GB1598094A - Sulphamoylbenzoic acid derivatives having aromatic substituents - Google Patents

Description

PATENT SPECIFICATION

( 11) 1 598 094 Application No 21700/80 ( 22) Filed 2 Dec 1977 Divided out of No 1598093 Convention Application No 2654795 Filed 3 Dec 1976 in Federal Republic of Germany (DE)

Complete Specification published 16 Sept 1981

INT CL 3 C 07 C 143/80 C 07 D 213/55 277/30 333/24 Index at acceptance C 2 C 1382 1510 1530 215 220 226 227 22 Y 246 250 251 254 256 Y 30 Y 321 32 Y 332 350 366 367 385 510 51 X 532 536 620 660 699 AA SF ( 54) SULPHAMOYLBENZOIC ACID DERIVATIVES ( 71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230 Frankfurt/Main 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-

The present invention provides a sulphamoylbenzoic acid derivative having an aromatic substituent, of the general formula l/2 CCOR I HN-25 in which i) represents a monocyclic or bicyclic radical comprising at least one aromatic carbocyclic or aromatic heterocyclic ring, which is unsubstituted or substituted by one or more substituents, any two or more of which may be the same or different, selected from halogen atoms, alkyl and alkoxy radicals having from 1 to 3 carbon atoms, methylenedioxy, usually 3,4 methylene dioxy, benzyloxy, -NO 2, -CN, OH, formyl and acetyl groups and carboxylate radicals -COOR in which R represents an alkyl radical, R' represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, or a salt thereof, with the exception of compounds in which i represents a phenyl group which is unsubstituted or substituted by one or more of the same or different substituents selected solely from halogen atoms, (Cl-C 3)alkyl, hydroxy and (Cl-C 3)alkoxy groups.

Subject to the proviso above ( may represent an aryl radical, preferably a substituted benzene ring or an unsubstituted or substituted naphthalene ring or a heterocylic ring system, that is, one containing one or more heterocyclic rings and optionally one or more carbocylic aromatic rings, for example a 5-membered or 6-membered heteroaryl ring, e g a thiophene, pyridine, pyrimidine, thiazole, pyrazole, pyrazine, pyridazine, quinoline or isoquinoline ring, which can be unsubstituted or substituted.

Compounds of the general formula I include 3 amino 4 ( 5 methyl 2 thienyl) 5 sulphamoylbenzoic acid, 3 amino 4 ( 5 formyl 2thienyl) 5 sulphamoylbenzoic acid, 3 amino 4 ( 2 thiazolyl) 5sulphamoylbenzoic acid, 3 amino 4 ( 6 methyl 2 pyridyl) 5 sulphamoylbenzoic acid, 3 amino 4 ( 3 pyridyl) 5 sulphamoylbenzoic acid, and 3 amino 4 ( 2 pyridyl) 5 sulphamoylbenzoic acid.

Compounds of the general formula I and their salts may be prepared, for example, by (a) hydrolysing a compound of the general formula A 2 Ar COOR 1 BE,-25 II in which G has the meaning given above, R' represents an alkyl group having from I to 4 carbon atoms, and B represents the protective group v O To us ( 21) ( 62) ( 31) ( 32) ( 33) ( 44) ( 51) ( 52) 1,598,094 3 RS in which RI represents a hydrogen atom or a (Cl-C 4)alkyl radical, and RI and R 5 may be the same or different and each represents a (Cl-C 4)alkyl radical or are bonded to one another to form, with the nitrogen atom, a saturatd ring, or R 3 and R' are bonded to one another to form, with the carbon atom and nitrogen atom to which they are attached, a saturated ring, and R 5 represents a (Cl-C 4)alkyl radical, or (b) hydrolysing a compound of the general formula W 2 25 in which e, and B have the meanings given above, and RI represents an alkyl group having from 1 to 4 carbon atoms, and reducing the compounds thus formed, to obtain the free carboxylic acid of the general formula I, and if desired, esterifying the acid or converting it to a salt.

The hydrolysis mentioned under (a) and (b) may be carried out under acid or alkaline conditions and removes the protective group B as well as forming the carboxylic acid.

An ester of the general formula II may be prepared from an ester of the general formula III by reduction The compound of the general formula III may be prepared from a compound of the general formula XXCOOR I in which B has the meaning given above, X represents a chlorine, bromine or iodine atom and R' represents an alkyl group having from 1 to 4 carbon atoms, by reaction with a compound of the general formula &Y (V) in which Y represents a halogen atom and ( has the meaning given above in the presence of copper powder.

Compounds of the general formulae III and II and their conversion into compounds of the general formula I are described and claimed in our copending application no.

50343/77 (Serial No 1598093).

The preparation of starting materials of the general formula IV is described in German Offenlegungsschrift 2,461,601.

It is known from the literature (for example Jerry March, Advanced Organic Chemistry, McGraw-Hill Book Company, and Kogakusha Company Ltd 1968, page 508) that compounds which contain SO 2 NH 2 groups cannot be subjected to condensation in the present of copper powder (Ullmann reaction) because side reactions take place which prevent the desired synthesis of biaryl compounds.

Surprisingly, a compound of the general formula IV in which the sulphonamide group is blocked by the protective group B can be reacted with an aryl halide of the general formula V in the presence of fine copper powder in accordance with the method of an Ullmann reaction to give a biaryl derivative of the general formula III in very good yields.

It is thought that formation of a biaryl compound under the relatively severe conditions of the Ullmann reaction is even promoted by the sulphamoyl group thus protected The good yields and the very specific course of the reaction suggest autocatalysis caused by a possible internal complexing of the intermediately formed Cu-organic compound by the basic N atom of the protective group and thus a stabilising of this intermediate stage.

The protective group represented by B is preferably H CH 3 1 / =C-N CH 3 Other suitable protective groups are, for example, those in which the substituents R 3, R 4 and R 5 have the meanings shown in Table A below.

TABLE A

R 4 R 5 90 CH 3 CH 3 CH 3 H C 2 H^ C 2 H^ C 4 Hg CH 3 CH 3 H CH 3 CH 3 H CH 3 C 2 H^ -CH 2-CH 2-CH 2 CH 3 CH 3 -CH 2-CH 2 CH 2 CH 2-CH 2In a compound of the general formula V, Y preferably represents an iodine or bromine atom.

The reaction of the compounds ot the general formulae I Vand V, together with the copper powder, is usually carried out at a temperature of from 50 to 200 C, preferably from 150 to 200 C, in the melt or in an inert high-boiling solvent When the reaction is carried out in solution, in some cases the copper powder may be added immediately and in other cases it should be added only when the reaction temperature has been reached If the reaction is carried out in the melt, it is advantageous to use nitrogen or another inert gas as a blanketing gas The higher-boiling organic solvents dimethylformamide, dimethylacetamide, tetramethylurea and N-methylpyrrolidone have proved to be especially suitable.

However, solvents such as dimethylsulphoxide, sulpholan, hexamethylphosphoric acid trisamide, pyridine, quinoline or various higher-boiling aromatic, aliphatic and alicyclic hydrocarbons may also be used The metallic copper is usually employed in the form of very fine commercial copper powder However, it may also be activated beforehand by washing commercial copper powder with a 0 02 molar aqueous solution of the disodium salt of ethylenediaminetetraacetic acid or by treating it with iodine.

The copper powder is usually employed in excess If a solvent is used, a slight excess ( 10-20 %) is frequently sufficient In the melt, on the other hand, a two-fold to fivefold excess is usually advantageous The copper powder may also be employed in combination with one or more copper salts, for example a copper(I) halide or Cu 2 O.

The conversion of the nitro group into the amino group may be effected by a process which is customary in the literature, for example by catalytic hydrogenation with hydrogen and Raney nickel as a catalyst.

However, it is also possible to use the customary noble metal catalysts, such as, for example, palladium on charcoal or platinum oxide.

The catalytic hydrogenation may be carried out in a manner known per se (for example "Organikum", Berlin, Deutscher Verlag der Wissenschaften, 5 Auflage, page 271-277, page 507-510) The reaction may be carried out in a solvent in the present of a catalyst Preferred solvents are organic solvents, such as, for example, methanol, ethanol, ethyl acetate, dioxan or other polar solvents, especially amides, e g.

dimethylformamide or dimethylacetamide, or, in method (b) above, the reaction may also be carried out in an aqueous solution of an alkali metal salt.

The hydrogenation may be carried out at room temperature and under normal pressure, or at elevated temperature and under elevated pressure, for example 50 and 50 atmospheres, in an autoclave.

The protective group B and the ester radical R" may be split off by hydrolysis carried out in the customary manner either under alkaline conditions, for example with a dilute alkali metal hydroxide or alkaline earth metal hydroxide, or under acid conditionswith a dilute inorganic acid.

Hydrolysis may be performed before or after reduction of the mitro group.

Thus, hydrogenation of a compound of the general formula III leads to a compound of the general formula II This compound is then hydrolysed to give a 3 amino 5 sulphamoyl benzoic acid substituted by an aromatic radical in the 4-position (compound I) The same compound may be obtained by hydrolysis of the compound III and then reduction.

To prepare an ester of the general formula I, the hydrolysed compound of the invention may be subsequently esterified in the customary manner with a (C C 4)aliphatic alcohol.

A large number of substituted diaryl compounds of the general formula II may be used as starting materials, some of which are mentioned below.

TABLE B (compounds of the general formula II) 3 amino 4 ( 5 methyl 2 thienyl) 5 N,N dimethyl-aminomethyleneaminosulphonylbenzoic acid methyl ester, 3 amino 4 ( 5 formyl 2 thienyl) 5 N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester, 100 3 amino 4 ( 2 thiazolyl) 5 N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester, 3 amino 4 ( 6 methyl 2 pyridyl) 5 N,N dimethylamino 105 methyleneaminosulphonylbenzoic acid methyl ester, 3 amino 4 ( 3 pyridyl) 5 N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester, and 110 3 amino 4 ( 2 pyridyl) 5 N,N dimethylaminomethyleneaminosulphonylben zoic acid methyl ester.

Compounds of the general formula II are useful intermediate products for the 115 synthesis of medicaments, in particular of diuretic agents and saluretic agents Thus, for example, compounds of the general formula II in which ( represents an unsubstituted or substitued phenyl radical can be used as starting materials for the synthesis of sulphamoyl-benzoic acid derivatives, having a diuretic and saluretic action, such as are described in German Offenlegungsschrift 2,442,696 The present invention provides compounds of the 1,598,094 1.598 094 general formula I which are new The compounds described in DOS 2,442,696 are not included in the invention.

The following Examples illustrate the invention.

Example 1:

(Preparation of starting material) 3-amino-4-( 2-thienyl-5-N,N-dimethyl aminomethvleneaminosulphonylbenzoic acid methyl ester II cm i 3 cou 13 1 C = N 025 H a) 3-nitro-4-( 2-thienyl)-5-N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester III 70 g of 3 nitro 4 chloro 5 N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester, 60 g of very fine copper powder and 100 g of 2bromothiophen are mixed thoroughly and the mixture is heated at 180 C for 6 hours under a nitrogen atmosphere It is then allowed to cool and is digested several times with diisopropyl ether, under the influence of heat (Excess 2-bromothiophen can be recovered from the diisopropyl ether) The solid product is dissolved in hot dimethylformamide, the solution is filtered and the filtrate is added dropwise to icewater The product which has precipitated (crude yield 59 g) is recrystallised from acetone/CH 3 OH or acetonitrile.

Yield 46 4 g.

Yellow crystals of melting point 232-233 C.

b) the nitro compound (la) is dissolved in dimethylformamide and hydrogenated with Raney nickel as the catalyst at 50 C and under 50 atmospheres for 8 hours The mixture is then filtered and the dimethylformamide solution is added dropwise to three times the amount of ice-water The amine which has precipitated is boiled up with CH 3 OH.

Analysis sample recrystallised from nitromethane.

Colourless crystals of melting point 220-221 .

Example 2:

(Preparation of starting material) 3-amino-4-( 3-thienyl-5-N,Ndimethylaminomethyleneaminosulphonylbenzoic acid methyl ester II m 2 s CNO N C N 270 a) 3-nitro-4-( 3-thienyl)-5-N,Ndimethylaminomethyleneaminosulphonylbenzoic acid methyl ester III g of 3 -nitro -4 -chloro -5 -N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester are mixed with 60 g of copper powder and 100 g of 3bromothiophen and the mixture is heated to C for 4-5 hours under nitrogen.

Working up analogous to Example (la).

Recrystallisation from glacial acetic acid or acetonitrile, melting point 197-198 C.

b) The nitro compound is dissolved in dimethylformamide and hydrogenated for 3 hours at room temperature and under normal pressure with Raney nickel as the catalyst After filtering the mixture, the filtrate is added dropwise to ice-water and the product which has precipitated is isolated.

Recrystallisation from CH 3 OH or CH 3 NO 2.

Melting point 220-221 C.

The compounds of Examples la and 2 a can be used to prepare 3 amino 4 ( 2 thienyl) 5 sulphamoylbenzoic acid, and 3 amino 4 ( 3 thienyl) 5 sulphamoylbenzoic acid, respectively by the method of the Comparative Example below.

These compounds can also be prepared by hydrolysis of the compounds of Examples lb and 2 b.

Comparative Example:

NH 2 C"OOH H 2 NO 25 4 3-amino-4-phenyl-5-sulphamoylbenzoic acid a) 3 nitro 4 phenyl 5 N,Ndimethylaminomethyleneaminosulphonylbenzoic acid methyl ester is heated under 95 reflux with 2 N Na OH until a clear solution has formed 3 nitro 4 phenyl 5 sulphamoylbenzoic acid is precipitated in the cold with 4 N HCI and recrystallized from hot water 100 Yellow crystals of melting point 209-211 C.

The amino compound is obtained by catalytic hydrogenation with Raney nickel in dimethylformamide 105 b) 3 amino 4 phenyl 5 N,N dimethylaminomethyleneaminosulphonylbenzoic acid methyl ester is saponified and precipitated as described under (a).

Recrystallisation from water 110 Melting point 244-246 C.

1,598,094

Claims (3)

WHAT WE CLAIM IS:-

1 A compound of the general formula C 2OR 1 1 ( a CO Ca' I in which (i represents a monocyclic or bicyclic radical comprising at least one aromatic carbocyclic or aromatic heterocyclic ring, and which is unsubstituted or substituted by one or more substituents, any two or more of which may be the same or different, selected from halogen atoms, alkyl and alkoxy radicals having from 1 to 3 carbon atoms, methylene-dioxy, benzyloxy, -NO 2, -C=-N, OH, formyl and acetyl groups and carboxylate radicals COOR in which R represents an alkyl radical, and R' represents a hydrogen atom or an alkyl group having from I to 4 carbon atoms, or a salt thereof, with the exception of' compounds in which ' represents a phenyl group which is unsubstituted or substituted by one or more of the same of different substituents selected solely from halogen atoms, (C 1 C 3) alkyl, hydroxy and (C 1-C 3) alkoxy groups.

2 A compound as claimed in claim 1, wherein (i represents an unsubstituted or substituted naphthalene, thiophene, pyridine, pyrimidine, thiazole, pyrazole, pyrazine, pyridazine, quinoline or isoquinoline ring or a substituted benzene ring.

3 Amino 4 ( 3 thienyl) 5sulphamoylbenzoie acid.

ABEL & IMRAY, Chartered Patent Agents, Northumberland House, 303-306 High Holborn, London, WC 1 V 7 LH.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

3 Any one of the compounds 3 amino 4 ( 5 methyl 2 thienyl) 5 sulphamoylbenzoic acid, 3 amino 4( 5 formyl 2 thienyl) 5 sulphamoylbenzoic acid, 3 amino 4 ( 2 thiazolyl) 5 sulphamoylbenzoic acid, 3 amino 4 ( 6 methyl 2 pyridyl) 5 sulphamoylbenzoic acid, 3 amino 4( 3 pyridyl) 5 sulphamoylbenzoic acid and 3 amino 4 ( 2 pyridyl) 5 sulphamoylbenzoic acid.

4 3 Amino 4 ( 2 thienyl) 5 sulphamoylbenzoic acid.