Citric Acid → (S)-3-oxo-cyclopentyl-N-pyrazin-2-yl-propionamide

Temperature

-10 °C

A mixture of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3-oxo-cyclopentyl)-propionic acid (544 mg, 1.58 mmol), methylene chloride (7 mL), toluene (5 mL), and a catalytic amount of N,N-dimethylformamide (10 μL, 0.13 mmol) under nitrogen was treated with oxalyl chloride (1.4 mL, 16.3 mmol). The reaction was stirred for 1 h (gas evolution). At this time, the reaction was then partially evaporated in vacuo at 25° C. to remove excess oxalyl chloride. The residue was co-evaporated with toluene (2×4 mL) and concentrated in vacuo to about 4 mL. The resulting brown slurry was added via a cannula over 15 min to a mixture of 2-aminopyrazine (189 mg, 1.99 mmol), methylene chloride (4 mL), and pyridine (170 μL, 2.1 mmol) cooled to −10° C. The reaction was allowed to warm to 25° C., where it was stirred for 18 h. At this time, the reaction was quenched with water (700 μL) followed by a 1M aqueous citric acid solution (5 ml, 5 mmol). The reaction then was diluted with ethyl acetate (40 ml) and a 1M aqueous citric acid solution (20 mL), mixed well, and the phases were separated. The organic phase was washed with a 1M aqueous citric acid solution (3×5 mL). The combined aqueous phases were back-extracted with ethyl acetate (30 mL). The combined organic phases were washed with a 10% aqueous potassium bicarbonate solution (3×25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a crude product (506.6 mg, 76%) as a brown foam. Flash chromatography (Merck Silica gel 60, 230–400 mesh, ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3-oxo-cyclopentyl-N-pyrazin-2-yl-propionamide (442 mg, 66%) as a tan foam. HPLC (Zorbax XDB-C8 150×5 mm, 20–100% acetonitrile/water over 20 min, 20 min run, 220 nm, 1 cc/min Rt=7.7 min) indicated 95:3 area % purity, and HPLC (Chiralpak AD-RH, 150×5 mm, 5 ethanol/5 methanol/4 water, 60 min run, 220 nm, 0.5 cc/min, Rt of 2(R), 3(S)=25.2 min; 2(R), 3(R)=39.2 min) showed 90.5% de.

1. customAt this time, the reaction was then partially evaporated in vacuo at 25° C.
2. customto remove excess oxalyl chloride
3. concentrationconcentrated in vacuo to about 4 mL
4. temperatureto warm to 25° C.
5. stirringwhere it was stirred for 18 h
6. customAt this time, the reaction was quenched with water (700 μL)
7. customThe reaction
8. customthe phases were separated
9. washThe organic phase was washed with a 1M aqueous citric acid solution (3×5 mL)
10. extractionThe combined aqueous phases were back-extracted with ethyl acetate (30 mL)
11. washThe combined organic phases were washed with a 10% aqueous potassium bicarbonate solution (3×25 mL)
12. dry with materialdried over anhydrous sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customto afford a crude product (506.6 mg, 76%) as a brown foam

ORD record

ord-0ae500e4a1874188aa07fbafbb476a0f

Source dataset

uspto-grants-2006_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07105671B2