Diisopropylethylamine → 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

HRID 245199Notes

Reaction equation

HRID 245199 reaction equation
[CH3:1][CH:2]([S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:11]([CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:32][CH2:31]1)=[C:10]2[C:42](O)=[O:43])(=[O:6])=[O:5])[CH3:3].[F:45][C:46]([F:56])([F:55])[C@@H:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[NH2:48].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[CH3:3][CH:2]([S:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=1)[C:11]([CH2:29][N:30]1[CH2:31][CH2:32][CH:33]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH2:34][CH2:35]1)=[C:10]2[C:42]([NH:48][C@H:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:46]([F:55])([F:56])[F:45])=[O:43])(=[O:5])=[O:6])[CH3:1]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674194216-[(1-Methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

Product 1

HCID 534764446-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideYield 79.5%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.220 g, 0.346 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.095 g, 0.450 mmol), N,N-diisopropylethylamine (0.012 mL, 0.069 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.288 mL of a 50% solution in ethyl acetate, 0.485 mmol) in dichloromethane (4 mL) was stirred at 0° C. for 2 h. The reaction mixture was warmed to room temperature and stirred overnight. The solution was diluted with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed twice with brine, 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 twice with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.218 g, 75% yield). 1H NMR (400 MHz, CDCl3) δ9.71 (br. s., 1H), 8.77 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=6.78 Hz, 1H), 7.63-7.69 (m, 2H), 7.59 (s, 1H), 7.53-7.58 (m, 2H), 7.42-7.47 (m, 3H), 6.19-6.29 (m, 1H), 4.08 (s, 3H), 3.80 (quin, J=6.84 Hz, 1H), 3.64-3.71 (m, 4H), 3.53-3.64 (m, 2H), 2.62 (br. s., 1H), 2.38-2.46 (m, 4H), 2.16-2.27 (m, 1H), 2.03 (t, J=10.92 Hz, 1H), 1.56-1.71 (m, 3H), 1.47-1.56 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 1.22-1.32 (m, 1H), 1.08-1.22 (m, 1H); MS (m/z) 793.2 (M+H+).

Workup

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

Sources & evidence

ORD record
ord-4dc0e875ae2c4dca8062df2943dc76b8
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

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