Development and Manufacture of the Inosine Monophosphate Dehydrogenase Inhibitor Merimepodib, VX-497

Abstract

A process for the manufacture of merimepodib (VX-497), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, has been developed and efficiently scaled to produce clinical supply. The process comprises five steps, incorporating simple and robust chemistry that ultimately yielded 96.5 kg with a purity of 100% (by HPLC analysis) and 99.7% w/w assay. Highlights of the process are the effective use of production-scale phosgene, manipulation of Schotten−Baumann reaction conditions to give a low pH procedure that avoids a critical impurity, and the use of online tools to better identify parameters of the API purification.

Synthesis and antiviral activity of a novel class of (5-oxazolyl)phenyl amines

“…3-Methoxy-4-(5-oxazolyl)-aniline 15 was synthesized according to the literature procedure [36]. 2-Methoxy-5-(5-oxazolyl)-aniline 20 was prepared by the reaction of 4-methoxy-3-nitrobenzaldehyde 18 with TosMIC and a reduction reaction of the nitro group.…”

CN Bond Formation Using Highly Effective and Reusable Nickel Ferrite Nanoparticles in Water

“…In addition, aryl amides are ubiquitous in many biologically active compounds. [22][23][24] Acetaminophen, acetaminosalol, and methacetin are among the most popular examples of this family of compounds ( Figure 1). All these along with many other nitrogencontaining compounds can be synthesized through the CÀN bond formation from the available starting materials.…”

Synthesis of the inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors

“…These compounds exhibited moderate activity in the range IC 50 value of 6.43-73.24 mM toward IMPDH-II and IC 50 value of 2.46 mM to 430 mM against mouse splenocyte proliferation. MPA 6 and 4 0 -hydroxymycophenolic acid (49) (Figure 7) were also isolated from mentioned sample. Their inhibitions were IC 50 value of 0.63 mM, 1.79 mM toward IMPDH-II, and IC 50 value of 0.32 mM, 1.10 mM against mouse splenocyte proliferation, respectively.…”

“…Additionally, activity of compound 50 toward K562 (IC 50 value of 0.29 mM) occurred to be better like of MPA 6, MAHA (27) and SAHA (50): 7.7, 4.8 and 0.75 mM, respectively. Merimepodib (54) (Scheme 10) is a potent IMPDH inhibitor (K i in the range of 6-10 nM for the both hIMPDHs) and drug candidate for hepatitis C developed by Vertex Pharmaceuticals (South Boston, MA) 31,49,50 . There was completed a Phase 2b clinical trial and synthesis of 54 optimized to commercial route.…”