Synthesis Optimization, Scale-Up, and Catalyst Screening Efforts toward the MGAT2 Clinical Candidate, BMS-963272

Kempson, James; Hou, Xiaoping; Li, Jianqing; Simmons, Eric M.; Meng, Wei; Hangeland, Jon J.; Devasthale, Pratik

doi:10.1021/acs.oprd.2c00036

Cited by 4 publications

(2 citation statements)

References 17 publications

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“…The asymmetric transfer hydrogenation (ATH) reaction is a potential solution to meet the regio-and stereoselectivity challenge in the synthesis of compound 1 since the reactivity of two carbonyl functional groups adjacent to pyridine would be different under special catalytic reaction conditions. In this study, the process optimization of the reaction, [14][15][16][17][18][19][20][21] including the screening of catalysts, solvents, bases, and hydrogen sources, was performed. When CAT05 was used as a catalyst, dichloromethane as a solvent, diisopropylethylamine as a base, and formic acid (HCOOH) as a hydrogen source, the process gave compound 1 with an overall yield of 92.1%, a high purity of more than 99.8%, and an ee value of 99.9%.…”

Section: Introductionmentioning

confidence: 99%

Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist

Luo,

Sun,

Wang

et al. 2024

Pharmaceutical Fronts

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Rimegepant is a calcitonin gene-related peptide antagonist used for acute treatment and prevention of migraine. We herein attempt to explore an efficient and practiced method for scale-up, regio- and enantioselective synthesis of (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1), a key intermediate of rimegepant. In this work, a Ru-catalyzed asymmetric transfer hydrogenation (ATH) reaction was a key step. The optimization of the reaction conditions involved exploring the reaction parameters including catalysts, bases, and solvents. The results suggested that the Ru-catalyzed ATH process using formic acid as the hydrogen donor could be operated under mild conditions at a low catalyst loading (0.5 mol%), affording a high yield (92.1% yield with 99.8% purity) and gratifying enantioselectivity (99.9% ee) of the target product (1). This work first reported the Ru-catalyzed ATH process in the synthesis of key intermediates of rimegepant. The optimized ATH process was easy to implement and cost-effective, making it particularly suitable for manufacturing scale production.

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Section: Introductionmentioning

confidence: 99%

Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist

Luo,

Sun,

Wang

et al. 2024

Pharmaceutical Fronts

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“…Multi-substituted dihydropyridinones are privileged frameworks, found in many biologically active natural compounds [1,2] and are included in the structures of a number of synthetic molecules with therapeutic properties [3][4][5]. Moreover, they can be easily converted into highly valuable derivatives [6] and employed as precursors in the synthesis of natural molecules with biological activity [7].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 3,4-Dihydropyridin-2-ones via Domino Reaction under Phase Transfer Catalysis Conditions

2023

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3,4-dihydropyridin-2-ones are of considerable importance due to the large number of these core structures exhibiting a diverse array of biological and pharmacological activities. The Michael-type addition of 1,3-dithiane-2-carbothioates to α,β-unsaturated N-tosyl imines, followed by intramolecular annulation driven by a sulfur leaving group, provides a practical reaction cascade for the synthesis of a variety of substituted 3,4-dihydropyridin-2-ones. In this work, the reaction was carried out under solid–liquid phase transfer catalysis (SL-PTC) conditions at room temperature, in short reaction times in the presence of cheap Bu4N+HSO4– and solid KOH. The new PTC method exhibited adequate functional group tolerance, proving to be a green and reliable method and easy to scale up to furnish rapid access to 3,4-dihydropyridin-2-ones after desulfurization from simple, readily available starting materials.

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Synthesis of Chiral 1,1,1-Trifluoro-α,α-disubstituted 2,4-Diketones via Palladium-Catalyzed Asymmetric Allylation

Chen

Ding

et al. 2023

Org. Lett.

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Trifluoromethyl ketones are important enzyme inhibitors and versatile synthons for the preparation of trifluoromethylated heterocycles and complex molecules. An efficient methodology for the synthesis of chiral 1,1,1trifluoro-α,α-disubstituted 2,4-diketones via palladium-catalyzed allylation with allyl methyl carbonates under mild conditions has been developed. This method surmounts the major obstacle of detrifluoroacetylation, and a chiral trifluoromethyl ketone library could be rapidly built up from simple substrates in good yields and enantioselectivities, thereby offering a new choice for scientists in pharmaceutical and material industries.

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Synthesis Optimization, Scale-Up, and Catalyst Screening Efforts toward the MGAT2 Clinical Candidate, BMS-963272

Cited by 4 publications

References 17 publications

Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist

Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist

Synthesis of 3,4-Dihydropyridin-2-ones via Domino Reaction under Phase Transfer Catalysis Conditions

Synthesis of Chiral 1,1,1-Trifluoro-α,α-disubstituted 2,4-Diketones via Palladium-Catalyzed Asymmetric Allylation

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