Potassium Carbonate → 2-[cis-2-Methyl-6-(trifluoromethyl)morpholin-4-yl]-5-nitrobenzaldehyde

HRID 1966323Notes

Reaction equation

HRID 1966323 reaction equation
ClC(OC(Cl)C)=O.C([N:15]1[CH2:20][C@H:19]([C:21]([F:24])([F:23])[F:22])[O:18][C@H:17]([CH3:25])[CH2:16]1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[K+].[K+].F[C:42]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:43]=1[CH:44]=[O:45].CN(C)CCNC>C(Cl)Cl>[CH3:25][C@H:17]1[O:18][C@@H:19]([C:21]([F:23])([F:22])[F:24])[CH2:20][N:15]([C:42]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:43]=2[CH:44]=[O:45])[CH2:16]1

Participants

8

Reactant 6

HCID 11430Potassium CarbonateHCID 673381,2-Ethanediamine, N1,N1,N2-trimethyl-HCID 81531DiisopropylethylamineHCID 5213051-Chloroethyl chloroformateHCID 27347702-Fluoro-5-nitrobenzaldehydeHCID 588470294-Benzyl-cis-2-methyl-6-(trifluoromethyl)morpholine

Product 1

HCID 588470172-[cis-2-Methyl-6-(trifluoromethyl)morpholin-4-yl]-5-nitrobenzaldehyde

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-Chloroethyl chloroformate (292 μL, 2.68 mmol, Aldrich) is added to a solution of 4-benzyl-cis-2-methyl-6-(trifluoromethyl)morpholine (324 mg, 1.25 mmol) in CH2Cl2 (6 mL) with stirring in an ice bath. The solution is allowed to warm to room temperature and stirred for 16 hours. The solvent is removed by rotary evaporation and the residue is dissolved in methanol (6 mL). This solution is heated to reflux for 4 hours and the methanol is removed by rotary evaporation. The residue is dissolved in CH3CN (5 mL) and treated with N,N-diisopropylethylamine (0.261 mL, 1.5 mmol, Aldrich). K2CO3 (190 mg, 1.37 mmol, Mallinkrodt) and 2-fluoro-5-nitrobenzaldehyde (254 mg, 1.5 mmol, Oakwood) are added and the mixture is heated at 60° C. for 36 hours. N,N,N′-trimethylethylenediamine (2.3 mL) is added and the reaction is stirred an additional 2 hours @60° C. The mixture is filtered and the solvent is removed by rotary evaporation. The residue is taken up in EtOAc (100 mL) and washed 2× with 1.0 M HCl, 1× with saturated NaHCO3 and 1× with brine (75 mL each). The organic layer is dried over Na2SO4 and filtered. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 25M+ using 20% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 100° C. yielding a yellow solid.

Workup

  1. stirringstirred for 16 hours
  2. customThe solvent is removed by rotary evaporation
  3. dissolutionthe residue is dissolved in methanol (6 mL)
  4. temperatureThis solution is heated
  5. temperatureto reflux for 4 hours
  6. customthe methanol is removed by rotary evaporation
  7. dissolutionThe residue is dissolved in CH3CN (5 mL)
  8. temperaturethe mixture is heated at 60° C. for 36 hours
  9. stirringthe reaction is stirred an additional 2 hours @60° C
  10. filtrationThe mixture is filtered
  11. customthe solvent is removed by rotary evaporation
  12. washwashed 2× with 1.0 M HCl, 1× with saturated NaHCO3 and 1× with brine (75 mL each)
  13. dry with materialThe organic layer is dried over Na2SO4
  14. filtrationfiltered
  15. customThe solvent is removed by rotary evaporation
  16. customthe product is purified on a Biotage Flash 25M+
  17. additionThe product containing fractions
  18. customthe solvent is removed by rotary evaporation
  19. customThe product is dried under vacuum at 100° C.
  20. customyielding a yellow solid

Sources & evidence

ORD record
ord-9c78b0083532460aa477cfdac3aa93a7
Source dataset
uspto-grants-2013_04
Patent number
US08420646B2

Reaction notes

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