JP5102985B2 - Method for producing fluorine-containing secondary amine compound - Google Patents

Description

  The present invention relates to a method for producing a fluorine-containing secondary amine compound. More specifically, the present invention relates to a method for producing a fluorine-containing secondary amine compound from a fluorine-containing aldehyde hemiacetal, a primary amine compound and a reducing agent.

  Fluorine-containing secondary amine compounds are extremely useful compounds that are widely used as intermediates for medicines and agricultural chemicals or raw materials for electronic materials. The following three methods are known as methods for synthesizing this fluorine-containing secondary amine compound. The first method is a method of reacting a fluorine-containing amine compound and a halide compound as disclosed in Patent Document 1, for example. In the case of this method, due to the strong electron withdrawing property of fluorine, there is a problem that the reactivity of the fluorine-containing amine compound as a raw material is low and the yield is low. For example, in the above publication, the yield of the target product is only 25% based on the halide compound while using 15 equivalents of a fluorine-containing amine. The second method is a method of reacting a primary amine compound and a fluorinated alkyl ester of trifluoromethanesulfonic acid as disclosed in Patent Document 2, Patent Document 3, and the like. In this method, although the reaction is relatively easy, three of the fluorine atoms contained in the raw material molecule are present in the by-product as a trifluoromethanesulfonate after completion of the reaction. For this reason, in order to carry out production in view of economic efficiency, it is necessary to recycle the trifluoromethanesulfonate, which causes a problem that the process becomes very complicated.

  The third method is a method of reacting a primary amine compound, a fluorinated aldehyde compound and a reducing agent as shown in Patent Document 4, Patent Document 5, Patent Document 6 and Patent Document 7, and the like. In this method, the reactivity of the raw material molecules is high, and all the fluorine atom groups contained in the raw material molecules can be introduced into the target product in principle, which can be said to be an efficient method. However, in Patent Document 4, the amines are limited to lower aliphatic amines, and in Patent Documents 5 to 7, extremely toxic sodium cyanoborohydride is used as a reducing agent. A problem occurs.

On the other hand, Non-Patent Document 1 reports that when a fluorine-containing aldehyde hemiacetal and an aromatic primary amine are reacted in an alcohol in the presence of an acid catalyst, an N, O-acetal compound is produced. However, nothing has been known about the production of fluorine-containing secondary amines using this.
WO 02/24663 pamphlet WO 02/12235 pamphlet WO 04/29043 pamphlet European Patent No. 156470 WO 01/16108 pamphlet WO 02/066645 pamphlet WO 05/085185 pamphlet J. Fluor. Chem., 125 (2004) 767

  The present invention has been made in view of these problems. That is, an object is to provide a method for producing a fluorine-containing secondary amine compound in a high yield from a primary amine compound and a fluorine-containing aldehyde hemiacetal without using a highly toxic reducing agent.

  In view of the above problems, the present inventors have intensively studied. As a result, an intermediate having a specific structure is produced from a primary amine compound and a fluorinated aldehyde hemiacetal, and then reduced to give a high yield of fluorinated 2 The inventors have found that a secondary amine compound can be obtained and have completed the present invention. That is, the present invention relates to the following gist.

  1. The following general formula (1)

(In the formula, X represents a fluorine atom or a hydrogen atom, n represents an integer of 1 to 10, and R ¹ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)
And a fluorine-containing aldehyde hemiacetal represented by the following general formula (2)

(In the formula, R ² is an unsubstituted aryl group having 6 to 30 carbon atoms, or an alkyl group, a halogenated alkyl group, an aryl group, an alkoxy group, a hydroxy group, a ketone group, an ester group, a carboxylic acid group, or an alkylthio group. And represents an aryl group having 6 to 30 carbon atoms substituted by a substituent selected from the group consisting of a thiol group, a cyano group, a nitro group and a halogen atom .)
In the alcohol solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, benzyl alcohol and phenol, an acid catalyst is present. The reaction is carried out under the following general formula (3)

(Wherein X, n, R ¹ and R ² are the same as defined above.)
The N, O-acetal compound represented by the general formula (4) is reacted with a reducing agent selected from molecular hydrogen or metal hydride in the presence of a catalytic hydrogenation reduction catalyst. )

(Wherein X, n and R ² are the same as defined above)
The manufacturing method of the fluorine-containing secondary amine compound represented by these.

2 . When producing the N, O-acetal compound represented by the general formula (3), the fluorine-containing aldehyde hemiacetal represented by the general formula (1) and the primary amine represented by the general formula (2) 2. The method for producing a fluorine-containing secondary amine compound according to 1, wherein the compound is reacted at a temperature of 50 to 150 ° C.

3 . Reducing agent, Ri molecular hydrogen der coexisted catalytic hydrogenation reduction catalyst, when performing a reduction reaction, item 1, characterized in Rukoto the presence of an acid catalyst or a fluorine-containing secondary described in the item 2 A method for producing an amine compound.

  According to the present invention, a fluorine-containing secondary amine compound can be produced in high yield from a primary amine compound and a fluorine-containing aldehyde hemiacetal without using a highly toxic reducing agent.

  In the present invention, the fluorine-containing aldehyde hemiacetal of the general formula (1) is reacted with the primary amine compound of the general formula (2) to produce the N, O-acetal compound of the general formula (3). This N, O-acetal compound is considered to be reduced by a reducing agent directly or via an imine intermediate (7) as shown in the following formula to produce a fluorinated secondary amine compound (4).

(Wherein Rf represents a perfluoroalkyl group having 1 to 10 carbon atoms, and R ¹ and R ² are the same as defined above)

The fluorine-containing aldehyde hemiacetal used in the present invention is represented by the general formula (1). In the general formula (1), X (CF ₂ ) n- is a perfluoroalkyl group or hydroperfluoroalkyl group having 1 to 10 carbon atoms, and R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms. is there. Examples of such fluorinated aldehyde hemiacetals include trifluoroacetaldehyde methyl hemiacetal, trifluoroacetaldehyde ethyl hemiacetal, trifluoroacetaldehyde n-propyl hemiacetal, trifluoroacetaldehyde isopropyl hemiacetal, trifluoroacetaldehyde n-butyl hemiacetal. , Trifluoroacetaldehyde isobutyl hemiacetal, trifluoroacetaldehyde t-butyl hemiacetal, trifluoroacetaldehyde n-hexyl hemiacetal, trifluoroacetaldehyde n-octyl hemiacetal, difluoroacetaldehyde methyl hemiacetal, perfluoropropanaldehyde methyl hemiacetal, perfluoroacetaldehyde Fluoro n-butane Aldehyde methyl hemiacetal and 2,2,3,3-tetrafluoro-propane aldehyde methyl hemiacetal, and the like.

Moreover, the primary amine compound used for this invention is represented by the said General formula (2). In the formula, R ² is an aryl group having 6 to 30 carbon atoms. Examples of the aryl group having 6 to 30 carbon atoms include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. These aryl groups may be substituted by a substituent, and examples of the substituent include alkyl groups, halogenated alkyl groups, aryl groups, alkoxy groups, hydroxy groups, ketone groups, ester groups, carboxylic acid groups, alkylthio groups, and thiols. Group, cyano group, nitro group, halogen atom and the like. Examples of such primary amine compounds include aniline, 1-naphthylamine, 2-naphthylamine, 2-methylaniline, 3-methylaniline, 4-methylaniline, 2,4-dimethylaniline, 4- (trifluoro Methyl) aniline, 4-phenylaniline, 3-methoxyaniline, 4-methoxyaniline, 4-hydroxyaniline, 4-acetylaniline, ethyl 4-aminobenzoate, 4-aminobenzoic acid, 4-methylthioaniline, 4-amino Mention may be made of thiophenol, 4-aminobenzonitrile, 4-nitroaniline, 4-fluoroaniline and the like.

As the fluorine-containing secondary amine compound of the general formula (4) obtained by the method of the present invention, for example,
N- (2,2,2-trifluoroethyl) aniline, N- (2,2,2-trifluoroethyl) -1-naphthylamine, N- (2,2,2-trifluoroethyl) -2-naphthylamine 2-methyl-N- (2,2,2-trifluoroethyl) aniline, 3-methyl-N- (2,2,2-trifluoroethyl) aniline, 4-methyl-N- (2,2, 2-trifluoroethyl) aniline, 2,4-dimethyl-N- (2,2,2-trifluoroethyl) aniline, N- (2,2,2-trifluoroethyl) -4- (trifluoromethyl) Aniline, 4-phenyl-N- (2,2,2-trifluoroethyl) aniline, 3-methoxy-N- (2,2,2-trifluoroethyl) aniline, 4-methoxy-N- (2,2 , 2-trifluoroethyl) Niline, 4-hydroxy-N- (2,2,2-trifluoroethyl) aniline, 4-acetyl-N- (2,2,2-trifluoroethyl) aniline, 4- [N- (2,2, 2-trifluoroethyl) amino] benzoic acid ethyl, 4- [N- (2,2,2-trifluoroethyl) amino] benzoic acid, 4-methylthio-N- (2,2,2-trifluoroethyl) Aniline, 4- [N- (2,2,2-trifluoroethyl) amino] thiophenol, 4- [N- (2,2,2-trifluoroethyl) amino] benzonitrile, 4-nitro-N- (2,2,2-trifluoroethyl) aniline, 4-fluoro-N- (2,2,2-trifluoroethyl) aniline and the like can be mentioned, but the inclusions included in the general formula (4) are included. If it is a fluorine secondary amine compound, this It is not limited to these examples.

  In the present invention, first, the fluorine-containing aldehyde hemiacetal of the general formula (1) and the primary amine compound of the general formula (2) are reacted to produce the N, O-acetal compound of the general formula (3). Although the usage-amount of the fluorine-containing aldehyde with respect to a primary amine compound is not specifically limited, Usually, it is 0.5-10 times in molar ratio. In producing N, O-acetal, a solvent is usually used. As the solvent, an alcohol solvent can be used.

  In addition, it is preferable to use alcohols as a solvent and to make an acid catalyst exist in order to easily form an N, O-acetal compound. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, n-hexanol, n-octanol, 2-ethylhexanol, cyclohexanol. , Benzyl alcohol and phenol. Although the usage-amount of an alcohol solvent is not specifically limited, Usually, it is 0.1-10 times by weight ratio with respect to a primary amine compound. The acid catalyst may be either a liquid acid or a solid acid. Examples of the liquid acid include sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. And carboxylic acids such as acetic acid, propionic acid and trifluoroacetic acid, mineral acids such as sulfuric acid, phosphoric acid and hydrochloric acid, or Lewis acids such as boron trifluoride etherate and titanium tetrachloride. Examples of solid acids include cation exchange resins, sulfated zirconia, and heteropolyacids. The usage-amount of an acid catalyst is 0.001-10 times in molar ratio with respect to a primary amine compound.

  Moreover, it is desirable that the temperature for producing N, O-acetal is 30 ° C to 200 ° C, preferably 50 ° C to 150 ° C. When the temperature is less than 30 ° C., the production rate of N, O-acetal is very slow, and when the temperature exceeds 200 ° C., side reactions may proceed. The reaction time is influenced by temperature, but is usually 10 minutes to 10 hours.

  The produced N, O-acetal compound can be isolated by a known extraction method, distillation method, crystallization method, chromatographic method or the like.

  Next, in the present invention, a fluorine-containing secondary amine compound is produced by reacting an N, O-acetal compound with a reducing agent selected from molecular hydrogen or metal hydride in the presence of a catalytic hydrogenation reduction catalyst. . In this case, the N, O-acetal compound may be used after being isolated, or a reducing agent is added to the reaction solution in which the N, O-acetal compound is produced by reacting the fluorine-containing aldehyde hemiacetal and the primary amine compound. A reduction reaction may be performed. In addition, when the raw material fluorine-containing aldehyde hemiacetal and primary amine compound do not react with the reducing agent, it is also possible to produce a N, O-acetal compound in the presence of the reducing agent in advance and then carry out the reduction reaction. It is.

  Examples of the catalytic hydrogenation reduction catalyst include a palladium-supported catalyst such as palladium-activated carbon, a platinum-supported catalyst such as platinum-activated carbon, and a sponge nickel catalyst. The amount of catalytic hydrogenation reduction catalyst used is usually 0.0001 to 0.1 in terms of the molar ratio of the metal component to the N, O-acetal compound. In addition, when performing catalytic hydrogenation reduction, if an acid catalyst is present, the reduction reaction easily proceeds, and a fluorine-containing secondary amine compound can be obtained in high yield. Any of a liquid acid and a solid acid may be used as the acid catalyst. Examples of the liquid acid include sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, acetic acid, Examples thereof include carboxylic acids such as propionic acid and trifluoroacetic acid, mineral acids such as sulfuric acid, phosphoric acid and hydrochloric acid, or Lewis acids such as boron trifluoride etherate and titanium tetrachloride. Examples of solid acids include cation exchange resins, sulfated zirconia, and heteropolyacids. The amount of the acid catalyst used in this case is 0.001 to 10 times in molar ratio to the N, O-acetal compound. The catalytic hydrogenation reduction is carried out in the presence of molecular hydrogen, and the pressure at this time is from atmospheric pressure to 5 MPa.

  In the case of the method of adding a metal hydride, examples of the metal hydride include aluminum hydride compounds such as lithium aluminum hydride and diisobutylaluminum hydride, tin hydride compounds such as tributyltin hydride, and sodium borohydride. And borohydride compounds such as potassium borohydride, lithium borohydride and diborane. Of these, borohydride compounds are preferably used in view of availability, safety, toxicity, and yield of the fluorine-containing secondary amine compound.

  Further, when the reduction reaction is performed, the reaction can be performed in the absence of a solvent, but a solvent is usually used. Although it does not specifically limit as a solvent, For example, alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, benzyl alcohol, and phenol, hexane , Alkanes such as octane and cyclohexane, aromatic compounds such as benzene, toluene, xylene and mesitylene, ethers such as diethyl ether, diisopropyl ether, monoglyme, diglyme, triglyme and tetrahydrofuran, ethyl acetate, n-butyl acetate and benzoic acid Esters such as ethyl acid, sulfides such as diethyl sulfide and di-n-butyl sulfide, nitriles such as acetonitrile, propionitrile and benzonitrile, dimethylformamide Dimethylacetamide, can be mentioned N- amides such as methylpyrrolidone, or sulfoxides such as dimethyl sulfoxide and the like. In the case where the N, O-acetal compound is not isolated, it is convenient in terms of operation to use the same solvent as that used for producing the N, O-acetal. Moreover, the reaction temperature at the time of performing a reductive reaction is -20 degreeC-150 degreeC, Preferably it is 0 degreeC-100 degreeC. The reaction time is affected by temperature, but is usually from 1 minute to 100 hours.

  In the case of the catalytic hydrogenation reduction method after the reduction reaction, after the catalyst is separated by filtration or the like, the fluorine-containing secondary amine compound can be isolated by an extraction method, a distillation method or a crystallization method. When using metal hydride, etc. as a reducing agent, add water and mineral acid, etc. to deactivate the reducing agent, and then isolate the fluorine-containing secondary amine compound by extraction, distillation or crystallization. can do.

Examples Hereinafter, the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.

Example 1
In a glass reactor, 4-methoxyaniline 0.50 g (4.1 mmol), methanol 10 ml, trifluoroacetaldehyde methyl hemiacetal 2.1 g (16 mmol) and p-toluenesulfonic acid monohydrate 0.020 g (0.11 mmol) ) And refluxed for 30 minutes (liquid temperature 65 ° C.). After cooling, 15 ml of toluene was added, methanol was distilled off under reduced pressure, 10% aqueous NaHCO ₃ (30 mL) and 10 ml of water were added to the remaining solution, and the mixture was extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated brine (20 ml) and dried with sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N, O-acetal compound 4-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline 0.90 g (Yield 94%) was obtained.

IR (neat): 3390, 2850, 1600, 1520, 1380, 1280, 1240, 1180, 1140, 900, 820, 780, 720, 650 cm ^-1 ;
¹ H -NMR (270 MHz, CDCl ₃ ) δ 3.47 (s, 3H, CH ₃ ), 3.76 (s, 3H, CH ₃ ), 4.02 (brs, 1H, NH), 4.83-4.92 (m, 1H, CH ), 6.72-6.84 (m, 4H, Ar-H);
¹⁹ F-NMR (90 MHz, acetone d6) δ -79.19 (d, J = 4.9 Hz)
EI-MS m / z 235 (M ⁺ , 92.98), 219 (1.04), 204 (47.97), 203 (18.81), 184 (6.09), 166 (100.00), 151 (28.15), 134 (33.67), 122 (25.23), 108 (14.54), 92 (8.40), 77 (8.55), 63 (10.34), 52 (2.87);
HR-MS (EI) m / z for C ₁₀ H ₁₂ O ₂ NF ₃ Calcd 235.0820, found 235.0823.

  A glass reactor was charged with 0.21 g (0.87 mmol) of 4-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline and 4 ml of methanol, and 0.065 g of sodium borohydride (1 0.7 mmol) was added and refluxed for 1 hour. After the reaction, methanol was distilled off under reduced pressure, and 10 ml of water was added to the residue, followed by extraction with ethyl acetate (20 ml × 2). The extract was washed with 10 ml of saturated saline and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.16 g (yield 90%) of 4-methoxy-N- (2,2,2-trifluoroethyl) aniline.

IR (neat): 3400, 1520, 1470, 1440, 1390, 1330, 1280, 1240, 1160, 1120, 1040, 950, 820, 730, 670, 640 cm ^-1 ;
¹ H -NMR (270 MHz, CDCl ₃ ) δ 3.66-3.75 (m, 2H, CH ₂ ), 3.66-3.75 (brs, 1H, NH), 3.75 (s, 3H, CH ₃ ), 6.64-6.68 (m , 2H, Ar-H), 6.79-6.83 (m, 2H, Ar-H);
¹⁹ F-NMR (90 MHz, acetone d6) δ -71.78 (t, J = 9.1 Hz)
EI-MS m / z 205 (M ⁺ , 97.69), 190 (100.00), 170 (11.56), 162 (12.62), 142 (4.97), 136 (73.87), 121 (16.08), 120 (14.99), 92 (10.38), 78 (6.49), 63 (7.51), 52 (5.03);
HR-MS (EI) m / z for C ₉ H ₁₀ ONF ₃ Calcd 205.0714, found 205.0708.

Example 2
In a stainless steel reactor, 0.47 g (2.0 mmol) of 4-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline obtained by the same method as in Example 1, 10 ml of methanol, 5 0.023 g of% palladium activated carbon and 0.020 g (0.11 mmol) of p-toluenesulfonic acid monohydrate were added. After substituting with nitrogen, a hydrogen pressure of 0.5 MPa was applied, heated to 60 ° C., and reacted for 2 hours. After completion of the reaction, the reaction solution was suction filtered to separate the catalyst, and the filtrate was quantitatively analyzed by ¹⁹ F-NMR. As a result, 4-methoxy-N- (2,2,2-trifluoroethyl) aniline ( ¹⁹ F -NMR: -71.78 ppm, t, J = 9.1 Hz) was 0.38 g (yield 94%).

Example 3
In a stainless steel reactor, 20 g of methanol, 4.9 g (38 mmol) of trifluoroacetaldehyde methyl hemiacetal, 4.2 g (34 mmol) of 4-methoxyaniline, 0.36 g (1.9 mmol) of p-toluenesulfonic acid monohydrate were added. The mixture was stirred at 60 ° C. for 1 hour. After cooling, the reaction solution was analyzed by ¹⁹ F-NMR using trifluoromethylbenzene as an internal standard. As a result, 4-methoxy-N- (2,2,2-trifluoro-1-), which is an N, O-acetal compound. Methoxyethyl) aniline ( ¹⁹ F-NMR: −79.19 ppm, d, J = 4.9 Hz) was produced in a yield of 72%.

To this solution, 0.36 g of 5% supported palladium-activated carbon was added, and after replacing with nitrogen, hydrogen pressure of 0.5 MPa was applied, heated to 60 ° C., and reacted for 2 hours. After completion of the reaction, the reaction solution was suction filtered to separate the catalyst, and the filtrate was quantitatively analyzed by ¹⁹ F-NMR. As a result, 4-methoxy-N- (2,2,2-trifluoroethyl) aniline ( ¹⁹ F -NMR: Production amount of -71.78 ppm, t, J = 9.1 Hz) was 6.5 g (yield 93%).

Example 4
A glass reactor was charged with 40 g of methanol, 9.7 g (75 mmol) of trifluoroacetaldehyde methyl hemiacetal, 14 g (116 mmol) of 4-methoxyaniline, 0.71 g (3.7 mmol) of p-toluenesulfonic acid monohydrate, The mixture was stirred at 67 ° C. for 1 hour. After cooling, the reaction solution was quantitatively analyzed by ¹⁹ F-NMR using trifluoromethylbenzene as an internal standard. As a result, 4-methoxy-N- (2,2,2-trifluoro-), which is an N, O-acetal compound, was obtained. 1-methoxyethyl) aniline ( ¹⁹ F-NMR: −79.19 ppm, d, J = 4.9 Hz) was produced in a yield of 68%.

To this solution, 2.8 g (75 mmol) of sodium borohydride was added and stirred at room temperature for 1 hour, then 20 g of methanol was added, and 2.8 g (75 mmol) of sodium borohydride was added again, and stirred at room temperature for 1 hour. . After adding 60 g of water to the reaction solution, it was extracted with 50 g of chloroform. When the chloroform layer was quantitatively analyzed by ¹⁹ F-NMR, 4-methoxy-N- (2,2,2-trifluoroethyl) aniline ( ¹⁹ F-NMR: −71.78 ppm, t, J = 9.1 Hz) Was 9.5 g (62% yield).

Example 5
In a stainless steel reactor, methanol 20 g, trifluoroacetaldehyde methyl hemiacetal 4.9 g (38 mmol), ethyl 4-aminobenzoate 5.6 g (34 mmol), p-toluenesulfonic acid monohydrate 0.36 g (1.9 mmol) ) And stirred at 60 ° C. for 1 hour. After cooling, the reaction solution was analyzed by ¹⁹ F-NMR using trifluoromethylbenzene as an internal standard. As a result, 4- [N- (2,2,2-trifluoro-1-methoxy) which is an N, O-acetal compound was obtained. Ethyl) amino] ethyl benzoate ( ¹⁹ F-NMR: −79.32 ppm, d, J = 4.9 Hz) was produced in 66% yield.

To this solution, 0.36 g of 5% supported palladium-activated carbon and 1.1 g (5.7 mmol) of p-toluenesulfonic acid monohydrate were added, and after replacing with nitrogen, a hydrogen pressure of 0.5 MPa was applied to reach 60 ° C. Heated and allowed to react for 28 hours. After completion of the reaction, the reaction solution was suction filtered to separate the catalyst, and the filtrate was quantitatively analyzed by ¹⁹ F-NMR. As a result, ethyl 4- [N- (2,2,2-trifluoroethyl) amino] benzoate was obtained. ( ¹⁹ F-NMR acetone d 6 -71.66 ppm, t, J = 9.1 Hz, EI-MS m / Z 247 (M ⁺ ), 219, 202, 178, 150, 124, 104, 91, 77, 69, 65, 43, 29) was 5.5 g (yield 65%).

Example 6
In a glass reactor, methanol 20 g, trifluoroacetaldehyde methyl hemiacetal 4.9 g (38 mmol), 4-aminobenzonitrile 4.0 g (34 mmol), p-toluenesulfonic acid monohydrate 0.36 g (1.9 mmol) And stirred at 60 ° C. for 1 hour. After cooling, the reaction solution was quantitatively analyzed by ¹⁹ F-NMR using trifluoromethylbenzene as an internal standard. As a result, 4- [N- (2,2,2-trifluoro-1) which is an N, O-acetal compound was obtained. -Methoxyethyl) amino] benzonitrile ( ¹⁹ F-NMR: −79.33 ppm, d, J = 4.9 Hz) was produced in a yield of 61%.

To this solution, 1.3 g (34 mmol) of sodium borohydride was added little by little, and after stirring for 1 hour at room temperature, 11 g of methanol was added, and 1.3 g (34 mmol) of sodium borohydride was added again, and then at room temperature for 1 hour. Stir. Further, methanol 27 was added to adjust the liquid temperature to 40 ° C., 2.6 g (68 mmol) of sodium borohydride was added little by little, and the mixture was stirred at 40 ° C. for 30 minutes. 30 g of water was added to the reaction solution, followed by extraction with 44 g of chloroform. When the chloroform layer was quantitatively analyzed by ¹⁹ F-NMR, 4- [N- (2,2,2-trifluoroethyl) amino] benzonitrile ( ¹⁹ F-NMR: −71.60 ppm, t, J = 9. 1 Hz, EI-MS m / Z 200 (M ⁺ ), 131, 102, 75, 69, 51, 39, 28) was 3.7 g (55% yield).

Reference example 1
A stainless steel reactor was charged with 22 g of toluene, 4.9 g (38 mmol) of trifluoroacetaldehyde methyl hemiacetal, and 1.8 g (25 mmol) of n-butylamine, and stirred at 60 ° C. for 1 hour. After cooling, the reaction solution was analyzed by ¹⁹ F-NMR using trifluoromethylbenzene as an internal standard. As a result, (2,2,2-trifluoro-1-methoxyethyl) n-butylamine which is an N, O-acetal compound ( ¹⁹ F-NMR: −78.60 ppm, d, J = 4.9 Hz) was produced in a yield of 35%.

To this solution, 0.26 g of 5% supported palladium-activated carbon and 0.26 g (1.4 mmol) of p-toluenesulfonic acid monohydrate were added, and after replacing with nitrogen, a hydrogen pressure of 0.5 MPa was applied to reach 60 ° C. Heated and allowed to react for 12 hours. After completion of the reaction, the reaction solution was suction filtered to separate the catalyst, and the filtrate was quantitatively analyzed by ¹⁹ F-NMR. As a result, N- (2,2,2-trifluoroethyl) -n-butylamine ( ¹⁹ F- NMR: −71.02 ppm, t, J = 9.8 Hz, EI-MS: m / z 155 (M ⁺ ), 112, 92, 86, 69, 65, 56, 42, 28) It was 5 g (yield 90%).

Reference example 2
The same operation as in Example 7 was performed except that p-toluenesulfonic acid monohydrate was not used.
After completion of the reaction, the reaction solution was suction filtered to separate the catalyst, and the filtrate was quantitatively analyzed by ¹⁹ F-NMR. As a result, N- (2,2,2-trifluoroethyl) -n-butylamine ( ¹⁹ F- NMR: −71.02 ppm, t, J = 9.8 Hz, EI-MS: m / z 155 (M ⁺ ), 112, 92, 86, 69, 65, 56, 42, 28) It was 4 g (yield 61%).

Example 7
A glass reactor was charged with 0.50 g (5.4 mmol) of aniline, 20 ml of methanol, 2.1 g (16 mmol) of trifluoroacetaldehyde methyl hemiacetal and 0.025 g (0.13 mmol) of p-toluenesulfonic acid monohydrate. The mixture was refluxed for 2 hours (liquid temperature: 65 ° C.). After cooling, 0.1 g of sodium bicarbonate was added and the insoluble solid was filtered. After washing with 15 ml of methanol, methanol was distilled off from the filtrate and washings under reduced pressure, and 10% aqueous NaHCO ₃ (30 mL) and 10 ml of water was added and extracted with ethyl acetate (20 ml × 2). The extract was washed with saturated brine (20 ml) and dried with sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 1.1 g (yield 91) of N- (2,2,2-trifluoro-1-methoxyethyl) aniline, which is an N, O-acetal compound. %).

IR (neat): 3400, 2950, 1610, 1520, 1505, 1380, 1280, 1260, 1190, 1150, 900, 850, 760, 720, 700 cm ^-1 ;
¹ H-NMR (270 MHz, CDCl ₃ ) δ 3.48 (s, 3H, CH ₃ ), 4.23-4.26 (brs, 1H, NH), 4.97-5.06 (m, 1H, CH), 6.75-7.29 (m, 5H, Ar-H);
EI-MS m / z 303 (1.09), 234 (0.56), 205 (M ⁺ , 39.36), 189 (0.34), 174 (38.91), 173 (4.73), 136 (100.00), 121 (8.17), 104 (42.18), 93 (23.38), 77 (31.27), 51 (9.76);
HR-MS (EI) m / z for C ₉ H ₁₀ ONF ₃ Calcd 205.714, found 205.0719

  A glass reactor was charged with 0.15 g (0.74 mmol) of N- (2,2,2-trifluoro-1-methoxyethyl) aniline and 5 ml of methanol, and 0.056 g (1.5 mmol) of sodium borohydride was added. In addition, the mixture was refluxed for 15 minutes. After the reaction, methanol was distilled off under reduced pressure, and 10 ml of water was added to the residue, followed by extraction with ethyl acetate (20 ml × 2). The extract was washed with 10 ml of saturated saline and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.092 g (yield 71%) of N- (2,2,2-trifluoroethyl) aniline.

IR (neat): 3420, 1610, 1520, 1450, 1400, 1340, 1280, 1260, 1160, 830, 760, 700, 670, 620 cm ^-1 ;
¹ H -NMR (270 MHz, CDCl ₃ ) δ 3.71-3.81 (m, 2H, CH ₂ ), 3.91 (brs, 1H, NH), 6.67-7.27 (m, 5H, Ar-H);
EI-MS m / z 205 (2.67), 175 (M ⁺ , 46.39), 156 (4.69), 136 (8.25), 124 (1.68), 106 (100.00), 104 (14.53), 77 (33.86), 69 (9.38), 51 (11.27);
HR-MS (EI) m / z for C ₈ H ₈ NF ₃ Calcd 175.0609, found 175.0601.

Example 8
In a glass reactor, 3-methoxyaniline 0.50 g (4.1 mmol), methanol 10 ml, trifluoroacetaldehyde methyl hemiacetal 2.1 g (16 mmol) and p-toluenesulfonic acid monohydrate 0.020 g (0.11 mmol) ) And refluxed for 1 hour (liquid temperature 65 ° C.). After cooling, 30 mL of 10% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (30 ml × 2). The extract was washed with saturated brine (20 ml) and dried with sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and N, O-acetal compound 3-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline 0.65 g (Yield 68%) was obtained.

IR (neat): 3370, 3000, 2950, 2850, 1720, 1620, 1530, 1500, 1470, 1380, 1310, 1280, 1260, 970, 880, 840, 770, 710, 690 cm-1;
¹ H -NMR (270 MHz, CDCl ₃ ) δ 3.48 (s, 3H, CH ₃ ), 3.79 (s, 3H, CH ₃ ), 4.25 -4.29 (brs, 1H, NH), 4.96 -5.05 (m, 1H , CH), 6.31 -6.46 (m, 3H, Ar-H), 7.12 -7.18 (m, 1H, Ar-H);
EI-MS m / z 235 (M ⁺ , 61.33), 219 (0.83), 204 (51.38), 203 (19.19), 184 (7.42), 166 (100.00), 151 (9.30), 134 (28.71), 123 (13.22), 107 (19.76), 92 (12.62), 77 (12.31), 63 (7.64), 51 (2.33);
HR-MS (EI) m / z for C ₁₀ H ₁₂ O ₂ NF ₃ Calcd 235.0820, found 235.0822.

  A glass reactor was charged with 0.24 g (1.0 mmol) of 3-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline and 3 ml of methanol, and 0.076 g of sodium borohydride (2 0.0 mmol) and refluxed for 1 hour. After the reaction, methanol was distilled off under reduced pressure, and 10 ml of water was added to the residue, followed by extraction with ethyl acetate (20 ml × 2). The extract was washed with 10 ml of saturated saline and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.18 g (yield 87%) of N- (2,2,2-trifluoroethyl) aniline.

IR (neat): 3440, 2950, 2850, 1610, 1605, 1520, 1500, 1400, 1280-1260, 1220, 1165, 1060, 960, 830, 770, 695 cm ^-1 ;
¹ H -NMR (270 MHz, CDCl ₃ ) δ 3.72-3.79 (m, 2H, CH ₂ ), 3.78 (s, 3H, CH ₃ ), 3.94 (brs, 1H, NH), 6.23-6.43 (m, 3H , Ar-H), 7.09-7.18 (m, 1H, Ar-H);

Comparative Example 1
The same operation as in Example 3 was performed except that p-toluenesulfonic acid monohydrate was not used. After heating at 60 ° C. for 1 hour, N, O-acetal compound 4-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline was not formed at all, and 4-methoxy- N- (2,2,2-trifluoro-1-hydroxyethyl) aniline was produced in a yield of 30%. To this solution, 0.36 g of 5% supported palladium-activated carbon was added, and after purging with nitrogen, a hydrogen pressure of 0.5 MPa was applied, heated to 60 ° C., and reacted for 2 hours. After completion of the reaction, the reaction solution was suction filtered to separate the catalyst, and the filtrate was quantitatively analyzed by ¹⁹ F-NMR. As a result, the amount of 4-methoxy-N- (2,2,2-trifluoroethyl) aniline produced. Was 1.1 g (yield 16%).

Comparative Example 2
A glass reactor was charged with 9.9 g of methanol, 2.4 g (19 mmol) of trifluoroacetaldehyde methyl hemiacetal, and 2.1 g (17 mmol) of 4-methoxyaniline, and the mixture was stirred at 60 ° C. for 1 hour. After cooling, the reaction solution was quantitatively analyzed by ¹⁹ F-NMR. As a result, 4-methoxy-N- (2,2,2-trifluoro-1-methoxyethyl) aniline, which is an N, O-acetal compound, was produced at all. 4-methoxy-N- (2,2,2-trifluoro-1-hydroxyethyl) aniline was produced in a yield of 32%.

To this solution, 2.6 g (68 mmol) of sodium borohydride was added and stirred at room temperature for 10 hours. After adding 15 g of water to the reaction solution, it was extracted with 15 g of chloroform. When the chloroform layer was quantitatively analyzed by ¹⁹ F-NMR, 4-methoxy-N- (2,2,2-trifluoro-1-hydroxyethyl) aniline was not produced at all, and 2,2 Only 2-trifluoroethanol was produced.

  By the method of the present invention, a fluorine-containing secondary amine compound can be produced in high yield from a primary amine compound and a fluorine-containing aldehyde hemiacetal without using a highly toxic reducing agent. The fluorine-containing secondary amine compound is very useful as an intermediate for medical and agricultural chemicals and a raw material for electronic materials.

Claims (3)

The following general formula (1)

(In the formula, X represents a fluorine atom or a hydrogen atom, n represents an integer of 1 to 10, and R ¹ represents a linear or branched alkyl group having 1 to 10 carbon atoms.)
And a fluorine-containing aldehyde hemiacetal represented by the following general formula (2)

(In the formula, R ² is an unsubstituted aryl group having 6 to 30 carbon atoms, or an alkyl group, a halogenated alkyl group, an aryl group, an alkoxy group, a hydroxy group, a ketone group, an ester group, a carboxylic acid group, or an alkylthio group. And represents an aryl group having 6 to 30 carbon atoms substituted by a substituent selected from the group consisting of a thiol group, a cyano group, a nitro group and a halogen atom .)
In the presence of an acid catalyst in an alcohol solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, benzyl alcohol, and phenol. The following general formula (3)

(Wherein X, n, R ¹ and R ² are the same as defined above.)
The N, O-acetal compound represented by the general formula (4) is reacted with a reducing agent selected from molecular hydrogen or metal hydride in the presence of a catalytic hydrogenation reduction catalyst. )

(Wherein X, n and R ² are the same as defined above)
The manufacturing method of the fluorine-containing secondary amine compound represented by these. When producing the N, O-acetal compound represented by the general formula (3), the fluorine-containing aldehyde hemiacetal represented by the general formula (1) and the primary amine represented by the general formula (2) The method for producing a fluorine-containing secondary amine compound according to claim 1, wherein the compound is reacted at a temperature of 50 to 150 ° C. Reducing agent, Ri molecular hydrogen der coexisted catalytic hydrogenation reduction catalyst, when performing a reduction reaction, a fluorinated according to claim 1 or claim 2, characterized in Rukoto the presence of an acid catalyst A method for producing a secondary amine compound.