合成路线1

The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.