Transcript Optimization and Scale-Up of a Suzuki

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
Suzuki-Miyaura Coupling
 The Suzuki reaction is the organic reaction of an
aryl-boronic acid with an aryl-halide catalyzed by a
palladium complex
Pd cat.
R1 B(OH)2
+
R1 R2
R2 X
Base
Akira Suzuki
Norio Myaura
Suzuki-Miyaura Coupling
Pd (0)
R1 R2
R2 Pd(II)
R1
MX
R2 X
R2 Pd(II)
R1M
X
Suzuki-Miyaura Coupling
tBu
tBu
Br
CO2Et
N
H
1 eq
1
0.05 eq
Pd(OAc)2,
+
0.05 eq
dppf
Et3N, DMAc, H2O
B(OH)2
1.2 eq
2
2 eq
H
CO2Et +
CO2Et
N
H
N
H
3
4
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
NH2
Cl-
+
S
NH2
Smopex-110
mercaptopropyl-modified silica
phosphotungstic acid (H3PW12O40)
triamine-derived silica
http://www.strem.com/code/index.ghc
Removal of Palladium by ExtractionPrecipitation 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.