Cesium carbonate → 1-(cyclohexyloxycarbonyloxy)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 882357Notes

Reaction equation

HRID 882357 reaction equation
[C:1](=[O:13])([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH:3](Cl)[CH3:4].[Cl:14][C:15]1[C:16]([F:55])=[C:17]([C@@H:21]2[C@:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:24]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:23][C@H:22]2[C:41]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:42])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Cl:14][C:15]1[C:16]([F:55])=[C:17]([C@@H:21]2[C@:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:24]([CH2:36][C:37]([CH3:39])([CH3:40])[CH3:38])[NH:23][C@H:22]2[C:41]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([O:50][CH:3]([O:2][C:1]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[O:13])[CH3:4])=[O:49])=[CH:46][C:45]=2[O:53][CH3:54])=[O:42])[CH:18]=[CH:19][CH:20]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 112295291-Chloroethyl Cyclohexyl CarbonateHCID 53358942Idasanutlin

Product 1

HCID 717388111-(cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoateYield 70.5%

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 cyclohexanol (Alfa Aesar, 1.33 g, 1.4 mL, 13.3 mmol) and pyridine (1.27 g, 1.3 mL, 16.1 mmol) in methylene chloride (11 mL) at −78° C. for 3 h to give 1-chloroethyl cyclohexyl carbonate. A portion of 1-chloroethyl cyclohexyl carbonate (253 mg, 1.22 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, 0.244 mmol) in the presence of cesium carbonate (487.4 mg, 1.5 mmol) in dimethylformamide (5 mL) overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 1-(cyclohexyloxycarbonyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (135.4 mg, 70% yield). MS (ES+) m/z calcd. for C40H44Cl2F2N3O7: [(M+H)+]: 786, found: 786

Workup

  1. customto give

Sources & evidence

ORD record
ord-50f13e5ccb474422aeed18346baf506a
Source dataset
uspto-grants-2015_03
Patent number
US08993614B2

Reaction notes

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