Going Green in Pharmaceuticals - Pharmaceutical Technology

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PharmTech Europe

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

Pharmaceutical Technology
Volume 33, Issue 2, pp. 44-46

Sepracor's route for trans-norsertraline

The 12 principles of green chemistry
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).

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,


1. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2008 Award Entries and Recipients" (Washington, DC, 2008), available at http://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).


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