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Патент USA US3092652

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319925642?
Patented June 4, 1963
2
spending A8<9)-7,1 1-dihalo-cyclopentanopolyhydrophen
3,092,642
anthrene compound (Compound 3); the latter compound
118(1932 -3-ACETOXY-ll-KETO-ERGOSTADEENE
is reacted with an aqueous solution of metal salt charac
terized as having a cation which forms water-insoluble
halides and an anion which is non-reactive with steriod
AND PROCESS FOR THE PREPARATION
THEREOF
Roger J. Tull, Plain?eld, and John M. Chernerda, Me
tuchen, NJL, assignors to Merck & (10., Inc, Railway,
N.J., a corporation of New Hersey
compounds, thereby producing the corresponding ll-keto
cyclopentanopolyhydrophenanthrene compound having a
No Drawing. Filed July 29, 1957, Ser. No. 674,597
8 Claims. ((31. 260-3972)
tion with a carbon atom adjacent thereto and gamma with
double bond connecting the carbon atom in the 8-posi
respect to the ll-keto substituent (Compound 4). This
This invention is concerned generally with steroid com
pounds having an oxygen atom attached to the carbon
atom in the ll-position of the molecule and with proc
esses for preparing these ll-oxygenated steroid com
pounds. More particularly, it relates to a novel process 15
for converting epoxides of A",<8)19(1D-cyclopentanopoly
compound is then treated with a base to form the corre
sponding Am) - 1l-keto-cyclopentanopolyhydrophenan
threne compound (Compound 5).
The reactions indicated hereinabove may be chemically
represented, insofar as rings B and C are concerned, as
follows :
r O_
l/
\,
_
/
Compound 1
or
X_ l/
}
0- ,/
A
0—
\I/ i _ Q
MK
_
\I u _
Compound3
Compound 2
l/ '_" \
Compound 5
\
Compound 4
hydrophenanthrene compounds to the corresponding
wherein X represents halogen.
A8(9)-l1-keto-cyclophentanopolyhydrophenanthrene com
The epoxides of Am“?(11>-cyclopentanopolyhydrophen
pounds, and to the intermediate compounds thus obtained. 40 anthrene compounds which we ordinarily empoly as start
The A8(9)~11-keto-cyclophentanopolyhydrophenanthrene
ing materials in carrying out the presently invented proc
compounds prepared in accordance with our novel pro
ess are those having a sterol side chain attached to the
cedure are valuable as intermediates in the synthesis of
carbon atom in the 17-position of the molecule such as
other steriod compounds having an oxygen atom attached
ergosteryl D-acetate epoxide, A'l'mllbzz-ergostadiene ep
to the ll-carbon atom, such as the adrenal hormones, 45 oxide, A19(11),22-3-acyloxy-ergostadiene epoxide, Amun
corticosterone, cortisone and Compound F.
cholestene epoxide, A19(19-3-acy1oxy-cholestene epoxide,
This application is a continuation-impart of copending
applications Serial No. 262,647, ?led December 20, 1951,
now abandoned, and Serial No. 621,985, ?led November
A719(11)-3-acetoXy-ch0lestene- epoxide, A7,9(11)122-3-acyl
oXy-stigmastadiene epoxide, Ali-9(IDJZ-B-acetoXy-Stigma
The A3(9)~1leketo-cyclopentanopolyhydrophenanthrene
lenic acid epoxide, A719(11)-3eacetoxy-bisnorallocholenic
compounds, subject of the present invention have at rings
B and C the following chemical structure:
acyloxy-ZO-keto-allopregnene epoxide, A7’9(11>-3-acetoxy
stadiene-epoxide, a bile acid side chain attached to the
14, 1956, now abondoned, the latter of which is a division 50 17~carbon atom such as A19(1D-3-acyloxy-cholenic acid
of application Serial No. 263,476, ?led December 26,
epoxide, a degraded bile acid side chain attached to the
1951, now Patent No. 2,798,082.
17-carbon atom such as A19(19-3-acyloxy-bisnorallocho
acid epoxide, a 17 acetyl substituent such as A'7-9(11)-3
20-keto-allopregnene epoxide, a sapogenin side chain such
as A7,9(11)-dehydrotigogenin acylate epoxide, A7»9(11)-de
hydrotigogenin acetate epoxide, and the ‘like.
O
60
In preparing these epoxides of A7’9(11)-cyclopentano
polyhydrophenanthrene compounds, utilized as starting
materials in our procedure, We ordinarily start with the
corresponding Algal) - cyclopentanopolyhydrophenan
threne compound, certain of which, such as ergosterol D
and 3-acyloxy derivatives thereof are described in the
These A89) - 11-keto-cyclopentanopolyhydrophenan 65
prior art. Other A'mm)-cyclopentanopolyhydrophenan
threne compounds can be prepared as follows: an epoxide
threne compounds can be prepared, starting with readily
of a Am"?(11)-cyclopentanopolyhydrophenanthrene com
available A5-cyclopentanopolyhydrophenanthrene com
pound, that is a A7-9,11-epoXy-cyclopentanopolyhydro
phenanthrene compound (Compound 1 hereinbelow), or
a MUD-7,8 - epoxy-cyclopentanopolyhydrophenanthrene
compound (Compound 2), is reacted with a hydrogen
halide under anhydrous conditions to form the corre
pounds such as cholesterol, by treating said A5-cyclopen
tanopolyhydrophenanthrene compound (Compound 6
hereinbelow) with N-bromosuccinimide, reacting the re
sulting A5-7-bromo-cyclopentanopolyhydrophenanthrene
compound (Compound 7) with a tertiary amine to form
3,092,642
4
.
3
utilized
as
starting
material
therein,
is
reacted
with
a hy
the corresponding A51'7-cyclopentanopolyhydrophenan
drogen halide such as hydrogen chloride, hydrogen bro
therene compound (Compound 8), reacting this com
pound with hydrogen in the presence of Raney nickel
mide, and the like, under anhydrous conditions, to pro
duce the corresponding A8<9)-7,ll-dihalo-cyclopentano
polyhydrophenanthrene compound. The reaction be
catalyst thereby selectively reducing the unsaturated link
age attached to the carbon atom in the 5-position to form
the corresponding A'l - cyclopentanopolyhydrophenan
tween the epoxide of the Al's(11)-cyclopentanopolyhydro
phenanthrene starting material and the hydrogen halide is
ordinarily conducted by bringing the reactants together in
threne compound (Compound 9) and bringing said A"
cyclopentanopolyhydrophenanthrene compound into inti
mate contact with a solution of mercuric acetate in acetic
acid thereby producing the corresponding Aidan-cyclo
a liquid medium inert under the reaction‘ conditions, as,
10 for example, in a hydrocarbon solvent such as benzene
or toluene, in an ethereal solvent such as diethyl ether,
in a chlorinated hydrocarbon solvent such as chloro
form, in a ketone such as acetone and the like. As to
pentanopolyhydrophenanthrene compound (Compound
10) . The reactions indicated hereinabove may be chemi
cally represented (insofar as rings B and C are con
cerned) as follows:
. .
Bromosuccimmlde
/
Compound 6
the hydrogen halide, it is ordinarily preferred to utilize
15 dry hydrogen chloride, and to conduct the reaction utiliz
ing cold ‘chloroform as the reaction solvent.
i/
\l
/_
/
—Br
tion is preferably carried out in the cold (i.e., at a tem
20 peratnre of about 0° C.), but temperatures up to about
25° C. can be employed, if desired.
The reaction between the epoxide of the Amun-cyclo
pentanopolyhydrophenanthrene compound and the hydro
Compound 7
7 Tertiary amine
gen halide results in the formation of the corresponding
/
25 Am)v - 7,11v - dihalo-cyclopentanopolyhydrophenanthrene
compound such as:
\
Qi/
I
/ \)
Hydrogen
\
__-—-—-—>
Raney nickel
Compound 8
A8(9>'22-7,ll-dihalo-ergostadiene,
A8<9):22-3-acyloxy-7,1l-dihalo-ergostadiene, A3(9)’22-3-ace
lii/
toxy - 7,1l-dichloro-ergostadiene, A8(9)-7,l1-dihalo-cho
lestene, AW) - 3 - acyloxy - 7,11 - dihalocholstene, Am)
3 - acetoxy - 7,lrl-dichloro-cholestene, A8(9),22-3-acyloxy
I
7,11 - dihalo-stigmastadiene, Am)!” - 3 - acetoxy - 7,11 -
/ \/i
dichloro-stigrnastadiene, Aw) - 3 - acyloxy-7,11-dihalo
Compound 9
Mercuric acetate
An excess
of hydrogen halide is preferably used in order to insure
complete formation of the dihalo compound. The reac
35
/
cholenic acid, A8(9)-3-8.C6t0XY-7,1LiliChIOI'O-ChOl?niC acid,
A8(9)-3-acyloXy-7,ll-dihalo-bisnorallocholenic acid, Aw’)
3-acetoxy-7,1l-dichloroebisnorallocholenic acid, Man-3
acyloxy - 7,1l-dihalo-20-keto-allopregnene, A8(9)-3-ace
[___--_-—
toxy-7, l l-dichloro-20-keto-allopregene, A8(9)-7,1l-dihalo
dehydrotigogenin acylate, A8<9)-7,1l-dichloro-dehydro
tigogenin acetate, and the like.
'
The A8(9) - 7,11-dihalo-cyclopentanopolyhydrophenan
Compound 10
The A'7-9(11)-cyclopentanopolyhydrophenanthrene com
pound thus obtained is then converted to the correspond
threne compound is then reacted with an aqueous solu
tion of a metal salt, characterized as having a cation which
forms water-insoluble halides and an anion which is non
reactive With the steroid’ compound, such as aqueous sil
45 ver nitrate, aqueous silver, oxide, aqueous mercnrous ni
trate, and the like, thereby forming the corresponding
11-keto-cyclopentanopolyhydrophenanthrene compound
having a double bond connecting the carbon atom in the
8-position with a carbon atom adjacent thereto and gamma
ing epoxide by reaction with perbenzoic acid thus forming
the corresponding A7-9,11-epoxy-cyclopentanopolyhydro
phenanthrene compound (Compound 1 hereinbelow) or 50 with respect to the ll-keto substituent. In conducting
this reaction, the A8(9)-7,1l-dihalo-cyclopentanopolyhy
the corresponding A961)-7,8-epoxy-cyclopentanopolyhy
drophenanthrene compound is ordinarily dissolved in a
drophenanthrene (Compound 2). This reaction may be
Water-miscible organic solvent such as acetone, and the
chemically represented (with respect to the chemical
resulting solution is mixed with an aqueous solution of
changes occurring in rings B and C) as follows:
’
55 the metal salt, whereupon an immediate reaction takes
/
place as is evidenced by the copious precipitation of the
metal halide. The resulting mixture is then diluted with
an additional quantity of the water-miscible organic sol
E;
\l/ u
p
vent and the resulting mixture is allowed to remain at
60 room temperature for about two hours in order to insure
completion of the reaction. The precipitated metal ha
lide is separated from the reaction mixture by ?ltration,
/\/
/\/
l , I_ 3218-1212 * Compoundl
and the ??-unsaturated-ll-keto-cyclopentanopolyhydro
phenanthrene compound formed in the reaction is re
65 covered from the ?ltered reaction solution.
This is con
veniently effected by diluting this solution with water,
.
V / \/l
v
acid
‘
a
Compound 10
l
whereupon said ?,y-unsaturated-ll-keto-cyclopentano
polyhydrophenanthrene compound precipitates and is re
_
/0
70
/
7
Compound 2
‘ iIn carrying out our novel process, the epoxide of the
A19(11>-cyclopentanopolyhydrophenanthrene compound,
covered by ?ltration.
The 11-keto-cyclopentanopolyhydrophenanthrene com
pounds, obtained with the foregoing procedure are ,Byy-un
saturated with respectto the '1 l-keto substituent (that is
they have a double bond connecting the 8-carbon atom
with a carbon atom adjacent thereto and gamma with re
75 spect to the ll-keto substituent), and include A?myzz-ll
3,092,642
keto-ergostadiene, Aw‘imz-lI-keto-ergostadiene, M09122
thereby removing the silver chloride, and the insoluble
3 - acyloxy-ll-keto-ergostadiene, Asu‘lbzz-fi-acyloxy-ll
material was washed with acetone. Several volumes of
water were added to the ?ltered solution, whereupon a
keto-ergostadiene, A"(8),22-3-actoxy-ll-keto-ergostadiene,
Awe)’22 - 3-acetoxy-1l-keto-ergostadiene,
A'7(8)-l1-keto
crystalline production precipitated. This crystalline prod
cholestene, A3094l-keto-cholestene, A7(8>-3-acyl0xy-1l
uct was recovered by ?ltration, washed with water and
keto - cholestene, A8(14)-3-acyloxy-1l-keto-cholestene,
Am) - 3-acetoxy-11-keto—cholestene, A8(14)-3-acetoxy-11
dried to give crude A22-3-acetoxy-1l-keto ergostadiene
having a double bond connecting the 8-carbon atom with
the carbon atom in the 7- or 14-position of the molecule.
The crude material was puri?ed by slurrying with a
keto-cholestene, A7(8),22-3-acyloxy-1l-keto-stigmastadiene,
A8(14>122-3-acyloxy-ll-keto-stigmastadieue, A'KSLZZG-ace
toxy-l l-keto-stigmastadiene, Aau‘lllm-fi-acetoxy-l1-keto—
stigmastadiene, A7(8)-3-acyloxy-1l-keto-cholenic acid,
A7(8)-3-acetoxy-1-l~keto-cholenic acid, A8(14)-3—acyloxy
10 mixture of ethyl acetate and petroleum ether, whereupon
ll-keto-cholenic acid, A8(14)-3-acetoxy-1l-keto-cholenic
substantially all of the product dissolved; the resulting so
lution was the ?ltered and the ?ltered solution was evapo
rated to dryness; the'residual material was recrystallized
from ether, and then from methanol to give substantially
A8(14)-3-acyloxy-1l-keto-bisnorallocholenic acid, Alan-3 15 pure A22-3-acetoxy~lll-keto-ergostadiene having a double
acetoxy'll-keto-bisnorallocholenic acid, A8(1‘9-3-acetoxy
bond connecting the carbon atom in the 8-position with
acid, 137(3) - 3 - acyloxy-l'l-keto-bisnorallocholenic-acid,
ll-keto-bisnorallocholenic acid, A7(8)-3-acyloxy-1l,20‘-di
that in the 7- or 14-position of the molecule; MP. 178
keto-allopregnene, A8(14)-3-acyloxy-l1,20-diketo-allopreg
181° C. Analysis.-Calc’d for Gaol-14603: C, 79.25; H.
10.20. Found: C, 79.17; H, 10.15.
20
Example 3
tigogenin-acylate, A3094 l-keto-dehydrotigogenin - acyl
ate, A'Ks) - 11 - keto - dehydrotigogenic-acetate, Alum-ll
Eleven milligrams of the A22-3-acetoxy-1l-keto-ergos
keto-dehydrotigogenin-acetate, and the like.
tadiene having a double bond connecting the carbon atom
nene, A7(8)-3-acetoxy-11,20-diketo-allopregnene, A8093
acetoxy-l1,20-diketo-allopregnene, A7(8)-1 l-keto-dehydro
These ??-unsaturated-ll-keto-cyclopentanopolyhydro
in the 8-position with the carbon atom in the 7- or 14
phenanthrene compounds are then converted to the desired 25 position of the molecule (prepared as described in Exam
A3(9)-11-keto-cyclopentanopolyhydrophenanthrene com
ple 2 hereinabove) were dissolved in methanol and 50
pound by treating the former with a base such as an
milligrams of potassium hydroxide was added to the
alkali metal hydroxide, an alkaline earth metal hydroxide,
resulting solution. The resulting solution was allowed
ammonium hydroxide, an equeous solution of an organic
to stand for about 15 hours at a temperature of about
base such as pyridine, and the like. It is ordinarily pre 30 25° C. The reaction solution was then worked up as
ferred to dissolve the alkali metal hydroxide and the 13,7
follows: The potassium hydroxide was neutralized by
unsaturated - 11-keto-cyclopentanopolyhydrophenanthrene
addition of acetic acid. Water was added and the meth
anol was removed by distillation. The water-insoluble
compound in alcohol, and to allow the resulting alcoholic
solution to stand at room temperature for an extended
precipitate was collected on a ?lter and recrystallized re
period of time, whereupon the [SN-unsaturated linkage 35 peatedly from methanol to give substantially pure A8693”
connecting the 8-carbon atom and the carbon atom in
3-hydroxy-l'l-keto-ergostadiene which was identi?ed by
the 7 or 14 position rearranges to join the carbon atoms
spectrophotometric analysis:
kgigu'tane
in the 8 and 9-positions. There is thus obtained the de
sired
AW) - 1l-keto-cyclopentanopolyhydrophenanthrene
compound such as A309) ,22-1l-keto-ergostadiene, A8(9),22-3 40
hydroxy-l l-keto-ergostadiene, A8(9)'22-3-hydroxy-1 l-keto
stigmastadiene, A8(9>-3-hydroxy~1l-keto-cholenic acid,
‘These
118(9) - 11 - keto-cyclopentanopolyhydrophenan
threne compounds such as A8(9),22-3-hydroxy-1l-keto
ergostadiene, A86‘),22 - 3-hydroxy-ll-keto-stigmastadiene,
A8(9>-3-hydroxy-11,20-diketo-allopregnene, A8<9)-11-keto
A3(9)'22-3-hydroxy-1l-keto-cholenic acid, A3(9)-3-hydroxy
dehydrotigogenin, and the like.
11,20 - diketo - allopregnene, A80?) -11 - keto-dehydrotigo
The following examples illustrate methods of carrying 45 genin, 3-acetates thereof, and the like, can be reduced
out the present invention, but it is to be understood that
these examples are given for purposes of illustration and
with metallic reducing agents, such as lithium in
liquid ammonia, or zinc dust in ethanolic hydrochloric
not of limitation.
acid solution to form the corresponding nuclearly satu
rated ll-keto-steroid. For example twenty grams of
Example 1
50 A8(9)'22-3-hydroxy-1l-keto-ergostadiene or its 3-acetate in
One-half gram of ergosteryl D-acetate epoxide (i.e.,
150 ml. dry ethyl ether were added with stirring to 2
the epoxide of A719(13122-3-acetoxy-ergostatriene) was dis
liters of liquid ammonia. Twelve grams of freshly cut
solved in 25 cc. of chloroform, the solution was cooled
lithium were then added, and the reaction mixture was
to about 0° C., and dry hydrogen chloride was bubbled
stirred at re?ux temperature for a period of about six
through the solution for a period of approximately 30 55 hours. One hundred and ?fty milliliters of absolute
minutes.
The reaction solution was distilled under re
ethanol was added to the reaction mixture over a period
duced pressure thereby removing the excess hydrogen
of 35 minutes. After all the ethanol had been added,
chloride and chloroform, and the residual oil was crystal
the blue color due to dissolved lithium disappeared.
lized from petroleum ether. The crystalline material
Forty milliliters of water was added to the resulting mix
was recovered by ?ltration, washed with petroleum ether 60 ture, and the ammonia was allowed to evaporate over
and dried to give substantially pure A8(9)|22-3-acetoxy-7,11
night through a mercury trap. The residual ethereal
dichloro-ergostadiene; M.P. l25—130° C.,dec. Analysis
layer was separated, washed With water, dried over sodium
Calc’d for C3oH46Cl2O2: C, 70.75; H, 9.12; CI, 13.91.
sulfate, and the ether was evaporated therefrom in vacuo,
Found: C, 70.33; H, 9.18; Cl, 13.96.
leaving a crude white solid.
Example 2
Two-tenths of a gram of A8(9)'22-3-acetoxy-7,ll-dichlo
65
This solid was dissolved in ether, chromatographed
over alumina and the alumina adsorbate was eluted, ?rst
with ether and then with a solution of 1% methanol in
ether. From the ether eluate there was obtained crystal
ro-ergostadiene was dissolved in 20 cc. of acetone, and
to the solution was added, with stirring, 10 cc. of a 0.1 N
line A22-ergostene-3/3-ol-1-1-one, M.P. 166-168" C.,
aqueous solution of silver nitrate. An immediated reac 70 (a)D25"c-=+31° (CHCl3). Calculated for C28H46O2:
tion took place accompanied by copious precipitation of
silver chloride. The reaction mixture was diluted with
an additional 20 cc. of acetone, and the resulting mixture
Theory: C, 81.2; H, 11.20. Found: C, 81.10; H, 10.91.
The conversion of these nuclearly unsaturated ll-keto
steroids, such as A22-ergostene-3B-ol-1l-one to allopreg
nane-3?-ol-1l,20-dione acetate is disclosed in J.A.C.S. 73,
of about 2 hours. The reaction slurry was then ?ltered, 75 2396 (May 1951); J.A.C.S. 73, 4052 (August 1951) use
was allowed to stand at room temperature for a period
3,092,642
the latter compound to prepare allopregnane-3?,17a,2l
triol-1l,20-dione 21-.acetate; the conversion of the last
named compound to cortisone acetate is set forth in
thereby forming the corresponding 1l-keto-cyclopentano—
polyhydrophenanthrene compound havinga double bond‘
Nature 168, page 28 (July 1951).
‘
‘ Various changes and modi?cations may be made in
connecting the carbon atom in the 8-position with-a carbon
atom adjacent thereto and gamma with respect to the 11
carryingout the present invention without departing from
the spirit and scope thereof.’ ‘Insofar as these changes and
modi?cations are within the purview of the annexed
claims, they are to be considered as part of our invention.
We claim:
7
8
with an aqueous solution of a metal salt, characterized
as having a cation which forms water-insoluble-halides;
keto
substituent.
>
,
~
- 5. The process, which comprises reacting A3(9),22-3
acetoxy-7,1l-dichloro-ergostadiene in solution in acetone
10 with aqueous silver nitrate to produce a A22-3-acetoxy-l l
keto-erg'ostadiene compound, having a double bond‘con
meeting the carbon atom in the 8-position with a carbon
atom adjacent thereto and gamma with respect to the 1-1
keto substituent.
1. The process which comprises reacting ergosteryl D
acetate epoxide with an excess of dry hydrogen chloride
in chloroform solution at a temperature below about 25°
C.’ to form A8(9)'22-3-acetoxy-7,1l-dichloro-ergostadiene,
6. The process which comprises reacting an‘ ll-keto
reacting this compound in solution in acetone with an 15 cyclopentanopolyhydrophenauthrene compound having a
aqueous solution of silver nitrate to produce a A8113
C-17 side chain selected from the group consisting of
acetoxy-l l-keto-ergostadiene compound having a double
bond connecting the carbon atom in the 8-position with a
carbon atom adjacent thereto and gamma with respect
to the ll-keto-substituent, and reacting the latter com
sterol side chain, bile acid side chain, degraded bile
acid side chain, 17-acetyl- side chain,rand ,sapogenin side
20
pound with potassium hydroxide in methanol at approxi
chain, and having a double bond connecting the carbon
atom in the' 8-position with a carbon atom adjacent
mately room temperature to form A3<9)’22-3-hydroxy-11
thereto and gamma with respect to the ll-keto substituent, with a base at approximately room temperature to‘ form
keto ergostadiene.
the corresponding A8(9>-l1-keto-cyclopentanopolyhydroa
'
2. The process which comprises reacting an excess of
compound.
'
a hydrogen halide under anhydrous conditions and at a 25 phenanthrene
7. The process which comprises reacting a A213
temperature below about 25° C. with an epoxide of a
acetoxy-ll-keto-ergostadiene having a double bond con
A7(8),9(11)-cyclopentanopolyhydrophenanthrene compound necting
the carbon’ atom in the 8-position with‘ a carbon
having a 0-17 side chain selected from the group con
atom adjacent thereto and gamma with respect to the 11
sisting oflsterol side chain, bile acid side chain, degraded
keto substituent, with potassium hydroxide in methanol
bile acid side chain, 17-acetyl side chain, and sapogenin 30 at approximately room temperature to produce Am)”
side chain, thereby formingithe corresponding Mun-7,11
3 -hydroxy- 1 l-keto-ergostadiene.
dihalo-cyclopentanopolyhydrophenanthrene compound.
8. A8<14)»22-3-acetoxy-l l-keto-ergostadiene. '
3. The process which comprisesreacting ergosteryl D
acetate epoxide With an excess of dry hydrogen chloride in
chloroform solution .at a temperature below about 25° C; 35
References Cited in the ?le of this patent’ '
UNITED STATES PATENTS
to produce A8(9)I22-3-acetoxy-7,1l-dichloro-ergostadiene.
4. The process which comprises reacting a A3(9)-7,1l
dihalo - cyclopentanopolyhydrophenanthrene compound
having a C-17 side chain selected from the group con
sisting of sterol side chain, bile acid side chain, degraded
bile acid side chain, 17-acetyl side chain, and sapogenin
side chain in solution in a water-miscible organic solvent
2,802,614
2,837,515‘
Laubach et a1 __________ __. Aug. 6, 1957
741,061
Great Britain _________ __ Nov; 23,1955
40
Chemerda et a1 _________ __ June 3, 1958
FOREIGN PATENTS‘
,
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