preparation and application of 6-bromo-3h-imidazo[4,5-b]pyridine_industrial additives

preparation and application background and overview of 6-bromo-3h-imidazo[4,5-b]pyridine

6-bromo-3h-imidazo[4,5-b]pyridine is a pharmaceutical intermediate that can be prepared by ring-closing 5-bromopyridine-2,3-diamine as raw material. there are reports in the literature that it can be used to prepare inhibitors targeting the pi3k-akt-mtor signaling pathway, such as 2-[4-[8-(3h)imidazole[4,5-b]pyridin-6-yl)-3-methyl ‑1h‑pyrazole[4,3‑c]quinolin‑1‑yl]phenyl]‑2‑methyl‑propionitrile.

preparation and application of 6-bromo-3h-imidazo[4,5-b]pyridine

dissolve 5-bromopyridine-2,3-diamine (200 mg, 1.06 mmol) in 5 ml of trimethyl orthoformate, add 0.5 ml of concentrated hydrochloric acid, heat to reflux and stir for 40 minutes. cool the reaction solution to room temperature of di-n-butyl carbonate, add 40 ml of water, adjust the ph value to 8 with 10 ml of 1m sodium hydroxide solution, extract with ethyl acetate (50 ml × 3), combine the organic phases, and wash with saturated sodium chloride solution (100 ml after purification, proceed directly to the next reaction. sm/z(esi)：199.9[m+1]

preparation and application of 6-bromo-3h-imidazo[4,5-b]pyridine

6-bromo-3h-imidazo[4,5-b]pyridine is used in the preparation of 2-aluminum magnesium carbonate [4-[8-(3h)imidazole[4,5-b]pyridin-6-yl) the method of ‑3‑methyl‑1h‑pyrazole [4,3‑c]quinolin‑1‑yl]phenyl]‑2‑methyl‑propionitrile is as follows:

the first step in the preparation and application of 6-bromo-3h-imidazo[4,5-b]pyridine, 6-(4,4,5,5-tetramethyl-1,3,2 ‑dioxaborolan‑2‑yl)‑3h‑imidazole[4,5‑b]pyridine

crude 6-bromo-3h-imidazole [4,5-b]pyridine 19b (185mg, 0.93mmol), diboron divalerate (331mg, 1.40mmol), 1,1′-bis(diphenyl phosphine) ferrocene] palladium dichloride (34 mg, 0.05 mmol) and potassium acetate (229 mg, 2.34 mmol) were dissolved in 10 ml n, n-dimethylformamide, heated to 130°c in the microwave, and stirred for 1 hour. add 30 ml of water to the reaction solution, extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with saturated sodium chloride solution (50 ml × 2), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product crude product 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3h-imidazole[4,5-b]pyridine 19c (160 mg, brown-black solid), the product was directly used in the next reaction without purification. msm/z(esi):246.2[m+1]

preparation and application of 6-bromo-3h-imidazo[4,5-b]pyridine step 2, 2‑[4‑[8‑(3h‑imidazole[4,5‑b]pyridine -6-yl)-3-methyl-1h-pyrazole [4,3-c]quinolin-1-yl]phenyl]-2-methyl-propionitrile

convert 2-[4-(8-bromo-3-methyl-1h-pyrazole[4,3-c]quinolin-1-yl)phenyl]-2-methyl-propionitrile 2f( 80 mg, 0.20 mmol), crude 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3h-imidazole[4,5-b]pyridine 19c (160 mg, 0.65 mmol), tetraphenylphosphine palladium (11 mg, cat.) and sodium carbonate (52 mg, 0.49 mmol) were dissolved in 5 ml dioxane and water (v/v = 4:1) mixed solvent , heated to reflux and stirred for 1.5 hours. add 40 ml of water to the reaction solution, extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with saturated sodium chloride solution (50 ml × 2), dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure, and use a silica gel column the residue obtained was purified by chromatography with eluent system a to obtain the title product 2-[4-[8-(3h-imidazole[4,5-b]pyridin-6-yl)-3-methyl-1h-pyridine azole [4,3-c]quinolin-1-yl]phenyl]-2-methyl-propionitrile 19 (16 mg, light brown solid), yield: 18.4%.

references

[1][invented in china] cn201110314450.4 heterocyclic quinoline derivatives and pharmaceutically acceptable salts thereof, their preparation methods and their medical applications