JP2515122B2 - Method for producing anthranilic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing anthranilic acid ester, more specifically, the following general formula (II): (In the formula, R ₁ represents an alkyl group) The present invention relates to a method for producing a 5-hydroxyanthranilic acid ester.

5-hydroxyanthranilic acid ester represented by the above general formula (II) and the following general formula (I) which is an alkoxy compound thereof, (In the formula, R ₂ represents an alkyl group, R ₁ is the same as above), and the 5-alkoxyanthranilic acid ester represented by
It can be widely used as an intermediate for medicines, agricultural chemicals, etc.
In particular, the compound represented by the general formula (III) having an anti-ulcer action and a gastrointestinal cytoprotective action found by the present inventors (In the formula, Y ₁ and Y ₂ represent hydrogen, halogen, alkoxy, alkyl, trifluoromethyl, amine and the like, R ₄ and
R ₅ represents hydrogen, chain or cyclic alkyl, aryl or aralkyl, and R ₂ is the same as above. However, R ₄ and
An important synthetic intermediate for a 2- (2-substituted amino-5-alkoxybenzylsulfinyl) benzimidazole derivative (excluding the case where both R _{5 s} are hydrogen) (Japanese Patent Application Laid-Open No. 61-221175, Japanese Patent Application No. 61-82268) Is.

2- (2-Dimethylamino-5-methoxybenzylsulfinyl) benzimidazole, which is one of the compounds represented by the general formula (III), can be obtained, for example, by the reaction steps shown below.

In addition, during the above reaction step, compound (iii) can also be obtained by the following reaction route.

Other compounds represented by the general formula (III) can also be obtained in the same manner as in the above reaction steps (I) and (II).

However, the steps of obtaining the compound (iii) in the above reaction steps were not sufficiently satisfactory as an industrial production method in terms of yield, operating method and the like.

In view of the above circumstances, the present inventors have diligently studied a method for obtaining a benzimidazole derivative represented by the general formula (III) that is operationally simple, and has a high yield. Was completed.

That is, the present invention has the general formula (In the formula, X is hydrogen or nitro, alkyl, halogen,
A compound represented by the general formula R ₁ OH (wherein R ₁ represents alkyl) is reacted with a compound represented by the general formula (Wherein R ₁ and X are the same as defined above), and the compound is then reduced to obtain a compound of the general formula (In the formula, R ₁ is the same as the above) The present invention relates to a method for producing a 5-hydroxyanthranilic acid ester.

By reacting the 5-hydroxyanthranilic acid ester represented by the general formula (II) obtained above with a compound represented by the general formula (R ₂ ) ₂ SO ₄ (wherein R ₂ represents alkyl) General formula (I) (In the formula, R ₁ and R ₂ are the same as the above), and a 5-alkoxyanthranilic acid ester can be obtained.

As the alkyl represented by the general formulas (I) and (II),
C ₁ -C ₅ lower alkyl is shown, and X represented by the general formula (IV) is hydrogen or a substituent such as nitro, alkyl, halogen, or alkoxy which can form a diazonium salt of the compound represented by the general formula (IV). If

In the esterification reaction of the compound represented by the general formula (IV), hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, a catalyst,
It can be carried out in the presence of an acid such as methanesulfonic acid at −10 ° C. to the boiling point of the solvent used, preferably 20 ° C. to 50 ° C., for 30 minutes to 50 hours, preferably 2 hours to 12 hours. As the reaction solvent, it is preferable to carry out by using a large excess of an alcohol body involved in the reaction represented by the general formula R ₁ OH (wherein R ₁ is the same as described above).

Then, in the reduction reaction of the compound represented by the general formula (V), a reducing agent such as ammonia, hydrazine and sodium hydrosulfite, preferably sodium hydrosulfite is used, and water or an alcoholic solvent such as methanol, ethanol and propanol is used. Solvent, acetone, tetrahydrofuran, dimethylformamide,
In a solvent mixed with water, such as dimethyl sulfoxide, preferably in water or an alcoholic solvent, 0 ° C to 100 ° C.
The reaction is carried out at 0 ° C, preferably 20 ° C to 60 ° C for 10 minutes to 24 hours, preferably 30 minutes to 2 hours.

5 represented by the general formula (II) obtained by the above method
-Hydroxyanthranilic acid ester, ethanol,
5-alkoxy represented by the general formula (I) is obtained by acting a dialkyl sulfuric acid at 0 to 40 ° C. in an organic solvent such as methanol, methyl ethyl ketone and acetone, preferably acetone, in the presence of a base such as potassium hydroxide. Anthranilic acid esters can be obtained.

The compound represented by the general formula (IV), which is a raw material, can be obtained, for example, by the method shown below.

compt.rend., 178, pp. 1285 to 1287 (1924) Nippon Chemistry Magazine 77 , pp. 1091-1093 (1956) The thus-obtained general formula (I) represented by 5-
The alkoxyanthranilic acid ester corresponds to the compound represented by the general formula (iii) in the above-mentioned synthetic step (I),
Thereafter, the benzimidazole derivative represented by the general formula (III) can be obtained by the same method.

As described above, according to the method of the present invention, a benzimidazole derivative represented by the general formula (III) can be obtained with a simple operation and a high yield.

 Next, the present invention will be described in more detail with reference to examples.

Reference Example 1 5-Hydroxy-2-phenylazobenzoic acid To 360 ml of water was added 151 ml of concentrated hydrochloric acid, 67.4 of aniline was added, and the internal temperature was cooled to 0 ° C or lower. A solution of 50 g of sodium nitrite in 145 ml of water was added dropwise over about 15 minutes while keeping the internal temperature at 5 ° C or lower. Furthermore, the mixture was stirred at the same temperature for 15 minutes to prepare a diazonium salt. To a solution prepared by adding 100 g of m-hydroxybenzoic acid to a solution of 450 ml of water containing 91.6 g of sodium hydroxide (purity: 95%) and dissolving the solution, a diazonium salt solution was quickly added dropwise at an internal temperature of 25 ° C over 5 minutes while stirring. After further stirring for 30 minutes, the insoluble matter was filtered off, and the filtrate was ice-cooled. 120 ml of concentrated hydrochloric acid was added dropwise at an internal temperature of about 10 ° C., and the precipitated crystals were collected by filtration, washed with water and dried to obtain 170 g of the title compound as a brown powder.

Example 1 Methyl 5-hydroxyanthranilate (1) 5-hydroxy-2-phenylazobenzoic acid 48.4
g (0.2 mol) was suspended in 480 ml of methanol and ice-cooled, and 20 ml of concentrated sulfuric acid was added dropwise at an internal temperature of 10 to 20 ° C over about 30 minutes. Then, the mixture was stirred at room temperature for 10 hours, and the solvent was distilled off under reduced pressure at 40 ° C or lower. To the residue was added 300 ml of water, extracted with chloroform, water,
After washing with saturated saline, it was dried with Glauber's salt. Glauber's salt was filtered off and the solvent was distilled off under reduced pressure to obtain 57 g of 5-hydroxy-2.
-Methyl phenylazobenzoate was obtained as a dark red oil. ¹ HNMR (CDCl ₃ ) δ: 3.94 (s, 3H), 6.84 to 8.00 (m, 8H) (2) The oily substance obtained above was dissolved in 256 ml of ethanol.
After heating to 0 ° C, a solution of 102 g of Na ₂ S ₂ O ₄ in 300 ml of water was added over about 15 minutes. After stirring for 1.5 hours, 10.2 g of powdered Na ₂ S ₂ O ₄ was further added, ethanol was distilled off under reduced pressure, and the precipitated oily matter was extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, and the precipitated crystals were added with ether and collected by filtration to obtain 21.5 g (64.4%) of methyl 5-hydroxyanthranilate as a brown powder. ¹ HNMR (CD ₃ OD) δ: 3.82 (s, 3H) 6.54 to 7.24 (m, 3H) Reference Example 2 Methyl 5-methoxyanthranilate Acetone 290 ml was cooled with ice water and crushed potassium hydroxide 7.0 g (purity 85% ) Was added, 14.7 g of methyl 5-hydroxyanthranilate was further added, and dimethylsulfate 1 was added with stirring.
A solution of 3.4 g of acetone in 30 ml was kept at around 5 ° C. and added dropwise over 30 minutes. After stirring for 15 minutes at this temperature, add 3.6 ml of acetic acid and add 1
The mixture was stirred for 5 minutes at the same temperature. The insoluble matter was removed by filtration, acetone was distilled off under reduced pressure at 40 ° C. or lower, 150 ml of ethyl acetate was added to the residue, and the mixture was washed twice with 150 ml of saturated sodium hydrogen carbonate solution. The organic layer was extracted twice with 150 ml of 1N-hydrochloric acid, and the hydrochloric acid solution was neutralized with 20% sodium hydroxide to PH 7.0 under cooling.

The precipitated oil was extracted with 150 ml of ether and cooled 0.5
It was washed with N sodium hydroxide and saturated saline. The ether layer was dried over sodium sulfate and evaporated under reduced pressure to obtain 12.75 g of a green oily substance.

NMR (CDCl ₃ ) δ: 3.74 (s, 3H) 3.86 (s, 3H) 6.48-7.40 (m, 3H) 5.16 (brs, 2H)

Claims (1)

(57) [Claims] 1. A general formula (Wherein, X represents hydrogen or a substituent such as nitro, alkyl, halogen, or alkoxy), and a compound represented by the general formula: R ₁ OH (wherein R ₁ represents an alkyl group) The compound of general formula (Wherein R ₁ and X are the same as defined above), and then the compound is reduced to give a compound of the general formula (In formula, R < ₁ > is the same as the above) The manufacturing method of 5-hydroxy anthranilic acid ester represented by these.