Synthesis of trovafloxacin using various (1 alpha,5 alpha,6 alpha)-3-azabicyclo[3.1.0]hexane derivatives

Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual ( 1 alpha,5 alpha,6 alpha)-3-azabicyclo[3.1.0]hexane ring system. The prototy pe of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6 alpha-nitro derivative 4 a re described, which leads to the key 6 alpha-nitro-3-azabicyclo[3.1.0]hexan e intermediate 10. The synthesis of 6 alpha-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected exo 6-amino derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected trovafloxacin compounds 20-22 in good yield. The ethyl ester of trovafloxac in 21 can also be accessed from the product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of prot ecting groups from 20-22 with methanesulfonic acid yields trovafloxacin mes ylate from which trovafloxacin zwitterion 1 can be liberated with base trea tment. Zwitterion 1 can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26.