The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide

TETRAHEDRON

卷:75

Article

Davies, Stephen G.¹  Fletcher, Ai M.¹  Peters, Matthew E.¹  Roberts, Paul M.¹  Thomson, James E.¹ 

[1] Univ Oxford, Dept Chem, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England

关键词: Methylphenidate;    Ritalin;    Asymmetric synthesis;    Lithium amide;    Aziridinium;    alpha-Aryl-beta-amino acid;   

DOI  :  10.1016/j.tet.2019.130713

来源: Elsevier

【 摘 要 】

The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an alpha-hydroxy-beta-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenyl-magnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding alpha-phenyl-beta-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C-C bonds, and crucially this methodology provides access to alpha-substituted-beta-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues. (C) 2019 Elsevier Ltd. All rights reserved.

【 授权许可】

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