Diisopropylethylamine → benzyl (2S)-2-[[(2S)-3-(difluoromethoxy)-2-[(2-morpholinoacetyl)amino]propanoyl]amino]-3-phenyl-propanoate

HRID 61303Notes

Reaction equation

Cl.[NH2:2][C@@H:3]([CH2:25][O:26][CH:27]([F:29])[F:28])[C:4]([NH:6][C@@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5].Cl.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][CH:27]([F:28])[O:26][CH2:25][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)[C:4]([NH:6][C@@H:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5]

Participants

Conditions

Temperature: 0 °C

Procedure

To a stirred solution of benzyl (2S)-2-[[(2S)-2-amino-3-(difluoromethoxy)propanoyl]amino]-3-phenyl-propanoate hydrochloride (1.65 g, 3.84 mmol), 2-morpholinoacetic acid hydrochloride (768 mg, 4.23 mmol) and HOBt hydrate (648 mg, 4.23 mmol) in DCM (20 mL) was added EDC hydrochloride (811 mg, 4.23 mmol). The resulting mixture was cooled to 0° C. and treated with DIPEA (0.736 mL, 4.23 mmoL), dropwise, warmed to room temperature and stirred overnight. The mixture was diluted with DCM (30 mL) and washed with saturated sodium bicarbonate (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo then chromatographed on silica gel eluting with 0%-100% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the compound of Formula XVII(a) (1.54 g, 77%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.72 (m, 1H), 7.35-6.90 (m, 10H), 6.12 (t, J=74 Hz, 1H), 5.14-5.04 (m, 2H), 4.81-4.75 (m, 1H), 4.65-4.55 (m, 1H), 4.26-4.20 (m, 1H), 3.93-3.87 (m, 1H), 3.65-3.50 (m, 4H), 3.15-2.90 (m, 4H), 2.45-2.35 (m, 4H).

Workup

temperaturedropwise, warmed to room temperature
washwashed with saturated sodium bicarbonate (2×50 mL)
dry with materialThe organic phase was dried over anhydrous sodium sulfate
filtrationfiltered
concentrationconcentrated in vacuo
customthen chromatographed on silica gel eluting with 0%-100% ethyl acetate in hexanes
concentrationThe product-containing fractions were concentrated in vacuo
customgiving the compound of Formula XVII(a) (1.54 g, 77%) as a white solid

Sources & evidence

ORD record: ord-70173c065afa4076ad30aa6e4a5f3812
Source dataset: uspto-grants-2016_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09441012B2

Reaction notes

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