反应详情

To a solution of LDA (13.6 mmol) in THF (50 ml) (prepared by a similar method to that used in Example 1) at -70° C. was added dropwise 4,5-dichloro-6-ethylpyrimidine (the product of part (ii)) (2.37 g, 13.3 mmol) and the resulting solution was stirred at this temperature for 10 minutes. A solution of 1-(2,4-difluorophenyl-2-(1H-1,2,4-triazol-1-yl)ethanone (2.97 g, 13.3 mmol) in THF (50 ml) was added to the reaction mixture at such a rate so as to maintain the reaction temperature below -50° C. After stirring at -70° C. for 1 hour and at -50° C. for a further 1 hour the reaction was quenched by the addition of 10% aqueous acetic acid (11 ml). The organic phase was separated, the aqueous phase extracted with ethyl acetate (2×20 ml) and the combined organic layers were dried over magnesium sulphate. After removal of the solvent under reduced pressure, the residue was triturated with diethyl ether (25 ml) and the unreacted ketone starting material (1.7 g) was removed by filtration. The filtrate was concentrated under reduced pressure and "flash" chromatography of the residue on silica using 65:35 ethyl acetate/diethyl ether as the eluant first provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the title compound, enantiomeric pair B as a solid (670 mg, 13%), m.p. 124° C. Found: C,47.78; H,3.33; N,17.13; C16H13Cl2F2N5O requires: C,48.00; H,3.25; N,17.50%.

1. customat -70° C.
2. temperatureto maintain the reaction temperature below -50° C
3. stirringAfter stirring at -70° C. for 1 hour and at -50° C. for a further 1 hour the reaction
4. customwas quenched by the addition of 10% aqueous acetic acid (11 ml)
5. customThe organic phase was separated
6. extractionthe aqueous phase extracted with ethyl acetate (2×20 ml)
7. dry with materialthe combined organic layers were dried over magnesium sulphate
8. customAfter removal of the solvent under reduced pressure
9. customthe residue was triturated with diethyl ether (25 ml)
10. customthe unreacted ketone starting material (1.7 g) was removed by filtration
11. concentrationThe filtrate was concentrated under reduced pressure and "flash" chromatography of the residue on silica using 65:35 ethyl acetate/diethyl ether as the eluant
12. customfirst provided
13. customafter combination and evaporation of appropriate fractions and trituration with diethyl ether