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Патент USA US3072651

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United States Patent O? ice
1
2
3,072,641
ing the 16a,17a-acetal or ketal, together with a tetrahy
dropyranyl group at carbon-21, as shown is compound 8
16 - OXYGENATED - 4 - PREGNENO - [3,2-c]
of Flow Sheet B.
PYRAZOLES AND PROCESS OF PRE
PARING THEM
The 1 l-oxygenated-16a,17a,2l-trihydroxy-4-pregnene
3,20-dione (or the Ate-analogs thereof) used as starting
Ralph F. Hirschmann, Scotch Plains, and Arthur A.
materials for the compounds shown in Flow Sheet A are
Patchett, Metuchen, N.J., assignors to Merck & Co.,
Inc., Rahway, N.J., a corporation of New Jersey
No Drawing. Filed Mar. 5, 1962, Ser. No. 177,169
23 Claims. (Cl. 260-2395)
This invention is concerned generally with novel
steroids and with processes of preparing the same. _More
particularly it relates to novel l113,160:,17rx-trihYdI'OXY-20
oxo - 4 - pregneno- _ and
3,072,641
Patented Jan. 8, 1963
prepared from the known 1l-oxygenated-17a,21-dihy
droxy-4-preg-nene-Ia?,ZO-dionesv as indicated on the Flow
Sheet for Starting Materials, in column 6, lines 1-40.
Among-the compounds which may be used as starting
10
materials are the following:
1 1,8,1604, 17a,21-tetrahydroxy-4-pregnene-3 ,20-dione,
6a-chloro-1 15,16a,17a,21-tetrahydroxy~4-pregnene-3 ,20
dione;
Ga-?uoro-l 118,16u,'17a,21-tetrahydroxy-4-pregnene~3,20?
dione;
6a-methyl-1 1e, l6a,17u,21-tetrahydroxy-4-pregnene-3,20
dione;
4,6-pregnadieno-[3,2-c]pyrazole
compounds and to the 16a,17a-acetals and ketals of these ,
[3,2-c]pyrazoles.
The novel compounds which form the subject of the
present invention have structural Formulas A ?and B.
20
6u-chloro-9a-?uoro-l 113,16a,17a,21-tetrahydroXy-4
pregnene-3,20-dione;
25
6a,9a-di?uoro-115,16a,17a,2l-tetrahydroxy-4-pregnene
3,20-dione; and
6u-methyl-9a-?uoro-116-1611,l7a,21-tetrahydroxy-4
pregnene-3 ,ZO-dione.
'
Detailed procedures for'preparing speci?c starting mate
rials included in Flow Sheet B, starting from known in
termiates are included in columns 28-30.
wherein the dotted line between carbons 6 and 7 indicates
thata 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 35
the dihydrogen phosphate, R is hydrogen acyl, alkyl,
aralkyl, cycloalkyl, aryl, a heterocyclic nucleus or sub?
stituted derivatives thereof, X refers to hydrogen or ?uoro,
Upon treatment of an ll-oxygenated 16a,17a,21-trihy
droxy-4-pregnene-3,20-dione (or a Abs-analog thereof),
having a protected side chain, with an alkyl formate and
sodium hydride in an inert atmosphere there is formed
the corresponding Z-hydroxymethylene derivative which
may be mixed with the formate esters thereof. The 2
hydroxymethylene-derivative is designated on Plow Sheet
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 l6a,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-c]pyrazo1e.
Upon treatment of the 2-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 monosub
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-c1pyrazole-steroids possess high 60
anti-in?ammatory activity and are especially effective 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 eife'cts.
In preparing our novel chemical compounds, the start 65
ing material utilized is an 11-oxygenated-16a,17a,21-tri
hydroxy-4-pregnene-3,2?O?dione, or a M's-analog thereof,
which has a protected cortical side chain. The side chain
wherein X, Y and R have the signi?cance above de?ned.
The above compounds are shown on Flow Sheet A as
of the steroid may be protected with an ethylenedioxy
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
3,072,641
3
separated by chromatography.
[3,2-c] pyrazoles having structure A are designated as the
1?-substituted-[3,2-clpyrazoles and the N-substituted com
pounds having structure B are designated as the 2?-sub
stituted [3,2-clpyrazoles.
Upon treatment of a Z-hydroxyrnethylene-compound
directly with a monosubstituted arylhydrazine, without
the intermediate formation of the 2-alkoxymethylene
derivative, one isomer is generally formed in preponderant
amounts, whereas when reacting the Z-alkoxymethylene
compound with a monosubstituted arylhydrazine, signi?
The N-substituted-l 15,21-dihydroxy-16a,17a-isopropyl
idenedioxy-20-oxo-4-pregneno-(or 4,6-pregnadieno) [3,2
c]pyrazole (compound 6 of Flow Sheet A) is converted
into the 2l-acyloxyderivative by treating with one equiva
lent of an acylating agent, e.g. a lower hydrocarbon ca-r
boxylic acid acylating agent such as benzoic anhydride,
tertiary butyl acetyl chloride; a lower alkanoic anhydride
cant amounts of both isomers are obtained. When these
reactions take place with rnonosubstituted-alkylhydrazines,
mixtures may be obtained when starting with the 2-hy
or lower alkanoyl halide such as acetic anhydride, pro
pionic anhydride; or a polybasic anhydride such a 5,,8
droxymethylene-steroid as well as with the 2-alkoxymeth
ylene-steroid. A mixture of isomers may also result from
the reaction of a monosubstituted-hydrazine with a 2-hy
droxymethylene-compound which possibly contains var
iable amounts of the 2-alkoxymethylene-compound due
to the operating procedures employed, for example, due
dimethyl-glutaric anhydride, succinic anhydride and the
like, in the presence of an organic base such as pyridine.
The N-unsubstituted-l1?,2l-dihydroxy-16a,17a-isopro
20
to recrystallization in the presence of a trace of alcohol
a solution of the 2-hydroxymethylene-compound from
which acid has not been completely removed.
Any formate ester groups present in the resulting
[3,2-c]pyrazole may be removed by treating with sodium 25
methoxide in methanol at room temperature for about
10 minutes.
zines, butylhydrazines, B-hydroxyethylhydrazine; cyclo
pyrazole;
30
alkylhydrazines; monosubstituted-hydrazines which may
6a-chloro-1118,16e,17a,21-tetrahydroxy-20-oxo-4-preg
neno [3 ,2-c] pyrazole;
6m-?uoro-115,1611,17a,21-tetrahydroxy-20-oxo-4-preg
neno-[ 3,2-c] pyrazole;
1 1 p,1601,17a,2l-tetrahydroxy-Ga-methyl-20-oxo-4-preg
be derived from any aromatic or heterocyclic ring nucleus
including phenylhydrazine and the substituted phenylhy
drazines, such as 0-, m-, and p-halophenylhydrazines, 0-, 35
m-, and p-tolyhydrazines, o-, m-, and p-alkoxyphenyl
hydrazines, o-, m-, and p-nitrophenylhydrazines, l-hydra
zinonaphthalene; 2-hydrazinopyridine, 3-hydrazinopyri
neno- [3,2-c] pyrazole;
9a-?l101'0-1 1B,16a,170:,21-tetrahydroxy-20-oxo-4-preg
neno- [3,2-c] pyrazole;
6a-chloro-9u-?uoro-11B,16a,1711,21-tetrahydroxy-2O-oxo
4-pregneno- [ 3,2-c]pyrazole;
dine, 4-hydrazinopyridine, 4-hydrazinopyridine oxide, and
Z-hydrazinopyrimidine; aralkylhydrazines, such as benzyl
pylidenedioxy - 20<>xo-4-pregneno-(or 4,6-pregnadieno)
[3,2-c]pyrazole is converted into the 21-acyl derivative
by reacting with 2 equivalents of the acylating agent to
form the N-acyI-ZI-acetate and then heating the latter
compound with aqueous acetic acid, whereupon the N-acyl
group is selectively removed.
The products of our invention include, among others,
the following:
11,8,l6u,17a,21-tetrahydroxy-20-oxo-4-pregneno-[3 ,2-c]
Among the monosubstituted hydrazines which may be
used for the process of our invention are: alkylhydrazines,
such as methylhydrazine, ethylhydrazine, propylhydra
4
the ketal shown in all the ?ow sheets is the l6u,17a-iso
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.
The N-substituted
40
hydrazine and phenylethylenehydrazine.
9u-?uoro-l 15,1611,1711,21-tetrahydroxy-6a-methyl-2O-oxo
There are thus produced the corresponding N-sub
stituted-[3,2-c]pyrazoles including: N-alkyl such as N
4-pregneno- [3,2-c]pyrazole.
methyl-, N-ethyl-, N-butyl, N-propyl-, N-(?-hydroxyeth
This invention also includes the 16a,17a-acetals and
yl)-; N-cycloalkyl-; N-substituted derivatives which may 45
ketals of the foregoing compounds, as well as the 1'- and
be derived from any aromatic or heterocyclic nucleus, in
2?-acyl-, 1?- and? 2'-alkyl-, the l?- and 2'-cycloalkyl-, the 1'
cluding N-phenyl- and the N-substituted-phenyl deriva
and 2?-aralkyl and the 1?- and 2?-substituted derivatives
tives such as 0-, m-, and p-halophenyl; o-, m-, and p
tolyl-; o-, m-, and p-alkoxyphenyl-, o-, m-, and p
nitrophenyl-; N-(l"-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 2l-acylates.
This invention also includes the Aha-analogs of all of
pyrimidyl)~; N-aralkyl-, such as N-benzyl- and N-phenyl
ethenyl-4-pregneno- or 4,6-pregnadieno-[3,2-c]pyrazoles.
the foregoing compounds.
In order to convert the 21-hydroxy group of an N
An ll-keto-group is reduced to the ll?-hydroxy-group
using sodium borohydride. The ZO-ethylenedioxy-group
55
is removed by heating the steroid, dissolved in a solvent
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.2l
The dihydroxy-steroid is converted into the l6oz,l7u
hydroxy compound is ?rst reacted with methane sulfonyl
acetal or ketal by treating with a carbonyl reactant of
the general formula:
substituted 1 1?,21-dihydroxy-l6a,17a-isopropylidenedioxy
60 chloride in a non-aqueous ?base .to form the 21-mesylate
(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
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?,l6ot,l7oc,
2l-tetrol in a ketone or aldehyde is treated with a trace
form the 21-desoxy-derivative (compound 22).
65
In order to convert the 21-hydroxy group of an N-un
substituted-1 1B,2l-dihydroxy-16a,17a-isopropylidenedioxy
20 - oxo-4-pregneno-(or 4,6-pregnadieno) [3,2-c]pyrazo1e
(compounds 6 and 13 of Flow Sheet C) into the 21
of perchloric acid and stirred at room temperature until 70 desoxy derivative, the 21-hydroxy group is ?rst converted
solution is complete. The ketones and aldehydes which
are suitable for this purpose include acetaldehyde, meth
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
into the 21-tetrahydropyranyl ether (compounds 7 and
12). This is accomplished by treating the steroid with
dihydropyran in the presence of an acidic reagent such 1
as concentrated hydrochloric acid. The steroid is then ,
reacted with acetic anhydride in a non-aqueous base to l
3,072,641
5
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
nzon
with a p-toluenesulfonic acid. The N-acetyl-Zl-hydroxy
20 - oxo-4-pregneno-(or 4,6-pregnadieno) [3,2-c1pyrazole
(compound 18) is then converted into the corresponding
uzoac
=o
5
0
-----on
>
H0
21-desoxy-derivative (compound 22) by the procedure
"90?
no
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 2l-desoxy-compounds of our invention include the
'
_..
following:
A
E"
Y
0
Y
B
This invention also includes the 16a,17u-acetals and
ketals of the foregoing compounds, as well as the 1?- and
2'-acyl-, the 1? and 2'-alkyl, the 1'- and 2'-cycloalkyl-,
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 16u,17u-acetals and ketals.
This invention also includes the M's-analogs of all of the
foregoing compounds.
The 2l-?uoro-deriv-atives of all of the above named
compounds are obtained by heating the corresponding 21
mesylate with an alkali metal ?uoride, preferably in a
solvent such as dimethylformamide.
The 2l-dihydrogen phosphate esters are prepared by
the reaction of the corresponding 21-iodo compound with
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
alkali metal hydroxide.
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 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
Trip/ac
1
0
\0
' Mon
55
60
The [3,2-c1pyrazolo compounds described in the fore
going structures form salts such as the hydrochloride,
sulfate, chlorate, perchlorate, picrate and trichloroace
65
tate, on treatment with the corresponding acid.
A further embodiment of our ?invention comprises
novel pharmaceutical compositions containing the novel
[3,2-c]pyrazolo compounds of the pregnane series, ex
empli?ed in the foregoing structures.v
_?
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.
70
OH
3,072,641
:
10
wherein X is a member of the group consisting of hydro
gen and ?uoro, Y is a men-ll? of the group consisting
of methyl, ?uoro and chloro and R is a member of the
group consisting of hydrogen, alkyl, cycloalkyl, aralkyl,
30
e (R=H)
?3 (Pan)
aryl, and a heterocyclic nucleus or substituted derivatives
thereof.
FIDW 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.
3,072,641
9
10
wherein the linkage indicated by the broken line between
FLOW SHEET C
?20H
.
carbon atoms 6 and 7 indicates that a double bond may
131410505113
be present in this position, and wherein X is a member
of the group consisting of hydrogen and ?uoro, and Y is
~-----o
on
a member of the group consisting of methyl, ?uoro and
--0>C<cHJ
chloro.
Example 1
A suspension of 610 mg. of 20-ethylenedioxy-6a,9a
di?uoro- 16a,170:,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-6a, .
9a - di?uoro-16a,17a,21-trihydroxy-2-hydroxymethylene
4-pregnene-3,11-dione, and/or formate esters thereof.
Example 2
A 25 mg. aliquot of 20-ethylenedioxy-6a,9u-di?uoro
l6a,17u,21 - trihydroxy - 2 - hydroxymethylene - 4 - preg
nene-3,l1-dione, and/or the formate esters thereof, is dis
solved 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 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-ethylenedioxy46a,'9a-di?uoro-lli6a,17a,21~trihy
droxy-l 1-oxo-4-pregneno-[3,2-c]pyrazole.
Example 3
To a solution of 0.5 millimole of 20-ethylene-dioxy
611,904 - di?uoro - .116u,17a,2l - trihydroxy - 2 - hydroxy
methylen'eL4-pregnene-3? I-dione, and/or the formate
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
net is removed by ?ltration. It is redissolved in 30 ml.
of methanol and 5 ml. of sodium methoxide in methanol
and left under nitrogen for 10 minutes.
The alkoxide V
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-20-ethylenedioxy-6a,
9a - di?uoro - 1?6oc,17oc,21 - trihydroxy -
_
26
11 - oxo - 4 -
pregneno-[3,2-c]pyrazoles.
A mixture of the 11'-methyl- and 2?-methyl-2?0-ethyl
enedioxy -'6a,9a - di?uoro - 16a,17u,21 - trihydroxy -
75 l1~oxo-4-pregneno-[3,2-clpyrazole is prepared by the
3,072,641
11
following route: A mixture of 1 gram of 20-ethylenedi
oxy - 6,a,9u - di?uoro - 16a,l7a,21 - trihydroxy - 2 - hy
droxy-methylene-4-pregnene-3,1l-dione, and/or the for
12
route: A mixture of 1 gram of 20-ethylenedioxy-6a,9a
di?UOI?O-l6ot,l7a,2l - trihydroxy-Z - hydroxymethylene-4
pregnene-3,ll dione, and its derived formatcs, 200 ml.
of methanol, and 200 mg. of p-toluenesulfonic acid is
mate esters thereof, 200 ml. of methanol, and 200 mg. of
allowed to stand at room temperature for two hours.
p~toluenesulfonic acid is allowed to stand at room tem
The reaction mixture is then diluted with water and ex
perature for two hours. The reaction mixture is then
tracted with ethyl acetate. The ethyl acetate extract is
diluted with water and extracted with ethyl acetate. The
washed
two times with 2 N aqueous sodium hydroxide
ethyl acetate extract is washed two times with 2 N aque
solution and then with water. The ethyl acetate extract
ous sodium hydroxide solution and then with Water. The
ethyl acetate extract is then dried and concentrated in 10 is then dried and concentrated in vacuo. The 20- ethyl
6n6dl0Xy?6a,9cc-dl?I10I?0 - l6rx,17a,2l - trihydroxy�meth
vacuo to give the desired 20-ethylenedioxy-6a,9a-di?uoro
oxymethylene-4-pregnene-3,ll-dione is obtained by chro
1�,17u,2l - trihydroxy - 2 ? methoxymethylene - 4 -
matography on acid-washed alumina and elution with
ether : chloroform mixtures.
A mixture of 500 mg. of the above 2-methoxymethyl
A mixture of 500 mg. of the above Z-methoxy-methyl
ene~derivative, 100 ml. of ethanol, and 1 ml. of methyl 15
ene-steroid,
100 m1. of ethanol, and 1 ml. of phenyl?
hydrazine is heated under nitrogen until dissolved, and
hydrazine is heated under nitrogen until dissolved, and
then allowed to stand under nitrogen at room tempera
pregnene-3 ,1 l-dione.
then allowed to stand under nitrogen at room tempera
ture over night. The reaction mixture is then diluted
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 20 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
two times with water. The ethyl acetate extract is then
dried, concentrated, and chromatographed on Florisil or
dried, concentrated, and chromatographed on Florisil1
silica gel to yield the 1'-methyl- and the 2'-methyl-20
or silica gel to yield the 1?-phenyl- and 2?-phenyl-20
ethylenedioxy - 604,90: - di?uoro - l6oc,17a,2l - trihy
25 ethylenedioxy-6a,9a - di?uoro - 16a,l7a,2l-trihydroxy
droxy-l l-oxo~4-pregneno- [ 3,2-c] pyrazole.
11-oXo~4-pregneno- [ 3,2-c] pyrazole.
In accordance with the above procedures, but starting
with the Z-hydroxymethylene-derivative which is obtained
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 1?
phenyl- and 2'-phenyl-derivatives.
?uoro - l6oz,17oc,2l - trihydroxy - 11 - oxo - pregneno -
In accordance with the above procedures, but using
[3,2-c1pyrazole 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-chlorophenylhydrazine, 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 rroom temperature over
2'-cyclohexyl-, l?- and 2'-p-tolyl-, 1?- and 2'-(p-chloro
phenyl)-, l?- and 2'-(p-methoxyphenyl)-, and l'- and
night. The product is ?ltered, washed with methylene
chloride, and the ?ltrate and washings are taken to dry
ness. The residue is treated with water and the prod
uct is ?ltered to give N-methyl-Z0-ethylenedioxy-6a,9a
40 2'-benzyl-20-ethylenedioxy ~ 611,90: - di?uOI'0-16a,l7a,2l
trihydroxy-l1-oxo-4-pregneno-[3,2-c1pyrazoles.
Example 5
A 111.5 mg. sample of 20-ethylenedioxy?6a,9a- di
di?uoro - 1-6a,17a,21 - tn'hydroxy - 11 - oxo - 4 - preg
neno-[3,2?c]pyrazole.
In accordance with the above procedures, by using 45 ?uoro-16a,17a,21 - trihydroxy-Z - hydroxymethylene - 4
other alkylating agents in place of methyl iodide, there
pregnene-3,11-dione, and/or the formate esters thereof,
are obtained the corresponding N-alkyl-20-ethylenedioxy
is suspended in 2.5 ml. of ethanol and treated with 24.5
mg. of sodium acetate, followed by the addition of 48.5
641,901. - di?uoro - ?1'6a,l-7oc,2l - trihydroxy - l1 - oxo - 4 -
pregneno-[3,2-c]pyrazole.
mg. of p-?uorophenylhydrazine hydrochloride. The air
In accordance with all of the above procedures but 50 in the system is replaced with nitrogen and the mixture
starting with the 2-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
A mixture of 90 mg. of ZO-ethylenedioxy-6a,9a-di?u
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
fate, ?ltered and concentrated to dryness in vacuo. It
pregnene-3,~1l-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
is redissolved in 8 ml. of methanol and 2 ml. of 1 M so 65 leaves 2?-(p-?uorophenyl) -20 - ethylenedioxy-6a,9a-di
?uOI'O-16oz,l7a,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
acid and the mixture is diluted with ethyl acetate and
washed with water. Removal of the dried solvent leaves 70
hydroxy-l1-oxo-4-pregneno - [3,2-c1pyrazole is prepared I
2? - phenyl - 20 - ethylenedioxy - 6a,9a - di?uoro - 16a,
by the following route: A mixture of 1 gram of 20-=
l7e,2 l-trihydroxy-l l-oxo-4-pregneno- [ 3 ,2-c] pyrazole.
oro - 16a,l7a,21 - trihydroxy - 2 - hydroxymethylene -4 ~
A mixture of the 1'-phenyl- and 2?-phenyl-20-ethyl
enedioxy-6a,9a - di?U0rO-l6cz,17ez,2l - trihydroxy-ll-oxo
4-pregneno-[3,2-c]pyrazole is prepared by the following 75
ethylenedioxy-6a,9a - di?uoro - l6oz,17a,21 - trlhydroxy-l
1Florisil is an activated magnesium silicate made accord
ing to U.S.P. 2,393,625.
13
3,072,641
14
2-hydr0xymethylene-4-pregnene-3,11-dione, and/ or the
formate esters thereof, 200 ml. of methanol and 200 mg.
sponding N-alkyl-, N-cycloalkyl-, N-aryl- or N-aralkyl
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 ace
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 16a,l7a-l<etal.
tate extract is washed two times with .2 N aqueous so
dium hydroxide solution and then with water. The ethyl
acetate extract is then dried and concentrated in vacuo.
The 20-ethylenedioxy-6a,9a - di?uoro-16a,17a,21-trihy
droxy-2-methoxymethylene-4-pregnene - 3,11-dione is ob l0
Example 9
The N-acetyl-6a,9a-di?uoro-l 1 f1,21-dihydroxy-l6ot,17u
isopropylidenedioxy - 20 - oxo-4-pregneno-[3,2-clpyrazole
tained by chromatography on acid washed alumina and
21-acetate is prepared from the 6a,9ot-(li?UOI?O-11B,l6oc,
elution with etherzchloroform mixtures.
1711,21 - tetrahydroxy - 20-oxo-4~pregneno-[3,2-c]pyraz
A mixture of 500 mg. of the 2~meth0xymethylene~
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. _After thirty
minutes, aqueous sodium bicarbonate is added and the
and then allowed to stand under nitrogen at room tem
acetone is removed in vacuo. The residue is ?ltered o?f,
perature over night. The reaction mixture is then diluted
air dried and then treated with 2 ml. of acetic anhydride
with ethyl acetate, washed two times with 2 N sulfuric
and 2 ml. of pyridine for eighteen hours at room tem
acid, two times with 2.5 N sodium hydroxide, and then
two times with water.
The ethyl acetate extracts are 20 perature.
This acetylated mixture is taken off on a ro
tator at the oil pump. The residue is crystallized from
a mixture of petroleum ether and ether to yield the N
then dried, concentrated, and chromatographed on acid
washed alumina to afford the 1'-(p-?uorophenyl)- and
acetyl - 6a,9a-?uoro-115,21-dihydroxy-16u,17a-isopropyl
2'-(p-?uorophenyl) - 20 - ethylenedioxy - 6a,9a-difiuoro
idenedioxy - 20 - oxo-4-pregneno-[3,2-c]pyrazole 21-ace
16u,17oc,21 - trihydroxy - ll-oxo - 4 - pregneno-[3,2-c]py
25 tate.
razole.
A solution of 5.73 g. of the N-acetyl-6a,9a-di?uor0-11B,
In accordance with all of the above procedures, but
21 - dihydroxy - 16a,17u-isopropylidenedioxy~20-oxo-4
starting with the 2-hydroxymethylene derivative which
pregneno-[3,2-c]pyrazole 2l-acetate in 60 ml. of 80%
is obtained from each of the starting materials which are
(v./v.) acetic acid is refluxed for 1.5 hours. This solu
listed in column 2, there are obtained the correspond 30 tion is diluted with 400 ml. of ice-water and extracted
with ethyl acetate. The ethyl acetate extracts are washed
ing 1'-(p-?uorophenyl)- and 2'-(p-I?uorophenyl)-deriv
with water and?with saturated sodium bicarbonate solu
atives.
tion, dried, and evaporated to dryness in'vacuo. The resi
Example 6
due is dissolved in 150 m1. of acetone containing 2 ml. of
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 removed in
of 250 mg. of 20-ethylenedioxy-6u,9u-di?uoro-16a,17a,21
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 60�,90t-di?ll0l?0
vent is removed in vacuo on a rotating evaporator, water
115,21 - dihydroxy ? 16a,17a-isopropylidenedioxy-ZO-oxo
is added and the product is collected by ?ltration. It is 40 4-pregnen0-[3,2-c]pyrazole 21-acetate.
recrystallized from methanol to afford 20-ethylendioxy
In accordance with the above procedures, but using an
60:,90: - di?uoro-11p,16a,1704,21-tetrahydroxy-4-pregneno
equivalent quantity of another acylating agent in place [3,2-c] pyrazole.
of acetic anhydride, there is obtained the corresponding
45 acyl derivatives.
Example 7
In accordance with all the procedures given in Ex
amples 1, 2, 3, 4, 5, 6, 7, 8 and 9, but starting in Example
A mixture of 2.9 grams of 20-ethylenedioxy-6a,9a-di
1 with the 20 '- ethylenedioxy-16a,17a,21-trihydroxy-4
fluoro - 1l?,l6a,l7oz,2l - tetrahydroXy-4-pregneno-[3,2-c]
pregnene-3,l1-dione 2l-acetate or the 6ot-chloro-, 6a
pyrazole, 100 ml. of methanol, and 6 ml. of a solution
?uoro-, 6a-methyl-, 9a-?uoro-, 6a-chloro-9ot-?uoro-, 6a
prepared by diluting 8 ml. of sulfuric acid with 100 ml.
methyl-9m-?uoro-derivatives thereof, in place of the 6a,
of water is re?uxed for one hour and then concentrated
90: - di?uoro - 20 - ethylenedioxy-16a,17a,21-trihydroxy-4
in vacuo. The product is extracted with ethyl acetate
pregnene-3,l1-dione 21-acetate, there is obtained the cor
and the extract is washed wtih aqueous sodium bicarbon
responding 1 1B,16a,17a-tetrahydroxy-20-oxo-4-pregneno
ate, salt, and then wtaer. The mixture is dried over mag 55 [3,2-c]pyrazole or the 6u-chloro, 6a-?1101'0, Got-methyl,
nesium sulfate and then taken to dryness to give 60�,90z
9a-?uoro, 6a-chloro-9a-?uoro or 9a-?uoro-6a-methyl-de
rivatives thereof; and the N-alkyl-, N-cycloalkyl-, N-aryl-,
N-aralkyl-, N-heterocyclic derivatives, the 16a,17u-aceto
di?uoro - 1l?,l60�,l7a,21-tetrahydroxy-Z0~oxo-4-pregneno
[3 ,2-c] pyrazole.
nides and the 21-acyloxy derivatives of all of the 1600,
Example 8
60
The 6a,9u - di?uoro-11;3,16a,17<x,2l-tetrahydroxy-ZO
oxo-4-pregneno-[3,2~c]pyrazo1e (100 mg.) is heated for
3 minutes with 10 m1. of acetone to which 1 drop of con
l7a-acetonides of the foregoing 11B,16a,17u-tetrahydroxy
20_-oxo-4-pregneno-[3,2-clpyrazoles.
Example 10
centrated hydrochloric acid has been added and then
611,90: - di?uoro - 11?,21-dihydroxy-l6a,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 611,90L-dl?UOX?O-ll?,21-dlhydr0Xy-l6a,l7ot 70 the solution is concentrated in vacuo. The residue is tritu
isopropylidenedioxy-20-oxo-4-pregneno- [ 3,2-c lpyrazole.
rated with petroleum ether and recrystallized from a mix
In accordance with the above procedure, but starting
ture of methylene chloride and petroleum ether or a mix
with an N-alkyl-, N-cycloalky1-, N-aryl-, or N-aralkyl-6a,
ture of ether and petroleum ether, to afford the 60:,9a-di- '
9a - di?uoro - 11;9,l6u,l7u,2l - tetrahydroxy-20-oxo-4
pregneno - [3,2-c]pyrazole, there is obtained the corre
?uoro - 11/3 - hydroxy-21-tetrahydropyranyloxy-l601,170;
75 isopropylidenedioxy-20-oxo-4-pregneno- [ 3,2-c] pyrazole.
3,072,641
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
methoxide in methanol and left under nitrogen for 10
minutes. The alkoxide is neutralized with acetic acid
In accordance with the above procedure, but starting
with 1111,21 - dihydroxy-16a,17a-isopropylidenedioxy-ZO
oxo?4-pregneno-[3,2-c]pyrazole or the 6oL-ChlO1'O-,6oz
?uoro-, 6a~methyl-, 9a-?uoro-, 6a-chloro-9a-?uoro-, or
9a-?uoro?6a-methyl-derivative thereof, there is obtained
and the mixture is diluted with ethyl ?acetate and washed
with water. Removal of the dried solvent leaves 6,9a-dl
the correspondingly substituted ll?-hydrOxy-Zl-tetra
?uoro _ 21 - tetrahydropyranyloxy-1113-hydroxy-16e,17a
hydropyranyloxy-16a,l7a-isopropylidenedioxy - 20 - oxo
isopropylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c]
4-pregneno-[3,2-clpyrazole.
pyrazole.
'
Example 11
10
Example 15
To a solution of 0.5 millimole of 6,9a~di?uoro-2l-tetra
_ 6,9a-dl?l10l?0 - 1113,21 - dihydroxy - 16a,17a - isopropyl
idenedioxy-4,6-pregnadiene - 3,20 - dione ZI-acetate (1.0
hydropyranyloxy - 11B - hydroxy-2-hydroxymethylene
16a,l7a-isopropylidenedioxy-4,6-pregnadiene - 3,20 - di
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
After 3 hours, most of the methanol is removed in vacuo
absolute ethanol is added 0.6 millimole of sodium acetate
and the product is extracted with ethyl acetate and water.
and then 0.6 millimole of methylhydrazine sulfate. The
Removal ?of the ethyl acetate affords crystals of 6,9rx-di
mixture is re?uxed under nitrogen for 40 minutes and
?uoro-116,21-dihydroxy - 16:1,170: - isopropylidenedioxy
then ?ltered hot. The ?ltrate is taken to dryness. It is
20 redissolved in 50 ml. of methanol and 10 ml. of 1.33 N
4,6-pregnadiene-3,20-dione.
Example 12
6,9a-di?uoro - 115,21 - dihydroxy - 160:,170: - isopropyl
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
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 6,9a-di?U01'0-21
sodium methoxide in methanol and left under nitrogen
for 10 minutes. The elk-oxide is neutralized with acetic
acid and the mixture is diluted with ethyl acetate and
washed with water. Removal of the dried solvent leaves
N-methyl-6,9a-di?uoro - 21 - tetrahydropyranyloxy-11e
hydroxy-16a,17a-isopropylidenedioxy - 20 - oxo - 4,6
pregnadieno-[3,2-c]pyrazole.
A mixture of 1'-methyl- and 2'-methyl-6,9a-di?uoro
'30
21 - tetrahydropyranyloxy - 11/3 - hydroxy - 16a,l7� - iso
propylidenedioxy-ZO-oxo ~ 4,6 - pregnadieno-[3,2-c]pyra
zole is prepared by the following route: One gram of
6,9a-di?ll0l'0 - 21 - tetrahydropyranyloxy-ll?ehydroxy-l
hydroxy/methylene - 1611,17? - isopropylidenedioxy - 4,6
tetrahydropyranyloxy-llit-hydroxy - 1611,1701 - isopropyla
idenedioxy-4,6-pregnadiene-3,20-dione.
pregnadiene-3,20-dione,
and/or the formats 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
added and the organic layer is washed two times with
3,20-dione (350 mg.) is dissolved in 25 ml. of dry, hot 40 2 N aqueous sodium hydroxide solution and then with
water. The ethyl acetate extract is then dried and con
benzene and the resulting solution is cooled to room
centrated in vacuo. The 6,9a-di?uoro-21-tetrahydr0
temperature and treated with 1.0 ml. of freshly distilled
The 6,9a-di?uoro-2l-tetrahydropyranyloxy - 1113 - hy
droxy-16u,17a'isopropylidenedioxy - 4,6 - pregnadiene
pyranyloxy - 11B - hydroxy - 2 - methoxy - methylene
ethyl formate. The air in the system is replaced with
16a,l7a-i50pr0pylid8n6diOXy - 4,6 - pregnadiene-3,20-dione
nitrogen and 560 mg. of sodium hydride (as a 58% dis
persion 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
45
mixture is poured into an excess of a saturated aqueous
solution of sodium dihydrogen phosphate and the product
is extracted four times with benzene.
The organic ex
50
tracts are washed three times with water and dried over
is obtained by chromatography on silica gel.
A mixture of 580 mg. of the above 2-methoxymethyl
cue-derivative, 10 ml. of ethanol, and 56 mg. (1.2 equiva
lents) of methylhydrazine is heated under nitrogen for
three hours 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 2
N sulfuric acid, two times with 2.5 N sodium hydroxide,
sodium sulfate. Removal of the solvent gives the crude
product which is dissolved in ether and puri?ed as the
sodium salt by extraction into a 10% solution of sodium
and then two times with water.
The ethyl acetate ex
tract is then dried, concentrated, and chromatographed on
The aqueous alkaline extracts are again 55 silica gel to yield the 1?-methyl- and the 2?-methyl-6,9a
di?uoro - 2 l-tetrahydropyranyloxy-l 1B-hydroxy-16a,17e
isopropylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2~c]pyr
of sodium dihydrogen phosphate and extracted into other
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
carbonate.
acidi?ed with an excess of a saturated aqueous solution
to give 6,90: - di?uoro - 21 - tetrahydropyranyloxy-11,9
hydroxy-2-hydroxymethylene - 1601,17? - isopropylidenedi
oxy-4,6-pregnadiene-3,20-dione,
and/or the
60
?uoro - 21 - tetrahydropyranyloxy-l1B-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-2l-tet
formate
esters thereof.
rahydropyranyloxy - l1?-hydroxy-l6a,Hat-isopropylidene
Example 14
05
dioxy-20-oxo-4,G-pregnadieno-[3,2-c]pyrazole in 10 ml.
droxy-2-hydroxymethylene - 1601,1711 - 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
lute ethanol and treated with a solution of hydrazine
hydrate (60 mg, 1.2 equivalents) dissolved in 1.0 ml. of
absolute ethanol. The mixture is re?uxed in a nitrogen
atmosphere for about 3 hours and then evaporated to
dryness under reduced pressure. The residue is washed
three times with cold water and the resulting amorphous
and 5 ml. of methyl iodide, the mixture is stirred at room
temperature over night. The product is ?ltered, washed .
with methylene chloride, and the ?ltrate and washings are ?
taken to dryness. The residue may be chromatographed?
on silica gel or Florisil to yield the l?- and 2?-methyl-6,9a
di?uoro - ZI-tetrahydropyranyloxy-l1,6-hydroxy-l6a,l7a
3,072,641
17
18
isopropylidenedioxy - 20~oxo-4,6-pregnadieno-[3,2-c]pyr
azoles.
2' - benzyl - 6,9a - di?uoro-2l-tetrahydropyranyloxy-115
hydroxy - 160:,170; - propylidenedioxy-20-oxo-4,6-pregna
dieno- [3,2-c] pyrazoles.
'
In accordance with the above procedures, but using
other alkylating agents in place of methyl iodide, there
are obtained the corresponding N-alkyl-6,9a-di?uoro-21
Example 17
tetrahydropyranyloxy - 1l?-hYdl?OXY-16OL,170t-lSOpI?OPyll
denedioxy-20-oxo-4,6-pregnadieno- [3,2-c] pyrazoles.
5'65 mg. sample of 6,9ot-di?uoro~2l-tetrahydropyran
In accordance with all of the above procedures, but
starting with the Z-hydroxymethylene derivatives of the
yloxy-l l/i-hydroxy - 2 - hydroxymethylene - 16a,17a - iso
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-di?uoro-2l-tetrahydro
15
pyranyloxy - 11l3-hydroxy-2-hydroxymethylene-16a,17a
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- to dryness. The resi
due is dissolved in ether, the ether layer is treated three
the formate esters thereof, and 130 mg. (1.2 equivalents)
times with 2.5 N hydrochloric acid, then three times with
of phenylhydrazine are re?uxed under nitrogen in 8 ml.
2.5 N sodium hydroxide and ?nally With water. The
of absolute ethanol for about three hours. The reaction 20 ether layer is dried over magnesium sulfate, ?ltered and
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
ml. 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
and 10 ml. of 1.33 N sodium methoxide in methanol and 25 is diluted with ethyl acetate and washed with water. Re
left under nitrogen for 10 minutes. The alkoxide is
moval of the dried solvent leaves 2'-(p-?uorophenyl)
neutralized with acetic acid and the mixture is diluted
6,9a-di?uoro - 21 - tetrahydropyranyloxy - 1113 - hydroxy
with ethyl acetate and washed with water. Removal of
16a,Nit-isopropylidenedioxy - 20-?oxo ~ 4,6 - pregnadieno
isopropylidenedioxy - 4,6-pregnadiene~3,20-dione
and/ or
the dried solvent leaves 2'-phenyl-6,9a-di?uoro-2l-tetra
[3,2-c]pyrazo1e.
hydropyranyloxy - 11B - hydroxy-16a,17a-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
hydroxy~l6a,Hot-isopropylidenedioxy - 20- 0x0 ?4,6-preg
21 - tetrahydropyranyloxy-l1/8-hydroxy-16a,17<x-propyl
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 6,9oc-di?ll0r0
21 - tetrahydropyranyloxy-l1?-hydroxy-Z-hydroxymeth
A mixture of l'-(p-?uorophenyl)- and 2?- (p~?uoro
phenyl) - 6,90: - di?uoro - 21 - tetrahydropyranyloxy-l1,91
route: One gram of 6,9a-di?uoro-2l-tetrahydropyranyl
35 oxy - 11B - hydroxy-2-hydroxymethylene-16a,17u-isopro
pylidenedioxy-4,6,7pregnadiene-3,20v-dione, and/or the for
ylene - 16a,17<x _ isopropylidenedioxy-6-methyl-4,6~preg
mate esters thereof, in 50 ml. of dry dioxane is treated with
nadiene-3,20-dione, and/or the formate esters thereof, in
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
um hydroxide solution and then with water. The ethyl
The ethyl acetate extract is then dried and concentrated in
vacuo. The 6,9a-dil?uoro-2ltetrahydropyranyloxy-l1p
acetate extract is then dried and concentrated in vacuo.
The 6,911: - di?uoro-2l-tetrahydropyranyloxy-1l?-hy
hydroxy-Z-methoxymethylene - 16u,17ct - isopropylidene
45
droxy - 2 - methoxymethylene-16a,Hot-isopropylidene
tography on neutral alumina.
dioxy-4,6-pregnadiene-3,20-dione is obtained by chroma
tography on silica gel.
A mixture of 580 mg. of the above 2-rnethoxymethyl
ene-steriod, 10 ml. of ethanol and 130 mg. (1.2 equiva
dioxy-4,6-pregnadiene-3,20-dione is obtained by chroma
.
A mixture of 500 mg. of the Z-methoxymethylene-de
rivatives 100 ml. of ethanol, and 1 ml. of p-?uorophenyl
hydrazine is heated under nitrogen until dissolved, and
60 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 l?-(p-fluorophenyl) and 2?-(p-?uorophenyl)-6,9a-di
and then two times with water. The ethyl acetate extract
?uoro-Zl-tetrahydropyranyloxy - 11p - hydroxy-16u,17a
is then dried, concentrated, and chromatographed on silica
isopropylidenedioxy - 2O - oxo - 4,6 - pregnadieno-[3,2-c]
gel or Florisil to yield the 1'-phenyl- and 2'-phenyl-6,9a
di?uoro - 21 - tetrahydropyranyloxy-ll?-hydroxy-16a,
pyrazole.
60
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
In accordance with all of the above procedures, but
starting with the 2-hydroxymethylene derivative which is
obtained from each of the starting materials which are
listed in column 2, there are obtained the corresponding
1?-( p-?uorophenyl ) - and 2?- ( p-?uorophenyl) -derivatives.
from each of the starting materials which are listed in 65
In accordance with the above procedure, but using
each of the monosubstituted hydrazines listed ?in col
column 2, there are obtained the corresponding 1?-phenyl
and 2?-phenyl-derivatives.
umn 3', there is obtained the corresponding 1'- and
2?-substituted derivatives of the above 6,9a-di?uoro-21
In accordance with the above procedures, but using
other substituted hydrazines, for example, cyclohexylhy
drazine, p-tolylhydrazine, p-chlorophenyl-hydrazine, p
70 tetrahydropyranyloxy-lIB-hydroxy e 160:,17a - isopropyli
methoxyphenylhydrazine, or benzylhydrazine in place of
phenylhydrazine, there are obtained the corresponding
1'- and 2?-cyclohexyl-, l?- and 2'-p-tolyl-, 1'- and 2?-p
chlorophenyl-, 1'- and 2'-p-methoxyphenyl-, and 1'- and 75
denedioxy-20-ox-o-4,6-pregnadieno-[3,2-c]pyraz0le.
Example 18
The 6,911 - di?uoro - 21 -tetrahydropyranyloxy-l1py
droxy-l6a,17a-isopropylidenedioxy-20-oxo - 4,6 ~ pregna
3,072,641
19
2.0
propylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2-c]pyra
dieno-[3,2-c]pyrazole (40.0 mg.) is dissolved in 0.5? ml.
zole, there is obtained the corresponding N-a1ky1-, N
of methanol and treated with 1.82 ml. of a solution of
cycloalkyl-, N-aryl-, or N-aralkyl-6,9a-di?uoro-11?,16a,
500 mg. of p-toluenesulfonic acid monohydr-ate in 25 ml.
1711,21 - tetrahydroxy-20-oxo-4,6-pregnadieno-[3,2-c]pyr
azolc.
of methanol. The mixture is 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
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 115,21-dihydroxy-16a,l7a-isopro
pylidenedioxy - 4,6-pregnadiene-3,20-dione 21-acetate, or
with 2 ml. of water. The product is dried over magne
the 6-chloro-, 6-?uoro-, 6-methyl-, 9a-?ll0I'O-, 6-ch1oro
sium sulfate, ?ltered and the solvent removed on a steam 10 9u-?uoro-, 9a-?uoro_6-methyl- derivative thereof, in place
bath. The residue is slurried with a small amount of
of the 6,9a-di?u01'o-115,21-dihydroxy - 16a,17a-isopro
methylene chloride, and the slurry ?ltered and dried in
pylidenedioxy - 4,6-pregnadiene-3,20-dione 21 - acetate,
vacuo to give 23.0 mg. of 6,9m-di?uoro-l15,2l-dihydroxy
there is obtained the corresponding 11?,16a,17a,21-tetra
l6e,17a-isopropylidenedioxy-20 - oxo - 4,6 - pregnadieno
15
[3,2-c]pyrazole.
In accordance with the above procedure, but starting
with an N-alkyl-, N-cycloalkyl-, N-aryl-, N-acyl-, or N-ar
hydroxy - 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole or the
6-chloro-, 6-?uoro-, 6-methyl-, 9a-?uoro-, 6-chloro-9a
?uoro- or 9a-?uoro-6-methyl-derivative thereof; and the
N-alkyl-, N-cycloalkyl-, N-aryl-, N-aralkyl-derivatives, the
alkyl-6,9u?di?uoro-21-tetrahydropyranyloxy- l 1 p-hydroxy
16a,17a. - acetonides and the 21-acyloxy derivative of all
16m,17e-isopropylidenedioxy-ZO? - oxo - 4,6 - pregnadieno
of the foregoing 160:,17ct-8C6l0l1id65, 11?,16a,17a~tetra
[3,2-c]pyrazole, 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-16a,17a-isopro
pylidenedioxy-200x04,G-pregnadieno- [3 ,2-c] pyrazole.
Example 21
Example 19
To a solution of 100 mg. of 6,9a-di?uoro-l15,21-dihy
To a solution of 100 mg. of 6,9a-di?uoro-21-tetrahy
25 dropyranyloxy - 11B-hydroxy-16'1J7u - isopropylidcne
dioxy - 20-oxo?4,6-pregnadieno-[3,2-c1pyrazole in 2 ml.
of pyridine is added 2 ml. of acetic anhydride. The mix
droxy - 160:,1711 - isopropylidenedioxy-ZO-oxo-4,6-pregna
dieno[3,2-c]pyrazole in 2 ml. of pyridine is added 2 ml.
ture is allowed to stand over night at room temperature.
of acetic anhydride. ?The mixture is allowed to stand
It is taken to dryness in vacuo to afford the N-acetyl-6,9a
overnight at room temperature. A mixture of ice and 30 di?uoro - 21-tetrahydropyranyloxy-11,8-hydroxy-16a,17a
water is then added. After standing for about 30 min
isopropylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c] pyr~
utes, the product is extracted with ethyl acetate. The
azole.
ethyl acetate extract is washed successively with water,
Without further puri?cation, this substance is dissolved
ice-cold 1 N sulfuric acid, saturated aqueous sodium bi
in 5 ml. of methanol containing 20 mg. of p-toluenesul
35
carbonate and water (until the aqueous layer is neutral).
fonic acid. The mixture is kept at room temperature for
The ethyl acetate solution is dried with anhydrous sodium
4 hours. The solvent is removed in vacuo, ethyl acetate
sulfate. The solvent is then distilled at about 40� C. in
is added and the organic layer is washed several times
vacuo to afford the N-acetyl-6,9a-di?uoro-115,21-dihy
with dilute sodium bicarbonate. The dried solvent is
droxy a 16a,17a - isopropylidenedioxy - 20 - oxo-4,6-preg~
removed to yield after chromatography on neutral alu
nadieno-[3,2-c]pyrazole 2l-acetate which is isolated by
mina N-acetyl - 6,9a - di?uoro-11,3,21-dihydroxy-16bt,l7a
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 - 11B,
azolc.
21 - dihydroxy-l6a,17a-isopropylidenedioxy-20-oxo-4,6
pregnadieno-[3,2-c]pyrazole 21-acetate in 60 ml. of 80%
(v./v.) acetic acid is re?uxed for 1.5 hours. This solu 45
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.
This residue is dissolved in 150 ml. of acetone con 50
taining 2 ml. of 70% perchloric acid. After thirty min
Example 22
To a solution of 85 mg. of N-acetyl?6,9a~di?uoro~115,
21 - dihydroxy-16a,17a-isopropylidenedioxy-20-oxo-4,6
pregnadieno -[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 a period of approximately 1
hour. Water is then added to the reaction mixture and
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-acetyl-6,9a-di?uoro-l1,3,21-dihydroxy
1611,1701 - isopropylidenedioxy - 20 ~ oxo-4,6-pregnadieno
moved to yield, after chromatography on neutral alumina,
[3,2-c1pyrazole 21-mesylate.
6,90: - di?uoro-11B,_21-dihydroxy-16a,17a-isopropylidene
In accordance with the above procedure, but stanting
with the N-a1kyl-, N-cycloalkyl-, N-aryl-, or N-aralkyl
dioxy-20-oxo-4,?-pregnadieno- [3 ,2-c] pyrazole 2 1 -acetate.
In accordance with the above procedures but using an
equivalent quantity of another .acylating agent in place
60 6m,9a _ di?uoro-l15,21-dihydroxy-l6a,l7a.isopropylidene
dioxy-20-oxo-4,6-pregnadiene-[3,2-c]pyrazlole, in place of
of acetic anhydride, there is obtained the corresponding
acyl derivatives.
Example 20
6,911 - di?uoro - 1113,21 - dihydroxy - 16a,17u - isopro
pylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c]pyrazole
the N-acyl-derivative there is obtained the corresponding
2l-mesylate.
Example 23
65
To 180 mg. of N-acetyl-6,9a-di?uoro-11?,21-dihydroxy
16a,17a - 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 6,9a-di 70
is heated at re?ux temperature for a period of approxi- ;
?uoro - 115,16a,171:,21-tetrahydroxy-20-oxo'4,6-pregna
mately 1 hour, and the reaction solution is cooled to room
dieno - [3,2-clpyrazole is collected by ?ltration and dried.
temperature and diluted with water. Extraction with
In accordance with the above procedure, but starting
with the corresponding N-alkyl-, N-cycloalkyl-, N?aryl-,
or N-aralkyl-, 6,9u-di?uoro-115,21-dihydroxy-16e,17a-iso
ethyl acetate followed by drying and removal of the
solvent affords N-acetyl-6,9a-di?uoro-ll?-hydroxy - 21
3,072,641
21
22
ture of 1701,21-epoxy-1 l/s-hydroxy-1601-methyl-20-oxo-2'
iodo _ 1601,1701 - isopropylidenedioxy-20-oxo-4,6-pregna
dieno-[3,2-c]pyrazole.
'
pheneyl-4-pregneno - [3,2-c]pyrazole and 21-?u0ro-11?,
Example 24
1701 ~ dihydroxy - 1601 - methyl - 20 - oxo - 2' - phenyl - 4
pregneno-[3,2~c]pyrazole, which compounds are sepa
The N-acetyl-6,901-di?uoro-11/3-hydroxy-21-iodo-1601,
rated by partition chromatography, or by chromatography
1701 - isopropylidenedioxy ? 20 - oxo - 4,6 - pregnadieno
on silica gel.
[3,2-c]pyrazole (100 mg.) is dissolved in a mixture of
Example 27
5 ml. of water and 5 ml. of ethanol. To the resulting sus
N - acetyl - 6,901 - di?uoro - '1 15 - hydroxy - 1601,1701
pension is added 500 mg. of sodium bisul?te, and the mix
ture is heated under re?ux for a period of about 1 'hour. 10 isopropylidenedioxy - 2O - oxo - 4,6 - pregnadieno-[32c]
?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 methanolvis removed in vacuo and the
acetate in vacuo, the residue is left overnight under nitro
product is extracted with ethyl acetate and washed with
gen in 5 ml. of methanol and 1 ml. of one molar sodium
water. Removal of the dried ethyl acetate affords 6,901
methoxide in methanol. The solvent is then removed in
di?uoro - 11B - hydroxy - 1601,1701 - isopropylidenedioxy
vacuo, ethyl acetate is added and, after a water wash, the
20-loxo-4,6-pregnadieno-[3,2-c]pyrazole.
solvent is dried and removed. Chromatography of the
residue on neutral alumina affords some 6,901-di?uoro
Example 28
1118 - hydroxy - 1601,1701 - isopropylidenedioxy- 20 - oxo-'
4,6-pregnadieno-[3,2-c]pyrazole.
I
6,901 - di?uoro - ll? - hydroxy ?- 1601,1701 - ?isopropyl
.20
Example 25
idenedioxy - 20 - oxo - 4,6 - pregnadieno - [3,2-c1pyrazole
(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. After 18 hours, the
Silver dihydrogen phosphate is prepared by the reac
tion of 32 g. of trisilver phosphate with 10 ml. of 100%
phosphoric acid with thorough mixing in a one-liter 3 25 6,901 - di?uoro - l1,8,1601,l701 - trihydroxy - 20 - oxo - 4,6
pregnadieno-[3,2-c]pyrazole is collected? by ?ltration and
necked round-bottomed ?ask. The silver dihydrogen
phosphate is washed with tWo portions of diethyl ether,
In accordance with all the procedures givenlin 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
to cover the silver dihydrogen phosphate, and the mixture 30 Example 21 with the 11,8-hydroxy-2l-tetrahydropyranyl
dried.
.
.
oxy - 1601,1701 - isopropylidenedioxy - 20 - oxo - 4 f preg
is heated to re?ux temperature. At this point 20 g. of
neno-[3,2-c]pyrazole or the 601-chloro-, 601-?uoro-, 601
N - acetyl - 6,901 - di?uoro - 11p - hydroxy - 21 - iodo
methyl-, 901-?uoro-, 601,901-di?uoro-, 601-chloro-91z-?uoro�,
1601,1701 - isopropylidenedioxy - 20,- oxo - 4,6 ~ pregna
dieno-[3,2-c]pyrazole is added and the mixture is re
601-methyl-901-?uoro-derivative thereof; or the ll?-hy
?uxed in a nitrogen atmosphere with stirring for 75 min
droxy - 21 - tetrahydropyranyloxy - 1601,1701 - isopropyl
utes. The reaction mixture is then cooled over a period
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
35
idenedioxy-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole or the
6-chloro-, 6-?uoro-, 6-methyl-, 901-?uor0-, 6-7Chl0I'O-9o1
?uoro-, 901-?uoro-601-methyl-derivative thereof, there is
obtained the corresponding 601-chloro-, 601-?uoro-, 901'-?u
sulting aqueous suspension is adjusted to 6.4 by the addi v40 oro-, 601,901-di?uoro-, 601-chloro-901-?uoro-, 601-methyl- or
901 - ?uoro - 601 - methyl - l'l,8,1601,1701 - trihydroxy P 20
tion of 23 ml. of saturated aqueous sodium carbonate
oxo-4-pregneno-[3,2-c]pyrazole; or the 6-chloro-, 6'-?u
solution. A precipitate is formed and separated by ?ltra
oro-, 6-methyl-, 901-?uoro-6-chloro-9a-?uoro or 901-?uoro
tion. The precipitate is washed with water until no
6 - methyl - 11,8,1601,1701 - trihydroxy - 20 - oxo - 4,6
ultraviolet absorbing material is detected in the wash
pregnadieno-[3,2-c]pyrazole, and the 1601,1701-acetonides
Water. The ?ltrate and wash water are combined and
45. of all of the foregoing compounds.
freeze dried to separate a solid material from the water.
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 11B - hydroxy - 21 - tetrahydropyranyloxy - 1601,1701 - iso
propylidenedioxy-20-oxo-4-pregneno- [3 ,2-c] pyrazole or
umn containing 60 g. of a cation exchange resin
the 601-chlor0-, 601-?uoro-, 601-methyl-, 9014?uoro-, 601,901
(?IR-120?) in its hydrogen form. The column is washed
with methanol until the washings contain no ultraviolet
di?uoro-, 601-chloro-9'01-?uoro-, 901-?uoro-601-methyl-de
absorbing material. The combined eluate and washings
rivative thereof; or the N-alkyl-, N-cycloalkyL, N-aryl- or
are concentrated to a volume of 15 ml., and 150 ml. of 55
ether are added. The precipitate which forms is recov
N-aralkyl - 11,6 - hydroxy - 21 - tetrahydropyranyl0xy-l601,
ered by ?ltration, washed with ether, and dried for about
16 hours in a desiccator, to give N-acetyl-6,901-di?uoro
?uoro-, 6-chloro-901-?uoro-, 901-?uoro-6-methyl, deriva
tives thereof, there is obtained the corresponding 601
11B - hydroxy - 1601,1701 - isopropylidenedioxy - 20 - oxo
4,6-pregnadieno-[3,2-c] pyrazole 21-dihydrogen phosphate.
The mono- and the dialkali metal salts of the 21-dihy
drogen phosphate compound are obtained by neutralizing
the 21-dihydrogen phosphate ester with an alkali metal
methoxide.
Example 26
To a solution of 62 mg. of N-acetyl-6,901-di?uoro-11,6,
1701 - isopropylidenedioxy - 20 - oxo - 4,6 - pregnadieno~
[3,2-c]pyrazole or the 6-chloro-, 6~?uoro'-, 6-methyl-, 901
60
chloro-, 601-?uoro-, 601-methyl-, 901-?uoro-, 601,901-1di?uoro-,
601-chloro-901-?uoro~, or 901-?uoro-601-methyl-, N-alkyl-,
N-cycloalkyl-, N-aryl-, or N-aralkyl-, 11,8,1601,1701-trihy
droxy-20-oxo-4-pregneno-[3,2-c]pyrazole; or the 6-chl0
ro-, 6-?uoro-, 601-chloro-901-?uor0-, or 901-?uoro-6-methyl
N-alkyl-, N-cycloalkyl-, N-aryl- or N-aralkyl-l 119,1601,1701
trihydroxy-20-oxo-4,6~pregnadieno-[3,2-c]pyrazole, and
the 1601,1701-acetonides of all of the foregoing compounds.
21 - dihydroxy - 1611,1701 - isopropylidenedioxy - 20 - oxo
4-pregneno-[3,2-c]pyrazole 2l-mesylate in 1 ml. of freshly
distilled anhydrous dimethylformamide is added enough
Example 29
The 6,901 - di?uoro - 21 - tetrahydropyranyloxy - 1119
anhydrous potassium ?uoride to assure a saturated solu 70 hydroxy - 1601,1701 - 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. Themixture is
3,072,641
23
24
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 oli
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
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 ZI-tetrahydro
solvent removed on a steam bath. The residue is slurried
pyranyloxy - 115 - hydroxy - l6u,17a - 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
60�,9ot - di?uoro - 113,21 - dihydroxy - 16a,17a - isopro
The 2 l-tetrahydropyranyloxy-l l?-hydroxy-l6u,l7a-iso
pylidenedioxy - 20 - oxo - 2? - phenyl - 4,6 - pregnadiene
propylidenedioxy - 6 - methyl - 4,6 - pregnadiene ~ 3,20
[3,2-c1pyrazole.
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.
To a solution of 85 mg. of 6,9a-di?uoro-l1,8,21-dihy
droxy - 1641,1741 - isopropylidenedioxy - 2O - oxo - 2?
phenyl-4,6-pregnadieno-[3,2-c]pyrazole in 0.5 ml. of pyr 15 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
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
recovered by extraction into ethyl acetate which is washed
with water, dried and removed to give 6,9a-di?uoro-11/3,
into an excess of a saturated aqueous solution of sodium
dihydrogen phosphate and the product is extracted four
times with benzene. The organic extracts are washed
three times with water and dried over sodium sulfate.
21 - dihydroxy - 16�,17a - isopropylidenedioxy - 20 - 0x0
2?-pheny1 - 4,6 - pregnadiene - [3,2 - c]pyrazole
Removal of the solvent gives the crude product which is
21
25 dissolved in ether and puri?ed as the sodium salt by
mesylate.
To 180 mg. of 6,9u-di?uor0-11,3,2l-dihydroxy-16a,17a
extraction into a 10% solution of sodium carbonate. The
isopropylidenedioxy - 20 - oxo - 2' . phenyl - 4,6 - preg
aqueous alkaline extracts are again acidi?ed with an ex
cess of a saturated aqueous solution of sodium dihydrogen
nadieno-[3,2-c]pyrazole 21-mesylate dissolved in .10 ml.
phosphate and extracted into ether and into chloroform.
of acetone is added 300 mg. of sodium iodide. The re
sulting mixture is heated at re?ux temperature for a period 30 The combined organic extracts are dried over sodium sul
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 - 11B - hydroxy - 2 - hydroxymethylene - 16a,
17a - isopropylidenedioxy - 6 - methyl - 4,6 - pregnadiene
traction with ethyl acetate followed by drying and re
moval of the solvent affords 6,9a-di?uoro-llp-hydroxy
35
21 - iodo - 1611,1711; - isopropylidenedioxy - 2? - phenyl - 20
oxo-4,6-pregnadieno- [ 3 ,2-c1PYrazole.
The
3,20-dione, and/or the formate esters thereof.
A mixture of 565 mg. of 2l-tetrahydropyranyloxy-l1,8
hydroxy - 2 - hydroxymethylene - l6tz,l7a - isopropyli
denedioxy - 6 - methyl - 4,6 - pregnadiene - 3,20 - dione
6,90: _ di?uoro - 11p - hydroxy - 21 - iodo - 16a,
and/ or the formate esters thereof, and 130 mg. (1.2 equiv
alents) of phenylhydrazine are refluxed under nitrogen
a mixture of 5 ml. of water and 5 ml. of ethanol. To 40 in 8 ml. of absolute ethanol for about three hours. The
reaction mixture is taken to dryness. Water is added
the resulting suspension is added 500 mg. of sodium
and the product is ?ltered to give an amorphous solid,
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
m1. 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-21-tetrahydro
and, after a water wash, the solvent is dried and removed.
Chromatography of the residue on neutral alumina affords 50 pyranyloxy - 11/3 _ hydroxy - 6 - methyl - l6a,17a - pro
17oz - isopropylidenedioxy - 20 - oxo - 2' - phenyl - 4,6
pregnadieno-[3,2-c]pyrazole (100 mg.) is dissolved in
pylidenedioxy-ZO-oxo?4,6-pregnadieno- [3 20] pyrazole.
6,9a - di?uoro - 11,8 - hydroxy - l6a,l7a - isopropylidene
dioxy-20-oxo-2?-phenyl-4,6-pregnadieno-[3,2-c]pyrazole.
A mixture of the l'-phenyl- and 2?-phenyl-21-tetrahy
6,90; - di?uoro - 11p - hydroxy - 16�,17u - isopropyli
dropyranyloxy - 11B - hydroxy _ 6 - methyl - 16a,l7ct - pro~
denedioxy - 20 - oxo - 2? - phenyl - 4,6 - pregnadieno
pylidenedioxy-20-oxo-4,6-pregnadieno-[3,2-c]pyrazole is
[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 2l-tetra
hydropyranyloxy - ll? - hydroxy - 2 - hydroxymethylene
60% formic acid. After twenty minutes, the solution is
cooled and then poured into ice and water.
After 18
hours, the 6,9u-difluoro-11,8,16a,l7u-trihydroxy-20-oxo-2'
phenyl-4,6-pregnadieno-[3,2-c]pyrazole is collected by ?l
tration and dried.
16a,17a _ 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.
Example 30
115,21 - dihydroxy - 160:,1711 - isopropylidenedioxy-6
methyl-4,6-pregnadiene-3,20-dione 21-acetate (1.0 g.) is 65
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
vacuo.
The 21 - tetrahydropyranyloxy - 11,6 - hydroxy
2 - methoxymethylene - 1641,1711 - isopropylidenedioxy - 6.
refluxed 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 2-meth0xymethyl
is extracted with ethyl acetate and water. Removal of 70
the ethyl acetate affords crystals of 1118,21-dihydroxy-l6a,
17a - isopropylidenedioxy - 6 - methyl - 4,6 - pregnadiene
3,20-dione.
11,8,21 - dihydroxy - 1611,1711: - isopropylidenedioxy-6
ethyl - 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
3,072,641
25
26
2 N sulfuric acid, two times with 2.5 N sodium hydroxide,
and then two times with water.
sion is added ?500 mg. of sodium bisul?te, and the mixture
The ethyl acetate extract
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 - 115 - hydroxy - 6 - methyl - 16a,
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 - 115 - hy
vacuo, ethyl acetate is added and, after a water wash,
droxy - l6u,17o� - 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 a?ords some 115-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
115-hydroxy-16a,Not-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 01f 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 1l5,16a,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
is then dried, concentrated, and chromatographed on silica
gel or Florisil to yield the 1'-phenyl- and 2'-phenyl-21
a steam bath. The residue is slurried with a small amount 20
[3,2-c]pyrazole is collected by ?ltration and dried.
of methylene chloride, and the slurry is ?ltered and dried
Example 31
in vacuo to give 23.0 mg. of 6-methyl-115,21-dihydroxy
16a,17u - isopropylidenedioxy - 20 - oxo - 4,6 - pregnadi
A suspension of 610 mg. of 20-ethylenedioxy-9a-?uoro
eno-[3,2-c]pyrazole.
The
16cc,170t,2l - trihydroxy-4-pregnene-3,1l-dione 21-acetate
115,21 - dihydroxy - l6a,17oc - 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
eno-[3,2-c]pyrazole is treated with a mixtrue of 1.5 ml.
suspension of about 54% sodium hydride in mineral oil
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
115,21 - dihydroxy - 16a,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
are separated and the aqueous phase is extracted with
ing, the compound is dissolved in methylene chloride, a
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 l15,21-dihydroxy-16a,
bicarbonate to remove impurities. The product is then
17oz - 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
hydrochloride is recrystallized.
'
115,21 - dihydroxy - 1611,17? - isopropylidenedioxy - 6
methyl - 20 - oxo - 2? - phenyl - 4,6 - pregnadieno-[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 and water. After 18 hours the
11,8,l6oz,l7ot,2l - tetrahydroxy - 6 - methyl - 20 - oxo - 2'
ide.
Acidi?cation of the alkaline extracts with dilute
hydrochloric acid gives a product which is taken up in
40
methylene chloride. The solution is ?ltered and evaporat
ed to dryness to give 20-ethylenedioxy-9a-?uoro-16a,17a,
21-trih\ydroxy-2-hydroxymethylene-4-pregnene-3,1 l-dione,
and/or formate esters thereof.
45
phenyl-4,6-pregnadieno-[3,2-c]pyrazole is collected by ?l
A 25 mg. aliquot of 20
ethylenedioxy-9q-?uoro-16a,17a,21-trihydroxy-2-hydroxy
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
tration and dried.
To a solution of 85 mg. of l15,21-dihydroxy-16a,l7ot
0� C., is added 0.03 ml. of methane sulfonyl chloride.
The resulting mixture is allowed to stand at a temperature
residue is extracted with hot methylene chloride. The
methylene chloride solution is ?ltered to remove insol
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 l15,21-dihydroxy-16u,17a-isopropyl
ethyl acetate and washed with water. Removal ofthe
of approximately 0� C. for a period of approximately 1
idenedioxy-6-methyl-20-oxo-2?-phenyl-4,6 - pregnadieno -
[3,2-c]pyrazole 21-mesylate.
~
To 180 mg. of 115,21-dihydroxy-16a,17u-isopropy1
dried solvent leaves 20-ethylenedioxy-9a-?uoro-16a,17a,
60
21-trihydroxy~l1-oxo-4-pregneno-[3,2-c]pyrazole.
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 2l-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,ymost 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
9a-?uoro-l 15,16a,17u,21-tetrahydroxy-4-pregneno-[3,2-c]
of the solvent affords 115-hydroxy-21-iodo-16a,17a
pyrazole.
1
isopropylidenedioxy-6-methyl-20-oxo-2'-phenyl-4,6 - preg
70
nadieno-[3,2-c]pyrazole.
A mixture of 2.9 grams of 20~ethylenedioxy-9a-?uoro
idenedioxy-6-methyl~20-oxo-2?-phenyl - 4,6 - pregnadieno
The 115-hydroxy-21-iodo-16u,Hut-isopropylidenedioxy
115,16a,17u,21-tetrahydroxy-4-pregneno-[3,2-c1pyrazole,
6-methyl - 20 - oxo-2?-phenyl - 4,6 - pregnadieno-[3,2-c1
100 ml. of methanol, and 6 ml. of a solution prepared by
diluting 8 ml. of sulfuric acid to 100ml. 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
3,072,641
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-11[3,l6cz,17w21
tetrahydroxy-ZO-oxo-4-pregneno- [3 ,2-c] pyrazole.
The 9a-?UO1'O-l l,B,16oz,l70:,21-128?tl?21hYd1'0XY-2O-0X0 - 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
trated hydrochloric acid has been added and then letting
28
removed to yield after chromatography on neutral alu
mina N-acetyl-9a-?uoro-d1B-21-dihydroxy - l6a,l7a - iso
propylidenedioxy-ZO-oxo-4-pregneno- [3 ,2-c] pyrazole.
To a solution of 85 mg. of N-acetyl-9a-?uoro-1l?-Zl
dihydroxy - l6oc,l7a - 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 a period of approximately 1 hour.
Water is then added to the reaction mixture and the pre
stand at room temperature for 24 hours. The mixture is 10
then poured into a dilute sodium bicarbonate solution and
extracted with ethyl acetate. The extracts are washed,
dried over magnesium sulfate and taken to dryness to
give the 9a-?uoro-llBil-dihydroxy-16u,17m-isopropyli
denedioxy-20-oxo-4-pregneno-[3,2-c]pyrazole.
The
N - acetyl - 9a - ?uoro - 115,21 - dihydroxy
cipitate which forms is recovered by extraction into ethyl
acetate which is washed with water, and dried and re
moved to give N-acetyl-9u-?uoro-l1,8,2l-dihydroxy-l6a,
l7a-isopropylidenedioxy-20-oxo-4-pregneno ? [3,2-c]pyra
15 zone 2l-mesylate.
To 180 mg. of N-acetyl-9tza?uoro-11?,21-dihydroxy-l6a,
17a-isopropylidenedioxy-20-oxo-4-pregneno - [3,2-c]pyra~
16a,17u - isopropylidenedioxy - 20 - oxo - 4 - pregneno
zole 2l-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
[3,2-c]pyrazole by stirring 250 mg. of the steroid in 15 20 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
[3,2-c1pyrazole 21-acetate is prepared from the 9a-?LlOI?O
11B,16a,17a,2l - tetrahydroxy - 20 - oxo - 4 - pregneno
and the acetone is removed in vacuo.
The residue is
affords N~acetyl-9a-?uoro-1l?-hydroxy-Zl籭odo-16a,17a
?ltered off, air dried and then treated with 2 ml. of acetic
[3 ,2-c] pyrazole.
anhydride and 2 ml. of pyridine for eighteen hours at 25 isopropylidenedioxy-20-oxo-4-pregnenoThe N - acetyl-9a-?uoro-1l?-hydroxy-Zl-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
from a mixture of petroleum ether and ether to yield
the N-acetyl-9a-?uoro-1113,21-dihydroxy-l6a,17a-isopro
pylidenedioxy-ZO-oxo-4-pregneno-[3,2-c]pyrazole 21-ace
tate.
A solution of 5.73 g. of the N-acetyl-9a-?uoro-l13,21
dihydroxy - 160:,l7ct - isopropylidenedioxy - 2O - oxo - 4
(100 mg.) is dissolved in a mixture of 5 ml. of water and
5 ml. of ethanol. To the resulting suspension is added
30 500 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 extracted with
ethyl acetate. After removal of the ethyl acetate in vacuo,
the residue is left overnight under nitrogen in 5 ml. of
pregneno-[3,2-c]pyrazo1e 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-l1?-hydroxy-16a,
tion, dried, and evaporated to dryness in vacuo. The 40 l7u-isopropylidenedioxy-20-oxo-4-pregneno - [3,2-c]pyra
residue is dissolved in 150 ml. of acetone containing 2
zole.
ml. of 70% perchloric acid. After thirty minutes, aque
ous sodium bicarbonate is added and the acetone is re
N-acetyl - 9a - ?uoro-llB-hydroxyd6a,l7a-isopropyli
denedioxy-20-oxo-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 removedv 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
9oz - ?uoro - 11?,21 - dihydroxy - 16a,l7a - isopropylidene
with ethyl acetate and washed with water. Removal of
dioxy-20-oxo-4-pregneno- [ 3 ,2-c] pyrazole 2 l -acetate.
9a-?uoro - 1118,21 - dihydroxy - l6tx,17a - isopropyl
idenedioxy-20-oxo-4-pregneno-[3,2-c1pyrazole (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 9rx-?uoro-ll?~hydroxy-16a,
l7a-isopropylidenedioxy - 20 - oxo-4-pregneno-[3,2-c]pyr
50 azole.
9a-?uoro - 11p - hydroxy-l6a,l7a-isopropylidenedioxy
20~oxo-4~pregneno-[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-?l10r0-11B,l6at,l7a
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 9m
by ?ltration and dried.
solution is concentrated in vacuo.
The residue is tri
?uoro - 11B - hydroxy - 21 - terahydropyranyloxy - 16oz,
l7a-isopropylidenedioxy-20-oxo-4-pregneno-[3,2 - c]pyra
The ZO-ethylenedioxy - l6a,l7oc,21 - trihydroxy-4-preg
nene-3,1l-dione 21-acetate compounds used as starting
zole.
60 materials for compound 1 of Flow Sheet A are prepared,
To a solution of 100 mg. of 9a-?u0ro-2l-tetrahydro
starting with the known 11B,17u,21-trihydroxy-4-preg
pyranyloxy-llB-hydroxy - 16ot,l7ot - isopropylidenedioxy
nene-3,20-dione, in accordance with the following pro
20-oxo-4-pregneno-[3,2-c1pyrazole in 2 ml. of pyridine is
cedures which are particularly described only with refer
added 2 ml. of acetic anhydride. The mixture is allowed
ence to 6a,9a-di?uoro-1l?,1711,21-trihydroxy-4-pregnene
to stand over night at room temperature. It is taken to 65 3,20-dione, but are generally applicable to all of the start
ing materials defined by compound 1.
dryness in vacuo to afford the N-acetyl-9a<?uoro~2l-tetra
A mixture of 500 mg. of 6a,9a~di?uoro-l1B,17a,2l-tri
hydropyranyloxy-llB-hydroxy - 1604,1704 - isopropylidene
dioxy-20-oxo-4-pregneno-[3,2-c1pyrazole.
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
3,072,641
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 11B,16oz,170:,21-t6t1?3hYClI?0XY-6rx
methyl-4~pregnene-3,20-dione and the known 9a-fluoro
l1,8,16a,17ot,21 - tetrahydroxy-6a-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
dione are converted into the corresponding 115,21-dihy
droxy - 6 -.methyl-1611,7a-isopropylidenedioxy-4,6-pregna
diene-3,20-dione Z-acetate and the 9a~?uoro derivative
thereof.
ethyl acetate is removed in vacuo. ? Chromatography on
basic alumina affords 3�,20-bis(ethylenedioxy)-6a,9a-di
The 6-chloro-, or the 6-chloro-9a-?uoro-111?,2l-dihy
?uoro~l1B,170�,2l-trihydroxy-S-pregnene 21-acetate.
droxy - 16ot,l7a - isopropylidenedioxy-4,6-pregnadiene-3,
A solution of 400 mg. of 3�,20-bis(ethylenedioxy)-6a, 10 20-dione 21-acetate is prepared from the 115,21-dihy
91x - di?uoro-l 1 p,17a,21-trihydroxy-5-pregnene ZI-acetate
droxy - 16,170L - isopropylidenedioxy-4,6-pregnadiene-3,
in 4 ml. of pyridine is added to the complex formed by
20-dione ZI-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 9a-?uoro - 11,8,21 - dihydroxy-16a,17a-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
32,20 - bis(ethylenedioxy) - 60�,9a - di?uoro-17a,21-dihy
6a,7a-epoxy - 9a - ?uoro-l1,6,21-dihydroxy-16a,17u-iso
droxy-S-pregnene-ll-one 21-acetate.
propylidenedioxy-4-pregnene-3,20-dione 21-acetate.
Thionyl chloride (0.45 ml.) is added dropwise to a
The 6a,7u-epoxy-9a-?uoro-11B,21-dihydroxy-16u,17a
magnetically stirred solution of 850 mg. of 35,20-bis 25 isopropylidenedioxy-4-pregnene-2,20-dione 21-acetate (0.5
(ethylenedioxy) - 6a,9ot-difluoro-17a,21-dihydroxy-5-preg
g.) is added to a 20 ml. of anhydrous chloroform which
nene-ll-one 21-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 affords the 21-hydroxy-3�,20-bis(ethyl
ml. of acetone and 0.2 ml. of 70% perchloric acid. Then
enedioxy)-6ot,9a-di?uoro-5,l6-pregnadiene-l l-one 21-ace
aqueous sodium bicarbonate is added and most of the ace
tone is removed in vacuo. The crude product is ex
tate.
A solution of 266 mg. of osmium tetroxide in 5 ml. of 35 tracted into ethyl acetate and chromatographed on neutral
alumina to afford 6-chloro-9a-?uoro-l1?,21-dihydroxy
benzene is added dropwise to a stirred solution of 465
mg. of 21-hydroxy-3�,20-bis(ethylenedioxy)-6a,9a-di?u
16a,17a - isopropylidenedioxy-4,6-pregnadiene-3,20I-dione
oro-5-16-pregnadiene-1l-one 21-acetate in 10 ml. of ben
zene and 0.3 ml. of pyridine. After one hour, there is
21-acetate.
The 6-?uoro- and the 6,9a-difluoro-1l?,21-dihydroxy
added 12 ml. of methanol and then a solution of 1.3 g. 40 16a,17a - isopropylidenedioxy-4,6-pregnadiene-3,20-dione
of sodium sul?te and 1.3 g. of potassium bicarbonate in
Zl-acetate are prepared from 6a,7a-epoxy-l1;8,21-dihy
18 ml. of Water. This mixture is stirred vigorously for
droxy - l6ot,l7oc - isopropylidenedioxy - 4 - pregnene-3,20
three hours and then ?ltered. The red-brown solid which
is collected is extracted exhaustively with hot ethyl ace
dione 21-acetate and the 9a-?uoro derivative according
to the following procedures:
tate. The combined organic layers are washed with 45
water and taken to dryness. Crystallization from meth
The 6a,7a-epoxy-9<x-?uoro-11?,21-dihydroxy-16u,17ot
isopropylidenedioxy-4-pregnene-3,ZO-dione ZI-acetate (2.0
anol affords 32,20-bis(ethylenedioxy)-6a,9ot-di?uoro-16a,
17a,21-trihydroxy-5-pregnene-1l-one 21-acetate.
A solution of 150 mg. of 3�,20-bis(ethylenedioxy)-6a,
9e-difluoro-16a,17:1,2l-trihydroxy-S-pregnene-1l-one 21
g.) is dissolved in 150 ml. of anhydrous chloroform and
cooled at 70� C. To this solution is added slowly with
stirring a mixture of 4.5 ml. of anhydrous tetrahydro
50 furan and 3.2 g. of_dry hydrogen ?uoride.
The reaction
acetate in 3 ml. of glacial acetic acid is heated on the
mixture is allowed to come to room temperature, and
steam bath for twenty minutes. It is then poured into ice
after 20 hours it is poured into iced potassium carbonate
and water and extracted into chloroform. The organic
solution. Ethyl acetate is added, the organic layer is
layer is washed with aqueous sodium bicarbonate until
separated, washed with water, dried and removed to yield
all of the acid has been removed. Evaporation of the 55 6?~fluoro - 7,11,8,21 - trihydroxy-16a,Hot-isopropylidene
dried chloroform layer leaves a residue which is chro
dioxy-4-pregnene-3,20-dione 21-acetate.
matographed over basic alumina to yield a fraction which
The 6B-?uoro-7a,1 113,21-trihydroxy-16a,Not-isopropyli
after crystallization from methanol is 20-ethylenedioxy
6a,9a-di?uoro - 16ot,17or,21 - trihydroxy-4-pregnene-3,11
dione ZI-acetate (compound 1 of Flow Sheet A).
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
temperature, this solution is slowly poured into a stirred
4~pregnene- (and 4,6-pregnadiene) 3,20-dione 21-acetate
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
The 11 16,21-dihydroxy - 16a,17a - isopropylidenedioxy
The known 9ot-?llO1?O-1l?,160c,170:,2l-t8t1?3hYd1?0XY-4
bicarbonate is then added and most of the acetone is re
pregnene-3,20-dione is converted into the 9u-?uoro-11B,
moved in vacuo.
Zl-dihydroxy - 16a,l7a - isopropylidenedioxy-4,6-pregna
ethyl acetate and after chromatography on neutral alu
diene-3,20-dione ZI-acetate by reaction ?rst with acetone
mina affords 6,9a-di?uoro-11,8,21-dihydroxy-16a,17u-iso
propylidenedioxy-4,6-pregnadiene-3,20-di0ne 2l-acetate.
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 21-acetate and ?nally with chloranil
to afford the 9tx-?uoro-11?,21-dihydroxy~16a,l7a-isopro
pylidene-dioxy-4,6-pregnadiene-3,20-dione 21-acetate.
The crude product is extracted into '
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.
3,072,641
32
31
4. A compound selected from the group consisting of
We claim:
1. A compound selected from the group consisting of
compounds having structural formulas A and B
6 - ?uoro - 11?,16a,17a,21 - tetrahydroxy - 20 - oxo - 2'
phenyl-4,6-pregnadieno-[3,2-c]pyrazole and the 16a,17a
acetonide thereof.
5. A compound selected from the group consisting of
H R?
is
6 - ?uoro - 11?,16u,17a,21 - tetrahydroxy - 20 - oxo - 2'
(p-?uorophenyl)-4,6-pregnadieno-[3,2-c1pyrazole and the
16a,17ot-8.C?t011id? thereof.
6. A compound selected from the group consisting of
10
6 - chloro - 11B,16m,17a,21 - tetrahydroxy - 20 - oxo - 4,6
pregnadieno-[3,Z-c]pyrazole and the l6a,l7a-acetonide
thereof.
7. A compound selected from the group consisting of
6 - chloro - l1,8,16u,17a,21 - tetrahydroxy - 20 - oxo - 2'
15
phenyl-4,6-pregnadieno-[3,2-c]pyrazole and the 16a,l7a~
acetonide thereof.
8. A compound selected from the group consisting of
wherein R? is a member of the group consisting of hy
droxy, lower hydrocarbon carboxylic acyloxy, tetrahydro
pyranyloxy, ?uoro, iodo, the methylsulfonyloxy radical,
6 - chloro - 11B,16u,l7a,21 - tetrahydroxy - 20 - oxo - 2?
(p-?uorophenyl)-4,6-pregnadieno-[3,2?c]pyrazole and the
the dihydrogen phosphate and the alkali metal salts of 20 160:,17cc-3C6t011ld8 thereof.
said dihydrogen phosphate, R is a member of the group
9. A compound selected from the group consisting of
consisting of hydrogen, lower alkyl, lower aralkyl, lower
11B,16o�,17m,21 - tetrahydroxy - 6 - methyl - 20 - oxo - 4,6
cycloalkyl, lower hydrocarbon aryl, halophenyl, lower
alkoxy phenyl, nitrophenyl, pyridyl, pyridyloxide and
pregnadieno-[3,2-c1pyrazole and the 16u,l7u-acetonide
thereof.
pyrimidyl, X is a member of the group consisting of 25
hydrogen and ?uoro, and Y is a member of the group
consisting of hydrogen, chloro, ?uoro and methyl; and
pharmacologically acceptable salts of the foregoing com
10. A compound selected from the group consisting of
11,3,161x,l7a,21 - tetrahydroxy - 6 -methyl - 20 ~ oxo - 2?
phenyl-4,6-pregnadieno-[3,2-c]pyrazole and the 1612,1711:
pounds.
acetonide thereof.
11. A compound selected from the group consisting of
2. A compound selected from the group consisting of
compounds having structures A and B
(p-?uorophenyl)-4,6-pregnadieno-[3,2-c1pyrazole and the
11?,16<x,l7a,2l - tetrahydroxy - 6 -methyl - 20 - oxo - 2'
1605,1711-3C6l0l1ld6 thereof.
12. A compound selected from the group consisting of
H R?
2.2.
6,9u _ di?uoro - 11,3,16a,17a,21 - tetrahydroxy - 20 ~ oxo
35
4,6-pregnadieno-[3,2-c]pyrazole and the l6a,17a-B.CC'[O
nide thereof.
13. A compound selected from the group consisting of
6,911 - ditluoro - 11?,160t,17oz,21 - tetrahydroxy - 20 - oxo
2?-phenyl-4,6-pregnadieno-[3,2-c]pyrazole and the 16m,
40 Wot-acetonide thereof.
14. A compound selected from the group consisting of
6,911 - di?uoro - 11?,16a,17a,21 - tetrahydroxy - 20 - 0x0
2'-(p-?uorophenyl)-4,6~pregnadieno-[3,2-c]pyrazole and
the l6a,17a-acetonide thereof.
15. A compound selected from the group consisting of
6 - chloro - 9a - ?uoro - ll/3,l6a,l7a,2l - tetrahydroxy - 20
oxo-4,6-pregnadieno-[3,2-c]pyrazole and the 16ot,l7a.
acetonide thereof.
16. A compound selected from the group consisting of
6 - chloro - 90c - ?uoro - 11,6,16a,17a,21 - tetrahydroxy - 20
oxo-Z'-phenyl?4,6-pregnadieno-[3,2-c1pyrazole and the
16a,17u-acetonide thereof.
17. A compound selected from the group consisting of
wherein R? is a member of the group consisting of hy
6 - chloro - 90c - ?uoro - 11/3,16a,17u,21 - tetrahydroxy - 20
droxy, lower hydrocarbon carboxylic acyloxy, ?uoro,
iodo, tetrahydropyranyloxy, the methylsulfonyloxy radi
oxo-2'-(p-?uorophenyl)-4,6-pregnadieno - [3,2-c]pyrazole
cal, the dihydrogen phosphate and the alkali metal salts
of said dihydrogen phosphate, R is a member of the group 60
consisting of hydrogen, lower hydrocarbon carboxylic
acyl, lower alkyl, lower hydrocarbon aryl, lower aralkyl,
lower cycloalkyl, halophenyl, lower alkoxy phenyl, nitro
phenyl, pyridyl, pyridyloxide and pyrimidyl, X is a mem
ber of the group consisting of hydrogen and ?uoro, Y is
a member of the group consisting of hydrogen, chloro,
?uoro and methyl, 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; and pharmacologically acceptable salts of all
of the foregoing compounds.
3. A compound selected from the group consisting of
6 - ?uoro - 11B,16a,17u,21 - tetrahydroxy - 20 - oxo - 4,6
and the 16a,17u-acetonide thereof.
18. A compound selected from the group consisting of
9a - ?uoro - ll?,l6a,17a,2l - tetrahydroxy - 6 - methyl
20-oxo-4,6-pregnadieno-[3,2-c]pyrazole and the 1611,1701.
acetonide thereof.
19. A compound selected from the group consisting of
90a _ ?uoro - 1lB,l6a,17oc,21 - tetrahydroxy - 6 - methyl
20-oxo-2'-phenyl-4,6-pregnadieno-[3,2-c]pyrazole and the
l6a,17a~acetonide thereof.
20. A compound selected from the group consisting of
9a - ?uoro - ll,8,l6a,l7a,2l - tetrahydroxy - 6 - methyl
20-oxo-2'-(p-?uorophenyl)-4,6-pregnadieno-[3,2-c1pyraz
ole and the l6a,l7a-acetonide thereof.
21. A compound selected from the group consisting of
9a - ?uoro - 11?,160n,17a,21 - tetrahydroxy ~ 20 - oxo - 4,6
pregnadieno-[3,2-c]pyrazole and the l6a,l7a-acet0nide
pregnadieno-[3,2-c]pyrazole and the 16a,17a-acetonide
75 thereof.
thereof.
3,072,641
22. A compound selected from the group consisting of
9;: - ?uoro - 11?,16a,17oc,21 - tetrahydroxy - 20 - oxo - 2'h
1-4,6gcgg?de
tgerreegcga d?leno � [3 ,2- CJpyrazOle and the 16a , 17?-
(p-?uorophenyl)-4,6-pregnadieno~[3,2-c]pyrazole and the
16a,17a-acetonide thereof.
.
.
References Cnted
m
the ?le of thls. patent
23. A compound selected from the group consisting of 5
90c - ?uoro - 11[3,16c4,17a,21 - tetrahydroxy ~ 20 - OX0 - 2'-
UNITED STATES PATENTS
2,945,852
Bergstrom ____________ __ July 19, 1960
6,9a-di?uoro
'30
21 - tetrahydropyranyloxy - 11/3 - hydroxy - 16a,l7� - iso
propylidenedioxy-ZO-oxo ~ 4,6 - pregnadieno-[3,2-c]pyra
zole is prepared by the following route: One gram of
6,9a-di?ll0l'0 - 21 - tetrahydropyranyloxy-ll?ehydroxy-l
hydroxy/methylene - 1611,17? - isopropylidenedioxy - 4,6
tetrahydropyranyloxy-llit-hydroxy - 1611,1701 - isopropyla
idenedioxy-4,6-pregnadiene-3,20-dione.
pregnadiene-3,20-dione,
and/or the formats 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
added and the organic layer is washed two times with
3,20-dione (350 mg.) is dissolved in 25 ml. of dry, hot 40 2 N aqueous sodium hydroxide solution and then with
water. The ethyl acetate extract is then dried and con
benzene and the resulting solution is cooled to room
centrated in vacuo. The 6,9a-di?uoro-21-tetrahydr0
temperature and treated with 1.0 ml. of freshly distilled
The 6,9a-di?uoro-2l-tetrahydropyranyloxy - 1113 - hy
droxy-16u,17a'isopropylidenedioxy - 4,6 - pregnadiene
pyranyloxy - 11B - hydroxy - 2 - methoxy - methylene
ethyl formate. The air in the system is replaced with
16a,l7a-i50pr0pylid8n6diOXy - 4,6 - pregnadiene-3,20-dione
nitrogen and 560 mg. of sodium hydride (as a 58% dis
persion 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
45
mixture is poured into an excess of a saturated aqueous
solution of sodium dihydrogen phosphate and the product
is extracted four times with benzene.
The organic ex
50
tracts are washed three times with water and dried over
is obtained by chromatography on silica gel.
A mixture of 580 mg. of the above 2-methoxymethyl
cue-derivative, 10 ml. of ethanol, and 56 mg. (1.2 equiva
lents) of methylhydrazine is heated under nitrogen for
three hours 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 2
N sulfuric acid, two times with 2.5 N sodium hydroxide,
sodium sulfate. Removal of the solvent gives the crude
product which is dissolved in ether and puri?ed as the
sodium salt by extraction into a 10% solution of sodium
and then two times with water.
The ethyl acetate ex
tract is then dried, concentrated, and chromatographed on
The aqueous alkaline extracts are again 55 silica gel to yield the 1?-methyl- and the 2?-methyl-6,9a
di?uoro - 2 l-tetrahydropyranyloxy-l 1B-hydroxy-16a,17e
isopropylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2~c]pyr
of sodium dihydrogen phosphate and extracted into other
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
carbonate.
acidi?ed with an excess of a saturated aqueous solution
to give 6,90: - di?uoro - 21 - tetrahydropyranyloxy-11,9
hydroxy-2-hydroxymethylene - 1601,17? - isopropylidenedi
oxy-4,6-pregnadiene-3,20-dione,
and/or the
60
?uoro - 21 - tetrahydropyranyloxy-l1B-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-2l-tet
formate
esters thereof.
rahydropyranyloxy - l1?-hydroxy-l6a,Hat-isopropylidene
Example 14
05
dioxy-20-oxo-4,G-pregnadieno-[3,2-c]pyrazole in 10 ml.
droxy-2-hydroxymethylene - 1601,1711 - 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
lute ethanol and treated with a solution of hydrazine
hydrate (60 mg, 1.2 equivalents) dissolved in 1.0 ml. of
absolute ethanol. The mixture is re?uxed in a nitrogen
atmosphere for about 3 hours and then evaporated to
dryness under reduced pressure. The residue is washed
three times with cold water and the resulting amorphous
and 5 ml. of methyl iodide, the mixture is stirred at room
temperature over night. The product is ?ltered, washed .
with methylene chloride, and the ?ltrate and washings are ?
taken to dryness. The residue may be chromatographed?
on silica gel or Florisil to yield the l?- and 2?-methyl-6,9a
di?uoro - ZI-tetrahydropyranyloxy-l1,6-hydroxy-l6a,l7a
3,072,641
17
18
isopropylidenedioxy - 20~oxo-4,6-pregnadieno-[3,2-c]pyr
azoles.
2' - benzyl - 6,9a - di?uoro-2l-tetrahydropyranyloxy-115
hydroxy - 160:,170; - propylidenedioxy-20-oxo-4,6-pregna
dieno- [3,2-c] pyrazoles.
'
In accordance with the above procedures, but using
other alkylating agents in place of methyl iodide, there
are obtained the corresponding N-alkyl-6,9a-di?uoro-21
Example 17
tetrahydropyranyloxy - 1l?-hYdl?OXY-16OL,170t-lSOpI?OPyll
denedioxy-20-oxo-4,6-pregnadieno- [3,2-c] pyrazoles.
5'65 mg. sample of 6,9ot-di?uoro~2l-tetrahydropyran
In accordance with all of the above procedures, but
starting with the Z-hydroxymethylene derivatives of the
yloxy-l l/i-hydroxy - 2 - hydroxymethylene - 16a,17a - iso
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-di?uoro-2l-tetrahydro
15
pyranyloxy - 11l3-hydroxy-2-hydroxymethylene-16a,17a
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- to dryness. The resi
due is dissolved in ether, the ether layer is treated three
the formate esters thereof, and 130 mg. (1.2 equivalents)
times with 2.5 N hydrochloric acid, then three times with
of phenylhydrazine are re?uxed under nitrogen in 8 ml.
2.5 N sodium hydroxide and ?nally With water. The
of absolute ethanol for about three hours. The reaction 20 ether layer is dried over magnesium sulfate, ?ltered and
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
ml. 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
and 10 ml. of 1.33 N sodium methoxide in methanol and 25 is diluted with ethyl acetate and washed with water. Re
left under nitrogen for 10 minutes. The alkoxide is
moval of the dried solvent leaves 2'-(p-?uorophenyl)
neutralized with acetic acid and the mixture is diluted
6,9a-di?uoro - 21 - tetrahydropyranyloxy - 1113 - hydroxy
with ethyl acetate and washed with water. Removal of
16a,Nit-isopropylidenedioxy - 20-?oxo ~ 4,6 - pregnadieno
isopropylidenedioxy - 4,6-pregnadiene~3,20-dione
and/ or
the dried solvent leaves 2'-phenyl-6,9a-di?uoro-2l-tetra
[3,2-c]pyrazo1e.
hydropyranyloxy - 11B - hydroxy-16a,17a-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
hydroxy~l6a,Hot-isopropylidenedioxy - 20- 0x0 ?4,6-preg
21 - tetrahydropyranyloxy-l1/8-hydroxy-16a,17<x-propyl
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 6,9oc-di?ll0r0
21 - tetrahydropyranyloxy-l1?-hydroxy-Z-hydroxymeth
A mixture of l'-(p-?uorophenyl)- and 2?- (p~?uoro
phenyl) - 6,90: - di?uoro - 21 - tetrahydropyranyloxy-l1,91
route: One gram of 6,9a-di?uoro-2l-tetrahydropyranyl
35 oxy - 11B - hydroxy-2-hydroxymethylene-16a,17u-isopro
pylidenedioxy-4,6,7pregnadiene-3,20v-dione, and/or the for
ylene - 16a,17<x _ isopropylidenedioxy-6-methyl-4,6~preg
mate esters thereof, in 50 ml. of dry dioxane is treated with
nadiene-3,20-dione, and/or the formate esters thereof, in
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
um hydroxide solution and then with water. The ethyl
The ethyl acetate extract is then dried and concentrated in
vacuo. The 6,9a-dil?uoro-2ltetrahydropyranyloxy-l1p
acetate extract is then dried and concentrated in vacuo.
The 6,911: - di?uoro-2l-tetrahydropyranyloxy-1l?-hy
hydroxy-Z-methoxymethylene - 16u,17ct - isopropylidene
45
droxy - 2 - methoxymethylene-16a,Hot-isopropylidene
tography on neutral alumina.
dioxy-4,6-pregnadiene-3,20-dione is obtained by chroma
tography on silica gel.
A mixture of 580 mg. of the above 2-rnethoxymethyl
ene-steriod, 10 ml. of ethanol and 130 mg. (1.2 equiva
dioxy-4,6-pregnadiene-3,20-dione is obtained by chroma
.
A mixture of 500 mg. of the Z-methoxymethylene-de
rivatives 100 ml. of ethanol, and 1 ml. of p-?uorophenyl
hydrazine is heated under nitrogen until dissolved, and
60 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 l?-(p-fluorophenyl) and 2?-(p-?uorophenyl)-6,9a-di
and then two times with water. The ethyl acetate extract
?uoro-Zl-tetrahydropyranyloxy - 11p - hydroxy-16u,17a
is then dried, concentrated, and chromatographed on silica
isopropylidenedioxy - 2O - oxo - 4,6 - pregnadieno-[3,2-c]
gel or Florisil to yield the 1'-phenyl- and 2'-phenyl-6,9a
di?uoro - 21 - tetrahydropyranyloxy-ll?-hydroxy-16a,
pyrazole.
60
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
In accordance with all of the above procedures, but
starting with the 2-hydroxymethylene derivative which is
obtained from each of the starting materials which are
listed in column 2, there are obtained the corresponding
1?-( p-?uorophenyl ) - and 2?- ( p-?uorophenyl) -derivatives.
from each of the starting materials which are listed in 65
In accordance with the above procedure, but using
each of the monosubstituted hydrazines listed ?in col
column 2, there are obtained the corresponding 1?-phenyl
and 2?-phenyl-derivatives.
umn 3', there is obtained the corresponding 1'- and
2?-substituted derivatives of the above 6,9a-di?uoro-21
In accordance with the above procedures, but using
other substituted hydrazines, for example, cyclohexylhy
drazine, p-tolylhydrazine, p-chlorophenyl-hydrazine, p
70 tetrahydropyranyloxy-lIB-hydroxy e 160:,17a - isopropyli
methoxyphenylhydrazine, or benzylhydrazine in place of
phenylhydrazine, there are obtained the corresponding
1'- and 2?-cyclohexyl-, l?- and 2'-p-tolyl-, 1'- and 2?-p
chlorophenyl-, 1'- and 2'-p-methoxyphenyl-, and 1'- and 75
denedioxy-20-ox-o-4,6-pregnadieno-[3,2-c]pyraz0le.
Example 18
The 6,911 - di?uoro - 21 -tetrahydropyranyloxy-l1py
droxy-l6a,17a-isopropylidenedioxy-20-oxo - 4,6 ~ pregna
3,072,641
19
2.0
propylidenedioxy - 20-oxo-4,6-pregnadieno-[3,2-c]pyra
dieno-[3,2-c]pyrazole (40.0 mg.) is dissolved in 0.5? ml.
zole, there is obtained the corresponding N-a1ky1-, N
of methanol and treated with 1.82 ml. of a solution of
cycloalkyl-, N-aryl-, or N-aralkyl-6,9a-di?uoro-11?,16a,
500 mg. of p-toluenesulfonic acid monohydr-ate in 25 ml.
1711,21 - tetrahydroxy-20-oxo-4,6-pregnadieno-[3,2-c]pyr
azolc.
of methanol. The mixture is 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
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 115,21-dihydroxy-16a,l7a-isopro
pylidenedioxy - 4,6-pregnadiene-3,20-dione 21-acetate, or
with 2 ml. of water. The product is dried over magne
the 6-chloro-, 6-?uoro-, 6-methyl-, 9a-?ll0I'O-, 6-ch1oro
sium sulfate, ?ltered and the solvent removed on a steam 10 9u-?uoro-, 9a-?uoro_6-methyl- derivative thereof, in place
bath. The residue is slurried with a small amount of
of the 6,9a-di?u01'o-115,21-dihydroxy - 16a,17a-isopro
methylene chloride, and the slurry ?ltered and dried in
pylidenedioxy - 4,6-pregnadiene-3,20-dione 21 - acetate,
vacuo to give 23.0 mg. of 6,9m-di?uoro-l15,2l-dihydroxy
there is obtained the corresponding 11?,16a,17a,21-tetra
l6e,17a-isopropylidenedioxy-20 - oxo - 4,6 - pregnadieno
15
[3,2-c]pyrazole.
In accordance with the above procedure, but starting
with an N-alkyl-, N-cycloalkyl-, N-aryl-, N-acyl-, or N-ar
hydroxy - 20-oxo-4,6-pregnadieno-[3,2-c1pyrazole or the
6-chloro-, 6-?uoro-, 6-methyl-, 9a-?uoro-, 6-chloro-9a
?uoro- or 9a-?uoro-6-methyl-derivative thereof; and the
N-alkyl-, N-cycloalkyl-, N-aryl-, N-aralkyl-derivatives, the
alkyl-6,9u?di?uoro-21-tetrahydropyranyloxy- l 1 p-hydroxy
16a,17a. - acetonides and the 21-acyloxy derivative of all
16m,17e-isopropylidenedioxy-ZO? - oxo - 4,6 - pregnadieno
of the foregoing 160:,17ct-8C6l0l1id65, 11?,16a,17a~tetra
[3,2-c]pyrazole, 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-16a,17a-isopro
pylidenedioxy-200x04,G-pregnadieno- [3 ,2-c] pyrazole.
Example 21
Example 19
To a solution of 100 mg. of 6,9a-di?uoro-l15,21-dihy
To a solution of 100 mg. of 6,9a-di?uoro-21-tetrahy
25 dropyranyloxy - 11B-hydroxy-16'1J7u - isopropylidcne
dioxy - 20-oxo?4,6-pregnadieno-[3,2-c1pyrazole in 2 ml.
of pyridine is added 2 ml. of acetic anhydride. The mix
droxy - 160:,1711 - isopropylidenedioxy-ZO-oxo-4,6-pregna
dieno[3,2-c]pyrazole in 2 ml. of pyridine is added 2 ml.
ture is allowed to stand over night at room temperature.
of acetic anhydride. ?The mixture is allowed to stand
It is taken to dryness in vacuo to afford the N-acetyl-6,9a
overnight at room temperature. A mixture of ice and 30 di?uoro - 21-tetrahydropyranyloxy-11,8-hydroxy-16a,17a
water is then added. After standing for about 30 min
isopropylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c] pyr~
utes, the product is extracted with ethyl acetate. The
azole.
ethyl acetate extract is washed successively with water,
Without further puri?cation, this substance is dissolved
ice-cold 1 N sulfuric acid, saturated aqueous sodium bi
in 5 ml. of methanol containing 20 mg. of p-toluenesul
35
carbonate and water (until the aqueous layer is neutral).
fonic acid. The mixture is kept at room temperature for
The ethyl acetate solution is dried with anhydrous sodium
4 hours. The solvent is removed in vacuo, ethyl acetate
sulfate. The solvent is then distilled at about 40� C. in
is added and the organic layer is washed several times
vacuo to afford the N-acetyl-6,9a-di?uoro-115,21-dihy
with dilute sodium bicarbonate. The dried solvent is
droxy a 16a,17a - isopropylidenedioxy - 20 - oxo-4,6-preg~
removed to yield after chromatography on neutral alu
nadieno-[3,2-c]pyrazole 2l-acetate which is isolated by
mina N-acetyl - 6,9a - di?uoro-11,3,21-dihydroxy-16bt,l7a
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 - 11B,
azolc.
21 - dihydroxy-l6a,17a-isopropylidenedioxy-20-oxo-4,6
pregnadieno-[3,2-c]pyrazole 21-acetate in 60 ml. of 80%
(v./v.) acetic acid is re?uxed for 1.5 hours. This solu 45
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.
This residue is dissolved in 150 ml. of acetone con 50
taining 2 ml. of 70% perchloric acid. After thirty min
Example 22
To a solution of 85 mg. of N-acetyl?6,9a~di?uoro~115,
21 - dihydroxy-16a,17a-isopropylidenedioxy-20-oxo-4,6
pregnadieno -[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 a period of approximately 1
hour. Water is then added to the reaction mixture and
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-acetyl-6,9a-di?uoro-l1,3,21-dihydroxy
1611,1701 - isopropylidenedioxy - 20 ~ oxo-4,6-pregnadieno
moved to yield, after chromatography on neutral alumina,
[3,2-c1pyrazole 21-mesylate.
6,90: - di?uoro-11B,_21-dihydroxy-16a,17a-isopropylidene
In accordance with the above procedure, but stanting
with the N-a1kyl-, N-cycloalkyl-, N-aryl-, or N-aralkyl
dioxy-20-oxo-4,?-pregnadieno- [3 ,2-c] pyrazole 2 1 -acetate.
In accordance with the above procedures but using an
equivalent quantity of another .acylating agent in place
60 6m,9a _ di?uoro-l15,21-dihydroxy-l6a,l7a.isopropylidene
dioxy-20-oxo-4,6-pregnadiene-[3,2-c]pyrazlole, in place of
of acetic anhydride, there is obtained the corresponding
acyl derivatives.
Example 20
6,911 - di?uoro - 1113,21 - dihydroxy - 16a,17u - isopro
pylidenedioxy - 20 - oxo-4,6-pregnadieno-[3,2-c]pyrazole
the N-acyl-derivative there is obtained the corresponding
2l-mesylate.
Example 23
65
To 180 mg. of N-acetyl-6,9a-di?uoro-11?,21-dihydroxy
16a,17a - 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 6,9a-di 70
is heated at re?ux temperature for a period of approxi- ;
?uoro - 115,16a,171:,21-tetrahydroxy-20-oxo'4,6-pregna
mately 1 hour, and the reaction solution is cooled to room
dieno - [3,2-clpyrazole is collected by ?ltration and dried.
temperature and diluted with water. Extraction with
In accordance with the above procedure, but starting
with the corresponding N-alkyl-, N-cycloalkyl-, N?aryl-,
or N-aralkyl-, 6,9u-di?uoro-115,21-dihydroxy-16e,17a-iso
ethyl acetate followed by drying and removal of the
solvent affords N-acetyl-6,9a-di?uoro-ll?-hydroxy - 21
3,072,641
21
22
ture of 1701,21-epoxy-1 l/s-hydroxy-1601-methyl-20-oxo-2'
iodo _ 1601,1701 - isopropylidenedioxy-20-oxo-4,6-pregna
dieno-[3,2-c]pyrazole.
'
pheneyl-4-pregneno - [3,2-c]pyrazole and 21-?u0ro-11?,
Example 24
1701 ~ dihydroxy - 1601 - methyl - 20 - oxo - 2' - phenyl - 4
pregneno-[3,2~c]pyrazole, which compounds are sepa
The N-acetyl-6,901-di?uoro-11/3-hydroxy-21-iodo-1601,
rated by partition chromatography, or by chromatography
1701 - isopropylidenedioxy ? 20 - oxo - 4,6 - pregnadieno
on silica gel.
[3,2-c]pyrazole (100 mg.) is dissolved in a mixture of
Example 27
5 ml. of water and 5 ml. of ethanol. To the resulting sus
N - acetyl - 6,901 - di?uoro - '1 15 - hydroxy - 1601,1701
pension is added 500 mg. of sodium bisul?te, and the mix
ture is heated under re?ux for a period of about 1 'hour. 10 isopropylidenedioxy - 2O - oxo - 4,6 - pregnadieno-[32c]
?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 methanolvis removed in vacuo and the
acetate in vacuo, the residue is left overnight under nitro
product is extracted with ethyl acetate and washed with
gen in 5 ml. of methanol and 1 ml. of one molar sodium
water. Removal of the dried ethyl acetate affords 6,901
methoxide in methanol. The solvent is then removed in
di?uoro - 11B - hydroxy - 1601,1701 - isopropylidenedioxy
vacuo, ethyl acetate is added and, after a water wash, the
20-loxo-4,6-pregnadieno-[3,2-c]pyrazole.
solvent is dried and removed. Chromatography of the
residue on neutral alumina affords some 6,901-di?uoro
Example 28
1118 - hydroxy - 1601,1701 - isopropylidenedioxy- 20 - oxo-'
4,6-pregnadieno-[3,2-c]pyrazole.
I
6,901 - di?uoro - ll? - hydroxy ?- 1601,1701 - ?isopropyl
.20
Example 25
idenedioxy - 20 - oxo - 4,6 - pregnadieno - [3,2-c1pyrazole
(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. After 18 hours, the
Silver dihydrogen phosphate is prepared by the reac
tion of 32 g. of trisilver phosphate with 10 ml. of 100%
phosphoric acid with thorough mixing in a one-liter 3 25 6,901 - di?uoro - l1,8,1601,l701 - trihydroxy - 20 - oxo - 4,6
pregnadieno-[3,2-c]pyrazole is collected? by ?ltration and
necked round-bottomed ?ask. The silver dihydrogen
phosphate is washed with tWo portions of diethyl ether,
In accordance with all the procedures givenlin 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
to cover the silver dihydrogen phosphate, and the mixture 30 Example 21 with the 11,8-hydroxy-2l-tetrahydropyranyl
dried.
.
.
oxy - 1601,1701 - isopropylidenedioxy - 20 - oxo - 4 f preg
is heated to re?ux temperature. At this point 20 g. of
neno-[3,2-c]pyrazole or the 601-chloro-, 601-?uoro-, 601
N - acetyl - 6,901 - di?uoro - 11p - hydroxy - 21 - iodo
methyl-, 901-?uoro-, 601,901-di?uoro-, 601-chloro-91z-?uoro�,
1601,1701 - isopropylidenedioxy - 20,- oxo - 4,6 ~ pregna
dieno-[3,2-c]pyrazole is added and the mixture is re
601-methyl-901-?uoro-derivative thereof; or the ll?-hy
?uxed in a nitrogen atmosphere with stirring for 75 min
droxy - 21 - tetrahydropyranyloxy - 1601,1701 - isopropyl
utes. The reaction mixture is then cooled over a period
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
35
idenedioxy-20-oxo-4,6-pregnadieno-[3,2-c] pyrazole or the
6-chloro-, 6-?uoro-, 6-methyl-, 901-?uor0-, 6-7Chl0I'O-9o1
?uoro-, 901-?uoro-601-methyl-derivative thereof, there is
obtained the corresponding 601-chloro-, 601-?uoro-, 901'-?u
sulting aqueous suspension is adjusted to 6.4 by the addi v40 oro-, 601,901-di?uoro-, 601-chloro-901-?uoro-, 601-methyl- or
901 - ?uoro - 601 - methyl - l'l,8,1601,1701 - trihydroxy P 20
tion of 23 ml. of saturated aqueous sodium carbonate
oxo-4-pregneno-[3,2-c]pyrazole; or the 6-chloro-, 6'-?u
solution. A precipitate is formed and separated by ?ltra
oro-, 6-methyl-, 901-?uoro-6-chloro-9a-?uoro or 901-?uoro
tion. The precipitate is washed with water until no
6 - methyl - 11,8,1601,1701 - trihydroxy - 20 - oxo - 4,6
ultraviolet absorbing material is detected in the wash
pregnadieno-[3,2-c]pyrazole, and the 1601,1701-acetonides
Water. The ?ltrate and wash water are combined and
45. of all of the foregoing compounds.
freeze dried to separate a solid material from the water.
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 11B - hydroxy - 21 - tetrahydropyranyloxy - 1601,1701 - iso
propylidenedioxy-20-oxo-4-pregneno- [3 ,2-c] pyrazole or
umn containing 60 g. of a cation exchange resin
the 601-chlor0-, 601-?uoro-, 601-methyl-, 9014?uoro-, 601,901
(?IR-120?) in its hydrogen form. The column is washed
with methanol until the washings contain no ultraviolet
di?uoro-, 601-chloro-9'01-?uoro-, 901-?uoro-601-methyl-de
absorbing material. The combined eluate and washings
rivative thereof; or the N-alkyl-, N-cycloalkyL, N-aryl- or
are concentrated to a volume of 15 ml., and 150 ml. of 55
ether are added. The precipitate which forms is recov
N-aralkyl - 11,6 - hydroxy - 21 - tetrahydropyranyl0xy-l601,
ered by ?ltration, washed with ether, and dried for about
16 hours in a desiccator, to give N-acetyl-6,901-di?uoro
?uoro-, 6-chloro-901-?uoro-, 901-?uoro-6-methyl, deriva
tives thereof, there is obtained the corresponding 601
11B - hydroxy - 1601,1701 - isopropylidenedioxy - 20 - oxo
4,6-pregnadieno-[3,2-c] pyrazole 21-dihydrogen phosphate.
The mono- and the dialkali metal salts of the 21-dihy
drogen phosphate compound are obtained by neutralizing
the 21-dihydrogen phosphate ester with an alkali metal
methoxide.
Example 26
To a solution of 62 mg. of N-acetyl-6,901-di?uoro-11,6,
1701 - isopropylidenedioxy - 20 - oxo - 4,6 - pregnadieno~
[3,2-c]pyrazole or the 6-chloro-, 6~?uoro'-, 6-methyl-, 901
60
chloro-, 601-?uoro-, 601-methyl-, 901-?uoro-, 601,901-1di?uoro-,
601-chloro-901-?uoro~, or 901-?uoro-601-methyl-, N-alkyl-,
N-cycloalkyl-, N-aryl-, or N-aralkyl-, 11,8,1601,1701-trihy
droxy-20-oxo-4-pregneno-[3,2-c]pyrazole; or the 6-chl0
ro-, 6-?uoro-, 601-chloro-901-?uor0-, or 901-?uoro-6-methyl
N-alkyl-, N-cycloalkyl-, N-aryl- or N-aralkyl-l 119,1601,1701
trihydroxy-20-oxo-4,6~pregnadieno-[3,2-c]pyrazole, and
the 1601,1701-acetonides of all of the foregoing compounds.
21 - dihydroxy - 1611,1701 - isopropylidenedioxy - 20 - oxo
4-pregneno-[3,2-c]pyrazole 2l-mesylate in 1 ml. of freshly
distilled anhydrous dimethylformamide is added enough
Example 29
The 6,901 - di?uoro - 21 - tetrahydropyranyloxy - 1119
anhydrous potassium ?uoride to assure a saturated solu 70 hydroxy - 1601,1701 - 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. Themixture is
3,072,641
23
24
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 oli
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
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 ZI-tetrahydro
solvent removed on a steam bath. The residue is slurried
pyranyloxy - 115 - hydroxy - l6u,17a - 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,
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