Diisopropylethylamine → (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester

Temperature

60 °C

A mixture of (L)-leucine methyl ester hydrochloride (0.79 g, 4.34 mmol) in acetonitrile (9.5 mL) was treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol) and acetonitrile (9.5 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 3.96 mmol) in acetonitrile (9.5 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.86 g, 59%) as a light, brown solid: HR-ES-MS m/z calculated for C18H20NO4F3 [M+H]+ 372.1417, observed 372.1418; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.29-1.55 (m, 1H), 1.56-1.68 (m, 1H), 1.73-1.90 (m, 1H), 3.66 (s, 3H), 4.19 (d, J=18.1 Hz, 1H), 4.26 (d, J=18.1 Hz, 1H), 4.75 (dd, J=11.4, 4.6 Hz, 1H), 4.95 (s, 1H), 7.64-7.78 (m, 4H).

1. additionAfter addition
2. temperatureAt this time, the reaction was cooled to 25° C.
3. temperatureheated to 80° C
4. customUpon reaching 80° C.
5. additionAfter the addition
6. temperaturewas heated to 100° C.
7. stirringstirred overnight
8. temperatureAt this time, the reaction mixture was cooled to 25° C.
9. concentrationconcentrated in vacuo
10. additionThe residue was diluted with dichloromethane (100 mL)
11. washwas washed with a 2N aqueous hydrochloric acid solution (1×100 mL)
12. dry with materiala saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate
13. filtrationfiltered
14. washrinsed with dichloromethane
15. concentrationconcentrated in vacuo
16. customPurification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes)

ORD record

ord-725e4719817841df99feb7c3bd70b8bf

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07741327B2