Carry Over of Impurities: A Detailed Exemplification for Glycopyrrolate (NVA237)

Allmendinger, Thomas; Bixel, Dominique; Clarke, Adrian; Geronimo, Laura Di; Fredy, Jean-Wilfried; Manz, Marco; Gavioli, Elena; Wicky, Regine; Schneider, M.; Stauffert, Fabien J.; Tibi, Markus; Valentekovic, Darko

doi:10.1021/op3001788

Cited by 10 publications

(5 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The α-ketoacid is a readily available synthetic building block to prepare lactates by nucleophilic additions with alkyllithiums or Grignard reagents . However, these reactions are susceptible to air and moisture, and the strong nucleophilicity of these reagents unavoidably result in undesirable side reactions . To this end, the new synthetic approaches to lactates, especially from different mechanistic manifolds, are in high demand.…”

mentioning

confidence: 99%

Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation

Xie

Huang

et al. 2019

J. Am. Chem. Soc.

View full text Add to dashboard Cite

The intermolecular radical addition to the carbonyl group is difficult due to the facile fragmentation of the resulting alkoxyl radical. To date, the intermolecular radical addition to ketones, a valuable approach to construct quaternary carbon centers, remains a formidable synthetic challenge. Here, we report the first visible-lightinduced intermolecular alkyl boronic acid addition to αketoacids enabled by the Lewis acid activation. The in situ boron complex formation is confirmed by various spectroscopic measurements and mechanistic probing experiments, which facilitates various alkyl boronic acid addition to the carbonyl group and prevents the cleavage of the newly formed C−C bond. Diversely substituted lactates can be synthesized from readily available alkyl boronic acids and ketoacids at room temperature merely under visible light irradiation, without any additional reagent. This boron activation approach can be extended to alkyl dihydropyridines as radical precursors with external boron reagents for primary, secondary, and tertiary alkyl radical additions. The pharmaceutically useful anticholinergic precursors are easily scaled up in multigrams under metal-free conditions in flow reactors.T he carbonyl group is a readily available building block for the synthesis of substituted alcohols. 1 While the nucleophilic addition to the carbonyl group is favorable and widely studied, the radical addition to the carbonyl group is difficult, as the resulting alkoxyl radical undergoes βfragmentation readily to reverse the reaction, especially for the radical addition to ketones (Scheme 1a). 2 To date, the intermolecular radical addition to ketones, 3,4 which is valuable to construct quaternary carbon centers, 5 remains a formidable synthetic challenge. Lactates are important biological metabolites, which are precursors of poly-α-hydroxy acids for targeted drug delivery, 6 and include many prescription drugs such as anticholinergic Oxybutynin and Glycopyrrolate (see Scheme 3b for structures). 7 The α-ketoacid is a readily available synthetic building block to prepare lactates by nucleophilic additions with alkyllithiums or Grignard reagents. 8 However, these reactions are susceptible to air and moisture, and the strong nucleophilicity of these reagents unavoidably result in undesirable side reactions. 9 To this end, the new synthetic approaches to lactates, especially from different mechanistic manifolds, are in high demand.Ketoacids currently undergo decarboxylative acyl radical formations in radical reactions, and their engagement as the radical acceptors remains unknown (Scheme 1b). 10 Organoborons are environmentally friendly and readily available, and are stable synthetic building blocks with Lewis acidity. 11 In this communication, we report the first alkyl boronic acids radical addition to ketoacids with the Lewis acid activation from organoborons, which can be extended to alkyl dihydropyridine radical addition to ketoacids in the presence of external boron reagents (Scheme 1c).

show abstract

mentioning

confidence: 99%

Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation

Xie

Huang

et al. 2019

J. Am. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…A key component of data submission to a regulatory organization is the tracking of impurities in a reaction. The tracking process can be calculated using the carryover of the impurity (or impurities) from one stage to another to improve the drug quality and account for all of the impurities . Each synthetic step can produce multiple impurities carried over from the previous synthetic step.…”

Section: Carryover Of Impuritymentioning

confidence: 99%

Consolidating and Managing Data for Drug Development within a Pharmaceutical Laboratory: Comparing the Mapping and Reporting Tools from Software Applications

Moser

Waked

DiMartino

2021

Org. Process Res. Dev.

View full text Add to dashboard Cite

We present a perspective on drug development for the synthesis of an active pharmaceutical ingredient (e.g., agomelatine) within a commercial technology called Luminata and compare the results to the current method of consolidating the reaction data into Microsoft Excel. The Excel document becomes the ultimate repository of information extracted from multiple sources such as the electronic lab notebook, the laboratory information management system, the chromatography data system, in-house databases, and external data. The major needs of a pharmaceutical company are tracking the stages of multiple reactions, calculating the impurity carryover across the stages, and performing structure dereplication for an unknown impurity. As there is no standardized software available to link the different needs throughout the life cycle of process development, there is a demand for mapping tools to consolidate the route for an API synthesis and link it with analytical data while reducing transcription errors and maintaining an audit trail.

show abstract

“…The goal of the study was therefore to investigate the fate of this epimer and potential artemisinin impurity along the chemical transformation to artemether ( 2 ) and to evaluate if a higher specification limit can be proposed for this isomer in the starting material. Similar carry‐over studies are especially important in the context of drug purity, justification of specifications and ultimately of patient safety [6] …”

Section: Introductionmentioning

confidence: 99%

“…Similar carry-over studies are especially important in the context of drug purity, justification of specifications and ultimately of patient safety. [6]…”

Section: Introductionmentioning

confidence: 99%

9‐epi‐Artemisinin – How a Single Stereo Center Affects Chemical Reactivity under Reductive Conditions

Anokwah

Furet

Denay

et al. 2022

Helvetica Chimica Acta

Self Cite

View full text Add to dashboard Cite

Artemisinin occurs as a minor by-product when artemisinin is obtained from natural or semi-synthetic sources. The preparation of β-artemether from artemisinin by reduction with sodium borohydride proceeds normally even when the 9-epimer is present. However, the 9-epimer undergoes rearrangement to peroxy acetals. The results are ascribed to the different stabilities of the corresponding dihydro-intermediates due to steric hindrance as suggested by quantum mechanical calculations.

show abstract

Carry Over of Impurities: A Detailed Exemplification for Glycopyrrolate (NVA237)

Cited by 10 publications

References 59 publications

Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation

Intermolecular Radical Addition to Ketoacids Enabled by Boron Activation

Consolidating and Managing Data for Drug Development within a Pharmaceutical Laboratory: Comparing the Mapping and Reporting Tools from Software Applications

9‐epi‐Artemisinin – How a Single Stereo Center Affects Chemical Reactivity under Reductive Conditions

Contact Info

Product

Resources

About