反应详情

To a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet, thermocouple and additional funnel is added (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 10.0 g, 0.0317 moles, 1 equivalent) followed by THF (175 mL) then cooled to −78°. Once the mixture is cooled, iodochloromethane (9.25 mL, 0.127 moles, 4 equivalents) is added in one portion via syringe. The addition funnel is charged with LDA (79 mL, 0.158 moles, 5 equivalents, 2.0 M in heptane/THF) and is subsequently added dropwise to the mixture keeping the internal temperature below −70°. Once the addition is complete, the contents are stirred for 15 min at which time acetic acid (47.2 mL, 0.824 moles, 26 equivalents) is added dropwise via the addition funnel keeping the internal temperature below −65°. Once this addition is complete, the mixture is stirred for 15 min then warmed to 0° and poured into water (500 mL), saline (500 mL) and methyl t-butyl ether (500 mL) then transferred to a separatory funnel. The phases are separated and the aqueous phase is extracted with methyl t-butyl ether (2×250 mL). The combined organic phases are washed with saturated sodium bicarbonate (500 mL), sodium sulfite (500 mL) and water (500 mL). The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a solid. The solid is recrystallized from heptane/i-propyl alcohol (10/l)to give the title compound, mp=139°; NMR (DMSO-d6) ° 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. customTo a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet
2. temperaturethen cooled to −78°
3. temperatureOnce the mixture is cooled
4. additionis subsequently added dropwise to the mixture
5. customthe internal temperature below −70°
6. additionOnce the addition
7. additionis added dropwise via the addition funnel
8. customthe internal temperature below −65°
9. additionOnce this addition
10. temperaturethen warmed to 0°
11. customthen transferred to a separatory funnel
12. customThe phases are separated
13. extractionthe aqueous phase is extracted with methyl t-butyl ether (2×250 mL)
14. washThe combined organic phases are washed with saturated sodium bicarbonate (500 mL), sodium sulfite (500 mL) and water (500 mL)
15. dry with materialThe organic phase is then dried over sodium sulfate
16. filtrationfiltered
17. concentrationconcentrated under reduced pressure
18. customto give a solid
19. customThe solid is recrystallized from heptane/i-propyl alcohol (10/l)to