Fluorine-containing pyrimidine compound and fluorine-containing pyrimidinone compound

Abstract

The present invention relates to a fluorine-containing pyrimidine compound and a fluorine-containing pyrimidone compound represented by general formulae (1), (2), and (3), in which W and X each independently represent a hydrogen atom, Cl, Br, I, a hydrocarbon group having 1-10 carbon atoms,-CnF2n + 1, a nitro group,-OA1,-SOmA1,-SA1,-NA1A2,-B (OA1) (OA2),-COA1,-COOA1, or-CONA1A2, Y represents a halogen atom, a hydrocarbon group having 1-10 carbon atoms,-CnF2n + 1, a cyano group, a nitro group,-OA1,-SOmA1,-SA1,-NA1A2,-B (OA1) (OA2),-COA1,- A1 and A2 each independently represent a hydrogen atom or a hydrocarbon group having 1-10 carbon atoms, and A3 represents a hydrocarbon group having 1-12 carbon atoms. # imgabs0 #

Description

[0001] This application is a divisional application based on the invention with application number 202180034008.8, application date May 18, 2021, applicant being Umate Co., Ltd., and invention name being “Fluorine-containing pyrimidine compounds and fluorine-containing pyrimidone compounds”. Technical Field

[0002] The present invention relates to fluorine-containing pyrimidine compounds and fluorine-containing pyrimidone compounds. Background Art

[0003] Fluorine-containing pyrimidine compounds are reported to have various biological activities. Among them, compounds having a pyridine ring at the 2-position of the pyrimidine ring and a trifluoromethyl group at the 5-position are expected to be used in the fields of medicine and pesticides.

[0004] More specifically, Patent Documents 1 and 6 report that 2-(4-pyridyl)-5-trifluoromethyl pyrimidine derivatives have human melanin aggregation hormone inhibitory activity and acetyl CoA carboxylase 2 inhibitory activity. In Patent Documents 2, 4, 5 and 7, 2-(3-pyridyl)-5-trifluoromethyl pyrimidine derivatives are reported to have fungicidal activity, insecticidal activity, orexin receptor inhibitory activity, focal adhesion kinase inhibitory activity and acetyl CoA carboxylase 2 inhibitory activity. In Patent Documents 2 and 3, 2-(2-pyridyl)-5-trifluoromethyl pyrimidine derivatives are reported to have fungicidal activity, insecticidal activity and herbicidal activity. From such a viewpoint, further activity improvement is expected, and it is interesting to introduce substituents to the 4-position and 6-position of the pyrimidine ring.

[0005] In addition, pyridylpyrimidine derivatives have been reported to have fungicidal activity. For example, Patent Document 8 reports that pyridylpyrimidine derivatives having various substituents exhibit preventive or therapeutic effects against various plant diseases such as rice blast, wheat eye disease, and apple scab.

[0006] Prior Art Literature

[0007] Patent Literature

[0008] Patent document 1: International Publication No. 2009 / 089482;

[0009] Patent document 2: International Publication No. 2015 / 016372;

[0010] Patent document 3: International Publication No. 1999 / 028301;

[0011] Patent document 4: International Publication No. 2010 / 063663;

[0012] Patent document 5: International Publication No. 2013 / 004332;

[0013] Patent document 6: International Publication No. 2015 / 056782;

[0014] Patent document 7: International Publication No. 2016 / 030229;

[0015] Patent document 8: Japanese Patent Application Publication No. 7-118235. Summary of the invention

[0016] Problem that the invention aims to solve

[0017] However, in the past, it was difficult to produce a fluorine-containing pyrimidine compound having a fluorine-containing substituent at the 5-position of the pyrimidine ring, a heterocyclic ring as a substituent at the 2-position, and substituents at the 4-position and 6-position, from the aspects of reactivity and selectivity, and no such fluorine-containing pyrimidine compound has been reported. The fluorine-containing pyrimidine compound is expected to have various biological activities, and a novel fluorine-containing pyrimidine compound having substituents at the 4-position and 6-position of the pyrimidine ring and a heterocyclic ring as a substituent at the 2-position is desired.

[0018] The present invention provides novel fluorine-containing pyrimidine compounds and fluorine-containing pyrimidone compounds which have been unknown in the past and which have substituents at the 4- and 6-positions of the pyrimidine ring and have a pyridine ring structure as a substituent at the 2-position.

[0019] Means of solving the problem

[0020] The fluorine-containing pyrimidine compound according to an embodiment of the present invention is represented by the following general formula (1), (2) or (3).

[0021] [Chemical formula 1]

[0022]

[0023] In the above general formulas (1) to (3),

[0024] W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), nitro, -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 ,

[0025] Y represents a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), cyano, nitro, -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 ,

[0026] Z represents a halogen atom or -OA 3 ,

[0027] A 1 and A 2 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms,

[0028] A 3 It represents a hydrocarbon group having 1 to 12 carbon atoms.

[0029] The fluorine-containing pyrimidone compound according to an embodiment of the present invention is represented by the following general formula (31), (32) or (33).

[0030] [Chemical formula 2]

[0031]

[0032] In the above general formulas (31) to (33),

[0033] R 3 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms,

[0034] W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), nitro, -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 -CONA1 A 2 ,

[0035] A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0036] In one embodiment of the present invention, W and X are hydrogen atoms.

[0037] Effects of the Invention

[0038] According to the present invention, there can be provided novel fluorine-containing pyrimidine compounds and fluorine-containing pyrimidone compounds having substituents at the 4- and 6-positions of the pyrimidine ring and having a pyridine ring structure as a substituent at the 2-position. DETAILED DESCRIPTION

[0039] (Fluorine-containing pyrimidine compounds)

[0040] The fluorine-containing pyrimidine compound of this embodiment is represented by the following general formula (1), (2) or (3).

[0041] [Chemical formula 3]

[0042]

[0043] In the above general formulas (1) to (3),

[0044] W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), nitro, -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 ,

[0045] Y represents a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), cyano, nitro, -OA 1 、-SO m A 1 (m is an integer from 1 to 3), -SA 1 、-NA 1 A2 ,-B(OA 1 )(OA 2 ),-COA 1 , -COOA 1 , or -CONA 1 A 2 ,

[0046] Z represents a halogen atom or -OA 3 ,

[0047] A 1 and A 2 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms,

[0048] A 3 It represents a hydrocarbon group having 1 to 12 carbon atoms.

[0049] When Z is a halogen atom, the halogen atom is F, Cl, Br or I, preferably F or Cl.

[0050] Z is -OA 3 When A 3 It represents a hydrocarbon group having 1 to 12 carbon atoms. It 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. Examples thereof include chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups. Chain hydrocarbon groups are not particularly limited as long as the total number of carbon atoms is 1 to 12. They may be straight-chain hydrocarbon groups or branched chain hydrocarbon groups. Aromatic hydrocarbon groups are not particularly limited as long as the total number of carbon atoms is 6 to 12. They may be aromatic hydrocarbon groups with or without substituents. In addition, the aromatic hydrocarbon group may have a condensed polycyclic structure. Alicyclic hydrocarbon groups are not particularly limited as long as the total number of carbon atoms is 3 to 12. They may be alicyclic hydrocarbon groups with or without substituents. In addition, alicyclic hydrocarbon groups may have a bridged ring structure.

[0051] Examples of the chain hydrocarbon group include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl;

[0052] Alkenyl groups such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl;

[0053] Alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl and dodecynyl, and the like.

[0054] Examples of the aromatic hydrocarbon group include phenyl, benzyl, tolyl, and naphthyl. The tolyl group may be any of o-tolyl, m-tolyl, and p-tolyl, and is preferably p-tolyl.

[0055] Examples of the alicyclic hydrocarbon group include saturated or unsaturated cyclic hydrocarbon groups, and examples of the cyclic hydrocarbon group include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, adamantyl, and norbornyl.

[0056] W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), nitro, boric acid, -OA 1 、-SO m A 1 (m is an integer from 1 to 3), -SA 1 、-NA 1 A 2 , -COOA 1 , or -CONA 1 A 2 , preferably represents a hydrogen atom, a halogen atom, or a hydrocarbon group having 1 to 10 carbon atoms, and particularly preferably represents a hydrogen atom. W and X may be the same or different from each other.

[0057] In W and X, the halogen atom is F, Cl, Br or I, preferably F or Cl.

[0058] In W and X, the hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is composed of carbon atoms and hydrogen atoms. For example, it can be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0059] W and X, -C n F 2n+1 The perfluoroalkyl group is not particularly limited as long as it is composed of carbon atoms and fluorine atoms, and may be linear or branched. In addition, n is an integer of 1 to 10, and preferably an integer of 1 to 3.

[0060] W and X, -OA 1 、-SO m A 1 、-SA 1 、-COA 1 , -COOA 1 A included in 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 When a hydrocarbon group having 1 to 10 carbon atoms is represented, for example, the above-mentioned A 3The hydrocarbon groups mentioned in the above are hydrocarbon groups having 1 to 10 carbon atoms. In addition, m is an integer of 1 to 3, and is preferably 1.

[0061] In W and X, -NA 1 A 2 A contained in 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 can be the same as or different from each other. 1 and A 2 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0062] In W and X, -B(OA 1 )(OA 2 ) 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 can be the same as or different from each other. 1 and A 2 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0063] W and X, in-cona 1 A 2 A contained in 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 can be the same as or different from each other. 1 and A 2 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0064] Y represents a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), cyano, nitro, -OA 1 、-SO m A 1 (m is an integer from 1 to 3), -SA 1 、-NA 1 A 2 ,-B(OA 1 )(OA2 ),-COA 1 , -COOA 1 , or -CONA 1 A 2 , preferably represents a halogen atom, -OA 1 、-SO m A 1 (m is an integer from 1 to 3), -SA 1 , or -NA 1 A 2 .

[0065] In Y, the halogen atom is F, Cl, Br or I, preferably F or Cl.

[0066] In Y, the hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is composed of carbon atoms and hydrogen atoms, and can be, for example, 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0067] Y, -C n F 2n+1 The perfluoroalkyl group is not particularly limited as long as it is composed of carbon atoms and fluorine atoms, and may be linear or branched. In addition, n is an integer of 1 to 10, and preferably an integer of 1 to 3.

[0068] Y,-OA 1 、-SO m A 1 、-SA 1 、-COA 1 , -COOA 1 A contained in 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups mentioned in the above are hydrocarbon groups having 1 to 10 carbon atoms. In addition, m is an integer of 1 to 3, and is preferably 1 or 2.

[0069] Y, -NA 1 A 2 A contained in 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 can be the same as or different from each other. 1 and A 2 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0070] Y, -B(OA 1 )(OA 2 ) 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 can be the same as or different from each other. 1 and A 2 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0071] Y in-cona 1 A 2 A contained in 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. 1 and A 2 can be the same as or different from each other. 1 and A 2 When it represents a hydrocarbon group having 1 to 10 carbon atoms, for example, it may be the above-mentioned A 3 The hydrocarbon groups listed in are hydrocarbon groups having 1 to 10 carbon atoms.

[0072] The fluorine-containing pyrimidine compound in the present embodiment has a specific substituent (pyridyl) at the 2-position of the pyrimidine ring and a specific substituent (Z, -CF3) at the 6-position and 5-position of the pyrimidine ring, so it can have excellent effects from the perspective of structural extensibility. In particular, the fluorine-containing pyrimidine compound in the present embodiment can expect the desired biological activity (for example, inhibitory activity of hormones and enzymes, bactericidal activity, insecticidal activity, herbicidal activity), for example, it can be used as a pharmacologically active compound or its intermediate, and it can be expected to be a fungicide or its intermediate that shows a preventive effect on a variety of plant diseases, especially pathogens such as cucumber powdery mildew. Specifically, the fungicide containing the fluorine-containing pyrimidine compound in the present invention is useful as a substance that shows a sterilization effect on the pathogen of cucumber powdery mildew. In addition, the pyridine ring structure at the 2-position of the pyrimidine ring may further have a substituent or may not have a substituent. In the case where the pyridine ring structure has a substituent, further characteristics are imparted to the fluorine-containing pyrimidine compound in the present embodiment. The fluorine-containing pyrimidine compound in this embodiment is useful in the field of electronic materials such as organic semiconductors and liquid crystals.

[0073] (Method for producing fluorine-containing pyrimidine compound)

[0074] The method for producing the fluorine-containing pyrimidine compound in the present embodiment can be, for example, appropriately modified and combined with the use of "Comprehensive Organic Transformation: A Guide to Functional Group Preparations, 3rd Edition". rd The fluorine-containing pyrimidine compound can be prepared by a known method described in references such as the fluorine-containing pyrimidine compound of the present embodiment.

[0075] Specific examples of the method for producing the fluorine-containing pyrimidine compound in the present embodiment include the following reactions.

[0076] <Nucleophilic substitution reaction or electrophilic addition reaction>

[0077] (A) Pyrimidine compounds containing 4-pyridyl

[0078] (a-1)

[0079] By reacting a pyridylpyrimidine derivative represented by the following general formula (4) with a nucleophilic reagent, a fluorine-containing pyrimidine compound represented by the following general formula (5) is obtained (step (a-1)).

[0080] [Chemical formula 4]

[0081]

[0082] (a-2)

[0083] In the general formula (5), Y 1 for -SA 1 Optionally, the fluorine-containing pyrimidine compound represented by the following general formula (6) is further reacted with hydrogen peroxide as an electrophilic reagent to oxidize S to obtain a fluorine-containing pyrimidine compound represented by the following general formula (7) (step (a-2)).

[0084] [Chemical formula 5]

[0085]

[0086] In the above general formula (7), Y 3 For-SO m A 1 , m is an integer from 1 to 3.

[0087] (a-3)

[0088] In the general formula (5), Y1 When Y is a halogen atom, the fluorine-containing pyrimidine compound represented by the following general formula (5-1) is reacted with an amine, an alkoxide, a thiolate, an organometallic reagent or a nucleophilic agent different from Y 1a The further reaction of the halogen atoms makes Y 1a The halogen atom of is substituted with a fluorine-containing pyrimidine compound of the following general formula (7-1) is obtained (step (a-3)).

[0089] [Chemical formula 6]

[0090]

[0091] In the above general formula (5-1), Y 1a is a halogen atom,

[0092] In the above general formula (7-1), Y 3a for -NA 1 A 2 OA 1 ,SA 1 , a hydrocarbon group having 1 to 10 carbon atoms or a hydrocarbon group different from Y 1a The halogen atom, A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0093] (a-4)

[0094] In the general formula (5), Y 1 and Z are -OA 3 When Y is substituted, the alkoxy group of the fluorine-containing pyrimidine compound represented by the following general formula (5-2) is optionally dealkylated, and the halogen atom as a nucleophile is further reacted, thereby 1b and Z a O-OA 3 The fluorine-containing pyrimidine compound of the following general formula (7-2) is obtained by respectively substituting (step (a-4)).

[0095] [Chemical formula 7]

[0096]

[0097] In the above general formula (5-2), Y 1b and Z a -OA 3 In the above general formula (7-2), Y 3b and Z b Each represents a halogen atom.

[0098] (a-5)

[0099] Optionally, Y is further reacted with the fluorine-containing pyrimidine compound represented by the general formula (7-2) and an amine, hydroxide ion, alkoxide or thiolate as a nucleophile. 3b substituted with a halogen atom, and optionally Z b The halogen atom of is substituted with a fluorine-containing pyrimidine compound of the following general formula (7-3) is obtained (step (a-5)).

[0100] [Chemical formula 8]

[0101]

[0102] In the above general formula (7-3), Y 3c Indicates -NA 1 A 2 OA 1 or SA 1 , Z b Indicates halogen atom or OA 1 . A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0103] (B) Pyrimidine compounds containing 3-pyridyl

[0104] (b-1)

[0105] By reacting a pyridylpyrimidine derivative represented by the following general formula (8) with a nucleophilic reagent, a fluorine-containing pyrimidine compound represented by the following general formula (9) is obtained (step (b-1)).

[0106] [Chemical formula 9]

[0107]

[0108] (b-2)

[0109] In the general formula (9), Y 1 for -SA 1 Optionally, the fluorine-containing pyrimidine compound represented by the following general formula (10) is further reacted with an oxidizing agent such as hydrogen peroxide as an electrophilic reagent to oxidize S to obtain a fluorine-containing pyrimidine compound represented by the following general formula (11) (step (b-2)).

[0110] [Chemical formula 10]

[0111]

[0112] In the above general formula (11), Y 3 For-SO m A 1 , m is an integer from 1 to 3.

[0113] (b-3)

[0114] In the general formula (9), Y 1 When Y is a halogen atom, the fluorine-containing pyrimidine compound represented by the following general formula (9-1) is optionally reacted with an amine, an alkoxide, a thiolate, an organometallic reagent or a nucleophilic agent different from Y. 1a The further reaction of the halogen atoms makes Y 1a The halogen atom of the fluorine-containing pyrimidine is replaced by a halogen atom to obtain a fluorine-containing pyrimidine compound represented by the following general formula (11-1) (step (b-3)).

[0115] [Chemical formula 11]

[0116]

[0117] In the above general formula (9-1), Y 1a is a halogen atom,

[0118] In the above general formula (11-1), Y 3a for -NA 1 A 2 OA 1 ,SA 1 , a hydrocarbon group having 1 to 10 carbon atoms or a hydrocarbon group different from Y 1a The halogen atom, A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0119] (b-4)

[0120] In the general formula (9), Y 1 and Z are -OA 3 When Y is substituted, the alkoxy group of the fluorine-containing pyrimidine compound represented by the following general formula (9-2) is optionally dealkylated, and the halogen atom as a nucleophile is reacted to replace Y 1b and Z a O-OA 3 , to obtain a fluorine-containing pyrimidine compound of the following general formula (11-2) (step (b-4)).

[0121] [Chemical formula 12]

[0122]

[0123] In the above general formula (9-2), Y 1b and Z a -OA 3 In the above general formula (11-2), Y 3b and Z b represent halogen atoms respectively.

[0124] (b-5)

[0125] Optionally, Y is further reacted with the fluorine-containing pyrimidine compound represented by the general formula (11-2) and an amine, hydroxide ion, alkoxide or thiolate as a nucleophile. 3b substituted with a halogen atom, and optionally Z b The halogen atom of is substituted with a fluorine-containing pyrimidine compound of the following general formula (11-3) is obtained (step (b-5)).

[0126] [Chemical formula 13]

[0127]

[0128] In the above general formula (11-3), Y 3c Indicates -NA 1 A 2 OA 1 or SA 1 , Z b Indicates halogen atom or OA 1 . A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0129] (C) Pyrimidine compounds containing 2-pyridyl groups

[0130] (c-1)

[0131] By reacting a pyridylpyrimidine derivative represented by the following general formula (12) with a nucleophilic reagent, a fluorine-containing pyrimidine compound represented by the following general formula (13) is obtained (step (c-1)).

[0132] [Chemical formula 14]

[0133]

[0134] (c-2)

[0135] In the general formula (13), Y 1 for -SA 1 Optionally, the fluorine-containing pyrimidine compound represented by the following general formula (14) is further reacted with an oxidizing agent such as hydrogen peroxide as an electrophilic reagent to oxidize S to obtain a fluorine-containing pyrimidine compound represented by the following general formula (15) (step (c-2)).

[0136] [Chemical formula 15]

[0137]

[0138] In the above general formula (15), Y 3 For-SO m A1 , m is an integer from 1 to 3.

[0139] (c-3)

[0140] In the general formula (13), Y 1 When Y is a halogen atom, the fluorine-containing pyrimidine compound represented by the following general formula (13-1) is optionally reacted with an amine, an alkoxide, a thiolate, an organometallic reagent or a nucleophilic agent different from Y. 1a The further reaction of the halogen atoms makes Y 1a The halogen atom of is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (15-1) (step (c-3)).

[0141] [Chemical formula 16]

[0142]

[0143] In the above general formula (13-1), Y 1a is a halogen atom,

[0144] In the above general formula (15-1), Y 3a for -NA 1 A 2 OA 1 ,SA 1 , a hydrocarbon group having 1 to 10 carbon atoms or a hydrocarbon group different from Y 1a The halogen atom, A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0145] (c-4)

[0146] In the general formula (13), Y 1 and Z are -OA 3 When Y is substituted, the alkoxy group of the fluorine-containing pyrimidine compound represented by the following general formula (13-2) is optionally dealkylated, and the halogen atom as a nucleophile is further reacted, thereby 1b and Z a O-OA 3 The substitutions are carried out respectively to obtain a fluorine-containing pyrimidine compound of the following general formula (15-2) (step (c-4)).

[0147] [Chemical formula 17]

[0148]

[0149] In the above general formula (13-2), Y 1b and Z a -OA 3 In the above general formula (15-2), Y 3b and Zb represent halogen atoms respectively.

[0150] (c-5)

[0151] Optionally, Y is further reacted with the fluorine-containing pyrimidine compound represented by the general formula (15-2) and an amine, hydroxide ion, alkoxide, or thiolate as a nucleophilic agent to obtain 3b The halogen atoms of Z b The halogen atoms are optionally substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (15-3) (step (c-5)).

[0152] [Chemical formula 18]

[0153]

[0154] In the above general formula (15-3), Y 3c for -NA 1 A 2 OA 1 or SA 1 , Z b Indicates halogen atom or OA 1 . A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0155] <Two-step process of hydrolysis reaction and halogenation>

[0156] (D) Pyrimidine compounds containing 4-pyridyl

[0157] (d-1)

[0158] By hydrolyzing a pyridylpyrimidine derivative represented by the following general formula (4), a pyridylpyrimidone derivative represented by the following general formula (16) is obtained (step (d-1)).

[0159] [Chemical formula 19]

[0160]

[0161] (d-2)

[0162] The obtained pyridylpyrimidone derivative represented by the general formula (16) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (19) (step (d-2)).

[0163] [Chemical formula 20]

[0164]

[0165] In the above general formula (19), Y 2 represents a halogen atom.

[0166] (E) Pyrimidine compounds containing 3-pyridyl

[0167] (e-1)

[0168] By hydrolyzing a pyridylpyrimidine derivative represented by the following general formula (8), a pyridylpyrimidone derivative represented by the following general formula (17) is obtained (step (e-1)).

[0169] [Chemical formula 21]

[0170]

[0171] (e-2)

[0172] The obtained pyridylpyrimidone derivative represented by the general formula (17) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (20) (step (e-2)).

[0173] [Chemical formula 22]

[0174]

[0175] In the above general formula (20), Y 2 represents a halogen atom.

[0176] (F) Pyrimidine compounds containing 2-pyridyl

[0177] (f-1)

[0178] By hydrolyzing a pyridylpyrimidine derivative represented by the following general formula (12), a pyridylpyrimidone derivative represented by the following general formula (18) is obtained (step (f-1)).

[0179] [Chemical formula 23]

[0180]

[0181] (f-2)

[0182] The obtained pyridylpyrimidone derivative represented by the general formula (18) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (21) (step (f-2)).

[0183] [Chemical formula 24]

[0184]

[0185] In the above general formula (21), Y 2 represents a halogen atom.

[0186] (G) Pyrimidine compounds containing 4-pyridyl

[0187] (g-1)

[0188] By dealkylating a pyridylpyrimidine derivative represented by the following general formula (22), a pyridylpyrimidone derivative represented by the following general formula (23) is obtained (step (g-1)).

[0189] [Chemical formula 25]

[0190]

[0191] (g-2)

[0192] The obtained pyridylpyrimidone derivative represented by the general formula (23) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (24) (step (g-2)).

[0193] [Chemical formula 26]

[0194]

[0195] In the above general formula (24), Y 2 represents a halogen atom.

[0196] (g-3)

[0197] In the general formula (24), Y 2 When Y is a halogen atom, the fluorine-containing pyrimidine compound represented by the general formula (24-1) reacts with an amine, a hydroxide ion, an alkoxide, a thiolate or a nucleophilic agent different from Y 2a The further reaction of the halogen atoms makes Y 2a The halogen atom of is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (24-2) (step (g-3)).

[0198] [Chemical formula 27]

[0199]

[0200] In the above general formula (24-1), Y 2a is a halogen atom,

[0201] In the above general formula (24-2), Y 2b for -NA 1 A 2 OA 1 ,SA 1 or different from Y 2a The halogen atom, A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0202] (H) Pyrimidine compounds containing 3-pyridyl

[0203] (h-1)

[0204] By hydrolyzing a pyridylpyrimidine derivative represented by the following general formula (25), a pyridylpyrimidone derivative represented by the following general formula (26) is obtained (step (h-1)).

[0205] [Chemical formula 28]

[0206]

[0207] (h-2)

[0208] The obtained pyridylpyrimidone derivative represented by the general formula (26) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (27) (step (h-2)).

[0209] [Chemical formula 29]

[0210]

[0211] In the above general formula (27), Y 2 represents a halogen atom.

[0212] (h-3)

[0213] In the general formula (27), Y 2 When Y is a halogen atom, the fluorine-containing pyrimidine compound represented by the general formula (27-1) reacts with an amine, a hydroxide ion, an alkoxide, a thiolate or a nucleophilic agent different from Y 2a The further reaction of the halogen atoms makes Y 2a The halogen atom of is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (27-2) (step (h-3)).

[0214] [Chemical formula 30]

[0215]

[0216] In the above general formula (27-1), Y 2a is a halogen atom,

[0217] In the above general formula (27-2), Y 2b for -NA 1 A 2 OA 1 ,SA 1 or different from Y 2a The halogen atom, A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0218] (I) Pyrimidine compounds containing 2-pyridyl

[0219] (i-1)

[0220] A pyridylpyrimidine derivative represented by the following general formula (28) is hydrolyzed to obtain a pyridylpyrimidone derivative represented by the following general formula (29) (step (i-1)).

[0221] [Chemical formula 31]

[0222]

[0223] (i-2)

[0224] The obtained pyridylpyrimidone derivative represented by the general formula (29) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (30) (step (i-2)).

[0225] [Chemical formula 32]

[0226]

[0227] In the above general formula (30), Y 2 represents a halogen atom.

[0228] (i-3)

[0229] In the general formula (30), Y 2 When Y is a halogen atom, the fluorine-containing pyrimidine compound represented by the general formula (30-1) reacts with an amine, a hydroxide ion, an alkoxide, a thiolate or a nucleophilic agent different from Y 2a The further reaction of the halogen atoms makes Y 2a The halogen atom of is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (30-2) (step (i-3)).

[0230] [Chemical formula 33]

[0231]

[0232] In the above general formula (30-1), Y 2a is a halogen atom,

[0233] In the above general formula (30-2), Y 2b Yes-NA 1 A 2 OA 1 ,SA 1 or different from Y 2a The halogen atom, A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0234] In the general formulas shown in the above steps, except for the cases with special restrictions,

[0235] R and R 1 represents a hydrocarbon group having 1 to 12 carbon atoms,

[0236] R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms,

[0237] W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), nitro, -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 ,

[0238] Y 1 represents a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n+1 (n is an integer from 1 to 10), cyano, nitro, -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 ,

[0239] Y 2 represents a halogen atom,

[0240] Z represents a halogen atom or -OA 3 ,

[0241] Z 2 Indicates a halogen atom, -OH or -OA 3 ,

[0242] A 1 and A 2each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and,

[0243] A 3 It represents a hydrocarbon group having 1 to 12 carbon atoms.

[0244] (Fluorinated pyrimidone compounds)

[0245] In the above (D) to (I), a fluorine-containing pyrimidine compound is obtained by a two-stage process, and in the first stage of the process, a pyridyl pyrimidone derivative is obtained as an intermediate product. Such a pyridyl pyrimidone derivative is equivalent to a fluorine-containing pyrimidone compound represented by the following general formula (31), (32) or (33). The fluorine-containing pyrimidone compound in the present invention is an intermediate product of the fluorine-containing pyrimidine compound in the present invention, and is therefore useful as an intermediate of a substance that exhibits the desired biological activity possessed by the fluorine-containing pyrimidine compound in this embodiment.

[0246] [Chemical formula 34]

[0247]

[0248] In the above general formulas (31) to (33),

[0249] R 3 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms,

[0250] W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 (n is an integer from 1 to 10), nitro, -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 ,

[0251] A 1 and A 2 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0252] The fluorine-containing pyrimidone compound represented by the above general formula (16), (17), (18), (23), (26) or (29) is halogenated using a halogenating agent to generate the fluorine-containing pyrimidone compound represented by the above general formula (31), (32) or (33), respectively.

[0253] In the above general formulae, W and X are the same as those defined in the fluorine-containing pyrimidine compounds represented by the above general formulae (1) to (3). W and X may be the same or different. 2 In the above general formulas, Z and Z 2 Each is the same as Z defined in the fluorine-containing pyrimidine compounds represented by the above general formulas (1) to (3), and Z or Z 2 The halogen atoms and -OA 3 The same groups as those defined in the fluorine-containing pyrimidine compounds represented by the above general formulae (1) to (3). 1 In the above general formulas, Y 1 The same as the group defined by Y in the fluorine-containing pyrimidine compounds represented by the general formulae (1) to (3) above (except for halogen atoms), in the case where Y 2 In the above general formulas, Y 2 The halogen atoms defined in the definition of are the same as those defined in the fluorine-containing pyrimidine compounds represented by the above general formulae (1) to (3). 1 In the above general formulas, R and R 1 In the fluorine-containing pyrimidine represented by the above general formula (1) to (3), A 3 The same as defined in the group, with R 2 In the above general formulas, R 2 are the same as those defined in the fluorine-containing pyrimidone compounds represented by the general formulae (31) to (33), respectively; R 3 The hydrocarbon group having 1 to 12 carbon atoms as defined in the definition of is the same as the group defined in the fluorine-containing pyrimidine represented by the above general formulae (1) to (3).

[0254] In the above general formulas, R, R 1 , R 2 and R 3 Preferably, it represents an alkyl group having 1 to 10 carbon atoms. In the above general formulae (4) to (33), W and X preferably represent a hydrogen atom, a halogen atom, or a hydrocarbon group having 1 to 10 carbon atoms, and particularly preferably represent a hydrogen atom. Such a hydrocarbon group may be, for example, A in the fluorine-containing pyrimidine compound represented by the above general formulae (1) to (3): 3 Among the hydrocarbon groups exemplified, an alkyl group having 1 to 10 carbon atoms is mentioned.

[0255] The nucleophilic substitution reaction using the above nucleophilic reagent is carried out, for example, by reacting it at 0 to 100° C. in the presence of a nucleophilic reagent (alcohol, amine, thiol, etc. treated with a base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium cyanide, potassium cyanide, potassium fluoride or sodium hydride) in an organic solvent (tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, cyclopentane, acetone, diethyl ether, etc.).

[0256] The electrophilic addition reaction using the above electrophilic reagent is carried out, for example, by reacting in an organic solvent (acetic acid, chloroform, dichloromethane, dimethylformamide, acetonitrile, etc.) in the presence of an electrophilic reagent (hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, potassium permanganate, etc.) at 0 to 65°C.

[0257] The above-mentioned hydrolysis reaction can be carried out in the presence of an acid or a base according to the method considered in general organic synthetic chemistry. Acids or bases and solvents can usually be used in this reaction. Acids and bases are not particularly limited as long as they are acids and bases for hydrolysis reactions. For example, one or more of them can be appropriately selected from inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid and trifluoroacetic acid; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkaline earth metal carbonates such as calcium carbonate and barium carbonate, etc., and mixed for use. The solvent is not particularly limited as long as it is a solvent for hydrolysis reactions, and any solvent that is inert to the reaction can be used. Such solvents may be selected from alcohols such as methanol, ethanol, and isopropanol; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, and sulfolane; nonpolar solvents such as dichloromethane; ethers such as diethyl ether, tert-butyl methyl ether, 1,4-dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; water, etc., or two or more thereof may be mixed and used. The reaction temperature is usually 0 to 150° C., and the reaction time is usually 0.5 to 72 hours.

[0258] As the above-mentioned halogenating agent, for example, thionyl chloride, phosgene, phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, phosphorus tribromide, etc. are mentioned. In the reaction with the halogenating agent, the reaction temperature is 50 to 150° C., the reaction time is 1 to 10 hours, and the amount of the halogenating agent (reagent) provided for the reaction is usually 1 to 10 equivalents relative to 1 equivalent of the pyridyl pyrimidine derivative (fluorine-containing pyrimidone compound). A solvent is not necessarily required in the reaction with the halogenating agent, but it is usually carried out in the presence of a solvent. As usable solvents, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chlorobenzene, etc. are mentioned.

[0259] Although the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments, and includes all aspects included in the concept of the present invention and the claims, and various modifications can be made within the scope of the present invention.

[0260] Example

[0261] Hereinafter, examples of the present invention will be described, but the present invention is not limited to these examples unless it exceeds the gist of the present invention. In addition, the room temperature is within the range of 20°C ± 5°C unless otherwise specified.

[0262] (Example 1)

[0263] <Production of 4,6-dimethoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0264] 0.11 g (0.40 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of methanol, and 1.0 ml of 28% sodium methoxide methanol solution was added, and stirred at room temperature for 1 day. Then, water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered and the filtrate was concentrated to obtain 0.11 g (0.38 mmol) of 4,6-dimethoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structural formula. The yield was 93%.

[0265] [Chemical formula 35]

[0266]

[0267] The results of the analysis are described below.

[0268] 1 H NMR (400MHz, CDCl3) δppm: 8.79 (dd, J=4.4, 1.6Hz, 2H), 8.26 (dd, J=4.8, 1.6Hz, 2H), 4.18 (s, 6H)

[0269] APCI-MS (m / z): 286.8 [M+H] +

[0270] (Example 2)

[0271] <Production of 6-methoxy-4-phenoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0272] 0.04 g (0.46 mmol) of phenol was dissolved in 1.5 ml of tetrahydrofuran (THF), and 0.05 g (0.47 mmol) of potassium tert-butoxide and 0.11 g (0.39 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine were added, and stirred at room temperature for 1 day. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered and the filtrate was concentrated to obtain 0.07 g (0.19 mmol) of 6-methoxy-4-phenoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structural formula. The yield was 48%.

[0273] [Chemical formula 36]

[0274]

[0275] The results of the analysis are described below.

[0276] 1 H NMR (400MHz, CDCl3) δppm: 8.77 (dd, J=4.8, 1.6Hz, 2H), 7.96 (dd, J=4.8, 1.6Hz, 2H), 7.44-7.49 (m, 2H), 7.30-7.34 (m, 1H), 7.18-7.24 (m, 2H), 4.22 (s, 3H)

[0277] APCI-MS (m / z): 349.0 [M+H] +

[0278] (Example 3)

[0279] <Production of 6-methoxy-4-(phenylmethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0280] 0.05 g (0.35 mmol) of benzyl alcohol was dissolved in 3.0 ml of dimethylformamide (DMF), and 0.01 g (0.35 mmol) of sodium hydride was added, followed by stirring at room temperature for 1 hour. Then, 0.10 g (0.35 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 16.7 hours and at 70°C for 16 hours, and then stirred at 100°C for 10.5 hours. After air cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.05 g (0.13 mmol) of 6-methoxy-4-(phenylmethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structural formula. The yield was 31%.

[0281] [Chemical formula 37]

[0282]

[0283] The analysis results are as follows.

[0284] 1 H NMR (400MHz, CDCl3) δppm: 8.78-8.80 (m, 2H), 8.19-8.23 (m, 2H), 7.30-7.48 (m, 5H), 5.65 (s, 3H), 4.16 (s, 2H)

[0285] APCI-MS (m / z): 361.7 [M+H] +

[0286] (Example 4)

[0287] <Production of 6-methoxy-N-propyl-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0288] 0.03 g (0.35 mmol) of n-propylamine was dissolved in 5.0 ml of DMF, and 0.02 g (0.53 mmol) of sodium hydride was added, followed by stirring at room temperature for 50 minutes. Then, 0.10 g (0.35 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was added, followed by stirring at room temperature for 16.7 hours and at 70°C for 8 hours. After air cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.09 g (0.29 mmol) of 6-methoxy-N-propyl-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structural formula. The yield was 79%.

[0289] [Chemical formula 38]

[0290]

[0291] The analysis results are as follows.

[0292] 1 H NMR (400MHz, CDCl3) δppm: 8.75 (dd, J=4.8, 1.6Hz, 2H), 8.22 (d, J=4.4, 1.6Hz, 2H), 5.67 (br, 1H ), 4.11 (s, 3H), 3.61 (dt, J=6.4, 6.8Hz, 2H), 1.71 (tq, J=7.6, 7.2Hz, 2H), 1.02 (t, J=7.6Hz, 3H)

[0293] APCI-MS (m / z): 313.9 [M+H] +

[0294] (Example 5)

[0295] (Preparation of N,N-Diethyl-6-methoxy-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine)

[0296] Dissolve 0.04 g (0.52 mmol) of diethylamine in 5.0 ml of DMF, add 0.02 g (0.58 mmol) of sodium hydride, and stir at room temperature for 1 hour. Then, add 0.10 g (0.37 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine, and stir at room temperature for 16.7 hours and at 70 °C for 16 hours. After air-cooling to room temperature, add water to the reaction solution, extract with ethyl acetate, and dry the organic phase with sodium sulfate. Filter the dried organic phase, concentrate the filtrate, and perform column purification to obtain 0.03 g (0.09 mmol) of N,N-diethyl-6-methoxy-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structural formula. The yield is 25%.

[0297] [Chemical Formula 39]

[0298]

[0299] The analysis results are as follows.

[0300] 1 H NMR (400 MHz, CDCl3) δ ppm: 8.74 (dd, J = 4.4, 1.2 Hz, 2H), 8.20 (dd, J = 4.4, 1.6 Hz, 2H), 4.12 (s, 3H), 3.59 (q, J = 7.2 Hz, 4H), 1.26 (t, J = 7.2 Hz, 6H)

[0301] APCI-MS (m / z): 326.8 [M+H] +

[0302] (Example 6)

[0303] (Preparation of 6-Methoxy-N-phenyl-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine)

[0304] 0.04 g (0.39 mmol) of aniline was dissolved in 5.0 ml of DMF, and 0.02 g (0.58 mmol) of sodium hydride was added, followed by stirring at room temperature for 1 hour. Then, 0.10 g (0.37 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 16.7 hours and at 70°C for 8 hours. After stirring at room temperature for 16 hours, the mixture was stirred at 70°C for 8 hours and at 100°C for 10.5 hours. After air cooling to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.03 g (0.08 mmol) of 6-methoxy-N-phenyl-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structural formula. The yield was 22%.

[0305] [Chemical formula 40]

[0306]

[0307] The analysis results are as follows.

[0308] 1 H NMR (400MHz, CDCl3) δppm: 8.73 (m, 2H), 8.14 (dd, J=4.8, 1.6Hz, 2H), 7.41-7.55 (m, 4H), 7.21-7.25 (m, 1H), 4.16 (s, 3H)

[0309] APCI-MS (m / z): 346.6 [M+H] +

[0310] (Example 7)

[0311] <Production of 6-methoxy-2-(3-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0312] 0.11 g (0.39 mmol) of 4-fluoro-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of DMF and 1.0 ml of water, and 5 drops of triethylamine were added. The mixture was stirred at 70°C for 7 hours and at 80°C for 16 hours. After air cooling to room temperature, water and acetic acid were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.01 g (0.05 mmol) of 6-methoxy-2-(3-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidone having the following structural formula. The yield was 12%.

[0313] [Chemical formula 41]

[0314]

[0315] The analysis results are as follows.

[0316] 1 H NMR (400MHz, CDCl3) δppm: 9.61 (dd, J=2.4, 0.8Hz, 1H), 8.72 (dd, J=4.8, 1.6, 1H), 8.61 (d dd, J=8.0, 2.0, 2.0Hz, 1H), 7.39 (ddd, J=7.6, 4.8, 0.8Hz, 1H), 5.50 (br, 1H), 4.12 (s, 3H)

[0317] APCI-MS (m / z): 270.1 [M+H] +

[0318] (Example 8)

[0319] <Production of 6-methoxy-4-(1-methylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine and 4,6-bis(1-methylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0320] 0.10 g (0.34 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of THF, 1.0 ml of isopropanol and 0.01 g (0.35 mmol) of sodium hydride were added, and the mixture was stirred at room temperature for 3 hours. Further, 0.02 g (0.48 mmol) of sodium hydride was added, and the mixture was stirred at 50 ° C for 7 hours. After air cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.01 g (0.03 mmol) of 6-methoxy-4-(1-methylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine. The yield was 9.6%.

[0321] [Chemical formula 42]

[0322]

[0323] The analysis results of 6-methoxy-4-(1-methylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0324] 1H NMR (400MHz, CDCl3) δppm: 8.78 (dd, J=4.8, 2.0Hz, 2H), 8.22 (dd, J=4.4, 1.6Hz, 2H), 5.61 (hept, J=6.0Hz, 1H), 4.16 (s, 3H), 1.45 (d, J=6.0Hz, 6H)

[0325] APCI-MS (m / z): 313.5 [M+H] +

[0326] At the same time, 0.02 g (yield 19%) of 4,6-bis(1-methylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine was obtained.

[0327] [Chemical formula 43]

[0328]

[0329] The analysis results of 4,6-bis(1-methylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0330] 1 H NMR (400MHz, CDCl3) δppm: 8.77 (dd, J=4.8, 2.0Hz, 2H), 8.20 (dd, J=4.4, 1.6Hz, 2H), 5.60 (hept, J=6.0Hz, 2H), 1.44 (d, J=6.0Hz, 12H)

[0331] APCI-MS (m / z): 341.5 [M+H] +

[0332] (Example 9)

[0333] <Production of 4-(1,1-dimethylethoxy)-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine and 4,6-bis(1,1-dimethylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0334] 0.50 g (1.83 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 6.0 ml of THF, and 0.043 g (3.85 mmol) of potassium tert-butoxide was added, and stirred at room temperature for 1 day. After the reaction solution was concentrated, column purification was performed to obtain 0.37 g (1.14 mmol) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine. The yield was 62%.

[0335] [Chemical formula 44]

[0336]

[0337] The analysis results of 4-(1,1-dimethylethoxy)-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0338] 1 H NMR (400MHz, CDCl3) δppm: 8.79 (dd, J=4.8, 1.6Hz, 2H), 8.20 (dd, J=4.4, 1.6Hz, 2H), 4.15 (s, 3H), 1.71 (s, 9H)

[0339] APCI-MS (m / z): 327.5 [M+H] +

[0340] At the same time, 0.04 g (yield 5%) of 4,6-bis(1,1-dimethylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine was obtained.

[0341] [Chemical formula 45]

[0342]

[0343] The analysis results of 4,6-bis(1,1-dimethylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0344] 1 H NMR (400MHz, CDCl3) δppm: 8.79 (dd, J=4.4, 1.6Hz, 2H), 8.14 (dd, J=4.8, 1.6Hz, 2H), 1.70 (s, 18H)

[0345] APCI-MS (m / z): 369.3 [M+H] +

[0346] (Example 10)

[0347] <Production of 4-chloro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0348] Step 1) Production of 6-methoxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone

[0349] 0.10 g (0.31 mmol) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 2.0 ml of methanol, and 4 drops of concentrated hydrochloric acid were added. After stirring at room temperature for 23 hours, the mixture was further stirred at 50°C for 4 hours. After air cooling to room temperature, the reaction solution was concentrated, and then washed and filtered with ethyl acetate to obtain 0.07 g of 6-methoxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structural formula. The yield was 87%.

[0350] [Chemical formula 46]

[0351]

[0352] The analysis results are as follows.

[0353] 1 H NMR (400MHz, CD3OD) δppm: 9.01 (dd, J=5.6, 1.2Hz, 2H), 8.88 (d, J=6.4Hz, 2H), 4.21 (s, 3H)

[0354] APCI-MS (m / z): 271.0 [M+H] +

[0355] Step 2) Production of 4-chloro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine

[0356] 0.105 g of the crude product of 6-methoxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in step 1) was dissolved in 1.0 ml of POCl3, stirred at 60°C for 4 hours, stirred at 100°C for 1.5 hours, and stirred at 110°C for 17.5 hours. After air cooling to room temperature, the reaction solution was added dropwise to ice, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.006 g (0.031 mmol) of 4-chloro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structural formula. The yield was about 8%.

[0357] [Chemical formula 47]

[0358]

[0359] The analysis results are as follows.

[0360] 1 H NMR (400MHz, CDCl3) δppm: 8.84 (s, 2H), 8.33 (d, J=5.2Hz, 2H), 4.25 (s, 3H)

[0361] APCI-MS (m / z): 390.4 [M+H] +

[0362] (Example 11)

[0363] Production of 4,6-dichloro-2-(4-pyridyl)-5-trifluoromethylpyrimidine

[0364] Step 1) Preparation of 6-hydroxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone 0.21 g (0.57 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of trifluoroacetic acid (TFA) was added, and stirred at room temperature for 3 hours. Then, the reaction solution was concentrated, washed and filtered with ethyl acetate to obtain 0.13 g (0.51 mmol) of 6-hydroxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structural formula. The yield was 89%.

[0365] [Chemical formula 48]

[0366]

[0367] The analysis results are as follows: The solubility of the obtained pyrimidone compound in the solvent used for APCI-MS measurement was poor, so the MS measurement could not be performed.

[0368] 1 H NMR (400MHz, DMSO-d6) δppm: 8.82 (dd, J=4.8, 2.0Hz, 2H), 7.97 (dd, J=4.4, 1.6Hz, 2H)

[0369] Step 2) Production of 4,6-dichloro-2-(4-pyridyl)-5-trifluoromethylpyrimidine

[0370] 0.10 g (0.38 mmol) of the crude product of 6-hydroxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in step 1) was dissolved in 1.0 ml of POCl3 and stirred under heating reflux for 1 hour. After air cooling to room temperature, the reaction solution was added dropwise to ice, and sodium bicarbonate was added for neutralization, and then extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.08 g (0.28 mmol) of 4,6-dichloro-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structural formula. The yield was 73%.

[0371] [Chemical formula 49]

[0372]

[0373] The analysis results are as follows.

[0374] 1 H NMR (400MHz, CDCl3) δppm: 8.86 (dd, J=4.8, 1.6Hz, 2H), 8.28 (dd, J=4.4, 1.6Hz, 2H)

[0375] APCI-MS (m / z): 294.5 [M+H] +

[0376] (Example 12)

[0377] <Production of 6-methoxy-4-[(4-methylphenyl)thio]-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0378] 0.1 g (0.81 mmol) of p-toluene thiophenol was dissolved in 5.0 ml of DMF, and 0.05 g (1.3 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.10 g (0.37 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 6 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.10 g (0.25 mmol) of 6-methoxy-4-[(4-methylphenyl)thio]-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structural formula. The yield was 52.7%.

[0379] [Chemical formula 50]

[0380]

[0381] The analysis results are as follows.

[0382] 1 H NMR (400MHz, CDCl3) δppm: 8.60 (dd, J=4.4, 1.2Hz, 2H), 7.72 (dd, J=4.8, 2.0Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.32 (d, J=8.0Hz, 2H), 4.17 (s, 3H), 2.49 (s, 3H)

[0383] APCI-MS (m / z): 377.5 [M+H] +

[0384] (Example 13)

[0385] <Production of 6-methoxy-4-[(4-methylphenyl)sulfinyl]-2-(4-pyridyl)-5-trifluoromethylpyrimidine and 6-methoxy-4-[(4-methylphenyl)sulfonyl]-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0386] To 0.10 g (0.25 mmol) of 6-methoxy-4-[(4-methylphenyl)thio]-2-(4-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 12, 1.0 ml of acetic acid and 6 drops of 30% hydrogen peroxide were added, and the mixture was stirred at room temperature for 30 hours. Water and sodium bicarbonate were added to the reaction solution, and the solution was adjusted to pH 5, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.11 g (0.11 mmol) of 6-methoxy-4-[(4-methylphenyl)sulfinyl]-2-(4-pyridyl)-5-trifluoromethylpyrimidine. The yield was 32.2%.

[0387] [Chemical formula 51]

[0388]

[0389] The analysis results of 6-methoxy-4-[(4-methylphenyl)sulfinyl]-2-(4-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0390] 1 H NMR (400MHz, CD3OD) δppm: 8.85 (dd, J=4.8, 2.0Hz, 2H), 8.38 (dd, J=4.8, 2.0Hz, 2H), 7.75 (d, J=8.0Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 4.23 (s, 3H), 2.37 (s, 3H)

[0391] APCI-MS (m / z): 393.5 [M+H] +

[0392] At the same time, 0.004 g (0.01 mmol) of 6-methoxy-4-[(4-methylphenyl)sulfonyl]-2-(4-pyridyl)-5-trifluoromethylpyrimidine was obtained, with a yield of 2.8%.

[0393] [Chemical formula 52]

[0394]

[0395] The analysis results of 6-methoxy-4-[(4-methylphenyl)sulfonyl]-2-(4-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0396] 1 H NMR (400MHz, CD3OD) δppm: 8.67 (br, 2H), 7.93 (d, J=8.4Hz, 2H), 7.66 (d, J=4.4Hz, 2H), 7.47 (d, J=8.0Hz, 2H), 4.27 (s, 3H), 2.56 (s, 3H)

[0397] APCI-MS (m / z): 409.5 [M+H] +

[0398] (Example 14)

[0399] <Production of 6-methoxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0400] 0.10 g (0.37 mmol) of 4-fluoro-6-methoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 5.0 ml of acetic acid, stirred at room temperature for 18.5 hours, and then stirred at 70°C for 8 hours. After cooling to room temperature, water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, the filtrate was concentrated, and then column purified to obtain 6-methoxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structural formula.

[0401] [Chemical formula 53]

[0402]

[0403] The analysis results are as follows.

[0404] 1 H NMR (400MHz, CDCl3) δppm: 10.97 (br, 1H), 8.72 (d, J = 4.4Hz, 1H), 8.43 (d, J = 7.6Hz, 1 H), 7.97 (ddd, J=8.0, 8.0, 1.6Hz, 1H), 7.58 (ddd, J=7.2, 4.8, 0.8Hz, 1H), 4.17 (s, 3H)

[0405] APCI-MS (m / z): 271.2 [M+H] +

[0406] (Example 15)

[0407] <Production of 4-cyano-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0408] 0.10 g (0.38 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of DMSO, and 0.03 g (0.65 mmol) of sodium cyanide was added. The mixture was stirred at room temperature for 23 hours, at 80°C for 5.5 hours, and at 100°C for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.003 g (0.01 mmol) of 4-cyano-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 3%.

[0409] [Chemical formula 54]

[0410]

[0411] The analysis results are described below.

[0412] 1 H NMR (400MHz, CDCl3) δppm: 8.86 (d, J=5.6Hz, 2H), 8.29 (d, J=6.0Hz, 2H), 4.31 (s, 3H)

[0413] APCI-MS (m / z): 280.4 [M+H] +

[0414] (Example 16)

[0415] <Production of 4-ethoxy-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0416] 0.12 g (0.42 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of ethanol, and 5 drops of 20% ethanol solution containing sodium ethoxide were added, and the mixture was stirred at room temperature for 22.8 hours. 5 drops of 20% ethanol solution containing sodium ethoxide and 1 ml of ethanol were further added, and the mixture was stirred at 50°C for 5.8 hours. 5 drops of 20% ethanol solution containing sodium ethoxide were further added, and the mixture was stirred at 50°C for 2 hours, and then water was added, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.11 g (0.37 mmol) of 4-ethoxy-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 87%.

[0417] [Chemical formula 55]

[0418]

[0419] The results of the analysis are described below.

[0420] 1 1H NMR (400 MHz, CDCl3) δ ppm: 8.79 (d, J = 5.2 Hz, 2H), 8.24 (d, J = 4.9 Hz, 2H), 4.65 (q, J = 7.3 Hz, 2H), 4.17 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H)

[0421] APCI-MS (m / z): 300.0 [M+H] +

[0422] (Example 17)

[0423] (Synthesis of 4,6-Dimethoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine)

[0424] 0.11 g (0.38 mmol) of 4-fluoro-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of methanol. 1.0 ml of a 28% methanol solution containing sodium methoxide was added, and the mixture was stirred at room temperature for 8.3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column chromatography to obtain 0.11 g (0.38 mmol) of 4,6-dimethoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 99%.

[0425] [Chemical Formula 56]

[0426]

[0427] The analysis results are as follows.

[0428] 1 1H NMR (400 MHz, CDCl3) δ ppm: 9.64 (d, J = 1.5 Hz, 1H), 8.75 (dd, J = 4.6, 1.5 Hz, 1H), 8.68 (ddd, J = 8.0, 4.6, 1.5 Hz, 1H), 7.43 (ddd, J = 8.0, 4.9, 0.9 Hz, 1H), 4.17 (s, 6H)

[0429] APCI-MS (m / z): 286.0 [M+H] +

[0430] (Example 18)

[0431] (Synthesis of N-Propyl-6-methoxy-2-(3-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine)

[0432] 0.05 g (0.80 mmol) of n-propylamine was dissolved in 5.0 ml of DMF, 0.02 g (0.38 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 45 minutes. Then, 0.10 g (0.38 mmol) of 4-fluoro-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 5.3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.10 g (0.32 mmol) of N-propyl-6-methoxy-2-(3-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 84%.

[0433] [Chemical formula 57]

[0434]

[0435] The results of the analysis are described below.

[0436] 1 H NMR (400MHz, CDCl3) δppm: 9.61 (dd, J=2.1, 0.9Hz, 1H), 8.71 (dd, J=6.4, 1.5Hz, 1H), 8.64 (ddd, J=8.0, 1.8, 1.8Hz, 1H), 7.39 (ddd, J=8.0, 4.9, 0.9Hz, 1H), 5.65 (br, 1H), 4.10 (s, 3H), 3.60 (dt, J=6.7, 6.7Hz, 2H), 1.70 (tq, J=7.6, 7.0Hz, 2H), 1.01 (t, J=7.3Hz, 3H)

[0437] APCI-MS (m / z): 313.8 [M+H] +

[0438] (Example 19)

[0439] <Production of 4,6-dimethoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0440] 0.11 g (0.39 mmol) of 4-fluoro-6-methoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of methanol, and 1.0 ml of a 28% methanol solution containing sodium methoxide was added, and the mixture was stirred at room temperature for 8.1 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.11 g (0.39 mmol) of 4,6-dimethoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 99%.

[0441] [Chemical Formula 58]

[0442]

[0443] The analysis results are as described below.

[0444] 1 H NMR (400 MHz, CDCl3) δ ppm: 8.86 (m, 1H), 8.48 (m, 1H), 7.87 (ddd, J = 8.0, 8.0, 1.8 Hz, 1H), 7.45 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 4.21 (s, 6H)

[0445] APCI-MS (m / z): 286.0 [M+H] +

[0446] (Example 20)

[0447] (Preparation of N-propyl-6-methoxy-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine)

[0448] Dissolve 0.07 g (1.21 mmol) of n-propylamine in 5.0 ml of DMF, add 0.02 g (0.40 mmol) of sodium hydride, and stir at room temperature for 45 minutes. Then, add 0.11 g (0.41 mmol) of 4-fluoro-6-methoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine and stir at room temperature for 5.3 hours. Add water to the reaction solution, extract with ethyl acetate, and dry the organic phase with sodium sulfate. Filter the dried organic phase, concentrate the filtrate, and perform column purification to obtain 0.10 g (0.33 mmol) of N-propyl-6-methoxy-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield is 80%.

[0449] [Chemical Formula 59]

[0450]

[0451] The analysis results are as described below.

[0452] 1H NMR (400MHz, CDCl3) δppm: 8.82 (ddd, J=4.9, 1.8, 0.9Hz, 1H), 8.42 (ddd, J=8.0, 1.2, 0.9Hz, 1H), 7.83 (ddd, J=7.6, 7.6, 1.8Hz, 1H), 7.40 (ddd, J=7.6, 4.9, 1.2Hz, 1H), 5.63 (br, 1H), 4.15 (s, 3H), 3.65 (dt, J=7.0, 5.8Hz, 2H), 1.70 (tq, J=7.3, 7.3Hz, 2H), 1.01 (t, J=7.3Hz, 3H)

[0453] APCI-MS (m / z): 312.8 [M+H] +

[0454] (Example 21)

[0455] <Production of 4,6-dibromo-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0456] 0.03 g of the crude product of 6-hydroxy-2-(4-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in step 1) of Example 11 was dissolved in 1.0 ml of dichloroethane, 2.0 g of POBr3 was added, and the mixture was stirred at 65°C for 40 minutes, at 80°C for 2 hours, at 90°C for 8 hours, and at 110°C for 9.5 hours. After air cooling to room temperature, the reaction solution was added dropwise to ice and extracted with ethyl acetate. After drying with magnesium sulfate, the mixture was filtered. After concentrating the filtrate, column purification was performed to obtain a trace amount of 4,6-dibromo-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0457] [Chemical formula 60]

[0458]

[0459] The results of the analysis are described below.

[0460] 1 H NMR (400MHz, CDCl3) δppm: 8.85 (dd, J=4.4, 1.6Hz, 2H), 8.28 (dd, J=4.8, 2.0Hz, 2H)

[0461] APCI-MS (m / z): 383.5 [M+H] +

[0462] (Example 22)

[0463] <Production of 6-methoxy-4-[(4-methylphenyl)thio]-2-(3-pyridyl)-5-trifluoromethylpyrimidine>

[0464] 0.04 g (0.33 mmol) of p-toluene thiophenol was dissolved in 5.0 ml of DMF, 0.01 g (0.25 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.10 g (0.36 mmol) of 4-fluoro-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 26 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 6-methoxy-4-[(4-methylphenyl)thio]-2-(3-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0465] [Chemical formula 61]

[0466]

[0467] The analysis results are as follows.

[0468] 1 H NMR (400MHz, CDCl3) δppm: 9.12 (dd, J=2.1, 0.9Hz, 1H), 8.63 (dd, J=4.9, 1.5Hz, 1H), 8.17 (ddd, J=8.0, 2.1, 1.8H z, 1H), 7.46 (d, J=8.3Hz, 2H), 7.31 (d, J=7.6Hz, 2H), 7.25 (ddd, J=8.0, 4.9, 0.6Hz, 1H), 4.16 (s, 3H), 2.48 (s, 3H)

[0469] APCI-MS (m / z): 377.3 [M+H] +

[0470] (Example 23)

[0471] <Production of 6-methoxy-4-[(4-methylphenyl)thio]-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0472] 0.04 g (0.34 mmol) of p-toluene thiophenol was dissolved in 5.0 ml of DMF, 0.01 g (0.23 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.10 g (0.37 mmol) of 4-fluoro-6-methoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 26.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.11 g (0.28 mmol) of 6-methoxy-4-[(4-methylphenyl)thio]-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 76.7%.

[0473] [Chemical formula 62]

[0474]

[0475] The analysis results are as follows.

[0476] 1 H NMR (400MHz, CDCl3) δppm: 8.74 (ddd, J=4.9, 2.8, 1.5Hz, 1H), 7.59 (m, 2H), 7.48 (m, 2H), 7.31 (m, 3H), 4.25 (s, 3H)

[0477] APCI-MS (m / z): 377.4 [M+H] +

[0478] (Example 24)

[0479] <Production of 6-chloro-4-fluoro-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0480] 0.10 g (0.35 mmol) of 4,6-dichloro-2-(4-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 11 and 0.02 g (0.34 mmol) of potassium fluoride were added to 25 ml of sulfolane dried under reduced pressure with 10 ml of toluene, and stirred at 148°C for 18.8 hours. Then, 0.02 g (0.34 mmol) of potassium fluoride was further added, and stirred at 148°C for 7 hours. After air cooling to room temperature, water was added and extracted with diethyl ether. After drying with magnesium sulfate, filtration was performed, and the filtrate was concentrated and then purified by column to obtain a trace amount of 6-chloro-4-fluoro-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0481] [Chemical formula 63]

[0482]

[0483] The analysis results are as follows.

[0484] 1 H NMR (400MHz, CDCl3) δppm: 8.74 (d, J=4.9Hz, 2H), 8.24 (d, J=5.4Hz, 1H)

[0485] APCI-MS (m / z): 277.0 [M+H] +

[0486] (Example 25)

[0487] <Production of 6-methoxy-N-(4-methylphenyl)-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0488] 0.24 g (2.22 mmol) of p-toluidine was dissolved in 6.1 ml of DMF, 0.09 g (2.27 mmol) of sodium hydride was added, and after stirring at room temperature for 30 minutes, 0.50 g (1.83 mmol) of 4-fluoro-6-methoxy-2-(2-pyridyl)-5-trifluoromethylpyridine was added, and the mixture was stirred at 100°C for 18.8 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.31 g (0.87 mmol) of 6-methoxy-N-(4-methylphenyl)-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 48%.

[0489] [Chemical formula 64]

[0490]

[0491] The results of the analysis are described below.

[0492] 1 H NMR (400MHz, CDCl3) δppm: 8.81 (m, 1H), 8.31 (d, J=8.0Hz, 1H), 7.80 (ddd, J=7.6, 7.6, 1.8Hz, 1 H), 7.49 (d, J=8.2Hz, 2H), 7.32-7.40 (m, 2H), 7.21 (d, J=8.3Hz, 2H), 4.21 (s, 3H), 2.37 (s, 3H)

[0493] APCI-MS (m / z): 360.1 [M+H] +

[0494] (Example 26)

[0495] <Production of 6-methoxy-N-(4-methylphenyl)-2-(3-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0496] 1.89 g (17.60 mmol) of p-toluidine was dissolved in 49.0 ml of DMF, and 0.72 g (17.98 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, 4.02 g (14.73 mmol) of 4-fluoro-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyridine was added, and the mixture was stirred at 100°C for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.71 g (1.98 mmol) of 6-methoxy-N-(4-methylphenyl)-2-(3-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 13%.

[0497] [Chemical formula 65]

[0498]

[0499] The results of the analysis are described below.

[0500] 1 H NMR (400MHz, CDCl3) δppm: 9.52 (m, 1H), 8.68 (dd, J=4.6, 1.2Hz, 1H), 8.54 (ddd, J=8.0, 1.5, 1.5Hz, 1H), 7.40 (d, J=8.3Hz, 2H), 7.35 (dd, J=8.0, 4.9Hz, 1H), 7.31 (br, 1H), 7.21 (d, J=8.3Hz, 2H), 4.13 (s, 3H), 2.38 (s, 3H)

[0501] APCI-MS (m / z): 360.0 [M+H] +

[0502] (Example 27)

[0503] <Production of 6-methoxy-N-(4-methylphenyl)-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0504] 0.24 g (2.27 mmol) of p-toluidine was dissolved in 6.1 ml of DMF, 0.09 g (2.30 mmol) of sodium hydride was added, and after stirring at room temperature for 30 minutes, 0.50 g (1.82 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyridine was added, and the mixture was stirred at 100°C for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.24 g (0.65 mmol) of 6-methoxy-N-(4-methylphenyl)-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 36%.

[0505] [Chemical formula 66]

[0506]

[0507] The results of the analysis are described below.

[0508] 1 H NMR (400MHz, CDCl3) δppm: 8.73 (dd, J=4.3, 1.4Hz, 2H), 8.13 (dd, J=4.3, 1.8Hz, 2H), 7.41 (d, J=8.3Hz, 2H), 7.33 (br, 1H), 7.23 (d, J=8.3Hz, 2H), 4.16 (s, 3H), 2.40 (s, 3H)

[0509] APCI-MS (m / z): 360.0 [M+H] +

[0510] (Example 28)

[0511] <Production of 6-chloro-N-(4-methylphenyl)-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0512] 0.04 g (0.36 mmol) of p-toluidine was dissolved in 1.1 ml of DMF, 0.02 g (0.45 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.10 g (0.34 mmol) of 4,6-dichloro-2-(4-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 11 was added, and the mixture was stirred at room temperature for 18.3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.11 g (0.30 mmol) of 6-chloro-N-(4-methylphenyl)-2-(4-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 89%.

[0513] [Chemical formula 67]

[0514]

[0515] The results of the analysis are described below.

[0516] 1 H NMR (400MHz, CDCl3) δppm: 8.74 (dd, J=4.6, 1.5Hz, 2H), 8.10 (dd, J=4.3, 1.8Hz, 2H), 7.51 (br, 1H), 7.39 (d, J=8.3Hz, 2H), 7.27 (d, J=8.3Hz, 2H), 2.42 (s, 3H)

[0517] APCI-MS (m / z): 365.1 [M+H] +

[0518] (Example 29)

[0519] <Production of 4,6-bis(1,1-dimethylethoxy)-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0520] 4.00 g (14.64 mmol) of 4-fluoro-6-methoxy-2-(2-pyridyl)-5-trifluoromethylpyridine was dissolved in 48.0 ml of THF, 4.14 g (36.89 mmol) of potassium tert-butoxide was added, and the mixture was stirred at 50°C for 29.8 hours. After the reaction solution was concentrated, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, dried with sodium sulfate, filtered, concentrated, and purified by column to obtain 2.34 g (6.34 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 43%.

[0521] [Chemical formula 68]

[0522]

[0523] The analysis results are as follows: In APCI-MS (m / z), m / z of a product resulting from the detachment of two tert-butyl groups was detected.

[0524] 1 H NMR (400MHz, CDCl3) δppm: 8.81 (ddd, J=4.6, 1.8, 0.9Hz, 1H), 8.29 (ddd, J=8.0, 1.2, 0.9H z, 1H), 7.82 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 7.38 (ddd, J=7.3, 4.6, 1.2Hz, 1H), 1.71 (s, 18H)

[0525] APCI-MS (m / z): 257.9 [Mt Bu] +

[0526] (Example 30)

[0527] <Production of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0528] 2.34 g (6.34 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 29 was dissolved in 10.5 ml of dichloromethane, 10.5 ml of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 15.7 hours. The reaction solution was concentrated, washed with ethyl acetate and filtered to obtain 1.55 g (6.01 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure. The yield was 95%.

[0529] [Chemical formula 69]

[0530]

[0531] The analysis results are as follows.

[0532] 1 H NMR (400MHz, DMSO-d6) δppm: 12.74 (br, 2H), 8.79 (ddd, J=4.6, 1.5, 0.9Hz, 1H), 8.27 (ddd, J =8.0, 1.2, 0.9Hz, 1H), 8.11 (ddd, J=7.6, 7.6, 1.8Hz, 1H), 7.72 (ddd, J=7.6, 4.6, 1.2Hz, 1H)

[0533] APCI-MS (m / z): 255.7 [M+H] -

[0534] (Example 31)

[0535] <Production of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0536] 1.00 g (3.88 mmol) of 6-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in Example 30 was dissolved in 10.0 ml of POCl3, 3 drops of DMF were added, and the mixture was stirred for 6 hours under heating reflux conditions. After air cooling to room temperature, the reaction solution was added dropwise to ice with sodium bicarbonate added for neutralization, and then extracted with ethyl acetate. After drying with sodium sulfate, it was filtered. The filtrate was concentrated and column purified to obtain 0.98 g (3.34 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 86%.

[0537] [Chemical formula 70]

[0538]

[0539] The analysis results are as follows.

[0540] 1 H NMR (400MHz, CDCl3) δppm: 8.92 (d, J=4.6Hz, 1H), 8.57 (d, J=8.0Hz, 1H), 7.93 (ddd, J=8.0, 8.0, 1.8Hz, 1H), 7.52 (ddd, J=7.6, 4.9, 1.2Hz, 1H)

[0541] APCI-MS (m / z): 293.8 [M+H] +

[0542] (Example 32)

[0543] <Production of 6-chloro-N-(4-methylphenyl)-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0544] 0.36 g (3.34 mmol) of p-toluidine was dissolved in 4.0 ml of DMF, 0.17 g (4.25 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.98 g (3.34 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 31 dissolved in 7.0 ml of DMF was added, and the mixture was stirred at room temperature for 21.7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.89 g (2.44 mmol) of 6-chloro-N-(4-methylphenyl)-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 73%.

[0545] [Chemical formula 71]

[0546]

[0547] The results of the analysis are described below.

[0548] 1 H NMR (400MHz, CDCl3) δppm: 8.84 (ddd, J=4.6, 1.8, 0.9Hz, 1H), 8.24 (ddd, J=8.0, 0.9, 0.9Hz, 1H), 7.80 (ddd, J=8.0, 7.6, 1.8H z, 1H), 7.52 (br, 1H), 7.45 (dd, J=8.3, 1.8, 1.8Hz, 2H), 7.41 (ddd, J=7.6, 4.9, 1.2Hz, 1H), 7.25 (d, J=9.2Hz, 2H), 2.40 (s, 3H)

[0549] APCI-MS (m / z): 365.0 [M+H] +

[0550] (Example 33)

[0551] <Production of 4,6-bis(1,1-dimethylethoxy)-2-(3-pyridyl)-5-trifluoromethylpyrimidine>

[0552] 4.00 g (14.63 mmol) of 4-fluoro-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyridine was dissolved in 48.0 ml of THF, and 4.12 g (36.68 mmol) of potassium tert-butoxide was added, and the mixture was stirred at 50°C for 29.8 hours. After the reaction solution was concentrated, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, dried with sodium sulfate, and filtered. After concentration, column purification was performed to obtain 2.2 g (6.0 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(3-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 41%.

[0553] [Chemical formula 72]

[0554]

[0555] The analysis results of 4,6-bis(1,1-dimethylethoxy)-2-(3-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0556] 1H NMR (400MHz, CDCl3) δppm: 9.56 (dd, J=2.1, 0.6Hz, 1H), 8.73 (dd, J=4.9, 1.5Hz, 1H) , 8.55 (dd, J=8.0, 2.1, 1.8Hz, 1H), 7.43 (ddd, J=8.0, 4.9, 0.9Hz, 1H), 1.70 (s, 18H)

[0557] APCI-MS (m / z): 370.1 [M+H] +

[0558] At the same time, 0.3 g (yield 5%) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine was also obtained.

[0559] [Chemical formula 73]

[0560]

[0561] The analysis results of 4-(1,1-dimethylethoxy)-6-methoxy-2-(3-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0562] 1 H NMR (400MHz, CDCl3) δppm: 9.60 (d, J=2.1Hz, 1H), 8.74 (dd, J=4.9, 1.8Hz, 1H), 8.62 (dd d, J=8.3, 2.1, 1.8Hz, 1H), 7.43 (ddd, J=8.0, 4.9, 0.6Hz, 1H), 4.14 (s, 3H), 1.70 (s, 18H)

[0563] APCI-MS (m / z): 328.1 [M+H] +

[0564] (Example 34)

[0565] <Production of 6-hydroxy-2-(3-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0566] 2.22 g (6.02 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(3-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 33 was dissolved in 10.0 ml of dichloromethane, 10.0 ml of trifluoroacetic acid (TFA) was added, and stirred at room temperature for 20.4 hours. Then, the reaction solution was concentrated, washed and filtered with ethyl acetate to obtain a crude product of 6-hydroxy-2-(3-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure.

[0567] [Chemical formula 74]

[0568]

[0569] The results of the analysis are described below.

[0570] 1 H NMR (400MHz, DMSO-d6) δppm: 13.10 (br, 2H), 9.15 (d, J=1.7Hz, 1H), 8.80 (dd, J=4. 9, 1.8Hz, 1H), 8.37 (ddd, J=8.0, 2.1, 1.8Hz, 1H), 7.61 (ddd, J=8.0, 4.9, 0.6Hz, 1H)

[0571] APCI-MS (m / z): 255.9 [M+H] -

[0572] (Example 35)

[0573] <Production of 4,6-dichloro-2-(3-pyridyl)-5-trifluoromethylpyrimidine>

[0574] 1.0 g of the crude product of 6-hydroxy-2-(3-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in Example 34 was dissolved in 10.0 ml of POCl3, 3 drops of DMF were added, and the mixture was stirred for 6 hours under heating reflux. After air cooling to room temperature, the reaction solution was added dropwise to ice with sodium bicarbonate added for neutralization, and then extracted with ethyl acetate. After drying with sodium sulfate, the mixture was filtered. The filtrate was concentrated and column purified to obtain 0.63 g (2.16 mmol) of 4,6-dichloro-2-(3-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0575] [Chemical formula 75]

[0576]

[0577] The results of the analysis are described below.

[0578] 1 H NMR (400MHz, CDCl3) δppm: 9.66 (d, J=1.5Hz, 1H), 8.83 (dd, J=4.9, 1.5Hz, 1H), 8.73 (ddd, J=8.0, 2.1, 1.8Hz, 1H), 7.49 (ddd, J=8.0, 4.9, 0.9Hz, 1H)

[0579] APCI-MS (m / z): 293.9 [M+H] +

[0580] (Example 36)

[0581] <Production of 6-chloro-N-(4-methylphenyl)-2-(3-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0582] 0.23 g (2.17 mmol) of p-toluidine was dissolved in 2.0 ml of DMF, 0.11 g (2.63 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, 0.63 g (2.16 mmol) of 4,6-dichloro-2-(3-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 35 dissolved in 8.0 ml of DMF was added, and the mixture was stirred at room temperature for 21.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.51 g (1.40 mmol) of 6-chloro-N-(4-methylphenyl)-2-(3-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 65%.

[0583] [Chemical formula 76]

[0584]

[0585] The results of the analysis are described below.

[0586] 1 H NMR (400MHz, CDCl3) δppm: 9.45 (dd, J=2.1, 0.6Hz, 1H), 8.72 (dd, J=4.9, 1.5Hz, 1H), 8.56 (ddd , J=8.0, 2.1, 1.8Hz, 1H), 7.49 (br, 1H), 7.36-7.40 (m, 3H), 7.25 (d, J=9.5Hz, 2H), 2.40 (s, 3H)

[0587] APCI-MS (m / z): 365.1 [M+H] +

[0588] (Example 37)

[0589] <Production of 6-methoxy-N-(4-methylphenyl)-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0590] 0.4 g (3.3 mmol) of p-toluidine was dissolved in 2.0 ml of DMF, 0.13 g (3.3 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 35 minutes. Then, 0.9 g (2.7 mmol) of 4-fluoro-6-methoxy-2-(3-n-propyl-2-pyridyl)-5-trifluoromethylpyridine dissolved in 7.0 ml of DMF was added, and the mixture was stirred at room temperature for 51.7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.7 g (1.7 mmol) of 6-methoxy-N-(4-methylphenyl)-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 61%.

[0591] [Chemical formula 77]

[0592]

[0593] The results of the analysis are described below.

[0594] 1 H NMR (400MHz, CDCl3) δppm: 8.14 (d, J=7.6Hz, 1H), 7.70 (dd, J=8.0, 7.6Hz, 1H), 7.64 (d, J=8.6Hz, 2H), 7.36 (br, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.18 (d, J=8.3Hz, 2H), 4.18 (s, 3H), 2.90 (t, J=7.6Hz, 1H), 2.36 (s, 3H), 1.92 (tq, J=7.3, 7.3Hz, 2H), 1.05 (t, J=7.3Hz, 3H)

[0595] APCI-MS (m / z): 403.0 [M+H] +

[0596] (Example 38)

[0597] <Production of 6-methoxy-2-(2-methoxy-5-pyridyl)-N-(4-methylphenyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0598] 0.03 g (0.3 mmol) of p-toluidine was dissolved in 1.0 ml of DMF, 0.02 g (0.6 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then 0.1 g (0.3 mmol) of 4-fluoro-6-methoxy-2-(2-methoxy-5-pyridyl)-5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 25 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.002 g (0.005 mmol) of 6-chloro-2-(2-methoxy-5-pyridyl)-N-(4-methylphenyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 2%.

[0599] [Chemical formula 78]

[0600]

[0601] The results of the analysis are described below.

[0602] 1 H NMR (400MHz, CDCl3) δppm: 9.14 (d, J=1.8Hz, 1H), 8.44 (dd, J=2.5, 8.6Hz, 1H), 7.40 (d, J=8.3Hz, 2H) , 7.26 (br, 1H), 7.21 (d, J=8.3Hz, 1H), 6.78 (d, J=8.3Hz, 2H), 4.11 (s, 3H), 4.00 (s, 3H), 2.38 (s, 3H)

[0603] APCI-MS (m / z): 390.5 [M] +

[0604] (Example 39)

[0605] <Production of 6-methoxy-2-(2-methoxy-5-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine>

[0606] 0.08 g (0.3 mmol) of p-toluene thiophenol was dissolved in 5.0 ml of DMF, and 0.02 g (0.5 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.09 g (0.3 mmol) of 4-fluoro-6-methoxy-2-(2-methoxy-5-pyridyl)-5-trifluoromethylpyridine was added. The mixture was stirred at room temperature for 16.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.1 g (0.2 mmol) of 6-methoxy-2-(2-methoxy-5-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 80%.

[0607] [Chemical formula 79]

[0608]

[0609] The results of the analysis are described below.

[0610] 1 H NMR (400MHz, CDCl3) δppm: 8.82 (d, J=2.5Hz, 1H), 7.95 (dd, J=8.9, 2.5Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 6.63 (d, J=8.6Hz, 1H), 4.12 (s, 3H), 3.97 (s, 3H), 2.47 (s, 3H)

[0611] APCI-MS (m / z): 407.4 [M] +

[0612] (Example 40)

[0613] <Production of 6-methoxy-2-(2-methoxy-5-pyridyl)-4-(phenylmethoxy)-5-trifluoromethylpyrimidine>

[0614] 0.05 g (0.5 mmol) of benzyl alcohol was dissolved in 3.0 ml of DMF, 0.03 g (0.7 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.09 g (0.3 mmol) of 4-fluoro-6-methoxy-2-(6-methoxy-3-pyridyl)-5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.08 g (0.2 mmol) of 6-methoxy-2-(2-methoxy-5-pyridyl)-4-(phenylmethoxy)-5-trifluoromethylpyrimidine having the following structure. The yield was 72%.

[0615] [Chemical formula 80]

[0616]

[0617] The results of the analysis are described below.

[0618] 1 H NMR (400MHz, CDCl3) δppm: 9.26 (ddd, J=7.6, 2.5, 0.6Hz, 1H), 8.54 (ddd, J=9.5, 8.6, 2.1Hz, 1 H), 7.30-7.50 (m, 5H), 6.83 (d, J=8.6Hz, 1H), 5.63 (s, 2H), 4.13 (s, 3H), 4.03 (d, J=8.6Hz, 3H)

[0619] APCI-MS (m / z): 391.5 [M] +

[0620] (Example 41)

[0621] <Production of 6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-2-(2-trifluoromethyl-5-pyridyl)-4-pyrimidinamine>

[0622] 0.04 g (0.4 mmol) of p-toluidine was dissolved in 5.0 ml of DMF, and 0.02 g (0.6 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.1 g (0.4 mmol) of 4-fluoro-6-methoxy-5-trifluoromethyl-2-(6-trifluoromethyl-3-pyridyl)pyridine was added. The mixture was stirred at room temperature for 26.8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.001 g (0.002 mmol) of 6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-2-(2-trifluoromethyl-5-pyridyl)-4-pyrimidinamine having the following structure. The yield was 1%.

[0623] [Chemical formula 81]

[0624]

[0625] The results of the analysis are described below.

[0626] 1 H NMR (400MHz, CDCl3) δppm: 9.59 (s, 1H), 8.72 (dd, J=8.3, 1.2Hz, 1H), 7.75 (d, J=8.0Hz, 1 H), 7.36 (d, J=8.3Hz, 2H), 7.34 (br, 1H), 7.22 (d, J=8.3Hz, 2H), 4.15 (s, 3H), 2.39 (s, 3H)

[0627] APCI-MS (m / z): 428.4 [M] +

[0628] (Example 42)

[0629] <Production of 6-methoxy-4-[(4-methylphenyl)thio]-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine>

[0630] 0.04 g (0.3 mmol) of p-toluene thiophenol was dissolved in 5.0 ml of DMF, and 0.02 g (0.6 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.1 g (0.3 mmol) of 4-fluoro-6-methoxy-5-trifluoromethyl-2-(6-trifluoromethyl-3-pyridyl)pyridine was added. The mixture was stirred at room temperature for 28.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.1 g (0.3 mmol) of 6-methoxy-4-[(4-methylphenyl)thio]-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine having the following structure. The yield was 89%.

[0631] [Chemical formula 82]

[0632]

[0633] The results of the analysis are described below.

[0634] 1 H NMR (400MHz, CDCl3) δppm: 9.23 (d, J=1.8Hz, 1H), 8.32 (dd, J=8.3, 1.2Hz, 1H), 7 .63(dd, J=8.3, 0.6Hz, 1H), 7.45(m, 2H), 7.31(m, 2H), 4.17(s, 3H), 2.48(s, 3H)

[0635] APCI-MS (m / z): 445.2 [M] +

[0636] (Example 43)

[0637] <Production of 6-methoxy-4-phenoxy-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine>

[0638] 0.04 g (0.3 mmol) of phenol was dissolved in 5.0 ml of DMF, 0.02 g (0.5 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.1 g (0.3 mmol) of 4-fluoro-6-methoxy-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyridine was added, and the mixture was stirred at room temperature for 30.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.1 g (0.3 mmol) of 6-methoxy-4-phenoxy-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine having the following structure. The yield was 97%.

[0639] [Chemical formula 83]

[0640]

[0641] The results of the analysis are described below.

[0642] 1 H NMR (400MHz, CDCl3) δppm: 9.41 (d, J=1.8Hz, 1H), 8.56 (dd, J=8.3, 1.2Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.26 (br, 1H), 7.43-7.47 (m, 2H), 7.29-7.33 (m, 1H), 7.16-7.19 (m, 2H), 4.22 (s, 3H)

[0643] APCI-MS (m / z): 415.4 [M] +

[0644] (Example 44)

[0645] <Production of 6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-2-(4-methylthio-2-pyridyl)-4-pyrimidinamine>

[0646] 0.02 g (0.1 mmol) of p-toluidine was dissolved in 1.0 ml of DMF, 0.01 g (0.3 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, then cooled to 0°C, 0.05 g (0.1 mmol) of 4-fluoro-6-methoxy-2-(4-methylthio-2-pyridyl)-5-trifluoromethylpyridine dissolved in 2 ml of DMF was added, and the mixture was stirred at room temperature for 22.6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain a trace amount of 6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-2-(4-methylthio-2-pyridyl)-4-pyrimidinamine having the following structure.

[0647] [Chemical formula 84]

[0648]

[0649] The results of the analysis are described below.

[0650] 1H NMR (400MHz, CDCl3) δppm: 8.56 (d, J=5.5Hz, 1H), 8.14 (d, J=2.1, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.32-7.54 (m, 1H), 7.18-7.21 (m, 3H), 4.22 (s, 3H), 2.48 (s, 3H), 2.37 (s, 3H)

[0651] APCI-MS (m / z): 406.3 [M] +

[0652] (Example 45)

[0653] <Production of 2-(2-bromo-3-pyridyl)-6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0654] 0.03 g (0.2 mmol) of p-toluidine was dissolved in 3.0 ml of DMF, and 0.01 g (0.4 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.09 g (0.3 mmol) of 2-(2-bromo-5-pyridyl)-4-fluoro-6-methoxy-5-trifluoromethylpyridine was added. The mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain a trace amount of 2-(2-bromo-3-pyridyl)-6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure.

[0655] [Chemical formula 85]

[0656]

[0657] The results of the analysis are described below.

[0658] 1 H NMR (400MHz, CDCl3) δppm: 9.23 (ddd, J=2.5, 0.6Hz, 1H), 8.38 (dd, J=8.3, 2.5Hz, 1H), 7.54 (dd, J=8.3, 0.6Hz, 1H), 7.36 (d, J=11.0Hz, 2H), 7.30-7.32 (m, 1H), 7.20 (d, J=8.0Hz, 1H), 4.13 (s, 3H), 2.38 (s, 3H)

[0659] APCI-MS (m / z): 440.3 [M+H] +

[0660] (Example 46)

[0661] <Production of 2-(2-bromo-5-pyridyl)-6-methoxy-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine>

[0662] 0.04 g (0.3 mmol) of p-toluene thiophenol was dissolved in 3.0 ml of DMF, and 0.02 g (0.5 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.10 g (0.3 mmol) of 2-(2-bromo-5-pyridyl)-4-fluoro-6-methoxy-5-trifluoromethylpyridine was added. The mixture was stirred at room temperature for 21.6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.02 g (0.03 mmol) of 2-(2-bromo-5-pyridyl)-6-methoxy-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 12%.

[0663] [Chemical formula 86]

[0664]

[0665] The results of the analysis are described below.

[0666] 1 H NMR (400MHz, CDCl3) δppm: 8.83 (d, J=2.5Hz, 1H), 8.01 (dd, J=8.3, 2.5Hz, 1H), 7.43-7.45 (m, 3H), 7.29 (d, J=8.3Hz, 2H), 4.14 (s, 3H), 2.47 (s, 3H)

[0667] APCI-MS (m / z): 457.1 [M+H] +

[0668] (Example 47)

[0669] <Production of 2-(2-bromo-5-pyridyl)-6-methoxy-4-phenoxy-5-trifluoromethylpyrimidine>

[0670] 0.03 g (0.3 mmol) of phenol was dissolved in 3.0 ml of DMF, 0.02 g (0.4 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.1 g (0.3 mmol) of 2-(2-bromo-5-pyridyl)-4-fluoro-6-methoxy-5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 19.8 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.13 g (0.3 mmol) of 2-(2-bromo-5-pyridyl)-6-methoxy-4-phenoxy-5-trifluoromethylpyrimidine having the following structure. The yield was 80%.

[0671] [Chemical formula 87]

[0672]

[0673] The results of the analysis are described below.

[0674] 1 H NMR (400MHz, CDCl3) δppm: 9.06 (d, J=2.0Hz, 1H), 8.21 (dd, J=8.6, 2.5Hz, 1H), 7.50 (d, J=8 .3Hz, 1H), 7.44 (t, J=7.8Hz, 2H), 7.30 (t, J=7.6Hz, 1H), 7.17 (d, J=8.0Hz, 2H), 4.19 (s, 3H)

[0675] APCI-MS (m / z): 427.0 [M+H] +

[0676] (Example 48)

[0677] <Production of 2-(2-dimethylamino-4-pyridyl)-6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0678] 0.03 g (0.3 mmol) of p-toluidine was dissolved in 3.0 ml of DMF, 0.02 g (0.4 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.08 g (0.3 mmol) of 2-(2-dimethylamino-4-pyridyl)-4-fluoro-6-methoxy-5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 41.4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.008 g (0.02 mmol) of 2-(2-dimethylamino-4-pyridyl)-6-methoxy-N-(4-methylphenyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 8%.

[0679] [Chemical formula 88]

[0680]

[0681] The results of the analysis are described below.

[0682] 1 H NMR (400MHz, CDCl3) δppm: 8.27 (d, J=5.5, 1H), 7.48 (s, 1H), 7.45 (d, J=8.3Hz, 2H), 7.41 (dd, J=5 .2, 1, 2Hz, 1H), 7.30-7.32 (m, 1H), 7.19 (d, J=8.6Hz, 2H), 4.40 (s, 3H), 3.14 (s, 6H), 2.37 (s, 3H)

[0683] APCI-MS (m / z): 403.3 [M] +

[0684] (Example 49)

[0685] <Production of 2-(2-dimethylamino-4-pyridyl)-6-methoxy-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine>

[0686] 0.04 g (0.3 mmol) of p-toluene thiophenol was dissolved in 1.0 ml of DMF, and 0.02 g (0.5 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.09 g (0.4 mmol) of 2-(2-dimethylamino-4-pyridyl)-4-fluoro-6-methoxy-5-trifluoromethylpyridine dissolved in 3.5 ml of DMF was added, and the mixture was stirred at room temperature for 17.5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.10 g (0.2 mmol) of 2-(2-dimethylamino-4-pyridyl)-6-methoxy-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 82%.

[0687] [Chemical formula 89]

[0688]

[0689] The results of the analysis are described below.

[0690] 1 H NMR (400MHz, CDCl3) δppm: 8.18 (d, J=5.2, 0.9Hz, 1H), 7.47 (d, J=8.3Hz, 2H), 7.28 (d, J=8.0Hz, 2H), 7.25-7.60 (m, 1H), 6.89 (s, 1H), 4.15 (s, 3H), 2.98 (s, 6H), 2.41 (s, 3H)

[0691] APCI-MS (m / z): 420.2 [M] +

[0692] (Example 50)

[0693] <Production of 2-(2-dimethylamino-4-pyridyl)-6-methoxy-4-phenoxy-5-trifluoromethylpyrimidine>

[0694] 0.04 g (0.4 mmol) of phenol was dissolved in 3.0 ml of DMF, 0.02 g (0.5 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.09 g (0.3 mmol) of 2-(2-dimethylamino-4-pyridyl)-4-fluoro-6-methoxy-5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 15.4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.09 g (0.2 mmol) of 2-(2-dimethylamino-4-pyridyl)-6-methoxy-4-phenoxy-5-trifluoromethylpyrimidine having the following structure. The yield was 85.6%.

[0695] [Chemical formula 90]

[0696]

[0697] The results of the analysis are described below.

[0698] 1 H NMR (400MHz, CDCl3) δppm: 8.21 (d, J=5.2, 0.9Hz, 1H), 7.41-7.47 (m, 2H), 7.19-7.31 (m, 5H), 7.20 (s, 3H), 3.04 (s, 3H)

[0699] APCI-MS (m / z): 390.3 [M] +

[0700] (Example 51)

[0701] <Production of 6-methoxy-2-(4-nitro-2-pyridyl)-4-phenoxy-5-trifluoromethylpyrimidine>

[0702] 0.04 g (0.4 mmol) of phenol was dissolved in 1.0 ml of DMF, 0.01 g (0.3 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, then cooled to 0°C, 0.06 g (0.2 mmol) of 4-fluoro-2-(4-nitro-2-pyridyl)-6-methoxy-5-trifluoromethylpyridine dissolved in 2.0 ml of DMF was added, and the mixture was stirred at room temperature for 23.3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.01 g of a crude purified product of 6-methoxy-2-(4-nitro-2-pyridyl)-4-phenoxy-5-trifluoromethylpyrimidine having the following structure.

[0703] [Chemical formula 91]

[0704]

[0705] The results of the analysis are described below.

[0706] 1 H NMR (400MHz, CDCl3) δppm: 9.05 (d, J=5.2, 0.6Hz, 1H), 8.72 (d, J=1.8Hz, 1H), 8.08 (dd, J =5.2, 2.1Hz, 1H), 7.45-7.51(m, 2H), 7.32-7.36(m, 1H), 7.23-7.26(m, 2H), 4.29(s, 3H)

[0707] APCI-MS (m / z): 392.3 [M] +

[0708] (Example 52)

[0709] <Production of methyl 2-[6-methoxy-4-[(4-methylphenyl)amino]-5-(trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylate>

[0710] 0.07 g (0.6 mmol) of p-toluidine was dissolved in 6.0 ml of DMF, 0.03 g (0.7 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 10°C, and 0.2 g (0.6 mmol) of 2-[(4-fluoro-6-methoxy-5-trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylic acid methyl ester was added, and stirred at room temperature for 62.6 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.02 g (0.05 mmol) of 2-[6-methoxy-4-(4-methylphenyl)amino-5-(trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylic acid methyl ester having the following structure. The yield was 8%.

[0711] [Chemical formula 92]

[0712]

[0713] The results of the analysis are described below.

[0714] 1H NMR (400MHz, CDCl3) δppm: 8.96 (dd, J=4.9, 0.9Hz, 1H), 8.87 (dd, J=1.5, 0.9, 1H), 7.94 (dd, J=4.9, 1.5Hz, 1 H), 7.53 (d, J = 8.3Hz, 2H), 7.38-7.41 (m, 1H), 7.23 (d, J = 8.3Hz, 2H), 4.22 (s, 3H), 4.00 (s, 3H), 2.38 (s, 3H)

[0715] APCI-MS (m / z): 418.6 [M] +

[0716] (Example 53)

[0717] <Production of methyl 2-[6-methoxy-4-[(4-methylphenyl)thio]-5-(trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylate>

[0718] 0.05 g (0.4 mmol) of p-toluene thiophenol was dissolved in 3.0 ml of DMF, and 0.02 g (0.5 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.1 g (0.3 mmol) of 2-[(4-fluoro-6-methoxy-5-trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylic acid methyl ester was added. The mixture was stirred at room temperature for 16.6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.10 g (0.2 mmol) of 2-[6-methoxy-4-[(4-methylphenyl)thio]-5-(trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylic acid methyl ester having the following structure. The yield was 75%.

[0719] [Chemical formula 93]

[0720]

[0721] The results of the analysis are described below.

[0722] 1 H NMR (400MHz, CDCl3) δppm: 8.88 (d, J=4.9, 0.9Hz, 1H), 8.23 ​​(m, 1H), 7.86 (dd, J=4.9, 1.5Hz , 1H), 7.50 (d, J=8.0Hz, 2H), 7.34 (d, J=8.3Hz, 2H), 4.25 (s, 3H), 3.97 (s, 3H), 2.49 (s, 3H)

[0723] APCI-MS (m / z): 435.9 [M] +

[0724] (Example 54)

[0725] <Production of methyl 2-[6-methoxy-4-phenoxy-5-(trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylate>

[0726] 0.03 g (0.3 mmol) of phenol was dissolved in 3.0 ml of DMF, 0.02 g (0.5 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.10 g (0.3 mmol) of 2-[(4-fluoro-6-methoxy-5-trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylic acid methyl ester was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.09 g (0.2 mmol) of 2-[6-methoxy-4-phenoxy-5-(trifluoromethyl)-2-pyrimidinyl]-4-pyridinecarboxylic acid methyl ester having the following structure. The yield was 74%.

[0727] [Chemical formula 94]

[0728]

[0729] The results of the analysis are described below.

[0730] 1 H NMR (400MHz, CDCl3) δppm: 8.91 (d, J=4.9Hz, 1H), 8.59 (m, 1H), 7.91 (dd, J=4.9, 1.5Hz, 1H), 7.45-7.49(m, 2H), 7.29-7.33(m, 1H), 7.25-7.27(m, 2H), 4.29(s, 3H), 3.95(s, 3H)

[0731] APCI-MS (m / z): 405.9 [M] +

[0732] (Example 55)

[0733] <Production of 6-methoxy-N-(4-methylphenyl)-2-(3-methyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0734] 0.02 g (0.2 mmol) of p-toluidine was dissolved in 1.0 ml of DMF, 0.02 g (0.4 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, then cooled to 0°C, and 0.05 g of a crude purified product of 4-fluoro-6-methoxy-2-(3-methyl-2-pyridyl)-5-trifluoromethylpyridine dissolved in 2.0 ml of DMF was added, and the mixture was stirred at room temperature for 17.1 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain a trace amount of 6-methoxy-N-(4-methylphenyl)-2-(3-methyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure.

[0735] [Chemical formula 95]

[0736]

[0737] The results of the analysis are described below.

[0738] APCI-MS (m / z): 374.3 [M] +

[0739] (Example 56)

[0740] <Production of 6-methoxy-2-(3-methyl-2-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine>

[0741] 0.03 g (0.2 mmol) of p-toluene thiophenol was dissolved in 1.0 ml of DMF, and 0.02 g (0.4 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(3-methyl-2-pyridyl)-5-trifluoromethylpyridine was added. The mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.01 g (0.03 mmol) of 6-methoxy-2-(3-methyl-2-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 21%.

[0742] [Chemical formula 96]

[0743]

[0744] The results of the analysis are described below.

[0745] 1H NMR (400MHz, CDCl3) δppm: 8.52 (dd, J=4.9, 0.9Hz, 1H), 7.44 (d, J=7.6Hz, 1H), 7.41 (d, J=8.0Hz , 2H), 7.21 (dd, J=8.0, 4.9Hz, 1H), 7.18 (d, J=8.0Hz, 2H), 4.15 (s, 3H), 2.38 (s, 3H), 1.84 (s, 3H)

[0746] APCI-MS (m / z): 391.5 [M] +

[0747] (Example 57)

[0748] <Production of 6-methoxy-2-(3-methyl-2-pyridyl)-4-phenoxy-5-trifluoromethylpyrimidine>

[0749] 0.03 g (0.3 mmol) of phenol was dissolved in 1.0 ml of DMF, 0.02 g (0.5 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 15°C, and 0.09 g of a crude purified product of 4-fluoro-6-methoxy-2-(3-methyl-2-pyridyl)-5-trifluoromethylpyridine dissolved in 2 ml of DMF was added, and the mixture was stirred at room temperature for 26.3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.06 g (0.2 mmol) of 6-methoxy-2-(3-methyl-2-pyridyl)-4-phenoxy-5-trifluoromethylpyrimidine having the following structure. The yield was 1.9% in two steps.

[0750] [Chemical formula 97]

[0751]

[0752] The results of the analysis are described below.

[0753] 1 H NMR (400MHz, CDCl3) δppm: 8.54 (dd, J=4.6, 0.9Hz, 1H), 7.50 (dd, J=7.6, 0.9Hz, 1H) ,7.27-7.41(m,2H),7.21-7.25(m,2H),7.14-7.16(m,2H),4.19(s,3H),2.16(s,3H)

[0754] APCI-MS (m / z): 361.3 [M] +

[0755] (Example 58)

[0756] <Production of 4,6-bis(1,1-dimethylethoxy)-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine and 4-(1,1-dimethylethoxy)-6-methoxy-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine>

[0757] 0.6 g (2.0 mmol) of 4-fluoro-6-methoxy-2-(3-n-propyl-2-pyridyl)-5-trifluoromethylpyridine was dissolved in 6.8 ml of THF, and 0.6 g (5.2 mmol) of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 18.8 hours. After the reaction solution was concentrated, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.4 g (0.9 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 44%.

[0758] [Chemical formula 98]

[0759]

[0760] The analysis results of 4,6-bis(1,1-dimethylethoxy)-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0761] 1 H NMR (400MHz, CDCl3) δppm: 8.08 (d, J=8.0Hz, 1H), 7.71 (dd, J=7.6, 7.6Hz, 1H), 7.22 (d, J= 7.6Hz, 1H), 2.86 (t, J=7.0Hz, 2H), 1.85-1.94 (m, 2H), 1.70 (s, 18H), 1.00 (t, J=7.3Hz, 3H)

[0762] APCI-MS (m / z): 411.9 [M] +

[0763] At the same time, 0.04 g (yield 5%) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine was also obtained.

[0764] [Chemical formula 99]

[0765]

[0766] The analysis results of 4-(1,1-dimethylethoxy)-6-methoxy-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0767] 1 H NMR (400MHz, CDCl3) δppm: 8.14 (d, J=7.6Hz, 1H), 7.73 (dd, J=7.6, 7.6Hz, 1H), 7.26-7.27 (m, 1H), 4 .17 (s, 3H), 2.90 (t, J = 7.6Hz, 2H), 1.87 (tq, J = 7.3, 7.3Hz, 2H), 1.71 (s, 9H), 1.03 (t, J = 7.5Hz, 3H)

[0768] APCI-MS (m / z): 369.9 [M] +

[0769] (Example 59)

[0770] <Production of 6-hydroxy-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0771] 0.4 g (0.9 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 58 was dissolved in 0.9 ml of dichloromethane, 0.9 ml of trifluoroacetic acid (TFA) was added, and stirred at room temperature for 3 hours. Then, the reaction solution was concentrated, washed and filtered with ethyl acetate to obtain 0.4 g of a crude purified product of 6-hydroxy-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure.

[0772] [Chemical formula 100]

[0773]

[0774] The results of the analysis are described below.

[0775] 1 H NMR (400MHz, DMSO-d6) δppm: 12.6 (br, 2H), 8.09 (d, J=7.0Hz, 1H), 7.99 (dd, J=8.0, 7.6Hz, 1H), 7.58 (d, J=7.0Hz, 1H), 2.83 (t, J=7.6Hz, 2H), 1.79 (tq, J=7.3, 7.3Hz, 2H), 0.94 (t, J=7.3Hz, 3H)

[0776] APCI-MS (m / z): 299.8 [M] +

[0777] (Example 60)

[0778] <Production of 4,6-dichloro-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine>

[0779] 0.4 g of the crude purified product of 6-hydroxy-2-(6-n-propyl-2-pyridinyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in Example 59 was dissolved in 1.8 ml of toluene and 0.4 ml of POCl3, and stirred for 6 hours under heating reflux conditions. After air cooling to room temperature, the reaction solution was added dropwise to ice to which sodium bicarbonate was added, and extracted with ethyl acetate. Then, it was dried with sodium sulfate and filtered. The filtrate was concentrated and column purified to obtain 0.2 g (0.7 mmol) of 4,6-dichloro-2-(6-n-propyl-2-pyridinyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 79% in 2 steps.

[0780] [Chemical Formula 101]

[0781]

[0782] The results of the analysis are described below.

[0783] 1 H NMR (400MHz, CDCl3) δppm: 8.33 (d, J=7.6Hz, 1H), 7.81 (dd, J=8.0, 7.6Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 2.96 (t, J=7.6Hz, 2H), 1.83 (tq, J=7.3, 7.6Hz, 2H), 1.02 (t, J=7.0Hz, 3H)

[0784] APCI-MS (m / z): 337.5 [M+H] +

[0785] (Example 61)

[0786] <Production of 6-methoxy-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0787] 0.04 g (0.1 mmol) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(6-n-propyl-2-pyridinyl)-5-trifluoromethylpyrimidine obtained in Example 58 was dissolved in 0.5 ml of dichloromethane, and 0.5 ml of trifluoroacetic acid (TFA) was added. After stirring at room temperature for 1.7 hours, the reaction solution was concentrated, washed with ethyl acetate and filtered to obtain 0.04 g of a crude purified product of 6-hydroxy-2-(6-n-propyl-2-pyridinyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure.

[0788] [Chemical formula 102]

[0789]

[0790] The results of the analysis are described below.

[0791] 1 H NMR (400MHz, CDCl3) δppm: 8.26 (d, J=7.0Hz, 1H), 7.86 (dd, J=7.6, 7.6Hz, 1H), 7.43 (d, J=7.0Hz, 1H), 4.18 (s, 3H), 3.10 (br, 1H), 2.87 (t, J=8.0Hz, 2H), 1.80 (tq, J=7.3, 7.3Hz, 2H), 0.99 (t, J=7.3Hz, 3H)

[0792] APCI-MS (m / z): 313.8 [M] +

[0793] (Example 62)

[0794] <Production of 4-chloro-6-methoxy-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine>

[0795] 0.04 g of the crude purified product of 6-methoxy-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in Example 61 was dissolved in 1.0 ml of toluene and 0.04 ml of POCl3, and stirred for 6 hours under heating reflux conditions. After air cooling to room temperature, the reaction solution was added dropwise to ice to which sodium bicarbonate was added, and extracted with ethyl acetate. Then, it was dried over sodium sulfate and filtered. The filtrate was concentrated and column purified to obtain 0.004 g (0.01 mmol) of 4-chloro-6-methoxy-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 12% in 2 steps.

[0796] [Chemical formula 103]

[0797]

[0798] The results of the analysis are described below.

[0799] 1H NMR (400MHz, CDCl3) δppm: 8.25 (d, J=7.6Hz, 1H), 7.78 (dd, J=8.0, 7.6Hz, 2H), 7.34 (d, J=8.0H z, 1H), 4.25 (s, 3H), 2.94 (t, J=7.6Hz, 2H), 1.84 (tq, J=7.6, 7.3Hz, 2H), 1.03 (t, J=7.3Hz, 3H)

[0800] APCI-MS (m / z): 331.6 [M] +

[0801] (Example 63)

[0802] <Production of 6-chloro-2-(4-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine>

[0803] 0.16 g (0.6 mmol) of 4,6-dichloro-2-(4-pyridyl)-5-trifluoromethylpyrimidine obtained by repeating Example 11 was dissolved in 3.0 ml of THF, 0.06 g (0.6 mmol) of triethylamine and 0.05 g (0.4 mmol) of p-toluene thiophenol were added, and the mixture was stirred at room temperature for 24.3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.13 g (0.3 mmol) of 6-chloro-2-(4-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 63%.

[0804] [Chemical formula 104]

[0805]

[0806] The results of the analysis are described below.

[0807] 1 H NMR (400MHz, CDCl3) δppm: 8.63 (dd, J=4.6, 1.8Hz, 2H), 7.70 (dd, J=4.6, 1.5Hz, 2H), 7.45 (d, J=8.3Hz, 2H), 7.36 (d, J=8.3Hz, 2H), 2.51 (s, 3H)

[0808] APCI-MS (m / z): 381.8 [M] +

[0809] (Example 64)

[0810] <Production of 6-chloro-4-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-pyrimidine>

[0811] 0.05 g (0.2 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 31 was dissolved in 1.0 ml of 1N NaOH aqueous solution and stirred at room temperature for 2.3 hours. The reaction solution was neutralized with 10% sulfuric acid aqueous solution, and the precipitated crystals were washed with water to obtain 0.02 g (0.06 mmol) of 6-chloro-4-hydroxy-2-(2-pyridyl)-5-(trifluoromethyl)-pyrimidine having the following structure. The yield was 39%.

[0812] [Chemical formula 105]

[0813]

[0814] The results of the analysis are described below.

[0815] 1 H NMR (400MHz, CDCl3) δppm: 11.23 (br, 1H), 8.72-8.73 (m, 1H), 8.49 (d, J=8.0Hz, 1H), 7.98 (ddd, J=8.0, 7.6, 1.5Hz, 1H), 7.61 (ddd, J=7.6, 4.9, 1.2Hz, 1H)

[0816] APCI-MS (m / z): 275.5 [M] +

[0817] (Example 65)

[0818] <Production of 6-chloro-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0819] 0.05 g (0.2 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 31 was dissolved in 1.0 ml of THF, 0.02 g (0.2 mmol) of triethylamine and 7 drops of 2M ammonia methanol solution were added, and stirred at room temperature for 4 hours. The reaction solution was concentrated, and the precipitated crystals were washed with diethyl ether to obtain a crude purified product of 6-chloro-2-(2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure.

[0820] [Chemical formula 106]

[0821]

[0822] The results of the analysis are described below.

[0823] 1H NMR (400MHz, CDCl3) δppm: 8.84-8.85 (m, 1H), 8.50 (d, J=8.0Hz, 1H), 7.87 (ddd, J=8.0, 7.6, 1.8Hz, 1H), 7.45 (ddd, J=7.3, 4.9, 0.9Hz, 1H), 5.96 (br, 2H)

[0824] APCI-MS (m / z): 274.6 [M] +

[0825] (Example 66)

[0826] <Production of 4-chloro-6-ethoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0827] 0.05 g (0.2 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 31 was dissolved in 1.7 ml of THF, 0.01 g (0.2 mmol) of sodium ethoxide was added, and the mixture was stirred at 0°C for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, the filtrate was concentrated, and then column purified to obtain a crude purified product of 4-chloro-6-ethoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0828] [Chemical formula 107]

[0829]

[0830] The results of the analysis are described below.

[0831] 1 H NMR (400MHz, CDCl3) δppm: 8.87-8.88 (m, 1H), 8.47 (d, J=8.0Hz, 1H), 7.86-7.90 (m, 1H), 7.45-7.49 (m, 1H), 4.73 (q, J=7.0Hz, 2H), 1.51 (t, J=7.0Hz, 3H)

[0832] APCI-MS (m / z): 303.5 [M] +

[0833] (Example 67)

[0834] <Production of 4,6-diethoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0835] 0.05 g (0.2 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 31 was dissolved in 1.7 ml of THF, cooled to 0°C, and then 0.13 g (0.3 mmol) of sodium ethoxide ethanol solution was added, followed by stirring at room temperature for 23 hours. The reaction solution was concentrated and then column purified to obtain 0.05 g (0.2 mmol) of 4,6-diethoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 88%.

[0836] [Chemical formula 108]

[0837]

[0838] The results of the analysis are described below.

[0839] 1 H NMR (400MHz, CDCl3) δppm: 8.84 (m, 1H), 8.43 (d, J=7.9Hz, 1H), 7.85 (ddd, J=8.0, 7.6, 1. 8Hz, 1H), 7.24 (ddd, J=7.6, 4.9, 1.2Hz, 1H), 4.68 (q, J=7.0Hz, 4H), 1.46 (t, J=7.0Hz, 6H)

[0840] APCI-MS (m / z): 313.7 [M] +

[0841] (Example 68)

[0842] <Production of 4,6-diphenoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0843] 0.03 g (0.3 mmol) of phenol was dissolved in 1.7 ml of THF, 0.01 g (0.3 mmol) of sodium ethoxide was added, and the mixture was stirred at room temperature for 30 minutes. Then, the mixture was cooled to 0°C, 0.05 g (0.2 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 31 was added, and the mixture was stirred at room temperature for 15.3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.04 g (0.10 mmol) of 4,6-diphenoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 55%.

[0844] [Chemical formula 109]

[0845]

[0846] The results of the analysis are described below.

[0847] 1 H NMR (400MHz, CDCl3) δppm: 8.63-8.64 (m, 1H), 7.89 (d, J=8.0Hz, 1H), 7.64 (ddd, J=7.6, 7.6, 1.5Hz, 1H), 7.44-7.48 (m, 5H), 7.29-7.31 (m, 6H)

[0848] APCI-MS (m / z): 409.4 [M] +

[0849] (Example 69)

[0850] <Production of 6-methoxy-4-methyl-2-(4-pyridyl)-5-trifluoromethylpyrimidine>

[0851] 0.10 g (0.38 mmol) of 4-fluoro-6-methoxy-2-(4-pyridyl)-5-trifluoromethylpyrimidine was dissolved in 1.2 ml of THF, and 0.4 ml of 1 M methyl lithium (about 3-5% ether solution) was added. After stirring at 0°C for 22.8 hours, 0.4 ml of 1 M methyl lithium (about 3-5% ether solution) was further added, and stirred for 7.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.003 g (0.01 mmol) of 6-methoxy-4-methyl-2-(4-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 3%.

[0852] [Chemical formula 110]

[0853]

[0854] The results of the analysis are described below.

[0855] 1 H NMR (400MHz, CDCl3) δppm: 8.79 (dd, J=4.3, 1.5Hz, 2H), 8.29 (dd, J=4.6, 1.5Hz, 2H), 4.19 (s, 3H), 2.73 (q, J=2.8Hz, 3H)

[0856] APCI-MS (m / z): 270.0 [M+H] +

[0857] (Example 70)

[0858] <Production of 6-methoxy-2-(5-methyl-2-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine>

[0859] 0.05 g (0.4 mmol) of p-toluene thiophenol was dissolved in 3.0 ml of DMF, and 0.02 g (0.6 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.1 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyridine was added. The mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.08 g (0.2 mmol) of 6-methoxy-2-(5-methyl-2-pyridyl)-4-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 57%.

[0860] [Chemical formula 111]

[0861]

[0862] The results of the analysis are described below.

[0863] 1 H NMR (400MHz, CDCl3) δppm: 8.56 (m, 1H), 7.46-7.49 (m, 3H), 7.37-7.39 (m, 1H), 7.29 (d, J = 8.0Hz, 2H), 4.24 (s, 3H), 2.47 (s, 3H), 2.35 (s, 3H)

[0864] APCI-MS (m / z): 391.9 [M] +

[0865] (Example 71)

[0866] <Production of 6-methoxy-2-(5-methyl-2-pyridyl)-4-phenoxy-5-trifluoromethylpyrimidine>

[0867] 0.05 g (0.5 mmol) of phenol was dissolved in 3.0 ml of DMF, and 0.02 g (0.6 mmol) of sodium hydride was added. After stirring at room temperature for 30 minutes, the mixture was cooled to 0°C, and 0.10 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyridine was added. The mixture was stirred at room temperature for 21.2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.13 g (0.4 mmol) of 6-methoxy-2-(5-methyl-2-pyridyl)-4-phenoxy-5-trifluoromethylpyrimidine having the following structure. The yield was 99%.

[0868] [Chemical formula 112]

[0869]

[0870] The results of the analysis are described below.

[0871] 1 H NMR (400MHz, CDCl3) δppm: 8.59 (m, 1H), 7.93 (d, J=8.3Hz, 1H), 7.51 (dd, J=8.0, 2.2Hz, 1H), 7.42-7.46(m, 2H), 7.28-7.30(m, 1H), 7.22-7.23(m, 2H), 4.27(s, 3H), 2.37(s, 3H)

[0872] APCI-MS (m / z): 362.0 [M+H] +

[0873] (Example 72)

[0874] <Production of 6-methoxy-N-(4-methylphenyl)-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0875] 0.09 g (0.8 mmol) of p-toluidine was dissolved in 6.0 ml of DMF, 0.03 g (0.9 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.2 g (0.7 mmol) of 6-fluoro-4-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyridine was added, and stirred at room temperature for 64 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.07 g (0.18 mmol) of 6-methoxy-N-(4-methylphenyl)-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 26%.

[0876] [Chemical formula 113]

[0877]

[0878] The results of the analysis are described below.

[0879] 1H NMR (400MHz, CDCl3) δppm: 8.63 (m, 1H), 8.20 (d, J = 8.0, 1H), 7.58-7.61 (m, 1H), 7.49 (d, J =8.3Hz, 2H), 7.33 (br, 1H), 7.20 (d, J = 8.3Hz, 2H), 4.21 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H)

[0880] APCI-MS (m / z): 374.8 [M] +

[0881] (Example 73)

[0882] <Production of 4,6-bis(1,1-dimethylethoxy)-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine>

[0883] 0.6 g (2.8 mmol) of 6-fluoro-4-methoxy-2-(2-trifluoro-5-pyridyl)-5-trifluoromethylpyridine was dissolved in 9.3 ml of THF, 0.8 g (7.0 mmol) of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 21.5 hours. After the reaction solution was concentrated, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, dried with sodium sulfate, filtered, concentrated, and purified by column to obtain 0.2 g (0.5 mmol) of 4,6-bis(1,1-dimethylethoxy)-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine having the following structure. The yield was 19%.

[0884] [Chemical formula 114]

[0885]

[0886] The results of the analysis are described below.

[0887] 1 H NMR (400MHz, CDCl3) δppm: 9.66 (d, J=1.8Hz, 1H), 8.70-8.23 (m, 1H), 7.82 (dd, J=8.0, 0.6Hz, 1H), 1.70 (s, 18H)

[0888] APCI-MS (m / z): 437.8 [M] +

[0889] (Example 74)

[0890] <Production of 6-hydroxy-2-5-(trifluoromethyl)-(2-trifluoromethyl-5-pyridyl)-4(3H)-pyrimidinone>

[0891] 0.2 g (0.5 mmol) of 4,6-bis(1,1-dimethylethoxy)-5-trifluoromethyl-2-(2-trifluoromethyl-5-pyridyl)pyrimidine obtained in Example 73 was dissolved in 0.5 ml of dichloromethane, 0.5 ml of TFA was added, and the mixture was stirred at room temperature for 3.7 hours. Then, the reaction solution was concentrated, washed and filtered with ethyl acetate to obtain 0.2 g of a crude purified product of 6-hydroxy-2-5-(trifluoromethyl)-(2-trifluoromethyl-5-pyridyl)-4(3H)-pyrimidinone having the following structure.

[0892] [Chemical formula 115]

[0893]

[0894] The results of the analysis are described below.

[0895] 1 H NMR (400MHz, DMSO-d6) δppm: 13.3 (br, 2H), 9.32 (d, J = 1.2Hz, 1H), 8.65 (dd, J = 8.3, 2.1Hz, 1H), 8.16 (d, J = 8.3Hz, 1H)

[0896] APCI-MS (m / z): 325.8 [M] +

[0897] (Example 75)

[0898] <Production of 4,6-bis(1,1-dimethylethoxy)-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine and 4-(1,1-dimethylethoxy)-6-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine>

[0899] 1.0 g (3.4 mmol) of 6-fluoro-4-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyridine was dissolved in 11.6 ml of THF, 1.0 g (8.7 mmol) of potassium tert-butoxide was added, and the mixture was stirred at room temperature for 21.3 hours. After the reaction solution was concentrated, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, dried with sodium sulfate, filtered, concentrated, and purified by column to obtain 0.3 g (0.9 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 25%.

[0900] [Chemical formula 116]

[0901]

[0902] The analysis results of 4,6-bis(1,1-dimethylethoxy)-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0903] 1 H NMR (400MHz, CDCl3) δppm: 8.62-8.63 (m, 1H), 8.18 (d, J=8.3, 1H), 7.61 (ddd, J=8.0, 2.1, 0.6Hz, 1H), 2.41 (s, 3H), 1.70 (s, 18H)

[0904] APCI-MS (m / z): 383.8 [M] +

[0905] At the same time, 0.2 g (yield 13%) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine was obtained.

[0906] [Chemical formula 117]

[0907]

[0908] The analysis results of 4-(1,1-dimethylethoxy)-6-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine are as follows.

[0909] 1 H NMR (400MHz, CDCl3) δppm: 8.66 (d, J=2.1Hz, 1H), 8.25 (d, J=8.0Hz, 1H), 7.64 (ddd, J=8.0, 2.1, 0.6Hz, 1H), 4.19 (s, 3H), 2.43 (s, 3H), 1.70 (s, 9H)

[0910] APCI-MS (m / z): 341.8 [M] +

[0911] (Example 76)

[0912] <Production of 6-hydroxy-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0913] 0.3 g (0.8 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 75 was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 17.4 hours. Then, the reaction solution was concentrated, washed and filtered with ethyl acetate to obtain 0.3 g of a crude purified product of 6-hydroxy-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure.

[0914] [Chemical formula 118]

[0915]

[0916] The results of the analysis are described below.

[0917] 1 H NMR (400MHz, DMSO-d6) δppm: 12.7 (br, 2H), 8.63 (m, 1H), 8.17 (d, J=8.3Hz, 1H), 7.91 (ddd, J=8.0, 2.1, 0.6Hz, 1H), 2.43 (s, 3H)

[0918] APCI-MS (m / z): 371.9 [M] +

[0919] (Example 77)

[0920] <Production of 4,6-dichloro-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine>

[0921] 0.3 g of the crude purified product of 6-hydroxy-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in Example 76 was dissolved in 1.7 ml of toluene and 0.4 ml of POCl3, and stirred for 6 hours under heating reflux conditions. After air cooling to room temperature, the reaction solution was added dropwise to ice to which sodium bicarbonate was added, and extracted with ethyl acetate. After drying with sodium sulfate, it was filtered. The filtrate was concentrated and column purified to obtain 0.2 g (0.6 mmol) of 4,6-dichloro-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 73% in 2 steps.

[0922] [Chemical formula 119]

[0923]

[0924] The results of the analysis are described below.

[0925] 1H NMR (400MHz, CDCl3) δppm: 8.73 (m, 1H), 8.46 (d, J=8.0Hz, 1H), 7.71 (ddd, J=8.0, 2.5, 0.9Hz, 1H), 2.47 (s, 3H)

[0926] APCI-MS (m / z): 307.8 [M] +

[0927] (Example 78)

[0928] <Production of 6-methoxy-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone>

[0929] 0.2 g (0.5 mmol) of 4-(1,1-dimethylethoxy)-6-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 75 was dissolved in 2.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 12.8 hours. Then, the reaction solution was concentrated, washed and filtered with ethyl acetate to obtain 0.2 g of a crude purified product of 6-methoxy-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure.

[0930] [Chemical formula 120]

[0931]

[0932] The results of the analysis are described below.

[0933] 1 H NMR (400MHz, DMSO-d6) δppm: 12.6 (br, 1H), 8.64 (m, 1H), 8.33 (d, J=8.0Hz, 1H), 7.93 (ddd, J=8.0, 2.1, 0.9Hz, 1H), 4.11 (s, 3H), 2.44 (s, 3H)

[0934] APCI-MS (m / z): 285.9 [M] +

[0935] (Example 79)

[0936] <Production of 4-chloro-6-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine>

[0937] 0.2 g of the crude purified product of 6-methoxy-2-(5-methyl-2-pyridyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone obtained in Example 78 was dissolved in 1.0 ml of toluene and 0.2 ml of POCl3, and stirred for 6 hours under heating reflux conditions. After air cooling to room temperature, the reaction solution was added dropwise to ice to which sodium bicarbonate was added, and extracted with ethyl acetate. After drying with sodium sulfate, it was filtered. The filtrate was concentrated and column purified to obtain 0.02 g (0.06 mmol) of 4-chloro-6-methoxy-2-(5-methyl-2-pyridyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 12% in 2 steps.

[0938] [Chemical formula 121]

[0939]

[0940] The results of the analysis are described below.

[0941] 1 H NMR (400MHz, CDCl3) δppm: 8.70 (d, J=2.1Hz, 1H), 8.39 (d, J=8.3Hz, 1H), 7.68 (d, J=8.0, 2.1, 0.6Hz, 1H), 4.25 (s, 3H), 2.45 (s, 3H)

[0942] APCI-MS (m / z): 303.8 [M] +

[0943] (Example 80)

[0944] <Production of 6-chloro-4-phenoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0945] 0.01 g (0.1 mmol) of phenol was dissolved in 1.0 ml of DMF, 0.006 g (0.2 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. Then, the mixture was cooled to 0°C, 0.04 g (0.1 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyridine dissolved in 2 ml of DMF was added, and the mixture was stirred at room temperature for 16.7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column to obtain 0.03 g of a crude purified product of 6-chloro-4-phenoxy-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0946] [Chemical formula 122]

[0947]

[0948] The results of the analysis are described below.

[0949] APCI-MS (m / z): 351.8 [M] +

[0950] (Example 81)

[0951] <Production of 6-chloro-4-methyl-2-(2-pyridyl)-5-trifluoromethylpyrimidine>

[0952] 0.1 g (0.3 mmol) of 4,6-dichloro-2-(2-pyridyl)-5-trifluoromethylpyridine was dissolved in 1.2 ml of THF, and 0.4 ml of about 3-5% methyl lithium was added, and stirred at 0°C for 29.2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.008 g of a crude purified product of 6-chloro-4-methyl-2-(2-pyridyl)-5-trifluoromethylpyrimidine having the following structure.

[0953] [Chemical formula 123]

[0954]

[0955] APCI-MS (m / z): 273.8 [M] +

[0956] (Example 82)

[0957] <Production of 6-chloro-N-(4-methylphenyl)-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine>

[0958] 0.04 g (0.3 mmol) of p-toluidine was dissolved in 3.0 ml of DMF, 0.02 g (0.2 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and 0.1 g (0.3 mmol) of 4,6-dichloro-2-(6-n-propyl-2-pyridyl)-5-trifluoromethylpyrimidine obtained in Example 60 was added, and stirred at room temperature for 15.8 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the organic phase was dried with sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and purified by column to obtain 0.09 g (0.2 mmol) of 6-chloro-N-(4-methylphenyl)-2-(6-n-propyl-2-pyridyl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 26%.

[0959] [Chemical formula 124]

[0960]

[0961] The results of the analysis are described below.

[0962] 1 H NMR (400MHz, CDCl3) δppm: 8.11 (dd, J=8.0, 0.9Hz, 1H), 7.71 (dd, J=8.0, 7.6Hz, 1H), 7.59 (d, J=8.3Hz, 2H), 7.53 (br, 1H), 7.28 (dd , J=7.6, 0.9Hz, 1H), 7.22 (d, J=8.0Hz, 2H), 2.92 (t, J=8.1Hz, 2H), 2.38 (s, 3H), 1.88 (tq, J=7.6, 7.3Hz, 2H), 1.03 (t, J=7.3Hz, 3H)

[0963] APCI-MS (m / z): 406.9 [M] +

[0964] (Evaluation test on cucumber powdery mildew)

[0965] Each fluorine-containing pyrimidine compound prepared in Examples 32 and 36 was dissolved in acetone and diluted to a concentration of 500 ppm. Next, a cucumber leaf disc (20 mm in diameter) was added to the diluted acetone solution to completely wet it, and the cucumber leaf disc was set in a manner that the back of the cucumber leaf disc was in contact with a separately prepared plain agar medium, and it was air-dried. After air-drying, the spore suspension of cucumber powdery mildew was evenly spread on the cucumber leaf disc and allowed to air-dry. Then, the cucumber leaf disc was placed in a thermostat (25°C, illuminated for 12 hours), and the lesion area was investigated after 14 days to calculate the control value. The results are shown in Table 1. In addition, the control value is calculated according to the following formula. In the following formula, "untreated" means that the cucumber leaf disc is only wetted with acetone as the test liquid, and "untreated area" means its partition.

[0966] [Table 1]

[0967] Test compound Prevention value Embodiment 32 57.1 Embodiment 36 67.9

[0968] [Mathematical formula 1]

[0969] Control value = {(average disease area of ​​untreated area - average disease area of ​​treated area) / average disease area of ​​untreated area} × 100

[0970] As shown in Table 1, it is found that the fluorine-containing pyrimidine compound of the present invention exhibits a fungicide effect on the pathogenic bacteria of cucumber powdery mildew and is effective as a compound exhibiting biological activity, particularly as a fungicide.

Claims

1. A fluorine-containing pyrimidine compound represented by the following general formula (1), (2) or (3), [Chemical formula 1] In the above general formulas (1) to (3), W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 , nitro, -OA 1 、-SO m A 1 、-SA 1 、-NA 1 A 2 ,-B(OA 1 )(OA 2 ),-COA 1 、-COOA 1 , or -CONA 1 A 2 , Y represents Cl, Br, I, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n+1 , cyano, nitro, -OA 1 、-SO m A 1 、-SA 1 、-NA 1 A 2 ,-B(OA 1 )(OA 2 ),-COA 1 、-COOA 1 , or -CONA 1 A 2 , Z represents a halogen atom or -OA 3 , A 1 and A 2 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, A 3 represents a hydrocarbon group having 1 to 12 carbon atoms, n is an integer of 1-10, and m is an integer of 1-3.

2. The fluorine-containing pyrimidine compound according to claim 1, wherein The W and X are hydrogen atoms.

3. A fluorine-containing pyrimidone compound represented by the following general formula (31), (32) or (33), [Chemical formula 2] In the above general formulas (31) to (33), R 3 represents a hydrogen atom or a chain hydrocarbon group having 1 to 12 carbon atoms, W and X each independently represent a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, a -C n F 2n+1 , nitro, -OA 1 、-SO m A 1 、-SA 1 、-NA 1 A 2 ,-B(OA 1 )(OA 2 ),-COA 1 、-COOA 1 , or -CONA 1 A 2 , A 1 and A 2 each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, n is an integer of 1-10, and m is an integer of 1-3.

4. The fluorine-containing pyrimidone compound according to claim 3, wherein The W and X are hydrogen atoms.

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