-------------------------------------------------------------------------------
N-alkyl-4,4-Diphenylpiperidines as CNS stimulants
found by Fuchem
-------------------------------------------------------------------------------
I was just farting-around on the net, when I ran into something interesting:
"4,4-Diarylpiperidines
Abstract
4,4-Diarylpiperidine compounds, preferably 4,4-diphenylpiperidine which are
substituted or unsubstituted in the 1-position of the piperidine nucleus, such
as 1-(lower alkyl)-4,4-diphenylpiperidines, 1-(lower alkyl)-4-phenyl-4-tolyl-
piperidines, and their substantially non-toxic, pharmaceutically-acceptable acid
addition salts, are highly effective central nervous system (CNS) stimulants
which are superior to known amphetamine-type stimulants. A novel and highly
advantageous process of making such 4,4-diarylpiperidine compounds comprises
reacting a 4-aryl-4-hydroxypiperidine compound which may be substituted in its
3-position by an aroyl group, with an aromatic hydrocarbon, in particular with
benzene, in the presence of a Friedel-Crafts-type catalyst."
Source --> http://water-cooler.com/WC/patentviewer/patent-4022786.html
-------------------------------------------------------------------------------
From same page:
REACTION
EXAMPLE 1
1-Methyl-4,4-diphenylpiperidine
20 g. of 1-methyl-4-hydroxy-4-phenylpiperidine are suspended in 150 ml. of
anhydrous benzene. 61.5 g. of finely pulverized anhydrous aluminum chloride are
added in portions thereto within 25 minutes while stirring. The reaction
temperature increases on starting addition of aluminum chloride to about
45.degree. C. After about 20 minutes the temperature is increased to and
maintained at about 50.degree. to 55.degree. C. for about one hour. The
resulting reaction solution is cooled to about 20.degree. C. and is poured into
a mixture of ice and concentrated hydrochloric acid. After warming the mixture
to room temperature, the hydrochloric acid layer together with the dark oil
formed on decomposition is separated from the benzene layer and is washed with
benzene. Water is added to said hydrochloric acid-oil phase, while stirring, in
portions and in an amount sufficient to produce an almost clear solution. Said
acid solution is rendered alkaline by the addition of 40% sodium hydroxide
solution whereby the mixture is well cooled. The alkalized mixture is repeatedly
extracted with ether. The combined ether extracts are dried over anhydrous
potassium carbonate and are concentrated by evaporation of the ether. 24 g. of
the crude base are obtained as residue in the form of yellowish oil. A water
clear oil boiling at 98.degree. to 103.degree. C./0.01 mm. Hg is recovered by
distillation of said crude oil in a high vacuum. The oil solidifies to crystals
on standing for a short period of time. After recrystallization from aqueous
dimethylformamide, the resulting 1-methyl-4,4-diphenylpiperidine has a melting
point of 71.degree. to 73.degree. C.
Its hydrochloride is produced by dissolving the base in acetic acid ethyl ester
and adding an ethereal hydrochloric acid solution thereto. After
recrystallization from acetic acid ethyl ester, the melting point of the
hydrochloride is 220.degree. to 223.degree. C.
EXAMPLE 2
1-Methyl-4,4-diphenylpiperidine
100 g. of 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine are suspended in 600
ml. of anhydrous benzene while stirring. 200 g. of finely pulverized, anhydrous
aluminum chloride are added in portions thereto within 25 minutes. The reaction
temperature increases to about 45.degree. C. when adding the first portion of
aluminum chloride. After about 20 minutes the reaction temperature of the
reaction mixture is maintained at 50.degree. to 55.degree. C. for about 1 hour.
The reaction mixture is then cooled to room temperature and is introduced into a
mixture of ice and concentrated hydrochloric acid while stirring. After heating
the mixture to room temperature, the benzene layer is separated from the
hydrochloric acid and oil layer which is washed with benzene. The hydrochloric
acid and oil layer is diluted, while stirring, with an amount of water
sufficient to cause substantially all the oil to be dissolved. The resulting
aqueous solution is then rendered alkaline by the addition of 40% sodium
hydroxide solution, while stirring, and the alkaline solution is extracted with
ether. The combined ether extracts are dried over anhydrous potassium carbonate
and are concentrated by evaporation of the ether. 83.5 g. of the crude base are
obtained as residue in the form of a dark oil. A light oil boiling at 98.degree.
to 103.degree. C./0.01 mm. Hg is recovered by distillation of said crude oil in
a high vacuum. The oil solidifies to crystals on standing for a short period of
time. After recrystallization from aqueous dimethylformamide, the resulting
1-methyl-4,4-diphenylpiperidine has a melting point of 71.degree. to 73.degree.C.
EXAMPLE 3
1-Ethyl-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine starting material by
1-ethyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with
benzene in the presence of aluminum chloride, 15 g. of crude
1-ethyl-4,4-diphenylpiperidine base boiling at 110.degree. to 123.degree.
C./0.01 mm. Hg are obtained. Its acid addition salt with maleic acid is produced
by the addition of maleic acid to its acetone solution. The maleic acid salt
melts at 239.degree. to 240.degree. C.
EXAMPLE 4
1-Isopropyl-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-isopropyl-3-benzoyl-4-
hydroxy-4-phenylpiperidine and reacting 55 g. thereof with benzene in the
presence of anhydrous aluminum chloride, 33 g. of crude 1-isopropyl-4,4-
diphenylpiperidine base boiling at 117.degree. to 125.degree. C./0.01 mm. Hg.
are obtained in the form of a yellowish viscous oil. On adding isopropanol
saturated with hydrogen chloride to its acetic acid ethyl ester solution, the
crystalline hydrochloride precipitates. After recrystallization from
isopropanol, the hydrochloride melts at 267.degree. C.
EXAMPLE 5
1-Phenethyl-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by
1-phenethyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof
with benzene in the presence of anhydrous aluminum chloride, 15 g. of
1-phenethyl-4,4-diphenylpiperidine base are obtained. On adding ether saturated
with hydrogen chloride to its acetic acid ethyl ester solution, the crystalline
hydrochloride precipitates. After recrystallization from isopropanol, the
hydrochloride melts at 202.degree. to 204.degree. C.
EXAMPLE 6
1-Isopropyl-4-phenyl-4-(p-tolyl)piperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by
1-isopropyl-3-(p-toluoyl)-4-hydroxy-4-(p-tolyl)piperidine and reacting 20 g.
thereof with benzene in the presence of 30 g. of aluminum chloride, 17 g. of the
hydrochloride of 1-isopropyl-4-phenyl-4-(p-tolyl)piperidine are isolated on
decomposing the reaction mixture with a mixture of ice and hydrochloric acid.
After recrystallization from isopropanol, the hydrochloride is obtained in
colorless leaflets of the melting point 271.degree. to 273.degree. C.
EXAMPLE 7
1-(3-Methoxypropyl)-4,4-diphenylpiperidine
30 g. of 1-(3-methoxypropyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine are
suspended in 225 ml. of anhydrous benzene. 50 g. of finely pulverized, anhydrous
aluminum chloride are added thereto within 20 minutes, while stirring. The
reaction temperature increases during said addition up to 60.degree. C. The
reaction mixture is then kept at from 50.degree. to 55.degree. C. for about 1
hour, is cooled to room temperature, and is added to a mixture of ice and
concentrated hydrochloric acid. The benzene layer is separated from the aqueous
layer by means of a separating funnel and is washed once with dilute
hydrochloric acid. The combined aqueous layers are rendered alkaline by the
addition of 40% sodium hydroxide solution. The precipitated base is separated by
repeated extraction with ether. The combined ether extracts are dried over
anhydrous potassium carbonate and the ether is distilled off. 21 g. of the crude
base remain as residue. On distillation in a high vacuum, pure
1-(3-methoxypropyl)-4,4-diphenylpiperidine is obtained in the form of a light
oil boiling at 130.degree. C./0.01 mm. Hg.
The crystalline fumaric acid salt of said base is obtained by the addition of
the calculated amount of fumaric acid to the solution of the base in
isopropanol. After recrystallization from isopropanol, the fumaric acid salt
melts at 189.degree. to 190.degree. C.
EXAMPLE 8
1-(1-Phenyl-2-propyl)-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-(1-phenyl-2-propyl)-3-
benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in
the presence of anhydrous aluminum chloride, 1-(1-phenyl-2-propyl)-4,4-
diphenylpiperidine hydrochloride is isolated on decomposing the reaction mixture
with a mixture of ice and concentrated hydrochloric acid. The yield of the crude
hydrochloride amounts to 16 g. After recrystallization from isopropanol, its
melting point is 172.degree. to 174.degree. C.
EXAMPLE 9
1-(2-Hydroxyethyl)-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by
1-(2-hydroxyethyl)-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g.
thereof with benzene in the presence of anhydrous aluminum chloride, 10 g. of
1-(2-hydroxyethyl)-4,4-diphenylpiperidine base boiling at from 160.degree. to
167.degree. C./0.01 mm. Hg are obtained. The hydrochloride obtained from the
isopropanol solution of said base has a melting point of 219.degree. to
221.degree. C.
EXAMPLE 10
1-Benzyl-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by
1-benzyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with
benzene in the presence of anhydrous aluminum chloride and decomposing the
reaction product with a mixture of ice and hydrochloric acid, 14 g. of the
hydrochloride of 1-benzyl-4,4-diphenylpiperidine are isolated in crystalline
form. After recrystallization from isopropanol, the hydrochloride melts at
239.degree. C.
EXAMPLE 11
1-(2-Phenoxyethyl)-4,4-diphenylpiperidine
When proceeding as described in Example 2 but replacing the corresponding
1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine by 1-(2-phenoxyethyl)-3-
benzoyl-4-hydroxy-4-phenylpiperidine and reacting 20 g. thereof with benzene in
the presence of anhydrous aluminum chloride, 13 g. of 1-(2-phenoxyethyl)-
4,4-diphenylpiperidine are obtained. Its boiling point is 145.degree. C./0.01
mm. Hg. The compound yields a fumaric acid salt melting at 199.5.degree. C.
The starting materials of the formulae II or IIa are dissolved or suspended in
an aromatic hydrocarbon having the formula ##STR7## wherein R.sub.3 has its
above-ascribed meaning. In the preferred embodiment anhydrous benzene or toluene
is used as the aromatic hydrocarbon. The Friedel-Crafts catalyst, preferably
anhydrous aluminum chloride or ferric chloride, or another Lewis acid, such as
antimony pentachloride, tin tetrachloride or zinc chloride, is used in at least
stoichiometric amounts in relation to compounds II and IIa, e.g. in a molar
ratio of catalyst: II or IIa of from about 6:1 to 2:1, preferably of from about
5:1 to 4:1, whereas the aromatic hydrocarbon having the formula ##STR8## wherein
R.sub.3 has its above-ascribed meanings, has two functions: it serves as a
reactant and its stoichiometric excess serves as solvent or suspending medium in
which the reaction proceeds.
The reaction is preferably carried out while cooling or at an elevated
temperature, preferably at temperatures between 0.degree. C. and 120.degree. C.,
in particular between 25.degree. and 75.degree. C., or at the boiling
temperature of the solvent or of the suspension.
Usually, the Friedel-Crafts-type catalyst is added to the reaction mixture at
room temperature. Thereby, the temperature of the mixture increases as the
reaction proceeds. The condensation is completed by continuing heating the
mixture, for example on a water bath, for a short period of time. The reaction
product, which is a complex of the catalyst and the final product of formula I,
Ia or I*, is readily decomposed by pouring the reaction mixture into a mixture
of ice water and concentrated acid, e.g. hydrochloric acid or sulfuric acid. On
addition of the acid the compounds of formula I, Ia or I* can be isolated in the
form of their acid-addition salts, which are readily crystallized from polar
solvents, e.g., acetic acid alkyl esters, lower alkanols, ethers or ketones. The
acid-addition salt is converted into the corresponding free base of formula I,
Ia or I* by rendering alkaline an aqueous acid solution containing I, Ia or I*
by the addition thereto of an aqueous alkaline solution, whereby the mixture is
cooled. The alkalized mixture can be extracted with ether. The ether extracts
contain the 4,4-diarylpiperidine base and are dried over known drying agents or
desiccants. By evaporation of the ether the crude base is obtained as a residue
which is purified by distillation or by recrystallization, e.g., from aqueous
dimethylformamide, lower alkanols or ketones.
The acid-addition salts of the 4,4-diphenylpiperidine compounds of formula I are
produced by methods known to the art, for instance, by dissolving the base in a
suitable solvent wherein the respective salt is insoluble and adding thereto the
corresponding acid which may also be dissolved in a suitable solvent. The
hydrochloride can be obtained directly by decomposing the reaction product,
obtained by proceeding as described hereinabove, with ice water-hydrochloric
acid. Of course, not only acid-addition salts with inorganic acids, such as the
hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and others, can
be produced but also acid-addition salts with organic acids, such as the salts
with acetic acid, propionic acid, and other alkanoic acids, maleic acid, fumaric
acid, lactic acid, citric acid, malic acid, tartaric acic, succinic acid,
glycine, alanine and other amino acids, benzoic acid, salicyclic acid, phthalic
acid, furoic acid, nicotinic acid, isonicotinic acid, and others. The preferred
acid addition salts are, of course, those salts which are substantially
non-toxic and pharmaceutically acceptable in amounts administered.
Said stimulating effect manifests itself by increased attentiveness, alertness,
and vigilance without causing locomotory activity accompanied by restlessness
and without inducing aggressiveness. The central nervous system (CNS)
stimulating 4,4-diphenylpiperidines of formulae I, I*, Ia through Ie and their
therapeutically-acceptable acid-addition salts thus possess considerable
advantages over the heretofore known and used central nervous system stimulating
agents of the amphetamine type. In contrast to said amphetamine-type compounds
the compounds of formulae I, I*, Ia through Ie do not cause a pronounced
increase in blood pressure nor general stimulation of the sympathetic nervous
system. Due to these pharmacological properties the compounds have proved of
value in therapy for all indications in which stimulation of the central nervous
system is required, such as in the treatment of chronic fatigue, depressions
especially in certain psychotic, senile, and psychoneurotic patients, obesity,
and others. Therefore the compounds of formulae I, I*, Ia through Ie and their
pharmacologically-compatible salts with organic or inorganic acids are useful as
medicaments; furthermore the compounds of formula Ib are valuable intermediates
for the preparation of compounds of formulae Ic, Id and Ie.
It has been found, that the CNS stimulating compounds of the invention, while
exhibiting similar stimulation of the central nervous system as the addicting
drugs, do not cause habituation, tolerance and hence do not lead to
drug-addiction. On repeated daily chronic administration of the same dose of the
new substances to mice, rats and dogs, the same degree of stimulation has been
reproduced. The animals tested did not develop habituation or tolerance as a
consequence of repeated administration. Disruption of a continuous treatment
over more than ten days did not provoke the appearance of withdrawal symptoms.
"To be the sum of all parts, in one place, at one time" - Andrew Graybeal
-------------------------------------------------------------------------------