1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide Hydrochloride

Uses

1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide Hydrochloride is a key intermediate in the synthesis of Riociguat, a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension.

Synthesis

In a 10 L four-necked flask, 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile 919.7 g (3.646 mol, 10 eq), MeOH 7 L was added, and MeONa 295 g (5.469 mol, 1.5 eq) was added with stirring, and stirred at room temperature for 2 h. Has disappeared, completely converted to the intermediate (7), added CH 3 C0 2 H 329 g (5.469 mol, 1.5 eq), NH 4 C1 293 g (5.469 mol, 1.5 eq), heated to reflux overnight, TLC monitoring reaction completely The temperature was lowered, a large amount of solid was precipitated, filtered, and washed with DCM to give 981 g of white solid as 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (8), which was used directly in the next step. The compound 8 981.0 g (3.646 mol, lO eq) was added to 5 L of methyl tert-butyl ether, stirred, suspended as a suspension, passed through HC1 gas for about 2.5 h, filtered, washed with DCM, and dried by filtration. 1103.7 g of white solid 1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide Hydrochloride. Total yield in two steps: 99.0%. Purity: 99%.