Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

Fluorine atoms have a unique combination of electronic and physical properties. As such, when incorporated into APIs, fluorine atoms often influence their protein binding affinity and lipophilicity. Fluorination can thus significantly impact the bioavailability of drug substances. “Fluorination is a key reaction in organic synthesis, as evidenced by the fact that between 15% to 20% of all medicines and agrochemicals on the market contain at least one fluorine atom in their structure, where fluorine is used to modify properties of the drugs like lipophilicity and bioavailability or metabolic stability,” states Rafael Antunes, director of API portfolio development with Hovione.

	Traditional and cost-effective fluorinating reagents are corrosive and often toxic and, therefore, require special handling and equipment. In addition, they cannot be used with intermediates containing other sensitive functionality. Thus, the synthesis of organic fluoro-compounds is not trivial at industrial scale--it requires special equipment, materials of construction, reaction conditions (sometimes cryogenic), and controls to tackle the difficulty in safely handling and disposing of fluorinating reagents, according to Antunes. “Reaction control is a fundamental aspect. The low selectivity (chemo-, regio-, and/or stereo-) of the reactions, the low stability of some fluorine-containing species, together with hazardous sampling and sample handling impose a heavy burden for the synthesis of fluorochemicals,” he adds.

	The search for safer, easy-to-handle, inexpensive, and selective fluorinating reagents has been underway for decades and continues today. Most recently, solid reagents are showing promise, at least for use by medicinal chemists. Even more promising are coupling reactions that allow the incorporation of fluorinated synthons through carbon-carbon rather than carbon-fluorine bond formation.


	Several solid fluorinating reagents have been introduced to the market. One example that has recently been attracting more interest is XtalFluor-E from Manchester Organics (developed in partnership with OmegaChem). (Diethylamino)difluorosulfonium tetrafluoroborate is an easily handled crystalline solid with enhanced thermal stability when compared to other reagents in this class, including a higher decomposition temperature with lower exothermic heat and higher onset temperature for self-accelerated decomposition (1), according to Dave Tovell, director of Manchester Organics. In addition, it does not generate free hydrogen fluoride (HF) and thus is usually compatible with glass equipment. The partnership has also demonstrated that this fluorinating reagent typically produces fewer elimination side products, and thus greater selectivity, than more traditional nucleophilic fluorinating reagents.

	With their attractive physical, reactivity, and health and safety profiles, these newer reagents are finding growing use at the discovery and early process phases of drug development. They do, however, carry a relatively higher cost than traditional fluorinating reagents (HF, potassium fluoride [KF] and fluorine gas [F

]) and thus are generally less economical for use on the commercial-scale.

Organometallic coupling reactions are most exciting


	Newer difluormethylation and trifluoromethylation chemistry, which involves the formation of carbon-carbon bonds rather than direct fluorination, is one of the most exciting developments in organofluorine chemistry in recent years, according to Tovell. “These reactions occur under mild conditions and often tolerate many different functional groups,” he notes.

	Hartwig’s trifluoromethyl(1,10-phenanthroline)copper ((Phen)Cu-CF3) reagent is an easily handled, thermally stable, single-component reagent for the trifluoromethylation of both electron-rich and electron-deficient aryl and vinyl iodides, including sterically-hindered iodoarenes, in high yields under mild conditions (2). Notably, aldehyde, nitroarene, ketone, and ester functionalities are tolerated. The reagent is sold under the trade name Trifluoromethylator by Catylix and is commercially available through Aldrich Chemical.

	Shibata developed a method for the electrophilic α-trifluoromethylation of β-ketoesters using the fluorinated Johnson reagent [(oxido)phenyl(trifluoromethyl)-λ

-sulfanylidene]dimethylammonium tetrafluoroborate (3). Meanwhile, hypervalent iodine(III)-CF

 reagents developed by Togni are widely used for the trifluoromethylation of thiols, alcohols, phosphines, and heteroarenes (4-8). The radical trifluoromethylation of heteroarenes using the Langlois reagent (sodium trifluoromethanesulfinate) or zinc(II) bis(trifluoromethanesulfinate) (Zn(SO2CF3)2) with tert-butyl hydroperoxide have also been achieved by Baran (9-11).

	Zinc difluoromethanesulfinate (DFMS), also developed by the Baran group (11), allows for the simple difluoromethylation of a wide range of heteroaromatic substrates in air. Nucleophilic difluoromethylation of carbonyls and imines can be achieved using (difluoromethyl)trimethylsilane (12), a reagent developed by Hu and coworkers.

	There are numerous other research groups developing selective and high-yielding nucleophilic and electrophilic difluoromethylation and trifluoromethylation strategies for substrates ranging from carbonyl compounds to alkenes. “These new techniques for the selective incorporation of fluorine atoms into complex organic molecules under mild conditions are very exciting advances for API synthesis. The pharmaceutical industry is under increasing pressure to reduce costs, and any new technologies that can improve route efficiencies and yields and do so cost effectively will attract significant attention,” asserts Tovell. He adds that it is still early days with respect to the development of these types of chemistry and he expects further improvements in the coming years.

Organometal-catalyzed direct fluorination also of interest


	Organometallic catalysts have also been applied to the direct fluorination of a variety of substrates. Two examples include Buchwald’s method for the nucleophilic fluorination of aryl triflates with cesium or potassium fluoride (13) and Ritter’s silver-catalyzed fluorination reaction in which aryl stannanes are converted to fluorides using silver triflate as the catalyst and F-TEDA-PF6, which is an anion-exchange product of Selectfluor (chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); F-TEDA-BF4) as the fluoride source (14).

	Antunes adds that the development of Selectfluor by Eric Banks (marketed by Air Products) is the most important ‘recent’ development. This reagent has transformed the production of fluorinated pharmaceuticals, with 134 patents published that cite Selectfluor, and approximately 80% of all fluorinated steroids produced using the agent. “This reagent bypasses hazardous fluorine processing steps and makes the production of drugs containing fluorine much cheaper and safer. Every year, around 25 tonnes (worth $7.5 million) of Selectfluor are used in the industry, making it the most commonly used electrophilic fluorinating agent in pharmaceutical manufacturing,” he notes.

Exploring the potential of flow chemistry


	The benefits of flow chemistry include reduced operating costs, a lower footprint, decreased capital expenditures combined with improved process efficiencies, control, and product quality, and the ability to perform chemical reactions that are not feasible or present significant hazards in batch operations. As a result, there is great interest in this technology for the synthesis of pharmaceutical intermediates and APIs.

	Not surprisingly, flow chemistry is a natural fit with fluorination reactions, particularly those involving conventional toxic and corrosive reagents. “Minimizing the quantity of reagents that are needed at any one time not only reduces the hazards associated with these reactions, but also allows for optimization of yields and selectivities,” Tovell explains. There are generally high expectations for flow chemistry to overcome many of the challenges of traditional fluorination reactions (the need for special equipment, to handle hazardous chemistries, and run strictly controlled reactions) due to more efficient mass and energy transfers, short residence times, and moisture free-operating conditions, agrees Antunes.

	These benefits shouldn’t be limited just to traditional fluorination chemistry, however. “Combination of flow chemistry with the newer difluoromethylation and trifluoromethylation techniques has the potential to provide low-cost, highly effective routes to complex fluorinated molecules,” says Tovell.

	Manchester Organics will be investigating the application of a continuous-flow approach to various fluorination strategies over the next few years. One of the challenges involves optimizing the conditions for reactions that require the use of solid reagents. There are numerous parameters to consider, such as the dilution factor, solvent choice, and reaction temperature. “There is a lot of work to be done, but we believe that this approach will enable the development of effective solutions for many of our customers that are looking for improved methods for the production of their fluorinated compounds,” Tovell observes.


	Since the first introduction of reagents with improved handling and toxicity profiles, such as (2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor), Selectfluor, and diethylaminosulfur trifluoride (DAST), there has been an explosion in the development of new fluorination methods.

	Access to solid reagents such as XtalFluor-E and FLUOLEAD from UBE Industries has led to even further advances in fluorination chemistry, with the number of literature reports on new techniques growing exponentially, according to Tovell. Studies of the reactivities of these various reagents combined with new data obtained using state-of-the-art analytical and modeling technologies are enabling researchers to gain a better understanding of the interactions of fluorine with other atoms in different molecular settings. Tovell believes that this new knowledge will lead to the development of even more effective fluorinating reagents that are highly selective (chemo-, regio-, and stereo), safer to use, can tolerate a wider range of functional groups, are environmentally acceptable, and can be produced at a cost level that will facilitate their use in commercial drug manufacturing.

. 75(10), 3401-3411 (2010).
	2. J.F. Hartwig et al., 

. 50(16), 3793-3798 (2011).
	3. N. Shibata et al., 

. 20, 3465-3468 (2008).
	4. A. Togni et al., 

 12(9), 2579-2586 (2006).
	5. A. Togni et al., A

. 46 (12), 754-757 (2007).
	6. A. Togni et al., 

. 13, 1575-1577 (2008).
	7. A. Togni et al., 

 73(19), 7678-7685 (2008).
	8. A. Togni et al., 

 88, 168-180 (2011).
	9. P.S. Baran et al., 

 108(35), 14411-14415 (2011).
	10. P.S. Baran et al., 

 134(3), 1494-1497 (2012).
	11. P.S. Baran et al., 

 492(7427), 95-99 (2012).
	12. J. Hu et al., 

13(19), 5342-5345 (2011).
	13. S. Buchwald et al.,

 325(5948), 1661-1664 (2009).
	14. T. Ritter et al., 

Articles

In the ongoing search for better fluorinating reagents, solid reagents and new coupling reactions are showing promise.

New Reagents and Reactions Advance Fluorination Chemistry

	The structural complexity of newer small-molecule drug candidates is increasing, with many containing several different heterocyclic substructures and numerous stereogenic centers. Preparing single isomers of these compounds can be quite challenging and requires the use of atom-efficient, low-waste, regio- and stereoselective reactions, according to Dave Green, vice-president of R&D with ANGUS Chemical Company. “A considerable amount of effort is being consumed to expand the utility of classic synthetic methods, often focusing on enantioselective catalysis or combining steps into what are now being called multi-component reactions (MCRs),” he observes.

	In particular, multi-component coupling reactions for the generation of heterocycles in fewer steps with high regioselectivity and reduced processing times, cost, and waste are attracting significant interest. A new cross-dehydrogenative, heteroaromatic carbon–hydrogen (C–H) silylation reaction catalyzed by the simple base potassium tert-butoxide (KOtBu) is also a potentially useful reaction for API synthesis.

	Older methods for the synthesis of heterocycles typically relied on the stepwise construction of linear frameworks followed by final cyclizations. “Today,” says Green, “reaction conditions and catalytic methods are being developed such that three or even four reactive components can be simultaneously combined, resulting in a cascade that leads to a highly functionalized product.” Nitroalkanes are often one of the building blocks used for the synthesis of nitrogen-containing heterocycles.

	In one example published by Maiti et al. in 2010 (1), fully substituted pyrroles were prepared with five independently selected substituents (four-component reaction) in a completely regioselective manner. “It is also notable that all of the starting materials used in the reaction are readily accessible monofunctional reagents,” Green notes. For reactions using nitromethane, isolated yields were often in the 70 to 80% range, and typically higher than those using nitroethane (1). The 3-ketopyrroles obtained from the reaction are highly versatile intermediates and can be used for a variety of synthetic applications, according to Green.

	Dehaen and co-workers reported a three-component coupling reaction between nitroalkanes, alkyl azides, and aldehydes that affords tri-substituted triazoles, again in a regioselective manner (2). This reaction proceeds via 1,3-dipolar cycloaddition of the azide with a nitroalkene formed 

. Tazobactam is one example of a current API that contains a 1,2,3-triazole moiety.

	ANGUS utilized MCR technology to synthesize 3-(N-methyl)-1-phenyl-1-propanol via a heterocyclic intermediate. The three-component reaction of formaldehyde and styrene with N-methyl hydroxylamine, which was readily prepared by selectively reducing nitromethane, proceeded through an isoxazolidine intermediate that was ring-opened to give only the desired regioisomer in nearly quantitative yield. This direct route to 3-(N-methyl)-1-phenyl-1-propanol is an important development, because this compound is the key intermediate in the manufacture of fluoxetine, according to Green. “By using the MCR technique, isolation of the methyl nitrone intermediate was avoided, preventing the issues associated with its propensity to oligomerize,” he explains.

	One of the challenges when preparing nitrogen-containing heterocycles via multi-component reactions that require the use of nitromethane or compounds like N-methylhydroxylamine (MHA) is the reactivity of these substances. Nitromethane, azides, and to a lesser extent MHA are energetic materials, and special handling requirements must be considered. “Minimization of the quantities of in-process and/or isolated materials is an excellent way to also minimize the potential energy release at any given point in the process,” Green says. He points to the recent development of commercially available micro-flow reactors as providing both laboratory- and production-scale options. “At the lab scale, a variety of process conditions and stoichiometries can be evaluated in order to define the safe operating limits for reagent concentrations/ temperature/pressure with essentially no potential energy release risk. In turn, scaling the best operating conditions in an analogous configuration greatly minimizes the risk associated with handling the larger volumes needed for commercial production,” he observes. 

	The substitution of carbon for fluorine is recognized as an attractive method for preparing drug candidates with improved lipophilicity and other attractive properties. More recently, compounds containing silicon-carbon bonds have attracted interest, because such derivatives are also often more stable and have improved solubilities and pharmacokinetic properties.

	To date, heteroaromatic organosilanes have been prepared using two rather limited methods: stoichiometric reaction of a heteroaromatic organometallic intermediate generated via a Grignard reaction with a silicon electrophile and catalytic C–H silylation mediated by a rhodium or iridium catalyst in the presence of an excess of a hydrogen acceptor. The functional group tolerance of these methods is minimal. In addition, they require the use of large quantities of reactive and/or expensive reagents. As a consequence, there is a desire for more general routes to organosilanes that are not only more cost-effective and practical on an industrial scale, but also provide access to novel compounds.

	
	Students in the Grubbs and Stoltz groups at the California Institute of Technology recently stumbled on an interesting reaction catalyzed by KOtBu. They were investigating the conversion of biomass to chemicals via the breakage of carbon-oxygen bonds using an iron catalyst, potassium tert-butoxide, and a hydrosilane as a hydride equivalent and observed that a control reaction with just KOtBu and the hydrosilane gave silylated heteroaromatics as byproducts (4).

	Using 1-methylindole as a model substrate, the reaction conditions were optimized for the selective production of a single organosilane in high yield. A catalytic amount (1-20 mol%) of KOtBu was found to be most effective, and cross dehydrogenative heteroaromatic C–H silylation occurs without the need for an acceptor, resulting in the generation of hydrogen gas as the only byproduct. Extensive studies were also performed to confirm that the KOtBu was indeed the catalyst (3).

	The reaction is noteworthy not only because it is novel, but also because of its scope, scalability, and the fact that it is catalyzed by an inexpensive, commercially available substance based on potassium, which is an abundant alkali metal and not a rare and expensive precious metal. Furthermore, the reaction proceeds under mild conditions, has no complicated byproducts, the product is readily isolated, and in many cases no solvent is required.

	With respect to the scope of the reaction, indoles with a variety of substituents on the nitrogen (N) molecule and at various positions on the arene ring, and many different electron-neutral and electron-rich N-, oxygen- and sulfur-containing heterocyclic compounds are tolerated, although carbonyl groups generally are not unless protected as acetals. In addition, bromide, iodide, cyano, and nitro substituents inhibit the reaction, while fluoride, chloride, trifluoromethyl, epoxide, N-alkyl aziridine, pyridine, and tertiary amine and phosphine groups do not (3).

	Simple arenes also undergo the dehydrogenative heteroaromatic C–H silylation reaction, but the reactivity depends on the substituents. Anisole affords the ortho-substituted silylated product, while toluene and similar compounds undergo directing-group-free C(sp3)–H silylation to generate silylated benzyl derivatives. The electronic nature of any oxygen substituents also determines the regioselectivity (on the ring or the substituent) of the silylation (3).

	Importantly for pharmaceutical applications, the reaction appears to be readily scalable; the neat reaction of N-methyl indole with 1.5 equivalents of triethylsilane at 45 °C was performed on a 100-gram scale followed by simple filtration and distillation, affording the desired C2 silylated product in 76% yield with high regioselectivity (> 20:1) (3).

	In addition, the facile silylation of APIs was achieved to demonstrate the potential for application of the reaction for late-stage modification of pharmaceutically relevant compounds. The antihistamine thenalidine and the antiplatelet drug ticlopidine were successfully subjected to the regioselective C–H silylation reaction (58–68% yield with high chemo- and regioselectivity) (3). Therefore, this method should be useful for the rapid synthesis of compound libraries. Different heteroarylsilanes obtained using the KOtBu chemistry were also converted to more complex molecules via silicon-directed Suzuki–Miyaura cross-coupling and Hiyama–Denmark cross-coupling reactions to demonstrate their synthetic utility (3).

Efficient syntheses are possible using multi-component and cross-dehydrogenative, heteroaromatic C–H silylation reactions

Advances in Heterocyclic Chemistry for API Synthesis

The structural complexity of newer small-molecule drug candidates is increasing, with many containing several different heterocyclic substructures and numerous stereogenic centers. Preparing single isomers of these compounds can be quite challenging and requires the use of atom-efficient, low-waste, regio-, and stereoselective reactions, according to Dave Green, vice-president of R&D with ANGUS Chemical Company. “A considerable amount of effort is being consumed to expand the utility of classic synthetic methods, often focusing on enantioselective catalysis or combining steps into what are now being called multi-component reactions (MCRs),” he observes.

	In particular, multi-component coupling reactions for the generation of heterocycles in fewer steps with high regioselectivity and reduced processing times, cost, and waste are attracting significant interest. A new cross-dehydrogenative, heteroaromatic carbon-hydrogen (C-H) silylation reaction catalyzed by the simple base potassium tert-butoxide (KOtBu) is also a potentially useful reaction for API synthesis.


	Older methods for the synthesis of heterocycles typically relied on the stepwise construction of linear frameworks followed by final cyclizations. “Today,” says Green, “reaction conditions and catalytic methods are being developed such that three or even four reactive components can be simultaneously combined, resulting in a cascade that leads to a highly functionalized product.” Nitroalkanes are often one of the building blocks used for the synthesis of nitrogen-containing heterocycles.


	In one example published by Maiti et al. in 2010 (1), fully substituted pyrroles were prepared with five independently selected substituents (four-component reaction) in a completely regioselective manner. “It is also notable that all of the starting materials used in the reaction are readily accessible monofunctional reagents,” Green notes. For reactions using nitromethane, isolated yields were often in the 70 to 80% range, and typically higher than those using nitroethane (1). The 3-ketopyrroles obtained from the reaction are highly versatile intermediates and can be used for a variety of synthetic applications, according to Green.

. Tazobactam is one example of a current API that contains a 1,2,3-triazole moiety.


	ANGUS utilized MCR technology to synthesize 3-(N-methyl)-1-phenyl-1-propanol via a heterocyclic intermediate. The three-component reaction of formaldehyde and styrene with N-methyl hydroxylamine, which was readily prepared by selectively reducing nitromethane, proceeded through an isoxazolidine intermediate that was ring-opened to give only the desired regioisomer in nearly quantitative yield. This direct route to 3-(N-methyl)-1-phenyl-1-propanol is an important development, because this compound is the key intermediate in the manufacture of fluoxetine, according to Green. “By using the MCR technique, isolation of the methyl nitrone intermediate was avoided, preventing the issues associated with its propensity to oligomerize,” he explains.


	One of the challenges when preparing nitrogen-containing heterocycles via multi-component reactions that require the use of nitromethane or compounds like N-methylhydroxylamine (MHA) is the reactivity of these substances. Nitromethane, azides, and to a lesser extent MHA are energetic materials, and special handling requirements must be considered. “Minimization of the quantities of in-process and/or isolated materials is an excellent way to also minimize the potential energy release at any given point in the process,” Green says. He points to the recent development of commercially available micro-flow reactors as providing both laboratory- and production-scale options. “At the lab scale, a variety of process conditions and stoichiometries can be evaluated in order to define the safe operating limits for reagent concentrations/temperature/pressure with essentially no potential energy release risk. In turn, scaling the best operating conditions in an analogous configuration greatly minimizes the risk associated with handling the larger volumes needed for commercial production,” he observes. 


	The substitution of carbon for fluorine is recognized as an attractive method for preparing drug candidates with improved lipophilicity and other attractive properties. More recently, compounds containing silicon-carbon bonds have attracted interest, because such derivatives are also often more stable and have improved solubilities and pharmacokinetic properties.

	To date, heteroaromatic organosilanes have been prepared using two rather limited methods: stoichiometric reaction of a heteroaromatic organometallic intermediate generated via a Grignard reaction with a silicon electrophile and catalytic C-H silylation mediated by a rhodium or iridium catalyst in the presence of an excess of a hydrogen acceptor. The functional group tolerance of these methods is minimal. In addition, they require the use of large quantities of reactive and/or expensive reagents. As a consequence, there is a desire for more general routes to organosilanes that are not only more cost-effective and practical on an industrial scale, but also provide access to novel compounds.


	Students in the Grubbs and Stoltz groups at the California Institute of Technology recently stumbled on an interesting reaction catalyzed by KOtBu. They were investigating the conversion of biomass to chemicals via the breakage of carbon-oxygen bonds using an iron catalyst, potassium tert-butoxide, and a hydrosilane as a hydride equivalent and observed that a control reaction with just KOtBu and the hydrosilane gave silylated heteroaromatics as byproducts (3).

	Using 1-methylindole as a model substrate, the reaction conditions were optimized for the selective production of a single organosilane in high yield. A catalytic amount (1-20 mol%) of KOtBu was found to be most effective, and cross dehydrogenative heteroaromatic C-H silylation occurs without the need for an acceptor, resulting in the generation of hydrogen gas as the only byproduct. Extensive studies were also performed to confirm that the KOtBu was indeed the catalyst (3).

	Simple arenes also undergo the dehydrogenative heteroaromatic C-H silylation reaction, but the reactivity depends on the substituents. Anisole affords the ortho-substituted silylated product, while toluene and similar compounds undergo directing-group-free C(sp3)-H silylation to generate silylated benzyl derivatives. The electronic nature of any oxygen substituents also determines the regioselectivity (on the ring or the substituent) of the silylation (3).

	In addition, the facile silylation of APIs was achieved to demonstrate the potential for application of the reaction for late-stage modification of pharmaceutically relevant compounds. The antihistamine thenalidine and the antiplatelet drug ticlopidine were successfully subjected to the regioselective C-H silylation reaction (58-68% yield with high chemo- and regioselectivity) (3). Therefore, this method should be useful for the rapid synthesis of compound libraries. Different heteroarylsilanes obtained using the KOtBu chemistry were also converted to more complex molecules via silicon-directed Suzuki-Miyaura cross-coupling and Hiyama-Denmark cross-coupling reactions to demonstrate their synthetic utility (3).

. 75(5), 1674-1683 (2010).
	2. W. Dehaen et al., Angew. 

. 53(38), 10155-10159 (2014).
	3. A. A. Toutov et al., 

: 
	When referring to this article, please cite it as C. Challener, “Advances in Heterocyclic Chemistry for API Synthesis,” 

Efficient syntheses are possible using multi-component and cross-dehydrogenative, heteroaromatic C-H silylation reactions.

The complexity of modern small-molecule drug candidates has increased rapidly in recent years as discovery and development teams seek novel compounds with unique therapeutic properties and attractive physicochemical characteristics. More complexity typically equates to more challenging syntheses and the need for organic transformations that proceed with exquisite selectivity--stereoselectivity, regioselectivity, and chemoselectivity. Often the desired pathway is only slightly different energetically than those that provide undesired products. Running reactions at very low temperature can provide greater control, and thus higher yields and purities of desired isomers. Low temperature is also used to control the reactivity of exothermic processes.

	Low-temperature reactions require special equipment, however, and can, in some cases, be more costly than reactions performed at room temperature. In other cases, dramatically improved yields and purities overcome the higher costs of cooling equipment and greater energy consumption required for low-temperature reactions. Even so, there is a desire to find alternative methods for achieving selectivity without the need to perform reactions at very low temperatures. Flow chemistry is one approach that is receiving increasing attention as a means for addressing both the need for higher selectivities and safer reaction conditions at higher temperatures.

Increasing complexity and need for selectivity


	Control of reactivity in the synthesis of pharmaceutical intermediates and active ingredients is crucial for obtaining the desired products in high yields and also cost-effectively. In addition to proper route design and engineering--and careful selection of raw materials, catalysts, and solvents--the appropriate use of pressure and temperature can be significant.

	Temperature is particularly important in reactions where the formation of very similar products that are only slightly different energetically is possible. Running such reactions at very low temperature can favor the desired product over unwanted isomers, whether they are stereoisomers (enantiomers or diastereomers or regioisomers [cis and trans]). Even desired chemoselectivity--the preferential reaction of one functional group over another--can be achieved at lower temperatures. In other cases, highly reactive intermediates that are unstable and decompose at room temperature may be sufficiently stable at low temperature. Processes with gaseous reactants typically can be performed more readily at colder temperatures below their boiling points.

	When combined with advanced synthetic chemistry, particularly organometallic synthesis, the use of low-temperature chemistry can often lead to more direct, cost-effective routes to sophisticated pharmaceutical compounds. Today, most pharmaceutical companies and contract manufacturers can perform low-temperature chemistry at reasonably large scale because it is now considered a fundamental capability.

	“Low-temperature reactions are widely used in pharmaceutical synthesis, with examples including metal-organic reactions such as lithiations and Suzuki couplings and other metal-catalyzed (asymmetric) reactions. Chlorinations, alkylations at temperatures of -30 °C, as well as reductions, Friedel-Crafts acylations, and deprotonation/addition reactions are other examples. Even reactions at temperatures as low as -75 °C, which are generally achieved using liquid nitrogen cooling systems, are more common today,” says Rhony Aufdenblatten, head of the customer proposal group for chemical and microbial manufacturing in Lonza’s Pharma and Biotech Segment. Lonza currently offers low-temperature capability using different cryogenic technologies up to the 10,000-L scale.

Importance of initial assessment and cooling technology


	One of the main challenges in performing low-temperature chemistry for pharma synthesis is the need to balance setup and operational costs for each individual process, which can only be determined by performing assessments on a case-by-case basis, according to Aufdenblatten. “While many producers do have some capability for low-temperature synthesis in one form or another, the appropriate type of cooling system for a given reaction depends on the nature of the process,” he explains.

	For very-low-temperature reactions, there are two basic cooling systems in use today: direct cooling of the reactor with liquid nitrogen or indirect cooling using a heat transfer fluid. Most often, the choice of cooling method is determined by the access to liquid nitrogen in the plant and the plant layout. While the use of liquid nitrogen to cool a secondary coolant flowing through a jacket around the reactor appears to be more common, some manufacturers do use liquid nitrogen directly in tubes surrounding the reactor because the cooling is more rapid and efficient. It can be difficult to maintain constant temperatures, however, and experienced operators are needed to run such systems.


	Regardless of the cooling method, it is important that the reactor be properly designed and constructed of appropriate materials with matched coefficients of thermal expansion. Otherwise, expansion and contraction of reactor components such as jackets, flanges, and valves may cause leaks or other damage.

	For large-scale low-temperature reactions, careful consideration of the reactor geometry is also important. Often, solvent viscosities increase at very low temperatures, which can affect the heat-transfer and mass-transfer properties of the reaction solution. Such behavior must be taken into account when determining how different reagents will be added to the reaction mixture to ensure thorough mixing and heat dissipation and to prevent local ‘hot spots’ that can result in inconsistent and undesired reaction outcomes.

	It is important to note, however, that with proper planning, reactor and cooling method design, and process engineering, low-temperature synthesis provides access to high-value pharmaceutical intermediates and ingredients that would otherwise be difficult to obtain in high yields and high purities.


	On the other hand, there are some exothermic reactions that require extremely low temperatures (-100 °C) to control, which can be very challenging to achieve and may not be practical on a large scale. For other processes, particularly those run at temperatures ranging from -60 °C to -80 °C, the cost of performing low-temperature reactions on a large scale can significantly impact the economics of the product.

	“The popularity of using flow chemistry as an alternative to low-temperature reactions has grown for these types of systems,” says Aufdenblatten. With flow chemistry, it is possible to perform hazardous reactions that cannot be safely implemented in large-scale batch reactors because reactants, intermediates, and products are only ever present at very low concentrations for very short residence times. As a result, control of process parameters, including temperature and pressure, is more precise.

	In addition, flow reactions allow for lowered utility costs because the temperatures are typically higher compared to those required for similar batch reactions, according to Aufdenblatten. He also notes that it is becoming more common to consider running low-temperature processes under flow conditions to potentially achieve higher selectivities and yields. “Often times, individuals from process development groups will attempt to avoid processes that run at very low temps,” he adds.

	Recently, researchers at the University of Cambridge and Dow Chemical Company developed a modular flow platform for cryogenic reactions in which batch-based low-temperature reactions are represented as a series of five flow coils with independent volumes (1). The utility of the platform was demonstrated by running several reaction types typically performed at low temperature, including Grignard reactions, heteroatom acetylation, and the functionalization of alkynes and heterocycles. A compound library of 20 polyfluorinated molecules was also prepared via a sequential metalation-quench procedure. A tube-in-tube reactor was also shown to be effective for adding gaseous reactants such as carbon dioxide.

:
	When referring to this article, please cite it as C. Challener, “Going Low Temperature," 

The use of low-temperature chemistry can often lead to more direct, cost-effective routes to sophisticated pharmaceutical compounds.

Low Temperature Needed for Complex Drug Candidates

:
	When referring to this article, please cite it as C. Challener, “Advances in Fluorination Chemistry for API Synthesis," 

Safer solid reagents and new coupling chemistry are important developments.

Advances in Fluorination Chemistry for API Synthesis

More complex drug candidates require more specialized and selective chemistry.