Carbon Dioxide → 4-Bromo-2,3,5,6-tetrafluorobenzoic acid
Reaction equation
CC1C=C(C2C(F)=C(F)C3C(=O)C([C:23]([OH:25])=[O:24])=CN4C(C)COC=2C=34)C=C(C)N=1.Br[C:30]1[C:35]([F:36])=[C:34]([F:37])[C:33]([Br:38])=[C:32]([F:39])[C:31]=1[F:40].C([Li])CCC.C(=O)=O>>[Br:38][C:33]1[C:34]([F:37])=[C:35]([F:36])[C:30]([C:23]([OH:25])=[O:24])=[C:31]([F:40])[C:32]=1[F:39]Participants
Reactant 4
Product 1
Procedure
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.
Sources & evidence
- ORD record
- ord-9953f40567fc43e2bb770ff2bfbd1a30
- Source dataset
- uspto-grants-1989_06
- Patent number
- US04839355
Reaction notes
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