Conversion of the Laboratory Synthetic Route of the N-Aryl-2-benzothiazolamine R116010 to a Manufacturing Method

A facile and large-scale preparation of the antitumor agent R116010 has been developed. The new synthetic process requires four steps: (i) Friedel−Crafts reaction of N-phenyl-2-benzothiazolamine with 2-chloropropionyl chloride, (ii) conversion of the α-chloroketone into the corresponding α-(dimethylamino)ketone and resolution of the latter, (iii) reduction of the chiral aminoketone with resultant formation of the β-amino alcohol and finally (iv) conversion of the amino alcohol into the β-aminoimidazole R116010. The key strategic improvement is the crystallization-induced diastereomeric dynamic resolution of the aminoketone, leading to the chiral ketone in 90% yield and 90% enantiomeric purity. This new process improves the overall yield from 0.26 to 18.8% without tedious chromatographic separations and hazardous reaction conditions.