Potassium isopropyl xanthate (PIX): An ultra-efficient palladium scavenger

Article abstract of DOI:10.1039/c7gc01765k

The increasing employment of palladium-catalyzed reactions in the synthesis of active pharmaceutical ingredients (APIs) has created a pressing need for ultra-efficient palladium removal of the resulting metal contaminants. This communication discusses the identification and development of Potassium Isopropyl Xanthate (PIX) as a simple, readily available and ultra-efficient palladium scavenger capable of removing residual palladium from the API to levels less than 1 ppm. In addition, the discovery of a synergistic effect of iodine, in combination with PIX and other palladium scavengers, to enhance palladium removal has further increased the efficiency of the palladium removal process. The PIX and I₂ system has been successfully applied to the ceftolozane sulfate 2nd generation manufacturing chemistry to reduce palladium in the API resulting from a late stage palladium-catalyzed coupling reaction to only 0.1 ppm.

Full text of DOI:10.1039/c7gc01765k

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Potassium isopropyl xanthate (PIX):
an ultra-efficient palladium scavenger†
Cite this: DOI: 10.1039/c7gc01765k
Received 15th June 2017,
Accepted 6th July 2017
Hong Ren,* Christopher A. Strulson, Guy Humphrey, Rong Xiang, Guangtao Li,
Donald R. Gauthier and Kevin M. Maloney
*
DOI: 10.1039/c7gc01765k
rsc.li/greenchem
The increasing employment of palladium-catalyzed reactions in in APIs, especially for high dose drugs. These important
the synthesis of active pharmaceutical ingredients (APIs) has restrictions have presented the pharmaceutical industry with
created a pressing need for ultra-efficient palladium removal of new scientific opportunities for innovation in palladium
the resulting metal contaminants. This communication discusses removal strategies to support the implementation of palla-
the identification and development of Potassium Isopropyl dium-catalyzed reactions in API manufacturing and the devel-
Xanthate (PIX) as a simple, readily available and ultra-efficient pal- opment of green and sustainable manufacturing processes.
ladium scavenger capable of removing residual palladium from the
Ceftolozane, the cephalosporin antibiotic component in
API to levels less than 1 ppm. In addition, the discovery of a syner- Zerbaxa™, was synthesized via a palladium-catalyzed C–N
gistic effect of iodine, in combination with PIX and other palladium cross-coupling as shown in Scheme 1. This reaction forms the
scavengers, to enhance palladium removal has further increased core structure of ceftolozane in a single, convergent step in
the efficiency of the palladium removal process. The PIX and I
system has been successfully applied to the ceftolozane sulfate and green process. However, the ensuing reaction stream was
nd generation manufacturing chemistry to reduce palladium in shown to contain >2000 ppm of palladium-related species. The
the API resulting from a late stage palladium-catalyzed coupling current ICH guidelines for palladium lead to a specification of
2
excellent yield, resulting in a significantly more sustainable
2
reaction to only 0.1 ppm.
<1 ppm of palladium in ceftolozane. Therefore, in order to
implement the highly convergent and sustainable palladium-
catalyzed C–N coupling, it became necessary to develop a
highly efficient palladium removal process.
Initial attempts to apply conventional palladium removal
options were met with limited success, confirming the chal-
lenges associated with palladium removal to the ppm level and
reinforcing the need to develop a novel palladium removal
strategy. Herein, we present the discovery and development of
a new palladium removal strategy based on the solubilization
of residual palladium with a novel xanthate scavenger and sub-
sequent crystallization to afford ceftolozane in high recovery
and with <1 ppm Pd.
The emergence and broad substrate scope of palladium-cata-
lyzed coupling reactions have revolutionized the number of
bond disconnections available to synthetic chemists and
allowed for the preparation of highly complex targets in the
pharmaceutical industry. In addition to building molecular
complexity, the use of catalytic processes is viewed as a green
1
and sustainable approach to complex molecule synthesis.
While providing the noteworthy benefits described above, the
deployment of palladium-catalyzed coupling reactions in the
pharmaceutical industry has provided a new challenge related
to palladium removal in Active Pharmaceutical Ingredients
(APIs). In particular, palladium-catalyzed reactions conducted
late in synthetic sequences often result in high levels of palla-
dium entrained in the final compounds. The ICH guidelines
−
1
for palladium list the daily permitted exposure at 100 mg day
−
1
for oral dosing and 10 mg day for IV dosing, resulting
in extremely low and challenging specifications for palladium
Department of Process Research and Development, Merck & Co., Inc., Rahway, 07065
NJ, USA. E-mail: kevin_maloney@merck.com, hong.ren@merck.com
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c7gc01765k
Scheme 1 Zerbaxa ceftolozane manufacturing route.
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In our synthesis, the ceftolozane reaction stream after the fied was the Silicycle thiourea resin that showed medium
palladium-catalyzed C–N coupling step contained ∼2000 ppm efficiency with 60–90% palladium removed to give
of palladium-related species (Scheme 1). Following an aqueous ∼10–20 ppm residual palladium in the final API and 95%
work-up sequence utilizing thioglycerol as a palladium scaven- recovery, but still failed to provide the requisite level of palla-
ger, a global deprotection and precipitation, the resulting dium removal.
intermediate 3-TFA contained ∼50 ppm of residual palladium
Having thoroughly screened solid phase palladium removal
species, representing a 20-fold reduction in palladium, but not agents with minimal success, we shifted our attention to solu-
close to our 1 ppm target. In order to further reduce the palla- tions based palladium chelating scavengers such as DEDTC
4
dium content in the final API, several approaches were (Scheme 2, option 3). In this method, the palladium chelating
explored. Our initial efforts toward palladium removal, along scavenger was added to a solution of the intermediate 3-TFA in
with other impurities, involved crystallization of the API. water at pH < 2.0 resulting in precipitation of the palladium-
Unfortunately, the highly efficient crystallization process devel- DEDTC complex, which can subsequently be removed by fil-
oped to reject organic impurities provided minimal palladium tration. In the case of DEDTC, residual palladium in 3-TFA was
rejection, typically resulting in palladium levels at ∼40 ppm. reduced from 50 to 10 ppm (80% removal). Although this
Although disappointing, this result was unsurprising given the result served as a promising lead, this approach presented
multiple binding sites for the metal on the highly polar cefto- several challenges with respect to the development of an
lozane structure.
efficient process. First, this approach required a large amount
O to precipitate the palladium DEDTC complex, leading
After our unsuccessful preliminary effort using crystalliza- of H
2
tion, we screened inexpensive and simple solid-phase adsor- to poor volume efficiency in the downstream crystallization
2
bents and activated carbons, such as Norit, Nuchar, aqua- and a correspondingly high Process Mass Intensity (PMI).
2
guard, decolorizing charcoal and Darco (Scheme 2, option 1, Second, extended aging of 3-TFA in H O led to its decompo-
see ESI† for more information), for palladium removal. In the sition. Finally, DEDTC is not stable under acidic conditions,
best case, treatment of intermediate 3-TFA with ∼10 wt% of rapidly decomposing at pH < 7.0. These factors, in combi-
aquaguard for 1 h at 22 °C reduced the palladium from nation, rendered this approach less favourable for our ceftolo-
5
0 ppm to 30 ppm (40% palladium removal). A variety of com- zane process.
3
mercially available solid-state specialty scavengers, such as
Having exhausted conventional approaches to achieve palla-
polymer-bound thioureas and sulfur-containing compounds, dium rejection, we pursued a novel strategy by which we
were also screened in removing residual palladium (Scheme 2, sought to identify a novel palladium scavenger that would
option 2, see ESI† for more information). The best resin identi- efficiently and selectively bind palladium, while remaining in
Scheme 2 Zerbaxa ceftolozane palladium removal: unprecedented challenges.
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Scheme 4 Evolving from DTC to PIX.
and MTBP 8 (Table 1). We determined that stirring an
aqueous acetonitrile/DMAc solution of intermediate 3-TFA
with xanthate 4 for 30 minutes was optimal for palladium
removal. The resulting mixture was taken through the crystalli-
zation protocol to consistently yield 3-sulfate with <1 ppm
palladium. It is interesting to note that potassium isopropyl
xanthate has been widely used in the recovery of heavy metals
from ores in the mining industry as well as in the manufacture
8
of fungicides, pesticides and polymers, but, to the best of our
knowledge, this example represents its first application to
remove palladium in a pharmaceutical process.
Scheme 3 Zerbaxa ceftolozane palladium removal with chelating
agents. Reaction conditions: 5 mol% scavenger wrt 3-TFA used in all the
experiments. 3-TFA and the scavenger were stirred in a mixture of
To assess the pH stability of PIX under the processing con-
ditions, 4 was dissolved in a model system consisting of the
process solvents (DMAC, water, and ACN), and the pH was
adjusted to specific values using TFA. The pH stability of 4 at
pH 2 is of particular importance, since this is the measured
pH of the crystallization process for ceftolozane 3-sulfate from
MeCN, DMAc and H
was then added, followed by the addition of MeCN (14 vol.) over 10 h at
5 °C. The product was collected by filtration. Palladium assays from
2 4 4
O (7 vol.) for 30 min at RT. 1 equiv. of NH HSO
1
ICP-MS.
3-TFA. By omitting intermediate 3-TFA in the measurement,
we were able to directly determine the impact of pH on PIX
stability. A direct-UV measurement method and a chromato-
solution, prohibiting complexation of the palladium with 3-
sulfate. Utilization of the known crystallization of 3-sulfate
would afford the API with a suitable palladium level, with con-
comitant rejection of the palladium in the mother liquors
Table 1 Screening of various PIX derivatives and MPTB
(option 4, Scheme 2). In addition, the novel palladium scaven-
ger would need to exhibit increased stability under acidic con-
ditions. To explore this new strategy, we screened a broad
range of soluble palladium chelating agents (Scheme 3).
Among all scavengers tested, dithiocarbamates and their
5
derivatives showed the most promise in rejecting palladium,
affording levels as low as 2 ppm when combined with the crys-
tallization process. This green and sustainable approach pro-
vided an extremely promising starting point for palladium
removal in the current crystallization, while avoiding introdu-
cing any additional steps or operations.
Despite this exciting result, the use of dithiocarbamates
posed a significant robustness challenge for the crystallization
process due to their extremely fast decomposition rates under
6
strongly acidic conditions. This competitive decomposition
pathway, triggered by protonation of the thiocarbamate nitro-
gen, resulted in variable palladium rejection from 2 to 5 ppm
7
in the final API. We hypothesized that replacing the nitrogen
with a less Lewis basic atom, such as oxygen or carbon, would
lead to slower decomposition rates in related compounds
(Scheme 4). Potassium isopropyl xanthate (PIX, 4) proved
optimal, both with respect to palladium rejection and com-
a
b
1
0 mol% scavengers used in experiments. Palladium assays by
mercial availability, among all xanthate derivatives tested, 4–7 ICP-MS.
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a
2
Table 2 Enhancing palladium removal via I oxidation
Palladium
scavenger
Feed palladium Final palladium Final palladium
b b
(ppm)
without I
2
2
(ppm) with I (ppm)
PIX
PEX
DTC
MPTB
75
42
65
24
0.9
2.0
8.5
0.7
1.2
5.0
8.0
14
0.3
0.68
1.8
0.3
0.8
2.2
4.4
5.5
2
-Methyl thiourea 65
TMT
Thioglycerol
Isocyanoacetate
25
120
25
a
Reaction conditions: 5 wt% scavengers wrt 3-TFA used in all the experi-
Fig. 1 Measuring palladium scavenger stability in acidic conditions ments. 3-TFA and the scavenger were stirred in a mixture of MeCN,
DEDTC was completely destroyed in <5 min under similar conditions).
DMAc and H O (7 vol.) for 30 min at RT. 1 equiv. of NH HSO was then
(
2
4
4
added, followed by the addition of MeCN (14 vol.) over 10 h at 15 °C.
The product was collected by filtration. Palladium assays from ICP-MS.
b
graphic method monitoring the UV absorbance at 319 nm
were employed to monitor degradation. The pH range from pH
2
the efficiency of the PIX–I system, this protocol was performed
on 30 kg scale to provide final API with a palladium level of a
mere 0.1 ppm (Scheme 5).
1
.7 to pH 5.4 was analyzed, and the results provided a clear
trend for pH stability wherein 4 is increasingly unstable as the
processing conditions become more acidic (Fig. 1). This trend
is consistent with prior observations concerning xanthate
In conclusion, we have developed a novel palladium
removal approach utilizing PIX as a highly efficient scavenger
to reduce palladium to ultra-low levels (<1 ppm). Our approach
ensures that the palladium species remain soluble during the
process, allowing for their rejection in the mother liquors. In
this iteration, potassium isopropyl xanthate (PIX), a readily
available and cheap reagent, proved optimal. The use of this
method requires neither additional filtration steps nor use of
specialized reagents, highlighting both its practicality and sus-
tainability. The method features the first use of PIX as an
9
stability. It is important to note that, despite the increase in
PIX degradation rate under acidic conditions, we were still able
to observe an appreciable concentration (0.008 mg mL−1) of 4
after 7 minutes in a pH 1.7 medium. Even at this low concen-
tration, we observed robust and reproducible scavenging of the
low levels of palladium (ppm range). In contrast, dithiocarba-
mates such as DEDTC were completely destroyed in <5 min
under similar conditions.
Having identified PIX as the optimal palladium scavenger,
we explored the synergistic impact of additives on palladium
removal. Considering 4 is an ionic scavenger and is likely a
ultra-efficient palladium scavenger in
a pharmaceutical
process and was demonstrated on 30 kg scale as part of the
ceftolozane (3-sulfate) manufacturing process. We also discov-
ered the synergistic effect of the addition of iodine to augment
1
0
better ligand for palladium(II) (Scheme 4) than palladium(0)
species, the presence of an oxidant may convert trace levels of
residual palladium(0) to palladium(II) and provide a still more
efficient removal of residual palladium. In an extensive screen
of common oxidants (see ESI†) in combination with 4, most
proved incompatible with our system – either destroying the 3-
TFA intermediate or having little effect on palladium rejection.
Iodine was the lone exception to these observations: the com-
bination of PIX and I resulted in a threefold reduction in pal-
2
ladium when compared to PIX alone (Table 2). In addition to
PIX, the combination of I
scavengers resulted in improved palladium rejection. A control
experiment using I , but omitting treatment with 4, resulted
in no reduction of residual palladium, thus confirming the
2
with several additional palladium
2
Scheme 5 Zerbaxa ceftolozane palladium removal with PIX on pilot
synergistic effect between PIX and I . To further demonstrate plant scale.
2
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the palladium removal with PIX. We believe this hybrid treat-
ment will be a broadly useful technique to apply when con-
fronted with a problematic API-palladium separation and
should be applicable to other metal species. Finally, the
implementation of the PIX–I2 process has enabled the in-
corporation of the palladium-catalyzed C–N cross-coupling
leading to a significantly greener and more sustainable
process to ceftolozane sulfate and, hence, Zerbaxa™.
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