Methyl iodide → 1-(((5S,7S)-3-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

HRID 715545Notes

Reaction equation

HRID 715545 reaction equation
[OH:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:37]I>CN(C)C=O>[CH3:37][O:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:3])[CH3:4]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 71227359Gsk-2798745

Product 1

HCID 712268581-(((5S,7S)-3-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrileYield 58.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (75 mg, 0.163 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was added sodium hydride (9.77 mg, 0.244 mmol) at RT. After 10 minutes, MeI (0.020 mL, 0.326 mmol) was added. The mixture stirred for an hour and was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water 0.1% TFA 30-70%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-3-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white powder (45 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=1.51 Hz, 1H), 8.47-8.53 (m, 2H), 8.39 (d, J=1.00 Hz, 1H), 7.84 (d, J=8.78 Hz, 1H), 7.60 (dd, J=8.53, 1.51 Hz, 1H), 4.17 (s, 2H), 3.88 (dd, J=23.09, 10.29 Hz, 2H), 3.09 (s, 3H), 2.00 (d, J=14.05 Hz, 1H), 1.89 (d, J=14.56 Hz, 1H), 1.59-1.78 (m, 3H), 1.30-1.56 (m, 9H), 1.08 (s, 3H). MS (m/z) 443.2 (M-OMe).

Workup

  1. customwas purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water 0.1% TFA 30-70%, 50 mL/min, 15 min)

Sources & evidence

ORD record
ord-c9e6f3db047f4c87898025f907879c48
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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