Applying Catalysis to Optimize API Synthesis

Organic chemists are tasked with optimizing synthetic routes for pharmaceutical compounds. Catalysts, both chemical catalysts and biocatalysts, play a crucial role in improving reaction efficiencies and conditions, increasing yield, and achieving desired stereoselectivity. Fine-chemical companies, contract manufacturers, and other researchers are advancing this field for producing pharmaceutical intermediates and APIs.

Company activity
Codexis, a company specializing in biocatalysis, recently reported on its development of industrial  biocatalysts for sulfide oxidation and Baeyer-Villiger-type monooxygenations (BVMO). These BVMO enzymes can be used to improve methods to manufacture chiral sulfoxides, which are important molecules for pharmaceutical synthesis. Codexis used these enzymes to develop biocatalytic processes for producing esomeprazole and armodafinil to improve enantiometric purity and reduce sulfone impurity, according to an Oct. 3, 2013 Codexis press release. The enzyme and API manufacturing processes are currently being scaled up for commercial supply. Codexis’ BVMO enzymes are commercially available as a screening kit that process chemists can use to develop new biocatalytic oxidation processes.

Earlier this year, Codexis partnered with Purolite, a provider of ion-exchange, catalyst, adsorbent, and specialty resins, to develop and market immobilized enzymes for the pharmaceutical industry. The enzymes are immobilized through binding to inert resins to allow for easier separation from a reaction mixture, and immobilization allows the enzymes to be used under different reactions conditions and re-used at a commercial scale. The collaboration is focused on immobilized transaminase enzymes.

Codexis also partnered earlier this year with the CMO AMRI in a nonexclusive, two-year agreement focused on identifying and implementing new and improved manufacturing routes for select APIs. Codexis is providing its directed evolution technology for enzyme discovery and optimization, and AMRI is providing process development and manufacturing capabilities, including using AMRI’s proprietary microbial strains.

Johnson Matthey Catalysis and Chiral Technologies (JMCCT) business unit, which provides heterogeneous, homogeneous, chiral, and biocatalytic technologies, is expanding its existing specialty ligand-manufacturing capability to include commercial-scale manufacturing up to 100 kilograms. The expansion is largely focused on the Buchwald ligands from the Massachusetts Institute of Technology. The Buchwald ligands offered by JMCCT are a class of dialkylbiaryl monophosphine ligands, which are used for the in-situ generation of active catalysts for coupling reactions in the manufacture of pharmaceuticals and specialty chemicals. The XPhos and SPhos ligands are used for Suzuki-Miyaura reactions, in particular with hindered aryl substrates and heteroaryl halides. In addition, the combination of Buchwald ligands, such as XPhos, SPhos, RuPhos, and BrettPhos with several palladium catalyst precursors, such as Pd(OAc)₂, Pd(dba)2 and Pd2(dba)₃, are used in combination for the in-situ generation of active catalysts. These catalysts can be applied in carbon-carbon, carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-born bond formations, including the Suzuki-Miyaura, Negishi, Sonogashira, Buchwald-Hartwig amination and carbonyl alpha-arylation reactions.

The biocatalysis company evocatal is relocating to Monheim, Germany, to a facility that doubles the company’s laboratory and production area to add additional capacity for research, process development, and production. The expansion adds new industrial fermenters to optimize the manufacture of biocatalysts up to the 100-L pilot scale. In addition, the new location will house multipurpose equipment for the synthesis of fine chemicals up to the kilogram scale.

Almac recently reported on its collaboration agreement with DSM Pharmaceutical Products in biocatalysis, which includes the successful transfer of enzymes for enzyme screening, process development, and scale-up manufacture. The agreement grants both companies access to their enzyme platform technologies, services, and expertise for API manufacturing. Almac is bringing expertise in enzyme identification, scale-up, and implementation into early-phase projects, and DSM is providing commercial-manufacturing expertise, which gives Almac a preferred partner for large-scale production. Since forming their agreement in 2012, Almac and DSM have initiated and completed multiple projects in the fields of ketoreductases, transaminases, bio-oxidations, and hydrolases. Almac also recently completed a knowledge transfer partnership with Queens University Belfast to develop, improve, and embed bioprocesses.

Advancing catalysis
Researchers at Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr, Germany recently reported on their work in immobilizing various catalysts on nylon and applying them in pharmaceutical synthesis among other reactions. Working in collaboration with scientists from the Deutsches Textilforschungszentrum in Krefeld, Germany and Sungkyunkwan University in Suwon, Korea, the researchers at the Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr developed a process for immobilizing different organic catalysts on textiles with the help of ultraviolet light. The fabric acts as a support for the substances on which a chemical reaction occurs.

The researchers used three organic catalysts: a base (dimethylaminopyridine, DMAP), a sulfonic acid, and a catalyst that functions as both an acid and a base, according to a Sept. 13, 2013 Max-Planck-Institut für Kohlenforschung press release.  To attach the catalysts to the nylon fibers, the chemists irradiated the textile to which a catalyst was applied with ultraviolet light for five minutes. All three catalysts converted approximately 90% of the source materials to the desired products.

Compared with other ways of immobilizing catalysts, organotextile catalysis has several advantages. In particular, it provides the reagents with a larger surface than other supports, such as plastic spheres or foils, with the larger surface enabling a more efficient reaction. Moreover, the nylon is flexible and inexpensive. In the approach for  immobilization of organocatalysts on the textile nylon using ultraviolet light, the catalyst and the textile material require no chemical modification for the immobilization (1). All of the prepared textile-immobilized organocatalysts (a Lewis basic, a Brønsted acidic, and a chiral organocatalyst) showed “excellent” stability, activity, and recyclability for various organic transformations, according to the researchers (1). They reported good enantioselectivity (> 95:5 enantiomeric ratio) that was maintained for more than 250 cycles of asymmetric catalysis. The researchers asserted that textile organocatalysis may be beneficial for various fields by offering inexpensive and accessible functionalized catalytic materials (1).

In another development, researchers at Boston College in Massachusetts reported on the enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. The researchers noted that catalytic enantioselective monosilylations of diols and polyols provide alcohol-containing molecules in high enantiomeric purity, but that these transformations require high catalyst loadings (20-30 mol%) and long reaction times (2-5 days) (2). To resolve those challenges, the researchers used an achiral cocatalyst structurally similar to a chiral catalyst. A combination of Lewis basic molecules served as an achiral nucleophilic promoter and the other molecule performed as a chiral stereoselectivity base. On the addition of 7.5-20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole), reactions typically proceeded within one hour, with high product yields and enantiomeric ratios (2). In certain examples, there were no reaction in the absence of the achiral base, but the presence of the achiral cocatalyst facilitated product formation in high enantiomeric purity (2). Overall, the new approach reduced the reaction time to less than an hour, down from a period of two to five days, reduced catalyst loading, and produced a more efficient transformation for enantioselective alcohol silylation, according to a July 2013 Boston College press release.

“The use of cocatalysts can be tricky, especially in procedures intended to deliver handedness in the molecules you want your reaction to produce,” said Amir Hoveyda, the Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College, in the Boston College press release. “What we’ve shown is that in this procedure, you can take two cocatalysts, which on the surface are competing with one another, and effectively keep them from interfering with one another.”

Hoveyda and Boston College Professor of Chemistry Marc Snapper have worked since 2006 on this method of catalysis. These catalysts, originally developed in their laboratories seven years ago, are valued for producing reactions that offer a high level of enantioselective purity. The relatively slow reaction time of two to five days was a key problem, but which was mitigated by applying a computational approach. The researchers used the cocatalyst model involving two Lewis base molecules, adding an achiral molecule to an already present chiral molecule. These cocatalysts operated in concert, with the chiral molecule activating alcohol and the additional achiral molecule (from commercially available 5-ethylthiotetrazole) activating silicon. Identification of the positive influence of ethylthiotetrazole proved to be the key component of the discovery, giving the team the ability to fine-tune the reaction and effectively control the interplay between the cocatalysts. Together, the Lewis bases served as a closely related Brønsted base to allow the catalyst to work faster while retaining high enantioselectivity.

References
1. Ji-Woong Lee, Science 341 (6151) 1225-1229 (2013).
2. A. Hoveyda, Nature Chemistry 5 (9)
768-774 (2013).