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

Bis(trimethylsilyl)trifluoroacetamide (16 mL., 60 mmol.) was added to a suspension of L-norleucine (2.62 g., 20 mmol.) in 40 mL of acetonitrile at 0° C. The suspension was allowed to warm to room temperature and was stirred for 2.5 hours, at which point, almost all of the solid dissolved. The reaction mixture was recooled to 0° C. and 2-trifluoromethyl-3-acetylthiopropionyl chloride (4.7 g., 20 mmol.) was added dropwise over 20 minutes as a solution in 10 mL of acetonitrile. After stirring at room temperature for 18 hours, the reaction was poured into 200 mL of water and the resulting mixture was extracted with ethyl acetate (500 mL). Brine was added to break up an emulsion which formed during this extraction. The aqueous layer was extracted once more with ethyl acetate (100 mL) and the combined organic layers were washed with brine, dried (MgSO4), and concentrated to afford an oily residue which was pre-absorbed on Celite. The crude product and Celite mixture was loaded onto an 8×30 cm silica gel column which was eluted as follows: 5 L hexane:ethyl acetate:acetic acid (750:250:25), 2 L hexane:ethyl acetate:acetic acid (700:300:25), 2 L hexane:ethyl acetate:acetic acid (500:500:25). The pure less polar fractions were concentrated and co-evaporated from heptane to afford a white solid which was recrystallized twice from ethyl acetate/hexane. Drying under high vacuum at room temperature for 18 hours afforded 1.95 g. of the title isomer A compound as a white powder, m.p. 176°-178° C., TLC Rf =0.30 (ethyl acetate:hexane:acetic acid, 30:70:1). [α]D =-133.3° (c=0.6, methanol).

1. dissolutionalmost all of the solid dissolved
2. customwas recooled to 0° C.
3. stirringAfter stirring at room temperature for 18 hours
4. extractionthe resulting mixture was extracted with ethyl acetate (500 mL)
5. additionBrine was added
6. customformed during this extraction
7. extractionThe aqueous layer was extracted once more with ethyl acetate (100 mL)
8. washthe combined organic layers were washed with brine
9. dry with materialdried (MgSO4)
10. concentrationconcentrated
11. customto afford an oily residue which
12. customwas pre-absorbed on Celite
13. washwas eluted
14. concentrationThe pure less polar fractions were concentrated
15. customto afford a white solid which
16. customwas recrystallized twice from ethyl acetate/hexane
17. customDrying under high vacuum at room temperature for 18 hours
18. customafforded 1.95 g

ORD-Eintrag

ord-fe602382e8684e9a9f4ddc258a850561

Quelldatensatz

uspto-grants-1993_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US05223516