Advances in Green Chemistry for Pharmaceutical Applications - Pharmaceutical Technology

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Advances in Green Chemistry for Pharmaceutical Applications
The pharmaceutical majors deploy green-chemistry strategies to improve the synthesis of active pharmaceutical ingredients and intermediates.


PTSM: Pharmaceutical Technology Sourcing and Management
Volume 4, Issue 9

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
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, 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
GlaxoSmithKline (GSK, London) developed the “Eco-Design Toolkit” as a way to provide bench-level chemists and engineers with access to 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 on solvents and bases with related environmental, health, and safety data; a fast life-cycle assessment for synthetic chemistry for streamlining evaluations of the environmental life cycle and measuring green metrics, including mass efficiency; a green packaging guide; and a chemicals legislation 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 nine-fold, and the estimated average life-cycle impacts were reduced four-fold as compounds moved to the last stage of development (1).

J&J improves route to darunavir
Johnson & Johnson (J&J, New Brunswick, NJ) used green-chemistry techniques to improve the synthesis of darunavir, the API in its protease inhibitor, “Prezista.” The improved process reduced waste and raw materials by 46 tons, reduced hydrogen gas by 4800 cubic meters and eliminated 96 tons of methylene chloride in 2006, the year in which the drug was approved.

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
Merck & Co. (Whitehouse Station, NJ) developed a greener process for producing raltegravir, the API in “Isentress.” 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 for the original process to 121. The new process also improved yield by 35% (1).

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-
1,3-dicarboxylate. The company optimized the process through significant streamlining,
resulting in the use of a single solvent, which is easily recovered and recycled. The key improvements involve: 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 non-aqueous conditions. The overall yield of the new synthesis is 89% and the API purity is 99.5% (1).

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/gcc/pubs/docs/
award_entries_and_recipients2008.pdf
, accessed Aug. 15, 2008.

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.

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