1-(5-Bromo-2-chloro-3-pyridinyl)ethanone

To a solution of compound 12b (2.0 g, 7.15 mmol) in anhydrous THF (15mL) was added methylmagnesium bromide (1M in THF, 8 mL, 8 mmol) dropwise at 0 °C under Argon atmosphere. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with sat. NHPreparation of 1-(5-bromo-2-chloropyridin-3-yl)ethanone (D-2-5). To a solution of compound4(2.0 g, 7.15 mmol) in anhydrous THF (15mL) was addedmethylmagnesium bromide(1M in THF, 8 mL, 8 mmol) dropwise at 0°Cunderargon atmosphere. The resulting mixture was stirred at room temperaturefor 30 min. The reaction was quenched with sat. NHStarting material 5-bromo-2- chloro-N-methoxy-N-methylnicotinamide (5.0 g, 17.89 mmol) was charged into a 250 ml round bottom flask and the flask was chilled to -78 A mixture of 1-(5-bromo-2-chloropyridin-3- yl)ethanone (980 mg, 3.97 mmol) and N, N-dimethylformamide dimethyl acetal (4.0 mL, 30 mmol) was stirred at 90C for 90 minutes in an oil bath. The mixture was cooled to room temperature, and concentrated under reduce pressure. The residue was diluted by addition of ethanol (13 mL) and water (6.5 mL), acetic acid (1.6 mL, 28 mmol) and methyl (2S)-2-hydrazinylpropanoate hydrochloride (0.859 g, 5.56 mmol) obtained in Example (16a) was added thereto at room temperature, and the mixture was stirred at 90C for 4 hours in an oil bath. The mixture was cooled to room temperature, and neutralized by addition of a 2.0 mol/L aqueous solution of sodium hydroxide, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of (2S)-2-[5-(5-bromo-2- chloropyridin-3-yl) -1H-pyrazol-1-yl]propanoic acid (1.39 g) as a mixture containing a positional isomer. To a solution of the crude product of (2S)-2-[5-(5-bromo-2- chloropyridin-3-yl) -1H-pyrazol-1-yl]propanoic acid (1.31 g) obtained in the above step in tetrahydrofuran (10 mL), a 0.92 mol/L solution of boran-tetrahydrofuran complex in tetrahydrofuran (6.5 mL, 6.0 mmol) was added under ice cooling, the mixture was stirred at the same temperature as above for 10 minutes and subsequently stirred at room temperature for 20 hours. The mixture was cooled in an ice water bath, a 1.0 mol/L aqueous solution of sodium hydroxide was added thereto, followed by extraction with a mixed solvent of ethyl acetate/nhexane = 4/1. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product of (2S)-2-[5-(5-bromo-2- chloropyridin-3-yl) -1H-pyrazol-1-yl]propan-1-ol (760 mg) as a mixture containing a positional isomer. To a solution of the crude product of (2S)-2-[5-(5-bromo-2- chloropyridin-3-yl) -1H-pyrazol-1-yl]propan-1-ol (760 mg) as a mixture containing positional isomers obtained in the above step in N, N-dimethylformamide (50 mL) was added potassium carbonate (829 mg, 6.00 mmol) at room temperature, and the mixture was stirred at 120C for 2 hours in an oil bath. The reaction mixture was cooled, and diluted by addition of a saturated aqueous solution of ammonium chloride, followed by extraction with a mixed solvent of ethyl acetate/n-hexane = 4/1. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, the residue was purified in an automatic chromatography apparatus (Yamazen Co. Ltd., High-flashTM column Amino, n-hexane/ethyl acetate = 96/4- 66/34) to obtain the title compound (597 mg, yield for 3 steps: 54%)?H NNR spectrum (CDC13, 400MHz) oe: 8.26 (1H, d, J =2.4 Hz), 8.19 (1H, d, J= 2.4 Hz), 7.55 (1H, d, J=1.8 Hz), 6.66 (1H, d, J = 1.8 Hz), 4.95-4.89 (1H, m), 4.59 (1H, dd, J = 13.1, 4.6 Hz), 4.44-4.43 (1H, m), 1.64 (3H, d, J= 7.3 Hz).A mixture of 1-(5-bromo-2-chloropyridin-3- yl)ethanone (4.85 g, 0.85 mmol) and N, N-dimethylformamide dimethyl acetal (15 mL, 113 mmol) was stirred at 85C for 90 minutes in an oil bath. The mixture was cooled to room temperature, and concentrated under reduce pressure. The residue was diluted by addition of ethanol (30 mL) and water (15 mL), acetic acid (3.3 mL, 58 mmol) and 2-hydrazinoethanol (1.83 mL, 26.9 mmol) was added thereto at room temperature, and the mixture was stirred at 90C for 4 hours in an oil bath. The mixture was cooled to room temperature, and neutralized by addition of a 1.0 mol/L aqueous solution of sodium hydroxide, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (n-hexane/ethyl acetate = 100/0- 0/100) to obtain 2-[5-(5-bromo-2-chloropyridin-3-yl)- 1H-pyrazol-1-yl]ethanol (3.62 g) as a mixture containing positional isomers. To a solution of 2-[5-(5-bromo-2- chloropyridin-3-yl)-1H-pyrazol-1-yl]ethanol (3.62 g) as a mixture containing positional isomers obtained in the above step in N, N-dimethylformamide (240 mL) was added potassium carbonate (3.31 g, 23.9 mmol) at room temperature, and the mixture was stirred at 120C for 2 hours in an oil bath. The reaction mixture was cooled, and an insoluble material was filtered off. The residue was washed with ethyl acetate, and the filtrate and the washes were combined. The solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (Yamazen Co. Ltd., High-flashTM column Amino, n-hexane/ethyl acetate = 100/0- 30/70) to obtain the title compound (101 mg, yield for 2 steps: 57%)?H NNR spectrum (CDC13, 400MHz) oe: 8.27 (1H, d, J =2.3 Hz), 8.18 (1H, d, J= 2.3 Hz), 7.55 (1H, d, J=2.0 Hz), 6.69 (1H, d, J = 2.0 Hz), 4.74-4.72 (2H, m), 4.62-4.60 (2H, m)

Molecular Weight:234.48
XLogP3:2.2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:232.92430
Monoisotopic Mass:232.92430
Topological Polar Surface Area:30
Heavy Atom Count:11
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes