Synthesis of (±)‐Pregabalin by Utilizing a Three‐Step Sequential‐Flow System with Heterogeneous Catalysts

Abstract

(±)-Pregabalin, a γ-amino acid derivative, has been synthesized by utilizing flow methods. A three-step sequentialflow reaction starting from commercial isovaleraldehyde and methyl malonate proceeded smoothly with heterogeneous catalysts to afford the precursor of pregabalin in yields of 75-100 %, and a space-time yield of 52

A Nickel‐Diamine/Mesoporous Silica Composite as a Heterogeneous Chiral Catalyst for Asymmetric 1,4‐Addition Reactions

“…Modernization of chemical synthesis through continuous‐flow processes is an emerging area of research, and of particular interest, is the incorporation of chiral heterogeneous catalysts in flow processes since optically active molecules are prevalent in pharmaceutical, agrochemical, and other biologically active compounds. As such, we examined the application of Ni‐ L2 @MCM‐41 as a chiral heterogeneous catalyst for the multi‐step sequential flow synthesis of γ‐lactam 5 , which is a precursor of (−)‐pregabalin . It was found that the desired product could be obtained in good yield and enantioselectivity (Scheme ).…”

A Nickel‐Diamine/Mesoporous Silica Composite as a Heterogeneous Chiral Catalyst for Asymmetric 1,4‐Addition Reactions

“…Modernization of chemical synthesis through continuousflow processes is an emerging area of research, [10,11] and of particular interest, is the incorporation of chiral heterogeneous catalysts in flow processes [7,12] since optically active molecules are prevalent in pharmaceutical, agrochemical, and other biologically active compounds.A ss uch, we examined the application of Ni-L2@MCM-41 as achiral heterogeneous catalyst for the multi-step sequential flow synthesis of glactam 5,w hich is ap recursor of (À)-pregabalin. [13] It was found that the desired product could be obtained in good yield and enantioselectivity (Scheme 1).…”

“…It was found that various 2-substituted nitroalkenes (2a-f), bearing primary and secondary aliphatic moieties,were viable substrates that could undergo the asymmetric process to deliver g-nitro bisesters 3a-f in good to excellent yields with excellent enantioselectivities (entries 1-6). We also found that bnitroalkenes bearing naphthyl (2m)and heteroaromatic (2no)m oieties were good Michael acceptors,p roviding the desired products 3m-o in excellent yields and good to excellent enantioselectivities (entries [13][14][15]. We also found that for electron-rich nitroolefin 2l,amore Lewis acidic catalyst Ni-L4@MCM-41, was required and 3l could be obtained in excellent yield with good enantioselectivity (entry 12).…”

“…We also found that for electron-rich nitroolefin 2l,amore Lewis acidic catalyst Ni-L4@MCM-41, was required and 3l could be obtained in excellent yield with good enantioselectivity (entry 12). We also found that bnitroalkenes bearing naphthyl (2m)and heteroaromatic (2no)m oieties were good Michael acceptors,p roviding the desired products 3m-o in excellent yields and good to excellent enantioselectivities (entries [13][14][15]). Furthermore, when conjugated nitroalkene 2pwas examined as asubstrate, it was found that the 1,4-adduct 3p could be exclusively obtained in excellent yield and enantioselectivity (entry 16).…”

Definitive Screening Design Optimization of Chemoenzymatic Process for (R)‐3‐(Carbamoylmethyl)‐5‐methylhexanoicacid: A Key Intermediate of Pregabalin

“…On scale these reactions carry a significant burden for safe operations, but can be used if no other options are available. Furthermore, a myriad of methodologies, namely asymmetric amination, [6] cyanation, [7] organocatalysis, [8,9] Mi-chael addition reactions on nitroalkanes, [10][11][12][13] ring closer metathesis approach, [14] exo-ring radical cyclization [15] and sequential flow system with heterogeneous catalyst [16] have developed to produce 1.…”