反应详情

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0) (6.63 g) and triphenylphosphine (5.98 g) were successively added to 1-methyl-2-pyrrolidinone (350 ml) with stirring at room temperature, and the mixture was stirred for 1 hr. A solution of 5-bromo-2-fluoro-4-methoxybenzoic acid methyl ester prepared in Example 2, Step II, in 1-methyl-2-pyrrolidinone and a solution of 3-chloro-2-fluorobenzylzinc bromide prepared in Example 2, Step I, in tetrahydrofuran were successively added dropwise. After the dropwise addition, the mixture was stirred at 85° C. for 2 hr and cooled. To the reaction mixture were added toluene (560 ml) and 12.5% aqueous ammonium chloride solution (980 ml) and the mixture was stirred. The organic layer was washed successively with 25% aqueous ammonium chloride solution (490 ml), 2% aqueous ethylenediamine solution (490 ml, twice) and 10% brine (490 ml, twice). After the washing, the solvent was concentrated under reduced pressure. Ethyl acetate (105 ml) and heptane (420 ml) were added to the residue to allow recrystallization to give 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester (106.8 g, yield 79.4%).

1. stirringthe mixture was stirred for 1 hr
2. additionAfter the dropwise addition
3. stirringthe mixture was stirred at 85° C. for 2 hr
4. temperaturecooled
5. stirringthe mixture was stirred
6. washThe organic layer was washed successively with 25% aqueous ammonium chloride solution (490 ml), 2% aqueous ethylenediamine solution (490 ml
7. concentrationAfter the washing, the solvent was concentrated under reduced pressure
8. additionEthyl acetate (105 ml) and heptane (420 ml) were added to the residue
9. customrecrystallization