DE1088504B - Process for the preparation of disulfamylaniline compounds - Google Patents

Description

FEDERAL REPUBLIC; GERMANY

GERMAN

kl. 12 q 6/03

INTERNAT. KL. C 07 C

PATENT OFFICE

EDITORIAL EDITORIAL 1088 504

M 39928 IVb / 12 q

REGISTRATION DATE: DECEMBER 12, 1958

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL. ·

SEPTEMBER 8, 1960

The invention relates to a new process for the preparation of disulfamylaniline compounds of the general formula

R ² ENT

- ¹

ρ NH ₂
1-SUN ₉ NHR ²

in which R ^{1 is} halogen, such as chlorine, bromine or fluorine, a lower alkyl radical having advantageously 1 to 5 carbon atoms, a lower alkoxy radical having advantageously 1 to 5 carbon atoms, a nitro or an amino group and R ^{2 is} hydrogen or a lower alkyl radical.

The process according to the invention can be represented by the following reaction sequence:

Process for the preparation of disulfamylaniline compounds

Applicant:

Merck & Co., Inc., Rahway, N. J. (V. St. A.)

Representative: E. Maemecke, Berlin-Lichterfelde West,

and Dr. W. Kühl, Hamburg 36, Esplanade 36 a,

Patent attorneys

X— / V-NO ₂ Χ— f ^

IJ .Na ₂ S ₂ ^

-NO, O, N- f

-X

II Frederick Charles Novello, Lansdala., Pa. (V, St. A.), has been named as the inventor

oxidation

NH ₉

SUN ₉ NHR ²

reduction

X amidation

SO ₂ NHR ²

X- / \ -NO ₂

\ X

III

SO ₂ Cl

1. ClSO ₃ H

2. Amidation

1. ClSO ₃ H

2. Amidation

R ¹ -

R ² HNSO ₂ -L

-NH ₂
LsO ₂ NHR ²

reduction

XR ² HNSO ₂ -

NO ₂ SOpNHR ²

VII

In the above reaction scheme, X is a halogen, a lower alkyl radical, a lower alkoxy radical or a nitro group, Hal is a halogen, in particular chlorine or bromine, and R ¹ and R ² have the above meanings. The remainder of Hai is either in the o- or in the p-position to the nitro group.

IV

The novel process illustrated above for the preparation of the disulfamylaniline compounds is to that a halonitrobenzene (I) is converted into the di (nitrophenyl) disulfide (II) by treatment with sodium disulfide convicted. The disulfide obtained in this way is combined with chlorine in an acidic medium to form a nitrobenzenesulfonyl chloride (III)

009 590/407

3 4

oxidized, and this is also pre-treated with sodium hydrosulphide with the help of ammonia or chemical reduction lower monoalkylamine can be taken into the corresponding, being the desired sulfamyl sulfonamide (V) transferred. The nitrobenzenesulfonamide forms aniline compound (VI).

is then reduced, whereby the nitro group is converted into a The sulfamylaniline (VI) is by reaction with

Amino group passes over, and the resulting aniline 5 at least 2 equivalents of chlorosulfonic acid, advantageous Compound (VI) is chlorosulfinated with chlorosulfonic acid and then with while heating to 50 to 100 ° C, and that Ammonia or a lower monoalkylamine to the sulfonyl chloride thus obtained is then mixed with ammonia desired 2,4-disulfanrylaniline compound (VII) amidated by amidation or a lower monoalkylamine, whereby set. the same reagents, proportions and

The disulfamylaniline compound (VII) can also be used for amidation of verdem Nitrobenzenesulfonylchloride (III) in the manner dar- binding III to compound V have been described. on are made that the sulfonyl chloride compound is obtained in this way the disulfamylaniline compound first with chlorosulfonic acid in the presence of an alkali (VII).

halides and then with ammonia or a never- The nitrobenzene sulfonyl chloride (III) can also be used in the

whose monoalkylamine are converted to disulfamylnitrobenzene (IV) 15 disulfamylaniline compound (VII), converts and then the nitro group to the amino group by first reducing the compound III with chlorosulfone, whereby the disulfamylanilinic acid is also chlorosulfonated in the presence of an alkali halide, connection (VII) receives. then the disulfamylnitrobenzene compound (IV) with

The new process according to the invention is amidated by ammonia or a lower monoalkylamine special value because it is possible with its help, 20 and finally the nitro group is reduunsymmetric to the amino group substituted disulfamylaniline compound. The chlorosulfonation of the compound III can be carried out in gene and in particular Disulfamylanilinver- Presence of any alkali halides, such as sodium, to represent bonds that are carried out on the nitrogen atom of the potassium or lithium chloride. For Sulfamyl radicals are substituted in the 2-position. practical purposes one can work with sodium chloride,

In order to carry out the process of the present invention, since it is readily available and inexpensive, and the reaction is made using a solution of sodium disulfide, it proceeds quite smoothly in its presence. Since the mixes this with a solution of the halogen chlorosulfonation in question with these reactants ziemnitrobenzene (I). The reactants can be violent if the nitrobenzenesulfonyl aqueous medium is added or dissolved in alcohol and chloride (III) is added to the chlorosulfonic acid, preferably in small proportions of 2 equivalents of halonitrobenzene, with stirring and cooling. When the entire amount of compound III has been added to at least 1 equivalent of sodium disulphide, apply; If necessary, however, one can also add a portion of the alkali metal halide, so that a larger amount of sodium disulfide is used. When carrying through the hydrogen halide at a moderate rate, it is advisable to use one of the wraps. The mixture is then preferably mixed in an oil bath with both solutions, e.g. B., heating the DisulfidlÖsung for another 35 to 100 to 200 ⁰ C. The amidation of the so obtained add dropwise, since the reaction is violent and ten disulfonylchlorides and the reduction of the nitroexotherm proceeds. After completion of the addition, the group of compound IV, as described above, a mixture, preferably on a steam bath to 50 to run, which is, however, equi-100 heated to at least 4 ⁰ C, with the di-nitrophenyddisulfid (II) valency of amidating have to work.
forms. Instead of sodium disulfide, it is also possible to use the disulfamylaniline potassium disulfide prepared according to the invention. compounds are, given their diuretic,

The disulfide (II) is then in a hydrochloric acid concentrated with acetic acid, natriuretic and / or saluretic effects or mixtures of concentrated pharmacotherapeutic agents. Also provide trated hydrochloric acid and nitric acid or acetic acid DisulfamylanUinverbindungen switch the valuable medium Zwischengesäuerten oxidized with chlorine, wherein one to 45 for the preparation sulfamylsubstituierter a temperature between about 25 and heated 7O ⁰ C. 5,6-benzo-1,2,4-thiadiazine-1,2,4-thiadiazine-1,2-dioxide compounds. Preferably, the chlorine is slowly bubbled through the diuretic, natriuretic and / or saline reaction mixture, which has enticental effects . The disulfamylaniline promising nitrobenzenesulfonyl chloride (III) forms. bonds as well as the 5,6-benzo-l, 2,4-thiadiazine

The nitrobenzenesulfonyl chloride (III) is then amidated by 5 ° 1,1-dioxide compounds when administered orally in reaction with at least 2 moles of ammonia or a form of tablets or capsules and the like, and in the case of lower monoalkylamines. Preferably, the reaction mixture is jectioned in solution in a dilute alkaline medium or in polyethylene glycol during the first 30 to 60 mi. In view of their grooves cooled in an ice bath and then ER at 50 to 100 ⁰ C pharmacotherapeutic properties which are heated to give the corresponding amide forms Nitrobenzolsulfon- particularly 55 compounds prepared in accordance with the invention (V). The ammonia used for amidation is valuable for the treatment of blood pressure and can be used in any form, e.g. B. as caused heart defects and other abnormal appearances or alcoholic ammonia, as liquid tongues that cause edema-like conditions in the body ammonia or by dissolving the sulfonyl chloride (III) in or an imbalance in the electrolyte of an organic solvent and causing gaseous concentration in the body, such as B. ammonia to form the sulfamyl derivative (V) in abnormal sodium retention.
initiates the solution.

The nitro group of the nitrobenzenesulfonamide (V) is Example 1

then reduced to the amino group, either to - ~, " _Λ -, · ,, -, ·, ·

catalytic route, e.g. B. by means of a platinum catalyst 6 ₅ 5-chloro-2,4-disulfamylanüm

tors or with palladium on charcoal, or at chemical level A. A solution of 360 g (1.5 mol) of crystalline

Shem way, z. For example, with iron in acidic or alkaline sodium sulfide in 1,500 cc of 90 ° / ₀ aqueous ethanol is beispeilsweise added medium with iron powder and hydrochloric acid 48 g (1.5 g atom) of finely ground sulfur, and d or with ferrous sulphate and Ammoniumhydroxj ^, or the mixture is heated on the steam bath until the sulfur, if R ^{1 is} a Nrbro group, a partial 70 can go into solution. The sodium disulfide solution thus obtained

is then dropwise to a solution of 384 g (2.0 mol) of kulare amount of 2-chloro-5-ethoxy-1-nitrobenzene and works

2,5-dichloro-l-nitrobenzene in 650 cc of 95 ° / _o sodium ethanol otherwise according to Example 1, Steps A and B, we obtain

added over 2 hours. The mixture is 5-ethoxy-2-sulfamyl-l-nitrobenzene in an

Heated for 3 hours on the steam bath and the crystalline booty of 30 ° / ₀ .

After cooling in an ice bath, the precipitate is suctioned off, in 5 stage B. A suspension of 0.1 mol of the resulting 1-1 beaker is transferred and thoroughly mixed with 500 ecm of 5-ethoxy-2-sulfamyl-1-nitrobenzene in a mixture of water stirred to remove the sodium chloride. of 50 ecm 10 ° / ₀ iger sodium hydroxide solution and 250 ecm 10 ° / ₀ iger The precipitate is filtered off, washed with 100 ecm alcohol ammonium hydroxide solution on the steam bath and dried at 55 ° C. It is obtained di- heated until the sulfamyl compound has dissolved (4-chloro-2-nitrophenyl) disulfide in a yield of 10. This solution is with a solution of 180 g Ferro-50 ° / ₀ . sulfate in 600 ecm of water was added and reaction stage B. In a mixture of 245 g (0.65 mol) di-mixture heated on the steam bath for a further 2 hours (4-chloro-2-nitrophenyl) disulfide, 11 concentrated salt - and filtered. The filtrate is acidified with hydrochloric acid, acid and 200 ecm concentrated nitric acid is a whereby 5-ethoxy-2-sulfamylaniline precipitates. The yield of chlorine flow at a rate of about 2 bubbles 15 is 65%.

initiated every second. By temporarily heating at level C. If you replace that in Example 1, level D,

the steam bath is the temperature in the course of reversed 5-chloro-2-sulfamylaniline by an equimole-

Maintained at 70 ^° C. for 2 hours. The 5-chloro-l-nitrobenzene kulare amount of 5-ethoxy-2-sulfamylanüin and works in

2-sulfonyl chloride is obtained from the remaining supernatant liquid after stage D of Example 1

separated by decantation, twice with 300 ecm 20 5-ethoxy-2,4-disulfamylaniline in a yield of

Washed in warm water, allowed to solidify and off- 30%. F. = 255 to 257 ° / ₀ .
filtered. The S-chloro-l-nitrobenzene-2-sulfonyl-

chloride becomes partially 500 ecm 28% ammonium Example 4
hydroxide solution added, whereupon in the course of

Cools in an ice bath for 30 minutes. Then the mixture becomes 5-propyl-2- (N-propylsulfamyl) -4-sulfamylaniline

Heated for 2 hours on the steam bath, cooled and the stage A. 35.4 g of p-propylacetanilide are partially

Product filtered off. By recrystallization from aqueous in the course of 15 minutes to a mixture of 35 ecm Alcohol is obtained from 5-chloro-2-sulfamyl-1-nitrobenzene in concentrated nitric acid and 35 ecm of glacial acetic acid a yield of 65%. Added cooling in an ice bath. After an hour at

Stage C. A suspension of 28.4 g (0.12 mol) of the so-called 30 0 to 10 ⁰ C, the mixture is poured onto ice. The resulting 5-chloro-2-sulfamyl-l-nitrobenzene in a solid body formed in this way is filtered off and then a mixture of 50 ecm methanol and 95 ecm water, 2 hours on the steam bath with 100 ecm 50 ° / ₀ iger which 4 g Contains cupric chloride, is heated on a steam bath with sulfuric acid, then cooled and heated to 70 ° C on ice. Then over the course of 3 ¹ Z ₂ hours are poured. By recrystallizing the 6 parts obtained in this way, 5 g each of iron powder and then each 35 solid substance from aqueous alcohol, 20 ecm of concentrated hydrochloric acid are added. The temperature 2-nitro-4-propylaniline in a yield of 65%. is kept between 70 and 8O ⁰ C. After the last stage B. 24.4 g of the 2-nitro-4-propyl-

Iron powder and concentrated hydrochloric acid aniline are added to a solution of 30 ecm more concentrated, the mixture is heated to 80 to 85 ° C for 2 hours, then sulfuric acid and 100 ecm water are added, and this is cooled to room temperature and filtered. The filtrate 40 mixture is cooled to 0-5 ° C. At this temperature it is cooled in an ice bath and aqueous sodium hydroxide solution is slowly added to a solution of 7 g of sodium neutralized, 5-chloro-2-sulfamylanuine in a nitrite in 20 ecm of water, the mixture is left for 2 hours with a yield of 72 ° / ₀ receives. 0 to 5 ° C and filtered. The filtrate is dripping

Stage D. A solution of 25 g of S-chloro ^ -sulfamyl- wise to a boiling mixture of 100 ecm water, aniline in 50 ecm chlorosulfonic acid is 2 hours on the 45 6.4 g copper sulfate, 15.6 g sodium bromide and 2 g Copper steam bath heated, cooled and poured onto ice. The powder added. The mixture is heated for a further 30 minutes, solid bodies which form in the process are filtered off, whereupon the mixture is cooled and extracted with ether, washed with water and partially concentrated to 150 ecm. The ether extract is washed with water and the ammonium hydroxide solution is added. Then the mixture is dried over sodium sulfate and heated to dryness on the steam bath for 1 hour, cooled and evaporated. 2-Nitro-4-propyl-1-bromobenzene is obtained in and the precipitate is filtered off and from aqueous in a yield of 60 ° / ₀ .

Recrystallized ethanol. 5-chloro-2,4-disulf stage C is obtained. A prepared according to Example 1, stage A, is obtained

amylaniline as colorless needles. F .. = 251 to 252 ° C. Solution of sodium disulfide in 1500 ecm 90% yield: 25 ° / ₀ . Ethanol is added dropwise with a solution of 2 mol

55 2-Nitro-4-propyl-1-bromobenzene, prepared according to the above

Examples provision in 95 ° / _o sodium ethanol in the course of 2 hours

_ offset. The mixture is ^{heated to 70 °} C. for 6 hours

5-chloro-2,4-disulfamylanihn _{and the Niedersoeh] ag after cooling in an ice bath}

If you replace that used in Example 1, Level A, suctioned off, transferred to a 1-1 beaker and thoroughly

2,5-dichloro-l-nitrobenzene borrowed by an equimolecular 60 with 500 ecm of water stirred to the sodium chloride

Amount of 3,4-dichloro-l-nitrobenzene and works to remove the rest. The precipitate that forms will

following the procedure of Example 1, stages A to D, filtered off, washed with 100 ecm of alcohol and heated to 55 ° C

5-chloro-2,4-disulfamylaniline is obtained as a colorless, dried one. Di- (4-propyl-2-nitrophenyl) di-

Needles. M.p. = 251-252 ° C; Yield: 25%. sulfide in a yield of 52%.

65 stage D. In a mixture of the di- (4-propyl-

Example 3 2-nitrophenyl) disulfide with acetic acid becomes a stream of chlorine

_cx . , ". ,. _ljr , ... at a rate of about 2 bubbles per second

5-Athoxy-2,4-disulfamylanum initiated. By temporarily heating on the steam

Stage A. If that in Example 1, Stage A is replaced, the temperature is increased over the course of 2 hours

applied 2,5-dichloro-1-nitrobenzene by an equimole- 70 kept 50 ° C. The 5-propyl-l-nitro-

benzene-2-sulfonyl chloride is obtained from the supernatant Liquid separated by decanting, washed twice with 300 ecm warm water each time, allowed to solidify and the product filtered off. The 5-propyl-nitrobenzene-2-sulfonyl chloride thus obtained is cooled in an ice bath and partially added to an aqueous solution of propylamine which is also cooled in an ice bath. As soon as one all the sulfonyl chloride has been added, the mixture is heated to 75 ° C. for 1 hour, cooled and the product filtered away. S-propyl-2-N-propylsulfamyl-1-nitrobenzene is obtained by recrystallization from aqueous alcohol in a yield of 53%.

Step E. A suspension of 5 g of the S-propyl thus obtained ^ -N-propylsulfamyl-l-nitrobenzene and 500 mg of a catalyst consisting of 5% palladium on charcoal in 100 cc of 50 ° / ₀ aqueous ethanol is in a Shaken hydrogen atmosphere until 3 moles of hydrogen are absorbed. The reaction mixture is then heated to boiling and the hot solution is filtered and concentrated until S-PropyUZ-N-propylsulfamylaniline crystallizes out. The yield is 75%.

Step F. The 5-propyl-2-N-propylsulfamylaniline thus obtained is then chlorosulfonated and amidated according to stage D of Example 1, 5-propyl-2-N-propylsulfamyl-4-sulfamylanüin obtained in a yield of 30%. F. = 259 to 261 ° C.

Example 5
5-nitro-2,4-disulfamylaniline

Level A. If you replace that in Example 1, Level A, used 2,5-di-chloro-l-nitrobenzene through an equimolecular Amount of 2,4-dinitro-l-bromobenzene and works Otherwise, following the procedures of steps A and B of Example 1, 2,4-dinitrobenzenesulfonamide is obtained in a yield of 33%.

Stage B. 24.7 g (0.1 mol) of the 2,4-dinitrobenzenesulfonamide thus obtained are dissolved in 500 ecm of methanol at 60 to 75 ° C. by adding 80 ecm of 10% aqueous sodium hydroxide solution. A solution of sodium hydrosulphide (prepared from 55.2 g of sodium sulphide and 19.3 g of sodium bicarbonate, dissolved in 100 ecm of water at 50 ° C.) is then added over a period of 10 to 15 minutes. The mixture is heated for 2 hours at 70 ⁰ C and then concentrated in vacuo, are stripped to 300 cc alcohol. The residue is cooled in an ice bath and the solid is filtered off, transferred to a beaker, and excess hydrochloric acid is added to give nitrosulfamylaniline. The precipitated product is filtered off, washed with water and recrystallized from dilute alcohol. The yield is 60%.

Stage C. 0.5 mol of the nitrosulfamylaniline obtained in this way or its mixture of isomers are added in portions to 200 ecm of chlorosulfonic acid cooled in an ice bath, with stirring. 175 g of sodium chloride are then added in portions over the course of 1 to 2 hours, whereupon the mixture is gradually heated to 150 ° C. in an oil bath. After 3 hours at 150 to 160 ° C., the flask is cooled in an ice bath and the contents are mixed with 1 liter of cold water. The product is extracted with ether and the extract is washed with water and dried over sodium sulfate. After the ether has been stripped off on the steam bath, the residue is partially added to 100 ecm of 28% ammonium hydroxide solution cooled in an ice bath. The mixture is heated on the steam bath for 1 hour, cooled and the product filtered off, washed with water and dried. Recrystallization from aqueous alcohol gives 5-nitro-2,4-disulfamylaniline in a yield of 25%. F. = 260 to 262 ° C. 7 *

Example 6
5-Ammo-2,4-disulf amylaniline

If the 5-propyl-2-N-propylsulfamyl-1-nitrobenzene used in step E of Example 4 is replaced by a equimolecular amount of Nitrosulfamylanüin, prepared according to stage B of Example 5, and works otherwise according to the procedure of steps E and F of example 4, 5-amino-2,4-disulfamylaniline is thus obtained in a yield of 25%. M.p. = 245 to 246 ° C (dec.).

Example 7
5-chloro-2,4-disulfamylamine

Stage A. The nitrosulfamylanuine used in Stage C of Example 5 is replaced by an equimolecular one Amount of S-chloro-1-nitrobenzene ^ -sulfonyl chloride, prepared after stage B of Example 1, and if the rest of the procedure is carried out according to Stage C of Example 5, 5-chloro-2,4-disulfamyl-1-nitrobenzene is obtained in a yield of 30%.

Stage B. Replaces the S-chloro ^ -sulfamyl-l-nitrobenzene used in Stage C of Example 1 by a equimolecular amount of the 5-chloro-2,4-disulfamyl-1-nitrobenzene thus obtained and if, for the rest, step C of Example 1 is used, 5-chloro-2,4-disulfamylaniline is obtained as colorless needles in a yield of 75%. F. = 251 to 252 ° C.

Claims (6)

Patent claim: 1. Process for the preparation of disulfamylaniline compounds of the general formula I. R ¹ -I R ² HNSO ₂ -L NH ₂
SO ₂ NHR ² in which R ^{1 is} halogen, such as chlorine, bromine or fluorine, a lower alkyl radical having advantageously 1 to 5 carbon atoms, a lower alkoxy radical having advantageously 1 to 5 carbon atoms, a nitro or an amino group and R ^{2 is} hydrogen or a lower alkyl radical, thereby marked indicates that a halonitrobenzene of the general formula II or III NO ₂
Shark or Shark NO, wherein X is halogen, a lower alkyl radical, a lower alkoxy radical or a nitro group and Hai denotes a halogen, in particular chlorine or bromine, and an alkali metal disulfide in solution to form the di- (4-X-2-nitrophenyl) disulfide or di- (2-X-4-nitrophenyl) -disulnd reacts, this with chlorine in an acidic medium for 5-X-1-nitrobenzene-2-sulfonyl chloride or 3-X-1-nitrobenzene-4-sulfonyl chloride oxidized, the latter with at least 2 equivalents of ammonia or a lower monoalkylamine to the corresponding Sulfonamide amidated, this by chemical or catalytic reduction of the nitro group to the amino group reduced, the aniline compound thus obtained by reaction with at least 2 equivalents Chlorosulfonic acid and then chlorosulfonated with at least 2 equivalents of ammonia or one lower monoalkylamine converts. 2. The method according to claim 1, characterized in that that at least 1 equivalent of sodium disulfide with 2 equivalents of the halonitrobenzene heated to a temperature between about 50 and 10O ⁰ C. 3. The method according to claim 1 and 2, characterized in that one in each of the two amidation stages the sulfonyl chloride with at least 2 equivalents of concentrated aqueous ammonium hydroxide solution implements. 4. The method according to claim 1 to 3, characterized in that that the nitro group of S-X-2-sulfamyl-l-nitrobenzene or of 3-X-4-sulfamyl-1-nitrobenzene reduced with iron powder and hydrochloric acid. 5. Process for the preparation of disulfamylaniline compounds of the general formula I des Claim 1, characterized in that the 5-Xl-nitrobenzene-2-sulphonyl chloride or 3-Xl-nitrobenzene-4-sulphonyl chloride obtained according to claim 1 is chlorosulphonated by heating with at least 2 equivalents of chlorosulphonic acid in the presence of an alkali halide, the reaction product by reaction with amidated at least 4 equivalents of ammonia or a lower monoalkylamine to the corresponding 5-X-2,4-disulfamyl-1-nitrobenzene and then reduced, where R ¹ , R ² and X have the above meanings. 6. The method according to claim 1 to 3 and 5, characterized in that in the case where R ^{1 is} the nitro group, a partial reduction is carried out using sodium hydrosulfide. ® 009 590/407 8.60