Tris(hydroxymethyl)aminomethane → 5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide

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Reaction Steps

To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 100 mg, 0.226 mmol) in dichloromethane (1.1 mL) was added 3-aminopyridin-2(1H)-one (26.1 mg, 0.237 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.039 mL, 0.226 mmol). After 48 h, the reaction was treated with tris-amine resin (silica supported amine 3, 100 mg, loading=1.76 mmol/g). After 45 minutes, the reaction was filtered though a silica gel plug, washing well with ethyl acetate. The filtrate was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organics were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of 50% to 100% ethyl acetate/hexanes to yield 5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide (32 mg, 32%). Mass spec: 439 (M+1). 1H NMR (CDCl3) δ 10.8 (s, 1H), 8.68 (dd, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.28-6.88 (m, 6H), 6.36 (dd, 1H), 4.25 (d, 2H), 2.38 (m, 1H), 0.95 (d, 6H).

Provenance & Evidence