Reaction #47395

Reaction equation

ethyl acetate

(E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester

N,N-diisopropylethylamine

(L)-leucine methyl ester hydrochloride

→

(S)-2-[4-(3ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester

Yield 28.3%

Solvents

acetonitrile

acetonitrile

Conditions

Workup

1. 1
   Temperaturethe resulting mixture refluxed for 14 h
2. 2
   FiltrationThe mixture was filtered
3. 3
   Otherto remove salts
4. 4
   Washthe filtrate washed successively with saturated ammonium chloride, water, and brine
5. 5
   DryingThe solution was dried over sodium sulfate
6. 6
   Filtrationfiltered
7. 7
   Otherevaporated
8. 8
   workup.DISSOLUTIONThe residue was dissolved in tetrahydrofuran (10 mL)
9. 9
   Othertransferred to an Emry Optimizer microwave reaction vessel
10. 10
    Temperatureheated at 160° C., for 4 h
11. 11
    OtherThe crude product obtained after aqueous work-up
12. 12
    Otherwas purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 100 g, 5% to 60% ethyl acetate/hexanes)

Procedure

To a solution of (L)-leucine methyl ester hydrochloride (6.00 g, 0.033 mol) dissolved in acetonitrile (50 mL) was added (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (6.05 g) in acetonitrile (10 mL) and N,N-diisopropylethylamine (7.27 g, 0.056 mol) and the resulting mixture refluxed for 14 h. The reaction mixture was cooled to room temperature and then poured into ethyl acetate. The mixture was filtered to remove salts and the filtrate washed successively with saturated ammonium chloride, water, and brine. The solution was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in tetrahydrofuran (10 mL) and then transferred to an Emry Optimizer microwave reaction vessel and heated at 160° C., for 4 h. The crude product obtained after aqueous work-up, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 100 g, 5% to 60% ethyl acetate/hexanes) to afford (S)-2-[4-(3ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.80 g, 28%) as an oil.

Source