As the typical process of fluorination for introducing fluorine atom into a substrate, heretofore, the direct fluorination using fluorine gas (F2) has been known (for example, refer to Patent Reference 1). When the substrate has a functional group such as oxygen, sulfur and halogen, processes in which the functional group is replaced with fluorine atom using an inorganic fluorinating agent such as hydrogen fluoride (occasionally referred to as HF, hereinafter) and sulfur tetrafluoride or an fluorinating agent other than inorganic fluorinating agents such as pyridine-9HF (the Olah reagent), a Yarovenko reagent of the fluoro-alkylamine type, a modified Ishikawa reagent of the fluoro-alkylamine type or diethylamionosulfur trifluoride (DAST), have been known (for example, refer to Non-Patent References 1 and 3).
When the substrate is a halogen compound, the halogen-fluorine exchange reaction is the most convenient means for introducing fluorine. In the halogen-fluorine exchange, alkali metal salts of fluorine are used frequently. For example, sodium fluoride and potassium fluoride have little toxicity or possibility of causing corrosion unlike HF and can be handled easily. Potassium fluoride (occasionally referred to as KF, hereinafter) prepared in accordance with the spray drying process is frequently used recently (for example, refer to Non-Patent References 2 and 4).
As the agent other than those described above, molecular compounds of HF and a Lewis base such as pyridine or triethylamine, or ammonium fluoride salts can be used for the halogen-fluorine exchange reaction (for example, refer to Non-Patent References 3 and 4 (page 178)).
The processes for fluorination described above have a problem in that fluorine gas, hydrogen fluoride and sulfur tetrafluoride have toxicity and may cause corrosion and explosion, and special apparatuses and technologies are required for the handling.
To overcome the above problem and introduce fluorine safely and easily, various nucleophilic and electrophilic fluorinating agents have been developed (for example, refer to Patent References 2 and 3 and Non-Patent Reference 1). Patent Reference 3 relates to α,α-difluoro-amines proposed by the present inventors which are represented by the following general formula (1), can overcome the above problem of conventional processes, exhibit excellent heat stability and can be handled easily:
wherein R0, R1 and R2 each represent hydrogen atom or an alkyl group, an aryl group, an alkylamino group or an arylamino group, which may have substituents, atoms and groups represented by R0, R1 and R2 may be same with or different from each other, and a ring may be formed by bonding of two or more groups represented by R0, R1 and R2.
The α,α-difluoroamine represented by general formula (1) can be produced in accordance with a conventional halogen-fluorine exchange reaction using as the precursor a halogen compound of an amide which is an α,α-dihaloamine represented by the following general formula (2):
wherein R0, R1 and R2 each represent hydrogen atom or an alkyl group, an aryl group, an alkylamino group or an arylamino group, which may have substituents, atoms and groups represented by R0, R1 and R2 may be same with or different from each other, a ring may be formed by bonding of two or more groups represented by R0, R1 and R2, and X represents chlorine atom, bromine atom or iodine atom.
The α,α-difluoroamine represented by general formula (1) of the object compound can be obtained by the halogen-fluorine exchange reaction of the α,α-dihaloamine represented by general formula (2) using HF or an alkali metal salt of fluorine such as NaF and KF prepared in accordance with the spray drying process as the fluorine source.
The process for producing a fluorine compound by the fluorine exchange using HF or an alkali metal salt of fluorine such as NaF and KF has heretofore been known widely. The condition of the reaction can be decided with reference, for example, to Non-Patent Reference 3. However, occasionally, the reaction rate is insufficient, and it takes a long time to complete the reaction.
For example, when the reaction of N,N-diethyl-α-chlorometatoluoyl-amidium chloride is conducted using KF, which is prepared in accordance with the spray drying process, has a relatively great specific surface area and exhibits a great activity, in acetonitrile as the solvent under the refluxing condition (82° C.) for 24 hours, the yield is at most 70%. A long processing time not only lowers productivity of the object fluoroamines, but also results in an increased cost, and thus is a problem as an industrial process.
As described above, when an α,α-difluoroamine is produced in accordance with the halogen-fluorine exchange reaction using KF, the relatively great cost of KF prepared in accordance with the spray drying process and the long time required for the reaction are the major causes of the increase in the cost of production, and a further increase in the productivity and a further decrease in the cost are required from the standpoint of the industrial production.
Some of the above problems can be overcome by using a molecular compound of HF and a Lewis base (occasionally referred to as “HF-Lewis base”, hereinafter) for the halogen-fluorine exchange reaction.
However, few examples of the application of HF-Lewis base to the production of the α,α-difluoroamine represented general formula (1) can be found. In particular, no references clearly describe that triethylamine-3HF comprising HF and triethylamine in relative amounts by mole of 3:1 (causing no corrosion and enabling to use a glass vessel; occasionally referred to as “Et3N-3HF”) exhibits a greater nucleophilicity than that of other HF-Lewis bases such as pyridine-9HF (the Olah reagent) and is advantageously used for the halogen-fluorine exchange reaction since the reaction is rapidly completed.
More specifically, in conventional processes, no examples can be found on the production of N,N-diethyl-α,α-difluoro(3-methyl)benzylamine using HF-Lewis base such as Et3N-3HF in the chlorine-fluorine exchange reaction of N,N-diethyl-α-chlorometatoluoylamidium chloride. No examples can be found on the production of similar α,α-difluoroamines using HF-Lewis base, either.
When the use, for example, of Et3N-3HF is applied to the production of α,α-difluoroamine, an unexpected difficulty arises as described in the following. When HF-Lewis base such as Et3N-3HF is used for the halogen-fluorine exchange reaction, the ratio of the amounts by mole of HF and the Lewis base is not always 1:1, and HF derived from HF-Lewis base used for the reaction is left remaining after the halogen exchange reaction is completed. This causes a serious problem in that separation of the product becomes difficult since molecular compounds are formed due to the interaction between HF and the nitrogen atom in the substrate or the product. Moreover, there is the possibility that the remaining HF causes corrosion. The process becomes complicated since steps for separation and purification must be added for obtaining the product.
No patents or references which mention the problems described above such as the problems in the industrial production of α,α-difluoroamine using Et3N-3HF or the means for solving the problems can be found.
[Patent Reference 1] Japanese Patent Application Publication No. Showa 63 (1988)-25570
[Patent Reference 2] Japanese Patent Application Laid-Open No. 2000-1477
[Patent Reference 2] Japanese Patent Application Laid-Open No. 2003-64034
[Non-Patent Reference 1] Yuki Gosei Kagaku Kyokaishi, 37, 1979, p. 606
[Non-Patent Reference 2] Yuki Gosei Kagaku Kyokaishi, 47, 1989, p. 258
[Non-Patent Reference 3] Journal of Organic Chemistry, 44, 1979, p. 3872
[Non-Patent Reference 4] Chemistry of Organic Fluorine Compounds II, Monograph, American Chem. Soc., 1995, p. 187