Chemistry Reference
In-Depth Information
10
Figure 16.3 Commercial synthesis of ibuprofen.
Adapted from US Patent 4 981 995.
carry out the key carbon-carbon bond-forming reaction at an earlier stage of
the synthesis, as shown in Route B.
35
Ibuprofen, a staple in everyday medicine cabinets, is produced by
palladium catalysis (Figure 16.3). The commercial production of
ibuprofen by Hoechst Celanese ended with the conversion of alcohol 10 to
ibuprofen, as described in one patent.
36
The removal of trace palladium
required an extensive purification process, warranting two additional
patents.
16,37
Some of the papers dedicated solely to palladium removal were authored
by 8-13 synthetic and analytical chemists, indicating that great manpower is
required in the pharmaceutical industry to remove palladium from
APIs.
22,23,38
It is dicult to separate palladium from APIs because it forms
complexes with functionalized organic molecules, many of which are sur-
prisingly stable during purification processes. Among the palladium-
organic molecule complexes is a well-characterized framework between
palladium and pyridine investigated by Fujita's group: a Pd
12
(pyridine)
24
spherical complex underwent a ligand exchange with a half-life of ~20
days.
39
In another study, cinchona alkaloid-palladium complexes were so
stable that they could be used as catalysts.
40
These examples highlight
strong bindings between palladium and drug-like scaffolds, accounting for
the diculty in removing residual palladium. Larger pyridine derivatives
prevent palladium black from forming.
41
One must consider whether pal-
ladium black (insoluble solid) is formed when filtration techniques are used
as part of palladium removal.
Different palladium complexes require different scavenging protocols to
reduce the palladium content effectively to
o
10 ppm. A combinatorial ap-
proach for metal removal with various solvents, scavengers and salts pro-
duces many dozens of samples for metal analysis;
19
it should be noted that
current analytical techniques are not amenable to large sample numbers.
Furthermore, palladium often binds tightly to organic compounds or pre-
cipitates as palladium black, hindering metal detection. Analytical samples
for spectroscopy are therefore prepared by treating metal-containing organic
materials with aqueous HCl, HNO
3
or aqua regia. Standard techniques for
metal analysis include inductively coupled plasma mass spectrometry (ICP-
MS), inductively coupled plasma optical emission spectrometry (ICP-OES)
and atomic absorption spectrometry (AAS). Additionally, ICP-MS, ICP-OES
and AAS instruments must be operated by well-trained analytical chemists.
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