Patent GB-1022214-A (GB)
Title: Novel 1,3-disubstituted-1,4-dihydro-4-oxo-1,7-naphthyridines and their preparation
IPC: C07D471/04
Filed: 1964-01-28
Abstract: The invention comprises compounds of the formula <FORM:1022214/C2/1> where X is carboxy, a carboxy salt, C2- 7 carbalkoxy, carbamoyl, cyano or another group convertible to carboxy by hydrolysis, R is C1-6 alkyl, R5 is hydrogen or C1-6 alkyl, and R6 and R8 are each hydrogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino or C2-6 alkanoylamine, and 7-N-oxides thereof.  The compounds may be prepared by reacting a compound of the formula <FORM:1022214/C2/2> with an ester of the formula R1An, where An is an anion of strong inorganic acid or an organic sulphonic acid, in the presence of an acid acceptor.  The free acids (X = carboxy) may also be prepared by hydrolysis of the corresponding esters (X = 3-carbalkoxy), or by hydrogenating the corresponding 7-N-oxides. The 7-N-oxides are prepared by either 1-N-alkylating the 4-hydroxy-3X-1,7-naphthyridine 7-N-oxides or by reacting a compound of formula I with an oxidizing agent.  The 6 - hydroxy - 1,4 - dihydro - 4 - oxo - 1 - R1 - 5-R5 - 8 - R8 - 1,7 - naphthyridine - 3 - carboxylic acids may also be prepared by converting the 6 - amino - 1,4 - dihydro - 4 - oxo - 1 - R1 - 5-R5 - 8 - R8 - 1,7 - naphthyridines into the corresponding diazonium salts and hydrolysing the diazonium salts.  The 6-amino-1,4-dihydro-4 - oxo - 1 - R1 - 5 - R5 - 8 - R8 - 1,7 - naphthyridines may also be prepared by reacting C1-alkyl 6 - acylamino - 1,4 - dihydro - 5-R5 - 8 - R8 - 1,7 - naphthyridine carboxylates with an ester R1An to obtain the corresponding C1-6 alkyl 6-acylamino-1,4-dihydro-4-oxo-1-R1-5-R5-8-R8-1, 7-naphthyridine carboxylates which are then hydrolysed with an acidic agent to remove both the ester and N-acyl groups.  The compounds of Formula II where X is a C2-7 carbalkoxy group and R8 is other than hydrogen are prepared by reacting a 3-amino-2-R8-5-R5-6-R6-pyridine with one molar equivalent of a dialkyl ethoxymethylenemalonate to yield a dialkyl N-(2-R8-5-R5-6-R6-3-pyridylamino)methylene malonate and then cyclizing this compound by heating in an appropriate solvlent.  The compounds of Formula II where X is a C2-7 carbalkoxy group and R8 is hydrogen are prepared by reacting a 3-amino-5-R5-6-R6-pyridine with a dialkyl ethoxymethylene malonate to yield a dialkyl N-(5-R5-6-R6-3-pyridylamino)methylene malonate, preparing the 1-oxide of this compound, cyclizing the 1-oxide by heating in an appropriate solvent to produce a 3 - carbalkoxy - 4 - hydroxy - 5 - R5 - 6 - R6-1,7-naphthyridine-7-oxide which is then hydrogenated to remove the 7-oxygen atom.  The compounds of Formula II where X is carboxy, and 7-N-oxides thereof, may also be prepared by hydrolysing the corresponding 3-C2-7 carbalkoxy derivatives.  3 - Cyano - 6,8 - dimethyl - 4 - hydroxy-1,7 - naphthyridine is prepared by cyclizing N - (2,6 - dimethyl - 3 - pyridyl)aminomethyl-enecyanoacetate, itself prepared by reacting 3 - amino - 2,6 - dimethyl - pyridine with ethyl ethoxymethylenecyanoacetate.  6 - Acetamido 2 methyl - 3 - amino pyridine is prepared by acylating 6-amino-2-methyl-3-nitro pyridine with acetic anhydride or acetyl chloride and hydrogenating the resulting 6-acetamido - 2 - methyl - 3 - nitro - pyridine.