1-isobutyl-5-methyl-1H-pyrazole synthesis

Yield:405548-41-6 93%

Reaction Conditions:

Stage #1: 1-isobutyl-1H-pyrazolewith n-butyllithium in tetrahydrofuran at -50 - -15; for 2 h;
Stage #2: methyl iodide in tetrahydrofuran at -30 - -10; for 2.16667 h;
Stage #3: with water in tetrahydrofuran at -10; for 0.333333 h;Product distribution / selectivity;

Steps:

1.4

A mechanical stirrer, Dimroth, a thermometer and a rubber stopper were attached to a 2L 4-neck flask and 1-isobutylpyrazole (104.0 g, 0.838 mol) synthesized in Example 1-1 was placed therein under a nitrogen atmosphere. Further, THF (500 ml) was added thereto to make a solution and the solution was cooled to -50°C. 10N n-Butyl lithium (100 ml, 1.000 mol) was added dropwise thereto over 30 minutes while stirring (so as the temperature was not to exceed -20°C). Thereafter, after the reaction mixture was stirred at from -20 to -15°C for 1.5 hours, the rubber stopper was replaced with a 200ml dropping funnel with pressure equalizing arm and a solution of methyl iodide (63 ml, 1.012 mol) in THF (100 ml) was added dropwise thereto over 40 minutes (so as the temperature was not to exceed -10°C). After the reaction mixture was stirred at from -30 to -15°C for 1.5 hours, water (200 ml) was added dropwise thereto over 20 minutes (so as the temperature was not to -10°C). The reaction mixture was raised to room temperature and concentrated up to approximately 500 ml. Water (500 ml) was added thereto and the mixture was extracted with ethyl acetate-hexane (2:1). The extract phase was washed with water and then brine, dried over anhydrous sodium sulfate and concentrated to obtain the desired compound (107.8 g, 0.780 mol). Yield: 93% NMR (270 MHz, CDCl3); δ (ppm): 0.91 (6H, d, J=6.9 Hz), 2.20 (1H, brhep, J=6.9 Hz), 2.27 (3H, s), 3.81 (2H, d, J=6.9 Hz), 5.98 (1H, d, J=1.1), 7.38 (1H, d, J=1.1 Hz).

References:

EP1580189,2005,A1 Location in patent:Page/Page column 32