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US 6,444,824 B1Granted
Process for production of piperidine derivatives
AssigneeAlbany Molecular Research, Inc.
InventorsThomas E. D'Ambra, Garry M. Pilling
Life of this patent
Estimating the term…
Abstract
The present invention relates to a method for preparing piperidine derivative compounds by converting, with a piperidine compound, regioisomers having the formula: where Z is and where m is 1 or 3-6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR5; R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR8R9; and R5, R8, and R9 are the same or different and are selected from the group consisting of hyrogen, an alkyl moiety, and an aryl moiety.
Claims42
A process of preparing a piperidine derivative compound of the formula:
- 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;
- R3 is —COOH or —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 reioisomer of the following formula:
- wherein
- Z is
- m is 1 or 3-6;
- Q and Y are the same or different and are selected from the group consisting of O, S, and NR5;
- R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR8R9;
- and
- R5, R8, and R9 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 bv a process selected from the proup consisting of:
- 1) acylatino, 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 non-Friedel-Crafts acylation conditions effective to produce the repioisomer,
- 2) 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 non-Friedel-Crafts reaction conditions effective to produce the regioisomer,
- 3) acylating an α,α-diunsubstitued-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 halopen;
- 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 consistinw of hydrogen, an alkyl moiety, and an aryl moiety
- under non-Friedel-Crafis reaction conditions effective to produce an α,α-diunsubstitued regioisomer precursor of the formula
- and
- methylating the α,α-diunsubstituted repioisomer precursor under conditions effective to produce the regioisomer, and
- 4) reacting a 4-(α,α-diunsubstituted-)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 non-Friedel-Crafts reaction conditions effective to produce an α,α-diunsubstitued regioisomer precursor of the formula
- and
- methylating the a α,α-diunsubstituted repioisomer precursor under conditions effective to produce the regioisomer;
- and
- converting the regioisomer to the piperidine derivative compound with a piperidine compound.
74 more elements
A process of preparing a regioisomer of the formula:
- wherein
- Z is
- m is 1 or 3-6;
- Q and Y are the same or different and are selected from the group consisting of O, S, and NR5;
- R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR8R9;
- R5, 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 non-Friedel-Crafts reaction conditions effective to produce the regioisomer.
19 more elements
A process of preparing a regioisomer of the formula:
- wherein
- Z is
- m is 1 or 3-6;
- Q and Y are the same or different and are selected from the group consisting of O, S, and NR5;
- R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR8R9;
- R5, 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 non-Friedel-Crafts reaction conditions effective to produce the regioisomer.
20 more elements
A process of preparing a regioisomer of the formula:
- wherein
- Z is
- m is 1 or 3-6;
- Q and Y are the same or different and are selected from the group consisting of O, S, and NR5;
- R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR8R9;
- R5, 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 prepared under non-Friedel-Crafts reaction conditions and having the formula:
- wherein said providing is selected from the group consisting of:
- 1) acylating an α,α-diunsubstituted-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 non-Friedel-Crafts acylation conditions effective to produce the α,α-diunsubstituted regioisomer precursor, and
- 2) acvlating a 4-(α,α-diunsubstituted)-toluic acid derivative 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
- 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 non-Friedel-Crafts reaction conditions effective to produce the α,α-diunsubstituted regioisomer precursor, and
- methylating the α,α-diunsubstituted regioisomer precursor under conditions effective to produce the regioisomer.
34 more elements
Dependencies are inferred from the claim text.