Synthesis of substituted imidazo[1,2-h][1,7]naphthyridines as H+/K+-ATPase inhibiting drug precursors via directed ortho-metalation of imidazo[1,2-a]pyridines.

[摘要]：Selective directed ortho-metalation (DOM) of 2,3-dimethyl-8-(pivaloylamino)imidazo[1,2-a]pyridine in the 7-position was achieved with tert-butyllithium. Subsequent reaction of the lithiated deriv. with tributylchlorostannane to the corresponding 7-trialkylstannyl analog and palladium-catalyzed Stille acylation with 3-arylpropenoic acid chlorides in the presence of lithium chloride gave the corresponding 7-acylated imidazopyridines in good yields. Cyclization to the target imidazonaphthyridines, which are precursors in the synthesis of gastric H+/K+-ATPase inhibiting drugs, was achieved by treatment with strong acid. For scaled-up prodn. of 2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]naphthyridin-7(8H )- one, a tin-free process has been developed. Accordingly, the 7-lithiated 2,3-dimethyl-8-(pivaloylamino)imidazo[1,2-a]pyridine was reacted directly with cinnamaldehyde and the resultant alc. oxidized with manganese dioxide to give the unsatd. 7-acylated imidazopyridine.

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