Triphosgene → (5R)-5-ethyl-5-methyl-3-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]imidazolidine-2,4-dione

HRID 527716Notes

Reaction equation

[NH2:1][C@:2]([CH3:28])([CH2:26][CH3:27])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:25])([CH3:24])[O:20][C:21]([CH3:23])=[N:22][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:4].Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.O>[CH2:26]([C@@:2]1([CH3:28])[NH:1][C:30](=[O:32])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]([CH3:25])([CH3:24])[O:20][C:21]([CH3:23])=[N:22][C:17]=4[CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:27]

Participants

Conditions

Temperature: 0 °C

Procedure

To a solution of (2R)-2-amino-2-methyl-N-[6-[(2,4,4-trimethyl-3,1-benzoxazin-5-yl)oxy]-3-pyridyl]butanamide (Intermediate 205, 143 mg, 0.37 mmol) and TEA (0.21 mL) in ethyl acetate (2.5 mL) at 0° C., triphosgene (44 mg, 0.15 mmol) dissolved in ethyl acetate (2.5 mL) was added drop wise in 10 min. The reaction mixture was stirred at 0° C. for 40 min. The reaction mixture was diluted with water (5 mL) and ethyl acetate (10 mL). Phases were separated and the aqueous was back-extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated and the residue was purified by flash chromatography on silica gel using ethyl acetate as eluent affording the title compound (115 mg) as white solid.

Workup

additionwas added drop wise in 10 min
customPhases were separated
extractionthe aqueous was back-extracted with ethyl acetate (2×10 mL)
washThe combined organic layers were washed with brine (15 mL)
dry with materialdried over Na2SO4
filtrationfiltered
concentrationconcentrated
customthe residue was purified by flash chromatography on silica gel

Sources & evidence

ORD record: ord-f2c74c2b39124f288bb3fae07153c34c
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09346790B2

Reaction notes

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