Practical Large-Scale Synthesis of Endothelin Receptor Antagonist S-0139

Abstract

Semisynthetic endothelin receptor antagonist S-0139 was synthesized in 14 steps from oleanolic acid 2 in a 20% overall yield on a multi-kilogram scale. Our previous synthesis of the oleanane skeleton was modified and improved to give phosphonate 9 as a key intermediate. The side chain on the 27-position was introduced by Horner-Wadsworth-Emmons olefination of phosphonate 9 with aldehyde 5. Aldehyde 5 was prepared in a one-pot reduction-acylation process starting from 5-hydroxy-2-nitrobenzaldehyde. The entire sequence of the synthesis can be done without chromatography and yields S-0139 of high purity.

Total Synthesis of (+)-Oxo-tomaymycin

“…Me 2 S-poisoned Pt/C catalyst in the presence of hydrogen led to an increase in cyclized product (entry 2). Finally, TiCl 3 (as 20% w/w solution in 2 N HCl) proved to be the reagent of choice to affect both ArNO 2 reduction and cyclization in a one-pot manner. The reduction was fast, and the acidic conditions facilitated the cyclization step .…”

Endothelin Receptor Antagonists - An Overview

“…(23) showed improved activity and good selectivity (Ki, ET A = 1 nM, ET B = 1 µM). Large-scale synthesis of 97-139 has been carried out [106]. However, in vivo potency of 97-139 was below expectations.…”

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

“…However, oxidation is not often used in large-scale manufacturing because of inherent safety concerns and waste of byproducts . In manufacturing a new type of endothelin A receptor antagonist S-0139, 4 , discovered at Shionogi Research Laboratories, − oxidation of the hydroxyl group posed a serious issue. The synthetic route to 4 from oleanolic acid 1 , of which the key step is the Barton reaction, was developed by Konoike et al , The hydroxyl group at the 3-C position of 1 was oxidized by Jones oxidation, and then a stream of ozonized oxygen was introduced to obtain 12α-hydroxy-3-oxooleanano-28,13-lactone, 3 , which is a key intermediate for the Barton reaction (Scheme ).…”

“…In manufacturing a new type of endothelin A receptor antagonist S-0139, 4 , discovered at Shionogi Research Laboratories, − oxidation of the hydroxyl group posed a serious issue. The synthetic route to 4 from oleanolic acid 1 , of which the key step is the Barton reaction, was developed by Konoike et al , The hydroxyl group at the 3-C position of 1 was oxidized by Jones oxidation, and then a stream of ozonized oxygen was introduced to obtain 12α-hydroxy-3-oxooleanano-28,13-lactone, 3 , which is a key intermediate for the Barton reaction (Scheme ). Jones oxidation, however, is not suitable for bulk chemical development because of the toxicity of chromium(VI) and a large quantity of metal waste.…”