Formic Acid → 4-Benzyl-2-(2-chloro-4-fluoro-phenyl)morpholine

HRID 880234Notes

Reaction equation

HRID 880234 reaction equation
C(O)=O.[CH2:4]([NH:11][CH2:12][CH2:13]O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=[O:18]>C(Cl)Cl>[CH2:4]([N:11]1[CH2:12][CH2:13][O:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[Cl:26])[CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1

Participants

5

Reactant 3

HCID 284Formic AcidHCID 4348BenzylethanolamineHCID 125933352-Chloro-4-fluorophenacyl bromide

Product 1

HCID 897261154-Benzyl-2-(2-chloro-4-fluoro-phenyl)morpholineYield 99.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Combine formic acid (98-100%; 0.30 mL, 8 mmol) and 2-benzylaminoethanol (1.21 g, 8 mmol) and cool the resulting mixture with an ice bath. Add 2-bromo-1-(2-chloro-4-fluoro-phenyl)ethanone (1.0 g, 4 mmol); heat the mixture to reflux; and stir at that temperature for 20 h. Dilute the mixture with DCM and wash with saturated aqueous Na2CO3 solution. Dry organic phases over MgSO4; filter; collect the filtrate; and concentrate under reduced pressure. Purify via flash column chromatography eluting with a gradient of 0-20% methyl tertiary-butyl ether in hexanes. Combine the product fractions and remove the solvents under reduced pressure to give the title compound as a yellow oil (1.22 g, 43%). MS (m/z): 306 (M+1).

Workup

  1. temperatureheat the mixture
  2. temperatureto reflux
  3. washwash with saturated aqueous Na2CO3 solution
  4. filtrationfilter
  5. customcollect the filtrate
  6. concentrationand concentrate under reduced pressure
  7. customPurify via flash column chromatography
  8. washeluting with a gradient of 0-20% methyl tertiary-butyl ether in hexanes
  9. customCombine the product fractions and remove the solvents under reduced pressure

Sources & evidence

ORD record
ord-dcceaae92c9a49aa93eed45e0fab0345
Source dataset
uspto-grants-2015_03
Patent number
US08993568B2

Reaction notes

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