JP5049067B2 - Method for producing fluorine-containing acyclic N, O-acetal compound - Google Patents

Description

  The present invention relates to a method for producing a fluorine-containing acyclic N, O-acetal compound. More specifically, the present invention relates to a method for producing a fluorine-containing acyclic N, O-acetal compound from a fluorine-containing aldehyde hemiacetal and a secondary amine compound.

  A fluorine-containing N, O-acetal compound is a compound characteristic of a fluorine-containing compound resulting from electron withdrawing properties of fluorine atoms and can be converted into various fluorine-containing amine derivatives (Non-Patent Document 1, Non-Patent Document 1). Document 2), a very useful compound as a raw material for medicines and agricultural chemicals or a raw material for electronic materials.

  The fluorine-containing N, O-acetal compound includes a cyclic N, O-acetal compound in which a nitrogen atom and an oxygen atom are present in the same carbon chain, and an acyclic N, O— in which the nitrogen atom and the oxygen atom are not in the same carbon chain. There are two types of acetal compounds. Most of the fluorine-containing N, O-acetals known so far are the former (Non-patent Document 3). Compared to the former, the synthesis of acyclic N, O-acetals in which the nitrogen atom and the oxygen atom are not on the same carbon chain is not easy, and the synthesis examples are limited.

  Non-Patent Document 1 and Patent Document 1 disclose a method of electrochemically alkoxylating a fluorinated amine compound to synthesize a fluorinated acyclic N, O-acetal compound. However, since this method requires a special apparatus, there is a problem in terms of obtaining an N, O-acetal compound easily industrially.

  Non-Patent Document 4 discloses a method of synthesizing a fluorine-containing acyclic N, O-acetal compound by reacting a trimethylsiloxy fluorine-containing amine compound with an alcohol, and Non-Patent Document 2 discloses a fluorine-containing hemiaminal compound. A method of reacting with a base and an alkyl halide is disclosed. In these methods, a fluorine-containing acyclic N, O-acetal compound is synthesized in a plurality of steps from a fluorine-containing aldehyde hemiacetal as a starting material, and there is a problem that the operation becomes complicated.

On the other hand, Non-Patent Document 5 discloses a method of synthesizing a fluorine-containing acyclic N, O-acetal compound by reacting a fluorine-containing aldehyde hemiacetal and an aromatic primary amine in an alcohol in the presence of an acid catalyst. Yes. This method does not require a special apparatus and can synthesize the target fluorine-containing acyclic N, O-acetal compound by a one-step reaction, and can be said to be an industrially advantageous method. However, this method is applicable only to aromatic primary amines, and in the case of secondary amines, there is a problem that the desired fluorine-containing acyclic N, O-acetal compound cannot be obtained.
JP 2005-256033 A J. Org. Chem., 59 (1994), 607 Synthesis, (2003), 185 J. Org. Chem., 71 (2006), 2159 J. Org. Chem., 67 (2002), 997 J. Fluor. Chem., 125 (2004), 767

  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 acyclic N, O-acetal compound that can use a secondary amine as a raw material in a one-step reaction without requiring a special apparatus.

  As a result of diligent investigations in view of the above problems, the present inventors have obtained a fluorine-containing acyclic N, O-acetal compound using a secondary amine as a raw material by reacting a fluorine-containing aldehyde hemiacetal with an amine compound under specific conditions. The inventors have found that it can be synthesized in high yield and have completed the 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 and R ³ are each independently a linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or an optionally substituted carbon number. Represents an aryl group of 6 to 30. In addition, R ² and R ³ may be bonded to each other at a terminal and with or without a hetero atom to form a cyclic structure.
The following general formula (3), wherein the secondary amine compound represented by the formula is reacted in an aprotic solvent at 50 to 200 ° C.

(Wherein X, n, R ¹ , R ² and R ³ are the same as defined above.)
The manufacturing method of the fluorine-containing acyclic N, O-acetal compound represented by these.

2. The method for producing a fluorine-containing acyclic N, O-acetal compound according to item 1, wherein the fluorine-containing aldehyde hemiacetal is used in a molar ratio of 1 to 10 times with respect to the secondary amine compound.

3. 3. The method for producing a fluorine-containing acyclic N, O-acetal compound according to item 1 or 2, wherein the aprotic solvent is a hydrocarbon solvent.

  According to the present invention, it is possible to provide a method for producing a fluorine-containing acyclic N, O-acetal compound using a secondary amine as a raw material in a one-step reaction without requiring a special apparatus.

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 C 1-10 perfluoroalkyl group or hydroperfluoroalkyl group, and R ¹ is a C 1-10 linear or branched alkyl group. 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.

The secondary amine compound used in the present invention is represented by the general formula (2). In the formula, R ² and R ³ are the same or non-identical linear or branched alkyl groups having 1 to 30 carbon atoms or aryl groups 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. These alkyl groups may be substituted with a substituent, and examples of the substituent 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, and a nitro group. Or a halogen atom etc. can be mentioned. 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.

R ² and R ³ may be bonded to each other at the terminal to form a cyclic structure. An example of such a secondary amine compound is given below. Aromatic secondary amines include N-methylaniline, N-ethylaniline, Nn-propylaniline, N-isopropylaniline, N-methyl-4-methylaniline, N-methyl-2,4-dimethylaniline, N-methyl-4- (trifluoromethyl) aniline, N-methyl-4-phenylaniline, N-methyl-4-methoxyaniline, N-methyl-4-hydroxyaniline, N-methyl-4-acetylaniline, 4 -(N-methylamino) benzoic acid ethyl, 4- (N-methylamino) benzoic acid, N-methyl-4- (methylthio) aniline, 4- (N-methylamino) thiophenol, 4- (N-methyl) Amino) benzonitrile, N-methyl-4-nitroaniline, N-methyl-4-fluoroaniline, N-methyl-1-naphthylamine, N-methyl Examples include 2-naphthylamine, diphenylamine, indoline, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline. Aliphatic secondary amines include dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, di-n-octylamine, dibenzylamine, N-methylbenzylamine, bis (2-methoxy) amine Bis (ethanol) amine, diallylamine, piperidine, pyrrolidine, piperazine, N-phenylpiperazine, morpholine, and the like. The usage-amount of a secondary amine compound is 0.1-1 times by mole ratio with respect to fluorine-containing aldehyde hemiacetal, Preferably, it is 0.2-1 times. When the amount of secondary amine compound used is less than 0.1, the operation of recovering unreacted fluorine-containing aldehyde hemiacetal becomes complicated, and when the amount of secondary amine compound used exceeds 1, fluorine-containing acyclic N, O -The yield of the acetal compound decreases.

  The fluorine-containing acyclic N, O-acetal compound obtained by reacting the fluorine-containing aldehyde hemiacetal and the secondary amine compound is represented by the general formula (3). Examples of such fluorine-containing acyclic N, O-acetal compounds include N- (2,2,2-trifluoro-1-methoxyethyl) dimethylamine, N- (2,2,2-trifluoro-1 -Methoxyethyl) diethylamine, N- (2,2,2-trifluoro-1-ethoxyethyl) diethylamine, N- (2,2,2-trifluoro-1-butoxyethyl) dieramine, N- (2,2 -Difluoro-1-methoxyethyl) diethylamine, N- (2,2,3,3-tetrafluoro-1-methoxypropyl) diethylamine, N- (2,2,2-trifluoro-1-methoxyethyl) di- n-propylamine, N- (2,2,2-trifluoro-1-methoxyethyl) diisopropylamine, N- (2,2,2-trifluoro-1-methoxyethyl) di-n Butylamine, N- (2,2,2-trifluoro-1-methoxyethyl) dibenzylamine, N- (2,2,2-trifluoro-1-methoxyethyl) di-2-chloroethylamine, 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) -indoline, N- (2,2,2-trifluoro-1-methoxyethyl) -1,2,3,4-tetrahydroquinoline, N- (2 , 2,2-trifluoro-1- Toxiethyl) -1,2,3,4-tetrahydroisoquinoline, N- (2,2,2-trifluoro-1-methoxyethyl) -piperidine, N- (2,2,2-trifluoro-1-methoxyethyl) ) -N'-phenylpiperazine and N- (2,2,2-trifluoro-1-methoxyethyl) -morpholine.

  In the present invention, an aprotic solvent is used when the fluorine-containing aldehyde hemiacetal and the amine compound are reacted. When a protic solvent such as alcohol is used, the target fluorine-containing acyclic N, O-acetal compound is hardly obtained. Examples of aprotic solvents include aliphatic hydrocarbons such as pentane, hexane, octane, cyclohexane and decalin, aromatic hydrocarbons such as benzene, toluene, xylene, styrene and tetralin, dichloromethane, chloroform and 1,2-dichloroethane. Halogenated hydrocarbons such as 1,1,2-trichloroethane and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, monoglyme, diglyme, triglyme, tetrahydrofuran and dioxane, methyl acetate, ethyl acetate, Esters such as n-butyl acetate, diethyl malonate, diethyl succinate, ethyl benzoate and diethyl phthalate, ketones such as acetone, ethyl methyl ketone and cyclohexanone, diethyl sulfide and Examples include sulfides such as di-n-butyl sulfide, nitriles such as acetonitrile, propionitrile, and benzonitrile, amides such as dimethylformamide, dimethylacetamide, and N-methylpyrrolidone, and sulfoxides such as dimethyl sulfoxide. it can. Among these aprotic solvents, aliphatic hydrocarbons or aromatic hydrocarbons are preferred from the viewpoint of the yield of the fluorinated acyclic N, O-acetal compound. The amount of the aprotic solvent used is 0.5 to 100 times, preferably 1 to 20 times by weight with respect to the fluorine-containing aldehyde hemiacetal.

  In the present invention, an acid may be present if necessary. 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. The amount of the acid catalyst used in this case is 0.001 to 0.2 times in molar ratio with respect to the secondary amine compound.

  The mixing order of the raw materials and the solvent is not particularly limited, and the fluorinated aldehyde hemiacetal, the secondary amine compound and the aprotic solvent may be mixed in any order.

  In the present invention, a fluorine-containing aldehyde hemiacetal and a secondary amine compound are reacted in an aprotic solvent under heating conditions. The reaction temperature at this time is 50 to 200 ° C. When the reaction temperature is less than 50 ° C., the reaction hardly proceeds. Moreover, when reaction temperature exceeds 200 degreeC, a side reaction will advance easily and the yield of the target fluorine-containing N, O-acetal compound may fall. The reaction time is affected by temperature, but is usually 10 minutes to 48 hours.

  This reaction is usually carried out in an inert gas atmosphere such as nitrogen, argon or carbon dioxide. Moreover, although it is normally performed under atmospheric pressure, it may be performed under pressure or under reduced pressure as necessary.

  After completion of the reaction, the fluorine-containing acyclic N, O-acetal compound as a reaction product can be purified by a known extraction method, distillation method, chromatograph or the like. Moreover, it is also possible to use the reaction solution as it is as a raw material for synthesizing the fluorine-containing amine derivative without purification.

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
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
In a glass reactor, 504 mg (3.8 mmol) of 1,2,3,4-tetrahydroquinoline, 25 ml of toluene, 1.97 g (15.1 mmol) of trifluoroacetaldehyde methyl hemiacetal and 20 mg of p-toluenesulfonic acid monohydrate 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
In a glass reactor, 1,2,3,4-tetrahydroisoquinoline 133 mg (1.0 mmol), toluene 10 ml, trifluoroacetaldehyde methyl hemiacetal 521 mg (4.0 mmol), p-toluenesulfonic acid monohydrate 10 mg were added. In addition, the mixture was 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. 235 mg (yield 96%) of 1-methoxyethyl) -1,2,3,4-tetrahydroisoquinoline 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 517 mg (3.2 mmol) of 1-phenylpiperazine, 25 ml of toluene, 1.97 g (15.1 mmol) of trifluoroacetaldehyde methyl hemiacetal and 30 mg of p-toluenesulfonic acid monohydrate at 90 ° C. Heated 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 504 mg (4.2 mmol) of N-methylbenzylamine, 25 ml of toluene, 2.16 g (16.6 mmol) of trifluoroacetaldehyde methyl hemiacetal and 30 mg of p-toluenesulfonic acid monohydrate, and 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. 657 mg (yield 68%) of 1-methoxyethyl) -N-methylbenzylamine was obtained.
IR (neat): 2970-2850, 1505, 1460, 1290, 1180-1120, 1060 cm ^-1
1 H-NMR (270 MHz, CDCl ₃ ) δ 2.41 (s, 3H, CH ₃ ), 3.51 (s, 3H, CH ₃ ), 3.85 (d, 1H, CH), 3.85 (d, 1H, CH), 4.20 (q, 1H, CH), 7.24-7.38 (m, 5H, Ar-H)
EI-MS m / z 233 (M ⁺ 1.16), 202 (5.33), 164 (55.71), 91 (100.00)

Comparative Example 1
The reaction was performed in the same manner as in Example 1 except that methanol was used as the solvent. After the reaction, purification was carried out in the same manner as in Example 1, but N-methylaniline as a raw material was recovered and N- (2,2,2-trifluoro-1-methoxyethyl) as an N, O-acetal compound. -Tetrahydroisoquinoline was not obtained.

  By the method of the present invention, a fluorine-containing acyclic N, O-acetal compound using a secondary amine compound as a raw material can be produced by a one-step reaction without requiring a special apparatus. Fluorine-containing acyclic N, O-acetal compounds are useful as intermediates for medical and agricultural chemicals and as raw materials 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 and R ³ are each independently a linear or branched alkyl group having 1 to 30 carbon atoms which may have a substituent, or an optionally substituted carbon number. Represents an aryl group of 6 to 30. In addition, R ² and R ³ may be bonded to each other at a terminal and with or without a hetero atom to form a cyclic structure.
The following general formula (3), wherein the secondary amine compound represented by the formula is reacted in an aprotic solvent at 50 to 200 ° C.
(Wherein X, n, R ¹ , R ² and R ³ are the same as defined above.)
The manufacturing method of the fluorine-containing acyclic N, O-acetal compound represented by these.   The method for producing a fluorine-containing acyclic N, O-acetal compound according to claim 1, wherein the fluorine-containing aldehyde hemiacetal is used in a molar ratio of 1 to 5 times with respect to the secondary amine compound.   The method for producing a fluorine-containing acyclic N, O-acetal compound according to claim 1 or 2, wherein the aprotic solvent is a hydrocarbon solvent.