A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate

A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1b), starting from 5-bromo-2-methoxypyridine (8) and 4-fluorobenzaldehyde (9), is described. Key steps in the process include lithium–bromine exchange of 8, addition of the resulting lithiate to aldehyde 9, regioselective nitration of pyridone 12, and Pd-catalyzed alkoxycarbonylation of bromopyridine 15b. Overall yield of the five-stage synthesis was 23%; intermediates 10, 12, 13, 15b, and final product 1b·HCl were isolated as filterable solids. Compounds 1a,b are important intermediates in the synthesis of 7-benzylnaphthyridinones (e.g., 2) and related HIV-1 integrase inhibitors.