CA1103677A

CA1103677A - 2-(.alpha.-PHENYLTOLYL)AZACYCLOALKANES, -AZACYCLOALKENES, DERIVATIVES AND A PROCESS FOR THE PREPARATION THEREOF

Info

Publication number: CA1103677A
Application number: CA295,695A
Authority: CA
Inventors: Lawrence L. Martin; Helen H. Ong; Vernon B. Anderson; Charles A. Crichlow
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1977-01-27
Filing date: 1978-01-26
Publication date: 1981-06-23
Also published as: BE863402A; FR2378770A1; HU179982B; NL7800969A; DE2802306A1; FR2378770B1; IL53904A0; ZA78493B; JPS5395963A; NO780290L; FI780237A7; GR74891B; DK38778A; ES466239A1; PT67585B; SE7801046L; PT67585A; GB1600654A; ATA57578A; IL53904A

Abstract

Abstract of the Disclosure Compounds of the formula 1 wherein X is C-R4 or C; Y is -(CH2)n- when X is CR4 and =CH-(CH2)n-1- when X is C; R is hydrogen, lower alkyl, phenyl-loweralkyl of the formula wherein p is 1, 2, 3 or 4 and R1 is hydrogen or halogen, hydroxy, benzoylloweralkyl of the formula wherein p and R1 are as defined above; phenyloxycarbonyl, benzoyl, benzoyloxy or

Description

t;77 This invention relates to novel azacycloalkanes, aza-cycloalkenes and derivatives thereof which are useful as anti-depressants, anticonvulsants, tranquilizers, analgetics and as intermediates therefor, to methods of preparing the same, to methods of treatment with pharmaceutically effective amounts thereof, and to pharmaceutical compositions containing such compounds as essential active ingredients.
To the best of our knowledge, the compounds of this invention have not heretofore been made, used, described or suggested.
Bauer et al., in U.S. Patent 3,959,475, describe substituted 1,3-dihydrospiro(isobenzofuran)s of the formula Rl N

~

in which R is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, haloyen, hydroxy, or methylenedioxy; Rl is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkenyl of 3 to 6 car-bon atoms, phenylalkyl of the formula-(CH2) -PhR, diphenylalkyl of the formula -(CH2)m-CH(PhR~2, diphenylmethoxyalkyl of the formula -(CH2)m-OCHPh2, alkanoyl of 2 to 6 carbon atoms, phenylalkanoyl of the formula -CO(CH2)x-PhR, benzoyl of the formula -COPhR, benzoylalkyl of the formula -(CH2)m-COPhR, phenylhydroxyalkyl of the formula -(CH2) CHOHPhR, alkoxycar-bonyl of 2 to 6 carbon atoms, phenyloxycar~onyl or cycloalkyl-carbonyl of 4 to 8 carbon atoms; R2 is alkyl of 1 to 6 carbon atoms or phenyl of the formula -PhRm; Y is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy or phenyl of the formula PhR; Ph is phenyl, m, n and nl are integers from 1 to 3; and x is an inte~er flom 1 to 4, as ~ell as the optical antipodes and the pharmaceutically acceptable acid addition salts thereof. Additionally, the same patent describes, as intermediates, o-hydroxyalkylphenylcycloazal ~ ols of the formula ,R
N
(CH~)n (CH2)n, ~ OH
m ~

and o-hydroxyalkylphenylcycloazalkanols or their ethers of the formula R
N
(CH ~ (CH2)n, R ~ H
~OR' I ~R2 in which R' ls hydrogen, alkyl or tetrahydropyranyl. These intermediate compounds were not found to demonstrate any biological activity.
Bauer et al., in U.S. Patent 3,962,259 describe, also as intermediates, o-hydroxymethylphenylcycloazalkanols and their ethers of the formula / N \
(CH~)n (CH2)n, ~ OH
m ~ CH2O~I

wherein R' is hydrogen or alkyl, R and Rl, m, n and n' are as defined earlier. These intermediates do not st:ructurally 3Q suggest the instantly descri~ed compounds and were not found to demonstrate biological activity.
Biel et al., in U.S. Patents 3,301,862 and 3,350,403, refer generically to intermediate compoullds of the formula Rl R2 H
wherein either or both Rl and R2 can be benzyl. This, as will be seen below, is pertinent because compounds described in the present application are technically within the scope of this broad generic disclosure. However, the Biel et al.patents neither suggest nor describe a single compound in which a benzyl group is bound to the 2- or ortho position of the phenyl ring, the only benzyl-containing intermediate specifi-cally identified being 4-t3-benzylphenyl)-4-hydroxypiperidine.
We have found the substitution of a benzyl in this 2- or ortho position to bear a critical relationship to biological, especially antidepressant activity. Additionally, there is no teaching of how to make the aforesaid intermediate compounds and no actual disclosure of a compound within the aforemen-tioned generic formula wherein the benzyl group is on this

2- or ortho position.
Similarly, Biel et al., in U.S. Patents 3,221,017 and 3,221,018,refer generically to 1,2,5,6-tetrahydropyridines of the form~la Rl R2 ~

wherein benzyl is included within the definition of Rl and R2, as intermediates in the preparation of 4-arylpyridines. These patents, like the aforementioned U.S. Patents 3,301,862 and

3,350,403, also neither suggest nor disclose a single compound within the scope of the present a~plication, the onl~ such ¦ intermediate identified in these patents being the 3-benzyl-substituted compound, 4-(3-benzylphenyl)-1,2,5,6-tetrahydro-pyridine. Neither Beil et al. patent discloses or suggests any biological activity for these intermediates.
It is apparent from the disclosure in the Biel et al.
patents, e.g., lines 14 to 18, column 5 of 3,221,013, that the starting materials used in the processes of Biel et al. are compounds which are either commercially available, well known in the art or easily prepared do not apply to any of the com-pounds, including the position isomers, disclosed and claimed in this application.
This invention relates to azacycloalkanes, azacyclo-alkenes and derivatives thereof of the formula ,~N ~
(CH~) Y
X

R2~3~R3 wherein X is C-R4 or C; Y is -(CH2)n- when X is CR4 and =(CH-(CH2)n 1- when X is C; R is hydrogen, loweralkyl, phenyl-loweralkyl of the formula -(CH2)p ~ ,lhydroxy, benzoyl-loweralkyl of the formula -(CH2)p-C ~ , cycloalkyllower-alkyl in which the cycloalkyl ringcontains from 3-6 carbon atoms, alkoxy carbonyl of from 2 to 6 carbon atoms~ phenyloxy-carbonyl, benzoyl, benzoyloxy, or -(CH2~ C ~ ; R , R and R are the same or different and each can be hy~rogen, halogen, alkoxy of 1 or 2 carbon atoms, loweralkyl, hydroxy or trifluoro-methyl; R is hydrogen or OR ; R is hydrogen, loweracyl, benzoyl or cycloalkanoyl in which the cycloalkyl ring ccntains from 3 to 6 carbon atoms; m is the integer 1 or 2; n is the integer 1, 2 or 3; the sum of m and n is 3 or 4; p is the integer 1, 2, 3 or 4; and the pharmaceutically acceptable acid addition salts thereof. In the above, the term "lower"

means the radical described contains from 1 to 5 carbon atoms.
Compounds which are preferred due to their biological activity are those wherein R is hydrogen, alkyl or hydroxy.
Most preferred compounds within this group are those wherein X is C-H.
Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inor-ganic 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.
Some compounds within the scope of this invention have greater pharmaceutical activity than others. The latter are nevertheless desirable as intermediates for the preparation of the more active compounds, as will kecome apparent from the following description of several methods of preparation.
Method A
A 2-bromodiphenylmethane of the formula Br Rl ~ H2 ~ - R3 R

in which Rl, R and R , with the exclusion of hydroxy, are as defined above, is converted to its lithio derivative by treat-ment with an alkyllithium at reduced temperature of about -80 to -30C in a solvent such as ether, hexane or tetrahydro-furan. The resulting 1ithio derivative is allowed to react witha compound of the formula R
N
(CH ~ CH2)n ,~

i wherein m and n and the sum of m and n being as defined above and R is loweralkyl, phenylloweralkyl or cycloalkylloweralkyl, at a temperature of -80 to -20C, preferably -60 ~o -30C, in a solvent such as ether, tetrahydrofuran or hexane to provide the corresponding N-substituted azacycloalkanol, a compound of the invention of the formula R
,,N ~
(CH ~ H2)n ~OH

Rl ~ R3 The starting 2-bromodiphenylmethane is prepared by reducing a corresponding 2-bromobenzophenone. One suitable method of carrying out this reduction is via the Clemmensen reduction. Another very suitable method involves the use of hydroiodic acid and phosphorus under reflux conditions. One suitable method of preparing a 2-bromobenzophenone is by react-ing a 2-bromobenzoyl chloride of the formula R3 L~ Br C-Cl o with a benzene of the formula R2 ~
under Friedel-Crafts conditions.
Method B
-An above N-substituted azacycloalkanol, described in Method A, wherein R is benzyl, can be hydrogenated, e.g., with a palladium on carbon catalyst to provide an N-unsubsti-tuted azacycloalkanol.
Method C
An ~-substituted azacycloalkanol, described in ~ethod A, can be esterified by treatment with an appropriate acid anhydride, acid or acid chloride to provide an ester of the invention wherein X is C-oR5 and R5 is loweracyl, benzoyl or cycloalkanoyl in which the cycloalkyl ring contains from 3 to 6 carbon atoms. In some instances yields may be enhanced by converting the azacycloalkanol to its lithio derivative which is in turn esterified.
Method D
An N-unsubstituted azacycloalkanol, described in Method B can be reacted in a known manner with benzoyl chloride to provide the corresponding N-benzoyl azacycloalkanol.
; Method E
An azacycloalkanol, described in Methods A or B is dehydrated to its corresponding azacycloalkene of the formula ~N
(CH2)n Rl ~ ~3 The dehydration can be carried out with one of several dehy-drating agents including trifluoroacetic acid, formic acid and a mixture of glacial acetic and concentrated hydrochloric acids and from ambient to the reflux temperature of the reac-tion mixture.
Method F
An azacycloalkene prepared according to Method E can be hydrogenated as described in Method B to prepare the corresponding N-unsubstituted or substituted azacycloalkane, a compound of the invention of the formula N

( ~ ~2)n Rl~R3 i77 wherein R ~ benzyl.
Method G
An N-substituted cycloazalkane, prepared according to Method F, wherein R is alkyl can be treated with a chlorofor-mate, e.g. an alkyl or phenyl chloroformate, at a temperatureof from 25 to 125C, in a solvent such as toluene, benzene or methylene chloride to provide the corresponding N-alkoxycar-bonyl or N-phenyloxycarbonylcycloazalkane, a compound of the invention.
Method H

¦ An N-alkoxycarbonyl or N-phenyloxycarbonylcycloazal-kane, prepared in Method G, is treated with a base such as sodium or potassium hydroxide in a solvent such as water or ethanol or with an acid such as hydrogen bromide in acetic acid at a temperature of from ambient to 125C. to provide the corresponding N-unsubstituted axacycloalkane, a compound of the invention.
Method I
An N-unsubstituted compound, prepared by Method B, C, E, F or H, can be converted to the corresponding N-benzoyl-oxy compound, a compound of the invention, by the addition of a cooled solution of benzoyl peroxide in a suitable organic solvent such as benzene.
Method J
An N-benzoyloxy compound, prepared in Method I, is converted to its corresponding N-hydroxy compound, a compound of the invention, by a method known to the art. One such method is the cleaving of the benzoyloxy group by the treat-ment with aqueous potassium or sodium hydroxide in ethanol and permitting the mixture to react at the reflux temperature of the reaction mixture.

Method K -~
An ester, prepared by Method C, can hy hydrogenated 7~

all the way to its corresponding azacycloalkane by a method know to the art. One such method involves using a paladium on carbon catalyst.
Method L
An N-unsubstituted compound, prepared by Method B, C, E, F or H can be reacted with a compound of the formula ClCH2 (CH2 ~ p 6~)~ Rl wherein p and Rl are as defined earlier, to produce a corre-sponding compound. This reaction can be carried out in the presence of an organic solvent such as n-butanol and an acid scavenger at ambient temperature to the reflux point of the reaction mixture.
Method M
A compound prepared in Method L can be subjected to hydrolysis by a method known to the art to provide an N-benzoylalkyl compound, a compound of the invention. One such method is carried out with a refluxing mixture of methanol and concentrated hydrochloric acid.
Method N
An alkoxy containing compound, wherein an alkoxy group is situated on a phenyl ring, can be dealkylated by a method known to the art to provide a corresponding phenolic compound. A preferred method is dealkylating with refluxing hydrobromic acid, under an inert atmosphere such as nitrogen.
The compounds of the invention are useful in the treatment of depression in marnmals, as demonstrated by their ability to inhibit tetrabenazine-induced ptosis in mice~inter-3Q national Journal of Neuropharmacology, 8r 73 (1969j], a standard assay for evaluating antidepressant properties. Thus, for instance, the intraperitoneal dosages at which the follow-ing compounds (ED50) effect a 50 % inhibition of the 6~7 tetrabenazine-induced ptosis in mice are:

Mg/Kg

4-[2-~-phenyltolyl)]piperidine hydrochloride 1.7 4-[2-(~-phenyltolyl)]-1,2,3,6-tetrahydropyridine 2.1 l-methyl-~-[2-(~-phenyltolyl)]piperidine hydrochloride 2.5 4-[2-(~-phenyltolyl)-4-piperidinol hydrochloride 5.4 4-{2-[~-(4-fluorophenyl)tolyl]}-1-methyl-1,2,3,6-tetrahydropyridine hydrobromide 8.0 4-~2-[~-(4-fluorophenyl)tolyl]~-1-methyl-4-piperidinol 8.2 l-methyl-4-~2-(~-phenyltolyl)]-1,2,3,~-tetrahydropyridine 8.8 l-methyl-4-[2-(~-phenyltolyl)]-4-piperidinol ~.0 l-hydroxy-4-[2-(~-phenyltolyl)]piperidine 3.0 Similarly a 25 mg/kg intraperitioneal dosage of 4-acetoxy-1-methyl-4-[2-(~-phenyltolyl)]piperidine hydrochloride effects a 40% inhibition of the tetrabenazine-induced ptosis.
These data illustrate that compounds of the invention are use-ful in the treatment of depression when administered in amounts ranging from 0.1 and 50 mg/kg.
Compounds of the invention are useful as analgesic agents due to their ability to alleviate pain in mammals. The analgesic utility of compounds of this invention is demonstra-ted in the 2-phenyl-1,4-quinone induced writhing assay in mice, a standard assay for analgesia [Proc. Soc. Exptl. ~iol. Med., _, 729(1957)]. Thus, for example, a 50~ inhibition in writh-ing is effected by the oral administration of 28.4 mg/kg of body weight of 4-acetoxy-1-methyl-4-[2-(~-phenyltolyl)]piperi-dine hydrochloride. Other representative compounds of the invention and their respective ability to inhibit said writhing is shown below in Table II.

~ 10 -TABLE II
% Inhibition Dose in mg/kg in Writhing l-methyl-4-[2-(~-phenyltolyl)]-4-piperidinol 50.0 po* 41 1-methyl-4-[2-(~-phenyltolyl)]-piperidine hydrochloride 61.7 po 50 4-[2-(~-phenyltolyl)]-1,2,3,6-tetrahydropyridine 7.8 sc** 50 l-methyl-4-[2-(~-phenyltolyl)3-4-propionyloxypiperidine hydro-chloride 8.9 sc 50 4-benzoyloxy-1-methyl-4-[2-(~-phenyltolyl)]piperidine hydro-chloride 12.8 sc 50 *po means oral administration **sc means subcutaneous administration These data show that the compounds o~ the invention are useful as analgesic agents at a dose of 0.1 to 50 mg/kg of body weight. For comparison, aspirin and propoxyphene hydrochloride, known analgesic agents, effect a 34% and 50%
inhibition of writhing, respectively, at a dose of 60mg/kg. p.o.
Compounds of the present invention are further use-ful as anticonvulsant agents for mammals, as determined by the method of Woodbury, L.A. and Davenport, V.D., in Arch, Int.
Pharmacodynam, Vol. 92, (1952) at pages 97-107. For example, the intraperitoneal dose of 17.6 mg/kg of body weight of 1-methyl-4-f2-~-(4-fluorophenyl)tolyl]~-1,2,3,6-tetrahydro-pyridine hydrobromide produces an 83% protection from the effect of supra maximal eletrco shock (SES). Intraperitoneal doses of other representative compounds of the invention and their ability to protect from the effect of SES is shown below in Table III.

~"

3~i77 TABLE III
Compound Dose mg/kg % SES Protection l-benzyl-3-[2-(~-phenyltolyl)]-3-pyrrolidinol hydrochloride 50 83 1-methyl-4-[2-(~-phenyltolyl)]-piperidine hydrochloride 50 83 l-methyl-4-~2-[~-(4-fluorophenyl)-tolyl]~-4-piperidinol 23.3 50 l-methyl-4-{2-[(4-methoxyphenyl)-tolyl]~ -1,2,3,6-tetrahydropyridine hydrobromide 25.6 50 l-methyl-4-[2-(~-phenyltolyl)]-4-piperidinol 36 50 l-phenethyl-4-[2-~-phenyltolyl)]-piperidine hydrobromide 37.5 50 l-methyl-4-[2-(~-phenyltolyl)]-4-propionyloxypiperidine hydrochloride 5~ 50 This data illustrates the utility of compounds of the invention for treatment of convulsion in mammals when 2~ administered in amounts ranging from about 1 to 50 mg/kg of body weight per day.
Compounds of the invention are still further useful as tranquilizers due to their ability to reverse toxicity of amphetamine as measured in the Amphetamine Aggregation Toxicity Reversal Assay [Chance, M.R.A., J. Pharmacol. Esper. Therap.
8~, ppe 214-219 (1946) and Proctor, C.D~, Putts, J.T., Lundy, R.O., and Greenfield, E.J., Arch. Int. Pharmacodynam., 163, (1), pp. 79-86 (1966)]. In our assay "aggregated mice" mean

5 mice/group placed in such a manner as to yield 20 cm2 of floor space per mouse. Animals are aggregated immediately after injection with amphetamine sulfate and then checked for survival up to 3 hours. For example, under these conditions an oral dosage of 20 mg~kg of ~ody weight of 1-[3-~-fluoro-ilS~3~ ~7 benzoyl)propyl]-4-[2-(~-phenyltolyl)~piperidine effects a 60%
protection against the intraperitoneal dose of 15 mg/kg of amphetamine sulfate. This data illustrates that compounds of the invention are useful as tranquilizers when administered in amounts ranging from 0.1 to 50 mg/kg.
Effective quantities of the compounds of the inven-tion may be administered to a patient by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solu-tions. The free base final products, while effective them-selves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience of crystallization, increased solubility and the like.
The active conpounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administration, the active com-pounds of the invention may be incorporated with excipients and used in the form of tahlets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least 0.5% of active compounds, but may be varied depending upon the particular form and may conveniently be between 4~ to about 70% of the weight o~ the unit. The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred com-positions and preparations according to the present invention are prepared so that an oral dosage unit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches, and the like may also cont~in the following ingredients: a binder such as microcrystalline cellulose, gum trangacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like; a lubricant such as magnesium stearate or ~terotex; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or sacharin may be added or a flavouring 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 mayke coated with sugar, shellac, or other enteric coatings agents. A syrup may contain, in addition to the active compounds, sucrose as a lS sweetening agent, and certain preservatives, dyes and colorings, and flavors. Materials used in preparing these various compo-sitions should be pharmaceutically pure and non-toxic in the amounts used.
For the purpose of parenteral therapeutics administra-tion, the active compounds of the invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but may be varied to be between 0.5 and about 50% of the weight thereof. The amount of active compounds in such compositions is such that a single 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 following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, ~lycerine, propylene glycol or other synthetic solvents; anti-bacterial agents such as benzyl alcohol or methyl parabens;
antioxiaants such as ascorbic acid or sodium bisulfite;

chelating agents such as ethylene diaminetetraacetic acid;buffers such as 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, dispos-able or multiple dose vials made of glass or plastic.
This invention is illustrated by the following examples:
l-methyl-4-[2-(~-phenyl-3-trifluoromethyltolyl)1-4-piperidinol;
1-n-butyl-4-[2-(~-phenyl-4-chlorotolyl)~-3-pyrroli-dinol;
4-[2-(~-phenyl-4-hydroxytolyl)]-1,2,3,6-tetrahydro-pyridine;
3-acetoxy-1-(3-phenylpropyl)-3-[2-(~-phenyl-4-ethoxy-tolyl)]pyrrolidine;
1-(3-phenethyl)-4-[2-(a-phenyl)tolyl]1,2,3,6-tetra-hydropyridine; and 4-[2-(~-phenyl-4-t.butyltolyl)-1-phenoxycarbonyl-piperidine.
This invention is further illustrated by the follow-ing examples and their preparation.
Example 1 To a stirring solution at -40C of 18.5 g of 2-bromo-diphenylmethane, 80 ml of tetrahydrofuran and 18 ml of anhy-drous hexanes is added over a 20 minute span 38 ml of a 2.2 M solution of n-butyllithium in hexane. A'ter total addition stirring is continued for 50 minutes after which time 8.84 g of l-methyl-4-piperidone in 25 ml of tetrahydrofuran is added with stirring over a 25 minute span while maintaining this low temperature. After total addition the solution is permitted to stir at this same temperature for 1.5 hours and then warmed to 0C. The reaction solution is hydrolyzed with 25 ml of water with ice-water cooling. The resulting suspension is diluted by the addition of 200 ml of water and 500 ml of hex-anes. The suspension is shaken vigorously, the aqueous phase separated and the organic phase washed with 200 ml of water.
The organic phase is suction filtered and the filter cake 5 washed well with hexane and dried. Recrystallization of the dried filter cake from toluene leaves colorless crystals, mp 163-165C., of l-methyl-4-~2-(c~-phenyltolyl)]-4-piperidinol.
Analysis:
Calculated for ClgH23NO: 81.08%C; 8-25%H; 4-98%N-Found: 80.91%C; 8.10%H; 4.909~N.
Examples 2-6 By following the manipulative procedure outlined above in Example 1 the reaction o~ 2-bromo-4'-methoxydiphenyl-methane and l-methyl-4-piperidone; 2-bromo-4'-fluorodiphenyl-methane and 1-methyl-4-piperidine; 2-bromo-2'-fluoro-4'-methyl-diphenylmethane and l-methyl-4-piperidone; 2-bromodiphenyl-methane and 1-(2-phenethyl)-4-piperidone; and 2'-br~ro-2,5 difluorodiphenyl-methane and l-methyl-4-piperidone provides 1-methyl-4- ~2-[~-(4~methoxyphenyl)tolyl]~ -4-piperidinol, 1-methyl-4-~2-[c~-~4-fluorophenyl)-tolyl]~-4-piperidinol, 1-methyl-4-~2-[~-~2-fluoro-4-methylphenyl)tolyl]~ -4-piperidinol, 1-(2-phenethyl)-4-[2-(c~-phenyl)tolyl~-4-piperidinol, and 1-methyl-4- {2-[c~-(2,5-difluoro-phenyl)tolyl]-4-pi~eridinol, respectively, as listed in Table sequentially as Examples 2-6.

Table 1 Analy~is Res~ryst'n m.p. Empirical Calculated Found Ex. Solvent C Formula %C %H %N %C %H %N
_ 2 isoprop. 142-144 C20H25NO277.14 8.09 4.2876.86 8.15 4.48 3 hexane 142-144 ClgH22FNO76.22 7.41 4.6876.14 7.44 4.71 4 benzene- 157-159 C20H24FNO76.64 7.68 4.4776.62 7.84 4.45 hexane toluene 135-138 C26H29N 84.04 7.88 3.7784.14 8.05 3.71

6 acetone- 150-152 ClgH21F2NO 71.89 6.67 4.41 71.72 6.30 4.47 Example 7 To a solution of 5.0 g of 2-bromo-2'-fluoro-4'-methyldiphenylmethane in 50 ml of tetrahydrofuran at -60C is added dropwise 9 ml (2.4m) of n-butyllithium. After total addition the solution is stirred for 30 minutes and then a solution of 3.41 g of 1-benzyl-4-piperidone in 10 ml of tetra-hydrofuran is added dropwise while maintaining the reaction temperature at -60C. The reaction mixture is kept at this temperature for 30 minutes and then poured into 400 ml of ice cooled water. The resulting mixture is extracted with ether and the ether extract dried, concentrated and the hydrochloride salt prepared. The salt is collected by filtration and dissolved in chloroform. The chloroform solution is washed with water, dried, filtered and the chloroform evaporated off leaving a white solid. The solid is recrystallized from a methanol-acetone-ether mixture to leave the salt mp 216-218C, of l-~enzyl-4-~2-[a-(2-fluoro-4-methylphenyl~tolyl]~-4-piperidinol-hydrochloride.
Analysis:
Calculated for C26H28FNO-HCl: 73.31%C; 6-86%H; 3.29%H.
Found: 73.12%C; 6.93~H; 3.06~H.
Example ~
To a solution of 5 6 g of 2'-bromo-2,5-difluorodi-phenylmethane in 18 ml of tetrahydrofuran at -50C is added dropwise 14 ml of n-butyllithium while maintaining the temperature below -50C. After total addition the reaction mixture is stirred at a temperature of from -60 to -70C for 30 minutes. A solution of 3.5 g of 1-benzyl-3-pyrrolidone in 5 ml of tetrahydrofuran is aaded dropwise, the reaction mixture is stirred at this temperature for 30 minutes, after which time ice is added and the resulting mixture extracted twice with 200 ml portions of ether. The combined ether extracts are shaken with 120 ml of lN hydrochloric acid which produces an oily residue. The ether and aqueous layers are carefully discarded and the oily residue is basified with dilute ammonium hydroxide. The basic solution is extracted with ether and the ether extract dried. The ether solution is treated with ethereal hydrogen bromide to produce a crystalline salt which is recrystallized from a methanol-ether mixture to provide the crystals mp 203-205C, of l-benzyl-3-~2-[a-(2,5-difluorophenyl)-tolyl]~-3-pyrrolidinol hydrobromide.
Analysis:
Calculated for C24H23F2NO'HBr: 62.59%C; 5.25~H; 3.04%N
Found: 62.51%C; 5.39%H; 3.05%N.
Example 9 By following the procedure outlined above in Example 8, substituting 1-benzyl-4-piperidone for 1-benzyl-3-pyrroli-done produces l-benzyl-4-{2-[~-(2,5-difluorophenyl)tolyl]}-4-piperidinol'hydrobromide, mp 143-146C.
Analysis:
Calculated for C25H25F2NO'HBr: 63.30~C; 5.52~H; 2.95%N; 16-~4%Br-Found: 63.28%C; 5.64~H; 3.01%N; 16.82%Br.
Example 10 To a solution at -50C of 5.6 g of 2-bromo-2'-fluoro-4'-methyldiphenylmethane in 15 ml of tetrahydrofuran is added dropwise 11 ml of 2.2 M butyllithium while maintaining the reaction temperature below -50C. After total addition stir-ring is continued at -60 to -70C for 30 minutes and then a solution of 3.5 g of 1-benzyl-3-pyrrolidone in 5 ml of tetra-hdyrofuran is added over a 5 minute span. After total addi-tion stirring is continued at this low temperature for 30 minutes, ice added, and then the organic material extracted twice with 200 ml portions of ether. The combined ether extracts are shaken vigorously with an excess of lN hdyrochloric acid which produces an oily residue which solidifies slowly upon standing. The solid is recrystallized from a methanol-~. ,~

acetone-ether mixture to give off-white prisms, mp 292-294C, of l-benzyl-3- ~2-[tY-(2-fluoro-4-methylphenyl)tolyl]~ -3-pyrroli-dinol hydrochloride.
Analysis:
Calculated for C25H26FNO HCl: 72.90%C; 6.60%H; 3.40%N; 8.60%Cl.
Found: 72.64%C; 6.77%H; 3.35%N; 8.44%Cl.
Example 11 By following the manipulative procedure outlinedabove in Example 10, substituting 1-(2-phenethyl)-4-piperidone for 1-benzyl-3-pyrrolidone produces the white powder, 262-263C, of 4- ~2-[c~-(2-fluoro-4-methylphenyl)tolyl]} -1-phenethyl-4-piperidinol hydrochloride.
Analysis:
Calculated for C27H30FNO HCl: 73.70%C; 7.10%H; 3.1~%N; 8.06%Cl.
Found: 73.49%C; 7.21%H; 3~00~oN; 8.15%C1.
Example 12 ~ o a stirring solution at -50C of 1~.5 g of 2-bromo diphenylmethane, 70 ml of tetrahydrofuran and 18 ml of hexane is added over a 30 minute span a 40 ml of 2.2 M hexane solu-20 tion of n-butyllithium. After total addition the solution is stirred at -50C for 30 minutes and then a solution of 14.8 g of l-benzyl-4-piperidone in 40 ml of tetrahydrofuran is added over a 30 minute span. After total addition the solution is stirred at -50C for 60 minutes, permitted to warm to -30C, 25 and then quenched with 40 ml of water. The reaction mixture is diluted with 400 ml of water and 500 ml of hexane. The organic and aqueous phases separated and the organic phase collected and washed with water. The washed organic phase is evaporated leaving an oil which is azeotropically dried with 30 benzene. The oil diluted with an equal volume of hexane -and the hexane mixture chilled at 5C for 2 hours. The upper phase is decanted and the hexane washing procedure is repeated twice. The ultimate lower phase is di~uted in 50 ml of tetrahydrofuran, acidified with a 5% hydrochloric acid solution causing a dark oil to separate as the upper phase. The biphasic mixture is extracted thrice with 75 ml portions of chloroform and the combined extracts are washed with water 5 and then a 5% sodium hydroxide solution. The organic solution is dried, filtered and the filtrate evaporated to an oil which is dissolved in ether and precipitated as hydrogen chloride salt. The salt is dried in vacuo at ambient temperature and then recrystallized from acetonitrile leaving slightly tan colored crystals, mp 190-191C, of l-benzyl-4-[2-(~-phenyl-tolyl)]-4-piperidinol hydrochloride.
Analysis:
Calculated for C25H27NO HCl: 76.2196C; 7.18%H; 3.56~N; 9.00%Cl.
Found: 76.2296C; 7.24%H; 3.47%N; 8.82%Cl.
~ Example 13 By following the manipulative procedure outlined above in Example 12, substituting 1-benzyl-3-pyrrolidone for l-benzyl-4-piperidone, produces 1-benzyl-3[2-(~-phenyltolyl)]-3-pyrrolidinol hydrochloride.
20 Analysis:
Calculated for C24H25NO HCl: 75.86~C; 6.91%H; 3.69%N; 9.33%C1.
Found: 75.62%C; 6.96%H; 3.69%N; 9.15%Cl.
Example 14 To a 500 ml Parr hydrogenation bottle charged with 1.0 g of a 10% palladium on carbon catalyst and 30 ml of iso-propyl alcohol under a nitrogen atmosphere is added a mixture of 5.0 g of 1-benzyl-3-[2-(c~-phenyltolyl)]-3-pyrrolidinol hydrochloride, Example 13, and 70 ml of isopropyl alcohol.
The reaction mixture is hydrogenated at 50 psi with heating and shaking for 30 minutes. After hydrogenating the mixture is permitted to cool to ambient temperature and suction fil-tered. The filter cake is washed well with methanol and the methanol wash combined with the isopropyl alcohol filtrate.

~1q3;3677 The combined wash and filtrate is evaporated leaving a solid which is recrystallized from isopropyl alcohol to leave color-less crystals, mp 211-211.5C (dec), of 3-~2-(~-phenyltolyl)~-3-pyrrolidinol hydrochloride.
Analysis:
Calculated for C17HlgNO HCl: 70.4496C; 6.97%H; 4.83%N; 12.23%Cl.
Found: 70.64%C; 7.09%H; 4.79%N; 12.27%Cl.
Example 15 By following the manipulative procedure outlined above in Example 14, the hydrogenation of 1-benzyl-4- [2-(a-phenyltolyl)]-4-piperidinol-hydrochloride, Example 12, pro-duces 4-[2-(a-phenyltolyl)~-4-piperidinol hydrochloride which is recrystallized from isopropyl alcohol with refrigeration gives the salt as colorless crystals, mp 226-227C (dec),.
15 Analysis:
Calculated for C18H21NO ~Cl: 71.15%C; 7.31%H; 4.61%N; 11.67%Cl.
Found: 71.24%C; 7.43%H; 4.42%N; 11.53%Cl.
Example 16 To a solution of 2.0 g of 1-(2-phenethyl)-4-[2-(a-20 phenyltolyl)]-4-piperidinol, Example 5, in 30 ml of tetrahydro-furan at -60C is added dropwise a solution of 2.8 ml of 2.4 M n-butylithium in hexane. After total addition the reaction mixture is stirred for 15 minutes while maintaining this reduced temperature and then 1 ml of benzoyl chloride is added 25 dropwise. The reaction mixture is permitted to stir at ambient temperature for 16 hours and then diluted with 40 ml of tetra-hydrofuran and 10 ml of water. The biphasic mixture separates and the organic phase is washed successively with 10 ml of a 5% sodium hydroxide solution and 10 ml of water, treated with 30 a slight excess of ethereal hydrogen chloride and then the solvent evaporated off. The oily residue is azeotropically dried with benzene and the solid residue is triturated with cold acetone, dissolved in chloroform and precipitated by 111r3;~677 gradual dilution with ether. The precipitate is dried to a colorless solid, mp 198-203C of 4-benzoyloxy-1-(2-phenethyl)-4-[2-(~-phenyltolyl)]piperidine hydrochloride.
Analysis:
Calculated for C33H33NO2 HCl: 77.38%C; 6.71%H, 2.74~N.
Found: 77.39%C; 6.90%H; 2.62~N.
Example 17 A solution of 10.3 g of 1-benzyl-4-~2-(~-phenyl-tolyl)]-4-piperidinol hydrochloride, Example 12, in 70 ml of chloroform is washed twice with 50 ml portions of a 5% sodium hydroxide solution, dried and the chloroform evaporated off leaving the free base as an oil. The oil is dissolved in 10 ml of ether and treated carefully with 30 ml of acetylchloride.
The resulting suspension is diluted with 30 ml of ether and stirred for 16 hours at ambient temperature. The precipitate is collected by filtration, washed well with ether and dried and then recrystallized from isopropyl alcohol to afford colorless crystals, mp 193-194C of 4-acetoxy-1-benzyl-4-~2-(~-phenyltolyl)]piperidine hydrochloride.
Analysis:
Calculated for C27H29NO2 HCl: 74.37~oC; 6.95%H; 3.21%N; 8.13%Cl.
Found: 74.19%C; 6.99%H; 3.14~N; 8.28~Cl.
Example 18 1.41 g of 1-methyl-4-[2-(a-phenyltolyl)]-4-piperi-dinol, Example 1, is treated with 4.0 ml of acetyl chloride with cooling and stirring. The resulting suspension is stirred at ambient temperature under nitrogen for one hour and then permitted to stand for 94 hours. The mixture is diluted with 10 ml of ether and filtered. The filter cake is washed with ether and then recrystallized from absolute ethanol to gi~e colorless crystals, mp 205-206C of 4-acetoxy-1-methyl-4-[2-(~-phenyltolyl)]piperidine hydrochloride.

Example 19 2.0 g of 1-methyl-4-[2-(~-phenyltolyl)]-4-piperidinol, free base of Example 1, is treated with 8.15 ml of cyclopropane carboxylic acid chloride with stirring and cooling. The result-5 ing suspension is stirred for 16 hours at ambient temperatureand then diluted with 25 ml of ether and permitted to stand for 144 hours. The precipitate is collected by suction filtration and the filter cake washed with ether, dried in vacuo at 40C for 16 hours leaving colorless crystals which 10 are recrystallized twice from isopropyl alcohol to give color-less crystals, mp 198-200C of 4-cyclopropylcarbonyloxy-1-methyl-4- [2- (~-phenyltolyl)]piperidine hydrochloride.
Analysis:
Calculated for C23H27NO2 HCl: 71.57%C; 7.33%H; 3.63%N; 9.18%Cl.
Found: 71.34%C; 7.50%H; 3.43~oN; 9.02%Cl.
Example 20 2.0 g of 1-methyl-4-[2-(c~-phenyltolyl)~-4-piperidinol, Example 1, is treated with 10 ml of benzoyl chloride with stir-ring and cooling. The reaction solution is diluted with 20 ml 20 of ether, stirred for two hours and the resultin~ precipitate collected by suction filtration. The filter cake is washed well with ether and dried in vacuo at 40C over sodium hydroxide pellets. The dried filter cake is recrystallized twice from a chloroformether mixture to give colorless crystals, mp 197-198C
25 of 4-benzoyloxy-1-methyl-4-[2~ phenyltolyl)]piperidine hydro-chlorid~.
Analysis:
Calculated for C26H27NO2 HCl: 74.00%C; 6.70%H; 3.32~N; 8.40%Cl Found:74.04%C; 6.76%H; 3.36~1`J; 8.66~Cl.
Example 21 2.0 g of 1-methyl-4-[~ -phenyltolyl)3-4-piperidinol, Example 1, is treated with 10 g of cyclobutanecarbonyl chloride with stirring and cooling. The reaction mis~ture is stirred for - ~3 -48 hours at ambient temperature, diluted with 15 ml of etherand then stirred for 2 hours. The resulting precipitate is collected by suction filtration, the filter cake washed well with ether and dried in vacuo over sodium hydroxide pellets.
5 The filter cake is recrystallized twice from an acetone-ether mixture to give colorless crystals, mp 194.5-195C of 4-cyclo-butylcarbonyloxy-l-methyl-4-[2-(~-phenyltolyl)]piperidine hydrochloride.
Analysis:
Calculated forC24H28NO2 HCl: 72.24%C; 7.34%H; 3.51%H; 8.88%Cl.
Found: 72.02%C; 7.57%~; 3.41g6H; ~.83%Cl.
Example 22 1.41 g of 1-methyl-4-~2-(u-phenyltolyl)]-4-piperi-dinol, Example 1, is treated with 5.0 ml of propionyl chloride 15 with stirring and cooling. The reaction mixture, at ambient temperature, is sitrred for 30 minutes and then permitted to stand for 137 hours under nitrogen. The mixture is diluted with 5.0 ml of ether, stirred for 5 minutes and resulting pre-cipitate collected by suction filtration. The ~ilter cake is 20 washed thoroughly with ether and recrystallized twice from isopropyl alcohol to give colorless crystals, mp 191-193C of l-methyl-4-[2-(o~-phenyltolyl)]-4-propionyloxypiperidine hydro-chloride.
Analysis:
Calculated forC22H27NO2 HCl: 70.65~oC; 7.56%H; 3.75%N; 9.48%Cl.
Found: 70.55%C; 7.65%H; 3.7496N; 9.57%Cl.
Example 23 A solution of 1.49 g of 1-methyl-4-[2-(c~-phenyl-tolyl)]-4-piperidinol, 4.5 ml of valeryl chloride and 30 ml 30 of chloroform is stirred for 16 hours at ambient temperature.
The solution is basified with a 5% sodium hydroxide solution and the basified solution is also stirred overnight at ambient temperature. The biphasic mixture separates and the organic portion is washed with water, dried and the solvent evaporated off leaving an oil. The oil is dissolved in absolute ethanol and converted to an oxalate salt. The solvent is evaporated off and the residue dried in vacuo for 7 days at 40C. The dried product is recrystallized from absolute-ethanol to give colorless crystals, mp 194-196C, of l-methyl-4-[2-(-phenyl-tolyl)]-4-valeryloxypiperidine oxalate.
Analysis:
Calculated for C24H31N2 C2H24 Found: 68.29%C; 7.16~H; 3.07%N.
Example 24 1.5 g of 1-methyl-4-~2- [a- (2-fluoro-4-methylphenyl) tolyl]~-4-piperidinol, Example 4, is treated carefully with

7 ml of benzoyl chloride with stirring and cooling. The reaction mixture is stirred for 16 hours at ambient tempera-ture and then diluted with 15 ml of ether. The resulting precipitate i5 filtered, washed with ether, converted to the free base which is column chromatographed on an alumina column using ether as the eluant~ The free base is converted to its hydrogen chloride salt which is recrystallized from a methanol-acetone-ether mixture to give a white powder, mp 218-219C of 4-benzoyloxy-4-~2-la-(2-fluoro-4-methylphenyl)tolyl3 methylpiperidine hydrochloride.
Analysis:
Calculated for C27H28FNO2 HCl: 71.43%C; 6.44%H; 3.09%N.
Found: 71.08%C; 6.55%H; 2.88~N.
Example 25 By following the manipulative procedure outlined above in Example 24, 1.97 g of 1-methyl-4-~2-[~-(2-fluoro-4-methylphenyl)tolyl]}-4-piperidinol, Example 4, is treated with 6.3 ml of propionyl chloride to produce 4-~2-[~-(2-fluoro-4-methylphènyl~tolyl]~-4-propionyl-oxy-1-methylpiperidine hydro-chloride which is recrystallized from an acetoneether mixture affording a product having an mp of 183-186C.
Analysis:
Calculated for C23H28FNO2 HCl: 68.05%C; 7.20%H; 3.45%~; 8.74%Cl.
Found: 67.89%C; 7.27%H; 3.42%N; 8.87%Cl.
Example 26 A suspension of 5.0 g of 3-[2-(~-phenyltolyl~-3-pyrrolidinol hydrochloride, Example 14, in 40 ml of methanol is diluted with water until a solution forms. The solution is treated with an excess of a 596 sodium hydroxide solution 10 and then the methanol removed on a rotary evaporator leaving a suspension. The suspension is diluted with 50 ml of water and extracted successively with a 100 ml and a 20 ml portion of chloroform. The combined chloroform extracts are washed once with 50 ml of a 5% sodium hydroxide solution and twice 15 with 50 ml portions of water and dried and the chloroform removed. The residue is subjected to azeotropic distillation with benzene and then dried in vacuo at 40C for 2 hours before being suspended in 30 ml of warmed chloroform contain-ing 2.2 g of triethylamine. To this suspension is added 20 dropwise 2.60 g of benzoyl chloride. After total addition, the resulting solution is stirred for 2 hours and then permit-ted to stand for 48 hours. The solution is diluted with 30 ml of chloroform, washed successively with a 50 ml portion of water and similar amount of a 596 sodium hydroxide and dried 25 and the solvent removed leaving a tacky foam. The foam is dissolved in 60 ml of ether (warming may be required), and the solution filtered thorugh glass wool. A precipitate forms which is collected by suction filtration and dried in vacuo at ambient temperature leaving a colorless solid, mp 113-116C, 30 of 1-benzoyl-3-~2-~-phenyltolyl)]-3-pyrrolidinol.

Analysis:
Calculated for C24H23NO2 8~.63%C; 6.50g6H; 3.92%N.
Found: 80.519~C; 6.62%H; 3.80~N.

Example 27 A solution of 8.0 g of 1-methyl-4-r2-(~-phenyltolyll]-4-piperidinol, Example 1, in 100 ml of 97% formic acid is refluxed with stirring for 16 hours. The solution is poured into 300 ml of water, made strongly basic with a 50% sodium hydroxide solution and the basic mixture extracted thrice with 100 ml of portions of chloroform. The combined chloro-form extracts are dried and the chloroform removed leaving an oil. The oil is dissolved in 20 ml of dimethylsulfoxide.
The solution is diluted with 250 ml of water leaving a cream colored solid which is recrystallized from dimethylsulfoxide to give colorless crystals, mp 55-57.5C of l-methyl-4-[2-(a-phenyltolyl)]-1,2,3,6-tetrahydropyridine.
Analysis:
Calculated for ClgH21N: 86.63%C; 8.05%H.
Found: 86.75~C; 8.29%H.
Example 28 A suspension of 3.0 g of 4-~2-(a-phenyltolyl)]-4-piperidinol hydrochloride, Example 15, in 25 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid is refluxed with stirring for 60 minutes. The solution is per-mitted to cool and then diluted with 100 ml of water and basi-fied with a 50% sodium hydroxide solution. The alkaline solu-tion is extracted thrice with 30 ml portions of chloroform and the combined chloroform extracts are dried and the chloroform removed leaving an oil which crystallizes upon standing. The crystals are recrystallized from hexane leaving cream colored crystals, mp 73-75C, of 4-[2-(a-phenyltolyl)]-1,2,3,6-tetra-hydropyridine.
Analysis:

Calculated for C18HlgN: 86.69~C; 7.70~H.
Found: 86.72%C; 7.85%H.

~ - - 27 -Exam~le 29 -By following the manipulative procedure outlined above in Example 28, 2.86 g of 1-(2-phenethyl2-4-[2-(a-phenyl-tolyl)]-4-piperidinol, Example 5, is dehydrated and treated to obtain colorless crystals, mp 98-100C, of 1-~2-phenethyl)-4-[2-a-phenyltolyl)]-1,2,3,6-tetrahydropyridine.
Analysis:
Calculated for C26H27N: 88.32%C; 7-71%H; 3-96%N-Found: 88.55~C; 7.79%H; 3.93%N.
Example 30 A mixture of 5.0 g of 1-methyl-4- ~-~a- (4-methoxy-phenyltolyl)]-4-piperidinol, Example 2, 30 ml of glacial acetic acid and 6 ml of concentrated hydrochloric acid is refluxed with stirring for 2 hours and then permitted to stand for 48 hours at ambient temperature. The reaction solution is poured into ice-water and then basified with a 50~ sodium hydroxide solution. The basic solution is extracted twice with 200 ml portions of chloroform and the combined chloroform extracts are dried, filtered and the chloroform removed under partial vacuum leaving an oil. The oil is dissolved in ether and the hydrogen bromide salt precipitated. The precipitate is collected by suction filtration and dried in vacuo at 40~C.
The dried precipitate is recrystallized from isopropyl alcohol to give, colorless crystals, mp 149-152C of l-methyl-4-~2-[a-(4-methoxyphenyl)tolyl]~-1,2,3,6-tetrahydropyridine hydrobromide.
Analysis:
Calculated for C20H23NO HBr: 64.17%C; 6.46~H; 21.35%Br.
Found: 64.09%C; 6.51%H; 20.98%Br.
Examples 31 & 32 By following the manipulative procedure outlined above in Example 30, 2.30 g of 4-{2-[a-(4-fluorophenyl)tolyl]~-l-methyl-4-piperidinol, Example 3, and 3.5 g of 1-benzyl-4-[2-(a-phenyltolyl)]-4-piperidinol hydrochloride, E~ample 12, are - 2~ -1~3677 dehydrated and treated to provide 4-2-~-(4-fluorophenyl) tolyl)~-l-methyl-1,2,3,6-tetrahydropyridine hydro~romide and l-benzyl-4-[2-(~-phenyltolyl~]-1,2,3,6-tPtrahydropyridine hydrochloride, respectively, as listed in Table 2 sequentially as Examples 31 and 32.
Table 2 Analysis m.p. Empirical Calculated Found Ex.C Formula %C %H %N %C %H %N

Cl9 20 62.99 5.84 3.87 62.76 5.91 3.76 316 223 C25H25N HCl79.86 6.98 9.43 80.10 7.02 9.58 Example 33 A suspension of 0.70 g of platinum oxide (Adam's catalyst) in 50 ml of 95~ ethanol is hydrogenated on a Parr shaker at 50 psi for three hours at ambient temperature. To this hydrogenated suspension is added a solution of 2.4 g of l-methyl-4-[2-(~-phenyltolyl)]-1,2,3,6-tetrahydropyridine, Example 27, in 50 ml of 95% ethanol and the resulting mixture is hydrogenated in similar fashion overnight. The mixture is filtered and the filtrated evaporated to a colorless oil which is taken up in ether. The ethereal solution is filtered, the filtrate treated with etheral hydrogen chloride which causes a hydrogen chloride salt to precipitate. The salt is collected by suction filtration which is recrystallized twice from isopropyl alcohol to provide colorless crystals, mp 220.5-222.5C, of l-methyl-4~[2-(~-phenyltolyl)Jpiperidine hydro-chloride.
Analysis:
Calculated for ClgH23N HCl: 75.59%C; 8.03%H, 11.74%Cl.
Found: 75.40%C; 8.08%H; 11.57~Cl.

Example 34 A suspension of 0.3 g of platinum oxide and 10 ml of absolute ethanol is hydrogenated on a Parr apparatus at ambient temperature at 50 psi ~or 15 minutes. To the hydrogenated r~

llC~677 suspension is added a solutiOn of 3.1 g of 1-phenethyl_4_~2-(-phenyltolyl)]-1,2,3,6-tetrahydropyridine, Example 29, in 100 ml of absolute ethanol. The reaction suspension is hydro-genated in similar fashion for 48 hours. The suspension is filtered and the filtrate treated with anhydrous bromide. The filtrate is concentrated on a rotary evaporator leaving an oil which solidifies upon standing. The solid is recrystallized from 150 ml of hot absolute ethanol followed by gradual dilu-tion with 350 ml of ether provides colorless crystals, mp 220-225C of l-phenethyl-4-[2-(~-phenyltolyl)piperidine hydro-bromide.
Analysis:
Calculated for C26H2gN HBr: 71.55%C; 6.93%H; 3.21%N.
Found: 7.154%C; 7.11%H; 3.12%N.
Example 35 A suspension of 0.5 g of platinum oxide and 25 ml of 95% ethanol is hydrogenated at 40 psi for 30 minutes at ambient temperature. To the hydrogenated suspension is added a solution of 2.5 g of 4-[2-(~-phenyltolyl)]-1,2,3,6-tetra-hydropyridine, Example 28, in 25 ml of 95% ethanol and the reaction suspension is hydrogenated in similar fashion for 24 hours. The hydrogenated suspension is suction filtered and the filtrate evaporated to a colorless oil. Hydrogenation is repeated on this oil. The oil obtained after the second hydro-genation is converted to the hydrochloride salt. The salt is subjected to hydrogenation using 400 mg of platinum oxide at 50 psi. The salt is then recrystallized from 30 ml of isopro-pyl alcohol leaving colorless crystals, mp 207.5-209.5C, of 4-[2-(~-phenyltolyl)]piperidine hydrochloride.
Analysis:
Calculated for Cl~H21N HCl: 75.10%C; 7.72%H; 4-87%N-Found: 75.13%C; 7.71%H; 4.80%N.

liq~;~677 Example 36 A mixture of 36.6 g of 4-~2~ (4-methoxyphenyl) tolyl]~-l-methyl-1,2,3,6-tetrahydropyridine hydrobromide, Example 30, 153 ml of absolute methanol and 1.5 g of platinum oxide is hydrogenated at 50 psi at ambient temperature for 48 hours. The suspension is suction filtered while still hot through a sintered glass Buchner funnel and the filter cake is washed with several portions of ~ot chloroform. The filtrate and the washings are combined and then the solvent removed leaving a solid which is dried in vacuo at 40C for 16 hours.
The solid is recrystallized from chloroform and the first five crops are dried in an Abderhalden pistol over xylene for 32 hours leaving colorless crystals, mp 182-185C, of 4-~2-[-t4-methoxyphenyl)tolyl]~-l-methylpiperidine hydrobromide.
Analysis:
Calculated for C20H25NO HBr: 63.83%C; 6.96~H; 3.72~N.
Found: 63.97%C; 7.06%H; 3.87%N.
Example 37 A solution of 24.9 g of 1-methyl-4-~2-(~-phenyl-tolyl)]piperidine hydrochloride, Example 33, in 100 ml of methylene chloride is washed twice with 50 ml portions of a 5% sodium hydroxide solution. The methylene chloride solution is dried and filtered and then a solution of 14.1 g of phenyl chloroformate in 100 ml of methylene chloride is added drop-wise with stirring over a 40 minute span. The solution is permitted to stir for 16 hours and then the solvent evaporated off leaving a solid residue. The residue is suspended in ether and collected by suction filtration. The filter cake is washed with ether and dried in vacuo at 40C over sodium hydroxide pellets. The dried filter ca~e is recrystallized from isopropyl alcohol leaving colorless crystals, mp 120-122C

of 4-~2~ phenyltolyl)]-1-phenoxycarbonylpiperidine.

67~

Analysis:
Calculated for C25H25NO2: 80.B2~C; 6.80%H; 3.77%N.
Found: 80.99%C; 6.80%H; 3.69~N.
Example 38 A mixture of 36.6 g of 4-{2-[~-(4-methoxyphenyl)-tolyl)~-l-methyl-1,2,3,6-tetrahydropyridine hydrobromide, Example 30, 153 ml of absolute methanol and 1.5 g o platinum oxide is hydrogenated at 50 psi at ambient temperature for 48 hours. The suspension is suction filtered hot through a sin-tered glass Buchner funnel and the filter cake is washed with several portions of hot chloroform. The filtrate and washings are combined and concentrated to dryness leaving a solid which is dried in vacuo at 40C for 16 hours. The solid is recrystal-lized from 450 ml of chloroform. The first 5 crops are combined and dried in an abderhalden pistol over xylene for 32 hours leaving colorless crystals, mp 182-185C of 4-{2-(a-(4-methoxy-phenyl)tolyl)~-l-methylpiperidine hydrobromide.
Analysis:
Calculated for C20H25NO HBr: 63.83%C; 6.96%H; 3.72%N.
Found: 63.97%C; 7.06%H; 3.87%N.
xample 39 A mixture of 6.89 g of 4-~2-[~-(4-methoxyphenyl)~-tolyl}-l-methylpiperidine, free base of Example 38, 85 ml of methylene chloride and 4.0 g of phenyl chloroformate is stirred for 16 hours. Then the solvent is removed on a rotary evapora-tor and the residue azeotroped with benzene. ~he solid residue is dried in vacuo a~ 40C and recrystallized from absolute ethanol leaving colorless crystals, mp 116-118C o~ 4-~2-[~-(4-methoxyphenyl~tolyl]~ phenoxycarbonylpiperidine.
Analysis:
Calcula~ed for C~6H27NO3: 77.77%C; 6.79%H; 3.4g%N.

Found: 77.85%C; 6.83%H; 3.46%N.

llC"3677 Example 40 A stirring suspension of 4.0 g of 4-~2-[~-(4-methoxyphenyl)tolyl]~-l-phenoxycarbonyl piperidine, Example 39, 110 ml of ethylene glycol and 14 ml of a solution pre-pared from 20 g of potassium hydroxide pellets in 22 ml ofwater is heated to reflux and then allowed to cool to ambient temperature followed by ice bath cooling to effect a precipi-tate. The precipitate is collected by filtration and dissolved in 100 ml of chloroform. The solution is washed with water, dried and filtered and the filtrate treated with an excess of hydrogen chloride gas. The solvent is removed on a rotary evaporator and the residue dried in vacuo at 40C leaving a crude solid which is recrystallized from ethanol leaving colorless crystals, mp 246-248C of 4-~2-[~-(4-methoxyphenyl) tolyl)~piperidine hydrochloride.
Analysis:
Calculated for ClgH23NO HCl: 71.79%C; 7.61%H; 4.41%N.
Found: 72.00~C; 7.75%H; 4.51~N.
Example 41 A solution of 5.37 g of 4-[2-(~-phenyltolyl)piperi-dine hydrochloride, Example 35, in 50 ml of chloroform is washed with an excess of a 5~ sodium hydroxide solution and dried and the solvent removed leaving a viscous oil. The oil is dissolved in 10 ml of benzene and added dropwise with stirring and ice-water bath cooling to a solution of 2.28 g of benzoyl peroxide in 75 ml of benzene. After total addition the reaction solution is stirred with ice-water ~ath cooling for 10 minutes and at the ambient temperature for 2.5 hours.
The solution is concentrated on a rotary evaporator at 40C
leaving an oil which is dissolved in 95% ethanol. The ethanolic solution is maintained at 5C for 48 hours with occassional stirring. After this time a crystalline precipi-tate is present which is collected b~ suction ~iltration, ~ - 33 -` ` i~03677 washed with 95~ ethanol and dried in vacuo at 40C. The dried product is recrystallized from 95% ethanol leaving cream colored crystals, mp 102-103C of l-benzoyloxy-4-[2-(-phenyl-tolyl)]piperidine.
Analysis:
Calculated for C25H25NO2: 80.82%C; 6.80%H; 3.77%N.
Found: 80.74%C; 6.86%H; 3.75%N.
Example 42 A suspension of 2.63 g of 1-benzoyloxy-4-[2~
10 phenyltolyl)]-piperidine, 25 ml of absolute ethanol and 20 ml of a 10% sodium hydroxide solution heated on a water bath at 100C for 40 minutes. After this time the suspension is permitted to cool to ambinet temperature, stirred at ambient ; temperature for 1.5 hours and then concentrated on a rotary evaporator to 1/3 of its original volume. The reaction solution is diluted with 50 ml of water and its pH adjusted to 6.0 with 5% hydrochloric acid leaving a suspension which is extracted twice with 50 ml portions of chloroform. The combined extracts are dried and the solvent removed leaving 2~ a solld residue which is recrystallized from 95% ethanol leav-ing colorless crystals, mp 142-147C of l-hydroxy-4-[2- (a-phenyltolyl)]piperidine.
Analysis:
,~ - . . .
Calculated for C~18H21~ 80.85~C; 7-93%H7 5-24%N-Found: 80.79%C; 8.04~H; 5.07%N.
Example 43 A stirring mixture of 6 g of 1-methyl-4-{2-~-(4-methoxyphenyl~tolyl]3piperidine hydrobromide, Example 38, and ~- 9.6 ml of a 48% hydrobromide solution is immersed in an oil bath (140C) for 30 minutes. The hot solution is poured ïnto cold water and 174 ml of concentrated ammonium hydroxide is a'dded effecting a precipitate. The precipitate is collected by filtration and the filter cake dried overnight in vacuo at ~ - - 34 -ambient temperature. The dried precipit~te is recrystallized from absolute ethanol leaving a pinkish crystalline solid, mp 229-232C of 4-~2-[~-(4-hydroxyphenyl)tolyl]~-1-methylpiperidine.
Analysis:
Calculated for ClgH23NO: 81.11%C; 8.31%H; 4.95%N; 5.41%0.
Found: 81.10~C; 8.24%H; 4.98%N; 5.69%0;
Example 44 To a stirring refluxing suspension of 5.76 g of 4-[2-(~-phenyl)tolyl]piperidine hydrochloride, Example 35, 18.0 g of potassium carbonate and 70 ml of n-butyl alcohol is added dropwise 8.70 g of 2-(3-chloropyrpyl)-2-(4-fluorophenyl)-1,3-dioxolane. After total addition the reaction mixture is refluxed with stirring for 16 hours, filtered and then the filtrate is concentrated to dryness leaving an oil which is dissolved in 75 ml of ether. The ether solution is filtered and the filtrate treated with ethereal hydrogen chloride. An oil separates as the lower phase which is washed twice with portions of ether and then dissolved in chloroform. The chloroform solution is evarporated to dryness leaving a tacky foam which is redissolved in 15 ml of chloroform and this solution diluted to the cloud point with ether. The mixture is stirred until a thick suspension is formed which is diluted with 20 ml of ether. A precipitate appears which is collected by suction filtration. The filter cake is washed well with ether followed by recrystallization from isopropyl alcohol leaving colorless crystals, mp 185-187C of 1-[3-(4-fluoro-benzoyl)propyl~-4-~2-(~-phenyltolyl)]piperidine ethylene ketal hydrochloride.
Analysis:
Calculated fGr C30H34FNQ2 HCl: 72.63%C; 7.13%H; 2.82%N.
Found: 72.62%C; 7.20%H; 2.79~N.
Example 45 A stirred solution of 3.0 g of 1-[3-(4-fluorobenzoyl~

propyl]-4-[2-(~-phenyltolyl)~piperidine ethylene ketal hydro-chloride, Exa~ple 44, 100 ml of methanol and 50 ml of concen-trated hydrochloric acid is refluxed for 2 hours. The hot solution is poured onto ice, and the reaction mixture basified with a 50~ sodium hydroxide solution, and the basic mixture extracted thrice with 100 ml portions of chloroform. The combined extracts are dried and the solvent evaporated off leaving an oil. The oil is taken up in 5 ml of hexane and stirring of the hexane solution effects a thick suspension of crystalline solid which is collected by suction filtration.
The solid is recrystallized form acetonitrile to give colorless crystals, mp 100-101.5~C of 1-[3-(4-fluorobenzoyl~propyl~-4-~2-( a -phenyltolyl)]piperidine.
Analysis:
Calculated for C28H30FNO: 80.92%C; 7.29~H; 4.57%F; 3.37%N.
Found: 81.07%C; 7.37%H; 4.72%F; 3.32%N.
` Example 46 A solution of 1.4 g of 4-~-2-[~-(2-fluDn~-methyl-phenyl)tolyl]phenyl~-l-phenethyl-4-piperidinol, Example 11, in 30 ml of tetrahydrofuran is cooled to -60C. To this cooled solution is added 1.5 ml of n-butyllithium and the resulting solution stirred for 15 minutes. To this solution is added dropwise 0.3 ml of propionyl chloride at this low temperature and after total addition the solution is permitted to reach ambient temperature. The solution is stirred at ambient temperature for 24 hours. The solution is diluted with water and extracted with chloroform. The chloroform extract is dried and filtered and the chloroform evaporated off leav-ing a white powder. The powder is recrystallized from a methanol-acetone-ether mixture to give the product, mp l9S-197C of 4-`2-[~-~2-fluoro-4-methylphenyl)tolyl]_-4-propionyl-oxy-l-phenethylpiperidine hydrochloride.

~1 - 36 -Analysis:
Calculated for C30H34FNO2 HCl: 72.63%C; 7.11%H; 2.82%N.
Found: 73.08~C; 7.35%H; 2.65%N.
Example 47 A mixture of 3 g of 4-~2-[-(4-methoxyphenyl)tolyl~}
piperidine hydrochloride, Example 40, and 48 ml of 48% HBr is refluxed on an oil bath (157C) with stirring for 32 minutes, cooled and then poured onto 48 ml of cooled water. The resulting suspension is quenched with 48 ml of concentrated ammonium hydroxide, stirred thoroughly and the solid is collected by suction filtration. The filter cake is dried in vacuo at 40C over sodium hydroxide pellets and then dissolved in 500 ml of hot absolute ethanol. 32 ml of triethylamine is added to the hot ethanolic solution. The hot solution is diluted with chloroform and then washed twice with water. The organic phase is collected, dried and filtered and then the solvent evaporated off leaving a solid product which is recrystallized from absolute ethanol in the presence of acti-vated charcoal to give yellowish crystals, mp 217-221~ of 4-~2-[~-(4-hydroxyphenyl)tolyl]~piperidine.
Allalysis:
Calculated for C18H21NO: 80.86%C; 7~92%H; 5.24~N.
Found: 80.75~C; 7.89~H; 5.10~N.
Example 48 A mixture of 4 g of 4-2-~-(4-fluorophenyl)tolyl~-l-methyl-1,2,3,6~tetrahydropyridine hydrobromide, Example 31, 0.3 g of platinum oxide and 150 ml of methanol is hydrogenated at 50 psi at ambient temperature for 48 hours. A~ter which time the suspension is suction filtered and the filtrate evaporated under reduced pressure. The solid residue is col-leGted and dried in vacuo at 40C and then recrystallized from isGpropanol to give colorless crystals, mp 183-186C, of 4-~2-[~-(4-fluorophenyl)tolyl3~-1-methylpiperidine hydrobromide.

Analysis:
Calculated for ClgH22FN HBr: 62.66%C; 6.36%H; 3.85%N; 5-22%F-Found:62.81%C; 6.39~H; 3.94~N; 5.06%F.
Example 49 A mixture of 28.6 g of 4-{2-[-(4-fluorophenyl)tolyl]}-l-methylpiperidine, free base of Example 48, 85 ml of methylene chloride and 17.2 g of phenyl chloroformate is stirred for 16 hours at ambient temperature followed by distillation of sol-vent on a rotary evaporator and azeotropic distillation of the residue with benzene. The resulting oil solidifies upon trituration with ether. The solid is recrystallized from absolute ethanol to give colorless crystals, mp 107-110C, of 4-{2 [a- (4-~luorophenyl)tolyl~-1-phenoxycarbonylpiperidine.
Analysis:
Calculated for C25H24FNO: 77.10%C; 6.21%H; 3.60%N.
Found:77.00%C; 6.18%H; 3.59%N.
Example 50 A mixture of 500 ml of ethylene glycol, a solution of 60 g of potassium hydroxide in 66 ml of water and 16.6 g of 4-~2-[~-(4-fluorophenyl~toly~-1-phenoxycarbonylpiperidine, Example 4~, is gradually heated to 200C with constant stirring and allowed to reflux. The mixture is then allowed to cool, flushed with nitrogen and allowed to stand for 48 hours. The mixture is suction filtered, and the filter cake dissolved in chloroform. To the chloroform solution water is added and extracted with ether. The combined extracts are dried, fil-tered and then treated with gaseous hydrobromic acid. The solvent is evaporated under reduced pressure to give a solid which is recrystallized twice from isopropanol to give color-less crystals, mp 227-231C, of 4-~2-~-(4-fluorophenyl)tolyl]~

piperidine hydrobromide.
Analysis:
Calculated for C18H20FN HBr: 61.72%C; 6.04%H; 4.00%N; 5.42%F.
Found:61.95%C; 5.88~H; 3.99%N; 5.43%F.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula I

I

wherein X is C-R4 or C; Y is -(CH2)n- when X is CR4 and =CH-(CH2)n-1- when X is C; R is hydrogen, lower alkyl, phenyl-loweralkyl of the formula wherein p is 1, 2, 3 or 4 and R1 is hydrogen or halogen, hydroxy, benzoylloweralkyl of the formula wherein p and R1 are as defined above; phenyloxycarbonyl, benzoyl, benzoyloxy or ; wherein p and R1 are as defined above, R2 and R3 are the same or different and each can be hydrogen, halogen, alkoxy of from 1 to 2 carbon atoms, lower alkyl and hydroxy; R4 is hydrogen or OR5; R5 is hydrogen, loweracyl, benzoyl or cycloalkanoyl in which the cycloalkyl ring contains from 3 to 6 carbon atoms; m is the integer 1 or 2; n is the integer 1, 2 or 3; the sum of m and n is 3 or 4; and the pharmaceutically acceptable acid addition salts thereof, in which a) a 2-bromodiphenylmethane of the formula II

II

is converted to its lithio derivative and the lithio derivative is permitted to react with a compound of the formula III

III

wherein m and n and the sum of m and n are as defined above and R is loweralkyl, phenylloweralkyl or cycloalkylloweralkyl to provide a compound of the formulaI wherein X is COH; or b) a compound of the formula I wherein R is benzyl is hydrogen-ated to provide a compound of the formula I wherein R is hydrogen; or c) a compound of the formula I wherein X is COH, optionally after conversion to a lithio derivative, is esterified to provide a compound of the formula I wherein X represents COR5 wherein R5 is as defined above but not hydrogen; or d) a compound of the formula I wherein X is COH is dehydrated by treatment with a dehydrating agent to provide a compound of the formula I wherein X is C and Y is =CH-(CH2)n-1-; or e) the compound prepared according to reaction d) is hydrogen-ated to provide a compound of the formula I wherein X is CH and Y is -(CH2)n-; or f) a compound of the formula I wherein R is lower alkyl or hydrogen is reacted with an alkyl or phenyl chloroformate to provide a compound of the formula I wherein R is alkoxycarbonyl or phenoxycarbonyl; or g) the compound prepared according to reaction f) is hydrolyzed to provide a compound of the formula I wherein R is hydrogen; or h) the compound prepared according to reaction g) is treated with benzoylperoxide to produce a compound of the formula I
wherein R is benzoyloxy; or i) the compound prepared according to reaction h) is hydrolyzed to produce a compound of the formula I wherein R
is hydroxy; or j) a compound of the formula I wherein R5 is loweracyl, benzoyl or cycloalkanoyl in which the cycloalkyl contains from 3 to 6 carbon atoms is hydrogenated to produce a compound of the formula I wherein R4 is hydrogen; or k) a compound of the formula I wherein R is hydrogen is reacted with a compound of the formula to provide a compound of the formula I wherein R is ; or l) the compound prepared according to reaction k) is hydrolyzed to prepare a compound of the formula I wherein R is -(CH2)p-COC6H5;
or m) a compound of the formula I wherein at least one of the radicals R1, R2 or R3 is alkoxy is dealkylated to provide a compound of the formula I wherein at least one of the radicals Rl, R2 and R3 is hydroxy, and to prepare a pharmaceutically acceptable acid addition salt, the compound of the formula I is reacted with a pharmaceutically acceptable acid.

2. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

3. A process for the preparation of l-methyl-4-[2-(a-phenyltolyl)]-4-piperidinol in which 2-bromodiphenylmethane in solution is reacted with n-butyllithium, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed and the resultant product is isolated therefrom.

4. l-Methyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.

5. A process for the preparation of 3-[2-(.alpha.-phenyltolyl)]-3-pyrrolidinol hydrochloride in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-3-pyrrolidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-3-[2-(.alpha.-phenyl-tolyl)]-3-pyrrolidinol, this is treated with hydrochloric acid and l-benzyl-3-[2-(.alpha.-phenyltolyl)]-3-pyrrolidinol hydrochloride is separated, this is hydrogenated in solution in the presence of a palladium on carbon catalyst and the resultant product is subsequently isolated.

6. 3-[2-(.alpha.-Phenyltolyl)]-3-pyrrolidinol hydrochloride whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.

7. A process for the preparation of 4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-4-piperidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, this is treated with hydrochloric acid to produce l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride, this is hydrogenated in solution in the presence of palladium on carbon and the resultant product is subsequently isolated.

8. 4-[2-(.alpha.-Phenyltolyl)]-4-piperidinol hydrochloride, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.

9. A process for the preparation of 4-acetoxy-1-methyl-4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride in which 2-bromodiphenylmethane in solution is reacted with n-butyllithium, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, the resultant l-methyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol is treated with acetyl chloride and the product is subsequently isolated.

10. 4-Acetoxy-l-methyl-4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.

11. A process for the preparation of l-methyl-4-[2-(.alpha.-phenyltolyl)]-4-propionyloxypiperidine hydrochloride in which 2-bromodiphenylmethane in solution is reacted with n-butyllithium, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, the resultant l-methyl-4-[2-(a-phenyltolyl)]-4-piperidinol is treated with propionyl chloride and the resultant product is subsequently isolated.

12. 1-Methyl-4-[2-(.alpha.-phenyltolyl)]-4-propionyloxypiperidine hydrochloride, whenever obtained according to a process as claimed in claim 11 or by an obvious chemical equivalent thereof.

13. A process for the preparation of 4-{2-[.alpha.-(2-fluoro-4-methylphenyl)tolyl]}-4-propionyloxy-1-methylpiperidine hydrochloride in which 2-bromo-2'-fluoro-4'-methyldiphenyimethane in solution is reacted with n-butyllithium, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, the resultant l-methyl-4- {2-[.alpha.-(2-fluoro-4-methylphenyl)tolyl]} -4-piperidinol is isolated and treated with propionyl chloride, the product is converted to the free base and separated, the separated product is treated with hydrochloric acid and the resultant product is subsequently isolated.

14. 4-{ 2-[.alpha.-(2-Fluoro-4-methylphenyl)tolyl]} -4-propionyl-oxy-l-methylpiperidine hydrochloride, whenever obtained according to a process as claimed in claim 13 or by an obvious chemical equivalent thereof.

15. A process for the preparation of l-methyl-4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydropyridine in which 2-bromodiphenylmethane in solution is reacted with n-butyllithium, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, the product is isolated therefrom, dissolved in formic acid and refluxed, an aqueous solution of the resultant product is formed and sodium hydroxide is added thereto and the resultant product is subsequently isolated.

16. 1-Methyl-4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydro-pyridine, whenever obtained according to a process as claimed in claim 15 or by an obvious chemical equivalent thereof.

17. A process for the preparation of l-methyl-4-{2-[.alpha.-(4-methoxyphenyl)tolyl]}-4-piperidinol, in which 2-bromo-4'-methoxydiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed and the resultant product is subsequently isolated.

18. 1-Methyl-4-{2-[.alpha.-(4-methoxyphenyl)tolyl]}-4-piperidinol, whenever obtained according to a process as claimed in claim 17, or by an obvious chemical equivalent thereof.

19. A process for the preparation of l-methyl-4-{2-[.alpha.-(4-fluorophenyl)-tolyl]}-4-piperidinol in which 2-bromo-4'-fluorodiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidine is sub-sequently added thereto, the reaction solution is hydrolyzed and the resultant product is subsequently isolated.

20. 1-Methyl-4-{2-[.alpha.-(4-fluorophenyl)-tolyl]}-4-piperidinol, whenever obtained according to a process as claimed in claim 19 or by an obvious chemical equivalent thereof.

21. A process for the preparation of l-methyl-4-{2-[.alpha.-(2-fluoro-4-methylphenyl)tolyl]}-4-piperidinol in which 2-bromo-2'-fluoro-4'-methyldiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed and the resultant product is subsequently isolated.

22. 1-Methyl-4-{2-[.alpha.-(2-fluoro-4-methylphenyl)tolyl]}-4-piperidinol, whenever obtained according to a process as claimed in claim 21 or by an obvious chemical equivalent thereof.

23. A process for the preparation of l-methyl-4-{2-[.alpha.-(2,5-difluorophenyl)tolyl]}-4-piperidinol in which 2'-bromo-2,5-difluorodiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidone is added thereto, the reaction solution is hydrolyzed and the resultant product is subsequently isolated.

24. 1-Methyl-4-{2-[.alpha.-(2,5-difluorophenyl)tolyl]}-4-piperidinol, whenever obtained according to a process as claimed in claim 23, or by an obvious chemical equivalent thereof.

25. A process for the preparation of 4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydropyridine in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-4-piperidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, this is treated with hydrochloric acid to produce l-benzyl-4- [2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride, this is hydrogenated in solution in the presence of palladium on carbon, the resultant 4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride in glacial acetic acid and hydrochloric acid is refluxed, the solution is cooled and basified with sodium hydroxide and the resultant product is subsequently isolated.

26. 4-[2-(.alpha.-Phenyltolyl)]-1,2,3,6-tetrahydropyridine, whenever obtained according to a process as claimed in claim 25 or by an obvious chemical equivalent thereof.

27. A process for the preparation of 4-{2-[.alpha.-(4-fluorophenyl)tolyl]}-1-methyl-1,2,3,6-tetrahydro-pyridine hydrobromide in which 2-bromo-4'-fluorodiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidine is subsequently added thereto, the reaction solution is hydrolyzed, l-methyl-4-{2-[.alpha.-(4-fluorophenyl)-tolyl]}-4-piperidinol is isolated and a mixture thereof with glacial acetic acid and hydrochloric acid is refluxed, the resultant solution is basified with sodium hydroxide, the resultant product is then treated with hydrobromic acid and the resultant product is isolated.

28. 4-{2-[.alpha.-(4-Fluorophenyl)tolyl]}-l-methyl-1,2,3,6-tetrahydropyridine hydrobromide, whenever obtained according to a process as claimed in claim 27, or by an obvious chemical equivalent thereof.

29. A process for the preparation of l-methyl-4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride, in which 2-bromodiphenylmethane is reacted in solution with n-butyllithium, l-methyl-4-piperidone is subsequently added thereto, the reaction mixture is hydrolyzed, the product is isolated therefrom, dissolved in formic acid and refluxed, an aqueous solution of the resultant product is formed, sodium hydroxide is added thereto, l-methyl-4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydropyridine is isolated, a suspension of platinum oxide in ethanol is hydrogenated and added to said tetrahydropyridine, the mixture is hydrogenated, the product is isolated, treated in solution with hydrochloric acid and the product is subsequently isolated.

30. 1-Methyl-4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride, whenever obtained according to a process as claimed in claim 29 or by an obvious chemical equivalent thereof.

31. A process for the preparation of 4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-4-piperidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, this is treated with hydrochloric acid to produce l-benzyl-4-[2-(a-phenyltolyl)]-4-piperidinol hydrochloride, this is hydrogenated in solution in the presence of palladium on carbon, the resultant 4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride in glacial acetic acid and hydrochloric acid is refluxed, the solution is cooled and basified with sodium hydroxide, 4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydropyridine is isolated, a suspension of platinum oxide and ethanol is hydrogenated, the tetrahydropyridine is added to the suspension, the suspension is hydrogenated, the product is isolated, treated with hydrochloric acid and the resultant product is subsequently isolated.

32. 4-[2-(.alpha.-Phenyltolyl)]piperidine hydrochloride, whenever obtained according to a process as claimed in claim 31 or by an obvious chemical equivalent thereof.

33. A process for the preparation of 4-{2-[.alpha.-(4-methoxyphenyl)-tolyl]}-1-methylpiperidine hydrobromide in which 2-bromo-4'-methoxydiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, the resultant l-methyl-4-{2-[.alpha.-(4-methoxyphenyl) tolyl]}-4-piperidinol is isolated, mixed with glacial acetic acid and hydrochloric acid and refluxed, the reaction solution is basified with sodium hydroxide, the resultant product is isolated and treated with hydrobromic acid, the resultant l-methyl-4-{2-[.alpha.-(4-methoxyphenyl)tolyl]}-1,2,3,6-tetra-hydropyridine hydrobromide is mixed with methanol and platinum oxide, the mixture is hydrogenated and the resultant product is subsequently isolated.

34. 4-{2-[.alpha.-(4-Methoxyphenyl)-tolyl]}-l-methylpiperidine hydrobromide, whenever obtained according to a process as claimed in claim 31 or by an obvious chemical equivalent thereof.

35. A process for the preparation of 4-{2-[.alpha.-(4-methoxyphenyl)tolyl]} piperidine hydrochloride in which 2-bromo-4'-methoxydiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, l-methyl-4-{2-[.alpha.-(4-methoxyphenyl)tolyl]}-4-piperidinol is subsequently isolated, mixed with glacial acetic acid and concentrated hydrochloric acid and refluxed, the solution is basified with sodium hydroxide, the product is treated with hydrobromic acid to produce l-methyl-4-{2-[.alpha.-(4-methoxyphenyl) tolyl]}-1,2,3,6-tetrahydropyridine hydrobromide, this product is hydrogenated in methanol in the presence of platinum oxide, 4-{2-[.alpha.-(4-methoxyphenyl)]tolyl}-l-methylpiperidine and methylene chloride and phenyl chloroformate are stirred, the product 4-{2-[.alpha.-(4-methoxyphenyl)-tolyl]}-1-phenoxycarbonyl-piperidine is formed into a suspension with ethylene glycol and an aqueous solution of potassium hydroxide, the suspension is refluxed, cooled, the product is isolated, treated with hydrogen chloride gas and the product is subsequently isolated.

36. 4-{2-[.alpha.-(4-methoxyphenyl)tolyl]} piperidine hydrochloride, whenever obtained according to a process as claimed in claim 35 or by an obvious chemical equivalent thereof.

37. A process for the preparation of l-hydroxy-4-[2-(.alpha.-phenyltolyl)]piperidine in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-4-piperidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, this is treated with hydrochloric acid to produce l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride, this is hydro-genated in the presence of palladium on carbon, the resultant 4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride is suspended in glacial acetic acid and hydrochloric acid, the suspension is refluxed, the suspension is basified with sodium hydroxide to the resultant 4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydropyridine, is added a suspension of platinum oxide in ethanol which has been hydrogenated, the resultant suspension is hydrogenated, the product is reacted with hydrochloric acid to produce 4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride, this is sub-sequently treated with benzoyl peroxide, l-benzoyloxy-4-[2-(.alpha.-phenyltolyl)]piperidine is subsequently isolated, suspended in ethanol and sodium hydroxide and heated, the pH
of the resultant solution is subsequently adjusted to 6.0 with hydrochloric acid and the product is subsequently isolated.

38. 1-Hydroxy-4-[2-(a-phenyltolyl)]piperidine, whenever obtained according to a process as claimed in claim 38 or by an obvious chemical equivalent thereof.

39. A process for the preparation of 4-{2-[.alpha.-(4-hydroxyphenyl)tolyl]} piperidine in which 2-bromo-4'-methoxydiphenylmethane is reacted with n-butyllithium in solution, l-methyl-4-piperidone is subsequently added thereto, the reaction solution is hydrolyzed, l-methyl-4-{2-[.alpha.-(4-methoxyphenyl)tolyl]}-4-piperidinol is subsequently isolated, mixed with glacial acetic acid and concentrated hydrochloric acid and refluxed, the solution is basified with sodium hydroxide, the product is treated with hydrobromic acid to produce l-methyl-4-{2-[.alpha.-(4-methoxyphenyl)tolyl]}-1,2,3,6-tetrahydropyridine hydrobromide, this product is hydrogenated in methanol in the presence of platinum oxide, 4-{2-[.alpha.-(4-methoxyphenyl)]tolyl}-l-methylpiperidine and methylene chloride and phenyl chloroformate are stirred, the product 4-{2-[.alpha.-(4-methoxyphenyl)-tolyl]}-1-phenoxycarbonylpiperidine is formed into a suspension with ethylene glycol and an aqueous solution of potassium hydroxide, the suspension is refluxed, cooled, the product is isolated, treated with hydrogen chloride gas, 4-{2-[.alpha.-(4-methoxyphenyl)tolyl]} piperidine hydrochloride is isolated, mixed with hydrobromic acid and refluxed, and then cooled, the resultant suspension is quenched with concentrated ammonium hydroxide, the precipitate is collected, dried and dissolved in ethanol, triethylamine is added to the soltuion and the resultant product is subsequently isolated.

40. 4-{2-[.alpha.-(4-Hydroxyphenyl)tolyl]} piperidine, whenever obtained according to a process as claimed in claim 39 or by an obvious chemical equivalent thereof.

41. A process for the preparation of l-[3-(4-fluorobenzoyl)propyl]-4-[2-(.alpha.-phenyltolyl)]piperidine ethylene ketal hydrochloride in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-4-piperidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, this is treated with hydrochloric acid to produce l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride, this is hydrogenated in solution in the presence of palladium on carbon, the resultant 4-[2-(a-phenyltolyl)]-4-piperidinol hydrochloride in glacial acetic acid and hydrochloric acid is refluxed, the solution is cooled and basified with sodium hydroxide, 4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydro-pyridine is isolated, a suspension of platinum oxide and ethanol is hydrogenated, the tetrahydropyridine is added to the suspension, the suspension is hydrogenated, the product is isolated, treated with hydrochloric acid, 4-[2-(.alpha.-phenyltolyl)]
piperidine hydrochloride is isolated and a suspension is formed with potassium carbonate and n-butyl alcohol, the suspension is added to 2-(3-chloropropyl)-2-(4-fluorophenyl)-dioxolane, the mixture is refluxed, the product is treated with hydrochloric acid, and the resultant product is subsequently isolated.

42. l-[3-(4-Fluorobenzoyl)propyl]-4-[2-(.alpha.-phenyltolyl)]
piperidine ethylene ketal hydrochloride, whenever obtained according to a process as claimed in claim 41 or by an obvious chemical equivalent thereof.

43. A process for the preparation of 1-[3-(4-fluorobenzoyl)propyl]-4-[2-(.alpha.-phenyltolyl)] piperidine in which 2-bromo diphenylmethane is reacted in solution with n-butyllithium, l-benzyl-4-piperidone is subsequently added thereto, the resultant solution is treated to isolate l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol, this is treated with hydrochloric acid to produce l-benzyl-4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride, this is hydrogenated in solution in the presence of palladium on carbon, the resultant 4-[2-(.alpha.-phenyltolyl)]-4-piperidinol hydrochloride in glacial acetic acid and hydrochloric acid is refluxed, the solution is cooled and basified with sodium hydroxide, 4-[2-(.alpha.-phenyltolyl)]-1,2,3,6-tetrahydropyridine is isolated, a suspension of platinum oxide and ethanol is hydrogenated, the tetrahydropyridine is added to the suspension, the suspension is hydrogenated, the product is isolated, treated with hydrochloric acid, 4-[2-(.alpha.-phenyltolyl)]piperidine hydrochloride is isolated and a suspension is formed with potassium carbonate and n-butyl alcohol, the suspension is added to 2-(3-chloropropyl)-2-(4-fluorophenyl)-dioxolane, the mixture is refluxed, the product is treated with hydrochloric acid, the resultant l-[3-(4-fluorobenzoyl) propyl]-4-[2-(.alpha.-phenyltolyl)]piperidine ethylene ketal hydrochloride is refluxed together with methanol and hydrochloric acid, the reaction mixture is cooled and basified with sodium hydroxide and the resultant product is subsequently isolated.

44. 1-[3-(4-fluorobenzoyl)propyl]-4-[2-(.alpha.-phenyltolyl)]
piperidine, whenever obtained according to a process as claimed in claim 43 or by an obvious chemical equivalent thereof.