Synthesis of Olodanrigan

Key words

olodanrigan - phenylalanine ammonia lyase - hydroamination - tetrahydroisoquinolines - Pictet–Spengler reaction

Significance

Olodanrigan (EMA401) is an angiotensin II type 2 antagonist that had been considered for the treatment of postherpetic neuralgia and neuropathic pain. This short synthesis of olodanrigan is presented in detail in three back-to-back papers. Part 1 concerns the optimized conversion of the phenylalanine C to the target molecule and includes the search for a suitable polymorph. Part 2 (Org. Process Res. Dev. 2020, 24, 1756) concerns development of a pyridine- and piperidine-free Knoevenagel–Doebner condensation using a catalytic amount of morpholine that delivered 25 kg of cinnamic acid C in 98% yield.

Comment

Part 3 (Org. Process Res. Dev. 2020, 24, 1763) describes the hydroamination of the cinnamic acid B using an engineered phenylalanine ammonia lyase enzyme to afford amino acid C. Enzyme loadings as low as 2.5 wt% (E/S = 1:40 w/w) and substrate concentrations between 1.17–0.39 M were compatible with the reaction conditions. The telescoped process from B via C to tetrahydroisoquinoline D was scaled up to a batch size of 2 kg, resulting in 81% conversion to C and a 59% isolated yield of D with high chiral purity (er = 99.9:0.1).

Publication History

Article published online:
17 November 2020