US3671528A - 5-phenyl-1,2,4-benzothiadiazepine-1,1-dioxides - Google Patents

5-phenyl-1,2,4-benzothiadiazepine-1,1-dioxides Download PDF

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US3671528A
US3671528A US648226A US3671528DA US3671528A US 3671528 A US3671528 A US 3671528A US 648226 A US648226 A US 648226A US 3671528D A US3671528D A US 3671528DA US 3671528 A US3671528 A US 3671528A
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benzoyl
chloride
amino
dioxide
benzothiadiazepine
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John B Wright
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Pharmacia and Upjohn Co
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/36—Seven-membered rings

Abstract

1,2,4-Benzothiadiazepine-1,1-dioxide derivatives are disclosed. These compounds can be prepared by condensation of a 2benzoylbenzenesulfonyl chloride with guanidine, amidine, or with 2-alkylisothiourea, followed by cyclization of the obtained condensation product, and, optionally, by subsequent hydrogenation. These compounds are useful as intermediates for mothproofing agents, herbicides, and pickling inhibitors.

Description

United States Patent Wright [451 June 20, 1972 [s41 5-PHENYL-1,2,4-
BENZOTHIADIAZEPINE-1,1-DIOXIDES [72] lnventor: John B. Wright, Kalamazoo, Mich.
[73] Assignee: The Upjohn Company, Kalamazoo, Mich. [221 Filed: June 23, 1967 I [21] Appl. No.: 648,226
[52] U.S. Cl. ..260/268 BC, 260/247.l, 260/293.57, 260/327 B, 260/543 R [51] Int. Cl. ..C07d 99/00 [58] Field of Search ..260/268, 268 BC, 327 B, 243
[56] References Cited UNITED STATES PATENTS 3,526,638 9/1970 Hromatka ..260/327 B 3,464,996 9/1969 Wright ..260/327 B Salzberg ..260/243 X 3,051,727 8/1962 Teotino ..260/327 3,090,783 5/1963 Yale ..260/268 X 3,163,644 12/1964 De Stevens ..260/268 X 3,203,954 8/1965 Wright ..260/243 3,377,357 4/1968 Traverso... 260/327 Primary Examiner-Donald G. Daus Attorney-Eugene O. Retter and John Kekich [57] ABSTRACT 4 Claims, No Drawings S-PHENYL- l ,2,4-BENZOTHIAI)IAZEPINE- l l -DIOXIDES BACKGROUND OF THE INVENTION The l,2,4-benzothiadiazepine-l,l-dioxide derivatives disclosed and claimed herein have not been reported previously in literature.
SUMMARY OF THE INVENTION The compounds contemplated herein can be represented by the formula In the above formula R can beamino, alkylamino containing from one to four carbon atoms, inclusive, dialkylamino containing from one to four carbon atoms, inclusive, in each alkyl portion thereof, N-alkyl-l-piperazinyl containing from one to four carbon atoms, inclusive, in the alkyl portion thereof, l-pyrrolidinyl, morpholino, piperidino, phenyl, alkylphenyl containing from one to four carbon atoms, inclusive, in the alkyl portion thereof, alkoxyphenyl containing from one to four carbon atoms, inclusive, in the alkyl portion thereof, or alkylthio containing from one to four carbon atoms, inclusive, in the alkyl portion thereof.
R and R can be alike or different, and can be alkyl containing from one to four carbon atoms, inclusive, alkoxy containing from one tofour carbon atoms, inclusive, halo or trifluoromethyl.
'The subscripts m and n in the above formula are integers having a value from to 3, inclusive.
Also contemplated and within the purview of the present invention are the 4,5-dihydro derivatives of the foregoing that can be represented by the formula R m 3C-R DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention shown by Formula I can be prepared by condensing, at room temperature, a 2- benzoylbenzenesulfonyl chloride (II) represented by the formula solo! with guanidine (III) H,NC(=NH )NI-I In an amidine QC(=NH)NH2 IV where Q represents phenyl, alkylphenyl, or alkoxyphenyl, or with a 2-alkylisothiourea (V) of the type followed by cyclization of the condensation product.
The reaction, i.e., the condensation, is usually carried out in an inert aqueous-organic solvent such as acetone-water, and the like, and in the presence of an alkali metal hydroxide or carbonate.
The cyclization can be achieved by refluxing the aforementioned reaction product .in an inert aromatic solvent such as xylene, toluene, benzene, and the like, and in the presence of an acid catalyst such as p-toluenesulfonic acid, concentrated sulfuric acid, orthophosphoric acid, aluminum trichloride, and the like.
Compounds shown by Formula I and having a primary or a secondary amino group as the substituent in the 3-position can be prepared by reacting the cyclized condensation product of a Z-benzoylbenzenesulfonyl chloride (II) and a 2-alkylisothiourea (V) with the corresponding amine, e.g., alkylarnine, dialkylamine, pyrrolidine, morpholine, piperidine, or N-alkylpiperazine.
Compounds of the type represented by Formula la can be prepared by hydrogenating the corresponding Formula I compound in the presence of an effective amount of a hydrogenation catalyst, for example, platinum, or the like. The hydrogenation can be carried out at atmospheric pressures or above, usually at a pressure in the range from about 1 atm. to about 50 atrn. A hydrogenation pressure in the range from about 1 to about 3 atmospheres is preferred. Optionally a solvent such as dioxane, acetic acid, or ethanol-diethylformamide mixtures can be employed.
Chemical reducing agents such as sodium borohydride, lithium aluminum hydride, or the like, can also be used.
In Formulas I, la, II, IV, and V, illustrative alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, see-butyl, and tertbutyl; illustrative alkoxy radicals are methoxy, ethoxy, the propoxy, and the butoxy radicals; illustrative alkylphenyl radicals are the methylphenyl, the ethylphenyl, the propylphenyl, and the butylphenyl radicals; and illustrative alkoxyphenyl radicals are the methoxyphenyl, the ethoxyphenyl, the propoxyphenyl, and the butoxyphenyl radicals.
Similarly, illustrative alkylamino radicals are methylamino, ethylamino, the propylamino, and the butylamino radicals; illustrative dialkylamino radicals are dimethylamino, diethylamino, N-methyl-N-ethylamino, the dipropylamino, the dibutylamino, etc.; andillustrative N-alkyI-l-piperazinyl radicals are N-methyl-l-piperazinyl, N-ethyl-l-piperazinyl, N- propyll -piperazinyl, N-butyll -piperazinyl, etc.
The alkylthio radicals contemplated herein are illustrated by methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc. The halo radicals contemplated herein are fluoro, chloro, bromo, and iodo.
The 2-benzoylbenzenesulfonyl chloride (II) that can be employed in the preparation of the compounds of this invention can be prepared in accordance with the procedure set forth in Remsen et al., Am. Chem. J. I7, 354 (I895). In addition, 2- aminobenzophenones (VI), a well-known class of compounds, can be reacted with nitrous acid and then with sulfur dioxide and cupric chloride in an acid medium, e.g., in hydrochloric acid, to produce the corresponding 2-benzoylbenzenesulfonyl chlorides (II) as shown below:
bromobenzophenone, 2-benzoyl-4'-bromobenzenesulfonyl chloride from 2-amino-4'-bromobenzophenone, 2-benzoyl-4- bromobenzenesulfonyl chloride from 2-amino-5- bromobenzophenone, 2-benzoyl-3-brornobenzenesulfonyl chloride from 2-amino-o-bromobenzophenone, 2-benzoyl- 4,o-dibromobenzenesulfonyl chloride from '2-amino-3,5- dibromobenzophenone, 2-benzoyl-4-bromo-2'- fluorobenzenesulfonyl chloride from 2-amino-2'-fluoro-5- bromobenzophenone, 2-benzoyl-4-bromo-5-methoxybenzenesulfonyl chloride from 2-amino-4-methoxy-5- bromobenzophenone, 2-benzoyl-4-bromo-4'-methylbenzenesulfonyl chloride from 2-amino-4'-methyl-5- bromobenzophenone, 2-benzoyl-2'-chlorobenzenesulfonyl chloride from 2-amino-2'-chlorobenzophenone, 2-benzoyl-6- chlorobenzenesulfonyl chloride from 2-amino-3- chlorobenzophenone, 2-benzoyl-5-chlorobenzenesulfonyl chloride from 2-amino-4-chlorobenzophenone, 2-benzoyl-4'- methylbenzophenone, 2-benzoyl-4'-methyl-3'- chlorobenzenesulfonyl chloride from 2-amino-3-chloro-4'- methylbenzophenone.
In a like manner, 2-amino-2'-chloro-4,5-dimethylbenzophenone yields 2-benzoyl-4,5-dimethyl-2'- chlorobenzenesulfonyl chloride, 2-amino-2',4-dichloro-4,5- dimethylbenzophenone yields 2-benzoyl-4,5-dimethyl-2,4- dichlorobenzenesulfonyl chloride, 2-amino-2',5 '-dlchloro-4,5- dimethylbenzophenone yields 2-benzoyl-4,5-dimethyl-2,5'- dichlorobenzenesulfonyl chloride, 2-amino2'-methoxy-5- chlorobenzophenone yields 2-benzoyl-4-chloro-2'-methoxybenzenesulfonyl chloride, 2-amino-4'-methoxy-5- chlorobenzophenone yields 2-benzoyl-4-chloro-4-methoxybenzenesulfonyl chloride, 2-amino-2' methoxy-5-chloro-5'- methylbenzophenone yields 2-benzoyl-5'-methyl 4-chloro-2'- methoxybenzenesulfonyl chloride, 2-amino-2'- fluorobenzophenone yields 2-benzoyl-2'-fluorobenzenesulfonyl chloride, 2-amino4-fluorobenzophenone yields- 2- benzoyl-4'-fluorobenzenesulfonyl chloride, 2-amino-5- fluorobenzophenone yields 2-benzoyl-4-fluorobenzenesulfo nyl chloride, 2-amino-2-fluoro-5-methylbenzophenone yields 2-benzoyl-4-methyl-2'-fluorobenzenesulfonyl chloride, 2 2- amino-2'-trifluoromethylbenzophenone yields 2-benzoyl-.2'-
trifluoromethylbenzenesulfonyl chloride, 2-amino-3 trifluoromethylbenzophenone yields 2-benzoyl-3 trifluoromethylbenzenesulfonyl chloride, 2-amino-4- trifluoromethylbenzophenone yields 2-benzoyl-5 trifluoromethylbenzenesulfonyl chloride, 2amino-2',5-
di(trifluoromethyl)benzophenone yields di(trifluoromethyl)benzenesulfonyl chloride.
Similarly, 2-amino-2'-methoxybenzophenone produces 2- 2-benzoyl-2 ,4-
benzoyl-2'-methoxybenzenesulfonyl chloride, 2-amino-4- methoxybenzophenone produces 2-benzoyl-5-methoxybenzenesulfonyl chloride, 2-amino-4'-methoxybenzophenone produces 2-benzoyl-4'-methoxybenzenesulfonyl chloride, 2-amino-5-methoxybenzophenone produces 2- benzoyl-4-methoxybenzenesulfonyl chloride, 2-amino-2',4-
dimethoxybenzophenone produces 2-benzoyl-2',5-dimethoxybenzenesulfonyl chloride, 2-amino-3 ,4-dimethoxybenzophenone produces 2-benzoyl-5,6-dimethoxybenzenesulfonyl chloride, 2-amino-3 ',4'-dimethoxybenzophenone produces 2-benzoyl-3 ,4 '-dimethoxybenzenesulfonyl chloride, 2-amino-4,4',5-trimethoxybenzophenone produces 2-benzoyl-4,4' ,S-trimethoxybenzenesulfonyl chloride, 2-amino-2',5-dimethyl-3'-methoxybenzophenone produces 2-benzoyl-2',4-dimethyl-3'-methoxybenzenesulfonyl chloride, 2-amino-2'3'-dimethyl-4'-methoxybenzophenone produces 2-benzoyl-4'-methoxy-2 ,3 dimethylbenzenesulfonyl chloride, 2-amino-2',5 '-dimethyl-4'- methoxybenzophenone produces 2-benzoyl-2,5 '-dimethyl-4'- methoxybenzenesulfonyl chloride, 2-amino-2',4-dimethyl-5- methoxybenzophenone produces 2-benzoyl- 4-methoxy-2,5- dimethylbenzenesulfonyl chloride, 2-amino-2'-methyl-5- methoxybenzophenone produces 2-benzoyl-4-methoxy-2'- methylbenzenesulfonyl chloride, 2-amino-3,4-dimethylbenzophenone produces 2-ben2oyl-5,6-dimethylbenzenesulfonyl chloride, 2-amino-3-propyl-5-butylbenzophenone produces 2-benzoyl-4-butyl-6-propylbenzenesulfonyl chloride, 2-amino-4-ethyl-4'-butylbenzophenone produces 2- benzoyl-4'-butyl-S-ethylbenzenesulfonyl chloride, etc.
Methods for preparation of Z-aminobenzophenones are taught by Lothrop et al., J. Am. Chem. Soc. 65, 363 (I943) and Stembach et al., J. Org. Chem. 27, 3781 and 3788 (1962).
Guanidine (Ill) is a well-known compound and is commercially availableJn preparing the compounds of the present invention, both guanidine and its corresponding acid addition salts can be employed.
The amidines (IV) are well known. Illustrative are benzamidine, p-rnethylbenzamidine, p-butylbenzamidine, pmethoxybenzarnidine, p-propoxybenzamidine, and the like. For the purposes of the present invention the amidines or their corresponding acid addition salts are equally suitable.
The 2-alkylisothioureas (V) are also well known compounds. Illustrative are Z-methylisothiourea, 2-ethylisothiourea, 2-propylisothiourea, etc. Both the 2-alkylisothioureas and their acid addition salts are equally suitable.
The compounds of this invention represented by Formula I where R is a primary, secondary, or tertiary amino grouping form salts with fluosilicic acid which are useful as mothproofing agents in accordance with U. S. Pat. Nos. 1,915,334 and 2,075,359. These compounds also form salts with thiocyanic acid which condense with formaldehyde to form resinous materials useful as pickling inhibitors in accordance with US. Pat. Nos 2,425,320 and 2,606,155, and with trichloroacetic acid, the,latter salts being useful as herbicides against Johnson grass, yellow foxtail, green foxtail, Bermudagrass, and quack grass.
The compounds of this invention where R is an alkylthio radical are useful as intermediates for the preparation of compounds within the scope of Formula] where R is an amino grouping.
The compounds of this invention where R is an aryl group, such as phenyl, alkylphenyl. or alkoxyphenyl, are useful as intermediates for the preparation of dihydro compounds of the type la. Such compounds are useful, in turn, as intermediates for rnothproofing agents, herbicides and pickling inhibitors.
The following examples further illustrate the present invention.
EXAMPLE I: Preparation chlorobenzenesulfonyl)benzamidine A solution was prepared of water (about 50 milliliters). acetone (about l00 milliliters) and sodium hydroxide (about 8 gram 0. 2 mole), and benzamidine hydrochloride (about of N-( 2-benzoyl-4- 15.6 grams, 0.1 mole) was added thereto with stirring. Thereafter, 2-benzoyl4-chlorobenzenesulfonyl chloride (about 31.55 grams, 0.1 mole), dissolved in about 100 milliliters of acetone, was combined therewith.
The resulting mixture was stirred at about room temperature for about 2.5 hours, then diluted with about 1 liter of water, cooled to about 5 C., and filtered. A precipitate was recovered and was washed with water. About 33.15 grams of yellow prisms melting at 218 to 220 C. was obtained. Recrystallization from 2-butanone produced colorless prisms melting at 221 to 222 C. The prisms were identified as N-( 2- benzoyl-4-chlorobenzenesulfonyl)benzamidine, obtained in about 83 percent yield.
Calcd: C, 60.22; H, 3.79; N, 7.03; S, 8.04; Cl, 8.89. p1
Found: C, 60.29; H, 3.84; N, 6.70; S, 8.10; Cl, 8.96. EXAMPLE 11: Preparation of 7-chloro-3,5-diphenyl-l,2,4- benzothiadiazepine-1,1-dioxide N-( 2-benzoyl-4-chlorobenzenesulfonyl )benzamidine (about 11.95 grams, 0.03 mole), dry xylene (about 200 milliliters), and p-toluenesulfonic acid (about 250 milligrams) were admixed and refluxed with stirring under a water trap for about 70 hours. About 0.4.milliliters of water was collected in the water trap during this time (theoretical amount when reaction gone to completion-0.54 milliliters).
After refluxing, the produced admixture was cooled to about room temperature and a brown solid was observed to precipitate out. The solid was removed by filtration and identified as the starting benzamidine. The filtrate was concentrated by evaporation in vacuo and the obtained residue was recrystallized from ethyl acetate. About 6.4 grams of yellow tinted prisms melting at 219 to 221 C. was produced. An additional recrystallization yielded a product melting at 220 to 221 C. The product was identified as 7-chloro-3,5-d iphenyl-l,2,4-benzothiadiazepine-1,l-dioxide, obtained in about 71 percent yield.
Analysis for CgoHmClNzOgSi Calcd.: C, 63.07; H, 3.44; Cl, 9.31; N, 7.36; S 8.42.
Found: C, 6300;1-1, 3.84; Cl, 9.39; N, 7.03; S, 8.22.
Following the procedures of Examples 1 and 11 but using pmethylbenzamidine hydrochloride instead of benzamidine hydrochloride as one of the reactants the 7-chloro3-(4 methylphenyl )-5-phenyll ,2,4-benzothiadiazepine-l 1 dioxide can be prepared, using p-butylbenzamidine or the corresponding hydrochloride the 7-chloro3-(4-butylphenyl)-5- phenyl-l ,2,4-benzothiadiazepine-l,1-dioxide can be prepared, using p-ethoxybenzamidine or the corresponding hydrochloride the 7-chloro-3-(4-ethoxyphenyl)5-phenyl l,2,4-benzothiadiazepine-l,l-dioxide can be prepared, using p-butoxybenzamidine or the corresponding hydrobromide the 7-chloro-3-(C4-butoxyphenyl)-5-phenyl-1,2,4- benzothiadiazepine-1,1-dioxide can be prepared, etc.
Similarly, the choice of a particular 2-benzoylbenzenesulfonyl chloride will determine the type and position of the substituents R and R in the compounds depicted by Formula l. Thus, reacting 2-benzoyl-6-bromobenzenesulfonyl chloride with benzamidine hydrochloride will produce 9-bromo3,5- diphenyl- 1 ,2,4-benzothiadiazepine-1 1 -dioxide, reacting 2- ben2oyl-4'-bromobenzenesulfonyl chloride with benzamidine hydrochloride will produce 3-phenyl-5-(4-bromophenyl)- 1 ,2,4-benzothiadiazepine-1,1-dioxide, reacting 2-benzoyl-4- chloro-3'-fluorobenzenesulfonyl chloride with benzamidine hydrochloride will produce 7-chloro-3-phenyl-5-( 3- fluorophenyl)-l,2,4-benzothiadiazepine-1,l-dioxide, reacting 2-benzoyl-2 '-methoxy-4-chloro-5 -methylbenzenesulfonyl chloride with benzamidine hydrochloride will produce 7- chloro-3-phenyl-5-(2-methoxy-5-methylphenyl)-1,2,4- benzothiadiazepine- 1 l -dioxide, reacting 2-benzoyl-2'- trifluoromethylbenzenesulfonyl chloride with benzamidine hydrochloride will produce 3-phenyl-5-(2- trifluoromethylphenyl l ,2,4-benzothiadiazepinel l-dioxide, etc.
EXAMPLE lll Preparation of 2-benzoyl-4-chlorobenzenesulfonylquanidine A solution was prepared by combining guanidine carbonate (about 6 grams), water (about 6 milliliters), a 20 weight percent aqueous sodium hydroxide solution (about 30 milliliters), and acetone (about 20 milliliters). To the resulting solution was slowly added, with stirring, 2benzoyl-4- chlorobenzenesulfonyl chloride (about 16.6 grams, 0.053 mole) dissolved in acetone (about milliliters). The addition was carried out over a time period of about 15 minutes. During the addition, the temperature of the resulting admixture was maintained below about 10 C.
After the addition was completed, the thick mixture produced was diluted with water (about 200 milliliters) and filtered. A damp filter cake was recovered and was recrystallized from ethanol. About 7.85 grams of colorless prisms melting at 240 to 244.5 C. was produced. The mother liquor of the foregoing recrystallization subsequently yielded another 0.85 grams of colorless prisms melting at 241.5 to 244 C. An additional recrystallization raised the melting point to 245 to 246 C. The colorless prisms were identified as 2-benzoyl-4- chlorobenzenesulfonylguanidine, obtained in about 44 percent yield.
Analysis for C H CIN O S:
Calcd.: C, 49.78; H, 3.58; N, 12.44; S, 9.49; Cl, 10.50.
Found C, 49.82; H, 3.73; N, 12.01; S, 9.37; Cl, 10.52. EXAMPLE IV: Preparation of 3-arnino-5-phenyl-7-chlorol ,2,4-benzothiadiazepinel l -dioxide 2-Benzoyl-4-chlorobenzenesulfonyl guanidine (about 15.8 grams, 0.047 mole), p-toluenesulfonic acid (about 750 milligrams), and dry xylene (about 250 milliliters) were combined and refluxed under a water trap for about hours, permitted to cool to about room temperature, and then filtered.
The recovered solid was recrystallized from ethanol and about 10 grams of colorless prismatic crystals melting at 268 to 270 C. was obtained. Another recrystallization from ethanol gave colorless prismatic crystals melting at 269 to 270 C. The crystals were identified as 3-amino-5-phenyl-7- chloro- 1 ,2,4-benzothiadiazepinel 1 -dioxide, obtained in about 66.6 percent yield.
Analysis for C H CIN O S:
Calcd.: C,52.59;H, 3.15;Cl, 11.09; N, 13.14; S, 10.03.
Found: C, 52.29; H, 2.83; Cl, 11.02; N, 13.02; S, 9.97.
In a manner analogous to Examples 111 and IV, using 2 benzoyl-4-chloro-4'-methoxybenzenesulfonyl chloride and guanidine carbonate the 3-amino-5-(4'methoxyphenyl)-7- chloro- 1 ,2,4-benzothiadiazepine-l l -dioxide can be prepared, using 2-benzoyl-5,6-dimethoxybenzenesulfonyl chloride and guanidine carbonate the 3-amino-5-phenyl-8,9-dimethoxyl,2,4-benzothiadiazepine-l,l-dioxide can be prepared, using Z-benzOyl-4,4,S-trimethoxybenzenesulfonyl chloride and guanidine carbonate the 3-amino-5-(4-methoxyphenyl)-7,8- dimethoxyl ,2,4-benzothiadiazepine- 1 l -dioxide can be prepared, using 2-benzoyl-2',4'-dimethyl-3'-methoxybenzenesulfonyl chloride and guanidine carbonate the 3- amino-5-(2',4'-dimethyl-3-methoxyphenyl)-1,2,4- benzothiadiazepine-l,l-dioxide can be prepared, using 2- benzoyl-4-butyl--propylbenzenesulfonyl chloride and guanidine carbonate the 3-amino5-phenyl-7-butyl-9-propyl- 1,2,4-benzothiadiazepine-1,1-dioxide can be prepared, etc. EXAMPLE V: Preparation of 5-methyl-2-benzoyl-4- chlorobenzenesulfonylisothiourea A solution of water (about 6.91 grams, 0.05 mole) and acetone (about 20 milliliters) was chilled in ice and 2- methylisothiourea sulfate (about 2.78 grams, 0.01 mole) was added thereto with stirring. Thereafier, 2-benzoyl-4- chlorobenzenesulfonyl chloride (about 6.31 grams, 0.02 mole) was added thereto, followed by an additional amount of water (about 20 milliliters). Stirring of the resulting admixture was continued for about one hour at which time more water (about 50 milliliters) was added, and the stirring continued for an additional 3.5 hours. After the addition of more water (about milliliters) the obtained mixture was permitted to stand overnight and then filtered.
The solid material recovered upon filtration was recrystallized from ethanol, and about 6.15 grams of yellow prismatic crystals melting at 160 to 162 C. were obtained. A further recrystallization from ethanol produced yellow-tinted prismatic crystals melting at l60.5 to 162.5 C. The crystals were identified as -methyl-2-benzoyl-4-chlorobenzenesulfonylisothiourea, obtained in about 83.5 percent yield.
Analysis for C l-l ClN O S Calc'd.: C, 48.84; H, 3.55; Cl, 9.61; N, 7.60; S, 17.38.
Found C, 48.98; H, 3.85; CI, 9.75; N, 7.58; S, 16.72. EXAMPLE V1: Preparation of 3-methylthio-5-phenyl-7- chlorobenzol ,2,4-thiadiazepine- 1 l-dioxide S-rnethyl-2-benzoyl-4-chlorobenzenesulfonylisothiourea (about 35.28 grams, 0.096 mole), p-toluenesulfonic acid (about 1 gram), and xylene (about 800 milliliters) were admixed and refluxed under a water trap for about 42 hours. The water collected in the trap exceeded the theoretical amount by about 0.1 milliliter.
After refluxing, the obtained mixture was permitted to cool to about room temperature, filtered, and then concentrated by evaporation in vacuo. The residue produced was recrystallized from ethyl acetate, and about 25.8 grams of yellow prismatic crystals melting at 203C to 205 C. were obtained. The crystals were identified as 3-methylthio-5-phenyl-7- chlorobenzo-1,2,4-thiadiazepine-l,l-dioxide, obtained in about 77 percent yield. 7
Analysis for C, H,,C1N,O,S
Calcd.: C, 51.35; H 3.15; Cl, 10.10; N, 7.99; S 18.28.
Found C, 51.57; H, 3.47; C1, 10.33; N, 8.16; S, 18.08. EXAMPLE V11: Preparation of 7-chloro-3-diethylamino-5- phenyl- 1 ,2,4-benzothiadiazepine-l 1 -dioxide A solution of 3-methylthio-5-phenyl-7-ch1orobenzo-l,2,4- thiadiazepine-Lbdioxide (about 3.51 grams, 0.01 mole), diethylamine (about 40 milliliters), and dioxane (about 75 milliliters) was refluxed for about 17 hours. Thereafter, any unreacted amine and the dioxane were removed by evaporation in vacuo, and the obtained residue recrystallized from ethyl acetate.
About 2.6 grams of yellow prismatic crystals melting at 210 to 212 C. were obtained. A second recrystallization from ethyl acetate produced yellow prismatic crystals melting at 211 to 212 C. The crystals were identified as 7-ch1oro-3- diethylamino-S-phenyll ,2,4-benzothiadiazepine.- l 1 -dioxide, obtained in about 69.5 percent yield.
Analysis for C H ClN O S:
Calc'd.: C, 57.52; H, 4.83; Cl, 9.43; N, 11. 18; S, 8.53.
Found C, 57.84; H, 4.76; Cl, 9.37; N, 11.08; S, 8.43.
In a manner similar to Example V11 but using n-butylamine instead of diethylamine, the 7-chloro-3-n-buty1amino-5-phenyl-l,2,4-benzothiadiazepine-1,l-dioxide can be prepared, using dipropylamine the 7-chloro-3-dipropylamino-5-phenyl- 1,2,4-benzothiadiazepine- 1,1-dioxide can be prepared, using ethylamine the 7-chloro-3-ethylamino-S-phenyl-1 ,2,4- benzothiadiazepine-l,l-dioxide can be prepared, using methylamine the 7-chloro-3-methylamino-5-phenyl-1,2,4- benzothiadiazepined l -dioxide can be prepared, etc. EXAMPLE Vlll: Preparation of 3-(4-methylpiperazino)-5- phenyl-7-chloro- 1 ,2,4-benzothiadiazepine- 1 1 -dioxide 3-Methylthio-Sphenyl-7-chlorobenzo- 1 ,2,3-thiadiazepine- 1,1-dioxide (about 3.5 grams, 0.01 mole) and l-methylpiperazine (about 15 milliliters) were combined and heated, with stirring, at about 50 C. for about 16 hours. Thereafier, any unreacted l-methylpiperazine was removed by evaporation in vacuo at about 50 C. The obtained residue was diluted with water and filtered.
A solid material was recovered upon filtration and was recrystallized from an ethanol-water mixture (weight ratio 1:1 About 1.95 grams of tan prismatic crystals melting at 197 to 199 C. was obtained. Recrystallization from isopropanol produced tan prismatic crystals melting at 197.5 to 199.5 C. The crystals were identified as 3-(4-methylpiperazino)-5- phenyl-7-chloro- 1 ,2,4-benzothiadiazepine- 1 1 -dioxide, obtained in about 49 percent yield.
Analysis for C H ClN,O S:
Calcd.: C, 56.64; H, 4.75; Cl, 8.80; N, 13.91; S, 7.96.
Found C, 56.32; H, 4.97; Cl, 8.81; N, 13.09; S, 7.94.
In a manner analogous to Example V111 but using l-n-butylpiperazine instead of l-methylpiperazine the 3-(4-n-butylpiperazine )5-phenyl-7-chloro- 1 ,2,4-benzothiadiazepine-1 ,1- dioxide can be prepared, using l-propylpiperazine the 3-(4- propyliperazino )-5-phenyl-7-chlorol ,2,4- benzothiacliazepine-l,l-dioxide can be prepared, using 1- ethylpiperazine the 3-(4-ethylpiperazino)-5-phenyl-7-chloro- 1,2,4-benzothiadiazepine-l,l-dioxide can be prepared, using pyrrolidine the 3-( l-pyrrolidinyl)-5-phenyl-7-chloro-1,2,3- benzothiadiazepine-l,l-dioxide can be prepared, using morpholine the 3-morpholino-5-phenyl-7-chloro-1,2,4- benzothiadiazepine-1,l-dioxide can be prepared, using piperidine the 3-piperidino-5-phenyl-7-chloro-l ,2,4- benzothiadiazepine-l ,l-dioxide can be prepared, etc. EXAMPLE 1X: Preparation of 7chloro-4,5-dihydro-3,5- diphenyll ,2,4-benzothiadiazepinel l -dioxide A solution of 7-chloro-3,5-diphenyl-1,2,4- benzothiadiazepine-l,l-dioxide (about 3.8 grams, 0.01 mole) in 10.1 weight ratio dioxane-acetic acid mixture (about 200 milliliters) was hydrogenated over Raney nickel at an initial pressure of about 3.4 atmospheres. The actual hydrogen uptake in about 4.5 hours was about 88.3 percent of the theoretical. Additional shaking of the reaction vessel resulted in no further uptake of hydrogen.
Thereafter, the raney nickel was removed by filtration and the filtrate concentrated by evaporation in vacuo. An oily residue was obtained and was stirred with water (about 25 milliliters) to bring about crystallization. Upon filtration, about 3.8 grams of a yellow solid melting at to 115 C. was recovered. Recrystallization from isopropanol produced about 2.4 grams of yellow crystalline needles melting at 219 to 221 C. The needles were identified as 7-chloro-4,5- dihydro-3,5-diphenyl-1,2,4-benzothiadiazepine-l 1 -dioxide obtained in about 63 percent yield.
Analysis for C H ClN O S:
Calc'd.: C, 62.74; H, 3.95; Cl, 9.26; N, 7.32; S, 8.37.
Found: c 62.79; H, 3.90; Cl, 9.1 l; N, 7.43; S, 8.31. EXAMPLE X: Preparation of 3-amino-4,5-dihydro-S-phenyl- 7-ch1oro-l ,2,4-benzothiadiazepine-l l -dioxide A solution of 3-amino5-phenyl-7-chloro1,2,4- benzothiodiazepine-l,l-dioxide (about 4.8 grams, 0.015 mole) in 10:1 weight ratio dioxane-acetic acid mixture (about milliliters) was hydrogenated over platinum oxide (about 250 milligrams) at an initial pressure of about 3.4 atmospheres. The theoretical uptake of hydrogen was attained in about 5 hours.
Thereafter, the platinum oxide was removed by filtration and the filtrate concentrated by evaporation in vacuo. The obtained residue was triturated with ether, filtered, and then recrystallized from benzene. The produced crystalline material was then recrystallized twice from ethanol. About 1.6 grams of colorless prismatic crystals melting at 303 C. (dec.) were recovered. The crystals were identified as 3-amino-4,5 dihydro-5-phenyl7-chloro-1,2,4-benzothiadiazepine-l l dioxide, obtained in about 33 percent yield.
Calc'd.: C, 52.26; H, 3.76; C1, 1 1.01; N, 13.06; S, 9.96.
Found C, 51.81;H, 3.98;Cl, 10.70; N, 12.80; S, 9.67.
lclaim:
l. A 1,2,4-benzothiadiazepine-l,l-dioxide represented by the formula 2. A l,2,4-benzothiadiazepine-l,l-dioxide represented by the formula 3. A l,2,4-benzothiadiazepine-l,l-dioxide represented by C1 the formula Patent N 5! Dated June Inventor(s)' John B W ri gh t It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as-shown below:
Column 5 l i ne 15-, for "8.89. pl read 8.89. Column 5, line 52, for "3434-" read 3-(4- Column 7, l i'ne 21, for
205 0 to" read 203 to Column 8, I ine 9, for "-1,2,5
read --l,2,4-
Signed and sealed this 2nd day of January 1973.
(SEAL) Attest:
EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM po'wso (1069) uscomm-oc scans-Pea k U 5. GOVERNMENT PRINTING OFFICE 1969 O' 355J]l

Claims (3)

  1. 2. A 1,2,4-benzothiadiazepine-1,1-dioxide represented by the formula
  2. 3. A 1,2,4-benzothiadiazepine-1,1-dioxide represented by the formula
  3. 4. A 1,2,4-benzothiadiazepine-1,1-dioxide represented by the formula
US648226A 1967-06-23 1967-06-23 5-phenyl-1,2,4-benzothiadiazepine-1,1-dioxides Expired - Lifetime US3671528A (en)

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DE3516616A1 (en) * 1984-08-30 1986-03-13 Bayer Ag, 5090 Leverkusen BENZODISULTAME
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Citations (9)

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Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US3051727A (en) * 1962-08-28 S-dihydro-l
US3090783A (en) * 1962-06-12 1963-05-21 Olin Mathieson Dihydrobenzothiadiazines
US3163644A (en) * 1959-10-16 1964-12-29 Ciba Geigy Corp Derivatives of 2-h-1, 2, 4-benzo thiadiazine-1, 1-dioxide
US3203954A (en) * 1963-07-15 1965-08-31 Upjohn Co Novel 3, 5-disubstituted-1, 2, 6-(2h)-thiadiazine-1, 1-dioxides
US3377357A (en) * 1966-06-27 1968-04-09 Lilly Co Eli 1, 2-benzothiazepine-1, 1-dioxides and their preparation
US3407198A (en) * 1966-08-10 1968-10-22 Upjohn Co 2h-1, 2, 3-benzothiadiazine-1, 1-dioxides
US3464996A (en) * 1967-05-16 1969-09-02 Upjohn Co 6h - dibenzo(c,g)(1,2,5)thiadiazocine - 5,5-dioxides and method for their production
US3526638A (en) * 1967-10-05 1970-09-01 Smithkline Corp Substituted 3,4-dihydro-1h-2,1,5-benzothiadiazocine-2,2-dioxides

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3051727A (en) * 1962-08-28 S-dihydro-l
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US3163644A (en) * 1959-10-16 1964-12-29 Ciba Geigy Corp Derivatives of 2-h-1, 2, 4-benzo thiadiazine-1, 1-dioxide
US3090783A (en) * 1962-06-12 1963-05-21 Olin Mathieson Dihydrobenzothiadiazines
US3203954A (en) * 1963-07-15 1965-08-31 Upjohn Co Novel 3, 5-disubstituted-1, 2, 6-(2h)-thiadiazine-1, 1-dioxides
US3377357A (en) * 1966-06-27 1968-04-09 Lilly Co Eli 1, 2-benzothiazepine-1, 1-dioxides and their preparation
US3407198A (en) * 1966-08-10 1968-10-22 Upjohn Co 2h-1, 2, 3-benzothiadiazine-1, 1-dioxides
US3464996A (en) * 1967-05-16 1969-09-02 Upjohn Co 6h - dibenzo(c,g)(1,2,5)thiadiazocine - 5,5-dioxides and method for their production
US3526638A (en) * 1967-10-05 1970-09-01 Smithkline Corp Substituted 3,4-dihydro-1h-2,1,5-benzothiadiazocine-2,2-dioxides

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