3-chloro-1H-pyrazole

3-Chloro-1H-pyrazole (1): Copper (II) chloride (65.0 g, 481 mmol) and cone. HCl (20 mL) were added to a solution of lH-pyrazol-3-amine (20.0 g, 241 mmol) in acetonitrile (600 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then isopentyl nitrite (56.4 g, 481 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days, and then quenched with aq. ammonia (10percent, 1 L). The aqueous phase was extracted with EtOAc (5 x 500 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 20: 1) to give the title compound (10.3 g, 42percent) as a green oil. Step B: Preparation of 3-ChloropyrazoleStep B: Preparation of 3-ChloropyrazoleTo trifluoroacetic acid (290 mE) was added dropwise thechioropyrazole product (160 g) from Step A, and the reactionmixture was stirred at room temperature for 1 .5 hours andthen concentrated at reduced pressure. The residue was takenup in hexane, insoluble solids were filtered off, and the hexanewas concentrated to afford the crude product as an oil. Thecrude product was further purified by chromatography onsilica gel using ether/hexane (40:60) as eluent to afford thetitle product as a yellow oil (64.44 g).‘H NMR (CDC13) ö 6.39 (s, 1H), 7.66 (s, 1H), 9.6 (br s, 1H). 1.75 g (0.017 mol), 2-(2-bromoethoxy)tetrahydro-2H-pyran 4.1g (0.02mol), potassium carbonate 5g (0.036mol), Tetrabutylammonium bromide 0.9g (2.8mmol), DMF 40ml, react overnight at room temperature, add water, EA extraction, wash, crude column chromatography to obtain 3.58g.Methyl-2-chloro-6-(trifluoromethyl)pyridine-4-carboxylate (143 mg, 0.59 mmol) was dissolved in 1, 4- dioxane (6 mL) and the resulting solution was flushed with argon for 10 min. Then 3-chloro-1H- pyrazole (77 mg, 0.72 mmol), potassium phosphate (191 mg, 0.90 mmol) and [tBuXPhosPd(allyl)]OTf (44 mg, 0.06 mmol) were added and the reaction was stirred for 18 h at 80C. The mixture was diluted with water and the aqueous layer was extracted with ethyl acetate (2x). The organic layers were combined, dried over Na2SO4, filtered and evaporated.The crude residue was purified by (0701) chromatography over silica gel ( cyclohexane + 0-20 % ethyl acetate) to afford methyl 2-(3- chloropyrazol-1-yl)-6-(trifluoromethyl)pyridine-4-carboxylate. (0702) 1H-NMR (400 MHz, CDCl3, ppm) d 8.7 (s, 1 H) 8.6 (d, J=2.57 Hz, 1 H) 8.1 (d, J=1.10 Hz, 1 H) 6.5 (d, J=2.57 Hz, 1 H) 4.1 (s, 3 H) (0703) LC-MS (method 1): Rt 1.14 min , m/z = 306 (M+H+).3-Chloro-l-nitro-pyrazole (2): Cone, nitric acid (63%, 2.5 g, 39 mmol) was added to a solution of 3-chloro-lH-pyrazole (4.0 g, 39 mmol) in glacial acetic acid (5.2 mL) at 0 C. After stirring for 1 hour, acetic anhydride (15.5 g, 152 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours then quenched with 10% sodium carbonate solution (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 10: 1) to give the title compound (4.1 g, 70%) as a yellow solid. 1H NMR (400 MHz, OMSO-d6): delta 8.91(d, 1H), 6.91 (d, 1H).3-Chloro-1H-pyrazole (1): Copper (II) chloride (65.0 g, 481 mmol) and cone. HCl (20 mL) were added to a solution of lH-pyrazol-3-amine (20.0 g, 241 mmol) in acetonitrile (600 mL) at 0 C. The reaction mixture was stirred at 0 C for 30 min, then isopentyl nitrite (56.4 g, 481 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days, and then quenched with aq. ammonia (10%, 1 L). The aqueous phase was extracted with EtOAc (5 x 500 mL) and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography (hexane: EtOAc= 20: 1) to give the title compound (10.3 g, 42%) as a green oil. 1H NMR (400 MHz, CDC13): delta 12.84 (bs, 1H), 7.62 (s, 1H), 6.29 (s, 1H).To a solution of 2-chloro-4-methyl-N-(1, 1, 1-trifluoropropan-2-yl)imidazo[1, 5- a]pyrimidine-8-carboxamide (70 mg, 0.23 mmol) in DMF (5 mL) was added K2CO3 (63 mg, 0.46 mmol) and To a stirred solution of ethyl 2-chloro-4-methylimidazo[1, 5-a]pyrimidine-8- carboxylate (300 mg, 1.25 mmol) in DMF (2.0 mL) was added A sealed tube was charged with Copper(I) oxide (5.82 muL, 0.244 mmol), salicylaldoxime (134 mg, 0.975 mmol), 3-chloro-lH-pyrazole (500 mg, 4.88 mmol), Cs2CO3 (3178 mg, 9.75 mmol) and Part A compound of Example 1(150 mg, 7.32 mmol) and MeCN (4.877 mL). The tube was purged with N2 and the reaction stirred at 82 0C for 5 h. After cooling to RT, the mixture was diluted with CH2Cl2 (10 mL) and filtered through a pad of CELITE. The filtrate was concentrated and purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 50:50) to afford 420 mg (38 % yield) of the title compound as a brown solid: 1H NMR (500 MHz, CD3OD) delta 9.88 (1 H, s), 8.34 (1 H, s), 7.62 (1 H, s), 7.07 (1 H, s), 2.48 (3 H, s). HPLC retention time 2.923 min., LCMS (ES): m/z 227 [M+H]+.: 3-Chloropyrazole is reacted with sodium hydride in DMF and then treated with 3-chloro-4-fluorobenzotrifluoride and heated to llOC for 2 hr to give 3-chloro-l-(2-chloro-4-trifluoromethylphenyl)pyrazole.

Molecular Weight:102.52
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:101.9984758
Monoisotopic Mass:101.9984758
Topological Polar Surface Area:28.7
Heavy Atom Count:6
Complexity:48.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes