Note: Descriptions are shown in the official language in which they were submitted.
; :
HOE 76/F 249
la7~3~7
This invention relates to benzoylpiperidylalkylindoles
and related compounds possessing tranquilizing properties
and to a process for the preparation thereof. Additionally,
some compounds of the invention also demonstrate anti-
hypertensive and analgesic properties.
To the best of our knowledge, the compounds of the
present invention have not heretofore been described.
Indoles exhibiting action on the cardiovascular system are
mentioned in United States Patent 3,527,761 (1970). United
States Patents 3,188,313 (1965) and 3,217,011 (1965)
' describe 1-(1,2 and 3-indolyl)-lower piperazine derivatives
and 1-(indolylglyoxalyl)piperidines, respectively as having
important biological activity. Additionally, United States
Patent 3,821,387 (1974) describes 3-(omega-substituted alkyl)-
indoles as being useful in the treatment of Parkinsonism.
However, the compounds of the present invention have
substantial structural differences with respect to the prior
art.
The compounds of the invention conform to the general
formula
CH~)n-~2- \ ~ ( ~ R
4 H :~
~J :.
.. .. .
` HOE 76/F 249
iO7t~3~7
wherein X is C=O or CHOH; R is hydrogen or methyl; R1 and
R2 are the same or different and stand for hydrogen, halogen,
straight or branched chain alkyl of up to 5 carbon atoms,
alkoxy of up to 5 carbon atoms, trifluoromethyl, hydroxy,
phenoxy or phenyl; R3 and R4 are hydrogen or methoxy; n is
the integer 1 or 2; and the acid addition salts thereof
prepare from pharmaceutically acceptable acids.
Acids useful for preparing the acid addition salts of
the invention include inorganic acids such as hydrochloric,
hydrobromic, sulfuric, nitric, phosphoric and perchloric acids,
as well as organic acids such as tartaric, citric, acetic,
succinic, maleic, fumaric and oxalic acids.
The compounds of the invention are prepared by either
of the two sequences of reactions described below wherein
R, R1, R2, R3, R4 and n are as defined earlier. The starting
compounds, the 4~xnzoyl-piperidines, are prepared from
N-acetylisonipecotic acid or from 1-acetylisonipecotamide
by the methods described by Robert L. Duncan, Jr. et al.,
J. Med. Chem. 1, 1, (1970~.
The 4-(hydroxybenzoyl)piperidines are prepared by a
somewhat different method. The N-acetyli~nipecotic acid
chloride is reacted with an alkoxy substituted benzene under
Friedel-Crafts condition to give a 1-acetyl-4-(alkoxybenzoyl)-
piperidine. The reaction of this piperidine with hydrogen
bromide produces hydrolysis of the acetyl group and
dealkylation of the alkoxy group, giving a corresponding
4-(hydroxybenzoyl)piperidine.
Additionally, a benzoylpiperidine can be prepared
` by the three step method outlined below.
-- 2
, :. : ", : ,
HOE 76/F 249
~78387
1. A 4-benzoyl-1-methylpiperidine is produced by the
reaction of a benzonitrile of the formula
NC~
1`2
with a Grignard reagent prepared from N-methyl-4-chloropiperidine
at a temperature of from 15 C.to the boiling point of the
solvent, if any, for from 1 to 15 hours. One preferred
method utilizers tetrahydrofuran as the solvent and allows
the mixture to react at reflux for 2 hours and then at
ambient temperature overnight.
2. The reaction of an above piperidine with a
substituted chloroformate such as phenylchloroformate
or an alkylchloroformate in the presence of an organic solvent
such as methylene chloride or toluene at a temperature of
from ambient to the boiling point of the solvent for from a
few minutes to 12 hours produces N-carbonyl compound of
the formula
O ~ ~ O; ~ R
wherein Y is phenyl or alkyl. A preferred chloroformate
is phenylchloroformate.
3. A benzoylpiperidine is prepared by cleaving the
carbonal moiety from the above N-carbonyl compound. A
preferred method of cleaving is carried out by dissolving
an N-carbonyl compound in an aqueous solution of 30 - 50 %
potassium hydroxide and an organic solvent such as ethanol
~. :
HOE 76/F 249
1078387 ---
and permitting the solution to react at a temperature of
from ambient to the boiling point of the solvent for from
1 hour to 60 hours.
METHOD I
A. A sample of 3~ bromoalkyl)indole is reacted with
a 4-benzoylpiperidine of the formula
~ ,~ ';1
in the presence of a suitable organic solvent such as
dimethylformamide, n-butanol, or dimethylsulfoxide, with or
without an acid scavenger such as potassium carbonate,
triethylamine or sodium bicarbonate, at a temperature of from
about 20 C to the boiling point of the solvent for from
30 minutes to 120 hours to give a compound of the invention
of the formula
U ~ C 2) -C~2-N ~ C~ ]
4 ll
B. These benzoylpiperidylalkylindoles can be reduced to
give a compound of the invention of the formula
~ ~ ~~ ) ()H ~ R
In one preferred method, sodium borohydride is utilized as
~' the reducing agent.
-- 4
.
HOE 76/F 249
1C~7838~
,
METHOD II
A. A sample of an indole of the formula -~
E3 - k~l ~ R
in a solvent such as anhydrous ether is allowed to react
with oxalyl chloride at a temperature of from -15 to 15 C
for from a couple of minutes to one hour to produce a mixture
of a corresponding 3-indoleglyoxyloyl chloride in the solvent
which is then added to a cooled solution of 4-benzoylpiperidine
in a suitable organic solvent such as chloroform optionally
containing an acid scavenger such as potassium carbonate and
allowing the mixture to react at a temperature of from 15 to
40C for a few minutes to 12 hours to produce a 4-benzoyl-1-
(indol-3-ylglyoxyloyl)piperidine of the formula
~ ~ - C -N ~ - C - ~ 1
B. An above (indol-3-ylglyoxyloyl)piperidine is
reduced to produce an arylhydroxymethylpiperidylethylindole
a compound of the invention of the formula illustrated in
Method I, step B in which n is 1. A preferred method utilizes
lithium aluminum hydride as the reducing agent, tetrahydrofuran
as a solvent, the boiling point of the solvent as the
reaction temperature and a reaction time of from a few minutes
to 5 hours.
The compounds of the invention are useful as tranquilizers
due to their depressant action on the central nervous system
-- 5
10783~7 HOE 76/F 249
of mammals. This activity is demonstrated in the mouse
observation procedure, a standard assay for central nervous
system depressants (Psychopharmacologia, 9, 259 (1966). Thus~
for example, the minimum effective dose (MED) at which
3- ~3-L4 - ( 4-fluorobenzoyl)piperidylJpropyl~indole hydrochloride
displays significant effects on behavior and reflex
depression together with musele relaxation is 1 mg/kg of body
weight. Similarly, MED's of other compounds are:
Compound MED
m
10 3-~2-~4-(4-fluorobenzoyl)piperidyl3ethyl~- 10
indole
3-[2-(4-benzoylpiperidyl)ethylJindole20
3-~2- L4 - ( 4-toluyl)piperidyl3ethy~ indole 40
Some compounds of the invention are also useful as
anti-hypertensive agents due to their ability to depress
blood pressure in mammals. Anti-hypertensive activity is
measured in the spontaneous hypertensive rate by the indirect
tail cuff method described in A. Schwartz, Ed., Methods in
Pharmacology, Vol. I, page 135, Appleton-Century-Crofts, New
York, New York 1971. In this procedure a group of five animals
are dosed orally with 100 mg of the compound per kg of body
weight in relating to a control group of the same number. The
antihypertensive activity in this test of some of the compounds
of the invention is illustrated in Table I. -
TABLE I
Compound Day 1 Day 3
mmHg mmHg
3-~2-(4-benzoylpiperidyl)ethyl~indole -53.8 -79.7
3-~2- t4 - ( 4-toluyl)piperidyl~ethyl~indole -63.6 -61.0
3-~2-L4-(4-~hlorobenzoyl)piperidyl~ ethyl~ indole -39.0 -67.8
3-~2-L4-(4-bromobenzoyl)piperidyl~ethyl~indole -15.8 -57.2
- 6 -
~783~7 HOE 76/F 249
Compounds of the invention are useful as analgesic
agents due to their ability to alleviate pain in mammals.
The activity of the compounds is demonstrated in the 2-phenyl-
1,4-benzoquinone-induced writhing test in mice, a standard
assay for analgesia (Proc. Soc. Exptl. Biol. Med., 95, 79
(1957)). For example at doses of 4.4, 11, 15, 20 and 35 mg/kg
of body weight, 3-~3-~4-(4-fluorobenzoyl)piperidyl~propyl~-
indole hydrochloride, 3-~2-L4-(4-toluyl~piperidylJethyl~indole,
3-~2- L4 - ( 4-fluorobenzoyl)piperidyl~ethyl~indole hydrochloride~
3-L2-(4-benzoylpiperidyl)ethyl~indole, and 3-~2-t4-(4-chloro-
benzoyl)piperidine]ethyl~indole, respectively, exhibit an
approximately 50 ~ inhibition of writhing.
The above date illustrates that the compounds of the
present invention are useful as tranquilizers and for the
treatment of hypertension and alleviation of pain when
administered to mammals at doses of from 0.1 to 100 mg/kg.
Examples of the compounds of the invention are: `
3-~2-C4-(4-hydroxybenzoyl)piperidyl~ethyl~indole;
3-{2-L4-(4-ethylbenzoyl)piperidylJethyl~indole;
3-{2-~4-(4-_-butylbenzoyl)piperidyl3ethyl~indole;
3-{2-[4-(4-ethoxybenzoyl)piperidyl~ethyl~indole;
3-~2-[4-(4-trifluoromethylbenzoyl)piperidyl~ ethylJindole;
3-{2-~4-(2-bromo-4-ethylbenzoyl)piperidylJethyl~indole;
3-~2-~4-(3,4-dichlorobenzoyl)piperidylJethyl3indole;
3-~2-~4-(4-chlorophenylhydroxymethyl)piperidylJethyl~-
indole;
3-~2-~4-t4-isopropylphenylhydroxymethyl)piperidylJethyl~ -
indole;
-- 7
.. :: : .. : . .
~783~7 HOE 76/F 249
5-methoxy-3-{3-L4-(3-methoxybenzoyl)piperidyl~propyl~-
indole; and
5,6-dimethoxy-2-methyl-3-~3-~4-(4-trifluoromethylphenyl-
hydroxymethyl)piperidyl3propyl~indole.
The compounds of the present invention may be administered
to a patient by a convenient route such as orally, intramuscu-
larly, intraveneously, subcutaneously or intraperitoneally. The
preferred route of administration is oral, for example, with
an inert diluent or with an edible carrier or in gelatin
capsules or tablets.
For the purpose of oral therapeutic administration, the
active compounds of this invention may be incorporated with
excipients and used in the form of tablets, troches, capsules
elixirs, suspensions, syrups, wafers, chewing gum, and the
like. These preparations should cont~in at least 0.5 % of
active compound, but may be varied depending upon the
particular form and may conveniently be between 7 % to about
70 % by weight of the unit. The amount of active compound in
such compositions is such that a suitable dosage will be
obtained. Preferred compositions and preparations according
to the present invention are prepared so that an oral dosage
unit form contains between 1 and 200 milligrams of active
compound.
The tablets, pills, capsules, troches, and the like may
also contain the following ingredients: a binder such as gum
tragacanth or gelatin; an excipient such as starch or
lactose, a disintegrating agent such as alginic acid, potato
starch and the like; a lubricant such as magnesium stearate;
~ and a sweetening agent such as sucrose or saccharin may be
- 8
- . . ... . .. .. ., , . , ~ . -, , . - . . -
., ~. : :: .i, .......... ,.. .. - ~ .... .. : . .
~,: , ' ' :
1~78387 HOE 76/F 249
added or a flavoring agent such as peppermint, methyl
salicylate, or orange flavoring. When the dosage unit form is
a capsule, it may contain, in addition to materials of the
above type, a liquid carrier such as a fatty oil. Other dosage
unit forms may contain other various materials which modify
the physical form of the dosage unit, for example, as coatings.
Thus, tablets or pills may be coated with sugar, shellac, or
both. A syrup may contain, in addition to the active compounds
sucrose as a sweetening agent, and certain preservatives, dyes
and colorings, and flavors. Materials used in preparing these
various compositions must be pharmaceutically pure and non-
toxic in the amounts utilized.
For the purpose of parenteral therapeutics administration,
the active compounds of the invention may be incorporated
into a solution of suspension. These preparations should con-
tain at least 0.1 % of active compound, but may be varied to
be between 0.5 and about 30 ~ of the weight thereof. The
amount of active compound in such compositions is such that
a suitable dosage will be obtained. Preferred compositions and
preparations according to the present invention are prepared
so that a parenteral dosage unit contains between 0.5 to 100
milligrams of active compound.
The solutions or suspensions may also include the follo-
wing components: a sterile diluent such as water for injection,
saline solution, fixed oils, polyethylene glycols, glycerine,
propylene glycol or other synthetic solvents; antibacterial
agents such as benzyl alcohol ~ methyl parabens; antioxidants
such as ascorbic acid or sodium bisulfite; chelating agents
such as ethylenediaminetetraacetic acid; buffers such as
: : .~" :: .: , :.: ~ .-
10783~7 HOE 76/F 249
acetates, citrates or phosphates and agents for the
adjustment of tonicity such as sodium chloride or dextrose.
The parenteral preparation can be enclosed in ampules,
disposable syringes or muItiple dose vials made of glass
or plastic.
The invention is further illustrated by the following
examples given for illustrative purposes.
E X A M P L E
A. A solution of 51.6 g of isonipecotic acid in 200 ml
of acetic anhydride is refluxed for 2 hours and allowed to
stir at ambient temperature for 16 hours. The solution is
concentrated and the resulting residue is triturated in ether.
The solid is collected by filtration and recrystallized from
an isopropyl alcohol-diisopropyl ether mixture giving 1-acetyl-
isonipecotic acid as a white solid.
B. ~ sample of 65.4 g of 1-acetylisonipecotic acid is
dissolved in 400 ml of thionyl chloride. The acid chloride
precipitates from solution and one liter of petroleum ether is
added. The mixture is filtered, the solid residue is washed
several times with petroleum ether and dried, giving 1-acetyl-
isonipecotoyl chloride as a white solid.
C. 70 g of 1-acetylisonipecotoyl chloride are slowly
added to a stirring mixture of 93.0 g of aluminum chloride in
150 ml of fluorobenzene. After total addition, the mixture is *
poured onto ice and the two resulting layers separate. The
aqueous layer is extracted twice with chloroform and the
extracts are added to the fluorobenzene which separated previous-
ly. The organic solution is dried and concentrated under
" reduced pressure leaving a crystalline white solid. The solid
*) refluxsd for one hour. The mixture is
- 10
., , ' ' . . ~ ' ' ,', . ` I ! ' '
'~, , ', .' ' '.'" "' ' ". ''' '' : ` '
': '."' ' :. ' . ' ''" ~
~0783~ 7 HOE 76/F 249
is recrystalli~ed from a ligroin-diisopropyl ether mixture,
producing 1-acetyl-4-(4-fluoro-benz~l)piperidine.
D. A solution of 70.6 g of 1-acetyl-4-(4-fluorobenzoyl)-
piperidine in 200 ml of 6N HCl is refluxed for 2 hours. The
cooled solution is extracted twice with ether, the aqueous
solution basified with sodium hydroxide and then extracted
with benzene. The benzene extracts are dried, filtered and
the filtrate is concentrated under reduced pressure. The
residual oil is dissolved in ether and HCl gas is bubbled into
the solution with stirring. The salt is collected by filtration5
washed with ether and dried. The salt is recrystallized from
isopropanol to give the solid product of 4-(4-fluorobenzoyl)-
piperidine hydrochloride, mp 222-224 C.
E. A stirred mixtrue of 10.1 g of 3-(2-bromoethyl)-
indole, 15.2 g of 4-(4-fluorobenzoyl)piperidine, and 15.0 g of
anhydrous potassium carbonate in 150 ml of n-butanol is
refluxed under nitrogen for three hours. The mixture is cooled,
filtered, and ether is slowly added to the filtrate to
precipitate a white solid, the starting piperidine, which is
removed by filtration. The solvent is removed under reduced
pressure, leaving a soft orange solid. The solid is dissolved
in absolute ethanol, the solution is cooled, and HCl gas is
bubbled into the solution. After standing about 5 minutes,
- the salt precipitates as off-white needles. The needles are
recrystallized from a methanol-ether mixture to give slightly
off-white needles, mp 267-269 C (dec.) of 3-{2-L4-(4-fluoro-
benzoyl)piperidyl] ethyl~ indole hydrochloride.Analysis:
` Calculated for C H FN O HCl: 68.29%C; 6.25%H; 7.24%N
~- Found: 68.08~C; 6.49%H; 7.32%N
1 1 _
,: - :: : : .
1~78387 HOE 76/F 249
By following the manipulative procedure of step E,
3-~2-L4-(3-trifluoromethyl)piperidyl]ethyl~indole is prepared
by substituting 4-(3-trifluoromethylbenzoyl)-piperidine for
4-(4-fluorobenzoyl)piperidine.
4-(3-trifluoromethylbenzoyl)piperidine is prepared in
the following manner: A solution of 102.5 g of 3-bromo-
benzotrifluoride in 25 ml of ether is added dropwise to a
stirring mixture of 11.5 g of magnesium turnin~s in 300 ml
of anhydrous ether to maintain a moderate reflux. After total
addition the resulting dark mixture is stirred for 1 hour at
ambient temperature. A solution of 60.0 g of 1-acetyl-4-
cyanopiperidine in 100 ml of tetrahydrofuran is slowly added
to this mixture and the mixture is stirred for 16 hours. An
excess of an aqueous solution of ammonium chloride is added
and the mixture is heated on a steam bath for 3 hours. The
mixture is allowed to cool, extracted with ~enzene and the
combined extracts are dried. The solvent is removed and the
residue is dissolved in ethanol and basified with sodium
hydroxide. The alkaline solution is refluxed for 3 hours,
cooled and extracted with benzene. The combined benzene
extracts are dried and the benzene is removed, leaving the
oil, 4-(3-trifluoromethylbenzoyl)piperidine, which is
converted to the hydrochloride, mp. 196-198 C.
E X A M P L E 2
A suspension of 2.8 g of 3-{2-L4-(4-fluorobenzoyl)-
piperidyl ethyl~indole, free base of Example 1(e), in
180 ml of isopropanol is added dropwise to a stirred
mixture of 102 g of sodium borohydride in 75 ml of
`~ isopropanol at 5 C. After total addition, the mixture
- 12
.. . -: :: : .. . ... : ;: :
. ~ .. , ~ . -: , . :
- . . - .. ~ : : :. . . . .
1~783~7 HOE 76/F 249
is permitted to reach ambient temperature, and is stirred
for 4.5 hours. The solution is poured into water, the
aqueous solution is extracted with methylene chloride, the
organic layer is dried, and the solvent is removed under
reduced pressure to give a yellow oil. The oil is stirred
vigorously in the presence of hexane, and is crystallized
to a white solid. The solid is recrystallized from acetonitrile
and then from an ethanol-water mixture to give a white powder,
mp 188-190C, of 3-~2-~4-(4-fluorophenylhydroxymethyl)-
10 piperidyl3ethyl~ indole.
Analysis:
Calculated for C22H25FN2O: 74.96%C; 7.15%H; 7.gs%N; s.39%F.
Found: 74.85~C; 7.22%H; 8.02%N; 5.05%F.
E X A M P L E 3
A. By following the manipulative procedures described
above in Example 1(c), and (d), 37.4 g of 1-acetylisonipecotoyl
chloride, (Example 1(b)) and 40 g of aluminum chloride
in 90 ml of chlorobenzene are reacted to produce 4-(4-chloro-
benzoyl)piperidine hydrochloride. The salt is recrystallized
thrice from an ethanol-ether mixture to give a white productJ
mp 233-235 C.
B. A solution of 13.0 g of 4-(4-chlorobenzoyl)-
piperidine hydrochloride, 10.7 g of triethylamine and 9.8 g
of 3-(2-bromoethyl)indole in 350 ml of dimethylformamide
is stirred at ambient temperature for 42 hours. Water is
added dropwise to the solution to precipitate a pale
yellow solid. The solid is collected washed with water
and dried. The solid is recrystallized from isopropanol
- to give off-white flakes, mp 174-176 C, of 3-~2-C4-(4-
- 13
. , . ......... . . . -, .
.
` 1~78387 HOE 76/F 249
chlorobenzoyl)piperidyl~ethyl~indole.
Analysis:
Calculated for C22H23ClN2O: 72.01%C; 6.31%H; 7.63~N; 9.66%Cl.
Found: 72.14%C; 6.26%H; 7.51%N; 9.76%Cl.
E X A M P L E 4
A. 32.0 g of 1-acetylisonipecotoyl chloride, Example 1(b)
are added portionswise to a stirred mixture of 45.3 g of
aluminum chloride, 28.3 g of bromobenzene and 120 ml of
ethylene dichloride. The solution is stirred overnight,
poured onto ice, the organic phase is collected, and the
aaueous layer is extracted with chloroform. The organic
solutions are combined, dried, and the solvent is removed
under reduced pressure to give a yellow oil which crystallizes
to a soft solid. The solid is triturated with ether, collected
and dried to give 1-acetyl-4-(4-bromobenzoyl)piperidine.
B. A sample of 30.9 g of 1-acetyl-4-(4-bromobenzoyl)-
piperidine is refluxed for 6 hours in 6N HCl, cooled, and
the resulting insoluble salt is collected. The salt is
recrystallized from an ethanol-ether mixture, then from
isopropanol to give off-white crystals, mp 225-227C,
4-(4-bromobenzoyl)pipexidine hydrochloride.
C. A sample of 14.6 g of 4-(4-bromobenzoyl)piperidine
hydrochloride is treated according to the manipulative
proo~hue described above in Example 3(b) to produce a yellow
solid. The solid is recrystallized from 95% ethanol(charcoal
treatment) and then from a toluene-cyclohexane mixture to
give an off-white solid, mp 178-180C, 3- ~-r4-(4-bromobenzoyl)-
piperidyl3ethyl~indole.
Analysis:
- 14
~: . . . . . . . . , , . . ;. . , : : . .
. : . , : . : : :: ::: : .: .: .:: .
,: . . :. . . . : . . :: ,. :, ' ,: ,, ~.. , " :
.. . . .. . .
~ HOE 76/F 249
1(1 783~7
Calculated for C22H23BrN2O: 64.23%C; 5.64~H; 6.81%N; 19.43%Br.
Found: 64.08%C; 5.55%H; 6.61%N; 19.34~Br.
E X A M P L E 5
A. By following the manipulative procedures described
above in Examples 1(c) and (d), 1-acetylisonipecotoyl chloride~
Example 1(b), toluene, and aluminum chloride are reacted to
produce 4-(4-toluyl)piperidine hydrochloride. The salt is
recrystallized thrice from a methanol-ether mixture (one
charcoal treatment) to give colorless needles, mp 275-277C
(dec.).
B. By following the manipulative procedure described
above in Example 3(b), 11.2 g of 4-(4-toluyl)piperidine, 6.1 g
of triethylamine and 11.2 g of 3-(2-bromoethyl)indole are trea-
ted to produce a white solid. The solid is recrystallized from
95% ethanol (charcoal treatment) to gi~e white flakes, mp 157.5-
159C, of 3-~2 -L4- ( 4-toluoyl)piperidylJethyl~indole.
Analysis:
Calculated for C23H26N2O: 79.72%C; 7.56%H, 8.08%N.
Found: 79.69%C; 7.55%H; 8.02%N.
E X A M P L E 6
_
A. By following the manipulative procedure described
above in Example 4(a), 32.0 g of 1-acetylisonipecotoyl
chloride, (Example l(b)) are added to a stirring solution
of 30.6 g of diphenylether and 45.3 g of aluminum chloride
in 100 ml of ethylene dichloride to produce a yellow oil
of 1-acetyl-4-(4-phenoxybenzoyl)piperidine.
B. A sample of 48.8 g of 1-acetyl-4-(4-phenoxybenzoyl)-
piperidine is refluxed for 6 hours in 6N HCl. Upon cooling
a white solid precipitateS from solution, is collected,
- 15
,
1~78387 HOE 76/F 249
washed with water, then acetone, and dried. The filtrate is
extracted with ether, the aqueous phase is basified with
sodium hydroxide and extracted with benzene. The benzene is
dried, and the solvent is removed under reduced pressure to
S give a solid which is converted to a hydrochloride. The salt
is recrystallized from an ethanol-ether mixture to give a
white solid, mp 219-220C, 4-~4-phenoxybenzoyl)piperidine
hydrochloride.
C. A solution of 10.3 g of 3-(2-bromoethyl)indole,
14.5 g 4-(4-phenoxybenzoyl)piperidine hydrochloride and
10 g of triethylamine in 350 ml of dimethylformamide is
treated according to the manipulative procedure described
above in Example 3(b) to produce a yellow solid. The solid
is recrystallized thrice from a benzene-hexane mixture (one
charcoal treatment) to give a pale yellow crystalline material,
mp 180C, of 3-~2-[4-(4-phenoxybenzoyl)piperidyl~ ethyl~ indole.
Analysis:
C28H28N2O2: 79.22~C; 6.65%H; 6.60%N
Found: 79.07~C; 6.65%H; 6.52~N.
E X A M P L E 7
A. A sample of anisole is treated according to the
manipulative procedu-res described above in Example 1(c)
and (d) to produce 4-(4-methoxybenzoyl)piperidine hydro-
chloride which, when recrystallized from isopropanol, had
a mp of 251-256C.
B. A solution of 11.4 g of 4-(4-methoxybenzoyl)-
piperidine, 10.1 g of 3-(2-bromoethyl)indole and 5.6 g
of triethylamine in 500 ml of dimethylformamide is
~ treated according to the manipulative procedure described
- 16
.~
,. ~ . . ; -, .: ,. : , , : :. ~
1~78387 HOE 76/F 249
above in Example 3(b) to produce a white solid. The solid is
recrystallized twice from 95% ethanol (one charcoal treatment)
to give silver-white flakes, mp 17S-177C of 3-~2-L4-(4-methoxy-
benzoyl)piperidylJethyl~indole.
5 Analysis:
Calculated for C23H26N2O2
Found: 76.27%C; 7.32%H; 7.83%N.
E X A M P L E 8
-
A. A sample of 18.0 of 1-acetyl-4-(4-methoxybenzoyl)-
piperidine, the intermediate of Example 7(a), is refluxed with
300 ml of 48 % hydrogen bromide under nitrogen for 4 hours.
The solution is permitted to stand for 16 hours at 5C~ causing
a white solid to precipitate. The solid is collected, washed
well with acetone and dried. Recrystallization from methanol
gives colorless needles, mp 273-275C, of 4-(4-hydroxybenzoyl)-
piperidine hydrobromide.
B. A mixture of 9.7 g of 4-(4-hydroxybenzoyl)piperidine
hydrobromide, 6.4 g of sodium bicarbonate and 7.0 g of
3-(2-bromoethyl)indole in 90 ml of dimethylsulfoxide is stirred
overnight under nitrogen at 50C. After cooling to ambient tem-
perature, water is added dropwise, precipitating a gummy
brown solid. The supernatant solution is decanted from the
solid, tritui^ated with water, collected, and dried. Recrystalli-
zation from an ethanol-water mixture gives an off-white solid
mp 212-214C (dec~ of 3-~2-~4-(4-hydroxybenzoyl)piperidyl~-
ethyl~indole
Analysis:
Calculated for C22H24N2O2:
; Found: 75.61%C; 6.85%H; 7.90%N.
17
~. , ,: : . . .: : , . :
. .
- HOE 76/F 249
``-` 1(~783~7
E X A M P L E 9
A. A sample of benzene is treated according to the -
manipulative procedures described above in Examples 1(c) and
(d) to produce 4-(benzoyl)piperidine hydrochloride. The salt
S is recrystallized from isopropanol to give a mp of 223-225C.
B. A solution of 10.4 g of 4-(benzoyl)piperidine, 6.1 g
of triethylamine and 11.2 g of 3-(2-bromoethyl)indole in 350 ml
of dimethylformamide is stirred at ambient temperature for
16 hours. Water is added dropwise, precipitating an off-white
solid. The solid is collected, washed with water and low
boiling petroleum ether, and dried. The solid is recrystallized
from 95% ethanol to give white flakes, mp 145-147C of
3-L2-(4-benzovlpiperidyl)ethyl~indole.
Analysis:
Calculated for C22H24N2~: 79.48%C; 7.28%H; 8.43%N.
Found: 79.51%C; 7.33%H; 8.49%N.
E X A M P L E_ 10
A. By following the manipulative procedure described above
in Example 4(a), 25 g of 1-acetylisonipecotoyl chloride are
added to stirred suspension of 25 g of aluminum chloride and
and 14 g of m-fluorotoluene in 220 ml of ethylene dichloride
to produce the oil, 1-acetyl-4-(2-fluoro-4-methylbenzoyl)-
piperidine.
B. A sample of 17.1 g of 1-acetyl-4-(2-fluoro-4-methyl-
benzoyl)piperidine is refluxed in 200 ml of 6N HCl for 24hours and then stirred for an additional 6 hours at ambient
temperature. The solution is extracted with ether, the aqueous
layer is basified with 6N NaOH, extracted with benzene, dried
and the solvent is removed under reduced pressure, leaving a
- 18
.. . ........... . . .............. ,... , . - :.
:.. .. ~. ,. - ..: . ,. .. .
- : , , :. : . ,; : ., . , : i : . -:
HOE 76/F 249
: ` 10783~7
yellow oil. The oil is added ethereal hydrogen chloride and
the resulting precipitate is collected, washed well with ether
and dried. The solid is recrystallized from a methanol-ether
; mixture to give the final solid product, mp 220-221C of
; 5 4-(2-fluoro-4-methylbenzoyl)piperidine hydrochloride.
C. A solution of 15.5 g of 3-(2-bromoethyl)indole,
17.5 g of 4-(2-fluoro-4-methylbenzoyl)piperidine hydrochloride
and 19 g of triethylamine in 500 ml of dimethylformamide is
stirred at ambient temperature for 64 hours. Water is
added dropwise, resulting in precipitate. The precipitate is
collected by filtration, washed well with water and dried.
The solid is recrystallized from a methanol-ether mixture and
from a benzene-hexane mixture to give off--~hite flakes,
mp 117-118C, of 3-~2-~4-(2-fluoro-4-methylbenzoyl)piperidyl~-
15 ethyl~indole.
Analysis:
Calculated for C23H25FNO2: 75.79~C; 6.92%H; 5.21%F; 7.6g~N.
Found: 75.96%C; 7.07%H; 5.15~F; 7.57%N.
E X A M P_L E _ 11
A. A sample o~ o-xylene is treated according to the
manipulative procedures described above in Example 1(c) to
give 1-acetyl-4-(3,4-dimethylbenzoyl)piperidine.
B. A sample of 21.3 g of 1-acetyl-4-(3,4-dimethylbenzoyl)-
piperidine is refluxed in 100 ml 95~ ethanol and 100 ml 35%
potassium hydroxide for 6 hours and then allowed to stir at
ambient temperature overnight. The aqueous layer is extracted
with benzene, the organic extracts are combined and dried.
The solvent is removed under reduced pressure leaving a yellow
oil. The oil is dissolved in ether and hydrogen chloride is
- 19
~ :: ,
HOE 76/F 249
1C~78387
bubbled into the solution. The resulting solid precipitate
is collected, washed well with ether and dried. The solid is
recrystallized thrice from an isopropanol-ether mixture to
give the salt, mp 258-259C, 4-(3,4-dimethylbenzoyl)piperidine
hydrochloride.
C. A solution of 9.6 g of 3-(2-bromoethyl)indole, 11.5 g
of 4-(3,4-dimethylbenzoyl)piperidine hydrochloride and 10.1 g
of triethylamine in 300 ml of dimethylformamide is treated
according to the manipulative procedure described in Example
3(b) to give an indole, which is purified on a silica gel
column, eluted with a 5 ~ methanol-benzene mixture and
recrystallized from an ethanol-water mixture to give the
solid, mp 172-173C, 3-~2-C4-(3,4-dimethylbenzoyl)piperidyl~ -
ethyl~indole.
15 Analysis:
Calculated for C24H28N2O: 79.96~C; 7.83~H; 7.77%N.
Found: 79.95%C; 7.90~H; 7.71%N.
E X A M P L E 12
A. 19.1 g of 1-acetylisonipecotoyl chloride, Example 1(b)
are added portionswise to a stirring suspension of 13 g of
~-butylbenzene and 27 g of aluminum chloride in 175 ml of
dichloroethane. The reaction mixture is refluxed for 1 hour,
cooled, and poured onto ice. The organic layer is separated
and the aqueous layer is extracted with chloroform. The organic
layers are combined, dried, and the solvent is removed under
reduced pressure leaving the oil, 1-acetyl-4-(4-t-butylbenzoyl)-
piperidine.
B. A sample of 27.6 g of 1-acetyl-4-(4-t-butylbenzoyl)-
piperidine is refluxed in 100 ml of ethanol and 100 ml of
- 20
~ . - . :,. :,,: , : ~ . :,. ..
1~783~7 HOE 76/F 249
35% aqueous potassium hydroxide for 6 hours, and then allowed
to stir~ambient temperature for 62 hours. The solution is
extracted with benzene, the benzene extracts are dried, and
the benzene is removed under reduced pressure leaving an oil.
The oil is dissolved in ether and hydrogen chloride gas iS
bubbled into the solution. The resulting beige precipitate is
collected and dried. The precipitate is recrystallized from
2-butanone to give the solid, mp 230-231C, 4-(4-t-butyl-
benzoyl)piperidine hydrochloride.
C. A solution of 9.4 g of 3-(2-bromoethyl)indole,
11.7 g of 4-(4-t-butylbenzoyl)piperidine hydrochloride and
9 g of triethylamine in 350 ml of dimethylformamide is treated
according to the manipulative procedure described in Example
3(b) to produce a yellow solid. The solid is recrystallized
from a methanol-water mixture (charcoal treatment) then twice
from a benzene-hexane mixture to give the off-white indole,
mp 173-174C, 3-~2-L4-(4-t-butylbenzoyl)piperidyl~ethyl~indole.
Analysis:
Calculated for C26H32N2O: 80.37%C; 8.30~H; 7-21%N-
Found: 80.15%C; 8.47%H; 7.07%N.E X A M P L E 13
A. 16.5 g of 1-acetylisonipecotoyl chloride, Example
1(b) are slowly added to a stirring mixture of 60 ml of
m-dimethoxybenzene and 20.0 g of aluminum chloride. Stirring
is continued for 1 hour at ambient temperature and then for an
additional 1 hour at about 100 DC . The reaction mixture is
allowed to cool to ambient temperature, poured into ice-water,
and extracted with chloroform. The combined extracts are
`- dried and the chloroform is removed leaving a yellow oil.
- 21
: . :: , ,, , , , . : :,, . , : .
.: : , ,.: ,... ,::. : ' .~ ,
HOE 76/F 249
1078387
The oil is triturated with hexane to effect a white solid
which is collected and dried. Recrystallization from ethyl
acetate yields colorless needles, mp 138-140C, 1-acetyl-4-
(2-hydroxy-4-methoxybenzoyl)piperidine.
Analysis:
Calculated for C15H19NO4: 64.96%C; 6.90%H; 5.05%N.
Found: 65.05%C; 6.98%H; 4.92%N.
B. A sample of 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)-
piperidine is treated according to the manipulative
procedure described above in Example 1(d) to give 4-(2-hydroxy-
4-methoxybenzoyl)piperidine.
C. A mixture of 4.0 g of 4-(2-hydroxy-4-methoxybenzoyl)-
piperidine, 3.3 g of 3-(2-bromoethyl)indole and 1.4 g of
sodium bicarbonate in 60 ml of dimethylsulfoxide is stirrea
at ambient temperature for 42 hours and at 60C ~or an
additional 6 hours. The reaction mixture is allowed to cool
; to ambient temperature and water is added dropwise to produce
a gummy, brown precipitate. The precipitate is collected and
triturated with ethanol to give a white solid which is
recrystallized twice from ethanol (one charcoal treatment)
to give silver-white flakes, mp 150-152C, 34 -~4-(2-hydroxy-4-
methoxybenzoyl)piperidyl~ethyl~indole.
Analysis:
Calculated for C23H26 2 3
Found: 73.23%C; 6.92%H; 7.32%N.
E X A M P L E 14
A. 18.7 g of 1-acetylisonipecotoyl chloride,
Example 1(b) are added slowly to a stirred mixture of
40.0 g of m-dimethoxybenzene and 19.2 g of aluminum chloride
- 22
10783~7 HOE 76/F 249
in 75 ml of carbon disulfide. The reaction mixture is
stirred at ambient temperature for an hour, poured into
ice-water and extracted with chLoroform, the combined extracts
are dried ànd the chloroform is removed, leaving a yellow oil.
The oil is trit~rated with ether to give a white solid,
which is recrystallized twice from ethyl acetate to
give the pure solid, m~ 132-134C, 1-acetyl-4-(2,4-dimet~oxy-
benzoyl)piperidine.
Analysis:
Ca cu ate o C16 21NO4: 65.95%C; 7.26%H; 4-80%N-
Found: 65.86%C; 7.30%H; 4.63%N.
B. By following the manipulative procedure described
above in Example 1(b), 7.4 g of 1-acetyl-4-(2,4-dimethoxy-
benzoyl)piperidine in 250 ml of 6N HCl are treated to give
a hydrogen chloride salt which is recrystallized once
from an ethanol-ether mixture and twice from ethanol
to give the compound, mp 198-200C, 4-(2,4-dimethoxy-benzoyl)-
piperidine hydrochloride.
Analysis:
Calculated for C14H19NO3HCl: 58.84%C; 7.05%H; 4.90%N; 12.41%Cl.
Found: 58.97~C; 7.02%H; 5.11%N; 12.54%Cl.
C. To a stirring solution of 8.0 g of 4-(2,4-dimethoxy-
benzoyl)piperidine hydrochloride and 6 ml of triethylamine in
250 ml of dimethylformamide is added a solution of 6.4 g of
3-(2-bromoethyl)indole in 50 ml of dimethylformamide. The
reaction mixture is permitted to stir at ambient temperature
for 72 hours and then 500 ml of water is added dropwise and
extracted with chloroform. The combined extracts are dried
- and most of the chloroform removed leaving a dark oil.
- 23
. . , -: .,
:' ' . -.,,,' '' :.: : ,.
', .~:,, . . ' :,
107~387 HOE 76/F 249
The oil is subjected to column chromotography on a silica gel
column and eluting with a 3% methanol in chloroform solution
to give 3-~2- ~4-(2,4-dimethoxybenzoyl)piperidyl~ethyl~ indole.
The indole is recrystallized thrice from an ethanol-water
5 mixture to give the pure indole, mp 110-112C.
Analysis:
24 28 2 3 C; . ; ~ -
Found: 73.4296C; 7.31%H; 7.18%N.
E X A M P L E 15
A. A few drops of ethyl bromide are added to a stirring
suspension, under nitrogen, of 3.2 g of magnesium turnings
in 10 ml of tetrahydrofuran. After a reaction begins, 17.7g
of N-methyl-4-chloropiperidine in 50 ml of tetrahydrofuran are
added dropwise while maintaining a moderate reflux. After total
15 addition, the reaction mixture is heated at reflux for 1 hour
and 15.2 g of 3-tolylnitrile in 10 ml of tetrahydrofuran are
slowly added. After this addition is complete the reaction
mixture is heated at reflux for an additional 2 hours and
then permitted to stir at ambient temperature for 16 hours.
20 The reaction mixture is poured into a solution of 35 g of
ammonium chloride in 500 ml of ice-water and heated on a steam
bath for 3 hours, cooled and extracted with benzene. The
combined benzene extracts are dried and most of the benzene
is removed, leaving an orange oil. The oil is dissolved in
25 ether and the oxalate salt is prepared by the addition of a
solution of anhydrous oxalic acid in isopropanol. The white
`~ oxalate salt is recrystallized twice from ethanol to give
the product, mp 183-185C, 1-methyl-4-(3-toluyl)piperidine
;~ oxalate.
-- 24
- - 107838~
HOE 76/F 249
Analysis:
Calculated for C14H19N-(CO2H)2: 62.53~C 6.89%H; 4.55%N.
Found: 62.32~C; 7.01%H; 4.52%N.
B. 18.8 g of phenylchloroformate are added dropwise
to a solution of 21.3 g of 1-methyl-4-(3-toluyl)piperidine
free base of the above, in 100 ml of methylene chloride
and the reaction mixture is stirred at ambient temperature
for 16 hours and the solvent removed leaving a dark brown
semisolid. The semisolid is suspended in 500 ml of lN
hydrogen chloride solution and extracted with ether. Some
of the desired material precipitates from the aqueous
phase and is collected. The ether extract is dried and
the ether removed under recuced pressure to give a brown
solid, which is stirred in a 50~ methanol-2% aqueous
potassium carbonate solution at ambient temperature for
16 hours. Filtration of the mixture provides more of the
desired product. The combined product is recrystallized
twice from an ethanol-water mixture to give the compound,
1-phenoxycarbonyl-4-(3-toluyl)piperidine, mp 127-130C.
Analysis:
r C12H21NO3: 74~28%C; 6.54%H; 4.33%N.
Found: 74.35%C; 6.62%H; 4.29%N.
C. A solution of 11.9 g of 1-phenoxycarbonyl-4-(3-toluyl)-
piperidine and 75 ml of an aqueous 50 % potassium hydroxide
solution in 300 ml of ethanol is heated at reflux for 24 hours
and then stirred at ambient temperature for an additional
36 hours. 100 ml of water are added, the ethanol is partially
removed, the resulting mixture is extracted with ether and
the combined ether extracts are extracted with 1N HCl. The
- 25
: . .,: , ,
1078387 HOE 76/F 249
aqueous solution is basified with an aqueous sodium hydroxide
solution, extracted with ether, the combined ether extracts
are dried, and the ether is removed, leaving a dark oil. The
oil is dissolved in ether and ethereal hydrogen chloride is
added to produce the salt which is collected by filtration,
dried and recrystallized thrice from an ethanol-water mixture
to give 4-(3-toluyl)piperidine hydrochloride, mp 196-197C.
Analysis:
Calculated for C13H17NOHCl: 65.13%C; 7.57%H; 5.83%N; 14.79%Cl.
Found: 64.90%C; 7.59%H; 5.73%N; 14.65~Cl.
D. 4.2 g of potassium carbonate are added to a stirred
solution of 3.8 g of 4-(3-toluyl)piperidine hydrochloride in
400 ml of dimethylformamide. The mixture is stirred at ambient
temperature for 1 hour and then a solution of 3.4 g of
3-(2-bromoethyl)indole in 100 ml of dimethylformamide is
introduced. The resulting mixture is stirred at ambient tem-
perature for 120 hours, filtered and 1.5 l of water added
dropwise to effect a precipitate. The precipitate is collected
and recrystallized thrice from ethanol (one charcoal treatment)
to give the indole, mp 171-173C, 3-2- ~ -(3-toluyl)piperidyl~ -
ethyl3indole.
Analysis:
Calculated for C23H26N2O: 79.93%C; 7.56%H; 8.09%N.
Found: 79.85%C; 7.71%H; 8.17%N.
25 E X A M P L E 16
A. By following the manipulative procedure outlined inExample 15~a), a sample of 2-fluorobenzonitrile is treated
to produce a hydrochloride salt which is recrystallized
~` twice from an ethanol-ether mixture to qive off-white crystals,
- 26
HOE 76/F 249
1078387
mp 167~169C, 4-(2-fluorobenzoyl)-~methylpiperidine
hydrochloride.
Analysis:
Calculated for C13H16FNO HCl: 60.58%C; 6.65~H; 5.43%N; 7.37%F.
Found: 60.30%C; 6.78%H; 5.43%N; 7.59%F.
B. 47.0 g of phenylchloroformate are added to a stirring
solution of 57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine
in 750 ml of toluene. The reaction mixture is refluxed for
5 hours, cooled to ambient temperature, filtered, and the
solvent is removed leaving a light colored oil. The oil is
triturated with hexane to give a crystalline material which
is recrystallized twice from an ethanol-water mixture and
once from ethanol to give the compound, mp 95-96C,
1-phenoxycarbonyl-4-(2-fluorobenzoyl)piperidine.
Analysis:
Calculated for C19H18FNO3: 69.71%C; 5.54%H; 4.28~N; 5.18%F.
Found: 69.45%C; 5.67~H; 4.13%N; 6.10%F.
C. A solution of 40.5 g of 1-phenoxycarbonyl-4-(2-fluor
benzoyl)piperidine in 500 ml of ethanol and 500 ml of an
aqueous 30% potassium hydroxide solution is stirred at a
temperature slightly below reflux for 16 hours, allowed to
cool to ambient temperature, diluted with water, and the
ethanol is partially removed under reduced pressure. The
resulting aqueous suspension is extracted with ether, the
combined ether extracts are extracted with 1N hydrogen
chloride and the aqueous acid solution is basified with an
aqu~ous sodlum hydroxide solution. The basic solution is
extracted with ether, the combined ether extracts are dried
.~
and the ether is removed under reduced pressure leaving a
- 27
.
:: ' ' ` ..................... :
.. . .
HOE 76/F 249
10783~7
dark oil. The oil is dissolved in a minimum amount of ethanol
and ethereal-hydrogen chloride is added dropwise to effect a
precipitate. The precipitate is collected by filtration, dried
and recrystallized twice from an ethano~ether mixture to give
a white solid, mp 185-187C, 4-(2-fluorobenzoyl)piperidine
hydrochloride.
Analysis:
Calculated for C12H14FNO-HCl: 59.14%C; 6.20%H; 5.74%N; 7.80%F.
Found: 58.90%C; 6.36%H; 5.50%N; 7.56%F.
D. A solution of 9.1 g of 3-(2-bromoethyl)indole in
Z 100 ml of dimethylformamide is added to a stirring solution
of 11.2 g of 4-(2-fluorobenzoyl)piperidine hydrochloride
and 13 g of potassium carbonate in 400 ml of dimethylformamide.
' The reaction mixture is stirred at ambient temperature for
J 15 24 hours, and then 800 ml of water are added dropwise,
yielding a dark precipitate. This mixture is again stirred
at ambient temperature for 24 hours and filtered to give
a yellow crystalline material which is recrystallized thrice
from an ethanol-water mixture to give an off-white crystalline
material, mp 106-108C, 3-{2-~4-(2-fluorobenzoyl~piperidyl~-
ethyl~indole.
Analysis:
Calculated for C22H23FN2O: 75.40~C; 6.62%H; 7.gg~N.
Found: 75.41%C; 6.59%H; 8.03%N.
25 E X A M P L E 17
A solution of 11.8 g of 3-~2-bromoethyl)-2-methylindole~
20.3 g of 4~4-toluyl)piperidine (Example 5(a)) in 500 ml of
dimethylformamide is treated according to the manipulative
procedure described in Example 3(b) to give the off-white
- 28
-, :
: ~ , .. . ,. , .,, :
, , ::: . .. ..
HOE 76/F 249
10783~7
solid, mp 192-194C, 2-methyl-3-{2-L4-(4-toluyl)piperidylJ-
ethyl~ indole from ethanol.
Analysis:
Calculated for C24H28N2O: 79.96%C; 7.83~H; 7.77%N. ;
5 Found: 79.82%C; 7.80~H; 7.69~N.
E X A M P L E 18
A. By following the manipulative procedure described
in Example 1S(a), (b) and (c), 2-tolylnitrile is treated
to produce 4-(2-toluyl)piperidine hydrochloride.
B. To a stirring solution of 4.2 g of 4-(2-toluyl)-
piperidine hydrochloride and 4.0 g of triethylamine in
150 ml of dimethylformamide is added 3.8 g of 3-(2-bromoethyl)-
indole. The resulting solution is stirred at ambient tempera-
ture for 70 hours and stirring is continued while 500 ml of
water are added dropwise. An oil appears which is extracted
from the solution with chloroform, the combined chloroform
extracts are dried and the excess chloroform is removed,
leaving an oil which crystallizes upon standing. The solid
product is recrystallized from cyclohexane and then twice
from an ethanol-water mixture to give flakes, mp 111-112C,
3-l2-L4-(2-toluyl)piperidyl3ethyl~indole.
Analysis:
Calculated for C23H26N2O: 79.73%C; 7.56%H; 8.09~N.
Found: 79.83%C; 7.69%H; 8.14%N.
E X A M P L E 19
A solution of 8.8 g of 3-t2-bromoethyl)-S-methoxy
indole in 100 ml of dimethylformamide is added to a
stirring mixture of 4-(4-toluyl)piperidine hydrochloride
` (Example 5(a~) and 10.1 g of potassium carbonate in
- 29
HOE 76/F 249
107~3~7
400 ml of dimethylformamide and the reaction mixture is
stirred at ambient temperature for 80 hours and then at
50C for 10 additional hours. It is cooled to ambient
temperature, filtered, and 2 liters of water are added
dropwise to produce a precipitate. The precipitate is
triturated with ether and eluted with a 5 % methanol in
benzene solution through a silica gel co~umn. The
precipitate is recrystallized from an ethanol-water mixture to
give off-white crystals, mp 131-133C, 5-methoxy-3-~2-L4-'4-
toluyl)piperidyl~ ethyl~indole.Analysis:
Calculated for C24H28N2 2
Found: 76.36~C; 7.45~H; 7.19%N.
E X A M P L E 20
A. By following the manipulative procedures outlined
I in Examples 1(a), (b), (c) and (d), a sample of biphenyl
¦ is treated to produce 4-(4-phenylbenzoyl)piperidine.
B. A solution of 10.4 g of 4-(4-phenylbenzoyl)-
piperidine, 8.8 g of 3-(2-bromoethyl)indole and 4.5 g
of triethylamine in 300 ml of dimethylformamide is treated
according to the manipulative procedure outlined in
Example 3(b) to produce 3-~2-L4-(4-phenylbenzoyl)piperidyl~-
ethyl~indole. The indole is recrystallized twice from
¦ an ethanol-water mixture (one charcoal treatment),
thrice from a pyridine-water mixture, and twice from an
~ acetone-water mixture to give the product, mp 189-192C.
¦ Analysis:
Calculated for C28H28N2O: 82.32%C; 6.91%H; 6.85%N.
Found: 81.90%C; 7~09~H; 6.80%N.
- 30
' ' . ' ' ~ - ': , , . . ':
: . . ':
HOE 76/F 249
107838~
E X A M P L E 21
A. 8.7 g of oxalyl chloride are added dropwise to a
stirring solution, cooled to about -10C, of 12.0 g of
5,6-dimethoxy-2-methylindole in 250 ml of ether. After
S addition is complete, the mixture is stirred for 10 minutes,
producing a bright orange precipitate of 5,6-dimethoxy-2-
methyl-3-indole glyoxylyl chloride which is immediately used
for the next step.
B. The above ether suspension of 5,6-dimethoxy-
2-methyl-3-indoleglyoxylyl chloride is added portionswise
I to a cooled stirring mixture of 4-benzoylpiperidine
(Example 9(a)), 150 ml of water, 150 ml of chloroform and
25 g of potassium carbonate. The mixture is stirred for
16 hours at ambient temperature, the organic layer is
- 15 separated and the solvent is removed, leaving a brown oil
which is triturated with cyclohexane and then stirred for
16 hours with ether. A white solid results which is
collected, dried and recrystallized thrice from methanol
to give the compound, mp 188-190C, 4-benzoyl-1-(5,6- -
dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine.
Analysis:
Calculated for C2s 26 2 5 69- 0%C; 6-
Found: 68.98%C; 6.20%H; 6.38~N.
C. A suspension of 20.2 g of 4-benzoyl-1-(5,6-
dimethoxy-2-methylindol-3-ylglyoxyloyl)piperidine in 200 ml
of tetrahydrofuran is added dropwise to a stirring solution,
under nitrogen at reflux, of 9.6 g of lithium aluminum
hydride in 210 ml of tetrahydrofuran. Stirring and refluxing
is continued for 3 hours, the mixture is cooled in an ice
- 31
,, , , , I ....... .... . . ... . . .
HOE 76/F 249
1078387
bath and the excess hydride is destroyed with water. The
mixture is filtered and the filtrate is concentrated under
reduced pressure, leaving an off-white foam which is
triturated with cyclohexane to give an off-white powder.
The oxalate salt is prepared by dissolving the free base
~ ddin~
in isopropanol and slowly/a solution of oxalic acid
in isopropanol. The insoluble oxalate salt is collected and
recrystallized from ethanol to give white crystals, mp
152-154C, 5,6-dimethoxy-2-methyl-3- ~-(4-phenylhydroxymethyl-
10 piperidyl)ethyl3indole oxalate.
Analysis:
Calculated for C25H32N23 (C2H)2
Found: 65.02%C; 6.87%H; 5.61%N.
E X A M P L E 22
A mixture of 6.2 g of 3-(3-bromopropyl)indole,
5.8 g of 4-(4-fluorobenzoyl)piperidine, free base of Example
1d, 3.8 g of potassium carbonate in 65 ml of dimethylforma-
mide is stirred under nitrogen at 50C for 16 hours. The mix-
ture is stirred while being allowed to cool to ambient tempe-
rature and then 180 ml of water are added slowly causing a
yellow oil to separate. The supernatant aqueous solution
is decanted from the oil and the oil is taken up in ether,
the ethereal solution is washed with water and dried and the
ether removed in vacuo leaving a white solid. The solid is
dissolved in absolute ethanol, and HCl gas bubbled into the
solution to produce a salt. Addition of ether to the solu-
tion causes the salt to precipitate. The salt is recrystal-
lized from isopropanol to give the white solid, mp 211-213C
of 3-~3-~4-(4-fluorobenzoyl)piperidyl~ propyl~ indole hydro-
- 32
.: . . . .. . .
. . . . . .. . . .
,, - . . -. ~ -,. , ,, .. :
.. ~ , . .. . ..
''' ' ' '" ~ ~ .
.
1078387 HOE 76/F 249
chloride.
Analysis:
Calculated for C23H25FNO2-HCl: 68.69~C; 6.54~H; 6.99%H; 8.84%Cl.
Found: 68.84%C; 6.60%H; 6.90%H; 8.65%Cl.
E X A M P L E 23
A sample of 3-3-~4-(4-fluorobenzoyl)piperidyl~-
propyl~indole, free base of Example 22, is reduced and
treated by the method described in Example 2 to give 3-~3-~4-
(4-fluorophenylhydroxymethyl)piperidyl~propyl~indole.
E X A M P L E 24
A sample of 3-(3-bromopropyl)-6-methoxy-2-methylindole
and 4-(3-fluorobenzoyl)piperidine are treated according to
the method described in Example 1e to give 6-methoxy-2-
methyl-3-~3-~4-(4-fluorobenzoyl)piperidyl3-propyl~ indole
hydrochloride.
E X A M P L E 25
A sample of 6-methoxy-2-methyl-3-~3-~4-(4-fluoro-
benzoyl)piperidyl3propyl~indole, free base of Example 24,
is reduced and treated by the method described in Example 2
to give 6-methoxy-2-methyl-3-~3- L4- (4-fluorophenyl-
hydroxymethyl)piperidyl~propyl~ indole.
- - 33
