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)-α-oxo-1-indolizineacetamide) was developed. A novel DMF/Me 2 SO 4 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.