4-Hydroxy-2-Quinolones. 233*. Synthesis and Diuretic Activity of 9-Bromo-7-Hydroxy-5-Oxo-2,3-Dihydro-1 H ,5 H -Pyrido[3,
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4-HYDROXY-2-QUINOLONES. 233*. SYNTHESIS AND DIURETIC ACTIVITY OF 9-BROMO-7-HYDROXY-5-OXO2,3-DIHYDRO-1H,5H-PYRIDO[3,2,1-ij]QUINOLINE6-CARBOXYLIC ACID ANILIDES I.V. Ukrainets1**, N. Yu. Golik1, and I. N. Chernenok1 The ethyl ester of 7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylic acid reaction with bromine in anhydrous acetic acid producing a mixture of the 9-bromo-substituted product and 6-ethoxycarbonyl-5,7-dihydroxy-2,3-dihydro-1H-pyrido[3,2,1-ij]quinolinium tribromide in a 1:1 ratio. It has been established experimentally that the diuretic activity of 9-bromo-7-hydroxy-5-oxo2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxanilides increases substantially in comparison with their non-brominated analogs. Keywords: 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic bromination, diuretic activity.
acids,
pyrido[3,2,1-ij]quinolines,
As shown previously, tricyclic 1-R-4-hydroxyquinolin-2-ones vary significantly in chemical properties from their bicyclic analogs. For example, the reaction of the 7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylic acid ethyl ester (1) with molecular bromine in aqueous acetic acid proceeds with bromination of not only the pyridine moiety of the molecule (which is common), but also the benzene moieties of the molecule as well [2]. The reaction of the tricyclic ester 1 with bromine in non-aqueous conditions also is not usual. In the case of the bicyclic 1-R-4-hydroxyquinolin-2-ones this method is a fairly simple and convenient route for the synthesis of 6-bromo-substituted derivatives [3]. However, attempts to apply it for the purpose-directed bromination of ester 1 in position 9 ended ambiguously. Thus, on adding dry molecular bromine to a solution of ester 1 in anhydrous acetic acid a yellow-orange substance was precipitated practically at once. The analysis proved it to be 6-ethoxycarbonyl-5,7-dihydroxy-2,3-dihydro-1H-pyrido[3,2,1-ij]quinolinium tribromide (2) [4]. In cases of other tricyclic quinolines under similar conditions complete the absence of bromination in the ring was noted [5]. Nevertheless, the desired 9-bromo-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxylic acid ethyl ester (3) was formed in this reaction, although its yield did not exceed 50%.
_______ *For Communication 232, see [1]. **To whom correspondence should be addressed, e-mail: [email protected]. 1
National University of Pharmacy, 53 Pushkinska St., Kharkiv 61002, Ukraine. _________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1420-1427, September, 2013. Original article submitted June 8, 2013. 0009-3122/13/4909-1323©2013 Springer Science+Business Media New York
1323
OH
O CO2Et O
N
Br
Br2, AcOH, AcONa 20°C
O
N
1
CO2Et
6 Br2, AcOH, 20°C
Me2CO
OH
OH CO2Et
+
N
CO2Et
Br +
OH
O
N
Br3– 2
3
90°C
OH
OH CO2H
CO2H
Br +
N
O
N
4
5
OH
OH CO2H
+
N
4a
O
CO2H
Br +
O
+
N
O
5a
In principle, ester 3 might have
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