Process for production of piperidine derivatives

A regioisomer having the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety;
• and
• A is the substituents of its ring, 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.

A process of preparing a regioisomer of the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety;
• and
• A is the substituents of its ring, 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
• acylating an α-α-disubstituted-methylbenzene derivative having the formula:
• wherein
• 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 formula:
• wherein
• X2 is a halogen;
• an alkali metal oxide;
• a moiety having the formula —OR10;
• a moiety having the formula —SR10;
• or an amine;
• and
• R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety
• under conditions effective to produce the regioisomer.

A process of preparing a regioisomer of the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety;
• and
• A is the substituents of its ring, 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:
• reacting a 4-(α-α-disubstituted)-toluic acid derivative having the formula:
• wherein
• X2 is hydrogen;
• a halogen;
• an alkali metal oxide;
• a moiety having the formula —OR10;
• a moiety having the formula —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:
• wherein
• 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
• under conditions effective to produce the regioisomer.

A process of preparing a regioisomer of the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety;
• and
• A is the substituents of its ring, 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 an α-α-diunsubstituted regioisomer precursor having the formula:
• and
• methylating the α-α-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer.

An α-α-disubstituted-methylbenzene derivative having the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety,
• with a proviso that when G1, G2, and G3 are OR8, R8 is not an alkyl moiety;
• A is the substituents of its ring, 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;
• and
• 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.

An α-α-diunsubstituted-methylbenzene derivative having the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety,
• with a proviso that when G1, G2, and G3 are OR8, R8 is not an alkyl moiety;
• A is the substituents of its ring, 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;
• and
• 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.

An oxobutyl derivative having the formula:

• wherein
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety,
• with a proviso that when G1, G2, and G3 are OR8, R8 is not an alkyl moiety;
• A is the substituents of its ring, 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;
• and
• X3 is a halogen or a hydroxy, alkoxy, or aryloxy moiety.

A piperidine derivative precursor having the formulae:

• wherein
• n 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;
• Z is -CG1G2G3,
• G1, G2, and G3 are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9;
• R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety;
• and
• 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.