An Improved Synthesis of the Selective EP4 Receptor Agonist ONO-4819

Abstract

An improved synthesis of the highly selective EP4-receptor agonist ONO-4819 has been developed. The previous synthesis suffered from several drawbacks, in which a critical one is the difficulty in the removal of byproducts leading to unsatisfactory quality of the active pharmaceutical ingredient (API). Furthermore, on stereoselective reduction of an enone intermediate by binaphthol-modified lithium aluminum hydride, low concentration of the reaction conditions and tedious purification procedures to remove excess binaphthol were critical issues for the manufacturing process of the API. In the improved process, we have developed improved conditions using gamma-thiobutyrolactone as sulfur source instead of potassium thioacetate to introduce the sulfur-containing C4 side chain without formation of byproducts. For stereoselective synthesis of the chiral alcohol, (-)-DIP-chloride reduction is found to be the best method, which can improve not only the enantioselectivity but also the workload for removing the chiral modifier in a purification process. Furthermore, benzoyl and tert-butyldimethylsilyl groups as protecting groups for hydroxyl functions were used for precise process controls of all intermediates. By changing these protecting groups, the purity of ONO-4819 was strictly controlled through crystalline intermediates. Thus, an improved robust process for ONO-4819 with a high chemical purity was developed.

Unified Strategy to Prostaglandins: Chemoenzymatic Total Synthesis of Cloprostenol, Bimatoprost, PGF2α, Fluprostenol, and Travoprost Guided by Biocatalytic Retrosynthesis

“…5). Oxidation of 11 with TEMPO and trichloroisocyanuric acid (TCCA) in ethyl acetate and dimethyl carbonate at 0 ℃ provided the desired crude C11-OH-PPB-protected Corey aldehyde 20 [63][64][65] , and set the stage for the C13-C14 HWE olefination. Addition of the crude aldehyde 20 to the solutions of phosphonates 21a-21d in dichloromethane in the presence of 30% aq.…”

Pot Economy in the Synthesis of Prostaglandin A1 and E1 Methyl Esters

“…Only 5 mol % of catalyst 3 is needed and each reagent is added in succession to the same pot, thus making the one-pot synthesis of 7 practical. The next reaction is the diastereoselective reduction of the ketone in the w-side chain; this transformation was successfully achieved by treatment of 7 with (À)-diisopinocamphenyl chloroborane (DIPCl) [21] to afford allyl alcohol 8 in 68 % yield and 96:4 d.r. at the C15 stereogenic center.…”

Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Rexinoids with Chemopreventive Potential

“…The position alpha to the carbonyl of 20 was deprotonated with sodium hydride to generate the anion coupling partner in situ. 34, 35 The intermediate 21 was hydrolyzed and decarboxylated in the presence of sodium hydroxide in aqueous ethanol at reflux to provide the indenoisoquinoline 4 . 36 Esterification of this indenoisoquinoline afforded the methyl ester 22 .…”