Ethylmorpholine → N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxamide

HRID 2081020Notes

Reaction equation

HRID 2081020 reaction equation
[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[CH:12][N:11]=2)[C:3]1=[O:20].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:52][C:53]1[C:58]([F:59])=[C:57]([F:60])[CH:56]=[CH:55][C:54]=1[CH2:61][NH2:62]>ClCCl.CN(C=O)C>[Cl:52][C:53]1[C:58]([F:59])=[C:57]([F:60])[CH:56]=[CH:55][C:54]=1[CH2:61][NH:62][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[CH:12][N:11]=2)[C:3](=[O:20])[N:2]1[CH3:1])=[O:9]

Participants

8

Reactant 5

HCID 7525EthylmorpholineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 27960291-Hydroxybenzotriazole hydrateHCID 671030001-(2-Chloro-3,4-difluorophenyl)methanamineHCID 671034023-Methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylic acid

Product 1

HCID 59252110N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxamideYield 34.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a suspension of 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylic acid (200 mg, 0.612 mmol) and N-ethylmorpholine (0.465 ml, 3.67 mmol) in dichloromethane (10 ml)/DMF (1 ml) was added 1-hydroxybenzotriazole hydrate (113 mg, 0.735 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.612 mmol) and the reaction mixture was stirred for 1 hour at room temperature. 1-(2-Chloro-3,4-difluorophenyl)methanamine (131 mg, 0.612 mmol) was then added and the reaction stirred overnight. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.612 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water, 3N citric acid solution, water then brine and separated through a hydrophobic frit and the organic layer concentrated under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give N-[(2-chloro-3,4-difluorophenyl)methyl]-3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxamide (95 mg, 33.8% yield). LC/MS [M+H]+=450, retention time=2.93 minutes.

Workup

  1. stirringthe reaction stirred overnight
  2. stirringthe reaction mixture was stirred for 3 hours
  3. washwashed with saturated sodium hydrogen carbonate solution, water, 3N citric acid solution, water
  4. custombrine and separated through a hydrophobic frit
  5. concentrationthe organic layer concentrated under vacuum
  6. customThe residue was purified by SP4 automated silica gel chromatography
  7. washeluting with 10-100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-6ae5cd609ffa433a8bfac6c3bb978c76
Source dataset
uspto-grants-2011_04
Patent number
US07932282B2

Reaction notes

Loading…