KR840002006B1 - Process for preparing 5-sulfamoyl-othanilic acids - Google Patents

Abstract

5-Sulfamoylorthanilic acids and their salts I [R = Cl, Br, Me, PhO or PhS (un)substituted with halo, alkyl, alkoxy, or CF3; Ar = furyl, thienyl , useful as diuretics, were prepd. Thus, 1,3-Cl2C6H2(SO2Cl)- 4,6 was treated with p-cresol in THF, NEt3, and NH3(g), the product 2,4,5-Cl2(H2NO2S)C6H2SO3C6H4Me-4 was esterified with PhOH, and the resulting 2,4,5-Cl(PhO)(N2NO2S)C6H2SO3H4Me -4 was treated with furfurylamine. This product (20% yield) I (R = PhO, Ar1 = 2-furyl) was sapond. with 2 N NaOH to give 75% I (R = PhO, R1 = 2-furyl).

Description

Method for preparing 5-sulfamoyl-ortanylic acid

The present invention relates to a 5-sulfamoyl-ortanyl acid compound of formula (I) and a physiologically acceptable salt thereof useful as a salt excretion agent.

In the above formula

R is alkyl, alkenyl, cycloalkyl or cycloalkylalkyl or phenyl, each having up to 10 carbon atoms; Ar is phenyl, thienyl or furyl.

If R is alkyl or alkenyl it may be straight or branched. The alkyl or alkylene preferably has 4 to 6 carbon atoms.

When R is a cyclic group, a 5-8 membered ring is preferable. Thus R can in particular be cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, n-butyl, isobutyl, n-pentyl or -nhexyl.

As Ar, 2-furyl and 2-thienyl are most preferable.

All physiologically acceptable cations, especially alkali or alkaline earth metal ions,

General formula (I) compound of this invention is manufactured by the following method; In other words

a) saponifying the ester of the following general formula (II) under alkaline conditions;

b) reacting a compound of formula (III) or a salt thereof with an amine of formula (IV)

c) The compounds of formula (I) and salts thereof can be prepared by oxidizing the following compounds of formula (V) or salts thereof to obtain sulfones and optionally converting the resulting compounds into free acids or salts.

In the above formula

R and Ar are as described above, X is halogen,

Z is aryl and Y is -S- or-SO-.

In reaction a), aromatic groups are generally suitable as group Z in the general formula (II) compound as starting material, but for industrial synthesis, it is particularly advantageous to use phenyl or cresyl esters which are easy to prepare.

The alkaline saponification reaction of the ester is preferably carried out in an aqueous medium using an inorganic base, in particular an excess of 1N to 5N sodium hydroxide or potassium hydroxide solution.

For example, phenyl or cresyl esters can be fully saponified over 1 hour in a steam bath using 2N aqueous sodium or potassium hydroxide solution. The saponification solution is neutralized at room temperature with an inorganic acid (preferably a saline) or an organic acid (eg acetic acid) and the final product immediately crystallizes out from the saponified solution in the form of sodium or potassium salts respectively. In general, potassium salts are less soluble in water than the corresponding sodium salts. The phenol liberated in the saponification reaction is precipitated with the reaction product in some cases, especially when cresyl, xylyl, nitrophenyl, chlorophenyl or napryl esters are used as starting materials instead of phenyl esters.

Residues of these phenols can be removed by washing the precipitate thoroughly with an organic solvent. For this purpose, solvents in which the product hardly dissolves are used, for example ethanol, isopropanol, diethyl ether, diisopropyl ether, acetone or tetra hydrofuran. Trace amounts of phenol that may remain after solvent washing can be removed by recrystallization of the product with aqueous alcohol.

Starting materials of the general formula (II) include the following 2,4-dicholo-5-sulfamoyl-benzenesulfonic acid aryl esters of the following formula (VI) as described in JP 2,718,871.

In reaction b), it is preferable to use the alkyl metal salt of the compound whose X is fluorine or chlorine as a starting material of general formula (III). The reaction with the amine of general formula (IV) is advantageously carried out at 80 ° to 100 ° C. when X is fluorine and at 120 ° to 140 ° C. when X is chlorine. To bind the formed hydrogen halide, an acid binder such as sodium carbonate, potassium carbonate or tertiary amine may be added to the reaction vessel. As the acid binder, it is particularly advantageous to use the base itself of the general formula (IV) in an excess of 2-mol to 3-mol. Solvents used in this reaction are particularly strong polar and water-miscible organic solvents such as dimethylsulfoxide or dimethylformamide.

After the reaction is complete, it is advantageous to distill off the solvent and excess amine to completely remove it.

Starting materials of the general formula (III) can be obtained by a simple method by oxidizing the compound of the general formula (VII) with H ₂ O ₂ or organic peracid and then alkaline saponification.

In reaction c), thioethers or sulfoxides of general formula (V) are oxidized to give the corresponding sulfones. If Ar is phenyl or thienyl, this oxidation reaction is advantageously carried out at 20 to 60 ° C. with perhydrool in glacial acetic acid or with peracetic acid / glacial acetic acid. Compounds of formula (V) wherein Ar is furyl are advantageously oxidized at room temperature using theoretical amounts of peracids in dilute solutions. Examples of suitable solvents for this reaction include mixtures of methylene chloride and dimethylformamide and examples of suitable oxidants are 3-chloroperbenzoic acid. It is advantageous to liberate the final product by removing the solvent after recrystallization with 1NKHCO ₃ or 1N NaHCO ₃ aqueous solution.

Starting materials of general formula (V) may be obtained by saponifying or oxidizing sulfonic acid aryl esters of general formula (VIII) to obtain sulfoxides followed by saponification thereof.

The compounds according to the invention are colorless, stable substances which readily crystallize when in the form of alkali metal, alkaline earth metal or ammonium salts. They do not dissolve particularly well in water at room temperature. These compounds can thus be particularly well recrystallized from water or water containing organic solvents such as alcohols, acetone, dioxane, tetrahydrofuran, or dimethylformamide. Of these metal salts, sodium salts dissolve best in water. They can thus be converted particularly easily to metal salts by double decomposition in aqueous solution with suitable water soluble salts.

Salts containing hydroxyamines (eg mono-, di-, tri-ethanolamine) or glucoseamines are much more soluble in water than sodium salts.

The compound may be liberated in the form of freesulfonic acid. Freesulfonic acid can be liberated by treating sodium salts with 5N HCl. However, free acids are not stable, especially when Ar is furyl.

Free acid is therefore less suitable for treatment. Meanwhile sodium and potassium salts are particularly suitable for the preparation of medicaments. Salts containing basic potassium-containing compounds (e.g. amylolide or trialterene), or basic antihypertensive agents (e.g. clonidine, dihydralazine or guanetidine) or β-blockers (e.g. propranolol, Salts containing timolol, fenbutolol or pindolol) are also of particular pharmaceutical importance.

The compounds of the present invention show excellent efficacy as salt excretion agents in the form of furosevid diuretics. Compared with known compounds of this type, the compounds of the present invention are particularly characterized in that they have a low removal rate of calcium and are clearly effective uric acid excretion agents.

The compound of the present invention is particularly suitable for human treatment, especially orally administered in the form of tablets, dragees or capsules containing 0.1 to 50 mg of active ingredient, and also administered intravenously using an aqueous solution for injection containing 0.1 to 10 mg of active ingredient. You may.

Example 1

Sodium N- (2-furylmethyl) -4-chlorohexylsulfonyl-5-sulfamoyl-ortanylate

55.5 g (0.1 mole) N- (2-furylmethyl) -4-cyclohexylsulfonyl-5-sulfamoyl-o

Yield: 44 g (88% of theory)

Melting Point: 300 ℃ (Decomposition)

Example 2

Potassium N- (2-furylmethyl) -4-cyclohexylsulfonyl-5-sulfamoyl-orlanylate

48.5 g (0.1 mole) of potassium N- (2-furylmethyl) -4-cyclohexyl mercapto- dissolved in 90 g of 3-chloroperbenzoic acid 42 g (0.22 mole) dissolved in 1.0 L of dimethylformamide at room temperature with stirring. 5-Sulfamoyl-ortanylate (melting point: 227 ° C. (decomposition), recrystallized from water) was added to the solution little by little. After standing at room temperature overnight, dimethylformamide was removed under vacuum, 1.0 L of water was added to the residue, and then 2N KOH was added to adjust the pH to 8. After standing at 15 ° C. for 1 hour, the intermediate product isolated in crystalline form was filtered, recrystallized with water, and purified by adding activated carbon.

Yield: 41 g (79% of theory)

Melting Point: 305 ℃ (Decomposition)

Example 3

Sodium N- (2-thienylmethyl) -4-cyclohexylsulfonyl-5-sulfamoyl-ortanyl

57.1 g (0.1 mole) of N- (2-thienylmethyl) -4-cyclohexylsulfonyl-5-sulfamoyl-ortanylic acid phenylester (melting point: 193 ° C) was converted to 2N NaOH in a similar manner as in Example 1. After saponification, the final product is liberated as in Example 1.

Yield: 48.5 g (84% of theory)

Melting Point: 310 ℃ (Decomposition)

Example 4

Sodium N-benzyl-4-cyclohexylsulfonyl-5-sulfamoyl-ortanylate

56.4 g (0.1 mol) of N-benzyl-4-cyclohexyl-sulfonyl-5-sulfamoyl-ortanylic acid phenylester was purified with 0.4 L of 2N NaOH in a similar manner to Example 1 and the final product was 30% Recrystallize from ethanol.

Yield: 43 g (84% of theory)

Melting Point: 296 ° C (Decomposition)

Example 5

Potassium N- (2-furylmethyl) -4-phenylsulfonyl-5-sulfamoyl-ortanylate

45.0 g (0.1 mole) of potassium 2-chloro-4-phenylsulfonyl-5-sulfamoyl benzenesulfonate at 125-130 ° C. with a mixture of 0.1 L of furfuryl amine and 0.1 L of dimethyl sulfoxide Stir for 2 hours. Excess furfurylamine and dimethyl sulfoxide are distilled under vacuum, 0.1 L of water is added to the residue, and 5N HCl is added to adjust the pH of the mixture to 7. After standing at room temperature for 1 hour, the final product precipitated in crystalline form was filtered and recrystallized with water.

Yield: 35 g (70% of theory)

Melting Point: 270 ° C (Decomposition)

Example 6

Sodium N- (2-furylmethyl) -4-cycloheptylsulfonyl-5-sulfamoyl-ortanylate

56.0 g (0.1 mol) of N- (2-furylmethyl) -4-cycloheptylsulfonyl-5-sulfamoyl-ortanylic acid phenyl ester (melting point: 163 DEG C, recrystallized from methanol) was prepared in a similar manner to Example 1. It is saponified with sodium hydroxide solution and the final product is liberated as in Example 1.

Yield: 44 g (86% of theory)

Melting Point: 284 ℃ (Decomposition)

Example 7

Potassium N- (2-furylmethyl) -4-n-butylsulfonyl-5-sulfamoyl-ortanylate

45.8 g (0.1 mol) of potassium N- (2-furylmethyl) -4-n-butylmercapto-5-sulfamoyl-ortanylate (melting point: recrystallized from 245 DEG C) was dissolved in 0.1 L of dimethyl sulfoxide. The solution was diluted with 0.3 L of methylene chloride, and then 48 g (0.25 mol) of 90% of 3-chloroperbenzoic acid was added with stirring at room temperature and left overnight at room temperature. The solvent is removed in vacuo and the residue is treated with 0.3 L of warm 1N KHNO ₃ to remove 3-chlorobenzoic acid and then purified and recrystallized from water with the final product remaining undissolved.

Yield: 24 g (49% of theory)

Melting Point: 330 ° C (Decomposition)

Example 8

0.1 mole of N- (2-furylmethyl) -4-n-propylsulfonyl-5-sulfamoyl-ortanylic acid phenyl ester (melting point: 145 DEG C, recrystallized from methanol) was saponified with NaOH in a similar manner to Example 1 And the final product is liberated in the same manner as in Example 1.

Yield: 35 g (76% of theory)

Melting Point: 320 ℃ (Decomposition)

Example 9

Sodium N- (furylmethyl) -4-cyclopentylsulfonyl-5-sulfamoyl-ortanylate

54.1 g (0.1 mol) of N- (2-furylmethyl-4-cyclopentylsulfonyl-5-sulfamoyl-ortanylic acid phenyl ester (melting point: 169 DEG C, recrystallized from methanol / dimethylformamide (1: 2)) The saponified final product is washed with water on a filter, washed with ethanol and then dried at 90 ° C. by adjusting the pH to 7 by adding HCl.

Yield: 40 g (82% of theory)

Melting Point: 285 ° C (Decomposition)

Example 10

Potassium N- (2-furylmethyl) -4-allylsulfonyl-5-sulfamoyl-ortanylate

51.3 g (0.1 mole) of N- (2-furylmethyl) -4-allyl mercapto-5-sulfamoyl-ortanyl acid ester (melting point: 138 ° C.) was stirred with 0.4 L of 2N KOH in a steam bath. Minute

The reaction solution was cooled to room temperature, neutralized with 5N HCl, and the mixture was evaporated. Dry and extract the residue with 0.1 L hot dimethylformamide and add 0.4 L diisopropyl ether to precipitate the final product in crystalline form from the filtrate solution.

Yield: 35 g (74% of theory)

Melting Point: 125 ℃ (Decomposition)

Example 11

Sodium N- (2-furylmethyl) -4-cyclohexylmethylsulfonyl-5-sulfamoyl-ortanylate

56.7 g (0.1 mol) of N- (2-furylmethyl) -4-cyclohexyl methylsulfonyl-5-sulfamoyl-ortanylic acid phenyl ester (melting point: 152 DEG C, recrystallized from methanol) with 0.4 L of 2N NaOH Stir together in a steam bath and warm for 45 minutes and liberate the final product in a similar manner to Example 1.

Yield: 46 g (90% of theory)

Melting Point: 350 ℃ (Decomposition)

Example 12

Sodium N- (2-furylmethyl) -4-methylsulfonyl-5-sulfamoyl-ortanylate

48.6 g (0.1 mole) of N- (2-furylmethyl) -4-methylsulfonyl-5-sulfamoyl-ortanyl acid phenyl ester (melting point: 175 ° C., recrystallized from methanol) was steamed with 0.4 L of 2N KOH Warm for 1 hour in the bath and liberate the final product in a similar manner to Example 1.

Yield: 36.5 g (81% of theory)

Melting Point: 225 ℃ (Decomposition)

Example 13

Sodium N- (2-thienylmethyl) -4-cyclopentylsulfonyl-5-sulfamoyl-ortanylate

55.7 g (0.1 mol) of N- (2-thienylmethyl) -4-cyclopentylsulfonyl-5-sulfamoyl-ortanylic acid phenyl ester (melting point: 194 DEG C, recrystallized from methanol) was mixed with 0.4 L of 2N NaOH. The mixture is heated for 1 hour in a steam bath to be saponified and liberated in the same manner as in Example 1.

Yield: 42.5 g (85% of theory)

Melting Point: 278 ℃ (Decomposition)

Example 14

Sodium N- (2-furylmethyl) -4-n-hexylsulfonyl-5-sulfamoyl-ortanylate

48.7 g (0.1 mol) of N- (2-furylmethyl) -4-n-hexylsulfonyl-5-sulfamoyl-ortanylic acid phenyl ester (melting point: 140 DEG C, recrystallized from methanol) was mixed with 0.4 L of 2N NaOH. The mixture was heated under reflux for 45 minutes and adjusted to pH 7 of the clear reaction solution by adding 5N HCl at room temperature. After 1 hour, the final product precipitated in crystalline form was filtered, washed with anhydrous ethanol and dried at 90 ° C.

Yield: 43 g (85% of theory)

Melting Point: 209 ℃ (Decomposition)

In addition to the above-mentioned compounds, the following compounds can also be obtained by a similar method:

Potassium N- (2-furylmethyl) -4-ethylsulfonyl-5-sulfamoyl-ortanylate, sodium N- (2-thiethylmethyl) -4-ethylsulfonyl-5-sulfamoyl-ortanylate Sodium N- (2-furylmethyl) -4-isopropylsulfonyl-5-sulfamoyl-ortanylate, sodium N- (2-thienylmethyl) -4-n-propylsulfonyl-5-sulfamoyl -Ortanylate, potassium N- (2-thienylmethyl) -4-n-butylsulfonyl-5-sulfamoyl-ortanylate, sodium N-benzyl-4-n-butylsulfonyl -5-sulfamoyl -Ortanylate, potassium N- (2-furylmethyl) -4-isobutylsulfonyl-5 -sulfamoyl-ortanylate, potassium N- (2-thienylmethyl) -4-isobutylsulfonyl-5 Sulfamoyl-ortanylate, sodium N- (2-thienylmethyl) -4-allylsulfonyl-5-sulfamoyl-ortanylate, potassium N- (2-furylmethyl) -4-n-pentylsul Ponyl-5-sulfamoyl-ortanylate, potassium N- (2-furylmethyl) -4-n-octylsulfonyl-5-sulfamoyl-ortanylate, potassium N- (2-furylmethyl) -4- Cyclo Lofilsulfonyl-5-sulfamoyl-ortanylate, sodium N- (2-furylmethyl) -4-cyclopropylsulfonyl-ortanylate, sodium N- (2-furylmethyl) -4-cyclobutylmethylsul Ponyl-5-sulfamoyl-ortanylate, potassium N- (2-furylmethyl) -4-cyclopentylmethylsulfonyl-5-sulfamoyl-ortanylate, sodium N- (3-furylmethyl) -4- Cyclohexylsulfonyl-5-sulfamoyl-ortanylate, sodium N- (2-thienylmethyl) -4-cycloheptylsulfonyl-5-sulfamoyl-ortanylate, potassium N- (2-furylmethyl) 4-cyclooctylsulfonyl-5-sulfamoyl-ortanylate, and sodium N- (2-furylmethyl) -5-cyclooctylmethylsulfonyl-5-sulfamoyl-ortanylate.

Claims (1)

Saponifying an ester of formula (II) under alkaline conditions, reacting a compound of formula (III) or a salt thereof with an amine of formula (IV), or oxidizing a compound of formula (V) or a salt thereof To prepare a compound of formula (I) and a physiologically acceptable salt thereof.

Wherein R is alkyl, alkenyl, cycloalkyl or cycloalkylalkyl or phenyl each having 10 or less carbon atoms, Ar is phenyl, thienyl or furyl, Z is aryl, X is halogen, and Y is -S- or- SO-.