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Патент USA US3080390

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United States Patent O?ice
1
3,68%,381
Patented Mar, 5, 1963
2
acids, which exist as an equilibrium mixture of the alde
hydo-acid and lactol forms as is represented below:
3,080,381
OPTIONALLY G-METHYLATED AND OPTIONAL
LY 17-ALKANOYLOXYGENATED Z-OXAPREG
NANE-3,20-DIONES, A-HOMO COMPOUNDS CQR
RESPONDING, AND 4,5-DEHYDRO AND 4,5;6,'7
BISDEHYDRO DERIVATIVES THEREOF
Raphael Pappo, Skolrie, Ill., assignor to G. i). Searle &
(30., Chicago, IiL, a corporation of ‘Delaware
No Drawing. Filed Feb. 16, 1962, Ser. No. 173,800
17 Claims. (Cl. 260-3433)
10
The present invention relates to A-ring oxygenhetero
cyclic steroids of the pregnane series and, more particular
ly, to optionally 6-methylated and optionally l7-alkanoyl~
oxygenated
2-oxapregnane-3,2-diones,
A-horno
com
pounds corresponding, and 4,5-dehydro and 4,5;6,7-bis 15
dehydro derivatives thereof, which can be represented by
the formula
CH3
CHi
20
it,
in which representation R and R’ have the identical mean
25 ings indicated supra. The 2-oxa-A4 compounds of this
invention which possess an oxygenated function at carbon
atom 17 are obtained directly by reduction of the latter
1,2-seco-2-oic acids, suitably by means of a reducing agent
such as sodium borohydride.
In the case of the instant
30 2-oxa-A4 compounds which lack a l7-oxygen-containing
wherein A is a methylene or ethylene radical, R can be
hydrogen ‘or ‘a (lower alkanoyl)oxy radical, R’ and R"
function, this reduction step results also in conversion of
the 20-ox-o group to a ZO-hydroxy function. Oxidation of
the resulting 20-hydroxy substances, suitably bymeans of
chromic acid, ‘affords the desired instant 2'-oxapregn-4-ene
can be hydrogen or a methyl radical, and the dotted lines ‘
indicate the optional presence of double bonds between 35 3,20-diones. These processes are speci?cally illustrated
‘by the reaction of pregna-1,4-diene-3,20-dione with potas~
carbon atoms 4 and 5 and between carbon atoms 6 and 7.
The lower alkanoyl radicals encompassed by the R term
are, typically, formyl, acetyl, propionyl, butyryl, valeryl,
sium chlorate and osmium tetroxide in aqueous tertiary
butyl alcohol to yield 1,2-dihydroxypregn-4-ene-3,20
di-one, cleavage of the latter 1,2-dial by means of lead
caproyl, and the branched-chain isomers thereof.
Star-ting materials suitable for the manufacture of the 40 tetracetate in aqueous acetic acid to produce 1,20-dioxo
l,2-seco-A~norpregn-3-en-2-oic acid, reduction of the lat:
instant l0-methyl-2-oxa compounds are the pregna-l,4
ter aldehyde-acid in chloroform with alkaline sodium
diene-3,20-diones of the structural formula
borohydride to afford 20-hydroxy-2-oxapregn-4-en-3-one,
CH3
CH3
=0
and oxidation of that ZO-hydroxy substance in acetone
45 with aqueous chromic acid to yield 2-oXapregn-4-ene-3,20
dione.
Catalytic hydrogenation of the instant 2-oxa-A4 com
pounds, preferably in the presence of a palladium catalyst,
affords the 2-oxa-4,5-dihydro compounds of this inven
50 tion. For example, the aforementioned 2-oxapregu-4-ene
3,20-dione in ethanol is treated with hydrogen in the
presence of 10% palladium-onacarbon catalyst to aiford
a mixture of the 50¢ and 5,9 isomers of 2-oxapregnane-3,20
Q__
dione, which are separable chromatographically. These
55 4,5-dihydro compounds are obtained also in the aforemen
R!
tioned sodium borohydride reduction process of the inter
mediate :aldehydo-acids. For example, the reduction of
wherein R is hydrogen or a (lower alkanoyDoxy group
1,20-dioxo - 1,2 - seco - A -, norpregn-B-en-Z-oic acid, de
and R’ is hydrogen or a methyl radical. These 1,4-dienes
are converted to the corresponding 1,2-diols, suitably by 60 scribed supra, attords also 20-hydroXy-2-0Xapregnan-3
CH3 iinR
|
reaction with potassium chlorate in the presence of a cata~
one.
lytic quantity of osmium tetroxide. Cleavage of these 1,2
diols, preferably by treatment with lead tetracetate, pro
duces the intermediate 1,2-seco-A-norpregn-3-en-2-oic
the 50c and 5B epimers of 2-oxapregnane-3,20-dione.
A method particularlysuitable for the preparation of
the 4,5;6,7-bisdehydro compounds of this invention uti
Chromic acid oxidation of that substance affords
4
3
stances are obtained by bromination of the corresponding
compounds of the formula
lizes as the starting material, a compound of the for
mula
CH3
CHa
=0
OH:
j.
I
10
15
RI
followed by reaction with an alkali metal acetate and
hydrolysis of the resulting 2a-ace'toxy compound. As a
speci?c example, l7a-acetoxypregn-4-ene-3,ZO-dione is
wherein R is a lower alkanoyl radical of the type de?ned
treated with N-bromosuccini'mide' in-carbon tetrachloride,
above, and R’ can be hydrogen or a methyl radical. As
and the resulting 6-bromo derivative is allowed to react
a speci?c example, 17a-acetoxy - 3 5 - hydroxy-6-methy1 20
with potassium acetate in acetic acid to yield 20¢,17oc-di
pregn-S-en-ZO-one is epoxidized, typically with perben
acetoxypregn-4-ene-3,ZO-dione. Hydrolysis of that ace
zoic acid, to produce 17ot-?CCtOXy-50t,6a-6pOXy-3?-hy
tate,
for example with potassium hydroxide in aqueous
droxy-6,8—methylpregnan-ZO-one together with the cor
methanol, affords l7ot-acetoxy - 2a - hydroxypregn-4-ene
responding 5B,6B-epoxide. Reaction of either of the 'lat
3,20-dione. The 2a-hydroxy intermediates containing a
ter 'epoxides in acetone with aqueous chromic acid af 25 6a-methyl substituent are preferably obtained by reacting
fords 17et-acetoxy - 50;,6/9 - dihydroxy-6a-methylpregnane
the 6a-methyl substances represented by the latter struc
3,2=0-dione, which yields 17a-acetoxy-6?-hydroxy-6a
tural formula with lead 'tetracetate in acetic acid. Hy
methylpregna-l,4-diene-3,2‘O—dione upon treatment with
drolysis of the resulting Za-acetoxy derivative affords the
dichlorodicyanoquinone in benzene. The corresponding
211 -hydroxy intermediates. Typically, 17a
isomeric 6m-hydroxy-6?-methyl compound vis obtained by 30 required
acetoxy-6a-methylpregn-4-ene-3,20-dione is allowed to re
reacting the aforementioned 17oz-acetoxy-5a,6a-epoxy
act with lead tetracetate in acetic acid to yield 2u,17a-di
3/S-hydroxy-63-methylpregnan-20-one with chromium tri
acetoxy-6a-methylpregn-4-ene-3,2l0-dione, which affords
oxide in pyridine to afford 17a-acetoxy-6ot-hydroxy-6B
l7ot-acetoxy - 2a - hydroxy-6a-methylpregn-4-ene-3,2'0-di
methylpregn-4-ene-3,20-dione, and allowing the latter
one upon reaction with potassium hydroxide in aqueous
compound to .react with dichlorodicyanoquinone in ben
35
zene, thus producing .l,7u'-acetoxy-6a-hydroxy-6?-methyl7
pregna-1,4-diene-3,20-dione. Either of the .two 69h)’,
droxy-G-methyl isomers can be utilized in the following
sequence of reactions to obtain the desired compounds of
this invention. Typically, l7a-acetoxy-6?1hydroxy-6a
methylpregna-l,4-diene-3,20-dione is converted to the
corresponding 1,2-g1ycol upon reaction with osmium te
40
methanol.
Reaction of the aforementioned Za-‘hYdI'OXY interme
diates with periodic acid in aqueous pyridine results in
cleavage of the A-ring to yield the corresponding 2,20
dioxo-2,3-secropregn-4-en-3-oic acids, which are in equi
hbnum with the lactol form, as is represented below:
.
.
.
troxide and potassium-chlorate in aqueous tertiary-butyl
alcohol. Cleavage of that glycol with lead tetracetate and
acetic acid aifords 17a-acetoxy-6?-hydroxy-6a-methyl~1
oxo-1,2-seco-A-norpregn-3-en-2-oic acid, which is con
verted to 17a-acetoxy-6B-hydroxy-6a-methyl-2-oxapregn
4-ene-3,20-dione by reduction, suitably with sodium boro
hydride in isopropyl .alcohol. Dehydration of that 6
hydroxy compound, suitably by heating in toluene solu
tion with p-toluenesulfonic acid or, alternatively, by re
action with phosphorus oxychloride in pyridine, results
in the instant l7a-acetoxy-6-methyl-Loxapregna'4,6-di
ene-3,20-dione.
Reaction of the latter 2-oxo-2,3-seco intermediates with
A process particularly advantageous for the manufac 55 a suitable reducing agent produces the corresponding 2
lure of the v3-oxa compounds of this invention utilizes as
the starting material a compound of the formula
hydroxy compounds, which are converted to the instant
3-oxa-4-ones by heating. Those intermediates lacking a
l7a-(lower alkanoyDoxy snbstituent produce 2,20-dihy
CH3
CH:
:0
CH? i___R
droxy derivatives upon reduction, thus necessitating an
60 additional oxidation step to regenerate the ZO-keto group.
The latter processes are speci?cally illustrated by the re
action of 2a-hydroxypregn-4-ene-3,20>dione with pe
riodic acid dihydrate in aqueous pyridine to afford 2,20
dioxo-2,3-secopregn-4-en-3-oic acid, which is treated with
65
aqueous sodium borohydride, resulting in 2,20-dihy
droxy-2,3 -secopregn-4-en-3-oic acid. The latter hy
HO——
0:
I'll
droxy-acid is heated at about 100° to yield 20-hydroxy-3
oxa-A-hornopregn-4a-en-4-one, which is oxidized, for ex
70 ample with chromium trioxide in acetone, thus producing
3-oxapregn-4a-ene-4,20~dione.
,
The 19-nor compounds of this invention are conven
iently manufactured by utilizing as a starting material,
wherein R is hydrogen or a (lower alkanoyDoxy radical,
6-.oxo-5a-pregnane-S'B,20?-di0l ~3,20-diaceta'te, described
and R’ is hydrogen or a methyl radical. Thelatter sub 75 by I. Iwai and J. Hiraoka, Chem. and Pharm. Bull.
3,080,381,
5
"t3
phorus oxychloride and pyridine to afford the desired
Japan, 7:395 (1959). Reaction of this material with
hydrogen and platinum oxide in acetic acid or reaction
with methyl magnesium bromide, followed by acidi?ca
tion and reacetylation, aifords the 6,8-hydroXy and 6,8
hydroxy-Ga-methyl compounds, respectively, of the struc
tural formula
2-oxa compounds of the structural formula
.
CH3
CH;
OK
I
CH3
we t
CHO C-—~CHa
CH3
1O
15
/
wherein R is hydrogen or a (lower alkanoyDoxy radical
and R’ is hydrogen or a methyl radical.
The latter processes are speci?cally illustrated by the
following sequence of reactions. The aforementioned
6-oxo-5a-pregnane-3[3,20?-diol 3,20-diacetate is treated
with hydrogen and platinum oxide in acetic acid to afford
5a-pregnane-35,6,43,20,8-triol 3,20-diacetate, which is con
verted to 6e,19-epoXy-5a-pregnane6d20?-diol 3,20-di
acetate by reaction with lead tetracetate. Hydrolysis of
wherein R’ is hydrogen or a methyl radical. Reaction
25 the latter di-ester by means of sodium hydroxide, fol
of the latter substances with lead tetracetate affords the
lowed by chromic acid oxidation produces 6,8,19-epoxy
corresponding 66,19-epoxy compounds, which are hydro
Sa-pregnane-3,ZG-dione. Bromination followed by de
lyzed, typically with alkali, to afford the 6,6,l9-epoxy
hydrobromination, typically by heating with collidine,
3,20-diols. Oxidation of these diols, for example with
chromic acid, produces the corresponding 65,19-epoxy
yields 6/3,l9-epoxy-5a-pregn-l-ene-3,ZO-dione, which is
treated with chromium trioxide to afford the correspond
3,20-diones. The latter diones are converted to the cor
ing 19-oxo compound. Treatment of that substance with
alkali followed by acetylation with acetic anhydride re
sults in 6,8-acetoxy-l9-nor-5a-pregn-1-ene-3,20-dione. Re;
responding l7a-acyloxy intermediates, suitably by the fol
lowing sequence of reactions. The 3-keto group is pro
tected by treatment with methanol and acid to yield the
action of this compound with lead tetracetate and osmium
dimethyl ketal, which is treated with oxygen in the pres—
tetroxide affords 6/3-acetoxy—l-hydroxy-2-oxa-19-nor-5a
ence of potassium tertiary-butoxide, then with zinc and
pregnane-3,20-dione. Reduction of the latter lactol, suit~
acetic acid to introduce the l7u-hydroxy moiety. Acyla
ably with sodium borohydride, followed by acidi?cation
tion of these 17¢x-01S, typically by means of a lower
and treatment with chromium trioxide produces 6,8-acet
alkanoic acid anhydride in the presence of the lower
oxy-Z-oxa-l9-nor-5ot-pregnane-3,20-dione. Reaction with
alkanoic acid affords the corresponding 17a-alkanoates. 40 alkali to afford the 6,8-01, then dehydration, typically
By the aforementioned processes are provided inter
with phosphorus oxychloride and pyridine, affords 2-oxa
mediates of the structural formula
l9-norpregn-4-ene-3,ZO-dione.
When the aforementioned 6-oXa-5ot-pregnane-3B,20_B
diol 3,20-diacetate is treated with methyl magnesium
bromide in tetrahydrofuran, the resulting product, after
acidi?cation and reacetylation, is 6u-rnethyl-Sa-pregnane
3p,6?,20[>’-triol 3,20-diacetate. Utilization of this starting
material in the processes described supra results in 60:
methyl-2~oxa-l9-norpregn-4-ene-3,ZO-dione.
50
The
aforementioned
6,8,l9-epoxy-5a-pregnane—3,20
dione can be converted to the corresponding 17a-acetoxy
compound by ketalization of the 3-oxo group with meth
anol in the presence of a mineral acid, then introductionv
of the 17-hydroxy group by reaction with oxygen in they
presence of potassium tertiary-butoxide followed by treat
ment with zinc and acetic acid, and ?nally acetylation
with acetic anhydride and acetic acid in the presence of
an acid catalyst. The resulting l7a-acetoxy-6?,l9-epoxy
Sa-pregnane-S‘JO-diOne can be converted to l7a-acetoxy
wherein R is hydrogen or a (lower alkaneyDoxy radical
and R’ is hydrogen or a methyl radical. Treatment of
Z-oxa-19-norpregn-4-ene-3,ZO-dione by the aforementioned
processes.
these intermediates with bromine followed by dehydro
The compounds of this invention display valuable phar
bromination, typically by heating with collidine, yields
macological properties. v‘They are hormonal agents as is
the corresponding l-dehydro compounds, which are oxi
dized with chromic acid, then treated with alkali and
activity. '
evidenced, for example, by their potent progestational
,
?nally acetylated to afford the corresponding 6,8-acetoxy 65 _ The invention will appear more fully from the examples
which follow. These examples are set forth by way of
l9-n0r substances. Cleavage of the 1,2-double bond, suit
ably by reaction with lead tetracetate and osmium tetrox
ide, followed by treatment with a reducing agent such as
illustration only and it will be understood that the inven
tion is not to be construed'as limited in spirit or in scope
sodium borohydride, then regeneration of the 20-oxo 70 by the details contained therein, as many modi?cations in
acyloxy substituent, affords the 6?-acetoxy-2-oxa-3,20—
materials and methods will be apparent from this dis
closure to those skilled in the art. In these examples,
diones. Reaction of these substances with alkali affords
the corresponding 6B~hydroxy compounds, which are de
temperatures are given in degrees centigrade ,(° C.).
Quantities of materials are expressed in parts by weight
group in the case of the compounds lacking the 17m
hydrated and isomerized, typically by means of phos 75 unless otherwise noted.
3,080,381
8
7
This application is a continuation-in-part of my co
pending application Serial No. 150,662, ?led November
7, 1961.
Example 1
A solution of 65; parts of pregna_l,4-diene-3,20-dione
in 1170 parts of‘ tertiary-butyl alcohol is diluted with
1300 parts of water, and ‘the resulting suspension is
treated successively with 12.42 parts of potassium chlorate
and 6.21 parts of osmium tetroxide. This suspension is
concentrated under nitrogen at room temperature to af~
ford a residue which is extracted with benzene. The
benzene layer is washed successively. with Water, aqueous
sodium hydroxide, and water, then dried over anhydrous
sodium sulfate, and concentrated to dryness at reduced
pressure. Recrystallization of this residue from isopropyl
alcohol affords pure 2-oxapregn-4-ene-3,20-dione, M.P.
about 168-169". It is further characterized by an ultra
violet absorption maximum at about 223.5 millimicrons
with a molecular extinction coe?icient of about 14,150,
stirred at room temperature for about 2 weeks, then is 10 and is represented by the structural formula
concentrated at room temperature and reduced pressure
CH3
CH3
to about 500 parts by volume. The black oily layer
which forms is separated and dissolved in 294 parts of
pyridine, treated with 10 parts of sodium bisul?te in 150
parts of ‘water, then stirred at room. temperature for about
15 hours. This mixture is extracted with benzene, and
=0
CH3
the organic layer is separated, Washed successively with
dilute hydrochloric acid, water,v aqueous sodium hydrox
ide, and water, dried over anhydrous sodium sulfate, and
evaporated to dryness at reduced pressure. Recrystal
lization of the residue from benzene aifords pure 1,2-di
hydroxypregn-4rene-3,ZO-dione, which melts at- about 162
1735‘; It, exhibit maxima- in. the infrared at about 2.80,
2:88, 3.41, 5.90, and 6.18 microns and also an ultraviolet 25
absorption maximum at about 239 millimicrons with a
molecular extinctionv coe?icient of about 12,100.
Example 2
To a solution of 355- parts of 1,2-dihydroxypregn-4
ene-3,2_0-dione in 84 partsv of acetic acid containing 12 30
parts of water is added 13.64 parts of lead tetracetate,
and thisv reaction mixture is stirred at 50-60° for about
1% hours. The. unreacted tetracetate is destroyed by
the, addition of 0.6 part of formic acid, and the result
ing solution is diluted with water, then extracted with
chloroform. The chloroform layer is washed successively
with, dilute aqueous potassium carbonate and water, dried
over anhydrous sodium sulfate, and evaporated to dryness
at reduced pressure. Trituration of the crystalline resi
due with boiling benzene yields 1,20-dioxo-1,2-seco-A
norpregn-3-en-2-oic acid, M.P. about 213-220“. It is
furtherv characterized by an ultraviolet absorption maxi
mum of about 226.5 millimicrons with a molecular ex
tinction coe?icient of about 14,300.
Example 3.
°/\l
‘bk/
Example 5
A solution of 50 parts of 17a-acetoxypregna-1,4-diene
3,20-dione in 1,092 parts of tertiary-butyl' alcohol is
diluted with 700 parts of water, and the resulting mix
ture is treated with 7 parts of potassium chlorate and
3.5 parts of osmium tetroxide. This reaction mixture
is stirred at room temperature for about 28 days, then
is concentrated at reduced pressure to a volume of about
200 parts. Extraction of this residual mixture with chlo~
roform affords an organic solution, which is concentrated
to dryness. Fractional crystallization of the residue from
benzene affords 17a-acetoxy-4,S-dihydroxypregn-l-ene
3,20adione
and
l7a-acetoxy-1,2-dihydroxypregn-4-ene
3,20-dione.
The substitution of an equivalent quantity of 17a~pro
pionoxypregna-l,4-diene-3,20-dione in the process of this
example results in 4,,5-dihydroxy-17a-propionoxypregn-1
ene-3,20-dione and 1,2-dihydroxy-17a-propionoxypregn
4-ene-3,20-dione.
Example 6
To 9 parts of the mixture of 17 u-acetoxy-4,5-dihydroxy
pregn - 1 - ene - 3,20 - dione and 17a. - acetoxy - 1,2 - di
hydroxypregn-4-ene-3,20-dione dissolved in 105 parts of
acetic acid containing 10 parts of water is added 30.3
‘ To. a solution of one part of 1,20-dioxo-1,2-seco-A
norpregn-3-en-2-oic acid in 19.4v parts of chloroform is
parts of lead tetracetate, and the resulting reaction mixture
is stirred at 50—60° for about 1% hours. This mixture is
added a solution of one part of sodium borohydride in
13,. parts of water containing 1.3 parts by volume of 10% 50 diluted with chloroform, then washed successively with
aqueous sodium hydroxide, and the resulting mixture is
water, dilute aqueous potassium carbonate, and water
dried over anhydrous sodium sulfate, and evaporated to
stirred at room, temperature for about four hours. The
layers are, then separated, and the organic solution is
dryness. Trituration of the residue with benzene followed
washed successively with dilute aqueous; sodium hydroxide,
by recrystallization from chloroform results in pure 17a
and water, dried over anhydrous sodium sulfate, and 55 acetoxy - 1,20 - dioXo - 1,2 - seco - A - norpregn - 3 - en
evaporated to dryness. The. residue is. crystallized from
2-oic acid, which melts at about 285-288”. It displays a
maxima in the ultraviolet at about 226 millimicrons with
ether tov a?iord a, mixture of the 20m and 20p isomers of
20-hydroxy-2-oxapregna4-en-3-one, melting at about 170a molecular extinction coe?icient of about 14,400.
By substituting an equivalent quantity of the mixture
176".
The aqueous alkaline layer from the chloroform ex 60 of 4,5 - dihydroxy - 17a - propionoxypregn - 1 ene - 3,20
dione and l,Z-dihydroxy-l7a-propionoxypregn-4-ene-3,20
traction is acidi?ed, then extracted with chloroform to
yield an organic solution, which is washed successively
dione in the procedure of this example, l,20-dioxo-l7a
with dilute sodium hydroxide and water, dried over an
propionoxy-1,2-seco-A-norpregn-3-en-2-oic acid is ob
hydrous sodium sulfate, and evaporated to dryness. Re
tained.
crystallization of the residue from ether affords a mix 65
Example 7
ture of ‘the epimeric 20-hydroxy-2-oxapregnan-3-ones,
A mixture of 2.73 parts of 17u-acetoxy-l,20-dioxo-l,2
melting at about 192-200“.
seco-A-norpregn—3-en-2-oic acid, 2.7 parts of sodium
Example 4
borohydride and 35.6 parts of isopropyl alcohol is stirred
To a solution of 6 parts of 20-hydroxy-2-oxapregn-4 70 at room temperature for about 10 minutes, at the end of
which time the mixture becomes homogeneous. This
en-3-one in 16'parts of acetone is added dropwise, 6
solution is allowed to stand at room temperature for about
parts by volume of an aqueous solution, 8 N in chromium
1% hours, then is cooled by means of an ice bath and
trioxide and 8 N in sulfuric acid. The addition of a
treated with 40 parts of acetone. This mixture is poured
small quanttiy of isopropyl alcohol results in destruc
tion of the excess reagent, and the resulting solution is 75 into an ice-cold solution containing 40 parts of acetone,
‘3,080,381
10
9
By substituting an equivalent quantity of 1,2-dihy
200 parts of Water, and 12 parts of concentrated hydro
chloric acid. Removal of the solvents by evaporation at
droxy - 6a - methyl - 17a - propionoxypregn - 4 - ene
3,20-dione and otherwise proceeding according to the
processes of this example, 6a-methyl-1,20-dioxo-17a-pro
pionoxy-1,2-seco-A-norpregn-3-en-2-oic acid is obtained.
reduced pressure affords a residue, which is extracted
with chloroform. The resulting organic solution is sep
arated, Washed successively with cold dilute aqueous
sodium hydroxide and water, dried over anhydrous so
dium sulfate, then evaporated to dryness at reduced pres
sure. Recrystallization of the residue from isopropyl alco
hol results in 17a-acetoxy-2-oxapregn-4-ene-3,20-dione,
Example 11
A solution of 7.39 parts of 1,2-dihydroxy-6a-methy1
which melts at about 269-275". It displays an ultraviolet 10 pregn-4-ene-3,20-dione in 170 parts of acetic acid con
taining 25 parts of water is treated with 27.28 parts of
absorption maximum at about 223.5 millimicrons with a
molecular extinction coe?icient of about 14,900. It is
represented by the structural formula
CH3
CH3
__
CH3
|
lead tetracetate, and the resulting reaction mixture is
heated with stirring at 50-60" for about 2 hours. The
addition of 1.2 parts of formic acid destroys the unre
15 acrted reagent. Water is then added, and the aqueous
mixture is extracted with chloroform. The organic layer
0
is puri?ed by successive washings with dilute aqueous
O /
jnO C-CH:
potassium carbonate and water, then is dried over anhy
drous sodium sulfate. Concentration to dryness in vacuo
20
produces 6a-methyl-1,20-dioxo-1,Zeeco-Amorpregn-S-en
2~oic acid.
Example 12
The substitution of an equivalent quantity of 6a-methyl
1,ZO-dioxo-1,2-seco-A—norpregn-3-en-2-oic acid in the pro
cedure of Example 3 results in 20d1ydroxy-6a-methyl
The substitution of an equivalent quantity of 1,20-dioxo
17a-propionoxy-1,2-seco-A-norpregn-3-en-2-oic acid in the
process of this example affords 17oc-propionoxy-2-oxa-\
2-oxapregn-4-en-3-one.
pregn-4-ene-3,20-dione.
Example 13
Example 8
30
By substituting an equivalent quantity of 20-hydroxy
6a-methyl-2-oxapregn-4-en-3-one and otherwise proceed
To a solution of 10 parts of l7a-acetoxy-6a-methyl
ing according to the processes of Example 4, 6a-methyl—
pregna~l,4-diene-3,20-dione in 70.6 parts of pyridineis
2-oxapregn-4-ene-3,20-dione is obtained. It is repre
added, at 5°, a solution of 6.64 parts of osmium tetroxide
sented by the structural formula
in 39.2 parts of pyridine. This reaction mixture is stored
at'room temperature for about 5 days, then is stirred with 35
a solution of 30 parts of sodium bisul?te in 500 parts of
water containing 294 parts of pyridine for about 15 hours.
CH5
CH3
This aqueous mixture is extracted with chloroform, and
the organic layer is Washed successively with Water, cold
dilute hydrochloric acid, and water, dried over anhydrous 40
sodium sulfate, and evaporated to dryness at reduced
pressure to afford 17a-acetoxy-1,2-dihydroxy-6u-methyl
pregn-4-ene-3,2O-dione.
G=O
CH3
.
-
The substitution of an equivalent quantity of 6a-methyl
17u-propionoxypregna-1,4-diene-3,20-dione in the process 45
of this example results in 1,2-dihydroxy-6oa-methyl-17o:
propionoxypregn-4-ene-3,20-dione.
Example 9
A solution of 10 parts of 6a-methylpregna-1,4-diene 50
3,20~dione in 75 parts of pyridine is cooled to about 5°,
then is treated with a solution of 5.7 parts of osmium
tetroxide in 40 parts of pyridine. After standing at room
temperature for about 5 days, a solution of 30 parts of
sodium bisul?te in 500 parts of water containing 300 55
parts of pyridine is added, and the resulting mixture is
stirred for about 16 hours.
Example 14
The substitution of an equivalent quantity of 17a-ace
toxy-6a - methyl - 1,20-dioxo-1,2~seco-A-norpregn-3-en-2
oic acid or 604 - methyl - 1,20 -dioxo-17a-propionoxy-1,2
Extraction of this aqueous
seco-A-norpregn-3-en-2-oic acid in the procedure of Ex
ample 7 results in 17a-acetoxy-6a-methyl-2-oxapregn-4
is Washed successively with Water, dilute hydrochloric
acid, and water, then dried over anhydrous sodium sul 60 ens-3,20-dione of the structural formula
fate, and concentrated to dryness in vacuo to afford 1,2—
mixture with chloroform yields an organic solution, which
dihydroxy-6oc-methylpregn-4-ene-3,20-dione.
Example 10
A solution of 3 parts of 17a-acetoxy-1,2-dihydroxy-6a 65
methylpregn-4-ene-3,ZO-dione in 35 parts of acetic acid
containing 3.3 parts of water is treated with ‘10.1 parts of
‘lead tetracetate. This reaction mixture is heated at 50—
60°, with stirring, for about 2 hours, then is cooled and
diluted with chloroform. The resulting mixture is washed 70
successively with water, aqueous potassium carbonate,
and Water. The washed chloroform solution is dried over
anhydrous sodium sulfate, then is evaporated to dryness
to produce 17a-acetoxy-6a-methyl-1,20-dioxo-1,2-seco
A-norpregn-3-en-2-oic acid.
75
CH3
CH3
CH3
_
0
: OC--CHs
(like //
8,080,381
12
11
Example 18
To asolution of 7.7 parts of 17a-acetoxy-3?-hydroxy
and 6a~methyli- 17a ~4propionoxyQ-oxapregn-4-ene-3,20
vdione of "the structural formula
6-methylpregn-5-en-20-one in 67 parts of methylene chlo
CHa
ride, cooled to 0-5°,‘is added dropwise with stirring 40
parts by volume of a 0.5 molar perbenzoic acid solution
CH3
O
=0
CH3
Q
5°
%
7
Y . |j--_0 oomorn
.
in benzene, at such rate that the temperature does not rise
above 25°. After the addition is completed, this mixture
is diluted with chloroform, then washed successively with
aqueous sodium hydroxide and water, dried over anhy
10 drous sodium sulfate, and evaporated to dryness at reduced
pressure. The resulting crystalline residue is recrystal
lized from methanol to afford pure l7a-acetoxy-5‘a,6a
\/
epoxy-313-hydroxy-6?-rnethylpregnan-2O-one, melting at
bHa
15
Example 15
The substitution of an equivalent quantity of ‘id-hy
droxy-6-methyl-17a-propionoxypregn-S-en-ZO- one in the
To a solution of one part of 2—oxapregn-4-ene-3.,20
dione ‘in 80 parts of ethanol is added 0.2 part of 1.0%
pa‘lladium-on-carbon catalyst, and this mixture is shaken
in a hydrogen atmosphere at atmospheric pressure .until
one molecular equivalent of hydrogen is absorbed. v'Ihe
catalyst is removed by ?ltration, and the ?ltrate is concen
processes of this example results in 5a,6a-epoxy-3/8-hy
droxy-é?-methyl-17a-propionoxypregnan-20-one.
Example 19
To a solution of 1.16 parts of 17a-acetoxy-5a,6a-epoxy
3;8~hydroxy-6?~methylpregnan-20-one in 16 parts of ace
tone is added 0.9 part by volume of an aqueous solution,
8 N in chromium trioxide and 8 N in sulfuric acid. This
mixture -is stirred at room temperature ?or about 3 min
utes, then is treated with 0.1 part of isopropyl alcohol to
‘destroy the excess reagent. Removal of the solvent at
trated :to dryness under nitrogen to ‘yield Z-oxapregnane
3,20-.dione. Chromatography of this crude product on
silica gel followed by elution with 50% ethyl acetate ‘
in benzene produces 2-oxa-5a-pregnane-3,20-dione, MP.
about 189-191‘, of the structural formula
7
about 215-219".
reduced pressure affords a residue, which is extracted with
‘CH:
chloroform. This organic extract is washed successively
with water, aqueous sodium hydroxide, and water, dried
over anhydrous sodium sulfate, and concentrated to dry
ness under reduced pressure. Recrystallization of the
residue from benzene affords pure 17a-acetoxy'5a,6;3
CH;
35
dihydroxy-6a - methylpregnane - 3,20 - dione, MP. about
258~261° (dec.) .
lBy substituting an equivalent quantity of 5a,6a-epoxy
3?-hydroxy-6p-methyhl7a - propionoxypregnan - 20 - one
and otherwise proceeding according to the hereindescribed
processes,
and 2-oxa-5/3-pregnane—3,ZO-dione of the structural for
mula
CH
:
GHa
=0
CH3
tion mixture is heated at re?ux for about 16 hours, then
is cooled and ?ltered. The ?ltrate is washed successively
i/\
0
°=k/
with aqueous sodium sul?te, aqueous sodium hydroxide
and water, then is dried over anhydrous sodium sulfate
50 and evaporated to dryness to afford 17u-acetoxy-6B-hy
droxy-6wmethylpregna-IA — diene - 3,20 - dione.
Recrys
tallization from benzene a?ords a pure sample melting at
H
Example 16
5a,6B-dihydroxy-6a-methyl - 17a - propionoxy
pregnane-BJO-dione is obtained.
Example 20
To a solution of 4 parts of 17a-acetoxy-5u,6B-dihydroxy
6a-methylpregnane-3,ZO-dione in 264 parts of benzene is
added 2.7 parts of dichlorodicyanoquinone, and this reac
55
about 274-2822 It is further characterized by an ultra
violet maximum at about 244 millimicrons with a molec
2 - oxapregn-4-ene-3,20-dione, l7aeacetoxye2-oxapregn-4
ular extinction coe??cient of about 15,200.
The substitution of an equivalent quantity of 50:,65
~ene-3',20-dione, .17a-acetoxy;6a-methyl-2-oxapregn-4-ene
3,20-dione, 6C¢€D161lhYl~17OL-PI‘OPlOIlOXY-2-0Xap1'6g1'1-4-6l1e
one in the procedure of this example affords 6B-hydroxy
The substitution'of an equivalent quantity of 6a-methyl
dihydroxy-6a-methyl-17a - propionoxypregnane - 3,20 - di
3,20-dione, or 170: -'propionoxy-2-oxapregn-4-ene43,20 60
dione in the procedure of Example 15 results in the 50c
and 5B isomers of 6ot-methyl-2-oxapregnane-3,20-dione,
17a-acetoxy-2-oxapregnane-3,20-dione, 17a - acetoxy-6a
methyl-2-oxapregnane-3,20~dione, 6oz - methyl-lh-propi
onoxy-2éoxapregnane-3,20-dione, and 17oc-PI‘OPlOI1OXY-2
’oxapregnane-3,20.-dione, respectively.
Example 17
The substitution of an equivalent quantity of 20-hy
droxy-2-oxapregnan-3-one in the procedure of Example
4 results in 2-oxapregnane'-3,20-dione. This epimeric
mixture is separated by adsorption on silica gel followed
by elution with 50% ethyl acetate in'benzene to yield
2-oxa-5a-pregnane-Ii,20-dione, M.P. about l89-191°,
and 2-oxa-5?-pregnane-3,20-dione.
65
6qt-methyl-l7gz-propionoxypregna-1,4-diene-3,20>dione.
Example 21
To a solution of, 6 parts of 17a-acetOXy-S‘a,6/8-dihydroxy
6a-methylpregnane-3,ZOLdione in 88 parts of benzene and
67" parts of methylene chloride is added 7 parts of Woelm
basic alumina (activity I), described by H. Brockmann
et al., Ben, 74, 73 (1941), and the mixture is stirred at
room temperature for about 60 hours. The catalyst is
removed by ?ltration and washed on the ?lter with 50%
benzene in methylene chloride. The ?ltrate is evaporated
to dryness to afford colorless prisms of 17a-acetoxy-6p
hydroxy-6wmethylpregn-4 - ene - 3,20 - dione, M.P.' about
223-225". It displays an ultraviolet maximum at about
237.5 millimicrons with a molecular extinction coe?icient
of about 13,200.
1%
13
this example, 1,2,6,8-trihydroxy-6wmethyl-17a-propion
By substituting an equivalent quantity of é?-hydroxy
Ga-methyl-17a-propionoxypregnane-3,20-dione and other
oxypregn-47ene-3,20-dione is obtained.
Example 27
wise proceeding according to the herein~described proc
esses, 6,8—hydroxy~6a-*nethyl-17a-propionoxypregn-4 - ene
3,2.0-dione is obtained.
A mixture of 4.1 parts of 17a-acetoxy-1,2,6?-trihy
Example 22
The substitution of 4.1 parts of 17ot-acetoxy-6?-hydroxy
droxy-6x-metl1ylpregn-4-ene-3,20-dione, 14.5 parts of
lead tetracetate, 35 parts of acetic acid, and 5 parts of
water is heated at 50—6‘0° for about 11/2 hourswith stir~
6e-methylpregn-4-ene-3,20-dione in the procedure of Ex
ring, then is treated with 0.6 part of formic acid and is
ample 20, results in 17ct-acetoxy-6/3-hydroxy-6a-methyl
pregna-1,4-diene-3,20-dione, identical with the product of 10 diluted with water. Extraction with chloroform affords
an organic solution, which is Washed successively with
Example 14.
dilute aqueous potassium carbonate and Water, dried over
Example 23
anhydrous sodium sulfate, and concentrated to dryness
at reduced pressure, resulting in l7u-acetoxy-6?-hydroxy
To a mixture of 3 parts of chromium trioxide with 30
parts of pyridine is added a solution of 1.5 parts of 17a
6ot-rnethyl—1,20-dioxo-1,2—seco-A-norpregn-3-en-2-oie acid.
acetoxy-Sa?a-epoxy-‘S{3-hydroxy-6B - methylpregnan - 20
The substitution of an equivalent quantity of 1,2,6B-tri
one, and the reaction mixture is stirred at room tempera
ture for about 21/2 hours, then is stored at room tempera
hydroxy - 6a - methyl - 170: - propionoxypregn-4-ene-3,20—
ture for about 16 hours. The suspension is diluted with
benzene and filtered. The ?ltrate is washed succes 20
sively with water, 5% aqueous sodium hydroxide, and
dione in the procedure of this example affords 6?-hy
droxy-6oi-methyhl,20-dioxo-17a-propi0noxy-L2-seco - A -
norpregn-3-en-2-oic acid.
water, dried over anhydrous sodium sulfate, and stripped
Example 28
oi solvent at room temperature and reduced pressure.
Recrystallization of the residue from benzene aifords 170L
acetoxy-6a-hydroxy-6,6-methylpregn-4 - ene - 3,20 - dione,
A mixture of 5.4 parts of 17a-acetoxy-G?-hydroxy-Sa
25
MP. about 246-249". It exhibits an ultraviolet maxi
mum at about 242 millirnicrons with a molecular extinction
methyl~1,20-dioxo-1,2-seco - A - norpregn-3-en-2-oic acid,
5.4 parts of sodium borohydride, and 70 parts of iso
propyl alcohol is stirred at room temperature for about 2
hours, then is cooled by means of an ice bath and treated
coef?cient of about 13,600.
with 80 parts of acetone. The resulting mixture is added
The benzene mother liquor is concentrated to dryness
to yield 17a—acetoxy-5a,6cc-epoxy-GB-methylpregnane-I’:,20 30 to an ice-cold solution consisting of 80 parts of acetone,
400 parts of water, and 24 parts of concentrated hydro
dione, MP. about 204-216".
chloric acid. This mixture is concentrated to dryness at
The substitution of an equivalent quantity of 5zx,6oc—
reduced pressure, and the resulting residue is extracted
epoxy-3,8-hydroxy—6,B-rnethyl-1,7a-propionoxypregnan - 20
with chloroform. The organic layer is then washed suc
one in the procedure of this example affords 6a-hydroxy
6,6-rnethyl-17a-propionoxypregn-4 - ene - 3,20 - dione and
‘ cessively with cold dilute aqueous sodium hydroxide and
5a,6a-epoxy-6[3-methyl - 17oz é propionoxypregnane - 3,20
water, is dried over anhydrous sodium sulfate, and is
concentrated to dryness at reduced pressure to afford 17a
dione.
Example 24
acetoxy-6/3-hydroxy-6a-methyl - 2 - oxapregn-4~ene-3,20
dione.
A solution of one part of 17a-acetoxy-5a,6e-epoxy-6B~
methylpregnane-3,20-dione in 20 parts of pyridine is al 40
lowed to stand at room temperature for about 16 hours,
pregn-S-en-Z-oic acid and otherwise proceeding accord
ing .to the herein-described processes 6,6-hydroxy-6ot
then is concentrated to dryness to afford 171x-acetoxy-6a
hydroxy-6?-methylprcgn-4-ene-3,20-dione, identical with
the product of Example 23.
Example 25
By substituting an equivalent quantity of 6p-hydroxy
60c - methyl - 1,20 - dioxo-17a-propionoxy-1,2-seco-A-nor
methyl-17ot-propionoxy-2-oxapregn-4-ene-3,20-dione is ob
45 tained.
Example 29
The substitution of 3.9 parts of 17OC-aC6tOXy-60t-hy
To a solution of one part of l7a-acetoxy-6i8-hydroxy
drox -6,B-methylpregn-4-ene-3,ZO-dione or 4 parts of 60a
hydroxy-6/3-methyl-17a-propionoxypregn-4-ene-3,ZO-dione
50 6mmethyl-2-oxapregm4-ene-3,ZO-dioue in 87 parts of
toluene is added 0.2 part of p-toluenesulfonic acid mono~
hydrate, and the reaction mixture is distilled slowly for
about 2 hours, then is cooled and Washed successively
in the procedure of Example 20 results in 17a-acetoxy
6.x-hydroxy-6/3~methylpregna-1,4-diene-3,20-dione and 60a
hydroxy-d?-methyl-17a-propionoxypregna-l,4-diene-3,20
dione, respectively.
with aqueous sodium bicarbonate and Water, dried over
"xample 26
55 anhydrous sodium sulfate, and concentrated to dryness at
To a solution of 38 parts of 17c<-acetoxy—6,8-hydroxy
6a-rnethylprcgna-1,4-diene-3,20-dione in 390 parts of
reduced pressure, resulting in 17a-acetoxy~6-methyl-2
oxapregna-4,6-diene-3,20-dione. It is represented by the
structural formula
tertiary-butyl alcohol containing 400 parts of water is
added 2.5 parts of osmium tetroxide and 4.9 parts of
potassium chlorate, and this mixture is kept at room tem
perature for about 14 days, then is concentrated at re
OH:
CH;
CH3
duced pressure and room temperature to a small volume.
The oily layer which separates is dissolved in 150 parts
of pyridine and treated with a solution of 6 parts of sodi 65
urn bisul?te in 90 parts of water. This mixture is strirred
for about 15 hours, then is extracted with benzene. The
benzene layer is washed successively With dilute hydro
chloric acid, water, aqueous sodium hydroxide, and water,
dried over anhydrous sodium sulfate and concentrated to 70
dryness at reduced pressure to yield 17o:-acetoXy-l,2,6/S
trihydroxy-6a-methylpregn-4-ene-3,20-dione.
Byv substituting an equivalent quantity of 6?-hydroxy
/
. 0A
or)
is
3
‘The substitution of an equivalent quantity of 65-‘
hydroxy~6wrnethyl - 17cc - propionoxy-2-oxapregn-4-ene
6a - methyl-17a-propionoxypregna - 1,4 - diene-3,20-dione,
3,20-dione in the procedure of this example results in 6
and otherwise proceeding according to the processes of
methyl-17tic-propionoxy—2-oxapregna-4,6-diene-3,20-dione.
8,080,881
.
Example 30
16
The substitution of an equivalent quantity of 17a-pro
pionoxypregn-4-ene-3,20~dione in the processes of this
example results in 2a-acetoxy-17a-propionoxypregn~4-ene
A mixture of 4 parts of 17oc-ElOEtOXY-GB-hYdI‘OXY-6oz
methyl-2-oxapregn-4-ene-3,20edione, 1.3 parts of phos
phorus oxychloride, and 10 parts of dry pyridine is stored
3,20-dione.
Example 34
The substitution of 9.7 parts of 2a,17a-diacetoxypregn~
4-ene-3,20—dione or 10 parts of 2a-acetoxy-l7a-propion
oxypregn-4-ene-3,20-dione in the procedure of Example 32
results in 17wacetoxy~2a-hydroxypregn-4-ene-3,ZO-dione
at room temperature for about 16 hours. Water and ice
are added, and the resulting aqueous mixture is extracted
with chloroform. The chloroform layer is separated,
washed successively with dilute hydrochloric acid, water,
dilute aqueous sodium hydroxide, and water, dried over
anhydrous sodium sulfate and evaporated to dryness in
and 2a - hydroxy-17a-propionoxypregn-li-eneé,20-dione,
respectively.
vacuo to afford 17a-acetoxy-6-methyl-2-oxapregna-4,6
Example 35
diene-3,20-dione, identical with the product of Example
29.
The substitution of an equivalent quantity of 6,8-hy1
droxy - 6a-methy1-17a-propionoxy-2-oxapregn-4-ene-3,20
A mixture of 4 parts of 17a-acetoxy-2a-hydroxy-6a
15
dione in the procedure of this example results in 6-methyl
methylpregn-4-ene-3,20-dione, 2.3 parts of periodic acid
dihydrate, 40 parts of pyridine, and 10 parts of water is
stirred at room temperature for about 36 hours. The re
17ot-propionoxy-2-oxapregna-4,6-diene-3,ZO-dione, identi
action mixture is then extracted with chloroform, and the
cal with the product of Example 29.
organic extract is washed successively with water and
Example 31
20 aqueous potassium carbonate. Extraction of this washed
solution with ice-cold 5% aqueous sodium hydroxide af
A mixture of 39 parts of 17a-acetoxy-6a-methylpregn
fords an alkaline extract, which is acidi?ed by means of
4-ene-3,20-dione, 53 parts of lead tetracetate and 630 parts
excess acetic acid. The resulting precipitate is extracted
of acetic acid is heated at 80~85° with stirring for about
with chloroform, and the chloroform extract is washed
2 hours, then is diluted with water and extracted with
benzene. The benzene extract is washed successively 25 with water, then is evaporated to dryness under nitrogen
to yield 17a-acetoxy-6a-methyl-2,20-dioxo-2,3-secopregn!
with water, aqueous sodium hydroxide, and Water, dried
4-en-3-oic acid.
'
over anhydrous sodium sulfate, and concentrated to dry
By substituting an equivalent quantity of 2u-hydroxy
ness. The resulting residue is dissolved in benzene and
l7a-propionoxypregn-4-ene-3,20~dione or 2a-hydroxy-6w
chromatographed on silica gel. Elution with 20% ethyl
acetate .in benzene affords 2a,17a-diacetoxy-6u-methyl 30 methyl-17a-propionoxypregn-4-ene-3,ZO-dione in the pro
cedure of this example, 17ot-propionoxy-2,20-di0xo-2,3
secopregn-4-en-3-oic acid and 6ot-methyl-17a-propionoxy
pregn-4-ene-3,20-dione.
By substituting an equivalent quantity of 6u-rnethyl
17a-propionoxypregn-4-ene-3,ZO-dione and otherwise pro
ceeding according to the processes of this example, 20:
acetoxy - 6a - methyl - 17ct-propionoxypregn-4-cue-3,20
dione is obtained.
2,20-dioxo-2,3-secopregn-4-ene3-oic acid are obtained.
A mixture of one part of 17oc-acetoxy-6a-methyle2,20
dioxo-2,3-secopregn~4-en-3-oic acid, 0.9 part of sodium
borohydride and 120 parts of anhydrous isopropyl alco
Example 32
A mixture of 10 parts of 2a,17a-diacetoxy-6u-methyl
pregn-'4-ene-3,20-dione, 1.3 parts of potassium hydroxide,
Example 36
35
.
40 hol is stirred at room temperature for about one hour,
then is cooled by means of an ice-bath and treated with
8 parts of acetone. The resulting mixture is added to an
240 parts of methanol, and 20 parts of water is stirred at
room'temperature for about 15 minutes, then is acidi?ed
ice-cold solution containing .40 parts of Water, 8 parts of
acetone and 2.4 parts of concentrated hydrochloric acid,
with acetic acid and concentrated to a small volume at
reduced pressure. The residue is diluted with Water, then
is concentrated to a small volume at reduced pres
extracted with chloroform. The organic extract is washed 45 then
sure. The residue is diluted with water and extracted with
successively with aqueous sodium hydroxide and water,
chloroform. The organic layer is washed with water,
dried over anhydrous sodium sulfate, and stripped of
dried over anhydrous sodium sulfate and stripped of sol
solvent at reduced pressure to yield 17a-acetoxy-2m-hy
vent at reduced pressure and room temperature to produce
droxy-6a-methylpregn-4-ene-3,20-dione.
17a-acetoxy-2-hydroxy-6a-methyl-20-oxo - 2,3-secopregn
The substitution of an equivalent quantity of 2a-acetoxy 50 4-en-3~oic acid. On the other hand, concentration of the
6a-methyl-17a-propionoxypregn-4-ene-3,20~dione in the
organic layer to dryness on the steam bath results in 170:_
procedure of this example results in 2a-hydroxy-6a-meth
acetoxy - 6a - methyl-3-oxa-A-homopregn-4a—ene-4,20
yl-l7a-propionoxypregn-4-ene-3,20-dione.
dione, which is represented by the structural formula
Example 33
CH3
CH1
55
To a solution of 37 parts of 17a-acetoxypregn-4-ene
3,20-dione in 800 parts of dry carbon tetrachloride is
added 20 parts of N-bromosuccinimide, and the reaction
mixture is heated at re?ux with stirring for about one
=0
?joooom
03s
hour, while being subjected to infrared irradiation. This 60
mixture is cooled, washed successively with water, aqueous
sodium sul?te and water, dried over anhydrous sodium
sulfate, and evaporated to dryness to yield 170t-?CCtOXy
6-bromopregn-4-ene-3,20-dione.
A mixture of the crude 17a-acetoxy-6-bromopregn-4 65
ene-3,20-dione, 120 parts of potassium acetate, and 788
I
(\
(kg-y élHa
parts of acetic acid is heated at re?ux for about one hour,
‘ The substitution of an equivalent quantity of 17a
then is cooled, diluted with water, and extracted with
propionoxy-2,20-dioxo-2,3-secopregn—4-en-3-o§c acid in
benzene. The benzene extract is washed successively with
water, dilute aqueous sodium hydroxide, and water, then 70 the processes of this example affords 2-hydroxy-17a
propionoxy-20-oxo-2,3-secopregn-4-en~3-oic acid and 170c
is dried over anhydrous sodium sulfate and stripped of
propionoxy-3~oxa-A-homopregn-4a-ene - 4,20-dione, While
solvent in vacuo, Chromatography of a benzene solution
the substitution of dot-methyl-17u-propionoxy-2,20-dioxo
of the residue on silica gel followed by elution with 20%
2,3-secopregn-4-en-3-oic acid results in 2-hydroxy-6a
ethyl acetate in benzene affords 2a,17ot-diacetoxypregn~
4-ene-3,20-dione.
75
methyl-ZO-oxo-l7u-propionoxy-2,3-secopregn-4-en - 3 - oic
3,080,881:
18
17
Example 42
acid and 6u-methyl-l7a-propionoxy-3-oxa-A-homopregn
4a-ene-4,20-dione.
The substitution of 3.9 parts of 17a-acetoxy-2a-hydroxy
pregn-4-ene-3,20-dione in the procedure of Example 35
results in 17oc-acetoxy-2,20-dioxo-2,3-secopregn-4-en-3-oic
acid.
Example 43
Example 37
The substitution of 3.1 parts of 2u-hydroxypregn-4~ene
3,20-dione or 3.2 parts of 2u-hydroxy-6a-methylpregn-4
ene-3,20-dione in the procedure of Example 35 results in
2,20-dioxo-2,3-secopregn-4-en-3-oic acid and Goa-methyl
2,20-dioxo-2,3-secopregn-4-en-3-oic acid, respectively.
By substituting one part of 17a-acetoxy-2,20-dioxo-2,3
secopregn-4-en-3-oic
acid and otherwise proceeding ac
Example 38
10
cording to the processes of Example 36, 17a-acetoxy-2
A mixture of one part of 2,20>-d€oxo-2,3-secopregn-4
hydroxy-20~oxo-2,3-secopregn-4-en-3-oic acid and 17a
en-3-oic acid, one part of sodium borohydride, and 100
acetoxy - 3 - oxa-A-hornopregn-4a-ene-4,20-di0ne are ob
parts of water is stirred at room temperature for about one
tained.
hour. The reaction mixture is cooled, acidi?ed with ex
What is claimed is:
cess hydrochloric acid and extracted with chloroform. 15
l. A member selected from the class consisting of
The organic extract is washed with water, dried over an
compounds of the formula
hydrous sodium sulfate, and concentrated at room tem
perature and reduced pressure to aiiord 2,20-dihydroxy
2,3-secopregn-4-en-3-oic acid. Evaporation of the solvent
on the steam bath, however, produces 20-hydroxy-3-oxa
CH3
CH3
20
A-homopregn-4a-en-4-one.
(i=0
Example 39
UH? |___R
A solution of one part of 20-hydroxy-3-oxa-A-homo
pregn-4a-en-4-one in 40 parts of acetone is treated with
one part by volume of an aqueous solution, 8 N in chro
mium trioxide and 8 N in sulfuric acid, at room temper
ature for about 5 minutes. To the reaction mixture is
then added 0.16 part of isopropyl alcohol. Concentration 30
/\_
'
0
°=k/ 1i‘,
of this mixture to dryness under nitrogen at room tem
perature produces a residue, which is extracted with ben
zene. The organic layer is washed successively with wa
ter, aqueous sodium hydroxide and water, dried over an
hydrous sodium sulfate, and evaporated to dryness at re 35 and the 4,5-dehydro and 4,5;6,7-bisdehydro derivatives
thereof, wherein R is selected from the group consisting
duced pressure to yield 3-oxa-A-homopregn-4a-ene-4,20~
of hydrogen and (lower alkanoyDoxy, and R’ is selected
dione of the structural formula
from the group consisting of hydrogen and methyl.
CH3
CH3
.
.
.
.
=0
OH:
2-oxapregn-4-ene-3,Z-dione.
2-oxapregnane-3,20-dione.
6a-methyl-2-oxapregn-4-ene-3,ZO-dione.
17a-acetoxy-6a-methyl-2-oxapregnane-3,ZO-dione.
. A compound of the ‘formula
45
CH:
CH3
50
Example 40
OHB/\ |:---oo0 (lower alkyl)
The substitution of one part of 6a-methyl-2,20-dioxo
2,3-secopregn-4-en-3-oic acid in the procedure of Example
38 results in 2,20-dihydroxy-6a-methyl-2,3-secopregn-4
en-3-oic acid and 20~hydroxy-6a-methyl-3-oxa-A-homo 55
pregn-4a-en-4-one.
Example 41
The substitution of one part of 20-hydroxy-6oc-methyl
3-oxa-A-homopregn-4a-en-4-one in the procedure of Ex 60
ample 39 results in 6a-methyl-3-oXa-A~homopregn-4a-ene
4,20-dione of the structural formula
CH3
CH3
I
7. l7a-acetoxy-2-oxapregrr-4-ene-3,20-dione.
‘8. A compound of the formula
CH3
CH3
65
0:0
=0
CHa
/\
O/\
/
Oi/
75
CH:
I-—-OCO (lower alkyl)
3,080,381
19
‘
9. l7a-acetoxy-i6a-methyl-2-oxapregn-4~ene-3,ZO-dione.
_
2t)
- 14. Acompound of the formula
’ 110. A compound of the formula
CH3
CH3
C‘Ha
CH3
=0
CH‘
j‘ --OO0 (lower alkyl)
10
5
’
(\OHa
0
.M
wherein R is selected from the group consisting of‘ hy
drogen and (lower alkanoyl)oxy and R’ is selected from
the group consisting of hydrogen and methyl.
15. 3-oxa-A-homopregn-4a-ene-4,20-dione.
16. A compound of the formula
11. 17a-acetoxy-2-oxapregnane-3,20~dione.
12. A compound of the formula
20 t
CH:
CH:
CH,
CH‘
.
CH:
=0
CH3
=0
i‘--o0o (lower alkyl)
25
' --oo0 (lower alkyl)
I
o/"‘\
30
0w
17. 17a-acetoxy-3-oxa-A-hornopregn-4a-ene-4,20-dione.
No references cited.
13. 17a-acetoxyd?-methyl-2-oxapregna-4,6-diene-3,20
'dione.
35
‘
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