Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-15
2001-05-29
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C558S432000
Reexamination Certificate
active
06239286
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of PCT International Applcation No. PCT/HU98/00067 which has an International filing date of Feb. 4, 1999, which designated the United States of America.
This invention relates to the new process for the preparation of compounds of general formula (I)—wherein R means hydrogen atom or C
2-6
alkyl group—and to the intermediates of general formula (II)—wherein the meaning of R is the same as above. Compounds of general formula (I) are important intermediates used in the course of preparation of active components of pharmaceuticals. They are e.g. applied in the synthesis of angiotensine II antagonists (PCT application, publication number WO-91/14679A).
Synthesis of 4-imidazolinones and their 2-substituted derivatives, constituting the main skeleton of compounds of general formula (I) is known from the literature (Bruckner: Szerves kémia Band III-1 page 296. Edition: Tankönyvkiadó, Budapest 1964). Takenaka and his co-workers described the preparation of 2-phenyl-4,4′-dialkyl-5-oxo-2-imidazolines in tetrahydrofuran-water heterogeneous system by a 5-12 hours reflux/Heterocycles 29 (6) p 1185 (1989)/. The above method is, however, difficult to implement since preparation of the appropriate carboxamides is problematic. The appropriate carboxamides are in general synthetised by partial hydrolysis of &agr;-aminonitriles, thus, by that of the &agr;-aminonitrile (II). Taking into account the sensitivity of the aminonitriles against alkalines and oxidants, from the known methods only the partial hydrolysis performed in concentrated acidic medium is considered as feasible.
The transformation of nitriles into carboxamides in strongly acidic medium, preferably in concentrated sulfuric acid, raises, however, a number of problems. To be able to stir the reaction mixture, sulfuric acid has to be applied in large excess. As a consequence, heating up the reaction mixture to 70° C. and cooling it down takes considerable time and keeping the reaction product for longer time in a concentrated sulfuric acidic medium will cause partial decomposition. This will cause the necessity of further purification steps. Since the aminocarboxamides are obtained in the form of sulfate salts, the amides have to be liberated. Neutralization of the large excess of acid means the addition of large amounts of base and also that of water, in order to keep the resulting salt in solution. The amino-carboxamide obtained is well solvated, its extraction from the reaction mixture requires a minimum 40-fold excess of the extracting solvent, even if the best—but from the aspect of health very unfavourable—chlorinated hydrocarbones are applied. These solvents, at that, can be recovered only with high losses.
Our aim was to work out a novel process for the preparation of the compounds of a general formula (I) eliminating the above problems.
We have found that if
a) the compound of formula (III) is reacted with a compound of general formula (IV)—wherein R means hydrogen atom or C
2-6
alkyl group, X means halogen atom, C
1-5
alkoxy group or hydroxyl group—and the resulting compound of general formula (II)—wherein the meaning of R is the same as given above—is transformed, in the presence of an oxidizing agent in a reaction medium with pH above 7, into the compound of general formula (I)—wherein the meaning of R is as defined above—, or
b) the compound of formula (III) is reacted with an anhydride of general formula (V)—wherein the meaning of R is the same as defined above—, and the resulting compound of general formula (II)—wherein the meaning of R is as given above—is transformed in the presence of an oxidizing agent, in a reaction medium with pH above 7, into the compound of general formula (I), or
c) a compound of general formula (II)—wherein the meaning of R is the same as defined above—is transformed in the presence of an oxidizing agent, in a reaction medium with pH above 7, into the compound of general formula (I), and, if desired, the resulting compounds of general formula (I), before or after isolation, are transformed into acid addition salts, or the compounds of general formula (I) are liberated from their acid addition salts, then the disadvantages of the known methods are avoided and the new method is also suitable for the “one-pot” synthesis of the compounds of general formula (I).
In the first, acylation step the use of acid chlorides is the most advantageous, in the presence of an organic solvent and an acid binding agent. As for organic solvents for example ethers (methyl tert.-butyl ether), aromatic hydrocarbones e.g. toluene, xylene or chlorinated hydrocarbones e.g. dichloroethane can be applied, as for acid binding agents inorganic bases, for example alkali metal carbonates, alkali-earth metal oxides, organic bases e.g. trialkylamines may be employed.
The resulting, if desired isolated, compounds of general formula (II) are new, they are not known from the literature.
Transformation of the compounds of general formula (II) was carried out in the presence of the above solvents or of alcohols, preferably by use of hydrogen peroxide, but other oxidising agents can also facilitate the reaction. Reactions performed in water-organic solvent mixtures may be accelerated by use of dissolution transfer, phase transfer catalyst or by intensive stirring. As phase transfer catalyst preferably substituted ammonium salts, as for example tetrabutyl ammonium hydroxides, hydrogen halogenides, hydrogen sulfates, as well as other ammonium derivatives containing equal or different subsituents can also be applied. The reaction is carried out in basic medium, above pH=7, for instance in the presence of sodium hydroxide, but other alkali metal hydroxides, as well as alkali metal carbonates, alkali-earth metal hydroxides, alkali-earth metal carbonates or anion-exchange resins may also be used.
Cyclisation may be accomplished in 0.5-2 hours.
The cyclisation step is preferably carried out at a temperature between 50-160° C. The whole process can be carried out in one reaction pot and the resulting compounds of general formula (I) contain, at the highest. 0.1% amount of contamination. The yield of the process is over 70%, calculated on the starting compound of formula (III). The compounds of general formula (I) are preferably isolated in the form of their organic or inorganic acid addition salts. Synthesis of the starting compound of formula (III) is known from the literature/it was synthetised according to the method of the PCT application, publ. number WO-91/14679 and of Org. Synt. 1955 3; (MS: (m/z) 110, 95, 81, 68, 54, 41, 28)/.
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patent: 5910595 (1999-06-01), Durrwachter
patent: 6037474 (2000-03-01), Drauz et al.
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Granger et al., Séance Du, vol. 250, No. 2, Apr. 4, 1960, pp. 2581-2583.
Sudo et al., Bulletin of the Chemical Society of Japan, vol. 36, No. 1, pp. 34-37, 1963.
Bernhart et al., Journal of Medicinal Chemistry, vol. 36, No. 22, 1993, pp. 3371-3380.
O'Brien et al., Journal of Medicinal Chemistry, vol. 37, No. 12, 1994, pp. 1810-1822.
Takenaka et al., Heterocycles, vol. 29, No. 6, 1989 pp. 1185-1189.
Bruckner, Szerves Kemisa, vol. III-1, 1964, p. 296.
Allen et al., Organic Syntheses, vol. 3, 1955, pp. 66-69, 84-86, 88-90.
Aranyosi Péter
Bognár Erzsébet
Castro Bertrand
Dubovszki Katalin
Gajary Antal
Birch & Stewart Kolasch & Birch, LLP
Powers Fiona T.
Sanofi-Synthelabo
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