Reaktion #51490

Reaktionsgleichung

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

Lösungsmittel

THF

methyl t-butyl ether

water

Reaktionsbedingungen

Aufarbeitung

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

Vorschrift

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.

Quelle