Efficient Removal of Metal Based Catalysts Using SiliaBond® DMT
François Béland, Geneviève Gingras, Nathalie Huther*, Steeves Potvin, Lynda Tremblay
SiliCycle® Inc. (www.silicycle.com) 2500 Parc-Technologique Blvd, Quebec City, Quebec, G1P 4S6, Canada
*([email protected])
Heck and Buchwald
Other type of reactions, such as Heck and Buchwald, imply the use of
palladium and as for the Suzuki coupling, palladium removal may be
problematic. Treatment with Si-DMT on these reactions gave the
ffollowing
ll i results:
lt
Introduction
In recent years, the time pressure associated with bringing candidate
drugs onto the market quickly has increased the number of transition
metal-catalyzed reactions being transferred from lead optimization to
early scale-up. The concentration limits for metal content are becoming
increasingly more challenging. The removal of metal residues from post
reaction mixtures has therefore become a major issue for the
pharmaceutical industry. Traditional methods used to remove metals
include chromatography, activated carbon, extraction, distillation and
recrystallization but, these offer poor selectivity and can lead to active
pharmaceutical ingredient (API) loss.
loss The development of solid supported
metal scavengers has significantly changed how chemists can prepare
APIs.
1. Negishi:
Conditions
1eq, 4h,
80 ºC
56.8
(86%)
4eq, 4h,
80 ºC
34.4
(92%)
4eq, 1h,
22 ºC
46.5
(89%)
4eq, 4h,
22 ºC
40.9
(90%)
2. Sonogashira:
Conditions
SiliaBond DMT is the silica bound equivalent of 2,4,6-trimercaptotriazine
(TMT). TMT has been reported to efficiently remove palladium and other
heavy metals from reaction mixtures by precipitation, but suffers from
limited solubility in organic solvents; Si-DMT overcomes this issue as it is
compatible with most solvents. It has been shown to remove a variety of
metals from organic reactions including Cd, Co, Cu, Fe, Ni, Pd, Pt and Rh
under a wide range of conditions and is the preferred scavenger for
ruthenium residues. The following results highlight some applications of
Si-DMT as a metal scavenger in synthesis.
Residual Pd
(ppm)
Suzuki
Before
treatment
407.0
Residual Pd
(ppm)
SiliaBond DMT
In Suzuki coupling, even if palladium is used in catalytic amounts,
quantities ranging from a few hundred to a few thousand ppm of residual
metal are typically left after workup. To investigate the efficiency of SiDMT in removing palladium residue in those processes, the following
Suzuki coupling reaction was performed.
Removal of other Metal Residues
Here is a selection of palladium mediated reaction that also involve other
metals and the scavenging results obtained by using Si-DMT:
Before 1eq, 4h, 4eq, 4h, 4eq, 1h,
treatment 80 ºC
80 ºC
22 ºC
148.6
122.4
(18%)
31.1
(79%)
4eq, 4h, 8eq, 4h, 4eq, 16h,
22 ºC
80 ºC
80 ºC
99.6
(33%)
81.6
(45%)
14.6
(90%)
3. Cyanation:
3.4
(90%)
Once again, Si-DMT allowed a significant reduction in the amount of
residual palladium.
Stille
Stille coupling is another type of palladium mediated reaction that also
involve the use of organotin compounds and hence, contamination by tin
residues is usually an issue. To probe the potential scavenging ability of
Si-DMT for a mixture of metal contaminants, a traditional Stille
coupling reaction was performed as follow:
Reaction
#
Conditions
1
Residual Pd
(ppm)
Residual Fe
(ppm)
Residual Pd
(ppm)
Residual Cu
(ppm)
Residual Pd
(ppm)
Residual Fe
(ppm))
(pp
1
2
2
3
3
In this case, we not only attempted to reduce the amount of palladium in
solution but we were also hoping to remove tin residues in a single
treatment. The results are summarized in the table below :
Treatment of the reaction mixture after work up with Si-DMT gave the
results shown in the following table:
Conditions
Residual Pd
(ppm)
Before
treatment
147.3
1eq, 4h,
80 ºC
45.9
(69%)
4eq, 4h,
80 ºC
1.7
(99%)
4eq, 1h,
22 ºC
16.9
(89%)
4eq, 4h,
22 ºC
13.9
(91%)
In this case, the use of 4 equivalents of Si-DMT for 4 hours at 80 ºC gave
the best result reaching less than 2ppm of residual palladium.
Conditions
Residual Pd
(ppm)
Before
treatment
145.1
1eq, 4h,
80 ºC
24.0
(84%)
4eq, 4h,
80 ºC
3.1
(98%)
4eq, 1h,
22 ºC
6.7
(95%)
4eq, 4h,
22 ºC
4.9
(97%)
1880
(19%)
1830
(21%)
Before
1eq, 4h,
treatment 60 ºC
167.0
56.2
119.1
10.5
366.5
151.5
4eq, 4h,
60 ºC
4eq, 1h,
22 ºC
4eq, 4h,
22 ºC
9.5
(94%)
8.3
(85%)
1.9
(98%)
0
(100%)
3.3
(99%)
20.3
((87%))
25.4
(84%)
9.9
(82%)
9.8
(92%)
0
(100%)
10.8
(97%)
18.6
((88%))
17.5
(90%)
9.0
(84%)
8.8
(93%)
0
(100%)
6.4
(98%)
19.9
((87%))
53.2
(68%)
18.9
(66%)
15.1
(87%)
2.2
(79%)
42.3
(89%)
33.4
((78%))
Conclusion
This study has demonstrated that not only SiliaBond DMT can be used as an
efficient scavenger for palladium residues after reaction workups but it can
also remove other metals. Si-DMT is therefore a very versatile metal
scavenger for common metal mediated synthetic transformations
The authors would like to thank Mr. Stéphane
p
Houle for his valuable contribution to this p
poster.
Residual Sn
(ppm)
2306
No
No
scavenging scavenging
Unfortunately, although palladium concentrations were significantly
reduced, the tin seems untouched by Si-DMT.*
* Tin residues can be succesfully removed using SiliaBond TAAcONa.