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Kae M. Bullock, Mark B. Mitchell, and Jennifer F. Toczko*

Optimization and Scale-Up of a Suzuki - Miyaura Coupling Reaction: Development of an Efficient Palladium Removal Technique. Kae M. Bullock, Mark B. Mitchell, and Jennifer F. Toczko*. Organic Process Research & Development 2008, 12, 896–899. Akira Suzuki. Norio Myaura.

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Kae M. Bullock, Mark B. Mitchell, and Jennifer F. Toczko*

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  1. Optimization and Scale-Up of a Suzuki-Miyaura Coupling Reaction: Development of an Efficient Palladium Removal Technique Kae M. Bullock, Mark B. Mitchell, and Jennifer F. Toczko* Organic Process Research & Development 2008, 12, 896–899

  2. Akira Suzuki Norio Myaura Suzuki-Miyaura Coupling • The Suzuki reaction is the organic reaction of an aryl-boronic acid with an aryl-halide catalyzed by a palladium complex

  3. Suzuki-Miyaura Coupling

  4. Suzuki-Miyaura Coupling

  5. Motive • As part of an ongoing drug discovery program in our laboratories 3 was identified as a key synthetic intermediate. • Best conditions needed to be developed that allowed crystallization of 3 from the reaction mixture in high purity with palladium levels <150 ppm.

  6. Calculated Limit for Heavy Metals Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004

  7. Palladium Removal Methods • Distillation • Adsorption • - Activated Carbon • - Smopex TM fibers • - Silica-Bound Scavengers • Crystallization • Extraction Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004

  8. Design of experiments (DOE) • Design of experiments (DOE) is the most efficient approach for organizing experimental work. • DOE selects a diverse and representative set of experiments in which all factors are independent of each other despite being varied simultaneously. • The result is a causal predictive model showing the importance of all factors and their interactions.

  9. Output of ligand-solvent-base screen

  10. DOE coefficient plot

  11. Results of Focused Screen

  12. Absorption of Palladium by Solid Phase Treatments

  13. Smopex-110 mercaptopropyl-modified silica phosphotungstic acid (H3PW12O40) triamine-derived silica Absorption of Palladium by Solid Phase Treatments http://www.strem.com/code/index.ghc

  14. Removal of Palladium by Extraction-Precipitation Treatment

  15. Conclusions • The ligand-solvent-base screen helped to define Suzuki- Miyaura reaction conditions. • The removal of palladium from the reaction mixture using a toluene extraction-NaHSO3 wash system as the most effective method. • Both the optimized reaction conditions and palladium removal technique were demonstrated on 20-L scale in 82% yield (>99.8% purity) and 100 ppm palladium.

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