FORM 2 THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]
"IMPROVED PROCESS FOR PREPARATION OF PROTON PUMP INHIBITORS"
(a) CIPLA LTD.
(b) 8, Bellasis Road, Mumbai Central, Mumbai - 400 008, 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:

DUPLICATE
58-MUM-2003
15-01-2003
2 2-12-2003

IMPROVED PROCESS FOR PREPARATION OF PROTON PUMP INHIBITORS
FIELD OF THE INVENTION
This invention relates to an improved process for preparation of proton pump inhibitors, more particularly to a simple and cost effective, eco-friendly and green chemistry process for oxidation of sulphides.
BACKGROUND OF THE INVENTION
Gastric Proton Pump Inhibitors (PPIs) are compounds having several substituted 2-(2-
pyridylmethyl)-sulfinyl-lH-benzimidazoles such as Lansoprazole (2-[[[3-methyl-4-
(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl] lH-benzimidazole, Omeprazole ((5-
methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]sulfinyl]-lH-benzimidazole,
Pantoprazole ((5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl] 1H-
benzimidazole and Rabeprazole (2-[[[4-(3-methoxy-propoxy)3-methyl-2-
pyridinyl]methyl]sulfinyl]-lH-benzimidazole. These compounds produce profound and sustained inhibition of gastric acid secretion. Responses of PPIs are more rapid than with other anti-secretory drugs. The PPIs work by completely blocking the production of stomach acid. They do this by inhibiting or shutting down a system in the stomach known as proton pump, the full name of which is "hydrogen-potassium adenosine triphosphate enzyme system". PPIs are the drug of choice in dyspepsia and peptic ulcers. In the treatment of peptic ulcers, the RRs of PPIs are superior to other drugs. PPIs are also drugs of choice in Zollinger-Ellyson syndrome.
The reported synthesis of these substituted 2-(2-pyridylmethyl)-sulfinyl-lH-benzimidazoles principally involves generally an oxidation process of a sulfide compound to a sulfinyl compound of formula I.
2


Prior art processes addressed at the preparation of 2-(2-pyridylmethyl)-sulfinyl-lH-benzimidazoles involve the synthesis of the corresponding thioether compound, and its subsequent oxidation to the sulfinyl or sulfoxy compound, by various methods such as reaction with hydrogen peroxide over a vanadium compound catalyst and reaction with peracids, peresters, ozone. There are several disadvantages associated with the known processes, primarily with respect to the nature of the thioether (or sulfide) compound being oxidized.
US Patent No. 4,628,098 to Nohara, et al. discloses a process for preparation of Lansoprazole by oxidation of its sulphides using peracids (m-chloro perbenzoic acid). The object of this invention was to prepare an anti-ulcer agent having actions of inhibiting gastric acid secretion, of protecting gastric mucosa and of antagonizing ulceration.
US Patent No. 5,840,552 to Holt, et al. discloses a process for preparation of Lansoprazole wherein sulphides are selectively bio-oxidised to isolate the pharmaceutically active enantiomer or enantiomerically enriched sulfoxide form, using microorganisms or microbial enzyme system.
US Patent No. 5,374,730, to Slemon, et al discloses a process for the preparation of Omeprazole and Lansoprazole wherein amide analogues of the thioether compounds are readily oxidized to the corresponding sulfinyl compounds and the sulfinyl compounds are hydrolyzed in alkaline medium to the corresponding carboxylic acid salts which can be decarboxylated to Omeprazole or Lansoprazole, as the case may be. The disclosure refers to the advantages in relation to the purity in which the final
3

products can be obtained, and the simplicity of the purification procedures. The amide compounds which are subjected to the oxidation step are crystalline solids, as opposed to oils, so that they are readily purified to a high degree of purity by relatively simply precipitation, crystallization and washing procedures. The carboxylates and carboxylic acid salts which are formed in the next synthetic step after oxidation are water soluble, whereas the final products, Omeprazole and Lansoprazole, are not. Accordingly, any un-reacted residues of these compounds and many other minor impurities in the final products are simply removable by an aqueous washing procedure. Avoidance of significant discoloration of the product is the other advantage disclosed.
US Patent No. 5,470,983 to Slemon, et al. titled 'Preparation of Omeprazole and ansoprazole, and intermediates useful therein' discloses processes for producing Lansoprazole from acetamide-sulfide compounds by a process of oxidation to form the amide sulfinyl compound, followed by alkaline hydrolysis to the sulfinyl carboxylate or salt, and decarboxylation.
US Patent No. 5,502,195, to Slemon, et al. is a Continuation-in-Part of application Ser. No. 276,378, which is in turn a division US Pat. No. 5,374,730. This disclosure is addressed at a process for preparation of Lansoprazole, which is identical to the processes recited in US Patent No.5, 470,983, wherein the acetamide sulphide is oxidized to amide sulfinyl compounds, which is then hydrolysed in alkaline medium to the carboxylic acid salts and then decarboxylated to form Lansoprazole.
US Patent No. 6,423,846 to Moon, et al. refers to the oxidation procedures employed in the prior art methods for converting a compound into Lansoprazole as having problems in that many byproducts are formed and the yield of Lansoprazole is low. EP Patent No. 134,400, GB Patent No. 2,134,523, US Pat. No. 4,628,098, Korean Patent No. 52,837 discloses m-chloroperbenzoic acid as the oxidant. Spanish Patent Nos. 550,057; 540,147 and 539,793 disclose sodium periodate, iodosomethylbenzene and iodosobenzene, respectively, as the oxidant employed. These prior art processes have been cited to be unviable because of the expensive oxidants used therein which is also resulting in the
4

production of many impurities and a low yield of the product in the range of about 60 to 80%.
All these prior art process either use expensive catalysts or hazardous oxidizing reagents such as peracids which are not suitable for commercial manufacture of these compounds. Also over-oxidation of the thioether compound to the corresponding sulphone analogue is a common problem encountered with prior art processes.
There has been a long felt need for efficient and safe methods for the selective oxidation of a sulphide compound of the formula II

to a sulfinyl compound of the formula I. The present invention provides an efficient, safe and industrially feasible method for preparing various substituted 2-(2-pyridylmethyl)-sulfinyl-1 H-benzimidazoles.
OBJECTIVES
The object of the present invention is to provide an improved process for selective oxidation of (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]thio] 1H-benzimidazole to the corresponding (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyI]-sulfinyl]lH-benzimidazole (Lansoprazole), using an eco-friendly, inexpensive and readily available reagent
Further object of the present invention is to provide an improved process for selective oxidation of ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]-thio]-lH-benzimidazole, to the corresponding ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
5

pyirdyl)methyl]-sulfinyl]-lH-benzimidazole (Omeprazole), using an eco-friendly, inexpensive and readily available reagent.
Other object of the present invention is to provide an improved process for selective oxidation of ((5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio] 1H-benzimidazole, to the corresponding ((5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl]lH-benzimidazole (Pantoprazole), using an eco-friendly, inexpensive and readily available reagent.
Other object of the present invention is to provide an improved process for selective oxidation of (2-[[[4-(3-methoxy-propoxy)3-methyl-2-pyridinyl]methyl]-thio]-lH-benzimidazole, to the corresponding (2-[[[4-(3-methoxy-propoxy)3-methyl-2-pyridinyl]methyl]-sulfinyl]-lH-benzimidazole (Rabeprazole), using an eco-friendly, inexpensive and readily available reagent.
SUMMARY OF THE INVENTION
The present invention provides a process for preparing a sulfmyl compound of the

formula I
Wherein R1 and R3 are selected from hydrogen, methyl or lower alkoxy , R2 are selected from substituted or unsubstitued lower alkoxy and R4 are selected from hydrogen or substituted or unsubstitued lower alkoxy,
Comprising oxidation of a sulfide compound of the formula II
6


Wherein R1, R2, R3 and R4 have the same meaning as mentioned above to produce by selective oxidation compound of the formula 1
The present invention further provides a process for preparing a sulfinyl compound of the formula I, comprising reacting a sulfide compound of the formula II with aqueous hypochlorite solution.
The present invention further provides a process for preparing a sulfinyl compound of the formula I, comprising reacting a sulfide compound of the formula II with aqueous hypochlorite solution optionally in the presence of a catalyst selected from pyridine, diisopropyl ethyl amine, N,N-dimethyl amino pyridine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing a sulfinyl compound of the

formula I
Wherein R1 and R3 are selected from hydrogen, methyl or lower alkoxy, R2 are selected from substituted or unsubstituted lower alkoxy and R4 are selected from hydrogen or substituted or unsubstituted lower alkoxy,
7

Comprising oxidation of a sulfide compound of the formula II

Wherein R1, R2, R3 and R4 have the same meaning as mentioned above to produce by selective oxidation compound of the formula I
In one embodiment, the present invention discloses a process for producing sulfinyl compounds. The process comprises dissolving or suspending the sulphide precursor in suitable solvents or mixture of solvents. Sodium hypochlorite is added slowly in a controlled manner at appropriate temperature conditions to give after simple work up procedures the sulfinyl compounds in very high yield and purity.
The present invention discloses a process for producing sulfinyl compounds comprising adding the corresponding sulphide to solvent, which solvent comprises water, lower alkyl alcohols, esters or ethers and chlorinated solvents or mixtures thereof. The preferred solvents are water, methanol, ethanol, isopropanol, di-isopropyl ether, dichloromethane, acetonitrile, ethyl acetate or mixture of two or more of these.
The process of the present invention is performed at temperatures varying from -30 to 50°C. However, the preferred temperatures are between 0°C to 30°C. Sodium hypochlorite as an aqueous solution is of varying strengths ranging from 2% to 30%, though we prefer to use a concentration in the range of 2% to 5% for ease of handling.
It is understood that the process of the present invention is performed using other related oxidizing agents such as sodium hypobromite or calcium hypochlorite.
8

The process of the present invention is performed optionally in the presence of suitable catalyst, organic amines such as pyridine, di-isopropyl ethyl amine, N,N-dimethyl amino pyridine to avoid formation of undesirable byproducts.
One can use commercially available sodium hypochlorite solutions, but it is advantageous to use a freshly prepared solution having about 0.5 % to 5 % of free sodium hydroxide. The presence of free sodium hydroxide not only stabilizes the hypochlorite but also has a positive impact on the reaction, since the products are known to be unstable to acidic conditions.
Alternatively, a solution of sodium hydroxide or any other alkali is added to the suspension or solution of the sulphide in the solvent or mixture of solvents before addition of the oxidizing solution.
The time taken for addition of the hypochlorite solution is range from several minutes to several hours depending on the strength of the solution and the exothermicity of the reaction. We prefer to perform the addition slowly over a period ranging from 30 minutes to 4 hours. The time taken for completion of the reaction can range from 2 hours to 10 hours.
The product is isolated from the reaction mass by adjusting the pH using aqueous organic or inorganic acids. Normally, the pH is adjusted between 6.0 to 9.5 more preferably between 7 to 7.5 using aqueous acetic acid, followed by filtration to isolate the product.
In another embodiment, the process comprises of purifying the resultant of process herein above described by dissolving it in mixture of methanol and aqueous sodium hydroxide solution. The pH of the clear solution is adjusted between 9.0 to 9.5 using aqueous ammonium acetate solution and product isolated by filtration.
The preferred compound prepared according to the process of the present invention is Lansoprazole.
9

The preferred compound prepared according to the process of the present invention is Omeprazole.
The preferred compound prepared according to the process of the present invention is Pantoprazole.
The preferred compound prepared according to the process of the present invention is Rabeprazole
The process of the present invention is illustrated by the following examples and in no way limits the scope of this invention. While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its scope, as defined by the appended claims
Example 1
Preparation of 2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl] methyl]-sulfinyl]-lH-benzimidazole Sodium. (Rabeprazole Sodium)
2-[[[4-(3-methoxy-propoxy)-3-methyl-2-pyridinyl]methyl]-thio]-lH-benzimidazole (10 grams) is suspended in 200 ml of purified water, sodium hydroxide (about 2gm) and pyridine (4 ml). To this is slowly added about 75 grams of approximately 3.8% sodium hypochlorite solution in 2 hours. The reaction mass is maintained at 5 - 8° C for 4 hours. After reaction completion, the excess sodium hypochlorite is decomposed using 5% aqueous sodium thiosulphate solution. The pH is adjusted between 8.0 to 9.0 using 10% ammonium acetate solution.
After pH adjustment the compound is isolated from the water layer by adding ethyl acetate followed by extraction. Concentrating said organic layer under vacuum yields a residue to which isopropyl acetate is added and stirred for about an hour's time, yielding
10

the desired product. The product is purified by dissolving it in a mixture of Acetone and triethylamine. The Rabeprazole base so obtained is dissolved in ethyl acetate and methanolic ammonia mixture to which methanolic sodium hydroxide is added and distilled off to a thick residue at low temperature. This is again redissolved in ethyl acetate and Rabeprazole sodium salt is isolated in solvent such as n-heptane/ n-hexane and dried.
Example 2
Preparation of 5-(difluoromethoxy)-2-[[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-lH-benzimidazole. (Pantoprazole)
5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]-thio]-lH-benzimidazole (10 grams) is dissolved in purified water (100 ml) and methanol (10 ml). 80 grams of 3.5% aqueous sodium hypochlorite solution having sodium hydroxide content upto 2.4-2.8% is added to the reaction mass maintaining 5 - 8° C in about 1 hour. Excess hypochlorite is decomposed using 5% aqueous sodium thiosulphate solution. pH of the reaction mass is adjusted to 8.0 - 9.5 using ammonium acetate. The solids are filtered, washed with chilled water and dried in an oven to give 8.5 g of the title compound.
Example 3
Preparation of (2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]-sulfinyl]lH-benzimidazole (Lansoprazole)
(2-[[[3-methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]-thio]lH-benzimidazole (10 grams) is suspended in 100 ml of a mixture of acetonitrile and water (7:3). A solution of sodium hydroxide is added to this suspension. 61 grams of sodium hypochlorite solution (4.2%) is added over a period of 4 hours maintaining a temperature of 5°C - 10°C. Excess hypochlorite is decomposed using 3% aqueous sodium metabisulfite solution. Acetone (50 ml) is added and the pH is adjusted between 7.5 to-8.5 using dilute acetic
11

acid. The solids are filtered, washed with chilled water and dried in an oven to give 8 g of the title compound. The product is slurried in acetone followed by purification by dissolving it in a mixture of acetone and aqueous sodium hydroxide solution. The pH of the clear solution is adjusted to about 7.0 -8.0 using dilute acetic acid solution and product is isolated by filtration, slurried in water and dried in an oven to give about 7g of the desired product.
Example 4
Preparation of ((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]sulfinyl]-lH-benzimidazole, (Omeprazole)
((5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyirdyl)methyl]-thio]-lH-benzimidazole, (20 grams) is suspended in 200 ml of dichloromethane. 140 grams of sodium hypochlorite solution (chlorine content: 3.6- 4.2%; Sodium hydroxide content: 2.8 -3.0 %) is added over a period of 3 hours maintaining a temperature of -5°C to 0°C. The organic layer is separated and extracted with 200 ml of 5% sodium hydroxide solution. The pH of the aqueous layer is adjusted to between 8-8.5 using dilute acetic acid. The solids are filtered, washed with chilled water and dried in an oven to give 17g of the title compound.
12

We claim:
1. A process for preparing a pyridine benzimidazole sulfinyl compound of formula (I) wherein the said process comprises a sulfide compound for formula (II) added to a solvent to form mixture;
adjusted the pH in the range 9 to 12 of the said reaction mixture using alkali metal hydroxide solution;
cooled down the above said mixture to a controlled temperature; added oxidizing agent to the said mixture, in a controlled manner; maintained oxidation reaction at a controlled temperature for a pre-determined period;
adjusted the pH range of the said reaction mixture; and the final product of formula (I) is precipitated and isolated.

Wherein R1, R2,and R4 are each selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or un-substituted lower alkoxy and R3 is selected from the group consisting of hydrogen and substituted or un-substituted lower alkyl
13

2. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claim 1 wherein the solvent selected from water, methanol, isopropanol, acetonitrile, dichloromethane, and ethyl acetate or mixtures thereof.
3. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claim 1 wherein the oxidizing agent is a aqueous hypochlorite or a hypobromite solution.
4. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1 and 3 wherein the oxidizing agent is aqueous sodium hypochlorite solution.
5. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1, 3 and 4 wherein the concentration of the sodium hypochlorite solution is between 2% to 5 %.
6. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1, 3, 4 and 5 wherein the sodium hypochlorite solution contains 0.5% to 5% of free sodium hydroxide.
7. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1, 3, 4, 5 and 6 wherein the oxidation is performed at a temperature ranging from -30 to 50°C.
8. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claim 1, wherein the addition of the hypochlorite solution is reaction is preceded by addition of an alkali solution. .

9. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed
in claim 1, wherein the reaction is performed optionally in presence of organic
14

bases selected from pyridine, diisopropyl ethyl amine, N,N-Dimethyl amino pyridine.
10. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claim 1 wherein the pH is adjusted in the range between 7.5 to 9.5 using dilute aqueous acid solutions or aqueous ammonium acetate solution.
11. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claim 1 where the pyridine benzimidazole sulfinyl compound is a proton pump inhibitor.
12. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1 to 11 wherein the pyridine benzimidazole sulfinyl compound is Omeprazole.
13. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1 to 11 wherein the pyridine benzimidazole sulfinyl compound is Lansoprazole
14. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1 to 11 wherein the pyridine benzimidazole sulfinyl compound is Pantoprazole
15. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1 to 11 wherein the pyridine benzimidazole sulfinyl compound is Rabeprazole.
16. A process for preparing a pyridine benzimidazole sulfinyl compound as claimed in claims 1 to 11 where in the pyridine benzimidazole sulfinyl compound is converted optionally to its pharmaceutically acceptable salts, hydrates and solvates thereof.
15

17. A pharmaceutical composition containing a pyridine benzimidazole sulfinyl
compound or its salt prepared according to any of the above claims.
18. A process for preparing a pyridine benzimidazole sulfinyl compound as
substantially described herein with reference to foregoing examples.
Dated this the 15th day of Jan 2003

DR. GOPAKUMAR G. NAIR
Agent for the Applicant
16