Advances in Small-Molecule Synthesis

Approaches in cyclization, palladium-catalyzed cross couplings, fluorination, and natural product synthesis help to optimize routes for select drugs.
Dec 02, 2010
Volume 34, Issue 12

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.

Cyclization approaches

Patricia Van Arnum
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).

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).

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