Efficient asymmetric synthesis of N-[(1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl]-2-pyridinecarboxamide for treatment of human papillomavirus infections

An efficient asymmetric synthesis of N-[( 1R)-6-chloro-2,3,4,9-tetrahydro- 1H-carbazol-1-yl]-2-pyridinecarboxamide 1, a potential treatment for human papillomavirus infections, is described. The key step in the synthesis of this molecule is an asymmetric reductive amination directed by chiral ( phenyl)ethylamines resulting in up to 96% disastereo facial selectivity. The synthesis is also highlighted by isolation of a unique 2-picolinic acid salt of ( 1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1- amine ( 13). Subsequent application of 1-propylphosphonic acid cyclic anhydride (T3P)for convenient amide formation from the two components of the salt provides the product 1 in high yield. The process research work leading to the final synthesis includes a racemic synthesis followed by resolution with chiral supercritical fluid chromatography, and an enantioselective reductive amination via chiral transfer hydrogenation catalyzed by Ru( II) complexes of N-[(1S, 2S)- 2-amino- 1,2-diphenylethyl]-1- naphthalenesulfonamide or (R)- BINAP. Highlighting the practicality of the synthesis, the process has been scaled up in 200-gallon reactors for delivery of multikilograms of the target compound 1 in over 99.5% enantiomeric purity.