CHEMICAL TECHNOLOGY
`
`Fluorinated
`pharmaceuticals
`
`Fluorinated compounds are of increasing interest as pharmaceuticals, and an
`extensive range of techniques for making them is now available.
`
`Dr Basil Wakefield, Ultrafine
`
`Although many pharmaceutical actives now
`
`bear little or no relationship to natural
`products, it is surprising how many are still
`related to natural predecessors.
` However,
`fluoro-organic compounds are very rare
`in
`nature - and the few that do occur are highly toxic.
`Moreover, elemental fluorine and hydrogen
`fluoride both have such a bad reputation as
`hazardous materials that many chemists were - and
`still are - averse to using them. How is it, then, that
`many fluorinated compounds are already in use as
`pharmaceuticals (and agrochemicals), and more
`and more are being developed? According to a
`
`… the
`introduction
`of fluorine
`into a
`biologically
`active
`compound
`improves its
`pharmacological
`properties …
`
`recent book, by 1990 around 220 fluorinated drugs
`were on the market, representing 8 per cent of
`launched synthetic drugs, and at the time of its
`publication around 1,500 were under development
`(1). Three general answers may be given: a) the
`fluoro-organic compound has inherent biological
`activity; b) the introduction of fluorine into a
`biologically active compound
`improves
`its
`pharmacological properties; and c) what has been
`described as ‘patent jumping’ (2).
`The pharmacological superiority of fluorinated
`compounds over their non-fluorinated analogues
`may be rationalised as follows. Although, contrary
`to popular misconceptions,
`covalently bound fluorine
`(C-F bond length 138
`pm) has a significantly
`larger steric requirement
`than hydrogen (C-H
`bond length 109 pm),
`fluorinated compounds
`usually have a sufficient
`similarity in size and
`shape to their non-fluo-
`rinated analogues to fit a
`given enzyme receptor,
`so that they tend to have
`similar inherent biological
`activity. On the other
`hand, the carbon-fluo-
`rine bond is very strong
`(485 KJ mol-1, com-
`pared with C-H, 416 KJ
`mol-1), so the fluorinat-
`ed compounds tend to
`be more resistant to
`metabolic degradation.
`The introduction of fluo-
`rine also generally confers
`increased lipophilicity.
`
`Figure 1. Some fluorinated aromatic and heterocyclic pharmaceuticals.
`
`74
`
`Innovations in Pharmaceutical Technology
`
`FUSTIBAL Ex. 1006
`
`

`
`CHEMICAL TECHNOLOGY
`
`Figure 2. The structure of the proton pump inhibitor, omeprazole (Losec, Astra).
`
`Pharmaceutical properties of
`organofluorine compounds
`
`As so many fluorine-containing drugs are on the
`market, only a small selection can be mentioned.
`Some well-known examples are shown in Figure 1,
`which displays the variety of both chemical
`structures and types of pharmaceutical activity, and
`also illustrates some of the reasons for the popularity
`of fluorinated pharmaceuticals.
`5-Fluorouracil is an example of a fluorinated
`compound with inherent pharmaceutical activity,
`and is one of the longest established fluorinated
`pharmaceuticals. It interferes with DNA and RNA
`synthesis by blocking the action of thymidylate
`synthetase, and is thus cytotoxic. However, it acts
`preferentially in fast-growing (cancerous) cells,
`
`Numerous
`non-fluorinated
`quinolone
`antibacterials
`have been
`made ...
`but the
`fluorinated
`compounds
`appear to have
`superior
`properties ...
`
`which consume it rapidly (3).
`Another long-established fluorinated pharma-
`ceutical is haloperidol (4), which is used to treat a
`number of psychoses, in particular Gilles de la
`Tourette’s syndrome. This example is unusual in
`that little is known about its mode of action and
`the non-fluorinated analogue has not been reported.
`However, it was the forerunner of a long line of
`fluorinated psychoactive compounds, of which
`perhaps the best known is the antidepressant,
`fluoxetine (Prozac™) (5). Details of the mode of
`action of this compound are still unclear, but it
`functions as a selective inhibitor of serotonin
`re-uptake. 5-Fluorouracil and haloperidol possess
`monofluorinated rings, but fluoxetine exemplifies
`the
`large number of biologically
`active
`trifluoromethylaromatic compounds.
`Another important kind of biological activity is
`shown by another monofluorinated aromatic
`compound, the antibacterial, ciprofloxacin (6).
`Numerous non-fluorinated quinolone antibacterials
`have been made, and many marketed, but the
`fluorinated compounds appear to have superior
`properties, so that several are on the market and
`more are under development. Ciprofloxacin is
`active against both Gram-positive and Gram-
`negative bacteria.
`Lansoprazole might be regarded as an example
`of ‘patent jumping’. It was introduced by Takeda
`as a rival to Astra’s ‘blockbuster’ proton pump
`inhibitor, omeprazole (Figure 2). Inevitably,
`
`Figure 3. Some fluoroaliphatic and alicyclic pharmaceuticals.
`
`76
`
`Innovations in Pharmaceutical Technology
`
`

`
`patent litigation ensued! The Astra-Hässle patent
`(7) covered compounds with a 4-ethoxy
`substituent in the pyridine ring, and a key dispute
`was whether this covered a 2,2,2-trifluoroethoxy
`substituent. Since the dispute was settled out of
`court, the argument is still not legally resolved.
`Almost all the compounds listed in reference
`(1) are aromatic compounds bearing fluoro or
`trifluoromethyl substituents. Fluorinated aliphatic
`compounds are much
`less widely used as
`pharmaceuticals but two categories are important:
`steroids and anaesthetics
`(see Figure 3).
`Fluorinated
`steroids
`are
`exemplified by
`flumethasone. Fluorine-substitution in steroids
`has been found beneficial in blocking metabolic
`pathways (particularly hydroxylation), and also in
`modifying the reactivity of adjacent oxygen func-
`tions. Anaesthetics are exemplified by halothane.
`Despite some disadvantages, halothane is still one
`of the most widely used inhalation anaesthetics,
`although various fluorinated ethers have been
`introduced as alternatives (see Ref 1, p 891). (It is
`noteworthy that although halothane is both an
`ozone destroyer and a greenhouse gas, there has
`not been an outcry against its use on these
`grounds.) Finally noteworthy are perfluorocarbons
`such as perfluorodecalin. These compounds can
`dissolve large volumes of oxygen and, following
`successful animal trials, have met with some clinical
`success as ‘artificial blood’ (see Ref 8, p369
`for reviews).
`
`Synthesis of fluorinated
`pharmaceuticals
`
`its own
`fluorine chemistry has
`Organic
`characteristics; the organic chemistry of the other
`halogens can not be extrapolated to fluorine.
`Furthermore, although methods for introducing
`fluorine
`into organic molecules have been
`developed over many years (8), many of the earli-
`er laboratory techniques are not suited to industri-
`al production. Accordingly, the high level of inter-
`est in fluorinated pharmaceuticals has led to
`corresponding activity in the development of
`improved methods
`for
`synthesising
`these
`compounds. As a result, useful fluorinated
`building blocks (most of them fluoroaromatic
`compounds) are now offered on a large scale (1),
`and new reagents and techniques are available
`(9). Some of
`these
`recent advances are
`highlighted below.
`
`• The classical method for preparing fluoroaromatic
`compounds was the thermal decomposition of
`aryldiazonium
`tetrafluoroborates
`(the Balz-
`Schiemann reaction). Various modifications have
`been made to this unpredictable and sometimes
`hazardous process, but the preferred industrial
`method is now diazotisation in anhydrous hydrogen
`
`CHEMICAL TECHNOLOGY
`
`Organic fluorine
`chemistry has
`its own
`characteristics -
`the organic
`chemistry of
`the other
`halogens
`cannot be
`extrapolated
`to fluorine
`
`fluoride. Hydrogen fluoride is of course very
`hazardous, but it is readily handled on a large scale
`provided that proper precautions are taken.
`
`organic
`brominated
`and
`• Chlorinated
`compounds are comparatively easily prepared, so
`exchange of fluorine for the other halogens is
`attractive. Once again, anhydrous hydrogen
`fluoride has been used as combined solvent and
`source of fluoride (either alone or in conjunction
`with compounds such as antimony pentahalides).
`Another widely used source of fluoride ions is
`potassium fluoride, which must be anhydrous and
`preferably finely divided. By the use of spray-dried
`potassium fluoride, usually in an anhydrous
`dipolar aprotic solvent such as sulfolane, multiple
`replacements of chlorine by fluorine are achievable.
`
`• Hydrogen fluoride and other sources of
`fluoride have been used to replace hydroxyl and
`selected ether functions by fluorine. Probably
`more important is the replacement of carbonyl
`functions: aldehyde and ketone groups by
`
`Figure 4. Laboratory-scale use of fluorine using the
`Fluorodec® LT generator (reproduced by
`permission of Fluorogas Ltd).
`
`gen-dimethyl and carboxylic acid groups by
`trifluoromethyl. The former transformation is
`accomplished by sulfur tetrafluoride (hazardous),
`by diethylaminosulfur
`trifluoride
`(DAST;
`less hazardous though
`less reactive) or by
`bis
`(2-methoxyethyl)aminosulfur
`trifluoride
`(Deoxofluor®, claimed to be a safe replacement for
`DAST (8)).
`
`The above may be regarded as indirect methods
`for introducing fluorine, involving F-. For ‘direct’
`introduction of fluorine, by replacement of hydrogen,
`sources of F• or F+ are required.
`
`• Elemental chlorine and bromine may be used
`for radical halogenation (for example, via
`photo-dissociation). In the case of fluorine, such
`reactions proceed only too well. As a consequence
`
`… the design
`of reagents
`capable of
`furnishing
`electrophilic
`fluorine …
`has required
`considerable
`invention
`
`Innovations in Pharmaceutical Technology
`
`77
`
`

`
`CHEMICAL TECHNOLOGY
`
`After graduating from Imperial College, London,
`(BSc and PhD), postdoctoral research in the USA
`(Louisville, Ky) and the UK (Reading) and a period
`in industry (Courtaulds), Dr Basil Wakefield spent
`most of his career at the University of Salford, where
`his research interests included polyhalogenated aro-
`matic and heteroaromatic compounds. In 1984, he
`was a co-founder with Feodor Scheinmann of
`Ultrafine, which arose from a university company set
`up to carry out custom syntheses for industry. On his
`retirement from the university, he joined the company
`- which now has a staff of almost 30 and offers a com-
`prehensive chemical service to pharmaceutical and
`biotechnology companies.
`
`References
`
`1. Becker A (1997). “Inventory of Industrial
`Fluoro-Biochemicals”, Eyrolles, Paris.
`
`2. Seebach D (1990). Angew Chem, Int Edn
`Engl, 29, 1320.
`
`3. Klein E. et al.
` In “Cancer
`(1972).
`Chemotherapy” (eds Brodsky I and Kahn S),
`Grune and Stratton, New York.
`
`4.
`
`Janssen PAJ. et al. (1959). J Med Chem, 1,
`281.
`
`5. Molloy BB (1974). Eli Lilly & Co, US
`401895.
`
`6. Grohe K. et al. (1980). Bayer, Ger Offfen DE
`3033157.
`
`7.
`
`Junggren UK et al. (1979). Hässle, EP
`005129.
`
`8. Lal GS et al. (1999). Chem Comm, 215.
`
`9. “Fluorine, the first hundred years” (1986).
`Eds Banks RE, Sharp DWA and Tatlow JC,
`Elsevier Sequoia, Lausanne and New York.
`
`10. Olah GA, Chambers RD and Surya Prakash
`GK (1992). “Synthetic Fluorine Chemistry”,
`Wiley, New York; Hudlicky P, Pavlath AE
`(eds)
`(1995). “Chemistry of Fluorine
`Compounds II”, American Chemical Society,
`Washington.
`
`11. Lal GS et al. (1996). Chem Rev, 96, 1737.
`
`Figure 5. Selectfluor® reagent.
`
`of the very weak F-F bond (dissociation energy
`only 159 KJ mol-1) and the very strong C-F bond
`(485 KJ mol-1), radical chain fluorination by
`elemental fluorine is so exothermic that incautious
`experiments on reactions of
`fluorine with
`hydrocarbons led to ignition or worse (9). Some of
`the methods for overcoming this problem are the
`use of high dilution
`in
`inert gases,
`low
`temperatures and moderators, and ‘slow release’
`techniques such as electrochemical generation of
`fluorine in situ and the use of high-valent metal flu-
`orides as fluorine carriers. All of these required spe-
`cial know-how and equipment, so they tended to
`be confined to specialised laboratories. Such
`laboratories continue to be
`invaluable, but
`equipment for generating and handling fluorine is
`now more generally available. Work with fluorine
`should still not be undertaken lightly and requires
`rigorous safety evaluation, but it can now be carried
`out in a ‘normal’ laboratory environment (see
`Figure 4).
`• Fluorine is the most electronegative element, so
`the design of reagents capable of furnishing
`electrophilic fluorine - F(cid:98)+, let alone F+ - has
`required considerable
`invention. Perchloryl
`fluoride, FClO3, worked fairly well but proved haz-
`ardous, and xenon difluoride is useful but very
`expensive. However, rationally designed reagents
`containing fluorine bonded to other electronegative
`atoms, oxygen and nitrogen, are now available (10).
`Fluoroxy-compounds, such as fluoroxytrifluo-
`romethane, CF3OF, and acyl hypofluorites,
`RCOOF, have to be prepared in situ (using
`fluorine), but studies on a large number of
`N-fluoro-compounds
`(11) have
`led
`to
`the
`development of some stable, crystalline reagents for
`electrophilic fluorination. These include the
`commercially available SelectfluorR reagent, Figure 5.
`A short article can only give an over-simplified
`and highly selective account of fluorinated pharma-
`ceuticals. However, I hope to have demonstrated
`that, rather than being viewed as unusual and
`esoteric, organofluorine compounds should be
`regarded as important mainstream pharmaceuticals,
`and advances in synthetic methodology now make
`them readily available.
`
`78
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`Innovations in Pharmaceutical Technology
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`

`
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`Fluorinated compounds are of increasing interest as pharmaceuticals, and an extensive range of
`techniques for making them is now available.
`
`Dr Basil Wakefield, Ultrafine (January 2000)
`
`Keywords: peptides, fine chemicals, active pharmaceutical ingredients, contract manufacturing,
`chiral, chiral synthesis, , chiral technology, intermediates, enantiomers, bulk pharmaceuticals,
`chemical synthesis, galenic development, raw materials, biocatalysts, botanicals, biochemistry,
`chemical analysis, solid phase combinatorial synthesis, specialty chemicals, intermediate synthesis,
`peptide chemistry, Ultrafine, Fluorinated pharmaceuticals, Fluorinated compounds
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