Dimethylformamide → 2-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate

HRID 2206431Notes

Reaction equation

HRID 2206431 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.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[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]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 10796Cesium carbonateHCID 79177tert-Butyl bromoacetateHCID 53358942Idasanutlin

Product 1

HCID 867040842-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoateYield 108.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

In a 50 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, 1 g, 1.62 mmol), tert-butyl 2-bromoacetate (316 mg, 240 μL, 1.62 mmol) and cesium carbonate (634 mg, 1.95 mmol) were combined with dry dimethyl formamide (10 mL) to give a white suspension. The tube was capped and heated at 50° C. After 10 min, the reaction mixture was cooled down to room temperature, poured into water and extracted with ethyl acetate (2×). The combined ethyl acetate layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 2-tert-butoxy-2-oxoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as light yellow solid (1280 mg), which was used without further purification.

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 ethyl acetate (2×)
  5. washThe combined ethyl acetate layers were washed with brine solution
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-d9bbbe5457d04a58b409785cfc155171
Source dataset
uspto-grants-2016_06
Patent number
US09371280B2

Reaction notes

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