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 245163노트

반응식

HRID 245163 반응식
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

참가 물질

8

반응물 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydride2회HCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674173713-(1,4'-Bipiperidin-1'-ylmethyl)-6-(ethylsulfonyl)-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

생성물 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-quinolinecarboxamide수율 67.8%

시약·촉매·용매 3

HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매HCID 516892Sodium Bicarbonate용매

반응 조건

온도
0 °C

실험 절차

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+).

후처리

  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

출처 및 근거

ORD 기록
ord-6b1a4ff4d59147888609eb0798ffe3f4
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08658636B2

반응 노트

불러오는 중…