AN IMPROVED PROCESS FOR THE PREPARATION OF RABEPRAZOLE
This invention relates to a process for synthesizing Rabeprazole Field of the Invention
This invention relates to a process for synthesizing Rabeprazole of formula (1) which is available in market under the brand name ACIPHEX® in its sodium salt form i.e. Rabeprazole sodium, which is used to prevent or treat peptic ulcers. The present invention particular!}, relates to a process whereby the Rabeprazole is produced in high yields and high purity. The present in\enlion more particularly relates to a process that is cost effective. Furthermore, the process disclosed in this invention is more compatible to the economics of manufacturing of the title compound and can be scaled up eventually leading to the commercialization of a process for the manufacture of Rabeprazole Sodium advantageously.

Background of the invention
Rabeprazole sodium is a proton pump inhibitor which can produce profound and sustained inhibition of gastric acid secretion with responses of Proton pump inhibitors being more rapid when compared with other anti-secretory drugs. Proton pump inhibitors work by inhibiting the production of stomach acid, by shutting down a system in the stomach known as proton pump (Hydrogen ■ ■ Potassium adenosine triphosphate enzyme system).


HP0268956 A2 and WO0K14I09 have disclosed the preparation of Rabeprazole. It describes the synthesis of Rabeprazoie sulphide. Rabepnrzoie ba.se and its sodium salt. Rabepra7ole sulphide ("2-[{4-(3-mcthox) propoxy)-3 -methyl pyridme-2-yl} methyl thio]-1T-benzimidazoIe) is prepared by condensation of 2- chloromcthyl-4-[3-methoxy propoxyi -3 -methyl pyridine and 2-mercapto benzimidazolc in cthanol by using sodium hydroxide. This mixture is stirred al 50° C for 3 hours. The solvent is distilled to obtain residue which is further purified by column chromatography using silica gel.
Rabeprazole is prepared by oxidizing 2- 4-(3-methoxy propoxy )-3 -methyl pvridine-2- methyl t|-Hl-ben7irnida/ole with m-('hioroperbenoic acid to afford the Rabepra/olc base and it is converted into Rabeprazole sodium.
WO 02/062786 discloses a process for preparation of Rabeprazole substantially free of a sulphone by-product therein the oxidation is carried out using tertiary butyl hydroperoxide in the presence of vanadyl his-acetyl acetonatc catalyst.
PCT Application PCT/CiH2O04/0Q0064 and International Publication Number WO
2004/063188 Al. discloses the preparation of Rabeprazole and benzimidazolc type of compounds. Accordingly Rabeprazole base is prepared by oxidizing Rabeprazole sulphide using sodium hypohalines. alkali lndroxide. presence of organic bases.
All the above processes disclosed in prior an are giv ing less \ ields id' Rabeprazole base, to overcome this, as a result of intense research, the inventors have arrived at an improved process for the preparation of Raheprazoie by using an oxidizing agent and suitable base m presence of water miseihle organic solvent. Water immiscible organic solvent was added to the reaction mixture and it was removed by distillation before

adjusting the pH of the reaction. Rabeprazole base obtained by direct precipitation or solvent extraction. Further. Rabeprazole base was reenstallised from chlorinated solvents and ethers, whie It abnormal \\ increase the fiield of the Raheprazolc base.
Summary of the: Invention
'' The" main objective of the present invention is to provide 2-(({4-{3-Methoxypropoxy)-3-methyl-2-p\ridin\i)methyl)sulfinyH-lH-ben2imidazole(i.e. Rabeprazole) of formula (1).

in high yields and high purity.
Another objective of the present invention is to provide commercially useful process to
afford Rabeprazole base, from which we can prepare Rabeprazole sodium.
Detailed Description of the Invention
i he main objective of the present invention U to pan ide 2-(((4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl)methyl)sultinyl)-lH-benzimidazole(i.e. Rabeprazole) of formula
in high yields and high purity.
Another objective of the present invention is to provide commercially useful process to
afford Rabeprazole base, from which we can prepare Rabeprazole sodium.
The present process for the preparation of Rabeprazole from Rabeprazole sulphide is
described below.

2-{(4-(3-methoxy propoxy)-3-methyl pyridine2-yl) methyl thio}-lH-benzo[d]imidazole (i.e. Rabeprazole sulphide) was added to a solution of alkali metal hydroxide and alcohol was added to the above solution. To this, a solution of alkali hypohalites was added at -30 to +10 °C. After completion of the reaction. Sodiumthiosulphate was added to the reaction mixture, stirred for 15 min and washed with water immiscible organic solvent. The reaction mixture was concentrated under reduced pressure to remove the organic solvents, and to this, again the water immiscible organic solvent was added and" the pH of the reaction mixture was adjusted to 7.5-8,5 by adding dilute acetic acid. The Rabeprazole base was isolated by filtration and dried under reduced pressure at a temperature not more than 40 - 60 °C. The yield of the Rabeprazole was about 90%.
Alternate way of preparing Rabeprazole was by directly isolating it from the reaction mixture without adding any water immiscible solvents. The obtained Rabeprazole extract was recrvstallised from chlorinated solvents and ethers like 1.4-dioxane. diethyl ether. MTBC. mosl preferably MTBI'. The process is schematically represented as below


water) and Methanol (400mU was added to the above solution. The reaction mixture was cooled to about 0° C and solution of Sodium Hypochlorite (620mL. l.Oeq, Assay 3.5%) was added to it for about 1 V-_ --2 hr at 0-5° C. After completion of the reaction, pellets of Sodiumthiosulphate (10g) were added to reaction mixture and stirred for about 15 min. Water (2000mL) was added to the reaction mixture and brought to 25- 30° C. The reaction mixture was washed twice with DCM (200.0ml..)- The reaction mixture was concentrated under reduced pressure up to approximate volume of 3100ml. DCM (300ml) was added to it. The reaction mixture was cooled to 5°C and pH adjusted to 8.1 by adding 50% acetic acid (75ml). Temperature was raised to 25 -30° C and the organic layer was separated from the aqueous layer. DCM (200mL) was added to it, stirred for 15 min and the organic layer was separated. To the combined DCM layers, activated carbon (5g) was added and stirred for 15 minutes. It was filtered and washed with DCM (150mL). The organic layer was concentrated under reduced pressure up to approximate volume of 200ml. Methyl tert.butyl ether (400ml) was added to the residue and stirred for 30 minutes at 0 - 5° C. The solid obtained was filtered and washed with 1:4 mixture of dichloromethane: methyl tert.butyl ether (200ml) and dried at 45° C under vacuum to obtain Rabeprazole compound. Yield: 85 g. Purity: 99.33%. Sulphone impurity: 0.09%
Example 2 Process for the preparation of Rabenrazole
2-{(4-(3~methoxy propoxy)-3-methyi p\ridine2-yl) methyl thio}-lH-benzo[d]imidazole (100g7 l.Oeq) was added to a solution of Sodium Hydroxide (50.Og. 4.3eq: in 400ml water). Methanol (400mL) was added to the above solution and stirred for dissolution. Reaction mixture was cooled to about 0°C and a solution of Sodium Hypochlorite ((2500ml. 1.5%) was slowly added to it at 0- 5T. After completion of the reaction. Sodiumthiosulphate (lOg) was added to reaction mixture and stirred for about 15min and the temperature of the reaction mass was brought to 25- 30 °C. The reaction mixture was washed with dichloromethane. The reaction mixture was subjected to methanol recovery

under reduced pressure. DCM was later added to it and the reaction mixture was cooled to 5°C. the pH was adjusted to 7.9 with dilute acetic acid. The organic layer was separated and the aqueous layer was re-extracted with more DCM. The combined organic layers were concentrated under reduced pressure and precipitated over methyl tert butyl ether. The solid obtained was filtered and washed with a solution of dichloromethane and methyl tert butyl ether and dried at 45 °C under vacuum to obtain "Rabeprazole compound. Yield: 87g. Purity: 99.32%, Sulphone impurity: 0.13%
Example 3 Process for the preparation of Rabeprazole sodium
2-{(4-(3-methoxy propoxyl-3-methyl pyridine2-yl) methyl sulfinyl }-lH-benzo[d]imidazole (20g) was added to a solution of sodium hydroxide in methanol (2.4g. in 40ml) and stirred to get a clear solution. The reaction mixture was subjected to carbon treatment. The filtered mother liquor was distilled completely and the resultant residue was dissolved in dichloromethane and precipitated over diisopropyl ether. The reaction mixture was filtered and washed with diisopropyl ether. The obtained solid was dried at 40-45 °C under reduced pressure to obtain the product as a white amorphous solid. Yield: 20 g. Purity.99.42 %. sulphone impurity: 0.16%
Example 4 Process for the preparation of Rabeprazole sodium
2-{(4-(3-methoxv propoxy)-3-methyl p\ridine2-yl) methyl sulfinyl }-lH-benzo[d]imidazole (60 g) was added to a solution of sodium hydroxide in methanol (7.2 g. in 120ml) and stirred to get a clear solution. The reaction mixture was subjected to carbon treatment. The filtered mother liquor was distilled completely and the resultant residue was dissolved in dichloromethane and precipitated over methyl tert butyl ether.

The reaction mixture was filtered and washed with methyl tert butyl ether. The obtained
solid was dried at 40-45 °C under reduced pressure to obtain the product as a white
amorphous solid.
Yield: 60.5 g.
Purity: 99.35%. sulphone impurity: 0.23%
Example 5 Process for the preparation of Rabeprazole sodium
2-{{4-(3-metboxy propoly)-3-methyl pyridinc2-y]) methyl sulfiny) ]--]H-benzo[d]imidazole (60g) was added to a solution of sodium hydroxide in methanol (7.2g. in 120ml) and stirred to get a clear solution. The reaction mixture was subjected to carbon treatment. The reaction mass was cooled to 0-5 °C. The temperature and vacuum of ATFD was adjusted to 50-55 °C and 45-50 Torr respectively. The chilled reaction mixture was kept in the ATFD instrument and the resultant solid was collected in the product collector under nitrogen atmosphere. The obtained solid was dried at 50-55 °C under reduced pressure to obtain the product as a white amorphous solid. Yield: 53 g. Purity: 99.5%. sulphone impurity: 0.30%
We Claim:
1. Process for the preparation of 2-(((4-(,3-Methoxypropoxy)-3-methyl-2-pyridinyl)methyl)sulfinyI)-lH-benzimidazo!e(i.e. Rabeprazole) comprising the steps of
a) Oxidizing the 2-{(4-(3-methoxy propoxy)-3-methyl pyridine2-yl) methyl thio]-lH-benzo[d]imidazole(i.e. Rabeprazole sulphide) with sodium hypohalite solution in a mixture of water and water miscible solvent using alkali metal hydroxide at temperature range of-10 to 25 °C.
b) Washing the reaction mixture using water immiscible organic solvents.

c) Concentrating the reaction mixture up to 1 to 5 volumes under reduced pressure at room temperature to 50°C.
d) pH of the reaction mixture adjusted to 7.5 - 8.5 by adding dilute organic acid.
e) Extracting of Rabeprazole with organic solvents.
f) Concentrating the extract.
g) Isolation of Rabeprazole by using ami solvents.
2. The process as claimed in claim I. the oxidizing agent is selected from the group
consisting of sodium hypochlorite, sodium expebromine and calcium In noehiorite.
3. The process as claimed in claim 1. wherein the said water misciblc solvent is selected
from the group consisting of C1-C3 alcohols, preferably methanol, ketones and nitriles.
4. The process as claimed in claim 1. wherein said alkali metal hydroxide is lithium
hydroxide. Sodium hydroxide, potassium hydroxide.
5. The process as claimed in claim 1. wherein the said oxidation is carried out at a
temperature of 0 to 25 °C.
6. 'the process as claimed in claim L wherein the said water immiscible solvnt is
selected from chloroform, dichloromethane. ethyl] acetate and the like, most preferably
d ichloro methane.
7. ■ The process as claimed in claim 1. wherein the said anti-solvent is selected from
Heptane. Hexane. pentane. disopropylether. MTBR and mixture thereof,