Method for producing fluorine-containing propenic acid compounds

Abstract

This invention provides a method for producing 2-(trifluoromethyl)propenoic acid derivatives, in which an oxygen substituent is introduced at the 3-position, from readily available and easy-to-handle raw materials through a simple reaction. [Solution] A method for producing a fluorine-containing propenoic acid compound, characterized by having the step of reacting a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative represented by general formula (2) with (i) a compound represented by general formula (5) or a salt thereof, and optionally further with (ii) a compound represented by general formula (6) or a salt thereof, to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by general formula (1). JPEG2026054622000016.jpg34138 (In the above general formulas (1), (2), (5), and (6), X is F or OR 3 Represents R 1 ~R 3 Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S).

Description

[Technical Field]

[0001] This invention relates to a method for producing fluorine-containing propenoic acid compounds. [Background technology]

[0002] Covalent inhibitors are attracting attention as excellent pharmaceuticals that combine high efficacy and sustained action because they strongly bind to target molecules via covalent bonds. Specifically, well-known examples include aspirin as an analgesic, penicillin as an antibacterial agent, clopidogrel as an anticoagulant, and omeprazole as a gastric acid secretion inhibitor.

[0003] Against this backdrop, the development of Michael acceptor-type covalent inhibitors containing propenic acid substructures has become increasingly active in recent years. For example, afatinib was approved by the Pharmaceuticals and Medical Devices Agency in 2014, followed by ibrutinib and osimertinib in 2016, dacomitinib in 2019, sotrasib in 2022, and ritrecitinib and futivatinib in 2023.

[0004] Furthermore, compounds containing a propenoic acid substructure are also used in the field of pesticides. For example, mevinphos and pyriminostrobin are used as insecticides, azoxystrobin and benzothiostrobin as fungicides, and chloranocryl and diphenopenten-ethyl as herbicides.

[0005] From this perspective, there is interest in introducing fluorine-containing substituents in the hope of further improving pharmacological activity. Specifically, Non-Patent Document 1 reports on the pharmacological effects of 3,3-difluoro-2-(trifluoromethyl)propenoic acid derivatives. Furthermore, Non-Patent Documents 2 and 3 disclose methods for producing 2-(trifluoromethyl)propenoic acid derivatives in which a nitrogen substituent is introduced at the 3-position.

[0006] However, the manufacturing method disclosed in Non-Patent Document 2 uses methyl 3,3-difluoro-2-(trifluoromethyl)propenoate as a raw material, and such compounds are unstable and expensive, making them difficult to obtain. Furthermore, the manufacturing method involves a step of thermal decomposition of an intermediate obtained from the reaction with trimethyl phosphite, making it inefficient.

[0007] While the manufacturing method disclosed in Non-Patent Document 3 eliminates the need for trimethyl phosphite, improvement was still desired in that it still uses 3,3-difluoro-2-(trifluoromethyl)propenoic acid ester. On the other hand, the manufacturing method disclosed in Patent Document 1 uses 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)propane as a raw material instead of 3,3-difluoro-2-(trifluoromethyl)propenoic acid ester, but this involves a long and inefficient process, first generating 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene in system, and then converting it to a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative.

[0008] Incidentally, in recent years, there has been interest in developing 2-(trifluoromethyl)propenoic acid derivatives in which an oxygen substituent is introduced at the 3rd position. Therefore, it is desirable to realize a method for producing 2-(trifluoromethyl)propenoic acid derivatives with an oxygen substituent at the 3rd position using readily available and easily handled compounds as raw materials, and through simple operations. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Hans-Dieter Fischer et.al, “Toxicology and applied pharmacology” Vol.14, 1969, P.114-118 [Non-Patent Document 2] Chemical Series, “Izvestiya Akademii Nauk SSSR”, Vol.6, 1975, Abstract

Non-Patent Document 3

Patent Document

[0010]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0011] The present invention provides a production method capable of producing a 2-(trifluoromethyl)propenoic acid derivative in which an oxygen substituent is introduced at the 3-position by a simple reaction using a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative that is easy to obtain and handle as a raw material.

Means for Solving the Problems

[0012] The method for producing a fluorine-containing propenoic acid compound according to an embodiment of the present invention includes a step of reacting a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative represented by the general formula (2) with (i) a compound represented by the general formula (5) or a salt thereof, and optionally, further (ii) a compound represented by the general formula (6) or a salt thereof to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by the general formula (1).

Chemical Formula

[0013] A method for producing a fluorine-containing propenoic acid compound according to one embodiment of the present invention comprises the step of further reacting a fluorine-containing propenoic acid compound represented by general formula (4), in which X is F in general formula (1), obtained by the reaction in (i) above, with a compound represented by general formula (6) or a salt thereof to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by general formula (3). [ka] (In the above general formulas (3), (4), and (6), R 1 ~R 3 Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S). [Effects of the Invention]

[0014] According to the present invention, it is possible to provide a method for producing a 2-(trifluoromethyl)propenoic acid derivative, in which an oxygen substituent is introduced at the 3-position, by a simple reaction using a readily available and easy-to-handle 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative as a raw material. [Modes for carrying out the invention]

[0015] Embodiments of the present invention will be described in detail below. However, the scope of the present invention is not limited to the specific examples described below.

[0016] (Method for producing fluorinated propenoic acid compounds) The method for producing a fluoropropenoic acid compound in the present embodiment includes a step (a) of reacting a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative represented by the following general formula (2) with (i) a compound represented by the general formula (5) or a salt thereof, and optionally further with (ii) a compound represented by the general formula (6) or a salt thereof to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by the following general formula (1).

[0017] [Chemical formula] (In the above general formulas (1), (2), (5) and (6), X represents F or OR 3 and R 1 ~R 3 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a hetero atom selected from the group consisting of a nitrogen atom (N), an oxygen atom (O) and a sulfur atom (S).)

[0018] The 2-(trifluoromethyl)propenoic acid derivative represented by the general formula (1) has an OR 3 group at the 3-position, so it has an oxygen substituent at the 3-position. Also, X represents F or OR 3 .

[0019] R 1 ~R 3 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group having 1 to 12 carbon atoms may be substituted or unsubstituted. Also, the hydrocarbon group having 1 to 12 carbon atoms may optionally contain a hetero atom selected from the group consisting of a nitrogen atom (N), an oxygen atom (O) and a sulfur atom (S).

[0020] The hydrocarbon group having 1 to 12 carbon atoms is not particularly limited as long as it is a hydrocarbon group consisting of carbon atoms and hydrogen atoms having 1 to 12 carbon atoms, and can include linear hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups. The linear hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 1 to 12, and may be a linear hydrocarbon group, a branched linear hydrocarbon group, a substituted linear hydrocarbon group, or an unsubstituted linear hydrocarbon group. If the hydrocarbon group is an aromatic hydrocarbon group, the aromatic hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 6 to 12, and may be a substituted aromatic hydrocarbon group or an unsubstituted aromatic hydrocarbon group. Furthermore, the aromatic hydrocarbon group may have a condensed polycyclic structure. If the hydrocarbon group having 1 to 12 carbon atoms is an alicyclic hydrocarbon group, the alicyclic hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 3 to 12, and may be a substituted alicyclic hydrocarbon group or an unsubstituted alicyclic hydrocarbon group. Furthermore, the alicyclic hydrocarbon group may have a cross-linked ring structure.

[0021] Examples of linear hydrocarbon groups include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, ter-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl groups; Alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl groups; Examples of alkynyl groups include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octinyl group, noninyl group, desinyl group, undecynyl group, dodecynyl group, and other alkynyl groups.

[0022] Furthermore, the chain-like hydrocarbon group may have a structure in which part of the hydrocarbon group contains an oxygen atom (O), such as an -O- bond, a -C(O)- bond, or a -C(O)O- bond.

[0023] Examples of aromatic hydrocarbon groups include phenyl, benzyl, tolyl, and naphthyl groups. The tolyl group may be o-tolyl, m-tolyl, or p-tolyl, with p-tolyl being preferred.

[0024] Examples of alicyclic hydrocarbon groups include saturated or unsaturated cyclic hydrocarbon groups. Examples of cyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, adamantyl, and norbornyl groups.

[0025] Furthermore, aromatic hydrocarbon groups or alicyclic hydrocarbons may have a structure in which some of the carbon atoms on the ring include oxygen atoms (O), nitrogen atoms (N), and sulfur atoms (S), that is, at least one of the carbon atoms on the ring may be a heteroatom selected from the group consisting of oxygen atoms (O), nitrogen atoms (N), and sulfur atoms (S).

[0026] If the linear hydrocarbon group has substituents, one of the hydrogen atoms in the linear hydrocarbon group may be substituted with an alkoxy group. Preferably, the alkoxy group is a carbon-1 to carbon-6 alkoxy group, such as a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tet-butoxy group, n-pentoxy group, n-hexyloxy group, etc.

[0027] The chain-like hydrocarbon group may be an aralkyl group in which one of the hydrogen atoms of the alkyl group is substituted with an aryl group. Preferably, the aralkyl group has 1 to 6 carbon atoms and an alkyl group substituted with an aryl group, such as a benzyl group, phenylethyl group, phenylpropyl group, naphthylmethyl group, etc.

[0028] The chain-like hydrocarbon group may have one hydrogen atom substituted with a heterocycle. Such a heterocycle may be monocyclic, bicyclic, or polycyclic, and may have at least one heteroatom selected from the group consisting of nitrogen (N), sulfur (S), and oxygen (O), and may be optionally substituted. If the heterocyclic group contains multiple heteroatoms, the heterocycle may have multiple identical or different heteroatoms. The heterocycle may be a fused ring, and may be either an alicyclic heterocycle or an aromatic heterocycle, or a combination thereof.

[0029] The monocyclic heterocycle is preferably a 3- to 12-membered ring, and more preferably a 5- to 9-membered ring. When the heterocycle is a monocyclic heterocycle, it may contain up to 5 heteroatoms. Each heteroatom is individually selected from O, S, and N, and at least one of the heteroatoms is N. Examples of monocyclic heterocycles include pyrrolidine, pyrroline, pyrrole, pyrazolidine, imidazolidine, pyrazoline, imidazoline, imidazole, pyrazole, triazole, tetrazole, (iso)oxazole, (iso)oxadiazole, (iso)thiazole, thiadiazole, pyridine, pyrrolidine, piperidine, piperazine, pyridazine, pyrimidine, pyrazine, triazine, thienopyridine, piperazinone, morpholine, thiomorpholine, thiomorpholine dioxide, oxazine, thiazine, azocan, azosine, azonan, azonin, and derivatives thereof.

[0030] The bicyclic heterocycle is preferably a 7-14 membered ring, and more preferably an 8-10 membered ring. A spiro ring may also be included in the bicyclic heterocycle. When the heterocycle is a bicyclic heterocycle, it may contain up to 10 heteroatoms. Each heteroatom is individually selected from O, S, and N, and it is preferable that at least one of the heteroatoms is N. Examples of bicyclic heterocycles include (iso)indole, aza(iso)indole, (aza)indazole, (aza)benzimidazole, (aza)benztriazole, benzothiopheine, hydrothienopyridine, (iso)quinoline, hydro(iso)quinoline, hydrophropyridine, and derivatives thereof.

[0031] The polycyclic heterocycle is preferably a 9-30 membered ring, and more preferably a 12-26 membered ring. A spiro ring may also be included in the polycyclic heterocycle. When the heterocycle is a polycyclic heterocycle, it may contain up to 15 heteroatoms. Each heteroatom is individually selected from O, S, and N, and it is preferable that at least one of the heteroatoms is N. Examples of polycyclic heterocycles include carbazole, phenazine, phenoxazine, phenothiazine, benzoindole, pyrroloquinoline, acridine, and derivatives thereof.

[0032] When a heterocycle has substituents, examples of substituents include halogen atoms, the aforementioned C1-C12 hydrocarbon groups, oxygen substituents such as hydroxyl groups, alkoxy groups, carbonyl groups, and carboxyl groups, nitrogen substituents such as amino groups, cyano groups, and nitro groups, and sulfur substituents such as sulfanyl groups, sulfoxy groups, and sulfone groups.

[0033] When an aromatic hydrocarbon group or alicyclic hydrocarbon group has substituents, examples of substituents include C1-C12 alkyl groups and C1-C6 alkoxyl groups as described above. Furthermore, when an aromatic hydrocarbon group or alicyclic hydrocarbon group is substituted with a C1-C12 alkyl group, the alkyl group may have a structure in which part of the alkyl group contains an oxygen atom (O), such as an -O- bond, a -C(O)- bond, or a -C(O)O- bond.

[0034] The method for producing the fluorinated propenoic acid compound in this embodiment involves reacting a fluorinated propenoic acid compound represented by the following general formula (4), in which X is F in the above-mentioned general formula (1), with a compound represented by general formula (6) or a salt thereof, so that in the above-mentioned general formula (1), X is OR 3 The process may include step (b) of obtaining a 2-(trifluoromethyl)propenoic acid derivative represented by the following general formula (3).

[0035] [ka] (In the above general formulas (3), (4), and (6), R 1 ~R 3 Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S).

[0036] In the above general formulas (3), (4), and (6), a substituted or unsubstituted C1-C12 hydrocarbon group may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S), and is defined in the same way as the above definition of a C1-C12 hydrocarbon group.

[0037] The compounds represented by the above general formulas (5) and (6) may also be used in the form of salts. Examples of such salts include hydrochloride salts, hydrobromide salts, acetate salts, sulfate salts, and so on.

[0038] The reaction described in (a) above can be represented as the following reaction equation (A). [ka]

[0039] The reaction described in (b) above can be represented as the following reaction equation (B). [ka]

[0040] Each of the above reactions may use a hydrogen halide scavenger as needed. A hydrogen halide scavenger is a substance that has the function of capturing the hydrogen fluoride (HF) produced. By using a hydrogen halide scavenger, the step of recovering hydrogen fluoride can be omitted, and fluorine-containing propenoic acid compounds can be obtained more simply.

[0041] Examples of hydrogen halide scavengers include inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride, and potassium fluoride; organic nitrogen derivatives such as pyridine, triethylamine, diisopropylethylamine, trynzylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, N-methylmorpholine, and 1,8-bis(dimethylamino)naphthalene; and phosphorus derivatives such as phosphazene bases.

[0042] In the reaction described in (a) above, in (i), an elimination reaction of the 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative represented by general formula (2) takes place, and one fluorine (F) atom in the resulting intermediate reactant becomes the OR group of the compound represented by general formula (5). 2 It is substituted with. Also, in (ii), when it is further reacted with a compound represented by general formula (6), the group OR 2 The fluorine (F) atom at position 3 of the fluorine-containing propenoic acid compound substituted with the group OR of the compound represented by general formula (6). 3 It is further replaced by this.

[0043] In the reaction (b) above, the fluorine (F) atom at the 3 position of the fluorine-containing propenoic acid compound represented by general formula (4) is converted into the OR group of the compound represented by general formula (6). 3 It will be replaced with.

[0044] The reaction temperature in the reactions (a) and (b) above is preferably 0 to 100°C, more preferably 5 to 50°C, and even more preferably 10 to 25°C. The reaction time in the reactions (a) and (bb) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 2 to 20 hours.

[0045] Organic solvents are preferred as solvents for the reactions (a) and (b) above. Examples include aprotic polar solvents such as tetrahydrofuran, monoglyme, diglyme, triglyme, tetraglyme, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidone, 4-methyltetrahydropyran, dimethylethylene urea, tetramethylurea, dimethyl sulfoxide, and sulfolane; or protic polar solvents such as methanol, ethanol, n-propanol, 2-propanol, and water; water-insoluble solvents such as hexane, dichloromethane, toluene, and diethyl ether; and two-phase solvents combining these solvents. Optionally, quaternary ammonium halides such as benzyltriethylammonium chloride, quaternary phosphonium halides, and crown ethers can be used as catalysts for the reactions (a) and (b) above.

[0046] The fluorine-containing propenoic acid compounds obtained by the above-described manufacturing method can exhibit excellent structural expandability, and in particular, further improvements in pharmacological activity can be expected. Therefore, they are useful for application in the fields of agrochemicals and pharmaceuticals, and can also be applied to fields such as organic semiconductors and liquid crystals.

[0047] Based on the embodiments described above, the present invention relates to the following [1] to [4]. [1] A method for producing a fluorine-containing propenoic acid compound, comprising the step of reacting a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative represented by general formula (2) with (i) a compound represented by general formula (5) or a salt thereof, and optionally further (ii) a compound represented by general formula (6) or a salt thereof, in the presence of a base, to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by general formula (1). [ka] (In the above general formulas (1), (2), (5), and (6), X is F or OR 3 This represents, R 1 ~R 3 Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S). [2] R 1 A method for producing the fluorine-containing propenoic acid compound described in [1] above, wherein the alkyl group having 1 to 12 carbon atoms is substituted or unsubstituted. [3] A method for producing a fluorine-containing propenoic acid compound, comprising the step of further reacting a fluorine-containing propenoic acid compound represented by general formula (4), in which X is F in general formula (1) described in [1] above, obtained by the reaction in (i) above, with a compound represented by general formula (6) or a salt thereof, to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by general formula (3). [ka] (In the above general formulas (3), (4), and (6), R 1 ~R 3 Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S). [4] R 1 A method for producing the fluorine-containing propenoic acid compound described in [3] above, wherein the alkyl group having 1 to 12 carbon atoms is substituted or unsubstituted.

[0048] Although embodiments of the present invention have been described above, the present invention is not limited to the embodiments described above, and includes all aspects included in the concept and claims of the present invention, and can be modified in various ways within the scope of the present invention. [Examples]

[0049] The following describes examples of the present invention, but the present invention is not limited to these examples unless it exceeds the spirit of the invention. The room temperature described below is in the range of 20°C ± 10°C.

[0050] (Example 1) Synthesis of methyl 3-fluoro-3-(1-butoxy)-2-(trifluoromethyl)-2-propenate At room temperature, 0.4 g (4.8 mmol) of 1-butanol and 1.0 g (4.8 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate were added to 50 g of toluene. Subsequently, 1.2 g (9.6 mmol) of diisopropylethylamine was added dropwise, and the mixture was heated under reflux. After stirring for 24 hours, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was then purified by silica gel column in a hexane-ethyl acetate mixed solvent (hexane:ethyl acetate = 7:3) to obtain 0.1 g of the compound shown below. The yield of the obtained compound was 9%.

[0051] [ka]

[0052] The analysis results were as follows: Mass spectrum (APCI, m / z): 230 ([M] + )

[0053] (Example 2) Synthesis of 3-fluoro-3-[2-(2'-methoxyethoxy)ethoxy]-2-(trifluoromethyl)-2-propenate methyl At room temperature, 50 g of toluene was mixed with 0.6 g (4.8 mmol) of diethylene glycol monomethyl ether and 1.0 g (4.8 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate. Subsequently, 2.8 g (9.6 mmol) of trybendylamine was added dropwise, and the mixture was heated under reflux. After stirring for 40 hours, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was then purified by silica gel column in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3) to obtain 0.4 g of the compound shown below. The yield of the obtained compound was 3%.

[0054] [ka]

[0055] The analysis results were as follows: Mass spectrum (APCI, m / z): 290 ([M] + )

[0056] (Example 3) Synthesis of methyl 3-ethoxy-3-(7-isoquinolino)-2-(trifluoromethyl)-2-propenate <Process 1> At room temperature, 50 g of hexane was mixed with 0.3 g (4.8 mmol) of ethanol and 1.0 g (4.8 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate. Subsequently, 1.2 g (9.6 mmol) of diisopropylethylamine was added dropwise, and the mixture was heated under reflux. After stirring for 48 hours, the mixture was allowed to stand and separate into layers, and the upper layer was collected.

[0057] <Process 2> The solvent in the upper layer was removed by vacuum distillation, the residue was dissolved in acetonitrile, and 0.8 g (5.5 mmol) of isoquinoline-7-ol was added. Subsequently, 1.3 g (8.3 mmol) of diazabicycloundecene was added dropwise, and the mixture was heated under reflux. After stirring for 48 hours, the solvent was removed by vacuum distillation, the residue was dissolved in ethyl acetate, and the mixture was purified by silica gel column in a hexane-ethyl acetate mixed solvent (hexane:ethyl acetate = 7:3) to obtain 10 mg of the following compound. The yield of the obtained compound was 0.5%.

[0058] [ka]

[0059] The analysis results were as follows: Mass spectrum (APCI, m / z): 341([M] + )

[0060] (Example 4) Synthesis of 3,3-bis[4-(1-octyloxy)carbonylphenoxy]-2-(trifluoromethyl)-methyl propenate At room temperature, 2.4 g (9.6 mmol) of octyl 4-pyroxybenzoate and 1.5 g (14.4 mmol) of N-methylmorpholine were added to 50 g of tetrahydrofuran. Subsequently, 1.0 g (4.8 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise, and the mixture was heated under reflux. After stirring for 8 hours, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was then purified by silica gel column in a hexane-ethyl acetate mixed solvent (hexane:ethyl acetate = 7:3) to obtain 0.1 g of the compound shown below. The yield of the obtained compound was 4%.

[0061] [ka]

[0062] The analysis results were as follows: Mass spectrum (APCI, m / z): 650 ([M] + ) 1 H-NMR (400MHz, CDCl3) δppm:7.95 (m,4H),6.96 (m,4H),4.28 (t,4H),3.78 (s,3H),1.74 (quin,4H),1.47-1.21 (m,20H),0.88 (t,6H)

[0063] (Example 5) Synthesis of methyl 3-fluoro-3-(4-methyl-5-thiazoleethoxy)-2-(trifluoromethyl)-2-propenate At room temperature, 0.7 g (4.8 mmol) of 4-methyl-5-thiazoleethanol and 1.0 g (4.8 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate were added to 75 g of tetrahydrofuran. Subsequently, 2.1 g (9.6 mmol) of 1,8-bis(dimethylamino)naphthalene was added dropwise, and the mixture was heated under reflux. After stirring for 38 hours, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was then purified by silica gel column in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3) to obtain 0.1 g of the compound shown below. The yield of the obtained compound was 5%.

[0064] [ka]

[0065] The analysis results were as follows: Mass spectrum (APCI, m / z): 313 ([M] + )

Claims

1. A method for producing a fluorine-containing propenoic acid compound, characterized by having the step of reacting a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative represented by general formula (2) with (i) a compound represented by general formula (5) or a salt thereof, and optionally further (ii) a compound represented by general formula (6) or a salt thereof, to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by general formula (1). 【Chemistry 1】 (In the above general formulas (1), (2), (5), and (6), X is F or OR ３ This represents, R １ ~R ３ Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S).

2. R １ A method for producing a fluorine-containing propenoic acid compound according to claim 1, wherein the alkyl group having 1 to 12 carbon atoms is substituted or unsubstituted.

3. A method for producing a fluorine-containing propenoic acid compound, comprising the step of further reacting a fluorine-containing propenoic acid compound represented by general formula (4), in which X is F in general formula (1) according to claim 1, obtained by the reaction in (i) above, with a compound represented by general formula (6) or a salt thereof, to obtain a 2-(trifluoromethyl)propenoic acid derivative represented by general formula (3). 【Chemistry 2】 (In the above general formulas (3), (4), and (6), R １ ~R ３ Each of these independently represents a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, which may optionally contain a heteroatom selected from the group consisting of nitrogen atoms (N), oxygen atoms (O), and sulfur atoms (S).

4. R １ A method for producing a fluorine-containing propenoic acid compound according to claim 3, wherein the alkyl group has 1 to 12 carbon atoms and is substituted or unsubstituted.

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