Methyl iodide → 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

HRID 406698Notes

Reaction equation

HRID 406698 reaction equation
[CH3:1][C:2]([CH3:34])([CH2:5][C@@:6]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].[CH3:35]I.[H-].[Na+]>C1COCC1>[CH3:34][C:2]([CH3:1])([CH2:5][C@@:6]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:35])[CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 596356372,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

Product 1

HCID 596356402,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrileYield 85%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (202 mg, 0.444 mmol) and MeI (110 μL, 4 equiv) in dry THF (5 mL) was cooled to 0° C. NaH (60% in mineral oil, 36 mg, 2 equiv) was added. After 10 min, the mixture was warmed to rt slowly and stirred for 3 h. LC-MS showed about 50% conversion. The mixture was heated for 1 h at 60° C. LC-MS found the reaction completed. After cooling to rt, the mixture was cooled to 0° C. and quenched with satd aq NH4Cl (3 mL). The mixture was then diluted with CH2Cl2 (20 mL), washed with 1% aq HCl (5 mL) and brine (4 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by prep HPLC to afford 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (177.4 mg, 85% yield) product as a light brown oil.

Workup

  1. temperatureThe mixture was heated for 1 h at 60° C
  2. temperatureAfter cooling to rt
  3. temperaturethe mixture was cooled to 0° C.
  4. customquenched with satd aq NH4Cl (3 mL)
  5. additionThe mixture was then diluted with CH2Cl2 (20 mL)
  6. washwashed with 1% aq HCl (5 mL) and brine (4 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationAfter filtration and concentration
  9. customthe residue was purified by prep HPLC

Sources & evidence

ORD record
ord-0c7276c76dc1481889c9dcda413ed41f
Source dataset
uspto-grants-2014_06
Patent number
US08754076B2

Reaction notes

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