Preparation of 1H-pyrrolo[2,3-B]pyridin-5-ol_Industrial additives

Preparation background and overview of 1H-pyrrolo[2,3-B]pyridin-5-ol

1H-pyrrolo[2,3-B]pyridin-5-ol, also known as 5-hydroxy-7-azaindole, is a pharmaceutical intermediate. 1H-pyrrolo[2,3-B]pyridin-5-ol can be used to synthesize ABT-199 (Venetoclax). ABT-199 (Venetoclax) is an experimental B-cell lymphoma factor-2 (BCL-2) inhibitor jointly developed by AbbVie and Roche. BCL-2 is a protein that prevents apoptosis of some cells, including lymphocytes. ABT-199 is designed to selectively inhibit the function of BCL-nitropyridine 2 factor, restore the cell communication system, and allow cancer cells to self-destruct to achieve the effect of treating tumors.

Preparation of 1H-pyrrolo[2,3-B]pyridin-5-ol

Preparation step 1 of 1H-pyrrolo[2,3-B]pyridin-5-ol: 5-bromo-1-(triisopropylsilyl)-pyrrolo[2,3-b ] Preparation of pyridine (Ⅱ/TIPS)

At room temperature, add ml of tetrahydrofuran to a 1L three-necked flask and start stirring. Add 5-bromo-7-azaindole (30g, 0.15mol) and potassium tert-butoxide (25.6g, 0.23mol) into the reaction flask. After stirring to dissolve, cool down in an ice-salt bath until the internal temperature is 0°C. Begin to add dropwise triisopropylsilyl chloride (30.8g, 0.16mol) diluted with 80ml tetrahydrofuran. After the addition is completed, keep the reaction at 0-5°C for 10-20 minutes. TLC control, the reaction is completed. Add 300ml of water to the reaction bottle, stir for 15 minutes and then separate the liquids. Extract the aqueous phase with methyl tert-butyl ether (200ml*2), combine the organic phases, wash the organic phase once with 500ml of saturated sodium chloride aqueous solution, separate the liquids, and organically After drying the phase over anhydrous sodium sulfate, the solvent was concentrated to obtain an oily substance. 50 ml of methanol was added and a solid precipitated. The solid was filtered and dried in a vacuum oven to obtain the compound of formula II. Yield: 49.5g, yield: 92.0%.

Preparation step 2 of 1H-pyrrolo[2,3-B]pyridin-5-ol: Preparation of 1H-pyrrolo[2,3-B]pyridin-5-ol (III)

At room temperature, add the compound of formula II (4.08g, 11.5mmol), copper acetylacetonate (0.6g, 2.3mmol), and BH dihydroxypyridine hydrochloride MPO (0.76g, 2.3 mmol), lithium hydroxide monohydrate (1.7g, 40mmol), 18ml DMSO, 4.5ml water, start stirring, replace with nitrogen, raise the temperature to the internal temperature of 130°C, and maintain the temperature for 1 hour. After the reaction of the raw materials in the central control is completed, stop heating, cool down to room temperature (20-30°C), add 100ml of water, adjust the pH to 6 with 2N dilute hydrochloric acid, if solid precipitates, filter it with suction, extract the water phase with 50ml*3 of ethyl acetate, and combine The organic phase was washed once with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain 1H-pyrrolo[2,3-B]pyridin-5-ol. Yield: 1.1g, yield: 72%.