4-Methylmorpholine → HCID 10369438, compound

HRID 2267618Notes

Reaction equation

HRID 2267618 reaction equation
[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37](O)=[O:38])[CH:32]=[C:33]([F:35])[CH:34]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:38])[CH:32]=[C:33]([F:35])[CH:34]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 1454243,5-Difluorophenylacetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 58997958HCID 58997958, compound

Product 1

HCID 10369438HCID 10369438, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-leucinamide (64g) (65 mg, 0.177 mmol) in dichloromethane (2 mL) was added 3,5-difluorophenylacetic acid (35 mg, 0.230 mmol), HOBt (31 mg, 0.230 mmol), NMM (25 mg, 0.248 mmol) and EDAC-HCl (44 mg, 0.230 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic extracts were washed in succession with saturated aqueous sodium bicarbonate and 1N aqueous HCl. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane:ethyl acetate to afford the title compound in a 1:1 mixture with the 2S,3R diastereomer (65 mg, 70%) as a white solid. TLC Rf=0.31 (6:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.82 (m, 6H), 1.21-1.55 (m, 3H), 3.48 (s, 2H), 4.28 (m, 1H), 5.15 (t, 1H, J=7.2 Hz), 5.76 (m, 2H), 6.27 (d, 1H, J=7.0 Hz), 6.78 (m, 3H), 7.06 (m, 1H), 7.15-7.42 (m, 8H), 7.55 (br s, 1H). MS APCI, m/z=510 (M+1). LC/MS: 2.40 min.

Workup

  1. extractionextracted with ethyl acetate three times
  2. washThe combined organic extracts were washed in succession with saturated aqueous sodium bicarbonate and 1N aqueous HCl
  3. customThe organic solution was dried
  4. filtrationfiltered
  5. customevaporated
  6. customThe residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane

Sources & evidence

ORD record
ord-5142cdb5e49e4cef9ac320b70eef682d
Source dataset
uspto-grants-2010_12
Patent number
US07858776B2

Reaction notes

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