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

HRID 882350Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 882350
[Cl:1][C:2]1[C:3]([F:42])=[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]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:49]([O:61][CH2:62]Cl)([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50]>CN(C)C=O>[C:52]([O:51][P:49]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])([O:61][CH2:62][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][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:42])[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]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:50])([CH3:55])([CH3:54])[CH3:53]

Komponenten

5

Edukt 3

HCID 10796Cesium carbonateHCID 11701630Di-tert-butyl (chloromethyl) phosphateHCID 53358942Idasanutlin

Produkt 1

HCID 717387574-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid di-tert-butoxy-phosphoryloxymethyl esterAusbeute 70,7 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel2×

Versuchsvorschrift

To a solution 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 (prepared as described in US20100152190A1, 200.0 mg, 0.324 mmol) in dimethylformamide (8 mL) was added cesium carbonate (529 mg, 1.62 mmol). The mixture was stirred for ˜20 min before di-tert-butyl chloromethyl phosphate (TCI, 236 mg, 0.9912 mmol) in dimethylformamide (1 mL) was added. The reaction mixture was allowed to stirr at room temperature for 3 h before it was partitioned between ethyl acetate and water, washed with water and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (hexane/ethyl acetate, 85/15 to 5/95) to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid di-tert-butoxy-phosphoryloxymethyl ester as a white solid (192 mg, 70% yield). LCMS (ES+) m/z calcd. for C40H49Cl2F2N3O8P [(M+H)+]: 838, found: 838.

Aufarbeitung

  1. additionwas added
  2. customwas partitioned between ethyl acetate and water
  3. washwashed with water
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationconcentrated
  6. customThe crude product was purified by flash chromatography (hexane/ethyl acetate, 85/15 to 5/95)

Quellen und Nachweise

ORD-Eintrag
ord-8efd9c016586451092ff2fe566754460
Quelldatensatz
uspto-grants-2015_03
Patentnummer
US08993614B2

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