KR800000746B1 - Process for the preparation of 5-sulfamoyl-anthranilic acids - Google Patents

Abstract

Title compds. (I, Ph = halogen, alkyl, etheified hydroxyl group-substituted phenyl; R = aralkyl, heteroaralky1, cycloalkyl-alkyl), useful as diuretics, were prepd. by reacting carboxylic acids(IV) with > 1 mole eq. wt. amines(V)at >120≰C. 2,4-Dichloro-5-sulfamoyl benzonitrile(II) was used as a starting material for IV.

Description

Method for preparing 5-sulfamoyl-anthranilic acid

The present invention reacts the carboxylic acid of the following general formula (IV) with at least 1 molar equivalent of the amine of the following general formula (V) at 120 ° C. or higher to prepare 5-sulfamoyl-anthranilic acid having the following general formula (I). It is about how to.

(In the formula (I), Ph represents a phenyl group substituted with one or two halogen atoms, an alkyl group or an ethylated hydroxyl group, R represents an aralkyl, heteroaralkyl or cycloalkyl-alkyl group and the aliphatic The moiety may be unsaturated or the aromatic moiety may contain oxygen or sulfur and may be substituted with halogen, alkyl or alkoxy groups.

Ph in the formula (IV) is as described above

R in the formula (V) is also as described above.)

Starting materials of formula (IV) can be prepared according to the following scheme.

(In the above formula, Ph is as described above and Me is an alkali metal.)

2,4-Dichloro-5-sulfamoyl benzonitrile of formula (II) used as starting material in the first step is described in Chemische Berichte Vol. First published in 99 (1966) p.350. The compound is reacted with 2,4-dichloro-5-sulfamoyl-benzophosphoric acid and thionyl chloride produced on an industrial scale in a simpler manner than that described in the above literature, and the resulting acid chloride is reacted with ammonia, The amide obtained is changed to nitrile by phosphorooxychloride.

The 2,4-dichloro-5-sulfamoyl-benzonitrile of formula (II) is then reacted with 2 equivalents of the alkali metal phenolate of formula Ph-O-Me at a temperature of 100 ° C to 150 ° C. It is preferable to carry out the reaction at a temperature of 110 to 140 ° C. using a kalium or natorium salt of phenol. Dimethylformamide, diethylformamide, dimethylsulfoxide, dimethylacetamide, tetramethylenesulfone, tetramethylurea, diethylene glycol dimethyl, in addition to 2 moles of the alkali metal phenolate necessary to keep the reaction mixture in the liquid state It is convenient to add acyclic aprotic solvents that are suitably miscible with water, such as ether or hexamethyl-phosphoric acid triamide.

Instead of the above solvent, a corresponding free phenol (Ph-OH) may be used as a solvent for the preparation of the compound of formula III by adding 2 molar equivalents of Ph-O-Me as a reactive component. However, this reaction is only beneficial if the phenol is sufficiently soluble in water or easily volatilized to vapor.

Alkali metal phenolates are solvents as described above in an instant mixture of 2 molar equivalents of alkali metal hydroxides (especially caustic soda) or 1 molar equivalent of alkali metal carbonates in a mixture of 2,4-dichloro-5-sulfamoyl benzonitrile and at least 2 equivalents of phenol. It can be prepared by adding in the presence of one of the solvents and slowly heating with stirring to reach the required reaction temperature. Instead of hydroxides or carbonates of alkali metals, other acid binders such as magnesium oxide, calcium oxide or triethylamine can also be generally used.

In addition to phenol, the following substituted phenols may be used as the reactive component of the general formula Ph-OH as described above: mono and dichlorophenol isomers, bromophenol isomers, mono and dimethylphenol isomers, ethylphenol isomers, mono and dimethoxyphenols. Isomers, mono and diethoxyphenol isomers, pinoxy and benzyloxyphenol isomers, chloromethoxyphenol isomers and chloromethyl and methoxymethyl phenol isomers.

The hot liquid phase reaction mixture is placed in water to complete the reaction, at which time the formed bisphenoxy derivative is usually precipitated as crystals. When poorly soluble phenol is used in water, it is always obtained by precipitation in amorphous form. In such a case, precipitation is easily separated by decanting the solution and treating with diethyl ether or dilute caustic soda solution.

Too much phenol can be separated by steam distillation.

The composition of formula (III) is easily purified by recrystallization from methanol, ethanol, isopropanol, nitromethane or a compound of ethyl acetate and petroleum ether.

The nitrile of formula (III) is then saponified to give the corresponding carboxylic acid of formula (IV).

The saponification reaction is conveniently carried out by heating an excess of caustic soda or caustic solution under reflux. The initial suspension can be brought to a clear solution between about 1 to 2 hours and then refluxed for about 30 minutes. When poorly soluble nitrile of formula (III) is used, the reaction time can be shortened by adding ethanol or dioxane. Acidification of the alkaline reaction solution and optionally filtration precipitates quantitatively the carboxylic acid of formula (IV). For purification, the precipitate is carefully washed with water and preferably recrystallized with a low molecular weight alcohol or dioxane such as ethanol or isopropanol. The yield obtained in this reaction step is at least 90% of the theoretical yield.

According to the reaction of the present invention, the carboxylic acid of formula (IV) is obtained by reacting at least one molar equivalent of an amine of the general formula R-NH ₂ , and the product of general formula (I) moves the phenoxy group to the ortho position relative to the carboxyl group. It can obtain at high rate by the method of substitution.

The reaction temperature required for the present reaction should be higher than 120 ° C., preferably 120 ° C. to 160 ° C., more preferably 130 ° C. to 150 ° C., at which point no significant side reactions occur on the other hand and the reaction is on the other side. This has the advantage of being completed in 2 to 4 hours.

The use of excess base without solvent results in a particularly good yield. In many cases, 3 to 4 molar equivalents of R-NH ₂ are sufficient to keep the reaction mixture in a liquid state. When using easily obtainable amine, it can be used up to 10 molar equivalent because the reaction product of Structural Formula (I) is difficult to dissolve in water-soluble acid and excess base can be separated by simple method. If the base to be used is difficult to obtain, it is beneficial to reduce the amount by adding an inert diluent that can be miscible with water such as glycoldiethyl ether or diethylene-glycoldimethyl ether instead of the excess base. It is also possible to add acid binders such as sodium hydroxide, potassium carbonate, pyridine or triethylamine or to use the carboxylic acid of formula (IV) as a salt of an alkali metal or an alkaline earth metal.

Reactive components of the general formula R-NH ₂ include, for example:

Furyl-methyl and furyl-ethylamine isomers, thienylmethyl and thienyl-ethylamine isomers, benzylamine, phenylethyl and phenylpropylamine isomers, mono and dichloro-benzylamine isomers, bromo-benzylamine isomers, mono and dimethyl -Benzylamine isomers, mono- and dimethoxy-benzylamine isomers, piperonylamine, chloromethyl, chloromethoxy- and methoxymethyl-benzylamine isomers, cinnamilamine, 2-phenoxy- and 2-phenyl- Thioethylamine, cyclo-pentyl- and cyclopentenyl-methylamine, cyclohexyl- and cyclo-hexenyl-methylamine, cycloheptyl and cyclooctyl-methylamine, tetrahydro-furyl and pyranyl-methyl amine and pyridyl Methylamine isomers.

To separate the final product of formula (I), the reaction mixture is optionally diluted with methanol, ethanol or acetone and then added to the aqueous hydrochloric acid solution. If R is unstable with acids such as furylmethyl or thienylmethyl groups, the reaction mixture is preferably added to a dilute acetic acid solution, then cooled to ice and hydrochloric acid to adjust the pH to 3. The final product of formula (I) is less soluble in acidic aqueous solution and precipitates in near quantitative yield. In this final reaction step, the crudely washed crude water is appropriately purified by recrystallization from a low molecular weight alcohol, nitromethane, dioxane, ethyl acetate, butyl acetate or a mixture of dimethylformamide and low molecular weight alcohol. The final yield is 70 to 90% of theory.

The final product, Structural Formula (I), is a compound with effective diuretic activity. Journal of Medicinal Chemistry Vol. 15, 79-83 (1971).

An advantage of the production process of the present invention is that it is much simpler and practically yields higher than the methods known in the literature. Known methods necessarily use expensive florobenzene derivatives to prepare starting materials.

The following table compares the yields of the compounds (Ia) to (Ic) compounds known in the literature with the yields of the process of the invention.

[table]

The smooth reaction achieved by the process of the invention is surprising. Although a reaction in which the phenoxy group bonded to the dinitrophenyl ring is nucleophilic substituted by piperidine and pyridine is known, a reaction in which a phenyl group is substituted by a nitrilo or sulfamoyl group is not known yet.

Next, examples of the present invention will be described.

Example 1

N- (2-Furylmethyl) -4-phenoxy-5-sulfamoyl-anthranilic acid

(a) 2,4-dichloro-5-sulfamoyl-benzamide

2.7 kg (10 mol) of 2,4-dichloro-5-sulfamoyl-benzoic acid are refluxed with 1.4 kg of thionyl chloride and 3.0 L of dioxane for 2 hours.

The reaction solution was then concentrated by vacuum distillation and the residue was added to 5 L of acetone and added to the solution of concentrated ammonia over 15 L over 30 minutes with stirring at room temperature. The reaction mixture was then concentrated in vacuo to half and 10 l of water added to precipitate the 2,4-dichloro-5-sulfamoylbenzamide as crystals. The product is dried by steam filtration by suction filtration and washing with water thoroughly. Yield 2.35 kg (87% of theory), Melting point 206-209 ° C

(b) 2,4-dichloro-5-sulfamoyl benzonitrile

1.35 kg (5 moles) of the above co-amide is rapidly heated to 90 to 100 ° C. while stirring with 2.0 L of phosphooxachloride. At this temperature, as the reaction takes place, the pre-suspended amide forms hydrochloric acid and turns into solution. After about 10 minutes the nitrile formed begins to crystallize out of the clear reaction solution. Stirring was continued for 15 minutes at 105 ° C, and then the hot reaction solution was added several times to 20 liters of water heated to 30 ° C in advance while stirring. The temperature is maintained between 30 and 35 ° while ice is added. After the addition was completed, the temperature was lowered to about 10 ° C., and 2,4-dichloro-5-sulfamoyl-benzonitrile precipitated with crystals was filtered by suction, washed with water to be neutral, and dried in a steam bath.

Yield: 1.15 kg (92% of theory), melting point 196-197 ° C

(c) 2,4-diphenoxy-5-sulfamoyl-benzonitrile

A mixture of 25 lg (1.0 mole) of 2,4-dichloro-5-sulfamoyl-benzonitrile, 400 ml of dimethylformamide, 200 g of phenol and 80 g of caustic soda is stirred at 130 ° C. for 30 minutes. The mixture is then cooled to about 90 ° C. When the viscosity decreases, salt precipitates and becomes turbid. At this time, it is put in 10 l of water. After standing at room temperature for 1 hour, the pale gray crystalline precipitate formed is suction filtered and washed several times with water. The still wet product after filtration is then recrystallized in isopropanol. The product is first dried in air and then dried in a steam bath until constant. The colorless crystals thus obtained still contain 1 molar equivalent of isopropanol.

Yield: 23 g (54% of theory), melting point 148 to 150 ° C

(d) 2,4-diphenoxy-5-sulfamoyl-benzoic acid

43 g (0.1 mol) of 2,4-diphenoxy-5-sulfamoyl-benzonitrile prepared in reaction (c) was heated with 0.8 L of 2N caustic soda for 2 hours in a steam bath. Next, 0.8 liter of 2N hydrochloric acid was added to the clear solution cooled to room temperature with vigorous stirring. After being left at room temperature for a while, the wet product obtained by suction filtration of the crystallized precipitate and washing several times with water is recrystallized with ethanol. The product dried in the steam bath still contains 1 molar equivalent of ethanol.

Yield: 39 g (90% of theory) Melting point: 213 to 214 ° C

(e) N- (2-furylmethyl) -4-phenoxy-5-sulfamoyl-anthranilic acid (final product)

43 g (1.0 mol) of 2,4-diphenoxy-5-sulfamoyl-benzoic acid prepared in Reaction (d) was stirred at 135 ° C with 90 ml of freshly distilled fulfurylamine for 4 hours under a stream of nitrogen. The slightly yellowish reaction solution cooled to about 80 ° C. is added to 1 L of 10% acetic acid with stirring, and then the pH of the mixture is adjusted to 3 with 5N hydrochloric acid. After being left at room temperature for a while, N- (2-furylmethyl) -4-phenoxy-5-sulfamoyl-anthranilic acid precipitated as crystals was washed with water, followed by ethanol and dried in a steam bath.

Yield: 31.6g (81% of theory), Decomposition point 236 ℃

The decomposition point after recrystallization with nitromethane is 241 ° C.

Example 2

N-benzyl-4-phenoxy-5-sulfamoyl-anthranilic acid

100 ml of benzylamine is used instead of 2-furylmethylamine.

Yield of crude product: 38g (97% of theory)

Melting Point: 237 ~ 239 ℃

Purified by recrystallization from ethanol

Yield: 34.4 g (86% of theory)

Melting Point: 244 ~ 246 ℃

Example 3

N- (2-thienylmethyl) -4-phenoxy-5-sulfamoyl-anthranilic acid

In place of 2-furylmethylamine, a mixture of 50 ml of 2-thienylmethylamine and 30 ml of diethylene glycol dimethyl ether was used, and the reaction temperature was 140 ° C. to proceed the reaction by the method of Example 1 (e).

The crude product is recrystallized from ethanol.

Yield: 30.6 g (74% of theory), Decomposition point: 231 ° C

Example 4

N- (3-Chlorobenzyl) -4-phenoxy-5-sulfamoyl-anthranilic acid

100 ml of 3-chlorobenzylamine was used instead of 2-flufurylamine, and the reaction product was reacted by the method (e) of Example 1 at 140 ° C and a reaction time of 5 hours, and the crude product precipitated as crystals was recrystallized twice with ethanol. .

Yield: 32.6 g (75% of theory), 256 deg.

Example 4

N- (4-Pyridyldimethyl) -4-phenoxy-5-sulfamoyl-anthranilic acid

100 ml of pyridylmethylamine is used instead of 2-flufurylamine and reacted by the method (e) of Example 1 within 4 hours. The yellow reaction solution was poured into 1 L of water to separate the precipitated by-products in the amorphous form. The pale yellow solution is acidified with dilute hydrochloric acid to pH 5.

The final product, initially precipitated in amorphous form, crystallizes upon standing at room temperature overnight. The precipitate is suction filtered and boiled in ethanol with little dissolution of the final product to obtain an incorporation of the byproduct.

Yield: 25.2 g of yellow crystals (63% of theory)

Decomposition Point: 254 ℃

Example 6

N- (2-methoxybenzyl) -4-phenoxy-5-sulfamoyl-anthranilic acid

43 g (0.1 mol) of 2,4-diphenoxy-5-sulfamoyl-benzoic acid prepared according to Example (c) was stirred with 80 ml of 2-methoxybenzylamine at 140 ° C. for 3.5 hours. The nearly colorless reaction solution cooled to about 80 ° C. is diluted with 150 ml of ethanol and the solution is added to 1.0 L of 1N hydrochloric acid at room temperature with stirring. The reaction product detected by the crystals was suction filtered, washed with water and then boiled with 0.3 L of ethanol for a while. At this point most of the crystals remain undissolved. After cooling to room temperature, suction filtration, washing with ethanol and finally drying in steam bath.

Yield 32.4 g (74% of theory), Decomposition point: 254 ° C

Example 7

N- (2-tetrahydrofurylmethyl) -4-phenoxy-5-sulfamoyl-anthranilic acid

The reaction was carried out by the method of Example 6 using 80 ml of 2-tetrahydrofurylethylamine instead of 2-methoxybenzylamine. Amorphous crude product is recrystallized from ethanol water.

Yield 31.0 g (79% of theory), Decomposition point 210-211 ° C

Example 8

N-cyclohexylmethyl-4-phenoxy-5-sulfamoyl-anthranilic acid

The reaction was reacted by the method of Example 6 using 100 ml of cyclohexylamine instead of 2-methoxybenzylamine. The crystallized crude product is recrystallized from ethanol.

Yield: 36.8 g (66% of theory), Decomposition point: 220 ° C

Example 9

N- (2-Furylmethyl) -4- (3-chlorophenoxy) -5-sulfamoyl-anthranilic acid

(a) 2,4-di (3-chlorophenoxy) -5-sulfamoyl-benzonitrile

This reaction is carried out by the method of Example 1 (c) using 260 g of 3-chlorophenol instead of phenol, and the reaction product initially precipitated with water in an amorphous state is water-isopropanol (about 10: 1). Add to the mixture and recrystallize.

The final purification is recrystallized from methanol.

Dry under pressure of 100 ° C. 2 toricelli.

Yield: 205 g (47% of theory), melting point 146 to 147 ° C

(b) 2,4-di- (3-chlorophenoxy) -5-sulfamoyl-benzoic acid

44 g (0.1 mol) of nitrile prepared in (a) are refluxed with 0.5 L of 2N caustic soda. After about 15 minutes a clear solution is obtained. Reflux is continued for 1 hour, cooled to room temperature and acidified with 5N hydrochloric acid. Soon carboxylic acid precipitates as crystals. The wet product washed with water is recrystallized from methanol.

Yield: 41 g (90% of theory) Melting Point: 202-204 캜

(c) final product

45.5 g (0.1 mol) of the carboxylic acid prepared in (b) are stirred with 100 ml of freshly distilled fulfurylamine for 4 hours at 140 ° C. under a nitrogen stream. The reaction solution cooled to 60 ° C. is diluted with 100 ml of ethanol and placed in 1 L of 1N hydrochloric acid and stirred. The crystallized precipitate is separated off, washed with water and recrystallized from ethanol. The crystals are dried at 100 ° C.

Yield: 32 g (76% of theory), Decomposition point: 240 ° C

Example 10

N- (2-Furylmethyl) -4- (4-methylphenoxy) -5-sulfamoyl-anthranilic acid

(a) 2,4-di (4-methylphenoxy) -5-sulfamoyl-benzonitrile

The reaction is carried out in the method of Example 1 (c) using 220 g of P-cresol instead of phenol. The crude product, initially precipitated in amorphous form, is recrystallized from methanol and dried at 100 ° C. under a pressure of 1 torr.

Yield: 185 g (47% of theory), Melting point: 155 to 156 ° C

(b) 2,4-di (4-methylphenoxy) -5-sulfamoyl-benzoic acid

39.5 g (0.1 mol) of the nitrile prepared in (a) were saponified with caustic soda solution as in Example 9 (b). The crude product is purified by recrystallization from methanol.

Yield: 34 g (82% of theory), melting point 238-239 ° C

(c) the final product

41.5 g (0.1 mol) of the carboxylic acid prepared in (b) are reacted with furfurylamine as in Example 9 (c) and the amorphous crude product is recrystallized from 50% ethanol and dried at 100 ° C.

Yield: 29 g (72% of theory), Decomposition point: 221 ° C

Example 11

N-benzylamino-4- (3-chlorophenoxy) -5-sulfamoyl-anthranilic acid

45.5 g (0.1 mol) of the carboxylic acid prepared in Example 9 (b) were reacted with 100 ml of benzylamine as in Example 9 (c), and the reaction product was purified by recrystallization with ethanol.

Yield: 38 g (88% of theory), Decomposition point: 246 to 247 ° C

Example 12

N- (2-Furylmethyl) -4- (4-methoxyphenoxy) -5-sulfamoyl-anthranilic acid

(a) 2,4-di (4-methoxyphenoxy) -5-sulfamoyl-benzonitrile

The reaction was reacted as in Example 1 (c) using 250 g of 4-hydroxy-anisole instead of phenol.

Yield: 190 g (44% of theory), melting point 164-166 deg.

(b) 2,4-di- (4-methoxyphenoxy) -5-sulfamoyl-benzoic acid

The nitrile prepared in (a) is saponified with 2N sodium hydroxide as in Example 9 (b). The melting point of the carboxylic acid after recrystallization with ethanol is 246 to 248 ° C.

(c) the final product

44.6 g of the carboxylic acid prepared in (b) are reacted with furfurylamine as in Example 9 (c). Recrystallize from ethanol and dry at 100 ° C.

Yield 34g (81% of theory) Decomposition: 216 ℃

Claims (1)

5-Sulfamoyl-anthranilinic acid having general formula (I) is prepared by reacting a carboxylic acid of general formula (IV) with at least 1 molar equivalent of an amine of the following general formula (V) at 120 ° C. or higher How to.

In the above structure, Ph represents a phenyl group which may have 1 to 2 halogen atoms, an alkyl group or an etherified hydroxyl group, and R represents an aralkyl, hetero aralkyl or cycloalkyl-alkyl whose aliphatic moiety may be unsaturated. Or the aromatic moiety may contain oxygen or sulfur or may be substituted with a halogen atom alkyl group or an alkoxy group.