IE46127B1 - Pyrrolo-benzoic acid derivatives and process for their preparation - Google Patents

Description

The invention relates to pyrrolobenzoic acid derivatives of the general formula wherein R represents a hydrogen atom or an alkyl group 5 having from 1 to 4 carbon atoms; each of R1 and , which may be the same or different, represents a hydrogen or a halogen atom, an alkyl ox alkoxy group having from 1 to 4 carbon atoms, or a trifluoromethyl, hydroxy, protected 1 11 hydroxy or protected amino group, or R and R together 10 represent a methylenedioxy group when occupying adjacent positions on the benzene ring; R represents a hydrogen atom or an alkyl group of 1-4 carbon 3 4 atoms, and each of R and R , which may be the same or different represents an alkyl group of 1-4 carbon atoms, or one 3 4 of R , R and R has the meaning given above and the other two represent an alkylene group, which alkylene group has 3 to 6 carbon atoms when formed from R. and R., and 2 to 5 3 4 carbon atoms for other combinations; 6 each of R and R , which may be the same or different, represents a hydrogen atom, a methyl group or an ethyl group; and X represents -0-, -S-, -NH-, or -CH2~; or a salt of a free acid of the general formula I. The invention also provides a process for preparing such compounds which comprises reacting a compound of the general formula above, with a compound of the general formula R R \_/ _ A (in) Alk-0 0 O-Alk' 6 wherein R and R have the meanings given above, and each of Aik and Aik' , which may be the same or different, represents an alkyl group having from 1 to 4 carbon atoms. The reaction 613 7 - 4 is preferably carried out using a weak organic acid as solvent. 1' If R and R together represent a methylenedioxy group, this is preferably in the 3.4-positions of the benzene ring.

A protected hydroxy or amino group represented by R1 1 · and/or R may for example be a benzyloxy, an acetoxy or acetylamino group. Thus there may be, for example, in the 4-position of the benzoic acid ring, one of the groups 3'- or 4-benzyloxyphenoxy; 3‘- or 4'-benzyloxyphenylthio; 3'- or 4'benzyloxyanilino; or 3'- or 4'-benzyloxybenzyl; or one of the . 10 corresponding 3‘- or 4'-acetoxy or 3'- or 4'-acetylamino substituted groups.

Certain starting compounds of the general formula II are described in German Offenlegungsschrift 2 461 601; other compounds of the general formula II may be prepared analogously.

The reaction of the amines II is suitably carried out in a weak organic acid, preferably in glacial acetic acid, at boiling point.

The presence of the protecting group at the sulphamoyl function generally increases the yield of the reaction of the invention considerably, in comparison to the analogous reaction in the presence of a free sulphamoyl group (see Patent Specification No. 42601) as may enable almost quantitative yields to be obtained.

The compounds of the general formula I are interesting intermediate products for the preparation of pharmaceutically active compounds especially for preparing diuretics such as those described in Patent Specification No. 42601« These compounds, which have in the 3-position a corresponding pyrrolidine ring substituted by R5 and R^, may be obtained by catalytic hydrogenation, for example using a noble metal - 5 catalyst, for example Pd/active carbon, PtO2, Rh[carbon or Pt/active carbon. The reduction may also be carried out using other reducing agents suitable for reducing pyrroles, for example zinc/glacial acetic acid or hydriodic acid and red phosphorus.

After the reduction, an acid or alkaline hydrolysis may be carried out to remove the sulphonamide protecting group and, if desired, the ester radical R.

It is surprising that compounds of the general formula I are suitable for preparing the pyrrolidino compounds, since it might have been expected that the protecting group of the sulphonamide radical vould be affected under the hydrogenation conditions necessary for the reduction of the pyrrole radical.

Numerous interesting compounds of the general formula I may be prepared by the process of the invention. In addition to the compounds mentioned in the Examples herein, there may also be prepared the compounds listed in Table A.

TABLE A 4-Phenoxy-3-(1-pyrrolo)-5,N,N-dimethylamino-methylene aminosulphonyl benzoic acid, 4-(4'-Methylphenoxy)-3-(1-pyrrolo)-5N,N-dimethylamino-methylene-amino-sulphonylbenzoic acid ethyl ester 4-(3'-Methylphenoxy)3-(1-pyrrolo)-5-N,N-dimethylaminomethylene-amine-sut>honylbenzoic acid methyl ester 4-(3'-Methoxyphenoxy)-3(1-pyrrolo)-5-N,N-dimethylaminomcthylene-amino-sulphonylbenzoic acid butyl ester 4-(3'-Hydroxyphenoxy)-3(1-pyrrolo)-5-N,N-dimethylaminomethylene-amino-sulphonylbenzoic acid methyl ester 4-(4'-Methylphenoxy)-3(3'-Methyl-l-pyrrolo,-5-N,N-dimethylamino methylene-amino-sulphonyl-benzoic acid methyl ester 46137 - 6 4-Phenoxy~3(3’-methyl-l-pyrrolo)-5-N,N-dimethylamino-methylene amino-sulphonylbenzoic acid ethyl ester 4-Benzyl-3(1-pyrrolo)-5-N,N-dimethylamino-methylene-aminosulphonyl-benzoic acid 4-(4'-Methylbenzyl)-3-(1-pyrrolo)-5-N,N-dimethylaminomethylene-amino-sulphonylbenzoic acid methyl ester 4-Benzyl-3(31-methyl-l-pyrrolo)-5-N,N-dimethylamino-methyleneamino-sulphonylbenzoic acid methyl ester 4-(4'-Methylbenzyl)3(3'-methyl-l-pyrrolo)-5-N, N-dimethyl10 amino-methylene-amino-sulphonylbenzoic acid methyl ester 4-(4'-Chlorobenzyl)-3(1-pyrrolo)-5-N,N-dimethylamino-methylene amino-sulphonylbenzoic acid methyl ester 4-(4'-Methylanilino)-3-(1-pyrrolo)-5-N,N-dimethylaminomethylene-amino-sulphonylbenzoic acid methyl ester 4-(4'-Methoxyanilino)-3(1-pyrrolo)-5-N,N-dimethylaminomethylene-amino-sulphonylbenzoic acid methyl ester 4-(3’-Methoxyanilino)-3(1-pyrrolo)-5-N,N-dimethylamino.methylene-amino-sulphonylbenzoic acid ethyl ester 4-(4'-Chloroanilino)-3(1-pyrrolo)-5-N,N-dimethylamino20 methylene-amino-sulphonylbenzoic acid butyl ester 4-(4'-Fluoranilino)-3(1-pyrrolo)-5-N,N-dimethylaminomethylene-amino-sulphonylbenzoic acid methyl ester 4-(4‘-Methylanilino)-3-(3'-methyl-l-pyrrolo)-5-N, N-dimethylamino-methylene-amino-sulphonylbenzoic acid methyl ester 4-(4’-Chloranilino)-3-(3'-methyl-l-pyrrolo)-5-N,N-dimethylamino-methylene-amino-sulphonylbenzoic acid methyl ester.

The following Examples illustrate the invention, except the final paragraphs of examples 1 and 3 which 4612? - Ί describe uses of the products of the invention.

EXAMPLE I 3-N-pvrrclo-4-phenoxy-5-N, N-dimethylaminomethylene amir.osulphonyl-benzoic acid methyl ester 5 100 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester and 53 g of 2,5-dimethoxytetrahydrofurane are refluxed for 15 minutes in 100 g of glacial acetic acid. The mixture is cooled to 10°C. the precipitated crystals are sucked off, washed with 20 ml of cold glacial acetic acid and dried in vacuo.

There are obtained 96 g of colourless to brownish crystals having a mt.Iting point of 173-175°C.

For further purification, another recrystallization may be carried out, if necessary, from isopropanol or acetic acid ethyl ester.

Conversion to 4-phenoxy-3(1-pyrrolidinyl)-5-sulphamoyl-benzoic acid g of 3-N-pyrrolo-4-phtnoxy-5-N,N-dimathylaminomethylene amino sulphonylbenzoic acid methyl ester are hydrogenated for 5 hours at 100°C and under a pressure of 100 atm. in 100 ml. of methanol and with the addition of 1 g of palladium/charcoal (at 10%). The catalyst is filterad off while hot, 8 g of 4phenoxy-3(1-pyrrolidinyl)-5-N,N-dimethylaminomethyleneaminesulphonyl-ben2oio acid methyl ester melting at 187-189°c crystallize from the solution upon cooling.

The product thus obtained is suspended in 100 ml of 2 N sodium hydroxide solution and refluxed until the solution is limpid. The free 4-phenoxy-3(1-pyrrolidinyl)-5-sulphamoylbenzoic acid precipitates by acidifying with 2 N hydrochloric acid to a pn of 3-4. Ο I s < - 8 Recrystallization from CH^OH/H^O.

Light yellow crystals melting at 226 - 228°C.

EXAMPLE 2 3-N-pyrrolo-4-(41-methylphenoxy)-5-N-dimethylaminomethyleneamino-sulphonyl-benzoic acid methyl esuer a) 3-nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylene amino-sulphonylbenzoic acid methyl ester A solution of 235 g (0.67 mole) of 3-nitro-4-chloro-5N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester and 140 g (0.96 mole) of potassium-4-methyl-phenolate in 1 litre of absolute dimethylformamide (DMP) is stirred at 901OO°C for 2 hours. The cold solution is then added slowly and dropwise to 4-5 1 of ice water while stirring vigorously. The precipitated product is sucked off, washed with H^O and recrystallized from CH^OH.

There are obtained light yellow crystals having a melting point of 200 - 201°. b) 3-amino-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylene amino-sulphonyl-benzoic acid methyl ester 171 g of 3-nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylene aminosulphonyl-benzoic acid methyl ester are hydrogenated with Raney nickel as a catalyst in dimethyl formamide at 50° and under 50 atm. pressure for 8 hours in an autoclave. The result is then filtered, the filtrate is condensed and the residue recrystallized from CH^OH. There are obtained colourless crystals having a melting point of 172 - 173°C. o) 3-N-pyrrOlo-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylene-amino-sulphonyl-beftzoic acid methyl ester 19.5 g (0.05 mole) of 3-amino-4-(4’-methylphenoxy)-5N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester and 7 ml (~0.075 mole) of 2,5-dimethoxytetrahydrofuran are refluxed in 150 ml of glacial acetic acid. - 9 After a reaction time of one hour the mixture is introduced dropwise into ice water. The precipitated light brown product is sucked off and recrystallized from CH^OH/acetone (the latter in a minor quantity).

There are obtained 17.5 - 18 g. having a melting point of 178 - 179°C.

EXAMPLE 3 3-N-pyrrolo-4-(4'-methoxyphenoxv)-5-N,N-dimethvlaminomethy.leneaminosulphonyl benzoic acid methyl ester a) 3-nitro-4- (4 ’-methoxyphenoxv) -5--N, N-dimethylaminomethyleneamino-sulphonyl benzoic acid methyl ester 0.4 mole (126 g) of 3-nitro-4-chloro-5-N,N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester and 72.5 g (--0.5 mole) of sodium-4-methoxyphenolate are refluxed in 600 ml of absolute DMP for 2 hours. The reaction mixture is then stirred into 4 1 of ice water and the precipitated product is sucked off.

There are obtained light-fellow crystals by recrystallization from CH^OH, having a melting point of 199 - 201°C. b) 3-amino-4(41-methoxyphenoxv)-5-N,N-dimethylaminomethylene-amino-sulphonyl benzoic acid methyl ester The reaction is carried out analogously to the process described in Example 2b. By recrystallization from CH^OH there are obtained colourless crystals having a melting point of 141 - 143°C. c) 3-N-pyrrolo-4-(4'-methoxyphenoxv)-5-N,N-dimethylamlnomethylene-aminosulphonyl benzoic acid methyl ester .37 g (0.05 mole) of 3-amino-4-(4'-methoxyphenoxy)-5N, N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester and 7 ml of 2,5-dimethoxytetrahydrofuran are refluxed in 150 ml of glacial acetic acid for about one hour. The - 10 cold mixture is then stirred into ice water, the precipitated product sucked off and washed with water There are obtained 20.8 g of crude product.

The crude product may be used as intermediate product without undergoing any additional purification process, i.e. the crude product may be hydrogenated catalytically and hydrolysed, as described above.

EXAMPLE 4 3-N-pyrrolo-4-(3'-methoxyphenoxy)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(31-methoxyphenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester By analogy to Example 3a, but carried out with sodium 3-methoxyphenolate and with a reaction time of 3 hours, there are obtained light-yellow crystals recrystallised from glycol monomethyl ether having a melting point of 201°C. b) 3-amino-4-(31-methoxyphenoxy)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester By analogy to Example 2b, on recrystallization from glycol monomethyl ether, colourless crystals having a melting point of 176 - 178°C were obtained. c) 3-N-pyrrolo-4-(3'-methoxyphenoxy)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester 12.7 g (0.03 mole) of 3-amino-4-(3'-methoxyphenoxy)-5N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester and 4.6 ml of 2,5-dimethoxytetrahydrofuran are refluxed for 30 minutes in 150 ml of glacial acetic acid. The product is then precipitated by stirring it into 1.5 1 of ice water and recrystallized from CH^OH/H^O. There are obtained beige crystals having a melting point of 165 - 166°C. - 11 EXAMPLE 5 3-N-pyrrolo-4-(4'-chlorophenoxy)-5-N N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(4'-chlorophenoxy)-5-N,N-dimethylaminomethyleneaminoaulphonyl-benzoic acid methyl ester A solution of 164 g cf 3-nitro-4-chloro-5-N,N-dimethylaminomethylent aminosulphonyl benzoic acid methyl ester and 117 g of potassium-p-chlorophenolate in 800 ml of freshly distilled DMP is refluxed from 2-3 hours. The reaction mixture is added dropwise while stirring vigorously into 4 times its quantity cf ice water. The resulting product is separated and boiled with CH^OH/acetone. Melting point: 227 - 228°C. b) 3-araino-4-(4!-chlorophenoxy)-5-N,N-dimethylaminomethylene amino-sulphonyl benzoic acid metnyl ester 130 g of the nitro compound (5a) are hydrogenated in 1 litre of DMF with Raney-nickel for nine hours, under a pressure of 50 atmospheres and at a temperature of 50°C. After having sucked off the Raney nickel, the solution is concentrated and the residue boiled with 3H OH. There is obtained a o colourless substance having a melting point of 207-208 C. c) 3-N-pyrrolo-4-(4'-chlorcPhenoxy)-5-N,N-dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester .6 g of the amino compound (5b) are refluxed for one hour in 150 ml of glacial acetic acid with 7 ml of 2,5-dimethoxytetrahydroruran. The substance is then precipitated by introducing the reaction mixture into 1.5 1 of ice water, suctioned off and recrystallized from CHjOH. There are obtained light brown crystals having a melting point of 165 C.

EXAMPLE 6 3-N-pyrrolo-4-(41—fluorophenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(41-fluorophenoxy)-5-N,N-dimethylaminomethyleneamino-sulphonyl benzoic acid methyl ester - 12 A solution of 210 g (0.6 mole) of 3-nitro-4-chloro-5N,N-dimethylaminoethylene aminosulphonyl benzoic acid methyl ester and 120 g of sodium-4-fluorophenolate in 800 ml of absolute DMF is stirred at 120 - 130°C for 3-4 hours. The cold solution is then slowly added dropwise into 4-5 1 of ice water while stirring vigorously. The precipitated product is suctioned off, washed thoroughly with water digested with acetone under heat and then recrystailized from glycol monomethyl ester. There are obtained light-yellow crystals having a melting point of 224 - 225°C. b) 3-amino-4-(41-fluorophenoxy)-5-N,N-dimethylaminomethylene amino-sulphonyl benzoic acid methyl ester 140 g of the nitro compound (6a) are dissolved in DMF and hydrogenated in the presence of Raney nickel at 50°C and under a pressure of 50 atmospheres for 8 hours. The Raney nickel is then suctioned off and the solution is added dropwise to ice water. The precipitated substance is separated and then washed consecutively with CH^OH and ether. The practically pure substance may be recrystailized from glycol monomethyl ether.

There are obtained colourless crystals having a melting point of 234 - 236°C. c) 3-N-pvrrolo-4-(41-fluorophenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester 17.5 g of amine ester (6b) and 6.5 ml of 2,5-dimethoxy25 tetrahydrofuran are refluxed in 15© ml of glacial acetic acid for about one hour. The mixture is then added dropwise to 1.5 1 of ice water, the precipitate product is filtered and recrystailized from CH^OH. There are obtained light-brown crystals having a melting point of 180°C.

EXAMPLE 7 3-N-pyrrolo-4-phenylthio-5-N.N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester - 13 15.8 g of 3-amino-4-phenylthio-5-N,N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester and 9.2 g of 2,5-dimethoxy-tetrahydrofuran are refluxed for half an hour in 150 ml of glacial acetic acid. By introducing the mixture into ice water the product precipitates and may be digested with hot CHjOH. The residue is recrystallized from glycol monomethyl ether. There are obtained lightyellow crystals having a melting point of 210 - 211°C.

EXAMPLE 8 3-N-pyrrolo~4- (4 1-methyIphenylthio) -5-N,I'T-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(41-methylphenylthio)-5-N,N-dimethylaminomethyleneamino3ulphonyl benzoic acid methyl ester A suspension of 70 g of 3-nitro-4-chloro-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester in 450 ml of absolute DMF is prepared and heated to 80°C. To this suspension is slowly added dropwise a solution of 40 g of potassium-p-thiocresolate in 400 ml of absolute DMF while stirring at 80°C for two hours. The mixture is then introduced into 4 1 of ice water while stirring is continued, the precipitated product is suctioned off, washed thoroughly with water and recrystallized from glacial acetic acid. There are obtained yellow crystals melting at 163 - 164°C. b) 3-amino-4-(41-methylphenylthio)-5-N.N-dimethvlaminomethyleneaminosulphonyl benzoic acid methyl ester 67.7 g of 3-nitro-4-(4‘-methylphenylthio)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester are dissolved in 800 ml of absolute DMF, Raney nickel is added and hydrogen is introduced for 8 hours at 50°C and under a pressure of 50 atmospheres. After having separated the catalyst, tha solution is utirred into 2 1 of ice water and the precipitated product is isolated. By recrystallization - 14 from CHgOH (adding active charcoal) there are obtained colourless crystals melting at 179°C. c) 3-N-pyrrolo-4-(4'-methylphenylthio)-5-N,N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester 18.3 g of amine ester (8b) are dissolved in 150 ml of glacial acetic acid and heated to the boiling point. 7 ml of 2,5-dimethoxy-tetrahydrofuran are then added. Suddenly, after about 10 minutes, the product crystallizes. Stirring under reflux is continued for another 15 minutes, the pre10 cipitated crystals are suctioned off in the cold and washed with glacial acetic acid. There are obtained light-yellow crystals melting at 242 - 243°C.

EXAMPLE 9 3-N-pyrrolo-4-(41-benzyloxyphenoxy)-5-N.N-dimethylamino15 methylene aminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester 87.5 g (0.25 mole) of 3-nitro-4-chloro-5-N,N-dimethyl~ aminomethylene-aminosulphonyl benzoic acid methyl ester are dissolved in 500 ml of anhydrous dimethyl formamide and 77.5 g (0.35 mole) of sodium-4-benzyloxyphenolate are added. While stirring vigorously, the reaction mixture is refluxed for 3-4 hours. After cooling the turbid solution is added dropwise into 3 1 of ice water. The yellow precipitate is sucked off, washed thoroughly with water and recrystallized from methanol. There are obtained 94 g of 3-nitro-4-(4'-benzyloxyphenoxy)-5N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester as yellow crystals melting at 132°C. b) 3-amino-4-(41-benzyloxyphenoxy-5-N, N-dimethylaminomethylene30 aminosulphonyl benzoic acid methyl ester g of 3-nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester are - 15 dissolved ip l.£ litres of dimethyl formamide and, in the presence of Raney nickel, hydrogenated at room temperature and under normal pressure for 6-7 hours. Filtering follows and the limpid solution is introduced dropwise into ice water.

The precipitated 3-amino-4-(4'-benzyloxyphenoxy)-5-N.N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester is recrystallized from methanol. There are obtained about 70 g of white crystals melting at 170% c) 3-N-pyrrolo-4- (4 ' -benzyloxyphenoxy) -5-N, N-dimet.hylaminomethylene-aminosulphonyl benzoic acid methvl ester 43.5 g of amine ester (9b) and 13 ml of 2,5-dimethoxytetrahydrofuran are refluxed for one hour in 250 ml of glacial acetic acid. The product is then precipitated by pouring the reaction mixture into ice water, followed by sucking off, washing with 1^0 and recrystallizing from CH^OH (adding active coal). Melting properties: The product sinters at 80°C, converts to a highly viscous oil which reaches its best fluidity rate of 105-110%.

EXAMPLE 10 3-N-pyrrolo-4-anilino-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester a) 3-nitro-4-anilino-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methvl ester 52.5 g of 3-nitro-4-chloro-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester are disso lved in 360 ml of absolute DMF and heated to 100%. 18 ml of aniline are then added dropwise while stirring and the reaction mixture is maintained at 100% for three hours. The product is precipitated by introducing the solution into 2 litres of i^e water, isolated and washed thoroughly with water. For pir ifying the product it it boiled with 250 ml of CH^OH and a minor quantity of acetone. There are obtained crystals 61-27 - 16 melting at 182 - 183°c. b) 3-amino-4-anilino-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester 40.7 g of nitro ester (10a) are dissolved in 600 ml of DMF and hydrogenated for 8 hours in the presence of Raneynickel as catalyst at 50°C and under a pressure of 50 atmospheres. The filtered solution is introduced into 2 litres of ice water while stirring, the precipitated product is isolated and recrystallized from glycol monomethyl ether. There are obtained colourless crystals melting at 227 - 228°C. c) 3-N-pyrrplo-4-anilino-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester 11.3 g of amine ester (10b) are dissolved in 130 ml of glacial acetic acid and of 4.5 ml of·1,2-dimethoxy-tetrahydrofuran are added. After refluxing for 15 minutes the mixture is stirred into 500 ml of ice water, the precipitated product is isolated and washed several times with water.

Finally it is recrystallized from CH^OH/C^H^OH, melting point: EXAMPLE 11 3-N-pvrrolo-4-(31,41-methylene dioxyphenoxy)-5-N,N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(3 ', 41-methylenedioxyphenoxy)-5-N,N-dimethylamino-methylene aminosulphonyl benzoic acid methyl ester g of 3-nitro-4-chloro-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester and 58 g of sodium3,4-methy lene dioxyphenolate are blended with 500 ml of absolute DMF stirred at 120°C for 2 hours. The mixture is introduced into 4 litres of ice water, while stirring is continued. The precipitated light-yellow product, separated and recrystallized from n-butanol or CH,0H/acetone, has a melting point of 216217°C. - 17 b) 3-amino-4-(3',4'-methylene dioxyphenoxy)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester g of the nitro compound described in Example Ila are dissolved in about 500 ml absolute BMP and hydrogenated for 8 hours in the presence of Raney nickel as catalyst, at room temperature and under a pressure of 50 atmospheres. The filtered solution is then introduced dropwise into ice water and the precipitated product is recrystallized from GH3OH after the separation. There are obtained colourless crystals melting at 190 - 191°C. c5 3-N-pyrrolo-4-(31,4'-methylene dioxyphenoxy)-5-N,N-dimethylaminamethylene aminosulphonyl benzoic acid methyl ester 11.5 g of “amino ester (Example lib) are refluxed for 1 hour in combination with 4 ml of 2,5-dimethoxytetrahydrofuran in 150 ml of glacial acetic acid. The product is precipitated by introducing the solution dropwise into 1.5 litre of ice water and recrystallized from glycol monomethyl ester, melting point: 2O6°C, EXAMPLE 12 3-N-pyrrolo-4- (4 '-methylanilino) -5-N,N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester a) 3-nitro-4-(4'-methylanilino)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester 0.2 mole of 3-ni-cro-4-chloro-5-N,N-dimethylaminomethyleneaminosulphonyl benzoic acid methyl ester is dissolved in 500 ml of dimethylformamide at 100°C and a solution of 0.33 mole of ptoluidine in 200 ml of absolute DMF is added dropwise. After 4 hours the mixture is stirred into ice water and the precipitated product is separated. By recrystallization from CH^OK there are obtained yellow crystals melting at 21O°C. 4Q127 b) 3-amino-4-(41-methylanilino)-5-N,N-dimethylaminomethylene aminosulphonyl benzoic acid methyl ester 62.4 g of 3-nitro-4-(4'-methylanilino)-5-N, N-dimethy1aminomethylene-aminosulphonyl benzoic acid methyl ester are dissolved in 1.5 litre of dimethylformamide aid hydrogenated for 8 hours at 50°C and under a pressure of 50 atmospheres in the presence of Raney nickel. The catalyst is then separated and the filtrate introduced into ice water while stirring. The melting point is 186 - 188°C. c) 3-N-pyrrolo-4-(41-methylanilino)-5-N,N-dimethylaminomethyleneaminosuIphonyl benzoic acid methyl ester 0.1 mole of 3-amino-4-(4'-methylanilino)-5-N,N-dimethylaminomethylene-aminosulphonyl benzoic acid methyl ester are dissolved in 400 ml of glacial acetic acid and refluxed. After having added 15 ml of 2,5-dimethoxytetrahydrofuran, heating is continued for further 30 minutes, the mixture is then introduced into 3 1 of ice water while stirring. The precipitated product may be recrystailized from CH^OH. Melting point: 169- 173°C.

Patent Specification No, of the general formula:- olaims compounds N R COOR wherein R is H or alkyl of 1 to 4 carbon atoms, and R1 is chlorine or methyl, together with salts of free acids of the - 19 above formula. Also claimed is a process of preparing such compounds by reacting a compound of the general formula :R ί R -N-C=NO,S '4 2 R A/ COOR in which R represents hydrogen atom or an alkyl group of 1 to 3 4 carbon atoms, and each of R and R , which may be the same or different, represents an alkyl group of 1 to 4 carbon atoms, or 2 3 4 one of R , R , and R has the meaning given above, and the other two represent an alkylene group, which alkylene group has 3 to 6 carbon atoms when formed from R, and R^, and 2 to 5 carbon atoms for other combinations, with a compound of the general formula :Alk-0 C-Alk' wherein Aik and Aik' which may be the same or different, each represents an alkyl group of 1 to 4 carbon atoms, and subjecting the resulting compound to acid or alkaline hydrolysis to give a free acid of the first quoted formula or a salt thereof. It will be observed that the first step of the process claimed corresponds to certain of the processes claimed in claim 1.

Claims (8)

1. CIAIMS :1. A process for the preparation of a compound of general formula 5 wherein R represents a hydrogen atom or an alkyl group having 1 1 1 from 1 to 4 carbon atoms; each of R and R , which may be the same or different, represents a hydrogen or a halogen atom, an alkyl or alkoxy group having from 1 to 4 carbon atoms, or a trifluoromethyl, hydroxy, protected hydroxy or protected amino 1 1' 10 group, or R and R together represent a methylenedioxy group when occupying adjacent positions on the benzene ring; R represents a hydrogen atom or an alkyl group of 1 to 4 3 4 carbon atoms, and each of R and R , which may be the same or different, represents an alkyl group of 1 to 4 carbon atoms, 2 3 4 15 or one of R , R and R has the meaning given above and the other two represent an alkylene group, which alkylene group has 3 to 5 carbon atoms when formed with R_ and R,, and 2 to 3 5 3 4 5 6 5. Carbon atoms for other combinations, each of R and R , which may be the same or different, represents a hydrogen 20 atom, a methyl group or an ethyl group; and X represents -0-, -S-, -ΝΗ-, or -CH,,-? or a salt of a free acid of the general formula I, which comprises reacting a compound of the general formula (II) above, with a compound of the general formula Aik.z (III) k O-Alk' 5 6 wherein R and R have the meanings given above, and each of Aik and Aik'.which may be the same or different, represents 10 an alkyl group having from 1 to 4 carbon atoms.

2. A process as claimed in claim 1, wherein the reaction cf the compound of the general formula II with the compound of the general formula III is carried out using a weak organic acid as solvent. 15

3. A process as claimed in claim 1, carried out substantially as described in any one of the Examples herein. - 22

4. A compound of the general formula meanings given in claim 1,

5. A compound as claimed in claim 4 and listed in Table A herein.

6. A compound as claimed in claim 4 and named in any one of the Examples herein.

7. A salt of a free acid of formula I as defined in claim 4

8. A compound as claimed in any one of claims 4 to 7, whenever prepared by a process as claimed in claim 1. Dated