Diisopropylethylamine → 2-((2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)pyrazin-2-yl)propan-2-yl)oxy)ethyl dimethylphosphinate

HRID 715548Notes

Reaction equation

HRID 715548 reaction equation
[OH:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[N:12][CH:13]=1)([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH3:47][P:48](Cl)([CH3:50])=[O:49]>ClCCl>[CH3:47][P:48]([CH3:50])(=[O:49])[O:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[CH:13]=[N:12][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[CH:10][N:9]=1)([CH3:7])[CH3:6]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 517954Dimethylphosphinic chlorideHCID 712275921-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-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

Product 1

HCID 712276992-((2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)pyrazin-2-yl)propan-2-yl)oxy)ethyl dimethylphosphinateYield 8.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 1-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-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 (60 mg, 0.119 mmol) in dichloromethane (DCM) (1127 μl) was added DIEA (62.3 μl, 0.357 mmol) and dimethylphosphinic chloride (40.1 mg, 0.357 mmol) at RT. The mixture was stirred for 2 hours, concentrated and reconstituted in DMSO/MeOH and filtered. The solution was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile: Water TFA 30-70%, 50 mL/min, 15 min.). The product was free based with PL-HCO3 resin SPE to yield 2-((2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)pyrazin-2-yl)propan-2-yl)oxy)ethyl dimethylphosphinate as a white solid (5.8 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=1.51 Hz, 1H), 8.60 (d, J=1.26 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.83 (d, J=8.53 Hz, 1H), 4.12-4.21 (m, 2H), 3.94-4.03 (m, 2H), 3.88 (dd, J=23.09, 10.04 Hz, 2H), 3.42 (t, J=4.77 Hz, 2H), 2.00 (d, J=13.30 Hz, 1H), 1.88 (d, J=14.05 Hz, 1H), 1.59-1.78 (m, 3H), 1.30-1.56 (m, 15H), 1.07 (s, 3H). MS (m/z) 581.3 (M+H+).

Workup

  1. concentrationconcentrated
  2. filtrationfiltered
  3. customThe solution was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile: Water TFA 30-70%, 50 mL/min, 15 min.)

Sources & evidence

ORD record
ord-349321e13bc2463a9f3f690dcd33d624
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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