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Industrial Phase-Transfer Catalysis Issue 18
page 1
© 2005 PTC Communications, Inc.
http://www.phasetransfer.com
Industrial
Phase-Transfer Catalysis
Achieving Competitive Advantage Using Phase-Transfer Catalysis in
Generic Pharmaceuticals and Agrochemicals
Marc Halpern
mhalpern@ptcorganics.com
PTC Organics, Inc., 900 Briggs Road, Suite 145, Mt. Laurel, New Jersey 08054 USA
tel 856-222-1146; fax 856-222-1124
Summary: The key to gaining competitive advantage in generic pharmaceuticals and agrochemicals is low-cost and
high-performance manufacturing. The driving force of low cost has led to a significant shift in production to emerging
market countries due to low labor cost. However, the low cost of labor alone may not be sufficient to achieve the
lowest cost possible if the process does not approach 100% atomic efficiency using the lowest cost raw materials.
Phase-transfer catalysis can be a key contributor to achieving the lowest cost and highest performance process,
even in competition with emerging market facilities due to significant increases in yield, selectivity, avoiding isolation
of intermediates, reducing excess reactants and replacing expensive strong base with inexpensive NaOH. This
article will illustrate specific examples of processes which could benefit from using phase-transfer catalysis to
achieve lower cost and higher performance for generic pharmaceuticals and agrochemicals.
continued on page 2
2-Day PTC Courses in 2005
Newark - February 15-16 and Chicago - April 12-13
course agenda & registration at
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PTC Consulting
Contact Marc Halpern (+1) 856-222-1146 or mhalpern@ptcorganics.com
Subscribers of the Phase-Transfer Catalyst Supplier Directory
shown at www.phasetransfer.com/suppliers/catdir.htm
Delta Finochem
PTC
Consulting
PTC
Courses page 2
Industrial Phase Transfer Catalysis Issue 18
2005 PTC Communications, Inc.
http://www.phasetransfer.com
Achieving Competitive Advantage Using Phase-Transfer Catalysis in
Generic Pharmaceuticals and Agrochemicals
The key for achieving competitive advantage in the generic pharmaceutical and agrochemical markets is
low cost manufacture for the products and intermediates. This article will illustrate examples of reactions
likely used for existing generic products and intermediates which either use phase-transfer catalysis or
should use phase-transfer catalysis to simultaneously achieve high performance and low cost.
This article should be especially interesting to [1] companies which produce pharmaceuticals or
agrochemicals, [2] companies which use a strategy of developing low cost processes for compounds with
patents expiring within the next few years. Even though phase-transfer catalysis has been well known for
over 30 years, many companies still did not incorporate PTC 15 or more years ago when they
commercialized their branded pharmaceutical or agrochemical processes. Thus, significant opportunity
exists for companies open and willing to incorporate high-performance low-cost PTC processes for the
generics and intermediates coming off patent.
A major purpose of this article is to point out that previously developed processes could have been
improved had they used PTC so that when you develop future processes for new chemical entities, generic
products or their intermediates, you will more appropriately consider PTC. Before discussing specific
products and intermediates, we would like to provide some general comments.
General Comments
China and India: The good news/bad news may be that it could be possible to achieve the lowest
theoretical cost for many common intermediates and starting materials when combining the low labor cost
in emerging market countries with superior PTC performance. One may even speculate that the use of
phase-transfer catalysis could eventually be the factor which may differentiate one Chinese producer from
another.
Retrofit: It should be noted that even though re-registration of processes can be prohibitive, there are cases
in which PTC retrofit of an existing process for pharmaceuticals and agrochemicals does make sense.
1
These include [1] developing advantageous PTC processes for non-regulated key early stage intermediates
and starting materials, [2] overcoming selectivity issues magnified during full scale production which
threaten meeting specification or [3] the rare case in which a pharmaceutical company announces it is
willing to consider changing the process (e.g., Pfizers announcement for atorvastatin). In addition, generic
agrochemicals are usually more amenable to process retrofit.
Workup: One lesson we have learned by participating in several PTC retrofits is that after achieving high
reactivity and selectivity, the next most important factor for success is effective and practical separation of
catalyst from the product. PTC offers advantage in workup and product isolation relative to using solvents
like DMSO, because we can almost always use solvents which easily form two phases with water and
separate the valuable product from the catalyst and inorganic waste materials like salts of leaving groups.
Index
Using Multiple Consecutive PTC Steps p. 4
verapamil, myclobutanil, fenbuconazole, chlorpheniramine
Improving Yield and Selectivity for Nitrile Intermediates p. 6
ibuprofen, atorvatstatin
N-Alkylation p. 8
replacing NaH
Esterification p. 9
cefeclor, diazinon, chlorpyrifos
Etherification p. 10
Condensation & Other Reactions p. 11
Table of PTC Reactions
p. 12 Industrial Phase Transfer Catalysis Issue 18
page 3
© 2005 PTC Communications, Inc.
http://www.phasetransfer.com
Cognis Aliquat Phase-Transfer Catalysts
The First Name in Phase-Transfer Catalysts
Did you know that Aliquat 336 was cited by name in Starks first classic paper and patent in
which he coined the term Phase-Transfer Catalysis in 1971? YesCognis Aliquat Phase-
Transfer Catalyst is truly the first name in phase-transfer catalysts.
Heres a useful guide for the most common phase-transfer catalysts:
Phase-Transfer Catalyst
When to choose these catalysts for high performance:
Aliquat 175
PTC with NaOH at mild to moderate temp with water wash
workup; provides low residual catalyst and low aqueous waste
Aliquat 134
Most PTC applications, usually with non-aqueous workup
(distillation, recrystallization, product extraction, other)
Aliquat 100
Most other standard PTC applications
Aliquat HTA-1
High-temperature PTC applications
Aliplex 186DB
When you need the power of a crown ether
*
Aliquat is a trademark of Cognis Corporation
For samples and technical information in the United States call John Giannone 610-873-4762
Outside the US? Call Chris Koob +1 520 629 3204
Cognis Corporation, 2430 N. Huachuca, Tucson, AZ USA 85745
ISO 9001 and ISO 14001 certified page 4
Industrial Phase Transfer Catalysis Issue 18
2005 PTC Communications, Inc.
http://www.phasetransfer.com
Following are examples of opportunities and missed opportunities relating to using phase-transfer catalysis
for generic pharmaceuticals and agrochemicals.
Using Multiple Consecutive PTC Steps to Achieve Advantage
Since PTC excels in > 35 reaction categories (see Table on page 12) which represent many of the most
common reactions used in pharmaceuticals and agrochemicals, there can be great advantage in
performing multiple consecutive PTC steps to achieve: [1] high yield, selectivity, reduced excess reactants
and reduced reaction time in each separate step, [2] less handling losses and reduced processing time by
avoiding isolation of intermediates and [3] highly flexible choice of a single solvent for all steps including for
an advantageous final workup.
Following are some examples of generic pharmaceuticals and agrochemicals which probably would have
achieved advantage had they been originally developed using PTC for multiple consecutive steps.
Verapamil
Verapamil is a generic pharmaceutical which is prepared by a multistep synthesis shown in Figure 1 and
lends itself well to the advantages of PTC. We do not know if the process uses PTC for all or even any of
the steps, but it should. For the first step, PTC excels for cyanation of benzyl chloride derivatives. For the
second step, PTC should provide selective mono-C-alkylation using the sterically hindered isopropyl
bromide, especially since it can be manipulated to be performed at a low temperature due to the lower
energy of activation which PTC often provides. The C-isopropylation would be followed by another PTC
C-alkylation in the third step. The final C-alkylation probably needs to be pushed due to steric hindrance,
but one must be careful not to induce dehydrochlorination of the ch