Modified Asymmetric Strecker Reaction of Aldehyde with Secondary Amine: A Protocol for the Synthesis of S-Clopidogrel (An Antiplatelet Agent)

Abstract

A first approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as chiral catalyst was developed. The catalytic system gave α-aminonitriles in excellent yields (up to 95%) and high enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled in the improved synthesis of (S)-clopidogrel (an antiplatelet agent).

Recent advances on asymmetric Strecker reactions

“…Khan et al also developed a straightforward approach for catalytic asymmetric Strecker reaction of aldehydes with a secondary amine in the presence of sodium fluoride using hydroquinine as catalyst 36 (Scheme 36). 70 The catalytic system gave α-aminonitriles in excellent yields (up to 95%) and high enantioselectivities (er up to 94:6). The efficacy of the chiral product was successfully fulfilled in the improved synthesis of (S)-Clopidogrel (an antiplatelet agent).…”

Developments in the synthesis of the antiplatelet and antithrombotic drug (S)‐clopidogrel

“…Another asymmetric approach for the two‐step synthesis of 1 was developed by Sadhukhan et al by chiral catalyst instead of making use of a chiral auxillary . A modified stereoselective Strecker reaction of 2‐chlorobenzaldehyde 78 with 5 in the presence of sodium monofluoride using hydroquinone 85 as a chiral catalyst gave enantiopure cyano compound 86 with excellent yield and good enantioselectivity; then the cyano group in it was subsequently transformed into ester functionality by hydrolysis along with immediate salt formation to afford 1 with 95% yield and 78:22 enantiomeric ratios (Scheme ).…”

“…To make this drug more common, useful, and cheap, its one‐pot, convenient, atom‐ and step‐economical, environmentally benign, low‐cost synthesis is essential. The literature reveals that the synthesis of (S)‐clopidogrel bisulphate is divided into four main parts, i.e., the application of 4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine hydrochloride, methyl amino(2‐chlorophenyl)acetate, mandelic acid derivatives, and Strecker Synthesis. An effort has been made to summarize briefly the different methods reported in the literature for the preparation of optically pure ( S )‐clopidogrel.…”

Magnetically separable g‐C3N4 hybrid nanocomposite: Highly efficient and eco‐friendly recyclable catalyst for one‐pot synthesis of α‐aminonitriles

“…Application of trimethylsilylcyanide (TMSCN), which is relatively easy to handle and highly soluble in organic solvents, instead of KCN and HCN as a cyanoanion source provides promising and safer routes to α‐aminonitriles . These limitations and the importance of this reaction in organic synthesis have attracted many chemists to focus on the design of suitable and new catalysts that work under mild and green conditions . Although some of these methods are satisfactory, some of these reported methods involve the use of expensive reagents, hazardous solvents, longer reaction times and tedious work‐up procedures.…”