Preparation of 5-bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine_Industrial additives

Preparation background and overview of 5-bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine

5-Bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine is a pharmaceutical intermediate that can be ring-closed from 6-bromo-4-methylpyridin-3-amine as raw material 5-Bromo-1H-pyrazolo[3,4-c]pyridine is prepared and then iodinated to give 5-bromo-1H-pyrazolo[3,4-c]pyridine. 5-Bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine can be used to prepare compound 3 propylene ethyl carbonate-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl) )-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine, this compound is a Pim kinase inhibitor and can be used to treat Pim kinase (Pim -1, Pim-2 and/or Pim-3) mediated disorders.

Preparation of 5-bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine

Preparation step 1 of 5-bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine, 5-bromo-1H-pyrazolo[3,4-c]pyridine Preparation

To a solution of 6-bromo-4-methylpyridin-3-amine (7.76g, 0.0415mol) in acetic acid (412.8mL, 7.260mol) was added 4.0 of sodium nitrite (2.87g, 0.0416mol) ml aqueous solution (Bioorg. Med. Chem. 15 (2007) 2441-2452). The reaction mixture was stirred for 15 minutes and allowed to stand at room temperature (rt) for 2 days (d). The reaction mixture was concentrated and diluted with EtOAc, then washed with NaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude tributyl borate was purified by chromatography (DCM/MeOH, eluting with 5% MeOH) to afford 5-bromo-1H-pyrazolo[3,4-c]pyridine (79.1% yield).

Preparation step 2 of 5-bromo-3-iodo-1H-pyrazolo[3,4-C]pyridine, 5-bromo-3-iodo-1H-pyrazolo[3,4- c] Preparation of pyridine

A solution containing 5-bromo-1H-pyrazolo[3,4-c]pyridine (168.0g, 848.4mmol) and NIS (286.3g, 1.27mol) in DMF (1.2L) was brought to room temperature. Stir. The reaction mixture was poured into water and filtered. The solid was washed with water and 5% Na₂S₂O₅. The crude product was dried under high vacuum overnight to give 5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine.

References

[1] CN201280050370.5 Pyrazolo[3,4-c]pyridine compounds and methods of use