* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
General procedure: Methyl iodide (4 mmol; 2 equiv.) was added to a solution of 1 (2 mmol) in various solvents (15 ml) and the mixture was refluxed overnight. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc: MeOH, 20:1→5:1) to obtain the products.
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h; Stage #2: at 20℃; for 19 h;
To a solution of MeOH (0.115 mL, 2.85 mmol) and THF (0.5 mL) at 0 °C was added sodium hydride (60percent dispersion, 1 14 mg, 2.85 mmol). After stirring for 15 min, Intermediate 3 IB (600 mg, 1.900 mmol) was added, and the resulting mixture was stirred at room temperature for 19 hours, diluted with water (3 mL) and extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield Intermediate 31 (0.480 g, 1.798 mmol, 95percent yield) as a beige color solid. MS (ES): m/z=267.9 [M+H]+. XH NMR (400 MHz, MeOD) δ ppm 8.68 (2 H, s), 3.99 (3 H, s).
Stage #1: With N-ethyl-N,N-diisopropylamine; trichlorophosphate In acetonitrile at 20℃; for 17 h; Cooling with ice; Reflux Stage #2: at 60℃; for 0.5 h;
Compound (M-41) (10.0 g, 39.5 mmol)Was suspended in acetonitrile (50 mL)DIPEA (15 mL, 87 mmol) was added at room temperature,Phosphoryl chloride (7.4 mL, 79 mmol)Was added under cooling with ice, and the mixture was stirred under heating reflux for 17 hours. After allowing to cool, the reaction solution was added dropwise to ice water,And neutralized with sodium carbonate (11.6 g, 138 mmol).Thereafter, the mixture was extracted with ethyl acetate,The organic layer was washed with saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Chloro compound (yield 10.6 g, yield 99percent)As a brown solid.Chloro form (10.6 g, 39.1 mmol)Was dissolved in THF (70 mL)Sodium methoxide (28percent methanol solution,14 mL, 59 mmol) was added,Followed by stirring at 60 ° C. for 30 minutes. After cooling down,Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Compound (VII-46) (yield 9.21 g, yield 88percent)As a yellow solid.
Reference：
[1] Patent: JP2018/145180, 2018, A, . Location in patent: Paragraph 0633; 0634; 635
6
[ 13626-17-0 ]
[ 124-41-4 ]
[ 25813-24-5 ]
Yield
Reaction Conditions
Operation in experiment
88%
at 60℃; for 0.5 h;
Compound (M-41) (10.0 g, 39.5 mmol) was suspended in acetonitrile (50 mL), DIPEA (15 mL, 87 mmol) wasadded at room temperature, phosphoryl chloride (7.4 mL, 79 mmol) was added under ice-cooling, and the mixture wasstirred with heating under reflux for 17 hr. The mixture was allowed to cool, and the reaction mixture was added dropwiseto ice water, and neutralized with sodium carbonate (11.6 g, 138 mmol). Thereafter, the mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give a chloro compound (yield 10.6 g, 99percent) as a brown solid. The chlorocompound (10.6 g, 39.1 mmol) was dissolved in THF (70 mL), sodium methoxide (28percent methanol solution, 14 mL, 59mmol) was added, and the mixture was stirred at 60°C for 30 min. The mixture was allowed to cool, water was addedto the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give compound (VII-46) (yield 9.21 g, 88percent) as a yellow solid
79%
at 20℃; for 144 h; Inert atmosphere; Schlenk technique
A solution of 3,5-dibromo-4-chloropyridine (240) (249 mg, 918 μmol) and sodium methoxide (198 mg, 3.67 mmols) in 10 mL of MeOH was stirred for six days at rt Subsequently, the reaction mixture was admixed with 10 mL of water and the aqueous layer was then extracted three times with 30 ml of EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was subsequently removed in vacuo. The purification was carried out by silica gel column chromatography (5percent EtOAc/PE). The product (192 mg, 721 μmol, 79percent) was obtained as a white solid. Rf: 0.44 (5percent EtOAc/PE). 1H NMR (500 MHz, CDCl3) δ = 8.54 (s, 2H), 3.95 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 160.84, 152.13, 116.00, 60.95. ESI-MS: m/z = 268.00 [M+H]+. HRMS (ESI): calculated for C6H6ON 79Br2: m/z = 265.88107 [M+H]+, found: m/z = 265.88105 [M+H]+. calculated for C6H6ON 79Br 81Br: m/z = 267.87902 [M+H]+, found: m/z = 267.87831 [M+H]+. calculated for C6H6ON 81Br2: m/z = 269.87697 [M+H]+, found: m/z = 269.87574 [M+H]+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 90℃; for 1h;Inert atmosphere;
A pressure vessel charged with a mixture of tetrakis(triphenylphosphine) palladium(O) (21.65 mg, 0.019 mmol), Intermediate 50 (128 mg, 0.412 mmol), sodium carbonate (199 mg, 1.873 mmol), and Intermediate 31 (100 mg, 0.375 mmol) was stirred at room temperature for 10 min under a nitrogen atmosphere. To the above mixture, ethanol (0.5 mL), DME (1 mL), and water (0.5 mL) were sequentially added. The resulting mixture was stirred at room temperature for 30 min, heated at 90 C for 1 hour, cooled and filtered. The filtrate was concentrated and purified by silica gelchromatography (12 g ISCO column, eluting with 0% to 50% EtOAc in CH2C12) to provide Example 185 (80 mg, 0.213 mmol, 56.9% yield) as a pale yellow solid. HPLC Ret timea: 2.943 min. MS (ES): m/z=373.0 [M+H]+. XH NMR (500 MHz, DMSO-d6) delta ppm 2.07 (s, 3 H) 3.04 (s, 3 H) 3.43 (s, 3 H) 7.1 1-7.14 (m, 1 H) 7.15 (s, 1 H) 7.23 (d, J=8.25 Hz, 1 H) 8.27 (s, 1 H) 8.70 (s, 1 H) 9.88 (s, 1 H).
To a solution of MeOH (0.115 mL, 2.85 mmol) and THF (0.5 mL) at 0 C was added sodium hydride (60% dispersion, 1 14 mg, 2.85 mmol). After stirring for 15 min, Intermediate 3 IB (600 mg, 1.900 mmol) was added, and the resulting mixture was stirred at room temperature for 19 hours, diluted with water (3 mL) and extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield Intermediate 31 (0.480 g, 1.798 mmol, 95% yield) as a beige color solid. MS (ES): m/z=267.9 [M+H]+. XH NMR (400 MHz, MeOD) delta ppm 8.68 (2 H, s), 3.99 (3 H, s).
General procedure: Methyl iodide (4 mmol; 2 equiv.) was added to a solution of 1 (2 mmol) in various solvents (15 ml) and the mixture was refluxed overnight. The reaction was monitored by TLC. After completion, the solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc: MeOH, 20:1?5:1) to obtain the products.
General procedure: To a round bottle flask containing 1 (2 mmol) was added methyl iodide (10 mmol; 5 equiv.) and the mixture was stirred at room temperature or refluxed overnight. The reaction was monitored by TLC. After completion, the resulting precipitate was separated by filtration and purified by recrystallization.
3,5-dibromo-1-isopropylpyridin-4(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In neat (no solvent); for 24h;Reflux;
General procedure: To a round bottle flask containing 1 (2 mmol) was added methyl iodide (10 mmol; 5 equiv.) and the mixture was stirred at room temperature or refluxed overnight. The reaction was monitored by TLC. After completion, the resulting precipitate was separated by filtration and purified by recrystallization.
Compound (M-41) (10.0 g, 39.5 mmol) was suspended in acetonitrile (50 mL), DIPEA (15 mL, 87 mmol) wasadded at room temperature, phosphoryl chloride (7.4 mL, 79 mmol) was added under ice-cooling, and the mixture wasstirred with heating under reflux for 17 hr. The mixture was allowed to cool, and the reaction mixture was added dropwiseto ice water, and neutralized with sodium carbonate (11.6 g, 138 mmol). Thereafter, the mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to give a chloro compound (yield 10.6 g, 99%) as a brown solid. The chlorocompound (10.6 g, 39.1 mmol) was dissolved in THF (70 mL), sodium methoxide (28% methanol solution, 14 mL, 59mmol) was added, and the mixture was stirred at 60C for 30 min. The mixture was allowed to cool, water was addedto the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give compound (VII-46) (yield 9.21 g, 88%) as a yellow solid
79%
In methanol; at 20℃; for 144h;Inert atmosphere; Schlenk technique;
A solution of <strong>[13626-17-0]3,5-dibromo-4-chloropyridine</strong> (240) (249 mg, 918 mumol) and sodium methoxide (198 mg, 3.67 mmols) in 10 mL of MeOH was stirred for six days at rt Subsequently, the reaction mixture was admixed with 10 mL of water and the aqueous layer was then extracted three times with 30 ml of EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was subsequently removed in vacuo. The purification was carried out by silica gel column chromatography (5% EtOAc/PE). The product (192 mg, 721 mumol, 79%) was obtained as a white solid. Rf: 0.44 (5% EtOAc/PE). 1H NMR (500 MHz, CDCl3) delta = 8.54 (s, 2H), 3.95 (s, 3H). 13C NMR (126 MHz, CDCl3) delta = 160.84, 152.13, 116.00, 60.95. ESI-MS: m/z = 268.00 [M+H]+. HRMS (ESI): calculated for C6H6ON 79Br2: m/z = 265.88107 [M+H]+, found: m/z = 265.88105 [M+H]+. calculated for C6H6ON 79Br 81Br: m/z = 267.87902 [M+H]+, found: m/z = 267.87831 [M+H]+. calculated for C6H6ON 81Br2: m/z = 269.87697 [M+H]+, found: m/z = 269.87574 [M+H]+.
(±)-(5-bromo-4-methoxypyridin-3-yl)(naphthalen-2-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: A solution of the pyridine (1.0 eq.) in dry. THF (0.1 M) was treated dropwise with s-BuLi solution (1.4 M in cyclohexane, 1 eq.) at 78 C and stirred at this temperature for 1 h. The reaction solution was then treated with a solution of the aldehyde or the isocyanate (2.5 eq.) in dry THF (1.2 M), and the reaction mixture was slowly warmed to rt overnight. After the addition of water and sat. amMonium chloride solution, the heterogeneous mixture was extracted three times with EtOAc. The combined organic layers were washed with sat. sodium chloride solution, dried over anhydrous magnesium sulfate, and the crude product was concentrated in vacuo. The product was isolated by means of flash chromatography on silica gel.
Compound (VII-46) (100 mg, 0.369 mmol) was dissolved in THF (0.75 mL), iPrMgCl?LiCl (1.3 mol/L THF solution,0.30 mL, 0.39 mmol) was added, and the mixture was stirred at room temperature for 30 min. Thereafter, DMF (86 mL,1.1 mmol) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with chloroform. The organic layer waswashed with saturated aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 95:5 ? 50:50) to give compound (VII-47) (yield 59.8 mg, 74%) as a white solid
74%
Compound (VII-46) (100 mg, 0.369 mmol) was dissolved in THF (0.75 mL)iPrMgCl · LiCl (1.3 mol / L THF solution, 0.30 mL, 0.39 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, DMF (86 muL, 1.1 mmol) was added,And the mixture was stirred at room temperature for 30 minutes.Saturated ammonium chloride aqueous solution was added to the reaction solution,And extracted with chloroform.The organic layer was washed with saturated aqueous ammonium chloride solution and dried over anhydrous sodium sulfate.After distilling off the solvent under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 ? 50: 50)To give Compound (VII-47)(Yield 59.8 mg, Yield 74%)As a white solid.
Compound (M-41) (10.0 g, 39.5 mmol)Was suspended in acetonitrile (50 mL)DIPEA (15 mL, 87 mmol) was added at room temperature,Phosphoryl chloride (7.4 mL, 79 mmol)Was added under cooling with ice, and the mixture was stirred under heating reflux for 17 hours. After allowing to cool, the reaction solution was added dropwise to ice water,And neutralized with sodium carbonate (11.6 g, 138 mmol).Thereafter, the mixture was extracted with ethyl acetate,The organic layer was washed with saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Chloro compound (yield 10.6 g, yield 99%)As a brown solid.Chloro form (10.6 g, 39.1 mmol)Was dissolved in THF (70 mL)Sodium methoxide (28% methanol solution,14 mL, 59 mmol) was added,Followed by stirring at 60 C. for 30 minutes. After cooling down,Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturated brine,And dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Compound (VII-46) (yield 9.21 g, yield 88%)As a yellow solid.
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