反应 #51490

反应方程式

acetic acid

(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester

iodochloromethane

LDA

→

title compound

tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate

溶剂

THF

methyl t-butyl ether

water

反应条件

后处理

1. 1
   其他To a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet
2. 2
   温度then cooled to −78°
3. 3
   温度Once the mixture is cooled
4. 4
   workup.ADDITIONis subsequently added dropwise to the mixture
5. 5
   其他the internal temperature below −70°
6. 6
   workup.ADDITIONOnce the addition
7. 7
   workup.ADDITIONis added dropwise via the addition funnel
8. 8
   其他the internal temperature below −65°
9. 9
   workup.ADDITIONOnce this addition
10. 10
    温度then warmed to 0°
11. 11
    其他then transferred to a separatory funnel
12. 12
    其他The phases are separated
13. 13
    萃取the aqueous phase is extracted with methyl t-butyl ether (2×250 mL)
14. 14
    洗涤The combined organic phases are washed with saturated sodium bicarbonate (500 mL), sodium sulfite (500 mL) and water (500 mL)
15. 15
    干燥The organic phase is then dried over sodium sulfate
16. 16
    过滤filtered
17. 17
    浓缩concentrated under reduced pressure
18. 18
    其他to give a solid
19. 19
    其他The solid is recrystallized from heptane/i-propyl alcohol (10/1.)

实验过程

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 (10/1.) to give the title compound, mp=139°; 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.

来源