Strategies in API Scale Up - Pharmaceutical Technology

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Strategies in API Scale Up
Process chemists employ a variety of approaches to improve yield, purity, and stereoselectivity.


Pharmaceutical Technology
Volume 37, Issue 1, pp. 52-54

All-carbon quaternary stereogenic centers in acyclic systems. A team of researchers led by Ilan Marek, professor at the Technion–Israel Institute of Technology in Haifa, described their work in forming all-carbon quaternary stereogenic centers in acyclic systems from alkynes (3). Construction of chiral all-carbon quaternary centers had been limited in previous aldol-based methodologies, according to a Nov. 28, 2012, Technion–Israel Institute of Technology press release. The researchers used a single-pot operation, starting from classical hydrocarbons, to form aldol products containing the desired all-carbon quaternary stereocenter through the concomitant formation of three new bonds, according to the release. A challenge in forming the all-carbon quaternary stereocenters in acyclic systems had been the preparation of all-carbon quaternary stereocenters in aldol adducts (3). The main problem that limits the formation of these stereocenters is the absence of an efficient method of preparing stereodefined trisubstituted enolates in acyclic systems. The researchers developed a different approach that involves the formation of two new stereogenic centers, including the all-carbon quaternary one, through a combined carbometalation–oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate (3). The researchers used this method to generate a series of aldol and Mannich products from ynamides. For his work in organic synthesis, Marek received the Royal Society Chemistry Organometallic Award in 2011 and the Janssen Pharmaceutica Prize for Creativity in Organic Synthesis in 2012.

Asymmetric carbon–hydrogen functionalization. Researchers at the Ecole Polytechnic Fédérale de Lausanne, School of Basic Sciences, Institute of Chemical Sciences and Engineering, Laboratory of Asymmetric Catalysis and Synthesis, in Lausanne, Switzerland, recently reported on the development of chiral cyclopentadienyl ligands as stereocontrolling elements in asymmetric carbon–hydrogen functionalization. The researchers sought to tackle a limitation in the application of metal complexes coordinated by a single cyclopentadienyl ligand as a catalyst in asymmetric reactions (4). The difficulty, they reported, has been designing cyclopentadienyl substituents that bias the coordination sphere. The researchers developed a class of C2-symmetric cyclopentadienyl derivatives that control the spatial arrangement of the transiently coordinated reactants around the central metal atom by developing rhodium (III) complexes with these ligands as highly enantioselective catalysts for directed carbon–hydrogen bond functionalizations of hydroxamic acid derivatives (4).

Scale-up of artemisinin

A cost-effective, large-scale synthesis for the natural product artemisinin, an antimalarial treatment, has been elusive, but researchers at the Indiana University (IU) developed a new approach that is moving toward that goal. The World Health Organization has set a target-per-gram cost for artemisinin of 25 cents or less, but the current cost is about $2.40 per gram, according to a Sept. 12, 2012, IU press release. "In 2005, the WHO claimed that the structure of artemisinin was too complex for cost-effective synthesis," said IU Bloomington College of Arts and Sciences chemistry professor Silas Cook, in the IU release.

Silas and other IU researchers' cost-effective approach to artemisinin uses cyclohexenone as a key starting material and basis for developing reaction cascades in producing artemisinin in a five-pot sequence on a gram
scale (5). "The key to the ultimate success of synthetic artemisinin will be the large-scale production of the drug," Cook said in the IU release. "As such, we had to completely rethink what qualified as suitable starting materials for this synthesis and invent new chemistry." The next challenge will be to move from gram-scale to kilogram-scale production.


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