Preparation background and overview of 6-bromo-3-cyanopyrazolo[1,5-A]pyridin-4-yl triflate
6-Bromo-3-cyanopyrazolo[1,5-A]pyridin-4-yl triflate is a pharmaceutical intermediate. There are reports in the literature that it can be used to prepare RET inhibitors. 6-Bromo-3-cyanopyrazolo[1,5-A]pyridin-4-yl triflate can be synthesized from 6-bromo-4-methoxypyrazolo[1,5-a]pyridine -3-Carbonitrile is prepared through a two-step reaction as raw material.
Preparation of 6-bromo-3-cyanopyrazolo[1,5-A]pyridin-4-yl triflate
Preparation step 1 of 6-bromo-3-cyanopyrazolo[1,5-A]pyridin-4-yl triflate: 6-bromo-4-hydroxypyrazolo [1,5-a]pyridine-3-carbonitrile
At room temperature, add 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (50g, 198.36mmol) and water (16.5mL) into a 1L single-mouth bottle. , 916mmol), sodium hydroxide (16.03g, 396.8mmol), DMAC (500mL), stir at room temperature for 5 minutes, then transfer to 0°C and slowly add dodecanethiol (97mL, 397mmol). After the addition is completed, the reaction is transferred to 45°C overnight. . Pour the reaction solution into 3L ice water, slowly add saturated citric acid aqueous solution to adjust pH=5, stir for half an hour, let it stand, filter, wash the filter cake multiple times with water and petroleum ether, and dry at 60°C to obtain 44.1g of yellow solid. Target product (yield 93.4%). Rf=0.35 (PE/EA=3:1). LC-MS: m/z=239.05[M+H]+.
Preparation step 2 of 6-bromo-3-cyanopyrazolo[1,5-A]pyridin-4-yl triflate: 6-bromo-3-cyanopyrazole Para[1,5-A]pyridin-4-yl trifluoromethanesulfonate
Add lithium metaborate 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (44.1g, 185mmol), pyridine (45mL, 559mmol), DCM ( 800 mL), when the temperature dropped to below -10°C, trifluoromethanesulfonic anhydride (50 mL, 297.2 mmol) was slowly added, stirred for 1 hour, and then naturally raised to room temperature to react overnight. Spin DCM to dryness under reduced pressure, dilute with water (25 methoxyphenylboronic acid 0 ml), extract with EA (500 ml × 3), collect the organic phase, wash with saturated brine (250 ml), dry over anhydrous sodium sulfate, filter, and obtain the filtrate Spin to dryness and purify by silica gel column chromatography (eluent PE/EA=50:1-25:1) to obtain 61.5g of a yellowish solid, which is the target product, with a yield of 89.7%. Rf=0.45 (PE/EA=5:1).
References
[1] [Invented in China] CN201911244557.9 RET inhibitor, its pharmaceutical composition and its use
