Cesium carbonate → 1-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate

HRID 882359Notes

Reaction equation

HRID 882359 reaction equation
[C:1](=[O:10])([O:6][CH:7]([CH3:9])[CH3:8])[O:2][CH:3](Cl)[CH3:4].[Cl:11][C:12]1[C:13]([F:52])=[C:14]([C@@H:18]2[C@:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:21]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[NH:20][C@H:19]2[C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([OH:47])=[O:46])=[CH:43][C:42]=2[O:50][CH3:51])=[O:39])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:11][C:12]1[C:13]([F:52])=[C:14]([C@@H:18]2[C@:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:21]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[NH:20][C@H:19]2[C:38]([NH:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([O:47][CH:3]([O:2][C:1]([O:6][CH:7]([CH3:9])[CH3:8])=[O:10])[CH3:4])=[O:46])=[CH:43][C:42]=2[O:50][CH3:51])=[O:39])[CH:15]=[CH:16][CH:17]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 117895851-Chloroethyl 1-methylethyl carbonateHCID 53358942Idasanutlin

Product 1

HCID 717388751-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoateYield 73.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Oakwood Products, 1.99 g, 1.5 mL, 13.9 mmol) was reacted with 2-propanol (785 mg, 1 mL, 13.0 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at room temperature for 4 h to give 1-chloroethyl isopropyl carbonate. A portion of 1-chloroethyl isopropyl carbonate (221.6 mg, 1.33 mmol) was then reacted with 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 (150.3 mg, 244 μmol) in the presence of cesium carbonate (478 mg, 1.47 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(isopropoxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (134.4 mg, 73% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N3O7: [(M+H)+]: 746, found: 746

Workup

  1. customto give

Sources & evidence

ORD record
ord-5e8101ca6483444fba38400323937a76
Source dataset
uspto-grants-2015_03
Patent number
US08993614B2

Reaction notes

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