rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile → rac 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester

HRID 909083Notes

Reaction equation

HRID 909083 reaction equation
[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41](N2C=CN=C2)=[O:42])[CH2:35][CH2:34]1)=[O:32]>C(Cl)Cl>[CH3:29][O:30][C:31]([CH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:41]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[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:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:42])[CH2:35][CH2:34]1)=[O:32]

Participants

4

Reactant 2

HCID 67095372rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrileHCID 670955844-{[(Imidazole-1-carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester

Product 1

HCID 51356972rac 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl esterYield 85.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.2 mg, 0.165 mmol) and 4-{[(imidazole-1-carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester (509.6 mg, 1.921 mmol) in CH2Cl2 (9 mL) was stirred at rt for 17 hrs and at reflux for 7 hrs. The reaction mixture was then purified by flash column to give rac 4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid methyl ester (87.7 mg, 85.1%). HRMS (ES+) m/z Calcd for C32H37Cl2F2N3O3+H [(M+H)+]: 620.2253; Found: 620.2254.

Workup

  1. temperatureat reflux for 7 hrs
  2. customThe reaction mixture was then purified by flash column

Sources & evidence

ORD record
ord-016df4e566e54301b4602f0906ac89a9
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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