Synthesis of Certain Heterocyclic Compounds Chemically Related to Antituberculous Drugs.

Research Abstract

The present thesis comprises a survey covering antimycobacterial drugs with known and unknown mode of action. The study involves the synthesis of ethyl benzothiazole-2-carboxylate (I). Hydrazinolysis of the ester I resulted in the hydrazide II. Condensation of the latter with some aromatic aldehydes afforded the arylidene derivatives IIIa-d. Cyclization of IIIa-d with acetic anhydride yielded substituted 1,3,4-oxadiazoles IVa-d. Also, reaction of the hydrazide II with isatin and certain acid anhydrides led to substituted indolin-3-ylidene V and amide derivatives VI & VII respectively. The investigation also involves the reaction of o-phenylenediamine with succinic anhydride to give 2-aminophenylamidosuccinic acid (VIII) which, on boiling under reflux for 3 hours in absolute ethanol, gave 3-(1H-benzimidazol-2-yl) propanoic acid (IX). Esterification with ethanol led to the corresponding ethyl ester X which upon reaction with hydrazine gave the hydrazide XI. Condensation of the latter with isatin led to indolin-3-ylidene derivative XII. Also, cyclization of the hydrazide XI with some aromatic acids afforded 2,5-disubstitued-1,3,4-oxadiazoles XIIIa-c. Cyclization of the hydrazide XI with acetylacetone yielded compound XIV. Moreover, 3-(1H-benzimidazol-2-yl) propanoic acid hydrazide (XI) was reacted with some aromatic aldehydes yielding arylidene derivatives XVa-e, which upon cyclization with acetic anhydride yielded substituted-1,3,4-oxadiazoles XVIa-d. In addition, reaction of the hydrazide XI with certain acid anhydrides led to substituted amide derivatives XVII & XVIII. On the other hand, ethyl (and/or phenyl) thiosemicarbazides XIXa&b were synthesized via reaction of the hydrazide XI with the corresponding isothiocyanate. The substituted thiosemicarbazides were then cyclized in presence of conc. H2SO4 to give 2,5-disubstituted-1,3,4-thiadiazol derivatives XXa&b, while cyclization of these substituted thiosemicarbazides in the presence of piperidine/H2O led to 1,2,4-triazoles XXIa&b which, upon alkylation with different alkyl and/or aryl halides, gave XXIIa-f. While cyclizayion of ethyl(and/or phenyl) thiosemicarbazides XIXa&b with chloroacetic acid afforded thiazolidinone derivatives XXIIIa&b. 5-Substituted-1,3,4-oxadiazole-2-thiol XXIV was prepared by heating the hydrazide XI with CS2 in the presence of alcoholic KOH. Alkylation of XXIV with different alkyl or aryl halides gave XVa-c. When XXIV was subjected to Mannich reaction conditions, by reacting it with formaldehyde and different secondary amines in ethanol, it gave the corresponding 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2-thiones XXVIa-e.

Research Keywords

Synthesis of Certain Heterocyclic Compounds Chemically Related to Antituberculous Drugs.