* 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.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3644 - 3649
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9928 - 9941
2
[ 38367-36-1 ]
[ 124-41-4 ]
[ 1450662-05-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
for 4 h; Reflux
2,4-dichloro-6-methylnicotinonitrile (45 g, 240 mmol) was dissolved in CH3OH (300 mL). NaOMe (30 percent in MeOH, 100 mL, 1680 mmol) was added. The mixture was refluxed for 4 h. After cooled to r.t, the reaction mixture was neutralized by HOAc. The solvent was removed under vacuum and the residue was washed with H20 (300 mL) and MTBE (100 mL). The resulting solid was coevaporated with dry THF (300 mL) to give the title compound as a dark- yellow solid. (40 g, yield 95 percent).
95%
for 4 h; Reflux
[00158] Step 4: 2,4-dimethoxy-6-methylnicotinonitrile: 2,4-dichloro-6- methylnicotinonitrile (45 g, 240 mmol) was dissolved in MeOH (300 ml). NaOMe (30 percent in MeOH, 100 ml, 1680 mmol) was added and the mixture was heated to reflux for 4 h. The reaction was then allowed to cool to rt and the reaction mixture was neutralized with acetic acid. The solvent was removed under vacuum and the residue was treated with H20 (300 ml) and MTBE (100 ml). The resulting solids were co-evaporated with THF (300 ml) to give 2,4- dimethoxy-6-methylnicotinonitrile as a dark- yellow solid. (40 g, yield 95 percent).
95%
for 4 h; Reflux
2,4-dimethoxy-6-methylnicotinonitrile. 2,4-dichloro-6-methylnicotinonitrile (45 g, 240 mmol) was dissolved in MeOH (300 mL). NaOMe (30 percent in MeOH, 100 mL, 1680 mmol) was added and the mixture was heated at reflux for 4 h. The reaction was then allowed to cool to ambient temperature and the basic solution neutralized by addition of acetic acid. The solvent was removed in vacuo and the residue was treated with H2O (300 mL) and MTBE (100 mL). The resulting solids were collected by filtration and co-evaporated with THF (300 mL) to give 2,4-dimethoxy-6-methylnicotinonitrile (40 g, 95percent) as a dark-yellow solid.
94%
at 80℃; for 4 h;
To a solution of 2 4-dichloro-6-methylnicotinonitrile (intermediate 129A, 20 g, 427.73 mmol) in methanol (200 ml) was added sodium methanolate (11.55 g, 875.44 mmol) and stirred at 80 °C for 4 h. After cooling to 18 °C, the reaction was neutralized by acetic acid. The solvent was removed invacuo and the residue was washed with water (800 ml) and methyl tert-butyl ether (800 ml). The resulting solid was concentrated in tetrahydrofuran (400 ml) to give 2,4-dimethoxy-6- methylnicotinonitrile (intermediate 130A, combined yield from 4 batches: 72 g, 94percent yield) as dark-yellow solid.‘H NMR (400 MHz, methanol-d4) ö [ppm] = 6.73 (s, 1 H), 3.99-4.00 (2 overlapping s, 6 H), 2.48(s,3H).
With sodium methylate In methanol at 0 - 60℃; for 14 h;
To a stirred solution of 2-chloro-4-((4-methoxybenzyl)oxy)-6-methylnicotinonitrile (0.4 g, 1.38 mmol)) in methanol (5 mL) at O °C, sodium methoxide (0.226 g, 4.16 mmol) was added and stirred at room temperature for 12h and the further heated at 60 °c for 2h. The progress of the reaction was monitored by TLC S LCMS. After consumption of the starting material, the reaction mixture was concentrated to dryness. The residue obtained was diluted with water and extracted with 10percent MeOH/DcM. The combined organie layers were washed brine, dried oyer anhydrous sodium sulphate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford an unseparable mixture of the title compound and 2,4-dimethoxy-6-methylnicotinonitrile (0.245 g)
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