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Патент USA US3093646

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United States Patent 0
3,093,636
1
vPatented June 11, 1963
1
3,093,636
'
0
.INTERMEDI‘A'I‘ES IN THE CONVERSION OF 11a
HYDROXY-DIOSGENIN TO CORTISONE
Carl Djerassi, Otto Halpern, and Octavio Mancera, Mexi
co City, Mexico, assignors, by mesne assignments, to
Syntex Corporation, a corporation of Panama
No Drawing. Filed Oct. 3, 1958, Ser. No. 765,056
Claims priority, application Mexico Oct. 4, 1957
22 Claims. (Cl. 260—239.55)
10
The present invention relates to cyclopentanophenan
oxidative
threne compounds and to a novel process relating thereto.
‘ More particularly, the present invention relates to a
degradation
.
a
.
o
CHI
, novel process for the production of cortisone, or other
5
cortical hormones which may be derived therefrom, start
‘with lla-hydroxy diosgenin andlto ,certain‘nbvel inter
0
mediates.
In U.S. Patent No. 2,776,969, granted January '8, 1957,
there is disclosed and claimed lla-hydroxy-diosgenin
(A5-22-isospirostcn-3p-lluidiol) aswell as certain esters '7
thereof and a method {for the preparation thereof.
do
I /
In accordance with the present invention we have dis
covered that lla-hydroxy-diosgenin may be converted
‘into cortisone by a process involving as a ?rst step the. a.
partial aeylation at 6-3 to form the 3-monoesters of 11a 25
hydroxy-diosgenin. The 3-monoesters are then oxidized
to produce ll-keto-diosgenin esters. Degradation of the
side chain of these compounds gives the corresponding
In the above equation R represents an ester group of a
novel 3-esters of A5I1G-pregnadien-3 ,B-ol-l 1',20~dione which‘ w. hydrocarbonrcarboxylic acid of less than 12 carbon atoms.
are then epoxidized to form the novel key intermediate
These may be those conventional in the art i.e. aliphatic,
cyclic or mixed cyclic-aliphatic. In general however, ‘for
the process the lower fatty acid esters are desirably used
16a,17a-oxido¢A5-pregnen-3?~ol-11,20-dione. If the pre
ferred oxidizing agent, alkaline hydrogen peroxide is
used, the ester group at C—3 is saponi?ed in this step.
The compound thus formed is then reesteri-?ed at C-3.
such' as acetate or propionate and
' '
As previously set forth, the l6u,l7a-oxido compound
resent these acyl groups.
and its esters just referred to are the key intermediates
I
may desirably rep
‘ ‘
‘In’ practicing the steps above- set ‘forth the hydroxyl
for the remainder of the present novel process which in
volves the further steps of bromination both to protect’
the 5,6 double bond and in position 21 (in one modi?ca
‘group at C—3 ‘of lla-hydroxy diosgenin was selectively
esteri?ed by treating the free compound with slightly over
tion bromination at 0-12 is also produced), reaction of
HBr with the oxide group at 16,17 to ‘prepare the 170:
one molar’ ‘equivalent of a lower fatty acid anhydride
such as acetic anhydride in pyridine solution and at a
hydroxy-16-1bromo compounds, sulbstitution of the 21-bro
mo by iodine and subsequently ‘by acetate, oxidation of,‘
temperature substantially below room temperature. The
3-mono lower fatty acid esters of lla-hydroxy-diosgenin
gthus prepared, were ‘then oxidized ‘by an oxidizing agent
‘for secondary hydroxyl ‘groups, chromium trioxide in
the B-hydroxy group to a 3-keto group, reconstitution of“
the 5,6~doub1e bond and removal of lbromo groups from
C—16 and 0-12.
aqueous acetic acid solution, forexample to form ll-keto
That portion of the process of the present invention
' diosgenin lower fatty acid esters. , ’ Oxidative degradation
involving the production of esters of 16a,l7oc-‘OXid0-.A5
pre-gnen-3?-ol-1L20dione is illustrated by the rfolllowmg
of the ‘sapogenin side chain byv the usual methods i.e.
heating under pressure with a lower fatty acid anhydride
equation:
, (preferably acetic) and treatment with chromium triox
ide in acetic acid etc. gave the 3-lower fatty acid esters
55
of A5'16-pregnadien-3B-ol-l1,2O-dione. The 16-,17-double
"(bond of these compounds were then epoxidized prefer
“ably with hydrogen peroxide in alkaline solution (i.e.
alkali metal hydroxide) to give 16u,17oc-oxido-A5-preg
,.
' nen-3p-o1-l1',20-dione ‘since/the ester group is simulta
‘ 6O
vneously saponi?ed. Conventional esteri?cation with low
.. er fatty acid anhydrides then gave the corresponding 3
‘; lower fattyacid esters ofthis oxido, compound.
The compounds ‘just described are inter-mediates tor
3,093,636
3
A
‘)1
alcohol such as methanol, to give the free tetrabromo
compound indicated in the equation.
the production of cortisone by ‘further process steps illus
trated by the following equation:
Treatment of the free tetrabromo compound with so
dium iodide in methanol or other lower aliphatic alco
5 hol gave the corresponding 21-iodo compound with the
of
Q
I bromination -
5,6-double bond reconstituted i.e. 16?-bromo-21-iodo-A5
pregnen-3/3,17a-diol-11,20-dione. This compound when
-—_->
R0
and then HBr
treated with potassium acetate gave the 2l-acetate of
l
R0
10
2
bromine at a temperature below room temperature gave
Br 2
the corresponding 5,6-dibromo compound which was then
oxidized to the corresponding 3-ketone to thus prepare
Br
l and
bromination
15 (after removal of the 5,6-dibrorno groups with zinc) the
hydrolysis
‘
21-acetate of 16a,17u-oxido-A5-pregnen-2Pol-3,11,20-tri
CHzOAC
(llHzBl‘
I "-"O
O
100——OH
0~/\|:
0
Tm
sodium iodide
‘__—__
Ho_
and KAe
H0
;
Br 2
cortisone acetate.
Another modi?cation of the process of the present in
25 vention starting with the same oxido compound and in
volving the production of intermediate 12-bromo com
’ pounds is illustrated in the following equation:
30
and zinc
CHQOAO
.
.0
to
rearrangement O
{22-30
'_"-"O
I‘
---.—_-->
CHzBr
CHzOAc
a
l
one. Treatment with strong mineral acid such as hydro
chloric acid rearranged the A5-double bond to the A4-dou
20 ble bond as indicated. Finally reaction of the 160t,17d
oxide group with hydrogen bromide and exchange of the
16,8-bromo for hydrogen by means of Raney nickel gave
Br
l oxidation
bromination,
o
16oz, 17a-oXido-A5-pregnen-3BJl-diol-l 1,20-dione. Treat
ment of this oxido compound in methylene chloride with
35
0'
Br
3
HBr and
40 R0
bromine R0
l HBr
LU
Raney
nickel
;
Br 2
Br
onioxc 45
Coir ’ 0* it
(rr—
T01];
‘ bromine,
i
onioae
3;1 _0
0Q
In the above equation 'R represents the same ester
sodium iodide
and KAc
Br
2
groups as heretofore set forth and Ac represents ace
tate.
At indicated in the above equation, the 3-esters, pref
erably lower fatty acid ester, of 16a,17oz-O)ddO-A5-preg 60
nen-S?-ol-ILZO-dione are ?rst brominated with bromine
preferably in carbon tetrachloride to form the correspond
ing 5,6-dibromo compound i.e. the lower fattye acid esters
Br
°
2
1 .... -0
50
55
OH|OAc
4}
bromine and
;
I
oxidation
HO
Br ;
Br
sodium iodide
and
rearrangement
zinc and
rearrangement
\
OHgOAO
of 5,6-di'bromo-16ot,17a-oxido-pregnan-35-ol-1 l,20-dione.
OHZOAO
O
These compounds may be isolated conventionally or the 65
O
reaction solution containing them treated directly with
hydrogen bromide in glacial acetic acid to form the cor
responding 3-lower fatty acid esters of 5,6,16/8-tribromo
pregnan-3B,17a-diol-11,20-dione. Here again these inter
mediates may be recovered or the solution treated again 70
with one more molar equivalent of bromine to form the
onO
corresponding 3-lower fatty acid esters of $6,165,21
tetrabromo-pregnan-S?,17u-diol-11,20-dione. The 3-ester
' group of these compounds was then hydrolyzed with
acid, such as dry hydrogen chloride in a lower aliphatic 75
°
I .... no
(_____
0
CHaOAc
(I:
HBr and
Raney nickel
lHBr
3,093,636
CHzOAC
bomb at 175-180" C. The mixture ‘was poured into
water and extracted with ether, and the extract was
washed with water, dried over anhydrous sodium sulfate,
‘?ltered and evaporated to dryness. The residual oil was
CHjOAO
ho
dissolved in 400 cc. of acetic acid and 420 cc. of ethylene
dichloride, cooled to 15° C. and treated dropwise with a
solution of 27 g. of chromium trioxide in 460 cc. of 80%
' ——0H
°
(\l
O
WV
Raney
och/fr
In the above equation R and Ac represent the same
groups as heretofore.
‘
'
As indicated above the modi?cation illustrated differs
from that previously described in that the double bond
of the starting material is ?rst brominated,then treated
with HBr and then again treated with bromine to form
the 3-lower fatty acid esters of, 5,6,12,16?,21-pentabromo
acetic acid, with stirring and maintaining the tempera
ture of the mixture below 15° C. After 2 hours at
10 room temperature it was poured into water, extracted
with chloroform, washed with water, dried over anhy
drous sodium sulfate and evaporated to dryness. The
residue was chromatographed in a column of unwashed
alumina, thus producing A5’16-pregnadien-3?-ol-11,20-di
15
one acetate.
'
A solution of 10 g. of A5J6-pregnadien-3/3-o1-l1,20
dione acetate in 700 cc. of methanol was cooled to 15°
‘C. and then treated with 20 cc. of 4 N aqueous sodium
hydroxide solution followed by 40 cc. of 30% aqueous
hydrogen peroxide solution, under stirring and maintain
ing the temperature of the mixture below 15° C. It was
kept overnight in the refrigerator and then poured into
2,750 cc. of ice water. The precipitate was collected by
?ltration, Washed with water and dried, thus producing
hydrolyzed to the free compound and this treated with
the crude 16m,17a-oxido-A5-pregnen-3/3-ol-11,20-dione.
sodium iodide to form 12,1GB-dibromo-Zl-iodo-M-preg 25 The
analytical sample was obtained by repeated crys
nen-3,3,17a-diol-11,20-dione. Treatment of this last com
tallization from methanol.
‘
pound with potassium acetate gave the 2l-acetate of 12
10 g. of the crude 16a,l7a-Qxido-AE-pregnen-318-01-11,
pregnan-3/3,17a-diol-.11,20-dione.
These esters are then
bromo 4611,17“ - oxido - A5 ~ pregnen - 35,21 - diol-ll,
20-dione was dissolved in 50 cc. of pyridine, mixed with
20-d-ione. This compound was treated with bromine to 30‘ ‘10 cc‘. of acetic anhydride and kept overnight at room
give the corresponding 5,6,12-tribromo compound
‘which was then oxidized to the 2l-acetate of 5,6,12-tri
bromo - 1-6a,17a - oxido - pregnan - 21 - ol - 3,11,20
a temperature.
After pouring into ice water the precipi
tate was collected, washed with water, dried and recrys- '
tallized from methanol, to yield 16u,l7cc-0Xid0-A5-pr€g
trione. From this compound, as indicated in the equa
nen-3?-ol-11,20-dione acetate.
'
tion, the bromine could either be completely removed 35 A ‘solution of 10 g. of 16m,17d-oxido-A5-pregnen-3?
with zinc or partially removed with sodium iodide, fol
.ol-11,20-dione acetate in a mixture of 100 cc. of acetic
lowed by rearrangement ‘as previously described to the
acid and 100 cc. of carbon tetrachloride was cooled to
corresponding M-compounds'. In any event the resulting
- 18° C. and treated with a solution of 4.2 g. of bromine
3-k6t0-A4-16m17ot-0Xld0 compounds are treated in the
‘ in 30 cc; of carbon tetrachloride. There was thus formed
same way by opening the epoxide with hydrogen bro 40 'a' solution ' of 5,6-dibromo-16a,17a-oxido-pregnen-3?-ol
mide and treatment with Raney nickel to remove either
11,20-dione acetate. ‘In another experiment this com
bromine at C-‘16 or both at C-l6 and C—12.'v
pound was isolated by concentrating the solution to dry
The following speci?c examples serve to illustrate but
ness under reduced pressure and recrystallizing the resi
are not intended to limit the present invention.
due from methanol.
The solution of‘ 5,6-dibromo-l6a,l7a-oxido-pregnen
Example I
.
45
3?-ol-11,20-dione acetate, obtained as described ‘above,
A solution of 50 g. of A5-22a,25D-spirosten-3?,1lu
,was treated with 15 cc. of 32% solution of hydrogen
diol (lla-hydroxyrdiosgenin) in 200 cc. of pyridine was
. bromide in glacial acetic acid, whereupon a solutionlof
‘cooled to 0° C. and slowly treated, with stirring with
5,6,16B-tribromo-pregnan-3B,17u-dio1-l1,20-dione acetate
11.5 cc. of acetic anhydride, while the temperature was
was
formed. In another experiment the solution was
maintained at 0° C. The mixture was kept standing 50 concentrated under reduced pressure and the bromohy
at a temperature around 0° C; for 6 hours, poured into
drin was isolated by crystallization of the ‘residue from
water and extracted with ethyl. vacetate; the extract was
consecutively washed with dilute hydrochloric acid, 5%
sodium carbonate solution and water, dried over anhy
drous sodium sulfate, ?lteredand evaporated to dryness.
The residue consisted of lla-hydroxy-diosgenin, B-mono
acetate. The analytical sample was obtained by chroma
tography.
, methanol.
The solution of .5,6,l6/8-tribromo-pregnan-318,17a-diol
11,20-dione acetate obtained as described above was
treated with 4.2 g. of bromine dissolved in 30 cc. of
carbon tetrachloride, that is, with one more molar equiva
lent of bromine; the bromine solution was added with
stirring at room temperature over a period of 40 minutes.
45 g. of the crude lla-hydroxy-diosgenin 3-acetate was 60 The mixture was kept standing for 15 minutes further
dissolved in 5100 cc. of 90% acetic acid and then slowly
. and then the carbon tetrachloride was removed under re
. duced pressure, avoiding overheating. The resulting sus
treated under stirring with a solution of 10 g. of chro
pension was poured into water and the precipitate formed
mium trioxide in 50 cc. of 80% acetic acid, which was
was collected, washed with water and dried‘ at 50° C.
, added in the course of half an hour. The mixture was
kept for 2 hours at room temperature, poured into ice 65 There was thus obtained the crude 5,6,l6/3,2l-tetrabromo
pregnan-3B,17a-diol-11,20¢dione 3-acetate. The analyti
water and extracted with ethyl acetate; the extract was
washed with 5% sodium carbonate solution and water,
>cal sample was obtained by recrystallization from
. dried over anhydrous sodium sulfate, ?ltered and evap
‘
methanol.
.
orated to dryness. The residue was chromatographed
3 g. of the crude 5,6,l65,2l-tetrabromo-pregnan-3?,
on activated alumina and the crystalline fractions eluted 70 17a-diol-11,20‘-dione 3-acetate was covered with 100 cc.
were recrystallized from methanol. There was thus
of methanol and a slow stream of dry hydrogen chloride
obtained 35 - acetoxy - A5 - 22a,25D - spirosten - ll-one,
was introduced into the mixture, with stirring and main
namely ll-keto-diosgenin acetate.
‘
V
v
30 g. of this 11-keto~diosgenin acetate in>300 cc. of
taining the temperature around 30° C. When the hy
drolysis of the acetoxyl group was complete the'color
: acetic anhydride was heated for 8 hours in a pressure 75 of the solution turned pale red and the stirring was con
3,093,636
"r'
1%
tinued for 45 minutes further. The mixture was diluted
with water and the precipitate was ?ltered, washed with
water and dried in vacuo, thus yielding the crude 5,6,
sulfate, ?ltered and evaporated to dryness. Crystalliza
l618,21-tetrabromo-pregnan-3,8,17u-diol-l1,20-dione. The
analytical sample was obtained by recrystallization from .
methanol.
The above crude 5,6,16,8,2l-tetrabromo-pregnan-Br?,
l7a-diol-11,20-dione was dissolved in 200 cc. of methanol,
mixed with 34 g. of sodium iodide, stirred for minutes
tion of the residue from acetone-hexane yielded 16a,17a
ox-ido-A4-preguen-2l-ol-3,l 1,20-trione 2 l-acetate.
To a solution of 5 g. of 16a,l7u-oxido-A4-pregnen-2l
ol-3,ll,20-trione acetate in 40 cc. of glacial acetic acid
there was added 30 cc. of a 30% solution of hydrogen
bromide in glacial acetic acid, under continuous stirring.
The color of the solution quickly changed and the brom‘o
hydrin, namely 16B-bromo-A4-pregnen-l7a,2l-diol-3,ll,
and then kept standing overnight. After diluting with 10 20~tn'one acetate, started to precipitate. 'Ilhe stirring was
water the iodination product was extracted with methyl
ene chloride and the extract was washed with 3% sodium
thiosulfate solution until decoloration, then with water
and evaporated under reduced pressure, avoiding over
heating. There was thus obtained l6l8-bromo-2l-iodo
A5-pregnen-3B,17a-diol-l1,20-dione in crude form. The
analytical sample was obtained by recrystallization from
acetone-methanol at low temperature.
The crude 1618-brorno-21-iodo-A5-pregnen-3B,l7a-diol
11,20-dione was dissolved in 300 cc. of acetone, treated
with 40 g. of recently fused potassium acetate and the
mixture was re?uxed for 4 hours. It was then concen
trated to a small volume, diluted with water and extracted
with ether. The extract was washed with water, dried
over anhydrous sodium sulfate, ?ltered and concentrated
to a small volume. Upon cooling there crystallized 16cc,
17a-oxid0-A5-pregnen-3B,2l-diol-l1,20-dione 21 - acetate.
The analytical sample was obtained by recrystallization
from acetone.
continued at room temperature for half an hour and the
mixture was then diluted with water. The precipitate was
collected by ?ltration and washed with water.
The an
alytical sample was obtained by recrystallization from
acetone-hexane.
5 g. of the still moist crude-bromohydrin obtained
above was added to a suspension of 7.5 g. of Raney nickel
in 150 cc. of methanol and the mixture was re?uxed for
2 hours. The catalyst was removed by ?ltration under
nitrogen and the ?ltrate was concentrated until precipita
tion. The precipitate was ?ltered from the cooled mix
ture, washed with water, dried and recrystallized from
acetone-hexane, thus furnishing cortisone 21-acetate which
was identical with an authentic sample of the product.
Example II
In another experiment, 10 g. of A5'16-pregnadien-3B
ol-11,20-dione acetate in mixture with 75 cc. of chloro
form and 1 1t. of methanol was treated with 40 cc. of
10 g. of 16a,17a-oxido-A5-pregnen-3/8,2l-diol-l1,20-di 30 30% hydrogen peroxide followed by 20 cc. of 5 N
sodium hydroxide solution, at temperatures around room
temperature, and the mixture was stirred for 16 hours; it
ride, cooled to 10° C. and treated under stirring with
was then acidi?ed with acetic acid and the resulting 16:1,
4.2 g. of bromine dissolved in 12 cc. of methylene chlo
17a-oxido-A5-pregnen-3B-ol-l1,20-dione was isolated by
ride, in the course of 20 minutes and maintaining the
temperature below 15° C. There was thus obtained a 35 extraction with chloroform.
one 21-acetate was dissolved in 50 cc. of methylene chlo
solution 5,6 - dibromo-ltia,l7a-oxido-pregnan-3?,2l-diol
11,20-dione 21-acetate which was used for the next stage
without isolation of the pure compound. The latter was
Example III
In another experiment 16a,17a-oxido-A5-pregnen-3l8-ol
obtained in another experiment by concentration of the
11,20-dione acetate in methylene chloride solution was
lowed by crystallization of the residue from acetone.
To the solution of 5,6-dibromo-16a,17u-oxido-pregnan
3?,21-diol-11,20-dione 2l-acetate, obtained as described
a solution ‘of 5,6-dibromo-l6a,l7or-oxido-pregnan-3?-ol
11,20-dione acetate in methylene chloride. This solution
was then treated with hydrogen bromide in acetic acid
methylene chloride solution under reduced pressure fol 40 treated with one molar equivalent of bromine to produce
and the resulting solution of 5,6,16/3-tribromo-pregnan-3?,
above, there was added 100 cc. of 90% acetic acid and
17a-diol-11,20-dione fir-acetate was treated with another
then 4 g. of chromium trioxide dissolved in 10 cc. of 45 molar
equivalent of bromine dissolved in methylene chlo
water, with stirring, in the course of half an hour and
ride. By addition of water and subsequent extraction
maintaining the temperature of the mixture below 25° C.
with methylene chloride and concentration under reduced
It was then stirred for 1 hour further at room tempera;
pressure, there was obtained 5,6,163,21-tetrabromo-preg
ture, diluted with water and 200 cc. of methylene chlo
nan-318,17a-diol-11,20-dione
S-acetate, identical with the
50
ride and the aqueous phase was re-extracted with meth~
product obtained in accordance with Example I.
ylene chloride. The combined organic solution was
Example I V
washed with water, dried over anhydrous sodium sulfate,
?ltered and evaporated to dryness under reduced pressure.
A solution of 10 g. of 16a,17a-oxido~A5-pregnen-3?~ol
There was thus produced 5,6-dlbl’0m0-160a,].70c-OXidO
11,20-dione acetate in 200 cc. of methylene chloride was
pregnan-2l-ol-3,l1,20-trione acetate in crude form. The 55 treated with 4.2 g. of bromine dissolved in 30 cc. of
analytical sample was obtained by recrystallization from
methylene chloride and with 15 cc. of glacial acetic acid
acetone-hexane.
containing 5 g. of dry ‘hydrogen bromide, at room tem
10 g. of crude 5,6-dibromo-16u,l7a-oxido-pregnan-21
perature. The solution was then heated to 40° C. and
ol-3,11,20~trione acetate was dissolved in 100 cc. of meth
treated with 8.4 g. of bromine dissolved in 60 cc. of
anol and then under stirring mixed with 4 g. of zinc dust, 60 methylene chloride, which was added in small portions
while the temperature was kept below 40° C. The stir
and waiting until decoloration before each addition and
ring was continued for half an hour further and the super~
under stirring. The mixture was stirred at 40° C. for 20
natant solution was decanted and ?ltered. There was
minutes further, the methylene chloride was removed by
thus obtained a clear solution of 16a,17a-oxido-A5-preg
distillation under reduced pressure, avoiding overheating,
nen-2l-ol-3,11,20-trione acetate. In ‘another experiment 65 and the suspension obtained was poured into ice water.
the compound was isolated by pouring the solution into
The precipitate was ?ltered, washed with water and dried
water, extracting with ether, washing with water, evapo
rating to dryness and recrystallizing the residue from ace
tone-‘hexane.
in vacuo. There was thus obtained the crude 5,6,12,165,
21-pentabromo-pregnan-3/3,17a-diol-1 1,20-dione 3-acetate.
The pure compound was isolated in another experiment
The solution of 16a,17u-oxido-A5-pregnen-21-01-3,ll, 70 after recrystallization from methanol.
20~trione ZI-acetate, obtained as described above, was
The crude 5,6,12,16/3,21-pentabromo-pregnan-3/8,17a
, treated with 3 cc. of concentrated hydrochloric acid and
stirred at room temperature for 10 minutes. After dilut
- ing with water, the product was extracted with methylene
diol-11,20-dione B-acetate was mixed with 100 cc. of
methanol and a slow stream of dry hydrogen chloride was
introduced into the solution for 90 minutes and keeping
chloride, washed with water, dried over anhydrous sodium 75 the temperature around 30° C. After diluting with water
3,093,636
‘the precipitate was ?ltered, washed with water anddried in
vacuo, thus yielding the free 5,6,12,l6?,2l-pentabromo~
pregnan-3B,l7a-dio1-l1,20-dione in crude form. In an
other experiment the pure substance was prepared by re
To a solution of 5 g. of 12,-bromo-16a,l7a-oxido-A4
pregnen-21-ol-3,l1,20¢trione acetate in 100 cc. of glacial
crystallization from methanol."
‘mechanical stirring. The color of the reaction mixture
quickly changed and the bromohydrin started to pre
1
acetic acid there was added 2 cc. of a 30% solution of
hydrogen bromide in acetic acid,‘ dropwise and under
, ,
The above crude 5,6,12,l65,21-pentabromo-pregt1‘an
3B,l7a-dio1-1l,20-dione was mixed with 200 cc. of meth
anol and v32 g. of sodium iodide, stirred ‘for 15 minutes
at room temperature and kept standing overnight. After
dilution with water, the product was extracted with 10
cipitate. The stirring'was continued at room temperature
for half an hour and the mixture was then diluted with
water, cooled and the precipitate was ?ltered and washed
‘methylene chloride, washed with 3%‘ sodium thiosulfate
with water; there was thus obtained 12,16/3-di'bromo-A4
pregnen-l7u,2l-diol-3,11,20-trione 2l-acetate in crude
solution until decoloration and with ‘water, dried ‘over
‘anhydrous sodium sulfate, ?ltered and evaporated to dry
The analytical sample was obtained by recrystallization
form which without drying was used for the next stage.
ness under reduced pressure in a bath kept at aitempera
ture below 35° C. There was thus obtained 12,1618 15
dibromo - 21 - iodo-M-pregnenG/B,17u-diol-11,20-dione in
crude form. The analytical sample was prepared by re
crystallization from acetone-methanol at low temperature.
from
acetone-hexane.
,
~
'
-
V
5. g. of the above crude wet bromohydrin was added to
.a suspension of '15 'g. of Raney nickel in 200 cc. of metha
nol and the mixture was re?uxed for.4 hours and ?ltered
under nitrogen; ‘the ?ltrate was concentrated until an
abundant precipitate separated and cooled. The, precipi
The crude r12,16;8-dibromo-21-iodo-A5-pregnen-3B,.l7a
diol-11,20-dione' was dissolved'in 300 cc. of acetone, 20 tate was ?ltered, washed with water, driedrand recrystal
mixed with 40 g. of recently fused potassium acetate .and
lized from acetone-hexane, thus giving cortisone ,21—ace
re?uxed for 4 hours. 'The mixture was concentrated to a
tate, identical with an authentic sample of ‘the compound.
small volume, diluted with water and extracted with
ether. The extract was washed with water, ‘dried over
.
anhydrous sodium sulfate, ?ltered and concentrated to a 25
small volume. Upon cooling there crystallized 12-bromo
16a,17a-oxido-A5~pregnen-35,2l-diol-l1,20-dione 21-ace_
tate. The analytical sample was obtained by crystalliza
-
Example'V'
.
-.
5 g. of the crude 5,6,12-tribromo#16a,l7a-oxido-preg
nan-21-ol-3,11,20-trione acetate, obtained as described in
Example IV, was mixed with 50 cc. of methanol and 3
g. of zinc dust which was added in small portions, with
stirring and maintaining the temperature below 40° C.
tion from acetone.
10 g. of the 12-bromo-16a,17a-oxido-A5-pregnen-3p, 30 The mixture was stirred for 1 hour ‘further and then ?l
tered, washing the ?lter with methanol. The combined
21-diol-ll,20-dione 21-acetate was dissolved in 50 cc.
?ltrate and washings aiforded a solution of 16a,17a-oxido
of methylene chloride, cooled to 110° C. and treated with
A5~pregnen-21-ol-|3,l1,20-trione acetate; in another ex—
4 g. of bromine dissolved in 10 cc. of methylene chlo
periment the pure compound was isolated by addition of
ride, with stirring and keeping the temperature below
15° C., in the course of 20 minutes. There was thus 35 water, ?ltration of the precipitate and crystallization from
acetone-hexane.
obtained a solution of 5,6,IZ-tI‘ibI'OmO-l6oc,17ct~0XidO
By treatment with hydrochloric acid the double bond
pregnan-3?,21-diol-11,20-dione 21-acetate which was used
of l6u,17ot-oxido~A5-pregnen-2l-ol-3,l1,20-trione was re
for the next stage without isolation of the pure com
arranged to the A‘ position, then formed its bromohydrin
pound. The latter was obtained in another experiment
by concentration of the methylene chloride solution un 40 and ?nally substituted the bromine atom of the latter ‘for
a hydrogen atom, thus yielding cortisone 21-acetate, identi
der reduced pressure and recrystallization of the residue
cal with the ?nal compound of Example 1V. These
from acetone.
reactions are similar to those of the transformation of
To the above solution of 5,6,12-tribromo-l6a,17u-oxido~
12-bromo-16a,l7a-oxido-d5dpregnen-2-1-ol-3,11,20 - trione
pregnan-3p,21-diol-11,20-dione ZI-acetate there was add
ed 100 cc. of 90% acetic acid and then ‘3.8 g. of chro 45 acetate into cortisone ZI-acetate described in Example IV.
We claim:
mium trioxide in 10 cc. of water in the course of half
1. A process for the production of the lower fatty
acid esters of 16a,17a-oxido-A5-pregnen-33-01-11,20-dione
an hour, with stirring and keeping the temperature :below
25° C.
The mixture was stirred for 1 hour vfurther at
comprising selectively acylating lla-hydroxy-diosgenin in
room temperature, diluted with Water and 200 cc. of
methylene chloride and the organic phase was separated. 50 an inert solvent at low temperature to form the 3-lower
fatty acid esters thereof, oxidizing the esters with ‘an
oxidizing agent to form the 3-lower ‘fatty acid esters of
The aqueous layer was re-extracted with methylene chlo
ride and the combined methylene chloride solution was
washed with water, dried over anhydrous sodium sulfate,
?ltered and evaporated to dryness under-reduced pres
ll-keto-diosgenin, oxidatively degrading the side chain
of the last mentioned esters to vformv the corresponding
3-lower fatty acid esters of A5'16-pregnadien-3B-ol-11,20
dione, epoxidizing the last mentioned compound with a
peroxidizing agent to form 1-6a,17a-oxido-A5-pregnen-3/3
analytical sample was obtained by recrystallization from
ol-ll1,20-dione
and esterifying this last mentioned com
acetone-hexane.
pound with a lower fatty acid anhydride.
10 g. of the crude 5,6,IZ-tribromo-16u,17u-oxido-preg
2. The process of claim 1 wherein the oxidizing agent
nan-21-ol-3,1l,20-trione acetate was dissolved in 200 cc. 60
is chromium trioxide in acetic acid and the peroxidizing
of methanol, mixed with 40 g. of sodium iodide and
agent is hydrogen peroxide in the presence of an alkali
then the reaction product was worked up as described
metal hydroxide.
above for the reaction of 5,6,12,165,21-pentabromo-3?,
3. A process for the production of cortisone acetate
17owdi0l-1L20-dl0n6 with sodium iodide. The pure sub
stance was obtained by recrystallization from acetone 65 comprising reacting -16a,17a-oxido-A5-pregnen-3/3-ol~l1,
20-dione acetate with bromine ‘and HBr to form a 5,6,
hexane. The crude 12<bromo-l6a,l7a-oxidoaA5-pregnen
1649,21-tetrabromo-17a-hydroxy derivative thereof, react
2.1-ol-3,1l,2=0-trione acetate was mixed with 1-00 cc. of
ing
the tetrabromo derivative with sodium iodide and
methanol followed by 3 cc. of concentrated hydrochloric
with potassium acetate to form a 2-1-acetate and remove
acid and the mixture was stirred at room temperature
the 5,6 and 16B bromo groups and reconstitute the
vfor 10 minutes. After diluting ‘with water the product 70 16u,l7a-oxido group, oxidizing the S-hydroxy group to
was extracted with methylene chloride, washed with water,
a 3-keto group, again reacting the compound thus formed
dried over anhydrous sodium sulfate, ?ltered and evapo
with HBr to ‘form a l6?-bromol7a-hydroxy compound
rated to dryness. The residue crystallized from acetone
and removing the lé?-bromo group.
hexane to furnish 12-bromo-16u,l7a-oxido-A4-pregnen
4. The process of claim 3 wherein the tetralbromo
derivative is ‘further substituted with bromine at 0-12.
21-01-3, l 1,20-trione acetate.
sure.
There was thus obtained the crude 5,6,l2-tribromo
16a,17a-oxido-pregnan-21-ol-3,11,20-trione acetate. The
55
3,093,636
11
12
5. The process of claim 3 wherein the 16,3-bromo group
is removed with Raney nickel.
16. 12,1618 - dibromo - 21-iodo~A5—pregnen-3?,17u-diol
1 1,20~dione.
6. The process of claim 4 wherein the 12-bromo group
and 16?-bromo group are removed with Raney nickel.
11,20-dione 21-monoaceta-te.
17. 12 - 'bromo - 16a,17a-oxido-A5-pregnen-3?,21-dio1
7. 5,6 - dibromo - 16a,17a-oxido-pregnan-3?-ol-11,20
18. 5,6,12 - tribromo - 16a,17a-oxido-pregnan-3?,21
dione acetate.
8. 5,6,165 - tribromo~pregnan-3l3,17a-diol-11,20-dione
diol-11,20-dione 21-monoacetate.
3~acetate.
3,1 1,20-trione acetate.
19. 5,6,12 - tribromo - 16a,17a-oxido-pregnan~21-ol
.
9. A compound selected vfrom ‘the class consisting of
20. 12 - bromo - 16a,17a-oxido-A5-pregnen-21-ol-3,11,
ZO-trione acetate.
5,6,16;8,21 - tetrabromo - pregnan-3B,17a-diol-11,20-dione
and its 3-mono lower fatty acid esters.
21. I12 - lbrorno - 16oz,17a-OXldO-A4-PICgHEI1-ZI-01-3,1'1,
10. 16,8 - bromo-21-iodo-A5-pregnen-3?,17a-diol-11,20
20-trione acetate.
22. 12,165 - dibromo-A4~pregnen-17a,21-diol-3,'1‘1,20
dione.
trione 21-acetate.
11. 16a,17<x - oxido-A5-pregnen-3?,21-diol-11,20—dione
21-monoacetate.
References Cited in the ?le of this patent
UNITED STATES PATENTS
12. 5,6 - dibromo-l6a,17a-oxido—pregnan-3?,2l-diol-l 1,
20~di~one 21-acetate.
13. 5,6 - dibromo-16a,17a-oxido-pregnan~21~o1-3,11,20
trione ZI-acetate.
14. *16a,17a - oxido-A5-pregnen-2J1-ol-3J1,20-trione-21
acetate.
15. A compound selected from the group consisting of
5,6,12,16?,21 - pentabromo-pregnan-3?,17a-diol-11,20’di
one and its 3-mono lower fatty acid esters.
2,0
2,596,562
2,602,804
2,684,364
2,752,339
2,776,969
2,816,108
2,899,428
Kaufmann et a1 _______ __ May 13,
Kendall ______________ __ July 8,
Jones ________________ __ July 20,
Julian et a1. __________ __ June 26,
Rosenkranz et a1 _________ __ Jan. 8,
Julian et \al ___________ .._ Dec. 10,
Rothman et al _________ .. Aug. 11,
1952
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