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 245163Notes

Reaction equation

HRID 245163 reaction equation
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

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydride2×HCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 67417371HCID 67417371, compound

Product 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-quinolinecarboxamideYield 67.8%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
0 °C

Procedure

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+).

Workup

  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

Sources & evidence

ORD record
ord-6b1a4ff4d59147888609eb0798ffe3f4
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

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