Practical Application of Oxidation Using a Novel Na₂WO₄−H₂O₂ System under Neutral Conditions for Scale-Up Manufacturing of 12α-Hydroxy-3-oxooleanano-28,13-lactone: Key Intermediate of Endothelin A Receptor Antagonist S-0139

Abstract

Novel alcohol oxidation using a Na2WO4−H2O2 system was applied to manufacture 12α-hydroxy-3-oxooleanano-28,13-lactone which is a key intermediate of S-0139. Oxidation of the hydroxyl group of oleanolic acid was optimized based on the design of experiment (DoE) approach. Statistical analysis was used to maximize the yield of the corresponding ketone and minimize the generation of byproducts. The safety evaluation of this oxidation was also conducted in detail, and pilot manufacturing was achieved.

Inhibition of Alpha-Glucosidase by Synthetic Derivatives of Lupane, Oleanane, Ursane and Dammarane Triterpenoids

“…2,3-Indole 3 demonstrated better activity with an IC 50 of 115.1 µM, this being 3.5-fold more active than acarbose. It is interesting to note that lactone 5 was inactive in contrast to its 3β-OH-analog, which showed significant α-glucosidase inhibitory activity [10,24].…”

Modified Quinoxaline‐Fused Oleanolic Acid Derivatives as Inhibitors of Osteoclastogenesis and Potential Agent in Anti‐Osteoporosis

“…As shown in Scheme , 3‐keto oleanolic acid ( 2 ) was obtained from oxidation of oleanolic acid ( 1 ) by hydrogen peroxide . The intermediate 3 was obtained via oxidation of 2 by air under t‐BuOK/t‐BuOH conditions.…”

Oxidation of Methyl 2-Cyano-3,4-seco-4(23)-Ene-Ursolate by Ozone

“…Examples include the synthesis from oleanolic acid of bardoxolone methyl (2-cyano-3,12-dioxooleane-1(2),9(11)-dien-28-oic acid methyl ester), which passed phase I clinical trials for treating cancer and phase II for treating chronic kidney disease in type 2 diabetes patients [4]. 3E,12D-Dihydroxyoleane-13E,28-lactone is a key intermediate in the synthesis of endothelin A receptor antagonists and a promising antidiabetic agent [5]. 12E-Hydroxyurs-11-ene-13E,28-lactone was produced by oxidative transformation of ursolic acid by ruthenium porphyrins and was active against A431 human skin cancer cells [5,6].…”

“…3E,12D-Dihydroxyoleane-13E,28-lactone is a key intermediate in the synthesis of endothelin A receptor antagonists and a promising antidiabetic agent [5]. 12E-Hydroxyurs-11-ene-13E,28-lactone was produced by oxidative transformation of ursolic acid by ruthenium porphyrins and was active against A431 human skin cancer cells [5,6].The structures of the starting substrates are known to affect considerably the oxidation of triterpenoids [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. For example, the reactivities of oleanolic and ursolic acid derivatives were found to differ during oxidation by dimethyldioxirane although these triterpenoids differ only by the location of the methyl in ring E [21].…”

“…3E,12D-Dihydroxyoleane-13E,28-lactone is a key intermediate in the synthesis of endothelin A receptor antagonists and a promising antidiabetic agent [5]. 12E-Hydroxyurs-11-ene-13E,28-lactone was produced by oxidative transformation of ursolic acid by ruthenium porphyrins and was active against A431 human skin cancer cells [5,6].…”