Abstract
Please visit our website for more information on this topic.
Herein, we provide a brief overview of the synthesis and applications of trifluoromethylpyridine (TFMP) and its derivatives in the agrochemical and pharmaceutical industries. Currently, 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. Several 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.
Introduction
Many recent advances in the agrochemical, pharmaceutical, and functional materials fields have been made possible by the development of organic compounds containing fluorine. Indeed, the effects of fluorine and fluorine-containing moieties on the biological activities and physical properties of compounds have earned fluorine a unique place in the arsenal of the discovery chemist. As the number of applications for these compounds continues to grow, the development of fluorinated organic chemicals is becoming an increasingly important research topic.
In the crop protection industry, more than 50% of the pesticides launched in the last two decades have been fluorinated. In addition, around 40% of all fluorine-containing pesticides currently on the market contain a trifluoromethyl group, making these compounds an important subgroup of fluorinated compounds.1) The biological activities of fluorine-containing compounds are considered to be derived from the unique physicochemical properties of fluorine (van der Waals radius, 1.47&#;Å),2) which, sterically, is the next smallest atom after hydrogen (van der Waals radius, 1.20&#;Å)2) but the atom with the largest electronegativity (3.98).3) In addition, because the carbon&#;fluorine bond is relatively short (1.38&#;Å) compared with the other carbon&#;halogen bonds, the bond has strong resonance. As a result, the Hammett constant (σp) of fluorine is 0.06,4) which is 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 is strongly electron withdrawing. Therefore, during compound development, the trifluoromethyl group can be treated as a purely electron-withdrawing group.
These unique properties of fluorine mean that substitution with a fluorine or fluorine-containing moiety can have a large impact on the conformation, acid dissociation constant, metabolism, translocation, and biomolecular affinity of a compound. 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 effort 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 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 s.7) In , 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 of TFMP and benzotrifluoride, there is a significant difference in 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 novel biological activity, lower toxicity, and advanced systemic and/or good selectivity; therefore, many efforts have been made to achieve the synthesis of TFMP. However, to make enough TFMP for use as a raw material for industrial production, it is important to establish a practical large-scale industrial manufacturing process. Details of the industrial manufacturing of TFMP and its use in the manufacture of various agrochemicals and pharmaceuticals are discussed in this review.
Scheme&#;1.&#;Liquid-phase synthesis of TFMP.
1.&#;Demand for TFMP isomers and development of TFMP derivatives
1.1.&#;Trends in the demand for TFMP isomers
Figure 1 shows the worldwide demand for TFMP isomers used as intermediates in the production of synthetic pesticides for the period from to .
Fig.&#;1.&#;Worldwide demand of TFMP intermediates; alpha (α)-, beta (β)- and gamma (γ)- mean the positions of a trifluoromethyl group from the nitrogen atom in the pyridine ring.
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 provided 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 to , 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 , fluazinam and haloxyfop were the two top-selling pesticides possessing the β-TFMP moiety. In addition, the total sales volumes of fluopicolide and fluopyram, which also contain the β-TFMP moiety, have gradually increased from to and are now around 1,000 tons/year. Picoxystrobin is the only pesticide manufactured using the α-TFMP intermediate with sales of more than 2,000 tons/year. However, sales of bicyclopyrone have markedly increased in the last few years, which has increased demand for α-TFMP. Around 500 tons/year of pesticides 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 scientific papers and patents) involving TFMP derivatives from to were examined using data obtained through crossover analysis of the STN International Registry9) and HCAplus databases10) (CAS, Columbus, Ohio, USA, and FIZ Karlsruhe, Eggenstein-Leopoldshafen, Germany). Since the development of economically feasible processes for the synthesis of several TFMP intermediates from 3-picoline in the early s, research and development activity involving TFMP derivatives has rapidly and consistently increased each year (Fig. 2).
Fig.&#;2.&#;Research and development activities of TFMP derivatives (&#;).
2.&#;Synthesis of TFMP derivatives
There are three main methods for preparing TFMP derivatives: chlorine/fluorine exchange using trichloromethylpyridine; construction of a pyridine ring from a trifluoromethyl-containing building block; or direct introduction of a trifluoromethyl group using a trifluoromethyl active species such as trifluoromethyl copper, which undergoes substitution reactions with bromo- and iodopyridines.11) The first two methods are currently the most commonly used; therefore, the discussion below focuses on those two methods.
2.1.&#;Chlorine/fluorine exchange using trichloromethylpyridine
Among TFMP derivatives, 2,3-dichloro-5-(trifluoromethyl)pyridine (2,3,5-DCTF), which is used as a chemical intermediate for the synthesis of several crop-protection products, is in the highest demand (production data estimated from the i-map Sigma database). Various methods of synthesizing 2,3,5-DCTF have been reported. For example, 2-chloro-5-methylpyridine or 2-chloro-5-(chloromethyl)pyridine can be chlorinated under liquid-phase conditions to afford the intermediate 2,3-dichloro-5-(trichloromethyl)pyridine (2,3,5-DCTC); subsequent vapor&#;phase fluorination of 2,3,5-DCTC produces 2,3,5-DCTF (Scheme 2).12&#;14)
Scheme&#;2.&#;Stepwise liquid-phase/vapor&#;phase synthesis of 2,3,5-DCTF.
An approach using stepwise vapor&#;phase chlorination followed by fluorination has also been reported (Scheme 3).15,16)
Scheme&#;3.&#;Stepwise vapor&#;phase synthesis of 2,3,5-DCTF.
Another well-known approach is simultaneous vapor&#;phase chlorination/fluorination at a high temperature (>300°C) with transition metal-based catalysts such as iron fluoride (Scheme 4).17,18) The simultaneous vapor&#;phase reaction has the advantage that 2-chloro-5-(trifluoromethyl)pyridine (2,5-CTF), a key intermediate for the synthesis of fluazifop, can be obtained in good yield via a simple one-step reaction. The number of chlorine atoms introduced to the pyridine ring can be controlled by changing the molar ratio of chlorine gas and the reaction temperature; however, the formation of some multi-chlorinated by-products is unavoidable. Fortunately, these unwanted by-products can be reduced to 3-(trifluoromethyl)pyridine (3-TF) by catalytic hydrogenolysis and then fed back into the reactor to reduce overall production costs.
Scheme&#;4.&#;Simultaneous vapor&#;phase synthesis of TFMPs.
The vapor&#;phase reactor used for this approach includes two phases: a catalyst fluidized-bed phase and an empty phase (Fig. 3). In the fluidized-bed phase, fluorination proceeds immediately after chlorination of the methyl group of 3-picoline, resulting 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.
huimeng supply professional and honest service.
Fig.&#;3.&#;Simultaneous vapor&#;phase reactor.
Similar reaction conditions can be applied to 2- or 4-picoline; representative products and yields are summarized in Table 1.
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
350&#;360
N/A
71.3
11.1
2.4
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.
Table 1. Substrate scope of various picolines.
For lutidines, the reaction proceeds under similar conditions, but the reaction temperature needs to be higher than that for picolines. Several novel compounds with two trifluoromethyl groups, such as chloro-bis(trifluoromethyl)pyridine, can be synthesized in 60 to 80% yield (Table 2).
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.
Table 2. Substrate scope of various lutidines.
2.2.&#;Cyclocondensation reaction by using a trifluoromethyl-containing building block
A number of cyclocondensation reactions for the synthesis of TFMP derivatives have been reported. The most commonly used trifluoromethyl-containing building blocks are ethyl 2,2,2-trifluoroacetate, 2,2,2-trifluoroacetyl chloride, ethyl 4,4,4-trifluoro-3-oxobutanoate, and (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (Fig. 4).
Fig.&#;4.&#;Common fluorine-containing building blocks.
5.&#;Animal health products
Two animal health products (Table 6) containing a TFMP moiety have been approved and commercialized.
No.
Development code
Common name
CF3 position
Efficacy disease
CAS No.
Approved date
a)
1
VB0PV6I7L6
Fluazuron
b)
β (5)
Tick control in beef cattle
-58-7
2
IS-741 IKV-741
Fuzapladib
β (5)
Acute pancreatitis drug for dogs
-87-6
c)
a)As of Dec. ; b)International Nonproprietary Name (https://druginfo.nlm.nih.gov/drugportal/); c)Fuzapladib sodium hydrate.
Table 6. Approved animal health products.
Fluazuron, a benzoyl-phenylurea derivative, is a well-known chemical class of chitin biosynthesis inhibitors and was developed exclusively for veterinary use by Ciba-Geigy.133) It shows good activity against ticks and mites of livestock and pets but none at all against insects. Fluazuron was approved as an animal health product in .134) TFMP is incorporated as a substructure in fluazuron, as shown in Fig. 12.
Fig.&#;12.&#;Chemical structure of fluazuron, Ciba-Geigy, parasiticide, .
Fuzapladib sodium hydrate (IKV-741, IS-741) was discovered and developed by ISK as an acute pancreatitis drug for dogs.
IS-741 had been a clinical candidate for patients with acute pancreatitis,135) but further development was cancelled in phase II. Later, this compound continued to be developed as a veterinary medicine and was approved as fuzapladib sodium hydrate in .136)
Fuzapladib sodium hydrate is synthesized from 2,5-CTF as a starting material, as shown in Scheme 36.137)
137)
Scheme 36. Synthesis of fuzapladib sodium hydrate.
Conclusion
Despite not occurring in nature,138) fluorine derivatives have attracted attention as a rich source of bioactive compounds. Herein, we have discussed the synthesis and applications of TFMP derivatives. In the more than 40 years since the first TFMP-based agrochemical was reported, research and development of TFMP derivatives has continued unabated, and many new bioactive molecules have been discovered. Although TFMP derivatives were first applied in the agrochemical industry, their use in the pharmaceutical industry is increasing. Early structural design introduced the TFMP motif into a compound to manipulate its physicochemical properties and obtain better biological activity. There are also reports that TFMP itself has various biological activities. For instance, 2-amino-3-chloro-5-(trifluoromethyl)pyridine is expected to show anti-tumor activity,139) and 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid, a metabolite of the fungicide fluopyram, is phytotoxic.140) More agrochemicals and pharmaceuticals containing TFMP are 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.
Figures & tables
Supplementary materials
Result List
Cited by
Comments
All Comments ( 0 )