Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation

Abstract

An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available 1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient ruthenium-catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr and 99.7% ee on a 100 g scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to scale-up. This process not only gives a desirable total yield but also avoids hazardous conditions and chromatographic purification. The robustness of this synthesis was successfully performed on a multigram scale to afford 1 with >99.9% de and >99.9% ee in 56.8% overall yield in nine steps.

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

“… LiCl: This reagent has been employed as a Lewis acid with PivCl (1.3 and 2 equiv) and TBTU (0.25 equiv) . This additive presumably coordinates to the carbonyl group of the activated acid to make it more electrophilic toward aminolysis. Oxyma: Several examples have been reported with DIC (catalytic to superstoichiometric amounts), and there is one example with TOTU (stoichiometric) . This reagent can be superior to HOBt to prevent racemization and does not display the explosive properties of HOBt and HOAt by DSC and ARC .…”

Enantio‐ and Diastereoselective Synthesis of Chiral Syn‐Aryl β‐Hydroxy α‐Amino Esters via Biocatalytic Dynamic Reductive Kinetic Resolution

“…Among others, dynamic reductive kinetic resolution (DYRKR) of racemic aryl α‐amino β‐keto esters represents a step‐ and atom‐economic approach to synthesize chiral aryl β‐hydroxy α‐amino esters, as the α‐protons of these substrates are acidic. In this regard, transition metals such as ruthenium and rhodium, derived chiral catalysts have been widely utilized for this specific DYRKR reaction, both in asymmetric hydrogenation and asymmetric transfer hydrogenation modes [3b,4d,6] . Depending on the conditions employed, syn ‐ and anti ‐aryl β‐hydroxy α‐amino esters could be accessed in a controllable manner with good‐to‐excellent diastereo‐ and enantioselectivity.…”

Recent Progress and Applications of Transition-Metal-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

“…In 2019, Zhang, Wang, and co-workers developed an efficient and scalable synthesis of eliglustat, a specific and potent inhibitor of glucosylceramide synthase, via a Ru-catalyzed ATH/DKR approach (Scheme 41). 54 The required two contiguous stereocenters were installed by ATH in the presence of the [RuCl(p-cymene)((R,R)-TfDPEN)] complex [(R,R)-CAT16], generated from (R,R)-TfDPEN and [Ru(p-cymene)Cl 2 ] 2 , and the HCO 2 H/Et 3 N (5:2) azeotrope as the hydrogen source. Slow addition of HCO 2 H was crucial to ensure high conversion and selectivity.…”