A Review on Synthetic Advances toward the Synthesis of Apremilast, an Anti-inflammatory Drug

Abstract

Psoriasis and psoriatic arthritis are immune-mediated chronic inflammatory disorders which predominantly involve skin and joints. Around the world, it has affected nearly 38 million people worldwide. In 2014, Celgene Corporation’s (S)-apremilast was introduced to treat patients suffering from the different types of psoriasis. In this review, we discuss the different strategies for the synthesis of (S)-apremilast which will help further develop novel routes for its synthesis.

Sodium Tungstate Dihydrate (Na2WO4·2H2O): A Mild Oxidizing and Efficient Reagent in Organic Synthesis

“…Template for SynOpen Thieme (F) Narode et al published a review of strategies for the synthesis of (S)-Apremilast ® . 10 One synthetic approach consists of eight steps, with the last being an oxidation in the presence of sodium tungstate dihydrate and 30% hydrogen peroxide to obtain (S)-Apremilast ® in 91% yield with 99.7% ee. 11 (G) Synthesis and studies of the biological activities of novel trifluoromethylpyridine amide derivatives containing sulfur moieties was reported by Guo et al Sixteen sulfoxidecontaining compounds were chemoselectively obtained by oxidation using sodium tungstate dihydrate in good yields.…”

“…(F) Narode et al published a review of strategies for the synthesis of ( S )-Apremilast ® . 10 One synthetic approach consists of eight steps, with the last being an oxidation in the presence of sodium tungstate dihydrate and 30% hydrogen peroxide to obtain ( S )-Apremilast ® in 91% yield with 99.7% ee. 11…”

Enantioselective synthesis of chiral β-hydroxy sulfonesviamanganese catalyzed asymmetric hydrogenation

“…5 Typically, apremilast, a drug for the treatment of plaque psoriasis and psoriatic arthritis, was synthesized from a chiral β-hydroxy sulfone via the Mitsunobu reaction. 6 On account of the considerable use of chiral β-hydroxy sulfones, many methods have been developed for their asymmetric synthesis in the past few years, 7 including resolution of racemic β-hydroxy sulfones, 8 enzyme-mediated oxidation and reduction of β-hydroxy sulfones, 9 asymmetric reduction of β-keto sulfones, 10 transition-metal-catalyzed asymmetric hydrogenation (AH), 11 and asymmetric transfer hydrogenation (ATH). 12 Among them, the transition-metal-catalyzed AH reaction is one of the most economical, practical, and convenient methods to prepare chiral β-hydroxy sulfones, possessing 100% atom economy.…”

Practical and Asymmetric Synthesis of Apremilast Using Ellman’s Sulfinamide as a Chiral Auxiliary

“…For instance, the increasingly popular biocatalytic synthesis by transaminase remains elusive for producing apremilast, despite its wide applications in preparing other chiral aliphatic amines [10,11]. Therefore, the synthesis of apremilast still mainly relies on chemical methods [12]. The discovery approach to access enantioenriched 1 is via kinetic resolution of its racemate mixture by using N-acyl-L-Leucine [13].…”

“…Chiral auxiliaries have also been extensively used in the asymmetric synthesis of chiral compounds, including apremilast [12]. Since the advent of enantiopure tert-butanesulfinamide [17] developed by Ellman and co-workers, this sulfur stereogenic center-based chiral auxiliary has proven versatile in diverse asymmetric synthesis [18].…”