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

HRID 882361Notes

Reaction equation

HRID 882361 reaction equation
[N:1]1([C:7]([O:9][CH:10](Cl)[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[C:15]([F:54])=[C:16]([C@@H:20]2[C@:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[C@H:23]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:22][C@H:21]2[C:40]([NH:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][C:44]=2[O:52][CH3:53])=[O:41])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:1]1([C:7]([O:9][CH:10]([O:49][C:47](=[O:48])[C:46]2[CH:50]=[CH:51][C:43]([NH:42][C:40]([C@H:21]3[C@H:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([Cl:13])[C:15]=4[F:54])[C@:24]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[F:34])([C:25]#[N:26])[C@H:23]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:22]3)=[O:41])=[C:44]([O:52][CH3:53])[CH:45]=2)[CH3:11])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 143240831-Chloroethyl morpholine-4-carboxylateHCID 53358942Idasanutlin

Product 1

HCID 717388761-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylateYield 74.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (2.64 g, 2 mL, 18.5 mmol) was reacted with morpholine (1.69 g, 1.7 mL, 19.4 mmol) and pyridine (1.68 g, 1.72 mL, 21.2 mmol) in methylene chloride (25 mL) at room temperature overnight to give the crude product, 1-chloroethyl morpholine-4-carboxylate. A portion of 1-chloroethyl morpholine-4-carboxylate (670.1 mg, 3.46 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 (200.5 mg, 0.325 mmol) in the presence of cesium carbonate (1.094 g, 3.36 mmol) in dimethylformamide (7 mL) overnight to give, 1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethyl morpholine-4-carboxylate as an off-white solid (186.5 mg, 74% yield). MS (ES+) m/z calcd. for C38H41Cl2F2N4O7: [(M+H)+]: 773, found: 773

Workup

  1. customto give

Sources & evidence

ORD record
ord-4c7707eaa69f401fbef3b5476ac1245d
Source dataset
uspto-grants-2015_03
Patent number
US08993614B2

Reaction notes

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