Priority Claim
This application claims the priority of an earlier application No: 1480/CHE/2005, filed on 17th October 2005.
Field of the Invention
The present invention relates to a one-pot synthetic preparation of benzimidazole type compound, particularly Pantoprazole and its pharmaceutically acceptable salts thereof, especially sodium salt, which is chemically known as sodium salt of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-Benzimidazole represented by the following Formula (I)

A benzimidazole-type compound or an alkali metal salt thereof has a strong inhibitory action on the so-called proton pump. In a general sense, they may be used for prevention and treatment of gastric-acid related diseases in mammals and especially in man, including e.g. gastro-esophageal reflux, gastritis, duodenitis, gastric ulcer and duodenal ulcer.
Pantoprazole is the active ingredient of a pharmaceutical production that is marketed in the United States by Wyeth-Ayerst Inc., under the brand name Protonix.RTM. Protonix.RTM is approved by the U.S.Food and Drug Administration for short-term treatment of erosive esophagitis associated with gastro esophageal reflux disease (GERD), maintenance of healing erosive esophagitis and pathological hypersecretory conditions including Zollinger-Ellison syndrome. According to the package insert for Protonix.RTM, the product contains a monosodium salt of pantaprazole in sesiquihydrate state of hydration.

Background of the Invention
Processes for the preparation of said benzimidazole-type compounds have been disclosed, for instance, in EP-0,005,129, EP-0,066,287, EP-0,174,726, EP-0,268,956 and WO 03/008406.
According to Example-6 of the US Patent 4758579 2-[(4,5-dimethoxy-2- pyridyl)methylsulfinyl]-5-(252,2-trifluoroethoxy)-lH-benzimidazole is prepared by dissolving 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-(2,2,2-trifluoroethoxy)-lH- benzimidazole in 15 ml of dioxane and adding 2.5 ml of IN sodium hydroxide solution. A mixture of 3 ml of 8% strength sodium hypochlorite solution and 3.5 ml of IN sodium hydroxide solution is added drop wise over the course of 2 hours while cooling to 0 to -5°C. after addition of 5 ml of 5% strength sodium thiosulfate solution, the mixture is concentrated to dryness, the residue is then taken up in water and the mixture is brought to pH 7 with phosphate buffer. The solid, which has precipitated out, is filtered off with suction, dried and recrystallized from ethyl acetate/diisopropyl ether. The yield was reported to be 55%.
This patent does not speak about the pH of the sodium hypochlorite solution, which will play major role in oxidation reaction.
According to Example 1 of the US Patent application 2005/0075370 Pantoprazole has been prepared by mixing 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-lH-benzimidazole and ethyl acetate is added to the flask followed by 18.8% aqueous sodium hydroxide and cooled to -10°C. 9.7% sodium hypochlorite is added drop wise over 15 minutes. The two phase mixture is stirred at room temperature for 3 hours. The phases are then separated, and 27% aqueous sodium metabisulfite (7 ml) is added to the aqueous phase to quench unreacted oxidant. The organic phase is washed with water, and the aqueous phase is washed twice with ethyl acetate. The organic phases are combined, dried over sodium sulfate, and evaporated under 20 mm Hg vacuum. The resulting oil is

triturated with methyl t-butyl ether and filtered to obtain Pantoprazole and the reported yield is 71%.
This patent suffers from the drawback, which is the presence of unreacted sulfide compound of formula (IV) (0.08%) as an impurity in Pantoprazole. The present invention overcomes this problem.
The WO02/062786 Patent discloses the selective oxidation process for the preparation of Benzimidazole-type compounds using tertiary butyl hydro peroxide in presence of catalyst selected from the group consisting of vanadyl bis-acetylacetonate, sodium meta-vanadate and vanadium pentoxide. Vanadium compounds are costly and produce high effluent.
Proton pump inhibitors of the benzimidazole-type are very susceptible to degradation under acidic or neutral conditions and particular reaction conditions are needed for their preparation
The main problem with the oxidation reaction to convert the sulfide intermediates of Formula (IV) into the sulfoxide compounds of formula (I) is over-oxidation, i.e. oxidation from sulfoxides of formula (I) to sulfones of formula (VI).

The formation of sulfones of formula (VI) due to over-oxidation is almost impossible to avoid and can be kept to a minimum by performing the oxidation reaction at a low temperature and restricting the amount of oxidizing agent. Typically the amount of oxidizing agent is less than 1 molar equivalent of the starting material, i.e. sulfide

intermediates of Formula (IV), which inevitably results in a less than 100% conversion of starting material. Usually the amount of oxidizing agent is a compromise between maximum conversion of starting material, maximum formation of sulfoxides of formula (I) and minimum formation of unwanted sulfones of formula (VI).
Furthermore removal of the sulfones of formula (VI) has often proved to be difficult, time-consuming and costly, in particular when high performance chromatography on an industrial scale is needed.
The present invention provides a one-pot synthetic preparation of Pantoprazole and its pharmaceutically acceptable salts, preferably sodium salt compound of formula (I), which avoids all the above mentioned problems, and is commercially viable.


Brief description of the Invention
In accordance with the present invention, a process provided for one-pot synthesis of Pantoprazole and its pharmaceutically acceptable salts thereof, preferably sodium salt which have the following formula (I)

Accordingly the first aspect of the invention is to provide One-pot synthetic preparation of sodium salt of pantaprazole which comprises the following steps;
a) Reacting the 5-difluromethoxy 2-mercapto benzimidazole compound of Formula
II)

with 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride compound of formula (III)

in presence of a base in a suitable polar solvent, followed by extracting the reaction mixture with water immiscible solvent like chloro solvent to give the compound of formula (IV)


b) Which in-situ (without distillation and isolation of compound of formula (IV)) reacting with an oxidizing agent in a suitable solvent and
c) Decomposing the reaction mixture by inorganic salts like Ammonium sulphate, Ammonium chloride, preferably Ammonium sulphate,
d) Extracting the reaction mixture with methylene chloride and removing the aqueous layer having unreacted sulfide of Formula (IV) and sulfone by-product which is formed at very minimum level in the reaction,
e) Concentrating the organic layer to get Pantoprazole, which is further converted into sodium salt using aqueous sodium hydroxide in a suitable solvent selected from ketone solvents, like acetone, propanone, butanone or acetonitrile, preferably acetone.
The second aspect of the present invention is to provide the process for the preparation of sulfide compound of general formula (VII)

wherein R2 is selected from methoxy, ethoxy, monohalomethoxy, dihalomethoxy and trihalomethoxy or hydrogen.


comprises of
(a) Reacting the compound of formula R with the compound of formula Ri in presence of a base in a suitable polar solvent, followed by extracting the reaction mixture with water immiscible solvent like chloro solvent to give the compound of general formula (VII).
The term “proton pump inhibitors of the benzimidazole-type”, “benzimidazole-type compounds” or “compound of formula (I)” is meant to include both the neutral form of said compounds and the alkaline salt forms of the said compounds. Alkaline salts forms are for instance the Mg2+,Ca2+,Na+,K+ or Li+ salts, preferably the Mg2+ or Na+ salts. Where applicable, the benzimidazole-type compounds of formula (I) include the racemic form, or a substantially pure enantiomer thereof, or alkaline salts of the single enantiomers.

Advantageous of the present invention
Ø One-pot synthesis of pantaprazole sodium with out isolating sulfide compound of formula (IV).
Ø Usage of water as a solvent medium for the preparation of sulfide compound of general formula (VII) and sulfide compound of formula (IV).
Ø Commercially viable and most economic process for industrial scale up.
Ø This improved process has an advantage that the decomposition step b) controls the over-oxidation of compound of formula (I) i.e., controls the formation of sulfone compound of formula (VI),
Ø Extraction step c) removes any formed sulfones of formula (VI) as well as unreacted sulfides of Formula (IV) whereby the organic layer only contains the desired benzimidazole-type compound of formula (I) which can be easily isolated the product using acetone and methylene chloride as a solvents.
Ø A further advantage of the improved process is that higher amounts of oxidizing agent can be used, giving a higher yield of the desired compound of formula (I) and fewer unreacted sulfides of Formula (IV), since any formed undesired sulfones of formula (VI) are easily removed by the first extraction step thereby making further purification of the isolated sulfoxides of formula (I) much more easy.
Any other oxidizing agent suitable for oxidizing sulfides of Formula (IV) and sulfide compound of general formula (VII). Preferably sodium hypochlorite is used. Said oxidizing agent is suitably used in an amount of 1.0 molar equivalents of starting material, i.e. sulfides of Formula (IV) and formula (VII). The optimal amount of oxidizing agent depends on the type of the oxidizing agent used, the specific sulfide of Formula (IV) and further reaction conditions such as solvent and temperature, and can easily be determined by the skilled person.
Particular benzimidazole-type compounds of formula (I) that can be prepared by the improved process of the present invention are pantoprazole, rabeprazole, omeprazole, lansoprazole and esomeprazole; in particular Pantoprazole.

Detailed description of the Invention
The present invention relates to a One-pot synthesis for the preparation of Pantoprazole and its pharmaceutically acceptable salts thereof, preferably sodium salt, which is chemically known as sodium salt of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-Benzimidazole represented by the following Formula (I)

Accordingly the first aspect of the present invention is to provide the One-pot synthetic process for the preparation of sodium salt of pantaprazole comprises the following steps;
(a) Reacting the 5 -difluromethoxy 2-mercapto benzimidazole compound of Formula (II)
with 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride compound of formula (III)
in presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, preferably sodium hydroxide in a suitable polar solvent like dimethyl formamide, dimethyl acetamide, dimethylsulfoxide, water and mixtures thereof, preferably water, followed by extracting the reaction mixture with a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetrachloride preferably methylene chloride to give the compound of formula (IV),

(b) Which in-situ (i.e. without distillation of solvent and without isolating the compound of formula (IV)) reacting with sodium hypochlorite having pH range from 7.5 to 12.0, preferably 8.0 to 11.0, more preferably 8.5 to 9.0 and assay ranging from 2.0 to 4.0, preferably 3.0 to 4.0 more preferably 3.0-3.5, in a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, preferably methylene chloride,
(c) Decomposing the reaction mixture by inorganic salts like Ammonium sulphate, Ammonium chloride preferably Ammonium sulphate to deactivate an oxidizing reagent which is left unreacted after the reaction i.e., to control over-oxidation of compound of formula (I),
(d) Extracting the reaction mixture with methylene chloride and removing the aqueous layer having unreacted sulfide of Formula (IV) and sulfone by-product which is formed at very minimum level in the reaction,

(e) Concentrating the organic layer to get Pantoprazole, which is further converted into its sodium salt using aqueous sodium hydroxide in a suitable solvent selected from ketone solvents, like acetone, propanone, butanone or acetonitrile preferably acetone, optionally washed with methylene chloride. HPLC Result: 99.91% [ Sulfone of formula (VI) is 0.05%]
The second aspect of the present invention is to provide the process for the preparation of sulfide compound of general formula (VII)

comprises of
(a) Reacting the compound of formula R with the compound of formula Ri in presence of a base such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, preferably sodium hydroxide in a suitable polar solvent like dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, water and mixtures thereof, preferably water, followed by extracting the reaction mixture with water immiscible solvent such as chloro solvents like methylene chloride, chloroform, or ester solvents like ethyl acetate to give the compound of general formula (VII).

The preferred embodiments according to the second aspect of the present invention are Pantoprazole sulfide compound of formula (IV), Omeprazole sulfide compound of formula (VIII), Lansoprazole sulfide compound of formula (IX) and Rabeprazole sulfide compound of formula (X).

The amount of sulfone compound of formula (VI) and compound of formula (I) was measured by HPLC Analysis, which is carried out using Inertsil C\s9 250 X 4.6, 5 jam, or equivalent, at the wavelength of 290 nm with the flow rate of L0 ml/min, at ambient temperature, load is 20 \xl9 runtime is 40 minutes, RT of the main peak is at about 9 minutes, the diluent is a mixture of 0.01 M borax solution (3.81 gr of borax in 1000 ml of water) and acetonitrile in the ratio of 1:1 and using dilute phosphoric acid as a buffer.

The above process schematically represented as follows

The examples mentioned below demonstrate specific preparations of the present invention. The examples are provided to illustrate the details of the invention and should not be construe the limit of the scope of the present invention.

Examples:
Example 1: Preparation of sodium salt of 5-(difluoromethoxy)-2[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-Benzimidazole (Pantoprazole sodium)
49.8g of 5-difluoromethoxy 2-mercaptobenzimidazole5 500ml water along with sodium hydroxide solution(22.5g of flakes in 27.5ml of water) is stirred for 15-20mins to get clear solution. A solution of 50g of 2-chloromethyl-2,4-dimethoxypyridine hydrochloride in 250ml water is slowly added at 25-35°C and stirred for 3 hours. Reaction mixture extracted thrice with methylene chloride followed by washed the organic layer with water to get the organic layer of sulfide compound of formula (IV). The obtained organic layer cooled to -5 to 0°C and slowly added 550g of 3.1% sodium hypochlorite having pH 8.75 and assay 3.2, at -5 to 0°C. Stirred the reaction mixture for 2.5 to 3.0 hours at -5 to 0°C. Quenched the reaction mixture with 56g of ammonium sulphate at below 10°C. Stirred for 20-30 minutes. Separated the organic phase, and extracted the aqueous phase twice with methylene chloride. Combined organic phase and washed with water. Dried the organic layer over sodium sulphate and distilled off the solvent under reduced pressure at below 45°C. 37.5 ml of acetone was added to the crude and distilled under reduced pressure at below 45°C and the crude was dissolved in 375 ml of acetone at 25-35°C. Heated to reflux and stirred for 20-30 minutes, then cooled to 18-23°C. Added aqueous sodium hydroxide solution (8.5g in 10ml of water) at 18-23°C. Stirred at 18-23°C for 45-60 minutes. Cooled the reaction mixture to 0-5°C and stirred for 2-3 hours. Filtered the compound and washed with chilled acetone (2x15ml), followed by optionally washed with methylene chloride. The obtained solid optionally purified using acetone to get pure compound. The amount of sulfone compound of formula (VI) and compound of formula (I) present in the obtained solid was measured using HPLC and the results are as follows.

Yield: 65 grams

Example 2: Preparation of Rabeprazole sulfide compound of formula (X)
A solution of 300g of 2-chloromethyl-4(3-methoxy propoxy)-3-methyl pyridine in 600ml water is slowly added to a solution of 170g of 2-Mercapto-lH- benzimidazole in 1200 ml of an aqueous solution of sodium hydroxide (113 gr) at 25-35°C. Stirred for 4 hours. Quenched the reaction mixture with water and extracted reaction mixture with methylene chloride. Separated the organic phase then washed the organic phase with water. This organic layer containing sulfide compound of formula (X) can be used directly for oxidation step with out distillation and isolation of sulfide compound.