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2,408,835
Patented Oct. 8, 1946
UNITED STA'l‘E s PATENT. OFFICE
- 2,408,835
STEROIDAL COMPOUNDS AND METHODS
FOR OBTAINING THE SAME
Romeo B. Wagner, State College, Pa., assignor to
Parke, Davis & Company, Detroit, Mich., a cor
poration of Michigan
No Drawing. Application May 15, 1944,
Serial No. 535,759
7 Claims. (Cl. 260—-239.5)'
1
I
2
Y
,
.
where Y1 and Y2 are the same members of the
The invention relates to new carbon ring satu
class consisting of
rated steroidal sapogenin compounds having hy
droxyl groups and/or groups hydrolyzable to hy
OH
droxyl at positions 2 and 3 of the steroid nucleus
H
and also one of these same groups or a ketone
group at position 12 of the steroid nucleus.
It is known that steroidal compounds, that is,
and groups hydrolyzable to
on
compounds containing a 10,13-dimethyl cyclo
pentanopolyhydrophenanthrene nucleus, are
present in plant tissues such as Beth root (Tril
10
and Y3 is a member of the class consisting of :0,
Zium erectum), Digitalis purpurea, etc. However,
the number of known plant sourcesof such ste
roidal compounds is relatively quite limited and
vII
the types of steroidal compounds which have thus
far been found in practical quantities in plant tis 15 and groups hydrolyzable to I
sues are also quite limited in number.'
Only one steroidal compound has been known
which occurs in plant tissue and which at the
same time has an oxygen atom attached to the
OH
11
C12 carbon atom of the steroidal nucleus. That 20 These compounds are new valuable starting
materials for the preparation of physiologically
compound is digoxigenin having a hydroxyl group
active substances such as sex hormones and the
(—OH) attached to the C12 carbon atom and be
like. They are especially valuable for the prep
ing a compound of the cardioactive type having no
aration of physiologically active steroidal com
practical value as an intermediate for sex hor
mone type products. Although digoxigenin is a 25 pounds of thetype derived from the mammalian
suprarenal cortex whichlhave an oxygen contain__
steroidal compound, it is not a sapogenin and
ing group in ring C of the cyclopentanopolyhy'a
its side chain attached to ring D of the steroid
drophenanthrene nucleus.I
nucleus is of a distinctly different type from the
In order to get a sapogenin fraction from
sapogenin type side chain present in the new
30 plants, for use in ‘obtaining the new compounds
genins of my invention.
7
of the invention, I use one of the methods de
I have now discovered that certain plants and
scribed in the following general procedure.
products derived therefrom can be treated by
physical and chemical methods in order to ob
GENERAL PROCEDURE FOR OBTAINING A SAPOGENIN
tain new valuable Ola-substituted steroidal sapo
FRACTION
genins.
-
_
The new compounds of the invention have the
general formula,
Ya
CH3
'
CH3
OH: I
CHa-CHa
/
CH—C\O———CHz/CH--CH3
D
g
O
2
.
35
In obtaining the new compounds, the plant or
part of the same which is to be extracted is cut
up, ground or shredded and then extracted either
with hot water or a lower aliphatic. alcohol such
as ethyl alcohol.
'
The plant may bedried before extraction, but
I prefer to extract the plant without any prelim
inary drying. I also prefer to use an alcohol sol
vent such as ethanol or about 95% hot aqueous
ethanol. For example, if one has about 25 kilo
grams of undried and cut up parts of the plants,
2,408,835
3
such as stems, soft roots, leaves or fruit, these‘
A sample of manogenin is boiled with acetic
anhydride, excess anhydride distilled oil and the
residue crystallized from methanol. It consists
of manogenin diacetate and has M. P. 253-255° C.
AnaL: Calc’d for C31H4aO-1t C, 70.2; H, 8.7.
can be covered over with about 32 liters of 95%
ethanol and heated under a re?ux condenser at
moderate steam bath temperature for about 12
hours. The hot extract can then be strained
through cheese cloth, the ?lter cake Washed with
two 7-liter portions of hot ethanol and then
squeezed dry. The extract and wash alcohol can
Found: C, 70.2; H, 8.6.
Example 2.—(Mea:ogenin from .S'amuela
be evaporated to a syrup and the syrup concen
trated by passing a current of air over its surface. 10
camerosana (TreZ.))
272 kgs. of the caudex from young plants of
When using hot water as the extracting agent,
the evaporation takes place much more slowly.
the species Samuela carnerosana Trel. were col
liberate the ,sapogenins. This is best accom
plished by aqueous or alcoholic strong mineral...
acid. For example, the above mentioned con
centrate from 25 kg. of plant'materiaLcanw-bes
the alcoholic extraction oft-the 2721kgssin accord
ance with the general procedure given above is
dissolved in 192 liters of ethanol and hydrolyzed
with. .43. liters ..of.. concentrated hydrochloric acid
lected during the month of March along the Rio
After evaporation, the concentrate containing
saponins .andelikeccombinationsmf. thensteroidall. Grande River at Black Gap in the Big Bend
sapogeninsz; must" be& hydrolyzed ini ordenztoc 15 reg-ioncoiq’I‘exas.‘ The alcoholic concentrate from
forr3i‘liours... The reaction mixture is then ex
hydrolyzed by re?uxing it for 2 hours withi-3 liters ;
trated with 160 liters of butyl alcohol.
of 2N ethanoli’c hydrochloric acid. . The reaction.
The
butanoln extract is: washed several times with
mixture is cooled and ?ltered..- Ifanye-considéne
water'andithemwitlri 10% caustic solution. The
butanol'layerv'visiwvashed free of alkali with water
and. evaporatediin vacuo. The solid residue is
powdered and thoroughly extracted with 160
liters of acetone. The acetone extract is then
able tar is present at this stage, it can be ground '
and digested several times with an equal volume
of hot alcohol. The combined alcoholic-?ltrates
are diluted with 20 liters of diethyl ether and‘th‘v
solution washed successively with watery. 5%».
evaporated.
sodium hydroxide and water and evaporated.
One half of the residue from evaporation of
Fatty_.esters.in the residue .thus obtained. can be
hydrolyzed by re?uxing‘th‘e residue with‘ 3“vol-l 30I the racetone nextractwis-"hydrolyzed .witlrzanrexcess
of‘alcoholicipotashior 30 minutes: Thereaction'a
umes of 10% alcoholic potash for 30“minutes.
mixture is 'COOlEdi to1359C. and extracted:with-40=i~
The cooled mixture from‘ the alkaline hydrolysis
liters 1 of: ether: and: the 1; ether .‘extr acttseparated,‘
is extracted with ether and the ethereal solution
washed with water and then evaporated to give
washed with: water andsevaporated: 'I’he1resid11ec
a sapogenin fraction whichaaissdissolvedjinaace-e -- 35 from theieva‘porati'on' is‘ lsepa-rated‘iinto; an ‘ace-7
tone-soluble fraction (fraction H,“ see crystalliza
tone, treated with active. charcoal such as the
product known as “Noritef’ and ?ltered. The
clari?ed ?ltered acetone’: solution contains the
sapogenin fraction of the plant and can be sepa
tion" chart) ‘ and" an» acetone-insoluble fraction;
B”; The ‘-B'—fr‘action- weighs-148 -‘ grams and ‘ is
further crystallized v-from"ether 'to ' give- an ether
rated from the acetone by evaporating the latter. 40
Such sapogenin fractions-consist of mixturesof
sapogenins. The individual sapogenins are next
isolated or separated out ‘of this fraction.
The above description :isra: general procedure‘:
which I use for obtaining a sapogenin fraction
or mixture. It is merely illustrative and is
capable of considerabler. variation, as will be
understood. by those skilled in the art. Any
known ‘method ‘of obtaining asapogenin fraction
by ,.' hydrolytic ‘and solvent extraction ‘procedures
maybe used, provided solvents 'areusedtwhich’:
make'vpossible the separation'and ‘isolation from
the-plant; tissue of ‘tlie‘greater part .zotjth'e h'y:
droxyl I and; ketone substituted 1 steroidal; sapoe
genius. liberated by , theh'ydrolyticlsteps. .
solublé fraction; _D,‘ and "an‘ eth'ereinsoluble frac-.
tion; C,weig'_l_1ing_46‘grams.;.
The ether-.insolubleir'action.(C) . is 'acetylated.
(e.; g.-_v with. .acetioanhydride) . and thenzcrystal
lized from methanolyand- ?nally .from ether.- The»
crystals have-M;
and‘ mixed. Mr. P. with
samogeniniacetate 0f:;195—?198°o C; Yield: is‘-;3.0.
grams:
Hydrolysis...’ of: this diacetates.‘ gives'
samogenin;~ M.=.P:‘ and-mixed M.fP;;.208-214"- C.
AnalJCalcfd forCi-zHdOi: C;-.75.0; H,"'10.'3.'
Found 2' 'CI‘ 74.8 f ‘12310.25
Tiles-properties ‘of-'samogenir'r and‘ its"diacetate '
are described in-J. Amer: Chem. Soc. vol.‘ 65;
pages '1199 ‘to‘1209..(I943).'.
The. sapogenins in..th‘e ethere-solublesfraction...
D; areacetylated ..and-.treated .'.with. 40 grams: ‘of. .
Girardfs ireagentsT- in . 1 .liter . oi ethanol
dew
Example 1.- (Man'ogenin- from ‘ Agave -'
H u'achizcensis Baker)
' scribed for A. HuachucensisfBakerlunderqExam
8 kilograms (8 kg.) of’: entire .plants“ of: this .
ple 4. -. The ketonefraction, E,-.is crystallized from
speciesare collected .imseptembereast of Tucson‘;
ether-.pentane;rM;.P. .195-'200°5 “CI, and weighs 34
Arizona. . The .sapogenin .fractionntthese plants
grams: This material: ‘is recrystallized .from 125'
is first obtained by- thengeneral’ procedure de
cc." of “ ether-‘to ' give 2a 'small' ethereinsoluble frac-'
scribed above. It is then taken up in and crystal
tion, M. P. and mixed M. P. with kammogenin'
lizedjfromacetone.“ The product has ‘a‘melting
diacetate, 258=-261° 'Cfand'weig‘hs1.5‘grams. See
point” (M: P.) " of ‘ 234-236x‘C." and‘ weighs ‘10.65
above article in J. A. C. S. 65, 119941209 (1943).‘
grams. It "is "recrystallized‘from' ether‘ ‘and then‘
Analysis for/kammogenin diacetate: Calc’d for
C31H4407251C; 70.4; H,‘9.4.r.. Found: C, 70.5; H, 8.7.
gives the" dihydroxy'ketone 'manogenin" of ”M.‘ P.‘
241 to 243° 0.
‘ A‘ solutlon‘of manogenin'in-ethanol‘is ‘treated
with; a‘ 2 %' solution ‘of ' ‘digitonir'r invethan'olg' Im
mediately: a‘ heavy -' white? precipitate or‘ the
digitonide of inanogenin‘isidrmedi‘
I
The etheri‘?ltrateHF, after; removal of kam
mogenin diacetate, iszdiluted with apentane, con
centrated and cooled to'give mexogenindiacetate,
M. P. and mixed M. P., 204_206‘?' C.'; 'yield'ris 25
grams.
Anal: Calc’d for C31H4607: C, 70:2;,H-,'8.7.
75 Found: C, 70.3; H, 9.0.
2.4085835
6
the March collection (272 kg.) of Samueldcar
The Girard’s non-ketone fraction, G, is frac
tionally crystallized from methanol to give an
additional 7 grams of samogenin diacetate, M. P.
and mixed M. P., 195-198?’ 0.
nerosana-Trel:
l H
steps is concentrated.cooled._'and ?ltered to give
a dark semi-solid mass.‘ This mass is hydrolyzed
with excess 20% alcoholic potash for 30 minutes.
-
L
,
~
'P._.‘172-180° C.,
C
,
acetate
..
=
.
._
.
.'
~
‘
In this case, however, no‘ >_
B‘
D
Smilagenin
is acetylated and treated with Girard’s reagent as 10
described previously.
'
ll
j ‘
The acetone-soluble fraction, H, from the above
The product from methanol,
:i
_
G
~.
E
-.
.,
Semogenin
~L
, diacetate
ketone fraction is obtained. The non-ketone
diacetate
, F
fraction is crystallized from acetone, M. P. and
mixed M. P. with smilagenin acetate, 148-150° C.,
15
yield being 30 grams.
Mexogenin
Kammogenln
diacetate
diacetate
Anal: Calc’d for C29H46O41 C, 75.9; H, 10.1.
Found: C, 75.9; H, 10.2.
A. Crystallization from acetone; B. Crystalliza
Hydrolysis of the acetate gives smilagenin,
tion from methanol and then ether; C. Acetyla
M. P. and mixed M. P., 184-186° C.
tion. Crystallization from methanol and then
Anal: Calc’d for C27H44O32 C, 77.8; H, 10.7. 20 ether; D. Evaporation. Acetylation. Treatment
Found: C, 77.8; H, 10.7.
with Girard’s reagent T; E. Crystallization of
ketone
fraction from ether; F. Dilution of ether
Memogem'n
mother liquor with pentane. Slow evaporation
The above described mexogenin diacetate can N and crystallization; G. Crystallization of non;
ketone fraction from methanol; H. Evaporation.
be hydrolyzed, e. g. with excess 20% alcoholic
Hydrolysis. Crystallization _from methanol.
potash, and the hydrolyzed product extracted
Acetylation. Treatment with Girard’s reagent T.
and crystallized from ether to give mexogenin of
(No ketone fraction obtained.) Crystallization
M. P. 245-246” C.
ofnon-ketonefraction from acetone.
"
’
'
Anal: Calc’d for 0271-14205! C, 72.6; H, 9.5.
Samogenin
:
'
I
Found: C, 72.9; H, 9.6.
’ "
'
Example 3.-—Synthesis of agavogem'n from'mdn
ogem'n
Boiling acetic anhydride converts it back into
its diacetate of M. P. 208° C. Mexogenin is
(a) By catalytic hydrogenation: An ‘ethereal
isomeric with manogenin. It is saturated to bro
solution'of 0.3 g. of manogenin containing sev-‘
mine-acetic acid solution. When added to ‘a 2% 35 eral drops of acetic acid is shaken with hydrogen
alcoholic solution of digitonin, it forms an insol
and Adams catalyst for three hours at room tem-‘
uble saponide very slowly.
perature and three atms. Agavogenin is crystal-'
Although mexogenin forms a monosemicarba
lized from aqueous methanol, M. P.‘233—240°.' A
zone, it is not a?ected by’ the conditions, ‘of a he. mixture with the starting‘ material (240°) gives
a‘melting point elevation, 242-247°.
'
mild Clemmensen reduction reaction, thereby in
Anal: Calc’d for 0271-14405: C, 72.3;
dicating the inert position of the carbonyl group.
Found: C, 72.2; H, 9.9.
>
I
In this respect, it is like the other l2-keto
The triacetate is prepared by re?uxing a solu
removes the carbonyl group, giving samog'enin. .3, tion of the triol in acetic anhydride for one hour.
The solvent is removed and the residue is crys
The reduction product when converted .to its di
tallized from methanol as plates, M. P. 226-228?’
acetate, is identical with samogenin diacetate.
Hence, the relationship of mexogenin to samo
Anal: Calc’d for CssHsoOsZ C, 69.0; H,"8.8.
genin is thereby further established. The trans
Found: C, 68.5; H, 8.7.
I
formation to samogenin can be illustrated as fol
(b) By sodium-ethanol reduction: To a solu
lows.
tion of one gram of manogenin diacetate in 300
cc. of absolute ethanol is added 23 g. of sodium
steroidal sapogenins. Wol?-Kishnerv reduction
C
'
’
‘
over a period of thirty minutes. 'After the so
dium has reacted the reaction mixture is diluted
O
with water and ether extracted. The ethereal
solution is washed free of alkali with 10% my
O
drochloric acid and‘ evaporated.
Wolff-Kishner
A
—-—>
reduction
Agavogenin
crystallizes from ether as White needles,_M. P.
238-2402 yield, 0.25 g. A mixture with material
from (a)_melts 240°.
‘
I
_
Anal: Calc’d'for C27H44O5I C, 72.3; H. 9.9.
H
Mexogenin
Found: C, 72.0; H, 9.8.
'
'
The triacetate is prepared by re?uxing with
C: ,um ‘acetic anhydride for one hour.
It is crystallized
from methanol as plates, M. P. and mixed M. P.
triacetate from (a) , 226-228".
'
Anal: _Calc’d for CasHaoOe'Z C, 69.0; H, 8.8.
Found: 0, 68.5; H, as. '
s
In addition to the above described properties
of agavogenin, it also is converted by mild (e. g.
25° C.) chromic anhydride oxidation to hecogenic
acid. The latter oxidation product is identical
Samogenin
with the hecogenic acid from mild oxidation by
Crystallization chart for the sapogenins from 75 CrOs of manogenin. Hence, agavogenin is 12
2,413.8;835
7
dihydro-manogenin. These changes can be '11
lustrated as follows.
‘
7“
-H
.Azavozenin
where ‘Y1 and Yz-are- the same members of the
classconsisting of
The examples given are for the purpose of il
lustrating the invention and can be varied in a
OH
good many Ways. For instance, acetic anhydride
H
is used as the acylating agent for the alcoholic 30 and groups hydrolyzable to
hydroxyl groups of the new compounds. How
‘OH
ever, one may use any of the known organic
agentsfor converting alcoholic OH to an ester
or» ether or other group capable of hydrolysis to
give ——OH. -Such agents are, for example, or
H
and Ya, is a member of the class consisting‘of =0,
ganic acid halides, acetyl chloride, benzoyl chloride, furoyl chloride, butyric anhydride, forma
‘
01!
tion of the alkali metal alcoholate followed by
reaction with an alkyl halide to form an ether,
and groups hydrolyzable to
use 01' triphenyl, methyl chloride to form the so 40
<03
called trityl ethers, halides such as sulfuryl chlo
ride, phosphorus chlorides and the like.
Ring dihydroxy compounds, such as mano
genin and mexogenin, or ring trihydroxy com
‘
pounds such as agavogenin can be completely ‘1
aoylated or etheri?ed at all of their ring hy
droxyls. Completely esteri?ed or acylated agavo
genin can be partially hydrolyzed at the number
2 and number 3 carbon atoms of the ring sys
H
What I clalmis:
1. A ring saturated ?zz-substituted steroidal
sapogenin or the fromula
tem to obtain derivatives partially esteri?ed or '
etheri?edat Cm but with free hydroxyls at C2 and
Cs. ,Similar derivatives can be made by using
alkali metal and alcohol, or hydrogen in pres
ence of a platinum catalyst, to reduce the C12
keto of completely esteri?ed or etherifled mano
genin or mexogenin to get the corresponding
compound with a free hydroxyl group at 012.
"V
where Y1 and Y: are the same-members of the
class consisting of
When hydrogen and a catalyst are used for re
duction, thegroups at C2 and C3 are not. hydro
lyzed and the C12 hydroxyl alone can then be 60
esteri?ed or etheri?ed to replace it by the same
or by a different ester or ether group from that
OH
and ester groups hydrolyzable to
at carbon atoms 2 and 3. Thus, it isv easy for
those skilled-in the art to prepare any of the
new compounds of the invention having the gen (55
eral formula,
CH:
UHF-CH:
7
<03‘
H
and Ya is a member of the class consisting 0! =0,
on
Q~H"‘C,Hl
H
and'ester groups hydrolyzable to
Yx=
YFL/
‘
75
'
0H
2,408,835
sapogenin of the formula
10
and ester groups hydrolyzable to
2. A ring saturated Cm-substituted steroidal
OH
'
<11
4. A 2,3 - dihydroxy - 12 - keto - ring saturated
steroidal sapogenin of formula C21H4205.
5. Manogenin of the formula, (7271-14205, the
structure of which is
10
O
CH;
CH3 1 CE! |
/
CHr-CH:
CH—O\
U l O_c§.
where Y1 and Y2 are the same members of the
class consisting of
OH
.
15
H
and ester groups hydrolyzable to
on
no
HO
H-OH!
/
1
u
H
20
6. Mexogenin of the formula, C2'zH420s, the
structure of which is
and Y3 1s a member of the class
on o
' I
on
CH;
CHI-‘CH2
cH-cm
25
and ester groups hydrolyzable tL
OH
30
3. A ring saturated Cur-substituted steroidal
7. Agavogenin of the formula, 0211-14405, the
structure of which is
HO
HO
where Y1 and Y2 are the same members of the
class consisting of
OH
H
45
o
ROMEO B. WAGNER.
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