Title of Invention	A PROCESS FOR MANUFACTURE OF SUBSTITUTED BENZIMIDAZOLES
Abstract	The present invention relates to an improved process for the preparation of substituted benzimidazoles, key intermediates in the synthesis of H+ / K+-ATPase irreversible inhibitors, more particularly Omeprazole, and is also an efficient antioxidant and photographic fog inhibitor.

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "A PROCESS FOR MANUFACTURE OF SUBSTITUTED BENZIMIDAZOLES" (a) IPCA LABORATORIES LTD. (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification particularly describes the nature of the invention and the manner in which it is to be performed. Field of invention [001] This invention relates to an improved process for the preparation of substituted benzimidazoles, key intermediates in the manufacture of H+ / K+-ATPase irreversible inhibitors such as Omeprazole, Lansoprazole, Pantoprazole & Rabeprazole, leading candidates in ulcer chemotherapy, starting from substituted o-aminoacetanilides. 2-Mercapto-5-methoxybenzimdazole, for example, being the key intermediate in the synthesis of Omeprazole, is also an efficient antioxidant & photographic fog inhibitor. Background and prior art [002] Reported synthetic processes in the prior art for the title compound comprises condensation of either 1,2-diamino benzenes (IV) 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 the title compound are described below: [003] According to JP 60,112,774, o-nitroanisidine is condensed with carbon disulfide in the presence of aqueous sodium hydrogen sulfide to give the title compound. [004] JP 06,279,416 describes the condensation of 4-amino-3-nitroanisole & carbon disulfide in aqueous solution of hydrochloric acid in presence of inorganic metal like Zinc & iron. [005] In JP 09,241,259 & JP 31,616,90, 4-methoxy-l,2-diaminobenzene is condensed with carbon disulfide in presence of potassium thiocyanate & bases like sodium hydroxide or potassium hydroxide. [006] JP 01,062,638, EP 253770 & US 4,968,597 describe the synthesis of 2-mercapto-5-methoxybenzimidazole by condensation of 4-methoxy-l,2-diaminobenzne with carbon disulfide in presence of bases like sodium hydroxide or potassium hydroxide. 007] 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 & polyglycol ether as a catalyst. [008] The closest prior art, Chem.Pharm.Bull 30 (8) 2714-2722 (1982) describes the synthesis of N-acetylbenzimidazole derivatives. As per the reported process, 4-substituted 2-aminoacetanilide is prepared by the reduction of corresponding nitro compound. Reduction of nitro group reported using Palladium on charcoal as catalyst. The cyclization of 2-amino acetanilide derivative is carried out using carbon disulfide in dimethyl formamide. It yields the mixture of N-acetyl benzimidazole derivative and benzimidazole. The yield of the required benzimidzole derivative is 11 %, making the process unviable for large scale operation. [009] The major drawback of the processes starting phenylenediamines (III) is their high susceptibility for oxidation leading to coloured impurities, very difficult to remove. The other reason for concern is the carcinogenic nature of these diamino compounds, leading to serious health hazards in operations at large volumes. [010] The process starting from nitro-anilines on the other hand involves uses inorganic reagents such as sodium hydrogen sulfide, sodium sulfide and metals like iron, zinc etc. for reductive cyclization with carbon disulfide. All these processes generate enormous amounts of effluent and elemental sulfur as by-product leading to sludge formation and problems in isolation and purification of the product. [011] In nutshell, all the mentioned processes are not very 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 title products, the subject of the patent application. Objectives [012] The main objective 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. [013] A further objective of the present invention is to provide replacement of the stoichiometric amounts of inorganic reducing agents by catalysts such as Raney-Ni making process environmentally friendly. [014] A further objective 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. Summary of the invention [015] This invention relates to an improved process for the preparation of substituted benzimidazoles, more particularly 2-mercapto-5-methoxy benzimidazole which is key intermediate in the synthesis of omeprazole, is also an efficient antioxidant and photographic fog inhibitor. Accordingly, the process for preparation of benzimidaole of Formula II comprises the following reaction steps: a) reducing a nitroacetamido benzene derivative of formula IV, wherein R is OMe or OCHF2, to form a compound of Formula I; b) Condensing and cyclizing the resultant amino acetamido benzene derivative of Formula (I) in the presence of a base using carbon disulfide as cyclizing agent under conditions effective to form the benzimidazoles of formula (II), wherein R is OMe or OCHF2; and c) Isolating the said benzimidazoles of formula (II) from the above reaction mass by adding hydrochloric acid. The crude product is purified by acid base treatment to obtain pure 2-mercapto-5-methoxy benzimidazole. Detailed Description [016] In accordance with the above basic objective of the present invention, there is provided a direct condensation of a-acetamidoanilines of the Formula-I with carbon- disulfide in the presence of KOH to get the desired benzimidazole of Formula-II, where R is 0s defined in Formula I, without hydrolyzing the acetamido groups and generating [017] The reaction conditions comprise carrying out 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 to preferably between 80-90°C for a period of 8-10 hours. [018] In another aspect of the invention there is provided a process for producing the acetamidoaniline of the Formula-I from the corresponding nitroacetamido product of Formula-IV, where R is as defined earlier, using Raney -Ni catalysed hydrogenation of ^N02 NHAc IV 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 p-anisidine is very well documented in the prior art (Organic Synthesis - collective volume-Ill, 662) [019] 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 Example 1 4-methoxy acetanilide: [020] p-anisidine (10 gm), Acetic anhydride (12 gm.) and 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.

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382-MUM-2003-ABSTRACT(17-4-2003).pdf

382-mum-2003-abstract(2-8-2004).doc

382-mum-2003-abstract(2-8-2004).pdf

382-MUM-2003-ABSTRACT(GRANTED)-(29-3-2007).pdf

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382-mum-2003-correspondence(ipo)-(24-4-2004).pdf

382-MUM-2003-DESCRIPTION(COMPLETE)-(17-4-2003).pdf

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382-mum-2003-fom 2(granted)-(17-4-2003).pdf

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382-mum-2003-fom 3(27-11-2003).pdf

382-MUM-2003-FORM 1(27-11-2003).pdf

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382-MUM-2003-FORM 2(COMPLETE)-(17-4-2003).pdf

382-MUM-2003-FORM 2(GRANTED)-(29-3-2007).pdf

382-MUM-2003-FORM 2(TITLE PAGE)-(COMPLETE)-(17-4-2003).pdf

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382-MUM-2003-FORM 26(25-6-2003).pdf

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382-mum-2003-form-pct-isa-210(17-4-2003).pdf

382-MUM-2003-SPECIFICATION(AMENDED)-(27-11-2003).pdf

382-mum-2003-we claim -(granted)-(2-8-2004).doc