DK142579B - Process for the preparation of 4-substituted 5-sulfamoyl-N-furfuryl-anthranilic acids. - Google Patents

Description

(11) PUBLICATION 142579 DENMARK (51), nt Cl · 3 c 07 0 307/52 (21) Application No 648/72 (22) Filed on 14 Feb. 1972 (24) Lebedee Feb 14 1972 ν '(44) Application submitted and petition published on 24 · HOV. 1 980

DIRECTORATE OF

PATENT AND TRADEMARKETS (») Priority requested from it

Feb 15 1971, 4672/71, GB

(71) a / S DUMEX (DUMEX LTD.), 57 Prague Boulevard, Copenhagen S, DK.

(72) Inventor: Svend Åge £ hristensen, Galschiøtsvej 15, Helsingør, DK.

(74) Plenipotentiary in the proceedings:

Office of Industrial Eneret v. Svend Schønnlng.

(54) Process for preparing 4-substituted 5-sulfamoyl-N-fur = furyl-anthranilic acids.

The invention relates to a particular process for the preparation of known 4-substituted 5-sulfamoyl-N-furfuryl-anthranilic acids of the formula:

X 1 NH-CH, -1 J

XI m

r02SO2 '^^' // ^ 'CO0 H

wherein X is halogen or a trifluoromethyl group, an alkoxy group having up to 6 C atoms or a phenoxy or alkyl phenoxy group having up to 4 C atoms in the alkyl moiety.

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Several anthranilic acid derivatives of this type are known, e.g. from German Patents Nos. 1,122,541 and 1,129.5ol, which have a diuretic or saluritic effect useful for therapeutic purposes, and in particular, 2-furfurylamine derivatives have proved particularly effective in this regard. However, their preparation according to the known methods has presented difficulties, e.g. due to simultaneous side reactions forming resin-like products. These difficulties are particularly evident in the preparation of the furfuryl-substituted compounds by reaction between furfurylamine and a correspondingly substituted 5-sulphyl benzoic acid, e.g. 2,4-dichloro-5-sulfamyl-benzoic acid.

Of the known known methods, Norwegian Patent Specification No. 121,839 discloses reacting a corresponding halogen-substituted sulfamylbenzoic acid derivative with an amine, e.g. furfurylamine, and according to Swedish Patent Specification No. 332,995, a corresponding sulfamylanthranilic acid derivative free amino group is reacted with a halide, e.g. furfurylklorid.

In both cases, therefore, there is a reaction between two reactants and the yields are not very good, namely 42% and 48% respectively.

The object of the invention is to provide a method by which these difficulties are avoided and the desired compounds are obtained in extremely good yields using relatively inexpensive and readily manufactured starting materials.

This is achieved by the process according to the invention, characterized in that a 4-substituted 5-sulfamoyl-anthranilic acid furfuryl ester of formula I - (II)

NH2S02 1 // ^ / I ^ C00-CH 2 - \ ^ 0J

where X has the meaning given above is rearranged by heating.

It has been found that the rearrangement is smooth and practically complete if, for example, heated to a temperature of about 150 ° C.

Thus, in contrast to the known methods, this is an intramolecular rearrangement, and the yield thereof has been practically driven up to 95%, ie. a practically quantitative yield.

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The rearrangement is conveniently carried out in solution as the solvent is refluxed.

The starting materials of formula II may be prepared in various ways known per se, but particularly conveniently prepared by a compound of formula: NH0 | I (out NH2SO2r ^^ 555v '<' '>' V '· - COOR' where X is as previously defined and R * is a C 1 -C 6 alkyl group, for example a methyl group, transesterified with furfuryl alcohol of and known per se, conveniently in the presence of a catalyst in the form of an alkali metal alkoxide, for example sodium methoxide.

The preparation of starting materials of formula II, wherein X represents a chlorine atom, may conveniently be effected by transesterification of the known compound of formula: II (IV) cooch3 with furfuryl alcohol.

The furfuryl-4-chloro-5-sulfamyl-2-amino-benzoate thus obtained has a melting point of 140.6-142.6 ° C and its constitution is determined by equivalence determination, NMR, UV and IR spectra.

In a particularly convenient embodiment of the present process, furfuryl alcohol according to the invention is used as a solvent during the rearrangement process, where, when the starting material is prepared in the manner described above, the rearrangement can be carried out without isolating the starting material.

The process according to the invention will now be described in more detail by some exemplary embodiments.

Example 1 4-Chloro-5-sulfamyl-2-furfurylaminobenzoic acid 26.5 g (0.1 mol) of methyl 4-chloro-5-sulfamyl-2-aminobenzoate are dissolved in 25 ml of furfuryl alcohol and 5.4 g of sodium methoxide are added. . The mixture is warmed to 110 ° C and the methanol formed is distilled off. The reaction mixture is then refluxed for 16 hours and the excess furfuryl alcohol distilled off. The residue is dissolved in 1N sodium hydroxide and the solution is extracted with ethylene chloride. The aqueous phase is treated twice with activated charcoal, then a mixture of 5% acetic acid and concentrated hydrochloric acid is added until the pH is 3, whereupon a precipitate is added and the reaction mixture is left in the refrigerator until the product is crystallized. 24.5 g of 4-chloro-5-sulfamyl-2-furfurylamino-benzoic acid are obtained, which after recrystallization from ethanol has a melting point of 20 ° C.

Example 2 4-Chloro-5-sulfamyl-2-furfurylamino-benzoic acid 29.6 g (0.1 mole) of 4-chloro-5-sulfamylisatinoic anhydride are dissolved in 50 ml of ethylene glycol dimethyl ether (diglyme) and 1 g of finely powdered sodium hydroxide is added. The mixture is refluxed for 15 hours and the solvent is distilled off under reduced pressure. By treating the evaporation residue as described in Example 1, 25 g of 4-chloro-5-sulfamyl-2-furfurylamino-benzoic acid are obtained, m.p.

Example 3 32.4 g of methyl 4-phenoxy-5-sulfamyl-2-aminobenzoate are heated with 25 ml of furfuryl alcohol and 5> 4 g of sodium methoxide until the methanol formed is evaporated. Then the mixture is refluxed and stirred vigorously for 16 hours. about 16 ° C under nitrogen. The excess solvent is then distilled off under reduced pressure and the residue is worked up as described in Example 1. A yield of 26 g of 4-phenoxy-5-sulfamyl-2-furfuryl-amino-benzoic acid is obtained which, after recrystallization from ethanol, has a melting point of 228 ° C. 231 ° C.