Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
105S9~5
1 This invention relates to novel pharmaceutical
compositions containing as an active ingredient compounds
which produce antipsychotic activity without extrapyramidal
symptoms and to a method of producing antipsychotic activity
without extrapyramidal symptoms which comprises administer~ing nontoxic effective quantities of said active ingredients
to an animal. Extrapyxamidal symptoms (EPS) are some of
the most undesirable and common side-effects produced by
antipsychotic or neuroleptic drugs. The compounds which
are the active ingredients used in the compositions and
methods of this invention have a neuropharmacological
profile indicative of potent antipsychotic activity but
essentially no liability to produce EPS.
The active ingredients used in the compositions
and methods of this invention are piperidylidene derivatives
of xanthene J thioxanthene and dibenzozepin of the following
general formulas:
Z_~Y\~ CH20~/~,(~) -
~ W, ~X Z~C~
R H3
25FORM~LA I FORMULA II
wherein, for formula I:
when Y represents oxygen7 X is 2-chloro9 2-fluoro,
2-trifluoromethyl~ 2-thiomethyl, 2-bromo or 2-cyano, Z is
hydrogen and R is methyl,
-- 2 --
1055945
1 when Y represents oxygen, X is 2-chloroy Z is
hydrogen and R is hydrogen, ethyl, ~-hydroxyethylg
n-propyl, 3-hydroxypropyl or cyclobutylmethyl,
when Y represents oxygen, X is 2-bromo9 Z is
hydrogen and R is hydrogen9 ~-hydroxyethyl or n-butyl~
when Y represents oxygen9 X is 2-trifluoromethyl9
Z is hydrogen and R is n-butyl,
when Y represents sulfur9 X is 2-or 3-chloro9
2-thiomethyl9 2-or 3-fluoro9 2-bromo or 2-cyano9 Z is
hydrogen and R is methyl,
when Y represents sulfur, X is 2-chloro9 Z is
hydrogen and R is ~-hydroxyethyl, ethyl9 n-butyl or cyclo-
butylmethyl; and
when Y represents oxygen, X is 2-fluoro9 Z is
lS 6-chloro and R is methyl;
when Y represents sulfur, X is 2-fluoro9 Z is
6-chloro or 6-fluoro and R is methyl, and
for formula II:
when X is 2-or 3-chloro, Z is hydrogen~ and
when X is hydrogen9 Z is 9-chloroO
Preferred o~pounds for use as active ingredients
are those of formula I wherein Y is oxygen9 X is 2-chloro9
Z is hydrogen and R is methyl, and of formula II wherein
- X is hydrogen and Z is 9-chloro.
Certain of the compounds of formulas I and II
are novel compounds and as such form a part of this inven-
tion. These compounds are as follows:
in formula I,
when Y represents oxygen9 X is 2-chlorog 2-fluoro
2-bromo9 2-thiomethyl or 2-cyano, Z is hydrogen and R is
methyl;
~0 S S9 4 5
1when Y represents oxygen, X is 2-fluoro, Z is
6-chloro and R is methyl,
when Y represents oxygen, X is 2-chloro, Z is
hydrogen and R is hydrogen9 ethyl9 ~-hydroxyethyl~ n-propyl
5or 3-hydroxypropyl,
when Y represents oxygen, X is 20bromo9 ~ is
hydrogen and R is hydrogen, ~-hydroxyethyl or n-butyl,
when Y represents oxygen9 X is 2-trifluoromethyl9
Z is hydrogen and R is n-butyl;
10when Y represents sulfur 9 X iS 2-cyano 9 Z iS
hydrogen and R is methyl, and
in formula II:
when X is hydrogeng Z is 9-chloro.
The nontoxic pharmaceutically acceptable acid
addition salts of the compounds of formulas I and II are
similarly useful in the compositions and methods of this
invention. Such salt~ are easily prepared by methods known
to the art. The base is reacted with either the calculated
amount of organic or inorganic acid in aqueous miscible
~-solvent 9 such as acetone or ethanol, with isolation of the
salt by concentration and cooling or an excess of the acid
in aqueous immiscible solvent, such as ethyl ether or
chloroform, with the desired salt separating directly.
Exemplary of such organic salts are those with maleic9
fumaric, benzoic, ascorbic9 pamoic, succinic, bismethylene-
salicylic, methanesulfonic, ethanedisulfonic, scetic9propionic, tartaric, salicylic, citric9 gluconic9 lactic9
malic, mandelic, cinnamic9 citraconic, aspartic, stearic9
palmitic, itaconic, glycolic9 p-aminobenzoic 3 glutamic,
benzenesulfonic and theophylline acetic acids as well
1055945
l as with 8-halotheophyllines 7 for example 8-bromotheo-
phylline. Exemplary of such inorganic salts are those
with hydrochloricl hydrobromic, sulfuric, cyclohexylsul-
famic, phosphoric and nitric acids. Of course, these salts
may also be prepared by the classical method of double
decomposition of appropriate salts which is well known to
the art.
The compounds of formulas I and II where R is
methyl are generally prepared from an appropriately substi-
tuted xanthone, thioxanthone or dibenzoxepinone by reaction
with an N-methylpiperidyl magnesium halide in an inert
organic solvent such as ether, for example ethyl ether 9
dioxane or tetrahydrofuran9 at from room temperature to
the reflux temperature of the solvent, for from 30 minutes
to 4 hours. The tricyclic carbinol intermediate is dehy-
drated to the olefin under acid or thermal conditions.
To prepare the compounds of formula I where R
is other than methyl 3 the N-methylpiperidylidene derivative
is treated with cyanogen bromide to give the N-cyanamide
~ which is treated with acid to obtain the N-unsubstituted
derivatives. The latt~r are N-alkylated by one of the
following methods:
a) direct alkylation with the appropriate alkyl
bromide;
b) acylation with the appropriate acyl ch~oride
to the corresponding amides followed by lithium aluminun
hydride reduction, or
c) reaction with ethylene oxide.
UOS. Patents 3,275,640 and 3,055,903 disclose
piperidylidene thioxanthenes; South African Patent 67/04371
-- 5 --
1055945
l discloses piperidylidene dibenzoxepin ~ and U~SO Patent
394709188 discloses piperidylidene xanthenes and thioxan-
thenes9 however~ none of these or equivalent prior art dis~
close the unique feature of the compounds of formula I,
namely antipsychotic activity with no EPS~ Belgian Patent
8089347 describes di~nuclear substituted thioxanthenes
having a heterocyclic propyl or propylidene side chain as
neuroleptics with reduced extrapyramidal symptoms.
There is evidence that antipsychotic drugs cause
EPS by interfering with neurotransmission in a nigrostriatal
dopaminergic pathwayO It is thought that they block dopamine
receptors in the neostriatum. Thereforeg the ability of a
drug to block striatal dopamine receptors is a measure of
its EPS liability.
To assess the potency of drugs in blocking
striatal dopamine receptors a procedure was used which was
developed by Ungerstedt [Ungerstedt and Arbuthnott9 Brain
ResO 24 485 (1970)~ Ungerstedt9 Acta physiolO scand.~
Suppl. 3679 49 (1971)] using rats with unilateral lesions
of the substantia nigra induced by inJection of 6-hydroxy-
dopamine. This treatment causes degeneration of the nigr~striatal dopaminergic pathway accompanied by a marked
decrease in the dopamine content of the neostriatum on
the side of the lesion. Animals with this lesion develop
postural and motor asymmetries which are altered ~y drugs
which affect dopaminergic activity. Amphetamine9 which
releases dopamine and norepinephrine from catecholaminergic
1~)5S945
1 neurons9 causes these rats to rotate unidirectionally
toward the side of the lesion. Since there is a much larger
amount of dopamine to be released by amphetamine from the
intact nigrostriatal neurons on the non~lesioned side than
from those remaining on the lesioned side9 the rotational
behavior is apparently due to a preponderance of activation
of striatal dopamine receptors on the intact side. The
ability of a drug to antagonize the rotational behavior is
therefore a measure of its ability to block striatal
dopamine receptors and is indicative of its potential to
produce EPS.
To predict the potential ability of a drug to
cause EPS9 the ratio of its ED50 (i~po) for antagonism of
amphetamine-induced rotation to its ED50 (i.p.~ for blockade
of shock avoidance acquisition in the rat9 a procedure for
assessing antipsychotic activity, (R/A ratio~ is calculated.
The ED50 values of some clinically established antipsychotics
in the avoiclance and rotational tests and the R/A ratios
are presented in Table I. Chlorpromazine has a R/A ratio
?0 of 103. Antipsychotics that have a considerably greater
propensity to cause EPS than chlorpromazine9 e.g.g tri~
fluoperazine9 haloperidol and pimozide~ have ratios of
0.3 to 0.5. The two antipsychotics known to produce EPS
to a lesser extent than chlorpromazine~ i.e~ thioridazine
and clozapine9 have ratios of 2.7 and 3.89 respectively.
Therefore a high R/A ratio predicts that a drug will have
a low potential to produce EPS.
3~
1055945
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1055945
l The specific piperidylidene derivatives of
formulas I and II having a large R/A ratio and therefore
should be essentially free of EPS liability are listed
below.
S I. 4-(2-chloro-9-thioxanthenylidene)-1-methylpiperi-
dine
IIo l-methyl-4-(2-methylthio-9-thioxanthenylidene~-
piperidine
III. 4-(3-chloro-9-thioxanthenylidene)-1-methylpiperi-
dine
IV~ 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine
V. l-methyl-4-(2-methylthio-9-xanthenylidene)piperi-
dine
VI. l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)-
lS piperidine
VII. 4-(2-chloro-11(6H)-dibenz[b,e]oxepinylidene~
methylpiperidine
VIII. 4-(2-fluoro-9-xanthenylidene)-1-methylpiperidine
IX. 4-(2-chloro-9-thioxanthenylidene)-1-(~-hydroxy-
~-0 ethyl)piperidine.
X. 4-(2-bromo~-xanthenylidene)-1-methylpiperidine
XI. 4-(2-cyano-9-xanthenylidene)-1-methylpiperidine
XII. 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperi-
dine
XIII. 4-(3-fluoro-9-thioxanthenylidene)-1-methylpiperi-
dine
XIV. 4-(2-bromo-9-thioxanthenylidene)-1-methylpiperidine
XV. 4-(6-chloro-2-fluoro-9-thioxanthenylidene)-1-
methylpiperidine
XVI. 4-(6-chloro-2-fluoro-9-xanthenylidene)-1-methyl~
piperidine
1055945
1XVII. 4-(2-chloro-9-thioxanthenylidene)-1-ethylpiperidine
XVIII. 4-(2-chloro-9-thioxanthenylidene)-1-n-butglpiperi-
dine
XIX. 4-~2~chloro-9-thioxanthenylidene)-1-cyclobutylmethyl-
5piperidine
XX. 4-(2-chloro-9-xanthenylidene~-piperidine
XXIo 4~ (2-chloro-9-xanthenylidene)-1-ethylpiperidine
XXII. 4-(2~chloro-9-xanthenylidene)-1-(~-hydroxyethyl~-
piperidine
10XXIII. 4-(2-chloro 9-xanthenylidene)-1-n-propylpiperidine
XXIV. 4-(2-chloro-9-xanthenylidene)-1-cyclobutylmethyl-
piperidine
XXV. 4-(2-bromo-9-xanthenylidene)-piperidine
XXVIo 4-(2-bromo-9-xanthenylidene)-1-(~-hydroxyethyl)-
15piperidine
XXVII. 4-(9-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-
methylpiperidine
XXVIII. 4-~2-cyano-9-thioxanthenylidene)-1-methylpiperidine
XXIX. 4-(296-difluoro-9-thioxanthenylidene)-l-methyl-
~-0piperidine
XXXO 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl~
piperidine
XXXI. 4-(2-trifluoromethyl-9-xanthenylidene)-1-n-butyl
piperidine
25XXXII. 4-(2-bromo-9-xanthenylidene)-1-n-butylpiperidine
XXXIII~ 4-(3-chloro-11(6H)-dibenz[b9e]oxepinylidene)-l-
methylpiperidine.
The ED50 values of these compounds in the a~oidance acquisi-
tion and rotational tests and their R/A ratios are presented
30in Table IIo
- 10 -
1055945
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1055945
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~0559~5
1 The compositions of this invention are prepared in
conventional dosage unit forms by incorporating a compound
of formulas I or II or a pharmaceutically acceptable salt
thereof, in a nontoxic amount sufficient to produce anti
psychotic activity without extrapyramidal symptoms in an
animal9 with a nontoxic pharmaceutical carrier according ~o
accepted proceduresO Preferably the compositions will con-
tain the active ingredient in an active but nontoxic amount
selected from about 1 mg. to about 300 mg.~ advantageously
from about 5 mg. to about 200 mg.~ of active ingredient
per dosage unit.
The pharmaceutical carrier employed may be9 for
example, either a solid or liquid, giving rise to a wide
variety of pharmaceutical forms. If a solid pharmaceutical
carrier is used, such as lactose9 magnesium stearate9 terra
alba9 sucrose9 talc9 stearic acid9 gelatin9 agar9 pectin9
acacia and the like9 the composition can be tableted9 used
as a pharmaceutical powder~ placed in a hard gelatin capsule
or in the form of a troche or lozenge. The amount of solid
?0 carrier will vary widely but preferably will be from about
25 mg. to about 1 g. If a liquid pharmaceutical carrier
is used, such as syrup9 peanut oil, olive oil~ sesame oil9
water and the like9 the composition will be in the form of
a soft gelatin capsule9 syrup, emulsion or a liquid suspen-
sion~ Similarly the carrier or diluent may include a timedelay material such as glyceryl monostearate or glyceryl
distearate alone or with a wax.
Parenteral dosage forms such as for intramuscular
administration are obtained by dissolving a water soluble
3~ salt of the active medicament in water or saline solution
- 14 -
1055945
1 in a concentration such that 1 ccO of the solution contains
from about 2 mgO to about 50 mgO of active ingredient. The
solution can then be filled into single ampuls or multiple
dose vialsO
In accordance with the method of this invention
a compound of formula I or II or a nontoxic acid addition
salt thereof is administered internally to an animal in need
of antipsychotic activity9 preferably with a pharmaceutical
carrier9 in a nontoxic amount sufficient to produce anti
psychotic activity without extrapyramidal symptoms, The
active medicament9 preferably in a dosage unit9 is adminis-
tered orally or intramuscularly in an active3 nontoxic
quantity selected from about 1 mg. to about 300 mgO of the
parent chemical of formula I or II. Advantageously equal
doses will be administered until a desired effect is ob-
tained9 such as two or three times a day~ The daily dosage
is selected from about 2 mg. to about 900 mg. of active
medicament9 advantageously from about 10 mg. to about
600 mg. When the method described above is carried out9
~0 antipsychotic activity is obtained with minimal EPSo
The followi~g examples illustrate specific pharma-
ceutical compositions and their use in accordance with the
method of this invention and as such are not to be con-
sidered as limitations thereo.
EXAMPLE 1
Ii~E~ . per capsule
4-(2-chloro-9-thioxanthenyli-50 (free base)
dene-l-methylpiperidine
(as an acid addition salt)
Magnesium stearate 2
Lactose 200
1055945
l The above ingredients are mixed~ passed through a #40
me~h screen9 remixed and filled into #2 capsules.
EXAMPLE 2
In~redients W/V Percenta,~es
4-(2-chloro-9-xanthenylidene)- Equivalent to 20 mg~ of
l-methylpiperidine (as a water free base per ml.
soluble acid addition salt)
~odium tartrate
Tartaric acid 0,7
Water for parenterals, q.s. 100
The above ingredients are dissolved in an amount of the
water equal to approximately 95% of the final volume9 mixed9
heated a~ required~ cooled to room temperature and the re-
mainder of water is added. The solution is ~iltered and
filled in ampuls.
The capsules or solution prepared as in Examples
1 or 2 are administered internally to an animal requiring
antipsychotic activity within the dose ranges set forth
hereinabove. Similarly other compounds of formulas I or II
can be formulated in the same manner to give pharmaceutical
?0 compositions useful in the methods of this invention.
EXAMPLE 3
To 4.3 g. (0.175 m.) of magnesium turnings just
covered with dry tetrahydrofuran at gentle reflux under
nitrogen is added l ml. of a tetrahydrofuran solution of
the base derived from 29.8 g. (0.175 m.) of 4-chloro-N-
methylpiperidine hydrochloride (base in about 50 ml. of
tetrahydrofuran). (The base was previously liberated by
use of ether, potassium hydroxide pellets9 l ml. of water;
triturating9 extracting with ether and evaporating in vacu-
the dried ether solution.) A small amount of ethereal
- 16 -
1055945
1 methyl magnesium bromide is added and when the reaction
starts the remainder of the base is diluted with about
150 ml. of tetrahydrofuran while stirring. This solution
is added dropwise over one-half hour while maintaining low
heat and the resulting mixture is refluxed and stirred
for one hour. At low reflux 27.0 g. (0.117 m.) of 2-chloro-
xanthone is added portionwise with stirring. The reaction
mixture is stirred and refluxed for one hour and then
quenched on a mixture of ice-water-ammonium chloride to
give an oil which solidified. Recrystallization from ethyl
acetate gives 2-chloro-9-(1-methyl-4-piperidyl)-xanthene-9-
ol, m.p. 206-208C.
A mixture of 12.5 g. (0.038 m.) of the xanthene-9-
ol, 14.0 g. (0.76 m.) of o-sulfobenzoic anhydride and 380 ml.
lS of propionic acid is refluxed for three hours. The reaction
mixture is heated in vacuo at 100C. and the resulting syrup
is dissolved in water, made strongly basic with 40% sodium
hydroxide solution, extracted with ether9 and the dried
extract is evaporated. The residual free base is dissolved
in ethyl acetate and maleic acid (4.4 g.) is added to yield
4-(2-chloro-9-xanthenylidene)-1-methylpiperidine maleate,
m.p. 206-207C.
EXAMPLE 4
The Grignard reagent from 68 g. (0.4 m.) of
4-chloro-N-methylpiperidine hydrochloride and 9.7 g.
(0.4 m.) of magnesium turnings in a total volume of 250 ml.
of tetrahydrofuran is obtained following the procedure of
Example 3. After all the halide is added, 75.6 g. (0.287 m.)
of 2-trifluoromethylxanthone is added portionwise and
refluxing/stirring are continued for one hour under nitrogen.
1055~45
1 The reaction mixture is quenched on ice-water-ammonium
chloride to give 9~ methyl~4-piperidyl) 2-trifluoro-
methylxanthene-9-019 m.p~ 179-183CD
Dehydration of the xanthene-9 ol (88.2 gO 9
0.24 mO~ is accompli~hed by refluxing with 88~1 g. (0048 mO7
of sulfobenzoic anhydride and 1O2 lo of propionic acid for
two hoursO The reaction mixture is heated in vacuo at
100Co and the residual syrup is dissolved in water and
made strongly basic with 40% sodium hydroxide solution.
Extraction with ether gives l-methyl-4-(2-trifluoromethyl-
9-xanthenylidene)-piperidine, m.p. 82-83C.
EXAMPLh 5
Following the procedure of Example 39 the Grignard
reagent formed from 2O4 gO (0~1 m.) of magnesium and 1303 gD
(0 01 mO) of 4-chloro-N-methylpiperidine is reacted with
1201 g. (0O05 mO) of 2~thiomethylxanthone to give 9-(1-
methyl-4-piperidyl)-2~thiomethylxanthene-9-ol9 m.p. 169Co
The xanthene-9-ol (10.8 g,9 0~032 m.) thus pre-
pared is dehydrated by refluxing with 11.6 gO (00064 mc) of
?0 sulfobenzoic anhydride and 258 mlO of propionic acid.
After work~up of the ~eaction mixture9 extraction with
methylene chloride followed by addition of ether precipi~
tates unreacted xanthene-9-ol which is removed by filtra-
tion. The filtrate is concentrated to give an oil which
is converted in ether to the maleate salt of 1-methyl-4-(2
methylthio-9-xanthenylidene)-piperidine9 mOp. 172-180Co
EXAMPLE 6
The Grignard reagent prepared from 0O53 g.
(0.0216 mO) of magnesium and 2.9 g. (0.0216 m.) of 4-
chloro-N-methylpiperidine is reacted with 2.3 g. (0O0108 mO)
- 18 -
105S945
1 of ~-fluoroxanthone as described in Example 3. The reac-
tion mixture is heated for four hours and then decomposed
with saturated ammonium chloride solution to yield 2-fluoro-
9-(l-methyl-4-piperidyl)-xanthene-9-ol9 m.p. 193-200C.
A mixture of 0.58 g. (0.002 m.) of the above pre-
pared xanthene-9-ol9 0.34 g. (0.004 m.~ of sulfobenzoic
anhydride and 20 mlO of propionic acid is refluxed for about
15 minutes and then stirred without heating until cooled.
The reaction mixture is evaporated in vacuo and the residue
is taken up in methylene chloride. The product is treated
with maleic acid to afford the maleate salt of 4-(2-fluoro-
9-xanthenylidene)-l-methylpiperidine9 m.p. 189-193C.
EXAMPLE 7
To a solution of 13.2 g. (0.0318 m.) of 4-(2-
chloro-9-thioxanthenylidene)-piperidine in 50 ml. of methan-
ol at 50C~ is added a solution of 2.2 g. (0.0383 m.) of
ethylene oxide in 30 ml. of methanol over ten minutes and
the mixture is refluxed for one and one-half hours. After
standing overnight at room temperature9 the reaction mixture
is filtered to yield 4-(2-chloro-9-thioxanthenylidene)-1-
(~-hydroxyethyl)-piperidine9 m.p. 178-180C.
EXAMPLE 8
To a stirred suspension of 2.43 g. (0.1 gO~atom~
of magnesium turnings in 5 ml. of tetrahydrofuran under
nitrogen is added several drops of ethyl bromide. After
the reaction is started9 13.4 g. (0.1 mole) of 4-chloro-1-
methylpiper;dine in 50 ml. of tetrahydrofuran is added at
a rate sufficient to cause reflux. The mixture is stirred
and refluxed for one hour 9 then it is cooled to 0C~ and
2006 g. (0O075 mole) of 2-bromoxanthone is added in portions~
1055~45
1 The stirred mixture is refluxed for four hours and then it
is poured into a solution of 26.5 g. (0.5 mole) of ammonium
chloride in 500 ml. of ice-water. The crystalline alcohol 9
2-bromo-9-(1-methyl-4-piperidyl)-xanthene-9-ol~ m.p.
201-2029 is filtered.
The above alcohol 20.0 g~ (0.05~ mole) is dis~
solved in 200 ml. of propionic acid and 20O0 g. (OoOll mole~
of sulfobenzoic anhydrideO The solution is refluxed for
one hour, concentrated in vacuo, and then the residue is
diluted with waterO The mixture is made alkaline with
2~5 N sodium hydroxide and extracted with ether~ The ether
extracts are dried and concentrated to give 4-(2-bromo-9-
xanthenylidene)-l-methylpiperidine9 which identified as its
maleate salt9 m.p. 206C. ~dec.)O
EXAMPLE 9
.. ..
To a stirred solution of 7.0 g. (0.065 mole~ of
cyanogen bromide in 150 ml. of benzene at 50-55C. is added
19.5 gO (0.055 mole) of 4-(2-bromo-9-xant~enylidene)-1-
methylpiperidine in 150 ml. of benzene. The solution is
~0 heated for 2.5 hours) then it is concentrated in vacuo~
The residue is dissolved in methylene chloride and the solu-
tion is washed with lN hydrochloric acid~ water and a
saturated aqueous solution of sodium chloride. The organic
solution is concentrated to give a semi-crystalline residue
which is refluxed for 16 hours with a solution of 225 mlO
of acetic acid and 25 ml. of 12N hydrochloric acid in 125
mlO of water. The solution is concentrated and the residue
is dissolved in water. After the solution is made alkaline
with sodium hydroxide, the mixture is extracted with ethyl
acetateO The extracts are concentrated and a solution of
- 20 -
105S945
1 the crystalline residue in acetonitrile is treated with
methanesulfonic acid in acetonitrile-ether .o give color-
less crystals 9 mOp ~ 257.5-258.5C.9 of 4-(2-bromo-9-xan-
thenylidene)piperidine methanesulfonate.
EXAMPLE 10
To 102 g. (0O05 mol) of magnesium turnings cover-
ed by tetrahydrofuran in an Argon atmosphere is added about
0.5 g. of 4-chloro-N-.nethylpiperidine (from 8.5 g. 9 0~025 mol
of the hydrochloride salt) and a small amount of ethyl
bromide. The mixture is heated until the reaction is ini-
tiated9 the remainder of the chloro compound in about 20 ml.
of tetrahydrofuran is added and the mixture is refluxed for
four hours. 2-~romothioxanthone (7.3 g., 0.025 mol) is
added and the mixture is refluxed for five hours 3 and then
stirred at room temperature three days. The reaction mix-
ture is poured into aqueous ammonium chloride and filtered
to give 2-bromo-9~ methyl-4-piperidyl)thioxanthene-9-ol 3
m.p. 225.5-226C.
A solution of 4.0 g. (0.0103 mol) of 2-bromo-9-
(1-methyl-4-piperidyl)-thioxanthene-9-ol in 20 ml. of con-
centrated hydrochloric acid is refluxed for 1.5 hours~ The
reaction mixture is evaporated to dryness and redissolved
in water. The aqueous solution is washed with ether, basi-
fied and extracted with ether. The dried extract is evap-
orated and the residue in acetonitrile is treated with
methanesulfonic acid to yield 4-(2-bromo-9-thioxanthenyli-
dene)-l-methylpiperidine methanesulfonate, m.p. 210-212C.
(dec.~.
EXAMPLE 11
To a solution of 4-(2-bromo-9-xanthenylidine)-
piperidine (205 g~, 0.0073 mol) in 50 ml. of ethanol9
- 21 -
10555~45
1 cooled to ca 0C. is added excess ethylene oxide (1.1 ml~,
0.022 mol.)O The reaction mixture is kept at 0C. After
30 minutes the ice-bath is removed and after an additional
205 hours9 a thick white precipitate is formed which is
filtered to give 4-(2-bromo-9 xanthenylidene)-l-(~-hydroxy-
ethyl~piperidine9 m.pO 142-146Co 9 methanesulfonate salt9
mOp. 247-248C.
EXAMPLE 12
To a stirred solution of 5.4 g, (0.051 mol) of
cyanogen bromide in 30 ml. of benzene at 50C. is added
gradually a solution of 14.7 g. (0.0426 mol) of 4-(2-chloro-
9-thioxanthenylidene)-1-methylpiperidine in 70 ml. of ben-
zene. The solution is heated at 50C. and stirring con-
tinued for 1O5 hours. Excess water is added and the solu-
tion is extracted with dilute hydrochloric acid. The ben-
zene is evaporated in vacuo and the crude cyanamide (14.9 g)
is refluxed with 12.4 g. (0.22 mol) of potassium hydroxide
in 125 ml. of 70% aqueous ethanol for 24 hours. The reac-
tion mixture is evaporated in vacuo, water is added and
?0 extracted with ether. Etheral hydrogen chlorlde is added
to form a hydrochloride salt which is then treated with
base to liberate 4-(2-chloro-9-thioxanthenylidene)piperi-
dine.
A solution of 0.~ g. (0.01 mol) of acetyl chloride
in 10 ml. of benzene is added to 6.3 g. (0.02 mol) of the
above-prepared piperidine in 30 ml. of benzene and the mix-
ture refluxed for one hour. The cooled reaction mixture is
extracted with waterg then dilute acetic acid. The organic
layer is washed with dilute sodium bicarbonate until neutral
and then ~vaporated in vacuo~ The oil residue (intermediate
- 22 -
1055~45
l amide) is dissolved in ether, dried and gradually added to
a suspension of 105 g. (0.04 mol) of lithium aluminum
hydride in 50 ml~ of etherl The mixture is stirred at room
temperature for 24 hours 9 treated cautiously with 2.1 mlO
of water and filtered. The filtrate is treated with
ethereal lydrogen chloride to give 4-(2-chloro-9-thioxan-
thenylidene)-l-ethylpiperidine hydrochloride9 m.p~ 253C,
(dec.)O
Similarly~ 6~3 gO (0.02 mol) of 4-(2-chloro-9-
thioxanthenylidene)piperidine in 30 ml. of benzene is
treated with a solution of 1.2 g. (0.01 mol) of cyclobutyl-
carboxylic acid chloride in 10 ml. of benzene. Following
the above workup procedureg the intermediate amide is
reduced with 1.5 g. (0.04 mol) of lithium aluminum hydride
in 50 ml, of ether. After isolation of the amine productg
the ether is evaporated in vacuo and a hexamate salt formed
of 4-(2-chloro-9~thioxanthenylidene)-1-cyclobutylmethyl-
piperidine, mOp. 180-182Co
Following the procedures as described above9
?0 4-(chloro-9-thioxanthenylidene)piperidine (6~3 g.9 OrO2 mol)
in 30 ml. of benzene is reacted with 1.0 g. (0.01 mol) of
butyryl chloride in 10 ml. of benzene, followed by reduction
of the intermediate amide with 1.5 g. (0.04 mol) of lithium
aluminum hydride to yield as a final product, 4-(2-chloro-
9 thioxanthenylidene)-l-butylpiperidine hydrochloride9
m.p. 259Co (dec.).
EXAMPLE 13
Sodium hydride (1.0 mol) is suspended in about
300 ml. of dimethylformamide and phenol (1.0 mol) in about
200 ml. of dimethylormamide is added dropwise9 keeping
~ 23 ~
lOS5945
1 the reaction temperature around 25C. The mixture is
stirred until hydrogen evolution is completed. 6-Chloro-
phthalide (1.0 mol) in about 250 ml. of dimethylformamide
is then added slowly. The resulting mixture is refluxed for
2 hours and allowed to stand at room temperature overnight.
The reaction mixture is diluted with ice/water and extracted
several times with ether. The aqueous fraction is acidified
with dilute hydrochloric acid and extracted with etherO
The ether is dried and concentrated to a gummy solid which
is recrystalliæed from a minimum volume of alcohol to give
2-phenoxymethyl-5-chlorobenzoic acid9 m~p. 149-155Co
A mixture of 1.0 mol. of the above prepared ben-
zoic acid~ supercel (570 g.) and xylene (about 2200 ml.)
is stirred and about 300 ml. of xylene is distilled off.
After cooling9 570 g. of phosphorus pentoxide is added along
with sufficient dry xylene to facilitate stirring. This
mixture is stirred at reflux for 17 hours, cooled and fil-
teredO The filter cake is washed well with xylene 9 then
with ether. The filtrates are combined and concentrated
.0 to an oil which crystallizes on trituration with hexane
yielding 9-chloro-ll-keto-6911-dihydrodibenzo[bJe]oxepine9
m.p~ 82-83C.
To the Grignard reagent obtained from 4-chloro-N-
methylpiperidine (0.70 mol) and magnesium (0,54 mol) in
tetrahydrofuran is added 0.38 mol of the above oxepinone
in 750 ml~ of tetrahydrofuran at a rate sufficient to main-
tain a gentle reflux~ The mixture is refluxed for about
90 minutes and stirred at room temperature overnight. The
reaction mixture is poured over ice, treated with ammonium
chloride and extracted several times with ether. The
- 24 -
lQ5~5~45
l combined ether fractions are dried and concentrated to give
9 chloro~ methyl-4-piperidyl)-6~11-dihydrodibenzo-
[b9e]oxepine-11~019 hydrochloride salt9 m.p. 150-160C,
The above oxepinol (0.5 mol) is stirred with
o~sulfobenzoic anhydride (1O15 mol) and propionic acid
~3400 ml.~O The mixture is heated on a ste~m bath for
one hourg cooled9 basified and extracted with methylene
chloride. The organic extract i5 dried and concentrated
in vacuo to an oil which is chromatographed on silica gel
eluted with chloroform. The collected oil crystallizes
when triturated with petroleum ether to yield 4-(9-chloro-
11(6H)-dibenz[b9e]oxepinylidene)-l-methylpiperidine9 mqpO
145-146C.~ hydrochloride salt9 m.p. 289C~ (dec.)O
EXAMPLE 14
A solution of cyanogen bromide (14.1 g.g 0.133
mol) in benzene (200 ml) at 35C~ is treated with a solu-
tion of 4-(2-chloro-9-xanthenylidene)-1-methylpiperidine
(31~2 g.9 OolO mol) in benzene (250 mlO) over 15 minutesO
The solution is heated to 55C. for four hours. The sol-
-~7~ vent is evaporated and the residue is recrystallized from
ethanol to give 4-(2-chloro-9-xanthenylidene)-1-cyanopiperi-
dine9 mqp~ 148-150C. A solution of the latter (27.2 gO 9
0O084 mol) in glacial acetic acid (450 ml.)9 water (250 ml.)
and concentrated hydrochloric acid is refluxed for 18 hours9
and the major portion of the solvent is evapo ated. The
residue is basified and extracted with ethylacetate. The
extracts are washed with water and the solvent evaporated.
The residue is triturated with ethanol~ filtered and the
filtrate is evaporated to leave 4-(2-chloro-9-xanthenyli-
dene)piperidine, The free base is dissolved in acetonitrile
- 25 -
~055945
l and treated with one equivalent of methanesulfonic acid
to yield 4-(2-chloro-9-xanthenylidene)piperidine methane-
sulfonate9 m.pO 256-260Co
EXAMPLE 15
.
A solution of 4-(2-chloro-9-xanthenylidene)piperi-
dine (1.5 gO 9 5 mmol) in 50 ml. of methanol at 0C. is
treated with ethylene oxide (5 mlO~. The solution is
allowed to come to 23Co 9 then heated to 40C. for one
hour and the solvent evaporatedO The residue is dissolved
in acetonitrile and treated with one equivalent of methane-
sulfonic acid to give 4-(2-chloro-9-xanth~nylidene)-1-
(~-hydroxyethyl)-piperidine methanesulfonate9 m.p. 242-244C~
EXAMPLE 16
A solution of 4-(2-chloro-4-xanthenylidene)-
lS piperidine (3.8 g., 12.8 mmol) and 2 ml. of triethylamine
in 75 ml. of benzene is treated with a solution of cyclo-
butylcarboxylic acid chloride (1.9 g., 16 mmol) in benzene
(25 mlO)O After two hours at 23C. the mixture is washed
with water, lN hydrochloric acid and 5% potassium carbonateO
?0 The organic solution is dried and evaporated to leave the
intermediate amideO A solution of the amide (4.95 g.) in
75 mlO of ether is added to a stirred slurry of lithium
aluminum hydride (3.0 g.) in ether (30 mlO)O ~he mixture
is refluxed for six hours and stirred at 23Co for two days~
Excess hydride is decomposed by the cautious addition of
6 ml. of water and 4.8 ml. of 10% sodium hydroxide and the
solid is filtered. The filtrate is treated with ethereal
hydrogen chloride and the precipitated salt is dissolved
in a mixture of water and benzene. The water is separated 9
washed with ether, basifiedg and extracted with ether.
- 26 -
1055945
1 The dried extract is evaporated and the residue is chroma-
tographed on an alumina column, eluting with ether. The
first fraction is evaporated to give 4-(2-chloro-9-xanthen-
ylidene)-l-cyclobutylmethylpiperidine. A solution of the
free base in acetonitrile is treated with one equivalent of
methanesulfonic acid to obtain the methanesulfonate salt9
m.p. 196-l97C.
EXAMPLE 17
A mixture of 4-(2-bromo-9-xanthenylidene)-1-methyl-
piperidine (7.0 g. 9 19.7 mmol), cuprous cyanide (3.5 g.)~
cupric sulfate pentahydrate (50 mg.) and sodium cyanide
(50 mg.) in 60 ml. of dimethylformamide is refluxed for
18 hours. The reaction mixture is poured into 10% aqueous
sodium cyanide (500 ml.) and extracted with ether. The
extract is washed with 10% aqueous sodium cyanide, water,
dried and the solvent is evaporated. The residue is
chromatographed on an alumina column, eluting with ether.
The second fraction gives the product as an oil which is
dissolved in ethanol and treated with one equivalent of
fumaric acid, yielding 4-(2-cyano-9-xanthenylidene) 1-
methylpiperidine ~umarate, m.p. 238-241C. (dec.).
EXAMPLE 18
A solution of 4-(2-chloro-9-xanthenylidene)piperidine
(2.0 g.9 6.75 mmol) in 5 ml. of acetic anhydride is heated
on a steam ba~h for 2.5 hours Acetone (30 ml.) and 50 ml.
of 20% aqueous potassium carbonate is added to the cooled
solution and the mixture stirred for one hour. Additional
water is added and the mixture is extracted with ether.
The extract is washed with lN hydrochloric acid, water and
dried. The solvent is evaporated to give the crude amide,
2.2 g. (recrystallized amide m.p. 165-166C.). The amide
is dissolved in 500 ml. of ether and added to a
- 27 -
1055945
1 stirred suspension of 2.0 g. of lithium aluminum hydride
in 200 ml. of ether. After two hours at 23C. excess
hydride is decomposed with water (4 ml.) and 10% sodium
hydrixode (3.2 ml.). The mixture is filtered and the fil-
trate is evaporatedO The residue is dissolved in a mixture
of methanol and ether and treated with one equivalent of
methanesulfonic acid~ The precipitated salt is filtered
and recrystallized from methanol/ether to give 4-(2-chloro-
9-xanthenylidene)- l-ethylpiperidine methanesulfonate,
m.pO 249-252~C.
EXAMPLE 19
A solution of 4-~2-chloro-9-xantherYlidene)-
piperidine (3~2 g., 10.8 mmol) and propyliodide (5 ml.) in
dimethylformamide (25 ml.) is stirred at 23C. for three
hours and at 100C. for one hour. The reaction mixture is
diluted with water and extracted with ether. The extract
is washed with water, dried and the solvent evaporated.
The residue is chromatographed on an alumina column9 using
ether as the eluent. The first fraction gives the product
which is con~rerted to the hydrochloride salt: 4-(2-chloro-
9-xanthe~ylidene) - l-propylpiperidine hydrochloride, m.pO
238-240~.
EXAMPLE 20
A mixture of 4.4 g. of 4-fluoroanthranilic acid
in 35 mlO of water and 7 ml. of hydrochloric acid is
diazotized with 2.0 g. of sodium nitrite in 6 ml. of water
at 0-5C. The resulting cold solution is added dropwise
to a mixture of 7.1 g. of potassium iodide, 2 ml. of sul-
furic acid and 10 ml. of water. The mixture is heated for
two hours to 100C. and steam distilled. The cooled
- 28 -
1055~45
1 residue gives 4-fluoro-~-iodobenzoic acid, m.p. 140-147 C.
A mixture of 4.7 g. of the above prepared benzoic
acid9 1.93 g. of thiophenol, 3.62 g. of potassium carbonate
and a catalytic amount of copper powder is stirred for one
hour with 50 ml. of nitrobenzene at 160-165C. The cooled
reaction mixture is poured into 100 mlO of water, strongly
acidified9 and extracted with chloroform. The extract is
washed with water, decolorized with charcoal and filtered.
The filtrate is extracted with 5% sodium bicarbonate solu-
tion. Acidification of the aqueous solution, followed by
extraction with ether and subsequent evaporation of the
dried extract yields 4-fluoro-2-(phenylthio)benzoic acid9
m.p. 193-200C.
This benzoic acid (3 g.) is heated for one hour
on a steam bath with 45 g. of sulfuric acid. The solution
is poured onto ice, filtered and the solid is washed with
water, then stirred with 5% sodium bicarbonate solution.
The solid is filtered, washed with water and dissolved in
chloroform. Evaporation of the dried chloroform solution
furnishes 3-fluoro-9-thioxanthone, m.p. 168C.
The Grignard reagent prepared from 0.62 g. of
magnesium turnings and 3.5 g. of 4-chloro-N-methylpiperi-
dine in tetrahydrofuran is treated with a solution of
3-fluoro-9-thioxanthone (3.0 g.) in 50 ml. of tetrahydro-
furan. The mixture is refluxed for four hours, cooled~
treated with saturated ammonium chloride solution and ex-
tracted with ether. The ethex extract is washed with water,
dried and concentrated to give 3-fluoro-9-(1-methyl-4-
piperidyl)-thioxanthene-9-ol, m.p. 120-130C.
- 29 -
105S9~5
1 The thioxanthene-9-ol (3.2 g.) is dehydrated by
refluxing for one hour with 3.68 g. of o-sulfobenzoic
anhydride and 60 ml. of propionic acid. The cooled reaction
mixture is poured into a mixture of ice and 40% sodium
hydroxide solution, then extracted with ether. The dried
extract is decolorized with charcoal, concentrated and the
residue9 dissolved-in ether, is treated with maleic acid
to yield 4-(3-fluoro-9-thioxanthenylidene)-1-methylpiperi-
dine maleate, m.p. 162-164C.
Similarly, 2-fluoro-9-thioxanthone (5.0 g.) is
reacted with the Grignard reagent derived from 1.06 g. of
magnesium turnings and 5.85 g. of 4-chloro-N-methylpiperi-
dine in tetrahydrofuran as described above to give the
corresponding 2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-
9-ol, m.p. 189-190C. The latter is dehydrated by the same
procedure to obtain 4-(2-fluoro-9-thioxanthenylidene)-1-
methylpiperidine as the maleate salt, m.p. 175-179C.
EXAMPLE 21
To a solution of 1.28 g. (0.01 mol) of p-fluoro-
~- thiophenol and 2.82 g. (0.01 mol) of 2-iodo-4-chlorobenzoic
acid in 20 ml. of pyridine is added 1.3 g. (0.01 mol) of
potassium carbonate, ~ith stirring. Additional pyridine is
adde~ until solution is clear and then 0.3 g. of cuprous
chloride is introduced. The resulting mixture is refluxed
overnight, poured into ice-water, stirred and filtered.
The aqueous solution is acidified and filtered. The solid
is dissolved in 5% sodium bicarbonate solution and this
solution is extracted with ether. The aqueous solution is
acidified, extracted with ether and the washed, dried
extract is concentrated to give 4-chloro-2-(4-fluorophenyl-
- 30 -
lO5SS~45
1 thio~benzoic acid, m.p. 204-213C. The latter (6.5 g.,
0.023 mol) is heated for one hour with 105 g. of sulfuric
acid to obtain 2-fluoro-6-chloro-9-thioxanthone, m.p. 222-
224C.
The Grignard reagent prepared from 5.9 gO (0.044
mol) of 4-chloro-N-methylpiperidine and l.l g. (0.044 mol)
of magnesium turnings in tetrahydrofuran is treated with
5.8 g. tO.022 mol) of the above-prepared thioxanthone. The
mixture is refluxed for four hours and worked up by the
usual procedure to yield 6-chloro-2-fluoro-9-(1-methyl-4-
piperidyl)-thioxanthene-9-ol, m.p. 133-142C.
Dehydration is accomplished by heating 6.4 g.
(0.018 mol) of the above thioxanthene-9-ol for one hour
with 6.5 g. (0.035 mol) of o-sulfobenzoic anhydride in
100 ml. of propionic acid. Workup of the reaction mixture
affords 4-(6-chloro-2-fluoro-9-thioxanthenylidene~ l-methyl-
piperidine, isolated as the hydrochloride salt, m.p. 264-
265C.
EXAMPLE 22
~ Following the procedures outlined in Example 21,
10.7 g. (0.038 mol) of 2-iodo-4-chlorbenzoic acidg 4~3 g.
(0.038 mol) of 4-fluorophenol 5.25 g. (0.038 mol) of
potassium carbonate and 1.14 g. of cuprous chloride in
180 ml. of pyridine are heated under reflux overnight to
give upon workup 4-chloro-2-(4-fluorophenoxy)-benzoic acid9
154-173C. Heating the acid (5.0 g., 0.019 mol) for one
hour with 75 g. of sulfuric acid yields the corresponding
2-fluoro-6-chloro-9-xanthone, m.p. 210C.
Reaction of the xanthone (4.9 g. J 0.0197 mol)
with the Grignard reagent derived from 5.3 g. (0.039 mol)
1055945
1 Of 4-chloro-N-methylpiperidine and 0.95 g. (0.039 mol)Mg
in tetrahydrofuran furnishes upon workup 6-chloro-2-fluoro-
9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 107-127C.
The xanthene-9-ol (1.7 g., 0.0049 mol) is dehy-
drated by heating for one hour with o-sulfobenzoic anhy-
dride (1.8 g. 9 0.0098 mol) in 35 mlO of propionic acid.
The product is isolated as its hydrochloride sal~9 4-(6-
chloro-2-fluoro-9-xanthenylidene)-1-methylpiperidine hydro-
chloride, m.pO 235~.
EXAMPLE 23
To a solution of 3.28 g. (0.0256 mol) of p-fluoro
thiophenol and 6.8 g. (0.0256 mol) of 2-iodo-4-fluoroben-
zoic acid in 40 ml. of pyridine is added 3.54 g. (0.0256
mol) of potassium carbonate at room temperature with
stirring. Additional pyridine is added to dissolve the
precipitate and then 1.54 g. of cuprous chloride is added.
The mixture is refluxed overnight, cooled, poured into ice-
water, stirred and filtered. The aqueous solution is
acidified, filtered and the solid dissolved in 5% sodium
bicarbonate solution, then extracted with ether. The
aqueous solution is acidified, extracted with ether 9 and
the dried extract is concentrated to give 4-fluoro-2-(4-
fluorophenylthio)benzoic acid, m.p. 209-218C. The latter
(3.0 g., 0O0113 mol) is cyclized by heating for one hour
with 45 g. of concentrated sulfuric acid to obtain 2,6-
difluorothioxanthone, m.p. 205-210C.
The Grignard reagent prepared from 2.7 g. (0.02
mol) of 4-chloro-N-methylpiperidine and 0.5 g. (0.02 mol)
of magnesium turnings in tetrahydrofuran is treated with
2.5 g. (0.01 mol) of 2,6-difluorothioxanthone at a rate
~O5 ~ 45
1 to maintain slow reflux. The mixture is refluxed for 8iX
hours, hydrolyzed with saturated ammonium chloride solution
and extracted with ether to yield 2,6-difluoro-9~ methyl-
4-piperidyl)-thioxanthene-9-ol, m.p. 207-209C~
The thioxanthene-9-ol (2.6 g.g 0.0075 mol) pre-
pared as above is heated with 2.8 g. (0.015 mol) of o-sulfo-
benzoic anhydride in 80 mlO of propionic acid. The product
is isolated by the usual procedure to give 4-(2,6-difluoro-
9-thioxanthenylidene)-1-methylpiperidine, m.p. 120-123C.
EXAMPLE 24
Sodium hydride (0.1 mol) is suspended in 60 ml.
of dry dimethylformamide and 0.1 mol of 3-chlorophenol in
about 60 ml. of dimethylformamide is added dropwise main-
taining the temperature at 25C. When hydrogen evolution
is completed, 0.1 mol of phthalide in about 60 ml. of
dimethylformamide is added slowly at 25C. The mixture is
refluxed for two hours, stirred at room temperature over-
night, poured into ice-water and extracted with ether. The
aqueous fraction is acidified with concentrated hydrochloric
acid and extracted with ether. The combined ether fraction
is dried and concentrated to give 2-(3-chlorophenoxymethyl)
benzoic acid, m.p. 154-155C.
Following the procedure of Example 13, the above
prepared benzoic acid is cyclized with phosphorus pentoxide
in xylene to furnish 3-chloro-11-keto-6,11-dihydrodibenz-
[bge]oxepine, m.p. 105-106C.
To the Grignard reagent prepared from 0.54 mol
of magnesium and 0.7 mol of 4-chloro-N-methylpiperidine in
tetrahydrofuran is added 0.38 mol of the ll-keto dibenzo-
xepine prepared above in tetrahydrofuran. The mixture is
- 33 -
~5~.~45
1 refluxed three hours, stirred at room temperature over-
nightJ poured into ice-water, treated with ammonium chloride
and extracted with ether. The ether extract is dried and
concentrated in vacuo to yield 3-chloro~ (1-r,lethyl-4-
piperidyl)-6911-dihydrodibenz[b9e]oxepine-ll-ol 9 m~p~ 199-
200C.
A mixture of 0.1 mol of the above oxepinol and
0.2 mol of o-sulfobenzoic anhydride in about 1200 ml. of
propionic acid is stirred on a steambath for about 45 min-
utes. Thè cooled reaction mixture is poured over ice~
basified with 30% sodium hydroxide solution and extracted
with chloroform. The dried extract is concentrated to give
4-(3-chloro-11(6H)-dibenz[b,e]oxepinylidene)-l-methylpiperi-
dine, m.p. 113-116C.
EXAMPLÆ 25
A mixture of 5.0 g. (13.5 mmol) of 4-(2-bromo-9-
thioxanthenylidene)-l-methylpiperidine (prepared as in
Example 10) and 2.42 g. (27 mmol) of cuprous cyanide in
30 ml. of dimethylformamide is refluxed with stirring for
18 hours. The reaction mixture is poured into 10% aqueous
sodium cyànide and extracted with ether. The extract is
washed with water, dried and the solvent evaporated. The
residue is chromatographed over an alumina column using
ether as the eluent. The first fraction is evaporated9
the residue is dissolved in ethanol and the solution is
treated with one equivalent of fumaric acid to precipitate
4-(2-cyano-9-thioxanthenylidene)-1-methylpiperidine
fumarate salt, m.p. 211-215C.
EXAMPLE 26
A solution of 3.5 g. (11.8 mmol) of 4-(2-chloro-
9-xanthenylidene)piperidine (prepar~d as in Example 14) 9
- 34 -
~05~945
l 2.0 g. (13.4 mmol) of 3-bromo-1-propanol and 50 mg. of
potassium iodide in 50 ml. of dimethylformamide is stirred
at 23C. for 18 hours and 100C. for 12 hours. The reaction
mixture is poured into water, basified and extracted with a
mixture of ether and ethyl acetate. The extract is washed
with water~ dried and the solvent evaporated. The residue
is chromatographed on an alumina column using ethyl acetate-
ether 1:1 as the eluent. The first fraction yields the
product which is treated with ethereal hydrogen chloride to
give 4-(2-chloro-9-xanthenylidene)-1-(3-hydroxypropyl)-
piperidine hydrochloride, m.p. 255-258C.
EXAMPLE 27
A mixture of 2.0g. (0.0058 mol) of 4-(2-bromo-9-
xanthenylidene)piperidine (prepared as in Example 9),
0.89 g. (0.70 ml., 0.0065`mol) of n-butyl bromide and a
few crystals of potassium iodide in 15 ml. of dimethylform-
amide is heated at 90-95C. for 2.5 hours under argon. The
reaction mixture is poured into water, basified with sodium
carbonate and extracted with ether. The extract is washed
~0 with water, dried and evaporated to an oil which is
chromatographed ovei alumina with chloroform to give an
oil which is converted to a methanesulfonic acid salt of
the product 4-(2-bromo-9-xanthenylidene)-1-n-butylpiperi-
dine, m.p. l99-200C.
EXAMPLE 28
To a solution of 18.6 g. (0.176 mol) of cyanogen
bromide in 200 ml. of dry benzene at 50C. is added gradu-
ally over four hours a solution of 57.9 g. (0.168 mol) of
l-methyl-4-(2-trifluoromethyl-9-xanthenylidene)piperidine.
The reaction mixture is heated and stirred for 1.5 hours,
- 35 -
~ OS 59 4 S
1 excess water is added and the benzene solution is extracted
with excess dilute acetic acid. The acetic acid extract is
washed with water and the benzene solution is evaporated to
give the l-cyano intermediate. The latter (20 g. 9 0.0561
mol) is refluxed for 18 hours with a solution of 420 ml. of
acetic acid9 280 ml. of water and 42 ml. of concentrated
hydrochloric acid.- The reaction mixture is concentrated
in vacuo to about 125 ml., diluted with 400 ml. of water and
extracted with ether. The aqueous layer is basified with
excess sodium hydroxide solution and the mixture is ex-
tracted with ether. Concentration of the ether extract
yields 4-(2-trifluoromethyl-9-xanthenylidene)piperidine.
A mixture of 4.0 g. (0.0121 mol) of the above
prepared piperidine and 15 ml. of butyric anhydride is re-
fluxed 2-3 hours. The reaction mixture is cooled, washed
and stirred with an excess of 20% aqueous potassium car-
bonate-acetone for three hours. This mixture is extracted
with ether and azeotroped with toluene. The crude amide
(5.0 g.) is dissolved in 30 ml. of ether and gradually
added to 0.9 g. (0.025 mol) of lithium aluminum hydride in
100 ml. of ether, with stirring. The mixture is stirred at
room temperature over~ight, decomposed with 1.8 ml. of
water added slowly and filtered. The solid is treated with
ethereal hydrogen chloride to give l-n-butyl-4-(2-trifluoro-
methyl-9-xanthenylidene)piperidine hydrochlorideJ
m.p. 251-252C.
EXAMPLE 29
A solution of 4-(2-chloro-9-xanthenylidene)-1-
methylpiperidine in acetonitrile is treated with one
equivalent of methanesulfonic acid to give the corresponding
methanesulfonate salt, m.p. 225-228C.
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