Diisopropylethylamine → (S)-2-[3-ethoxycarbonyl-2-(4-methoxy-phenoxy)-allylamino]-4-methyl-pentanoic acid methyl ester

Temperature

60 °C

A mixture of (L)-leucine methyl ester hydrochloride (0.64 g, 3.56 mmol) in acetonitrile (8.9 mL) was treated with N,N-diisopropylethylamine (0.57 mL, 3.49 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 (0.57 mL, 3.49 mmol) and acetonitrile (8.9 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (1.02 g, 3.23 mmol) in acetonitrile (8.09 mL). After the addition was complete, the reaction mixture was heated to 100° 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, 20-30% ethyl acetate/hexanes) afforded (S)-2-[3-ethoxycarbonyl-2-(4-methoxy-phenoxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.84 g, 68%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H), 1.30-1.50 (m, 2H), 1.63-1.81 (m, 1H), 3.60 (s, 3H), 3.77 (s, 3H), 3.88 (dd, J=6.5, 3.2 Hz, 1H), 3.96 (d, J=6.9 Hz, 1H), 4.01 (d, J=6.9 Hz, 1H), 4.61 (s, 1H), 7.02 (s, 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. temperaturethe reaction mixture was heated to 100° 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, 20-30% ethyl acetate/hexanes)

ORD record

ord-3151b13af8404a7c8a5d8e35194aa035

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07741327B2