Facile and practical synthesis of a cannabinoid-1 antagonist via regio- and stereoselective ring-opening of an aziridinium ion

Villhauer, Edwin B.; Shieh, Wen‐Chung; Du, Zhengming; Vargas, Kevin; Ciszewski, Lech; Lu, Yansong; Girgis, Michael; Lin, Melissa; Prashad, Mahavir

doi:10.1016/j.tet.2009.09.054

Cited by 9 publications

(6 citation statements)

References 21 publications

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“…• General remarks: DMTMM has received little attention from process chemists, and only one example on scale was found in the literature. 133 Unlike CDMT, which may require acid preactivation to minimize coupling of the amine with the activator, DMTMM-mediated amide bond formation does not require acid preactivation and can be carried out in an all-in fashion. As for CDMT, the byproduct 1,3-dimethoxy-5-hydroxytriazine is watersoluble and easily purged during workup via acidic/ basic washes.…”

Section: O-[(cyano)(ethoxycarbonyl)methyleneamino]-nnn′n′-tetramethyl...mentioning

confidence: 99%

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Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Magano

2022

Org. Process Res. Dev.

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This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients.

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Section: O-[(cyano)(ethoxycarbonyl)methyleneamino]-nnn′n′-tetramethyl...mentioning

confidence: 99%

“…The only example of the use of DMTMM for amide bond formation was reported by Novartis in the USA, who used it for the preparation of cannabinoid-1 antagonist candidate 361 for the treatment of obesity and diabetes (Scheme 125). 133 Highlights of the amidation step leading to amide intermediate 360 are as follows:…”

Section: Ecf Case Studiesmentioning

confidence: 99%

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Magano

2022

Org. Process Res. Dev.

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“…This straightforward methodology would avoid the synthesis of isolated DMT-Ams(X), reduce production complexity, and solvent use and allow to achieve a library of dehydro-condensation agents, modulated according to specific requirements. Nowadays, a few data are available on dehydro-condensation reactions carried out with similar protocols [ 43 , 45 ] and often referring to very specific substrates in rather limited reaction conditions [ 46 , 47 , 48 , 49 , 50 ]. Only recently, Kitamura [ 34 ] and Kunishima [ 35 ] reported a similar protocol for amide condensation reactions, albeit in the presence of amido- or imido-chlorotriazines.…”

Section: Introductionmentioning

confidence: 99%

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

et al. 2021

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Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as promising dehydro-condensation agents for amide synthesis, although suffering of limited stability and high costs. In the present work, a simple protocol for the synthesis of amides mediated by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tert-amine has been described and data are compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X: Cl− or ClO4−). Different tert-amines (Ams) were tested for the synthesis of various DMT-Ams(Cl), but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all CDMT/tert-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best reaction conditions, CDMT and 1,4-dimethylpiperazine gave N-phenethyl benzamide in 93% yield in 15 min, with up to half the amount of tert-amine consumption. The efficiency of CDMT/tert-amine was further compared to more stable triazine quaternary ammonium salts having a perchlorate counter anion (DMT-Ams(ClO4)). Overall CDMT/tert-amine systems appear to be a viable and more economical alternative to most dehydro-condensation agents employed today.

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“…According to Table S5, the AMP x -promoted reactions have PMI RRC values ranging from about 3–10. The PMI RRC of the AMP im1 reaction is 3.5, which is similar to those using EDC (3.2), (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 2.2), and COMU (3.7) but lower than that using pivaloyl chloride (PV, 11.4) (Scheme B). Considering that the AMP x coupling reactions require only a single reagent, it is simpler to set up compared to those requiring multiple reagents.…”

Section: Resultsmentioning

confidence: 53%

2-Azaaryl-1-methylpyridinium Halides: Aqueous-Soluble Activating Reagents for Efficient Amide Coupling in Water

Nguyen

Tran

Taylor

et al. 2022

ACS Sustainable Chem. Eng.

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In this work, a class of 2-azaaryl-1-methylpyridinium (AMP x ) reagents capable of promoting amidation processes in 100% water is reported. The process mass intensity of the AMP x -promoted reactions is similar to or lower than that of reactions using conventional coupling reagents, which suggests that the former has potential as a green amide synthesis method. It was found that the N-methylimidazole-based AMP im1 could be used to couple a wide range of carboxylic acids with amines, including natural amino acids to form peptide bonds. Tandem oxidation–amidation and reduction–amidation reactions in the presence of AMP im1 were achieved with up to moderate efficiency. It is proposed that the azaarene in AMP x plays multiple roles in the amide bond forming process, including as a leaving group, activator, and base.

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Facile and practical synthesis of a cannabinoid-1 antagonist via regio- and stereoselective ring-opening of an aziridinium ion

Cited by 9 publications

References 21 publications

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis

2-Azaaryl-1-methylpyridinium Halides: Aqueous-Soluble Activating Reagents for Efficient Amide Coupling in Water

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