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Патент USA US3056789

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United States Patent O?ice
1
3,056,779
Patented Get. 2, 1962
2
No. 74,470, ?led December 8, 1960 by Oskar Jeger et al.
The latter process consists in reacting lead tetraacetate
3,056,779
PROCESS FOR THE OXIDATION OF
with IS-unsubstituted 20-hydroxy-pregnanes in the pres
ZO-HYDROXY-PREGNANES
ence of iodine, oxidizing the resulting products with chro
Albert Wettstein, Riehen, and Georg Antler, Karl Heusler, 5 mium trioxide in the presence of silver chromate and,
and Peter Wieland, Basel, Switzerland, assignors to Ciha
if desired, liberating an esteri?ed Ila-hydroxyl group by
Corporation, a corporation of Delaware
hydrolysis or introducing a free hydroxyl group by micro
No Drawing. Filed Feb. 16, 1961, Ser. No. 89,638
biological oxidation and oxidizing any free lloc-hYdI‘OXYl
Claims priority, application Switzerland Feb. 18, 1960
group present to the oxo group.
2 Claims. (Cl. 260—239.57)
10
The starting materials may contain further substituents
The present invention relates to a process for the oxida
tion of 20-hydroxyapregnanes, more especially a process
in the ring system, particularly in one or more of the posi
for the oxidation of 18:11-lactones of 11,8:20~dihydroxy~
such as esteri?ed hydroxyl groups, or free or ketalized
oxo groups, alkyl, such as methyl groups or halogen
pregnane-lS-acids which may contain a ketalized oxo
tions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 16, 17 or 21,
15 atoms. They may also contain double bonds, for exam
group in the 3-position.
ple starting from carbon atom 5. Especially important
20-hydroxy-pregnanes are, as a rule, readily oxidizable
starting materials are the 18:20-lactones of 9a-halogen
to 20'ketones with various oxidizing agents in acid or also
in weakly alkaline solution, particularly with compounds
11,8:20/3-dihydroxy-pregnane-l8-acids the preparation of
of hexavalent chromium in glacial acetic acid or with a
which consists in reacting an 18:20-lactone of a 9:11;?
pyridine chromate complex. It has been observed, how 20 oxido-ZO-hydroxy-pregnane-1S-acid with a hydrohalic
ever, that in 18:11-lactones of 11,8:20-dihydroxy-preg
nane-lS-acids the ZO-hydroxy group can only be oxidized
with di?iculty by pyridine chromate both in an anhydrous
acid, or reacting an 18:20-lactone of A9(11)-20-hydroxy
pregnene-18-acid with a hypohalous acid. The so
obtained compounds yield the 18:11-lactones of 11:20
and in an aqueous solution, since it is evident that the
hydroxyl group and the lactone group in?uence each
di»hydroxy-9e-halogen-pregnane-18-acids after oxidation
other, slowing down oxidation and even partially prevent
ing it. In attempts to oxidize 18:11-1actones of 115:20
dihydroxy-pregnane-lS-acids in several cases of oxidation
with pyridine chromic acid, even with a long reaction time
with sodium borohydride with translactonisation.
The 18:11-lactones of 1l?-hydroxy~20-oxo-pregnane
and at a temperature up to 40° C., oxidation to the 20
ketone was always incomplete. In some cases oxidation
did not take place at .all.
It has now been found that 18:11-lactones of saturated
of the ll-hydroxyl group to an oxo group and reduction
18-acids obtained as endproducts are important intermedi
ates for the preparation of 18-0xygenated corticoids of
the type of aldosterone or 9a~halogen-aldosterone.
The following examples illustrate the invention:
Example 1
225 mg. of sodium dichromate and 900 mg. of crystal
or unsaturated 11B:20-dihydroxy~pregnane-18-acids can
be oxidized easily and in excellent yield to form the cor 35 line sodium acetate are dissolved in 4.5 ml. of glacial ace
tic acid and 0.45 ml. of Water. To this solution there are
responding ZO-ketones when oxidation is carried out with
added 160 mg. of the 18:11-1actone of A5-3-ethylenedioxy
a compound of hexavalent chromium in acidic solution.
1113:ZOB-dihydroxy-pregnene-18-acid and the whole is
It has been surprisingly found that oxidation can even
stirred for 4 days at 20-25 ° C. The dark solution is then
be carried out in the presence of a ketal group in acidic
solution without the ketal group being split. This is sur 40 poured into 100 ‘ml. of ice-water and extracted several
times with methylene chloride. The extracts are washed
prising considering the known susceptibility of ketals to
with sodium bicarbonate solution and ‘with water, dried
acids. It is especially important to retain a ketal group,
and evaporated. There are obtained 122 mg. of a crystal
when, starting from a resulting 20-ketone, other reac
line residue which contains, in addition to a little starting
tions must also be carried out in which free keto groups,
for example in the 3-position, interfere, for example, in 45 material and a little of the 18:1l-1actone of M8 :20-dioxo
1lp-hydroxy-pregnene-lS-acid, as main product the 18:11
the reaction for the introduction of a 21-oxygen function
and the like.
lactone of A5-3-ethylenedioxy-1 1?-hydroxy-20-oxo - preg¢
nene-l S-acid. After chromatography on 12 grams of
The oxidation according to the present process takes
silica gel there are obtained 95 mg. of the latter compound
an especially rapid course and gives a good yield when
50
melting at 239.5—240.5 ° C. from the fractions eluted from
the reaction is performed in acetone solution with chro
a mixture of benzene and ethyl acetate (9: 1).
mic acid-sulfuric acid at a low temperature, that is to say
advantageously between —20° and +10° C. The excess
Example 2
mineral acid is preferably neutralized before working up
1.0 gram of the 18:11-lactone of A5-3-ethylenedioxy
by the addition of sodium or potassium acetate. The oxi
dation of the ketal-lactones may also be carried out in 55 11,8:ZOB-dihydroxy-pregnene-l8-acid is dissolved in 25 ml.
of acetone. The solution is cooled to —~10° C. and there
glacial acetic acid with chromium trioxide when a larger
is added with vigorous stirring 1.25 ml. of a solution of
quantity of sodium acetate or potassium acetate is added.
13.3 grams of chromium trioxide and 11.5 ml. of concen~
The 20-hydroxy-lactones used as starting material can
trated sulfuric acid diluted ‘with Water to make up 50.0 ml.
be prepared, for example, according to a known process
from ll-oxygenated 18:20-oxido-pregnaues by acylolytic
cleavage to 18:20-di-acyloxy'pregnanes, hydrolysis and
60 After 10 minutes the reaction mixture is poured into 100
ml. of an aqueoue sodium acetate solution of 10%
oxidation to 18:20-lactones of ll-oxo-ZU-hydroxy-preg
strength, the crystalline precipitate is ?ltered off and
nane-l8-acids.
washed well with Water. After drying, there are obtained
904 mg. of the pure 18:11-lactone of A5-3-ethylenedioxy
The latter yield on reduction with so
dium borohydride with translactonization the 18:11-lac
tones of 115220 - dihydroxy - pregnane - 18 - acids.
The
18:20-lactones of ZO-hydroxy-ll-oxo-pregnane-lS-acids
are also obtainable by another process which is described
in US. patent application Ser. No. 74,486, ?led Decem~
her 8, 1960, by Charles Meystre et al., in US. patent ap
plication Ser. No. 74,487, ?led December 8, 1960, by
Charles Meystre et a1. and in US. patent application Ser.
65 11,B-hydroxy-ZO-oxoapregnene - 18 - acid melting at 232
236° C.
Example 3
In an analogous manner to that described in Example 2
70 there are obtained from 273 mg. of the 18:11-1actone of
A5-3-ethylenedioxy-9e-bromo-1lBzZO? - dihydroxy - preg
nene-18-acid 231 mg. of the pure 18:11-1actone of A5-3
3,056,779
4
6
is obtained by crystallization from a mixture of ether and
methylene chloride the pure 18:1l-lactone of A5-3-eth
ethylenedioxy-9a-bromo-1l?-hydroxy-ZO - oxo - pregnene
18-acid.
The bromlactone used as starting material is prepared
ylenedioxy-9a-?uoro-l1?-hydr0xy-20-oxo - pregnene - 18
acid.
The ?uorolactone used as starting material is prepared
as follows:
240 mg. of the 18:20-lactone of A4-3-oxo—11a:20;3-dihy
droxy-pregnene-18-acid are dissolved in 3 ml. of methylene
chloride and after adding 1.0 ml. of pyridine and 300 mg.
of para-toluene-sulfonic acid chloride the whole is allowed
as follows:
250 mg. of the 18:20-lactone of A5-3-ethylenedioxy
9:11,8-oxido-20,8-hydroxy-pregnene-18-acid are dissolved
in 1.5 ml. of methylene chloride and slowly added to a
The reaction
mixture is then diluted with methylene chloride, washed 10 mixture cooled to --60° C. of 10.3 ml. of tetrahydro
furan, 3.6 ml. of methylene chloride and 5.0 ml. of an
with dilute sulfuric acid and with water. By crystalliza
hydrous hydro?uoric acid. When the addition is com
tion of the residue of the methylene chloride solution
plete, the whole is allowed to stand for 15 minutes at
from a mixture of methylene chloride and ether there are
--60° C., then for 3 hours at 0° C. and then poured into
obtained 255 mg. of the 18:20-lactone of A4-3-oxo-11a
to stand for 3 days at room temperature.
tosyloxy - 205 - hydroxy - vpregnene - 18 - acid melting at
15 a cold solution of sodium bicarbonate.
The mixture is
then extracted with methylene chloride, the extracts are
142—144° C. (with decomposition); optical rotation
[a]D=+48° (in chloroform); absorption maximum in
washed with water, dried and evaporated. The residue
(240 mg.) is ?ltered through 12 grams of silica gel. The
18:11-l-act0ne of A4-3-oxo-9u-?uoro-1l?z20?-dihydroxy
ultraviolet spectrum at 229 mn (e=24,800); infrared
bands at 5.69/1. ('y-lactone); 5.96” and 6.17” (A4-3-ke
20 pregnene-18-acid is eluted with a mixture of benzene and
tone); 6.24M, 844p and 854a (tosylate).
ethyl acetate, and with ethyl acetate.
170 mg. of the 18:20-lactone of A4-3-oxo-1lu-tosyloxy
20?-hydroxy-pregnene-l8-acid are stirred in 5 ml. of a
solution of lithium chloride in dimethylformamide of 10%
strength for 4 hours at 100° C. under nitrogen.
The reaction mixture is poured into 50 ml. of water, the
solid precipitate is suctioned OH and washed well with
water.
105 mg. of this compound are dissolved in 2 ml. of gla
cial acetic acid and after the addition of 200 mg. of
chromium trioxide in 0.5 ml. of water the whole is al
25 lowed to stand for 5 hours at 25° C. Working up in the
ordinary manner yields a crude product which, when crys
tallized from methylene chloride and ether, yields the
pure 18:1l-lactone of A4-3:2O-dioxo-9v¢~?uoro-1lp-hy
There are obtained 120 mg. of the 18:20-lactone
of A“111-3—oxo-ZO?-hydroxypregnadiene - 18 - acid which
droxy-pregnene-l 8-acid.
after crystallization from a mixture of methylene chloride
and ether and sublimation at 180° C. under 0.05 mm. 30
pressure of mercury melts at 205—210° C.; optical rotation
[MDT-+16“ (in chloroform); ultraviolet spectrum maxi
mum at 239 mn (£216,850); infrared bands at 5.68n
285 mg. of the 18:11-lactone of A4-3-oxo-9ot-?uoro
11B:20?-dihydroxy-pregnene-l8~acid are dissolved in 100
ml. of benzene and, after the addition of a solution of 20
mg. of pana-toluene-sulfonic ‘acid in 10 ml. of ethylene
glycol, boiled for 6 hours under re?ux using a water
(5-ring lactone); 5.98” and 6.17;}. (A4-3-ketone); further
35 separator. The mixture is cooled, 20 ml. of saturated
bands at 7.42M, 8.15”, 8.68”, 9.10p. and 9.85”.
sodium bicarbonate solution are added with stirring, and
500 mg. of the 18:20-lactone of n4i9‘ll-3-oxo-20?-hy
droxy-pregnadiene~1S-acid are dissolved in 10 ml. of pure
dioxane, and the solution is treated with 300 mg. of N
bromosuccinimide and 1 ml. of perchloric acid of 10%
the solution diluted with 50 ml. of benzene. The organic
solution is separated, washed with water, dried and evap
the excess hypobromous acid is destroyed by the addition
of sodium sul?te solution and the mixture poured into 75
ml. of ice-water. The resulting precipitate is taken up in
dized directly as described above.
When instead of anhydrous hydro?uoric acid a solution
of hydrogen chloride in methanol is used for the cleavage,
The residue consists of the crude 18:1l-lactone of A4-3
droxy-pregnene-18~acid is obtained which, as described
above for the 9-?uoro-compound, is converted into the
18 : 1 l-lactone of A5-3—ethylenedioxy-9a-chlor0-l lfB-hy
orated in a water~jet vacuum. There are obtained 290
strength after the addition of 2 ml. of water. The reac 40 mg. of crude 18:11-lactone of A5-3-ethylenedioxy-9u
?uoro-l1B:ZO?-dihydroxy-pregnene-l8-acid which is oxi
tion mixture is stirred for 15 minutes at room temperature,
methylene chloride, the solution dried and evaporated. 45 the 18:11-lactone of A4-3-oxo-9a-chloro-1l?:20?-dihy
oxo-9a-bromo-1 15:20?-dihydroxy-pregnene-18-acid which
is puri?ed by chromatography on silica gel.
By ketalization of the 18:11-lactone of A4-3-oxo-9ot
bromo-l1,8:20B-dihydroxy-pregnene-18-acid with ethylene
glycol and para-toluene-sulfonic acid in benzene there is
obtained the 18:1l-lactone of A5-3-ethylenedioxy-9u
bromo-l1B:20B-dihydroxy-pregnene-l8 - acid used above
as starting material.
Example 4
droxy-20-oXo-pregnene- 1 S-acid.
50
What is claimed is:
1. ‘Process for the manufacture of a member selected
from the group consisting of 3-ketals of '18:11-lactones of
11—hydroxy-3,20-dioxo-pregnane-18=acids and the corre
sponding compounds having a double bond in the S-posi
55 tion, which comprises oxidizing a member selected from
the group consisting of 3-ketals of 18:11-lactones of 11,
20-dihydroxy-3—oxo-pregnane-18-acids and the corre
sponding compounds having a double bond in the 5
position with a compound of hexavalent chromium in acid
and there are then added with stirring 1.15 ml. of a 60 solution;
chromic acid-sulfuric acid solution described in Example
2. Process as claimed in claim 1, wherein the oxidation
2 and the whole is stirred for 20 minutes at a temperature
is carried out with chromium trioxide and sulfuric acid
of —5° to 0° C. ‘100 ml. of a sodium acetate solution of
in acetone.
10% strength are added ‘and the solution is extracted sev
eral times with methylene chloride. The crude product 65
References Cited in the ?le of this patent
obtained from the methylene chloride extracts is puri?ed
UNITED STATES PATENTS
970 mg. of the 18: ll-lactone of A5-3—ethylenedioxy-9a
fluoro-l1,8:20?-dihydroxy-pregnene-18-acid are dissolved
in 25 ml. of acetone. The solution is cooled to —5° C.
by chromatography on silica gel. From the fractions
eluted with a mixture of benzene and ethyl acetate there
2,959,586
Kerwin et al. __ ____ ____ Nov. 8, 1960
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