Synthesis of [3H] and [2H6]AZD6642, an inhibitor of 5‐lipoxygenase activating protein (FLAP)

Lindelöf, Åsa; Ericsson, Cecilia; Simonsson, Roger; Nilsson, Göran N.; Grönberg, Gunnar; Elmore, Charles S.

doi:10.1002/jlcr.3409

Cited by 6 publications

(1 citation statement)

References 19 publications

(22 reference statements)

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“…Consequently, the tritiated analogues were prepared using a specific iridium phosphine carbene catalyst in the presence of tritium to further understand drug metabolism and pharmacokinetic properties (Scheme 153). 402 Dopamine receptors, especially those in the D2 family, play a significant role in a variety of disorders involving the central nervous system including Parkinson's disease (PD), restless leg syndrome (RLS), Huntington's chorea, multiple system atrophy (MSA), and so on. As an example, for small molecules which bind with high affinity to these receptors, Subburaju and coworkers developed tritium incorporated MCL-536 which helps to quantify D2 high sites in schizophrenia and PD patients in vivo (Scheme 154).…”

Section: Drug Developmentmentioning

confidence: 99%

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

et al. 2022

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Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017−2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.

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Section: Drug Developmentmentioning

confidence: 99%

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

et al. 2022

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Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange

Kerr

Knox

Paterson

2020

Labelled Comp Radiopharmac

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The initial discovery and establishment of a family of novel iridium catalysts possessing N-heterocyclic carbene units alongside bulky phosphine ligands allowed selected substrates to be labelled using deuterium or tritium gas at desirably low catalyst loadings via an ortho-directed C-H insertion process.Such a method has broad applicability and offers distinct advantages within the pharmaceutical industry, directly facilitating the ability to carefully monitor a potential drug molecule's biological fate. Over the past decade since these initial protocols were divulged, many additional advances have been made in terms of catalyst design and substrate scope. This review describes the broadened array of new iridium catalysts and associated protocols for direct and selective C-H activation and hydrogen isotope insertion within a number of new chemical entities of direct relevance to the pharmaceutical industry.

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Iridium complexes with monodentate N-heterocyclic carbene ligands

Sipos

Dorta

2018

Coordination Chemistry Reviews

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the stoichiometry, both [(IMes)Ir(COE)(N 2)Cl] and [(IMes) 2 Ir(COE)Cl] (198 in Scheme 75) were successfully isolated. 44 Finally, as Scheme 20 in Section 4.4 shows, a series of stable (NHC) 2 Ir(COE)Cl complexes were isolated either by the free carbene or the silver transmetallation method. Scheme 7. The synthesis of half-sandwich NHC-Ir(III) 24. The most commonly used precursor for the synthesis of NHC-Ir(III) complexes is [Cp*IrCl 2 ] 2. In 2000, Herrmann showed that treatment of [Cp*IrCl 2 ] 2 with 1 equivalent of ICy per iridium yielded 24 in an excellent 90% yield (Scheme 7). 45 Termaten et al. employed the same procedure for the synthesis of (IiPr Me)Ir(Cp*)Cl 2 (26a in Scheme 8). 15 An alternative synthetic route to access free NHCs was described in 1993 by Kuhn and Kratz, who prepared free carbenes via the reduction of thiones 25 by metallic potassium in THF (Scheme 8). 46 Using this method, Yamaguchi and coworkers prepared 26a-c by cannulating the solution of the in situ generated NHCs to a solution of [Cp*IrCl 2 ] 2 in THF (Scheme 8). 47 Scheme 8. Synthesis of NHC-Ir(III) from free carbenes. 4.2. Alkoxy metal precursors and base-assisted one-pot methods It was Köcher and Herrmann who first developed a one pot procedure in which [Ir(COD)(µ-OEt)] 2 was prepared in situ by reacting [Ir(COD)Cl] 2 with four equivalents of NaOEt. Subsequently, four equivalents of 1,3-bis(diphenylmethyl)imidazolium bromide were added and the air and moisture stable 27 was isolated two days later (Scheme 9). 48 Interestingly, despite the fact that a large excess of the NHC salt was employed, formation of a cationic biscarbene complex was not observed. Scheme 9. NHC-Ir complex synthesis from an in situ generated metal-alkoxide. The procedure starting with the alkoxy metal precursor gave bis-NHC substituted complexes (28) when sterically less demanding NHC salts were applied (Scheme 10). Notably, even a 2.2:1 ratio of NHC:Ir was sufficient to isolate 28a-c in good yields (67-86%). Iridium and rhodium bis-NHC complexes with chelating N-N bridged NHCs were prepared in the same way. 39 Scheme 10. Cationic biscarbene complexes. Recently, Savka and Plenio described a one-step synthesis to access (NHC)M(COD)Cl (M = Rh, Ir) as well as (NHC)M(CO) 2 Cl complexes by employing a relatively weak base (K 2 CO 3) in acetone under air (Scheme 11). 49 Scheme 11. One pot synthesis of (NHC)Ir(COD)Cl and (NHC)Ir(CO) 2 Cl complexes. 4.3. The silver transmetallation method Scheme 12. The silver transmetallation method. The silver transmetallation method for the synthesis of NHC-iridium complexes was first published by Crabtree and coworkers. 50 The NHC-silver adducts (29) were generated in excellent yields by modifying the original procedure of Wang and Lin. 51 Subsequent treatment of [Ir(COD)Cl] 2 at room temperature gave 30a and 30b in 81 and 68% yield, respectively (Scheme 12). X-ray analysis of the yellow crystals of 30a revealed square planar geometry around the iridium center. Complexes 30 smoothly reacted with CO to form bis-carbonyl compound...

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Synthesis of [³H] and [²H₆]AZD6642, an inhibitor of 5‐lipoxygenase activating protein (FLAP)

Cited by 6 publications

References 19 publications

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Recent advances in iridium(I) catalysis towards directed hydrogen isotope exchange

Iridium complexes with monodentate N-heterocyclic carbene ligands

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