3-BROMO-5-METHYL-1H-PYRAZOLE

S2. 1.9 g of 3-amino-5-methylpyrazole (2), 15mL concentrated hydrobromic acid, 2.8g cuprous bromide mixed into 100mL three-necked flask, Heated to 70 ;Take about 1.5g sodium nitrite dissolved in 5mL water, Using a constant pressure funnel slowly dropping into a three-necked flask;After the addition is completed, The reaction solution was stirred at 70 for 30min, After cooling to room temperature, 20 mL THF was added, 20mL water;The mixture was extracted three times with 30 mL of ether, the organic layer was washed with sodium thiosulfate solution, dried over magnesium sulfate, filtered through silica gel, The solvent was distilled off under reduced pressure to give 3-methyl-5-bromopyrazole (3) in a yield of 62percent;1.9 g of 3-amino-5-methylpyrazole (19), 15 mL of concentrated hydrobromic acid, and 2.8 g of cuprous bromide were placed in a 100 mL three-necked flask and heated to 70 °C.Approximately 1.5 g of sodium nitrite was dissolved in 5 mL of water and slowly added dropwise to a three-necked flask using a constant pressure funnel.After the completion of the addition, the reaction solution was stirred at 70 ° C for 30 min, then cooled to room temperature, and 20 mL of THF (tetrahydrofuran) and 20 mL of water were added.It was extracted three times with 30 mL of diethyl ether. The organic layer was washed with sodium thiosulfate solution and dried over magnesium sulfate.After filtration with silica gel, the solvent was evaporated under reduced pressure to give 1.7 g of 3-methyl-5-bromopyrazole (20) in a yield of 52percent.S2. 1.9 g of 3-amino-5-methylpyrazole (2), 15mL concentrated hydrobromic acid, 2.8g cuprous bromide mixed into 100mL three-necked flask, Heated to 70 ;Take about 1.5g sodium nitrite dissolved in 5mL water, Using a constant pressure funnel slowly dropping into a three-necked flask;After the addition is completed, The reaction solution was stirred at 70 for 30min, After cooling to room temperature, 20 mL THF was added, 20mL water;The mixture was extracted three times with 30 mL of ether, the organic layer was washed with sodium thiosulfate solution, dried over magnesium sulfate, filtered through silica gel, The solvent was distilled off under reduced pressure to give 3-methyl-5-bromopyrazole (3) in a yield of 62percent;1.9 g of 3-amino-5-methylpyrazole (19), 15 mL of concentrated hydrobromic acid, and 2.8 g of cuprous bromide were placed in a 100 mL three-necked flask and heated to 70 °C.Approximately 1.5 g of sodium nitrite was dissolved in 5 mL of water and slowly added dropwise to a three-necked flask using a constant pressure funnel.After the completion of the addition, the reaction solution was stirred at 70 ° C for 30 min, then cooled to room temperature, and 20 mL of THF (tetrahydrofuran) and 20 mL of water were added.It was extracted three times with 30 mL of diethyl ether. The organic layer was washed with sodium thiosulfate solution and dried over magnesium sulfate.After filtration with silica gel, the solvent was evaporated under reduced pressure to give 1.7 g of 3-methyl-5-bromopyrazole (20) in a yield of 52percent.A solution of A solution of 1.7 g of 3-methyl-5-bromopyrazole (20) was dissolved in 20 mL of 0.1 M hydrochloric acid, placed in a 100 mL three-necked flask, and heated to 50 C.About 1.5 g of potassium permanganate was dissolved in 5 mL of water, and slowly added dropwise to a three-necked flask using a constant pressure funnel.After the completion of the addition, the reaction solution was stirred at 70 C for 30 min, then cooled to room temperature, the pH of the solution was adjusted to acidity, 20 mL of EtOAc was added and extracted three times. The organic layer was adjusted to pH and washed with water.The yield was 87%.S3. 1.7 g of 3-methyl-5-bromopyrazole (3) was dissolved in 20 ml of 0.1 M hydrochloric acid, Placed in 100mL three-necked flask, Heated to 50 ;Take about 1.5g potassium permanganate dissolved in 5mL of water, Using a constant pressure funnel slowly dropping into a three-necked flask;After the addition is completed, The reaction solution was stirred at 70 for 30min, After cooling to room temperature, the pH of the solution was adjusted to acidicity, 20 mL of EtOAc was added and the mixture was extracted three times. The pH of the organic layer was made alkaline and washed with water to give 5-bromo-1H-3-pyrazolecarboxylic acidThe yield is 85%;S2. 1.9 g of 3-amino-5-methylpyrazole (2), 15mL concentrated hydrobromic acid, 2.8g cuprous bromide mixed into 100mL three-necked flask, Heated to 70 ;Take about 1.5g sodium nitrite dissolved in 5mL water, Using a constant pressure funnel slowly dropping into a three-necked flask;After the addition is completed, The reaction solution was stirred at 70 for 30min, After cooling to room temperature, 20 mL THF was added, 20mL water;The mixture was extracted three times with 30 mL of ether, the organic layer was washed with sodium thiosulfate solution, dried over magnesium sulfate, filtered through silica gel, The solvent was distilled off under reduced pressure to give 3-methyl-5-bromopyrazole (3) in a yield of 62%;1.9 g of 3-amino-5-methylpyrazole (19), 15 mL of concentrated hydrobromic acid, and 2.8 g of cuprous bromide were placed in a 100 mL three-necked flask and heated to 70 C.Approximately 1.5 g of sodium nitrite was dissolved in 5 mL of water and slowly added dropwise to a three-necked flask using a constant pressure funnel.After the completion of the addition, the reaction solution was stirred at 70 C for 30 min, then cooled to room temperature, and 20 mL of THF (tetrahydrofuran) and 20 mL of water were added.It was extracted three times with 30 mL of diethyl ether. The organic layer was washed with sodium thiosulfate solution and dried over magnesium sulfate.After filtration with silica gel, the solvent was evaporated under reduced pressure to give 1.7 g of 3-methyl-5-bromopyrazole (20) in a yield of 52%.To a stirred solution of 2-chloro-N-(4, 4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087Aj (0.3 g, 1.146 mmol) in acetonitrile (10 mL) was added 3- bromo-5-methyl-lh-pyrazole (0.276 g, 1.7 19 mmol) and cesium carbonate (0.74 g, 2.29 mmol). The reaction mixture was irradiated in microwave at 150 C for 2 h. The reaction mixture was filtered to remove cesium carbonate. Filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford 0.400 g of 2-(3-bromo-5-methyl- 1H-pyrazol- 1- yl)-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [01 32j, Compound 220 as an off-white solid. MS(M+1)= 386.0. 'H NMR (400 MHz, DMSO-d6) 7.69 (d, I = 7.7 Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.04 (s, 1H), 2.55 (s, 3H), 2.24 (s, 3H), 2.07 - 1.92 (m, 6H), 1.59-1.53 (m, 2H).

Molecular Weight:161.00
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:159.96361
Monoisotopic Mass:159.96361
Topological Polar Surface Area:28.7
Heavy Atom Count:7
Complexity:66.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes