Fluorine-containing propenoic acid compound and production method therefor

Abstract

The present invention relates to a fluorine-containing propenoic acid compound represented by general formula (1). In general formula (1), X represents -N((RA1)mA2)(OnA3), R represents a nitrogen atom or a sulfur atom, Y represents a halogen atom, -N((NA4)kA5)(OlA6), -OA7, or -SA8, Z represents -OhA9 or -N((NA10)iA11)(OjA12), A1 to A12 each independently represent a C1-C12 hydrocarbon group, any two of A1, A2, and A3 may be bonded to each other to form a ring, any two of A4, A5, and A6 may be bonded to each other to form a ring, any two of A10, A11, and A12 may be bonded to each other to form a ring, and h to n are each an integer of 0 or 1.

Description

Fluorine-containing propenoic acid compound and method for producing the same

[0001] The present invention relates to a fluorine-containing propenoic acid compound and a method for producing the same.

[0002] Covalent inhibitors bind strongly to target molecules via covalent bonds, and are therefore attracting attention as excellent pharmaceuticals that combine high efficacy with long-lasting activity. Specific examples include aspirin as an analgesic, penicillin as an antibiotic, clopidogrel as an anticoagulant, and omeprazole as a gastric acid secretion inhibitor.

[0003] Against this background, the development of Michael acceptor-type covalent inhibitors having a propenoic acid partial structure has been 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, sotorasib in 2022, and ritrecitinib and futibatinib in 2023.

[0004] Compounds with a propenoic acid partial structure are also used in the field of agricultural chemicals, such as insecticides mevinphos and pyriminostrobin, fungicides azoxystrobin and benzothiostrobin, and herbicides such as chloranocryl and diphenopentene-ethyl.

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

[0006] However, the production method disclosed in Non-Patent Document 2 uses methyl 3,3-difluoro-2-(trifluoromethyl)propenoate as a raw material, and such a compound is unstable and difficult to obtain. The production method disclosed in Non-Patent Document 3 uses a silylamine derivative as a raw material, and this compound is also unstable, and decomposition by moisture is particularly pronounced.

[0007] On the other hand, there has been interest in introducing a further substituent at the 3-position of a 3-fluoro-2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent introduced at the 3-position. For example, Non-Patent Document 4 discloses a method for producing a 2-(trifluoromethyl)propenoic acid derivative having a bisaziridinylated 3-position. However, symmetrical substituents have been introduced at the 3-position, and asymmetric derivatization at the 3-position has not been achieved.

[0008] For this reason, methods for producing 2-(trifluoromethyl)propenoic acid derivatives in which the 3-position is asymmetrically derivatized have been investigated. For example, Non-Patent Document 5 discloses a method for producing a 2-(trifluoromethyl)propenoic acid derivative in which a nitrogen nucleophile and a sulfur nucleophile are substituted at the 3-position. Furthermore, Non-Patent Document 6 discloses a method for producing a 2-(trifluoromethyl)propenoic acid derivative in which an oxygen nucleophile and a sulfur nucleophile are substituted at the 3-position. However, these production methods require the prior introduction of a sulfur substituent at the 3-position of the 3-fluoro-2-(trifluoromethyl)propenoic acid derivative. Introduction of such a sulfur substituent requires the use of an unstable reagent prepared immediately before use, as disclosed in, for example, Non-Patent Document 7, and furthermore, there are concerns that the operation is cumbersome and the steps are long.

[0009] From this viewpoint, it is desired to develop a method for producing a 3-fluoro-2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent introduced at the 3-position, or a 2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent and a nitrogen, oxygen, or sulfur substituent introduced at the 3-position, by a simple operation using a compound that is easy to handle and readily available as a raw material.

[0010] Hans-Dieter Fischer et.al, “Toxicology and applied pharmacology” Vol.14, 1969, P.114-118Seriya Khimicheskay, “Izvestiya Akademii Nauk SSSR”, Vol.1, 1976, AbstractKhimii, “Zhurnal Organicheskoi”, Vol.22, 1986, AbstractNauk SSSR, “Doklady Akademii”, Vol.218, 1974, AbstractRussian Chemical Bulletin, Vol.50, 2001, Abstract(p.1645-1647)Russian Chemical Bulletin, Vol.51, 2002, Abstract(p.1020-1027)Russian Chemical Bulletin, Vol.50, 2001, Abstract(p.1044-1046)

[0011] Therefore, the present inventors have found that it is possible to easily produce a 3-fluoro-2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent introduced at the 3-position, or a 2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent and a nitrogen, oxygen, or sulfur substituent introduced at the 3-position, from a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative or a synthetic equivalent thereof, which are easily available and easy to handle, and have thereby completed the present invention.

[0012] The present invention provides a production method that enables the synthesis, by a simple reaction, of a fluorinated propenoic acid compound having a nitrogen substituent introduced at the 3-position, or a fluorinated propenoic acid compound having a nitrogen substituent and a nitrogen, oxygen, or sulfur substituent introduced at the 3-position, using a 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative or a synthetic equivalent thereof as a starting material; and provides the fluorinated propenoic acid compound obtained by the production method.

[0013] The fluorine-containing propenoic acid compound according to an embodiment of the present invention is represented by the following general formula (1). (In the above general formula (1), X is —N((RA１ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, Y represents a halogen atom, -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.

[0014] The method for producing a fluorinated propenoic acid compound according to an embodiment of the present invention includes a step of reacting a fluorinated propenoic acid compound represented by the following general formula (5) with a compound represented by the following general formula (7) or a salt thereof in the presence of a base to obtain a fluorinated propenoic acid compound represented by the following general formula (6): (In the above general formulas (5), (6), and (7), X is —N((RA １ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, W is -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms;１０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.

[0015] A method for producing a fluorinated propenoic acid compound according to one embodiment of the present invention further comprises a step of carrying out an elimination reaction of a fluorinated isobutyric acid compound represented by the following general formula (4), and reacting the obtained intermediate reactant with a compound represented by the following general formula (8) or a salt thereof in the presence of a base, thereby obtaining a fluorinated propenoic acid compound represented by the general formula (5): (In the above general formulas (4) and (8), X and Z are as defined in the above general formulas (5) and (6).)

[0016] A method for producing a fluorinated propenoic acid compound according to one embodiment of the present invention further comprises the step of carbonylating a fluorinated isobutene compound represented by the following general formula (3) in the presence of a nucleophile, and reacting the obtained intermediate reactant with a compound represented by the following general formula (9) or a salt thereof in the presence of a base, thereby obtaining a fluorinated propenoic acid compound represented by the general formula (4): (In the above general formula (3), W is as defined in the above general formula (7), and in the above general formula (9), Z is as defined in the above general formulas (5) and (6).)

[0017] The method for producing a fluorinated propenoic acid compound according to one embodiment of the present invention further comprises a step of carrying out an elimination reaction of a fluorinated isobutane compound represented by the following general formula (2) to obtain a fluorinated isobutene compound represented by the general formula (3): (In the above general formula (2), W is as defined in the above general formula (7).)

[0018] According to the present invention, it is possible to provide a production method capable of synthesizing, by a simple reaction, a fluorine-containing propenoic acid compound having a nitrogen substituent introduced at the 3-position, or a fluorine-containing propenoic acid compound having a nitrogen substituent and a nitrogen, oxygen, or sulfur substituent introduced at the 3-position, using an easily available 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid derivative or a synthetic equivalent thereof as a starting material, and to provide the fluorine-containing propenoic acid compound obtained by the production method.

[0019] Hereinafter, embodiments of the present invention will be described in detail, but the scope of the present invention is not limited to the specific examples described below.

[0020] <Fluorine-Containing Propenoic Acid Compound> The fluorine-containing propenoic acid compound of the present embodiment is represented by the following general formula (1), in which a nitrogen substituent has been introduced at the 3-position and which may further have a nitrogen, oxygen or sulfur substituent at the 3-position.

[0021] (In the above general formula (1), X is —N((RA １ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ Any two of the groups may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, Y represents a halogen atom, -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.

[0022] X is -N((RA １ ) ｍ A ２ ) (O ｎ A ３ ), the fluorine-containing propenoic acid compound represented by general formula (1) has a nitrogen substituent at the 3-position. The nitrogen substituent may be a tertiary amino group, or A １ , A ２ and A ３ may be a heterocycle containing a N atom as a ring atom (heteroatom) formed by bonding any two groups from the following: R represents a nitrogen atom or a sulfur atom, and m represents an integer of 0 or 1. Therefore, when m=1, the nitrogen substituent further contains a nitrogen atom (N atom) or a sulfur atom (S atom), and when n=1, the nitrogen substituent further contains an O atom.

[0023] A １ , A ２ and A ３ Each independently represents a hydrocarbon group having 1 to 12 carbon atoms, which may be substituted or unsubstituted. １ , A ２ and A ３When A is a substituted or unsubstituted hydrocarbon group having 1 to 12 carbon atoms, it is not particularly limited as long as it is a hydrocarbon group having 1 to 12 carbon atoms and consisting of carbon atoms and hydrogen atoms, and examples thereof include a chain hydrocarbon group, an aromatic hydrocarbon group, and an alicyclic hydrocarbon group. The chain hydrocarbon group is not particularly limited as long as it has a total of 1 to 12 carbon atoms, and may be a straight chain hydrocarbon group or a branched chain hydrocarbon group, and may be a chain hydrocarbon group having a substituent or a chain hydrocarbon group having no substituent. １ , A ２ and A ３ When A is an aromatic hydrocarbon group, the aromatic hydrocarbon group is not particularly limited as long as it has a total of 6 to 12 carbon atoms, and may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group having no substituent. In addition, the aromatic hydrocarbon group may have a condensed polycyclic structure. １ , A ２ and A ３ When is an alicyclic hydrocarbon group, the alicyclic hydrocarbon group is not particularly limited as long as it has a total carbon number of 3 to 12, and may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group having no substituent. In addition, the alicyclic hydrocarbon group may have a bridged ring structure.

[0024] Examples of the chain hydrocarbon group include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, and dodecynyl.

[0025] Examples of the aromatic hydrocarbon group include a phenyl group, a benzyl group, a tolyl group, and a naphthyl group. The tolyl group may be any of an o-tolyl group, an m-tolyl group, and a p-tolyl group, with a p-tolyl group being preferred.

[0026] Alicyclic hydrocarbon groups include saturated or unsaturated cyclic hydrocarbon groups, and examples of cyclic hydrocarbon groups include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, an adamantyl group, and a norbornyl group.

[0027] When the chain hydrocarbon group has a substituent, one of the hydrogen atoms of the chain hydrocarbon group may be substituted with an alkoxyl group. The alkoxyl group is preferably an alkoxyl group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, and an n-hexyloxy group. The chain hydrocarbon group may also be an aralkyl group in which one of the hydrogen atoms of the alkyl group is substituted with an aryl group. The aralkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with an aryl group, and examples thereof include a benzyl group, a phenylethyl group, a phenylpropyl group, and a naphthylmethyl group.

[0028] When the aromatic hydrocarbon group and the alicyclic hydrocarbon group have a substituent, examples of the substituent include the above-mentioned alkyl groups and alkoxy groups having 1 to 6 carbon atoms.

[0029] A １ , A ２ and A ３Any two of the groups may be bonded to each other to form a ring. Such a ring may be, for example, a 3- to 12-membered, more preferably a 5- to 9-membered, alicyclic hydrocarbon group or aromatic hydrocarbon group, and these hydrocarbon groups may be optionally substituted. Specific examples include the alicyclic hydrocarbon groups and aromatic hydrocarbon groups described above. Furthermore, such a ring may form a heterocycle having at least one heteroatom selected from the group consisting of a nitrogen atom (N), a sulfur atom (S), and an oxygen atom (O). The heterocycle may be an optionally substituted monocyclic, bicyclic, or polycyclic heterocycle. When the heterocyclic group contains multiple heteroatoms, the heterocycle may contain multiple heteroatoms that are the same or different. One of the heteroatoms contained in the heterocyclic group, preferably N, is directly bonded to the propene skeleton of the fluorine-containing propenoic acid compound. The heterocycle may be a fused ring, an alicyclic heterocycle, an aromatic heterocycle, or a combination thereof.

[0030] 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 five heteroatoms. Each heteroatom is independently selected from O, S, and N, with at least one heteroatom being 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, azocane, azocine, azonane, azonine, and derivatives thereof.

[0031] The bicyclic heterocycle is preferably a 7- to 14-membered ring, and more preferably an 8- to 10-membered ring. The bicyclic heterocycle may also contain a spiro ring. When the heterocycle is a bicyclic heterocycle, it may contain up to 10 heteroatoms. Each heteroatom is independently selected from O, S, and N, and it is preferred 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, benzothiophene, hydrothienopyridine, (iso)quinoline, hydro(iso)quinoline, hydrofuropyridine, and derivatives thereof.

[0032] The polycyclic heterocycle is preferably a 9- to 30-membered ring, and more preferably a 12- to 26-membered ring. The polycyclic heterocycle may also contain a spiro ring. When the heterocycle is a polycyclic heterocycle, it may contain up to 15 heteroatoms. Each heteroatom is independently selected from O, S, and N, and it is preferred that at least one of the heteroatoms is N. Examples of polycyclic heterocycles include carbazole, phenazine, phenoxazine, phenothiazine, benzoindole, pyrroloquinoline, acridine, and derivatives thereof.

[0033] When the heterocycle has a substituent, the substituent may be a halogen atom, a C-C 10 Examples of the substituents include hydrocarbon groups such as those listed above, oxygen substituents such as hydroxyl, alkoxy and carbonyl groups, nitrogen substituents such as amino, cyano and nitro groups, and sulfur substituents such as sulfanyl, sulfoxy and sulfone groups.

[0034] In Y, the halogen atom is F, Cl, Br or I, preferably F or Cl, and particularly preferably F.

[0035] Y is -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), when A ４ , A ５ and A ６is the same as defined for X above. k represents an integer of 0 or 1, and when k=1, Y is a nitrogen substituent containing two N atoms, and when l=1, Y is a nitrogen substituent containing an additional O atom.

[0036] In Y, -OA ７ , -SA ８ A included in ７ , A ８ represents a hydrocarbon group having 1 to 12 carbon atoms. ７ , A ８ represents a hydrocarbon group having 1 to 12 carbon atoms, for example, １ , A ２ and A ３ Among these, the hydrocarbon group may have 1 to 12 carbon atoms.

[0037] In Y, A ４ , A ５ and A ６ When any two groups among the above are bonded to each other to form a ring, Y may form a heterocycle having at least one heteroatom selected from the group consisting of a nitrogen atom (N), a sulfur atom (S) and an oxygen atom (O). ４ , A ５ and A ６ is the above A １ , A ２ and A ３ is the same as the heterocycle defined in

[0038] In Z, -O ｈ A ９ A included in ９ represents a hydrocarbon group having 1 to 12 carbon atoms. ９ represents a hydrocarbon group having 1 to 12 carbon atoms, for example, １ , A ２ and A ３ and when h=1, Z may contain an oxygen substituent.

[0039] Z is -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) represents A １０ , A１１ and A １２ is the same as defined for X above. i represents an integer of 0 or 1, and when i=1, Z is a nitrogen substituent containing two N atoms, and when j=1, Z is a nitrogen substituent containing an additional O atom.

[0040] In Z, A １０ , A １１ and A １２ When any two groups among these are bonded to each other to form a ring, Z may form a heterocycle having at least one heteroatom selected from the group consisting of a nitrogen atom (N), a sulfur atom (S) and an oxygen atom (O). １０ , A １１ and A １２ is the above A １ , A ２ and A ３ is the same as the heterocycle defined in

[0041] The fluorine-containing propenoic acid compound of this embodiment can have excellent effects in terms of structural expandability, and in particular, can be expected to have further improved pharmacological activity. Furthermore, since a symmetrical substituent can be introduced at the 3-position, asymmetric derivatization at the 3-position can be achieved. More specifically, it is possible to obtain a 3-fluoro-2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent introduced at the 3-position, or a 2-(trifluoromethyl)propenoic acid derivative having a nitrogen substituent and a nitrogen, oxygen, or sulfur substituent introduced at the 3-position. Furthermore, the fluorine-containing propenoic acid compound of this embodiment is useful not only in the fields of agricultural chemicals and pharmaceuticals, but also in the fields of electronic materials such as organic semiconductors and liquid crystals.

[0042] (Method for Producing Fluorinated Propenoic Acid Compound) The method for producing a fluorinated propenoic acid compound in this embodiment includes a step (a) of reacting a fluorinated propenoic acid compound represented by the following general formula (5) with a compound represented by the following general formula (7) or a salt thereof in the presence of a base to obtain a fluorinated propenoic acid compound represented by the following general formula (6):

[0043] (In the above general formulas (5), (6), and (7), X is —N((RA１ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, W is -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.

[0044] The method for producing a fluorinated propenoic acid compound in this embodiment further includes a step (b) of carrying out an elimination reaction of a fluorinated isobutyric acid compound represented by the following general formula (4), and reacting the obtained intermediate reactant with a compound represented by the following general formula (8) or a salt thereof in the presence of a base, thereby obtaining a fluorinated propenoic acid compound represented by the general formula (5):

[0045] (In the above general formulas (4) and (8), X is —N((RA １ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.

[0046] The method for producing a fluorinated propenoic acid compound in this embodiment further includes a step (c) of carbonylating a fluorinated isobutene compound represented by the following general formula (3) in the presence of a nucleophile, and reacting the obtained intermediate reactant with a compound represented by the following general formula (9) or a salt thereof in the presence of a base, thereby obtaining the fluorinated propenoic acid compound represented by the general formula (4):

[0047] (In the above general formula (3), W is —N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and in the above general formula (9), Z is -O ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.

[0048] The method for producing a fluorinated propenoic acid compound in this embodiment further includes a step (d) of carrying out an elimination reaction of a fluorinated isobutane compound represented by the following general formula (2) to obtain a fluorinated isobutene compound represented by the general formula (3):

[0049] (In the above general formula (2), W is —N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ Any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, and l represents an integer of 0 or 1.

[0050] In the fluorine-containing propenoic acid compound represented by the general formula (6), when W=F, it corresponds to the fluorine-containing propenoic acid compound represented by the general formula (5). That is, the fluorine-containing propenoic acid compound represented by the general formula (1) may include the fluorine-containing propenoic acid compound represented by the general formula (6) and the fluorine-containing propenoic acid compound represented by the general formula (5). In addition, in each of the above general formulas, A １ ~A １２ and the ring are the same as defined in the fluorine-containing propenoic acid compound represented by the above general formula (1).

[0051] The above reaction (a) as a whole is represented by the following reaction formula (A).

[0052] The above reaction (b) as a whole is represented by the following reaction formula (B).

[0053] The reaction (c) above is expressed as the following reaction formula (C) as a whole. In the following reaction formula, the nucleophile may be represented as "Nu" for convenience. Furthermore, "NuWF" represents the reaction of a nucleophile cation substituted with W with F. － It represents salt of.

[0054] The reaction (d) above is expressed as the following reaction formula (D) as a whole.

[0055] In each of the above reactions, the compounds represented by the general formulas (7) to (9) may be in the form of a salt. When the compounds represented by the general formulas (7) to (9) are in the form of a salt, the H moiety of the compound is cationized to form (H ＋ The counter ion is not particularly limited as long as it is a monovalent anion, and examples thereof include F － , Cl － ,Br － , I － and the like, trifluoroacetate anion, paratoluenesulfonate anion, trifluoromethanesulfonate anion, nonafluorobutanesulfonic acid, bis(trifluoromethylsulfonyl)imide anion, tetrafluoroborate anion, and the like.

[0056] When a base is used in each of the above reactions, examples of the base 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, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, and diazabicyclooctane; and phosphorus derivatives such as phosphazene bases.

[0057] In each of the above reactions, when a nucleophile is used, examples of the nucleophile include tertiary amines such as triethylamine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane, imidazole derivatives such as 1-methylimidazole, and pyridine derivatives such as pyridine and 4-dimethylaminopyridine.

[0058] In each of the above reactions, a hydrogen halide scavenger may be used as needed. The hydrogen halide scavenger is a substance that has the function of capturing hydrogen fluoride (HF) that is produced. By using the hydrogen halide scavenger, the step of recovering hydrogen fluoride can be omitted, and the fluorine-containing propenoic acid compound can be obtained more simply.

[0059] 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, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, and diazabicyclooctane; and phosphorus derivatives such as phosphazene bases.

[0060] In the above reaction (a), the fluorine (F) atom of the fluorine-containing propenoic acid compound represented by the general formula (5) is substituted with the group W of the compound represented by the general formula (7).

[0061] In the above reaction (b), an intermediate reactant obtained by the elimination reaction of the fluorine-containing isobutyric acid compound represented by the general formula (4) is reacted with a compound represented by the general formula (8) in the presence of a base, whereby one fluorine atom (F) possessed by the intermediate reactant is substituted with a group X of the compound represented by the general formula (8).

[0062] In the above reaction (c), an intermediate reactant obtained by carbonylating a fluorine-containing isobutene compound represented by general formula (3) in the presence of a nucleophile is reacted with a compound represented by general formula (9) in the presence of a base, whereby the fluorine (F) atom directly bonded to the carbon atom of the carbonyl group is substituted with group Z of the compound represented by general formula (9).

[0063] In the above reaction (d), an elimination reaction of a fluorinated isobutane compound represented by the following general formula (2) is carried out, whereby HF is eliminated to produce a fluorinated isobutene compound represented by the general formula (3):

[0064] Each of the above reactions (a) to (d) may be carried out in the presence of a fluoride ion scavenger, if necessary. The fluoride ion scavenger is preferably a salt of a cation of lithium, sodium, magnesium, potassium, calcium, or tetramethylammonium with an anion of trifluoroacetic acid, heptafluorobutyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, nonafluorobutanesulfonic acid, bis(trifluoromethanesulfonyl)imide, bis(nonafluorobutanesulfonyl)imide, N,N-hexafluoropropane-1,3-disulfonylimide, tetraphenylboric acid, tetrakis[3,5-bis(trifluoromethyl)phenyl]boric acid, or tetrakis(pentafluorophenyl)boric acid. Among these, potassium salts or sodium salts are preferred, and sodium salts are more preferred. It is believed that the cations derived from the fluoride ion scavenger capture fluorine ions liberated during the reaction and precipitate as a salt that has low solubility in organic solvents, thereby accelerating the reaction and enabling the production of a fluorinated propenoic acid compound in high yield.

[0065] The reaction temperature in the above reactions (a) to (d) 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 above reactions (a) to (d) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 2 to 20 hours.

[0066] The solvent used in the above reactions (a) to (d) is preferably an organic solvent, and examples thereof include aprotic polar solvents such as tetrahydrofuran, monoglyme, diglyme, triglyme, tetraglyme, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidone, 4-methyltetrahydropyran, dimethylethyleneurea, tetramethylurea, dimethyl sulfoxide, and sulfolane; protic polar solvents such as methanol, ethanol, n-propanol, 2-propanol, and water; non-aqueous solvents such as hexane, dichloromethane, toluene, and diethyl ether; and two-phase solvents combining these solvents. Furthermore, as a catalyst for the above reactions (a) to (d), a quaternary ammonium halide such as benzyltriethylammonium chloride, a quaternary phosphonium halide, a crown ether, or the like can be optionally used.

[0067] Based on the above embodiments, the present invention relates to the following [1] to [5]: [1] A fluorine-containing propenoic acid compound represented by the following general formula (1): (In the above general formula (1), X is —N((RA １ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ Any two of the groups may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, Y represents a halogen atom, -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.) [2] A method for producing a fluorine-containing propenoic acid compound represented by the following general formula (6), comprising a step of reacting a fluorine-containing propenoic acid compound represented by the following general formula (5) with a compound represented by the following general formula (7) or a salt thereof in the presence of a base, to obtain the fluorine-containing propenoic acid compound represented by the following general formula (6): (In the above general formulas (5) and (6), X is —N((RA １ ) ｍ A ２ ) (O ｎ A ３ ), R represents a nitrogen atom or a sulfur atom, A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, W is -N((NA ４ ) ｋ A ５ ) (O ｌ A６ ), -OA ７ , -SA ８ represents, ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; ４ , A ５ and A ６ any two groups among these may be bonded to each other to form a ring, k represents an integer of 0 or 1, l represents an integer of 0 or 1, and Z is -O. ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1, i represents an integer of 0 or 1, and j represents an integer of 0 or 1.) [3] A method for producing a fluorine-containing propenoic acid compound according to the above item [2], further comprising a step of carrying out an elimination reaction of a fluorine-containing isobutyric acid compound represented by the following general formula (4), and reacting the obtained intermediate reactant with a compound represented by the following general formula (8) or a salt thereof in the presence of a base, thereby obtaining a fluorine-containing propenoic acid compound represented by the general formula (5). (In the above general formulae (4) and (8), X and Z are as defined in the above general formulae (5) and (6).) [4] A method for producing a fluorine-containing propenoic acid compound according to the above item [3], further comprising the step of carbonylating a fluorine-containing isobutene compound represented by the following general formula (3) in the presence of a nucleophile, and reacting the obtained intermediate reactant with a compound represented by the following general formula (9) or a salt thereof in the presence of a base, thereby obtaining the fluorine-containing propenoic acid compound represented by the above general formula (4): (In the above general formula (3), W is as defined in the above general formula (7), and in the above general formula (9), Z is as defined in the above general formulas (5) and (6).) [5] A method for producing a fluorinated propenoic acid compound according to the above item [4], further comprising a step of obtaining a fluorinated isobutene compound represented by the general formula (3) by carrying out an elimination reaction of a fluorinated isobutane compound represented by the following general formula (2): (In the above general formula (2), W is as defined in the above general formula (7).)

[0068] Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, but includes all aspects encompassed by the concept of the present invention and the scope of the claims, and can be modified in various ways within the scope of the present invention.

[0069] Examples of the present invention will be described below, but the present invention is not limited to these examples as long as they do not deviate from the spirit of the present invention. Note that the room temperature described below is in the range of 20°C ± 10°C.

[0070] Example 1 Synthesis of Methyl 3-fluoro-3-(1-piperidinyl)-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 0.4 g (4.7 mmol) of piperidine and 1.0 g (9.4 mmol) of triethylamine were added to 50 g of tetrahydrofuran (THF). Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and purified with a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 0.5 g of the compound represented by the following formula (10). The isolation yield of the obtained compound was 42%.

[0071]

[0072] The analytical results were as follows: Mass spectrum (APCI, m / z): 255 ([M] ＋ )

[0073] Example 2 Synthesis of Methyl 3-fluoro-3-[N-(phenylmethyl)benzenemethaneamino]-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 0.9 g (4.7 mmol) of N-(phenylmethyl)benzenemethaneamine and 1.2 g (9.4 mmol) of diisopropylethylamine were added to 50 g of hexane. Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in hexane and purified with a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 1.2 g of the compound represented by the following formula (11). The isolation yield of the obtained compound was 72%.

[0074]

[0075] The analytical results were as follows: Mass spectrum (APCI, m / z): 367 ([M] ＋ ) １ H-NMR (400MHz, CDCl ３ ) δppm: 7.38-7.13 (m, 10H), 4.35 (s, 4H), 3.73 (s, 3H)

[0076] Example 3 Synthesis of methyl 3-fluoro-3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-propenoate Under ice-water cooling, 0.9 g (8.6 mmol) of triethylamine was added to 100 g of methanol. Subsequently, 1.0 g (4.3 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)propane was added dropwise so that the internal temperature did not exceed 10 ° C., and the temperature was raised to room temperature. After stirring at room temperature for 4 hours, the contents were cooled with ice-water and 0.8 g (4.3 mmol) of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride was added. Subsequently, 1.3 g (13 mmol) of triethylamine was added dropwise so that the internal temperature did not exceed 10 ° C., and the temperature was raised to room temperature. After stirring for 16 hours at room temperature, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and purified on a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3) to obtain 0.4 g of the compound represented by the following formula (12). The isolated yield of the obtained compound was 30%.

[0077]

[0078] The analytical results were as follows: Mass spectrum (APCI, m / z): 309 ([M] ＋ )

[0079] Example 4 Synthesis of methyl 3-fluoro-3-[2-ethoxy-N-(2-ethoxyethyl)ethanamino]-2-propenoate: Under ice-water cooling, 0.4 g (4.7 mmol) of 1-methylimidazole was added to a mixed solution of 20 g of dimethylformamide (DMF) and 20 g of methanol. Subsequently, 1.0 g (4.7 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1-propene was added dropwise so that the internal temperature did not exceed 10 ° C., and the mixture was heated to room temperature. After stirring for 4 hours at room temperature, the contents were cooled with ice-water, and 0.9 g (4.7 mmol) of 2-ethoxy-N-(2-ethoxyethyl)ethanamine hydrochloride was added. Subsequently, 2.1 g (14 mmol) of triethanolamine was added dropwise so that the internal temperature did not exceed 10 ° C., and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was evaporated under reduced pressure, and the residue was dissolved in hexane and purified on a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3) to obtain 0.5 g of the compound represented by the following formula (13). The isolated yield of the obtained compound was 34%.

[0080]

[0081] The analytical results were as follows: Mass spectrum (APCI, m / z): 331 ([M] ＋ )

[0082] Example 5 Synthesis of methyl 3-fluoro-3-[N-[4-(1,1-dimethylethyl)phenyl]benzo[b]thiophene-3-amino]-2-propenoate At room temperature, 1.3 g (4.7 mmol) of N-[4-(1,1-dimethylethyl)phenyl]benzo[b]thiophene-3-amine and 1.3 g (9.4 mmol) of diisopropylethylamine were added to 80 g of THF, and 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise. After stirring for 48 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was purified using a silica gel column with a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 0.2 g of the compound represented by the following formula (14). The isolated yield of the obtained compound was 9%.

[0083]

[0084] The analytical results were as follows: Mass spectrum (APCI, m / z): 451 ([M] ＋ )

[0085] Example 6 Synthesis of Methyl 3-(1-methylethoxy)-3-[1-(2-butylimidazolyl)]-2-propenoate: Under ice-water cooling, 0.6 g (4.7 mmol) of 2-butylimidazole and 1.8 g (14 mmol) of diisopropylethylamine were added to 50 g of 2-propanol. Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was purified on a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 0.3 g of the compound represented by the following formula (15). The isolated yield of the compound obtained was 22%.

[0086]

[0087] The analytical results were as follows: Mass spectrum (APCI, m / z): 334 ([M] ＋ )

[0088] Example 7 Synthesis of Methyl 3-[N-(phenylmethyl)benzenemethaneamino]-3-[[4-(1,1-dimethylethyl)phenylmethyl]thio]-2-propenoate Under ice-water cooling, 1.0 g (2.7 mmol) of methyl 3-fluoro-3-[N-(phenylmethyl)benzenemethaneamino]-2-(trifluoromethyl)-2-propenoate and 0.5 g (2.7 mmol) of 4-(1,1-dimethylethyl)benzenemethanethiol were added to 50 g of THF. Subsequently, 0.4 g (2.7 mmol) of diazabicycloundecene was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 24 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and purified using a silica gel column with a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), yielding 0.03 g of the compound represented by the following formula (16). The isolated yield of the obtained compound was 2%.

[0089]

[0090] The analytical results were as follows: Mass spectrum (APCI, m / z): 527 ([M] ＋ )

[0091] Example 8 Synthesis of Methyl 3-fluoro-3-[N-(phenylmethoxy)methaneamino]-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 1.2 g (4.7 mmol) of N-(phenylmethoxy)methaneamine trifluoroacetate and 1.8 g (14 mmol) of diisopropylethylamine were added to 50 g of hexane. Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in hexane and purified with a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 0.9 g of the compound represented by the following formula (17). The isolated yield of the obtained compound was 61%.

[0092]

[0093] The analytical results were as follows: Mass spectrum (APCI, m / z): 307 ([M] ＋ )

[0094] Example 9 Synthesis of Methyl 3-fluoro-3-(1,2,3,4-tetrahydroquinolino)-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 0.6 g (4.7 mmol) of 1,2,3,4-tetrahydroquinoline and 1.2 g (9.4 mmol) of diisopropylethylamine were added to 50 g of hexane. Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in hexane and purified with a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 0.7 g of the compound represented by the following formula (18). The isolated yield of the obtained compound was 51%.

[0095]

[0096] The analytical results were as follows: Mass spectrum (APCI, m / z): 303 ([M] ＋ ) １ H-NMR (400MHz, CDCl ３ ) δppm: 7.17-6.98 (m, 4H), 3.63 (dd, 2H), 3.37 (s, 3H), 2.86 (dd, 2H), 2.07 (tt, 2H)

[0097] Example 10 Synthesis of Methyl 3-fluoro-3-[N-(benzyl)anilino]-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 0.9 g (4.7 mmol) of N-benzylaniline and 1.0 g (9.4 mmol) of triethylamine were added to a mixed solution of 25 g of tetrahydrofuran (THF) and 25 g of hexane. Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and purified with a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate=7:3), yielding 1.1 g of the compound represented by the following formula (19). The isolation yield of the obtained compound was 66%.

[0098]

[0099] The analytical results were as follows: Mass spectrum (APCI, m / z): 353 ([M] ＋ ) １ H-NMR (400MHz, CDCl ３ ) δppm: 7.37-7.12 (m, 10H), 4.92 (s, 2H), 3.28 (s, 3H)

[0100] Example 11 Synthesis of methyl 3-fluoro-3-[N-(methyl)pyrroloamino]-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 0.5 g (4.7 mmol) of N-methyl-pyrrol-1-amine and 1.2 g (9.4 mmol) of diisopropylethylamine were added to 50 g of tetrahydrofuran (THF). Subsequently, 1.0 g (4.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10 ° C., and the mixture was heated to room temperature. After stirring for 16 hours at room temperature, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and purified with a silica gel column using a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate = 7:3), yielding 0.1 g of the compound represented by the following formula (20). The isolation yield of the obtained compound was 6%.

[0101]

[0102] The analytical results were as follows: Mass spectrum (APCI, m / z): 266 ([M] ＋ )

[0103] Example 12 Synthesis of methyl 3-fluoro-3-[2-(phenylmethoxy)carbonyl)-1-pyrazolidinyl]-2-(trifluoromethyl)-2-propenoate Under ice-water cooling, 0.5 g (2.5 mmol) of benzyl pyrazolidine-1-carboxylate and 0.5 g (2.6 mmol) of diisopropylethylamine were added to 12 ml of tetrahydrofuran (THF). Subsequently, 0.5 g (2.6 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propanoate was added dropwise so that the internal temperature did not exceed 10°C, and the mixture was heated to room temperature. After stirring for 17 hours at room temperature, silica gel column purification was performed using a mixed solvent of hexane and ethyl acetate, and 0.9 g of the compound represented by the following formula (21) was obtained. The isolation yield of the obtained compound was 94%.

[0104]

[0105] The analytical results were as follows: Mass spectrum (APCI, m / z): 376.2 ([M] ＋ )

Claims

A fluorine-containing propenoic acid compound represented by the following general formula (1): (In the above general formula (1), X is -N((RA １ ) ｍ A ２ ) (O ｎ A ３ ) and R represents a nitrogen atom or a sulfur atom; A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1; n represents an integer of 0 or 1; Y is a halogen atom, -N((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents A ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, A ４ , A ５ and A ６ any two groups among the above may be bonded to each other to form a ring, and k represents an integer of 0 or 1; l represents an integer of 0 or 1; Z is -O ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, A １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1; i represents an integer of 0 or 1; j represents an integer of 0 or 1. 　 A method for producing a fluorine-containing propenoic acid compound represented by the following general formula (6), comprising a step of reacting a fluorine-containing propenoic acid compound represented by the following general formula (5) with a compound represented by the following general formula (7) or a salt thereof in the presence of a base to obtain a fluorine-containing propenoic acid compound represented by the following general formula (6): (In the above general formulas (5) and (6), X is -N((RA １ ) ｍ A ２ ) (O ｎ A ３ ) and R represents a nitrogen atom or a sulfur atom; A １ , A ２ and A ３ each independently represents a hydrocarbon group having 1 to 12 carbon atoms; A １ , A ２ and A ３ any two groups among these may be bonded to each other to form a ring, m represents an integer of 0 or 1, n represents an integer of 0 or 1, W is -N ((NA ４ ) ｋ A ５ ) (O ｌ A ６ ), -OA ７ , -SA ８ represents A ４ , A ５ , A ６ , A ７ and A ８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, A ４ , A ５ and A ６ any two groups among the above may be bonded to each other to form a ring, and k represents an integer of 0 or 1; l represents an integer of 0 or 1; Z is -O ｈ A ９ , -N((NA １０ ) ｉ A １１ ) (O ｊ A １２ ) and A ９ , A １０ , A １１ and A １２ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, A １０ , A １１ and A １２ any two groups among these may be bonded to each other to form a ring, h represents an integer of 0 or 1; i represents an integer of 0 or 1; j represents an integer of 0 or 1.

3. The method for producing a fluorine-containing propenoic acid compound according to claim 2, further comprising a step of carrying out an elimination reaction of a fluorine-containing isobutyric acid compound represented by the following general formula (4), and reacting the obtained intermediate reactant with a compound represented by the following general formula (8) or a salt thereof in the presence of a base, thereby obtaining the fluorine-containing propenoic acid compound represented by the general formula (5): (In the above general formulas (4) and (8), X and Z are as defined in the above general formulas (5) and (6).) 　 The method for producing a fluorine-containing propenoic acid compound according to claim 3, further comprising the step of carbonylating a fluorine-containing isobutene compound represented by the following general formula (3) in the presence of a nucleophile, and reacting the obtained intermediate reactant with a compound represented by the following general formula (9) or a salt thereof in the presence of a base, thereby obtaining the fluorine-containing propenoic acid compound represented by the general formula (4): (In the above general formula (3), W is as defined in the above general formula (7), In the above general formula (9), Z is as defined in the general formulas (5) and (6).

5. The method for producing a fluorinated propenoic acid compound according to claim 4, further comprising a step of carrying out an elimination reaction of a fluorinated isobutane compound represented by the following general formula (2) to obtain a fluorinated isobutene compound represented by the general formula (3): (In the above general formula (2), W is as defined in the above general formula (7).)

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