KR820001260B1 - Process for the preparation of aminophenolether - Google Patents

Abstract

Twenty-five title compds. (I; R = lower alkyl, alkenyl, benzyl) useful as intermediates for medicine, were prepd. by reaction of alkali aminophenolate(II; M = alkali metal) and III(X = halo) in the presence of alkali metal hydroxide and quaternary ammonium or phosphonium salt. Thus, 13.1 g II(M = Na), 2 g NaOH, 50 g III(R = Me2CH), 1.68 g(n-C5H11)4N+Cl- in 100 ml PhCl reacted for 10 hr at 60≰C to give 14.9 g I(b.p., 119≰C/10 mmHg; yield 98%).

Description

How to prepare amino phenol ether

The present invention relates to a process for preparing aminophenol ethers in high selectivity, high purity.

Aminophenol ethers are useful as raw materials and intermediates for medicines, pesticides and flavorings, and various production methods are known. It is known to prepare aminophenylalkylethers, for example by directly reacting aminophenols with halogenated alkyls. However, in this method, since N-alkylaminophenol (b) and N-alkylaminophenylalkyl ether (c) are produced as by-products besides the desired amino phenylalkyl ether, as shown in the following reaction scheme, aminophenylalkyl ether It is difficult to selectively manufacture bays only in high yield.

In the formula, R ₁ represents an alkyl group, X represents a halogen atom.

The following methods have been proposed to solve these difficulties.

(1) A method for preparing aminophenyl alkyl ethers by acetylating amino groups of aminophenols to convert them into acetamino groups, and then hydrolyzing the acetamino groups (Japanese Pharmaceutical Journal No. 74 (1954), pp. 872-875). Reference)

(2) A method of preparing aminophenylalkyl ether by reacting a hydroxyl group of aminophenol with sulfochloride to convert it to a sulfonic acid ester group (-SO ₃ Ar), and then reacting with metal alcohol art as an alkalizing agent. (See Japanese Pharmacy Magazine Vol. 74 (1954), pp. 872-875)

(3) A method for producing aminophenylalkyl ether by directly alkylating aminophenol using dialkyl sulfate as alkylating agent. (See J. of Organic Chemister, Volume 22 (1957), pages 333-334)

However, the method of (1) is costly to prepare the target compound aminophenylalkylether because only the number of steps is required, and thus it is not satisfactory as an industrial method, and the methods of (2) and (3) are both There is a drawback that the selectivity and yield of aminophenyl alkyl ethers are lowered because the production of by-products of N-alkylaminophenol and N-alkylaminophenyl ether cannot be sufficiently suppressed.

It is an object of the present invention to overcome the drawbacks of the prior art, and another object is to prepare aminophenol ethers in high selectivity, high purity in an economical way.

MEANS TO SOLVE THE PROBLEM The present inventors consist of an alkali amino phenol light represented by the following general formula (I), and the organic halide compound represented by the following general formula (II) which consists of an alkali metal hydroxide, a quaternary ammonium salt, and a quaternary phosphonium salt. The present invention has been completed by providing a method for preparing aminophenol ether, which is characterized by reacting in anhydrous state in the presence of a quaternary salt selected from the group.

Wherein M represents an alkali metal atom, R represents a C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkenyl group or benzyl group, and X represents a halogen atom.

The following compounds are used in the method of the present invention.

Suitable alkali amino phenola arts include amino sodium phenol la art, amino potassium phenol la art, and amino lithium phenol light.

Suitable organic halides (formula RX) include linear or branched C ₁ -C ₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl and heptyl groups Halogenated alkenyls and benzyl halides having C ₁ -C ₆ alkenyl groups such as halogenated alkyls, allyl, isopropenyl, 1-butenyl, 2-butenyl and 2-pentenyl groups. As the halogen atom, chlorine or a cancel atom is preferable.

In the case of using isopropyl halide, an excess amount of a halide can be used as a solvent.

Suitable alkali metal hydroxides used in the method of the present invention include sodium hydroxide, potassium hydroxide and lithium hydroxide, which can be used for the reaction as solids such as granular, powdery and flake shaped.

Suitable quaternary ammonium salts and quaternary phosphonium salts used in the process of the present invention include benzyltriethylammonium bromide, benzyltributylammonium chloride, benzyltriamylammonium chloride, benzyltrioctylammonium chloride, trioctylmethylammonium chloride, Benzyltrialkyl such as isobutyltributylammonium bromide, hexadecyltributylphosphonium bromide, tetrapropylammonium bromide, tetrabutylammonium chloride, tetraamylammonium bromide, tetraamylammonium chloride, tetrahexylammonium bromide and tetrabutylphosphonium chloride Ammonium salts, benzyltrialkylphosphonium salts, tetraalkylammonium salts, tetraalkylphosphonium salts, triphenylalkylphosphonium salts and triphenylbenzylphosphonium salts.

The quaternary ammonium salts or quaternary phosphonium salts are benzyl tri-C ₁ to C ₁₆ alkylammonium salts, tetra-C ₁ to C ₁₆ alkyl ammonium salts, triphenylbenzylphosphonium salts, benzyl tri-C ₁ to C ₁₆ It is preferable to select from alkyl phosphonium salts, tetra-C ₁ -C ₁₆ alkylphosphonium salts, and triphenyl C ₁ -C ₁₆ alkylphosphonium salts.

In the process of the present invention, it is preferable to use an organic solvent to smoothly proceed the reaction.

Suitable organic solvents include organic solvents other than ketones and alcohols, such as pyridine, tetrahydroxyfuran dioxane, acetonitrile, toluene, xylene, chlorobenzene, dichlorobenzene, chlorotoluene, chloroform and carbon tetrachloride.

The reaction of the present invention can be carried out by stirring the alkali aminophenyllaart and the organic halides in an organic solvent in the presence of a solid alkali metal hydroxide and a quaternary ammonium salt or quaternary phospho salt.

The reaction can be carried out at atmospheric pressure, the reaction temperature depends on the type of solvent, but is usually carried out at less than 80 ℃. The reaction time can also be arbitrarily selected within the range of 1 to 20 hours.

The ratio of the organic halide to the alkali aminophenol laart is stoichiometrically, and it is preferable to use an excess of the organic halide in the range of 1.1 to 8.0 moles with respect to 1 mole of the alkali aminophenol laart.

It is preferable to use 0.5-5.0 mol of alkali metal hydroxides with respect to 1 mol of alkali amino phenol raat. As for the quaternary ammonium salt or the quaternary phosphonium salt, it is preferable to use 1 mol% or more and about 5 mol% with respect to 1 mol of alkali aminophenol raat.

It is preferable to use 250-2,000 ml of solvent for 1 mol of alkali amino phenol raat.

In the method of the present invention, the solid alkali metal hydroxide which is passed after completion of the reaction is dissolved by filtration or water, dissolved by liquid separation, and then the solvent is removed to obtain crude aminophenol ether. Crude aminophenol ether can be distilled and refine | purified.

In addition, the method of the present invention reacts an alkali aminophenol laart by reacting aminotenol and an alkali metal hydroxide in the solvent in the presence of a quaternary salt selected from the group consisting of quaternary ammonium salts and quaternary phosphonium salts. This can be achieved by removing the water to be produced and then removing the water and then adjusting the alkali metal hydroxide as it is or by adding an organic halide.

In the method of this invention, aminophenol ether which is a target compound is obtained by high selectivity and high purity, without reacting water as a solvent and performing reaction under anhydrous state.

In the method of the present invention in which an aminophenol ether is prepared by reacting an alkali aminophenol laat with an organic halide, the reaction is carried out in the anhydrous state in the presence of an alkali metal hydroxide and a quaternary ammonium salt or a quaternary phosphonium salt. Therefore, the production of by-products is almost completely suppressed, so that the desired aminophenol ether compound can be obtained with high selectivity and high yield.

The present invention will be described in more detail with reference to the following examples, which do not limit the scope of the invention.

Example 1

13.1 g (0.1 mol) of sodium 3-aminophenollaart, 2 g (0.05 mol) of granular sodium hydroxide, 50 g (0.64 mol) of isopropyl chloride, 1.68 g (0.005 mol) of tetrapentyl ammonium chloride ) And 100 ml of chlorobenzene as a solvent, and reacted with stirring at 60 ° C. After reacting for 10 hours, 70 ml of water was added to the reaction mixture. The phases were separated and washed with water, and then the solvent and isopropyl chloride were distilled off to give 15.0 g of crude 3-aminophenylisopropyl ether. As a result of gas chromatography analysis, the purity of the product was 99.5%, and the by-product N-isopropyl 3-aminophenylisopropyl ether was found to be 0.5%. Crude yield was 100% and yield and selectivity were very high.

The crude product was distilled off and purified, and 14.9 g of 3-aminophenylisopropyl ether having a boiling point of 119 ° C / 10 mmHg was obtained. Yield 98%.

Example 2-10

3-Aminophenylisopropyl ether was prepared according to the method of Example 1 except for using each quaternary ammonium salt or quaternary phosphonium salt described in Table 1 in place of tetrapentylammonium chloride. The results are shown in the first table.

TABLE 1

[Examples 11-25]

Each aminophenol ether was prepared according to the method of Example 1, except that each of those listed in Table 2 used alkaline aminophenol laart and an organic halide. The results are shown in Table 2 together with alkali aminophenols and organic halides.

TABLE 2

Comparative Example 1

21.8 g of 3-aminophenol, 39.3 g of isopropyl chloride, 16 g of sodium hydroxide and 150 ml of methanol were stirred at 85 ° C for 5 hours. After completion of the reaction, the solvent and isopropyl chloride were filtered off to obtain 11.2 g of crude 3-aminophenyl isopropyl ether.

As a result of gas chromatography analysis, the purity of 3-aminophenylisopropyl ether was 75.6%, and the content in the product was 11.5% of N-isopropyl-3-aminophenol and N-isopropyl-3-aminophenyl isopropyl ether. Was 12.8%. The yield was 36.2%.

Comparative Example 2

The reaction was carried out according to the method of Example 1, except that 48% aqueous solution of sodium hydroxide was used to obtain crude 3-aminophenyl isopropyl ether having 80.0%. (N-isopropyl 3-aminophenyl isopropyl ether content 20.0%) The yield was 45%.

Claims (1)

An agent selected from the group consisting of alkali metal hydroxide, quaternary ammonium salts and quaternary phosphonium salts of the alkali aminophenolate represented by the following general formula (II) and the organic halide family represented by the following general formula (III) Process for preparing aminophenol ether of formula (I), characterized in that the reaction is carried out under substantially anhydrous conditions in the presence of a quaternary salt.

In the formula, M represents an alkali metal atom, R represents a lower alkyl group, a lower alkenyl group or a benzyl group, and X represents a halogen atom.