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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. 1H-NMR (400 MHz, CDCl3) δ: 7.93 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 2.71 (3H, s). ESI-MS found: 190 [M+H]+
205 mg
at 0 - 70℃; for 72 h;
(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. 1H-NMR (400 MHz, CDCl3) δ: 7.93 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 2.71 (3H, s).
With methanol; sodium tetrahydroborate; at -10 - 20℃; for 2h;
Example 17c 1-(2,6-Dichloro-pyridin-3-yl)-ethanol Sodium borohydride (0.816 g, 21.6 mmol) was added in small portions to a solution of <strong>[412018-50-9]1-(2,6-dichloro-pyridin-3-yl)-ethanone</strong> (Example 17b, 4.1 g, 21.6 mmol) in MeOH (100 mL) at -10 C. The reaction mixture was allowed to warm to r.t. over 2 h. The reaction was then quenched with water (1 mL) and solvents were removed under reduced pressure. The residue was purified by flash column chromatography using 10% EtOAc in hexane to afford the title compound (4.15 g, quantitative). 1H NMR (400 MHz, CDCl3) delta ppm 1.50 (d, 3H) 5.21 (qd, 1H) 7.32 (d, 1H) 7.94 (d, 1H).
Example 17b 1-(2,6-Dichloro-pyridin-3-yl)-ethanone A solution of methylmagnesium bromide in ether (3.0 M, 9.36 mL, 28.1 mmol) was added dropwise to a solution of 2,6-dichloro-N-methoxy-N-methyl-nicotinamide (Example 17a, 5.5 g, 23.4 mmol) in anhydrous THF (100 mL) at -5 C. under a nitrogen atmosphere. The reaction mixture was stirred at -5 C. for 2 h, thereafter quenched with saturated solution of NH4Cl and allowed to warm to r.t. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was immediately purified on a small plug of silica gel using a gradient of 0 to 10% EtOAc in hexane to afford the title compound (4.1 g, 92%). 1H NMR (400 MHz, CDCl3) delta ppm 2.71 (s, 3H) 7.37 (d, 1H) 7.92 (d, 1H).
N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,5-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine[ No CAS ]
N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,5-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine[ No CAS ]
N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,5-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine[ No CAS ]
N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,5-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine[ No CAS ]
Reference Example 3 A solution of 8.00 g of <strong>[412018-50-9]3-acetyl-2, 6-dichloropyridine</strong> in 12 mL of DMADA was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent; hexane : ethyl acetate = 3:1 ? 1:3], and suspended in a mixed solvent of ethyl acetate and diisopropyl ether, and the solid was filtered to obtain 3.91 g of (E)-1-(2, 6-dichloropyridin-3-yl)-3-dimethylamino-2-buten-1-one as a yellow solid. 1H-NMR (CDCl3) delta:2.67 (s, 3H), 3.08 (brs, 6H), 5.25 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.74 (d, J =8.1 Hz, 1H).
In tetrahydrofuran; diethyl ether; at 70℃; for 72h;
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 0C, and then the reaction mixture was stirred at 70C 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. 1H-NMR (400 MHz, CDCl3) delta: 7.93 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 2.71 (3H, s). ESI-MS found: 190 [M+H]+
205 mg
In tetrahydrofuran; diethyl ether; at 0 - 70℃; for 72h;
(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 0C, and the mixture was then stirred at 70C 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. 1H-NMR (400 MHz, CDCl3) delta: 7.93 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 2.71 (3H, s).
In tetrahydrofuran; at 0 - 20℃; for 15h;
[0005911 To a stirred solution of compound 3 (1 g, 1 eq) in THF (10 mL),methyl magnesium iodide ( 2.8 mL, 2eq) was added at 0C 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 quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 X 25 mL). Combined organic extracts were washed with brine and 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 30% EtOAc-hexane to afford the title compound 4. ?H NMR (400 MHz, CDC13) oe: 8.61 (s, 1H), 7.45 (s, 1H), 2.68 (s, 3H).
6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86 mg
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]+
500 mg
With hydrazine hydrate; In tetrahydrofuran; at 0 - 50℃; for 3h;
To the solution of <strong>[412018-50-9]1-(2,6-dichloropyridin-3-yl)ethan-1-one</strong>(800mg, 4.2lmmol), in THF(15 mL), hydrazine hydrate (421mg, 8.42lmmol) was added drop wise at 0C and stined at 50Cfor 3h. After completion of reaction, reaction mixture was concentrated under reduced pressure.The crude compound obtained was purified by silica gel colunm chromatography using 20%ethyl acetate in hexane as eluent to give title compound (500mg, 72%).?HNMR (300MHz, DMSO-d6): oe 13.4(s, 1H), 8.26-8.23 (d, 1H), 7.20-7.17 (d, 1H), 2.47 (s, 3H). LCMS: mlz = 168.0 (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]+
6-chloro-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; at 50℃; for 2h;
[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).
6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With N-ethyl-N,N-diisopropylamine; In ethanol; for 2.5h;Reflux;
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]+.
In ethanol; at 20℃;
[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).
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)
N-[1-(2,6-dichloropyridin-3-yl)ethylidene]-2-methylpropane-2-sulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.9 g
With titanium(IV) tetraethanolate; In dichloromethane; at 50℃;
PREPARATION EXAMPLE 4 A mixture of <strong>[412018-50-9]1-(2,6-dichloropyridin-3-yl)ethan-1-one</strong> (78.8 g), CH2Cl2 (300 mL), 2-methylpropane-2-sulfinamide (60.6 g), and titanium tetraethoxide (284.4 g) was stirred at 50 C. overnight. Additional titanium tetraethoxide (50.0 g) was added, and the mixture was stirred at 50 C. for 4 hours. The mixture was cooled to room temperature and then aq. NaHCO3 was slowly added. The mixture was then filtered through a pad of Celite, and the Celite pad was washed with CH2Cl2. The filtrate was concentrated, suspended in EtOAc, and then washed with sat. aq. NaHCO3. The organic layer was dried over Na2SO4, concentrated, and then purified by silica gel column chromatography (EtOAc/hexanes) to give N-[1-(2,6-dichloropyridin-3-yl)ethylidene]-2-methylpropane-2-sulfinamide (63.9 g) as an oil.
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