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Патент USA US2403903

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Patented July 16, ‘1946
2,403,903
UNITED‘ STATES PATENT OFFICE
MANUFACTURE OF PIPERIDINE
’ DERIVATIVES
Franz Bergel, Nathan Chadwick Hindley, Alex
ander Lang Morrison, and Heinrich Binder
" knecht, Welwyn Garden City, England, assign
0rs,':,by mesne assignments, to Ho?mann-La
Roche Inc., Nut‘ley, N. J., a corporation of New
Jersey
No Drawing. Application April 8, 1943, Serial No.
482,325. In Great Britain April 27, 1942
7 Claims. (Cl. 260-294)
I
1
.
This invention is concerned with an improve
ment in or modi?cation of the invention of our
speci?cation Serial No. 433,340.
‘In the aforesaid speci?cation Serial No. 433,340
there is claimed inter alia the preparation of
cyclic bases by treating u:a-bis-(;3’-halogen
alkyl)-ary1-aceto-nitriles with primary amines.
These cyclic bases can readily be hydrolysed to
the corresponding carboxylic acids by heating
2
carry out the alcoholysis of the above 4-aryl
piperidine-4-nitriles by the standard methods
given in chemical literature were unsuccessful.
The methods given in chemical literature for the
alcoholysis of nitriles consists in heating the ni
trile withwan equimolecular proportion of concen
trated sulphuric acid and 10 molecular propor
tions of alcohol at 130-140° in a sealed vessel for
several hours (cf. Backunts & R. Otto Ber. 1876, 9,
with concentrated hydrochloric acid at 130° C. 10 1590; Spiegel, Ber. 1911, 44, 1115).
and from these acids the esters can be obtained
We have also found that ammonium chloride
by any of the usual methods.
may advantageously be added to the mixture of
In British Speci?cation No. 501,135 which also
nitrile, sulphuric acid, alcohol and water.
Errample 1.—5 parts by weight of l-methyl-4
describes the manufacture of 4-arylplperidine-4
nitriles the nitriles are obtained by condensing 15 phenylpiperidine-4-nitrile, 8.7 parts by weight of
an arylacetonitrile having a free methylene group
‘ 98% sulphuric acid, 1.2 parts by Weight of water,
1.34 parts by weight of ammonium chloride and
with an amine of the formula
10 parts by weight of absolute ethyl alcohol were
heated together in a sealed tube at 140-150° C. for
N-R
20 eight hours. After cooling, the contents of the
tube were poured on to 100 parts by weight of ice
and suf?cient caustic soda solution added to make
Where X and Y are p-halogenalkyl groups and R
the solution alkaline. The oil left undissolved
is an aryl radical, an alkyl radical, an aralkyl
was extracted with ether, the ether solution dried
radical, or a cycloalkyl radical, in the presence of 25 over anhydrous sodium sulphate, the ether re
an agent capable of splitting off hydrogen halide,
moved and the residual oil distilled at 12 mms.
and the hydrolysis of the nitriles thus obtained is
pressure when the ethyl ester of 1—methyl-4
carried out by heating the nitriles with alcoholic
phenylpiperidine-4-carboxylic acid came over at
solutions of caustic alkalis at elevated tempera
160-165“ C. The picrate formed from this base
tures. The further conversion of the acids to 30 had a melting point of 189-191° C.
esters by known methods is described.
Example 2.—5 parts by weight of l-methy1-4
The object of the present inventionis to provide
phenylpiperidine-4-nitrile, 25 parts by weight of
a simple process whereby the esters of 4-aryl
98% sulphuric acid and 10 parts by weight of ab
piperidine-4-carboxylic acids (which are of well
solute ethyl alcohol were heated in a sealed tube
known pharmacological value, exhibiting spasmo 35 at 140-150“ C. for eight hours. On working up
lytic and analgesic properties) can be prepared
the contents of the tube exactly as described in
from the corresponding nitriles in a single step.
Example 1 the ethyl ester of 1,-methyl-4-phenyl
According to the present invention 4-arylpiper
piperidine-4-carboxylic acid was obtained.
idine-4-nitriles are heated at elevated tempera
We claim:
‘
tures preferably in a sealed vessel with a mixture 40
1. A process for the manufacture of an ester of
of an alcohol, sulphuric acid and water, the
a 4-arylpiperidine-4-carboxylic acid which com
amount of water employed being between 0.5 and
prises heating a 4-arylpiperidine-4-nitrile with
2.5 molecular equivalents of the nitrile used.
a mixture of an alcohol, sulphuric acid and water,
Where ordinary concentrated sulphuric acid (98%
the total amount of water being between 0.5 and
sulphuric acid) is used then if sufficient of it is 45 2.5 molecular equivalents of the nitrile used, and
taken to allow for its normal water content of 2%
separating the ester from this reaction mixture
to provide for the necessary molecular equivalent
after completion of the heating.
of water, further addition of water is not neces
2. A process for the manufacture of an ester of
sary. If however less sulphuric acid is used, the
a 4-arylpiperidine-4-carboxylic acid which com
necessary amount of water must be added to the 50 prises heating a 4-arylpiperidine-4-nitrile with a
alcohol and sulphuric acid. The amount of a1
mixture of ethyl alcohol, sulphuric acid and wa
cohol used is not critical and a convenient amount
ter, the total amount of water being between 0.5
is 10 molecular proportions for 1 molecular pro
and 2.5 molecular equivalents of the nitrile used,
portion of nitrile.
~
and separating the ester from this reaction mix
These results were unexpected as attempts to 55 ture after completion of the heating.
Y/
2,403,903
3
_4
3. A process for the manufacture of an ester of
a 4-arylpiperidine-4-carboxylic acid which com
prises heating a 4-arylpiperidine-4-nitrile with a
trile used, and separating the ester from this re
action mixture after completion of the heating.
6. A process for the manufacture of the ethyl
mixture of ethyl alcohol, ammonium chloride, sul
phuric acid and water, the total amount of water
being between 0.5 and 2.5 molecular equivalents
of the nitrile used, and separating the ester from
this reaction mixture after completion of the
heating.
ester of 1 - methyl -4-phenylpiperidine-4-nitrile
which comprises heating 5 parts by weight of 1—
methyl-4-phenylpiperidine-Li-nitrile, 8.7 parts by
weight of 98% sulphuric acid, 1.2 parts by Weight
of water, 1.34 parts by weight of ammonium chlo
ride and 10 parts by weight of absolute ethyl al~
4. A process for the manufacture of the ethyl 10 cohol together in a sealed tube at Mil-150° C. for
ester of 1-methyl-4-phenylpiperidine~4~carbox~
8 hours, andisolating the ester from the reaction
ylic acid which comprises heating 1—methyl-4
mixture after cooling.
phenylpiperioline-4-nitrile in a mixture of ethyl
7. A process for the manufacture of the ethyl
ester of 1 - methyl -4-phenylpiperidine-4-nitrile
alcohol, sulphuric acid and water, the total
which comprises heating 5 parts by Weight of 1
amount of Water being between 0.5 and 2.5 molec
ular equivalents of the nitrile used, and isolating -
methyl-4~pheny1piperidine-4-nitrile, 25 parts by
the ester from the reaction mixture after com
weight of 98% sulphuric acid and 10 parts by
pletion of the heating.
Weight of absolute ethyl alcohol in a sealed tube
at 140-150“ ‘C. for 8 hours, and separating the
‘
5. A process for the manufacture of an ester of
4-arylpipericline-4—carboxy1ic acid which com
prises heating a 4-ary1piperidine—4=-nitri1e with a
mixture of an alcohol, sulphuric acid and water in
a sealed. tube, the total amount of water being be
tween 0.5 and 2.5 molecular equivalents of the ni
ester from the reaction mixture after cooling.
FRANZ BERGEL.
NATHAN CHADWICK HINDLEY.
ALEXANDER LANG MORRISON.
HEINRICH RINDERKNECHT.
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