Diisopropylethylamine → 3-(1,4'-bipiperidin-1'-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

HRID 245163ノート

反応式

HRID 245163 の反応式
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[N:19]1([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[C:33]([C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[CH:53]=4)=[N:34][C:35]4[C:40]([C:41]=3[C:42](O)=[O:43])=[CH:39][C:38]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[C:37]([O:50][CH3:51])[CH:36]=4)[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[F:62][C:63]([F:73])([F:72])[C@@H:64]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[NH2:65].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[N:19]1([CH:25]2[CH2:26][CH2:27][N:28]([CH2:31][C:32]3[C:33]([C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:59])([F:61])[F:60])[CH:53]=4)=[N:34][C:35]4[C:40]([C:41]=3[C:42]([NH:65][C@H:64]([C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C:63]([F:72])([F:73])[F:62])=[O:43])=[CH:39][C:38]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[C:37]([O:50][CH3:51])[CH:36]=4)[CH2:29][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1

参加物

8

反応物 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydride2 回HCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674173713-(1,4'-Bipiperidin-1'-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

生成物 1

HCID 866756073-(1,4'-bipiperidin-1'-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide収率 67.8%

試薬・触媒・溶媒 3

HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒HCID 516892Sodium Bicarbonate溶媒

反応条件

温度
0 °C

実験手順

T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide, 0.253 mL of a 50% solution in ethyl acetate, 0.425 mmol) was added to a solution of 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.304 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.395 mmol), N,N-diisopropylethylamine (10.60 μL, 0.061 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The reaction mixture was diluted with saturated NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.160 g, 65% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (br. s., 1H), 8.50 (br. s., 1H), 7.97 (br. s., 1H), 7.87 (d, J=7.53 Hz, 2H), 7.80 (s, 1H), 7.71-7.78 (m, 1H), 7.65 (br. s., 2H), 7.42-7.51 (m, 3H), 6.22 (quin, J=8.60 Hz, 1H), 4.10 (s, 3H), 3.40-3.61 (m, 3H), 3.12-3.27 (m, 1H), 2.05-2.44 (m, 6H), 1.58-1.82 (m, 2H), 1.03-1.52 (m, 12H), 0.77-1.00 (m, 2H); MS (m/z) 777.2 (M+H+).

後処理

  1. temperaturewarmed to room temperature
  2. stirringstirred overnight
  3. extractionextracted with methylene chloride (three times)
  4. washThe combined organic extracts were washed with brine (two times)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in DMSO
  9. custompurified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA)
  10. additionThe fractions containing the product
  11. extractionextracted with methylene chloride (three times)
  12. washThe combined organic extracts were washed with brine (two times)
  13. dry with materialdried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated

出典と根拠

ORDレコード
ord-6b1a4ff4d59147888609eb0798ffe3f4
出典データセット
uspto-grants-2014_02
特許番号
US08658636B2

反応ノート

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