Large‐Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals

Magano, Javier

doi:10.1002/9783527658909.ch22

Cited by 27 publications

(15 citation statements)

References 122 publications

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“…Therefore, process chemists must develop a specific and highly efficient palladium-scavenging protocol for each API to meet the safety regulation. This is accomplished through screenings of dozens of potential workup protocols and scavengers, among other purification techniques. − This process generates several dozens of samples in which to quantify palladium. Meanwhile, new scavengers continue to emerge, ,− adding options to explore.…”

Section: Introductionmentioning

confidence: 99%

Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence

Lukomski

Pohorilets

Koide

2019

Org. Process Res. Dev.

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Chemists frequently encounter problems associated with trace palladium in synthetic samples because palladium is widely used in synthetic organic chemistry. We previously reported a colorimetric method for trace palladium quantification, the only high-throughput method implemented in the pharmaceutical industry. However, slight changes from the published reaction conditions have caused reproducibility problems, with little understanding of underlying molecular mechanisms. In the current study, we took a combinatorial approach to investigate the method and found that excess NaOH was a culprit for the lack of reproducibility. We changed the reaction conditions and procedure accordingly, which substantially improved reproducibility. The reaction under current conditions followed Michaelis–Menten kinetics, allowing for predicting reaction rates on the basis of the substrate concentrations. The current method showed 57 and 72% average error, respectively, when drugs spiked with known amounts of palladium and synthetic samples with unknown amounts of palladium were analyzed. The trend of palladium concentrations determined by the current method boded well with actual palladium concentrations.

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Section: Introductionmentioning

confidence: 99%

Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence

Lukomski

Pohorilets

Koide

2019

Org. Process Res. Dev.

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“…Other metal-catalyzed coupling reactions have also become increasingly utilized to make advanced intermediates or final products . Since the coupling conditions can tolerate a high degree of complexity, the metal-catalyzed reaction is often positioned late in the synthetic scheme, thus restricting opportunities for impurity rejection . Because of the high enantioselectivity achieved, homogeneous catalytic hydrogenation has become a chosen method for preparing enantiopure intermediates on a large scale.…”

Section: Introductionmentioning

confidence: 99%

Dithiocarbamates: Reagents for the Removal of Transition Metals from Organic Reaction Media

Gallagher

2014

Org. Process Res. Dev.

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Dithiocarbamates (DTCs) are ligands known to chelate with Cu and other transition metals to form insoluble complexes. Wastewater treatment protocols have utilized DTCs to remove trace (ppb) metals from waste streams. We have extended the applicability of DTCs to a protocol that readily enables control of the residual Cu in isolated material in a quick and cost-effective manner. Formation of the chelate complex typically results in purging of Cu and a variety of other metals in an array of reaction media to ≤10 ppm. Furthermore, the simplicity of the method makes it very attractive for large-scale applications late in a synthetic sequence because of the low toxicity and efficient removal of the metal complex by filtration.

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“…A transition‐metal free synthesis would be particularly intriguing in terms of eliminating a tedious purification process in the complex molecule synthesis, especially for those intermediates or the final product that are in an oil form and not purifiable via recrystallization. [ 20 ] A lithium‐naphthalene system [ 21 ] was adopted for debenzylation in presence of the silyl group. To our surprise, a silyl‐migrated product 19 (60% yield) caused contamination during the process.…”

Section: Resultsmentioning

confidence: 99%

A Modular Synthesis of Antitumor Macrolide (–)‐Lasonolide A^†

et al. 2020

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Summary of main observation and conclusion Lasonolide A was identified as a potent antitumor macrolide towards various cancer cell lines. The two tetrahydropyrans bearing multiple stereogenic centers as well as the polyene linkage attracted a dozen synthetic research groups to launch the total synthesis. Based on the synthetic methods developed in our group, namely, the hydroboration of allene and its subsequent allylation as well as the iterative hydroboration of allene and oxidation, the polyol subunits were efficiently constructed and then integrated into the final target. A new Julia olefination reagent, double‐headed sulfone, was designed to promote the rapid coupling of two aldehydes bearing multiple functional groups to secure the whole carbon framework. Another highlight of our approach is the application of a traceless protecting group, 9‐BBN (9‐borabicyclo[3.3.1]nonane), to hide the secondary alcohol for debenzylation, and for the first time, to mask the carboxylic acid for Julia olefination under strong basic conditions.

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Large‐Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals

Cited by 27 publications

References 122 publications

Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence

Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence

Dithiocarbamates: Reagents for the Removal of Transition Metals from Organic Reaction Media

A Modular Synthesis of Antitumor Macrolide (–)‐Lasonolide A^†

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Large‐Scale Applications of Transition Metal Removal Techniques in the Manufacture of Pharmaceuticals

Cited by 27 publications

References 122 publications

Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence

Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence

Dithiocarbamates: Reagents for the Removal of Transition Metals from Organic Reaction Media

A Modular Synthesis of Antitumor Macrolide (–)‐Lasonolide A†

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A Modular Synthesis of Antitumor Macrolide (–)‐Lasonolide A^†