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Патент USA US3033757

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3,033,747
United States Patent() ”
Patented May 8, 1962
1
2
group derived from mono- and dicarboirylic acids contain
3,033,747
ing only carbon, hydrogen arid oxygen up to a total of ten
carbon atoms and the alkali metal and alkaline earth
175-(DIHYDROXYPROPANOYU-SUBSTITUTED
STEROIDS
.
v
I’ metal salts of the said dicarboxylie' acids, as well as acetals
Ellis R. Pinson, Jr., Waterford, Eugene J. Agnello, Lyme,
and Gerald D. Laubach, Niantic, Conm, assignors to ' ‘
Chas. P?zer & Co., Inc., New York, N.Y., a corporation
of
Delaware
‘
v
_
,
'No Drawing.
'
3 Claims.
Filed May
‘ (Cl.
11, 167-65)
1960, Ser. No. ' 28,180 -:
ly referred to- as dioxolanes.
10
' This application is concerned with new and useful
steroid compounds.
and ketals formed by reaction of both hydroxyl groups
with the carbonyl function of lower alkyl 'aldehydes and
ketones. This latter class of compounds may be generical
The preferred compounds within the purview of this
invention include those having the formulas:
More particularly it is concerned
with certain steroids having adrenocortical activity char
acterized by having unique chemical teatures in the carbon 15
atom side chain at the 17p-position. . It is concerned also
with a method of making these valuable compounds and
with pharmaceutical compositions containing them to
gether with pharmaceutically acceptable excipients.
The essence of this invention is the discovery that 20
adrenocortically active steroids heretofore characterized
by the presence ‘of an a-hydroxy acetyl group at the 17p:
position are also therapeutically useful when the. a-hy-f
droxy acetyl group is replaced with -a dihydroirylatedi
propanoyl group.
,
-‘
121-
.
0:
Adrenocortically active steroids now constitute avvwell
de?ned class in the art, and include therapeutically active
agents having a wide range of‘ applications in the medical
?eld. Cortisone, hydrocortisone, prednisone, prednil-t
30
solone, 2-methyl-prednisolone, 6-rnethyl-predniso1one; 16-‘
methyl-predn'isolone, 9a-?uoro-hydrocortisone vand others’
have been found to be useful as systemic and topical ,antirll
écHa
in?amatory agents and for other medical uses. ' Theyhave 35
Q om-o\ /R1
for example been used in the treatment of rheumatoid dis-»
l A
eases and allergies. They are pregnane derivatives having
a cyclopentanopolyhydrophenanthrene nucleus. They gen-
,CH-O
erally have a double bond at the 4-position, a keto group 3
40
at the 3-position and an oxygen function at the Ill-posi
I
tion. Certain 9,11-dihalopregnene derivatives have ad-_:
renocortical activity. The compounds within the purview
of this invention belong to the class of
active steroids.
‘in-0H
Y
R4
X.
CHM’
adrenocortically
'
o=
The compounds of this invention may be represented:
by the formula:
1'
l
R2
R--M '
wherein R is a cyclopentanopolyhydrophenanthrene ‘nu-1'
cleus characterized by having adrenocortical activity when;
CH:
ornont
substituted at the 17B-position with an a-hydroxy acetyl
group and M is a dihydroxylated propanoyl group which
replaces the 171S-(a-hydroXy acetyl) group.
As used in this application, the term “dihydroxylated
propanoyl group” means a propanoyl group with hydroxyl
_
:
(11110125
1
{i=0
1
groups on the a- and ?-carbon atoms substituted at the
R4
2:
l7i3-position of a cyclopentanopolyhydrophenanthrene 60
nucleus which has adrenocortical activity when substituted
with a 17?-(a-hydroxy acetyl) group. ‘It includes also
compounds in which an hydroxyl group or groups in the
propanoyl moiety is acylated with an acyl hydrocarbon
"-011
-Y_/\
6.5.
ona/i
R1
O:
|
'
' ,_
Rs
3,033,747
and
10
In the above structures; ‘X is hydrogen; halogen, inethoxy
or ethoxy; Y is ?-hydroxyl' or keto; R1" is hydrogen or
_20 methyl; R2 is hydrogen, ?uorine, chlorine or’ methyl; 3;;
25
0
30
whereinRa is an acyl group; R5 and R‘ are hydrogen or
acyl, an .acylegroup wherever located containing only
carbon, hydrogen and oxygen, being derived from mono
35 or dicarboxylic acids containing up to ten carbon atoms;
and R7 and R8 which may be the same or Vdi?erent in a
particular [compound are hydrogen or lower alkyl each
containing up to four carbon atoms except that both Ri
and R8 cannot'behydrogen in, a particular compound. In
40
the :preierred compounds represented above, the carbon
atom at the’ sixteen position is always substituted with
atleast one hydrogenandat least three of R1, R2, R3 and
the second substituent on the number sizgteen carbon atom
will always ‘be hydrogen. The water solubility of com—
45‘
‘i953?
pounds derived from tdicarboxylic acids is enhanced by
conversion to alkali metal or alkaline earth metal salts by
reaction with a suitable base such 'asisodium carbonate or
calcium’ hydroxide; These salts are included within the
purview of ‘this invention.
-
Starting compounds which ‘are useful in the preparation
50
of ‘the valuable compounds of this invention include those.
having the formula:
>
- wherein
R--N
has the same meaning as above andN, which
55 is located at the HIS-position, is a vpropenoyl group.
Starting compounds useful for the preparation ofethe
preferred compounds of this invention include those hav
ing structures identical withjthe-ones shown above except
- that the substituent at the Uri-position is replaced with a
60 prqpenqyl. grown Atypical starting compound is 21
methylene-Al-4¢pregnadiene~ll?,l7ct-diol-3,_20-dione, hav
ing the structure:
"
'
'
_
CH3
CH1
65
7
H‘
=f0
3,033,747
6
5
Free alcohols are formed from the corresponding
The starting materials are converted to the valuable.
compounds of this invention by reaction with osmium
tetroxide. The desired result is best effected by reacting 1
esters by gentle hydrolysis, for example, with dilute hy
about a 20% molar excess can be used so as to insure
sitions.
drogen chloride in aqueous methanol or with potassium
equimolar portions of steroid and oxidizing agent in a . carbonate in aqueous methanol. Since the rate at which
esters formed from primary and secondary alcohols may
lower ether solvent containing up to eight carbon atoms ’
‘ be hydrolyzed varies considerably, this hydrolysis reac
at a temperature of from about 20 to about 30° C. for a
period of from about sixteen to about seventy-two hours.
tion may be utilized to form compounds in which there
are diverse acyl hydrocarbon groups at the various po
An excess of osmium tetroxide say, ‘for example, up to
complete reaction of the valuable steroid starting mate 10
rial although this is not necessary.
Illustrative solvents
include, for example, dioxane, diethyl ether, tetrahydro
furan, dimethyl ethylene glycol and other glycol ethers
groups derived from mono‘ and dicarboxylic acids con
taining only carbon, ‘hydrogen and oxygen up to a total
of ten carbon atoms.‘ In the event that the‘ groupis de-'
rived from a dicarboxylic acid, it is often advantageous
containing up to a total of eight carbon atoms. The
preferred solvent is dioxane because of its good solu 15 to- treat a therapeutically active compound with a base
bility characteristics with respect to both steroid and oxi
derived from an alkali metal or alkaline earth metal to
dizing agents. Further, it is readily removed by evap
prepare a metal salt. These bases include, for example,
sodium, potassium, barium and calcium hydroxide as
During the course of the reaction, an intermediate
well as the corresponding carbonates'and bicarbonates.
osmate ester precipitates and this is readily converted to
Products so prepared are especially useful because of
a dihydroxy compound by known methods. It is pos
their increased solubility in Water. I
sible, for example, to decompose the ester by treatment
Those skilled in the art will recognize that the number
oration.
ar “
I ._
The term “acylated hydroxyl group” include those
..
'
with various polyhydric compounds in alkaline solution,
for example, mannitol in aqueous potassium hydroxide.
2-carbon atom, i.e., the a-carbon atom, in the propanoyl
moiety is asymmetric and that, therefore, the compounds
In a preferred method, the osmate ester is decomposed 25 within the purview of this invention exist asoptical iso
mers. It is intended to include both isomers within the
composes the ester and precipitates the osmium as a sul
purview of the invention. ‘ It is possible to separate the
?de which is readily removed by ?ltration. The best
isomers, for example, by chromatography, but it is not, I
yields are obtained if su?icient hydrogen sul?de is bub~
necessary to do so since both are active. For most
by treatment with hydrogen sul?de. This reagent de
bled into the reaction mixture so as to form a saturated 30
therapeutic purposes, therefore, it is immaterial whether
solution. The desired product is readily recovered from
a pure optical isomer or a mixture is used.‘
the ?ltrate by evaporation preferably in vacuo. It may
If it is desired to separate the isomers this can be
be puri?ed by recrystallization from a suitable solvent,
readily accomplished by paper chromatography accord
for example, 1:1 ethyl acetate-methanol.
ing to means well known in the art. For example, the
It will be noted by reference to the formulas set forth 35 free alcohols can be separated on paper using chloroform
above that it is speci?cally intended to include within the
as the mobile phase and formamide as the stationary
purview of this invention not only compounds having free
phase. The esters can be separated using a ‘1:3 mixture
hydroxyl groups at the 16-position and the a and ,B-posi
of chloroform and benzene as the mobile phase and
tions of the propanoyl moiety, but also these same com
formamide as the stationary phase. Each?product may
pounds in which one or more of these groups is esteri?ed 40 be isolated by dissolving it from the ~paper using a
with an acyl hydrocarbon group containing up to ten
suitable solvent such as ethyl acetate or chloroform. ‘
carbon atoms, that is, the group is an acylated hydroxyl
The biologically active compounds of this invention
group. Compounds of this nature are readily prepared
may be administered alone or in combination with ac'-"
by standard methods well known in the art. They are
ceptable pharmaceutical carriers, the choice of which is
most simply prepared by mixing the reactants and allow 45
determined by‘the preferred route of administration, the
ing them to stand together for a period of time at from
solubility of the compound and standard pharmaceutical,
20° C. to 30° C.
The duration of the reaction will
practice. In general, the dosage of these compounds is.
depend upon the reactivity of the acylating agent and with
of approximately the same order of magnitude as the‘
some acylating agents gentle heat may hasten reaction.
Most conveniently, the acylating agent is an anhydride‘ 50 dosages of hydrocortisone, and these compounds are use»
ful to treat the types of pathological conditions often
and the duration of the reaction is from eight to twenty
treated with hydrocortisone. Because of their great
four hours. Using an anhydride, the reaction is best
adrenocortical activity, it is sometimes possible to use,
carried out in the presence of a basic reagent, suitably
dosages of these compounds which are lower than those
m amine. Pyridine is especially convenient because it is
'
a
a liquid with excellent solubility characteristics. Often 55 of hydrocortisone.
For oral administration, the compounds may be ad
the pyridine can serve notonly as the alkaline reagent
ministered in the form of tablets containing excipients
but also as the solvent. Thus, the ester is formed by
dissolving the steroid and the anhydride in pyridine and ~ such as starch or milk sugar. vAqueous suspensions and
elixirs which may be sweetened or ?avored may also be
allowing the mixture to stand for from about eight to
about twenty-four hours. Of course, other solvents well 60 used. ,To apply these therapeutic agents topically, they_‘-_
may be prepared in the form of ointments and salves in
known to those skilledlin the art may be successfully
employed.m_y
~
‘
'
'
suitable bases especially non-aqueous petrolatum type
bases. For intro-articular injection aqueous suspensions
>
Most often the acylated hydroxyl groups will be
identical, but it is possible to preparecompounds. within
may be vemployed. In this case various suspendingand'
wetting agents may. be added to the compositions to ob-‘
the purview of this invention‘inwhich the groups are,
penoyl compound in which the hydroxyl group at ‘the
tain a suspension not tending to settle ‘out easily or to pack;
down in the bottle in which it is stored. lntramuscul a1‘ I
sixteen position is already acylated, and subsequently.
and subcutaneous dosage forms may also be prepared by»v
acylate the two hydroxyl groups in the a and [St-positions" 70
standard pharmaceutical practice. -
Since the hydroxyl group at the a~position is a secondary
hydroxyl group and the one in the ?-position is primaryv
they may be acylated, ,as is well known, independently of
preparation of 9a-?uoro-21-hydroxymethyl-A4-pregnene
dissimilar.
For example, one can utilize a starting pro
in the propanoyl moiety with another acylating agent.‘
each other.
'
~
’
_
The synthetic scheme set ‘forth below illustrates. the
1113,17u,21-trio1-3,20-dione, one of the compounds'of this.
invention. It exempli?es also the general method by.
75 which the compounds of this invention are prepared.
Theacetonides within the purview of this invention are 45 carbonate and then transformed into a quaternary com
pound by reaction with an alkyl halide in accordance with‘
the art. ‘They may he prepared, forexample,'by the pro
procedures well known in the art; "
'
,
cedure described ‘by Woodward et al. in the Journal of
' The conversion of 'thequaternary compound to a pro;
the American Chemical Society, vol. 74, page 4241
penoyl compound is described and claimed in copending
(1952). In this procedure, the steroid compound is taken 50 and concurrently ?led patent application, Serial No.
up in the carbonyl compound, for example, acetone, 1 28,179 which also claims the products. Theoconversion’
methyl ethyl 'ketone or di-n-butyl ketone which has been
is effected by maintaining the quaternary compound in
prepared by procedures well known to those skilled in
dried over a suitable drying \agent such as anhydrous
potassium carbonate. Anhydrous copper sulfate is added
an aqueous solution at a pH of from about 7 to about 12
at a temperature of from about 20° C. to about 30° C.
and the mixture agitated for from about 24 to about 48 55 for a ‘period of from about 1 to about 6 hours.
hours. The mixture is then ,?ltered and the desired prod
uct recovered, for example, by removal of the solvent in
vacuo. Other methods of forming acetals and ketals are
‘also applicable. For example, the steroid maybe taken
pose ofillustration and ‘are not to be construed as limita
tions of this invention, many variations of which are
possible without departing ‘from the spirit or~s_cope thereof.‘
up in the liquid aldehyde or ketone and re?uxedin ‘the 60.
_
presence of a catalytic amount ofa mineral acid such as
concentrated hydrochloric acid, ‘for from about 1 to about
10 minutes. The desired product is precipitated by .th
addition of water.
‘
The following examples are given solely for the ‘pur
EXAMPLE I
ZI-Hydroxymethyl-Alg‘i-Rregnadiene-l 15,1 70;,21 -Triol
'
'
3,20-Dione
>
A mixture containing 1.4 g. of 21-methylene-A1'4-preg
The preparation of the quaternary alkyl ammonium 65 nadiene-l118,17a4diol—3,20-dione (prepared as described
bromide is described and the product is claimed vin co
in copending and concurrently ?led patent application
pending and concurrently ?led patent application, Serial
No. 28,178. This application describes the preparation
of a tertiary amine acid addition salt by reaction of a 21
Serial No. 28,179) and 1.00 g. of osmium tetroxide in SD
mLIof dioxane wassallowed to stand at 25° C. for48
‘ hours. The mixture was ?ltered and .thet?ltrate saturated
desoxy steroid with formaldehyde and an amine acid ad 70 with hydrogen'sul?de. The saturated ?ltrate was allowed
dition salt at a temperature of fromabout 90° C. to about '
140° C- for from about 2 to about 24 hours in an alkanol
solvent containing upto ?ve carbon atoms. The steroid
acid additionsalt is converted'to a free base'by neutralize? ‘ "
to stand for 1/2 hour and’ ?ltered. The solvent was re-_
moved'in vacuo and the residue'recrystallized twice from
1:1 ethyl acetate-methanol mixture.
.
‘
‘
A. max.-=243 mu, e= 14,700. Calculated forCnHsoOu.
tion with an acid reagent such as aqueous sodium bi 75 0:67.67; H=7.75. Found: C=67.54; H=8.10.
3,033,7475
9
.
10
pregnadiene-l1?,17a-dio1-3,20-dione together with a 20%
EXAMPLE n
molar excess of osmium tetroxide in 75 ml. of tetrahydro
furan was allowed to'stand at 30° C. for 16 hours. The
mixture was ?ltered and the ?ltrate saturated with hydro
21 ~Hydroxymethyl-A‘l-Pregnéne-l 1,8,1 7u,21-Triol- .
3,ZO-Dione
gen sul?de. -The_ hydrogensul?de saturated, ?ltrate was
#A mixture containing equimolar quantities of osmium
?ltered and the solvent removed in vacuo to yield the de
tetroxide and 21 - methylene - A4 - pregnene-lrlBJh-diol
sired product as avresidue.
3,20-dione in 50 ml. of dibutyl ether was allowed to stand
for 72 hours at 20° C. The mixture was‘ ?ltered and the
EXAMPLE VI-II
?ltrate saturated with hydrogen ‘sul?de. The hydrogen
sul?de saturated ?ltrate was allowed to stand for 1 hour 10
and the back precipitate removed by ?ltration. The sol
3,11 ,ZO-Trione 16-Acetate
vent was removed in vacuo to yield the desired product
asa residue.
‘
‘
'
A mixture containing 1.4 ,g. of 2l-methylene-A4-pr'eg
'
EXAMPLE in
nene-16a,17a#dio1-3,20-dione 16-acetate (prepared as de-‘
15
21 -Hydroxymethyl-A174'6-Pregnatriene-I 175,1 741,2] a
1 Tri0l-3 ,20—Di0ne
Avrmixture containing 21-methylene-A1i‘l?-pregnatriene
1113,17a-diol-3,20-dione together with a 20% molar ex
cess of osmium tetroxide in 75 ml. of tetrahydrofuran was
allowed to stand at 30° C. ‘for 16 hours. The mixture
was ?ltered and the ?ltratesaturated with hydrogen sul
?de. The hydrogen sul?de saturated ?ltrate was ?ltered
and the solvent removed in vacuo to yield the desired 25
'
product as a residue.
. >
‘
scribed in copending and concurrently~ ?led patent applica:
tion Serial No.‘ 28,179) and 1.00 guof osmium tetroxide in‘
50 ml. of dioxane was allowed to stand at 25"? C. lfor48,
hours; The mixture was ?ltered and the ?ltrate saturated
with hydrogen sul?de. The saturated ?ltrate was allowed
to stand ‘for 1/2 hour and ?ltered. The solvent was re
moved in vacuo and the residue recrystallized twice from.
1:1 ethyl acetate-methanol mixture.
The following list sets forth some of, the compounds
within the purview of'this invention prepared by the pro
cedures set forth in the ‘foregoing examples. The list is
given ‘to avoid unnecessary repetition of experimental de
tails. _
_
.
.
,
"
.
EXAMPLE WY
7i;
'
ethyl->211-Hydroxymethyl-A1A-Pregnadiene
'
30
6a-?uoro-21-hydroxymethyl-A4-pregnene-1 1B,17oz,21-1;ri01
3,20-dione
>11;3_,1'7u,21-Tri0l-3,20-Dione
.
V
6 a-?uoro-21-hydroxymethyl-A4-pregnene-17a,21-dio1-3, 1 1,
._ ;A mixture ‘containing 1.4 g. of 2-methyl-21-methy1ene
A1-4-pregnadiene-11?,17a-diol-3,20-dione (prepared as de—
scribed in copending and concurrently ?led patent applica
tion Serial No. 28,179) and 1.00 g. of osmium tetroxide. 35
in 50 ml. of dioxane was allowed to stand at 25° C. for
48 hours. The mixture was ?ltered and the ?ltrate satu
rated with hydrogen sul?de. The saturated ?ltrate was
allowed to stand for 1/2 hour and ?ltered. The solvent
was removed in vacuo and the residue recrystallized twice
from 1:1 ethyl acetate-methanol mixture.
'
20-trione
.
.
,
60¢,9ut-di?1101'0-2 1-hydroxymethyl-A‘Lpregnene-1 118, 17a,21
triol-3 ,20-dione
'
‘
6d-?uoro-2 1-hydroxymethy1-A1»4-pregnadiene-1 11S, 170:,21
triol-3,20-dione
.
'
6a,9u-di?uoro-21-hydroxymethyl-A1A-pregnadiene-1 15,
EXAMPLE V
17a,21-.t1'i01-3,20-di0116
’
.
6a,9'a-di?uoro-21-hydroxymethyl-A1»4-pregnadiene-17a,
45
'
21-diol-3,11,20-trione
'
6 a,9a'-difluoro-2 1-hydroxymethyl-A4-pregnene-17 u,2l- .
A mixture containing equimolar quantities of osmium
tetroxide and 6oc-?ll01'0 - 21 - methylene-A‘i-pregnene-ll?,
diol-3,1 1,20-trione
_ 6a-?uoro-9a-chloro-21-hydroxymethyl-A4-pregnene-1 1B,
17a-diol-3,20-dione in 50 ml. of dibutyl ether was al
lowed to stand for 72 hours at 20° C. The mixture was 50 60c-?ll0I'0-9 a-chloro-21-hydroxymethyl-A4-pregnene- 17 a,
214iiol-3,11,20-trione
?ltered and the ?ltrate saturated with hydrogen sul?de.
The hydrogen sul?de saturated ?ltrate was allowed to
stand for 1 hour and the black precipitate removed by
6ow?uoro-9m-bromo-21-hydroxymethyl-A4-pregnene-17a,
21-diol-3,1 1,20-trione .
?ltration. The solvent was removed in vacuo to yield
55
the desired product as a residue.
EXAMPLE VI
17a,21-diol-3,1,1,20-trione
‘
6u-?uoro-21-hydroxymethyl-A4-pregnene-17a,21-diol-3, 1 1',
20-trione
16a-Methyl-21-Hydr0xymethyl-Alri-Pregnadiene
11,8,1 7qt,21-Triol-3,20-Di0ne
60L-?llO1‘O-9OL-[brOIIlO-2 1-hydroxymethyl-A1'4-pregnadiene
60 6u-?uoro-21-hydroxymethyl-A1A-pregnadiene-17a,2l-diol- 3,1 1,20-trione
A mixture containing 16u-methyI-ZI-methyIene-AII4
pregnadiene-l lB,17a-diol-3,20-dione together with a 20%
,
'
.
6m-?uoro-21-hydroxymethyl-M-pregnadiene-11B,16a,21- ‘
triol-3,20-dione v
6u-?uoro-21Qhydroxymethyl-A‘i-pregnadiene- 1 15,16“, 170:, >
molar excess of osmium tetroxide in 75 ml. of tetra
hydrofuran was allowed to stand at 30° C. for 16 hours. 65
21-tetrol-3,20-dione
l
The mixture was ?ltered and ‘the ?ltrate saturated with‘
6m-?uoro-21-hydroxymethyl-M-pregnene-16a, 17cc,2l-1;Ii01—
hydrogen sul?de.
The hydrogen sul?de saturated ?l
3,11,20-trione
yield the desired product as a residue._
' EXAMPLE v11
-
-
6 oc-?llOI'O-Z 1-hydroxymethyl-A1'4-pregnadiene-1 15,1611,
trate was ?ltered and the solvent removed in vacuo to
17a,21-tetrol-3,20-dione
'
"
70 6oz-?uoro-21-hydroxymethyl-A1A-pregnadiene-16a, 17a,2 1- '
16B-Methyl-21-Hydroxymethyl-Alri-Pregnadiene
11,8,17a,21-Tri0l-3,20-Di0ne
A mixture containing 16a-methyl-21-methylene-A1|4 75..
triol-3,1 1,20-trione
'
6u-methyl-9a-?uoro-21=hydroxymethy1-A1,4-pregnadiene- ',
11B,17a,21-trio1-3,20-dione
'
,
6pt-methyl-9or-bromo-21-hydroxymethyl-A1A-pregnadiene
1 1?,17oz,21-tri01-3,20-di0ne
: _'
3.03334?
- 1,2 .
10
15
zt-hy ‘vexymethyrm?tpreguadtenefma,mandrel-3,; 1, .
20
25
A variety of mono-, di- and trieste'rs of the foregoing
oz- and B-propanoyl compounds, including the 16-hydroxyl
ated compounds, were prepared in accordance with stand
30
ard methods. These include. the acetates, . propanoates,
propenoa'tes,’ ‘ ‘ octanoates; ‘ ' ‘ ben'zoates, ’ eycl'ohexanoates,
decanoates, butenoates; hemiglutarates and hemisucci
nates' ' l'nr'the case of acidjlesters‘,_-'the- compounds ‘were
conyerted to»
metal or" alkaline earth metal‘ salts
byreaction-with-a suitable base'sueh as sodium or barium
hydroxide.
’ (Compounds within the-purview- of this invention having
an l'l-keto-substituent are’ prepared by oxidation of the
40.
corresponding l-l‘fhyd'rox-ylated"compounds or by vusing 11
keto compounds as’ starting materials‘; In the event that
the ?nal-‘product is tohbe oxidized, it’ is best 'to protect
other hydroxyl groups by esteri?cation prior to oxidation;
To do otherwise may lead to a mixture of products as a
result of simultaneous oxidation of labile hydroxyl groups.
45
The oxidation?is. effected. according. to means~~ well- known
in the art’i'n'cluding, fon'example, oxidation- with ‘chro
miurn trioxide or the chromic ‘acid-pyridine complex.
PREm-BATroN on-acntmLs AND KETALS
The ‘following. example is illustrative. of two of. the:
50 methods ' which are. used‘ to prepare ’ the carbonyl ‘deriva
tives ofinyention, including those. prepared. from the“
Qompoundsof the. previous. examplesr Those prepared.
by these methods include. the. Ia‘cetal'sj and. ketals. ?'om:
55
aceta‘ldehyde,v propionaidehydektbutyraldehyde,. acetone,
di-isopropyl ketone, methyl ethyl ketone and di-n-butyl
ketone.
’
21 - hydroxymethyl - A“ - pregnadiene - 11?,l7u,2l
trio1-3',_2.0=dione;. (1100;_mg.'_) was; taken-up'in IOU-m1. of
acetone which had been-‘previously dried over anhy
To this mixture there was
60 drous potassium carbonate.
added: 495 ing; o'fanhydrous copper'sulfate andithe mix~
ture. was .stirredat room temperature forftwoirdays; The:
mixture? was: ?ltered, dried.‘ over anhydrous potassiumv
65
carbonate, again ?ltered and? the excess solvent removed
in vacuo. The- residue was tritur-ated with ether contain
ing- a few drops of acetone; and thedesired product re
covered by- ?ltration.
9oz - ?uoro ~ 21 Phydroxymethyl - A14‘ - pregnadiene
70 (350 mg.) 'was taken. uplin 25 ml. of propionaldehyde
containing two drops of concentrated hydrochloric acid.
The mixture was;re?uxed-{0L5minutesandv allowed to
stand at room temperature for eight'hours, The desired
product was precipitated by. the addition of water and
75.
isolated'by'?ltration.
'7
'
"
i
3,033,747.
13
What is claimed is: -
1.1%Am mm.mat
sum
,
ms
mm.
w
c
M..nv0% em
\m,
m/
dz3
mmB
m
m
a
Y
w.
no“
H
4R
C
AIV
mm mX,0i.
0dt1
netss/lJiRng
vm.
a/
\
.. v
_
u
o
78c
ROAw
V
.
‘Dam/:1
is“
m
m
Ho\
/0_.
cl3olRc u.
m
H
%
5
_
milk
“an
“3m
Lnm
m\/000R
=
H
4.
H
n
O
0
vx,a,
/5R
_
mcml. cClo-,lixa
A
v
m
Y’
H
tm
Om
X
st
R
v
W
Y.
_
v
30 and
35
40
45
wherein R1 is selected from the group consisting of hydro
gen and methyl; R2 is selected from the group consisting
50 of hydrogen, ?uorine, chlorine and methyl; R3 is selected
from the group consisting of hydrogen and hydroxyl; R4
is selected from the group consisting of
55
I
H
and
60
0 H3
C1120 R:
(ilHORu
%;
Y
X
CH3,"
65
}
R5, R6 and R9 are selected from the group consisting
03
of hydrogen and acyl groups containing only carbon, hy
R4
drogen and oxygen and derived from 'mono— and di
carboxylic acids containing up to ten carbon atoms; X
70 is selected from the group consisting of hydrogen, halogen,
methoxy and ethoxy; Y is selected from the group con
sisting of B-hydroxyl and keto; and R7 and R8 are selected
from the group consisting of hydrogen and lower alkyl
each containing up to four carbon atoms, at least one
75 of R7 and R8 being alkyl in a particular compound.
.
__
15
'
8,08%,74-7
’
'
'
16
V
_
p
w
2. A pharmaceutical composition comprising a compound as claimed in claim 1 together with a pharmaceuti-
20° C. to abont 30° C. for a period of from about 16 to
'a'b‘o'nt ‘72"hours'" and decomposing resulting osmate ester
cally acceptable carrier.
by reaction with hydrogen sul?de;
3. In a process for the preparation of a compound as
claimed in claim 1 the steps which comprise contacting 5the corresponding l7i3-propenoy1 compound with osmi-
um tetroxide in a lower ether solvent containing'up
to eight carbon atoms‘ at a tempei-ature of from about
'
Referencesccifed in the ?le of this Pate"t
‘
p
__
'
UNITED-STATES PATENTS
2,389,325
Reichstein __________ _V___ Nov. 20, 1945
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