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

Temperature

0 °C

A stirred suspension of L-phenylalanine (7.60 g, 46 mmol) in 45 mL of dry acetonitrile under argon was cooled to 0° C. and bis(trimethylsilyl)trifluoroacetamide (24.7 mL, 92 mmol) was added. The reaction mixture was allowed to stir and slowly warm to room temperature. After 4 hours, practically all of the amino acid was in the solution, which was light yellow in color. 2-Trifluoromethyl-3-acetylthio propionyl chloride (4.69 g, 20 mmol), dissolved in 10 mL of acetonitrile, was added dropwise over a period of about 45 minutes at 5° C. and thereafter the reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was evaporated under reduced pressure to give a light yellow oil. The oil was partitioned between water (75 mL) and ethyl acetate (100 mL). The entire mixture was filtered to remove a white precipitate (phenylalanine), and the organic layer was separated. The aqueous phase was extracted once more with 50 mL of ethyl acetate. The combined ethyl acetate extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give 20.1 g of the crude mixture of diastereomers as a light yellow solid. A 2.0 g portion of the product was flash chromatographed on silica gel (125:1 silica gel to compound), using ethyl acetate:hexanes:acetic acid, 100:100:1 as the eluent, to yield 0.370 g of the faster eluting diastereomer (isomer A) and 0.383 g of the slower eluting diastereomer (isomer B). The remaining 18.1 g of crude material was flash chromatographed similarly to yield 2.67 g of isomer A and 2.92 g of isomer B. The combined yield of isomer A was 3.04 g as a white crystalline solid, m.p. 183°-185° C., TLC Rf =0.30 (200:100:1 ethyl acetate:hexanes:acetic acid), [α]D =-98.8° (c=1.00, methanol).

1. temperatureslowly warm to room temperature
2. additionwas added dropwise over a period of about 45 minutes at 5° C.
3. temperatureto warm to room temperature
4. stirringstir overnight
5. customThe mixture was evaporated under reduced pressure
6. customto give a light yellow oil
7. customThe oil was partitioned between water (75 mL) and ethyl acetate (100 mL)
8. filtrationThe entire mixture was filtered
9. customto remove a white precipitate (phenylalanine)
10. customthe organic layer was separated
11. extractionThe aqueous phase was extracted once more with 50 mL of ethyl acetate
12. extractionThe combined ethyl acetate extract
13. washwas washed with brine
14. dry with materialdried over anhydrous magnesium sulfate
15. customevaporated
16. customto give 20.1 g of the crude mixture of diastereomers as a light yellow solid
17. customchromatographed on silica gel (125:1 silica gel to compound)
18. customhexanes:acetic acid, 100:100:1 as the eluent, to yield 0.370 g of the
19. washfaster eluting diastereomer (isomer A) and 0.383 g of the
20. washslower eluting diastereomer (isomer B)
21. customchromatographed similarly
22. customto yield 2.67 g of isomer A and 2.92 g of isomer B

ORD record

ord-1fac600e863b474e88462b5bda9ee5c6

Source dataset

uspto-grants-1995_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05414017