Selected Applications of Transition Metal‐Catalyzed Carbon–Carbon Cross‐Coupling Reactions in the Pharmaceutical Industry

Shen, Hong C.

doi:10.1002/9781118309872.ch2

Cited by 31 publications

(14 citation statements)

References 355 publications

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“…The advantages of micellar reaction conditions were further highlighted by comparing the transformation of 2-bromoiodobenzene ( Table 5, Entry 1, magnetic stirring, 80 %) with an analogous reaction in THF without the aqueous solution of TPGS-750-M, affording a markedly reduced conversion ( Table 5, Entry 2, 40 %). 1 Moreover, the use of micellar reaction conditions provided an improved impurity profile and a suitable mass transfer ideal for scale-up of the process.…”

Section: Resultsmentioning

confidence: 99%

A General Protocol for Robust Sonogashira Reactions in Micellar Medium

Jakobi

Gallou

Sparr

et al. 2019

Helvetica Chimica Acta

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A robust and general protocol for a sustainable copper‐free Sonogashira cross coupling under micellar aqueous reaction conditions with high turnover was developed. By using the commercially available catalyst CataCXium A Pd G3 and THF as co‐solvent, various alkyne substrates were efficiently cross‐coupled with a broad range of aryl halides, providing improved yields and low catalyst loadings. The reaction parameters were optimized to render the process operationally simple, robust and scalable. The method gives access to alkynylated arenes, heterocyclic compounds, and monofunctionalized products from dihalogenated substrates with an improved selectivity achieved by the micellar aqueous reaction conditions.

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Section: Resultsmentioning

confidence: 99%

A General Protocol for Robust Sonogashira Reactions in Micellar Medium

Jakobi

Gallou

Sparr

et al. 2019

Helvetica Chimica Acta

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“…One of the objectives in organic synthesis is the production of complex polyfunctional bioactive drug molecules with high purity. In recent years, the usage of catalysts based on rare earth metals is common for the synthesis of active pharmaceutical ingredients (API) in the pharmaceutical industry. − One such process that is finding more and more applications in the synthesis of biologically active compounds is olefin metathesis. − It enables the formation of new C–C double bonds and relies mainly on the complexes of two transition metals, ruthenium and molybdenum. − The development of modern catalysts, especially Grubbs and Hoveyda–Grubbs second-generation Ru-complexes (Figure ), as well as their polar analogues that are easier to be separated after the reaction (like StickyCat PF 6 , Figure ), has significantly facilitated the synthesis of even complex organic compounds and enabled a substantial reduction of the catalyst loading . Nevertheless, the reliance on heavy metals for organic synthesis potentially leads to metal contamination because traditional purification methods like column chromatography and recrystallization is inefficient in purifying complex polyfunctional chemical substances such as APIs in downstream processes .…”

Section: Introductionmentioning

confidence: 99%

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest

Toh

Patrzałek

Nienałtowski

et al. 2021

ACS Sustainable Chem. Eng.

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In recent years, the development of continuous-flow reactors has attracted growing attention from the synthetic community. Moreover, findings in the precise control of the reaction parameters and improved mass/heat transfer have made the flow setup an attractive alternative to batch reactors, both in academia and industry, enabling safe and easy scaling-up of synthetic processes. Even though a majority of the pharmaceutical industry currently rely on batch reactors or semibatch reactors, many are integrating flow technology because of easier maintenance and lower risks. Herein, we demonstrate an operationally simple flow setup for homogeneous ring-closing metathesis, which is applicable to the synthesis of active pharmaceutical ingredients precursors or analogues with high efficiency, low residence time, and in a green solvent. Furthermore, through the addition of a soluble metal scavenger in the subsequent step within the flow system, the level of ruthenium contamination in the final product can be greatly reduced (to less than 5 ppm). To ensure that this method is applicable for industrial usage, an upscale process including a 24 h continuous-flow reaction for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow fashion by adjusting the tubing size and flow rate accordingly.

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“…Transition metal-catalyzed cross coupling has revolutionized carbon–carbon formation by enabling selective and efficient reactions of organic electrophiles and various nucleophiles . Among these methods, the palladium-catalyzed Suzuki–Miyaura reaction of organic halides electrophiles and organoboron nucleophiles is one of the most commonly applied strategies for C–C bond formation in chemical synthesis. , The safe handling, relative stability, and broad availability of boron-based nucleophiles distinguishes the Suzuki–Miyaura reaction from other cross coupling methods that rely on reactive organolithium, Grignard, or zinc nucleophiles that can be incompatible with functional groups found in late stage intermediates and are dangerous to handle on a large scale .…”

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confidence: 99%

Insight into Transmetalation Enables Cobalt-Catalyzed Suzuki–Miyaura Cross Coupling

2016

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Among the fundamental transformations that comprise a catalytic cycle for cross coupling, transmetalation from the nucleophile to the metal catalyst is perhaps the least understood. Optimizing this elementary step has enabled the first example of a cobalt-catalyzed Suzuki–Miyaura cross coupling between aryl triflate electrophiles and heteroaryl boron nucleophiles. Key to this discovery was the preparation and characterization of a new class of tetrahedral, high-spin bis(phosphino)pyridine cobalt(I) alkoxide and aryloxide complexes, (iPrPNP)CoOR, and optimizing their reactivity with 2-benzofuranylBPin (Pin = pinacolate). Cobalt compounds with small alkoxide substituents such as R = methyl and ethyl underwent swift transmetalation at 23 °C but also proved kinetically unstable toward β–H elimination. Secondary alkoxides such as R = iPr or CH(Ph)Me balanced stability and reactivity. Isolation and structural characterization of the product following transmetalation, (iPrPNP)Co(2-benzofuranyl), established a planar, diamagnetic cobalt(I) complex, demonstrating the high- and low-spin states of cobalt(I) rapidly interconvert during this reaction. The insights from the studies in this elementary step guided selection of appropriate reaction conditions to enable the first examples of cobalt-catalyzed C–C bond formation between neutral boron nucleophiles and aryl triflate electrophiles, and a model for the successful transmetalation reactivity is proposed.

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Selected Applications of Transition Metal‐Catalyzed Carbon–Carbon Cross‐Coupling Reactions in the Pharmaceutical Industry

Cited by 31 publications

References 355 publications

A General Protocol for Robust Sonogashira Reactions in Micellar Medium

A General Protocol for Robust Sonogashira Reactions in Micellar Medium

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest

Insight into Transmetalation Enables Cobalt-Catalyzed Suzuki–Miyaura Cross Coupling

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