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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US648226A
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John B Wright
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • 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

Definitions

  • the l,2,4-benzothiadiazepine-l,l-dioxide derivatives disclosed and claimed herein have not been reported previously in literature.
  • 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 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.
  • an inert aromatic solvent such as xylene, toluene, benzene, and the like
  • 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.
  • a Z-benzoylbenzenesulfonyl chloride II
  • V 2-alkylisothiourea
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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- bromobenz
  • 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-methoxybenzenesul
  • di(trifluoromethyl)benzophenone yields di(trifluoromethyl)benzenesulfonyl chloride.
  • 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
  • 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.
  • 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.
  • R is a primary, secondary, or tertiary amino grouping
  • R is a primary, secondary, or tertiary amino grouping
  • 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.
  • 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.
  • 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.
  • 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-benzoylbenzenesulfonyl chloride 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- fluoropheny
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US648226A 1967-06-23 1967-06-23 5-phenyl-1,2,4-benzothiadiazepine-1,1-dioxides Expired - Lifetime US3671528A (en)

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FR (1) FR1571016A (xx)
GB (1) GB1195933A (xx)
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DE3516616A1 (de) * 1984-08-30 1986-03-13 Bayer Ag, 5090 Leverkusen Benzodisultame
DE3517845A1 (de) * 1985-05-17 1986-11-20 Bayer Ag, 5090 Leverkusen Benzolactamsultame

Citations (9)

* Cited by examiner, † Cited by third party
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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IL30009A0 (en) 1968-07-25
FR1571016A (xx) 1969-06-13
BE716945A (xx) 1968-12-23
GB1195933A (en) 1970-06-24

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