반응 #47363

반응 방정식

N,N-diisopropylethylamine

(L)-leucine methyl ester hydrochloride

N,N-diisopropylethylamine

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

→

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

수율 35.0%

용매

acetonitrile

acetonitrile

acetonitrile

반응 조건

후처리

1. 1
   workup.ADDITIONAfter addition
2. 2
   온도At this time, the reaction was cooled to 25° C.
3. 3
   온도heated to 80° C
4. 4
   기타Upon reaching 80° C.
5. 5
   workup.ADDITIONAfter the addition
6. 6
   온도the reaction mixture was heated to 80° C. where it
7. 7
   workup.STIRRINGstirred overnight
8. 8
   온도At this time, the reaction mixture was cooled to 25° C.
9. 9
   농축was concentrated in vacuo
10. 10
    workup.ADDITIONThe residue was diluted with dichloromethane (75 mL)
11. 11
    세척was washed with a 2N aqueous hydrochloric acid solution (1×100 mL)
12. 12
    건조a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate
13. 13
    여과filtered
14. 14
    농축concentrated in vacuo
15. 15
    기타Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes)

실험 절차

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).

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