METHOD OF PREPARING DIFLUORINATED ALCOHOL COMPOUND

Abstract

A method of preparing a difluorinated alcohol compound is provided. The difluorinated alcohol compound can be easily synthesized when an aldehyde and N-fluorobenzenesulfonimide are reacted in the presence of L-proline, and thus the method has advantage in that preparation processes are simple and reagents are economical and safe, compared to the related-art methods. Therefore, the preparation method can be effectively applied to prepare a difluorinated alcohol used in various applications for raw materials such as functional medicines, agricultural chemicals, polymerizable compounds, etc.

Claims

1. A method of preparing a difluorinated alcohol, comprising reacting an aldehyde and a fluorine-containing compound, wherein the fluorine-containing compound comprises any one selected from the group consisting of N-fluorobenzenesulfonimide, Selectfluor, 1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (NFTh), and N-fluoropyridinium pyridine heptafluorodiborate (NFPy).

2. The method of claim 1, wherein the reaction of the aldehyde and the fluorine-containing compound is performed in the presence of any one compound selected from the group consisting of L-proline, D-proline, (S)-α allyl-proline hydrochloride, (R)-pyrrolidine-2-carboxylic acid methyl ester, H-D-pro-O-ethyl hydrochloride, and D-proline methyl ester hydrochloride.

3. The method of claim 1, wherein the aldehyde is represented by the following Formula 1: ##STR00026## wherein R.sub.1 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group.

4. The method of claim 3, wherein R.sub.1 in Formula 1 is an unsubstituted phenyl group, or a phenyl group substituted with —OCH.sub.3, —CH.sub.3, —F, —Cl, —Br, —CF.sub.3, —CN, or —NO.sub.2.

5. The method of claim 1, wherein the aldehyde is represented by the following Formula 2: ##STR00027## wherein R.sub.2 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and R.sub.3 represents any one selected from the group consisting of a hydrogen atom, an unsubstituted C.sub.1 to C.sub.20 alkyl group, and a substituted C.sub.1 to C.sub.20 alkyl group.

6. The method of claim 5, wherein R.sub.2 in Formula 2 is an unsubstituted phenyl group, or a phenyl group substituted with —OCH.sub.3, —CH.sub.3, —F, —Cl, —Br, —CF.sub.3, —CN, or —NO.sub.2, and R.sub.3 is a hydrogen atom, —CH.sub.3, or C.sub.2H.sub.5.

7. The method of claim 1, wherein the aldehyde is represented by the following Formula 3: ##STR00028## wherein R.sub.4 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and n is in a range of 1 to 20.

8. The method of claim 3, wherein the difluorinated alcohol is represented by the following Formula 4: ##STR00029## wherein R.sub.1 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group.

9. The method of claim 8, wherein R.sub.1 in Formula 4 is an unsubstituted phenyl group, or a phenyl group substituted with —OCH.sub.3, —CH.sub.3, —F, —Cl, —Br, —CF.sub.3, —CN, or —NO.sub.2.

10. The method of claim 5, wherein the difluorinated alcohol is represented by the following Formula 5: ##STR00030## wherein R.sub.2 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and R.sub.3 represents any one selected from the group consisting of a hydrogen atom, an unsubstituted C.sub.1 to C.sub.20 alkyl group, and a substituted C.sub.1 to C.sub.20 alkyl group.

11. The method of claim 10, wherein R.sub.2 in Formula 5 is an unsubstituted phenyl group, or a phenyl group substituted with —OCH.sub.3, —CH.sub.3, —F, —Cl, —Br, —CF.sub.3, —CN, or —NO.sub.2, and R.sub.3 is a hydrogen atom, —CH.sub.3, or C.sub.2H.sub.5.

12. The method of claim 7, wherein the difluorinated alcohol is represented by the following Formula 6: ##STR00031## wherein R.sub.4 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and n is in a range of 1 to 20.

13. A method of preparing a difluorinated alcohol, comprising reacting an aldehyde and a fluorine-containing compound, wherein the fluorine-containing compound comprises any one selected from the group consisting of N-fluorobenzenesulfonimide, Selectfluor, 1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (NFTh), and N-fluoropyridinium pyridine heptafluorodiborate (NFPy), a first solvent is used in a fluorination reaction, a second solvent is used in a reduction reaction, and the first solvent and the second solvent are different from each other.

14. The method of claim 13, wherein the reaction of the aldehyde and the fluorine-containing compound is performed in the presence of any one compound selected from the group consisting of L-proline, D-proline, (S)-α allyl-proline hydrochloride, (R)-pyrrolidine-2-carboxylic acid methyl ester, H-D-pro-O-ethyl hydrochloride, and D-proline methyl ester hydrochloride.

15. The method of claim 13, wherein the first solvent used in the fluorination reaction comprises any one compound selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), and acetonitrile (ACN).

16. The method of claim 13, wherein the second solvent used in the reduction reaction comprises any one compound selected from the group consisting of methanol, ethanol, butanol, and isopropanol.

17. The method of claim 1, further comprising: adding sodium borohydride after the reaction of the aldehyde and the fluorine-containing compound.

18. The method of claim 17, wherein the addition of the sodium borohydride comprises stirring reaction mixture at room temperature for 1 hour to 6 hours.

19. The method of claim 1, wherein the reaction temperature is in a range of 0° C. to 100° C.

20. The method of claim 1, wherein the reaction time is in a range of 2 hours to 24 hours.

Description

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0041] Exemplary embodiments of the present invention will be described in detail below. While the present invention is shown and described in connection with exemplary embodiments thereof, it will be apparent to those skilled in the art that various modifications can be made without departing from the scope of the invention.

[0042] Unless specifically stated otherwise, all the technical and scientific terms used in this specification have the same meanings as what are generally understood by a person skilled in the related art to which the present invention belongs. In general, the nomenclature used in this specification and the experimental methods described below are widely known and generally used in the related art.

[0043] The method of preparing a difluorinated alcohol according to one exemplary embodiment of the present invention may include reacting an aldehyde and a fluorine-containing compound.

[0044] NF-based reagents such as N-fluorobenzenesulfonimide, Selectfluor, 1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (NFTh), N-fluoropyridinium pyridine heptafluorodiborate (NFPy), and the like may be used as the fluorine-containing compound. The use of N-fluorobenzenesulfonimide is most preferred since the N-fluorobenzenesulfonimide is inexpensive and has a high yield, and a small amount of byproducts are produced.

[0045] The reaction may be carried out using a reaction compound. Also, examples of the reaction compound that may be used herein may include L-proline, D-proline, (S)-α allyl-proline hydrochloride, (R)-pyrrolidine-2-carboxylic acid methyl ester, H-D-pro-O-ethyl hydrochloride, D-proline methyl ester hydrochloride, etc. The use of L-proline is most preferred since the L-proline has a high yield and is inexpensive.

[0046] When the aldehyde, the fluorine-containing compound, and the reaction compound are present at a ratio of 1:(2 to 4):(0.1 to 4), the yield may be highest, and byproducts may be produced at a slowly increasing rate. In particular, the ratio of the aldehyde, N-fluorobenzenesulfonimide and L-proline is most preferably in a range of 1:(2 to 4):(0.1 to 4). It is not desirable that each of the components is present in an amount less than in this molar ratio, as the yield may be lowered. On the other hand, in terms of economy, it is not preferred that each of the components is present in an amount greater than in this molar ratio, as byproducts may be produced.

[0047] In the method of preparing the difluorinated alcohol, a first solvent used in a fluorination reaction, and a second solvent used in a reduction reaction may be different from each other.

[0048] The first solvent is preferably used in the fluorination reaction. Polar aprotic solvents such as dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile (ACN), and the like may be used as the first solvent. The use of dimethylacetamide (DMAc) is most preferred in terms of high yield and less byproducts.

[0049] The second solvent is preferably used in the reduction reaction. Alcohol-based solvents such as methanol, ethanol, butanol, isopropanol, and the like may be used as the second solvent. The use of methanol is most preferred in terms of high yield.

[0050] A compound represented by the following Chemical Formula 1 may be used as the aldehyde, but a compound represented by the following Formula 1 is particularly preferred:

##STR00007## [0051] wherein R represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group; and

##STR00008## [0052] wherein R.sub.1 may represent any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group.

[0053] Preferably, R.sub.1 may be an unsubstituted phenyl group. Optionally, R.sub.1 may be a phenyl group substituted with OCH.sub.3, CH.sub.3, F, Cl, Br, CF.sub.3, CN, or NO.sub.2.

[0054] More preferably, R.sub.1 may be represented by one of the following Formulas.

##STR00009## ##STR00010## [0055] (wherein * represents a group used to link a residue of Formula 1-1 to the R.sub.1 group.)

##STR00011##

[0056] A compound represented by the following Formula 2 may be preferably used as the aldehyde:

##STR00012## [0057] wherein R.sub.2 may represent any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic grouped, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and R.sub.3 may represent any one selected from the group consisting of a hydrogen atom, an unsubstituted C.sub.1 to C.sub.20 alkyl group, and a substituted C.sub.1 to C.sub.20 alkyl group.

[0058] Preferably, an unsubstituted phenyl group may be used as R.sub.2. Optionally, a phenyl group substituted with OCH.sub.3, CH.sub.3, F, Cl, Br, CF.sub.3, CN, or NO.sub.2 may be used as R.sub.2. More preferably, a compound represented by one of the following Formulas may be used as R.sub.2.

##STR00013## ##STR00014## [0059] (wherein * represents a group used to link a residue of Formula 2-1 to the R.sub.2 group.)

##STR00015##

[0060] Preferably, a hydrogen atom, CH.sub.3, or C.sub.2H.sub.5 may be used as R.sub.3.

[0061] A compound represented by the following Formula 3 may be used as the aldehyde according to one exemplary embodiment of the present invention:

##STR00016## [0062] wherein R.sub.4 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and n is in a range of 1 to 20.

[0063] The compound prepared by the method of preparing a difluorinated alcohol according to one exemplary embodiment of the present invention may be represented by Formula 4:

##STR00017## [0064] wherein R.sub.1 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group.

[0065] According to another exemplary embodiment of the present invention, R.sub.1 in Formula 4 may be an unsubstituted phenyl group. Optionally, R.sub.1 may be a phenyl group substituted with OCH.sub.3, CH.sub.3, F, Cl, Br, CF.sub.3, CN, or NO.sub.2.

[0066] More preferably, R.sub.1 may be represented by one of the following Formulas.

##STR00018## ##STR00019## [0067] (wherein * represents a group used to link a residue of Formula 4-1 to the R.sub.1 group.)

##STR00020##

[0068] The compound prepared by the method of preparing a difluorinated alcohol according to one exemplary embodiment of the present invention may be represented by the following Formula 5:

##STR00021## [0069] wherein R.sub.2 may represent any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and R.sub.3 may represent any one selected from the group consisting of a hydrogen atom, an unsubstituted C.sub.1 to C.sub.20 alkyl group, and a substituted C.sub.1 to C.sub.20 alkyl group.

[0070] Preferably, R.sub.2 may be an unsubstituted phenyl group. Optionally, R.sub.2 may be a phenyl group substituted with OCH.sub.3, CH.sub.3, F, Cl, Br, CF.sub.3, CN, or NO.sub.2. R.sub.3 may be a hydrogen atom, —CH.sub.3, or C.sub.2H.sub.5.

[0071] More preferably, a compound represented by one of the following Formulas may be used as R.sub.2.

##STR00022## ##STR00023## [0072] (wherein * represents a group used to link a residue of Formula 5-1 to the R.sub.2 group.)

##STR00024##

[0073] The difluorinated alcohol may be a compound represented by the following Formula 6:

##STR00025## [0074] wherein R.sub.4 represents any one selected from the group consisting of an unsubstituted C.sub.1 to C.sub.20 alkyl group, a substituted C.sub.1 to C.sub.20 alkyl group, an unsubstituted phenyl group, a substituted phenyl group, an unsubstituted heterocyclic group, a substituted heterocyclic group, an unsubstituted cyclohexyl group, and a substituted cyclohexyl group, and n is in a range of 1 to 20.

[0075] The method may further include adding sodium borohydride after the reaction of the aldehyde and the fluorine-containing compound.

[0076] Also, the addition of the sodium borohydride may include stirring reaction mixture at room temperature for 1 hour to 6 hours.

[0077] The temperature at which the aldehyde and the N-fluorobenzenesulfonimide are reacted may be in a range of 0° C. to 100° C. When the reaction temperature is less than 0° C., a lot of time may be required for the reaction, and the yield may be low. On the other hand, when the reaction temperature is greater than 100° C., the reaction byproducts may rapidly increase. Preferably, the reaction temperature may be room temperature.

[0078] Also, the reaction time may be in a range of 1 hour to 24 hours.

[0079] When the reaction time is shorter than 1 hour, the yield may be very low. On the other hand, when the reaction time is longer than 24 hours, the reaction byproducts may increase. Preferably, the reaction time may be in a range of 1 hour to 6 hours.

Example 1: Preparation of β,β-difluorobenzenepropanol

[0080] 50 g of 3-phenylpropionaldehyde, 13 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 235 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 62 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain β,β-difluorobenzenepropanol with a yield of 86%.

Example 2: Preparation of 2,2-difluoro-2-phenylethanol

[0081] 50 g of phenylacetaldehyde, 14 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 262 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 83 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-phenylethanol with a yield of 72%.

Example 3: Preparation of 2,2-difluoro-2-(4-methoxyphenyl)ethanol

[0082] 50 g of 2-(4-methoxyphenyl)acetaldehyde, 11 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 209 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 56 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-methoxyphenyl)ethanol with a yield of 90%.

Example 4: Preparation of 2,2-difluoro-2-(4-methylphenyl)ethanol

[0083] 50 g of 2-(4-methylphenyl)acetaldehyde, 13 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 235 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 96 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-methylphenyl)ethanol with a yield of 83%.

Example 5: Preparation of 2,2-difluoro-2-(4-fluorophenyl)ethanol

[0084] 50 g of 2-(4-fluorophenyl)acetaldehyde, 12 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 228 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 76 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-fluorophenyl)ethanol with a yield of 68%.

Example 6: Preparation of 2,2-difluoro-2-(4-chlorophenyl)ethanol

[0085] 50 g of 2-(4-chlorophenyl)acetaldehyde, 11 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 204 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 75 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-chlorophenyl)ethanol with a yield of 69%.

Example 7: Preparation of 2,2-difluoro-2-(4-bromophenyl)ethanol

[0086] 50 g of 2-(4-bromophenyl)acetaldehyde, 8 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 158 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 39 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-bromophenyl)ethanol with a yield of 67%.

Example 8: Preparation of 2,2-difluoro-2-(4-trifluoromethylphenyl)ethanol

[0087] 50 g of 2-(4-trifluoromethylphenyl)acetaldehyde, 9 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 167 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 54 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-trifluoromethylphenyl)ethanol with a yield of 60%.

Example 9: Preparation of 2,2-difluoro-2-(4-cyanophenyl)ethanol

[0088] 50 g of 2-(4-cyanophenyl)acetaldehyde, 12 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 217 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 67 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-cyanophenyl)ethanol with a yield of 58%.

Example 10: Preparation of 2,2-difluoro-2-(4-nitrophenyl)ethanol

[0089] 50 g of 2-(4-nitrophenyl)acetaldehyde, 10 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 191 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 62 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain 2,2-difluoro-2-(4-nitrophenyl)ethanol with a yield of 57%.

Example 11: Preparation of β-difluoro-γ-methylbenzene propanol

[0090] 50 g of 3-phenyl butyl aldehyde, 11 g of L-proline, and 250 mL of dimethylacetamide were put into a 1,000-mL reactor equipped with a stirring apparatus, and stirred at room temperature for 30 minutes. 213 g of N-fluorobenzenesulfonimide was added thereto, and stirred at room temperature for 4 hours. When the reaction was completed, water and organic solvent were added to chemical compound containing the aldehyde, the L-proline and the dimethylacetamide. Since then, water layer and organic solvent layer containing the chemical compound was produced. Under depressurization, the organic solvent layer of the layers was separated. In sequence, the organic solvent was removed from the organic solvent layer and then residue of the organic solvent layer was dissolved in 250 mL of methanol. After the temperature was reduced to 0° C., 36 g of sodium borohydride was added. After the temperature was warmed to room temperature, the resulting mixture was stirred for 2 hours. When the reaction was completed, a layer was separated to obtain β-difluoro-γ-methylbenzene propanol with a yield of 80%.

[0091] Accordingly, to improve the problems of the prior-art methods which are uneconomical due to the use of an expensive reagent and complicated synthesis process, the present inventors have simply synthesized a difluorinated alcohol by reacting N-fluorobenzenesulfonimide and an aldehyde in the presence of L-proline.

[0092] Since such a difluorinated alcohol compound can be introduced as a pharmaceutical intermediate, and can be prepared through a one-step process. As a result, a conventional multi-step complicated synthesis process can be simplified, thereby reducing production costs without using an additional reagent or requiring a production process. Owing to these characteristics, the method of the present invention is suitable for mass producing the difluorinated alcohol.

[0093] It will be apparent to those skilled in the art that various modifications can be made to the above-described exemplary embodiments of the present invention without departing from the scope of the invention. Thus, it is intended that the present invention covers all such modifications provided they come within the scope of the appended claims and their equivalents.