反应详情

温度

-78 °C

N-t-Butoxycarbonyl(3,5-difluorophenyl)alanine methyl ester (1.3 g, 4.1 mmol) in toluene (20 mL) is placed under nitrogen and cooled to −78° C. To the stirred solution is added, dropwise over 10 min, 12.0 mL of a 1 M solution of Dibal in toluene. After 1 h, 2 mL of methanol is added dropwise, and the solution is poured into an aqueous solution of Rochelle salts cooled in an ice bath. The mixture is stirred and the organic material is extracted into ethyl ether. The organic phase is washed with water and brine, dried over Na2SO4, and concentrated to N-t-butoxycarbonyl(3,5-difluorophenyl)alanal as a white solid, 1.2 g (quantitative). N-t-Butoxycarbonyl(3,5-difluorophenyl)alanal (700 mg, 2.45 mmol) and L-alanyl-N1-isobutyl-L-valinamide (EXAMPLE 1, 700 mg, 2.87 mmol) are combined with sodium triacetoxyborohydride (1.0 g, 4.7 mmol) in 14 mL of THF containing 0.30 mL (5.0 mmol) of acetic acid. The mixture is allowed to stir 18 h. The reaction is quenched with 1 N NaHCO3 and the product is taken up in 200 mL of ethyl acetate and several mL of methanol. The organic phase is washed with more bicarbonate, and then with brine, and dried over Na2SO4. It is concentrated to a solid, which is chromatographed over silica gel, eluting with 25% to 30% acetone in dichloromethane. The product-containing fractions are concentrated to afford 432 mg (0.84 mmol, 34%) of the title product as a white solid. HRMS (ESI) calcd for C26H42F2N4O4+H1 513.3252, found 513.3259.

1. additionTo the stirred solution is added, dropwise over 10 min
2. additionthe solution is poured into an aqueous solution of Rochelle salts
3. temperaturecooled in an ice bath
4. extractionthe organic material is extracted into ethyl ether
5. washThe organic phase is washed with water and brine
6. dry with materialdried over Na2SO4
7. concentrationconcentrated to N-t-butoxycarbonyl(3,5-difluorophenyl)alanal as a white solid, 1.2 g (quantitative)
8. stirringto stir 18 h
9. customThe reaction is quenched with 1 N NaHCO3
10. washThe organic phase is washed with more bicarbonate
11. dry with materialwith brine, and dried over Na2SO4
12. concentrationIt is concentrated to a solid, which
13. customis chromatographed over silica gel
14. washeluting with 25% to 30% acetone in dichloromethane
15. concentrationThe product-containing fractions are concentrated