3-Amino-5-fluoro-1H-pyraz...

To a solution of compound 4a (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and EtTo a solution of compound 4 (50 g, 321.7 mmol) in 1- butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 h. To a solution of compound 4 (50 g, 321.7 mmol) in1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 5-Fluoro-lH-pyrazolo [3, 4-b]pyridin-3-amine (5) [00148] To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol) , and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and Et2<0 (2x) and dried in vacuo overnight to give compound 5 (44 g, 88percent) as a yellow solid. 5-Fluoro-lH-pyrazolo[3, 4-b]pyridin-3-amine (5); [00189] To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2x) and Et2-Chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) was dissolved in -butanol (300 mL), and thenhydrazine monohydrate (16.82 mL, 293 mmol) was added, followed by hydrochloric acid(4N in 1, 4-dioxane) (0.244 mL, 0.977 mmol). The reaction mixture was maintained at70°C for 4 h, and the resulting yellow crystalline solid was collected by filtration (12.5 g, 84percent yield). MS (m/z) 153 (M+HDissolve 2-chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) in 1-butanol (300 mL) and then add hydrazine monohydrate (16.82 mL, 293 mmol). Hydrochloric acid (4N in dioxane) (0.244 mL, 0.977 mmol) was then added. The reaction mixture was maintained at 70°C for 4 hours and the resulting yellow crystalline solid (12.5 g, 84percent yield) was collected by filtration.Step 3. 2-Chloro-5-fluoro-3-pyridinecarbonitrile (15.3 g, 98 mmol) was dissolved in 1-butanol (300 mL) ), And then added hydrazine monohydrate (16.82 mL, 293 mmol), Hydrochloric acid (4N in dioxane) (0.244 mL, 0.977 mmol) was then added.The reaction mixture was maintained at 70C for 4 hours.The resulting yellow crystalline solid (12.5 g, 84percent yield) was collected by filtration.2-Chloro-5-fluoronicotinonitrile (1.95 g, 12.50 mmol) was dissolved in n-butanol (30 mL).Then hydrazine hydrate (80percent, 8 mL, 125 mmol) was added thereto.The resulting mixture was warmed to 120 ° C and stirred for 6 hours.After cooling to room temperature, a small amount of solid was precipitated, and the mixture was allowed to stand in an ice water bath for 1 hour.A large amount of solid was precipitated, suction filtered, and the filter cake was washed with water (20 mL) at 0 ° C.Then vacuum dry, The title compound was obtained as a pale yellow solid (1. 36 g, 73percent).To a solution of 2-chloro-5-fluoronicotinonitrile (1.95 g, 12.50 mmol) in n-butanol (30 mL) was added hydrazine hydrate (80percent, 8 mL, 125 mmol). The mixture was heated to 120 °C and stirred for 6 h, then cooled to rt and there was a little solid precipitated out. The mixture was placed in an ice-bath for 1 h, and there was a lot of solid precipitated out. Then the mixture was filtered by suction. The filter cake was washed with 0 °C water (20 mL) and dried in vacuo to give the title compound as a light yellow solid (1.36 g, 73percent).‘H NIVIR (400 MHz, CDC13) (ppm): 12.07 (s, 1H), 8.38 (dd, J 2.5, 1.8 Hz, 1H), 7.97 (dd, J 8.8, 2.7 Hz, 1H), 5.55 (s, 2H).Weigh 2-chloro-5-fluoro-pyridine-3-carbonitrile (8.0 g, 51 mmol) in a 250 ml flask.Ethylene glycol (80 mL) and hydrazine hydrate (24 mL, 494 mmol) were added thereto.The temperature was raised to 180 ° C and refluxed overnight. Cool to room temperature and add water (50 mL).Stir at room temperature for 10 minutes and filter.The filter cake was washed with water (30 mL) and tetrahydrofuran (30 mL, -10 ° C).Dry in vacuo to a yellow solid (5.0 g, 64.0percent).A stirred solution of 2.-chloro.5-fluoro.-pyridine3..carbonitriie (50 g, 3.30 mo) and N2H4.H20(100 mL) in EtOH (500 mL) was heated at 100 °C for 2 h. After TLC (petroleum ether:EtOAc = 2:1) showed the completion of the reaction, the solvent was removed underreduced pressure. The residue, after being washed with EtOAc several times afforded thetitle compound (30.6 g, 62percent yield) as a solid. MS: 153.0 [M+H].Example 4A5-Fluoro-lH-pyrazolo[3, 4-b]pyridin-3-amineA suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was introduced in 1, 2-ethanediol (380 ml) and subsequently admixed with hydrazine hydrate (1 19.6 ml, 2.459 mol) The mixture was heated at reflux with stirring for 4 h. On cooling, the product precipitated. The yellow crystals were admixed with water (380 ml) and subjected to extractive stirring at RT for 10 min. Then the suspension was filtered with suction over a frit, and the filter product was washed with water (200 ml) and with -10°C cold THF (200 ml). The residue was dried under a high vacuum over phosphorus pentoxide.Yield: 22.8 g (61percent of theory) Example 4AExample 5A 5-Fluoro-1H-pyrazolo[3, 4-b]pyridine-3-amine Example 5A Example 22A Example 4A A suspension of 38.5 g (245.93 mmol) of 2-chioro- 5-fluoronicotinonitrile was initially charged in 1 , 2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml) was then added. With stirring, the mixture was heated at reflux for 4 h. On cooling, the product precipitated out. Water (380 ml) was added to the crystals, and the mixture was stirred at RT for 10 mm. The suspension was then filtered off with suction through a frit and washed with water (200 ml) and with —10° C-cold THF (200 ml). Drying under high vacuum over phosphorus pentoxide.10422] Yield: 22.8 g (61percent of theory)10423] ‘H NMR (400 MHz, DMSO-d5): ö=5.54 (s, 2H), 7.96 (dd, 1H), 8.38 (m, 1H), 12.07 (m, 1H).Formation of 5-fluoro-lH-pyrazolo[3, 4-6]pyridin-3-amine (132a)To the mixture of 2-chloro-5-fiuoropyridine-3-carbonitrile, 131a, (29.6 g, 157.1 mmol) in n-butanol (492 mL) was added hydrazine hydrate (76.4 mL, 1.6 mol). This mixture was heated to reflux for 4.5 h and cooled down. n-Butanol was removed under reduced pressure and water (300 mL) was added resulting in a yellow precipitate. The suspension was filtered and washed with water twice, followed by a MTBE wash. The yellow solid was dried in a vacuum oven to give 18 g of the desired product: 1H NMR (300 MHz, DMSO- 6) δ 12.08 (s, 1H), 8.38 (dd, J = 2.7, 1.9 Hz, 1H), 7.97 (dd, J = 8.8, 2.7 Hz, 1H), 5.56 (s, 2H). LCMS Gradient 10-90percent, 0.1percent formic acid, 5 minutes, C18/ACN, Retention Time = 1.25 minutes (M+H) 152.95.A suspension of 38.5 g (245.93 mmol) of 2-chloro-5-fluoronicotinonitrile was initially charged in 1, 2-ethanediol (380 ml), and hydrazine hydrate (119.6 ml) was then added.

Molecular Weight:152.13
XLogP3:0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Exact Mass:152.04982434
Monoisotopic Mass:152.04982434
Topological Polar Surface Area:67.6
Heavy Atom Count:11
Complexity:154
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes