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

HRID 2054392Notes

Reaction equation

HRID 2054392 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.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

8

Reactant 6

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

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 (maintained internal temperature below −70° C. during addition). 1-Benzhydryl-azetidin-3-ol (250.0 g, 1.045 mol) was then added as a solution in dichloromethane (1.25 liter) to −78° C. solution over a duration of 40 minutes (maintained internal temperature 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 was then allowed to come to room temperature slowly and stir for 20 hours. Aqueous 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 precipitates 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 hours 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. temperatureover a duration of 40 minutes (maintained internal temperature below −70° C. during addition)
  2. temperature(maintained internal temperature below −70° C. during addition)
  3. customto come to room temperature
  4. stirringstir for 20 hours
  5. customreaction solution over 30 minutes
  6. stirringby stirring for 10 minutes at room temperature
  7. customThe heavy dichloromethane layer (clear yellow in color) was then separated
  8. stirringwith stirring over a 30 minute period
  9. customAt this pH the desired product precipitates from solution as a colorless solid
  10. stirringThe pH=9 solution was stirred for 30 minutes
  11. filtrationthe precipitated product was collected by filtration
  12. washThe collected solid was washed with 1.0 liter of water
  13. customair dried for 36 hours

Sources & evidence

ORD record
ord-5c571bb6ba094ffa826b5feeea31b41f
Source dataset
uspto-grants-2008_02
Patent number
US07329658B2

Reaction notes

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