PROCESS FOR PRODUCTION OF PIPERIDINE DERIVATIVES

Abstract: The present invention discloses processes for preparing piperidine derivative compounds of formulae (I) or (II) wherein n is 0 or 1; R<1> is hydrogen or hydroxy; R<2> is hydrogen; or, when n is 0, R<1> and R<2> taken together form a second bond between the carbon atoms bearing R<1> and R<2>, provided that when n is 1, R<1> and R<2> are each hydrogen; R<3> is -COOH or -COOR<4>; R<4> is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents. One process comprises providing a regioisomer of formula (III) wherein Z is -CG<1>G<2>G<3>, (IV) or (V), m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR<5>; G<1>, G<2>, and G<3> are the same or different and are selected from the group consisting of OR<8>, SR<8>, and NR<8>R<9>; X<3> is halogen, OR<15>, SR<15>, NR<15>R<16>, OSO2R<15>, or NHSO2R<15>; R<6> and R<7> are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR<8>, SR<8>, and NR<8>R<9>; and R<5>, R<8>, R<9>, R<15>, and R<16> are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and converting the regioisomer to the piperidine derivative compound with a piperidine compound. Another process for producing piperidine derivative compounds comprises providing an alpha , alpha -disubstituted-methylbenzene derivative having formula (VI) wherein X<1> is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions and converting the alpha , alpha -disubstituted-methylbenzene derivative to the piperidine derivative compound with a piperidine compound. In yet another process, a 4-( alpha , alpha -disubstituted)-toluic acid derivative having formula (VII) wherein X<2> is a halogen; an alkali metal oxide; a moiety having formula -OR<10>; a moiety having formula -SR<10>; or an amine; and R<10> is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety, is provided and converted to the piperidine derivative compound with a piperidine compound.

Description: PROCESS FOR PRODUCTION OF PIPERIDINE DERIVATIVES FIELD OF THE INVENTION The present invention relates to processes for the production of piperidine derivatives. BACKGROUND OF THE INVENTION Terfenadine, 1 -(p-tert-butylphenyl)-4-[4 -(α-hydroxydiphenylmethyl)-l '- piperidinyl j-butanol is a non-sedating anti-histamine. It is reported to be a specific H 1 - receptor antagonist that is also devoid of any anticholingeric, anti-serotonincrgic, and anti-adrenergic effects both in vitro and in vivo. See D. Mc l avish, K.L. Goa, M. Ferrill, Drugs. 1990, 39, 552; C.R. Kmgsolving, N.L. Monroe, Λ.Λ. Carr, Pharmacologist. 1973, 15, 221 ; J.K. Woodward, N.L. Munro, Arzneim-Forsch. 1982, 32, 1 154; K.V. Mann, K.J. Tietze, Clin. Pharm. 1989, 6, 331. A great deal of effort has been made investigating structure-activity relationships of terfenadine analogs, and this is reflected in the large number of U.S. patents disclosing this compound and related structures as follows: U.S. Patent No. 3,687,956 to Zivkovic U.S. Patent No. 3,806,526 to Carr, et. al. U.S. Patent No. 3,829.433 to Carr, et. al. U.S. Patent No. 3,862,173 to Carr, el. al. U.S. Patent No. 3,878,217 to Carr, et. al. U.S. Patent No. 3,922.276 to Duncan, et. al. U.S. Patent No. 3,931 ,197 to Carr, et. al. U.S. Patent No. 3.941 ,795 to Carr, et. al. U.S. Patent No. 3,946,022 to Carr, et. al. U.S. Patent No. 3.956,296 to Duncan, et. al. U.S. Patent No. 3,965,257 to Carr, et. al. U.S. Patent No. 4,742,175 to Fawcett, et. al. In animal and human metabolic studies, terfenadine has been shown to undergo extensive hepatic first-pass metabolism, and after usual dosages it cannot be detected in plasma unless very sensitive assays are used. A specific hepatic cytochrome P-450 enzyme converts terfenadine to the major metabolite 4-[4-[4-(hydroxydiphenylmethyl)-l - piperidinyl]-l -hydroxybutyl]- -α-dimethylphenylacetic acid, also known as terfenadine carboxylic acid metabolite. This metabolite can be readily detected in plasma and is considered to be the active form of orally administered terfenadine. Side effects reported with terfenadine are cardiac arrhythmias (ventricular tachyarrhythmias, torsades de points, ventricular fibrillation), sedation, GI distress, dry mouth, constipation and/or diarrhea. The most serious of these, and potentially life threatening, are cardiac arrhythmias, which are related to terfenadine's ability to prolong the cardiac QT interval, and are only reported in patients administered terfenadine with liver disease or who also take the antifungal drug ketoconazole or the antibiotic erythromycin. As a result of these adverse events, the FDA, in 1992, required terfenadine to include a warning label. Although OTC formulations of terfenadine are purportedly being developed, the potentially serious side effects seen in some patients will be a significant obstacle for regulatory approval. Since cardiac side effects of terfenadine have been reported in patients with impaired liver function, as well as in patients also taking antibiotics known to suppress hepatic enzyme function, it was speculated that the cardiac side effects were due to accumulation of terfenadine and not due to accumulation of terfenadine carboxylic acid metabolite. Patch clamp studies in isolated feline ventricular myocytcs support the contention that terfenadine, and not the carboxylic acid metabolite, is responsible for cardiac side effects. At a concentration of 1 μM, terfenadine caused a greater than 90% inhibition of the delayed rectifier potassium current. At concentrations up to 5 μM, the terfenadine carboxylic acid metabolite had no significant effect on the potassium current in this assay (See R.L. Woosley, Y. Chen, J.P. Frieman, and R.A. Gillis, JAMA 1993, 269, 1532). Since inhibition of ion transport has been linked to cardiac abnormalities such as arrhythmias, these results indicate that terfenadine carboxylic acid is likely not liable to cause cardiac arrhythmias, at dose levels at which there is a distinct risk of such a side effect being caused by terfenadine itself. Carebastine, 4-[4-[4-(diphenylmcthoxy)-l -piperidinyl]-l -oxobutyl]-α,α- dimethylphenylacetic acid, is the carboxylic acid metabolite of ebastine. 1 -(p-tert- butylphenyl)-4-[4'-( -diphenylmethoxy)- l '-piperidinyI |-butanol. Both compounds possess potent selective histamine H, -receptor blocking and calcium antagonist properties and should prove useful in the treatment of a variety of respiratory, allergic, and cardiovascular disease states. These compounds relax bronchial and vascular smooth muscle in vitro and in vivo and inhibit the constrictor influence of noradrenaline, potassium ions, and various other agonist drugs. The compounds also inhibit responses of intestinal and tracheal preparations to histamine, acetylcholinc, and barium chloride and block the bronchoconstriction induced by histamine aerosol in guinea pigs in doses less than 1 mg/kg animal body weight administered orally. They also possess antianaphylactin properties in the rat, inhibit the skin lesions to a variety of anaphylactic mediators (histamine. 5-hydroxytryptaminc, bradykinin, LCD 4 , etc.), and antagonize the Schultz- Dale response in the sensitive guinea-pig. Piperidine derivatives related to the terfenadine carboxylic acid metabolite are disclosed in the following U.S. patents: U.S. Patent No. 4,254,129 to Carr. et. al. U.S. Patent No. 4,254, 130 to Carr. et. al. U.S. Patent No. 4,285,957 to Carr, et. al. U.S. Patent No. 4,285,958 to Carr, ct. al. In these patents, 4-[4-[4-(hydroxydiphcnylmethyl)- 1 -piperidmyl ]- 1 -hydroxybutyl]-α, - dimethylbenzeneacetic acid and related compounds are prepared by alkylation of a substituted piperidine derivative of the formula: with an ω-haloalkyl substituted phenyl ketone of the formula: O CH , ! h a l o - — ( C H } C — R > 6 wherein the substituents halo, R 1 , R 2 , n, Z, and R 6 are described in column 6 of U.S. Patent No. 4,254,130. In similar fashion, U.S. Patent No. 4,550,1 16 to Soto et al. describes preparation of piperidine derivatives related to carebastine by reacting the ω-haloalkyl substituted phenyl ketone with a substituted hydroxypipcridine derivative of the formula: N H U.S. Patent No. 4,254,130 indicates that ω-haloalkyl substituted phenyl ketones, wherein Z is hydrogen, are prepared by reacting an appropriate straight or branched lower alkyl C ( . 6 ester of α-α-dimethylphenylacetic acid with a compound of the following formula: h a l o ( CH 2 ) m C h a l o under the general conditions of a Friedel-Crafts acylation, wherein halo and m are described in column 1 1 of U.S. Patent No. 4,254, 129. The reaction is carried out in carbon disulfide as the preferred solvent. Other procedures for producing terfenadine carboxylic acid metabolite are disclosed in PCT Application Nos. WO95/00492, WO94/03170, and WO95/00480. The present invention is directed toward an improved process for preparation of terfenadine carboxylic acid metabolite and carebastine derivatives. SUMMARY OF THE INVENTION The present invention is directed to processes for preparing piperidine derivative compounds of the formulae CH, or B CH ' 3 wherein n is 0 or 1 ; R 1 is hydrogen or hydroxy; R 2 is hydrogen; or. when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 , provided that when n is 1 , R 1 and R 2 are each hydrogen; R 3 is —COOH or —COOR 4 ; R 4 is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents or a salt thereof. In one aspect of the invention, the piperidine derivative compound is prepared by providing a regioisomer having the following formula: A CH , < ( o CH . wherein Xi'G 2 Cr ( C R 6 R 7 o or ( CR°R ' ) r m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 , G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 . X 3 is halogen, OR 15 , SR 15 , NR 15 R 16 , OS0 2 R ] -\ or NHSO 2 R 15 ; R 6 and R 7 arc the same or different and are selected from the group consisting of hydrogen, an alk> l moiety, an aryl moiety, OR 8 , SR 8 , and NR R 9 ; and R 5 . R 8 , R 4 , R 1 5 , and R 16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety. The regioisomer is then converted to the piperidine derivative having a keto group with a piperidine compound. In another aspect of the present invention, the piperidine derivative compound is prepared by providing an α,α-disubstituted-mcthylbenzene derivative having the formula: CH - wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate. alkylhalo silicon, trialkyl silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions and converting the α,α-disubstituted-methylbenzene derivative with a piperidine compound under conditions effective to produce the piperidine derivative compound. In another aspect of the present invention, the piperidine derivative compound is prepared by providing a 4-(α.α-disubstituted)-toluic acid derivative having the formula: o CH . CH 3 wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 ; or an amine; and R' ϋ is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety and converting the 4-(α,α-disubstituted)-toluic acid derivative with a piperidine compound under conditions effective to produce the piperidine derivative compound. The invention further relates to a regioisomer having the formula: x 3 O CH 3 The present invention is also directed to processes for preparing a regioisomer having the formula: X O CH 3 In one aspect of the present invention, the process for preparing the regioisomer includes acylating an α,α-disubstituted-methylbenzene derivative having the formula: A CH , X 1 — / j ' , » C z V. ' I CH 3 wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkylhalo silicon, trialkyl silicon, a substituted sulfonic estci, or substituents useful in organometallic coupling reactions with a compound having the formulae - x 3 - 1 1 o or x 3 wherein X 2 is hydrogen, a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 . or an amine and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to produce the regioisomer. In another aspect of the present invention, the process for preparing the regioisomer includes reacting a 4-(α,α-disubstituted)-toluic acid derivative having the formula: o A CH 3 X 2 c — ,; i A CH . wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 ; or an amine and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety with a compound having the formula: x 3 wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, alkylhalo silicon, trialkyl silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the regioisomer. In yet another aspect of the present invention, the process for preparing the regioisomer includes providing an α.α-diunsubstituted regioisomer precursor having the formula: and meth lating the α,α-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer. 1 he present invention is also directed towards 4-(α,α-disubstιtuted)-toluic acid derivatives and 4-(α,α-diunsubstituted)-toluιc acid derivatives having, respectively, the formulae: CH , and O - CH , - wherein Z is — CG'G G 3 , : C R 6 R 7 o or ( C R D R ) r m is an integer from 1 to 6; Q and Y arc the same or different and are selected from the group consisting of O, S, and NR- "1 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R y ; X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 ; or an amine; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; R 5 , R 8 , R 9 , and R κι are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and A is the substituents of its ring, each of which may be different or the same and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing piperidine derivative compounds having the formulae: C - R ( O ) , CH , CH , or CH 3 wherein n is 0 or 1 : R 1 is hydrogen or hydroxy; R 2 is hydrogen; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 , provided that when n is 1 , R 1 and R 2 are each hydrogen; R 3 is —COOH or —COOR 4 ; R 4 is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and arc selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents or a salt thereof. These piperidine deπvative compounds may be in the form of 4- diphenylmethylpiperidine derivatives represented by the following lor ulae- CH or CH 3 where A, B, D, and R 3 are defined above. The piperidine derivative compounds also include 4-(hydroxydiphenylmethyl)piperidine derivatives according to the following formulae: \ / c OH ( CH . C — C H , or OH CH . CH , where A, B, D, and R 3 are defined above. Another useful class of piperidine derivative compounds are 4-diphenylmethylenepiperidine derivatives in accordance with the following formulae: C H , or CH . where A, B, D, and R 3 are defined above. Another useful class of piperidine derivative compounds are 4- diphenylmethoxypiperidine derivatives having the following formulae: CH O or CH 3 where A, B, D, and R 3 are defined above. Examples of R 4 are substituted or unsubstituted, straight or branched alkyl groups, including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-methylbenzyl gioups and substituted or unsubstituted aryl groups, including phenyl. tolyl, and xylyl groups Illustrative examples of compounds prepared by the process of the present invention are as follows: 4-[4-[4-(hydroxydiphenylmethyl)-l -piperidinyl]-l -hydroxybutyl]-α,α- dimethylbenzeneacetic acid, 4-[4-f4-(diphenylmethyl)-l -piperidinyl]-l -hydroxybutyl]-α,α- dimethylbenzcneacetic acid; 4-[4-[4-(diphenylmethylene)-l -piperidinyl]- l-hydroxybutylJ-α,α- dimcthylbenzencacetic acid; 4-[4-[4-(hydroxydiphenylmethyl)-l -piperidinyl J-l -hydroxybut> , l]-α,α-dimethyl 3-hydroxybenzeneacctic acid; 4-[4-[4-(hydroxydiphenylmcthyl)-l -piperidinyl]-l -hydroxybutyl]-α,α-dimcthyl 2-hydroxybenzeneacetic acid; 4-|4-f4-(diphenylmethylene)-l-piperidinyl]-l -hydroxybutyl]-α,α-dimethyl-3- hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethylene)-l -piperidinyl]-l -hydroxybutyl J-α,α- dimethylbenzeneacetic acid; ethyl 4-[4-|4-(hydroxydipheπylmethy ] )- l -piperidinyl ]- l -hydiOxybutyl |-α,α- dimethylbcnzeneacetate; n-pentyl 4-[4-[4-(diphenylmethyl)-l -pipcridinyl]- ! -hydroxybutyl )-α,α- dimethylbenzeneacetate; ethyl 4-[4-[4-(diphenylmethylene)-l -pipcridinyl j-l -hydroxybutylJ-α,α- dimcthylbenzeneacetate; methyl 4-[4-[4-(hydroxydiphenyhOethyl)-l -piperidinyl]-l -hydroxyl ityl]-a,a- dimethylbenzeneacetate; ethyl 4-|4-f4-(hydiOxydiphenylmcthyl)- l -pipcridinylJ- l -hydiOxybutyl]-α,α- dimethyl-(3-hydroxybenzene)acctate; n-propyl 4-[4-f4-(hydroxydiphenylmethyl)-l -piperidinylJ- l -hydroxybutylJ-α,α- dimethyl-(2-hydroxybenzene)acetate; n-hexyl 4- 4-[4-(diphcnylmethylene)- 1 -pipcridinyl ]- 1 -hydroxybutyl J-α,α- dimethyl-(3-hydroxybcnzcne)acetate; ethyl 4-[4-[4-(diphenylmethylcnc)-l-piperidinyl]-l -hydroxybutyl]-α,α- dimethylbenzeneacetate; 4-f4-|4-(diphenylmethoxy)- l -pipcridinyl]- l -hydroxybutyl]-tt,α- dimethylbenzcneacetic acid; 4-f4-|4-(diphenylmethoxy)-l -piperidinyl]-l -hydroxybutyl]-tt,α-dimethyl-3- hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethoxy)- l -pipcridinyl]- l -hydroxybutyl]-α,α-dimethyl-2- hydroxybenzeneacetic acid; 4-|4-[4-(diphenylmethoxy)-l-piperidinyl ]-l -hydroxybutyl |-α,α-dimethyl-3- hydroxybenzeneacetic acid; 4-[4-[4-(diphenylmethoxy)-l -piperidmyl]- l -hydroxybutyl]-α,α- dimethylbenzeneacetic acid; n-pentyl 4-[4-[4-(dipheny Imethoxy )-l -pιpeπdinyl ]-l -hydroxybutyl]-α. - dimethylbenzeneacetate, ethyl 4-[4-[4-(dφhenylmethoxy)- l -piperidmyl]- 1 -hydroxybutyl]-α, α- dimethylbenzeneacetate, eth\ 1 4-[4-[4-(diphenylmethox\ )- 1 -piperidi 11- 1 -hydroxybutyl |-α.α-dnnethyl- (3-hydroxybenzene)acctate; n-propyl 4-[4-[4-(diphenylmethoxy)-l-pιperidmyl |- l -hydroxybutyl]-α,α- dimethyl -(2-hydroxybenzene)acetate; n-hexyl 4-[4-[4-(dipheny Imethoxy )- 1 -piperidinylj- 1 -hydroxybutyl j-α,u-dιmethyl- (3-hydroxybenzene)acctate; and ethyl 4-[4-|4-(diphenylmethoxy)- 1 -piperidmyl]- 1 -hydroxybutyl]-α, α- dimethylbenzeneacetate Particularly prcfeπed are compounds of the formulae: C - OH <f A. , ! ( C — OH COOH CH, and )> CH O CH. Optionally, both diphenyl groups from the piperidine compound may be alkyl (e.g., methyl) substituted at the position para to the methylene, such as CH, CH. Λ ' -\ ' X C - OH CH, CH. CH, C OH O CH, ;CH ? ) 3 —c ^ ( \\ _ COOH CH, CH. CH, CH O or O C H , C H , 2 ) ' 3 - C COOH CH . The compounds prepared by the methods of the present invention can be pharmaceutically acceptable salts in the form of inorganic or organic acid or base addition salts of the above compounds. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric, and phosphoric acids. Suitable organic acids include carboxylic acids, such as, acetic, propionic, glycolic. lactic, pyruvic. malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzυic, and mandelic acid. Sulfonic acids, such as, methanesulfonic, ethanesulfonic, and β-hydroxyethane-sulfonic acid are also suitable acids. Non-toxic salts of the compounds of the above-identified formulae formed with inorganic and organic bases include, for example, those alkali metals, such as, sodium, potassium, and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of group IIIA, for example, aluminum, organic amines, such as. primary, secondary, or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, methylaminoethanol, and piperazine. These salts are prepared by conventional means, for example, by treating the piperidine derivative compounds of the formulae: . i ■ - R 1 < ? ) n 0 CH , ' CH, ) , " X / CH . or R 1 ( θ ; OH CH , / ( CH . CH- A CH 3 where A, B, D, n, R 1 , R 2 , and R 3 are defined above, with an appropriate acid or base. The piperidine derivative compounds prepared by the methods of the present invention can be utilized as the biologically active components in pharmaceutical compositions. These compounds are useful as antihistamines, antiallergy agents, and bronchodilators. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions. The compounds prepared by the methods of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous membranes, such oo as, that of the nose, throat, and bronchial tubes. Such application to mucous membranes can be achieved with an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form. The quantity of the compound administered will vary depending on the patient and the mode of administration and can be any effective amount. The quantity of the compound administered may vary over a wide range to provide in a unit dosage an effective amount of from about 0.01 to 20 mg/kg of body weight of the patient per day to achieve the desired effect. For example, the desired anlihistamine, antiallcrgy, and bronchodilator effects can be obtained by consumption of a unit dosage form such as a tablet containing 1 to 50 mg of the compound of the present invention taken 1 to 4 times daily. I he solid unit dosage forms can be of the conventional type. This solid form can be a capsule, such as an ordinary gelatin type containing the compound of the present invention and a carrier, for example, lubricants and inert fillers such as. lactose, sucrose. or cornstarch. ln another embodiment, these compounds are tableted with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch. or gelatin, disintegrating agents such as, cornstarch, potato starch, or alginic acid, and a lubricant like stearic acid or magnesium stearate. The compounds prepared according lo this invention may also be administered in injectable dosages by solution or suspension of the compounds of the present invention in a physiologically acceptable diluent with a pharmaceutical carrier. Such carriers include sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. For use as aerosols, the compounds in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. These compounds may be administered in a non-pressurized form, such as in a nebulizer or atomizer. The compounds made according to the present invention can be used to treat warm blooded animals, birds, and mammals. Examples of such beings include humans, cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice, and guinea pigs. According to one aspect of the present invention, the piperidine derivative compounds are prepared by providing a regioisomer of the following formula: A C H ' 3. O C H 3 and converting the regioisomer to the piperidine derivative compounds of the invention having a keto group with a piperidine compound. The resulting piperidine derivative compounds with a keto group can then be converted by reduction to the above-described piperidine compounds with a hydroxyl group. Λ is the substituents of its ring, each of which may be different or the same and is selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, and other substituents. X 3 can be halogen, such as chloride, bromide, or iodide, a hydroxy or alkoxy having the formula OR 1 - 1 , a thiol or an alkylthio derivative having the formula SR 15 , an amine having the formula NR 15 R 16 , a sufonic ester having the formula OS0 2 R 15 (such as methanesulfonate or tosylate) or a sulfonamide having the formula NHS0 2 R , :> . R 15 and R U are the same or different and are selected from the group consisting of hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight- chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-mcthylbcnzyl, preferably having from 1 to 7 carbon atoms; and an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl. Z can be a carbon atom to which arc bonded three electron rich groups, such as moieties having the formula CG'G 2 G 3 . G 1 , G 2 , and G 3 can be the same or different and are illustratively selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 , where R 8 and R 9 are the same or different and can be hydrogen; an alkyl moiet)'. including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n- hexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; or an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl groups. Examples of such a Z include triethoxymethyl or trimethoxymethyl moieties. Z can also be a heterocyclic moiety having the formulae: \\ C R b R ' ) , O or -/ ( CR 6 R 7 ) where m is an integer from 1 to 6 and Q and Y are independently oxygen, sulfur, or a substituted or unsubstituted amine having the formula NR 1 . R can be hydrogen: an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl, and 4-mcthylbenzyl, preferably having from 1 to 7 carbon atoms; or an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, and xylyl groups. It is to be understood that R 6 and R 7 , the two substituents bonded to each methylene (i.e. Cl group), of which there arc m in the above formulae, are independently selected from each other. In addition, it is to be understood that R 6 groups and R 7 groups on one methylene can be the same or different than those on other methylcnes. Each R 6 and each R 7 can be hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, 2- methylpentyl, cyclohexyl, benzyl, and 4-methylbenzyl. preferably having from I to 7 carbon atoms; an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, xylyl, and naphthyl; or a moiety having the formulae OR 8 , SR 8 , or NR 8 R 9 , where R 8 and R 9 are defined as they were above where Z had the formula CG 1 G 2 G 3 . Preferred examples of Z include isoxazoline moieties having the formula: i- R 7 o ' \ n l 3 wherein R 6 , R 7 , R 12 , and R 1 3 are the same or different and can be hydrogen; an alkyl moiety, including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl. neopentyl, n-hexyl, 2-methylpentyl, cyclohexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, xylyl, and naphthyl; or a moiety having the formulae OR 8 , SR 8 , or NR 8 R 9 . where R 8 and R 9 are as defined as they were above. Preferably, m is 2, and R 12 and R 13 are hydrogen. More preferably, R 12 and R 13 are hydrogen, and R 6 and R 7 are each an alkyl moiety having from 1 to 7 carbon atoms. Most preferably, Z is 4,4-dimethylisoxazolin-2-yl, where each of R 12 and R 13 is hydrogen and R 6 and R 7 is methyl. A variety of methods can be used to provide these regioisomers. Processes For Producing The Regioisomer In one embodiment of the present invention, the regioisomer is produced by acylating an α,α-disubstituted-methylbcnzene derivative having the formula: CH , with a compound having the formulae: o or x ~ c Ξ≡≡ N under conditions effective to produce the regioisomer having the formula: CH , In this embodiment, the acylation agent is a butyl derivative. ln another embodiment of the present invention, the acylation agent is a 4-(α,α- disubstituted)-toluic acid derivative. In this embodiment, the regioisomer is produced by reacting a 4-(α,α-dιsubstitutcd)-toluιc acid derivative having the formula: CH 3 with a compound having the formula: x 3 - x 1 under conditions effective to acylate the compound, producing the regioisomer. Irrespective of whether the regioisomer is produced using the process employing a butyl derivative acylation agent or the process employing a 4-(α,α-disubstituted)-toluic acid derivative acylation agent, X 1 can be a halogen; trialkyl or triaryl tin; trialkyl or triaryl boratc; alkylhalo silicon; trialkyl silicon; or a substituted sulfonic ester, such as tosylate, mcsylate, or triflale, with any alkyl groups being straight or branched and preferably having 1 to 4 carbon atoms. Alternatively, X 1 can be a substituent useful in organometallic coupling reactions, including lithium or magnesium compounds derived from bromine or iodine. As used herein, alkylhalo silicon is a tetravalent silicon atom bonded to at least one halogen and at least one alkyl group. The remaining silicon valency is bonded to either a second halogen or a second alkyl. One particularly useful alkylhalo silicon has the formula -SiCH 3 F 2 . X 2 , in either embodiment, can be hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 . or an amine. Suitable amines are those having the formulae -NR 10 R" or -NR l u (OR π ); saturated cyclic amines, such as those having the formulae: ( C H 2 ' P - N "N - R 1 0 or \ - N O \ / or heteroaryl amines, such as imidazole, pyrazole, and the like. R 10 and R π arc the same or different and are selected from the group consisting of hydrogen; an alky l moiety. including substituted or unsubstituted, branched or straight-chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n- hexyl, benzyl, and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; and an aryl moiety, including substituted or unsubstituted aryl moieties, such as phenyl, tolyl. and xylyl groups: p is an integer, preferably from 2 to 8. In practicing the process employing a butyl derivative acylation agent, suitable acylation agents include include 4-substituted butanal or a 4-substituted butyric acid derivative. Illustrative examples of 4-substituted butyric acid derivatives are 4- substituted butyric acid halides, alkali metal 4-subslituted butyric acid salts, 4-substituted butyric acid esters, or 4-substituted butyric acid amides. Suitable 4-substituted butyric acid halides include 4-substituted butyric acid fluoride, 4-substitutcd butyric acid chloride, and 4-substitutcd butyric acid bromide. Where an alkali metal salt of 4-substituted butyric acid is employed as the acylating agent, suitable alkali metals include lithium, sodium, and potassium. The 4-substituted butyric acid amide can be an N-unsubstituted amide, such as 4- substituted butyric acid amide; an N-monosubstituted amide, such as N-methyl-4- substituted butyric acid amide, N-ethyl-4-substitutcd butyric acid amide, N-propyl-4- substituted butyric acid amide, and N-hexy -4-substituted butyric acid amide; or an N,N- disubstituted amide. Suitable N,N-disubstituted amides include N,N-dimethyl-4- substituted butyric acid amide, N-methyl-N-ethyl-4-substituted butyric acid amide, N- methyl-N-propyl-4-substituted butyric acid amide, N-methyl-N-he.xyl-4-substituted butyric acid amide, N.N-diethyl-4-substituted butyric acid amide, N-ethyl-N-propyl-4- substituted butyric acid amide, N-ethyl-N-hexyl-4-substituted butyric acid amide, N,N- dipropyl-4-substituted butyric acid amide, N-propyl-N-hexyl-4-substituted butyric acid amide, and N,N-dihexyl-4-substituted butyric acid amide. N,N-disubstituted butyric acid amides having the formula -NR 10 (OR' '), such as N-methyl-N-methoxy-4-substituted butyric acid amide, N-methyl-N-ethoxy-4-substituted butyric acid amide, N-ethyl-N- methoxy-4-substituted butyric acid amide, N-ethyl-N-ethoxy-4-substitutcd butyric acid amide, are particularly useful. Suitable N,N-disubstituted amides also include cyclic amides, such as butyric acid morpholine amide, butyric acid piperazine amide, butyric acid imidazole amide, and butyric acid pyrazole amide, as well as those having the formula: o where p is an integer, preferably from 2 to 8, examples of which include N,N-ethylene-4- substituted butyric acid amide, N,N-propylene-4-substituted butyric acid amide, N,N- butylcne-4-substituted butyric acid amide, and N,N-pentylene-4-substituted butyric acid amide. Irrespective of whether the regioisomer is produced using the process employing a butyl derivative acylation agent or the process employing a 4-(α,α-disubstitutcd)-toluic acid derivative acylation agent, the acylation reactions are carried out in a suitable solvent in the presence of an appropriate catalyst for about 1 to 120 hours and at temperatures of about -78°C to the reflux temperature of the solvent. Suitable solvents for acylation include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride, chloroform, or carbon tetrachloridc; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran and diethylether; or dioxanc. In practicing either of the above processes, a variety of catalysts may be utilized when A is hydrogen. Suitable catalysts include palladium catalysts, like palladium chloride, palladium acetate, tetrakis(triphenylphosphinc) palladium(O), dichlorobis(triphenylphosphine) palladium(Il), or bcnzyIchlorobis(triphenyl- phosphine)palladium(II); or nickel-phosphine catalysts. Acylation may also be carried out in the presence of added lithium chloride or triphenylphosphine. The latter acylation reaction is known in the art as organometallic cross-coupling reactions and is conducted by the general procedures of D. Milstein, et al., J. Qrg. Chem.. 1979, 44, 1613 ("Milstein (1979)"); J.W. Labadie, et al., J. Qrg. Chem.. 1983, 48, 4634 ("Labadie"); C. Sahlberg, et al., Tetrahedron Letters. 1983, 24, 5137 ("Sahlberg"); D. Milstein, et al., J.Am. Chem. SOIL, 1978, 100, 3636 ("Milstein ( 1978)"); and K. Tamao, et al., Tetrahedron, 1982, 38, 3347 ("Tamao"), all of which arc hereby incorporated by reference. Where acylation is carried out using the process employing a butyl derivative acylation agent, the reaction can also be promoted by addition of an acylation promoter which, when reacted with the methylbenzene derivative, displaces X 1 from the carbon to which it is bonded, forming a reactive carbanion salt. One suitable acylation promoter is butyl lithium, which is particularly effective when X 2 is an amine. When X 2 is chloride, preferred acylation promoters are magnesium metal or tetraalkyl tin. Acylation promoters, especially organometallics such as butyl lithium, are highly reactive with carbonyl groups, for this reason, the Z moiety is chosen to minimize reactivity of the carbon beta to the benzene ring. In particular, when employing an acylation promoter, particularly inert Z moieties having the formula: \ ( CR S R ' ) m Q - "' such as isoxazolidium groups, are preferred. The α,α-disubstituted-methylbenzene derivative having the formula: A CH 3 A - x 1 /( ' V . _ c — z \ - A CH . can be provided by reacting an α,α-diunsubstituted-methylbcnzene derivative having the formula: with a methvlating agent under conditions effective to produce the α,α-disubstituted- methylbenzenc derivative . The methylation reaction is carried out in a suitable solvent and in the presence of a suitable non-nucleophilic base, such as potassium t-butoxide, sodium hydride, lithium diisopropylamide ("LDA"), lithium hexamethyldisilazidc ("LHMDS"), potassium hexamethyldisilazide ("KHMDS"), sodium or lithium tetramethylpiperidine, or related strong bases, for about 1 to about 120 hours, at temperatures from about -78°C to room temprature. Preferably, the reaction is conducted under an inert, dry atmosphere, such as N-, or Ar gas, in an inert, dry solvent. Suitable solvents for methylation include: hydrocarbon solvents, such as benzene, toluene, xylene. or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride, or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran. t-butyl methyl ether, and diethylether; or dioxane. At least two molar equivalents and, preferably, between 2.1 and 3 molar equivalents of methvlating agent are employed and added over the course of the reaction, either continuously or in two or more slugs. Suitable mcthylating agents include iodomethane, bromomcthane, chloromethane, dimethyl sulfate, and the like. The α,α-diunsubstituted-methylbenzene derivatives having the formula: can be prepared by reacting the correponding α,α-diunsubstituted benzyl ic acid of the formula: with an appropriate aminoalkyl derivative ha ing the formula: I I 2 N-(CR 6 R 7 ) m -Q-I l under conditions effective to produce the α,α-diunsubstituted-methylbenzene derivative. This reaction is conducted in a suitable solvent for about 1 to about 120 hours and at a temperature ranging from 0°C to the reflux temperature of the solvent. Suitable solvents for this reaction include: hydrocarbon solvents, such as benzene, toluene, xylcne, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichlorethane. methylene chloride, chloroform, or carbon tetrachloride; carbon disulfide; dimelhvlformamide; etheral solvents, like tetrahydrofuran and diethylether; or dioxane. Preferably, the solvent is maintained at reflux in an apparatus having a means for removing water, such as a Dean-Stark trap. In many cases, it is advantageous to convert the α,α-diunsubstituted-benzylic acid derivative to the corresponding acid halide, such as by treatment with thionyl chloride, prior to reaction with the aminoalkyl derivative. Alternatively, the α,α-disubstituted-methylbenzene derivative having the formula: can be prepared from the corresponding α,α-disubstitutcd-benzyhc acid derivative having the formula: CH 3 by reacting the α,α-disubstituted-benzylic acid derivative with the above aminoalkyl derivative under the conditions described above with respect to the α,α-diunsubstituted- benzylic acid conversion. The α.α-disubstituted-benzylic acid derivative used to prepare the α,α- disubstituted-methylbenzene derivative can be synthesized by methylating the corresponding α,α-diunsubstituted-benzylic acid derivative. Conditions suitable to carry out this methylation are the same as those described above with respect to methylation of α,α-diunsubstituted-methylbenzene derivatives. Where acylation is carried out with a 4-(α,α-disubstituted)-toluic acid derivative having the formula: o CH , the 4- α.α-disubstituted)-toluic acid derivative can be provided by reacting a 4-(α,α- diunsubstituted)-toluic acid derivative having the formula: o with a methylating agent under conditions effective to produce the 4-(α,α-disubstituted)- toluic acid derivative . Suitable methylation conditions are the same as those described above. The 4-(α,α-diunsubstituted)-toluic acid derivatives having the formula: can be prepared by reacting the correponding 4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative having the formula: o with an appropriate aminoalkyl derivative having the formula: H 2 N-(CR 6 R 7 ) m -Q-H under conditions effective to produce the 4-(α,α-diunsubstituted)-toluic acid derivative. Conditions suitable to effect this reaction are the same as those given above for rcacfion of α,α-diunsubstituted-methylbenzene derivatives with aminoalkyl derivatives. Alternatively, the 4-(α.α-disubstituted)-toluic acid derivative having the formula: * 2 ( C CRR* D RR 7 ' ) , can be prepared from the corresponding 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having the formula: CH 3 by reacting the 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative with the above aminoalkyl derivative under the conditions described above with respect to the reaction of α,α-diunsubstituted-benzylic acid derivatives with aminoalkyl derivatives. The 4-(α-carboxy-α,α-disubstituted)-toIuic acid derivative used to prepare the 4- (α,α-disubstituted)-toluic acid derivative can be synthesized by methylating the corresponding 4-(α-carboxy-α,α-diunsubstituted)-toluic acid derivative. Conditions suitable for carrying out this methylation are the same as those described above with respect to methylation of α,α-diunsubstituted-methylbcnzene derivatives. The regioisomer of the present invention having the formula: CH 3 \ i ' A " z O CH 3 can also be prepared from a corresponding α.α-diunsubstituted regioisomer precursor having the formula: A A ! ( - CH 2 Z x 3 - O by methylation using reagents and conditions described above with respect to the methylation of α,α-diunsubstituted-methylbenzcne derivatives. When employing this route, the α,α-diunsubstituted regioisomer precursor is convenienlly prepared from an α,α-diunsubstituted-methylbenzene derivative having the formula: by acylating the α,α-diunsubstitutcd-methylbenzene derivative with an acylation agent having the formula: x 3 ^' or x 3 ' — N under conditions effective to produce the α,α-diunsubstituted regioisomer precursor. Acylation conditions suitable for this reaction are the same as those described above with respect to acylation of α,α-disubstituted-methylbenzene derivatives. Alternatively, the α,α-diunsubstituted regioisomer precursor can be prepared from a 4-(α,α-diunsubstituted)-toluic acid derivative having the formula: o by reacting the 4-(α,α-diunsubstituted)-loluic acid derivative with a compound having the formula: X 3 " X 1 under conditions effective to produce the α,α-diunsubstituted regioisomer precursor. This reaction is can be carried out under the same reaction conditions as those described above with respect to acylation of α,α-disubstituled-methylbcnzene derivatives. Processes Of Converting The Regioisomer to The Piperidine Derivative Having A Keto Group Once the regioisomer is provided, it is then converted to the piperidine derivative with a piperidine compound. In one aspect of the present invention, the regioisomer can be hydrolyzed under conditions effective to form a first intermediate compound having the formula: The regioisomer is converted to the first intermediate compound by treating the regioisomer with a mineral acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid. The hydrolysis reaction is carried out in a suitable solvent, optionally in the presence of a catalytic amount of base for about 0.5 to 24 hours and a temperature of about -40 degrees C to the reflux temperature of the solvent. Suitable solvents for the hydrolysis reaction include hydrocarbon solvents, such as, benzene, toluene, xylene. or cyclohexane; ethereal solvents such as ether, tetrahydrofuran, dioxane. or dimethoxyethane; or halogenated hydrocarbons, such as, chlorobenzene, methylene chloride, carbon tetrachloride. chloroform, or dichloroethane. If desired, the acid group of the first intermediate compound can be esterified by techniques well known to those skilled in the art, such as by evaporating an alcoholic solution of the acid and a mineral acid, such as a methanolic, ethanoiic, propanolic, or butanolic solution of hydrochloric, hydrobromic, or hydroiodic acid, to dryness to form an ester having the formula: A CH , ) "> C - COOR ' <- / CH , After hydrolysis and optional este ification, the first intermediate compound or ester thereof can be reacted with a piperidine compound of the formula: B under conditions effective to form the piperidine derivative compound having a keto group of the formula: cooR CH , This alkylation reaction is carried out in a suitable solvent preferably in the presence of a base and, optionally, in the presence of a catalytic amount of potassium iodide for about 4 lo 120 hours at a temperature of about 70°C to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone or methyl ethyl ketone; hydrocarbon solvents, such as, benzene, toluene, or xylene; halogenated hydrocarbons, such as, chlorobenzene or methylene chloride; or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as a trialkylamine, for example, triethylamine or pyridine, or an excess of the piperidine compound can be used. When the piperidine derivative is in the form of an ester, it can be hydrolyzed to a carboxylic acid. Piperidine derivative compounds of the present invention having n equal to 1 can also be prepared by the following alternative alkylation procedure. Subsequent to hydrolysis and optional esterificalion, the first intermediate compound having the formula: CH , O is reacted with 4-hydroxypiperidine in an organic solvent, such as toluene, dioxane, xylene, methyl isobutyl ketone, methyl ethyl ketone, or N,N-dimcthylformamide, at a temperature between 80° and 140°C and in the presence of an acid-binding agent, such as an alkali metal carbonate or bicarbonate, to form an N-substituted hydroxypiperidine having the formula: OH The N-substituted hydroxypiperidine is then reacted with a diphenylmonohalomethane having the formula: - J B 7 <'- A XX CH wherein X 4 is a halogen, under conditions effective to form the piperidine derivative compound ol ' the formula: CH 3 The reaction is preferably carried out in an inert organic solvent, for example, toluene, xylene. dioxane, methyl isobutyl ketone, methyl ethyl ketone, or N,N- dimethylformamide, at a temperature between 80° and 140°C in the presence of an acid- binding agent such as an alkali metal carbonate or bicarbonate. The diphenylmonohalomethane can be obtained commercially, or it can be prepared by the methods known in the art, for example, by reaction of the corresponding diphenylmethanol with a phosphorous or thionyl chloride or bromide in an inert organic solvent. This alternative alkylation method is preferred when R 3 in the first intermediate compound is -COOH. Irrespective of the alkylation procedure employed, when R 3 is -COOalkyl, the alkylation reaction can be followed by base hydrolysis to convert R 3 substituents that are -COOalkyl groups to -COOH groups. Such base hydrolysis involves treatment of the piperidine derivative with an inorganic base, such as sodium hydroxide, in an aqueous lower alcohol solvent, such as aqueous methanol, ethanol, isopropyl alcohol, or n- butanol, at reflux temperature for about 1/2 hour to 12 hours. Piperidine compounds where n = 0 and each of R 1 and R 2 is hydrogen or where n=0 and R 1 is hydroxy and R 2 is hydrogen are commercially available or may be prepared according to procedures well known in the art (e.g. F.J. McCarty, CH. Tilford, M.G. Van Campen, J. Am. Chem. Soc.. 1961 , 26, 4084, which is hereby incorporated by reference). Piperidine compounds wherein n = 0 and R 1 and R 2 form a second bond between the carbon atoms bearing R 1 and R 2 may be prepared by dehydration of the corresponding compound wherein R 1 is hydroxy by procedures generally known in the art. Piperidine compounds wherein n = 1 and R 1 and R 2 are both hydrogen are prepared by condensation of an appropriately substituted diphenylmonohalomethane, such as diphenylchloromethane, diphenylbromomethane, and di(p-tolyl)chloromethane, with a 1 - alkoxycarbonyl-4-hydroxypipcridinc in a suitable solvent, such as toluene, xylene, dioxane. methyl isobutylketone, methyl ethyl ketone, or N,N-dimethylformamide. The reaction is conducted at a temperature between 80°C and 140°C and in the presence of a base, such as an alkali metal carbonate or bicarbonate. Following the reaction, hydrolysis with alkali metal hydroxide in an organic solvent, such as ethanol or isopropanol. at the boiling point of the solvent, yields the 4- diarylmethoxy)-piperidιne free base. In another aspect of the present invention, the piperidine derivative compound is produced by converting the regioisomer having the formula A CH 3 o CH, to a piperidine derivative precursor having the formula: A — R 1 ( 0 ) A CH . with a piperidine compound having the formula: A \ / A - V ' ~ R' ( 0 ) n r i N H under conditions effective to form the piperidine derivative precursor This alkylation reaction is carried out in a suitable solvent preferably in the presence of a base and, optionally, in the presence of a catalytic amount of potassium iodide for about 4 to 120 hours at a temperature of about 70°C to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents, such as, ethanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone and methyl ethyl ketone; hydrocarbon solvents, such as, benzene, toluene, or xylene; halogenated hydrocarbons, such as, chlorobenzene or methylene chloride; or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate, or potassium bicarbonate or organic bases, such as a trialkyiamme. for example, triethylamine or pyridine, or an excess of the piperidine compound can be used. Alternatively, piperidine derivative precursors of the present invention having n equal to 1 can be prepared by reacting the regioisomer having the formula: O CH 3 with 4-hydroxypiperidine in an organic solvent, such as toluene, dioxane, xylene, methyl isobutyl ketone, methyl ethyl ketone, or N,N-dimethylformamide, at a temperature between 80° and 140°C and in the presence of an acid-binding agent, such as an alkali metal carbonate or bicarbonate, to form an N-substituted hydroxypiperidine having the formula: OH CH 3 The N-substituted hydroxypiperidine is then reacted with a diphenylmonohalomethane having the formula: B / .. D (■ ■ ' ' X i /' f X" ' χ:)j ( .;.'/ ^ CH -^ I I X 4 wherein X 4 is a halogen, under conditions effective to form the piperidine derivative precursor of the formula: C R 1 ( o ; R 2 The reaction is preferably carried out in an inert organic solvent, for example, toluene, xylene, dioxane, methyl isobutyl ketone, methyl ethyl ketone, or N,N- dimethyl formamide, at a temperature between 80° and 140°C in the presence of an acid- binding agent such as an alkali metal carbonate or bicarbonate. According to yet another aspect of the present invention, piperidine derivatives having a keto group are prepared from an α,α-disubstituted-methylbenzene derivative having the formula: A CH 3 / X 1 — ( ( ' ) \ — c A ,' I CH 3 In this preparation, the α,α-disubstituted-methylbenzene derivative is converted to a piperidine derivative precursor having the formula: ( 0 ) n . ^— R 2 1 • N ' ° A CH 3 ^ ( CH 2 ' 3 CH 3 with a piperidine compound, preferably a 4-(4-substituted-piperidin-l-yl)butanal or a 4- (4-substitutcd-piperidin-l -yl)butyric acid derivative compound. 4-(4-substituted-piperidin-l -yl)butanals and 4-(4-substituted-piperidin-l - yl)butyric acid derivative compounds suitable for use in this acylation reaction include those having the formula: < ° > n R 2 O ( CH 2 ) 3 - C X 2 where X 2 is as defined above. This conversion is carried out in a suitable solvent in the presence of an appropriate catalyst for about 1 to 120 hours and al temperatures of about -78°C to the reflux temperature of the solvent. Suitable solvents for this acylation include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride. chloroform, or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran and diethylether; or dioxane. A variety of catalysts may be utilized when A is hydrogen. Suitable catalysts include palladium catalysts, like palladium chloride, palladium acetate, tetrakis(triphenylphosphine) palladium(O), dichlorobis(triphenylphosphine) palladium(II), or benzylchlorobis(triphenylphosphine)palladium(II); or nickcl-phosphine catalysts. The acylation reaction may also be carried out in the presence of added lithium chloride or triphenylphosphine. The latter cross-coupling reactions is typically conducted by the general procedures of Milstein (1979), Labadie, Sahlberg. Milstein (1 78), and Tamao, all of which are hereby incorporated by reference. The acylation reaction can also be promoted by addition of an acylation promoter which, when reacted with the methylbenzene derivative, displaces X 1 from the benzene ring, forming a reactive carbanion salt. One suitable acylation promoter is butyl lithium, which is particularly effective when X 2 is an amine. When X 2 is chloride, preferred acylation promoters are magnesium metal or tetraalkyl tin. Other suitable 4-(4-substituted-piperidin-l -yl)butanals and 4-(4-substituted- piperidm-l -yl)butyric acid derivatives include 4-(4-hydroxy-piperidin-l -yl)butanal and 4- (4-hydroxy-piperidin-l-yl)butyric acid derivatives having the formula: OH o ( CH ? ) . In this process, which is useful in preparing piperidine derivative precursors where n is the α,α-disubstituted-methylbenzene derivative is converted with the 4-(4-hydroxy- piperidin-l-yl)butyric acid derivative under conditions effective to produce an N- substituted hydroxy piperidine having the formula: OH CH . The N-substituted hydroxy piperidine is then converted to piperidine derivative precursors with a diphenylmonohalomethane as described above. Alternatively, the N-substituted hydroxy piperidine can be hydrolyzed under conditions effective to produce an N-subslitutcd piperidine compound having the formula: OH C H . Suitable hydrolysis conditions are as described below with regard to hydrolysis of the piperidine derivative precursor. The hydrolyzed N-substituted piperidine compound can then be converted to the piperidine derivative using a diphenylmonohalomethane as described above. In still another aspect of the present invention, piperidine derivatives having a keto group are prepared from a 4-(α,α-disubslituted)-toluic acid derivative having the formula: O A C H , c A ' > c - C H 3 In this preparation, the 4-(α,α-disubstituted)-toluic acid derivative is converted to a piperidine derivative precursor having the formula: C — R (ό) n R 2 with a piperidine compound, preferably a 3-(4-substituted-piperidin- l -yl)propane, such as those having the formula: B D -7 . > x 1 \ f ( o ; ( CH , ) . -X 1 where X 1 is as defined above. This conversion is carried out in a suitable solvent in the presence of an appropriate catalyst for about 1 to 120 hours and at temperatures of about - 78°C to the reflux temperature of the solvent. Suitable solvents and catalysts arc the same as those described above in connection with the conversion of α,α-disubstituted- methylbenzene derivatives to piperidine derivative precursors. Other suitable 3-(4-substituted-piperidin-l -yl)propane derivatives include 3-(4- hydroxy-piperidin-l -yl)propane derivatives having the formula: 0H ( C H 2 ) 3 - — X 1 In this process, which is useful in preparing piperidine derivative precursors where n is 1. the 4-(α,α-disubstituted)-toluic acid derivative is converted with the 3-(4-hydroxy- piperidin-l -yl)propane derivative under conditions effective to produce an N-substituted hydroxy piperidine having the formula: OH C H . The N-substituted hydroxy piperidine is then converted to piperidine derivative precursors with a diphenylmonohalomethane, before or after hydrolysis of the N- substituted hydroxy piperidine to the conversion of the N-substituted piperidine compound having the formula: OH CH 3 as described above. Irrespective of the alkylation procedure employed, the piperidine derivative precursor is then converted to the piperidine derivative compound having the formula: D , ~ > 1 ' ' 'v ) ' ' \ ~ - C R 1 ( ? > n R 2 COOH This conversion can be effected by treatment of the piperidine derivative precursor with a mineral acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid in a suitable organic solvent, for about 0.5 to 24 hours and a temperature of about -40 degrees C to the reflux temperature of the solvent. Suitable solvents include alcohols, such as methanol, ethanol, isopropanol, and various glycols; hydrocarbon solvents, such as, benzene, toluene, xylene, or cyclohexane; ethereal solvents such as ether, tetrahydrofuran. dioxane, or dimethoxyethane; or halogenated hydrocarbons, such as, chlorobenzenc, methylene chloride, carbon tetrachloride, chloroform, or dichlorocthane. Alternatively, this conversion can be effected in vivo by administering the piperidine derivative percursor to a subject, and permitting the subject to metabolize the piperidine derivative precursor to the piperidine derivative compound. The amounts and modes of administration arc the same as those discussed above for administration of piperidine derivative compounds of the present invention. Processes for Reduction of Keto Group in Piperidine Derivatives and Piperidine Derivative Precursors As discussed above, the process of the present invention is useful in producing piperidine derivatives with either a keto group or a hydroxyl group. Derivatives with keto groups can be converted to similar compounds with hydroxyl groups by reduction reactions which are well known in the art. Reduction can be carried out with sodium borohydride or potassium borohydride in lower alcohol solvents, such as, mcthanol, ethanol, isopropyl alcohol, or n-butanol. When lithium aluminum hydride or diborane are used as reducing agents, suitable solvents are ethers, for example, diethyl ether, tetrahydrofuran, or dioxane. These reduction reactions arc carried out at temperatures ranging from about 0°C to the reflux temperature of the solvent, and the reaction time varies from about 0.5 to 8 hours. Catalytic reduction with hydrogen may also be employed using, for example, Raney nickel, palladium, platinum, or rhodium catalysts in lower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol or acetic acid or their aqueous mixtures, or by the use of aluminum isopropoxide in isopropyl alcohol. Reduction using sodium borohydride is generally preferred over catalytic reduction when forming carboxylic acids or esters. The piperidine derivative containing a hydroxy group thus prepared can optionally be separated into its enantiomerically pure components by conventional methods. For example, the raccmic mixture of piperidine derivative enantiomers can be converted to a racemic mixture of diastereomers with a reactive chiral agent. The diastereomers are then separated by, for example, rccrystallization or chromatography, and the pure enantiomer is recovered by cleaving Ihe reactive chiral agent. Alternatively, the racemic mixture of piperidine derivative enantiomers can be chromatographically separated using chiral stationary phases or by recrystallization by using chiral solvents. Piperidine derivatives having keto groups can also be converted to enantiomerically pure piperidine derivatives having hydroxy groups by using chiral reducing agents. For example, reduction using ( i )-B-chlorodiisopropinocamphenyl- boranc produces the piperidine derivative having R chirality at the carbon to which the hydroxy group is bonded. Alternatively, by using (-)-B-chlorodiisopropinocamphenyl- borane produces the S enantiomer. Other suitable chiral reducing agents are (R) and (S)- oxazaborolidine/BH 3 , potassium 9-0-( 1 ,2:5, 6-di-O-isopropylidine-α-D-glucofuransoyl)- 9-boratabicyclo [3.3.1 ]nonane, (R) and (S)-B-3-pinanyl-9-borabicyclo[3.3.1 jnonane, NB- enantride, lithium (R)-(+) and (S)-(-)-2,2'-dihydrox) - l , l '-binaphthyl alkoxyl aluminum hydride, (R)-(+) and (S)-(-)-2,2'-dihydroxy-6,6'-dimcthylbiphenyl borane-amine complex, tris((( l S, 2S, 5R)-2-isoprophy-5-methyl-cyclohex-l -yl )mcthyl)aluminum, ((( 1 R, 3R)-2.2- dimethylbicyclo 2.2.1 ]hept-3-yl)methyl)beryllium chloride, (R)-BINAP-ruthenium complex/H 2 , and 6,6'-bis(diphenγlphosphino)-3,3'-dimethoxy-2,2',4,4'-tetramethyl-l ,r- bi phenyl When esters with hydroxyl groups have been formed, base hydrolysis can be used lo produce a carboxylic acid. Such procedures are well known and generally involve treatment with an inorganic base, such as, sodium hydroxide or potassium hydroxide, in an aqueous lower alcoholic solvent, such as aqueous methanol, ethanol, isopropyl alcohol, or n-butanol. Base hydrolysis is carried out at a temperature from about room temperature to the solvent reflux temperature for about 1/2 hour to 12 hours. In like manner, piperidine derivative precursors bearing a keto group and having the formula- i > > ? X) ( 0 ) n CH, can be reduced to piperidine derivative precursors bearing a hydroxyl group having the formula: The piperidine derivative precursors bearing a hydroxyl group can be converted to the piperidine derivative having the formula: CH . in vitro, such as by treating the piperidine derivative precursor bearing a hydroxyl group with strong acid, as discussed above, or, alternatively, in vivυ, by administering the piperidine derivative precursor bearing a hydroxyl group to a subject. The present invention is further illustrated by the following examples. EXAMPLES Example 1 - Preparation of 4-bromo-α-(4,4-dimethylisoxazolin-2-yl)toluene A mixture of 4-bromophenylacetic acid ( 172 g, 0.800 mole), 2-amino-2-methyl-l - propanol (1 15 mL, 1.20 mole), and 900 mL xylenes were refluxed for 24 hours in an apparatus equipped with a Dean-Stark trap. The mixture was then cooled, filtered, and concentrated to afford a crystalline solid. The solid was slurried in hexanes, and filtered to afford 147 g of a white solid. The hexane filtrate was then concentrated, slurried with hexanes. and filtered to afford another 13 g of 4-bromo-α-(4,4-dimcthylisoxazolin-2- yl)toluene as a white solid. The combined yield was 160 g (75%). Example 2 - Preparation of 4-bromo-α,α-dimethy.-α-(4,4-dimethylisoxazoiin-2- yl)toluene A 250 mL three neck round bottomed flask was charged with 5.0 g (0.0186 mole) of 4-bromo-α-(4,4-dimethylisoxazolin-2-yl)toluene, prepared according to Example 1 , and 50 mL of dry THF under N 2 . KHMDS, 27 mL (0.0279 mole, 1 .5 eq), was then slowly added over 10 minutes. A color change to deep orange was observed. After stirring the mixture for 15 minutes at room temperature, 1.16 mL (0.01 6 mole, 1 equiv.) of methyl iodide was added in one portion. The reaction exothermed to 46°C, and white solid precipitated while the solution retained a pale yellow tint. After stirring for 1 hour, another 27 mL (0.0279 mole, 1 .5 equiv. ) of KHMDS was added causing the temperature of the reaction to rise from 27° to 30°C and the color to change to orange. The reaction was stirred for an additional 20 minutes and, thereafter, a second equivalent of CH 3 I was added. An aliquot was removed, quenched with water, and extracted with ethyl acetate. TLC analysis (4: 1 hexane/ethyl acetate) showed the presence of the more polar 4-bromo- α-methyl-α-(4,4-dimethylisoxazolin-2-yl)toluene ("mono adduct"). An additional 0.2 mL of CH 3 1 was added which turned the pale yellow solution to white. The reaction mixture was then added to 100 mL 10% acetic acid/water along with 250 mL methylene chloride. The organic layer was washed twice with 50 mL brine and dried with sodium sulfate. After concentration and drying at room temperature and a pressure of 0.1 mm Hg overnight, 5.65 g (103%) of a yellowish solid was obtained. The solid was dissolved in 30 mL isopropanol and 20 mL of water was slowly added until an oil had formed. To the mixture. 5 mL of isopropanol was added with heating to dissolve all of the oil. The oil crystallized upon cooling in an ice bath, yielding 4.61 g (0.0156 mmole, 84%) of pure 4- bromo-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene no trace of mono adduct. Example 3 - Preparation of 4-(4-ehloro-l-oxobutyl)-α,α-dimethyl-α-(4,4- dimethyIisoxazolin-2-yl)toluene A solution of 4-bromo-α,α-dimcthyl-α-(4,4-dimethylisoxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 mL THF is cooled to -78°C, n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at -78°C for 30 minutes. While keeping the temperature below -75°C, 4- chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at -78°C for 30 minutes. The mixture is allowed to warm to - 15°C and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na 2 S0 4 , and concentrated. The residue is cooled lo 0°C, treated with minimal acetonitrile, and filtered, to afford 4-(4-chloro- l -oxobutyl)- α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)tolucne. Example 4 - Preparation of 4-(4-chloro-l-oxobutyl)-α,α-dimcthylphenylacetic acid A mixture of 4-(4-chlorυ- l -oxobutyl)-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2- yljtoluene, prepared according to Example 3, (47.8 g, 0.15 mole), 150 mL concentrated hydrochloric acid, and 150 mL 1 ,4-dioxane is brought to reflux for 1 8 hours. The mixture is extracted three times with ethyl acetate. The organics are washed with saturated NaCl solution, dried over MgSϋ , and concentrated. Crude product is purified by column chromatography using silica gel, and eluting with hexanc/ethyl acetate/acetic acid. Cleaner fractions are combined and recrystallized from methylene chloride/hexanes to afford 4-(4-chloro- l -oxobutyl)-α,α-dimethylphcnylacetic acid. Example 5 - Preparation of Methyl 4-(4-chloro-l-oxobutyl)-α,α- dimethylphenylacetate A solution of 4-(4-chloro-l-oxobutyl)-α,α-dimethylphenylacetic acid, prepared according to Example 4, (15 g, 0.056 mole) in 450 mL of a HCl-saturated methanol is refluxed for 1 hour. The mixture is concentrated to dryness and partitioned between ethyl acetate and water. The aqueous phase is extracted twice again with ethyl acetate. The combined organic phases are dried over MgS0 and concentrated to an oil The oil is purified by column chromatography using silica gel, and eluting with hexanes/ethyl acetate. Clean fractions are combined and concentrated lo afford methyl 4-(4-chloro-l - oxobutyl)-α,α-dimcthylphenylacctate. Example 6 - Preparation of Methyl 4-[4-[4-(Hydroxydiphenylmethyl)-l-piperidinylJ- l-oxobuty.l-α,α-dimethyIphenylacetate A solution of 12.6 g of methyl 4-(4-chloro-l -oxobutyl)-α,α- dimethylphenylacetate, prepared in accordance with Example 5, in 500 mL of toluene in a one liter three neck flask with mechanical stirring is added 8.8 g of 4-(α,α- diphenyl)piperidinemethanol and 23 g of K 2 C0 3 and the mixture is refluxed for 7 hr. The cooled reaction mixture is then filtered and concentrated in vacuo. The residue is dissolved in Et-,0 and treated with excess ethereal HCl. The mixture is then concentrated to a solid. The solid is treated with EtOAc and collected by filtration. The product is then partitioned between EtOAc and 2N Na-,C0 3 . The organics arc dried over MgS0 4 , filtered, and concentrated in vacuo to afford methyl 4-[4-[4-(hydroxydiphcnylmcthyl)-l - piperidinyl - 1 -oxobutylJ-α,α-dimethylphenylacctatc. Example 7 - Preparation of Methyl 4-[4-|4-(Hydroxydiphenylmethyl)-l-piperidinyl|- l-hydroxybutyI]-α,α-dimethylphenylacetate A solution of 13.5 g of methyl 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinylJ-l- oxobutyl]-α,α-dimethylphenylacetate, prepared in accordance with Example 6, in 250 mL of CH OH is cooled in an ice ClI 3 OII bath, and 1.8 g of NaBII 4 is added in portions. After 1 hr, the mixture is concentrated to a solid. The residue is partitioned between EtOAc and saturated aqueous NaHC0 3 . The aqueous portion is extracted with EtOAc. The combined organics are washed with saturated aqueous NaCl, dried over MgS0 4 , filtered, and concentrated in vacuo to afford methyl 4-[4-|4-(hydroxydiphenylmethyl)-l- piperidinyl ]-l -hydroxybutyl J-α.α-dimethylphcnylacctate as a foam. Example 8 - Preparation of 4-[4-[4-IIydroxydiphenylmethyl)-l-piperidinyl]-l- hydro.γybutyI]-α,α-dimethylphenylacetic Acid To a solution of 9.5 g of methyl-4-[4-[4-(hydroxydiphenylmethyl)- l -piperidinylJ- l -hydroxybutyl]-α,α-dimethyiphenylacetate, prepared in accordance with Example 7, in 300 mL of CH 3 OH and 150 mL of I I 2 0, is added 10 g of NaOH. ' I he mixture is refluxed for 1 hr, then cooled. The CFI 3 OH is removed in vacuo. ' I he concentrate is diluted with H 2 ϋ and CFICI 3 , and the pH is adjusted to approximately 5.5 to 6.0. The phases are separated, and the aqueous phase is extracted with CHC1 3 . The combined organics are dried over MgS0 , filtered, and stripped to afford crude product. The crude product is dissolved in CH 2 C1 2 and chromatographed on Davisil Grade 633 Si0 2 eluting with a gradient of CHC1 3 , to 10% CH 3 OH in CHC1 , to 25% CH 3 OH in CFICI 3 . The product containing fractions are concentrated to afford 4-[4-[4- hydroxydiphenylmethyl)-l -piperidinylJ-l -hydroxybutyl]-α,α-dimethylphenylacctic acid. Example 9 - Preparation of Methyl 4-[4-|4-(Bis(4-nιethylphenyI)hydroxymethyl)-l- piperidinyI]-l-oxobutyI]-α,α-dirnethyIphenylacetate To a solution of 6.4 g (0.017 mol) of methyl 4-(4-chloro-l -oxobutyl)-α,α- dimethylphenylacetate, prepared in accordance with Example 5, in 500 mL of toluene in a one liter round bottom flask equipped with a mechanical stirrer is added 5.1 g (0.017 mol) of 4-(α,α-bis(4-methylphenyl)-piperidinemethanol, followed by 1 1 .8 g (0.086 mol) of solid potassium carbonate. The solution is heated to reflux for 24 hr. After cooling, the mixture is filtered, and the toluene is removed in vacuo. The residue is partitioned between ethyl acetate and 2 N sodium carbonate solution. The aqueous layer is extracted twice with ethyl acetate, the combined organic layers are dried with sodium sulfate, and the ethyl acetate is removed in vacuo to provide methyl 4-|4-[4-(bis(4- methylphenyl)hydroxymethyl)-l -pipcridinyl]- 1 -oxobutyiJ-α.α-dimclhylphenylacetate. Example 10 - Preparation of Methyl 4-|4-|4-(Bis(4-Methylphcnyl)hydroxymethyl)-l- pipcridinyl]-l-hydroxybutylj-α,α-dimcthylphenylacetate ' o a -10°C solution of 6.8 g (0.013 mol) of methyl 4-[4-[4-(bis(4- methylphenyl)hydroxymethyl)-l-piperidinyl]-l -oxobutylj-α,α-dimcthylphenylacetate, prepared in accordance with Example 9, in 150 mL of methanol in a 500 mL round bottom flask equipped with a mechanical stirrer is slowly added 0.86 g (0.023 mol) of sodium borohydride, and the reaction is stirred for 2 hr. The methanol is removed in vacuo. and the residue is partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate, the combined organic layers are dried with sodium sulfate, and the ethyl acetate is removed in vacuo to provide crude product. The resultant material is purified by column chromatography (Davisil grade 633 silica gel, packed in methylene chloride, material applied in chloroform, and eluted with a gradient of 2% methanol to methylene chloride to 5% methanol to methylene chloride) to afford methyl 4-[4-[4-(bis(4- methylphenyl)hydroxymethyl)-l -pipcridinyl]- l-hydroxybutyl]-α,α- dimethylphenylacetate. Example 11 - Preparation of 4-[4-[4-(Bis(4-methylphenyI)hydroxymethyl)-l- piperidinyl]-l-hydroxybutyl]-α,α-dimethylphenylacetic Acid To 350 mL of methanol in a 1 L round bottom flask equipped with a mechanical stirrer is added 5.3 g (9.8 mmol) of methyl 4-|4-[4-(bis(4-methylphenyl)hydroxymethyl)- l -piperidinyl]-l-hydroxybutyl]-α,α-dimethylphenylacetate, prepared in accordance with Example 10, 5.1 g (0.13 mol) of solid sodium hydroxide, and 100 mL of water. The mixture is heated to reflux for 3 hr. After cooling, the methanol is removed in vacuo. and 6 N hydrochloric acid is added dropwise until the solution was no longer basic (pFI = 7). The solution is extracted three times with ethyl acetate. The organic layers are combined, and precipitation is induced. The solid is washed with ether to provide 4-[4-[4-(bis(4- methylphenyl)hydroxymethyl)- l -piperidinyl -l -hydiOxybutyl]-α,ot-dimethylphenylacetic acid, as the dihydrate. Example 12 - Preparation of 4-(l-Hydroxy-4-chlorobutyl)-α,α-dimcthylphenylacetic acid To a solution of 50 mg of 4-(4-chloro-l -oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 4, in 3 mL of methanol is added 50 mg of NaBII . The mixture is stirred for 30 minutes, acidified with 2N HCl, and the methanol is removed in vacuo. The concentrate is extracted with EtOAc. The organics are dried over Na S0 4 , filtered, and concentrated to afford 4-(l-hydroxy-4-chlorobutyl)-α,α- dimethylphenylacetic acid. Example 13 - Preparation of 4-[4-(4-(Hydroxydiphenylmethyl)-l-piperidinylj-l- oxobutyl]-α,α-dimethyIphenylacetic acid A mixture of 800 mg of 4-(4-chloro-l -oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 4, 800 mg of 4-(α,α-diphenyl)piperidinemethanol, and 2.4 g of K 2 CO 3 in 25 mL of toluene is stirred for 48 hours at room temperature. The mixture is concentrated in vacuo. The residue is treated with EtOAc, filtered, and concentrated to afford 4-[4-[4-(hydroxydiphenylmethyI )-l -pipcridinyl]- l -oxobutyl]-α,α- dimethylphenylacctic acid. Example 14 - Preparation of 4-[4-[4-Hydroxydiphenylmethyl)-l-piperidinyl|-l- hydroxy utyl |-α,α-dimethylphenylacetic Acid A mixture of 4-[4-[4-(hydroxydiphcnylmethyl)-l -pipcridinyl]- 1 -oxobutyl]-α,α- dimethylphenylacetic acid, prepared in accordance with Example 13, and 300 mg of NaBH 4 in 25 mL of CH 3 OH is stirred overnight at room temperature. The mixture is then concentrated in vacuo. The residue is partitioned between EtOAc and H 2 0. The aqueous portion is treated with concentrated HCl until pH 6, then extracted with EtOAc. The organics are concentrated in vacuo. The residue is dissolved in EtOAc, filtered, and concentrated in vacuo to an oil. The oil is dissolved in CH3OH and concentrated to a solid. The solid is slurried with EtOAc, filtered, and rinsed with EtOAc to afford 4-[4-[4- hydroxydiphenylmethyl)-l -piperidinyI]-l -hydroxybutyl j-α,α-dimethylphenylacetic acid. Example 15 - Alternative Preparation of 4-(4-chloro-l-oxobutyl)-α,α-dimethyl-α- (4,4-dimcthyIisoxazolin-2-yl)toluenc Magnesium (96 mg, 3 mM) was suspended in tetrahydrofuran. A small crystal of iodine was added to activate the magnesium. Solid 4-bromo-α.α-dimethyl-α-(4,4- dimethylisoxazolin-2-yl)toluene (600 mg. 2 mM), prepared in accordance with Example 2, was added, and the mixture was stirred for 6 hours at room temperature, then for 6 hours at reflux, and then cooled to room temperature. After adding 4-chlorobutyronitrile. the mixture was stirred overnight and then poured into cold, dilute acid. The acid solution was extracted with ethyl acetate, and the organic layer was separated and dried with sodium sulfate. Removal of the solvent under reduced pressure afforded an almost colorless oil in 93% yield. Spectral analysis was consistent with 4-(4-chloro-l -oxobutyl)- α,α-dimethyl-α-(4,4-dimethylisoxazolin-2-yl)toluene. Example 16 - Preparation of 4-formyl-α,α-dimethyl-α-(4,4-dimethylisoxazolin-2- yl)toluene A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimcthylisoxazolin-2-yl)toluenc (1 g. 3.4 mM mole), prepared in accordance with Example 2, was chilled to -78 °C in a dry ice bath, and to this was added a solution of 2M butyl lithium (3.4 mM). The mixture was stirred for 15 minutes, 2 mL of DMF was added, the dry ice bath was removed, and the mixture was allowed to warm to 0°C. The 0°C solution was poured into cold brine and extracted with ethyl acetate. The organic layer was separated and dried with sodium sulfate. Removal of the solvent under reduced pressure and afforded a white solid whose proton NMR spectrum was consistent with 4-formyl-α,α-dimethyl-α-(4,4- dimethylisoxazolin-2-yl)toluene. Although the invention has been described in detail for the purpose of illustration, it is understood that such detail is solely for that purpose, and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the following claims.

Claims: WHAT IS CLAIMED: 1. A process of preparing a piperidine derivative compound of the formula: A ° A CH 3 (CH,), " C 'X ) ■ C-— R CH 3 or (O) n R^ CH '3 wherein n is 0 or 1; R 1 is hydrogen or hydroxy; R 2 is hydrogen; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 , provided that when n is R 1 and R 2 are each hydrogen; R 3 is —COOH or — COOR 4 ; R 4 is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents, said process comprising: providing a regiosomer of the following formula: A CH , o CH, wherein Z is — AG'G 2 G 3 , or /, N - , m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 . and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 , X 3 is halogen, OR' 5 , SR 15 , NR 15 R 16 , OS0 2 R 15 . or NHS0 2 R 15 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; and R 5 , R 8 , R 9 , R 15 , and R 16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiet}-. and an aryl moiet}- and converting the regioisomer to the piperidine derivative compound with a piperidine compound. 2. A process according to claim 1 , wherein said providing the regioisomer comprises: acylating an α,α-disubstituted-methylbenzene derivative having the formula- C H 3 X ι /^λ C H 3 wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl bo rate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound having the formulae: x 2 X 3 ' I I or x 3 wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R ! ϋ is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to produce the regioisomer. 3. A process according to claim 2, further comprising: reacting an α,α-diunsubstituted-methylbenzcne derivative having the formula: X 1 ( ! - CH 2 - Z with a methylating agent under conditions effective to produce the α,α-disubstituted- mcthylbenzene derivative. 4. A process according to claim 3, wherein Z has the formula: \ (CR 6 R 7 ) m N Q and further comprising reacting an α.α-diunsubstiluted ben/ylic acid derivative having the formula: A with an aminoalkyl derivative having the formula. H 2 N - (CR 6 R 7 ) m Q - H under conditions effective to produce the α,α-diunsubstituted-methylbenzene derivative. 5. A process according to claim 2 wherein Z has the formula: (CR 6 R 7 ), Q and further comprising: reacting an α,α-disubstituted benzylic acid derivative having the formula: CH , with an aminoalkyl derivative having the formula- H 2 N ; CR 6 R 7 Q under conditions effective to produce the α,α-disubstituted-mcthylbenzene derivative. 6. A process according to claim 1. wherein said providing the regioisomer comprises: reacting a 4-(α,α-disubstitutcd)-toluic acid derivative having the formula: o CH , c — \ — C CH 3 wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formul -OR 10 ; a moiety having the formula -SR 10 . or an amine; and R'° is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety with a compound having the formula: wherein X 1 is a halogen, trialkyl or triaryl tin. trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the regioisomer. 7. A process according to claim 6 further comprising: reacting a 4-(α,α-diunsubstιtuted)-toluic acid derivative having the formula- with a methylating agent under conditions effective to produce the 4-(α.α-disubstituted)- toluic acid derivative 8 A process according to claim 7. wherein Z has the formula. N -- (CR 6 R 7 and further comprising reacting a 4-(α-carboxy-α.α-diunsubstituted)-toluic acid derivative having the formula: O A X 2 -- C A I CH 2 — COOH with an aminoalkyl derivative having the formula: H 2 N ;CR 6 R 7 Q under conditions effective to produce the 4-(α.α-diunsubstituted)-loluic acid derivative. 9. A process according to claim 6, wherein Z has the formula: (CR B R 7 Q and further comprising: reacting a 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having the formula: CH 3 -\ \ I ) ' C — COOH C H with an aminoalkyl derivative having the formula: H 2 N ( CR 6 R 7 ) m Q H under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative. 10. A process according to claim 1 , wherein said providing the regioisomer comprises: providing an α,α-diunsubstituted regioisomer precursor having the formula: /( CH Z Z O and methylating the α,α-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer. 1 1 . A process according to claim 10, wherein said providing the α,α- diunsubstituted regioisomer precursor comprises: acylating an α,α-diunsubstitutcd-methylbenzene derivative having the formula: wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound having the formulae: x 2 x 3 O or x λ 3 - ^" '""" ^ C ^≡ N wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R'° is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to produce the α,α-diunsubstituted regioisomer precursor. 12. A process according to claim 10, wherein said providing the α,α- diunsubstituted regioisomer precursor comprises: reacting a 4-(α,α-diunsubstituted)-toluic acid derivative having the formula: wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety with a compound having the formula: χ 3 \. \ χ 1 wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the α.α-diunsubstituted regioisomer precursor. 13. A process according to claim 1 , further comprising: reducing the piperidine derivative compound under conditions effective to form a hydroxylatcd piperidine derivative compound of the formula- OH A CH 3 ( C H . CH -X 7 i r — c- CH , 14. A process according to claim 13, wherein the hydroxylated piperidine derivative compound has the formula: XXL "/ OH C H 3 15. A process according to claim 13, wherein the hydroxylated piperidine derivative compound has the formula: X: < CH O OH CH 3 (C !H, ) _ - C ! — A /TA ,AX C I - COOH I \ A H CH, 16 A process according to claim 1 , wherein the piperidine derivative compound has the formula: X I ' \ C OH I N ° CH 3 (CH 2 ) 3 C < \ )' ■ C COOH CH 17. A process according to claim 1, wherein the piperidine derivative compound has the formula: CH O C H , 18 A process according to claim 1 , wherein said converting comprises: hydrolyzing the regioisomer of the formula- o CH , under conditions effective to form a first inlermediate compound of the formula: CH . O 19. A process according to claim 18, wherein said converting further comprises: reacting the first intermediate compound with a piperidine compound of the formula: B c " (0)π N H under conditions effective to form the piperidine derivative compound of the formula: C-— R 1 (o: R' O CH, (CH, ), - C ( , { > )) — C COOH CH, 20. A process according to claim 18, wherein said converting further comprises: esterifying the first intermediate compound to the ester thereof, having the formula: and reacting the ester with a piperidine compound of the formula: <°>n N H under conditions effective to form the piperidine derivative compound of the formula: <° ) n O CH, / \ (CH ) -^ i -C — COOR 2, ' 3 CH. 21. A process according to claim 20, further comprising: hydrolyzing the piperidine derivative compound of the formula: CH , to a piperidine derivative compound of the formula: B CH , 22. A process according to claim 18, wherein n is 1 and wherein said converting further comprises: reacting the first intermediate compound with 4-hydroxypιperidine under conditions effective to produce an N-substituted hydroxypiperidine having the formula: OH CH. (CH '2, ) ' .3 C ' ' ^ - C COOH CH and reacting the N-substituted hydroxypiperidine with a diphenyl halomethanc having the formula B / CH wherein X 4 is a halogen under conditions effective to form the piperidine compound derivative of the formula. CH O CH 23 A process according to claim 1, wherein said converting comprises: reacting the regioisomer with a piperidine compound of the formula- B < ° > n — R ' N H under conditions effective to form the piperidine derivative precursor of the formula: ' • CH , 24. A process according to claim 23. further comprising converting the piperidine derivative precursor to the piperidine derivative compound of the formula: C — R 1 :o: o CH, (CH, λλ C - COOH 2 ) ' 3 CH, 25. A process according to claim 23, lurther comprising reducing the piperidine derivative precursor under conditions effective to form a hydroxylated piperidine derivative precursor oflhe formula: C R, :o; OH CH, (CH CH- > ■ )s ' . — C 2 I 3 CH. 26. A process according to claim 25, further comprising converting the hydroxylated piperidine derivative precursor to a hydroxylated piperidine derivative compound of the formula: ir (0) n R, OH CH, (CH, ), CH A A C - COOH CH. T 11. A process according to claim 1, wherein n is 1 and wherein said converting further comprises: reacting the regioisomer with 4-hydroxypipcridine under conditions effective to produce an N-substituted-hydroxypiperidine having the formula: OH o A CH 3 CH. CH, and reacting the N-substituted hydroxypiperidine with a diarylhalomethane having the formula: B χ D < ■ - I -CH i X 4 wherein X 4 is a halogen under conditions effective to form the piperidine derivative precursor of the formula: B (o; O A CH, (CH ? ) A 2 ' 3 CH, 28. A process according to claim 27, further comprising converting the piperidine derivative precursor to the piperidine derivative compound of the formula: fl A X \ , / (O)n CH. 29. A process according to claim 27, further comprising reducing the piperidine derivative precursor under conditions effective to form a hydroxylated piperidine derivative precursor of the formula- 30 A process according to claim 29, lurthei comprising converting the hydroxylated piperidine precursor to a hydioxvlatcd piperidine derivative compound of the formula C — R . :?) „ R 2 I CH 3 A process of preparing a piperidine derivative compound of the formula 1 C R :o: CH, (CH, ) — c- ' ' C R J CH. or B rl v < ,\ A C - R 1 (o; R OH CH, N (CH 2 ) 3 CH- \_ / CH. wherein n is 0 or 1 , R 1 is hydrogen or hydroxy, R 2 is hydrogen, or, when n is 0, R 1 and R 2 taken togethei form a second bond between the carbon atoms bearing R 1 and R 2 , provided that when n is R 1 and R 2 are each hydrogen. R 3 is — COOl I or —COOR 4 . R is an alkyl or aryl moiety. Λ, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents, said process comprising: providing an α,α-disubstituted-methylbenzene derivative having the formula: C H . ,AΓ - C — z CH . wherein Z is - 'G 2 G 3 \\ C R 6 R 7 ) r O or ( CR U R ' ) n Q m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 arc the same or different and are selected from the group consisting of OR 8 . SR 8 . and NR 8 R 9 . X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions; R 6 and R 7 arc the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 . SR 8 , and NR 8 R 9 ; and R\ R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety and converting the α,α-disubstitulcd-methylbenzene derivative to the piperidine derivative compound with a piperidine compound. 32. A process according to claim 31 , wherein said providing the α,α-disubstituted-methylbenzene derivative comprises: reacting an α.u-diunsubstituted-methylbenzene derivative having the formula: CH . with a methylating agent under conditions effective to produce the α,α-disubstituted- methylbenzene derivative. 33. J process according to claim 32, wherein Z has the formula: A ^ ( CR 6 R 7 ) m Q said process further comprising: reacting an α,α-disunsubstituted benzyl ic acid derivative having the formula: x ■ ,i - (. ' ' j V;> C —H 2, -- COOH with an aminoalkyl derivative having the formula: H , N - - ( CR 6 R 7 ) Q H under conditions effective to produce the α,α-diunsubstituted-methylbenzene derivative. 34. A process according to claim 31 , wherein Z has the formula: - N / ( CR 6 R 7 ) Q -" and wherein said providing the α,α-disubstituted-methylbenzene derivative comprises: reacting an α,α-disubstituted benzylic acid derivative having the formula- CH , with an aminoalkyl derivative having the formula: H 2 N - ( CR 6 R 7 ) m - Q — H under conditions eficctive to produce the α,α-disubstιtuted-methylbcnzenc derivative. 35 A process according to claim 31 , further comprising: reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula: B H CH , A / ( CH 2- ' . CH — 3 CH 3 36. A process according to claim 35, wherein the hyrdroxylated piperidine derivative compound has the formula: OH OH CH. (CH 2 ) 3 -- C {( )) — C COOH J / CH. !7 A process according to claim 35. wherein the hydroxylated piperidine derivative compound has the formula: OH CH, I I CH 2 ) 3 C I ( /(-A y / - C — COOH CH. 38. A process according to claim 31 , wherein the piperidine derivative compound has the formula: OH O CH. (CH 2 ) 3 C - < ' ' — C -COOH CH. 39 A process according to claim 31 , wherein the piperidine deπvative compound has the formula 7 \ ' ' " ^ xX ' χX x C N O CH 3 (CH 2 ) 3 C < ( ' ' X C — COOH CH. 40 A process according to claim 31 , wherein said converting comprises: reacting the α-α-disubstituted-methylbenzene derivative with a 4- (4-substituted)piperidin-l-yl)butanal or a 4-(4-substituted)piperidin-l-yl)bulyric acid derivative having the formula: / A- \ i \ A A- C — R <o) n 0 CH, ). wherein X 2 is a hydrogen; halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 . or an amine; and R'° is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to form a piperidine derivative precursor having the formula: /- 1 1 <?>π H, CH 3 41. A process according to claim 40, wherein said converting further comprises: hydrolyzing the piperidine derivative precursor of the formula: R 1 ( O ) CH 3 under conditions effective to form the piperidine derivative having the formula. B r r \ I A X A : o ; CH, 42. A process according to claim 31. wherein n is 1 and wherein said converting comprises: reacting the α,α-disubstιtutcd-methylbenzene derivative with a 4- (4-substitutcd-piperidin-l -yl)butanal or a 4-(4-substitutcd-piperidin-l -yl)butyric acid derivative having the formula: OH O (CH, ). wherein X 2 is hydrogen; a halogen: an alkali metal oxide, a moiet} having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to produce an N-substituled hydroxypiperidine having the Iormula OH o CH. (CH, ). CH 3 and converting the N-substituted hydroxypiperidine with a diarylhalomethane having the formula: B If > CH wherein X 4 is a halogen under conditions effective to form the piperidine derivative compound of the formula: CH CH. 43. A process of preparing a piperidine derivative compound of the formula: B C — R 1 :o; CH, or C— R 1 CH 3 wherein n is 0 or 1; R 1 is hydrogen or hydroxy: R 2 is hydrogen; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2 , provided lhat when n is 1, R 1 and R 2 are each hydrogen; R 3 is —COOH or— COOR 4 ; R 4 is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents, said process comprising: providing a 4-(α,α-disubstituted)-toluic acid derivative having the formula: O CH. A CH. wherein Zis— CG'G 2 C C R 6 R 7 O or ( C R G R 7 m is an integer from 1 to 6; Q and Y arc the same or different and are selected from the group consisting of (), S, and NR 5 ; G 1 , G 2 , and G 3 are the same or di fferent and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 , X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 1 0 . or an amine; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR R 9 ; and R 5 . R 8 , R 9 , and R 10 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety and converting the 4-(α,α-disubstιtuted)-toluic acid derivative to the piperidine derivative compound with a piperidine compound. 44. A process according lo claim 43, wherein said providing the 4-(α,α- disubstituted)-toluic acid derivative comprises: reacting a 4-(α.α-diunsubstituted)-toluic acid derivative having the formula: with a methylating agent under conditions effective to produce the 4-(α,α-disubstituted)- toluic acid derivative. 45. A process according to claim 44, wherein Z has the formula: A 6 7 (CR 6 R 7 ) m Q said process further comprising: reacting a 4-(α-carboxy-α,α-disunsubstituted)-toluic acid derivative having the formula: o A X 2 C ' ' ) CH, COOH with an aminoalkyl derivative having the formula- H,N (CR 6 R 7 Q under conditions effective to produce the 4-(α,α-diunsubstituted)-toluic acid derivative. 46. A process according to claim 43, wherein Z has the formula: N - (CR 6 R' ) r and wherein said providing the 4-(α,α-disubstitutcd)-toluic acid derivative comprises: reacting a 4-(α-carboxy-α,α-disubstituted)-toluic acid derivative having the formula: CH 3 with an aminoalkyl derivative having the formula: H,N (CR C R 7 ) m Q — H under conditions effective to produce the 4-(α,α-disubstituted)-toluic acid derivative. 47. A process according to claim 43, further comprising: reducing the piperidine derivative compound under conditions effective to form a hydroxylated piperidine derivative compound of the formula: (O), - R' OH CH. (CH. CH A CH, 48. A process according to claim 47, wherein the hydroxylated piperidine derivative compound has the formula: ' ' / OH OH CH, H CH 49 A process according to claim 47, wherein the hydroxylated piperidine derivative compound has the formula: λ A A < CH OH CH. ;CH 2 ) 3 — c — (( )X ~ - C - COOH CH 50. A process according to claim 43, wherein the piperidine derivative compound has the formula: X — OH CH. (CH 2 ) 3 C ' ' C — COOH CH, 51. A process according to claim 43, wherein the piperidine derivative compound has the formula: CH O C H 3 A ' 2 ' 3 C COOH CH 3 52. A process according to claim 43, wherein said converting comprises: reacting the 4-(α,α-disubstituted)-toluic acid with a 3-(4- substituted )piperidin-l -yl)propane derivative having the formula: N j ( CH 2 ) 3 — X 1 wherein X' is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to form a piperidine derivative precursor having the formula: C - R 1 <?>n O A CH 3 (CH, C - Z CH 3 53. A process according to claim 52, wherein said converting further comprises: hydrolyzing the piperidine derivative precursor of the formula: under conditions effective to form the piperidine derivative having the formula: ! -- > < X - i I C H 3 54 A process according to claim 43 wherein n is 1 and wherein said converting comprises: reacting the 4-(α,α-dιsubstιtuted)-toluic acid derivative with a 3- (4-substιtuted-piperidin-l -yl)propane derivative having the formula: OH ( C H 2 ) 3 χ i wherein X' is a halogen, trialkyl or triaryl tin, trialkyl or triaryl boratc, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce an N-substitutcd hydroxypiperidine having the formula: 0H CH. and con\ertιng the N-substituted hvdi oxy piperidine with a diaiylhalomcthane having the Iormula ( ) ' CH wherein X 4 is a halogen undei conditions effective to form the piperidine derivative compound of the Iormula f, ~ A CH O O CH. /A CH 2 ) 3 C- C COOH CH, 55 A regioisomei having the formula A CH 3 CH 3 wherein Zis— CG'G^ , Y \ \ / ) N (CR 6 R 7 O or m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 , X 3 is halogen, OR 15 , SR 15 , NR^R 1 , OS0 2 R'-\ or NHSϋ 2 R 15 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiet}-, an aryl moiety, OR 8 , SR 8 . and NR R 9 ; R 5 , R 8 , R 9 , R 15 . and R 16 arc the same or different and are selected from the group consisting of hydrogen, an alkyl moiet}-, and an aryl moiety; and A is the substituents of its ring, each of which may be different or the same and arc selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy. and other substituents. 56. A regioisomer according to claim 55. wherein Z is -R 7 R 1 2 O \ R 6 and R 7 are each methyl, and R 12 and R 1 are each hydrogen. 57. A process of preparing a regioisomer of the formula- A CH, x 3 o CH. wherein Zis— CG'G 2 G 3 , -Q ;CR 6 R 7 ), O or N — \ <CR 6 ' ) m m is an integer from 1 to 6; and Y arc the same or different and are selected from the group consisting of O, S, and NR 5 ; G ' , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ; X 3 is halogen, OR 15 , SR 15 , NR 1 R'<\ OS0 2 R 15 , or NHS0 2 R 15 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; R 5 , R 8 , R 9 . R 15 , and R 16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and A is the substituents of its ring, each of which may be different or the same and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents, said process comprising: acylating an α,α-disubstituted-methylbenzene derivative having the formula- CH 3 wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound having the formulae: , 2 X 3 ' o or wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to produce the regioisomer. 58. A process according to claim 57 further comprising: reacting an α,α-diunsubstituted-methylbenzene derivative having the formula: x 1 — XJ/- CH 2 — z with a methylating agent under conditions effective to produce the α-α-disubstituted- methylbenzene derivative. 59. A process according to claim 58, wherein Z has the formula: -A (C -R 6 R 7 ) m Q ' and further comprising: reacting an α,α-disunsubstιtuted benzylic acid derivative having the formula: A with an aminoalkyl derivative having the formula: H 2 N - (CR 6 R 7 ) m Q H under conditions effective to produce the α,α-diunsubstituted-methylbenzenc derivative. 60. A process according to claim 57, wherein Z has the formula: (CR 6 R 7 ), Q said process further comprising: reacting an α,α-disubstituted benzylic acid derivative having the formula: CH, with an aminoalkyl derivative having the formula: under conditions effective to produce the α.α-disubstituted-methylbcnzenc derivative. A process of preparing a regioisomer of the formula: O CH. wherein Z is — CG' G 2 G 3 , AA ( CR 6 R 7 ) r or m is an integer from 1 to 6; Q and Y are the same or different and arc selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ; X 3 is halogen, OR 15 , SR 15 , NR 15 R'7 OS0 2 R 1 5 . or NHS0 2 R 1 5 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; R 5 , R 8 , R 9 , R 15 , and R 16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and A is the substituents of its ring, each of which may be different or the same and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy. alkoxy, and other substituents, said process comprising: providing an α,α-diunsubstituted regioisomer precursor having the formula: / ' i \ X 3 3 ' ' - - o and mcthylating the α.α-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer. 62. A process according to claim 61 , wherein said providing the α,α- diunsubstituted regioisomer precursor comprises: acylating an α,α-diunsubstituted-methylbcnzene derivative having the formula: wherein X' is hydrogen; a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound having the formula: x 3 or wherein X 2 is a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 . or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under conditions effective to produce the α.α-diunsubstituted regioisomer precursor. 63. A process according to claim 61 , wherein said providing the α,α- diunsubstituted regioisomer precursor comprises: acylating a 4-(α,α-diunsubstitutcd)-toluic acid derivative having the formula: wherein X 2 is a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety with a compound having the formula: X 3 A 1 wherein X 1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the α,α-diunsubstituted regioisomer precursor. 64. A process of preparing a regioisomer of the formula: o CH , wherein Z is — CG'G 2 G 3 , w Q ( CR 6 R 7 ) r o or m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ; X 3 is halogen, OR 1 5 , SR 1 5 , NR 15 R 16 , OS0 2 R 1 5 , or NHS0 2 R 15 ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiet}-, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; R 5 , R 8 , R 9 , R 15 , and R 16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and A is the substituents of its ring, each of which may be different or the same and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents, said process comprising: reacting a 4-(α,α-disubstituted)-toluic acid derivative having the formula: CH 3 wherein X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine; and R l ϋ is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety with a compound having the formula: χ 3 ~ ^ A ~ \ χ ι wherein X 1 is a halogen, trialkyl or triaryl tin. trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the regioisomer. 65. A process according to claim 64 further comprising: reacting a 4-(α,α-diunsubstituted)-toluic acid derivative having the formula: with a methylating agent under conditions effective to produce the 4-(α-α-disubstituted)- toluic acid derivative. 66. A process according to claim 65, wherein Z has the formula: — / 6 7 ( CR 6 R 7 , X Q -^ and further comprising: reacting a 4-α-carboxy-α,α-disunsubstituted)-toluic acid derivative having the formula: with an aminoalkyl derivative having the formula: H 2 N ;CR 6 R 7 ) under conditions effective to produce the 4-(α,α-diunsubstituted)-toluic acid derivative. 67. A process according to claim 64, wherein Z has the formula: / N - (CR 6 R 7 Q -^ said process further comprising: reacting an 4-α-carboxy-α,α-disubstitutcd)-toluic acid derivative having the formula: CH. with an aminoalkyl derivative having the formula: H 2 N (CR 6 R 7 ) m Q H under conditions effective to produce the 4-(α,α-disubstituted)-tolυic acid derivative. 68. A 4-(α,α-disubstituted)-toluic acid derivative having the formula: CH 3 wherein Z is — CG'G G 3 , Y \ X — Q - N ( CR 6 R 7 ) r or \ ( C 6 R ? ) m Q m is an integer from 1 to 6; 0 and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ; X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 . or an amine; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR 8 , SR 8 , and NR 8 R 9 ; R 5 , R 8 , R 9 , and R 10 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and A is the substituents of its ring, each of which may be different or the same and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents. 69. A 4-(α,α-disubstituted)-toluic acid derivative according to claim 68, wherein Z is 2 R and R 7 are each methyl, R 12 and R 13 are each hydrogen, and X 2 is N(CH 3 )(OCH . 70. A 4-(α.α-diunsubstituted)-toluic acid derivative having the formula: A whcrein Z is — CG'G - Q N ( CR 6 R 7 or „ ,7 - m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR 5 ; G 1 , G 2 , and G 3 are the same or different and are selected from the group consisting of OR 8 , SR 8 , and NR 8 R 9 ; X 2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula -OR 10 ; a moiety having the formula -SR 10 , or an amine ; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety. OR 8 , SR 8 , and NR 8 R 9 ; R 5 , R 8 , R 9 , and R 10 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and A is the substituents of its ring, each of which may be different oi the same and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents. 71. A 4-(α,α-diunsubstituted)-toluic acid derivative according to claim 70, wherein Z is R 6 and R 7 are each methyl, R 12 and R 13 are each hydrogen, and X 2 is N(CH 3 )(OCH 3 ).

Inventors: D AMBRA THOMAS E, PILLING GARRY M, D'AMBRA, THOMAS, E., PILLING, GARRY, M.
Applicants: ALBANY MOLECULAR RES INC, ALBANY MOLECULAR RESEARCH, INC.
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P37, C07D211, C07D261, C07D263