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 74718

Reaction equation

HRID 74718 reaction equation
[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

Participants

6

Reactant 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

Product 1

HCID 86685718(3R,4S,5S)-tert-butyl 4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoateYield 113.1%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-6880f5f967504a58b794a36642235c7d
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Linked notes

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