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

HRID 245179Notes

Reaction equation

HRID 245179 reaction equation
[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37](O)=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:40]([CH3:43])(=[O:42])=[O:41])[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]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([NH:47][C@H:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]([F:54])([F:55])[F:44])=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:2]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 711829497-(Ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

Product 1

HCID 534761117-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideYield 36.4%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

7-(ethyloxy)-6-(methylsulfonyl)-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 of a 50% solution in ethyl acetate, 0.424 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h. The solution was 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 (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 CH2Cl2 (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated in vacuo to afford 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.086 g, 35% yield). 1H NMR (400 MHz, CDCl3) δ9.88 (br. s., 1H), 8.79 (s, 1H), 7.81 (s, 1H), 7.78 (d, J=6.02 Hz, 1H), 7.64-7.69 (m, 2H), 7.53-7.60 (m, 3H), 7.43-7.48 (m, 3H), 6.25 (quin, J=7.65 Hz, 1H), 4.36 (q, J=6.94 Hz, 2H), 3.66-3.71 (m, 4H), 3.53-3.65 (m, 2H), 3.33 (s, 3H), 2.64 (br. s., 1H), 2.38-2.46 (m, 4H), 2.20 (br. s., 1H), 2.04 (t, J=10.92 Hz, 1H), 1.56-1.66 (m, 9H); MS (m/z) 779.3 (M+H+).

Workup

  1. extractionextracted with methylene chloride (3 times)
  2. washThe combined organic extracts were washed with brine (two times)
  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 CH2Cl2 (3 times)
  10. washThe combined organic extracts were washed with brine (2 times)
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-51119239949a4a72bbb0db2025d19767
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

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