Hydrochloric Acid → 1-(Diphenylmethyl)azetidin-3-one

HRID 915837Notes

Reaction equation

HRID 915837 reaction equation
C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([N:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[OH-].[Na+]>ClCCl>[CH:11]([N:24]1[CH2:27][C:26](=[O:28])[CH2:25]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 65578Oxalyl chlorideHCID 3304481-(Diphenylmethyl)azetidin-3-olHCID 13524712HCID 13524712, compound

Product 1

HCID 37355581-(Diphenylmethyl)azetidin-3-oneYield 74.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-78 °C

Procedure

Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane (3.75 liters) and the resulting solution was cooled to −78° C. Dimethyl sulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20 minutes while maintaining internal temperature of the reaction below −70° C. during addition. 1-Benzhydrylazetidin-3-ol (250.0 g, 1.045 mol) was then added as a solution in dichloromethane (1.25 liter) to the −78° C. solution of DMSO/oxalyl chloride over a duration of 40 minutes (note—internal temperature maintained below −70° C. during addition). The solution was stirred for 1 hour at −78° C. followed by the addition of triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintained internal temperature below −70° C. during addition). The reaction mixture was then allowed to come to room temperature slowly and stir for 20 hours. 1.0 M hydrochloric acid (3.2 liters, 3.2 mol) was added to the crude reaction solution over 30 minutes, followed by stirring for 10 minutes at room temperature. The heavy dichloromethane layer (clear yellow in color) was then separated and discarded. The remaining acidic aqueous phase (clear, colorless) was treated with 50% sodium hydroxide (150 ml, 2.1 mol) with stirring over a 30-minute period. The final aqueous solution had a pH=9. At this pH, the desired product precipitated from solution as a colorless solid. The pH=9 solution was stirred for 30 minutes and then the precipitated product was collected by filtration. The collected solid was washed with 1.0 liter of water and then air dried for 36 hr to give 1-benzhydrylazetidin-3-one (184.1 g, 74%) as an off-white solid: +ESI MS (M+1 of hydrated ketone) 256.3; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.49 (m, 4H), 7.27-7.30 (m, 4H), 7.18-7.22 (m, 2H), 4.60 (s, 1H), 3.97 (s, 4H).

Workup

  1. temperaturewhile maintaining internal
  2. customtemperature of the reaction below −70° C.
  3. additionduring addition
  4. temperature(maintained internal temperature below −70° C. during addition)
  5. customto come to room temperature
  6. stirringstir for 20 hours
  7. customreaction solution over 30 minutes
  8. stirringby stirring for 10 minutes at room temperature
  9. customThe heavy dichloromethane layer (clear yellow in color) was then separated
  10. stirringwith stirring over a 30-minute period
  11. customAt this pH, the desired product precipitated from solution as a colorless solid
  12. stirringThe pH=9 solution was stirred for 30 minutes
  13. filtrationthe precipitated product was collected by filtration
  14. washThe collected solid was washed with 1.0 liter of water
  15. customair dried for 36 hr

Sources & evidence

ORD record
ord-f51e55413af049b99bdb8420e0c37e2e
Source dataset
uspto-grants-2007_09
Patent number
US07268133B2

Reaction notes

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