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- temperature technology." 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 are employed.
chemical sectors. 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 Temperature (˚C) Source: Albemarle 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.
scale glassware. 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 genic conditions." 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 Dimethyl fluoromalonate 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 Tel: +1.800.535.3030 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- Industriepark Höchst 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- Katzbergstrasse 1 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 Website: 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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