2042
HARRYL. YALE,KATHRYN LOSEEAND
vent gave the pure product, m.p. 165-167'. T h e yield was 8 g. (39%). Compounds X I I , XI11 and XV were similarly prepared by substituting ethyl chloroacetate, chloroacetaldehyde dimethyl acetal and 8-chloroethyl 8-hydroxyethyl ether, respectively, for the P-chloroethyl vinyl ether in the above synthesis. a - M e t h y l 4 { 3-[2-(trifluoromethyl)-l0-phenothiazinyl] propyl) -piperazinemethanol Dimaleate (VIII) (A).-A mixture of 19.8 g. (0.05 mole) of IV, 12.4 g. (0.1 mole) of pchloroethyl carbamate, 6.9 g. (0.05 mole) of anhydrous potassium carbonate and 100 ml. of anhydrous toluene was stirred and refluxed for 18 hours, filtered, and the filtrate concentrated t o dryness on the steam-bath in vacuo. T o the residual oil in 250 ml. of warm acetonitrile was added a solution of 13.4 g. of maleic acid in 150 ml. of warm acetonitrile. T h e mixture was warmed for 0.5 hr., cooled and the solid filtered. It weighed 5 g. A recrystallization from water gave 3.5 g. (10% yield) of product, m.p. 210-212' dec. A mixture m.p. with I a was 160-200'. T h e above dimaleate was dissolved in a minimum amount of warm water and the base liberated with an excess of 20% aqueous potassium hydroxide solution. The base was extracted into ether, the ether solution was washed with water and dried. T h e filtered ether solution was cooled and treated with a slight excess of ethereal hydrogen chloride. T h e very hygroscopic salt which separated was filtered and recrystallized from absolute ethanol t o give the pure dihydrochloride ; m .p . 20k208'. (B).-A mixture of 3.9 g. (0.01 mole) of IV, 1.32 g. (0.03 mole) of acetaldehyde and 100 ml. of anhydrous toluene sealed in a Carius tube was heated 18 hours a t 93". T h e tube was cooled, opened and the toluene solution concentrated in vacuo t o give a black tar. This was extracted with 50 ml. of boiling acetonitrile, and the acetonitrile solution decanted from the insoluble material. T o the acetonitrile solution was added a solution of 2.32 g. (0.02 mole) of maleic acid in 20 ml. of warm acetonitrile. The dark tan solid which separated on cooling was filtered and washed withOa little acetonitrile. The solid weighed 1.0 g., m.p. 188-190 Recrystallization first from 95% ethanol and then from water gave 0.3 g. of material, m.p. 210-212' dec. A mixture m a p . with VIIIa was 210-212' dec., and the infrared spectra of the two compounds were identical. Anal. Calcd. for C ~ ~ H ~ ~ F ~ N ~ O S . N, ~ C6.28; I H ~ OS,~ : 4.79. Found: N, 6.56 S, 4.97. 4-{ 3-[2-(Trifluoromethyl)-lO-phenothiazinyl] -propyl 1 piperazine-ethanol 5-Oxide Hydrochloride.-Four and onehalf grams (0.01 mole) of I in 200 ml. of 9570 ethanol and a ethanol solution of 1.8 g. of oxalic acid in 50 ml. of were mixed rapidly. Subsequently, the mixture was hedtcd under reflux for 0.5 hr., cooled, and the dioxalate filtered. It was an extremely iiisolublc compound, 1n.p. 215-217"
-
.
[CONTRIBUTION FROM
TIIE SQUIBB
JACK
BERNSTEIN
VOl. 82
dec. One recrystallization from 95% ethanol raised the m.p. t o 220-221' dec. This dioxalate, 250 ml. of 9570 ethanol, 100 mi. of water and 1.3 g. of 30y0 hydrogen peroside were refluxed for 24 hours, then concentrated in vucuo on the steam-bath. The residual yellow gum was dissolved in water, and the solution treated with an excess of 10% aqueous sodium hydroxide solution. T h e liberated base was insoluble in ether but could be extracted with chloroform. T h e chloroform extracts were dried and concentrated. T h e residual oil was dissolved in 10 ml. of isopropyl alcohol and the solution treated with ethereal hydrogen chloride. The crystalline solid which separated was filtered and recrystallized from chlorobznzene t o give 2 g. (4070 yield) of product, m.p. 213-215 . Anal. Calcd. for CzzH26F3S302S.HC1:C, 53.92; H , 5.56; N, 8.58; C1, 7.24; S, 6.54. Found: C , 53.83; €1, 5.46; N,8.43; C1, 7.28; S,6.71. 4-[3- [lo-(7-Nitro-2-trifluoromethyl)-phenothiazinyl] -propyl)-1-piperazine-ethanol Dimaleate (X).-A mixture of 31.2 g. (0.1 mole) of 7-nitro-2-(trifluoromethyl)-phenothiazine, 4.3 g. (0.11 mole) of sodium amide and 300 ml. of diethylene glycol dimethyl ether was heated t o 90" and 18.9 g. of trimethylene chlorobromide added dropwise. T h e mixture was then stirred and heated for 18 hours a t 145O, cooled and to it was added 22.5 g. of sodium iodide and 26 g. of 1-piperazine-ethanol. Subsequently, the reaction was allowed t o proceed for 18 hours at 115O, the mixture diluted with 300 ml. of anhydrous xylene and filtered. T h e filtrate was concentrated on the steam-bath in vucuo, and the residue, in acetonitrile, converted t o the maleic acid salt. T h e crude salt was twice recrystallized from 9570 ethanol to give 12 g. (17% yield) of pure product, m.p. 185-187' dec. Anal. Calcd. for C ~ ~ H ~ S F ~ N ~ O ~ S C, .~C 50.42; ~H~O~: H , 4.65; N, 7.84. Found: C, 50.41; H, 4.85; N, 7.61. 10-[3-(4-Methyl-l-piperazinyl)-propyl] -7-nitro-2-( trifluoromethyl)-phenothiazine (XI).-A mixture of 31.2 g. (0.1 mole) of 7-nitro-2-(trifluoromethyl)-phenothiazine, 4.3 g. (0.11 mole) of sodium amide and 300 ml. of diethylene glycol dimethyl ether was heated to 90" and treated dropwise with 21.2 g. of 4-methyl-1-piperazinepropyl chloride. The mixture was then heated to 135' and maintained for four hours a t this temperature, cooled, and filtered. The filtrate was concentrated on the steam-bath in vacuo. When the residual oil was treated with acetonitrile, crystallization occurred, T h e solid was filtered to give 31 g. of crude product, m.p. 124-126". After one recrystallization from hexane, there mas obtained 23 g. (51% yield) of pure product, m.p. 127-128'. Anal. Cdlcd. for c2111$3S10~s: C, 55.73; 11, 5.12; N,12.38. Fouiid: C, 55.99; €1, 5.00; N, 12.01.
NEWBRUNSWICK, N. J.
INSIITUTE
FOR
MEDICAL KESEARCH]
6-(Trifluoromethyl)-l,2,4-benzothiadiazine-7-sulfonamide-1,l-dioxide and Related Compounds BY HARRYL. YALE,KATHRYN LOSEEAND
JACK
BERNSTEIN
RECEIVED AUGUST 21, 1959 The synthesis o f G - ( tri~uoroinethyl)-l,2,4-benzotl1iadiazine-7-st~lfo~~a1nide-l,l-dioxide (11) and its 3-rnethyl- ( X I I I ) arid (V) aiid its 3-ethyl- (XV) dcrivatives, 3,4-dihydro-6-(trifluorornethpl)-1,2,4-benzothiadiazine-7-sulf~~~amide-l,l-dioxide ( X X I I I ) is ethyl derivative ( V I ) , as well as 3-oxo-6-(trifluoromethyl)-1,2,4-benzothiadiazine-7-sulfonamide-l,l-dioxide described. Both I1 and V have demonstrated clinical usefulness as diuretic agents. The effect on the diuretic activity of these compounds caused by the replacement of a benzene by a pyridine nucleus has also been ascertained by synthesizing (XVIII), 3,4-dihydro-1,2,4-pyrido [2,3-e]thiadiazine-7-sulfonamidel,2,4-pyrido [2,3-e]thiadiazine-7-sulfonamide-l,l-dioxide 1,l-dioxide ( X I X ) and 6-methyl-1,2,4-pyrido[2,3-e]thiadiazine-7-sulfonamide-l,l-dioxide (XX). Elucidation of the (I), precursors, restructures of the acetyl and propionyl derivatives of 5-amino-a,~~,a-trifluoro-2,4-toluenedisulfonamide spectively, of XI11 and XV, has involved t o a considerable extent a study of the infrared spectra of these derivatives. These data are presented and discussed.
The clinical effectiveness of B-chloro-1,2,4-benzo- etic agentlbvc suggested to us the synthesis of the thiadiazine-7-sulfonainide-l,l-dioxide1~ as a diur- corresponding 6-(trifluoromethyl) derivative. This reasoning was based On the Observation that the ( 1 ) (a) F. C. Iiovello and J. & Sprague, I. THISJ O U R N A L , 79, 2028 (1957): (b) R. V. Ford and C. L. Spurr, Southern SOL.Clin. Research M c c f i a , 1, 26 ( l Q 5 7 ) ,through A m . J . M c d . , 22, 965 (1957); ( c ) R. V.
Ford, J. H.Moyer and C. L. Spurr, A . M . A . Arch. o j I n f . Med.. 100, 582
(1957).
April 20, 1960
6-(~RIFLUOROMETHYL)-~,~,~-BENZOTHIADIAZINE-~-SULFONAR.ZIDE1,l-DIOXIDE
substitution of a chlorine atom by a trifluoromethyl group in various classes of organic compounds has led to a number of clinically useful drugs.2 We are now reporting the synthesis of 6-(trifluoromethyl)1,2,4-benzothiadiazine- 7 -sulfonamide- 1 , l -dioxide3 (11) which has been found to be a useful diuretic agent.4a,b,c In addition, we have prepared 3,4dihydro - 6 - (trifluoromethyl) - 1,2,4 - benzothiadiazine-7-sulfonamide-l,1-dioxide (V),K which has been reported to possess similar pharmacological activity,% along with its 3-ethyl derivative VI. These compounds were obtained by the sequence of reactions shown in Chart I. CHARTI
2043
CHARTI1
a
S02NH2. 100'
+
AczO
NHr VI1 Ac,O CSH,N
aso~Hz SHCOCHj
1
/ZOO'
do' . aSl: w SHz
LOO'
N X
N(COCHj), IX
CHj
methyl)-1,2,4-benzothiadiazine-l, 1-dioxidegwas recovered unchanged from a similar treatment with acetic anhydride, the acetylation could not have occurred in the thiadiazine ring but rather a t the 7-position in XIII. These reactions are summarized in Chart 111. CHART111 C l i ; C O \ H S O ~ S O ~ l \ H C O C
