Process Development and Scale-Up of a PPARγ Agonist: Selection of the Manufacture Route

Abstract

Two short, high-yielding routes to the selective PPARγ agonist GSK376501A were developed and carried out on scale. The key bond -forming reaction in each synthesis was the substitution of a 3,5-difluoro or 3,5-dibromo aryl intermediate with 2-methoxyethanol. A nucleophilic aromatic (S N Ar) substitution reaction under basic conditions was developed for the aryl fluoride substrate. The 3,5-dibromo aryl halide intermediate required copper-catalyzed conditions to achieve substitution of the second bromide. In addition, a 2-methoxyethanol decomposition pathway to generate methanol and ethylene oxide under basic reaction conditions as well as its effect on impurity formation, was elucidated. Both the difluoro and dibromo intermediates were considered as the basis for the final route of manufacture. The difluoro substrates were chosen due to straightforward chemistry, controllable impurity profile, and ease of fluoride removal.

Palladium Nanoparticles on Graphite Oxide: A Recyclable Catalyst for the Synthesis of Biaryl Cores

“…1 A trillion dollars of business per year is involved around these top selling drug molecules. 2 Figure 1 exemplifies a few top selling drug molecules, highlighting the biaryl core present in these molecules, such as antihypertensive drugs valsartan 3 and telmisartan 4 and agrochemical agent boscalid, 5 while recent researchers from GlaxoSmithKline focused on the synthesis of a selective PPARγ modulator (SPPARMγ) 6 with superior insulin sensitivity applicable for the treatment of type 2 diabetes mellitus. At present, the use of noxious phosphine based homogeneous palladium catalysts is considered as a viable route for the effective syntheses of such a biaryl core, 7 with inherent hassles like the contamination of precious metals with the product as well as the "use and throw" nature of the homogeneous catalysts.…”

Impact of Group 13 Metals on Cp2TiCl2 Reduction and Structural Characterization of Resulting Compounds

“…This compound undergoes further transformations involving loss of Cp and Cl ligands to give [Ti­(OEt­OMe) 4 ] species. A GC–MS study of the volatiles showed the formation of several organic products such as methanol, 2-furanol, and methyl tetrahydrofurfuryl ether; this suggests radical-assisted decomposition of MeO­EtOH …”

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

“…Ullmann coupling of 87 and 2-methoxyethanol was considered by Toczko et al at GlaxoSmithKline as one of the key assembling strategies for the manufacturing route to GSK376501A (88), a selective peroxisome proliferatoractivated receptor gamma modulator (PPARγ) for the treatment of type 2 diabetes mellitus (T2DM) (Scheme 34). 129 Initial evaluation of S N Ar conditions led to the formation of monosubstituted product 89, and further conversion of this intermediate to the desired product 88 under S N Ar conditions required rather harsh conditions such as a large excess of alkoxide and long reaction time, etc. Alternatively, the researchers found that relatively milder Cucatalyzed coupling conditions were effective to convert 87 to the desired product 88.…”