Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]([NH2:17])[CH2:6][C:7]([F:16])([F:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>ClCCl.O>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]([NH:17][C:32]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:33])[CH2:6][C:7]([F:16])([F:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1To a mixture of (S)-2-amino-4,4-difluoro-5-phenyl-pentanoic acid methyl ester hydrochloride (2.50 g, 8.94 mmol) and diisopropyl amine (22.3 mmol, 2.89 g) in dry dichloromethane (40 mL) under N2 is added drop wise morpholine carbonyl chloride (13.4 mmol, 2.0 g). The mixture is stirred at room temperature for 15 hours, and then diluted with water (50 mL). The aqueous layer is extracted with dichloromethane (30 mL). The organic layers are dried over magnesium sulfate and then concentrated in vacuum. Purification over 110 g silica gel, eluting with EtOAc:Heptane (1:1, then 2:1) affords (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid methyl ester (2.82 g, 88.5%).
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