Water → Tert-butyl 3-(2-methyl-4-(morpholinomethyl)phenoxy)azetidine-1-carboxylate

HRID 1035176Notes

Reaction equation

HRID 1035176 reaction equation
[H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:17].CS(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:17][CH:23]1[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]1

Participants

6

Reactant 4

HCID 962WaterHCID 24758Sodium hydrideHCID 10753243Tert-butyl 3-(methanesulfonyloxy)azetidine-1-carboxylateHCID 666533412-Methyl-4-(morpholin-4-ylmethyl)phenol

Product 1

HCID 58043147Tert-butyl 3-(2-methyl-4-(morpholinomethyl)phenoxy)azetidine-1-carboxylateYield 75%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Conditions

Temperature
80 °C

Procedure

A mixture of NaH (55-65% disp. in oil, 0.55 g, 12.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 2-methyl-4-(morpholin-4-ylmethyl)phenol—see WO 2006133567—(2.0 g, 9.6 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.2 g, 12.5 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The residue was purified by column chromatography on SiO2 using 10-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.6 g (75%) of 12A as an oil. 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.34-2.49 (m, 4H), 3.40 (s, 2H), 3.62-3.76 (m, 4H), 3.94-4.07 (m, 2H), 4.23-4.35 (m, 2H), 4.79-4.92 (m, 1H), 6.38 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).

Workup

  1. temperaturewas cooled by an ice-bath
  2. additionwas added drop-wise over 10 minutes
  3. temperaturecooled to RT
  4. extractionthe mixture was extracted three times with EtOAc (100 mL)
  5. customThe residue was purified by column chromatography on SiO2 using 10-75% EtOAc/heptane as eluent
  6. customThe product was further purified

Sources & evidence

ORD record
ord-b40495e0bbb74592a90d2154f6ee614b
Source dataset
uspto-grants-2013_10
Patent number
US08546375B2

Reaction notes

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