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Step J.2: (6-Chloro-pyridazin-3-yl)-(2-methyl-6-nitro-phenyl)-amineSodium hydride (60percent oil dispersion, 593 mg, 14.83 mmol) was suspended in DMF (16.1 mL). 3-amino-6-chloropyridazine (1921 mg, 14.83 mmol) was added in small portions, causing a yellow coloration and a strong gaseous evolution. The resulting slurry was stirred for 10 minutes at rt and <strong>[437-86-5]2-fluoro-3-nitrotoluene</strong> (0.785 mL, 6.45 mmol) was added as a neat liquid, causing a dramatic shift to a deep red colour. The resulting reaction mixture was stirred at rt for 50 minutes. The medium was carefully quenched in 30 mL MeOH and 10 mL water. The medium was evaporated to a thick oil. The crude was tak- en up in EtOAc (50 mL) and sonicated for few minutes. The solid materials were removed by filtration and the filtrate was washed successively with saturated aqueous sodium bicarbonate solution (2 x 50 mL), 1 M aqueous HCI (50 mL) and brine (50 mL). The combined organics were dried over Na2S04 and concentrated to yield the title com- pound as a cristalline, yellow solid, m = 1.63 g (96percent). HPLC/MS (method A) tR1.20 minute, M+H 265 .
tert-butyl 6-((6-chloropyridazin-3-yl)carbamoyl)-2-azaspiro[3.3]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With chloro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 100℃; for 0.333333h;Microwave irradiation;
2-Azaspiro[3.3]heptane-2,6-dicarboxylic acid 2-tert-butyl ester (200 mg, 0.83 mmol) and 3-amino-6-chloropyridazine (193 mg, 1.49 mmol) were dissolved in DCE (3 mL), and DIPEA (0.29 mL, 1.66 mmol) and PyClU (551 mg, 1.66 mmol) were added. The reaction mixture was heated to 100 C under microwave irradiation for 20 min, after which time the reaction mixture was cooled to r.t. and diluted with H2O, and the aqueous layer was extracted with DCM. The combined organic extracts were filtered through a phase separator and concentrated, and the crude residue was purified by column chromatography (hex/EtOAc) to give the title compound as a white solid (80 mg, 27%). ES-MS [M+H]+ = 297.2 (minus t-butyl).
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