Patent ID: 6153754
Filing Date: 2000-11-28
Classification: A61P,C07D

Abstract:
A process of preparing a piperidine derivative compound of the formula: ##STR78## wherein n is 0 or 1;R.sup.1 is hydrogen or hydroxy;R.sup.2 is hydrogen;or, when n is 0, R.sup.1 and R.sup.2 taken together form a second bond between the carbon atoms bearing R.sup.1 and R.sup.2, provided that when n is 1, R.sup.1 and R.sup.2 are each hydrogen;R.sup.3 is --COOH or --COOR.sup.4 ;R.sup.4 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: ##STR79## wherein Z is ##STR80## m is 2; Q and Y are the same or different and are selected from the group consisting of O, S, and NR.sup.5 ;R.sup.6 and R.sup.7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR.sup.8, SR.sup.8, and NR.sup.8 R.sup.9 ; andR.sup.5, R.sup.8, and R.sup.9 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 .alpha.,.alpha.-disubstituted-methylbenzene derivative having the formula: ##STR81## wherein X.sup.1 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 reactionswith a compound having the formula: ##STR82## wherein X.sup.2 is a halogen; an alkali metal oxide; a moiety having the formula --OR.sup.10 ; a moiety having the formula --SR.sup.10 ; or an amine; andR.sup.10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moietyunder non-Friedel-Crafts acylation conditions effective to produce the regioisomer,2) reacting a 4-(.alpha.,.alpha.-disubstituted)-toluic acid derivative having the formula: ##STR83## wherein X.sup.2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula --OR.sup.10 ; a moiety having the formula --SR.sup.10 ; or an amine; andR.sup.10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moietywith a compound having the formula: ##STR84## wherein X.sup.1 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 reactionsunder non-Friedel-Crafts reaction conditions effective to produce the regioisomer,3) acylating an .alpha.,.alpha.-diunsubstituted-methylbenzene derivative having the formula: ##STR85## wherein X.sup.1 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 reactionswith a compound having the formula: ##STR86## wherein X.sup.2 is a halogen; an alkali metal oxide; a moiety having the formula --OR.sup.10 ; a moiety having the formula --SR.sup.10 ; or an amine; andR.sup.10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moietyunder non-Friedel-Crafts reaction conditions effective to produce an .alpha.,.alpha.-diunsubstituted regioisomer precursor of the formula ##STR87## and methylating the .alpha.,.alpha.-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer, and4) reacting a 4-(.alpha.,.alpha.-diunsubstituted-)toluic acid derivative having the formula: ##STR88## wherein X.sup.2 is hydrogen; a halogen; an alkali metal oxide; a moiety having the formula --OR.sup.10 ; a moiety having the formula --SR.sup.10 ; or an amine; andR.sup.10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moietywith a compound having the formula: ##STR89## wherein X.sup.1 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 .alpha.,.alpha.-diunsubstituted regioisomer precursor of the formula ##STR90## and methylating the .alpha.,.alpha.-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer;andreacting the regioisomer with a piperidine base to form the piperidine derivative compound.