DESC:FIELD OF THE INVENTION
[0001] The present invention relates to a green process for the preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole of formula (I),
(I)
The process for preparation of the compound of formula (I) comprises O-alkylation of N-(4-hydroxyphenyl)acetamide, nitration of N-[(4-(difluoromethoxy)phenyl]acetamide, reduction of N-[4-(difluoromethoxy)-2-nitrophenyl]acetamide followed by cyclization. 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (I) is the key intermediate for the preparation of pantoprazole sodium.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] The active ingredient in most of the proton pump inhibitors, particularly, prazoles is benzimidazole group. In view of this, benzimidazoles are key intermediates in the process of preparation of prazole compounds, omeprazole, pantoprazole, lansoprazole etc.
[0004] PCT patent publication, WO2004/092142A1 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 cyclizing agent under conditions effective to form the benzimidazole derivative. The acetamido benzene derivative has the formula (I),
(I), wherein: R is OMe or OCHF2.
[0005] Chem. Pharm. Bull. (1982), 30 (8) 2714-2722, discloses the synthesis of N- acetylbenzimidazole derivatives. 4-Substituted 2-aminoacetanilides were 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-aminoacetanilide derivative is carried out using carbon disulfide in dimethyl formamide. This process yields a mixture of N-acetylbenzimidazole and benzimidazole derivatives. The yield of the required benzimidzole derivative is 11 %, making the process unviable for a commercial scale operation.
[0006] Chinese patent application, CN102311391A provides a method for preparing 2-mercapto-5-difluoromethoxy-1H-benzimidazole. The method comprises adding 2-nitro-4-difluoromethoxyaniline to catalyst, Raney-Ni to obtain 2-amino-4-difluoromethoxyaniline and the obtained reduction products are used for preparing 2-mercapto-5-difluoromethoxy-1H-benzimidazole.
[0007] Use of Raney Nickel or Palladium catalyst used in the reduction reaction results in incomplete reaction with intermediates. In some of experiments intra molecular cyclization product i.e. 2-methylbenzimidazole was formed as major product. These are the drawbacks of prior art process using Raney nickel or palladium catalyst in the reduction reaction.
[0008] Greener process is a simple process from a multistep process to produce intermediary chemicals for manufacturing that can be done in one or two step with minimum ingredients and little to no waste. It uses fewer chemicals, relies on safer chemicals, creates less waste and works under normal temperature and pressure.
[0009] This is particularly troubling when producing pharmaceuticals where multiple steps are required to transform starting materials into commercial products. In these cases, activating groups increase chemical waste, since activation often requires an additional step in the overall sequence and frequently creates equal amounts of a by-product.
[0010] Researchers are looking for natural ways to improve efficiency during reduction reactions. One way is to replace activating reagents with catalysts. Unlike activating reagents, catalysts can be used in small quantities. This would dramatically reduce chemical waste; catalysts can be frequently recovered after a reaction.
[0011] There is, therefore, an unmet need to develop a green and economical process for preparation of benzimidazole derivatives, key intermediates for preparing proton pump inhibitors which address the drawbacks of the prior art process.

OBJECTS OF THE INVENTION
[0012] The main objective of the present invention is to provide a simple and eco-friendly greener process for the preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (Pantoprazole intermediate).
[0013] Another objective of the present invention is to provide an improved process for the preparation of N-[4-(Difluoromethoxy)phenyl]acetamide.
[0014] Another objective of the present invention is to provide a process for the preparation of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide.
[0015] Yet another objective of the present invention is to provide a process for the preparation of Pantoprazole sodium sesquihydrate using 5-Difluoromethoxy-2-mercapto-1H- benzimidazole prepared according to the present invention.

SUMMARY OF THE INVENTION
[0016] The present invention provides a green process for the preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole of formula (I),
(I)
wherein the process comprising the steps of:
(a) reacting a compound of formula (A),
(A)
with CHClF2 (Freon gas) in acetonitrile solvent to obtain a compound of formula (C),
(C);
(b) reacting the compound of formula (C) with nitric acid in chlorinated solvents to obtain a compound of formula (D),
(D);
(c) reducing the compound of formula (D) using a green catalyst, G-CAT as a reducing agent in present of a neutralizing agent and a solvent selected from lower alcohol, water, aqueous alcohol or a mixture thereof to obtain a compound of formula (E); and

(E)
(d) cyclizing the compound of formula (E) using carbon disulphide (CS2) in presence of base and a solvent selected from water, alcohol or a mixture thereof to obtain the compound of formula (I).
[0017] In another aspect of the present invention, the above said process is shown in the following scheme.

[0018] In another aspect, the chlorinated solvent used in the step (b) of the process of the present invention is selected from trichloromethane, dichloromethane, dichloroethane, tetrachloromethane, trichloroethylene and perchloroethylene.
[0019] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION
[0020] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0021] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
[0022] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[0023] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
[0024] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
[0025] All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0026] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0027] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0028] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
[0029] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0030] It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
[0031] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0032] The term, “G-CAT” as used herein refers to a proprietary customized catalytic formulation and has been used as reducing agent. This catalyst is commercially available and procured from Newreka Green Synth Technologies Pvt. Ltd, Mumbai, India. The composition of the catalyst is provided in the PCT patent publication, WO2011048535A1.
[0033] The term, “R-CAT” as used herein refers to a proprietary customized catalytic formulation and has been used as neutralizing agent. This catalyst is commercially available and procured from Newreka Green Synth Technologies Pvt. Ltd, Mumbai, India. The composition of the catalyst is provided in the PCT patent publication, WO2011048535A1.
[0034] The term, “lower alcohol” or alcohol as used herein refers to C1-6alcohol selected form methanol, ethanol, propanol, isopropanol and butanol.
[0035] In a general embodiment, the present invention relates to a process for the preparation of benzimidazole derivative as provided in the following scheme.

[0036] In the process of the present invention, an unknown impurity has been formed which is not able to remove completely from the product while preparing the compound of formula (C). It required further purification. Surprisingly, we found that stirring the reaction mass with hydrochloric acid leads to the conversion of impurity into starting material. The starting material can be removed easily from product by simple washing of organic layer with lye solution.
[0037] In an embodiment, the product formation in the process of present invention is very clear and substantially free of intermediates due to the catalyst, G-CAT used in nitro to amine reaction. Moreover, it gave good quality product and yield. G-CAT is not pyrophoric and no hydrogen source is required in the form of gas. It takes hydrogen source from water. After reaction conversion, the catalyst is separated by simple filtration and the product is isolated by concentration of filtrate.
[0038] In cyclization reaction, after reaction completion, washing the solution of reaction mass at basic pH with chloroform solvent removed the colored impurities as well as unreacted intermediates. The product can be isolated by adjusting the pH of aqueous solution to 7.0-8.0 in very good quality with respect to colour and purity.
[0039] In certain embodiments, the compound of formula (C) can be converted to the compound of formula (D) using nitric acid in presence of chlorinated solvents. The chlorinated solvent is selected from the group consisting of dichloromethane, trichloromehtane, 1,2-dichloroethane, dichloropropanes, dichlorobutanes and dichloropentanes. Preferably, the chlorinated solvent is selected from the group consisting of trichloromethane, dichloromethane, dichloroethane, tetrachloromethane, trichloroethylene and perchloroethylene. More Preferably, trichloromethane.
[0040] According to the present invention, the intermediate, compound of formula (E) may be isolated if desired, or the reaction sequence can be carried forward without isolation of said intermediate. In addition, all the reaction steps of the above process can also be carried out under reaction conditions suitable for commercial use, and typically proceed at reaction rates suitable for large scale operations.
[0041] In an aspect, the present invention relates to a process for preparation of compound of formula (I) comprising the steps of:
(a) reducing a compound of formula (D) using a green catalyst, G-CAT as a reducing agent in presence of a neutralizing agent and a solvent selected from lower alcohol, water, aqueous alcohol or a mixture thereof to obtain a compound of formula (E); and

(b) cyclizing the compound of formula (E) using carbon disulphide (CS2) in presence of base using solvent selected from water, alcohol or a mixture thereof to obtain the compound of formula (I);
.
[0042] In certain embodiments, the compound of formula (D) can be converted to compound of formula (E) using the catalyst, G-CAT for the first time. The reducing step also uses the catalyst, R-CAT for the first time as neutralizing agent. The conversion of the compound of formula (D) to the compound of formula (E) using the catalyst G-CAT and R-CAT is resulted in the green process. The unreacted catalyst can be recovered and re-used for further conversion.
[0043] In some embodiments, the cyclizing of the compound of formula (E) can be carried out in presence of base and solvent. The base that can be used for this purpose includes organic and inorganic base. Preferably, the base may be an inorganic base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium hydroxide and lithium hydroxide. The base may be an organic base such as triethylamine, N, N-diisopropylethylamine (DIPEA), N,N-diisopropylamine, ethanolamine, diethanolamine, triethanolamine or N-methylglucamine. More preferably, the base can be sodium hydroxide and sodium carbonate. The solvent that can be used for this purpose includes water, methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof.
[0044] In an embodiment, the present invention relates to a process for preparation of pantoprazole of formula (Ia) comprising the steps of:
(a) reacting a compound of formula (A),
(A)
with CHClF2 (Freon gas) in acetonitrile solvent to obtain a compound of formula (C),
(C);
(b) reacting the compound of formula (C) with nitric acid in chlorinated solvents to obtain a compound of formula (D),
(D);
(c) reducing the compound of formula (D) using a green catalyst, G-CAT as a reducing agent in present of a neutralizing agent and a solvent selected from lower alcohol, water, aqueous alcohol or a mixture thereof to obtain a compound of formula (E),
(E)
(d) cyclizing the compound of formula (E) using carbon disulphide (CS2) in presence of base using solvent selected from water, alcohol or a mixture thereof to obtain a compound of formula (I); and
(I)
(e) converting the compound of formula (I) to the pantoprazole of formula (Ia),
(Ia).
[0045] According to the present disclosure, the compound of formula (I) can be converted to pantoprazole of formula (Ia) by any method known in the art.
[0046] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
[0047] The present invention is further explained in the form of following examples. However, it is to be understood that the following examples are merely illustrative and are not to be taken as limitations upon the scope of the invention.
Example 1: Preparation of N-[4-(Difluoromethoxy)phenyl]acetamide
[0048] N-(4-Hydroxyphenyl)acetamide (100 g) was charged into acetonitrile (625 mL) at 25 – 30 °C. Simultaneous addition of 48% caustic soda lye solution (92.5 mL) and purging of Freon gas (Chlorodifluoromethane) was carried out at 50 – 60 °C for 10-16 hours. Reaction mass was cooled to 25 – 30 °C and layers were separated. Caustic soda lye solution (48%, 22.50 mL) was charged into organic layer and stirred for 30 minutes. The aqueous layer was separated to remove unreacted N-(4-Hydroxyphenyl)acetamide. Concentrated hydrochloric acid was charged (1.0 vol.) into organic layer and stirred at room temperature. The aqueous and organic layers were separated. The organic layer was washed with caustic lye solution, concentrated and water (250 mL) was added at 90 – 95 °C. The pH of the reaction mass was adjusted to 12 – 14 using caustic soda lye solution at 25 – 30 °C. The product formed was filtered and solid was washed with water (50 mL). The product was dried at 65-70?.
Yield: 97 g; HPLC purity: > 96%.
Example 2: Preparation of N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide
[0049] Nitric acid (155 mL, 70%) and chloroform (300 mL) were charged into RB flask at 25 – 30 °C. The reaction mixture was cooled to 10-15?. N-[4-(Difluoromethoxy)phenyl] acetamide (100 g) was added slowly at 10 – 15 °C and temperature was maintained for 3 hours. After completion of reaction, layers were separated. Aqueous layer was extracted with chloroform (2 x 100 mL). Organic layers were combined and washed with water (200 mL). The aqueous layer was extracted with chloroform (50 mL). Water (250 mL) was charged into organic layer and pH was adjusted to 11 – 12 using caustic soda lye solution at 25 – 35 °C. The clear organic layer was separated and concentrated to get the title compound (Yellow crystalline powder).
Yield: 113 g; HPLC purity: 98.79%.
[0050] The main aqueous layer after chloroform extraction was recycled in subsequent batches, which minimized the effluent load.
Example 3: Preparation of N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide
[0051] Nitric acid (155 mL, 70%) and Dichloromethane (300 mL) were charged into RB flask at 25 – 30 °C. The reaction mixture was cooled to 10-15 ?. N-[4-(Difluoromethoxy) phenyl]acetamide (100 g) was added slowly at 10 – 15 °C and temperature was maintained for 3 hours. After completion of reaction, layers were separated. Aqueous layer was extracted with Dichloromethane (2 x 100 mL). Organic layers were combined and washed with water (200 mL). The aqueous layer was extracted with dichloromethane (50 mL). Water (250 mL) was charged into organic layer and pH was adjusted to 11 – 12 using caustic soda lye solution at 25 – 35 °C. The clear organic layer was separated and concentrated to get the title compound.
Yield: 106 g; HPLC purity: 98.62%.
Example 4: Preparation of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide
[0052] Methanol (400 mL), Water (100 mL) and G-CAT (175 g) were charged into RB flask at 25-30 °C. The reaction mass was heated to reflux temperature and N-[4-(Difluoromethoxy)-2-nitrophenyl)]acetamide (100 g) in methanol ( mL) was added drop wise for about 2-3 hours at reflux temperature. After reaction completion, the reaction mass pH was adjusted to 9.5 -10.5 using R-CAT. The reaction mass was filtered and the residue was washed with methanol (2 x 200 mL) followed by water (100 mL). The filtrate was concentrated under vacuum.
Yield: 84 g; HPLC purity: 98.35%.
Example 5: Preparation of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide
[0053] Methanol (400 mL), Water (100 mL) and G-CAT (175 g) were charged in RB flask at 25-30 °C. The reaction mass was heated to reflux temperature and N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide (100 g) was charged into reaction mass in five equal portions subsequently by maintaining reaction temperature 70-75 °C for 1-2 hours between each interval.. The reaction mass pH was adjusted to 9.5-10.5 using R-CAT. The reaction mass was filtered and the residue was washed with methanol (2 x 200 mL) followed by water (100 mL). The filtrate was concentrated under vacuum.
Yield: 87 g; HPLC purity: 99.40%.
Example 6: Preparation of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide
[0054] G-CAT (75 g) and water (600 mL) were charged into RB flask at 25-30 °C and the contents were heated to 70-75 °C. G-CAT (100 g) and N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide (100 g) was charged into reaction mass in five equal portions subsequently by maintaining reaction temperature 70-75 °C for 1-2 hours between each interval. Reaction mass pH was adjusted 9.5-10.5 using R-CAT at 70-75 °C. The catalyst was filtered and washed water at 70-75 °C. The clear filtrate was concentrated under vacuum.
Yield: 65 g; HPLC purity: 97.74 %.
Example 7: Preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (Formula (I))
[0055] G-CAT (75 g) and water (600 mL) were charged into RB flask at 25-30 °C and the contents were heated to 70-75 °C. G-CAT (100 g) and N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide (100 g) was charged into reaction mass in five equal portions subsequently by maintaining reaction temperature 70-75 °C for 1-2 hours between each interval. Reaction mass pH was adjusted 9.5-10.5 using R-CAT at 70-75 °C. The catalyst was filtered and washed with methanol followed by water at 70-75 °C. The filtrate was concentrated under vacuum and the concentrate was diluted with methanol (200 mL) and water (100 mL). Sodium hydroxide (60 g) was charged into reaction mass and carbon disulphide (114 g) was added drop wise at 25-30 °C. The reaction mass was stirred at 90-95 °C for 8-12 hours. After reaction completion, the solvent was distilled out and added water. The pH of the reaction mass was adjusted to 11-13 using sodium hydroxide solution. The clear solution was washed with chloroform. The aqueous layer was treated with carbon and filtered. The pH of the filtrate was adjusted to 7.0-8.0. The solid product formed was filtered and washed with water. The wet material was dried at 60-65 °C.
Yield: 52 g; HPLC purity: 99.12%.

Example 8: Preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (Formula (I))
[0056] To the solution of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide (equivalent to 100 g N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide) in methanol (200 mL), sodium hydroxide solution [sodium hydroxide (60 g) and water (100 mL)] was charged at below 25 – 35 °C. Carbon disulphide (114 g) was added drop wise at 25 – 35°C. After addition, reaction mass was maintained at 50 – 65 °C for 8 – 12 hours. After completion of reaction, solvent was distilled out under reduced pressure and water (100 mL) was charged at 25 – 30 °C. The pH was adjusted to 2.5 – 3.5 using dilute hydrochloric acid and stirred for 2 hours at 25 – 30 °C. The product formed was filtered and washed with water. The wet material was charged into water (400 mL) and pH of the mass was adjusted to 12 – 14 using caustic lye solution. The resultant solution was decolourized with charcoal and filtered. The filtrate pH was adjusted to 2.5 – 3.5 using dilute hydrochloric acid. The product formed was filtered and washed with water (100 mL). The wet material was dried for 12 hours at 60-65? to obtain the title compound.
Yield: 78 g, HPLC purity: 99.21 %.
Example 9: Preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (Formula (I))
[0057] To the solution of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide (equivalent to 100 g N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide) in methanol (200 mL), sodium hydroxide solution (sodium hydroxide 60 g and water 100 mL) was charged below 25 – 35 °C. Carbon disulphide (113.20 g) was added drop wise at 25 – 35°C and the reaction mass was stirred at 50 – 65 °C for 8 – 12 hours. After completion of the reaction, solvent was distilled out under reduced pressure and added water (600 mL) at 25 – 30 °C. The reaction mass pH was adjusted to 10-12 using 48% caustic soda lye solution. The clear solution obtained was washed with chloroform at 25 – 30 °C. The clear aqueous layer was treated with activated carbon (10 g) and filtered. The filtrate pH was adjusted to 7.0–8.0 using dilute hydrochloric acid. The product formed was filtered and washed with water (100 mL). The wet material was dried for 10-12 hours at 60-65? to obtain the title compound.
Yield: 73 g, HPLC purity: 99.33 %.
Example 10: Preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (Formula (I))
[0058] To the solution of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide (equivalent to 100 g N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide) in methanol (200 mL), Carbon disulphide (113.20 g) was charged below 25 – 35 °C. Sodium hydroxide solution (sodium hydroxide 60 g and water 100 mL) was added drop wise at 25 – 35 °C. The reaction mass was heated to 50 – 65 °C and stirred for 8 – 12 hours. After completion of the reaction, solvent was distilled out under reduced pressure and added water (600 mL) at 25 – 30 °C. The reaction mass pH was adjusted to 10-12 using 48% caustic soda lye solution. The clear solution obtained was washed with chloroform at 25 – 30 °C. The clear aqueous layer was treated with activated carbon (10 g) and filtered. The filtrate pH was adjusted to 7.0–8.0 using dilute hydrochloric acid. The product formed was filtered and washed with water (100 mL). The wet material was dried for 10-12 hours at 60-65? to obtain the title compound.
Yield: 70 g, HPLC purity: 99.20 %.
Example 11: Preparation of 5-Difluoromethoxy-2-mercapto-1H-benzimidazole (Formula (I))
[0059] To the solution of N-[2-Amino-4-(difluoromethoxy)phenyl]acetamide (equivalent to 100 g N-[4-(Difluoromethoxy)-2-nitrophenyl]acetamide) in methanol (300 mL), Carbon disulphide (113.20 g) was charged below 25 – 35 °C. Sodium carbonate solution (Sodium carbonate 106 g and water 300 mL) was added drop wise at 25 – 35 °C. The reaction mass was heated to 50 – 65 °C and stirred for 8 – 12 hours. After completion of the reaction, solvent was distilled out under reduced pressure and added water (600 mL) at 25 – 30 °C. The reaction mass pH was adjusted to 10-12 using 48% caustic soda lye solution. The clear solution obtained was washed with chloroform at 25 – 30 °C. The clear aqueous layer was treated with activated carbon (10 g) and filtered. The filtrate pH was adjusted to 7.0–8.0 using dilute hydrochloric acid. The product formed was filtered and washed with water (100 mL). The wet material was dried for 10-12 hours at 60-65? to obtain the title compound.
Yield: 72 g, HPLC purity: 99.60 %.
[0060] A skilled artisan will appreciate that the quantity and type of each ingredient can be used in different combinations or singly. All such variations and combinations would be falling within the scope of present disclosure.
[0061] The foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.
ADVANTAGES OF THE PRESENT INVENTION
[0062] Advantages of using acetonitrile in the preparation of N-[4-(Difluoromethoxy) phenyl]acetamide
(1) Very good yield and quality of product achieved.
(2) No Phase transfer catalyst is required for reaction.
(3) No other solvents used for extraction and/or isolation of product.
(4) Simple isolation of product using water.
(5) Recovery and reusability of solvent.
[0063] Advantages of using G-CAT in the process of present invention over prior art
(1) Very good reaction conversion when compared to high-pressure catalytic
hydrogenation.
(2) Easy to handle and eco-friendly catalyst. No inert atmosphere required.
(3) The spent catalyst obtained after reduction reaction is reusable by other
industries especially cement industries.
(4) Gives good quality of the product and yield.
,CLAIMS:1. A process for the preparation of 5-difluoromethoxy-2-mercapto-1H-benzimidazole of formula (I),
(I)
wherein the process comprising the steps of:
(a) reacting a compound of formula (A),
(A)
with CHClF2 (Freon gas) in acetonitrile solvent to obtain a compound of formula (C),
(C);
(b) reacting the compound of formula (C) with nitric acid in chlorinated solvents to obtain a compound of formula (D),
(D);
(c) reducing the compound of formula (D) using a green catalyst, G-CAT as a reducing agent in present of a neutralizing agent and a solvent selected from lower alcohol, water, aqueous alcohol or a mixture thereof to obtain a compound of formula (E); and
(E)
(d) cyclizing the compound of formula (E) using carbon disulphide (CS2) in presence of base using solvent selected from water, alcohol or a mixture thereof to obtain the compound of formula (I).
2. The process as claimed in claim 1, wherein the chlorinated solvents in step (b) is selected from the group consisting of dichloromethane, trichloromethane, dichloroethanes, dichloropropanes, dichlorobutanes, dichloropentanes and mixture thereof.
3. The process as claimed in claim 1, wherein the lower alcohol or alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol and mixture thereof.
4. The process as claimed in claim 1, wherein the neutralizing agent is a catalyst, R-CAT.
5. The process as claimed in claim 1, wherein the base in step (c) is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium hydroxide and lithium hydroxide.
6. The process as claimed in claim 1, further comprises converting the compound of formula (I) to obtain pantoprazole of formula (Ia),
.
7. A process for preparing a compound of formula (I) comprising the steps of:
(a) reducing a compound of formula (D) using a green catalyst, G-CAT as a reducing agent in present of a neutralizing agent and a solvent selected from lower alcohol, water, aqueous alcohol or a mixture thereof to obtain a compound of formula (E); and

(b) cyclizing the compound of formula (E) using carbon disulphide (CS2) in presence of base using solvent selected from water, alcohol or a mixture thereof to obtain the compound of formula (I);
.
8. The process as claimed in claim 6, wherein the neutralizing agent is a catalyst, R-CAT.
9. The process as claimed in claim 6, wherein the lower alcohol or the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol or mixture thereof.
10. The process as claimed in claim 6, wherein the base in step (b) is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium hydroxide and lithium hydroxide.