JPH0748332A - Process for producing N-alkanoyl-3-nitro-4-phenoxyaniline - Google Patents

Abstract

(57) [Summary] (Modified) [Purpose] 5 useful as anti-inflammatory agents, analgesics, antipyretics, etc.
Provided is a method for producing an intermediate N-alkanoyl-3-nitro-4-phenoxyaniline which is important as a raw material for synthesizing an amino-2-phenoxysulfoneanilide compound. [Structure] Expression [In the formula, R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ] N-alkanoyl-4-chloro-3-nitroaniline represented by the formula is subjected to a condensation reaction with phenol using an alkali metal hydroxide, an alkaline earth metal hydroxide or an alkali metal carbonate to give a formula [In the formula, R has the same meaning as described above. ] N-alkanoyl-3-nitro-4-phenoxyaniline represented by the formula: N-alkanoyl-3-nitro-4
-A method for producing phenoxyaniline.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention relates to Japanese Patent Application No. 4-15255.
Intermediate N-alkanoyl-3-nitro-4-phenoxyaniline important as a raw material for synthesizing 5-amino-2-phenoxysulfoneanilide compounds useful as anti-inflammatory agents, analgesics, antipyretics, etc. Manufacturing method.

[0002]

2. Description of the Related Art As a method for producing N-alkanoyl-3-nitro-4-phenoxyaniline, the present inventors have disclosed in Japanese Patent Application No. 4-116,208, 4-fluoro-3-nitroacetanilide as a starting material. The method used is described.

However, N obtained by a simpler method than 4-chloro-3-nitroaniline which is industrially available at low cost
-Alkanoyl-4-chloro-3-nitroaniline is condensed with phenol using an industrially easy-to-use alkali metal hydroxide, alkaline earth metal hydroxide or alkali metal carbonate to give N-alkanoyl- 3-nitro-4
-No method for producing phenoxyaniline has been reported.

[0004]

Generally, chlorine atoms and bromine atoms on the benzene ring are less reactive than the fluorine atoms in the nucleophilic substitution reaction, and the yield of the substitution product is low.
In fact, even in the nucleophilic substitution reaction of halonitrobenzene with phenol, benzyl alcohol, etc., chloronitrobenzene and bromonitrobenzene require more radical conditions or catalysts than fluoronitrobenzene,
Low yield of displacement product [Synthetic Com
communications, 20 (18) 2855 (19
90)].

From the above, an intermediate which is important as a raw material for synthesizing a 5-amino-2-phenoxysulfoneanilide compound described in Japanese Patent Application No. 4-152554, which is useful as an anti-inflammatory agent, analgesic agent, antipyretic agent, etc Although a method for synthesizing N-alkanoyl-3-nitro-4-phenoxyaniline from N-alkanoyl-4-fluoro-3-nitroaniline has been reported, N-alkanoyl-4-, which is industrially available at low cost, has been reported. It has been a problem that a method for producing chloro-3-nitroaniline in a simple and high yield has not been reported so far.

[0006]

Means for Solving the Problems As a result of intensive studies aimed at solving the above problems, the present inventors have found that the following industrially inexpensive 4-chloro-3-nitroaniline is used as a starting material. The manufacturing method shown in the reaction route was examined, and 4-
N-alkanoyl-4-chloro-3-nitroaniline obtained by a simpler method than chloro-3-nitroaniline is an industrially easy-to-use alkali metal hydroxide, alkaline earth metal hydroxide or alkali metal. N-alkanoyl-
The present invention was completed by finding that 3-nitro-4-phenoxyaniline can be easily obtained in high yield.

[Reaction path]

That is, the present invention provides the formula I

[0009]

[In the formula, R represents a hydrogen atom or a carbon atom of 1
~ 4 alkyl groups are shown. ] N-alkanoyl-4-chloro-3-nitroaniline represented by the formula] is condensed with phenol using an alkali metal hydroxide, an alkaline earth metal hydroxide or an alkali metal carbonate to give a compound of formula II

[0011]

[In the formula, R has the same meaning as described above. ] N-alkanoyl-3-nitro-4-phenoxyaniline represented by
It is a method for producing 3-nitro-4-phenoxyaniline.

The manufacturing method of the present invention will be described below.

The alkyl group having 1 to 4 carbon atoms in the present invention is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or the like.

The alkali metal hydroxides are sodium hydroxide, potassium hydroxide, etc., the alkaline earth metal hydroxides are calcium hydroxide, barium hydroxide, etc., and the alkali metal carbonates are sodium carbonate, Examples include potassium carbonate.

This condensation reaction is carried out without solvent or with benzene, toluene, xylene, dimethylsulfoxide, N, N-dimethylformamide, pyridine, hexane, cyclohexane, tetralin, t-butyl alcohol, isopropyl ether, tetrahydrofuran, dioxane, quinoline, water. In a solvent such as room temperature to the boiling point of the solvent, preferably at a reaction temperature of 50 ° C to 130 ° C.

This reaction is carried out using potassium fluoride, tris [2-
(2-Methoxyethoxy) ethyl] amine (TDA-
1), tricaprylyl methyl ammonium chloride (Aliquat336), 1,4,7,10,13,
The reaction can be promoted by adding 16-hexaoxacyclooctadecane (18-crown-6), benzyltrimethylammonium bromide or the like.

[0018]

INDUSTRIAL APPLICABILITY According to the present invention, N-alkanoyl-4-chloro-3 can be obtained by a simple method using 4-chloro-3-nitroaniline, which is industrially available at low cost, as a starting material.
-N-alkanoyl-3-nitro-4-phenoxyaniline can be easily produced in high yield via nitroaniline, and 5-amino- which is useful as an anti-inflammatory agent, an analgesic agent, an antipyretic agent, etc. It has become possible to industrially provide an important synthetic intermediate for a 2-phenoxysulfoneanilide compound.

[0019]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples.

Reference Example 1 Synthesis of 4-chloro-3-nitroacetanilide Triethylamine 12 was added to 500 ml of a dichloromethane solution containing 173 g of 4-chloro-3-nitroaniline under ice cooling.
After adding 1 g, 112 g of acetic anhydride was added dropwise over 30 minutes.

After stirring at room temperature for 5 hours, the mixture was extracted with dichloromethane, the dichloromethane layer was washed successively with water, diluted hydrochloric acid and saturated saline, and dried over anhydrous magnesium sulfate. The crystals obtained by distilling off the solvent were washed with ethanol to obtain 210 g of light brown 4-chloro-3-nitroacetanilide. (Yield 98%) m. p. 149-150 ° C

Example 1 Synthesis of 3-nitro-4-phenoxyacetanilide 13.5 g of potassium hydroxide (powder) was added to a solution of 500 ml of toluene containing 22.6 g of phenol, and heated to distill half of toluene. It was azeotropically dehydrated.
Toluene (250 ml) and 4-chloro-3-nitroacetanilide (42.9 g) were added, the mixture was refluxed for 2 hours, the solvent was evaporated, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water, dried over magnesium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from ether-n-hexane to give pale yellow 3-nitro-4-phenoxyacetanilide 4
9.0 g was obtained. (Yield 90%) m. p. 100-100.5 ° C

Example 2 Synthesis of 3-nitro-4-phenoxyacetanilide A mixture of 84.7 g of phenol and 58.2 g of tris [2- (2-methoxyethoxy) ethyl] amine (TDA-1) was added with potassium hydroxide ( Powder) Add 50.5g 13
After stirring at 0 ° C. for 30 minutes to remove water (steam) formed, 129 g of 4-chloro-3-nitroacetanilide was added to 20
The mixture was added over 1 minute, and the mixture was stirred at the same temperature for 3 hours.

The reaction solution was returned to room temperature and extracted with dichloromethane. The dichloromethane layer was washed successively with water, diluted hydrochloric acid and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was recrystallized from ether-n-hexane to obtain 139 g of pale yellow 3-nitro-4-phenoxyacetanilide. (Yield 85%) m. p. 100-100.5 ° C

Reference Example 2 5-nitro-4-phenoxyacetanilide 54.5 g
2.7 g of 5% palladium-carbon was added to a 250 ml solution of ethanol containing, and the mixture was subjected to catalytic reduction by stirring at room temperature in a hydrogen atmosphere. After removing palladium-carbon by filtration, the filtrate was distilled off to give colorless crystals of 3-amino-4-phenoxyacetanilide 4
7.5 g was obtained. (Yield 98%) m. p. 96-97 ° C

Reference Example 3 3-amino-4-phenoxyacetanilide 36.3 g
17.2 g of methanesulfonyl chloride was added dropwise to a 180 ml solution of pyridine containing the above under ice cooling, and the mixture was stirred at room temperature for 3 hours.

Ice water and 6N hydrochloric acid were added to the reaction solution for neutralization, and the precipitated crystals were collected by filtration, washed with water and recrystallized with ethanol to give colorless prism crystals of N- (5-acetylamino-2-).
Phenoxyphenyl) methanesulfonamide 42.3 g
Got (Yield 88%) m. p. 171-173 ° C

Reference Example 4 N- (5-acetylamino-2-phenoxyphenyl)
300 ml of acetic acid containing 60.9 g of methanesulfonamide
21.0 g of 60% nitric acid was added dropwise to the solution with heating at 80 ° C. over 30 minutes, and the mixture was stirred at the same temperature for 1 hour.

The reaction solution was returned to room temperature, ice water was added, and the precipitated crystals were collected by filtration, washed with water and recrystallized with ethanol to give N- (5-acetylamino-4-nitro-) of pale yellow prism crystals.
2-phenoxyphenyl) methanesulfonamide 55.
7 g was obtained. (Yield 83%) m. p. 185-186 ° C

Reference Example 5 A suspension of 250 ml of ethanol containing 50.0 g of N- (5-acetylamino-4-nitro-2-phenoxyphenyl) methanesulfonamide at room temperature containing 56 ml of water containing 14.0 g of sodium hydroxide. The solution was added and stirred for 3 hours.

The reaction solution was neutralized with 3N hydrochloric acid under ice cooling, and the precipitated crystals were collected by filtration, washed with water and recrystallized with isopropyl alcohol to give yellow needle crystals of N- (5-amino-4).
40.3 g of -nitro-2-phenoxyphenyl) methanesulfonamide was obtained. (Yield 89%) m. p. 173.5-174.5 ° C

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A formula [In the formula, R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ] N-alkanoyl-4-chloro-3-nitroaniline represented by the formula is subjected to a condensation reaction with phenol using an alkali metal hydroxide, an alkaline earth metal hydroxide or an alkali metal carbonate to give a compound of the formula [In the formula, R has the same meaning as described above. ] N-alkanoyl-3-nitro-4-phenoxyaniline represented by the formula: N-alkanoyl-3-nitro-4
-A method for producing phenoxyaniline.