Method for producing 5-n-butyl-2-benzoglioxaline methyl carbamate

Abstract

The invention pertains to a preparation method of 5-n-butyl-2-benzimidazole methyl formate, that is, parbendazole, and includes five reaction steps of acetylation, nitrification, hydrolysis, reduction and ring formation; n-butyl aniline is taken as the raw material, acetic anhydride is firstly used for acetylation, nitric acid is then used for nitrification, potassium hydroxide solution is used for hydrolysis, after that, Pd / C is used for the reduction to form 4-n-butyl-o-phenylenediamine, finally a ring closing agent of methyl formate cyanamide is used for ring closing, thus preparing the 5-n-butyl-2-benzimidazole methyl formate. The technique adopts p-n-butyl aniline which is cheap and easy to obtain as the raw material, the acetylation and the nitrification are completed in a same reactor, thus simplifying operation procedure and reducing production cost. The acetic anhydride is adopted as an acetylation reagent for protecting amino group, the reaction conditions are mild, and the acetic acid and the excessive acetic anhydride which are generated by the reaction can be used as a solvent and a dehydrating agent, thus reducing the amount of the waste acid. Palladium carbon is adopted as a catalyst for the reduction of the amino group, and the catalyst can be recycled and is characterized by high conversion rate, green and clean properties.

Description

technical field

[0001] The invention belongs to a method for preparing methyl 5-n-butyl-2-benzimidazole carbamate, that is, palbendazole. The palbendazole involves five reaction steps of acetylation, nitration, hydrolysis, reduction and ring closure. Background technique

[0002] 5-n-Butyl-2-benzimidazole methyl carbamate (Pabendazole), is a broad-spectrum and highly effective anthelmintic, it targets hidden tubular nematodes, Spiralia nematodes, Ascaris suum, Haemonchus, Strongyloides , Gastrointestinal nematodes, gastric trichostrongylus, thin neck nematodes, Adam's apple nematodes and intestinal nematodes are highly effective. At present, there is no related literature reporting its synthesis method in China.

[0003] At present, only US 3480682 reports the preparation of pabendazole by using p-n-butylaniline as a raw material through steps such as acetylation, nitration, hydrolysis, reduction, ring formation, and rearrangement. Stannous, cyanogen bromide, pyridine, etc...

Examples

example 1

[0020] In a 250mL four-necked flask equipped with a thermometer and a stirring device, add 30.81g (0.3021mol) of acetic anhydride (refined anhydrous) and a small amount of concentrated sulfuric acid, control the temperature at about 50°C, and dropwise add 15.0g (0.1007mol) For n-butylaniline, keep the reaction at 45-50°C for about 1 hour, then cool the reaction liquid, and then pour it into a large amount of ice-water mixture, white crystals will precipitate out, and use NaCO 3 The solution was washed until neutral, filtered with suction, and dried to obtain a crude product. Then recrystallize from n-heptane to obtain 16.62 g of p-n-butylacetanilide with a yield of 87.0%. Melting point: 104℃~105℃.

example 2

[0022] In a 250mL four-necked flask with a thermometer and a stirring device, add 51.36g (0.5035mol) of acetic anhydride (refined anhydrous) and a small amount of concentrated sulfuric acid, control the temperature at about 50°C, and drop 15.0g (0.1007mol) For n-butylaniline, keep the reaction at 45-50°C for about 1 hour, then cool the reaction liquid, and then pour it into a large amount of ice-water mixture, white crystals will precipitate out, and use NaCO 3 The solution was washed until neutral, filtered with suction, and dried to obtain a crude product. Then recrystallize from n-heptane to obtain 17.02 g of p-n-butylacetanilide with a yield of 88.5%. Melting point: 104℃~105℃.

example 3

[0024] In a 250mL four-neck flask equipped with a thermometer and a stirring device, add 61.63g (0.6078mol) of acetic anhydride (refined anhydrous) and a small amount of concentrated sulfuric acid, control the temperature at about 50°C, and dropwise add 15.0g (0.1007mol) Add n-butylaniline dropwise, keep the reaction at 50°C-55°C for about 1 hour, then cool the reaction solution, then pour it into a large amount of ice-water mixture, white crystals precipitate out, use NaCO 3 The solution was washed until neutral, filtered with suction, and dried to obtain a crude product. Then recrystallize from n-heptane to obtain 17.19 g of p-n-butylacetanilide with a yield of 90.0%. Melting point: 104℃~105℃.

[0025] Synthesis of 4-n-butyl-2-nitroacetanilide

technical field

[0001] The invention belongs to a method for preparing methyl 5-n-butyl-2-benzimidazole carbamate, that is, palbendazole. The palbendazole involves five reaction steps of acetylation, nitration, hydrolysis, reduction and ring closure. Background technique

[0002] 5-n-Butyl-2-benzimidazole methyl carbamate (Pabendazole), is a broad-spectrum and highly effective anthelmintic, it targets hidden tubular nematodes, Spiralia nematodes, Ascaris suum, Haemonchus, Strongyloides , Gastrointestinal nematodes, gastric trichostrongylus, thin neck nematodes, Adam's apple nematodes and intestinal nematodes are highly effective. At present, there is no related literature reporting its synthesis method in China.

[0003] At present, only US 3480682 reports the preparation of pabendazole by using p-n-butylaniline as a raw material through steps such as acetylation, nitration, hydrolysis, reduction, ring formation, and rearrangement. Stannous, cyanogen bromide, pyridine, etc...

Examples

example 1

[0020] In a 250mL four-necked flask equipped with a thermometer and a stirring device, add 30.81g (0.3021mol) of acetic anhydride (refined anhydrous) and a small amount of concentrated sulfuric acid, control the temperature at about 50°C, and dropwise add 15.0g (0.1007mol) For n-butylaniline, keep the reaction at 45-50°C for about 1 hour, then cool the reaction liquid, and then pour it into a large amount of ice-water mixture, white crystals will precipitate out, and use NaCO 3 The solution was washed until neutral, filtered with suction, and dried to obtain a crude product. Then recrystallize from n-heptane to obtain 16.62 g of p-n-butylacetanilide with a yield of 87.0%. Melting point: 104℃~105℃.

example 2

[0022] In a 250mL four-necked flask with a thermometer and a stirring device, add 51.36g (0.5035mol) of acetic anhydride (refined anhydrous) and a small amount of concentrated sulfuric acid, control the temperature at about 50°C, and drop 15.0g (0.1007mol) For n-butylaniline, keep the reaction at 45-50°C for about 1 hour, then cool the reaction liquid, and then pour it into a large amount of ice-water mixture, white crystals will precipitate out, and use NaCO 3 The solution was washed until neutral, filtered with suction, and dried to obtain a crude product. Then recrystallize from n-heptane to obtain 17.02 g of p-n-butylacetanilide with a yield of 88.5%. Melting point: 104℃~105℃.

example 3

[0024] In a 250mL four-neck flask equipped with a thermometer and a stirring device, add 61.63g (0.6078mol) of acetic anhydride (refined anhydrous) and a small amount of concentrated sulfuric acid, control the temperature at about 50°C, and dropwise add 15.0g (0.1007mol) Add n-butylaniline dropwise, keep the reaction at 50°C-55°C for about 1 hour, then cool the reaction solution, then pour it into a large amount of ice-water mixture, white crystals precipitate out, use NaCO 3 The solution was washed until neutral, filtered with suction, and dried to obtain a crude product. Then recrystallize from n-heptane to obtain 17.19 g of p-n-butylacetanilide with a yield of 90.0%. Melting point: 104℃~105℃.

[0025] Synthesis of 4-n-butyl-2-nitroacetanilide