Phenol → 2-(4-Chloro-phenyl)-5-{4-[2-(2,2-dimethyl-morpholin-4-yl)-ethoxy]-3-methoxy-phenyl}-5H-thiazolo[5,4-c]pyridin-4-one

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Reaction Steps

Dissolve 2-(2,2-dimethyl-morpholin-4-yl)-ethanol (88 mg, 0.55 mmol) in 4.5 mL THF (4.5 mL). Add 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (211 mg, 0.55 mmol). This forms a slurry to which is added 217 mg (0.83 mmol) of triphenylphosphine (217 mg, 0.83 mmol) followed by 161 μL (0.83 mmol) of diisopropyl azodicarboxylate (DIAD). The reaction then becomes a solution. Heat the reaction to 80° C. for 16 h. Pour into 1N NaOH (200 mL) and extract with CH2Cl2 (2×150 mL). Purify via silica gel chromatography, using a gradient of 0% to 10% (2N NH3 in MeOH)/CHCl3 as eluent, to obtain a mixture of product and starting phenol. Dissolve the mixture in CH2Cl2 (300 mL) and extract with 5N NaOH (5×100 mL) until all the phenol is removed from the organic layer. Wash the organic layer with brine (100 mL) and concentrate. Dissolve the residue in CH2Cl2 (30 mL) and treat with 4M HCl in dioxane (100 μL). Diethyl ether is added until the solution becomes cloudy. Let sit at room temperature for 1.5 h then filter the resulting precipitate to give 18 mg (6%) of the desired product. MS (ES+) 526.0 (M+1)+, 1H NMR (400 MHz, (CD3OD): δ 8.11 (d, J=8.5 Hz, 2H), 7.66 (d, J=7.3 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.09 (d, J=7.3 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 4.51-4.43 (m, 2H), 4.07-4.00 (m, 2H), 3.93-3.90 (m, 1H), 3.89 (s, 3H), 3.70-3.56 (m, 4H), 3.26-3.19 (m, 1H), 3.07 (d, J=12.2 Hz, 1H), 1.44 (s, 3H), 1.30 (s, 3H).

Provenance & Evidence