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Патент USA US2408835

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Patented 0a.s,194e
‘
s
2,408,834
_
v
REISSUEB
‘UNITED ‘STATES PATENT» OFFICE
2,408,834
’
STEROIDAL CONIPOUNDS AND ‘METHODS
FOR OBTAINING THE SAME
Romeo vB. Wagner, State College, Pa., 'assignor 'to
Parke, Davis & Company, Detroit,
Mich.;'a
“core
~ '
poratio'n-of Michigan
NoDrawing. Application May 15, 1944,
Serial No. 535,758 I »
'5 Claims.
w
> ‘
(Cl. 260‘23915) _
The invention relates to new steroidal sa-
tive steroidal compounds of the typed'erived'from'
pogenin type compounds and methods for Yob~
the mammalian suprarenal cortex
taining the same.
oxygen containing group'in ring 0' of the cyclo
‘
'
_
.
I have obtained for the v?rst ‘time the hereto-
pentanopolyhydrophenanthrene nucleus.
fore .unknown
steroidal
sapogemn which
compound
hereinafter
to as
rockogen'in
has 5
the
followingreferred
structural
formula.
OH:
CH’
OH
‘OH’ ‘
’
/
GENERAL'PROCEDUREFRACTION
FOR ‘OBTAINING A SAPOGENIN
In obtaining ‘the new compounds, the plant or
CEBU-Ha
4}
.
‘
part of the same which is to be extracted 'is‘cut
_
p
10 up, ground or ‘shredded and then extracted either
'H'*c\o-0§i
-CH‘“C'H*
with hot ‘water or a7 lower aliphatic
alcohol
such
~
'
as ethyl ‘alcohol.
The :plant may be dried before extraction, but
I ‘prefer ‘to extract the ‘plant without v‘any
I
‘
p
?
_
15 preliminary drying.
,
‘I
I also prefer to
anal
cohol solvent such as ethanol orabout 95% ‘hot
. ,
aqueous ethanol. For example, if one "has about
HOX/A/
plants; such as stems, soft roots, leaves ‘or fruit;
H
20 these can ‘be covered over with about 32 liters of
139:0,‘
I.
_
OH
25 two 7-liter portions of hot ethanol and then
squeezed dry The extract and wash alcohol can
y
evaporated to a syrup and the syrup con
cen'trated by passing a current of ‘air over its sur
‘
.
and groups hydrolyzablefto
H
,
a ,
' ‘ _
30 ‘slowly.
agent, the evaporation ‘takes place ‘much more
7
H the invention have the
_. The new compoundsof
After evaporation, the‘ concentrate containing
saponins andmust
like combinations
.of in
the order
steroidal
sapogenin's
be hydrolyzed,
"to
0H
following'general formula,
‘
'
_ liberate the sapogenins. This ‘is best accom
Y
CH.
CHECK:
on, I on, |
/
\
.
_ CH__Q\
——
D
. \/_
JA
CH‘Cm
o_._e§,
3° plished by aqueous or alcoholic strong mineral
acid. ‘For'exampl'e, the above mentioned con
centrate from 25 kg. of ‘plant material .can be hy
drolyzed ‘by re?uxing it 'for'2‘hours with 3 liters
l
40 of 2N ethanolic hydrochloric acid The reaction
B
y
X_\/\/
_
c I
where x and Y are members of the class =0,
<QH
H
‘ _ t0 '
and'grGHPS hydrolyzable
_ ,
>
of hot. alcohol. The combined alcoholic ?ltrates
45 are diluted with 20 liters of diethyl ether and the
sodiumlghydr-oxide and water and evaporated.
i
7' OH.
These compounds are new valuable starting ma-
hydrolyzed
by alcoholic
refluxing potash
the residue
with
3 vol
50 lanes
of ‘10%
for 30
minutes.
The cooled mixture from the alkaline hydrolysis
a sapogenin fraction which is dissolved in ace
terials for the preparation of physiologically ac- 55 tone, treated with active-charcoal such as the
v
2,408,834.
.T.
..
3
.
Calc’d for Carl-14204:
4
C, 75.3; H, 9.8.
product known as “Norite" and ?ltered. The
clari?ed ?ltered acetone solution contains the
Found:
C, 74.9;
H, 9.8.
The ?rst
mother
liquor is evaporated to dryness.
sapogenin fraction of the plant and can be sep
the acetone by evaporating the lat
whitecrystals, M. P. and niixedlvl, P. with rocko~
The residue is
genin from (a), 209-210;" yield- some:
, arated from
ter. Such sapogenin fractions consist of mix
tures of_ sapogenins: The individual, sapogenins
1
Ariel; 'Calc’d'for C2'IH4I4O4: C, 75.0","H, 10.3.
Found:
C, 74.9; H, 10.4,
“The diacetate is prepared with boiling acetic
anhydride .and the product is crystallized from
are next isolated or separated out of this frac
a general procedure
tion.
The above description is
which I use for obtaining a sapogenin fraction or.
from methanol as
M. P. and mixed 15.1’.
with,
rockogenin
diacetate
from (a), M P. 205
mixture. It is merely illustrative and is capable
,7
.
of considerable variation, as will be understood by
.2 Calc’d'ifo'r CnHmOa: C, 72.1; H, 9.4.
T'Analxi
methodior,‘ ‘' .2070.
those skilledsapogenin
in the art. Any known
hydrolytic and
hecogenin ace
(0)‘ Rockogem'n acetate from g. of the acetate
procedures may
make possible ‘they I > tate.-‘-An ethereal solution of 0.5
and Adams
vided solvents are used which
with hydrogen
the plant
ketone
tissue‘
subof‘ v‘ ' ofhecogenlin is shaken
above.
Rockogenin 3-mono
catalyst as described from methanol as white
the greater part of the hydroxyl
and by the hy
liberated
acetate . crystallizes
10 .
'
' methanol‘ as white needles,
20
drolytic steps,
.
_
pl'ates.M.-P.
Anal; Calc’d
2l1-213°.
for ‘Cad-14605; ‘ C,, v734; H,.' 9.8.
.
Example. 1.'-‘-Hecogenin from ‘Agave, .toumeyana
a
1
Found: C, 73.8; H, 9.7.
'. '
v
_,
.
'
When re?uxed with acetic anhydride for one
.Trel‘
5 kg. of medium age plants of the species Agave 25 hour it forms rockogenin ‘diacetate, 1M‘. '2. and
mixed M. P., 203-205‘. ,_ '
..
_.
-.
.
.
toumeyana Trel., collected; above the tunnel on
Example 3.--Szmth.esis of hecogenone
route 60-70, east of Superior, Arizona, in Novem
treated by the above described gen
(a) Fnom hec0genin.-A_ solution of 0.1 g. or
eral procedurein'or'der to obtain a I sapog'e
hecogenin in 30 cc. of acetic acid is mixed with
iractionlwhich consists largely of hecogenin, the 30 a solution of 0.1 g. of chrornlc anhydride in 5 cc.
starting material for the synthesis‘ of rockogenin
acetic'acid. vAfter standing thirty min
described in Example 2. The sapogenin fraction
from ether is acetylated and crystallized'irom
methanol-ethyl acetate togive plates of heco
utes at 25°, water is added and the product is
gen'in acetate, M. P. 246-2482 Yield, 13g. ,
layer gives no acid fraction. The ethereal solu
tion is concentrated and cooled to give white
needles of hecogenone, M. P, 237-240°. .7; H, 9.4.
AnaL: Calc’d for CmHmOr. C, 75
ether extracted. An alkali wash of the ethereal
solution followed by acidificationv
Anal.‘:d Calc’d for Casi-14405: C, 73.7; H, 9.4.
Foundi 0,755.4; H, 9.3.'f
‘Y '
'
"The acetate is’hydr'olyzed ' and the product'is
crystallized
".AnaL-z- Calc’d
from for
methanol,
CwzHizOra'
M. P,C,265-268".
75.35 H, 9.8;
Foundi‘C, 75.0; H, 9.7,
‘
.-
Found: C, 75.5; H, 9A.
.,
._
40 I, (5) From rockoge?irlLl-The above mother liquor
from the preparationfoi rockogenin by catalytic
l
reduction'of hecogenin described
under, ‘Example
‘
. vThe residuefdise
Example 2.-—Synthesis of rockogenin from. heco
.
'
.
genin
'
.
.
,
,
solved in 25 cc. of acetic acid is oxidized with a
solution of 0.15 g. of chromic anhydride in 10 cc.
of 80% acetic acid for thirty minutes at 20°. The
product is isolated as described above and crys
(a) By catalytic hydrogenatiom-e-An ethereal
solution of ‘0.3 g. of hecogenin containing several
drops of acetic acidis shaken with.hydrogenfand
0.2 .g. ‘of. Adams catalyst for twohoursat room
temperature 'and three atoms. _ After ?ltering the
solventfislrenioved. I The oily residue is re?uxed
with acetic anhydride‘ror one hour. ‘ The solvent
50
tallized from ether as ‘white needles, M. P. and
mixed M. P. with hecogenone, 237-240°; yield
C, 75.7; H, 9.4.
0.1 g.
Anal: Calc’d for Carl-140042
,
,
_, I
_,
. ,
Hecogenone "has the; ielewins structural: .102.
is removed in vacuo on the steam bath and‘rocko
genin'fdiacetate is crystallized from methanol“ as
long‘ needles, M. P. 204-206"; yield, 0.12 g.
'
Found: C, 7.5.5;_H, 9.4,._
j1
_.-.
Calc’d' ior C31H4a0a2, C, 72.1; H, 9.4.
Found: C,71.9';H, 9.2.
‘
'
‘
the aqueous
f
'
>
._
.1‘
.
.1
mula
’
‘ When hydrolyzed 'with5% alcoholicpotassium
hydroxide ‘for twenty minutes on the steam bath,
the 'diacetate is .-~converted' to the" rockog'enin
which crystallizes" from methanolv as
,
'
dies, M. P."208-—210°. Repeated crystallizations
from ether gives material melting 217-2202 ‘
60
. ‘
'AnaLY‘Calc’d for (1211714404? C, 75.0; H, 10.3.
Found: C, 74.5; H, 10.2; ‘
,
'
auction-4T6 a' sold
‘
" '(b) By sodium-ethanol 1' in 100 cc. of absolute 65
tion of 300mg-of hecogenin
ethanolwis added 7 'g. of 'sodium'insmall
strips
The mixture
‘is
‘over a ‘period of thirty minutes.
cooled and poured
_
Ring dihydroxy compounds-,such as rockosenin.
r
_
can be diacylated at the ring ‘hydroxyls' and
'
‘solid ‘is extracted with ‘ether and theethereal
partially saponifled .to obtain a mono-acylated
solution is washed with water, 10% hydrochloric
acid’and water. The eth'erealsolution is con?
and cooled to give white crystals, M. P.
centrated
233-244“, wt, 160 mg. :Recrystallization from
ether gives starting material
melting260-262"; a
(265°) ' melted‘ 262-265°.
hydroxy derivative which can then be oxidized
75
withchromic acid at ‘the free hydroxyl'to give
the corresponding
monoacylated
ketone.
acylated ketone-upon
hydrolysis
gives the
‘latter
2,408,834
and ester groups hydrolyzable to
OH
3. The new steroidal sapogenln, roekogemn, 01'
The monoacylated ketone can be hy
drolyzed to the free hydroxy keto e, for example
the formula,
by methanolic potassium hydroxide.
CH HOCH CH3 /CH2—C€1
What I claim is:
'
1- A crz-substituted steroidal sapogenln 01' the 10
' err-o
0114211;
formula,
ona]YcH:CH
$11’ /
“gas
O
A
HO
D
l
H
4. The new steroidal sapogenln compound hav
ing the formula,
20
on O CH (fH' / CHr-CH:
' I
' CH-C
CH-CH!
Where X and Y are members of the class =0,
OH
O
/\
H
and ester groups hydrolyzable to
D
\/
B
OH
rt
H
2- A C1z—keto steroidal sapogenin of the for
30
mula,
5. The method of synthesizing rockogenln
which comprises reducing hecogenin having the
formula
OH:
OI
CH:
4}CH:
‘
/ CHHCH:
H—C\
CH-CH:
was,
X_ A
35
I
40
where X is a member of the class =0,
OH
H
45
ROMEO B. WAGNER.
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