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

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).

1. temperaturewas cooled to 0°-5° C.
2. customresulted in a clear lemon color solution
3. stirringon additional stirring for one hour at room temperature
4. temperatureThe reaction mixture was cooled to 0°-5° C.
5. additionwas added dropwise over 45 minutes
6. stirringAfter stirring for 1.5 hours at 0°-5° C. to room temperature
7. customcompletion of the reaction
8. customThe reaction mixture was evaporated under reduced pressure
9. customto give a yellow oily residue which
10. customwas partitioned between ethyl acetate (75 mL) and water (50 mL)
11. extractionThe aqueous phase was further extracted with ethyl acetate (4×50 mL)
12. washthe combined extracts were washed with 75 mL of brine
13. dry with materialdried (MgSO4)
14. customevaporated
15. customto give 10.3 g
16. customchromatographed on 75 g
17. customof silica gel eluting with ethyl acetate:hexanes:acetic acid, 100:100:1 to yield 0.15 g
18. washof the faster eluting diastereomer (isomer A) and 0.12 g
19. washof slower eluting diastereomer (isomer B)
20. customchromatographed similarly (silica gel, 1300 g.) which
21. customgave 2.5 g
22. additionof a mixture of both the diastereomers, and 1.5 g
23. customThe mixed fractions were rechromatographed
24. customto give 0.5 g
25. customtriturated with hexanes containing a few drops of ethyl acetate
26. filtrationfiltered
27. customdried
28. customto yield 2.57 g

ORD-Eintrag

ord-50f1ed7ee4d4404d9d4ddc4e5e84e326

Quelldatensatz

uspto-grants-1993_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05223516