JP2003073373A - Fluoromethyl group-containing heterocyclic compound and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for readily and inexpensively producing a heterocyclic compound having a fluoromethyl group from a diketene, useful as a physiologically active substance and to provide a new compound produced by the method. SOLUTION: A diketene is reacted with fluorine and a bimolecular condensation reaction of the reaction product or a reaction of the reaction product with a bifunctional nitrogen nucleophilic reaction agent is carried out to provide the compound of the formula (1a), (2a), (3) or (4) [Q<1> and Q<2> are each independently a single bond, -(C=O)-, -(C=S)- or -(CH2 )n - and n is an integer of >=1; R<1> to R<4> are each independently an alkyl group, an aralkyl group, an aryl group, an alkenyl group, a cycloalkyl group, hydrogen atom or the like].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fluoromethyl group-containing heterocyclic compound and a method for producing the same.

[0002]

PRIOR ART Fluororesin, fluororubber, fluoro paint,
As a fluorine-containing organic compound used for a fluorine-based material such as a surface modifier and an inert solvent, a compound in which some or all of hydrogen atoms in the molecule are fluorinated is well known.
Further, as a fluorine-containing organic compound used in a liquid crystal material or a fluorine-based physiologically active substance such as a pharmaceutical or an agricultural chemical, a partially fluorinated compound is well known (see “Advances in Fluorine-based Bioactive Substances”). And applied development ”, supervised by Takeo Taguchi, CMC, 2000.“ Organofluorine Compounds ”,
T. Hiyama, Springer Verlarg, 2000). Further, a heterocyclic compound having a fluorine atom is expected to have physiological activity as a drug or pesticide, and many researches and developments have been made on a compound in which a fluorine atom is directly substituted on a heterocycle and a compound in which a perfluoroalkyl group is substituted. Has been done.

Diketene is a dimer of ketene and is widely used as a synthetic intermediate for pharmaceuticals, agricultural chemicals, organic materials and the like. As an example of the reaction using diketene, an example of reacting diketene with fluorine gas and then reacting with a nucleophilic reactant to synthesize a γ-fluoroacetoacetic acid derivative (JP-A-11-322663), bifunctional An example is known in which a nucleophilic reactive agent such as a reactive nitrogen nucleophilic reactive agent is reacted with diketene to obtain an acetoacetyl derivative, and then the heterocyclic compound having a methyl group is obtained by ring closure (Comprehensive Heterocycline).
ic Chemistry, I. Edited by Katritzky, Pergamon Press Lt
d. , 1984). However, it has been difficult to fluorinate the methyl group of a methyl group-containing heterocyclic compound synthesized from diketene by a conventional method to convert it into a fluoromethyl group-containing heterocyclic compound.

[0004]

That is, the present invention provides a method for easily and inexpensively producing a heterocyclic compound having a fluoromethyl group, which is useful as a physiologically active substance, from diketene, and a novel compound produced by the method. For the purpose of provision.

[0005]

Means for Solving the Problems The present inventors have proposed a method of reacting diketene with fluorine and then conducting a bimolecular condensation reaction in the presence of a base, or a bifunctional amino compound, an amidine derivative, and a hydrazine compound. It was found that a heterocyclic compound having a fluoromethyl group can be easily and inexpensively produced by a method of reacting with a bifunctional nitrogen nucleophilic reagent selected from Further, it was found that the reaction can be carried out in the same reaction vessel without taking out the fluorinated reaction product which is a reaction intermediate.

That is, according to the present invention, a compound represented by the following formula (1a) and a compound represented by the following formula (1b) are obtained by reacting diketene with fluorine and then conducting a bimolecular condensation reaction in the presence of a base. The present invention provides a method for producing a fluoromethyl group-containing heterocyclic compound, which obtains one or more compounds selected from the above compounds. Further, by reacting diketene with fluorine, and then reacting with a bifunctional nitrogen nucleophilic reagent and ring-closing in the molecule, a compound represented by the following formula (2a) and a compound represented by the following formula (2b) The present invention provides a method for producing a fluoromethyl group-containing heterocyclic compound, which obtains one or more compounds selected from the above compounds, a compound represented by the following formula (3) or a compound represented by the following formula (4). Furthermore, a novel fluoromethyl group-containing heterocyclic compound is provided.

[0007]

[Chemical 12]

[0008]

[Chemical 13]

(In the formula, Q ¹ is a single bond,-(C = O)-,-
(C = S) - or - (CH _{2) n} - indicates, n is an integer of 1 or ^more, R 1, ^{R 2} are each independently a hydrogen atom,
Optionally substituted alkyl group, optionally substituted heteroatom-containing alkyl group, optionally substituted alkenyl group, optionally substituted heteroatom alkenyl group, optionally substituted A cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group is shown. )

[0010]

[Chemical 14]

(In the formula, Q ² is a single bond,-(C = O)-,-
(C = S) - or - (CH _{2) n} - it indicates, n is an integer of 1 or more, R ³ is a hydrogen atom, an optionally substituted alkyl group, a hetero atom which may be substituted Alkyl groups containing, optionally substituted alkenyl groups, optionally substituted heteroatom containing alkenyl groups, optionally substituted cycloalkyl groups, optionally substituted aralkyl groups or substituted Is an aryl group. )

[0012]

[Chemical 15]

(In the formula, R ⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted hetero atom-containing alkyl group, an optionally substituted alkenyl group,
An alkenyl group containing an optionally substituted heteroatom,
It represents a cycloalkyl group which may be substituted, an aralkyl group which may be substituted or an aryl group which may be substituted. )

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION First, the definition of the group of each compound of the present invention will be explained. In the present specification, R ¹ , R ² ,
R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted hetero atom-containing alkyl group, an optionally substituted alkenyl group, or an optionally substituted one. It represents an alkenyl group containing a good hetero atom, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group.

When R ¹ , R ² , R ³ or R ⁴ is an alkyl group, it preferably has 1 to 20 carbon atoms, and more preferably 1 to 10 carbon atoms. As the alkyl group, a linear or branched alkyl group is preferable from the viewpoint of easy availability of the compound. Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, octyl group, decyl group, undecyl group, dodecyl group, tetradecyl group, octadecyl group. , Eicosyl group and the like.

When R ¹ , R ² , R ³ or R ⁴ is a substituted alkyl group, a hydrogen atom of the above alkyl group
A group in which at least one is substituted with a monovalent substituent is preferable. The monovalent substituent is selected from a group other than an optionally substituted aryl group, and is a halogen atom, a cyano group, an optionally protected carboxyl group, an optionally protected hydroxyl group, or an optionally protected group. Amino group, alkoxycarbonyl group, cycloalkyl group, optionally substituted aryloxy group, optionally substituted benzyloxy group, alkyl group substituted with alkenyl group, and alkyl group substituted with halogen atom, Examples include groups such as alkoxy groups. The monovalent substituent is preferably a halogen atom, a halogenated alkyl group, an aryloxy group, a halogenated aryloxy group or an alkoxy group. Examples of the substituted alkyl group include 2-fluoroethyl group, 4
-Fluorobutyl group, 2- (2-fluoroethyl) butyl group, phenoxymethyl group, p-fluorophenoxymethyl group, p-nitrophenoxymethyl group, methoxymethyl group, (1-ethoxy) ethoxymethyl group, 4-benzyl Oxymethyl group, 6-benzyloxyhexyl group, 4
A -benzyloxy-2-fluorobutyl group and a 4-benzyloxy-3-fluorobutyl group are preferable.

The alkyl group containing a hetero atom is an alkyl group in which a hetero atom such as an oxygen atom, a nitrogen atom or a sulfur atom is bonded to the bonding end of the alkyl group. R ¹ , R
^{When 2} , R ³ or R ⁴ is an alkyl group containing a hetero atom, a group in which a divalent hetero atom (for example, etheric oxygen atom, thioetheric sulfur atom, etc.) is bonded to the bonding terminal of the above alkyl group is Alkoxy groups are particularly preferable.

Examples of the alkoxy group include a methoxy group,
Ethoxy group, n-propoxy group, isopropoxy group, n
-Butoxy group, isobutoxy group, sec-butoxy group,
tert-butoxy group, pentyloxy group, hexyl
Xy, heptyloxy, octyloxy, unde
Syloxy group, dodecyloxy group, detradecyloxy
Group, octadecyloxy group, eicosyloxy group, etc.
Can be mentioned. R¹, R ^Two, R^ThreeOr R^FourWas replaced
When it is an alkoxy group, a hydrogen atom of the above alkoxy group
A group in which one or more of the above are substituted with a monovalent substituent is preferable. The
As the monovalent substituent, 1 in the substituted alkyl group can be used.
The same groups as the valent substituents can be mentioned.

When R ¹ , R ² , R ³ or R ⁴ is an alkenyl group, it preferably has 2 to 10 carbon atoms, and more preferably has 3 to 8 carbon atoms. Examples of alkenyl groups include 2
-Butenyl group, 2-pentenyl group, 2-hexenyl group,
A 2-octenyl group, a 4-octenyl group, etc. are mentioned.
When R ¹ , R ² , R ³ or R ⁴ is a substituted alkenyl group, a group in which at least one hydrogen atom of the above alkenyl group is substituted with a monovalent substituent is preferable. Examples of the monovalent substituent include the same groups as the monovalent substituents in the substituted alkyl group. Examples of the substituted alkenyl group include 2-fluoro-2-butenyl group, 3-fluoro-2-butenyl group, 4-benzyloxy-2-butenyl group, 6-benzyloxy-4-hexenyl group, 4-benzyloxy- group. Examples thereof include 2-fluoro-2-butenyl group and 4-benzyloxy-3-fluoro-2-butenyl group.

When R ¹ , R ² , R ³ or R ⁴ is a cycloalkyl group, a cycloalkyl group whose ring portion has 3 to 12 carbon atoms is preferable. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a cyclododecyl group and the like. When R ¹ , R ² , R ³ or R ⁴ is a substituted cycloalkyl group,
A group in which one or more hydrogen atoms of the cycloalkyl group are substituted with a monovalent substituent is preferable. As the monovalent substituent,
The same group as the monovalent substituent in the substituted alkyl group can be mentioned, and a halogen atom is preferable. The alkyl group as the monovalent substituent is a straight chain having 1 to 8 carbon atoms or 1 to 8 carbon atoms.
And a branched alkyl group of 8. Examples of the substituted cycloalkyl group include 2-fluorocyclopropyl group, 3-fluorocyclobutyl group, 3-chlorocyclobutyl group, 3-fluorocyclopentyl group and the like.

Examples of the case where R ¹ , R ² , R ³ or R ⁴ is an aralkyl group include a benzyl group, a phenethyl group and a trityl group. R ¹ , R ² , R
^{When 3} or R ⁴ is a substituted aralkyl group,
A group in which one or more hydrogen atoms of the above aralkyl group are substituted with a monovalent substituent is preferable. Examples of the monovalent substituent include the same groups as the monovalent substituents in the substituted alkyl group. Preferred substituted aralkyl groups include halogenated aralkyl groups. The optionally substituted aralkyl group is benzyl group, p
A -fluorobenzyl group and an o-fluorobenzyl group are particularly preferable.

When R ¹ , R ² , R ³ or R ⁴ is an aryl group, the aryl group is a group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as a phenyl group and a naphthyl group (eg, 2-naphthyl group, 3-naphthyl group, etc.)
Is exemplified. When R ¹ , R ² , R ³ or R ⁴ is a substituted aryl group, a group in which at least one hydrogen atom of the aryl group is substituted with a monovalent substituent is preferable. The monovalent substituent is preferably an alkyl group, an aryl group or a halogen atom. Examples of substituted aryl groups include p-
Examples thereof include a fluorophenyl group, an o-fluorophenyl group, a p-tolylphenyl group and a 4-biphenyl group.

In the present specification, Q ¹ and Q ² each independently represent a single bond,-(C = O)-,-(C = S)-or-(CH ₂ ) _n- (CH _{2) n} - in n
Represents an integer of 1 or more. 1-6 are preferable and, as for n, 1 is especially preferable.

As the diketene used in the present invention, a commercially available product can be used as it is, but since it is colored and polymerized when left at room temperature for several weeks, it is usually preferable to distill it just before use and use it immediately. For the reaction between diketone and fluorine,
It is preferable to use fluorine gas. Furthermore, it is preferable to carry out the fluorination reaction in a liquid phase using fluorine gas. Hereinafter, the reaction will be described by taking a fluorination reaction in a liquid phase as a typical example. The fluorination reaction in the liquid phase is preferably carried out by introducing fluorine gas into a solution in which diketene is dissolved in a solvent. The solvent is preferably selected from organic solvents which do not react with diketene. As the organic solvent, an inert solvent is preferable, and hexane, cyclohexane, benzene, toluene, chlorotoluene, xylene,
Particularly preferred are dichloromethane, chloroform, carbon tetrachloride, dichloroethane, acetonitrile and the like. The amount of solvent is
Usually, the capacity is preferably 0.1 to 100,000 times the capacity of diketene, and particularly preferably 10 to 1,000 times the capacity.

The fluorine gas may be used as it is, but it is preferable to use fluorine gas diluted with an inert gas in order to facilitate the control of the reaction. As the inert gas, it is preferable to use nitrogen gas, argon gas or the like. The fluorine gas concentration in the diluted fluorine gas is
0.5 vol% to 50 vol% is preferable, and especially 1 vo
1% to 20 vol% is preferable. The amount of fluorine used in the fluorination reaction is 0.1 to 1 relative to diketene used in the reaction.
The molar amount is preferably 000-fold and particularly preferably 0.5 to 50-fold.

The temperature of the reaction between diketene and fluorine is -9.
0 ° C to room temperature (25 ° C) is preferable, -70 ° C to -20 ° C.
Is particularly preferable. The reaction time of this fluorination reaction changes depending on the flow rate of the fluorine gas, but the time until the fluorine is no longer consumed is preferable, and the normal reaction time is 0.
About 1 to 10 hours is preferable. The flow rate of fluorine gas is 1
× 10 ⁻⁴ L / min to 1 × 10 ⁴ L / min is preferable, and 1 × 10 ⁻³ L / min to 1 × 10 ³ L / min is particularly preferable. Further, after the introduction of the fluorine gas is completed, it is preferable to introduce an inert gas such as nitrogen gas into the solvent to replace the unreacted fluorine gas remaining in the reaction system.

Next, in the present invention, the diketene fluorinated compound is subjected to a bimolecular condensation reaction (hereinafter referred to as the first reaction) or a reaction with a difunctional nitrogen nucleophilic reaction agent (hereinafter referred to as the The second to fourth reactions will be described later). Here, it is not necessary to take out the product of the fluorination reaction, and in the present invention, the following 1st reaction to 4th reaction can be carried out using the reaction vessel in which the fluorination reaction has been carried out.

The first reaction is a bimolecular condensation reaction carried out in the presence of a base after the fluorination reaction, and by this reaction, a compound represented by the following formula (1a) and a compound represented by the following formula (1b). One or more fluoromethyl group-containing heterocyclic compounds selected from the following compounds, that is, fluoromethyl group-substituted pyran derivatives are obtained. Organic bases used in the bimolecular condensation reaction include trimethylamine, triethylamine, tripropylamine, tributylamine, triisopropylamine, diisopropylethylamine, pyridine, 1,8
-Diazabicyclo [5.4.0] -7-undecene,
1,4-diazabicyclo [2.2.2] octane, 4-
Dimethylaminopyridine, 4-morpholinopyridine,
Examples thereof include sodium acetate, potassium acetate and sodium propionate, with triethylamine being particularly preferred. The amount of the organic base is preferably 0.1 to 100 times the mol of diketene.

The bimolecular condensation reaction can be preferably carried out by adding an organic base to the reaction product of the fluorination reaction and stirring. Since the reaction temperature of the bimolecular condensation reaction is preferably carried out near room temperature, when the fluorination reaction is carried out under cooling conditions, stirring is continued while cooling is stopped and the reaction temperature is returned to room temperature. Is preferred. The reaction time of the bimolecular condensation reaction is preferably 0.1 to 24 hours, and the reaction pressure is preferably atmospheric pressure. The reaction is preferably continued with stirring until a fluoromethyl group-containing heterocyclic compound is obtained.

[0030]

[Chemical 16]

The compound represented by the formula (1a) and the compound represented by the formula (1b) produced in the first reaction are tautomers, and compounds having both of these structures are usually present. To do.

In the second reaction of the present invention, a diketene fluorinated compound is reacted with a difunctional amino compound represented by the following formula (11) to give a compound represented by the following formula (2a). And a reaction for obtaining one or more fluoromethyl group-containing heterocyclic compounds selected from the compounds represented by the following formula (2b). Here, Q ¹ , R ¹ and R ² are as described above. When R ¹ and R ² are the same group, formula (2a) and formula (2b) are the same.

[0033]

[Chemical 17]

[0034]

[Chemical 18]

The reaction with the bifunctional amino compound is carried out by introducing an inert gas into the reaction crude liquid after the fluorination reaction to replace unreacted fluorine gas, and then adding the bifunctional amino compound and stirring. Preferably. Since the reaction temperature of the second reaction is preferably around room temperature, when the fluorination reaction is carried out under cooling conditions, it is preferable to stop cooling and continue stirring while returning the reaction temperature to room temperature. The reaction time of the second reaction is preferably 0.1 to 24 hours, and the reaction pressure is preferably atmospheric pressure. Further, the amount of the compound represented by the formula (11) is preferably 0.1 to 10 times mol relative to diketene.

Examples of the compound represented by the formula (11) include urea or a urea derivative represented by the following formula (5),
In this case, a uracil derivative having a fluoromethyl group selected from the compound represented by the following formula (2c) and the compound represented by the following formula (2d) is obtained. However,
R ¹ and R ² are as described above. Specific examples of the compound represented by the formula (5) include 1,3-dimethylurea,
1,3-diethylurea, 1,3-diphenylurea, 1,
Examples thereof include 3-dibenzylurea and 1,3-di (p-methoxyphenyl) urea.

[0037]

[Chemical 19]

[0038]

[Chemical 20]

The third reaction of the present invention is to react a fluorinated diketene with an amidine derivative represented by the following formula (6) to give a fluoromethyl group-containing heterocycle represented by the following formula (3). This is a reaction for obtaining a formula compound. However,
Q ² and R ³ are as described above, and as the aryl group for R ^3, in addition to the groups mentioned above, 4- (2-
The (4-carboxamidinylphenyl) ethenyl) phenyl group is also preferred.

The reaction with the amidine derivative is carried out by substituting the unreacted fluorine gas in the reaction crude liquid after the fluorination reaction, then adding the amidine derivative represented by the following formula (6) and stirring the mixture. preferable. Since the reaction temperature of the third reaction is preferably around room temperature, when the fluorination reaction is carried out under cooling conditions, cooling is stopped and the reaction is continued by stirring while returning the reaction temperature to room temperature. preferable.
The reaction time of the third reaction is preferably 0.1 to 24 hours,
The reaction pressure is preferably atmospheric pressure. The amount of the amidine derivative represented by the following formula (6) is preferably 0.1 to 10 times the mol of diketene.

[0041]

[Chemical 21]

[0042]

[Chemical formula 22]

As the compound represented by the formula (6), the following formula (6
When the amidine represented by a) is used, the following formula (3
A pyrimidine derivative having a fluoromethyl group represented by a) is obtained. However, R ³ is as described above.

[0044]

[Chemical formula 23]

[0045]

[Chemical formula 24]

Specific examples of the amidine represented by the formula (6a) include benzamidine, acetamidine, stilbene-4,4-dicarboxazimine and the like. Expression (6
As the amidine represented by a), a commercially available amidine can be used as it is, but when it is a salt such as a hydrochloride, it may be used in the reaction after performing an appropriate pretreatment such as neutralization.

The fourth reaction of the present invention is to react a fluorinated diketene compound with a hydrazine compound represented by the following formula (7) to give a pyrazolone having a fluoromethyl group represented by the following formula (4). This is a reaction for obtaining a derivative. However, R ⁴ is as described above.

[0048]

[Chemical 25]

[0049]

[Chemical formula 26]

The reaction with the hydrazine compound is carried out by introducing an inert gas into the reaction crude liquid after the fluorination reaction to replace the unreacted fluorine gas, and then adding the hydrazine compound represented by the formula (7). It is preferably carried out by stirring. Since the reaction temperature of the fourth reaction is preferably around room temperature, when the fluorination reaction is carried out under cooling conditions, it is preferable to stop the cooling and carry out the reaction by stirring while returning the reaction temperature to room temperature. . The reaction time is preferably 0.1 to 24 hours, and the reaction pressure is preferably atmospheric pressure. The amount of the hydrazine compound represented by the formula (7) was 0.
The molar amount is preferably 1 to 10 times. Specific examples of the hydrazine compound include 1,2-dimethylhydrazine, 1,2-diethylhydrazine, and 1,2-diphenylhydrazine. As the hydrazine compound, a commercially available hydrazine and hydrazine compound can be used as they are, but in the case of a salt such as a hydrochloride, it may be used in the reaction after performing an appropriate pretreatment such as neutralization. .

The reaction product obtained by the production method of the present invention is obtained by subjecting the reaction crude liquid produced in the reaction to washing with an acid such as hydrochloric acid, saturated saline, or water, or post-treatment with a combination of these washings. After that, the reaction solvent is preferably distilled off under reduced pressure. When the solvent is distilled off under reduced pressure, it is preferable to first add anhydrous magnesium sulfate, anhydrous potassium carbonate, anhydrous sodium sulfate or the like as a drying agent for treatment, and then distill off the solvent. When the product is a compound that crystallizes, it is preferably purified by recrystallization in a suitable solvent. The product may be purified by chromatography using silica gel or the like. In addition, as a solvent that can be used in the case of recrystallization, an ordinary organic solvent can be used, and for example, hexane, cyclohexane, diethyl ether, ethyl acetate, dioxane, butyl acetate, t-butyl dimethyl ether, toluene, or a mixed solvent thereof. Etc.

The reaction mechanism of the present invention is considered as follows. That is, first, when diketene is reacted with fluorine, γ-fluoroacetoacetyl fluoride (FCH
_It is believed that ₂ C (O) CH ₂ C (O) F) forms as a reaction intermediate. γ-fluoroacetoacetyl fluoride is dimerized by a bimolecular condensation reaction in the presence of a base to form a compound represented by the above formula (1a) or (1
The compound represented by b) is produced. In addition, when a bifunctional nitrogen compound such as a bifunctional amino compound, an amidine derivative or a hydrazine derivative is added to this reaction intermediate, they react with each other to form a corresponding γ-fluoroacetoacetyl compound (for example, A compound represented by the formula (8a), a compound represented by the following formula (8b), a compound represented by the following formula (9), and a compound represented by the following formula (10) are produced. However, R ¹ , R ² , R ³ , and R ⁴ are as described above.

[0053]

[Chemical 27]

[0054]

[Chemical 28]

[0055]

[Chemical 29]

Further, this γ-fluoroacetoacetyl compound is closed within the molecule to give a fluoromethyl group-containing heterocyclic compound having a corresponding fluoromethyl group. The heterocyclic compound having a fluoromethyl group obtained by the method of the present invention is useful as a physiologically active substance, and can be used as a raw material for medicines.

[0057]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto. Example 1 3-Fluoroacetyl-6-fluoromethyl-4-hydroxypyran-2 (H) -one [Compound represented by Formula (1a) and its tautomer represented by Formula (1b)] Compound represented]] A solution of diketene (840 mg, 10 mmol) in chloroform (40 mL) was cooled to -60 ° C and stirred. After purging the system with nitrogen gas, the solution is flushed with nitrogen gas at atmospheric pressure.
Fluorine gas diluted to 4% 4480 mL (10 mmol)
Was introduced at a flow rate of 60 mL / min, and then the fluorine gas in the system was sufficiently replaced with nitrogen gas. Triethylamine (3.04 g, 30 mmol) was added to the reaction solution, cooling was stopped,
While returning the reaction temperature to room temperature, the reaction pressure was kept at atmospheric pressure, and the mixture was stirred for 3 hours. The reaction solution was washed twice with a 2 mol / L hydrochloric acid solution and then with saturated saline. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crystals. This was recrystallized from ether to give the title compound (46
0 mg, yield 45%) was obtained as pale brown flaky crystals.

Melting point: 113-114 ° C. Calculated for _{C 7 H 6 F 2 O 4} : C, 47.26; H, 3.12. Found: C, 47.07; H, 2.96. IR (KBr): 3447, 1718, 1651, 156
4, 1448 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1
5.53 (1H, s), 5.16 (2H, d, J = 45.8)
Hz), 5.51 (2H, d, J = 47.6Hz), 6.
36 (1H, s).

(Example 2) 6-fluoromethyl-1,3-dimethylpyrimidine-
Synthesis example of 2,4-dione [compound in which R ¹ and R ² in formula (2c) are both methyl groups] A solution of diketene (168 mg, 2 mmol) in chloroform (80 mL) was cooled to −60 ° C. and stirred. After purging the system with nitrogen gas, the solution is flushed with nitrogen gas at atmospheric pressure.
After introducing 1344 mL (3 mmol) of fluorine gas diluted to 100% at a flow rate of 40 mL / min, the fluorine gas in the system was sufficiently replaced with nitrogen gas. 1,3-dimethylurea (176 mg, 2 mmol) was added to the reaction solution, cooling was stopped,
Keeping the reaction pressure at atmospheric pressure while returning the reaction temperature to room temperature,
Stir for 6 hours. The reaction solution was washed twice with water, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The residue was recrystallized from ethyl acetate to give the title compound (124m
g, yield 36%) was obtained as colorless flaky crystals.

Melting point: 76-77 ° C. C ₇ H ₉ FN ₂ O ₂ Calculated: C, 48.91; H, 5.2
9; N, 16.32. Found: C, 48.84; H, 5.27; N, 16.2
7. IR (KBr): 3358, 1666, 1439c
m ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 3.36 (3H, s),
3.43 (3H, s), 5.18 (2H, d, J = 46.
3) 5.87 (1H, s).

Example 3 6-Fluoromethyl-1,3-dibenzylpyrimidine-
Synthesis example of 2,4-dione [a compound in which R ¹ and R ² in the formula (2c) are both benzyl groups] A solution of diketene (840 mg, 10 mmol) in chloroform (60 mL) was cooled to −60 ° C. and stirred. After substituting the inside of the system with nitrogen gas, at atmospheric pressure, this solution was diluted with nitrogen gas to 5% fluorine gas 4480 mL (10 mmO).
After introducing 1) at a flow rate of 60 mL / min, the fluorine gas in the system was sufficiently replaced with nitrogen gas. 1,3-Dibenzylurea (3.26 g, 13.6 mmol) was added to the reaction solution, cooling was stopped, the reaction pressure was kept at atmospheric pressure while returning the reaction temperature to room temperature, and the mixture was stirred for 6 hours. The reaction solution was washed twice with water, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography and developed with ether to give the title compound (1.3 g, yield 40%) as a colorless oil.

Calcd for C ₁₉ H ₁₇ FN ₂ O ₂ : C, 70.2
5; H, 5.35; N, 8.98. Found: C, 70.36; H, 5.28; N, 8.64. IR (KBr): 1670, 1454, 1394, 13
50, 1213 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 5.01 (2H, d, J
= 46.33), 5.09 (2H, s), 5.17 (2
H, s), 7.14-7.48 (10H, m).

Example 4 6-Fluoromethyl-2-phenylpyrimidine-4 (3
Synthesis example of H) -one [compound in which R ³ in the formula (3a) is a phenyl group] A solution of diketene (336 mg, 4 mmol) in chloroform (80 mL) was cooled to −60 ° C. and stirred. After replacing the inside of the system with nitrogen gas, 1792 mL (4 mmol) of fluorine gas diluted to 5% with nitrogen gas was added to this solution at atmospheric pressure.
Was introduced at a flow rate of 40 mL / min, and then the fluorine gas in the system was sufficiently replaced with nitrogen gas. Benzamidine (1.44 g, 12 mmol) was added to the reaction solution, cooling was stopped,
Keeping the reaction pressure at atmospheric pressure while returning the reaction temperature to room temperature,
Stir for 3 hours. The reaction solution was washed with a saturated sodium hydrogen carbonate solution and further with water. The organic phase was dried over anhydrous potassium carbonate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography and developed with hexane: ethyl acetate (2: 1) to give the title compound (140 mg, yield 1
7%) was obtained as colorless needle crystals.

Melting point: 211-212 ° C. Calculated for C ₁₁ H ₉ FN ₂ O: C, 64.91; H, 4.5.
0; N, 13.78. Detected value: C, 64.70; H, 4.44; N, 13.7
2. IR (KBr): 3074, 1665, 1545c
m ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 5.33 (2H, d, J
= 44.99), 5.60 (1H, s), 7.54 to 7.
61 (3H, m), 8.16 (2H, s).

Example 5 5-Fluoromethyl-1,2-diphenylpyrazole-
3-one [a compound of the formula (4) in which R ⁴ is a phenyl group]
Synthesis example of A solution of diketene (168 mg, 2 mmol) in chloroform (80 mL) was cooled to −60 ° C. and stirred. After the system was replaced with nitrogen gas, 896 mL (2 mmol) of fluorine gas diluted with nitrogen gas to 5% was introduced into this solution at atmospheric pressure at a flow rate of 40 mL / min, and then the fluorine gas in the system was replaced with nitrogen gas. Replaced well. Hydrazobenzene (442 mg, 2.4 mmol) was added to the reaction solution, cooling was stopped, and the reaction pressure was kept at atmospheric pressure while returning the reaction temperature to room temperature and stirred for 3 hours. The reaction solution was washed twice with 2 mol / L hydrochloric acid, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography, developed with hexane: ethyl acetate (1: 5),
The title compound (226 mg, yield 42%) was obtained as colorless needle crystals.

Melting point: 90-91 ° C. Calculated for C ₁₆ H ₁₃ FN ₂ O: C, 71.53; H, 4.8.
3; N, 10.23. Detected value: C, 71.63; H, 4.88; N, 10.4
4. IR (KBr): 3034, 1664, 1454, 13
94, 1350, 1244 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 5.02 (2H, d, J
= 47.00), 5.87 (1H, s), 7.11 to 7.3
9 (10H, m).

[0067]

INDUSTRIAL APPLICABILITY According to the present invention, a fluoromethyl group-containing heterocyclic compound is obtained by reacting diketene with fluorine, followed by a bimolecular condensation reaction in the presence of a base or a reaction with a bifunctional compound. It can be manufactured efficiently. Further, the method of the present invention has an advantage that it can be carried out as a continuous reaction in the same reaction vessel without taking out the fluorinated compound from the reaction vessel.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Motonori Mori             Royal 2-16-8 Midori, Aomori City, Aomori Prefecture             Chatelier B202 F-term (reference) 4C062 DD32                 4H039 CA42 CH10

Claims (7)

[Claims] 1. The following formula (1) is obtained by reacting diketene with fluorine and then conducting a bimolecular condensation reaction in the presence of a base.
A process for producing a fluoromethyl group-containing heterocyclic compound, which comprises obtaining one or more compounds selected from the compound represented by a) and the compound represented by the following formula (1b). [Chemical 1] 2. The following formula (2a) is obtained by reacting diketene with fluorine and then reacting with a bifunctional amino compound represented by the following formula (11) and ring-closing in the molecule.
A method for producing a fluoromethyl group-containing heterocyclic compound, which comprises obtaining one or more compounds selected from the compound represented by the formula (1) and the compound represented by the following formula (2b). [Chemical 2] [Chemical 3] (However, Q ¹ is a single bond,-(C = O)-,-(C = S)-
Or - (CH _{2) n} - indicates, n is an integer of 1 or more, R ^1, R ² are each independently a hydrogen atom, an optionally substituted alkyl group, hetero atom which may be substituted Containing alkyl group, optionally substituted alkenyl group, optionally substituted heteroatom containing alkenyl group, optionally substituted cycloalkyl group, optionally substituted aralkyl group or substituted Represents an optionally substituted aryl group. ) 3. A compound represented by the following formula (3) is obtained by reacting diketene with fluorine, and then reacting an amidine derivative represented by the following formula (6) with ring closure in the molecule. A process for producing a fluoromethyl group-containing heterocyclic compound, comprising: [Chemical 4] [Chemical 5] (However, Q ² is a single bond,-(C = O)-,-(C = S)-
Or - (CH _{2) n} - indicates, n is an integer of 1 or more, R ³ is a hydrogen atom, an optionally substituted alkyl group, an alkyl group containing a hetero atom which may be substituted, it is substituted An optionally substituted alkenyl group, an optionally substituted heteroatom-containing alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group. . ) 4. A compound represented by the following formula (4) is obtained by reacting diketene with fluorine and then reacting with a hydrazine compound represented by the following formula (7) and ring-closing in the molecule. A method for producing a heterocyclic compound containing a fluoromethyl group, which is characterized. [Chemical 6] [Chemical 7] (However, R ⁴ contains a hydrogen atom, an optionally substituted alkyl group, an optionally substituted hetero atom-containing alkyl group, an optionally substituted alkenyl group, or an optionally substituted hetero atom. An alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group is shown.) 5. The method for producing a fluoromethyl group-containing heterocyclic compound according to claim 1, wherein the following reaction is carried out by reacting diketene with fluorine and removing the resulting fluorinated product. 6. The reaction with fluorine is carried out in a liquid phase.
6. The method for producing a fluoromethyl group-containing heterocyclic compound according to any one of to 5. 7. The following formulas (1a), (1b), (2a),
A fluoromethyl group-containing heterocyclic compound represented by any one of (2b), (3), and (4). [Chemical 8] [Chemical 9] (However, Q ¹ is a single bond,-(C = O)-,-(C = S)-
Or - (CH _{2) n} - indicates, n is an integer of 1 or more, R ^1, R ² are each independently a hydrogen atom, an optionally substituted alkyl group, hetero atom which may be substituted Containing alkyl group, optionally substituted alkenyl group, optionally substituted heteroatom containing alkenyl group, optionally substituted cycloalkyl group, optionally substituted aralkyl group or substituted Represents an optionally substituted aryl group. ) [Chemical 10] (However, Q ² is a single bond,-(C = O)-,-(C = S)-
Or - (CH _{2) n} - indicates, n is an integer of 1 or more, R ³ is a hydrogen atom, an optionally substituted alkyl group, an alkyl group containing a hetero atom which may be substituted, it is substituted An optionally substituted alkenyl group, an optionally substituted heteroatom-containing alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group. . ) [Chemical 11] (However, R ⁴ contains a hydrogen atom, an optionally substituted alkyl group, an optionally substituted hetero atom-containing alkyl group, an optionally substituted alkenyl group, or an optionally substituted hetero atom. An alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group is shown.)