Diphenylphosphinic chloride → ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate

HRID 1807278ノート

反応式

HRID 1807278 の反応式
[Cl:1][C:2]1[C:3]([F:31])=[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])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:56]([O:58][C:59]([C:61]1[CH:66]=[N:65][C:64]([NH2:67])=[CH:63][N:62]=1)=[O:60])[CH3:57]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[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:67][C:64]2[N:65]=[CH:66][C:61]([C:59]([O:58][CH2:56][CH3:57])=[O:60])=[N:62][CH:63]=2)=[O:30])[CH:5]=[CH:6][CH:7]=1

参加物

6

反応物 4

HCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 22271413Ethyl 5-Aminopyrazine-2-carboxylateHCID 666882513-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid

生成物 1

HCID 67380471ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate収率 26.2%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒2 回

実験手順

A solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (79.9 mg, 0.171 mmol) in dichloromethane (3 ml) was treated with DIPEA (89.0 mg, 0.685 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (103 mg, 0.428 μmol, Aldrich) and stirred for 30 mins under argon before 5-AMINO-PYRAZINE-2-CARBOXYLIC ACID ETHYL ESTER (30.4 mg, 0.173 mmol, Ark Pharm) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with H2O. The organic layer was washed with sat NaHCO3, H2O, and sat NaCl and purified by flash chromatography using ethyl acetate and n-hexanes to give ethyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)pyrazine-2-carboxylate (27.6 mg, 26%) which was used in the next step.

後処理

  1. additionwas added
  2. extractionextracted with H2O
  3. washThe organic layer was washed with sat NaHCO3, H2O
  4. custompurified by flash chromatography

出典と根拠

ORDレコード
ord-92f6a8773c944c539fa9e57be2b5cf78
出典データセット
uspto-grants-2013_01
特許番号
US08354444B2

反応ノート

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