Granted Patent B2

US 7,498,443 · App. 10/944,309 · Granted Mar 3, 2009

Abstract

Claims (22)

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

wherein

R 4 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, —OSO 2 R 5 , 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 —OSO 2 R 5 , wherein R 5 is chosen from alkyl, fluoroalkyl, aryl, and substituted aryl;

with an isobutyrate equivalent compound of formula IV

wherein R 8 is a trialkylsilyl,

in the presence of a transition metal catalyst having a metal selected from the group comprising of Ni and Pd, and ZnF 2 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 —OSO 2 R 5 , wherein R 5 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 R 8 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.

Assignments (7)