Two approaches for the synthesis of levo-praziquantel

Shou, Haowen; He, Zhaoting; Peng, Gang; Su, Weike; Yu, Jian

doi:10.1039/d1ob00453k

Cited by 15 publications

(12 citation statements)

References 57 publications

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“…Shou et al have developed two synthetic routes, involving mechanochemical steps, for the synthesis of R-PZQ (Scheme 18). [56] The first route involves a racemic aza-Henry/ acylation reaction, followed by an hydrogenation of the nitro group. Then, a chiral resolution using L-tartaric acid allowed to isolate the desired enantiomer, albeit with a poor yield.…”

Section: Indazole Derivative: Axitinibmentioning

confidence: 99%

“…The drawbacks of these methods are the need to use large amounts of solvent, protection/deprotection steps, toxic reagents, or difficult purifications to obtain the expected compound. Hence, Shou et al have developed two synthetic routes, involving mechanochemical steps, for the synthesis of R-PZQ (Scheme 18) [56]. The first route involves a racemic aza-Henry/ acylation reaction, followed by an hydrogenation of the nitro group.…”

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Sustainable Mechanosynthesis of Biologically Active Molecules

et al. 2022

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Synthetic mechanochemistry, the use of mechanical force produced by milling, grinding or extruding, as an activation technique, provides access to chemical entities of all kinds. This Review is focused on examples reported so far of known Active Pharmaceutical Ingredients (APIs), and effectively evaluated bioactive molecules, all prepared by mechanosynthesis. Three families of molecules are discussed: heterocyclic compounds, metal complexes and peptides. Advantages of the mechanochemistry approach are highlighted especially from a green chemistry and efficacy point of view.

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Section: Indazole Derivative: Axitinibmentioning

confidence: 99%

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confidence: 99%

Sustainable Mechanosynthesis of Biologically Active Molecules

et al. 2022

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“…For the purpose of eschewing the THIQs protection and deprotection steps in the synthesis of PZQ, N ‐chloroacetyl‐THIQs were chosen as the starting material to react with nitromethane, however, only an unexpectedly oxidative ring‐opening product was obtained [13b] . Alternatively, the PZQ and its R ‐isomer could be prepared from 3,4‐dihydroquinolines and nitromethane by three‐ or four‐step reactions including mechanochemical (asymmetric) aza ‐Henry/acylation reaction, hydrogenation reaction, (chiral resolution) and solvent‐free acylation/ring‐closing reaction [13h] . These concise routes rendered the construction of enantiopure Praziquental in gram scale, featured with time‐saving and green properties.…”

Section: Mechanochemical C−h Functionalization For Apis and Bioactive...mentioning

confidence: 99%

Mechanochemical C−X/C−H Functionalization: An Alternative Strategic Access to Pharmaceuticals

Yang

et al. 2022

Eur J Org Chem

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In the pursuit of clean pharmaceutical production, chemists in medicinal industry require access to new sustainable methodologies to reduce and even eliminate pollution, which is mainly produced by the overuse of organic solvents during chemical synthesis of active pharmaceutical ingredients (APIs). In this context, the solvent-free/less mechanochemical functionalization of small molecules has gradually emerged as a powerful strategy for the green synthesis and modification of APIs, bioactive compounds, and functional materials. In this review, we present an overview of mechanochemical CÀ X/CÀ H functionalization applications to medicinal chemistry, involving cross-coupling, cross-dehydrogenative coupling, oxidative coupling (via CÀ H activation pathway), and direct coupling (via radical pathway) as key steps for the preparation of APIs and bioactive compounds.

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“…Moreover, multistep chemical transformations are required to recycle the undesired ( S )-enantiomer. Consequently, current chiral resolution-based preparation of ( R )-PZQ is not only atom-uneconomic and environmentally unfriendly but also not economically viable compared to the facile synthesis of racemic PZQ, rendering the goal of replacing the clinical use of PZQ by ( R )-PZQ unsuccessful to date. ,, On the other hand, enantioselective synthesis of ( R )-PZQ was occasionally reported, including those using chiral auxiliary, chiral ruthenium complex-catalyzed asymmetric transfer hydrogenation, and organo-catalytic asymmetric aza-Henry reaction. − Nevertheless, all of these syntheses suffered from limitations, such as unsatisfactory stereoselectivity and the requirement of high loadings of expensive chiral catalysts and/or ligands. − Hence, the development of a stereoselective, green, sustainable, and cost-effective synthesis of ( R )-PZQ is highly desirable. In fact, the development of the low-cost preparation of enantiomerically pure ( R )-PZQ has been assigned by WHO as a crucial priority for the research and development on PZQ in future. , …”

Section: Introductionmentioning

confidence: 99%

Engineered Monoamine Oxidase-Catalyzed Deracemization of Sterically Hindered Acylaminomethyl-tetrahydroisoquinoline: Asymmetric Synthesis of (R)-(−)-Praziquantel and Its Analogues

Liu

et al. 2023

ACS Sustainable Chem. Eng.

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At present, praziquantel (PZQ) is the only drug utilized in clinics for the control and treatment of all forms of schistosomiasis, which is a neglected tropical disease infecting over 200 million people. As only the R-isomer of PZQ is biologically active and devoid of associated undesired properties, the development of a stereoselective, sustainable, and cost-effective synthesis of (R)-PZQ is of paramount significance. Herein, a known monoamine oxidase variant, MAO-N-D11D, which showed a specific activity of merely 0.003 U/mg toward 1-cyclohexanecarboxylaminomethyl-tetrahydroisoquinoline (THIQ) (1a), a synthetic intermediate to PZQ, was extensively engineered using combinatorial active-site saturation test/iterative saturation mutagenesis and site-saturation mutagenesis, resulting in the identification of an evolved variant, referred to as LJY-FM, exhibiting 134-fold elevated specific activity (0.401 U/mg) and 260-fold enhanced catalytic efficiency (26,989 min–1 M–1) toward 1a relative to MAO-N-D11D, respectively. After optimizing protein expression and reaction conditions, gram-scale deracemization of 50 mM of 1a catalyzed by variant LJY-FM was executed in the presence of ammonia borane, with (R)-1a, a critical intermediate to (R)-PZQ, being furnished with 76% isolated yield and 96% ee. Subsequent transformation of (R)-1a to (R)-PZQ was achieved in 82% yield. Moreover, eight 1-acylaminomethyl-THIQ derivatives, (R)-1b to (R)-1i, were prepared in 44–99% isolated yields with 90 to >99% ee through a LJY-FM-catalyzed deracemization process. To the best of our knowledge, our work represents the first application of monoamine oxidase to the synthesis of (R)-PZQ or its synthetic intermediates. We expect the efficient, stereoselective, and sustainable synthesis of (R)-PZQ established in the current study to be harnessed for the eventual development of a cost-effective, green production route of this antischistosomal agent, thereby leading to the realization of replacing the clinical use of praziquantel by (R)-praziquantel in the future.

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Two approaches for the synthesis of levo-praziquantel

Abstract: Two pathways for the preparation of levo-praziquantel are herein reported, which involves mechanochemical (asymmetric) aza-Henry/acylation reaction, hydrogenation reaction, (chiral resolution) and solvent-free acylation-ring closing reaction.

Cited by 15 publications

References 57 publications

Sustainable Mechanosynthesis of Biologically Active Molecules

Sustainable Mechanosynthesis of Biologically Active Molecules

Mechanochemical C−X/C−H Functionalization: An Alternative Strategic Access to Pharmaceuticals

Engineered Monoamine Oxidase-Catalyzed Deracemization of Sterically Hindered Acylaminomethyl-tetrahydroisoquinoline: Asymmetric Synthesis of (R)-(−)-Praziquantel and Its Analogues

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