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

HRID 1058230Notes

Reaction equation

HRID 1058230 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH:31]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C:32]([F:35])([F:34])[F:33])=[N+]=[N-].C(Cl)CCl.[C:49]([N:56]1[CH2:63][CH2:62][CH2:61][C@H:57]1[C:58](O)=[O:59])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1C=NC2N(O)N=NC=2C=1>O.CN(C=O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([CH:31]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:32]([F:35])([F:34])[F:33])=[C:24]([CH:29]=1)[CH2:23][NH:20][C:58](=[O:59])[C@@H:57]1[CH2:61][CH2:62][CH2:63][N:56]1[C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50]

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 11776TriphenylphosphineHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 181649HOAtHCID 18672426N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine

Product 1

HCID 69939157N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

Triphenylphosphine (0.157 mg, 0.60 mmol) was added to a stirred solution of N-{1-[2-(azidomethyl)-4-chlorophenyl]-2,2,2-trifluoroethyl}-N-(4-methoxyphenyl)amine (0.199 mg, 0.538 mmol) in water (1 mL) and water (30 μL). After 16 h the volatiles were evaporated in vacuo, the residue was dissolved in methanol (1 mL), potassium hydroxide (1 pellet) was added and the mixture was stirred at 60° C. for 15 min. The reaction mixture was then cooled and partitioned between ether and water. The organic layer was dried (Na2SO4) and evaporated to a gum. EDC (154.7 mg, 0.81 mmol) was added to a stirred mixture of this crude amine, N-Boc-L-proline (115.8 mg, 0.54 mmol) and HOAT (36.6 mg, 0.27 mmol) in DMF (3 mL). After 16 h, the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography on silica gel (eluting with EtOAc/CHCl3, 1:5) to give N-(5-chloro-2-{1-[(4-methoxyphenyl)amino]-2,2,2-trifluoroethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (196 m g) as a glass: MS: 542.3 (M+1).

Workup

  1. customAfter 16 h the volatiles were evaporated in vacuo
  2. dissolutionthe residue was dissolved in methanol (1 mL)
  3. additionpotassium hydroxide (1 pellet) was added
  4. temperatureThe reaction mixture was then cooled
  5. custompartitioned between ether and water
  6. dry with materialThe organic layer was dried (Na2SO4)
  7. customevaporated to a gum
  8. waitAfter 16 h
  9. concentrationthe mixture was concentrated
  10. customthe residue was partitioned between EtOAc and 10% NaHCO3 solution
  11. washThe organic layer was washed with water and brine
  12. dry with materialdried (Na2SO4)
  13. customevaporated to a gum
  14. customThis was purified by chromatography on silica gel (eluting with EtOAc/CHCl3, 1:5)

Sources & evidence

ORD record
ord-6fe77555da6f4cc2b2575a90f9815e5f
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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