Process Development for Scale-Up of a Novel 3,5-Substituted Thiazolidine-2,4-dione Compound as a Potent Inhibitor for Estrogen-Related Receptor 1

Abstract

The development of a reproducible process for multihundred gram production of (Z)-5-((1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazol-5-yl)methylene)-3-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)thiazolidine-2,4-dione (26), a potent and selective inhibitor of estrogen-related receptor 1 (ERR1), is described. This multihundred gram synthesis was achieved via magnesium perchlorate-catalyzed regioselective epoxide ring-opening of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (9) with thiazolidine-2,4-dione (6, TZD) to form a diastereomeric mixture tert-butyl 4-(2,4-dioxothiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (17), of which the 3-hydroxyl group was functionally transformed to 3-fluoro derivative 19 after treatment with Deoxo-Fluor. Chiral separation of 19 provided the desired diastereomer (3R,4R)-21 that was converted to the secondary amine 23 TFA salt. Reductive amination of 23 produced the key intermediate N-methyl 24. Knoevenagel condensation of 24 with 1-(4-chloro-2-(trifluoromethyl)benzyl)-1H-indazole-5-carbaldehyde (5) produced the final product 26 in 10% overall yield (99.7% HPLC area% with ≥99.5% de) after a convergent eight synthetic steps with the only column purification being the chiral HPLC separation of 3R,4R-21 from 3S,4S-22.

Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors

“…13 Reduction of the azide generated protected 3-alkoxy 4-amino piperidines 6 suitable for palladium-catalyzed coupling with the chloro naphthyridines 7a,b, as previously described. 6 Deprotection then followed under acidic conditions.…”

“…The residue was loaded on to a 5 g SCX-2 cartridge, washed with MeOH (20 mL), and eluted with a 2 N NH 3 solution in MeOH. The ammoniac fractions were concentrated in vacuo to give 8-(((3R,4R)-3-isobutoxypiperidin-4-yl)amino)-3-methyl-1,7-naphthyridin-2(1H)-one (12) 8-(((3R,4R)-3-(Cyclohexylmethoxy)piperidin-4-yl)amino)-3-methyl-1,7-naphthyridin-2(1H)-one (13).…”

Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

“…Alternatively, the isomeric key intermediate 17b was prepared in four steps from the commercially available epoxide 13 ( Scheme 2 B). Ring opening 42 and subsequent oxidation of the corresponding alcohol 14a followed by intramolecular cyclization of 15 afforded compound 16 . Finally, as discussed for the synthesis of 12b , standard reactions transformed 16 to 17b .…”

The formation of all-cis-(multi)fluorinated piperidines by a dearomatization–hydrogenation process

“…1b). However, the difficult pre-decoration of substrates with defined stereochemistry is required17,18. Other synthetic routes based on radical intermediates have been recently reported, with a minor focus on the generation of fluorinated piperidines19,20.…”