Dimethylformamide → HCID 131735865, compound

HRID 2206426Notes

Reaction equation

HRID 2206426 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.Cl.Cl[CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]1)=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[ClH:1].[CH3:54][N:51]1[CH2:52][CH2:53][N:48]([C:46](=[O:47])[CH2:45][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)[CH2:49][CH2:50]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 125636611-(2-Chloroacetyl)-4-Methylpiperazine HClHCID 53358942Idasanutlin

Product 1

HCID 131735865HCID 131735865, compoundYield 154.1%

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), 2-chloro-1-(4-methylpiperazin-1-yl)ethanone, hydrochloride (34.6 mg, 162 μmol) and cesium carbonate (111 mg, 341 μmol) were combined with dry dimethyl formamide (2 mL) to give a white suspension. The tube was capped and heated at 50° C. with stirring. After 1.5 h, the reaction mixture was cooled down to room temperature. It was poured into water and extracted with methylene chloride (2×). The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (24 g pre-packed silica gel column, eluted with methanol in methylene chloride) 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-(4-methyl-piperazin-1-yl)-2-oxo-ethyl ester, hydrochloride as an off-white solid (99 mg, 81% yield). The product was mixed with acetonitrile (2 mL) to form a suspension. A few drops of 1N aqueous hydrochloric acid were added to the mixture. The suspension became clear solution. It was frozen and lyophilized to give an off-white solid as hydrochloride salt. LCMS (ES+) m/z calcd. for C38H42Cl2F2N5O5 [(M+H)+]: 756. found: 756.

Workup

  1. customto give a white suspension
  2. customThe tube was capped
  3. temperaturethe reaction mixture was cooled down to room temperature
  4. extractionextracted with methylene chloride (2×)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by flash chromatography (24 g pre-packed silica gel column, eluted with methanol in methylene chloride)

Sources & evidence

ORD record
ord-03cc6dad91a2431f9942e84986ec10fd
Source dataset
uspto-grants-2016_06
Patent number
US09371280B2

Reaction notes

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