Biological evaluation of novel benzisoxazole derivatives as PPARδ agonists

Development of an Efficient New Route to PPARδ Agonist Fonadelpar: Formation of the C–C Bond by Claisen Condensation

“…The aldehyde 17 was prepared from methyl 4-methyl-3-oxopentanoate 9 in a four-step sequence, as shown in Scheme . According to the reported method, compound 10 was obtained by cyclization of 4-(trifluoromethyl)­benzothioamide with raw material 9 after chlorination using sulfonyl chloride, and the product was purified by recrystallization in isopropanol/water. Reduction of 10 with 1.5 equiv of Red-Al yielded only 69% of alcohol 11 .…”

“…3 Another intermediate 12 was prepared from methyl 4methyl-3-oxopentanoate 9 through chlorination and cyclization with 4-(trifluoromethyl)thiobenzamide, followed by ester reduction and chlorination of hydroxyl. 4 The main challenge includes the following: (i) the whole synthetic route was long with a longest linear sequence of 11 steps and afforded less than 4% overall yield from 2 (3.3%) or 9 (3.9%). (ii) The ethylene linker of 1 was constructed by coupling the intermediates 8 and 12 using a C-alkylation reaction, which had a low yield due to the massive generation of N-alkylated byproduct, and the C−C coupling occurred only under strictly anhydrous conditions in our attempt.…”

“…Intermediate 8 was generated from 4-methyl-3-nitrophenol 2 through nitro reduction, acetylation, Fries rearrangement, oximation, and intramolecular cyclization . Another intermediate 12 was prepared from methyl 4-methyl-3-oxopentanoate 9 through chlorination and cyclization with 4-(trifluoromethyl)­thiobenzamide, followed by ester reduction and chlorination of hydroxyl . The main challenge includes the following: (i) the whole synthetic route was long with a longest linear sequence of 11 steps and afforded less than 4% overall yield from 2 (3.3%) or 9 (3.9%).…”

Benzisoxazole: a privileged scaffold for medicinal chemistry

“…The influence of this approach is exemplified in the discovery of other new potential drugs or therapeutic applications by refining privileged structures in pharmacological agents. 83 Sakuma et al 84 synthesized a novel series of benzisoxazole derived analogs and these were screened for their peroxisome proliferator-activated receptor d agonist activity. Compound 77 exhibited potent human PPARδ transactivation activity.…”