5-BROMO-1H-PYRAZO[3,4-B]PYRIDINE

Preparation of 5-bromo-1H-pyrazolo[3, 4-b]pyridine (D-1-3). 5-Bromo-2-fluoro-pyridine-3-carbaldehyde (4.1g, 20mmol) obtained from Preparation Example 129-1 was dissolved in ethanol (50ml). After adding hydrazine hydrate (5.0ml, 100mmol), the mixture was stirred for 8 hours at 100 and then distilled under reduced pressure. Water was added thereto and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.8g, 40percent).[1499] NMR:To a stirred solution of 5-bromo-2-fluoronicotinaldehyde (XV) (250 g, 1.23 mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25°C. The reaction was then heated to 75~80°C and stirred for 12 h. The solvent was removed under reduced pressure at 45°C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5 -bromo- lH-pyrazolo[3, 4- b]pyridine (XVI) (135 g, 0.68 mol, 55.4percent yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for CeLLtBrNs mlz 199.1 (M+H).To a stirred solution of 5-bromo-2-fluoronicotinaldehyde (XV) (250 g, 1.23mol, 1.0 eq) in EtOH (2.50 L) was added hydrazine hydrate (221 g, 4.41 mol, 3.6 eq) at 25°C. The reaction was then heated to 7580°C and stirred for 12 h. The solvent was removed under reduced pressure at 45°C. The residual crude solid was triturated in water (750 mL) and EtOH (250 mL). The resultant suspension was filtered and washed with ethanol to give 5-bromo-1H- pyrazolo[3, 4-bjpyridine (XVI) (135 g, 0.68 mol, 55.4percent yield) as yellowish solid which was used directly for the next step without further purification. ESIMS found for C6H4BrN3 mlz 199.1 (M+H).A solution of 1 H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3, 4-b]pyridine x80 (yield: 2.1 percent; LC-MS (MHlH-Pyrazol-5-amine (5.3 g, 64 mmol) and 2-bromomalonaldehyde(9.9 g, 64 mmol) were suspended in acetic acid (100 mL). The reaction mixture was heated Preparation 6; 5 -Bromo- 1 H-pyrazolo [3 , 4-b] pyridine; Dissolve 2-bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux under nitrogen for 2 h. Concentrate under reduced pressure and dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad of diatomaceous earth and concentrate under reduced pressure. Purify via chromatography (silica gel, hexane to 50percent ethyl acetate/50percent hexane) to obtain 365 mg (11percent) of the title compound as a light EPO

Molecular Weight:198.02
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:196.95886
Monoisotopic Mass:196.95886
Topological Polar Surface Area:41.6
Heavy Atom Count:10
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes