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

HRID 245169Notes

Reaction equation

HRID 245169 reaction equation
[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:10]([CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]1)=[C:9]2[C:41]([OH:43])=O)(=[O:5])=[O:4])[CH3:2].[F:44][C:45]([F:55])([F:54])[C@@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:47].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+]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:10]([CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[CH2:33][CH2:34]1)=[C:9]2[C:41]([NH:47][C@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:45]([F:44])([F:54])[F:55])=[O:43])(=[O:5])=[O:4])[CH3:2]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674174906-(Ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

Product 1

HCID 534761106-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideYield 70.3%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.303 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.393 mmol), N,N-diisopropylethylamine (10.57 μL, 0.061 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.252 mL as a 50% solution in ethyl acetate, 0.424 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h, then warmed to room temperature overnight. The solution was diluted with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed 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 with brine, dried over Na2SO4, filtered, and concentrated to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.166 g, 67% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.79 (br. s., 1H), 8.78 (s, 1H), 7.81 (s, 1H), 7.76-7.80 (m, 1H), 7.65-7.69 (m, 2H), 7.60 (s, 1H), 7.53-7.59 (m, 2H), 7.42-7.49 (m, 3H), 6.20-6.31 (m, 1H), 4.11 (s, 3H), 3.65-3.71 (m, 4H), 3.54-3.65 (m, 2H), 3.47 (q, J=7.28 Hz, 2H), 2.59-2.71 (m, 1H), 2.38-2.46 (m, 4H), 2.17-2.28 (m, 1H), 2.04 (t, J=11.04 Hz, 1H), 1.49-1.65 (m, 6H), 1.32 (t, J=7.53 Hz, 3H); MS (m/z) 779.2 (M+H+).

Workup

  1. extractionextracted with methylene chloride (3 times)
  2. washThe combined organic extracts were washed 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 with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-c0b35f3184e142149ae29b67cf139c96
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

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