Method for producing 5-aryl nicotinaldehydes

Abstract

The invention relates to a process for the preparation of 5-arylnicotinaldehydes by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex, characterized in that the molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands.

1. A process for the preparation of a 5-arylnicotinaldehyde of formula I 
                 
 
       in which
 A is a phenyl radical or naphthyl radical, each of which is unsubstituted, monosubstituted or polysubstituted by R, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCF 2 CF 3  or —OH and in which one or more CH groups is optionally replaced by N, and  
 R is H, a straight-chain or branched alkyl radical having 1 to 15 carbon atoms which is monosubstituted by —CF 3  or at least monosubstituted by fluorine, where, in addition, one more CH 2  groups is optionally independently replaced by —S—, —O—, —O—CO—, —CO—O— or —CH═CH— in such a way that heteroatoms are not directly adjacent,  
 
       said process comprising reduction of a corresponding 5-arylnicotinic acid by catalytic hydrogenation in the presence of carboxylic anhydrides and a palladium/ligand complex, wherein molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands. 
     
     
       2. A compound of formula I 
                 
 
       in which A is a 4-fluorophenyl group. 
     
     
       3. A process according to  claim 1 , further comprising reacting said 5-arylnicotinaldehyde with a primary amine to give a corresponding imine, and reducing to produce an N-alkylated amine. 
     
     
       4. A process according to  claim 1 , further comprising reacting a compound of formula I with a primary amine to give a corresponding imine, and reducing to produce an N-alkylated amine. 
     
     
       5. A process according to  claim 3 , wherein the N-alkylated amine is one of formula X 
                 
 
       in which
 R′ and R″, independently of one another, are H, straight-chain or branched alkyl radical having 1 to 15 carbon atoms which is monosubstituted by —CF 3  or at least monosubstituted by fluorine, where, in addition, one more CH 2  groups is optionally independently replaced by —S—, —O—, —O—CO—, —CO—O— or —CH═CH— in such a way that heteroatoms are not directly adjacent, or are F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCF 2 CF 3 , —OCHFCF 3  or —OH, and A is as defined above.  
 
     
     
       6. A process according to  claim 4 , wherein the N-alkylated amine is one of formula X 
                 
 
       in which
 R′ and R″, independently of one another, are as defined for R or are F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OCF 3 , —OCHF 2 , —OCF 2 CF 3 , —OCHFCF 3  or —OH, and A is as defined above.  
 
     
     
       7. A process according to  claim 5 , wherein the N-alkylated amine is (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman. 
     
     
       8. A process according to  claim 6 , wherein the N-alkylated amine is (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman. 
     
     
       9. A compound of formula II 
                   
         wherein A is  4   - fluorophenyl.   
     
     
       10. A compound of formula II 
                     wherein A is phenyl monosubstituted or polysubstituted by R, —CN, —CF   3   , —OCF   3   , —OCHF   2   , —OCF   2   CF   3   , OCHFCF   3    or OH and in which one or more CH groups is optionally replaced by N, and R is a  - straight - chain or branched alkyl radical having  1  to  15  carbon atoms which is monosubstituted by —CF, or at least monosubstituted by fluorine, where in addition, one or more CH   2    groups is optionally independently replaced by —S—, —O—, —O—CO—, —CO—O— or —CH═CH— in such a way that heteroatoms are not directly adjacent,        or A is naphthyl which is unsubstituted, monosubstituted or polysubstituted by R, F, Cl, Br, I, —CN, —NO   2   , —CF   3   , —OCF   3   , —OCHF   2   , —OCF   2   CF   3   , OCHFCF   3    or OH and in which one or more CH groups is optionally replaced by N, and R is H, a straight - chain or branched alkyl radical having  1  to  15  carbon atoms which is monosubstituted by —CF   3    or at least monosubstituted by fluorine, where in addition, one or more CH   2    groups is optionally independently replaced by —S—, —O—, —O—CO—, —CO—O— or —CH═CH— in such a way that heteroatoms are not directly adjacent.     
     
     
       11. A compound of formula III 
                     wherein A is phenyl monosubstituted or polysubstituted by R, —CN, —CF   3   , —OCF   3   , —OCHF   2   , —OCF   2   CF   3   , OCHFCF   3    or OH and in which one or more CH groups is optionally replaced by N, and R is a  - straight - chain or branched alkyl radical having  1  to  15  carbon atoms which is monosubstituted by —CF   3   , or at least monosubstituted by fluorine, where in addition, one or more CH   2    groups is optionally independently replaced by —S—, —O—, —O—CO—, —CO—O— or —CH═CH— in such a way that heteroatoms are not directly adjacent,        or A is naphthyl which is unsubstituted, monosubstituted or polysubstituted by R, F, Cl, Br, I, —CN, —NO   2   , —CF   3   , —OCF   3   , —OCHF   2   , —OCF   2   CF   3   , OCHFCF   3    or OH and in which one or more CH groups is optionally replaced by N, and R is H, a straight - chain or branched alkyl radical having  1  to  15  carbon atoms which is monosubstituted by —CF   3    or at least monosubstituted by fluorine, where in addition, one or more CH   2    groups is optionally independently replaced by —S—, —O—, —O—CO—, —CO—O— or CH═CH— in such a way that heteroatoms are not directly adjacent, and R   3    is methyl, ethyl, n - propyl, n - butyl, sec - butyl or tert - butyl.