Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-05
2001-05-08
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06229021
ABSTRACT:
TECHNICAL FIELD
The invention solves a method of preparation of a pharmaceutical substance 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, which is known under its generic name omeprazole.
DESCRIPTION OF THE RELATED ART
According to the Swedish patent SE 4231, omeprazole is prepared by oxidation of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H benzimidazole, (further referred to as the compound I) with m-chloroperoxybenzoic acid.
In the PCT application published under WO 91/118895 is described an improved method of preparation of omeprazole by oxidation of the compound I again with m-chloroperoxybenzoic acid, but in an alkaline medium.
Also other patents provide for preparation of omeprazole by oxidation of the compound I with different oxidizing agents.
In the European patent EP 484 265 preparation of omeprazole by oxidation of the compound I with hydrogen peroxide in the presence of molybdenum salts as catalysts is described.
The European patent EP 302 720 has patented preparation of omeprazole by oxidation of the compound I with hydrogen peroxide using vanadium catalysts. The British patent GB 2 239 453 describes preparation of omeprazole by photo-chemic oxidation of the compound I.
Other way of omeprazole preparation is oxidation of the compound I by magnesium peroxyphatalate provided for in the European patent EP 533 264, and oxidation by iodosobenzene or iodosotoluene described in the Spanish patent ES 539 793. The Spanish patent ES 543 816 describes preparation of omeprazole by oxidation of the compound I with m-chloroperoxybenzoic acid powder.
Disadvantages of these preparation methods are that prepared omeprazole is contaminated by starting substance and there are many side products produced during the reactions, including especially 5-methoxy-2-[[(4-methoxy-3,5-dimethyl -2-pyridinyl)-methyl]sulphonyl]-1H-benzimidazole as a product of following omeprazole oxidation.
The procedures mentioned above utilize relatively expensive oxidizing reagents.
The possible using of peroxyacetic acid in the preparation of compounds of this type is only generally mentioned, together with many other oxidizing agents (see, e.g. Houben-Weyl Vol. E11/Part 1, p. 702-752, EP 533 264, EP 298 440 . . . ).
The most frequently described oxidizing reagent in the preparation of omeprazole from the compound I is m-chloroperoxybenzoic acid.
The object of the present invention is the use of peroxyacetic acid as an oxidizing agent in the preparation of omeprazole from the compound I. Surprisingly, we have found, that the use of peroxyacetic acid as an oxidizing agent instead of m-chloroperoxybenzoic acid in the preparation of omeprazole provides a crude product of unexpectedly high purity. Practically, the product is not contaminated by hardly removable sulphone impurity, 5-methoxy-2-[[(4-metoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphonyl]-1H-benzimidazole, as in the case of omeprazole preparation by means of m-chloroperoxybenzoic acid.
The object of the present invention is to provide a method for the preparation of omeprazole, which utilizes a very cheap oxidizing agent. Furthermore, a such method for preparation of omeprazole is provided, in which neither toxic components nor components requiring expensive liquidation are formed, as in the case of other oxidizing reagents described in connection with the preparation of omeprazole (e.g. m-chloroperoxybenzoic acid, molybdenum and vanadium catalysts, magnesium peroxyphthalate, iodosobenzene and iodosotoluene).
When the reaction is completed, omeprazole is simply isolated from the organic phase, and acetic acid formed from the oxidizing agent remains in the aqueous phase and is liquidated in very easy and cheap way.
SUMMARY OF THE INVENTION
The mentioned disadvantages of the presently known methods for the omeprazole preparation are eliminated by a method of preparation of omeprazole according to the present invention, which comprises the reaction of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-1H-benzimidazole (the compound I) with peroxyacetic acid in a two-phase water and chlorinated organic solvent medium, in alkaline pH, subsequent separation of water and organic phases after the reaction and isolation of omeprazole from organic phase.
The peroxyacetic acid is used in amount of 0,8 to 2,0 molar equivalents to the compound I, advantageously in the amount of 0,9 to 1,1 molar equivalent.
The pH of reaction mixture during the reaction is maintained from 7,1 to 9,5. The best is, however, to work with the pH ranging from 8,0 to 8,5.
The temperature of reaction mixture is maintained during the reaction from 0° C. to 25° C., the best range from 1° C. to 5° C.
As chlorinated organic solvent can be used dichloromethane, chloroform, or dichloroethane, using of dichloromethane is preferable.
When the reaction is completed, organic and water phases are separated, and omeprazole is isolated from the organic phase.
The advantage of the process according to the present invention is that very cheap peroxyacetic acid is used for the oxidation. Another advantage of the process according to the present invention is that omeprazole is isolated from the organic phase after completion of the reaction, and the acetic acid formed from the peroxyacetic acid during the reaction remains in the aqueous phase. This waste aqueous phase contains no toxic components and can be liquidated in an easy and cheap way.
The principal advantage of the process according to the present invention is that the prepared omeprazole is of high purity and practically contains no initial substance as well as the hardly removable sulphone impurity, 5-methoxy-2-[[(4-metoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphonyl]-1H-benzimidazole.
The present invention will be further illustrated in practical embodiments, without being limited to them.
REFERENCES:
patent: 5391752 (1995-02-01), Hoerrner et al.
patent: 298 440 A1 (1988-07-01), None
patent: 0 533 264 A1 (1993-03-01), None
patent: WO 91/18895 (1991-12-01), None
patent: WO 97/22603 (1997-06-01), None
Gattnar Ond{haeck over (r)}ej
Heleyová Katarina
Je{haeck over (z)}ek Ladislav
Oremus Vladimir
Varga Ivan
McKane Joseph K.
Murray Joseph
Slovakofarma, A.S.
Zarley McKee Thomte Voorhees & Sease
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