Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-08-18
2000-01-18
Fan, Jane
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21186
Patent
active
060159065
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of 4-(nitrophenyl)dihydropyridines.
These products are widely used due to their remarkable pharmaceutical properties, and up to now they were prepared according to different synthetic methods. For example, Hantzsch's synthesis (Ann. 215, 1, 72; 1882) is made use of to prepare in a single step the 3,5-dicarboxylic acid symmetric esters, using a mole of aldehyde, 2 moles of acetoacetic ester and ammonia.
On the other hand, for the preparation of the asymmetric esters, Knoevenagel synthesis is employed, (Ber. 31, 370; 1898) first reacting an aldehyde with an acetoacetate in the presence of piperidine, subsequently treating the resulting benzylidene derivative with the suitable aminocrotonate.
Knoevanagel condensation is exhaustively described by G. Jones in Organic Reactions, 15, 1967, p. 204-599.
A number of methods and patents concerning the preparation of dihydropyridines exist in literature.
Among these, EP 0,124,743 and EP 0,173,126 disclose the preparation of the benzylidene derivatives with suitable catalysts, such as piperidine acetate in the first Patent and, inter alia, o-anisidine and m-toluidine in the second Patent. On the other hand, EP 319,814 discloses the final closure reaction of one of these important dihydropyridines, catalyzed by diisopropylamine acetate or dimethylbenzylamine acetate.
Now it has surprisingly been found that dihydropyridine asymmetric esters can be prepared in high yield and purity, with remarkable savings in time and energy, and therefore with a low cost, using as reaction catalysts organic salts that up to now have never been considered.
The dihydropyridines of the invention have the general formula (I) ##STR1## wherein R.sub.1 is a nitro group at the 2 or 3 position; R.sub.2 and R.sub.3, which are different from each other, are a methyl, ethyl, isopropyl, 2-methoxyethyl or isobutyl group, whereas R.sub.4 and R.sub.5 are methyl groups.
Compounds (I) are prepared, according to the invention, from a benzylidene derivative of general formula (II) ##STR2## wherein R.sub.1, R.sub.2 and R.sub.4 have the meanings defined above, by reaction with an enamine derivative of general formula (III) ##STR3## wherein R.sub.3 and R.sub.5 have the meanings defined above.
The benzylidene derivative (II) is in turn prepared by reacting a benzaldehyde of general formula (IV) ##STR4## wherein R.sub.1 has the meanings defined above, with an acetoacetic ester of general formula (V) ##STR5## wherein R.sub.2 and R.sub.4 have the meanings defined above.
Both the above reactions can be carried out in a lower C.sub.1-4 alcohol and are catalyzed by dimethylamine benzoate or p-anisate.
The use of the catalyst according to the invention makes it surprisingly possible to carry out the reaction necessary for the preparation of (II) in mild conditions (reaction temperature ranging from 20.degree. to 40.degree. C.). In this way, the formation of undesired side-products is restricted and a highly pure intermediate (II) is obtained in a high yield, with remarkable energetic savings and therefore at lower costs.
The use of dimethylamine benzoate or anisate in the subsequent reaction, moreover, makes it possible for (I) to form already after a few hours heating, also affording in this case the advantage of energetic savings and consequent low costs.
On the contrary, when the reaction for the preparation of the main product (I) is carried out with no use of catalysts, heating under reflux up to 24 hours is necessary (as disclosed, for example, in EP 124,743).
Moreover, the use of dimethylamine anisate or benzoate minimizes the formation of the main undesired impurities of these dihydropyridines, i.e. the corresponding dicarboxylic symmetric esters of general formula (II) wherein R.sub.2 and R.sub.3 are the same.
In the process of the invention, the catalyst moles range from 0.01 to 0.06 per mole of nitrobenzaldehyde and from 0.005 to 0.015 per mole of nitrobenzylidene derivative.
From the comparison between the data deducible from the Registry of To
REFERENCES:
CA 114:122068, Serra et al., 1991.
CA 116:59220, Serra et al., 1992.
European.Pharmacopoeia Supplement 1998 pp. 396-397.
Manghisi Elso
Perego Bruno
Fan Jane
Lusochimica S.p.A.
Schneider Walter H.
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