4-BROMO-1H-PYRAZOLE-3-CARBOXYLIC ACID

Bromine (800 mg, 5.0 mmol) was added to a solution of pyrazole-3-carboxylic 20 acid (500 mg, 4.5 mmol) in acetic acid (20 mL). The mixture was stirred at rtrt for18 h followed by addition of water (100 mL) and extraction with diethyl ether(3x30 mL). The combined organic phases were washed with water (50 mL) andconcentrated to give .the title product (750 mg, 87percent) as a pale yellow solid.'H NMR (DMSO-d(, , 400 MHz) 5 7.92 (s, 1H). 25General procedure: To a solution of Intermediate 7 (110 mg, 0.37 mmol), 3-methoxybenzene-1, 2- diamine (50 mg, 0.34 mmol) and DIPEA (0.2 mL, 1 mmol) in DMF (2 mL) was added HATU (160 mg, 0.41 mmol). The reaction mixture was stirred at r.t. for 48 h, then partitioned between DCM and water. The organic phase was separated, then dried and concentrated in vacuo. The crude residue was purified by flash column chromatography (0-100% EtOAc/hexanes) to give the title compound (28.7 mg, 20%) as a white solid. LCMS (Method 5): [M+H]+ m/z 415, RT 1.31 minutes.NaH (60% dispersion in mineral oil, 11.3 g, 282 mmol, 3.0 eq) was added in portions to a mixture of Ste 2: (0585) Preparation of 4-bromo-N-(2, 2-dimethoxyethyl)-1H-pyrazole-3-carboxamide: (0586) [00242] To a stirred solution of Concentrated sulfuric acid (0.24 mL, 4.3 mmol) was added to a suspension of 4-bromo-1H-pyrazole-3-carboxylic-acid (860 mg, 4.3 mmol) in t-BuOH (2.1 mL, 22 mmol). The reaction mixture was stirred at 100 C. for 2 h. Most of the solvent evaporated during the heating and a white solid remained in the flask. After cooling to room temperature, the pH was adjusted to 4 by adding saturated aq. NaHCO3. The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-bromo-1-tert-butyl-1H-pyrazole-3-carboxylic-acid (1.0 g, 89%) as a white solid. 1H NMR (300 MHz, DMSO) delta 1.52 (s, 9H), 8.23 (s, 1H), 12.92 (br s, 1H).General procedure: The fragment carboxylic acid (0.35 mmol) was dissolved in dimethylformamide (0.2 M, 1.75 mL), then 14 (42.6 mg, 0.35 mmol), HBTU (128 mg, 0.34 mmol), and HOBT (51.8 mg, 0.38 mmol) were added, followed by diisopropylethylamine (175 muL, 1.047 mmol). The reaction was stirred at 23 C for 16 h. TLC at 16 h showed conversion to product. The reaction was quenched with H2O (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and saturated aqueous NaCl (10 mL). The organic layer was dried over MgSO4, filtered, and evaporated. Purification with flash column chromatography with CH3OH/CH2Cl2 ( CH3OH gradient 0 ' 5 %).The tert-butyl 4-[4-bromo-3-(dimethylcarbamoyl)pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: di(imidazol-1-yl)methanone (1910 mg) was added portionwise to a suspension of

Molecular Weight:190.98
XLogP3:0.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:189.93779
Monoisotopic Mass:189.93779
Topological Polar Surface Area:66
Heavy Atom Count:9
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes