Bromine → 122033-62-9
Reaction equation
[F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14]Br>>[Br:14][C:9]1[C:8]([F:13])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[C:10]=1[F:11]Participants
Procedure
The 4-fluoro substituent of 2,3,4,5-tetrafluorobenzoic acid was replaced by bromine by a series of reactions analogous to the sequence VIII→IX→X→II in Flow Sheet C, to produce 4-bromo-2,3,5-trifluorobenzoic acid (XI). The latter is then converted to a series of reactions analogous to the sequence IV→V→VI→VII of Flow Sheet A to yield an alkyl N-(1-hydroxy-2-alkyl)-3-amino-2-(4-bromo-2,3,5-trifluorobenzoyl)propenoate (XII). Selective cyclization of XII with lithium carbonate affords an alkyl 7-bromo-6,8-difluoro-1,4-dihydro-1-(2-hydroxy-2-alkyl)quinoline-3-carboxylate (XIII). Coupling with 2,6-dimethyl-4-(trialkylstannyl)pyridine then yields alkyl 6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-1,4-dihydro-1-(2-hydroxy-2-alkyl)quinoline-3-carboxylate (XIV). The latter is then converted to its mesylate (XV) with methanesulfonyl chloride. The mesylate is cyclized with hydrogen sulfide and sodium hydride to form the ester I (R'=H, X=S) which by hydrolysis is converted to the free acid (I; R and R'=H, X=S). The cyclization takes place by saturating a solution or suspension of XV with hydrogen sulfide, then treating it with excess sodium hydride while cooling the reaction in a Dry Ice bath and then allowing the reaction to warm to ambient temperature.
Sources & evidence
- ORD record
- ord-cbaf90e7058c403d8b318ed48a600ae5
- Source dataset
- uspto-grants-1989_06
- Patent number
- US04839355
Reaction notes
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