JP3161690B2 - Method for producing 2-mercaptoimidazole fused ring compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula

[0002]

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Wherein X is a nitrogen atom or C—R, and R and R ¹ are each a hydrogen atom, a lower alkoxy group,
It represents a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy group or a halo lower alkoxy group. 2-mercaptobenzimidazole compound or 2-mercaptoimidazo [4,5-b]
The present invention relates to a method for producing a pyridine compound (Compound II).

[0004] In this specification, a lower alkoxy group is a linear or branched alkoxy group having 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy or cyclopropyl. A group which may be substituted with a cyclic alkyl group such as a methoxy group is shown.

[0005] The lower alkyl group is a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group or a propyl group.

The lower alkoxy lower alkyl group is a straight or branched alkyl group having 1 to 3 carbon atoms and substituted by a straight or branched alkoxy group having 1 to 3 carbon atoms. It represents a methyl group, a methoxyethyl group, a methoxypropyl group or an ethoxypropyl group.

[0007] The lower alkoxy group is a linear or branched alkoxy group having 1 to 3 carbon atoms, which is substituted with a linear or branched alkoxy group having 1 to 3 carbon atoms. A methoxy group, a methoxyethoxy group, a methoxypropyloxy group or an ethoxypropyloxy group;

The halo-lower alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms containing 2 to 4 halogen atoms, and is a difluoromethoxy group, 2,2,
It represents a 2-trifluoroethoxy group and the like, and examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

The compound represented by the general formula

[0010]

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(Wherein, X, R and R ¹ have the same meanings as described above), which is useful as an intermediate for producing an antipeptic ulcer agent.

[0012]

2. Description of the Related Art As a method for producing a fused 2-mercaptoimidazole compound, for example, a compound having an adjacent functional group such as a 1,2-phenylenediamine compound and a thiocyanate (NaSCN, KSCN or NH ₄ SC
A process for producing a 2-mercaptobenzimidazole compound by reacting N) with N) is disclosed in JP-B-61-44867. A method for producing a 2-mercaptoimidazole monocyclic or condensed ring compound using carbon disulfide has been known for a long time. For example, a method for producing a 2-mercaptobenzimidazole compound obtained by reacting a 1,2-phenylenediamine compound with carbon disulfide is disclosed in JP-B-59-462.
No. 23 discloses this.

[0013]

[Problems to be solved by the invention]
In 44867, thiocyanates are used alone as imidazole ring-forming reagents, and in a reaction using thiocyanates, the solvent is water and C _1-.
In the case of C ₁₀ alcohol, the reaction temperature is as high as 110 to 200 ° C., which is not suitable for a substrate having poor thermal stability. actually,
2,3-Diamino-6-methoxypyridine derived from 2-amino-6-methoxy-3-nitropyridine by catalytic reduction was obtained, and this was tried to form an imidazole ring with potassium thiocyanate. In the reaction (1), the production of the target product was slight under the conditions of heating to reflux, and the decomposition of the substrate proceeded. When carbon disulfide is used, it often evaporates out of the reaction system together with by-produced hydrogen sulfide during the reaction. ) Used. For example, in the formation of an imidazole ring of 2,3-diamino-6-methoxypyridine, the amount of carbon disulfide used must be at least three times the molar amount of the substrate in order to obtain the desired product in high yield. Since carbon disulfide is specified as a special flammable substance and has high toxicity, it is preferable to carry out the reaction in a necessary minimum amount. Therefore, the use of each of these reagents alone needed to remedy these drawbacks.

[0014]

The present inventors have conducted studies to solve the above-mentioned problems, and as a result, have found that a 1,2-phenylenediamine compound or a 2,3-diaminopyridine compound can be converted into a thiocyanate compound in the presence of a base. And carbon disulfide at the same time, the reaction temperature is low, and the amount of carbon disulfide used is low, and the corresponding 2-mercaptobenzimidazole compound or 2-mercaptoimidazo [4, It has been found that a 5-b] pyridine compound can be produced, and the present invention has been completed.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS General formula

[0016]

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(Wherein, X, R and R ¹ have the same meanings as described above) or a 1,2-phenylenediamine compound or a 2,3-diaminopyridine compound (compound I)
Is reacted with carbon disulfide and thiocyanate in the presence of a base. Hereinafter, the present invention will be described in detail. In the compound I as a raw material for production and the corresponding compound II,
The substituents X, R and R ¹ have the same meaning as described above.

The synthesis of compound II can be carried out by reacting the corresponding compound I with carbon disulfide and thiocyanates in the presence of a base.

The base is, for example, an alkali hydroxide such as sodium hydroxide or potassium hydroxide.

The solvent is an alcohol such as methanol, ethanol, isopropyl alcohol, butyl alcohol, isobutyl alcohol or t-butyl alcohol, or an alcohol to which water is appropriately added. The amount of the solvent to be used is 1 to 100 times, preferably 2 to 50 times, the weight of compound I.

Examples of the thiocyanates include potassium thiocyanate, sodium thiocyanate and ammonium thiocyanate.

The amount of the carbon disulfide and the thiocyanate used is 0.6 to 3 times, preferably 1 to 2 times the weight of Compound I, respectively.

The concentration of the base is 1 to 30% by weight, preferably 5 to 10% by weight. The reaction temperature ranges from room temperature to the boiling point of the solvent, and is preferably from 30 to 80 ° C.

[0024]

The production examples of compound II are described below by way of examples. Note that these examples do not limit the scope of the present invention.

Example 1 2-mercapto-5-methoxyimidazo [4,5-b]
Preparation of pyridine

[0026]

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5.6 g of potassium hydroxide in 300 ml of water
(0.10 mol) was added and dissolved, and 10.0 g of 2-amino-6-methoxy-3-nitropyridine (5 g) was added to this solution.
9.1 mmol), 10% palladium-carbon 0.40 g
Was added and stirred, and 200 ml of methanol was further added. The reaction was stirred at room temperature under a normal pressure hydrogen atmosphere until hydrogen consumption ceased. Thereafter, the catalyst was filtered off from the reaction solution under a nitrogen atmosphere. This 2,3-diamino-6
Under a nitrogen atmosphere, 8.6 g (88 mmol) of potassium thiocyanate and 5.4 ml (89 mmol) of carbon disulfide were added to the filtrate containing methoxypyridine, and the temperature was raised at 0.7 ° C./min. Heated nearby for 8 hours. Thereafter, the mixture was cooled to room temperature, adjusted to pH 4 to 7 by dropwise addition of 5% sulfuric acid under water cooling, and the precipitated crystals were collected by filtration, washed with water, dried, and then dried.
Recrystallized from 0% aqueous methanol to give 2-mercapto-5
-Methoxyimidazo [4,5-b] pyridine 9.9 g
(93%) as colorless crystals.

Mp 234-236 ° C.

NMR (DMSO-d ₆ ) δ _ppm : 3.83 (3H,
s), 6.56 (1H, d, J = 8.5Hz), 7.44 (1H, d, J = 8.5Hz), 12.52 (1H,
s), 12.96 (1H, s).

Example 2 2-mercapto-5-methoxyimidazo [4,5-b]
Preparation of pyridine

[0031]

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Potassium hydroxide 5 in 50 ml of methanol
6 g (0.10 mol) was added and dissolved. After cooling the solution, 10.0 g (59.1 mmol) of 2-amino-6-methoxy-3-nitropyridine and 0.30 g of 10% palladium-carbon were added. added. The reaction was stirred at room temperature under an atmosphere of hydrogen at normal pressure until hydrogen consumption ceased. Thereafter, the catalyst was filtered off from the reaction solution under an argon atmosphere.
8.1 g of potassium thiocyanate was added to the filtrate containing 2,3-diamino-6-methoxypyridine under an argon atmosphere.
(83 mmol) and 5.0 ml (83 mmol) of carbon disulfide were added, the temperature was raised at 0.7 ° C./min, and the solution was heated at about 70 ° C. for 8 hours. Thereafter, the mixture was cooled to room temperature, and the cooled liquid was added dropwise with stirring to 125 ml of methanol to which 2.7 ml of sulfuric acid had been added. Was collected by filtration, washed with water, dried and then recrystallized from 50% aqueous methanol to give 2-
10.0 g (93.4%) of mercapto-5-methoxyimidazo [4,5-b] pyridine were obtained as colorless crystals.

Mp 234-236 ° C.

NMR (DMSO-d ₆ ) δ _ppm : 3.83 (3H,
s), 6.56 (1H, d, J = 8.5Hz), 7.44 (1H, d, J = 8.5Hz), 12.52 (1H,
s), 12.96 (1H, s).

Example 3 Preparation of 2-mercapto-5-methoxybenzimidazole

[0036]

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5-methoxy-2-nitroaniline 20.
0 g (119 mmol) was dissolved in 400 ml of methanol, 1.6 g of 10% palladium-carbon was added to the solution, and the mixture was stirred at room temperature under a normal pressure hydrogen atmosphere until hydrogen consumption was stopped. Thereafter, the catalyst was filtered off from the reaction solution under a nitrogen atmosphere. To the filtrate containing 4-methoxy-1,2-phenylenediamine, 600 ml of water was added under a nitrogen atmosphere, and further 11.2 g (0.20 mol) of potassium hydroxide, 17.2 g (176 mmol) of potassium thiocyanate, 10.8 ml (178 mmol) of carbon disulfide was added, the temperature was gradually raised, and the solution was heated at about 75 ° C. for 4 hours.
Thereafter, the mixture was cooled to room temperature, adjusted to pH 4 to 6 by dropwise addition of 5% sulfuric acid under water cooling, and the precipitated crystals were collected by filtration, washed with water and dried, and 19.8 g of 2-mercapto-5-methoxybenzimidazole (92 g) was added. .3%) as colorless crystals.

Mp 258 ° C.

NMR (DMSO-d ₆ ) δ _ppm : 3.75 (3H,
s), 6.69 (1H, s), 6.73 (1H, d, J = 8.6Hz), 7.03 (1H, d, J = 8.6H
z), 12.37 (1H, s), 12.41 (1H, s).

[0040]

The 2-mercaptobenzimidazole compound or 2-mercaptoimidazopyridine compound is, for example, a 1,2-phenylenediamine compound or 2,3
-It can be easily produced in high yield by reacting a diaminopyridine compound with carbon disulfide and thiocyanates in the presence of a base such as an alkali hydroxide.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 471/04 C07D 235/28 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (In the formula, X is a nitrogen atom or C—R, and R and R ¹ each represent a hydrogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy group, or a halo lower alkoxy group. .)
Reacting a compound represented by the formula with carbon disulfide and a thiocyanate in the presence of a base. (Wherein, X, R and R ¹ have the same meanings as described above.) A method for producing a fused 2-mercaptoimidazole compound represented by the formula: 2. Compounds of the formula I in which X is a nitrogen atom or C—H and R ¹ is a methoxy group can be obtained in the presence of a base in an amount of 5 to 10% by weight based on the weight of the compound. 2. The process according to claim 1, wherein the reaction is carried out at a temperature of from 30 to 80 [deg.] C. with an amount of carbon disulfide and thiocyanate.