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Патент USA US3020306

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3,2039%
Patented Feb. 6, 195;’?
2
The condensation step is effected at normal tempera
3,020,296
tures in a weakly alkaline medium with the aid of a con
PREPARATION OF ESTRADIOL AND INTER
MEDIATES THEREOF
densing agent in the presence of an inert solvent. Pre
ferred condensing agents are the alkali metal and alkaline
earth metal salts of barbiturates. The barbiturates may
Gerard Nomine, Noisy-le-Sec, Daniel Bertin, Montrouge,
and Jean Tessier, Paris, France, assignors to Les La
boratoires Francais de Chimiotherapie, Paris, France,
be barbituric acid or substituted barbituric acids such as
a corporation of France
S-ethyl-S-isoamyl arbituric acid, S-butyl-S-ethyl barbituric
acid, 5,5-diethyl barbituric acid, S-ethyl-S-(l-methyl
N0 Drawing. Filed Oct. 25, 1960, Ser. No. 64,733
Claims priority, application France Nov. 6, 1959
5 Claims. (Cl. 260-39745)
butyl) barbituric acid and S-ethyl-S-phenyl barbituric acid.
10 Suitable inert solvents are lower alkanols such as ethanol.
The present invention relates to a novel process for
the preparation of estradiol, one of the well-known sex
hormones. The invention further relates to novel inter
The dehydration is effected at re?ux temperatures in
the presence of an alkali metal or alkaline earth metal
alcoholates in an inert solvent such as ethanol. Preferred
alcoholates are sodium and potassium derivatives of lower
mediates, namely, 175-acyloxy-19-nor-A8(9)-androstene-5
ol-3-one compounds of the formula:
15 aliphatic alcohols such as methanol, ethanol, propanol and
butanol.
‘Jolie
’
The isomerization step is effected by heating 19-nor
A4'9<1°)-androstadiene-1713-01 - 3 - one at elevated tempera
tures of the order of 150° to 200° C. in the presence of‘
20
2
OH
a suitable isomerization catalyst. A preferred catalyst
is palladized carbon black.
The starting materials for the process of the invention
may be prepared by the process described in the co
H
pending, commonly assigned United States patent applica
wherein Ac is the acyl radical of an organic carboxylic 25 tion Serial No. 6,111, ?led February 2, 1960. The said
acid of 1 to 18 carbon atoms, and the two 5 epimers
process comprises hydrolyzing [twin-(9,10) - 3 - methyl-7
thereof.
methoxy - 3,4 - [3' - benzoyloxy cyclopentano(2’,1’)]
An object of the invention is to obtain estradiol by a
hexahydronaphthalenes under acidic conditions.
novel sequence of simple steps.
The acyl radical of the compounds of the invention
A further object of the invention is the production of 30 is the acyl radical of organic carboxylic acid having 1
the novel intermediates for estradiol, namely, l7;8-acyl~ v to 18 carbon atoms. Suitable carboxylic caids are the
oxy-19-nor-A8<9)-androstene - 5 - o1-3-one and 19-nor
alkanoic and alkenoic acids such as acetic acid, trimethyl
A4,9(1°>~androstadiene-l7?-ol-3-one.
acetic acid, propionic acid, 4,4-dimethyl pentanoic acid,
These and other objects and advantages will become
IO-undecanoic acid; cycloalkyl alkanoic acids such as 1%
35 cyclopentyl propionic acid; arylalkanoic acids such as
more obvious from the following detailed description.
The process of the present invention comprises con~
phenylpropionic acid; cycloalkyl acids such as hexahydro
densing Mums-methyl - 7 - oxo-3,4-[3'-acyloxy cyclo
benzoic acid and hexahydro-terephthalic acid; and phenyl
pentano(2’,1’)]octahydronaphthalenes of the formula:
carboxylic acids such as benzoic acid or 3,5-dinitrobenzoic
40
U-OAc
acid.
In the following examples there are described several
preferred embodiments to illustrate the invention. How
ever, it should be understood that the invention is not
intended to be limited to the speci?c embodiments. The
melting points are the instantaneous melting points de
0_
I
wherein Ac has the above designation, with methyl vinyl
ketone to form l7,8-acyloxy-19-nor-A3(9)-androstene-5-ol
3-one, dehydrating and simultaneously saponifying the
latter product to form 19-nor-A4'9(1°)-androstadiene-17B
termined on the Maquenne block.
" Example ].—Preparati0n of the 17?-benz0yl0xy 19-nor
A8(9)-andr0stene-5-ol-3-one and separation of the two
5 epimers
1 gram of 119-10 Iii-methyl 7-oxo 3,4[3’-benzoyloxy cyclo
ol-3-one which is isomerized to estradiol. The reaction 50 pentano (2’,1')] octahydronaphthalene, melting point
scheme of the invention is shown in Table I.
127° C., obtained by hydrolysis of the rim/W911“) 3
methyl-7-rnethoxy-3,4-[3’-benzoyloxy cyclopentano (2',
TABLE I
1’)] hexahydronaphthalene with oxalic acid, according
' I -OAe
?)U—OAc
(i) H
/
. .
to the process described in copending, commonly assigned
United States patent application Serial No. 6,111, ?led
February 2, 1960, was introduced into 2.5 cc. of ethanol.
After ?ve minutes of agitation 0.054 gm. of methylvinyl
ketone in 0.5 cc. of ethanol were added. Then 0.04 gm.
I
on
H
of sodium salt of S-ethyl-S-isoamyl barbituric acid in 1
cc, of ethanol containing 30% water were added. The
reaction mixture was agitated for two hours in an at
mosphere of nitrogen and there was added in small
amounts 3.2 cc. of an ethanolic solution of methylvinyl
ketone having the same concentration as that above.
The reaction mixture was then alkalized with 1 cc.
0:
I
———~
Isomerization
III
of a 0.1 -N aqueous potassium hydroxide solution, and
crystallization was started by scratching and addition of
water. After allowing the mixture to stand for 72 hours
at room temperature, the precipitate was vacuum ?ltered
H0
IV
and recrystallized from ethanol, then from isopropyl
ether.
The crystals were dried and 460 mg. of white
3,020,296
=3
that the invention is limited only as de?ned in the ap
crystals were recovered constituting a mixture of the two
S-epimers of IZB-benzoyloxy-19-nor-A8<9)-androstene-5-ol
pended claims.
acetic acid.
city-cyclopentano (2’,1’)] octahydronapthalenes of the
We claim:
3~one, 11 (wherein Ac=C5H5CO), having a melting point
1. A process for the preparation of estradiol which
of 220-222° C.
The two epimers were separated by solution in hot 5 comprises condensing A900) - 3 - methyl-7-oxo-3,4[3’-acyl
The first product which crystallized and
formula
which was called epimer A, had a helting point of 247 "
249° C., and was present in the form of White hexagonal
plates poorly soluble in methanol, very poorly soluble
in isopropyl ether, soluble in hot ethanol and insoluble 10
in water and dilute aqueous acids or alkalis. The second
product which crystallized from the mother liquor after
standing for 24 hours, and which was called epimer B,
had a melting point of 247°—249° C., and was present in
the form of White prisms, soluble in hot alcohol and hot 15
acetic acid. The melting point of the mixture of epimer
wherein Ac is the acyl radical of an organic carboxylic
acid having 1 to 18 carbon atoms with methylvinyl ketone
A and epimer B was about 235-237“ C.
Example 2.-—-Preparati0n of estradiol from Compound 11,
Ac=C6H5CO
0
to form 17,8-acyloxy-19-nor-A9(9)-androstene-5-ol-3-ones
20 of the formula
(a) De7zydrmi0n.—-140 mg. of Compound II,
Alum...
AC=C5H5CO
constituting a mixture of the two 5 epimers, were intro
duced in 12 cc. of a sodium ethylate solution containing 25
1.2 gm. of sodium in 50 cc. of ethanol. The reaction
mixture was heated to re?ux in a nitrogen atmosphere for
5 minutes, cooled, then 1 cc. of acetic acid was added.
The reaction mixture was turned into water and extracted
with ether. The extracts were combined, washed with 30 wherein Ac has the above de?nition, dehydrating the
water, with sodium bicarbonate, and again with water,
latter in the presence of an alkaline alcoholate to form
dried, and evaporated to dryness under vacuum to furnish
19-nor-A4,9(1°)-androstadiene-l7?-ol-3-one and isomeriz
a residue of 98.2 mg. of 19-nor-A4-9(m-androstadiene
ing said dehydrated compound in the presence of pal
17,8-ol-3-one (Compound II, Ac=C6H5CO). The prod
ladized carbon black to estradiol.
uct was puri?ed by chromatography on silicagel and 35
2. The process of claim 1 wherein the condensation is
eluted with methylene chloride containing 16% acetone.
carried on in the presence of sodium derivatives of bar
The product had a melting point of 168.5-169.5 ° C. and
biturates.
and an ultra-violet spectra hmaxg=304 mp, e= 19,800, in
3. A process forthe preparation of estradiol which
comprises condensing A9(1°)-3-methyl-7-oxo-3,4-[3’-ben
?exion 238 mp, e=4,700. This product occurred in the
4
O
zoyloxy cyclopentano (‘2Z1’)]octahydronaphthalene with
form of white prisms soluble in cold alcohol, acetic acid
and acetone, soluble in hot isopropyl ether and insoluble
methylvinyl ketone in the presence of a sodium derivative
in water and dilute aqueous acids and alkalis.
of the barbiturates to form 17?-benzoyloxy-19-nor-A8(9)
Analysis.-—C18H24O2; molucular weight=272.4. Cal
androstene-S-ol-B-one, dehydrating the latter in the pres
culated: C, 79.36%; H, 8.88%. Found: C, 79.5%; H, 45 ence of an alkaline alcoholate to form 19-nor-A4-9(1°)
androstadiene-l7?-ol-3-one and isomerizing said dehy
8.7%.
This product is not described in the literature.
drated compound in the presence of palladized carbon
(b) Isomerization.—Into a 1 cc. ampoule were intro
black to estradiol.
duced 1.43 mg. of 19—nor-A4'9(1°)-androstadiene-17,8-01-3
one, 5 mg. of palladized carbon black containing 10% 50
palladium and 0.2 cc. of p-cymene, previously boiled in
the presence of several mg. of palladized carbon black.
4. A compound of the formula
The ampoule was sealed under vacuum and heated to
170-180° C. under agitation for 21/2 hours. After cooling,
the ampoule was broken and the contents added to ether. 55
The suspension was ?ltered and the etheral solution was
evaporated to dryness under vacuum. The residue was
raw racemic estradiol which can be identi?ed by chroma
wherein Ac is the acyl radical of an organic carboxylic
tography on paper and by its usual color reactions.
Various modi?cations of the process and the products 60 acid having 1 to 18 carbon atoms.
5. 17?-benzoxy - 19 - nor-A8(9)-androstene-5-ol-3~one.
of the present invention may be made without departing
No references cited.
from the spirit or scope thereof, and it is to be understood
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