1,2-Dichloroethane → N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide

HRID 1058235Notes

Reaction equation

HRID 1058235 reaction equation
C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:15]([F:17])[F:16].[C:27]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36](O)=[O:37])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([CH:14]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]([F:17])[F:16])=[C:7]([CH:12]=1)[CH2:6][NH:5][C:36](=[O:37])[C@@H:35]1[CH2:39][CH2:40][CH2:41][N:34]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 181649HOAtHCID 18672348N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine

Product 1

HCID 69939286N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamideYield 50.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

EDC (0.171 g, 1.25 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorophenyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.314 g, 0.96 mmol), N-BOC-L-proline (0.207 g, 0.96 mmol) and HOAT (0.171, 1.25 mmol) in DMF (2.0 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic layer was washed with 1M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and reduced in vacuo and the residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-50% ethyl acetate/hexanes gradient) to give N-(5-chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g) as a foam; LC-MS m/z=524.3.

Workup

  1. customAfter 18 h the mixture was partitioned between EtOAc and water
  2. washThe organic layer was washed with 1M citric acid, saturated aqueous NaHCO3 and brine
  3. dry with materialdried (Na2SO4)
  4. customthe residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 10-50% ethyl acetate/hexanes gradient)

Sources & evidence

ORD record
ord-a6ff06d5ad6f41d1851c3c2bd8530a22
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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