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.