JPH09124576A - Production of imines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To rapidly produce imines, capable of preventing reactional apparatuses, etc., from corroding without producing a corrosive acidic substance during reaction and useful as intermediates for medicines and agrochemicals in high yield by condensing primary amines with ketones in the presence of a titanium alkoxide as a catalyst. SOLUTION: (A) Primary amines of formula I [R<1> and R<2> are each H, an alkyl, an aryl, pyridyl or furyl; (n) is 0 or 1] (e.g. α-methylbenzylamine) are reacted with (B) ketones of formula II (R<3> and R<4> are each an alkyl, an aryl, pyridyl or furyl) (e.g. benzophenone) in the presence of a titanium alkoxide (e.g. titanium tetraisopropoxide) as a catalyst to afford the objective imines of formula III (e.g. N-diphenylmethylidene-α-phenylethylamine). For example, the component (B) is used in a molar amount of preferably 0.95-1.05 times based on the component (A) and the condensing reaction is preferably carried out at 50-150 deg.C for 1-10hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing imines, and more particularly to a method for producing imines characterized by condensing primary amines with ketones using a titanium alkoxide as a catalyst. .

[0002]

BACKGROUND OF THE INVENTION Imines are useful compounds as intermediates for medicines and agricultural chemicals.
In particular, when the imines are prochiral, reduction of the imines can give optically active secondary amines that can be used as raw materials for compounds showing pharmacological activity. Therefore, production by various methods has hitherto been attempted. For example, a method for producing N- (α-methylcyclohexylmethylidene) -4-methoxybenzylamine by refluxing 4-methoxybenzylamine and cyclohexylmethylketone in toluene for several days.
(J.Am.Chem.Soc., 116, 8952 ( 1994)), at room temperature and α- methylbenzylamine 4-phenyl butan-2-one in toluene, followed by stirring for 1 week, N-(alpha -Methyl-γ-
A method for producing phenylpropylidene) -α-phenylethylamine (Tetrahedoron Asymm., 4 , 215 (1993)) and the like are known. However, these methods have a problem that a long reaction time of several days to one week is required and the yield is low. In addition, by refluxing α-methylbenzylamine and 4-methoxyacetophenone in toluene for 12 hours using a complex of α-methylbenzylamine and zinc chloride as a catalyst, N- (α-methyl-4-methoxybenzylidene)- Method for producing α-phenylethylamine (J. Am. Chem. Soc., 95 , 2971 (1973)), using α-methylbenzylamine and 4,4-dimethylpentan-2-one as benzene with titanium tetrachloride as a catalyst. The method for producing N- (α-methylneopentylidene) -α-phenylethylamine by stirring at room temperature for 25 hours (J. Am. Chem. Soc., 93 , 5
153 (1971)) and the like are known. However, these methods have problems that hydrogen chloride generated during the reaction causes amine hydrochloride as a by-product to reduce the yield and corrodes the reaction apparatus.

The inventors of the present invention have conducted extensive studies to find a method for producing imines which does not have such a problem. As a result, when a primary amine and a ketone are condensed, a titanium alkoxide is used as a catalyst to accelerate the condensation. Furthermore, they have found that imines can be obtained in high yield, and in addition, they do not generate corrosive acidic substances during the reaction, and can also prevent corrosion of a reaction apparatus or the like, and completed the present invention.

[0004]

That is, according to the present invention, a titanium alkoxide is used as a catalyst, and the general formula [I] is used. (In the formula, R ¹ and R ² represent a hydrogen atom, an alkyl group, an aryl group, a pyridyl group or a furyl group, but they are not hydrogen atoms at the same time. The aryl group, the pyridyl group and the furyl group are alkyl, alkoxy. , A halogen atom, halogenomethyl and nitro may be substituted. N represents 0 or 1) and a general formula [II]. (In the formula, R ³ and R ⁴ represent an alkyl group, an aryl group, a pyridyl group or a furyl group, and the aryl group, the pyridyl group and the furyl group are substituted with a group selected from alkyl, alkoxy, a halogen atom, halogenomethyl and nitro. A general formula [III] for condensing a ketone represented by (In the formula, R ¹ , R ² , R ³ , R ⁴ , and n have the same meanings as described above.) An industrially excellent method for producing an imine compound is provided.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the present invention, the primary amines used as a raw material are those represented by the general formula [I]. In the formula, R ¹ and R ² are, for example, hydrogen atom, methyl, ethyl, n-propyl, i- 1 to 1 carbon atoms such as propyl, n-butyl, i-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl
The alkyl group of 6, an aryl group such as phenyl and naphthyl, a pyridyl group, and a furyl group. Further, these aryl group, pyridyl group and furyl group are alkyl,
It may be substituted with a group selected from alkoxy, a halogen atom, halogenomethyl and nitro, and in this case, alkyl has, for example, the same carbon number of 1 to 1 as described above.
6 is alkyl, alkoxy is methoxy, ethoxy, propoxy, butoxy, etc., halogen atom is fluoro, chloro, bromo, etc., and halogenomethyl is trifluoromethyl, trichloromethyl, tribromomethyl, etc. However, R ¹ and R ² are not hydrogen atoms at the same time.

Representative compounds of the primary amines [I] include, for example, benzylamine, α-phenylbenzylamine, 2-bromobenzylamine, 4-chlorobenzylamine, α- (4'-chlorophenyl) -4-chloro. Benzylamine, 2-ethylbenzylamine, 4-methoxybenzylamine, α-methylbenzylamine, 1- (2'-chlorophenyl)
Ethylamine, 1- (4'-bromophenyl) ethylamine, 1
-(2'-methylphenyl) ethylamine, 1- (2'-methoxyphenyl) ethylamine, 1- (2'-nitrophenyl) ethylamine, 1- (3'-trifluoromethylphenyl) ethylamine, 1- (4 ' -Trichloromethylphenyl) ethylamine, 1
-(2 ', 4'-Dichlorophenyl) ethylamine, 1- (2', 3'-
Dichlorophenyl) ethylamine, benzylamines such as 1- (2 ', 5'-dichlorophenyl) ethylamine, naphthylmethylamine, naphthylalkylamines such as 1- (2'-naphthyl) ethylamine, aniline, 4-toluidine, 2,
Examples thereof include aryl amines such as 3-xylidine, 3-anisidine, 4-phenetidine, and naphthylamine, and heterocyclic amines such as 1- (3′-furyl) ethylamine and 1- (2′-pyridyl) ethylamine. These amines may be optically active forms.

[0007] Furthermore, ketones are another starting material, which is represented by the general formula [II], R ^3, examples of R ^4, for example, the R ^1, R ² the same 1 to carbon atoms The alkyl group of 6, an aryl group such as phenyl and naphthyl, a pyridyl group, and a furyl group. Further, these aryl group, pyridyl group and furyl group may be substituted with a group selected from alkyl, alkoxy, halogen atom, halogenomethyl and nitro, and in this case, as alkyl, alkoxy, halogen atom and halogenomethyl, Examples thereof are the same as those represented by R ¹ and R ² .

Representative compounds of the ketones [II] are:
For example, acetophenone, propiophenone, benzophenone, methylnaphthyl ketone, isobutylphenone, 4-
Phenyl-2-butanone, 2-chloroacetophenone, 4-bromoacetophenone, 2-methylacetophenone, 2-methoxyacetophenone, 3-trichloromethylacetophenone, 4-trifluoromethylacetophenone, 2,3-dichloroacetophenone, 2,4- Dichloroacetophenone, 2,5-
Aromatic ketones such as dichloroacetophenone and 3,4-dichloroacetophenone, acetone, methyl ethyl ketone,
Aliphatic ketones such as methyl isobutyl ketone, pinacolone, cyclohexyl methyl ketone, 2-acetylfuran,
Heterocyclic amines such as 3-acetylpyridine may be mentioned.

These ketones [II] are usually 0.5 to 2 mole times, preferably 0.95 times the primary amines [I].
~ 1.05 molar times used.

The present invention is characterized by using a titanium alkoxide as a catalyst. Specific examples of the compound include titanium tetraisopropoxide,
Examples thereof include titanium tetraethoxide, titanium tetramethoxide, titanium tetra-n-butoxide, titanium tetraoctoxide, titanium tetrastearoxide, and the like, with titanium tetraisopropoxide being preferred. The amount of the catalyst used is usually 0.001 to 0.01 with respect to the primary amine [I].
The molar ratio is preferably 0.005 to 0.01.

The reaction in the present invention can also be carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, for example, aromatic solvents such as benzene, toluene, xylene and chlorobenzene, dioxane, ether such as methyl-t-butyl ether and the like.
Tellurium solvent, hexane, aliphatic solvent such as heptane, 1,
Examples thereof include halogen-based solvents such as 2-dichloroethane, chloroform and carbon tetrachloride. When a solvent is used, the amount thereof is usually about 1 to 20 times by weight, preferably about 3 to 10 times by weight, of the primary amine [I].

The reaction in the present invention can be carried out under either normal pressure or reduced pressure, but preferably,
It is carried out under the conditions of 200 Torr to normal pressure. Further, during the reaction, it is preferable to remove the produced water outside the system.

The reaction temperature is usually 30 to 150 ° C. under reduced pressure,
It is preferably 30 to 120 ° C, and usually 30 to 200 ° C under normal pressure.
C., preferably 50 to 150.degree. Reaction time is usually 1
~ 10 hours.

The imines [III] thus produced are isolated by removing the catalyst from the reaction solution by a method such as filtration. When a solvent is used, it is isolated by further distilling the solvent from the obtained filtrate.
In this case, the filtrate may be washed with water before the solvent is distilled off for further purification.

Thus, the imines [III] are produced. Specific compounds thereof are N- (α-methyl-γ-phenylpropylidene) -α-phenylethylamine and N- (α-
Phenylbenzylidene) -α-phenylethylamine, N-
(α-methyl-2'-naphthylmethylidene) -α-phenylethylamine, N- (α-methyl-2 ', 4'-dichlorobenzylidene) -α- (2', 4'-dichlorophenyl) ethylamine, N-
(α-Methyl-2'-chlorobenzylidene) -α- (2'-chlorophenyl) ethylamine, N- (α-methyl-2 ', 3'-dibromobenzylidene) -α- (2', 3'-dibromophenyl) ) Ethylamine, N- (α-methyl-3'-pyridylmethylidene) benzylamine, N- (α-methyl-2'-furylmethylidene)
Benzylamine, N- (α-methylcyclohexylmethylidene) -2-methylbenzylamine, N- (α-methylpropylidene) benzylamine, N- (α-methylcyclohexylmethylidene) -4-methoxybenzylamine, N -(α-Methyl-2'-methylbenzylidene) benzylamine, N- (α-
Methyl-2'-methylbenzylidene) phenylethylamine, N- (α-methyl-t-butylmethylidene) benzylamine, N- (α-i-propylphenylmethylidene) aniline, N- (α-methylbenzylidene) -α- (2'-Nitrophenyl) ethylamine, N- (α-methylbenzylidene) -α
-(4'-trichloromethylphenyl) ethylamine, N- (
Examples include α-methylbenzylidene) -α- (3′-trifluoromethylphenyl) ethylamine.

[0016]

According to the present invention, when a primary amine [I] and a ketone [II] are condensed, a titanium alkoxide is used as a catalyst, so that the imine [III] can be produced rapidly and in high yield. And during the reaction,
It does not generate corrosive acidic substances and can prevent corrosion of the reaction device.

[0017]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 50.2 g of α-methylbenzylamine, 74.8 of benzophenone
g and toluene 258 g in a mixture of titanium tetraisopropoxide 1.16 g (α-methylbenzylamine 0.0
(1 mol times), and then refluxed for 5.5 hours while removing generated water outside the system to obtain 113.2 g (yield 98%) of N-diphenylmethylidene-α-phenylethylamine. 1 g of α-methylbenzylamine remained (2% based on the charged amount of 50.2 g).

Comparative Example 1 1.16 g of titanium tetraisopropoxide in Example 1
In place of the above, 0.56 g of zinc chloride (0.01 mol times relative to α-methylbenzylamine) was used, and the reflux time was set to 14.5 hours. α-Phenylethylamine 92.7g
(Yield 80%) was obtained. 10 g of α-methylbenzylamine
(20% based on the charged amount of 50.2 g, including the hydrochloride of the amine).

Example 2 1.16 g of titanium tetraisopropoxide (0.01 mol times relative to α-methylbenzylamine) was added to a mixture of 50 g of α-methylbenzylamine, 61.2 g of 4-phenyl-2-butanone and 256.8 g of toluene. After the addition, the resulting water was refluxed for 1 hour while being removed from the system. After the reaction was completed, a part of the reaction solution was collected and analyzed by gas chromatography.
Obtained N- (α-methyl-γ-phenylpropylidene)-
The amount of α-phenylethylamine was 90.4 g (yield 88%).
6 g of α-methylbenzylamine (12 for every 50 g of charge)
%) It remained.

Comparative Example 2 1.16 g of titanium tetraisopropoxide in Example 2
N- (α-methyl-γ-phenylpropylidene) -α was obtained by following the procedure of Example 2 except that 0.56 g of zinc chloride (0.01 mol times relative to α-methylbenzylamine) was used instead of -Phenylethylamine 76.7 g (yield 74%) was obtained. 13 g of α-methylbenzylamine remained (26% based on the charged amount of 50 g, including the hydrochloride of the amine).

Comparative Example 3 0.32 g of titanium tetrachloride (0.01 mol times relative to α-methylbenzylamine) in a mixture of 20.4 g of α-methylbenzylamine, 25 g of 4-phenyl-2-butanone and 111 g of toluene.
After adding, the resulting water was refluxed for 11 hours while removing it to the outside of the system to obtain 29.9 g (yield 70%) of N- (α-methyl-γ-phenylpropylidene) -α-phenylmethylamine. It was 6.1 g of α-methylbenzylamine (20.4 g charge amount)
Against 30%. Also included is the hydrochloride salt of the amine. ) It remained.

Example 3 To a mixture of 50.2 g of benzylamine, 51.4 g of 2-acetylfuran and 257.8 g of toluene was added 1.34 g of titanium tetraisopropoxide, and the mixture was refluxed for 7 hours while removing the produced water out of the system. By doing so, 89.9 g (yield 96%) of N- (α-methyl-2′-furylmethylidene) benzylamine was obtained. 2 g of benzylamine remained (4% based on the charged amount of 50.2 g).

Example 4 To a mixture of 50.2 g of 4-methoxybenzylamine, 46.2 g of cyclohexylmethylketone and 264.8 g of toluene was added 1.02 g of titanium tetraisopropoxide (0.01 mol times relative to 4-methoxybenzylamine). , N- (α
-Methylcyclohexylmethylidene) -4-methoxybenzylamine (117.4 g, yield 94%) was obtained. 4-Methoxybenzylamine remained 3 g (6% based on the charged amount of 50.2 g).

Comparative Example 4 Titanium tetraisopropoxide in Example 4 1.02 g
In place of the above, 0.49 g of zinc chloride (0.01 mol times relative to 4-methoxybenzylamine) was used, and the reflux time was changed to 3 hours.
76.1 g (yield 86%) of methylcyclohexylmethylidene) -4-methoxybenzylamine was obtained. The amount of 4-methoxybenzylamine remained was 7 g (14% based on the charged amount of 50.2 g, including the hydrochloride of the amine).

Example 5 50.2 g of benzylamine, 47.1 g of pinacolone and toluene
Titanium tetraisopropoxide 1.
After adding 39 g (0.01 mol times to benzylamine), the resulting water was removed from the system and refluxed for 7 hours to give N- (α-methyl-t-butylmethylidene) benzylamine 70.1 g (yield 85%). 7.5 g of benzylamine remained (15% based on the charged amount of 50.2 g).

Example 6 (S)-(-)-α-methylbenzylamine (optical purity 93% ee) 30
After adding 0.71 g of titanium tetraisopropoxide to a mixture of g, 4-phenyl-2-butanone (36.7 g) and toluene (150 g), N- ( 57.8 g (yield 92%) of α-methyl-γ-phenylpropylidene) -α-phenylethylamine was obtained. 2.4 g of (S)-(-)-α-methylbenzylamine (charged amount
8% remained for 30 g).

Reference Example 1 N- (α-methyl-γ-phenylpropylidene) -α-phenylethylamine obtained in Example 6 (57.8 g) in toluene solution (180.1 g) was added with 5% hydrochloric acid (200 g) at 60 ° C. for 1 hour. After stirring
The mixture was allowed to stand at the same temperature for 30 minutes for liquid separation to obtain an aqueous layer and a toluene layer. After adding 150 g of 27% sodium hydroxide aqueous solution to the obtained aqueous layer, the mixture was extracted twice with 100 g of heptane and the heptane was distilled off to give (S)-(-)-α-methylbenzylamine 2
0.1 g was obtained. The optical purity of this product was analyzed by liquid chromatography to find that it was 93% ee, and it was found that the configuration of the primary amine of the starting material was maintained in the operations of Example 6 and Reference Example 1.

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Claims (1)

[Claims] 1. A titanium oxide having a general formula [I] as a catalyst. (In the formula, R ¹ and R ² represent a hydrogen atom, an alkyl group, an aryl group, a pyridyl group or a furyl group, but they are not hydrogen atoms at the same time. The aryl group, the pyridyl group and the furyl group are alkyl, alkoxy. , A halogen atom, halogenomethyl and nitro may be substituted. N represents 0 or 1) and a general formula [II]. (In the formula, R ³ and R ⁴ represent an alkyl group, an aryl group, a pyridyl group or a furyl group, and the aryl group, the pyridyl group and the furyl group are substituted with a group selected from alkyl, alkoxy, a halogen atom, halogenomethyl and nitro. A general formula [III] characterized by condensing a ketone represented by (In the formula, R ¹ , R ² , R ³ , R ⁴ , and n have the same meanings as described above.).