J. Pestic. Sci. 46(2): 125-142 (2021)

J. Pestic. Sci. 46(2), 125–142 (2021) DOI: 10.1584/jpestics.D21-012

Review

Synthesis and application of trifluoromethylpyridines as a key structural motif in active agrochemical and pharmaceutical ingredients

Masamitsu Tsukamoto,1,* Tadashi Nakamura,1 Hirohiko Kimura2 and Hitoshi Nakayama3

1 Bioscience Business Headquarters, Ishihara Sangyo Kaisha, Ltd., 1–3–15 Edobori, Nishi-ku, Osaka 550–0002, Japan 2 Central Research Institute, Ishihara Sangyo Kaisha, Ltd., 2–3–1 Nishi-shibukawa, Kusatsu, Shiga 525–0025, Japan 3 Healthcare Business Development Headquarters, Ishihara Sangyo Kaisha, Ltd., 1–3–15 Edobori, Nishi-ku, Osaka 550–0002, Japan (Received February 13, 2021; Accepted April 2, 2021)

Herein, we provide a brief overview of the synthesis and applications of trifluoromethyl pyridine (TFMP) and its derivatives in the agrochemical and pharmaceutical industries. Cur- rently, the major use of TFMP derivatives is in the protection of crops from pests. Fluazifop- butyl was the first TFMP derivative introduced to the agrochemical market, and since then, more than 20 new TFMP-containing agrochemicals have acquired ISO common names. Sev- eral TFMP derivatives are also used in the pharmaceutical and veterinary industries; five pharmaceutical and two veterinary products containing the TFMP moiety have been granted market approval, and many candidates are currently undergoing clinical trials. The biological activities of TFMP derivatives are thought to be due to the combination of the unique physicochemical properties of the fluorine atom and the unique characteristics of the pyridine moiety. It is expected that many novel applications of TFMP will be discovered in the future.

Keywords: trifluoromethylpyridine, intermediate, chemical properties, agrochemicals, pharmaceuticals, vapor–phase reaction.

addition, around 40% of all fluorine-containing pesticides cur- Introduction rently on the market contain a trifluoromethyl group, making Many recent advances in the agrochemical, pharmaceutical, and these compounds an important subgroup of fluorinated com- functional materials fields have been made possible by the de- pounds.1) The biological activities of fluorine-containing com- velopment of organic compounds containing fluorine. Indeed, pounds are considered to be derived from the unique physico- the effects of fluorine and fluorine-containing moieties on the chemical properties of fluorine (van der Waals radius, 1.47 Å),2) biological activities and physical properties of compounds have which, sterically, is the next smallest atom after hydrogen (van earned fluorine a unique place in the arsenal of the discovery der Waals radius, 1.20 Å)2) but the atom with the largest elec- chemist. As the number of applications for these compounds tronegativity (3.98).3) In addition, because the carbon–fluorine continues to grow, the development of fluorinated organic bond is relatively short (1.38 Å) compared with the other chemicals is becoming an increasingly important research topic. carbon–halogen bonds, the bond has strong resonance. As a re- 4) In the crop protection industry, more than 50% of the pesti- sult, the Hammett constant (σp) of fluorine is 0.06, which is cides launched in the last two decades have been fluorinated. In similar to that of hydrogen. Interestingly, the electronegativity of the trifluoromethyl group is 3.46,5) and its Hammett constant is 0.54,4) indicating that, unlike fluorine, the trifluoromethyl group * To whom correspondence should be addressed. is strongly electron withdrawing. Therefore, during compound E-mail: [email protected] development, the trifluoromethyl group can be treated as a pure- Published online May 20, 2021 ly electron-withdrawing group. © Pesticide Science Society of Japan 2021. This is These unique properties of fluorine mean that substitution an open access article distributed under the Creative Commons Attri- with a fluorine or fluorine-containing moiety can have a large bution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND impact on the conformation, acid dissociation constant, metab- 4.0) License (https://creativecommons.org/licenses/by-nc-nd/4.0/) olism, translocation, and biomolecular affinity of a compound. 126 M. Tsukamoto et al. Journal of Pesticide Science

This has meant that bioisosteric replacement of hydrogen with fluorine has become a useful means of designing compounds with unique biological properties. For similar reasons, much ef- fort has been made to develop synthetic methods for introducing trifluoromethyl groups into aromatic rings. The first synthesis of an aromatic compound bearing a trifluoromethyl group was reported in 1898 by Swarts,6) who treated benzotrichloride with antimony trifluoride to afford benzotrifluoride; the same transformation using hydrogen fluoride was subsequently achieved under liquid-phase reaction conditions in the 1930s.7) In 1947, the introduction of a trifluoromethyl group into a pyridine ring to afford trifluoromethylpyridine (TFMP) using a synthetic procedure similar to that used for benzotrifluoride but involving chlorination and fluorination of picoline (Scheme 1) was first reported.8) Comparing the physicochemical properties Fig. 1. Worldwide demand of TFMP intermediates; alpha (α)-, beta (β)- and gamma (γ)- mean the positions of a trifluoromethyl group from the of TFMP and benzotrifluoride, there is a significant difference in nitrogen atom in the pyridine ring. the hydrophobic constant (e.g., 3-(trifluoromethyl)pyridine 1.7 versus benzotrifluoride 3.0), which can be expected to provide TFMP-containing compounds with many advantages, such as cides possessing the β-TFMP moiety. In addition, the total sales novel biological activity, lower toxicity, and advanced systemic volumes of fluopicolide and fluopyram, which also contain the and/or good selectivity; therefore, many efforts have been made β-TFMP moiety, have gradually increased from 2014 to 2018 to achieve the synthesis of TFMP. However, to make enough and are now around 1,000 tons/year. Picoxystrobin is the only TFMP for use as a raw material for industrial production, it is pesticide manufactured using the α-TFMP intermediate with important to establish a practical large-scale industrial manufac- sales of more than 2,000 tons/year. However, sales of bicyclopy- turing process. Details of the industrial manufacturing of TFMP rone have markedly increased in the last few years, which has and its use in the manufacture of various agrochemicals and increased demand for α-TFMP. Around 500 tons/year of pesti- pharmaceuticals are discussed in this review. cides containing the γ-TFMP intermediate are manufactured; therefore, the demand for γ-TFMP is relatively small.

1.2. Research and development of TFMP derivatives Research and development activities (i.e., the outputs of scien- tific papers and patents) involving TFMP derivatives from 1980 Scheme 1. Liquid-phase synthesis of TFMP. to 2019 were examined using data obtained through crossover analysis of the STN International Registry9) and HCAplus da- 1. Demand for TFMP isomers and development of tabases10) (CAS, Columbus, Ohio, USA, and FIZ Karlsruhe, TFMP derivatives Eggenstein-Leopoldshafen, Germany). Since the development 1.1. Trends in the demand for TFMP isomers of economically feasible processes for the synthesis of several Figure 1 shows the worldwide demand for TFMP isomers used TFMP intermediates from 3-picoline in the early 1980s, research as intermediates in the production of synthetic pesticides for the period from 2012 to 2018. The production volume of each TFMP isomer (Fig. 1) was estimated based on the following data sources: the sales volume of each formulated agrochemical, which was obtained from i-map Sigma (https://kynetecwebsc.com/documentation/ i-map/3.29.0/), a database for the crop protection market pro- vided by the market research company Kynetec (Newbury, UK); the concentration of each active ingredient in the formulated product; and the synthetic yield described in the patent for each agrochemical containing a TFMP moiety. Every year from 2012 to 2018, the demand was greatest for β-TFMP, followed by α-TFMP and γ-TFMP. In addition, the demand for each of the three TFMP isomers increased each year. Examining the sales of the pesticides individually, globally in Fig. 2. Research and development activities of TFMP derivatives 2018, fluazinam and haloxyfop were the two top-selling pesti- (1980–2019). Vol. 46, No. 2, 125–142 (2021) Trifluoromethylpyridine as a key structural motif in active ingredients 127 and development activity involving TFMP derivatives has rapidly and consistently increased each year (Fig. 2). 2. Synthesis of TFMP derivatives

There are three main methods for preparing TFMP derivatives: Scheme 3. Stepwise vapor–phase synthesis of 2,3,5-DCTF. chlorine/fluorine exchange using trichloromethylpyridine; con- struction of a pyridine ring from a trifluoromethyl-containing Another well-known approach is simultaneous vapor–phase building block; or direct introduction of a trifluoromethyl group chlorination/fluorination at a high temperature >( 300°C) with using a trifluoromethyl active species such as trifluoromethyl transition metal-based catalysts such as iron fluoride (Scheme copper, which undergoes substitution reactions with bromo- 4).17,18) The simultaneous vapor–phase reaction has the advan- and iodopyridines.11) The first two methods are currently the tage that 2-chloro-5-(trifluoromethyl)pyridine (2,5-CTF), a key most commonly used; therefore, the discussion below focuses intermediate for the synthesis of fluazifop, can be obtained in on those two methods. good yield via a simple one-step reaction. The number of chlorine atoms introduced to the pyridine ring can be controlled by 2.1. Chlorine/fluorine exchange using trichloromethylpyridine changing the molar ratio of chlorine gas and the reaction tem- Among TFMP derivatives, 2,3-dichloro-5-(trifluoromethyl) perature; however, the formation of some multi-chlorinated pyridine (2,3,5-DCTF), which is used as a chemical interme- by-products is unavoidable. Fortunately, these unwanted by- diate for the synthesis of several crop-protection products, is in products can be reduced to 3-(trifluoromethyl)pyridine (3-TF) the highest demand (production data estimated from the i-map by catalytic hydrogenolysis and then fed back into the reactor to Sigma database). Various methods of synthesizing 2,3,5-DCTF reduce overall production costs. have been reported. For example, 2-chloro-5-methylpyridine or The vapor–phase reactor used for this approach includes two 2-chloro-5-(chloromethyl)pyridine can be chlorinated under phases: a catalyst fluidized-bed phase and an empty phase (Fig. liquid-phase conditions to afford the intermediate 2,3-dichloro-5- 3). In the fluidized-bed phase, fluorination proceeds immedi- (trichloromethyl)pyridine (2,3,5-DCTC); subsequent vapor–phase ately after chlorination of the methyl group of 3-picoline, result- fluorination of 2,3,5-DCTC produces 2,3,5-DCTF (Scheme 2).12–14) ing in the production of 3-TF. In the next step, further nuclear chlorination of the pyridine ring is performed in the empty phase to give 2,5-CTF as the major product, which can be subsequently converted to 2,3,5-DCTF. At the same time, 2-chloro- 3-(trifluoromethyl)pyridine (2,3-CTF), which can be used to produce several commercial products, as discussed in sections 3 and 4, is also obtained as a minor product. Scheme 2. Stepwise liquid-phase/vapor–phase synthesis of 2,3,5-DCTF. Similar reaction conditions can be applied to 2- or 4-picoline; representative products and yields are summarized in Table 1. For lutidines, the reaction proceeds under similar conditions, An approach using stepwise vapor–phase chlorination fol- but the reaction temperature needs to be higher than that for lowed by fluorination has also been reported (Scheme 3).15,16) picolines. Several novel compounds with two trifluoromethyl

Scheme 4. Simultaneous vapor–phase synthesis of TFMPs. 128 M. Tsukamoto et al. Journal of Pesticide Science

3. Agrochemicals 3.1. TFMP derivatives as agrochemicals The ISO common names for 22 agrochemicals containing a TFMP moiety, listed in the Compendium of Pesticide Common Names (http://www.alanwood.net/pesticides/index.html), are shown in Table 3. Prior to 1990, all compounds except dithiopyr employed 3- or 5-trifluoromethyl-substituted pyridines as a partial structure. These compounds are synthesized from 2,5-CTF or 2,3,5-DCTF derived from 3-picoline. However, since 1990, other substitution patterns, mainly 6-trifluoromethyl-substituted pyridine derivatives, have increased. A 4-trifluoromethyl-substituted pyridine moiety is adopted in relatively few agrochemicals, and only flonicamid and pyroxsulam have been commercialized.

3.2. Herbicide Fluazifop-butyl, the first herbicide incorporating a TFMP sub- Fig. 3. Simultaneous vapor–phase reactor. structure, was commercialized by Ishihara Sangyo Kaisha, Ltd. (ISK), in 1982.19,20) Fluazifop-butyl acts as an acetyl-CoA car- groups, such as chloro-bis(trifluoromethyl)pyridine, can be syn- boxylase (ACCase) inhibitor.21) Translocation with foliar appli- thesized in 60 to 80% yield (Table 2). cation and herbicidal activities were improved by introducing a TFMP moiety into the lead compound, such as nitrofen. These 2.2. Cyclocondensation reaction by using a trifluoromethyl- favorable features of the pyridine derivative are far superior to containing building block the corresponding benzene analogue and showed excellent her- A number of cyclocondensation reactions for the synthe- bicidal activity on perennial grass weeds.22) As shown in Scheme sis of TFMP derivatives have been reported. The most com- 5, 2,5-CTF was employed as a key intermediate for the synthesis. monly used trifluoromethyl-containing building blocks are Fluazifop-butyl is known to have an asymmetric center on the ethyl 2,2,2-trifluoroacetate, 2,2,2-trifluoroacetyl chloride, propionate moiety, with only the (R)-enantiomer being active. ethyl 4,4,4-trifluoro-3-oxobutanoate, and (E)-4-ethoxy- After the commercialization of fluazifop-butyl (racemate), a ste- 1,1,1-trifluorobut-3-en-2-one (Fig. 4). reoselective synthetic process for optically active fluazifop-butyl was established, and it is now marketed as fluazifop-P-butyl. Haloxyfop-methyl was developed by Dow Chemical for post-

Table 1. Substrate scope of various picolines.a)

Substrates and reaction temp. (°C) Products and yields (GC PA%) CFB phase Empty phase TF type CTF type DCTF type

3-Picoline

335 320 86.4 6.6 0.0 380 380 7.4 64.1 19.1

2-Picoline

N/A 71.3 11.1 2.4 350–360 450 5.4 62.2 13.9

4-Picoline

380 380 7.4 64.1 19.1 a)Abbreviations: CFB, catalyst fluidized bed; PA%, peak area percent; TF, trifluoromethylpyridine; CTF, chloro(trifluoromethyl)pyridine; DCTF, dichloro(trifluoromethyl)pyridine; N/A, data not available. Vol. 46, No. 2, 125–142 (2021) Trifluoromethylpyridine as a key structural motif in active ingredients 129

Table 2. Substrate scope of various lutidines.a)

Substrates and reaction temp. (°C) Products and yields (GC PA%) CFB phase Empty phase BTF type CBTF type DCBTF type

2,4-Lutidine

420 420 5.8 78.8 13.0

2,5-Lutidine

420 460 14.1 59.0 18.6

2,6-Lutidine

440 N/A 69.6 0.0 0.0 420 520 2.5 45.6 31.4

3,4-Lutidine

420 400 9.0 60.0 16.0

3,5-Lutidine

360 N/A 89.3 10.7 0.0 380 440 14.4 62.2 21.4 a)Abbreviations: CFB, catalyst fluidized bed; PA%, peak area percent; BTF, bis(trifluoromethyl)pyridine; CBTF, chloro-bis(trifluoromethyl)pyridine; DCBTF, dichloro-bis(trifluoromethyl)pyridine; N/A, data not available. emergence grass control in many dicotyledonous crops.23) Like marily in turf and ornamentals. Thiazopyr29) is a pre-emergence fluazifop-butyl, haloxyfop-methyl targets ACCase enzyme.24) herbicide and has long residual control of annual grass weeds. The chemical structures of these two compounds are very close According to the Herbicide Resistance Action Committee to each other, whereas 2,3,5-DCTF is utilized for the prepara- (HRAC) classification,30) the mode of action of dithiopyr and tion of haloxyfop-methyl (Fig. 5). The herbicidal spectrum of thiazopyr is classified as Group 3, which inhibits root growth by haloxyfop-methyl overlaps that of fluazifop-butyl but exhibits blocking cell division as a microtubulin assembly inhibitor.31) The longer residual soil activity.25) summarized synthetic pathways are shown in Scheme 7. The syn- Flazasulfuron, which was first reported by ISK in 1986,26) is a thesis of both compounds starts with a cyclocondensation reac- sulfonylurea-type acetolactate synthase (ALS)-inhibiting herbi- tion of 3-methylbutanal and ethyl 4,4,4-trifluoro-3-oxobutanoate cide that is selective on turf, sugarcane, and perennial crops such as a key trifluoromethyl-containing building block to give tet- as citrus and grape.22) In the process of evaluating physicochem- rahydro-2H-pyran (1). Then1 is converted to compound 2 as a ical and biological properties, it was found that flazasulfuron common intermediate of dithiopyr and thiazopyr.32) was readily decomposed and/or metabolized under various conditions through an intramolecular nucleophilic aromatic substitution reaction triggered by the large electronegativity of the trifluoromethyl moiety on the pyridine ring.27) This observation could be a breakthrough to overcome the carry-over problem with sulfonylurea herbicides and led to the invention of nicosul- furon. 2,3-CTF is employed as a key component in the preparation of flazasulfuron, as shown in Scheme 6. Dithiopyr, discovered by the Monsanto Company,28) is a pre- emergence and early post-emergence herbicide that is used pri- Fig. 4. Common fluorine-containing building blocks. 130 M. Tsukamoto et al. Journal of Pesticide Science

Table 3. Trifluoromethylpyridine containing agrochemicals.a)

b) c) No. ISO common name CF3 position Indication CAS No. Year of introduction 1 Fluazifop β (5) H 69335-91-7 1982 (racemic) 2 Fluazifop-P β (5) H 83066-88-0 1987d) 3 Haloxyfop β (5) H 69806-34-4 1986 (racemic) 4 Haloxyfop-P β (5) H 95977-29-0 1993e) 5 Chlorfluazuron β (5) I 71422-67-8 1989 6 Fluazinam β (5) F 79622-59-6 1988 7 Dithiopyr α (6) H 97886-45-8 1990 8 Flazasulfuron β (3) H 104040-78-0 1989 9 Picoxystrobin α (6) F 117428-22-5 2001 10 Thiazopyr α (6) H 117718-60-2 1997 11 Flupyrsulfuron α (6) H 150315-10-9 1997 12 Flonicamid γ (4) I 158062-67-0 2003 13 Pyridalyl β (5) I 179101-81-6 2004 14 Fluopicolide β (5) F 239110-15-7 2006 15 Bicyclopyrone α (6) H 352010-68-5 2015 16 Pyroxsulam γ (4) H 422556-08-9 2007 17 Fluopyram β (5) F 658066-35-4 2012 18 Sulfoxaflor α (6) I 946578-00-3 2012 19 Fluazaindolizine β f) N 1254304-22-7 N/A 20 Fluopimomide β (5) F 1309859-39-9 2018g) 21 Acynonapyr β (5) I 1332838-17-1 2020h) 22 Cyclobutrifluram α (2) N 1460292-16-3 N/A a)Abbreviations: H, herbicide; I, insecticide; F, fungicide; N, nematicide; N/A, data not available. b)Compendium of Pesticide Common Names. c)PhillipsMcDougall: Product Directory 2016 Market. d)Fluazifop-P-butyl. e)Haloxyfop-P-methyl, Pesticide Properties DataBase (http://sitem.herts.ac.uk/ aeru/ppdb/). f)6-(Trifluoromethyl)imidazo[1,2-a]pyridine. g)2019 China Pesticide Suppliers Guide. h)Launched in Japan (https://www.nippon-soda.co.jp/ nougyo/news/pdf/20201014_1.pdf).

Scheme 5. Synthesis of fluazifop.19)

Flupyrsulfuron-methyl-sodium is an ALS-inhibiting cereal herbicide discovered by DuPont.33) Selective control of Alope- Scheme 6. Synthesis of flazasulfuron.26) curus myosuroides, Apera spica-venti, and a wide range of broadleaf weeds is obtained through post-emergence application.34) The chemical structure of flupyrsulfuron-methyl-sodium and a typical preparation method of 2-sulfamoyl-6-(trifluoromethyl) nicotinic acid methyl ester (3) as a key intermediate are shown in Scheme 8.35) Crop selectivity derives from the rapid metabolism degradation of flupyrsulfuron-methyl-sodium in wheat and very slow metabolism in sensitive weeds.36) Since the electron-deficient pyridine moiety is substituted by strong electron- Fig. 5. Chemical structure of haloxyfop, herbicide, 1986. withdrawing groups, such as trifluoromethyl and methoxycar- Vol. 46, No. 2, 125–142 (2021) Trifluoromethylpyridine as a key structural motif in active ingredients 131

rate of metabolism.45) As shown in Scheme 10, the pyridone intermediate 5 is synthesized by the Horner–Wadsworth–Emmons reaction using (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as a trifluoromethyl-containing building block.46)

Scheme 7. Synthesis of dithiopyr.28) and thiazopyr.29) bonyl moieties, it is susceptible to the aromatic nucleophilic sub- 37) stitution and degrades quickly in soil, water, and sediment. Scheme 10. Synthesis of pyroxsulam.41)

3.3. Insecticide Chlorfluazuron,47) discovered by ISK, has a typical benzoylurea- type structure, which is well known as an insect growth regulator (IGR). Chlorfluazuron exhibits excellent insecticidal activity against specific target insects, such as Lepidoptera, Diptera, and Orthoptera, at their larval stages through the chitin biosynthesis- inhibition mechanism. As shown in Fig. 6, chlorfluazuron showed higher insecticidal activity against the common cut- Scheme 8. Synthesis of flupyrsulfuron-methyl-sodium.33) worm as compared with the lead compound diflubenzuron.22) 2,3,5-DCTF was employed as a starting raw material for the syn- Bicyclopyrone38) was discovered as a 4-hydroxyphenylpyruvate thesis of chlorfluazuron, as shown in Scheme 11. dioxygenase (HPPD)-inhibiting herbicide for use in corn and launched by Syngenta in 2015. Intermediate 4 was prepared by a cyclization reaction using (E)-4-ethoxy-1,1,1-trifluorobut-3-en- 2-one as shown in Scheme 9.39) The pyridyl nitrogen in bicyclopyrone has the effect of reducing hydrophobicity and increasing acidity. It can be inferred that these characteristics may have led to improvement in the bioavailability of pre-emergent appli- 40) cations, compared with the corresponding phenyl analogue. Fig. 6. Insecticidal activity against 5th instar larvae of common cutworm.

Scheme 9. Synthesis of bicyclopyrone.38)

Pyroxsulam,41) discovered by Dow AgroSciences LLC, is 47) an ALS-inhibiting herbicide with the characteristic triazolo Scheme 11. Synthesis of chlorfluazuron. pyrimidine and 2-methoxy-4-(trifluoromethyl)pyridine substruc- tures.42,43) It was developed for the control of key weeds in cereal Flonicamid was discovered by ISK as a novel insecticide to crops such as wheat. High herbicidal activity on grass species was control aphids.48) The initial screening of various TFMP ana- achieved with 2-methoxy-4-(trifluoromethyl)phenyl analogues, logues revealed that some nicotinamide derivatives showed in- but these compounds were found to cause significant injury to teresting activity against aphids, as shown in Fig. 7.49) Structural wheat, unlike pyridine analogues.44) The selectivity of pyroxsulam optimization using compound 6 as a lead compound led to the to wheat relatives is connected primarily with differences in the discovery of flonicamid, which has a unique 4-trifluoromethyl- 132 M. Tsukamoto et al. Journal of Pesticide Science

Fig. 7. Chemical structures of the lead compound 6 and flonicamid. Scheme 14. Synthesis of sulfoxaflor.56) substituted pyridine moiety. Flonicamid is a chordotonal organ modulator and is classified as Group 29 according to the In- secticide Resistance Action Committee (IRAC) mode of action N-phenylsulfonylimidazopyridine-2-carboxamide derivatives classification.50) The synthesis route of the 4-(trifluoromethyl) were found via high-throughput screening of DuPont’s inter- nicotinic acid is shown in Scheme 12.51) nal compound libraries against a root-knot nematode. Fluazain- dolizine61) was selected as the optimal compound after structural optimization aiming at both the reduction of phytotoxicity and the improvement of biological activity. The trifluoromethyl group at the 6-position of the imidazopyridine moiety is partic- ularly important for nematicidal activity. Therefore, fluazaindolizine shows activity superior to the corresponding unsubstituted or halogen-substituted imidazopyridine derivatives.62) Accord- 48) Scheme 12. Synthesis of flonicamid. ing to the IRAC classification, the mode of action of fluazaindolizine is UN, but it seems to be novel, because there is no ac- Pyridalyl was discovered and reported by Sumitomo Chemi- tivity against the target sites of current commercial nematicides. cal Co., Ltd.52,53) It has a 5-(trifluoromethyl)pyridine moiety as 2-Amino-3-chloro-5-(trifluoromethyl)pyridine (2,3,5-ACTF), a key substructure in the molecule. According to the IRAC, the which can be prepared from 2,3,5-DCTF, was employed as a mode of action of pyridalyl is classified as unknown (UN).50,54) starting material, as shown in Scheme 15. After structural optimization, the insecticidal activity of TFMP derivatives on lepidopterous pests was found to be superior to that of the corresponding phenyl analogues. The chemical structure and synthetic route of pyridalyl are shown in Scheme 13.55)

Scheme 15. Synthesis of fluazaindolizine.61)

Scheme 13. Synthesis of pyridalyl.52) Acynonapyr63) is a new acaricide discovered by Nippon Soda Sulfoxaflor,56,57) commercialized by Dow AgroSciences LLC in and is active on spider mites of Tetranychus and Panonychus. 2012, is an insecticide targeting sap-feeding pests. The sulfoxyi- Acynonapyr has a characteristic chemical structure in which mine functional group is rare and characteristic as a pesticide. azabicyclo[3.3.1]nonane core 864) and the 5-(trifluoromethyl) The IRAC has classified sulfoxaflor as the only insecticide in pyridine ring are connected via an ether bond, as shown in Group 4, Subgroup 4C.50) At the beginning of the novel sulfoxyi- Scheme 16. The mode of action of acynonapyr has not yet been mine analogue research, phenyl derivatives that exhibited weak classified but is presumed to be disturbance of the neurotrans- fungicidal activity were explored. However, when the phenyl moi- mitter system by acting on inhibitory glutamate receptors.65) ety was replaced with a hetero-aromatic ring such as pyridine, insecticidal activity was observed. As a result of further structural optimization, it was found that the 6-(trifluoromethyl)pyridine moiety was the optimal substructure, showing excellent insecticidal activity.58,59) A practical preparation route of sulfoxaflor is shown in Scheme 14. A critical pyridine sulfide intermediate, 7, is prepared via an enamine-mediated cyclocondensation reaction by Scheme 16. Synthesis of acynonapyr.63) using (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as a trifluoromethyl-containing building block.60) Vol. 46, No. 2, 125–142 (2021) Trifluoromethylpyridine as a key structural motif in active ingredients 133

The first patent claimed for cyclobutrifluram was published America and Asia and for soybean crops in South America in in 2013 by Syngenta.66) Cyclobutrifluram has been reported the mid 2000s. One structural characteristic of picoxystrobin as a nematicide and is characterized by a novel carboxamide is a pyridine ring in which the 6-position is substituted with a structure that has a cis-substituted four-membered ring com- trifluoromethyl group. Two procedures for the preparation of prised of a specific absolute configuration at each of two posi- 6-(trifluoromethyl)pyridin-2(1 H)-one (11) have been reported: tions.67,68) Although there is no information on the mechanism a cyclocondensation method starting from (E)-4-ethoxy-1,1,1- of action, its chemical structure is reminiscent of fluopyram, trifluorobut-3-en-2-one and direct fluorination of 2-picoline with the same nematicidal effect. 2-(Trifluoromethyl) through a chlorine/fluorine exchange reaction, as shown in nicotinic acid is expected to be a critical raw material for the Scheme 19.77–79) synthesis of cyclobutrifluram. Several preparation methods of 2-(trifluoromethyl)nicotinic acid have been reported in previ- ous literature.69–71) One of the representative synthetic methods is a cyclocondensation reaction starting from compound 9, derived from Vilsmeier salt, as shown in Scheme 17.72) Ethyl 4,4,4-trifluoroacetoacetate can be condensed with compound 9 to form compound 10, followed by intramolecular cyclization to obtain 2-(trifluoromethyl)nicotinic acid.

Scheme 19. Synthesis of picoxystrobin.76)

Bayer’s chemists focused on the 3-chloro-5-(trifluoromethyl) pyridine residue based on the “Agrophore Approach”80) and discovered two commercial fungicides.81) It is quite interesting that the same fungicidal mechanism is inferred from the similarity of both chemical structures, but they are different according to the FRAC classification. Fluopicolide induces the delocaliza- tion of spectrin-like proteins in oomycete fungi, which is a new mode of action classified as FRAC code 43. On the other hand, Scheme 17. Synthesis of cyclobutrifluram.66) fluopyram is a succinate dehydrogenase inhibitor (SDHI, FRAC code 7) fungicide that is effective on ascomycete pathogens and 3.4. Fungicide plant-parasitic nematodes.82) Chemical structures and outlines Fluazinam, discovered by ISK,73) is a broad-spectrum fungicide, of the synthesis route for both fluopicolide83) and fluopyram84) and its mode of action is the uncoupling of oxidative phosphor- are shown in Scheme 20. ylation, classified as Fungicide Resistance Action Committee (FRAC) code 29.74) Substituent effects on the pyridine ring were examined using the fungicidal activity against Botrytis cinerea. It was found that the trifluoromethyl-substituted pyridine derivative showed higher fungicidal activity than the corresponding chloro-, nitro-, and cyano-substituted derivatives.75) 2,3,5-DCTF is utilized in the synthesis of fluazinam, as shown in Scheme 18.

Scheme 20. Synthesis of fluopicolide83) and fluopyram.84)

Fluopimomide85) was developed by Shandong Sino-Agri United Biotechnology Co., Ltd., and approved in China in 2017. As shown in Fig. 8, it has a chemical structure very similar to the preced- 73) Scheme 18. Synthesis of fluazinam. ing fungicide, fluopicolide, but its EC50 against Pseudoperonospora cubensis is relatively low, and the observed downward transporta- Picoxystrobin76) was discovered as a strobilurin fungicide and tion is different from that of fluopicolide.86) A nematicidal effect developed by Syngenta for the European market. After a while, has also been reported for fluopimomide.87) 5-(Trifluoromethyl) it was passed to DuPont and developed for wheat in North pyridine is incorporated as a substructure as well as fluopicolide, 134 M. Tsukamoto et al. Journal of Pesticide Science

vestigated. Tipranavir with a TFMP moiety showed about tenfold higher antiviral activity than the corresponding phenyl analogue. The first synthesis93) of tipranavir using a chiral auxiliary was reported in 1997, but later, a practical asymmetric synthesis was also reported. The introduction of 5-(trifluoromethyl)pyridine- Fig. 8. Chemical structure of fluopimomide, Sino-Agri union, fungi- 2-sulfonyl chloride (12) prepared from 2,5-CTF is achieved in cide, 2018. the final synthesis step, as shown in Scheme 21.94) whereas the substituents on the benzene ring are characteristic. According to the FRAC classification, both compounds are reported to have the same mode of action and are classified as code 43. 4. Pharmaceuticals Scheme 21. Synthesis of tipranavir.92) 4.1. Overview of TFMP derivatives in the pharmaceuticals In 2010, it was estimated that up to 20% of pharmaceuticals prescribed or administered in the clinic contained a fluorine Enasidenib is an oral isocitrate dehydrogenase-2 (IDH2) in- atom.88) More recently, however, this has increased to over 40%. hibitor developed by the Celgene Corp. under a global, exclusive It is noteworthy that 19.2% of those fluorinated drugs contain a license from Agios Pharmaceuticals, Inc.95) trifluoromethyl group.89) In 2017, the United States Food and Drug Administration Five pharmaceuticals (Table 4) containing a TFMP moiety (FDA) approved enasidenib for adults with relapsed and refrac- as a partial structure have been approved and commercialized tory acute myelogenous leukemia (AML) with an IDH2 mutation. so far. Furthermore, since various drug candidates containing a The synthesis of enasidenib consists of six steps, depicted in TFMP moiety are currently undergoing clinical trials, new drugs Scheme 22.96) One structural characteristic of enasidenib is that are expected to be introduced to the market in the near future. two differentα -TFMPs are introduced into both ends of the Representative examples of drugs under development and their molecule. common names are listed in Table 5.90)

4.2. Approved drugs In 2005, Boehringer Ingelheim succeeded in developing and commercializing tipranavir,91) which was discovered by Phar- macia & Upjohn (currently Pfizer, Inc.),92) as a non-peptide anti- human immunodeficiency virus (HIV) drug. In the course of structural optimization, for all synthesized compounds, not only the HIV protease binding activity but also the relationship between pharmacokinetic parameters, such as in vitro antiviral activity and half-life in blood, was comprehensively in- Scheme 22. Synthesis of enasidenib.95)

Table 4. Approved drugs.

a) b,c) No. Development code Common name CF3 position Efficacy disease CAS No. Approval date 1 PNU-140690 Tipranavir β (5) Antivirals, 174484-41-4 2005/6/22 FDA HIV-1 infection 2005/10/25 EMA 2 AG-221 CC-90007 Enasidenib α (2 and 6) Antineoplastic, 1446502-11-9 2017/8/1 FDA Acute myeloid Leukemia 3 ARN-509 JNJ-927 Apalutamide β (5) Antineoplastic, 956104-40-8 2018/2/14 FDA Prostate Cancer 2019/1/14 EMA 2019/3/26 PMDA 4 MK-1439 Doravirine γ (4) Antivirals, 1338225-97-0 2018/8/30 FDA HIV-1 infection 2018/11/22 EMA 2020/1/14 PMDA 5 PLX3397 Pexidartinib α (6) Antineoplastic, 1029044-16-3 2019/9/5 FDA Giant cell tumor of tendon sheath a)International Nonproprietary Name (https://druginfo.nlm.nih.gov/drugportal/); b)As of Dec. 2020. c)Abbreviations: FDA, Food and Drug Administra- tion; EMA, European Medicines Agency; PMDA, Pharmaceuticals and Medical Devices Agency. Vol. 46, No. 2, 125–142 (2021) Trifluoromethylpyridine as a key structural motif in active ingredients 135

Table 5. Drugs in development.

b) No. Development code Common name CF3 position Efficacy disease CAS No. Development stage 1 CVL-751 PF- Tavapadon β (3) Antiparkinsonians 1643489-24-0 Phase III (USA) 06649751 2 CDZ173 Leniolisiba) β (5) Immunodeficiency disorders 1354690-24-6 Phase II/III (USA,EU) 3 CORT125134 Relacorilanta) γ (4) Prostate cancer Cushing 1496510-51-0 Phase II/III (USA, EU) syndrome 4 PQR309 Bimiralisiba) γ (4) Head and neck squamous 1225037-39-7 Phase II (USA) cell cancer (HNSCC) 5 QBW-251 Icenticaftora) β (5) Chronic obstructive 1334546-77-8 Phase II (USA, EU, JP) pulmonary disease (COPD) 6 SL-801 CBS9106 Felezonexor β (5) Antineoplastic 1076235-04-5 Phase I (USA) 7 LXH254 Naporafenib α (2) Antineoplastic 1800398-38-2 Phase I (USA, EU, JP) a)International Nonproprietary Name (https://druginfo.nlm.nih.gov/drugportal/); b)As of Dec. 2020.

Several synthetic methods of 2-(trifluoromethyl)pyridine (13) A detailed review of the development of synthetic approaches and 2-(trifluoromethyl)pyridin-4-amine (14), shown in Scheme to apalutamide has been published.101) An example of the syn- 23, were reported previously.97,98) thetic route is shown in Scheme 24, in which 2,3-CTF is employed as a key intermediate.

Scheme 23. Synthesis of TFMP intermediates. Scheme 24. Synthesis of apalutamide.99)

Apalutamide,99) developed by Janssen Pharmaceuticals, Inc., is a second-generation nonsteroidal androgen receptor (AR) Doravirine,102) developed by the Merck Sharp & Dohme antagonist with a strong binding affinity to AR. In 2018, it Corp., is a new non-nucleoside reverse transcriptase inhibi- was approved by the FDA for the treatment of non-metastatic tor (NNRTI), and it was approved by the FDA in 2018 for the castration-resistant prostate cancer (nmCRPC). As shown in treatment of HIV infection in adult patients. Similar to other Fig. 9, the chemical structure of apalutamide is very similar to NNRTIs, doravirine exerts its antiviral effect through a noncom- that of enzalutamide (FDA approved in 2012) with two minor petitive inhibition of the HIV-1 reverse transcriptase but has a modifications: (a) a gem-dimethyl group on the imidazoline ring more favorable drug interaction profile compared with earlier of enzalutamide is bonded at each end to form a four-membered NNRTIs, as it neither inhibits nor induces the cytochrome P450 cyclic structure, and (b) the benzene ring of enzalutamide is re- 3A4 (CYP3A4) enzyme.103) placed with a pyridine ring. Apalutamide possesses in vitro ac- In structural optimization, a conversion of the methyl group tivity comparable to that of enzalutamide but with greater anti- on the pyridone ring to a trifluoromethyl group was found to tumor efficacy in castration-resistant prostate cancer (CRPC) improve plasma stability and enzyme inhibition.104,105) xenograft models and lower potential to cause seizures as an ad- A robust kilo-scale synthesis route of doravirine, shown in verse effect in the central nervous system.100) Scheme 25, has been reported,106) but details of the preparation

Fig. 9. Chemical structure of enzalutamide and apalutamide. Scheme 25. Synthesis of doravirine.102) 136 M. Tsukamoto et al. Journal of Pesticide Science

using (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one, as shown in Scheme 28.111–113)

Fig. 10. Chemical structure of PLX647 and pexidartinib. method of 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (15) have not been described in the literature. As an alternative synthesis route for the key pyridine intermediate of doravirine, a flow reactor makes it possible to use Scheme 28. Synthesis of 6-(trifluoromethyl)nicotinaldehyde (16). (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as a starting raw material instead of 15, as shown in Scheme 26.107) 4.3. Drugs in development Tavapadon (CVL-751),114) discovered by Pfizer, Inc., is a potent partial agonist at the D1/D5 receptors and it is being developed by Cerevel Therapeutics as a treatment for Parkinson’s disease.115) 2,3-CTF is employed as a key intermediate for the preparation of CVL-751 as shown in Scheme 29.

Scheme 26. Alternative synthesis route of doravirine.

Pexidartinib,108) discovered by Plexxikon, Inc., is an orally active and potent colony-stimulating factor-1 receptor (CSF-1R) 109) kinase inhibitor (IC50 value 13 nM). In 2019, the FDA approved Daiichi Sankyo’s pexidartinib cap- Scheme 29. Synthesis of tavapadon.114) sules for the treatment of adult patients with symptomatic teno- synovial giant cell tumors (TGC Ts) associated with severe mor- bidity or functional limitations and not amenable to improve- Leniolisib (CDZ173),116) discovered by Novartis AG, is cur- ment with surgery. rently in clinical studies by Pharming in patients suffering from As shown in Fig. 10, pexidartinib is the compound in activated PI3Kδ syndrome (APDS)/p110 delta activating mu- which a chlorine atom is introduced at the 5-position of the tation causing senescent T cells, lymphadenopathy, and immu- 1H-pyrrolo[2,3-b]pyridine moiety of PLX647 (lead compound), nodeficiency (PASLI). In structural optimization, conversion of and the benzene ring is replaced with a pyridine. The CSF-1R ki- the methyl group on the pyridine moiety to a trifluoromethyl nase inhibitory activity is about twofold higher, and the nitrogen group was found to increase PI3Kδ potency by a factor of five. atom of the pyridine ring contributes to the stabilization of the Leniolisib was found to have the optimal hydrophilic property to CSF-1R kinase conformation. ensure good solubility and metabolic stability.117) A novel synthetic route (Scheme 27) was designed and dem- 2,3-CTF is employed as a key intermediate for the preparation onstrated.110) 6-(Trifluoromethyl)nicotinaldehyde (16) was used of leniolisib, as shown in Scheme 30. as a key intermediate for the synthesis of pexidartinib. Compound 16 is synthesized by a cyclocondensation reaction

Scheme 30. Synthesis of leniolisib.116)

Relacorilant (CORT125134)118) is being developed by Corcept Therapeutics, Inc. It is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that may benefit from the modulation of cortisol activity. In structural optimization, Scheme 27. Synthesis of pexidartinib.108) the introduction of a trifluoromethyl group to the 4-position on Vol. 46, No. 2, 125–142 (2021) Trifluoromethylpyridine as a key structural motif in active ingredients 137 the pyridyl moiety was found to increase HepG2 tyrosine amino transferase assay potency by a factor of four. Relacorilant is currently being evaluated in a phase II clinical study in patients with Cushing’s syndrome.119) 2-Bromo-4-(trifluoromethyl)pyridine (17) prepared from (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one is employed as a key intermediate for the preparation of relacorilant as shown in Fig. 11. Chemical structure of RAF709 and naporafenib (LXH254). Scheme 31.120) intermediate of leniolisib), which can be prepared from 2,3-CTF, is employed as a key intermediate for the preparation of icenticaftor, as shown in Scheme 33.125) Chromosome region maintenance 1 (CRM1) plays an important role in the nuclear export of cargo proteins bearing nuclear exporting signal sequences. Felezonexor (CBS9106),126) which was discovered by the CanBas Co., Ltd., is a novel reversible CRM1 inhibitor and a promising clinical candidate developed by Stemline Therapeutics, Inc.127) 2,6-Dichloro-3-(trifluoromethyl)pyridine (2,6,3-DCTF) is 118) Scheme 31. Synthesis of relacorilant. employed as a starting material for the preparation of felezonexor, as shown in Scheme 34. Bimiralisib (PQR309)121) is being developed by PIQUR Ther- apeutics AG. It has been selected after structural optimization as the best phosphoinositide 3-kinase(PI3K) inhibitor with a balanced targeting of the mammalian target of the rapamycin (mTOR) kinase.122) Bimiralisib evolved as the lead compound of a series of dimorpholinotriazine-based compounds and is currently being tested in phase II clinical trials. 2-Amino-4-(trifluoromethyl)pyridine (18), which can be pre- Scheme 34. Synthesis of felezonexor.126) pared from 2,4-CTF, is employed as a key intermediate for the preparation of bimiralisib, as shown in Scheme 32.123) RAF709128) was a potent, selective, efficacious rapidly acceler- ated fibrosarcoma (RAF) kinase inhibitor and well tolerated in preclinical models, but the high human intrinsic clearance pre- cluded further development and prompted further investigation of close analogues. In further structural optimization studies, the mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of naporafenib (LXH254), as shown in Fig. 11.129,130) Naporafenib was advanced to human studies and is currently being assessed in phase I trials by the Novartis Pharmaceuticals Corporation. An optimized synthetic route for naporafenib, which was Scheme 32. Synthesis of bimiralisib.121)

Icenticaftor (QBW-251), which is a potentiator of the cystic -fi brosis membrane conductance regulator (CFTR)124) used for the treatment of chronic obstructive pulmonary disease (COPD), is being developed by Novartis AG. 5-Bromo-2-methoxy-3-(trifluoromethyl)pyridine (the same

Scheme 33. Synthesis of icenticaftor.124) Scheme 35. Synthesis of naporafenib.129) 138 M. Tsukamoto et al. Journal of Pesticide Science

Table 6. Approved animal health products.

a) No. Development code Common name CF3 position Efficacy disease CAS No. Approved date 1 VB0PV6I7L6 Fluazuronb) β (5) Tick control in beef cattle 86811-58-7 1994 2 IS-741 IKV-741 Fuzapladib β (5) Acute pancreatitis drug for dogs 351999-87-6c) 2018 a)As of Dec. 2020; b)International Nonproprietary Name (https://druginfo.nlm.nih.gov/drugportal/); c)Fuzapladib sodium hydrate. used to supply larger quantities of material for in vivo studies, in, we have discussed the synthesis and applications of TFMP is outlined in Scheme 35. 2-(Trifluoromethyl)isonicotinic acid derivatives. In the more than 40 years since the first TFMP- (19) is introduced in the last step of the synthesis, as shown based agrochemical was reported, research and development in Scheme 35.131,132) For the synthesis of compound 19, ethyl of TFMP derivatives has continued unabated, and many new 2,2,2-trifluoroacetate is used as a key precursor. bioactive molecules have been discovered. Although TFMP derivatives were first applied in the agrochemical industry, their 5. Animal health products use in the pharmaceutical industry is increasing. Early struc- Two animal health products (Table 6) containing a TFMP moi- tural design introduced the TFMP motif into a compound to ety have been approved and commercialized. manipulate its physicochemical properties and obtain better Fluazuron, a benzoyl-phenylurea derivative, is a well-known biological activity. There are also reports that TFMP itself has chemical class of chitin biosynthesis inhibitors and was devel- various biological activities. For instance, 2-amino-3-chloro-5- oped exclusively for veterinary use by Ciba-Geigy.133) It shows (trifluoromethyl)pyridine is expected to show anti-tumor activ- good activity against ticks and mites of livestock and pets but ity,139) and 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic none at all against insects. Fluazuron was approved as an animal acid, a metabolite of the fungicide fluopyram, is phytotoxic.140) health product in 1994.134) TFMP is incorporated as a substruc- More agrochemicals and pharmaceuticals containing TFMP are ture in fluazuron, as shown in Fig. 12. expected to be introduced to the market in the near future. For discovery chemists, confirming the biological activity of TFMP derivatives during the structural optimization stage of the design process may open several useful avenues for future research.

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