JPH08268972A - Production of 5-bromo-6-methoxy-1-naphthalene carboxylic acid - Google Patents

Abstract

PURPOSE: To obtain a compound useful as an intermediate for synthesizing a therapeutic medicine for diabetic complications by oxidizing an easily available 6-methoxy-1-alkylnaphthalene with air in a liquid phase. CONSTITUTION: A method for producing 5-bromo-6-methoxy-1-naphthalene carboxylic acid comprises oxidizing (A) a 6-methoxy-1-alkylnaphthalene and/or its oxidation intermediate with (D) molecular oxygen in the presence of (C) a catalyst comprising a heavy metal compound and a bromine compound in (B) a solvent containing an aliphatic carboxylic acrid. The component A is preferably 6-methoxy-1-methylnaphthalene. The bromine compound of the component C is preferably used in an amount of 0.1-1.0 gram atom per mole of the component A. On the reaction, bromine is preferably added to the oxidation reaction solution after the oxidation reaction to cause a bromination reaction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing 5-bromo-6-methoxy-1-naphthalenecarboxylic acid (hereinafter referred to as 5BMNA).

[0002]

BACKGROUND OF THE INVENTION 5-BMNA and 5-bromo-6-methoxy-1 obtained by alkylesterification of 5BMNA.
-Naphthalenecarboxylic acid alkyl ester (hereinafter 5BM
NR) is an important intermediate for producing a physiologically active substance, for example, Tolrestat, which is a therapeutic drug for diabetic complications.

Conventionally, as a method of manufacturing 5BMNA, 6
-Methoxy-1-naphthalenecarboxylic acid is brominated in acetic acid solution using bromine (Japanese Patent Publication No. 3-69898), 6-methoxy-1-naphthalenecarboxylic acid alkyl ester is brominated with acetic acid or methylene chloride. A method of brominating using bromine in a halogenated alkane solvent such as ethylene or carbon tetrachloride (Japanese Patent Publication No. 3-69898).
Japanese Patent Publication No. 6-21105), a method in which 2-furancarboxylic acid and anisole are reacted in the presence of aluminum chloride, then methylated with dimethyl sulfate, and then brominated with bromine in the presence of water (Japanese Patent Laid-Open Publication No. Sho. 61-260041), a method of brominating 6-methoxy-1-naphthalenecarboxylic acid alkyl ester with bromine in the presence of hydrogen peroxide in a solvent such as acetic acid and methanol (German Patent No. 4318069). Etc. have been proposed.

The methods disclosed in JP-B-3-69898 and JP-B-6-21105 are excellent methods for producing 5BMNA and 5BMNR, but 6-hydroxy-1-naphthalenecarboxylic acid as a raw material is used. There is a problem that it is difficult to obtain an acid or 6-methoxy-1-naphthalenecarboxylic acid. 6-hydroxy-
Various methods are known as a method for producing 1-naphthalenecarboxylic acid or 6-methoxy-1-naphthalenecarboxylic acid. For example, a method of cyanating 6-methoxytetralone (Japanese Patent Publication No. 6-21105), a method of amidoalkylating 2-naphthalenesulfonic acid (Japanese Patent Laid-Open No. 63-122662), 1,6-clave acid. To cyanate (Royle, Schedler,
J. Chem. Soc. Vol. 123, 1641 (1
923), etc.), a method for sulfonating 1-naphthalenecarboxylic acid (Royle, Schedler, J. Che.
m. Soc. Vol. 123, 1641 (1923)
Etc.).

[0005]

The above 6-hydroxy-
All of the methods for producing 1-naphthalenecarboxylic acid or 6-methoxy-1-naphthalenecarboxylic acid require expensive starting materials, reagents, and cyan compounds that are difficult to handle in terms of occupational safety and environment. Therefore, implementation on an industrial scale is extremely difficult.

An object of the present invention is to provide a process for producing 5BMNA using a compound other than 6-hydroxy-1-naphthalenecarboxylic acid or 6-methoxy-1-naphthalenecarboxylic acid, which is difficult to obtain, as a starting material. .

[0007]

[Means for Solving the Problems] The inventors of the present invention have made extensive studies to achieve the above object. As a result, by oxidizing 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate with molecular oxygen in the presence of a catalyst consisting of a heavy metal compound and a bromine compound in a solvent containing an aliphatic carboxylic acid, It has been clarified that 5BMNA can be obtained, and further, that the yield of 5BMNA is improved by adding bromine to the oxidation reaction liquid to cause a bromination reaction, and reached the present invention.

That is, the present invention is 6-methoxy-1-
Alkylnaphthalene and / or its oxidation intermediate,
A method for producing 5-bromo-6-methoxy-1-naphthalenecarboxylic acid, characterized by oxidizing with molecular oxygen in the presence of a catalyst composed of a heavy metal compound and a bromine compound in a solvent containing an aliphatic carboxylic acid. Is.

Further, the present invention provides a method in which a 6-methoxy-1-alkylnaphthalene and / or an oxidation intermediate thereof is used as a molecule in the presence of a catalyst containing a heavy metal compound and a bromine compound in a solvent containing an aliphatic carboxylic acid. 5-Bromo-6-methoxy-1 which is characterized by adding bromine to the oxidation reaction solution and oxidizing the solution after oxidizing with gaseous oxygen.
-A method for producing naphthalenecarboxylic acid.

[0010]

In the present invention, 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate is used as a starting material. 6-Methoxy-1-alkylnaphthalene is 3-methoxytoluene, 3-methoxyethylbenzene, 3-methoxy-n-propylbenzene, and the like.
1,3-butadiene was added to methoxyalkylbenzene in the presence of an alkali metal catalyst, and then cyclized with an acid catalyst to give 6-methoxy-1-alkyltetralin.
Then, it can be industrially produced by dehydrogenation. However, 6-methoxy-1-used in the present invention
Needless to say, the alkylnaphthalene is not limited to the one obtained by the above-mentioned production method, and any one obtained by any production method can be used.
Preferred 6-methoxy-1-alkylnaphthalene is 6
Although it is -methoxy-1-methylnaphthalene, an oxidation intermediate of 6-methoxy-1-alkylnaphthalene such as 6-methoxy-1-formylnaphthalene and 6-methoxy-1-acylnaphthalene can also be used as a raw material.

In the present invention, a solvent containing an aliphatic carboxylic acid is used. As the aliphatic carboxylic acid,
It is a lower aliphatic carboxylic acid such as acetic acid, propionic acid, butyric acid and bromoacetic acid, and is preferably acetic acid. The content of the lower aliphatic carboxylic acid in the solvent is at least 50% by weight.
As described above, it may be diluted with another solvent such as benzene or bromobenzene, and may contain water as long as it does not inhibit oxidation. The amount of the solvent used is not particularly limited as long as it can handle the 5BMNA produced after the completion of the oxidation reaction, and is usually 6-methoxy-
It is used in an amount of 2 to 50 times by weight based on 1-alkylnaphthalene and / or its oxidation intermediate.

The heavy metal compound used as a catalyst in the present invention is not particularly limited as long as the oxidation reaction can proceed, and examples thereof include cobalt, manganese, cerium,
Examples thereof include acetates such as nickel, iron and chromium, propionates, carbonates, bromides and hydroxides, and cobalt compounds and / or manganese compounds are particularly preferable. These heavy metal compounds may be used alone or in combination of two or more. The amount of heavy metal compound used is
0.005 with respect to 1 mol of the raw material 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate
Is in the range of .about.2.0 gram atoms, preferably 0.02 to 0.5 gram atoms.

Examples of the bromine compound used in combination with the heavy metal compound in the present invention include alkali metal bromides,
Examples thereof include inorganic bromides such as alkaline earth metal bromides, hydrogen bromide, hydrobromic acid, ammonium bromide, and organic bromides such as ethyl bromide, bromoform, and bromoacetic acid, but preferably inorganic bromine. It is a compound. The amount of the bromine compound used is 0.1 to 1.0 gram atom, preferably 0. 0, per 1 mol of the raw material 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate.
2 to 0.9 gram atom. The reason is that if the amount of the bromine compound used exceeds 1.0 gram atom per 1 mol of the raw material, the yield of 5BMNA is reduced, which is not preferable.

The oxidation reaction temperature is generally 60 to 200.
C., preferably 80 to 180.degree. The reaction pressure may be such that the oxidation reaction system can be maintained in the liquid phase at the reaction temperature,
Generally, the pressure is from normal pressure to 40 kg / cm ² · G. As the molecular oxygen in the present invention, in addition to air and pure oxygen, pure oxygen diluted with an inert gas can be used, but normally air is generally used as it is.
After the completion of the oxidation reaction, solid-liquid separation of the oxidation reaction liquid gives 5BMNA as an oxidation product. The oxidation product can be further improved in purity by washing with an oxidation reaction solvent such as acetic acid.
The oxidation reaction mother liquor obtained together with the oxidation product by solid-liquid separation of the oxidation reaction liquid is, if necessary, water by-produced is removed by means of distillation or the like, and the catalyst concentration of the heavy metal compound or bromine compound is adjusted. It can also be recycled for the oxidation reaction.

Further, in the present invention, after the completion of the oxidation reaction, bromination reaction is carried out by adding bromine to the oxidation reaction solution without solid-liquid separation of the oxidation reaction solution to give 5B.
The yield of MNA can also be increased. The amount of bromine used is usually 1 mol or less with respect to 1 mol of the raw material 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate. The reason is that even if 1 mol or more of bromine is used with respect to 1 mol of the raw material, there is no problem, but there is no advantage and it is economically disadvantageous. The bromination reaction temperature may be the above-mentioned oxidation reaction temperature, but the bromination reaction proceeds smoothly even at room temperature. Further, in the bromination reaction, for example, sodium acetate or the like can be added in order to capture hydrogen bromide produced as a by-product. The bromination reaction time is not particularly limited, and about 1 hour is usually sufficient. After completion of the bromination reaction, 5BMNA can be obtained by solid-liquid separation of the bromination reaction solution. The bromination reaction mother liquor removes water by-produced in the oxidation reaction, hydrogen bromide by-produced in the bromination reaction, alkali metal bromide (sodium bromide when sodium acetate is added), etc. as necessary. After adjusting the catalyst concentrations of the heavy metal compound and the bromide, they can be recycled for the oxidation reaction.

[0016]

Example 1 A 6-methoxy-1-methylnaphthalene 20 was placed in a titanium autoclave with an internal volume of 500 ml equipped with a gas discharge pipe with a reflux condenser, a gas injection pipe, a continuous feed pump for raw materials, and a stirrer. 0.0 g (0.116 mol), acetic acid 230
g, cobalt acetate tetrahydrate 4.98 g (0.020 gram atom), manganese acetate tetrahydrate 4.90 g (0.
020 g atom), 10.29 g of sodium bromide
(0.10 gram atom) was charged and the reaction pressure was 10 kg /
cm ² · G, reaction temperature 100 ° C, exhaust gas flow rate 60 Nl
Air was blown in so that it would be / min, and the oxidation reaction was carried out until there was no oxygen absorption. After completion of the oxidation reaction, the oxidation reaction product was cooled to room temperature, taken out, and suction-filtered to obtain a crude crystal, which was washed with a small amount of acetic acid and then dried to obtain 5BMNA1.
4.4 g was obtained. This was combined with the oxidation reaction mother liquor obtained by filtering off the crude crystals and 5BMNA contained in the acetic acid washing liquid, and 46.1 based on the starting material 6-methoxy-1-methylnaphthalene.
The yield was mol%. The analysis of 5BMNA was performed by gas chromatography.

Comparative Example 1 In the same titanium autoclave as in Example 1, 20.0 g (0.116 mol) of 6-methoxy-1-methylnaphthalene, 230 g of acetic acid and 4.98 of cobalt acetate tetrahydrate were added.
g (0.020 gram atom), manganese acetate / tetrahydrate 4.90 g (0.020 gram atom), sodium bromide 12.35 g (0.12 gram atom) were charged, and the reaction pressure was 10 kg / cm ^2. G, reaction temperature was 100 ° C., air was blown in so that the flow rate of exhaust gas was 60 Nl / min, and an oxidation reaction was carried out until oxygen absorption stopped. After the oxidation reaction,
The oxidation reaction product was cooled to room temperature and taken out. No crystal precipitation was observed in the reaction product, and 5BMNA was used as the raw material 6-
The yield was 2.9 mol% based on methoxy-1-methylnaphthalene.

Example 2 40.0 g (0.232 mol) of 6-methoxy-1-methylnaphthalene, 230 g of acetic acid, and cobalt acetate tetrahydrate of 9.96 were placed in the same titanium autoclave as in Example 1.
g (0.040 gram atom), manganese acetate tetrahydrate 9.80 g (0.040 gram atom) and sodium bromide 8.23 g (0.08 gram atom) were charged, and the reaction pressure was 30 kg / cm ^2. G, reaction temperature was 140 ° C., air was blown in so that the flow rate of exhaust gas was 96 Nl / min, and an oxidation reaction was carried out until oxygen absorption stopped. After completion of the oxidation reaction, the oxidation reaction product was cooled to room temperature, taken out, and suction-filtered to obtain crude crystals, which were washed with a small amount of acetic acid and then dried to give 5B.
27.9 g of MNA was obtained. This was a yield of 26.6 mol% based on the starting material 6-methoxy-1-methylnaphthalene, together with the oxidation reaction mother liquor from which crude crystals were separated by filtration and 5BMNA contained in the acetic acid washing liquid.

Example 3 In the same titanium autoclave as in Example 1, 60.0 g (0.348 mol) of 6-methoxy-1-methylnaphthalene, 230 g of acetic acid and cobalt acetate tetrahydrate 14.9 were used.
g (0.060 gram atom), manganese acetate tetrahydrate 14.7 g (0.060 gram atom) and sodium bromide 12.35 g (0.12 gram atom) were charged, and the reaction pressure was 30 kg / cm ^2. G, reaction temperature was 140 ° C., air was blown in so that the flow rate of exhaust gas was 96 Nl / min, and an oxidation reaction was carried out until oxygen absorption stopped. After the oxidation reaction,
The oxidation reaction product was cooled to room temperature, taken out, and suction-filtered to obtain crude crystals, which were washed with a small amount of acetic acid and then dried to give 5
59.0 g of BMNA was obtained. This was a yield of 21.3 mol% based on the raw material 6-methoxy-1-methylnaphthalene, together with the oxidation reaction mother liquor from which crude crystals were filtered off and 5BMNA contained in the acetic acid washing liquid.

Example 4 In the same titanium autoclave as in Example 1, 20.0 g (0.116 mol) of 6-methoxy-1-methylnaphthalene, 230 g of acetic acid and 4.98 of cobalt acetate tetrahydrate were added.
g (0.020 gram atom), manganese acetate tetrahydrate 4.90 g (0.020 gram atom), sodium bromide 5.15 g (0.050 gram atom) were charged, and the reaction pressure was 10 kg / cm ^2. G, a reaction temperature of 100 ° C., air was blown in so that the exhaust gas flow rate was 60 Nl / min, and an oxidation reaction was carried out until oxygen absorption disappeared to prepare an oxidation reaction liquid. 18.38 g of bromine molecules (0.
115 mol), sodium acetate 14.11 g (0.17
(2 gram atom) was added, and the mixture was stirred at 30 ° C. for 1 hour to cause a bromination reaction. After the bromination reaction, the reaction solution was taken out and suction-filtered to obtain crude crystals, which were washed with a small amount of acetic acid and then dried to obtain 21.7 g of 5BMNA having a purity of 84.0%. This is 65.3 based on the raw material 6-methoxy-1-methylnaphthalene.
The yield was mol%.

Example 5 The bromination reaction mother liquor from which crude crystals were filtered off in Example 4 was concentrated to a liquid weight of 75%, and the precipitated sodium bromide was removed by suction filtration. This filtrate was reused in the oxidation reaction and tested in the same manner as in Example 4 to obtain 5BMNA. This was used as the first recycling reaction, and the same reaction was repeated 3 times to determine the purity and yield of 5BMNA in each cycle. Table 1 shows the results. As shown in Table 1, although the purity of 5BMNA slightly decreases, 5BMNA
The yield of NA is significantly improved with the increase in the number of cycles.

[0022]

[Table 1]

[0023]

As described above, according to the method of the present invention, 5BMNA can be obtained by liquid phase air oxidation of 6-methoxy-1-alkylnaphthalene, which is easily available. It is valuable as

Claims (5)

[Claims] 1. Oxidation of 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate with molecular oxygen in the presence of a catalyst composed of a heavy metal compound and a bromine compound in a solvent containing an aliphatic carboxylic acid. A method for producing 5-bromo-6-methoxy-1-naphthalenecarboxylic acid, which comprises: 2. The method according to claim 1, wherein the bromine compound is used in an amount of 0.1 to 1.0 gram atom per mol of 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate. A method for producing -bromo-6-methoxy-1-naphthalenecarboxylic acid. 3. 5-Bromo-6-methoxy-1 according to claim 1, wherein the 6-methoxy-1-alkylnaphthalene is 6-methoxy-1-methylnaphthalene.
-Method for producing naphthalenecarboxylic acid. 4. A 6-methoxy-1-alkylnaphthalene and / or its oxidation intermediate is oxidized with molecular oxygen in the presence of a catalyst consisting of a heavy metal compound and a bromine compound in a solvent containing an aliphatic carboxylic acid. After that, bromine is added to the oxidation reaction liquid to cause a bromination reaction, which is a method for producing 5-bromo-6-methoxy-1-naphthalenecarboxylic acid. 5. The 5-bromo-6-methoxy-1 according to claim 4, wherein the 6-methoxy-1-alkylnaphthalene is 6-methoxy-1-methylnaphthalene.
-Method for producing naphthalenecarboxylic acid.