WO2004092142A1

WO2004092142A1 - An improved process for manufacture of substituted benzimidazoles

Info

Publication number: WO2004092142A1
Application number: PCT/IN2003/000314
Authority: WO
Inventors: Ketan Dhansukhal Vyas; Dharmendra Singh; Sanjay Nandavadekar; Sanjay Bhise; Atul Jadhav; Hemal Desai
Original assignee: Ipca Laboratories Limited
Priority date: 2003-04-17
Filing date: 2003-09-17
Publication date: 2004-10-28
Also published as: AU2003282376A1

Abstract

The present invention relates to a process for the production of benzimidazole derivatives comprising providing an amino acetamido benzene derivative; and condensing and cyclising the aminoacetamido benzene derivative in the presence of a base and in the presence of a cyclising agent under conditions effective to form the benzimidazole derivative. The acetamido benzene derivative has the formula (I) wherein R is OMe or OCHF2. The resulting substituted benzimidazoles are key intermediates in the synthesis of H+/K+-ATPase irreversible inhibitors, most particularly Omeprazole.

Description

AN IMPROVED PROCESS FOR MANUFACTURE OF SUBSTITUTED

BENZIMIDAZOLES

Related Application

This application claims priority from India National patent application serial No. 382/MUM/2003, filed 17 April 03.

Field of invention

The invention relates to the field of medicine and pharmacology. More specifically, the invention relates to an improved process for the preparation of substituted benzimidazoles.

Background and Prior Art

Benzimidazoles are key intermediates in the manufacture of H⁺ / K⁺-ATPase irreversible inhibitors such as Omeprazole, Lansoprazole, Pentoprazole & Rabeprazole, leading candidates in ulcer chemotherapy.

Reported synthetic routes to benzimidazoles include condensation of either 1,2- diamino benzenes (IN) with carbon disulphide or reductive cyclization of o- nitroanisidines with carbon disulphide in the presence of reducing agents. Some of the important reported methods for the synthesis of benzimidazoles are described below:

According to JP 60,112,774, o-nitroanisidine is condensed with carbon disulfide in the presence of aqueous sodium hydrogen sulfide to give 2-mercaptobenzimidazole.

JP 06,279,416 describes the condensation of 4-amino-3-nitroanisole and carbon disulfide in aqueous solution of hydrochloric acid in presence of an inorganic metal such as zinc or iron.

In JP 09,241,259 and JP 31,616,90, 4-methoxy-l,2-diaminobenzene is condensed with carbon disulfide in presence of potassium thiocyanate and a base such as sodium hydroxide or potassium hydroxide.

JP 01,062,638, EP 253770 and US 4,968,597 describe the synthesis of 2-mercapto-5- methoxybenzimidazole by condensation of 4-methoxy-l,2-diaminobenzene with carbon disulfide in presence of a bases such as sodium hydroxide or potassium hydroxide. As per the process described in Jingxi huagong (1999), 16 (3) 52-53, 2-nitro-4- methoxyaniline is condensed with carbon disulfide in presence of sodium hydrogen sulfide in water and polyglycol ether as a catalyst.

Chem.Pharm.Bull. (1982), 30 (8) 2714-2722, describes the synthesis of N- acetylbenzimidazole derivatives. As per the reported process, 4-substituted 2- aminoacetanilide is prepared by the reduction of the corresponding nitro compound. Reduction of nitro group is reported using palladium on charcoal as catalyst. The cyclization of 2-amino acetanilide derivative is carried out using carbon disulfide in dimethyl formamide. This process yield a mixture of N-acetyl benzimidazole derivative and benzimidazole. The yield of the required benzimidzole derivative is 11 %, making the process unviable for a commercial scale operation.

A major drawback of synthetic routes starting with phenylenediamines (III) is their high susceptibility for oxidation leading to coloured impurities, which are difficult to remove satisfactorily. Another reason for concern is the carcinogenic nature of these diamino compounds, leading to serious health hazards in operations at large volumes.

Synthetic routes starting from nitro-anilines on the other hand involve the use of inorganic reagents such as sodium hydrogen sulfide, sodium sulfide and metals like iron, zinc etc. for reductive cyclization with carbon disulfide. All theses processes generate large quantities of effluent and elemental sulfur as by-product leading to sludge formation and problems in isolation and purification of the product.

The aforementioned prior art processes therefore suffer from a number of drawbacks. They are not plant friendly and require repeated purification for getting the product of desired quality, which ultimately leads to increased cost of manufacture. Hence, there is a need for development of economically as well as environmentally friendly process for the production of benzimidazoless, the subject of the present invention.

Summary of the Invention

The present invention has as its first object the provision of an improved process for the manufacture of benzimidazoles and, in particular, substituted benzimidazoles such as 2-mercapto-5-metlιoxybenzimidazole which are useful in the subsequent preparation of drugs of the prazole class.

A further object of the present invention is to provide a simple, environmentally friendly process for the manufacture of substituted benzimidazoles having desired quality for transforming the latter into the corresponding prazoles of high purity. According to the present invention, there is provided a process for the production of benzimidazole derivatives comprising: a) providing an amino acetamido benzene derivative; and b) condensing and cyclising the aminoacetamido benzene derivative in the presence of a base and in the presence of a cyclising agent under conditions effective to form the benzimidazole derivative.

Detailed Description

In one preferred process according to the invention, the acetamido benzene derivative has the formula (I):

wherein R is OMe or OCHF₂.

The product benzimidazole preferably has the formula (II):

wherein R has the same meaning as in formula (I).

Preferably, the process of the invention takes place without generating any, or any substantial amount, of the corresponding phenylene diamine of formula (III):

wherein R has the same meaning as in formula (I).

In one preferred process according to the present invention, there is provided a process for the production of benzimidazole derivatives comprising: a) providing a nitroacetamido benzene derivative; b) reducing the nitroacetamido benzene derivative under conditions effective to produce a corresponding aminoacetamido benzene derivative; and c) condensing and cyclising the aminoacetamido benzene derivative in the presence of a base and in the presence of a cyclising agent under conditions effective to form the benzimidazole derivative. Preferably, the nitro acetamido benzene derivative is of formula (IN):

wherein R has the same meaning as in formula (I).

This invention therefore relates to an improved process for the preparation of substituted benzimidazoles, most particularly 2~mercapto-5-methoxy benzimidazole which is a key intermediate in the synthesis of Omeprazole, and is also an efficient antioxidant and photographic fog inhibitor.

In accordance with the above basic objective of the present invention, there is

provided a direct condensation of α-acetamidoanilines of the formula (I) with carbon

disulphide in the presence of KOH to get the desired benzimidazole of formula (II), where R is as defined in formula (I), without hydrolyzing the acetamido groups and generating the corresponding phenylenediamine of formula (III).

The reaction conditions may comprise carrying out the reaction between acetamidoaniline (I) with carbon disulfide in the molar ratio of 1.5 - 5.0, preferably 2.0 in aqueous alcoholic KOH in a molar ratio from 1.5 - 5.0, preferably 2.0 at a temperature ranging from 75-90°C, preferably between 80-90°C for a period of 8-10 hours.

In another aspect of the invention there is provided a process for producing the acetamido aniline of formula (I) from the corresponding nitro acetamido product of formula (IV), where R is as defined earlier, using Raney -Ni to provide catalysed hydrogenation of the nitro group to give a clean transformation under 2-20 kg. hydrogen pressure, preferably 10-12 kg, for 1-2 hours at temperature ranging from room temperature to 70°C, preferably at 65-70°C. The synthesis of nitro acetamido derivatives from -anisidine is very well documented in the prior art (Organic Synthesis - collective volume-Ill, 662).

A further advantage of the present invention is to provide replacement of the stoichiometric amounts of inorganic reducing agents by catalysts such as Raney-Ni, making the process of the invention more environmentally friendly.

Yet another advantage of the present invention is to get better yield and satisfactorily pure product by using protected diamino compound as starting material instead of free diamino compound. The objects, advantageous and means of attaining the same as also the scope of the present invention will hereinafter be illustrated in greater details by way of the following non-limiting examples. It should be understood that the invention is not intended to be limited to the specific examples.

Examples

4-methoxy acetanilide:

p-anisidine (10 gm), Acetic anhydide (12 gm.) & acetic acid (20 ml) are added in water (50 ml.) at 30-35°C. The reaction mixture is heated to 45-50°C for 2-3 hours. The reaction mass is cooled. Water (50 ml.) is added to reaction mass with stirring & filtered to get 4-methoxy acetanilide. The yield of the product is 11 gm.

2-nitro-4-methoxy acetanilide:

[021] Water (22 ml), acetic acid (17 ml.) are added to the 4-methoxy acetanilide (11 gm.). Cool the mixture to 10°C and nitric acid 70% (6.6 ml.) is added in 10 minutes. Reaction mixture is heated to 45°C and stirred at 45-55°C for 2 hours. After cooling the reaction mixture to room temperature, water (44 ml.) is added & the precipitated product is then filtered.

2-nitro-4-methoxy acetanilide so obtained weighs 13 gm. after drying.

2-Amino-4-methoxy acetanilide:

[022] The nitro compound (13 gm.) is dissolved in methanol (130 ml.) to which Raney Nickel (0.67) is added. Hydrogenation is carried out at 10-12 kg hydrogen pressure for 2.0 hours at 65-70°C. On completion of the reaction, the catalyst is filtered & the solvent is removed to get the crystalline amino product. The yield of the product is 9 gm.

2-mercapto-5-methoxy benzimidazole:

[023] Water (20 ml.), potassium hydroxide (6.5 gm.), ethanol (7 ml.) & carbon disulfide (7 ml.) are added to the amino acetanilide (9.0 gm.). Slowly the reaction mixture is heated to 80-90°C & maintained for 8-10 hours. The reaction mixture is cooled to 10-15°C. Cone. Hydrochloric acid solution (9 ml.) is added to reaction mass to precipitate the product. The crude product is purified by acid base treatment to obtain pure 2-mercapto-5-methoxy benzimidazole. The yield of the product is 8 gm.

Claims

1. A process for the production of benzimidazole derivatives comprising: a) providing an amino acetamido benzene derivative; and b) condensing and cyclising the aminoacetamido benzene derivative in the presence of a base and in the presence of a cyclising agent under conditions effective to form the benzimidazole derivative.

2. A process according to claim 1, wherein the acetamido benzene derivative has the formula (I):

wherein R is OMe or OCHF₂.

3. A process according to claim 1 or claim 2, wherein the product benzimidazole has the formula (II):

wherein R has the same meaning as in formula (I).

A process according to any one of claims 1 to 3, which takes place without generating any, or any substantial amount, of the phenylene diamine of formula (III):

wherein R has the same meaning as in formula (I).

5. A process according to any one of claims 1 to 4 comprising providing a nitroacetamido benzene derivative and reducing the nitroacetamido benzene derivative under conditions effective to produce the corresponding aminoacetamido benzene derivative for condensation and cyclisation.

6. A process according to claim 6, wherein nitro acetamido benzene derivative is of formula (IN):

wherein R has the same meaning as in formula (I).

7. A process according to claim 5 or claim 6, wherein the nitroacetamido benzene derivative is reduced using Raney Ni as reducing agent.

8. A process according to any one of claims 5 to 7, wherein the hydrogen pressure used in the reduction step is 10-12 kg.

9. A process according to any one of claims 5 to 8, wherein the temperature for the reduction of nitro derivative used is 30 to 70° C.

10. A process according to claim 9, wherein the preferable temperature for the reduction of nitro derivative used is 65 to 70° C

11. A process according to any one of claims 1 to 10, wherein the nitro acetamido benzene derivative is 2-nitro-4-methoxy acetanilide.

12. A process according to any one of claims 1 to 10, wherein the nitro acetamido benzene derivative is 2-nitro-4-difluoromethoxy acetanilide.

13. A process according to any one of claims 1 to 12, wherein the cyclizing agent used is carbon disulphide.

14. A process according to claim 13, wherein molar ratio of amino acetamido benzene derivative to carbon disulphide used is 1.5-5.0.

15. A process according to claim 14, wherein preferable molar ratio of amino acetamido benzene derivative to carbon disulphide is 2.0.

16. The process according to any one of claims 1 to 15, wherein the base used in condensation and cyclization process is potassium hydroxide.

17. The process according to any one of claims 1 to 16, wherein the condensation and cyclisation reaction is carried out at a temperature of from 75-90° C.

18. The process according to claim 17, wherein the reaction is carried out at a temperature of from 80-90° C.

19. A process according to any one of claims 1 to 18, where concentrated hydrochloric acid is used to precipitate the final product.

20. A process according to any one of claims 1 to 19, wherein the final product is purified by acid-base treatment.

21. A process according to any one of claims 1 to 20, wherein the final product is 2-mercapto-5-methoxy benzimidazole.

22. A process according to any one of claims 1 to 20, wherein the final product is 2-mercapto-5-diflouro methoxy benzimidazole