Aniline → methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,5-difluorobenzoate

HRID 1807322Notes

Reaction equation

HRID 1807322 reaction equation
[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58](=[O:68])[C:59]1[CH:64]=[C:63]([F:65])[C:62]([NH2:66])=[CH:61][C:60]=1[F:67].NC1C=CC=CC=1>C(Cl)Cl>[CH3:56][O:57][C:58](=[O:68])[C:59]1[CH:64]=[C:63]([F:65])[C:62]([NH:66][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[CH:61][C:60]=1[F:67]

Participants

7

Reactant 5

HCID 6115AnilineHCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 59249226(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acidHCID 67271045Methyl 4-amino-2,5-difluorobenzoate

Product 1

HCID 53357230methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2,5-difluorobenzoate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (300 mg, 0.64 mmol) in methylene chloride (5 mL), DIPEA (Aldrich, 2.57 mmol, 0.45 ml) was added followed by diphenylphosphinic chloride (Aldrich, 1.93 mmol, 0.37 ml). The mixture was stirred for 5 min. and 4-amino-2,5-difluoro-benzoic acid methyl ester (Prepared by methylation of the corresponding acid. 201 mg, 0.76 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% sodium carbonate (6 mL) and the mixture was stirred for 15 min. The organic layer was separated and the solvent was reduced to about 3 ml. The solution was loaded onto a 40 g silica gel column and eluted with 2% EtOAc/CH2Cl2 to give a mixture of the desired product and aniline. The crude was again chromatographed on a reverse phase column and eluted with 50-95% acetonitrile/water to give a white solid. 82 mg. (ES+) m/z Calcd: [(M+H)+]: 636. found: 636.

Workup

  1. addition201 mg, 0.76 mmol) was added
  2. stirringthe mixture was stirred overnight
  3. customThe reaction was quenched with 10% sodium carbonate (6 mL)
  4. stirringthe mixture was stirred for 15 min
  5. customThe organic layer was separated
  6. washeluted with 2% EtOAc/CH2Cl2
  7. customto give

Sources & evidence

ORD record
ord-7b9019e4def04ceaa7b577d669195ddf
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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