JP2001322984A - New fluorinating agent and method for producing fluorine-containing compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a fluorinating agent extremely effective for fluorinating compounds having an alcoholic hydroxyl group, a phenolic hydroxy group, thiophenol group, aldehyde group, carboxylic acid group, ketone and a halogenated compound, especially that having oxygen-containing functional group, a method for producing the same, and a method for producing the various fluorine-containing compounds by utilizing the same. SOLUTION: This fluorinating agent is expressed by the general formula (1) [wherein, A is a substituted or non-substituted alkyl or a substituted or non-substituted alkoxy; (n) is 0-4; R1, R2 are each a 1-6C substituted or non- substituted lower alkyl and allowed to be the same or different], and the method for producing the fluorinated compound is provided by reacting the above agent with a compound selected from a group consisting of alcohols, phenols, thiophenols, aldehydes, carboxylic acids ketones and halogenated compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a fluorine-containing compound, a fluorinating agent and a method for producing the same.

[0002]

2. Description of the Related Art Generally, it is known that a fluorination reaction involves a danger and poor selectivity in the use of fluorine gas and an electrolytic reaction.
Compared to these conventional fluorinating agents, Dupont DA
ST (diethylaminosulfate fluoride) is well known as a fluorinating agent for selectively and efficiently producing a fluorine compound by reacting with a compound containing an alcoholic hydroxyl group or a compound containing a carbonyl group. However, there is still a problem in safety in terms of production and use, and it is economically problematic due to the high cost. Therefore, development of a novel fluorinating agent that is safe and economical in production and use and highly selective in the reaction has been an issue.

[0003] In order to solve the above-mentioned problems, we have proposed a novel fluorinating agent, bis-dialkylamino-difluoromethane (Japanese Patent Application Laid-Open No. 12-38370). The fluorinating agent has almost the same fluorination performance as DAST, and is advantageous in the production method, usage method and economical efficiency. However, in the case of a fluorination reaction at a high temperature (about 120 ° C. or more), the reaction reagent is used. Alternatively, there is a problem that part of the urea formed after the fluorination reaction is altered.

An object of the present invention is to solve the above-mentioned problems of the prior art and to propose a further improved fluorinating agent and its production and use.

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, the general formula (1)

Embedded image (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. Is excellent as a fluorinating agent such as an alcoholic hydroxyl group, a phenolic hydroxyl group, a thiophenol group, a carboxyl group, an aldehyde group, a ketone, a halide, and the like, and its production and use in a fluorination reaction Has found that it can be performed extremely safely and easily without requiring any special device. Furthermore, they have found that the fluorinating agent of the present invention is stable even in a reaction at a high temperature.

[0006]

That is, the present invention provides the following (1) to (11). (1) General formula (1)

Embedded image (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. ), Alcohols, phenols,
A process for producing a fluorine-containing compound, comprising reacting a compound selected from the group consisting of thiophenols, aldehydes, carboxylic acids, ketones, and halides.

(2) General formula (1)

Embedded image (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. A fluorinating agent represented by). (3) The fluorinating agent represented by the general formula (1) is represented by the formula (2)

[0008]

Embedded image The fluorinating agent according to (2), which is 2,2-difluoro-N, N'-dimethylbenzimidazole represented by the formula: (4) General formula (1)

[0009]

Embedded image (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. ). (5) Equation (2)

[0010]

Embedded image 2,2-difluoro-N, N′-dimethylbenzimidazole represented by the formula:

(6) General formula (3)

Embedded image Wherein R ³ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aralkyl group, and a compound having an alcoholic hydroxyl group represented by the general formula: Reacting the fluorinating agent represented by (1) with a general formula (3-1)

[0012]

Embedded image (Wherein, R ³ has the same meaning as described above.) (7) General formula (4)

[0013]

Embedded image (In the formula, Q represents an oxygen or sulfur atom, c is an integer of 1 to 5, Y1 represents an electron-withdrawing substituent, and b represents 1
And b + c ≦ 6. Wherein the fluorinating agent represented by the general formula (1) is reacted with the phenol or thiophenol compound represented by the general formula (1).

[0014]

Embedded image (Wherein, Y, b and c have the same meanings as described above). (8) General formula (5)

[0015]

Embedded image (Wherein, R ⁴ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aryl group). Reacting the fluorinating agent represented by the general formula (1) with a general formula (5-1)

[0016]

Embedded image (Wherein, R ⁴ has the same meaning as described above.)

(9) General formula (6)

Embedded image (Wherein, R ⁵ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aryl group.) Reacting the fluorinating agent represented by the general formula (1) with the general formula (6-1)

[0018]

Embedded image (Wherein, R ⁵ has the same meaning as described above.) (10) The fluorinating agent is represented by the formula (2)

[0019]

Embedded image (6) to (9), which is 2,2-difluoro-N, N′-dimethylbenzimidazole represented by the formula: (11) General formula (7)

[0020]

Embedded image (Wherein X ₁ and X ₂ represent a chlorine or bromine atom;
A, which may be the same or different, represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4. R ¹ and R ^{2 each} have 1 to 6 carbon atoms
Represents a substituted or unsubstituted lower alkyl group, which may be the same or different. Wherein a halogen exchange reaction is carried out between the compound represented by the formula (1) and an alkali metal salt of a fluorine atom or a tetraalkylammonium fluoride in a non-reactive solvent, represented by the general formula (1) described in (2). Method for producing a fluorinating agent.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The fluorinating agent of the present invention has the general formula (1)

[0022]

Embedded image (Wherein, A, R ¹ and R ² have the same meanings as described above).

In these general formulas, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0-4. Preferably, when n is 0, it is a hydrogen atom, or a methyl group, an ethyl group, a methoxy group or the like.

R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms. Preferably, methyl, ethyl, n-propyl, isopropyl, n-
It is a lower alkyl group such as a butyl group.

Preferred examples of the compound represented by the general formula (1) include the following compounds, but the present invention is not limited to the examples shown here.

(Examples of compounds) 2,2-difluoro-N,
N'-dimethyl (or diethyl or di-n-propyl o
r diisopropyl or di-n-butyl) -benzimidazole, 2,2-difluoro-N, N'-dimethyl (o
r diethyl or di-n-propyl or diisopropyl o
r di-n-butyl) -5-methyl-benzimidazole, 2,2-difluoro-N, N'-dimethyl (or
Diethyl or di-n-propyl or diisopropyl or
Di-n-butyl) -4-methyl-benzimidazole,
2,2-difluoro-N, N'-dimethyl (or diethyl or di-n-propyl or diisopropyl or di-n
-Butyl) -5-ethyl-benzimidazole, 2,2
-Difluoro-N, N'-dimethyl (or diethyl or
Di-n-propyl or diisopropyl or di-n-butyl) -5-methoxy-benzimidazole, 2,2-difluoro-N, N'-dimethyl (or diethyl or di-n-propyl or diisopropyl or di-n-butyl)
-5-ethoxy-benzimidazole and the like.

Particularly preferably, 2, represented by the formula (2),
2-difluoro-N, N'-dimethyl-benzimidazole or 2,2-difluoro-N, N'-dimethyl-5-methyl-benzimidazole, 2,2-difluoro-N, N'-dimethyl-4- Methyl-benzimidazole.

The fluorinating agent represented by the general formula (1) of the present invention can be produced by the following method. That is, the general formula (7)

[0029]

Embedded image (Wherein X ₁ , X ₂ , A, R ¹ , and R ² have the same meanings as described above) and an alkali metal salt of fluorine or tetraalkylammonium fluorides. It can be produced by performing a halogen exchange reaction in a non-reactive solvent. As the compound represented by the general formula (7), a compound in which X ₁ and X ₂ are each a chlorine atom is usually used, but a compound in which a bromine atom may be used. Specifically, 2-chloro-N, N'-dialkyl-benzimidazolidium-chloride, 2-chloro-
N, N'-dialkyl-5-alkyl-benzimidazolidium chloride, 2-chloro-N, N'-dialkyl-4-alkyl-benzimidazolidium chloride, 2-chloro-N, N'-dialkyl-5 -Alkoxy-benzimidazolidium-chloride, 2-chloro-
N, N′-dialkyl-4-alkoxy-benzimidazolidium-chloride and the like.

The compound represented by the general formula (7) used as a raw material for producing the compound represented by the general formula (1) is N, N'-dialkyl-benzimidazole-2-
N or N, N'-dialkyl-benzimidazol-2-one having a lower alkyl substituent (or an alkoxy substituent) at the 4- or 5-position on phosgene or thionyl chloride, thionyl bromide, phosphorus trichloride, tribromide It can be produced by halogenating with a halogenating agent such as phosphorus.

For example, to produce 2-chloro-N, N'-dimethyl-benzimidazolidium chloride,
N, N'-dimethyl-benzimidazol-2-one is dissolved in monochlorobenzene, and usually dissolved in 80-130.
The reaction may be usually performed for several hours to several tens of hours while blowing phosgene at ° C.

In the production of the fluorinating agent represented by the general formula (1) of the present invention, the amount of the alkali metal salt of fluorine used in the halogen exchange reaction is N, N'-dialkyl-alkyl.
It is usually preferably at least 2 equivalents, more preferably 2 to 5 equivalents, based on benzimidazolidium-halide.
The reaction solvent for halogen exchange is not particularly limited as long as it is a non-reactive solvent that does not react with the raw materials and the compound to be produced. Preferably acetonitrile, dimethylformamide, 1,3
-Dimethyl-2-imidazolidinone, glyme, diglyme and the like.

The amount of the reaction solvent is not particularly limited, but is preferably 1 to 50 times the amount of the reaction substrate in view of reaction efficiency and operability. Reaction temperature is usually 20 ° C
To 150 ° C, preferably 50 to 120 ° C.
It is also possible to carry out the halogen exchange reaction in the presence of a tetraalkylammonium salt, a tetraalkylphosphonium salt, 18-crown-6, or the like, which is a phase transfer catalyst.

The compound of the general formula (7) is reacted with a tetraalkylammonium fluoride to form the compound of the general formula (1)
When the compound of formula (7) is produced, the amount of the tetraalkylammonium fluoride to be used is usually 2 to 3 equivalents to the compound of general formula (7). The reaction solvent is preferably dichloromethane, and the reaction temperature is usually −10 to 30 ° C.
The reaction time is usually 1 to 3 hours.

The obtained fluorinating agent represented by the general formula (1) can be used for the next fluorination reaction as it is in the halogen exchange reaction solution, or the reaction solvent is distilled off by filtering off inorganic salts. After that, it can be used for the next fluorination reaction.

The fluorination reaction using the fluorinating agent of the present invention is extremely easy and can be carried out using a usual reaction apparatus. For example, when an alcohol is charged to the reaction solution after the reaction and stirred at room temperature for usually several minutes to several hours, the corresponding fluorine compound can be synthesized in high yield.

Hereinafter, the fluorination reaction using the fluorinating agent of the present invention will be described in detail. The present invention comprises reacting a fluorinating agent represented by the general formula (1) with a compound selected from the group consisting of alcohol, phenol, thiophenol, aldehyde, carboxylic acid, ketone, and halide, It can be a fluorine-containing compound. (1) Conventionally, direct conversion of an alcoholic hydroxyl group to a fluorine group has been a highly versatile and attractive method among fluoro compound synthesis methods. Examples of the fluorinating agent effective for this conversion reaction include hydrogen fluoride as an acidic reactant, pyridine- (HF) n, and Yarobe of fluoroalkylamine.
nko reagent or diethylamine-hexafluoropropene adduct (hereinafter abbreviated as PPDA), tetravalent sulfur compound SF ₄ or diethylaminosulfur trifluoride (hereinafter DAS)
T) and PhPF ₄ of a pentavalent phosphorus compound.

As described above, hydrogen fluoride has drawbacks such as difficulty in handling due to toxicity, corrosiveness, danger of explosion during the reaction, and necessity of special equipment and technology. is there. The fluorination power of pyridine- (HF) n is superior to hydrogen fluoride itself, but not so high as compared to other fluorination agents.

Yaroven of fluoroalkylamine
The ko reagent is a fluorinating reagent obtained by adding diethylamine to chlorotrifluoroethene, and fluorinates many primary and secondary alcohols under mild conditions in a solvent, but has its own stability. Low (closed and can be stored for several days in a cool, dark place) [J. Gen. Che. USS
R, 19, 2125 (1959)]. PPDA is more stable, easier to handle and has the same reactivity.
Is often used.

Recently, as a new type of fluorinating reagent of the fluoroamine type, N, N-diisopropyl-α-
Fluorenamines have been reported. [Tetrahe
drone Lett. , 30, 3077 (198
9)]. These reagents are useful as fluorinating reagents for alcoholic hydroxyl groups, but are difficult to carry out industrially in view of the complexity and economics of their synthesis.

In addition, DAST and the like also have the same problem as described above in the substitution of an alcoholic hydroxyl group with a fluorine group. We have proposed a novel fluorinating agent, bis-dialkylamino-difluoromethane, in JP-A No. 12-38370, and have shown that this is effective for the direct conversion reaction of alcoholic hydroxyl groups to fluorine groups.

As in our prior application, the fluorinating agent of the present invention is safe and easy to handle, and a fluorinated product can be obtained with high selectivity in the fluorination reaction. By using the fluorinating agent of the present invention, it is possible to carry out a fluorination reaction of an alcoholic hydroxyl group which has solved the problems of the conventional fluorinating agent.

The production of a fluorine compound from a compound having an alcoholic hydroxyl group using the fluorinating agent of the present invention is as follows.

That is, the general formula (3):

Embedded image (Wherein, R ³ has the same meaning as described above), and a compound having an alcoholic hydroxyl group represented by the following formula (3-1):

[0045]

Embedded image (Wherein, R ³ has the same meaning as described above).

Examples of the alcohol having a hydroxyl group to be fluorinated include methyl alcohol, ethyl alcohol and n-
Propyl alcohol, n-butyl alcohol, isobutyl alcohol, 2-methyl-1-butanol, n-amyl alcohol, neoamyl alcohol, isoamyl alcohol, n-hexyl alcohol, 2-methyl-1-pentanol, 2-ethyl-1 -Butanol, n-heptyl alcohol, n-octyl alcohol, 2-ethylhexyl alcohol, n-nonyl alcohol, 3,5,5
-Trimethyl-1-hexanol, n-decyl alcohol, n-undecyl alcohol, n-dodecyl alcohol, allyl alcohol, methallyl alcohol, crotyl alcohol, benzyl alcohol, phenethyl alcohol, cinnamyl alcohol, propargyl alcohol, etc. Primary alcohol; and isopropyl alcohol, s
ec-butyl alcohol, sec-amyl alcohol,
sec-isoamyl alcohol, 1-ethyl-1-propanol, 4-methyl-2-pentanol, 1-methylhexyl alcohol, 1-ethylpentyl alcohol,
1-methylheptyl alcohol, cyclohexyl alcohol, 2-methylcyclohexanol, 3-methylcyclohexanol, 4-methylcyclohexanol, se
Secondary alcohols such as c-phenethyl alcohol; and alcohols such as tertiary alcohols such as tert-butyl alcohol, tert-amyl alcohol, 1-methylcyclohexanol and α-terpineol. However, it is not limited to these.

From the alcohols represented by the general formula (3), the corresponding alkyl fluorides which are the fluorine compounds represented by the general formula (3-1) can be obtained.

The amount of the fluorinating agent to be used is usually 1 equivalent or more based on the hydroxyl group of the alcohol. Hydrogen fluoride generated by the reaction can be captured using a base such as a tertiary amine.

The reaction solvent is not particularly limited as long as it is a solvent that does not react with the fluorinating agent and the fluorine compound generated by fluorination of the alcohol, but preferably acetonitrile, dichloromethane, ethylene dichloride, dimethylformamide, 1,3, -Dimethyl-2-imidazolidinone, o-dichlorobenzene, glyme, diglyme and the like.

The reaction temperature depends on the reaction solvent and the reactivity of the hydroxyl group of the alcohol, but is usually preferably from -40 ° C to 150 ° C, particularly preferably from -20 ° C to 8 ° C.
It is in the range of 0 ° C. However, when the generated fluorine compound has a low boiling point or has a structure that easily causes dehydrofluorination, it is necessary to suppress the reaction temperature as much as possible. The fluorine compound generated by the reaction can be easily removed from the reaction mixture by distillation or the like.

(2) Very few examples of the direct conversion reaction of a phenolic hydroxyl group to a fluorine group. We refer to Japanese Unexamined Patent Publication
No. 038370 proposes a novel fluorinating agent, bis-dialkylamino-difluoromethane, which has been shown to be effective for the direct conversion reaction of phenolic hydroxyl groups to fluorine groups. As in our prior application, the fluorinating agent of the present invention can also be suitably used for the fluorination reaction of a phenolic hydroxyl group. Further, a fluorination reaction of thiophenol is also possible. However, this reaction tends to involve by-products of sulfide or disulfide compounds.

Further, by the fluorination reaction of the phenolic hydroxyl group, an aromatic fluorine compound can be produced by regioselectively introducing a fluorine atom into the aromatic ring. The reaction method is as follows.

That is, the general formula (4):

Embedded image (Wherein Q, Y, b and c have the same meanings as described above), by reacting a phenol or thiophenol compound with the fluorinating agent of the present invention to obtain a compound represented by the general formula (4- 1):

[0054]

Embedded image (In the formula, Y, b and c have the same meaning as described above.)
To produce a fluorine compound represented by the formula:

As the phenolic compound to be fluorinated, at least one or more electrophilic substituents (for example, —NO ₂ , —CN, —CF ₃ , —CHO, —
COOH, -CO-, etc.). Preferred examples include o-nitrophenol, p-nitrophenol, o-cyanophenol, p-cyanophenol, p-hydroxy-benzaldehyde, o-hydroxy-benzaldehyde, p-hydroxy-benzoic acid methyl ester, p-hydroxy -Trifluoromethylbenzene, o-hydroxy-trifluoromethylbenzene,
4,4'-di-hydroxy-benzophenone, p-hydroxy-benzoic acid, o-nitrothiophenol, p-nitrothiophenol and the like. However, it is not limited to these. From the phenols or thiophenols represented by the general formula (4), a corresponding fluorine compound represented by the general formula (4-1) is obtained.

The amount of the fluorinating agent to be used is usually 1 equivalent or more based on the hydroxyl group or thiophenol group of phenol. Hydrogen fluoride generated in the reaction can be captured using a base such as a tertiary amine.

The reaction solvent is not particularly limited as long as it does not react with a fluorinating agent and a fluorine compound formed by fluorination of phenol or thiophenol. Preferably, the solvent is acetonitrile, dichloromethane, ethylene dichloride, dimethylformamide, or the like. o-Dichlorobenzene, 1,3-dimethyl-2-imidazolidinone, glyme, diglyme and the like.

The reaction temperature depends on the reactivity of the reaction solvent and the hydroxyl group or thiophenol group of the phenol, but is preferably usually 0 ° C. to 190 ° C. in view of the reaction rate and the stability of the fluorinating agent of the present invention. ° C, particularly preferably in the range of 20 ° C to 170 ° C.

The fluorine compound produced by the reaction can be easily removed from the reaction mixture by distillation or the like.
Further, 2,2-difluoro-N, N'-dialkylbenzimidazole can be recovered as N, N'-dialkylbenzimidazol-2-one after the completion of the reaction.
In particular, even when the reaction is carried out at a high temperature (150 ° C. in the example), N, N ′
-The recovery rate as dialkylbenzimidazol-2-one is high.

(3) Direct conversion of oxygen from an aldehyde group to a fluorine group is also a useful method in the synthesis of fluorine compounds. Among the known fluorinating agents, there are examples in which SF ₄ and DAST are used for the direct fluorination reaction of an aldehyde group or a carbonyl group of a ketone. However, it is hard to say that these fluorinating agents are sufficient because the use thereof is largely restricted for the reasons described above.

We have proposed a novel fluorinating agent, bis-dialkylamino-difluoromethane, in Japanese Patent Application Laid-Open No. 12-38370, and demonstrated that this is effective for the direct conversion reaction of aldehyde groups to difluoromethylene groups. Indicated. Similarly, with the fluorinating agent of the present invention, the synthesis of a compound having a difluoromethylene group can be effectively achieved by fluorination of aldehydes. The method is as follows.

That is, the general formula (5):

Embedded image Wherein R ⁴ represents a substituted or unsubstituted, saturated or unsaturated alkyl group or a substituted or unsubstituted, saturated or unsaturated aryl group; Of the general formula (5)
-1):

[0063]

Embedded image (Wherein, R ⁴ has the same meaning as described above). Thus, direct fluorination of oxygen of an aldehyde group can be effectively achieved using the fluorinating agent of the present invention.

Compounds whose aldehyde group is fluorinated include formaldehyde, acetaldehyde, acrolein, methacrolein, propionaldehyde, butyraldehyde, isobutyraldehyde, valeraldehyde, isovaleraldehyde, hexaaldehyde, heptaldehyde, octylaldehyde, nonyl aldehyde,
Aliphatic aldehydes such as decylaldehyde; aromatic aldehydes such as benzaldehyde, p-nitrobenzaldehyde, anisaldehyde and phthalaldehyde; and alicyclic aldehydes such as cyclohexanecarboxaldehyde. A fluorine compound represented by the general formula (5-1) corresponding to these aldehydes is obtained.

The amount of the fluorinating agent used is usually preferably 1 equivalent or more based on the aldehyde group. The reaction solvent is not particularly limited as long as it is a solvent that does not react with the fluorinating agent and the compound having an aldehyde group and the reaction product, but is preferably acetonitrile, dichloromethane, chloroform, ethylene dichloride, N-methylpyrrolidinone, dimethylformamide, 1,3-dimethyl-2-imidazolidinone, o-dichlorobenzene, glyme, diglyme and the like. The reaction temperature is preferably in the range of usually 0 to 190 ° C, particularly preferably 20 to 180 ° C.

The fluorine compound produced by the reaction can be easily removed from the reaction mixture by distillation or the like, and 2,2-difluoro-N, N′-dialkylbenzimidazole can be removed from the reaction mixture after completion of the reaction. It can be recovered as a dialkylbenzimidazol-2-one.

(4) As the fluorinating agent used for the conversion reaction from carboxylic acid to carboxylic acid fluoride, Y
arovenko reagent, hexafluoropropene (PP
DA), diethylaminosulfur trifluoride (hereinafter, DAST)
And the like). However, Yarov
Regarding the enko reagent, the storage stability of the reagent is said to be slightly lower, and PPDA is considered to be a more stable reagent, but special equipment is required for the production of hexafluoropropene, which is the raw material. You.

DAST is useful not only for efficiently fluorinating carboxyl groups to give carboxylic acid fluorides, but also as a fluorinating reagent for oxygen-containing functional groups such as hydroxyl groups and carbonyl groups of primary, secondary and tertiary alcohols. However, there are problems such as the need for special manufacturing equipment, the high cost of DAST, and the high risk of explosion. Also,
WO96 / 04297 discloses tetraalkyl-fluoroformamidinium hexafluorophosphate as a fluorinating agent having an excellent carboxylic acid group. The number of processes has increased, making it uneconomical.

We have proposed a novel fluorinating agent, bis-dialkylamino-difluoromethane, in JP-A No. 12-38370, and have shown that this is effective for the conversion reaction of carboxylic acid groups to carboxylic acid fluorides. Was.
Similarly, the fluorinating agent of the present invention can also perform a conversion reaction from a carboxylic acid group to a carboxylic acid fluoride. The obtained fluorine-containing compound is a compound that has recently attracted attention as an intermediate in the field of life science or the field of functional materials.

The production of carboxylic acid fluoride using the fluorinating agent of the present invention is as follows. That is, the general formula (6):

Embedded image (Wherein, R ⁵ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aryl group.) By reacting the fluorinating agent of the present invention, the compound represented by the general formula (6)
-1):

[0071]

Embedded image (Wherein, R ⁵ has the same meaning as described above).

The carboxylic acids used in the fluorination reaction include, for example, formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, 3-methylbutanoic acid, vivalic acid,
Hexanoic, heptanoic, octanoic, nonanoic, decanoic, lauric, myristic, palmitic, stearic, phenylacetic, diphenylacetic, acetoacetic, phenylpropionic, cinnamic, oxalic, malonic, Aliphatic monocarboxylic acids and dicarboxylic acids such as succinic acid, methylsuccinic acid, 1,5-pentanedicarboxylic acid, adipic acid, 1,7-heptanedicarboxylic acid, suberic acid, azelaic acid, sebacic acid, dodecane diacid, eicosane diacid and the like Acid; cyclohexanecarboxylic acid, 1-methyl-1-cyclohexanecarboxylic acid, 2-methyl-1-cyclohexanecarboxylic acid, 3-methyl-1-cyclohexanecarboxylic acid, 1,3-dicyclohexanedicarboxylic acid, 1,4-cyclohexane Alicyclic monocarboxylic acids such as dicarboxylic acids and Carboxylic acid; benzoic acid, o- toluic acid, m- toluic acid, p- toluic acid, 4-isopropyl benzoic acid, 4-tert-butylbenzoic acid, o-
Methoxy benzoic acid, m-methoxy benzoic acid, p-methoxy benzoic acid, dimethoxy benzoic acid, trimethoxy benzoic acid, o-nitro benzoic acid, m-nitro benzoic acid, p-nitro benzoic acid, phthalic acid, isophthalic acid, terephthalic acid Aromatic monocarboxylic and dicarboxylic acids such as indole-2-carboxylic acid, indole-3-carboxylic acid,
And heterocyclic carboxylic acids such as nicotinic acid. However, it is not limited to these. From these carboxylic acids, corresponding acid fluorides represented by the general formula (6-1) are obtained.

The amount of the fluorinating agent to be used is usually 1 equivalent or more based on the carboxyl group. The reaction is usually
Performed in a reaction solvent, the reaction solvent used is not particularly limited as long as the solvent does not react with the fluorinating agent to be used, and the generated carboxylic acid fluoride, preferably acetonitrile, dichloromethane, ethylene dichloride, dimethylformamide, 1,3-dimethyl-2-imidazolidinone, o-dichlorobenzene and the like.

The reaction temperature depends on the reactivity of the reaction solvent and the carboxyl group, but is usually preferably from -40 ° C. to 1 ° C. in order to suppress the reaction rate and the generation of byproducts.
00 ° C, particularly preferably -20 ° C to 80 ° C. The carboxylic acid fluoride generated by the reaction can be easily removed from the reaction mixture by distillation or the like.
Further, 2,2-difluoro-N, N'-dialkylbenzimidazole can be recovered as N, N'-dialkylbenzimidazol-2-one after the completion of the reaction.

[0075]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.
In addition, 2,2-difluoro- in Examples 1 and 2 was used.
N, N'-dimethylbenzimidazole (hereinafter DFD)
The concentration of MB) was measured by high performance liquid chromatography (hereinafter abbreviated as HPLC) after derivatizing DFDMB by reacting it with aniline. The concentration of fluorine ions (hereinafter abbreviated as F ⁻ ) was measured by an absorptiometry using an alizarin complexone reagent. Analysis of chloride ion was performed by silver nitrate titration.

(Synthesis Example 1) Synthesis of N, N'-dimethylbenzimidazol-2-one (DMBI) 100 g of benzimidazol-2-one and 400 g of dimethylformamide were mixed with 1 L of 1 L equipped with a stirrer, thermometer and cooling condenser. It was charged in a reaction vessel and dissolved with stirring. Next, while stirring was continued, 50 g of potassium tert-butoxide was charged and maintained at 19 to 40 ° C. for 30 minutes. Next, 63.15 g of iodomethane was gradually charged and maintained for 30 minutes. During this time, the reaction temperature was maintained at 30 to 60 ° C. Further, alternately three times, potassium tert-butoxide
After repeating charging of 50 g and 63.15 g of iodomethane, the reaction was terminated. 400 ml of water and 400 ml of dichloromethane were added to the reaction mass, followed by stirring and extraction.
After separating and washing the dichloromethane layer with water, dehydration and dichloromethane distillation were carried out to obtain 92.5 g of crude DMBI. Finally, recrystallization and purification were performed using carbon tetrachloride.
88 g of MBI was obtained (GC purity 99%, yield 73
%).

(Synthesis Example 2) 2-chloro-N, N'-dimethylbenzimidazolidium-chloride (CDMBI)
45 g of DMBI and 175 g of monochlorobenzene obtained in the above synthesis were placed in a reaction vessel, and a chlorination reaction with phosgene was carried out (reaction temperature: 100 ° C., reaction time: 15 h).
After completion of the reaction, filtration, washing and drying were carried out to obtain 35 g of white crystals of CDMBI (purity: 100%, yield: 58%).

Example 1 Synthesis of 2,2-difluoro-N, N'-dimethyl-benzimidazole (DFDMB) 2.01 g of CDMBI obtained in Synthesis Example 2 in a nitrogen box
(9.3 mmol) and 50 ml of dichloromethane dehydrated with molecular sieves were placed in a small reaction vessel, and 2.02 g of tetramethylammonium fluoride purity 96.8% was added thereto while stirring with a magnetic stirrer.
(21.0 mmol) was dividedly charged in about 5 minutes. During this time, the reaction temperature rose from room temperature 16 ° C to 27 ° C.

Thereafter, the reaction mixture was sealed and reacted for 2 hours.
After the completion of the reaction, 63 g of a dichloromethane layer was taken out by filtration. Take a part of the dichloromethane layer, measure the chlorine content and
PLC and GC analyzes were performed. From the analysis results, DFDM
It was found that 5.35 mmol of B and 2.72 mmol of DMBI had been produced (reaction yield of DFDMB 57%). The remaining dichloromethane layer was divided into two parts, and one of them was distilled off under reduced pressure, and the remaining residue was dissolved in 2 ml of acetonitrile, and this was used as a sample solution for NMR measurement. The remaining half of the dichloromethane layer was subjected to distillation under reduced pressure to remove dichloromethane, and the residue (solid) was taken out and used as a sample for DI-MS measurement. The analytical values are shown below.

Chlorine content: not detected DI-MS: 184 (M) ⁺ , 165 (MF) ^{+ 1} H-NMR (δ, ppm, CH ₃ CN solvent, CH ₃ CN
(Standard, 23 ° C.): 3.15 (s, 6H, —CH ₃ ×)
2), 6.73 (m, 2H, -CH x 2), 6.89
(M, 2H, —CH × 2) ¹³ C-NMR (δ, ppm, CH ₃ CN solvent, CDCl ₃
Reference, -20 ℃): 26.5 (s , -CH 3 × 2),
105.6 (s, -CH x 2), 120.0 (-CH x
2), 129.0 (t, J _CF = 230 Hz, −CF ₂ ×
2), 133.0 (-CH x 2),

Example 2 Synthesis of 2,2-difluoro-N, N'-dimethyl-benzimidazole (DFDMB) In a nitrogen box, the CDMBI 0.5 obtained in Synthesis Example 2 was synthesized.
0 g (2.31 mmol) and 15 ml of dichloromethane dehydrated with molecular sieves are placed in a small reaction vessel,
While stirring this with a magnetic stirrer, the purity of tetramethylammonium fluoride was 86.9%.
0.487 g (4.55 mmol) were charged in portions over about 5 minutes. During this time, the reaction temperature rose from room temperature 20 ° C. to 28 ° C. Thereafter, the reaction mixture was sealed and the reaction was carried out for 1 hour. After completion of the reaction, 19 g of dichloromethane layer was taken out by filtration.
A part of the dichloromethane layer was taken, and fluorine ions and chlorine ions were measured. The amount of fluorine ions was 4.65 mmol.
Detection and chloride ion were not detected. HPLC,
According to the GC analysis result, 1.95 mmol of DFDMB and DMB
It was found that 0.37 mmol of I was produced (reaction yield of DFDMB 84%).

Example 3 Synthesis of 2,2-difluoro-N, N′-dimethyl-benzimidazole (DFDMB) CDMBI obtained in Synthesis Example 2 in a small autoclave
2.0 g (9.26 mmol), spray-dried KF 2.15
g (37 mmol) and 40 ml of acetonitrile dehydrated with molecular sieves were charged, sealed, and reacted at 100 ° C. for 30 hours. After completion of the reaction, the acetonitrile layer was taken out by filtration, and the measurement of fluorine ion and chlorine ion was performed.
45 mmol detection, 0.467 mmol chloride ion detection. In addition, from the results of HPLC and GC analysis, DFDMB
It was found that 3.16 mmol and 5.11 mmol of DMBI had been formed. However, since chloride ions were detected, 2-fluoro-N, N ′ partially containing chloride ions.
-It seems that dimethyl-benzimidazolidium chloride was formed.

Example 4 Synthesis of benzyl fluoride 5 g (0.50 mmol) of the acetonitrile solution of DFDMB obtained in Example 3 was placed in a small reaction vessel, and 0.054 g of benzyl alcohol was added thereto while stirring with a magnetic stirrer. (0.50 mmol) / acetonitrile 2 m
of solution were added dropwise. After reacting at room temperature for 1 hour, GC measurement of the reaction mass was performed. From the calculation result of the measured value,
Benzyl fluoride 0.274 mmol (reaction yield 54
%), Benzyl chloride 0.066 mmol (reaction yield 13
%) Had been formed.

Example 5 Synthesis of benzyl fluoride DFDM obtained by the same method as in Example 2 was placed in a small reaction vessel.
7 g (0.67 mmol) of a dichloromethane solution of B was added,
A solution of 0.072 g (0.67 mmol) of benzyl alcohol / 5 ml of dichloromethane was added dropwise thereto while stirring with a magnetic stirrer. After reacting at room temperature for 1 hour, GC measurement of the reaction mass was performed. From the calculation result of the measured values, benzyl fluoride 0.61 mmol (reaction yield 9
1%).

Example 6 Synthesis of p-fluorobenzoic acid methyl ester A small reaction vessel was charged with a purity of 53.4 obtained in the same manner as in Example 1.
% DFDMB 1.307 g (3.80 mmol), o-dichlorobenzene 10 ml, p-hydroxybenzoic acid methyl ester
0.385 g (2.528 mmol)], and stirred under a magnetic stirrer under a slight pressure of nitrogen gas.
The reaction was performed at 50 ° C. for 5 hours. After cooling, the mixture was filtered, and the filtrate was analyzed by GC and GC-MS. G
C-MS measurement confirmed the formation of p-fluorobenzoic acid methyl ester (M ⁺ 152). According to the GC measurement value, the conversion of methyl p-hydroxybenzoate 5
Formation of 5% p-fluorobenzoic acid methyl ester
0.324 mmol, selectivity 23%. In addition, 3.601 mmol of N, N'-dimethylbenzimidazol-2-one produced by the reaction was detected. This corresponds to 95% of the DFDMB used.

Comparative Example 1 Synthesis of methyl p-fluorobenzoate In a small reaction vessel, 0.715 g (5.25 mmol) of 2,2-difluoro-1,3-dimethylimidazolidin (DFI), 10 mmol of o-dichlorobenzene, -Hydroxybenzoic acid methyl ester (0.50 g, 3.29 mmol) was charged, and the mixture was reacted at 150 ° C. for 5 hours under a slight pressure of nitrogen gas while stirring with a magnetic stirrer. After cooling, the mixture was filtered, and the filtrate was analyzed by GC and GC-MS. According to GC-MS measurement, p-fluorobenzoic acid methyl ester (M ⁺
152) generation was confirmed. According to the GC measurement value, the conversion of p-hydroxybenzoic acid methyl ester was 61%, the formation of p-fluorobenzoic acid methyl ester was 0.361 mmol,
Selectivity 18% 2.9556 mmol was detected. This corresponds to 56% of the DFI used.

Comparative Example 2 Synthesis of methyl p-fluorobenzoate In a small reaction vessel, 0.783 g (5.21 mmol) of 2,2-difluoro-1,3-dimethylpyrimidine (DFDMP), o-
10 mmol of dichlorobenzene and 0.53 g (3.477 mmol) of methyl p-hydroxybenzoate were charged, and the mixture was reacted at 150 ° C. for 5 hours under a slight pressure of nitrogen gas while stirring with a magnetic stirrer. After cooling, the mixture was filtered, and the filtrate was analyzed by GC and GC-MS. The formation of p-fluorobenzoic acid methyl ester (M ⁺ 152) was confirmed by GC-MS measurement. G
From the measured C values, the conversion of p-hydroxybenzoic acid methyl ester was 63%, the production of p-fluorobenzoic acid methyl ester was 1.180 mmol, and the selectivity was 34%. In addition, 5.21 mmol of N, N'-dimethylpropyleneurea produced by the reaction was detected. This is 100 of DFI used
%.

Example 7 Synthesis of α, α-difluorotoluene DFDM obtained in the same manner as in Example 2 was placed in a small reaction vessel.
16.0 g of a dichloromethane solution of B (DFDMB 1.142 mmol),
o-dichlorobenzene 10ml, benzaldehyde 0.101g
(0.952 mmol)] and dichloromethane was distilled out of the system at 85 ° C. under a slight pressure of nitrogen gas while stirring with a magnetic stirrer. Thereafter, the temperature was raised to 150 ° C., and the reaction was carried out for 5 hours. After cooling, the mixture was filtered, and the filtrate was analyzed by GC and GC-MS. GC-
From the measurement of MS, it was found that α, α-difluorotoluene (M ⁺
1 The generation of 28) was confirmed. According to GC measurement values, formation of α, α-difluorotoluene 0.50 mmol, reaction yield 5
2.5%.

Example 8 Synthesis of Benzoic Acid Fluoride DFDM obtained in the same manner as in Example 2 was placed in a small reaction vessel.
6.43 g of a dichloromethane solution of B (DFDMB 0.459
mmol), 10 ml of o-dichlorobenzene and 0.101 g (0.952 mmol) of benzaldehyde], and the mixture was stirred at 20 ° C. under a slight pressure of nitrogen gas while stirring with a magnetic stirrer.
The reaction was performed for 0.5 hours. After completion of the reaction, the dichloromethane layer was subjected to GC-MS measurement, and it was confirmed that benzoic acid fluoride (M ⁺ 124) was formed. No other reaction products were detected.

[0090]

The compounds relating to the fluorinating agent of the present invention include alcohols, phenols, thiophenols, aldehydes,
A highly selective fluorinating agent that is safe and easy to handle for compounds containing carboxylic acids, ketones, and halides. In addition, the fluorinating agent of the present invention can be produced economically without requiring special equipment or technology. Further, the present fluorinating agent is stable in a fluorination reaction at 120 to 150 ° C., and is characterized by a high urea recovery rate after completion of the reaction. The fluorinating agent of the present invention can be manufactured by an industrial method which solves the problems of the prior art, and is excellent as a fluorinating agent for organic compounds, particularly compounds having an oxygen-containing functional group. Effect.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 25/13 C07C 25/13 51/29 51/29 53/38 53/38 57/64 57/64 ( 72) Inventor Junko Naruse 30 Asamuta-cho, Omuta-shi, Fukuoka Prefecture Mitsui Chemicals, Inc. 30 Asamuta-cho, Omuta-shi Mitsui Chemicals, Inc. F term (reference) 4H006 AA02 AC30 BJ50 BS90

Claims (11)

[Claims] 1. A compound of the general formula (1) (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. ), Alcohols, phenols,
A process for producing a fluorine-containing compound, comprising reacting a compound selected from the group consisting of thiophenols, aldehydes, carboxylic acids, ketones, and halides. 2. A compound of the general formula (1) (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. A fluorinating agent represented by). 3. The fluorinating agent represented by the general formula (1) is represented by the formula (2): The fluorinating agent according to claim 2, which is 2,2-difluoro-N, N'-dimethylbenzimidazole represented by the following formula: 4. A compound of the general formula (1) (In the formula, A represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4.
R ¹ and R ² represent a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms, which may be the same or different. ). 5. The compound represented by the general formula (1) is a compound represented by the formula (2): 2,2-difluoro-N, N′-dimethylbenzimidazole represented by the formula: 6. A compound of the general formula (3) Wherein R ³ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aralkyl group, and a compound having an alcoholic hydroxyl group represented by the general formula: Reacting the fluorinating agent represented by (1) with the general formula (3-1): (Wherein, R ³ has the same meaning as described above.). 7. A compound of the general formula (4) (In the formula, Q represents an oxygen or sulfur atom, c is an integer of 1 to 5, Y1 represents an electron-withdrawing substituent, and b represents 1
And b + c ≦ 6. Wherein the fluorinating agent represented by the general formula (1) is reacted with the phenol or thiophenol compound represented by the general formula (1). (Wherein, Y, b and c have the same meanings as described above). 8. A compound of the general formula (5) (Wherein, R ⁴ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aryl group). Reacting the fluorinating agent represented by the general formula (1) with the general formula (5-1) (Wherein, R ⁴ has the same meaning as described above.). 9. A compound of the general formula (6) (Wherein, R ⁵ represents a substituted or unsubstituted, saturated or unsaturated alkyl group, or a substituted or unsubstituted, saturated or unsaturated aryl group.) Reacting the fluorinating agent represented by the general formula (1) with the general formula (6-1) (Wherein, R ⁵ has the same meaning as described above.). 10. The fluorinating agent is represented by the formula (2): The method according to claims 6 to 9, which is 2,2-difluoro-N, N'-dimethylbenzimidazole represented by the following formula: 11. A compound of the general formula (7) (Wherein X ₁ and X ₂ represent a chlorine or bromine atom;
A, which may be the same or different, represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkoxy group, and n is 0 to 4. R ¹ and R ^{2 each} have 1 to 6 carbon atoms
Represents a substituted or unsubstituted lower alkyl group, which may be the same or different. The compound represented by the general formula (1) according to claim 2, wherein the compound represented by the formula (1) is subjected to a halogen exchange reaction in a non-reactive solvent with an alkali metal salt of a fluorine atom or a tetraalkylammonium fluoride. For producing a fluorinating agent to be used.