Going Green in Pharmaceuticals

February 2, 2009
Patricia Van Arnum

Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Pharmaceutical Technology, Pharmaceutical Technology-02-02-2009, Volume 33, Issue 2

The pharmaceutical majors forward projects in biocatalysis, solvent replacement, and other approaches in green chemistry.

Going green by incorporating more environmentally friendly approaches to the synthesis of active pharmaceutical ingredients (APIs) and intermediates can help to increase manufacturing efficiency and costs. In keeping with the fundamentals of green chemistry (see sidebar, "The 12 principles of green chemistry)" pharmaceutical companies are using strategies such as solvent reduction and replacement, refining a chemical route, and biocatalysis to optimize certain API syntheses while achieving improved environmental profiles.

Patricia Van Arnum

Eli Lilly's production of a neurokinin 1 antagonist

Eli Lilly and Company (Indianapolis, IN) developed a green-chemistry approach for the commercial production of an investigational new drug candidate, LY686017, an antagonist of the neurokinin 1 subtype of the tachykinin receptor. The drug, {2-[1-(3,5-bis-trifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]-triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, is in Phase II clinical trials. Lilly demonstrated the commercial route on a pilot-plant scale in 2006 at its facilities in Indianapolis. Two prior synthetic routes were executed at the pilot-plant scale at its Indianapolis and Mont Saint Guibert, Belgium, facilities (1).

Eli Lilly used a metric similar to but not identical to Sheldon's Environmental (E)-factor, which evaluates the environmental impact of a chemical process by calculating the ratio of kilograms of waste to kilograms of product (2). Lilly's e-factor measures the total mass of all raw materials, including water, which are used to produce each kilogram of API. The new route for LY686017 has a net e-factor of 146 kg/kg of API, which is an 84% reduction compared with the original route of the drug. Key technology in the new route included a chemoselective nucleophilic aromatic substitution, which produced the drug in high entaniomeric excess (> 99%) despite the complexity of the structure and the potential for positional isomers from all five aromatic rings (1, 3).

(ILLUSTRATION BY M.MCEVOY, IMAGES: FRANK LUKASSECK, RYAN MCVAY, MEDIOIMAGES/PHOTODISC/GETTY IMAGES FIGURES ARE COURTESY OF US FOOD AND DRUG ADMINISTRATION.)

J&J's route to darunavir

Johnson & Johnson (New Brunswick, NJ) used green chemistry to improve the synthesis of darunavir, the API in its protease inhibitor, "Prezista" (see Figure 1). The new process reduced waste and raw materials by 46 tons, reduced hydrogen gas by 4800 m3 , and eliminated 96 tons of methylene chloride in 2006, the year when the drug was approved. The key gains of the route were: reduced solvent use; the separation of the acidification and quenching steps to eliminate the formation of hydrogen gas and the replacement of hydrochloric acid with methane sulfonic acid and addition of acetone to react with excess hydride to form isopropanol; and the replacement of a solvent system containing methylene chloride and triethylamine with a system containing acetonitrile and pyridine (1).

Figure 1: Chemical structure for darunavir.

Merck's green process for raltegravir

Merck & Co. (Whitehouse Station, NJ) developed a green process for producing raltegravir, the API in "Isentress" (see Figure 2). Isentress was approved in 2007 to treat HIV. An important part of the process involves replacing the reagent methyl iodide with trimethylsulfoxonium iodide. With this change and other improvements, the E-factor for the process was reduced from 388 to 121. The new process also improved yield by 35% (1).

Figure 2: Chemical structure for raltegravir.

Sepracor's route for trans-norsertraline

Sepracor (Marlborough, MA) developed a green route to (1R, 4S)-trans-norsertraline, a chiral amine structurally similar to sertraline, the API in Pfizer's (New York) "Zoloft," by using a catalytic asymmetric hydrogenation that replaces a process based on a stoichiometric chiral auxiliary. The approach involved making an enamide substrate for asymmetric hydrogenation for the large-scale stereoselective process for the API. The company's first approach began with (S)-tetralone and a chiral auxiliary (R)-tert-butylsulfinamide, but the company developed a second-generation process for large-scale commercial applications that involved the catalytic asymmetric hydrogenation of the enamide (1, 4). The company refined the enamide methodology using toluene as the solvent and eliminating methanol and a more energy-consuming distillation. It also used a rhodium-based catalyst to improve the stereoselectivity of the reaction. The second-generation process reduced waste by 30%, reduced cycle time by 41%, and improved yield by 15% (1, 4).

The 12 principles of green chemistry

Roche's synthesis for a pyridinylimadazole-based drug

Roche Carolina (Florence, SC) improved a route for a pyridinylimadazole-based drug that functions as a p38(4) mitogen-activated protein kinase inhibitor. One of the fragments involved in the original synthetic route is 3-aminopentane-1,5-diol. This aminodiol intermediate is highly water-soluble, making it difficult to isolate from an aqueous reaction mixture. Extraction from the aqueous system required a very large volume of the organic solvent, dichloromethane. Purification of the resulting viscous liquid is performed either by distillation or via a crystalline salt, but requires multiple steps. The process was sufficient to produce the API for Phase I–II, but an improved route was needed for commercial manufacture (1).

In the new process, 3-aminopentane-1,5-diol is synthesized in two isolated steps and four chemical reactions that start from readily available and inexpensive dimethyl acetone-1,3-dicarboxylate. The company optimized the process through significant streamlining, resulting in the use of a single solvent that is easily recovered and recycled. The key improvements involve the following: sodium borohydride reduction of dimethyl 3-N-tert-butoxycarbonylaminoglutarate, an one-pot deprotection, and purification of the 3-aminopentane-1,5-diol using an acidic resin under nonaqueous conditions. The overall yield of the new synthesis is 89%, and the API purity is 99.5% (1).

GSK's green -chemistry toolkit

GlaxoSmithKline (GSK, London) developed the "Eco-Design Toolkit" to provide bench-level chemists and engineers green-chemistry information and tools for process research and development and manufacturing. The toolkit has five modules: a green chemistry and technology guide; a materials guide to solvents and bases with related environmental, health, and safety data; a fast life-cycle assessment for synthetic chemistry that streamlines evaluations of the environmental life cycle and measures green metrics, including mass efficiency; a green packaging guide; and a guide that identifies legislation phasing out hazardous substances. Using the toolkit, GSK reported that in 2006, the mass percent of chemicals of concern for all new products decreased ninefold, and the estimated average life-cycle impacts were reduced fourfold as compounds moved to the last stage of development (1).

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com

References

1. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2008 Award Entries and Recipients" (Washington, DC, 2008), available at www.epa.gov/greenchemistry/pubs/docs/award_entries_and_recipients2008.pdf, accessed Jan. 15, 2009.

2. R.A. Sheldon, "The E Factor: Fifteen Years On," Green Chem. 9 (12), 1273–1283 (2007).

3. M.E. Kopach, "A Practical and Green Chemical Approach for the Manufacture of NK1 Antagonist LY686017," presented at The 12th Annual Green Chemistry and Engineering Conference, New York, June 25, 2008.

4. P. Van Arnum, "Advances in Asymmetric Synthesis," Pharm. Technol. 31 (9), 58–65 (2007).