2-(Trifluoromethyl)aniline → N-(2-trifluoromethyl-phenyl)-malonamic acid benzyl ester

HRID 1766828Notes

Reaction equation

HRID 1766828 reaction equation
[C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-:5])=O.C(N(CC)C(C)C)(C)C.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([F:24])([F:33])[F:34])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1

Participants

6

Reactant 4

HCID 69222-(Trifluoromethyl)anilineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 22247814Benzyl malonate

Product 1

HCID 68616692N-(2-trifluoromethyl-phenyl)-malonamic acid benzyl esterYield 57.6%

Reagents, catalysts & solvents 1

HCID 22350042dichloromethane N,N-dimethylformamideSolvent

Procedure

A solution of mono-benzyl malonate (890 mg, 4.6 mmol) in 3:1 CH2Cl2/DMF (24 mL) was treated sequentially with N,N-diisopropylethylamine (2.0 mL, 11.5 mmol), 2-trifluoromethyl-phenylamine (0.6 mL, 4.6 mmol), and HATU (2.1 g, 5.5 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(2-trifluoromethyl-phenyl)-malonamic acid benzyl ester as an oil (894 mg, 57% yield). This material was dissolved in EtOAc (35 mL). The resultant solution was charged with 10% Pd/C (178 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo to provide N-(2-trifluoromethyl-phenyl)-malonamic acid (621 mg, 95% yield). A portion of this material (100 mg, 0.4 mmol) was combined with [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (150 mg, 0.4 mmol, prepared as described in WO PCT 0250019) and dissolved in 6 mL of 3:1 CH2Cl2/DMF. The resultant solution was charged sequentially with N,N-diisopropylethylamine (0.35 mL, 1.5 mmol) and HATU (182 mg, 0.48 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(2-trifluoromethyl-phenylcarbamoyl)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (54 mg, 28% yield). MS found: (M+Na)+=514.5.

Workup

  1. concentrationconcentrated in vacuo
  2. custompartitioned between EtOAc and sat. NH4Cl
  3. extractionThe aqueous phase was extracted with EtOAc (1×)
  4. washThe combined organic extracts were washed with sat. NaHCO3 and brine
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-142dadb1c4704d7a83f1e85495a18967
Source dataset
uspto-grants-2007_06
Patent number
US07230133B2

Reaction notes

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