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 245158Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 245158
[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

Komponenten

8

Edukt 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

Produkt 1

HCID 534758903-(1,4'-bipiperidin-1'-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamideAusbeute 31,4 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
50 °C

Versuchsvorschrift

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

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-24a576e3e23c4211b3ef586cbcf24e4a
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658636B2

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