KR20100117221A - Preparation method of organo fluoro compound, preparation method of product obtained by a nucleophilic substitution using bifunctional compound as solvent - Google Patents

Abstract

PURPOSE: A fabricating method of an organic fluoro compound with the high yield, and a manufacturing method of a nucleophilic displacement product are provided to improve the speed of the displacement reaction using a bi-functional compound as a solvent. CONSTITUTION: A manufacturing method of a nucleophilic displacement product comprises a step of reacting alkyl halide or alkyl sulfonate, with metal salt or ammonium salt inside an organic solvent. The organic solvent is a bi-functional compound marked with chemical formula 1. In the chemical formula 1, R1, R2, and R3 are hydrogen or a C1~C10 alkyl group. The metal salt is selected from the group consisting of lithium salt, sodium salt, potassium salt, rubidium, and cesium salt.

Description

PREPARATION METHOD OF ORGANO FLUORO COMPOUND, PREPARATION METHOD OF PRODUCT OBTAINED BY A NUCLEOPHILIC SUBSTITUTION USING BIFUNCTIONAL COMPOUND AS SOLVENT}

The present invention relates to a process for the preparation of organofluoro compounds and nucleophilic substitution products by reacting alkyl halides, alkyl sulfonates or aryl sulfonates with metal salts or ammonium salts in a bifunctional solvent.

Organofluoro compounds, unlike general organic compounds, have unique chemical and physiological properties and are useful in various fields such as medicine, pesticides, dyes and polymers (Gerstenberger, MRC; Haas, A. Angew. Chem., Int. Ed. Engl. 1981 , 20, 647; Filler, R. In Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications , Filler, R., Ed., Studies in Organic Chemistry 48, Elservier, New York, 1993 , p 1-23).

Various methods of preparing such organofluoro compounds have been reported and described in detail below.

Alcoholic solvents, which are usually protic in the nucleophilic substitution reaction, are known to slow down the reaction rate and reduce the reactivity by lowering the ground state energy by solvating the nucleophile (J. McMurry, Organic Chemistry, 6 ^th ed .; Thomson: 2005; pp 356).

In particular, it has been known that a process for preparing an organofluoro compound through a nucleophilic substitution reaction using a fluorine salt proceeds only under severe conditions due to limited solubility and low nucleophilicity in their organic solvents.

For example, a method for preparing an organofluoro compound has been reported by reacting an alkyl halide and potassium fluoride under ethylene glycol solvent conditions (FW Hoffmann, J. Am . Chem) . . Soc., 1948, 70, 2596). However, since the method is inferior in reactivity due to the low solubility of the potassium fluoride, it is required to react for a long time at a high temperature of 140 ° C. or higher during the preparation of the organofluoro compound, and the product is obtained in low yield.

In order to improve the solubility of the fluorine salt and increase the reactivity of the fluoride, Riota et al., Using a 18-crown-6 ether having a strong bond with a metal ion as a catalyst, a relatively low temperature of 80 ~ 90 ℃ And a process for preparing organofluoro compounds in good yield under mild conditions (CL Liotta, J. Am . Chem . Soc ., 1974 , 96, 2250 ). However, the method requires a long reaction time of 100 hours or more, fluoride acts as a base to generate a large amount of alkene, a side reaction, and furthermore, 18-crown-6 ether is expensive.

Cox et al. Reported that when tetrabutylammonium fluoride was used as the fluorine salt, organofluoro compounds were prepared in excellent yield under mild reaction conditions (DP Cox, J. Terpinski, W. Lawrynowicz, J. Org. Chem. 1984 , 49, 3216). However, even when the organic fluoro compound is prepared using the tetrabutylammonium fluoride, since water is always present, a problem in which a large amount of alcohol, a secondary reactant by water, is generated as shown in Scheme 1 and tetrabutyl. It is accompanied by alkene, a side reaction that occurs due to the high basicity of ammonium fluoride.

In order to solve the problem that these side reactions are generated, 5-8 equivalents of ionic liquids and potassium fluoride have been reported to complete the fluorination reaction with high selectivity in a short time (DW Kim, CE Song, DY Chi, J. Am. Chem. Soc. 2002, 124, 10278; Korean Patent No. 0441153). However, there is a disadvantage that an expensive ionic liquid must be used in excess and an anion of the ionic liquid can be used as a reactant in the substitution reaction, so that only a specific ionic liquid should be used.

On the other hand, the most efficient method using the metal fluoride developed to date, there is a method for preparing an organic fluoride compound in a relatively mild conditions using cesium fluoride in a bulky alcohol solvent (DY Chi, J. Am. Chem, Soc. J. Am. Chem. Soc. 2006, 128, 16394; Korean Patent No. 0789847). When the reaction proceeds under the above conditions, the organic fluoride compound can be successfully obtained in a high yield in a short time under relatively mild conditions, but there is a problem in industrial applications because only expensive cesium fluoride should be used.

The present inventors have intensively studied to solve the problems of the above-described preparation methods for producing an organofluoro compound, and as a result, an organofluoro compound and a nucleophilic substitution using a difunctional compound represented by the following formula (1) as a solvent When preparing the product of the reaction, it was found that the product of the organofluoro compound and the nucleophilic substitution reaction can be obtained in high yield and high selectivity without generation of side reactants.

It is an object of the present invention to increase the rate of substitution reaction by using a bifunctional compound as a solvent in the process of preparing a nucleophilic substitution reaction product, thereby shortening the reaction time to obtain a high yield, highly selective nucleophilic substitution reaction product. To provide a process for the preparation of a nucleophilic substitution reaction product.

Another object of the present invention is to increase the rate of substitution reaction by using a bifunctional compound as a solvent in the process of preparing an organofluoro compound to shorten the reaction time to obtain a high yield, highly selective organofluoro compound, It is to provide a method for producing an organofluoro compound.

It is another object of the present invention to provide the use of a bifunctional compound as a solvent in a process for preparing a nucleophilic substitution product via a nucleophilic substitution reaction by reacting an organic source with a nucleophilic source.

In order to achieve the above object, the present invention is a method for preparing a nucleophilic substitution reaction product by reacting an alkyl halide or alkyl sulfonate with a metal salt or an ammonium salt in an organic solvent, wherein the organic solvent is a bifunctional represented by the following formula (1) It provides a method for producing a nucleophilic substitution reaction product, characterized in that the compound.

The present invention also provides a method for preparing an organofluoro compound by reacting an alkyl halide or an alkyl sulfonate with a fluorine salt under an organic solvent, wherein the organic solvent is a difunctional compound represented by Chemical Formula 1 above. It provides a method for producing a compound.

R ₁ and R ₂ in Chemical Formula 1 And R ₃ are each independently hydrogen or a C ₁ -C ₁₀ alkyl group, n is an integer of 1 or 2 and m is an integer of 1-10.

In Formula 1, R ₁ is hydrogen or methyl, R ₂ is hydrogen or methyl, and R ₃ is more preferably hydrogen, methyl or ethyl.

The method for preparing an organofluoro compound and the method for preparing a nucleophilic substitution reaction product according to the present invention use a difunctional compound as a solvent to shorten the reaction time compared to the prior art, thereby yielding high yield, high selective organofluoro compound and Nuclear substitution reaction products can be obtained, with the effect of significantly reducing the production of side reactions.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

The present invention is a method of preparing a nucleophilic substitution reaction product by reacting an alkyl halide or alkyl sulfonate with a metal salt or an ammonium salt in an organic solvent, wherein the organic solvent is a nucleophilic compound represented by the following Chemical Formula 1. Provided is a method for preparing a substitution reaction product.

[Formula 1]

R ₁ and R ₂ in Chemical Formula 1 And R ₃ are each independently hydrogen or a C ₁ -C ₁₀ alkyl group, n is an integer of 1 or 2 and m is an integer of 1-10.

In Formula 1, R ₁ is hydrogen or methyl, R ₂ is hydrogen or methyl, and R ₃ is more preferably hydrogen, methyl or ethyl.

In Formula 1, when R ₃ is hydrogen, n is preferably 1, and m is an integer of 2 to 7. In Formula 1, when R ₃ is a C ₁ to C ₁₀ alkyl group, n is 2 and m is 5 to 10. It is preferable that it is an integer.

Method for producing a nucleophilic substitution reaction product according to the present invention can be carried out as shown in Scheme 2 using a bifunctional compound represented by the formula (1) as a solvent.

Wherein R-X is alkyl halide or alkyl sulfonate, M is lithium, sodium, potassium, cesium, rubidium or ammonium, Nu is an anion nucleophile, and RNu is a nucleophilic substitution product.

In the method for preparing a nucleophilic substitution product of the present invention, when a nucleophilic substitution reaction product is prepared by reacting an alkyl halide or alkyl sulfonate with a metal salt or an ammonium salt as shown in Scheme 2, the bifunctional compound of Formula 1 is a solvent. It is characterized by using as.

In the process of preparing a nucleophilic substitution reaction product according to the present invention, when the bifunctional compound of Chemical Formula 1 is used as a solvent, the product of the nucleophilic substitution reaction in high yield is obtained by shortening the reaction time by increasing the rate of substitution reaction. can do. Hereinafter, the action of the bifunctional compound when the nucleophilic substitution reaction product is prepared will be described in detail with reference to FIG. 1.

FIG. 1 is a view schematically illustrating a mechanism of action of a bifunctional compound when the bifunctional compound of Formula 1 is used as a solvent in a method of preparing a nucleophilic substitution reaction product in which an alkyl halide or alkyl sulfonate is reacted with a metal salt. Referring to FIG. 1, the bifunctional compound represented by Chemical Formula 1 has a non-covalent electron pair of ether group oxygen of a bifunctional compound as provided in a metal cation to form a coordination bond to form a coordination bond, as shown by arrow 1, and the nucleophilicity of the anion. It acts to increase. As indicated by arrow 2, the bifunctional compound increases the nucleophilicity and lowers the basicity by allowing hydrogen of the hydroxy group at the terminal of the bifunctional compound to hydrogen bond with the anion nucleophile of the metal salt, thereby increasing the distance from the metal cation. Play a role. In addition, the bifunctional compound serves to increase the leaving property of the leaving group by the hydrogen bonding of the leaving group of the alkyl halide or alkyl sulfonate with hydrogen of the hydroxyl group at the end of the bifunctional compound, as indicated by arrow 3.

The bifunctional compound represented by Formula 1 is triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol Kohl, decaethylene glycol, dipropylene glycol, tripropylene glycol, tetrapropylene glycol, pentapropylene glycol, hexapropylene glycol, heptapropylene glycol, octapropylene glycol, Nonapropylene glycol, decapropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tetraethylene glycol monomethyl ether, pentaethylene glycol monomethyl ether, hexaethylene Glycol monomethyl ether, heptaethylene glycol mono methyl ether, octaethylene glycol monomethyl ether, nonaethylene glycol monomethyl ether, Carethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, tetraethylene glycol monoethyl ether, pentaethylene glycol monoethyl ether, hexaethylene glycol Monoethyl ether, heptaethylene glycol monoethyl ether, octaethyl glycol glycol monoethyl ether, nonaethylene glycol monoethyl ether, decaethylene glycol monoethyl ether and the like, and more preferably Among the compounds of triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol, decaethylene glycol May be selected or mixtures thereof. The bifunctional compound of Formula 1 has a different chemical reactivity depending on its length and substituents. The bifunctional compound of Formula 1 may be used as a single solvent, a mixed solvent of difunctional compounds of Formula 1, or a mixed solvent of difunctional compounds of Formula 1 with an organic solvent to increase the solubility of metal salts or ammonium salts, It increases the rate of substitution by the counterion of the ammonium salt and serves to suppress side reactions. Therefore, any non-covalent electron pair of ether group oxygen of the bifunctional compound of Formula 1 can be used as long as it can coordination sufficiently with the metal salt or ammonium salt.

In the method for producing a nucleophilic substitution reaction product according to the present invention, the metal salt is preferably lithium salt, sodium salt, potassium salt, rubidium salt, cesium salt, more preferably potassium salt, cesium salt, rubidium salt, More preferably potassium salt. The anion nucleophile bonded to the metal or ammonium in the metal salt or ammonium salt may be a halide nucleophile, an oxygen nucleophile, a sulfur nucleophile, a nitrogen nucleophile, or a carbon nucleophile. These metal salts or ammonium salts may be adsorbed by any one support selected from Celite, Molecular sieve, Alumina and Silica gel.

In a method for preparing a nucleophilic substitution reaction product according to the present invention, the most preferable combination of the metal salt and the difunctional compound of formula (1) is the potassium salt, and the difunctional compound of the formula (1) is triethylene glycol , Tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, hepethylene glycol, octaethylene glycol, nonaethylene glycol, decaethylene glycol, mixed solvents of these compounds or The mixed solvent which mixed these compounds with the organic solvent can be used.

The present invention provides a method for preparing a nucleophilic substitution reaction product by reacting an alkyl halide or alkyl sulfonate with a metal salt or an ammonium salt, using the compound represented by Chemical Formula 1 as a solvent and reacting at 70 to 130 ° C. In particular, the reaction can be carried out at 90 ~ 120 ℃.

The metal salt or ammonium salt is preferably reacted with 1 to 10 equivalents to a substrate such as alkyl sulfonate, alkyl halide, and more preferably 3 to 5 equivalents.

The present invention also provides a method for preparing an organofluoro compound by reacting an alkyl halide or an alkyl sulfonate with a fluorine salt under an organic solvent, wherein the organic solvent is a difunctional compound represented by Chemical Formula 1 above. It provides a method for producing a compound.

The method for preparing an organofluoro compound according to the present invention is a method for preparing a nucleophilic substitution reaction product as described above, except that a fluorine salt including a metal salt or an ammonium salt to which an fluoride is bonded is used to prepare the organofluoro compound. The same is done.

As the fluorine salt used in the method for producing an organofluoro compound according to the present invention, it is preferable to use alkali metal fluoride and ammonium fluoride including alkali metal selected from the group consisting of potassium, rubidium and cesium. The ammonium fluorides include quaternary ammonium fluorides including tetrabutylammonium fluoride and benzyltrimethyl ammonium fluoride; Tertiary ammonium fluorides including triethylammonium fluoride, tributylammonium fluoride; Secondary ammonium fluoride including dibutylammonium fluoride, dihexylammonium fluoride; It may be selected from the group consisting of primary ammonium fluoride, including butyl ammonium fluoride, hexyl ammonium fluoride.

The fluorine salt is preferably reacted with 1 to 10 equivalents to a substrate such as alkyl sulfonate, alkyl halide, and more preferably 3 to 5 equivalents.

In the method for preparing the nucleophilic substitution reaction product and the method for preparing the organofluoro compound of the present invention, the halide in the alkyl halide or alkyl sulfonate used to prepare the organofluoro compound is used as the halide except for F.

The present invention also provides the use of a bifunctional compound represented by the following formula (1) as a solvent in a method for producing a nucleophilic substitution product through a nucleophilic substitution reaction by reacting an organic source and a nucleophile source.

[Formula 1]

R ₁ and R ₂ in Chemical Formula 1 And R ₃ Are each independently hydrogen or a C ₁ -C ₁₀ alkyl group, n is an integer of 1 or 2 and m is an integer of 1-10.

When a nucleophilic substitution product is prepared through a nucleophilic substitution reaction by reacting an organic material source with a nucleophilic source, it is not known to use the bifunctional compound of Formula 1 as a solvent, and when using it as a solvent within a short time It has the advantage of being able to produce nucleophilic substitution products in high yield.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

< Example >

Example  One - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of triethylene glycol 0.5 mL to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (19 mg, 93%).

Example  2 - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (18.8 mg, 92%).

Example  3 - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of hexaethylene glycol to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (17.9 mg, 88%).

Example  4 - Organofluoro  Preparation of compounds

A reaction solution was prepared by adding 2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) in a 0.5 mL octaethylene glycol single solvent. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (17 mg, 83%).

Example  5 - Organochloro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (37 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-chloropropoxy) naphthalene (21.8 mg, 99%).

Example  6 - Organobromo  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium bromide (60 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1 hour. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-bromopropoxy) naphthalene (26.2 mg, 99%).

Example  7 - Organic Iodo  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium iodide (83 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1 hour. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-iodopropoxy) naphthalene (30.9 mg, 99%).

Example  8-Preparation of Organic Cyanide Compound

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium cyanide (33 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 4- (2-naphthaleneoxy) butannitrile naphthalene (20.9 mg, 95%).

Example  9-Preparation of Organoacetyl Compound

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium acetate (49 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 3- (2-naphthaleneoxy) propyl acetate (24.2 mg, 99%).

Example  10- Organothiocyanation  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium thiocyanate (49 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours and half, and the reaction solution was extracted three times with 7 mL of ethyl ether. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a vacuum distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-thiocyanated propoxy) naphthalene (24.1 mg, 99%).

Example  11- Organofluoro  Preparation of compounds

2- (3-bromopropoxy) naphthalene (26 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (17.4 mg, 85%).

Example  12- Organofluoro  Preparation of compounds

2- (3-iodopropoxy) naphthalene (31 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a 0.5 mL tetraethylene glycol single solvent to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (16.2 mg, 79%).

Example  13- Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of propylene glycol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (13.1 mg, 64%).

Example  14- Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of triethylene glycol monoethyl ether. Was prepared. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (8.6 mg, 42%).

Example  15- Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and cesium fluoride (76 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (14.5 mg, 71%).

Example  16- Organofluoro  Preparation of compounds

2- (3-paratoluenyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. . The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (18.4 mg, 90%).

Example  17- Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and tetrabutylammonium fluoride (130 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of tetraethylene glycol to prepare a reaction solution. It was. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1 hour. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (17.6 mg, 86%).

Comparative example  One - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (280 mg, 1.0 mmol) and potassium fluoride (290 mg, 5.0 mmol) with 18-crown-6 (529 mg, 2.0 mmol) and acetonitrile 3.2 mL Into a mixed solvent of to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 24 hours. The reaction solution was extracted three times with 7 ml of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a vacuum distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (82 mg, 40%).

Comparative example  2 - Organofluoro  Preparation of compounds

A reaction solution was prepared by adding 2- (3-methanesulfonyloxypropoxy) naphthalene (280 mg, 1.0 mmol) and potassium fluoride (290 mg, 5.0 mmol) to 5 ml of acetonitrile (CH3 CN) in a single solvent. It was. The reaction solution was stirred at a reaction temperature of 100 ° C. for 24 hours. As a result of the experiment, the reaction did not proceed at all.

Comparative example  3 - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (280 mg, 1.0 mmol) and potassium fluoride (290 mg, 5.0 mmol) were added to a single solvent of [bmim] [OTf] 5.0 ml to prepare a reaction solution. It was. The reaction solution was stirred at a reaction temperature of 100 ° C. for 4 hours. The reaction solution was extracted three times with 7 mL of ethyl ether, and the extract was dried over anhydrous sodium sulfate, filtered, and concentrated using a reduced pressure distillation unit. The concentrate was subjected to column chromatography (ethyl acetate: n-hexane = 1:20) to obtain 2- (3-fluoropropoxy) naphthalene (162 mg, 79%).

Comparative example  4 - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of t-butanol to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. As a result of the experiment, the reaction did not proceed at all.

Comparative example  5 - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a 0.5 mL t-amyl alcohol in a single solvent to prepare a reaction solution. The reaction solution was stirred at a reaction temperature of 100 ° C. for 1.5 hours. As a result of the experiment, the reaction did not proceed at all.

Comparative example  6 - Organofluoro  Preparation of compounds

2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) were added to a single solvent of 0.5 mL of triethylene glycol dimethyl ether to prepare a reaction solution. Prepared. The reaction solution was stirred at 100 ° C. for 1.5 hours, but the reaction did not proceed at all.

Comparative example  7 - Organofluoro  Preparation of compounds

Mixing 2- (3-methanesulfonyloxypropoxy) naphthalene (28 mg, 0.1 mmol) and potassium fluoride (29 mg, 0.5 mmol) with 0.25 mL of triethylene glycol dimethyl ether and 0.25 mL of t-butanol In a solvent to prepare a reaction solution. The reaction solution was stirred at 100 ° C. for 1.5 hours, but the reaction did not proceed at all.

The reaction time, temperature and yield required to obtain the products of the organofluoro compound and the nucleophilic substitution reaction prepared in Examples and Comparative Examples are shown in Table 1 below.

As shown in Table 1, the organic fluoro compound and the products of the nucleophilic substitution reaction prepared using the difunctional compound of Chemical Formula 1 according to the present invention as a solvent are faster than the organic fluoro compound prepared in Comparative Example. It can be seen that it was obtained in a high yield within.

FIG. 1 schematically illustrates the mechanism of action of a bifunctional compound when the bifunctional compound of Formula 1 is used as a solvent in the preparation of a nucleophilic substitution reaction product in which an alkyl halide or alkyl sulfonate is reacted with a metal salt.

Claims (25)

A method of preparing a nucleophilic substitution product by reacting an alkyl halide or alkyl sulfonate with a metal salt or an ammonium salt in an organic solvent, Method for producing a nucleophilic substitution reaction product characterized in that the organic solvent is a bifunctional compound represented by the following formula (1): [Formula 1]

R ₁ and R ₂ in Chemical Formula 1 And R ₃ is hydrogen or a C ₁ -C ₁₀ alkyl group, n is an integer of 1 or 2 and m is an integer of 1-10. The method of claim 1, Wherein said metal salt is selected from the group consisting of lithium salts, sodium salts, potassium salts, rubidium and cesium salts. The method of claim 1, In Chemical Formula 1, R ₁ is hydrogen or methyl, R ₂ is hydrogen or methyl, and R ₃ is hydrogen, methyl or ethyl. The method of claim 1, In Formula 1, R ₃ is hydrogen, n is 1, m is a method for producing a nucleophilic substitution reaction product, characterized in that an integer of 2 to 7. The method of claim 1, In Chemical Formula 1, R ₃ is a C ₁ -C ₁₀ alkyl group, n is 2, m is a method for producing a nucleophilic substitution reaction product, characterized in that an integer of 5 to 10. The method of claim 1, The bifunctional compound represented by the formula (1) is triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol Glycol, decaethylene glycol, dipropylene glycol, tripropylene glycol, tetrapropylene glycol, pentapropylene glycol, hexapropylene glycol, heptapropylene glycol, octapropylene glycol Nonapropylene glycol, decapropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tetraethylene glycol monomethyl ether, pentaethylene glycol monomethyl ether, hexa Ethylene glycol monomethyl ether, heptaethylene glycol monomethyl ether, octaethylene glycol monomethyl ether, nonaethylene glycol monomethyl ether, Carethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, tetraethylene glycol monoethyl ether, pentaethylene glycol monoethyl ether, hexaethylene glycol At least one compound selected from the group consisting of monoethyl ether, heptaethylene glycol monoethyl ether, octaethyl glycol glycol monoethyl ether, nonaethylene glycol monoethyl ether, and decaethylene glycol monoethyl ether Method for producing a nucleophilic substitution reaction product characterized in that. The method of claim 6, The bifunctional compound is triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol and decaethylene glycol A process for producing a nucleophilic substitution reaction product, characterized in that at least one compound selected from the group consisting of lycols. The method of claim 1, The bifunctional compound represented by Chemical Formula 1 is a nucleophilic substitution reaction characterized in that it is used as a single solvent, a mixed solvent of difunctional compounds of Formula 1 or a mixed solvent of difunctional compounds of Formula 1 with an organic solvent. Method of Preparation of the Product. The method of claim 1, Wherein said metal salt is adsorbed on a support selected from the group consisting of celite, molecular sieve, alumina and silica gel. The method of claim 1, The anion nucleophile in the metal salt or ammonium salt is a method of producing a nucleophilic substitution reaction product, characterized in that selected from the group consisting of halide nucleophiles, oxygen nucleophiles, sulfur nucleophiles, nitrogen nucleophiles and carbon nucleophiles. The method of claim 1, Wherein said metal salt or ammonium salt is reacted in an amount of 1 to 10 equivalents based on alkyl halide or alkyl sulfonate. The method of claim 11, The metal salt or ammonium salt is reacted with 3 to 5 equivalents to the alkyl halide or alkyl sulfonate. A method of preparing an organofluoro compound by reacting an alkyl halide or an alkyl sulfonate with a fluorine salt in an organic solvent, Method for producing an organic fluoro compound, characterized in that the organic solvent is a bifunctional compound represented by the following formula (1): [Formula 1]

R ₁ and R ₂ in Chemical Formula 1 And R ₃ is hydrogen or a C ₁ -C ₁₀ alkyl group, n is an integer of 1 or 2 and m is an integer of 1-10. The method of claim 13, Wherein said fluorine salt is selected from alkali metal fluorides and ammonium fluorides comprising alkali metals selected from the group consisting of potassium, rubidium and cesium. The method of claim 14, The ammonium fluorides include quaternary ammonium fluorides including tetrabutylammonium fluoride and benzyltrimethyl ammonium fluoride; Tertiary ammonium fluorides including triethylammonium fluoride, tributylammonium fluoride; Secondary ammonium fluoride including dibutylammonium fluoride, dihexylammonium fluoride; A method for producing an organofluoro compound, characterized in that it is selected from the group consisting of butylammonium fluoride, primary ammonium fluoride including hexylammonium fluoride. The method of claim 13, In Formula 1, R ₁ is hydrogen or methyl group, R ₂ is hydrogen or methyl group, R ₃ is a method for producing an organofluoro compound, characterized in that hydrogen, methyl or ethyl group. The method of claim 13, In Formula 1 R ₃ is hydrogen, n is 1, m is a method for producing an organofluoro compound, characterized in that an integer of 2 to 7. The method of claim 13, In Formula 1, R ₃ is a C _{1 ~} C ₁₀ alkyl group, n is 2, m is a method for producing an organofluoro compound, characterized in that an integer of 5 to 10. The method of claim 13, The bifunctional compound represented by Formula 1 is triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol Kohl, decaethylene glycol, dipropylene glycol, tripropylene glycol, tetrapropylene glycol, pentapropylene glycol, hexapropylene glycol, heptapropylene glycol, octapropylene glycol, Nonapropylene glycol, decapropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, tetraethylene glycol monomethyl ether, pentaethylene glycol monomethyl ether, hexaethylene Glycol monomethyl ether, heptaethylene glycol monomethyl ether, octaethylene glycol monomethyl ether, nonaethylene glycol monomethyl ether, Carethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, tetraethylene glycol monoethyl ether, pentaethylene glycol monoethyl ether, hexaethylene glycol At least one compound selected from the group consisting of monoethyl ether, heptaethylene glycol monoethyl ether, octaethyl glycol glycol monoethyl ether, nonaethylene glycol monoethyl ether, and decaethylene glycol monoethyl ether Method for producing an organofluoro compound, characterized in that. The method of claim 19, The bifunctional compound is triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, octaethylene glycol, nonaethylene glycol and decaethylene glycol Process for producing an organofluoro compound, characterized in that at least one compound selected from the group consisting of lycol. The method of claim 13, The bifunctional compound represented by Chemical Formula 1 may be used as a single solvent, a mixed solvent in which difunctional compounds of Formula 1 are mixed, or a mixed solvent in which difunctional compound of Formula 1 is mixed with an organic solvent. Manufacturing method. The method of claim 13, The fluorine salt is a method for producing an organofluoro compound, characterized in that adsorbed on a support selected from the group consisting of celite, molecular sieve, alumina and silica gel. The method of claim 13, The fluorine salt is a method for producing an organofluoro compound, characterized in that the reaction with 1 to 10 equivalents relative to the alkyl halide or alkyl sulfonate. 24. The method of claim 23, The fluorine salt is a method for producing an organofluoro compound, characterized in that reacted with 3 to 5 equivalents relative to alkyl halide or alkyl sulfonate. In the method for preparing a nucleophilic substitution product through a nucleophilic substitution reaction by reacting an organic material source and a nucleophile source, a bifunctional compound represented by the following Chemical Formula 1 is used as a solvent: [Formula 1]

R ₁ and R ₂ in Chemical Formula 1 And R ₃ is hydrogen or a C ₁ -C ₁₀ alkyl group, n is an integer of 1 or 2 and m is an integer of 1-10.

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