Process Development and Large-Scale Synthesis of a PDE4 Inhibitor

Abstract

An efficient, scalable synthesis of the PDE4 inhibitor, 6-[1methyl-1-(methylsulfonyl)ethyl]-8-(3-{(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl)quinoline benzenesulfonate (10) is described. The synthesis is highly convergent, generating the penultimate 9 by coupling aldehyde 7 and oxadiazole 8 in a Knoevenagel reaction. The process consists of a total of nine chemical steps, five of which comprise the sequence to prepare aldehyde 7 via Skraup reaction, bromination, sulfone formation, methylation and Suzuki-Miyaura cross-coupling, and a two-step sequence for the synthesis of oxadiazole 8 that includes the methylamidoxime and oxadiazole steps. The final two steps are Knoevenagel coupling and salt formation. The process produced the drug candidate 10 in 46% overall yield from 2-bromo-4-methylaniline (1) on multikilogram scale.

Heterogeneous Catalysis for Cross-Coupling Reactions: An Underutilized Powerful and Sustainable Tool in the Fine Chemical Industry?

“…In their synthesis of PDE4 inhibitor 59 , Conlon et al. at Merck utilized a Pd-catalyzed Suzuki–Miyaura coupling reaction between heteroaryl bromide 56 and boronic acid 57 . The initial conditions provided to the process chemistry team utilized Pd­(PPh 3 ) 4 , but unfortunately, this resulted in high levels of residual Pd contamination.…”

A Scaleable Synthesis of 3-Hydroxy-1,5-naphthyridine-4-carbaldehyde

“…10 The highly exothermic Skraup reaction (Scheme 3) was scaled up successfully by carefully controlling the addition rate of glycerol to the heated reaction mixture. Following the reported procedure of a quinoline synthsis, 11 we found the reaction gave the product in 31-48% yield using methanesulfonic acid. By switching to 75% H 2 SO 4 , the reaction yield was improved to 57-72%.…”

Highly Efficient Dye‐Sensitized Solar Cells Based on Panchromatic Ruthenium Sensitizers with Quinolinylbipyridine Anchors

“…The targeted anchor required a key starting material, namely, functional 8‐bromoquinolines Q30–Q33, which were prepared by the Skraup reaction 12. These compounds were then converted into the corresponding tributylstannyl derivatives, which were treated with diethyl 6‐bromo‐2,2′‐bipyridine‐4,4′‐dicarboxylate under Stille cross‐coupling conditions to affording the Qbpy anchors L30–L33 (Scheme ).…”