FLAVENE. JOHNSON
74
[CONTRIBUTION FROM THE
AND
CLIFFS. HAMILTON
Vol. 71
DEPARTMENT OF CHkFIIIITRY, AVERVLABORATORY, UNIVERSITY OF NEBRASKA]
Certain Derivatives of 2-Aminobenzothlazole B Y FLAVEPJ E.JoHNWN' AND CLIFF
Alkyl aryl and heterocyclic aryl sulfones containing a p-amino group have shown marked bacteriostatic3 and antitubercular3 activity. This is particularly true of derivatives containing the thiazole ring.4 Sulfides and sulfoxides have also shown chemotherapeutical activity.6 The present investigation was undertaken to embody the above characteristics in one compound by synthesizing sulfur containing derivatives of 2-aminobenzothiazole, for example 6-methylmercapto2-aminobenzothiazole (V)
s. HAMILTON Experimental
Sodium p-Nitrothiophenate (I) .-This compound was
prepared according t o the procedure of Stacyd using a 75Yo ethanol-water solution as the reaction medium. The solution was kept a t reflux temperature during the entire reaction to yield 84% of the desired salt. 4-Methyhercaptonitrobenzene (11).-The procedure as employed by Waldron and Reid? was used t o prepare the coypound in 70-75% yields; m. p., 68-69', lit.' 67" and 71 4-Methylmercaptoaniline Hydrochloride (111).4Methylmercaptonitrobenzene (45 g., 0.32 mole) was reduced in three runs (15 g. each), by means of hydrogen and Raney nickel in acetone solution. Six hours were required for complete reduction and the product was isolated as a salt by passing dry hydrogen chloride gas through the solution. The product removed by jiltration weighed 44.5 g. (94%) and was identified by formation:f the benzoyl derivative; m. p. 176-178", lit.* 177-178 Y 4-Methylmercaptophenylthiourea (IV) .-The meth$ 4-Methylmercsptonitrobenzene (11) was pre- used was 'ha,' of WertheimQ; yield 86%, m. p. 200-201 , pared by a series of conventional methods, re- lit.P 198-199 2 -Amino 6 methylmercaptobenzotole (V) .-4duced to the amine and converted to 4-methylMethylmercaptophenylthiourea (58 g., 0.29 mole) was mercaptophenylthiourea (IV). Oxidation of IV suspended in 200 ml. of dry chloroform in a 600-ml. roundwith bromine gave 2-amino-6-methyhercapto- bottomed flask. Liquid bromine (58 g., 0.362 mole) in benzothiazole (V) in good yields. After pro- dry chloroform (100 ml.) was carefully added. The reactecting the amino group cornpound V was oxi- tion flask was placed under a reflux condenser provided with a trap t o catch hydrogen bromide vapors and caredized to 2-amino-6-methylsulfonylbenzothiazole fully warmed for forty minutes. The solvent was then de(VIII) in excellent yields. canted and fresh chloroform added followed by twenty 2-Amino-6-methylsulfonylbenzothiazole was minutes of heating. The solid which remained was dealso prepared by oxidizing compound TI to 4- canted free of solvent and dried. The yellow amorphous material was triturated with sulfurous acid solution and methylsulfonylnitrobenzene (IX), reducing it to washed with water. The hydrobromide salt obtained was the amine and treating the compound obtained dissolved in 1.5 1. of hot water, filtered free of impurities with ammonium thiocyanate, then with bromine and made alkaline with ammonium hydroxide. The solid to give a low yield of compound VIII. This separating on cooling was recrystallized from 50% ethanolwater solution; yield, 51.2 g. (89.5%) of light tan plates synthesis proved that the mercapto sulfur and melting a t 160-151 . not the ring sulfur was undergoing oxidation. 2-Acetamido-6-methytmercaptobenzothiazole (VI) Conversion of compound VIII to 2-chloro-6- 2-Amino-6-methylmercaptobenzothiazole(15 g., 0.8 mole) rnethylsulfonyl-benzothiazole (XI) proceeded was dissolved by warming in technical grade acetic anhyand treated in the conventional manner to obtain smoothly employing a modified Sandmeyer re- dride 18.1 g. (99%) of cream-colored crystals, which recrystalaction. An attempt to use the same reaction on lized from 95% ethanol and had a m. p. of 198-200'. compound V produced two products, Z-chloro-6A d . Calcd. for C ~ O H ~ O N ~ N, O S11.75. Z: Found: N, rnethylsdfhylbenzothiazole (XVI) at 0' and 12.03. 2-chloro-6-methylmercaptobenzothiazole (XXI) 2 -Acetamido-6-methylsulfonylbenzot~ole (VII) .-2a t -20'. Compounds XVI and XXI were later Acetamido-6-rnethylmercaptobenzothiazole (18.1 g., 0.8 mole) was dissolved in 340 ml. of glacial acetic acid by oxidized to XI by means of hydrogen peroxide. on a steam-bath. Hydrogen peroxide solution Chloro compounds XI, X V I and XXI were all warming (60 ml., 30%) in glacial acetic acid (40 mt.) was added and successfully condensed with benzylamine, piperi- the mixture warmed t o 80" on n steam-bath. After standdine, 6-diethylaminobutylarnine and y-diethyl- ing a t room temperature for one hour the reaction solution was placed in the refrigerator overnight. The white ffuffy anlinopropylamine to produce the remainder of crystals that separated were removed by filtration, washed the compounds shown in the accompanying with water and dried; yield 15.7 g. (76.5'%), m. p. 305tables. 307"" All of the sulfone derivatives and a represcntaA m Z . C A x ~ .for C10HION203S~: N, 10.36. Found: tive member of the sulfoxide and sulfide series N, 10.52. 2-Amino-6-meth~lsulfonyfbenzothiazole (VXXX) (Method have been submitted for pharmacolo~cals(-rwi I) .--2 -Acetamide-6 -meth ylsulf onylbenzothiazole ( 15.7 g , testing. 0.6 mole) wa4 heated a t reflux temperature with hydro(1) Parke, Davis and Company fellow. chloric acid (1.V, 240 ml.) for thirty minutes. The white
.
.
.
-
.-
.-
.
(2) Fourtieau,
