JPS62905B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for producing amine derivatives. More specifically, the present invention relates to the general formula () (In the formula, R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen atom, a hydroxyl group, a trihalogenomethyl group, a phenyl group, a phenoxy group, a phenylthio group, a linear or branched C ₁ to _{C 6} alkyl group) , represents an alkenyl group, an alkoxyl group, an alkylthio group, a dialkylamino group, an alkylsulfonyl group, and n
represents an integer from 1 to 3, and when n is 2 or more
R ₃ may be the same or different, and
R ₁ and R ₂ may be connected through the same or different atoms, and X represents a halogen atom. ) and the general formula () (In the formula, R ₄ and R ₅ are hydrogen atoms, halogen atoms,
Hydroxyl group, trihalogenomethyl group, phenyl group, phenoxy group, phenylthio group, linear or branched C ₁ - _{C 6} alkyl group, alkenyl group, alkoxyl group, alkylthio group, dialkylamino group, alkylsulfonyl group Representation, R ₄ and R ₅
may be connected through the same or different atoms) are condensed to form the general formula () (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) is obtained, and then hydrolyzed to obtain a nitrile compound of the general formula () (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) A general formula () consisting of obtaining an amide compound represented by the following and then subjecting it to a decomposition reaction under alkalinity (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above.) This is an improved method for producing an amine derivative represented by the following formula. The compound represented by the above general formula (), which is the object of the present invention, is an important compound as an optical resolving agent in medicines, agricultural chemicals, etc., and at the same time is an important intermediate in pharmaceuticals with excellent pharmacological effects, such as anticholesterol agents. It is an object of the present invention to provide a method for producing the compound at low cost and very advantageously industrially. Conventionally, as a method for synthesizing a compound represented by the general formula (), for example, in the above formula, R ₁ =4-CH ₃ ,
In the example where R ₂ , R ₃ , R ₄ , R ₅ = H, n = 1, (A) Compt. Rend.
) Vol. 240, p. 100 (1955), (B) Z.
The methods described in Physiol, Chem), Vol. 289, p. 220 (1952), (C) Japanese Patent Publication No. 5350 of 1982, and (D) Japanese Patent Publication No. 6311 of 1984 are known. However, in method (A), an amine derivative is obtained by dechlorinating and reducing a chlornitroso derivative using a large amount of nickel as an intermediate raw material, and the synthesis of the chlornitroso derivative is complicated and difficult. The reduction process also has a low yield and cannot be used as an industrial production method, and method (B) involves condensing expensive p-methylbenzaldehyde and nitrobenzyl to obtain nitromethylstilbene as an intermediate, which is then reduced. However, this method not only has problems with the economic efficiency of the raw materials, but also the explosive nature of nitrobenzyl, which poses a serious obstacle to industrialization, and increases equipment costs. There are also safety problems, so it can be said that this method cannot be used for industrialization. In addition, as in method (B), method (C) uses nitrobenzyl as a raw material, so there is a similar risk of explosion, making industrialization difficult. Furthermore, method (D) is expressed as However, this method has the following drawbacks. The first step concerns the stability of the diazonium salt. In the second step, the reaction between diazonium salt and olefin occurs competitively with the Meerwein reaction.
Sandmyer reactions produce unnecessary by-products and generally have low yields. The third step is a reaction in the presence of ammonia, which produces many by-products and is also disadvantageous in terms of equipment. Under these circumstances, the present inventors have researched a new method for synthesizing the amine derivative represented by the general formula (), and have developed a method based on a novel route that is completely different from the conventional route, and which can be used to synthesize the various types of synthesis described above. The present inventors have found an extremely advantageous method that solves all the drawbacks of the method, obtains the desired product in high yield and purity, and is easy to implement industrially in each step, and has completed the present invention. That is, the present invention has (1) general formula () (In the formula, R ₄ and R ₅ have the same meanings as above) and the acetonitrile compound represented by the general formula () (In the formula, R ₁ , R ₂ , R ₃ , X and n have the same meanings as above.) A halogen compound represented by the formula (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) A process for obtaining a nitrile compound represented by the following. (2) Next, the compound of the general formula () is hydrolyzed (step) to form the compound of the general formula () (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above). (3) Next, a step of alkali decomposition (first step) of the compound of general formula (). General formula () consisting of three steps (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above.) The present invention will be explained in detail below. The compound of general formula () is synthesized by subjecting the compound of general formula () and the compound of general formula () to a condensation reaction (first step) in the presence of a base. Examples of the compound of general formula () used as a starting material here include benzyl chloride or bromide o, m or p-chlorobenzyl chloride or bromide o, m or p-bromobenzyl chloride or bromide o, m or p-fluorobenzyl Chloride or Bromide o, m or p-methoxybenzyl chloride or bromide o, m or p-ethoxybenzyl chloride or bromide o, m or p-phenoxybenzyl chloride or bromide o, m or p-phenylthiobenzyl chloride or Bromide o, m or p-methylthiobenzyl chloride or bromide o, m or p-dimethylaminobenzyl chloride or bromide o, m or p-methylsulfonylbenzyl chloride or bromide o, m or p-isopropenylbenzyl chloride or bromide o, m or p-methylbenzyl chloride or bromide o, m or p-ethylbenzyl chloride or bromide o, m or p-propylbenzyl chloride or bromide o, m or p-butylbenzyl chloride or bromide o, m or p-isopropylbenzyl Chloride or Bromide o, m or p-isobutylbenzyl chloride or bromide o, m or p-trichloromethylbenzyl chloride or bromide o, m or p-trifluoromethylbenzyl chloride or bromide o, m or p-hydroxymethylbenzyl chloride or Bromide 3,4-dimethoxybenzyl chloride or bromide 3,4-dichlorobenzyl chloride or bromide 3,5-dichlorobenzyl chloride or bromide 2,4-dichlorobenzyl chloride or bromide 3,4-dimethylbenzyl chloride or bromide 2 ,5-dimethylbenzyl chloride or bromide 2,4-dimethylbenzyl chloride or bromide 3,4-methyleneoxybenzyl chloride or bromide 3,4-dibromobenzyl chloride or bromide 2,5-dibromobenzyl chloride or bromide 2,4 -dibromobenzyl chloride or bromide 3,4-difluorobenzyl chloride or bromide 2,5-difluorobenzyl chloride or bromide 2,4-difluorobenzyl chloride or bromide o, m or p-methyl-α-methylbenzyl chloride or bromide o, m or p-methyl-α-methoxybenzyl chloride, bromide o, m or p-methylsulfonyl-α-methoxybenzyl chloride or bromide, phenethyl chloride or bromide, phenylpropyl chloride and the like. Similarly, examples of compounds of general formula () which are starting materials include benzyl nitrile o, m or p-chlorobenzyl nitrile o, m or p-bromobenzyl nitrile o, m or p-chlorobenzyl nitrile o, m or p- Methoxybenzyl nitrile o, m or p-ethoxybenzyl nitrile o, m or p-phenoxybenzyl nitrile o, m or p-phenylthiobenzyl nitrile o, m or p-methylthiobenzyl nitrile o, m or p-dimethyl Aminobenzyl nitrile o, m or p-methylsulfonylbenzyl nitrile o, m or p-isopropenylbenzyl nitrile o, m or p-methylbenzyl nitrile o, m or p-ethylbenzyl nitrile o, m or p-propylbenzyl nitrile o, m or p-butylbenzyl nitrile o, m or p-isopropylbenzyl nitrile o, m or p-isobutylbenzyl nitrile o, m or p-trichloromethylbenzyl nitrile o, m or p-trifluoromethylbenzyl nitrile o, m- or p-hydroxybenzylnitrile 3,4-dimethoxybenzylnitrile 3,4-dichlorobenzylnitrile 2,5-dichlorobenzylnitrile 2,4-dichlorobenzylnitrile 3,4-dimethylbenzylnitrile 2,5-dimethyl Benzyl nitrile 2,4-dimethylbenzyl nitrile 3,4-methyleneoxybenzyl nitrile 3,4-dibromobenzyl nitrile 2,5-dibromobenzyl nitrile 2,4-dibromobenzyl nitrile 3,4-difluorobenzyl nitrile 2 , 5-difluorobenzyl nitrile, 2,4-difluorobenzyl nitrile, and the like. In the reaction between the compound of general formula () and the compound of general formula (), the raw material ratio is usually 1 mole of the compound of general formula () to
The range of 0.1 to 3 moles of the compound is selected, but if it is less than 1 mole, the unreacted compound of general formula () is used as a solvent and after the reaction,
It can be separated from the reaction mixture by means such as crystallization or distillation and reused. Further, when the amount is more than 1 mole, the unreacted compound of general formula () can be similarly separated and recovered and reused. However, since the halogen group of the compound of the general formula () is generally highly reactive, an excess of the compound of the general formula () is condensed with the generated compound of the general formula (), resulting in the formation of the compound of the general formula (). (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) is produced as a by-product. Since this compound causes a decrease in the yield of the compound of general formula (), it is preferable to react the compound of general formula () in equal moles or less. However, since the compound of general formula () does not undergo the decomposition reaction described below, it does not affect the next step. Reaction solvents include commonly used solvents such as water, methanol, ethanol, isopropyl alcohol, hexanol, butanol, t-butanols, benzene, toluene, xylene, chlorobenzenes, hexane, heptane, methylcellosolve, dioxane, and tetrahydrofuran. , dimethylformamide, ether, dimethyl sulfoxide, etc. are used singly or in mixtures, but as mentioned above, the compound of general formula () can also be used as a solvent. In this case, when the general formula (), the compound of the general formula (), and the product of the general formula () are solid at room temperature, it is more suitable for operation to select a solvent that dissolves it. Note that the compound of general formula () is usually produced by halogenating the compound of general formula () below, (In the formula, R ₁ , R ₂ , R ₃ , and n have the same meanings as described above.) In the present invention, in the production method, the reaction rate is lowered and the selectivity of monohalide is increased, so that the general formula () Once the compound is produced, the compound can be used as it is as a solvent without separating the unreacted compound of general formula () from the reaction product. The bases used include alkali metals,
Examples include alkali metal hydroxide, alkali metal carbonate, alkali metal alkoxy, and alkali metal hydride. The amount used is usually 1 to 8 per reaction raw material.
Preferably, the range is 1 to 4 times the mole.
The number of moles of base consumed in this reaction is equimolar to the starting compound of general formula (), and the excess remains unreacted, but the remaining base may be separated or removed. It can also be used in the next process as is. Furthermore, in order to obtain a compound of general formula (),
By adding a catalytic amount of an organic quaternary ammonium salt or a tertiary amine, the reaction rate is relatively improved and the reaction rate is increased, so it is preferable to use these as a catalyst. Examples of organic quaternary ammonium salts or tertiary amines include: Tetra-n-butylammonium chloride, bromide or hydroxide Tetraethylammonium chloride, bromide or hydroxide Triethylbenzylammonium chloride, bromide or hydroxide Triethylamine, trimethylamine, tributylamine , tripropylamine, etc.
These may be used alone or as a mixture. The amount of the catalyst to be added is arbitrary within the range of 1/200 to 1/5 mol, but is generally about 1/100 mol, based on 1 mol of the compound of general formula () as a raw material. The catalyst used here can be recovered and reused after the reaction. The reaction temperature is arbitrary in the range of -20°C to 200°C, but preferably in the range of 0°C to 100°C. There is no particular restriction on the reaction pressure, and either normal pressure or increased pressure may be used. Further, the reaction format may be either a batch method or a continuous method. The compound of general formula () can be obtained in good yield by operations such as separation, concentration, distillation, and crystallization from the reaction mixture obtained by such a reaction, but in order to obtain the compound of general formula () in the next step, It is not always necessary to isolate the compound of general formula (), and the reaction mixture may proceed to the next step as it is. In the hydrolysis (step) to obtain the compound of general formula () from the compound of general formula (), the reaction method can be any method such as hydrolysis using a base, hydrolysis using an acid, hydrolysis using a metal catalyst, etc. Any method can be chosen without being restricted. In addition,
At this time, the presence of an organic quaternary ammonium salt or a tertiary amine is very effective because the reaction proceeds at a relatively low temperature and the reaction rate is improved. Here, examples of the base include alkali metal hydroxide, alkali metal carbonate, alkoxyalkali metal, alkaline earth metal hydroxide, etc., and examples of the acid include sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, nitric acid, and hydrobromic acid. , formic acid, etc. Examples of the metal catalyst include copper sulfate, copper oxide, copper chloride, copper hydride, copper acetate, copper-vanadium alloy, copper-magnesium chromium silicate, chromium oxide, manganese dioxide, palladium chloride, rhodium chloride, and ruthenium. The reaction is usually carried out in the presence or absence of a solvent, but when a solvent is used, the reaction is carried out in the presence or absence of a solvent. A solvent is applied. The organic quaternary ammonium salt or tertiary amine used to obtain the compound of general formula () from the compound of general formula () and the compound of general formula () mentioned above is applicable. The number of moles used is also the same. The reaction temperature is generally arbitrary within the range of 0°C to 300°C, but preferably 20°C to 250°C. There is no particular restriction on the reaction pressure, and either normal pressure or pressurization may be used. The reaction format may be either liquid phase or gas phase, and either batch method or continuous method may be used. In this reaction, in addition to the target compound of general formula (), a compound of general formula () which is further hydrolyzed (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) is produced as a by-product and causes a decrease in the yield of the target compound of general formula (). However, in this case as well, it is possible to suppress the compound of general formula () by reducing the reaction rate, recovering the unreacted compound of general formula (), and reusing it. Furthermore, when a base is used as a hydrolysis reagent, the presence of hydrogen peroxide or dimethyl sulfoxide has the effect of suppressing the by-product of the compound of general formula (). In this case, the number of moles of hydrogen peroxide used is arbitrary, 1 mole or more of hydrogen peroxide per 1 mole of the compound of general formula (), but preferably 2 to 10 moles.
mol is adopted, in which case the reaction temperature is 20℃~80℃
A range of 0.degree. C. is preferred. Although the reaction time depends on the number of moles of hydrogen peroxide used, the reaction time is usually 30 minutes to 10 hours. When hydrogen peroxide is used, the reaction proceeds even with water alone as a solvent, but the combined use of alcohols such as methanol, ethanol, and isopropanol helps to homogenize the reaction system and increase the reaction rate. preferable.
The number of moles of dimethyl sulfoxide used when a base and dimethyl sulfoxide are used in combination is arbitrary, 1 mole or more per 1 mole of the compound of general formula (), but preferably the solubility for the compound of general formula () and dimethyl sulfoxide 2 to 10 mol is adopted from an economical point of view since it is somewhat difficult to recover because it dissolves well in water. The reaction temperature is 60
Any range from ℃ to 150℃, but preferably
A range of 80°C to 130°C is adopted. The reaction time is usually completed within 10 hours. In addition, a particularly advantageous point in the hydrolysis reaction of the compound of general formula () to the compound of general formula () of the present invention is that the compound of general formula () in the previous step and the compound of general formula () are In the process of obtaining the compound (), the compound of the general formula (), which is produced as a slight by-product, is not hydrolyzed in this hydrolysis reaction and remains unreacted, and is easily separated from the desired amine derivative in the final step. Therefore, the hydrolysis reaction can be carried out as a mixture with the compound of the general formula () without isolating or removing the general formula (). Through such a reaction, the compound of general formula () can be obtained in good yield from the resulting reaction mixture through operations such as liquid separation, concentration, distillation, and crystallization, but it is the final target product of the next step. In order to obtain the amine derivative represented by the general formula (), it is not necessarily necessary to isolate the compound represented by the general formula (), and the reaction mixture may proceed to the next step as it is. Hereinafter, the step (first step) of obtaining the final target amine derivative represented by the general formula () through alkaline decomposition of the compound represented by the general formula () will be described. This reaction is generally called the Hofmann reaction by the action of a halogen, an alkali metal hypohalite salt, or an alkaline earth metal hypohalite salt in the presence of a base. The compound () can be obtained. Incidentally, if an organic quaternary ammonium salt or a tertiary amine is present at this time, the reaction proceeds at a relatively low temperature and the reaction rate is also improved, which is very effective. Here, examples of the base include alkali metal hydroxide, alkali metal carbonate, alkoxy metal, and alkaline earth metal hydroxide. These bases may be used in an amount of 2 moles or more per mole of the compound of general formula (), but from an economical standpoint, a range of 2 to 10 moles is preferred. Examples of the halogen include bases, bromine, fluorine, and the like. These halogens may be present in an amount of 1 mole or more per mole of the compound of general formula (), but preferably in a range of 1 to 5 moles. Further, at this time, it is more preferable to use 4 or more moles of the base per 1 mole of the compound of general formula (). Examples of the alkali metal hypohalite salts or alkaline earth metal salts of hypohalite include sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, calcium hypochlorite, Examples include calcium hypobromite. These alkali metal hypohalite salts or earth metal hypohalite salts may be used in an amount of 1 mole or more per mole of the compound of general formula (), but preferably 1 to 1 mole, as in the case of using a halogen. 5
A molar range is used. As the organic quaternary ammonium salt or tertiary amine, the organic quaternary ammonium salt or tertiary amine used when obtaining the compound of the general formula () from the compound of the general formula () described above and the compound of the general formula () are used. grade amine is applied, and the number of moles used is also the same. As the reaction solvent, the solvent used when obtaining the compound of general formula () from the compound of general formula () and the compound of general formula () described above is used. When using alcohols such as methanol and ethanol as a reaction solvent, the general formula () (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above, and R ₆ represents an alkyl group such as a methyl group or an ethyl group.) Although it may be converted into a compound of general formula () through a process, the present invention is not restricted in any way to the production of this intermediate. The reaction temperature is generally arbitrary within the range of -20°C to 150°C, but preferably -10°C to 100°C. There is no particular restriction on the reaction pressure, and either normal pressure or increased pressure may be used. Regarding the reaction format, a batch method or a continuous method may be used. The reaction time is usually completed within 20 hours. From the reaction mixture obtained by such a reaction, the compound of general formula () can be obtained in good yield by operations such as liquid separation, concentration, distillation, and crystallization. The compound of general formula () obtained here includes, for example, α-phenyl-β-phenylethylamine α-(o-, m- or p-chlorophenyl)
-β-Phenylethylamine α-(o-, m- or p-bromophenyl)
-β-phenylethylamine α-(o-, m- or p-fluorophenyl)
-β-Phenylethylamine α-(o-, m- or p-methoxyphenyl)-β-Phenylethylamine α-(o-, m- or p-ethoxyphenyl)-β-Phenylethylamine α- (o-, m- or p-phenoxyphenyl)-β-phenylethylamine α-(o-, m- or p-phenylthiophenyl)-β-(o-, m- or p-chlorophenyl ) Ethylamine α-(o-, m- or p-methylthiophenyl)-β-(o-, m- or p-bromophenyl) Ethylamine α-(o-, m- or p-dimethylaminophenyl)-β -(o-, m- or p-fluorophenyl)ethylamine α-(o-, m- or p-methylsulfonylphenyl)-β-(o-, m- or p-methoxyphenyl)ethylamine α-(o -, m- or p-isopropenylphenyl)-β-(o-, m- or p-ethoxyphenyl)ethylamine α-(o-, m- or p-tolyl)-β-
(o-, m- or p-phenoxyphenyl)ethylamine α-(o-, m- or p-ethyl phenyl)
-β- (o-, m- or p-methylthiophenyl) ethylamine α- (o-, m- or p-propylphenyl) -β- (o-, m- or p-phenylthiophenyl) Ethylamine α-(o-, m- or p-butylphenyl)
-β-(o-, m- or p-dimethylaminophenyl) ethylamine α-(o-, m- or p-isopropylphenyl) -β-(o-, m- or p-methylsulfonylphenyl) Ethylamine α-(o-, m- or p-isobutylphenyl)-β-(o-, m- or p-isopropenylphenyl) Ethylamine α-(o-, m- or p-trichloromethylphenyl) -β-(o-, m- or p-isobutylphenyl) ethylamine α-(o-, m- or p-trifluoromethylphenyl) -β-(o-, m- or p-isopropylphenyl) Ethylamine α-(o-, m- or p-hydroxymethylphenyl)-β-(o-, m- or p-butylphenyl)Ethylamine α-phenyl-β-(o-, m- or p-propylphenyl) ) Ethylamine α-phenyl-β-(o-, m- or p-ethylphenyl)ethylamine α-phenyl-β-(o-, m- or p-tolyl)ethylamine α-phenyl-β-(o-, m- or p-trichloromethylphenyl)ethylamine α-phenyl-β-(o-, m- or p-trifluoromethylphenyl)ethylamine α-(3,4-dimethoxyphenyl)-β-phenylethylamine α- (3,4-dichlorophenyl)-β-phenylethylamine α-(3,5-dichlorophenyl)-β-phenylethylamine α-(2,4-dichlorophenyl)-β-phenylethylamine α-(3,4- xylyl)-β-phenylethylamine α-(2,5-xylyl)-β-(3,4-dimethoxyphenyl)ethylamine α-(2,4-xylyl)-β-(3,4-dichlorophenyl)ethylamine α-(3,4-methyleneoxyphenyl)-β
-(3,5-dichlorophenyl)ethylamine α-(3,4-dibromphenyl)-β-
(2,4-dichlorophenyl)ethylamine α-(2,5-dibromphenyl)-β-
(3,4-xylyl)ethylamine α-(2,4-dibromphenyl)-β-
(2,5-xylyl)ethylamine α-(3,4-difluorophenyl)-β-
(2,4-xylyl)ethylamine α-(2,5-difluorophenyl)-β-
(3,4-methyleneoxyphenyl)ethylamine α-phenyl-β-(3,4-dibromphenyl)ethylamine α-phenyl-β-(2,5-dibromphenyl)ethylamine α-phenyl-β-(2,4- dibromphenyl)ethylamine α-phenyl-β-(3,4-difluorophenyl)ethylamine α-phenyl-β-(2,5-difluorophenyl)ethylamine α-phenyl-β-methyl-β-(o-, m-
or p-tolyl)ethylamine α-phenyl-β-methoxy-β-(o-, m
-or p-tolyl)ethylamine α-phenyl-β-methoxy-β-(o-, m
- or p-methylsulfonylphenyl) ethylamine 1-(o-, m- or p-methylphenyl)
Examples include -3-phenylpropylamine, 1-(2,4-dichlorophenyl)-3-phenylpropylamine, and 1-(3,4-methoxyphenyl)-4-phenylbutylamine. EXAMPLES The present invention will be explained below using Examples, but it goes without saying that the present invention is not limited only to these Examples. Example 1 1.0 mol of benzyl nitrile (-1), 0.6 mol of p-methylbenzyl chloride (-1)), 4.0 mol of sodium hydroxide and 0.01 mol of tetra-n-butylammonium bromide were added in the same proportion to (-1). The reaction was carried out at 60° C. for 2 hours using 3 parts by weight of water as a solvent for 3 parts by weight of toluene and sodium hydroxide. After the reaction is completed, the aqueous layer is separated and the organic layer is distilled to extract toluene and unreacted benzyl nitrile.
0.42 mol was recovered and the concentrated residue was further distilled to obtain α
-Phenyl-β-(p-tolyl)propionitrile (bp 135-145°C) (-1) 0.54 mol was obtained. The yield was 95% based on the reacted raw material nitrile (-1). Next, 1.0 mol of (-1) obtained here, 0.25 mol of sodium hydroxide, 4.0 mol of hydrogen peroxide (35
% aqueous solution) and 0.01 mol of tetra-n-butylammonium bromide were mixed at 50°C with 3 parts by weight of methanol for (-1) and 3 parts by weight of water for sodium hydroxide as solvents. Allowed time to react. After the reaction was completed, methanol was distilled off, filtered and washed with water to obtain α-phenyl-β-(p-tolyl)propionamide (-1) (mp 150-151°C) in a yield of 98% or more. Next, add 1.0 mol of (-1) obtained here and 10 mol of sodium hydroxide to 3 mol of (-1).
Double parts by weight of methanol was added as a solvent, 1.3 mol of bromine was added dropwise over 2 hours while stirring at 0°C, and after keeping at 60°C for 2 hours, an additional 0.01 mol of tetra-
n-Butylammonium bromide was added and the mixture was reacted under reflux for 10 hours. After the reaction, methanol was distilled off, extracted and separated with toluene, toluene was distilled off from the obtained organic layer, and α-phenyl-β-(p-
Tolyl)ethylamine (bp131.0℃) yield 98%
I got it above. Reference Example 1 1.0 mol of (-1) obtained in Example 1 and 0.33 mol of sodium hydroxide were added to (-1).
The reaction was carried out at 110° C. for 4 hours using 1.8 parts by weight of dimethyl sulfoxide as a solvent. After the reaction is complete, dimethyl sulfoxide is distilled off, filtered, and washed with water to obtain α-phenyl-β-(p-tolyl).
Propionamide (-1) was obtained in a yield of over 97%. Reference Example 2 1.0 mol of (-1) obtained in Example 1 and 4 mol of potassium hydroxide were reacted under reflux for 3 hours using t-butanol in an amount of 5 times the weight of (-1) as a solvent. After the reaction was completed, t-butanol was distilled off, water was added in an amount twice that of (-1), and the mixture was filtered and washed with water to obtain (-1) in a yield of over 98%. Reference Example 3 1.0 mol of (-1) obtained in Example 1 was converted into (-
140 in 65% H ₂ SO ₄ at twice the weight of 1).
The reaction was carried out at ~145°C for 1 hour. After the reaction was completed, it was cooled and neutralized with a 45% aqueous sodium hydroxide solution.
After filtering and washing with water, (-1) was obtained in a yield of over 85%. Reference Example 4 1.0 mol of (-1) obtained in Example 1 was preheated to 90°C and pumped from below into a jacketed reaction tube filled with manganese dioxide to react. The temperature of the reaction tube was 90°C and the average residence time was 1 hour. Gas chromatography analysis of the reaction mixture flowing from the top revealed that the conversion of nitrile was
At 30%, we obtained (-1) with a selectivity of 95% or higher. Example 2 To 1.0 mol of (-1) obtained in Example 1 and 3 mol of sodium methoxide, 3 mol of (-1) was added.
Add twice the weight of methanol as a solvent, and heat at 0°C.
While stirring, 1.3 mol of bromine was added dropwise over 2 hours, kept at 60°C for 2 hours, and then added with 10 mol of potassium hydroxide and 0.7 parts by weight of water based on potassium hydroxide (-1). A mixed solvent of 3 parts by weight of methanol was added and the mixture was reacted under reflux for 5 hours. After the reaction was completed, methanol was distilled off, and after extraction and separation with toluene, toluene was distilled off from the obtained organic layer to obtain α-phenyl-β-(p-tolyl)ethylamine in a yield of 98% or more. . Example 3 2,4-dimethylbenzylnitrile (-2)
1.0 mol, 3,4-dichlorobenzyl chloride (-2) 0.6 mol, potassium hydroxide 4.0 mol and tetra-n-butylammonium hydroxide
The reaction was carried out at 60°C for 2 hours using the same parts by weight of benzene per 0.01 mol (-2) and water in 3 parts by weight per potassium hydroxide as solvents. After the reaction was completed, the aqueous layer was separated, and 0.43 mol of 2,4-dimethylbenzylnitrile, which had not reacted with benzene, was recovered from the organic layer by distillation. Analysis of the concentrated residue by gas chromatography revealed α-2,4-xylyl-β
-(3,4-dichlorophenylpropionitrile (-2) selectivity is based on the reacted raw material nitrile (
-2), it was 94%. Next, the concentrated residue obtained here, sodium carbonate
0.25 mol, hydrogen peroxide 4.0 mol (35% aqueous solution) and triethylbenzylammonium chloride 0.01
The moles were reacted at 50° C. for 4 hours using isopropanol in an amount of 3 times the weight of the concentrated residue and water in an amount of 3 times the weight of sodium carbonate as solvents. After the reaction was completed, the reaction product was analyzed by gas chromatography, and it was found that α-2,4-xylyl-β-(3,4
-dichlorophenyl)propionamide (-
The selectivity of 2) is 96 for (-2) in the concentrated residue.
% or more. Next, 1.5 mol of NaCC (10%
Aqueous solution) was added dropwise over 2 hours, and the mixture was further heated at 60°C for 4 hours. After the reaction was completed, the isopropanol was distilled off, extracted and separated with toluene, and the resulting organic layer was analyzed by gas chromatography.
The selectivity of -2,4-xylyl-β-(3,4-dichlorophenyl)ethylamine was 90% or more based on amide (-2) in the reaction mixture. Example 4 m-hydroxybenzylnitrile (-3)
1.0 mol, benzyl chloride (-3) 0.6 mol,
4.0 moles of sodium hydroxide and triethylamine
0.03 mol was reacted at 60° C. for 4 hours using the same parts by weight of toluene for (-3) and 3 parts by weight of water for sodium hydroxide as solvents. After the reaction is completed, the aqueous layer is separated and the organic layer is distilled to extract toluene and unreacted m-hydroxybenzylnitrile.
0.44 mol was recovered. Analysis of the concentrated residue by gas chromatography revealed that the selectivity of α-(m-hydroxyphenyl)-β-phenylpropionitrile (-3) was higher than that of the reacted raw material nilyl (
-3), it was 93%. Next, the concentrated residue obtained here, 0.25 mol of sodium hydroxide, and 4.0 mol of hydrogen peroxide (35% aqueous solution)
and 0.02 mol of tributylamine were reacted at 50° C. for 3 hours using ethanol in an amount of 3 times the weight of the concentrated residue and water in an amount of 3 times the weight of sodium hydroxide as solvents. After the completion of the reaction, the reaction product was analyzed by gas chromatography, and the selectivity of α-(m-hydroxyphenyl)-β-phenylpropionamide (-3) was found to be higher than that of nitrile (-3) in the concentrated residue.
-3), it was over 97%. Next, 1.3 moles of bromine was added dropwise to the reaction mixture obtained here and 7.0 moles of sodium hydroxide while stirring at 0°C over 2 hours, and the temperature was kept at 60°C for 2 hours, followed by further reaction under reflux for 10 hours. Ta. After the reaction is complete, ethanol is distilled off, extracted and separated with toluene,
Analysis of the obtained organic layer by gas chromatography revealed α-(m-hydroxyphenyl)
The selectivity of -β-phenylethylamine was over 90% relative to amide (-3) in the reaction mixture. Examples 5 to 24 Table 1 shows the results obtained according to each of the above examples. 【table】

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are hydrogen atoms, halogen atoms, hydroxyl groups, trihalogenomethyl groups, phenyl groups, phenoxy groups, phenylthio groups, linear or branched C ₁ ~ _C6 alkyl group, alkenyl group, alkoxyl group, alkylthio group, dialkylamino group, alkylsulfonyl group, n represents an integer from 1 to 3, n
is 2 or more, R ₃ may be the same or different, and R ₁ and R ₂ and R ₄ and R ₅ may be connected through the same or different atoms. ) by hydrolyzing the nitrile compound represented by the general formula () (wherein R ₁ , R ₂ , R ₃ , R ₄ .R ₅ and n have the same meanings as above) is obtained, and then subjected to a decomposition reaction under alkaline conditions. () (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above.) A method for producing an amine derivative represented by the following formula. 2 General formula () (In the formula, R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen atom, a hydroxyl group, a trihalogenomethyl group, a phenyl group, a phenoxy group, a phenylthio group, a linear or branched C ₁ to _{C 6} alkyl group) , represents an alkenyl group, an alkoxyl group, an alkylthio group, a dialkylamino group, an alkylsulfonyl group, and n
represents an integer from 1 to 3, and when n is 2 or more
R ₃ may be the same or different, and R ₁ and
R ₂ may be linked through the same or different atoms, and X represents a halogen atom. ) and the general formula () (In the formula, R ₄ and R ₅ are hydrogen atoms, halogen atoms,
Represents a hydroxyl group, trihalogenomethyl group, phenyl group, phenoxy group, phenylthio group, linear or branched C ₁ to C ₆ alkyl group, alkenyl group, alkoxyl group, alkylthio group, dialkylamino group, alkylsulfonyl group. , R ₄ and R ₅ may be connected through the same or different atoms) to form the general formula () (wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) is obtained, and then hydrolyzed to obtain a nitrile compound of the general formula () (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above) is obtained and then decomposed under alkaline conditions. () (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and n have the same meanings as above.) A method for producing an amine derivative represented by the following formula.