2-Amino-3-(trifluoromethyl)pyridine-5-boronic acid pinacol ester

A mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (180 g) and 1, 4-dioxane (3600 mL) was stirred in a flask. Bis(pinacolato)diboron (284.47 g), potassium acetate (109.95 g) and l, l-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM complex (18 g), were then added under stirring at a temperature of about 25 to 30°C. Reaction mass was heated to 95 to 100°C and maintained for 15-16 hr. After the completion of reaction, the mass was cooled to 25 to 30°C, filtered through celite bed and the bed was washed with ethyl acetate (1800 mL). The filtrate was distilled out completely under vacuum to get crude title compound (450 g). Purification The crude title compound was dissolved in methanol (1800 mL) in a round bottom flask. Charcoal (45 g) and silica gel (60-120 mesh size, 450 g) were added to the mass and maintained under stirring at a temperature of about 25 to 30°C for 1 h. The mass was filtered through celite bed and washed the bed with methanol (450 mL). The filtrate was added into a flask containing cold water (6750 mL) at 0-5°C, over a period of 1 h. The precipitated solid was filtered out, washed with cold water (900 mL). The wet compound was unloaded and dried at 45 to 50°C to obtain the title compound (209 g). Yield: 97.47percent Purity: 98.43percent An orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi(1 , 3, 2-dioxaborolane)(5.90 g, 23.24 mmol), KOAc (4.07 g, 41 .5 mmol) and PdCIAn orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4, 4, 4′, 4′, 5, 5, 5′, 5′-octamethyl-2, 2′-bi(1, 3, 2-dioxaborolane) (5.90 g, 23.24 mmol), KOAc (4.07 g, 41.5 mmol) and PdCl[0429] To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (46B, 1.21 g, 5.0 mmol) in DME (50 mL) were added bis(pinacolato)diboron (1.65 g, 6.5 mmol), Pd(dppf)ClGeneral procedure: Commercial 1a (50mmol) was dissolved in dichloromethane (80mL), mixture was cooled to 0C, solution of NH3 in MeOH (4mol/L, 12.5mL) was added by dripping slowly, after 30min, the mixture maintained at 0C for 1h. The reaction mixture was filtered, and the insoluble material was washed with ethyl acetate (20mL) and water (30mL) to get 2a (8.66g), yield 90%. Compound 2a (50mmol) was dissolved in THF (40mL), then absolute ethyl alcohol (20mL), water (20mL), Fe (4eq) and ammonium chloride (2eq) were added. The mixture was refluxed until raw material disappeared. The reaction mixture was filtered and filter liquor was evaporated by reducing pressure to get 3a (2.4g), yield 33%. Compound 3a (17mmol) was dissolved in DMF (30mL), triethylamine (3eq) was added, and acetyl isothiocyanate (1eq) was added by dripping slowly, the mixture was stirred at room temperature for 30min, then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.5eq) was added and stirred overnight at room temperature. Pulled the mixture into ice water, using concentrated HCl regulates pH to 1, the mixture was filtered, the residue was dried and washed by water to give 4a (2.0g), yield 60%. Compound 4a (10mmol), 5a/5b/5c/5d/5e (1.2eq), 120mL 1, 4-dioxane, 10mL water, Pd(dppf)Cl2 (0.1eq), and NaHCO3 (1eq) were added to a round-bottomed flask, mixture was stirred for 12h at 90C. Solvent was removed by reduced pressure distillation, residue was purified by preparative HPLC (MeCN+0.05% TFA, H2O 0.1%+TFA), Ta-e were finally obtained from above steps, yield 0.58-5.5%.Into a vial was weighed (+-)-(1S, 2S)-N-(8-amino-6-chloro-2, 7-naphthyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (60.0 mg, 0.175 mmol),

Molecular Weight:288.08
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:1
Exact Mass:288.1256924
Monoisotopic Mass:288.1256924
Topological Polar Surface Area:57.4
Heavy Atom Count:20
Complexity:360
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes