4-Methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile → 6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methylpyridine-3-carbonitrile

HRID 1187151Notes

Reaction equation

[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][O:9]2)[N:5]=[CH:4][C:3]=1[C:11]#[N:12].[OH:13][C@H:14]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCO>[OH:9][CH:8]([C:6]1[N:5]=[CH:4][C:3]([C:11]#[N:12])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C@H:14]([OH:13])[C:22]2[CH:31]=[CH:30][C:25]3[C:26](=[O:29])[O:27][CH2:28][C:24]=3[C:23]=2[CH3:32])[CH2:17][CH2:18]1

Participants

Conditions

Temperature: 140 °C

Procedure

To a microwave tube were added 4-methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile (40 mg, 0.25 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (69 mg, 0.25 mmol, as a free base), and EtOH (3.0 mL). The mixture was heated in the microwave for 60 min at 140° C. The solvent was evaporated and the crude product was purified by chiral prep SFC (30% MeOH (0.1% DEA)/CO2 on OJ column) to provide 6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methylpyridine-3-carbonitrile as individual isomers. Further, the products were treated with 1 M HCl in diethyl ether to give the final products as HCl salts.

Workup

customThe solvent was evaporated
customthe crude product was purified by chiral prep SFC (30% MeOH (0.1% DEA)/CO2 on OJ column)

Sources & evidence

ORD record: ord-5e5211dc1fe24f0185d4c673f68e5ecf
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08673920B2

Reaction notes

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