反应详情

ICH2Cl (3.54 g, 1.46 mL, 19, 0.82 mmol, 1.25 equivalent) and THF (5 mL) are added to (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 5 g, 15.86 mmol, 1 equivalent). The mixture is cooled to −78° and LDA (22.3 mL, 44.60 mmol, 2.25 equivalents, 2.0 M) is added dropwise maintaining an internal temperature below −60°. Once the addition is complete, the contents are stirred for 30 min at −78° at which time n-butyllithium (15.3 mL, 19.82 mmol, 1.25 equivalents; 1.3M in hexanes) is added dropwise maintaining an internal temperature below about −60°. The reaction is stirred for 30 min then quenched into 0° hydrochloric acid (1N). Ethyl acetate is added and the phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, NMR (DMSO-d6) δ 7.47, 7.06-7.14, 4.78, 4.49, 3.20, 2.82 and 1.40; CMR (DMSO-d6) δ 200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30.

1. temperatureThe mixture is cooled to −78°
2. temperaturemaintaining an internal temperature below −60°
3. additionOnce the addition
4. additionis added dropwise
5. temperaturemaintaining an internal temperature below about −60°
6. customthen quenched into 0° hydrochloric acid (1N)
7. additionEthyl acetate is added
8. customthe phases are separated
9. extractionthe aqueous phase is extracted with ethyl acetate
10. washThe combined organic phases are washed with saturated sodium bicarbonate
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure