Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides

A process for preparing a compound having the formula:

• wherein A is a phenyl;
• R10 is hydrogen halogen, alkyl, methoxy, cyano, nitro, trifluoromethyl, carbamoyl, pyrrolidine-1-carbonyl, cyclopropanecarbonylamino, 3-chloro-6-methyl, and 2-chloro-5-methyl;
• X is chosen from:
• i) —OH;
• ii) —OR3;
• iii) —NR4R5;
• and
• iv) —OM1;
• R3 is C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl;
• C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkenyl;
• or C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkynyl, or benzyl;
• R4 and R5 are each independently hydrogen, C1-C12 linear, C3-C12 branched or C3-C12 cyclic alkyl;
• C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkenyl;
• or C2-C12 linear, C3-C12 branched or C3-C12 cyclic alkynyl;
• benzyl;
• or R4 and R5 can be taken together with the nitrogen atom to form a 3 to 10 member ring, wherein the ring can optionally contain one or more heteroatoms chosen from oxygen (O), nitrogen (N), or sulfur (S);
• M1 is a pharmaceutically acceptable cation;
• R7a and R7b are each independently:
• i) hydrogen;
• or
• ii) C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl;
• R8 is chosen from hydrogen, methyl, or ethyl;
• and
• the index n is an integer from 1 to 4;
• or a pharmaceutically acceptable salt thereof,
• comprising:
• A) reacting a boronic acid with a 3,5-dihalo-2-cyanopyridine having the formula:
• each Z is independently chloro or bromo, in the presence of a catalyst, to form a 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine having the formula:
• B) reacting the 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine formed in step (A) with an alkoxide anion having the formula:
• ⊖OR2
• wherein R2 is C1-C12 linear alkyl or C3-C12 branched alkyl, to form a 5-aryl or 5-heteroaryl-3-alkoxy-2-cyanopyridine having the formula:
• C) reacting the 5-aryl or 5-heteroaryl-3-alkoxy-2-cyanopyridine formed in step (B) with an acid to form a 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxypyridine having the formula:
• and
• D) reacting the 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxypyridine formed in step (C) with a compound having the formula:
• wherein the boronic acid is chosen from phenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2-chlorophenylboronic acid, 3-chlorophenylboronic acid, 4-chlorophenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenyl-boronic acid, 4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyano-phenylboronic acid, 4-cyanophenylboronic acid, 2-nitrophenylboronic acid, 3-nitrophenylboronic acid, 4-nitrophenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluoromethylphenylboronic acid, 2-carbamoylphenylboronic acid, 3-carbamoylphenylboronic acid, 4-carbamoylphenyl-boronic acid, 2-(pyrrolidine-1-carbonyl)phenylboronic acid, 3-(pyrrolidine-1-carbonyl)phenylboronic acid, 4-(pyrrolidine-1-carbonyl)phenylboronic acid, 2-(cyclopropanecarbonylamino)phenylboronic acid, 3-(cyclopropanecarbonyl-amino)phenylboronic acid, 4-(cyclopropanecarbonylamino)phenylboronic acid, 3-chloro-6-methylphenylboronic acid, and 2-chloro-5-methylphenylboronic acid.