6-(Oxiran-2-yl)nicotinonitrile → 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)pyridine-3-carbonitrile

HRID 1187150Notes

Reaction equation

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

Participants

Conditions

Temperature: 140 °C

Procedure

To a microwave tube were added isomer B of 6-(oxiran-2-yl)pyridine-3-carbonitrile (330 mg, 2.26 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (686 mg, 2.48 mmol, as a free base), and EtOH (7.0 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 silica gel MPLC (0→10% CH2CH2:MeOH) 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)pyridine-3-carbonitrile as a single isomer. Further, the product was treated with 1 M HCl in diethyl ether to give the final product as an HCl salt. 1H NMR (500 MHz, DMSO-d6), δ 8.92 (s, 1H), 8.28 (dd, J=1.9 Hz, J=2.0 Hz, 1H), 7.68-7.63 (m, 3H), 5.48 (d, J=4.8 Hz, 1H), 5.37 (d, J=2.2 Hz, 2H), 5.20 (d, J=3.9 Hz, 1H), 5.03 (m, 1H), 4.78 (m, 1H), 2.64 (dd, J=4.1, 1H), 2.55-2.41 (m, 8H), 2.33 (dd, J=3.7 Hz, 1H), 2.24 (s, 3H); LC/MS: (IE, m/z) [(M+1)]+=423.04 (57A).

Workup

customThe solvent was evaporated
customthe crude product was purified by silica gel MPLC (0→10% CH2CH2:MeOH)

Sources & evidence

ORD record: ord-6eb722cc724c421485e095c08389c839
Source dataset: uspto-grants-2014_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08673920B2

Reaction notes

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