Pacritinib

The third molecule which we are going to present here at “API of the Month” is pacritinib, a selective oral Janus kinase inhibitor (JAK2) used for the treatment of adults with intermediate or high-risk myelofibrosis with a platelet count below 50 × 109/L. Pacritinib sold under the brand name Vonjo (CTI BioPharma) was approved on 28th of February 2022 with an oral, 200 mg dose, twice daily (1, 2).

As mentioned last month, protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, where inappropriate tyrosine kinase activity (JAK1, JAK2, JAK3, and Tyk2) can lead to a variety of biological cellular responses related to already known autoimmune and hematological disorders (3). With its selective inhibition of JAK2 without accessing JAK1, VONJO is the first approved therapy that specifically addresses the needs of patients with cytopenic myelofibrosis
Synthetic strategies towards pacritinib are focused on the synthesis of intermediates 10 or 13, used in the last step for the Grubbs metathesis reaction. Discovery protocol starts from the alkylation of 5-nitrosalicylaldehyde (1)
with 1,2-dichloroethane in the presence of K2CO3 in DMF at 100°C leading to 2-(2-chloroethoxy)-5-nitrobenzaldehyde (2), which upon treatment with NaBH4 in THF/Water affords the corresponding benzylic alcohol (3). O-alkylation of alcohol (3) with allyl bromide in the presence of KOH and Bu4NHSO4 at room temperature gives 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (4), which then undergoes reduction of nitro group with Fe in the presence of NH4Cl in EtOH/Water to yield the corresponding aniline (5).