JP3436314B2 - Method for producing 2-mercapto-5-methoxybenzimidazole - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides 2-mercapto-5-methoxybenzimidazole, which is useful as a pharmaceutical intermediate, directly from 4-amino-3-nitroanisole by a one-step method in a high purity and a high yield. The present invention relates to a simple and inexpensive manufacturing method.

[0002]

2. Description of the Related Art A conventional method for producing 2-mercapto-5-methoxybenzimidazole from 4-amino-3-nitroanisole is 3,4-diaminoanisole as an intermediate thereof, as shown in the general formula (2). It is via.
(T. Kametani, K. Fukumoto, F .;
Satoh, H .; Yagi, J .; Chem. Soc
(C), 1968, 3084 and H.M. E. Fierz
David, L .; Blankey, H .; Streif
f, Helv. Chim. Acta, 1946, 29,
1718) and cyclization of the intermediate using CS ₂ affords the desired 2-mercapto-5-methoxybenzimidazole. (JP-A-1-6
2638)

The above is represented by the formula 1 [Formula 2] as follows.

[Chemical 2]

However, in the above-mentioned production method, 3,4-diaminoanisole is very unstable and is easily oxidized by air, so that the yield is remarkably lowered and a by-product is apt to be produced. Therefore, the yield of 2-mercapto-5-methoxybenzimidazole was 50 to 60%.

[0005]

As described above, according to the conventional method for producing 2-mercapto-5-methoxybenzimidazole by the two-step reaction, the intermediate is unstable and is easily oxidized by air, and the yield thereof is low. In view of liable to cause the formation of organisms, the present invention does not isolate the intermediate 3,4-diaminoanisole, but directly from 4-amino-3-nitroanisole by a one-step method to obtain high-quality 2-mercapto-.
It is an object of the present invention to provide a method for producing 5-methoxybenzimidazole in high yield at low cost.

[0006]

The present invention is a production method represented by the following reaction formula, wherein 4-amino-3-nitroanisole is used as a raw material, MeOH / H ₂ O is used as a solvent, and a reducing agent is used. By a one-step method in which a reduction reaction is carried out using zinc or iron and hydrochloric acid and a cyclization reaction is carried out using CS ₂ , 2-mercapto- A method for producing 5-methoxybenzimidazole. In a preferred embodiment, 4-
Powdered zinc or iron is 3 to 4 times molar amount, hydrochloric acid is 0.1 to 4 times molar amount, and C to amino-3-nitroanisole.
S ₂ is used in a molar amount of 1.5 to 3 times, and the liquid to be mixed and reacted is kept at 50 to 70 ° C.

[0007]

[Chemical 3]

The present invention does not divide the reduction reaction in the previous step and the cyclization reaction in the subsequent step as shown in the above-mentioned general formula [Chemical Formula 2], but by allowing both reactions to proceed at the same time, It is possible to obtain 2-mercapto-5-methoxybenzimidazole from 4-amino-3-nitroanisole with high quality and high yield.

The reducing agent M (zinc or iron) in the present invention is preferably in the form of powder having high purity and large surface area from the viewpoint of reaction rate. The hydrochloric acid that contributes to the reduction is suitably an aqueous solution containing 36% by weight of hydrogen chloride. It is practical to use inexpensive and highly soluble methanol as the reaction solvent. When M is zinc, the amount of hydrochloric acid is preferably 4 times the molar amount of the original stoichiometric amount with respect to the substrate, and is preferably 4 times the molar amount. The amount of zinc is preferably 3 to 4 times the molar amount in terms of purity in powder form, CS
_The amount of ₂ is preferably 1.5 to 3 times. Any further excess is economically disadvantageous. In a reaction system using zinc as a reducing agent, by-product zinc chloride reacts with by-product hydrogen sulfide in the cyclization reaction to generate 2 equivalents of hydrogen chloride, which leads to reduction of 4-amino-3-nitroanisole. Contribute.

The temperature of the reaction solution is 50 to 50 at which reflux is observed.
It is desirable to heat up to 70 ° C., and at a temperature below this temperature, the reaction proceeds slowly and is not practical. The maximum reflux temperature in this reaction system is about 70 ° C. Since zinc chloride remaining in the system is difficult to separate and remove from the viewpoint of solubility, sodium sulfide is used to convert it to insoluble zinc sulfide, and at the same time, 2-mercapto-5-methoxybenzimidazole is converted into a water-soluble sodium salt. By guiding, the isolation is easy. The desired 2-mercapto-5-methoxybenzimidazole can be easily produced by neutralizing the obtained reaction product containing 2-mercapto-5-methoxybenzimidazole sodium salt as a main component with an equivalent amount of hydrochloric acid. can do.

When the reducing agent M is iron, unlike the case where the reaction mechanism is zinc, the reduction reaction proceeds by heating and stirring with a catalytic amount of hydrochloric acid. The amount of iron is preferably 4 to 5 times the molar amount of the substrate, and the stirring efficiency and temperature greatly influence the reaction rate.
The upper limit of the reaction temperature is 70 ° C. by azeotropic reflux of CS ₂ and a solvent, and 6 hours are required to complete the reaction. In this case, the amount of CS ₂ is economically preferable to be 1.5 times the molar amount, and if the amount is more or less than that, it is practically disadvantageous because the reaction progress is delayed in relation to the azeotropic reflux temperature. After completion of the reaction, iron oxide (including unreacted iron) can be easily removed by filtration. Comparing the case where the reducing agent M is zinc and the case where it is iron, the latter case is superior in yield by about 10%, and is suitable for the industrial production method from the viewpoint of being inexpensive and simple.

The present invention will be described below with reference to examples.
The invention is not limited to these examples only.

Example 1 4-Amino-3-nitroanisole 10 was placed in a glass round bottom reaction vessel (300 ml, equipped with a stirrer).
g, 13 g of powdered zinc and 70 ml of methanol were added and stirred under a nitrogen atmosphere, and then 24.1 g of 36% hydrochloric acid was added dropwise. With stirring maintained for 1 hour, 13.6 g CS ₂ and 50 ml methanol are added. The temperature inside the apparatus is maintained at 50 to 55 ° C. and stirring is continued for 4 hours. At the same temperature, 47.1 g of sodium sulfide nonahydrate, 5 g of diatomaceous earth as a filter aid, 1 g of activated carbon and 50 ml of methanol were added, and 1 hour and 30 minutes,
After maintaining the stirring, the mixture is filtered with a filter paper. The obtained filtered solution is placed in a reaction vessel and 36% hydrochloric acid is gradually added dropwise while keeping the temperature at room temperature. The light brown crystals that crystallized were collected by filtration to obtain 9.2 g of 2-mercapto-5-methoxybenzimidazole in a yield of 86%. The content analysis of this product by high performance liquid chromatography is 94%.

[0013]

Example 2 In the same manner as in Example 1, in a reaction vessel of 21 under a nitrogen atmosphere, 80 g of 4-amino-3-nitroanisole, 106.3 g of iron powder, 120 g of water and 560 ml of methanol.
Was added and 4.8 g of 36% hydrochloric acid was added dropwise, and then CS ₂ was added.
Is added and the mixture is stirred under reflux for 6 hours. The hydrogen sulfide of the exhaust gas is discharged through the cooler above the container. After confirming that the raw material 4-amino-3-nitroanisole was consumed, 4
79.0 g of an 8% aqueous sodium hydroxide solution was added and the mixture was sufficiently stirred, and then the iron compound was removed by a filter paper. The obtained filtered solution is treated with 36% hydrochloric acid 96.5 g in the same manner as in Example 1 to obtain 76.7 g of 2-mercapto-5-methoxybenzimidazole in a yield of 90%. The content analysis of this product by high performance liquid chromatography is 99
%.

[0014]

INDUSTRIAL APPLICABILITY According to the present invention, 2-mercapto-5-methoxybenzimidazole has been conventionally produced from 4-amino-3-nitroanisole via 3,4-diaminoanisole as an intermediate. Unstable and easily oxidized by air to give the product 2-mercapto-5
-The purity and yield of methoxybenzimidazole were extremely low. Therefore, the present inventors have proposed that 2-mercapto-5 can be directly produced from 4-amino-3-nitroanisole in a one-step reaction.
A method for producing -methoxybenzimidazole has been found, and it has become possible to easily and easily produce the target substance of the final product with high purity, high yield, low cost.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-50-84537 (JP, A) JP-A-48-28430 (JP, A) JP-A-64-62638 (JP, A) West German patent application publication 2358244 (DE, A1) European Patent Application Publication 130729 (EP, A2) (58) Fields searched (Int.Cl. ⁷ , DB name) C07D 235/28 CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A production method represented by the following reaction formula:
4-amino-3-nitroanisole is used as a raw material, methanol and water (hereinafter abbreviated as MeOH / H ₂ O) are used as solvents, and a reducing reaction is performed using zinc or iron as a reducing agent and hydrochloric acid, and CS ₂ A method for producing 2-mercapto-5-methoxybenzimidazole by a one-step method in which the intermediate 3,4-diaminoanisole is isolated by a cyclization reaction using. [Chemical 1] 2. Powdered zinc or iron in an amount of 3 to 4 times the molar amount of 4-amino-3-nitroanisole and 0.1% of hydrochloric acid.
The method for producing 2-mercapto-5-methoxybenzimidazole according to claim 1, wherein the molar ratio is about 4 to 4 times and CS ₂ is about 1.5 to 3 times. 3. The 2-mercapto-5 according to claim 1, wherein the liquid to be mixed and reacted is kept at 50 to 70 ° C.
Method for producing methoxybenzimidazole.