Preparation and application background and overview of 4-bromopyridine-2-carbonitrile
4-Bromopyridine-2-carbonitrile is also called 4-bromocyanopyridine, 4-aminopyridine-bromo-2-cyanopyridine. 4-bromopyridine-2-carbonitrile can be first oxidized to prepare 4-bromopyridine 1-oxide from 4-bromopyridine hydrochloride, and then cyano group is substituted to obtain 4-bromopyridine-2-carbonitrile. 4-Bromopyridine-2-carbonitrile can be used as a starting material for the synthesis of the anti-tumor drug sorafenib.
Preparation and application of 4-bromopyridine-2-carbonitrile
A.4-Bromopyridine 1-oxide at room temperature. To a suspension of 4-bromopyridine hydrochloride (5.0 g, 25.9 mmol) in dichloromethane (50 mL) was added triethylamine (2.62 g, 25.9 mmol). After stirring for 0.5h, 3-chloroperoxybenzoic acid (4.46g, 25.9mmol) was added in batches, and the reaction mixture was stirred at room temperature for 5h. The solution was washed with saturated aqueous sodium thiosulfate solution (30 mL), saturated aqueous sodium carbonate solution (30 mL) and brine (30 mL), and dried over sodium sulfate. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (eluting with 50-100% ethyl acetate in methanol) to give 4-bromopyridine 1-oxide as a solid (2.1 g, 44.8% yield) .
B.4-Bromopyridine-2-carbonitrile. Dissolve 4-bromopyridine 1-oxide (2.0 g, 11.56 mmol), trimethylsilyl cyanide (3.43 g, 34.68 mmol) and triethylamine (2.34 g, 23.12 mmol) in acetonitrile (10 mL). The mixture was stirred at 110 °C for 3 h under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified on a silica gel column (eluting with 20% ethyl acetate in petroleum ether) to give 4-bromopyridine-2-carbonitrile (1.52 g, 72.4% yield). 1HNMR (MHz, chloroform-d) δ (ppm) 8.56 (d, J=4.2Hz, 1H), 7.88 (s, 1H), 7.73 (d, J=4.2Hz, 1H).
Preparation and application of 4-bromopyridine-2-carbonitrile
4-Bromopyridine-2-carbonitrile can be used to prepare sorafenib as follows:
(1) Dissolve 183g (1mol) 4-bromo-2-cyanopyridine in 1L tetrahydrofuran, add 118g (1.08mol) p-aminophenol and 50% sodium hydroxide solution (70g sodium hydroxide + 70ml water); heat and reflux for 5.5 hours; heat and evaporate tetrahydrofuran; add 1L of water to the concentrated solution, and then add concentrated hydrochloric acid to adjust the pH to 5.5. The brown solid gradually precipitates, and is suction-filtered. After the filter cake is air-dried, 204.2g of brown solid is obtained. , which is intermediate 1 (carry out the next reaction with a purity of 100%). Mass spectrometry ESI-MS gave the molecular ion peak of intermediate 1 as 231[M+H]+.
(2) Add 204.2g of intermediate 1 to 500ml of chloroform, then add 260g of thionyl chloride (2.18mol), heat to reflux for 1.5 hours, and then directly evaporate to dryness (distillation under reduced pressure at 60°C, if necessary Increase the temperature and continue heating until no residual thionyl chloride is detected), and 220.2g of intermediate 2 is obtained;
(3) Then directly dissolve 220.2g of intermediate 2 in 650ml of DMF, then add 175g of potassium carbonate, and then add dropwise 30% methylamine solution (63g of methylamine + 147ml of water, pre-cooled to -5~ 5℃), during the dropping process, control the temperature of the reaction solution to 5~10℃; after the dropwise addition is completed, continue to react at 5~10℃ for 1.5 hours, then add water dropwise to gradually precipitate the solid matter, and stop dropping after the solid matter is completely precipitated. Add; then suction filtration, the filter cake is then added with isopropanol for recrystallization, and finally after suction filtration and drying, 207.5g of light brown solid substance compound 7 is obtained. HPLC is 99.93%, and the total yield is 85.4% (using 4-bromo-2 -cyanopyridine). Through thin layer chromatography, the band was consistent with the standard material band of 4-(4-aminophenoxy)-2-(methylcarbamoyl)pyridine. Mass spectrometry ESI-MS gave the molecular ion peak of intermediate 1 as 244 dimethyl sulfoxide [M+H]+.
(4) Dissolve 1600g of compound 7 in 6mL of ethyl acetate and stir evenly at room temperature to obtain a suspension. Dissolve 1604.8g of compound 9 (4-chloro-3-(trifluoromethyl)phenyl isocyanate) in 1600 mL of ethyl acetate (endothermic); after stabilization, add dropwise to the ethyl acetate solution of the above compound 7 , the temperature is controlled at 20~30℃, and the dripping is completed in 30min-60min. During the dropwise addition, the suspension gradually became clear, and then a large amount of precipitate precipitated. After completion of dropping, stir at room temperature for 4 hours. Then, after suction filtration and rinsing the filter cake with ethyl acetate, light brown powder was obtained. Add 21L of absolute ethanol to the light brown powder to recrystallize, heat to reflux to dissolve, then lower to room temperature and stir for 1-2 hours to crystallize. Filter, rinse with absolute ethanol, and dry to obtain 2883g of sorafenib, a light reddish brown powder. Yield 94.2%, HPLC: 99.86%.
References
[1][China invention, China invention authorization] CN200980144169.1 aminotriazolopyridine and its use as a kinase inhibitor
[2] [Chinese invention, Chinese invention authorization] CN201610259723.2 A preparation method of sorafenib tosylate
