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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. - PowerPoint PPT Presentation
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Optimization and Scale-Up of a Suzuki-Miyaura Coupling Reaction: Development of an Efficient Palladium Re
moval Technique
Kae M. Bullock, Mark B. Mitchell, and Jennifer F. Toczko*
Organic Process Research & Development 2008, 12, 896–899
Suzuki-Miyaura Coupling
The Suzuki reaction is the organic reaction of an aryl-boronic acid with an aryl-halide catalyzed by a palladium complex
Akira Suzuki Norio Myaura
B(OH)2R1 + R2 XBase
Pd cat.R1 R2
Suzuki-Miyaura Coupling
Pd (0)
R2 Pd(II) XR2 Pd(II) R1
MX R1M
R1 R2 R2X
Suzuki-Miyaura Coupling
NH
CO2EtNH
CO2EtNH
CO2Et
Br tBu
B(OH)2
tBu
H
Pd(OAc)2, dppf
Et3N, DMAc, H2O+ +
1 2 3 4
0.05 eq
2 eq
1 eq 1.2 eq
0.05 eq
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.
Calculated Limit for Heavy Metals
Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004
Palladium Removal Methods
Distillation Adsorption - Activated Carbon - Smopex TM fibers - Silica-Bound Scavengers
Crystallization Extraction
Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004
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.
Output of ligand-solvent-base screen
DOE coefficient plot
Results of Focused Screen
Absorption of Palladium by Solid Phase Treatments
Absorption of Palladium by Solid Phase Treatments
triamine-derived silica
mercaptopropyl-modified silica phosphotungstic acid (H3PW12O40)
http://www.strem.com/code/index.ghc
Smopex-110
S
NH2
+
NH2
Cl-
Removal of Palladium by Extraction-Precipitation Treatment
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.
