Performance Characteristics of Mass Spectrometry-Based Analytical Procedures for Quantitation of Nitrosamines in Pharmaceuticals: Insights from an Inter-laboratory Study.

With the discovery of carcinogenic nitrosamine impurities in pharmaceuticals in 2018 and subsequent regulatory requirements for risk assessment for nitrosamine formation during pharmaceutical manufacturing processes, storage or from contaminated supply chains, effective testing of nitrosamines has become essential to ensure the quality of drug substances and products. Mass spectrometry has been widely applied to detect and quantify trace amounts of nitrosamines in pharmaceuticals. As part of an effort by regulatory authorities to assess the measurement variation in the determination of nitrosamines, an inter-laboratory study was performed by the laboratories from six regulatory agencies with each of the participants using their own analytical procedures to determine the amounts of nitrosamines in a set of identical samples. The results demonstrated that accurate and precise quantitation of trace level nitrosamines can be achieved across multiple analytical procedures and provided insight into the performance characteristics of mass spectrometry-based analytical procedures in terms of accuracy, repeatability and reproducibility.

Modular total syntheses of the marine-derived resorcylic Acid lactones cochliomycins a and B using a late-stage nozaki-hiyama-kishi macrocyclization reaction.

The natural products cochliomycin A (1) and cochliomycin B (2), two resorcylic acid lactones obtained from marine sources, have been prepared in a concise and stereocontrolled manner from the readily accessible building blocks 4-6. Olefin cross-metathesis, trans-esterification and Nozaki-Hiyama-Kishi (NHK) macrocyclization reactions were employed in the key steps. Hydrolysis of the immediate precursor to cochliomycin B affords the resorcylic acid lactone zeaenol (24).

Synthesis of 2,4,6-trisubstituted pyridines via an olefin cross-metathesis/Heck-cyclisation-elimination sequence.

Heck reactions were performed on α,ß-unsaturated-δ-sulfonamido intermediates, derived from cross metathesis, to allow the instalment of substituents at the ß position. Subsequent one-pot cyclisation/elimination provides an operationally simple, catalytic and convergent synthesis of 2,4,6-trisubstituted pyridines.

Heteroaromatic synthesis via olefin cross-metathesis: entry to polysubstituted pyridines.

The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,ß-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.

1,3-Dipolar cycloaddition-decarboxylation reactions of an azomethine ylide with isatoic anhydrides: formation of novel benzodiazepinones.

A nonstabilized azomethine ylide reacts with a wide range of substituted isatoic anhydrides to afford novel 1,3-benzodiazepin-5-one derivatives, which are generally isolated in high yield. The transformations involve 1,3-dipolar cycloaddition reactions of the ylide with the anhydrides to give transient, and in a representative case spectroscopically observable, oxazolidine intermediates that undergo ring-opening-decarboxylation-ring-closing reaction cascades to yield the 1,3-benzodiazepin-5-one products.

Olefin cross-metathesis-based approaches to furans: procedures for the preparation of di- and trisubstituted variants.

Olefin cross-metathesis (CM)-based protocols enable short, flexible and regiocontrolled access to substituted furan derivatives. Specifically, CM of allylic alcohol and enone components provides γ-hydroxyenone intermediates that are cycloaromatized to the final furan derivatives on exposure to either acid or a discrete Heck arylation step. This latter process concomitantly introduces an extra substituent onto the furan target with complete control of regiochemistry. The methodology described here serves as the basis for developing other CM-based entries to diverse heteroaromatic compounds. This protocol describes in detail the following stages of the furan procedures: (i) the tandem formation and acid-catalyzed cyclization of the γ-hydroxyenone to afford a 2,5-disubstituted furan directly; (ii) CM of an allylic alcohol with an enone to provide an isolated γ-hydroxyenone; and (iii) Heck arylation of this γ-hydroxyenone to afford a 2,3,5-trisubstituted furan. The reaction procedure given for the formation of the 2,5-disubstituted furan (option A) takes ∼26.5 h to complete. The procedure described for the formation of the 2,3,5-trisubstituted furan (option B) takes ∼52.5 h.

Synthesis of substituted pyridines and pyridazines via ring closing metathesis.

RCM can be used to make aromatic heterocycles, namely pyridines and, for the first time, pyridazines; the key step after RCM involves elimination of sulfinate to provide the aromatic system.