DE1124503B - Process for the preparation of 3, 4-dihydro-1, 2, 4-benzothiadiazine-1, 1-dioxydes - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY '· y KL. 12p 10 / fi

INTERNAT. KL. C 07 d

GERMAN

PATENT OFFICE

EXPLAINING EDITORIAL 1124 503

C 24174 IVd / 12ρ

REGISTRATION DATE: 27. F E B RU AR 1959

NOTIFICATION OF THE REGISTRATION AND ISSUE OF THE EXPLORATION PAPER:

MARCH 1, 1962

The subject of patent application C 18496 IVd / 12p (German Auslegeschrift 1 112 079) is a method for the production of 3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxyden the general formula

R, - ENT

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 radicals or halogen atoms and R _{4 represents} a halogen atom, an alkyl radical or an etherified hydroxyl group, and salts of these compounds, with the exception of o-chloro ^ -sulfamyl-S ^ -dihydro-1,2,4-benzothiadiazine-1,1-dioxide.

The compounds mentioned are made in accordance with patent application C 18496 IVd / 12p (German Auslegeschrift 1 112 079) produced by either

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

R ₅ -HNO ₆ S.

NH-R, '

SO ₂ NH-R ₁ '

Method of manufacture

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

1,1-dioxides

Addition to patent application C 18496 IVd / 12 ρ (German Auslegeschrift 1112 079)

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dr.-Ing. Dr. jur. F. Redies,

Dr. rer. nat. B. Redies and Dr. rer. nat. D. Tiirk, patent attorneys, Opladen, Rennbaumstr.

George de Stevens, New Providence, N.J., and Lincoln Harvey Werner, Summit, N.J.

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

CR ₂

R ₈ -HNO ₁ S

O

or

R ₅ -HNO ₈ S.

O

hydrogenated with a dimetal hydride or electro-

wherein R ₁ 'and R ₃ ' represent hydrogen atoms or lytically reduced

^A } kyl ^re f5, or _{your sake with a and optionally} s subsequently obtained compound aldehyde of the formula R ₂ -CHO, _{where R 2} converts the _{d in which RR} and / or R _{5 has} hydrogen, or represents _{50 atoms?} & _{in a} manner known per se b) a 1,2,4-benzothiadiazine-l, 1-dioxide of the general or acylated and / or obtained salts in the free my formula compounds or obtained free compounds in

209 517/397

their salts transferred. In procedure a) the aldehyde can be in the form of an acetal or a polymer be used; furthermore, this procedure can be carried out in the presence of an acid. It has now been found that 3,4-dihydrol, 2,4-benzothiadiazine-l, l-dioxyde of the general formula

CH —R

H ₂ NO ₂ S

NH

wherein R is a bromomethyl, dichloromethyl, dimethylamino-methyl, diethylamino-methyl, 1,1-dimethyl-2-diethylamino-ethyl, 2-fluoro-phenyl-, 3-fluoro-ao phenyl-, 2-methyl-phenyl-, 3-methyl-phenyl-, 3-hydroxyphenyl-, 4-isopropyl-phenyl-, 1-phenyl-ethyl- or 2-phenyl-ethyl radical, and the salts thereof are obtained when either

a) 2,4-Disulfamyl-5-chloro-aniline of the formula ^a3

NH ₂

H ₂ NO ₂ S

SO ₂ NH ₉

or the salts thereof with an aldehyde of the formula R —CHO or

b) a 1,2,4-benzothiadiazine-1,2-dioxide of the general formula

H ₂ NO ₂ S

ι-R

or the corresponding tautomeric compound is hydrogenated with a dimetal hydride or electrolytically reduced

and optionally salts obtained in a manner known per se into the free compounds or free compounds obtained converted into their salts.

In procedure a), the aldehyde of the formula R - CHO can also be used in the form of an acetal will. The reaction is advantageously carried out in the presence of an acid, such as an anhydrous one Mineral acid, for example a hydrohalic acid, e.g. B. hydrochloric acid or hydrobromic acid or sulfuric acid. It can also be carried out in an alkaline medium. Man works in the absence or 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 a inert gas such as nitrogen. Salts of 2,4-disulfamyl-5-chloro-aniline can be used as starting materials use in this reaction, especially alkali metal salts or salts with acids, primarily with inorganic acids such as hydrohalic acid e.g. B. hydrochloric acid or hydrobromic acid.

The starting material used for this reaction is known.
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, is carried out in the presence of a solvent, preferably in aqueous alkali hydroxide solutions, e.g. B. lithium, sodium or potassium hydroxide, or an ether such as diethylene glycol dimethyl ether, or a liquid carboxamide, such as a formamide, z. B. formamide or dimethylformamide. The reduction can be carried out at room temperature or at an elevated temperature, if appropriate in the presence of an inert gas such as nitrogen.

The starting materials used for this process method can be based on known ones Way received, e.g. B. by reacting the 2,4-disulfamyl-5-chloro-aniline with a carboxylic acid of the formula R-COOH.

Depending on the reaction conditions, the new compounds are obtained in free form or in the form their salts. Metal salts obtained can e.g. B. by reaction with aqueous acids, such as mineral acids, z. B. hydrohalic acids, for example hydrochloric acid or sulfuric acid, into the free compounds be transferred. These in turn can be converted into metal salts, such as alkali metal salts by treating e.g. B. with a metal hydroxide such as sodium or potassium hydroxide in a solvent such as an alkanol, e.g. B. methanol or Ethanol, or in water and subsequent evaporation of the solvent or by reaction the free compound in an ether, such as p-dioxane or diethylene glycol dimethyl ether, with an alkali metal hydride or -amid, ζ. B. sodium or potassium hydride or sodium or potassium amide. Included mono- or poly-salts can be obtained.

The new compounds can also exist in the form of their optical antipodes. Preserved Racemates let see separate into their antipodes in the usual way.

The new S ^ -dihydro-l ^^ benzothiadiazin-l ^ -dioxyde are diuretic and natriuretic and are intended to be used as remedies.

The invention is described in more detail in the examples. The temperatures are in degrees Celsius specified.

example 1

A mixture of 2.5 g of 5-chloro-2,4-disulfamylaniline, 1.2 g of 2-fluoro-benzaldehyde, 1 cm ^{3 of} a saturated solution of hydrochloric acid in ethyl acetate and 50 cm ^{3 of} diethylene glycol dimethyl ether is heated to 90 ° for 1 hour heated. Then a third of the solvent is evaporated and the remainder is poured into water. The mixture is allowed to stand at room temperature, the water is decanted off and the residue is washed again with water. The 3- (2'-fluorine-

10

thiadiazine-1,1-dioxide is made from a mixture of Recrystallized ethanol and water; M.p. 248 to 250 °; Yield 1.3g.

The following connections are established in an analogous manner:

3- (3'-Fluoro-phenyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1 -dioxide;

M.p. 227 to 229 °;

3- (2'-Methyl-phenyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1 -dioxide;

M.p. 263 to 266 ° ;.

3- (3'-methyl-phenyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide;

232-233 °;

3- (3'-Hydroxyphenyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1 -dioxide;

Mp 238-240 °;

3- (4'-Isopropyl-phenyl) -6-chloro-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide,

which, upon crystallization, likely includes ^{ethanol ao;} M.p. 225 °;

3-bromomethyl-6-chloro-7-sulfamyl-3,4-dihydrol, 2,4-benzothiadiazine-1,1-dioxide; M.p. 215 to 216 °; 3-dichloro-methyl-6-chloro-7-sulfamyl-3,4-dihydro-

l, 2,4-benzothiadiazine-l, l-dioxide; F. 242 to 244 °. ^a5

Example 2

A mixture of 5.7 g of 5-chloro-2,4-disulfamylanilin, 3.2 g of diethylamino-pivalaldehyde and about 0.1 g of sodium hydroxide in 60 cm ³ 90 ° / ₀ aqueous alcohol is heated for 1 hour on the steam bath. Two thirds of the solvent are then evaporated off, water is added and the solution is neutralized with dilute aqueous hydrochloric acid. The precipitate is separated off, the 3- (l ', l'-dimethyl-2-diethylamino-ethyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxide in dimethylformamide and adds water. The crystallized product melts at 288 to 290 °; Yield 2.5g.

Example 3

To a solution of 5.8 g of 5-chloro-2,4-disulfamylaniline in 30 cm ^{3 of} diethylene glycol dimethyl ether are added 10 cm ^{3 of} a 2 normal solution of hydrochloric acid in anhydrous ethyl acetate and 3.7 g of 1,1-diethoxy-2- diethylamino-ethane. The reaction mixture is boiled on the steam bath for 1 hour, whereby two layers are formed, and the diethylene glycol dimethyl ether layer is separated off after cooling. ^{30 cm 3 of} water are added to the lower layer and sodium carbonate and 30 cm ^{3 of} ether are added, a crystalline precipitate being formed. After filtering off the 3- (diethylamino-methyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide is recrystallized 3 times from aqueous dimethylformamide; Mp 196 ° (decomposition); Yield 5.8g.

If the l, l-diethoxy-2-diethylaminoethane is replaced by 3.22 g of l, l-diethoxy-2-dimethylaminoethane and If the procedure is otherwise as described above, 2.5 g of 3- (dimethylamino-methyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1 are obtained -dioxide; 184 ° (decomposition).

Example 4

A solution of 5-chloro-2,4-disulfamyl-aniline in 30 cm ^{8 of} diethylene glycol dimethyl ether is treated with 1 cm ^{3 of} a saturated solution of hydrochloric acid in ethyl acetate and 2.68 g of 3-phenyl-propionaldehyde. The mixture is heated to 70 to 90 ° for 1 hour, then evaporated to a small volume under reduced pressure and 30 cm ^{8 of} water are added. The 3- (2'-phenyl-ethyl) -6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine -1,1-dioxide crystallizes, is filtered off and recrystallized from ethanol. It melts at 117 to 119 °, it probably contains crystal alcohol; the compound dried at 80 ° melts at 174 to 175 °; Yield 75%

Example 5

A mixture of 5.6 g of 5-chloro-2,4-disulfamylaniline, 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 of} diethylene glycol dimethyl ether is on the steam bath for 1 hour heated, then evaporated to half its volume, diluted with water and worked up as in Example 4. The 3- (l '-Phenyl-äthyty-o-cMor ^ -sulfamyl-S ^ dihydro-1,2,4-benzothiadiazine-1,1-dioxide is obtained in the form of yellow crystals, which after recrystallization from aqueous ethanol Melting 226 to 228 °; Yield 5.7 g.

Claims (1)

PATENT CLAIMS: 1. Process for the preparation of 3,4-dihydrol, 2,4-benzothiadiazine-l, l-dioxyden the general formula H ₂ NO ₂ S CH-R NH where R is bromomethyl, dichloromethyl, dimethylamino - methyl, diethylamino - methyl, 1,1 - dimethyl - 2 - diethylamino - ethyl, 2 - fluorophenyl, 3-fluorophenyl, 2-methylphenyl -, 3-methyl-phenyl, 3-hydroxyphenyl, 4-isopropylphenyl, 1-phenyl-ethyl or 2-phenyl-ethyl radical, and their salts according to patent application C18496 IVd / 12p (German Auslegeschrift 1 112079) , characterized in that one either a) 2,4-Disulfamyl-5-chloro-aniline of the formula NHo H ₂ NO ₂ S SO ₂ NH ₂ or the salts thereof with an aldehyde of the formula R - CHO or 7 8 b) a l, 2,4-benzothiadiazine-l, l-dioxide of the all- and optionally in a manner known per se common formula obtained salts into the free compounds or Ci obtained free compounds converted into their salts. 5 2. The method according to claim 1, characterized in that in procedure a) the _v Aldehyde used in the form of an acetal. H ₂ NO ₂ S ' ^ /? ° \ 3. Process according to claims 1 and 2, O O characterized in that the procedural or the corresponding tautomeric compound io, a) in the presence of an acid or in hydrogenated with a dimetal hydride or carried out in an alkaline medium,
electrolytically reduced © 209 517/397 2.62