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Патент USA US2301260

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2,301,260:
Patented Nov. 10, 1942
UNITED sraresesrsar ioérrios
MEDICINAL COMPOUNDS '
John Stanley Herbert Davies and Leslie Alder
man Elson, Blackley, Manchester, England, as
signors to Imperial Chemical Industries Lim
ited, a corporation of Great Britain
No Drawing. Application December 29, 1941, Se
rial No. 424,840. _In Great Britain January 4,
1941
8 Claims.
(Cl. 26il—613)
The Grignard reaction is well known. It in
, This invention relates to the manufacture of
volves forming an organomagnesium compound
new chemical compounds useful as medicinals,
by interaction of magnesium with an alkyl or
aryl halide in dry ether and then bringing this
and particularly as oestrogenic agents.
It is an object of this invention to provide new
chemical compounds which are useful as oestro
7 into reaction with an aldehyde, a ketone or a
carboxylic acid or derivative thereof.
genic agents. A further object‘ is to provide
processes for the manufacture'of the said com
pounds.
'
These objects are achieved by the present in
vention whereby there are provided new chemi
cal compounds, namely the tri-p-anisyl-alkyl
It was
described by Grignard in Comptes rendues,
volume 130, page 1322, and has become a very
widely used synthetic process-see, for example,
“Organornetallverbindungen," Part I,
10' Runge,
Organomagnesiumverbindungen, Stuttgart 1932.
The u-alkyl-deoxyanisoins used as starting ma
terials may conveniently be made by the method
described by Dodds and others in the Proceed
ethylenes of the formula
(D) CHsO.CsH4
ings of the Royal Society, part B, 1939, vol. 27,
O=CR.C&H4.0CH3 (p")
pp. 148 and 156.
(p’) CH30.C6H4
wherein R, stands for a radical selected from the
'
The following examples illustrate, but do not
limit, the invention.
group consisting of methyl and ethyl.
The parts are by weight. 7
Example 1
The said new ‘compounds can be made by
causing a-methyl- or a-ethyl-deoxyanisoin to 20
A Grignard reagent is prepared by ‘adding 18.5
undergo ‘a Grignard reaction with anisyl mag
parts of p-bromoanisole to 2.45 parts of mag
nesium bromide or‘iodide, hydrolysing the prod
nesium suspended in 100 parts of dry ether. To
-uct so formed to the carbinol of formula
this there are then gradually added 27 parts of
(13) OHz.OCeH4
25
C-—CR.CsH4OCHa (P")
(p)I
CH3.0C6H4Q) H H|
to a solution of 200 parts of ammonium chloride
in 1000 parts of water. Stirring is continued
R as before being methyl or ethyl, and then
dehydrating the latter by known means for ex
ample by heating in vacuo or in presence of sul
phuric or phosphoric acid or acetyl chloride or
for 1/2 hour. The ether layer is then separated
off, the aqueous layer extracted with a further
quantity of ether and the .two ether solutions
combined and dried over calcium chloride. The
ether is then distilled off. The crude oily car
acetic anhydride.
This series of reactions can be represented as
follows, B being methyl or ethyl and X being Br
a-methyl-deoxyanisoin. When all has been
added, the mixture is boiled under re?ux for
2 hours, cooled and then added, with stirring,
0 binol so-obtained is then boiled for 3 hours with
three times its volume of acetyl chloride. The
mixture is then poured on to ice. The tri-p
or I.
anisyl-methylethylene, which at ?rst separates
l
CH3.O.CaH4
C
CH3.0.CQH4/ (IJMgX
CR.CaH4.0.CHs
H
1 hydrolyse
out as an oil, solidi?es on standing.
4:0
It is then
puri?ed by crystallisation from methanol, where
by it is obtained in the form of colourless crystals
of M. P. 118° C.
Example 2
A Grignard reagent is prepared by adding a
solution of 30 parts of p-bromoanisole in 40 parts
of dry ether to 3.9 parts of magnesium suspended
in 60 parts of dry ether. To this solution there
is gradually added, with stirring, a solution of
22.5 parts of a—ethyl-deoxyanisoin in '70 parts
50 of dry ether. When all has been added the mix
ture is allowed to stand for one hour, boiled under
reflux for 3 hours and then allowed to stand for
18 hours. It is then added to a stirred ice-cold
solution of 200 parts‘of ammonium chloride in
1000 parts of water. The etherlayer is sepa
2
2,301,260
rated off, the aqueous layer extracted with a
further quantity of ether and the two ether solu
tions combined and dried over anhydrous sodium
sulphate. The ether is then distilled off. The
residue is a gum. This is heated for 1/2 hour at
to interact with a compound of the formula
CH3O.CeH4.MgX, R in'the formulae representing
a radical selected from the group consisting of
methyl and ethyl, and X an atom selected from
the group consisting of Br and I, hydrolysing the
product so formed to the carbinol of formula
200° C. under a, pressure of 20 mm. of mercury
and is then distilled under high vacuum. The
(D) CHsO.CtH4
tri-p-anisylethylethylene distils over at 2l8—220°
C. at 0.3 mm. It is then puri?ed by crystallisa
tion from methanol whereby it is obtained in the 10
form of colourless needles of M. P. 90—92° C.
R having the same meaning as before, and de
While the above examples illustrate speci?c
hydrating the latter.
embodiments of the invention, it will be apparent
5. Process which comprises interacting a
to one skilled in the art that many other modi?
cations can be made without departing from the 15 methyl-cleoXy-anisoin with anisyl magnesium
bromide, hydrolysing the product with aqueous
spirit and scope thereof, and accordingly it is to
ammonium chloride to form lzl'zz-tri-p-anisyl
be understood that the invention is not limited
propanol-l and dehydrating the latter to form
to the particular embodiments above described,
tri-p-anisyl-methyl-ethylene.
but only as de?ned in the following claims.
6. Process which comprises interacting a-ethyl
We claim:
1. Tri-p-anisyl-alkyl-ethylenes of the formula 20 deoxy-anisoin with anisyl magnesium bromide,
hydrolysing the product with aqueous ammoni
um chloride to form 1:1’:Z-tri-p-anisyl-butanol
O=C R.O0H4.0 CH3 (p”)
l and dehydrating the latter to form tri-p-anisyl
(p’)
onaootni
ethyl-ethylene.
'
'7. The processes which comprise interacting
alpha-methyl-deoxyanisoin with anisyl magnesi
um iodide, hydrolizing the product obtained to
2. Tri-p-anisyl-methyl-ethylene.
form 1:1':Z-tri-p-anisyl-propanol-1 and dehy
3. Tri-p-anisyl-ethyl-ethylene.
drating the latter to form tri-p-anisyl-methyl
4. Process for the manufacture of tri-p-anisyl 30 ethylene.
alkyl-ethylenes of the formula
wherein R stands for a radical selected from the 25
group consisting of methyl and ethyl.
8. The processes which comprise interacting
(D) CHaO.CsH4
alpha-methyl-deoxyanisoin with anisyl magnesi
um iodide, hydrolizing the product with aqueous
C=CR-CGH4.0CH3 (11”)
ammonium chloride to form 1:1':2-tri-p-anisyl
(p’) OH3O-C6H4
which comprises causing a compound of the
formula
(p) CH30.C6H4.CO.CHR.C6H4.0CH3
(p’)
35 propanol-l and dehydrating the latter to form
tri-p-anisyl-methyl-ethylene.
JOHN STANLEY HERBERT DAVIES.
LESLIE ALDERMAN ELSON.
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