Sepracor's route for trans-norsertraline
The 12 principles of green chemistry
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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, 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
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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