JP2000053650A - Production of fluorinating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To safely and readily obtain a compound useful as a selective fluorinating agent of an oxygen-containing functional group such as hydroxy group in good yield by subjecting a specific compound to halogen exchange reaction with an alkali metal salt of fluorine by using a specific urea compound as a reacting solvent. SOLUTION: A compound of formula II [R1 to R4 are each an alkyl or the like; R1 and R3 or the like may be bonded to constitute a ring; X1 and X2 are each chlorine or the like and can covalently be bonded to the same carbon] (e.g. 2-chloro-1,3-dimethylimidazolinium chloride) is subjected to halogen exchange reaction with an alkali metal of fluorine, preferably at 60-100 deg.C for 20-24 hr by using a compound of formula I (R5 to R8 are each an alkyl or the like; R5 and R7 or the like may be bonded to constitute a ring) (e.g. 1,3- dimethyl-2-imidazolidinone) to provide the objective compound of formula III (preferably 2,2-difluoro-1,3-dimethylimidazolidine).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a novel fluorinating agent.

[0002]

2. Description of the Related Art Many methods have been known for halogenating organic compounds for a long time. Commonly used halogenating agents include hydrogen halides, phosphorus compounds of halogens, sulfur compounds of halogens, simple halogens, etc., which are highly corrosive and toxic, and require special equipment for handling. There are many things that require technology. Therefore, from the viewpoints of handling, safety, and reactivity, research and development of halogenated reagents are still ongoing. In particular, the fluorination reaction is slower than many halogenation reactions.

[0003] As fluorinating agents conventionally used in the fluorination reaction, there are fluorine, hydrogen fluoride, sulfur tetrafluoride and the like. These conventional fluorinating agents are toxic, corrosive, and so on.
Handling is difficult due to the danger of explosion during the reaction, and special equipment and techniques are required. In addition, there is a problem that the selectivity of the fluorine bond required in the reaction is not good. On the other hand, development of new products utilizing fluorine compounds has been carried out in various fields including functional materials and physiologically active substances, and various fluorinating agents have been developed in recent years in accordance with these.

[0004] As a representative fluorinating agent for oxygen-containing functional groups such as a hydroxyl group and a carboxyl group which has been developed today, US Pat. No. 3,976,691 discloses DAST (diethylamino). Sulfur trifluoride). DAST is introduced as an excellent fluorinating agent for an alcoholic hydroxyl group or a carbonyl group oxygen.
The reaction is carried out at a low temperature of from −60 ° C. to a highly dangerous sulfur tetrafluoride and diethylaminotrimethylsilane, and special production equipment is required. In terms of safety, there have been reports of explosions in the manufacture and use of DAST. [J. Fluorine Che
m. , 42 137 (1989)].

[0005] WO 96/04297 discloses tetraalkyl-fluoroformamidinium hexafluorophosphate as an excellent fluorinating agent for a carboxyl group. The method for producing this substance is to react tetraalkyl-chloroformamidinium chloride with potassium hexafluorophosphate to synthesize tetraalkyl-chloroformamidinium hexafluorophosphate, and then react potassium tetrafluoride with potassium fluoride. An alkyl-fluoroformamidinium hexafluorophosphate has been obtained. The need for potassium hexafluorophosphate increases the cost of raw materials and the number of manufacturing steps, making it uneconomical.

Although it is described as being excellent as a reagent for fluorinating a carboxyl group, there is no description of a substitution reaction of a hydroxyl group with fluorine. Then, the present inventors used 1,3-dimethyl-2-fluoroimidazolinium hexafluorophosphate synthesized according to the production method described in WO 96/04297, and used benzyl alcohol and n-octanol to form hydroxyl groups. A substitution reaction with fluorine was performed, but no formation of the desired product was found.

As described above, as a fluorinating agent for an oxygen-containing functional group, the development of a fluorinating agent which can be used industrially is still insufficient in view of its production method, selectivity and yield of the reaction, and economic efficiency. It is hard to say that it has been done.

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

Embedded image

[0009] (wherein, R ₁ to R ₄ represents an alkyl group or an aryl group, may be the same or different. Also, R ₁
And R ₃ may combine to form a ring, or R ₁ and R ₂ or R ₃ and R ₄ may combine to form a ring. One of the fluorine atoms may be an ion pair as an anion. ) Is a hydroxyl group, a carboxyl group,
It is excellent as a selective new fluorinating agent for oxygen-containing functional groups such as formyl group or ketone group, and it is extremely safe and easy to use in fluorination reaction without any special equipment or technology. I found what I could do.

Further, the compound represented by the general formula (1) is a compound represented by the general formula (2)

Embedded image (Wherein, R _{1 to} R ₄ have the same meanings as described above, and X ₁ and X ₂
Represents a chlorine or bromine atom, which may be the same or different, and X ₁ and X ₂ may be covalently bonded to the same carbon. ) Can be obtained from the compound represented by the formula (1) by a halogen exchange reaction, and thus can be safely and industrially produced without requiring any special equipment or technique.

Furthermore, the fluorinating agent represented by the general formula (1) is economically advantageous because it can be recovered and reused as urea as a raw material of the general formula (2) after the fluorination reaction. I found it.

[0012]

Means for Solving the Problems Accordingly, the present inventors have
As a result of further intensive studies on an efficient method for producing the compound represented by the general formula (1), the compound represented by the general formula (3) was used as a reaction solvent.

[0013]

Embedded image

[0014] (wherein, R ₅ to R ₈ represents an alkyl group or an aryl group, may be the same or different. Also, R ₅
And R ₇ may combine to form a ring, or R ₅ and R ₆ or R ₇ and R ₈ may combine to form a ring. When the reaction is carried out using the urea compound represented by the formula (1), the compound represented by the formula (1) is produced in good yield, and the compound represented by the formula (1) is distilled from the reaction mixture. When the compound represented by the general formula (1) is used, since the boiling point difference between the compound represented by the general formula (1) and the compound represented by the general formula (3), which is a reaction solvent, is large and fractionation can be easily performed, ) Was found to be possible to take out.

In addition, the compound represented by the general formula (1)
_{1 to} R ₄ and R ₅ to R _{4 of the} urea compound represented by the general formula (3)
When R ₈ is the same, the resulting compound represented by the general formula (1) is not isolated by distillation, but is fluorinated in the state of a solution of the compound represented by the general formula (3) as a reaction solvent. When used in the reaction, the compound represented by the general formula (1) is converted into a compound represented by the general formula (3) as a reaction solvent after the fluorination reaction, and thus is represented by the general formula (3). The step of recovering the compound from the reaction solvent can be omitted. Therefore, they have found that they are very effective from an industrial point of view, and have completed the present invention.

That is, the present invention provides:

Embedded image (Wherein, R _{1 to} R ₄ have the same meanings as described above) in a method for producing a compound represented by the general formula (2):

[0017]

Embedded image (Wherein, R _{1 to} R ₄ , X ₁ and X ₂ have the same meanings as described above) and a halogen exchange reaction between an alkali metal salt of fluorine and a compound represented by the general formula (3) )

[0018]

Embedded image (Wherein, R _{5 to} R ₈ have the same meanings as described above), wherein the urea compound represented by the general formula (1) is used.
And a compound represented by the formula (4):

[0019]

Embedded image In the method for producing 2,2-difluoro-1,3-dimethylimidazolidin represented by the general formula (5):

[0020]

Embedded image (Wherein X ₃ and X ₄ represent a chlorine or bromine atom and may be the same or different, and X ₃ and X ₄ may be covalently bonded to the same carbon). -Halogeno-
2,2-difluoro-characterized by a halogen exchange reaction between 1,3-dimethylimidazolinium halide and an alkali metal salt of fluorine, and using 1,3-dimethyl-2-imidazolidinone as a reaction solvent. 1,3-
It is intended to provide a method for producing dimethyl imidazolidine.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
R _{1 to} R ₄ of the compound represented by the general formula (1) and the raw material compound represented by the general formula (2) produced by the method of the present invention.
Is an alkyl group or an aryl group, preferably an alkyl group or an aryl group having 1 to 6 carbon atoms, and the alkyl group may be linear or branched. That is, methyl group, ethyl group, n-propyl group, isopropyl group, n
-Butyl group, n-hexyl group, phenyl group and the like, which may be the same or different.

Further, R ₁ and R ₃ may combine to form a 5-membered or 6-membered hetero ring containing two nitrogen atoms. Examples of such a ring include an imidazolidine ring. Further, R ₁ and R ₂ , and R ₃ and R ₄ may be bonded to each other to form a heterocyclic ring having a nitrogen atom and having 3 to 5 carbon atoms. Examples of such rings include:
Examples include a pyrrolidine ring and a piperidine ring.

The fluorine atom bonded to the carbon atom of the compound represented by the general formula (1) may be of an ion pair type as an anion.

Specific examples of the compound represented by the general formula (1) include bis-dimethylamino-difluoromethane and bis-dimethylamino-difluoromethane.
Diethylamino-difluoromethane, bis-di (n-propyl) amino-difluoromethane, bis-diisopropylamino-difluoromethane, bis-di (n-butyl) amino-difluoromethane, bis-di (n-hexyl) amino-difluoro Methane, 2,2-difluoro-
1,3-dimethylimidazolidine, 2,2-difluoro-1,3-diethylimidazolidine, 2,2-difluoro-1,3-di (n-propyl) imidazolidine, 2,
2-difluoro-1,3-diisopropylimidazolidine, 2,2-difluoro-1,3-di (n-butyl) imidazolidine, N, N-dimethyl-N ,, N, -methyl, phenyl-difluoromethane, Bis (1-piperidyl) difluoromethane and the like can be mentioned. 2,2-Difluoro-1,3-dimethylimidazolidine is particularly preferred.

X ₁ and X ₂ of the compound represented by the general formula (2) used as a raw material for producing the compound represented by the general formula (1) represent a chlorine atom or a bromine atom. And may be covalently bonded to the same carbon.

The compound represented by the general formula (2) used as a raw material for producing the compound represented by the general formula (1) is obtained by converting a tetraalkylurea or a tetraalkylthiourea with phosgene or thionyl chloride, phosphorus trichloride And halogenation with a halogenating agent such as phosphorus tribromide. For example, 2-chloro-
The production of 1,3-dimethylimidazolinium chloride
It can be easily produced by the method described in JP-A-59-25375.

In the production of the compound 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 based on the amount of the compound represented by the general formula (2) Preferably at least 2 equivalents, more preferably 2
~ 5 equivalents. If the amount is less than 2 equivalents, unexchanged halide may remain, which is insufficient. Even if the amount is more than 5 equivalents, the reaction result does not improve much.

As the alkali metal salt of fluorine used in the method of the present invention, cesium fluoride, rubidium fluoride, potassium fluoride, sodium fluoride and the like can be used. Spray-dried potassium fluoride for the fluorination reaction is preferred.

R _{5 to} R ₈ in the urea compound represented by the general formula (3), which is a reaction solvent in the method of the present invention, are the same as R _{1 to} R ₄ described above and satisfy the formula. There is no particular limitation as long as it is present.
3,3, -tetramethylurea, 1,1,3,3-tetraethylurea, 1,1,3,3, -tetra-n-propylurea, 1,1,3,3, -tetraisopropylurea, 1,1,3,3, -tetra-n-butylurea, 1,1,3,3, -tetra-n-hexylurea,
1,3-dimethyl-2-imidazolidinone, 1,3-diethyl-2-imidazolidinone, 1,3-di-n-propyl-2-imidazolidinone, 1,3-diisopropyl-2-imidazolidin Non, 1,3-di-n-butyl-2
-Imidazolidinone, 1,1,3-trimethyl-3-phenylurea, bis (1-piperidyl) ketone and the like. In addition, R _{1 to} R ₄ of the compound represented by the general formula (1)
Is particularly preferably equal to each of R _{5 to} R ₈ of the urea compound of the general formula (3).

The amount of the compound represented by the general formula (3), which is a reaction solvent, is not particularly limited. However, from the viewpoint of reaction efficiency and operability, the amount is preferably 1 to 1 relative to the reaction substrate.
It is 10 to 10 times by weight, more preferably 3 to 5 times by weight.

The reaction temperature is usually 0 ° C. to 150 ° C., preferably 60 ° C. to 10 ° C. in view of the reaction rate and the stability of the product.
It is in the range of 0 ° C. The reaction time is usually 15 to 30 hours,
Preferably, it is 20 to 24 hours. In the present invention, the halogen exchange reaction can be carried out in the presence of a phase transfer catalyst such as a quaternary alkyl ammonium salt or a quaternary alkyl phosphonium salt.

The compound represented by the general formula (1) formed by the reaction can be easily removed from the reaction mixture by distillation. Alternatively, the inorganic salt can be separated from the reaction mixture by filtration and used as a compound solution represented by the general formula (3) of the compound represented by the general formula (1) in the fluorination reaction. When R _{1 to} R ₄ are equal to R _{5 to} R ₈ , the compound represented by the general formula (1) is converted to a solvent represented by the general formula (3) after the fluorination reaction, The step of recovering the compound represented by the general formula (3) can be omitted, which is industrially particularly advantageous.

[0033]

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.
The concentration of 2,2-difluoro-1,3-dimethylimidazolidinone (hereinafter abbreviated as DFI) in the 1,3-dimethyl-2-imidazolidinone solvent in Example 1 was DFI.
Was reacted with aniline for derivatization, and then measured by high performance liquid chromatography (hereinafter abbreviated as HPLC). The concentration of fluorine ions (hereinafter abbreviated as F ⁻ ) was measured by an absorptiometry using an alizarin complexone reagent.

Example 1 2,2-Difluoro-1,3-dimethylimidazolidine
Synthesis of (DFI) 2-chloro-1,3-dimethylimidazolinium chloride (42.03 g, 0.2486 mol) and spray-dried potassium fluoride (60.67 g, 1.0442 m)
ol) and 1,3-dimethyl-2-imidazodinone (14
6.5 g) was charged into a 300 ml four-necked flask in a nitrogen box, and reacted at 85 ° C. for 24 hours under a nitrogen atmosphere. After the reaction, the reaction mixture was cooled to 25 ° C., and the DFI concentration in the reaction solution was measured by HPLC. The DFI concentration in the reaction solution was 18.26% by weight, and the yield was 97.8%. Subsequently, the inorganic salt was filtered off from the reaction solution, and the inorganic salt was washed with DMi. DF was obtained from the filtrate of the obtained reaction solution by vacuum distillation.
28.47 g (purity: 98.5%) of I was obtained (take-out yield: 84.1%).

[0035]

First, the general formula (1) produced by the present invention
Are safe, easy-to-handle, highly selective halogenating agents for compounds having an oxygen-containing functional group such as a hydroxyl group and a carboxyl group, and are particularly useful as fluorinating agents. This compound can be safely and easily manufactured and removed without using any dangerous chemicals and without requiring special equipment, and provides a process which is industrially very useful.

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Fukumura Remarks 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Chemicals Co., Ltd. (72) Inventor Teruyuki Nagata 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Chemicals, Inc. F term (reference) 4H006 AA02 AC30 BB18 BB20 BM71 BU32 FE74

Claims (2)

[Claims] 1. A compound of the general formula (1) (Wherein, R _{1 to} R ₄ represent an alkyl group or an aryl group;
They may be the same or different. Further, R ₁ and R ₃ may combine to form a ring, or R ₁ and R ₂ or R ₃ and R ₄ may combine to form a ring. One of the fluorine atoms may be an ion pair as an anion. In the method for producing the compound represented by the formula (2), the compound represented by the general formula (2): (Wherein, R _{1 to} R ₄ have the same meanings as described above, and X ₁ and X ₂
Represents a chlorine or bromine atom, which may be the same or different, and X ₁ and X ₂ may be covalently bonded to the same carbon. ) And a halogen exchange reaction of an alkali metal salt of fluorine with a compound represented by the general formula (3): (Wherein, R _{5 to} R ₈ represent an alkyl group or an aryl group;
They may be the same or different. Further, R ₅ and R ₇ may combine to form a ring, or R ₅ and R ₆ or R ₇ and R ₈ may combine to form a ring. A method for producing a compound represented by the general formula (1), characterized by using a urea compound represented by the following formula: 2. Formula (4) In the method for producing 2,2-difluoro-1,3-dimethylimidazolidin represented by the general formula (5): (Wherein X ₃ and X ₄ represent a chlorine or bromine atom and may be the same or different, and X ₃ and X ₄ may be covalently bonded to the same carbon). -Halogeno-
2,2-difluoro-characterized by a halogen exchange reaction between 1,3-dimethylimidazolinium halide and an alkali metal salt of fluorine, and using 1,3-dimethyl-2-imidazolidinone as a reaction solvent. 1,3-
A method for producing dimethyl imidazolidine.