Ethyl Acetate → 1-(2-(Pyrimidin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea

HRID 1874215ノート

反応式

HRID 1874215 の反応式
[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=1)C(O)=O.C1(P([N:48]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[F:51][C:52]([F:56])([F:55])[CH2:53][NH2:54].CCO[C:60](C)=[O:61]>C1(C)C=CC=CC=1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[CH2:7][C:8]([NH:48][C:60]([NH:54][CH2:53][C:52]([F:56])([F:55])[F:51])=[O:61])([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:22])[F:21])[CH:13]=1

参加物

6

反応物 4

HCID 8857Ethyl AcetateHCID 9773Ethanamine, 2,2,2-trifluoro-HCID 199401P,P-Diphenylphosphinic azideHCID 594590353-(Pyrimidin-2-yl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid

生成物 1

HCID 235820261-(2-(Pyrimidin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea収率 16%

試薬・触媒・溶媒 1

HCID 1140Toluene溶媒

反応条件

温度
110 °C

実験手順

To a mixture of 3-(pyrimidin-2-yl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (20 mg, 0.042 mmol) and diphenyl phosphoryl azide (70 mg, 0.254 mmol) in toluene (1.5 mL) was added TEA (88 μL, 0.63 mmol) dropwise and the reaction mixture was heated at 110° C. for 20 min. 2,2,2-Trifluoroethanamine (7 μL, 0.084 mmol) was added and the reaction mixture was stirred at 110° C. for 1 h. The reaction mixture was allowed to cool to rt and diluted with EtOAc (25 mL). The organic layer was washed with H2O (25 mL), 1 N HCl (25 mL) and saturated NaHCO3 (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Shimadzu-YMC-Sunfire 5μ column, 30×100 mm eluting with 40-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm). The product that eluted at retention time of 9.42 min was isolated as a clear oil, and further purified by Prep TLC (Uniplate, Silica Gel GF, 20×20 cm, 1000 Microns) using Hexane/EtOAc (1/2) to yield 1-(2-(pyrimidin-2-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 279) as a white solid (4 mg, 16% yield). LCMS: RT=1.867 min [M+H] 568.87 (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=3.973 min, Purity 100% (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) 8.52 ppm, 2H, d, J=4.83 Hz; 7.98 ppm, 1H, s; 7.33 ppm, 5H, m; 7.23 ppm, 2H, s; 7.08 ppm, 3H, t, J=5.05 Hz; 4.61 ppm, 1H, t, J=6.37 Hz; 3.85 ppm, 2H, s; 3.77 ppm, 2H, ddd, J=15.71, 9.12, 9.01 Hz.

後処理

  1. temperatureto cool to rt
  2. washThe organic layer was washed with H2O (25 mL), 1 N HCl (25 mL) and saturated NaHCO3 (25 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by preparative HPLC (Shimadzu-YMC-Sunfire 5μ column, 30×100 mm eluting with 40-100% MeOH (90% in H2O, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm)
  7. washThe product that eluted at retention time of 9.42 min
  8. customwas isolated as a clear oil
  9. customfurther purified by Prep TLC (Uniplate, Silica Gel GF, 20×20 cm, 1000 Microns)

出典と根拠

ORDレコード
ord-bb1b574ff5fc4928baddc31bcc867a19
出典データセット
uspto-grants-2012_11
特許番号
US08304403B2

反応ノート

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