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

HRID 245188Notes

Reaction equation

HRID 245188 reaction equation
[CH3:1][CH:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:38]([OH:40])=O)=[C:10]([CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:41]([CH3:44])(=[O:43])=[O:42])[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]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:38]([NH:48][C@H:47]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:46]([F:45])([F:55])[F:56])=[O:40])=[C:10]([CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH2:30][CH2:31]3)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:41]([CH3:44])(=[O:42])=[O:43])[CH3:1]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674183557-[(1-Methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

Product 1

HCID 534763317-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideYield 54.9%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 mg, 0.315 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.072 g, 0.409 mmol), N,N-diisopropylethylamine (10.99 μL, 0.063 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.262 mL of a 50% solution in ethyl acetate, 0.440 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h. The solution was warmed to room temperature overnight, diluted 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 in vacuo. The residue was purified via HPLC (Waters, Sunfire 30×100 mm, 25-60% CH3CN/H2O with 0.1% TFA) to afford 7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.137 g, 52% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ9.85 (br. s., 1H), 8.79 (s, 1H), 7.81 (s, 1H), 7.75-7.80 (m, 1H), 7.64-7.69 (m, 2H), 7.52-7.59 (m, 3H), 7.42-7.48 (m, 3H), 6.25 (t, J=6.90 Hz, 1H), 4.91 (dt, J=6.02, 12.05 Hz, 1H), 3.65-3.72 (m, 5H), 3.52-3.65 (m, 2H), 3.31 (s, 3H), 2.64 (br. s., 1H), 2.38-2.45 (m, 4H), 2.20 (br. s., 1H), 2.03 (t, J=10.67 Hz, 1H), 1.66 (br. s., 4H), 1.59 (d, J=11.54 Hz, 2H), 1.54 (s, 3H), 1.53 (s, 3H); MS (m/z) 793.3 (M+H+).

Workup

  1. extractionextracted with methylene chloride (three times)
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified via HPLC (Waters, Sunfire 30×100 mm, 25-60% CH3CN/H2O with 0.1% TFA)

Sources & evidence

ORD record
ord-ccfb70949b5a4d9eab42dd083e6d4bc9
Source dataset
uspto-grants-2014_02
Patent number
US08658636B2

Reaction notes

Loading…