I&EC 67 |
| Bisphosphonates have found significant use in pharmaceutical industry as well as in ion sequestering and detergent applications. Blockbuster osteoporosis drug, sodium alendronate, is currently commercialized by several pharmaceutical companies. Cabot is interested in making aniline derivatized bisphosphonates for its applications. Herein we present scale-up process study of one particular molecule, EBP, 2-(4-aminophenyl)-1-hydroxyethylidene-1,1-bisphosphonic acid, mono sodium salt. The synthesis of EBP involves the reaction of 4-aminophenylacetic acid (APAA) with phosphorous trichloride (PCl3) and phosphorous acid in the presence of methane sulfonic acid (MSA). This is followed by hydrolysis and subsequent precipitation of EBP at a pH of around 4.3. A 12 factor, 22 experiment, screening design of experiments (DOE) was performed by varying the concentrations of all the starting chemicals, additional water, temperatures, times at various stages of the reaction, and hydrolysis conditions. Results from screening DOE showed that increasing amounts of all the reactants relative to APAA, adding PCl3 at a slower rate, reacting at higher temperature and reducing water of hydrolysis increased yield of EBP. The reaction hold times could be reduced from 16 to 8 hours without impacting yield. Yields could be increased from about 27% to 65% and results validated. Characterization and level reduction of major impurities from the reaction are also discussed. |
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IEC Poster Session
8:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- Exhibit Hall - B2, Poster
Sci-Mix
Division of Industrial & Engineering Chemistry |