Reaktion #64799

Reaktionsgleichung

bis(trimethylsilyl)trifluoroacetamide

ethyl acetate

2-trifluoromethyl-3-acetylthiopropionyl chloride

bis(trimethylsilyl)trifluoroacetamide

L-leucine

→

N-[2-[(Acetylthio)methyl]-3,3,3-trifluoro-1-oxopropyl]-L-leucine

Lösungsmittel

methanol

acetic acid

hexane

acetonitrile

acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturwas cooled to 0°-5° C.
2. 2
   Sonstigeresulted in a clear lemon color solution
3. 3
   workup.STIRRINGon additional stirring for one hour at room temperature
4. 4
   TemperaturThe reaction mixture was cooled to 0°-5° C.
5. 5
   workup.ADDITIONwas added dropwise over 45 minutes
6. 6
   workup.STIRRINGAfter stirring for 1.5 hours at 0°-5° C. to room temperature
7. 7
   Sonstigecompletion of the reaction
8. 8
   SonstigeThe reaction mixture was evaporated under reduced pressure
9. 9
   Sonstigeto give a yellow oily residue which
10. 10
    Sonstigewas partitioned between ethyl acetate (75 mL) and water (50 mL)
11. 11
    ExtraktionThe aqueous phase was further extracted with ethyl acetate (4×50 mL)
12. 12
    Waschenthe combined extracts were washed with 75 mL of brine
13. 13
    Trocknendried (MgSO4)
14. 14
    Sonstigeevaporated
15. 15
    Sonstigeto give 10.3 g
16. 16
    Sonstigechromatographed on 75 g
17. 17
    Sonstigeof silica gel eluting with ethyl acetate: hexanes:acetic acid, 100:100:1 to yield 0.15 g
18. 18
    Waschenof the faster eluting diastereomer (isomer A) and 0.12 g
19. 19
    Waschenof slower eluting diastereomer (isomer B)
20. 20
    Sonstigechromatographed similarly (silica gel, 1300 g.) which
21. 21
    Sonstigegave 2.5 g
22. 22
    workup.ADDITIONof a mixture of both the diastereomers, and 1.5 g
23. 23
    SonstigeThe mixed fractions were rechromatographed
24. 24
    Sonstigeto give 0.5 g
25. 25
    Sonstigetriturated with hexanes containing a few drops of ethyl acetate
26. 26
    Filtrationfiltered
27. 27
    Sonstigedried
28. 28
    Sonstigeto yield 2.57 g

Vorschrift

A stirred suspension of L-leucine (2.62 g., 20 mmol) in 35 mL of dry acetonitrile under argon was cooled to 0°-5° C. and bis(trimethylsilyl)trifluoroacetamide (10.62 mL, 40 mmol) was added. The reaction mixture was allowed to stir while slowly warming to room temperature. After 2 hours, another 3.5 mL (13 mmol) of bis(trimethylsilyl)trifluoroacetamide was added which resulted in a clear lemon color solution on additional stirring for one hour at room temperature. The reaction mixture was cooled to 0°-5° C. and 2-trifluoromethyl-3-acetylthiopropionyl chloride (4.69 g., 20 mmol.) dissolved in 8 mL of acetonitrile was added dropwise over 45 minutes. After stirring for 1.5 hours at 0°-5° C. to room temperature, TLC shows completion of the reaction. The reaction mixture was evaporated under reduced pressure to give a yellow oily residue which was partitioned between ethyl acetate (75 mL) and water (50 mL). The aqueous phase was further extracted with ethyl acetate (4×50 mL), the combined extracts were washed with 75 mL of brine, dried (MgSO4), and evaporated to give 10.3 g. of a yellow semi-solid residue. A 0.68 g. portion of this crude material was flash chromatographed on 75 g. of silica gel eluting with ethyl acetate: hexanes:acetic acid, 100:100:1 to yield 0.15 g. of the faster eluting diastereomer (isomer A) and 0.12 g. of slower eluting diastereomer (isomer B). The remaining 9.6 g. of crude material was flash chromatographed similarly (silica gel, 1300 g.) which gave 2.5 g. of isomer A, 2.7 g. of a mixture of both the diastereomers, and 1.5 g. of isomer B. The mixed fractions were rechromatographed using the same conditions to give 0.5 g. of isomer A and 1.25 g. of isomer B. Both the 2.5 g. and 0.5 g. portions of isomer A were combined, triturated with hexanes containing a few drops of ethyl acetate, filtered, and dried to yield 2.57 g. of the title isomer A product as a white crystalline solid, m.p. 150°-152° C., TLC Rf =0.40 (100:50:1 ethyl acetate:hexane:acetic acid), [α]D =-146.9° (c=1.00, methanol).

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