Development of a practical synthesis of STA-5312, a novel indolizine oxalylamide microtubule inhibitor

An efficient synthesis of the novel microtubule inhibitor STA-5312 (3-[(4-cyanophenyl)methyl]-N-(3-methyl-5-isothiazolyl)-alpha-oxo-1-indolizineacetamide) was developed. A novel DMF/Me2SO4 directed regioselective synthesis of the 3-(4-cyanobenzoyl)-indolizine (4) was a critical transformation within the four-step process. Alternatively, a CuCl mediated synthesis of 3-(4-cyanobenzyl)indolizine (5) was also developed. All intermediates were obtained in high quality and were used directly for the next step without extensive purification. The drug substance itself was purified by recrystallization from a mixture of THF and water, resulting in a high purity product (HPLC > 98%). The process was applied successfully in the manufacturing of kilograms of GMP API.