Synthesis of Spirocyclic Indazole Derivative

Example 2

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To 1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (Int III-1) (1.4 g, 4.2 mmol) was added DMF (15 mL), N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (1.3 g, 4.2 mmol) and KOH (466 mg, 8.3 mmol). The resulting solution was stirred at 100° C. After 12 h the reaction mixture was allowed to cool to rt and directly purified using C18-flash chromatography (eluting with 0% to 100% MeCN in water (0.05% FA)) followed by chiral HPLC (CHIRAL ART Cellulose-SB, 2×25 mm, 5 μm; mobile Phase A: MTBE (2 mm NH₃ in MeOH); mobile Phase B: i-PrOH; gradient: isocratic 50% B for 21.5 min; flow rate: 20 mL/min) to afford N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (28.0 mg, 1%) as a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ 8.75 (d, 1H), 8.62 (s, 1H), 8.59 (d, 1H), 8.15 (s, 1H), 8.04 (dd, 1H), 7.21-7.28 (m, 2H), 4.71-4.79 (m, 1H), 4.23 (s, 3H), 2.68 (s, 3H), 2.59-2.69 (m, 2H), 2.44 (t, 2H), 2.07-2.33 (m, 6H), 1.45-1.55 (m, 2H). m/z (ESI+), [M+H]⁺=474.