JP2009029765A - Method for producing fluorine-containing amine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a fluorine-containing amine compound, by which a fluorine-containing N,O-acetal compound can be reduced without using a highly toxic reducing agent to produce the fluorine-containing amine compound in a high yield. <P>SOLUTION: This method for producing the fluorine-containing amine compound comprises reducing a fluorine-containing N,O-acetal compound with a borane amine complex. The borane amine complex includes aliphatic amine complexes, aromatic amine complexes, and borane pyridine complexes independently substituted with hydrogen atoms, alkyl groups or amino groups. The borane pyridine complex is excellent in the aspect of yield, and especially 2-picoline borane is advantageous in the aspect of handleability related to safety. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for producing a fluorine-containing amine compound. More specifically, the present invention relates to a method for producing a fluorine-containing amine compound by reducing a fluorine-containing N, O-acetal compound with a borane amine complex.

  Fluorine-containing 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 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 an 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, Patent Document 4 has a problem that the amine compound is limited to a lower aliphatic amine. On the other hand, in Patent Documents 5 to 7, since extremely toxic sodium cyanoborohydride is used as a reducing agent, problems such as disposal occur in mass production.

On the other hand, the fluorine-containing N, O-acetal compound is a compound derived from a fluorine-containing aldehyde compound and an amine compound as shown in Non-Patent Document 1 or Non-Patent Document 2. By each method, a fluorine-containing N, O-acetal compound using a primary amine and a secondary amine as raw materials can be obtained. However, nothing has been known so far regarding a method for obtaining a fluorine-containing amine by reducing the fluorine-containing N, O-acetal compound.
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 Synthesis, (2003), 185

  The present invention has been made in view of these problems. That is, an object of the present invention is to provide a method for producing a fluorine-containing amine compound in a high yield by reducing a fluorine-containing N, O-acetal compound without using a highly toxic reducing agent.

  As a result of diligent investigations in view of the above problems, the present inventors have found that a fluorine-containing amine compound can be obtained in a high yield by reducing a fluorine-containing N, O-acetal compound using a specific reducing agent. The invention has been completed. That is, the present invention relates to the following gist.

1. The following general formula (1)

(In the formula, X is a fluorine atom or a hydrogen atom, n is an integer of 1 to 10, R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, and R ² and R ³ are each independently a hydrogen atom or A linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or an aryl group having 6 to 30 carbon atoms which may have a substituent, R ² , R ³ is a terminal, and may be bonded to each other with or without a heteroatom to form a cyclic structure.
The fluorine-containing N, O-acetal compound represented by the formula is reduced with a borane amine complex, and the following general formula (2)

(Wherein X, n, R ² and R ³ are the same as defined above)
The manufacturing method of the fluorine-containing amine compound represented by these.

2. The borane amine complex is represented by the following general formula (3)

(Wherein R ^{4 to} R ⁸ each independently represents a hydrogen atom, an alkyl group or an amino group.)
2. The method for producing a fluorine-containing amine compound according to item 1, which is a borane pyridine complex represented by the formula:

3. 3. The method for producing a fluorine-containing amine compound according to 1 or 2, wherein the borane amine complex is 2-picoline borane.

  According to the present invention, a fluorine-containing amine compound can be produced in a high yield by reducing a fluorine-containing N, O-acetal compound without using a highly toxic reducing agent.

  In the present invention, the fluorine-containing N, O-acetal compound of the general formula (1) is used as a raw material.

In the general formula (1), X (CF ₂ ) n- is a C 1-10 perfluoroalkyl group or hydroperfluoroalkyl group, for example, a trifluoromethyl group, a difluoromethyl group, a pentafluoroethyl group, 1 , 1,2,2-tetrafluoroethyl group, perfluoropropyl group, perfluoroisopropyl group, perfluorobutyl group, perfluorohexyl group, perfluorooctyl group, perfluorodecyl group and the like.

R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t- A butyl group, n-hexyl group, cyclohexyl group, n-octyl group, n-decyl group, etc. can be mentioned. In the formula, R ² and R ³ are the same or non-identical and have a hydrogen atom or a linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or a substituent. Represents an optionally substituted aryl group having 6 to 30 carbon atoms. Examples of the alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-hexyl group, cyclohexyl group, and n-octyl. Group, n-decyl group, eicosane group and the like. Examples of the substituent of the alkyl group include an aryl group, an alkoxy group, a hydroxy group, a ketone group, an ester group, a carboxylic acid group, an alkylthio group, a thiol group, a cyano group, a nitro group, and a halogen atom. Examples of the aryl group having 6 to 30 carbon atoms include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Examples of the substituent of the aryl group include alkyl groups, halogenated alkyl groups, aryl groups, alkoxy groups, hydroxy groups, ketone groups, ester groups, carboxylic acid groups, alkylthio groups, thiol groups, cyano groups, nitro groups, and halogen atoms. Can be mentioned. R ² and R ³ may be bonded together to form a cyclic structure with or without a heteroatom. Examples of such fluorine-containing N, O-acetal compounds include, for example, N- (2,2,2-trifluoro-1-methoxyethyl) amine, N- (2,2,2-trifluoro-1) -Methoxyethyl) methylamine, N- (2,2,2-trifluoro-1-ethoxyethyl) methylamine, N- (2,2,2-trifluoro-1-butoxyethyl) methylamine, N- ( 2,2-difluoro-1-methoxyethyl) methylamine, N- (2,2,3,3-tetrafluoro-1-methoxypropyl) methylamine, N- (2,2,3,3,3-penta Fluoro-1-methoxypropyl) methylamine, N- (2,2,2-trifluoro-1-methoxyethyl) ethylamine, N- (2,2,2-trifluoro-1-methoxyethyl) -n-propyl Amine, N- (2,2,2-trifluoro-1-methoxyethyl) isopropylamine, N- (2,2,2-trifluoro-1-methoxyethyl) -n-butylamine, N- (2,2,2-trimethyl) Fluoro-1-methoxyethyl) benzylamine, N- (2,2,2-trifluoro-1-methoxyethyl) -2-methoxyethylamine, N- (2,2,2-trifluoro-1-methoxyethyl) 2-chloroethylamine, N- (2,2,2-trifluoro-1-methoxyethyl) -dimethylamine, N- (2,2,2-trifluoro-1-methoxyethyl) diethylamine, N- (2 , 2,2-trifluoro-1-methoxyethyl) di-n-propylamine, N- (2,2,2-trifluoro-1-methoxyethyl) -di-n-butylamine, N- (2,2 , 2-tri Fluoro-1-methoxyethyl) -aniline, N- (2,2,2-trifluoro-1-methoxyethyl) -2-methoxyaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -3-methoxyaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -4-methoxyaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -4-chloro Aniline, N- (2,2,2-trifluoro-1-methoxyethyl) -4-cyanoaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -N-methylaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -N-ethylaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -N-methyl-4-methylaniline, N- (2,2,2-trifluoro 1-methoxyethyl) -N-methyl-4-methoxyaniline, N- (2,2,2-trifluoro-1-methoxyethyl) -1-naphthylamine, N- (2,2,2-trifluoro-1) -Methoxyethyl) indoline, N- (2,2,2-trifluoro-1-methoxyethyl) -1,2,3,4-tetrahydroquinoline, N- (2,2,2-trifluoro-1-methoxy) Ethyl) -1,2,3,4-tetrahydroisoquinoline, N- (2,2,2-trifluoro-1-methoxyethyl) piperidine, N- (2,2,2-trifluoro-1-methoxyethyl) -N'-phenylpiperazine, N- (2,2,2-trifluoro-1-methoxyethyl) morpholine and the like can be mentioned.

  These fluorine-containing N, O-acetal compounds can be synthesized from an amine compound and a fluorine-containing aldehyde hemiacetal. J. Fluor. Chem., 125 (2004) 767 synthesized a fluorine-containing N, O-acetal compound by reacting a primary aromatic amine and a fluorine-containing aldehyde hemiacetal in an alcohol in the presence of an acid catalyst. How to do is described. Synthesis, (2003), 185, a secondary amine compound and a fluorine-containing aldehyde hemiacetal are reacted to form a hemiaminal and then reacted with a base and an alkyl halide to synthesize a fluorine-containing N, O-acetal compound. A method is described. It is also possible to produce a fluorine-containing N, O-acetal compound by reacting a secondary amine and a fluorine-containing aldehyde hemiacetal in a nonpolar solvent under heating conditions.

  The fluorine-containing amine compound obtained by the method of the present invention is represented by the general formula (2), for example, (2,2,2-trifluoroethyl) amine, N- (2,2,2-trifluoroethyl) Methylamine, N- (2,2-difluoroethyl) methylamine, N- (2,2,3,3-tetrafluoropropyl) methylamine, N- (2,2,3,3,3-pentafluoropropyl) ) Methylamine, N- (2,2,2-trifluoroethyl) ethylamine, N- (2,2,2-trifluoroethyl) -n-propylamine, N- (2,2,2-trifluoroethyl) ) Isopropylamine, N- (2,2,2-trifluoroethyl) -n-butylamine, N- (2,2,2-trifluoroethyl) benzylamine, N- (2,2,2-trifluoroethyl) ) -2-Metoki Ethylamine, N- (2,2,2-trifluoroethyl) -2-chloroethylamine, N- (2,2,2-trifluoroethyl) dimethylamine, N- (2,2,2-trifluoroethyl) Diethylamine, N- (2,2,2-trifluoroethyl) di-n-propylamine, N- (2,2,2-trifluoroethyl) di-n-butylamine, N- (2,2,2- Trifluoroethyl) aniline, N- (2,2,2-trifluoroethyl) -2-methoxyaniline, N- (2,2,2-trifluoroethyl) -3-methoxyaniline, N- (2,2 , 2-trifluoroethyl) -4-methoxyaniline, N- (2,2,2-trifluoroethyl) -4-chloroaniline, N- (2,2,2-trifluoroethyl) -4-cyanoaniline , N- (2,2,2- Trifluoroethyl) -N-methylaniline, N- (2,2,2-trifluoroethyl) -N-ethylaniline, N- (2,2,2-trifluoroethyl) -N-methyl-4-methyl Aniline, N- (2,2,2-trifluoroethyl) -N-methyl-4-methoxyaniline, N- (2,2,2-trifluoroethyl) -1-naphthylamine, N- (2,2, 2-trifluoroethyl) indoline, N- (2,2,2-trifluoroethyl) -1,2,3,4-tetrahydroquinoline, N- (2,2,2-trifluoroethyl) -1,2, , 3,4-tetrahydroisoquinoline, N- (2,2,2-trifluoro-ethyl) piperidine, N- (2,2,2-trifluoroethyl) -N'-phenylpiperazine and N- (2,2 , 2-Trifluoroethyl) morpho It can be cited down like, is the it is not limited to these examples as long as the fluorine-containing amine compounds encompassed by the general formula (2).

  In the present invention, a fluorine-containing amine is synthesized by reacting a fluorine-containing N, O-acetal compound with a borane amine complex and reducing it. By using the borane amine complex, it is possible to reduce the fluorine-containing N, O-acetal, which is difficult to carry out the reduction reaction with other reducing agents, to obtain the target fluorine-containing amine. For example, a fluorine-containing N, O-acetal compound derived from a primary aniline having a substituent at the ortho position, or a fluorine-containing N, O-acetal compound derived from a secondary amine is sodium borohydride. Whereas a reducing agent such as cannot be reduced at all, when a borane amine complex is used, the reduction reaction can be carried out in a high yield.

Examples of borane amine complexes include borane aliphatic amine complexes such as methylamine borane, ethylamine borane, t-butylamine borane, dimethylamine borane, diethylamine borane, trimethylamine amine, and triethylamine borane, borane aromatic amine complexes such as diethylaniline borane and the general formula Examples thereof include a borane pyridine complex represented by (3). In General formula (3), R < ⁴ > -R < ⁸ > is the same or non-identical, and is an alkyl group or amino groups, such as a hydrogen atom, a methyl group, and an ethyl group. Examples of the borane pyridine complex of the general formula (3) include pyridine borane, 2-picoline borane, 3-picoline borane, 4-picoline borane, 2,4-lutidine borane, 2-aminopyridine borane and the like. Among these borane amine complexes, the borane pyridine complex of the general formula (3) is excellent in terms of the yield of the fluorine-containing amine compound, and in particular, 2-picoline borane has an advantage in terms of handling related to the safety of the borane pyridine complex. . The amount of the borane amine complex used is 0.5 to 10 times in molar ratio to the fluorine-containing N, O-acetal compound.

  In addition, 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, Alcohols, such as methanol, ethanol, and n-propanol, Alkanes, such as hexane, Aromatic compounds, such as toluene, Ethers, such as diethyl ether and tetrahydrofuran, Acetic acid Examples thereof include esters such as ethyl. The amount of the solvent used is usually 1 to 50 times by weight with respect to the fluorine-containing N, O-acetal.

  In the method of the present invention, the reduction reaction may be performed in the presence of an acid. The presence of the acid may improve the yield. As the acid, either a liquid acid or a solid acid may be used. Examples of the liquid acid include carboxylic acids such as acetic acid, propionic acid and trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid, and the like. And sulfonic acids, 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. In this case, the amount of the acid catalyst used is 0.01 to 100 times in molar ratio to the N, O-acetal compound. In particular, when a liquid acid is used, it is also effective to use the acid as a solvent.

  Moreover, the reaction temperature at the time of performing a reductive reaction is -20 degreeC-200 degreeC, Preferably it is 0 degreeC-150 degreeC. The reaction time is affected by temperature, but is usually from 1 minute to 100 hours.

  After the reduction reaction, the fluorine-containing amine compound can be isolated by a known extraction method, distillation method, crystallization method, chromatograph or the like.

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

Reference Example 1 Synthesis of N- (2,2,2-trifluoro-1-methoxyethyl) -2-methoxyaniline In a glass reactor, 2.11 g (16.2 mmol) of trifluoroacetaldehyde, 500 mg of 2-methoxyaniline ( 4.06 mmol), 10 ml of methanol and 20 mg of p-toluenesulfonic acid monohydrate were added and refluxed for 4 hours. After the reaction, 30 ml of an 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 and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane 1:10), and N- (2,2,2-trifluoro-1-methoxyethyl) -2- 765 mg (80% yield) of methoxyaniline was obtained.

Example 1
A glass reactor was charged with 235 mg (1.0 mmol) of N- (2,2,2-trifluoro-1-methoxyethyl) -2-methoxyaniline and 2.5 ml of acetic acid, and 128 mg (1.2 mmol) of 2-picoline borane. ) And stirred at room temperature for 1 hr. 10 ml of 10% hydrochloric acid was added to the reaction solution and stirred for 30 minutes, and then neutralized by adding a 10% aqueous sodium carbonate solution and solid sodium carbonate. The solution was extracted with ethyl acetate (20 ml × 2), and then the extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent ethyl acetate: n-hexane 1: 4), and 136 mg of N- (2,2,2-trifluoroethyl) -2-methoxyaniline ( Yield 66%) was obtained.
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)

Reference example 2
A glass reactor was charged with 300 mg (2.8 mmol) of N-methylaniline, 6 ml of toluene and 1.46 g (112 mmol) of trifluoroacetaldehyde methyl hemiacetal and heated at 130 ° C. for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane 1:20), and N- (2,2,2-), which is an N, O-acetal compound. 421 mg (yield 69%) of trifluoro-1-methoxyethyl) -N-methylaniline was obtained.
IR (neat): 3000, 2950, 2830, 1610, 1510, 1460, 1410, 1350, 1320, 1300, 1280, 1220, 1180, 1150, 1120, 1080, 1040, 1010, 950, 870, 810, 760, 720 , 700, 640 cm ^-1
1 H-NMR (270 MHz, CDCl ₃ ) δ 2.92 (s, 3H, CH ₃ ), 3.34 (s, 3H, CH ₃ ), 5.08 -5.14 (q, 1H, CH), 6.87 -7.33 (m, 5H , Ar-H)
EI-MS m / z 219 (M ⁺ 27.14), 216 (1.17), 188 (39.51), 168 (3.44), 150 (100.00), 135 (6.33), 113 (3.26), 106 (12.88), 91 ( 4.34), 77 (19.73), 63 (3.60), 51 (4.74)

Example 2
A glass reactor was charged with 100 mg (0.46 mmol) of N- (2,2,2-trifluoro-1-methoxyethyl) -N-methylaniline and 2 ml of acetic acid, and 59 mg (0.65 mmol) of 2-picoline borane. The mixture was stirred at room temperature for 1 hr. The reaction solution was added with 5 ml of 10% hydrochloric acid and stirred for 30 minutes, and then neutralized by adding 10% aqueous sodium carbonate solution and 30 ml. The solution was extracted with ethyl acetate (20 ml × 2), and then the extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent ethyl acetate: n-hexane 1: 4), and 53 mg of N- (2,2,2-trifluoroethyl) -N-methylaniline ( Yield 72%).
IR (neat): 1610, 1510, 1380, 1170, 1150, 1100, 1000, 980, 830, 760, 700, 670 cm ^-1
1 H-NMR (270 MHz, CDCl ₃ ): 3.05 (s, 3H, CH ₃ ), 3.81 -3.90 (q, 2H, CH ₂ ), 6.79 -6.83 (m, 3H, Ar-H), 7.24 -7.29 (m, 2H, Ar-H)
EI-MS m / z 189 (M + 46.68), 120 (100.00), 105 (12.94), 104 (11.95), 77 (16.78)

Reference Example 3 Synthesis of N- (2,2,2-trifluoro-1-methoxyethyl) -1,2,3,4-tetrahydroquinoline 504 mg of 1,2,3,4-tetrahydroquinoline in a glass reactor 3.8 mmol), 25 ml of toluene, 1.97 g (15.1 mmol) of trifluoroacetaldehyde methyl hemiacetal and 20 mg of p-toluenesulfonic acid monohydrate were added and heated at 90 ° C. for 2 hours. After the reaction, ethyl acetate (20 ml) was added, and this solution was washed with 10% aqueous sodium hydrogen carbonate solution (20 ml × 2) and then saturated brine (20 ml) and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane 1: 4), and N- (2,2,2-trifluoro-1) which is an N, O-acetal compound. -Methoxyethyl) -1,2,3,4-tetrahydroquinoline 695 mg (yield 75%) was obtained.
IR (neat): 2950, 2930, 1610, 1510, 1310, 1270, 1150, 750 cm ^-1
1 H -NMR (270 MHz, CDCl ₃ ) δ 1.81-2.04 (m, 2H, CH ₂ ), 2.75-2.89 (m, 2H, CH ₂ ), 3.17-3.26 (m, 1H, CH), 3.40 (s , 3H, CH ₃ ), 3.44-3.53 (m, 1H, CH), 5.22 (q, 1H, CH), 6.71-6.78 (m, 2H, Ar-H), 7.02-7.11 (m, 2H, Ar- H)
EI-MS m / z 245 (M ⁺ , 36.03), 214 (22.63), 176 (100.00)

Example 3
A glass reactor was charged with 204 mg (0.83 mmol) of N- (2,2,2-trifluoro-1-methoxyethyl) -1,2,3,4-tetrahydroquinoline and 2 ml of acetic acid, and 182 mg of 2-picoline borane. (1.70 mmol) was added and stirred at 140 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, 10 ml of 10% hydrochloric acid was added to the residue and stirred for 30 minutes, and then neutralized by adding 10% aqueous sodium carbonate and 30 ml. The solution was extracted with ethyl acetate (20 ml × 2), and then the extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane 1: 4), and N- (2,2,2-trifluoroethyl) -1,2,3. 164 mg (yield 92%) of 4-tetrahydroquinoline was obtained.
EI-MS m / z 215 (M ⁺ , 58.83), 146 (100.00)

Reference Example 4 Synthesis of N- (2,2,2-trifluoro-1-methoxyethyl) -1,2,7,8-tetrahydroisoquinoline 133 mg of 1,2,7,8-tetrahydroisoquinoline in a glass reactor 1.0 mmol), 10 ml of toluene, 521 mg (4.0 mmol) of trifluoroacetaldehyde methyl hemiacetal, and 10 mg of p-toluenesulfonic acid monohydrate were added and heated at 90 ° C. for 2.5 hours. After cooling, 20 ml of 10% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with toluene (20 ml × 2). The toluene layer was washed with saturated brine (20 ml) and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane 1: 4), and N- (2,2,2-trifluoro-) which is an N, O-acetal compound. 1-methoxyethyl) -1,2,7,8-tetrahydroisoquinoline (235 mg, yield 96%) was obtained.
IR (neat): 2950, 2850, 1280, 1170, 1150, 1110 cm ^-1
1 H -NMR (270 MHz, CDCl ₃ ) δ 2.86 (t, 2H, CH ₂ ), 2.98-3.07 (m, 1H, CH), 3.14-3.22 (m, 1H, CH), 3.47 (s, 3H, CH ₃ ), 3.83 (d, 1H, CH), 4.03 (d, 1H, CH), 4.25 (q, 1H, CH), 7.00-7.15 (m, 4H, Ar-H)
EI-MS m / z 245 (M ⁺ , 27.14), 244 (22.20) 214 (22.63), 176 (100.00)

Example 4
A glass reactor was charged with 212 mg (0.865 mmol) of N- (2,2,2-trifluoro-1-methoxyethyl) -1,2,7,8-tetrahydroisoquinoline and 3.5 ml of acetic acid, and 2-picoline. Borane (112 mg, 1.04 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, 10 ml of 10% hydrochloric acid was added to the residue and stirred for 30 minutes, and then neutralized by adding 10% aqueous sodium carbonate and 30 ml. The solution was extracted with ethyl acetate (20 ml × 2), and then the extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane 1: 4), and N- (2,2,2-trifluoroethyl) -1,2,7, 169 mg (yield 91%) of 8-tetrahydroisoquinoline was obtained.
EI-MS m / z 215 (M ⁺ , 74.20), 214 (100.00), 146 (36.98), 104 (86.70)

Reference Example 5 Synthesis of N- (2,2,2-trifluoro-1-methoxyethyl) -N′-phenylpiperazine In a glass reactor, 517 mg (3.2 mmol) of 1-phenylpiperazine, 25 ml of toluene, trifluoroacetaldehyde 1.97 g (15.1 mmol) of methyl hemiacetal and 30 mg of p-toluenesulfonic acid monohydrate were added and heated at 90 ° C. for 2 hours. After the reaction, 20 ml of ethyl acetate was added, and this solution was washed with 10% aqueous sodium hydrogen carbonate solution (20 mL × 2) and then with saturated brine (20 ml) and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane 1: 4), and N- (2,2,2-trifluoro-) which is an N, O-acetal compound. 725 mg (yield 83%) of 1-methoxyethyl) -N′-phenylpiperazine was obtained.
IR (neat): 2950, 2900, 2830, 1605, 1505, 1460, 1280, 1240, 1180, 1160, 1140, 1020, 760, 690 cm ^-1
1 H -NMR (270 MHz, CDCl ₃ ) δ 2.90-2.97 (m, 2H, CH ₂ ), 3.03-3.12 (m, 2H, CH ₂ ), 3.15-3.20 (m, 4H, CH ₂ × 2), 3.51 (s, 3H, CH ₃ ), 4.12 ((q, 1H, CH), 6.85-7.00 (m, 3H, Ar-H), 7.24-7.31 (m, 2H, Ar-H)
EI-MS m / z 274 (M ⁺ , 100.00), 259 (22.47), 243 (30.92), 205 (69.23), 132 (27.29) 105 (42.65), 104 (25.22)

Example 5
A glass reactor was charged with 195 mg (0.71 mmol) of N- (2,2,2-trifluoro-1-methoxyethyl) -N′-phenylpiperazine and 2 ml of acetic acid, and 152 mg (1.42 mmol) of 2-picoline borane. And stirred at 140 ° C. for 30 minutes. The reaction solution was mixed with 10 ml of 10% hydrochloric acid and stirred for 30 minutes, and then neutralized with 10% aqueous sodium carbonate solution and 40 ml. The solution was extracted with ethyl acetate (20 ml × 2), and then the extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent, ethyl acetate: n-hexane 1: 4), and N- (2,2,2-trifluoroethyl) -N′-phenylpiperazine 166 mg (Yield 96%) was obtained.
Elemental analysis theory C, 59.01; H, 6.19; N, 11.47 Measured C, 59.04; H, 6.23; N, 11.72
IR (KBr): 2850, 2830, 1610, 1515, 1460, 1320, 1270, 1170, 1150, 1105, 760, 690 cm ^-1
1 H -NMR (270 MHz, CDCl ₃ ) δ 2.83 (t, 4H, CH ₂ × 2), 3.03 (q, 2H, CH ₂ ), 3.21 (t, 4H, CH ₂ × 2), 6.84-6.94 ( m, 3H, Ar-H), 7.23-7.30 (m, 2H, Ar-H)
EI-MS m / z 244 (M ⁺ , 100.00), 132 (18.89), 106 (24.17), 105 (64.74)

Comparative Example 1
The reaction was performed in the same manner as in Example 1 except that 5 ml of methanol was used as a solvent, 114 mg (3.0 mmol) of sodium borohydride was used as a reducing agent, and the reaction time was 2 hours under reflux conditions. Purification was carried out in the same manner as in Example 1, but the target N- (2,2,2-trifluoroethyl) -2-methoxyaniline was not obtained, and the starting material N- (2,2,2 -Trifluoro-1-methoxyethyl) -2-methoxyaniline was obtained in 202 mg (86% recovery).

Comparative Example 2
The reaction was performed in the same manner as in Example 2 except that 5 ml of methanol was used as a solvent, 52 mg (1.4 mmol) of sodium borohydride was used as a reducing agent, and the reaction time was 2 hours under reflux conditions. Purification was carried out in the same manner as in Example 2, but the target N- (2,2,2-trifluoroethyl) -N-methylaniline was not obtained.

  According to the present invention, a fluorine-containing amine compound can be produced in a high yield by reducing a fluorine-containing N, O-acetal compound without using a highly toxic reducing agent. The fluorine-containing 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 is a fluorine atom or a hydrogen atom, n is an integer of 1 to 10, R ¹ is a linear or branched alkyl group having 1 to 10 carbon atoms, and R ² and R ³ are each independently a hydrogen atom or A linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or an aryl group having 6 to 30 carbon atoms which may have a substituent, R ² , R ³ is a terminal, and may be bonded to each other with or without a heteroatom to form a cyclic structure.
The fluorine-containing N, O-acetal compound represented by the formula is reduced with a borane amine complex, and the following general formula (2)
(Wherein X, n, R ² and R ³ are the same as defined above)
The manufacturing method of the fluorine-containing amine compound represented by these. The borane amine complex is represented by the following general formula (3)
(Wherein R ^{4 to} R ⁸ each independently represents a hydrogen atom, an alkyl group or an amino group.)
The method for producing a fluorine-containing amine compound according to claim 1, which is a borane pyridine complex represented by the formula:   The method for producing a fluorinated amine compound according to claim 1 or 2, wherein the borane amine complex is 2-picoline borane.