Chiral Drug Discovery and Development – From Concept Stage to Market Launch

Federsel, Hans‐Jürgen

doi:10.1016/b0-08-045044-x/00054-7

Cited by 7 publications

(3 citation statements)

References 98 publications

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“…From a processing point of view, however, the number of isolations that need to be carried out along the route of synthesis is of even higher importance, and therefore, the total number of only four truly isolated stages [ 5 , 11 , 13 , and 1 (excluding the final product AR-A2 × HBr)] gives a clear indication of the excellent efficiency that was achieved. Finally, with a large portion of drug compounds being chiral, efficient methods for their preparation in high enantiomeric purity are essential. , For AR-A2, this meant using ( S )-1-phenylethylamine as a crucial component in the construction work, where the stereogenic center was installed using a diastereoselective hydride reduction protocol running at 96% de.…”

Section: Discussionmentioning

confidence: 99%

Construction of a Chiral Central Nervous System (CNS)-Active Aminotetralin Drug Compound Based on a Synthesis Strategy Using Multitasking Properties of ( S)-1-Phenylethylamine

et al. 2007

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This Account describes the design and development of a scalable synthesis for the drug molecule AR-A2 (1) starting from the discovery route originating in medicinal chemistry. Special emphasis is placed on the introduction of the correct (R) stereochemistry on C2, which was ultimately achieved in a diastereoselective imine-reducing step applying NaBH4. After optimization, this transformation was operated on a large pilot-plant scale (2000 L), offering the desired product (11) in 55% yield and 96% diastereomeric excess at a 100 kg batch size. From a synthesis strategy point of view, the choice of (S)-1-phenylethylamine (9) was crucial not only for its role as a provider of the NH2 functionality and the stereo-directing abilities but also as an excellent protecting group in the subsequent N-arylation reaction, according to the Buchwald-Hartwig protocol. As one of the very first examples in its kind, the latter step was scaled up to pilot manufacturing (125 kg in 2500 L vessel size), delivering an outstanding isolated yield of 95%. This consecutive series of chemical transformations was completed with an environmentally friendly removal of the phenethyl appendage. In addition, an elegant method to synthesize the tetralone substrate 6, as well as a novel and robust procedure to use imidazole as a buffer for the selective formation of the mono-HBr salt of AR-A2, will be briefly described.

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Section: Discussionmentioning

confidence: 99%

Construction of a Chiral Central Nervous System (CNS)-Active Aminotetralin Drug Compound Based on a Synthesis Strategy Using Multitasking Properties of ( S)-1-Phenylethylamine

et al. 2007

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“…A further lesson established by this investigation was the ways in which stereogenic centers were installed in the 54% of the cohort of molecules that displayed chirality (Figure ). Thus, the conclusion is that in a pharmaceutical industry scenario >50% of the cases will rely on supply of the required stereochemically defined building blocks from external sources.…”

Section: Making Molecules: An Expanding Toolboxmentioning

confidence: 99%

Chemical Process Research and Development in the 21st Century: Challenges, Strategies, and Solutions from a Pharmaceutical Industry Perspective

Federsel

2009

Acc. Chem. Res.

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In process research and development (PR&D), the generation and manipulation of small-molecule drugs ranges from bench-scale (laboratory) chemistry to pilot plant manufacture to commercial production. A broad range of disciplines, including process chemistry (organic synthesis), analytical chemistry, process engineering (mass and heat transfer, unit operations), process safety (chemical risk assessment), regulatory compliance, and plant operation, must be effectively applied. In the critical handover between medicinal chemistry and PR&D, compound production is typically scaled up from a few hundred grams to several kilograms. Can the methodologies applied to the former also satisfy the technical, safety, and scalability aspects that come into play in the latter? Occasionally, the transition might occur smoothly, but more often the situation is the opposite: much work and resources must be invested to design a process that is feasible for manufacturing on pilot scale and, eventually, for commercial production. Authentic examples provide enlightening illustrations of dos and don'ts for developing syntheses designed for round-flask operation into production-scale processes. Factors that are easily underestimated or even neglected in the laboratory, such as method robustness, chemical hazards, safety concerns, environmental impact, availability of starting materials and building blocks in bulk quantities, intellectual property (IP) issues, and the final cost of the product, will come into play and need to be addressed appropriately. The decision on which route will be the best for further development is a crucial event and should come into focus early on the R&D timeline. In addition to scientific and technical concerns, the parameter of speed has come to the forefront in the pharmaceutical arena. Although historically the drug industry has tolerated a total time investment of far more than 10 years from idea to market, the current worldwide paradigm requires a reduction to under 10 years for the specific segment covering preclinical development through launch. This change puts enormous pressure on the entire organization, and the implication for PR&D is that the time allowed for conducting route design and scale-up has shrunk accordingly. Furthermore, molecular complexity has become extremely challenging in many instances, and demand steadily grows for process understanding and knowledge generation about low-level byproduct, which often must be controlled even at trace concentrations to meet regulatory specifications (especially in the case of potentially genotoxic impurities). In this Account, we paint a broad picture of the technical challenges the PR&D community is grappling with today, focusing on what measures have been taken over the years to create more efficiency and effectiveness.

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“…Chiral compounds often exhibit considerably different biological activities due to the highly specific nature of the chiral ligand-recognition site interaction [31,32]. The enantiomers, along with the corresponding racemates, require specific biological, pharmacological and toxicological studies before being launched in clinical practice [33].…”

Section: Introductionmentioning

confidence: 99%

Focus on Chirality of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Famiglini

Silvestri

2016

Molecules

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Chiral HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are of great interest since one enantiomer is often more potent than the corresponding counterpart against the HIV-1 wild type (WT) and the HIV-1 drug resistant mutant strains. This review exemplifies the various studies made to investigate the effect of chirality on the antiretroviral activity of top HIV-1 NNRTI compounds, such as nevirapine (NVP), efavirenz (EFV), alkynyl-and alkenylquinazolinone DuPont compounds (DPC), diarylpyrimidine (DAPY), dihydroalkyloxybenzyloxopyrimidine (DABO), phenethylthiazolylthiourea (PETT), indolylarylsulfone (IAS), arylphosphoindole (API) and trifluoromethylated indole (TFMI) The chiral separation, the enantiosynthesis, along with the biological properties of these HIV-1 NNRTIs, are discussed.

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Chiral Drug Discovery and Development – From Concept Stage to Market Launch

Cited by 7 publications

References 98 publications

Construction of a Chiral Central Nervous System (CNS)-Active Aminotetralin Drug Compound Based on a Synthesis Strategy Using Multitasking Properties of ( S)-1-Phenylethylamine

Construction of a Chiral Central Nervous System (CNS)-Active Aminotetralin Drug Compound Based on a Synthesis Strategy Using Multitasking Properties of ( S)-1-Phenylethylamine

Chemical Process Research and Development in the 21st Century: Challenges, Strategies, and Solutions from a Pharmaceutical Industry Perspective

Focus on Chirality of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

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