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

Temperature

60 °C

A mixture of (L)-leucine methyl ester hydrochloride (0.90 g, 4.96 mmol) in acetonitrile (12.4 mL) was treated with N,N-diisopropylethylamine (0.80 mL, 4.87 mmol). After addition was complete, the mixture was stirred at 60° C. for 45 min. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.80 mL, 4.87 mmol) and acetonitrile (12.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.45 g, 4.51 mmol) in acetonitrile (11.3 mL). After the addition was complete, the reaction mixture was heated to 80° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 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 sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.53 g, 35%) as a yellow oil: HR-ES-MS m/z calculated for C17H19NO4F2 [M+Na]+ 362.1174, observed 362.1174; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.5 Hz, 3H), 0.91 (d, J=6.5 Hz, 3H), 1.34-1.51 (m, 1H), 1.59 (ddd, J=13.8, 9.4, 4.4 Hz, 1H), 1.71-1.87 (m, 1H), 3.64 (s, 3H), 4.11-4.31 (m, 2H), 4.71 (dd, J=11.3, 4.4 Hz, 1H), 4.94 (s, 1H), 7.07-7.27 (m, 1H), 7.42-7.70 (m, 2H).

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. temperaturethe reaction mixture was heated to 80° C. where it
7. stirringstirred overnight
8. temperatureAt this time, the reaction mixture was cooled to 25° C.
9. concentrationwas concentrated in vacuo
10. additionThe residue was diluted with dichloromethane (75 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 sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customPurification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes)

ORD record

ord-7696d7ff133f47e5ae7ec75d086b52ca

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07741327B2