Synthesis of BI 894416 and BI 1342561, two potent and selective spleen tyrosine kinase inhibitors, labeled with carbon 14 and with deuterium

(R)-4-((R)-1-((6-(1-[tert-butyl]-1H-pyrazol-4-yl)-2-methyl-2H-pyrazolo[3,4-d]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (BI 894416, 1) and (R)-4-((R)-1-((6-(1-[tert-butyl]-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-yl)oxy)ethyl)pyrrolidin-2-one (BI 1342561, 2) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2-methyl-2H-pyrazolo[4,3-c]pyridine in 1 versus 2,3-dimethyl-2H-indazole in 2. In the carbon 14 synthesis, 1-(1-[tert-butyl]-1H-pyrazol-4-yl)ethan-1-one-1-¹⁴C ([¹⁴C]-8) was prepared from the cyanation of 4-bromopyrazole using zinc [¹⁴C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [¹⁴C]-8 was then used to access these two bicyclic moieties via pyrano-pyrazoles [¹⁴C]-11 and [¹⁴C]-12, which were further transformed in few more steps to [¹⁴C]-(1) and [¹⁴C]-2. Both inhibitors contain a tert-butyl group. Introducing tert-butyl-d₉ will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1, for example, are the result of tert-butyl oxidation, like alcohol 3, acid 4, and the further N-demethylation of 4 to 5. The detailed preparation of these deuterium-labeled metabolites is also described.