Triethylamine → 1-(3',4'-Dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid 2-acetylamino-1-(acetylaminomethyl)-ethyl ester

HRID 76238Notes

Reaction equation

HRID 76238 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]3)=[CH:11][C:10]=2[F:21])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[C:28]([NH:31][CH2:32][CH:33](O)[CH2:34][NH:35][C:36](=[O:38])[CH3:37])(=[O:30])[CH3:29].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:28]([NH:31][CH2:32][CH:33]([O:19][C:18]([C:15]1([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[C:10]([F:21])[CH:11]=2)[CH2:17][CH2:16]1)=[O:20])[CH2:34][NH:35][C:36](=[O:38])[CH3:37])(=[O:30])[CH3:29]

Participants

10

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chloride2×HCID 332254HCID 332254, compoundHCID 9996409Chf-5074

Product 1

HCID 717661191-(3',4'-Dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid 2-acetylamino-1-(acetylaminomethyl)-ethyl ester

Reagents, catalysts & solvents 5

HCID 6228DimethylformamideCatalystHCID 142844-(Dimethylamino)pyridineCatalystHCID 1049PyridineSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

1-(3′,4′-Dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (0.30 g, 0.92 mmol) was dissolved in dry DCM (30 mL); two drops of DMF and oxalyl chloride (78 uL, 0.92 mmol) were added; and the reaction mixture was stirred at r.t. under nitrogen atmosphere for 30 minutes. Additional oxalyl chloride (39 uL, 0.46 mmol) was added and the reaction was stirred for 15 minutes. This solution was added dropwise to a solution of N-(3-acetylamino-2-hydroxypropyl)acetamide (synthesized as reported on J. Org. Chem., 2000, 65(4), 1200, which is incorporated herein by reference in its entirety) and triethylamine (385 uL, 2.76 mmol) in dry DCM (2 mL) and dry DMF (2 mL). 4-Dimethylaminopyridine (34 mg, 0.28 mmol) and dry pyridine (1.5 mL) were added, and the reaction mixture was stirred overnight at r.t. The reaction mixture was extracted with DCM/H2O, and the organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated to dryness. The residue was purified by gradient flash chromatography (eluent DCM to DCM/methanol 97/3 v/v) affording the title compound which was further purified by preparative HPLC to obtain 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 2-acetylamino-1-(acetylaminomethyl)ethyl ester (105 mg, 24% yield) as a white solid.

Workup

  1. stirringthe reaction was stirred for 15 minutes
  2. customsynthesized
  3. stirringthe reaction mixture was stirred overnight at r.t
  4. extractionThe reaction mixture was extracted with DCM/H2O
  5. washthe organic phase was washed with brine
  6. dry with materialdried over sodium sulphate
  7. filtrationfiltered
  8. customevaporated to dryness
  9. customThe residue was purified by gradient flash chromatography (eluent DCM to DCM/methanol 97/3 v/v)

Sources & evidence

ORD record
ord-f3a23f4e3ab04b369e85ffbd7a28a5ab
Source dataset
uspto-grants-2014_09
Patent number
US08835494B2

Reaction notes

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