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Step 25 ,6-Dichloro-l H-indazolTo a solution of 4,5-dichloro-2-methylaniline (1.69 g, 9.6 mmol) in CHC13 (25 ml) at 0C was slowly added acetic anhydride (2.09 ml, 22.1 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. A thick white precipitate had gradually formed. Potassium acetate (283 mg, 2.88 mmol) was added followed by slow addition of isoamyl nitrite (2.78 ml, 20.6 mmol). The reaction mixture was heated at reflux overnight. The homogeneous deep orange reaction mixture was cooled to room temperature and concentrated. Water (10 mL) was added and the mixture was reconcentrated to an orange solid. This solid was suspended in cone. HCl (15 mL) and heated at 60C for 2 h then cooled to 0C and neutralized with 50% NaOH. Extracted with EtOAc, dried over MgS04 and concentrated to an orange solid. This solid was dissolved in THF/MeOH (1 :1 , 25 mL) and 10%> NaOH (3 mL) was added. The deep maroon reaction mixture was stirred at room temperature for 5 min then neutralized with 1.0 M HCl and diluted with water. The mixture was extracted with EtOAc (2 x) then dried over MgS04 and concentrated. The residue was absorbed onto silica gel and purified by chromatography with 30% to 50% EtOAc/hexanes to afford 1.50 g (84%) of 5, 6-dichloro-l H-indazole as a light orange solid. 1H NMR (CDC13, 300 MHz): ? (ppm) 8.04 (s, 1H), 7.89 (s, 1H), 7.68 (s, 1H).
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In toluene; at 110℃; for 48.0h;Inert atmosphere; Microwave irradiation; Sealed tube;
Step 22 -(5 ,6 -Dichloro -indazo 1- 1carboxylic acid [(R)-2-(4-cyano-piperidin-l-yl)-l-cyclopropyl-2-oxo-ethyl]-amideIn a 5 mL microwave vial were placed copper(I) iodide (6 mg, 0.033 mmol), K3PO4 (146 mg, 0.69 mmol), 5,6-dichloro-lH-indazole (74 mg, 0.39 mmol), 2-iodo-5-(2-trimethylsilanyl- ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-l -yl)-l - cyclopropyl-2-oxo-ethyl]-amide (200 mg, 0.33 mmol), toluene (1.2 mL), and trans-N,N'- dimethylcyclohexane-l ,2-diamine (9 mg, 0.066 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110C for 48 h. The reaction mixture was cooled to room temperature and diluted with EtOAc then filtered over a Buchner funnel, rinsing with EtOAc. The filtrate was concentrated and the resultant residue was purified by silica gel chromatography with 0% to 2% MeOH/CH2Cl2 (0.5% NH4OH) to afford 215 mg (98%) of 2- (5 ,6 -dichloro -indazo 1- 1 -yl)-5 -(2 -trimethylsilanyl-ethoxymethyl)-5 H-pyrro lo [2 ,3 -b ]pyrazine-7 - carboxylic acid [(R)-2-(4-cyano-piperidin-l-yl)-l-cyclopropyl-2-oxo-ethyl]-amide as a light yellow foam.
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