Biocatalytic route to atorvastatin

Improving protein purification through high-performance membranes

The synthesis eliminated the use of cyanide or azide moieties to introduce nitrogen because it is already present in the lactol. In contrast to the original synthesis, the DERA enzyme set both stereocenters with high selectivity in water at room temperature. Converting the resulting lactol into isopropyl acetonide atorvastatin (IAA) involved only four high-yield chemical steps (oxidation, esterification, deprotection, Paal Knorr). The IAA product was isolated as a solid, and IAA was converted to atorvastatin (1). The new synthesis eliminated the previous high-pressure hydrogenation step with its associated metal catalysts. It also avoided pyrophoric n-butyl lithium and its associated butane waste gas. FDA approved the new manufacturing process in April 2010, and Pfizer manufactured commercial-scale validation batches in 2011 and is currently transitioning to full-scale commercial manufacture, according to the EPA's Presidential Green Chemistry Challenge Awards report (1).

The Grignard reaction is a well-established reaction in organic chemistry but it poses some challenges in scaling up to commercial scale: strongly exothermic activation and reaction steps; heterogeneous reactions with potential problems suspending and mixing the reaction mixture; and operational hazards posed by ethereal solvents such as diethyl ether (1). Eli Lilly developed safer Grignard chemistry using a continuous stirred tank reactor (CSTR) that allows continuous formation of Grignard reagents with continuous coupling and quenching operations, a process in which the company submitted an entry to the 2012 EPA Presidential Green Chemistry Challenge Awards (1). According to the entry, the CSTR approach mitigated hazards by operating at a small reaction volumes, performed metal activation only once for each campaign, and used 2-methyltetrahydrofuran as a Grignard reagent and reaction solvent, resulting in products with enhanced chemo- and stereoselectivity. Relative to batch processing, the continuous approach allowed steady-state control and overall reductions up to 43% in magnesium, 10% in Grignard reagent stoichiometry, and 30% in process mass intensity (1).

Improved solvents for making diaryl aldimines

Imines are intermediates used in many pharmaceutical syntheses. Diaryl aldimines, for example, are used in the synthesis of the anticancer drug Taxol (paclitaxel) and the anticholesterol drug Zetia (ezetimibe) (1). Traditional syntheses of diaryl aldimines often require hazardous solvents and include energy-intensive, multihour reflux steps. Although some imine syntheses use more benign solvents or conditions, they still require long reaction times, recrystallization, or other environmentally harsher procedures. Jacqueline Bennett, professor in the Department of Chemistry and Biochemistry, State University of New York (SUNY) Oneonta and the SUNY Research Foundation, developed a process that used ethyl L-lactate as a solvent to synthesize imines. The process was submitted as an entry to the 2012 US EPA's Presidential Green Chemistry Challenge Awards (1). According to the awards summary report, the method was efficient under ambient conditions, required less solvent than other methods, had a median yield of more than 92%, and had a median reaction time of less than 10 min (1). The resulting imines were generally sufficiently pure without recrystallization as the polarity of ethyl L-lactate was modulated by adding water. The starting materials remained dissolved, but the imine crystallized out of solution as it formed (1). Although traditional methods often drive reactions forward by removing water, this method drove the reaction forward by removing the product through crystallization, according to the summary report (1). Bennett and her research team have synthesized nearly 200 imines using this method and filed a US patent for the process (1, 6).

Ethylene in fine-chemical synthesis

Another interesting entry to the US EPA's Presidential Green Chemistry Challenge Awards involved the use of ethylene in fine-chemical synthesis developed by T. V. RajanBabu, professor in the Department of Chemistry, Ohio State University (1). According to the awards summary report, practical methods using carbon feedstock sources as starting materials to form enantioselective carbon–carbon bonds are not common. A broadly applicable reaction using ethylene to install vinyl groups enantiomerically, as developed by RajanBabu, could have significant impact in fine-chemical synthesis.

RajanBabu and his team developed highly catalytic (substrate–catalyst ratio up to 7,412:1) protocols for nearly quantitative (isolated yields of more than 99% and highly selective (approximately 100% regioselectivity; enantiomeric ratios of more than 99:1) codimerization of ethylene and various functionalized vinylarenes, 1,3-dienes, and strained alkenes. These reactions proceeded under mild conditions (–52 °C to 25 °C; 1 atmosphere of ethylene) to produce intermediates, such as 3-arylbutenes, which can be transformed to nonsteroidal anti-inflammatory drugs (NSAIDs) in two steps. These reactions consume both starting materials, leaving no side products. Successes include highly enantioselective syntheses of common NSAIDs, such as ibuprofen, naproxen, flurbiprofen, and fenoprofen, from the corresponding styrenes and ethylene (1).

Cyclic and acyclic 1,3-dienes also underwent efficient enantioselective addition of ethylene. Syntheses of several 1-vinylcycloalkenes and 1-substituted-1,3-butadienes achieved yields up to 99% (1). The approach has also been applied to other biologically relevant classes of compounds, including bisabolanes, herbindoles, trikentrins, steroid D-ring 20S- or 20R-derivatives, (–)-desoxyeseroline, pseudopterosin A–F, G–J, and K–L aglycones, and helioporins (1).