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4,4,4-Trifluoro-3-(trifluoromethyl)crotonic acid → (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide

HRID 1712763
ノート
印刷プレビュー

反応式

HRID 1712763 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:31][CH:32]([CH3:34])[CH3:33].[F:35][C:36]([F:47])([F:46])[C:37]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:39](O)=[O:40]>C(#N)C>[F:35][C:36]([F:46])([F:47])[C:37]([C:42]([F:43])([F:44])[F:45])=[CH:38][C:39]([NH:16][C@:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:31][CH:32]([CH3:34])[CH3:33])[CH:4]=1)([C:17]1[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:40]
参加物実験手順後処理出典と根拠反応ノート

参加物

4

反応物 2

HCID 156694,4,4-Trifluoro-3-(trifluoromethyl)crotonic acidHCID 59458471(R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine

生成物 1

HCID 23582231(R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide収率 74%

試薬・触媒・溶媒 1

HCID 6342Acetonitrile
溶媒
2 回

実験手順

A round bottom flask was charged with IIDQ polystyrene resin (493 mg, 1.5 mmol/g, 0.74 mmol) and acetonitrile (5 mL) and sealed with a rubber septum. The suspension was vacuumed and reflushed with argon three times. To the resulting slurry was added a solution of (R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedures 109, 110, 111, 112, 113, 114, (180 mg, 0.37 mmol) and 4,4,4-trifluoro-3-(trifluoromethyl)crotonic acid (93 mg, 0.45 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and purified by ISCO chromatography (40 g column) using hexane/EtOAc (0-15% over 30 min) to give (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)but-2-enamide (Example 291) as a white solid at a retention time of 20 min (199 mg, 74% yield). LCMS: RT=2.18 min [M+H] 674.33 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.25 min, Purity 98% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 3H, m; 7.02 ppm, 1H, dd, J=10.55, 8.79 Hz; 6.95 ppm, 3H, m; 6.85 ppm, 1H, s; 6.67 ppm, 3H, d, J=7.03 Hz; 6.62 ppm, 1H, m; 6.13 ppm, 1H, s; 5.88 ppm, 1H, tt, J=53.00, 2.86, 2.75 Hz; 4.36 ppm, 1H, ddd, J=11.97, 6.15, 6.04 Hz; 3.99 ppm, 1H, d, J=13.18 Hz; 3.71 ppm, 1H, d, J=13.18 Hz; 1.26 ppm, 6H, m.

後処理

  1. customsealed with a rubber septum
  2. customprepared
  3. filtrationThe reaction mixture was filtered
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. custompurified by ISCO chromatography (40 g column)
  6. customhexane/EtOAc (0-15% over 30 min)

出典と根拠

ORDレコード
ord-f8cbefc476fa44918c79c704e2e8c91b
出典データセット
uspto-grants-2010_09
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US07790770B2

反応ノート

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