Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-06-11
2004-04-06
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S303100, C548S341500
Reexamination Certificate
active
06716990
ABSTRACT:
TECHNICAL FIELD
The invention relates to processes and intermediates for the preparation of imidazopyridines. These are needed as intermediates in the preparation of medicaments for the treatment of peptic ulcers.
PRIOR ART
The International Patent Application WO98/42707 describes 2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-ones and various processes for their preparation.
DESCRIPTION OF THE INVENTION
The invention relates to intermediates and processes for the preparation of compounds which can be employed for the preparation of the active compounds described in International Patent Application WO98/42707. In particular, the invention relates to compounds of the formula 1
in which A
1
and A
2
are each hydrogen or together form a bond, R4 is hydrogen, methyl or trifluoro-methyl, and to their precursors and intermediates and processes for their preparation.
The invention relates in a first aspect to compounds of the formula 2
in which
R1 and R2 together are O (oxygen) or an ethylenedioxy radical (—O—CH
2
—CH
2
—O—),
R3 is hydrogen or cyano (CN),
R4 is hydrogen, methyl or trifluoromethyl
and their salts and their N-oxides.
Possible salts of compounds of the formula 2 are especially all acid addition salts. Particular mention may be made here of the salts of the customarily used inorganic and organic acids. Those suitable are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid or citric acid, where the acids can be employed in salt preparation—depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired—in an equimolar quantitative ratio or one differing therefrom.
Compounds of the formula 2 in which R1 and R2 are an ethylenedioxy radical (—O—CH
2
—CH
2
—O—), R3 is hydrogen and R4 is hydrogen, methyl or trifluoromethyl, can be prepared in the form of their N-oxides, for example according to the following reaction scheme (scheme 1):
Starting from the compounds of the formula 2 obtained according to scheme 1, in which R1 and R2 are an ethylenedioxy radical (—O—CH
2
—CH
2
—O—), R3 is hydrogen, and R4 is hydrogen, methyl or trifluoromethyl, compounds of the formula 2 can be prepared in which R3 is cyano (CN), according to the process according to the invention outlined in scheme 2:
The invention thus relates in a further aspect to a process for the preparation of the compound of the formula 2 in which R1 and R2 together are O (oxygen), R3 is cyano (CN) and R4 is hydrogen, methyl or trifluoromethyl, and their salts. The process comprises first alkylating the N-oxide of the compound of the formula 2, in which R1 and R2 together are an ethylenedioxy radical (—O—CH
2
—CH
2
—O—), R3 is hydrogen and R4 is hydrogen, methyl or trifluoromethyl, then reacting it with a cyanide and finally working up in a suitable manner.
The person skilled in the art is familiar on the basis of his/her expert knowledge which alkylating agents can be employed and under what conditions alkylation must be carried out. Suitable alkylating agents are, for example, dialkyl sulfates (in particular dimethyl sulfate), alkyl halides (in particular methyl iodide) or alkyl tosylates (such as methyl p-toluenesulfonate). The alkylation is carried out in inert solvents (e.g. toluene, halogenated hydrocarbons, such as dichloromethane, or ethers, such as diethyl ether) under customary conditions.
Suitable cyanides are preferably alkali metal cyanides, in particular sodium cyanide or potassium cyanide. Advantageously, the introduction of the cyano group is performed under catalytic conditions, in particular in the presence of tetrabutylammonium cyanide (TBACN). The reaction is preferably carried out in two-phase systems or in polar solvents, such as dimethylformamide (DMF).
The complete conversion of the ketal into the ketone which, if appropriate, is still necessary after introduction of the cyano group is preferably carried out under mild acidic conditions, for example in formic acid.
The invention further relates to the further reaction of the compounds of the formula 2, in which R1 and R2 together are O (oxygen), R3 is cyano (CN) and R4 is hydrogen, methyl or trifluoromethyl, to give compounds of the formula 1.
The further reaction consists in a cyclization step to give compounds of the formula 1, in which A
1
and A
2
are each hydrogen, to which is added, if desired, an oxidation step to give compounds of the formula 1, in which A
1
and A
2
together are a bonding dash. The cyclization and oxidation step can be illustrated by the following scheme 3:
For cyclization, the compound of the formula 2, in which R1 and R2 together are O (oxygen), R3 is cyano (CN) and R4 is hydrogen, methyl or trifluoromethyl, is reacted with a suitable deprotonating agent in an inert solvent. Suitable deprotonating agents which may be mentioned are, for example, alkali metal alkoxides, such as sodium methoxide or in particular potassium tert-butoxide. The oxidation (dehydrogenation) is carried out in a manner likewise known per se to the person skilled in the art using known dehydrogenating agents (such as sulfur or selenium) or in particular using known oxidants, preferably using manganese dioxide.
The following examples serve to explain the invention in greater detail without restricting it. Likewise, further compounds of the formulae 1 and 2, whose preparation is not described explicitly, can be prepared in an analogous manner or in a manner familiar per se to the person skilled in art using customary process techniques.
The abbreviation RT stands for room temperature, HV for high vacuum, h for hour(s) and min for minutes.
REFERENCES:
patent: 6197783 (2001-03-01), Senn-Bilfinger et al.
patent: 0033094 (1981-08-01), None
patent: 98/37080 (1998-08-01), None
patent: 98/42707 (1998-10-01), None
Fuchss Thomas
Scheufler Christian
Senn-Bilfinger Jörg
Ulrich Wolf-Rüdiger
Altana Pharma AG
Juneau Todd L.
Nath Gary M.
Nath & Associates PLLC
Sackey Ebenezer
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