1,2-Dichloroethane → 3-(1,4'-bipiperidin-1'-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

HRID 245158ノート

反応式

HRID 245158 の反応式
[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24](O)=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:41][C:42]([F:52])([F:51])[C@@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:44].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O1CCCC1>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([NH:44][C@H:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:42]([F:51])([F:52])[F:41])=[O:25])=[CH:21][C:20]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:19][CH:18]=4)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

参加物

8

反応物 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11789718(alphaR)-alpha-(Trifluoromethyl)benzenemethanamineHCID 674183633-(1,4'-Bipiperidin-1'-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid

生成物 1

HCID 534758903-(1,4'-bipiperidin-1'-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide収率 31.4%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
50 °C

実験手順

A mixture of 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.174 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.046 g, 0.261 mmol), EDC (133 mg, 0.695 mmol), HOBT (26.6 mg, 0.174 mmol), and N,N-diisopropylethylamine (0.303 mL, 1.737 mmol) in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was stirred at 50° C. overnight. The solvent was removed in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized 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 to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.040 g, 30% yield). 1H NMR (400 MHz, CDCl3) δ 10.22 (br. s., 1H), 8.75 (s, 1H), 8.31 (d, J=9.03 Hz, 1H), 8.23 (dd, J=2.01, 8.78 Hz, 1H), 7.77-7.84 (m, 2H), 7.65-7.72 (m, 2H), 7.54-7.60 (m, 2H), 7.46 (dd, J=1.76, 5.02 Hz, 3H), 6.26 (br. s., 1H), 3.60-3.78 (m, 2H), 3.15 (s, 3H), 2.66 (br. s., 1H), 2.38 (br. s., 4H), 2.18 (br. s., 1H), 2.12 (br. s., 1H), 1.53-1.64 (m, 10H), 1.37-1.46 (m, 2H); MS (m/z) 733.3 (M+H+). Human TRPV4 FLIPR pIC50=8.5

後処理

  1. customThe solvent was removed in vacuo
  2. dissolutionThe residue was dissolved in DMSO
  3. custompurified via HPLC (Waters, 20-60% MeCN/H2O with 0.1% TFA)
  4. additionThe fractions containing the product
  5. extractionextracted with methylene chloride (3 times)
  6. washThe combined organic extracts were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

出典と根拠

ORDレコード
ord-24a576e3e23c4211b3ef586cbcf24e4a
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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