Vol. 73 [CONTRIBUTION FROM THE
DEPARTMENT OF CHEMISTRY, BROOKLYN COLLEGE]
Dialkylaminoalkyl Esters of 2-Amino-6-carboxybenzothiazole BY IRVING ALLANKAYEAND I. MELVILLEROBERTS Several esters of 2-amino-G-carboxybenzothiazolewere prepared as potential pharmaceuticals by the thiocyanation of the corresponding esters of p-aminobenzoic acid. One compound (IIC) was prepared also by an exchange reaction between diethylaminoethanol and 2-amino-6-carbethoxybenzothiazole.In the catalytic hydrogenation of three esters of p-nitrobenzoic acid in ethanol, an ester-exchange with the medium was observed.
Interest in the preparation of compounds con- have exhibited antitubercular activity; the latter taining the thiazole nucleus as chemotherapeutic is said to be about three quarters as effective as agents has been stimulated by the successful appli- streptomycin in vitro against human tubercle bacation of several such compounds in the treatment cilli.7 Asterol dihydrochloride [2-diethylamino-Gof various diseases. The vitamin, thiamine, the (0- diethylaminoethoxy) - benzothiazole dihydroonly natural product which has thus far been found chloride] is commercially available as a potent to contain the thiazole nucleus,’ sulfathiazole, the fungistatic agent,s A number of 2-amino-6-alkmost potent of the sulfa drugs in general use,2 and oxybenzothiazoles‘ have been prepared9 and tested promizole (4-aminophenyl-2’-aminothiazolyl-5’-sul-for antimalarial activity. lo One, 2-amino-6f ~ n e )a, tuberculotherapeutic ~ agent, are among the ethoxybenzothiazole, has received some attention better-known thiazoles used in present-day medi- as it is a powerful local cine. The versatility of the thiazoles is further The intermediate p-aminobenzoic acid esters demonstrated by the fact that some of these com- (I, €3, D-G) were prepared by a modification of a pounds possess antimalarial activity,* that 2-(4- previously described methodIz2 from the correthiazoly1)-ethylamine has biological properties sim- sponding p-nitrobenzoic acid esters. The latter, ilar to those of histamine6 and that 2-aminothiazole prepared from dialkylaminoalkanols and p-nitroexhibits antithyroid activityS6 benzoyl chloride, were not isolated but redyced diOn the basis of the foregoing it seemed that the rectly to the corresponding p-aminobeazoates. incorporation of the thiazole nucleus into the di- These esters have almost invariably been isolated alkylaminoalkyl p-arninobenzoate structure might and characterized as their salts. For the subsepotentiate the local anesthetic activity of this quent thiocyanation reaction, i t seemed preferable group of esters or result in a class of compounds to employ these intermediates as the free bases. having a more favorable therapeutic index. To Therefore, they were isolated in this form by distiltest this hypothesis several esters of 2-amino-6- lation in vacuo, or by crystallization. One of these carboxy-benzothiazole, represented by 11, were esters has not been described previously (I, G) prepared. The structures of the two well-known while three others have been characterized only as local anesthetics, Procaine (IC) and Rutyn (IE) are salts (I, D, E and F). shown for comparison. This procedure is simple and convenient, giving high yields of pure products. However, difficulty ”2 I was encountered in the preparation of three compounds (I, B, D and E) when the p-nitrobenzoic acid esters were hydrogenated in ethanol in the presence of either Raney nickel or palladium-charcoal. The reduction products were found to conI C-OR tain considerable amounts of lower boiling material I/ and only small amounts, if any, of the expected p 0 aminobenzoates. The more volatile by-products TI T were subsequently identified as aminoalcohols, deA,R = rived from the alcoholic fragments of the esters, and R,R = ethyl p-aminobenzoate. When the reductian was C, R = D,R = conducted in benzene, rather than ethanol, the E,R = expected 9-aminobenzoic acid esters were isolated F, R = in good yields, with neither of these by-products apG, R = pearing. These results would seem to indicate Of the relatively few 2-amino-6-substituted- that an ester-exchange reaction had occurred in the benzothiazoles described in the literature some have ethanolic medium. The reductions were run a t shown diverse biological properties. Both the 2- elevated temperatures, since no attempt was made amino-6-nitro and the 2,6-diaminobenzothiazoles (7) B. L. Freedlander and P. A French, Proc. SOC.E x p f l . Bid.Mcd., (1) G. L. Jenkins and W. H.Hartung, “The Chemistry of &genic Medidnai Products,” John Wiley and Sons, Inc , New York, N . Y., 1944, pp, 617-621. (2) E. H. Northey, “The Sulfonamides and Allied Compounds,” Reinhold Publishing Corp., New York, N. Y., 1948, p, 34. (3) L. L. Bambas, Trrrs J O U U ~ A L ,67, 671 (1945). (4) F. Brody and M. T. Bogert. ib
