Process for the production of antiulceratives

Details Process for the production of antiulceratives Process for the production of antiulceratives

2002-04-29

2004-02-03

Seaman, D. Margaret (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06686474

ABSTRACT:

CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of international patent application no. PCT/EP00/10580, filed Oct. 27, 2000, designating the United States of America, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany patent application no. 199 51 960.9, filed Oct. 28, 1999.
BACKGROUND OF THE INVENTION
This invention relates to a process for the production of benzimidazole derivatives suitable as antiulceratives, in particular omeprazole or pantoprazole.
Antiulceratives are today used on a large scale for the treatment of ulcers, in particular stomach ulcers (gastric ulcers). There are many different causes for stomach ulcers and many people are prescribed drugs to provide relief. Treatment is usually with substances which inhibit the proton pumps, H
+
K
+
ATPase, located in the stomach wall. Known representatives of this therapeutic category are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole, generic name omeprazole, and 5-(difluoromethoxy)-2-[3,4-dimethoxy-2-pyridyl)methylsulfinyl]benzimidazole, generic name pantoprazole. Omeprazole in particular is a known proton pump inhibitor, for which a considerable number of production processes have been developed. The synthesis of omeprazoles and structurally related compounds typically comprises several stages. In the case of omeprazole of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1H-benzimidazole, which is also known as pyrmetazole, the final step is usually oxidation of a sulfide, to yield the corresponding sulfinyl, in particular to yield omeprazole. This final oxidation step is of great significance to the yield, purity and also economic viability of the entire production process and various proposals have accordingly been made in the prior art for this synthesis step.
In EP 0 005 129, which claimed protection for the substance omeprazole, oxidation is described as with the assistance of oxidising agents such as m-chloroperbenzoic acid in a solvent. This solvent is not specified in any further detail, but the Examples only make reference to trichloromethane, ethanol, benzene and hydrochloric acid. Yields and product purity were, however, not satisfactory.
EP 0 533 264 discloses an oxidation process in which magnesium ammonoperoxyphthalate is used. This reaction conventionally performed in solvents which contain water, water-miscible solvents or water-immiscible solvents, or preferably, combinations of these three types of solvent. Various solvents are listed, for example low molecular weight alcohols as the water-miscible solvent and toluene as the water-immiscible solvent. However, neither ketones nor explicitly acetone are mentioned and also not preferred.
EP 0 484 265 describes various possibilities for the production of omeprazole, wherein the last reaction step, the oxidation of pyrmetazole to omeprazole is performed with a per-acid, preferably m-chloroperbenzoic acid, in an acidic medium with pyrmetazole salts, if the solvent is not methanol. In contrast, when methanol is used, as is preferred, pyrmetazole is used and the oxidation is performed with hydrogen peroxide in the presence of a catalyst such as ammonium molybdate and an inorganic base.
EP 302 720 describes oxidation with hydrogen peroxide in the presence of vanadium compounds. This document lists a series of compounds as solvents, among which ethanol, methanol, acetone and acetonitrile are preferred. Although acetone is used in this case, the use of hydrogen peroxide with a catalyst is disclosed as essential to the invention. This constitutes the nub of the inventive concept of said application.
GB 2 239 453 furthermore describes the oxidation of pyrmetazole by photochemical oxidation by exciting appropriate compounds with light in order to oxidise pyrmetazole to yield omeprazole.
WO 98/09962 describes an oxidation with peroxyacetic acid in a two-phase medium of water and a chlorinated organic solvent at an alkaline pH. Dichloromethane is stated to be particularly preferred in this case.
WO 91/18895 corresponds to European patent EP 0 533 752. This document describes oxidation with m-chloroperoxybenzoic acid in an inert solvent, wherein methylene chloride is preferred, at a pH of around 8.0 to 8.6, wherein the actual essence of the reaction is the addition of alkyl formate to the aqueous phase. In this case too, acetone is not mentioned at all and, in principle, the route via chloroperoxybenzoic acid in dichloromethane already known from EP 0533752 is adopted.
WO 97/22603 discloses a process in which the final reaction steps are all performed in the same solvent system. Oxidation is here again performed with m-chloroperoxybenzoic acid. Preferred solvent systems are media immiscible with water, for example carbon tetrachloride, trichloroethane, chloroform, methylene chloride or toluene. Toluene is in particular preferred in this process.
EP 240 158 relates to benzimidazole derivatives as antiulceratives. In this case, oxidation is performed with per-compounds, such as m-chloroperoxybenzoic acid, in halogenated hydrocarbons, such as chloroform or dichloromethane, and/or alcohols, such as methanol, ethanol or butanol.
U.S. Pat. No. 4,619,997 discloses corresponding benzimidazole derivatives, in which the derivatives are oxidised with any known oxidising agents, in particular peroxy acids, but also for example with hypochlorite solution. The reaction preferably proceeds in inert solvents, such as benzene, methylene chloride or chloroform.
Further relevant documents in this connection are ES 539 739, in which iodosobenzene and iodosotoluene are proposed as oxidising agents, and ES 543 816, which proposed m-chloroperoxybenzoic acid in powder form for the oxidation.
The large number of proposed process variants alone makes it clear that there is further need for improvement. The majority of these processes known from the prior art thus exhibit the disadvantage that they often give rise to low yields, in particular of omeprazole, or that the omeprazole obtained is contaminated with starting materials or secondary products. A common feature, however, is that, even if these disadvantages are not so pronounced, all the preferred or explicitly described production processes are performed with chlorinated organic solvents such as dichloromethane or trichloromethane or other compounds such as toluene which are undesirable from an environmental or medical standpoint. All these compounds are known to have a negative impact on the environment and as more stringent regulatory requirements are being imposed and the costs that are inevitably associated therewith, there is thus a clear need to bring about an improvement in comparison with the prior art.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The object of the present invention is accordingly to provide a process for the production of benzimidazole derivatives, in particular omeprazole and pantoprazole, suitable as antiulceratives, which process, while achieving elevated yields and high purity of the final products, allows solvents to be used which are more compatible with environmental and health concerns.
The present application accordingly provides a first process for the production of antiulceratives of the formula I:
in which
R
1
, R
2
and R
3
are independently selected from
hydrogen,
C1-C8 alkyl,
C3-C8 cycloalkyl,
C2-C8 fluoroalkyl and
C1-C8 alkoxy,
R
4
and R
5
are independently selected from
hydrogen,
C1-C8 alkyl,
C3-C8 cycloalkyl,
CH
2
-C3-C8 cycloalkyl,
C1-C8 alkoxycarbonyl,
C1-C8 alkoxy,
C1-C8 fluoroalkoxy,
CF
3
,
C2-C8 fluoroalkyl and
—C(O)O—C1-C8 alkyl, and
R
6
is selected from
hydrogen and
C1-C2 alkyl,
in which process a compound of the formula II:
in which R
1
, R
2
, R
3
, R
4
, R
5
and R
6
have the above-stated meaning, is reacted with oxidising agents, in particular peroxy compounds, preferably m-chloroperoxybenzoic acid, in a solvent. A catalyst may optionally be added during said reaction. The pH

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