Organic Process Research & Development 2010, 14, 939–941
An Efficient Method for Removal of Residual Palladium from Organic Solution of
Faropenem Sodium in the Pd(II)-Catalyzed Cleavage of Allyl Faropenem
Jian-Ping Huang, Xu-Xiang Chen, Shuang-Xi Gu, Lei Zhao, Wen-Xue Chen, and Fen-Er Chen*
Department of Chemistry, Fudan UniVersity, Shanghai 200433, China
Abstract:
system in the presence of sodium 2-ethylhexanoate and CH2Cl2/
EtOAc/H2O following the reported procedure.3a This method
was not viable for large-scale preparation because it required a
difficult chromatographic separation. Hence, an improvement
more amenable to the manufacture of 1 was sought. To our
surprise, the deprotection proceeded smoothly to provide desired
1 in 86.5% yield and avoided chromatograph by employing
PdCl2(PPh3)2/PPh3 as catalyst system in the presence of sodium
2-ethylhexanoate, EtOAc, and 2.5 equiv of H2O (Scheme 1).
Under the same reaction system, other conventional palladium
catalysts such as Pd(PPh3)4, Pd(OAc)2, and PdCl2 were carried
out to give 1 in 64%, 65%, and 73% yield, respectively.
Moreover, the deprotection procedure was performed using
Pd/C as catalyst, maintaining 5-50 kg pressure of hydrogen
gas to furnish 1 in 20-43% yield in the presence of sodium
bicarbonate, water, and ethyl acetate following the literature.3d
Unfortunately, the levels of palladium in all isolated products
1 using different catalysts were too high (1500-1600 ppm) to
attain acceptable residual limit (less than 10 ppm), We therefore
turned our efforts to reduce the palladium content of crude
product 1.
A considerable body of literature describing the methods for
removing residual palladium from pharmaceutical intermediates
as well as APIs is presented and involves a review.4 These
common methods for reducing the level of Pd to acceptable
levels divide into four categories: adsorption, extraction, crystal-
lization, and distillation. Adsorption is the most commonly
utilized technique. By adsorbing palladium to a solid scaffold,
the palladium complex is filtered out to leave a non-palladium
reaction mixture (supposing a solvent is employed in which
the scaffold is insoluble); or by complexing palladium to a liquid
phase, the resulting palladium complex can become more solube
in the solvent system, and then the desired compound is
crystallized to leave the palladium complex in the mother
liquor.5 Extraction is usually used when there is a significant
solubility difference between the palladium compound and the
An improved palladium(II)-catalyzed cleavage of the allyl group
in allyl faropenem 2 into faropenem sodium 1 is described. The
development of an efficient method for the removal of palladium
impurities from the crude product 1 upon treatment with
polystyrene-bound 2,4,6-trimercapto-s-triazine (polystyrene-bound
TMT) led to a drastic decrease of residual palladium level from
1500-1600 ppm to less than 10 ppm in the final isolated product.
The palladium(II)-catalyzed cleavage and palladium removal
process demonstrated on 10 kg scale are highly convenient and
efficient.
Introduction
As part of an ongoing faropenem and its analogues research
program in our laboratory,1 the cleavage of allyl group in 2
was identified as a key step for the preparation of 1, a penem
antibiotic with ꢀ-lactamase stablility and broad-spectrum anti-
bacterial activity.2 To date, although several palladium catalysts
have been documented in the literature for the deprotection of
the allyl groups of 2 into 1,3 the most common method for this
cleavage in industry involves the use of Pd(PPh3)4/PPh3/base
catalytic system. However, a moderate yield was achieved when
repeating the cleavage conditions on 2-L scale, and the high
levels of residual Pd (>1500 ppm) identified in the isolated 1
did not meet the demand for heavy metals content, which is
generally below 10 ppm for an active pharmaceutical ingredient
(API).4 Therefore, the development of an efficient and conve-
nient cleavage of the allyl group in 2 and removal of residual
palladium from the reaction mixture is of great importance in
the preparation of 1 on large scale. Herein, an expedient and
high-yielding method for the cleavage of the allyl group of 2
into 1 catalyzed by PdCl2(PPh3)2/PPh3/base as well as efficient
removal of residual Pd from crude 1 using polystyrene-bound
TMT as scavenger is being disclosed.
Results and Discussion
At the outset, the cleavage of the allyl group in 2 was
repeated in our laboratory using Pd(PPh3)4/PPh3 as catalyst
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* To whom correspondence should be addressed. Telephone: +86-21-
65643811. Fax: +86-21-65643811. E-Mail: rfchen@fudan.edu.cn.
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10.1021/op100094p 2010 American Chemical Society
Published on Web 06/10/2010
Vol. 14, No. 4, 2010 / Organic Process Research & Development
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