Water → HCID 86660872, compound

HRID 1035179Notes

Reaction equation

HRID 1035179 reaction equation
[H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH:24]([OH:26])=[O:25].[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[C:9]([CH3:14])[CH:8]=1)[CH3:3]

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 450888774-[(Dimethylamino)methyl]-2-methylphenol

Product 1

HCID 86660872HCID 86660872, compoundYield 91%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
80 °C

Procedure

A mixture of NaH (55-65% disp. in oil, 0.35 g, 8.7 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 4-[(dimethylamino)methyl]-2-methylphenol—commercially available—(1.1 g, 6.7 mmol) in DMF (5 mL) was added drop-wise over 10 minutes. The mixture was stirred for 30 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.84 g, 7.3 mmol) in DMF (5 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (100 mL) was added and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were dried through a phase separator and the solvent was removed by evaporation. The residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-50% acetonitrile in water/acetonitrile/formic acid (95/5/0.2), 100 mL/min. Fractions were collected, pooled and concentrated in vacuo. DCM was added and the solution was filtered through a phase separator and concentrated by evaporation. There was obtained 1.93 g (91%) of 16A as a colourless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.37 (s, 3H), 2.62 (s, 6H), 3.97 (s, 2H), 3.92-4.04 (m, 2H), 4.24-4.35 (m, 2H), 4.81-4.92 (m, 1H), 6.59 (d, 1H), 6.62 (s, 1H), 7.35 (d, 1H), 8.42 (s, 1H).

Workup

  1. temperaturewas cooled by an ice-bath
  2. temperaturecooled to RT
  3. extractionthe mixture was extracted three times with EtOAc (50 mL)
  4. customThe combined organic phases were dried through a phase separator
  5. customthe solvent was removed by evaporation
  6. customThe residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm)
  7. customFractions were collected
  8. concentrationconcentrated in vacuo
  9. additionDCM was added
  10. filtrationthe solution was filtered through a phase separator
  11. concentrationconcentrated by evaporation

Sources & evidence

ORD record
ord-3d3e68b287ec4c70bd2137194a54d200
Source dataset
uspto-grants-2013_10
Patent number
US08546375B2

Reaction notes

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