In search of sustainability: process R&amp;D in light of current pharmaceutical industry challenges

Federsel, Hans‐Jürgen

doi:10.1016/j.drudis.2006.09.012

Cited by 44 publications

(23 citation statements)

References 60 publications

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“…Unfortunately, we were not able to obtain crystals from this white solid, and therefore it was studied by NMR spectroscopy. The obtained substance was almost completely insoluble in chloroform, and therefore the NMR studies were carried out in MeOH-d 4 . These studies have shown that the complex contained 1a and diethyl tartrate 4 in a 1:1 stoichiometry.…”

Section: Stoichiometric Studies To Detect Reaction Intermediatesmentioning

confidence: 99%

“…[1][2][3] This process is one of the few large-scale asymmetric catalytic applications that satisfies the rigorous selection criteria of atom economy and ecoefficiency required for modern industrial manufacturing processes. [4] Accordingly, the esomeprazole process has become an important source of inspiration and reference point for academic research to develop new efficient asymmetric catalytic methods relevant for the pharmaceutical industry and for the synthesis of specialized chemicals. Optically active sulfoxides, [5][6][7][8][9][10] in general, represent an important class of pharmaceuticals and drug intermediates.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process: Effects of the Imidazole Backbone for the Enantioselection

2009

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Abstract:The asymmetric sulfoxidation reaction of imidazole-based prochiral sulfides was studied to explore the mechanistic details of the highly efficient esomeprazole process, which is one of the few industrial scale catalytic asymmetric procedures. The synthetic studies revealed that the smallest subunit governing the selectivity in the esomeprazole process is an imidazole ring. Thus, by using the esomeprazole procedure methyl imidazole sulfide could be oxidized as efficiently as its several functionalized derivatives, including pyrmetazol. However, alkylation of the imidazole nitrogen led to a major drop of the enantioselectivity. Our atmospheric pressure chemical ionization-mass spectrometry (APCI/MS) studies indicate that addition of small amounts of water to the reaction mixture facilitates the formation of mononuclear titanium species, which are the active catalytic intermediates of the selective oxidation reaction. One of the most important features of the esomeprazole procedure is that amine additives increase the enantioselectivity of the oxidation process. The NMR studies of the presumed reaction intermediates show that under catalytic conditions the amines are able to coordinate to titanium and dissociate the coordinated imidazole substrate. The density functional theory (DFT) modelling studies provided new insights in the mechanism of the asymmetric induction. It was found that the oxidation requires a lower activation energy if the imidazole sulfide precursor does not coordinate to titanium. Two possible reaction paths were explored for this out of sphere oxidation mechanism. The most important interaction governing the enantioselection is hydrogen bonding between the N À H of the imidazole ring and the chiral tartrate ligand on titanium. Furthermore, the oxidation reaction imposes an important structural constraint to the TS structure involving a linear arrangement of the peroxide oxygens and the sulfur atom. This constraint and the N coordination of imidazole leads to a very strained structure for the inner sphere mechanism of the oxidation, which leads to a much higher activation barrier than the corresponding out of sphere process, and therefore it is unlikely.

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Section: Stoichiometric Studies To Detect Reaction Intermediatesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process: Effects of the Imidazole Backbone for the Enantioselection

2009

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“…Each corner of the triangle represents different software tools, which, when linked together, can create a powerful help in route and process design At the Medicinal Chemistry -Process R&D interface the diversity expressed in the form of a multitude of chemical structures being prepared and investigated by the former is matched by an exploration of a variety of syntheses leading to the target molecule by the latter. From both ends it is essential to cover enough space so that important aspects are not left out, but also to narrow down the number of options to enable focusing of efforts [15]. Fig.…”

Section: Process Randd Under the Magnifying Glassmentioning

confidence: 99%

The Integration of Process R&D in Drug Discovery - Challenges and Opportunities

Federsel¹

2006

CCHTS

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In today's situation where a lot of attention is put on the whereabouts of the pharmaceutical industry, especially focusing on productivity, pricing policies, time lines, and competition, there is an increased need for a critical revision of work practices in the business. The prevailing prioritization of time-to-market is now more and more shifting over to also put quality, risk management, and effectiveness/efficiency in the limelight. Resources in terms of people and money will continue to be constrained and, therefore, best collaborative principles have to be adopted between different parts of the organization. Only by operating this way will we maximize the output. One of the most important key performance indicators in pharma R&D is the number of newly appointed candidate drugs (CDs). However, it is not only a matter of counting numbers but, more so, to nominate compounds with the best properties and likelihood to survive. In that vein the demands on Process R&D have gone up considerably over recent years and there is now a pronounced need to make forecasts on cost of goods for the API (active pharmaceutical ingredient), scalability issues, IP matters, route design etc. On top of this, there is as always an expectation that the supply of material needed to conduct the various studies is timely, fully reliable, and flexible, even if volumes and delivery dates fluctuate widely. To successfully be able to cope with this challenging and sometimes stressful situation a back-integration into earlier parts of Drug Discovery is a must and, hence, connecting to new projects will have to be initiated already during the LO-stage (lead optimization). The consequences of this and its further implications will constitute the core part of the paper.

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“…The pharmaceutical industry has to meet various challenges (Federsel 2006), e.g. how to safely handle (Alfonsi et al 2008) or omit (Shearouse et al 2009) solvents.…”

Section: Introductionmentioning

confidence: 99%

Pharmaceuticals in the environment: an educational perspective

Eissen

Backhaus

2011

Environ Sci Pollut Res

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Tasks that were presented to students regarding the topic 'pharmaceuticals in the environment' contributed to a better understanding of the possible risks of medical care on an introductory level. The tasks have been incorporated into a logic series of worksheets (Online Resource) with sample solutions available. Alternatively, the material would be appropriate for the preparation of a corresponding lecture on this topic.

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In search of sustainability: process R&D in light of current pharmaceutical industry challenges

Cited by 44 publications

References 60 publications

Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process: Effects of the Imidazole Backbone for the Enantioselection

Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process: Effects of the Imidazole Backbone for the Enantioselection

The Integration of Process R&D in Drug Discovery - Challenges and Opportunities

Pharmaceuticals in the environment: an educational perspective

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