Background and overview of the preparation method of 3,5-dibromo-1-methylpyridin-2(1H)-one
3,5-dibromo-1 -Methylpyridin-2(1H)-one is a pharmaceutical intermediate. It can be brominated from 2-hydroxypyridine as raw material to obtain 3,5-dibromo-2-hydroxypyrimidine, and then methylated to obtain 3,5- For dibromo-1-methylpyridin-2(1H)-one, the methylating reagent can be selected from methyl iodide or methyl p-toluenesulfonate.
Preparation method of 3,5-dibromo-1-methylpyridin-2(1H)-one
Preparation method report 1 of 3,5-dibromo-1-methylpyridin-2(1H)-one,
The compounds 2-hydroxypyridine (425.0 kg, 1 equivalent) and CH3CN (4713 kg) were added to the reactor with stirring, and the temperature was adjusted to 5 to 20°C. N-bromosuccinimide (1631.0 kg, 2.05 equiv) was added to the reactor with stirring over 30 hours while maintaining the temperature below 20°C. The temperature was adjusted to 5 to 15°C and stirred at this temperature for 4 hours. The reaction product mixture was sampled and the compound 2-hydroxypyridine was not detectable by HPLC. The mixture was cooled to -5 to 5°C over 3 hours and stirred at this temperature for 6 hours. Na2S2O3·5H2O (77 kg in 425 kg of water) was added to the mixture over 90 minutes while maintaining the temperature at -5 to 5°C. The mixture was filtered, and compound 3,5-dibromo-1H-pyridin-2-one was isolated as a wet filter cake by filtration. The wet filter cake was rinsed with CH3CN (850kg). Solid compound 3,5-dibromo-1H-pyridin-2-one and water (6800 kg) were added to the reactor, and the mixture was stirred at 45-55°C for 2 hours. The mixture was filtered to isolate compound 3,5-dibromo-1H-pyridin-2-one. Solid compound 3,5-dibromo-1H-pyridin-2-one and water (6800 kg) were added to the reactor, and the mixture was stirred at 45-55°C for 2 hours. The mixture was filtered, and 912 kg of compound 3,5-dibromo-1H-pyridin-2-one was obtained in a yield of 81%. Purity by HPLC was 99.2% by volume of dimethoxytetrahydrofuran and 99.9% by weight by HPLC.
Put compound 3,5-dibromo-1H-pyridin-2-one (752kg, 99.9% content determination, HPLC detection, 1 equivalent) and dimethylformamide into the reactor. K2CO3 (728 kg, 1.77 eq) and water (5654 kg) were added to the reactor at 20-30°C with stirring and the mixture was cooled to 5-10°C. PTSM (843kg, 1.52 equiv) was added dropwise while maintaining the temperature at 10-15°C. The mixture was stirred at 15-25°C for 20 hours. The reaction product mixture was sampled and 1% of compound 3,5-dibromo-1H-pyridin-2-one was detected by HPLC. The reaction mixture was cooled to 0-5°C and stirred at this temperature for 3 hours. The mixture was filtered, and compound 3,5-dibromo-1-methylpyridin-2(1H)-one was isolated as a wet filter cake, which was then washed with water (2923 L). Absolute ethanol (4496L) was added to the reactor, and stirred and mixed with the wet filter cake of compound 3,5-dibromo-1-methylpyridin-2(1H)-one. The mixture was stirred at 20-25°C for 3 hours, then cooled to 0-5°C and stirred for 3 hours. The mixture was filtered to isolate compound 3,5-dibromo-1-methylpyridin-2(1H)-one, which was dried under reduced pressure at a temperature below 40°C for 20 hours to obtain a yield of 679.3kg of compound 3. 5-Dibromo-1-methylpyridin-2(1H)-one. The conversion of compound 3,5-dibromo-1H-pyridin-2-one to compound 3,5-dibromo-1-methylpyridin-2(1H)-one is 99%, with a purity of 93 area%, containing 2.8 %by-product.
Preparation method report 2 of 3,5-dibromo-1-methylpyridin-2(1H)-one.
Add 3,5 – A solution of dibromo-1H-pyridine-2-cyanophenylboronic acid ketone (5g, 19.8mmol) in DMF (170ml), K2CO3 (6.01g, 43.5mmol) was added and the suspension was stirred for 15 minutes. Mel (1.36 mL, 21.8 mmol) was added to the mixture and the reaction mixture was stirred at room temperature for 18 hours. Water (200 ml) was added to the mixture and the aqueous layer was extracted with EtOAc (3×200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was triturated with Et2O to give 2 g of the title compound. The filtrate was evaporated under reduced pressure, and the second batch of product (2.0 g) was obtained after trituration with Et2O. The filtrate was concentrated and the material was purified by flash chromatography on silica gel using a mixture of EtOAc and hexane as eluent to afford the title compound (4.5 g total, 85%). 1H NMR (500MHz, CDCl3) δ 7.78 (d, J=2.5Hz, 1H), 7.42 (d, J=2.5Hz, 1H), 3.59 (s, 3H). MS(ESI)[M+H]+266.01,267.99,269.99.
References
[1] From PCT Int. Appl., 2018109050, 21 Jun 2018
[2] From PCT Int. Appl., 2017024412, 16 Feb 2017
