* 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.
5-Bromo-2-amino-6-methylpyridine (5g) was added to pyridine hydrogen fluoride (35 mL).The reaction was cooled to -20 ° C and then KNO 2 (2.7 g) was added.The reaction was continued for 4 hours after rising to room temperature.The reaction mixture was poured into 200 mL of ice water and extracted with dichloromethane (50 mL EtOAc).The extracts were combined, washed with 1N hydrochloric acid, and concentrated to give 5-bromo-2-fluoro-6-methylpyridine (4 g, yield 78percent).
Reference：
[1] Patent: CN108341769, 2018, A, . Location in patent: Paragraph 0021-0023; 0025-0027
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 22, p. 3979 - 3982
3
[ 773837-37-9 ]
[ 375368-83-5 ]
[ 1173897-86-3 ]
Yield
Reaction Conditions
Operation in experiment
15%
at 100℃; for 2 h;
NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100° C., poured into H2O (100 mL) and extracted with ethyl acetate (2.x.100 mL). The organic layers were dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 10 g, eluting with 10percent ethyl acetate in petroleum ether) to give the title compound (0.6 g, 15percent) as white solid; MS (D): m/e=197.0 [M+H]+.
15%
at 100℃; for 2 h;
NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100°C, poured into H20 (100 mL) and extracted with ethyl acetate (2 x lOOmL). The organic layers were dried over Na2S04, concentrated and purified by flash column chromatography (silica gel, 10 g, eluting with 10percent ethyl acetate in petroleum ether) to give the title compound (0.6 g, 15percent) as white solid; MS (EI): m/e = 197.0 [M+H]+.
15%
at 100℃; for 2 h;
a) 5-Bromo-6-methyl-pyridine-2-carbonitrile NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100 °C, poured into H20 (100 mL) and extracted with ethyl acetate (2 x lOOmL). The organic layers were dried over Na2S04, concentrated and purified by flash column chromatography (silica gel, 10 g, eluting with 10percent ethyl acetate in petroleum ether) to give the title compound (0.6 g, 15percent) as white solid; MS (EI): m/e = 197.0 [M+H]+.
5-bromo-2-fluoro-6-methylpyridine (5kg) was dissolved in concentrated sulfuric acid (50kg).After the reaction was warmed to 60 ° C, CrO3 (16 kg) was added in portions. After the addition was completed, the reaction was continued for 18 hours. TLC monitors the reaction. After the reaction was completed, the reaction was neutralized by adding NaOH (20percent) to neutrality. Further ethyl acetate extraction (50 L X 3) was added.After combining the extracts, they were dried and concentrated. The crude product obtained was beaten with n-hexane. Filter and dry to obtain pure 3-bromo-6-fluoropicolinic acid (3.8 kg, yield 58percent).
45%
With potassium permanganate In water for 5 h; Reflux
Water (1600 mL) was added to 3-bromo-6-fluoro-2-methylpyridine (60 g, 0.32 mol), mechanically stirred and heated to reflux , potassium permanganate (220 g, 1.4 mol) was added to the flask in 11 portions at intervals of 15 min, after the addition, the reflux was continued for 5 h. The reaction solution was cooled to room temperature, suction filtered, and the filtrate was adjusted to pH 5 with dilute hydrochloric acid, then, the filtrate was spun dry, and then anhydrous ethanol (500 ml) was added thereto, and the mixture was stirred under reflux for 30 min, filtered while hot, and the filtrate was dried to give 3-bromo-6-fluoro-2-picolinic acid (31 g, 45percent).
Reference：
[1] Patent: CN108341769, 2018, A, . Location in patent: Paragraph 0021; 0022; 0024; 0025; 0026; 0028
[2] Patent: CN108503581, 2018, A, . Location in patent: Paragraph 0031-0032; 0039; 0041; 0043
1-(2,6-dichloro-phenyl)-6-[4-(4-fluoro-phenylsulfanyl)-phenylsulfanyl]-3-(4-methoxy-benzyl)-3,4-dihydro-1<i>H</i>-pyrido[3,2-<i>d</i>]pyrimidin-2-one[ No CAS ]
6-fluoro-2-methyl-3-methylsulfanylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 3-bromo-6-fluoro-2-methylpyndine (3 25 g, 17 1 mmol) and TMEDA (3 35 mL, 22 2 mmol) in toluene (200 mL) at -75C under argon was added 1 6 M n- butyllithium in hexane (12.8 mL, 20.5 mmol) over 10 min, and the mixture stirred for 50 min before dimethyldisulfide (1 84 mL, 20.5 mmol) was added. The reaction was stirred for Ih at 750C then warmed to 20C and quenched with saturated NH4CI solution (40 mL). The organic phase was collected, washed with brine, dried (MgSO4) and the solvent was removed under vacuum to give a residue which was purified by column chromatography (IH-EtOAc, 39:1) to furnish 6-fruoro-2-methyl-3-methylsulfanyrpyridme. To a solution of this compound (330 mg, 2.10 mmol) in DCM (7 mL) at O0C was added 77% 3-chloroperbenzoic acid (970 mg, 4.30 mmol) over 15 min A further aliquot of DCM (5 mL) was added and the mixture stirred for 1 hThe reaction mixture was diluted with DCM (25 mL), washed with Na2Ctheta3 (15 mL) and the organic phase was collected through a hydrophobic frit. The solvent was removed under vacuum to furnish the title compound. RT = 2.13 min, mlz (ES+) = 189.89 [M + H]+ (Method A).
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