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Патент USA US3035061

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3,035,051
United States Patent 0 "Ice
$112011
i=0
3,035,051
E -3-KETO
Za-{JYANO OR Z-HYDROXYME
STEROIDS
Henry M. Kissman and Arlene M. Hotfman, Nanuet,
.1.
N.Y., and Martin J. Weiss, Oradell, N.J., assignors to 5
American Cyanamid Company, New York, N.Y., a
corporation of Maine
No Drawing. Filed Sept.'12, 1960, Ser. No. 55,134
19 Claims. (Cl. 260-23955)
Patented May 15, 1962
iHzO—lower
alkanoyl
=0
lower alkyl
\ /
0
/ \
10
This invention relates to new steroid compounds. More
particularly, it relates to 2u-cyano steroids of the preg
nane and androstane series and to Z-hydroxymethylene
steroids which are intermediates for the ?nal products
and methods of preparing the same.
15
The novel 2a-cya11o A4-3-keto steroids of the present
invention can be illustrated by the following general for
mula:
re
lower alkyl ,
(EH20
C=O
I
Q
0- — - - -0
/
lower alkyl
\ /
GEL-O
/C\lower alkyl
(‘JEN-lower alkanoyl
C=O
20
b-m-o \
’\
CH~0
25
lower alkyl
/
/ \
O
lower alkyl
0112011
I O-—OH2
in which —C1——C2— is a divalent radical selected from
the group consisting of:
C
30
/ l
l 0—- H!
——OH
/ \
and
35
is a trivalent radical of the group consisting of:
4O
and
45
50
and
.m
a
.mm em
T. a .m
1 0CL m m.
molo i
p
m
_
w
a
.un0c
o
m
m
.m
0 “R
55
ol oil-I
ao
\
/
H
60
CHaOH
(fr-lower alkanoyl
C
65
0 H2O —l0wer alkanoyl
70
_
m
3,035,051
and
4
3
and ultraviolet absorption data, in the light of present
understandings of these phenomena according to recent
0
and present chemical literature. Such designations of
the alpha con?guration for the cyano substi-tuent, thus,
omo-ii-cm
I O—CH:
are dependent upon the state of the art presently under
0/ ]
stood by organic chemists.
As a result of the immediately foregoing considera
tions, no part of the speci?cation of the present applica4
‘\O—CHz
tion ?led in consideration of the state of the art should
C-—-H
10 be considered materially defective if in the future it ‘should
/ \(IDH,
be established that the con?guration of the Z-cyano sub
stituent of the Z-cyano-M-Ii-keto steroids of this invention
radicals.
The Zu-cyano A4-3-keto steroids of this invention are
is opposite to that now deducible.
It should be still further noted that the 2-cyano-A1'4-3
prepared by a novel method which ‘comprises treating the
corresponding hydroxymethylene steroid with O,N-bis 15 keto steroids of this invention (see hereinabove) are not
subject to the possible ambiguity of structure discussed
tri?uoroacetylhydroxylamine, usually in approximately
immediately above, because the presenceof the 1,2-dou
equivalent amounts, in an inert solvent such as benzene
ble bond precludes stereoisomerism involving the 2-posi
containing an equivalent of a tertiary amine base such as
pyridine at a temperature ranging from 20° C. to 120°
C., usually from about 60° C. to 90° C. for a period of
time ranging from 30 minutes to 24 hours, usually one or
two hours.
tion.
The novel Z-hydroxymethylene-M-S-l<eto steroids of
this invention are, for example, 2-hydroxymethylene-4
pregnene-3,20-dione, 2l-hydroxy-2-hydroxymethylene-4
7
pregnene-3,20-dione, 2 - hydroxymethylene-l7a,20;20,21
Under the de?ned conditions, ?ree 17,8-hydroxy1 and
bismethylenedioxy-4-pregnene-3,l l-dione, 9u-?t101'0-1 1;?
21-hydroxyl, but not ll?-hydroxyl groups will undergo
at least partial tri?uoroacetylation. In these circumstances 25 hydroxy - 2 - hydroxymethylene - 16oc,17oc - isopropyli
denedioxy-Z l- (tetrahydropyran-Z-yloxy) -4—pregnene-3 ,20
it is best to add an additional equivalent of O,N-bis-tri
dione and 9a-?uoro-l15,21-dihydroxy-Z-hydroxymeth
?uoroacetylhydroxylamine to the reaction mixture for
Y16l16-16oc, 17a-isopropylidenedioxy-4-pregnene-3,20—dione.
each vulnerable hydroxyl group present in the steroid
These compounds are prepared by treating the appro
molecule. The intermediate tri?uoroacetylated deriva
tives can then be converted into the free steroids by mild 30 priate A4-3-keto steroid with a lower alkyl \formate (e.g.,
ethyl for-mate) in the presence ‘of an alkaline condensing
alkaline or acid hydrolysis.
agent, such as sodium hydride or a sodium alkoxide in
The products can be obtained by the usual work-up pro
cedures-including washing, evaporation of solvent and
a solvent inert to the reactants such as benzene at about
recrystallization.
room temperature for 10 to 72 hours, usually ‘about 16
-
The 2a-cyano-A4-3-keto steroids of this invention are, 35 hours preferably under an atmosphere of nitrogen.
The products are isolated ?rst by extraction into aque
ous alkali, thus being separated from alkali-insoluble un
in general, white crystalline solids having infrared ab
sorption bands at about 4.5,“ (CEN) and 5.9a
reacted starting material. Acidi?cation gives crude prod
ucts which may be further puri?ed by standard recrystal
lization techniques.
and typical A4-3-ketone ultraviolet absorption at about 40 It is necessary that the compound submitted to the
240 my. (when determined ‘in neutral medium). These
above-described formylation reaction have its side-chain
compounds are soluble in aqueous alkali and can be re
suitably blocked so as to prevent C-2l formylation
generated therefrom by acidi?cation.
and/or in the instance of ‘side-chains having hydroxy
The 2-cyano-A1»4-3-keto steroids of this invention are
prepared from the corresponding 2u-cyano-A4-3-keto
45
steroids by treating the latter with a 1,2-dehydrogenating
agent such as 2,3-dichloro-5,6-dicyanobenzoquinone.
The above reaction is usually carried out in an inert
solvent such as dioxane at re?ux temperature for a period
of about 24 hours. The product is isolated by evapora
tion of solvent, addition of benzene (which does not dis
solve the bulk of the 2,3-dichloro-5,6-dicyanohydroqui
none formed in the reaction), and ?ltration, washing with
hydrolysis.
50
solve, evaporation of the solvent benzene, and recrystal
lization of product ?rom the residue.
The 2-cyano-A1-4-3-keto steroids of this invention are,
tautomeric form and they are herein so de?ned.
in general, white crystalline solids, relatively insoluble in
It is
understood that the speci?cation will not be materially
water and soluble in lower alkyl alkanols, acetone, ethyl
60
The process, described above, of reacting an hydroxy—
methylene steroid with O,N-bis-tri?uoroacetylhydroxyl
amine proceeds under steric in?uences and steroisomers
may be formed (i.e., either the 2a-cyano-A4-3-keto steroids
65
or the 2?-cyano-A4-3-keto steroids may be formed).
As shown above, the predominant isomers are indi
cated as having the 2-cyano substituent in the alpha con
?guration. This alpha con?guration has been designated
The 2-hydroxymethylene-A4-3-keto steroids of this in
vention are, in general, yellow crystalline solids having,
ultraviolet absorption maxima, when determined in neu
tral media, at about 248—252 nm and about 305 mp, the
later maximum generally being of lesser intensity. In
accordance with the usual conventions of the art, the 2
hydroxymethylene-A4-3-keto steroids of this invention are
considered to be in the enol (i.e., hydroxymethylene)
aqueous alkali to remove what hydroquinone does dis
acetate and the like.
groups present at C~17 or C-21 base-catalyzed rearrange
ments. When the 2-hydroXymethylene-A4-3-ketone with
the deblocked side-chain is desired, cleavage of the block
ing groups can be achieved by the usual conditions of acid
defective in case it should be shown later that these com
pounds exist, in whole or in part, in diiferent tautomeric
forms. The tautomeric forms can be as follows:
oil a
The compounds of the presentinvention have shown
central nervous system depressant properties of the tran
and to provide a de?nite basis for a speci?cation con 70 quilizer or muscle relaxant type. These compounds can
be used as the ‘active component in pharmaceutical prepa
stituting a useful contribution to the art.
rations such as tablets, capsules, pills, powders etc. for the
At the same time it should be made clear that the alpha
aleviation of anxiety.
'
con?guration so designated for the 2-cyano substituent is
In addition, the compounds 2a-cyano-9m-iluoro-115J1
based’ upon theoretical considerations, on analyses of
molecular rotation data and on interpretations of infrared 75 dihydroxy - 160;,17a - isopropylidenedioxy — 4 - pregnene
in order to provide a de?nite exposition of the invention
3,035,051
5
3,20-dione,
9a-?uoro-l1,B-hydroxy-2-hydroxymethylene
then neutralized with a few drops of pyridine. The sol
vent is removed under reduced pressure and the residue
16¢,17u - isopropylidenedioxy - 21 - (tetrahydropyran-Z
is dissolved in methylene chloride, washed with water,
dried over magnesium sulfate, ?ltered and evaporated.
The residue is crystallized from methylene chloride-ether
to give 1.15 g. (65%) with melting point 165—l70°.
yloxy) -4-pregnene-3,20-dione and 9a-?uoro-11/3-hydroxy
2 - hydroxymethylene - 16a,170c - isopropylidenedioXy-4
pregnene—3,20-dione have glucocorticoid activity when
measured by the usual ‘assays.
The hydroxymethylene derivatives and the blocked
Recrystallization from the same solvent pair gives a sam
ple with melting point 167—172°.
cyano derivatives of this invention are also useful chemi
cal intermediates for the preparation of the deblocked 2
EXAMPLE IV
cyano compounds. Thus, the blocked 2-hydroxymethylene 10
derivatives on treatment with O,N-bis-tri?uoroacetylhy
2 - Hydroxymerhylenedeoxycorticosterone 20 - Ethylene
Ketal (20 - Ethylenedioxy - 21 - Hydroxy - Z-Hydroxy
droxylamine gives the corresponding blocked nitriles, de
blocking of which by hydrolytic procedures ‘gives the free
methylene-4-Pregnen-3-One
20-ketones and/or 21-ols, or l7-ols.
Deoxycorticosterone acetate 20-ethylene ketal [F.
Sondheirner, et al. Tetrahedron 5, ‘15 (1959)] (12.4 g.,
An alternative hydrolytic deblocking of the 2-hydroxy
methylene derivatives followed by treatment with O,N
bis-triiluoroacetylhydroxylamine gives the unblocked 2
cyano ‘derivatives. In addition, both the blocked and
deblocked cyano and hydroxymethylene derivatives may
29.8 mmole) is deacetylated in 350 cc. .of 1 N meth
anolic sodium methoxide solution under nitrogen at room
temperature for 45 minutes. After neutralization with
1.5 cc. of glacial acetic acid, the mixture is evaporated
be converted into other useful steroids.
and the residue distributed between chloroform and wa
The following examples show in detail the preparation
of representative 2a-cyano and 2-hydroxymethy1ene-A4-3
ter. The chloroform phase is dried and evaporated to
give a crystalline residue [deoxycorticosterone 20-ethyl
ene ketal (ZOPethylenedioxy-Zl~hydroxy-4epregnen-3
one)] which is recrystallized from ether-hexane; 10.08
g. (90%), melting point 156-158" C. A sample recrys
tallized twice from ether shows melting point 163-165 °;
keto steroids of the present invention.
EXAMPLE I
O,N-Bis-(Tri?u0r0acetyl) -Hydroxylamf7ze
A mixture of 6.95 g. (100 mmoles) of hydroxylamine
[a]D2§+100° (c. 1.30 in CHCl3);
hydrochloride and 50 cc. of \tri?uoroacetic anhydride is
AKB:
6.02,. (5.); MMH 242 m). (5 16,840)
heated with stirring under re?ux for one hour. All of
the solid goes into solution during this period. The mix 30 A mixture of 1.87 g. (5 mmole) of deoxycorticoste
rone ZO-ethylene ketal, 2 cc. of ethyl formate, 1 g. of so—
ture is evaporated under reduced pressure and the oily
dium hydride-oil suspension and 100 cc. of benzene is
residue is crystallized ‘from a small amount of methylene
stirred under nitrogen for 16 hours. Reaction is started
chloride-pentaue. The white crystalline solid is collected,
washed with pentane and is dried under reduced pressure _ by the addition of a few drops of ethanol. The mixture
is worked up by extraction with water and neutralization
at room temperature over phosphorus pentoxide. There
with sodium dihydrogen phosphate as described in Ex
is obtained 14 g. of product (62%) with melting point
ample II. There is obtained a crystalline solid which is
59—60° C'. (sublimes).
recrystallized from methylene chloride-ether to give 1.27
g. (60%) of a light yellow product with melting point
max.
20-Ethylen edioxy-Z-Hydroxym ethylene-4-Pregnen
3 -One
A mixture of progesterone ZO-ethylene ketal [It/l. Gut,
J. Org. Chem., 21, 1327 (1956)] (7.16 g., 20 moles),
3.4 g. of sodium hydride-oil dispersion, 6 cc. of ethyl
formate and 130 cc. of dry benzene is stirred under ni
trogen. The reaction is started by the addition of a few
40
184—190° C. The analytical sample is recrystallized
from a large volume of ether; melting point 191—l92°
C. positive enol test; [a]D25+41.2° (c. 1.12 in CHCl3);
REE; 6.07;; (s.) broad band, 6.36;.‘ (in); RES‘! 252 mu
(5 11,880) and 307 mp. (e 3625) in acid, 252 mu (6 11,880)
and 306 my (5230) in methanol, 244 mu (6 14,500)
and 357 m,“ (6 11,070) in base
drops of absolute ethanol and stirring is continued for
EXAMPLE V
18 hours. Benzene (150 cc.) is added to the dark
2-Hydr0xymethylenedeoxycorticosz‘erone
(21 -Hydroxy
brown suspension and then a few drops of ethanol to de
50
Z-Hydroxymethylene-4-Pregnene-.3,20—Di0ne)
stroy excess sodium hydride. The mixture is extracted
three times with water and then with several portions
To a solution of 1.36 g. (3.38 mmole) of Z-hydroxy
of cold 1% aqueous potassium hydroxide solution until
methylenedeoxycorticosterone 20-etl1ylene ketal in 175
the extracts no longer give a positive enol test. The
combined extracts are neutralized through the addition
of 30% aqueous sodium dihydrogen phosphate solution
and the mixture is extracted with several portions of
chloroform. The combined chloroform solutions are
washed with a little water, dried and evaporated. The
cc. of acetone is added 340 mg. of p-toluene-sulfonic acid
and the mixture is stirred at room temperature for 22
hours. After neutralization with a few drops of pyri
dine, the mixture is evaporated at room temperature and
the residue is dissolved in methylene chloride, washed
several times with water, dried and evaporated. The
residue is crystallized with ether to give 2.8 g. (36%) 60 residue is triturated with ether to yield 959 mg. (79%)
of a yellow solid with melting point 145-l52° C. A
of product with melting point 162-168". Recrystalliza
sample of this compound obtained in a similar experi
tion from methylene chloride-ether gives material with
ment is recrystallized twice from ether; melting point
melting point 167—172°.
160~l64° C.; [a]D25+42.4-°, (c., 1.03 in CHCls);
REE; 6.06;]. (s.) broad band, 632,1 (111.); R255?‘ 252 mu
(6 14,900) and 305 mu (5 4050) in acid, 249 m,“ (e 13,550)
and 305 me (e 5030) in methanol, 245 my (e 15,670)
and 356 my (5 12,220) in base.
EJCAMPLE III
Z-Hydroxymethylene-4-Pregnene-3,20-Di0ne
EXAMPLE VI
Z-Hydroxymez‘hylenehydrocortfsone ZO-Ethylene Ketal
(20 - Ethylenedioxy - 2 - Hydroxymethylene - 115,170‘,
21-Trihydroxy~4-Pregnem3-One)
Sodium (276 mg. 12 mmoles) is dissolved in 50 cc. of
absolute methanol and the solvent ‘is removed under re
duced pressure in a 100° C. bath. To the residual so
dium methoxide is added 25 cc. of dry benzene, 18 cc.
To a solution of Z-hydroxymethyleneprogesterone 20
of puri?ed ethyl formate and 1.2 g. (2.95 mmole) of hy
ethylene ketal (2 g., 5.18 mmole) in 250 cc. of acetone
drocortisone 20-ethylene ketal (ZO-ethylenedioxy-ll?,
is added 500 mg. of p-toluenesulfonic acid and the mix
ture is stirred at room temperature for 24 hours and is 75 17a,2l-trihydroxy-4-pregnen-3-one) [H. M. Kissman et
3,035,051
7
Q
.
o
al., 5. Am. Chem. Soc., 82, 2312 (1960)]. The mixture
evaporated to give 0.97 g. of starting material. The
is stirred at room temperature under nitrogen for 18
hours. Chlorotorm and cold 30% aqueous sodium di
hydrogen phosphate solution is added and the layers are
separated. The aqueous phase is extracted several times
dark-yellow water extracts are neutralized through the
with chloroform and the combined extracts are washed
evaporated to give 1.13 g. (66% yield corrected for re
addition of 30% aqueous sodium dihydrogen phosphate
solution. The mixture is extracted with several portions
of chloroform and the combined extracts are dried and
covered starting material) of yellow glass. This mate
rial is crystallized partially from ether to give 460 mg.
(26.8%, corrected for recovered starting material) of
until ‘these extracts no longer give a positive ferric chlo 10 bright yellow solid with melting point 120-128". For
ride test. The combined extracts are neutralized with
analysis, the material is recrystallized from ether; melting
sodium dihydrogen phosphate solution and the mixture
point 125-128"; [a]D25+68.5° (c., 1.02 in CHClg);
is extracted with methylene chloride. These methylene
A513; 5.78;; (s.), 6.07” (s.) broad band, 6.32;; (111.);
chloride extracts are combined, washed with a little wa
1.113213 246 m” (6 13,900) and 305 my (6 2470) in acid,
ter, dried and evaporated to give 830 mg. of yellow glass.
248 Inn (6 12,500) and 807 my (5 4180) in methanol,
Crystallization from hot ethyl acetate gives 462 mg.
242 rn;l (e 14,000) and 358 mu (6 9600) in base
(37%) with melting point 224-231" C. A sample is
The gum from the mother liquors gives a positive enol
recrystallized several times from this solvent; melting
test and can also be converted to the corresponding 20:
with water, dried and evaporated. The residue is dis
solved in methylene chloride and the solution is extracted
with portions of cold 1% potassium hydroxide solution
point 233—236° C.; [a]D25+47.10 (0., 0.66 in CHCIB);
REE; 6.05/1. (s.), 6.211L (m.) shoulder; M252“ 252 ma
(5 13,600) and 307 ma (6 2810) in acid, 250 mu (512,200)
and 308 my (5 4460) in methanol, 247 m” (5 13,892)
and 356 mu (6 11,400) in base
EXAMPLE V11
1 7a,20:20,21 ~Bisme?zylenedioxy-2 -Hydr0xymethylene-4
cyano-9u-?uoro-11;3,21-dihydroxy-16a,17a-isopropylidene
dioxy-4-pregnene~3,20-dione.
EXAMPLE IX
9a - Elnora - 116,21-Dilzydroxy-Z-Hydroxymethylene-16a,
1 7 a-IsopropylidenedioxyA-Pregnene-?’ ,ZO-Dione
A solution or" 9a-?uoro-11;3-hydroxy-Z-hydroxymethyl
ene - 160t,17oc - isopropylidenedioxy-2l(tetrahydropyran-Z
Pregnene-S-J 1 ~Di0ne
yloxy)-4-pregnene-3,20-dione (300 mg.) in 30 cc. of 60%
A mixture of 4.02 g. (10 mole) of 17e,20;20,21-bis
acetic acid is stirred at room temperature for 30 minutes
methylenedioxy-4-pregnene-3,ll-dione [11. E. Beyler et 30 and is then evaporated at room temperature. The residue
al., J. Amer. Chem. Soc., 82, 178 (1960)], 2.0 g. of
is dissolved in methylene chloride-water and the organic
sodium hydride-oil suspension, 4 cc. of ethyl formate and
phase is washed with a little water and is dried over
200 cc, of dry benzene is stirred under nitrogen for 16
magnesium sulfate, ?ltered and evaporated. The residue
hours and is then worked up as described in Example 11.
is crystallized from ether to give 159 mg, melting point
There is obtained a crude residue which is crystallized
220—227°; positive ferric chloride and blue tetrazolium
from methylene chloride-ether to give a light yellow
tests. Recrystallization from methylene chloride-ether
solid, 3.46 g. (81%) melting point 205—211° C. For
raises the melting point to 228—232°.
analysis, material obtained in a similar experiment is re
crystallized from the same solvent mixture; melting point
206~209° C.; [a]DZ5+9.2° C. (c., 0.875 in CHCl3);
40
REE; 5.89;; (s.), 6.06M (s.), 6.29M (KL); XXSQH 248 my
(10,980) and 305 my (6 3830) in acid, 248 my (a 9920)
and 305 my (a 4950) in methanol, 243 m,“ (6 12,660)
and 362 In” (e 12,000) in base
EXAMPLE VH1
9a - F l'uoro - 1j?-Hydroxy-Z-Hydr0xymethyleize-1604,17!»
Isopropylz'denedioxy - 21 - (T etrahydropyran-Z-Yloxy)
4-Pregnene-3,20-Di0ize
A solution of 0.5 g. of l118,21-dihydroxy-9a-?uoro-l6oc, ’
17a-isopropylidenedioxyprogesterone [1. Amer. Chem.
Soc., 80, 2338 (1958)] in 20 cc. of dihydropyran is
cooled to 0° C. There is added with stirring dropwise
1 cc. of concentrated hydrochloric acid at a rate slow
enough to keep the internal temperature between 10-20".
The mixture is then stirred at room temperature for one
hour. Hexane (100 cc.) is added and the mixture is
cooled in the refrigerator overnight. The solid which
precipitates out during this time is collected by ?ltration
and is washed thoroughly with hexane and is air dried.
The substance is recrystallized from ethyl acetate to give
0.4 g. of 9a-i'luoro-1l?-hydroxy-l6u,17a-isopropylidene
dioxy - 21 - (tetrahydropyran- Z-yloxy)J-pregnene-LZO
dione with melting point 200-205 ° (1.;
A511’, 5.80;‘ and 5.96,“ (carbonyl region)
A mixture of 2.6 g. (5 nirnole) of 9a-flllOrO-11?-hy
' droxy-l 62x, l7a-is opropylidene dioxy—2 l- (tetrahydropyran
2-yloxy)-4-pregi ene-3,20-dione, 2 cc. of ethyl formate, l
g. of sodium hydride-oil suspension and 100 cc. of dry
benzene is stirred under nitrogen. The reaction is started
with the addition or" a few drops of absolute ethanol and
stirring is continued for 23 hours. Ether (100 cc. is
added to the mixture which is then extracted with several
portions of water. The organic phase is dried and
EXAMPLE X
A solution or" 1.28 g. (4.05 mmoles) of 2-hydroxy
methylene-17?-hydroxy-4-androsten-3-one [Weisenborn et
al., J. Amer. Chem. Soc, 76, 552 (1959)] and 1.82 g. (8.1
mmoles) of O,N-bis-trifluoroacetyl)-hydroxylamine in 50
cc. of benzene and 2.42 cc. of pyridine is allowed to re?ux
with stirring for two hours. The cooled solution is washed
with two 10 cc. portions of water and the benzene phase
is dried and evaporated. The residue is triturated with
ether to give 1.16 g. (70%) of a crystalline solid with
melting point 2l2—216° C. Recrystallization from
methylene chloride-ether gives a sample with melting
point 212—217° C.; [a]D25+83.3° (c., 0.91 in CHCla);
REE; 4.4314 (w.), 5.61;; (s.), 5.91;i (s.), 6.15;; (W.); AQEQH
249 my (6 14,720) in acid, 242 my. (6 16,400) in meth—
anol, 330 my (6 6250) in base
The conversion of Z-hydroxymethylene-l7?~hydroxy-4
androsten-3-one to the 2oc~cyanotestosterone tri?uoroace
tate (Za-cyano-l7B-tri?uoroacetyl-4-audrosten-3-one) can
be carried out by stirring the reactants at room tempera
ture for 24 hours. After the usual workup, the desired
compound is isolated in 57% yield.
EXAMPLE XI
2u-Cyanotestosz‘erone (2ot-Cyan0i-17?-Hydr0xy-4
Androsten-3—One)
A suspension of 124 mg. (0.3 mmole) of the product of
Example X (Za-cyanotestosterune 17-tri?uoroacetate) in
5 cc. of methanol containing 0.6 cc. of 10% aqueous
potassium carbonate solution is stirred under nitrogen for
three hours. Most of the original solid goes into solu
tion during this period and another solid precipitates out.
After neutralization with a few drops of acetic acid, the
3,035,051
10
rial with melting point 193-195 ° (some earlier sintering);
mixture is evaporated. The residue is distributed be
tween water and methylene chloride and the organic phase
is washed with a little water and is dried and evaporated.
The yellow residue is decolorized with activated charcoal
in ether and is then crystallized and recrystallized from
loclnz5+2l2° (c., 0.95 in CHCIS);
REE; 4.441,“ (5.); 5.89-5.94,“ (s), 6.14,“ (m), no absorp
tion at 9.5;; (ketal region); NLEQH 250 me (a 16,300) in
acid, 242 H111 (6 16,300) in methanol, 330 In]; (e 6450)
in base
ether-hexane; 61 mg. (64%); melting point l55—l56°;
[oc]D25+119°; (c., 0.54 in CHClg);
EXAMPLE WI
REE; 2.82,u (111.), 4.43;.’ (W), 5.91;; (5.) broad peak,
Conversion of Z-Hydroxymethyleneprogesterone to 20:
6.16;; (m.); MYEQH 248 m” (6 17,970) in acid, 242 In,“
Cyanoprogesterone
10
(5 15,600 in methanol, 332 my (6 6710) in base
A solution of 342 mg. (1 mmole) of 2-hydroxymethyl~
eneprogesterone (Example III) in 15 cc. of dry benzene
is stirred under re?ux with 225 mg. (1 mmole) of O,N-bis
(trifluoroacetyl)—hydroxylamine and 0.3 cc. of pyridine for
To a chilled solution of 313 mg. (l mmole) of 2a 15 two hours. The yellow solution is cooled, diluted with 15
cyanotestosterone (Example XI) in 5 cc. of pyridine is
cc. of benzene and is then washed with several portions
added 1 cc. of acetic anhydride and the mixture is stirred
of Water. The dried solution (magnesium sulfate) is freed
in an ice bath for one hour at room temperature for 16
from solvent under reduced pressure and the residue is
hours. It is then added dropwise with stirring to 100 cc.
crystallized with ether and collected by ?ltration. The
of ice water and the solid which precipitates is collected,
solid is recrystallized from methylene chloride-ether to
washed well with Water and is dissolved in 35 cc. of
give 186 mg. (55%) of material with melting point
chloroform. The solution is washed once with water and
190—l95°.
is dried over magnesium sulfate, ?ltered and evaporated
EXAMPLE XVII
under reduced pressure. The residue (360 mg.) is dis
EXAMPLE XII
2a Cyanotestosterone Acetate
2 a-C'yanodeoxycorticosterone (2a-Cyan0-21-Hydr0xy-4
solved in 10 cc. of methanol and is stirred at room tem
Pregnen-3,20»Dione)
perature for ?ve minutes with 0.05 ml. of 10% aqueous
sodium hydroxide solution. The yellow mixture is neu
The reaction of Z-hydroxymethylenedeoxycorticosterone
tralized with a few drops of acetic acid and is evaporated
ZO-ethylene lretal (Example IV) (402 mg, l mmole) with
under reduced pressure at room temperature. The residue
450
(2 mmoles) of 0*,N-bis-(tri?uoroacetyl)-hydroxyl
is partitioned between water and methylene chloride and 30 amine and 0.7 cc. of pyridine in 15 cc. of benzene is car
the organic phase is washed once with water, dried over
ried out as described in Example X. The product, 200
magnesium sulfate and evaporated under reduced pres
cyano-ZO-ethylenedioxy-Z1-tri?uoroacetoxy-4-pregnen — 3
sure. The residue is crystallized and recrystallized from
one, is isolated as a glass (470 mg.) and is crystallized
ether to give 218 mg. of 2a-cyanotestosterone acetate.
from methanol. ‘It is dissolved with warming in 20 cc. ‘of
methanol, aqueous potassium carbonate solution (10%, 1
cc.) is added and the mixture is stirred under nitrogen for
EXAMPLE Xlll
2a-Cyzm0z‘est0ster0ne Propiomzte
one hour. There is then added 20 cc. of methanol and
1 cc. of 8% aqueous sulfuric acid and the mixture is
In the same manner, but using propionic anhydride and
heated under reflux for one hour. The acid is neutralized
crystallizing from acetone-hexane, there is obtained from 40 by stirring with an anion exchange resin (OH form) and
313 mg. (‘1 mmole) of 2e-cyanotestosterone 277 mg. of 2m
the solution obtained after ?ltration and washing of the
cyanotestosterone propionate.
resin with methanol is evaporated. The residue is dis
solved in ethyl acetate and water and the organic phase
EXAMPLE XiV
is separated, washed with a little water, dried and evapo
2a-Cyan0-20-EthyleI1edi0xy-4-Pregnen-S-One
rated. The residue is crystallized from methylene chlo
ride-ether, 184 mg. (52%) melting point 174—176° C.
The reaction of 386 mg. (l mmole) of ZO-ethylenedioxy
The analytical sample is recrystallized from a large volume
Z-hydroxymethylene-4-pregnen-3-one, prepared in Exam
of ether with activated charcoal; melting point l83~184°
ple II, with 225 mg. (l mmole) of O,N-bis-(tritluoroace
tyl)-hydroxylamine in 10 cc. of benzene and 0.3 cc. of
50
pyridine is carried out as described in Example X. The
crystalline residue is collected and washed with ether, 290
MYIZQH 248 ml.’ (6 15,200) in acid, 242 my (6 15,280) in
methanol, 3311 my (5 3325) in base
mg. (76%), melting point 258—260° C. [a]D25+115° (c.,
0.97 in CHC13);
15.13;, 4.43;; ('07.), 5.89,“ (S.), 6.141.:
AELEQE 249 my 55
(6 17,200) in acid, 242 my (6 17,270) in methanol,
To a chilled solution of 395 mg. (1 mmole) of Zea-Cy
EXAMPLE XV
60
and 3 cc. of ethanol. The mixture is heated on the steam
bath for one hour and is then evaporated. The residue
is dissolved in methylene chloride and water and the
mixture is stirred in an ice bath for 30 minutes and at
is extracted with several portions of chloroform.
Z-hydroxymethylene-4-pregnen-3-one as described in Ex
ample XIV. The crystalline product is dissolved partial
anodeoxycorticosterone (Example XVII) in 5 cc. of dry
pyridine is added 1.2 cc. of propionic anhydride and the
room temperature overnight. The solution is then added
slowly to 100 cc. of ice water and the resulting mixture
Crude 2a-cyano-20-ethylenedioxy-4-pregnen-3-one is
prepared from 700 mg. (1.83 mmoles) of ZO-ethylenedioxy
ly without drying in 10 cc. of water, 10 cc. of acetic acid
EXAMPLE XVIII
2a-Cyanodeoxycorticosterone 21-Pr0pi0nate
330 me (e 6440) in base
2a-Cyanoprogesterone (2u-Cyanc-4-Pregnene-3,20
Dione)
C.; [odD25+175° (c., 0.84, in EtOI-I), +208° (c., 0.41);
13,533.‘. 2.86/1. (m), 4.43” (w), 5.85—5.95,u (s.), 6.16/1 (m);
65
The
total extracts are washed with water and are dried over
magnesium sulfate, ?ltered and ‘evaporated under reduced
pressure. The residue is dissolved in 10 cc. of methanol
and the solution is stirred with 0.05 cc. of 10% aqueous
sodiurn hydroxide solution for three minutes and is then
organic phase is dried and evaporated. The residue is 70 neutralized with acetic acid. The solution is evaporated
and the residue is partitioned between methylene chloride
crystallized with ether and recrystallized (with activated
and water. The organic phase is washed with water,
charcoal) from methylene chloride-ether, 331 mg. (54%
C. For analysis, the material is recrystallized with acti
dried over magnesium sulfate, and evaporated under re
duced pressure. The partially crystalline residue is col
vated charcoal from a large volume of ether to give mate
75 lected with a small amount of ether and is recrystallized
over-all from starting material), melting point 191-195"
11
3,035,051
1?.
EXAMPLE XXIII
from acetone-hexane to give 206 mg. of 2a-cyanodeoxy
corticosterone 21-propionate,
hi5; 4.42;;, 5.80;;, 5.95;;, 810;;.
2u-Cyan0hydr0c0rtis0ne 21 -Acetate
Acetic anhydride (1 cc.) is added to a chilled solution
of 329 mg. (1 mmole) of 2a-cyanohydrocortisone (Exam
ple XXII) in 5 cc. of dry pyridine and the mixture is kept
EXAMPLE XIX
2ct-Cyanodeoxycorticosterone 21 -Acetate
at room temperature for 16 hours. The solution is then
added dropwise with stirring to 100 cc. of ice water and
the solid which separates is collected, washed with water
and dissolved in chloroform. The solution is dried over
In the same manner but using 1 cc. of acetic anhydride
there is obtained from 200 mg. Za-cyanodeoxycorticoster
one (Example XVII) 118 mg. of 2a-cyanodeoxycorti—
costerone 21-acetate.
10 magnesium sulfate, ?ltered and evaporated under reduced
pressure to leave a residue which is crystallized from ether
EXAMPLE XX
to give 354 mg. of a white substance, melting point 215
224". This material (125 mg.) is dissolved in 8 cc. of
Conversion of 2-Hydroxymethylenedeoxycorticosterone
t0 2a-Cyanodeoxycorticosterone
A solution of 358 mg. (1 mmole) of 2-hydroxy-methyl
enedeoxycorticosterone (Example V) 450 mg. of (2
methanol and solution is stirred for ?ve minutes at room
15 temperature with 0.05 cc. of 10% aqueous sodium hy
droxide solution and is then neutralized with a few drops
of acetic acid. The mixture is evaporated under reduced
pressure and the residue is dissolved in chloroform and
mmole) of O,N—bis-(tri?uoroacetyl)-hydroxylamine and
0.7 cc. of pyridine in 15 cc. of dry benzene is allowed to
re?ux for two hours and is then diluted with 25 cc. of ben 20 water. The organic phase is dried with magnesium sul
fate, ?ltered and evaporated under reduced pressure. The
zene. The solution is washed with several portions of
residue is crystallized from ether to give 88 mg. of prod
uct which, after two recrystallizations ‘from methylene
water, dried over magnesium sulfate and evaporated
under reduced pressure. The residue is collected with
ether and is dissolved in 15 cc. of methanol. Aqueous
chloride-ether, shows melting point 23 3-238°.
potassium carbonate solution (10%) is added to the mix 25
ture, which is stirred ‘under nitrogen for one hour and is
then neutralized with a few drops of acetic acid. The
mixture is evaporated under reduced pressure and the
residue is mixed with water and methylene chloride. The
organic phase is separated, washed with a little water and 30
is dried over magnesium sulfate, ?ltered and evaporated
under reduced pressure. The residue is collected with
ether and is recrystallized from a small amount of ethyl
acetate to give 103 mg. (33%), melting point 176-180“.
EXAMPLE XXI
EXAMPLE XXIV
1 7a,20;20,21-Bismethylenedioxy-Za-Cyano-Il-Pregnane
3,11-Di0ne
A mixture of 430 mg. (l mmole) of 2-hydroxy
methylene — l7a,20;20,21 - bismethylenedioxy-4-pregnene—
3,11-dione (Example VII) and 225 mg. (1 mmole) of
O,N-bis-(tri?uoroacetyl)-hydroxylamine is heated in 10 cc.
of benzene and 0.3 cc. of pyridine for one hour. The
mixture which becomes quite dark during this period
35 is diluted with 10 cc. of benzene and is washed with
Tri?uoroacetyl-4-Pregn en-3-0ne
several small portions of water. Evaporation of the dried
benzene phase left a dark gum which is puri?ed by solu
The reaction of 250 mg. (0.5 mmole) of 2-hydroxy
Treatment of the supernatant with activated charcoal
2a-Cyan0-20-Ethylenedi0xy-11;8,1 7a-Dihydr0xy-21 -
tion in acetone-hexane and decantation from a black oil.
~methylenehydrocortisone ZO-ethylene ketal (Example V1)
with 225 mg. (1 mmole) of O,N-bis-(tri?uoroacetyl)-hy
and partial evaporation with the addition of hexane gives
a white crystalline product, 107 mg. (25% ), melting point
droxylamine and 0.3 cc. of pyridine in 10 cc. of benzene
is carried out as described in Example X. The product is
crystallized from ether-hexane to give 87 mg. (30%) with
223-228° C. Several recrystallizations from ether
methylene chloride gives an analytical sample with melt
ing point 232-233°; [u]D25+9l.2° (c., 0.428 in Cl-lCla);
melting point 197—207° C. A sample recrystallized from 45
A525, 4.42;; (w.), 5.80;; (s.), 5.94;; (s.), 6.15;; (m.), REE“
ether with activated charcoal shows melting point 225
243 ml; (6 15,900) in acid, 238 111;; (6 14,350) in meth
277"; [u]D25—|-92.2° (c., 0.93 in CHCl3);
anol, 332 m;; (e 6200) in base
REE; 2.82;; (m.), 4.44;; (W.), 5.57;; (s.), 5.91;; (s.) broad
peak, 6.15;; (m.); X25523 248 m;; (e 16,100) in acid,
EX AMPLE XXV
EXAMPLE XXII
Za-Cyanocortisone (Zu-CyanO-I 7a,21-Dihydr0xy
4-Pregnene-3,11 ,ZO-Trione)
242 m;; (5 15,300) in methanol, 331 1:11;; (6 6320) in base 50
17u,20;20,21-bismethylenedioxy—2a-cyano-4-pregnene-3,
Za-CyanohydrocOrtisone (2u-Cyan0-115,17o;,21 -
ll-dione, 120 mg. (0.28 mmole) is heated with 5 cc. of
55 60% formic acid on the steam bath for 30 minutes. The
The compound prepared in Example XPG (200 mg.,
solution is evaporated and water is added to the residue.
0.38 mmole) in 7 cc. of methanol and 0.7 cc. of a 10%
The suspension is extracted with several portions of ethyl
aqueous potassium carbonate solution is stirred under ni
acetate and the combined extracts are dried and evapo
trogen for one hour. There is then added 18 cc. of meth
rated. The residue is crystallized from ethyl acetate,
anol and 1 cc. of an 8% aqueous sulfuric acid solution 60 53 mg. (50%), melting point 240-243“ C. The recrys
and the mixture is heated under re?ux with stirring for
tallizations from that solvent with activated charcoal
Trihydr0xy-4-Pregnene-3,20-Dione
one hour.
After neutralization with an anion exchange
resin (OH form), the ?ltrate and washings are evapo
rated. The residue is dissolved in a mixture of ethyl ace
tate and water and the water layer is washed with several 65
portions of ethyl acetate. The combined organic layers
are washed with a little ‘water, dried and evaporated to
give a residue which is crystallized from a small amount
gives a sample with melting point 246-247 °; [0;] D25+194°
(c., 0.638 dioxane);
REE; 2.86;; (m.), 4.45;; (W.), 5.90;; (s.) broad peak, 6.15;;
(m.),‘ ALEQH 242 m;; (6 18,500) in acid, 235 111;; (5 18,500)
1n methanol, 331 ml; (6 4930) in base
EXAMPLE XXVI
of hot ethyl acetate; 72 mg. (49%), melting point 220
2a-Cyan0cortis0ne 21 -Pr0pionate
222° C. A sample recrystallized twice from ethyl acetate 70
with activated charcoal shows melting point 235-237 °;
To a stirred, chilled solution of 385 mg. (1 111111016) of
[a]D25+l72° (c., 0.262 in methanol);
2u-cyanocortisone (Example XXV) in 5 cc. of dry
pyridine is added 1.2 cc. of propionic anhydride. The
km" 2.90;; (s.) broad peak, 4.45;; (w.), 5.84;; (m.), 5.95;;
(55’; 6.17;; (m.); its? 249 m;; (6 14,900) in acid, 243
m;; (5 14,330) in methanol, 330 m;; (e 5035) in base
yellow solution is stirred at room temperature for 16
75 hours and is then added dropwise to 60 cc. of ice water.
3,035,051
13
14
The light yellow precipitate which forms is collected,
EXAMPLE XXIX
dissolved in chloroform and the solution is washed with
a little water, dried and partially decolorized over mag
nesium sulfate and activated charcoal, ?ltered and evapo
rated under reduced pressure. The crystalline residue is
redissolved in 10 cc. of methanol and the solution is stirred
for a few minutes with 0.05 cc. of 8% acqueous potassium
hydroxide solution. The mixture is then neutralized with
a few drops of acetic acid and is evaporated under reduced
Conversion of 9a-Flu0ro~11,3,2]-Dihydroxy-2-Hydr0xy
methylene - 160:,17a - Isopropylidenedioxy-4-Pregnene
3,20-Dione to 2a-Cyan0-9a-Fluor0-1l 13,21 -Dihydr0xy
16a,] 7u-lsopropy lidenedi0xy-4-Pregnene-3,20-D ione
A solution of 464 mg. (1 mmole) of 9a-?uoro—1 15,211
dihydroxy-Z-hydroxymethylene - 1605,1711 - isopropylidene
dioxy-4-pregnene-3,20-dione (Example IX), 450 mg. (2
mmole) of O,N-bis-(tri?uoroacetyl')-hydroxylamine and
pressure. The residue is partitioned between methylene
chloride and water and the organic phase is washed with
0.7 cc. of pyridine in 15 cc. of benzene is allowed to
re?ux for two hours. The cooled solution is diluted
with 25 cc. of ‘benzene and is washed with water, dried
over magnesium sulfates, ?ltered and evaporated under
residue is recrystallized from acetone-hexane to yield
311 mg. of product.
15 reduced pressure. The residue is dissolved in 15 cc. of
methanol and is treated under nitrogen with 1 cc. of 10%
EXAMPLE XXVII
aqueous potassium carbonate solution for one hour at
room ‘temperature. The solution is neutralized with
2a-Cyano-9a-Flu0ro-11,8,2]-Dihydr0xy-16a,17oa
acetic acid and is ‘evaporated under reduced pressure.
Isopropyliderzedi0xy-4-Pregnene-3,20-Dione
The residue is dissolved in methylene chloride and water
The reaction of 9a-fluoro-11,B-hydroxy-Z-hydroxymeth 20 and the organic phase is washed with Water, dried over
ylene-16a,17a-isopropylidenedioxy-21-(tetrahydropyran-2
magnesium sulfate and evaporated under reduced pres—
yloxy)-4-pregnene-3,20-dione (Example VIII) (274 mg.,
sure. The residue is recrystallized from acetone-hexane
a small amount of water, dried over magnesium sulfate,
?ltered and evaporated under reduced pressure. The solid
0.5 mmole) with 225 mg. (1 mmole) of O,N-bis-(tri
to give 188 mg. (41% with melting point 290-295°
?uoroacetyl)-hydroxylamine and 0.4 cc. of pyridine in
(dec.).
10 cc. of benzene is carried out as described in Example X.
EXAMPLE XXX
The product, [Za-CYElIlO-9cz-?110rO-llB-hydr0Xy-16oz,17u
is opropylidene dioxy-2 1- (tetrahydropyr an-2-yloxy ) -4-preg
Z-Cyano-l ,4-iPregnadiene-3,20-Di012e
none-3,20-dione], (300 mg.) from this reaction is dissolved
A solution of 170 mg. (0.5 mmole) of Zen-cyano
in 20 cc. of methanol containing 1 cc. of 8% aqueous
progesterone (Example XVI) and 171 mg. of 2,3-di
sulfuric acid and the solution is stirred at room tem 30 chloro-5,6-dicyanobenzoquinone [1. Chem. Soc. 3569
perature for one hour. The mixture is neutralized by
(1954)] in 25 cc. of puri?ed dioxane is allowed to re?ux
stirring with an anion exchange resin (OH form) and
for 18 hours. The mixture is then evaporated under re
the ?ltrate and washings are evaporated. The residue is
duced pressure and the residue is mixed with 40 cc. of
crystallized from methanol with activated charcoal to 35 benzene and ?ltered. The benzene solution is washed
give 124 mg. (54%) with melting point 285-2900 (dec.).
A sample is recrystallized from acetone-hexane; melting
point 293-296° C. (dec.); [a]D25+13Z° (c., 0.58 in
acetone);
REE; 2.98,, (m.), 4.44;, (w), 5.82,, (s.), 5.91,, (s), 6.13,;
several times with Water and is then dried and partially
decolorized with magnesium sulfate and activated char
coal. The ?ltered solution is evaporated under reduced
pressure and the residue is crystallized with ether to
40 give 141 mg. (84%) with melting point 222-224"
(m.); A3552‘! 244 mp. (5 17,750) in acid, 238 my (6 17,300)
AMEOH 253 111,, an’ 4.41,, (ON), 5.81,, (20-k6‘b0118), 5.95,,
(3-ketone), 6.10,“ and 0.20,“ (0:0)
max.
in methanol, 333 m,“ (e 5990) in base
The base soluble (+FeCl3 test) gum from the mother
max.
liquors of the 2-hydroxymethylene derivative prepared
in Example VIII when taken through this reaction 45
sequence gives a 27% yield of the desired crystalline
A solution of 409 mg. (1 mmole) of 2oc-cyano-testoste
rone trifluoroacetate (Example X) in 40 cc. of puri?ed
EXAMPLE XXVIII
dioxane is re?uxed with 342 mg. of 2,3-dichloro-5,6
2 ca-CyanO-Qa-Fluoro-J 1 5,21 -D z'hydroxy-J 6 0a,] 7a-Is0pr0 50 dicyanohenzoquinon'e for 16 hours. The cooled solution
is evaporated and the residue is taken up in 30 cc. of
pylidenedioxy-4-Pregnene-3,20-D ion e 21 -A cetate
benzene and ?ltered. The benzene solution is washed
To a chilled, stirred solution of 230 mg. (0.05 mmole)
with several portions of Water and is dried over mag
of 2a-cyano-9a-?uoro - 115,21 - hydroxy-16a,17a-isopro
nesium sulfate. The ?ltered solution is freed ‘from solvent
pylidenedioxy-4-pregnene-3,20-dione (Example XXVII) 55 under reduced pressure and the residue is crystallized
in 4 cc. of dry pyridine is added 0.6 cc. of acetic anhydride.
from other to give 327 mg, melting point 255—2.57°;
The solution is stored at room temperature for 16 hours
[a]D25~—24-.7° (0., 1.33 in CHCl3);
Zea-cyano compound.
‘and is Then added to 35 cc. of water.
The mixture is
155;. 4.49”, 562,1, 5.95% 6.02,, (W), 6.12,, (w.), 6.23,,
(W); A332? 245 m“ (6 10,987)
extracted with several portions of chloroform and the
total extracts are washed with water, dried over mag
We claim:
nesium sulfate and evaporated under reduced pressure.
The residue is redissolved in 8 cc. of methanol and 0.03
1. The compound 2a-cyanotestosterone trifluoroacetate.
2. The compound 2zx-cyanotestosterone.
cc. of 10% sodium hydroxide in Water is added. The
3. The compound 2a-cyano-ZO-ethylenedioxy-4-preg
mixture is shaken manually for a few minutes and is
nen-3-one.
then neutralized with a few drops of acetic acid and is 65
4. The compound 2a-cyanodeoxycorticosterone.
5. The compound 2a-cyano-20-ethylenedioxy-l 1,6,1701
evaporated under reduced pressure. The residue is dis—
tributed between chloroform and Water and the chloro
dihydroxy-21-tri?uoroacetoxy-4-pregnen-3-one.
form phase is dried over magnesium sulfate, ?ltered and
evaporated under reduced pressure to leave a crystalline
residue which is recrystallized from methylene chloride
ether to yield 176 mg. of product showing
18.1011
h5g1 299,14,
(s.); A2152‘;
4.44;; 239
(W),my5.79;;
(6 17,700);
(5.), 5.95”
335 (S),
mp. (e
6.13;;
5970) in
ase
70
6. The compound 2a-cyanohydrocortisone.
7. The compound 2a-cyano-17a,20,20,2l-bismethylene
dioxy-4-pregnene-3,1l-dione.
8. The compound Za-CYBBOCOI‘?SOHG.
9. The compound 20: - cyano - 9o; - ?uoro-11,8,2l-dihy
droxy-l6a,17oc - isopropylidenedioxy - 4 - pregnene - 3,20
75 dione.
3,035,051
16
15
and
10. The compound 2a-cyanoprogesterone.
11. The compound Z-cyano-1,4-pregnadiene-3,20-dione.
12. The compound 2-cyano-17B-hydroxy-1,4-androsta
dien-3-one.
110(5)
‘C
.
/
H, \
and the corresponding
13. The compound 2-hydroxymethylene-17a,2G;20,21,
bisrnethylenedioxy-4-pregnene-3, 1 l-dione.
methylene - 16a,17a-isopropylidenedioxy-21-(tetrahydro
groups
1,2-double bonded
derivatives.
18. A compound selected from those having the
pyran-Z-yloxy) -4-pregnene-3,20-dione.
formula:
14. The compound 9a-?uoro-l1/3-hydroXy-2-hydroxy
15. The compound 9a-?uoro-1/1,8,21-dihydroxy-2~hy
droxymethylene-l 6 a, 17 a-isopropylidenedioXy-4-pregnene
3,20-dione.
16. A process of preparing 2a-cyanoA4-3-ketosteroids
10
(I)R
which comprises treating a A4-3-ketosteroid having in the
2-position a radical selected :from the group consisting of 15
formyl and tautomeric forms of formyl radicals with
O,N-bis-tri?uoroacetylhydroxylamine and recovering said
compound therefrom.
17. A compound selected from those having the
formula:
wherein R is a member of the group consisting of hydro
20 gen, lower alkanoyl and tri?uoroacetyl radicals and the
corresponding 1,2-double bonded derivatives.
19. A compound of the formula:
mm
C Hr-Rg
25
my
wherein R1 is a member of the group consisting of hydro
gen and hydroxyl radicals, R2 is a member of the ‘group
consisting of hydrogen, hydroxy, lower alkanoyloxy and
tri?uoroacetoxy radicals, Z is a member of the group
consisting of oxygen and ethylenedioxy radicals and X
is a member of the group consisting of
/
(EH7, 0:?
wherein R1 and R2 are lower alkyl and R3 is a member
- of the group consisting of hydrogen, hydroxyl, lower
alkanoyloxy vand tri?uoroacetoxy radicals.
/
40
References Cited in the ?le of this patent
UNITED STATES PATENTS
Ringold et al ___________ __ Aug. 2,‘ 1960
2,947,762
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