5-(6-Methoxy-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

5-(6-Methoxy-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide
• [0124]
  A suspension of 140 mg of an isomeric mixture of methyl 5-(6-methoxy-3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compounds B6a and B6b) in 20 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 130 °C for 5 h in the microwave cavity. The reaction mixture is concentrated to dryness, the residue dissolved in 4 ml acetonitrile and 3 ml acidic buffer (KH₂PO₄, pH=2) and the isomers are separated and purified by preparative HPLC (acidic buffer/acetonitrile, 7/3 (v/v)). The acetonitrile is removed under vacuum and the aqueous solution is treated with NH₄OH until pH 8-9 is reached. The aqueous solution is extracted with dichloromethane three times and the combined organic layers are dried and concentrated to dryness under vacuum to yield the title compound.
  The structural assignment of the regioisomer is unequivocally established by two-dimensional ¹H NMR experiments (NOESY, COSY).
  NOE-crosspeaks are detected between H-8 and H-7, H-7 and H-4', H-4' and H-2:
  

  

  ¹H NMR (400 MHz, D₆-DMSO): δ = 3.94 (s, 3H, H-8), 5.56 (s, 2H, H-9), 6.79 (bs, 1 H, H-18), 7.11 (s, 1 H, H-7), 7.64-7.70 (m, 3H, including s, 1 H, H-4' at 7.68; bs, 1 H, H-18 and 1 H out of H-12, H-13, H-14, H-15), 7.77-7.86 (m, 3H, three H's out of H-12, H-13, H-14, H-15), 8.64 (s, 1 H, H-2), 8.69 (s, 1 H, H-4). MS (MH⁺ found) = 449.1

SEE

http://www.google.com/patents/EP2017277A1?cl=en








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