DE3607343A1 - Process for the preparation of 4-hydroxy-1,2-benzoisothiazol-3(2H)one 1,1-dioxide and salts thereof - Google Patents

Abstract

There is described an advantageous process for the preparation of 4-hydroxy-1,2-benzoisothiazol-3(2H)one 1,1-dioxide, which can be used as a sweetener, and of its physiologically acceptable salts, starting from inexpensive compounds of the general formula II <IMAGE> in which Y denotes the hydroxyl group, a halogen atom, the radical OR or the group NR3R4, R1 denotes a nucleophilically exchangeable group or the radical -OR and R2 denotes a hydrogen atom or the carboxyl group. These compounds are reacted with alcoholates of metals of Main Groups 1 and 2 of the Periodic Table under anhydrous conditions at elevated temperatures. The resulting salts can be converted into 4-hydroxy-1,2-benzoisothiazol-3(2H)one 1,1-dioxide.

Description

Process for the preparation of 4-hydroxy-1,2-benz-

isothiazol-3 (2H) -one-l, l-dioxide and its salts The present invention relates to a new process for the preparation of 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l, which can be used as a sweetener -dioxids of the formula I, and its physiologically harmless salts, for example the alkali and alkaline earth salts, in particular the sodium, potassium, ammonium or calcium salt.

There are already processes for making the connection Formula I known (see European Patent No.

0 038 458), but the reaction pathways encompassing many reaction steps follow and use expensive chemicals and therefore not process-technically satisfactory.

Among other things, it is proposed to use 4-alkoxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide subject to an ether cleavage; besides being the required So far, ethers have been difficult to access, become costly or not very environmentally friendly Chemicals such as boron tribromide, pyridine hydrochloride or alkali cyanides are used or the yields remain unsatisfactory, as in the case of potassium bromide. It will also described that in 1,2-benzisothiazol-3 (2H) -one-l, l-dioxides which are in the 4-position carry a nucleofuge group, this nucleofuge group in the presence of alkalis and copper catalysts can be exchanged directly for the hydroxyl group; those precursors in which the nucleofugic leaving group is pseudohalogen or the diazonium cation means, are, however, again not easily accessible; is the leaving group a Halogen atom, the conversion only works in special, aggressive reagents protected pressure autoclaves, e.g. in glass autoclaves; it also turned out that the yields given in the cited patent when attempting to enlarge of the reaction mixture drastically - to about 10% of theory - drop.

It has now been found that 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide of the formula I or its salts can be obtained in excellent yield and in one process step by substituting 1,2-Benzisothiazole-l, 1-dioxide of the general formula II, in which Y is the hydroxyl group, a halogen atom, the radical OR "or the group -NR3R4, R1 is a nucleophilically exchangeable group or the radical OR and R2 is the hydrogen atom or the carboxy group, with alcoholates of the general formula III, R'OM (III) in which M is an equivalent of a metal of the first or second main group of the periodic table, to temperatures of 100 to 2500C, preferably 140 to 220 "C, are heated.

If in a compound of the general formula II Y is the hydroxyl group, the tautomeric formula IIa, are present. Instead of the free acids IIa, the corresponding alkali metal or alkaline earth metal salts can also be used in the reaction - under certain circumstances with advantage.

If in a compound of the general formula II Y is a halogen atom, a group -OR "or -NR3R4, R1 a halogen atom, the nitro group or the remainder -OR and R2 the carboxy group, these radicals are each as a halide, ether (R'OR "), amine (HNR3R4), halide, nitrite, ether (R'OR), carbonate or alkyl carbonate (R'OCOO ()) split off. Nucleophilically exchangeable groups R1 are in particular halogen atoms, preferably fluorine, chlorine or bromine atoms, or the nitro group.

R, R 'and R ", which can be the same or different from one another, mean alkyl, (cycloalkyl) alkyl or aralkyl groups with 1 to a total of 25 carbon atoms, where the carbon chains are straight or branched, by heteroatoms, such as oxygen, interrupted, substituted by hydroxyl groups and also olefinic double bonds contain can. As alcoholates of the general formula III are preferred those derived from primary alcohols, for example from n-propanol, 2-methyl-l-propanol, 3-methyl-l-propanol, l-octanol, l-decanol, l-undecanol, l-tetradecanol, l-hexadecanol, l-octadecanol, oleyl alcohol, l-eicosanol, 2-phenylethanol, 4-phenyl-l-butanol, 3-phenyl-propanol, 4-biphenylethanol. Methanol, ethanol, Tetraethylene glycol and 1,4-butanediol.

The alcoholates of the general formula III are obtained by reaction of alkali or alkaline earth metals, hydrides or amides with the preferably anhydrous respective alcohols R'OH. Instead of uniform alcoholates, for example potassium methoxide, Sodium methoxide, magnesium methoxide, sodium (4-hydroxy-butoxide), potassium tert-butoxide, mixtures of these can also be used. For the production of alcoholates comes also the action of alkali and alkaline earth hydroxides and oxides, such as sodium hydroxide, Potassium hydroxide, calcium hydroxide and sodium oxide on alcohols of the formula R'OH in Question; the resulting water of reaction is preferred before the reaction with the starting materials of the general formula II removed by distillation; this variant is hers simple and safe implementation because of particularly advantageous. The reaction also works with alkali or alkaline earth carbonates or cyanides, e.g. with potassium carbonate or sodium cyanide, in the presence of alcohols of the general formula R'OH.

The alcoholates of the general formula are used as solvents III underlying alcohols R'OH are preferred. However, the reaction can also be carried out in structurally different alcohols ROH or in dipolar, aprotic solvents, for example dimethyl sulfoxide, sulfolane, dimethylformamide or hexamethylphosphoric acid triamide, be performed.

Mixtures of the solvents mentioned are also suitable.

The reaction is sensitive to moisture, which is why in the reaction medium existing water before contact with the starting materials of the general formula II should be removed if possible. Reduce larger amounts of water in the approach the yield of the desired 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide is drastic or lead to different products.

In the general formula II, R3 and R4 are identical or different can be hydrogen, branched or unbranched alkyl or alkenyl radicals having 1 to 8 carbon atoms, optionally replaced by one or more hydroxyl groups substituted or by oxygen or sulfur atoms or one optionally alkyl-substituted imino groups can be interrupted, or phenyl radicals, which optionally can be substituted by alkyl, halogen or hydroxyl groups. R3 and R4 can but also together with the intermediate nitrogen atom a heterocyclic one 4- to 8-membered ring form. The remainder -NR3R4 means, for example, the Amino, methylamino, dimethylamino, diethylamino, octylamino, (2-hydroxyethyl) amino, [Bis- (2-hydroxyethyl] amino-, l-azetidinyl-, l-pyrrolidinyl-, l-piperidinyl-, hexahydro-lH-l-azepinyl- or 4-morpholinyl group.

If R1 is a nucleofugic leaving group in a starting compound of the general formula II, the reaction proceeds according to the following scheme: (if R2 = CO2H) The byproducts detected in small amounts indicate that the reaction mainly follows the path that has been drawn to a greater extent.

If the alcoholate used is 4-hydroxybutanolate, transetherification takes place intramolecular and the split off ether R'OR 'is tetrahydrofuran.

If a compound of the general formula II is used as the starting material, in which R1 is the chlorine atom, R2 is the hydrogen atom and Y is the amino group, the reaction proceeds according to the following general equation: As can be seen from the above equations, the reaction requires at least 2 equivalents of base, namely if in the starting material II R1 is OR and Y is the hydroxyl group, OR "or NR3R4. On the other hand, R1 is a nucleofugal group, in particular a halogen atom or the nitro group , and Y is a halogen atom, at least one further equivalent of base is required in each case.Two further equivalents of base are required if in the 1,2-benzisothiazol-3 (2H) -one-l, l-dioxides of the general formula II R2 the If smaller amounts of base are used, the reaction is incomplete. The reaction can be carried out in a pressure autoclave or, if the alcohols used have sufficiently high boiling points, also without the application of pressure. Preference is given to working under an inert gas, which results in a particularly pure and uncolored end product is obtained.

During the implementation, new anhydrous salts of the general formula Ta containing two equivalents of an alkaline earth or alkali metal on, which by treatment with weak inorganic or organic acids, e.g. with acetic acid, in salts of the general formula Ib, with 1 equivalent of an alkali or alkaline earth metal or by the action of mineral acids, preferably hydrochloric acid, can be converted into the free 4-hydroxy-1,2-benzisothiazole-3 (2H) -onl, l-dioxide of the formula I.

Preferred starting materials are 4-chloro-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide (William Davies, J. Chem. Soc. (London) 119 (1), 880-881ff. (1921); F. Becke and H. Hagen, Liebigs-Ann. Chem. 729, 146-151 (1969)), 4-nitro-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide (Glenn H. Hamor, J. Am.

Pharm. Assoc. 49, 280-283 (1960)) and 4-chloro-3 (2H) -oxo-1,2-benzisothiazole-5-carboxylic acid 1,1-dioxide, that from m-xylene via the previously known 3-chloro-2,4-dimethylbenzenesulfonamide (IG Farbenind., D.R.P. 491 220; Friedlaender 16, 336; Beilstein 11 (II), 79) Oxidation with alkaline potassium permanganate solution is easily accessible. The output connections of the general formula II, in which Y is halogen, OR "or NR3R4, are either known tEP-B-0 038 458 and EP-B-0 033 984) or by analogy with known Establish methods.

Another object of the invention is a method for production of compounds of the general formula II in which R1 is the radical OR 'and Y is the hydroxyl group means.

Up to now, such connections have only been accessible in awkward ways. The method is based on the fact that the nucleophilic exchange of the described above The radical R1 against the radical OR 'in such compounds of the general formula II, in which Y is the hydroxy group and R1 is a nucleofugal group, e.g. a halogen atom or the nitro group, means already at something lower than those mentioned above Temperatures takes place; by correct choice of temperature and amount of base the reaction can therefore be steered in such a way that only compounds of the general formula II arise in which Y is the hydroxyl group and R1 is the radical OR '. For this procedure the amount of base must not exceed 2 equivalents, provided that R2 is the hydrogen atom is. The reaction temperatures are between 80 and 1400C, preferably 100 and 1200C. If R2 is the carboxy group, another equivalent of base is required. the other reaction conditions correspond to those above for the preparation of 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide I or its salts Ia and Ib mentioned.

The feasibility of the invention with excellent yield running one-pot process for the production of 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide from 1,2-benzisothiazole-l, l-dioxides of the general formula II, in which R1 is a nucleophile interchangeable group means even more surprising than when heated of 4-chlorosaccharin with alkali hydroxides in an aqueous medium to temperatures from 100 to 2000C almost exclusively products are formed from an opening of the isothiazole ring emerge, depending on the conditions predominantly 2-chloro-6- (aminosulfonyl) -benzoic acid or 3-hydroxybenzenesulfonamide.

The following examples are intended to explain the invention in more detail: Example 1 4-Hydroxy-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide To the solution of 0.41 g (17.83 mmol) of sodium in 25 ml of anhydrous methanol were given 1.80 g (8.44 mmol) of 4-methoxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide and heated the mixture obtained after injecting nitrogen with 10 bar for 15 hours long in a magnetic stirring autoclave to a temperature of 2100C, after cooling Dimethyl ether could be clearly detected in a sample taken from the gas space (GC-MS): m / e: 46 (M +), 45 The brownish discolored suspension was in a water jet vacuum concentrated, the residue dissolved in a little water, filtered and but with 10% hydrochloric acid carefully put Congo sour. The resulting precipitate was once more from Recrystallized a little hot water, after which 1.45 g (86% of theory) of colorless Crystals of m.p. 2280C were obtained.

Example 2 4-Methoxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide 2,176 g (10 mmol) of 4-chloro-1,2-benzisothiazol-3 (2H) -one-l-dioxide was added to the solution of 0.47 g (20.44 mmol) of sodium in 25 ml of anhydrous methanol and under a nitrogen pressure of 10 bar in a 100 ml magnetic stirrer autoclave for 10 hours at 1100C heated. The cooled mixture was freed from the solvent; the residue was in a little water dissolved, after adding a spatula tip of activated charcoal filtered hot, then acidified with 10% hydrochloric acid. The precipitate obtained was filtered off, dried and extracted twice from benzene / ethyl acetate (1: 1 v / v) recrystallized.

1.85 g (87% of theory) of colorless crystals of melting point were obtained. 2240C.

Example 3 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide Die Solution of 14.5 g (0.0666 mol) of 4-chloro-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide in 100 ml of anhydrous methanol was with the solution of 4.6 g (0.2 mol) of sodium in 100 ml of anhydrous methanol combined and in a shaking autoclave under a Nitrogen pressure of 10 bar heated to 2000C for 18 hours. After cooling down it was the reaction mixture is freed from the solvent, the residue obtained in 70 ml Added water, filtered hot after the addition of 0.5 g of activated charcoal, the filtrate with approx. 15 ml conc. Acidified hydrochloric acid. It was left at ambient temperature overnight stand from 0 to 50C, sucked off the deposited precipitate and crystallized it twice more with 50 ml of hot water each time. 10.42 g (79% of theory) were obtained on colorless crystals of melting point 227-2280C.

Example 4 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide 3,5 g (0.152 g-atom) of sodium were slowly increasing the internal temperature of 100 to 1500C and while passing dry nitrogen in 50 g of anhydrous 1,4-butanediol dissolved. After adding 10.9 g (0.05 mol) of 4-chloro 1,2-benzisothiazole-3 (2H) -one-l, l-dioxide, the internal temperature rose to 1800C within 10 minutes increased and held at this value for 5 minutes. The resulting tetrahydrofuran was continuously removed by distillation on the descending condenser. After completion the reaction was given the 1,4-butanediol (43 g), which can be reused distilled off under reduced pressure, the residue taken up in 60 ml of water, the The solution obtained is extracted twice with 10 ml of diethyl ether each time. The aqueous-alkaline Phase was concentrated with approx. 12 ml. Hydrochloric acid acidified against Congo red as an indicator. After recrystallization of the sand-colored precipitate from 2 times 50 ml of water each time 8.56 g (86% of theory) of colorless crystals with a melting point of 227-228 ° C. are obtained.

Example 5 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide In 50 8.1 g (0.15 mol) of sodium methylate were dissolved in g of anhydrous 1,4-butanediol, whereupon by slowly increasing the internal temperature to 1300C the contained in equilibrium Methanol was removed by distillation. To the mixture obtained was added 10.9 g (0.05 Mol) 4-chloro-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide and increased the temperature within 15 minutes to 1800C. The further implementation and processing corresponded to the information in Example 4. 7.9 g (79% of theory) of colorless were obtained Crystals of m.p. 2280C.

Example 6 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide In one 250 ml three-necked flask equipped with a stirrer, gas inlet tube and Claisen attachment with descending cooler, were bubbling with nitrogen and 6.2 g (0.155 mol) of sodium hydroxide in 60 g of 1,4-butanediol at 1800C with stirring solved. The water in equilibrium was meanwhile together with a little 1,4-butanediol distilled off. The resulting solution was allowed to cool to 1000C, added 10.9 g (0.05 mol) of 4-chloro-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide and increased the temperature to 1250C. In a sample taken at this point in time, after acidification with hydrochloric acid by means of 1H-NMR 4- (4-hydroxybutoxy) -1,2-benzisothiazol-3 (2H) -one-1,1-dioxide detect: 1 (d6-DMSO / CD3OD): 7.2-8.2 ppm (3H-m); 4.6-5.5 ppm (broad, 2H, interchangeable H); 4.27 ppm (2H-t; J = 6Hz); 3.57 ppm (2H-t; J = 5Hz); 1.4-2.1 ppm (4H-m) The mixture was quickly heated to 1800C and left at this temperature for 5 minutes. the The initially thin mixture was different as the reaction progressed cheesy precipitate. The resulting tetrahydrofuran was continuously distilled off. The progress of the reaction could be checked by thin-layer chromatography (polygram thin-layer plate, Macherey & Nagel, Art. No.

805 021; Eluent: dichloromethane / cyclohexane / methanol / conc. ammonia 102: 23: 23: 3 v / v / v / v /).

The excess butanediol (53 g) that can be reused was distilled off under reduced pressure, the residue was dissolved in 60 ml of water, mixed with 0.5 g of activated charcoal and filtered boiling hot. This solution was after cooling in a mixture of 13 ml of concentrated hydrochloric acid and 10 ml of water stirred in so that a crystalline precipitate formed. One left over Standing overnight at an ambient temperature of 0 to 50C, sucked the crystals washed them once with 12 and once with 8 ml of ice water and crystallized them again from 80 ml of hot water. 8.0 g (80% of theory) were obtained colorless crystals, m.p. 2280C.

oO U lo4 Example 7 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide monosodium salt A reaction mixture prepared in complete accordance with Example 6 was made freed from excess 1,4-butanediol after the reaction has ended. The residue was dissolved in 40 ml of water, filtered hot after stirring with 0.5 g of activated charcoal, the filtrate was treated with 3.1 g (0.052 mol) of acetic acid and overnight at ambient temperature left to stand from 0 to 50C. The resulting colorless precipitate was filtered off with suction, Washed twice with 3 ml of ice-cold ethanol each time and at 80 ° C. in a vacuum drying cabinet dried.

M.p.> 3300C (Z.).

Yield 8.8 g (80% of theory).

C7H4NNaO4S (221.16) Calcd .: C 38.02 H 1.82 N 6.33 S 14.50 Found: 37.82 1.81 6.34 14.29 Example 8 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide Die Suspension of 4.5 g (0.08 mol) of calcium oxide in 86 g of 1,4-butanediol was passed through heated by nitrogen at 2000C for 1 hour. Volatile constituents were distilled off in the process. In the clear solution obtained, after cooling to 1000C, 5.5 g (0.0253 mol) 4-chloro-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide and then heated under Stir for 15 minutes at 21,000 and finally for 1 hour at 2300C. It distilled Tetrahydrofuran over. After the completion of the reaction, the excess 1,4-butanediol became in the Distilled off in vacuo, the residue taken up in 30 ml of hot water, after addition filtered hot from 0.1 g of activated charcoal. The filtrate was concentrated by adding dropwise Hydrochloric acid made Congo acidic. After standing for three hours with ice bath cooling the resulting crystals were sucked off. 3.58 g (71% of theory) were obtained on colorless crystals of melting point 227-2280C (water).

Example 9 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide The solution of 10.9 g (0.05 mol) of 4-chloro-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide in 100 ml of anhydrous Methanol was with the solution of 3.6 g (0.148 g-atom) of magnesium in 100 ml of dry Combined methanol and under a nitrogen pressure of 10 bar for 6 hours in heated to 2200C in a tumble autoclave. The reaction mixture obtained was evaporated, the residue obtained acidified with concentrated hydrochloric acid, evaporated again, the product thus obtained is boiled several times with tetrahydrofuran. The evaporation residues the combined tetrahydrofuran extracts were once aqueous from 50 ml hot hydrochloric acid and recrystallized once from 30 ml of boiling water. One received 4.48 g (45% of theory) of colorless crystals with a melting point of 2280C.

Example 10 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide Die Mixture of 3.5 g (0.0161 mol) of 4-chloro-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide, 3.5 g (0.0714 mol) of sodium cyanide and 40 g of anhydrous 1,4-butanediol was under Passing nitrogen through, heated to 230 ° C. for 5 hours. After completion the Tetrahydrofuran formation, the mixture was freed from excess butanediol, the residue worked up as in Example 9 and finally once from solvent aqueous hydrochloric acid and recrystallized once from boiling water.

2.04 g (64% of theory) of colorless crystals of melting point were obtained. 227-2280C.

Example 11 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide Die Mixture of 3.6 g (0.0165 mol) of 4-chloro-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide, 6.9 grams (0.05 moles) of anhydrous potassium carbonate and 51 grams of dry 1,4-butanediol was heated to 240 ° C. for 1 hour while passing nitrogen through. After the Tetrahydrofuran formation was continued as in Example 10. 1.85 was obtained g (56% of theory) of the sought-after 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide in the form of colorless crystals with a melting point of 227-2280C.

Example 12 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide The solution of 6.8 g (0.0312 mol) of 4-chloro-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide in 20 ml of anhydrous Benzyl alcohol was anhydrous with the solution of 2.2 g (0.096 g-atom) of sodium in 50 ml Benzyl alcohol combined and 15 hours with stirring and bubbling of nitrogen refluxed.

After removing the solvent by vacuum distillation, the The residue was dissolved in 50 ml of water, and the solution was carefully extracted with ether. Then became the aqueous-alkaline phase acidified with chloroacetic acid and with ethyl acetate shaken out exhaustively. The organic extracts were made discarded. The aqueous phase was made Congo acidic with 10% hydrochloric acid and in vacuo concentrated to a total volume of 25 ml. It was left at ambient temperature overnight from 0 to 50C, the crystals formed sucked off and crystallized them twice more from hot water. 1.25 g (20% of theory) of colorless were obtained Crystals of m.p. 227-2280C.

Example 13 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide To 7.4 g (0.104 g-atom) of sodium in 55 g of tetraethylene glycol were added to the solution g (0.034 mol) of 4-chloro-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide and heated the mixture while passing nitrogen through and stirring at 1750 ° C. for 1 hour. Then the solvent became Distilled off in a fine vacuum, the residue worked up as in Example 4. Man received 5.22 g (77% of theory) of colorless crystals of melting point 226-2280C (water).

Example 14 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide To to the solution of 1.07 g (0.0465 g-atom) of sodium in 30 ml of anhydrous n-butanol 3.4 g (0.0156 mol) of 4-chloro, 2-benzisothiazol-3 (2H) -one-l, l-dioxide and boiled while passing dry nitrogen through it under reflux for 20 hours. The thus obtained Mixture was evaporated under reduced pressure, the residue between water and ether distributed. The aqueous phase was acidified with chloroacetic acid, then exhaustively extracted with ethyl acetate. The organic extracts were made discarded. The water Serious phase was made acidic and with Methylene chloride extracted several times. The methylene chloride extracts left behind after evaporation a honey-like residue, which according to GC / MS investigation in consisted essentially of 4- (butoxy) -1,2-benzoisothiazol-3 (2H) -one-1,1-dioxide.

m / e = 255 (M +), 226, 212, 199, 136.

This residue was taken up in 10 ml of dry n-butanol, with the solution of 0.72 g (0.0313 g atom) of sodium in 20 ml of dry n-butanol combined and under a nitrogen pressure of 10 bar in a stirred autoclave for 2 hours Heated in l900C. The reaction mixture obtained was worked up as in Example 1 and after recrystallization from water gave 1.75 g (56% of theory) of the sought 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide of m.p. 227-2280C.

Example 15 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide Prepared analogous to Example 6, but using 4-nitro-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide as starting material. The yield of colorless crystals of m.p.

227-2280C was 82% of theory.

Example 16 4-Hydroxy-l, 2-benzisothiazol-3 (2H) -one-l, l-dioxide a) 4-chloro-3 (2H) -oxo-1,2-benzisothiazole-5-carboxylic acid-1,1-dioxide To the solution of 3.0 g (0.0283 mol) of sodium carbonate in 200 ml of water were added successively 3.0 g (0.0137 Mole) 3-chloro 2,4-dimethylbenzenesulfonamide and 9.0 g (0.0569 mol) Potassium permanganate. The mixture was refluxed for 2 hours and added again 4.0 g (0.0253 mol) of potassium permanganate and refluxed again for 2 hours. The cooled reaction mixture was filtered and the filtrate was acidified with hydrochloric acid and extracted exhaustively with ethyl acetate.

The combined extracts were dried over sodium sulfate, from Freed solvent and left behind colorless crystals, which after recrystallize from toluene / ethyl acetate (3: 1 v / v) at 2850C (Z.) melted.

Yield: 2.0 g (56% of theory).

b.) 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide The mixture of 1.072 g (0.0191 mol) of potassium hydroxide and 5 g of 1,4-butanediol was 1 hour on descending cooler heated to 1200C. While stirring, 1.0 g (0.00382 mol) 4-chloro -3 (2H) -oxo-1,2-benzisothiazole-5-carboxylic acid-1,2-dioxide and heated another 2 hours at 2200C. It distilled, especially shortly after reaching this Temperature, a volatile substance. Then the temperature of the mixture increased to 2300C and the solvent was distilled off. The residue was in Dissolve as little water as possible, but by adding 10% hydrochloric acid dropwise it is acidic to the Congo and filtered after standing for 5 hours in an ice bath. The filter residue was recrystallized twice more from a little hot water. 0.60 g (79% of Theory) on colorless crystals with a melting point of 227-2280C.

Example 17 4-Hydroxy-1,2-benzisothiazol-3 (2H) -one-1,2-dioxide 2,122 g (0.01 mol) of 3-amino-4-methoxy-1,2-benzisothiazole-1,1-dioxide (m.p. 273-2760C) were obtained with the solution of 0.46 g (0.02 g atom) of sodium in 10 g of anhydrous 1,4-butanediol how implemented in example 4. In addition to the formation of tetrahydrofuran ammonia was detected. 1.64 g (8296 of theory) were obtained colorless crystals, m.p. 227-2280C.

Example 18 4-Hydroxy-1,2benzisozhiazol-3 (2H) -one-1,1-dioxide 2,166 g (0.01 mol) 3-amino-4-chloro-1,2-benzisothiazole-1,1-dioxide (melting point 261-2630C [ethanol]) were with the solution of 0.69 g (0.03 g atom) of sodium in 10 g of anhydrous 1,4-butanediol implemented as in Example 4. 1.60 g (80% of theory) of colorless crystals were obtained of m.p. 227-2280C (water)

Claims (10)

Claims 1.) New process for the preparation of 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide of the formula I, and its physiologically harmless salts, characterized in that substituted l, 2-benzisothiazole-l, l-dioxides of the general formula II, in which Y is the hydroxyl group, a halogen atom, the radical -OR "or the group -NR3R4, R1 is a nucleophilically exchangeable group or the radical -OR and R2 is a hydrogen atom or the carboxy group, with alcoholates of the general formula III, R '- OM (III) in which M is an equivalent of a metal of the first or second main group of the periodic table, heated under anhydrous conditions to temperatures of 140 to 2500C, where in the above formulas R, R 'and R "are the same or different from one another can be, alkyl, (cycloalkyl) alkyl or aralkyl groups with 1 to 25 carbon atoms, in which the carbon chains are straight or branched, interrupted by heteroatoms, substituted by further hydroxyl groups and can also have double bonds, and R3 and R4, which are the same or can be different from each other, hydrogen, branched or unbranched alkyl or alkenyl groups with 1 to 8 carbon atoms, which may be du One or more hydroxyl groups can be substituted or interrupted by oxygen or sulfur atoms or an alkyl-substituted imino group, or phenyl radicals, which can optionally be substituted by alkyl, halogen or hydroxyl groups, where R3 and R4 also together with the nitrogen atom in between can represent a heterocyclic 4- to 8-membered ring, and that the salts of the general formula Ia obtained after the reaction, then by acidification into the salts of the general formula Ib, and, if desired, the salts of the formulas Ia and Ib are converted into the compound of the formula I by means of mineral acids. 2.) The method according to claim 1, characterized in that a connection of the general formula II, in which R1 is a nucleophilically exchangeable group and R2 and Y are as defined in claim 1, with the alcoholates of the formula III according to claim 1 under anhydrous conditions at temperatures between 140 and 2500C are implemented, initially forming the salts of the general formula Ia, which then by acidification in the salts of general formula Ib or in the Compound of formula I are converted. 3.) The method according to claim 1, characterized in that a connection of the general formula II, in which R1 represents the radical OR with those specified in claim 1 Represents meanings or the radical OR 'according to claim 1 and R2 and Y as in claim 1 are defined, in the presence of at least 2 equivalents or, if Y is a halogen atom is, 3 equivalents of an alcoholate of the general formula III according to claim 1 or, if R2 is a carboxy group, from a further 2 equivalents of alcoholate below anhydrous conditions at temperatures from 140 to 2500C to compounds the general formula Ia is implemented and the resulting salt of the general formula Ia by acidification into one of the general formula Ib or the salts Ia and Ib, if desired, converted into the compound of formula 1 by means of mineral acids will. 4.) Process according to claims 1 to 3, characterized in that that instead of the compounds of the general formula II, provided that R2 is the carboxy group or Y denotes the hydroxyl group, the alkali metal or alkaline earth metal salts of which are used. 5.) Process according to claims 1, 2 and 3, characterized in that that a compound of the general formula II is used in which R1 is a halogen atom, preferably denotes the chlorine atom or the nitro group. 6.) Process according to claims 1 to 5, characterized in that that as alcohols for the preparation of the alcoholates of the general formula III n-propanol, 2-methyl-l-propanol, 3-methyl-l-butanol, l-octanol, l-decanol, l-undecanol, l-tetradecanol, l-hexadecanol, l-octadecanol, oleyl alcohol, l-eicosanol, 2-phenylethanol, 4-phenyl-l-butanol, 3-phenyl-propanol, 4-biphenylethanol, methanol, ethanol, tetraethylene glycol and 1,4-butanediol can be used. 7.) Process according to claims 1 to 6, characterized in that that as alkali or alkaline earth alcoholates magnesium methoxide, sodium (4-hydroxybutoxide), Potassium (4-hydroxybutanolate), the sodium or Potassium alcoholates or those when exposed to alkali and alkaline earth carbonates and cyanides on the alcohols on which the alcoholates of the formula III are based resulting mixtures are used. 8.) Process according to claims 1 to 7, characterized in that that the alkali or alkaline earth metal alkoxides used from the corresponding alcohols and alkali or alkaline earth hydroxides are produced and that in equilibrium located water before contact with the starting compounds of the general Formula II is removed by distillation. 9.) Process for the preparation of a salt of the general formula Ib, in which M is as defined in claim 1, characterized in that an anhydrous salt of the general formula Ta, in which M is as defined in claim 1, is acidified with a weak acid. 10.) Process for the preparation of 4-hydroxy-1,2-benzisothiazol-3 (2H) -one-l, l-dioxide, characterized in that an anhydrous salt of the general formula Ia, in which M is as defined in claim 1, is acidified with medium-strength or strong acids. 11.) Process for the preparation of the compounds of the general formula II, in which R2 is as defined in claim 1, R1 is the radical OR ', where R' is as defined in claim 1, and Y is the hydroxyl group, characterized in that a compound of the general formula II, in which Y is the hydroxyl group and R1 represents a nucleofuge group, with alcoholates of the general formula III, - - OM (III) in which R 'and M is as defined in claim 1, is reacted at temperatures between 80 and 1400C.