Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-23
1999-09-28
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514338, 5462737, A61K 3144, C07D40112, C07D40312
Patent
active
059589558
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel process for the synthesis of nzimidazole, known under the generic name omeprazole. Moreover, the present invention also relates to manufacture of a pharmaceutical preparation thereof and its use in medicine.
BACKGROUND OF THE INVENTION AND PRIOR ART
Omeprazole is an inhibitor of gastric acid secretion making it useful as an antiulcer agent U.S. Pat. No. 4,255,431 (corresponding to EP 0 005 129) discloses a process for the preparation of this class of substituted benzimidazoles. Said process comprises a couple of reaction steps. The three last steps of the process utilize more than one solvent and requires isolation of intermediates to give the final product omeprazole. The resulting product is contaminated with starting materials and by-products.
WO 91/18895 describes an improved process for synthesis of omeprazole. This process describes the oxidation step and a work-up procedure of omeprazole. The oxidation step utilizes m-chloroperoxybenzoic acid in a methylene chloride/water system at substantially constant pH of about 8.0 to 8.6. The work-up procedure includes crystallization of omeprazole by the addition of an alkyl formate.
Another process for the manufacture of omeprazole is described in U.S. Pat. No. 5,391,752. This process also describes only the oxidation step. Said oxidation step utilizes magnesium monoperoxyphtalate as an oxidazing agent. The resulting product is contaminated with starting material and by-products.
Yet another process for the manufacture of compounds showing structural similarities to omeprazole is disclosed in U.S. Pat. No. 4,619,997. The intermediates are isolated, but not purified, and different solvent systems are used in the chemical steps throughout the process.
In the light of the above there was still a need for a new convenient and more efficient process to manufacture omeprazole.
SUMMARY OF THE INVENTION
In the following the improved process is described. Scheme I below describes three main reaction sequences in the manufacture of omeprazole. In the scheme the complete chemical names as well as short names for the starting material and the different intermediates are stated. The starting material as well as the reactants used are readily available by procedures described in the literature. ##STR1##
Scheme I
Advantages of the improved process of the present invention are disclosed in the following paragraphs.
One object of the present invention is to provide a process for the manufacture of omeprazole with all three reaction steps, described above, being carried out without any isolation or purification of the intermediates, and carried out in one main solvent system common for the whole sequence. Such a process eliminates time consuming steps for isolation or purification of intermediates or solvent change in the process and thus making the process more efficient with a high production capacity. A further important benefit of such a process is that the handling of toxicological and suspected mutagenic intermediates such as pyrmethyl chloride, due to isolation or purification, is eliminated.
Another preferred object of the present invention is to provide a process utilizing a solvent system which is environmentally friendly to avoid outlet of harmful solvents. There is a general interest from environmental groups both inside and outside the pharmaceutical industry that the industry shall develop and use environmentally friendly processes. In some countries the authorities also have made restrictions on the outlet of harmful chlorinated solvents into the air.
Surprisingly, the novel process of the present invention gives omeprazole in a high purity without any isolation or purification of intermediates. The omeprazole obtained may optionally be further processed in a purification step and/or optionally processed into pharmaceutically acceptable salts.
Another object of the present invention is to provide a process for an optional purification step of omeprazole.
Further, the present reaction sequ
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Gustavsson Anders
Kallstrom .ANG.ke
Astra Aktiebolag
Rotman Alan L.
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