Boehringer Ingelheim Blazes Trail In Scaling Up Metathesis Reaction

In 2005 and 2006, Boehringer Ingelheim researchers published what they claimed was the first reported scale-up of a ring-closing metathesis (RCM) reaction to make a macrocyclic hepatitis C protease inhibitor called BILN 2061 (Org. Process Res. Dev. 2005, 9, 513 and J. Org. Chem. 2006, 71, 7133). Although the synthetic approach was highly desirable, the researchers had to deal with some serious problems to scale it up.

The process of making a 15-membered ring is intrinsically problematic from an entropic standpoint, the team says, even if another cyclization method had been chosen. The advantage of RCM is that it gave them access to all the building blocks required, and only the Z-geometrical isomer was obtained. They considered many alternative routes, but the current one was the most direct and convergent.

The team faced numerous challenges in scaling up the reaction, including high catalyst loading, long reaction times, dilute solutions, unwanted dimerization, and metal removal issues. They settled on using the first-generation Hoveyda-Grubbs catalyst from Materia at a few mole percent after testing a limited number of catalysts. It became immediately evident that the product/dimer ratio was concentration dependent, not catalyst dependent, they say. The success of the reaction depended instead on solvent, concentration, and structural features of the starting material.

For example, by switching from commonly used dichloromethane to toluene as the solvent, the team boosted reaction temperatures and reduced reaction time from 24 hours to a few hours. Because RCM is a reversible reaction, the reaction still had to be run in very dilute solution and the ethylene by-product removed to drive it forward. The researchers solved the problem of high dilutions by using a method they expect to describe soon in the literature.

Definition of the synthetic route took about six months, followed by four to five months to produce the first pilot-plant batch. Although the researchers succeeded in producing more than 400 kg of material this way, they then tried a nitro-substituted Grela catalyst. This switch led to only 0.7 mol % catalyst loading, a 30-minute reaction time, and a product of similar quality under the same conditions. Boehringer Ingelheim is hoping to patent this process and ones for running RCM under continuous flow conditions and in supercritical fluids.

Transition-metal catalysts usually are not used in the final synthesis step, particularly at high loadings, because the metal must be removed in a single step. In general, once the catalyst loading has been minimized, say to 0.1 mol %, it is often not difficult to remove it, the researchers say, and the usefulness of the synthetic approach makes any extra work worth it.

Chromatography-based catalyst removal methods, although practical in the lab, aren't at large scale. So to meet regulatory requirements of less than 10 ppm of residual ruthenium, the team tried several other methods, including metal scavenging, chelation, and extraction. All worked to some extent. Eventually, the team developed several wash procedures and what they say is a practical, economical, and environmentally friendly method using supercritical CO₂ (Org. Process. Res. Dev. 2006, 10, 937).

Their advice to others attempting to scale up relatively new technologies is that many of them can be made practical. Nevertheless, they say, one must weigh the pros and cons. They suggest that RCM may be worth using when there are few other possible approaches to the desired compound, but better alternatives may exist for simple molecules.

Most of the cost of the BILN 2061 molecule resides in the expensive building blocks, whose production constitutes 16 of the 25 synthesis steps it takes to make BILN 2061. The company's newest optimized RCM adds very little in terms of both catalyst cost and manufacturing expenses, the team adds. Thus, they believe that an optimized RCM reaction will be compatible with most relatively complex modern drug syntheses.

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