2004 Greener Synthetic Pathways Award
Bristol-Myers Squibb Company
Development of a Green Synthesis for Taxol® Manufacture
via Plant Cell Fermentation and Extraction
Innovation and Benefits: Bristol-Myers Squibb manufactures paclitaxel, the active ingredient in the anticancer drug, Taxol®, using plant cell fermentation (PCF) technology. PCF replaces the conventional process that extracts a paclitaxel building block from leaves and twigs of the European yew. During the first five years of commercialization, PCF technology will eliminate an estimated 71,000 pounds of hazardous chemicals and materials, eliminate 10 solvents and 6 drying steps, and save a significant amount of energy.
Paclitaxel, the active ingredient in the anticancer drug Taxol®, was first isolated and identified from the bark of the Pacific yew tree, Taxus brevifolia, in the late 1960s by Wall and Wani under the auspices of the National Cancer Institute (NCI). The utility of paclitaxel to treat ovarian cancer was demonstrated in clinical trials in the 1980s. The continuity of supply was not guaranteed, however, because yew bark contains only about 0.0004 percent paclitaxel. In addition, isolating paclitaxel required stripping the bark from the yew trees, killing them in the process. Yews take 200 years to mature and are part of a sensitive ecosystem.
The complexity of the paclitaxel molecule makes commercial production by chemical synthesis from simple compounds impractical. Published syntheses involve about 40 steps with an overall yield of approximately 2 percent. In 1991, NCI signed a Collaborative Research and Development Agreement with Bristol-Myers Squibb (BMS) in which BMS agreed to ensure supply of paclitaxel from yew bark while it developed a semisynthetic route (semisynthesis) to paclitaxel from the naturally occurring compound 10-deacetylbaccatin III (10-DAB).
10-DAB contains most of the structural complexity (8 chiral centers) of the paclitaxel molecule. It is present in the leaves and twigs of the European yew, Taxus baccata, at approximately 0.1 percent by dry weight and can be isolated without harm to the trees. Taxus baccata is cultivated throughout Europe, providing a renewable supply that does not adversely impact any sensitive ecosystem. The semisynthetic process is complex, however, requiring 11 chemical transformations and 7 isolations. The semisynthetic process also presents environmental concerns, requiring 13 solvents along with 13 organic reagents and other materials.
BMS developed a more sustainable process using the latest plant cell fermentation (PCF) technology. In the cell fermentation stage of the process, calluses of a specific taxus cell line are propagated in a wholly aqueous medium in large fermentation tanks under controlled conditions at ambient temperature and pressure. The feedstock for the cell growth consists of renewable nutrients: sugars, amino acids, vitamins, and trace elements. BMS extracts paclitaxel directly from plant cell cultures, then purifies it by chromatography and isolates it by crystallization. By replacing leaves and twigs with plant cell cultures, BMS improves the sustainability of the paclitaxel supply, allows year-round harvest, and eliminates solid biomass waste. Compared to the semisynthesis from 10-DAB, the PCF process has no chemical transformations, thereby eliminating six intermediates. During its first five years, the PCF process will eliminate an estimated 71,000 pounds of hazardous chemicals and other materials. In addition, the PCF process eliminates 10 solvents and 6 drying steps, saving a considerable amount of energy. BMS is now manufacturing paclitaxel using only plant cell cultures.
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