(E)-6-Iodo-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Uses

(E)-6-Iodo-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole is an intermediate used to prepare Axitinib (A794650) . Axitinib is used in cancer therapy. Axitinib (AG-013736) is a selective small molecule inhibitor of VEGF receptor tyrosine kinases 1, 2 and 3 and the platelet-derived growth factor (PDGF) receptor that targets the catalytic domain of the tyrosine kinase and induces ATP-competitive inhibition with limited activity against other protein kinases . It is an indazole derivative, its molecular formula is C22H18N4OS and its molecular weight is 386.5 Da^[1].

Synthesis

6-amino-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole (100 g) dissolved in acetic acid (6.5 L) is added over 1.5 hours to a solution of sodium nitrite (35 g) dissolved in water (3.0 L) at 0℃ (-3 ± 3°C). The mixture is stirred for 1 hour at 0℃, and a solution of hydrochloric acid (560 mL diluted in 1 L of water) at 0℃ is added over 15 minutes. The mixture is stirred for 1 hour at 0℃. The formation of the diazonium salt is monitored by HPLC. Dicholoromethane (400 ml) at O0C is added over 10 minutes to the diazonium salt solution at 0℃, and a solution of potassium iodide (207. 25 g) dissolved in water (300 ml) at O0C is added over 1.5 hours. The reaction mixture is agitated for 3 hours at 0℃ (until complete by HPLC). The mixture is then poured into a solution of sodium bisulfite in process water [Sodium bisulfite (200g) dissolve in process water (500mL) at 27± 3°C] and Dicholoromethane (400 ml) below 270C, agitated, and the layers separated. The aqueous layer is extracted with Dichloromethane (100 ml) at 27℃ and combined. A solution of aqueous ammonia (100 ml) at 27± 3°C is added over 40 minutes to the combined organic layers until the aqueous phase is basic (pH = 9 to 12). Distill out dichloromethane and add methanol and heat to 50 ± 3°C and stir it at this temperature for 15 min and then stir for 30 min at RT, followed by washing with methanol. Add dichloromethane and heat to 45± 3°C and add activated carbon at this temperature. Followed by addition of methanol and dichloromethane (if required) and stir the reaction mixture at 27± 3°C for 30 min and cool it to 0±3°C and stir 1 hr and wash with methanol to provide (E)-6-Iodo-3-[2- (pyridine-2yl)ethenyl]-1 -(tetrahydro-2H- pyran-2-yl)-1H-indazole.

References

[1] LESLIEISLA. Avelumab and axitinib in the treatment of renal cell carcinoma: safety and efficacy.[J]. Expert Review of Anticancer Therapy, 2020, 20 5: 343-354. DOI:10.1080/14737140.2020.1756780.