Aryl- and heterocyclic-methanamines are prepared by reacting a hydroxy-aryl carbinol or a heterocyclic carbinol with a primary or a secondary amine in the presence of a cationic effect reagent.

BACKGROUND OF THE INVENTION 
1. Cross-reference to Related Applications 
This application is related to European Patent Application 88.303646.9, 
filed Apr. 22, 1988, incorporated herein by reference, and claims priority 
therefrom. Cross-reference is also made to U.S. Ser. No. 042,181, filed 
Apr. 24, 1987 now U.S. Pat. No. 4,829,065, issued May 9, 1989 and to its 
continuation-in-part U.S. Ser. No. 260,969, filed contemporaneously 
herewith now U.S. Pat. No. 5,043,447 and both incorporated herein by 
reference, where preparation of 
1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]p 
iperazine (a compound within the scope of compounds made by the present 
invention) and its uses are taught. 
2. Field of the Invention 
The present invention relates to synthetic chemical reactions between 
alcohols and primary or secondary amines, particularly in the preparation 
of certain aryl- and heterocyclic-methanamines. The invention is also 
directed to the chemical compositions, particularly pharmaceutical active 
agents, and amphoteric phenolamines used as intermediates in the 
photographic, color, phytosanitary and pharmaceutical industries. 
BACKGROUND INFORMATION 
The synthetic reactions employed in the past for making aryl- and 
heterocyclic-methanamines suffered from several disadvantages. Often, 
these reactions were quite complicated, involving many steps (typically 
including protection and de-protection). At industrial scale, they 
entailed the manipulation of large quantities of hazardous chemicals 
(e.g., NaOH, hydrogen gas, thionyl chloride), giving rise to problems of 
corrosion, toxicity, explosion, smell and environmental considerations. 
Additionally, the reagents used therein (e.g., palladium catalysts) were 
often expensive. 
A typical synthesis of hydroxy-benzylamines entailed the following steps: 
##STR1## 
Similarly, a typical synthesis of heterocyclic methanamines entailed the 
following steps: 
##STR2## 
Thus, in view of the disadvantages of the prior synthetic processes, it has 
remained desired to provide a process for the synthesis of aryl- and 
heterocyclic-methanamines, which involves fewer and less complicated 
steps, employs safer and less expensive reagents, and produces high yields 
in less time. It has further been desired to provide such a process, which 
can be carried out in a single reaction vessel. The synthetic processes of 
the present invention provide such a reaction and satisfy the foregoing 
requirements. 
SUMMARY OF THE INVENTION 
Aryl- and heterocyclic-methanamines represented by Formula I: 
##STR3## 
wherein: Z is a group of the formula HO-Ar- where Ar is phenyl, 
substituted phenyl, or naphthyl, or 
Z is a five to seven membered optionally substituted heterocyclic group of 
the formula: 
##STR4## 
where X is a succession of one or two groups selected from --C.dbd.C--, 
--C.dbd.N--, --C.dbd.C--C-- and --C.dbd.N--C--, or 
Z is a condensed heterocyclic group selected from optionally substituted 
indole and optionally substituted quinoline; 
R is a substituent giving a global electron donor effect, selected from the 
group including: hydrogen, lower alkyl, phenyl, substituted phenyl, or 
naphthyl; 
R.sup.1 is hydrogen, alkyl, phenyl, substituted phenyl, or naphthyl; 
R.sup.2 is hydrogen, alkyl, phenyl, substituted phenyl, or naphthyl; 
or NR.sup.1 R.sup.2 taken together forms a heterocycle where R.sup.1 and 
R.sup.2 together are lower alkylene of four to six carbon atoms, or lower 
alkylene of three to five carbon atoms plus one member that is --O--, 
--S-- or 
##STR5## 
where R.sup.3 is hydrogen, lower alkyl of one to five carbon atoms, aryl, 
arylalkyl or diarylalkyl; 
are prepared by reacting a carbinol of the formula: 
##STR6## 
where R.sup.4 is hydrogen or alkyl; with a primary or secondary amine of 
the formula: 
EQU H--NR.sup.1 R.sup.2 
in the presence of a cationic effect reagent. The cationic effect reagent 
is a metal hydroxide and a metal salt.

DETAILED DESCRIPTION OF THE INVENTION 
Definitions and General Parameters 
The following definitions are set forth to illustrate and define the 
meaning and scope of the various terms used to described the invention 
herein. 
As used herein, the term "alkyl" refers to a fully saturated monovalent 
radical containing only carbon and hydrogen, and which may be a branched 
or straight chain radical. This term is further exemplified by radicals 
such as methyl, ethyl, t-butyl, pentyl, pivalyl, and heptyl. 
The term "cycloalkyl" refers to carbocyclic radicals, such as 
cyclopropylmethyl and adamantyl. 
The term "lower alkyl" refers to a branched or straight chain monovalent 
alkyl radical of one to six carbon atoms. This term is further exemplified 
by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 
i-butyl (or 2-methylpropyl), i-amyl, n-amyl, and hexyl. 
The term "cyclic lower alkyl" refers to carbocyclic radicals of three to 
six carbon atoms, such as cyclopropylmethyl. 
The term "alkylene" refers to a fully saturated divalent radical containing 
only carbon and hydrogen, and which may be a branched or straight chain 
radical. This term is further exemplified by radicals such as methylene, 
ethylene, n-propylene, t-butylene, i-pentylene, and n-heptylene. 
The term "lower alkylene" refers to a divalent alkyl radical of one to six 
carbon atoms. This term is further exemplified by such radicals as 
methylene, ethylene, n-propylene, i-propylene, n-butylene, t-butylene, 
i-butylene (or 2-methylpropylene), isoamylene, pentylene, and n-hexylene. 
The term "aryl" or "Ar" refers to a monovalent unsaturated aromatic 
carbocyclic radical having a single ring (e.g., phenyl) or two condensed 
rings (e.g., naphthyl), which can optionally be mono-, di- or 
tri-substituted, independently, with hydroxy, lower alkyl, lower alkoxy, 
chloro, and/or fluoro. 
As used herein, the term "halo" refers to fluoro, bromo, chloro and iodo. 
"Optional" or "optionally" means that the subsequently described event or 
circumstance may or may not occur, and that the description includes 
instances where said event or circumstance occurs and instances in which 
it does not. For example, "optionally substituted phenyl" means that the 
phenyl may or may not be substituted and that the description includes 
both unsubstituted phenyl and phenyl wherein there is substitution. 
As used herein, the terms "inert organic solvent" or "inert solvent" mean a 
solvent inert under the conditions of the reaction being described in 
conjunction therewith [including, for example, benzene, toluene, 
acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), 
chloroform, methylene chloride (or dichloromethane), diethyl ether, 
methanol, pyridine and the like]. Unless specified to the contrary, the 
solvents used in the reactions of the present invention are inert organic 
solvents. 
Unless specified to the contrary, the reactions described herein take place 
at atmospheric pressure over a temperature range from about 10.degree. C. 
to about 100.degree. C., more preferably from about 40.degree. C. to about 
80.degree. C., and most preferably at the reflux temperature of the 
reaction mixture. 
Isolation and purification of the compounds and intermediates described 
herein can be effected, if desired, by any suitable separation or 
purification procedure such as, for example, filtration, extraction, 
crystallization, column chromatography, thin-layer chromatography or 
thick-layer chromatography, or a combination of these procedures. Specific 
illustrations of suitable separation and isolation procedures can be had 
by reference to the examples hereinbelow. However, other equivalent 
separation or isolation procedures can, of course, also be used. 
Synthesis of the Compounds of Formula I 
As used in the Reaction Schemes, the substituents Z, Ar, X, R.sup.1, 
R.sup.2, R.sup.3, R.sup.4 and NR.sup.1 R.sup.2, are the same as described 
in the Summary of the Invention. 
##STR7## 
Referring to Reaction Scheme 1, approximately equimolar equivalents of a 
carbinol (Formula 1) and an amine (Formula 2) are added to a reaction 
vessel in the presence of a cationic effect reagent. The reaction takes 
place in a medium in which said starting materials are soluble, but in 
which said final product (Formula I) is insoluble, at a temperature from 
about 20.degree. C. to about 140.degree. C., preferably at the reflux 
temperature of the reaction mixture, for a time from about 1 to about 48 
hours, preferably 4 to 24 hours. 
The Carbinols 
The carbinols useful in the reactions of the present invention must have a 
conjugate structure with an acidic character. These two characteristics 
are required for the carbocation formation in the presence of the cationic 
effect reagent. 
Hydroxy-aryl carbinols 
The starting materials of Formula 1 where Z is a group of the formula 
HO--Ar--, include the compounds where Ar is phenyl, substituted phenyl, or 
naphthyl. Preferred hydroxy-aryl carbinols include hydroxy-phenyl 
carbinols (e.g., 2-hydroxybenzyl alcohol, 3-hydroxybenzyl alcohol, 
4-hydroxybenzyl alcohol, 3-hydroxy-4-methoxybenzyl alcohol and 
4-hydroxy-3-methoxybenzyl alcohol, commercially available from Aldrich 
Chemical of Milwaukee, Wis., and 4-hydroxy-3,5-dimethoxybenzyl alcohol, 
commercially available from Lancaster Synthesis Ltd. of Wyndham, N.H.) and 
6-hydroxy-2-naphthyl-carbinols (e.g., 6-hydroxy-2-naphthylenemethanol, 
which can be prepared from the corresponding aldehyde by methods known to 
those skilled in the art). 
Heterocyclic carbinols 
The starting materials of Formula 1 where Z is a five to seven membered 
heterocyclic group of the formula: 
##STR8## 
optionally substituted at any available location on the heterocycle, 
include the compounds where X is a succession of one or two groups 
selected from --C.dbd.C--, --C.dbd.N--, --C.dbd.C--C-- and --C.dbd.N--C--. 
Preferred heterocyclic and condensed heterocyclic carbinols include 
2-imidazolyl-carbinols [e.g., 4-(hydroxymethyl)imidazole], 
3-indolyl-carbinols (e.g., 3-indolemethanol), 4-quinolyl-carbinols (e.g., 
2,4-quinolinediol) and 4-pyrazolyl-carbinols (e.g., 4-pyrazolemethanol), 
each of the foregoing examples being commercially available from Aldrich. 
The Amines 
Primary and Secondary Amines 
The primary and secondary amines useful in the reactions of the present 
invention include: 
primary aliphatic amines such as alkylamines (e.g., propyl, n-butyl, 
t-butyl, and hexyl) and cycloalkylamines (e.g., cyclopentyl, 
cyclohexyl-amine, and adamantadine); 
secondary aliphatic amines (e.g., diethylamine, di-isopropylamine, 
dibutylamine, piperidine); 
arylamines (e.g., benzylamine), 
primary aralkylamines (e.g., phenethylamine); and 
secondary aralkylamines (e.g., N-methyl-phenethylamine), 
each of the foregoing examples being commercially available, for example, 
from Aldrich. 
Heterocyclic Amines 
Heterocyclic amines useful in the reactions of the present invention 
include: 
optionally substituted piperazines [e.g., piperazine, phenylpiperazine, 
1-(2-methoxyphenyl)piperazine, and 1-(4-chlorophenyl)piperazine), 
commercially available from Aldrich, and 
diphenylmethyl-piperazines, prepared, e.g., by the procedures of Hamlin et 
al., J. Am. Chem. Soc., 71, 31 (1949) or Cheeseman, J. Chem. Soc., 115-123 
(1975)]. 
The Cationic Effect Reagent 
The cationic effect is induced by a combination of a metal hydroxide and a 
metal salt. The metal hydroxide is preferably an alkaline metal hydroxide 
(most preferably potassium or sodium hydroxide). The metal salt is 
preferably a metal halide or a metal perchlorate (more preferably a 
lithium halide or a lithium percholorate, and most preferably lithium 
bromide). 
The ratio of metal hydroxide to salt can vary from 1:20 to 20:1 on a molar 
scale. It is preferred that the hydroxide be used in a smaller quantity 
than the salt, most preferably about 0.1 molar equivalents of alkaline 
hydroxide to 1.0 molar equivalent of metal salt. 
The Reaction Medium 
The reaction medium can be heterogeneous or homogeneous. 
Heterogeneous reaction media include, e.g., a mixture of an aqueous solvent 
(such as water) and either an aromatic solvent (such as benzene, toluene 
or xylene) or an aliphatic solvent (such as dichloromethane and 
dichloroethane), preferably in a ratio from 1:10 to 10:1 v/v. A phase 
transfer catalyst [e.g., 3-octyl ammonium chloride ("Aliquat 366") or 
tetrabutyl ammonium bromide ("TBAB")] is preferably used when employing 
heterogeneous media. 
Homogeneous reaction media include, e.g., hydroalcoholic mixtures and 
organic solvents. Non-aqueous homogeneous reaction media is preferred, 
especially toluene. 
Preparation of the Salts of Formula I 
Once the compounds of Formula I have been prepared according to the process 
of the present invention, their pharmaceutically acceptable salts may be 
prepared according to methods commonly employed in the art. 
Compounds Made by the Present Invention 
Compounds prepared by the above-described preferred process of the 
invention may be identified (e.g., using mass spectroscopy, NMR 
spectroscopy, or preferably, atomic absorption spectroscopy) by the 
presence of a slight, but detectable amount of a metal salt, e.g., a 
lithium compound used in the process as a reagent (e.g., LiBr) or produced 
in it as a side product (e.g., LiOH). 
While it is well known that pharmaceuticals must meet pharmacopoeia 
standards before approval and/or marketing, and that synthetic reagents or 
side products should not exceed the limits prescribed by pharmacopoeia 
standards, final compounds prepared by a process of the present invention 
may have minor, but detectable, amounts of such materials present. It is 
important to monitor the purity pharmaceutical compounds for the presence 
of such materials, which presence is additionally disclosed as a method of 
detecting use of a process of the invention. 
Preferred Processes and Last Steps 
Aryl- and heterocyclic-methanamines are prepared by reacting a hydroxy-aryl 
carbinol or a heterocyclic carbinol with a primary or a secondary amine in 
the presence of a cationic effect reagent. 
Particularly preferred as the cationic effect reagent are potassium or 
sodium hydroxide, and a lithium halide or a lithium perchlorate, most 
preferably lithium bromide. 
Preferred Compound 
A preferred compound made by the process of the present invention is 
1-diphenylmethyl-4-[(2-(-4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl] 
piperazine. 
EXAMPLES 
The following examples are given to enable those skilled in the art to more 
clearly understand and to practice the present invention. They should not 
be considered as limiting the scope of the invention, but merely as being 
illustrative and representative thereof. 
EXAMPLE 1 
1-(2-Methoxyphenyl)-4-[(4-hydroxyphenyl)methyl]piperazine 
4-Hydroxyphenyl methanol (124 g, 1 mole) and 192 g (1 mole) of 
1-(2-methoxyphenyl)piperazine, together with 56 g (1 mole) of potassium 
hydroxide and 8.7 g (0.1 mole) of lithium bromide and 32.2 g (0.1 mole) of 
Aliquat 366 were dissolved in a mixture of 1 liter of toluene and 1 liter 
of water. The reaction mixture was refluxed for 24 hours, and then allowed 
to cool to room temperature. The organic layer was decanted and extracted 
twice with 500 ml of a 10% sodium hydroxide solution. The basic aqueous 
liquor was treated with ammonium acetate to provoke precipitation of the 
desired product. After filtration and drying under vacuum overnight at 
50.degree. C., 167 g (0.56 mole, 56% yield) of the title product was 
obtained as small white leaflets melting at 172.degree. C. 
EXAMPLE 2 
1-(2-Methoxyphenyl)-4-[(4-hydroxyphenyl)methyl]piperazine 
2A. Formula I Where Z is 4-Hydroxyphenyl, --N--R.sup.1 R.sup.2 is 
1-(2-methoxyphenyl)piperazine, and R is Hydrogen 
One mole of 4-hydroxyphenyl methanol (124 g) and 192 g (2 moles) of 
1-(2-methoxyphenyl)piperazine were dissolved in 1.5 liters of toluene. One 
mole (87 g) of lithium bromide and 0.1 mole (5.6 g) of potassium hydroxide 
were added portionwise, under stirring, and the reaction medium was heated 
to reflux for 5 hours. The reaction mixture was then allowed to cool to 
room temperature, and extracted twice with 500 ml of a 1N sodium 
hydroxide. The basic aqueous liquor was washed with 300 ml of toluene and 
then acidified to pH 7 with acetic acid to provoke precipitation of the 
desired product. The precipitate thus obtained was filtered off and then 
recrystallized from isopropanol, giving 238.4 g (0.80 mole, 80% yield) of 
the title product, melting at 172.degree. C. 
2B. Formula I Varying Z 
Similarly, following the procedure of Part A above, but replacing 
4-hydroxyphenyl methanol with: 
2-hydroxybenzyl alcohol; 
3-hydroxybenzyl alcohol; 
4-hydroxybenzyl alcohol; 
4-hydroxy-3-methoxybenzyl alcohol; 
4-hydroxy-3-methoxybenzyl alcohol; 
4-hydroxy-3,5-dimethoxybenzyl alcohol; 
6-hydroxy-2-naphthylenemethanol; 
4-(hydroxymethyl)imidazole; 
3-indolemethanol; 
4-pyrazolemethanol; 
1-(4-hydroxyphenyl)-1-propanol; and 
1-(4-hydroxyphenyl)benzyl alcohol, 
there is obtained: 
1-(2-methoxyphenyl)-4-(2-hydroxybenzyl)piperazine 
1-(2-methoxyphenyl)-4-(3-hydroxybenzyl)piperazine; 
1-(2-methoxyphenyl)-4-(4-hydroxybenzyl)piperazine; 
1-(2-methoxyphenyl)-4-(4-hydroxy-3-methoxybenzyl)piperazine; 
1-(2-methoxyphenyl)-4-(4-hydroxy-3-methoxybenzyl)piperazine; 
1-(2-methoxyphenyl)-4-(4-hydroxy-3,5-dimethoxybenzyl)piperazine; 
1-(2-methoxyphenyl)-4-[(6-hydroxy-2-naphthyl)methyl]piperazine; 
1-(2-methoxyphenyl)-4-[(4-imidazolyl)methyl]piperazine; 
1-(2-methoxyphenyl)-4-[(3-indole)methyl]piperazine; 
1-(2-methoxyphenyl)-4-[(4-pyrazole)methyl]piperazine; 
1-(2-methoxyphenyl)-4-[(4-hydroxyphenyl)-1-propyl]piperazine; and 
1-(2-methoxyphenyl)-4-[(4-hydroxyphenyl)phenylmethyl]piperazine. 
2C. Formula I Varying -NR.sup.1 R.sup.2 
Similarly, following the procedure of Part A above, but replacing 
1-(2-methoxyphenyl)piperazine with: 
propylamine; 
n-butylamine; 
t-butylamine; 
hexylamine; 
cyclopentylamine; 
cyclohexylamine; 
adamantadine; 
diethylamine; 
di-isopropylamine; 
dibutylamine; 
piperidine; 
benzylamine; 
phenethylamine; 
N-methyl-phenethylamine; 
piperazine; 
phenylpiperazine; and 
1-(4-chlorophenyl)piperazine), 
there is obtained: 
N-propyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-n-butyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-t-butyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-hexyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-cyclopentyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-cyclohexyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-adamantyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-diethyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-di-isopropyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-dibutyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-[(4-hydroxyphenyl)methyl]piperidine; 
N-benzyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-phenethyl-N-[(4-hydroxyphenyl)methyl]amine; 
N-methyl-N-phenethyl-N-[(4-hydroxyphenyl)methyl]amine; 
1-[(4-hydroxyphenyl)methyl]piperazine alone or mixed with 
1,4-di-[(4-hydroxyphenyl)methyl]piperazine; 
1-phenyl-4-[(4-hydroxyphenyl)methyl]piperazine; and 
1-(4-chlorophenyl)-4-[(4-hydroxyphenyl)methyl]piperazine). 
2D. Formula I Varying -NR.sup.1 R.sup.2 
Similarly, following the procedure of Part A above, but replacing 
1-(2-methoxyphenyl)piperazine with: 
N-(diphenylmethyl)piperazine; 
N-[di-(2-methylphenyl)methyl]piperazine; 
N-[di-(3-methylphenyl)methyl]piperazine; 
N-[di-(4-methylphenyl)methyl]piperazine; 
N-[di-(2-t-butylphenyl)methyl]piperazine; 
N-[di-(3-t-butylphenyl)methyl]piperazine; 
N-[di-(4-t-butylphenyl)methyl]piperazine; 
N-[di-(2-methoxyphenyl)methyl]piperazine; 
N-[di-(3-methoxyphenyl)methyl]piperazine; 
N-[di-(4-methoxyphenyl)methyl]piperazine; 
N-[di-(2-chlorophenyl)methyl]piperazine; 
N-[di-(3-chlorophenyl)methyl]piperazine; 
N-[di-(4-chlorophenyl)methyl]piperazine; 
N-[di-(4-fluorophenyl)methyl]piperazine; 
N-benzylpiperazine; 
N-[1-(4-chlorophenyl)-1-(phenyl)methyl]piperazine; 
N-(2,2-diphenylethyl)piperazine; 
N-[3-(phenyl)-3-(4-methoxyphenyl)propyl]piperazine; and 
N-(4,4-diphenylbutyl)piperazine, 
there is obtained: 
1-(diphenylmethyl)-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(2-methylphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(3-methylphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(4-methylphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(2-t-butylphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(3-t-butylphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(4-t-butylphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(2-methoxyphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(3-methoxyphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(4-methoxyphenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(2-chlorophenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(3-chlorophenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(4-chlorophenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[di-(4-fluorophenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-benzyl-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[1-(4-chlorophenyl)-1-(phenyl)methyl]-4-[(4-hydroxyphenyl)methyl]piperazi 
ne; 
1-(2,2-diphenylethyl)-4-[(4-hydroxyphenyl)methyl]piperazine; 
1-[3-(phenyl)-3-(4-methoxyphenyl)propyl]-4-[(4-hydroxyphenyl)methyl]piperaz 
ine; and 
1-(4,4-diphenylbutyl)-4-[(4-hydroxyphenyl)methyl]piperazine. 
EXAMPLE 3 
1-Diphenylmethyl-4-[(2-(-4-methylphenyl)-5-methyl-1 
H-imidazol-4-yl)methyl]piperazine 
3A. Formula I Where Z is 4-[2-(-4-Methylphenyl)-5-methyl-1H-imadazole, 
-N-R.sup.1 R.sup.2 is Diphenylmethylpiperazine, and R is Hydrogen 
One mole of 4-hydroxymethyl-2-(4-methylpheny)-5-methyl-1H-imidazole (202 g) 
was dissolved in 2 liters of 95% ethanol, then 252 g (1 mole) of 
N-(diphenylmethyl)piperazine was added portionwise. This was followed by 
the addition of 1 liter of water, 60 g (1.5 mole) of sodium hydroxide (as 
12N solution) and 8.7 g (0.1 mole) of lithium bromide. The reaction medium 
was refluxed for 5 hours, allowed to cool to room temperature, and was 
stirred overnight. The precipitate that formed was filtered and purified 
by reslurrying from 1.2 liters of an ethanol-water mixture (60/40) to 
produce the 383.6 g of the title compound (0.88 mole, 88% yield), having a 
melting point of 238.degree. C. 
3B. Formula I Varying Z 
Similarly, following the procedure of Part A above, but replacing 
4-hydroxymethyl-2-(4-methylphenyl)-5-methyl-1H-imidazole with: 
2-hydroxybenzyl alcohol; 
3-hydroxybenzyl alcohol; 
4-hydroxybenzyl alcohol; 
4-hydroxy-3-methoxybenzyl alcohol; 
4-hydroxy-3-methoxybenzyl alcohol; 
4-hydroxy-3,5-dimethoxybenzyl alcohol; 
6-hydroxy-2-naphthylenemethanol; 
4-(hydroxymethyl)imidazole; 
3-indolemethanol; and 
4-pyrazolemethanol, 
there is obtained: 
1-diphenylmethyl-4-(2-hydroxybenzyl)piperazine 
1-diphenylmethyl-4-(3-hydroxybenzyl)piperazine; 
1-diphenylmethyl-4-(4-hydroxybenzyl)piperazine; 
1-diphenylmethyl-4-(4-hydroxy-3-methoxybenzyl)piperazine; 
1-diphenylmethyl-4-(4-hydroxy-3-methoxybenzyl)piperazine; 
1-diphenylmethyl-4-(4-hydroxy-3,5-dimethoxybenzyl)piperazine; 
1-diphenylmethyl-4-[(6-hydroxy-2-naphthyl)methyl]piperazine; 
1-diphenylmethyl-4-[(4-imidazolyl)methyl]piperazine; 
1-diphenylmethyl-4-[(3-indole)methyl]piperazine; and 
1-diphenylmethyl-4-[(4-pyrazole)methyl]piperazine. 
3C. Formula I Varying -NR.sup.1 R.sup.2 
Similarly, following the procedure of Part A above, but replacing 
N-(diphenylmethyl)piperazine with: 
propylamine; 
n-butylamine; 
t-butylamine; 
hexylamine; 
cyclopentylamine; 
cyclohexylamine; 
adamantadine; 
diethylamine; 
di-isopropylamine; 
dibutylamine; 
piperidine; 
benzylamine; 
phenethylamine; 
N-methyl-phenethylamine; 
piperazine; 
phenylpiperazine; 
1-(2-methoxyphenyl)piperazine; and 
1-(4-chlorophenyl)piperazine), 
there is obtained: 
N-propyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-n-butyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-t-butyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-hexyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-cyclopentyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine 
; 
N-cyclohexyl-N-[(2-(4-methylphenyl)-5methyl-1H-imidazol-4-yl)methyl]amine; 
N-adamantyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-diethyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-di-isopropyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amin 
e; 
N-dibutyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperidine; 
N-benzyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-phenethyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]amine; 
N-N-methyl-phenethyl-N-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methy 
l]amine; 
1-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl-methyl]piperazine, alone 
or mixed with 
1,4-di-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine; 
1-phenyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine 
; 
1-(2-methoxyphenyl)-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl 
]piperazine; and 
1-(4-chlorophenyl)-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl] 
piperazine). 
3D. Formula I Varying -NR.sup.1 R.sup.2 
Similarly, following the procedure of Part A above, but replacing 
N-(diphenylmethyl)piperazine with: 
N-[di-(2-methylphenyl)methyl]piperazine; 
N-[di-(3-methylphenyl)methyl]piperazine; 
N-[di-(4-methylphenyl)methyl]piperazine; 
N-[di-(2-t-butylphenyl)methyl]piperazine; 
N-[di-(3-t-butylphenyl)methyl]piperazine; 
N-[di-(4-t-butylphenyl)methyl]piperazine; 
N-[di-(2-methoxyphenyl)methyl]piperazine; 
N-[di-(3-methoxyphenyl)methyl]piperazine; 
N-[di-(4-methoxyphenyl)methyl]piperazine; 
N-[di-(2-chlorophenyl)methyl]piperazine; 
N-[di-(3-chlorophenyl)methyl]piperazine; 
N-[di-(4-chlorophenyl)methyl]piperazine; 
N-[di-(4-fluorophenyl)methyl]piperazine; 
N-benzylpiperazine; 
N-[1-(4-chlorophenyl)-1-(phenyl)methyl]piperazine; 
N-(2,2-diphenylethyl)piperazine; 
N-[3-(phenyl)-3-(4-methoxyphenyl)propyl]piperazine; and 
N-(4,4-diphenylbutyl)piperazine, 
there is obtained: 
1-[di-(2-methylphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine; 
1-[di-(3-methylphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine; 
1-[di-(4-methylphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine; 
1-[di-(2-t-butylphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol- 
4-yl)methyl]piperazine; 
1-[di-(3-t-butylphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol- 
4-yl)methyl]piperazine; 
1-[di-(4-t-butylphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol- 
4-yl)methyl]piperazine; 
1-[di-(2-methoxyphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol- 
4-yl)methyl]piperazine; 
1-[di-(3-methoxyphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol- 
4-yl)methyl]piperazine; 
1-[di-(4-methoxyphenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol- 
4-yl)methyl]piperazine; 
1-[di-(2-chlorophenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine; 
1-[di-(3-chlorophenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine; 
1-[di-(4-chlorophenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine, the trihydrochloride salt of which has a reported 
melting point of about 225.degree. C.; 
1-[di-(4-fluorophenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4 
-yl)methyl]piperazine, the trihydrochloride salt of which has a reported 
melting point of about 210.degree. C.; 
1-benzyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine 
; 
1-[1-(4-chlorophenyl)-1-(phenyl)methyl]-4-[(2-(4-methylphenyl)-5-methyl-1H- 
imidazol-4-yl)methyl]piperazine; 
1-(2,2-diphenylethyl)-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)meth 
yl]piperazine; 
1-[3-(phenyl)-3-(4-methyoxyphenyl)propyl]-4-[(2-(4-methylphenyl)-5-methyl-1 
H-imidazol-4-yl)methyl]piperazine; and 
1-(4,4-diphenylbutyl)-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)meth 
yl]piperazine. 
EXAMPLE 4 
1-(2-Methoxyphenyl)-4-[(3-indolyl)methyl]piperazine 
4A. Formula I Where Z is 4-[3-(indolyl)methyl], -N-R.sup.1 R.sup.2 is 
1-(2-methoxyphenyl)piperazine, and R is Hydrogen 
One mole (147 g) of indole-3-carbinol and one mole (192 g) of 
1-(2-methoxyphenyl)piperazine were dissolved in 1.5 liters of ethanol 60%. 
One mole (87 g) of lithium bromide and 0.1 mole (5.6 g) of potassium 
hydroxide were added, then the reaction medium was heated at reflux under 
stirring for 24 hours. After the reaction medium had cooled to 60.degree. 
C., hydrochloric acid was added until persistence of an acidic pH. Then 
189 g of the dihydrochloride salt of the title product was allowed to 
crystallize by cooling at 0.degree. C. overnight, producing a global yield 
of 59% (m.p. 188.degree.-190.degree. C. with decomposition.) 
While the present invention has been described with reference to the 
specific embodiments thereof, it should be understood by those skilled in 
the art that various changes may be made and equivalents may be 
substituted without departing from the true spirit and scope of the 
invention. In addition, many modifications may be made to adapt a 
particular situation, material, composition of matter, process, process 
step or steps, to the objective, spirit and scope of the present 
invention. All such modifications are intended to be within the scope of 
the claims appended hereto.