Carbon Dioxide → 4-Bromo-2,3,5,6-tetrafluorobenzoic acid

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Reaction Steps

The above Flow Sheet A illustrates the preparation of 10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine6-carboxylic acid. 1,4-Dibromo-2,3,5,6-tetrafluorobenzene (III) is metalated with butyllithium and then caused to react with carbon dioxide to give 4-bromo-2,3,5,6-tetrafluorobenzoic acid (IV). The latter is converted to its acid chloride (V) which reacts with a half ester of malonic acid in the presence of butyllithium to afford an alkyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate (VI). The benzoylacetate (VI) is then treated with molar equivalent amounts of dimethylformamide (DMF) dimethyl acetal and 2-amino-1-alkanol to produce an alkyl N-(1-hydroxy-2-alkyl)-3-amino-2-(4-bromo-2,3,5,6-tetrafluorobenzoyl)propenoate (VII). The latter is then cyclized by heating with a base, preferably potassium carbonate, to give a compound of Formula II (R'=F). The alkyl 10-bromo-8,9-difluoro-3-alkyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (II) is then caused to react with a 2,6-dimethyl-4-(trialkylstannyl)pyridine in the presence of a palladium complex catalyst thereby producing a compound of Formula I where R'=F and X=O. The latter can then be converted to the free acid (I; R=H, R'=F, X=O) by a conventional hydrolysis reaction with base or acid.

Provenance & Evidence