2002 Greener Synthetic Pathways Award

Pfizer, Inc.

 

Green Chemistry in the Redesign of the Sertraline Process

 

Innovation and Benefits: Pfizer dramatically improved its manufacturing process for sertraline, the active ingredient in its popular drug, Zoloft®. The new process doubles overall product yield, reduces raw material use by 20–60 percent, eliminates the use or generation of approximately 1.8 million pounds of hazardous materials, reduces energy and water use, and increases worker safety.

Summary of Technology: Sertraline is the active ingredient in the important pharmaceutical, Zoloft®. Zoloft® is the most prescribed agent of its kind and is used to treat an illness (depression) that each year strikes 20 million adults in the United States, and that costs society $43.7 billion (1990 dollars). As of February 2000, more than 115 million Zoloft® prescriptions had been written in the United States.

Applying the principles of green chemistry, Pfizer has dramatically improved the commercial manufacturing process of sertraline. After meticulously investigating each of the chemical steps, Pfizer implemented a substantive green chemistry technology for a complex commercial process requiring extremely pure product. As a result, Pfizer significantly improved both worker and environmental safety. The new commercial process (referred to as the "combined" process) offers substantial pollution prevention benefits including improved safety and material handling, reduced energy and water use, and doubled overall product yield.

Specifically, a three-step sequence in the original manufacturing process was streamlined to a single step in the new sertraline process. The new process consists of imine formation of monomethylamine with a tetralone, followed by reduction of the imine function and in situ resolution of the diastereomeric salts of mandelic acid to provide chirally pure sertraline in much higher yield and with greater selectivity. A more selective palladium catalyst was implemented in the reduction step, which reduced the formation of impurities and the need for reprocessing. Raw material use was cut by 60 percent, 45 percent, and 20 percent for monomethylamine, tetralone, and mandelic acid, respectively.

Pfizer also optimized its process using the more benign solvent ethanol for the combined process. This change eliminated the need to use, distill, and recover four solvents (methylene chloride, tetrahydrofuran, toluene, and hexane) from the original synthesis. Pfizer's innovative use of solubility differences to drive the equilibrium toward imine formation in the first reaction of the combined steps eliminated approximately 310,000 pounds per year of the problematic reagent titanium tetrachloride. This process change eliminates 220,000 pounds of 50 percent sodium hydroxide, 330,000 pounds of 35 percent hydrochloric acid waste, and 970,000 pounds of solid titanium dioxide waste per year.

By eliminating waste, reducing solvents, and maximizing the yield of key intermediates, Pfizer has demonstrated significant green chemistry innovation in the manufacture of an important pharmaceutical agent.


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