Cynthia.qxp 4/8/09 10:23 Page 32
Low temperature chemistry
Keep your cooltechnology with Dr Cynthia ChallenerIorder to maximise selectivity for the desired prod-
uct is paramount for the development of cost-
according to the chemistry involved but carefulselection of raw materials, catalysts and solvents andthe use of certain pressures and temperatures oftenplay important roles.
The use of temperatures down to -80ºC or even
duced at room temperature, very low temperaturescan often allow selective formation.
In other cases, highly reactive intermediates will
decompose at room temperature but will be stableenough at cold temperatures to enable the reactionto occur in good yields. Processes that involve gasescan also be much more manageable when carriedout at temperatures below the boiling point of suchsubstances.
"We see low temperature technology as one of
many enabling technologies with potential applica-
Albemarle uses liquid nitrogen cooling on this 10-litre, low temperature laboratory apparatus
tions across all market sectors," observes Tony Jones,head of marketing and sales in Saltigo 's pharma
nomic synthesis of a broad variety of products, like
work with," explains company president Rick Du
business. "As our customers move towards more
boronic acids, aldehydes, styrenes, halogenated
Boisson. "Reactions with these reactive gaseous
sophisticated molecules with more challenging syn- products and many others.
compounds may also require the use of cryogenic
thesis requirements, there is growing interest in low
Ash Stevens developed capability in low tem-
Low temperature processes are not suitable for all
Dr Adriano Indolese, head of process develop-
needs of its customers. "This technology has
ment for RohnerChem agrees that low tempera-
become one important part of a general toolbox of
tures make it possible to achieve the level of selec-
technologies for the pharma industry," says presi-
duced at lab- and pilot plant-scale by SynQuest, for
tivity necessary for the production of the increasing-
dent and CEO Dr Stephen Munk.
example, would not be economically feasible using
ly complex molecules required by the pharmaceuti-
Simply having cryogenic assets is not enough,
cryogenic methods. Instead, high pressure systems
however. Established expertise in this area and a
broad portfolio of other technologies are required to
Scaling up more traditional processes can pose
For Archimica , cryogenic chemistry is a very
deliver high quality products and services. Unlike
challenges as well. For instance, vessels intended for
important core technology that makes it possible to the
low temperature operation require special attention.
produce a wide range of speciality building blocks
SynQuest Labs has developed expertise in the use
and intermediates. Dr Andreas Meudt, managing
of low temperature distillation processes.
jected to the low temperature conditions are of par-
director of global R&D and new business develop-
"We specialise in the small-scale manufacture and
ticular concern, according to Todd Aplin, R&D man-
ment, says that the technology's real value lies in
ager of Albemarle
combination with expertise in organometallics and have found that low temperature distillation is an
ness. "Failure to properly match each material's
selective reductions. Such chemistries allow the eco-
related problems," he says
For those companies using liquid nitrogen to pro-
vide cooling, a choice must be made between
applying it directly to the jacket and using liquid
"The cooling method will be dictated by the plant
layout and the logistics of transferring the liquid
nitrogen," says Aplin. In addition, the vent for the
nitrogen gas must be located in a remote area with
access limited to prevent worker exposure to oxy-
Most companies seem to prefer to use liquid
cool directly. Saltigo, Ash Stevens, SynQuest and
Figure 1 - Internal heat transfer coefficients for three typical solvents in a 3,750 litre reactor
RohnerChem elected to use a secondary coolant to
July/August 2009 Speciality Chemicals Magazine
Cynthia.qxp 4/8/09 10:23 Page 33
Low temperature chemistry
Figure 2 - Lithiation reactions using lithium granules at Archimica: a - Substitution of aromatic halide by lithium granules; b - General lithium technology for
deprotonations without butylithium; c - Trifluoromethylpyridines
achieve low reactor temperatures. Materials of con-
"Careful consideration of the geometry used for
"Unfortunately, using low temperature conditions
struction include hastelloy, stainless steel and lab-
the addition of reactants and how the reaction mix-
does not guarantee the desired results," Aplin notes.
ture will be mixed are needed to help ensure that
"Low temperatures will typically prevent side reac-
Archimica, on the other hand, uses a specially
the large-scale operation will give results similar to
tions of the BuLi, but the aryl lithium intermediate
designed cooling system which has liquid nitrogen
the development work it was based upon," stresses
can still have a limited stability". Aryl lithiums con-
flowing though metal tubes and does not require a
Aplin. He adds that pre-cooling reactants to the
taining nitrogen can be especially unstable, so a
secondary cooling system. The reaction mixture
desired operating temperature is helpful in prevent-
continuous operation is preferred over batch in such
does not have any direct contact with the liquid
ing local ‘hot spots' that can lead to problems with
nitrogen, but cooling is very efficient and fast,
by-product formation and yield.
He continues: "When scaling up HM reactions,
according to Meudt, and allows even lower temper-
For example, halogen-metal (HM) exchange
one must develop a thorough understanding of the
atures than in secondary cooling systems.
reactions, such as lithium-halogen exchange using
stability of the aryl lithium intermediate at a range of
Issues with increased solvent viscosities must also
n-butyl lithium (BuLi) and an aryl bromide, are com-
temperatures and times. Not only does this data pro-
be considered, Aplin adds. Operating at low tem-
monly conducted at low temperatures for many rea-
vide acceptable operating ranges at full scale, it will
perature conditions can result in surprisingly high
sons. BuLi can be sufficiently active that it reacts with
also aid in troubleshooting any issues that may arise."
solvent viscosities. This can and does have a nega-
solvent or other species instead of the desired start-
Aplin adds that the products from HM reactions
tive impact on internal heat transfer coefficients.
ing material resulting in unwanted by-product for-
can be very sensitive to the work-up conditions as well.
Figure 1 shows internal heat transfer coefficients for
mation. Once formed, the desired aryl lithium can
At scale, it may be preferable to quench the reaction
three typical solvents in a large reactor. A similar
be sufficiently unstable that its decomposition dom-
while at low temperature to avoid by-product forma-
mass transfer coefficient effect also operates.
inates the reaction.
tion. Meudt, however, disagrees to some extent.
Figure 3 - Examples of low temperature chemistry at RohnerChem: a) Suzuki coupling, b) Carboxylation reaction
Speciality Chemicals Magazine July/August 2009
Cynthia.qxp 4/8/09 10:23 Page 34
Low temperature chemistry
the granules and other reagents without exposure to
and carefully quenching with water while still at a
air. "Developing this was crucial to the success of this
low temperature results in the elimination of tar for-
method, as any exposure of the granules to air results
mation and gives a higher desired para regioselec-
in decreased yields," Meudt remarks.
tivity in the isolated product," Aplin says. Even at low
With the special delivery system, yields for lithia-
temperature, the acylation of an activated aromatic
tions using the lithium granules are often 10-20%
using aluminum chloride and acid chloride goes to
higher than those done with BuLi. The alkyl lithium
completion in about one hour.
is produced in situ and is present in only minute con-
In the last two years, Albemarle has added 3,750
centrations at any given time. As a result, it reacts
litres of non-GMP capacity to complement its exist-
almost immediately, leading to higher yields and
ing cryogenic pilot facility in Tyrone, Pennsylvania.
selectivities (Figure 2).
The company also added over 10,000 litres of cryo-
Another benefit is the ability to create an almost
genic cGMP capacity to its multi-product API and
endless array of possible lithiating reagents.
intermediates facility in Orangeburg, South Carolina.
Commercially available alkyl lithiums are limited.
Reactions are typically run at internal temperatures of
With this approach, however, Archimica can, for
-70°C to -80°C in these new reactors (pictured).
example, produce cyclohexyl lithium or hundreds of
Saltigo has also invested in low temperature
different reagents, then choose the one that provide
chemistry in response to demands from the market
the highest selectivity and yield for a given reaction.
for a suitable range of technologies for scale-up and
This means increased yields and cost savings. In
commercialisation. "Our experience in low tempera-
addition, the cost of the lithium granules or the alkyl
ture chemistry makes it possible to predict scale-up
halide used to form the in situ lithiating reagent is
characteristics accurately, maximising process yields,
lower than that of the pre-formed alkyl lithium
improving productivity and attaining an exceptional-
reagents, so further savings can be achieved. The
ly high degree of selectivity with associated high
technology does not work for every single lithiation
product quality," Jones claims
reaction but Meudt believes that there could be sig-
The company's low temperature equipment,
Low temperature reactor at RohnerChem
nificant cost savings where it replaces BuLi. In
ranging from 100 to 12,000 litres, has been
"In more than 100 cryogenic reactions which
Archimica's experience, the probability of success
designed to be integrated into both its dedicated
Archimica has scaled up over the past ten years, the
for this technology is approximately 80%.
product units and its multipurpose facilities. Internal
stability of the organolithium intermediate has never
Like lithiation reactions, Friedel-Crafts acylation
reactor temperatures down to -100°C can be
been an issue, even if the substrate contains other
chemistry has been widely used for the synthesis of
functional groups with nitrogen, oxygen or halide,"
speciality chemicals. Aplin says that this has not
"We can increase our cooling capacity to match
he says. "One key is the selection of a suitable sol-
been done at low temperature but Albemarle has
the thermodynamics of each reaction by employing
vent that can completely suppress side reactions like
developed such a process that allows access to supe-
electrically-driven cryogenic compressor units," says
rearrangements to isomeric products under cryo-
rior products with less effort than more convention-
Jones. As well as giving excellent low temperature
al conditions. One example is the acylation of an
control, these units are designed to operate effi-
In addition to these engineering challenges, there is
aromatic ether (anisole or diphenyl ether) with an
ciently and thus minimise energy costs. Saltigo car-
also a strong perception in the industry that cryogenic
acid chloride (acetyl chloride or propionyl chloride)
ries out a very broad range low temperature reac-
technologies are too expensive compared to the ben-
using aluminum chloride in DCM.
tions, for example reductions with complex
efits they provide. Again, Meudt argues otherwise.
"It is common to observe the formation of difficult
hydrides, every form of organometallic, Grignard
"In our experience, the cooling costs are far out-
to remove tarry by-products in carrying out this
and catalytic reactions and reactions with different
weighed by higher yields and additional product
reaction at 25°C. Conducting the reaction at -40°C
purity. By combining cryogenic chemistry with othertechnologies like hydrogenations, enzymatic chem-
istry and cross-couplings, a broad variety of APIs and
intermediates can be accessed by short and high-
yielding syntheses," he says.
Archimica's investments in cryogenic equipment
reflect this positive view. It has more than 60 m3 of
-100ºC reactor volume, including eight full-scale
reactor trains (8,000 litre cryogenic reactors in both
hastelloy and stainless steel), plus pilot (500-3,000
litres) and kilo-lab (50 litres) equipment. With its
cooling technology, temperatures of -80°C can be
achieved in very short time periods while very small(±2°C) temperature ranges can be kept for very
long periods of time, according to Meudt.
Whilst Archimica has broad capabilities in cryo-
genic chemistry including lithiations ortho to halo-
gens, lithiations with BuLi, other alkyl lithiums or
LDA and reductions with LAH, NaBH4, Selectride
and other modified reagents, its unique technology
for lithiations using lithium granules rather than BuLi
is of particular interest.
The company developed a special system which
includes a special metal tube incorporating an internalvalve to provide an inert atmosphere, for introducing
Figure 4 - Low temperature fractional distillation of z-1,1,1,2,3-pentafluoropropene
July/August 2009 Speciality Chemicals Magazine
Cynthia.qxp 4/8/09 10:23 Page 35
Low temperature chemistry
RohnerChem's capability in low temperature
mer Girindus site at Künesbeck in Germany, where
For more information, please contact:
chemistry relates to its core expertise in the synthe-
SynQuest's parent company, Central Glass of Japan,
sis of speciality aromatic building blocks for APIs and
has a GMP facility. At that site, 100, 500 and 1,200
other applications, according to Indolese.
litre stainless steel reactors can be taken down to
"Cryogenic technology makes it possible for us to
R&D Manager - Fine Chemistry Services
synthesise aromatic building blocks not easily accessi-
At its own facility, SynQuest operates glass reac-
451 Florida Street
ble via traditional chemistry. We consider it to be an
tors of up to 100 litres. Typical low temperature
extension of our core business offering," he says. The
chemistry here includes ammoniations with liquid
company also has expertise in the production and use
ammonia and lithiations with butyl lithium. For
of organometal ic catalysts and Grignard reagents.
processes using elemental fluorine, which is
Grignard reactions, lithiations, Suzuki couplings,
extremely reactive, temperature control is critical for
carboxylations and reactions with acyl chlorides are
both selectivity and safety.
key examples of the low temperature chemistry that
"Even at -78ºC, it is sometimes difficult to achieve
Rohner carries out in its 60, 400 and 2,500 litre
the preferred level of selectivity," says Adam Alty,
hastelloy reactors and at laboratory scale (Figure 3).
the company vice president.
Most reactions are done at low temperature in order
In addition, a key raw material of the company -
Managing Director NBD/Global R&D
to achieve higher levels of selectivity, which result in
hexafluoropropene - exists as a gas, and low tem-
improved yields and purities.
perature reaction conditions are necessary for
D-65926 Frankfurt am Main
Ash Stevens offers a broad range of technologies
processes using this compound. SynQuest converts
and considers low temperature chemistry to be an
hexafluoropropene into several different building
Tel: +49 69 305 34519
important tool that enables the company to produce blocks used by the pharmaceuticals industry and
APIs in the most efficient and cost effective manner
other fine chemical-consuming sectors (Figure 4).
possible. "Our cryogenic capabilities are integrated
Many other substances manufactured at
with our other offerings, which magnifies the bene-
SynQuest are also gases and they require special
fits they provide," states Munk.
distillation methods. The company has developed
One specific example is the use of the Matteson
expertise in low temperature gas distillation for these
Dr Stephen A. Munk
homologation reaction to prepare a chiral boronic
products. The desired compound is separated from
ester, a reaction that involves formation of a C-C
impurities by passing it through a condenser filled
5861 John Lodge Freeway
bond with very high asymmetric selectivity. This
with dry ice in a liquid, often acetone. The purified
chemistry proceeds at low temperature and Ash
product is collected in cylinders that are cooled with
Stevens uses it in the synthesis of the API borte-
liquid nitrogen or dry ice to a temperature below the
zomib, which is found in the drug Velcade.
boiling point of the gas.
Tel: +1 313 872-6400
Cryogenic temperatures are necessary to provide
"This low temperature distillation method is a
the desired level of enantioselectivity, Munk adds.
rather specialised technology and any employees
"For us, the real power of low temperature chemistry
operating the equipment must have special train-
is the ability to induce a chiral centre with very high
ing," Du Boisson comments. He adds that most peo-
selectivity. There is only a very small difference in
ple in the plant have well over ten years of experi-
Dr Adriano Indolese
energies between enantiofaces when inducing a chi-
ence in low temperature distillation processes.
Head of Process Development
ral centre; carrying out reactions at such a low tem-
Whether purifying or reacting a gaseous com-
perature makes it possible to differentiate between pound, synthesising a single enantiomer of a com-
these energy states and follow one path selectively." plex chiral molecule or controlling the selectivity of
The company also carries out other organometal-
a process involving a highly reactive raw material,
Tel.: +41 61 825 1542
lic chemistry at low temperature, such as lithiations low temperature capabilities make it possible to
with BuLi and reactions with LDA. Whilst the equip-
achieve high yields of the desired product, often
ment it uses was not custom-built for Ash Stevens,
more cost-effectively than traditional methods.
Munk stresses that suppliers were extensively evalu-
"Although low temperature chemistry poses
ated and the reactors and cooling equipment was
unique challenges to the process chemist and engi-
chosen very carefully.
neer, through careful study and planning, cryogenic
Head of Marketing & Sales Pharma
"I recommend that anyone looking to add cryo-
operations can provide high value chemical prod-
genic capabilities to their offerings spend time find-
ucts that may be difficult to access by other means,"
ing the right equipment vendor that best fits with his
or her operations. You absolutely need a supplier
And most of these manufacturers expect the
Phone: +49 2173 2033 651
you can trust and rely on," he says.
demand for such capabilities to increase. "We clear-
Having access to reliable equipment is certainly a
ly expect further growth in the use of cryogenic
necessity when handling highly reactive substances technologies but we also expect that the number ofsuch as elemental fluorine and other fluorinated
serious players in this field will come down to a few,
compounds, which is the speciality of SynQuest. The
in line with the ongoing focus of Big Pharma on few
company has developed many fluorinated com-
selected suppliers," Meudt states.
pounds that have helped in the search for replace-
"Further, we do not expect that biocatalytic or
ments for CFC and HCFC refrigerants, solvents for
other new technologies, including micoreactor tech-
electronic applications, building blocks for synthesis nology, will be a serious threat to low temperature
of pharmaceuticals and fine chemicals and analytical chemistry over the next decade. As we have the
reference standards, all of which are produced on a
assets already and the cooling costs are only very
Tel: +1 386 462 0788
small per kilo of product, the only real reason for
Larger quantities of products requiring low tem-
microreactors should be higher yields and we have
perature chemistry can be manufactured at the for-
not observed this for all reactions tested so far."
Speciality Chemicals Magazine July/August 2009
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