DE1181712B - Process for the preparation of 3-sulfamyl-4-halogen-benzoylhydrazines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German class: 12q-13

Number: 1181712

File number: S 74348 IVb / 12 q

Filing date: June 14, 1961

Opening day: November 19, 1964

The invention relates to a method of manufacture of 3-sulfamyl-4-halogen-benzoylhydrazines of the general formula

halogen
Γ "> - SO ₂ NH ₂

CO-NH-NH-R

in which R is a lower alkyl or a phenyl, chlorine, nitrophenyl, sulfamylphenyl, chlorosulfamylphenyl or tolyl radical, which is characterized in that one in a known manner 3-sulf amyl-4-halogen-benzoyl chloride with a hydrazine the general formula

R - NH - NH ₂

in which R has the meaning given.

The process according to the invention is carried out as follows: A suspension of 3-sulfamyl-4-chlorobenzoyl chloride in chloroform with a solution of a hydrazine of the given general formula in triethylamine and chloroform and stirred for 24 to 48 hours at room temperature. It is then evaporated to dryness, the residue is taken up in ethyl acetate and washed with water washed. After drying over magnesium sulfate, the ethyl acetate is reduced under reduced pressure evaporated and the remaining hydrazide purified by methods known per se.

The new sulfonamides are solid, crystallized compounds at room temperature. You stand out characterized by pharmacodynamic properties. They should be used in therapy as diuretics, sodium uretics and chloruretics are introduced, with particular importance for their therapeutic use: that their effect also occurs after oral administration.

The new compounds also provide valuable intermediates for the manufacture of drugs represent.

In the examples which explain the process, all temperatures are given in degrees Celsius.

example 1

To a solution of 5.0 g of isopropylhydrazine and 6.1 g of triethylamine in 180 ecm of chloroform within one hour a suspension of 15.0 g of 3-sulfamyl-4-chlorobenzoyl chloride in 120 ecm chloro process for the production of 3-sulfamyl-4-halogen-benzoylhydrazines

Applicant:

S ^ ndoz A. G., Basel (Switzerland)

Represent

Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Ernst Jucker, Binningen,

Dr. Adolf J. Lindenmann, Basel (Switzerland)

Claimed priority:

Switzerland of June 15, 1960 (6799),

of September 5, 1960 (10 024),
of March 15, 1961 (3117),
dated April 26, 1961 (4889)

form at 20 to 25 ° with stirring and the reaction mixture then 48 hours at room temperature stirred further. It is then evaporated to dryness, the residue in 300 ecm ethyl acetate taken up and washed with 100 ecm of water. After drying over magnesium sulfate the ethyl acetate is distilled off in vacuo and the dark brown oily residue with excess methanolic hydrochloric acid added. The solution is concentrated to a small volume and lets stand at room temperature, whereby 1-isopropyl-2- (3'-sulfamyl-4'-chloro-benzoyl) -hydrazine-hy- Hydrochloride slowly begins to precipitate in crystalline form. After 24 hours it is filtered off and the hydrochloride recrystallized from ethanol-ether. F. 206 to 207 ° (Decomposition).

Example 2

To a solution of 6.5 g of phenylhydrazine and 6.1 g of triethylamine in 180 ecm of absolute chloroform is within one hour a suspension of 150.0 g of 3-sulfamyl-4-chloro-benzoic acid chloride in 120 ecm absolute Chloroform was added at 20 to 25 ° with stirring and then the reaction mixture Stirred for hours at room temperature.

409 728/465

It is then evaporated to dryness, and the residue is taken up in approximately 300 ecm of ethyl acetate and washed well with water. After drying over magnesium sulfate, the ethyl acetate becomes distilled off in vacuo and the residue, the 1-phenyl-2- (3'-sulfamyl-4'-chlorobenzoyl) hydrazine, from ethyl acetate — petroleum ether for crystallization brought. After recrystallization from methanol-petroleum ether, the hydrazine derivative melts at 185 to 187 °. ; . · ■ :.

Example 3

To a solution of 8.5 g of 4-chloro-phenylhydrazine and 6.1 g of triethylamine in 200 ecm of chloroform is a suspension of 15.0 g within one hour 3-sulfamyl-4-chlorobenzoyl chloride in 180 ecm chloroform at 20 to 25 ° with stirring and then the reaction mixture for 50 hours at room temperature stirred further. The reaction mixture is then left to dryness for another 20 hours stirred further at 20 to 25 °. It is filtered off, the filter residue is slurried in 50 ecm warm Water (about 30 to 32 °), the suspension is stirred for a short time and filtered off. After drying jm Vacuum at 20 to 25 ° is the filter residue, the l-phenyl-2- (3'-sulfamyl-4'-fluoro-benzoyl) - hydrazine, recrystallized from methanol. F. 179 to 180 °.

The 3-sulfamyl used as starting material

o 4-fluoro-benzoyl chloride was prepared as follows:

a) 3-chlorosulfonyl-4-fluoro-benzoic acid

A solution of 14.0 g of 4-fluoro-benzoic acid in 52.0 g of chlorosulfonic acid is on for 10 hours 130 ° heated. The solution is then cooled to room temperature and poured onto ice, with 3 - chlorosulfonyl - 4 - fluoro - benzoic acid separates out. It is filtered off, the filter residue is taken

evaporated, the residue in 300 ecm acetic acid-20 in ether, separates from some water and dries ethyl ester was added and the ether solution over magnesium sulfate with 200 ecm of water. The ether washed. After drying over magnesium solution, it is then concentrated and washed with petroleum ether sulfate, the ethyl acetate is distilled off in vacuo and the residue, the 1- (4 "-chlorophenyl) -

added, whereby the 3-chlorosulfonyl-4-fluoro-benzoic acid precipitates in crystalline form. After recrystallization from benzene-petroleum ether, the acid melts 138 to 139 °.

2- (3'-sulfamyl-4'-chlorobenzoyl) hydrazine, with methanol to crystallize: brought to and from methanol-

Recrystallized petroleum ether. F. 224 to 225 °. ,. " _O "

■ -'- b) 3-Sulfamyl-4-fluoro-benzoic acid

B e ι s ρ 1 e 1 4 _{Ul g of} 3-chlorosulfonyl-4-fluoro-benzoic acid are slowly added to a solution of 9.1 g of 4-nitro-phenylhydrazine 3 ° with stirring and vigorous cooling

and 6.1 g of triethylamine in 280 ecm of chloroform is 150 ecm of an absolute, _ saturated

within one hour a suspension of 15.0 g of 3-sulfamyl-4-chlorobenzoyl chloride in 20 ecm of chloroform added at 20 to 25 ° with stirring and the reaction mixture then 48 hours at room temperature stirred further. It is then evaporated to dryness, the residue with 300 ecm ethyl acetate and 200 ecm of water are added. It is filtered off, the water portion in the filtrate is separated off and combined the filter residue with the ethyl acetate content. It is evaporated to dryness and the residue is crystallized, the 1- (4 "-nitro-phenyl) -2- (3'-sulfamyl-4-'chlorbenzoyl) hydrazine, from acetone at. mp. 283 to 284 °. 150 ecm of an absolute, _ saturated ethanol Ammonia solution is added, with complete dissolution occurring. Then the reaction solution is still Stirred for 2 hours at room temperature. The solution is concentrated and the resulting pulp is added about 150 ecm of ether and filtered off. The filter residue, 3-sulfamyl-4-fluoro-benzoic acid is used directly after drying in vacuo.

c) 3-sulfamyl-4-fluorobenzoy] chloride

Example 5

To a suspension of 11.0 g of 4-sulfamyl-phenylhydrazine and 6.1 g of triethylamine in 200 ecm of chloroform becomes a suspension within one hour of 15.0 g of 3-sulfamyl-4-chlorobenzoyl chloride in 180 ecm of chloroform at 20 to 25 ° with stirring added and the reaction mixture then stirred for a further 48 hours at room temperature. It is then evaporated to dryness, the residue is taken up in 300 ecm ethyl acetate and mixed with Washed 200 ecm of water. After drying over magnesium sulfate, the ethyl acetate is im Distilled off in vacuo and the residue, the 1- (4 "-Sulfamylphenyl) -2- (3'-siilfamyl-4'-chlorobenzoyl) hydrazine, deposited from methanol-ether and recrystallized from the same solvent mixture. F. 176 ° (with beginning of decomposition). A mixture of 15.5 g of S-sulfamyM-fluorobenzoic acid (Crude product) and 31.0 g of thionyl chloride is heated to 100 ° for 1 hour. Thereupon the reaction mixture evaporated to dryness in vacuo, the residue boiled twice with 150 ecm benzene each time and filtered off from undissolved material. The benzene is then distilled off in vacuo and the residue, the S-sulfamyM-fluoro-benzoyl chloride, from benzene recrystallized. 115 to 116 degrees.

Example 7 Example 6

A suspension of 4.6 g
benzoyl chloride in 50 ecm chloroform is admixed with 4.2 g of phenylhydrazine with stirring over the course of 30 minutes, the temperature rising to 35 °.

To a suspension of 5.5 g of 3-sulfamyl-phenyl-hydrazine and 3.0 g of triethylamine in 300 ecm of chloroform are stirred within one hour 20-25 ° 7.5 g S-sulfamyl ^ -chlorobenzoyl chloride added and the reaction mixture then stirred for a further 48 hours at room temperature. It is then evaporated to dryness, the residue with 300 ecm ethyl acetate and 200 ecm water added and shaken until complete solution has occurred. You separate the layers, dry them Ethyl acetate solution over magnesium sulfate and 3-sulfamyl-4-fluorine-65, the solvent is distilled off in vacuo. Of the The residue, a red oil, is then rubbed with acetone, the l- (3 "-Sulfamyl-phenyl) -2 - (3 '- sulf amyl - 4' - chlorobenzoyl) - hydrazine crystalline

ruled out. It is filtered off and recrystallized from methanol-ether. F. 230 to 233 ° (beginning Decomposition).

- - B e i s ρ i e 1 8

A suspension of 3.8 g of 3-sulfamyl-4-ch, lorphenylhydrazine hydrochloride in 75 ecm of chloroform is mixed with 3.0 g of triethylamine. 3.7 g of 3-sulfamyl-4-chloro-benzoyl chloride are then added over the course of 30 minutes at 20 to 25 ° with stirring and the reaction mixture is then stirred for a further 72 hours at room temperature. It is then evaporated to dryness in vacuo, the residue is mixed with 600 ecm of ethyl acetate and 200 ecm of water and shaken well with warming, during which almost complete solution occurs. The layers are separated, the ethyl acetate solution is dried over magnesium sulfate and the solvent is distilled off in vacuo. The residue is taken up in a little methanol. After standing for a long time at room temperature, the 1- (3 "-Sulfamyl-4" - chloro - phenyl) - 2 - (3 '- sulfamyl - 4' - chloro - benzoyl) hydrazine separates out in crystalline form.

The residue, after the ethyl acetate has been distilled off, can also be chromatographed over aluminum oxide be, the l- (3 "-Sulfamyl-4" -chlorophenyl) -2- (3'-sulfamyl-4'-chlorobenzoyl) hydrazine with a mixed solvent of chloroform and methanol (1: 1) is eluted. The hydrazine derivative melts at 267 bis after recrystallization from methanol 269 ° (decomposition).

The 3-sulfamyl-4-chlorophenylhydrazine hydrochloride used as the starting material was made as follows:

a) 207 g of 3-amino-6-chlorobenzenesulphonic acid amide in 500 ecm of water are mixed with 225 g of aqueous 30% hydrochloric acid while cooling with ice and vigorous stirring and then diazotized at 0 to 5 ° with 250 ecm 4 of sodium nitrite solution. After addition of 110 g solid sodium chloride is stirred for a further 30 minutes at this temperature, and then transmits the filtered diazonium salt at 2 to 5 ° quickly in a weakly phenolphthaleinalkalisch reacting bisulfite solution, prepared from 750 cc of 40% sodium bisulfite solution and an aqueous, about 30 ⁰ / cent Caustic soda, a. After stirring for 1 hour in an ice bath, the reaction mixture is slowly warmed to room temperature and then heated to 80 ° for a further hour. _{Then enough aqueous 30 ° / 0} hydrochloric acid is carefully run in at this temperature until the reaction solution is acidic to the Congo, heated further to 95 ° and kept at this temperature until no more SO ₂ escapes. Animal charcoal is added, the hot solution is filtered and the filtrate is evaporated in a water jet vacuum. After drying, the residue is extracted exhaustively with hot methanol. Concentration of the methanolic solution gives 3-sulfamyl-4-chloro-phenylhydrazine hydrochloride, which can be recrystallized from water or water-ethanol. M.p. 217 to 219 ° (decomposition).

b) 10.3 g of S-amino-o-chlorobenzenesulfonic acid amide, suspended in a mixture of 34 ecm water and 11.3 ecm concentrated hydrochloric acid, are stirred diazotized within 20 minutes at 0 ° with a solution of 3.8 g of sodium nitrite in 10.0 ecm of water, complete dissolution occurs. Then, with further stirring at 0 °, a solution of 30.5 g of tin chloride in 51 ecm of concentrated hydrochloric acid were added dropwise. The reaction mixture is then allowed to run for 30 minutes at 0 ° and stirred for 60 minutes at room temperature. It is then filtered from a yellow one Precipitate is removed, the filtrate is evaporated to dryness in vacuo and the residue is evaporated in vacuo to remove residual water three times with 150 to 200 ecm of ethanol each time. Thereupon the arrears Boiled with 80 ecm of ethanol, filtered, and the filtrate is mixed with 700 to 800 ecm of ether. Man filtered off again from precipitated inorganic salts and the filtrate evaporated to dryness. Ethanol — ether can now be extracted from the residue crystallize the 3-sulfamyl-4-chlorophenylhydrazine hydrochloride, which after recrystallization with Melts from 217 to 219 ° (decomposition).

3-Amino-6-chlorobenzenesulphonic acid amide was prepared as follows: 400 g of iron are 40 ecm concentrated hydrochloric acid and heated to 80 ° after adding 700 ecm of water. Be on it with thorough stirring, 237 g of S-nitro-o-chloro-benzenesulphonic acid amide added in small portions such that the reaction temperature is about 80 °. After the reaction mixture has been heated to 80 ° for a further hour and to 90 ° for 1 hour, After cooling, the insoluble black precipitate is filtered off and washed with water and extracted it twice with 11 boiling ethanol each time. After evaporation of the ethanol im 3-Amino-6-chloro-benzenesulphonic acid amide is obtained as a crystalline residue under a water jet vacuum from 167 to 169 °.

Example 9

To a solution of 4.7 g of 4-tolylhydrazine hydrochloride and 6.0 g of triethylamine in 150 ecm of chloroform are within 30 minutes at 20 to 25 ° 7.6 g 3-sulfamyl-4-chlorobenzoyl chloride was added with stirring and the reaction mixture is then stirred for a further 48 hours at room temperature. Thereon it is evaporated to dryness in vacuo, the residue is taken up in 100 ecm ethyl acetate and washed with 100 ecm of water. After drying over magnesium sulfate, the ethyl acetate is obtained distilled off in vacuo and the residue chromatographed over aluminum oxide, the 1- (4 "-Tolyl) -2- (3'-sulfamyl-4'-chloro-benzoyl) hydrazine is eluted with a mixed solvent of chloroform-methanol (9: 1). After recrystallization from methanol, the hydrazine derivative melts at 205 ° to 207 °.

Claims (1)

Claim: Process for the preparation of 3-sulfamyl-4-halogen-benzoyl-hydrazines the general formula halogen NH-NH-R in which R is a lower alkyl or a phenyl, chlorophenyl, nitrophenyl, sulfamylphenyl, Means chlorosulfamylphenyl or tolyl radical, thereby characterized in that a 3-sulfamyl-4-halo-benzoyl chloride is used according to methods known per se with a hydrazine of the general formula R-NH-NH ₂ in which R has the meaning given. Publications considered: Karr er, "Textbook of Organic Chemistry", 9th edition (1943), p. 240. 409 728/465 11.64 © Bundesdruckerei Berlin