Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
  • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
  • A01P3/00—Fungicides

Definitions

• the present invention relates to a fluorinated pyrimidine compound and a fluorinated pyrimidinone compound.
• fluorine-containing pyrimidine compounds have various biological activities.
• compounds having a pyridine ring at the 2-position of the pyrimidine ring and a trifluoromethyl group at the 5-position are expected to be used in the fields of pharmaceuticals and agrochemicals.
• Patent Documents 1 and 6 report that 2- (4-pyridyl) -5-trifluoromethylpyrimidine derivatives have human melanin aggregation hormone inhibitory activity and acetyl-CoA carboxylase 2 inhibitory activity. .. In Patent Documents 2, 4, 5 and 7, 2- (3-pyridyl) -5-trifluoromethylpyrimidine derivatives have bactericidal activity, insecticidal activity, orexin receptor inhibitory activity, focal kinase inhibitory activity and acetyl-CoA carboxylase 2 inhibitory activity. It has been reported to have.
• Patent Documents 2 and 3 report that 2- (2-pyridyl) -5-trifluoromethylpyrimidine derivatives have bactericidal activity, insecticidal activity and herbicidal activity. From this point of view, we are interested in introducing substituents to the 4- and 6-positions of the pyrimidine ring in anticipation of further improvement in activity.
• Patent Document 8 reports that pyridylpyrimidine derivatives having various substituents show prophylactic or therapeutic control effects on many plant diseases such as rice blast, wheat eye print disease, and apple scab. Has been done.
• a fluorine-containing pyrimidine having a fluorine-containing substituent at the 5-position of the pyrimidine ring, a heterocycle as a substituent at the 2-position, and a substituent at the 4-position and the 6-position is difficult, and such a fluorine-containing pyrimidine compound has not been reported.
• the fluorine-containing pyrimidine compound is expected to have various biological activities, and a novel fluorine-containing pyrimidine compound having a substituent at the 4-position and the 6-position of the pyrimidine ring and a heterocycle as a substituent at the 2-position is It was desired.
• the present invention provides a novel fluorine-containing pyrimidine compound and a fluorine-containing pyrimidinone compound having a substituent at the 4-position and the 6-position of the pyrimidine ring and a pyridine ring structure as a substituent at the 2-position, which have not been known in the past. It is something to do.
• the fluorine-containing pyrimidine compound according to the embodiment of the present invention is represented by the following general formula (1), (2), or (3).
• W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1-10), a nitro group, -OA 1, -SO m a 1 (m is an integer of 1 ⁇ 3), - SA 1 , -NA 1 a 2, -B (OA 1) (OA 2), - COA 1, -COOA 1 or-ConA 1, Represents
• a 2 Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n 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 ⁇ 3),
• the fluorine-containing pyrimidinone compound according to the embodiment of the present invention is represented by the following general formula (31), (32), or (33).
• R 3 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms.
• W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1-10), a nitro group, -OA 1, -SO m a 1 (m is an integer of 1 ⁇ 3), - SA 1 , -NA 1 a 2, -B (OA 1) (OA 2), - COA 1, -COOA 1 or-ConA 1, Represents A 2 A 1 and A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. )
• the W and X are hydrogen atoms.
• the fluorine-containing pyrimidine compound of the present embodiment is represented by the following general formula (1), (2), or (3).
• W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1-10), a nitro group, -OA 1, -SO m a 1 (m is an integer of 1 ⁇ 3), - SA 1 , -NA 1 a 2, -B (OA 1) (OA 2), - COA 1, -COOA 1 or-ConA 1, Represents
• a 2 Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1 to 10), a cyano group, a nitro group, -OA 1, -SA 1, -SO m
• the halogen atom is F, Cl, Br or I, and preferably F or Cl.
• a 3 represents a hydrocarbon group having 1 to 12 carbon atoms, and is not particularly limited as long as it is a hydrocarbon group having 1 to 12 carbon atoms and consisting of a carbon atom and a hydrogen atom.
• Examples thereof include chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups.
• the chain hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 1 to 12, and may be a linear hydrocarbon group or a branched chain hydrocarbon group.
• the aromatic hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 6 to 12, and even if it is an aromatic hydrocarbon group having a substituent, it is an aromatic hydrocarbon group having no substituent. May be good.
• the aromatic hydrocarbon group may have a condensed polycyclic structure.
• the alicyclic hydrocarbon group is not particularly limited as long as the total number of carbon atoms is 3 to 12, and even if the alicyclic hydrocarbon group has a substituent, the alicyclic hydrocarbon group does not have a substituent. May be. Further, the alicyclic hydrocarbon group may have a bridging ring structure.
• Examples of the chain hydrocarbon group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a ter-butyl group, a pentyl group and a hexyl group.
• Alkyl groups such as heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group;
• An alkenyl group such as an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, a dodecenyl group;
• Examples thereof include an alkynyl group such as an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a nonynyl group, a decynyl
• Examples of the aromatic hydrocarbon group include a phenyl group, a benzyl group, a tolyl group, and a naphthyl group.
• the trill group may be any of an o-tolyl group, an m-tolyl group and a p-tolyl group, and a p-tolyl group is preferable.
• Examples of the alicyclic hydrocarbon group include a saturated or unsaturated cyclic hydrocarbon group, and examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, an adamantyl group, and a norbornyl group.
• the groups can be mentioned.
• W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1-10), a nitro group, a boronic acid group, -OA 1, -SO m a 1 (m is an integer of 1 ⁇ 3), - SA 1 , -NA 1 a 2, represents -COOA 1 or-ConA 1 a 2,, a hydrogen atom, a halogen atom or It is preferable to represent a hydrocarbon group having 1 to 10 carbon atoms, and it is particularly preferable to represent a hydrogen atom. W and X may be the same or different, respectively.
• the halogen atom is F, Cl, Br or I, and preferably F or Cl.
• a hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is a hydrocarbon radical consisting of carbon and hydrogen atoms, e.g., carbon in the hydrocarbon groups listed above A 3 It can be a hydrocarbon group having a number of 1 to 10.
• —C n F 2n + 1 is not particularly limited as long as it is a perfluoroalkyl group composed of a carbon atom and a fluorine atom, and may be linear or branched. Further, n is an integer of 1 to 10, and preferably an integer of 1 to 3.
• -OA 1, -SO m A 1, -SA 1, COA 1, A 1 included in -COOA 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. If A 1 represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10. Further, m is an integer of 1 to 3, and is preferably 1.
• a 1 and A 2 contained in -NA 1 A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• a 1 and A 2 may be the same or different from each other. If A 1 and A 2 each represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10.
• a 1 and A 2 contained in -B (OA 1 ) (OA 2 ) each independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• a 1 and A 2 may be the same or different from each other. If A 1 and A 2 each represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10.
• a 1 and A 2 contained in -CONA 1 A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, respectively.
• a 1 and A 2 may be the same or different from each other. If A 1 and A 2 each represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10.
• Y is a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n 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 ⁇ 3), - SA 1 , -NA 1 a 2, -B (OA 1) (OA 2), - COA 1, represents -COOA 1 or -CONA 1 a 2,, halogen atom , -OA 1, -SO m a 1 ( m is an integer of 1 ⁇ 3), - SA 1 , or preferably represents a -NA 1 a 2.
• the halogen atom is F, Cl, Br or I, and preferably F or Cl.
• a hydrocarbon group having 1 to 10 carbon atoms is not particularly limited as long as it is a hydrocarbon radical consisting of carbon and hydrogen atoms, e.g., carbon atoms in the hydrocarbon group listed above A 3 It can be 1 to 10 hydrocarbon groups.
• Y -C n F 2n + 1 is not particularly limited as long as it is a perfluoroalkyl group consisting of carbon atoms and fluorine atoms, be linear or may be branched. Further, n is an integer of 1 to 10, and preferably an integer of 1 to 3.
• a 1 included in -COOA 1 represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. If A 1 is a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10. Further, m is an integer of 1 to 3, preferably 1 or 2.
• a 1 and A 2 contained in -NA 1 A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• a 1 and A 2 may be the same or different from each other. If A 1 and A 2 each represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10.
• a 1 and A 2 contained in ⁇ B (OA 1 ) (OA 2 ) independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• a 1 and A 2 may be the same or different from each other. If A 1 and A 2 each represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10.
• a 1 and A 2 contained in -CONA 1 A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• a 1 and A 2 may be the same or different from each other. If A 1 and A 2 each represents a hydrocarbon group having 1 to 10 carbon atoms, for example, the number of carbon atoms in the hydrocarbon group listed above A 3 can be a hydrocarbon group having 1 to 10.
• the fluorine-containing pyrimidine compound in the present embodiment has a specific substituent (pyridyl group) at the 2-position of the pyrimidine ring and a specific substituent (Z, -CF 3 ) at the 6-position and the 5-position of the pyrimidine ring. It can have an excellent effect from the viewpoint of structural expandability.
• the fluorine-containing pyrimidine compound in the present embodiment can be expected to have desired biological activity (for example, inhibitory activity of hormones and enzymes, fungicidal activity, insecticidal activity, herbicidal activity), and for example, a compound having pharmacological activity or an intermediate thereof.
• the bactericidal agent containing a fluorine-containing pyrimidine compound in the present invention is useful as a substance showing a sterilizing effect on the pathogenic bacterium of powdery mildew of cucumber.
• the pyridine ring structure located on the 2-position of the pyrimidine ring may or may not have a substituent.
• the fluorine-containing pyrimidine compound in the present embodiment is imparted with further properties.
• the fluorine-containing pyrimidine compound in the present embodiment is useful in the field of electronic materials such as organic semiconductors and liquid crystals.
• Y 3a is -NA 1 A 2 , OA 1 , SA 1 , a hydrocarbon group having 1 to 10 carbon atoms, or a halogen atom different from Y 1a, and is A 1 and A 2.
• Y 1a Independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• Y 3c is -NA 1 A 2 , OA 1 or SA 1
• Z b represents a halogen atom or OA 1.
• a 1 and A 2 are independent of each other.
• Y 3a is -NA 1 A 2 , OA 1 , SA 1 , a hydrocarbon group having 1 to 10 carbon atoms, or a halogen atom different from Y 1a, and is A 1 and A 2.
• Y 3a is -NA 1 A 2 , OA 1 , SA 1 , a hydrocarbon having 1 to 10 carbon atoms or a halogen atom different from Y 1a , and A 1 and A 2 are. Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms.
• the halogen atom of Z b is substituted to obtain the fluorine-containing pyrimidine compound of the following general formula (15-3) (step (c-5)).
• Y 3c is -NA 1 A 2 , OA 1 or SA 1
• Z b represents a halogen atom or OA 1.
• a 1 and A 2 are independent of each other.
• Y 2b is a halogen atom different from -NA 1 A 2 , OA 1 , SA 1 or Y 2a , and A 1 and A 2 are independently hydrogen atoms or Represents a hydrocarbon group having 1 to 10 carbon atoms.
• Y 2b is a halogen atom different from -NA 1 A 2 , OA 1 , SA 1 or Y 2a , and A 1 and A 2 are independently hydrogen atoms or Represents a hydrocarbon group having 1 to 10 carbon atoms.
• Y 2b is a halogen atom different from -NA 1 A 2 , OA 1 , SA 1 or Y 2a , and A 1 and A 2 are independently hydrogen atoms or Represents a hydrocarbon group having 1 to 10 carbon atoms.
• R and R 1 represent a hydrocarbon group having 1 to 12 carbon atoms.
• R 2 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms.
• W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1-10), a nitro group, -OA 1, -SO m a 1 (m is an integer of 1 ⁇ 3), - SA 1 , -NA 1 a 2, -B (OA 1) (OA 2), - COA 1, -COOA 1 or-ConA 1, Represents A 2 Y 1 is a hydrocarbon group of 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1 to 10), a cyano group, a nitro group, -OA 1, is -SO m A 1 (m 1 to 3.
• a 1 and A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and each of them 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.
• a fluorine-containing pyrimidine compound is obtained through a two-step step, and in the first step, a pyridylpyrimidineone derivative is obtained as an intermediate product.
• a pyridylpyrimidinone derivative corresponds to a fluorine-containing pyrimidinone compound represented by the following general formula (31), (32) or (33). Since the fluorinated pyrimidinone compound in the present invention is an intermediate product of the above-mentioned fluorinated pyrimidine compound in the present invention, it is useful as an intermediate of a substance exhibiting desired biological activity of the fluorinated pyrimidine compound in the present embodiment.
• R 3 represents a hydrogen atom or a hydrocarbon group having 1 to 12 carbon atoms.
• W and X are each independently a hydrogen atom, a halogen atom, a hydrocarbon group having 1 to 10 carbon atoms, -C n F 2n + 1 (where n is an integer of 1-10), a nitro group, -OA 1, -SO m a 1 (m is an integer of 1 ⁇ 3), - SA 1 , -NA 1 a 2, -B (OA 1) (OA 2), - COA 1, -COOA 1 or-ConA 1, Represents A 2 A 1 and A 2 independently represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms. )
• each of W and X is the same as that defined in the fluorine-containing pyrimidine compounds represented by the above-mentioned general formulas (1) to (3), respectively.
• W and X may be the same or different, respectively.
• each of Z and Z 2 is the same as Z defined in the fluorine-containing pyrimidine compounds represented by the above general formulas (1) to (3), respectively.
• the halogen atom and -OA 3 defined in the definition of Z or Z 2 are the same as those defined in the fluorine-containing pyrimidine compounds represented by the above-mentioned general formulas (1) to (3).
• Y 1 is as defined in Y in the fluorine-containing pyrimidine compound represented by the above-mentioned general formula (1) to (3) (excluding a halogen atom) is the same as, in the above general formula with Y 2, a halogen atom as defined in the definition of Y 2 is defined in the fluorine-containing pyrimidine compound represented by the above-mentioned general formula (1) to (3) It is the same as what was done.
• R and R 1 are the same as those defined in A 3
• R 2 are each as R 3 defined in the fluorine-containing pyrimidinone compound represented by the general formula (31) - (33) the same
• R 3 hydrocarbon group having 1 to 12 carbon atoms which in defined in definition is the same as a 3 defined in the fluorinated pyrimidines represented by the above-mentioned general formula (1) to (3).
• R, R 1 , R 2 and R 3 preferably represent an alkyl group having 1 to 10 carbon atoms.
• W and X preferably represent a hydrogen atom, a halogen atom or a hydrocarbon group having 1 to 10 carbon atoms, and particularly preferably represent a hydrogen atom.
• Such hydrocarbon groups include, for example, alkyl having a carbon number of 1 to 10 in the hydrocarbon groups listed in A 3 In the fluorine-containing pyrimidine compound represented by the above-mentioned general formula (1) to (3) Can be the basis.
• the nucleophilic substitution reaction using the above nucleophile is carried out, for example, in an organic solvent (tetrahexyl, dimethylformamide, dimethylsulfoxide, sulfolane, acetone, diethyl ether, etc.) and a nucleophile (nalium methoxydo, sodium ethoxydo, etc.).
• the reaction is carried out at 0 to 100 ° C. in the presence of potassium tert-butoxide, sodium cyanide, potassium cyanide, potassium fluoride, or an alcohol, amine, thiol, etc. treated with a base such as sodium hydride.
• the electrophilic addition reaction using the above electrophile is carried out, for example, in an organic solvent (acetic acid, chloroform, dichloromethane, dimethylformamide, acetonitrile, etc.) and an electrophile (hydrogen peroxide, peracetic acid, metachloroperbenzoic acid, hyper). It is carried out by reacting at 0 to 65 ° C. in the presence of potassium manganate or the like).
• the above hydrolysis reaction can be carried out in the presence of an acid or a base according to a method considered in general synthetic organic chemistry.
• an acid or a base and a solvent can be used for this reaction.
• the acid and base are not particularly limited as long as the hydrolysis reaction proceeds, and for example, an inorganic acid such as hydrochloric acid and sulfuric acid; an organic acid such as acetic acid and trifluoroacetic acid; lithium hydroxide, sodium hydroxide and hydroxylation.
• Alkaline metal hydroxides such as potassium; Alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; Alkaline metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; Alkaline soil such as calcium carbonate and barium carbonate
• the solvent is not particularly limited as long as the hydrolysis reaction proceeds, and any solvent may be used as long as it is inert to the reaction.
• Such a solvent examples include alcohols such as methanol, ethanol and isopropyl alcohol; aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, dimethylacetamide and sulfolane; non-polar solvents such as dichloromethane; One or two or more of ethers such as diethyl ether, tert-butylmethyl ether, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane; etc. can be appropriately selected and mixed and used. ..
• the reaction temperature is usually 0 to 150 ° C., and the reaction time is usually 0.5 to 72 hours.
• halogenating agent examples include thionyl chloride, phosgene, phosphorus oxychloride, phosphorus pentachloride, phosphorus oxybromide, phosphorus tribromide and the like.
• the reaction temperature is typically 50 to 150 ° C.
• the reaction time is 1 to 10 hours
• the amount of the halogenating agent (reagent) applied to the reaction is pyridyl. It is usually 1 to 10 equivalents with respect to 1 equivalent of a pyrimidine derivative (fluorinated pyrimidinone compound).
• the reaction with the halogenating agent does not necessarily require a solvent, but is generally carried out in the presence of a solvent.
• the solvent that can be used include aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as chlorobenzene.
• room temperature is within the range of 20 ° C ⁇ 5 ° C.
• Example 1 ⁇ Production of 4,6-dimethoxy-2- (4-pyridyl) -5-trifluoromethylpyrimidine> Dissolve 0.11 g (0.40 mmol) of 4-fluoro-6-methoxy-2- (4-pyridyl) -5-trifluoromethylpyrimidine in 1.0 ml of methanol, and add 1.0 ml of 28% sodium methoxide methanol solution. In addition, it was stirred at room temperature for 1 day. Then, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate.
• Example 2 ⁇ Production of 6-Methoxy-4-phenoxy-2- (4-pyridyl) -5-trifluoromethylpyrimidine> 0.04 g (0.46 mmol) of phenol was dissolved in 1.5 ml of tetrahydrofuran (THF), and 0.05 g (0.47 mmol) of potassium tert-butoxide and 4-fluoro-6-methoxy-2- (4-pyridyl)- 0.11 g (0.39 mmol) of 5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate.
• THF tetrahydrofuran
• Example 4 ⁇ Production of 6-methoxy-N-propyl-2- (4-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine> 0.03 g (0.35 mmol) of n-propylamine was dissolved in 5.0 ml of DMF, 0.02 g (0.53 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 50 minutes. Then, 0.10 g (0.35 mmol) of 4-fluoro-6-methoxy-2- (4-pyridyl) -5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 16.7 hours and at 70 ° C. for 8 hours.
• Example 6 ⁇ Production of 6-Methoxy-N-Phenyl-2- (4-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine> 0.04 g (0.39 mmol) of aniline was dissolved in 5.0 ml of DMF, 0.02 g (0.58 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Then, 0.10 g (0.37 mmol) of 4-fluoro-6-methoxy-2- (4-pyridyl) -5-trifluoromethylpyrimidine was added, and the mixture was stirred at room temperature for 16.7 hours and at 70 ° C. for 8 hours.
• Example 7 ⁇ Manufacturing of 6-methoxy-2- (3-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone> Dissolve 0.11 g (0.39 mmol) of 4-fluoro-6-methoxy-2- (3-pyridyl) -5-trifluoromethylpyrimidine in 1.0 ml of DMF and 1.0 ml of water, add 5 drops of triethylamine, and 70 The mixture was stirred at ° C. for 7 hours and at 80 ° C. for 16 hours.
• Step 2 Production of 4-Chloro-6-methoxy-2- (4-pyridyl) -5-trifluoromethylpyrimidine 6-methoxy-2- (4-pyridyl) -5- (4-pyridyl) obtained in step 1) 0.105 g of a crude product of trifluoromethyl) -4 (3H) -pyrimidineone was dissolved in 1.0 ml of POCl 3 and stirred at 60 ° C. for 4 hours, 100 ° C. for 1.5 hours and 110 ° C. for 17 and a half hours. After air cooling to room temperature, the reaction solution was added dropwise to ice, extracted with ethyl acetate, and the organic phase was dried over sodium sulfate.
• Step 2 Production of 4,6-dichloro-2- (4-pyridyl) -5-trifluoromethylpyrimidine 6-Hydroxy-2- (4-pyridyl) -5- (trifluoro) obtained in step 1) 0.10 g (0.38 mmol) of the crude product of methyl) -4 (3H) -pyrimidineone was dissolved in 1.0 ml of POCl 3 and stirred under heated reflux conditions for 1 hour. After air-cooling to room temperature, the reaction solution was added dropwise to ice, sodium hydrogen carbonate was added and neutralized, the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate.
• Example 13 ⁇ 6-Methoxy-4- [(4-Methylphenyl) sulfinyl] -2- (4-pyridyl) -5-trifluoromethylpyrimidine and 6-methoxy-4-[(4-methylphenyl) sulfonyl] -2- Production of (4-pyridyl) -5-trifluoromethylpyrimidine> To 0.10 g (0.25 mmol) of 6-methoxy-4-[(4-methylphenyl) thio] -2- (4-pyridyl) -5-trifluoromethylpyrimidine obtained in Example 12, 1.0 ml of acetic acid , 6 drops of 30% hydrogen peroxide solution was added, and the mixture was stirred at room temperature for 30 hours.
• Example 21 ⁇ Production of 4,6-dibromo-2- (4-pyridyl) -5-trifluoromethylpyrimidine> 0.03 g of the crude product of 6-hydroxy-2- (4-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone obtained in step 1) of Example 11 was added to 1.0 ml of dichloroethane. After dissolution, 2.0 g of POBr 3 was added, and the mixture was stirred at 65 ° C. for 40 minutes, 80 ° C. for 2 hours, 90 ° C. for 8 hours, and 110 ° C. for 9.5 hours.
• reaction solution was added dropwise to ice and extracted with ethyl acetate. After drying with magnesium sulfate, it was filtered. After concentrating the filtrate, column purification was performed to obtain 4,6-dibromo-2- (4-pyridyl) -5-trifluoromethylpyrimidine having a trace amount of the following structure.
• Example 24 ⁇ Production of 6-chloro-4-fluoro-2- (4-pyridyl) -5-trifluoromethylpyrimidine> 0.10 g (0.35 mmol) of 4,6-dichloro-2- (4-pyridyl) -5-trifluoromethylpyrimidine obtained in Example 11 and fluoride were added to 25 ml of sulfolane dried under reduced pressure using 10 ml of toluene. 0.02 g (0.34 mmol) of potassium was added, and the mixture was stirred at 148 ° C. for 18.8 hours. Then, 0.02 g (0.34 mmol) of potassium fluoride was further added, and the mixture was stirred at 148 ° C.
• Example 28 ⁇ Production of 6-chloro-N- (4-methylphenyl) -2- (4-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine> 0.04 g (0.36 mmol) of p-toluidine was dissolved in 1.1 ml of DMF, 0.02 g (0.45 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 30 minutes. 0.10 g (0.34 mmol) of 6-dichloro-2- (4-pyridyl) -5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 18.3 hours.
• Example 30 ⁇ Manufacturing of 6-hydroxy-2- (2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone> 2.34 g (6.34 mmol) of 4,6-bis (1,1-dimethylethoxy) -2- (2-pyridyl) -5-trifluoromethylpyrimidine obtained in Example 29 was dissolved in 10.5 ml of dichloromethane. Then, 10.5 ml of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 15.7 hours, the reaction solution was concentrated, washed and filtered with ethyl acetate, and 6-hydroxy-2- (2-) having the following structure. Pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone 1.55 g (6.01 mmol) was obtained. The yield was 95%.
• TFA trifluoroacetic acid
• Example 31 ⁇ Production of 4,6-dichloro-2- (2-pyridyl) -5-trifluoromethylpyrimidine> 1.00 g (3.88 mmol) of 6-hydroxy-2- (2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone obtained in Example 30 was dissolved in 10.0 ml of POCl 3. , 3 drops of DMF were added, and the mixture was stirred under heating and reflux conditions for 6 hours. After cooling to room temperature, the reaction solution was added dropwise to ice containing baking soda to neutralize the mixture, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the mixture was filtered. The filtrate was concentrated and column-purified to obtain 0.98 g (3.34 mmol) of 4,6-dichloro-2- (2-pyridyl) -5-trifluoromethylpyrimidine having the following structure. The yield was 86%.
• Example 32 ⁇ Production of 6-chloro-N- (4-methylphenyl) -2- (2-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine>
• Example 34 Manufacturing of 6-hydroxy-2- (3-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone> 2.22 g (6.02 mmol) of 4,6-bis (1,1-dimethylethoxy) -2- (3-pyridyl) -5-trifluoromethylpyridin obtained in Example 33 was dissolved in 10.0 ml of dichloromethane. Then, 10.0 ml of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 20.4 hours.
• TFA trifluoroacetic acid
• reaction solution is concentrated, washed and filtered with ethyl acetate, and crudely produced 6-hydroxy-2- (3-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone having the following structure. I got something.
• Example 35 ⁇ Production of 4,6-dichloro-2- (3-pyridyl) -5-trifluoromethylpyrimidine> 1.0 g of the crude product of 6-hydroxy-2- (3-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone obtained in Example 34 was dissolved in 10.0 ml of POCl 3. Three drops of DMF were added, and the mixture was stirred under heating and reflux conditions for 6 hours. After cooling to room temperature, the reaction solution was added dropwise to ice containing baking soda to neutralize the mixture, and the mixture was extracted with ethyl acetate. After drying over sodium sulfate, the mixture was filtered. The filtrate was concentrated and column-purified to obtain 0.63 g (2.16 mmol) of 4,6-dichloro-2- (3-pyridyl) -5-trifluoromethylpyrimidine having the following structure.
• Example 36 ⁇ Production of 6-chloro-N- (4-methylphenyl) -2- (3-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine>
• Example 40 ⁇ Production of 6-Methoxy-2- (2-Methoxy-5-pyridyl) -4- (Phenylmethoxy) -5-trifluoromethylpyrimidine> Dissolve 0.05 g (0.5 mmol) of benzyl alcohol in 3.0 ml of DMF, add 0.03 g (0.7 mmol) of sodium hydride, stir at room temperature for 30 minutes, cool to 0 ° C., and 4-fluoro-. 0.09 g (0.3 mmol) of 6-methoxy-2- (6-methoxy-3-pyridyl) -5-trifluoromethylpyridine was added, and the mixture was stirred at room temperature for 19 hours.
• Example 59 ⁇ Production of 6-Hydroxy-2- (6-n-propyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone> 0.4 g (0.9 mmol) of 4,6-bis (1,1-dimethylethoxy) -2- (6-n-propyl-2-pyridyl) -5-trifluoromethylpyridine obtained in Example 58 was added. It was dissolved in 0.9 ml of dichloromethane, 0.9 ml of trifluoroacetic acid (TFA) was added, and the mixture was stirred at room temperature for 3 hours.
• TFA trifluoroacetic acid
• reaction solution is concentrated, washed and filtered with ethyl acetate, and 6-hydroxy-2- (6-n-propyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H) having the following structure. ) -0.4 g of a crude product of pyrimidinone was obtained.
• Example 60 ⁇ Production of 4,6-dichloro-2- (6-n-propyl-2-pyridyl) -5-trifluoromethylpyrimidine> Toluene 1. It was dissolved in 8 ml and 0.4 ml of POCl 3 and stirred under heating and reflux conditions for 6 hours. After air cooling to room temperature, the reaction solution was added dropwise to ice containing baking soda and extracted with ethyl acetate. Then, it was dried over sodium sulfate and filtered.
• Example 61 ⁇ Production of 6-methoxy-2- (6-n-propyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone> 0.04 g (0.1 mmol) of 4- (1,1-dimethyletoshiki) -6-methoxy-2- (6-n-propyl-2-pyridyl) -5-trifluoromethylpyrimidine obtained in Example 58.
• Example 62 ⁇ Production of 4-chloro-6-methoxy-2- (6-n-propyl-2-pyridyl) -5-trifluoromethylpyrimidine> Toluene 1. It was dissolved in 0 ml and 0.04 ml of POCl 3 and stirred under heating and reflux conditions for 6 hours. After air cooling to room temperature, the reaction solution was added dropwise to ice containing baking soda and extracted with ethyl acetate. Then, it was dried over sodium sulfate and filtered.
• Example 63 ⁇ Production of 6-chloro-2- (4-pyridyl) -4-[(4-methylphenyl) thio] -5-trifluoromethylpyrimidine> 0.16 g (0.6 mmol) of 4,6-dichloro-2- (4-pyridyl) -5-trifluoromethylpyrimidine obtained by repeating Example 11 was dissolved in 3.0 ml of THF, and 0.06 g of triethylamine ( 0.6 mmol) and 0.05 g (0.4 mmol) of p-toluenethiol were added, and the mixture was stirred at room temperature for 24.3 hours.
• Example 64 ⁇ Production of 6-chloro-4-hydroxy-2- (2-pyridyl) -5- (trifluoromethyl) -pyrimidine> 0.05 g (0.2 mmol) of 4,6-dichloro-2- (2-pyridyl) -5-trifluoromethylpyrimidine obtained in Example 31 was dissolved in 1.0 ml of a 1N NaOH aqueous solution, and 2. The mixture was stirred for 3 hours. The reaction solution is neutralized with a 10% aqueous sulfuric acid solution, the precipitated crystals are washed with water, and 6-chloro-4-hydroxy-2- (2-pyridyl) -5- (trifluoromethyl)-having the following structure is used. 0.02 g (0.06 mmol) of pyrimidine was obtained. The yield was 39%.
• Example 65 ⁇ Production of 6-chloro-2- (2-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine> 0.05 g (0.2 mmol) of 4,6-dichloro-2- (2-pyridyl) -5-trifluoromethylpyrididine obtained in Example 31 was dissolved in 1.0 ml of THF, and 0.02 g (0.) of triethylamine was dissolved. 2 mmol) and 7 drops of 2M ammonia-methanol solution were added, and the mixture was stirred at room temperature for 4 hours.
• Example 66 ⁇ Production of 4-chloro-6-ethoxy-2- (2-pyridyl) -5-trifluoromethylpyrimidine> 0.05 g (0.2 mmol) of 4,6-dichloro-2- (2-pyridyl) -5-trifluoromethylpyridine obtained in Example 31 was dissolved in 1.7 ml of THF, and 0.01 g of sodium ethoxide (. 0.2 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate.
• Example 70 ⁇ Production of 6-methoxy-2- (5-methyl-2-pyridyl) -4-[(4-methylphenyl) thio] -5-trifluoromethylpyrimidine> Dissolve 0.05 g (0.4 mmol) of p-toluenethiol in 3.0 ml of DMF, add 0.02 g (0.6 mmol) of sodium hydride, stir at room temperature for 30 minutes, cool to 0 ° C., and 6-. Fluoro-4-methoxy-2- (5-methyl-2-pyridyl) -5-trifluoromethylpyridine 0.1 g (0.4 mmol) was added, and the mixture was stirred at room temperature for 20 hours.
• Example 74 Manufacturing of 6-hydroxy-2-5- (trifluoromethyl)-(2-trifluoromethyl-5-pyridyl) -4 (3H) -pyrimidinone> 0.2 g (0.5 mmol) of 4,6-bis (1,1-dimethylethoxy) -5-trifluoromethyl-2- (2-trifluoromethyl-5-pyridyl) pyrimidine obtained in Example 73 was added. It was dissolved in 0.5 ml of dichloromethane, 0.5 ml of TFA was added, and the mixture was stirred at room temperature for 3.7 hours.
• reaction solution is concentrated, washed and filtered with ethyl acetate, and 6-hydroxy-2-5- (trifluoromethyl)-(2-trifluoromethyl-5-pyridyl) -4 (3H) having the following structure. ) -0.2 g of a crude product of pyrimidinone was obtained.
• reaction solution is concentrated, washed and filtered with ethyl acetate, and has the following structure: 6-hydroxy-2- (5-methyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H)-. 0.3 g of a crude purified product of pyrimidinone was obtained.
• Example 77 ⁇ Production of 4,6-dichloro-2- (5-methyl-2-pyridyl) -5-trifluoromethylpyrimidine> 0.3 g of the crude product of 6-hydroxy-2- (5-methyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone obtained in Example 76 was added to 1.7 ml of toluene. It was dissolved in 0.4 ml of POCl 3 and stirred under heating and reflux conditions for 6 hours. After air cooling to room temperature, the reaction solution was added dropwise to ice containing baking soda and extracted with ethyl acetate. After drying over sodium sulfate, the mixture was filtered.
• the filtrate is concentrated and column-purified to obtain 0.2 g (0.6 mmol) of 4,6-dichloro-2- (5-methyl-2-pyridyl) -5-trifluoromethylpyrimidine having the following structure. rice field. The yield was 73% in the two steps.
• Example 78 ⁇ Manufacturing of 6-methoxy-2- (5-methyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone> 0.2 g (0.) of 4- (1,1-dimethylethiki) -6-methoxy-2- (5-methyl-2-pyridyl) -5-trifluoromethylpyrimidine obtained by carrying out Example 75. 5 mmol) was dissolved in 2.0 ml of dichloromethane, 1.0 ml of TFA was added, and the mixture was stirred at room temperature for 12.8 hours.
• reaction solution is concentrated, washed and filtered with ethyl acetate, and has the following structure: 6-methoxy-2- (5-methyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H)-. 0.2 g of a crude purified product of pyrimidinone was obtained.
• Example 79 ⁇ Production of 4-chloro-6-methoxy-2- (5-methyl-2-pyridyl) -5-trifluoromethylpyrimidine> 0.2 g of a crude product of 6-methoxy-2- (5-methyl-2-pyridyl) -5- (trifluoromethyl) -4 (3H) -pyrimidinone obtained in Example 78 was added to 1.0 ml of toluene. It was dissolved in 0.2 ml of POCl 3 and stirred under heating and reflux conditions for 6 hours. After air cooling to room temperature, the reaction solution was added dropwise to ice containing baking soda and extracted with ethyl acetate. After drying over sodium sulfate, the mixture was filtered.
• the filtrate is concentrated, column-purified, and has the following structure: 4-chloro-6-methoxy-2- (5-methyl-2-pyridyl) -5-trifluoromethylpyrimidine 0.02 g (0.06 mmol) Got The yield was 12% in 2 steps.
• Example 82 ⁇ Production of 6-chloro-N- (4-methylphenyl) -2- (6-n-propyl-2-pyridyl) -5- (trifluoromethyl) -4-pyrimidineamine> 0.04 g (0.3 mmol) of p-toluidine was dissolved in 3.0 ml of DMF, 0.02 g (0.2 mmol) of sodium hydride was added, the mixture was stirred at room temperature for 30 minutes, cooled to 0 ° C., and cooled to Example 60.
• the fluorine-containing pyrimidine compound in the present invention shows a sterilizing effect on the pathogenic bacterium of powdery mildew of cucumber and is effective as a compound showing biological activity, particularly as a bactericidal agent.

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