Process for the preparation of a magnesium salt of a substituted

Details Process for the preparation of a magnesium salt of a substituted Process for the preparation of a magnesium salt of a substituted

1997-07-10

2000-09-26

Fan, Jane

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546118, 5483037, C07D40112

Patent

active

061244643

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/SE97/00674 Apr. 22, 1997 now WO 97/41114 Nov. 6, 1997.


FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of magnesium salts of substituted sulfinyl heterocyclic compounds containing an imidazole moiety as well as the use of the produced magnesium salts in medicine. More particularly, the present invention relates to the preparation of magnesium salts of substituted benzimidazoles such as the magnesium salts of omeprazole and of its single enantiomers.


BACKGROUND OF THE INVENTION AND PRIOR ART

Substituted benzimidazoles such as for instance the compounds with the generic names omeprazole, lansoprazole, pantoprazole, pariprazole and leminoprazole have properties making the compounds useful as inhibitors of gastric acid secretion. This class of compounds is known as proton pump inhibitors of H.sup.+ K.sup.+ ATPase inhibitors. There are a large number of patents and patent applications disclosing such proton pump inhibitors and processes for their preparation.
There is a general need in industry that pharmaceutically active compounds should be produced by processes giving products with properties making them suitable for pharmaceutical preparations, such as being easy to handle in a full scale production and having good storage stability.
WO 95/01977 discloses a novel magnesium salt of omeprazole with a specific degree of crystallinity making the product suitable for pharmaceutical formulations. The novel product is prepared by a process comprising the following steps; reacting omeprazole with magnesium alcoholate; separating inorganic salts from the reaction mixture; crystallizing the magnesium salt of omeprazole and isolating the product. The magnesium alcoholate is formed from metallic magnesium which requires special process conditions. The use of magnesium alcoholate in the process constitutes a potential difficulty with the formation of relatively insoluble magnesium salts, such as magnesium hydroxide. Filtration of such magnesium hydroxide is complicated because of gelling and extremely small particle size. The prior process is rather complicated, is water sensitive and requires special conditions. The prior process also has a large equipment requirement in the form of three reaction vessels and a separator. Therefore, there is a need for a more efficient process resulting in shorter manufacturing time, less reaction equipment and giving a higher yield pro volume.
The present invention provides improvements over the process disclosed in WO 95/01977 for the preparation of the magnesium salts of omeprazole and of other substituted benzimidazoles. Process for the preparation of certain salts of the single enantiomers of omeprazole, such as the magnesium salts, and processes for their preparation are described in EP 94917244.9.
As discussed in WO 95/01783 the magnesium salts of proton pump inhibitors, such as the magnesium salt of omeprazole, are especially suitable for the manufacturing of pharmaceutical formulations, such as tablets. The magnesium salts are stable, they may be easily purified by crystallization, and are easy to handle in pharmaceutical procedures and processes.


SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of magnesium salts of substituted sulfinyl heterocycles containing an imidazole moiety and especially of substituted benzimidazole derivatives. The process results in a high yield pro volume, requires less equipment, is less time consuming, environmental friendly and more economically efficient than processes described in the above mentioned patent applications. According to the novel process a magnesium salt of a substituted sulfinyl heterocycle containing an imidazole moiety is prepared by mixing the substituted sulfinyl heterocycle containing an imidazole moiety with a weak base, preferably an amine or ammonia, and a magnesium source, such as an organic or inorganic magnesium salt or a combination of such salts. By the novel process of the present invention formation

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patent: 5693818 (1997-12-01), Von Unge
patent: 5714504 (1998-02-01), Lindberg et al.
Okabe et al. "Preparation of Benzimidazole Derivatives", Chem. Abs. 108: 683, 1988.

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