Patricia Van Arnum
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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.
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).
(ILLUSTRATION BY M.MCEVOY, IMAGES: FRANK LUKASSECK, RYAN MCVAY, MEDIOIMAGES/PHOTODISC/GETTY IMAGES FIGURES ARE COURTESY OF
US FOOD AND DRUG ADMINISTRATION.)
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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).
J&J's route to darunavir
Figure 1: Chemical structure for darunavir.
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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).
Merck's green process for raltegravir
Figure 2: Chemical structure for raltegravir.
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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).
