Cesium carbonate → 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl ester

HRID 882355Notes

Reaction equation

HRID 882355 reaction equation
[C:1]([O:4][CH2:5]I)(=[O:3])[CH3:2].[Cl:7][C:8]1[C:9]([F:48])=[C:10]([C@@H:14]2[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:17]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:16][C@H:15]2[C:34]([NH:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=2[O:46][CH3:47])=[O:35])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][O:43][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:37]([NH:36][C:34]([C@H:15]2[C@H:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[C:9]=3[F:48])[C@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])([C:19]#[N:20])[C@H:17]([CH2:29][C:30]([CH3:32])([CH3:33])[CH3:31])[NH:16]2)=[O:35])=[C:38]([O:46][CH3:47])[CH:39]=1)(=[O:3])[CH3:2]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 11820084Iodomethyl acetateHCID 53358942Idasanutlin

Product 1

HCID 717388104-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl esterYield 19.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A portion of this iodomethyl acetate (661 mg, 3.31 mmol) was added to a suspension of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200.1 mg, 0.325 mmol) and cesium carbonate (964.4 mg, 2.93 mmol) in dimethylformamide (8 mL) and the reaction was stirred in the dark overnight. It was then taken up in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90) to give chiral-4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid acetoxymethyl ester as a white solid (42.8 mg, 19% yield). MS (ES+) m/z calcd. for C34H34Cl2F2N3O6: [(M+H)+]: 688, found: 688

Workup

  1. washwashed with water and brine
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated
  4. customThe crude product was purified by flash chromatography (hexane/ethyl acetate, 80/20 to 10/90)

Sources & evidence

ORD record
ord-b68745d85fa244a6955527173608cb19
Source dataset
uspto-grants-2015_03
Patent number
US08993614B2

Reaction notes

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