Triphosgene → Kv3 modulator 5

HRID 2278335Notes

Reaction equation

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

Participants

Conditions

Temperature: 0 °C

Procedure

To a solution of (2R)-2-amino-N-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]butanamide (Intermediate 21, 24 mg, 0.068 mmol) in dry DCM (3 ml) TEA (0.028 ml, 0.2 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (15 mg, 0.05 mmol) in dry DCM (1.5 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (11 mg) as a white solid.

Workup

customThe reaction was quenched with water (10 ml) and two phases
customwere separated
dry with materialThe organic layer was dried (Na2SO4)
filtrationfiltered
customevaporated
customthe residue was purified
custompurified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents

Sources & evidence

ORD record: ord-d1f7b8b6892b4569af7b4c20bd2453d0
Source dataset: uspto-grants-2015_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09133175B2

Reaction notes

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