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Advances in Green Chemistry for Pharmaceutical Applications
Lured by improved process conditions and economics, incorporating green chemistry into the synthesis of active pharmaceutical ingredients (APIs) and intermediates is of ongoing importance to the pharmaceutical industry. Solvent reduction and replacement and biocatalysis are some of the tools used to optimize select API syntheses.
Each year, the Environmental Protection Agency’s Presidential Green Challenges Awards recognize advances in green chemistry or environmentally favored approaches in all fields of chemistry. A review of entries for the 2008 awards, which were announced earlier this year, shows several large pharmaceutical companies among the contenders.
Eli Lilly optimizes production of neurokinin 1 antagonist
Lilly demonstrated the commercial route on a pilot-plant scale in 2006 at its facilities in Indianapolis, Indiana. Two prior synthetic routes were executed at the pilot-plant scale at the company’s Indianapolis and Mount Saint Guibert, Belgium, facilities (1).
Eli Lilly used a metric similar to but not identical to Sheldon’s E-factor, which measures 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 include a chemoselective nucleophilic aromatic substitution, which produced the drug in high entaniomeric excess (> 99%) despite the complexity of the structure and potential for positional isomers for all five aromatic rings (1,3).
Codexis develops biocatalytic route for montelukast intermediate
Codexis (Redwood City, CA) developed an improved route to (S,E)-2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3- hydroxypropyl)-benzoate (MLK-III), a chiral intermediate used in the synthesis of the anti-asthma drug “Singulair” (montelukast sodium) using biocatalysis. In the traditional approach, the ketone reduction to this chiral alcohol requires at least 1.8 equivalents of the reductant (–)-β-chlorodiisopinocampheylborane ((–)-DIP-Cl) in tetrahydrofuran at −20 to −25 °C. After quenching, an extraction removes spent borate salt waste. The reduction produces the S-alcohol in 97% ee and requires crystallization to give 99.5% ee in 87% yield (1).
Using another approach, Codexis developed a biocatalytic reduction for MLK-III using a ketoreductase biocatalyst evolved to reduce MLK-II. Codexis evolved the ketoreductase to increase its activity and stability by more than 2000-fold, replacing one-third of the amino acids in its active site in the process and under improved reaction conditions: 100 g/L in isopropanol–water–toluene at 45 °C. Isopropanol is the reductant, which the ketoreductase uses to regenerate its catalytic cofactor, NADPH, producing acetone as the coproduct. The process runs as a slurry-to-slurry conversion with product precipitation driving the reaction to completion. The precipitated chiral alcohol is of high chemical purity and stereopurity. Codexis has scaled up the manufacture of MLK-III using this biocatalytic reduction and has provided samples of MLK-IV to manufacturers of generic montelukast. The company is planning commercial-scale manufacture on a multiton scale in 2008 (1).
GSK develops green chemistry toolkit
J&J improves route to darunavir
The key gains in the route were: reduced solvent use; 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 replacement of a solvent system containing methylene chloride and triethylamine with a system containing acetonitrile and pyridine (1).
Merck develops greener process for raltegravir
Roche betters route for pyridinylimadazole-based drug
Roche developed an improved 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 either by distillation or via crystalline salt, but requires multiple operational steps. This process was sufficient to produce the API for Phase I and Phase 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 starting from readily available and inexpensive dimethyl acetone-
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/gcc/pubs/docs/
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.