LUTZ,CODINGTON, ROWLETT, DEINFZT AND BAILEY
lSl0
[CONTRIBUTION FROM THE COBB CHEMICAL.
LABORATORY OF THE
Vol. 68
UNIVERSITY O F VIRGINIA]
Antimalarials. 7-Chloro-4-hydroxy- and 4,7-Dichloro-1-methylcarb~styrils~ BY ROBERT!E. LUTZ,JOHN F. CODINGTON,~~ RUSSELL J. ROWLETT, J R . , * ~ADOLFJ. DEINET AND PHILIP S. B A I L E Y ~ ~ 2,4,7-Tric~iloroquinoline (VII) was made pre- bostyril (11) by means of diazomethane, gave the viously as an intermediate in the synthesis of some same product, 7-chloro-4-methoxy-1-methylcarnovel dialkylaminoalkylaminoquinolines which bostyryl (IV). The relationship between the two l-methylcarwere desired for testing as possible antimalarial drugs.3 This paper deals with the synthesis of bostyrils, IT and 111, and 2,4,7-trichloroquinoline certain incidental N-methylation products which and its derivatives, is of particular interest in eonwere obtained during this work, and with a second nection with the N-methylation of carbostyrils ~ synthetic approach to 2,4,7-trichloroquinoline by means of d i a ~ o m e t h a n e . ~7-Chloro-4-hydroxycarbostyril (V) reacted with methyl iodide through these compounds. The synthesis of 4,7-dichloro-l-methylcarbo- and alkali to give the N-methyl derivative (11); styril (111) was accomplished in three steps from and 4,7-dichlorocarb~styril(VI) reazted similarly 4-chloroanthranilic as follows : (a) meth- to give 111. In the methylation of 4,7-dichlorocarylation by means of dimethyl sulfate to N-meth- bostyril with diazo-ethane, N -methylation to I11 yl-4-chloroanthranilic acid (I) according to the was the chief result but a small amount of the method of Willstatter and Kahn,4 (b) acylation oxygen-alkyl derivative, 4,7-dichloro-2-methoxyand cyclizatiion to 7-chloro-4-hydroxy-1-methyl-quinoline, was also formed and i ~ o l a t e d . ~ bThe carbostyril (11) by means of acetic anhydride, above synthesis of the N-methylation products of according to the method of hIeister Lucius and the two carbostyrils (V and VI) from 4-chloro-NBriining for making 4-hydroxy-1-rnethylcarbo- methylanthranilic acid serves as confirmation of styril itself,6 and (c) hydrochlorination in the the structures and of the mode of the methylations. usual way with phosphorus oxychloride.
Fig. 1.
The conversion of 4,7-dichloro-l-methylcarboMethanolysis of 4,7-dichloro-1-methylcarbostyril (111) by means of sodium methoxide, and styril (111) into 2,4,7-trichloroquinoline(VII) by methylation of 7-chloro-4-hydroxy-1-methylcar-means of phosphorus pentachloride, following the analogous and facile conversion of l-methyl(1) T h e work described in this paper was done under a contract. carbostyril into 2-~hloroquinoline,~ failed to go aprecommended by 1:he Committee on Medical Research, between the preciably at 170' ; however, the reaction proOffice of Scientific Research and Development and t h e University of Virginia. ceeded satisfactorily in a sealed tube a t 220'. (2) Present addresses: (a) National Institute of Health, Bethesda, Preceding this synthesis, a model synthesis of Md.; (b) Jackson Laboratory, d u P o u t de Nemours a n d Co., Wil2,4-dichloroquinoline (X) by the same scheme had mington, Del.; (c) University of Texas, Austin, Texas. been run. 4-IIydroYy-1-methylcarbostyril (WIT), (3) (a) Lutz, Ashburn, Freek, Jordan, Leakc. Martin. Rtiwlett and Wilson, l'rrrs J O U R N A L . 68, 1255 (10.46); (b) Rtiwlrtt and Lutz, which hdd been prepared6 from N-methylanthraibid., 68, 1 2 % (lO4t;): ( c ) I . u t z , Ashbum and R
