High Enantioselective and Large-Scale Production of Ursodeoxycholic Acid by Combination of Pd- and Hydroxysteroid Dehydrogenase-Catalyzed Hydrogenation

Abstract

Ursodeoxycholic acid (UDCA) was synthesized from commercially available phytosterol-derived bisnoralcohol with an overall yield of 57% by a six-step process. The absolute configuration of the 3,5,7-stereogenic centers in UDCA was determined using Pd-catalyzed and hydroxysteroid dehydrogenase (HSDH)-catalyzed hydrogenation conducted under normal temperature and atmospheric pressure conditions. To investigate the stereoselectivity and regioselectivity of the catalyst and assess the final purity of the product, all potential impurities were synthesized and analyzed using HPLC with charged aerosol detection (CAD). The developed process demonstrated cost-effectiveness and suitability for large-scale production of UDCA with an ICH-grade quality. Our Pd-catalyzed and HSDH-catalyzed hydrogenation techniques could also be applied in the synthesis of alphaxalone and brexanolone.

Kilogram-Scale Synthesis of 11β-Hydroxyandrosterone

“…With sufficient quantity of the desired 5α-H intermediate 24 in hand, optimization of the final stereoselective reduction to C3α–OH 2 could be undertaken. Enzymatic ketone reduction was not explored at this time, but recent examples on similar steroidal substrates have been shown to be successful on a large scale . Superhydrides, both lithium and sodium, gave a poor conversion with considerable starting material 24 remaining and reduction selectively to the undesired C3β-epimer 30 (Table , Entries 1 and 2).…”