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Patricia Van Arnum was executive editor of Pharmaceutical Technology.
Approaches in cyclization, palladium-catalyzed cross couplings, fluorination, and natural product synthesis help to optimize routes for select drugs.
Organic chemists face the challenge of making molecules of interest for the pharmaceutical industry. This task may present itself at the medicinal chemistry stage to make initial quantities of a drug under study and continues throughout development to commercial manufacture, where issues of quality, operability, and cost factor into the scale-up of a synthesis. Some recent approaches use a diverse arsenal ranging from cyclization strategies to palladium-catalyzed coupling and other transition-metal catalyzed couplings, to developing a synthetic route for a medicinal natural product.
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Researchers at GlaxoSmithKline (London) recently reported on a synthetic route to an important benzopyran intermediate of a 5HT4 receptor agonist. Agonists for the 5HT4 receptor are being studied for treating certain gastrointestinal disorders. The researchers' challenge was to find a viable route for scaling up manufacturing of the active ingredient to be used as the 5HT4 receptor agonist. The compound under study was 5-amino-6-bromo-chroman-8-carboxylic acid [1-(tetrahydro-pyran-4-ylmethyl)-piperdin-4-ylmethyl]-amide (1).
Patricia Van Arnum
As the researchers reported, 5-amino-6-bromo-chroman-8-carboxylic acid is a key component of 5-amino-6-bromo-chroman-8-carboxylic acid [1-(tetrahydro-pyran-4-ylmethyl)-piperdin-4-ylmethyl]-amide. Although a high-temperature Claisen rearrangement was a successful route for producing 5-amino-6-bromo-chroman-8-carboxylic acid for initial supplies, it was not a successful route for producing the compound on a large scale due to quality and operability issues. The task, therefore, was to come up with alternate routes for producing the benzopyran intermediate. The researchers' approach focused on constructing the benzopyran skeleton using cyclization from various precursors and evaluating the effectiveness and efficiency of the ensuing syntheses (1).
The first approach involved constructing the benzopyran skeleton by the Diels–Alder reaction between a substituted dihydropyran and 3,6-dichloropyridazine or pyrones. Upon further study, however, the researchers found that the high temperature required for the Diels–Alder reaction caused decomposition of the dihydropyran and pyrone substrates investigated in this reaction. Attempts to lower the temperature by using Lewis acids for the cycloaddition were not successful (1).
In another approach, formation of the benzopyran skeleton involved an etherification reaction as the final step. But that route also faced challenges, namely achieving the desired chemoselectivity as both the anilide and the phenolic groups competed for the activated species, thereby giving rise to a mixture of cyclized products. Although the researchers considered double protecting the aniline, the length of this synthesis led the researchers to consider other alternatives (1).
The third approach considered was based on a cyclization strategy in which the sp2 –sp3 carbon-carbon bond in the benzopyran is the key step and is constructed last in the process. In this context, two methods were explored: a metal-catalyzed cycloisomerization and an intramolecular Friedel–Crafts reaction. In the first approach, the researchers developed a gold-catalyzed cycloisomerization of an aryl-propargyl ether. The formation of the pyran ring is regiospecific and proceeds via reaction between the aromatic carbon atom adjacent to the phenolic oxygen atom and the terminal alkyne carbon atom. The second approach was predicated on an intramolecular Friedel–Crafts cyclization of a 3-aryloxy propionic acid substrate followed by reduction of the newly generated carbonyl group. Both of these routes were found to be of similar efficiency and cost and improved upon the initial medicinal chemistry route (1).
Palladium-catalyzed coupling. Palladium-catalyzed cross-coupling, in which the metal is used to catalyze the formation of carbon–carbon bonds, is an important reaction in organic synthesis, particularly for complex molecules such as pharmaceutical compounds. The importance of these reactions was underscored by the awarding of the 2010 Nobel Prize for Chemistry to Richard F. Heck, Professor Emeritus at the University of Delaware in Newark, Ei-ichi Negishi, the Herbert C. Brown Distinguished Professor of Chemistry at Purdue University in West Lafayette, Indiana, and Akira Suzuki, Distinguished Professor Emeritus at Hokkaido University in Sapporo, Japan, for the development of palladium-catalyzed cross coupling.
The Heck reaction is a palladium-catalyzed cross coupling of organyl halides with olefins. The Negishi reaction is a palladium-catalyzed cross coupling of organozinc compounds with organohalides. Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides (2). The legacy of any advance is reflected in how it is applied, and these reactions play an important role in organic synthesis and the development of medicinal compounds.
Christopher W. Jones, a professor of chemical and biomolecular engineering at the Georgia Institute of Technology in Atlanta, was awarded the Ipatieff Prize from Northwest University earlier this year for advancing understanding of the interface between homogeneous and heterogeneous catalysis (3). His work involved elucidating the reaction pathways for palladium-catalyzed carbon–carbon coupling reactions, including Heck and Suzuki coupling reactions, using several Pd(II) pincer complex catalysts. His research showed that these reactions proceed by a Pd(0)–Pd(II) catalytic cycle as opposed to a Pd(II)–Pd(IV) catalytic cycle, which many thought was the case using the purportedly stable Pd(II) pincer complexes. He synthesized Pd(II) pincer complexes supported on solids and used testing based on kinetics, spectroscopy, and catalyst poisoning to show that the reactions proceed via a Pd(0)-Pd(II) catalytic cycle. His research also showed the reactions are mediated by palladium species that are leached from the immobilized (heterogeneous) phase to the solution (homogeneous) phase. From this work, he developed so-called palladium "scavengers" to examine the different roles played by homogeneous and heterogeneous species in these reactions (3–6).
Jones also is part of the Georgia Institute of Technology's Center for Drug Design and Delivery's Pharmaceutical Pipeline Project, which addresses challenges in drug development and manufacturing. The project consists of the three entities within the university: the Drug Design Consortium, the Drug Development Consortium, and the Drug Delivery Consortium. The Drug Development Consortium is involved with improving drug manufacturing. The consortium's work includes using supercritical fluids as a solvent-replacement strategy, crystallization-control methods applied to Crixivan (indinavir), an AIDS drug manufactured by Merck & Co. (Whitehouse Station, NJ), and applying membrane technology for drug isolation. The Drug Design Consortium focuses on the delivery of novel chemical entities and the optimization of existing chemical entities to generate promising therapies. Some projects include the design of histone deacetylase inhibitors, the biosynthetic engineering of natural products to explore structure–function relationships, and natural product research using marine organisms.
Georgia Tech also is the lead institution in the Center for Pharmaceutical Development, a newly established National Science Foundation Industry/ University Cooperative Research Center. The Georgia Tech site in the center focuses on the development of novel and improved biocatalysis for more selective and environmentally benign manufacturing. It also developed an accelerated assay to detect aggregation in therapeutic proteins.
Although useful, palladium-catalyzed coupling can be costly both because of the palladium and the ligand used with the transition metal in the catalyst. Researchers at the Leibniz Institute for Catalysis at the University of Rostock in Germany have addressed that problem by developing a new family of phosphane ligands, which are recyclable, and therefore could help to bring down the cost of certain palladium-catalyzed coupling reactions. Specifically, the researchers developed recyclable imidazolium phosphanes that work effectively in palladium-catalyzed carbon–oxygen, carbon–nitrogen, and carbon–carbon bond-forming reactions. The homogeneous palladium catalyst can be recycled directly from the reaction without any heterogenization (7).
Palladium-catalyzed cross-coupling of aryl halides and amines, known as Buchwald–Hartwig amination, is a key tool for constructing arylamines in organic synthesis. Researchers at Dalhousie University in Halifax, Nova Scotia, recently reported on a new phosphine ligand, which, when combined with palladium, selectively reacts ammonia or hydrazine with a broad range of aryl halides and tosylates, including reactions at room temperature in the case of ammonia (8, 9). The ligand employed in the chemistry, Mor-DalPhos, consists of an adamantyl-substituted phosphorus and a morpholino fragment bridged by a phenylene unit. The reactivity and selectivity of Mor-DalPhos/Pd with ammonia and hydrazine makes it an attractive choice in carbon–nitrogen couplings in which primary anilines and aryl hydrazines are the desired target compounds. Notably, aryl hydrazines are key intermediates in the preparation of nitrogen-containing heterocycles such as indoles, indazoles, and pyrazoles. Before this work by the Stradiotto group, however, the synthesis of aryl hydrazines directly from hydrazine sources had not been reported (8, 9). Strem Chemicals (Newburyport, MA) is marketing the ligand.
Synthesis of natural products . Researchers at the University of California in Berkeley recently reported on the synthesis of the alkaloid complanadine A, a dimer of another natural product called lycodine. The pseudo-symmetry of this molecule adds to the challenge of its synthesis. Medicinally, complanadine A is thought to aid in the production of nerve growth factors, something of interest for regenerative medicine and Alzheimer's disease research. Complanadine A is isolated from club moss, which grows naturally in the wild. However, the difficulty of isolating significant quantities of complanadine A from this natural source has limited further biological research on the molecule. The Berkeley researchers synthesized complanadine A using a common tetracyclic precursor to the two halves of the dimer. A crucial part of the synthesis was developing an iridium-catalyzed carbon–hydrogen functionalization to produce a boronic ester, which was followed by a Suzuki coupling (10, 11).
Silver-catalyzed coupling. Fluorine-based compounds are important building blocks in pharmaceutical synthesis. Researchers led by Tobias Ritter, associate professor in the Department of Biology and Chemistry at Harvard University, recently reported on a new cross-coupling reaction that attached fluorine atoms onto aromatic substituents. The reaction uses silver oxide to catalyze the fluorination of aryl tin compounds with the electrophilic fluorinating reagent
N-chloromethyl-N-fluorotriethylenediammonium hexafluorophosphate. The researchers asserted that the reaction is the first example of silver catalysis being applied for carbon–heteroatom bond formation by cross-coupling chemistry. Carbon-fluorine bond formation by transition-metal catalysis is difficult, and only a few methods for the synthesis of aryl fluorides have been developed, according to the researchers. Typically, transition metal-catalyzed fluorination reactions for synthesizing functionalized arenes use palladium in the catalyst (12).
An advantage of the silver-catalyzed fluorination reaction is its versatility in terms of the variety of functional groups that can be tolerated and the breadth of the substrate scope. The researchers showed that the cross-coupling reaction can be used to fluorinate polypeptides, polyketides, and alkaloids and can be tolerated by various functional groups, including vinyl ethers, dienones, alcohols, allylic alcohols, ethers, esters, and oxetanes (12).
New approaches to fluorination are useful for not only producing fluorinated molecules for use in pharmaceuticals, but such approaches also can be applied in imaging techniques. A long-term goal of the research by Ritter and his team is the development of new methods for the synthesis of small-molecule-tracers for positron emission tomography (PET), an imaging technique to study biological processes in vivo. PET with the isotope 18F is currently limited by the absence of general chemistry that can introduce fluorine into molecules at a late stage. The approach to carbon–fluorine bond formation using high-valent transition metal fluorides via oxidation of aryl transition metal complexes with electrophilic fluorination reagents is one approach to resolve that challenge (12).
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
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