Preparation of 4,4′-dibromo-2,2′-bipyridine_Industrial additives

Preparation background and overview of 4,4′-dibromo-2,2′-bipyridine

4,4′-Dibromo-2,2′-bipyridine is an important pharmaceutical intermediate. The actual photos are as follows:

4,4′-dibromo-2,2′-bipyridine

The current synthesis routes reported are as follows:

1. Garcia‑Lago, Ramon et al. reported a one-step reaction using 4,4’‑dinitro‑N,N’‑dioxide‑2,2’‑bipyridine as the substrate to directly prepare 4,4’‑dioxy Bromo-2,2′-bipyridyl:

2. HolgerStaats et al. reported the preparation of 4,4′-dibromo-2,2′-bipyridine using 4,4′-dibromo-N,N’-dioxide-2,2′-bipyridine as a substrate. .

Preparation of 4,4′-dibromo-2,2′-bipyridine

Preparation method 1 of 4,4′-dibromo-2,2′-bipyridine:

Add 50ml of water into a 100ml four-necked flask, then add 7.5g (48mmol) 2,2′-bipyridine, 1.6g (0.0048mmol) sodium tungstate and 2.2g (0.0048mmol) trioctyl methyl sulfate Ammonium hydride, heat up to 60°C, slowly add 18.75ml (182.4mmol) 30% hydrogen peroxide dropwise, react for 5 hours, monitor by HPLC without raw materials, filter, wash three times with water, and dry to obtain 7.2g of 2,2′-bipyridyl nitrogen oxide , yield 80%, purity 99.4% (HPLC). 1H-NMR of 2,2′-bipyridyl nitrogen oxide (DMSO-d6): 8.31-8.33 (d,J=6.3Hz,2H) 7.39-7.62(m,6H).

Add 35ml (657mmol) concentrated sulfuric acid and 40ml 30% oleum into a 250ml four-necked flask. Add 25g (133mmol) 2,2′-bipyridine nitrogen oxide in batches. Raise the temperature to 110°C and add 80ml (1942mmol) dropwise. ) fuming nitric acid, react for 5 hours after the dropwise addition, and monitor by HPLC. Pour the reaction solution into ice water, filter, recrystallize and dry to obtain 18.5g of yellow solid, with a yield of 50.2% and a purity of 99.2%. 1H‑NMR of 4,4’‑dinitro‑2,2’‑bipyridyl nitrogen oxide (DMSO‑d6): 8.69 (d,2H,J=3.3Hz) 8.60 (d,2H,J=7.2Hz )8.36 (dd trichloropyridine, 2H, J=7.2Hz, J=3.3Hz), as shown in Figure 2.

In a 250ml four-necked flask, add 80ml acetic acid, then add 10g (35.9mmol) 4,4′-dinitro-2,2′-bipyridyl nitrogen oxide, heat to reflux, and add dropwise 19.89g (107.7 mmol)/60ml acetyl bromide acetic acid solution, HPLC monitors that there is no raw material, add 17g (89.8mmol) tin chloride to it, after all reduction, pour the reaction solution into ice water, adjust the pH to 10, filter, and use ethyl acetate for the mother liquor Extract, spin dry, recrystallize and dry to obtain 6.7g of 4,4′-dibromo-2,2′-bipyridine, with a yield of 59.4% and a purity of 99.2%. 1H‑NMR (DMSO‑d6) of 4,4′-dibromo-2,2′-bipyridine: 8.59 (d,2H,J=1.8Hz) 8.50 (d,2H,J=5.1Hz) 7.79 (dd ,2H,J=5.1Hz,J=1.8Hz).

Preparation method two of 4,4′-dibromo-2,2′-bipyridine:

1).Synthesis of N,N’-dioxide-2,2′-bipyridine

250mL reaction flask, mechanical stirring, reflux condenser, put 30.0g2,2′-bipyridine into the reaction flask, add 200.0mL glacial acetic acid, stir and dissolve, heat the oil bath to the internal temperature of 75℃, add dropwise 65.33g30. 0% hydrogen peroxide, the reaction is exothermic, and the internal temperature rises. An external bath is required to cool down to control the dripping temperature at 70~80°C. After the hydrogen peroxide dripping was completed, the reaction was incubated at 75°C for 16 hours. HPLC detected that 2,2′-bipyridyl disappeared and the intermediate content was less than 0.7%. Cool the reaction solution to 8°C, add dimethyl sulfide dropwise to quench the excess hydrogen peroxide. The reaction is obviously exothermic, and control the dripping temperature to not exceed 20°C. Starch potassium iodide test paper indicates the quenching end point. After the dropwise addition, the reaction solution was concentrated and the solvent was evaporated. The residue was slurried with 35.0g 88.3%.

2).Synthesis of 4,4′-dinitro-N,N’-dioxide-2,2′-bipyridine

1.0L reaction bottle, install the tail gas absorption device, put 480.0mL concentrated sulfuric acid into the reaction bottle, cool the internal temperature to 10℃ in the external bath, add 100.0gN,N’-dioxide-2,2′-coupled in batches Pyridine releases heat when dissolving. Control the feeding speed so that the temperature of added warm sodium bicarbonate is between 20 and 25°C. After adding, stir to completely dissolve the solid. Cool the external bath and lower the internal temperature to -2°C. Add 167.0 mL of 95% fuming nitric acid dropwise. The reaction will be exothermic. Control the dropping temperature between 5 and 8°C. After the addition is completed, keep stirring and continue stirring for 20 minutes. Then the oil bath will heat up. , the internal temperature is between 95 and 100°C for insulation reaction. After 24 hours of reaction, HPLC detected that the N,N’-dioxide-2,2′-bipyridine content was less than 1.0%. Cool down until the internal temperature drops to -5°C. Add 1.13Kg of ice-water mixture into a 5.0L beaker, and slowly pour the reaction solution into the ice-water mixture. When pouring, it will exotherm violently, and a large amount of red-brown gas will be released. Control the internal temperature not to exceed 5°C. After the reaction solution is ice-lyzed, stir at -5~0°C for 4 hours, then filter. The filter cake is washed with 90.0g saturated Na2CO3 solution, 90.0g×3 ice water and 90.0g absolute ethanol, and dried under vacuum at 30°C to obtain yellow color. 67.11g of solid powder, HPLC purity: 89.2% (HPLC), yield: 46.4%. The crude product was not purified and used directly in the next reaction.

3).Synthesis of 4,4′-dibromo-N,N’-dioxide-2,2′-bipyridine

500.0mL reaction flask, ice-water condenser, install tail gas absorption device, pump 150.0mL glacial acetic acid into the reaction flask, add 10.0g 4,4′-dinitro-N,N’-dioxide under stirring at room temperature ‑2,2’‑bipyridine and 54.3 mL acetyl bromide were heated in the oil bath. The solids were stirred for 20 minutes and then completely dissolved. When the solution was close to reflux, the solids in the reaction solution were re-precipitated. After maintaining the reflux reaction for 2.0h, TLC control 4,4′-dinitro-N,N’-dioxide-2,2′-bipyridine disappears. The temperature was lowered to an internal temperature of 50°C, and the reaction solution was concentrated to remove acetyl bromide/glacial acetic acid. After the concentration is completed, add it to a beaker containing 20.0g of crushed ice water, and cool the internal temperature to 10°C in an external bath. Use 32% NaOH to adjust the pH value to 10-11, adjust the temperature to not exceed 20°C, filter, and use the filter cake in sequence. Beat and wash with 55.0g ice water and 30.0g absolute ethanol. The filter cake was vacuum dried at 30-50°C to obtain 11.25g of earthy yellow solid, yield: 88.6%. The crude product was not purified and used directly in the next reaction.

4).Synthesis of 4,4′-dibromo-2,2′-bipyridine

250.0mL reaction flask, reflux condenser, mechanical stirring, put 100.0mL concentrated hydrochloric acid into the flask, and add 10.0g 4,4′-dinitro-N,N’-dioxide-2,2′- at room temperature. For bipyridine, add 13.04g stannous chloride in batches. The feeding temperature should not exceed 30°C. After the addition is completed, heat the internal temperature in the oil bath to 50°C and keep the reaction for 4 hours. TLC will follow the reaction to the raw material 4,4′-dinitro. -N,N’-dioxide-2,2′-bipyridine disappears and the reaction ends. Cool, adjust the pH to 8-10 with NaOH, extract with ethyl acetate, layer, wash with water, dry, and concentrate by rotary evaporation. Control the water bath temperature at 30-50°C to obtain 6.82g of off-white crystal powder, purity: 98.7% (HPLC ), yield: 75.1%.