4-DIPHENYLMETHYL PIPERIDINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION

Abstract: The present invention is related to a novel process for preparing certain piperidine derivatives of formulae (I) and (II) wherein R1 represents hydrogen or hydroxy, R2 represents hydrogen; or R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2; n is an integer of from 1 to 5; R3 is -CH2OH, -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof.

Description: DIPHENYLMETHYL PIPERIDINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION BACKGROUND OF THE INVENTION This is a continuation-in-part of application Serial 08/9370, filed January 26, 1993 which is a continuation of application Serial No. 07/867,261, filed April 10, 1992, abandoned. The present invention is related to a novel process f preparing certain piperidine derivatives which are useful as antihistamines, antiallergy agents and bronchodilators [United States Patent No. 4,254,129, March 3, 1981, Unite States Patent No. 4,254,130, March 3, 1981 and United States Patent No. 4,285,958, April 25, 1981]. These piperidine derivatives can be described by the following formulas: wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -CH 2 OH, -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof. The novel process for preparing the piperidine derivatives of formula (I) and formula (II) of the present invention offers high yields and ease of purification. SUMMARY OF THE INVENTION The present invention provides a novel process for preparing the piperidine derivatives of formula (I) and formula (II) wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -CH 2 OH, -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optica isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cβ alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; and (c) reacting the ω-h iatlo hydroxyethylphenylketone with a piperidine compound of the formula wherein Ri and R 2 are as defined above in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH; (d) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH; (e) optionally reacting the piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH to produce a piperidine carboxyphenylketone ester derivative of formula (II) wherein R 3 is -COOalkyl. (f) optionally reacting the piperidine carboxyphenylketone derivative of formula (II) wherein R 3 i -COOH or the piperidine carboxyphenylketone ester derivativ of formula (II) wherein R 3 is -COOalkyl with a suitable reducing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH or the piperidine carboxyphenylalcohol ester of formula (I) wherei R 3 is -COOalkyl; (g) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 i -COOH to produce a piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R 3 is -COOalkyl; and (h) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH, the piperidine carboxyphenylketone ester derivative of formula (II) wherei R 3 is -COOalkyl, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH or the piperidine carboxyphenylalcohol ester of formula (I) wherei R 3 is -COOalkyl with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-g are optionally protected or unprotected. Alternatively, the present invention provides a novel process for preparing the piperidine derivatives of formula (I) comprising the steps of: (a) reacting the ω-halo hydroxyethylphenylketone with a suitable reducing agent to produce a ω-halo hydroxyeth Iphenylalcohol; (b) reacting the ω-halo hydroxyethylphenylalcohol with a piperidine compound of the formula wherein Ri and R 2 are as defined above, in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH; (c) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH; and (d) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH to produce the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R 3 is -COOalkyl. (e) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH or the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R 3 is -COOalkyl with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-d are optionally protected or unprotected. In addition, the present invention provides a novel process for preparing the piperidine derivatives of formula (I) comprising the steps of: (a) reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH with a suitable reducing agent to produce a piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH; (b) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH; and (c) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH to produce the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R 3 is -COOalkyl. (d) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH, the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH or the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R 3 is -COOalkyl with an appropriate deprotecting reagent,with the proviso that each of the hydroxy groups present in the compounds described in steps a-c are optionally protected or unprotected. r As used herein, straight or branched alkyl groups having from 1 to 6 carbon atoms as referred to herein are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-bexyl. The piperidine derivatives of the formula (I) and formula (II) can form pharmaceutically acceptable salts. Pharmaceutically acceptable acid addition salts of the compounds of this invention are those of any suitable inorganic or organic acid. 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, and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4- hydroxybenzoic, aπthranillic, cinnamic, salicyclic, 4- aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids, such as, methanesulfonic, ethanesulfonic and β-hydroxyethanesulfonic acid. Non-toxic salts of the compounds of the above-identified formula formed with inorganic or organic bases are also included within the scope of this invention and include, for example, those of 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. The salts are prepared by conventional means as, for example, by treating a piperidine derivative of formula (I) or formula (II) with an appropriate acid or base. The novel process for preparing the piperidine derivatives of formula (I) and formula (II) is outlined in Scheme A. In Scheme A, all substituents are as previously defined unless otherwise indicated. Scheme A ACYLATION Scheme A Cont, A' = hydrogen, protected hydroxy or hydroxy B = Halo or OH D = hydrogen or a suitable protecting group Ri' and R 2 ' - hydrogen, protected hydroxy, hydroxy or taken togther to form a second bond between the carbon atoms bearing Ri' and R = Ci-Cβ alkyl or hydrogen Scheme A provides a general synthetic procedure for preparing the piperidine derivatives of formula (I) and formula (II) . In step a, the carboxy functionality of an appropriate benzeneacetic acid compound of structure (1), wherein R is hydrogen or Ci-Cg alkyl, is reduced to give the corresponding phenethyl alcohol of structure (2), wherein D is hydrogen. For example, reduction' of the appropriate benzeneacetic acid of structure (1),. wherein R is hydrogen, using, for example, sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, diborane or aluminum hydride with diborane being preferred. Reduction of the appropriate benzeneactic acid of structure (1), wherein R is Ci-Cg alkyl r using, for example, lithium aluminum hydride, lithium borohydride, sodium bis(2-methoxyethoxy)aluminum hydride, aluminum hydride, lithium triethylborohydride and lithium tri-sec-butylborohydride with lithium aluminum hydride being preferred. Suitable solvents are ethers, for example, diethyl ether, tetrahydrofuran or dioxane. These reduction reactions are carried out at temperatures ranging from about 0 β C to the reflux temperature of the solvent, and the reaction time varies from about 1/2 hour to 8 hours. The starting benzeneacetic acid compounds of structure (1) are known in the art of are prepared by procedures well known in the art. For example, the benzeneacetic acid compound of structure (1) wherein R is Ci-Cβ alkyl and A 1 is hydroxy may be prepared by treating a hot solution of 1 equivalent of an appropriate straight or branched alkyl Cι~ 6 ester of 3-trifluoroacetoxyphenylacetic acid in dimethoxyethane with a base, such as, sodium hydride under a nitrogen atmosphere followed by the addition of 2.1 equivalents of methyliodide in dimethoxyethane to the mixture over about a 20 minute period. The mixture is refluxed for about 3 hours then concentrated to remove most of the solvent after which diethyl ether, then water are added cautiously. The organic layer is separated, extracted with ether, dried over magnesium sulfate and distilled to give the appropriate ester of the benzeneacetic acid compound of structure (1) wherein A' is a trifluoroacetoxy protected hydroxy and R is Ci-Cβ alkyl. To a solution of the methylated ester in 50% alcohol/water is added 3X molar amount of potassium carbonate. The solution is stirred at about 25°C for about 8 hours then concentrated to a semisolid at reduced pressure at about 50°C and upon cooling water is added and the mixture is neutralized with dilute hydrochloric acid then extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated to give the appropriate ester of the benzeneacetic acid compound of structure (1) wherein A' is hydroxy and R is Ci-Cβ alkyl. The esters of the benzeneacetic acid compounds of structure (1) wherein A' is a trifluoroacetoxy protected hydroxy and R is Cχ-C 6 alkyl are known in the art, for example, from ethyl m- hydroxyphenylacetate by treatment with trifluoroacetic anhydride. Alternatively, the phenethyl alcohol compounds of structure (2) may be prepared by Friedel-Crafts acylation of an appropriate benzene compound with a suitable protected 2-methyl-2-propenyl alcohol compound. For example, the phenethyl alcohol compound of structure (2) wherein A' is hydrogen, hydroxy or a suitably protected hydroxy may be prepared by reacting an appropriate 2- methyl-2-propenyl alcohol compound with an appropriate benzene compound in the presence of AICI 3 . In step b, the appropriate phenethyl alcohol of structure (2), wherein A' is hydrogen, hydroxy or a suitably protected hydroxy, is acylated with the ω-halo compound of structure (3) wherein B is halo under Freidel- Crafts conditions to give the corresponding ω-halo hydroxyethylphenylketone of structure (4) wherein A 1 is described as above. For example, the ω-halo hydroxyethylphenylketone of structure (4), wherein A' is hydrogen, hydroxy or a protected hydroxy, may-be prepared by reacting an appropriate phenyethyl alcohol of structure (2), wherein A' is hydrogen, hydroxy or a protected hydroxy, with a appropriate ω-halo compound of structure (3) wherein B is halo, which are known in the art or are prepared by procedures well known in the art, under the general conditions of a Friedel-Crafts acylation using a suitable Lewis acid. The reaction is carried out in a solvent, such as carbon disulfide, ethylene chloride, tetrachloroethane or nitrobenzene with methylene chloride being the preferred solvent. The reaction time varies from about 1/2 hour to 8 hours, preferably 1 to 5 hours and the reaction temperature varies from about 0°C to 25°C. The ω-halo hydroxyethylphenylketone of structure (4) wherein A' is hydrogen, hydroxy or a protected hydroxy is recovered from the reaction zone by an aqueous quench followed by extraction as is known in the art. The ω-halo hydroxyethylphenylketone of structure (4) wherein A' is hydrogen, hydroxy or a protected hydroxy may be purified by procedures well known in the art, such as crystallization. Alternatively, the appropriate phenethyl alcohol of structure (2) wherein A 1 is hydroxy may be acylated with the ω-halo compound of structure (3) wherein B is hydroxy in the presence of a Lewis acid to give the corresponding halo hydroxyethylphenylketone of structure (4) as described in Arch. Pharm. 306, 807 1973. In general, an appropriate phenethyl alcohol of structure (2), wherein A' is hydroxy, and the ω-halo compound of structure (3), wherein B is hydroxy, are melted together at about 50°C, then cooled to about 10°C after which a Lewis acid is added in an amount about 2.2 times the molar amount of the appropriate phenethyl alcohol of structure (2), wherein A' is hydroxy, employed. The mixture is heated at about 70°C for about 2 hours after which a 30% sodium acetate solution is added and extracted with ether. The organic layer is dried and the solvent evaporated to give the ω-halo hydroxyethylphenylketone of structure (4) wherein A' is hydroxy. The ω-halo hydroxyethylphenylketone of structure (4) may be purified by procedures well known in the art, such as crystallization. Suitable Lewis acids for the acylation reaction described in step b are well known and appreciated in the art. Examples of suitable Lewis acids are boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride and zinc chloride. The selection and utilization of suitable Lewis acids for the acylation reaction of step b is well known and appreciated by one of ordinary skill in the art. The starting ω-halo compounds of (3) are commercially available of easily prepared by generally known methods. While not necessary for utilization in the acylation reaction of step b, the hydroxyethyl functionality of those phenethyl alcohols of structure (2) may be protected with a suitable .protecting group. The selection and utilization of suitable protecting groups for the phenethyl alcohols of structure (2) is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Syntheses", Theodora W. Greene, Wiley (1981). For example, suitable protecting groups for the hydroxyethyl functionality include ethers such as tetrahydrothiopyranyl, tetrahydrothiofuranyl, 2-(phenylselenyl)ethyl ether, o- nitrobenzyl ether, trimethylsilyl ether, isopropyldimethylsilyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilyl ether; and esters, such as acetate ester, isobutyrate ester, pivaloste ester, adamantoate ester, benzoate ester, 2,4,6-τtrimethylbenzoate (mesitoate) ester, methyl carbonate, p-nitrophenyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate and N-phenylcarbamate, with acetoxy being preferred. For those ω-halo hydroxyethylphenylketone of structure (4), wherein A 1 is hydrogen, hydroxy or a protected hydroxy and D is hydrogen, the Friedel-Crafts acylation may result in acylation of the hydroxyethyl functionality and will require deprotection prior to the oxidation reaction described in optional step d. Suitable deprotecting agents and methods are described in optional step d, infra. While also not necessary for utilization in the acylation reaction of step b, the phenol functionality of those phenethyl alcohols of structure (2), wherein A' is hydroxy may be protected with a suitable protecting group. For example, suitable protecting groups for the phenolic hydroxy include methyl ether, 2-methoxyethoxymethyl ether (MEM), cyclohexyl ether, o-nitrobenzyl ether, 9-anthryl ether, t-butyldimethylsilyl ether, acetate, benzoate, methyl carbamate, benzyl carbamate, aryl pivaloate and aryl methanesulfonate. In step c, the ω-halo functionality of the appropriate ω-halo hydroxyethylphenylketone of structure (4) is alkylated with the appropriate piperidine compound of structure (5) to give the corresponding piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH. For example, the alkylation reaction is carried out in a suitable solvent preferably in the present of a base and optionally in the presence of a catalytic amount of an iodide source, such as potassium or sodium iodide, for about 4 to 120 hours and at temperatures of about 70°C to the reflux temperature of the solvent. Suitable solvent for the alkylation reaction include alcohol solvents such as, methanol, ethanol, isopropyl alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl 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 an appropriate piperidine compound of structure (5) may be used. For those piperidine compounds of structure (5), wherein Ri is hydroxy, it is preferred that Ri be unprotected for utilization in the alkyation reaction of step c but those hydroxy functionalities present in the piperidine compounds of structure (5), wherein Ri is hydrox may be protected with a suitable protecting group. The selection and utilization of suitable protecting groups for the piperidine compounds of structure (5), wherein Ri is hydroxy is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Syntheses", Theodora W. Greene, Wiley (1981). For example, suitable protecting groups for those hydroxy functionalities present include ethers such as tetrahydrothiopyranyl, tetrahydrothiofuranyl, 2- (phenylselenyl)ethyl ether, o-nitrobenzyl ether, trimethylsilyl ether, isopropyldimethylsilyl ether, t- butyldimethylsilyl ether, t-butyldiphenylsilyl ether, tribenzylsilyl ether, triisopropylsilyl ether; and esters, such as acetate ester, isobutyrate ester, pivaloate ester, adamantoate ester, benzoat-e ester, 2,4,6-trimethylbenzoate (mesitoate) ester, methyl carbonate, p-nitrophenyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate and N-phenylcarbamate. The piperidine compounds of structure (5) wherein Ri and R 2 are hydrogen and where Ri is hydroxy " and R 2 is hydrogen are readily available to one or ordinary skill in the art. The piperidine compounds of structure (5) wherein i and R 2 form a second bond between the carbon atoms bearing Ri and R 2 may be prepared by dehydration of the corresponding compound wherein Ri is hydroxy by procedures generally known in the art. In optional step d, the hydroxyethyl functionality of the appropriate piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH is oxidized to give the corresponding piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is COOH. For example, oxidation of the appropriate piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH may be achieved using a variety of oxidizing agents and methods. One such method involves a two-step procedure in which the hydroxyethyl functionality of the appropriate piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH is first oxidized to the corresponding aldehyde functionality using, for example, Swern Oxidation conditions (dimethyl sulfoxide, oxyalyl chloride and triethylamine) , as is known in the art. The Swern Oxidation is carried out in suitable aprotic organic solvents such as methylene chloride at temperatures ranging from about -78°C to room temperature, and the reaction time varies from about 1/2 hour* to 8 hours. Other suitable reagents for the oxidation of the hydroxyethyl functionality of the appropriate piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH to the corresponding aldehyde functionality are Dess-Martin reagent, chromium (IV) oxide, nickel peroxide, sodium dichromate, potassium dichromate, t-butyl chromate, silver oxide, argentic picolinate manganese dioxide lead tetraacetate, dicyclohexylcarbodiimide, 2,3-dichloro-5,6- dicyanoquinone, tetrachloro-l,2-benzoquinone, 2,2,6,6- tetramethylpiperidinyl-1-oxy (TEMPO) or quinolinium chlorochromate. The intermediate aldehyde compound is then oxidized further to give the corresponding piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH using, for example, potassium permanganate. The potassium permanganate oxidation is carried out in a suitable acidic medium such as hydrochloric acid/acetone at a temperature ranging from about 0°C to room temperature and the reaction time varies from about 1/2 hour to 8 hours. Other suitable reagents for the oxidation of the intermediate aldehyde to the corresponding piperidine carboxyphenylketone derivative of formula (II) wherein R 3 i -COOH are chromium (IV) oxide, silver (I) oxide, silver oxide, argentic picolinate, peroxide, nitric acid, m- chloroperbenzoic acid and peracetic acid. Another method involves a one-step procedure in which the hydroxyethyl functionality of the appropriate piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH is oxidized directly to the carboxy functionality to give the corresponding piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH. Oxidizing reagents suitable for direct, one-step oxidation of the hydroxyethyl functionality to the carboxy functionality include,, for example, chromaium (IV) oxide, potassium permanganate, nitric acid, nitrogen dioxide, ruthenium (VIII) oxide, nickel peroxide, silver oxide, t- butyl chromate and xenic acid. Oxidation using Swern Oxidation conditions, nickel- peroxide, chromium (IV) oxide, silver oxide, sodium dichromate, potassium dichromate, manganese dioxide, 2,3- dichloro-5,6-dicyanoquinone and tetrachloro-1,2- benzoquinone is preferred for those piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH wherein R and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 . As one skilled in the art would appreciate, those piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH wherein the hydroxyethyl functionality is protected must be reacted with an appropriate deprotecting reagent prior to the oxidation reaction described in step d. The selection and utilization of appropriate deprotecting reagents is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Syntheses", Theodora W. Greene, Wiley (1981). Examples of appropriate deprotecting reagents are mineral acids, strong organic acids, Lewis acids, aqueous mineral bases, catalytic hydrogenation and the like. For example, cleavage of an acetate ester protecting group on the hydroxyethyl functionality of the piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH can be achieved by using a base, such as sodium methoxide in methanol as is known in the art. Other methods known in the art for acetate ester cleavage include potassium carbonate in methanol, methanolic ammonia, sodium hydroxide/pyridine in methanol and potassium cyanide in ethanol. In optional step e, the ketone functionality of the appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OD or -COOH is reduced to give the corresponding piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OD or -COOH. For example, reduction of the appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OD or -COOH, using, for example, sodium borohydride, potassium borohydride, sodium cyanoborohydride, or tetramethylammonium borohydride is carried out in lower alcohol solvents, such as, methanol, ethanol, isopropyl alcohol or n-butanol at temperatures ranging from about 0°C to the reflux temperature of the solvent, and the reaction time varies from about 1/2 hour to 8 hours. Other suitable reducing agents are, for example, lithium tri-tert- butylaluminohydride and diisobutylaluminum hydride. These reduction reactions are carried out in suitable solvents diethyl ether, tetrahydrofuran or dioxane at temperatures ranging from about 0°C to the reflux temperature of the solvent, and the reaction time varies from about 1/2 hour to 8 hours. Catalytic reduction may also be employed in the preparation of appropriate piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OD or -COOH from an appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OD or -COOH, 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 or potassium borohydride is preferred over catalytic reduction for those piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OD or -COOH wherein Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 . In addition, a chiral reduction of the appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -CH 2 0D or -COOH, using, for example, (+)-B- chlorodiisopinocamphenylborane gives the corresponding (R)- piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 0D or -COOH and (-)-B- chlorodiisopinocamphenylborane gives the corresponding (S)- piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OD or -COOH. 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]nonane, NB-Enantride, Lithium (R)-(+) and (S)-(-)-2,2 l -dihydroxy-l,l'-binaphthyl alkoxyl aluminum hydride, (R)-(+) and (S)-(-)-2,2*- dihydroxy-6,6'-dimethylbiphenyl borane-amine complex, trist[(lS,2S,5R)-2-isopropyl-5-methyl-cyclohex-l- yl]methyl]aluminum, [ [ (lR,3R)-2,2- dimethylbicyclo[2.2.1]hept-3-yl]methyl]beryllium chloride, (R)-BINAP-ruthenium complex/H 2 and 6,6'- bis(diphenylphosphino)-3,3'-dimethoxy-2,2' ,4,4'- tetramethyl-l,l'-biphenyl. As one skilled in the art would appreciate, the carboxy functionalities of the piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -COOH and piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is -COOH may be" esterified by techniques and procedures well known and appreciated by one of ordinary skill in the art to give the corresponding piperidine carboxyphenylketone ester derivatives of formula (II) wherein R 3 is -COOalkyl and piperidine carboxyphenylalcohol ester derivatives of formula (I) wherein R 3 is -COOalkyl. For example, one such method involves reacting an appropriate piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH with an excess of an appropriate HOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched in the presence of a small amount of mineral acid, e.g. sulfuric acid at reflux. Another suitable method involves reacting an appropriate piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH or piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 i -COOH with an excess of diazomethane in a suitable solvent such as ether at room temperature to give the methyl ester. In addition, the piperidine carboxyphenylketone ester derivatives of formula (II) wherein R 3 is -COOalkyl or piperidine carboxyphenylalcohol ester derivatives of formula (I) wherein R 3 is -COOalkyl may also be prepared by reacting an appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -COOH or piperidine carboxyphenylalcohol derivatives of .formula (I) wherein R 3 is -COOH with an excess of 2,2-dimethoxypropane in a suitable solvent such as methanol at 0°C to room temperature to give the methyl ester. Another suitable method involves first reacting an appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -COOH with thionyl chloride in a suitable solvent such as methylene chloride to give an intermediate acid chloride, followed by addition of a suitable alcohol of the formula HOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched. As one skilled in the art would appreciate, the reduction of the ketone functionality of the appropriate piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -COOH described in optional step e can be conducted on the ω-halo hydroxyethylphenylketone of structure (4) or piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH. For example, reduction of an appropriate ω-halo hydroxyethylphenylketone of structure (4) using the techniques and methods described previously in step e gives the corresponding ω-halo hydroxyethylphenylalcohol. The resulting benzylic alcohol-functionality may be optionally protected using the protecting groups described previously for hydroxyethyl in step b. The ω-halo hydroxyethylphenyl¬ alcohol so formed is then subjected to the alkylation reaction with an appropriate piperidine compound of structure (5) described previously in step c to give the corresponding piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is protected or unprotected -CH 2 OH. The appropriate piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH is then subjected to the oxidation reaction described previously in step d using a selective oxidizing agent such as 2,2,6,6-tetramethylpiperidinyl-l-oxy (TEMPO) or quinolinium chlorochromate to give the intermediate aldehyde followed by oxidation with silver oxide to give the corresponding piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH. Reduction o an appropriate piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is protected or unprotected -CH 2 OH using the techniques and methods described previously in step e gives the corresponding piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R 3 is -CH 2 OH which is then subjected to the oxidation reaction described previously in step d using a selective oxidizing agent such as 2,2,6,6- tetramethylpiperidinyl-1-oxy (TEMPO) or quinolinium chlorochromate to give the intermediate aldehyde followed by oxidation with silver oxide to give the corresponding piperidine carboxyphenylalcohol derivative of formula (I) wherein R 3 is -COOH. As one skilled in the art would appreciate, the benzeneacetic acid compounds of structure (1), the phenethyl alcohols of structure (2), the ω-halo hydroxyethylphenylketones of structure (4), piperidine compounds of structure (5), piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -COOH, the piperidine carboxyphenylketone ester derivatives of formula (II) wherein R 3 is -COOalkyl, the piperidine hydroxyethylphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is COOH or the piperidine carboxyphenylalcohol ester derivatives of formula (I) wherein R 3 is -COOalkyl which bear hydroxy or phenolic functionalities may be protected prior to use in the synthesis depicted in Scheme A using suitable protecting groups as described previously in step b. As one skilled in the art would appreciate, the benzeneactic acids of structure (1), the phenethyl alcohols of structure (2), the ω-halo hydroxyethylphenylketones of structure (4), piperidine compounds of structure (5), piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylketone derivatives of formula (II) wherein R 3 is -COOH or the piperidine carboxyphenylketone ester derivatives of formula (II) wherein R 3 is -COOalkyl, the piperidine hydroxyethylphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OH, the piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is COOH or the piperidine carboxyphenylalcohol ester derivatives of formula (I) wherein R 3 is COOalkyl which bear protected hydroxy or phenolic functionalities may be reacting with prior appropriate deprotecting reagents prior to use in the synthesis depicted in Scheme A. The selection and utilization of appropriate deprotecting reagents is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Syntheses", Theodora W. Greene, Wiley (1981). Examples of appropriate deprotecting reagents are mineral acids, . strong organic acids, Lewis acids, aqueous mineral bases, catalytic hydrogenation and the like. For example, cleavage of an acetate ester protecting group on the hydroxyethyl functionality of any of the ω- halo hydroxyethylphenylketones of structure (4), piperidine compounds of structure (5), piperidine hydroxyethylphenylketone derivatives of formula (II) wherein R 3 is -CH 2 OH or piperidine hydroxyethylphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OH can be achieved by using a base, such as sodium methoxide in methanol as is known in the art. Other methods known in the art for acetate ester cleavage include potassium carbonate in methanol, methanolic ammonia, sodium hydroxide/pyridine in methanol and potassium cyanide in ethanol. Cleavage of β-methoxyethoxymethyl (MEM) protecting groups on any of those ω-halo hydroxyethylphenylketones of structure (4), piperidine compounds of structure (5), piperidine hydroxyethylphenylketone derivative of formula (II) wherein R 3 is -CH 2 OH, piperidine carboxyphenylketone derivative of formula (II) wherein R 3 is -COOH, piperidine carboxyphenylketone ester derivatives of formula (II) wherein R 3 is -COOalkyl, piperidine carboxyphenylalcohol derivatives of formula (I) wherein R 3 is -COOH, piperidine carboxyphenylalcohol ester derivatives of formula (I) wherein R 3 is -COOalkyl or piperidine hydroxyethylphenylalcohol derivatives of formula (I) wherein R 3 is -CH 2 OH wherein A is hydroxy, for example, can be achieved by using trifluoroacetic acid at room temperature or using 5 to 8 equivalents of powdered anhydrous zinc bromide in methylene chloride at about 25°C by the general procedure of E. J. Corey et al., Tetrahedron Letters, 11, 809-812 1976. The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "μL" refers to microliters; "μg" refers to micrograms; and "μM" refers to micromolar. Example 1 4-[4-[4-(Hydroxydiphenylmethyl)-l-piperidinyl]-l- hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride METHOD A Step a: 2,2-Dimethyl-phenethyl acetate Dissolve α,α-dimethylphenyl acetic acid (140.Og, 0.853mol) in anhydrous tetrahydrofuran (lOOmL) and place under a nitrogen atmosphere. Add, by dropwise addition, a solution of lithium aluminum hydride (639mL of a l.OM solution in tetrahydrofuran, 24.3g, 0 f ;639mol) over a period of approximately 2 hours. Quench with deionized water (24mL), with 15% aqueous sodium hydroxide (24mL) and again with deionized water (72mL). Stir the milky white mixture for 20 minutes, filter through filter aid, dry (MgSO and filter through filter aid once more. Evaporate the solvent in υacuo to give 2,2-dimethylphenethyl alcohol as a clear yellow oil. Dissolve 2,2-dimethylphenethyl alcohol (llβ.Og, 0.786mol) in pyridine (700mL). Add, by dropwise addition, acetic anhydride (222mL, 240.7g, 2.358mol) and stir overnight at room temperature. Evaporate the solvent in υacuo and purify by distillation to give the title compound as a clear colorless oil; bp 75°C @ 0.4mmHg. METHOD B Dissolve 2-methyl-2-propenyl acetate (1.28mmol) in benzene (80mL) and add to a stirred solution of AICI 3 (172.3g, 1.29mol) in benzene (800mL) at -10°C over 45 minutes under a stream of nitrogen. Stir at 5°C for 20 minutes, pour onto ice (800g) and stir for 10 minutes. Separate the organic phase, dry (MgSθ 4 ) and evaporate the solvent in υacu (30 β C/60 torr). Purify by distillation to give the title compound. Step b: 4-(4-Chloro-l-oxobutyl)-2,2-dimethylphenethyl acetate Charge a flask with aluminum chloride (223g, 1.68mol) and methylene chloride (200mL). Place under a nitrogen atmosphere, cool to 0°-5°C and add, by dropwise addition, ω-chlorobutyryl chloride (188.6g, 1.34mol). After acid chloride addition is complete, add, by dropwise addition, 2,2-dimethylphenethyl acetate (128.Og, 0.67mol), keeping the temperature at approximately 0°C. Continue stirring at 0°C for 2 hours, quench by/ slowly pouring over approximately 2L of crushed ice. Add methylene chloride (500mL) and stir for 5 minutes. Separate the organic phase and extract the aqueous phase with methylene chloride (300mL). Combine the organic phases and wash with saturated aqueous sodium hydrogen carbonate (3X200mL), with deionized water (200mL) and brine (200mL). Dry (MgSO*) and stir for 30 minutes before filtering. Evaporate the solvent in υacuo and purify by chromatography (ethyl acetate/hexane) to give the title compound as an orange/brown oil. IR (neat) 3239, 2970, 1741, 1684, 1607, 1408, 1375, 1233, 1040, 998, 844, 823 cπrl; !H NMR (CDC1 3 ) δ 7.93 (d, 2H, J = 9.0Hz), 7.46 (d, 2H, J = 9.0 Hz), 4.14 (s, 2H), 3.68 (t, 2H, J = 7.5 Hz), 3.16 (t, 2H, J = 7.5 Hz), 2.2 (m r 2H), 2.00 (s, 3H), 1.38 (s, 6H); 1 C NMR (CDCI 3 ) δ 198.5, 170.9, 151.9, 134.8, 127.9, 126.2, 72.4, 44.6, 38.6, 35.2, 26.7, 25.7, 20.8; MS (Cl, CH 4 ) m/z (rel. intensity) 297 (MH+, 56), 261 (59), 237 (100), 219 (52). Step c: 4-[4-[4-(Hydroxydiphenylmethyl)-l-piperidinyl]-l- oxobutyl] -2,2-dimethylphenethyl alcohol Mix 4-(4-chloro-l-oxobutyl)-2,2-dimethylphenethyl acetate (99.5g, 0.335mol), α,α-diphenyl-4-piperidinemethanol (101.8g, 0.335mol), potassium hydrogen carbonate (83.8g, 0.838mol), potassium iodide (l.OOg, 0.006mol), toluene (600mL) and water (220mL). Stir at reflux for 72 hours, add toluene (200mL) and deionized water (lOOmL). Filter through filter aid while at 80°C and separate the organic phase. Dry (MgSθ 4 ), filter and purify by chromatography (ethyl acetate) to give 4-[4-[4-(hydroxydiphenylmethyl)-l- piperidinyl]-l-oxobutyl]-2,2-dimethylphenethyl acetate as an oily solid. IR (KBr) 3690, 3608, 3012, 2950, 2810, 1734, 1681, 1607, 1470, 1448, 1376, 1253, 1040, 997, 704, 667 cm-l; 1H NMR (CDC1 3 ) δ 7.90 (d, 2H, J = 8.2 Hz), 7.4 (m, 5H) , 7.3 (m, 5H), 7.2 (m, 2H) , 4.14 (s, 2H) , 3.0 (m, 4H) , 2.4 (m, 3H), 2.0 (m, 3H), 1.95 (s, 3H) , 1.4 (m, 4H), 1.38 (s, 6H) ; 13C NMR (CDCI 3 ) δ 199.4, 170.9, 151.7, 145.8, 135.1, 128.1, 128.0, 126.5, 126.2, 125.7, 79.3, 72.5, 57.6, 53.7, 43.8, 38.6, 36.1, 25.7, 21.2, 20.8; MS (Cl, CH 4 ) m/z (rel. intensity) 528 (MH+, 100), 510 (63), 450 (12), 293 (14). Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1- oxobutyl]-2,2-dimethylphenethyl acetate (69.0g, 0.131mol) in methanol (2.5L) and add 10% aqueous sodium hydroxide (769mL, 1.92mol). Stir at reflux for 1.5 hours, cool to 68°C and evaporate the solvent in υacuo to a residue (700mL). Add chloroform (IL) and stir until solids are dissolved. Separate the organic phase and extract the aqueous phase with chloroform (3X300mL). Combine the organic phases, dry (MgSθ 4 ) and evaporate the solvent in υacuo and recrystallize (toluene) to give the title compound as a cream-colored powder; mp 135-137 β C. IR (KBr) 3609, 3011, 2950, 2809, 2772, 1680, 1606, 1492, 1470, 1448, 1366, 1282, 1238, 1044, 791, 704, 668 c -lj IH NMR (CDC1 3 ) δ 7.93 (d, 2H, J = 8.2 Hz), 7.4 (m, 5H) , 7.3 (m, 5H), 7.2 (m, 2H) , 3.64 (s, 2H) , 2.9 (m, 4H) , 2.4 (m, 3H), 1.9 (M, 5H), 1.38 (s, 6H) , 1.3 (m, 4H); 13C NMR (CDCI 3 ) δ 199.6, 152.1, 145.9, 135.2, 128.2, 126.4, 125.7, 79.5, 72.7, 57.8, 53.9, 44.0, 40.4, 36.2, 26.1, 25.2, 22.2; MS (Cl, CH 4 ) m/z (rel. intensity) 486 (MH+, 100), 468 (81), 408 (19), 293 (23). METHOD A Step d: 4-[4-[4-(Hvdoxydiphenylmethyl)-l-piperidinyπ-l- oxobutyl]-α,α-dimethylbenzeneacetic acid hydrochloride Dissolve oxalyl chloride (1.57g, 12.4mmol) in methylene chloride (17mL) r cool to -55°C and place under a nitrogen atmosphere. Add, by dropwise addition, a solution of dimethylsulfoxide (1.77g, 1.61mL) in methylene chloride (4.5mL). Stir for 15 minutes and add, by dropwise addition, a solution of 4-[4-[4-(hydoxydiphenylmethyl)-l- piperidinyl]-1-oxobutyl]-2,2-dimethylphenethy1 alcohol (5.0g, 10.3mol) in methylene chloride (33mL). Stir for 30 minutes and add, by dropwise addition, triethylamine (7.2mL). Stir for 15 minutes and then allow to warm to -10°C. Add a solution of oxone (12.66g) in deionized water (50mL). Stir for 15 minutes and add methylene chloride (25mL). Separate the organic phase, wash with brine, dry (MgS04) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) to give 4-[4-[4- (hydoxydiphenylmethy1)-1-piperidinyl]-1-oxobuty1]-α,α- di ethylbenzeneacetaldehyde. IH NMR (CDCI 3 ) δ 9.52 (s, IH) , 7.95 (d, 2H, J = 8.2 Hz), 7.5 (m, 4H), 7.36 (d, 2H, J = 8.2 Hz), 7.3 (m, 4H), 7.2 (m, 2H), 2.9 ( , 4H), 2.4 (m, 4H), 2.0 (m, 4H) , 1.50 (s, 6H) , 1.4 (m, 4H); 13C NMR (CDC1 3 ) δ 202, 199.9, 146.2, 136.2, 128.7, 128.3, 127.1, 126.6, 125.9, 79.4, 57.7, 53.8, 50.6, 43.9, 42.5, 36.2, 25.9, 22.3, 21.5; MS (Cl, CH 4 )'m/z (rel. intensity) 484 (MH+, 76), 466 (100), 454 (19), 406 (16), 293 (16), 233 (19), 183 (49, 155 (54). Dissolve 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1- oxobutyl]-α,α-dimethylbenzeneacetaldehyde (3.40g, 7.03mmol) in acetone (30mL) and cool to 15°C. Add, by dropwise addition, IN hydrochloric acid (10.5mL). After addition of the hydrochloric acid is complete, add, by dropwise addition, a solution of potassium permanganate (1.82g, 11.51mmol) in acetone (80mL). Stir at room temperature for 6 hours, filter and wash the filter cake with acetone (60mL). Evaporate the filtrate inυacuo, dilute with methylene chloride (500mL), dry (MgSθ 4 ) and filter. Evaporate the solvent inυacuo and purify by chromatography (ethyl acetate) to give the title compound as a pale yellow solid. IR (KBr) 3420, 3057, 2964, 1677, 1604, 1569, 1470, 1448, 1406, 1363, 1249, 1189, 1099, 750, 705 cm-l, J H NMR (CDCI3) δ 7.75 (d, 2H, J = 8.2 Hz), 7.4 (m, 6H) , 7.2 (m, 4H), 7.1 (m, 2H) , 3.9 (br. s, 2H) , 3.1 ( , 2H), 2.9 (m, 2H), 2.6 (m, 2H), 2.3 (m, 2H) , 1.9 (m, 3H) , 1.7 (m, 2H) . 1.44 (s, 6H), 1.4 (m, 2H); 13C NMR (CDCI 3 ) δ 199.4, 147.2, 134.5, 127.7, 127.5, 126.2, 125.7, 78.4, 57.3, 53.5, 46.6, 43.5, 35.6, 26.8, 25.9, 21.3; MS (Cl, CH ) m/z (rel. intensity) 500 (MH+, 79), 482 (62), 456 (100), 422 (30), 366 (42). METHOD B Mix 4-[4-[4-(hydoxydiphenylmethyl)-1-piperidin l]-1- oxobutyl]-2,2-dimethylphenethyl alcohol (9.7mmol), chloroform (20mL), acetonitrile (20mL), water (30mL) and H 5 I0 6 (5.6g, 24.3mmol). Add RuCl 3 «5H 2 0 (0.15g, 0.49mmol) and stir at room temperature for 2 hours. Dilute the reaction mixture with methylene chloride (200mL), wash with saturated NaHS0 3 (2X100ML) and dry (MgS0 4 ) . Filter, evaporate the filtrate in υacuo (20°C/60 torr) and purify by silica gel chromatography to give the title compound. METHOD C Mix K 2 S 2 θ 8 (2.8g, 10.2mmol), KOH (85%, 1.95g, 30mmol) and water (20mL). Add RuCl 3 «5H 2 0 (30mg, 0.2mmol) and stir at room temperature for 5 minutes. Dissolve 4-[4-[4- (hydoxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2- dimethylphenethyl alcohol (0.97mmol) in acetone (14mL) and acetonitrile (2mL) and add to the above solution. Stir at room temperature for 2.5 hours, filter and neutralize the filtrate with IN HCl to pH 5. Extract with methylene chloride (2X50mL), dry (MgSθ 4 ), evaporate the solvent in υacuo (20°C/60 torr) and purify by silica gel chromatography to give the title compound. Step e: 4-[4-[4-(Hvdroxydiphenylmethyl)-l-piperidinyl]-l- hydroxybutyl]-α,α-dimethylbenzeneacetic acid hydrochloride Add sodium borohydride (0.105g, 2.77mmol) to a solution of sodium hydroxide (0.053g, 1.33mmol) in deionized water (2mL) and add, by dropwise addition, to a solution of 4-[4- [4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α- dimethylbenzeneacetic acid hydrochloride (0.70g, 1.31mmol) in ethanol (30mL). Stir at room temperature for 3.5 hours at pH 7-8. Evaporate the solvent in υacuo and stir the residue with methylene chloride (15mL) and deionized water (15mL). Dry (MgS0 4 ), acidify to pH 3 with gaseous hydrogen chloride and evaporate the solvent. Add ether with stirring, filter the white solid and wash with additional ether. Dry to give the title compound. IR (KBr) 3403, 3058, 2971, 1718, 1634, 1492, 1471, 1448, 1393, 1227, 1150, 1099, 1069, 839, 750, 706 cm-1; IH NMR (CDC1 3 ) δ 7.50 (d, 4H, J = 8.2 Hz), 7.3 (m, 8H) , 7.2 (m, 2H), 4.66 (t, IH, J = 5.6 Hz), 3.5 (m, 2H), 3.0 (m, 4H), 2.8 (m, 2H), 1.7 (m, 8H) , 1.53 (s, 6H) ; 13C NMR (CDC1 3 ) 6 181.1, 147.4, 146.1, 144.4, 129.5, 128.0, 127.4, 127.2, 79.9, 73.9, 57.0, 54.1, 42.7, 36.8, 27.1, 25.7, 21.7; MS (Cl, CH ) m/z (rel.. intensity) 502 (MH+, 50), 485 (33), 484 (100), 458 (25), 454 (33), 424 (17). Example 2 (R)-4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1- hydroxybutyl]-α,ct-dimethylbenzeneacetic, ethyl ester • Dissolve (+)-B-chlorodiisopinocamphenylborane (2.5g, 7.8mmol) in anhydrous tetrahydrofuran (5mL). Add a solution of 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]- l-oxobutyl]-α,α-dimethylbenzeneacetic, ethyl. ester (2g, 3.54mmol) in anhydrous tetrahydrofuran (5mL). Stir at room temperature for 3 days and cool to 0°C. Add water (lmL) and 30% hydrogen peroxide (2mL) and stir for 20 minutes. Add methylene chloride (30mL) and wash with brine (30mL), then aqueous sodium hydrogen carbonate (30mL), then brine (30mL). Dry (MgSθ 4 ), evaporate the solvent in υacuo and purify by chromatography (1:19 methanol:ethyl acetate) to give the title compound as a solid; mp 87-90°C. IR (KBr) 3436, 3058, 2932, 2813, 1725, 1632, 1599, 1470, 1448, 1255, 1147, 1097, 830, 749, 704 cm-l; IH NMR (CDCI 3 ) δ 7.5 (m, 4H), 7.3 (m, 8H) , 7.2 (m, 2H) , 4.6 (m, IH), 4.08 (q, 2H, J = 7.5 Hz), 3.1 (m, IH) , 3.0 (m, 1H) , 2.4 (m, 3H) , 2.0 (m, 3H) , 1.7 (m, 5H) , 1.53 (s, 6H) , 1.5 (m, 2H) , 1.42 (s, 2H), 1.15 (t, 3H, J = 7.5 Hz); [αl 20 D +39.4° (c = 0.99, CHC1 3 ). Example 3 (S)-4-[ -[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1- hydroxybutyl]-α,α-dimethylbenzeneacetic acid, ethyl ester Dissolve (-)-B-chlorodiisopinocamphenylborane (2.5g, 7.8mmol) in anhydrous tetrahydrofuran (5mL). Add a solution of 4-[4-[4-(hydrCfxydiphenylmethyl)-l-piperidinyl]- l-oxobutyl]-α,α-dimethylbenzeneacetic acid, ethyl ester (2g, 3.54mmol) in anhydrous tetrahydrofuran (5mL). Stir at room temperature for 3 days and cool to 0°.C. Add water (ImL) and 30% hydrogen peroxide (2mL) and stir for 20 minutes. Add methylene chloride (30mL) and wash with brine (30mL), then aqueous sodium hydrogen carbonate (30mL), then brine (30mL). Dry (MgSθ 4 ), evaporate the solvent inυacuo and purify by chromatography to give the title compound.

Claims: • WHAT IS CLAIMED IS: 1. A compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or R X and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts and individual optical isomers thereof. 2. A compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts and individual optical isomers thereof. 3. A compound of the formula whεreir. Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; D is C(=0)CH 3 or C(=0)C 6 H 5 ; and pharmaceutically acceptable salts and individual optical isomers thereof. 4. A compound of the formula wherein R λ represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; D is C(=0)CH 3 or C(=0)C 6 H 5 ; and pharmaceutically acceptable salts and individual optical isomers thereof. 5- A process for preparing a piperidine α-formyl benz lalcohol compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts and individual optical isomers thereof, comprising the steps of: (a) reacting a compound of the formula wherein Ri, R 2 , n and A are defined above with a suitable oxidizing agent with the proviso that when A is hydroxy, A may be optionally protected or unprotected and the benzylic alcohol may be optionally protected or unprotected; and (b) optionally reacting the piperidine α-formyl benzylalcohol compound with a suitable deprotecting agent. 6. A process for preparing a piperidine α-formylphenyl ketone compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts and individual optical isomers thereof, comprising the steps of: (a) reacting a compound of the formula wherein Ri, R 2 , n and A are defined above with a suitable oxidizing agent with the proviso that when A is hydroxy, A may be optionally protected or unprotected; and (b) optionally reacting the piperidine α-formylphenyl ketone compound with a suitable deprotecting agent. 7. A process for preparing a piperidine α-acetyl benzylalcohol compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; D is C(=0)CH 3 or C(=0)C 6 H 5 ; and pharmaceutically acceptable salts and individual optical isomers thereof, comprising the steps of: (a) reacting a compound of the formula wherein Ri, R 2 , n, and A are defined above with a suitable acylating agent with the proviso that when A is hydroxy, A may be optionally protected or unprotected and the benzylic alcohol may be optionally protected or unprotected; and (b) optionally reacting the piperidine α-acetyl benzylalcohol compound with a suitable deprotecting agent. 8. A process for preparing a piperidine α-acetylphenyl ketone compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; D is C(=0)CH 3 or C(=0)C 6 H 5 ; and pharmaceutically acceptable salts and individual optical isomers thereof, comprising the steps of: (a) reacting a compourid of the formula wherein Ri, R 2 , n and A are defined above with a suitable acylating agent with the proviso that when A is hydroxy, A may be optionally protected or unprotected; and (b) optionally reacting the piperidine α-acetylphenyl ketone compound with a suitable deprotecting agent. 9. A process for preparing a compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cg alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; and (c) reacting the ω-halo hydroxyethylphenylketone with a piperidine compound of the formula wherein Ri and R 2 are as defined above in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone; (d) reacting the piperidine hydroxyethylphenylketone with a suitable oxidizing agent to produce a piperidine formylphenylketone; (e) reacting the piperidine formylphenylketone with a suitable oxidizing agent to produce a piperidine carboxyphenylketone; (f) reacting the piperidine carboxyphenylketone with a suitable reducing agent to produce a piperidine carboxyphenylalcohol; (g) optionally reacting the piperidine carboxyphenylalcohol to form a piperidine carboxyphenylalcohol ester; and (h) optionally reacting the piperidine carboxyphenylalcohol or the piperidine carboxyphenylalcohol ester with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-g are optionally protected or unprotected. 10. A process according to Claim 9 wherein the piperidine hydroxyethylphenylketone of step c is reacted with a suitable oxidizing agent to produce a piperidine carboxyphenylketone. 11. A process according to Claim 10 wherein the oxidizing agent is ruthenium(VIII) oxide. 12. A process for preparing a compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cβ alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula wherein wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; and (c) reacting the ω-halo hydroxyethylphenylketone with a piperidine compound of the formula wherein R and R 2 are as defined above in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone; (d) reacting the piperidine hydroxyethylphenylketone with a suitable oxidizing agent to produce a piperidine formylphenylketone; -Si¬ te) reacting the piperidine formylphenylketone with a suitable oxidizing agent to produce a piperidine carboxyphenylketone; (f) optionally reacting the piperidine carboxyphenylketone to form a piperidine carboxyphenylketone ester; and (g) optionally reacting the piperidine carboxyphenylketone or the"piperidine carboxyphenylketone ester with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-f are optionally protected or unprotected. 13. A process according to Claim 12 wherein the piperidine hydroxyethylphenylketone of step c is reacted with a suitable oxidizing agent to produce a piperidine carboxyphenylketone. 14. A process according to Claim 13 wherein the oxidizing agent is ruthenium(VIII) oxide. 15. A process for preparing a compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -CH 2 OH; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cg alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula o (CH 2 ) n — Hal wherein wherein B is halo or hydroxy, Hal represents Cl, B or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; (c) reacting the ω-halo hydroxyethylphenylketone with a piperidine compound of the formula wherein Ri and R 2 are as defined above in the presence of suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone; and (d) optionally reacting the piperidine hydroxyethylphenylketone with an appropriate deprotecting reagent. with the proviso that each of the hydroxy groups present in the compounds described in steps a-c are optionally protected or unprotected. 16. ' A process according to Claims 9, 10 or 11 wherein the reducing agent of step f is (+)-B- chlorodiisopinocamphenylborane. 17. A process according to Claims 9, 10 or 11 wherein the reducing agent of step f is (-)-B- chlorodiisopinocamphenylborane. 18. A process for preparing a compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or i and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cβ alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; (c) reacting the ω-halo hydroxyethylphenylketone with a suitable reducing agent to produce a ω-halo hydroxyethylphenylalcohol; (d) reacting the ω-halo hydroxyethylphenylalcohol with a piperidine compound of the formula wherein Ri and R 2 are as defined above, in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylalcohol; (e) reacting the piperidine hydroxyethylphenylalcohol with a suitable oxidizing agent to produce a piperidine formylphenylalcohol; (f) reacting the piperidine " formylphenylalcohol with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol; (g) optionally reacting the piperidine carboxyphenylalcohol to form a piperidine carboxyphenylalcohol ester; and (h) optionally reacting the piperidine carboxyphenylalcohol or the piperidine carboxyphenylalcohol ester with an appropriate deprotecting reagent. with the proviso that each of the hydroxy groups present in the compounds described in steps a-g are optionally protected or unprotected. 19. A process according to Claim 18 wherein the piperidine hydroxyphenylalcohol of step d is reacted with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol. 20. A process according to Claim 19 wherein the oxidizing agent is ruthenium (VIII) oxide. 21. A process for preparing a compound of the formula wherein R l represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -CH 2 OH; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Ce alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula B' "(CH 2 ) n — Hal wherein wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; (c) reacting the ω-halo hydroxyethylphenylketone with a suitable reducing agent to produce a ω-halo hydroxyethylphenylalcohol; (d) reacting the ω-halo hydroxyethylphenylalcohol with a piperidine compound of the formula wherein Ri and R 2 are as defined above, in the presence of suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylalcohol; and (e) optionally reacting the piperidine hydroxyethylphenylalcohol with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-d are optionally protected or unprotected. 22. A process according to Claim 18, 19 or 20 wherein the reducing agent of step c is (+)-B- chlorodiisopinocamphenylborane. 23. A process according to Claim 18, 19 or 20 wherein the reducing agent of step c is (-)-B- chlorodiisopinocamphenylborane. 24. A process according to Claim 21 wherein the reducing agent of step c is (+)-B- chlorodiisopinocamphenylborane. 25. A process according to Claim 21 wherein the reducing agent of step c is (-)-B- chlorodiisopinoca phenylborane. 26. A process for preparing a compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or Ri and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R 3 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; each of A is hydrogen or hydroxy; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cβ alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; (c) reacting the ω-halo hydroxyethylphenylketone with a piperidine compound of the formula wherein Ri and R 2 are as defined above, in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone; (d) reacting the piperidine hydroxyethylphenylketone with a suitable reducing agent to produce a piperidine hydroxyethylphenylalcohol; (e) reacting the piperidine hydroxyethylphenylalcohol with a suitable oxidizing agent to produce a piperidine formylphenylalcohol; (f) reacting the piperidine formylphenylalcohol with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol; (g) optionally reacting the piperidine carboxyphenylalcohol to form a piperidine carboxyphenylalcohol ester; and (h) optionally reacting the piperidine carboxyphenylalcohol or the piperidine carboxyphenylalcohol ester with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-g are optionally protected or unprotected. 27. A process according to Claim 26 wherein the piperidine hydroxyethylphenylketone is reacted with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol. 28. A process according to Claim 27 wherein the oxidizing agent is ruthenium(VIII) oxide. 29. A process for preparing a compound of the formula wherein Ri represents hydrogen or hydroxy; R 2 represents hydrogen; or R l and R 2 taken together form a second bond between the carbon atoms bearing Ri and R 2 ; n is an integer of from 1 to 5; R] is -CH 2 OH; and pharmaceutically acceptable salts and individual optical isomers thereof comprising the steps of: (a) reacting a benzeneacetic acid compound of the formula wherein A is as defined above and R is hydrogen or Ci-Cβ alkyl with a suitable reducing agent to give a phenethyl alcohol; (b) reacting the phenethyl alcohol with a ω-halo compound of the formula x (CH 2 ) n — Hal wherein wherein B is halo or hydroxy, Hal represents Cl Br ,_ or I and n is as defined above, in the presence of a suitable Lewis acid to produce a ω-halo hydroxyethylphenylketone; (c) reacting the ω-halo hydroxyethylphenylketone with 15 a piperidine compound of the formula 25 wherein R and R 2 are as defined above, in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone; 30 (d) reacting the piperidine hydroxyethylphenylketone with a suitable reducing agent to produce a piperidine hydroxyethylphenylalcohol; and 35 (e) optionally reacting the piperidine hydroxyethylphenylalcohol with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-d are optionally protected or unprotected. 30. A process according to claim 26 wherein the reducing agent of step d is (+)-B- chlorodiisopinocamphenylborane. 31. A process according to claim 26 wherein the reducing agent of step d is (-)-B- chlorodiisopinocamphenylborane. 32. A process according to claim 29 wherein the reducing agent of step d is (+)-B- chlorodiisopinocamphenylborane. 33. A process according to claim 29 wherein the reducing agent of step d is (-)-B- chlorodiisopinocamphenylborane.

Inventors: KAMINSKI MICHELE A, KING CHI-HSIN RICHARD, KAMINSKI, MICHELE, A., KING, CHI-HSIN, R.
Applicants: MERRELL DOW PHARMA, MERRELL DOW PHARMACEUTICALS INC.
Application year: 1993
Main classification: C07D211
IPC codes: C07D211