Method for producing fluorinated pyrimidone compound

Abstract

To provide a simple method for producing a fluorinated pyrimidone compound that offers potential for diverse derivatization as an intermediate for pharmaceuticals or agrochemicals.SOLUTION: A method for producing a fluorinated pyrimidone compound comprises a step of preparing a fluorinated pyrimidone compound represented by general formula (3) through the reaction of a hexafluoroisobutyric acid ester represented by general formula (1) with an amidinopyridine represented by general formula (2).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing a fluorine-containing pyrimidone compound.

Background Art

[0002] Nitrogen-containing heterocyclic compounds have various pharmacological activities. Among them, pyridine and pyrimidine derivatives are important in both prokaryotes and eukaryotes. Therefore, many drugs having a pyridyl / pyrimidine structure have been developed. Specifically, Ceralasertib as a serine / threonine kinase inhibitor, Fimepinostat and Mocetinostat as histone deacetylase inhibitors, Buparlisib as a phosphatidylinositol 3-kinase inhibitor, Nilotinib and Imatinib as tyrosine kinase inhibitors, Gisadenafil as a phosphodiesterase 5 inhibitor, Clazosentan as an endothelin A receptor antagonist, and the like can be mentioned.

[0003] Regarding the pharmacological activity of drugs having a pyridyl / pyrimidine structure, for example, in Patent Documents 1 to 3, pyrimidine compounds having a pyridine ring at the 2-position and a trifluoromethyl group at the 5-position have been synthesized and reported to have control antibacterial activity against rice blast, cucumber powdery mildew, and gray mold.

[0004] However, in the synthesis of the compounds described in Patent Documents 1 to 2, since the number of reaction steps is large, the target product may not be obtained efficiently. For example, in the method described in Patent Document 2, the dealkylation of the alkyl group on the pyrimidine ring proceeds via a t-butoxy group. Therefore, when newly synthesizing a derivative of a fluorine-containing pyrimidone compound having a pyrimidone structure instead of a pyrimidine structure as a nitrogen-containing heterocyclic compound, it is preferable that dealkylation is not required.

[0005] In Patent Document 3, although a simple production method of a 4-pyrimidone compound having a hydrocarbon group in which sulfur (S) or nitrogen (N) is arbitrarily substituted at the 2-position and a trifluoromethyl group at the 5-position has been reported, there is no mention of a 4-pyrimidone compound having a pyridine ring at the 2-position. Therefore, it is desired to develop a simple production method of a 4-pyrimidone compound having a pyridine ring at the 2-position and a trifluoromethyl group at the 5-position.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] The present invention provides a simple production method of a fluorine-containing pyrimidone compound that can be expected to have various derivatizations as an intermediate for pharmaceuticals or agricultural chemicals.

Means for Solving the Problems

[0008] In the production method of the fluorine-containing pyrimidone compound according to the present embodiment, a step of obtaining a fluorine-containing pyrimidone compound represented by the following general formula (3) is included by reacting a hexafluoroisobutyric acid ester represented by the following general formula (1) with an amidinopyridine represented by the following general formula (2).

Chemical Formula

[0009] In the method for producing another fluorine-containing pyrimidone compound according to the present embodiment, a pentafluoromethacrylic acid ester represented by the following general formula (4) and an amidinopyridine represented by the following general formula (2) are reacted to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). A method for producing a fluorine-containing pyrimidone compound having a step of

Chemical formula

[0010] In the method for producing another fluorine-containing pyrimidone compound according to this embodiment, a fluoroisobutane derivative represented by the following general formula (5) and an amidinopyridine represented by the following general formula (2) are reacted in the presence of a nucleophile to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). A method for producing a fluorine-containing pyrimidone compound having a step of [Chemical formula] (In the above general formulas (2), (3), and (5), R 1 represents a hydrocarbon group having 1 to 10 carbon atoms, R 2 is a hydrogen atom, a halogen atom, -C j F 2j+1 , a nitro group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A 1 )(O k A 2 ), -O m SO(O l A 1 ), -O m SO 2 (O l A 1 ), -O m NA 1 A 2 , or -O m B(O l A 1 )(O k A 2 ), j represents an integer of 1 to 10, k represents an integer of 0 to 1, l represents an integer of 0 to 1, m represents an integer of 0 to 1, n represents an integer of 0 to 4, A 1 and A 2 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R 2When there are a plurality of them, the plurality of Rs 2 may be the same or different from each other, and may be connected to each other to form a ring structure.)

[0011] In the method for producing another fluorine-containing pyrimidone compound according to this embodiment, a fluoroisobutene derivative represented by the following general formula (6) and an amidinopyridine represented by the following general formula (2) are reacted in the presence of a nucleophile to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). A method for producing a fluorine-containing pyrimidone compound having a step of

Chemical formula

Advantages of the Invention

[0012] According to the present invention, a simple method for producing a fluorine-containing pyrimidone compound capable of expecting various derivatizations as an intermediate for pharmaceuticals or agricultural chemicals can be provided.

Modes for Carrying Out the Invention

[0013] <Method for Producing Fluorine-Containing Pyrimidone Compound> The synthesis of the fluorine-containing pyrimidone compound can be mainly classified into a method of introducing fluorine into a predetermined compound and a method of using a fluorine-containing compound as a starting material in advance (building block method). The former is not only restricted by the substituents that can coexist under the fluorine introduction reaction conditions, but also often requires the introduction of a "mark" such as bromine or iodine in advance at the fluorine introduction position, which is inefficient. On the other hand, in the latter, although the fluorine introduction position depends on the raw material, in this embodiment, a fluorine-containing pyrimidone compound represented by the general formula (3) in which fluorine is introduced at a position where introduction has been difficult by the conventional method is synthesized by reacting a fluorine-containing compound represented by the general formula (1), (4), (5) or (6) described later with an amidinopyridine represented by the general formula (2) described later. As a result, it is possible to simply and efficiently synthesize the target product by an economical production method that does not use expensive halogen elements, transition metal catalysts, etc. In particular, since the fluorine-containing compounds represented by (5) or (6) also have low toxicity, it is possible to more safely synthesize the fluorine-containing pyrimidone compound represented by the general formula (3).

[0014] (First Embodiment) In the first embodiment, there is a step (reaction (a)) of obtaining a fluorine-containing pyrimidone compound represented by the following general formula (3) by reacting a hexafluoroisobutyric acid ester represented by the following general formula (1) with an amidinopyridine represented by the following general formula (2).

[0015]

Chemical formula

[0016] In the fluorine-containing compound represented by the general formula (1), R 1 represents a hydrocarbon group having 1 to 10 carbon atoms. The hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is a hydrocarbon group composed of 1 to 10 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 the total number of carbon atoms is 1 to 10, and it may be a straight-chain hydrocarbon group or a branched-chain hydrocarbon group. When the hydrocarbon group having 1 to 10 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 10, and it may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group having no substituent. Further, the aromatic hydrocarbon group may have a condensed polycyclic structure. When the hydrocarbon group having 1 to 10 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 10, and it may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group having no substituent. Further, the alicyclic hydrocarbon group may have a bridged ring structure.

[0017] Examples of the chain hydrocarbon group include alkyl groups such as 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, heptyl group, octyl group, nonyl group, and decyl group; alkenyl groups such as ethenyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group, and decenyl group; Examples of the alkynyl group include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, nonynyl group, decynyl group and the like.

[0018] Examples of the aromatic hydrocarbon group include phenyl group and naphthyl group.

[0019] Examples of the alicyclic hydrocarbon group include saturated or unsaturated cyclic hydrocarbon groups. Examples of the cyclic hydrocarbon group include cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group, adamantyl group, norbornyl group and the like.

[0020] When the aromatic hydrocarbon group or the alicyclic hydrocarbon group has a substituent, examples of the substituent 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.

[0021] R 1 is preferably an alkyl group having 1 to 10 carbon atoms, more preferably an alkyl group having 1 to 5 carbon atoms. When R 1 is an alkyl group, the fluorine-containing compound represented by the general formula (1) can be easily prepared. When R 1 is an alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms, for example, among the hydrocarbon groups having 1 to 10 carbon atoms mentioned above, an alkyl group having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms can be used.

[0022] In the amidinopyridine represented by the general formula (2) and the fluorine-containing pyrimidone compound represented by the general formula (3), R 2 is a hydrogen atom, a halogen atom, -C j F 2j+1 , a nitro group, -O m A 1 , -O m CO(O l A 1 ), -O m PO(O l A1 )(O k A 2 )、 -O m SO(O l A 1 )、 -O m SO 2 (O l A 1 )、 -O m NA 1 A 2 、 or -O m B(O l A 1 )(O k A 2 ) represents.

[0023] R 2 In, the halogen atom is F, Cl, Br or I, and preferably F or Cl.

[0024] R 2 In, -C j F 2j+1 is not particularly limited as long as it is a perfluoroalkyl group composed of a carbon atom and a fluorine atom, and may be linear or branched. Also, j represents an integer from 1 to 10, and preferably an integer from 1 to 5.

[0025] R 2 In, -O m A 1 、 -O m CO(O l A 1 )、 -O m SO(O l A 1 )、 or -O m SO 2 (O l A 1 ) contains A 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. A 1 When represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it can be a hydrocarbon group having 1 to 10 carbon atoms among the hydrocarbon groups mentioned above for R 1 . Also, l represents an integer from 0 to 1, preferably 0, and m represents an integer from 0 to 1, preferably 0.

[0026] R 2 in which, -O m PO(O l A 1 )(O k A 2 )、-O m NA 1 A 2 、or -O m B(O l A 1 )(O k A 2 ) the A contained in 1 and A 2 each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. A 1 and A 2 may be the same or different from each other. A 1 and / or A 2 when representing a hydrocarbon group having 1 to 10 carbon atoms, for example, it can be a hydrocarbon group having 1 to 10 carbon atoms among the hydrocarbon groups exemplified by the above R 1 . Also, k is an integer from 0 to 1, preferably 0, l represents an integer from 0 to 1, preferably 0, and m is an integer from 0 to 1, preferably 0.

[0027] R 2 in which, n represents an integer from 0 to 4, preferably an integer from 0 to 2. R 2 When there are a plurality of R 2 , the plurality of R 2 may be the same or different from each other, and may be connected to each other to form a ring structure. When any two adjacent groups among the plurality of R 2

[0028] are bonded to each other to form a ring, a 4- to 8-membered ring composed of carbon atoms and hydrogen atoms may be formed.The reaction between the hexafluoroisobutyric acid ester represented by the general formula (1) and the amidinopyridine represented by the general formula (2) is represented by the following reaction formula (A). By the above reaction (a), a cyclic pyrimidone structure is formed between the hexafluoroisobutyric acid ester represented by the general formula (1) and the amidino group of the amidinopyridine represented by the general formula (2). At the 2-position of the pyrimidone structure, a group derived from the pyridine structure in the amidinopyridine represented by the general formula (2) is located. Further, at the 4-position, 5-position, and 6-position of the pyrimidone structure, =O, -CF 3 and -F derived from the hexafluoroisobutyric acid ester are respectively located.

[0029] [Chemical formula]

[0030] In the above reaction (a), the amidinopyridine represented by the general formula (2) may be in the form of a salt. When the amidinopyridine represented by the general formula (2) is in the form of a salt, for example, at least one of the amino moiety (-NH 2 ) and the imino moiety (=NH) constituting the amidino group of the amidinopyridine represented by the general formula (2) is cationized (-NH 3 + ) and (=NH 2 + ), and forms a salt with a counter ion. The counter ion is not particularly limited as long as it is a monovalent anion. For example, halide ions such as F - , Cl - , Br - , I - etc. can be mentioned.

[0031] In the method for producing the fluorine-containing pyrimidone compound according to the present embodiment, for example, the reaction (a) can be carried out in one step in the presence of a hydrogen halide scavenger. The hydrogen halide scavenger has a function of scavenging hydrogen fluoride (HF) formed from a hydrogen atom derived from the amidino group in the amidinopyridine represented by the general formula (2) and a fluorine atom derived from the hexafluoroisobutyric acid ester represented by the general formula (1) in the reaction (a). As the hydrogen halide scavenger, inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride and potassium fluoride, and organic nitrogen derivatives such as pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene and diazabicyclooctane can be used.

[0032] The above reaction (a) may be carried out in the presence of a fluoride ion scavenger. The hexafluoroisobutyric acid ester represented by the general formula (1) and the amidinopyridine represented by the general formula (2) or a salt thereof are used as a fluoride ion scavenger, and lithium, sodium, magnesium, potassium, calcium or a cation of tetramethylammonium, and 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. It is preferable to react in the presence of a salt with an anion. Among these, the use of a potassium salt or a sodium salt is preferable, and the use of a sodium salt is more preferable. The cation derived from the fluoride ion scavenger captures the fluorine ions liberated from the hexafluoroisobutyric acid ester represented by the general formula (1) during the reaction and is precipitated as a salt with low solubility in the organic solvent, thereby promoting the reaction. Thus, it is considered that the fluorine-containing pyrimidone compound represented by the general formula (3) can be obtained in a high yield.

[0033] The reaction temperature of the above reaction (a) is preferably 0 to 100 °C, more preferably 5 to 50 °C, and even more preferably 10 to 20 °C. Also, the reaction time of the above reaction (a) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 2 to 12 hours.

[0034] Examples of the solvent used in the above reaction (a) include aprotic polar solvents such as tetrahydrofuran, monoglyme, diglyme, triglyme, tetraglyme, acetonitrile, dimethylformamide, dimethylacetamide, methylpyrrolidone, dimethylethyleneurea, tetramethylurea, dimethylsulfoxide, and sulfolane, or biphasic solvents composed of a protic polar solvent such as water and a water-insoluble solvent such as dichloromethane, toluene, and diethyl ether. As the catalyst for the reaction (a) above, quaternary ammonium halides such as benzyltriethylammonium chloride, quaternary phosphonium halides, crown ethers, etc. can be optionally used.

[0035] (Second Embodiment) In the second embodiment, there is a step (reaction (b)) of obtaining a fluorine-containing pyrimidinone compound represented by the following general formula (3) by reacting a pentafluoromethacrylic acid ester represented by the following general formula (4) with an amidinopyridine represented by the following general formula (2).

[0036] [Chemical formula]

[0037] In the pentafluoromethacrylic acid ester represented by the general formula (4), R 1 is the same as that defined in the hexafluoroisobutyric acid ester represented by the general formula (1) described above, and preferably represents an alkyl group having 1 to 10 carbon atoms. Such an alkyl group can be, for example, an alkyl group having 1 to 10 carbon atoms among R 1 in the general formula (1) described above.

[0038] Also, R 2 and n in the above general formula (2) are the same as those defined in the first embodiment, and R 2 and n in the above general formula (3) are also the same as those defined in the first embodiment.

[0039] The reaction between the pentafluoromethacrylic acid ester represented by the general formula (4) and the amidinopyridine represented by the general formula (2) is represented by the following reaction formula (B). In the above reaction (b), a cyclic pyrimidone structure is formed between the pentafluoromethacrylic acid ester represented by the general formula (4) and the amidino group of the amidinopyridine represented by the general formula (2). At the 2-position of the pyrimidone structure, a group derived from the pyridine structure in the amidinopyridine represented by the general formula (2) is located. Further, at the 4-position, 5-position and 6-position of the pyrimidone structure, =O, -CF 3 and -F derived from the pentafluoromethacrylic acid ester are respectively located.

[0040]

Chemical formula

[0041] In the above reaction (b), the amidinopyridine represented by the general formula (2) may be in the form of a salt. When the amidinopyridine represented by the general formula (2) is in the form of a salt, for example, at least one of the amino moiety (-NH 2 ) and the imino moiety (=NH) constituting the amidino group of the amidinopyridine represented by the general formula (2) is cationized (-NH 3 + ) and (=NH 2 + ), and a form in which a counter ion forms a salt can be mentioned. The counter ion is not particularly limited as long as it is a monovalent anion. For example, halide ions such as F - , Cl - , Br - , I - etc. can be mentioned.

[0042] The reaction temperature of the above reaction (b) is preferably 0 to 100°C, more preferably 5 to 50°C, and even more preferably 10 to 20°C. Also, the reaction time of the above reaction (b) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 4 to 24 hours. In the reaction of the above reaction (b) as well, the same solvents, catalysts, hydrogen halide scavengers, and fluoride ion scavengers as those in the above reaction (a) may be used.

[0043] (Third Embodiment) In the third embodiment, a step (reaction (c)) of obtaining a fluorinated pyrimidone compound represented by the following general formula (3) is carried out by reacting a fluoroisobutane derivative represented by the following general formula (5) with an amidinopyridine represented by the following general formula (2) in the presence of a nucleophile.

[0044] [Chemical formula]

[0045] In the fluoroisobutane derivative represented by the general formula (5), R 1 is the same as that defined in the hexafluoroisobutyric acid ester represented by the above general formula (1), and preferably represents an alkyl group having 1 to 10 carbon atoms. Such an alkyl group can be, for example, an alkyl group having 1 to 10 carbon atoms among the above-mentioned R 1 in the general formula (1).

[0046] Also, R 2 and n in the above general formula (2) are the same as those defined in the first embodiment, and R 2 and n in the above general formula (3) are also the same as those defined in the first embodiment.

[0047] The reaction between the fluoroisobutane derivative represented by the general formula (5) and the amidinopyridine represented by the general formula (2) is represented by the following reaction formula (C). In the above reaction (c), a cyclic pyrimidone structure is formed between the fluoroisobutane derivative represented by the general formula (5) and the amidino group of the amidinopyridine represented by the general formula (2). At the 2-position of the pyrimidone structure, a group derived from the pyridine structure in the amidinopyridine represented by the general formula (2) is located. Further, at the 4-position, 5-position, and 6-position of the pyrimidone structure, =O, -CF 3 and -F derived from the fluoroisobutane derivative are respectively located. In the following reaction formula (C), the nucleophile is shown as "Nu" for convenience.

[0048] [Chemical formula]

[0049] In the above reaction (c), the amidinopyridine represented by the general formula (2) may be in the form of a salt. When the amidinopyridine represented by the general formula (2) is in the form of a salt, for example, at least one of the amino moiety (-NH 2 ) and the imino moiety (=NH) constituting the amidino group of the amidinopyridine represented by the general formula (2) is cationized (-NH 3 + ) and (=NH 2 + ), and a form in which a counter ion forms a salt can be mentioned. The counter ion is not particularly limited as long as it is a monovalent anion. For example, halide ions such as F - , Cl - , Br - , I - etc. can be mentioned.

[0050] In the above reaction (c), 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 1-butylimidazole; and pyridine derivatives such as pyridine and 4-dimethylaminopyridine.

[0051] The reaction temperature of the above reaction (c) is preferably 0 to 100°C, more preferably 5 to 50°C, and even more preferably 10 to 20°C. Also, the reaction time of the above reaction (c) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 4 to 24 hours. In the reaction of the above reaction (c), the same solvents, catalysts, hydrogen halide scavengers, and fluoride ion scavengers as those in the above reaction (a) may be used.

[0052] (Fourth Embodiment) In the fourth embodiment, there is a step (reaction (d)) of obtaining a fluorinated pyrimidon compound represented by the following general formula (3) by reacting a fluoroisobutene derivative represented by the following general formula (6) with an amidinopyridine represented by the following general formula (2) in the presence of a nucleophile.

[0053] [Chemical formula]

[0054] In the fluoroisobutene derivative represented by the general formula (6), R 1 is the same as defined in the hexafluoroisobutyric acid ester represented by the above general formula (1), and preferably represents an alkyl group having 1 to 10 carbon atoms. Such an alkyl group can be, for example, an alkyl group having 1 to 10 carbon atoms among those in R 1 in the above general formula (1).

[0055] Also, R 2 and n in the above general formula (2) are the same as defined in the first embodiment, and R 2And n is also the same as that defined in the first embodiment.

[0056] The reaction between the fluoroisobutene derivative represented by the general formula (6) and the amidinopyridine represented by the general formula (2) is represented by the following reaction formula (D). In the above reaction (d), a cyclic pyrimidone structure is formed between the fluoroisobutene derivative represented by the general formula (6) and the amidino group of the amidinopyridine represented by the general formula (2). At the 2-position of the pyrimidone structure, a group derived from the pyridine structure in the amidinopyridine represented by the general formula (2) is located. Further, at the 4-position, 5-position, and 6-position of the pyrimidone structure, =O, -CF 3 and -F derived from the fluoroisobutene derivative represented by the general formula (6) are located, respectively. In the following reaction formula (D), the nucleophile is shown as "Nu" for convenience.

[0057]

Chemical formula

[0058] In the above reaction (d), the amidinopyridine represented by the general formula (2) may be in the form of a salt. When the amidinopyridine represented by the general formula (2) is in the form of a salt, for example, at least one of the amino moiety (-NH 2 ) and the imino moiety (=NH) constituting the amidino group of the amidinopyridine represented by the general formula (2) is cationized (-NH 3 + ) and (=NH 2 + ), and a form in which a counter ion forms a salt can be mentioned. The counter ion is not particularly limited as long as it is a monovalent anion. For example, halide ions such as F - , Cl - , Br - , I - etc. can be mentioned.

[0059] The reaction temperature of the above reaction (d) is preferably 0 to 100°C, more preferably 5 to 50°C, and even more preferably 10 to 20°C. Also, the reaction time of the above reaction (d) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 4 to 24 hours. In the reaction of the above reaction (d) as well, the same solvents, catalysts, hydrogen halide scavengers, and fluoride ion scavengers as in the above reaction (a) may be used, and the same nucleophiles as in the above reaction (c) may be used.

[0060] (fluorine-containing pyrimidone compound) In this embodiment, the fluorine-containing pyrimidone compound represented by the general formula (3) synthesized has a pyridine-based structure at the 2-position of the pyrimidone ring and specific substituents (-CF 3 , -F) at the 5- and 6-positions. Therefore, it can have excellent effects from the perspective of structural expandability, and in particular, desired pharmacological activities can be expected. Also, when the pyridine-based structure has substituents, further properties can be imparted to the obtained fluorine-containing pyrimidone compound. Further, since the substituents at the 4- and 6-positions of the pyrimidone ring are different groups (=O and -F), it can be easily derivatized into an asymmetric structure and can also be expected to be used as an intermediate. More specifically, derivatives can be obtained by modifying =O by reacting the fluorine-containing pyrimidone compound under acidic conditions. Also, derivatives can be obtained by modifying -F by reacting the fluorine-containing pyrimidone compound under basic conditions. Further, the fluorine-containing pyrimidone compound synthesized in this embodiment is useful, for example, not only in the fields of pharmaceuticals and agricultural chemicals but also in the fields of electronic materials such as organic semiconductors and liquid crystals.

[0061] As described above, the embodiments of the present invention have been explained, but the present invention is not limited to the above embodiments, includes all aspects included in the concept and claims of the present invention, and can be variously modified within the scope of the present invention.

Examples

[0062] Examples of the present invention will be described below. However, the present invention is not limited to these examples as long as it does not exceed the gist thereof. Also, unless otherwise specified, room temperature is assumed to be in the range of 20°C ± 5°C.

[0063] (Example 1) (Synthesis of 6-Fluoro-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidone Using Hexafluoroisobutyric Acid Ester) Under ice-water cooling, 1.2 g (7.7 mmol) of 2-amidinopyridine hydrochloride and 1.6 g (7.7 mmol) of methyl 3,3,3-trifluoro-2-(trifluoromethyl)propionate were added to 50 g of N-methylpyrrolidone. Subsequently, 3.0 g (23 mmol) of diisopropylethylamine was added dropwise to this solution so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature. After stirring for about 16 hours, the reaction mixture was poured into 300 ml of water, the precipitate was collected by filtration, and then dissolved in ethyl acetate and purified by silica gel column chromatography. The yield of the obtained compound was 1.1 g, and the yield was 56%.

[0064] The analysis results were as follows. APCIMS m / z: 259 ([M] + ) 1 H-NMR (400 MHz, CDCl 3 ) δppm: 8.74 (d, 1H), 8.46 (d, 1H), 8.00 (dd, 1H), 7.62 (dd, 1H)

[0065] (Example 2) (Synthesis of 6-Fluoro-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidone Using Pentafluoromethacrylic Acid Ester) Under ice-cooling, 1.2 g (7.7 mmol) of 2 - amidinopyridine hydrochloride and 1.4 g (7.7 mmol) of methyl 3,3 - difluoro - 2 - (trifluoromethyl)acrylate were added to 30 g of 1,3 - dimethyl - 2 - imidazolidinone. Subsequently, 1.5 g (15 mmol) of triethylamine was added dropwise to this solution so that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After stirring for about 16 hours, the reaction mixture was poured into 300 ml of water, the precipitate was collected by filtration, and then dissolved in ethyl acetate and purified by silica gel column chromatography. The yield of the obtained compound was 0.8 g, and the yield was 39%. Also, the analysis results were the same as those in Example 1.

[0066] (Example 3) (Synthesis of 6 - fluoro - 2 - (2 - pyridyl) - 5 - (trifluoromethyl) - 4 - pyrimidinone using a fluoroisobutene derivative) Under ice - cooling, 1.5 g (7.0 mmol) of 1,3,3,3 - tetrafluoro - 1 - methoxy - 2 - (trifluoromethyl) - 1 - propene was added to 40 g of 1,3 - dimethyl - 2 - imidazolidinone. Subsequently, 0.9 g (7.0 mmol) of 1 - butylimidazole was added dropwise to this solution so that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After stirring for about 1 hour, the reaction mixture was cooled under ice - cooling, 1.1 g (7.0 mmol) of 2 - amidinopyridine hydrochloride was added to the reaction mixture so that the internal temperature did not exceed 10 °C, and then 2.7 g (21 mmol) of diisopropylethylamine was added dropwise, and the temperature was raised to room temperature. After stirring for about 16 hours, the reaction mixture was poured into 300 ml of water, the precipitate was collected by filtration, and then dissolved in ethyl acetate and purified by silica gel column chromatography. The yield of the obtained compound was 0.7 g, and the yield was 38%. Also, the analysis results were the same as those in Example 1.

[0067] (Example 4) (Synthesis of 6 - fluoro - 2 - (2 - pyridyl) - 5 - (trifluoromethyl) - 4 - pyrimidinone using a fluoroisobutane derivative) Under ice-cooling, 0.9 g (4.0 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-(trifluoromethyl)propane was added to 30 g of N,N-dimethylformamide. Subsequently, 0.8 g (8.0 mmol) of triethylamine was added dropwise to this solution so that the internal temperature did not exceed 10 °C, and the temperature was raised to room temperature. After stirring for about 1 hour, the reaction mixture was cooled with ice-water, and 0.6 g (4.0 mmol) of 2-amidinopyridine hydrochloride was added to the reaction mixture so that the internal temperature did not exceed 10 °C. Subsequently, 1.2 g (12 mmol) of triethylamine was added dropwise, and the temperature was raised to room temperature. After stirring for about 16 hours, the reaction mixture was poured into 300 ml of water, the precipitate was collected by filtration, and then dissolved in ethyl acetate and purified by silica gel column chromatography. The yield of the obtained compound was 0.3 g, and the yield was 26%. Also, the analysis results were the same as in Example 1.

Claims

1. A process for producing a fluorine-containing pyrimidone compound, comprising reacting a hexafluoroisobutyric acid ester represented by the following general formula (1) with an amidinopyridine represented by the following general formula (2) to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). 【Chemical 1】 (In the above general formulas (1) to (3), R １ represents a hydrocarbon group having 1 to 10 carbon atoms, R ２ represents a hydrogen atom, a halogen atom, -C ｊ F ２ｊ＋１ , a nitro group, -O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO(O ｌ A １ )(O ｋ A ２ ), -O ｍ SO(O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ NA １ A ２ , or -O ｍ B(O ｌ A １ )(O ｋ A ２ ), and j represents an integer from 1 to 10, k represents an integer from 0 to 1, l represents an integer from 0 to 1, m represents an integer from 0 to 1, n represents an integer from 0 to 4, A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ２ When there are a plurality of R's ２ they may be the same or different from each other, and may be connected to each other to form a ring structure.)

2. A process for producing a fluorine-containing pyrimidone compound, comprising reacting a pentafluoromethacrylic acid ester represented by the following general formula (4) with an amidinopyridine represented by the following general formula (2) to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). [Chemical 2] (In the above general formulas (2) to (4), R １ represents a hydrocarbon group having 1 to 10 carbon atoms, R ２ represents a hydrogen atom, a halogen atom, -C ｊ F ２ｊ＋１ , a nitro group, -O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO(O ｌ A １ )(O ｋ A ２ ), -O ｍ SO(O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ NA １ A ２ , or -O ｍ B(O ｌ A １ )(O ｋ A ２ ), and j represents an integer from 1 to 10, k represents an integer from 0 to 1, l represents an integer from 0 to 1, m represents an integer from 0 to 1, n represents an integer from 0 to 4, A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ２ When there are a plurality of R's ２ they may be the same or different from each other, and may be connected to each other to form a ring structure.

3. A process for producing a fluorine-containing pyrimidone compound, comprising reacting a fluoroisobutane derivative represented by the following general formula (5) with an amidinopyridine represented by the following general formula (2) in the presence of a nucleophile to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). [Chemical Formula 3] (In the above general formulas (2), (3), and (5), R １ represents a hydrocarbon group having 1 to 10 carbon atoms, R ２ represents a hydrogen atom, a halogen atom, -C ｊ F ２ｊ＋１ , a nitro group, -O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO(O ｌ A １ )(O ｋ A ２ ), -O ｍ SO(O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ NA １ A ２ , or -O ｍ B(O ｌ A １ )(O ｋ A ２ ), and j represents an integer from 1 to 10, k represents an integer from 0 to 1, l represents an integer from 0 to 1, m represents an integer from 0 to 1, n represents an integer from 0 to 4, A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ２ When there are a plurality of R's ２ they may be the same or different from each other, and may be connected to each other to form a ring structure. )

4. A process for producing a fluorine-containing pyrimidone compound, comprising reacting a fluoroisobutene derivative represented by the following general formula (6) with an amidinopyridine represented by the following general formula (2) in the presence of a nucleophile to obtain a fluorine-containing pyrimidone compound represented by the following general formula (3). 【Chemical Formula 4】 (In the above general formulas (2), (3), and (6), R １ represents a hydrocarbon group having 1 to 10 carbon atoms, R ２ represents a hydrogen atom, a halogen atom, -C ｊ F ２ｊ＋１ , a nitro group, -O ｍ A １ , -O ｍ CO(O ｌ A １ ), -O ｍ PO(O ｌ A １ )(O ｋ A ２ ), -O ｍ SO(O ｌ A １ ), -O ｍ SO ２ (O ｌ A １ ), -O ｍ NA １ A ２ , or -O ｍ B(O ｌ A １ )(O ｋ A ２ ), and j represents an integer from 1 to 10, k represents an integer from 0 to 1, l represents an integer from 0 to 1, m represents an integer from 0 to 1, n represents an integer from 0 to 4, A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ２ When there are a plurality of R's ２ they may be the same or different from each other, and may be connected to each other to form a ring structure. )

5. The aforementioned R １ is an alkyl group having 1 to 10 carbon atoms, and the production method according to any one of claims 1 to 4.

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