Diphenylphosphinic chloride → 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 {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide

HRID 1807254

反応式

HRID 1807254 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.[NH2:56][C:57]1[CH:62]=[CH:61][N:60]([CH2:63][CH2:64][O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])[C:59](=[O:73])[CH:58]=1>ClCCl>[C:69]([Si:66]([CH3:68])([CH3:67])[O:65][CH2:64][CH2:63][N:60]1[CH:61]=[CH:62][C:57]([NH:56][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[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]2)=[O:30])=[CH:58][C:59]1=[O:73])([CH3:72])([CH3:71])[CH3:70]

参加物

6

反応物 4

HCID 73910Diphenylphosphinic chlorideHCID 81531DiisopropylethylamineHCID 592494614-amino-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2(1H)-oneHCID 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 72243958rac-(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 {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide収率 11.4%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

To a mixture 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 (0.2 g, 0.428 mmol) in dichloromethane (20 mL) was added iPr2NEt (138 mg, 1.07 mmol), followed by the addition of diphenylphosphinic chloride (Aldrich) (203 mg, 0.856 mmol). The mixture was stirred at room temperature for 30 min, then 4-amino-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2(1H)-one (115 mg, 428 μmol) was added. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 5% to 80% EtOAc in hexanes) to give 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 {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg, 11%).

後処理

  1. stirringThe reaction mixture was stirred at room temperature for 3 h
  2. concentrationconcentrated
  3. customThe residue was purified by flash chromatography (silica gel, 40 g, 5% to 80% EtOAc in hexanes)

出典と根拠

ORDレコード
ord-473d18ef5b1949fa83567606f788e380
出典データセット
uspto-grants-2013_01
特許番号
US08354444B2

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