JPH0428702B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing new or known benzimidazole derivatives. The compounds produced by the method of the present invention have the general formula It is expressed as where R ¹ is hydrogen, halogen, C _1-4 alkyl, C _1-3 alkoxy or trifluoromethyl, R ⁵ is amino or C _1-4 alkoxycarbonylamino, and R ⁶ is thiocyanato or the general formula - is a group of S-R ⁴ , where R ⁴ is a lone pair of electrons when a metal cation, preferably an alkali metal or alkaline earth metal cation, forms a salt with a negative sulfur atom; otherwise R ⁴ is hydrogen, a metal atom, preferably an alkali metal or alkaline earth metal, or a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, cyclohexyl, benzyl or 2-phenyl-ethyl group. Compounds of the general formula in which R ⁵ is amino and R ⁶ is thiocyanato,
or its salt is a new substance. Some compounds of the general formula are known to have anthelmintic effects, and others are useful as intermediates in the production of compounds with other beneficial drug properties. There is no known method for producing a compound represented by the general formula in which R ⁶ is a thiocyanato group on an industrial scale. However, a method for producing such compounds is described in Hungarian Patent Specification No. 169272. According to the method, 1,2-diamino-4-thiocyanato-benzene is produced by reducing 1-amino-2-nitro-4-thiocyanato-benzene with a large excess of stannous chloride at -40°C in concentrated hydrochloric acid.
Benzene is extracted from the reactant mixture with chloroform and extracted with 1,3-bis-(methoxycarbonyl)-S in an aqueous acetic acid solvent with evolution of mercaptan.
-Reacted with methyl-isothio-urea 5,(6)-
Thiocyanato-2-methoxycarbonylamino-
Benzimidazole is obtained. This method requires expensive reagents [stannous chloride and 1,3-bis-
(methoxycarbonyl)-S-methyl-isothio-
The problem is that it requires the use of urea] and that there is a high risk of environmental pollution. These drawbacks make this method unsuitable for industrial scale production. Direct thiocyanate esterification of 2-benzimidazole carbamic acid of the general formula is not known. As a prior art, thiocyanate esterification of various heterocyclic compounds has been disclosed [S. Patai: “The Chemistry of Cyanatesand
their Thio Derivatives”Part2.page883／
1977/Wiley: Pharmazie, 32 (4), 195/
1977/], but the thiocyanate esterification reaction of benzimidazole derivatives has not been carried out. Moreover, even chlorination, which is chemically related to thiocyanate esterification, is not described in the prior art for benzimidazole. Although the chlorination of 2-substituted benzimidazoles belonging to another class of compounds has been disclosed, the halogenation always leads to 4,(7)-halogeno- and 4,
A mixture of various products is formed, such as (6)(5,7)-dihalogeno-benzimidazole. As a method for obtaining carbamic acid 5,(6)thiocyanatobenzimidazole of the general formula with high purity and high yield, the general formula (R ¹ and R ⁵ are the same as above) with chlorine gas and a compound with the general formula R-SCN () (R is a metal atom or ammonium group)
We have discovered a method for selectively converting thiocyanate into thiocyanate by reacting with In a preferred embodiment of this method, chlorrodane obtained by reacting a thiocyanate of the general formula with chlorine gas was used as the thiocyanate esterification agent. Preferably, the thiocyanate of the general formula is reacted with chlorine gas in an anhydrous organic solvent to obtain chlorrodane, and the reactant mixture is added to a solution of the compound of the general formula and the organic solvent. Alternatively, it will be appreciated that a solution of a compound of the general formula may be added to chlorrodane. This method can also be achieved by introducing chlorine gas into a solution or suspension prepared in advance of the compound of the general formula, the compound of the general formula, and an organic solvent. In this case, the chlorrodane generated at that position will directly react with the compound of the general formula. In the above-mentioned variants of the process according to the invention, the molar ratio between the compound of the general formula and chlorrodane is between 1:1 and 1:5, preferably between 1:1 and 1:3. In another preferred embodiment of this variant of the process according to the invention, 1-3 mol of the thiocyanate of the general formula are added to a solution made of an anhydrous organic solvent or solvent mixture and 1 mol of the compound of the general formula, and to 15℃~
Anhydrous gaseous chlorine is introduced into the solution at a temperature of 40°C. Alternatively, chlorine gas can be dissolved in an organic solvent and added as a solution to the solution or suspension of the general formula and the compound of the general formula. It is preferable to add chlorine gas or its solution in a short period of time. As the thiocyanate of the general formula, an alkali metal, alkaline earth metal or heavy metal thiocyanate or ammonium thiocyanate is used, preferably potassium thiocyanate, sodium thiocyanate or ammonium thiocyanate. As the organic solvent and/or diluent, an aprotic polar solvent in which the component to be the solute is easily soluble is preferably used. Such organic solvents and/or
or as a diluent dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide, lower carboxylic acid esters preferably acetates or formic acid amides, C _1-4 alcohols, chlorinated hydrocarbons preferably chloroform, dichloromethane, tetrachloromethane or dichloroethane, Or there is nitromethane or acetonitrile. The reaction temperature is within the range of 0-100°C, preferably 15-40°C. As mentioned above, the known process for preparing 5,(6)-thiocyanato-benzimidazolyl derivatives, which is described in Hungarian patent specification No. 169272, is accompanied by considerable difficulties. It is known from the prior art that the thiocyanato group is extremely active and that this group is prone to various transformations, so that the reduction of the nitro group and the formation of the benzimidazole ring requires complex methods. Ta. In both alkaline and acidic media, thiocyanate esters form disulfide and thiol compounds and mixtures of these compounds together with other products [Houben-Weyl:
Methoden der organischen Chemie，Reviews
49, 77/1951/]. It is well known that the thiocyanato group is extremely sensitive to reducing agents, and it was thought that thiol and disulfide would be produced as a result of the reaction.
It was not foreseeable that only nitro groups could be selectively reduced. The catalytic hydrogenation reaction of nitro groups in a neutral medium could not be considered without neglecting this side reaction. This is because the thiocyanato group is a strong catalyst poison. The inventors have surprisingly found that 5,(6)-thiocyanato-benzimidazolyl derivatives of the general formula can be produced by a very simple method that allows production on an industrial scale with high yields. In this manufacturing method, the general formula (where R ¹ is the same as above) is selectively reduced with iron in a neutral or mildly acidic water/organic heterogeneous solvent system to give the general formula (where R ¹ is the same as above) and this compound V is converted into a cyanamide of general formula R ⁷ -NHCN () (where R ⁷ is the same as above) in water or a water/organic solvent system in the presence of an inorganic acid. hydrogen or _C14 alkoxycarbonyl) at elevated temperature, or
Alternatively, a 5,(6)-thiocyanato-benzimidazoline derivative can be obtained by reacting the compound of general formula (V) with a halogenocyan of general formula HlgCN (where Hlg is chlorine or bromine) in an organic solvent. It was found that according to the above method, the nitro group is selectively reduced, and the thiocyanato group is neither reduced nor hydrolyzed, leading to the present invention. This eliminates the need for expensive reactants and eliminates the need for reactions at extremely low temperatures. Furthermore, since the thiocyanato group does not decompose even when heated in a relatively strongly acidic medium, it is possible to form a benzimidazole ring without using the disadvantageous 1,3-bis-(alkoxycarbonyl)-S-methyl-isothiourea. I understand that it is possible to do so. In a preferred embodiment of the reaction, the nitro group is between 2.25 and
It is reduced using 3.5 gram atoms of iron. It is best to use iron by pulverizing it and scattering it. Preferably,
Pretreat the iron with 0.005-0.2 molar acid or salt.
The pretreatment is preferably carried out at a temperature of room temperature to 100°C,
Preferably it is carried out at 90°C to 95°C. As the acid, preferably sulfuric acid or hydrochloric acid can be used, and as the salt, preferably ammonium chloride, ferrous sulfate, ferric chloride, ammonium sulfate or calcium chloride can be used. The reaction medium used depends on the solubility of the starting materials. Reaction media include, for example, water-miscible organic solvents, preferably acetone, dioxane, lower alcohols, or water,
More preferably, methanol is used. The reduction reaction temperature can be between 20 and 100°C, and if convenient, the reaction can also be carried out at the boiling point of the reactant mixture. The reaction time depends on the type of starting material and reaction conditions, but can be from several minutes to 1 to 2 hours. The amount of acid or salt and reaction conditions are preferably selected so that the reaction time is 15 to 60 minutes. The reaction of compounds with general formula V is preferably carried out in an acidic aqueous medium. The pH of the reactant mixture is 2-
6, preferably 3-4. During the cyclization reaction,
To maintain the pH of the solution at the desired acidity, an aqueous acid solution is preferably added to the solution. reaction temperature 25
-100°C, preferably 70-100°C. As the acid, an organic acid or an inorganic acid can be used, preferably hydrochloric acid or sulfuric acid. The reaction is preferably carried out by dissolving the compound of general formula V in an aqueous acid solution, preferably 5N hydrochloric acid, under heating, and mixing the resulting solution with an aqueous calcium salt solution of the compound of general formula. Alternatively, the calcium salt of carbalkoxycyanamide of the general formula may be omitted from isolation, and carbalkoxycyanamide obtained by reacting industrial chemical grade calcium cyanamide with chloralkyl formate may be directly cyclized. In a preferred embodiment of the process, a thiocyanato-orthophenylene-diamine of general formula V is dissolved in a mixture of water and an organic solvent, preferably ethanol, and is reacted with a cyanamide of general formula. The reaction of a compound of general formula V with a halogenocyan of general formula is preferably carried out at a temperature of 0 to 40 DEG C. in a suitable organic solvent such as a lower alcohol, such as methanol, ethanol or isopropanol, preferably ethanol. Treatment of the reactant mixture with an alkali hydroxide (preferably sodium hydroxide or potassium hydroxide) or an alkali carbonate (e.g. sodium carbonate or potassium carbonate) provides a 5,(6)-thiocyanato-benzimidazolyl derivative of the general formula. It will be done. According to the method of the invention, 5,(6)-thiocyanato-
By producing benzimidazolyl derivatives, the drawbacks of known production methods can be overcome. The process uses very inexpensive starting materials that are available in large quantities and provides high yields of the desired 5,(6)-thiocyanato-benzimidazolyl derivatives. Further, according to the present invention, represented by the general formula,
R ⁶ is a group of the general formula -S-R ⁴ , R ¹ , R ⁵ and
A method is provided for the preparation of compounds in which R ⁴ is as defined above. A compound of the general formula where R ⁶ is a compound of the general formula -S-
Those in the R ⁴ group in which R ⁵ is an alkoxycarbonylamino group are known compounds. Many of the compounds have useful anthelmintic properties and can be used in human and veterinary treatment as anthelmintic agents. Other such compounds include those that serve as useful intermediates for the production of the above-mentioned final products. Compounds represented by the general formula where R ⁶ is the general formula -S-R ⁴ group and R ⁵ is an alkoxycarbonylamino group are USPS No. 3480642, 3574485, 3915986,
3956499 and 4152522 and DEPS No.2364351
It can be manufactured according to the method described. In any of the above methods, it is expressed as a general formula.
A compound in which R ⁶ is a general formula -S-R ⁴ group and R ⁵ is an alkoxycarbonylamino group has a 1,2-diamino- Manufactured from thiobenzene derivatives. The difference between the above known methods is that the 1,2
The difference lies in the method for producing -diamino-4-thiobenzene derivatives. U.S. Pat. 2-acetamido-4-
Alkylthio-nitro-benzenes are obtained which are converted to 1,2-diamino-4-alkylthio-benzenes by hydrolysis and reduction. 2-acetamido-4-chloro-nitro-benzene is produced by nitrating m-chloro-acetanilide, but the desired product must be separated from the by-product 3-chloro-4-nitroacetanilide. [J.Org.Chem. 12 799/1947/]. Although the reaction can be carried out normally, the yield is low [J.
Org.Chem. 42 554/1977] According to another known method, 1,2-diamino-4-alkylthio-benzene derivatives are prepared by thiocyanate esterification of aniline to give 4-thiocyanato-aniline, which is then acetylated. Te4-
Thiocyanato-acetanilide is obtained, which is then nitrated to obtain 2-nitro-4-thiocyanato-acetanilide, which is then selectively reduced.
Obtained through alkylation, hydrolysis, and reduction reactions. [Ber. 59 , 1960/1926/; J.Chem.Soc. 1928 ,
1364; DE-PS No. 2363351.] Recently, another method for producing 1,2-diamino-4-thiocyanato-benzene has been described (US-PS No. 4152522) which avoids the above multi-step process. According to this method, 4-thiocyanato-2-nitro-aniline prepared by esterifying O-nitro-aniline with thiocyanate is used as a starting material. 4
-Thiocyanato-2-nitro-aniline is reacted with an alkali cyanide and an alkyl halide to produce 4-alkylthio-2-nitro-aniline, which is then reduced to give the desired 1,2-diamino-4- Thiocyanato-benzene is obtained. The key point of the above method is to introduce the alkylthio group prior to the formation of the benzimidazolylalkyl albamic acid ring, which is sensitive to various chemical actions. According to the method described in DE−PS No.2820375,
The alkylthio group is generated in the final step by reduction of the corresponding bis-benzimidazole-disulfide and subsequent alkylation. Under certain conditions,
It is known from the prior art and from some of the patent specifications cited above that thiocyanato groups can be converted into alkylthio groups. However, this conversion is only possible in certain cases and requires special reaction conditions, since secondary products consisting mainly of disulfides are easily formed during this conversion. Furthermore, this method cannot be used when a group that is easily hydrolyzed is present in the molecule. DE-PS No.2363351 uses 1-acetamino-2-nitro-4-thiocyanato-benzene at 18
React with allium hydroxide and propyl bromide in methanol at a temperature of -20°C. However, in this case, not only propylthioic acid is produced but also hydrolysis of the acetyl group occurs, so the amino group must be acylated again. According to a new process for the above reaction (US-PS No. 4152522), alkali cyanide or alkaline earth cyanide is used in place of potassium hydroxide to make the reaction conditions more mild. Methods for the preparation of several of the above compounds are disclosed; moreover, thiocyanatobenzimidazolyl carbamate is known from DE-PS No. 2363351 mentioned above, but the thiocyanato group of benzimidazolylalkyl carbamate, which is sensitive to hydrolysis, The reaction of converting into an alkylthio group has never been done before. The inventors surprisingly discovered that R ⁶ is expressed by the general formula
It has been found that a compound having the general formula SR ⁴ can be produced in high yield and purity by a simple method. According to the method discovered by the inventors, the general formula (where R ¹ and R ⁵ are as defined above) with a basic nucleophile, and optionally the general formula obtained by this reaction. compound (where R ¹ and R ⁵ are as described above,
If the alkali metal or alkaline earth metal cation forms a salt with a negative sulfur atom, R ⁴ ′ is a lone pair of electrons, otherwise R ⁴ ′ is hydrogen or a metal atom, preferably an alkali metal atom or an alkaline earth metal atom) with the general formula R ⁴ ″-Q (where R ⁴ ″ is C _1-6 alkyl,
C _2-6 alkenyl, C _2-6 alkynyl, cyclohexyl, benzyl or 2-phenyl-ethyl; Q is halogen, hydroxy, 1/2SO ₄ , 1/3
PO ₃ , SO ₃ C ₆ H ₅ or SO ₃ C ₆ H ₄ CH ₃ ), a compound of the general formula and R ⁶ is of the general formula −SR ⁴ is prepared. Furthermore, according to the present invention, represented by the general formula,
R ⁶ is a group of the general formula -SR ⁴ , R ¹ , R ⁵ and R ⁴
is the above-mentioned compound and its salt, comprising (a) a step of reacting a compound of the general formula with a basic nucleophilic compound, and if necessary, reacting the compound of the general formula obtained here with a compound of the general formula; a step of reacting with an alkylating agent; or (b) general formula ^{( c _} ) reacting a mixture of a compound of general formula and a compound of general formula with a basic nucleophilic compound for the preparation of a compound of general formula As basic nucleophiles, organic or inorganic bases can be used, such as alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonate, alkali metal or alkaline earth metal alkoxide or allyl oxide, ammonium hydroxide, tertiary amine, alkali metal or alkaline earth metal azide, alkali metal or alkaline earth metal cyanide. or preferably alkali metal or alkaline earth metal sulfides, particularly preferably sodium sulfide. Alkylating agents of the general formula include C _1-3 alcohols, alkyl halides, preferably alkyl bromides, or Alkyl sulfate, alkyl phosphite,
Alkyl phosphates or benzenesulfonic acid esters or p-toluenesulfonic acid esters are used. The reaction can be carried out in water and/or an organic solvent. Water-miscible organic solvents may also be used;
Preferably C _1-3 alcohols (e.g. methanol,
Ethanol, isopropanol, n-propanol), acetone, dioxane, dimethylformamide, pyridine, dimethylsulfoxide or mixtures thereof are used. The reaction can also be carried out in water and a non-water miscible organic solvent in the presence of a phase transfer catalyst such as tetrabutylammonium chloride, trimethylbenzylammonium chloride or triethylbenzylammonium chloride. The reaction temperature can be between 0°C and the boiling point of the reactant mixture, preferably between 10 and 40°C. When alcohol is used as the alkylating agent, the temperature is preferably 80 to 100°C. In a preferred embodiment of this method, the reaction of the compound of the general formula, the alkylating agent of the general formula and the basic nucleophile is carried out in the same reaction vessel. Alternatively, a compound of the general formula may be mixed with an alkylating agent of the general formula, and a basic nucleophilic compound may be added to the mixture. Compounds of the general formula are preferably used, and the amount of basic nucleophilic compound is equimolar. According to this embodiment of the method, the desired product is obtained in almost quantitative yield without any side reactions. If the components are used in stoichiometric proportions, the undesirable effects of sulfides and the negative effects of the thiocyanate ions formed are avoided. No disulfides or other by-products are formed, and the alkyl carbamate group does not undergo any chemical changes. The salts of the compounds of the general formula may be acid addition salts, which include organic or inorganic acids commonly used in such salt-forming reactions, such as hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, (maleic acid, fumaric acid, lactic acid, tartaric acid, etc.). Salt production can be carried out by known methods. The method of the invention has several advantages over known methods. The method is suitable for industrial-scale production, uses starting materials that are available in large quantities and are extremely cheap, and the process does not pose any risk of environmental pollution. Next, the present invention will be explained in more detail with reference to Examples, but the scope of protection of the present invention is not limited to the Examples. Unless otherwise specified hereinafter, the terms "propyl" and "butyl" shall mean "n-propyl" and "n-butyl." Example 1 5.5 g of anhydrous gaseous chlorine were introduced into a solution of 5 g of 2-(methoxycarbonylamino)-benzimidazole and 7.5 g of anhydrous potassium thiocyanate.
The reactant mixture was then diluted with 100 ml of water and then
The pH of the solution was adjusted to 4 by adding 5N sodium hydroxide solution. The precipitate was filtered, washed with water, and dried at 60°C, resulting in 5.6 g of 5(6)-thiocyanato-2.
-(methoxycarbonylamino)-benzimidazole was obtained. The melting point was 252-254°C (decomposed) and the yield was 90%. Example 2 A solution of 7.5 g of anhydrous potassium thiocyanate and 60 ml of acetic anhydride was added to 70 ml of carbon tetrachloride containing 5.32 g of chlorine under stirring at 10-15°C. The reactant mixture was then stirred for an additional 15 minutes before a solution of 5 g of 2-(methoxycarbonylamino)-benzimidazole and 25 ml of acetic anhydride was added thereto. The reactant mixture is then stirred at room temperature and then poured into water, after separation of the carbon tetrachloride layer, the water layer is clarified with activated carbon and a 5N sodium hydroxide solution is added to the solution. Adjusted the PH to 4. The resulting precipitate was filtered, washed with water, and dried at 60°C. The melting point of the obtained 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole was 248-250°C (decomposition). Example 3 (Reference example) After activating 63 g of iron powder by heating it with a mixture of 12 ml of 5N hydrochloric acid and 30 ml of water for 30 minutes on a water bath, 270 ml of water was added to this, and the suspension was Cooled to ℃. A hot solution of 58.5 g of 4-thiocyanato-2-nitro-aniline and 180 ml of 96% ethanol was added to the suspension with stirring, and the temperature of the reactant mixture rose slowly. When the temperature reached 75°C, ice cooling was applied to keep the internal temperature of the reactant mixture below 85°C. The exothermic phase of the reaction lasted 3-4 minutes. The reactant mixture was then heated to the boiling point until no starting material was detected by thin layer chromatography (approximately 15 minutes). After filtering the warm reactant mixture, 225 ml of hot water was added to the filtrate;
The solution was clarified with activated carbon, allowed to warm, filtered again and the filtrate was gently stirred to crystallize. The mixture containing the crystalline material was heated at 0°C for 5~
After stirring for 6 hours, the crystals were filtered, washed with cold 25% ethanol, and dried in vacuo to yield 41.6 g of 4-thiocyanato-1,2-diaminobenzene. The yield was 79% and the melting point was 108-110°C. Example 4 (reference example) 2-nitro-4-thiocyanato-aniline,
A solution of 2.2 g of ammonium chloride and 15 ml of water was added dropwise to a suspension of 22.3 g of iron powder, 50 ml of 96% ethanol, and 50 ml of water with stirring at the boiling point of the reactant mixture. After stirring for an additional 15 minutes, the hot reactant mixture becomes warm and is filtered, adding water to the filtrate.
Added 250ml. After cooling, the precipitated crystals were filtered, and 12.2 g of 4-thiocyanato-1,
2-diamino-benzene was obtained. The yield of the compound was 74% and the melting point was 108-110°C. Example 5 (reference example) 2-nitro-4-thiocyanato-aniline,
A solution of 2.2 g of ferrous chloride and 4 ml of water was added dropwise to a suspension of 22.3 g of iron powder, 40 ml of 96% ethanol, and 50 ml of water with stirring at the boiling point of the reactant mixture. After stirring for a further 10 minutes, the reactant mixture was filtered and then 200 ml of water were added to the filtrate. Crystals precipitate on cooling. After filtering this crystal
12.3 g of 4-thiocyanato-1,2-diamino-
Benzene was obtained. The yield of the compound was 74.5% and the melting point was 108-110°C. Example 6 16.5 g of 1,2-diamino-4-thiocyanato-benzene was dissolved in 20 ml of 5N hydrochloric acid at 80°C, and this warm solution was added to a solution of calcium salt of carbomethoxy-cyanamide and 50 ml of water heated to 80°C. Added over 10 minutes. The temperature of the reactant mixture rose to 93-95°C. After the above addition was completed, 5N hydrochloric acid was added as needed to adjust or maintain the pH of the solution in the range of 3 to 4. Crystal precipitation started after a few minutes. The pH was maintained between 3 and 4 by occasional addition of 5N hydrochloric acid. After the salt addition was complete, the reactant mixture was further stirred for 15 minutes and then washed with water and hot methanol to yield 22.4 g of 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole. . The yield of the compound was 90.5%, and its molecular weight was 248 according to mass spectrometry. Example 7 36 g of industrial reagent grade calcium cyanamide (corresponding to 0.22 g of pure calcium cyanamide) are vigorously stirred in 114 ml of water at 30° C. for 1 hour and then added with 20.5 ml of ethyl chloroformate (25.4 g). g;
0.269 mol) was added dropwise over 30 minutes at the above temperature.
After stirring the reactant mixture for an additional hour, impurities were removed by filtration. Next, the purified filtrate was heated to 80°C, and to this was added 33 g (0.20 mol) of 1,2-diamino-4-thiocyanato-benzene heated to 80°C.
and 40 ml of 5N hydrochloric acid was added. When this reactant mixture was treated as described in Example 6,
41 g of 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole were obtained.
The yield of the compound was 83%. The properties of the compound were the same as the compound obtained in Example 6. Example 8 The method described in Example 7 was followed except that a solution made of 1,2-diamino-4-thiocyanato-benzene and a mixture of 50 ml of 5N hydrochloric acid/40 ml of 96% ethanol was added to the carbomethoxy-cyanamide. Ivy. The reactant mixture was treated as described in Example 7 to yield clean crystalline 5(6)-thiocyanate.
2-(methoxycarbonylamino)-benzimidazole was obtained. Example 9 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole was suspended in 25 ml of 96% methanol, and 1.25 g of propyl bromide was suspended in 25 ml of 96% methanol.
added. Next, add this to non-anhydrous sodium sulfide
When a solution consisting of 2.4 g and 2 ml of water was added dropwise at 20-25° C. over 30 minutes with vigorous stirring, a yellow solution was formed at first, but soon crystals began to precipitate. The product was filtered, washed with water, and dried to yield 2.50 g of 5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole. The yield of the compound is 94% and the melting point is 212-
It was 213℃. Example 10 124 g of 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole was suspended in 1.5 l of 96% ethanol, and 62.5 g of propyl bromide was suspended in 1.5 l of 96% ethanol.
added. Next, add this to non-anhydrous sodium sulfide
When a solution consisting of 120 g and 200 ml of water was added dropwise at 20-25° C. over 30 minutes with vigorous stirring, a brown solution was formed at first, but soon crystals began to precipitate. The product was filtered, washed with water and dried to yield 127 g of 5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole. The yield of the compound is 96% and the melting point is 212
It was -213℃. Example 11 24.8 g of 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole was suspended in 100 ml of dimethyl sulfoxide, and a solution consisting of 29.0 g of non-anhydrous sodium sulfide and 100 ml of methanol was added to this at 20°C. The mixture was added dropwise over 3-5 minutes to produce a clear pale yellow solution. When 15 g of propyl bromide was added to the solution at the same temperature as above, crystal precipitation started within 1-2 minutes. The mixture was stirred for an additional 30 minutes and then the pH was adjusted to 7 by adding 5N hydrochloric acid. Thereafter, the precipitated crystals were filtered, washed with water and alcohol, and dried under vacuum at 60°C to obtain 26.0 g of 5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole. The yield of the compound is 98% and the melting point is
The temperature was 214-215℃. Examples 12-23 The compounds listed in the table below were prepared by methods similar to those described in Examples 9-11 using the corresponding starting materials as raw materials.
In the compound of the general formula, R ⁵ is methoxycarbonylamino. [Table] Example 24 Non-anhydrous sodium sulfide was added to a solution of 2.48 g of 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole and 60 ml of 85% acetone.
After 40 minutes of adding a solution of 2.9 g and 5 ml of water, the reactant mixture was clarified and filtered. Acetone was added to the obtained yellow solution to precipitate 5(6)-thiol-2.
The sodium salt of -(methoxycarbonylamino)-benzimidazole was filtered, washed with acetone and then dried over potassium hydroxide in vacuo. The yield of the product is 2.3 g and the melting point is 300−
The temperature was 305℃ (decomposition). The results of spectrum analysis were as follows. IR: 1705cm ^-1 (ester carbonyl) 3150-2200cm ^-1 (benzimidazole; N) 802cm ^-1 (1,2,4-3-substituted benzene) H-NMR: Absorption of exchangeable protons at 6.388ppm . Raman spectrum: There is an absorption band specific to SH groups at 2555 cm ^-1 . Example 25 2.3 g of the sodium salt prepared according to the method described in Example 24 was dissolved in 25 ml of 50% ethanol, and the pH of the mixture was adjusted to 5 with hydrochloric acid. The precipitated 5(6)-thiol-2-(methoxycarbonylamino)-benzimidazole was filtered and washed. The product obtained is 1.65g and its melting point is
It was 261-262℃. The results of elemental analysis were calculated values: N% = 18.82; S% = 14.36%; actual values: N% = 18.30; S% = 14.35. Example 26 2.45 g of sodium salt of 5(6)-thiol-2-(methoxycarbonylamino)-benzimidazole
was suspended in 35 ml of 65% by volume acetone, the liquid was clarified with activated carbon, filtered and 1.3 g of propyl bromide was added to the filtrate at a temperature of 10-15°C. After 30 minutes, the pH of the mixture was adjusted to 6, and the formed crystals were filtered and washed, resulting in 2.5 g of 5(6).
-Propylthio-2-(methoxycarbonylamino)-benzimidazole was obtained. The melting point of the compound was 214°C (decomposition). Example 27 2.23 g of 5(6)-thiol-2-(methoxycarbonylamino)-benzimidazole was dissolved in 30 ml of 60% ethanol containing 0.8 g of sodium hydroxide.
1.3 g of propyl bromide was added to this solution at a temperature of 10-15°C. Stir the reactant mixture for 30 minutes, then
Adjust the pH to 6 and generate 5(6)-propylthio-
After filtering off the 2-(methoxycarbonylamino)-benzimidazole, 2.4 g of product was obtained, melting point 212-214 DEG C. (decomposition). Example 28 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole 49.66 g (0.2 mol)
was suspended in 600 ml of 65% acetone aqueous solution, and to this was added 58 g (0.24 mol) of non-anhydrous sodium sulfide and water.
100 ml of the solution was added over 5 minutes at 20°C to 25°C to obtain a pale yellow solution. This solution contained a small amount of precipitate. The solution was clarified with 4 g of activated charcoal, filtered and then washed twice with 20 ml of 65% acetone each time. A solution of 30 g (0.24 mol) of propyl bromide and 100 ml of acetone was added to the clear solution obtained here over a period of 5 minutes at 10-15°C. The reactant mixture was then stirred for 1 hour, and then 5N hydrochloric acid was added to adjust the pH of the solution to 6.
After further stirring the mixture for 30 minutes, the precipitated product was filtered, then suspended twice in 60 ml of 50% by volume acetone, washed twice with 30 ml of acetone, and dried. , 47.3g
5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole was obtained as snow-white fine crystals. Product yield is 89%
It was hot. Example 29 5(6)-thiocyanato-2-(methoxycarbonylamino)-benzimidazole 24.8 g (0.1 mol)
was suspended in 300 ml of a 65% by volume acetone aqueous solution with vigorous stirring, and 30 g of propyl bromide was added thereto. Additionally, add 22g of potassium hydroxide to this suspension.
When added as a 40% aqueous solution at 15℃, 1
A pale yellow solution was obtained after -2 minutes. The final product of the reaction is analyzed by thin layer chromatography (silica gel).
G ₂₅₄ plate/developing agent: 9:1 mixture of chloroform and acetic acid/detection: ultraviolet irradiation). After the reaction is complete (3-4 hours), the pH of the solution is adjusted to 6 with 5N hydrochloric acid.
Adjusted to. The reactant mixture is then allowed to stand for a short time,
The precipitated crystals were filtered and washed with an aqueous acetone solution and water to obtain 20.5 g of 5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole. The melting point of the product is 210−212
It was warm at ℃. Example 30 The method described in Example 29 was followed except that 70% aqueous methanol was used instead of 65% acetone.
19.8 g of 5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole was obtained. The melting point of the product was 209-211°C. Example 31 32g of sodium hydroxide instead of potassium hydroxide
Following the method described in Example 29 but using a 40% aqueous solution consisting of 19.7 g of 5(6)-propylthio-2-(methoxycarbonylamino)-benzimidazole was obtained. The melting point of the product was 211-213°C. Example 32 2-amino-4-thiocyanato-aniline
After dissolving 8.25 g in 60 ml of acetone, a solution of 6.1 g of bromo cyanide and 20 ml of methanol was added dropwise thereto. After letting the reactant mixture stand overnight,
This was evaporated to dryness, the residue was dissolved in water, and the pH of the solution was adjusted to 8 with 2N aqueous sodium hydroxide. The precipitated crystals were filtered, washed with water, and dried to obtain 8.3 g of 2-amino-5-thiocyanato-1H-benzimidazole. Its melting point was 204-205°C (decomposition).

Claims (1)

[Claims] 1. General formula (Here, R ¹ is hydrogen, halogen, C _1-4 alkyl,
C _1-3 alkoxy or trifluoromethyl, R ⁵ is amino or C _1-4 alkoxycarbonylamino, and R ⁶ is thiocyanato) or a salt thereof, the method comprising: formula compound (where R ¹ and R ⁵ are as above)
by reacting with gaseous chlorine and a thiocyanate of the general formula R-SCN, where R is a metal atom or an ammonium group, and if necessary converting the resulting compound of the general formula into its salt. how to. 2. The method according to claim 1, which comprises introducing gaseous chlorine into a solution or suspension consisting of a compound of the general formula, a compound of the general formula, and an organic solvent. 3. The method according to claim 1, characterized in that the compound of the general formula is reacted with chloro-rhodan obtained by reacting the compound of the general formula with gaseous chlorine. 4. The method according to any one of claims 1 to 3, characterized in that the reaction is carried out in the presence of an organic solvent or a diluent. 5. The method according to claim 4, wherein the organic solvent or diluent is an aprotic polar solvent, preferably dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide, a lower carboxylic acid or an ester thereof, Preferably acetic acid, acetate or formate, C _1-4 alcohols, chlorinated hydrocarbons,
A process characterized in that preferably carbon tetrachloride, chloroform or dichloroethane, nitromethane or acetonitrile or mixtures thereof are used. 6. The method according to claim 5, characterized in that acetic acid is used as the organic solvent or diluent. 7. Process according to claim 1, characterized in that as the compound of the general formula an alkali metal, alkaline earth metal or ammonium thiocyanate is used, preferably potassium thiocyanate or sodium thiocyanate. How to do it. 8. The method according to any one of claims 1 to 3, characterized in that 1 to 5 mol, preferably 1 to 3 mol of chlorrhodan is used per 1 mol of the compound of the general formula. Method. 9. A method according to any one of claims 1 to 8, characterized in that the reaction is carried out at a temperature of 0°C to 100°C, preferably 15°C to 40°C. 10 General formula (Here, R ¹ is hydrogen, halogen, C _1-4 alkyl,
C _1-3 alkoxy or trifluoromethyl, R ⁵ is amino or C _1-4 alkoxycarbonylamino, R ⁶ is an atomic group of the general formula -S-R ⁴ , and R ⁴ is a negative metal cation. When forming a salt with a sulfur atom, it is a lone pair of electrons, otherwise R ⁴ is hydrogen, a metal atom or C _1-6 alkyl,
C _2-6 alkenyl, C _2-6 alkynyl, cyclohexyl, benzyl, or 2-phenyl-ethyl group)
A method for producing a compound or a salt thereof represented by (A) general formula (wherein R ¹ and R ⁵ are the above-mentioned atomic groups) with an organic or inorganic base, preferably an alkali metal or alkaline earth metal carbonate, alkoxide, aryloxide, ammonium hydroxide, amine. , an alkali metal or alkaline earth metal azide, an alkali metal or alkaline earth metal sulfide, or an alkali metal or alkaline earth metal hydrosulfide. , general formula compound (where R ¹ and R ⁵ are the above-mentioned atomic groups, R ⁴ ′ is a lone pair of electrons if the metal cation forms a salt with a negative sulfur atom, otherwise R ⁴ ′ is hydrogen or a metal atom), and optionally the product is further treated with an alkylating agent of the general formula R ⁴ ″-Q, where R ⁴ ″ is C _1-6 alkyl,
C _2-6 alkenyl, C _2-6 alkynyl, cyclohexyl, benzyl, or 2-phenyl-ethyl group, Q is hydroxy, halogen, 1/2SO ₄ , 1/3
PO ₃ , 1/3PO ₄ , SO ₃ C ₆ H ₅ or SO ₃ C ₆ H ₄ CH ₃ (wherein R ¹ , R ⁵ and R ⁴ ″ are the above-mentioned atomic groups), a compound of the general formula is reacted with the basic nucleophilic compound described above and a compound of the general formula or (C) reacting a mixture of a compound of general formula and an alkylating agent of general formula X with said basic nucleophilic compound to prepare a compound of general formula XI, and if necessary A method for converting a compound of the general formula into a salt thereof. 11. A method according to claim 10, characterized in that sodium sulfide is used as the alkali sulfide. 12. Claim 10 2, wherein the alkylating agent is a C _1-3 alcohol, an alkyl halide, an alkyl sulfate, an alkyl phosphate, a benzenesulfonate or a trisulfonate, preferably an alkyl bromide. 13. The method according to claim 10, characterized in that the reaction is carried out in water and/or an organic solvent. 14. 15. The method according to claim 10, characterized in that C _1-3 alcohol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, pyridine or a mixture thereof is used as the organic solvent. 16. The method according to claim 15, characterized in that the reaction is carried out in a non-aqueous solvent in the presence of a phase transfer catalyst. A process characterized in that a chlorinated hydrocarbon, preferably carbon tetrachloride or chlorobenzene, or another hydrocarbon, preferably toluene, or an aryl ether, preferably anisole or diphenyl ether, is used as the solvent. 17. The method according to claim 16, characterized in that henzyltrimethylammonium chloride or benzyltriethylammonium chloride is used as a phase transfer catalyst. 18. The method according to claim 10. The method described, wherein the alkylating agent is represented by the general formula X,
Q is halogen, 1/2SO ₄ , 1/3PO ₃ , 1/3PO ₄ , SO ₃
Using _a compound _{that is C6H5} or _{SO3C6H4CH3 ,}
A process characterized in that the reaction is carried out at a temperature of 0°C to 100°C, preferably 10°C to 40°C.