Sodium hydride → tert-Butyl 3-(thiazol-5-ylmethoxy)-azetidine-1-carboxylate

HRID 82996Notes

Reaction equation

HRID 82996 reaction equation
[H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Cl.Cl[CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[S:22]1[C:18]([CH2:17][O:3][CH:4]2[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]2)=[CH:19][N:20]=[CH:21]1

Participants

6

Reactant 4

HCID 24758Sodium hydride2×HCID 81531DiisopropylethylamineHCID 2756801Tert-butyl 3-hydroxyazetidine-1-carboxylateHCID 223194575-(Chloromethyl)-1,3-thiazole hydrochloride

Product 1

HCID 68338107tert-Butyl 3-(thiazol-5-ylmethoxy)-azetidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

Sodium hydride (60% in oil, 292 mg, 7.30 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (602 mg, 3.47 mmol) in dimethylformamide (8 mL) at room temperature. The reaction mixture was stirred for 30 minutes prior to the addition of a solution of 5-(chloromethyl)thiazole hydrochloride (1.18 g, 6.85 mmol) and diisopropylethylamine (2.42 mL, 13.89 mmol) in dimethylformamide (3 mL) at 0° C. The reaction mixture was then heated up to 80° C. and stirred overnight. Since the LCMS monitoring still indicated the presence of starting material, an additional portion of sodium hydride (60% in oil, 139 mg, 3.47 mmol) was added. The reaction mixture was then stirred again at 80° C. After 17 hours stirring at 80° C., the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a solution of sodium hydroxide (5×50 mL) and with brine (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using petroelum ether/dichloromethane/ethyl acetate (7/0/3 to 2/0/8, then 0:5:5 to 0/2/8) as eluent. A second purification was performed on silica gel, using petroelum dichloromethane/acetone (9/1 to 8/2) as eluent. The title product was obtained as a yellow oil (150 mg, 16%).

Workup

  1. stirringstirred overnight
  2. stirringThe reaction mixture was then stirred again at 80° C
  3. stirringAfter 17 hours stirring at 80° C.
  4. customthe reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL)
  5. customThe aqueous phase was separated
  6. extractionextracted with ethyl acetate (2×40 mL)
  7. washThe combined organic phases were washed with a solution of sodium hydroxide (5×50 mL) and with brine (3×100 mL)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated to dryness
  11. customThe residue was purified by chromatography on silica gel
  12. customA second purification

Sources & evidence

ORD record
ord-fcbcb06371434fc880c7bc08ed378353
Source dataset
uspto-grants-2014_09
Patent number
US08846711B2

Reaction notes

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