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Patented Sept. 3,_ 1946
,1 ‘
2,406,885
s’rA'rEs ‘ PATENT OFFICE
,
v -, v‘
2,406,885
SAPOGENIN
OXIDATION
‘
PRODUCTS
.,
AND
PROCESS FOR PREPARING THE SAME
‘ \
Russell Earl'xMarker, State College, Pa., assignor
1' to/Parke, Davis & Company, Detroit, Mich., a
5 corporation of Michigan"
No'Di'awing. Original application August 3, 1940,
Serial No. 351,147. Divided and this applicaa
. v
tionlNovember 22,1943, Serial No. 511,340
y
' isolaim‘s, > (01. 260-3971)
Jjj
3‘
.f ‘ The‘ ‘invention relates to 'sapogeninoxidation
product's; andmore vparticularly to‘compounds
‘which’ may be described‘
‘ Czé-keto acids, having
v v
as
in ring D the following formula,
‘ " '
CHa (I?
‘
10.
mann, J. Am. Chem.‘S‘oc.‘61, 846, 1516, 2724, 3479,
15
The steroidal sapogenins'havaingeneral, the
formula
C27H42-4O3-5, _ of
which the
genin contain one type of side chain‘ characterited
by the fact that a sapogenin of this type is readily
CaHmOz is known to be present as a side chain
20
The following sapogenins differ from one an
otherlrnainlyuin regardtoathe connections be-_
'
"
,
‘
'.
HO
‘CH3
'A’
‘
using alcoholic . hydrochloric acid, and amal
tives in which the side chain has 4 more hydrogen
atoms than in the sapogenins themselves. Tigo
CH3
.
‘
reduced according to the Clemmensen procedure
gamated zinc (Marker and ,Rohrmann, J. Am.
Chem. Soc. 61, 846 (1939)) to give tetrahydro
derivatives, that is to say, new sapogenin deriva
tween rings ‘A’ and’ B, 'the degree ,of. saturation
of the ring system, and the number of sub
stituents attached to these rings.
(1939); (i2, 647, 896, 1162) that the side chain
of the naturally occurring’ sapogenins exists in
1 two modi?cations. Sarsasapogenin‘and neotigoé
portion
attached to ring D of the__ steroid skeleton.
Sarsasapogenln
‘ __Recently ‘it has been found (Marker and‘ Ruhr
where R is a member ofnthe class consisting of
—OH and groups hydrolyzable to -OH.
This application is a division of my copending
application, Serial No. 351,147,“ filed August 3, 19%10.
Dlosg'ernln‘ ‘I
genin, gitogenin, digitogenin, chlorogenin and
diosgenin behave differently from sarsasapo
genin and neotigogenin in that they are not re
duced byvthe Clemmensen procedure, that is to
‘
"
‘ say, they are recovered unchanged after boiling
with
‘__. H: _ ‘
l
H
Tigogenin
Gltogemn
.- .C‘Hz
,
_
5
others which are cited in the references listed,
appear to me to be best explained by assuming
1
‘
,
HO
I
’
HO
,
‘
-
,
40
,
'
w
"H
‘
Digitogenin
HR
*
1'11
"
and Y amal
sarsasapogenin itself yields. Theseyfacts, and
O‘Ha‘
’
acid
under the conditions of the Clemmensen reduce
tion to the same tetrahydrosarsasapogenin that
~
HO__/\/\_
alcoholic hydrochloric
gamated zinc. Isosarsasapogenin is converted
H
r‘
(:Jhlorog'enin
45
that thetwo types of steroidal sapogenin side
chains differ in regard to optical isomerism about
C22.
Accordingly, when it ‘is necessary to dis
tinguish between isomers about C22 I represent
the :two types. of side chains ‘byformulae of
the following type:
1 .
,
‘ I
‘
2,406,885
4
from the group consisting of compounds of hexa
valent chromium and compounds of heptavalent
CH:
CH;
CH;
/ E /0——CH1
1
C
CH~CHa
V ‘ $\CH2——C§a
H°
\/
H
Sarsasapogenin
(“Sarsasapogenin type" side chain)
manganese. The reaction mixture is separated
into alkali-soluble and alkali-insoluble fractions,
and each of these fractions is further separated
into its components by crystallization, partition
between immiscible solvents, conversion into in
soluble derivatives, high vacuum distillation,
chromatographic adsorption or other methods
10 adapted to the properties of the substances to be
isolated.
My invention also comprehends certain new
classes of steroidal sapogenin oxidation products.
One of these classes of compounds may be repre-i
CH:
'* CHI
CH:
'
(\
H0
sented by the following formula
15
é
/ 1E /CHr-CE:
\/
C\
CH-CH;
(L O—-——C§a
nA
20
CH:
CHI
CH: O
4}
l
Yl_
/Y
Y
H\/
Y
A
B
25
Isosarsasapogenin
(“Tigogenin type” side chain)
where the symbol nA represents 11, carbon-t0
carbon double bonds in the A-B portion of the
Chem. Soc. 62, 896 (1940) . Ordinarily where 30 steroid nucleus, n having one of the values 0 and
1, Y1, Y2 and Y: are substituents attached-to
isomerism about C22 is not of importance, the
methylene carbon atoms in the A—B portion of
formula for the sarsasapogenin type of side
the steroid nucleusI said substituents being se
chain will be used for con?gurations both of sar
lected from the class consisting of
See especially Marker and Rohrmann, J. Am.
sasapogenin and tigogenin type.
These two types of sapogenin side chains ap
pear to be subject to an equilibrium, the velocity
of attainment of which is catalyzed by acidic re
agents. The equilibrium is in?uenced by the
con?guration of the hydrogen atom at C5, and it
groups hydrolyzable to
appears that the following rule holds true. For
compounds of the allo series (cholestane type)
the tigogenin type of side chain is the more sta
OH
ble, while for compounds of the regular series
(coprostane type) at C5 the sarsasapogenin side 45
chain is the more stable.
For the purpose of greater clari?cation, the
Marker-Rohrmann formulation of the side chain
of the steroidal sapogenins will be used in de
H
and groups hydrolyzable to
H
scribing the invention. It is to be understood, 50
however, that the processes and products of the
present invention may be obtained by the use of
is a member of the class consisting of (=0) and
the methods herein to be described and these
groups hydrolyzable to (=0), and R is a mem
ber of the class consisting of —OH and groups
processes and products are claimed without any
hydrolyzable to -—OH.
implications that the reactions and structures
By the term “methylene carbon atom” is
involved will ultimately be proved to be as rep
resented herein.
-
meant a carbon atom having not more than tWo
carbon atoms attached to it. The methylene
I have found that the steroidal sapogenins and
certain derivatives thereof may be oxidized to 60 carbon atoms in the A--B portion of the steroid
nucleus are carbon atoms 1, 2, 3, 4, 6 and '7.
give new sapogenin oxidation products which are
Groups which are hydrolyzable to (=0) in
valuable as intermediates for the preparation of
clude groups such as =N-O-H, =N-NH-acyl,
steroidal hormones.
and =N-NH2. Groups which are hydrolyzable to
In practicing my invention I proceed as fol
lows: The sapogenin or the derivative thereof
halogen
OH
O-acyl O-aralkyl
which is to be oxidized is ?rst treated with re
, and
agents to protect nuclear hydroxyl groups and/or
H
H
double bonds. For instance, nuclear hydroxyl
groups are treated with acylating, aralkylating
< include <H
or halogenating agents to form the correspond- »
Groups hydrolyzable to-OH include —O-alkyl,
ing -O-acyl, ~—O-aralkyl or halogen derivative.
--NH2, and halogen.
Nuclear double bonds are protected by addition
of hydrogen halide or halogen. Then the nu
My invention may be illustrated by the follow
ing partial formulae in which only transforma
tions of the side chain attached to ring D are
clearly protected sapogenin or derivative thereof
is oxidized, preferably with a reagent selected
3 shown;
'
‘ 2,406,885
CH,
CH1".
6H
:
. .
' _
‘
VCR.
CH:
CH:—CH:
_
CH-CHa
(l)\o—-caz
D
. CHI
_ B—-CH|CHa HCHaOE
cat.
'
hydrog
'
'
Sapogenln
2526000.
‘
éH .
’
Dlhydrosapogenln
12sec.
C
‘ 01-0;
CH:
CH:
\
CHI
n
(EH-?r-CHICILCHCOOH
25-
70°C.
0
' 0
—
Sapogenoic acid
CH‘
CH:
\
/K'JH
CH:
EH-CHaCHaJJHOOOB
a N,
Semantic acid
CH:
10-
\
/(5
.
10913830
'
-——»
100°C.
~ /
.=
CnKeto acid
CH:
-_COOH
(‘3710:
70-100
OH; 0. H
eno-Blllanlc
_
acid.
E=O
25
--——s
70°C. N
&
> On Lactone
25-
‘
-—»
10° 0.
7
oxo‘sapogenin
.
‘(O-100° C.
My invention may be further illustrated by the
following examples:
nor-cholanic acid, may be‘ represented by the
formula:
Example 1
Dihydrosarsasapogenin, M. P. 165—166° C., is
' ‘
4.5
CH:
prepared by the method described by Marker and
Rohrmann, J. Am. Chem. Soc., 61, 846 (1939).
l3
A mixture of 20 g. of dihydrosarsasapogenin,
M. P. 165—166° C., and 200 cc. of acetic anhydride 50
is re?uxed for thirty minutes. The acetic‘ an
hydride is evaporated in vacuo and the residual
sirup dissolved in 400 cc. of acetic acid. The
well stirred solution is heated at 90-95‘? C. on a
steam-bath while 44 g. of chromic anhydride in
H
Example ‘2
250 cc. of 80% acetic acid is added over a period 55
of two hours, after which the mixture is heated
for an additional two hours. The mixture is con
‘To a solution of ,1 g. of'sarsasapogenin acetate
‘ethereal solution, after thorough washing with
water, is washed twice with 3% sodium hydroxide
. diluted with water and extracted with ether. The
in 100 cc. of aceticacid at 20° C. is added 50 cc.
centrated in vacuo to a volume of about 100 cc.
of l N aqueous potassium permanganate solu
The residual material is diluted with water and
tion. The temperature is maintained at 18 to 20°
the precipitated solids taken up in ether. The 60
solution to remove the acidic fraction.
C. for ?fteen hours, after which the mixture is
ethereal extract is washed well with water and
then with 3% sodium hydroxide solution.
The sodium hydroxide washings containing the 65 ' The sodium hydroxide washings containing the
acidic material from the oxidation is heated on
acidic fraction from the oxidation is heated on
the steam-bath for twenty minutes to complete
the steam-bath for ?fteen minutes to ‘complete
the hydrolysis. The cooled mixture is acidi?ed
the
hydrolysis. Acidi?cation of the cooled solu
with hydrochloric acid and the precipitated acids
‘ tion with hydrochloric acid yields a white solid
taken up in ether. Upon standing, the ethereal
solution deposits 600 mg. of small compact white 70 which is taken up in ether and crystallized from
' this solvent to give 225 mg. of white crystals. The
crystals which are recrystallized once from meth
product is recrystallized from methanol to ‘give
anol to givea product, M. P. 285-288°‘C. dec.
a
product, M. P. 286-288° C. dec. 7 This is the C22
This is the C22 keto acid, M. P. 285-287“ C. dec.‘
This
substance,“ . 3-(p)-hydroxy-16-keto-bis
acid
amplql
7.5 keto
identical .with that described'in Ex
.
.
<
_
;
.
2,406,885
" 7
rived from sarsasapogenin. It may be represent
Example 3
ed by the following formula:
Ha
Evaporation of the ether solution containing
the neutral products gives a sirup which is hydro
lyzed with hot ethanolic potassium hydroxide. UT
Dilution of the resulting solution with water gives
a slight precipitate which is taken up in ether
and discarded. The aqueous alkaline solution is
acidi?ed with hydrochloric acid and the precipi
tated material taken up in ether. After sublima 10
tion in high vacuum at ISO-180° the product is
an
H
crystallized from ether-pentane to give white
needles, M. P. 198-200° C. This is the C22 lactone
related to sarsasapogenin. It may be represent
ed by the formula:
It has a melting point of 285-28? C. dec. (gas
evolution), and it analyzes for the formula
15 C22H34O2.
' Better yields of this acid may be obtained by
CH3
CH3
conducting the oxidation of sarsasapogenin ace
|
C
tate at 80-85° 0., using two parts of chromic an
hydride to one part of sarsasapogenin acetate.
20 However, the yield of other oxidation products is
less at these higher temperatures.
This C22 keto acid is very sparingly soluble in
ether, acetone, chloroform and ethyl acetate, but .
it is fairly soluble in methanol and ethanol.
25 _ The methyl ester of the above C22 keto acid
may be obtained by allowing a suspension of 200
To a solution of 800 mg. of ‘the above men
mg. of the keto acid in 20 cc. of methanol-ether
tioned lactone in 30 cc. of glacial acetic acid is
(1:1) containing an excess of diazomethane to
added a solution of 2 g. of chromic anhydride in
stand over night. Then the solvent is evaporated
40 cc. of 80% acetic acid. The resulting solu
tion is heated on the steam-bath at 90° C. for 30 and the residue crystallized from the ether-pen
tane to give clusters of small plates which melt
three hours. The mixture is diluted with water
ric acid and the solid acid extracted with ether.
The ether upon slow evaporation deposits com
at 124-126" C., solidify at 127° C. and remelt at
159° C.
Other esters of this acid may be prepared, for
example, by treatment with an appropriate alco
hol and a suitable catalyst. For example, 200 mg.
of the C22 keto acid may be refluxed with 100 cc.
of 1% ethyl alcoholic hydrogen chloride for three
pact white crystals. These, after crystallization
hours.
from ether-methanol, melted at 285-287° C. dec.,
and give no depression with a sample of the C22
small volume, diluted with water and extracted
with ether. The ethereal layer is separated,
washed with dilute sodium hydroxide solution and
water, and the ether evaporated. The residue is
crystallized from ether~pentane to give white nee
dles of the ethyl ester, melting point 163-464o C.
Derivatives of the ketone grouping may be ob
tained by treating the acid or its esters with ke
tone reagents having a reactive NHz grouping.
and extracted with ether. The ethereal extract
is washed well with water and then extracted with
3% sodium hydroxide solution. The sodium hy
droxide extract is heated for twenty minutes on
the steam-bath, cooled, acidi?ed with hydrochlo
keto acid, M. P. 285-287° C-
.
Treatment of the methyl ester of the keto acid
with boiling acetic anhydride for thirty minutes
followed by decomposition of the excess acetic
anhydride with water yields a methyl ester ace
tate which crystallizes from ether-pentane as
compact white crystals, M. P. l98-199.5° C.
Treatment of the acid with hydroxylamine hy
drochloride under the usual conditions gives an
oxime which crystallizes from aqueous methanol
as small compact white crystals, M. P. 206-208°
C‘. dec.
Example 4
To a solution of 20 g. of sarsasapogenin acetate
in 500 cc. of glacial acetic acid at 60-70° is added
Then the solution is concentrated to a
For example, a solution of 100 mg. of the C22 keto
acid, 100 mg. of semicarbazide hydrochloride and
150 mg. of sodium acetate in 10 cc. of alcohol and
2 cc. of water is re?uxed on the steam-bath for
one hour. The solution is diluted with Water and
the white solid collected and crystallized from
ether to give a semicarbazone of melting point
204-207° C. dec.
Other sapogenins may be treated in accordance
slowly over a period of 4 hours, a solution of 12
with the directions of this example to give anal
g. of chromic anhydride in 200 cc. of 90% acetic
ogous products. Such sapogenins include tigog
acid. The mixture is stirred an hour longer,
then alcohol is added and the solution evaporated 60 enin, gitogenin and diosgenin. The latter con
tains a nuclear double bond which is protected
to a sirup. This sirup is dissolved in ether and
by addition of bromine prior to oxidation. In
the ethereal solution extracted with 3% sodium
stead of protecting the hydroxyl groups by acetyl
hydroxide solution.
The alkaline extract is warmed On a steam
bath for a few minutes and then it is cooled and
acidi?ed. The precipitated solid is crystallized
from dilute acetone to give sarsasapogenoic acid
of melting point 187-189° C,
'
The mother liquor is evaporated to dryness and
the residue dissolved in a small amount of ether.
‘After this concentrated ethereal solution has
stood at room temperature for several days, small
compact white crystals are deposited. These
are collected, washed with ether and recrystal
lized from methanol to give the C22 keto acid de
ation during the oxidation, other protecting
agents may be used. For example, the sapogenin
may be benzoylated, benzylated or halogenated,
for example, by treatment with phosphorus pen
tachloride in carbon disul?de.
Example 5
To 10 cc. of fuming nitric acid maintained at
20° C. by an external cooling bath is added 1 g. of
sarsasapogenin acetate in small portions. After
awhile when the sarsasapogenin acetate has com
pletely dissolved, the solution is diluted with water
2,406,885
10
and the gummy precipitate collected. This
gummy precipitate is boiled for a short time with
alcoholic sodium hydroxide. Then the solution is
separating the alkali soluble fraction, thereby oo
taining an alkali metal salt of a steroid acid
having in ring D the structure,
diluted, extracted with ether and the alkaline
layer separated. This alkaline extract is acidi?ed
‘
CH;
'
(EH. 0
and the precipitated acid taken up in ether. The
ethereal layer is separated and most of the ether
D
removed. On standing for several days, this con
0
centrated ethereal solution deposits crystals of
the C22 keto acid derived from sarsasapogenin. 10
where M represents an alkali metal, and hydro
This acid ‘has the formula C22H34O4, and it melts
lyzing said fraction.
at 285-287° C. dec. (gas evolution).
2. Process for preparing 3-e-hydroxy-16-keto
It will be apparent that in View of this disclo
bis-nor-cholanic acid which comprises subjecting
sure my invention is capable of numerous varia
tions with regard to conditions of reaction, re 15 sarsasapogenin acetate to oxidation at 40-100° C.
by treatment with a strong oxidizing agent, sep
agents and sapogenins employed.
arating the alkali soluble fraction, hydrolyzing
Steroidal sapogenins on which this invention
said fraction and crystallizing 3-,8-hydroxy-16
may be practiced include not only the aglycones
keto-bis-nor-cholanic acid.
of the naturally occurring steroidal sapogenins,
but also their nuclear transformation products,
1. e., the substances derived from the aglycones
by changes in rings A and/or B which leave the
side chain attached to ring D still intact and like
that in the aglycones. Thus, this invention may
20
be practiced on steroidal sapogenins‘such as smil
25
agenin, sarsasapogenone, 3-desoxysarsasapogenin,
3. An acid having the formula
CH:
CH:
/\ I
the‘ sarsasapogenyl chlorides, and the like.
It is apparent that sapogenins having in the
side chain either con?guration with regard to
C22 may be employed in practicing this invention, 30
that is to say, compounds having a side chain
either of the type of sarsasapogenin or of the type
tigogenin may be oxidized in the manner set forth
in this speci?cation, and regardless of the con
?guration of the side chain of the sapogenin oxi 35
dized the structure of the oxidation products re
main the same, for example, sarsasapogenin and
isosarsasapogenin give the same oxidation prod
ucts.
CH:
11-00011
\/=0
(a)
H
‘
HO
4. An ester having the formula
CHI
CH’
OH‘
on coo on
'_
/\
‘_
I
,
=0
(B) H
no
What I claim as my invention is:
_
1. Process for obtaining sapogenin oxidation
products which comprises subjecting a member of
the class consisting of steroidal sapogenins,
40
5. A compound having the formula,
.
CH:
sapogentic acids, dihydrosapogenins, sapogenoic
/
acids, and C22 lactones, to vigorous oxidation at 45
40-100° C. by treatment with a strong oxidizing
agent after previously protecting hydroxyl groups
therein with a member of the class consisting of
acylating agents, aralkylating agents, and halo
genating agents, thereby producing a C22 keto
acid having in ring D the structure
CH:
D
CH:
CH:
50'
H>k/
n-coon
I ;=0
(5)31
where R is selected from the class consisting of
hydrogen and alkyl radicals and R1 is selected
from the class consisting of —0H and groups
hydrolyzable to ---OH.
RUSSELL EARL MARER.
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