# Patent

## Title
Process for production of carebastine

## Abstract

Processes are disclosed for preparing piperidine derivative compounds of the formulae I, II or III:

## Background
FIELD OF THE INVENTION
The present invention relates to processes for the production of piperidine derivatives.
BACKGROUND OF THE INVENTION
Carebastine, 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1oxobutyl ]-α,α-dimethylphenylacetic acid, is the carboxylic acid metabolite of ebastine, [4′-tert-butyl-4-(diphenylmethoxy)piperidino]butyrophenone.




Both compounds possess potent selective histamine H1-receptor blocking and calcium antagonist properties and exhibit similar utility to terfenadine and fexofenadine as potent non-sedating antihistamines useful in the treatment of allergic rhinitis and urticaria.
U.S. Pat. No. 4,550,116 to Soto et al. describes preparation of piperidine derivatives related to carebastine by reacting the ω-haloalkyl substituted phenyl ketone with a substituted hydroxypiperidine derivative of the formula:




U.S. Pat. No. 4,254,130 indicates that ω-haloalkyl substituted phenyl ketones, wherein Z is hydrogen, are prepared by reacting an appropriate straight or branched lower alkyl C1-6 ester of α-α-dimethylphenylacetic acid with a compound of the following formula:




under the general conditions of a Friedel-Crafts acylation, wherein halo and m are described in column 11 of U.S. Pat. No. 4,254,129. The reaction is carried out in carbon disulfide as the preferred solvent.

It has been found that the Friedel-Crafts methods have two significant shortcomings: (1) only acyl halides or anhydrides can be used; (2) in the particular case of the fexofenadine intermediate phenyl ketones, a higher regioselectivity of the Friedel-Crafts acylation would be desirable.
In another approach, which is the subject of a series of patents to D'Ambra and others (U.S. Pat. Nos. 5,589,487; 6,153,754 and 6,201,124), carebastine is synthesized by a regioselective method employing non-Friedel-Crafts acylation. The processes of the D'Ambra patents involve acylation of an aromatic ring at a position already para-substituted with a reactive species. Acylation can be carried out by a variety of techniques, including a butyl derivative acylating agent, a 4-(α,α-disubstituted)-toluic acid derivative acylating agent, or an organometallic coupling reaction. Since such procedures do not involve replacement of hydrogen on an aromatic ring, they are distinguished from electrophilic aromatic substitutions like the Friedel-Crafts acylation reaction.
The present invention is directed toward an improved process for preparation of carebastine and related piperidine derivatives.
SUMMARY OF THE INVENTION
The present invention relates to processes for preparing piperidine derivative compounds of the formulae I, II or III:




wherein

R4 is H, alkyl or aryl;
A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl, alkoxy, and aryloxy. A first process comprises providing a compound of formula Ia, IIa or IIIa




wherein X is any group displaceable by an oxidative metallic addition, and converting the compound of formula Ia, IIa or IIIa to I, II or III respectively by reacting with isobutyrate or an isobutyrate equivalent.

A second process for preparing piperidine derivative compounds of the formulae I, II or III comprises providing a compound of formula XIa, XIIa or XIIIa




and converting the compound of formula XIa, XIIa or XIIIa to I, II or III respectively by reacting with a benzhydryl component of formula XIV;





wherein LG′ is a leaving group displaceable by OH or O⊖. In this process the compounds of formulae XIa, XIIa or XIIIa may be provided by the oxidative metallic addition of isobutyrate or an isobutyrate equivalent to a compound of formula Va, VIa or VIIa:





followed by condensation with an OH-protected 4-hydroxypiperidine and deprotection.

In another aspect the invention relates to a process for preparing an α,α-dimethyl-4-acylphenylacetate of the formula V, VI or VII:




wherein LG is a leaving group displaceable by a secondary amine. The process comprises providing a compound of formula Va, VIa or VIIa





and converting the compound of formula Va, VIa or VIIa to V, VI or VII respectively by reacting with isobutyrate or an isobutyrate equivalent.

In another aspect, the invention relates to a process for preparing piperidine derivative compounds of the formula III:




The process comprises providing a compound of formula XIIIa





and converting the compound of formula XIIIa to III by reacting with a benzhydryl component of formula XIV





In another aspect, the invention relates to a process for preparing piperidine derivative compounds of the formula XXX:




The process comprises providing a compound of formula XXXI





wherein PG is a protecting group for an alcohol function; and converting the compound of formula XXXI to XXX by reacting with isobutyrate or an isobutyrate equivalent and cleavage of the protecting group.

In another aspect, the invention relates to a process for preparing a compound of formula XXXI comprising reacting a compound of formula VIa




with a compound of formula XXXII





In another aspect, the invention relates to a process for preparing piperidine derivative compounds of the formula I:




The process comprises:

(a) reacting a compound of formula VIa





with isobutyrate or an isobutyrate equivalent to provide an α,α-dimethyl-4-acylphenylacetate of the formula VI:





(b) reacting the α,α-dimethyl-4-acylphenylacetate of formula VI with a protected 4-hydroxypiperidine to provide a protected 4-(hydroxy)piperidino]butyrophenone;

(c) deprotecting the protected 4-(hydroxy)piperidino]butyrophenone to provide a 4-(hydroxy)piperidino]butyrophenone of formula XIa





(d) converting the compound of formula XIa to I by reacting with a benzhydryl component of formula XIV





In another aspect the invention relates to compounds of formula




in which Xa is —OSO2R5, —N2+, —OH or —B(OR6)(OR7), wherein R5 is chosen from fluoro, alkyl, fluoroalkyl, aryl, heteroaryl and substituted aryl; and R6 and R7 are chosen from H and C1-C20 hydrocarbon.



DETAILED DESCRIPTION OF THE INVENTION
Throughout this application, various references are referred to. The disclosures of each of these publications in their entireties are hereby incorporated by reference as if written herein.
Definitions
In this specification the terms and substituents are defined when introduced and retain their definitions throughout.
Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl groups are those of C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
C1 to C20 Hydrocarbon includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.
Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
Oxaalkyl refers to alkyl residues in which one or more carbons has been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like.
Acyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through an carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons.
Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S. The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like.
Substituted alkyl, aryl, cycloalkyl, etc. refer to alkyl, aryl or cycloalkyl, wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.
The term “halogen” means fluorine, chlorine, bromine or iodine.
Terminology related to “protecting”, “deprotecting” and “protected” functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group that is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as “protecting groups”. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry [See e.g. Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wuts, 2nd Edition; John Wiley & Sons, New York (1991)].
The abbreviations Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluensulfonyl and methanesulfonyl respectively. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations” is incorporated herein by reference.
The present invention relates to processes for preparing piperidine derivative compounds of the formulae I, II or III. In these compounds, A, B, and D may be different or the same, and are selected from the group consisting of hydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl, alkoxy, and aryloxy. Examples of compounds of formula I, II and III are those in which all of A, B and D are hydrogen and those in which A is hydrogen and B and D are halogens, e.g. fluorine, at the para positions.
The compounds of formula I in which R4 is alkyl or aryl may be hydrolyzed to produce carebastine. When R4, A, B, and D are all hydrogen, the compounds of formula I are carebastine and are produced by a direct single-step reaction. The compounds of formula II may be produced from I by reduction with hydrides, boranes or other reducing agents, as well known in the art, [see e.g. U.S. Pat. Nos. 5,589,487 and 6,743,941] to produce “dihydrocarebastine” analogs. Conversely, the compounds of formula II may be oxidized to I with oxidizing agents, such as manganese dioxide, as well known in the art [see Manganese Compounds as Oxidizing Agents in Organic Chemistry, Diether Arndt, Open Court Publishing, LaSalle, Ill., 1981] to produce carebastine and its ring-substituted analogs. The compounds of formula III may be converted to compounds of formula I by the procedure described by Kawai et al. J. Org. Chem. 59, 2620-2622 (1994).




The compounds of formulae I, II and III are prepared by a process in which a compound of formula Ia, IIa or IIIa




is reacted with isobutyrate or an isobutyrate equivalent. The substituent X may be chlorine, bromine, iodine, —OSO2R5, —N2+, —OH or —B(OR6)(OR7), wherein R5 is chosen from fluoro, alkyl, fluoroalkyl, aryl, heteroaryl and substituted aryl; R6 and R7 are chosen from H and C1-C20 hydrocarbon, including cyclic structures, e.g. dioxaboroles. Compounds in which X is —OSO2R5, may be prepared from compounds in which X is —OH by sulfonation with the appropriate sulfonyl halide or anhydride in the presence of a base, as well known in the art. Compounds in which X is —N2+ may be prepared from the corresponding aniline or nitrobenzene by processes well known in the art. [See e.g. Herr et al. Org. Proc. Res. Dev. 6, 677-681 (2002) and Siegrist et al. Org. Proc. Res. Dev. 7, 429-431 (2003).] Compounds in which X is —B(OR6)(OR7) may be prepared from the corresponding halides by the method of Ishiyama et al. [J. Org. Chem. 60, 7508-7510 (1995)].

The isobutyrate or an isobutyrate equivalent may be of the formula VIII or IV:




wherein R8 is a protecting group for a ketene acetal, [See Protective Groups in Organic Synthesis by T. W. Greene, op. cit.] The protecting group for a ketene acetal may be a simple alkyl, such as methyl or ethyl, a dialkylphosphoryl or, preferably, a trialkylsilyl group, such as trimethylsilyl or t-butyldimethylsilyl. The compounds of formula VIII are commercially available or are synthesized by procedures well-known in the art. The compounds of formula IV are also known in the art and may be synthesized as described by Liu and Hartwig [J. Am. Chem. Soc. 126, 5182-5191 (2004)]. The isobutyrate or isobutyrate equivalent may also be of the formulae XIX-XXII:





although these equivalents are less preferred. As will be evident to the artisan, the conditions for the final hydrolysis of ester to carboxylate to prepare carebastine and its ring-substituted analogs will be modified to accommodate the thioester or amide.

The coupling reactions are carried out in a suitable solvent in the presence of an appropriate catalyst for about 1 to 120 hours and at temperatures of about −78° C. to the reflux temperature of the solvent. Suitable solvents for coupling include: hydrocarbon solvents, such as benzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, such as chlorobenzene, dichloroethane, methylene chloride, chloroform, or carbon tetrachloride; esters, such as ethyl acetate and isopropyl acetate; carbon disulfide; dimethylformamide; ethereal solvents, like tetrahydrofuran and diethylether; or dioxane.
The reaction between the compounds of formulae I-III and IV or VIII is catalyzed by a transition metal. The transition metal catalyst is a Group 8B transition metal, that is, a metal selected from iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, and platinum. More preferably, the Group 8 metal is palladium, platinum, or nickel, and most preferably, palladium. The Group 8 metal may exist in any oxidation state ranging from the zero-valent state to any higher variance available to the metal. The preferred catalysts for condensations are palladium acetate, palladium chloride, palladium bromide, palladium acetylacetonate, bis(tri-o-tolyl)phosphine palladium dichloride, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium [(Ph3P)4Pd] and bis(dibenzylideneacetone) palladium [(dba)2Pd].
The chelating ligand my be a neutral molecule or charged ion. The chelating ligand is also required to contain at least one element from Group 5B of the Periodic Table, preferably, at least one element of nitrogen, phosphorus, or arsenic, and more preferably nitrogen or phosphorus. Preferred ligands for the coupling with VIII are 1,1′-bis(di-o-tolylphosphino)ferrocene (DTPF); 1,1′-bis(diphenylphosphino)ferrocene (DPPF); 1-di-t-butylphosphino-2-methylaminoethyl ferrocene; [2′-(diphenylphosphino)[1,1′-binaphthalen]-2-yl]diphenylphosphine oxide (BINAP) and 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (tol-BINAP). Preferred ligands for the coupling with IV are trialkyl or triarylphosphines, such as tri-t-butylphosphine, triphenylphosphine and (tri-o-tolyl)phosphine.
Conditions for metal catalyzed couplings are described with references in Diederich and Stang, Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH (1998) and in particular detail in U.S. Pat. No. 6,057,456. In addition to palladium catalysts, as described below, one may employ other transition metals.
In formula Ia-IIIa, as well as in Va and VIa below, X is preferably bromide or triflate, as shown in the examples below, but other substituents suitable for metal catalyzed coupling reactions may be used in their place. For example, diazonium salts may be used as described in Sakakura et al JCSP1 1994, 283-288. It will be apparent to the person of skill that, when A is chlorine, in order to have reasonable yields of single positional isomers, X should be chosen to be other than chlorine.
When the starting material is of the formula VIII, a base must be used. Non-limiting examples of suitable bases include alkali metal hydroxides, such as sodium and potassium hydroxides; alkali metal alkoxides, such as sodium or potassium t-butoxide; metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, and magnesium carbonate; alkali metal aryl oxides, such as potassium phenoxide; alkali metal amides, such as sodium and lithium amide; tertiary amines, such as triethylamine and tributylamine; hydride bases, such as sodium and potassium hydride, (hydrocarbyl)ammonium hydroxides, such as benzyltrimethylammonium hydroxide and tetraethylammonium hydroxide; diaza organic bases, such as 1,8-diazabicyclo[5.4.0]-undec-7-ene and 1,8-diazabicyclo-[2.2.2.]-octane, and silyl compounds such as potassium hexamethyldisilazide (KN(Si(CH3)3)2). Preferably, the base is an alkali alkoxide or a silyl-containing compound. The molar ratio of base to Ia, IIa or IIIa ranges from about 1:1 to about 3:1, and is usually between about 1:1 and 2:1.
When the starting material is of the formula IV, a metal salt is used instead of a base. Exemplary salts are ZnF2 and Zn(OtBu)2.
In another aspect the invention relates to a process for preparing an α,α-dimethyl-4-acylphenylacetate of the formula V, VI or VII:




wherein LG is a leaving group displaceable by a secondary amine, particularly a group displaceable by a piperidine, for example a halogen or a sulfonate. LG is preferably bromine, chlorine, methansulfonate, toluenesulfonate or triflate. The process comprises providing a compound of formula Va, VIa or VIIa:





and converting the compound of formula Va, VIa or VIIa to V, VI or VII respectively by reacting with isobutyrate or an isobutyrate equivalent. The process parallels the process shown above for I, II and III from Ia, IIa and IIIa in that the reaction conditions and reagents are substantially the same. Compounds of formula Va and VIa, in which A is hydrogen are commercially available from Acros Organics, Geel, Belgium. The compounds of formula VIIa may be prepared according to the method of Godt [J. Org. Chem. 62, 7471(1997)]:





A useful iron-catalyzed process, which could be used to synthesize any of I-VII, is described by Fürstner et al J. Am. Chem. Soc. 124, 13856-13863 (2002):




The α,α-dimethyl-4-acylphenylacetates of the formulae V, VI and VII may be further reacted with a piperidine derivative as described in U.S. Pat. Nos. 4,550,116; 5,750,703; 6,153,754; 6,242,606 and others.
The second route to piperidine derivative compounds of the formulae I, II or III passes through intermediates of formula XIa, XIIa or XIIIa




The compound of formula XIa, XIIa or XIIIa may be reacted with a benzhydryl component of formula XIV;





wherein LG′ is a leaving group displaceable by OH or O63. Examples of such groups include iodine, bromine, chlorine, and sulfonates. Methansulfonate, toluenesulfonate and triflate are examples of useful sulfonates. The reaction is carried out in an inert solvent, preferably in the presence of a base. Bases that deprotonate the alcohol of XIa, XIIa or XIIIa, such as sodium hydride, are preferred.

In this process the compounds of formulae XIa, XIIa or XIIIa may be provided by the oxidative metallic addition of isobutyrate or an isobutyrate equivalent to a compound of formula Va, VIa or VIIa:




followed by condensation with an OH-protected 4-hydroxypiperidine and deprotection. Alcohol and amine functionalities are protected with any of the well-known protecting groups. [See Greene and Wuts Protective Groups in Organic Synthesis Second Edition John Wiley & Sons, New York 1991, pages 1-118 and 309-370 which are incorporated herein by reference.]. Preferred protecting groups are t-butyldimethylsilyl for the alcohol and benzyl for the amine. Methods for protecting and deprotecting with these groups are found in Greene and Wuts on pages 77 and 364 respectively. The synthesis is described below in Scheme 7.

An alternative route to carebastine and related compounds proceeds through compounds of the formula XXX:




which may be prepared by reacting compounds of formula XXXI





with isobutyrate or an isobutyrate equivalent and cleavage of the protecting group. The compounds of formula XXXI may be made by reacting a compound of formula VIa





with a compound of formula XXXII





This route is described below in Scheme 8.

Exemplary processes that fall within the scope of the invention are illustrated in the schemes below. These schemes also illustrate the interrelatedness of the processes and intermediates.









































EXAMPLE 1
One gram of 9 was dissolved in 20 mL of DMF and 18 mg of P(tBu)3, 41 mg of Pd(dba)2, 230 mg of ZnF2 and 1.2 g of 5 were added. A mixture was stirred at 80° for 18 hours, cooled to room temperature, diluted with ether and washed with water. The organic layer was dried over sodium sulfate, filtered and stripped in vacuo. The resulting product was flash chromatographed on silica gel using 4:1 hexane ethyl acetate to yield 1.0 g (91%) of 10. A repeat of the reaction on larger scale using 15 g of 9 provided 15.2 g (93%) of 10.
EXAMPLE 2
Five grams of 9 was dissolved in 50 mL of methylene chloride and cooled to 0° C. To the solution was added 5.78 g of trimethylsilyl iodide. The mixture was stirred for 30 minutes and excess sodium bisulfite solution was added with vigorous stirring at room temperature. The layers were separated and the aqueous layer extracted twice with methylene chloride. Combined organic layers were dried, filtered and stripped in vacuo to provide 7.7 g (98%) of 1. The reaction was repeated on a larger scale using 15 g of 9 to produce 22.5 g of 1 (96%) yield.
EXAMPLE 3
Six grams of potassium carbonate, 5.8 g of piperidine 2 and 7.6 g of 1 are combined in 100 mL of DMF. The suspension is stirred at room temperature until TLC in 4:1 hexane-ethyl acetate indicates a complete reaction. The reaction mixture is poured into 400 mL of water and extracted three times with methylene chloride. The combined organic extracts are dried, filtered and reduced in vacuo. The resulting product is flash chromatographed on silica gel using ethyl acetate containing 10% triethylamine to yield 3.
EXAMPLE 4
Seven grams of 3 is dissolved in 100 mL of methanol, cooled to 0° C. and 1.1 g of sodium borohydride is added. The mixture is stirred 1 hour, concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The bicarbonate layer is extracted twice with ethyl acetate, the combined organic layers are dried over sodium sulfate and the solution is reduced in vacuo to provide 4.
EXAMPLE 5
Two grams of 4 is dissolved in 30 mL of DMF. To this are added 16.2 mg of P(tBu)3, 36.6 mg of Pd(dba)2, 209 mg of ZnF2 and 1.056 g of 5. The mixture is heated at 80° C., cooled, diluted with ether and worked up as in example 1. The resulting product is flash chromatographed on silica gel using 9:1 ethyl acetate-triethylamine to provide 7.
EXAMPLE 6
One hundred fifty milligrams of 6 is slurried in 5 mL of water and 10 mL of methanol. To the slurry is added 175 mg of sodium hydroxide. The slurry is refluxed for one hour, cooled to room temperature and the methanol removed in vacuo. The resulting aqueous solution is distributed between water and chloroform, the chloroform layer is discarded, the aqueous layer is adjusted to pH 2.3 and extracted with chloroform. The organic layer is dried, filtered and reduced in vacuo to provide carebastine.
EXAMPLE 7
Five grams of 1 was combined with 2.64 g of 2 and 2.0 g of potassium carbonate and 80 mL of DMF. The mixture was stirred at room temperature for two hours, poured into 400 mL of water and extracted three times into methylene chloride. The combined organic layers were dried, filtered and reduced in vacuo. The resulting product was flash chromatographed on silica gel using 9:1 ethyl acetate-triethylamine to provide 2.0 g (54%) of 3.
EXAMPLE 8
One and seven-tenths grams of 3, 90 mg of P(tBu)3, 300 mg of Pd(dba)2, 250 mg of ZnF2 and 1.1 g of 5 were dissolved in 330 mL of DMF under argon. The mixture was heated to 80° for two hours, cooled to room temperature, diluted with ether and worked up as described in example 1. The resulting product was filtered through silica to provide 1.2 g (67.8%) of 6.
EXAMPLE 9
Two grams of 20, 170 mg of P(tBu)3, 560 mg of Pd(acac)2, 474 mg of ZnF2 and 2.0 g of 5 were combined in 50 mL of DMF under argon. The mixture was heated to 80° C. and monitored by HPLC. When reaction was complete, the mixture was cooled to room temperature and 250 mL of water was added. The mixture was extracted three times with ether, dried, filtered and reduced in vacuo. The resulting product was flash chromatographed in 4:1 hexane-ethyl acetate to provide 1.89 g (85%) of 8.
EXAMPLE 10
Two grams of the triflate analog of 20 were reacted as in the foregoing example with 134 mg P(tBu)3, 433 mg of Pd(acac)2, 375 mg of ZnF2 and 1.58 g of 5 to provide 1.56 g (90% yield) of 8.
EXAMPLE 11
Piperidinol 25 is reacted with chlorodiphenylmethane as described in Fujii et al. Arzneim.-Forsch. 44, 527-538 (1994) to provide 6.

## Claims

1. A process for preparing piperidine derivative compounds of the formula I:



wherein
R4 is H, alkyl or aryl;
A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl, alkoxy, and aryloxy;

said process comprising:
(a) reacting a compound of formula VIa




wherein
X is a group chosen from chlorine, bromine, iodine, —OSO2R5, and diazonium salt displaceable via oxidative metallic addition; and
LG is a leaving group displaceable by a secondary amine, said leaving group chosen from chlorine, bromine, iodine, and —OSO2R5, wherein R5 is chosen from alkyl, fluoroalkyl, aryl, and substituted aryl;
with an isobutyrate equivalent compound of formula IV




wherein R8 is a trialkylsilyl,
in the presence of a transition metal catalyst having a metal selected from the group comprising of Ni and Pd, and ZnF2 to provide an α,α-dimethyl-4-acylphenylacetate of the formula VI:




(b) reacting said α,α-dimethyl-4-acylphenylacetate of formula VI with a protected 4-hydroxypiperidine to provide a protected [4-(hydroxy)piperidino]butyrophenone;
(c) deprotecting said protected [4-(hydroxy)piperidino]butyrophenone to provide a [4-(hydroxy)piperidino]butyrophenone of formula XIa




(d) converting the compound of formula XIa to I by reacting with a benzhydryl component of formula XIV;




wherein LG′ is a leaving group displaceable by OH or O⊖ resulting from the deprotonation of the piperidinyl hydroxyl group of compound XIa.

2. A process according to claim 1 for preparing carebastine wherein a compound of formula XIab



is reacted, in the presence of a base, with a benzhydryl component of formula XIVa;




wherein LG′ is a leaving group, said leaving group chosen from chlorine, bromine, iodine, and —OSO2R5, wherein R5 is chosen from alkyl, fluoroalkyl, aryl, and substituted aryl, displaceable by OH or O⊖ resulting from the deprotonation of the piperidinyl hydroxyl group of compound XIab, and carrying out further process steps to provide carebastine.

3. A process according to claim 1 wherein X is displaced by the isobutryate equivalent compound of formula IV by reaction in the presence of a phosphorus compound chosen from trialkyl phosphine, triaryl phosphine, and mixed alkyl/aryl phosphine, and the transition metal catalyst.

4. A process according to claim 1 wherein R8 is a trimethylsilyl group.

5. A process according to any of claims 1 or 2 wherein LG′ is chosen from iodine, bromine, chlorine, methanesulfonate, toluenesulfonate, and triflate.