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PROCESS FOR THE PREPARATION OF S-OMEPRAZOLE AND ITS SALT

IP.com Disclosure Number: IPCOM000201306D
Publication Date: 2010-Nov-10
Document File: 17 page(s) / 88K

Publishing Venue

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Abstract

The present disclosure relates to a process for the preparation of S-omeprazole or its salt having defined enantiomeric excess. The present disclosure also relates to a method of preparing S-omeprazole or its salt having enantiomeric excess of about 99.7% or below from S-omeprazole or its salt having enantiomeric excess of about 99.8% or above.

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PROCESS FOR THE PREPARATION OF S-omeprazole AND ITS SALT

Abstract

The present disclosure relates to a process for the preparation of S-omeprazole or its salt having defined enantiomeric excess.  The present disclosure also relates to a method of preparing S-omeprazole or its salt having enantiomeric excess of about 99.7% or below from S-omeprazole or its salt having enantiomeric excess of about 99.8% or above.

Omeprazole is chemically referred as 5-methoxy-2-[[(4methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H­benzimidazole of Formula I.  Omeprazole is a mixture of the S- and R-isomers referred as S-omeprazole and R-omeprazole respectively.

FORMULA I

The S-omeprazole is also known as esomeprazole and is chemically referred as 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}benzimidazol of Formula II.

Formula II

S-Omeprazole is available in the market in the form of sodium or magnesium salt for the treatment of Gastroesophageal Reflux Disease (GERD), risk reduction of NSAID-associated gastric ulcer and pathological hypersecretory conditions including Zollinger-Ellison syndrome.  In combination with amoxicillin and clarithromycin, it is useful for the treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori.

The processes for preparing esomeprazole, or its salts are provided in European Patent Nos. 1,020,461; 1,856,101; 1,948,637; and 1,607,395; PCT Publication Nos. WO 94/27988; 97/02261; and 96/02535.

WO 92/08716 describes a separation method of the enantiomers of omeprazole, wherein the method involves chromatographic separation of the enantiomers of omeprazole as diastereomeric ether derivatives and subsequent hydrolysis.  WO 94/27988 describes a separation method of the enantiomers of omeprazole, wherein the method involves chromatographic separation of the enantiomers of omeprazole as mandeloyl derivatives and subsequent hydrolysis.  WO 94/27988 also provides processes for preparing sodium and magnesium salts of S- and R-omeprazole.  The sodium salt of S-omeprazole is prepared by treating S-omeprazole contaminated with 3% of R-omeprazole with aqueous sodium hydroxide in the presence of 2-butanone and toluene.  The sodium salt of S-omeprazole is reported to have an enantiomeric excess of 99.8% or above.  The magnesium salt of S-omeprazole is prepared by treating the sodium salt of S-omeprazole with magnesium chloride in aqueous condition.  The magnesium salt of S-omeprazole is reported to have an enantiomeric excess of 99.9%.  According to WO 94/27988, the above enantiomeric excess of the magnesium salt of S-omeprazole is the same or better as the optical purity of the starting material.

WO 97/02261 and WO 96/02535 provide processes for the preparation of S-omeprazole by asymmetric oxidation.  The enantiomeric excess of the resultant S-omeprazole is enhanced by crystallizations and the removal of the racemate by filtration.

The processes for the preparation of S-o...