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