NO143154B - PROCEDURE FOR THE PREPARATION OF SULFAMOYL BENZO ACIDS - Google Patents

Description

The object of the invention is a further method

preparation of diuretically active sulfamoylbenzoic acids of the general formula I

wherein A means linear or branched alkyl groups of 1-4

carbon atoms, which may optionally be substituted with halogen, a carbocyclic ring with 3-5 carbon atoms, X means one of the groups 2 2 2

OR or SR, where R means phenyl which is optionally substituted with methyl, fluorine, chlorine, benzyloxy, hydroxy, nitro or amino,

or X means N-methylpiperazine and R means hydrogen or an alkyl-

residue with 1-6 carbon atoms, the method being characterized by nitrating sulphamoylbenzoic acid derivatives with the general formula III

in which Y means a halogen atom, R has the above meaning and B means

tyre a protecting group with the general formula:

4 5 6 in which R , R and R mean the same or different lower alkyl groups, R 4 can also mean hydrogen and/or each time two of the substituents R<4>, R<5> and R<6> can also be connected cyclically with each other, are nitrated and the compounds of formula IV formed

if R means hydrogen is esterified and reacts the formed compounds with formula IV, in which B and Y have the above meaning with connection

moieties of formula XH, in which X has the above meaning^and redu-

seres the formed compounds of formula V

in which R' means an alkyl radical with up to 6 C atoms and B and X have the above meaning, react the thus formed compounds of the general formula VI in which B, X and R' have the above meaning, with compounds of the general formula VII in which the residue A has the indicated meaning and L means a "leaving group", and reduces the formed compounds with the general formula VIII: in which the residues A, B, R' and X have the above meaning with boron hydrogen optionally in the presence of Lewis acids or by complex borohydrides in the presence of Lewis acids and hydrolyzes the formed compounds of the general formula IX

in which A, B, X and R' have the above meaning, to compounds of formula I, in which R represents a hydrogen atom and optionally esterifies the acids formed in the usual way.

The sulfamoylbenzoic acid of formula I is Pharmaceutica, especially the valuable Diuretica and Saluretica.

A method for producing these compounds is already known from DOS 2.3^5.229.

The method according to the invention has special advantages in relation to the method according to the above-mentioned German application, it is also surprising, as the smooth course of some reaction steps could not be predicted.

Thus, when the protection group B is introduced into the halobenzoic acid with the general formula II, it surprisingly succeeds in nitrating this under mild conditions, which is of particular importance for production on a technical scale.

The benzoic acid derivatives of formula III used according to the invention are available by various methods. The conversion takes place particularly simply, as the starting point is the sulfamovelbenzoic acid derivatives with formula known from the literature

II

by various condensation methods, which are known from the literature.

The following literature should be mentioned, for example:

J. Org. Chem. 25 (1960), 352-356; Zh. Org. Kim

8 (1972), 286 - 291 in Liebig's Ann. Chem. 750 (1971), 42; Zh.

Org. Chem 6 (1970), 9, 1885; B. 94 (1961), 2731 - 2737; Eng. Ch. 78 (1966), 147-148; Eng. Ch. 80 (1968), 281-282; B. 97 (1964), 483-489; B 96 (1963), 802-812; J. Org. Chem. 27, (1962),

4566 - 4570; Eng. Ch. 74 (1962), 781 - 782 and Doklady Akad. SSSR 145 (1962), 584.

As compounds with the general formula III, according to the invention, e.g. apply the following derivatives.

The compounds of formula III are prepared according to the above-mentioned literature methods or analogy to these. Instead of the acids listed above, the respective methyl or ethyl esters can also be used, for example.

The nitration of the benzoic acid derivatives with formula III can take place in different ways. For example, one can in-

introduce the benzoic acid derivatives into one of the usual nitration mixtures for the nitration of slow-reacting aromatics (compare the textbook "Organicum", page 288, edition 1967). Alternatively, the method can also be carried out so that the benzoic acid derivatives of formula III are dissolved in oleum and the nitration is controlled by the dropwise addition of nitric acid.

It is surprising that it succeeds only by introducing the protection group B into the sulfonamide residue and nitrating the benzoic acid derivatives with the general formula III without other groups in the molecule changing.

The reaction temperature is roughly between 55 and 130°C, temperatures of 55-90°C are preferably observed.

As a favorable method it has been found to introduce the substance into a nitrating acid of oleum and fuming nitric acid

and heating the reaction mixture to approx. 6o-8o°C.

The progress of the nitration can be followed by thin-layer chromatography. At the end of the reaction, the isolation of the final product takes place according to methods known in the literature, for example by placing the reaction mixture on ice and filtering off precipitated crystals.

For nitration, acids or esters of the general formula III can be used, in which the residues Y, B and R have the meanings given at the outset. In the nitration of the esters of formula III, the acids of formula IV (down R=H) are obtained in smaller quantities, in addition to the esters of formula IV.

The mixture can be separated in the usual way, e.g. by treatment with aqueous sodium carbonate. The compounds of formula IV formed, in which R means hydrogen, are now esterified in the usual way.

For esterification of the carboxyl group, e.g. the carboxylic acid in its acid chloride, which on addition of alcohols gives the corresponding esters of formula IV.

As alcohol for esterification, lower alkyl alcohols with 1 to 6 carbon atoms such as methanol, ethanol, propanol, butanol, pentanol, isopropanol or hexanol are particularly suitable.

The alcohols can be used in stoichiometric amounts, however it is advantageous to use them in a 5~20 times molar excess or to use them simultaneously as a solvent.

In the next step, the compounds are transferred by formula

IV optionally after esterification of the carboxyl groups with compounds of formula XH in connection with formula V.

Surprisingly, it was found that compounds of the general formula IV, in which R is alkyl, can be reacted under anhydrous conditions with compounds of the general formula XH with good results.

Any additional functional groups present in XH such as additional OH groups or NH2_gr,upper are blocked by usual protective groups, e.g. acylation.

The reaction can be carried out without a solvent. However, it is more advantageous to carry out the reaction in

a solvent. Particularly suitable are organic solvents such as ether and tert.-carboxamides, especially diglymo, dimethylformamide or hexamethylphosphoric acid tris-amide (HMPT).

The thiophenol and phenol derivatives of formula XH are reacted in the form of their anions, the alkali salts having proved particularly suitable and here especially the sodium and potassium salts.

The reaction can take place in the presence or absence of a solvent. Without a solvent, you heat e.g. the components at temperatures of 100-200°C, preferably 10-180°C. The thus formed products can be isolated in the usual way, for example by dissolving the melt products in a solvent and subsequent precipitation by adding water or an organic non-solvent.

Particularly advantageous, however, is the turnover with phenolates or thiophenolates in solvents at temperatures of 100-200°C, preferably 120-160°C. ! in'

Solvents include organic solvents, especially tertiary carboxamides, polyethers or high-boiling solvents such as HMPT or tetramethylene sulfone. Particularly advantageous is the conversion of esters of formula IV into tertiary carboxamides, such as, for example, dimethylformamide or dimethylacetamide. Depending on the choice of reaction temperature, the reaction is completed after 1-6 hours.

The isolation of the final products with formula V takes place as usual, for example one can first of all filter out the inorganic salts and then precipitate the reaction product by adding a non-solvent or one can introduce the reaction mixture into water or ice and isolate the precipitated reaction product.

The reduction of the nitro group in the benzoic acid derivatives of formula V can be carried out in different ways according to regulations known in the literature, e.g. by catalytic hydrogenation.

Raney nickel is preferably used as a catalyst. However, you can also use the usual precious metal catalysts such as e.g. palladium on charcoal or platinum oxide.

The catalytic hydrogenation is carried out in a manner known per se (e.g. Organikum, pages 271 - 277, pages 507 - 510). The reaction takes place in a solvent in the presence of a catalyst.

Organic solvents such as e.g. methanol or ethanol, acetic esters, dioxane or other polar solvents, especially amides such as dimethylformamide, dimethylacetamide or HMPT.

One hydrates at room temperature and under normal pressure or at elevated temperature and elevated pressure, e.g. 50°C and 100 atmospheres in the autoclave.

The 3-acylaminobenzoic acid derivatives of the general formula VIII are available by various methods. For example, they are obtained by reacting the amino compounds

VI with carboxylic acid derivatives capable of amide formation, such as e.g. carboxylic acid anhydride or carboxylic acid halides in the usual way. As "leaving group" L in the compounds of the general formula VII is e.g. of particular importance halogen, trialkylammonium, pyridinium or the group O-Co-A. Pore drawn compounds of formula VII are e.g. butyric acid chloride, butyric anhydride, cyclopropane carboxylic acid chloride, cyclobutane carboxylic acid chloride

The reaction with these compounds takes place under the conditions of the so-called Schotten-Baumann reaction. They can be easily pursued by thin-layer chromatography, as the compounds VI fluorine at 366 m^u, while the compounds VIII do not fluorine

looks.

Various borohydrides such as e.g. diborane, possibly diborane in the presence of Lewis acids. They can be introduced into the reaction mixture under corresponding protective measures, such as e.g. an-

conversion of nitrogen as an inert gas. It is easier to take up the boron hydrogens, which e.g. diborane in solvent and to

apply the solution to reduction. As a solvent, ethers are particularly suitable, e.g. tetrahydrofuran or diethylene glycol dimethyl ether.

When complex borohydrides are allowed to act in the presence

of Lewis acids you usually get even better yields.

The complex hydrides used in the reduction method

of boron are alkali boranates or alkaline earth boranates, preferably, however, sodium borohydride.

As Lewis acids within the scope of the invention, aluminum chloride, titanium tetrachloride and boron trifluoride and its adducts, such as boron trifluoride etherate, apply in particular. Hereby, there is the possibility that when converting the boron trifluoride etherate, it can e.g. with sodium borohydride, diborane occurs in situ (compare Fieser, Fieser: Reagent for Organic Synthesis,

John Wiley and Sons, Inc., New York, Volume 1, page 199).

For the achievement of a special turnover and in particular

pure end products, it is advantageous to have the Lewis acid together with the compounds of formula VIII and to introduce the boron hydrogen or the complex boron hydride.

It is particularly advantageous to use the Lewis acid in excess and to use the complex borohydride or the boron hydrogens in at least a stoichiometric amount, referred to the number of amide groups to be reduced.

The reduction is carried out in a solvent.

Ethers, for example, come into consideration as solvents

such as tetrahydrofuran or diethylene glycol dimethyl ether (diglyme). The solvent in which the reduction is carried out can be

same as that in which the boron hydrogen is possibly dissolved, may, however, also deviate from this.

The reduction can be carried out in a wide temperature range. The reduction can be carried out cold, e.g. at -10°C at room temperature or a slightly elevated temperature. The reduction duration depends on the reaction components used and the selected temperature.

A preferred embodiment of the method according to the invention consists of having the benzoic acid derivatives of formula VIII in an inert solvent together with the Lewis acid and adding a solution of boron hydrogen or the complex borohydride, optionally of a suspension of the complex borohydride in the same or another solvent at 0°C and then stir for a short time. The complex borohydride can also be added directly in solid form. In order to accelerate the reaction, the reaction can be carried out, possibly also at a higher temperature, or after the addition of the reducing agent has been added, heat up to 50°C for about 1 hour.

Another embodiment consists in having substances to be reduced together with the complex borohydride and at -10°C to room temperature adding the Lewis acid. - Sodium borohydride is particularly useful as a complex borohydride. The course of the reaction can be checked by means of thin-layer chromatography by the appearance of the intense blue fluorescence (in the range of 366 nm) of the formed compounds of formula IX. In the reduction according to the invention, the double bonds present in group A can optionally be reduced.

The isolation of the end products can take place in different ways. A preferred work-up method consists in freeing the solution of the reaction product by adding water and small amounts of acid for any reducing agent still present and then precipitating the formed benzoic acid ester by adding a non-solvent. When using diethylene glycol dimethyl ether, water in particular is not suitable as a solvent. The formed benzoic acid esters of formula IX mostly crystallize approximately quantitatively.

The 5-sulfamylbenzoic acid according to the invention with

formula I (R=H) is obtained by alkaline hydrolysis of the compounds of general formula IX, heating the compounds of formula IX for several hours in caustic soda or caustic soda on a steam bath. Thereby, the esters as well as the protective group B are saponified and any further protective groups present are split off.

You can also directly obtain 5-sulfamoylbenzoic acid of formula I (R=H), partially evaporating the reaction mixture after destroying the excess reducing agent. Base is added and heated for a longer time. As a base serves e.g. baking soda. The 5-sulfamylbenzoic acid of formula I can thereby be directly isolated in the form of their salts. During acidification, free acids are obtained.

It is also possible to introduce a protection group

B in a later reaction step, e.g. in compounds of formula

IV, V, VI or V_II, in which B then means 2 hydrogen atoms and on

in this way arrive at compounds of formula IX, in which R' also

may be replaced with R.

For the preparation of the corresponding ester of formula I, in which R represents an alkyl residue, the acids are esterified on water

equal way, e.g. as mentioned above.

The free carboxylic acids can by reaction with corresponding bases such as alkali, alkaline earth or ammonium hydroxide

acids or carbonates are transferred in their pharmaceutically acceptable salts.

In the method according to the invention it allows

produce a large number of highly effective pharmaceuticals,

especially Diuretics and Saluretics.

■ Example 1

3- n- butylamino- 4- phenoxy- 5- sulfamoyl- benzoic acid

a) 4- chloro- 5~ N, N- dimethylaminomethyleneaminosulfonyl- benzoic acid.

To a solution of 58.9 g (0.25 mol) 4-chloro-5~

Sulfamoylbenzoic acid in 183 g (2.5 mol) dimethylformamide (DMF) is added dropwise at -10°C to 90 ml (1.25 mol) thionyl chloride. The solution is then allowed to come to room temperature and stirred for 2 hours and poured onto ice, the precipitate is filtered and washed neutrally with water. 4-chloro-5~N,N-dimethylaminomethyleneaminosulfonylbenzoic acid is obtained (in very good yield) as crystals of m.p. 266-267°C.

b) 3- nitro- 4- chloro- 5- N, N- dimethylaminomethyleneaminosulfonylbenzoic acid

42 ml fuming nitric acid is added dropwise to 60 ml of 20% oleum under ice-cooling, then 34.9 g (0.12 mol) of 4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid is slowly introduced. After 8 hours of stirring at 75°C, the solution is cooled to room temperature, put on ice and the precipitate is washed neutrally with water. 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid is obtained in crystals of m.p. 274-276°C.

c) 3- nitro- 4- chloro- 5~ N, N- dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester

50.4 g (0.15 mol) of 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid is refluxed for 1 hour in a solution of 150 ml of thionyl chloride, which contains 5 drops of DMF. After removal of excess thionyl chloride in vacuo, the solid acid chloride is suspended in 200 ml of methanol. The suspension is refluxed for 1 hour, then cooled and filtered and washed with cold methanol.

3-nitro-4-chloro-5~N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester is obtained, crystals of melting point 168 - 169°Cv Another crystal modification of melting point 155°C can also occur. d) 3-nitro-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfony1-benzoic acid methyl ester.

A solution of 105 g (0.3 mol) 3-nitro-4-chloro-5-N,N-dimethyl-aminomethyleneaminosulfonyl-1-benzoic acid methyl ester and 47.5 g (0.36 = mol) potassium phenolate in 600 ml DMP is boiled for 2 hours during reflux. After cooling and filtering the potassium chloride, the solution is placed on ice/water and stirred for one hour. The precipitate is filtered, washed with water and dried.

After dissolving the crude product in 900 ml of acetone, clarify with charcoal, evaporate to 500 ml and dilute with 1 liter of methanol. The precipitate is filtered after stirring for 1 hour at 10°C and washed with cold methanol.

3-nitro-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester is obtained as crystals of melting point 191 - 193°C. e) 3-amino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester. 6l g (0.15 mol) of 3-nitro-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester is hydrated in d'i-methylformamide with Raney nickel at room temperature and normal pressure for 8 hours. After filtering the catalyst, the DMF solution is poured onto ice. 3-amino-4-phenoxy-5-N,N-dimethyl-aminomethyleneamino-sulphonyl-benzoic acid methyl ester is obtained, crystals of melting point 255 - 256°C. f) 3-n-butyrylamino-4-phenoxy-5-N,N-dimethylaminomethyleneamino-sulfony 1-berizoic acid methyl ester. 10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester are heated together with 2.6 ml of pyridine in 100 ml of absolute dioxane to boiling. A solution of 5.3 g of butyric acid chloride in 50 ml of absolute acetone is slowly added to this. After 1\ - 2 hours, the reaction is finished.

The solution is evaporated, the remaining oil is taken up with a little methanol and the mixture is dropped into ice water with vigorous stirring.

3-n-butyrylamino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester precipitates and is sucked off.

Recrystallization from Cl^OH/HgO, melting point 177 - 178°C.

g) 3-n-butylamino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. 10 g of the butyryl compound prepared under f) is suspended in 100 ml of absolute diglyme, 6 ml of BF-^-etherate is added and then a solution of 1.4 g of NaBH^ in 50 ml of absolute diglyme is added dropwise at room temperature. You let it stir for approx. 1 hour and.splits excess reducing agent by adding a little water, (foaming). It is then filtered and the product is precipitated by adding a further 200 ml of cold water.

The formed 3_n-butylamino-4-phenoxy-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester, which is contaminated with approx. 5% 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzosvremetyl ester, recrystallized from CH 2 OH. Melting point 111 - 112°C.

h) 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid

The raw product formed under point g) is heated

with 2 N NaOH to clear solution under reflux. It is then allowed to cool and 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid is precipitated with 2 N HCl.

Recrystallization from ethanol/water, melting point 234 - 235°C. Example 2. a) 3~(3'-chloropropionylamino)-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. 10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulphonyl-benzoic acid methyl ester are heated to boiling together with 3.6 ml of pyridine in 100 ml of absolute dioxane. To this, a solution of 7 g of w-chloropropionic acid chloride in 50 ml of absolute acetone is dripped. After 4 hours, the solution is evaporated, taken up with a little CH3OH and, while stirring, dropped into ice water. The 3-(3'-chloropropionylamino)-4-phenoxy-5-N,N-dimethyl-amino-methyleneaminosulfonyl-1-benzoic acid methyl ester thus precipitated is recrystallized from CH-3OH/H2, melting point 190°C. b) 3"(3'-chloropropylamino)-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulfony-1-benzoic acid methyl ester.

Same procedure as mentioned under example 1 g). The product is recrystallized from CH^OH, melting point 150 - 151°C. Example 3-

3- cyclopropylmethylamino- 4- phenoxy- 5- sulfamoyl- benzoic acid

One obtains 3-nitro-4-chloro-5_N,N-dimethylaminomethylene-aminosulfony Ibenzoic acid methyl ester, crystals of melting point 168 - 169°Ct Another crystal modification of melting point 155°C can also occur. d) 3-nitro-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfony1-benzoic acid methyl ester.

A solution of 105 g (0.3 mol) 3~nitro-4-chloro-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester and 47.5 g (0.36 = mol) potassium phenolate in 600 ml DMP is boiled for 2 hours during reflux. After cooling and filtering the potassium chloride, the solution is placed on ice/water and stirred for one hour. The precipitate is filtered, washed with water and dried.

After dissolving the crude product in 900 ml of acetone, clarify with charcoal, evaporate to 500 ml and dilute with 1 liter of methanol. The precipitate is filtered after stirring for 1 hour at 10°C and washed with cold methanol.

3~nitro-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester is obtained as crystals of melting point 191 - 193°C. e) 3-amino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester. 6l g (0.15 mol) of 3-nitro-4-phenoxy-5~N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester is hydrated in dimethylformamide with Raney nickel at room temperature and normal pressure for 8 hours. After filtering the catalyst, the DMF solution is poured onto ice. 3-amino-4-phenoxy-5-N,N-dimethyl-aminomethyleneamino-sulphonyl-benzoic acid methyl ester is obtained, crystals of melting point 255 - 256°C. f) 3-n-butyrylamino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. 10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulphonyl-benzoic acid methyl ester are heated together with 2.6 ml of pyridine in 100 ml of absolute dioxane to boiling. A solution of 5.3 g of butyric acid chloride in 50 ml of absolute acetone is slowly added to this. After 1^-2 hours, the reaction is finished.

The solution is evaporated, the remaining oil is taken up with a little methanol and the mixture is dropped into ice water with vigorous stirring.

3-n-butyrylamino-4-phenoxy-5~N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester precipitates and is sucked off.

Recrystallization from CH-jOH/^O, melting point 177 - 178°C.

g) 3-n-butylamino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. 10 g of the butyryl compound produced under f) is suspended in 100 ml of absolute diglyme, 6 ml of BF^ etherate is added and then a solution of 1.4 g of NaBH^ in 50 ml of absolute diglyme is added dropwise at room temperature. You let it stir for approx. 1 hour and split excess reducing agent by adding a little water, (foaming). It is then filtered and the product is precipitated by adding a further 200 ml of cold water.

The formed 3~n-butylamino-4-phenoxy-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester, which is contaminated with approx. 5% 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzosvremetvi ester, recrystallized from CH^OH. Melting point 111 - 112°C.

h) 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid

The raw product formed under point g) is heated

with 2.N NaOH to clear solution under reflux. It is then allowed to cool and 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid is precipitated with 2 N HCl.

Recrystallization from ethanol/water, melting point 234 - 235°C Example 2. a) 3-(3'-chloropropionylamino)-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. 10 g of 3~amino-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulphonyl-benzoic acid methyl ester are heated to boiling together with 3.6 ml of pyridine in 100 ml of absolute dioxane. To this, a solution of 7 g o)-chloropropionic acid chloride in 50 ml absolute acetone is dripped. After 4 hours, the solution is evaporated, taken up with a little CH2OH and, while stirring, dropped into ice water. The 3-(3'-chloropropionylamino)-4-phenoxy-5-N,N-dimethyl-amino-methyleneaminosulfonyl-1-benzoic acid methyl ester thus precipitated is recrystallized from CH-3OH/H2, melting point 190°C. b) 3-(3<1->chloropropylamino)-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulfony-1-benzoic acid methyl ester.

Same procedure as discussed under example 1 g). The product is recrystallized from CH^OH, melting point 150 - 151°C. Example 3-

3-cyclopropylmethylamino-4-phenoxy-5"sulfamoyl-benzoic acid

a) 3-Cyclopropanecarboxamido-"<4>-phenox<y>-5-N,N-dimeth<y> lamino-methyleneaminosulfony-1-benzoic acid methyl ester.

9.2 ml (0.1 mol) of cyclopropanecarboxylic acid chloride in 100 ml of absolute acetone. After 2\ hours of heating under reflux, it is cooled, filtered with charcoal and the solution is evaporated on a rotary evaporator. The solid residue is carefully washed with acetone and then dried. Melting point 220 - 222°C. b) 3-cyclopropylmethylamino-4-phenoxy-5-N,N-dimethylamino-methylene-aminosulfonyl-benzoic acid methyl ester.

23-g (0.052 mol) of 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester is suspended in a solution of 250 ml of absolute diglyme and 15 ml of BP^-etherate. At room temperature, a solution of 3.5 g of NaBH^ in 200 ml of absolute diglyme is added dropwise with rapid stirring, stirred for 3 hours at room temperature, the excess sodium borohydride is split with 20 ml of water and the solution is kept on ice. After standing overnight in the cold, it is suctioned off, dried and recrystallized from glacial acetic acid. Crystals of melting point 150 - 152°C.

c) 3-cyclopropylmethylamino-4-phenoxy-5-sulfamoyl-benzoic acid

The product formed under b) is heated with 2 N NaOH

to clear solution under reflux. It is then allowed to cool and the 3-cyclopropylmethylamino-4-phenoxy-5-sulfamoylbenzoic acid is precipitated with 2 N HCl. Recrystallization from glacial acetic acid. Melting point 234°C.

Example 4. 3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamoyl-benzoic acid a) 3-nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester.

A solution of 105 g (0.3 mol) 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester and 53 g (0.36 mol) potassium 4-methylphenolate in 600 ml DMF is boiled for 3 hours.. during reflux. After cooling and filtering the potassium chloride, the solution is placed on ice/water and stirred for 1 hour. The precipitate is filtered, washed with water and dried. After dissolving the crude product in 900 ml of acetone, clarify with charcoal, evaporate to 500 ml and dilute with 1 liter of methanol. The precipitate is filtered after stirring for 1 hour at 10°C and washed with cold methanol. 3-nitro-4(4-methylphenoxy)-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester is obtained as crystals of melting point 196 - 198°C. b) 3-amino-4(4'-methylphenoxy)-5-N,N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester. A solution of 80 g of 3-nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylene-aminosulphonyl-benzoic acid methyl ester in 400 ml of DMF is hydrated with around 10 g of Raney nickel for 8 hours at 40°C and 50 atmospheres. After filtering the catalyst, the DMF solution is poured onto ice. The precipitate is suctioned off, dried and recrystallized from methanol. 3-Amino-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester is obtained, crystals of melting point 168 - 169°C. c) 3-cyclopropanecarboxamido-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester.

A solution of 26.1 g of cyclopropanecarboxylic acid chloride in 250 ml absolute dioxane. After 1 J hour, the reaction is complete. The solution is evaporated and recrystallized from acetone or methanol. This gives 3_cyclopropanecarboxamido-4-(4'-methylphenoxy)-5-N,N7dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester, crystals of melting point 201 - 203°C. d) 3-cyclopropylmethylamino-4(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. A solution of 9*5 g of NaBH^ in 500 ml of absolute diglyme. It is allowed to stir for 4 hours at 0°C and 2 hours at room temperature, the excess reducing agent is then split by the addition of water and the product is precipitated by the further addition of 3 liters of ice water. The formed 3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-N,N-dimethylamino-'methylphenaminosulfonyl-benzoic acid methyl ester, which is contaminated with approx. 5$ 3-Cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamoyl-benzoic acid methyl ester is recrystallized from methanol, mp 158-1590c. a) 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester.

To a boiling solution of 19 g (0.05 mol) of 3-amino-4-phenoxy-5-NjN-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester in 100 ml of absolute dioxane and 5 ml of pyridine, 9.2 ml (0.1 mol) of cyclopropanecarboxylic acid chloride in 100 ml absolute acetone. After 2\ hours of heating under reflux, it is cooled, filtered with charcoal and the solution is evaporated on a rotary evaporator. The solid residue is carefully washed with acetone and then dried. Melting point 220 - 222°C. b) 3-cyclopropylmethylamino-4-phenoxy-5-N,N-dimethylamino-methylene-aminosulfonyl-benzoic acid methyl ester.

23 g (0.052 mol) of 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester is suspended in a solution of 250 ml of absolute diglyme and 15 ml of BF 2 -etherate. At room temperature, a solution of 3.5 g of NaBH^ in 200 ml of absolute diglyme is added dropwise with rapid stirring, stirred for 3 hours at room temperature, the excess sodium borohydride is split with 20 ml of water and the solution is kept on ice. After standing overnight in the cold, it is suctioned off, dried and recrystallized from glacial acetic acid. Crystals of melting point 150 - 152°C.

c) 3-cyclopropylmethylamino-4-phenoxy-5-sulfamoyl-benzoic acid

The product formed under b) is heated with 2 N NaOH

to clear solution under reflux. It is then allowed to cool and the 3-cyclopropylmethylamino-4-phenoxy-5-sulfamoylbenzoic acid is precipitated with 2 N HCl. Recrystallization from glacial acetic acid. Melting point 234°C.

Example 4.

3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamoyl-benzoic acid a) 3~nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester.

A solution of 105 g (0.3 mol) 3.-nitro-4-chloro-5_N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester and 53 g (0.36 mol) potassium 4-methylphenolate in 600 ml DMF is boiled for 3 hours - during backflow. After cooling and filtering the potassium chloride, the solution is placed on ice/water and stirred for 1 hour. The precipitate is filtered, washed with water and dried. After dissolving the crude product in 900 ml of acetone, clarify with charcoal, evaporate to 500 ml and dilute with 1 liter of methanol. The precipitate is filtered after stirring for 1 hour at 10°C and washed with cold methanol. 3-nitro-4(4-methylphenoxy)-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester is obtained as crystals of melting point 196 - 198°C. b) 3-amino-4(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

A solution of 80 g of 3-nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylene-aminosulphonyl-benzoic acid methyl ester in 400 ml of DMF is hydrated with around 10 g of Raney nickel for 8 hours at 40°C and 50 atmospheres. After filtering the catalyst, the DMF solution is poured onto ice. The precipitate is suctioned off, dried and recrystallized from methanol. 3-amino-4-(4'-methylphenoxy)-5-N,N~ dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester is obtained, crystals of melting point 168 - 169°C. c) 3-cyclopropanecarboxamido-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

A solution of 26.1 g of cyclopropanecarboxylic acid chloride in 250 ml absolute dioxane. After 1 J hour, the reaction is complete. The solution is evaporated and recrystallized from acetone or methanol. 3-Cyclopropanecarboxamido-4-(4<1->methylphenoxy)-5~N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester is obtained, crystals of melting point 201 - 203°C. d) 3-cyclopropylmethylamino-4(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester. 65 g of 3-cyclopropanecarboxamido-4(4'-methylphenoxy)-5~N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester are suspended in 600 ml of absolute diglyme, 40 ml of BF^-etherate is added and then added dropwise at 0-5°C a solution of 9.5 g of NaBH^ in 500 ml of absolute diglyme. It is allowed to stir for 4 hours at 0°C and 2 hours at room temperature, the excess reducing agent is then split by the addition of water and the product is precipitated by the further addition of 3 liters of ice water. The formed 3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5_N,N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester, which is contaminated with approx. 5% 3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamoyl-benzoic acid methyl ester is recrystallized from methanol, melting point 158 - 159<0>c. e) 3-cyclopropylmethylamino-4-(4-methylphenoxy)-5-sulfamoylbenzoic acid.

The product formed under d) is heated with 2 N

NaOH to clear solution under reflux. Then you let

it cools and precipitates J-cyclopropylmethylamino-^-(^-methyl-phenoxy)-5-sulfamoylbenzoic acid with 2N HCl. Recrystallization from glacial acetic acid, melting point 230 - 232°C.

Example 5»

3-cyclopropylmethylamino-4-(4'-fluorophenoxy)-5-sulfamoylbenzoic acid. a) 3-nitro-4-(4'-fluorophenoxy)-5_N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.

A solution of 210 g (0.6 mol) 3-nitro-4-chloro-5~N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester and 120 g sodium 4-fluorophenolate in 800 ml absolute DMF is stirred for 3-4 hours at 120-130 °C. The cold solution is then dripped slowly with vigorous stirring into 4-5 liters of ice water. The precipitated product is filtered off, washed well with water, digested with hot acetone and then recrystallized from glycol monomethyl ether. Light yellow crystals of melting point 224 - 225°C. b) 3-amino-4-(4'-fluorophenoxy)-5-N,N-dimethylaminomethyleneamino-sulfonylbenzoic acid methyl ester. 140 g of the nitro compound (18a) are dissolved in DMF and hydrated with Raney nickel at 50°C and 50 atmospheres for 8 hours. The Raney nickel is then aspirated and the solution is dripped into ice water. The precipitated substance is separated and washed with CH 2 OH and then with ether. The practically pure sboff can be recrystallized from glycol monomethyl ether. White crystals of melting point 234 - 236°C. c) 3-cyclopropanecarboxamido-4-(4'-fluorophenoxy)-5~N,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester..

9.2 ml ( 0.1 mol) of cyclopropanecarboxylic acid chloride in 100 ml of absolute acetone. After lg hours of heating during the return run. cool to 0°C. 3-Cyclopropanecarboxamido-4-(4'-fluorophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester precipitates crystalline, filtered off, washed first with some cold acetone, then with cold water and dried. Melt-

point 201 - 202°C.

d) 3-cyclopropylmethylamino-4-(4'-fluorophenoxy)-5-N,N-dimethyl-aminomethyleneaminosulfony-1-benzoic acid methyl ester.

Analogous to example 3b, recrystallization from methanol.

Melting point 165 - 166°C.

e) 3-cyclopropylmethylamino-4-(4'-fluorophenoxy)-5-sulfamoylbenzoic acid.

The product formed under point d) is heated with

2 N NaOH to clear solution under reflux. It is allowed to cool, clarified with charcoal and 3-cyclopropylmethylamino-4-(4'-fluorophenoxy)-5-sulfamoylbenzoic acid is precipitated with 2 N HCl. Recrystallization from methanol, melting point 228 - 229°C.

Example 6.

3-cyclopropylmethylamino-4-(4'-chlorophenoxy)-5-sulfamoylbenzoic acid.

a) 3-nitro-4-(4'-chlorophenoxy)-5-N,N-dimethylaminomethyleneamino-

j sulfonyl-benzoic acid methyl ester.

A solution of 164 g of 3-nitro-4-chloro-5~N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester and 117 g of potassium p-chlorophenolate in 800 ml of freshly distilled DMF is heated for 2-3 hours under reflux. The reaction mixture is added dropwise with vigorous stirring to 4 times the amount of ice/H^O. The thus precipitated product is separated and boiled off with CH 2 OH/acetone. Melting point 227 - 228°C. b) 3-amino-4-(4'-chlorophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

130 g of the nitro compound (20a) are hydrated in 1 liter of DMF with Raney nickel for 9 hours at 50 atmospheres and 50°0. The solution is evaporated after extraction of Raney nickel and the residue is boiled off with CH-^OH.

White substance of melting point 207 - 208°C.

c) 3-cyclopropanecarboxamido-4-(4'-chlorophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

The reaction is carried out analogously to example 5c.

Melting point 195 - 196°C.

d) 3-cyclopropylmethylamino-4-(4<1->chlorophenoxy)-5~N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

The reaction is carried out analogously to example 3b, recrystallization from methanol. Melting point 186 - 187°C. e) 3-cyclopropylmethylamino-4-(4'-chlorophenoxy)-5-sulfamoylbenzoic acid.

Analogous to example 5e, recrystallization from methanol,

melting point 247-248°C.

Example 7.

3-cyclopropylmethylamino-4-(4•-benzyloxyphenoxy)-5-sulfamoylbenzoic acid.

a) 3-nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester. Dissolve 87.5 g (0.25 mol) of 3-nitro-4-chloro-5-N,N-dimethyl-aminomethyleneamino-sulfonylbenzoic acid methyl ester in 500 ml of anhydrous dimethylformamide and add 77.5 g (0.35 mol) of sodium-4 -benzyl oxyphenolate. With good stirring, the reaction mixture is heated under reflux for 3-4 hours. After cooling, the cloudy solution is dripped into 3 liters of ice/water. The precipitated yellow precipitate is filtered off, washed well with water and recrystallized from methanol. 94 g of 3-nitro-4-(4<1->benzyloxy-phenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester are obtained in yellow crystals of melting point 132°C. b) 3-amino-4-(4'-benzyloxyphenoxy)-5~N,N-dimethylaminorethylene-aminosulphonyl-benzoic acid methyl ester. 94 g of 3-nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester are dissolved in 1.5 liters of dimethylformamide and nitrated with Raney nickel at room temperature and normal pressure for 6-7 hours. It is then filtered and the clear solution is dripped into ice/water. The precipitated 3-amino-4-(4'-benzyl-oxyphenoxy)-5~N,N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester is recrystallized from methanol. You get approx. 70 g in white crystals of melting point 170°C. c) Cyclopropanecarboamido-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

To a boiling solution of 14.5 g (0.03 mol) 3-amino-4-(4'-benzyloxyphenoxy)-5~N,N-dimethylaminomethyleneamino-sulfonylbenzoic acid methyl ester in 150 ml of absolute dioxane and 3 ml of pyridine is added dropwise 5, 5 ml cyclopropane carboxylic acid chloride in 50 ml absolute acetone. After 6 hours of heating under reflux, cool to 0°C. 3_cyclopropanecarboxamido-4-(4'-benzyloxy-phenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester precipitates out, is sucked off and washed with acetone and ether. Melting point 210 - 211°C. d) 3-cyclopropylmethylamino-4- (4'-Benzyloxyphenoxy)-5-sulfamoylbenzoic acid.

5.6 g of the product formed under c) is suspended in

a solution of 50 ml of absolute diglyme and 4 ml of BP^ etherate. At room temperature, a solution of 1 g of NaBHjj in 50 ml of absolute diglyme is added dropwise with rapid stirring. It is stirred for 2 hours at 20°C and then cooled and can be put on ice. The crude product is filtered and heated with 2 N NaOH for 1 hour under reflux. It is then cooled, clarified with charcoal and 3-cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)-5-sulfamoylbenzoic acid is precipitated with 2 N HCl. Recrystallization from glacial acetic acid, melting point 235 - 236°C.

Example 8.

3-Cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamoylbenzoic acid. 2 g of 3-cyclopropylmethylamino-4-(4'-benzyloxy)-5-sulfamoylbenzoic acid are suspended in 50 ml H 2 O, brought into solution with 5 ml 2 N NaOH and hydrated with Raney nickel at 50°C, 50 atmospheres Hp for 4 hours. After filtering the catalyst, 3-cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamoylbenzoic acid is precipitated with 2 N HCl. The precipitate is sucked off, washed well with water and dried. Melting point 265 - 266°C.

Example 9.

3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoylbenzoic acid. a) 3-cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

In 30 ml of fuming nitric acid, 5 g of 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester are introduced in portions at -10°C to -20°C. Stir for 10 minutes, keep the solution on ice. 3-Cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester precipitates out crystalline, is filtered off with suction and washed thoroughly with water. Melting point 215 - 216°C. b) 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

22 g (0.045 mol) of 3-cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester are suspended in a solution of 150 ml of absolute dioxygen

! san with 12.8 ml of BF^-etherate and heated at 55-60°C. By this one

temperature, a solution of 3 g of NaBH^ in 100 ml of absolute diglyme is added dropwise with rapid stirring. After stirring for 1 hour at 50°C, the solution is cooled to 0°C, excess NaBH/j is split with a little water and put on ice. 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)~5-N,N-dimethylaminomethyleneaminosulfony1-benzo-

acid methyl ester, crystallizes, is filtered off with suction and washed with water, dried and boiled off with methanol. Melting point 233 - 235°C. c) 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoylbenzoic acid. 17 g of 3-cyclopropylmethylamino-4-(4<1->nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester are suspended in 400 ml of 1 N NaOH and stirred for 3 hours at 95°C. It is then allowed to cool and 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoylbenzoic acid is precipitated with concentrated HCl (pH 1).

Recrystallization from methanol by evaporation ay the solution. Melting point 230°C during decomposition.

Example 10.

3~ cyclopropylmethylamino-4-(4'- aminophenoxy)~ 5~ sulfamoylbenzoic acid. 3 g (0.0074 mol) of 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoylbenzoic acid are hydrated in 50 ml of methanol with 10% Pd/C at 20°C and 10 atmospheres H for 8 hours. After filtering the catalyst, the methanolic solution is evaporated and 3-cyclopropylmethylamino-4-(4'-aminophenoxy)-5-sulfamoylbenzoic acid is precipitated with ether. Melting point 175°C during decomposition. Example 11.

3~ cyclopropylmethylamino- 4- phenylthio- 5- sulfamoylbenzoic acid.

a) 3-nitro-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester.

A solution of 210 g (0.6 mol) of 3-nitro-4-chloro-5,N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester and 108 g (0.66 mol) of potassium thiophenolate in 800 ml of DMF is refluxed for 2 hours. The solution is placed on ice, the precipitate is filtered off with suction, washed with water, dried and recrystallized from acetone.

3-nitro-4-phenylthio-5-N,N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester is obtained. Crystals of melting point 205 - 207°C. b) 3-amino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester. 110 g (0.26 mol) of 3-nitro-4-phenylthio-5-N,N-dimethyl-aminomethyleneaminosulfonyl-benzoic acid methyl ester are hydrated in 400 ml of DMF with Raney nickel at 50° C. and 100 atmospheres for 8 hours. After filtering the catalyst, the DMF solution is poured onto ice. The precipitate is suctioned off, washed with water, dried and recrystallized from acetone. 3-amino-4-phenylthio-5-N,N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester is obtained. Crystals of melting point 214 - 215°C. c) 3-cyclopropanecarboxamido-4-phenylthio-5-N,N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester.

To a boiling solution of 22 g (0.056 mol) of 3-amino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-1-benzoic acid methyl ester in 125 ml of absolute dioxane and 5.8 ml (0.11 mol) of pyridine are added dropwise 6.1 g (0.067 mole) of cyclopropanecarboxylic acid chloride in 125 ml of absolute acetone. After two hours of heating under reflux, it is cooled, filtered with charcoal and evaporated on a rotary evaporator. The residue is resuspended in acetone and filtered. The crude product is recrystallized from DMP/methanol.

3-Cyclopropanecarboxamido-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester is obtained, crystals of melting point 245 - 247°C.

d) 3-cyclopropylmethylamino-4-phenylthio-5-sulfamoyl-benzoic acid. 14.4 g (0.031 mol) of 3-cyclopropanecarboxamido-4-phenylthio-5-N,N-dimethylaminemethyleneaminosulfonyl-benzoic acid methyl ester is suspended in a solution of 55 ml of absolute diglyme and 8.1 ml of BF, etherate. At room temperature, add drippings

rapid stirring a solution of 2.36 g (0.062 mol) NaBH^ in 55 ml of absolute diglyme, stirring for 5 hours at 20 - 30°C and pouring on ice. The crude product is filtered and recrystallized from methanol.

8.8 g of the reduced compound is boiled with 70 ml of 2 N NaOH under reflux until a clear solution is formed.

It is then allowed to cool and 3-cyclopropylmethylamino-4-phenylthio-5-sulfamoyl-benzoic acid is precipitated with 2 N HCl. Recrystallization from methanol/water (3:1) gives crystals of melting point 214 - 215°C

Example 12.

3- cyclobutylamino- 4- phenylthio- 5- sulfamoylbenzoic acid.

a) 3-cyclobutanecarboxamido-4-phenylthio-5-N,N-dimethylamino- m ethyleneaminosulfonyl-benzoic acid methyl ester. To a boiling solution of 23.6 g (0.06 mol) 3- amino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester in 150 ml of dioxane and 7.5 ml of pyridine is added dropwise to 12.7 ml (0.12 mol) of cyclobutanecarboxylic acid chloride in 150 ml of abso lye acetone. After 1 hour of heating under reflux, evaporate on a rotary evaporator and suspend the residue in 500 ml acetone, filtered and washed with acetone. You get 3-cyclobutanecar- boxamido-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfony1-benzoic acid. Melting point 230 - 232°C. b) 3-cyclobutylmethylamino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester. 28 g (0.062 mol) of 3-cyclobutanecarboxamido-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester are suspended in a solution of 280 ml of absolute diglyme and 16.5 ml of BFj etherate. At room temperature, a solution of 5.5 g of NaBH^ in 250 ml of diglyme is added dropwise with rapid stirring, stirred for half an hour at 40-50°C, cooled, the excess NaBH^ is split with a little water and the solution is kept on ice. After standing overnight, the precipitate is suctioned off, dried and recrystallized from methanol/water. 3-cyclobutylmethyl-amino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester is obtained. Crystals of melting point 193 - 195°C.

c) 3~ cyclobutylamino-4-phenylthio-5-sulfamoylbenzoic acid.

5 g of 3-cyclobutylmethylamino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester is suspended in 100 ml of 1 N NaOH and hydrolyzed at 95 - 100°C for 1 hour. It is then clarified with activated carbon, cooled and acidified with concentrated HC1 (pH 2).

3-cyclobutylmethylamino-4-phenylthio-5-sulfamoylbenzoic acid precipitates, is washed with water, dried and recrystallized from glacial acetic acid. Crystals of melting point 227 - 228°C.

Example 13.

3-cyclopropylamino-4-N-methylpiperazino-5-sulfamoylbenzoic acid (HCl salt).

a) 3-nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneamino-sulfony-1-benzoic acid methyl ester. 34.9 g (0.1 mol) 3-nitro-4-chloro-5-N,N-dimethylamino-methyleneaminosulfonyl-benzoic acid methyl ester, 11 g = 12.22 ml (0.11 mol) N-methylpiperazine, 11, 1 g = 15.2 ml (0.11 mol) of triethylamine in 150 ml of DMF is heated for 2 hours at 85°C. After cooling, pour in approx. 1 liter of ice water, the precipitate is suctioned off, washed with water, dried and recrystallized from vinegar. This gives 3-nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulphonyl-benzoic acid methyl ester, crystals of melting point 181 - 182°C. b) 3-amino-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester.

82.6 g (0.2 mol) of 3-nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester is hydrated in 750 ml of DMF with Raney nickel at 50° C. and 100 atmospheres for 12 hours.

After filtration from the catalyst, the DMF solution is placed on ice.

After recrystallization from methanol, 3-amino-4-N-methyl-piperazino-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester is obtained, crystals of melting point 208 - 209°C. c) 3-cyclopropanecarboxamido-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

Analogous to example 3a, recrystallization from water, melting point 155 - 157°C. d) 3-cyclopropylmethylamino-4-N-methylpiperazino-5-N,N-dimethyl-aminorethyleneaminosulfonyl-benzoic acid methyl ester.

16 g' (0.035 mol) of 3-cyclopropanecarboxamido-'t-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfony1-benzoic acid methyl ester is suspended in a solution of 100 ml of absolute ! diglyme and 18.5 ml of BF^ etherate. At room temperature, a solution of 2.7 g of NaBH^ in 100 ml is added dropwise with rapid stirring

absolute diglyme, stir for 3 hours at 55°C, cool, split

<!> the excess NaBH^ with some water and has the solution on ice. The crude product is filtered and recrystallized from methanol. This gives 3-cyclopropylmethylamino-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester; crystals of melting point 194°C. e) 3-cyclopropylmethylamino-4-N-methylpiperazino-5-sulfamoylbenzoic acid (HCl salt).

5 g of 3-cyclopropylmethylamino-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester are heated in 40 ml of 2 N NaOH for 2 hours under reflux. It is then allowed to cool, clarified with charcoal and 3-cyclopropyl-methylamino-4-N-methylpiperazine-5-sulfamoylbenzoic acid is precipitated with concen-

! diluted hydrochloric acid (pH 3). The mother liquor is decanted and the residue is stirred with acetone. Melting point 280°C during decomposition.

Example 14.

3- nitro- 4- chloro- N, N- dimethylaminomethyleneaminosulfony1- benzoic acid. To 60 ml 20% oleum is added drop by drop under ice-cooling

in 42 ml fuming nitric acid. The solution is heated to 90°C

and then slowly introduce 34.9 g (0.12 mol) of 4-chloro-5~N,N-dimethylaminomethyleneaminosulfonylbenzoic acid. The temperature rises during the introduction to 100°C. After 3 hours of stirring at 90°C, cool to room temperature, put on ice and wash the precipitate

neutral. 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid is obtained in crystals of melting point 274 - 276°C.

Claims (1)

Process for the preparation of diuretically active sulfamoylbenzoic acids of the general formula I: in which A means linear alkyl groups with 1-4 carbon atoms, which may optionally be substituted with a halogen atom, a carbocyclic ring with 3-5 carbon atoms,.X means the groups OR<2 >2 • ? or SR , where R means phenyl which is optionally substituted with methyl, fluorine, chlorine, benzyloxy, hydroxy, nitro or amino, or X means N-methyl-piperazine and R means hydrogen or an "alkyl residue with 1-6 carbon atoms, characterized by that sulfamoylbenzoic acid derivatives of the general formula III wherein Y means a halogen atom, R has the above meaning and B means a protecting group of the general formula li c f. in which R , R-3 and R mean the same or different lower alkyl groups, R can also mean hydrogen and/or whenever two of the substituents R^, R^ or R^ can also be cyclically connected to each other, nitrated, and the formed compounds of formula IV if R represents hydrogen, is esterified and the formed compounds of formula IV, in which B and Y have the above meaning, are reacted with a compound of formula XH, in which X has the above meaning and the formed compound of formula V in which R' means an alkyl residue with up to 6 C atoms and B and X have the above meaning, is reduced, and the thus formed compounds of the general formula VI in which B, X and R' have the above meaning are reacted with compounds of the general formula VII in which the residue A has the indicated meaning and L means a "leaving-group", the compounds formed with the general formula VIII in which the residues A, B, R' and X have the above-mentioned meaning, are reduced by means of boron hydrogen optionally in the presence of Lewis acids or by complex borohydrides in the presence of Lewis acids and the formed compounds of the general formula IX in which A, B, X and R<1> have the above-mentioned meaning, are hydrolysed to compounds of formula I, in which R means a hydrogen atom and, if necessary, the acids formed are esterified in the usual way.