Yield:847818-62-6 37.6%

Reaction Conditions:

Stage #1: 4-bromo-1,3,5-trimethylpyrazolewith n-butyllithium in tetrahydrofuran at -78; for 1.5 h;
Stage #2: with Trimethyl borate in tetrahydrofuran at -10; for 2 h;
Stage #3: with hydrogenchloride;water in tetrahydrofuran at -10; for 0.5 h;

Steps:

98.A

Example 98.; Preparation of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(l,3,5-trimethyl-7H-pyrazol-4-yl)- imidazo[1,2-b]pyridazine.; A. l,3,5-Trimethylpyrazole-4-boronic acid.; To a dry flask is added 300 mg (1.59 mmol) of 4-bromo-l,3,5-trimethyl pyrazole to 4.0 ml THF. The mixture is cooled to -78°C and leq of n-BuLi (1.6 M) is added via syringe. The mixture is stirred 1.5 hrs, and 0.19ml of trimethylborate (1.08 eq) is added. The reaction mixture is stirred 2 hrs, allowing bath to reach -10°C, then 1.5 ml of 5N HCl is added and stirred 30 minutes longer. The aqueous layer is extracted 3 times with ethyl acetate. The combined organics are dried over MgSO4, filtered, and evaporated to an oil. The oil is dissolved in methanol/methylene chloride and re-evaporated. The residue is triturated with acetone/ethyl acetate then filtered to obtain title compound as a white solid 92.1 mg (37.6%). ¹H-NMR (DMSOd₆): ￡5.92 (s); 3.72 (s, 3H); 2.34 (s, 3H); 2.26 (s, 3H) ppm.

References:

WO2006/102194,2006,A1 Location in patent:Page/Page column 95