Water → (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

HRID 2405931Notes

Reaction equation

HRID 2405931 reaction equation
[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([OH:13])=O)[CH:7]=1)#[N:2].CN1CCOCC1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].O>CC1CCCO1>[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][CH2:9][C@@:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:33][O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[O:13])[CH:7]=1)#[N:2]

Participants

6

Reactant 4

HCID 962WaterHCID 79724-MethylmorpholineHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 70817983(2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid

Product 1

HCID 86710241(2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamideYield 28%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Procedure

To a solution of the crude (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid in 2-methyltetrahydrofuran (20 mL) was added N-methyl morpholine (0.494 g, 4.83 mmol, 3 eq) and CDMT (0.424 g, 2.42 mmol, 1.5 eq). The solution was allowed to stir at room temperature for one hour. O-tetrahydro-2H-pyran-2-yl-hydroxylamine (0.283 g, 2.42 mmol, 1.5 eq) was added to the solution, and the reaction mixture was allowed to stir for an additional hour at room temperature. Water (20 mL) was added, and the solution was extracted with 2-methyltetrahydrofuran (100 mL). The aqueous layer was re-extracted with 2-methyltetrahydrofuran (150 mL) and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product mixture was purified by flash chromatography on a 40 g silica column eluting with 70-100% EtOAc/Heptane to give (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (165 mg, 28% yield over two steps) as a white solid. LC-MS M−H 369.4.

Workup

  1. stirringto stir for an additional hour at room temperature
  2. extractionthe solution was extracted with 2-methyltetrahydrofuran (100 mL)
  3. extractionThe aqueous layer was re-extracted with 2-methyltetrahydrofuran (150 mL)
  4. washthe combined organic layers were washed with brine
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product mixture was purified by flash chromatography on a 40 g silica column
  9. washeluting with 70-100% EtOAc/Heptane

Sources & evidence

ORD record
ord-27d04173371f4bb59c09227ad150358a
Source dataset
uspto-grants-2014_08
Patent number
US08809333B2

Reaction notes

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