DE1112079B - Process for the preparation of 3, 4-dihydro-1, 2, 4-benzothiadiazine-1, 1-dioxydes - Google Patents

Description

GERMAN

PATENT OFFICE

C 18496 IVb / 12p

REGISTRATION DATE: 27. F E B RU AR 1959

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: AUGUST 3, 1961

The invention relates to a process for the preparation of 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxydes the general formula

Method of manufacture

of 3,4-dihydro-1,2,4-benzothiadiazine

1,1-dioxides

R-,

¹ NO ₂ S '

H'

V ' ] -S CH- -R ₂ I. i N - Ri (T O

wherein R ₁ , R ₃ and R _{5 represent} hydrogen atoms, alkyl radicals, especially with 1 to 5 carbon atoms, or acyl radicals, R _{2 represents} a hydrogen atom, an alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl or Pentyl group, a vinyl group, an aryl group, especially a mono- or bicyclic aryl group, e.g. B. a phenyl, naphthyl (1) or naphthyl (2) group, an aralkyl group, e.g. B. a benzyl, 2-phenylethyl, naphthyl (l) - or - (2) -methyl group, or a heterocyclic radical which can also be bonded to the thiadiazine ring via an alkyl radical, e.g. B. a furyl, thienyl, pyridyl, quinolyl, furfuryl or thenyl radical, wherein the alkyl group can carry a hydroxy, alkoxy or dialkylamino group or a halogen atom and the aryl groups and heterocyclic radicals by alkyl, hydroxy , Alkoxy, mercapto or alkyl mercapto groups, e.g. B. methoxy or methyl mercapto groups, dialkyl amino groups, e.g. B. the dimethylamino group, sulfamyl radicals or halogen atoms can be substituted and R _{4 represents} a halogen atom, an alkyl radical, especially with 1 to 5 carbon atoms, or an etherified hydroxy group, and the salts, especially with the alkali metal salts of these compounds, with the exception of 6-chloro-7 -sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide.

The acyl radicals are particularly those of monocarbonic acid esters, z. B. alkoxy formic acid, aliphatic carboxylic acids, primarily with 1 to 5 carbon atoms, such as alkanecarboxylic acids, e.g. B. acetic or propionic acid, aromatic carboxylic acids such as benzoic acid or substituted benzoic acids, or aralkanecarboxylic acids, such as phenylacetic acid, may be mentioned.

The new i ^ -Dihydro-l ^^ -benzothiadiazin-ljl-dioxyde show diuretic and natriuretic effectiveness and are said to be used as remedies.

First and foremost, the compounds of the formula given above and their salts are distinguished by an excellent diuretic activity, in which applicants:
CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority:

V. St. v. America of April 9th (No. 727 242),

June 9 (No. 740 582) and July 29, 1958 (No. 751 620)

George deStevens, New Providence, NJ,
and Lincoln Harvey Werner, Summit, NJ

(V. St. Α.),
have been named as inventors

R ₁ , R ₃ and R _{5 represent} hydrogen atoms or an alkyl radical with 1 to 5 carbon atoms and at most two of these radicals also represent an aliphatic acyl radical with 1 to 5 carbon atoms, R _{2 represents} a hydrogen atom which is unsubstituted or substituted by a halogen atom, a hydroxy, Alkoxy or dialkylamino group substituted alkyl with 1 to 8 carbon atoms, a phenyl, pyridyl, thienyl, thenyl, furyl or furfuryl group or a phenylalkyl group and R ₄ denotes a halogen atom, an alkoxy group with 1 to 5 carbon atoms or an alkyl group with Represents 1 to 5 carbon atoms.

From this group stand out with regard to their effectiveness the compounds of the formula given above or their salts, in which R ₁ , R ₃ and R _{5 have} the meaning shown above and R _{2 represents} a hydrogen atom which is unsubstituted or by dialkylamino or hydroxyl groups a chlorine atom-substituted alkyl radical with 1 to 5 carbon atoms, the benzyl or phenylethyl radical and R _{4 represents} a halogen atom, such as a bromine, fluorine or especially a chlorine atom, or an alkyl radical with 1 to 5 carbon atoms.

As particularly effective compounds, for. B. mentioned are the 3-n-propyl and 3-isopropyl

109 650/409

ö-chloro-T-sulfamyl-S ^ -dihydro-l ^^ - benzothiadiazine-1,1-dioxide, the 3-n-butyl- and the S-isobutyl-ö-chlorodi

oxide, the S-

hydro-l, 2,4-benzothiadiazine-l, l-dioxide, the 3-ethoxymethyl-o-chloro-T-sulfamyl-S ^ -dihydro-l ^^ - benzothiadiazine-1,1-dioxide, the S-benzyl-δ-chloro-T-sulfamyl-3,4 - dihydro -1,2,4- benzothiadiazine -1,1- dioxide, the 2-methyl- and the 4-methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide and the 2-me-

4-benzothiadiazine-1,1-dioxide and its salts.

The new connections will be obtained if you either

a) a 2-sulfamyl-aniline compound of the general formula

R-, .NH-R ₃ '

R ₅ -

; no "s

SO ₂ NH-R ₁

in which R ₄ and R _{5 have} the abovementioned meaning and R ₁ and R _{3 represent} hydrogen atoms or alkyl radicals, or their salts with an aldehyde of the formula R ₂ CHO, in which R _{2 has} the abovementioned meaning, or reacts
b) a l, 2,4-benzothiadiazine-l, l-dioxide of the general formula

NO ₂ S

ζ-

CR ₂
NR ₁

or

Ii

CR ₂

NO ₂ S

H'

O O

hydrogenated with a dimetal hydride or electrolytically reduced

and optionally subsequently obtained compounds in which R ₁ , R ₃ and / or R _{5 represent} hydrogen atoms, alkylated or acylated in a manner known per se and / or obtained salts converted into the free compounds or obtained free compounds converted into their salts.

In procedure a), the reaction components are used for the reaction with formaldehyde preferably in a molar ratio of about 1: 1. The higher amounts of aldehyde increase the yields as a result of a reaction with the

. NO ₂ S group
H ^X

reduced. The aldehyde of the formula R ₂ CHO can also be in the form of an acetal, ζ. B. dimethoxymethane, diethoxymethane, 1,1-dimethoxyethane or 1,1-diethoxyethane or one of its polymers, e.g. B. paraformaldehyde or trioxane can be used. The reaction is advantageously carried out in the presence of an acid such as an anhydrous mineral acid, for example a hydrohalic acid, e.g. B. hydrochloric acid or hydrobromic acid or sulfuric acid. You work in absentia or

ίο preferably in the presence of solvents, such as an ether, e.g. B. p-dioxane or diethylene glycol dimethyl ether, or a formamide, e.g. B. dimethylformamide, at room temperature or elevated temperature and at normal or elevated pressure or in the presence of an inert gas such as nitrogen. Salts of 2-sulfamylanilines can be used as starting materials use in this reaction, especially alkali metal salts or salts with acids, primarily Line with inorganic acids such as hydrohalic acid, e.g. B. hydrochloric acid or hydrobromic acid. The starting materials to be used for this reaction are known or can be used per se known methods. So you can get the 2-sulfamyl-aniline by reacting a Aniline of the formula

Riv% / NH - Ro

wherein R ₃ and R _{4 have} the meaning given above, with a halosulfonic acid, for. B. chlorosulfonic acid, and subsequent reaction with ammonia, preferably liquid or in aqueous solution, or with an amine of the formula H ₂ N - R ₁ 'or H ₂ NR ₅ , in which R ₁ ' and R _{5 have} the meaning given above. This reaction can also be carried out in stages by first introducing only one halosulfonyl group, then converting it into the sulfamyl radical and then introducing the second halosulfonyl group and then converting it into the amide as well. In this way, starting materials can be obtained in which the substituents of the amide group are different from one another.

The hydrogenation of the l ^^ - Benzothiadiazine-ljl-dioxyde with dimetal hydrides according to procedure b), primarily with alkali metal borohydrides, such as lithium, potassium or especially sodium borohydride, are carried out in the presence of a solvent by, preferably in aqueous alkali metal hydroxide solutions, e.g. B. lithium, sodium or potassium hydroxide solutions, or an ether, such as diethylene glycol dimethyl ether, or a liquid carboxamide, such as a formamide, e.g. B. formamide or dimethylformamide. The reduction can be at Room temperature or at elevated temperature, optionally in the presence of an inert gas, such as Nitrogen.

The starting materials used for this process method are known or can be obtained in a manner known per se.
The alkylation obtained 3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxides with substitutable nitrogen atoms is carried out in a manner known per se, for. B. by treating a solution of 3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxyden in aqueous alkali metal

hydroxide solution, such as lithium, sodium or potassium. The same compound is obtained if you use the

hydroxide solution, with a reactive ester acetaldehyde by 0.9 g of 1,1-dimethoxyethane or

an alcohol, such as a dialkyl sulfate, e.g. Di- replaced by 1,2g 1,1-diethoxyethane.

methyl or diethyl sulfate. Mono-

or win polysubstituted products. 5 Example 2

Furthermore, 3,4-dihydro-1,2,4-ben-

zothiadiazine-l, l-dioxyde, in which R ₁ , R ₃ and R ₅ are taken in place of that used in Example 1

Represent hydrogen atoms, in known acetaldehyde a corresponding amount of propionic

Way by reacting with an acylating agent, aldehyde or 2-ethoxy-acetaldehyde and proceeded in

such as an organic carboxylic acid or its functional io others, as described in this example, is obtained

tional derivatives, for example a halide, one the S-ethyl-ö-chloro-T-sulfamyl-S ^ -dihydro-l ^^ -

z. B. the chloride or the anhydride, in mono-, benzothiadiazine-l, l-dioxide, F. 265 to 267 ° (Zer-

Transfer di- or triacyl derivatives. This reaction settlement), or the S-ethoxymethyl-o-chloro-T-sulfamyl-

can be in the presence or absence of condensate 3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide; F. 186

carry out sations and / or solvents. Works 15 to 190 °; Yield 1.4g.

one with an acid anhydride, one takes the.

Reaction preferably in the presence of a liquid example

organic base, e.g. B. a trialkylamine, especially a mixture of 3.4 g of 5-bromo-triethylamine, or a pyridine, such as pyridine or 2,4-disulfamyl-aniline, 15 cm ^{3 of} anhydrous diethylene collidine, is preheated. When using an acid halide 20 glycol dimethyl ether, 0.5 cm ^{3 of} ethyl acetate, it is preferable to start from a metal salt, such as the one containing 109.5 g of hydrochloric acid per 1000 cm ³ , silver salt, or an alkali metal salt, e.g. B. sodium and 0.33 g of paraformaldehyde to 80 to 90 ° and holds or potassium salt, the 3,4-dihydro-l, 2,4-benzothia- 1 hour at this temperature. It is cooled on diazine-l, l-dioxyde. As a solvent used from room temperature, the reaction mixture is concentrated primarily organic solvents such as 25 under reduced pressure to a third of its aliphatic ketones, z. B. acetone. The liquid volume and diluted with water. The basic condensation agent can also be used as a crystallized product, which is filtered off and water is used as a solvent. recrystallized. The 6-bromo-7-sulfamyl-

Depending on the reaction conditions, the 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is obtained; F. 285 °

new compounds in free form or in form 30 (decomposition); Yield 2g.

their salts. Metal salts obtained can e.g. B. by.

Reaction with aqueous acids such as mineral acid, for example

z. B. hydrohalic acid, for example hydrochloric acid. Add to a solution of 1.0 g of 5-fluoro

or sulfuric acid, into the free compounds via 2,4-disulfamyl-aniline (mp 233 to 236 °) in 5 cm ³

be guided. These in turn can be converted into diethylene glycol dimethyl ether, 0.1 g paraformaldehyde

Metal salts, such as alkali metal salts, transferred through and 0.2 cm ^{3 of} a saturated solution of chlorine

Treat z. B. with a metal hydroxide, such as hydrogen in ethyl acetate and heated the

Sodium or potassium hydroxide, in a solution reaction mixture for 1 hour at 80 to 90 °. After this

medium, such as an alkanol, e.g. B. methanol or cooling the solution under reduced pressure

Ethanol, or concentrated in water and then concentrated, water added and the aqueous solution

Evaporate the solvent or concentrate again by reaction. The crystalline precipitate will

the free compound in an ether, such as p-dioxane, filtered off and recrystallized from water. You get

or diethylene glycol dimethyl ether solution, with a 0.5 g o-fluoro-T-sulfamyl-S ^ -dihydro-l ^^ - benzo-

Alkali metal hydride or amide, e.g., sodium or thiadiazine-1,1-dioxide; F. 229 to 231 °.

Potassium hydride or sodium or potassium amide. 45

Mono- or poly-salts can be obtained in this way. Example 5

The new compounds can also be in shape

their optical antipodes are present. Obtained to a solution of 5.8 g of 5-chloro-2,4-disulfamyl-

Racemates can be converted into their aniline in 30 cm ^{3 of} diethylene glycol dimethyl ether in the usual way

Separate antipodes. 50 one 2.2 g of benzaldehyde and 1 cm ^{3 of} a saturated

The invention is illustrated in the following examples of a solution of hydrogen chloride in ethyl acetate,

described in more detail. The temperatures are in Celsius. The reaction mixture is heated to 80 to 90 ° for 1 hour

degrees indicated. heated, after cooling under reduced pressure

evaporated and diluted with water, whereupon

Example 1 55 separates an oil, which by treatment with ether

is brought to crystallization. The thus obtained

A mixture of 2.9 g of 5-chloro-S-phenyl-o-chloro ^ -sulfamyl-S ^ -dihydro-l ^^ - benzo-

2,4-disulfamyl-aniline, 20 cm ^{3 of} anhydrous diethylenethiadiazine-l, l-dioxide is made from aqueous ethanol

glycol dimethyl ether, 0.44 g of acetaldehyde and 0.5 cm ³ recrystallized. It melts at 246 to 249 °; yield

of a hydrochloric acid solution in ethyl acetate 60 4.0 g.

ester (109.5 g hydrochloric acid per liter) on Rpionipl (s
80 to 90 ° and holds at this temperature for 1 hour. ßeibpiei ο
The reaction mixture is allowed to under reduced pressure, 2.9 g of 5-chloro-2,4-disulfamyl-aniline concentrated under pressure, water is added and the lower 15 cm ^{3 of} diethylene glycol dimethyl ether with 0.75 g of iso-precipitate is filtered off. The latter is recrystallized from 65 butyraldehyde in the presence of 0.5 cm ^{3 of} an ethanol or aqueous ethanol. This gives saturated hydrochloric acid-ethyl acetate solution in which S-methyl-o-chloro ^ -sulfamyl-S ^ -dihydro-l ^^ - ben- 80 to 90 ° react. The crystalline 3-isopropylzothiadiazine-1,1-dioxide; M.p. 258 to 260 °; Yield 1.2g. 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 from dimethylformamide by adding hot water and melts at 304-306 °; Yield 2.6g.

Example 7

One leaves 0.75 g of n-butyraldehyde in 10 cm ^{3 of} diethylene glycol dimethyl ether with 2.9 g of 5-chloro-2,4-disulfamylaniline in the presence of 0.3 cm ^{3 of} a saturated hydrochloric acid-ethyl acetate solution for 1 hour at 80 to 90 ° react, concentrated under reduced pressure and diluted 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 to 256 °; Yield 2.3g.

Example 8

A mixture of 2.9 g of 5-chloro-2,4-disulfamylaniline, 1.2 g of 2-thiophene-carboxaldehyde, 0.5 cm ^{3 of} a saturated solution of hydrogen chloride in ethyl acetate and 15 cm ^{3 of} diethylene glycol dimethyl ether is added for 1 hour 80 to 90 "and then concentrated under reduced pressure. After adding water, an oil precipitates which slowly crystallizes. The 3- (2'-thienyl) -6-chloro-7-sulfamyl-3,4-dihydro obtained in this way 1,2,4-benzothiadiazine -1,1-dioxide is recrystallized from ethanol, melting at 222 ° to 225 °, yield 0.7 g.

Example 9

A solution of 4.62 g of 5-methoxy-2,4-disulfamyl-aniline in 70 cm ^{3 of} diethylene glycol dimethyl ether with 0.4 g of paraformaldehyde and 1.0 cm ^{3 of} a saturated hydrochloric acid solution in ethyl acetate is heated to 80 to 90 hours for 2 hours °. The reaction mixture is concentrated under reduced pressure and diluted with water, whereupon the 6-methoxy-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide precipitates. After recrystallization from aqueous ethanol, it melts at 254 to 257 "; yield 3.3 g.

Example 10

2.2 g of pyridine-4-aldehyde and 1 cm ^{3 of} a saturated hydrochloric acid-ethyl acetate solution are added to a solution of 5.8 g of 5-chloro-2,4-disulfamylaniline in 30 cm ^{3 of diethylene glycol dimethyl ether.} The reaction mixture is left to stand at room temperature for 1 hour, heated to 80 to 95 'for a further hour and evaporated under reduced pressure. The residue is diluted with water, the supernatant solution is decanted from the oily precipitate and ethanol is added. The 3- (4'-pyridyl) -6-chloro-7-suIfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide slowly crystallizes. It melts above 310 °; Yield 1.0g.

Example 11

A solution of 5.4 g of 2,4-disulfamyl-5-methylaniline in 40 cm ^{3 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 ethyl acetate and kept at one temperature for 1 hour from 80 to 100 ⁼ held. The reaction mixture is concentrated under reduced pressure and water is added. The precipitate is filtered off and recrystallized from a mixture of equal parts of dimethylformamide and water. The 6-methyl-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide thus obtained melts at 263 to 265 °; Yield 3.2g.

Example 12

A mixture of 2.9 g of 5-chloro-2,4-disulfamylaniline, 1.0 g of 2-furaldehyde, 0.5 cm ^{3 of} a concentrated solution of hydrochloric acid in ethyl acetate and 15 cm ^{3 of} diethylene glycol dimethyl ether is added to 80 to 1 hour Heated to 90 °, then concentrated under reduced pressure and added water, an oil separating out. This can be crystallized from aqueous ethanol. After recrystallization from aqueous ethanol, the 3- (2'-furyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,2,4-benzothiadiazine-1,2-dioxide melts at 214 ° to 218 ° ; Yield 0.5g.

Example 13

0.9 g of isovaleraldehyde and 0.5 cm ^{3 of} a saturated hydrochloric acid solution in ethyl acetate are added to a solution of 2.9 g of 5-chloro-2,4-disulfamylaniline in 15 cm ^{3 of diethylene glycol dimethyl ether.} The reaction mixture is heated to 80 to 90 ° for 1 hour, then evaporated under reduced pressure and diluted with water. The water is decanted off and ethanol is added to the remaining oil. The S-isobutyl-o-chloro ^ -sulfamyl-S ^ -dihydro-l ^^ - benzothiadiazine-1,1-dioxide crystallizes, is filtered off and recrystallized from a mixture of dimethylformamide and water; M.p. 241 to 245 °; Yield 1.1g.

Example 14

A mixture of 2.9 g of 5-chloro-2,4-disulfamylaniline, 1.53 g of chloroacetaldehyde diethyl acetal and 0.5 cm ^{3 of} a saturated hydrochloric acid-ethyl acetate solution in 15 cm ^{3 of} diethylene glycol dimethyl ether is increased to 80 for 1 hour Heated to 90 ° and then evaporated under reduced pressure. Water and ether are added to the residue, which slowly crystallizes. The 3-chloromethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide obtained in this way is recrystallized from aqueous ethanol; Mp 235 ° (decomposition); Yield 2.0g.

Example 15

1.2 g of phenylacetaldehyde and 0.5 cm ^{3 of} a saturated hydrochloric acid solution in ethyl acetate are added to a solution of 2.9 g of 5-chloro-2,4-disulfamylaniline in 15 cm ^{3 of diethylene glycol dimethyl ether.} The reaction mixture is heated to 90 to 100 ° for 2 hours, then evaporated under reduced pressure. The residue is mixed with water, whereupon a syrupy precipitate is formed. The water is decanted off 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; M.p. 247 to 250 °; Yield 0.6g.

Example 16

A mixture of 2.9 g of 5-chloro-2,4-disulfamylaniline, 15 cm ^{3 of} diethylene glycol dimethyl ether, 1.1 g of n-valeraldehyde and 0.5 cm ^{3 of} a saturated solution

9 10

of hydrochloric acid in ethyl acetate is identical to that described in Example 18 for 2 hours

heated to 80 to 90 °. The reaction product is evaporated.

mixture under reduced pressure, add water Example 20
to the residue and decanted from the precipitated oil

away. By taking up in ethanol and leaving to stand 5 1 g of S-propyl-ö-chloro-V-sulfamyl-l ^^ - ben at room temperature, some of the starting material zothiadiazine-l, l-dioxide precipitates in 20 cm ^{3 of} dimethylformamide, which is filtered off. The filtrate becomes dry and 30 cm ³ 2 of normal aqueous sulfuric acid are added. evaporated, the residue treated with benzene, this solution is then in the cathode compartment of an aqueous ethanol and gives 1.3 g of 3-n-butyl electrolytic cell with a mercury cathode o-chloro-T-sulfamyl-S ^ -dihydro-l ^^ - benzothiadiazine io of 20.5 cm ³ surface. The cathode compartment is made of 1,1-dioxide, which after recrystallization from the anode compartment through a porous clay membrane melts aqueous ethanol at 176 to 179 °. separates. The anolyte consists of a

Mixture of 2 parts by volume of dimethylformamide

Example 17 ^unc * 3 parts by volume 2 normal aqueous sulfur

15 acid. A platinum electrode is used as the anode.

A mixture of I ₃ Og 5-chloro-2,4-disulfamyl- One works at 15 to 20 °. The initial current density

N-methyl-aniline, 10 cm ^a diethylene glycol-dimethyl- is 0.163 Amp./cm ^a , which according to the reaction time

ether, 0.09 g paraformaldehyde and 0.25 cm ³ drops to 0.059 amps / cm ^{2 every 24 minutes.} That

saturated solution of hydrochloric acid gas in anhydrous reference potential compared to a standard calomel

Ethyl acetate for 1 hour at 80 to 100 ° 20 electrode is -1.3 volts.

heated. After cooling, the reaction mixture is neutralized after the reduction, the cathodes are concentrated under reduced pressure, water is added to the liquid with 35 cm ³ 2 normal aqueous sodium residue and the crystalline 4-methyl hydroxide and evaporated to a small volume, 6-chlorine -7-suh ° amyl-3,4-dihydro-1,2,4-benzothiadiazine filtered and the filtrate evaporated to dryness. 1,1-dioxide is recrystallized from aqueous ethanol; 25 treated the residue with water, filtered the mp 225-227 °; Yield 0.5g. S-propyl-o-chloro ^ -sulfamyl-S ^ -dihydro-l ^^ - benzo-

thiadiazine-l, l-dioxide and crystallizes it out

Example 18 water around. It melts at 254 to 256 °. A mixed melt sample this product with that of Example 7

A mixture of 2.0 g of 5-chloro-2,4-di- (N-methyl- 30 obtained compound shows no melting point

sulfamyl) aniline, 20 cm ³ diethylene glycol dimethyl depression. Yield 0.8g.

ether, 0.18 g paraformaldehyde and 0.5 cm ^{3 of} one. .

saturated solution of hydrochloric acid gas in anhydrous example II

Ethyl acetate is about 1 hour to a solution of 3-benzyl-6-chloro-7-sulfamyl-

80 to 90 ° heated, then cooled, under reduced 35 l, 2,4-benzothiadiazine-l, l-dioxide in diethylene glycol

Evaporated pressure and the residue with water dimethyl ether is treated with sodium borohydride

diluted. The water is decanted off, ethanol and the mixture for 1 hour at room temperature

Water was added, whereupon a crystalline settling was allowed to stand. After filtering, the solution is put on the

shock forms, which is filtered off. The pH value obtained in this way is 7, the precipitate is filtered off and crystalline

2-Methyl-6-chloro-7- (N-methylsulfamyl) -3,4-dihydro- 40 lizes the 3-benzyl-6-chloro-7-sulfamyl-

l, 2,4-benzothiadiazine-l, l-dioxide is in ethanol 3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide, the

dissolved and filled with water. Identical to the product obtained in Example 15 after removal

filter it melts at 203 to 206 °; Yield 0.5g. is. Yield 28%.

The starting material used in this example can be obtained as follows:

material can be obtained as follows: 3.25 g of 5-chloro 45 A solution of 5-chloroaniline-2,4-di-

aniline-2,4-disulfonyl chloride are mixed with 20 cm ^{3 of} a sulfonyl chloride in phenylacetyl chloride for 1 day

Stand 25% aqueous solution of methylamine for 30 minutes at room temperature and treat the obtained

at room temperature and 15 minutes on the steam- N-phenylacetyl-S-chloroaniline ^^ - disulfonyl chloride with

bad treated. The reaction mixture is cooled with an excess of liquid ammonia. After this

filtered and the isolated 5-chloro-2,4-di- (N-methyl- 5 ° evaporation of the excess ammonia at

sulfamyl) aniline twice from aqueous ethanol (1: 1) room temperature and heating the residue

recrystallized; F. 186 to 190 °. 200 ° for 3 hours you get the S-benzyl-o-chloro

7-sulfamyl-l, 2,4-benzothiadiazine-l, l-dioxide.

^Beis P ^ie119 "Example 22

2.6 g of 6-chloro-7-suh ^c amyl-3,4-dihydro-1,2,4-benzo- To a solution of 5.9 g of 5-chloro-2,4-disulfamyl-

thiadiazine-1,1-dioxide are in 11 cm ³ of 1 normal aniline in 30 cm ^{3 of} diethylene glycol dimethyl ether (are

aqueous sodium hydroxide solution and 40 cm ^{3 of} water to 1 cm ^{3 of} a 2 normal solution of hydrochloric acid in

solved. It is cooled to 10 °, 1.4 g of dimethyl ethyl acetate and 3.2 g of ethoxyacetaldehyde sulfate are added and stirred for 1 hour at 10 ° and a further 60 diethylacetal and heated the mixture for 1 hour

Hour at room temperature. Then the 80 to 90 ° is filtered. After cooling, you steam under

Precipitate (yield 2.4 g) is crystallized under reduced pressure and water is added, whereupon

four times from aqueous ethanol and so an oily product is obtained. After the dean

2-Methyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzotation of the water and addition of ether crystallized thiadiazine-l, l-dioxide with a temperature of 240 to 245 °. 65 3-ethoxymethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,

The 2-methyl-6-chloro-2,4-benzothiadiazine-l, l-dioxide can be filtered off and removed from the mother liquor

7- (N-methylsulfamyl) -3,4-dihydro-1,2,4-benzothia- three times from a mixture of ethanol and water (1: 1)

Isolate diazine-1,1-dioxide of mp 203-206 °, which is recrystallized; 186-190 °; Yield 2.4g.

, 109 650/409

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of 3,4-dihydrol, 2,4-benzothiadiazine-l, l-dioxyden the general formula R _s jj CH-R ₂
} , -NR ₁ O O in which R ₁ 'and R ₃ ' are hydrogen atoms or alkyl radicals, or their salts are reacted with an aldehyde of the formula R ₂ CHO or
b) a l, 2,4-benzothiadiazine-l, l-dioxide of the general formula ; No, s O O wherein R ₁ , R ₃ and R _{5 represent} hydrogen atoms, alkyl or acyl _{radicals, R 2 represents} a hydrogen atom, an alkyl, vinyl, aryl or aralkyl group or a heterocyclic radical which can also be bonded to the thiadiazine ring via an alkyl radical , where the alkyl group can carry a hydroxy, alkoxy or dialkylamino group or a halogen atom and aryl groups and heterocyclic radicals can be substituted by alkyl, hydroxy, alkoxy, mercapto, alkylmercapto, dialkylamino or sulfamyl groups or halogen atoms and R ₄ represents a halogen atom, an alkyl group or an etherified hydroxy group, and salts of these compounds, except 6-chloro-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide, DA by marked that one either
a) a 2-sulfamyl-aniline compound of the general formula or VA, ; no ₂ s OO NH-R ₈ ' R, NO ₂ S SO ₂ NH-R ₁ ' hydrogenated with a dimetal hydride or electrolytically reduced and optionally subsequently obtained compounds in which R ₁ , R ₃ and / or R _{5 represent} hydrogen atoms, alkylated or acylated in a manner known per se and / or obtained salts converted into the free compounds or obtained free compounds converted into their salts. 2. The method according to claim 1, characterized in that in procedure a) the Aldehyde is used in the form of an acetal or one of its polymers. 3. Process according to Claims 1 and 2, characterized in that the procedure a) works in the presence of an acid. When announcing the registration, three priority documents (certified photocopies) and a right of priority transfer declaration has been interpreted. Θ 109 650/409 7.61