NO130998B

NO130998B -

Info

Publication number: NO130998B
Application number: NO14509962A
Authority: NO
Inventors: T Ploetz; K Wimmer
Original assignee: Feldmuehle Anlagen Prod
Priority date: 1961-07-14
Filing date: 1962-07-13
Publication date: 1974-12-09
Also published as: DE1411296A1; FI48211B; SE328763B; NO130998C; GB1017372A; CH402587A; FI48211C

Description

Fremgangsmåte til fremstilling av sulfamyl-3,4-dihydro-l,2,4-benzoetiadiazin-1,1 -dioksyder. Process for the preparation of sulfamyl-3,4-dihydro-1,2,4-benzoethiadiazine-1,1-dioxides.

Oppfinnelsens gjenstand er en fremgangsmåte til fremstilling av 3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyder med den generelle formel The object of the invention is a process for the production of 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides with the general formula

og salter, særlig med alkalimetaller, av disse forbindelser. Her betyr R,, R,, og R5 vannstoff eller alkylrester, spesielt med 1—5 karbonatomer, R2 betyr vannstoff, en eventuelt substituert alifatisk kullvannstoffrest, en eventuelt substituert aryl- and salts, especially with alkali metals, of these compounds. Here, R1, R1, and R5 mean hydrogen or alkyl residues, especially with 1-5 carbon atoms, R2 means hydrogen, an optionally substituted aliphatic hydrocarbon residue, an optionally substituted aryl

eller aralkylrest eller en eventuelt substituert monocyklisk heterocyklisk rest med nitrogen-, oksygen- eller svovel som heteroatomer, som eventuelt også kan være forbundet over en alkylrest med tiadiazinringen. R, betyr alkylrester, spesielt med 1—5-kullstoffatomer, foretrede hydroksylgrupper eller halogenatomer, og hvos R.,, or aralkyl radical or an optionally substituted monocyclic heterocyclic radical with nitrogen, oxygen or sulfur as heteroatoms, which can optionally also be connected via an alkyl radical to the thiadiazine ring. R, means alkyl radicals, especially with 1-5 carbon atoms, etherified hydroxyl groups or halogen atoms, and if R.,,

R.j og R5 betyr hydrogen og R, betyr klor, betyr R, en alkylrest. Som alifatiske kull-vannstoffrester skal det spesielt nevnes R.j and R.sub.5 mean hydrogen and R, means chlorine, R means an alkyl radical. As aliphatic coal-hydrogen residues, special mention should be made

alkylrester, som metyl-, etyl-, propyl-, isopropyl-, butyl- eller pentylrester, eller alkenylrester, som vinyl- eller 1-propenyl-rester, eller arylrester, spesielt mono- alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl or pentyl radicals, or alkenyl radicals, such as vinyl or 1-propenyl radicals, or aryl radicals, especially mono-

eller bicykliske arylrester, f. eks. fenyl-, naftyl-(l)- eller naftyl-(2)-rester eller aralifatiske rester, f. eks. benzyl-, 2-fenyl- or bicyclic aryl residues, e.g. phenyl, naphthyl-(1) or naphthyl-(2) residues or araliphatic residues, e.g. benzyl-, 2-phenyl-

etyl-, naftyl-(1)- eller -(2)-metylrester. Monocykliske, heterocykliske rester er i første • rekke furyl-, tienyl- eller pyridyl-rester, som også kan være bundet over en alkylrest til tiadiazinringen som furfuryl- ethyl, naphthyl-(1)- or -(2)-methyl residues. Monocyclic, heterocyclic residues are primarily • furyl, thienyl or pyridyl residues, which can also be linked via an alkyl residue to the thiadiazine ring such as furfuryl

eller tenylrest. Som substituenter av disse rester skal det f. eks. nevnes alkylrester, or tinyl residue. As substituents of these residues, e.g. alkyl residues are mentioned,

frie, forestrede eller foretrede hydroksyl- free, esterified or etherified hydroxyl-

eller merkaptogrupper, f. eks. acetoksy-, fenoksy-, metylendioksy- eller metylmer-kaptogrupper, sulfamylrester, aminogrup- or mercapto groups, e.g. acetoxy, phenoxy, methylenedioxy or methylmer capto groups, sulphamyl residues, amino groups

per. slik som dimetylaminogruppen, eller halogenatomer. per. such as the dimethylamino group, or halogen atoms.

Det er kjent at 6-substituerte 7-sulfamyl-l,2,4-benzotiadiazin-l,l-dioksyder, It is known that 6-substituted 7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxides,

særlig 6-klor-7-sulfamyl-1,2,4-benzotiadia-zin-l,l-dioksyd, har diuretisk og natriure- especially 6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide, has diuretic and natriuretic

tisk virkning (sammenlign Novello et al., J.A.C.S. 79, 1957, 2028). Det var nu over-raskende å fastslå at de nye 3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyder har en vesentlig bedre diuretisk og natriuretisk virkning. De skal anvendes som legemidler. tical effect (compare Novello et al., J.A.C.S. 79, 1957, 2028). It was surprising to find that the new 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides have a significantly better diuretic and natriuretic effect. They must be used as medicines.

I første rekke er forbindelsene med formelen In the first place are the compounds with the formula

og deres salter utmerket ved en fremra-gende diuretisk virkning, hvori R7, R9 og Rn betyr vannstoff eller en alkylrest med 1—5 kullstoffatomer, R8 hetyr vannstoff, en.usubstituert eller med halogen, frie eller foretrede hydroksyl- eller aminogrupper substituert alifatisk kullvannstoffrest med 1—8 kuUvannstoffatomer, en ifenyl-, pyri-dyl-, tienyl-, tenyl-, furyl- eller forfuryl-rest eller en fenylalkylrest, og R]0 betyr halogen, ålkoksy med 1—5 kullstoffatomer, eller alkyl med 1-—5 kullstoffatomer og hvori R7 hetyr en alkylrest med 1—5 kullstoffatomer, når R8, R3 og Rn betyr vannstoff og Rin klor. Av denne gruppe utmerker seg, med hensyn ipå sin virkning, også forbindelsene med den generell formel and their salts distinguished by an outstanding diuretic effect, in which R7, R9 and Rn mean hydrogen or an alkyl residue with 1-5 carbon atoms, R8 is hydrogen, an unsubstituted or with halogen, free or etherified hydroxyl or amino groups substituted aliphatic carbon hydrogen residue with 1-8 carbon atoms, a ifenyl, pyridyl, thienyl, thenyl, furyl or forfuryl residue or a phenylalkyl residue, and R]0 means halogen, alkoxy with 1-5 carbon atoms, or alkyl with 1- -5 carbon atoms and in which R7 means an alkyl residue with 1-5 carbon atoms, when R8, R3 and Rn mean hydrogen and R1 chlorine. Of this group, the compounds with the general formula also stand out, with regard to their effect

eller deres salter, hvori R7, Rfl og R,, har den ovennevnte betydning og Rl2 betyr vannstoff, en usubstituert eller med amino-eller hydroksylgrupper eller kloratomer substituert alkylrest med 1—5 kullstoffatomer, benzyl- eller fenyletylresten og R13 betyr halogen, slik som brom, fluor, særlig klor, eller alkylrest med 1—5 kullstoffatomer, og hvori R7 betyr en alkylrest med 1—5 kullstoffatomer, i tilfelle Rfl, Rn og R12 ibetyr vannstoff og R,., klor. or their salts, in which R7, Rf1 and R1, have the above-mentioned meaning and R12 means hydrogen, an unsubstituted or substituted by amino or hydroxyl groups or chlorine atoms alkyl residue with 1-5 carbon atoms, the benzyl or phenylethyl residue and R13 means halogen, such as bromine, fluorine, especially chlorine, or an alkyl radical with 1-5 carbon atoms, and in which R7 means an alkyl radical with 1-5 carbon atoms, in case Rfl, Rn and R12 mean hydrogen and R,., chlorine.

Som særlig virksomme forbindelser skal f. eks. nevnes 3-n-propyl- og 3-isopropyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-ben-zotiadiazin-l,l-dioksyd, 3-n-butyl- og 3-isobutyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, 3-klorme-tyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, 3-etoksymetyl-og 3-fenyl-oksymetyl-6-klor-7-sulfamyl- As particularly effective compounds, e.g. mention is made of 3-n-propyl- and 3-isopropyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, 3-n-butyl- and 3 -isobutyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, 3-chloromethyl-6-chloro-7-sulfamyl-3,4-dihydro -1,2,4-benzothiadiazine-1,1-dioxide, 3-ethoxymethyl-and 3-phenyl-oxymethyl-6-chloro-7-sulfamyl-

3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, 3-benzyl- og 3-(2'-fenyletyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd, 2-metyl- og 4-metyl-6-klor-7-suifamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd og 2-metyl-6-klor-7-metyl-sulfamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd og deres salter. 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, 3-benzyl- and 3-(2'-phenylethyl)-6-chloro-7-sulfamyl-3,4-dihydro-1, 2,4-benzothiadiazine-1,1-dioxide, 2-methyl- and 4-methyl-6-chloro-7-sulfyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide and 2-methyl-6-chloro-7-methyl-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide and their salts.

De nye forbindelser skal anvendes som legemiddel i form av farmasøytiske prepa-rater, som inneholder disse forbindelser sammen med farmasøytiske, organiske eller anorganiske, faste eller flytende bære-stoffer, som er egnet for enteral, f. eks. oral, eller parenteral administrasjon. The new compounds are to be used as medicine in the form of pharmaceutical preparations, which contain these compounds together with pharmaceutical, organic or inorganic, solid or liquid carriers, which are suitable for enteral administration, e.g. oral or parenteral administration.

De nye forbindelser fåes når man omsetter et 2-sulfamyl-anilin med formelen The new compounds are obtained when a 2-sulfamyl-aniline is reacted with the formula

eller et av deres salter, hvori R4 og R5 har or one of their salts, wherein R 4 and R 5 have

den ovennevnte betydning og R', og R':1the above meaning and R', and R':1

betyr vannstoff eller en alkylrest, med et aldehyd med formelen R2CHO, hvori R2means hydrogen or an alkyl residue, with an aldehyde of the formula R2CHO, in which R2

har den ovennevnte betydning, og behandler de erholdte forbindelser med substituerbare kvelstoffatomer, hvis ønskes, i hvert fall når R',', R2, R'., og R, betyr vannstoff og R, betyr et kloratom, med et middel som innfører en alkyl st. Fortrinnsvis foretar man omsetningen med aldehydet i nærvær av en syre, slik som en mineralsyre, f. eks. en halogen-vannstoffsyre, f. eks. saltsyre eller bromvannstoffsyre eller svovelsyre, om ønsket i vannfri form. Aldehydet med formelen R2CHO kan også anvendes i form av et av dets polymere eller reaksjonseg-nede funksjonelle derivater, f. eks. paraformaldehyd, trioksan, heksametylentetra-min eller et acetal, f. eks. dimetoksymetan, dietoksymetan, 1,1-dimetoksyetan eller 1,1-dietoksyetan. Reaksjonen utføres i første rekke med omtrent ekvivalente mengder av reaksjonskomponentene. Ved større mengder aldehyd forminskes eventuelt ut-byttet på grunn av en reaksjon med R5HNOgS-gruppen. Reaksjonen kan utføres i fravær eller fortrinnsvis i nærvær av opp-løsningsmidler, slik som en eter, f. eks. p-dioksan eller dietylen-glykol-dimetyleter, eller et formamid, f. eks. dimetylformamid, ved romtemperatur eller forhøyet temperatur og ved normalt eller forhøyet trykk eller i nærvær av en inert gass, slik som kvelstoff. Som salter av 2-sulfamyl-ani- has the above-mentioned meaning, and treats the obtained compounds with substitutable nitrogen atoms, if desired, at least when R',', R2, R', and R, means hydrogen and R, means a chlorine atom, with an agent which introduces a alkyl st. Preferably, the reaction is carried out with the aldehyde in the presence of an acid, such as a mineral acid, e.g. a halogen-hydrogen acid, e.g. hydrochloric acid or hydrobromic acid or sulfuric acid, if desired in anhydrous form. The aldehyde with the formula R2CHO can also be used in the form of one of its polymeric or reactive functional derivatives, e.g. paraformaldehyde, trioxane, hexamethylenetetramine or an acetal, e.g. dimethoxymethane, diethoxymethane, 1,1-dimethoxyethane or 1,1-diethoxyethane. The reaction is carried out primarily with approximately equivalent amounts of the reaction components. In the case of larger amounts of aldehyde, the yield is possibly reduced due to a reaction with the R5HNOgS group. The reaction can be carried out in the absence or preferably in the presence of solvents, such as an ether, e.g. p-dioxane or diethylene glycol dimethyl ether, or a formamide, e.g. dimethylformamide, at room temperature or elevated temperature and at normal or elevated pressure or in the presence of an inert gas, such as nitrogen. As salts of 2-sulfamyl-ani-

liner anvender man ved denne reaksjon særlig et slikt med alkalimetaller eller med syrer, i første rekke med anorganiske syrer, slik som halogenvannstoffsyre, <f. eks. saltsyre eller bromvannstoffsyre. liners are used in this reaction in particular with alkali metals or with acids, primarily with inorganic acids, such as hydrohalic acid, <f. e.g. hydrochloric acid or hydrobromic acid.

Det er kjent at man kan få dihydro-benztiadiazin-l,l-dioksyder, som er usub-stituerte i ibenzoringen, ved omsetning av o-sulfamyl-aniliner med aldehyder (sammenlign Freeman & Wagner, J. org. Chem. 16, 1951, 815 og følgende). Omsetninger av aldehyder med o-p-disulfamyl-aniliner er imidlertid ikke beskrevet. Det var nu over-raskende å fastslå at også ved tilstede-værelse av en videre sulfamylgruppe fore-gikk ringslutningen til dihydro-benztiadia-zin-l,l-oksydet. It is known that dihydro-benzthiadiazine-1,1-dioxides, which are unsubstituted in the ibenzo ring, can be obtained by reaction of o-sulfamyl-anilines with aldehydes (compare Freeman & Wagner, J. org. Chem. 16, 1951 , 815 et seq.). However, reactions of aldehydes with o-p-disulfamyl-anilines have not been described. It was now surprising to determine that even in the presence of a further sulphamyl group the ring closure to the dihydro-benzthiadiazine-1,1-oxide took place.

De utgangsstoffer som anvendes for denne reaksjon er kjent eller kan fremstilles etter i og for seg kjente fremgangs-måter. Således kan man få 2-sulfamyl-anilinene ved omsetning av et anilin med formelen The starting materials used for this reaction are known or can be prepared according to procedures known per se. Thus, the 2-sulfamyl-anilines can be obtained by reacting an aniline with the formula

hvori R', og'R- har den ovenfor angitte betydning, med en halogensulfonsyre, f. eks. klorsulfonsyre, og påfølgende reaksjon med ammoniakk, fortrinnsvis flytende eller i vandig oppløsning, eller med et amin med formelen in which R', and'R- has the above meaning, with a halosulfonic acid, e.g. chlorosulfonic acid, and subsequent reaction with ammonia, preferably liquid or in aqueous solution, or with an amine of the formula

R--NH2 henholdsvis H2N-R', R--NH2 respectively H2N-R',

hvori R', og R- har den ovenfor angitte betydning. Derved kan man også foreta denne omsetning trinnvis, slik at man først bare innfører en halogensulfonylgruppe, deretter overfører denne i sulf amylresten og deretter innfører den annen halogensulfonylgruppe, og overfører denne da likeledes til amidet. På denne måte kan det fåes utgangsstoffer, hvori substituentene i amidgruppen kan være forskjellige fra hverandre. in which R' and R- have the meaning given above. Thereby, this reaction can also be carried out step by step, so that first only one halogensulfonyl group is introduced, then this is transferred to the sulf amyl residue and then the other halogensulfonyl group is introduced, and this is then likewise transferred to the amide. In this way, starting materials can be obtained, in which the substituents in the amide group can be different from each other.

I erholdte sulf amyl-3,4-dihydro-1,2,4-benzotiadiazin-l,l-dioksyder med substituerbare kvelstoffatomer kan man erstatte, vannstoffatomene i kvelstoffgrupperingen på 1 og for seg kjent måte med alkylrester. Således kan man innføre alkylrester, slik som metyl- eller etylrester, ved omsetning av en oppløsning av de erholdte sultfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyder i vandig alkalimetallhydroksyd-oppløsning, slik som litium, natrium- eller kaliumhydroksydoppløsning, med en reak-sjonsdyktig ester av en alkohol, slik som et dialkylsulfat, f. eks. dimetyl- eller dietylsulfat. Derved kan det fremstilles mono- eller polysubstituerte produkter. In the sulf amyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides obtained with substitutable nitrogen atoms, the hydrogen atoms in the nitrogen grouping of 1 can be replaced in a manner known per se with alkyl residues. Thus, one can introduce alkyl residues, such as methyl or ethyl residues, by reacting a solution of the sultfamil-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides obtained in an aqueous alkali metal hydroxide solution, such as lithium, sodium or potassium hydroxide solution, with a reactive ester of an alcohol, such as a dialkyl sulphate, e.g. dimethyl or diethyl sulfate. Mono- or poly-substituted products can thereby be produced.

Alt etter, reaksjonsbetingelsene får man de nye forbindelser i fri form av deres salter. Erholdte metallsalter kan over-føres, f. eks. ved reaksjon med vandige sure midler, slik som mineralsyre, f. eks. halogenvannstoffsyre, f. eks. saltsyre eller svovelsyre, til de frie forbindelser. Disse kan igjen overføres til metallsaltene, slik som alkalimetallsalter, ved behandling f. eks. med et metallhydroksyd, slik som natrium- eller kaliumhydroksyd, i et oppløs-ningsmiddel slik som et alkanol, f. eks. metanol eller etanol, eller i vann og påføl-gende avdampning av oppløsningsmidlet eller ved å la den frie forbindelse reagere i en eter, slik som p-dioksan eller dietylen-glykol-dimetyleteroppløsning med et al-kalimetallhydrid eller -amid, f. eks. natrium- eller kaliumhydrid eller -amid. Derved kan det fåes mono- eller polysalter. Depending on the reaction conditions, the new compounds are obtained in the free form of their salts. Obtained metal salts can be transferred, e.g. by reaction with aqueous acidic agents, such as mineral acid, e.g. hydrohalic acid, e.g. hydrochloric or sulfuric acid, to the free compounds. These can in turn be transferred to the metal salts, such as alkali metal salts, by treatment, e.g. with a metal hydroxide, such as sodium or potassium hydroxide, in a solvent such as an alkanol, e.g. methanol or ethanol, or in water and subsequent evaporation of the solvent or by allowing the free compound to react in an ether, such as p-dioxane or diethylene glycol dimethyl ether solution with an alkali metal hydride or amide, e.g. sodium or potassium hydride or amide. Mono- or poly-salts can thereby be obtained.

De nye forbindelser kan også foreligge i form av deres optiske antipoder. Erholdte racemater kan oppdeles i sine antipoder på vanlig måte. The new compounds can also exist in the form of their optical antipodes. Racemates obtained can be separated into their antipodes in the usual way.

Oppfinnelsen beskrives nærmere i de følgende eksempler. Temperaturene er an-gitt 1 °C. The invention is described in more detail in the following examples. The temperatures are indicated at 1 °C.

Eksempel 1. Example 1.

Man oppvarmer en blanding av 2,9 g 5-klor-2,4-disulfamyl-anilin i 20 cm<3> vannfri dietylenglykol-dimetyleter, 0,44 g acetaldehyd og 0,5 cm<3> av en klorvannstoff-syreoppløsning i eddiksyreetylester (109,5 klorvannstoffsyre pr. liter) til 80—90°C og holder i 1 time ved denne temperatur. Reaksjonsblandingen inndampes under forminsket trykk, tilsettes vann og bunnfallet frafiltreres. Dette siste omkrystalliseres av etanol eller vandig etanol. Man får således 3-metyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd med smeltepunkt 258—260°C. A mixture of 2.9 g of 5-chloro-2,4-disulfamylaniline in 20 cm<3> of anhydrous diethylene glycol dimethyl ether, 0.44 g of acetaldehyde and 0.5 cm<3> of a hydrogen chloride-acid solution in acetic acid ethyl ester (109.5 hydrochloric acid per litre) to 80-90°C and hold for 1 hour at this temperature. The reaction mixture is evaporated under reduced pressure, water is added and the precipitate is filtered off. The latter is recrystallized from ethanol or aqueous ethanol. Thus, 3-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with a melting point of 258-260°C is obtained.

Den samme forbindelse får man hvis man erstatter acetaldehydet med 0,9 g 1,1-dimetoksyetan eller med 1,2 g 1,1-dietoksyetan. The same compound is obtained if one replaces the acetaldehyde with 0.9 g of 1,1-dimethoxyethane or with 1.2 g of 1,1-diethoxyethane.

Eksempel 2. Example 2.

Tar man i stedet for det acetaldehyd som ble anvendt i eksempel 1 en tilsvarende mengde propionaldehyd eller 2-etoksy-acetaldehyd og forøvrig går fram som beskrevet i dette eksempel,- får man 3-etyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiain-l,l-dioksyd med smeltepunkt 265—267°C (dec.) henholdsvis 3-etoksyme-tyl-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-l,l-dioksyd med smeltepunkt 186—190°C. If, instead of the acetaldehyde that was used in example 1, a corresponding amount of propionaldehyde or 2-ethoxy-acetaldehyde is taken and otherwise proceed as described in this example, - you get 3-ethyl-6-chloro-7-sulfamyl-3, 4-dihydro-1,2,4-benzothiadiain-1,1-dioxide with melting point 265—267°C (dec.) respectively 3-ethoxymethyl-6-chloro-7-sulfamyl-3,4-dihydro-1 ,2,4-benzothiadiazine-1,1-dioxide with melting point 186-190°C.

Eksempel 3. Example 3.

Man oppvarmer en blanding av 3,4 g 5- brom-2,4-sulfamyl-anilin i 15 cm<3> vannfri dietylenglykol-dimetyleter, 0,5 cm<3 >eddiksyreetylester, som inneholder 109,5 g klorvannstoffsyre pr. 1000 cm<3> og 0,33 g paraformaldehyd til 80—90°C og holder 1 time ved denne temperatur. Man avkjøler til romtemperatur, inndamper reaksjonsblandingen under forminsket trykk til y3 av sitt volum og fortynner med vann. Det utkrystalliserte produkt frafiltreres og ombrystalliseres av vann. Man får således 6- brom-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd med smeltepunkt 285°C (dec.) A mixture of 3.4 g of 5-bromo-2,4-sulfamyl-aniline is heated in 15 cm<3> of anhydrous diethylene glycol dimethyl ether, 0.5 cm<3> of acetic acid ethyl ester, which contains 109.5 g of hydrochloric acid per 1000 cm<3> and 0.33 g of paraformaldehyde to 80-90°C and hold for 1 hour at this temperature. Cool to room temperature, evaporate the reaction mixture under reduced pressure to y3 of its volume and dilute with water. The crystallized product is filtered off and recrystallized from water. Thus, 6-bromo-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is obtained with a melting point of 285°C (dec.)

Eksempel 4. Example 4.

En oppløsning av 1,0 g 5-fluor-2,4-disulfamylanilin med smeltepunkt 233— 236°C i 5 cm3 dietylenglykoldimetyleter, 0,1 g paraformaldehyd og 0,2 cm3 av en mettet oppløsning av saltsyregass i eddiksyreetylester og oppvarmer reaksjonsblandingen i 1 time til 80—90°C. Etter avkjøling inndampes under forminsket trykk, det tilsettes vann og den vandige oppløsning inndampes påny. Det krystallinske bunnfall frafiltreres og omkrystalliseres av vann. Man får således 6-fluor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd med smeltepunkt 229—231°C. A solution of 1.0 g of 5-fluoro-2,4-disulfamylaniline with a melting point of 233-236°C in 5 cm3 of diethylene glycol dimethyl ether, 0.1 g of paraformaldehyde and 0.2 cm3 of a saturated solution of hydrochloric acid gas in ethyl acetate and heating the reaction mixture in 1 hour at 80-90°C. After cooling, it is evaporated under reduced pressure, water is added and the aqueous solution is evaporated again. The crystalline precipitate is filtered off and recrystallized from water. Thus, 6-fluoro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with a melting point of 229-231°C is obtained.

Eksempel 5. Example 5.

En oppløsning av 5,8 g 5-klor-2,4-disulfamylanilin i 30 cm<3> dietylenglykol-dimetyleter tilsettes 2,2 g benzaldehyd og 1 cm<3> av en mettet oppløsning av saltsyregass i eddiksyreetylester. Reaksjonsblandingen oppvarmes i 1 time til 80—90°C, og etter avkjøling inndampes under forminsket trykk og fortynnes med vann; hvoretter det utskilles en olje som bringes til krystallisasjon ved behandling med eter. Det således erholdte 3-fenyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd omkrystalliseres fra vandig etanol. Det smelter ved 246—249°C. A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline in 30 cm<3> of diethylene glycol dimethyl ether is added to 2.2 g of benzaldehyde and 1 cm<3> of a saturated solution of hydrochloric acid gas in acetic acid ethyl ester. The reaction mixture is heated for 1 hour to 80-90°C, and after cooling is evaporated under reduced pressure and diluted with water; after which an oil separates, which is brought to crystallisation by treatment with ether. The 3-phenyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide thus obtained is recrystallized from aqueous ethanol. It melts at 246-249°C.

Anvender man en ekvivalent mengde 4-klorbenzaldehyd eller 3,4,5-trimetoksy-benzaldehyd i stedet for benzaldehydet, får man på tilsvarende måte 3-(4'-klorfenyl)- If an equivalent amount of 4-chlorobenzaldehyde or 3,4,5-trimethoxy-benzaldehyde is used instead of the benzaldehyde, 3-(4'-chlorophenyl)-

6-klor-7-sulfamyl-3,4-dihydro-l,2,4-ben-zotiadiazin-l,l-dioksyd med smeltepunkt 255—256°C, henholdsvis 3-(3',4',5'-trimet-oksyfenyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd. 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with melting point 255-256°C, respectively 3-(3',4',5'- trimethoxyphenyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

Eksempel 6. Example 6.

Man lar 2,9 g 5-klor-2,4-disulfamyl-anilin i 15 cm<3> dietylenglykol-dimetyleter reagere med 0,75 g isobutyraldehyd i nærvær av 0,5 cm<3> av en mettet saltsyreeddik-syre-etylesteroppløsning ved 80—90°C. Det krystallinske 3-isopropyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd faller ut etter omtrent 10 minutter. Det omkrystalliseres etter frafiltrering av dimetylformamid ved tilsetning av varmt vann og smelter ved 304—306°C. 2.9 g of 5-chloro-2,4-disulfamyl-aniline in 15 cm<3> of diethylene glycol dimethyl ether are allowed to react with 0.75 g of isobutyraldehyde in the presence of 0.5 cm<3> of a saturated hydrochloric acid-acetic acid- ethyl ester solution at 80—90°C. The crystalline 3-isopropyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide precipitates after about 10 minutes. It is recrystallized after filtering off dimethylformamide by adding hot water and melts at 304-306°C.

Eksempel 7. Example 7.

Man lar 0,75 g n-butyraldehyd i 10 cm<3 >dietylenglykol-dimetyleter reagere med 2,9 g 5-klor-2,4-disulfamylanilin i nærvær av 0,3 cm<3> av en mettet saltsyreoppløsning-eddiksyreetylesteroppløsning 1 time ved 80 —90°C, inndamper under forminsket trykk og fortynner reaksjonsblandingen med vann. Bunnfallet frafiltreres og omkrystalliseres fra vandig etanol. Det således erholdte 3-n-propyl-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-l, 1 -dioksyd smelter ved 254—256°C. 0.75 g of n-butyraldehyde in 10 cm<3 >diethylene glycol dimethyl ether is allowed to react with 2.9 g of 5-chloro-2,4-disulfamylaniline in the presence of 0.3 cm<3> of a saturated hydrochloric acid solution-acetic acid ethyl ester solution 1 hour at 80-90°C, evaporate under reduced pressure and dilute the reaction mixture with water. The precipitate is filtered off and recrystallized from aqueous ethanol. The 3-n-propyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide thus obtained melts at 254-256°C.

Eksempel 8. Example 8.

En blanding av 2,9 g 5-klor-2,4-disul-famylanilin, 1,2 g 2-tiofen-karboksaldehyd, 0,5 cm cm<3> av en mettet oppløsning av klorvannstoff i eddiksyreetylester og 15 cm<3> dietylenglykol-dimetyleter oppvarmes i 1 time ved 80—90°C og inndampes deretter under forminsket trykk. Etter tilsetning av vann faller det ut en olje, som krystalliserer langsomt. Det således erholdte 3-(2'-tienyl)-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-l ,1-dioksyd omkrystalliseres av etanol. Det smelter ved 222—225°C. A mixture of 2.9 g of 5-chloro-2,4-disul-familaniline, 1.2 g of 2-thiophene-carboxaldehyde, 0.5 cm cm<3> of a saturated solution of hydrogen chloride in ethyl acetate and 15 cm<3 > diethylene glycol dimethyl ether is heated for 1 hour at 80-90°C and then evaporated under reduced pressure. After adding water, an oil precipitates out, which crystallizes slowly. The 3-(2'-thienyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide thus obtained is recrystallized from ethanol. It melts at 222-225°C.

Anvender man i stedet for tiofenkar-boksaldehydet en tilsvarende mengde 2-tiofenacetaldehyd, får man på analog måte 3-tenyl-6-klor-7-sulfamyl-3,4-di-hydro-1,2,4-benzotiadiazin-1,1-dioksyd med sm.p. 210—215°C. If, instead of the thiophencarboxaldehyde, a corresponding amount of 2-thiophenacetaldehyde is used, 3-thenyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1 is obtained in an analogous way. 1-dioxide with m.p. 210-215°C.

Eksempel 9. Example 9.

Man oppvarmer en oppløsning av 4,62 g 5-metoksy-2,4-disulfamyl-anilin i 70 cm<3 >dietylenglykol-dimetyleter med 0,4 g paraformaldehyd og 1,0 cm<3> av en mettet salt-syreoppløsning i eddikssyreetylester i 2 timer til 80—90°C. Reaksjonsblandingen inndampes under forminsket trykk og fortynnes med vann, hvoretter 6-metoksy-7-sulfamyl-3,4-dihydro-l,2,4-benztiadiazin-1,1-dioksyd faller ut. Det smelter etter omkrystallisasj on fra vandig etanol ved 254 —257°C. A solution of 4.62 g of 5-methoxy-2,4-disulfamylaniline in 70 cm<3 >diethylene glycol dimethyl ether is heated with 0.4 g of paraformaldehyde and 1.0 cm<3> of a saturated hydrochloric acid solution in acetic acid ethyl ester for 2 hours at 80-90°C. The reaction mixture is evaporated under reduced pressure and diluted with water, after which 6-methoxy-7-sulfamyl-3,4-dihydro-1,2,4-benzthiadiazine-1,1-dioxide precipitates. It melts after recrystallization from aqueous ethanol at 254-257°C.

Eksempel 10. Example 10.

En oppløsning av 5,8 g 5-klor-2,4-disulfamylanilin i 30 cm? dietylenglykol-dimetyleter tilsettes 2,2 g pyridin-4-aldehyd og 1 cm3 av en mettet saltsyreeddik-syre-etylesteroppløsning. Man lar reaksjonsblandingen stå i 1 time ved romtemperatur, oppvarmer en videre time til 80 —95°C og inndamper under forminsket trykk. Man fortynner resten med vann, de-kanterer fra ovenstående oppløsning fra det oljeaktige bunnfall og tilsetter etanol. 3-(4'-pyridyl)-6-klor-7-sulfamyl-3,4-di-hydro-l,2,4-benzotiadiazin-l,l-dioksyd krystalliserer langsomt. Det smelter ved over 310°C. A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline in 30 cm? diethylene glycol dimethyl ether, 2.2 g of pyridine-4-aldehyde and 1 cm3 of a saturated hydrochloric acid-acetic acid-ethyl ester solution are added. The reaction mixture is allowed to stand for 1 hour at room temperature, heated for a further hour to 80-95°C and evaporated under reduced pressure. The residue is diluted with water, the above solution is decanted from the oily precipitate and ethanol is added. 3-(4'-pyridyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes slowly. It melts at over 310°C.

Eksempel 11. Example 11.

En oppløsning av 5,4 g 2,4-disulfamyl-5-metylanilin i 40 cm3 dietylenglykol-dimetyleter blandes med 0,6 g paraformaldehyd og 1,5 cm<3> av en konsentrert opp-løsning av saltsyre i eddiksyreetylester og holdes i 1 time ved en temperatur på 80 —100°C. Man inndamper reaksjonsblandingen under forminsket trykk og tilsetter vann. Bunnfallet frafiltreres og omkrystalliseres fra en l:l-blanding av dimetylformamid og vann. Det således erholdte 6-metyl-7-sulfamyl-3,4-dihydro-<l,2,4-benzo-tiadiazin-l,l-dioksyd smelter ved 263— 265°C. A solution of 5.4 g of 2,4-disulfamyl-5-methylaniline in 40 cm3 of diethylene glycol dimethyl ether is mixed with 0.6 g of paraformaldehyde and 1.5 cm<3> of a concentrated solution of hydrochloric acid in acetic acid ethyl ester and kept in 1 hour at a temperature of 80 -100°C. The reaction mixture is evaporated under reduced pressure and water is added. The precipitate is filtered off and recrystallized from a 1:1 mixture of dimethylformamide and water. The 6-methyl-7-sulfamyl-3,4-dihydro-1,2,4-benzo-thiadiazine-1,1-dioxide thus obtained melts at 263-265°C.

Eksempel 12. Example 12.

En blanding av 2,9 g 5-klor-2,4-disulfamyl-anilin, 1,0 g 2-furaldehyd, og 0,5 cm<3> av en konsentrert saltsyreoppløsning i eddiksyreetylester og 15 cm<3> dietylenglykol-dimetyleter oppvarmes i 1 time til 80 —90°C, deretter inndempes under forminsket trykk og tilsettes vann, hvorved det utskilles en olje. Denne kan krystalliseres ved behandling med vanlig etanol. Etter omkrystallisasjon ifra vandig etanol smelter 3- (2'furyl) -6-klor-7-sulf amyl-3,4-di-hydro-l,2,4-benzotiadiazin-l,l-dioksydet ved 214—218°C. A mixture of 2.9 g of 5-chloro-2,4-disulfamyl-aniline, 1.0 g of 2-furaldehyde, and 0.5 cm<3> of a concentrated hydrochloric acid solution in acetic acid ethyl ester and 15 cm<3> of diethylene glycol dimethyl ether is heated for 1 hour to 80-90°C, then reduced under reduced pressure and water is added, whereby an oil separates. This can be crystallized by treatment with ordinary ethanol. After recrystallization from aqueous ethanol, the 3-(2'furyl)-6-chloro-7-sulfa amyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide melts at 214-218°C .

Eksempel 13. Example 13.

En oppløsning av 2,9 g 5-klor-2,4-disulfamylanilin i 15 cm3 dietylenglykol-dimetyleter tilsettes 0,9 g isovaleraldehyd og 0,5 cm<3> av en mettet saltsyreoppløsning A solution of 2.9 g of 5-chloro-2,4-disulfamylaniline in 15 cm3 of diethylene glycol dimethyl ether is added to 0.9 g of isovaleraldehyde and 0.5 cm<3> of a saturated hydrochloric acid solution

i eddiksyreetylester. Reaksjonsblandingen in acetic acid ethyl ester. The reaction mixture

oppvarmes i 1 time til 80—90°C, deretter heated for 1 hour to 80—90°C, then

inndampes under forminsket trykk og fortynnes med vann. Vannet fradekanteres og den resterende olje tilsettes etanol. 3-isobutyl-6-klor-7-sulfåmyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd krystalliserer, frafiltreres og omkrystalliseres fra en blanding av dimetylformamid og vann. evaporated under reduced pressure and diluted with water. The water is decanted and ethanol is added to the remaining oil. 3-isobutyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes, is filtered off and recrystallized from a mixture of dimethylformamide and water.

Smeltepunkt 241—245°C. Melting point 241-245°C.

Eksempel 14. Example 14.

En blanding av 2,9 g 5-klor-2,4-disul-famylanilin, 1,54 g kloracetaldehyd-dietylacetal og 0,5 cm<3> av en mettet saltsyre-eddiksyreetylesteroppløsning i 15 cm<3> dietylenglykol-dimetyleter oppvarmes i 1 time til 80—90°C og inndampes deretter A mixture of 2.9 g of 5-chloro-2,4-disul-familaniline, 1.54 g of chloroacetaldehyde-diethyl acetal and 0.5 cm<3> of a saturated hydrochloric acid-acetic acid ethyl ester solution in 15 cm<3> of diethylene glycol-dimethyl ether is heated for 1 hour at 80-90°C and then evaporated

under forminsket trykk. Resten tilsettes under reduced pressure. The rest is added

deretter vann og eter, og denne rest krystalliserer langsomt. Det således erholdte then water and ether, and this residue crystallizes slowly. The thus obtained

3-klormetyl-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-1,1-dioksyd omkrystalliseres fra vandig etanol. Smeltepunkt 235° C (dekomponering). 3-Chloromethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is recrystallized from aqueous ethanol. Melting point 235° C (decomposition).

Eksempel 15. Example 15.

En oppløsning av 2,9 g 5-klor-2,4-disulfamylanilin i 15 cm<3> dietylenglykol-dimetyleter tilsettes 1,2 g fenylacetaldehyd og 0,5 cm<3> av en mettet saltsyreoppløsning i eddiksyreetylester. Reaksjonsblandingen oppvarmes i 3 timer til 90—100°C. Deretter inndampes under forminsket trykk, vann tilsettes, hvorved det dannes et sirupøst bunnfall. Vannet fradekanteres og resten krystalliseres ved tilsetning av etanol. Det således erholdte 3-benzyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd omkrystalliseres fra en blanding av dimetylformamid og vann. Smeltepunkt 247—250°C. A solution of 2.9 g of 5-chloro-2,4-disulfamylaniline in 15 cm<3> of diethylene glycol dimethyl ether is added to 1.2 g of phenylacetaldehyde and 0.5 cm<3> of a saturated hydrochloric acid solution in acetic acid ethyl ester. The reaction mixture is heated for 3 hours to 90-100°C. It is then evaporated under reduced pressure, water is added, whereby a syrupy precipitate is formed. The water is decanted and the residue is crystallized by adding ethanol. The 3-benzyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide thus obtained is recrystallized from a mixture of dimethylformamide and water. Melting point 247-250°C.

Tar man ekvivalente mengder 4-klor-fenylacetaldehyd, 3,4,5-trimetoksyfenyl-acetaldehyd eller 3-metylfenylacetaldehyd i stedet for fenylacetaldehyd og forøvrig går frem som beskrevet ovenfor, får man tilsvarende 3- (4'-klorbenzyl) -6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd med sm.pkt. 224—226°C, henholdsvis 3-<(3',4',5'-trimetoksybenzyl) -6-klor-7-sulfamyl-3,4-dihydro-l,2,4-taenzo-tiadiazin-l,l-dioksyd eller 3-<(3'-metylben-zyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd. If you take equivalent amounts of 4-chloro-phenylacetaldehyde, 3,4,5-trimethoxyphenyl-acetaldehyde or 3-methylphenylacetaldehyde instead of phenylacetaldehyde and otherwise proceed as described above, you get the corresponding 3-(4'-chlorobenzyl)-6-chloro -7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with m.p. 224—226°C, respectively 3-<(3',4',5'-trimethoxybenzyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-thaenzo-thiadiazine-1,1 -dioxide or 3-<(3'-methylbenzyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

Behandler man en oppløsning av det erholdte 3-benzyl-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-l, 1 - diok- Treating a solution of the obtained 3-benzyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1, 1 - dioc-

syd i vandig natriumhydroksyd med dimetylsulfat ved 10—20°C i 1 time og videre 1 time ved romtemperatur, får man en blanding av 2-metyl-3-benzyl-6-klor-7-suifamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd og 2-metyl-3-benzyl-6-klor-7-N-metylsulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd som ved hjelp av fraksjonert krystallisasjon kan oppdeles i sine komponenter. boiled in aqueous sodium hydroxide with dimethyl sulfate at 10-20°C for 1 hour and a further 1 hour at room temperature, a mixture of 2-methyl-3-benzyl-6-chloro-7-sufamil-3,4-dihydro-1 is obtained ,2,4-benzothiadiazine-1,1-dioxide and 2-methyl-3-benzyl-6-chloro-7-N-methylsulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide which can be separated into its components by means of fractional crystallization.

Ekesempel 16. Example 16.

En blanding av 2,9 g 5-iklor-2,4-disulfa-mylanilin, 15 cm<3> dietylenglykol-dimetyleter, 1,1 g n-valeraldehyd og 0,5 cm<3> av en mettet oppløsning av saltsyre i eddiksyreetylester oppvarmes i 2 timer til 80— 90°C. Man inndamper reaksjonsblandingen under forminsket trykk, tilsetter resten vann og avdekanterer fra utfelt olje. Ved å oppta denne i etanol og henstand ved romtemperatur, faller det ut noe utgangsmateriale som frafiltreres. Filtratet inndampes til tørrhet, resten behandles med benzol, deretter med vandig etanol og gir 3-n-butyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, som etter omkrystallisasjon fra vandig etanol smelter ved 176—179°C. A mixture of 2.9 g of 5-ichloro-2,4-disulfa-mylaniline, 15 cm<3> of diethylene glycol dimethyl ether, 1.1 g of n-valeraldehyde and 0.5 cm<3> of a saturated solution of hydrochloric acid in acetic acid ethyl ester is heated for 2 hours to 80-90°C. The reaction mixture is evaporated under reduced pressure, water is added to the residue and decanted from the precipitated oil. By absorbing this in ethanol and allowing it to stand at room temperature, some starting material falls out and is filtered off. The filtrate is evaporated to dryness, the residue is treated with benzene, then with aqueous ethanol to give 3-n-butyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, which after recrystallization from aqueous ethanol melts at 176-179°C.

Eksempel 17. Example 17.

En blanding av 1,0 g 5-klor-2,4-disulfamyl-N-metylanilin, 10 cm<3> dietylenglykol-dimetyleter, 0,09 g paraformaldehyd og 0,25 cm<3> av en mettet oppløsning av saltsyregass i vannfri eddiksyreetylester oppvarmes i 1 time til 80—100°C. Etter av-kjøling inndampes reaksjonsblandingen under forminsket trykk, resten tilsettes vann og det krystallinske 4-metyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd omkrystalliseres fra vandig etanol. Sm.pkt. 225—227°C. A mixture of 1.0 g of 5-chloro-2,4-disulfamyl-N-methylaniline, 10 cm<3> of diethylene glycol dimethyl ether, 0.09 g of paraformaldehyde and 0.25 cm<3> of a saturated solution of hydrochloric acid gas in anhydrous acetic acid ethyl ester is heated for 1 hour to 80-100°C. After cooling, the reaction mixture is evaporated under reduced pressure, water is added to the residue and the crystalline 4-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is recrystallized from aqueous ethanol. Sm.pt. 225-227°C.

Eksempel 18. Example 18.

En blanding av 2,0 g 5-klor-2,4-di-(N-metyl-sulfamyl)-anilin, 20 cm3 dietylen-glykol-dimetyleter, 0,18 g paraformaldehyd og 0,5 cm<3> av en mettet oppløsning av saltsyregass i vannfri eddiksyreetylester oppvarmes 1 time til omtrent 80—90 °C, deretter avkjøles, inndampes under forminsket trykk og resten fortynnes med vann. Vannet fradekanteres, etanol og vann tilsettes, hvorved det dannes et krystallinsk bunnfall som frafiltreres. Det således erholdte 2-metyl-6-klor-7- (N-metylsulfa-myl)-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd oppløses i etanol og tilsettes vann for utfelling. Etter frafiltrering smelter det ved 203—206°C. A mixture of 2.0 g of 5-chloro-2,4-di-(N-methyl-sulfamyl)-aniline, 20 cm3 of diethylene glycol dimethyl ether, 0.18 g of paraformaldehyde and 0.5 cm<3> of a saturated solution of hydrochloric acid gas in anhydrous ethyl acetate is heated for 1 hour to approximately 80-90 °C, then cooled, evaporated under reduced pressure and the residue diluted with water. The water is decanted off, ethanol and water are added, whereby a crystalline precipitate is formed which is filtered off. The 2-methyl-6-chloro-7-(N-methylsulfa-myl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide thus obtained is dissolved in ethanol and water is added for precipitation. After filtration, it melts at 203-206°C.

Det utgangsmateriale som er anvendt i dette eksempel kan fåes som følger: 3,25 g 5-klor-anilin-2,4-disulfonylklorid behandles med 20 cm<3> av en 25 pst.ig oppløs-ning av metylamin i 30 minutter ved romtemperatur og 15 minutter på dampbad. Reaksjonsblandingen avkjøles, filtreres og det isolerte 5-klor-2,4-di-(N-metylsulfa-myl)-anilin omkrystalliseres to ganger av vandig etanol (1:1). Sm.p. 186—190°C. The starting material used in this example can be obtained as follows: 3.25 g of 5-chloro-aniline-2,4-disulfonyl chloride is treated with 20 cm<3> of a 25% solution of methylamine for 30 minutes at room temperature and 15 minutes in a steam bath. The reaction mixture is cooled, filtered and the isolated 5-chloro-2,4-di-(N-methylsulfa-myl)-aniline is recrystallized twice from aqueous ethanol (1:1). Sm.p. 186-190°C.

Eksempel 19. Example 19.

2,6 g 6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd oppløses i 11 cm<3> av en l-n. vandig natriumhydrok-sydoppløsning og 40 cm<8> vann. Man av-kjøler til 10°C, tilsetter 1,4 g dimetylsulfat og rører 1 time ved 10°C og en videre time ved romtemperatur. Deretter frafiltrerer man bunnfallet, omkrystalliserer det fire ganger fra vandig etanol og får således 2-metyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzo-tiadiazin-l,l-dioksyd med smeltepunkt 240—245°C. 2.6 g of 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are dissolved in 11 cm<3> of a 1-n. aqueous sodium hydroxide solution and 40 cm<8> of water. Cool to 10°C, add 1.4 g of dimethylsulphate and stir for 1 hour at 10°C and a further hour at room temperature. The precipitate is then filtered off, it is recrystallized four times from aqueous ethanol, thus obtaining 2-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzo-thiadiazine-1,1-dioxide with melting point 240-245°C.

Fra moderluten kan 2-metyl-6-klor-7-(<N-metylsulfamyl)-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd med sm.p. 203— 206°C, isoleres, hvilket er identisk med det produkt som er beskrevet i eksempel 18. From the mother liquor, 2-methyl-6-chloro-7-(<N-methylsulfamyl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with m.p. 203—206°C, is isolated, which is identical to the product described in example 18.

Utgangsmaterialet kan f. eks. fåes idet man oppvarmer en blanding av 2,9 g 5-klor-2,4-disulfamyl-anilin i 15 ml vannifritt dietylenglykol-dimetyleter, 0,5 ml eddiksyreetylester, inneholdende 109,5 g saltsyre pr. 1000 ml, og 0,33 g paraformaldehyd til 80—90°C og holder blandingen i 1 time ved denne temperatur. Man avkjøler til romtemperatur, inndamper reaksjonsblandingen under forminsket trykk til Y3 av dens volum og fortynner med vann. Det utkrystalliserte produkt frafiltreres og omkrystalliseres av vann. Man får således 6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzo-tiadiazin-l,l-dioksyd som smelter ved 266 —268°C. The starting material can e.g. is obtained by heating a mixture of 2.9 g of 5-chloro-2,4-disulfamylaniline in 15 ml of anhydrous diethylene glycol dimethyl ether, 0.5 ml of acetic acid ethyl ester, containing 109.5 g of hydrochloric acid per 1000 ml, and 0.33 g of paraformaldehyde to 80-90°C and keep the mixture for 1 hour at this temperature. Cool to room temperature, evaporate the reaction mixture under reduced pressure to Y3 of its volume and dilute with water. The crystallized product is filtered off and recrystallized from water. Thus, 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzo-thiadiazine-1,1-dioxide is obtained which melts at 266-268°C.

Eksempel 20. Example 20.

En blanding av 2,5 g 5-klor-2,4-disul-famylanilin, 1,4 g 2-karboksy-benzaldehyd, 1 cm<3> av en mettet oppløsning av saltsyre i eddiksyreetylester og 50 cm<3> dietylenglykol-dimetyleter oppvarmes i 1 time til 90°C, deretter avdampes % av oppløsningsmidlet og resten helles i vann. Man lar det stå ved romtemperatur, avdekanterer vannet og vasker resten påny med vann. Det således erholdte 3-(2'-karboksyfenyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd omkrystalliseres fra en blanding av etanol og vann. Smeltepunkt 340—345°C. A mixture of 2.5 g of 5-chloro-2,4-disul-familaniline, 1.4 g of 2-carboxy-benzaldehyde, 1 cm<3> of a saturated solution of hydrochloric acid in acetic acid ethyl ester and 50 cm<3> of diethylene glycol- dimethyl ether is heated for 1 hour to 90°C, then % of the solvent is evaporated and the remainder is poured into water. You let it stand at room temperature, decant the water and wash the rest again with water. The thus obtained 3-(2'-carboxyphenyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is recrystallized from a mixture of ethanol and water. Melting point 340-345°C.

Tar man i det ovenstående eksempel i stedet for 2-karboksy-benzaldehyd andre aldehyder eller acetaler med lavere alko-holer, f. eks. metanol eller etanol, får man følgende forbindelser: 3- (2'-fluorf enyl) -6-klor-7-sulf amyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, sm.p. 248—250°C. In the above example, instead of 2-carboxybenzaldehyde, other aldehydes or acetals with lower alcohols are taken, e.g. methanol or ethanol, the following compounds are obtained: 3-(2'-fluorophenyl)-6-chloro-7-sulfa amyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, sm. p. 248-250°C.

3- (3'-f luorf enyl) -6-klor-7-sulf amyl-S^-dihydro-l^^-benzotiadiazin-l^-dioksyd, sm.p. 227—229°C. 3-(3'-fluorophenyl)-6-chloro-7-sulf amyl-S,-dihydro-1,-benzothiadiazine-1,-dioxide, m.p. 227-229°C.

3-(2'-metylfenyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, sm.p. 263—266°C. 3-(2'-methylphenyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 263-266°C.

3- (3'-metylf enyl) -6-klor-7-sulfamyl-3,4-dihydro- 1,2,4-benzotiadiazin-1,1 -dioksyd, sm.p. 232—235°C. 3-(3'-methylphenyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 232-235°C.

3-(3'-hydroksyfenyl)-'6-klor-7-sulfamyl-3,4-dihydro-l ,2,4-benzotiadiazin-l ,1 - dioksyd, sm.p. 238—240°C. 3-(3'-hydroxyphenyl)-'6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 238-240°C.

3-(4'-isopropylfenyl)-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-1,1-dioksyd, som ved krystallisasjon sannsynligvis omfatter etanol, sm.p. 225°C. 3-(4'-isopropylphenyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, which on crystallization probably comprises ethanol, m.p. 225°C.

3-brommetyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, sm.p. 215—216°C. 3-bromomethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 215-216°C.

3-diklormetyl-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-1,1 -dioksyd, sm.p. 242—244°C. 3-dichloromethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, m.p. 242-244°C.

Eksempel 21. Example 21.

En blanding av 5,7 g 5-klor-2,4-disulfa-mylanilin, 3,2 g dietylamino-pivalaldehyd og 1 tablett natriumhydroksyd i 60 cm<3 >90 pst.ig vandig alkohol oppvarmes på dampbad i 1 time. Deretter avdamper man % av oppløsningsmidlet, tilsetter vann og nøytraliserer oppløsningen med fortynnet vandig saltsyre. Man fraskiller bunnfallet, oppløser det således erholdte 3-(l',l'-dimetyl-2-dietylamino-etyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd i dimetylformamid og tilsetter vann. Det krystallinske produkt smelter ved 288 —290°C. A mixture of 5.7 g of 5-chloro-2,4-disulfa-mylaniline, 3.2 g of diethylamino-pivalaldehyde and 1 tablet of sodium hydroxide in 60 cm<3>90% aqueous alcohol is heated on a steam bath for 1 hour. % of the solvent is then evaporated, water is added and the solution is neutralized with dilute aqueous hydrochloric acid. One separates the precipitate, dissolves the 3-(1',1'-dimethyl-2-diethylamino-ethyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1 thus obtained, l-dioxide in dimethylformamide and adding water. The crystalline product melts at 288-290°C.

Eksempel 22. Example 22.

En blanding av 5,6 g 5-klor-2,4-sulfa-mylanilin 4,0 g l,l-dietoksy-2-piperidino- A mixture of 5.6 g of 5-chloro-2,4-sulfa-mylaniline 4.0 g of 1,1-diethoxy-2-piperidino-

etan og 7 cm<3> eddiksyreetylester, mettet med saltsyregass i 50 cm<3> dietylenglykol-dimetyleter oppvarmes i 1 time på dampbad. Det utfelte krystallinske produkt frafiltreres og omkrystalliseres av etanol. Man får således 3-piperidino-metyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd-hydroklorid med sm.p. 208 210°C. ethane and 7 cm<3> acetic acid ethyl ester, saturated with hydrochloric acid gas in 50 cm<3> diethylene glycol dimethyl ether are heated for 1 hour on a steam bath. The precipitated crystalline product is filtered off and recrystallized from ethanol. One thus obtains 3-piperidino-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide hydrochloride with m.p. 208 210°C.

Hydrokloridet oppløses i vann, oppløs-ningen innstilles nøytralt med natriumkarbonat, hvorved 3-piperidinmetyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd faller ut. Sm.p. 150-152°C. The hydrochloride is dissolved in water, the solution is made neutral with sodium carbonate, whereby 3-piperidinemethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide precipitates. Sm.p. 150-152°C.

Eksempel 23. Example 23.

En oppløsning av 5,8 g 5-klor-2,4-disulfamylanilin i 30 cm<3> dietylenglykol-dimetyleter tilsettes 1 cm<3> av en 2-n. opp-løsning av saltsyre i vannfri eddiksyreetylester og 4,2 g fenoksyacetataldehyd-dietylacetal. Reaksjonsblandingen oppvarmes 1 time til 80—90°C, oppløsningsmidlet inndampes under forminsket trykk og resten behandles med heksan. Ved tilsetning av vann krystalliserer 3-fenoksy-metyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd, som om-krystallisert fra vandig dimetylformamid, smelter ved 262—264°C. A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline in 30 cm<3> of diethylene glycol dimethyl ether is added to 1 cm<3> of a 2-n. solution of hydrochloric acid in anhydrous acetic acid ethyl ester and 4.2 g of phenoxyacetate aldehyde-diethyl acetal. The reaction mixture is heated to 80-90°C for 1 hour, the solvent is evaporated under reduced pressure and the residue is treated with hexane. On addition of water, 3-phenoxy-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes, as recrystallized from aqueous dimethylformamide, melting at 262 -264°C.

Eksempel 24. Example 24.

En blanding av 5,8 g 5-klor-2,4-disul-famylanilin, 3,5 g acetaminoacetaldehyd-dietylacetal, fremstilt ved behandling av aminoeddiksyrealdehyd-dietylacetal, med eddiksyreanhydrid, kokepunkt 101—104°C ved 0,6 Torr, 1 cm<3> av en 2-n. oppløsning av saltsyre i vannfri eddiksyreetylester og 30 cm<3> dietylenglykol-dimetylester oppvarmes i 1 time på dampbad. Etter avkjøling inndamper man under forminsket trykk og frafiltrerer det krystallinske produkt. Etter omkrystallisasjon fra vandig etanol smelter 3-acetaminometyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksydet ved 258—260°C. A mixture of 5.8 g of 5-chloro-2,4-disul-familaniline, 3.5 g of acetaminoacetaldehyde-diethyl acetal, prepared by treating aminoacetaldehyde-diethyl acetal, with acetic anhydride, boiling point 101-104°C at 0.6 Torr, 1 cm<3> of a 2-n. solution of hydrochloric acid in anhydrous acetic acid ethyl ester and 30 cm<3> of diethylene glycol dimethyl ester are heated for 1 hour on a steam bath. After cooling, the mixture is evaporated under reduced pressure and the crystalline product is filtered off. After recrystallization from aqueous ethanol, the 3-acetaminomethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide melts at 258-260°C.

Eksempel 25. Example 25.

En ' oppløsning av 5,8 g 5-klor-2,4-disulfamylanilin i 30 cm<3> dietylenglykol-dimetyleter tilsettes 10 cm<3> av en 2-n. opp-løsning av saltsyre i vannfritt etylacetat og 3,7 g l,l-dietoksy-2-dietylamino-etan. Man koker reaksjonsblandingen 1 time på dampbad, hvorved det dannes to lag, og skiller fra dietylenglykol-dimetyleterlaget etter avkjøling. Det nedre lag tilsettes 30 cm<3> vann og det tilsettes natriumkarbonat og 30 cm<3> eter, hvorved det dannes et krystallinsk bunnfall. Etter frafiltrering' omkrystalliseres 6-klor-3-dietylamino-metyl-7-sulfamyi-3,4-dihydro-l,2,4-benzotia-diazin-l,l-dioksydet 3 ganger fra vandig dimetylformamid. Sm.p. 196°C (under dekomponering). A solution of 5.8 g of 5-chloro-2,4-disulfamylaniline in 30 cm<3> of diethylene glycol dimethyl ether is added to 10 cm<3> of a 2-n. solution of hydrochloric acid in anhydrous ethyl acetate and 3.7 g of 1,1-diethoxy-2-diethylaminoethane. The reaction mixture is boiled for 1 hour on a steam bath, whereby two layers are formed, and separated from the diethylene glycol-dimethyl ether layer after cooling. 30 cm<3> of water is added to the lower layer and sodium carbonate and 30 cm<3> of ether are added, whereby a crystalline precipitate is formed. After filtration, the 6-chloro-3-diethylamino-methyl-7-sulfanyl-3,4-dihydro-1,2,4-benzothia-diazine-1,1-dioxide is recrystallized 3 times from aqueous dimethylformamide. Sm.p. 196°C (during decomposition).

Erstatter man l,l-dietoksy-2-dietyl-aminoetan med 3,22 g l,l-dietoksy-2-dime-tylaminoetan og forøvrig går frem som beskrevet ovenfor, får man 3-dimetylamino-metyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd med sm.p. 184°C (dekomponering). If you replace 1,1-diethoxy-2-diethylaminoethane with 3.22 g of 1,1-diethoxy-2-dimethylaminoethane and otherwise proceed as described above, you get 3-dimethylamino-methyl-6-chloro-7- sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with m.p. 184°C (decomposition).

Eksempel 26. Example 26.

En blanding av 5,8 g 5-klor-2,4-disul-famylanilin, 2,9 g l,l-dietoksy-2-metyl-aminoetan og 10 cm3 av en 2-n. saltsyre-oppløsning i vannfri eddiksyreetylester og 30 cm<3> dietylenglykol-dimetyleter behandles slik som beskrevet i det foregående eksempel. Det krystallinske produkt som fåes etter nøytralisering med natriumkarbonat opptas i eddiksyreetylester, opp-løsningen inndampes og det tilsettes heksan, hvorved det utkrystalliserer 3-metyl-amino-metyl-6-klor-7-sulfamyl-3,4-di-hydro-1,2,4-benzotiadiazin-1,1 -dioksyd. Det smelter etter omkrystallisasjon fra vandig etanol ved 163°C (dekomponering). A mixture of 5.8 g of 5-chloro-2,4-disul-familaniline, 2.9 g of 1,1-diethoxy-2-methylaminoethane and 10 cm 3 of a 2-n. hydrochloric acid solution in anhydrous acetic acid ethyl ester and 30 cm<3> of diethylene glycol dimethyl ether are treated as described in the previous example. The crystalline product obtained after neutralization with sodium carbonate is taken up in acetic acid ethyl ester, the solution is evaporated and hexane is added, whereby 3-methyl-amino-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1 crystallizes out ,2,4-benzothiadiazine-1,1-dioxide. It melts after recrystallization from aqueous ethanol at 163°C (decomposition).

Eksempel 27. Example 27.

En oppløsning av 5-klor-2,4-disulfa-mylanilin i 30 cm<3> dietylenglykol-dimetyl-. eter behandles med 1 cm<3> av en mettet oppløsning av saltsyre i eddiksyreetylester og 2,68 g 3-fenylpropionaldehyd. Man oppvarmer blandingen 1 time til 70—90°C, inndamper deretter under forminsket trykk til lite volum og tilsetter 30 cm<3> vann. 6-klor-3- (2'-f enyletyl) -7-sulf amyl-3,4-dihydro- 1,2,4-benzotiadiazin-1,1-dioksyd krystalliserer, frafiltreres og omkrystalliseres av etanol. Det smelter ved 117—119°C, idet det sannsynligvis inneholder etanol, og, etter at det ble tørket ved 80°C, ved 174—175°C. A solution of 5-chloro-2,4-disulfa-mylaniline in 30 cm<3> diethylene glycol-dimethyl-. ether is treated with 1 cm<3> of a saturated solution of hydrochloric acid in acetic acid ethyl ester and 2.68 g of 3-phenylpropionaldehyde. The mixture is heated for 1 hour to 70-90°C, then evaporated under reduced pressure to a small volume and 30 cm<3> of water is added. 6-Chloro-3-(2'-phenylethyl)-7-sulfa amyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes, is filtered off and recrystallized from ethanol. It melts at 117-119°C, probably containing ethanol, and, after being dried at 80°C, at 174-175°C.

På samme måte kan det ved å anvende de tilsvarende utgangsmaterialer fåes ana-loge forbindelser, slik som f. eks. en fenyl-etylrest som i 3-stilling er substituert med metyl, isopropyl, metoksy, metylendioksy, nitro, dimetylamino, klor-, brom- eller fluor og i 6-stilling i stedet for kloret inneholder et bromatom eller en metylgruppe. In the same way, by using the corresponding starting materials, analogous compounds can be obtained, such as e.g. a phenyl-ethyl residue which is substituted in the 3-position with methyl, isopropyl, methoxy, methylenedioxy, nitro, dimethylamino, chlorine, bromine or fluorine and in the 6-position instead of the chlorine contains a bromine atom or a methyl group.

Eksempel 28. Example 28.

En blanding av 5,6 g 5-klor-2,4-disul-famylanilin, 2,6 g 2-fenyl-propionaldehyd, 1 cm<3> av en mettet oppløsning av saltsyregass i eddiksyreetylester og 25 cm<3 >dietylen-glykol-dimetyleter oppvarmes på dampbad i 1 time, deretter inndampes til halvparten av volumet, fortynnes med vann og opparbeides slik som i foregående eksempel. 3-(l'-fenyletyl)-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd fåes i form av gule krystaller som etter omkrystallisasjon av vaiidig etahol smelter ved 226—228°C. A mixture of 5.6 g of 5-chloro-2,4-disul-familaniline, 2.6 g of 2-phenyl-propionaldehyde, 1 cm<3> of a saturated solution of hydrochloric acid gas in ethyl acetate and 25 cm<3 >diethylene- glycol dimethyl ether is heated on a steam bath for 1 hour, then evaporated to half the volume, diluted with water and worked up as in the previous example. 3-(1'-phenylethyl)-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is obtained in the form of yellow crystals which, after recrystallization from aqueous ethanol, melt at 226-228°C.

Eksempel 29.. Example 29..

En oppløsning av 5,9 g 5-klor-2,4-disulfamylanilin i 30 cm<3> dietylenglykol-dimetyleter tilsettes 1 cm<3> av en 2-n. opp-løsning av saltsyre i eddiksyreetylester og 3,2 g etoksyacetaldehyd-dietylacetal og blandingen oppvarmes 1 time til 80—90°C. Etter avkjøling inndamper man under forminsket trykk og tilsetter vann, hvoretter det utskilles et oljeaktig produkt. Etter dekantering av vannet og tilsetning av eter krystalliserer 3-etoksymetyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadiazin-1,1-dioksyd, som frafiltreres og omkrystalliseres 3 ganger fra en blanding 1:1 etanol-vann. Sm.p. 186—190°C. A solution of 5.9 g of 5-chloro-2,4-disulfamylaniline in 30 cm<3> of diethylene glycol dimethyl ether is added to 1 cm<3> of a 2-n. solution of hydrochloric acid in acetic acid ethyl ester and 3.2 g of ethoxyacetaldehyde-diethyl acetal and the mixture is heated for 1 hour to 80-90°C. After cooling, it is evaporated under reduced pressure and water is added, after which an oily product separates. After decanting off the water and adding ether, 3-ethoxymethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes, which is filtered off and recrystallized 3 times from a mixture 1:1 ethanol-water. Sm.p. 186-190°C.

Eksempel 30. Example 30.

9,4 g 3-metyl-6-klor-7-sulfamyl-3,4-dihydro-1,2,4-benzotiadiazin-1,1-dioksyd oppløses i en blanding av 33 cm<3> av en l-n. vandig natriumhydroksydoppløsning og 120 cm<3> vann. Det uoppløste frafiltreres, deretter avkjøles til 10°C, 2,4 g dimetylsulfat tilsettes og det hele står ved denne temperatur i 1 time. Man holder det videre i en time ved romtemperatur, filtrerer reaksjonsblandingen og omkrystalliserer resten to ganger fra en l:l-blanding av etanol og vann. Man får således 2,3-dimetyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-toenzo-tiadiazin-l,l-dioksyd med sm.p. 274— 276°C. 9.4 g of 3-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide are dissolved in a mixture of 33 cm<3> of a l-n. aqueous sodium hydroxide solution and 120 cm<3> of water. The undissolved material is filtered off, then cooled to 10°C, 2.4 g of dimethylsulphate is added and the whole is left at this temperature for 1 hour. It is kept for a further hour at room temperature, the reaction mixture is filtered and the residue is recrystallized twice from a 1:1 mixture of ethanol and water. One thus obtains 2,3-dimethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-toenzo-thiadiazine-1,1-dioxide with m.p. 274— 276°C.

Omkrystallisasj ons-moderlutene inndampes, hvorved resten blir fast og lar seg krystallisere fra metanol. Man omkrystalliserer fra vandig etanol. 2,3-dimetyl-6-klor-7 (N-metylsulfamyl)-3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd smelter ved 248 —251°C. The recrystallization mother liquors are evaporated, whereby the residue becomes solid and can be crystallized from methanol. It is recrystallized from aqueous ethanol. 2,3-Dimethyl-6-chloro-7-(N-methylsulfamyl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide melts at 248-251°C.

Utgangsmaterialet kan fåes som følger: En blanding av 2,9 g 5-klor-2,4-disulfa-mylanilin, 20 cm<3> vannfri dietylenglykol-dimetyleter, 0,44 g acetaldehyd og 0,5 cm<3 >av en saltsyreoppløsning i eddiksyreetylester (109,5 g klorvannstoffsyre pr. liter) oppvarmes til 80—90°C og holdes i 1 time ved denne temperatur. Reaksjonsblandingen inndampes under forminsket trykk, deretter tilsettes vann og det utkrystalliserte produkt frafiltreres. Det således erholdte 3-metyl-6-klor-7-sulfamyl-3,4-di-hydro-1,2,4-benzotiadiazin-1,1 -dioksyd med sm.p. 258—260°C kan omkrystalliseres fra vandig etanol. The starting material can be obtained as follows: A mixture of 2.9 g of 5-chloro-2,4-disulfa-mylaniline, 20 cm<3> of anhydrous diethylene glycol dimethyl ether, 0.44 g of acetaldehyde and 0.5 cm<3 >of a hydrochloric acid solution in acetic acid ethyl ester (109.5 g hydrochloric acid per liter) is heated to 80-90°C and kept for 1 hour at this temperature. The reaction mixture is evaporated under reduced pressure, then water is added and the crystallized product is filtered off. The thus obtained 3-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide with m.p. 258-260°C can be recrystallized from aqueous ethanol.

Eksempel 31. Example 31.

En oppløsning av 12,2 g 6-klor-7-sulfamyl-3,4-dihydro-l ,2,4-benzotiadiazin-1,1-dioksyd, fremstilt som beskrevet i eksempel 19, i en blanding av 55 cm<3> l-n. vandig natriumhydroksyd og 200 cm<3> vann tilsettes 6,9 cm<3> dietylsulfat. Reaksjonsblandingen omrøres ved 10—20°C i 5y2 time og deretter står det hele natten over ved romtemperatur. Det viskøse bunnfall skilles fra, oppløses i litt etanol og skilles ved filtrering fra ikke-reagert utgangsmateriale. Etter henstand av filtratet ved romtemperatur krystalliserer 2-etyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzotiadia-zin-l,l-dioksyd, som omkrystalliseres av vandig etanol. Smeltepunkt 195—198°C. A solution of 12.2 g of 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide, prepared as described in Example 19, in a mixture of 55 cm<3 > l-n. aqueous sodium hydroxide and 200 cm<3> of water are added to 6.9 cm<3> of diethyl sulfate. The reaction mixture is stirred at 10-20°C for 5-2 hours and then left overnight at room temperature. The viscous precipitate is separated, dissolved in a little ethanol and separated by filtration from unreacted starting material. After standing the filtrate at room temperature, 2-ethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes, which is recrystallized from aqueous ethanol. Melting point 195-198°C.

Eksempel 32. Example 32.

En oppløsning av 10,6 g 3-n-butyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzo-tiadiazin-l,l-dioksyd i 66 cm<3> av en l-n. vandig natriumhydroksydoppløsning og 120 cm<3> vann avkjøles til 20°C, og 4,2 g dimetylsulfat tilsettes langsomt. Deretter omrører man reaksjonsblandingen i 1 time ved denne temperatur, deretter nok en time ved romtemperatur og ekstraherer 3 ganger med eddiksyreetylester. Det organiske lag tørkes over natriumsulfat, oppløs-ningsmidlet inndampes, hvoretter man får en amorf blanding av 2-metyl-3-n-butyl-6-klor-7-sulfamyl-3,4-dihydro-l,2,4-benzo-tiadiazin-l,l-dioksyd og 2-metyl-3-n-butyl-6-klor-7- (N-metylsulf amyl) -3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd. Den smelter ved 90—96°C (under dekomponering og skumming). A solution of 10.6 g of 3-n-butyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzo-thiadiazine-1,1-dioxide in 66 cm<3> of a l-n. aqueous sodium hydroxide solution and 120 cm<3> of water are cooled to 20°C, and 4.2 g of dimethyl sulfate are added slowly. The reaction mixture is then stirred for 1 hour at this temperature, then another hour at room temperature and extracted 3 times with ethyl acetate. The organic layer is dried over sodium sulfate, the solvent is evaporated, after which an amorphous mixture of 2-methyl-3-n-butyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzo is obtained -thiadiazine-1,1-dioxide and 2-methyl-3-n-butyl-6-chloro-7-(N-methylsulfa amyl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1- dioxide. It melts at 90-96°C (during decomposition and foaming).

Eksempel 33. Example 33.

En oppløsning av 3,42 g 5-klor-2,4-di-(N-etylsulfamyl)-anilin i 25 cm<3> dietylen-glykol-dimetyleter tilsettes 0,3 g paraformaldehyd og 0,5 cm<3> av en mettet oppløs-ning av saltsyre i eddiksyreetylester. Blandingen oppvarmes i 1 time til 80—90°C, deretter inndampes oppløsningsmidlet og resten tilsettes vann. Man fradekanterer vannet, oppløser resten i litt varm etanol, hvorved 2-etyl-6-klor-7-(N-etylsulf amyl) - 3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyd krystalliserer. Etter omkrystallisasjon fra vandig etanol smelter det ved 163—166°C. To a solution of 3.42 g of 5-chloro-2,4-di-(N-ethylsulfamyl)-aniline in 25 cm<3> of diethylene glycol dimethyl ether is added 0.3 g of paraformaldehyde and 0.5 cm<3> of a saturated solution of hydrochloric acid in acetic acid ethyl ester. The mixture is heated for 1 hour to 80-90°C, then the solvent is evaporated and water is added to the remainder. The water is decanted off, the residue is dissolved in slightly warm ethanol, whereby 2-ethyl-6-chloro-7-(N-ethylsulfamyl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide crystallizes. After recrystallization from aqueous ethanol, it melts at 163-166°C.

Eksempel 34. Example 34.

Lar man, slik som i det foregående eksempel, 4,0 g 5-klor-2,4-di-.(N-n-tautyl-sulfamyl)-anilin i 20 cm<3> dietylenglykol-dimetyleter reagere med 0,3 g paraformaldehyd i nærvær av 0,5 cm<3> av en mettet oppløsning av klorvannstoff i eddiksyreetylester, får man 2-n-butyl-6-klor-7-'(N-n-butylsulfamyl)-dihydro-l,2,4-benzotia-diazin-l,l-dioksyd med sm.p. 170—171°C. As in the previous example, 4.0 g of 5-chloro-2,4-di-(N-n-tautyl-sulfamyl)-aniline in 20 cm<3> of diethylene glycol dimethyl ether is allowed to react with 0.3 g of paraformaldehyde in the presence of 0.5 cm<3> of a saturated solution of hydrogen chloride in acetic acid ethyl ester, 2-n-butyl-6-chloro-7-(N-n-butylsulfamyl)-dihydro-1,2,4-benzothia- diazine-1,1-dioxide with m.p. 170-171°C.

Patentpåstand: Fremgangsmåte til fremstilling av 3,4-dihydro-l,2,4-benzotiadiazin-l,l-dioksyder med den generelle formel og salter av disse forbindelser, hvor R,, R,, og R- betyr hydrogen eller alkylrester, R2 betyr hydrogen, en eventuelt substituert alifatisk kullvannstoffrest, en eventuelt substituert aryl- eller aralkylrest eller en eventuelt substituert monocyklisk heterocyklisk rest med nitrogen-, oksygen- eller svovelatomer som heteroatomer, som eventuelt også over en alkylrest kan. være forbundet med tiadiazinringen, R4 betyr alkylrester, foretrede hydroksylgrupper eller halogenatomer, og hvis R2, R:1 og R3 betyr hydrogen og R, betyr klor, betyr R, en alkylrest, karakterisert ved at man omsetter et 2-sulfamyl-anilin med formel Patent claim: Process for the preparation of 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides of the general formula and salts of these compounds, where R,, R,, and R- means hydrogen or alkyl radicals, R2 means hydrogen, an optionally substituted aliphatic hydrocarbon radical, an optionally substituted aryl or aralkyl radical or an optionally substituted monocyclic heterocyclic radical with nitrogen, oxygen - or sulfur atoms as heteroatoms, which may optionally also be above an alkyl residue. be connected to the thiadiazine ring, R4 means alkyl residues, etherified hydroxyl groups or halogen atoms, and if R2, R:1 and R3 means hydrogen and R means chlorine, R means an alkyl residue, characterized by reacting a 2-sulfamyl-aniline of formula

eller et av dets salter, hvori R, og R3 har den ovennevnte betydning og R,, og R,, betyr hydrogen eller en alkylrest, med et aldehyd med formel RgCHO, hvori R2 har den ovennevnte betydning, og 'behandler de erholdte forbindelser med substituerbare nitrogenatomer om ønskes, men i ethvert-fall når R,, R2 R3 og R5 betyr hydrogen og R4 betyr et kloratom, med et middel som or one of its salts, in which R, and R3 have the above meaning and R,, and R,, mean hydrogen or an alkyl radical, with an aldehyde of formula RgCHO, in which R2 has the above meaning, and 'treat the obtained compounds with substitutable nitrogen atoms if desired, but in any case when R1, R2, R3 and R5 are hydrogen and R4 is a chlorine atom, by means of

innfører en alkylrest, og resp. eller når ønsket, overfører dannede salter i de frie forbindelser' eller omdanner dannede frie forbindelser i deres salter. introduces an alkyl residue, and resp. or when desired, transfers formed salts into the free compounds' or converts formed free compounds into their salts.

Claims

1. Method for the continuous production of single-layer fiber fabric webs such as paper, cardboard and other non-natural and/or synthetic fibers on a long-wire paper machine, whose wire, at least in the area of the fabric application, is designed as a slanted wire (10) with a horizontal fabric inflow direction and behind which wire (10) for the dewatering of the fiber-substance suspension there are several suction boxes (6) arranged one above the other with independent and adjustable negative pressures so regulated with increasing negative pressure from the bottom suction box to the top that web formation takes place with uniform fiber deposition over the entire web formation area , characterized in that the suspension is given laminar flow by means of partitions (3), that the pressures are regulated so that the speed of the suspension is the same over the entire flow cross-section and that the backwater flow behind the wire (10) is controlled in laminar flow in the same direction as the suspension.

2. Method according to claim 1, characterized in that the suspension speed is 2 to 5 times the wire speed.