CLIAMS:We Claim:

1. A process for the preparation of N-methyl esomeprazole of formula IIa and IIb or pharmaceutically acceptable salt thereof,

Formula IIa Formula IIb

which comprises reaction of Esomeprazole sodium with dimethylsulphate in presence of inorganic base and solvent to provide N-methyl esomeprazole.

2. The process of claim 1, wherein the inorganic base is selected from the group of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate.

3. The process of claim 1, wherein the base is sodium hydroxide.

4. The process of claim 1, wherein the reaction of step a) conducted at a temperature of about 20 to about 35 °C.

5. The process of claim 1, wherein the solvent is selected from the group of water, alcohol, esters or combination thereof.

6. The process of claim 1, wherein the solvent is water.

7. The purity of compound of N-methyl esomeprazole according to claim 1, is greater than 95% by HPLC.

8. The process of claim 1, wherein the pharmaceutically acceptable salt compound of Formula II is Magnesium salt.

9. The process of claim 1, wherein the compound of formula II further subjected to demethylation to provide pure esomeprazole or its pharmaceutically acceptable salt.
,TagSPECI:4. DESCRIPTION

The present invention provides a process for preparing impurity of Esomeprazole or its pharmaceutically acceptable salt, for example, N-methyl esomeprazole known as mixture of isomers of Formula IIa and Formula IIb, which is useful as reference marker or a key intermediate to quantify its presence in Esomeprazole.

Formula IIa Formula IIb

Esomeprazole Magnesium, chemically known as bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl)
magnesium trihydrate of Formula I:

Formula I

Esomeprazole Mg is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and Zollinger-Ellison syndrome. Esomeprazole is the S-enantiomer of omeprazole.

U.S. Patent No. 4,255,431 discloses Omeprazole and therapeutically acceptable salts thereof. US 4,738,974, US 5,714,504 and US 5,877,192 discloses specific alkaline salts of omeprazole.

PCT application No. 94/27988 discloses resolution processes of racemates of omeprazole. The process involves enantioselective synthesis of the sulfoxide either as a single enantiomer or in an enantiometrically enriched form.

Various patent references, for example, WO 96/02535, US 6369085, WO 04/02982, WO 04/046134, etc.., discloses a process for the preparation of esomeprazole magnesium salt.

WO 2011/140446 A2 discloses a particulate pharmaceutical composition comprising esomeprazole or its pharmaceutically acceptable salts, wherein levels of one or both of impurity A (desmethoxydehydro) and impurity C (N-methylomeprazole), as described herein, are less than about 5%, or less than about 1 %, of the label esomeprazole content.

Shin jai Moo et al., in Journal of the American Chemical Society (2004), 126(25), 7800-7811 discloses N-methylation of 2-methylsulfinyl benzimidazoles using dimethyl sulfate in presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in dicloromethane followed by purification using expensive column chromatography technique.

However, the prior art does not provide any directions to prepare pure compound of N-methyl omeprazole or N-methyl esomeprazole, which will be useful as reference marker for Esomeprazole and omeprazole.

The skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).

To use of a compound as a reference marker requires recourse to a sample of substantially pure compound.

Therefore, there is a need to develop a simple and inexpensive process to provide pure compound of isomers of formula IIa and formula IIb, which will be useful as reference marker as well as a key intermediate to provide pure esomeprazole.

The present inventors developed a simple, conventional and industrial feasible process to provide compound of Formula IIa and IIb or pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides a process for the preparation of N-methyl esomeprazole of formula IIa and IIb or pharmaceutically acceptable salt thereof, which comprises reaction of Esomeprazole sodium with dimethylsulphate in presence of inorganic base in presence of solvent to provide N-methyl esomeprazole.

The suitable inorganic base used for the methylation reaction includes but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and the like. In an embodiment, the present invention utilizes sodium hydroxide as an inorganic base for formation of N-methyl esomeprazole.

The solvent of the present invention may selected from the group of water, alcohol such as methanol, ethanol, isopropyl alcohol, and the like; esters such as ethyl acetate, isopropyl acetate and the like; and mixtures thereof. In an embodiment, the present invention involves use of water for the conducting the reaction.

The reaction may be conducted at a temperature of about 20 to about 60 °C for period of about 2 to 3 hours or more. The reaction of the present invention is conducted preferably at room temperature in presence of water and sodium hydroxide.

The resultant compound of the present invention may have the purity greater than 95% determined by HPLC.

The pharmaceutically acceptable salt of the present invention includes magnesium, calcium, barium, strontiium, amino acid such as L-glutamic acid, L-lysine, L-glycine, arginine and the like or derivatives of amino acids.

The compound of Formula IIa and Iib of the present invention is reacted with demethylation reagents to provide pure esomeprazole or its pharmaceutically acceptable salt as per the process known in the art. The demethylated reagents may be selected from BeCl2, boran tribromide, Alkali organomides [for example, NaN(SiMe3)2], SnO2, methane sulfonic acid in presence of oscillating electromagnetic field.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLE:

Example-1: Process for the preparation of N-methyl esomeprazole

To the solution Esomeprazole sodium (20 g) and sodium hydroxide (2 g) in water (100ml) at room temperature, was added dimethylsulphate (8.2 g). The reaction mass was stirred for 3hours and the precipitated product was filtered, washed with water and dried. The amount of the methylated product obtained was 6 g.

The HPLC analysis showed a mixture of isomers with a purity of 8.5 % (RRT1.06) and 91.45% (1.08 RRT) respectively. This was further confirmed by spiking in HPLC with the sample containing the impurities.

The structures both are isomers, based on the analytical data.

1H NMR (400 MHz, CDCl3): d 2.2(3H, s), 2.27(3H,s), 3.69(3H,s), 3.89(3H,s),3.94(3H,s), 4.91(2H,s), 6.78(1H,d), 6.94-6.97(1H,dd), 7.67(1H,d), 8.11(1H,s).

Mass: 360.2 (M+1).