Dimethylformamide → HCID 72548157, compound

HRID 2206428Notes

Reaction equation

HRID 2206428 reaction equation
[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+].CN(C)C=O.Cl[CH2:55][C:56]([N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1)=[O:57]>O>[N:58]1([C:56](=[O:57])[CH2:55][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 74040Morpholine, 4-(chloroacetyl)-HCID 53358942Idasanutlin

Product 1

HCID 72548157HCID 72548157, compoundYield 86.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

In a 15 mL pressure tube, 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, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dry dimethyl formamide (5 mL). 2-Chloro-1-morpholinoethanone (26.5 mg, 21.1 μL, 162 μmol) was added to the mixture with stirring. The tube was capped and heated at 50° C. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 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 2-morpholin-4-yl-2-oxo-ethyl ester as an off-white solid (104 mg, 86% yield) as product. LCMS (ES+) m/z calcd. for C37H39Cl2F2N4O6 [(M+H)+]: 743. found: 743.

Workup

  1. customThe tube was capped
  2. temperaturethe reaction mixture was cooled down to room temperature
  3. extractionextracted with ethyl acetate (2×)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-5d56971d3a164193ae26a2d5fe6f0d94
Source dataset
uspto-grants-2016_06
Patent number
US09371280B2

Reaction notes

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