A Convenient Method for Synthesis of Enantiomerically Enriched Methylphenidate from N-Methoxycarbonylpiperidine

Abstract

[formula: see text] This report describes a new method to prepare optically active methylphenidate starting from piperidine. The method consists of a transformation of N-methoxycarbonylpiperidine to the corresponding alpha-methoxylated carbamate I by utilizing electrochemical oxidation followed by the coupling reaction with optically active Evans imides II to produce optically active methylphenidate derivatives III with high stereoselectivities, threo-(2R,2'R)-Methylphenidate (IV; Ar = Ph; Ritalin) was easily prepared from III in three steps.

The economies of synthesis

“…19 One previous asymmetric route relied on the use of a chiral auxiliary in an aldol reaction ( 46 → 47 ), which provided material with excellent diastereoselectivity 20. However, the use of this stoichiometric reagent is costly from the perspective of atom economy and requires a number of steps to install and then later remove.…”

Asymmetric carbon–carbon bond‐forming reaction at the 2‐position of a piperidine skeleton

“…6,7 Use of a chiral Lewis acid may be most promising for an asymmetric carbon-carbon bondforming reaction of 6a with nonchiral carbon nucleophiles. However, the reaction of 5a with dimethyl malonate using chiral titanium complexes gave unsatisfactory results.…”

Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride

“…While some enantioselective approaches are short, they do not provide 1 of the desired enantiomeric purity necessary for drug development. Enantioselective synthesis approaches to produce 1, however, will become viable, particularly those based on approaches reported by us (Novartis), [35] Matsumura, [39,40] and Seido. [45] …”

“…[39,40] described a convenient method for the preparation of (2R,2'R)-(+)-threomethylphenidate (1) free base starting from the easily available N-methoxycarbonylpiperidine (43; Scheme 13) involving a highly stereoselective coupling reaction of the a-methoxylated carbamate 44 with the Evans imide 45 as the key step. An electrochemical a-methoxylation of 43 in methanol afforded the N-protected a-methoxypiperidine 44 in 85% yield.…”