DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

CONTINUOUS FLOW MICRO MIXING REACTOR TECHNOLOGY FOR THE PREPARATION OF PANTOPRAZOLE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATERMARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The invention relates to a continuous flow micro mixing reactor technology for the preparation of Pantoprazole, its optically active enantiomers, pharmaceutically acceptable salts, polymorphs, hydrates or solvates thereof. Particularly, the invention relates to an efficient micromixer based continuous flow process for the synthesis of Pantoprazole by using combination of Continuous Stirred Tank Reactor (CSTR) and Plug Flow Reactor (PFR).

BACKGROUND OF THE INVENTION
Pantoprazole Sodium Sesquihydrate is chemically, sodium 5-(difluoromethoxy)-2- [[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-lH-benzimidazole sesquihydrate. Pantoprazole marketed as sodium salt in the United States by Wyeth-Pharms Inc and was protected by US 4,758,579 and sold under the brand name PROTONIX®.

US Patent 4,758,579 claims that Pantoprazole and many other fluoroalkoxy substituted benzimidazoles are inhibitors of gastric acid secretion. The '579 patent describes that the Pantoprazole can be prepared by oxidation of 5- (difluoromethoxy)-2-(((3,4-dimethoxypyridine-2-yl)methyl)thio)-lH-benzimidazole during reaction with m-chloroperbenzoic acid in methylene chloride, yielding Pantoprazole base. Further reaction with aqueous sodium hydroxide solution gives Pantoprazole sodium, which is then purified by crystallization from methanol. The drawback of reaction is oxidation carried out with m-chlorobenzoic acid is costly as well as forms benzoic acid as a byproduct. The crude Pantoprazole is further purified by crystallization, which adds an additional step and hampers yield of the product. Moreover, patent does not explain the state of hydration, purity and form of the Pantoprazole sodium.

US Patent 7,683,177 describes a process for the preparation of Pantoprazole sodium using sodium hypochlorite as an oxidizing agent in the oxidation step followed by addition of an anti-solvent. However, the process overcomes the problem of over-oxidation by limiting the formation of sulphone impurity which otherwise is difficult to eliminate, by known purification methods such as recrystallization due to the formation of mixed crystals with sulphoxide. However, it involves the use of an additional solvent, as an anti-solvent, for isolation, which increases cost of the process.

WO 2006/064249 describes a process for the preparation of Pantoprazole sodium comprising the reaction of 2-mercapto-5-difluoromethoxy benzimidazole with 2- chloromethyl-3, 4-dimethoxypyridine hydrochloride in the presence of a base and a phase-transfer catalyst followed by treatment with aqueous sodium hypohalite solution.

WO 2007/026188 describes a process for the preparation of Pantoprazole sodium using sodium hypochlorite in the presence of a phase-transfer catalyst.

There are various prior art references, which are disclosing the synthesis of Pantoprazole which employ traditional technologies such as batch processes. However, after thorough exploration it was observed that these processes are often associated with impurities like sulfone and sulphide. These impurities are difficult to separate due to close resemblances in physiochemical property between them and Pantoprazole.

Few inventors also reported synthesis of benzimidazole drugs (includes Pantoprazole) by using continuous flow micromixing reactor technology wherein this technology decreases reaction time of sulfoxidation with minimization of the formation of sulfone impurities and improvement of the yield. Chemical reactors are vessels, wherein chemical reactions are carried out; their performance determines the reliability and suitability of a process, its environment safety, the consumption of energy and the raw materials required. Of all the known chemical reactors, the continuous flow reactors are well suited for carrying out reactions, wherein high yield and purity is desired and best utilized continuous flow reactors are Micro Reactor, Plug Flow Reactor, Advanced Flow Reactor (AFR), Spinning Disk Reactor, Loop Reactor, Static Mixer, Continuous Stir Tank Reactor (CSTR) etc.

Takuya Noguchi et al. in Chem. Comm., 2008 (26), 3040 discloses an oxidation reaction from sulfide to sulfoxide using hydrogen peroxide as an oxidizer and a T-shaped micromixer.

WO2012/004802 discloses a continuous micromixer based process for the synthesis of sulphoxide compounds with a reaction time of less than or equal to one minute having selectivity of 92-93% towards the sulphoxide compounds, However, the process has several drawbacks with respect to (i) selection of oxidizing agent (ii) selectivity (iii) use of solvent, (iv) micromixer design etc. WO '802 refers that the reaction of imidazo[4,5-b]pyridine compound using oxidizing agent dissolved in solvent to obtain sulphoxide, wherein the commonly used oxidizing agents such as hydrogen peroxide, sodium hypochlorite gives only of 2 to 3% conversion, which is highly undesirable on commercial scale. The only oxidizing agent giving more than 82% conversion is a costly reagent and its use is discouraged on commercial scale and is uneconomical. Further, the applicant does not disclose any example related to Pantoprazole.

Indian Patent Application 2966/CHE/2010 illustrates preparation of Pantoprazole by employing the continuous flow micro mixing reactor technology.

Organic Process Research & Development (2013), 17 (10), 1272-1276 describes the synthesis of benzimidazole core drugs, such as lansoprazole, Pantoprazole, and rabeprazole by using a continuous flow micromixing reactor technology. This article depicts that time required for sulfoxidation is decreased from 3 h to ~1 s with minimization of sulfone impurities thereby increasing the yield.

A Continuous Stir Tank Reactor (CSTR) consists of an impeller continuously stirs the contents ensuring proper mixing of the reagents to achieve a specific output. However, there are portions that are not well mixed due to stagnant volumes, recirculation eddies, and mixing bypasses

A plug flow reactor is a tubular reactor is fundamentally a continuous reactor where there are no moving parts other than pumps that deliver the reactants. The key assumption is that as a plug flows through a PFR, the fluid is perfectly mixed in the radial direction but it experiences no axial mixing, i.e. contiguous cross-sections cannot exchange mass with each other.

However, the reactors when used alone suffers with the non-ideal behavior such as formation of Stagnant zones or dead zones, Short-Circuiting and Channeling or Bypassing. The prior art continuous flow micro mixing reactor technology suffers with problem in well mixing which leads to low yields, less purity and formation of unnecessary side products such as sulfones.

The inventors of the present invention developed a novel process design wherein it combines reactors Continuous Stirred Tank Reactor (CSTR) and Plug Flow Reactor (PFR) for primary and secondary oxidation of Pantoprazole sulfide respectively followed by continuous quenching. This new design for process of preparation of Pantoprazole does not have detectable level of sulfone and sulfide impurities measured by HPLC which makes the process feasible at industrial level.

OBJECTIVE OF INVENTION
The primary object of the present invention is to provide an improved process for the preparation of Pantoprazole, its optically active enantiomers, pharmaceutically acceptable salts, polymorphs, hydrates or solvates thereof using novel combination of Continuous Stirred Tank Reactor (CSTR) and Plug Flow Reactor (PFR) which eliminates the drawbacks of prior art traditional process.

The another object of the present invention is to provide a cost effective and industrially feasible process for producing Pantoprazole, its optically active enantiomers, pharmaceutically acceptable salts, polymorphs, hydrates or solvates thereof, wherein the process provides high yield and high purity of the desired product by reducing the formation of impurity, preferably sulfone and sulfide impurity in a consistent and reproducible manner.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides an improved process for producing Pantoprazole, its optically active enantiomers, pharmaceutically acceptable salts, polymorphs, hydrates or solvates thereof comprising the steps of:
a) preparing solution A by dissolving Pantoprazole sulfide in a solvent;
b) preparing solution B by dissolving oxidizing agent in a solvent;
c) carrying out primary oxidation by reacting solution A and solution B in a continuous stirred tank reactor (CSTR);
d) carrying out secondary oxidation in a plug flow reactor (PFR);
e) quenching the reaction mass in a reactor;
f) optionally treating reaction mass with static mixture;
g) carrying out extraction in a solvent followed by concentrating the reaction mass to obtain the residue;
h) crystallizing the obtained residue in a solvent.
In another embodiment, the present invention provides an improved process for the preparation of Pantoprazole sodium sesquihydrate comprising the steps of
a) preparing solution A by dissolving Pantoprazole sulfide in solution containing sodium hydroxide, water and acetonitrile;
b) preparing solution B by dissolving sodium hypochlorite in water and sodium hydroxide;
c) carrying out primary oxidation by reacting solution A and solution B in a Continuous Stirred Tank Reactor (CSTR);
d) carrying out secondary oxidation in a Plug Flow Reactor (PFR);
e) quenching the reaction mass into sodium thiosulfate in Continuous Stirred Tank Reactor;
f) treating reaction mass with static mixture followed by extracting in methylene chloride;
g) concentrating the reaction mixture of step (f) to obtain the residue;
h) converting the residue into Pantoprazole sodium sesquihydrate by treating with sodium hydroxide and water.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1: Schematic presentation of the new design for process of preparation of Pantoprazole wherein it combines Continuous Stirred Tank Reactor (CSTR) and Plug Flow Reactor (PFR) for primary and secondary oxidation of Pantoprazole sulfide respectively followed by continuous quenching.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a commercially viable and economical process comprises a novel process design wherein it combines Continuous Stirred Tank Reactor (CSTR) and Plug Flow Reactor (PFR) for primary and secondary oxidation of Pantoprazole sulfide respectively followed by continuous quenching for producing Pantoprazole, its optically active enantiomers, pharmaceutically acceptable salts, polymorphs, hydrates or solvates thereof This new design provides desired product in high yield and high purity with enhanced in-process control on impurities specifically sulphone impurity in shorter reaction time.

The process according to the present invention for producing Pantoprazole, its optically active enantiomers, pharmaceutically acceptable salts, polymorphs, hydrates or solvates thereof comprising the steps of:
a) preparing solution A by dissolving Pantoprazole sulfide in a solvent;
b) preparing solution B by dissolving oxidizing agent in a solvent;
c) carrying out primary oxidation by reacting solution A and solution B in a Continuous Stirred Tank Reactor (CSTR);
d) carrying out secondary oxidation in a Plug Flow Reactor (PFR);
e) quenching the reaction mass in a reactor;
f) optional treating reaction mass with static mixture followed by extraction in a solvent;
g) concentrating the reaction mixture of step (f) to obtain the residue;
h) crystallizing the obtained residue in a solvent.
According to the present invention, the solvent used for the preparation of solution A is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol and the like; aromatic hydrocarbon such as toluene, xylene and the like, ethers such as diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; esters such as ethyl acetate, methyl acetate and the like, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aprotic polar solvents such as ?,?-dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, and the like; water or mixtures thereof.
According to the present invention, the preparation of solution A is carried out in presence of a base, wherein the base is selected from organic or inorganic. The organic base is selected from amines such as triethylamine, diisopropylamine, diisopropylethylamine, piperidine and the like, alkali metal alkoxide such as sodium methoxide, potassium methoxide and the like. The inorganic base is selected from the ammonia, alkali and alkaline earth metal carbonate, bicarbonate, hydroxide, hydride and the like wherein alkali and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, magnesium, calcium, barium and the like.
According to the present invention, the oxidizing agent in solution B is selected from the group comprising of hydrogen peroxide, alkyl hydro peroxide, aryl alkyl hydro peroxide, alkali or alkaline earth metal, hypohalite, wherein the alkali or alkaline earth metal is selected from a group comprising of sodium, lithium, potassium, magnesium, calcium and the halite is selected from the group comprising of fluorite, chlorite, bromite and the like. The solvent is selected form the group comprising of alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol and the like; aromatic hydrocarbons such as toluene, xylene and the like, ethers such as diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; esters such as ethyl acetate, methyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aprotic polar solvents such as ?,?-dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, and the like; water or mixtures thereof.
According to the present invention, the preparation of solution B is carried out in presence of a base, wherein the base is selected from organic or inorganic. The organic base is selected from amines such as triethylamine, diisopropylamine, diisopropylethylamine, piperidine and the like, alkali metal alkoxide such as sodium methoxide, potassium methoxide and the like. The inorganic base is selected from the ammonia, alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, hydride and the like wherein alkali and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, magnesium, calcium, barium and the like.
According to the present invention, the oxidation reaction is carried out in a continuous mode, wherein the reactor carries material as a flowing stream and reactants are continuously fed into the reactor and emerge as continuous stream of product.
According to the present invention, primary oxidation of Pantoprazole sulfide is carried out by reacting solution A and solution B in a Continuous Stirred Tank Reactor (CSTR). The reaction is carried out by simultaneous feeding of two streams at a temperature of -20 to 100°C. Further, secondary oxidation is carried out in Plug Flow Reactor (PFR).
According to the present invention, prior to the reaction in step (d), the plug flow reactor maintained at 0-5°C. The flow rate is adjusted to obtain the sulfide left unreacted is less than 2% by qualitative HPLC analysis.
According to the present invention, quenching in step (e) is carried out in a reactor by passing sodium thiosulfate solution. The quenching is carried at a temperature of 10 to 30°C. The reactor is selected from Continuous stirred tank reactors.
According to the present invention, static mixture is consists of mixture of solvents and solvent is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol and the like; aromatic hydrocarbon such as toluene, xylene and the like, ethers such as diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; esters such as ethyl acetate, methyl acetate and the like, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aprotic polar solvents such as ?,?-dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, and the like; water or mixtures thereof.
The static mixture is used in the present invention helps to maintain continuous quenching of reaction mass.
The solvents used in step (f) and (h) is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol and the like; aromatic hydrocarbon such as toluene, xylene and the like, ethers such as diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; esters such as ethyl acetate, methyl acetate and the like, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; aprotic polar solvents such as ?,?-dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, and the like; water or mixtures thereof.
The major advantages noticed in the present invention as compared to prior art batch processes are high yield, high purity, consistency, absence or least formation of sulphone, sulfide and/or unknown impurity.
These distinctively identified advantages of the reactions in reactor are due to continuous flow nature of the reaction and novel process design having combination of Continuous Stirred Tank Reactor (CSTR) and Plug Flow Reactor (PFR) for primary and secondary oxidation of Pantoprazole sulfide respectively, followed by continuous quenching thereby reduces the contact time between desired product and the oxidizing agent.
The present invention is further described in greater detail as illustrated in the non- limiting examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein.
EXAMPLES
Example 1: Preparation of Pantoprazole Sodium Sesquihydrate
PREPARATION OF SOLUTION - A:
Solution A: In a round bottom flask, 26.3 g of sodium hydroxide was charged followed by 280 ml DM water at 25-30°C and 400 ml of Acetonitrile was added. The reaction mass was stirred for 10 min. and 240.0 g of Pantoprazole sulphide wet material was added at 25-30°C. This reaction mass was stirred for 15-30 min at 25-30°C. After defined Stirring Solution will go for clear solution.

PREPARATION OF SOLUTION - B:
Solution B: In a round bottom flask, 9.4 g sodium hydroxide was dissolved in 50 ml DM Water at 25-30°C and cooled to 0-5°C. The 1625 g of sodium hypochlorite was added to above sodium hydroxide solution at 0-5°C and stirred for 10-15 min at 25-30°C.
The above separately prepared Solution-A and Solution-B feed through continuously CSTR (Continuous Stirred Tank Reactor) at 0-5°C and then feed in to PFR at 0-5°C for formation of Pantoprazole Sodium. The eluting reaction mass from PFR was continuously quenched by the aqueous solution of sodium thiosulphate solution (25.6 g sodium thiosulphate was dissolved in 1140 ml DM water) in another CSTR (Continuous Stirred Tank Reactor) at 15-20°C. The reaction mass feed into removable static mixture. The organic layer separated and aqueous layer was collected. pH of aqueous layer was adjusted to 10±0.5 with diluted acetic acid at 20-25°C and aqueous layer was extracted with methylene chloride (650 ml x 2 times). Organic layers were combined and washed with DM water. Sodium hydroxide solution was added to the organic layer at 25-30°C and stirred for 3 to 4 hours. The precipitate was formed. The solvent was distilled under vacuum completely at 35-40°C and 375 ml of Acetonitrile was added to distillated mass at 25-30°C.The temperature of reaction mass was raised to 45-50°C to get clear solution in 10-15 minutes. Slowly cooled to 25-30°C in an hour. 8 ml of DM water was added and reaction mass was seed with pure Pantoprazole Sodium Sesquihydrate. The reaction mass was stirred for 2 hours at 0-5°C. The solid was filtered and dried under vacuum at 40-45°C to obtain titled compound.
Output weight: 135.0 g
Yield: 1.35 (w.r.t Pantoprazole Chloro compound)
HPLC Purity: 99.80%
Sulphone impurity: 0.03%
Sulphide impurity: 0.01% ,CLAIMS:WE CLAIM:

1. A process for the preparation of Pantoprazole, or its pharmaceutically acceptable salts comprising the steps of:
a) preparing solution A by dissolving Pantoprazole sulfide in a solvent;
b) preparing solution B by dissolving oxidizing agent in a solvent;
c) carrying out primary oxidation by reacting solution A and solution B in a Continuous Stirred Tank Reactor (CSTR);
d) carrying out secondary oxidation in a Plug Flow Reactor (PFR);
e) quenching the reaction mass in a reactor;
f) optional treating reaction mass with static mixture followed by extraction in a solvent;
g) concentrating the reaction mixture of step (f) to obtain the residue;
h) optionally, crystallizing the obtained residue in a solvent.
2. The process as claimed in claim 1, wherein step a) and b) are carried in the presence of base.

3. The process as claimed in claim 1, wherein the solvent used at any stage is selected from same or different solvent of water, alcohols, esters, ethers, ketones, nitriles, acyclic, cyclic and aromatic hydrocarbons, chlorinated solvents, aprotic polar solvents and mixtures thereof.

4. The process as claimed in claim 4, wherein the solvent used at step a), b), f) and h) is selected from water, methylene chloride, and acetonitrile and mixture therof.

5. The process as claimed in claim 1, wherein the oxidizing agent in solution B is selected from peroxides, hypohalites or mixtures thereof,

6. The process as claimed in claim 5, the oxidizing agent is sodium hypochlorite.

7. The process as claimed in claim 1, wherein the quenching of the reaction mass of step e) is carried out by using sodium thiosulfate in Continuous Stirred Tank Reactor.

8. The process as claimed in claim 1, wherein static mixture is mixture of solvents selected from the water, alcohols, esters, ethers, ketones, nitriles, acyclic, cyclic and aromatic hydrocarbons, chlorinated solvents and aprotic polar solvents.