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Патент USA US3069436

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Patented Dec. 18, 1962
crystallization from dry toluene to yield N-(4-toluene
sulfonyl) -N,N- ( [3,{i-dichloro ) -diethyl amine.
To a solution of 592.5 parts of this compound and
Paul A. J. .lanssen, Vosseiaar, near Turnhout, Belgium,
270 parts of 4-?uorophenylacetonitrile in 2000 parts of
assignor to Research Lahoratorium Dr. C. Janssen N.V.,
5 dry toluene are added portionwise 345 parts of a 50%
Beerse, Belgium, a company of Belgium
suspension by Weight of sodamide in xylene while the
No Drawing. Filed Apr. 27, 1960, §er. No. 24,919
temperature is maintained at about 45-50° C. After
3 Claims. (Cl. 260--294.'7)
the initial reaction has subsided, the mixture is heated
The present invention relates to a new group of cyano
slowly to boiling and then re?uxed for 2 hours. After
piperidine derivatives and more particularly to l-aroyl 10 cooling, water is added to decompose the mixture. The
propyl-4-aryl-cyanopiperidines of the general structural
precipitate is collected, washed with 2-propanol, and dried
to yield 1 - (4 - toluenesulfonyl) - 4-cyano - 4 - (?uoro
phenyl)piperidine melting at about 1865-188o C.
Ar s. 0152 CH2 n2 N\
By substituting the appropriate starting materials in
15 the above procedure, the following compounds are ob
wherein Ar and Ar’ are phenyl, tolyl, or halophenyl radi
cals. The halophenyl radical represented can be ?uoro
1 - (4 - toluenesulfonyl) - 4 - cyano - 4 ~ (3 - tolyl)
phenyl, chlorophenyl, bromophenyl, or iodophenyl.
The compounds of this invention show activity both as
hypnotic and analgesic agents.
The preparation of the compounds described herein
is carried out by heating an aroylpropyl halide of the
1 - (4 - toluenesulfonyl) - 4 - cyano - 4 ~ (4 - tolyl)
1 - (4 - toluenesulfonyl) - 4 - cyano - 4 -(3 - ?uoro
1 - (4 - toluenesulfonyl) - 4 - cyano - 4 - (4 - iodo
l - (4 - toluenesulfonyl) - 4 - cyano - 4 - (4 - chloro
with an appropriately selected 4-aryl-4-cyanopiperidine.
The organic bases of this invention form pharmaceuti
cally acceptable salts with a variety of inorganic and
Example 2
A mixture of 52.5 parts of l-(4-toluenesulfonyl)-4
cyano-4-(4-chlorophenyl)piperidine, 26.4 parts of phenol,
lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, ' 322 parts of a 30% solution of hydrogen bromide in acetic
benzoic, gluconic, ascorbic, and related acids. They also
acid is heated for 24 hours at about 40° C., cooled, and
form quaternary ammonium salts with a variety of organic
?ltered. The precipitate is saved. The ?ltrate is poured
esters of sulfuric, hydrohalic and aromatic sulfonic acids.
into dry ether and the solid which precipitates is collected
Among such esters are methyl chloride and bromide,
strong organic acids, including sulfuric, phosphoric, hy
drochloric, hydrobromic, hydriodic, sulfamic, citric,
ethyl chloride, propyl chloride, butyl chloride, isobutyl
chloride, benzyl chloride and bromide, phenethyl bromide,
naphthylmethyl chloride, dimethylsulfate, diethylsulfate,
methyl benzenesulfanate, ethyl toluenesulfonate, ethyl
ene chlorohydrin, propylene chlorohydrin, allyl bromide,
methallyl bromide and crotyl bromide.
and combined with the precipitate saved from above. This
combination is dissolved in water. The solution is then
boiled with activated charcoal, rendered alkaline, and
extracted with ether. The extract is then evaporated to
yield 4-cyano-4-(4-chlorophenyl)piperidine melting at
about 77-78.5° C.
By substituting equivalent quantities of the starting
The preparation of these compounds will appear more
materials in the above procedure, the following com
fully from a consideration of the following examples
pounds are obtained:
which are given for the purpose of illustration only and
45 . 4-cyano-4-pheny1piperidine.
are not to be construed as limiting the invention in spirit
or in scope. In these examples quantities are indicated
as parts by weight, temperatures in degrees centigrade
(° C.), and pressure in millimeters of mercury (mm.).
4-cyano-4- (4-iodophenyl) piperidine.
Example 1
Example 3
To a mixture of 119 parts of N,N-(1B,,6-dihydroxy)di
ethyl amine and 54 parts of 2 N sodium carbonate are
A mixture of 5.4 parts of 'y-chlorobutyrophenone, 5.5
added 190.5 parts of 4-toluenesulfony1 chloride. This
parts of 4-cyano-4-phenylpiperidine, 7.8 parts of sodium
mixture is heated to about 95° C. for about one hour and 55 carbonate, and 0.1 part of potassium iodide in 120 parts
then cooled to 0° C. and ?ltered. The ?ltrate is ex
of 4-methyl-2-pentanone is refluxed for 115 hours, cooled,
tracted with ether. After evaporation of the ether, the
and partitioned between water and ether. The ether layer
residue is crystallized from a mixture of 2-propanol and
is separated, diluted with additional ether and dried.
petroleum ether by chilling at ——20° C., and then re
Hydrogen chloride gas is passed through the solution.
crystallized from a 1:3 by volume mixture of ethanol 60 The solid precipitate is collected on a ?lter and then re‘
and acetone to yield N-(Li-toluenesulfonyl)-N,N-(;3,?-di
crystallized from acetone by chilling at —20° C. to yield
hydroxy)diethyl amine. A mixture of this compound
1 - ('y - benzoylpropyl) - 4 - cyano - 4 - phenyl — piperidine
and 690 parts of thionyl chloride is heated gently at 125°
hydrochloride melting at about 206—207.6° C.
C. for about an hour and then cooled. The excess thionyl
chloride is evaporated and the residue is puri?ed by
By substituting 4-cyano-(3-?uorophenyl)-piperidine
in the procedure of the above paragraph, l-(y-benzoyl
propyl)-4-cyano-4-(3-?uorophenyl)piperidine hydrochloW16 of ‘the structural formula
Arnixture of 4 parts of 'y-chloro-4-?uorobutyrophenone,
9.1 parts of 4-cyano-4-(4-chlorophenyl)-piperidine, 0.1
part of potassium iodide, and 120 parts of toluene is
heated in a sealed tube for 90 hours at about 120° C.
Example 7
and then cooled. The ?ltrate is washed with water, dried,
decolorized with activated charcoal, and evaporated. The
15 Obtamed-
residue is dissolved in a mixture of diisopropyl ether and
Example 4
10 ether. TIgydrogen chloride gas is passed through the solu
e solid which
reci itates is collected on a ?lter
> To a suspensmn of 341 parts of alummum chlonde
and then dissolved in iiot gater. Upon acidifying the
in 1740 parts of. carbon
. . disul?de are
. added .96 parts of
hot a queous solution
to a pH of about 1 ‘and coohng,
?uorflienfzelg Yvlihgtlérvnig‘ gndtci’glmé' $111116 tile tfem'
p?lra ube :5 lal?lalg a a 251 d Aft"
th6 P3339
c Om n W e on. e are a . e '
a 11.011. IS
solid precipitates. The solid is collected on a ?lter and
completed, the COOllIlg bath is removed and the stirring
is continued
about 2 hours.
crystallized from 2-propano1 to yield 1-[7-(4-?uoro
benzoyl)propyl] - 4-cyano-4-(4-chlorophenyl)piperidine
hydrochloride melting at about 242 5_243 so C
. reaction
. mixture is
. .
. the ?rst paragraph of
By substituting
chlorobenzene 1n
pougecé msgl etwa?lfi'ed'ghzfoarggntiggyesr (lliusepar?tig’
Example 4, 'y,4-dichlorobutyrophenone is obtained. This
was 51 W1d Taher’?m t .v
tare ‘
ytr t :1 o (11 m S121 a d’
. a e .18 cfmFen' ae .un er re “Ge
compound is then substituted for 'y-chloro-4-?uorobutyro
20 phenone and 4-cyano-4-(4-iodophenyl)piperidine for 4
pressure, and the res1du_e_1s distilled to yield 'ygchloro-4?rgigg‘rlgghenone bo?mg at about 136442 C‘ at 6
The free base of 4-cyano-4-phenylpiperidine hydrochlo-
cyano_4_(4_chlomphenyl)piperidine in the Procedure of
the ‘above paragraph and 1-['y-(4~ch1orobenzoyl)propyl]
fgggélo'ii'w'lodophenyl) P1P emdme hydrochlonde 1s ob‘
ride is liberated by dissolving 14.2 parts of the salt in 25
water, rendering the solution alkaline, extracting the solu
Example 8
A Grignard reagent of 3-?uorophenylmagnesium bro
mide is prepared by reacting 6.7 parts of magnesium with
tion with ether, and drying and evaporating the ether
extract. The residue, 6.4 parts of 'y-chloro-4-?uoro
butyrophenone, 0.1 part of potassium iodide, and 120
94.5 parts of 3-bromo?uorobenzene in 80 parts of ether.
Then 21 parts of 'y-chlorobutyronitrile in 64 parts of ether
parts of toluene is heated in a sealed tube for 96 hours 30 are added and the mixture is re?uxed under nitrogen for
at 110—l20° C., cooled, and ?ltered. The ?ltrate is par
two hours with stirring. The mixture is then allowed to
titioned between water and ether, and the layers are sep
stand ‘at room temperature for 15 hours and the excess
arated. The organic layer is ?rst dried and then hydrogen
Grignard reagent is decomposed by the addition of 56
chloride gas is introduced into the solution. The precipi
parts of concentrated hydrochloric acid and 50 parts of
tate is collected, crystallized from a 2:1 mixture of ace- 35
Water. The organic layer is separated, dried over anhy
tone and 2-propanol, and then recrystallized from a 3:1
sodium sulfate, ?ltered, and concentrated under re~
mixture of acetone and 2-propanol by allowing the solu
duced pressure. The residue is distilled to yield 'y-chloro
tion to stand for 2 days at room temperature to yield
3-?uorobutyrophenone ‘boiling at about l05-125° C. at 2
hydrochloride melting at about 224.5-230.4° I C.
Example 5
mm. pressure.
Substitution of 'y-chloro-3-?uorobutyrophenone in the
procedure of Example 6 yields 1-['y-(3-?uorobenzoyl)
slzAllJna?éuiffogf’cgggtgjfpégpjgaggimgfpgzgto (if
By_subst1tut1ng 3-b1'om0t01ue‘ne 1n the ?rst paragraph
potassium iodide, and 120 parts of toluene is heated in ‘15 °f.th1s examplet Y'°h1°P°'3imethylbmyrf’phemne 1S ob'
a sealed tube at about 120° C., cooled, and then ?ltered.
The ?ltrate is washed with water, boiled with activated
tamed’ An eqmmolar .‘subsntutQn of ‘this Compound for
'7'cm“0'4'?uor'obutymphcnone m the Procedure of EX'
charcoal, and then evaporated. The residue is dissolved
ample 6 yl‘f'lds. 1_-[v43-methylbenzoybpropyl]~4-cyano
in diisopropyl ether. The solution is chilled at ——20°
4'(4't°lyl)p1pendme of the structural formula
C. to yield 1-['y-(4-?uorobenzoyl)propyl]-4-cyano-4-(3- 50
tolyl)piperidine melting at about 79.6-72.8° C. as a pre-
6 CWCHT CH2, 5H2
cipitate. The hydrochloride of this compound melts at
239.5-242" C.
By substituting bromobenzene in the ?rst paragraph
of Example 4, 'y-chloro-4-bromobutyrophenone is. ob- 5'0
tained. An equimolar substitution of this compound for
Y 'y-chloro-4-?u0robutyrophenone in the above paragraph
What is claimed is:
1. A compound of the formula
and otherwise following the outlined procedure, yields 1-
['y - (4 - bromobenzoyDpropyl] - 4 - cyano-4-(3-tolyl)-
piperidine. The compound has the structural formula
Ar z
Br _©_ co-cnz-caz-cnz-u
/ w- \
Example 6
65 wherein Ar and Ar’ are members of the class consisting
A mixture of 4 parts of 'y-chloro-4-?uorobutyrophenone,
8.2 parts of 4-cyano-4-(4-tolyl)piperidine, 0.1 part1 of
of phenyl, tolyl, and halophenyl.
4_p21-1eI1‘y-l'pi[1;ridi(:e ?UOI'ObGHZOYDpropyl] . 4 - cyan‘).
potassium iodide, and 120 parts of toluene is heate 1n
a sealed tube for 90 hours at 1200 c. and then ?ltered. 70 (43-01113 [TYéfgine?mmbemyl)PwPYH - 4 - crane - 4
The ?ltrate is washed with water, dried over sodium sul-
fate, boiled with activated charcoal, and then evaporated.
y pm 1
The residue is crystallized from diisopropyl ether by
chilling at _20° c. to yield l-[y-(4-?uorobenzoyl)
propyl]-4-cyano-4-(4-t0lyl)~piperidine melting at about 75
925.965“ c,
References Cited in the ?le of this patent
Eisleb ________________ __ July 1, 1941
Gardner ............. -- Sept. 24, 1957
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