Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
  • C07D231/20—One oxygen atom attached in position 3 or 5
  • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
• • 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
  • C07D401/12—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 linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to a fluorine-containing pyrazolone compound and a method for producing the same.
• Compounds with a pyrazolone ring are known to have various pharmacological actions, and among them, 3-pyrazolone compounds with substituents at the 1st and 2nd positions are used in the fields of medicine and agrochemicals.
• Examples of compounds with a 1,2-disubstituted 3-pyrazolone ring include pharmaceutical anti-inflammatory drugs such as nifenazone, propyphenazone, dipyrone, antipyrine, and aminopyrine.
• Examples of agricultural chemicals include fenpyrazamine as a fungicide and pinoxaden as a herbicide.
• Patent document 1 JP Patent Publication 61-118371 discloses a method for producing a 3-pyrazolone compound having a substituent at the 1-position, a trifluoromethyl group at the 4-position, and a heteroatom substituent at the 5-position.
• Non-patent documents 1 and 2 disclose the introduction of a substituent onto the pyrazolone ring of a compound having a pyrazolone ring.
• Non-Patent Document 1 reports that in a reaction for introducing a substituent into the 2-position of a pyrazolone ring of a compound having a 3-pyrazolone ring structure substituted at the 1-position, the reaction for introducing a substituent into the oxygen at the 3-position of the pyrazolone ring may compete with the reaction for introducing a substituent into the oxygen at the 3-position of the pyrazolone ring.
• Non-Patent Document 2 reports that in a reaction for introducing a substituent into the 1-position of a pyrazolone ring of a compound having a 3-pyrazolone ring structure substituted at the 2-position, the reaction for introducing a substituent into the oxygen at the 3-position of the pyrazolone ring may compete with the reaction for introducing a substituent into the oxygen at the 3-position of the pyrazolone ring.
• the present invention aims to provide a previously unknown 1,2-disubstituted-3-pyrazolone compound having a trifluoromethyl group at the 4-position and a specific substituent at the 5-position, as well as a production method that can easily produce the pyrazolone compound without producing any O-substitution as a by-product.
• X represents a halogen atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 , or -N ⁇ A 4 ;
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• a 1 , A 2 , A 3 , and A 4 each independently represent an organic group having 1 to 12 carbon atoms.
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• a 1 represents an organic group having 1 to 12 carbon atoms;
• W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, or a phosphonium cation.
• the present invention relates to a method for producing a fluorine-containing pyrazolone compound having the formula: [3] A step of reacting a fluoroisobutanoic acid fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1b): (In the above general formulae (1b), (2), (5) and (6), X 1 represents a halogen atom other than a fluorine atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 or -N ⁇ A 4 ; Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 ,
• the present invention relates to a method for producing a fluorine-containing pyrazolone compound having the formula: [4] A step of reacting a fluoroisobutene derivative represented by the following general formula (3) with a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1a):
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• a 1 represents an organic group having 1 to 12 carbon atoms;
• R represents a hydrocarbon group having 1 to 12 carbon atoms.
• the present invention relates to a method for producing a fluorine-containing pyrazolone compound having the formula: [5]
• X 1 represents a halogen atom other than a fluorine atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 or -N ⁇ A 4
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 ,
• the present invention relates to a method for producing a fluorine-containing pyrazolone compound having the formula: [6]
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• R represents a hydrocarbon group having 1 to 12 carbon atoms;
• V represents a halogen atom, -OA 5 , or -SO m A 5 (wherein m is an integer of 0 to 2);
• a 1 and A 5 each independently represent an organic group having 1 to 12 carbon
• the present invention relates to a method for producing a fluorine-containing pyrazolone compound having the formula: [7]
• X 1 represents a halogen atom other than a fluorine atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 or -N ⁇ A 4
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 ,
• the present invention provides a novel fluorine-containing 1,2-disubstituted-3-pyrazolone compound that has a trifluoromethyl group at the 4-position and a unique substituent at the 5-position, as well as a manufacturing method that can easily produce the fluorine-containing pyrazolone compound without producing an O-substituted by-product.
• the fluorine-containing pyrazolone compound of the present invention is represented by the following general formula (1).
• X represents a halogen atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 , or -N ⁇ A 4 ;
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• a 1 , A 2 , A 3 , and A 4 each independently represent an organic group having 1 to 12 carbon atoms.
• the fluorine-containing pyrazolone compound of the present invention has specific substituents (-CF 3 , -X) at the 4th and 5th positions of the pyrazolone ring, and therefore has excellent effects from the viewpoint of structural expandability.
• desired biological activity for example, hormone or enzyme inhibitory activity, fungicidal activity, insecticidal activity, herbicidal activity
• the fungicidal activity can be exemplified by fungicidal activity against bacteria that have harmful effects on the human body and agricultural crops such as rice.
• a derivative can be obtained by substituting -CF 3 by reacting a fluorine-containing pyrazolone compound.
• a derivative can be obtained by modifying -X by reacting a fluorine-containing pyrazolone compound under basic conditions.
• the fluorine-containing pyrazolone compound of one embodiment is also useful in the field of electronic materials such as organic semiconductors and liquid crystals.
• the group X represents a halogen atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 , or -N ⁇ A 4.
• a 1 , A 2 , A 3 , and A 4 each independently represent an organic group having 1 to 12 carbon atoms, with A 1 , A 2 , and A 3 being monovalent groups and A 4 being a divalent group.
• a 1 , A 2 , A 3 , and A 4 may be organic groups having 1 to 12 carbon atoms, and may contain hydrogen atoms, oxygen atoms, sulfur atoms, and nitrogen atoms in addition to carbon atoms.
• a 1 , A 2 , and A 3 can include chain hydrocarbon groups having 1 to 12 carbon atoms (e.g., alkyl groups, alkenyl groups, alkynyl groups), aromatic hydrocarbon groups (e.g., phenyl groups), alicyclic hydrocarbon groups (e.g., cyclopropyl groups, cyclobutyl groups, cyclohexyl groups, cyclopentyl groups, adamantyl groups), heterocyclic groups, -COA 6 , -C n H 2n -A 7 , -C n H 2n -O-A 7 (n is an integer of 1 to 11, A 6 is an organic group having 1 to 11 carbon atoms, and A 7 is an organic group having 1 to
• Examples of A 6 include a furyl group, a benzofuryl group, and a thienyl group.
• Examples of A 7 can include an alkyl group having 1 to 12-n carbon atoms, a phenyl group, a pyridyl group, a naphthyl group, and a thienyl group).
• the chain-like hydrocarbon group may be a branched chain-like hydrocarbon group or an unbranched chain-like hydrocarbon group.
• the aromatic hydrocarbon group may be an aromatic hydrocarbon group having a substituent or an aromatic hydrocarbon group having no substituent.
• the aromatic hydrocarbon group may have a condensed polycyclic structure.
• the alicyclic hydrocarbon group may be an alicyclic hydrocarbon group having a substituent or an alicyclic hydrocarbon group having no substituent.
• the alicyclic hydrocarbon group may have a bridged ring structure.
• the heterocyclic group may be a heterocyclic group containing one or more heteroatoms (oxygen atom, sulfur atom, nitrogen atom) as ring atoms, and may have a monocyclic structure or a condensed polycyclic structure.
• the group X is preferably a halogen atom, -O-NA 1 A 2 , or -NA 1 A 2 .
• a 1 , A 2 , and A 3 are preferably an alkyl group, -COA 6 , -C n H 2n -A 7 , or -C n H 2n -O-A 7 .
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z are bonded together to form a ring.
• Y and Z each independently represent a phenyl group, an alkyl group having 1 to 12 carbon atoms, -COA 1 (A 1 is an alkyl group having 1 to 12 carbon atoms), or -COOA 1 (A 1 is an alkyl group having 1 to 12 carbon atoms), a benzyl group, or Y and Z are bonded together to form a ring.
• examples of the ring include a ring in which Y and Z together constitute -C n H 2n - and form a ring structure between the nitrogen atoms at the 1st and 2nd positions of the pyrazolone ring.
• a ring having a structure of -Y-Z-C n H 2n - is formed, and although the number of ring atoms forming such a ring is not limited, the number of ring atoms is preferably 4 to 12, more preferably 5 to 10, and even more preferably 6 to 8.
• the ring formed by bonding Y and Z may or may not have a substituent.
• a method for producing a fluorine-containing pyrazolone compound includes the steps of: (a) A step of reacting a fluoroisobutanoic acid fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1a): (In the above general formulas (1a), (2) and (6), Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring; A 1 represents an organic group having 1 to 12 carbon atoms; W + represents an ammonium cation, an imidazolium cation, a pyridinium cation, or a
• a 1 can be the same group as A 1 above.
• the ammonium cation include a triethylmethylammonium cation, a butyltrimethylammonium cation, and an N-methylquinuclidinium cation.
• the imidazolium cation include a 1-butyl-3-methylimidazolium cation, a 1,3-dimethylimidazolium cation, and a 1-benzyl-3-methylimidazolium cation.
• Examples of the pyridinium cation include a 1-methyl-4-dimethylaminopyridinium cation, a 1-methylpyridinium cation, and a 1,4-dimethylpyridinium cation.
• Examples of the phosphonium cation include a tricyclohexylmethylphosphonium cation, a triphenylmethylphosphonium cation, and a tributylmethylphosphonium cation.
• Examples of the salt of the compound represented by formula (6) include the hydrochloride, trifluoroacetate, and paratoluenesulfonate of the compound represented by formula (6).
• the step of obtaining the fluorine-containing pyrazolone compound of (a) is carried out in the presence of a fluoride ion scavenger. It is preferable to react the fluoroisobutanoic acid fluoride derivative represented by the above general formula (2) with the compound represented by the above general formula (6) or a salt thereof in the presence of a fluoride ion scavenger.
• the fluoride ion scavenger is not particularly limited as long as it is a substance having a function of capturing fluorine ions, and examples of the fluoride ion scavenger include lithium, sodium, magnesium, potassium, calcium, tetramethylammonium, trifluoroacetic acid, heptafluorobutyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, nonafluorobutanesulfonic acid, bis(trifluoromethanesulfonyl)imide, bis(nonafluorobutanesulfonyl)imide, N,N-hexafluoropropane-1,3-disulfonylimide, tetraphenylboric acid, tetrakis[3,5-bis(trifluoromethyl)phenyl]
• the cation derived from the fluoride ion scavenger captures the fluorine ion liberated from the fluoroisobutanoic acid fluoride derivative represented by general formula (2) during the reaction and precipitates it as a salt with low solubility in organic solvents, accelerating the reaction and allowing the fluorine-containing pyrazolone compound represented by the above general formula (1a) to be obtained in high yield.
• reaction (a) in which a fluorine-containing pyrazolone compound represented by general formula (1a) is obtained by reacting a fluoroisobutanoic acid fluoride derivative represented by general formula (2) with a compound represented by general formula (6) is represented by the following reaction formula (A).
• the reaction (A) can be carried out in one step. Therefore, the fluorine-containing pyrazolone compound of the general formula (1a) can be easily obtained.
• the compound of the general formula (1a) is formed from the fluoroisobutanoic acid fluoride derivative represented by the general formula (2) and the compound represented by the general formula (6). At the 4th and 5th positions of the pyrazolone structure, -CF3 and -F derived from the fluoroisobutanoic acid fluoride derivative are located, respectively.
• the reaction (a) above is preferably carried out in the presence of a hydrogen halide scavenger.
• the hydrogen halide scavenger is a substance that has the function of scavenging hydrogen fluoride (HF) formed from hydrogen atoms derived from the compound of general formula (6) in the reaction formula (A) above and fluorine atoms derived from the fluoroisobutanoic acid fluoride derivative of general formula (2).
• hydrogen halide scavenger examples include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium fluoride, potassium fluoride, and organic nitrogen derivatives such as pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, and phosphazene bases.
• organic nitrogen derivatives such as pyridine, triethylamine, diisopropylethylamine, diazabicyclononene, diazabicycloundecene, methyltriazabicyclodecene, diazabicyclooctane, and phosphazene bases.
• the reaction temperature during the reaction (a) above is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C.
• the reaction time during the reaction (a) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.
• Solvents used in the above reaction (a) include, for example, ethers such as tetrahydrofuran, diethyl ether, dioxane, monoglyme, diglyme, triglyme, and tetraglyme; aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile; and aprotic polar solvents such as dimethylformamide, dimethylacetamide, methylpyrrolidone, dimethylethyleneurea, tetramethylurea, dimethylsulfoxide, and sulfolane.
• ethers such as tetrahydrofuran, diethyl ether, dioxane, monoglyme, diglyme, triglyme, and tetraglyme
• aromatic hydrocarbons such as benzene, toluene, and xylene
• nitriles such as acetonitrile
• a method for producing a fluorine-containing pyrazolone compound includes the steps of: (b) A step of reacting a fluoroisobutanoic acid fluoride derivative represented by the following general formula (2) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1b):
• X 1 represents a halogen atom other than a fluorine atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 or -N ⁇ A 4 ;
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -CO
• a 1 , A 2 , A 3 and A 4 can be the same groups as A 1 , A 2 , A 3 and A 4 described above.
• Examples of the salt of the compound represented by formula (6) include the hydrochloride, trifluoroacetate, and paratoluenesulfonate of the compound represented by formula (6).
• the step of obtaining the fluorine-containing pyrazolone compound of (b) is carried out in the presence of a fluoride ion trapping agent.
• the fluoroisobutanoic acid fluoride derivative represented by the above general formula (2) is reacted with the compound represented by the above general formula (5) and the compound represented by the above general formula (6) or a salt thereof in the presence of a fluoride ion trapping agent.
• the fluoride ion trapping agent is not particularly limited as long as it is a substance having a function of trapping fluorine ions, and examples thereof include fluoride ion trapping agents similar to the fluoride ion trapping agent used in the above step (a).
• the cation derived from the fluoride ion trapping agent traps the fluorine ions liberated from the fluoroisobutanoic acid fluoride derivative represented by the general formula (2) during the reaction and precipitates them as a salt with low solubility in organic solvents, thereby accelerating the reaction, and it is considered that the fluorine-containing pyrazolone compound represented by the above general formula (1b) can be obtained in high yield.
• reaction (b) between the fluoroisobutanoic acid fluoride derivative represented by the general formula (2) and the compounds represented by the general formulas (5) and (6) is represented by the following reaction formula (B).
• the reaction (B) can be carried out in one step. Therefore, the fluorine-containing pyrazolone compound of the general formula (1b) can be obtained simply.
• a cyclic pyrazolone ring structure is formed between the fluoroisobutanoic acid fluoride derivative represented by the general formula (2) and the compound of the general formula (6), and the 4th and 5th positions of the pyrazolone ring structure are respectively located with -CF3 derived from the fluoroisobutanoic acid fluoride derivative and -X1 derived from the compound of the general formula (5).
• the reaction temperature during the reaction (b) above is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C.
• the reaction time during the reaction (b) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.
• the same hydrogen halide scavenger and solvent as in the reaction (a) above can be used.
• a method for producing a fluorine-containing pyrazolone compound includes the steps of: (c) A step of reacting a fluoroisobutene derivative represented by the following general formula (3) with a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1a):
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• a 1 represents an organic group having 1 to 12 carbon atoms;
• R represents a hydrocarbon group having 1 to 12 carbon atoms.
• a 1 can be the same group as A 1 above.
• R include hydrocarbon groups having 1 to 10 carbon atoms in A1 . More specifically, examples of R include chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups having 1 to 10 carbon atoms.
• chain hydrocarbon groups examples include alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, and decyl group; alkenyl groups such as ethenyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group, and decenyl group; and alkynyl groups such as ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group, nonynyl
• Examples of aromatic hydrocarbon groups include phenyl group.
• Examples of the alicyclic hydrocarbon group include saturated or unsaturated cyclic hydrocarbon groups, and examples of the cyclic hydrocarbon group include a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, an adamantyl group, etc.
• R is preferably an alkyl group having 1 to 10 carbon atoms. When R is an alkyl group having 1 to 10 carbon atoms, the raw material of the fluorine-containing pyrazolone compound can be easily prepared.
• Examples of the salt of the compound represented by formula (6) include the hydrochloride, trifluoroacetate, and paratoluenesulfonate of the compound represented by formula (6).
• the step (c) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a nucleophilic reagent.
• the nucleophilic reagent include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine.
• the step (c) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a fluoride ion trapping agent.
• the fluoroisobutene derivative represented by the general formula (3) is preferably reacted with the compound represented by the general formula (6) or a salt thereof in the presence of a fluoride ion trapping agent.
• the fluoride ion trapping agent is not particularly limited as long as it is a substance having a function of trapping fluorine ions, and examples thereof include fluoride ion trapping agents similar to the fluoride ion trapping agent used in the step (a).
• the cation derived from the fluoride ion scavenger captures the fluorine ion liberated from the fluoroisobutene derivative represented by general formula (3) during the reaction and precipitates it as a salt with low solubility in organic solvents, accelerating the reaction and allowing the fluorine-containing pyrazolone compound represented by general formula (1a) to be obtained in high yield.
• reaction (c) of a fluoroisobutene derivative represented by general formula (3) with a compound represented by general formula (6) in the presence of a nucleophilic reagent, 1-methylimidazole is represented by the following reaction formula (C).
• the reaction (C) can be carried out in one step. Therefore, the fluorine-containing pyrazolone compound of the general formula (1a) can be obtained simply.
• a cyclic pyrazolone ring structure is formed between the fluoroisobutene derivative of the general formula (3) and the two nitrogen atoms derived from the compound of the general formula (6), and -CF3 and -F derived from the fluoroisobutene derivative are located at the 4th and 5th positions of the pyrazolone ring structure, respectively.
• the reaction temperature during the reaction (c) above is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C.
• the reaction time during the reaction (c) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.
• the same hydrogen halide scavenger and solvent as in the reaction (a) above can be used.
• a method for producing a fluorine-containing pyrazolone compound includes the steps of: (d) A step of reacting a fluoroisobutene derivative represented by the following general formula (3) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1b):
• X 1 represents a halogen atom other than a fluorine atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 or -N ⁇ A 4 ;
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 ,
• a 1 , A 2 , A 3 and A 4 can be the same groups as A 1 , A 2 , A 3 and A 4 described above.
• R include, among A 1 , A 2 , and A 3 , hydrocarbon groups having 1 to 10 carbon atoms. More specifically, examples of R include chain hydrocarbon groups, aromatic hydrocarbon groups, and alicyclic hydrocarbon groups having 1 to 10 carbon atoms.
• chain hydrocarbon groups examples include alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups; alkenyl groups such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl groups; and alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl groups.
• alkyl groups such as methyl, ethyl,
• An example of the aromatic hydrocarbon group is a phenyl group.
• An example of the alicyclic hydrocarbon group is 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, and an adamantyl group.
• R is preferably an alkyl group having 1 to 10 carbon atoms. When R is an alkyl group having 1 to 10 carbon atoms, the raw material of the fluorine-containing pyrazolone compound can be easily prepared.
• Examples of the salt of the compound represented by formula (6) include the hydrochloride, trifluoroacetate, and paratoluenesulfonate of the compound represented by formula (6).
• the step of obtaining the fluorine-containing pyrazolone compound of (d) is preferably carried out in the presence of a nucleophilic reagent.
• a nucleophilic reagent examples include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine.
• the step of obtaining the fluorine-containing pyrazolone compound of (d) is preferably carried out in the presence of a fluoride ion scavenger.
• the fluoroisobutene derivative represented by the general formula (3) is preferably reacted with the compound represented by the general formula (5) and the compound represented by the general formula (6) or a salt thereof in the presence of a fluoride ion scavenger.
• the fluoride ion trapping agent is not particularly limited as long as it has the function of trapping fluorine ions, and may be the same as the fluoride ion trapping agent used in the above step (a).
• the cation derived from the fluoride ion trapping agent traps the fluorine ion liberated from the fluoroisobutene derivative represented by the general formula (3) during the reaction and precipitates it as a salt with low solubility in organic solvents, accelerating the reaction and allowing the fluorine-containing pyrazolone compound represented by the general formula (1b) to be obtained in high yield.
• reaction (d) of the fluoroisobutene derivative represented by general formula (3) with the compounds represented by general formulas (5) and (6) in the presence of 1-methylimidazole, a nucleophilic reagent is represented by the following reaction formula (D).
• the reaction (D) can be carried out in one step. Therefore, the fluorine-containing pyrazolone compound of the general formula (1b) can be obtained simply.
• a cyclic pyrazolone ring structure is formed between the fluoroisobutene derivative of the general formula (3) and the two nitrogen atoms derived from the compound of the general formula (6), and -CF3 derived from the fluoroisobutene derivative and -X1 derived from the compound of the general formula (5) are located at the 4th and 5th positions of the pyrazolone ring structure, respectively.
• the reaction temperature during the above reaction (d) is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C.
• the reaction time during the above reaction (d) is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.
• the same hydrogen halide scavenger and solvent as in the above reaction (a) can be used.
• a method for producing a fluorine-containing pyrazolone compound includes the steps of: (e) A step of reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1a):
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 , a benzyl group, or a carbamoyl group, or Y and Z combine together to form a ring;
• R represents a hydrocarbon group having 1 to 12 carbon atoms;
• V represents a halogen atom, -OA 5 , or -SO m A 5 (wherein m is an integer of 0 to 2);
• a 1 and A 5 each independently represent an organic group having 1 to 12 carbon
• A1 and R can be the same groups as A1 and R described above.
• V is preferably a halogen atom, more preferably a fluorine atom.
• A5 can include a methyl group, a phenyl group, and a trifluoromethyl group.
• Examples of the salt of the compound represented by formula (6) include the hydrochloride, trifluoroacetate, and paratoluenesulfonate of the compound represented by formula (6).
• the step (e) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a nucleophilic reagent.
• the nucleophilic reagent include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine.
• the step (e) of obtaining a fluorine-containing pyrazolone compound is preferably carried out in the presence of a fluoride ion trapping agent.
• the fluoroisobutane derivative represented by the general formula (4) and the compound represented by the general formula (6) or a salt thereof are preferably reacted in the presence of a fluoride ion trapping agent.
• the fluoride ion trapping agent is not particularly limited as long as it is a substance having a function of trapping fluorine ions, and examples thereof include fluoride ion trapping agents similar to the fluoride ion trapping agent used in the above step (a).
• the cation derived from the fluoride ion scavenger captures the fluorine ion liberated from the fluoroisobutane derivative represented by general formula (4) during the reaction and precipitates it as a salt with low solubility in organic solvents, accelerating the reaction and allowing the fluorine-containing pyrazolone compound represented by the above general formula (1a) to be obtained in high yield.
• reaction formula (E) The above reaction (e) of the fluoroisobutane derivative represented by the general formula (4) with the compound represented by the general formula (6) is represented by the following reaction formula (E).
• the reaction (E) can be carried out in one step. Therefore, the fluorine-containing pyrazolone compound of the general formula (1a) can be obtained simply.
• a cyclic pyrazolone ring structure is formed between the fluoroisobutane derivative of the general formula (4) and the two nitrogen atoms derived from the compound of the general formula (6), and -CF3 and -F derived from the fluoroisobutane derivative are located at the 4th and 5th positions of the pyrazolone ring structure, respectively.
• the reaction temperature during the reaction (e) above is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C.
• the reaction time during the reaction (e) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.
• the same hydrogen halide scavenger and solvent as in the reaction (a) above can be used.
• a method for producing a fluorine-containing pyrazolone compound includes the steps of: (f) A step of reacting a fluoroisobutane derivative represented by the following general formula (4) with a compound represented by the following general formula (5) and a compound represented by the following general formula (6) or a salt thereof to obtain a fluorine-containing pyrazolone compound represented by the following general formula (1b):
• X 1 represents a halogen atom other than a fluorine atom, -OA 1 , -S(O l )A 1 (wherein l is an integer of 0 to 2), -O-NA 1 A 2 , -NA 1 A 2 , -NA 3 -NA 1 A 2 or -N ⁇ A 4 ;
• Y and Z each independently represent an aromatic hydrocarbon group having 1 to 12 carbon atoms, an alkyl group, -COA 1 , -COOA 1 ,
• a 1 , A 2 , A 3 , A 4 and R can be the same groups as A 1 , A 2 , A 3 , A 4 and R above.
• V is preferably a halogen atom, more preferably a fluorine atom.
• A5 can include a methyl group, a phenyl group, and a trifluoromethyl group.
• Examples of the salt of the compound represented by formula (6) include the hydrochloride, trifluoroacetate, and paratoluenesulfonate of the compound represented by formula (6).
• the step of obtaining the fluorine-containing pyrazolone compound of (f) is preferably carried out in the presence of a nucleophilic reagent.
• a nucleophilic reagent examples include 1-methylimidazole, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, and triphenylphosphine.
• the step of obtaining the fluorine-containing pyrazolone compound of (f) is preferably carried out in the presence of a fluoride ion scavenger.
• the fluoroisobutane derivative represented by the general formula (4) is preferably reacted with the compound represented by the general formula (5) and the compound represented by the general formula (6) or a salt thereof in the presence of a fluoride ion scavenger.
• the fluoride ion trapping agent is not particularly limited as long as it has the function of trapping fluorine ions, and may be the same as the fluoride ion trapping agent used in the above step (a).
• the cation derived from the fluoride ion trapping agent traps the fluorine ion liberated from the fluoroisobutane derivative represented by the general formula (4) during the reaction and precipitates it as a salt with low solubility in organic solvents, accelerating the reaction and allowing the fluorine-containing pyrazolone compound represented by the general formula (1b) to be obtained in high yield.
• reaction (f) of the fluoroisobutane derivative represented by the general formula (4) with the compounds represented by the general formulas (5) and (6) is represented by the following reaction formula (F).
• the reaction (F) can be carried out in one step. Therefore, the fluorine-containing pyrazolone compound of the general formula (1b) can be obtained simply.
• a cyclic pyrazolone ring structure is formed between the fluoroisobutane derivative of the general formula (4) and the two nitrogen atoms derived from the compound of the general formula (6), and -CF3 derived from the fluoroisobutane derivative and -X1 derived from the compound of the general formula (5) are located at the 4th and 5th positions of the pyrazolone ring structure, respectively.
• the reaction temperature during the reaction (f) above is preferably -20°C or higher and lower than the boiling point temperature of the organic solvent, more preferably 0 to 50°C, and even more preferably 10 to 30°C.
• the reaction time during the reaction (f) above is preferably 0.5 to 48 hours, more preferably 1 to 36 hours, and even more preferably 10 to 25 hours.
• the same hydrogen halide scavenger and solvent as in the reaction (a) above can be used.
• solution 2 After preparing solution 2 by dissolving 1.3 g (4.0 mmol) of a salt consisting of 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid fluoride anion and 1-methyl-4-dimethylaminopyridinium cation in 30 g of THF, solution 2 was added dropwise to solution 1 so that the internal temperature did not exceed 10 ° C., and the temperature was raised to room temperature. After about 16 hours, the resulting reaction mixture was added dropwise to a mixed solution consisting of 1.0 g (8.0 mmol) of DIPEA and 30 g of THF under ice-water cooling so that the internal temperature did not exceed 10 ° C., and the temperature was raised to room temperature.
• the salt consisting of 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid fluoride anion and 1-methyl-4-dimethylaminopyridinium cation, and tert-butyl 3-(isopropyl)carbazate correspond to the fluoroisobutanoic acid fluoride derivative of general formula (2) and the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m/z): 312 ([M] + ).
• Example 2 Preparation of N-((1-acetyl-5-oxo-2-phenyl-4-trifluoromethyl-1H-pyrazol-3-yl)oxy)-N-methylfuran-2-carboxamide Under ice-water cooling, 10 g (43 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane was dissolved in 80 g of THF to obtain a solution. Then, 6 g (43 mmol) of diisopropylethylamine was added dropwise to the solution so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 1 was added dropwise to a mixed solution of 4.8 g (43 mmol) of quinuclidine and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 2 was added dropwise to a mixed solution of 5 g (43 mmol) of diethylene glycol monomethyl ether and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 3 was added dropwise to a mixed solution of 6 g (43 mmol) of N-methylfurohydroxamic acid, 11 g (86 mmol) of diisopropylethylamine, and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 4 was added dropwise to a mixed solution of 7 g (43 mmol) of 1-acetyl-2-phenylhydrazine, 6 g (43 mmol) of diisopropylethylamine, and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• the yield of the obtained compound of the following formula (H) was 0.5 g (isolation yield 3%).
• 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane, N-methylfurohydroxamic acid, and 1-acetyl-2-phenylhydrazine correspond to the fluoroisobutane derivative of general formula (4), the compound of general formula (5), and the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m/z): 409 ([M] + ).
• reaction mixture 1 was added dropwise to a mixed solution of 3.1 g (30 mmol) of 1-hexanol and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 2 was added dropwise to a mixed solution of 4.8 g (30 mmol) of bis(3-methoxypropyl)amine, 6.0 g (60 mmol) of triethylamine, and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature.
• reaction mixture 3 was added dropwise to a mixed solution of 4.8 g (30 mmol) of hexahydropyridazine dihydrochloride, 9.0 g (90 mmol) of diisopropylethylamine, and 20 g of methanol under ice-water cooling so that the internal temperature did not exceed 10° C., and the temperature was raised to room temperature.
• the yield of the obtained compound of the following formula (I) was 0.5 g (isolation yield 5%).
• 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene, bis(3-methoxypropyl)amine, and hexahydropyridazine dihydrochloride correspond to the fluoroisobutene derivative of general formula (3), the compound of general formula (5), and the salt of the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m / z): 365 ([M] + )
• reaction mixture 1 was added dropwise to a mixed solution of 0.9 g (8.7 mmol) of 1-hexanol and 2 ml of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• 0.5 g (8.7 mmol) of 1,1,3,3-tetramethylguanidine and 0.9 g (8.7 mmol) of triethylamine were added dropwise to the obtained reaction mixture 2 under ice water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 3 was cooled with ice water, and 1.1 g (8.7 mmol) of 3-pyrazolidinone hydrochloride and 1.8 g (17.5 mmol) of triethylamine were added, and the temperature was raised to room temperature.
• the obtained reaction mixture 4 was purified with a silica gel column to produce a trace amount of 2-(1,7-dioxo-2-(trifluoromethyl)-6,7-dihydro-pyrazolo[1,2-a]pyrazolo-3-yl)-1,1,3,3-tetramethylguanidine represented by the following formula (J).
• 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene, 1,1,3,3-tetramethylguanidine, and 3-pyrazolidinone hydrochloride correspond to the fluoroisobutene derivative of general formula (3), the compound of general formula (5), and the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m / z): 319.3 ([M] + )
• the salt consisting of 3,3,3-trifluoro-2-(trifluoromethyl)propanoic acid fluoride anion and 1,3-dimethylimidazolium cation, N-benzylpropan-1-amine, and tert-butyl-2-benzylhydrazine carboxylate correspond to the fluoroisobutanoic acid fluoride derivative of general formula (2), the compound of general formula (5), and the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m / z): 489.7 ([M] + )
• Example 6 Preparation of 1,2-diethyl-5-(methyl(pyridin-2-ylmethyl)amino)-4-(trifluoromethyl)-pyrazol-3-one 1.9 g (8.2 mmol) of 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene was added dropwise to a mixed solution of 0.8 g (8.2 mmol) of triethylamine and 29 ml of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 1 was added dropwise to a mixed solution of 0.8 g (8.2 mmol) of 1-hexanol and 2 ml of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• 0.3 g (8.2 mmol) of 3-(methylaminomethyl)pyridine and 0.8 g (8.2 mmol) of triethylamine were added dropwise to the obtained reaction mixture 2 under ice water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• reaction mixture 3 was cooled with ice water, and 1.3 g (8.2 mmol) of 1,2-diethylhydrazine dihydrochloride and 2.5 g (24.5 mmol) of triethylamine were added, and the temperature was raised to 50°C.
• the obtained reaction mixture 4 was purified with a silica gel column to produce a trace amount of 1,2-diethyl-5-(methyl(pyridin-2-ylmethyl)amino)-4-(trifluoromethyl)-pyrazol-3-one represented by the following formula (L).
• 1,3,3,3-tetrafluoro-1-methoxy-2-trifluoromethyl-1-propene, 3-(methylaminomethyl)pyridine, and 1,2-diethylhydrazine dihydrochloride correspond to the fluoroisobutene derivative of general formula (3), the compound of general formula (5), and the salt of the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m / z): 382.3 ([M] + )
• Example 7 Preparation of 2-acetyl-5-(2-ethoxyethoxy)-1-phenyl-4-(trifluoromethyl)-pyrazol-3-one Under ice-water cooling, 10 g (43 mmol) of 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane was dissolved in 80 g of THF to obtain a solution. Then, 6 g (43 mmol) of diisopropylethylamine was added dropwise to the solution so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• the obtained reaction mixture 1 was added dropwise to a mixed solution of 4.8 g (43 mmol) of quinuclidine and 20 g of THF under ice-water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• the obtained reaction mixture 2 was added dropwise to a mixed solution of 8 g (86 mmol) of 2-ethoxyethanol and 20 g of THF under ice water cooling so that the internal temperature did not exceed 10°C, and the temperature was raised to room temperature.
• 11 g (86 mmol) of diisopropylethylamine was added dropwise to the obtained reaction mixture 3 at room temperature, and the temperature was raised to 60°C.
• reaction mixture 4 was added dropwise to a mixed solution of 7 g (43 mmol) of 1-acetyl-2-phenylhydrazine, 6 g (43 mmol) of diisopropylethylamine, and 20 g of THF at room temperature, and the temperature was raised to 60°C.
• 1,1,1,3,3-pentafluoro-3-methoxy-2-trifluoromethyl-propane, 2-ethoxyethanol, and 1-acetyl-2-phenylhydrazine correspond to the fluoroisobutane derivative of general formula (4), the compound of general formula (5), and the compound of general formula (6), respectively.
• the analytical results of the obtained target substance are as follows: Mass spectrum (APCI, m / z): 358.3 ([M] + )

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