Eli Lilly & Co. process chemist David Mitchell’s wife, Pearlette, doesn’t always like it when he pulls out his smartphone to check the latest journal e-alert. He never knows if the latest paper to hit his in-box will contain a solution he needs for an efficient new kilogram-scale synthesis of a drug candidate. So anytime his pocket buzzes, Mitchell takes a look.
Living Up To The Process Challenge
Keeping up with the literature is just one of the daily activities in the life of a drug industry process chemist. These are the pharmaceutical middlemen who take milligram-to-gram-scale synthetic procedures from chemists in the discovery lab and escort them to production teams waiting to use them in a manufacturing plant to make kilogram to ton amounts of an approved drug.
Along the way, process chemists are designing and building new starting reagents, finding shortcuts to reduce the amount of chemicals used, checking molecule subunits and functional groups for possible toxic troublemakers, and sidestepping reactions that generate waste. They put together pharmaceutical jigsaw puzzles, all while moving drug development along quickly and minimizing costs.
“A day in the life of a process chemist is never dull,” Mitchell said. “And it is not without its challenges.”
Mitchell was one of some five dozen process chemists who gathered in Orlando last month for the 30th Organic Process Research & Development conference offered by Scientific Update. During the past 15 years, this British consulting firm, which provides professional training for industrial chemists and chemical engineers, has been hosting these international forums for process chemists to come together to discuss mutual challenges.
In Orlando, Mitchell made a first disclosure of the chemistry for preparing aminopyrazole intermediates. These compounds are being prepared for a project to make Chk1 inhibitors. Chk1 is a phosphorylating enzyme that helps regulate cell cycles, and compounds that inhibit Chk1’s activity are being investigated for treating cancer.
Attending the process chemistry conferences is a good way for chemists to broaden their research horizons and learn about the latest developments in the field, Mitchell told C&EN. Much of the learning comes from the presentations and extensive discussions that typically take the form of case studies in which presenters from different companies share their experiences without giving away any company secrets.
In one presentation in Orlando, Jason A. Mulder of Boehringer Ingelheim described the challenge of scaling up the fluorination of a versatile synthetic intermediate that his company is using to make a family of new anti-infective drug candidates.
Fluorine-containing molecules are of growing importance to the pharmaceutical and other industries. Just a single ﬂuorine atom can significantly modify the physical and chemical properties of molecules. But natural organoﬂuorine compounds are rare in plants and have never been found in animals. So they must be obtained by synthesis. This high demand and low natural supply has fed the imaginations of many chemists who are seeking easy, safe, low-cost methods for adding fluorine or fluorine-containing groups at precise locations in molecules.
Mulder’s target was synthesizing methyl 6-chloro-5-(trifluoromethyl)nicotinate on a 100-kg scale at a reasonable cost. At first, Mulder and his colleagues considered buying and modifying a trifluoromethylated precursor. But the one they needed cost about $800 per kg on a 100-kg scale, which was too much, he said. The team then turned to finding a method to make the fluorinated nicotinate from scratch (Org. Process Res. Dev. 2013, 10.1021/op400061w).
The researchers first conducted a retrosynthesis analysis, a kind of thought experiment in which a chemist works backward on paper to disassemble a target molecule to see the best way to make it. They reasoned that the most affordable approach would be to start with 4-hydroxynicotinic acid, a precursor that only cost $70 per kg. The method involved converting the precursor to a heteroaryl halide intermediate and then adding the trifluoromethyl group.
As Mulder explained, many fluorinating reagents and processes exist for installing trifluoromethyl groups on aromatic rings. His team found more than a dozen options available in the chemical literature. Most of these reactions were designed to work on aryl groups on a milligram scale, however. Part of the challenge was picking an approach that would work efficiently on a heterocyclic ring at a 100-kg scale and could be carried out without the specialized equipment that fluorinations typically need.
When it comes to fluorinating reagents, some of the most popular ones are the most expensive, Mulder noted. Trifluoromethyltrimethylsilane, known as the Ruppert-Prakash reagent, is the most widely used source of CF3 for trifluoromethylations. However it costs about $1,000 per kg, or $142 per mol, he said. Many new “designer” CF3 reagents are derived from the Ruppert-Prakash reagent and are even more expensive.
“We quickly concluded these were not the most cost-effective for scale-up,” Mulder said. The researchers continued their search and zeroed in on methyl chlorodifluoroacetate. Although the compound would take some massaging to serve as a trifluoromethylating reagent, at $12 per mol on a 100-kg scale, the price was right.
With their reagents in hand, the team set out to develop a catalytic reaction. Another cost issue process chemists face is finding a molecular catalyst or a ligand that isn’t restricted from use by patent protection so the company doesn’t have to pay a licensing fee or premium price for it. Mulder and his colleagues developed a generic system by combining a copper salt with a common phenanthroline ligand.
Copper stabilized by the ligand facilitates formation of difluoromethyl carbene, which couples with fluoride ion added to the reaction to form CF3 ions. The ligand-stabilized copper then coordinates to the heteroaryl ring to displace iodide and transfer CF3 to the ring. The reaction worked with good yield but not without a couple of monkey wrenches thrown in.
For one thing, the team couldn’t achieve a catalytic process on the scale they needed because of competing impurity formation—the larger the reaction, the lower the yield. Running reactions that involve CF3 ion can be problematic because of side reactions of difluoromethyl carbene, Mulder said. The major impurities in this case were by-products with an unwanted fluoroalkyl side chain.
During the reaction, the CF2 carbene likely generates multiple fluorinated alkyl copper species that compete with CuCF3 and react with the iodide, Mulder explained. This radical addition, or telomerization, is how fluorinated polymers such as polytetrafluoroethylene are made. The team actually could see formed polymer floating in the reaction vessel.
To curb carbene formation and telomerization, the researchers had to use just the right amount of copper and fluoride ion. But after running hundreds of reactions using the catalytic route with modified conditions, none of the options proved to be optimal. Although the catalytic process was preferred for its lower copper cost and reduced burden of removing copper salts at the end of the reaction, the team opted to simply use a stoichiometric amount of copper, which cut down on carbene formation and reduced the impurities.
“Our final result was a safe, efficient, scalable process with low impurities that was successfully integrated into the scaled-up synthesis of new drug candidates with an overall cost reduction of 10%,” Mulder concluded. He reiterated that although many trifluoromethylation procedures are available, “finding one that works well on a large scale and at low cost remains a challenge.”
Yet another challenge for process chemists is deciding which solvent to use. In an ideal world, chemists would like to use no solvent. But on a large scale, solvent is critical to achieving good mixing and maintaining temperature control.
Among solvents, water is always given consideration. Many organic molecules are insoluble in water, however, or they are so miscible with water that they are hard to separate. Chemists have come up with clever ways to work around solubility issues, such as using surfactants or cosolvent systems. Still, process chemists must carefully select solvents according to well-known criteria: utility, health, safety, cost, and environmental impact.
Several pharmaceutical and specialty chemical companies have devised solvent selection guides to simplify decision making. Typically the guides rank solvents as preferred, usable, and undesirable in tables that are color-coded green, yellow, and red, respectively. In 2010, the American Chemical Society Green Chemistry Institute’s (GCI) Pharmaceutical Roundtable created a solvent selection guide to harmonize multiple guides into a single resource for process industries.
But just because a solvent is recognized as being preferred, that doesn’t mean it gets a green light for use in all real-world applications, noted Shunji Sakamoto, a sales manager at specialty chemical company Zeon Corp. Take the case of the solvent cyclopentyl methyl ether (CPME), for example.
Zeon introduced CPME in 2005 as a preferred alternative for methyl tert-butyl ether, 1,4-dioxane, and tetrahydrofuran, which are useful and popular ether solvents but rate poorly because of health, safety, or environmental concerns. Compared with the traditional ether solvents, it has higher hydrophobicity and therefore is easier to separate from water. The solvent also forms lower amounts of explosive peroxides and has better stability under acidic and basic conditions. CPME enables processes to be carried out with less solvent.
Given its better performance and greener profile, demand for CPME initially was very strong, Sakamoto said. Chemists at Merck & Co. went so far as to independently assess the toxicology profile of CPME, along with another orphan solvent, 2-methyltetrahydrofuran (MeTHF). The company’s process chemists were in support of using these solvents in pharmaceutical process development (Org. Process Res. Dev. 2011, DOI: 10.1021/op100303c).
The Merck team carried out lab bioassay and rat studies to establish permitted daily exposure levels of the solvents in accordance with industry classification rules, rating the solvents as noncarcinogenic and having low toxicity. Yet some companies are starting to give up on using CPME and MeTHF, Sakamoto pointed out, because they don’t have the blessing of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, or ICH, which develops guidelines that aim to align international regulatory requirements.
One of the ICH guidelines, Q3C, covers solvents, classifying them into four groups by toxicity and health risk and prescribing limits of residual levels. It is the de facto global standard for solvent selection.
Pharmaceutical companies are reluctant to use solvents that are not listed in the ICH guideline, Sakamoto explained, because it takes too much time and money to justify residual levels of such solvents in an active pharmaceutical ingredient. “Many process chemists are facing the ICH wall as well as we are,” he lamented. “In short, to be classified in the ICH guidelines is very necessary and critical to facilitate use of new solvents in the chemical industry.”
The ICH guideline can’t be changed by a simple request of a solvent manufacturer, Sakamoto added, so he and his colleagues are lobbying the Japanese representatives to ICH and appealing to pharmaceutical companies and the GCI Pharmaceutical Roundtable in an effort to get CPME added to the ICH guidelines. In the meantime, Sakamoto and process chemists throughout the industry must stand back and wait, which is yet another of their challenges.