반응 #47333

반응 방정식

N,N-diisopropylethylamine

(L)-leucine methyl ester hydrochloride

N,N-diisopropylethylamine

4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester

→

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

수율 52.0%

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
   온도was heated to 100° C.
7. 7
   workup.STIRRINGstirred overnight
8. 8
   온도At this time, the reaction mixture was cooled to 25° C.
9. 9
   농축concentrated in vacuo
10. 10
    workup.ADDITIONThe residue was diluted with dichloromethane (100 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 magnesium sulfate
13. 13
    여과filtered
14. 14
    세척rinsed with dichloromethane
15. 15
    농축concentrated in vacuo
16. 16
    기타Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes)

실험 절차

A mixture of (L)-leucine methyl ester hydrochloride (0.94 g, 5.17 mmol) in acetonitrile (11 mL) was treated with N,N-diisopropylethylamine (0.84 mL, 5.08 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 (0.84 mL, 5.08 mmol) and acetonitrile (11 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 4.71 mmol) in acetonitrile (11 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)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 52%) as a red/orange oil: HR-ES-MS m/z calculated for C17H19NO4FCl [M+H]+ 356.1060, observed 356.1060; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.36-1.54 (m, 1H), 1.62 (ddd, J=14.0, 9.6, 4.6 Hz, 1H), 1.81 (ddd, J=14.0, 11.4, 4.6 Hz, 1H), 3.66 (s, 3H), 4.22 (d, J=18.3 Hz, 1H), 4.28 (d, J=18.3 Hz, 1H), 4.74 (dd, J=11.4, 4.6 Hz, 1H), 5.07 (s, 1H), 7.33 (td, J=8.1, 1.4 Hz, 1H), 7.48-7.55 (m, 1H), 7.58 (ddd, J=8.1, 6.7, 1.4 Hz, 1H).

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