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

HRID 245209Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 245209
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:55]([OH:57])=O)=[C:27]([CH2:42][N:43]3[CH2:48][CH2:47][CH:46]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH2:45][CH2:44]3)[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[N:29]2)=[CH:24][C:23]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:60])=[O:59])[CH3:20].[F:64][C:65]([F:75])([F:74])[C@H:66]([NH2:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.ClCCl.C(=O)(O)[O-].[Na+]>[CH2:19]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26]([C:55]([NH:73][C@H:66]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:65]([F:64])([F:74])[F:75])=[O:57])=[C:27]([CH2:42][N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)[CH2:47][CH2:48]3)[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[N:29]2)=[CH:24][C:23]=1[S:58]([CH:61]([CH3:63])[CH3:62])(=[O:59])=[O:60])[CH3:20]

Komponenten

8

Edukt 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674183257-(Ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

Produkt 1

HCID 534764457-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideAusbeute 36,2 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6344DichloromethaneLösungsmittelHCID 8857Ethyl AcetateLösungsmittelHCID 516892Sodium BicarbonateLösungsmittel

Versuchsvorschrift

T3P in ethyl acetate (1.273 mL of a 50% solution, 2.001 mmol) was added to a stirred solution of 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1 g, 1.539 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.391 g, 1.847 mmol), and N,N-diisopropylethylamine (0.538 mL, 3.08 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 16 h, diluted with saturated aqueous sodium bicarbonate, and extracted with methylene chloride (three times). The combined organic extracts were washed with saturated sodium bicarbonate, brine, dried, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-5% methanol/methylene chloride) to afford 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.450 g, 34% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ10.00 (br. s., 1H), 8.48 (br. s., 1H), 7.97 (s, 1H), 7.86 (d, J=7.55 Hz, 2H), 7.71-7.78 (m, 2H), 7.60-7.68 (m, 2H), 7.42-7.47 (m, 3H), 6.20 (quin, J=8.81 Hz, 1H), 4.39 (q, J=6.80 Hz, 2H), 3.72-3.86 (m, 1H), 3.50 (br. s., 4H), 3.44 (br. s., 1H), 3.18 (br. s., 1H), 2.39 (br. s., 1H), 2.33 (br. s., 1H), 2.26 (br. s., 4H), 2.11 (br. s., 1H), 1.68 (br. s., 2H), 1.53 (br. s., 1H), 1.44 (t, J=6.80 Hz, 3H), 1.12-1.37 (m, 7H), 0.74-0.99 (m, 2H); MS (m/z) 807.2 (M+H+).

Aufarbeitung

  1. extractionextracted with methylene chloride (three times)
  2. washThe combined organic extracts were washed with saturated sodium bicarbonate, brine
  3. customdried
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified via column chromatography (ISCO, 0-5% methanol/methylene chloride)

Quellen und Nachweise

ORD-Eintrag
ord-dbdfcc2c7ee244bcb3033b9beb9fdd18
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658636B2

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