4-Methylmorpholine → (3R,4S,5S)-tert-butyl 4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoate

HRID 2282802

Reaktionsgleichung

Reaktionsgleichung von HRID 2282802
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:45][O:46][C@@H:47]([C@@H:56]([NH:61][CH3:62])[C@@H:57]([CH3:60])[CH2:58][CH3:59])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:61]([CH3:62])[C@@H:56]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:47]([O:46][CH3:45])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1

Komponenten

6

Edukt 4

HCID 79724-MethylmorpholineHCID 184502-Chloro-4,6-dimethoxy-1,3,5-triazineHCID 688217FMOC-L-valineHCID 14730240(3r,4s,5s)-Tert-butyl 3-methoxy-5-methyl-4-(methylamino)heptanoate hydrochloride

Produkt 1

HCID 86685718(3R,4S,5S)-tert-butyl 4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoateAusbeute 113,1 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 73012-MethyltetrahydrofuranLösungsmittel

Versuchsvorschrift

To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-valine (18.53 g, 54.60 mmol, 1.3 eq.) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.58 g, 54.6 mmol, 1.3 eq.) in 2-methyltetrahydrofuran (118.00 mL, 0.34 M) was added N-methylmorpholine (6.52 mL, 59.1 mmol, 1.5 eq.) followed by #4 (11.80 g, 39.9 mmol, 1 eq.). After 3 hours, the reaction was quenched with water (50 mL) and stirred for 15 minutes. The aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a colorless oil, which was purified by silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane) to give #5 (26.2 g, 91%) as a colorless foam. LC-MS (Protocol I) m/z 581.3 [M+H+]1604.3 [M+Na+], retention time=4.993 minutes; 1H NMR (400 MHz, DMSO-d6), possibly a mixture of rotamers, characteristic major signals: δ 7.88 (d, J=7.4 Hz, 2H), 7.71 (d, J=7.4 Hz, 2H), 7.62 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.4, 7.4 Hz, 2H), 7.27-7.34 (m, 2H), 4.13-4.32 (m, 4H), 3.70-3.82 (br m, 1H), 3.24 (s, 3H), 2.92 (br s, 3H), 2.54 (dd, J=15.7, 2.4 Hz, 1H), 2.17 (dd, J=15.4, 9.4 Hz, 1H), 1.95-2.07 (m, 1H), 1.70-1.83 (br m, 1H), 1.40 (s, 9H), 0.83-0.94 (m, 9H), 0.69 (t, J=7.2 Hz, 3H).

Aufarbeitung

  1. customthe reaction was quenched with water (50 mL)
  2. customThe aqueous layer was separated
  3. extractionback-extracted with 2-methyltetrahydrofuran (50 mL)
  4. washThe combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give a colorless oil, which
  9. customwas purified by silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane)

Quellen und Nachweise

ORD-Eintrag
ord-ffbe6ed289de45489271cff1aec2a80b
Quelldatensatz
uspto-grants-2015_09
Patentnummer
US09138486B2

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