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 245179ノート

反応式

HRID 245179 の反応式
[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]

参加物

8

反応物 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

生成物 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-quinolinecarboxamide収率 36.4%

試薬・触媒・溶媒 3

HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒HCID 516892Sodium Bicarbonate溶媒

実験手順

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+).

後処理

  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

出典と根拠

ORDレコード
ord-51119239949a4a72bbb0db2025d19767
出典データセット
uspto-grants-2014_02
特許番号
US08658636B2

反応ノート

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