KR810001175B1 - Process for preparing condensed isothiazolo-3(2h)-one-1,1-dioxides - Google Patents

Abstract

Title compds. (I; X = O, S; R1 = H, Me, Et; R2 Me, Et) and their salts useful as sweetening agents, were prepd. by cyclization of II(R3 = H, C4-19 ter-alkyl; R4 = OH, C1-10alkoxy, phenyl- or naphthyl-substituted aryloxy, C1-3 phenylalkoxy, halogen). Thus, 3.05 g II (R1 = Et; R2 = Me; R3 = ter-Bu; R4 = OH) was heated with 20 ml polyphosphate at 65oC, 30min followed by cooling and washing with ice to give 2.1 g I.

Description

[Name of invention]

Method for preparing concentrated isothiazolo-3 (2H) -one-1,1-dioxide

Detailed description of the invention

The present invention relates to concentrated isothiazolo-3 (2H) -one-1,1-dioxides and their salts with inorganic or organic bases which are effective as sweeteners and to methods of preparing pharmaceutical compositions containing these components.

In the above structural formula

X is oxygen or sulfur atom.

R ₁ is a hydrogen atom or a methyl or ethyl group

R ₂ represents a methyl or ethyl group.

The use of cyclate or saccharin as a sweetener is well known, but toxicologically toxic in large amounts. Recently, there is no substitute for commercial use. In addition, a single natural component, dipeptide or oxatiage has not been tested in any of the products produced so far, which has strong sweetness and no taste or aftertaste, and thus can be used as a substitute for conventional sweeteners.

Concentrated isothiazolo-3 (2H) -one-1,1-dioxide and their physiologically nontoxic, salts with inorganic and organic bases have at least equal sweetness as compared to conventional sweeteners and moreover have an unpleasant taste or toxicity It was found to be better in that there were no side effects.

It was not foreseen that the concentrated isothiazolo-3 (2H) -one-1,1-dioxides of formula (I) and their salts had a unique strong sweetness because of the known compound 5-methyl-saccharin (See JG Lombardino. J. Org Chem 36, 1843 (1971)) and their alkali salts showed little sweetness when compared to saccharin, which is a compound of the formula (I) CH = CH- group, as is well known because -CH = CH- group has almost the same effect as -S- on ring structure.

Therefore, to the general public, the compounds of formula (I) are thieno [3,2-d] isothiazolo-3 [2H] -one-1 as described in German Publication No. 2,534,689 in terms of its sweetness. It is known to lag behind, 1-dioxide.

Comparing isothiazolo-3 (2H) -one-1,1-dioxide of formula (I) with DT-OS 2,534,689, the following properties are excellent.

a) Alkyl group R ₂ of the dioxide molecule of the present invention actually enhances taste (for example there is no unpleasant aftertaste in saccharin) and furthermore, if there is an alkyl group in the 5-position, it enhances metabolism. The compounds also have toxicological and metabolic properties.

b) Starting materials such as furan or thiophene with alkyl groups at the α-position allow simple injection of sulfo groups at the α'-position and carboxy groups at the β'-position, resulting in high yields and high purity of the final product. Therefore, the dioxide of the present invention can be more easily obtained.

c) sweetness is stronger.

As salts of concentrated isothiazolo-3 (2H) -one-1,1-dioxide, any physiologically toxic salts are suitable.

Alkali salts such as sodium, potassium or ammonium salts are preferred, and sodium salts are particularly preferred. Furthermore, alkaline earth salts such as calcium salts and other metal salts that are water soluble and non-toxic are also possible.

The compound of formula (I) is prepared as follows. The 2-sulfamoyl-3-carboxylic acid derivatives of the following formula (II) are closed by treatment with phosphoric acid, polyphosphoric acid, sulfuric acid and mixtures thereof at 0 ° to 100 ° C, preferably 50 to 70 ° C.

In the above structural formula

X, R ₁ and R ₂ are as defined above

R ₃ is hydrogen or a C 4 to C 19 tertiary alkyl group

R ₄ is a hydroxy group, an alkoxy group having 1 to 10 carbon atoms, an aryloxy group; an aryl group such as phenyl or napryl group, or a phenyl (or naphthyl-) alkoxy or halogen having 1 to 3 carbon atoms in the alkylene moiety. Nucleophilic exchangeable groups, such as an atom, are shown.

The final product formed is separated by a conventional method such as adding ice or purifying the obtained precipitate.

The reaction is simply heated to 100 to 250 ° C. or carried out, for example in the presence of O-dichlorobenzene or toluene. However, it can react in basic conditions, such as presence of sodium methylate.

Starting materials of formula (II) are prepared, for example, in the following manner.

From thiophene or furan to form the corresponding sulfochloride with sulfonic chloride or phosphorus pentachloride and conversion to sulfonamide of formula (III) using an amine of formula H ₂ NR ₃ (R ₃ is as above). .

In the above structural formula

R ₁ , R ₂ , R ₃ and X are as above.

The sulfonamide of the formula (III) is treated with lithium alkyl, such as -butyllithium, dissolved in a hydrocarbon such as hexane, at -40 DEG C, using dried tetrahydrofuran or a similar ether as a solvent, followed by -60 with carbon dioxide. Handle at °. After acidification with hydrochloric acid the corresponding product 2-sulfamoyl-3-carboxylic acid is isolated.

The final product of formula (II) is liberated and purified by conventional methods. From the test results, starting materials of structural formula (II) where R ₁ is hydrogen, R ₂ is methyl, R ₃ is tertiary alkyl and X is sulfur are obtained from 60-70% of the total yield theory from ₂ -methylthiophene. Could be

Concentrated isothiazolo-3 (2H) -one-1,1-dioxide of formula (I) is an acidic compound which is used as a sweetener either by itself or in the form of their physiologically toxic salts. These salts can be obtained by reacting the dioxide of formula (I) with suitable organic and inorganic bases. Preferably, hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide or ammonium hydroxide are used.

As mentioned above, the compounds of formula (I) and their physiologically poisonous salts have effective properties as sweeteners.

The following materials (A, B, C, D, E, F) were tested by several investigators for sweetness and taste quality against a known sweetener (U.V.W). Similarly, control was performed with substance X.

5-Methyl-furo [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide = A

5-Methyl-thieno [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide = B

5-Methyl-thieno [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide sodium salt = C

5-Methyl-thieno [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide calcium salt = D

4,5-dimethyl-thieno [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide = E

4,5-dimethyl-thieno [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide sodium salt = F

Cyclamate = U

Saccharin = V

Saccharin-Sodium = W

Thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide = X

(Reference DT-OS 2,534,689)

a) measurement of the limit concentration;

Substances A, B, C, D, E and F and the control compounds U, V and W were prepared in an aqueous solution at concentrations of 1: 2500, 1: 25000, 1: 50000, 1: 10000 and 1: 200000 and tested for five tastes. Self-rating was evaluated as follows: Very sweet. (= 3 points), sweet (= 2 points), slightly sweet (= 1 point), not sweet (= 0 points), this test is H.G. Schutz and F.J. Test according to the law of Pilgrim (Food Research 22,206 (1957)): The detectable dilution is defined as the concentration at which the mean is 1.0.

The results obtained are shown in the following table.

b) Determination of relative sweetness as compared to saccharose

Relative sweetness of sweeteners compared to saccharose (sugar cane sugar) (sometimes referred to as sweetness) varies greatly with concentration, so the relative sweetness of saccharin is 200 at normal concentrations (according to 2-10% saccharose). Varies between and 700. Therefore, about 3% saccharose solution is used as a control for the determination of relative sweetness of the above-mentioned compounds.

More detailed measurements of relative sweetness continue in accordance with the methods of R. Pauli (Chemilker-Zeitung 44,744 (1920)) and T. Paul (Chemiker-Zeitung 45,38 (1921)), tested by four investigators in each series. The results obtained are shown in the following.

(+ This value is as pointed out in DT-OS 2534689 on the previous page).

c) judgment of the quality of taste;

Conventional sweeteners, in particular saccharin, failed to taste saccharose, sometimes leaving a distinctive or aftertaste. However, substances A-F are excellent in showing pure sweetness. Substances A-C are like the taste of saccharose (sugarcane sugar).

The substances of formula (I) were also tested for pharmacological effects, acute toxicity and mutagene effect.

d) testing on pharmacological effects;

Substance C was subjected to the following pharmacological test.

This material did not show muscle relaxation or control inhibition effects when administered to mice, and mice were able to sustain in rotating cylinders at doses of 200 mg / kg P.O. At the same dose, the mice's natural motility in the light beam cage was measured, but the material did not affect the original natural motility of the mouse.

In addition, the intrinsic motility of rats was not affected by the measurement of the rat's intrinsic motility by Fuhrer and Felclhofer (Arzneim Forschll, 1027, (1961)) in the electron activity cage. Furthermore, the body temperature of the rats was not affected by the dose of 200 mg / kg P.O. This measurement was performed 1,2,3 and 4 days after oral administration of the substance, and the control group received only distilled water.

Substance C had no effect on mice anesthetized with hexobarbital. Administer 25 mg / kg P.O. and test for loss of Stell reflex. Anesthesia time was not affected.

When mice were dosed at 200 mg / kg P.O. and stimulated with Haffner tweezers, there was no effect on pain-induced defensive response.

Substance C did not affect the change by the electroshock of mice (dose of 200 mg / kg P.O.). Substance C also did not affect the low temperature of male mice induced by reserpin.

Three doses of 200 mg / kg P.O. of this material did not cause ulceration in the intestinal tract of rats. Minimal suitability testing of rabbit eyes gives the following results: The 1% solution did not cause pupillary spots or red spots on the conjunctiva and local anesthesia.

Substance C does not cause beats or contractions in the atrium of the isolated heart of rats. When anesthetized cats were dosed with iV at doses of 1.0, 3.0 and 10.0 mg / kg, they had no effect on blood pressure, pulse and breathing. Administration of this substance at a concentration of 1 × 10 ⁻⁴ mol / l of this substance had no effect on the aggregation of platelets derived from ADP, thrombin and Klgen into plasma-filled plasma of healthy persons. Administration of substance C (200 mg / kg PO) to male rats fed water had no effect on the secretion of Na ⁻¹ , K ⁻¹ , Cl ⁻ and liquid. Substance C has no effect as bacteriostatic and bacteriostatic agents.

e) preliminary acute toxicity

Acute toxicity is measured after oral administration of this substance to cancer, male and female mice. This material is used as a water-soluble or suspended in methyl cellulose (tylose). The following table shows animals that died 1 to 7 days after administration of the indicated doses.

No toxic symptoms were observed during the observation period. No animals died, but completely normal behavior.

f) experiment on mutagenicity

The most important thing required for sweeteners is that they should not be harmful to health. However, most sweeteners did not meet this requirement. For example, saccharin is mutagenic (R.P. Batzinger. SYL On and E Bueding 198, 944 (1977)) and is therefore dangerous to use as a sweetener.

Substances C and D were measured for mutagenicity using an AMES-device (Mutation Reserch 31,347 364 (1975)).

Genetic identification of Salmonella typhimurium TA98, TA100 and Escherichia coli WP2 (P), which are bacterial strains that grow to show a broad spectrum of damage caused by DNA molecules (base substitution, tissue-change mutagenesis, obliteration) Use as a reagent. Salmonella Lipimorium TA1535, TA1537 and TA1538 are also used for the testing of substance C.

Tests on other bacteria can also be performed in this way to test the effects of microsomal enzymes and their corresponding cognition on the present substance and furthermore to find differences in effection. This test is performed with or without an activation device. Normal in vitro activated S-9 suspensions (plasma reticulum fractions), i.e. mice not fed with pretreatment and arolor 1254 (500 mg / kg), are used. S-9 fraction doses are tested at three different concentrations.

Concentrations of substance C are 0.1 and 0.5 mg / plate

The concentrations of substance D are 5, 10, 15 and 20 mg / plate.

The highest dose unit in the in vitro-dilution method did not inhibit bacteria. Substances C and D do not cause strains and do not increase the rate of mutagenesis according to tests. The effect of activation fraction on enzyme induction and reversible rate could not be measured.

Colonies on the plate of this material are within the native range of each test strain.

In this experiment, substances C and D did not cause base substitution (S. typhimurium TA1535, TA100, E. coli WP2 (P)) and tissue modification (S, typhimurium TA1537, TA1538, TA98), thus causing mutagenic effects. You can see that there is no.

The following example describes the preparation of the active ingredient of the sweetener.

Example 1

5-Methyl-furo [3,2-d] isothiazolo-2 (2H) -one-1,1-dioxide 20,5 g (0.1 mole) of 5-methyl-2-sulfamoyl-furan-3-carboxylic acid And 20.8 g (0.1 mol) of phosphorus pentachloride are added to 50 ml of dehydrated toluene and refluxed for 8 hours. Filtrate and cool the hot mixture to crystallize 11.8 g (62.5% of theory) of 5-methyl-furo- [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide. .

Recrystallization twice from benzene yields 7.9 g (37% of theory) of the product. Melting Point: 195 ~ 196 ℃ (Decomposition)

IR (KBr): 1730 and 1690 cm ^-1 (CO)

1 H-NMR (CDCl ₃ + CD ₃ OD): δ = 6.5 (S, 1, 4-H) 2.5 (S, 3, CH ₃ ) and 1 exchangeable proton

MS: M + 187m / e

C ₆ H ₅ NO ₄ S (187.18)

Calculation: C38.50 H2.69 N7.48 S17.13

Found: 38.80 2.75 7.46 17.35

Starting materials are made as follows.

1 L of ethylene chloride is mixed with 260 g (3.17 moles) 2-methylfuran and 507 (3.17 moles) complex of sulfur trioxide-pyridine and stirred for 3 days. The reaction mixture is mixed with 3 liters of hot water while stirring and the aqueous phase is separated. The pH is adjusted to 7.5 with sodium bicarbonate and evaporated to dryness. The residue was extracted several times by refluxing with isopropanol and 248 g (43% of theory) of 5-methyl-furan-2-sulfonic acid sodium salt as crystal phase were obtained from the cooling fraction mixed with isopropanol. 248 g (1.35 moles) of 5-methyl-furan-2-sulfonic acid sodium salt at 30-50 ° C. are partially mixed with 281 g (1.35 moles) of phosphorus pentachloride and stirred at 50 ° C. for 15 minutes. The mixture is poured on ice and extracted with ether. This ether phase is washed with neutral material and evaporated to dryness. The residue (200 g of 5-methyl-furan-2-sulfonic acid chloride) was dissolved in 500 ml of ether, and this solution was added dropwise to a solution of 280 ml (2.7 mol) of tert-butyl amine in 500 ml of ether at 5 to 10 ° C. do. After stirring for 2 hours at room temperature and reflux, the reaction mixture is washed with ice water, dilute hydrochloric acid and water and evaporated. Recrystallization of the residue from cyclohexane yields 180.5 g (61.5% of theory) of N-tert-butyl-5-methyl-furan-2-sulfonamide. Melting Point: 113 ~ 114 ℃

1 H-NMR (CDCl ₃ ): δ = 6.9 (d, 1, J = 2Hz, 3-H), 6.1 (d, 1, J = 2Hz, 4-H), 4.6 (S, 1, NH, interchangeable ), 2.37 (S, 3, CH ₃ ), 1.25 (S, 9, C (CH ₃ ) ₃ );

C ₉ H ₁₅ NO ₃ S (217.29)

Calculation: C49.75 H6.94 N6.43 S14.71

Found: 49.50 6.97 6.47 15.00

500 ml of a 15% solution of butyl lithium (52.5 g or 0.82 mole) dissolved in hexane was dehydrated in 81 g of (0.37 mole) N-tert-butyl-5-methylfuran-2-sulfonamide (cooled to -60 ° C) in 1 liter. Add dropwise to the solution dissolved in tetrahydrofuran. The reaction mixture is heated to −20 ° C. in 2 hours and stirred at this temperature for 20 minutes. The mixture is then cooled to -60 ° C and carbon dioxide is slowly introduced. When the exotherm is stopped, the mixture is heated to −20 ° C. and 136 ml of 1/2 concentrated (about 18%) hydrochloric acid is added dropwise carefully with warming to 0 ° C. (CO ₂ evolution). The reaction mixture is evaporated and added to aqueous sodium hydrogen carbonate solution. The aqueous solution is extracted with ether, acidified with hydrochloric acid to pH 1 to 2, extracted twice with ether and evaporated to dryness. The resulting impure product was recrystallized from benzene to give 81.1 g (84% of theory) of 2- (N-tertbutyl) -sulfamoyl) -5-methyl-furan-3-carboxylic acid.

1R (CH ₂ Cl ₂ ): 1730 and 1690 cm ^-1 (CO)

1H-NMR (CDCl ₃ ): δ = 6.55 (d, 1, J = 0.5Hz, 4-H), 5.7 (S, 1, NH, interchangeable), 2.36 (d, 3, J = 0.5Hz, CH ₃ ), 1.25 (S, 9, C (CH ₃ ) ₃ ) and one exchangeable proton)

C ₁₀ H ₁₅ NO ₅ S (261.30)

Calculation: C45.97 H5.79 N5.36 S12.27

Found: 46.30 5.88 5.18 12.20

Boiling and 42 g (0.12 mole) of 2- (N-tert-butyl) -sulfamoyl-5-methyl-furan-3-carboxylic acid are heated to 150 ° C. for 2 hours in a round flask. After reflux the solution is treated with activated charcoal, filtered and evaporated. 22.8 g (69% of theory) of 5-methyl-2-sulfamoyl-furan-3-carboxylic acid are obtained as crystals.

Melting Point: 191 ℃

C ₆ H ₇ NO ₅ S (205.20)

Calculation: C36.12 H3.44 N6.83 S15.63

Found: 34.95 3.50 6.88 16.00

Example 2

5-Methyl-furo [3.2d] isothiazolo-3 (2H) -one-1,1-dioxide sodium salt

100 ml of 1.0 g (5.3 mmol) of 5-methyl-furo [3.2-d] isothiazolo-3 (2H) -one-1,1-dioxide and 230 mg (5.3 mmol) of 55% sodium hydride-oil dispersion Was refluxed in dehydrated tetrahydrofuran for 1.5 hours. After cooling, the obtained crystals are aspirated, washed with petroleum ether and dried over phosphorus pentoxide.

1.05 g (95% of theory) of 5-methyl-furo [3.2-d] isothiazolo-3 (2H) -one-1,1-dioxide sodium salt are obtained. Melting Point: 280 ℃ or higher (Decomposition starts at 210 ℃)

C ₆ H ₄ NNaO ₄ S (201.16)

Calculation: C34.45 H1.93 N6.70 S15.33

Found: 34.20 2.08 6.56 15.30

Example 3

5-Ethyl-furo [3,2-d] -isothiazolo-3 (2H) -one-1,1-dioxide

5.0 g (0.023 mole) of 5-ethyl-2-sulfamoyl-furan-3-carboxylic acid are mixed with 4.75 g (0.023 mole) of phosphorus pentachloride in 300 ml of dehydrated toluene and refluxed for 8 hours. After the mixture is filtered, the filtrate is evaporated in vacuo.

The residue was recrystallized from carbon tetrachloride to give 2.1 g (46% of theory) of 5-ethyl-furo [3.2-d] isothiazolo-3 [2H] -one-1,1-dioxide. Melting Point: 133 ℃

C ₇ H ₇ NO ₄ S (201.21)

Calculated Value: C41.79 H3.51 N6.96 S15.84

Found: 41.53 3.35 6.97 15.83

Starting materials are prepared as follows.

Similar to the preparation of 5-methyl-2-sulfamoyl-furan-3-carboxylic acid (cf. starting material of Example 1), 2-ethylfuran and sulfur trioxide-pyridine complexes were sulfonated to give 32.5% of the theoretical 5- The sodium salt of ethyl furan-2-sulfonic acid is obtained. Chlorination with phosphorus pentachloride and reaction with tert-butylamine reacted with 5-ethyl-N-tert-butyl-furan-2-sulfonamide [(melting point 71-72 ° C.) from petroleum ether: 1 H-NMR (CDCl ₃ ): δ-6.95 (d, 1, J = 2 Hz, 3-H), 6.15 (d, 1, J = 2 Hz, 4-H), 4.7 (S, 1, NH, interchangeable), 2.73 (q, 2, CH ₂ ), 1.30 (m, 12, -CH ₂ -CH ₃ and C (CH ₃ ) ₃ ] are obtained in a yield of 48% of theoretical amount. 5-ethyl-2- (N-tert-butyl) -sulfamoyl-furan-3-carboxylic acid (melting point: 118-119 ° C.) (in cyclohexane) by melting with butyllithium or carboxylating with carbon dioxide This yields a yield of 59% of the theoretical amount, which is heated under drying conditions for 2 hours to 160 ° C. 5-ethyl-2-sulfamoyl-furan-2-carboxylic acid [melting point: 186 ° C. (in ethyl acetate)].

1 H-NMR ([d ₆ ] -DMSO): δ = 6.6 (S, 1, 4-H), 2.73 (q, 2, CH ₂ ), 1.25 (t, 3, CH ₃ ) and two exchangeable protons This is obtained in a yield of 87% of the theoretical amount.

C ₇ H ₉ NO ₅ S (219.22)

Calculated Value: C38.35 H4.14 N6.39 S14.63

Found: 38.33 4.04 6.70 14.56

Example 4

4,5-dimethyl-furo [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide 4,1- 4,5- dimethyl-2- sulfamomoyl-furan-3- Manufactured from carboxylic acids

A mixture of 1.0 g (4.6 mmol) of 4,5-dimethyl-2-sulfamoyl-furan-3-carboxylic acid and 0.96 g (4.6 mmol) of phosphorus pentachloride in toluene was reacted in a similar manner to Example 1 0.68 g (73% of theory) of 4,5-dimethyl-furo [3,2-d] isothiazolo-3- (2H) -one-1,1-dioxide is obtained. Rf value: 0.21 (silica gel 60F 254, thickness 0.25 mm, eluent ethylene chloride: ethyl acetate: glacial acetic acid (100: 30: 5)

C ₇ H ₇ NO ₄ S (201.21)

Calculation: C41.79 H3.51 N6.96 S15.94

Found: 41.50 3.56 6.92 15.98

Starting materials are prepared by the following method.

2,3-dimethyl-furan (KC Rice and JR, Dyer J. Heterocycl. Chem 12, by analogous methods of preparation of 5-methyl-2-sulfamoyl-furan-3-carboxylic acid (see starting material of Example 1)) 1325 (1975)) is converted to 4,5-dimethyl-furan-2-sulfonic acid sodium salt using sulfur trioxide-pyridine complex and treated with phosphorus pentachloride and tert-butylamine to yield N-tert-butyl-4, 5-dimethyl-furan-3-sulfonamide is obtained in a yield of 34% of theoretical amount.

Melting point: 95 to 96 ° C. (in petroleum ether), (1H-NMR (CDCl ₃ ): = 6.85 (S, 3, 5-CH ₃ ), 2.00 (S, 3, 4-CH ₃ ), 1.26 (S, 9, c (CH ₃ ) ₃ followed by metallization with butyllium and carboxylation with carbon dioxide to give 4,5-dimethyl-2- (N-tert-butyl) -sulfamoyl-furan-3- Carboxylic acids are obtained in a yield of 70%.

Melting point: 114 to 115 ° C (in petroleum ether), heating and drying in a major to convert carboxylic acid to 4,5-dimethyl-2-sulfamoyl-furan-2-carboxylic acid.

Yield: 16% of theoretical amount

C ₇ H ₉ NO ₅ S (219.22)

Calculated Value: C38.35 H4.14 N6.39 S14.63

Found: 38.40 4.01 6.45 14.50

4.2 g (2.3 mmoles) of 2 from 2- (tert-butyl) -4,5-dimethyl-furo [3,2-d] isodiazolo-3 (2H) -one-1,1-dioxide -(Tert-butyl) -4,5-dimethyl-furo [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide is heated in vacuo to 175 ° C. for 2 hours. After cooling, the residue was purified by chromatography (eluent: ethylene chloride: ethyl acetate: glacial acetic acid 100: 30: 5) to give 35 mg (7.5% of theory) of 4,5-dimethyl-furo [3,2-d] isothia Zolo-3 (2H) -one-1,1-dioxide is obtained.

C ₇ H ₇ NO ₄ S (201.21)

Calculation: C41.79 H3.51 N6.96 S15.94

Found: 41.60 3.65 7.02 15.85

Starting materials are prepared as follows.

1.7 g (6.2 mmol) of 4,5-dimethyl-2- (N-tert-butyl) -sulfamoyl-furan-3-carboxylic acid is mixed with 5 g of polyvalent phosphoric acid and heated to 60 ° C. for 30 minutes. It is poured on ice, extracted with methylene chloride, and the organic phase is washed with sodium bicarbonate solution and water and evaporated. 0.65 mg (41% of theory) 2- (tert-butyl) -4,5-dimethyl-furo [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide Obtained.

C ₁₁ H ₁₅ NO ₄ S (257.31)

Calculation: C51.35 H5.88 N5.44 S12.46

Found: 51.20 5.91 5.32 12.32

Example 5

5-Methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

5.1 5-Methyl-2- (N-tert-butyl) -sulfamoyl-thiophene-3-carboxylic acid

139 g (0.5 mole) of 5-methyl-2- (N-tert-butyl) -sulfamoyl-thiophene-3-carboxylic acid was newly prepared polyvalent phosphoric acid (cooled to 60 ° C. and 570 g of phosphorus pentoxide at 140 ° C. And 250 ml of 85% phosphoric acid) dropwise. The reaction mixture is stirred at this temperature for 30 minutes. After pouring on ice, the precipitated crude product is filtered off, washed with ice water and dried. Recrystallization from methanol yields 98.5 g (97% of theory) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide. Melting Point: 231 ℃

IR (KBr): 3200 (NH), 1740 (CO), 1325 and 1150 cm ^-1 (SO ₂ ), 1 H-NMR ([d ₆ ] DMSO): δ = 7.2 (d, 1, J = 1 Hz, 4- H), 2.6 (d, 3, J = 1 Hz, CH ₃ ) and one exchangeable proton.

C ₆ H ₅ NO ₃ S ₂ (203.23)

Calculation: C34.46 H2.48 N6.89 S31.55

Found: 35.35 2.64 7.10 31.40

Starting materials are prepared as follows.

291 g (2.5 moles) of chlorosulfonic acid are added dropwise to 208 g (1.0 moles) of phosphorus pentoxide with stirring and cooling. After the formation of hydrogen chloride, 98 g (1.0 mole) of 2-methyl-thiophene is added dropwise with stirring at 10 ° C. After the addition is complete, stir for 10 more parts. The mixture is poured onto 2.5 kg of ice and the sulfochloride obtained is washed five times with 500 ml of ether. The organic phase is washed twice with 200 ml of water and evaporated to dryness in vacuo. The residual oil is absorbed into 200 ml of tetrahydrofuran and added dropwise with stirring to a solution of 183 g (2.5 moles) of tert-butylamine in 100 ml of tetrahydrofuran. The mixture is stirred for 1 hour at room temperature and for 20 minutes at a bath temperature of 70 ° C. The tert-butylamine-hydro chloride crystals formed are filtered off and washed with ether. The collected filtrate is evaporated and the residue is taken up by ether. After washing with 2n hydrochloric acid and water the residue is dried over sodium sulfate and then evaporated again. Recrystallization of the resulting impure product in cyclohexane yields 182 g (78% of theory) of N-tert-butyl-5-methyl-thiophene-2-sulfonamide. Melting Point: 89 ℃

117 g (0.5 mole) N-tert-butyl-5-methyl-thiophene-2-sulfonamide is dissolved in 1 L of dried tetrahydrofuran and cooled to -40 ° C. Under a nitrogen atmosphere, 640 ml of a 15% solution of n-butyl-lithium dissolved in hexane (1.05 mol) is added dropwise to the solution at a temperature below -40 ° C. After the addition, the mixture was stirred at -20 ° C, cooled to -60 ° C and carbon dioxide was introduced. After vigorous exothermic reaction at -50 ℃, add carbon dioxide for 10 minutes. The mixture is heated to −10 ° C., carefully acidified with concentrated hydrochloric acid (about 110 ml) and evaporated to dryness. The residue is taken up in ether (about 3 l) and washed with water (about 2.5 l).

114 g (82% of theory) of 5-ethyl-2- (N-tert-jutyl) -sulfamoyl-thiophene-3-carboxylic acid after recrystallization of the impure product with benzene after drying and evaporating the ether phase. Melting Point: 178 ℃

IR (CH ₂ Cl ₂ ): 1730 and 1690 cm ^-1 (CO), 1335 and 1160 (SO ₂ ): 1 H-NMR (CDCl ₃ + CD ₃ OD): δ = 7.2 (d, 1, J = 0.5 Hz, 3-H), 2.52 (d, 3, J = 0.5, CH ₃ ), 1.26 (S, 9, C (CH ₃ ) ₃ , 1 exchangeable proton.

C ₁₀ H ₁₅ NO ₄ S ₂ (277.37)

Calculation: C43.30 H5.45 N5.05 S23.12

Found: 43.50 5.48 4.92 22.82

5.2 Reaction of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid with polyphosphoric acid

0.5 g (2.26 mmol) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid was reacted in a similar manner to Example 5.1 to 0.44 g (96% of theory) of 5-methyl-thieno [3, 2-d] isothiazolo-3 (2H) -one-1,1-dioxide is obtained. Melting Point: 231 ° C (in Methanol)

C ₆ H ₅ NO ₃ S ₂ (203.23)

Calculation: C35.46 H2.48 N6.89 S31.55

Found: 35.50 2.50 6.78 31.48

Starting materials are prepared as follows.

A mixture of 5.0 g (18 mmol) of 2- (N-tert-butyl) -sulfamoyl-5-methyl-diophen-3-carboxylic acid and 20 ml of 0-dichlorobenzene is heated with stirring at 140 ° C. The reaction mixture is cooled and then partitioned into dilute aqueous solution of ether and the same amount of sodium hydroxide. After separation of the ether phase the aqueous portion is acidified with hydrochloric acid and the precipitated material is suction filtered. The residue was recrystallized from ethyl acetate / cyclohexane to give 3.3 g (83% of theory) 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid. Melting Point: 198 ℃

C ₆ H ₉ NO ₄ S ₂ (221.26)

Calculation: C32.57 H3.19 N6.33 S28.98

Found: 32.89 3.30 6.34 28.90

5.3 Reaction of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid with phosphorus pentachloride

A mixture of 0.5 g (2.26 mmol) of 5-ethyl-2-sulfamoyl-thiophene-3-carboxylic acid and 0.5 g (2.2 mmol) of phosphorus pentachloride in 3 ml of dehydrated toluene was refluxed for 9 hours. The mixture was reacted in a similar manner to Example 1 to 0.41 g (89% of theory) of 5-methyl-thieno [3,2-d] isothiazolo-3- (2H) -one-1,1 -Dioxide is obtained. Melting Point: 231 ° C (in Methanol)

5.4 Method of heating 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid in the presence of a catalytic amount of toluene sulfonic acid

0.1 g (0.45 mmol) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid is dissolved in 50 ml of dehydrated toluene in the presence of 5 mg of P-toluene sulfonic acid and heated in a water separation funnel for 10 hours. Evaporate to dryness in vacuo and separate by column chromatography.

0.40 mg (49% of theory) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide is obtained. Melting Point: 231 ° C (in Methanol)

5.5 from 2-tert-butyl-5-methyl-thieno [3,2-d] isothiadiazolo-3 (2H) -one-1,1-dioxide

0.2 g (0.77 mmol) N-tert-butyl-5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide and 0-dichlorobenzene Reflux for 8 hours. After cooling, the reaction mixture is partitioned between an aqueous solution of ether and sodium bicarbonate. The separated aqueous solution is acidified and extracted with methylene chloride. Evaporation and recrystallization in methanol yielded 0.13 g (83% of theory) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide. Melting Point: 231 ℃

C ₆ H ₅ NO ₃ S ₂ (203.23)

Calculation: C35.46 H2.48 N6.89 S31.55

Found: 35.50 2.50 6.78 31.48

Starting materials are prepared as follows.

A mixture of 3.0 g (10.8 mmol) of 2- (N-tert-butyl) -sulfamoyl-5-methyl-thiophene-3-carboxylic acid and 2.25 g (10.8 mmol) of phosphorus pentachloride in 60 ml of toluene Reflux for 7 hours. The reaction mixture is filtered hot, cooled and 300 ml of ether is added. The mixture is washed with sodium bicarbonate solution and water, dried and evaporated. The residue was recrystallized from cyclohexane to 1.5 g (54% of theory) of 2-tert-butyl-5-methyl-taeno [3,2-d] isothiazolo-3 (2H) -one-1 , 1-dioxide is obtained. Melting Point: 80 ~ 81 ℃

C ₁₀ H ₁₃ N ₃ S ₂ (259.35)

Calculation: C46.31 H5.05 N5.40 S24.73

Found: 46.39 5.15 5.44 24.45

5.6 from 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid-ethylester

2.4 g (10.2 mmol) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid-methylester are added to a solution in which 0.24 g (0.2 mmol) of sodium is dissolved in 50 ml of dehydrated methanol. It was refluxed for 4 hours and then evaporated to dryness in vacuo.

Most of the residue is dissolved in ethanol, and after suction filtration, ether of the filtrate is added. 2.1 g (91% of theory) of 5methyl-dieno [3,2-d] is obtained in the crystal phase of a sothiazolo-3 (2H) -one-1,1-dioxide sodium salt.

Melting Point: 325 ℃ (Decomposition)

C ₆ H ₄ NNaO ₃ S ₂ (225.22)

Calculation: C32.00 H1.79 N6.22 S28.47

Found: 32.00 1.91 6.13 28.50

When dissolved in water and acidified with hydrochloric acid, this crystal is converted to 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide. Melting Point: 231 ℃

Starting materials are prepared as follows.

A mixture of 3.0 g (13 mmol) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid and 150 ml methanolic hydrochloric acid is stirred for 2 hours at room temperature. The reaction mixture is evaporated and dissolved in ether. Washed with a diluted solution of sodium bicarbonate and water, evaporated and dried in vacuo and recrystallized from methanol / water to give 2.9 g (95% of theory) of 5-methyl-2-sulfamoyl-thiophene-3-carboxylic acid methyl ester. do. Melting Point: 137 ~ 138 ℃

C ₇ H ₉ NO ₄ S ₂ (235.29)

Calculation: C35.73 H3.86 N5.95 S27.25

Found: 36.20 4.00 5.95 27.50

Example 6

Salt of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

6.1 5-Methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide sodium salt

20.3 g (0.1 mole) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1 in a solution of 4.0 g (0.1 mole) of sodium hydroxide dissolved in 50 ml of water 1-dioxide is added to a solution dissolved in 500 ml of ethanol. The mixture is evaporated to dryness and recrystallized from ethanol / ether. 17.5 g (78% of theory) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide sodium salt are obtained. Melting Point: 325 ℃ (Decomposition)

IR (KBr): 1630cm ^-1 (CO)

C ₆ H ₄ NaO ₃ S ₂ (225.22)

Calculation: C32.00 H1.79 N6.22 S28.47

Found: 32.20 1.88 6.01 28.15

6.2 5-Methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide calcium salt

500 ml of methanol is added to 0.49 g (12.3 mmol) of calcium and refluxed to react. 5.0 g (24.6 mmol) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide are added to the resulting suspension. The resulting solution is evaporated and the residue is recrystallized from a small amount of ethanol / ether. 3.9 g (71% of theory) of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide-calcium salt are obtained.

Melting Point: 306 ~ 308 ℃ (Decomposition)

C ₁₂ H ₈ CaN ₂ O ₆ S ₄ (444.55)

Calculated Value: C32.42 H1.81 N6.31 S28.85

Found: 32.55 2.05 6.12 28.88

6.3 5-Methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide-ammonium salt

Obtained in a yield of 81% of theory from 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide and aqueous ammonia in a similar manner as in Example 2.1 do.

Melting Point: 224 ° C (with Ethanol / Ether)

C ₆ H ₈ N ₂ O ₃ S ₂ (220.28)

Calculation: C32.72 H3.66 N12.72 S29.11

Found: 32.90 3.46 12.62 29.20

6.4 5-Methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide potassium salt

84% yield of theory from aqueous solution of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide and potassium hydroxide in a similar manner to Example 2.1 Obtained as

Melting Point: 297 ° C (with Ethanol / Ether)

C ₈ H ₄ KNO ₃ S ₂ (241.34)

Calculation: C29.86 H1.67 N5.80 S26.57

Found: 29.81 1.74 5.94 26.35

Example 7

5-ethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

42.0 g (0.144 mol) of 5-ethyl-2 (N-tert-butyl) -sulfamoyl-thiophene-3-carboxylic acid is added to 150 ml of polyvalent phosphoric acid and heated to 80 ° C. for 20 minutes. The reaction mixture is poured onto ice and the precipitated impure product is filtered off. The filtrate is washed with water and dried. Recrystallization from benzene and ethyl acetate yields 15.9 g (51% of theory) of 5-ethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide.

Melting Point: 143 ℃

IR (CH ₂ Cl ₂ ): 3350 (NH), 1740 (CO) 1340 and 1150 cm ^-1 (SO ₂ )

C ₇ H ₇ NO ₃ S ₂ (217.27)

Calculation: C38.70 H3.25 N6.45 S29.52

Found: 38.50 3.24 6.33 29.80

Starting materials are prepared as follows.

222 g (1.07 mole) of phosphorus pentachloride is added gradually to 310 g (2.7 mole) of sulfonic chloride with stirring and cooling. When generation of hydrogen chloride ceased, 100 g (0.89 moles) of 2-ethyl-thiophene was added dropwise with stirring at 20 ° C. After the addition, the reaction mixture is poured into ice and extracted with ether. The ether solution is washed to neutrality and evaporated to dryness. The residue is absorbed into tetrahydrofuran and added dropwise to a solution of 169 g of tert-butylamine dissolved in 200 ml of tetrahydrofuran. After refluxing for 3 hours, the reaction mixture was filtered to precipitate the precipitated tert-butylamine hydrochloride and dried in vacuo. The residue is taken up in ether, washed with dilute hydrochloric acid and water and evaporated to dryness. 147 g of impure product was obtained, which was purified by silica gel column chromatography (4 kg of silica gel 40 for column chromatography, particle size: 0.2 to 0.5 mm: eluent: cyclohexane / acetate 4: 1). Amount of 53%) of 5-ethyl-N-tert-butyl-thiophene-2-sulfonamide.

Melting Point: 38 ℃

C ₁₀ H ₁₇ NO ₂ S ₂ (247.39)

Calculation: C48.55 H6.93 N5.66 S25.92

Found: 48.20 6.86 5.72 25.60

56.8 g (0.23 mole) of 5-ethylene-N-tert-butyl-thiophene-2-sulfonamide is dissolved in 500 ml of dry tetrahydrofuran and cooled to -20 ° C. 310 ml of a 15% solution of n-butyllithium (0.5 mol) in hexane is added dropwise at this temperature. After stirring for 2 hours, the reaction mixture was poured into solid taso dioxide, evaporated and partitioned into water and ether. The aqueous phase is acidified and washed with ether. The ether extract is evaporated and recrystallized in cyclohexane / petroleum ether. 42 g (63% of theory) of 5-ethyl-2- (N-tert-butyl) -sulfamoyl-thiophene-3-carboxylic acid are obtained.

Melting Point: 135 ℃

C ₁₁ H ₁₇ NO ₄ S ₂ (291.40)

Calculation: C45.34 H5.88 N4.81 S22.01

Found: 45.40 5.91 4.90 22.00

Example 8

5-ethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide sodium salt

10.5 g (48 mmol) of 5-ethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide is dissolved in ethanol. This solution is adjusted to pH 7 with sodium hydroxide solution. 6.6 g (57.5% of theory) of 5-ethyl-thieno [3,2-d] -isothiazolo-3 (2H) -one-1,1- when recrystallized from tetrahydrofuran after evaporation in vacuo Dioxide sodium salt is obtained.

Melting Point: 273 ~ 275 ℃ (Decomposition)

C ₇ H ₆ NNaO ₃ S ₂ (239.26)

Calculation: C35.14 H2.53 N5.86 S26.80

Found: 34.90 2.67 5.69 26.70

Example 9

4,5-dimethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

20.0 g (68.6 mmol) of 2- (N-tert-butyl) -sulfamoyl-4,5-dimethyl-thiophene-3-carboxylic acid are added to 100 ml of polyvalent phosphoric acid and heated to 80 ° C. for 1 hour. The reaction mixture is then poured on ice and the resulting crystals (14 g) filtered off, dried and recrystallized twice from benzene. 12.5 g (84% of theory) of 4,5-dimethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide is obtained.

Melting Point: 187 ℃

IR (CH ₂ Cl ₂ ): 3350 (NH), 1730/1720 (CO), 1340 and 1175 cm ^-1 (SO ₂ )

1 H-NMR (CDCl ₃ ): δ = 7.5 (1, NH, exchangeable), 2.5 (3, S, 5-CH ₂ ), 2.35 (3, S, 4-CH ₃ )

C ₇ H ₇ NO ₃ S ₂ (217.27)

Calculation: C38.70 H3.25 N6.45 S29.52

Found: 38.50 3.21 6.39 29.35

Starting materials are prepared as follows:

2-ethyl-thiophene (see starting material in Example 7) was reacted with 4,5-dimethyl-thiophene-2-sulfonic acid chloride with sulfonic acid chloride / phosphorus pentachloride followed by tert-butylamine In a similar manner to 22.0 g (0.196 mole) of 2,3-dimethylthiophene is converted to 25.0 g of N-tert-butyl-4,5-dimethyl-thiophene-2-sulfonamide.

Yield: 51.5% of theoretical amount

Melting Point: 102 ℃ (with Petroleum Ether)

1 H-NMR (CDCl ₃ ): δ = 7.35 (S, 1,3-H), 4.8 (S, 1, NH, exchangeable), 2.45 (S, 3,5-CH ₃ ), 2.2 (S, 3 , 4-CH ₃ ), 1.35 (S, 9 (CH ₃ ) ₃ )

C ₁₀ H ₁₇ NO ₂ S ₂ (247.39)

Calculation: C48.55 H6.39 N5.66 S25.92

Found: 48.40 6.97 5.66 25.70

When n-butyllithium and tetrahydrofuran are reacted at -60 ° C to -20 ° C and carbon dioxide is reacted at -60 ° C to -20 ° C, 26.3g (90% of theory) of 2- (N-3 class- Butyl) -sulfamoyl-4,5-dimethyl-thiophene-3-carboxylic acid (manufacturing method is similar) is obtained.

Melting Point: 193 ~ 194 ℃ (in benzene)

IR (kBr): 3230 (NH and OH), 1725 and 1710 (CO), 1310 and 1130 cm ^-1 (SO ₂ ).

1 H-NMR (CDCl ₃ + CD ₃ OH): δ = 2.4 (S, 3,5-CH ₃ ), 2.28 (S, 3,4-CH ₃ ) 1.3 (S, 9, (ClCH ₃ ) ₃ ), And two exchangeable protons.

Example 10

Salts of 4,5-dimethyl-dieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

10. 1 4, 5-Dimethyl-pieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide sodium salt

50 ml of 1.16 g (13.8 mmol) sodium bicarbonate in 3.0 g (13.8 mmol) of 4,5-dimethyl-dieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide Dissolve in aqueous solution dissolved in water. This solution is evaporated in vacuo and recrystallized in ethanol. 2.5 g (76% of theory) of 4,5-dimethyl-dieno [3,2-d] isothiazolo-3 (H) -one-1,1-dioxide-sodium salt are obtained.

Melting Point: 250 ℃ or higher (decomposition)

C ₇ H ₆ NNaO ₃ S ₂ (239.26)

Calculation: C35.14 H2.59 N5.85 S26.80

Found: 35.40 2.70 5.88 26.90

10.2 4,5-dimethyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide-calcium salt

50 ml of boiling water containing 37 mg (0.5 mmol) of calcium hydroxide and 217 mg (1 mmol) of 4,5-dimethyl-thieno [3,2-p] isothiazolo-3 (2H) -one-1,1-dioxide Add to The nearly clear solution is filtered and evaporated to 1 ml. 180 mg (76% of theory) of 4,5-dimethyl-thieno [3,2-d] -isothiazolo-3 (2H) -one-1,1-dioxide calcium salt are obtained as crystals.

Melting Point: 320 ℃ (Decomposition)

C ₁₄ H ₁₂ N ₂ O ₆ S ₄ Ca (472.26)

Calculation: C35.58 H2.56 N5.93 S27.14

Found: 35.30 2.71 5.74 26.84

Example 11

4-ethyl-5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

3.05 g (10 mmol) of 4-ethyl-5-methyl-2- (N-tert-butyl) -sulfamoyl-thiophene-4-carboxylic acid is heated to 65 ° C. for 30 minutes with 20 ml polyhydric acid. . This reaction mixture is then poured on ice. The precipitated resultant crystals are filtered off, washed with ice water and rolled. 2.1 g (91% of theory) of 4-ethyl-5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide are obtained.

Rf value: 0.19 (TLC-prefabricated plate, silica gel 60F, thickness of 254 layers 0.25 mm; eluent ethylene chloride / ethyl acetate / glacial acetic acid 100: 30: 5)

C ₈ H ₉ NO ₃ S ₂ (231.29)

Calculation: C41.54 H3.92 N6.06 S27.73

Found: 41.35 3.90 6.14 27.62

Starting materials are prepared as follows.

Similar to reacting 2-methyl-thiophene (see Example 5) with phosphorus pentachloride and sulfonic acid chloride, 3-ethyl-2-methyl-thiophene (W. Steinkopf, A. Mercckoll and H Strauch, Liebigs Ann. chem 545,45 (1940) is reacted and the resulting sulfochloride is treated with tert-butylamine, metalized with n-butyllithium and carboxylated with carbon dioxide to 4-ethyl-5-methyl-2- (N -Tert-butyl) -sulfamoyl-thiophene-3-carboxylic acid is obtained by a method analogous to the shape of 5-methyl-2- (N-tert-butyl) -sulfamoyl thiophene-3-carboxylic acid.

Rf value: 0.27 (TLC-prefabricated plate, silica gel 60 F 254, layer thickness 0.25 mm, eluent: ethylene chloride / ethyl acetate / glacial acetic acid 100: 30: 5)

C ₁₂ H ₁₉ NO ₄ S ₂ (305.42)

Calculation: C47.19 H6.27 N4.59 S21.00

Found: 46.95 6.31 4.52 20.92

The compounds of formula (I) or salts thereof may be combined with the pharmaceutical composition by conventional methods into tablets, powders or solutions. The following example illustrates this.

Example I

Sweetener solution containing 20 mg of sodium salt of 5methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide in 1 ml

The following foam is dissolved in 100 ml of distilled water continuously at 60 ° C.

1 ml (about 25 drops) of a solution containing 20 mg of the sweetener has a taste corresponding to about two flavors of sugar cubes.

Example II

Sweetener tablets containing 5 mg of 4,5-diethyl-dimeno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

Composition components of the tablets:

The sweetener is mixed with sodium bicarbonate and sorbet and extruded in humid air up to 60% humidity to form tablets. One tablet has the corresponding sweetness of one sugar cube.

Example III

Tablet for sweetener containing 10 mg of calcium salt of 5-methyl-thieno [3,2-d] isothiazolo-3 (2H) -one-1,1-dioxide

Final component of the tablet:

10 mg of calcium salt

Sorbite 40mg

The tablet is extruded by mixing the sweetener with sorbet. One tablet has the sweetness equivalent to one sugar cube.

Claims (1)

To prepare a concentrated isothiazolo-3 (2H) -one-1,1-dioxide and a salt thereof of the following formula (I), characterized by ring closure of the 2-sulfamoyl-3-carboxylic acid derivative of formula (II) How to

In the above structural formula X is oxygen or sulfur atom R ₁ is a hydrogen atom or a methyl or ethyl group R ₂ represents methyl or ethyl group,

In the above structural formula X, R ₁ and R ₂ are the same as in the above structural formula R ₃ is hydrogen or a 4 to 19 tert-alkyl group, R ₄ represents a hydroxy group, an alkoxy group having 1 to 10 carbon atoms, an aryloxy group having an aryl moiety or a phenyl or naphthyl group, a phenylalkoxy group having 1 to 3 carbon atoms or a halogen atom at the alkylene moiety.