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Патент USA US3080372

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United States Patent ()g?igce
3,080,362
Patented Mar. V5, 1963‘
2
1 ,
process of the invention. Both catalytic and LiAlH4'1 re
v
'
Y
-
duction are unsatisfactory.
3,080,362
PROCESS FOR THE REDUCTION OF CARDENO
LIDE AND BUFADIENOLIDE STEROIDS
Christoph Tamm, Riehen, Switzerland. assignor to
- Sandoz, A.G., Basel, Switzerland,‘ a Swiss ?rm
. No Drawing. Filed Jan. 9, 1961, Ser. No. 81,231
_ 'Claims priority, application Switzerland Jan. 21, 1960
5 Claims. (Cl. 260-239.57)
-
Y
A known exception to the behavior of the usual reducing
agents is that of aluminum amalgam and of aluminum
isopropylate which, in the case of strophanthidin reduces
the remote aldehydic carbonyl to the corresponding alco
hol (strophanthidol) while leaving the unsaturation in
the lactone ring intact. The conditions of reaction are;
however, generally more severe with the aluminium amal
'_ The present invention relates to the novel selective re 10 gam or aluminum isopropoxide reducing agent than with
the lithium tritertiary butoxy aluminum hydride reducing
duction of the isolated carbonyl group in steroids of the
agent of the invention since the invention may ‘employ
cardenolide and bufadienolide series to the corresponding
the reagent at 0° C. in inert'organic solvent, for example,
alcohol by a novel process employing an inert organic
tetrahydrofurane solution to effect successful selective yet
solvent solution of lithium tritertiary butoxy aluminum
15 complete, carbonyl reduction in as little as 15 minutes and
hydride.
not more than 1 hour, the unsaturation in the lactone ring
These steroids of the cardenolide and bufadienolide
of the cardenolide series remaining intact. The advantage
series represent compounds of unusual complication (see
of such mild treatment is believed by the very nature of
“Natural Products Related to Phenanthrene” Fieser and
Fieser, third edition, A.C.S. Monograph 70, Reinhold
the unusually complicated and chemically sensitive steroid
~
Publishing Co., pp. 507-8). These steroids of these 20 to be obvious.
' More important is the fact that while aluminum amal~
named series occur in nature and are characterized by
their ability to exert a speci?c powerful action of the
cardiac muscle of man and animals, in one group being
gam and-‘aluminum isopropylate can both effect selective
reduction of aldehyde in strophanthidinythese reagents
products of plant synthesis found in seeds and bark leaves
are not ‘wholly unsuccessful for reduction of carbonyl
aglycone from hydrolysis of digitoxin glycoside, and in
another group being products elaborated in the organism
morecostlyiclass of compounds in which hexadienolide
such as digitoxigenin, for example, a sugar free cardiac 25 group only in ‘the bufadienolide series which is a still
of the toad and found in the skin secretions of the animal,
such as bufalin.
These drugs are rare and expensive.
.
unsaturation presents a much more di?icult problem than
in the cardenolide series due to the doubling of the un
saturation in the lactone ring. Aluminum isopropylate
In the form of 30 was also used to reduce the isolated 3-keto group in scil
larenon (A4-3-ketone) yileding the allylic alcohol, scil
the naturally occurring glycosides known as plant heart
larenin.
.
poisons and toad poisons, they are often of variable char
Aluminum amalgam is completely unsuitable in the
acter, the poison being present in very small quantities
bufadienolide series because it reduces the hexadienolide
frequently in combination with inactive-'saponins, digito
nins, which render puri?cation di?icult and these poisons 35 ring. The procedural-advantage provided by the mild
reduction treatment by the dissolved reducing agent of
being extremely sensitive to action of enzymes, acids and
the invention is thus had for steroid members of both
bases. The cardiotonic principle of the poison is asso
series, bufadienolides and cardenolides. A further ad
ciated not with the sugar residue of the glycoside but
vantage lies in the fact that the problem of selection of
rather with the steroid residue and the steroid residue pro
appropriate reducing agent of diiferent groupings in these
vides the basic chemical complication and sensitivity.
series is overcome by the present reducing agent which is
It is an object of the invention therefore to provide im
equally selectivefor carbonyl-in both series, and costly
proved procedures for selective reduction of a limited
mistakes based upon mistaken selection of reducing agent
class of the steroid residues in which the isolated carbonyl
can be avoided.
I
group in the 3 and 19 positions is reduced to the alcohol
Sodium borohydride (NaBH4) has also been suggested
without disturbing the carbon to carbon double bonds in 45
for the reduction of the angular C19 aldehyde group in
the compounds of the cardenolide and bufadienolide
series.
cardenolides and bufadienolides as well as the reduction of
- The speci?c structural difficulty in these steroid series
3-keto groups in 3-keto-cardenolides but it has been ob
saturation of the carbon to carbon double bond is due to
for the butenolide ring of the cardenolide series. How~
ever, this reducing agent has a more serious disadvantage
served that the hexadienolide ring in the bufadienolide
prohibiting selective reduction ‘of the isolated carbonyl
groups inrthe steroid residue utilizing the ordinary car 50 series is not stable in the presence of this reducing agent.
Accordingly, this reagent demonstrates a greater resistance
bonyl reducing agents without at the same time causing
the speci?clocation of the double bond in these steor‘id
series, the butenolide ring of the cardenolide series being
an alpha-beta unsaturated gamma lactone while the hexa
dienolide‘ring of the bufadiene'series is an alpha-beta
gamma-delta unsaturated delta lactone. Taking an exam
pleof the ?rst class, the butenolide ring in strophanthidin
when it is used in the presence of mannitol or under other
conditions in that it is extremely difficult to purify the
desired reduction product and eliminate all of the boron
from the product due to the use of this boron containing
reducing agent. Boron impurities make puri?cation by
recrystallization very dif?cult and result in a great loss
of the‘cardenolide series, contains two unsaturated centers,
‘
the carbon to carbon double, bond of the unsaturated 60 of valuable material.
Accordingly, a further object of the invention is to
lactone and the aldehyde group of the lactone. Catalytic
provide a generally applicable method for selective re
hydrogenation is known to attack ?rst the double bond
duction of isolated carbonyl group in steroids of the
in the lactone ring (see Fieser and Fieser, loc. cit., pp.
cardenolide and bufadienolide series characterized by the
516-517) and the product, dihydrostrophanthidin still
bears the intact aldehydic group remote in the steroid 65 use of lithium tritertiary butoxy aluminum hydride as the
sole reducing agent under low temperature conditions,
from the ring which can be oxidized to the corresponding
e.g., about 0° C. up to 20° C. in an inert organic-solvent
acid.
such as tetra'nydrofurane, whereby the desired selectively
'- Reduction of the aldehyde group isolated in the steroid
reduced steroid may be recovered after reaction for not
residue from the lactone while leaving the lactone un
_
I 7
saturation intact and thus the lactone ring intact is not 70 more than about 1 hour.
possible by catalytic hydrogenation yet is surprisingly
By the use of these very mild conditions with the novel
e?ected. under extremely ~Y mild conditions by the novel
method S-epibufalin is easily prepared from S-dehydr‘og
3,080,862
3
‘ii
bufalin the keto group in the 3 position being reduced
EXAMPLE 2
at 0° C. in 15-60 minutes.
The C19 aldehyde group can
3-Epi-Bufalz'n From 3-Dehydro-Bufalin
be reduced at 0° C. for 8 hours or at 20° C. in 1 hour
By the process as set forth in Example 1(b) above,
a solution of 80 mg. of B-dehydro-bufalin, melting point
219-231° and pure by paper chromatography standards,
was dissolved in tetrahydrofuran and reduced with about
in strophanthidin to recover strophanthidol. Similarly,
the C19 aldehyde group in hellebrigenin is reduced under
the same conditions to hellebrigenol and 3-O~acetyl
strophanthidin is reduced to 3-O-acetyl<strophanthidol.
In the following examples which illustrate but do‘not
5 cc. of the “reduction solution” of Example ,1 (a) at a
limit the invention all values of temperature are given
temperature of 0° for 15 minutes. The reduced crude
product in an amount of 8.0 mg. was worked up by the
in degrees centigrade and the-melting points vare cor;
10
rected.
same procedure of Example 1(b), e.g., ?rst checking the
purity by separating the components by paper chroma
tography to disclose only the. reduced product, .3-epi
EXAMPLE 1
3-Epi-Digit0xigenin From 3-Dahydro-Digitoxr'genin
bufalin, and no bufalin by this method of separation and
second by recrystallization. By .crystallizing the mate.
rial from acetone-methanol-ether mixture, 73. mg. of
(a) Preparation ofsolution of lithium tritertiary bu
toxy aluminum hydride in inert organic solvent: In 250
cubic ‘centimeters of anhydrous diethyl ether there were
suspended 2.5 grams of lithium aluminum hydride which
were brought into solution by heating under re?ux for 30
crystals having melting point of 225-241“ and after re
crystallizing from 1:1 methanol-acetone, 60 mg. of 3-epi
bufalin, melting point 235-2592 [a]D22=—}.-,12Ot°if*1.5°
minutes and ?ltered, the ?ltrate (207 cubicvcentimeters) '
(_c=1.689 in methanol) were recovered.
containing 1.71 grams of LiAlH4 as determined by titra
tion. 'In ‘the titration 1 cubic‘ centimeter of the ether
EXAMPLE 3
Strophanthidol From Strophanthidin
solution was decomposed with about 10 cubic centi
meters .ofilzl methanol and water and the liberated
By the process as set forth in Example 1(b.) above,_a
solution of 4-00 _mg_. of ‘strophanthidin, melting point
139-143°, was reduced with the, proportional amountof
“reduction solution” of Example 1(a) at a temperature
of 0° C. for v1 hour and-a crude reduction product was
lithium hydroxide titrated with 0.1 N HCl with phenol
phthalein indicator.
To 205 cubic centimeters of the ethyl solution of
LiAlH4 there were added, dropwise, and at room tem
perature with agitation, 10.03 grams of anhydrous ter
tiary butanol dissolved in 100 cubic centimeters of ab 30 recovered in an amount of .417 mg. By paper. chroma
tography the crude reductionproductwas demonstrated
solute ether. A white precipitate of the lithium triter
to contain both starting strophanthidin andstrophanthidol
tiary butoxy aluminum hydride was separated from the
reduction
product. The productwas, chromatographed
remaining ether by. decantation and this separated pre
with 20 grams of A120; and,about.52 fractionscollected
cipitate was dissolved in 100 cubic centimeters of freshly
by eluting‘with chloroform containing trace amounts of
distilled tetrahydrofuran. This tetrahydrofuransolution
methanol,‘ the fractions and treatment identi?ed below.
Fractions 1,-8 (combined) eluted with chloroform
containing 0.25% methanol, yielded 13 mg. of solid ma
terial: which showed a paper spot havingan .Rf'value'of
constitutes the “reduction solution” of this and the re
maining examples . herein.
(b) Reduction with reduction solution: A solution of
161 milligrams of. S-dehydro-digitoxigenin
(melting
0.87 by the paper chromatographic technique of Ex
point 198-201") was prepared in 8 cubic centimeters of
tetrahydrofuran and cooled to 0° C. To this solution
there'were added 8 cubic centimeters of the. “reduction
solution’? prepared in (a) above and ‘the mixture was left
standing for '15 minutes at 0° C.
ample 1-
At the end of the re
action period, the solution-was decomposed with 70
cubic centimeters of 5% acetic acid in water and then
extracted with chloroform.
The chloroform extract was
then washed ?rst with saturated potassium bicarbonate
solution, then with water and ?nally dried over anhydrous
sodium sulfate. The volatile solvent wasremoved under '
.vacuum and the. residue comprised 161 milligrams of
crude reduction product. This crude reduction product
gave from. methanol-ether chromatographically pure 3
.epi-digitoxigenin in an amount of 123 milligrams, melting
point 275-282°. The mother liquor representing 36
Fractions. 10-14 eluted with chloroform containing
0.2% methanol were combined and crystallized from 1:1
Fractions 33-52 (combined) eluted with chroform plus
2% methanolthen plus. 5%- methanol, yield 170 mg.;
demonstrated to be pure strophanthidol by paper chroma
tography.
In the manner detailed above, a total of 120 mg. of
EXAMPLE 4
3-O-Acetyl-Str0phanthidol From 3-0-A'cetyl
Strophanthidin
By the process as set forth in Example 1(b), a solution
of 170mg. of 3-O-acetyl-strophanthidin, double melting
methanol-ether and crystals were recovered in an amount
points 183-191°/215-220°, was reduced with the pro
portional amount of “reduction solution" of Example
of 26mg. This. product was further puri?ed by paper
chromatography tov separate about 50% of the product
as digitoxigenin and about 50% of the product as 3-epi
1(a) at a temperature of 0° C. for 1 hour and. a crude
reduction product was recovered inan amount of 185 mg.
digitoxigenin.
The product examined by paper chromatography showed
only B-O-acetyl-strophanthidol and it was crystallized
70 from 1:1 acetone-ether to provide 155 mg. of crystalline
3-O-acetyl-strophanthidol, melting point‘ 221-231". The
epi-digitoxigenin containing only traces of digitoxigenin
mother, liquor from recrystallization was examined by
paper chromatography and demonstrated to contain only
a trace of 3-O-acetyl-strophanthidin with practically all
as demonstrated by paper chromatogram. Thus the to
tal recovery was 144.5 mg. of ,3-epi-digitoxigenin and 13
mg. of digitoxigenin.
tography.
phanthidol, reduction product, was recovered.
the aluminacolumn.
Fractions 1-9 eluted with chloroformcontaining 0.2%
60
methanol gave only traces of amorphous material.
crystallized from 1:1 methanol-ether, yield 8 mg. of 3
anol, yield 78 mg.; demonstrated as strophanthidin by
paper chromatography.
Fractions 27-32 (combined) eluted with chloroform
plus 2% methanol, yield 85 mg; demonstrated as 50/50
mixture strophanthidin-strophanthidol by paper chroma
55 styrophauthidin starting material and of 220 mg. of stro
milligrams was chromatographed on 3.6 grams of alu
minum oxide (A1203) and some 20 fractions eluted from
Fractions 15-20 eluted from the alumina column with
chloroform containing 1% methanol were combined and
'
Fractions 14-26 (combined) eluted with chloroform
plus 0.5%_methanol than-with chloroform plus 1% meth
75
ofthe product therein being 3-O-acetyl-strophanthidol.
3,080,362
6
.
EXAMPLE 5
and yield of product with obvious advantages which ?ow
Hellebrigenol From Hellebrigenin
therefrom.
Although the above examples show use of lithium in
By the process as set forth in Example 1(b), a solution
tertiary butoxy aluminum hydride in separate solvent
solution, the compound may be prepared separately and
of 52 mg. of hellebrigenin, melting point 220-226°, was
reduced with the “reduction solution” of Example 1(a)
dissolved in the same inert solvent in which the starting
steroid is dissolved.
at a temperature of 0° C. for 15 minutes and there were
In the foregoing examples only tetrahydrofuran has
recovered 57 mg. of crude reduction product, which was
been illustrated as the inert solvent for the reduction
tested by paper chromatography for purity, and demon 10 reaction; other inert solvents may be used, for example,
dioxan.
Having thus disclosed the invention, there is claimed:
1. A method for the selective reduction of isolated
carbonyl group in the 3 and in the 19 positions in steroids
grams of A1203 and the following fractions eluted.
Combined fractions 1-3, eluted with chloroform, yield 15 of the cardenolide and bufadienolide series comprising
reacting a carbonyl bearing compound of said series dis
1.5 mg. of amorphous solid material.
solved in an inert organic solvent with lithium tritertiary
Combined fractions 4-10, eluted with chloroform
butoxy aluminum hydride to reduce said carbonyl group
rnethanol 99:1, yield 12 mg. of solid material demon
only and isolating the reduced compound.
strated to be pure hellebriginen by paper chromatography;
2. A method as claimed in claim 1 wherein said lithium
recrystallized from acetone-methanol-ether gave 7 mg. of 20
tritertiary butoxy aluminum hydride is ?rst dissolved in
crystalline product, melting point 222-225".
inert organic solvent and said reaction is carried out at
Combined fractions 11-29, eluted with 99:1. 98:2 and
about 0°-20° C. for a period varying from about 15 min~
95:5 chloroform-methanol, yielded 32 mg. of material,
utes to 8 hours, the longer time being used at the lower
demonstrated by paper chromatography to be pure helle
temperature.
brigenol; recrystallizing from acetone-methanol-ether to
3. A method as claimed in claim 1 wherein said inert
yield 26 mg. of crystals having double melting points
organic solvent is tetrahydrofuran.
155-167°/221—224°.
4. A method as claimed in claim 2 wherein said inert
The foregoing examples illustrate the method of the
solvent which dissolves said lithium tritertiary butoxy
strated to contain the reduced material as the principal
product with the starting material as a minor product.
The crude mixture was then chromatographed with 3
invention which is useful for the preparation of various 30 aluminum hydride is the same solvent as used to dissolve
intermediate products of technical importance in the man
the starting steroid.
5. A method as claimed in claim 4 wherein said organic
ufacture of cardiac glycosides as well as intermediate
solvent is tetrahydrofuran.
products for the manufacture of cortico steriods, the ad
vantages of low temperature, short reaction time, and
References Cited in the ?le of this patent
selective carbonyl reduction being achieved in a new and 35
Wheeler
et al.: Canadian Journal of Chemistry, vol.
highly advantageous yet extremely simple manner to
36, pages 1431-1436 (1958).
effect economy of materials, improvement in both purity
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