Patent ID: 6448406
Filing Date: 2002-09-10
Classification: A61P,C07D

Abstract:
A process of preparing a piperidine derivative compound of the formula: whereinn is 0 or 1; R1 is hydrogen or hydroxy; R2 is hydrogen; or, when n is 0, R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2, provided that when n is 1, R1 and R2 are each hydrogen; R3is â€”COOH or â€”COOR4; R4 is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents, said process comprising:providing a regioisomer of the following formula: â€ƒwherein Z is â€”CG1G2G3; G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9; X3 is halogen, OR15, SR15, NR15R16, OSO2R15, or NHSO2R15; and R8, R9, R15, and R16 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety, wherein said providing is carried out by a process selected from the group consisting of:1) acylating an &agr;,&agr;-disubstituted-methylbenzene derivative having the formula: â€ƒwherein X1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound having the formulae: or whereinX2 is hydrogen; a halopen; an alkali metal oxide; a moiety having the formula â€”OR10; a moiety having the formula â€”SR10; or an amine; and R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under non-Friedel-Crafts reaction conditions effective to produce the regioisomer,2) reacting a 4-(&agr;,&agr;-disubstituted)-toluic acid derivative having the formula: â€ƒwherein X2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula â€”OR10; a moiety having the formula â€”SR10; or an amine; and R10 is selected from the group consisting of hydrogen, an alkyl moiety and an aryl moiety with a compound having the formula: whereinX1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under non-Friedel-Crafts reaction conditions effective to produce the regioisomer,3) acylating an &agr;,&agr;-diunsubstituted-methylbenzene derivative having the formula: â€ƒwherein X1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound having the formulae: whereinX2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula â€”OR10; a moiety having the formula â€”SR10; or an amine; and R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety under non-Friedel-Crafts reaction conditions effective to produce an &agr;,&agr;-diunsubstituted regioisomer precursor of the formula: andmethylating the &agr;,&agr;-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer, and 4) reacting a 4-(&agr;,&agr;-diunsubstituted)-toluic acid derivative having the formula: â€ƒwherein X2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula â€”OR10; a moiety having the formula â€”SR10, or an amine; and R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety with a compound having the formula: whereinX1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions under non-Friedel-Crafts reaction conditions effective to produce an &agr;,&agr;-diunsubstituted regioisomer precursor having the formula: andmethylating the &agr;,&agr;-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer and reacting the regioisomer with a piperidine base to form the piperidine derivative compound.