DE1220436B - Process for the preparation of sulfamylanthranilic acids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German class: 12 q - 6/04

Number: 1220436

File number: F 44276IV b / 12 q

Filing date: October 21, 1964

Opening day: July 7, 1966

From the German Auslegeschrift 1174 797 is a process for the production of sulfamylanthranilic acids known, in the case of the dihalosulfamylbenzoic acid ester with amines to form sulfamylanthranilic acid esters implemented and then saponified to the free carboxylic acid.

It has now surprisingly been found that sulfamylanthranilic acids of the general formula can be used

NH-R

COOH

in which R denotes the benzyl, furfuryl or thenyl group, obtained when S-sulfamyl ^ chloro-6-halo-benzoic acid halides, 3-sulfamyl-4-chloro-6-halo-benzoic acid amides or 3-sulfamyl-4-chloro -6-halo-benzoic acid hydrazide reacts with amines of the general formula NH ₂ R, in which R has the meaning given above, and the correspondingly substituted 4-chloro-5-sulfamylanthranilic acid amides obtained, optionally without their isolation, are saponified under alkaline conditions

The 3 - sulfamyl - 4 - chloro - 6 - halogen - benzoic acid halides are S-sulfamyM-chloro-ö-fluoro-benzoic acid chlorides, bromides or iodides, 4,6-dichloro-3-sulfamylbenzoic acid chlorides, bromides or iodides as well as S- SulfamyW-chloro-ö-bromo-benzoic acid halides, bromides or iodides in question. To convert these halides with benzyl, furfuryl or thenylamine, at least 2 moles of the amines mentioned are required for 1 mole of the substituted 6-halo-benzoic acid halides, since on the one hand the halogen atom in the 6-position and on the other hand the acid halide with 1 mole each of the amines mentioned reacted. In general, however, a much larger excess of amine is used, since 2 moles of hydrogen halide are released and have to be bound in this reaction. When using furfuryl or thenylamine as technically difficult to access amines ate condensation partners, it is advisable to reduce the excess amine and to add a tertiary organic base, such as triethylamine, pyridine or dimethylaniline, to bind the hydrogen halide. Advantageously, transmits the halides at temperatures between 0 and 20 ⁰ C in portions with stirring into excess amine component, a, with the corresponding dihalo-sulfamylbeMzoesäureamid forms, and the reaction then transferred by heating at temperatures between 0 € A process for preparing
of sulfamylanthranilic acids

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning, Frankfurt / M.

Named as inventor:

Dr. Karl Sturm, Frankfurt / M.-Unterliederbach;

Dr. Walter Siedel, Bad Soden (Taunus)

and 130 ° C, preferably between 80 and 110 ⁰ C, to the end. The reaction time is generally 30 to 120 minutes.

To isolate the primarily formed amides from the reaction solution, the latter is expediently diluted in Stirred in acetic acid and the mixture obtained by adding dilute while cooling with ice Hydrochloric acid adjusted to a pH of 4 to 5. The sulfamylanthranilic acid amide separates then in most cases becomes solid and is filtered off. From the filtrate can recover the amines used in excess with practically no losses.

The saponification of the sulfamylanthranilic acid amides obtained as intermediates is carried out by 2 to 5 hours Reflowing heating is carried out in 10 to 20 times the amount of 1- to 2N sodium or potassium hydroxide solution. In any case, the result is a clear solution when heated, so that the addition of an organic Solvent unnecessary. The reaction solution is then advantageously made up with glacial acetic acid pH between 7.5 and 8.0, if necessary, filtered from little separated unsaponified material and the end product is precipitated by hydrochloric acid at a pH of 2.5.

Carrying out the process according to the invention, starting from sulfamylbenzoic acid halides, however, it is also possible if the sulfamylanthranilic acid amides formed in the meantime are made from the reaction solution are not isolated, but the alkaline saponification of these amides immediately is carried out with the reaction mixture obtained.

The preparation of the sulfamylbenzoic acid halides required for this procedure, e.g. SulfamyrbenzoesäurecMoride, takes place according to methods known per se, e.g. by boiling the appropriate Benzoic acids with excess thio

609 588/411

3 4

nyl chloride optionally with the addition of an indifferent-described. The inventive method

rent solvent, - such. B. dioxane. After he ^: can after this procedure again without

subsequent implementation, d. H. after 1 to 2 hours, isolation of the anthranilic acid obtained as an intermediate

the solvent and excess thionyl chloride can be carried out amide. The other benefit that

stripped off in vacuo and the residue obtained 5 substantially reduced reaction temperatures would

directly in the manner described above to '■ Um- already in the implementation of the corresponding acid

Settlement with amines used ·:, '\ halide carried out.

The progressiveness of the invention, the production of the process as starting

driving against the 3-sulfamyl-4-chloro-6-halogen-

known method, / in which from the SuIfamyl- io benzoic acid amide or hydrazide succeeds z. Am

benzoic acid chlorides, esters are first prepared in the usual way by reacting the corresponding esters

the, which then with the amines to the ent- Halides with amines or hydrazines at deep

speaking anthranilic acid esters are implemented, temperatures, optionally in the presence of an

lies mainly in the fact that a reaction stage (the different organic solvents.

Production of the ester) is saved. The production 15 The course of the method according to the invention is the sulfamylanthranil obtained according to the process extremely surprising, since not foreseeable acids is therefore compared to the German war that a carbonamide group that either .beim Auslegeschrift 1174 797 · known processes ent- Starting material present or intermediate greatly simplified. The advantage of the inventive implementation with the amines mentioned is obtained according to the procedure compared to those from the German 20 and the generally no pronounced aktivie patents 1122 541 and 1129 501 known generating character, -the ortho-halogen process for the production of sulfate amylanthranic acid atom activated in such a way that it interacts with the amines mentioned lies in the lower reaction temperature. The out-smooth is exchanged, while the para-standing In the process according to the invention, the chlorine atom remains unaffected. Likewise, it was not closed significantly increased, because as a result of the lower 25 expect activation by the carbonamide reaction temperatures no resinification, = and group goes so far that the reaction temperatures Side reactions, caused by the instability of the compared to the carboxylic acids significantly reduced basic group in the 2-position at higher temperatures. After all, it was above all excessive appear. surprising to find that the difficult to saponify

Another advantageous embodiment of the bare carbonamide group by alkaline saponification

The method according to the invention is that, is cleaved under conditions in which the

2-Halogen-4-Cuor-5-sulfamyl-benzoic acid amide with a labile basic residue in the 2-position is not split off

Amines of the general formula NH ₂ R is implemented or changed. Rather, one would have expected

will. Such amides can, for example, require that in particular the thenylamino and

are used: S-sulfamyl-ö-fluoro ^ -chlor-benzoeT 35 furfurylamine residue are split off in the 2-position

acid amide, methyl amide, dimethyl amide, ethyl amide, would before the carbonamide group is saponified. .- ■,

-diäthylamidj-propylamidj ^ -hydroxyäthylamidj-S-hy'- The among other things from the German Aüslegeschrift

droxypropylamide and allylamide. In the same way 1174 797 already known. Process products are

can also use the corresponding 2-chloro and 2-bromine valuable diuretics and saluretics. -. ;

4-chloro-sulfamyl-benzoic acid amides, which by AlkyJ.-: 40 ..... ·

groups are mono- or disubstituted ,, used. B e i s ρ i e 1 1

will. The substituents of the carbonamide group - · ",,,. , ,, 11 _r · ■ * 1 · -, '■■

Araliphatic radicals such as benzyl or 3-sulfamyl-4-cWor-6-furfuryla _m nober * oesaure can also be used.

Phenethyl residues, be, they can also be aromatic a) 25.3 g S-sulfamyl ^ -chlor-o-fluorobenzoic acid-

Nature, such as B. with the correspondingly substituted 45 amide (0.1 mol) and 40 ecm freshly distilled fur

Benzoic anilides. The nitrogen atom of,. furylamin are stirred for 2 hours on the

Carbonamide group can also be linked to a saturated steam bath. The reaction solution is carried

heterocyclic ring system, i.e. it can then be absorbed into 0.41 10% acetic acid and sucked in

3-Surfamyl-6-halogen-4-chloro-benzoic acid pyrrolidide, cooling to O ⁰ C from the colorless, crystalline precipitate,

-piperidide, -morpholide or in Para position substitute 50 The washed with water, moist product is

be ated piperacides. · By refluxing for 2 hours in 0.3 1

It is also advantageous to saponify 6-fluoro (chlorine, bromine) 2N NaOH. D ^ reaction solution diluted

^ cUor-S-sulfamyl-benzoic acid hydrazide, the Hy _{7 of} which is mixed with the same volume of water, represents them with

drazidgruppe if necessary, e.g. with lower alkyl glacial acetic acid, to pH 8.0 and discolor it

radicals or aryl radicals is substituted, for reaction 55 by stirring in 1 g of activated carbon. From the

use with the amines mentioned. The end product is precipitated from the filtrate by hydrochloric acid

The reaction with benzyl, furfuryl or thenyl a pH of 2.5 with ice cooling from and

amine takes place. According to the for the acid halides it dries, after washing with water, on the

described way. However, the implementation succeeds in steam bath. Yield 31.5 g (91% of theory),

here already with 1 mole of amine to 1 mole of the benzoin 60 decomposition point 206 ⁰ C.

acid amides, although generally an over ₇ The same compound is obtained if one

shot is used. Here, too, you can use the amount instead of the 3-sulfamyl-4-chloro-6-fluorobenzoic acid

reduce the amine used when halide amide 26.8 g of the 3-sulfamyl-4-chloro-6-fluorobenzoe-

hydrogen-binding. Agents such as those described above using acid hydrazides as starting material,

were added. The processing corresponds to 65. The same connection is obtained when one

also that described for the acid halides. instead of 3-sulfamyl-4-chloro-6-fluorobenzoic acid

Way, the saponification of sulfamylanthranilic acid amides 28.0 g of 3-Smfamyl-4-chloro-6-fluorobenzoe-

amide to the process products was used above, from ^, acid dimethylamids. - ,

b) 27.2 g of 3-Suh ^c amyl-4-chloro-6-fluorobenzoyl chloride (0.1 mol) at 0 to 10 ⁰ C in portions with stirring in 60 cc of freshly distilled furfurylamine was added, then the mixture within 10 minutes heated to 9O ⁰ C and stirred for 2 hours at this temperature. The intermediate product precipitated in crystalline form by stirring the reaction solution in 0.5 l of 10% acetic acid is filtered off with suction, saponified by refluxing for 3 hours in 0.3 l of 2N NaOH and the end product is isolated as described under a). Yield 28.2 g (85% of theory), decomposition point 206 ° C.

Example 2
S-sulfamyM-chloro-o-benzylaminobenzoic acid

a) 26.9 g of 3-sulfamyl-4,6-dichlorbenzoesäureamid (0.1 mol) are dissolved in 60 cc of benzylamine is heated for 2 hours under stirring to HO ⁰ C. The reaction mixture is then introduced into 0.5110% strength acetic acid, the intermediate product which has precipitated out in crystalline form is filtered off with suction and saponified by refluxing for 2 hours in 0.3 l of 2N NaOH. The end product is isolated as in Example 1, a) and purified by recrystallization from ethanol. yield

25.2 g (74% of theory), decomposition point 244 ° C. The same connection is obtained when on

Place of 3-sulfamyl-4,6-dichlorobenzoic acid amide

25.3 g of the 3-sulfamyl-4-chloro-6-fluorobenzoic acid amide is used.

The same compound is obtained if instead of the 3-Suh ^c amyl-4,6-dichlorobenzoic acid amide 29.7 g of S-sulfamyl ^ o-dichloro-benzoic acid ethylamide or 34.5 g of 3-sulfamyl-4,6-dichloro -benzoic acid anilide can be used.

b) It carries at 0 to 10 ⁰ C. 25.3 g of 3-sulfamyl-4-chloro-6-fluorobenzoyl chloride (0.1 mole) portionwise with stirring in 80 cc of a benzylamine, the implementation performs 2stündiges heating at 90 ⁰ C. to the end and works on as described under a).

Yield 28.0 g (82% of theory), decomposition point 244 ° C.

Example 3
3-sulfamyl-4-chloro-6- (2-thenylamino) benzoic acid

31.4 g of 3-Suh ^c amyl-4-chloro-5-bromobenzoic acid amide (0.1 mol) are in 60 ecm of freshly distilled 2-thenylamine for 2 hours with stirring on the

ίο Steam bath heated, the condensation product through Cases with 0.5110% acetic acid and isolated by Boiling for 2 hours with 0.3 1 of 2N NaOH analogously to Example 1, a) saponified. After recrystallizing from Ethanol-water: yield 27.0 g (87% of theory), Decomposition point 202 ° C.

Claims (1)

Claim: Process for the preparation of sulfamylanthranilic acids the general formula NH-R H ₂ NO ₉ S COOH in which R denotes the benzyl, furfuryl or thenyl group, characterized in that S-sulfamyl-chloro-o-halogen-benzoic acid halides, 3-sulfamyl-4-chloro-6-halogenbenzoic acid amides or S-sulfamyl ^ -chlor- O-halo-benzoic acid hydrazides are reacted with amines of the general formula NH ₂ R, in which R has the meaning given above, and the correspondingly substituted 4-chloro-5-sulfamylanthranilic acid amides obtained, optionally without their isolation, are saponified under alkaline conditions. Considered publications:
German publication No. 1174 797.