54965-21-8

Basic information

• Product Name: Albendazole
• Synonyms: [5-(PROPYLTHIO)-1H-BENZIMIDAZOL-2-YL]CARBAMIC ACID, METHYL ESTER;[5-(PROPYLTHIO)BENZIMIDAZOL-2-YL]CARBAMIC ACID METHYL ESTER;(5-PROPYLSULFANYL-1H-BENZOIMIDAZOL-2-YL)-CARBAMIC ACID METHYL ESTER;ALBAZINE;ALBEN;ALBENDAZOLE;ALBENZA;AKOS NCG1-0064
• CAS NO: 54965-21-8
• Molecular Formula: C₁₂H₁₅N₃O₂S
• Molecular Weight: 265.33
• EINECS: 259-414-7
• Product Categories: Pharmaceutical;Active Pharmaceutical Ingredients;API;Intermediates & Fine Chemicals;Pharmaceuticals;Veterinaries;Miscellaneous Compounds;Aromatics;Heterocycles;Sulfur & Selenium Compounds;Animal Pharmaceuticals;Pharmaceutical intermediate;OVRETTE;Vermifuge
• Mol File: 54965-21-8.mol

Chemical Properties

• Melting Point: 208-210 °C
• Appearance: Colourless crystalline solid
• Density: 1.2561 (rough estimate)
• Refractive Index: 1.6740 (estimate)
• Storage Temp.: 0-6°C
• Solubility: Practically insoluble in water, freely soluble in anhydrous formic acid, very slightly soluble in methylene chloride, practically insoluble in ethanol (96 per cent).
• PKA: 10.72±0.10(Predicted)
• Water Solubility: 0.75mg/L(209 oC)
• Merck: 14,210
• CAS DataBase Reference: Albendazole(CAS DataBase Reference)
• NIST Chemistry Reference: Albendazole(54965-21-8)
• EPA Substance Registry System: Albendazole(54965-21-8)

Safety Data

• Hazard Codes: T,Xn
• Statements: 61-36/37/38-48/22-63-33
• Safety Statements: 53-45-37/39-26-36/37-24/25
• WGK Germany: 2
• RTECS: FD1100000
• Hazardous Substances Data: 54965-21-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Albendazole is used as an antihelmintic agent for treating infections caused by various parasites. It is effective against sensitive cestodes and nematodes by blocking glucose uptake, leading to the depletion of glycogen reserves and a subsequent reduction in adenosine triphosphate levels. This results in the paralysis and death of the parasites.
Albendazole is used to treat the following infections:
1. Neurocysticercosis, a rare brain infection caused by the pork worm (Taenia solium).
2. Microsporidiosis, a parasitic infection that causes severe diarrhea.
Additionally, Albendazole is used to treat infections caused by the following parasites:
1. Acaris lumbricoides (roundworm)
2. Ancylostoma duodenale (hookworm)
3. Necator americanus (hookworm)
4. Enterobius vermicularis (pinworm)
5. Trichuris trichiura (whipworm)
The drug also has effects on getting rid of or directly killing tapeworms and cysticerci, making it useful in the treatment of hydatid disease and nervous system infections caused by tapeworm infections.
Used in Veterinary Medicine:
Albendazole is also used in veterinary medicine to eliminate various kinds of nematodes parasitizing inside animal bodies, including whipworm, hookworm, and other parasitic worms.
Brand Name:
Albendazole is marketed under the brand name Alenza (GlaxoSmithKline).

Pharmacology and mechanism of action

Albendazole is a benzimidazole carbamate derivative which is structurally related to mebendazole. It was originally introduced as a veterinary drug in 1975 and later as a human anthelminthic drug. It has a wide spectrum of activity against intestinal nematodes (hook worm, Ascaris lumbricoides, Enterobius vermicularis, Strongyloides stercoralis, Trichuris trichiura and Capillaria philippinensis), systemic nematodes (Trichinella spiralis and cutaneous larva migrans) and cestodes (Echinococcus granulosis, E. multilocularis and neurocysticercosis) [1]. Albendazole is active against both larval and adult stages of intestinal nematodes and ovicidal against Ascaris lumbricoides and Trichuris trichiura [1]. Its main metabolite, albendazole sulphoxide, may largely be responsible for the pharmacological effects of the drug.The mechanism of action of albendazole is similar to that of other benzimidazoles (see mebendazole).

Indications

Single or mixed infections caused by Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma duodenale, Trichuris trichiura. Albendazole may be effective against cutaneous larva migrans and Strongyloides stercoralis, but controlled studies are needed to confirm its advantage over thiabendazole. Limited data indicate that albendazole is useful in neurocysticercosis [2,3]. Albendazole seems to be the drug of choice for the treatment of inoperable hydatid cases, but its long term benefit needs further assessment.

Indications

Albendazole appears to cause cytoplasmic microtubular degeneration, which in turn impairs vital cellular processes and leads to parasite death.There is some evidence that the drug also inhibits helminth-specific ATP generation by fumarate reductase.

Side effects

After a single dose treatment of albendazole 400 mg, minor and transient side effects such as epigastric pain and diarrhoea were seen. Less than 6% of treated patients experience these effects [4]. During the treatment of hydatid disease, where higher doses are used for longer time periods, side effects were more common and severe. In two randomized double-blind multicentre phase I and II studies [5,6] involving 139 patients given high doses of the drug, about 20% of the patients showed side effects. These included elevation of serum transaminases (6 patients), leucopenia (3 patients), gastrointestinal symptoms (8 patients), severe headache (4 patients), loss of hair (3 patients), urticaria and itching (2 patients), fever and fatigue (1 patient), and thrombocytopenia (1 patient).

Side effects

Various mild intestinal and other upsets usually resolve without treatment. With extended use, as for larval tapeworm infections, hepatic abnormalities or leukopenia may require discontinuation of treatment. In rare cases granulocytopenia, pancytopenia, agranulocytosis or thrombocytopenia may occur. It should not be given during pregnancy since it may cause fetal harm; women should be cautioned against becoming pregnant within a month of completing treatment.

Contraindications and precautions

There are no known contraindications to the drug during single dose treatment of intestinal nematodes. During treatment against hydatid disease, liver transaminases, leukocyte and platelet counts must be monitored regularly.

Preparations

? Zentel? (SmithKline Beecham). Tablets 400 mg. Suspension 2%. ? Eskazole? (SmithKline Beecham). Tablets 400 mg.

Solubility

It is slightly soluble in acetone or chloroform, but insoluble in water; it is also slightly soluble in hot diluted hydrochloric acid, and soluble in methanol, ethanol, and acetic acid.

Pharmacodynamics

Albendazole is a kind of benzimidazole derivatives. It is rapidly metabolized in vivo into the sulfoxide, sulfone and 2-polyamine sulfone alcohol. It can selectively and irreversibly suppress the glucose uptake of intestinal nematodes, thus resulting in endogenous glycogen depletion of the worm; at the same time, it also inhibit the activity of fumarate reductase, and thus preventing the generation of adenosine triphosphate, finally causing death of the parasites. Similar as mebendazole, through causing the denaturation of cytoplasmic microtubules of intestinal parasites and binding to the tubulin, it causes clogging of intracellular transport, causing the accumulation of Golgi endocrine particles; cytoplasm is further gradually dissolved, causing the final death of the parasites. This product can completely kill hookworm eggs, pinworm eggs, spin wool eggs, tapeworm eggs and cysticercosis whip eggs and partially kill Ascaris’ eggs.

Usage and dosage

Roundworm disease and pinworm disease: take 400mg daily per time. Hookworm disease, whipworm disease, stercoralis disease: take 400mg each time, 2 times a day, continue for 3 days. Trichinella spirallis disease, take 600mg or 800mg daily in 2 times; a course of treatment is one week. Neurocysticercosis take daily 18mg/kg in 2 times of oral administration; 10 days is a course of treatment; you can also extend the course to one month according to the specific disease situation. Hydatid disease: take 20mg/kg daily in 2 times of oral administration with the course being 1 month; it usually needs multiple times of treatment.

synthesis

The synthesis of albendazole can be performed in four steps starting with 4-nitro aniline. In the first step ortho-nitro aniline (2) is substituted with thiocyanate in para position in the presence of an oxidant such as chlorine. The reaction follows an aromatic substitution in which 2-nitrothiocyanoaniline (3) is produced. Afterwards bromopropane reacts with the product from step one to obtain 4-(Propylthio)-2-nitroaniline (4). This is achieved by the mechanism of a nucleophile substitution. In the third step the nitro-group is reduced to the amine to prepare the molecule for the imidazoleformation. Following the methylcyancarbamate is added. Now the two amine groups of 4-(propylthio) benzene-1,2-diamine (5) react with the carbamate while building an heteroaromatic system. Simultaneously ammonia is condensed and albendazole is generated.The synthesis of albendazole

References

1. Rossignol JF, Mausonneuve H (1984). Albendazole: a new concept in the control of intestinal helminthiasis. Gastroenterol Clin Biol, 8, 569–576. 2. Cruz M, Cruz I, Horton J (1991). Albendazole versus praziquantel in the treatment of cerebral cysticercosis: Clinical evaluation. Trans R Soc Trop Med Hyg, 85, 244–247. 3. Takayanagui OM, Jardim E (1992). Therapy of neurocysticercosis. Comparison between albendazole and praziquantel. Arch Neurol, 49, 290–294. 4. Coulaud JP, Rossignol JF (1984). Albendazole: a new single dose anthelminthic. Acta Tropica (Basel), 41, 87–90. 5. Davies A, Dixon H, Pawlowski ZS (1989). Multicentre clinical trials of benzimidazole carbamates in human cystic echinococcosis (phase 2). Bull World Health Organ, 67, 503–508. 6. Davis A, Pawlski ZS, Dixon H (1986). Multicentre clinical trials of benzimidazole-carbamates in human echinococcosis. Bull WHO, 64, 383–388.

Originator

Zentel ,SK and F ,France ,1981

Manufacturing Process

A mixture of 6.65 g of 3-chloro-6-nitroacetanilide, 3.2 ml of propylmercaptan, 5.6 g of 50% sodium hydroxide and 100 ml of water is heated at reflux overnight. The cooled mixture is filtered to give the desired 2-nitro-5- propylthioaniline, MP 69.5-71.5°C after recrystallization from ethanol then hexane-ether. NMR (CDCl3) 40%. The aniline (2.5 g) is hydrogenated with 1.9 ml of concentrated hydrochloric acid, 100 ml ethanol and 5% palladium-on-charcoal to give 4-propylthio-ophenylene- diamine hydrochloride. A mixture of 2.5 ml of 50% sodium hydroxide in 5 ml of water is added to a mixture of 1.9 g of cyanamide, 2.2 g of methylchloroformate, 3.5 ml of water and 3 ml of acetone over 45 minutes below 10°C, pH raised to 6.5. A molar equivalent solution of the diamine in 100 ml of ethanol is added. The mixture is heated until the easily volatile solvents are expelled, to about 85°C, then maintained at this temperature with some water added for one-half hour. The product, methyl 5-propylthio-2-benzimidazolecarbamate, is separated, washed to give a colorless crystalline solid, MP 208-210°C.

Therapeutic Function

Anthelmintic

Antimicrobial activity

Albendazole is active against trichostrongyles and exhibits useful activity against tissue-dwelling larvae of Trichinella spiralis, larvae of animal hookworms (causing cutaneous larva migrans) and microfilariae of various filarial species. It also exhibits some activity against cysticercosis and hydatid stages of Echinococcus granulosus and Echinococcus multilocularis. It has been successfully used in infections with the protozoon Giardia lamblia and for microsporidiosis.

Biochem/physiol Actions

Binds to tubulin and inhibits microtubule assembly.

Mechanism of action

Albendazole is given orally and is poorly and variably absorbed (5%) because of its poor water solubility. Oral bioavailability is increased as much as five times when the drug is given with a fatty meal instead of on an empty stomach. Concurrent treatment with corticosteroids increases plasma concentrations of albendazole. The drug is rapidly metabolized in the liver to an active sulfoxide metabolite.The half life of the metabolites is 8 to 12 hours.

Pharmacokinetics

Albendazole is better absorbed after oral absorption than other benzimidazole carbamates. It is extensively metabolized to the anthelmintically active albendazole sulfoxide, producing plasma concentrations of the metabolite of about 1.3 mg/L 2–5 h after a 400 mg oral dose. The half-life is about 8 h and the major route of excretion is via the bile. Plasma protein binding of the sulfoxide is around 70%.

Clinical Use

Albendazole has a broad spectrum of activity against intestinal nematodes and cestodes, as well as the liver flukes Opisthorchis sinensis, Opisthorchis viverrini, and Clonorchis sinensis. It also has been used successfully against Giardia lamblia. It is widely used throughout the world for the treatment of intestinalnematode infection. It is effective as a single-dose treatmentfor ascariasis, New and Old World hookworm infections,and trichuriasis. Multiple-dose therapy with albendazole caneradicate pinworm, threadworm, capillariasis, clonorchiasis,and hydatid disease. The effectiveness of albendazole againsttapeworms (cestodes) is generally more variable and lessimpressive. It also is effective in treating cerebral and spinal neurocysticercosis, particularly when given with dexamethasone.Albendazole is recommended for treatment of gnathostomiasis.

Synthesis

Albendazole, methyl-[5-(propylthio)-1H-benzoimidazol-2-yl]carbamate (38.1.18), is also made by the heterocyclization of a derivative of phenylenediamine to a derivative of benzimidazole. In order to do that, 3-chloro-6-nitroacetanylide is reacted with propylmercaptane to make 3-propylthio-6-nitroacetanylide (38.1.6). Reducing the nitro group in this compound with hydrogen using a palladium on carbon catalyst gives 4-(propylthio)-o-phenylenediamine (38.1.7). Reacting the resulting derivative of o-phenylenediamine with cyanamide and then with the methyl chloroformate gives the desired albendazole.

Veterinary Drugs and Treatments

Albendazole is labeled for the following endoparasites of cattle (not lactating): Ostertagia ostertagi, Haemonchus spp., Trichostrongylus spp., Nematodius spp., Cooperia spp., Bunostomum phlebotomum, Oesphagostomum spp., Dictacaulus vivaparus (adult and 4th stage larva), Fasciola hepatica (adults), and Moniezia spp. In sheep, albendazole is approved for treating the following endoparasites: Ostertagia circumcincta, Marshallagia marshalli, Haemonchus contortus, Trichostrongylus spp., Nematodius spp., Cooperia spp., Oesphagostomum spp., Chibertia ovina, Dictacaulus filaria, Fasciola hepatica, Fascioides magna, Moniezia expansa, and Thysanosoma actinoides. Albendazole is also used (extra-label) in small mammals, goats and swine for endoparasite control. In cats, albendazole has been used to treat Paragonimus kellicotti infections. In dogs and cats, albendazole has been used to treat capillariasis. In dogs, albendazole has been used to treat Filaroides infections. It has been used for treating giardia infections in small animals, but concerns about bone marrow toxicity have diminished enthusiasm for the drug’s use.

InChI:InChI=1/C12H15N3O2S/c1-3-6-18-8-4-5-9-10(7-8)14-11(13-9)15-12(16)17-2/h4-5,7H,3,6H2,1-2H3,(H2,13,14,15,16)

Synthetic route

6-(propylthio)-1H-benzo[d]imidazol-2-amine + methyl chloroformate (79-22-1) → Albendazole (54965-21-8)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 0.216667h; Sealed tube; Microwave irradiation;	86%
With sodium hydroxide	26.95 g

4-(propylthio)-1,2-phenylenediamine (66608-52-4) + O-methyl-N-(methoxycarbonyl)-isourea (40943-37-1) → Albendazole (54965-21-8)

Conditions	Yield
With ethylenediaminetetraacetic acid; acetic acid In methanol at 110℃; for 5h; Inert atmosphere; Reflux;	65.1%

propyl bromide (106-94-5) + methyl 5-nitrobenzoimidazole-2-carbamate (40483-97-4) → Albendazole (54965-21-8)

Conditions	Yield
With potassium carbonate; sodium thiosulfate; copper dichloride In water at 135℃; for 20h;	58%

ricobendazole (54029-12-8, 122063-20-1, 122063-21-2) → Albendazole (54965-21-8)

Conditions	Yield
With aluminum (III) chloride; tetrabutyl-ammonium chloride; aluminium In 1,2-dichloro-ethane at 20℃; for 6h; Electrolysis; Inert atmosphere; Green chemistry;	74%
With 1,2,3-trimethoxybenzene; oxalyl dichloride In chloroform at 0℃; for 0.00166667h; Inert atmosphere; chemoselective reaction;	73%

methyl-N-cyano carbamate (21729-98-6) + 4-(propylthio)-1,2-phenylenediamine (66608-52-4) → Albendazole (54965-21-8)

Conditions	Yield
With hydrogenchloride In water; acetone at 85℃; Large scale;	520 kg
With hydrogenchloride In water at 80℃; for 0.5h; pH=4 - 5;	26.05 g

sodium salt of cyanocarbamic acid methyl ester + 4-(propylthio)-1,2-phenylenediamine (66608-52-4) → Albendazole (54965-21-8)

Conditions	Yield
Stage #1: 4-(propylthio)-1,2-phenylenediamine With hydrogenchloride In water; acetone at 80 - 85℃; Industry scale; Stage #2: sodium salt of cyanocarbamic acid methyl ester at 20 - 85℃; pH=4 - 4.5;

Upstream product

• 34840-23-8 1,3-Dicarbomethoxy-S-methylisothiourea 
• 66608-52-4 4-(propylthio)-1,2-phenylenediamine 
• 141421-17-2 1,3-dihydro-5-n-propylthio-2H-benzimidazole-2-spirocyclohexane 
• 420-04-2 CYANAMID 
• 79-22-1 methyl chloroformate 
• 740075-69-8 methyl 1-[(4-aminomethyl)benzoyloxy]-5-(propylthio)-2-benzimidazole-carbamate 
• 105530-56-1 2-[(methoxycarbonyl)-amino]-1H-benzimidazole-5-sulphonylchloride hydrochloride salt 
• 106-94-5 propyl bromide 
• 88-74-4 2-nitro-aniline 
• 54029-45-7 2-nitro-4-thiocyanoaniline 
• 54393-89-4 1-amino-2-nitro-4-n-propylthiobenzene 
• 21729-98-6 methyl-N-cyano carbamate 
• 40943-37-1 O-methyl-N-(methoxycarbonyl)-isourea 
• 2234-82-4 1-propylmagnesium chloride 

Downstream Products

• 54029-12-8 ricobendazole 
• 80983-36-4 5-(propylthio)-1H-benzimidazol-2-ylamine 
• 76567-28-7 albendazole sulfone 

Relevant articles and documents

Anthelmintic activity of albendazole against liver flukes, tapeworms, lung and gastrointestinal roundworms

A new derivative, albendazole, of the benzimidazole group of anthelmintics which is active against nematode, cestode and trematode species, was found.

Scalable electrochemical reduction of sulfoxides to sulfides

A scalable reduction of sulfoxides to sulfides in a sustainable way remains an unmet challenge. This report discloses an electrochemical reduction of sulfoxides on a large scale (>10 g) under mild reaction conditions. Sulfoxides are activated using a substoichiometric amount of the Lewis acid AlCl3, which could be regeneratedviaa combination of inexpensive aluminum anode with chloride anion. This deoxygenation process features a broad substrate scope, including acid-labile substrates and drug molecules.

Preparation method of albendazole

The invention discloses a preparation method of albendazole, which comprises the following steps of: dissolving 4-propylthio-o-phenylenediamine in methanol, cooling, keeping the temperature at 0-5 DEGC, slowly dropwise adding cyanogen chloride for reaction under the condition of uniform stirring, and regulating and keeping the pH value at 4-5 in the process; heating to 35-45 DEG C after dropwiseadding is finished, carrying out heat preservation for 1-2 hours, then carrying out atmospheric distillation to recover methanol to obtain a solid-liquid mixed aqueous solution, and carrying out cooling, filtering and drying to obtain 6-propylthio-2-amino-1-hydrogen-benzo [d] imidazole; adding the obtained product into methanol, stirring, cooling, maintaining the temperature at 5-10 DEG C, slowlydropwise adding methyl chloroformate, and adjusting and maintaining the pH value at 6-7; after dropwise adding is finished, heating to 35-45 DEG C, keeping the temperature for 1-2 hours, distilling atnormal pressure to recover methanol, cooling to 15-20 DEG C, and performing filtering and drying to obtain an albendazole product. The method has the advantages of mild process conditions, low cost of used raw materials, water saving, strong reaction activity, good selectivity, high product yield and good product quality.

Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides

Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.

Albendazole synthesis method

The invention discloses an albendazole synthesis method. The albendazole synthesis method includes reacting ammonium thiocyanate with chlorine gas in a lower alcohol solvent to obtain chlorothiocyanate, reacting ortho-nitroaniline with the chlorothiocyanate in the lower alcohol solvent to obtain 4-thiocyano-2-nitroaniline, reacting the 4-thiocyano-2-nitroaniline with a sodium hydroxide solution toobtain 4-sodium sulfonate-2-nitroaniline, performing hydrochloric acid acidification to obtain 4-mercapto-2-nitroaniline, subjecting the 4-mercapto-2-nitroaniline and propylene to Markovnikov addition reaction to obtain 4-propylthio-2-nitroaniline, and reacting 4-propylthio-o-phenylenediamine with methylcyanocarbamate to obtain albendazole. The albendazole synthesis method has the advantages thata novel synthetic route is applied to prepare the albendazole, the defects of high impurity quantity and low yield in the current production process are overcome, the chlorothiocyanate is prepared toserve as an intermediate and then reacts with the ortho-nitroaniline, and impurities can be avoided effectively; the propylene is introduced for the addition reaction, raw materials are clean and free from pollution, introduction of highly toxic sodium cyanide is avoided, the total yield is high, and the albendazole synthesis method has a good industrialization prospect.

Synthesizing method of [5-(rosickyite)-1H-benzimidazole-2-radical]methyl carbamate

The invention discloses a synthesizing method of [5-(rosickyite)-1H-benzimidazole-2-radical]methyl carbamate. The method comprises the following steps: 1) making methyl-benzimidazole-2-methyl carbamate, concentrated sulfuric acid and a nitrating agent to react for 2-10 h under the temperature of -10 to 2 DEG C to obtain 5-nitrobenzimidazole-2-methyl carbamate; 2) adding 5-nitrobenzimidazole-2-methyl carbamate, 1-bromopropane or 1-chloropropane, thiosulfate, alkali and copper salt to a solvent A; carrying out a reaction for 5-20 h to obtain albendazole; adding 5-nitrobenzimidazole-2-methyl carbamate, tri-n-propyltin chloride, sulphur, potassium fluoride, alkali and copper salt to a solvent B; stirring and carrying out a reaction for 5-20 h to obtain albendazole; or adding 5-nitrobenzimidazole-2-methyl carbamate, n-propylboronic acid, sulphur, alkali and copper salt to a solvent C; carrying out a reaction for 5-20 h to obtain albendazole. The synthesizing method is short in synthesizingroute, simple in synthesizing and separating, low in risk, environmentally friendly, and safe.

Microwave-Assisted Nickel-Catalyzed Synthesis of Benzimidazoles: Ammonia as a Cheap and Nontoxic Nitrogen Source

An efficient and convenient Ni-catalyzed C-N bond formation for the synthesis of various benzimidazoles from various 2-haloanilines, aldehydes, and ammonia in a concise manner is reported. This protocol uses commercially available, nonhazardous, clean ammonia as a reaction partner instead of other nitrogen sources. Benzimidazoles, as the sole products, were obtained in high to excellent yields (up to 95%).

A preparing method of albendazole

A preparing method of albendazole is disclosed. The method adopts 2-nitro-4-thiocyanatoaniline as a raw material, and includes salifying with an aqueous sodium hydroxide solution in an n-propanol solvent under nitrogen protection, reacting with bromopropane, and separating to obtain an n-propanol solution of 2-nitro-4-(propylthio)aniline, and therefore a problem that an impurity that is methyl 5-(methylthio)benzoimidazol-2-yl carbamate in products is high in content because steps of salifying in methanol with sodium sulfide and then reacting with bromopropane in processes at present is overcome. A technique of reducing the 2-nitro-4-(propylthio)aniline by utilizing hydrazine hydrate is adopted to replace a technique of reducing with sodium sulfide at present, thus overcoming a problem that sulfur-containing waste water is high in amount and difficult to treat in the sodium sulfide reduction technique. A methanol solution of methyl O-methyl isourea formate is adopted as a ring closing agent, thus overcoming a problem that waste water is high in amount in processes at present when cyanamide and an aqueous methyl formate solution are adopted as ring closing agents. The method is advantaged by a small waste water amount, capability of being environmental friendly, high product purity, and the like.

Method for preparing albendazole with chloropropane in place of bromopropane

The invention discloses a method for preparing albendazole with chloropropane in place of bromopropane, and belongs to the technical field of synthesis of imidazole compounds. The method comprises the following steps of firstly, sequentially adding carbendazol, sodium thiocyanate and glacial acetic acid into a reactor, performing uniform stirring, raising the temperature to 35 DEG C, slowly and dropwise adding a hydrogen peroxide solution under a stirring state, and performing a reaction so as to obtain solid 5-sulfhydryl benzimidazole-2-carbaminic acid methylester; preparing a chlorobenzene Grignard reagent by using 1,2-bromofume Grignard reagent; and then adding a phase transfer catalyst namely benzyl triethyl ammonium chloride to the solid 5-sulfhydryl benzimidazole-2-carbaminic acid methylester, slowly and dropwise adding a tetrahydrofuran solution of sodium hydride under the stirring state, performing a reaction for 30 minutes, beginning to slowly and dropwise drop the chlorobenzene Grignard reagent under the stirring condition, and performing a reaction so as to obtain an albendazole product. According to the method disclosed by the invention, the chloropropane is used for replacing the bromopropane which is relatively higher in price, so that not only is the investment cost of reaction raw materials reduced, but also the yield and the purity of the albendazole are guaranteed to be increased.

PROCESS FOR PREPARATION OF ALBENDAZOLE

The present invention discloses a novel, cost-effective process for preparation of a benzimidazole carbamates compound. Specifically, it relates to the process for the preparation of anti-parasite bulk drug albendazole. The process comprises a) thiocyanating 2-nitroaniline of formula VI with ammonium thiocyanated in presence of a halogen to obtain 2-nitro-4-thiocyanoaniline of formula V; b)propylating 2-nitro-4-thiocyanoaniline of formula V with propylbromide in presence of n-propanol and a base in absence of a phase transfer catalyst to obtain 4-propylthio-2-nitroaniline of formula III; C) reducing the nitro group of 4-propylthio-2-nitroaniline prepared in step b) by reacting an aqueous alkali metal sulphide or an alkaline metal sulphide to obtain 4-propylthio-o-phenylenediamine of formula II; and d)condensing 4-propylthio-o-phenylenediamine of formula II with alkali or alkaline earth metal salt of methylcyano carbamate in presence of an acid to form Albendazole of formula I.