Development and a Practical Synthesis of the JAK2 Inhibitor LY2784544

Abstract

The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon–carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert-butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C–C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.

Rapid Wolff–Kishner reductions in a silicon carbide microreactor

“…9 The use 5 of silanes or borohydrides along with a Lewis acid is also common. 10 These and most other methods all have large waste streams, making them particularly environmentally unfriendly and costly on large scale. For example, researchers at Eli Lilly recently performed a TFA-promoted triethylsilane reduction of a 10 diaryl ketone to the corresponding methylene on 100 mol scale; however an alternative route was sought due to challenges associated with the disposal of the fluoride and silane waste.…”

Development of a Stepwise Reductive Deoxygenation Process by Ru‐Catalysed Homogeneous Ketone Reduction and Pd‐Catalysed Hydrogenolysis in the Presence of Cu Salts

“…[24] Homogeneous catalysts [9,[11][12][13][14][15] and 1 [1,2] were prepared according to literature procedures. HPLC analysis: Waters XBridge C18 column, 4.6 150 mm, 3.5 mm particle size; flow rate = 1.…”

“…LY2784544 is a JAK2 inhibitor currently undergoing clinical investigations for the treatment of myeloproliferative disorders. [1,2] To date, this deoxygenation has been accomplished in a single step by the treatment of 1 with six equivalents of triethylsilane in the presence of twelve equivalents of trifluoroacetic acid as a promoter and solvent. [2] Although the isolated yields and purity for this transformation are high, the desire to avoid large amounts of fluoride-and silicon-containing waste prompted us to investigate alternatives.…”

“…Trichlorosilane with triethylamine worked well, [3] but the volatile nature of trichlorosilane and a difficult reaction workup eliminated this method from contention. Hypophosphorus acid/iodine reductions were also effective, [4] but iodide-induced catalyst poisoning was encountered in the downstream chemistry, [2] which caused us to abandon this approach. Wolff-Kishner reduction and numerous other methods were found to be ineffective, which highlights the surprising difficulty of the desired transformation.…”

Selective JAK Inhibitors

“…The morpholine group is believed to help solubilize the compound. Process research studies describe a vanadium oxide-catalyzed C-H oxidation in order to install the benzylic morpholine moiety [47]. In a TEL-JAK cellbased assay, 36, although not as potent as AZD1480 and ruxolitinib against TEL-JAK2, was more selective over TEL-JAK1 and JAK3 (15-and 25-fold selectivity, respectively).…”