Fluorine-containing pyrimidine compound, fluorine-containing pyrimidinone compound, and bactericide

Abstract

The present invention relates to a fluorine-containing pyrimidine compound represented by general formula (1). (Y represents a halogen atom, a C1-10 hydrocarbon group, or the like, Het represents a 5-or 6-membered heteroaryl or fused heterocycle containing 1-5 heteroatoms (excluding the case in which Het is pyridyl), n represents an integer of 1-4, L represents a hydrogen atom, a halogen atom, a C1-10 hydrocarbon group, or the like, and when n represents an integer of 2, 3, or 4, each L may be the same as or different from each other.)

Description

Fluorine-containing pyrimidine compounds, fluorine-containing pyrimidinone compounds, and fungicides

[0001] The present invention relates to a fluorine-containing pyrimidine compound, a fluorine-containing pyrimidinone compound, and a fungicide.

[0002] Fluorine-containing pyrimidine compounds have been reported to have various biological activities. Among them, compounds having a heterocyclic ring such as a diazine ring, an azole ring, a thiophene ring, a thiazole ring, a furan ring, or an oxazole ring as a substituent at the 2-position of the pyrimidine ring are considered to be promising for use in the pharmaceutical and agricultural chemical fields.

[0003] Specifically, Patent Document 1 reports that 3-[4-(trifluoromethyl)pyrimidin-2-yl]-1,2,4-oxadiazole derivatives have aphidicidal activity. Patent Document 2 reports that 2-(3-thienyl)-5-fluoropyrimidine derivatives have cytostatic activity. Patent Document 3 reports that 2-(2-furyl)-pyrimidine derivatives and 2-(pyrimidin-2-yl)-thiazole derivatives have Mycobacterium tuberculosis inhibitory activity. Patent Document 4 reports that 1-[4-(trifluoromethyl)pyrimidin-2-yl]-1H-pyrazole derivatives have good affinity for trace amine-associated receptors. Patent Document 5 discloses the fungicidal and insecticidal activity of compounds having a 2-(2-pyrazyl)-pyrimidine structure and a 2-(2-pyrimidyl)-pyrimidine structure. From this perspective, there is interest in introducing substituents at the 4th and 6th positions of the pyrimidine ring in the hope of further improving activity.

[0004] International Publication No. WO 2012 / 025460, International Publication No. WO 2006 / 004776, International Publication No. WO 2011 / 019405, International Publication No. WO 2014 / 041007, International Publication No. WO 2015 / 016372

[0005] However, in the past, from the viewpoints of reactivity and selectivity, it has been 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- and 6-positions, and no such fluorine-containing pyrimidine compound has been reported. Such fluorine-containing pyrimidine compounds are expected to have various biological activities, and there has been a demand for novel fluorine-containing pyrimidine compounds having substituents at the 4- and 6-positions of the pyrimidine ring and a heterocyclic ring as a substituent at the 2-position.

[0006] The present invention provides novel fluorine-containing pyrimidine compounds and fluorine-containing pyrimidinone compounds which have substituents at the 4- and 6-positions of the pyrimidine ring and a specific heterocycle as a substituent at the 2-position, which have not been previously known, and fungicides containing them.

[0007] The fluorine-containing pyrimidine compound according to an embodiment of the present invention is represented by the following general formula (1).

[0008] (In the above general formula (1), Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a cyano group, a nitro group, -OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -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 Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl), n is an integer of 1 to 4, L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １, -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents, １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms; ３ represents a hydrocarbon group having 1 to 12 carbon atoms, and １ , A ２ , l and m may be the same or different, and when n is an integer of 2, 3 or 4, each L may be the same or different.

[0009] In one embodiment of the present invention, in the above general formula (1), L is a hydrogen atom.

[0010] The fluorine-containing pyrimidinone compound according to an embodiment of the present invention is represented by the following general formula (2).

[0011] (In the above general formula (2), R represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms, Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (excluding the case where Het is pyridyl), n is an integer of 1 to 4, L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １A ２ represents, １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and when n represents an integer of 2, 3, or 4, each L may be the same or different.

[0012] In one embodiment of the present invention, in the above general formula (2), L is a hydrogen atom.

[0013] A fluorine-containing pyrimidine compound according to another embodiment of the present invention is represented by the following general formula (3).

[0014] (In the above general formula (3), Z is a halogen atom or —OA ３ X represents a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ or -NA １ A ２ k represents an integer of 0 to 3; Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl); L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ or -CONA １ A ２ n is an integer of 1 to 4; １ and A ２each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms; ３ represents a hydrocarbon group having 1 to 12 carbon atoms, and in L and X, each A １ , A ２ , l and m may be the same or different from each other, when k is an integer of 2 or 3, each X may be the same or different from each other, and when n is an integer of 2, 3 or 4, each L may be the same or different from each other.

[0015] The fungicide according to an embodiment of the present invention contains a fluorine-containing pyrimidine compound represented by the above general formula (1) or (3).

[0016] According to the present invention, it is possible to provide novel fluorine-containing pyrimidine compounds and fluorine-containing pyrimidinone compounds having substituents at the 4- and 6-positions of the pyrimidine ring and a predetermined heterocyclic ring as a substituent at the 2-position.

[0017] <Fluorine-Containing Pyrimidine Compound> The fluorine-containing pyrimidine compound according to one embodiment of the present invention is represented by the following general formula (1).

[0018] (In the above general formula (1), Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a cyano group, a nitro group, -OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -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 ３Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl), n is an integer of 1 to 4, L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents, １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms; ３ represents a hydrocarbon group having 1 to 12 carbon atoms, and １ , A ２ , l and m may be the same or different, and when n is an integer of 2, 3 or 4, each L may be the same or different.

[0019] When Z is a halogen atom, the halogen atom is F, Cl, Br or I, preferably F or Cl.

[0020] Z is -OA ３ If A ３represents a hydrocarbon group having 1 to 12 carbon atoms, and is not particularly limited as long as it is a hydrocarbon group consisting of carbon atoms and hydrogen atoms having 1 to 12 carbon atoms, and examples thereof include a chain hydrocarbon group, an aromatic hydrocarbon group, and an alicyclic hydrocarbon group. The chain hydrocarbon group is not particularly limited as long as it has a total of 1 to 12 carbon atoms, and may be a linear hydrocarbon group or a branched chain hydrocarbon group. The chain hydrocarbon group may also have a substituent. The aromatic hydrocarbon group is not particularly limited as long as it has a total of 6 to 12 carbon atoms, and may be a substituted or unsubstituted aromatic hydrocarbon group. The aromatic hydrocarbon group may also have a fused polycyclic structure. The alicyclic hydrocarbon group is not particularly limited as long as it has a total of 3 to 12 carbon atoms, and may be a substituted or unsubstituted alicyclic hydrocarbon group. The alicyclic hydrocarbon group may also have a bridged ring structure.

[0021] Examples of the chain hydrocarbon group include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, and dodecenyl; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, and dodecynyl.

[0022] Examples of the aromatic hydrocarbon group include a phenyl group, a benzyl group, a tolyl group, and a naphthyl group. The tolyl group may be any of an o-tolyl group, an m-tolyl group, and a p-tolyl group, with a p-tolyl group being preferred.

[0023] Alicyclic hydrocarbon groups include saturated or unsaturated cyclic hydrocarbon groups, and examples of cyclic hydrocarbon groups include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, an adamantyl group, and a norbornyl group.

[0024] When the chain hydrocarbon group has a substituent, at least one hydrogen atom of the chain hydrocarbon group may be substituted with an alkoxyl group or an aralkyl group. The alkoxyl group is preferably an alkoxyl group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tet-butoxy group, an n-pentoxy group, or an n-hexyloxy group. The aralkyl group is preferably an alkyl group having 1 to 6 carbon atoms substituted with an aryl group, such as a benzyl group, a phenylethyl group, a phenylpropyl group, or a naphthylmethyl group.

[0025] When the aromatic hydrocarbon group and the alicyclic hydrocarbon group have a substituent, examples of the substituent include the above-mentioned alkyl groups and alkoxyl groups having 1 to 6 carbon atoms. The aromatic hydrocarbon group and the alicyclic hydrocarbon group may have one substituent, or two or more substituents. When the aromatic hydrocarbon group and the alicyclic hydrocarbon group have two or more substituents, the respective substituents may be the same or different.

[0026] Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms, excluding the case where Het is pyridyl. The heteroatom is preferably at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Het also contains 1 to 5 heteroatoms as ring atoms (ring atoms), and may contain at least 1, at least 2, at least 3, or at least 4 heteroatoms. The atom of Het bonded to the pyrimidine ring may be a carbon atom or a heteroatom. Het may contain one, two, or three types of heteroatoms as ring atoms. When Het contains multiple heteroatoms as ring atoms, the atoms may be the same or different from each other. The number of ring atoms constituting the fused heterocycle is not particularly limited, and can be, for example, at least 5, at least 6, at least 8, at least 9, at least 10, at least 13, at least 14, at least 16, at least 18, at least 20, or at least 22. The fused heterocycle is not particularly limited as long as it has a polycyclic structure containing two or more rings, and the number of rings may be, for example, two or more, three or more, four or more, or five or more. The fused heterocycle constituting Het may be an aromatic fused heterocycle or an alicyclic fused heterocycle, but is preferably an aromatic fused heterocycle, and the number of π electrons of the fused heterocycle is more preferably 10, 14, or 18. Furthermore, it is preferable that the atoms constituting the aromatic ring of the fused heterocycle are bonded to a pyrimidine ring. When Het satisfies these conditions, it is possible to control the dynamics and improve the affinity for a receptor using a polycyclic aromatic hydrocarbon as a ligand. This makes it possible to impart more effective biological activity to the fluorine-containing pyrimidine compound.

[0027] When Het is heteroaryl, it preferably represents pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl.

[0028] When Het is a fused heterocycle containing a heteroatom, for example, the number of ring atoms can be 9 or 10, the ring atoms can be 1, 2, 3, or 4 nitrogen atoms, and the fused heterocycle can be composed of two rings.Furthermore, the fused heterocycle can be, for example, a fused heterocycle containing 13 ring atoms, the ring atoms can be 1, 2, 3, or 4 heteroatoms, and the fused heterocycle can be composed of three rings. Examples of the group composed of a fused heterocycle include a benzotriazolyl group, a methylindolyl group, an indolyl group, an isoindolyl group, a quinolyl group, an isoquinolyl group, a naphthyridyl group, a benzofuryl group, a pyrrolidyl group, an indolizinyl group, a benzothienyl group, an isobenzofuranyl group, a dibenzofuranyl group, a chromenyl group, an indazolyl group, a purinyl group, a pteridinyl group, a quinolidinyl group, a naphthyridinyl group, a quinoxalinyl group, a cinnolinyl group, a benzothiazolyl group, a benzisothiazolyl group, Examples of the fused heterocyclic group include an aryl group, a quinazolinyl group, a phthalazinyl group, a benzoxazolyl group, a benzimidazolyl group, a pyridopyrimidinyl group, an isochromanyl group, a chromanyl group, an indolinyl group, an isoindolinyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, a dihydrophthalazinyl group, a carbazolyl group, a phenazinyl group, an acridinyl group, a phenanthridinyl group, a thianthrenyl group, a phenoxazinyl group, and a phenothiazinyl group. Preferred examples of the group composed of a fused heterocycle include a benzotriazolyl group, a methylindolyl group, a quinolyl group, a benzothiazolyl group, and a dibenzofuranyl group.

[0029] When Het is a fused heterocycle, the ring atom of Het that is bonded to the pyrimidine ring or the pyrimidinone ring described below may be a carbon atom.

[0030] The fused heterocycle may be a fused ring containing a 6-membered ring structure and / or a 5-membered ring structure, or may be a fused ring not containing a 6-membered ring structure.

[0031] When Het is heteroaryl, the ring atom of Het that is bonded to the pyrimidine ring or the pyrimidinone ring described below may be a carbon atom.

[0032] L represents a substituent that Het has, and n is an integer of 1 to 4. L is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ and 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. When a plurality of L's are present, n is an integer of 2, 3, or 4, and when n is an integer of 2, 3, or 4, each L may be the same as or different from another.

[0033] In L, the halogen atom is F, Cl, Br or I, and is preferably F or Cl.

[0034] In L, the hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is a hydrocarbon group consisting of carbon atoms and hydrogen atoms. ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0035] In L, -C ｌ F ２ｌ＋１is not particularly limited as long as it is a perfluoroalkyl group consisting of carbon atoms and fluorine atoms, and may be linear or branched. 1 is an integer of 1 to 10, and preferably an integer of 1 to 3.

[0036] In L, -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 represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed above, the hydrocarbon group may be a hydrocarbon group having 1 to 10 carbon atoms, and preferably a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms. Furthermore, m is an integer of 1 to 3, and preferably 2.

[0037] In L, -NA １ A ２ A included in １ and A ２ A each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. １ and A ２ may be the same or different. １ and A ２ represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0038] In L, -B(OA １ ) (OA ２ ) A included in １ and A ２ A each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. １ and A ２ may be the same or different. １ and A２ represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0039] In L, -CONA １ A ２ A included in １ and A ２ A each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. １ and A ２ may be the same or different. １ and A ２ represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0040] When Het is a 5- or 6-membered heteroaryl, at least one L is an aromatic hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ and -OA １ A in １ may represent an aromatic hydrocarbon group having 1 to 10 carbon atoms.

[0041] Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１(l is an integer of 1 to 10), a cyano group, a nitro group, -OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents a halogen atom, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , or -NA １ A ２ It is preferred that

[0042] In Y, the halogen atom is F, Cl, Br or I, and preferably F or Cl.

[0043] In Y, the hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is a hydrocarbon group consisting of carbon atoms and hydrogen atoms. ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0044] In Y, -C ｌ F ２ｌ＋１ is not particularly limited as long as it is a perfluoroalkyl group consisting of carbon atoms and fluorine atoms, and may be linear or branched. 1 is an integer of 1 to 10, and preferably an integer of 1 to 3.

[0045] In Y, -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. １represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed above, the hydrocarbon group may be a hydrocarbon group having 1 to 10 carbon atoms, and preferably a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms. Furthermore, m is an integer of 1 to 3, and preferably 1 or 2.

[0046] In Y, -NA １ A ２ A included in １ and A ２ A each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. １ and A ２ may be the same or different. １ and A ２ represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0047] In Y, -B(OA １ ) (OA ２ ) A included in １ and A ２ A each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. １ and A ２ may be the same or different. １ and A ２ represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0048] In Y, -CONA １ A ２ A included in １ and A ２ A each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. １and A ２ may be the same or different. １ and A ２ represents a hydrocarbon group having 1 to 10 carbon atoms, for example, ３ Among the hydrocarbon groups listed in 1. above, a hydrocarbon group having 1 to 10 carbon atoms can be used, and a chain hydrocarbon group having 1 to 10 carbon atoms or an alicyclic hydrocarbon group having 3 to 10 carbon atoms is preferred.

[0049] The fluorine-containing pyrimidine compound in another embodiment of the present invention is represented by the following general formula (3).

[0050] (In the above general formula (3), Z is a halogen atom or —OA ３ X represents a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ or -NA １ A ２ k represents an integer of 0 to 3; Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl); L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ n is an integer of 1 to 4; １ and A ２each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms; ３ represents a hydrocarbon group having 1 to 12 carbon atoms, and in L and X, each A １ , A ２ , l and m may be the same or different from each other, when k is an integer of 2 or 3, each X may be the same or different from each other, and when n is an integer of 2, 3 or 4, each L may be the same or different from each other.

[0051] Z, Het, L, and A in general formula (3) １ ~A ３ The definitions of Z, Het, L, and A in the general formula (1) are the same as those of the general formula (1) described above. １ ~A ３ are the same as those defined above.

[0052] X in the general formula (3) is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ , -OA １ , -SO ｍ A １ , -SA １ , and -NA １ A ２ The definitions of each of the above are as follows: a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ , -OA １ , -SO ｍ A １ , -SA １ , and -NA １ A ２ are the same as those defined for each of

[0053] k is selected from the integers 0, 1, 2, and 3, and when a plurality of Xs are present, k represents an integer of 2 or 3.

[0054] When a plurality of X's are present and all of the plurality of X's are hydrocarbon groups, the total number of carbon atoms of the hydrocarbon groups of the plurality of X's may be 5 or more.

[0055] <Uses of Fluorine-Containing Pyrimidine Compound> The fluorine-containing pyrimidine compound of this embodiment is useful in the fields of medicine and agrochemicals and organic electronic materials, and can also be used as an intermediate for obtaining further useful compounds. The fluorine-containing pyrimidine compound of this embodiment may be used in the form of a salt, and examples of such salts include hydrochloride, hydrobromide, acetate, sulfate, etc.

[0056] The application in the field of agricultural chemicals can be, for example, harmful fungi control agent, arthropod control agent and herbicide.As harmful fungi control agent, the fluorine-containing pyrimidine compound in this embodiment can be used to control various cultivated plants such as wheat, rye, barley, oat, rice, corn, grass, banana, cotton, soybean, coffee tree, sugarcane, grape tree, fruit tree and ornamental plant; vegetables such as cucumber, bean, tomato, potato and gourd; and many fungi that are on the seeds of these plants.

[0057] The fluorine-containing pyrimidine compound of this embodiment is suitable for controlling, for example, the following plant diseases caused by harmful fungi: rice blast (Primularia oryzae), southern leaf blight (Cochliobolus miyabeanus), sheath blight (Rizoctonia solani), etc.; wheat powdery mildew (Erysiphe graminis), head blight (Gibberella zeae), (red) rust (Puccinia striiformis, P. graminis, P. recondita, P. hordei), snow rot (Typhula sp., Micronectriella nivalis), naked smut (Ustilago tritici, U. nuda), cattail smut (Tilletia caries), eyespot (Pseudocercosporella herpotrichoide), scald (Rhynchosporium secalis), leaf blight (Septoria tritici), leaf spot (Leptosphaeria nodorum), net blotch (Pyrenophora teres), hazel (Helminthosporium zonatum Ikata), etc.; citrus black spot (Diaporthe citri), scab (Elsinoe fawcetti), fruit rot (Penicillium digitatum, P. italicum), brown rot (Phytophthora citrophthora, P. nicotianae), black spot (Phyllostictina citricarpa), canker (Xanthomonas citri), etc.; Monilia disease (Monilinia mali), canker (Valsa mali), powdery mildew (Podosphaera leucotricha), leaf spot (Alternaria mali), black spot (Venturia inaequalis), black spot (Mycospherella pomi), anthracnose (Colletotrichum acutatum), ring spot (Botryosphaeria berengeriana), red rot (Gymnosporangium yamadae), brown rot (Monilinia fructicola), etc.;Pear black spot (Venturia nashicola, V. pirina), black spot (Alternaria kikuchiana), red spot (Gymnosporangium haraeanum), brown spot (Monilinia fructicola), etc.; peach brown spot (Monilinia fructicola), black spot (Cladosporium caepophilum), Phomopsis rot (Phomopsis sp.), etc.; grape black rot (Elinoe ampelina), late rot (Colletotrichum acutatum), powdery mildew (Uncinula necaator), rust (Phakopsora ampelopsidis), black rot (Guignardia bidwellii), downy mildew (Plasmopara viticola), brown rot (Monilinia fructigena), black scab (Cladosporium viticolum), gray mold (Botrytis cinerea), etc.; persimmon anthracnose (Gloeosporium kaki), leaf drop (Cercospora kaki, Mycoshaerella nawae); cucurbit anthracnose (Colletotrichum lagenarium), powdery mildew (Sphaerotheca fuliginea, Oidiopsis taurica), vine blight (Didymella bryoniae), vine wilt (Fusarium oxysporum), downy mildew (Pseudoperonospora cubensis), late blight (Phytophthora sp.), seedling damping-off (Pythium sp.), etc.; tomato ring spot (Alternaria solani), leaf mold (Cladosporium fulvum), late blight (Phytophthora infestans), foot rot (Fusarium solani), etc.; brown spot of eggplant (Phomopsis vexans), powdery mildew (Erysiphe cichoracearum), etc.; black spot of cruciferous vegetables (Alternaria japonica), white spot (Cercosporella brassicae), soft rot (Erwinia carotovora), etc.;Onion rust (Puccinia allii), etc.; soybean purple spot (Cercospora kikuchii), black rot (Elsinoe glycines), black spot (Diaporthe phaseolorum var. sojae), etc.; kidney bean anthracnose (Colletotrichum lindemthianum), etc.; peanut black spot (Cercospora personata), brown spot (Cercospora arachidicola), etc.; pea powdery mildew (Erysiphe pisi), etc.; potato summer blight (Alternaria solani), late blight (Phytophthora infestans), leaf rot fungus (Rhizoctonia solani), etc.; strawberry powdery mildew (Sphaerrotheca humuli), etc.; tea net blight (Exobasidium reticulatum), white spot (Elsinoe leucospila), etc.; tobacco red spot (Alternaria longipes), powdery mildew (Erysiphe cichoracearum), anthracnose (Colletotrichum tabacum), downy mildew (Peronospora tabacina), late blight (Phytophthora nicotianae), wildfire (Pseudomonus syringae), etc.; brown spot of sugar beet (Cercospora beticola), damping-off (Aphanomyces cochliodes), etc.; black spot of rose (Diplocarpon rosae), powdery mildew (Sphaerotheca pannosa), etc.; brown spot of chrysanthemum (Septoria chrysanthemi-indici), white rust (Puccinia horiana), etc.; gray mold of various crops (Botrytis cinerea), sclerotinia sclerotiorum, etc.;

[0058] <Method for Producing Fluorine-Containing Pyrimidine Compound> The method for producing a fluorine-containing pyrimidine compound in this embodiment may be, for example, the method described in Comprehensive Organic Transformation: A Guide to Functional Group Preparations, 3ｒｄ The fluorine-containing pyrimidine compound can be produced by appropriately modifying and combining known methods described in reference documents such as "The Phenomenon of Fluorine-Containing Pyrimidines," ...

[0059] A specific example of the method for producing a fluorine-containing pyrimidine compound in this embodiment is the following reaction.

[0060] [Nucleophilic Substitution Reaction or Electrophilic Addition Reaction] (A) Heterocycle-Containing Pyrimidine Compound (a-1) A pyrimidine derivative represented by the following general formula (4) is reacted with a nucleophile to obtain a fluorine-containing pyrimidine compound represented by the following general formula (5) (step (a-1)).

[0061]

[0062] (a-2) In general formula (5), Y １ Ga-SA １ In this case, optionally, S is oxidized by further reacting a fluorine-containing pyrimidine compound represented by the following general formula (6) with hydrogen peroxide as an electrophile to obtain a fluorine-containing pyrimidine compound represented by the following general formula (7) (step (a-2)):

[0063] (In the above general formula (7), Y ２ is -SO ｍ A １ and m is an integer of 1 to 3.

[0064] (a-3) In general formula (5), Y １ is a halogen atom, optionally containing a fluorine-containing pyrimidine compound represented by the following general formula (5-1) and an amine, alkoxide, thiolate, organometallic reagent or Y as a nucleophile: １ａ Further reaction with a halogen atom different from Y １ａ The halogen atom of the compound (7-1) is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (7-1) (step (a-3)).

[0065] (In the above general formula (5-1), Y １ａ is a halogen atom, and in the general formula (7-1), Y ２ａ Ha-NA １ A ２ , O.A. １ , S.A. １ , a hydrocarbon group having 1 to 10 carbon atoms or Y １ａ is a halogen atom different from A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0066] (a-4) In general formula (5), Y １ and Z is -OA ３ In this case, the alkoxy group of the fluorine-containing pyrimidine compound represented by the following general formula (5-2) is optionally dealkylated, and then reacted with a halogen atom as a nucleophile to obtain Y １ｂ and Z ａ No-OA ３ are substituted, respectively, to obtain a fluorine-containing pyrimidine compound of the following general formula (7-2) (step (a-4)).

[0067] (In the above general formula (5-2), Y １ｂ and Z ａ are -OA respectively ３ In the general formula (7-2), Y ２ｂ and Z ｂ Each represents a halogen atom.)

[0068] (a-5) Optionally, the fluorine-containing pyrimidine compound represented by the general formula (7-2) is further reacted with an amine, hydroxide ion, alkoxide or thiolate as a nucleophile to give Y ２ｂ and optionally Z ｂ The halogen atom of the compound (7-3) is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (7-3) (step (a-5)).

[0069] (In the above general formula (7-3), Y ２ｃ Ha-NA １ A ２ , O.A. １ or SA１ and Z ｂ is a halogen atom or OA １ Represents. A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0070] [Two-step process of hydrolysis reaction and halogenation] (B) Heterocycle-containing pyrimidine compound (b-1) By hydrolyzing a pyrimidine derivative represented by the following general formula (4), a pyrimidinone derivative represented by the following general formula (8) can be obtained (step (b-1)).

[0071]

[0072] (b-2) The resulting pyrimidinone derivative represented by the general formula (8) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (9) (step (b-2)).

[0073] (In the above general formula (9), Y ２ represents a halogen atom.)

[0074] (C) Heterocycle-Containing Pyrimidine Compound (c-1) A pyrimidinone derivative of the following general formula (11) can be obtained by dealkylating a pyrimidine derivative of the following general formula (10) (step (c-1)).

[0075]

[0076] (c-2) The resulting pyrimidinone derivative represented by the general formula (11) is halogenated to obtain a fluorine-containing pyrimidine compound represented by the following general formula (12) (step (c-2)).

[0077] (In the above general formula (12), Y ３ represents a halogen atom.)

[0078] (c-3) In general formula (12), Y ３ａ a fluorine-containing pyrimidine compound represented by the general formula (12-1), wherein is a halogen atom, and an amine, hydroxide ion, alkoxide, thiolate or Y ３ａFurther reaction with a halogen atom different from Y ３ａ The halogen atom of the compound (12-1) is substituted to obtain a fluorine-containing pyrimidine compound of the following general formula (12-2) (step (c-3)).

[0079] (In the above general formula (12-1), Y ３ａ is a halogen atom, and in the general formula (12-2), Y ３ｂ Ha-NA １ A ２ , O.A. １ , S.A. １ or Y ３ａ is a halogen atom different from A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.

[0080] (D) Heterocycle-containing pyrimidine compound (d-1) A fluorine-containing pyrimidine compound represented by the following general formula (3) can be obtained by reacting aniline represented by the following general formula (13) or a derivative thereof with a fluorine-containing pyrimidine compound represented by the following general formula (14) in an organic solvent in the presence of a basic substance (step (d-1)).

[0081] (In the above general formula (14), Y ４ represents a halogen atom.)

[0082] (d-2) An aryl halide represented by the following general formula (15) or a derivative thereof is reacted with a fluorine-containing pyrimidine compound represented by the following general formula (16) to obtain a fluorine-containing pyrimidine compound represented by the following general formula (3) (step (d-2)).

[0083] (In the above general formula (15), W represents a halogen atom.)

[0084] In each of the general formulae shown in each of the above steps, unless otherwise specified, R and R １ represents a hydrocarbon group having 1 to 12 carbon atoms; R ２represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms, Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl), n is an integer of 1 to 4, L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents Y １ represents a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a cyano group, a nitro group, -OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ Each X is independently a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, or —C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ or -NA １ A ２ wherein k is an integer of 0 to 3; ３ represents a halogen atom, Z represents a halogen atom or -OA ３ represents Z１ represents a halogen atom, —OH or —OA ３ represents, １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and ３ represents a hydrocarbon group having 1 to 12 carbon atoms, and in L and X, each A １ , A ２ , l and m may be the same or different from each other, when k is an integer of 2 or 3, each X may be the same or different from each other, and when n is an integer of 2, 3 or 4, each L may be the same or different from each other.

[0085] <Fluorine-Containing Pyrimidinone Compound> In the above (B) to (C), a fluorine-containing pyrimidine compound is obtained via a two-step process, and a pyrimidinone derivative is obtained as an intermediate product in the first step. Such a pyrimidinone derivative corresponds to a fluorine-containing pyrimidinone compound represented by the following general formula (2). The fluorine-containing pyrimidinone compound of the present invention is an intermediate product of the fluorine-containing pyrimidine compound of the present invention described above, and is therefore useful as an intermediate for a substance exhibiting the desired biological activity possessed by the fluorine-containing pyrimidine compound of this embodiment.

[0086] (In the above general formula (2), R represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms, Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (excluding the case where Het is pyridyl), n is an integer of 1 to 4, L represents a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA１ , or -CONA １ A ２ represents, １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and when n represents an integer of 2, 3, or 4, each L may be the same or different.

[0087] In each of the above general formulas, Het and L are the same as those defined in the fluorine-containing pyrimidine compound represented by the above general formula (1). １ are the same as Z defined in the fluorine-containing pyrimidine compound represented by the general formula (1), and Z or Z １ and halogen atoms as defined in the definition of —OA ３ is the same as defined in the fluorine-containing pyrimidine compound represented by the above general formula (1). １ In each of the above general formulas having the formula １ is the same as defined for Y in the fluorine-containing pyrimidine compound represented by the above general formula (1) (excluding halogen atoms), and Y ２ In each of the above general formulas having the formula ２ The halogen atoms defined in the definition of are the same as those defined in the fluorine-containing pyrimidine compound represented by the general formula (1). １ In each of the above general formulas having the formula １ is the same as A in the fluorine-containing pyrimidine represented by the above general formula (1). ３ is the same as defined in ２ In each of the above general formulas having R ２ are the same as R defined in the fluorine-containing pyrimidinone compound represented by the general formula (2), and R, R １ and R ２ The hydrocarbon group having 1 to 12 carbon atoms as defined in the definition of A in the fluorine-containing pyrimidine represented by the above general formula (1) ３ is the same as

[0088] In each of the above general formulas, R, R １ and R ２ preferably represents a hydrocarbon group having 1 to 10 carbon atoms. In addition, in each of the above general formulae, Het preferably represents pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, or pyrrolyl. L 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. Such a hydrocarbon group can be, for example, A in the fluorine-containing pyrimidine compound represented by the above general formula (1), ３ Among the hydrocarbon groups listed in 1., alkyl groups having 1 to 10 carbon atoms can be used.

[0089] The nucleophilic substitution reaction using the above-mentioned nucleophile is carried out in an organic solvent such as tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), sulfolane, acetone, diethyl ether, alcohols such as methanol, ethanol, and tert-butanol, or acetonitrile, in the presence of a nucleophile such as an alcohol, amine, or thiol treated with a base, such as an inorganic base such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium cyanide, potassium cyanide, potassium fluoride, or sodium hydride, or an organic base such as triethylamine or N,N-diisopropylethylamine (DIPEA), at 0 to 100° C. The reaction time is usually 0.5 to 72 hours, and preferably 3 to 45 hours.

[0090] The electrophilic addition reaction using the electrophilic agent is carried out, for example, in an organic solvent such as acetic acid, chloroform, dichloromethane, dimethylformamide, or acetonitrile in the presence of an electrophilic agent such as hydrogen peroxide, peracetic acid, metachloroperbenzoic acid, or potassium permanganate at 0 to 65°C.

[0091] The hydrolysis reaction can be carried out in the presence of an acid or a base in accordance with a method generally considered in organic synthetic chemistry. This reaction typically uses an acid or a base and a solvent. The acid and base are not particularly limited as long as they promote the hydrolysis reaction. For example, one or more of the following can be appropriately selected and mixed and used: inorganic acids such as hydrochloric acid and sulfuric acid; organic acids such as acetic acid and trifluoroacetic acid (TFA); 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; and alkaline earth metal carbonates such as calcium carbonate and barium carbonate. The solvent is not particularly limited as long as it promotes the hydrolysis reaction, and any solvent inert to the reaction may be used. Such a solvent can be used by appropriately selecting and mixing one or more from the following: alcohols such as methanol, ethanol, isopropyl alcohol, etc.; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, sulfolane, etc.; nonpolar solvents such as dichloromethane, etc.; ethers such as diethyl ether, tert-butyl methyl ether, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, etc.; water, etc. The reaction temperature is usually 0 to 150° C., and the reaction time is usually 0.5 to 72 hours.

[0092] Examples of halogenating agents used in the halogenation include thionyl chloride, phosgene, phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, and phosphorus tribromide. In the reaction with the halogenating agent, the reaction temperature is typically 50 to 150°C, the reaction time is 1 to 10 hours, and the amount of halogenating agent (reagent) used in the reaction is usually 1 to 10 equivalents per equivalent of the pyrimidine derivative (fluorine-containing pyrimidinone compound). Although a solvent is not necessarily required in the reaction with the halogenating agent, the reaction is generally carried out in the presence of a solvent. Usable solvents include aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as chlorobenzene.

[0093] Although the embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, but includes all aspects encompassed by the concept of the present invention and the scope of the claims, and can be modified in various ways within the scope of the present invention.

[0094] Examples of the present invention will be described below, but the present invention is not limited to these examples as long as they do not deviate from the spirit of the present invention. Furthermore, unless otherwise specified, room temperature is assumed to be within the range of 20°C ± 5°C.

[0095] Example 1 Preparation of 6-methoxy-4-(phenylmethoxy)-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine 0.05 g (0.5 mmol) of benzyl alcohol was dissolved in 2.0 ml of DMF, and 0.012 g (0.3 mmol) of sodium hydride (60%, dispersed in liquid paraffin) was added. After stirring at room temperature for 30 minutes, 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine was added and stirred at 80°C for 15.2 hours. After cooling to room temperature, water was added to the reaction solution, which was then 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 silica gel column chromatography (column purification) to obtain 0.03 g of crude 6-methoxy-4-(phenylmethoxy)-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure.

[0096]

[0097] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.63 (s, 2H), 8.35 (s, 1H), 7.46-7.48 (m, 2H), 7.37-7.42 (m, 2H), 7.30-7.35 (m, 1H), 5.65 (s, 2H), 4.17 (s, 3H) APCI-MS (m / z): 363.4 [M+H] ＋

[0098] Example 2 Production of 6-methoxy-4-phenoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine 0.02 g (0.2 mmol) of phenol was dissolved in 2.0 ml of DMF, and 0.012 g (0.5 mmol) of sodium hydride (60%, dispersed in liquid paraffin) was added. After stirring at room temperature for 30 minutes, 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine was added and stirred at 50°C for 15.2 hours. After cooling to room temperature, water was added to the reaction solution, which was then 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 using a column to obtain 0.02 g of crude 6-methoxy-4-phenoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure:

[0099]

[0100] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.37 (s, 2H), 9.27 (s, 1H), 7.42-7.48 (m, 2H), 7.29-7.34 (m, 1H), 7.15-7.20 (m, 2H), 4.22 (s, 3H) APCI-MS (m / z): 349.3 [M+H] ＋

[0101] Example 3: Preparation of 4,6-bis(1,1-dimethylethoxy)-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine 0.2 g (0.7 mmol) of 4-fluoro-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine was dissolved in 2.0 ml of DMF, and 0.2 g (1.8 mmol) of potassium tert-butoxide was added and stirred at room temperature for 24.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction 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 0.005 g of crude 4,6-bis(1,1-dimethylethoxy)-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure:

[0102]

[0103] The analytical results of 4,6-bis(1,1-dimethylethoxy)-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.58 (s, 2H), 9.33 (s, 1H), 1.69 (s, 18H) APCI-MS (m / z): 371.5 [M+H] ＋

[0104] At the same time, 0.009 g of a crude product of 4-(1,1-dimethylethoxy)-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure was also obtained.

[0105]

[0106] The analytical results of 4-(1,1-dimethylethoxy)-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine were as follows. １ H NMR (400MHz, CDCl ３ ) δppm: 9.62 (s, 2H), 9.35 (s, 1H), 4.14 (s, 3H), 1.70 (s, 9H) APCI-MS (m / z): 329.5 [M+H] ＋

[0107] Example 4 Production of 4,6-dimethoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of methanol, and 0.02 g (0.3 mmol) of sodium methoxide was added thereto, followed by stirring under heating and reflux for 2.3 hours. The reaction solution was then concentrated to obtain 0.05 g of a crude product of 4,6-dimethoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure.

[0108]

[0109] The analytical results were as follows: APCI-MS (m / z): 286.6 [M] ＋

[0110] Example 5 Preparation of 6-methoxy-2-(5-pyrimidyl)-5-(trifluoromethyl)-4-pyrimidineamine 0.1 g (0.4 mmol) of 4-fluoro-6-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine was dissolved in 1 ml of THF, 0.04 g (0.4 mmol) of triethylamine was added, and the mixture was cooled to 0°C. 0.3 ml of a 2 M ammonia methanol solution was added, and the mixture was stirred at room temperature for 26 hours, and then the reaction solution was concentrated. The resulting crystals were washed with ether to give a crude product of 6-methoxy-2-(5-pyrimidyl)-5-(trifluoromethyl)-4-pyrimidineamine having the following structure.

[0111]

[0112] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.61 (s, 2H), 9.32 (s, 1H), 5.56 (br, 2H), 4.13 (s, 3H) APCI-MS (m / z): 271.6 [M] ＋

[0113] Example 6 Production of 4,6-dimethoxy-2-(4-methyl-5-pyridazinyl)-5-trifluoromethylpyrimidine 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(4-methyl-pyridazin-5-yl)-5-trifluoromethylpyrimidine was dissolved in 1 ml of methanol, and 0.02 g (0.3 mmol) of sodium methoxide was added thereto, followed by stirring for 22.8 hours under heated reflux conditions. The reaction solution was then concentrated to obtain 0.05 g of a crude product of 4,6-dimethoxy-2-(4-methyl-5-pyridazinyl)-5-trifluoromethylpyrimidine having the following structure.

[0114]

[0115] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.80 (d, J = 0.5Hz, 1H), 9.17 (s, 1H), 4.14 (s, 6H), 2.79 (s, 3H) APCI-MS (m / z): 300.5 [M] ＋

[0116] Example 7 Preparation of 6-methoxy-N-(4-methylphenyl)-2-(4-pyridazinyl)-5-trifluoromethyl-4-pyrimidineamine 0.05 g (0.2 mmol) of 6-fluoro-4-methoxy-2-(4-pyridazinyl)-5-trifluoromethylpyrimidine was dissolved in 1 ml of acetonitrile, and 0.03 g (0.3 mmol) of p-toluidine and 0.05 g (0.5 mmol) of triethylamine were added and stirred at 50°C for 22.2 hours. After air-cooling to room temperature, water was added to the reaction solution, which 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 0.05 g (0.1 mmol) of 6-methoxy-N-(4-methylphenyl)-2-(4-pyridazinyl)-5-trifluoromethyl-4-pyrimidineamine having the following structure. The yield was 79%.

[0117]

[0118] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.95 (dd, J=2.1, 1.2Hz, 1H), 9.33 (dd, J=5.2, 1.2Hz, 1H), 8.22 (dd, J=5. 2, 2.1Hz, 1H), 7.34-7.40 (m, 3H), 7.22-7.26 (m, 2H), 4.17 (s, 3H), 2.41 (s, 3H) APCI-MS (m / z): 361.6 [M] ＋

[0119] Example 8 Production of 4-ethoxy-6-methoxy-2-(4-pyrimidyl)-5-trifluoromethylpyrimidine 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(4-pyrimidyl)-5-trifluoromethylpyrimidine was dissolved in 1 ml of ethanol, and 4 drops of 20% sodium ethoxide ethanol solution were added. After stirring at 50°C for 17 hours, the reaction solution was concentrated to obtain 0.05 g (0.2 mmol) of 4-ethoxy-6-methoxy-2-(4-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 98.8%.

[0120]

[0121] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.49 (d, J = 1.2 Hz, 1H), 8.97 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 5.2, 1 .5Hz, 1H), 4.68 (q, J=7.0Hz, 2H), 4.21 (s, 3H), 1.47 (t, J=7.3Hz, 3H) APCI-MS (m / z): 300.5 [M] ＋

[0122] Example 9 Preparation of 6-methoxy-4-[(4-methylphenyl)thio]-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine 0.03 g (0.2 mmol) of p-toluenethiol was dissolved in 1 ml of DMF, and 0.015 g (0.375 mmol) of sodium hydride (60%, dispersed in liquid paraffin) was added. After stirring at room temperature for 40 minutes, 0.05 g (0.2 mmol) of 6-fluoro-4-methoxy-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine was added and stirred at room temperature for 42.9 hours. After cooling to room temperature, water was added to the reaction solution, which was then 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 using a column to obtain 0.01 g (0.03 mmol) of 6-methoxy-4-[(4-methylphenyl)thio]-2-(5-pyrimidyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 21.1%.

[0123]

[0124] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.23 (s, 1H), 9.15 (s, 2H), 7.43-7.47 (m, 2H), 7.29-7.33 (m, 2H), 4.17 (s, 3H), 2.48 (s, 3H) APCI-MS (m / z): 378.6 [M] ＋

[0125] Example 10 Production of 4,6-dimethoxy-2-(2-methanesulfonyl-5-furyl)-5-trifluoromethylpyrimidine 0.05 g (0.1 mmol) of 4-fluoro-6-methoxy-2-(2-methanesulfonyl-5-furyl)-5-trifluoromethylpyrimidine was dissolved in 1 ml of methanol, 0.03 g (0.6 mmol) of sodium methoxide was added, and the mixture was stirred under reflux for 6.5 hours. The reaction solution was then concentrated to obtain 0.04 g (0.1 mmol) of 4,6-dimethoxy-2-(2-methanesulfonyl-5-furyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 84.5%.

[0126]

[0127] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.40 (d, J=3.7Hz, 1H), 7.29 (d, J=3.7Hz, 1H), 4.13 (s, 6H), 3.26 (s, 3H) APCI-MS (m / z): 352.3 [M] ＋

[0128] Example 11 Preparation of 2-(2-methanesulfonyl-5-furyl)-6-methoxy-N-(4-methylphenyl)-5-trifluoromethyl-4-pyrimidineamine 0.1 g (0.3 mmol) of 6-fluoro-4-methoxy-2-(5-methanesulfonyl-2-furyl)-5-trifluoromethylpyrimidine was dissolved in 1 ml of acetonitrile, and 0.04 g (0.4 mmol) of p-toluidine and 0.04 g (0.4 mmol) of triethylamine were added, followed by stirring at 80°C for 5.6 hours. After air-cooling to room temperature, water was added to the reaction solution, followed by extraction 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 0.08 g (0.2 mmol) of 2-(2-methanesulfonyl-5-furyl)-6-methoxy-N-(4-methylphenyl)-5-trifluoromethyl-4-pyrimidineamine having the following structure. The yield was 61.3%.

[0129]

[0130] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.48-7.44 (m, 2H), 7.31-7.37 (m, 1H), 7.25 (s, J = 3.7Hz, 1H), 7.23 ( d, J = 3.7Hz, 1H), 7.21-7.17 (m, 2H), 4.11 (s, 3H), 3.23 (s, 3H), 2.37 (s, 3H) APCI-MS (m / z): 427.2 [M] ＋

[0131] Example 12 Preparation of methyl 2-[6-methoxy-4-(phenylmethoxy)-5-(trifluoromethyl)-2-pyrimidinyl]-5-thiophenecarboxylate 0.04 g (0.3 mmol) of benzyl alcohol was dissolved in 2.0 ml of THF, and 0.02 g (0.8 mmol) of sodium hydride (60%, dispersed in liquid paraffin) was added. After stirring at room temperature for 30 minutes, 0.05 g (0.1 mmol) of 6-fluoro-4-methoxy-2-[5-(methoxycarbonyl)-2-thienyl]-5-(trifluoromethyl)pyrimidine was added. The mixture was stirred at room temperature for 14.4 hours and then at 50°C for 6.6 hours. After cooling to room temperature, water was added to the reaction mixture, which was then 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 using a column to obtain a trace amount of crude methyl 2-[6-methoxy-4-(phenylmethoxy)-5-(trifluoromethyl)-2-pyrimidinyl]-5-thiophenecarboxylate having the following structure.

[0132]

[0133] The analytical results were as follows: APCI-MS (m / z): 424.7 [M] ＋

[0134] Example 13 Preparation of 6-methoxy-4-(phenylmethoxy)-2-[2-(methanesulfonyl)-1-methyl-1H-imidazol-4-yl]-5-(trifluoromethyl)pyrimidine 0.02 g (0.2 mmol) of benzyl alcohol was dissolved in 2.0 ml of THF, and 0.02 g (0.8 mmol) of sodium hydride (60%, dispersed in liquid paraffin) was added. After stirring at room temperature for 30 minutes, 0.05 g (0.1 mmol) of 6-fluoro-4-methoxy-2-[2-(methanesulfonyl)-1-methyl-1H-imidazol-4-yl]-5-(trifluoromethyl)pyrimidine was added. The mixture was stirred at 80°C for 4 hours and air-cooled to room temperature. Water was then added to the reaction mixture, which was then 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 subjected to column purification to obtain 0.01 g of a crude product of 6-methoxy-4-(phenylmethoxy)-2-[2-(methanesulfonyl)-1-methyl-1H-imidazol-4-yl]-5-(trifluoromethyl)pyrimidine having the following structure.

[0135]

[0136] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.80 (s, 1H), 7.52-7.49 (m, 2H), 7.30-7.41 (m, 3H), 5.61 (s, 2H), 4.12 (s, 3H), 4.08 (s, 3H), 3.54 (s, 3H) APCI-MS (m / z): 443.3 [M+H] ＋

[0137] Example 14 Production of 4,6-dimethoxy-2-(3-isoxazolyl)-5-(trifluoromethyl)pyrimidine 0.05 g (0.2 mmol) of 4-fluoro-6-methoxy-2-(3-isoxazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, and 0.02 g (0.4 mmol) of sodium methoxide was added thereto, followed by stirring at 50°C for 15.4 hours and then under reflux for 7.9 hours. The reaction solution was concentrated and subjected to column purification to obtain 0.05 g of crude 4,6-dimethoxy-2-(3-isoxazolyl)-5-(trifluoromethyl)pyrimidine having the following structure.

[0138]

[0139] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.55 (d, J=1.5Hz, 1H), 7.01 (d, J=1.5Hz, 1H), 4.16 (s, 6H) APCI-MS (m / z): 276.1 [M+H] ＋

[0140] Example 15 Production of 4,6-dimethoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine 0.05 g (0.2 mmol) of 6-fluoro-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, and 0.01 g (0.3 mmol) of sodium methoxide was added thereto, followed by stirring under heating and reflux for 4.9 hours. The reaction solution was then concentrated to obtain 0.05 g of a crude product of 4,6-dimethoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine having the following structure.

[0141]

[0142] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 8.55 (dd, J=0.6, 2.8Hz, 1H), 7.87 (dd, J=1.5, 0.9Hz, 1H), 7. 87 (dd, J=1.5, 0.9Hz, 1H), 6.51 (dd, J=2.8, 1.5Hz, 1H), 4.16 (s, 6H) APCI-MS (m / z): 276.0 [M+H] ＋

[0143] Example 16 Preparation of N,N-diethyl-4-methoxy-2-(5-nitro-2-furanyl)-5-(trifluoromethyl)-6-pyrimidineamine 0.06 g (0.8 mmol) of diethylamine was dissolved in 5.0 ml of DMF, and 0.02 g (0.42 mmol) of sodium hydride was added. After stirring at room temperature for 45 minutes, 0.10 g (0.34 mmol) of 6-fluoro-4-methoxy-2-(5-nitro-2-furanyl)-5-trifluoromethylpyrimidine was added and stirred at room temperature for 68 hours. Water was added to the reaction solution, followed by extraction 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 0.03 g (0.08 mmol) of N,N-diethyl-6-methoxy-2-(5-nitro-2-furanyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 24.0%.

[0144]

[0145] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.40 (d, J=4.0Hz, 1H), 7.32 (d, J=3.7Hz, 1H), 4.10 (s, 3H), 3.58 (q, J=7.0Hz, 4H), 1.24 (t, J=7.0Hz, 6H) APCI-MS (m / z): 360.8 [M] ＋

[0146] Example 17 Preparation of 4-methoxy-N-propyl-2-(5-nitro-2-furanyl)-5-(trifluoromethyl)-6-pyrimidineamine 0.03 g (0.6 mmol) of n-propylamine was dissolved in 5.0 ml of DMF, and 0.04 g (0.9 mmol) of sodium hydride was added. After stirring at room temperature for 45 minutes, 0.10 g (0.3 mmol) of 6-fluoro-4-methoxy-2-(5-nitro-2-furanyl)-5-trifluoromethylpyrimidine was added and stirred at room temperature for 74.6 hours. Water was added to the reaction solution, followed by extraction 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 0.04 g (0.13 mmol) of 6-methoxy-N-propyl-2-(5-nitro-2-furanyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 37.9%.

[0147]

[0148] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.40 (d, J = 4.0Hz, 1H), 7.36 (d, J = 3.7Hz, 1H), 5.68 (d, J = 4.9Hz, 1H), 4.08 (s, 3H), 3.57 (dt, J=6.7, 6.1Hz, 2H), 1.68 (tq, J=7.3, 7.3Hz, 2H), 1.01 (t, J=7.3Hz, 3H) APCI-MS (m / z): 346.7 [M] ＋

[0149] Example 18 Preparation of N,N-diethyl-4-methoxy-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5-(trifluoromethyl)-4-pyrimidineamine 0.05 g (0.6 mmol) of diethylamine was dissolved in 1.1 ml of DMF, 0.02 g (0.6 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 35 minutes. 0.09 g (0.31 mmol) of 6-fluoro-4-methoxy-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5-(trifluoromethyl)pyrimidine was then added, and the mixture was stirred at room temperature for 66.9 hours. Water was added to the reaction solution, which was then 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 chromatography to obtain 0.08 g (0.2 mmol) of N,N-diethyl-4-methoxy-2-(1-methyl-1H-1,2,3-triazol-5-yl)-5-(trifluoromethyl)-4-pyrimidinamine having the following structure. The yield was 74.3%.

[0150]

[0151] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.28 (s, 1H), 7.47 (s, 3H), 4.07 (s, 3H), 3.55 (q, J = 7.0Hz, 4H), 1.24 (t, J = 7.0Hz, 6H) APCI-MS (m / z): 330.7 [M] ＋

[0152] Example 19 Preparation of 4-methoxy-6-[(4-methylphenyl)thio]-2-(1-methyl-1,2,3-triazol-5-yl)-5-trifluoromethylpyrimidine 0.03 g (0.2 mmol) of p-toluenethiol was dissolved in 1.1 ml of DMF, 0.02 g (0.4 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 35 minutes. Then, 0.05 g (0.2 mmol) of 6-fluoro-4-methoxy-2-(1-methyl-1,2,3-triazol-5-yl)-5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 66.3 hours. After cooling to room temperature, water was added to the reaction mixture, which was then 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 0.05 g (0.12 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]-2-(1-methyl-1,2,3-triazol-5-yl)-5-trifluoromethylpyrimidine having the following structure. The yield was 38.3%.

[0153]

[0154] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.06 (s, 1H), 9.15 (s, 2H), 7.41-7.46 (m, 2H), 7.27-7.30 (m, 2H), 4.11 (s, 3H), 3.66 (s, 3H), 2.44 (s, 3H) APCI-MS (m / z): 381.3 [M] ＋

[0155] Example 20 Preparation of 4,6-dimethoxy-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine 0.009 g (0.03 mmol) of 6-fluoro-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, 0.005 g (0.09 mmol) of sodium methoxide was added, and the mixture was stirred at 50° C. for 26.1 hours to obtain 0.006 g of 4,6-dimethoxy-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 64.3%.

[0156]

[0157] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.68 (s, 1H), 4.48 (s, 3H), 4.13 (s, 6H) APCI-MS (m / z): 333.5 [M] ＋

[0158] Example 21 Production of Methyl 4-(4,6-dimethoxy-5-trifluoromethyl-2-pyrimidinyl)-2-furancarboxylate 0.08 g (0.2 mmol) of methyl 4-(6-fluoro-4-methoxy-5-trifluoromethyl-2-pyrimidinyl)-2-furancarboxylate was dissolved in 1 ml of methanol, 0.02 g (0.3 mmol) of sodium methoxide was added, and the mixture was stirred at 50° C. for 66.5 hours. The reaction solution was then concentrated to obtain 0.07 g (0.2 mmol) of methyl 4-(4,6-dimethoxy-5-trifluoromethyl-2-pyrimidinyl)-2-furancarboxylate having the following structure. The yield was 82.4%.

[0159]

[0160] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 8.31 (d, J = 0.9 Hz, 1H), 7.76 (d, J = 0.6 Hz, 1H), 4.09 (s, 3H), 3.95 (s, 3H) APCI-MS (m / z): 332.7 [M] ＋

[0161] Example 22 Preparation of 2-(3-isoxazolyl)-6-methoxy-N-(2,4-dimethylphenyl)-5-(trifluoromethyl)-4-pyrimidineamine 0.1 g (0.4 mmol) of 2-(3-isoxazolyl)-4-fluoro-6-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 1.3 ml of acetonitrile, and 0.07 g (0.6 mmol) of 2,4-dimethylaniline and 0.1 g (1.0 mmol) of triethylamine were added. The mixture was stirred at 60°C for 16.3 hours and then under reflux for 6 hours, then cooled to room temperature, water was added, and the reaction solution was extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, concentrated, and column purified to give 0.066 g (0.18 mmol) of 2-(3-isoxazolyl)-6-methoxy-N-(2,4-dimethylphenyl)-5-(trifluoromethyl)-4-pyrimidineamine having the following structure. The yield was 45.4%.

[0162]

[0163] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.43 (d, J = 1.5Hz, 1H), 7.49 (d, J = 8.9Hz, 1H), 7.16 (d, J = 4.6Hz, 1H), 7.08 (s, 1H ), 7.07 (d, J = 7.0Hz, 1H), 6.70 (d, J = 1.8Hz, 1H), 4.15 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H) APCI-MS (m / z): 365.4 [M+H] ＋

[0164] Example 23 Preparation of N-(2,4-dinitrophenyl)-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)-6-pyrimidineamine 0.1 g (0.3 mmol) of 6-fluoro-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)pyrimidine was dissolved in 1.1 ml of acetonitrile, and 0.04 g (0.2 mmol) of triethylamine and 0.06 g (0.8 mmol) of 2,4-dinitroaniline were added thereto, followed by stirring for 23.8 hours under heated reflux conditions. After cooling to room temperature, water was added to the reaction solution, which was then 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 chromatography to obtain 0.02 g of a crude product of N-(2,4-dinitrophenyl)-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)-6-pyrimidinamine having the following structure.

[0165]

[0166] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 11.01 (d, J = 4.0 Hz, 1H), 9.17 (d, J = 2.8 Hz, 1H), 8.94 (d, J = 9.8 Hz, 1H), 8.51 (dd, J =9.8, 2.8Hz, 1H) 7.84 (d, J = 4.0Hz, 1H), 7.02 (d, J = 4.0Hz, 1H), 4.16 (s, 3H), 2.63 (s, 3H) APCI-MS (m / z): 487.8 [M] ＋

[0167] Example 24 Preparation of N,N-diethyl-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)-6-pyrimidineamine 0.04 g (0.52 mmol) of diethylamine was dissolved in 1.1 ml of DMF, 0.02 g (0.6 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 45 minutes. 0.11 g (0.3 mmol) of 6-fluoro-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)pyrimidine was added, and the mixture was stirred at room temperature for 42.8 hours. Water was added to the reaction mixture, which was then 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 0.08 g (0.2 mmol) of N,N-diethyl-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)-6-pyrimidinamine having the following structure. The yield was 65.0%.

[0168]

[0169] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.76 (d, J=3.7Hz, 1H), 6.70 (d, J=4.0Hz, 1H), 4.05 (s, 3H), 3.52 (q, J=7.0Hz, 4H), 2.58 (s, 3H), 1.22 (t, J=7.0Hz, 6H) APCI-MS (m / z): 377.9 [M] ＋

[0170] Example 25: Preparation of 2-(3-isoxazolyl)-6-methoxy-4-(phenylmethoxy)-5-(trifluoromethyl)pyrimidine 0.05 g (0.5 mmol) of benzyl alcohol was dissolved in 1.3 ml of THF, and 0.05 g (0.3 mmol) of triethylamine was added. After stirring at room temperature for 30 minutes, 0.1 g (0.4 mmol) of 4-fluoro-2-(3-isoxazolyl)-6-methoxy-5-(trifluoromethyl)pyrimidine was added. The mixture was stirred at 80°C for 44.3 hours. After cooling to room temperature, water was added to the reaction mixture, which was then 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 using a column to obtain 0.1 g (0.3 mmol) of 2-(3-isoxazolyl)-6-methoxy-4-(phenylmethoxy)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 79%.

[0171]

[0172] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.56 (d, J = 1.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.41-7.29 (m, 3H), 6.99 (d, J = 1.8Hz, 1H), 5.63 (s, 2H), 4.16 (s, 3H) APCI-MS (m / z): 352.2 [M+H] ＋

[0173] Example 26: Preparation of 2-(3-isoxazolyl)-6-methoxy-4-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine 0.06 g (0.5 mmol) of p-toluenethiol was dissolved in 1.3 ml of THF, and 0.06 g (0.4 mmol) of triethylamine was added. After stirring at room temperature for 30 minutes, 0.1 g (0.4 mmol) of 4-fluoro-2-(3-isoxazolyl)-6-methoxy-5-(trifluoromethyl)pyrimidine was added and stirred at room temperature for 47.6 hours. After cooling to room temperature, water was added to the reaction solution, which was then 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 using a column to obtain 0.08 g (0.2 mmol) of 2-(3-isoxazolyl)-6-methoxy-4-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 51.8%.

[0174]

[0175] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.36 (d, J = 1.5Hz, 1H), 7.46-7.41m, 2H), 7.41-7.46 (m, 2H), 7.27-7.30 (m, 2H), 6.16 (d, J = 1.5Hz, 1H), 4.18 (s, 3H), 2.46 (s, 3H) APCI-MS (m / z): 368.1 [M+H] ＋

[0176] Example 27 Preparation of 4-methoxy-N-(3,4-dimethylphenyl)-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)-6-pyrimidineamine 0.05 g (0.5 mmol) of 6-fluoro-4-methoxy-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of acetonitrile, and 0.04 g (0.4 mmol) of triethylamine and 0.03 g (0.2 mmol) of 3,4-xylidine were added, followed by stirring under heated reflux for 62.3 hours. After air-cooling to room temperature, water was added to the reaction solution, which was then 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 chromatography to obtain 0.04 g of a crude product of 4-methoxy-N-(3,4-dimethylphenyl)-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)-6-pyrimidinamine having the following structure.

[0177]

[0178] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.35 (d, J = 0.9Hz, 1H), 8.82 (d, J = 6.1Hz, 1H), 8.54 (d, J = 8.6Hz, 1H), 8.41 (dd, J = 8.6, 0.9Hz, 1H), 8.10 (m, 1H), 7.56 (d , J = 1.8Hz, 1H), 7.45-7.40 (m, 1H), 7.39 (dd, J = 8.3, 2.5Hz, 1H), 7.18 (d, J = 8.3Hz, 1H), 4.26 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H) APCI-MS (m / z): 425.5 [M] ＋

[0179] Example 28 Preparation of 4-methoxy-6-[(4-methylphenyl)thio]-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)pyrimidine 0.03 g (0.2 mmol) of p-toluenethiol was dissolved in 1.0 ml of THF, and 0.02 g (0.1 mmol) of triethylamine and 0.05 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)pyrimidine were added, followed by stirring under heated reflux for 63 hours. After air-cooling to room temperature, water was added to the reaction solution, which was then 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 chromatography to obtain 0.05 g (0.1 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 75.7%.

[0180]

[0181] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.28 (d, J = 0.9 Hz, 1H), 8.79 (d, J = 5.8 Hz, 1H), 8.19 (d, J = 8.6, 0.6 Hz, 1H), 8.01 (ddd, J = 6.1, 0. 9, 0.9Hz, 1H), 7.82 (d, J = 8.6Hz, 1H), 7.54-7.50 (m, 2H), 7.36-7.32 (m, 2H), 4.31 (s, 3H), 2.51 (s, 3H) APCI-MS (m / z): 428.4 [M] ＋

[0182] Example 29: Preparation of 4-methoxy-2-[2-(1,6-naphthyridyl)]-6-phenoxy-5-(trifluoromethyl)pyrimidine 0.02 g (0.2 mmol) of phenol was dissolved in 1 ml of THF, and 0.03 g (0.2 mmol) of triethylamine and 0.05 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[2-(1,6-naphthyridyl)]-5-(trifluoromethyl)pyrimidine were added, followed by stirring under heated reflux for 39.1 hours. After cooling to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.04 g (0.1 mmol) of 4-methoxy-2-[2-(1,6-naphthyridyl)]-6-phenoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 36.5%.

[0183]

[0184] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.31 (d, J=0.6Hz, 1H), 8.80 (d, J=6.1Hz, 1H), 8.33 (dd, J=8.6, 0.6Hz, 1H), 8.23 ​​(d, J=8.6Hz, 1H) , 8.04 (d, J = 5.8, 1.8, 0.9 Hz, 1H), 7.51-7.45 (m, 2H), 7.35-7.30 (m, 1H), 7.29-7.25 (m, 2H), 4.34 (s, 3H) APCI-MS (m / z): 398.8 [M] ＋

[0185] Example 30 Preparation of 4,6-dimethoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)pyrimidine 0.06 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, 0.04 g (0.7 mmol) of sodium methoxide was added, and the mixture was stirred at 50° C. for 26 hours to obtain 0.04 g (0.1 mmol) of 4,6-dimethoxy-2-[5-(methylsulfanyl)-2-thienyl]-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 64.8%.

[0186]

[0187] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.86 (d, J=4.0Hz, 1H), 7.00 (d, J=3.7Hz, 1H), 4.08 (s, 6H), 2.60 (s, 3H) APCI-MS (m / z): 336.9 [M] ＋

[0188] Example 31 Preparation of 4,6-dimethoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine 0.06 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, and 0.03 g (0.7 mmol) of sodium methoxide was added. The mixture was stirred at 50°C for 47.6 hours, concentrated, water was added, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. Filtration and concentration were carried out to obtain 0.07 g (0.2 mmol) of 4,6-dimethoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 100.0%.

[0189]

[0190] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 7.44 (d, J=2.5Hz, 1H), 7.04 (d, J=2.1Hz, 1H), 4.15 (s, 6H), 4.04 (s, 3H) APCI-MS (m / z): 288.5 [M] ＋

[0191] Example 32 Preparation of N-(2,4-dichlorophenyl)-4-methoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)-6-pyrimidineamine 0.04 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine was dissolved in 2.0 ml of DMF, and 0.03 g (0.2 mmol) of 2,4-dichloroaniline and 0.03 g (0.7 mmol) of NaH were added, followed by stirring at room temperature for 17.6 hours. After cooling to room temperature, water was added to the reaction solution, which was then 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 chromatography to obtain 0.03 g (0.1 mmol) of N-(2,4-dichlorophenyl)-4-methoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)-6-pyrimidinamine having the following structure. The yield was 53.5%.

[0192]

[0193] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.54 (d, J = 8.9Hz, 1H), 7.93 (q, J = 5.2Hz, 1H), 7.43 (d, J = 2.5Hz, 1H), 7.42 (d, J = 2 .5Hz, 1H), 7.33 (dd, J=8.9, 2.5Hz, 1H), 6.92 (d, J=2.1Hz, 1H), 4.18 (s, 3H), 4.03 (s, 3H) APCI-MS (m / z): 418.8 [M] ＋

[0194] Example 33 Preparation of 4-methoxy-6-[(4-methylphenyl)thio]-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine 0.05 g (0.4 mmol) of p-toluenethiol was dissolved in 1.0 ml of THF, and 0.03 g (0.3 mmol) of triethylamine and 0.07 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine were added, followed by stirring under heated reflux for 50.4 hours. After air-cooling to room temperature, water was added to the reaction solution, which was then 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 chromatography to obtain 0.07 g (0.2 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]-2-[3-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 78.1%.

[0195]

[0196] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.48-7.44 (m, 2H), 8.29-7.25 (m, 2H), 7.25 (d, J = 2.5Hz, 1H), 6.21 (d, J = 2.1Hz, 1H), 4.18 (s, 3H), 3.96 (s, 3H), 2.45 (s, 3H) APCI-MS (m / z): 380.6 [M] ＋

[0197] Example 34 Preparation of 4,6-dimethoxy-2-(1-triazolyl)-5-(trifluoromethyl)pyrimidine 0.008 g (0.03 mmol) of 6-fluoro-4-methoxy-2-(1-triazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 2 ml of methanol, and 0.005 g (0.09 mmol) of sodium methoxide was added. The mixture was stirred at room temperature for 18.3 hours, concentrated, water was added, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. Filtration and concentration were carried out to obtain 0.016 g of a mixture of 4,6-dimethoxy-2-(1-triazolyl)-5-(trifluoromethyl)pyrimidine having the following structure.

[0198]

[0199] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.18 (s, 1H), 8.19 (s, 1H), 4.18 (s, 6H) APCI-MS (m / z): 275.5 [M] ＋

[0200] Example 35 Preparation of 4,6-dimethoxy-2-[2-(1-methylimidazolyl)]-5-(trifluoromethyl)pyrimidine 0.01 g (0.05 mmol) of 6-fluoro-4-methoxy-2-[2-(1-methylimidazolyl)]-5-(trifluoromethyl)pyrimidine was dissolved in 2 ml of methanol, and 0.01 g (0.2 mmol) of sodium methoxide was added. The mixture was stirred at 50°C for 41.1 hours, concentrated, water was added, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate. Filtration and concentration were carried out to obtain 0.01 g of a mixture of 4,6-dimethoxy-2-[2-(1-methylimidazolyl)]-5-(trifluoromethyl)pyrimidine having the following structure.

[0201]

[0202] The analytical results were as follows: APCI-MS (m / z): 288.4 [M] ＋

[0203] Example 36: Preparation of methyl 4-[4-methoxy-6-(4-methylphenyl)thio-5-trifluoromethyl-2-pyrimidinyl]-2-furancarboxylate 0.04 g (0.3 mmol) of p-toluenethiol was dissolved in 3.0 ml of THF, and 0.03 g (0.3 mmol) of triethylamine and 0.07 g (0.2 mmol) of methyl 4-(6-fluoro-4-methoxy-5-trifluoromethyl-2-pyrimidinyl)-2-furancarboxylate were added, followed by stirring at 40°C for 66.3 hours. After air-cooling to room temperature, water was added to the reaction solution, followed by extraction 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 0.10 g (0.2 mmol) of methyl 4-[4-methoxy-6-(4-methylphenyl)thio-5-trifluoromethyl-2-pyrimidinyl]-2-furancarboxylate having the following structure. The yield was 100.0%.

[0204]

[0205] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.72 (s, 1H), 7.44-7.39 (m, 2H), 7.33-7.27 (m, 2H), 7.26 (s, 1H), 4.08 (s, 3H), 3.91 (s, 3H), 2.47 (s, 3H) APCI-MS (m / z): 424.2 [M] ＋

[0206] Example 37 Preparation of 4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)-2-thiazolyl]pyrimidine 0.06 g (0.5 mmol) of p-toluenethiol was dissolved in 2.0 ml of THF, and 0.03 g (0.3 mmol) of triethylamine and 0.07 g (0.2 mmol) of 6-fluoro-4-methoxy-5-(trifluoromethyl)-2-[4-(trifluoromethyl)-2-thiazolyl]pyrimidine were added, followed by stirring under heated reflux for 42.1 hours. After air-cooling to room temperature, water was added to the reaction solution, which was then 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 chromatography to obtain 0.07 g (0.2 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)-2-thiazolyl]pyrimidine having the following structure. The yield was 76.9%.

[0207]

[0208] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.80 (d, J = 0.9Hz, 1H), 7.46-7.42 (m, 2H), 7.32-7.28 (m, 2H), 8.01 (ddd, J = 6.1, 0.9, 0.9 Hz, 1H), 7.82 (d, J=8.6Hz, 1H), 7.54-7.50 (m, 2H), 7.36-7.32 (m, 2H), 4.22 (s, 3H), 2.46 (s, 3H) APCI-MS (m / z): 451.3 [M] ＋

[0209] Example 38: Preparation of 2-(5-bromo-2-pyrimidyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine 0.03 g (0.3 mmol) of p-toluenethiol was dissolved in 2.0 ml of THF, and 0.01 g (0.1 mmol) of triethylamine and 0.02 g (0.06 mmol) of 2-(5-bromo-2-pyrimidyl)-6-fluoro-4-methoxy-5-trifluoromethylpyrimidine were added, followed by stirring under heated reflux for 42 hours. After air-cooling to room temperature, water was added to the reaction solution, followed by extraction 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 0.02 g (0.05 mmol) of 2-(5-bromo-2-pyrimidyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-trifluoromethylpyrimidine having the following structure. The yield was 80.9%.

[0210]

[0211] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.87 (s, 2H), 7.51-7.47 (m, 2H), 7.24-7.20 (m, 2H), 4.18 (s, 3H), 2.40 (s, 3H) APCI-MS (m / z): 458.2 [M+H] ＋

[0212] Example 39 Preparation of 4-methoxy-2-[1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-6-phenoxy-5-(trifluoromethyl)pyrimidine 0.03 g (0.3 mmol) of phenol was dissolved in 2 ml of THF, and 0.03 g (0.3 mmol) of triethylamine and 0.08 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-5-(trifluoromethyl)pyrimidine were added, followed by stirring at 40° C. for 65.5 hours and then under reflux for 23.2 hours. After cooling to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column chromatography to obtain 0.06 g (0.2 mmol) of 4-methoxy-2-[1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-6-phenoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 67.0%.

[0213]

[0214] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.43-7.37 (m, 2H), 7.28-7.23 (m, 1H), 7.17-7.13 (m, 2H), 4.21 (q, J = 1.5Hz, 3H), 4.18 (s, 3H) APCI-MS (m / z): 419.5 [M] ＋

[0215] Example 40 Preparation of 4-methoxy-2-[1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-N-propyl-5-(trifluoromethyl)-6-pyrimidineamine 0.03 g (0.5 mmol) of n-propylamine was dissolved in 2 ml of THF, and 0.03 g (0.3 mmol) of triethylamine and 0.07 g (0.2 mmol) of 6-fluoro-4-methoxy-2-[1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-5-(trifluoromethyl)pyrimidine were added, followed by stirring under heated reflux for 65.3 hours. After cooling to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column chromatography to obtain 0.06 g (0.2 mmol) of 4-methoxy-2-[1-methyl-5-(trifluoromethyl)-1H-1,2,3-triazol-4-yl]-N-propyl-5-(trifluoromethyl)-6-pyrimidinamine having the following structure. The yield was 86.3%.

[0216]

[0217] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 5.65 (br, 1H), 4.29 (q, J = 1.5Hz, 1H), 4.06 (s, 3H), 3.54 (dt, J =6.7, 6.7Hz, 3H), 1.64 (tq, J=7.6, 7.3Hz, 2H), 0.97 (t, J=7.3Hz, 3H) APCI-MS (m / z): 384.5 [M] ＋

[0218] Example 41 Preparation of N,N-diethyl-4-methoxy-2-(2-dimethylamino-5-pyrimidyl)-5-(trifluoromethyl)-6-pyrimidineamine 0.05 g (0.3 mmol) of diethylamine was dissolved in 1.2 ml of THF, and 0.05 g (0.5 mmol) of triethylamine and 0.1 g (0.3 mmol) of 6-fluoro-4-methoxy-2-(2-dimethylamino-5-pyrimidyl)-5-(trifluoromethyl)pyrimidine were added. The mixture was stirred at 50°C for 43.8 hours, concentrated, water was added, 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 0.04 g of a crude product of N,N-diethyl-4-methoxy-2-(2-dimethylamino-5-pyrimidyl)-5-(trifluoromethyl)-6-pyrimidineamine having the following structure.

[0219]

[0220] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.24 (s, 2H), 4.05 (s, 3H), 3.53 (q, J = 7.0Hz, 4H), 3.29 (s, 6H), 1.22 (t, J = 7.0Hz, 6H) APCI-MS (m / z): 370.4 [M] ＋

[0221] Example 42: Preparation of 2-(2-furanyl)-4-methoxy-6-(1,1-dimethylethoxy)-5-(trifluoromethyl)pyrimidine 0.5 g (1.9 mmol) of 6-fluoro-2-(2-furanyl)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 6.4 ml of THF, and the solution was stirred with 0.4 g (3.9 mmol) of t-BuOK at room temperature for 23.9 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and drying the organic phase over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.5 g (1.5 mmol) of 2-(2-furanyl)-6-(1,1-dimethylethoxy)-4-methoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 76.4%.

[0222]

[0223] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.63 (dd, J=1.8, 0.9Hz, 1H), 7.28 (dd, J=3.4, 0.6Hz, 1H), 6.56 (dd, J=3.4, 1.5Hz, 1H), 4.09 (s, 3H), 1.67 (s, 9H) APCI-MS (m / z): 260.4 [M-tBu] ＋

[0224] Example 43: Preparation of 2-(2-furanyl)-4-methoxy-5-(trifluoromethyl)-4(3H)-pyrimidinone 0.4 g (1.3 mmol) of 2-(2-furanyl)-6-(1,1-dimethylethoxy)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 3.2 hours. The reaction solution was concentrated to give 0.41 g of a mixture of 2-(2-furanyl)-4-methoxy-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure:

[0225]

[0226] The analysis results were as follows: １ H NMR (400MHz, DMSO-D6) δppm: 13.22 (br, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 6.83-6.81 (m, 1H), 4.03 (s, 3H) APCI-MS (m / z): 260.4 [M] ＋

[0227] Example 44: Preparation of 6-chloro-2-(2-furanyl)-4-methoxy-5-(trifluoromethyl)pyrimidine 0.4 g of crude 2-(2-furanyl)-4-methoxy-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 3.2 ml of toluene and POCl ３The resulting solution was dissolved in 0.7 ml of toluene and stirred for 6 hours under reflux. After cooling to room temperature, the reaction mixture was added dropwise to ice containing sodium bicarbonate and extracted with ethyl acetate. The mixture was dried over sodium sulfate and then filtered. The filtrate was concentrated and purified using a column chromatography column to obtain 0.3 g (0.09 mmol) of 6-chloro-2-(2-furanyl)-4-methoxy-5-(trifluoromethyl)pyrimidine. The yield for the two steps was 7.4%.

[0228]

[0229] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.69 (dd, J=0.9, 0.9Hz, 1H), 7.45 (d, J=3.4Hz, 1H), 6.61 (dd, J=3.4, 1.8Hz, 1H), 4.16 (s, 3H) APCI-MS (m / z): 278.3 [M] ＋

[0230] Example 45: Preparation of 4-methoxy-6-(1,1-dimethylethoxy)-2-(2-pyrazyl)-5-(trifluoromethyl)pyrimidine 0.5 g (1.8 mmol) of 6-fluoro-4-methoxy-2-(2-pyrazyl)-5-trifluoromethylpyrimidine was dissolved in 6.4 ml of THF, and the solution was stirred with 0.3 g (2.8 mmol) of t-BuOK at room temperature for 24.1 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and drying the organic phase over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.4 g (1.1 mmol) of 4-methoxy-6-(1,1-dimethylethoxy)-2-(2-pyrazyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 60.8%.

[0231]

[0232] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 9.59 (d, J=1.2Hz, 1H), 8.79 (dd, J=2.5, 1.5Hz, 1H), 8.70 (d, J=2.5Hz, 1H), 4.19 (s, 3H), 1.72 (s, 9H) AAPCI-MS (m / z): 272.4 [M-tBu] ＋

[0233] Example 46: Preparation of 4-methoxy-2-(2-pyrazyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone 0.3 g (0.1 mmol) of 6-(1,1-dimethylethoxy)-4-methoxy-2-(2-pyrazyl)-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 3.2 hours. The reaction solution was concentrated to obtain 0.41 g of a mixture of 4-methoxy-2-(2-pyrazyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure:

[0234]

[0235] The analysis results were as follows: １ H NMR (400MHz, DMSO-D6) δppm: 13.24 (br, 1H), 9.57 (s, 1H), 8.96-8.95 (m, 1H), 8.88-8.86 (m, 1H), 4.13 (s, 3H) APCI-MS (m / z): 272.4 [M] ＋

[0236] Example 47 Preparation of 6-chloro-4-methoxy-2-(2-pyrazyl)-5-(trifluoromethyl)pyrimidine 0.5 g of a mixture of 4-methoxy-2-(2-pyrazyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 3.5 ml of toluene and POCl ３ The resulting solution was dissolved in 0.8 ml of toluene and stirred for 6 hours under reflux. After cooling to room temperature, the reaction mixture was added dropwise to ice containing sodium bicarbonate and extracted with ethyl acetate. The mixture was dried over sodium sulfate and then filtered. The filtrate was concentrated and purified by column chromatography to obtain 0.2 g (0.7 mmol) of 6-chloro-4-methoxy-2-(2-pyrazyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield for the two steps was 69.6%.

[0237]

[0238] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.69 (s, 1H), 8.85-8.83 (m, 1H), 8.78-7.76 (m, 1H), 4.28 (s, 3H) APCI-MS (m / z): 290.3 [M] ＋

[0239] Example 48: Preparation of 2-(2-furanyl)-4-methoxy-6-(phenylmethoxy)-5-(trifluoromethyl)pyrimidine 0.1 g (0.5 mmol) of benzyl alcohol was dissolved in 1.5 ml of THF, and 0.1 g (1.2 mmol) of triethylamine was added. After stirring at room temperature for 30 minutes, 0.1 g (0.5 mmol) of 6-fluoro-2-(2-furanyl)-4-methoxy-5-(trifluoromethylpyrimidine) was added and stirred under heated reflux conditions for 17 hours. After air-cooling to room temperature, water was added to the reaction solution, which was then 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 0.1 g of crude 2-(2-furanyl)-4-methoxy-6-(phenylmethoxy)-5-(trifluoromethyl)pyrimidine having the following structure:

[0240]

[0241] The analytical results were as follows: APCI-MS (m / z): 350.5 [M] ＋

[0242] Example 49: Preparation of N-benzyl-N-(1-phenylethyl)-2-(1-pyrazolyl)-5-(trifluoromethyl)-6-pyrimidineamine 0.1 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 2.0 ml of acetonitrile, and 0.08 g (0.6 mmol) of DIPEA and 0.09 g (0.4 mmol) of N-benzyl-1-phenylethanamine were added and stirred under heated reflux conditions for 39.6 hours. After air-cooling to room temperature, water was added to the reaction solution, which 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 crude N-benzyl-N-(1-phenylethyl)-2-(1-pyrazolyl)-5-(trifluoromethyl)-6-pyrimidineamine having the following structure:

[0243]

[0244] The analytical results were as follows: APCI-MS (m / z): 453.0 [M] ＋

[0245] Example 50: Preparation of 6-(2-fluorophenyl)-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine 0.1 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 2.0 ml of acetonitrile, and 0.08 g (0.7 mmol) of 2-fluoroaniline and 0.6 g (0.5 mmol) of DIPEA were added. The mixture was stirred for 39.6 hours under heated reflux conditions. After cooling to room temperature, water was added to the reaction mixture, which was then 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 using a column to obtain 0.01 g (0.03 mmol) of 6-(2-fluorophenyl)-4-methoxy-2-(1-pyrazolyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 9.3%.

[0246]

[0247] The analysis results were as follows: １ H NMR (400MHz, CDCl３ ) δppm: 8.37 (d, J=2.5Hz, 1H), 8.24 (dd, J=8.0, 8.0Hz, 1H), 7.84 (d, J=0.6Hz, 1 H), 7.66 (br, 1H), 7.27-7.13 (m, 3H), 6.46 (dd, J=2.5, 1.5Hz, 1H), 4.18 (s, 3H) APCI-MS (m / z): 353.2 [M] ＋

[0248] Example 51 Preparation of 4,6-dimethoxy-2-(4-thiazolyl)-5-(trifluoromethyl)pyrimidine 0.1 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(4-thiazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, and 0.05 g (0.9 mmol) of sodium methoxide was added. The mixture was stirred at 50°C for 16.3 hours, after which water was added, extraction with ethyl acetate was performed, and the organic phase was dried over sodium sulfate. Filtration and concentration were performed to obtain 0.11 g (0.4 mmol) of 4,6-dimethoxy-2-(4-thiazolyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 100.0%.

[0249]

[0250] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.98 (d, J = 2.5Hz, 1H), 8.44 (d, J = 2.1Hz, 1H), 4.17 (s, 6H) APCI-MS (m / z): 291.6 [M] ＋

[0251] Example 52: Preparation of 4-methoxy-N-propyl-2-(4-thiazolyl)-5-(trifluoromethyl)-6-pyrimidineamine 0.11 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(4-thiazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 2 ml of THF, and 0.05 g (0.8 mmol) of n-propylamine and 0.05 g (0.5 mmol) of triethylamine were added and stirred under heated reflux for 15.3 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.11 g (0.4 mmol) of 4-methoxy-N-propyl-2-(4-thiazolyl)-5-(trifluoromethyl)-6-pyrimidineamine having the following structure. The yield was 86.9%.

[0252]

[0253] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.95 (d, J = 2.1Hz, 1H), 8.35 (d, J = 2.1Hz, 1H), 5.59 (br, 1H), 4.11 (s, 3H), 3.62 (dt, J=7.3, 5.8Hz, 3H), 1.69 (tq, J=7.3, 7.3Hz, 2H), 1.01 (t, J=7.3Hz, 3H) APCI-MS (m / z): 318.6 [M] ＋

[0254] Example 53 Preparation of 2-(5-chloro-1-methyl-1H-imidazol-2-yl)-4-methoxy-6-phenoxy-5-(trifluoromethyl)pyrimidine 0.08 g (0.3 mmol) of 2-(5-chloro-1-methyl-1H-imidazol-2-yl)-6-fluoro-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 2 ml of THF, and 0.05 g (0.5 mmol) of PhOH and 0.04 g (0.4 mmol) of triethylamine were added, followed by stirring under heated reflux for 18.9 hours. After cooling to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then purified by column chromatography to obtain 0.07 g (0.3 mmol) of 2-(5-chloro-1-methyl-1H-imidazol-2-yl)-4-methoxy-6-phenoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 100.0%.

[0255]

[0256] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.47-7.41 (m, 2H), 7.31-7.26 (m, 1H), 7.17-7.13 (m, 3H), 4.23 (s, 3H), 3.34 (s, 3H) APCI-MS (m / z): 384.5 [M] ＋

[0257] Example 54 Production of N,N-diethyl-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)-6-pyrimidineamine 0.11 g (0.3 mmol) of 6-fluoro-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 2.0 ml of THF, and 0.04 g (0.5 mmol) of diethylamine and 0.06 g (0.6 mmol) of triethylamine were added, followed by stirring at room temperature for 38.3 hours. Water was added to the reaction solution, followed by extraction 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 0.04 g (0.1 mmol) of N,N-diethyl-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)-6-pyrimidineamine having the following structure. The yield was 34.3%.

[0258]

[0259] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.30 (dd, J=7.3, 0.6Hz, 1H), 7.49-7.46 (m, 2H), 7.32 (dd, J=8.0, 8.0Hz, 4H), 7.18 (d, J=3.1Hz, 1H), 4.18 (s, 3H), 3.86 (s, 1H), 3.62 (q, J=7.0Hz, 4H), 1.26 (t, J=7.0Hz, 6H) APCI-MS (m / z): 378.3 [M] ＋

[0260] Example 55 Preparation of 4,6-dimethoxy-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine 0.1 g (0.3 mmol) of 6-fluoro-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, and 0.05 g (0.9 mmol) of sodium methoxide was added. The mixture was stirred under heated reflux for 38.8 hours, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. Filtration and concentration were carried out to obtain 0.08 g (0.2 mmol) of 4,6-dimethoxy-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 79.7%.

[0261]

[0262] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.38 (d, J=7.6Hz, 1H), 7.53 (d, J=8.1Hz, 1H), 7.50 (d, J=3.1Hz, 1H ), 7.34 (d, J=8.0Hz, 1H), 7.22 (d, J=3.1Hz, 1H), 4.22 (s, 6H), 3.88 (s, 3H) APCI-MS (m / z): 337.4 [M] ＋

[0263] Example 56 Preparation of 2-(4-(1-methyl)indolyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine 0.08 g (0.6 mmol) of p-toluenethiol was dissolved in 3.0 ml of THF, and 0.05 g (0.3 mmol) of triethylamine and 0.03 g (0.09 mmol) of 6-fluoro-2-(4-(1-methyl)indolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine were added, followed by stirring under heated reflux for 18.8 hours. After air-cooling to room temperature, water was added to the reaction solution, which was then 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 0.04 g of a crude product of 2-(4-(1-methyl)indolyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine having the following structure.

[0264]

[0265] The analytical results were as follows: APCI-MS (m / z): 429.3 [M] ＋

[0266] Example 57 Preparation of N-(2,6-dichloro-4-nitrophenyl)-4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)-6-pyrimidineamine 0.06 g (0.2 mmol) of 6-fluoro-4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 6 ml of acetonitrile, and 0.09 g (0.4 mmol) of 2,6-dichloro-4-nitroaniline and 0.03 g (0.7 mmol) of sodium hydride were added, followed by stirring at room temperature for 17.4 hours. After cooling to 0°C, water was added to the reaction solution, which was then 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 chromatography to obtain 0.04 g (0.09 mmol) of N-(2,6-dichloro-4-nitrophenyl)-4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)-6-pyrimidinamine having the following structure. The yield was 37.7%.

[0267]

[0268] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.33 (s, 2H), 7.76 (s, 1H), 7.34 (s, 1H), 7.27 (br, 1H), 7.37 (ddd, J=7.8, 4.9, 1.4Hz, 1H), 7.26 (br, 1H), 4.21 (s, 3H) APCI-MS (m / z): 450.9 [M] ＋

[0269] Example 58: Preparation of 4-methoxy-2-(2-oxazolyl)-6-phenoxy-5-(trifluoromethyl)pyrimidine 0.04 g (0.5 mmol) of phenol was dissolved in 2 ml of THF, and 0.06 g (0.6 mmol) of triethylamine and 0.11 g (0.4 mmol) of 6-fluoro-4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine were added, followed by stirring under heated reflux for 19.8 hours. After cooling to room temperature, water was added to the reaction solution, which was then extracted with ethyl acetate and dried over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.11 g (0.3 mmol) of 4-methoxy-2-(2-oxazolyl)-6-phenoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 79.5%.

[0270]

[0271] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.76 (d, J=0.6Hz, 1H), 7.48-7.42 (m, 2H), 7.35 (d, J=0.6Hz, 1H), 7.31-7.26 (m, 1H), 7.24-7.21 (m, 2H), 4.24 (s, 3H) APCI-MS (m / z): 337.6 [M] ＋

[0272] Example 59: Preparation of 6-(1,1-dimethylethoxy)-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine 0.5 g (1.7 mmol) of 6-fluoro-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 5.7 ml of THF, and the solution was stirred at room temperature for 24.2 hours with 0.3 g (2.6 mmol) of t-BuOK. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 using a column to obtain 0.3 g of crude 6-(1,1-dimethylethoxy)-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine having the following structure.

[0273]

[0274] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.12 (d, J = 0.9Hz, 1H), 4.19 (s, 3H), 2.59 (s, 3H), 1.69 (s, 9H) APCI-MS (m / z): 291.5 [M-tBu] ＋

[0275] Example 60: Preparation of 4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)-6(3H)-pyrimidinone 0.3 g of a mixture of 6-(1,1-dimethylethoxy)-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidines was dissolved in 3.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 2.1 hours. The reaction solution was concentrated to give 0.33 g of a mixture of 4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure:

[0276]

[0277] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 7.36 (m, 1H), 4.17 (s, 3H), 2.59 (d, J = 0.9Hz, 3H) APCI-MS (m / z): 291.7 [M] ＋

[0278] Example 61 Preparation of 6-chloro-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine 0.3 g of a mixture of 4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 3.0 ml of toluene and POCl ３ The resulting solution was dissolved in 0.5 ml of ethyl acetate and stirred for 6 hours under reflux conditions. After cooling to room temperature, the reaction mixture was added dropwise to ice containing sodium bicarbonate and extracted with ethyl acetate. The mixture was dried over sodium sulfate and then filtered. The filtrate was concentrated and purified using a column chromatography column to obtain 0.05 g of crude 6-chloro-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine having the following structure:

[0279]

[0280] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.20 (d, J = 0.6 Hz, 1H), 7.23 (s, 3H), 2.61 (d, J = 0.6 Hz, 3H) APCI-MS (m / z): 309.7 [M] ＋

[0281] Example 62: Preparation of 4,6-dimethoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine 0.1 g (0.3 mmol) of 6-fluoro-4-methoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine was dissolved in 1 ml of methanol, and 0.05 g (0.9 mmol) of sodium methoxide was added. The mixture was stirred under heated reflux for 38.8 hours, concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate. Filtration and concentration were carried out to obtain 0.1 g (0.3 mmol) of 4,6-dimethoxy-2-(4-methyl-2-thiazolyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 96.1%.

[0282]

[0283] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.15 (d, J = 0.9Hz, 1H), 4.18 (s, 6H), 2.60 (d, J = 0.9Hz, 3H) APCI-MS (m / z): 305.7 [M] ＋

[0284] Example 63: Preparation of 4-methoxy-6-[(4-methylphenyl)thio]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine 0.15 g (1.2 mmol) of p-toluenethiol was dissolved in 3.0 ml of THF, and 0.13 g (1.2 mmol) of triethylamine and 0.20 g (1.2 mmol) of 6-fluoro-4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine were added. The mixture was stirred under heated reflux for 19.5 hours. After air-cooling to room temperature, water was added to the reaction mixture, which was then 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 column purified to obtain 0.26 g (0.7 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 90.0%.

[0285]

[0286] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.69 (s, 1H), 7.48 (d, J = 8.0Hz, 2H), 7.31 (s, 1H), 7.28 (d, J = 8.6Hz, 2H), 4.19 (s, 3H), 2.44 (s, 3H) APCI-MS (m / z): 367.6 [M] ＋

[0287] Example 64 Preparation of 4-methoxy-6-[(4-methylphenyl)sulfinyl]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine, 4-methoxy-6-[(4-methylphenyl)sulfonyl]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine, and 4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)-6(3H)-pyrimidinone To 0.3 g (0.8 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine, 2.0 ml of acetic acid and 0.2 ml of 30% aqueous hydrogen peroxide were added and stirred at room temperature for 29.8 hours. Water and sodium bicarbonate were added to the reaction mixture to adjust the pH to 5, followed by extraction 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 chromatography to obtain 0.08 g (0.21 mmol) of 4-methoxy-6-[(4-methylphenyl)sulfinyl]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 25.6%.

[0288]

[0289] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.96 (d, J=2.6Hz, 1H), 7.77 (d, J=6.4Hz, 2H), 7.48 (d, J=2.5Hz, 1H), 7.30-7.26 (m, 2H), 4.24 (s, 3H), 2.37 (s, 3H) APCI-MS (m / z): 383.4 [M] ＋

[0290] At the same time, 0.013 g of a crude product of 4-methoxy-6-[(4-methylphenyl)sulfonyl]2-(2-oxazolyl)-5-(trifluoromethyl)pyrimidine having the following structure was also obtained.

[0291]

[0292] The analytical results were as follows: APCI-MS (m / z): 399.4 [M] ＋

[0293] At the same time, 0.066 g (0.25 mmol) of 4-methoxy-2-(2-oxazolyl)-5-(trifluoromethyl)-6(3H)-pyrimidinone was also obtained, with a yield of 30.9%.

[0294]

[0295] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 10.72 (br, 1H), 7.97 (d, J = 2.1Hz, 1H), 7.47 (d, J = 1.8Hz, 1H), 4.17 (s, 3H) APCI-MS (m / z): 261.5 [M] ＋

[0296] Example 65: Preparation of 4-methoxy-6-[(4-methylphenyl)thio]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine 0.13 g (1.0 mmol) of p-toluenethiol was dissolved in 3.0 ml of THF, and 0.12 g (1.1 mmol) of triethylamine and 0.27 g (0.9 mmol) of 6-fluoro-4-methoxy-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine were added, followed by stirring under heated reflux for 18.9 hours. After air-cooling to room temperature, water was added to the reaction solution, followed by extraction 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 0.19 g (0.5 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 53.6%.

[0297]

[0298] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.38 (s, 1H), 8.99 (s, 3H), 7.45-7.41 (m, 2H), 7.29-7.26 (m, 2H), 4.14 (s, 3H), 2.44 (s, 3H), 2.17 (s, 3H) APCI-MS (m / z): 392.3 [M] ＋

[0299] Example 66 Preparation of 4-methoxy-6-[(4-methylphenyl)sulfinyl]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine and 4-methoxy-6-[(4-methylphenyl)sulfonyl]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine To 0.14 g (0.36 mmol) of 4-methoxy-6-[(4-methylphenyl)thio]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine were added 1.5 ml of acetic acid and 0.15 ml of 30% aqueous hydrogen peroxide, and the mixture was stirred at room temperature for 29.8 hours. Water and sodium bicarbonate were added to the reaction mixture to adjust the pH to 5, followed by extraction 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 chromatography to obtain 0.055 g (0.14 mmol) of 4-methoxy-6-[(4-methylphenyl)sulfinyl]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine having the following structure. The yield was 37.0%.

[0300]

[0301] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 9.79 (s, 1H), 9.21 (s, J = 4.8, 1H), 7.71 (d, J = 8.3Hz, 2H), 7.30 (d, J = 8.3Hz, 2H), 4.21 (s, 3H), 2.85 (s, 3H), 2.38 (s, 3H) APCI-MS (m / z): 408.4 [M] ＋

[0302] At the same time, 0.027 g (0.06 mmol) of 4-methoxy-6-[(4-methylphenyl)sulfonyl]-2-(5-methyl-4-pyridazinyl)-5-trifluoromethylpyrimidine having the following structure was also obtained in a yield of 17.5%.

[0303]

[0304] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 9.36 (s, 1H), 8.10 (s, 1H), 7.68 (d, J = 7.6Hz, 2H), 7.30 (d, J = 7.6Hz, 2H), 4.19 (s, 3H), 2.85 (s, 3H), 2.38 (s, 3H) APCI-MS (m / z): 424.4 [M] ＋

[0305] Example 67: Preparation of 6-(1,1-dimethylethoxy)-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)pyrimidine 0.2 g (0.7 mmol) of 6-fluoro-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 2.5 ml of THF, and the solution was stirred at room temperature for 23.9 hours with 0.1 g (1.1 mmol) of t-BuOK. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which 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 0.1 g of crude 6-(1,1-dimethylethoxy)-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)pyrimidine having the following structure.

[0306]

[0307] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.56 (s, 1H), 4.47 (s, 3H), 4.09 (s, 3H), 1.68 (s, 9H) APCI-MS (m / z): 319.0 [M-tBu] ＋

[0308] Example 68: Preparation of 2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)-4(2H)-pyrimidinone 0.1 g of crude 6-(1,1-dimethylethoxy)-2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 4.2 hours. The reaction solution was concentrated to give 0.1 g of a mixture of 2-(1-methyl-3-nitro-1H-pyrazol-5-yl)-4-methoxy-5-(trifluoromethyl)-4(2H)-pyrimidinone having the following structure:

[0309]

[0310] The analytical results were as follows: APCI-MS (m / z): 317.8 [M−H] －

[0311] Example 69 Preparation of 2-(4-(3-ethyl-5-methylisoxazolyl))-6-(1,1-dimethylethoxy)-4-methoxy-5-(trifluoromethyl)pyrimidine 0.2 g (0.6 mmol) of 2-(4-(3-ethyl-5-methylisoxazolyl))-6-fluoro-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 2.2 ml of THF, and the solution was stirred with 0.4 g (3.3 mmol) of t-BuOK at room temperature for 23.8 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate and drying the organic phase over sodium sulfate. The dried organic phase was filtered, and the filtrate was concentrated and then column purified to obtain 0.2 g (0.06 mmol) of 2-(4-(3-ethyl-5-methylisoxazolyl))-6-(1,1-dimethylethoxy)-4-methoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 9.9%.

[0312]

[0313] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 4.07 (s, 3H), 2.96 (q, J = 7.6Hz, 2H), 2.72 (s, 3H), 1.56 (s, 9H), 1.34 (t, J = 7.3Hz, 3H) APCI-MS (m / z): 304.0 [M-tBu] ＋

[0314] Example 70 Preparation of 2-(4-(3-ethyl-5-methylisoxazolyl))-4-methoxy-5-(trifluoromethyl)-4(3H)-pyrimidinone 0.023 g of 2-(4-(3-ethyl-5-methylisoxazolyl))-6-(1,1-dimethylethoxy)-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 5.9 hours. The reaction solution was concentrated to obtain 0.02 g of a mixture of 2-(4-(3-ethyl-5-methylisoxazolyl))-4-methoxy-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure.

[0315]

[0316] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 6.24 (br, 1H), 4.10 (s, 3H), 2.95 (q, J = 7.3Hz, 2H), 2.70 (s, 3H), 1.33 (t, J = 7.6Hz, 3H) APCI-MS (m / z): 304.1 [M+H] ＋

[0317] (Example 71) <Production of 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine> 0.23 g (1.9 mmol) of p-toluenethiol was dissolved in 4.5 ml of THF, 0.18 g (1.8 mmol) of triethylamine, and 0.38 g (1.3 mmol) of 6-fluoro-2-(4-fluoro-1-pyrazolyl)-4-methoxy-5-(trifluoromethyl)pyrimidine were added, and the mixture was stirred under heated reflux for 27.5 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 column purified to obtain 0.33 g (0.85 mmol) of 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 64%.

[0318]

[0319] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.63 (d, J = 4.3, 0.9 Hz, 1H), 7.45-7.42 (m, 2H), 7.35 (dd, J = 4.6, 0.9Hz, 1H), 7.34-7.30 (m, 2H), 4.18 (s, 3H), 2.47 (s, 3H) APCI-MS (m / z): 385.0 [M] ＋

[0320] Example 72: Preparation of 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)sulfinyl]-5-(trifluoromethyl)pyrimidine and 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)sulfonyl]-5-(trifluoromethyl)pyrimidine. To 0.3 g (0.9 mmol) of 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)thio]-5-(trifluoromethyl)pyrimidine were added 2.0 ml of acetic acid and 0.2 ml of 30% aqueous hydrogen peroxide, and the mixture was stirred at room temperature for 19.1 hours. Water and sodium bicarbonate were added to the reaction mixture to adjust the pH to 5, followed by extraction 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 chromatography to obtain 0.08 g of a mixture of 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)sulfinyl]-5-(trifluoromethyl)pyrimidines having the following structure.

[0321]

[0322] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.60 (dd, J=4.9, 0.9Hz, 1H), 7.81 (dd, J=4.3, 0.6Hz, 1H), 7.7 1 (d, J = 8.3Hz, 2H), 7.29 (d, J = 8.3Hz, 2H), 4.22 (s, 3H), 2.38 (s, 3H) APCI-MS (m / z): 401.3 [M+H] ＋

[0323] At the same time, 0.02 g of crude 2-(4-fluoro-1-pyrazolyl)-4-methoxy-6-[(4-methylphenyl)sulfonyl]-5-(trifluoromethyl)pyrimidine having the following structure was also obtained.

[0324]

[0325] The analytical results were as follows: APCI-MS (m / z): 417.3 [M+H] ＋

[0326] At the same time, 0.02 g of crude 2-(4-fluoro-1-pyrazolyl)-4-methoxy-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure was also obtained.

[0327]

[0328] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 8.24 (d, J = 3.7, 1H), 7.72 (m, 1H), 4.09 (s, 3H) APCI-MS (m / z): 279.2 [M+H] ＋

[0329] Example 73 Preparation of 4,6-bis(1,1-dimethylethoxy)-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)pyrimidine and 4-methoxy-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)-6(3H)-pyrimidinone 0.3 g (0.9 mmol) of 6-fluoro-4-methoxy-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)pyrimidine was dissolved in 3.0 ml of THF, and the solution was stirred with 0.5 g (4.6 mmol) of t-BuOK at room temperature for 22.8 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction 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 using a column to obtain 48 mg (0.1 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 13.5%.

[0330]

[0331] The analytical results were as follows: However, in APCI-MS (m / z), the m / z of the product from which the two tert-butyl groups had been removed was detected. １ H NMR (400MHz, CDCl ３ ) δppm: 6.51 (d, J = 0.9Hz, 1H), 2.51 (d, J = 0.9Hz, 3H), 1.67 (s, 18H) APCI-MS (m / z): 262.6 [M-tBu]＋

[0332] At the same time, 10 mg (0.04 mmol) of 4-methoxy-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure was also obtained in a yield of 3.8%.

[0333]

[0334] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 6.66 (dd, J=0.9Hz, 1H), 4.12 (s, 3H), 2.56 (d, J=0.6Hz, 3H) APCI-MS (m / z): 276.3 [M+H] ＋

[0335] Example 74 Preparation of 6-hydroxy-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)-4(3H)-pyrimidinone 0.048 g (0.1 mmol) of 4,6-bis(1,1-dimethylethoxy)-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 6.0 hours. The reaction solution was concentrated to obtain 0.03 g of a mixture of 6-hydroxy-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure:

[0336]

[0337] The analytical results were as follows: APCI-MS (m / z): 304.1 [M+H] ＋

[0338] Example 75 Preparation of 4,6-dichloro-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)pyrimidine 0.03 g of a mixture of 6-hydroxy-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 1.0 ml of toluene and POCl ３The resulting solution was dissolved in 0.5 ml of toluene and stirred for 6 hours under reflux. After cooling to room temperature, the reaction mixture was added dropwise to ice containing sodium bicarbonate and extracted with ethyl acetate. The mixture was dried over sodium sulfate and then filtered. The filtrate was concentrated and purified using a column to obtain 0.05 g of crude 4,6-dichloro-2-(3-(5-methylisoxazolyl))-5-(trifluoromethyl)pyrimidine having the following structure:

[0339]

[0340] The analytical results were as follows: APCI-MS (m / z): 304.1 [M+H] ＋

[0341] Example 76: Preparation of 6-(1,1-dimethylethoxy)-4-methoxy-2-(2-quinolino)-5-(trifluoromethyl)pyrimidine, 4-methoxy-2-(2-quinolino)-5-(trifluoromethyl)-6(3H)-pyrimidinone, and 4-(1,1-dimethylethoxy)-2-(2-quinolino)-5-(trifluoromethyl)-6(3H)-pyrimidinone. 0.3 g (0.8 mmol) of 6-fluoro-4-methoxy-2-(2-quinolino)-5-(trifluoromethyl)pyrimidine was dissolved in 2.6 ml of THF, and the solution was stirred with 0.1 g (1.3 mmol) of t-BuOK at room temperature for 22.8 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then 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 using a column to obtain 145 mg (0.4 mmol) of 6-(1,1-dimethylethoxy)-4-methoxy-2-(2-quinolino)-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 49.9%.

[0342]

[0343] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 8.42 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 9.5 Hz, 1H), 7.89 (dd, J = 8.3, 1.2 Hz, 2H), 7.78 (ddd, J = 8.6, 6.7, 1.2Hz, 1H), 7.62 (ddd, J = 8.1, 6.7, 1.2Hz, 1H), 4.26 (s, 3H), 1.75 (s, 9H) APCI-MS (m / z): 322.3 [M-tBu] ＋

[0344] At the same time, 45 mg (0.05 mmol) of 4-methoxy-2-(2-quinolino)-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure was also obtained in a yield of 18.2%.

[0345]

[0346] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 11.23 (br, 1H), 8.47 (d, J = 8.6Hz, 1H), 8.41 (d, J = 8.6Hz, 1H), 8.18 (d, J = 8.6Hz, 1H), 7.95 (d , J=8.3Hz, 1H), 7.87 (ddd, J=8.6, 7.0, 1.5Hz, 1H), 7.72 (ddd, J=8.0, 7.0, 0.9Hz, 1H), 4.23 (s, 3H) APCI-MS (m / z): 322.3 [M+H] ＋

[0347] At the same time, 3 mg (0.008 mmol) of 4-(1,1-dimethylethoxy)-2-(2-quinolino)-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure was also obtained in a yield of 5.3%.

[0348]

[0349] The analysis results were as follows: １ H NMR (400MHz, CDCl ３) δppm: 11.16 (br, 1H), 8.41 (d, J = 8.3Hz, 1H), 8.34 (d, J = 8.6Hz, 1H), 8.18 (d, J = 8.6Hz, 1H), 7.94 (dd, J=8.3, 1.2Hz, 1H), 7.86 (ddd, J=8.6, 7.0, 1.5Hz, 1H), 7.71 (ddd, J=8.3, 7.0, 1.2Hz, 1H), 1.75 (s, 9H) APCI-MS (m / z): 364.3 [M] ＋

[0350] Example 77: Preparation of 6-(1,1-dimethylethoxy)-2-(3-furanyl)-4-methoxy-5-trifluoromethylpyrimidine, 4,6-bis(1,1-dimethylethoxy)-2-(3-furanyl)-5-trifluoromethylpyrimidine, and 4-(1,1-dimethylethoxy)-2-(3-furanyl)-5-(trifluoromethyl)-6(3H)-pyrimidinone. 0.5 g (1.9 mmol) of 6-fluoro-2-(3-furanyl)-4-methoxy-5-trifluoromethylpyrimidine was dissolved in 6.3 ml of THF, and the solution was stirred with 0.6 g (5.8 mmol) of t-BuOK at room temperature for 24 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 180 mg of crude 6-(1,1-dimethylethoxy)-2-(3-furanyl)-4-methoxy-5-trifluoromethylpyrimidine having the following structure.

[0351]

[0352] The analytical results were as follows: APCI-MS (m / z): 361.3 [M-tBu] ＋

[0353] At the same time, 180 mg of a crude product of 4,6-bis(1,1-dimethylethoxy)-2-(3-furanyl)-5-trifluoromethylpyrimidine having the following structure was also obtained.

[0354]

[0355] The analytical results were as follows: APCI-MS (m / z): 347.2 [M-tBu] ＋

[0356] At the same time, 48 mg (0.2 mmol) of 4-(1,1-dimethylethoxy)-2-(3-furanyl)-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure was also obtained in a yield of 8.2%.

[0357]

[0358] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 13.66 (br, 1H), 8.60 (s, 1H), 7.55 (dd, J = 1.5, 1.5Hz, 1H), 7.19 (d, J = 1.8Hz, 1H), 1.67 (s, 9H) APCI-MS (m / z): 247.2 [M-tBu] ＋

[0359] Example 78 Preparation of 2-(3-furanyl)-6-hydroxy-5-(trifluoromethyl)-4(3H)-pyrimidinone 180 mg of crude 4,6-bis(1,1-dimethylethoxy)-2-(3-furanyl)-5-trifluoromethylpyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 6.0 hours. The reaction solution was concentrated to give 200 mg of a mixture of 6-hydroxy-2-(3-furanyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure:

[0360]

[0361] The analytical results were as follows: APCI-MS (m / z): 247.1 [M+H] ＋

[0362] Example 79: Preparation of 4,6-dichloro-2-(3-furanyl)-5-trifluoromethylpyrimidine. 0.2 g of a mixture of 6-hydroxy-2-(3-furanyl)-5-(trifluoromethyl)-4(3H)-pyrimidinone was dissolved in 1.0 ml of toluene and POCl. ３The resulting solution was dissolved in 0.5 ml of toluene and stirred for 6 hours under reflux. After cooling to room temperature, the reaction mixture was added dropwise to ice containing sodium bicarbonate and extracted with ethyl acetate. The mixture was dried over sodium sulfate and then filtered. The filtrate was concentrated and purified using a column to obtain 0.1 g of crude 4,6-dichloro-2-(3-furanyl)-5-trifluoromethylpyrimidine having the following structure:

[0363]

[0364] The analytical results were as follows: APCI-MS (m / z): 284.1 [M+H] ＋

[0365] Example 80: Preparation of 2-(3-furanyl)-4-methoxy-5-(trifluoromethyl)-6(3H)-pyrimidinone 0.3 g of a mixture of 6-(1,1-dimethylethoxy)-2-(3-furanyl)-4-methoxy-5-trifluoromethylpyrimidines was dissolved in 3.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 2.1 hours. The reaction solution was concentrated to obtain 0.3 g of a mixture of 2-(3-furanyl)-4-methoxy-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure:

[0366]

[0367] The analytical results were as follows: APCI-MS (m / z): 261.2 [M+H] ＋

[0368] Example 81 Preparation of 6-chloro-2-(3-furanyl)-4-methoxy-5-(trifluoromethyl)pyrimidine 0.3 g of a mixture of 2-(3-furanyl)-4-methoxy-5-(trifluoromethyl)-6(3H)-pyrimidinone was dissolved in 3.0 ml of toluene and POCl ３ The resulting solution was dissolved in 0.5 ml of toluene and stirred for 6 hours under reflux. After cooling to room temperature, the reaction mixture was added dropwise to ice containing sodium bicarbonate and extracted with ethyl acetate. The mixture was dried over sodium sulfate and then filtered. The filtrate was concentrated and purified using a column to obtain 0.05 g of crude 6-chloro-2-(3-furanyl)-4-methoxy-5-(trifluoromethyl)pyrimidine having the following structure:

[0369]

[0370] The analytical results were as follows: APCI-MS (m / z): 279.6 [M+H] ＋

[0371] Example 82: Preparation of 6-(1,1-dimethylethoxy)-2-[5-(1-methyl-1H-pyrazolyl)]-4-methoxy-5-(trifluoromethyl)pyrimidine and 4,6-bis(1,1-dimethylethoxy)-2-[5-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine 0.1 g (0.4 mmol) of 6-fluoro-4-methoxy-2-[5-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine was dissolved in 1.3 ml of THF, and the solution was stirred with 0.1 g (1.2 mmol) of t-BuOK at room temperature for 24 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then 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 using a column to obtain 96 mg (0.3 mmol) of 6-(1,1-dimethylethoxy)-2-[5-(1-methyl-1H-pyrazolyl)]-4-methoxy-5-(trifluoromethyl)pyrimidine having the following structure. The yield was 60.4%.

[0372]

[0373] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.51 (d, J = 1.8 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 4.37 (s, 3H), 4.07 (s, 3H), 1.66 (s, 9H) APCI-MS (m / z): 331.2 [M+H] ＋

[0374] At the same time, 10 mg of 4,6-bis(1,1-dimethylethoxy)-2-[5-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine having the following structure was also obtained in a yield of 5.6%.

[0375]

[0376] The analysis results were as follows: １ H NMR (400MHz, CDCl ３ ) δppm: 7.50 (d, J=1.8Hz, 1H), 6.99 (d, J=2.1Hz, 1H), 4.35 (s, 3H), 1.65 (s, 18H) APCI-MS (m / z): 373.3 [M+H] ＋

[0377] Example 83 Preparation of 6-hydroxy-2-[5-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)-4(3H)-pyrimidinone 10 mg of 6-bis(1,1-dimethylethoxy)-2-[5-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)pyrimidine was dissolved in 1.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 6.0 hours. The reaction solution was concentrated to give 10 mg of a mixture of 6-hydroxy-2-[5-(1-methyl-1H-pyrazolyl)]-5-(trifluoromethyl)-4(3H)-pyrimidinone having the following structure:

[0378]

[0379] The analytical results were as follows: APCI-MS (m / z): 261.1 [M+H] ＋

[0380] Example 84 Preparation of 2-[5-(1-methyl-1H-pyrazolyl)]-4-methoxy-5-(trifluoromethyl)-6(3H)-pyrimidinone 0.1 g of 6-(1,1-dimethylethoxy)-2-[5-(1-methyl-1H-pyrazolyl)]-4-methoxy-5-(trifluoromethyl)pyrimidine was dissolved in 3.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 2.1 hours. The reaction solution was concentrated to give 0.1 g of a mixture of 2-[5-(1-methyl-1H-pyrazolyl)]-4-methoxy-5-(trifluoromethyl)-6(3H)-pyrimidinone having the following structure.

[0381]

[0382] The analytical results were as follows: APCI-MS (m / z): 275.1 [M+H] ＋

[0383] <Evaluation Test Against Rice Blast (500 ppm)> The fluorine-containing pyrimidine compounds (drugs) prepared in Examples 14, 30, and 48 were dissolved in DMSO to a concentration of 50,000 ppm. 30 μL of each drug and DMSO were added to 3 mL of dissolved PDA medium (potato dextrose agar medium), stirred with a pipette, and placed in a well of a 6-well plate to solidify (three replicates per well). Rice blast fungus (Pyricularia oryzae) grown in PDA medium was excised together with the medium using a 0.4 cm diameter bio-punch. These were placed in the center of PDA medium in a 6-well plate containing the drug and grown at 27°C. After 3 days, the diameter of the hyphal septa was measured, and the hyphal elongation inhibition rate (%), which is the control value, was calculated as a ratio of the diameter in DMSO. This evaluation test was performed three times, and the average of the measured control values ​​is shown in Table 1.

[0384]

[0385] <Evaluation test against gray mold (500 ppm)> The fluorine-containing pyrimidine compound (drug) prepared in Example 14 was dissolved in DMSO and diluted to a concentration of 50,000 ppm. 30 μL of the diluted DMSO solution was added to 3 ml of dissolved PDA medium, stirred with a pipette, and placed in a well of a 6-well plate to solidify (final concentration 500 ppm, 3 replicates each). Gray mold fungus (Botrytis cinerea A118) grown in PDA medium was cut out together with the medium using a 0.4 cm diameter bio-punch, and these were placed in the center of PDA medium in a 6-well plate containing DMSO solution and grown at 27 ° C. After 2 days, the diameter of the hyphae was measured, and the inhibition rate of hypha elongation (%) was calculated as a percentage of the diameter in DMSO, which is the control value. This evaluation test was performed three times, and the average of each measured control value is shown in Table 2.

[0386]

[0387] <Evaluation Test Against Rice Sheath Blight (500 ppm)> The fluorine-containing pyrimidine compound (drug) prepared in Example 14 was dissolved in DMSO and diluted to a concentration of 50,000 ppm. 30 μL of the diluted DMSO solution was added to 3 ml of PDA medium, stirred with a pipette, and placed in a well of a 6-well plate to solidify (final concentration 500 ppm, 3 replicates per well). Rice sheath blight fungus (Rhizoctonia solni AG-1 1A) grown in PDA medium was excised together with the medium using a 0.4 cm diameter bio-punch. These were placed in the center of PDA medium in a 6-well plate containing DMSO solution and grown at 27°C. After 2 days, the diameter of the hyphal septum was measured, and the inhibition rate (%) of hyphal elongation, which is the control value, was calculated as a ratio of the diameter in DMSO. This evaluation test was performed three times, and the average of the measured control values ​​is shown in Table 3.

[0388]

[0389] From the above, it can be seen that the fluorine-containing pyrimidine compounds of the present invention exhibit a fungicidal effect against pathogens of rice blast, rice sheath blight and gray mold, and are therefore useful as biologically active compounds, particularly as agents for controlling harmful fungi.

Claims

A fluorine-containing pyrimidine compound represented by the following general formula (1): (In the above general formula (1), Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a cyano group, a nitro group, -OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents Z is a halogen atom or -OA ３ represents Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl); n is an integer from 1 to 4, L is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents A １ 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, In L and Y, each A １ , A ２ , l and m may be the same or different; When n is an integer of 2, 3, or 4, each L may be the same or different.

2. The fluorine-containing pyrimidine compound according to claim 1, wherein L is a hydrogen atom. 　 A fluorine-containing pyrimidinone compound represented by the following general formula (2): (In the above general formula (2), R represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms, Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl), n is an integer from 1 to 4, L is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents A １ and A ２ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, When n is an integer of 2, 3, or 4, each L may be the same or different. 　 The fluorine-containing pyrimidinone compound according to claim 3, wherein L is a hydrogen atom. 　 A fluorine-containing pyrimidine compound represented by the following general formula (3): (In the above general formula (3), Z is a halogen atom or -OA ３ represents X is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ or -NA １ A ２ represents k represents an integer of 0 to 3; Het represents a 5- or 6-membered heteroaryl or fused heterocycle containing 1 to 5 heteroatoms (except when Het is pyridyl); L is a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C ｌ F ２ｌ＋１ (l is an integer of 1 to 10), a nitro group, —OA １ , -SO ｍ A １ (m is an integer of 1 to 3), -SA １ , -NA １ A ２ , -B(OA １ ) (OA ２ ), -COA １ , -COOA １ , or -CONA １ A ２ represents n is an integer from 1 to 4, 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, In L and X, each A １ , A ２ , l and m may be the same or different; When k is an integer of 2 or 3, each X may be the same or different from each other, and when n is an integer of 2, 3, or 4, each L may be the same or different from each other. 　 A fungicide comprising the fluorine-containing pyrimidine compound according to claim 1 or 5.

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