Method for producing chlorinated fluorine-containing pyrimidine compounds

Abstract

To provide a method for producing a chlorinated fluorine-containing pyrimidine compound from a fluorine-containing pyrimidinone compound with an aromatic hydroxy group, aiming for high yield.SOLUTION: A method for producing a chlorinated fluorine-containing pyrimidine compound includes reacting a fluorine-containing pyrimidinone compound with at least one aromatic hydroxy group with a chlorinating agent in the presence of a catalyst represented by the following general formula (wherein R1 represents a C1-12 hydrocarbon group, and R2-R6 independently represent a hydrogen atom, a C1-12 hydrocarbon group, OR7 or NR7R8, where any two adjacent groups of R1-R6 may bond together to form a ring).SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Conventionally, chlorinating agents such as phosphoryl chloride, thionyl chloride, and oxalyl chloride have been used to chlorinate aromatic hydroxyl groups in heterocyclic and aromatic compounds. However, the chlorination reaction of aromatic hydroxyl groups may not proceed smoothly in the absence of a catalyst.

[0003] Amide derivatives such as dimethylformamide and dimethylacetamide, and urea derivatives such as tetramethylurea and dimethylimidazolinone are known catalysts that promote chlorination reactions. However, although dimethylformamide has excellent activity as a catalyst for chlorination reactions, Non-Patent Literature 1 reports that under certain reaction conditions it can produce dimethylcarbamoyl chloride, a mutagenic substance, raising safety concerns. On the other hand, other amide derivatives and urea derivatives can be used as alternative catalysts to dimethylformamide, but a common problem with these compounds is their high polarity. When water is used for workup, they emulsify, making separation from the aqueous phase difficult and raising concerns about the loss of the target product into the aqueous phase. Furthermore, these compounds generally have high boiling points, making removal by distillation difficult.

[0004] To avoid problems arising from the use of such amide derivatives and urea derivatives as catalysts, the use of ion-pair compounds consisting of ammonium ions and chloride ions is known as an alternative catalyst system.

[0005] For example, Patent Document 1 reports a reaction example using trimethylamine hydrochloride, Non-Patent Document 2 reports a reaction example using triethylamine hydrochloride, and Non-Patent Document 3 reports a reaction example using diethylaniline hydrochloride. Furthermore, Patent Document 2 reports a reaction example using benzyltriethylammonium chloride as a quaternary ammonium chloride, Non-Patent Document 4 reports a reaction example using tetramethylammonium chloride, and Non-Patent Document 5 reports a reaction example using tetrabutylammonium chloride. However, even when these ammonium salt-based ion-pair compounds are used as catalysts, the catalytic activity may be insufficient in some cases.

[0006] It is known that tertiary amines are added to enhance the catalytic activity of ammonium salt-based ion-pair compounds. Non-patent document 6 reports a reaction example using a tetramethylammonium chloride-dimethylaniline system, non-patent document 7 reports a reaction example using a benzyltriethylammonium chloride-diisopropylethylamine system, and patent document 3 reports a reaction example using tetrabutylammonium chloride-diethylaniline. However, the use of additional catalysts can lead to increased manufacturing costs. Therefore, it is desirable to use a catalyst that exhibits high activity without the addition of tertiary amines or the like. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2009 / 019099 [Patent Document 2] International Publication No. 2015 / 028622 [Patent Document 3] International Publication No. 02 / 062123 [Non-patent literature]

[0008] [Non-Patent Document 1] Organic Process & Development, 1997, Vol. 1, p. 182 [Non-Patent Document 2] Journal of Medicinal Chemistry, 2002, Vol. 45, pp. 3865-3877 [Non-Patent Document 3] Chemistry Letters, 2009, Vol. 38, pp. 174-175 [Non-Patent Document 4] Invest New Drugs, 2012, Vol. 30, pp. 2035-2045. [Non-Patent Document 5] Chemical Communications, 2015, Vol. 51, pp. 14123-14126, Supporting Information, pp. 1-33. [Non-Patent Document 6] Tetrahedron Letters, 2017, Vol. 58, pp. 4166-4168 [Non-Patent Document 7] ChemMedChem, 2008, Vol. 3, pp. 1893-1904 [Overview of the project] [Problems that the invention aims to solve]

[0009] Against this backdrop, the inventors investigated various catalysts that exhibit high activity without the addition of tertiary amines or the like in reaction systems where ammonium salt-based ion-pair compounds alone do not exhibit sufficient catalytic activity. As a result, they discovered that by changing the cation of the ion-pair compound from ammonium to pyridinium, the ion-pair compound exhibits high catalytic activity in the chlorination reaction of aromatic hydroxyl groups of heterocyclic and aromatic compounds, thus completing the present invention.

[0010] The present invention provides a method for producing chlorinated fluorine-containing pyrimidine compounds from fluorine-containing pyrimidinone compounds having aromatic hydroxyl groups in high yield.

[0011] In the method for producing a chlorinated fluorine-containing pyrimidine compound according to this embodiment, a fluorine-containing pyrimidinone compound having at least one aromatic hydroxyl group is reacted with a chlorinating agent in the presence of a catalyst represented by the following general formula (1).

Chemical formula

Advantages of the Invention

[0012] According to the present invention, a chlorinated fluorine-containing pyrimidine compound can be produced in a high yield from a fluorine-containing pyrimidinone compound having an aromatic hydroxyl group.

Embodiments for Carrying Out the Invention

[0013] <Method for Producing Chlorinated Fluorine-Containing Pyrimidine Compound> In this embodiment, a fluorine-containing pyrimidinone compound having at least one aromatic hydroxyl group is reacted with a chlorinating agent in the presence of a specific catalyst. As a result, a chlorination reaction of the fluorine-containing pyrimidinone compound having an aromatic hydroxyl group occurs, and a chlorinated fluorine-containing pyrimidine compound can be produced in a high yield.

[0014] (catalyst) In this embodiment, a compound represented by the following general formula (1) is used as a catalyst. Ion-pair compounds of pyridinium ions and chloride ions, as shown in general formula (1), exhibit high catalytic activity in the chlorination reaction of aromatic hydroxyl groups, allowing for the production of chlorinated fluorine-containing pyrimidine compounds in high yield. Furthermore, even when the compound shown in general formula (1) is used alone, without the addition of additional catalysts such as tertiary amines, the chlorination reaction of fluorine-containing pyrimidinone compounds having aromatic hydroxyl groups is sufficiently promoted. As a result, chlorinated fluorine-containing pyrimidine compounds can be produced in high yield from fluorine-containing pyrimidinone compounds having aromatic hydroxyl groups, thereby suppressing production costs associated with the use of additional catalysts and the recovery of residual catalyst after the reaction.

[0015] [ka]

[0016] In the above general formula (1), R 1 This represents a hydrocarbon group with 1 to 12 carbon atoms. R 2 , R 3 , R 4 , R 5 and R 6 Each of these independently consists of a hydrogen atom, a hydrocarbon group with 1 to 12 carbon atoms, and OR 7 or NR 7 R 8 This represents, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Any two adjacent groups may be bonded to each other to form a ring. R 7 and R 8 Each of these independently represents a hydrocarbon group with 1 to 12 carbon atoms.

[0017] The above R 1 ~R 8 In this context, 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, alicyclic hydrocarbon groups, etc. 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 straight-chain hydrocarbon group or a branched linear hydrocarbon group. If the hydrocarbon group having 1 to 12 carbon atoms 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 an aromatic hydrocarbon group with substituents or an aromatic hydrocarbon group without substituents. 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 an alicyclic hydrocarbon group with substituents or an alicyclic hydrocarbon group without substituents. Furthermore, the alicyclic hydrocarbon group may have a cross-linked ring structure.

[0018] 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.

[0019] Examples of aromatic hydrocarbon groups include the phenyl group and the naphthyl group.

[0020] 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.

[0021] When an aromatic hydrocarbon group or alicyclic hydrocarbon group has substituents, examples of substituents include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, ter-butyl group, pentyl group, hexyl group, and the like.

[0022] R 1 It is preferably an alkyl group having 1 to 10 carbon atoms, and more preferably an alkyl group having 1 to 5 carbon atoms. 1 Because R is an alkyl group, compounds represented by general formula (1) can be easily prepared. 1 When is an alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, for example, it can be an alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, from among the hydrocarbon groups having 1 to 12 carbon atoms listed above.

[0023] R 2 , R 3 , R 4 , R 5 and R 6 Preferably, at least two of them are hydrogen atoms, more preferably at least three are hydrogen atoms, even more preferably at least four are hydrogen atoms, and it is particularly preferable that all of them are hydrogen atoms. Also, R 2 , R 3 , R 4 , R 5 and R 6 At least one of them is a hydrocarbon group with 1 to 12 carbon atoms, OR 7 or NR 7 R 8 If substituted, a hydrocarbon group having 1 to 12 carbon atoms or NR 7 R 8 Preferably, at least R 3 or R 4is a hydrocarbon group having 1 to 12 carbon atoms or NR 7 R 8 is more preferable.

[0024] R 2 、R 3 、R 4 、R 5 and R 6 When at least one of R 2 、R 3 、R 4 、R 5 and R 6 is a hydrocarbon group having 1 to 12 carbon atoms, for example, among the hydrocarbon groups having 1 to 12 carbon atoms mentioned above, an alkyl group having 1 to 12 carbon atoms is preferable, and an alkyl group having 1 to 5 carbon atoms is more preferable. Also, R 2 、R 3 、R 4 、R 5 and R 6 may be the same as or different from each other.

[0025] R 2 、R 3 、R 4 、R 5 and R 6 When at least one of R 7 R 8 is NR 7 and R 8 may be the same as or different from each other. R 7 and R 8 is preferably, for example, an alkyl group having 1 to 12 carbon atoms among the hydrocarbon groups having 1 to 12 carbon atoms mentioned above, and more preferably an alkyl group having 1 to 5 carbon atoms. Also, R 2 、R 3 、R 4 、R 5 and R 6 When at least two of R 7 R 8 are NR 2 、R 3 、R 4 、R 5 and R 6They may be the same as or different from each other.

[0026] R 1 、R 2 、R 3 、R 4 、R 5 及びR 6 When any two adjacent groups among them are bonded to each other to form a ring, they may form a 4- to 7-membered ring composed of carbon atoms and hydrogen atoms, or may further form a 4- to 7-membered heterocyclic ring containing a nitrogen atom.

[0027] (Fluorine-containing pyrimidinone compound) The fluorine-containing pyrimidinone compound, which is a starting material in the production method of this embodiment, has at least one aromatic hydroxyl group. Such a fluorine-containing pyrimidinone compound is, for example, a compound represented by the following general formula (2), (3) or (4), and the oxygen atom and hydroxyl group of the pyrimidinone skeleton, and further the hydroxyl group optionally present in the pyridyl skeleton are chlorinated.

[0028]

Chemical formula

[0029] In the above general formulas (2) to (4), W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n+1 (n is an integer from 1 to 10), a nitro group, -OA 1 、-SO m A 1 (m is an integer from 1 to 3), -SA 1 、-NA 1 A 2 、-B(OA 1 )(OA 2 )、-COA 1 、-COOA 1 、or -CONA 1 A 2 represents, A 1 及びA 2Each of these independently represents either a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0030] In W and X, the halogen atom is F, Cl, Br, or I, and is preferably F or Cl.

[0031] In W and X, the hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is a hydrocarbon group consisting of carbon atoms and hydrogen atoms, for example, the above R 1 ~R 8 Among the hydrocarbon groups listed, it can be a hydrocarbon group having 1 to 10 carbon atoms.

[0032] In W and X, -C n F 2n+1 The perfluoroalkyl group is not particularly limited as long as it consists of carbon atoms and fluorine atoms, and may be linear or branched. Also, n is an integer from 1 to 10, and preferably an integer from 1 to 3.

[0033] In W and X, -OA 1 , -SO m A 1 , -SA 1 COA 1 ,-COOA 1 A included in 1 This represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 If R represents a hydrocarbon group with 1 to 10 carbon atoms, for example, the above R 1 ~R 8 Among the hydrocarbon groups listed, it can be a hydrocarbon group having 1 to 10 carbon atoms. Also, m is an integer from 1 to 3, and is preferably 1.

[0034] In W and X, -NA 1 A 2 A included in 1 and A 2 Each of these independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 These may be the same or different. 1and A 2 If R represents a hydrocarbon group with 1 to 10 carbon atoms, for example, the above R 1 ~R 8 Among the hydrocarbon groups listed, it can be a hydrocarbon group having 1 to 10 carbon atoms.

[0035] In W and X, -B(OA) 1 )(OA 2 A included in ) 1 and A 2 Each of these independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 These may be the same or different. 1 and A 2 If R represents a hydrocarbon group with 1 to 10 carbon atoms, for example, the above R 1 ~R 8 Among the hydrocarbon groups listed, it can be a hydrocarbon group having 1 to 10 carbon atoms.

[0036] In W and X, -CONA 1 A 2 A included in 1 and A 2 Each of these independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 These may be the same or different. 1 and A 2 If R represents a hydrocarbon group with 1 to 10 carbon atoms, for example, the above R 1 ~R 8 Among the hydrocarbon groups listed, it can be a hydrocarbon group having 1 to 10 carbon atoms.

[0037] (Chlorinated fluorine-containing pyrimidine compounds) By reacting a fluorine-containing pyrimidinone compound represented by the above general formula (2), (3), or (4) with a chlorinating agent, chlorinated fluorine-containing pyrimidine compounds represented by the following general formulas (5), (6), or (7) are produced, respectively.

[0038] [ka]

[0039] In the above general formulas (5) to (7), W and X are, independently, a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, and -C n F 2n+1 (n is an integer from 1 to 10), nitro group, -OA 1 , -SO m A 1 (m is an integer between 1 and 3), -SA 1 ,-NA 1 A 2 , -B(OA) 1 )(OA 2 ), -COA 1 ,-COOA 1 , or -CONA 1 A 2 This represents, A 1 and A 2 Each of these independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0040] In the above general formulas (5) to (7), W and X are the same as those defined in the fluorine-containing pyrimidinone compounds represented by the above general formulas (2) to (4). Therefore, in the above general formulas (5) to (7), W and X are defined as halogen atoms, hydrocarbon groups having 1 to 10 carbon atoms, and -C n F 2n+1 nitro group, -OA 1 , -SO m A 1 , -SA 1 ,-NA 1 A 2 , -B(OA) 1 )(OA 2 ), -COA 1 ,-COOA 1 and -CONA 1 A 2 These are the same as those defined for the fluorine-containing pyrimidinone compounds represented by the general formulas (2) to (4) described above.

[0041] In the above general formulas (2) to (7), the hydrocarbon group having 1 to 10 carbon atoms is preferably an alkyl group having 1 to 10 carbon atoms. Such a hydrocarbon group is, for example, in the compound represented by the above general formula (1), the above R 1 ~R 8 Among the hydrocarbon groups listed above, alkyl groups having 1 to 10 carbon atoms can be used. Furthermore, in the above general formulas (2) to (7), W and X are each preferably independently a hydrogen atom, a halogen atom, or a hydrocarbon group having 1 to 10 carbon atoms, and it is particularly preferable that both are hydrogen atoms.

[0042] (Chlorine agent) Chlorination is preferably performed using a compound selected from the group consisting of phosphoryl chloride, thionyl chloride, and oxalyl chloride, with phosphoryl chloride being more preferable. In the chlorination reaction between the chlorinating agent and a fluorine-containing pyrimidinone compound having an aromatic hydroxyl group, the reaction temperature is typically 50 to 150°C, and the reaction time is 0.5 to 30 hours. The amount of chlorinating agent used in the chlorination reaction is usually 1 to 8 equivalents per equivalent of the fluorine-containing pyrimidinone compound. A solvent is not always necessary in the reaction with the chlorinating agent, but it is generally carried out in the presence of a solvent. Examples of solvents that can be used include organic solvents such as acetonitrile, propanenitrile, and benzonitrile. When a solvent is used, the chlorination reaction may be carried out under reflux while heating at or above the boiling point of the organic solvent used.

[0043] Based on the embodiments described above, the present invention relates to the following [1] to [5]. [1] A method for producing a chlorinated fluorine-containing pyrimidine compound, characterized by reacting a fluorine-containing pyrimidinone compound having at least one aromatic hydroxyl group with a chlorinating agent in the presence of a catalyst represented by the following general formula (1). [ka] (In the above general formula (1), R 1 This represents a hydrocarbon group with 1 to 12 carbon atoms. R2 , R 3 , R 4 , R 5 and R 6 Each of these independently consists of a hydrogen atom, a hydrocarbon group with 1 to 12 carbon atoms, and OR 7 or NR 7 R 8 This represents, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Any two adjacent groups may be bonded to each other to form a ring. R 7 and R 8 Each of these independently represents a hydrocarbon group with 1 to 12 carbon atoms. [2] The aforementioned R 1 The manufacturing method described in [1] above, wherein is an alkyl group having 1 to 10 carbon atoms. [3] The method for producing a product according to [1] or [2] above, wherein the fluorine-containing pyrimidinone compound is a compound represented by the following general formula (2), (3), or (4). [ka] (In the above general formulas (2) to (4), W and X are independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, and -C n F 2n+1 (n is an integer from 1 to 10), nitro group, -OA 1 , -SO m A 1 (m is an integer between 1 and 3), -SA 1 ,-NA 1 A 2 , -B(OA) 1 )(OA 2 ), -COA 1 ,-COOA 1 , or -CONA 1 A 2 This represents, A 1 and A 2Each of these independently represents either a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. [4] The method for producing a product according to any one of [1] to [3] above, wherein the chlorinated fluorine-containing pyrimidine compound is a compound represented by the following general formula (5), (6), or (7). [ka] (In the above general formulas (5) to (7), W and X are, independently, a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, and -C n F 2n+1 (n is an integer from 1 to 10), nitro group, -OA 1 , -SO m A 1 (m is an integer between 1 and 3), -SA 1 ,-NA 1 A 2 , -B(OA) 1 )(OA 2 ), -COA 1 ,-COOA 1 , or -CONA 1 A 2 This represents, A 1 and A 2 Each of these independently represents either a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. [5] The manufacturing method according to any one of [1] to [4] above, wherein the chlorinating agent is selected from the group consisting of phosphoryl chloride, thionyl chloride, and oxalyl chloride.

[0044] 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]

[0045] Examples of the present invention are described below, but the present invention is not limited to these examples unless it exceeds the spirit of the invention. Unless otherwise specified, room temperature is defined as being within the range of 20°C ± 5°C. Quantitative means that the yield of the product (chlorinated fluorine-containing pyrimidine compound) is 95% or higher.

[0046] (Example 1) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the presence of 1-butylpyridinium chloride catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.17 g (0.98 mmol) of 1-butylpyridinium chloride were added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and further neutralized with sodium bicarbonate solution, and then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. Subsequently, the filtrate was concentrated to quantitatively obtain 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0047] [ka]

[0048] (Comparative Example 1) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the absence of a catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride was added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. The filtrate was then concentrated, and the yield of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine was 55%.

[0049] (Comparative Example 2) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the presence of tetrabutylammonium chloride catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.27 g (0.98 mmol) of tetrabutylammonium chloride were added. The mixture was stirred under heating reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, and then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. The filtrate was then concentrated, yielding 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in 76% yield.

[0050] (Example 2) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the presence of 1-ethylpyridinium chloride catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.14 g (0.98 mmol) of 1-ethylpyridinium chloride were added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. Subsequently, 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine was quantitatively obtained by concentrating the filtrate.

[0051] (Example 3) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the presence of 1-propylpyridinium chloride catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.15 g (0.98 mmol) of 1-propylpyridinium chloride were added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. Subsequently, 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine was quantitatively obtained by concentrating the filtrate.

[0052] (Example 4) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine using 1-butyl-3-methylpyridinium chloride as a catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.18 g (0.98 mmol) of 1-butyl-3-methylpyridinium chloride were added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. Subsequently, 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine was quantitatively obtained by concentrating the filtrate.

[0053] (Example 5) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the presence of 1-butyl-4-methylpyridinium chloride catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.18 g (0.98 mmol) of 1-butyl-4-methylpyridinium chloride were added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, and then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. Subsequently, 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine was quantitatively obtained by concentrating the filtrate.

[0054] (Example 6) <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine in the presence of 4-dimethylamino-1-neopentylpyridinium chloride as a catalyst> 0.5 g (1.95 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 8.0 ml of acetonitrile, and 1.8 ml of phosphoryl chloride and 0.22 g (0.98 mmol) of 4-dimethylamino-1-neopentylpyridinium chloride were added. The mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, it was added dropwise to water and neutralized with sodium bicarbonate solution, then extracted with ethyl acetate. The extracted organic phase was dried over sodium sulfate and filtered. Subsequently, 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine was quantitatively obtained by concentrating the filtrate.

Claims

1. A method for producing a chlorinated fluorine-containing pyrimidine compound, characterized by reacting a fluorine-containing pyrimidinone compound having at least one aromatic hydroxyl group with a chlorinating agent in the presence of a catalyst represented by the following general formula (1), The fluorine-containing pyrimidinone compound is a compound represented by the following general formula (2), (3), or (4): The chlorinated fluorine-containing pyrimidine compound is a compound represented by the following general formula (5), (6), or (7): A method for producing a fluorine-containing pyrimidine compound, wherein the chlorinating agent is selected from the group consisting of phosphoryl chloride, thionyl chloride, and oxalyl chloride. 【Chemistry 1】 (In the above general formula (1), R １ This represents a hydrocarbon group with 1 to 12 carbon atoms. R ２ 、 R ３ 、 R ４ 、 R ５ and R ６ each independently represents a hydrogen atom, a hydrocarbon group having 1 to 12 carbon atoms, OR ７ or NR ７ R ８ and represents R １ , R ２ , R ３ , R ４ , R ５ and R ６ Any two adjacent groups may be bonded to each other to form a ring. R ７ and R ８ Each of these independently represents a hydrocarbon group having 1 to 12 carbon atoms. 【Chemistry 2】 (In the above general formulas (2) to (4), W and X independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n+1 (where n is an integer from 1 to 10), a nitro group, -OA 1, -SO m A 1 (where m is an integer from 1 to 3), -SA 1, -NA 1 A 2, -B(OA 1)(OA 2), -COA 1, -COOA 1, or -CONA 1 A 2. A1 and A2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 【Transformation 3】 (In the above general formulas (5) to (7), W and X independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n+1 (where n is an integer from 1 to 10), a nitro group, -OA 1, -SO m A 1 (where m is an integer from 1 to 3), -SA 1, -NA 1 A 2, -B(OA 1)(OA 2), -COA 1, -COOA 1, or -CONA 1 A 2. A1 and A2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

2. The aforementioned R １ The manufacturing method according to claim 1, wherein is an alkyl group having 1 to 10 carbon atoms.

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