The synthesis of 2-phenyl-3-aminopyridine, a key intermediate in the preparation of 2-phenyl-3-aminopiperidine, from 2-chloro-3-aminopyridine is described using an imine as a protecting group for an aminopyridine. The in situ protection of 2-chloro-3-aminopyridine with benzaldehyde followed by Suzuki coupling with phenylboronic acid and subsequent acid hydrolysis provided the titled compound in a single, high-yielding step from inexpensive and commercially available starting materials.

The synthesis of the anti-cancer compound 2-methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)phenylamino]quinazolin-6-yl}-E-allyl)acetamide (CP-724,714) (1) on multikilogram scale using several different synthetic routes is described. Application of the Sonogashira, Suzuki, and Heck couplings to this synthesis was investigated to identify a safe, environmentally friendly, and robust process for the production of this drug candidate. A convergent and selective synthesis of the candidate was identified which utilizes a Heck coupling of a protected allylamine to install the critical olefin.

Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6α-nitro-3-azabicyclo[3.1.0]hexane intermediate 10. The synthesis of 6α-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 trovafloxacin 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 protecting groups from 20-22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin zwitterion 1 can be liberated with base treatment. Zwitterion 1 can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26.Trovafloxacin 1 is a new and powerful antibiotic that is active against a wide variety of microorganisms. 1 It contains the interesting 3-azabicyclo[3.1.0]hexane ring system. 2 This paper describes the synthesis and chemistry of a number of new (1α,5α,6α)-3-azabicyclo[3.1.0]hexanes and new naphthyridone coupled intermediates that can be used to make trovafloxacin. Possible mechanisms to interesting intermediates and the formation of some side products are also discussed.The reaction of N-benzylmaleimide 2 and bromonitromethane 3 in the presence of base 3 is used to assemble the bicyclic ring system of 4. Many bases can be used, but yields are often below 15%. Amidine bases are useful, particularly 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine 4 (DMTHP). This base improves the yield to the 30-35% range when the reaction is carried out at about Ϫ10 ЊC. The reaction can be carried out in many solvents but toluene is preferred because removal of the many tar like side products formed during the reaction is somewhat easier. It appears that the reaction produces almost exclusively the exo or 6α-nitro product 4. The endo or 6β-nitro product 5 is detected at very low level, in the range 0.5-1.5% relative to exo 4, in the presence of a base. The endo compound 5 can be formed by epimerization of 4 in the presence of potassium carbonate in acetonitrile. The equilibrium favours the exo form to a very significant extent and the endo-exo equilibrium is approximately 2 : 98 when measured by HPLC. The endo compound 5 has been isolated from the mother liquors of an equilibrium mixture by fractional crystallization and fully characterized by X-ray crystallography (see Fig. 1b). Steric hindrance is not a complete barrier to the synthesis of 6-substituted endo 3-azabicyclo[3.1.0]hexane products. For example, ethyl diazoacetate reacts with 1-benzyloxycarbonyl-2,5-dihydropyrrole in the presence of rhodium acetate to form both the 6α-ethoxycarbonyl and 6β-ethoxycarbonyl substituted 3-azabicyclo[3.1.0]hex...

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