Continuous Flow Selective Direct Fluorination Using

Continuous Flow Selective Direct Fluorination Using Fluorine Gas

12

G. Sandford Durham University, Durham, United Kingdom

Chapter Outline 1. Introduction 339 2. Continuous Flow Processes Using Fluorine Gas 2.1

341

Durham Continuous Flow Direct Fluorination Equipment 341 2.1.1 Single-Channel Flow Reactors for Direct Fluorination 342 2.1.2 Multi-Channel Flow Reactors for Direct Fluorination 343

3. Selective Direct Fluorination by Continuous Flow Processes 3.1 3.2 3.3

343

Fluorination of Aromatic Systems 344 Fluorination of 1,3-Dicarbonyl Systems 345 Fluorination of Aniline Derivatives 347

4. Conclusions 347 References 348

1. Introduction A crucial stage in the synthesis of all fluorinated organic compounds is the construction of the carbonefluorine bond whether at the late stage of a synthetic strategy or for the preparation of a fluorinated “building block” that is used as a substrate for transformation into more structurally sophisticated systems.1,8,22 In particular, syntheses of fluorinated derivatives for the pharmaceutical industry, from the discovery phase to the manufacturing scale are, in many cases, very challenging given the structural complexity of many advanced pharmaceutical intermediates (API) and marketed drugs. Consequently, over the years, a range of fluorinating reagents have been developed to meet the varied synthetic requirements of the life science industry1 and many reagents are commercially available from the usual specialty and bulk chemical suppliers. The choice of fluorinating agent to use for any particular transformation depends on a number of factors including functional group tolerance, synthetic process, appropriate substrate, availability, facilities, and expertise. In particular, the reaction scale plays a role in choosing a particular fluorinating agent. For example, medicinal chemists requiring 10e20 mg of a fluorinated molecule for biological screening assays need easily handled, nontoxic, shelf-stable, and noncorrosive reagents that are Modern Synthesis Processes and Reactivity of Fluorinated Compounds. http://dx.doi.org/10.1016/B978-0-12-803740-9.00012-3 Copyright © 2017 Elsevier Inc. All rights reserved.

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Modern Synthesis Processes and Reactivity of Fluorinated Compounds

amenable for use in automated parallel synthesis and purification systems. For such applications, the cost of a reagent is not a consideration and purification is usually performed automatically by column chromatography using preloaded silica gel cartridges. In contrast, larger scale syntheses to produce multi-kilogram quantities of fluorinated product for advanced clinical trials and manufacturing, the cost of API production, and the ease of purification, usually by recrystallization, become very important factors in the choice of the fluorinating agent and synthetic strategy used. In general, therefore, reagents used for the discovery and early clinical trial phases of a drug development campaign are often very different from those used on the manufacturing scale, principally due to reagent cost, ease of API production, and purification.15 All fluorinating reagents are derived from anhydrous hydrogen fluoride (aHF), which is manufactured on a very large scale from mined fluorspar.16 Consequently, fluorinating agents that are sufficiently inexpensive for use on the manufacturing scale are, in general, aHF, KF, and F2, which are easily accessible in one or two steps from fluorspar raw material. Systems such as Selectfluor, diethylaminosulfur trifluoride (DAST), Deoxo-Fluor and other electrophilic fluorinating agents of the N-F class are, in general, too expensive for manufacturing procedures, although, of course, some exceptions exist.2 Anhydrous HF is the most widely used fluorinating agent in manufacturing including extensive application for the synthesis of fluoro- and trifluoromethyl aromatic derivatives, which appear in the majority of fluorinated drug structures, despite the extreme hazards associated with using this very volatile (bp 19 C), highly corrosive and toxic reagent. KF is used for some halogen exchange processes for the synthesis of some appropriately activated fluoroheterocyclic systems, for example, although the low solubility and harsh reaction conditions required for useful yield preclude the general applicability of this fluoride ion source. In contrast, the use of fluorine gas for the manufacture of APIs and downstream pharmaceutical products has received little attention, perhaps due to the lack of suitable synthetic methodology available, until recent years. The general perception that fluorine is too reactive for effective use as a selective fluorinating agent has also hampered the development of F2 as a reagent for organic synthesis despite the fact that F2 is synthesized by electrolysis of aHF and is, therefore, relatively inexpensive. Indeed, 5-fluorouracil (oncology) has been manufactured for over 50 years by direct fluorination of uracil in aqueous acetic acid and, in 2001, a process for the synthesis of the 5-fluoropyrimidine subunit of the antifungal agent fluconazole (V-Fend, Pfizer) using F2 began operation.4 These two successes point to the opportunities for using F2 for the synthesis of fluorinated APIs on the manufacturing scale. In this chapter, we discuss how direct fluorination reactions using F2 can be used for the synthesis of fluorinated derivatives of interest to life science programs by continuous flow procedures that are, in principle, suitable for scale-up. There is a considerable effort worldwide directed towards developing a vast array of continuous flow procedures, and reactor design is an especially important area.14,23 There are many advantages associated with using continuous flow reactors for chemical synthesis at both the laboratory and manufacturing stages, and those discussed

Continuous Flow Selective Direct Fluorination Using Fluorine Gas

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widely include high throughput; use of very small quantities of material when appropriate; reduced waste streams; low manufacturing, operation, and maintenance costs; low power consumption; increased precision and accuracy; and disposability. Continuous flow processes may also lead to increased performance of a system due to optimization of contact between reagents because of very rapid mixing in such devices. The concept of “scale-out” by running many reactors in parallel is also very appealing where bench operation would exactly mirror the manufacturing situation, thus reducing the resources required for good manufacturing practice accreditation. Additionally, there are special advantages to developing continuous flow reactors for potentially hazardous processes, where the inventory of reactants is sufficiently small in any one reactor section, such that levels of control and safety could be achieved, which would not be possible by conventional means. This chapter is not a comprehensive review of all processes involving fluorine gas in continuous flow reactor processes but highlights some of the opportunities available and derived from research reported by the Durham group.17,19,21

2. Continuous Flow Processes Using Fluorine Gas When performing a synthetic procedure using a gaseous reagent, careful consideration of the experimental technique is required due to inherent associated handling issues. Batch processes, in which gaseous reagents are passed through the rapidly stirred liquid phase, have been used very successfully for many years. However, gas mass transfer into the liquid phase, gaseliquid mixing via a small interfacial area, difficulties in heating or cooling a multiphase process, and handling waste gas streams efficiently have led to the development of complementary continuous flow technology for both the laboratory and manufacturing stages. The passage of gas and liquid substrate streams through a small-volume reactor channel by a continuous flow process offers far easier reaction control, increased safety due to the relatively small amounts of gas and liquid reagents in contact at any given time, more effective reaction temperature control leading to increased reaction selectivity, and better phase mixing, which allows more controlled gas mass transfer.18 Several types of flow reactor have been used for gaseliquid reactions including falling film, gas-permeable tube-in-tube membrane systems, and “mesh-” modified microor mesoscale systems, and these have been reviewed in 2015.18

2.1

Durham Continuous Flow Direct Fluorination Equipment

At Durham University (United Kingdom), several continuous flow reactor systems have been developed during a research program that began in 1995, and the most frequently used single- and multichannel systems used in Durham for fluorine gas reactions are described briefly in the following sections.5,7,9 Full details of the equipment and experimental procedures may be obtained from the appropriate cited references and not repeated here.

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2.1.1

Modern Synthesis Processes and Reactivity of Fluorinated Compounds

Single-Channel Flow Reactors for Direct Fluorination

The first reactor designed for reactions involving fluorine gas was reported in 1999.5,7 The reactor (Fig. 12.1) is, essentially, a nickel metal block that has a 0.5-mm-diameter reaction channel etched into its surface. A transparent polychlorotrifluoroethylene (PCTFE) plate and a bolted stainless-steel sheet complete the reactor channel. Fluorine gas and other reagent streams are introduced into the reactor channel via stainless-steel tubing, and the product outflow is collected. The temperature of the reaction block may be controlled by an external, circulating heating/cooling cryostat. Gas and liquid reagents are introduced into the reactor channel at prescribed rates by commercially available gas mass flow controller and either a syringe or high-performance liquid chromatography pump addition, respectively. In this reactor design, the gas and liquid flow concurrently down the reactor channel by laminar or “pipe” flow, as viewed through the PCTFE window, which enables excellent phase mixing and gas transport into the liquid phase. Substrate solution

Channel width & depth ca. 500 micrometers

F2 / N2

70 mm

Top View

100 mm

Products Substrate solution

Side View

F2 / N2

Products

30 mm

70 mm Stainless steel

Coolant channel

(CF2CFCI)n

Nickel Thermocouple channel

Figure 12.1 Durham single-channel laminar flow reactor.

A simpler single-channel continuous flow system is composed of a 0.1-mminternal-diameter stainless-steel tube fitted with a T-piece union that enables introduction of both gas and liquid feedstocks. The tube can be coiled to allow the entire apparatus to be submerged in a cooling or heating fluid as appropriate depending upon the reaction conditions.

Continuous Flow Selective Direct Fluorination Using Fluorine Gas

2.1.2

343

Multi-Channel Flow Reactors for Direct Fluorination

For larger scale syntheses, use of single-channel systems that have a much longer path length may allow higher throughput of material but, scaling out, which uses a reactor that presents a number of channels in parallel, offers a complementary approach. Multichannel reactors (Fig. 12.2) for direct fluorination have been developed at Durham9 and allow the synthesis of 100 g quantities of the product material in an 8h reaction using a 9-channel parallel reactor. Gas Reagent In

Liquid Reagent In Product Out

Figure 12.2 Multichannel continuous laminar flow reactor.

The reactor, described in detail elsewhere, basically consists of a steel base block that incorporates two substrate reservoirs within the body of the block and a stainless-steel reactor channel plate of typically 9, 18, or 30 channels that are 0.5 mm wide and 0.5 mm deep. Transparent PTCFE and stainless-steel window plates compress the reactor system together. Continuous operation of various fluorination processes over long reaction time periods of 150 h have been performed with no loss of yield or conversion. The use of fluorine gas in any of the continuous flow systems described earlier, of course, requires experience and expertise in handling fluorine gas mixtures, careful passivation of all metal surfaces and reaction channels, and correct choice of appropriate resistant valves and mass flow meters before operation can begin.

3. Selective Direct Fluorination by Continuous Flow Processes Various selective direct fluorination reactions using fluorine gas are presented in the following subsections using the laminar flow systems described earlier to illustrate the opportunities available using this usually undervalued and underused reagent.19

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Modern Synthesis Processes and Reactivity of Fluorinated Compounds

Given the low expense of fluorine gas and low capital expenditure required to purchase or construct a continuous gas flow reactor system and subsequent scale-up opportunities, all reactions are, in principle, appropriate for scale-up for applications within the life science industries.

3.1

Fluorination of Aromatic Systems

Reactions of aromatic derivatives with fluorine gas in acidic media such as formic or sulfuric acids give rise to products consistent with an electrophilic aromatic substitution process (Scheme 12.1).6 As with other halogenation reactions, mixtures of fluorinated aromatic products are formed due to activation of several sites of the aromatic substrate and, in many cases, polyfluorination. Substrates that bear an electron-donating group para to an electron-withdrawing group, however, give rise to mainly monofluorinated derivatives. For example, 4-methoxynitrobenzene gives high yields of 3-fluoro-4methoxynitrobenzene along with some difluorinated by-products. Reaction control may be mediated by the continuous flow reactor system, giving rise to less difluorinated by-product compared with the more usual batch processes, because the monofluorinated product flows out of the reaction channel preventing further fluorination.

Scheme 12.1 Fluorination of 1,4-disubstituted aromatic derivatives.

The larger gaseliquid interface possible in a small-diameter continuous flow system allows even very unreactive aromatic systems to react efficiently with fluorine. A series of 1,3-dinitrobenzene substrates gave the corresponding 5-fluorinated products upon reaction with fluorine in formic acid in a flow process (Scheme 12.2).12 Related batch fluorination processes require the use of at least 5e10 equivalents of fluorine to be passed through a rapidly stirred solution of the dinitrobenzene substrate due to slow reaction and loss of unreacted fluorine gas to the attached scrubbing system. Benzaldehyde derivatives react with fluorine gas to give the corresponding fluoroaromatic or aryl carboxylic acid fluoride products depending on the nature of the substrate (Scheme 12.3).13 Aromatic substrates bearing electron-donating groups such as methoxy give fluoroaromatic derivatives as the major products because, in

Continuous Flow Selective Direct Fluorination Using Fluorine Gas

345

Scheme 12.2 Fluorination of 1,3-disubstituted aromatic derivatives.

these cases, the aromatic ring is sufficiently nucleophilic to undergo electrophilic substitution. In contrast, benzaldehyde derivatives bearing electron-withdrawing groups such as trifluoromethyl are deactivated toward electrophilic attack, and displacement of the aldehydic proton to give the carboxylic acid fluoride occurs. The acid fluoride can be isolated as the corresponding ester by the addition of an appropriate alcohol into the crude reaction mixture. Although fluorination of the arene ring is consistent with an electrophilic substitution process, the mechanism for the fluorination of the aldehyde group is less clear, but the selectivity of the process also suggests that an electrophilic process is more likely especially under such favorable acidic reaction conditions (Scheme 12.3).

Scheme 12.3 Fluorination of benzaldehyde derivatives.

3.2

Fluorination of 1,3-Dicarbonyl Systems

Continuous flow fluorination of ranges of 1,3-diketone, ketoester, and diester substrates have been studied extensively10,11 given the importance of fluorinated dicarbonyl derivatives as building blocks for the pharmaceutical industry. Ethyl

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Modern Synthesis Processes and Reactivity of Fluorinated Compounds

acetoacetate mainly gives the desired 2-fluoro-derivative upon continuous flow fluorination in formic acid at 0e5 C. Some difluorinated products are formed, but these can be readily separated from the monofluorinated system by simple aqueous washing of the crude product material (Scheme 12.4).

Scheme 12.4 Fluorination of 1,3-diketone and 1,3-ketoester derivatives.

Meldrum’s acid gives a mixture of mono- and difluorinated systems on reaction with fluorine in a flow system, and these products are most easily separated by addition to ethanol and distillation of the corresponding ethyl diesters (Scheme 12.5).11

Scheme 12.5 Fluorination of Meldrum’s acid.

Sequential gaseliquid/liquideliquid flow processes allow the preparation of fluoropyrazoles in a two-step, one continuous flow process.3 The single-channel reactor system described earlier can be adapted to include three inputs of fluorine: 1,3dicarbonyl substrate and hydrazine solution, which enables sequential fluorination of the dicarbonyl substrate, followed by cyclization to the pyrazole product by established condensation reactions (Fig. 12.3). For example, pentane-2,4-dione can be transformed in one process to 4-fluoro-3,5-dimethyl pyrazole in high yield using a three-input flow reactor system (Scheme 12.6).

Continuous Flow Selective Direct Fluorination Using Fluorine Gas

347

Fluorine sodalime scrubber

flow reactor substrate solution

hydrazine solution

catch pot

Figure 12.3 Flow reactor for sequential gaseliquid/liquideliquid flow processes.

Scheme 12.6 Synthesis of 4-fluoro-3,5-dimethylpyrazole.

3.3

Fluorination of Aniline Derivatives

Synthesis of aryleNF2 systems can be achieved by reaction of the appropriate aniline derivatives with fluorine.20 Passing a sixfold excess of fluorine and perfluoro-2nitroaniline or a related perfluroaniline system concurrently through a continuous flow reactor gave good yields of the corresponding difluoroamine product (Scheme 12.7). Perfluorinated aniline derivatives were used as substrates since no competing fluorination of the aryl ring is possible.

Scheme 12.7 Synthesis of Ar-NF2 derivatives.

4. Conclusions In summary, easily constructed single- and multichannel continuous flow reactors may be used for selective direct fluorination of a range of aromatic, 1,3dicarbonyl and amine substrates using fluorine gas. These processes could, in principle, be scaled up if required using either longer path length single-channel reactors or multichannel systems. The use of fluorine gas can be particularly beneficial for large-scale synthesis due to the low cost of this reagent, and process development chemists should consider the use of continuous flow processes using fluorine gas in development and manufacturing phases of new fluorinated pharmaceuticals and agrochemicals.

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Modern Synthesis Processes and Reactivity of Fluorinated Compounds

References 1. Baasner, B.; Hagemann, H.; Tatlow, J. C. In Houben-Weyl Organofluorine Compounds, Vol. E10a; Thieme: Stuttgart, 2000. 2. Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry. Principles and Commercial Applications; Plenum: New York, 1994. 3. Breen, J. R.; Sandford, G.; Yufit, D. S.; Howard, J. A. K.; Fray, J.; Patel, B. Continuous Gas/ Liquid e Liquid/Liquid Flow Synthesis of 4-Fluoropyrazole Derivatives by Selective Direct Fluorination. Beilstein J. Org. Chem. 2011, 7, 1048e1054. 4. Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Process Development of Voriconazole: A Novel Broad-Spectrum Triazole Antifungal Agent. Org. Process Res. Dev. 2001, 5, 28e36. 5. Chambers, R. D.; Spink, R. C. H. Microreactors for Elemental Fluorine. Chem. Commun. 1999, 883e884. 6. Chambers, R. D.; Hutchinson, J.; Sparrowhawk, M. E.; Sandford, G.; Moilliet, J. S.; Thomson, J. Fluorination of 1,4-Disubstituted Aromatic Compounds. J. Fluor. Chem. 2000, 102, 169e173. 7. Chambers, R. D.; Holling, D.; Sandford, G.; Spink, R. C. H. Gas-Liquid Thin Film Microreactors for Selective Direct Fluorination. Lab Chip 2001, 1, 132e137. 8. Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, 2004. 9. Chambers, R. D.; Fox, M. A.; Holling, D.; Nakano, T.; Okazoe, T.; Sandford, G. Versatile Thin-Film Gas-Liquid Multi-Channel Microreactors for Effective Scale-Out. Lab Chip 2005, 5, 191e198. 10. Chambers, R. D.; Fox, M. A.; Sandford, G. Selective Direct Fluorination of 1,3-Ketoesters and 1,3-Diketones Using Microreactor Technology. Lab Chip 2005, 5, 1132e1139. 11. Chambers, R. D.; Fox, M. A.; Holling, D.; Nakano, T.; Okazoe, T.; Sandford, G. Versatile Gas-Liquid Microreactors for Industry. Chem. Eng. Technol. 2005, 28, 344e352. 12. Chambers, R. D.; Fox, M. A.; Sandford, G.; Trmcic, J.; Goeta, A. Direct Fluorination of Deactivated Aromatic Systems Using Microreactor Techniques. J. Fluor. Chem. 2007, 28, 29e33. 13. Chambers, R. D.; Sandford, G.; Trmcic, J.; Okazoe, T. Direct Fluorination of Benzaldehyde Derivatives. Org. Process Res. Dev. 2008, 12, 339e344. 14. Ehrfeld, W.; Hessel, V.; Lowe, H. Microreactors. New Technology for Modern Chemistry; Wiley-VCH: New York, 2000. 15. Gadamasetti, K. G. Process Chemistry in the Pharmaceutical Industry; Marcel Dekker: New York, 1999. 16. Harsanyi, A.; Sandford, G. Organofluorine Chemistry: Applications, Sources and Sustainability. Green Chem. 2015, 17, 2081e2086. 17. Hutchinson, J.; Sandford, G. Elemental Fluorine in Organic Chemistry. Top. Curr. Chem. 1997, 193, 1e43. 18. Mallia, C. J.; Baxendale, I. R. The Use of Gases in Flow Synthesis. Org. Process Res. Dev. 2015, 20. ASAP article. 19. McPake, C. B.; Sandford, G. Selective Continuous Flow Processes Using Fluorine Gas. Org. Process Res. Dev. 2012, 16, 844e851. 20. McPake, C. B.; Murray, C. B.; Sandford, G. Continuous Flow Synthesis of Difluoroamine Systems by Direct Fluorination. Aust. J. Chem. 2013, 66, 145e150. 21. Sandford, G. Elemental Fluorine in Organic Synthesis (1997e2006). J. Fluor. Chem. 2007, 128, 90e104. 22. Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006. 23. Wiles, C.; Watts, P. Microreaction Technology in Organic Synthesis; CRC Press: Boca Raton, 2011.