AU2007200674B2 - Novel antihistaminic piperidine derivatives and intermediates for the preparation thereof - Google Patents

Description

AUSTRALIA Patents Act COMPLETE SPECIFICATION (ORIGINAL) Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Aventis Pharmaceuticals, Inc. Actual Inventor(s): Timothy A Ayers, Paul W Brown Address for Service and Correspondence: PHILLIPS ORMONDE & FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: NOVEL ANTIHISTAMINIC PIPERIDINE DERIVATIVES AND INTERMEDIATES FOR THE PREPARATION THEREOF Our Ref : 794121 POF Code: 1432/1432 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- -1a NOVEL ANTIHISTAMINIC PIPERIDINE DERIVATIVES AND INTERMEDIATES FOR THE PREPARATION THEREOF The present application is a divisional of Australian patent application number 5 2003268868, which is in turn a divisional of Australian patent application number 45746/99 the entire disclosures of which are incorporated herein by reference. BACKGROUND OF THE INVENTION This invention relates to intermediates useful for the preparation of novel 10 piperidine derivatives of formula (1) OH OH 'NN OH N R1 R2 wherein 15 R 1 is H or C 1

-C

6 alkyl wherein the C 1

C

6 alkyl moiety is straight or branched;

R

2 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof. 20 Terfenadine, a-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1 piperidinebutanol, is a known antihistaminic agent which is currently available commercially under the name Seldane* with a recommended dosage of 60 mg b.i.d. 25 (See PHYSICIAN'S DESK REFERENCE, 52nd Edition, 1998, pp. 1238-1244, Medical Economics Data, a division of Medical Economics Company, Inc. Montvale, New Jersey). Terfenadine is disclosed in U.S. Patent 3,878,217, issued April 15, 1975. Sorken and Heel have provided a review of the pharmacodynamic properties 5 and therapeutic efficacy of terfenadine [Drugs L, 34-56 (1985)]. Terfenadine undergoes extensive ( 99 %) first. pass metabolism to two primary metabolites (fexofenadine) and an inactive dealkylated metabolite. -Fexofenadine, a.k.a. 4-[1-hydroxy-4-[4-(hydroxydiphenyimethyl)-1 -piperidinyl]butyl-a,a-dimethyl benzeneacetic acid, has been disclosed as an antihistaminic agent having oral 10 activity in U.S. Patent No. 4,254,129, issued March 3, 1981. It is currently available commercially under the name Allegra* (See PHYSICIAN'S DESK REFERENCE, 52nd Edition, 1998, pp. 1189-1190, Medical Economics Data, a division of Medical Economics Company, Inc. Montvale, New Jersey). The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia as at the priority date of any of the claims. 5 - 2a SUMMARY OF THE INVENTION An aspect of the present invention is to provide novel piperidine derivatives of 5 formula (1) useful for the treatment of allergic disorders. It is a further aspect to provide a process for the preparation of said derivatives and to provide novel intermediates useful for preparation of the same. Additionally, it is an aspect of the present invention to provide a method of treating a patient suffering from an allergic disorder comprising administering to said patient an 10 effective antiallergic amount of a compound of formula (1). Furthermore, it is an aspect of the present invention to provide a composition comprising an assayable amount of a compound of formula (1) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. Another aspect of the present invention is to provide novel processes for the 15 preparation of intermediates useful for the synthesis of fexofenadine and related compounds. In one aspect, the present invention provides a process for preparing a compound of the formula 0 C0 2

R

1 20 wherein

R

1 is C 1 -Cealkyl and the C 1 -Cealkyl moiety is straight or branched: comprising the steps of: (a) reacting a benzene acetic acid ester of the formula C0 2

R

1 25 wherein

R

1 is C-C 6 alkyl and the C 1

-C

6 alkyl moiety is straight or branched; with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para and meta substituted w-halo-a-keto-benzeneacetic acid ester of the formula SPEC-794121 JOL 30.9.10 - 2b 0 x C0 2

R

1 wherein

R

1 is as previously defined herein and X is Cl, Br, or I; 5 (b) hydrolyzing the mixture of para and meta substituted (w-halo-a-keto substituted benzene acetic acid to provide a mixture of para and meta substituted (cyclopropylcarbonyl)benzene acetic acid ester of the formula 0

CO

2 H ; and (c) selectively crystallizing and isolating the substantially pure 4 10 cyclopropylcarbonyl)benzene acetic acid. In another aspect, the present invention provides a process for preparing a compound of the formula 0 0 wherein X is Cl, Br, or 1; 15 comprising the steps of: (a) reacting a compound of the formula IN. U0 'N11 0 with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para- and meta- substituted (4-halo-1-oxobutyl)-N-methoxy-N-methyl 20 benzeneacetamide of the formula 0 0 SPEC.794121 JOL3Ii.IO1 - 2c wherein X is Cl, Br, or I; (b) selectively crystallizing and isolating substantially pure [4-(4-halo-1 oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide of the formula 0 NN x 50 wherein X is Cl, Br, or I. In a further aspect, the present invention provides a process for preparing a compound of the formula OH OHN N OH / R1 10 R2 wherein

R

1 is H or C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched;

R

2 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or 15 stereoisomers or pharmaceutically acceptable acid addition salt thereof; comprising: (a) reacting a compound of the formula IN" 0 with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a 20 mixture of para- and meta- substituted (4-halo-1-oxobutyl)-N-methoxy-N-methyl benzeneacetamide of the formula SPEC-794121 JOL 30X WI1 - 2d 0 O x N wherein X is Cl, Br, or 1; (b) selectively crystallizing and isolating substantially pure [4-(4-halo-1 5 oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide of the formula 1 0 U x N 0 wherein X is Cl, Br, or 1; (c) hydrolyzing the substantially pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N 10 methyl-benzeneacetamide to provide a (cyclopropylcarbonyl)benzeneacetic acid of the formula 0 0H (d) esterifying the (cyclopropylcarbonyl)benzeneacetic acid to provide a (cyclopropylcarbonyl)benzeneacetic acid ester of the formula 0 OR, 15 0 wherein

R

1 is C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched; (e) acylating the (cyclopropylcarbonyl)benezeneacetic acid ester to provide a [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula 0 R1 20

R

2 0 2 C C0 2

R

3 wherein SPEC-794121 JOL301.10 - 2e R 1 is H;

R

2 and R 3 are each independently C 1

-C

6 alkyl wherein the C-C 6 alkyl moiety is straight or branched; (f) optionally alkylating the [4-(cyclopropylcarbonyl)phenyl]propanedioic acid 5 diester to provide a [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula 0 R

R

2

O

2 C Co 2

R

3 wherein

R

1 is C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched and R 2 and 10 R 3 each independently C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched; (g) reacting the [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula 0 R1~ R2O2C CO2R3 15 wherein

R

1 is H or C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched

R

2 and R 3 are each independently 0 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched, with a suitable hydrogen halide to produce a [4-(4-halo-1-oxo-butyl)phenyl]propanedioic 20 acid diester of formula O x R1 R2O2C CO2R3 wherein

R

1 is H or C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched; SPEC-794121 101. 30 .10 - 2f R 2 and R 3 are each independently C 1

-C

6 aIkyl wherein the 0 1

-C

6 aIkyl moiety is straight or branched; X is Cl, Br, or 1; (h) reacting the [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester with a 5 compound of formula OH HN to produce a [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester compound of formula OH 0% H. N R1,

R

2 0 2 C C0 2

R

3 10 wherein

R

1 is H or C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched;

R

2 and R 3 are each independently C 1

-C

6 alkyl wherein the C 1 -Csalkyl moiety is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; 15 (i) reacting the [4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester compound with a suitable selective reducing agent to give a 4-[1-hyd roxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a (hydroxymethyl)-benzeneacetic acid ester compound of formula SPEC-79412I JOL 30810 - 2g OH OH N OH / R1 R2 wherein

R

1 is H or C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched;

R

2 is -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is 5 straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; and (j) optionally hydrolyzing the 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-1 piperidinyl]butyl]-a-(hydroxymethyl)-benzeneacetic acid ester compound to produce a compound of formula N OH OHN OH ---- R1 10 R2 wherein

R

1 is H or C 1

-C

6 alkyl wherein the C 1

-C

6 alkyl moiety is straight or branched;

R

2 is -COOH; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; 15 with the proviso that each of the keto groups present in the compounds described in steps c-h are optionally protected or unprotected. In a further aspect, the present invention provides use of the compound of formula SPEC-794121 JOL 30 8 1O - 2h OH OH % OH N R1 R2 for the manufacture of a medicament for the treatment of histamine-mediated allergic disorders, wherein

R

1 is H or C1-C6 alkyl and the C1-C6 alkyl moiety is straight or branched; 5 R 2 is -COOH or -COOalkyl and the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; stereoisomers or pharmaceutically acceptable acid addition salt thereof. In a further aspect, the present invention also provides a method of treating histamine-mediated allergic disorders in a subject comprising the step of administering to 10 said subject an effective amount of a compound of formula OH OH OH N R1 R2 for the manufacture of a medicament for the treatment of histamine-mediated allergic disorders, wherein

R

1 is H or C1-C6 alkyl and the C1-C6 alkyl moiety is straight or branched; 15 R 2 is -COOH or -COOalkyl and the alkyl moiety has from I to 6 carbon atoms and is straight or branched; stereoisomers or pharmaceutically acceptable acid addition salt thereof. Upon further study of the specification and appended claims, further aspects and advantages of this invention will become apparent to those skilled in the art. SPEC-794121 JOL308.10 DETAILED DESCRIPTION OF THE INVENTION Compounds of the formula (I) can be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. 5 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, isobutyl, tert-butyl, and straight- and branched-chain pentyl and hexyl. The piperidine derivatives of the formula (1) can form pharmaceutically acceptable salts. Pharmaceutically acceptable acid addition salts of the compounds 10 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 15 aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid, sulfonic acids, such as, methanesulfonic, ethanesulfonic and P-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, 20 those of alkali metals, such as, sodium, potassium and lithium, alkaline earth metals, for example, calcium and magnesium, light metals of group lIlA, 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 25 piperidine derivative of formula (1) with an appropriate acid or base. The novel process for preparing the piperidine derivatives of formula (1) is set, forth in Scheme A. in Scheme A, R 1 , and R 2 are C- C 6 alkyl wherein the C- C 6 alkyl moiety is straight or branched;

R

3 is H or C-C 6 alkyI wherein the C-Calkyl moiety is straight or branched; and X is CI, Br or I.

SCHEME A O J + CH 3 ONHCH Step A

K

2 C0 3 2 0 StepB I 0 X 2 + X X

AIC

3 /DCM 3 Step C 0 X EtOAc 4 0 4 StepD O KO4/EtOH 0 5 0 Step E 5 + ROH

H

2 SO4 6

-S

SCHEME A Cont. 0 0R J + R 3 X Step F

R

3 6 + R 2 0 0 R 2 + 3 R

R

1 0 2 C CO 2 R2 7 Step G 0 x 7 + HX

R

3 R0 C -0-R, 8 Step H 0 +R N 10 St J3 N 2

C

3

R

1 0 2 C 0 R, 9 H Step I N .9 R I reduction 3,1

R

1 0 2 OH 1 0 10Step J H N% NaOH/H 2 0R HOOC OH 1 -6 Scheme A provides a general synthetic procedure for preparing the compounds of formula (I). In step A, a phenylacetyl halide (1) wherein X is Cl, Br, or I, is reacted with N O-dimethylhydroxylamine hydrochloride to provide N-methoxy-N-methyl 5 benzeneacetamide (2). For example, a suitable phenylacetyl halide (1) is contacted with a molar excess of potassium carbonate in a suitable solvent such as toluene. Suitable phenylacetyl halides include phenylacetyl chloride, phenylacetyl bromide or phenylacetyl iodide. A preferred phenylacetyl halide is phenylacetyl chloride. A io molar equivalent of N-0-dimethylhydroxylamine hydrochloride dissolved in water is then added. The reaction mixture is stirred for a period of time ranging from 1 to 24 hours at a temperature range of from O'C to 60'C. A preferred stirring time is 3 hours. A preferred temperature is 25'C. N-methoxy-N-methyl-benzeneacetamide is (2) is recovered from the reaction zone by extractive methods as are known in the 15 art. In step B, N-methoxy-N-methyl-benzeneacetamide (2) is acylated with a suitable 4-halo-substituted butyrylhalide of the formula 0x wherein each X is independently Cl, Br or 1; 20 under Friedel-Crafts conditions to give a mixture of para, meta substituted w-halo-a keto-benzeneacetamide (3). Surprisingly, the para isomer is readily isolated by subsequent crystallization as set forth in step C. For example,. in step B, N-methoxy-N-methylbenzeneacetamide (2) is contacted with suitable 4-halo-substituted butyrylhalide under the general 25 conditions of a Friedel-Crafts acylation using a suitable Lewis acid. Examples of suitable 4-halo-substituted butyrylhalides include 4-chlorobutyrylchloride, 4 bromobutyrylbromide, and the like. A preferred 4-halo-substituted butyrylhalide is 4 chlorobutyrylchloride. The reaction is carried out in a solvent, such as carbon disulfide, 1,2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane, nitromethane, 30 diethyl ether, carbon tetrachloride, methylene chloride, tetrachloroethane or nitrobenzene with dichloromethane being the preferred solvent. The reaction time -7 varies from about 1/2 hour to 25 hours at a temperature range of from 00C to 400C. A preferred stirring time is 6 hours. A preferred temperature is 40 0 C. The mixture of para, meta substituted w-halo-a-keto-benzeneacetamide (3) is recovered from the reaction zone by an aqueous quench followed by extractive methods as are known in 5 the art. 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 10 acylation reaction of step B is well known and appreciated by one of ordinary skill in the art. The para-substituted w-halo-a-keto-benzeneacetamide (3) is purified by recrystallization techniques as set forth in step C. For example, the product of the extractive methods as set forth in step B is 1s stirred in a suitable organic solvent such as a mixture of heptane/ethyl acetate (ca. 4:1) and collected. The solid is dissolved in a suitable solvent such as ethyl acetate at a temperature range of from 250C to 76*C. A preferred temperature is 760C. The solution is then contacted with charcoal. This mixture is then filtered and diluted with a suitable solvent such as heptane. The resultant slurry is then heated until a 20 homogenous solution is obtained. Substantially pure para-substituted w-halo-a-keto benzeneacetamide (4) crystallizes upon standing at room temperature. In step D, the substantially pure para-substituted w-halo-a- keto benzeneacetamide (4) is hydrolyzed to give the 4 (cyclopropylcarbonyl)benzeneacetic acid (5). 25 For example, the substantially pure para-substituted w-halo-a-keto benzeneacetamide (4) is contacted with a molar excess of an appropriate base such as potassium hydroxide in a suitable solvent such as ethanol. The reactants are typically stirred together for a period of time ranging from 1 to 24 hours at a temperature range of from 00C to 78*C. A preferred stirring time is 18 hours. A 30 preferred temperature is 25*C. The 4-(cyclopropylcarbonyl)benzeneacetic acid (5) is recovered from the reaction zone by acidification and extractive methods as are known in the art. In step E, the 4-(cyclopropylcarbonyl)benzeneacetic acid (5) is esterified to give the corresponding 4-(cyclopropylcarbonyl)benzeneacetic acid ester (6). For example, the appropriate 4-(cyclopropylcarbonyl)benzeneacetic acid (5) is reacted with an excess of an appropriate

C-C

6 alcohol which is straight or branched in the presence of a catalytic amount of mineral acid, such as hydrochloric acid or 5 sulfuric acid, hydrochloric acid being preferred, at a temperature range of from 25*C to 78 0 C. The reactants are typically stirred together for a period of time ranging from 2 to 72 hours. A preferred stirring time is 24 hours. A preferred temperature is 25 0 C. The corresponding 4-(cyclopropylcarbonyl)benzeneacetic acid ester (6) is recovered from the reaction zone by basification and extractive methods as are 10 known in the art. It can be purified by silica gel chromatography. In step F, the appropriate 4-(cyclopropylcarbonyl)benzeneacetic acid ester (6) is acylated with the appropriate acylating agent to give the corresponding [4 (cyclopropylcarbonyl)phenyl]propanedioic acid diester (7). For example, the appropriate 4-(cyclopropylcarbonyl)benzeneacetic acid ester 15 (6) is reacted with a slight molar excess of a suitable acylating agent. Suitable acylating agents include dialkylcarbonates, such as, dimethylcarbonate or diethylcarbonate;.or chloroformates, such as, methyl chloroformate or ethyl chloroformate. The reaction is typically conducted in a suitable aprotic solvent in the presence of a suitable non-nucleophilic base from about 0.5 hour to 7 days and at a 20 temperature of about 0*C to the reflux temperature of the solvent. A preferred stirring time is 3 days. A preferred temperature is 25 0 C.- Suitable solvents for the acylation reaction include tetrahydrofuran, dioxane, or tert-butyl methyl ether. A preferred solvent is tetrahydrofuran. Suitable non-nucleophilic bases for the acylation reaction include inorganic bases, for example, sodium bicarbonate, potassium bicarbonate, or 25 hydrides, for example, sodium hydride or potassium hydride or alkoxides, for example, potassium tert-butoxide. A preferred base is sodium bis(trimethylsilyl)amide. The derivative formed upon acylation is optionally alkylated with a suitable alkylating agent in situ subsequent to the acylation. Suitable alkylating agents 30 include alkyl halides, such as, iodomethane, chloromethane or bromomethane; or dialkylsulfates, such as, dimethylsulfate or diethylsulfate. The reactants are typically stirred together for a period of time ranging from 1 to 48 hours at a temperature range of from 0*C to 30 0 C. A preferred stirring time is 24 hours. A preferred -9 temperature is 25*C. The corresponding [4-(cyclopropylcarbonyl)phenyl)propanedioic acid diester (7) is recovered from the reaction zone by extractive methods as are known in the art. It can be purified by silica gel chromatography and/or recrystallization. 5 While not necessary for utilization in the acylation and subsequent alkylation in step F, the keto functionality of the 4-(cyclopropylcarbonyl)benzeneacetic acid ester (6) may be protected with a suitable protecting group. The selection and utilization of suitable protecting groups for the keto group of structure (6) is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Synthesis", 10 Theodora W. Greene, Wiley (1981). For example, suitable protecting groups for the keto functionality include acyclic ketals such as dimethyl ketal; cyclic ketals such as 1,3-dioxanes and 1,3-dioxalanes; acyclic dithioketals such as S,S-dimethyl ketal; cyclic dithio ketals such as 1,3-dithiane and 1,3-dithiolane derivatives; acyclic monothio ketals; cyclic monothio ketals such as 1,3-oxathiolanes. 15 In step G, the appropriate [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester (7) is ring-opened to give the corresponding [4-(4-halo-1-oxo butyl)phenyl]propanedioic acid diester (8). For example, the appropriate [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester (7) is contacted with a suitable hydrogen halide such as hydrogen chloride, 20 hydrogen bromide, or hydrogen iodide in a suitable organic solvent or in the absence of solvent. Suitable organic solvents include alcohol solvents, such as, ethanol, methanol, isopropyl alcohol, or n-butanol; hydrocarbon solvents, such as, benzene, toluene or xylene; halogenated hydrocarbons, such as chlorobenzene, chloroform or methylene chloride or dimethylformamide or acetic acid or dioxane at a temperature 25 range of from 0*C to 1.00 0 C. The absence of solvent is preferred. The reactants are typically stirred together for a period of time ranging from 1 hour to 24 hours. A preferred stirring time is 4 hours to 16 hours. A preferred temperature range is 60 0 C to 80*C. If solvent is present, the [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid' diester (8) is recovered from the reaction zone by extractive methods as are known in 3o the art and subsequent evaporation of the solvent. In step H, the halo functionality of the appropriate [4-(4-halo-1-oxo butyl)phenyl)propanedioic acid diester (8) is alkylated with a-(4-pyridyl)benzhydrol (commercially available from Aldrich Chemicals) to give the corresponding [4-[4-[4- -10 (hydroxydiphenylmethyl)-1-piperidinyl]1-oxobutyl]phenyl]propanedioic acid diester (9). For example, the alkylation reaction is carried out in a suitable solvent preferably in the presence of a non-nucleophilic base and optionally in the presence 5 of a catalytic amount of an iodide source, such as potassium or sodium iodide. The reaction time varies from about 4 hours to 7 days and the reaction varies from about 250C to the reflux temperature of the solvent. A preferred stirring time is 3 days. A preferred temperature is the reflux temperature of the solvent. Suitable solvent for the alkylation reaction include alcohol solvents such as, methanol, ethanol, isopropyl 1o alcohol, or n-butanol; ketone solvents, such as, methyl isobutyl ketone; hydrocarbon solvents, such as, benzene, toluene or xylene, and mixtures thereof with water; halogenated hydrocarbons, such as, chlorobenzene or methylene chloride or dimethylformamide. A preferred solvent is toluene/water (10:4). Suitable non nucleophilic bases for the alkylation reaction include inorganic bases, for example, is sodium bicarbonate, potassium bicarbonate, or potassium carbonate or organic bases, such as, a trialkylamine, for example, triethylamine, or pyridine, or an excess of a-(4-pyridyl)benzhydrol may be used. A preferred base is potassium carbonate. The corresponding [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidiny]-1 oxobutyl]phenyl]propanedioic acid diester (9) is recovered from the reaction zone by 20 extractive methods as are known in the art. It can be purified by silica gel chromatography. While not necessary for the utilization in the alkylation of step H, the keto functionality of the [(4-halo-1-oxo-butyl)phenylpropanedioic acid diester (8) may be protected with a suitable protecting group. The selection and utilization of suitable 25 protecting groups for the keto group of structure (8) is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Synthesis", Theodora W. Greene, Wiley (1981). For example, suitable protecting groups for the keto functionality include acyclic ketals such as dimethyl ketal; cyclic ketals such as 1,3; dioxanes and 1,3-dioxalanes; acyclic dithioketals such as S,S-dimethyl ketal; cyclic 30 dithio ketals such as 1,3-dithiane and 1,3-dithiolane derivatives; acyclic monothio ketals; cyclic monothio ketals such as 1,3-oxathiolanes. In step 1, the appropriate [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester (9) is reduced selectively to the -11 corresponding 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidiny]butyl}.

(hydroxymethyl)-benzeneacetic acid ester (10). This is accomplished by utilizing a suitable selective reducing agent. A suitable selective reducing agent is a reagent or combination of reagents which will selectively reduce only one ester of the 5 propanedioic acid diester functionality to the corresponding hydroxymethyl moiety while not reducing the second ester of the propanedioic acid diester functionality. Suitable selective reducing agents include lithium tri-tert-butoxyaluminohydride or the combination of a suitable silane and a suitable titanocene-based catalyst. For example; the appropriate [4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 10 oxobutyqphenyl]propanedioic acid diester (9) is contacted with a suitable selective reducing agent such as lithium tri-tert-butoxyaluminohydride in a suitable solvent such as tetrahydrofuran, diethyl ether, or dioxane. A preferred solvent is tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 0.5 hours to 168 hours at a temperature range of from 0*C to 65 0 C. A is preferred stirring time is 48 hours. A preferred temperature is 25 0 C. Catalytic reduction may also be employed in the preparation of 4-[1-hydroxy-4 14-(hydroxydiphenylmethyl)-1 -piperidinylqbutyl]-a-(hydroxymethyl)-benzeneacetic acid ester (10) from an appropriate [4-[4-[4-(hydroxyd ip henylmethyl)-1:-piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester (9), using, for example, a suitable 20 titanocene-based catalyst in which a suitable silane, such as, polymethylhydrosiloxane, serves as the stoichiometric reductant. Suitable titanocene-based catalysts. include the active catalytic species commonly known as "Cp 2 TiH". It is well known by one of ordinary skill in the art that the active catalytic species "Cp 2 TiH" may be generated, for example, by the addition of 2 equivalents of 25 ethyl magnesium bromide to 1 equivalent of Cp 2 TiCl 2 in a suitable solvent such as tetrahydrofuran. For example, the catalytic reduction is carried out in a suitable solvent such as tetrahydrofuran or diethyl ether or dioxane at temperatures ranging from about 25*C to the reflux temperature of the solvent. A preferred temperature for use with the. 30 catalytic reduction is 650C. The reaction time varies from about 8 hours to 24 hours. A preferred stirring time is 18 hours. The 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl) 1-piperidinyl]butyl)-a-(hydroxymethyl)-benzeneacetic acid ester (10) is recovered from the reaction zone after work-up with Bu 4 NF and utilization of extractive -12 methods as are known in the art. It can be purified by silica gel chromatography. In addition, a chiral catalytic reduction may also be employed in the preparation of enantiomerically pure 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 piperidinyl]butyl]-a-(hydroxymethyl)-benzeneacetic acid ester (10) from an 5 appropriate [4-[4-[4-(hydroxydiphenylmethy)-1-piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester (9), using an appropriate chiral titanocene system, such as, for example, is described in Journal of the American Chemical Society, 116, 11667-11670 (1994). As one skilled in the art would appreciate, the [4-[4-[4 1o (hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioic acid diester (9) wherein the keto group is protected must be reacted with an appropriate deprotecting reagent prior to the reduction reaction described in step I. 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 Synthesis", Theodora 15 W. Greene, Wiley (1981). For example, cleavage of a dimethylketal protecting group on the keto functionality of the [4-[4-[4-(hydroxydiphenylmethyl)-1-piperdiny]-1 oxobutyqphenyl]propanedioic acid diester (9) can be achieved by using iodotrimethylsilane or dilute acid as is known in the art. In step J, the appropriate 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 20 piperidinyt]butyl]-a-(hydroxymethyl)-benzeneacetic acid ester (10) is optionally hydrolyzed to the corresponding 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 piperidinyl]butyl]-a-(hydroxymethyl)-benzeneacetic acid (11). For example, hydrolysis may be achieved using methods known in the art such as potassium carbonate in methanol, methanolic ammonia, potassium 25 carbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassium cyanide in ethanol and sodium hydroxide in aqueous alcohols, with sodium hydroxide being preferred. The reaction is typically carried out in an aqueous lower alcohol solvent, such as methanol, ethanol, isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol or 30 pyridine. A preferred solvent is a mixture of tetrahydrofuran/methanol/water (3:2:1). The reaction is typically carried out at temperatures ranging from room temperature to the reflux temperature.of the solvent. A preferred temperature is 650C. The reactants are typically stirred together for a period of time ranging from 1 to 24 hours.

-13 A preferred stirring time is 4 hours. The 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl) 1-piperidinyl]butyl]-a-(hydroxymethyl)-benzeneacetic acid (11) is recovered from the reaction zone by acidification and extractive methods as are known in the art. Of course it is understood that the compound of formula (I) may exist in a 5 variety of stereoisomers. The compound has more than one chiral center. For example, the benzylic carbon to which the carboxyl, hydroxymethyl and methyl groups attach may exist in the (R) or the (S) form. In addition, the benzylic carbon to which the hydroxy, hydrogen and alkyl amino groups attach may exist in the (R) or the (S) form. It is further understood that the present invention encompasses those 10 compounds of formula (I) in each of their various structural and stereo isomeric configurations as individual isomers and as mixtures of isomers. Ah alternative novel process for the preparation of 4 (cyclopropylcarbonyl)benzeneacetic acid is set forth in Scheme B. This compound is useful for the synthesis of compounds of formula (I) as well as fexofenadine and 15 related compounds. In Scheme B, R 1 is C 1

-C

6 alkyl and the C 1

-C

6 alkyl moiety is straight or branched.

-14 Scheme B 0 step g X rx C0 2 R CO2RI 2 0 step 1 2

CO

2 H .33 Step g.

CO

2 H 4. In step a of Scheme B, the appropriate benzeneacetic acid ester (1) wherein

R

1 is C 1 -Cralkyl and the C-Cealkyl moiety is straight or branched, is acylated with a 5 suitable 4-halo-substituted butyrylhalide of the formula 0 X .X wherein each X is independently CI, Br, or I, under Friedel-Crafts conditions to give a mixture of the corresponding para, meta substituted w-halo-a-keto-benzeneacetic acid ester (2) wherein X is Cl, Br, or I. 10 For example, in step a, the appropriate benzeneacetic acid ester (1) is contacted with a 4-halo-substituted butyrylhalide under the general conditions of a Friedel-Crafts acylation using a suitable Lewis acid. Examples of suitable 4-halo substituted butyrylhalides include 4-chlorobutyrylchloride, 4-bromobutyrylbromide, and the like. A preferred 4-halo-substituted butyrylhalide is 4-chlorobutyrylchloride. is The reaction is carried out in a solvent, such as carbon disulfide, 1,2-dichloroethane, -15 n-hexane, acetonitrile, 1-nitropropane, nitromethane, diethyl ether, carbon tetrachloride, methylene chloride, tetrachloroethane or nitrobenzene with dichloromethane being the preferred solvent. The reaction time varies from about 1/2 hour to 25 hours at a temperature range of from 0*C to 400C. A preferred stirring 5 time is 6 hours. A preferred temperature is 40 0 C. The mixture of para, meta substituted w-halo-a-keto-benzeneacetic acid ester (2) is recovered from the reaction zone by an aqueous quench followed by extractive methods as are known in the art. Suitable Lewis acids for the acylation reaction described in step a are well 10 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 a is well known and appreciated by one of ordinary skill in the art 15 In step b of Scheme B, the mixture of meta- and para-substituted .- halo-a keto-benzeneacetic acid ester (2) is hydrolyzed to give a mixture of meta- and para substituted (cyclopropylcarbonyl)benzeneacetic acid (3). For example, the mixture of meta- and para-substituted w-halo-a-keto benzeneacetic acid (2) is contacted with a molar excess of an appropriate base such 20 as lithium hydroxide or potassium hydroxide in a suitable solvent such as ethanol. The reactants are typically stirred together for a period of time ranging from 1 to 24 hours at a temperature range of from 0*C to 78 0 C. A preferred stirring time is 18 hours. A preferred temperature is 25*C. The meta- and para-substituted (cyclopropylcarbonyl)benzeneacetic acid (3) is'recovered from the reaction zone by 25 acidification and extractive methods as are known in the art. Surprisingly, the substantially pure para isomer is readily isolated by subsequent crystallization as set forth in step c of Scheme B. For example, the product of the extractive methods as set forth in step b is dissolved in a suitable organic solvent such as a mixture of heptane/ethyl acetate 30 (ca. 4:1) with heating to reflux. The solution is treated with charcoal and filtered. Upon cooling, the resultant solid is collected and recrystallized from a suitable organic solvent such as ethyl acetate/heptane. Substantially pure para-substituted (cyclopropylcarbonyl)benzeneacetic acid (4) crystallizes upon standing at room -16 temperature. As shown previously herein, 4-(cyclopropylcarbonyl)benzeneacetic acid has utility as an intermediate in the synthesis of compounds of formula (I). 4 (Cyclopropylcarbonyl)benzeneaceic acid may also be used as an intermediate in the 5 process of preparing compounds of formula (7) as shown in Scheme C. Compounds of formula (7) include fexofenadine and related compounds.

SCHEME C 0 0 0 step a Istep b R 2 N ~ 'R 3 COOH C0 2 RI C0 2 R3 1 .2 3 stop c * R OH WN OH 4 N _ _ _ _ O R 1 N .! stepdR 3

R

2 5 OH. OH N stops 0 OR N U-I, OH OH &OH. 6 stop f N OH - N5 0

R

3

R

2 7 .is. In step a of Scheme C, the 4-(cyclopropylcarbonyl)benzeneacetic acid (1) is esterified to give the corresponding 4-(cyclopropylcarbonyl)benzeneacetic acid ester (2) wherein Ri is C-C 6 alkyl and the C-C 6 alkyl moiety is straight or branched, under conditions as set forth in Scheme A, Step E. 5 In step b of Scheme C, the 4-(cyclopropylcarbonyl)benzeneacetic acid ester (2) is alkylated with a suitable alkylating agent to provide a corresponding alkylated [4-(cyclopropylcarbonyl)phenyl]benzeneacetic acid ester (3) wherein

R

1 is as previously defined in step a and R 2 and R 3 are each independently

C

1

-C

6 alkyl wherein the C-C 6 alkyl moiety is straight or branched. 10 For example, the reaction is typically conducted in a suitable aprotic solvent in the presence of a suitable non-nucleophilic base. Suitable solvents for the alkylation reaction include diglyme, tetrahydrofuran, dioxane, or tert-butyl methyl ether. A preferred solvent is diglyme. Suitable non-nucleophilic bases for the alkylation reaction include sodium bis(trimethylsilyl)amide, inorganic bases, for example, 15 sodium bicarbonate, potassium bicarbonate, or hydrides, for example, sodium hydride or potassium hydride or alkoxides, for example, potassium tert-butoxide. A preferred base is potassium tert-butoxide. Suitable alkylating agents include alkyl halides, such as, iodomethane, chloromethane or bromomethane; or dialkylsulfates, such as, dimethylsulfate, or diethylsulfate. The reactants are typically stirred together 20 for a period of time ranging from 1 to 48 hours at a temperature range of from 0*C to 800C. In step c of Scheme C, the appropriate alkylated [4 (cyclopropylcarbonyl)phenyl]benzeneacetic acid ester (3) is ring opened to provide. the corresponding [4-(4-halo-1-oxo-butyl)phenyl] benzene acetic acid ester (4) 25 wherein

R

1 , R 2 and R 3 are as previously defined in step b and X is CI, Br or 1. The reaction occurs under conditions set forth in step G of Scheme A. In step d, the appropriate [4-(4-haIo-1-oxo-butyI)phenyl] benzene acetic acid ester (4) is alkylated with a-(4-pyridyl)benzhydrol to produce a [4-[4-[4 (hydroxydiphenylmethyl)-l-piperidinyl]-1-oxobutyl]phenyl]benzeneacetic acid ester 30 (5) wherein

R

1 , R 2 and R 3 are as previously defined in step b, under conditions that were previously disclosed in United States Patent No. 4,254,129, the disclosure of which is herein incorporated by reference. In step e of Scheme C, the appropriate [4-[4-[4-(hydroxydiphenylmethyl)-1- -19 piperidinyl]-1 -oxobutyl]phenyl]benzeneacetic acid ester (5) is reacted with a suitable reducing agent to produce a 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 piperidinyl]butylgbenzeneacetic acid ester (6) wherein R 1 , R 2 and R 3 are as previously defined in step b, under conditions that were previously disclosed in United States 5 Patent No. 4,254,129. Suitable reducing agents include, for example, sodium borohydride or potassium borohydride. Catalytic reduction using, for example, Raney nickel, palladium, platinum, or rhodium catalysts, may also be employed in step e of Scheme C. In step f of Scheme C, the 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 10 piperidinyl]butyl]benzeneacetic acid ester (6) is optionally hydrolyzed to produce the 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinylgbutyl]beneneacetic acid (7) wherein R 2 and R 3 are as previously defined in step b, under conditions that were previously disclosed in United States Patent No. 4,254,129. While not necessary for utilization in alkylation steps b and d, the keto 15 functionality of the 4-(cyclopropylcarbonyl)benzeneacetic acid ester (6) may be protected with a suitable protecting group. The selection and utilization .of.suitable protecting groups for the keto group of structure (6) is well known by one of ordinary skill in the art and is described in "Protective Groups in Organic Synthesis", Theodora W. Greene, Wiley (1981). For example, suitable protecting groups for the keto 20 functionality include acyclic ketals such as dimethyl ketal; cyclic ketals such as 1,3 dioxanes and 1,3-dioxalanes; acyclic dithioketals such as S,S-dimethyl ketal; cyclic dithio ketals such as 1,3-dithiane and 1,3-dithiolane derivatives; acyclic monothio ketals; cyclic monothio ketals such as 1,3-oxathiolanes. The following examples present typical syntheses as described in Schemes A 25 B and C. Starting materials for use in Schemes A, B and C are readily available to one of ordinary skill in the art. 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 (throughout the specification), the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL refers to milliliters; 30 "bp" refers to boiling point; "mp" refers to melting point;.""C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "pL" refers to microliters; "pg" refers to micrograms; and "pM" refers to micromolar.

-20 EXAMPLES OF SYNTHESIS SET FORTH IN SCHEME A Steo A: Preparation of N-Methoxy-N-methyl-belzeneacetamide Dissolve potassium carbonate (100 g, 720 mmol) in water (100 mL). Add a 5 solution of phenylacetyl chloride (50 g, 320 mmol) in toluene (250 mL). Then add a solution of N-0-dimethylhydroxylamine hydrochloride (32 g, 330 mmol) in water (100 mL) dropwise over one hour. After three hours, carefully add 10% hydrochloric acid (250 mL) and tert-butyl methyl ether (125 mL). Separate the organic phase, wash with 10% hydrochloric acid and saturated sodium hydrogen carbonate solution. Dry 10 over anhydrous magnesium sulfate and concentrate to give the title compound (55 g, 95%). Step B Preparation of [4-(4-Chloro-1 -oxobutvl)1-N-methOxv-N-methvI benzeneacetamide 15 Cool a slurry of aluminum chloride (87 g, 650 mmol) in methylene chloride (100 mL) with an ice bath. Add 4-chlorobutyryl chloride (51 g, 360 mL) dropwise over 0.5 hours. Add N-methoxy-N-methylbenzeneacetamide (53 g, 300 mmol) over 0.5 hours. Allow the resultant solution to warm to room temperature. Then heat at reflux for 6 hours. Cool the solution to room temperature. Pour the solution into ice (1L) 20 and add methylene chloride (1 L). Separate the organic phase. Extract the aqueous phase with methylene chloride (2 x 500 mL). Dry the combined organics over anhydrous magnesium sulfate and concentrate to provide a solid which contains a ca. 1:1 mixture of the title compound and the meta isomer. 25 Step : Cystallization of f4-(4-Chloro -1 -oxobutvI')l-N-nethox-N-meth vI benzeneacetamide Slurry the solid obtained in step B in heptane/ethyl acetate (ca. 4:1) and then collect it. Dissolve the solid in hot ethyl acetate and treat the resultant solution with ca. 5 g of charcoal. Filter through diatomaceous earth and add heptane (60 mL). 30 Heat the slurry until a homogenous solution is obtained. Allow the solution to stand ovemight at room temperature. Filter the resultant crystalline solid and wash with heptane to provide purified [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl benzeneacetamide (20 g). Allow the mother liquor to stand for 5 days and coHect a -21 second crop of the crystalline solid (3.0 g) to obtain a total of 23 g (28%) of the purified [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide. Step D: Preparation of 4-(Cyclopropylcarbonyl)benzeneacetic acid 5 Add purified [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide (9.4 g, 330 mmol) to a solution of potassium hydroxide (22.0 g) in ethanol (160 mL). Stir 18 hours. Pour the solution into dilute hydrochloric acid (30 mL of concentrated hydrochloric acid in 500 mL of water). Extract the solution with three 500-mL portions of ethyl acetate. Dry the combined organic phases over anhydrous io magnesium sulfate and concentrate to give the title compound (6.4 g, 95%). Step E: Preparation of 4-(cyclopropvlcarbonyl) benzeneacetic acid, ethyl ester Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in ethanol (150 mL) containing concentrated sulfuric acid (10 drops). Stir 24 hours. Add triethylamine 15 (2 mL) and concentrate the solution. Dissolve the residue in water/ethyl acetate. Wash the organic phase with saturated sodium hydrogen carbonate solution, dry over anhydrous magnesium sulfate and concentrate. Purify by silica gel chromatography (400 mL silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (7.0 g, 88%). 20 Step E: Preparation of 4-(cyclopropylcarbonyl) benzeneacetic acid, methyl ester Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid in methanol (100 mL) containing concentrated sulfuric acid (10 drops). Stir 24 hours. Add triethylamine (2 mL) and concentrate the solution. Dissolve the residue in water/ethyl acetate. Wash 25 the organic phase with saturated sodium hydrogen carbonate solution,. dry over anhydrous magnesium sulfate and concentrate. Purify by silica gel chromatography (400 mL silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (4.6 g, 68%). 30 Step F: Preparation of [4-(cyclopropvlcarbonvl)phenvllmethyl-propanedioic acid, diethyl ester Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid, ethyl ester (6.5 g, 28 mmol) and diethylcarbonate (4.0 g, 34 mmol) in tetrahydrofuran (100 mL). Add 62 -22 mL (62 mmol) of a 1.0 molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran over 0.5 hours. Stir 28 hours. Add iodomethane (5.3 g, 35 mmol). Stir 2 days. Add water and ethyl acetate. Wash organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (200 5 g silica gel, ethyl acetate/heptane as eluent) to give the title compound (1.43 g, 17%). Step F: Preparation of [4-(cvclopropvlcarbonvl)phenvlmethyl-propanedioic acid, dimethyl ester Dissolve 4-(cyclopropylcarbonyl)benzeneacetic acid, methyl ester (1.5 g, 6.0 10 mmol) and dimethylcarbonate (930 mg, 10.3 mmol) in tetrahydrofuran (10 mL). Add 20 mL (20 mmol) of a 1.0 molar solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran over 0.5 hours. Stir 3 days. Add iodomethane (5.3 g, 35 mmol). Stir 24 hours. Add water and ethyl acetate. Wash organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (50 15 g silica gel, ethyl acetate/heptane as eluent) to give the title compound (315 mg, 16%). Additionally, the following compounds can be prepared by the synthetic procedure depicted in Step F: 20 [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl methyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, methyl propyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl methyl diester [4-(cyclopropytcarbonyl)phenyl]methyl-propanedioic acid, methyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, hexyl methyl diester 25 [4-(cyclopropyicarbonyl)phenyl]methyl-propanedioid acid, ethyl propyl diester {4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl ethyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, ethyl hexyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dipropyl ester 30 [4-(cyclopropylcarbonyl)phenygmethyl-propanedioic acid, butyl propyl diester [4-(cyclopropylcarbonyl)phenyl]nethyl-propanedioic acid, pentyl propyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedoic acid, hexyl propyl diester [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dibutyl ester -23 [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, butyl pentyl diester [4-(cyclopropylcarbonyl)phenylgmethyl-propanedioic acid, butyl hexyl diester [4-(cyclopropylcarbonyl)phenylgmethyl-propfahedioic acid, dipentyl ester [4-(cyclopropylcarbonyl)phenyllmethyl-propanedioic acid, hexyl pentyl diester 5 [4-(cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, dihexyl ester [4-(cyclopropylcarbonyl)phenygethyl-propanedioic acid, diethyl ester [4-(cyclopropylcarbonyl)phenylethyl-propanedioic acid, dimethyl ester [4-(cyclopropycarbonyl)phenylethyl-propanedioic acid, ethyl methyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, methyl propyl diester 1o [4-(cyclopropylcarbonyl)phenylethyl-propanedioic acid, butyl methyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, methyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, hexyl methyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, ethyl propyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl ethyl diester 15 [4-(cyclopropylcarbonyl)phenylethyl-propanedioic acid, ethyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, ethyl hexyl diester. [4-(cyclopropylcarbonyl)phenylgethyl-propanedioic acid, dipropyl ester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl propyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, pentyl propyl diester 20 [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, hexyl propyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, dibutyl ester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, butyl hexyl diester [4-(cyclopropylcarbfonyl)phenyUethyl-propanedioic acid, dipentyl ester. 25 [4-(cyclopropylcarbonyl)phenylethyl-propanedioic acid, hexyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]ethyl-propanedioic acid, dihexyl ester [4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, diethyl ester [4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, dimethyl ester [4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, ethyl methyl diester 30 [4-(cyclopropylcarbonyl)phenylpropyl-propanedioic acid, methyl propyl diester [4-(cyclopropylcarbonyl)phenllpropyl-propanedioic acid, butyl methyl diester [4-(cyclopropylcarbonyl)phenyl]propyl-propanedioic acid, methyl pentyl diester [4-(cyclopropylcarbofnyl)phenyl]propyl-propanedioic acid, hexyl methyl diester -24-' 14 -(cyclop rop.ylcarbonyl)phenylPropyl-propafedioic acid, ethyl propyl diester [4-(cyclopropylcarbofy)phefl]propyl-propanioic id butyl ethyl diester [4-(cycIop ropylearbolyl)phelyl]propylropanedioic acid, ethyl pentyl d jester

[

4 -(cyclopropylcarboflyl)phefljlpropyl-ropanedioic acid, ethyl hexyl diester 5 [4-(cyclopropyl-arbofyl)phefyl]propyl-propanioic id dipropyl ester

-[

4 .. (cyclopropylcarboflYl)PhelIPropy[-propanedioic acid, butyl propyl diester

[

4 -(cyclopropylcarboflyl)phelyUPropy[-propanedioic acid, pentyl propyl diester

[

4 -. (cyclopropylcarboflpheflylpropylpropanedioic -acid, hexyl propyl diester

[E

4 (cyclopropylcarbbflyl)phelyl]propylIpropanedioic acid, dibutyl ester 10 [ 4 -(cyclopropylcarboflyl)phelyl]propylpropanedioic acid, butyl pentyl diester

[

4 -(Cyclopropylcarboflyl)pheflyUpr~opylropanedioic acid, butyl hexyl dieter

[

4 -. (cyclopropylcarboflYl)Phenyl]propyl-Propanedioic acid, dipentyl ester

E

4 -(cyclopropylcarboflyl)pheflyl]Propylpropanedioic acid, hexyl pentyl diester * [ 4 .. (cyclopropylcarboflyl)PheflylPropylpropanedioic acid, dihexyl ester 15 [ 4 (cyclopropylrcarboflyl)pheflbutylpropanedioic acid, diethyl* ester

[

4 -(yclopropylcarbonyl)pheflyl]butylpropanedioic acid, dimethyl ester

[

4 -(cyclopropylcarbonyl)phenybut ylpropanedioic acid, ethyl methyl diester

[

4 -;(cyclopropylcarboflyl)pheflyibutylfropanedioic acid, methyl propyl diester

*[

4 -. (cyclopropylcarboflyl)phenyl]butylpropanedioic acid, butyl methyl diester. 20 [ 4 -. (cyclopropylcarboflyl)phefllbutylpropanedioic acid, methyl pentyl diester.

[

4 -(cyclopropylcarboflyl)pheflyl]but~i-proPanedioic acid, hexyl methyl diester

I

4 -. (cyclopropylcarboflyl)phelyi~butylpropanedioic acid, ethyl propyl diester

[

4 .. (cyclopropylcarboflyl)pheflbutAl-Propanedioic acid, butyl ethyl diester

[

4 -(cyclopropylcarboflyl)phelbLutylpropanedioic acid, ethyl pentyl diester 2-5 [ 4 -(cycopropylcarbofyl)phenyl]buylpropanedioic -acid, ethyl heixyl d lester

[

4 -(cyclopropylcarbofl)pheflygbutlpropanedioic acid, d ipropyl ester

[

4 -(cyclopropylcarboflyl)pheflygbutyI-propanedioic acid, butyl propyl diester [4-(cyclop ropylcarboflyl)pheflyl]butyl-propanedioic acid, pentyl propyl diester

[

4 -(cyclopropylcarboflyl)phelyl]bLutyfIpropanedioic acid, hexyl propyl diester 30 [ 4 -(cycopropylcarboflyl)pheflylgutylproPanedioic acid., dibutyl ester

[

4 -(cyclopropycarboflyl)pheflyl]butyIpropanedioic acid, butyl pentyl d jester

[

4 -(cyclopropylcarboflyl)pheflyl]butylpropanedioic acid, butyl hexyl diester

[

4 -. (cyclopropylcarboflyl)pheflyl]butylpropanedioic acid, dipentyl ester -25 [4..(cyclopropylcarbolyl)PhelyIbutyl-propafedioic acid, hexyl pentyl d jester [4. (cyclopropylcarboflyl)pheflygbutyl-propafedioic acid, dihexyl ester [4-(cyclopropylcarboflyl)phefyl]peltyl-propafedioici, diethyl ester [4-(cyclopropylcarboflyl)phelyl]pefltyl-*propafedioic acid, d imethyl ester 5. [4-(cyclopropylcarbofly)phelpeltyl-propaledioic acid, ethyl methyl diester [4-(cyclopropylcarboflyl)phelyUpel-propafedioic acid, methyl propyl diester 14-(cyclopropcarboflyl)phely]petyl-propafledioic acid, butyl methyl diester [14-(cyclopropylcarboflyl)phelyJpetyl-*Pro* aedioic acid, methyl pentyl diester. 14 (cyclopropylcarboflyl)pheflyl]pefltyl-propafledioic acid, hexyl methyl diester 10 [4-(cyclopropylcarbofly)pheflyUpeftylfpropaflioic acid, ethyl propyl diester 1 4-(cyclopro'pylcarboflyl)phelyoeltyl-propaedioic acid, butyl ethyl diester. * j4(cyloprpyl~rbflylPhelyl]eflYI~rO~aled~icacid, ethyl pentyl diester 14-(cyclopropylcarboflyl)phely]petyl-propafedioic acid, ethyl hexyl diester 14-(cyclopropylcarbofl)phely]peltyl-propafedioic acid, dipropyl ester 15 [4-(cyclopropylcarboflyl)pheflyl]peftyl-propafledioic acid, butyl propyl diester [4-(cyclopropylcarboflyl)phelyUpefl-~propafldioic acid, pentyl propyl diester* [4-(cyclopropycarboflyl)pheflyl]peftyl-Propafedioic acid,. hexyl propyl diester [4-(cyclopropyicarboflyl)phelyl]pefltlpropanedioic acid', dibutyl ester [4-(cyclopropylcarboflyl)pheflyl]pefltyk-propaedioic acid, butyl pentyl diester 20 [4-(cyclopropyr-arboflyl)pheflyl]peftlpropanedioic acid, butyl hexyl diester [4-(cyclopropylcarboflyl)phefly]pefltylpropanedioic acid, dipentyl ester [4-{cyc opr 'opylcarboflyl)pheflyl]pefltyl-propafledioic acid, hexyl pentyl1 diester [4-(cyclopropylcarboflyl)pheflyl]peftl-pIropanedioic acid, dihexyl ester [4-(cyclopropylcarboflyl)pheflyl]hexylpropafedioic acid, diethyl ester 2.5 [4-(cycl opropyIcarboflyl)pheflyghexyl-propafedioic acid, dimethyl ester [4-(cyclopropylcarboflyl)pheflyghexylpropafedioic acid,' ethyl methyl diester [4-(cyclopropylcarboflyl)pheflyqhexylfpropafedioic acid, methyl propyl diester [4-*(cyclopropylcarboflyl)pheflyhexylpropanedioic acid, butyl methyl diester [4-(cyclopropylcarboflyl)phefyhexylpropanedioic acid, methyl pentyl diester 30 [4-(cyclopropylcarboflyl)p heflyhexylkpropafedioic acid, hexyl methyl d jester [4-(cyclopropylcarbofyl)phefyl]hexyI-propanedioic acid, ethyl propyl d iester [4-(cyclopropylcarboflyl)pheflyl]hexylkpropafedioic acid, butyl ethyl diester 14-(cycloropylcarboflyl)pheflyl]hexyl-propanedicic acid, ethyl pentyl d jester -26 [4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, ethyl hexyl diester [4-(cyclopropylcarbonyl)phenyl]hexyl-propanediOic acid, dipropyl ester [4-(cyclopropycarbonyl)phenyl]hexyl-propanedioic acid, butyl propyl diester [4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, pentyl propyl diester 5 [4-(cyclopropylcarbonyl)phenylghexyl-propanedioic acid, hexyl propyl diester [4-(cyclopropycarbonyl)phenyl]hexyl-propanedioic acid, dibutyl ester [4-(cyclopropylcarbonyl)phenyl~hexyl-propanedioic acid, butyl pentyl diester [4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, butyl hexyl diester [4-(cyclopropycarbonyl)phenyl]hexyl-propanedioic acid, dipentyl ester 10 [4-(cyclopropylcarbonyl)phenyl]hexyl-propanedioic acid, hexyl pentyl diester [4-(cyclopropylcarbonyl)phenylghexyl-propanedioic acid, dihexyl ester Step G: Preparation of [4-(4-chloro-1 -oxobutvl)phenvllmethyl-propanedioic acid. diethyl ester 15 Bubble hydrogen chloride gas through a solution of [4 (cyclopropylcarbonyl)phenyl]methyl-propanedioic acid, diethyl ester (570 mg, 2.0 mmol) in ethanol (4 mL) for 5 minutes. Heat the solution to reflux. After 18 hours, cool the solution to room temperature and bubble nitrogen through the solution for 1 hour. Add ethyl acetate and water to the residue. Dry the organic 20 phase over anhydrous magnesium sulfate and concentrate. Dissolve the crude product in ethanol (50 mL) and bubble hydrogen chloride gas through the solution for 10 minutes. Heat the solution to reflux. After stirring 2 days, concentrate the solution. Add water and ethyl acetate to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (150 25 g silica gel, 20% ethyl acetate/heptane as eluent) to give the title compound (409 mg, 59%). Step G: Preparation of f4-(4-chloro-1-oxobutvl)phenyllmethyl-propanedioic acid, dimethyl ester 30. Bubble hydrogen chloride gas through a solution of [4 (cyclopropylcarbonyl)phenylmethyl-propanedioic acid, dimethyl ester (315 mg, 1.1 mmol) in ethanol (3 mL) and toluene (9 mL) for 10 minutes. Heat the solution to 68 0 C. After 4 hours, cool the solution to room temperature and bubble nitrogen -27 through the solution for 1 hour. Add ethyl acetate and water to the residue. Dry the organic phase over anhydrous magnesium sulfate and concentrate to give the title compound (321 mg, 91%). 5 Additionally, the following compounds can be prepared by the synthetic procedure depicted in Step G: [4-(4-bromo-1 -oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester [4-(4-iodo-1 -oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester [4-(4-bromo-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester 10 [4-(4-iodo-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester Furthermore, compounds derived from all permutations of substituents as set forth in the illustrative examples following Step F can be prepared by the synthetic procedure depicted in Step G. i5 Step H: Preparation of [4-4-r4-(hydroxydiphenlmethyl)-1-iperidinvil-1 oxobutvilohenvmethyl-propanedioic acid; diethyl ester Mix together [4-(4-chloro-1 -oxobutyl)phenyl]methyl-propanedioic acid, diethyl ester (380 mg, 1.1 mmol), potassium carbonate (450 mg, 3.2 mmol), a-(4 pyridyl)benzhydrol (500 mg, 1.9 mmol), water (4 rmL) and toluene (10 mL). Heat the 20 mixture to reflux. After 7 days, cool to room temperature. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (200 g of silica gel, 10% methanol/chloroform as eluent) to give the title compound (627 mg, 99%). 25 Step H: Preparation of [4-[4-r4-(hydroxydiphenvlmethyl)-1-piperidinvl-1 oxobutvllphenyllmethyl-propanedioic acid, dimethyl ester Mix together [4-(4-chloro-1 -oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester (300 mg, 0.92 mmol), potassium carbonate (350 mg, 2.5 mmol), a-(4 pyridyl)benzhydrol (500 mg, 1.9 mmol), water (3 mL) and toluene (7 mL). Heat the 30 mixture to reflux. After 5 days, cool to room temperature. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (150 g of silica gel, 10% methanol/chloroform as eluent) to give the title compound (387 mg, 76%).

-28 Additionally, compounds derived from all permutations of substituents as set forth in the illustrative examples following Step F can be prepared by the synthetic procedure depicted in Step H. 5 Step 1: Preparation of 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyllbutyl] a-(hydroxymethyl)-a-methyl-benzeneacetic acid, ethyl ester Dissolve [4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 oxobutyljphenyl]methyl-propanedioic acid, diethyl ester (515 mg, 0.88 mmol) in tetrahydrofuran (5 mL) and cool the solution with an ice bath. Add lithium tri-tert 10 butoxyaluminohydride (10 mL of a I molar solution in tetrahydrofuran, 10 mmol) portionwise over 20 minutes. After 2 hours, allow the solution to warm to room temperature. After 48 hours, cool the solution with an ice bath and add a 10% potassium hydrogen sulfate aqueous solution (10 mL). Wash the organic phase with brine, dry over anhydrous magnesium sulfate, and concentrate. Purify by flash 15 chromatography (150 g of silica gel, 5% methanoVchloroform as eluent) to give the compound (321 mg, 67%). Additionally, the following compounds can be prepared by the synthetic procedure depicted in Step 1: 20 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)l--piperidinyl]butyl]-a-(hydroxymethyl)-a methyl-benzeneacetic acid, methyl ester 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinylbutyl]-a-(hydroxymethyl)-a methyl-benzeneacetic acid, propyl ester 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]butyl]-a-(hydroxyrhiethyl)-a 25 methyl-benzeneacetic acid, butyl ester 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-l -piperidinyl]butyl]-a-(hydroxymethyl)-a methyl-benzeneacetic acid, pentyi ester 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]butyl]-a-(hydroxymethyl)-a methyl-benzeneacetic acid, hexyl ester 30 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]butyl]-a-(hydroxymethyl)-a ethyl-benzeneacetic acid, methyl ester 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a ethyl-benzeneacetic acid, ethyl ester -29 4-[l -hydroxyA-[4-(hydroxydiphelylmethyD-l -piperidinyl]butyl]-a-(hydroxymethyl)-a ethyl-benzefleaceti~c acid, propyl ester 4-[l -hydroxy-4-[4-(hydroxydiphelmlethyl)-1 -piperidinyl]butyl]-a-(hydroxyflethyl)-a-' ethyl-benzefleacetic acid, butyl ester 5 4-[l -hydroxy-4-[4-(hydroxydipheflylmlethyl)-1-piperidinyljbutyl]-Q-(hydroxymethYl)-a ethyl-benzefleacetic acid, pentyl ester 4-[l -hydroxy-4-[4.(hydroxydiphelylmethyl)-1 -piperidinyl]butyl]-a-(hydroxyflethyl)-a-. ethyI-benzefleacetic acid, hexyl ester 4-[1 -hydroxy-4-[4-(hydroxydiphelylmethyl)-l-piperidinyI]outyl]-a-(hyd roxymethy l)-a 10 propyl-beflzefeac eic acid, methyl ester 4-[1 -hydroxy-4-[4-(hydroxydipheflylmethyl)-l -piperidinylgbuty]-a.-(hydroxyrnethyl)-a propyI-benzefleacetic acid, ethyl ester 44 hoc--4-[ly royihnlehl 1 piperidiny]butyI]-cI-(hydroxyrfethyl)-a pro*yl-benzefleacefic acid, propyl ester 15 4-[l -hydroxy-4-[4-(hydroxydiphefly~nethl)l piperidiny[butyC-(hydroxy'methy) a propyl-benzefleacetic acid, butyl ester 4-El -hydroxyA 4(hydroxydiphenlmethyl)-l -piperidinygbutyU-a-(hydroxymethy) propyI-benzefleacetic acid, pen tyl ester 4-El -hydroxy-4-[4-(hydroxydipheflmethyll piperidinygbutyI]-a-(hyd roxymethyl)-a-. 20propyI-beflzefeacetic acid, hexyl ester 4-El -hydroxy-4-[4-(hydroxydiphenyimethy)-l piperidinyl]butyl]-a-(hyd roxymet hyt)-a butyI-benzefleacetic acid, methyl ester 4-El -hydroxy-4-[4-(hydrokydiphenylmethyl)-l -piperidinygbutyq-O-(hydroxymfethyl)-a butyl-benzefleacetic acid, ethyl ester 25 4-[l -hydroxy-4-[4-(hydr~oxydiPheflmethyl)-l -piperidinyl]butyl]-(hydroxymethyl) butyl-benzeneacetic acid, propyl ester 4-El -hydroxy4-[4{hydroxydiphenylmethy)-1 -piperidinyl]butyl]-a-(hydroxymethyl)-a butyl-beflzefeacefic acid, butyl ester 4-1 .. hydroxy-44(hydroxydipheflymethyl)-1 -piperidinylbuty]-a-(hyd roxymethyl)-z 30o butyl-benzefleacefic acid, pentyl ester 4-El -hydroxy-4- 4-(hydroxydipheflylmethyl)1 -piperdinyl]butyl-a-(hyd roxymethyl)-a butyl-benzeneacetic acid, hexyl ester 4-El -hydroxy4-[4-(hydroxydiphenymrethyl)- -piperidinyl~butyl]-a-(hyd roxymethyl)-z- -30 pentyl-benzeneacetic acid, methyl ester 4-[I-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]buty]-a-(hydroxymethyl)-o pentyl-benzeneacetic acid, ethyl ester 4-[L-hydroxy-4-[4-(hydroxydiphenylmethyl)-i-piperidinylbutyl]-a-(hydroxymethyl)-a 5 pentyl-benzeneacetic acid, propyl ester 41-hydroxy-4-4-(hydroxydiphenylmethyl)-1-piperdinyl]butyl]-a-(hyd rxymethyl)-a pentyl-benzeneacetic acid, butyl ester 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a pentyl-benzeneacetic acid, pentyl ester 1o 441-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]buty-a-(hydroxymethyl)-a pentyl-benzeneacetic acid, hexyl ester 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyq-a-(hydroxymethyl)-a hexyl-benzeneacetic acid, methyl ester 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]butyl-a-(hydroxymethyl) 15 hexyl-benzeneacetic acid, ethyl ester 4-[1-hydroxy-4-[4-(hydroxydiphenymethyl-pipeidiny butyl-a-(hydroxymethyl)-a hexyl-benzeneacetic acid, propyl ester 4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]buty]-a-(hydroxymethyl)-a hexyl-benzeneacetic acid, butyl ester 20 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-i-piperdinyl]buty]-a-(hydroxymethyl)hexyl-benzeneacetic acid, pentyl ester 4-[L-hydroxy-444-(hydroxydiphenylmethyl)-l-piperidinyl]butyl]-a-(hydroxymethyl)-a hexyl-benzeneacetic acid; hexyl ester 25 Step J: Preparation of 4-[1-hvdroxV-4-l4-(hydroxydiphenylmeth I -Diperidinyllbuti -a-(hydroxmethl)methlbenzeneacetic acid Dissolve 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a (hydroxymethyl)-a-methyl-benzeneacetc acid, ethyl ester (200 mg, 0.37 mmol) in methanol (8 mL) and tetrahydrofuran (12 mL). Add 1.6 mL (1.6 mmol) of a 1 molar 30 solution of aqueous sodium hydroxide. After 4 hours, cool the solution to room temperature and add 10% hydrochloric acid (ca. 1 mL) dropwise until pH is 5-6. Concentrate the solution and purify by flash chromatography (50 g of silica gel, methanol/chloroform gradient elution) to give the title compound (127 mg, 66%).

-31 Additionally, the following compounds can be prepared by the synthetic procedure depicted in Step J: 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a 5 ethyl-benzeneacetic acid 4-[l-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a propyl-benzeneacetic acid 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a butyl-benzeneacetic acid 10 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a pentyl-benzeneacetic acid 4-[i-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a hexyl-benzeneacetic acid 15 EXAMPLES OF SYNTHESIS SET FORTH IN SCHEME B To a slurry of AIC1 3 (210 g, 1.6 mol) in methylene chloride (200 mL).cooled in an. ice bath is added 4-chlorobutyryl chloride (121 g) dropwise while maintaining the pot temperature below 10C. After 10 minutes, ethyl benzeneacetic acid (118 g, 0.72 20 mol) is added dropwise maintaining the pot temperature below 10*C. The mixture is stirred at room temperature for 1 hour, then heated to 400C. After 4 hours, the solution is cooled to room temperature and poured onto crushed ice (2L). Methylene chloride (IL) is added. The organic phase is separated. The aqueous phase is extracted with two 1 L portions of methylene chloride. The combined organics are 25 dried (MgSO4) and concentrated. Toluene (1L) is added and the solution is concentrated to ca. 500 mL. Ethanol (500 mL) is added. The solution is heated to 700C and HCI (g) is bubbled through for 20 minutes. The solution is sparged with N 2 and concentrated. Chromatography through silica gel (2.5 L) using an ethyl acetath/heptane gradient gives a 1:1 mixture of meta, para ethyl (4-chloro-1 30 oxobutyl)benzene acetic acid (119 g). To a slurry of LiOH (23.5g, 0.56 mol) in water (100 mL) and ethanol (100 mL) is added the 1:1 mixture of meta, para ethyl (4-chloro 1-oxobutyl)benzene acetic acid (50g, 0.19 mol). The reaction becomes exothermic and is cooled with an ice bath. After 1 hour, the solution is allowed to warm to room -32 temperature. After 18 hours, the mixture is concentrated. Water (400 mL) and conc. HCI are added (until pH 4). Ethyl acetate (600 mL) is added. The organic phase is separated,. washed with brine and dried (MgSO4). The solution is heated on a steam bath and charcoal (ca. 3 g) is added. The mixture is filtered through Celite and 5 concentrated. The residue is dissolved in ethyl acetate (300 mL) and heptane (600 mL) with heating. Seed crystals are added. After cooling an organic oil appears. Heptane (500 mL) is added and the mixture is heated to reflux, treated with charcoal (ca. 5 g), filtered and seeded. A solid forms and is collected. 1 H NMR shows ca. 4:1 mixture of para:meta isomers. Recrystallization from ethyl acetate/heptane gives 4 10 (cyclopropylcarbonyl)benzeneacetic acid (4.3g, 11 %). EXAMPLES OF SYNTHESIS AS SET FORTH IN SCHEME C Step a: Preparation of 4-(cyclopropylcarbonyl) benzeneacetic acid, ethyl ester 15 See preparation under Step E, Scheme A, disclosed previously herein. Step b: Preparation of [4-(cyclopropvlcarbonyDl--a-dimethylbenzeneacetic acid, ethyl ester In a 2L, glass, jacketed reactor is loaded the 4-(cyclopropylcarbonyl) . 20 benzeneacetic acid, ethyl ester (232 g, I mole), diglyme (150 mL) and-methyl chloride (127 g, 2.5 mole). In a heated addition vessel is loaded potassium tert butoxide (182.4 g, 1.6 mole) and diglyme (1050 mL). The jacket for the reactor is set at -10 0 C and the addition vessel contents are heated to 60 0 C. The base solution is added to the reactor at a rate which keeps the intemal temperature of the reaction 25 below 25*C. After the base addition; sodium ethoxide as a 21 % solution in ethanol (86 g, 0.3 mole) is added to quench any excess methyl chloride. The entire reaction mixture is then agitated with toluene (900 mL) and water (1200 mL) containing sodium bicarbonate (8.4 g). The phases are separated and the organic layer is washed with additional water (200 mL) to remove any residual potassium chloride 30 salts. Without phase separating, the entire solution is then acidified to pH=3 with concentrated HCI. The organic is then stripped of solvents to afford the title compound.

-33 Step c: Preparation of 4-(4-chloro-1 -oxobuty)-a,a-dimethylbenzeneacetic acid. ethyl ester To a 4L reactor equipped with a gas inlet, overhead stirrer and temperature control, is charged [4-(cyclopropylcarbonyl)]-a,a-dimethylbenzeneacetic acid, ethyl 5 ester (500 g). The oil is heated to 60 0 C and the head space is evacuated. HCI is then added raising the pressure to 10 psig. After 4 hours, the excess HCI is vented and the oil is sparged with nitrogen for 5 minutes. Step d: Preparation of Ethyl 44-[4-(hvdroxvdiphenylmethyl-1-piperidinvll-1 1o oxobutyl1-a-a-dimethVbenzeneacetate hydrochloride According to the described procedure of Carr et al., United States Patent No. 4,254,129, a mixture of 4.5 g (0.0163 mole) of a,a-diphenyl-4-piperidemethanol, 6.1 g (0.0205 mole) of ethyl 4-(4-chloro-1-oxobuty)-a,a-dimethylphenylacetate, 5 g (0.05 mole) of potassium bicarbonate and 0.05 g of potassium iodide in 50 ml of toluene is 15 stirred and refluxed for 72 hours then filtered. Ether then ethereal hydrogen chloride is added to the filtrate, and the resulting precipitate collected and recrystallized several times from methanol-butanone and butanone to give ethyl 4-[4-[4 (hydroxydiphenylmethyl)-l-piperidinyl]-1 -oxobutyl]-a,a-dimethylbenzeneacetate hydrochloride. M.P.205.5*-208 0 C. 20 Step e: Preparation of Ethyl 4-[4[4-(hydroxvdiphenylmethyl)-1 -piperidinvln-1 hydroxvbutvll-a,a-dimethylbenzeneacetate According to the described procedure of Carr et al., United States Patent No. 4,254,129, a solution of 5.64 g (0.01 mole) of ethyl 4-[4[4-(hydroxydiphenylmethyl)-1 25 piperidinyl]-1-oxobutyl]-a,a-dimethylbenzeneacetate hydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and 0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 hour until the infrared shows no evidence of a ketone carbonyl function. The solution is filtered and the filtrate concentrated leaving a residue which is recrystallized from butanone and methanol-butanone to give ethyl 4 30 [4[4-(hydroxydiphenylmethyl)-1-peperidiny]-1-hydroxybuty]-a,a dimethylbenzeneacetate HCl, M.P. 185*-187*C.

-34 Step f: 4-r4I4-(Hydroxydiphenvlmethyl)-1-piperidinyl-1 -hydroxvbutyll-a,a dimethylbenzeneacetic acid According to the described procedure of Carr et al., United States Patent No. 4,254,129, to a solution of 0.6 g of ethyl 4-[4[4-(hydroxydiphenylrmethyl)-1 5 piperidinyl]-hydroxybutyl]-a,a-dimethylbenzeneacetate in 20 ml of absolute ethanol is added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3 1/2 hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 10% Aqueous HCI is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added. The resulting 1o precipitate is recrystallized from methanolbutanone to give 4-[4[4 (hydroxydiphenylmethyl)-l-piperidinyl]-1-hydroxybutyl]-a,a-dimethylbenzeneacetc acid, M.P. 195*-197*C. The piperidine derivative of formula (I) is used according to the present is invention as a histamine Hrreceptor antagonist and as such will provide relief of symptoms associated with histamine-mediated allergic disorders in patients suffering therefrom. Histamine-mediated allergic disorders are diseases or conditions which have a histamine-mediated allergic component such as, for example, seasonal allergic rhinitis, perennial rhinitis, idiopathic urticaria, asthma and the like. Relief of 20 symptoms of an allergic disorder by treatment according to the present invention refers to a decrease in symptom severity over that expected in the absence of treatment and does not necessarily indicate a total elimination of the disease. Antihistaminic potential is measured by affinity of a test compound for [ 3 H] pyrilamine binding sites associated with the antagonist component of H 1 25 histaminergic receptors in animal brain membranes. Affinity for this receptor is indicative of the potential of a test compound to interact with central and peripheral Hr-histaminergic receptors. The following method is used to determine the affinity of test compounds for.

[

3 H] pyrilamine binding sites in rat cortex. 30 The brains of young male rats are removed. The cortici are dissected and stored at -20*C or immediately used. The tissue is homogenized in 10 ml of ice-cold 50 nM K/NaPO4 buffer (pH 7.4) using a Polytron (setting 6 for 15 seconds). The homogenate is centrifuged at 40,000 g for 15 minutes at 4 0 C. The pellet is resuspended in the same buffer in order to have 100 mg wet weight/ml buffer. The incubation tubes contain 50 mM K/NaPO 4 buffer, promethazine -(2.10-6M final) or test compound, 3 H pyrilamine (2 nM final) and homogenate (10 mg wet weight per tube) in a final volume of 250-1000 ml. After a 30 minute incubation at room temperature 5 each incubation is terminated by rapid filtration through Whatman GF/B glass fiber filters, presoaked in water when using a Brandel cell harvester, or used as such when the filtration is performed with a 96 well Skatron cell harvester. The filters are rinsed with 3 x 3 ml 0.9% NaCl (Brandel) or prewetted and rinsed for 10 sec with NaCl (Skatron). The filters are either transferred to scintillation vials and 10 ml 10 Quicksafe A is added for liquid scintillation spectrometry or a thin layer of solid scintillant is melted onto the filters and the filters then counted using a betaplate beta counter. Specific binding of 3 H pyrilamine is measured as the excess over blanks taken in the presence of 2.10-6 M promethazine. Protein content of the membranes is determined by the method of Lowry et al., J. Biol. Chem. 193, 265-275 (1951). 15 Displacement curves are analyzed using the GraphPad (GraphPad Software, Inc.) or similar program to obtain Hill slopes and ICso values. The Ki value is then determined with the Cheng-Prusoff equation described by Cheng et al., in Biochem. Pharmacol., 22, 3099-3108 (1973), using the KD for 3 H pyrilamine as obtained from previous saturation experiments performed under the same conditions. 20 The K for 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyl}-a (hydroxymethyl)-a-methyl-benzeneacetic acid is 3.6 x 107 indicating that the piperidine derivative of formula (I) is useful for the treatment of histamine-mediated allergic disorders. As used herein, the term "patient" refers to an adult person who is suffering 25 from a histamine-mediated allergic disorder. It is understood that for purposes of the present invention, the term "adult" refers to a person of 12 years of age or older who would typically be treated for allergic disorders with an antihistamine dosage as recommended for adults. The identification of those patients who would benefit from the present 30 invention is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination and medical/family history, those patients who are suffering from an allergic disorder that is histamine-mediated.

-3& The quantity of novel compound administered will vary depending on the mode of administration and can be any effective antiallergic amount. The quantity of novel 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 5 patient per day to achieve the desired effect. For example, the desired antihistamine, antiallergy and bronchodilator effects can be obtained by administering the piperidine compound of formula (I) to a patient in a daily amount of from about 10 mg to about 50 mg. A preferred daily dose is from about 20 rig to about 40 mg. The most preferred daily dose is about 30 mg. .1 it is of course understood that the daily dose may be administered to a patient according to a dosage regimen in single or multiple dosage units. For example, a daily dose may be administered in a regimen requiring one, two, three, or four unit doses. Typically, these unit doses will be of equal strength and will be administered on a time schedule so that each dose is approximately equally spaced throughout the 15 day. For example, a daily dose requiring a once a day dosage regimen may be administered about every 24 hours; a daily dose requiring a twice-a-day dosage regimen. may be administered about every 12 hours; a daily dose requiring a three times-a-day dosage regimen may be administered about every 8 hours; a daily dose requiring a four times-a-day dosage regimen may be administered about every 6 .20 hours. The piperidine derivative of formula (1) can be administered according to the present invention in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, the piperidine derivative of formula (I) can be administered orally, subcutaneously, transdermally, 25 intranasally, and the like. Oral administration is preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disease state to be treated, the stage of the disease, and other relevant circumstances. The compounds can be administered alone or in the form of a pharmaceutical 30 composition with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration and standard pharmaceutical practice. The piperidine derivative of formula (1), while effective itself, may be formulated and administered in the form of its -37 pharmaceutically acceptable acid addition salt for purposes of stability, convenience of crystallization, increased solubility and the like. In addition, an individual polymorph, solvate, or individual stereoisomer of the piperidine derivative of formula (1) [i.e, (R,R)-4-[1-hydroxy-4-[4-(hydroxydiphenymethyl)-1-piperidinyl]butyl]-a 5 (hydroxymethyl)-a-methyl-benzeneacetic acid; (R,S)-4-[1-hydroxy-4-[4 (hydroxydiphenylmethyl)-1 -piperidinyl]butyl]-a-(hydroxymethyl)-a-methy benzeneacetic acid; (S,S)-4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-1 piperidinyljbutyl]-a-(hydroxymethyl)-a-methyl-benzeneacetic acid and (S,R)-4-[1 hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-a-(hydroxymethyl)-a 10 methyl-benzeneacetic acid] may be used. The present invention contemplates compositions comprising the piperidine derivative of formula (1) in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions. An is assayable amount of the piperidine derivative of formula (I) is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of the piperidine derivative of formula (I) will generally vary from about 0.001 % to about 75% of the composition by weight Inert carriers can be any material which does not 20 degrade or otherwise covalently react with the piperidine derivative of formula (I). Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients. 25 More particularly, the present invention contemplates a pharmaceutical composition in solid unit dosage form comprising an amount of the piperidine derivative of formula (I) from about 15 mg to about 30 mg in admixture with a pharmaceutically acceptable carrier. As used herein, the term "solid unit dosage form" contemplates a solid dosage form for oral administration such as a tablet, 30 capsule, and the like, as well as solid dosage forms for parenteral administration such as a transdermal patch, and the like. The pharmaceutical compositions are prepared in a manner well known in the -38 pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in.the 5 form of tablets, capsules, solutions, suspensions, transdermal patch, and the like. The piperidine derivative of formula (I) may be administered orally, for example, with an inert diluent or with an edible carrier. It may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the piperidine derivative of formula (1) may be incorporated with 10 excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of the invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between about 4% to about 70% of the weight of the unit. The amount of the compound present in compositions is 15 such that a suitable dosage will be obtained upon administration. Preferred compositions and preparations according to the present invention are prepared so that an oral unit dosage form contains between about 15 mg to about 30 mg. Most preferred unit doses for oral administration are those which contain about 15 mg to about 30 mg. 20 The tablets, pills, capsules, and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel T m , com starch, carbonate salts such as sodium bicarbonate or calcium carbonate, and the like; lubricants such as magnesium stearate or Sterotexm; 25 glidents such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify 30 the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills . may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing -39 these various compositions should be pharmaceutically pure and non-toxic in the amounts used. Preferred excipients are corn starch, gelatin, lactose, magnesium stearate and sodium bicarbonate. Oral unit dosage forms may be formulated to provide immediate or sustained 5 release characteristics. These forms may be formulated according to conventional techniques and procedures to give the desirable dissolution and bioavailability characteristics. In addition, the piperidine derivative of formula (1) may be incorporated into a solution or suspension for oral or parenteral administration. These preparations io should contain at least 0.1% of the piperidine derivative of formula (1), but may be varied to be between 0.1 and about 50% of the weight thereof. The amourit of the piperidine derivative of formula (1) in such compositions is such that a suitable dosage will be obtained upon oral or parenteral administration. 15 The solutions or suspensions may also include the one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene 20 diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. Transdermal dosage forms for administering the piperidine derivative of formula (I) can be prepared by conventional techniques well known in the art of pharmaceutical science such as by incorporating the piperidine derivative of formula 25 (1) into various polymeric reservoir matrix materials. These polymeric matrix materials may include pressure sensitive acrylic, silicone, polyurethane, ethylene vinyl acetate copolymers, polyolefins, and rubber adhesive matrices, medical grade silicone fluids, and medical grade silicone elastamers, which are well known in the art for forming reservoirs for transdermal delivery of drugs. 30 It is further contemplated that the piperidine derivative of formula (1) according to the present invention, may be formulated with a. variety of other active ingredients which -40 are commonly combined with antihistamines, such as a decongestant, including pseudoephedrine and the like; analgesics such as acetaminophen and the like, non steroidal anti-inflammatory agents such as ibuprofen and the like. Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

Claims (18)

1. A process for preparing a compound of the formula 0 5 CO 2 R 1 wherein R 1 is C 1 -C 6 aIkyI and the C 1 -C 6 alkyI moiety is straight or branched: comprising the steps of: (a) reacting a benzene acetic acid ester of the formula 10 CO 2 R 1 wherein R 1 is C 1 -C 6 alkyl and the C 1 -C 6 alkyI moiety is straight or branched; with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para and meta substituted w-halo-a-keto-benzeneacetic acid ester of the 15 formula 0 x Co 2 R 1 wherein R 1 is as previously defined herein and X is CI, Br, or 1; (b) hydrolyzing the mixture of para and meta substituted (w-halo-a-keto 20 substituted benzene acetic acid to provide a mixture of para and meta substituted (cyclopropylcarbonyl)benzene acetic acid ester of the formula 0 CO 2 H and SPEC-794121 JOL30.8.10 - 42 (c) selectively crystallizing and isolating the substantially pure 4 cyclopropylcarbonyl)benzene acetic acid.

2. A process according to claim 1 wherein X is Cl. 5

3. A process for preparing a compound of the formula 0 N x 0 wherein X is Cl, Br, or 1; comprising the steps of: 10 (a) reacting a compound of the formula N 0 with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para- and meta- substituted (4-halo-1-oxobutyl)-N-methoxy-N-methyl benzeneacetamide of the formula 0 ' N11o x 15 0 wherein X is Cl, Br, or 1; (b) selectively crystallizing and isolating substantially pure [4-(4-halo-1 oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide of the formula 0 N'N 20 0 wherein X is Cl, Br, or 1.

4. A process according to claim 3 wherein the 4-halo-substituted butyrylhalide is 4 25 chlorobutyrylchloride. SPEC-794121 JOL 30.III - 43 5. A process according to claim 4 wherein the [4-(4-halo-1-oxobutyl)]-N-methoxy-N methyl-benzeneacetamide is [4-(4-chloro-1 -oxobutyl)]-N-methoxy-N-methyl benzeneacetamide.

5

6. A process for preparing a compound of the formula OH OH N OH / --- R 2 wherein R 1 is H or C 1 -Cealkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; 10 R 2 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; comprising: (a) reacting a compound of the formula N 15 0 with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para- and meta- substituted (4-halo-1-oxobutyl)-N-methoxy-N-methyl benzeneacetamide of the formula 0 x 0 20 wherein X is Cl, Br, or 1; (b) selectively crystallizing and isolating substantially pure [4-(4-halo-1 oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide of the formula SPEC-794121 JOL 30.9.10 - 44 0 N x 0 wherein X is Cl, Br, or 1; (c) hydrolyzing the substantially pure [4-(4-halo-1-oxobutyl)]-N-methoxy-N 5 methyl-benzeneacetamide to provide a (cyclopropylcarbonyl)benzeneacetic acid of the formula 0 OH (d) esterifying the (cyclopropylcarbonyl)benzeneacetic acid to provide a (cyclopropylcarbonyl)benzeneacetic acid ester of the formula 0 OR, 10 0 wherein R 1 is C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; (e) acylating the (cyclopropylcarbonyl)benezeneacetic acid ester to provide a [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula 0 R1 15 R 2 2 C 2R3 wherein R 1 is H; R 2 and R 3 are each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; 20 (f) optionally alkylating the [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester to provide a [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula SPEC-794121 JOL 30.. 10 -45 0 R x R 2 0 2 C Co 2 R 3 wherein R 1 is C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched and R 2 and R 3 each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or 5 branched; (g) reacting the [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula 0 R1 R2O2C C0 2 R 3 wherein 10 R 1 is H or 0 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched R 2 and R 3 are each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched, with a suitable hydrogen halide to produce a [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester of formula 0X x R1 15 R 2 02C CO2R3 wherein R, is H or C 1 -C 6 alkyl wherein the 0 1 -C 6 alkyl moiety is straight or branched; R 2 and R 3 are each independently C 1 -C 6 alkyl wherein the 0 1 -C 6 alkyl moiety is straight or branched; 20 X is Cl, Br, or I; (h) reacting the [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester with a compound of formula SPEC.794121 JOL 311111 - 46 OH H N to produce a [4-[4-[4-(hydroxydiphenylmethyl)- 1-piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester compound of formula OH 0 N R1N R 2 0 2 C CO 2 R 3 5 wherein R 1 is H or C 1 -C 6 alkyI wherein the C 1 -C 6 alkyl moiety is straight or branched; R 2 and R 3 are each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; 10 (i) reacting the [4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 oxobutyl]phenyl]propanedioic acid diester compound with a suitable selective reducing agent to give a 4-[1 -hydroxy-4-(4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyl]-a (hydroxymethyl)-benzeneacetic acid ester compound of formula OH OH N OH / R1 R2 15 wherein R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; R 2 is -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; and SPEC-794121 JOL 30.. 10 - 47 (j) optionally hydrolyzing the 4-[1 -hydroxy-4-[4-(hydroxydiphenylmethyl)-1 piperidinyl]butyl]-a-(hydroxymethyl)-benzeneacetic acid ester compound to produce a compound of formula OH OHN N OH R, R2 5 wherein R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; R 2 is -COOH; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; 10 with the proviso that each of the keto groups present in the compounds described in steps c-h are optionally protected or unprotected.

7. A process according to claim 6 wherein the [4-(4-halo-1-oxobutyl)]-N-methoxy-N methyl-benzeneacetamide of step c) is [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl 15 benzeneacetamide.

8. A process according to claim 6 wherein R 1 of the compound produced in step j) is methyl. 20

9. Use of the compound of formula OH OH NN OH N R, R 2 for the manufacture of a medicament for the treatment of histamine-mediated allergic disorders, wherein SPEC.794121 JOL3(i8.1O - 48 R 1 is H or C1-C6 alkyl and the C1-C6 alkyl moiety is straight or branched; R 2 is -COOH or -COOalkyl and the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; stereoisomers or pharmaceutically acceptable acid addition salt thereof. 5

10. A compound of the formula 0 C02 R 1 wherein R 1 is C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched; 10 prepared by the process of claim 1 or claim 2.

11. A compound of the formula O0 0 wherein X is Cl, Br, or I; 15 prepared by the process of any one of claims 3 to 5.

12. A compound of the formula OH OHN N OH / -- R 2 wherein 20 R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; R 2 is -COOH or -COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or stereoisomers or pharmaceutically acceptable acid addition salt thereof; SPEC-794121 JOL 30.8.10 - 49 prepared by the process of any one of claims 6 to 8.

13. A method of treating histamine-mediated allergic disorders in a subject comprising the step of administering to said subject an effective amount of a compound of formula OH OH N.N OH N R 1 5 R2 for the manufacture of a medicament for the treatment of histamine-mediated allergic disorders, wherein R 1 is H or C-C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched; R 2 is -COOH or -COOalkyl and the alkyl moiety has from 1 to 6 carbon atoms and 10 is straight or branched; stereoisomers or pharmaceutically acceptable acid addition salt thereof.

14. A process according to claim 1 substantially as hereinbefore described.

15 15. A process according to claim 3 substantially as hereinbefore described.

16. A process according to claim 6 substantially as hereinbefore described.

17. Use according to claim 9 substantially as hereinbefore described. 20

18. A method according to claim 13 substantially as hereinbefore described. SPEC-794 121 JOL 30. III