WO2003101452A1

WO2003101452A1 - Process for the preparation of highly pure rabeprazole sodium salt

Info

Publication number: WO2003101452A1
Application number: PCT/IN2003/000208
Authority: WO
Inventors: Dandala Ramesh; Sivakumaran Meenakshisunderam; K. Ray U.
Original assignee: Aurobindo Pharma Ltd.
Priority date: 2002-06-03
Filing date: 2003-06-02
Publication date: 2003-12-11
Also published as: WO2003101452A8; AU2003237598A1; AU2003237598A8

Abstract

A method for the preparation of (±)-sodium-2-[[[4-(3- methoxypropoxy)-3- methyl-pyridinyl]methyl]sulfinyl]-1H-benzimidazole(Rabeprazole sodium) of formula (I), which comprises dissolving Rabeprazole of Formula (II) in aqueous sodium hydroxide until complete dissolution has taken place and thereafter subjecting the so obtained solution to lyophilization to obtain highly pure Rabeprazole sodium of Formula (I) in dry form.

Description

TITLE

_PR_OC_{ESS F}O_R T_{HE PR}E_PARATION OF HIGHLY PURE RABEPRAZOLE SODIUM ^SAL^T

PRIOR ART

There are a large number of patents and patent applications disclosing differently substituted 2-(2-pyridinylmethylsulphinyl)-lH-benzimidazoles. This class of compounds is inhibitors of gastric acid secretion and hence is useful as anti-ulcer agents. Several methods are already known to prepare the same.

Rabeprazole sodium can be represented by the Formula I.

Formula I

US Patent 5,045,552 as well as WO 01/04109 have disclosed the preparation of Rabeprazole sodium by known traditional procedures, such as dissolution of the product in a mixture of stoichiometric quantity of aqueous sodium hydroxide and ethanol, evaporation of the solvent to remove water as an azeotropic mixture, drying the residue at low pressure and then crystallization of the residue with scantly polar solvent such as diethyl ether, tert-butyl methyl ether etc.

This procedure of preparing sodium salt has numerous disadvantages such as large volume of solvents is required to azeotropically remove water and to crystallize out the product, which are difficult to recycle or dispose of in an environmentally acceptable manner. A further disadvantage of this process is the presence of higher residual solvent content in the product resulting in lower potency. This method is not suitable for industrial scale preparation of Rabeprazole sodium.

OBJECTS OF THE INVENTION

It is therefore an object of this invention to propose an improved method for the preparation of Rabeprazole sodium without the use of organic solvents.

It is another object of present invention to avoid the evaporation of azeotropic mixture disclosed in the prior art.

It is a further object of the present invention to prepare highly pure Rabeprazole sodium in dry form, in quantitative yield and having higher potency.

We have studied the drawbacks of the prior art and the use of organic solvents complicates the preparation of Rabeprazole sodium and makes it commercially non-viable. After considerable studies, we have now unexpectedly discovered that the title compound can be easily prepared by using only an aqueous solution.

The instant invention provides an alternative simplified industrially viable process for the production of the compound of Formula I.

In accordance with this invention, Rabeprazole, (±)-2-[[[4-(3-methoxypropoxy)-3-methyl-2- pyridinyl]methyl]sulfιnyl]-lH-benzimidazole, of Formula II is dissolved in water having one

Formula II

equivalent of sodium hydroxide. The quantity of water is in the range of 3 to 7 parts by volume and preferably it is 5 parts by volume. The desired Rabeprazole sodium is obtained directly by lyophilizing the solution. Major advantages realized in the instant invention as compared to prior art are increased product purity and absence of residual solvent impurity. No solvent is required to isolate the product and hence no mother liquor is obtained which is difficult to regenerate. The solvent employed is only water, thus offering great ecological advantage. Apart from all these, quantitative yield of Rabeprazole sodium is obtained.

We now describe the invention with reference to the following Example:

Example

Sodium hydroxide (5.62 g) was dissolved in DM water (200 ml) and cooled to 4-5°C. Rabeprazole (50 g) was added and mixture stirred to obtain a clear solution. The solution was treated with 2 g of carbon DC-enoanticromos for 30 min at 5-10°C. Carbon was removed by filtration and residue washed with DM water (2x25 ml). The contents were lyophilized using standard method. Rabeprazole sodium was obtained as a white powder.

Yield: 52 g (97% of theory). Assay: 99.5%. No residual solvent was detected in the product by GC.

Claims

WE CLAIM

1. A method for the preparation of (±)-sodium-2-[[[4-(3-methoxypropoxy)-3-methyl- pyridinyl]methyl]sulfinyl]-lH-benzimidazole (Rabeprazole sodium) of Formula I,

Formula I

which comprises dissolving Rabeprazole of Formula II

Formula II

in aqueous sodium hydroxide until complete dissolution has taken place and thereafter subjecting the so obtained solution to lyophilization to obtain highly pure Rabeprazole sodium of Formula I in dry form.

2. A method according to Claim 1 wherein exactly one mole equivalent of sodium hydroxide as to Rabeprazole of Formula II is used.

3. A method according to Claim 1, wherein the quantity of water used is 3 to 7 parts by volume and preferably 5 parts by volume of Rabeprazole of Formula II.

4. A method substantially as herein described.