1-(2,6-dichloropyridin-3-yl)ethanone

To a solution of the compound [151-1] obtained in the process (1) (487 mg) in tetrahydrofuran (10 mL) was added 2M diethyl ether solution of methylmagnesium iodide (1.24 mL) at 0°C, and then the reaction mixture was stirred at 70°C for 72 hours. To the reaction mixture was added an aqueous solution of ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (205 mg) as a colorless oil. (2) Synthesis of 1-(2, 6-dichloropyridin-3-yl)ethanone [108-2] (hereinafter referred to as a compound [108-2]) The compound [108-1] (487 mg) was dissolved in tetrahydrofuran (10 mL). To the solution was added 2.0M diethyl ether solution of methylmagnesium iodide (1.24 mL) at 0°C, and the mixture was then stirred at 70°C for 72 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The obtained organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (205 mg) as a colorless oil. PREPARATION EXAMPLE 4 A mixture of To the solution of 2, 6-dichloronicotinic acid (2.0gm, 10.4lmmol) in THF (20 mL), was added CH3MgBr (12 mL) drop wise at 0C which was stined at RT for 12h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution; dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound (1.lg).?HNMR (300MHz, DMSO-d6): oe 8.25-8.23(d, 1H), 7.72-7.69 (d, 1H), 2.59 (s, 3H). LCMS:mlz = 190.0 (M-1)o a solution of l-(2, 6-dichloropyridin-3-yl)ethanone (2.21 g, 11.6 mmol, Eq: 1.00) in ethanol (90 ml) was added methylhydrazine (643 mg, 735 mu, 14.0 mmol, Eq: 1.20) and N, N- diisopropylethylamine (1.5 g, 2.03 ml, 11.6 mmol, Eq: 1.00) and the reaction was heated to reflux for 2.5h. The solution was concentrated, dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford the desired product as yellow cristals (1.57 g, 74 ). MS (m/z) = 182.1 [M + H]+.[0006021 To a stirred solution of compound 4 (0.8 g, leq)in ethanol (10 mL), methyl hydrazine(0.54 g, 2 eq)was added and stirred at room temperature for 15 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (3 x 25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compoundS. LCMS (mlz): 181.90 (M+1).[0005921 To a stirred solution of compound 4 (0.3 g, leq)in ethanol (5 mL), methyl hydrazine(0.l6mL, 2 eq)was added and heated at 50C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (2 X 25 mL). Combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 20% EtOAc-hexane to afford the title compound 5. LCMS (mlz): 182.00 (M+1).(3) Synthesis of 6-chloro-3-methyl-1H-pyrazolo[3, 4-b]pyridine [108-3] (hereinafter referred to as a compound [108-3]) The compound [108-2] (205 mg) was dissolved in dichloromethane (2.7 mL), and to the solution was added titanium(IV) tetraisopropoxide (0.63 mL) at room temperature, and the mixture was stirred at room temperature for 15 minutes. Hydrazine monohydrate (0.11 mL) was then added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water, and the mixture was stirred for 30 minutes, the insoluble material was separated by filtration, and rinsed with chloroform. The filtrate was concentrated under reduced pressure to give a white solid. The obtained solid was suspended in ethanol (1.5 mL), and the suspension was subjected to microwave irradiation at 150C for 20 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (86 mg) as a white solid. 1H-NMR (400 MHz, CDCl3) delta: 10.18-10.08 (1H, br), 7.96 (1H, d, J = 8.3 Hz), 7.14 (1H, d, J = 8.3 Hz), 2.57 (3H, s). ESI-MS found: 168 [M + H]+To a solution of the compound [151-2] obtained in the process (2) (205 mg) in dichloromethane (2.7 mL) was added titanium tetraisopropoxide (0.63 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 15 minutes. Next, to the reaction mixture was added hydrazine monohydrate (0.11 mL), and stirred at room temperature for 3 hours. The reaction mixture was quenched with water, and stirred for 30 minutes, and then the insoluble materials were separated by filtration, and the insoluble materials were washed with chloroform. The filtrate was concentrated under reduced pressure to give a white solid. To the obtained solid, ethanol (1.5 mL) was added and the reaction mixture was subjected to microwave irradiation at 150C for 20 minutes. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (86 mg) as a white solid. 1H-NMR(400-MHz, CD3OD) delta: 10.15 (1H, brs), 7.97 (1H, d, J = 8.3 Hz), 7.15 (1H, d, J = 8.3 Hz), and 2.58 (3H, s). ESI-MS found: 168 [M+H]+To the solution of

Molecular Weight:190.02
XLogP3:2.5
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:188.9748192
Monoisotopic Mass:188.9748192
Topological Polar Surface Area:30
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes