Direct Asymmetric Reductive Amination for the Synthesis of (S)-Rivastigmine.

Guorui Gao,Mingxin Chang,Shaozhi Du,Yang Yang,Xue Lei,Haizhou Huang

doi:10.3390/molecules23092207

Abstract

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium–phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.

Highlights

Results and DiscussionStarting from reeadily aavvaailable aanndd cchheeaapp mm--hhyyddrrooxxyyaacceettoopphenone 11,, ((SS))--rivastigmine was synthesized in four steps in high yyiieellddss aanndd eeee ((SScchheemmee 11))
Received: 20 July 2018; Accepted: 28 August 2018; Published: 31 August 2018 Received: 20 July 2018; Accepted: 28 August 2018; Published: 31 August 2018 Abstract: In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has bAebesntraacchti:eIvnetdhiussairntgicdleirwecetdaesmymonmsetrtaritce rheodwucatsivyemammeitnriactitoontaalssythnethkeesyistorafn(Ssf)o-rrimvaasttiiognmiinnfeohuarssbteepens
Starting from reeadily aavvaailable aanndd cchheeaapp mm--hhyyddrrooxxyyaacceettoopphenone 11, ((SS))--rivastigmine was synthesized in four steps in high yyiieellddss aanndd eeee ((SScchheemmee 11))

Summary

Results and Discussion

Starting from reeadily aavvaailable aanndd cchheeaapp mm--hhyyddrrooxxyyaacceettoopphenone 11,, ((SS))--rivastigmine was synthesized in four steps in high yyiieellddss aanndd eeee ((SScchheemmee 11)). The H8-BINOL-based L6 furnished slightly lower enantiomeric excess than L1 (entry 13). The commercially available MonoPhos was examined, and it provided moderate to good yield and enantiopurity (entry 14). We;hfuenrththeer cdaetcarleyasstilnogadthinegcawtaalsydset cloreaadsiendgttoo00..52mmooll%%, tthhee ereeaacntdioynieylidelodf dthreoprepaecdtioslnigrhemtlyaitnoe8d8%thewsiathmeee; fautr9t6h%er; H2 pressure was decreased to 50 atm, the reaction ee remained the same but the yield dropped to 90% (Menoltecruyle6s )2.01F8u, r2t3h, xerFOloRwPEeEriRnRgEtVhIeEWpressure to 30 atm, the yield for the reaction dropped to 75% bu4t tohf e8 enantioselectivity increased slightly to 98% (entry 7). Tehneanfaticoisleelreecmtivoivtyal(oSfchhtheeemmdeeip11)h)..enylmethyl group was carried out with Pd/C as the catalyst and H2 as the reductant leading to primary amine product 6 in 97% yield, without any erosion of the enantioselectivity (Scheme 1). AAggaaiinn, in this step the enantiopurity of the fifinal product was not affected Throughh this 4-step procedure, the fifinal product (S)-rivastigmine was synthesized in 82% overall yield and 96% ee. AApppplliiccaattiioonn ooff ddiimmeetthhyyllaammiinnee ffoorr tthhee ssyynntthheessiiss ooff ((SS))--rriivvaassttiiggmmiinnee. FFllaasshh ccoolluummnn cchhrroommaattooggrraapphhyy wwaass ppeerrffoorrmmeedd oovveerr ssiilliiccaa ggeell ((330000––440000 mmeesshh))

Characterization

Preparation of Compound 3

Preparation of Compound 5

Preparation of Compound 6

Conclusions