Ethylene Glycol → 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

HRID 715546Notes

Reaction equation

HRID 715546 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].OS(O)(=O)=O.[CH2:40](O)[CH2:41][OH:42]>O>[OH:42][CH2:41][CH2:40][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 174Ethylene GlycolHCID 1118Sulfuric AcidHCID 71227359Gsk-2798745

Product 1

HCID 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-carbonitrileYield 21%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
60 °C

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 (500 mg, 1.086 mmol, example 147) in ethylene glycol (4.93 mL) was added concentrated H2SO4 (0.5 mL, 9.38 mmol) at RT and heated at 60° C. overnight. The reaction mixture was cooled to RT, diluted with water, and extracted 5×DCM. The combined DCM layers were washed with brine, concentrated, and purified by reverse phase HPLC (Waters Sunfire 30×150 mm column, acetonitrile:water 0.1% TFA long 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 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 as a white solid (121 mg, 21%). MS (m/z) 505.3 (M+H+).

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. extractionextracted 5×DCM
  3. washThe combined DCM layers were washed with brine
  4. concentrationconcentrated
  5. custompurified by reverse phase HPLC (Waters Sunfire 30×150 mm column, acetonitrile:water 0.1% TFA long 20-60%, 50 mL/min, 15 min)

Sources & evidence

ORD record
ord-066da4f4130a40f7a6e8404f0544f0f7
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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