-1 1-oxo-4-pregneno- [ 3 ,2-c]pyrazo1e.
A mixture of the 1’-phenyl- and 2’-phenyl-20-ethyl
€I16diOXy-6a,9a - di?uoro-16a,l7u,2l - trihydroxy-ll-oxo
4-pregneno-[3,2-c]pyrazole is prepared by the following
by the following route: A mixture of 1 gram of 20
ethylenedioxy-6a,9a - di?uoro - l6a,l7uz,2l - trihydroxy
1Florisil is an activated magnesium silicate made accord
ing to U.S.P. 2,393,625.
3,072,640
13
14
2-hydroxymethylene-4-pregnene-3,l1-dione, and/or the
sponding N-alkyl-, N-cycloalkyl-, N-aryl- or N-aralkyl
formate esters thereof, 200 ml. of methanol and 200 mg.
of p-toluenesulfonic acid is left at room temperature for
two hours. The reaction mixture is then diluted with
water and extracted with ethyl acetate. The ethyl vace
601,911 - di?uoro-115,21-dihydroxy-16a,l7a-isopropylidene
dioxy - 20 - oxo-4-pregneno-[3,2-c]pyrazole.
In accordance with the above procedure, but using an
equivalent quantity of another ketone such as acetophe
none, there is obtained the corresponding 1611,170L-tk6t31.
tate extract is washed two times with 2 N aqueous so
dium hydroxidesolution and then with water. The ethyl
acetate extract is then dried and concentrated in vacuo.
The 20-ethylenedioxy-6a,9a - dl?ll0I‘O-16ot,l7ot,21 - trihy
droxy-Z-methoxymethylene-4-pregnene - 3,1l-dione is ob
10
tained by chromatography on acid Washed alumina and
isopropylidenedioxy - 20 - oxo~4-pregneno-[3,2-c1pyrazole_
elution with ether:chloroform mixtures.
ZI-acetate is prepared from the 6a,9a-di?uOrO-ll?,l6ot,
-
17a,21 -. tetrahydroxy - 20-oxo-4-pregneno-[3,2-c1pyraz
A mixture of 500 mg. of the Z-methoxymethylene
ole by stirring 250 mg. of the steroid in 15 ml. of acetone
derivative, 100 ml. of ethanol, and 1 ml. of p-?uoro
phenylhydrazine is heated under nitrogen until dissolved, 15 containing 5 drops of 70% perchloric acid. vAfter thirty
and then allowed to stand under nitrogen at room tem
minutes, aqueous sodium bicarbonate is added. and the
perature over night. The reaction mixture is then diluted
with ethyl acetate, washed two times with 2 N sulfuric
acid, two times with 2.5 N sodium hydroxide, and then
acetone is removed in vacuo. The residue is ?ltered off,
air dried and then treated with 2 ml. of acetic anhydride
and 2 m1. of pyridine for eighteen hours at room tem
The ethyl acetate extracts are 20 perature. This acetylated mixture is taken oil’ on a ro
tator at the oil pump. The residue is crystallized from
then dried, concentrated, and chromatographed on acid
two times with water.
a mixture of petroleum ether and ether to yield the N
washed alumina to afford the 1'-(p-?uorophenyl)- and
acetyl - 6a,9a-?uoro-l15,21-dihydroxy-l6a,l7a-isopropyl
2'-(p-?uor0phenyl) - 20 - ethylenedioxy - 6a,9a-di?uoro
idenedioxy - 20 - oxo-4-pregneno-[3,2-c]pyrazole 2l-ace
l6oz,l7oc,2l - trihydroxy - ll-oxo - 4 - pregneno-[3,2-c1py
25 tate.
razole.
A solution of 5.73 g. of the N-acetyl-6a,9a-di?uor0-l1B, In accordance with all of the above procedures, but
21 - dihydroxy - 16a,17a-isopropylidenedioxy-Z0-oxo-4
starting with the 2-hydroxymethylene derivative which
pregneno-[3,2-c1pyrazole 2l-acetate in 60 ml. of 80%
is obtained from each of the starting materials which are
(v./v.) acetic acid is re?uxed for 1.5 hours. This solu
listed in column 2, there are obtained the correspond
ing l'-(p-?uorophenyl)- and 2’-(p-ifiuorophenyl)-deriv
30 tion is diluted with 400 ml. of ice-water and extracted
with ethyl acetate. The ethyl acetate extracts are washed
with water and with saturated sodium bicarbonate solu
tion, dried, and evaporated to dryness in vacuo. The resi
due is dissolved in 150 ml. of acetone containing 2 ml. of
atives.
Example 6
Sodium borohydride (200 mg.) is added to a solution 35 70% perchloric acid. After thirty minutes, aqueous sodi
um bicarbonate is added and the acetone is removedvin
of 250 mg. of ZO-eihYICIIBCliOXY-Ga,9ot-di?1l0l‘0-16a,l7ot,2l
vacuo. The product is extracted into chloroform which
trihydroxy-1l-oxo-4-pregneno-[3,2-c1pyrazole, in 10 cc. of
is washed with water, dried and removed in vacuo to yield
dimethyl formamide. After 18 hours, most of the sol
after chromatography on neutral alumina 6a,9a-di?uoro
vent is removed in vacuo on a rotating evaporator, water
115,21 - dihydroxy - l6a,17a-isopropylidenedioxy-20i-oxo
is added and the product is collected by ?ltration. It is 40 4-pregneno- [ 3 ,2-c] pyrazole 2 l-acetate.
recrystallized from methanol to afford 20-ethylendioxy
In accordance with the above procedures, but using an
602,90: - di?uoro-11,6,l6a,17a,2l-tetrahydroxy-4-pregneno
equivalent quantity of another acylating agent in place
of acetic anhydride, there is obtained the corresponding
[3,2-clpyrazole.
Example 7
45
acyl derivatives.
In accordance with all the procedures given in Ex
amples l, 2, 3, 4, 5, 6, 7, 8 and 9, but starting in Example
A mixture of 2.9 grams of ZO-ethylenedioxy-6u,9a-di
1 with the 20 '- ethylenedioxy-16a,17a,21-trihydroxy-4
pregnene-3,ll-dione 2l-acetate or the 60L-ChlOI'O-, 6oz
pyrazole, 100 ml. of methanol, and 6 ml. of a solution
prepared by diluting 8 ml. of sulfuric acid with 100 ml. 50 ?uoro-, 6a-methyl-, 9a-?uoro-, 6a-chloro-9a-?uoro-, 60¢
methyl-9a-?uoro-derivatives thereof, in place of the 60:,
of water is re?uxed for one hour and then concentrated
9oz - di?uoro - 20 - ethylenedioxy-16a,17u,21-trihydroxy-4
in vacuo. The product is extracted with ethyl acetate
pregnene-3,ll-dione 2l-acetate, there is obtained the cor
and the extract is washed wtih aqueous sodium bicarbon
responding 1 l B,16a,l7a-tetrahydroxy-20-oxo-4-pregneno
ate, salt, and then wtaer. The mixture is dried over mag 55 [3,2-c]pyrazole or the 6a-chloro, 6a-?uoro, 6a-methyl,
nesium sulfate and then taken to dryness to give 60¢,9ot
9a-fluoro, 6cc-ChlOI‘O-9ot-l'lll0f0 or 9a-?uoro-6a-methyl-de
?uoro - 11p,16a,17a,21 - tetrahydroxy-4-pregneno-[3,2-c]
rivatives thereof; and the N-alkyl-, N-cycloalkyl-, N-aryl-,
N-aralkyl-, N-heterocyclic derivatives, the 16a,17a-aceto
di?uoro - 11,8,16vt,17a,2l-tetrahydroxy-20-oxo-4-pregneno
[3,2-c]pyrazole.
nides and the 2l-acyloxy derivatives of all of the 16m,
Example 8
60
The 601,911 - di?uoro-11,8,l6a,17a,2l-tetrahydroxy-ZO
oxo-4-pregneno-[3,2-c]pyrazole (100 mg.) is heated for
3 minutes with 10 ml. of acetone to which 1 drop of con
centrated hydrochloric acid has been added and then
l7a-acetonides of the foregoing 11,3,16a,l7a-tetrahydroxy
20-oxo-4-pregneno- [3 ,2-c ] pyrazoles.
Example 10
6a,9a - di?uoro - 11?,21-dihydroxy-16a,l7a-isopropyl
letting stand at room temperature for 24 hours. The mix 65 idenedioxy - 20 - oxo-4-pregneno-[3,2-c]pyrazole (500
ture is then poured into a dilute sodium bicarbonate solu
mg.) is suspended in 25 ml. of 2,3-dihydropyran. A few
tion and extracted wtih ethyl acetate. The extracts are
drops‘ of concentrated hydrochloric acid are added and
washed, dried over magnesium sulfate and taken to dry
magnetic stirring is continued‘ for 6 hours, whereupon
ness to give the 6a,9a-di?uoro-l1B,2l-dihydroxy-l6a,l7a 70 the solution is concentrated in vacuo. The residue is tritu
isoproPylidenedioxy-ZO-oxo-4-pregneno- [3 ,Z-c] pyrazole.
rated with petroleum ether and recrystallized from a mix
In accordance with the above procedure, but starting
with an N-alkyl-, N-cycloalkyl-, N-aryl-, or N-aralkyl-Ga,
ture of methylene chloride and petroleum ether or a mix
9m - di?uoro - 11,8,16a,17a,2l - tetrahydroxy-20—oxo-4
?uoro - 11/8 - hydroxy-2l-tetrahydropyranyloxy-16a,17a
pregneno - [3,2-c]pyrazole, there is obtained the corre
75 isopropylidenedioxy-20-oxo-4-pregneno- [ 3 ,2-c] pyrazole. .
ture of ether and petroleum ether, to afford the 6a,9a-di
3,072,640
15
16
solid is dried at 80° C. for 1 hour in high vacuum. It is
redissolved in 30 ml. of methanol and 5 ml. of sodium
In accordance with the above procedure, but starting
with 1111,21 - dihydroxy-l6a,l7a-isopropylidenedioxy-20
methoxide in methanol and left under nitrogen for 10
minutes. The alkoxide is neutralized with acetic acid
and the mixture is diluted with ethyl ‘acetate and washed
with water. Removal of the dried solvent leaves 6,9a-di
oxo-4-pregneno-[3,2-c]pyrazole or the 6a-ch1or0-,6a
?uoro-, 6rx-methyl-, 9u-?uoro-, 6a-chloro-9a-?uoro-, or
9u-?uoro-6a-methyl~derivative thereof, there is obtained
the correspondingly substituted IIB-hydroxy-Zldetra
?uoro - 21 - tetrahydropyranyloxy-l1,B-hydroxy-16a,17u
isopropylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c]~
hydropyranyloxy-16a,l7u-isopropylidenedioxy - 20 - oxo
4-pregneno-[3,2-c]pyrazole.
pyrazole.
Example 11
10
Example 15
To a solution of 0.5 millimole of 6,9a-ditlu0ro-21-tetra
6,9a-di?uoro - 115,21 - dihydroxy . 1604,17“ - isopropyl
hydropyranyloxy - 11B - hydroxy-2-hydroxymethylcne
16a,17a-isopropylidenedioxy-4,6-pregnadiene - 3,20 - di
idenedioxy-4,6-pregnadiene - 3,20 - dione ZI-acetate (1.0
g.) is re?uxed with a mixture of 1.0 g. of potassium bi
carbonate in 10 ml. of water and 90 ml. of methanol. 15 one, and/or the formate esters thereof, in about 3 ml. of
absolute ethanol is added 0.6 millimole of sodium acetate
After 3 hours, most of the methanol is removed in vacuo
and then 0.6 millimole of methylhydrazine sulfate. The
and the product is extracted with ethyl acetate and water.
mixture is re?uxed under nitrogen for 40 minutes and
Removal of the ethyl acetate affords crystals of 6,9a-di
then ?ltered hot. The ?ltrate is taken to dryness. It is
?uoro-l1/S,21-dihydroxy - 16a,17a - isopropylidenedioxy
20 redissolved in 50 ml. of methanol and 10 ml. of 1.33 N
4,6-pregnadiene-3,20-dione.
sodium methoxide in methanol and left under nitrogen
Example 12
for 10 minutes. The alkoxide is neutralized with acetic
acid and the mixture is diluted with ethyl acetate and
6,9a-di?uoro - 1118,21 - dihydroxy _ 16u,l7a - isopropyl
washed with water. Removal of the dried solvent leaves
idenedioxy-4,6-pregnadiene-3,20-dione (500 mg.) is sus 25
pended in 25 ml. of 2,3-dihydropyran. A few drops of
concentrated hydrochloric acid are added and magnetic
stirring is continued for 6 hours, whereupon the solution
N-methyl-6,9a-di?u0r0 - 21 - tetrahydropyranyloxy-ll?
hydroxy-loa,l7a-isopropylidenedioxy - 20 - oxo - 4,6
pregn adieno- [ 3,2-c] pyrazole.
A mixture of 1’-methyl- and 2'-methyl~6,9a-di?uoro
is concentrated in vacuo. The residue is triturated with
21 - tetrahydropyranyloxy - 11,3 - hydroxy - 1611,1711 - iso‘
petroleum ether and recrystallized from a mixture of 30 propylidenedioxy-ZO-oxo - 4,6 - pregnadieno-[3,2-c]pyra
methylene chloride and petroleum ether or a mixture of
zole is prepared by the following route: One gram of
ether and petroleum ether, to afford the 6,9a-di?ll0I'O-21
6.9a-di?uoro - 21 - tetrahydropyranyloxy-ll,6—hydroxy-2
hydroxymethylene - 1611,1711: - isopropylidenedioxy - 4,6
tetrahydropyranyloxy-ll?-hydroxy - 1601,170: - isopropyl
idenedioxy-4,6~pregnadiene-3,20-dione.
pregnadiene-3,20-dione,
and/or the
formate
esters
35 thereof, in 50 ml. of dry dioxane is treated with excess
Example 13 ,
ethereal diazomethane for one hour. The reaction mix
ture is taken to near dryness in vacuo, ethyl acetate is
The 6,9u-di?uoro-2l-tetrahydropyranyloxy - ll? - hy
droxy-16a,17u-isopropylidenedioxy - 4,6 - pregnadiene
added and the organic layer is washed two times with
2 N aqueous sodium hydroxide solution and then with
3,20~dione (350 mg.) is dissolved in 25 ml. of dry, hot 40 water. The ethyl acetate extract is then dried and con
centrated in vacuo. The 6,9a-di?uoro-21-tetrahydro
temperature and treated with 1.0 ml. of freshly distilled
pyranyloxy - 11B - hydroxy - 2 - methoxy - methylene
ethyl formate. The air in the system is replaced with
1611,l7a-isopropylidenedioxy - 4,6 - pregnadiene-3,20-dione
nitrogen and 560 mg. of sodium hydride (as a 58% dis
obtained by chromatography on silica gel.
persion in mineral oil) is added. The system is again 45 is A
mixture of 580 mg. of the above Z-methoxymethyl
evacuated and ?lled with nitrogen, and the mixture -is
ene-derivative, 10 ml. of ethanol, and 56 mg. (1.2 equiva
stirred magnetically at room temperature overnight. The
lents). of methylhydrazine is heated under nitrogen for
mixture is poured into an excess of a saturated aqueous
three hours and then allowed to stand under nitrogen at
solution of sodium dihydrogen phosphate and the product
benzene and the resulting solution is cooled to room
is extracted four times with benzene.
The organic ex
tracts are washed three times with water and dried over
room temperature over night.
The reaction mixture is
50 then diluted with ethyl acetate, washed two times with 2
N sulfuric acid, two times with 2.5 N sodium hydroxide,
sodium sulfate. Removal of the solvent gives the crude
and then two times with water. The ethyl acetate ex
product which is dissolved in ether and puri?ed as the
tract is then dried, concentrated, and chromatographed on
sodium salt by extraction into a 10% solution of sodium
silica gel to yield the l’-methyl- and the 2’~methyl-6,9a
carbonate. The aqueous alkaline extracts are again 55
difluoro - 2l-tetrahydropyranyloxy-llB-hydroxy-l6a,l7a
acidi?ed with an excess of ' a saturated aqueous solution
isopropylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2-c]pyr
of sodium dihydrogen phosphate and extracted into ether
azole.
and into chloroform. The combined organic extracts
A mixture of the l’-methyl and the 2'-methyl-6,9a-di
are dried over sodium sulfate and evaporated to dryness
to give 6,9a - di?uoro - 21 - tetrahydropyranyloxy-l1,6
60
hydroxy-2-hydroxymethylene - 160:,170: - isopropylidenedi
oxy-4,6-pregnadiene-3,20-dione,
and/or the
?uoro - 21 - tetrahydropyranyloxy-ll?-hydroxy-l6a,l7a
isopropylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2-c1pyr
azoles may also be prepared by the following procedure:
A solution of about 0.47 millimole of 6,9a-di?uoro-21-tet
formate
esters thereof.
rahydropyranyloxy - 1lB-hydroxy-l6u,17a-isopropylidene
Example 14
65
dioxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole in 10 ml.
droxy-2-hydroxymethylene - 16a,l7a - isopropylidenedi
of benzene is treated with 30—38 mg. of about 51% sodi
um hydride (in oil suspension) after the addition of 2—3
oxy-4,6-pregnadiene-3,20-dione,
ml. of dimethylformamide (dried over calcium hydride)
The 6,9a-di?uoro-2l-tetrahydropyranyloxy - ll? - hy
and/or
the
formate
esters thereof, (565 mg.) is dissolved in 9.0 ml. of abso
and 5 ml. of methyl iodide, the mixture is stirred at room
lute ethanol and treated with a solution of hydrazine 70 temperature over night. The product is ?ltered, washed
hydrate (60 mg, 1.2 equivalents) dissolved in 1.0 ml. of
with methylene chloride, and the ?ltrate and washings are
absolute ethanol. The mixture is re?uxed in a nitrogen
taken to dryness. The residue may be chromatographed
atmosphere ‘for about 3 hours and then evaporated to
on silica gel or Florisil to yield the l’- and 2’-methyl-6,9a
dryness under reduced pressure. The residue is washed
di?uoro
- 2l-tetrahydropyranyloxy-ll?-hydroxy-l6a,l7a
75
three times with cold water and the resulting amorphous
3,072,640
17
18
isopropylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2-c]pyr
azoles.
2’ - benzyl - 6,9a - di?uoro-21-tetrahydropyranyloxy-11p?
hydroxy - 16a,17a - propylidenedioxy-20-ox0-4,6-pregna
In accordance with the above procedures, but using
dieno-[3,2-c]pyrazoles.
other alkylating‘agents in place of methyl iodide, there
are obtained the corresponding N-alkyl-6,9a-di?uoro-21
-
Example 17
tetrahydropyranyloxy - 11/3-hydroxy-16a,17a-isopropyli
denedioxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazoles.
5'65 mg. sample of 6,9u-di?uoro-2l-tetrahydropyran
In accordance with all of the ‘above procedures, but
yloxy-l l?-hydroxy - 2 - hydroxymethylene - 16a,17a .- iso
starting with the Z-hydroxymethylene derivatives of the,
propylidenedioxy-4,6-pregnadiene-3,20-dione and/ or the
compounds listed on pages 3-4, there are obtained the 10 formate esters thereof is suspended in 10 ml. of ethanol ,
corresponding 1’-methyl- and 2'-methyl derivatives.
and treated with 100 mg. (1.2 equivalents) of sodium
acetate, followed with the addition of 195 mg. ( 1.2 equiv
Example 16
alents) of p-?uorophenylhydrazine hydrochloride. The
A mixture of 565 mg.‘ of 6,9a-cli?uoro-2l-tetrahydro
15
pyranyloxy - 11p-hydroxy-2-hydroxymethylene7l6a,17a
isopropylidenedioxy - 4,6-pregnadiene-3,20-dione
air in the system is replaced with nitrogen and the mixture
is quickly brought to re?ux temperature. After re?uxing
for one hour the mixture is taken todryness. The resi
and/ or
due is dissolved in ether, the ether layer is treated three
times with 2.5 N hydrochloric acid, then three times with
2.5 N sodium hydroxide and ?nally with water. The
ether layer is dried over magnesium sulfate, ?ltered and
the formate esters thereof, and 130 mg. (1.2 equivalents)
of phenylhydrazine are re?uxed under nitrogen in 8 ml.
of absolute ethanol for about three hours. The reaction 20
mixture is taken to dryness. Water is added and the
concentrated to dryness in vacuo. It is redissolved in 50
product is ?ltered to given an amorphous solid, which is
m1. of methanol and 10 ml. of 1.33 N sodium methoxide
washed successively with water, dilute acid, water, and
in methanol and left under nitrogen for 10 minutes. The
petroleum ether. It is redissolved in 50 ml. of methanol
alkoxide is neutralized with acetic acid and the mixture
1 and 10 ml. of 1.33 N sodium methoxide in methanol and
25 is diluted with ethyl acetate and washed with water.
left under nitrogen for 10 minutes. The alkoxide is
neutralized with acetic acid and the mixture is diluted
with ethyl acetate and washed with water. Removal of
6,9a-di?uoro - 21 - tetrahydropyranyloxy - 1113 - hydroxy
16a,17a-isopropylidenedioxy - 20-‘oxo - 4,6 - pregnadieno
the dried solvent leaves 2'-phenyl-6,9a-di?uoro-2l-tetra
[3,2-c1pyrazole.
hydropyranyloxy - 11/9 - hydroxy-16a,Not-propylidenedi
30
oxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.
A mixture of the 1'-phenyl- and 2’-phenyl-6,9a-di?uoro
nadieno-[3,2-c]pyrazole is prepared by the following
idenedioxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole is pre
pared by the following route: One gram of 6,9a-di?uoro
. A mixture of 1'- (p-?uorophenyl)- and 2'-(p-?uoro
phenyl) - 6,9a - di?uoro - 21 - tetrahydropyranyloxy-ll?
hydroxy-16a,17 a~isopropylidenedioxy - 20' - oxo - 4,6-preg
21 - tetrahydropyranyloxy-l 1B-hydroxy~16a,l7a-propyl
21 - tetrahydropyranyloxy-l1B-hydroxy-Z-hydroxymeth
Re
moval of the dried solvent leaves 2'-(p-?uorophenyl)
route: One gram of 6,9a-di?uoro-21-tetrahydropyranyl
35 oxy - 11,8 - hydroxy-2hydroxymethylene-16a,17a-isopro
ylene - 160:,170: - isopropylidenedioxy-6-methyl-4,6-preg
nadiene-3,20-dione, and/or the formate esters thereof, in
pylidenedioxy-4,6gpregnadiene-3,20-dione, and/or the for
mate esters thereof, in 50 ml. of dry dioxane is treated with
excess etheral diazomethane for one hour. ‘The reaction
50 ml. of dry dioxane is treated with excess ethereal diazo
mixture is taken to near dryness in vacuo, ethyl acetate is
methane for one hour. The reaction mixture is taken to 40 added and the organic layer is washed two times with 2 N‘
near dryiness in vacuo, ethyl aceate is added and the
aqueous sodium hydroxide solution and then with water.
organic layer is washed two times with 2 N aqueous sodi
The ethyl acetate extract is then dried and concentrated in
um hydroxide solution and then with water. The ethyl
vacuo. The 6,9a-diliuoro-2ltetrahydropyranyloxy-l1,3
acetate extract is then dried and concentrated in vacuo.
hydroxy-Z-methoxymethylene - 16u,17u - isopropylideneThe 6,904 - di?uoro-2l-tetrahydropyranyloxy-1l?-hy 45 dioxy-4,6-pregnadiene-3,20-dione is obtained by chroma
droxy - 2 - methoxymethylene-16a,17a-isopropylidene
tography on neutral alumina.
dioxy-4,6-pregnadiene-3,20-di0ne is obtained by chroma
A mixture of 500 mg. of the 2-methoxymethylene-de
tography on silica gel.
rivatives 100 ml. of ethanol, and 1 ml. of p-?uorophenyl
A mixture of 580 mg. of the above 2-methoxymethyl
hydrazine is heated under nitrogen until dissolved, and
ene-steriod, 10ml. of ethanol and 130 mg. (1.2 equiva 50 then allowed to stand under nitrogen at room temperature
lents) of phenylhydrazine is heated under nitrogen until
overnight. The reaction mixture is then diluted with ethyl
dissolved, and then allowed to stand under nitrogen at
acetate, washed two times with 2 N sulfuric acid, two times
room temperature overnight. The reaction mixture is
with 2.5 N sodium hydroxide, and then two times with
then diluted with ethyl acetate, washed two times with 2
water. The ethyl acetate extracts are then dried, concen
N sulfuric acid, two times with 2.5 N sodium hydroxide, 55 trated, and chromatographed on neutral alumina to afford
the 1’-(p-fluorophenyl) and 2’-(p-?uorophenyl)-6,9a-di
and then two times with Water. The ethyl acetate extract
?uoro-21-tetrahydropyranyloxy - 11,6 - hydroxy-16a,17a
is then dried, concentrated, and chromatographed on silica
isopropylidenedioxy - 20 ~ oxo - 4,6 - pregnadieno-[3,2-c]
gel or Florisil to yield the 1'-phenyl- and 2’-phenyl-6,9a
di?uoro - 21 ~ tetra-hydropyranyloxy-l1,B-hydroxy-16a,
17a - propylidenedioxy-20-oxo-4,6-pregnadieno-[3,2-c]
pyrazole.
In accordance with the above procdures, but starting
with the 2-hydroxymethylene-derivative which is obtained
from each of the starting materials which are listed in 65
column 2, there are obtained the corresponding 1’-phenyl
and 2'-phenyl-derivatives.
In accordance with the above procedures, but using
other substituted hydrazines, for example, cyclohexylhy 70
drazine, p-tolylhydrazine, p-chlorophenyl-hydrazine, p
methoxyphenylhydrazine, or benzylhydrazine in place of
phenylhydrazine, there are obtained the corresponding
1'- and 2'-cyclohexyl-, 1'- and 2'-p-to1yl-, 1'- and 2'-p
chlorophenyl-, 1'- and 2’-p-methoxyphenyl-, and 1'- and 75
pyrazole.
‘
In accordance with all of the above procedures, but
starting with the Z-hydroxymethylene derivative which is
obtained from each of the starting materials which are
listed in column 2, there are obtained the corresponding
l'-( p-?uorophenyl ) - and 2’- (p-?uorophenyl ) derivatives.
In accordance with the above procedure, but using
each of the monosubstituted hydrazines listed in col
umn 3, there is obtained the corresponding 1’- and
2’-substituted derivatives of the above 6,9a-di?uoro-21
tetrahydropyranyloxy-l lB-hydroxy -' 16a,17a - is0propyli
denedioxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.
Example 18
The 6,900 - di?uoro - 21 - tetrahydropyranyloxy-l 1/8-hy-_
droxy-16a,17u-isopropylidenedioxy-20-oxo - 4,6 - pregna
3,072,640
19
20
'
dieno-[3,2-c]pyrazole (40.0 mg.) is dissolved in 0.5‘ ml.
propylidenedioxy - 20-oxo-4,6-pregnadieno~[3,2-c]pyra
of methanol and treated with 1.82 ml. of a solution of
cycloalkyl-, N-aryl-, or N-aralkyl-6,90:-di?uoro-11?,l60:,
zole, there is obtained the corresponding N-alkyl-, N~
500 mg. of p-toluenesulfonic acid monohydrate in 25 ml.
of methanol. The mixture is kept at room temperature
170:,21 - tetrahydroxy-20-oxo-4,6-pregnadieno-[3,2-c]pyr
azole.
for 4 hours. The solvent is removed in vacuo and the
In accordance with all the procedures given in Examples
11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, but starting in
Example 11 with the 1113,2l-dihydroxy-160:,l7a-isopro
residue treated with 3 ml. of ethyl acetate. The insoluble
material is ?ltered off and the organic layer is washed
twice with 2 ml. of 10% sodium bicarbonate and twice
with 2 ml. of water. The product is dried over magne
pylidenedioxy - 4,6-pregnadiene-3,20-dione 2l-acetate, or
the 6-chloro-, 6-?uoro-, 6-methyl-, 90:-?uoro-, 6’chloro~
sium sulfate, ?ltered and the solvent removed on a steam 10 9o:-?uoro-, 90:-?uoro-6-methyl- derivative thereof, in place
bath. The residue is slurried with a small amount of
of the '6,90:-di?uoro-115,21-dihydroxy - 160:,170:-isopro
methylene chloride, and the slurry ?ltered and dried in
vacuo to give 23.0 mg. of 6,9a-difluoro-11,8,21-dihydroxy
pylidenedioxy - 4,6-pregnadiene-3,20-dione 21 - acetate,
there is obtained the corresponding ll?,160:,170:,21-tetra~
160:,170:-isopropylidenedioxy-20 - oxo - 4,6 - pregnadieno
15
[3,2-c1pyrazole.
hydroxy - 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole or the
6-chlorol, 6-?uoro-, 6-methyl-, 90:-?uoro-, 6-chloro-9a
In accordance with the above procedure, but starting
with an N-alkyl-, N—cycloalkyl-, N-aryl-, N-acyl-, or N-ar
?uoro- or 90:-?uoro-6-methyl-derivative thereof; and the
a1kyl-6,90:-di?uoro-2l-tetrahydropyranyloxy-l l?-hydroxy
160:,170: - acetonides and the 21-acyloxy derivative of all
N-alkyl-, N-cycloalkyl-, N-aryl-, N-aralkyl-derivatives, the
160:,17a-isopropylidenedioxy-20‘ - oxo - 4,6 - pregnadieno
of the foregoing 160:,170:-acetonides, 11?,160:,170:-tetra
[3,2-c1pyrazole, there is obtained the corresponding sub 20 hydroxy
- 20-oxo-4,6-pregnadieno-[3,2-c]pyrazoles.
stituted - 6,90: - di?uoro-115,21-dihydroxy-16u,l70:-isopro
pylidenedioxy-20~oxo-4,G-pregnadieno- [3 ,2-c] pyrazole.
Example 21
Example 19
To a solution of 100 mg. of 6,9a-di?uoro-2l-tetrahy
To a solution of 100 mg. of 6,90:-di?uoro-115,21-dihy
25 dropyranyloxy - 11/8-hydroxy-160,170: - isopropylidene
dioxy - 20~oxo-4,6-pregnadieno-[3,2-c]pyrazole in 2,ml.
of pyridine is added 2 ml. of acetic anhydride. The mix
droxy - 160:,170: - isopropylidenedioxy-20-oxo-4,6-pregna
dieno[3,2-c]pyrazole in 2 ml. of pyridine is added 2 ml.
of acetic anhydride. The mixture is allowed to stand
ture is allowed to stand over night at room temperature.
It is taken to dryness in vacuo to afford the N-acetyl-6,90:
A mixture of ice and 30 di?uoro - 21-tetrahydropyranyloxy-11?-hydroxy-l6u,l70:
overnight at room temperature.
water is then added. After standing for about 30 min
utes, the product is extracted with ethyl acetate. The
ethyl acetate extract is washed successively with water,
ice-cold 1 N sulfuric acid, saturated aqueous sodium bi
carbonate and water (until the aqueous layer is neutral).
The ethyl acetate solution is dried with anhydrous sodium
sulfate. The solvent is then distilled at about 40° C. in
vacuo to a?ord the N-acetyl-6,90:-di?uoro-l1,8,21-dihy
droxy -\ 160:,170: - isopropylidenedioxy - 20 - oxo-4,6~preg
nadieno-[3,2-c]pyrazole 21-acetate which is isolated by
isopropylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c] pyr
azole.
Without further puri?cation, this substance is dissolved
in 5 ml. of methanol containing 20 mg. of p-toluenesul
fonic acid. The mixture is kept at room temperature for
4 hours. The solvent is removed in vacuo, ethyl acetate
is added and the organic layer is washed several times
with dilute sodium bicarbonate. The dried solvent is
40 removed to yield after chromatography on neutral alu
35
mina N-acetyl - 6,90: - di?uoro-11B,21-dihydroxy-16b:,170:
isopropylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c] pyr
the addition of water and ?ltration.
A solution of 5.73 g. of N - acetyl - 6,90: - di?uoro - 115,
azole.
21 - dihydroxy-l60:,17a-isopropylidenedioxy-20-oxo-4,6
pregnadieno-[3,2-c]pyrazole ill-acetate in 60 ml. of 80%
(v./v.) acetic acid is re?uxed for 1.5 hours. This solu 45
Example 22
To a solution of 85 mg. of N-acetyl-6,90:-di?uoro-115,
tion is diluted with 400 ml. of ice-water and extracted with
21 - dihydroxy-160:,170:-isopropylidenedioxy-20-oxo-4,6
ethyl acetate. The ethyl acetate extracts are washed
pregnadieno -[3,2-c]pyrazole in 0.5 ml of pyridine, cooled
with Water and with saturated sodium bicarbonate solu
to 0° C., is added 0.03 ml. of methane sulfonyl chloride.
tion, dried, and evaporated to dryness in vacuo.
The resulting mixture is allowed to stand at a temperature
This residue is dissolved in 7150 ml. of acetone con 50 of approximately 0° C. for a period of approximately 1
hour. Water is then added to the reaction mixture and
taining 2_ ml. of 70% perchloric acid. After thirty min
the precipitate which forms is recovered by extraction into
utes, aqueous sodium bicarbonate is added and the ace
ethyl-acetate which is washed with water, dried and re
tone is removed in vacuo. The product is extracted into
chloroform which is washed with water, dried and re 55 moved to give N-acety1-6,90:-di?uoro-11,3,21-dihydroxy
160:,170: - isopropylidenedioxy - 20 - oxo-4,6-pregnadieno
moved to yield, after chromatography on neutral alumina,
[3,2-c] pyrazole ZI-mesylate.
6,90: - di?uoro-l1,3,21-dihydroxy-16a,170:-isopropylidene
In accordance with the above procedure, but starting
with
the N-alkyl-, Ncycloalkyh, N-aryl~, or Ndaralkyl~
In accordance with the above procedures but using an
equivalent quantity of another acylating agent in place 60 60:,90: - di?uoro-115,2l-dihydroxy-160:,17a-isopropylidene
dioxy-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole 21-acetate.
dioxy-20-oxo-4,6-pregnadiene-[3,2-c]pyrazole, in place of
of acetic anhydride, there is obtained the corresponding
the N-acyl-derivative there is obtained the corresponding
acyl derivatives.
21-mesylate.
Example 20
6,90: - di?uoro - 1113,21 - dihydroxy - 160:,170: - isopro
pylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c]pyrazole
Example 23
65
To 180 mg. of N-acetyl-6,90:-di?uoro-l1,8,21-dihydroxy
160:,170: - isopropylidenedioxy-20-oxo-4,6 - pregnadieno
(1.5 g.) is added to 150 ml. of re?uxing 60% formic acid.
[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of acetone
After twenty minutes, the solution is cooled and then
is
added 300' mg. of sodium iodide. The resulting mixture
poured into ice and water. After 18 hours, the 6,90:-di 70
is heated at re?ux temperature for a period of approxi
?uoro - 11;8,160:,170:,21-tetrahydroxy-20-oxo-4,6-pregna
mately 1 hour, and the reaction solution is cooled to room
dieno - [3,2-c]pyraz.ole is collected by ?ltration and dried.
temperature and diluted with water. Extraction with
In accordance with the above procedure, but starting
ethyl acetate followed by drying and removal of the
or N-aralkyl-, 6,9a-difluoro-1 1 13,2 1-dihydroxy-160:, l70:—iso 75 solvent affords N-acetyl-6,90:-di?uoro-1l?-hydroxy - 21~
with the corresponding N~alky1-, N-cycloalkyl-, N~aryl-,
3,072,640
21
-
iodo _ 16ot,17a - isopropylidenedioxy-ZO-oxo-4,6-pregna
22
ture of i7a,21-epoxy-1l?-hydroxy-l6a~methyl-20-oxo-2'
dieno- [ 3 ,2-c] pyrazole.
pheneyl-4-pregneno - [3,2-c]pyrazole and 21-.?uoro-11p,
Example 24
The N-acetyl-6,9a-di?uoro-11;3-hydroxy-21-iodo-16a,
17a - dihydroxy --16a - methyl - 20 - oxo- 2' .- phenyl - 4
pregneno-[3,2-c]pyrazole, which compounds are sepa
rated by partitionchromatography, or by chromatography
17a - isopropylidenedioxy - 20 - oxo - 4,6 - pregnadieno
on silica gel.
[3,2-c]pyrazole (100 mg.) is dissolved in a mixture of
5 ml. of water and 5 ml. of ethanol. To the resulting sus
pension is added 500 mg. of sodium bisul?te, and the mix
;-
~
l
.
-
Example 27
‘N - acetyl - 6,9a'- di?uoro - 11B - hydroxy - 16u,17a
ture is heated under re?ux for a period of about 1 hour. 10 isopropylidenedioxy - 20 — oxo - 4,6 - pregnadieno-[3,2-c]
pyrazole (60 mg.) is treated under nitrogen with 1.0 ml.
The reaction solution is cooled, diluted with water, and
of one molar sodium methoxide in 10 ml. of methanol.
extracted with ethyl acetate. After removal, of the ethyl
After 1 hour, the methanol is removed in vacuo and the
product is extracted with ethyl acetate and washed with
water. Removal of the dried ethyl acetate affords 6,9a-,
acetate in vacuo, the residue is left overnight under nitro
gen in 5 ml. of methanol and 1 ml. of one molar sodium
methoxide in methanol. The solvent is then removed in
vacuo, ethyl acetate is added and, after a water wash, the
di?uoro - 115 -'hydroxy - 16a,17a - isopropylidenedioxy
20-oxo-4,6-pregnadieno-[3,2-c]pyrazole.
solvent is dried and removed. Chromatography of the
residue on neutral alumina affords some ,6,9a-di?uoro
Example 28
11/3 - hydroxy - 16a,17a - isopropylidenedioxy - 20 - oxo
4,6~pregnadieno-[3,2-c]pyrazole.
20
Example 25
6,90: - di?uoro - 11/3 - hydroxy - 16u,17u - isopropyl
idenedioxy - 20 - oxo -'4,6 - pregnadieno - [3,2-c]pyrazole
(1.5 g.) is added to 150 ml.v of re?uxing 60% formic
acid. After twenty minutes, the‘ solution is cooled and
Silver dihydrogen phosphate is prepared by the reac
then poured into ice and water.
tion of 32 g. of trisilver phosphate with 10 ml. of 100%
phosphoric acid ‘With thorough mixing in a one-liter 3
After 18 hours‘, the
6,9a - di?uoro - 11?,l6ot,17o¢ - trihydroxy - 20 - oxo - 4,6
necked round-bottomed ?ask. The silver dihydrogen 25 pregnadieno-[3,2-c]pyrazole is collected by ?ltration and
dried.
phosphate is washed with two portions of diethyl ether,
In accordance with all the procedures given in Exam
which are removed by decantation, to remove some of the
ples 21, 22, 23, 24, 25, 26', 27, and 28, but starting in
phosphoric acid. About 200 ml. of acetonitrile are added
Example 21 with the 1LB-hydroxy-Zlétetrahydropyranyl
to cover the silver dihydrogen phosphate, and the mixture
is heated to re?ux temperature. At this point 20 g. of 30 oxy - 16u,17o¢ - isopropylidenedioxy '- 20 - oxo - 4 - preg
N - acetyl - 6,90: - di?uoro - 11,3 - hydroxy - 21 - iodo
neno-[3,2-c]pyrazole or the 6a-chloro-, 6a-?uoro-, 6a
16a,17a - isopropylidenedioxy - 20 - oxo - 4,6 - pregna
methyl-, 9a-?uoro-, 6a,9a-di?UOrO-, 6u-chl0ro-9a-?uoro-,
6a-methyl-9a-?uoro-derivative thereof; or the 11B-hy~
?uxed in a nitrogen atmosphere with stirring for 75 min~ 35 droxy - 2.1 - tetrahydropyranyloxy - 16u,17a - isopropyl
,idenedioxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole or the
utes. The reaction mixture is then cooled over a period
dieno-[3,2-c]pyrazole is added and the mixture is re
of about one hour to room temperature. Then 200 g. of
ice water are added, and the acetonitrile is removed in
vacuo at a temperature below 25°C. The pH of the re
sulting aqueous suspension is adjusted to 6.4 by the addi 40
tion of 23 m1. of saturated aqueous sodium carbonate
90: - ?uoro - 6a - methyl - 11/3,16a,17a - trihydroxy - 20
oxo-4-pregneno-[3,2-cjpyrazole; or the‘ 6-chloro-, 6-?u
oro-, 6-methyl-, 9a-?uoro-6-chloro-9a-?uoro or 9a-?uoro
solution. A precipitate is formed and separated by ?ltra
tion.
6-chloro-, 6-?uoro-, 6-methy1-, 9a-?uoro-, 6-ChlOI‘O-9rx
?uoro-, 9a-?uoro-6a-methyl-derivative thereof, there is
obtained the cor-responding 6a-chloro-, 6a-?uoro-, 9ot‘?u-v
oro-, 60t,9a-Cli?l.lO1‘O-, 6ot-chloro-9a-?uoro-, 6a-me‘thyl- or
The precipitate is washed with water until no
6 - methyl - 11p,16a,l7a - trihydroxy - 20 - oxo -. 4,6
ultraviolet absorbing material is detected in the wash
water. The ?ltrate and wash water are combined and 45 pregnadieno-[3,2-c]pyrazole, and the
of all of the foregoing compounds.
freeze dried to separate a solid material from the water.
l6m,l7a-acetonides
'
In accordance with all the procedures given in Exam
The solid material is triturated with a total of 770 ml. of
ples 22, 23, 24, 25, 26 and 28, but starting in Example 22
methanol in seven portions. The methanol-insoluble ma
with an N-alkyl-, N-cycloalkyl-, N-aryl-, or N-aralkyl
terial is separated by ?ltration. The ?ltrate is then con
centrated in vacuo to 200 ml. and passed through a col 50 115 - hydroxy - 21 - tetrahydropyranyloxy ~ l6a,17u - iso
propylidenedioxy-20-oxo-4-pregneno-[3,2-c1pyrazole or
umn containing 60 g. of a cation exchange resin
the 6a-chloro-, 6u-?uoro-, 6a-me>thyl-, 9a-t?uoro-, 6a,9u
(“IR-120”) in its hydrogen form. The column is washed
with methanol until the washings contain no ultraviolet
absorbing material. The combined eluate and washings
di?uoro-, 6a~chloro-9u-?uoro-, 9a-?uoro-6a-methyl-de
rivative thereof; or the N-alkyl-, N-cycloalky1-, N-aryl- or
are concentrated to a volume of 15 m1., and 150 m1. of 55
ether are added. The precipitate which forms is recov
ered by ?ltration, washed with ether, and dried for about
[3,2-c]pyrazole or the 6-chloro-, 6-?uoro-, 6-methyl-, 9oz
tives thereof, there is obtained the corresponding 6a
11B - hydroxy - 16a,l7a - isopropylidenedioxy - 20 - oxo
The mono- and the dialkali metal‘ salts of the 21-dihy
17a - isopropylidenedioxy _ 20 - 0x0 - 4,6 - pregnadieno
?uoro-, 6-chloro-9a-?uoro-, 9u-?uoro-6-methyl, deriva
16 hours in a desiccator, to give N-acetyl-6,9a-di?uoro
4,6-pregnadieno- [3,2-c] pyrazole 21-dihydrogen phosphate.
N-aralkyl - 11,8 - hydroxy - 21 - tetrahydropyranyloxy-16a,
60
chloro-, 6a-?uoro-, 6a-methyl-, 9a-?uoro-, 6a,9a~di?uoro-,
6a-chloro-9a-?uoro-, or 9a-?uoro-6a-methyl-, N-alkyl-,
drogen phosphate compound are obtained by neutralizing
N-cycloalkyl-, N-aryl-, or N-aralkyl-, 11,B,16a,l7a-trihy
the 2l-dihydrogen phosphate ester with an alkali metal
methoxide.
droxy-20-oxo-4-pregneno-[3,2-c1pyrazole; or the 6-chlo
ro-, 6-?uoro-, 60L-Cl1lOI‘O-90L-?ll0l‘O-, or 9a-?uoro-6-methyl—
Example 26
To a solution of 62 mg. of N-acetyl-6,9u-di?uoro-11B,
21 - dihydroxy - 16ot,17oc - isopropylidenedioxy - 20 - oxo
4-pregneno-[3,2-c]pyrazole 21-mesylate in 1 ml. of freshly
distilled anhydrous dimethylformamide is added enough
N-alkyl-, N-cycloalkyl-, N-aryl_ or N-aralkyl-11?,16a,17a
trihydroxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole, and
the 16a,l7a-acetonides of all of the foregoing compounds.
Example 29
The 6,90: - di?uoro - 21 - tetrahydropyranyloxy - 11,3
anhydrous potassium ?uoride to assure a saturated solu 70 hydroxy - l6oc,17ot - isopropylidenedioxy - 20 - oxo - 2’
tion. The mixture is heated at 110° C. for 20 hours.
phenyl - 4,6 - pregnadieno - [3,2 - c]pyrazole (40.0 mg.)
Water is added to the cooled solution and the product is
is dissolved in 0.5 ml. of methanol and treated with 1.82
‘extracted into chloroform, dried over sodium sulfate and
ml. of a solution of 500 mg. of p~toluenesulfonic acid
evaporated to dryness. The resulting product is a mix 75 monohydrate in 25 ml. of methanol. The mixture is
3,072,640
23
24
suspended in 25 ml. of 2,3-dihydropyran. A few drops
of concentrated hydrochloric acid is added and magnetic
stirring is continued for 6 hours, whereupon the solution
kept at room temperature for 4 hours. The solvent is
removed in vacuo and the residue treated with 3 ml.
of ethyl acetate. The insoluble material is ?ltered off
and the organic .layer is washed twice with 2 ml. of 10%
sodium bicarbonate and twice with 2 ml. of water. The
product is dried over magnesium sulfate, ?ltered and the
is concentrated in vacuo. The residue is triturated with
petroleum ether and recrystallized from a mixture of
methylene chloride and petroleum ether or a mixture of
ether and petroleum ether, to afford the 21-tetrahydro
solvent removed on a steam bath. The residue is slurried
pyranyloxy - 11B - hydroxy - 16u,l7a - isopropylidene‘
with a small amount of methylene chloride, and the
slurry is ?ltered and dried in vacuo to give 23.0 mg. of
dioxy - 6 - methyl - 4,6 - pregnadiene - 3,20 - dione.
10
6a,9a - di?uoro - 1113,21 - dihydroxy - 16a,17u . isopro
The 2l-tetrahydropyranyloxy-l1p-hydroxy-16a,17a-iso
propylidenedioxy - 6 - methyl - 4,6 - pregnadiene - 3,20
pylidenedioxy - 20 - oxo - 2' - phenyl - 4,6 - pregnadieno
dione (350 mg.) is dissolved in 25 ml. of dry, hot benzene
and the resulting solution is cooled to room temperature
and treated with 1.0 ml. of freshly distilled ethyl formate.
[3,2-c]pyrazole.
To a solution of 85 mg. of 6,9a-di?uoro-11B,2l-dihy
droxy - l6a,17u ~ isopropylidenedioxy - 20 - oxo - 2’
The air in the system is replaced with nitrogen and 560
mg. of sodium hydride (as a 58% dispersion in mineral
oil) is added. The system is again evacuated and ?lled
with nitrogen, and the mixture is stirred magnetically
at room temperature overnight. The mixture is poured
phenyl-4,6-pregnadieno-[3,2-c1pyrazole in 0.5 ml. of pyr
idine, cooled to 0° C., is added 0.03 ml. of methane
sulfonyl chloride. The resulting mixture is allowed to
stand at a temperature of approximately 0° C. for a period
of approximately 1 hour. Water is then added to the
reaction mixture and the precipitate which forms is 20 into an excess of a saturated aqueous solution of sodium
dihydrogen phosphate and the product is extracted four
recovered by extraction into ethyl acetate which is washed
times with benzene. The organic extracts are washed
with water, dried and removed to give 6,9a-di?uoro-1l?,
21 - dihydroxy — 16a,l7a - isopropylidenedioxy - 20 - oxo
three times with water and dried over sodium sulfate.
2'-phenyl - 4,6 - pregnadieno - [3,2 - c]pyrazole
Removal of the solvent gives the crude product which is
dissolved in ether and puri?ed as the sodium salt by
21
mesylate.
nadieno-[3,2-c]pyrazole 2l-mesylate dissolved in 10 ml.
extraction into a 10% solution of sodium carbonate. The
aqueous alkaline extracts are again acidi?ed with an ex
cess of a saturated aqueous solution of sodium dihydrogen
of acetone is added 300 mg. of sodium iodide. The re
sulting mixture is heated at re?ux temperature for a period
The combined organic extracts are dried over sodium sul
To 180 mg. of 6,9a-di?uoro-ll?,2l-dihydroxy-l6e,l7a
isopropylidenedioxy - 20 - oxo - 2’ _ phenyl - 4,6 - preg
phosphate and extracted into ether and into chloroform.
of approximately 1 hour, and the reaction solution is
fate and evaporated to dryness to give ZI-tetrahydro
cooled to room temperature and diluted with water. Ex
pyranyloxy - 11/3 - hydroxy - 2 - hydroxymethylene - 16m,
170: - isopropylidenedioxy - 6 - methyl - 4,6 - pregnadiene
traction with ethyl acetate followed by drying and re
moval of the solvent affords 6,9a-di?uoro-1lift-hydroxy
21 - iodo - 16a,17a - isopropylidenedioxy - 2’ - phenyl - 20'
oxo-4,6-pregnadieno-[3,2-c1pyrazole.
The
35
3,20-dione, and/or the formate esters thereof.
A mixture of 565 mg. of 2l-tetrahydropyranyloxy-ll?
hydroxy - 2 - hydroxymethylene . 1605,1711 - isopropyli
6,9oc - di?uoro - 11B - hydroxy - 21 - iodo - 16a,
17a - isopropylidenedioxy - 20 - oxo - 2' - phenyl - 4,6
pregnadieno-[3,2-c]pyrazole (100 mg.) is dissolved in
a mixture of 5 ml. of water and 5 ml. of ethanol.
To
denedioxy - 6
- methyl - 4,6 - pregnadiene - 3,20 - dione
and/or the formate esters thereof, and 130 mg. (1.2 equiv
alents) of phenylhydrazine are re?uxed under nitrogen
in 8 ml. of absolute ethanol for about three hours. The
reaction mixture is taken to dryness. Water is added
and the product is ?ltered to give an amorphous solid,
the resulting suspension is added 500 mg. of sodium
bisul?te, and the mixture is heated under re?ux for a
which is washed successively with water, dilute, acid,
period of about 1 hour. The reaction solution is cooled,
water, and petroleum ether. It is redissolved in 50 ml.
diluted with water, and extracted with ethyl acetate. After
removal of the ethyl acetate in vacuo,' the residue is left 45 of methanol and 10 ml. of 1.33 N sodium methoxide in
methanol and left under nitrogen for 10 minutes. The
over night under nitrogen in 5 ml. of methanol and 1
alkoxide is neutralized with acetic acid and the mixture
ml. of one molar sodium methoxide in methanol. The
is diluted with ethyl acetate and washed with water. Re
solvent is then removed in vacuo, ethyl acetate is added
moval of the dried solvent leaves 2’-phenyl-2l-tetrahydro
and, after a water wash, the solvent is dried and removed.
Chromatography of the residue on neutral alumina affords 50 pyranyloxy - 11/8 - hydroxy - 6 - methyl - 1641,17a - pro
pylidenedioxy-ZO-oxo‘4,6-pregnadieno- [3 ,2-c] pyrazole.
6,9a - di?uoro - 11,8 - hydroxy - 16a,l7a - isopropylidene
dioxy-20-oxo-2’-phenyl-4,6-pregnadieno-[3,2-c]pyrazole.
A mixture of the l'-phenyl- and 2’-phenyl-2l-tetrahy
dropyranyloxy - 11B - hydroxy - 6 - methyl - 16a,17a - pro
6,9a - di?uoro - 11/3 - hydroxy - 16a,17a - isopropyli
pylidenedioxy-20eoxo-4,6-pregnadieno-[3,2-c]pyrazole is
denedioxy - 20 - oxo - 2’ - phenyl - 4,6 - pregnadieno
[3,2-c]pyrazo_le (1.5 g.) is added to 150 ml. of re?uxing 55 prepared by the following route: One gram of 21-tetra
hydropyranyloxy - 11B - hydroxy - 2 - hydroxymethylene
60% formic acid. After twenty minutes, the solution is
cooled and then poured into ice and water.
After 18
hours, the 6,9a-di?uoro-1 15,161,17a-trihydroxy-20-oxo-2'
phenyl-4,6-pregnadieno-[3,2-c]pyrazole is collected by ?l
tration and dried.
Example 30
115,21 - dihydroxy - l6oc,17ot - isopropylidenedioxy-6
methyl-4,6-pregnadiene-3,20-dione 21-acetate (1.0 g.) is
l6a,l7a - isopropylidenedioxy - 6 - methyl - 4,6 - pregna
diene-3,20-dione, and/or the formate esters thereof, in
50 ml. of dry dioxane is treated with excess ethanol diazo
60 methane for one hour. The reaction mixture is taken to
near dryness in vacuo, ethyl acetate is added and the
organic layer is washed two times with 2 N aqueous
sodium hydroxide solution and then with water. The
ethyl acetate extract is then dried and concentrated in
65 vacuo.
The 21 - tetrahydropyranyloxy - 11B - hydroxy~
2 - methoxymethylene - 16ot,17cc - isopropylidenedioxy - 6
re?uxed with a mixture of 1.0 g. of potassium bicarbonate
methyl-4,6-pregnadiene-3,20-dione is obtained by chro
in 10 ml. of water and 90 ml. of methanol. After 3 hours
matography
on silica gel.
most of the methanol is removed in vacuo and the product
A mixture of 580 mg. of the above Z-methoxymethyl
is extracted with ethyl acetate and water. Removal of 70
the ethyl acetate affords crystals of 11B,21-dihydroxy-l6a,
17a - isopropylidenedioxy - 6 - methyl - 4,6 - pregnadiene
3,20-dione.
115,21 - dihydroxy - l6u,17ot - isopropylidenedioxy-6
methyl - 4,6 - pregnadiene - 3,20 - dione (500 mg.)
is
ene-steroid, 10 ml. of ethanol, and 130 mg. (1.2 equiva
lents) of phenylhydrazine is heated under nitrogen until
dissolved, and then allowed to stand under nitrogen at
room temperature over night. The reaction mixture is
then diluted with ethyl acetate, washed two times with
3,072,640
25
26
2 N sulfuric acid, two times with 2.5 N sodium'hydroxide,
and then two times with water. The ethyl acetate extract
is then dried, concentrated, and chromatographed on silica
gel or Florisil to yield the 1’-phenyl- and 2'-phenyl-21
sion is added 500 mg. of sodium bisul?te, and the mixture
is heated under re?ux for a period of about 1 hour. The
reaction solution is cooled, diluted with water, and ex
tracted with ethyl acetate. After removal of the ethyl
tetrahydropyranyloxy - 11,6 - hydroxy - 6 - methyl -‘ 16oz,
acetate in vacuo, the residue is left overnight under nitro
17a - propylidenedioxy - 20 - oxo - 4,6 - pregnadieno
gen
in 5 ml. of methanol and 1 ml. of one molar sodium
[3,2-c]pyrazole.
methoxide in methanol. The solvent is then removed in
The 6 - methyl - 21 - tetrahydropyranyloxy » 11/8 - hy
vacuo, ethyl acetate is added and, after a Water Wash,
droxy - 1604,1711 - isopropylidenedioxy - 20 - oxo - 4,6
the solvent is dried and removed. Chromatography of
pregnadieno-[3,2-c]pyrazole (40.0 mg.) is dissolved in 10' the residue on neutral alumina affords some ll?-hydroxy
0.5 ml. of methanol and treated with 1.82 ml. of a solu
16a,17ot-isopropylidenedioxy-6-methyl-20-oxo~2’ - phenyl
tion of 500 mg. of p-toluenesulfonic acid monohydrate
4,6-pregnadieno-[3,2-c]pyrazole.
in 25 ml. of methanol. The mixture is kept at room tem
ll?-hydroxy-16a,17ot-isopropylidenedioxy - 6 - methyl
perature for 4 hours. The solvent is removed in vacuo
20-oxo-2’-phenyl-4,6-pregnadieno-[3,2-c]pyrazole
(1.5 g.)
and the residue treated with 3 ml. of ethyl acetate. The 15 is added to 150 ml. of re?uxing 60% formic acid. Af
insoluble material is ?ltered off and the organic layer is
ter twenty minutes, the solution is cooled and then poured
washed twice with 2 ml. of 10% sodium bicarbonate and
into
ice and Water. After 18 hours, the >11/3,16a,17a
twice with 2 ml. of water. The product is dried over
trihydroxy-6-methyl-20-oxo-2'-phenyl - 4,6 - pregnadieno
magnesium sulfate, ?ltered and the solvent removed on
[3,2-c]pyrazole is collected by ?ltration and dried.
a steam bath. The residue is slurried with a'small amount 20
of methylene chloride, and the slurry is ?ltered and dried
Example 31
in vacuo to give 23.0 mg. of 6-methyl-1113,21-dihydroxy
16u,17a - isopropylidenedioxy - 20 - oxo — 4,6 - pregnadi
A suspension of 610 mg. of 20-ethylenedioxy-9u-?uoro
eno-[3,2-c]pyrazole.
l6ot,l7u,2l - trihydroxy-4-pregnene-3,1l-dione 21-acetate
1113,21 - dihydroxy - 16a,17a - isopropylidenedi
25 in 50 ml. of dry benzene is stirred in a nitrogen atmos—
oxy - 6 - methyl F 20 - oxo - 2’ - phenyl - 4,6 - pregnadi
phere with 1 ml. of ethyl formate and 450 mg. of a
suspension of- about 54% sodium hydride in mineral oil
The
eno-[3,2-c]pyrazole is treated with a'mixtrue of 1.5 ml.
of pyridine and 1.5 ml. of acetic anhydride and the mix
at room temperature for 19 hours. Then an additional 1
ture is allowed to stand at room temperature over night.
ml. of ethyl formate and 350 mg. of sodium hydride is
The solvents are removed in vacuo, water is added and the 30 added. After two hours, the reaction mixture is chilled
1113,21 - dihydroxy - l6a,17a - isopropylidenedioxy.- 6
in an ice bath and acidi?ed with an excess of an aqueous
methyl - 20 - oxo - 2' - phenyl - 4,6 - pregnadieno-[3,2-c]
solution of sodium dihydrogen phosphate. The layers
pyrazole 21-acetate is removed by ?ltration. After dry
ing, the compound is dissolved in methylene chloride, a
are separated and the aqueous phase is extracted with
ether, with ethyl acetate and with methylene chloride.
few drops of 2.5 N HCl are added and the mixture is 35 The combined organic layers are extracted with sodium
taken to dryness. The resulting ll?,2l-dihydroxy-l6a,
bicarbonate to remove impurities. The product is then
17a - isopropylidenedioxy - 6 - methyl - 20 - oxo ,- 2'
extracted into a 2% aqueous solution of sodium hydrox
phenyl - 4,6 - pregnadieno - [3,2 - c] pyrazole 21 - acetate
ide. Acidi?cation of the alkaline extracts with dilute
hydrochloride is recrystallized.
11,8,21 - dihydroxy - 160:,17oc - isopropylidenedioxy - 6
40 hydrochloric acid gives a product which is taken up in
methylene chloride. The solution is ?ltered and evaporat
methyl - 20 - oxo - 2’ - phenyl - 4,6 - pregnadieno-[3,2-c]
ed to dryness to give 20-ethylenedioxy-9a-?uoro-16a,17a,
pyrazole (1.5‘ g.) is added to 150 ml. of re?uxing 60%
formic acid. After twenty minutes, the solution is cooled
and then poured into ice and water.
21-trih'ydroxy-2-hydroxymethylene-4-pregnene-3,l l-dione_,
and/or formate esters thereof. A 25 mg. aliquot of 20
After 18 hours the
1lB,16oc,l7ot,2l - tetrahydroxy - 6 - methyl - 20 - oxo - 2’
45
ethylenedioxy-9a-?uoro-16a,17a,2l-trihydroxy-Z-hydroxy
60
21-trihydroxy-1 l--oxo-4-pregneno- [ 3,2-c] pyrazole.
methylene-4-pregnene-3,1l-dione, and/or the formate
esters thereof, is dissolved in 0.6 ml. of ethanol. An
0.032 ml. aliquot of a reagent, prepared by dissolving
0.48
ml. of hydrazine hydrate in 0.96 ml. of ethanol, is
isopropylidenedioxy-6-methyl-20-oxo-2'-phenyl-4,6 - preg
added and the mixture is re?uxed under nitrogen for 45
nadieno-[3,2-c]pyrazole in 0.5 ml. of pyridine, cooled to 50 minutes.
The volatiles are removed in vacuo and the
0° C., is added 0.03 ml. of methane sulfonyl chloride.
residue is extracted with hot methylene chloride. The
The resulting mixture is allowed to stand at a temperature
methylene chloride solution is ?ltered to remove insol
of approximately 0° C. for a period of approximately 1
ubles and taken to dryness. It is redissolved in 3 ml. of
hour. Water is then added to the reaction mixture and
methanol and 0.5 ml. of sodium methoxide in methanol
55
the precipitate which forms is recovered by. extraction
and left under nitrogen for 10 minutes. The alkoxide is
into ethyl acetate which is washed with water, dried and
neutralized with acetic acid and the mixture is diluted with
removed to give 115,21-dihydroxy-16a,l7a-isopropyl
ethyl acetate and washed with water. Removal of the
idenedioxy-6~methyl-20-oxo-2'-phenyl-4,6 - pregnadieno dried solvent leaves 20-ethylenedioxy-9a-?uoro-16a,17a,
[3,2-cjpyrazole 21-mesylate.
phenyl-4,6-pregnadieno-[3,2-c]pyrazole is collected by ?l-.
tration and dried.
To a solution of 85 mg. of llB,21-dihydroxy-16u,17a
To 180 mg. of l1,8,21-dihydroxy-16a,17a-isopropyl
Sodium borohydride (200 mg.) is added to a solution
of 250 mg. of 20-ethylenedioxy-9a-?uoro-16a,17a,21-tri
[3,2-c]pyrazole 21-mesylate dissolved in 10 ml. of ace
hydroxy-l1-oxo-4-pregneno-[3,2-c]pyrazole, in 10 cc. of
tone is added 300 mg. of sodium iodide. The resulting
dimethyl formamide. After 18 hours, most of the sol
mixture is heated at re?ux temperature for a period of
approximately 1 hour, and the reaction solution is cooled 65 vent is removed in vacuo on a rotating evaporator, water
is added and the product is collected by ?ltration. It is
to room temperature and diluted with water. Extrac
recrystallized from methanol to afford 20-ethylenedioxy
tion with ethyl acetate followed by drying and removal
idenedioxy-6-methyl-20-oxo-2'-phenyl - 4,6 - pregnadieno
of the solvent affords 1l?-hydroxy-Z1-iodo-16a,17a
isopropylidenedioxy-6-methyl-20-oxo-2’-phenyl-4,6 - preg
nadieno-[3,2-c]pyrazole.
9a-?uoro-l 1,6,161x,17a,21-tetrahydroxy-4-pregneno-[3,2-c]
70 pyrazole.
A mixture of 2.9 grams of 20-ethylenedioxy-9a-?uoro
The 1 1B-hydroxy-21-iodo-16m,Not-isopropylidenedioxy
11?,16a,17u,21- tetrahydroxy-4-pregneno- [ 3 ,2-c] pyrazole,
6-methyl - 20 - oxo-2'-phenyl - 4,6 _ pregnadieno-[3,2-c]
100 ml. of methanol, and 6 ml. of a solution prepared by
diluting 8 ml. of sulfuric acid to 100 ml. of water is re
pyrazole (100 mg.) is dissolved in a mixture of 5 ml.
‘of water and 5 ml. of ethanol. To the resulting suspen 75 ?uxed for one hour and then concentrated in vacuo. The
3,072,640
27
product is extracted with ethyl acetate and the extract is
washed with aqueous sodium bicarbonate, salt, and then
water. The mixture is dried over magnesium sulfate and
then taken to dryness to» give 9a-?u01'O-1l?,l6ot,17ou2l
tetrahydroxy-20-oxo-4-pregneno-[3,2-c1pyrazole.
The 9a-?uoro-l 1B,16a,17a,21-tetrahydroxy-20-oxo - 4 -
pregneno-[3,2-c]pyrazole (100 mg.) is heated for 3 min
utes with 10 ml. of acetone to which 1 drop of concen
28
removed to yield after chromatography on neutral alu
mina N-acetyl-9e-?uoroa1 IB-ZI-dihydroxy - 16a,l7a - iso
propylidenedioxy-20-oxo-4-pregneno-[3,2-c]pyrazo1e.
To a solution of 85 mg. of N-acetyl-9a-?uoro-1113-21
dihydroxy - 16m,17u - isopropylidenedioxy-20-oxo-4-preg
neno-[3,2~c]pyrazole in 0.5 ml. of pyridine, cooled to 0°
C., is added 0.03 ml. of methane sulfonyl chloride. The
resulting mixture is allowed to stand at a temperature of
approximately 0° C. for aperiod of approximately 1 hour.
trated hydrochloric acid has been added and then letting
Water is then added to the reaction mixture and the pre
stand at room temperature for 24 hours. The mixture is 10 cipitate which forms is recovered by extraction into ethyl
then poured into a dilute sodium bicarbonate solution and
acetate which is washed with water, and dried and re
extracted with ethyl acetate. The extracts are washed,
moved to give N-acetyl-9'a-?uoro»ll?,21-dihydroxy-l6a,
dried over magnesium sulfate and taken to dryness to
17u-isopropylidenedioxy-20-oxo-4-pregneno - [3,2-c1pyra
give the 9a-?uoro~11?,21-dihydroxy-16a,Not-isopropyli
zone
21-mesylate.
15
denedioxy-20-oxo-4-pregneno- [ 3 ,2-c] pyrazole.
The
N - acetyl - 9a - ?uoro - 1113,21 - dihydroxy
To 180 mg. of N-acetyl-9cta?uoro-11?,21-dihydroxy-16a,
17a-isopropylidenedioxy-ZO-oxo-4-pregneno - [3,2-0] pyra~
l6a,l7a - isopropylidenedioxy - 2O - oxo - 4 - pregneno
zole 21-mesylate dissolved in 10 ml. of acetone is added
300 mg. of sodium iodide. The resulting mixture is
heated at re?ux temperature for a period of approximately
20
[3,2-c]pyrazole by stirring 250 mg. of the steroid in 15
1 hour, and the reaction solution is cooled to room tem
ml. of acetone containing 5 drops of 70% perchloric acid.
perature and diluted with water. Extraction with ethyl
After thirty minutes, aqueous sodium bicarbonate is added
acetate followed by drying and removal of the solvent
and the acetone is removed in vacuo. The residue is
affords N-acetyl-9a-?uoro-l 1?-hydroxy-21-iodo-1611,171»
?ltered off, air dried and then treated with 2 ml. of acetic
anhydride and 2 ml. of pyridine for eighteen hours at 25
The N - acetyl-9a-?uoro-l 1 B-hydroxy-21-iodo-l6a,17a
room temperature. This acetylated mixture is taken off
isopropylidenedioxy-ZO-oxo - 4 - pregneno-[3,2-c] pyrazole
on a rotator at the oil pump. The residue is crystallized
(100 mg.) is dissolved in a mixture of 5 ml. of water and
from a mixture of petroleum ether and ether to yield
5 ml. of ethanol. To the resulting suspension is added
the N-acetyl-9a-?uoro-1 15,21-dihydroxy-16a,17a-is0pro
500 mg. of sodium bisul?te, and the mixture is heated
pylidenedioxy-20-oxo-4-pregneno-[3,2-c]pyrazole 2l-ace 30 under
re?ux for a period of about 1 hour. The reaction
tate.
'
solution is cooled, diluted with water, and extracted with
A solution of 5.73 g. of the N-acetyl-9a-?uoro-1119,21
ethyl acetate. After removal of the ethyl acetate in vacuo,
dihydroxy - 16a,17u - isopropylidenedioxy - 20 - oxo - 4
the residue is left overnight under nitrogen in 5 ml. of
pregneno-[3,2-c]pyrazole 2l-acetate in 60 ml. of 80%
methanol and 1 ml. of one molar sodium methoxide in
(v./v.) acetic acid is re?uxed for 1.5 hours. This solu 35 methanol. The solvent is then removed in vacuo, ethyl
tion is diluted with 400 ml. of ice-water and extracted
acetate is added and, after a water wash, the solvent is
with ethyl acetate. The ethyl acetate extracts are washed
dried and removed. Chromatography of the residue on
with water and with saturated sodium bicarbonate solu-.
neutral alumina affords some 9a-?uoro-11?-hydroxy-l6a.
tion, dried, and evaporated to dryness in vacuo. The
l7a-isopropylidenedioxy-20-oxo-4-pregneno - [3,2-clpyra
residue is dissolved in 150 ml. of acetone containing 2
zole.
ml. of 70% perchloric acid. After thirty minutes, aque
N-acetyl - 9oz - ?uoro-ll?-hydroxy-lGaJ7a-isopropyli
[3,2-c1pyrazole 21-acetate is prepared from the 9OL-?lJOI'O
11f3,16a,17u,21 - tetrahydroxy - 2O - oxo - 4 - pregneno
isopropylidenedioxy-20’oxo-4-pregneno-[3,2-c]pyrazole.
ous sodium bicarbonate is added and the acetone is re
denedioxy-20-ox0-4-pregneno-[3,2-c]pyrazole (60 mg.) is
moved in vacuo. The product is extracted into chloro
treated under nitrogen with 1.0 ml. of one molar sodium
form which is washed with water, dried and removed 45 methoxide in 10 ml. of methanol. After 1 hour, the meth
in vacuo to yield after chromatography on neutral alumina
anol is removed in vacuo and the product is extracted
9a - ?uoro - 1113,21 - dihydroxy - 16u,17a - isopropylidene
with ethyl acetate and washed with water. Removal of
dioxy-20-oxo-4-pregneno- [ 3,2~c ] pyrazole 2 l-acetate.
9a - ?uoro - 115,21 - dihydroxy - 16a,17a - isopropyl
idenedioxy-20-oxo-4-pregneno-[3,2~c]pyrazole (500 mg.)
is suspended in 25 ml. of 2,3-dihydropyran. A few drops
of concentrated hydrochloric acid are added and mag
netic stirring is continued for 6 hours, whereupon the
the dried ethyl acetate affords 9a-?uoro-l1/3-hydroxy—l6a,
Net-isopropylidenedioxy - 20 - oxo-4-pregneno-[3,2-c]pyr
50 azole.
9rz-?LlOl‘O - ll? - hydroxy-16a,Not-isopropylidenedioxy
20-oxo-4-pregnen0-[3,2-c]pyrazole (1.5 g.) is added to
150 ml. of re?uxing 60% formic acid. After twenty
minutes, the solution is cooled and then poured into ice
turated with petroleum ether and recrystallized from a 55 and water. After 18 hours, the 9a-?uoro-1l?,16a,17a
mixture of methylene chloride and petroleum ether or
trihydroxy-20-oxo-4-pregneno-[3,2-c]pyrazole is collected
a mixture of ether and petroleum ether, to afford the 90:
by ?ltration and dried.
solution is concentrated in vacuo.
The residue is tri
?uoro - 11B - hydroxy - 21 — terahydropyranyloxy - 16a,
17a-isopropylidenedioxy-20-oxo-4-pregneno-[3,2 - c]pyra
zole.
To a solution of 100 mg. of 9a-?uoro-21-tetrahydro
pyranyloxy-l l?-hydroxy - 16¢,17a - isopropylidenedioxy
20~oxo-4-pregneno-[3,2-c]pyrazole in 2 ml. of pyridine is
The ZO-ethylenedioxy - 160t,l70t,21 - trihydroxy-4-preg
nene-3,1l-dione 21-acetate compounds used as starting
materials for compound 1 of Flow Sheet A are prepared,
starting with the known 115,17a,2l-trihydroxy-4-preg
nene-3,20-dione, in accordance with the following pro
cedures which are particularly described only with refer
ence to 6a,9a-di?uoro-115,17ot,21-trihydroxy-4-pregnene
It is taken to 65 3,20-dione, but are generally applicable to all of the start
added 2 ml. of acetic anhydride. The mixture is allowed
to stand over night at room temperature.
dryness in vacuo to afford the N-acetyl-9a~?uoro-2l-tetra
hydropyranyloxy-lIB-hydroxy - 1611,1711 - isopropylidene
dioxy-20-oxo-4-pregneno-[3,2-c]pyrazole.
ing materials de?ned by compound 1.
A mixture of 500 mg. of 60:,9oz-dl?ll0fO-ll?,17a,2l-ll'i
hydroxy-4-pregnene-3,ZO-dione, 4 ml. of ethylene glycol,
Without further puri?cation, this substance is dissolved 70 25 ml. of benzene and 25 mg. of p-toluenesulfonic acid
monohydrate is re?uxed in a Dean-Stark water separator
in 5 ml. of methanol containing 20 mg. of p-toluenesul
for 8 hours. The reaction mixture is then cooled and
fonic acid. The mixture is kept at room temperature
some pyridine and ethyl acetate are added. After ex
for 4 hours. The solvent is removed in vacuo, ethyl ace
traction with dilute sodium bicarbonate, the organic layers
tate is added and the organic layer is washed several times
with dilute sodium bicarbonate. The dried solvent is 75 are dried and removed in vacuo. The entire crude ma
29
3,072,640
terial is dissolved in 2 ml.-of pyridine and 2 ml. of acetic
anhydride, and then left overnight at room temperature.
The reaction mixture is then taken to dryness on a ro
30
Similarly, the known 11/3,16a,l7a,21-tetrahydroxy-6a
methyl-4-pregnene-3,20-dione and the known 9a-?uoro
11?,16a,17a,21 - tetrahydroxy-6ot-methyl-4-pregnene-3,20-
tating evaporator at the oil pump. The residue is dis
solved in ethyl acetate and washed with dilute sodium bi~
carbonate. The ethyl acetate layer is then dried and the
ethyl acetate is removed in vacuo. Chromatography on
dione are converted into the corresponding 113,21-dihy
droxy - 6 - methyl-16u,7a-isopropylidenedioxye4,6-pregna
diene-3,20-dione 2-acetate and the 9a~?uoroderivative
thereof.
,
,
basic alumina affords 3§,20-bis(ethylenedioxy)-6a,9a-di
. The 6-chloro~, or the 6-chloro-9a-?uoro-11,3,21-dihy
?uoro-l 113,l7a,21-trihydroxy-5-pregnene 2 l-acetate.
droxy - 160L,17a - isopropylidenedioxy-4,6-pregnadiene-3,
A’ solution of 400 mg. of 3§,20-bis(ethy1enedioxy)~6m, 10 20-dione ZI-acetate is prepared from the 11,3,21-dihy
9a - di?uor-o-l118,17u,2l-trihydroxy-S-pregnene 2l-acetate
droxy'- l6a,l7a - isopropylidenedioxy-4,6-pregnadiene-3,
in 4 ml. of pyridine is added to the complex formed by
20-dione 2l-acetate, or its-9a-?uoro-derivative, respec
the addition of 400 mg. of chromium trioxide to 4 ml.
tively according to the following procedures: '
of pyridine. The mixture is thoroughly mixed and left at
.The 9ot-?ll0r0 - 115,21 - dihydroxy-16a,17u-isopropyli
room temperature over night. The reaction mixture is 15 denedioxy - 4,6 - pregnadiene-3,20-dione 21-acetate (4.76
poured into water. The aqueous mixture is extracted with
g.), is dissolved in 500 ml. of methylene chloride. To
ether and then twice with ethyl acetate. The combined
this is added'with cooling 250 ml. of an ether solution of
solvent extracts are washed with dilute aqueous sulfuric
perphthalic acid (0.5 meq. per ml.). After 18 hours the
acid at about 0° C. and then with dilute sodium bicarbon
reaction mixture is extracted with aqueous sodium car
ate. The organic solvent is dried and removed in vacuo. 20 bonate, dried and concentrated in vacuo. Crystallization
The residual material is puri?ed by crystallization to give
from a mixture of methylene chloride and ether affords
35,20 - bis(ethylenedioxy) - 6u,9a - di?uoro-l7u,2l-dihy
droxy-S-pregnene-ll-one 21-acetate.
'
6a,7a-epoxy - 90c - ?uoro-l1,3,21-dihydroxy-16a,17a-iso
propylidenedioxy-4-pregnene-3,20-dione 21-acetate.
Thionyl chloride (0.45 ml.) is added dropwise to a
The 6a,7a-epoxy-9a-?uoro-l1/i,2l-dihydroxy-16a,17a
magnetically stirred solution of 850 mg. of 32,20-bis 25 isopropylidenedioxy-4-pregnene-2,20-dione 21-acetate (0.5
(ethylenedioxy) - 6u,9a-di?uoro-17a,2l-dihydroxy-S-preg
g.) is added to a 20 ml. of anhydrous chloroform which
nene-ll-one ZI-acetate in 5 ml. of pyridine at —5° C.
has been previously saturated with dry hydrogen chlo
After 18 hours at this temperature the reaction mixture
ride gas; After 8 hours at room temperature the reaction
is, poured into a stirred iced sodium bicarbonate solution.
mixture is extracted with cold potassium carbonate solu- .
The product is extracted into chloroform and the chloro 30 tion and the organic layer is separated, dried and re
form layer is then dried and removed. Chromatography
moved. The residue is stirred for thirty minutes with 20
over basic alumina alfords the 21¢hydroxy-3§,20-bis(ethyl
ml. of acetone and 0.2 ml. of 70% perchloric acid. Then
enedioxy)-6a,9ot-di?uoro-5,16-pregnadiene-1l-one 21-ace
aqueous sodium bicarbonate is added and most of the ace
tate.
tone is removed in vacuo. The crude product is ex~
A solution of 266 mg. of osmium tetroxide in 5 ml. of 35 tracted into ethyl acetate and chromatographed on neutral
benzene is added dropwise to a stirred solution of 465
alumina to afford 6-chloro-9u-?uoro-l1/3,21-dihydroxy
mg. of 2l-hydroxy-3§,20-bis(ethylenedioxy)-6a,9a-di?u
oro-5-16-pregnadiene-ll-one 21-acetate in 10 ml. of ben
16a,l7a - isopropylidenedioxy-4,6-pregnadiene;3,ZO-dione
2 l-acetate.
zene and 0.3 ml. of pyridine. After one hour, there is
The 6-?uoro- and the 6,9u-di?noro-1118,21-dihydroxy
added 12 ml. of methanol and then a solution of 1.3 g. 40 16a,17u - isopropylidenedioxy-4,6-pregnadiene-3,20-dione
of sodium sul?te and 1.3 g. of potassium bicarbonate in
2l-acetate are prepared from 6u,7a-epoxy-1lB,21-dihy
18 ml. of water. This mixture is stirred vigorously for
droxy - 16a,l7a - isopropylidenedioxy - 4 - pregnene-3,20
three hours and then ?ltered. The red-brown solid which
dione 21-acetate and the 9a-?ll0r0 derivative according
is collected is extracted exhaustively with hot ethyl ace
to the following procedures:
tate. The combined organic layers are Washed with 45
The 6a,7a-epoxy-9a-?uoro-ll/3,21-dihydroxy-16a,17u
water and taken to dryness. Crystallization from meth
isopropylidenedioxy-4-pregnene-3,20-dione 2l-acetate (2.0
anol affords 3§,20-bis(ethylenedioxy)-6a,9a-di?uoro-16a,
g.) is dissolved in 150 ml. of anhydrous chloroform and
l704,21-_trihydroxy-5-pregnene-11-one 2 l-acetate.
cooled at 70° C. To this solution is added slowly with
A solution of 150 mg. of 3§,20-bis(ethylenedioxy)~6a,
stirring a mixture of 4.5 m1. of anhydrous tetrahydro
9u-difluoro~16a,17a,2l-trihydroxy-S-pregnene-1 l-one 21
acetate in 3 ml. of glacial acetic acid is heated on the
steam bath for twenty minutes. It is then poured into ice
and water and extracted into chloroform. .The organic
layer is washed with aqueous sodium bicarbonate until
50 furan and 3.2 g. of_dry hydrogen ?uoride.
The reaction
mixture is allowed to come to room temperature, and
after 20 hours it is poured into iced potassium carbonate
solution. Ethyl acetate is added, the organic layer is
separated, washed with water, dried and removed to yield
all of the acid has been removed. Evaporation of the 55 6?-?uoro - 7a,11?,21 - trihydroxy-loa,Hot-isopropylidene
dried chloroform layer leaves a residue which is chro
matographed over basic alumina to yield a fraction which
after crystallization from methanol is ZO-ethylenedioxy
60¢,9ot-dl?l101'0 - 16a,l7a,21 - trihydroxy-4-pregnene-3,11
dione ZI-acetate (compound 1 of Flow Sheet A).
dioxy-4-pregnene-3,20-dione 2l-acetate.
The 6/3-?uor0-7a,11,B,2l-trihydroxy-l6a,l7a-isopropy1i~
denedioxy-4-pregnene-3,20-dione 21-acetate is added to
50 ml. of anhydrous chloroform saturated with dry hy
60 drogen chloride gas. After standing 8 hours at room
The l1?,21-dihydroxy . 160;,170; - isopropylidenedioxy
temperature, this solution is slowly poured into a stirred
iced solution of potassium bicarbonate. The organic
compounds used as starting materials for compound 8 of
layer is separated, washed, dried and taken to dryness.
Flow Sheet B are prepared from known intermediates
The residue is stirred for thirty minutes with 50 ml. of
using the following procedures:
65 acetone and 0.5 ml. of perchloric acid. Aqueous sodium
4-pregnene- (and 4,6-pregnadiene) 3,20-dione 21-acetate
The known 9u-?uoro-l1,8,l6a,l7ot,21-tetrahydroxy-4
pregnene-3,20-dione is converted into the 9a-?uoro-l1?,
2l-dihydroxy - 16zx,17a - isopropylidenedioxy-4,6-pregna
diene-3,20~dione 2l-acetate by reaction ?rst with acetone
in the presence of a trace of perchloric acid to form the
acetonide, then with acetic anhydride in the presence of
pyridine to give the Zl-acetate and ?nally with chloranil
to afford the 9a-?uoro-llB,21-dihydroxy-16u,17a-isopro
pylidene-dioxy-4,6-pregnadiene-3,20-dione 21-acetate.
bicarbonate is then added and most of the acetone is re
moved in vacuo.v The crude product is extracted into
ethyl acetate and after chromatography on neutral alu
mina affords 6,9a-di?uoro-1lB,21-dihydroxy-l6a,17a-iso
propylidenedioxy-4,6-pregnadiene-3,20-dione 2l-acetate.
Various changes and modi?cations may be made in
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
75 claims, they are to be considered as part of our invention.
'
3,072,640
31
32
orophenyl)-4-pregneno-[3,2-c]pyrazole and the 16a,l7a
We claim:
acetonide thereof.
9. A compound selected from the group consisting of
1. A compound selected from the group consisting of
compounds having structural formulas A and B
6a~chloro-1113,16a,17a,21-tetrahydroxy - 2O - oxo-4-preg
neno-[3,2-c]pyrazole and the 16¢,17a-acetonide thereof.
10. A compound selected from the group consisting of
6u-chloro-11a,16a,17a,21-tetra.hydroxy-20-oxo - 2’ - phen
yl-4-pregneno-[3,2-c]pyrazole and the 16a,17a-acetonide
10
thereof.
11. A compound selected from the group consisting of
6a-chloro - 11;‘3,16a,17a,2l-tetrahydroxy - 20 - oxo-2'-(p
?uoro-phenyl)-4-pregneno-[3,2-c1pyrazole and the 160:,
17u-acetonide thereof.
12. A compound selected from the group consisting of
wherein R’ is a member of the group consisting of hy
15
droxy, lower hydrocarbon carboxylic acyloxy, tetrahydro
pyranyloxy, ?uoro, iodo, the methylsulfonyloxy radical,
13. A compound selected from the group consisting of
11 {3,l6a,17a,2l-tetrahydroxy - 6a — methyl-20-oxo-2’-phen
the dihydrogen phosphate and the alkali metal salts of
said dihydrogen phosphate, R is a member of the group
consisting of hydrogen, lower alkyl, lower aralkyl, lower
yl-4-pregneno-[3,2-c]pyrazo1e and the ‘l6a,17a-acetonide
20 thereof.
14. A compound selected from the group consisting of
cycloalkyl, lower hydrocarbon aryl, halophenyl, lower
alkoxy phenyl, nitrophenyl, pyridyl, pyridyloxide and
11B,16a,17a,2l-tetrahydroxy-6a-methyl - 20 - oxo-2'-(p
?uorophenyl)-4-pregneno-[3,2-c]pyrazole and the 16:1,
pyrimidyl, X is a member of the group consisting of hy
drogen and ?uoro, and Y is a member of the group con
sisting of hydrogen, chloro, fluoro and methyl; and phar
25
17u-acetonide thereof.
15. A compound selected from the group consisting of
9a-fluoro-11B,16u,17a,21-tetrahydroXy - 20 - oxo-4-preg
macologically acceptable salts of the foregoing com
neno-[3,2-c]pyrazole and’ the 16a,l7a-acetonide thereof.
pounds.
2. A compound selected from the group consisting of
compounds having structures A and B
1-1,8,16e,17:1,21-tetrahydroxy-6a-methyl -' 20 - oxo-4-preg
neno-[3,2-c]pyrazole and the l6a,17a-acetonide thereof.
16. A compound selected from the group consisting of
9a - fluoro-l1,8,16a,1711,21-tetrahydroxy-20-oxo-2'-phenyl
30
4-pregneno-[3,2-c]pyrazole and the 16a,17a-acetonide
thereof.
17. A compound selected from the group consisting of
9a - ?uoro-l1,6,16rx,17a,2l-tetrahydroxy-ZO-oxo-2'-(p-?u
orophenyl)-4-pregneno-[3,2-c]pyrazole and the 16a,l7a- ‘
acetonide thereof.
18. A compound selected from the group consisting of
6a,9a-di?uoro-11B,16a,17a,21-tetrahydroxy - 20 - ox0-4
pregneno-[3,2-c]pyrazole and the
16a,l7a-acetonide
thereof.
19. A compound selected from the group consisting of
wherein R’ is a member of the group consisting of hy
phenyl-4-pregneno-[3,2-C]pyrazole and
droxy, lower hydrocarbon carboxylic acyloxy, ?uoro, IOdO,
tetrahydropyranyloxy, the methylsulfonyloxy radical, the
the
1601,1701
acetonide thereof.
20. A compound selected from the group consisting of
dihydrogen phosphate and the alkali metal salts of said
6a,9a-di?uoro-115,1601,17a,21-tetrahydroxy - 20 - ox0-2'
dihydrogen phosphate, R is a member of the group con
(p~?uorophenyl)-4-pregneno-[3,2-c]pyrazole and the l6a,
sisting of hydrogen, lower hydrocarbon carboxylic acyl,
17a-acetonide thereof.
21. A compound selected from the group consisting of
lower alkyl, lower hydrocarbon aryl, lower aralkyl, lower
cycloalkyl, halophenyl, lower alkoxy phenyl, nitrophenyl,
6a - chloro-9a-fluoro-l113,16a,17a,2l-tetrahydroxy-ZO-oxo
pyridyl, pyridyloxide and pyrimidyl, X is a member of the
group consisting of hydrogen and ?uoro, Y is a member 50 4-pregneno-[3,2-c1pyrazole and the l6u,l7a-acetonide
thereof.
of the group consisting of hydrogen, chloro, ?uoro and
22. A compound selected from the group consisting of
methyl, P and Q are each selected from the group con
6l1-Ch10l'O-9d'?UOI'O - l1/i,l6a,l7a,2l - tetrahydroxy-ZO
sisting of hydrogen, alkyl and aryl, and together with the
carbon to which they are joined, P and Q are cycloalkyl;
and pharmacologically acceptable salts of all of the fore
oxo-2’-phenyl-4-pregneno-[3,2-c]pyrazole and the 160:,
55
going compounds.
3. A compound selected from the group consisting of
11B,16a,17u,21-tetrahydroxy-20-oxo-4-pregneno - [3,2-c]
17u-acetonide thereof.
23. A compound selected from the group consisting of
6u-chloro‘9a-?uoro - 1l/3,l6a,l7oc,2l - tetrahydroxy-ZO
oxo-2’-(p-?uorophenyl)-4-pregneno - [3,2-c]pyrazole and
pyrazole and the 160:,17u-3C8t011id6 thereof.
the 16a,l7a-acetonide thereof.
24. A compound selected from the group consisting of
113,16a,17a,21-tetrahydroxy-20-oxo-2'-phenyl - 4 - preg
neno[3,2-c]pyrazole and the 16a,17a-acetonide thereof.
oxo-4-pregneno-[3,2-c]pyrazole and the 16a,17a-3Cet0nid6
4-pregneno-[3,2-c]pyrazole and the l6a,17u-acetonide
oxo-2'-phenyl—4-pregneno-[3,2~c]pyrazole and the 160:,
4. A compound selected from the group consisting of 60
9a-fluoro-1l?,16a,17a,21-tetrahydroxy - 6a - methyl-20
thereof.
5. A compound selected from the group consisting of
25. A compound selected from the group consisting of
11,3,16u,17a,21-tetrahydroXy-20-oxo-2’-(p - ?uorophenyl) 65 9a-?uoro-l1B,l6a,l7a,21-tetrahydroxy - 6a - methyl-20
thereof.
6. A compound selected from the group consisting of
6oc-?l101'0 - l1B,16a,170r,21 - tetrahydroxy-20-oxo-4-preg
neno[3,2-c]pyrazole and _the 16a,17a-acetonide thereof.
17u-acetonide thereof.
26. A compound selected from the group consisting of
9a-?uoro-1l?,16a,17a,21-tetrahydroxy - 6a - methyl-20
7. A compound selected from the group consisting of 70 ox0-2’-(p-?uorophenyl)-4-pregneno - [3,2-c]pyrazole and
the 16a,‘17a-acetonide thereof.
6a - ?uoro-l 1p,16a,17u,2l-tetrahydroxy-Z0-oxo-2'-phenyl
References Cited in the ?le of this patent
4-pregneno-[3,2-c1pyrazole and the 16a,17a-acetonide
UNITED STATES PATENTS
thereof.
8. A compound selected from the group consisting of 75
2,945,852
Bergstrom ____________ __ July 19, 1960
6a - ?uoro - 11,8,16a,170:,21-tetrahydroxy-20-oxo-2’-(p-?u
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