KR800001133B1 - Process for preparing 5-sulfamoyl benzoic acid substituted by heterocyclic compound - Google Patents

Abstract

Title compds. (I; R1, R2 = H, C1-4 alkyl, alkoxymethyl, phenoxymethyl, phenylthiomethyl; R3 = H, C1-4 alkyl, C5-6 cycloalkyl, Ph, benzyl, benzhydryl, C3-5 alkanoyloxymethyl; x = halogen, CF3, CCl3, alkyl, alkoxy; A = single bond, substituted alkylene), useful diuretic, were prepd. from 3-substituted sulfamoyl benzoic acid derivs.(II, z = two H, one O) by redn. with HB complex in the presence of Lewis acid or various methods.

Description

Method for preparing 5-sulfamoylbenzoic acid derivative having a heterocyclic substituent

The present invention relates to a 5-sulfamoylbenzoic acid derivative having a heterocyclic substituent of the following formula (I) and a method for preparing a salt with a physiologically toxic base or acid.

In the above structural formula

R ¹ and R ² are the same or differently hydrogen or alkyl having 1 to 4 carbons, and when R ¹ is hydrogen, R ² is also alkoxymethyl, phenoxymethyl or phenylthiomethyl having 2 to 5 carbon atoms in the alkyl group,

R ³ is hydrogen, alkyl having 1 to 4 cycloalkyl having 5 to 6 carbon atoms (one of which carbon may be substituted by oxygen or sulfur), phenyl or benzyl (where phenyl nucleus is nitro group, alkyl having 1 to 3 carbons) Group, alkoxy or halogen of 1 to 3 carbon atoms), benzhydryl or alkanoyloxymethyl of 5 to 5 carbon atoms,

X is halogen, CF ₃ , CCl ₃ , straight or branched saturated or unsaturated alkyl or alkoxy, benzyl, benzyl, where benzyl may be substituted by hydroxy, amino, lower alkyl or lower alkoxy having up to 6 carbon atoms or OR ⁴ , SR ⁴ , SO-R ⁴ , SO ₂ -R ⁴ , and NR ⁴ R ⁵ , where R ⁴ is Hal, OH, NH ₂ , CF ₃ , NO ₂ , alkyl or alkoxy having 1 to 4 carbon atoms or SO ₂ NH ₂ Phenyl substituted with a group or straight or branched chain alkyl of 1 to 4 carbon atoms substituted with phenyl, pyridyl, furyl or thienyl, R ⁵ is hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, NR ⁴ R ⁵ is Is a saturated heterocyclic ring of 5 to 6 atoms interrupted by an O-, N- or S- atom),

의 그룹(여기서 Y는 단일결합/또는 탄소수 1내지 4의 알킬렌그룹이고 R⁶및 R⁷은 같거나 다르게 수소, 할로겐 또는 탄소수 1내지 4의 알킬이다)이다.Y is a single bond, or an alkylene having 3 or less carbon atoms, interrupted by O-, N- or S-atoms or substituted with a halogen atom and / or an alkyl, aralkyl, branched aryl group or mononuclear heteroaromatic ring and is also ortho- Phenylene group or

Where Y is a single bond / or alkylene group of 1 to 4 carbon atoms and R ⁶ and R ⁷ are the same or differently hydrogen, halogen or alkyl of 1 to 4 carbon atoms.

Preferred Structural Formula (I) compounds of the present invention are those wherein R ¹ and R ² are hydrogen, or R ¹ is hydrogen, R ² is alkyl of 1 to 4 carbon atoms, R ³ is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl , X is benzyl, -OR ⁴ , SR ⁴ , -SO-R ⁴ , wherein R ⁴ is Cl, OH, CF ₃ , straight or branched chain alkyl of 1 to 3 carbon atoms, alkylamino, dialkylamino or 1 to 2 carbon atoms Is alkoxy or phenyl substituted once or several times with NH ₂ ), and A is a compound of unsaturated alkylene having 2 or less carbon atoms substituted once or several times with a single bond or halogen atom, phenyl or lower alkyl, in particular X is phenoxy, Of note are compounds that are phenylthio, phenylsulfinyl and benzyl.

The preparation method of the present invention is characterized in that the 3-substituted sulfamoylbenzoic acid derivative of formula (II) is reduced to a complex of boride or hydrogen boride in the presence of Lewis acid.

In the above structural formula

R ¹ , R ² , R ³ , A and X are as described above, hydroxy, amino or mercapto groups are protected by conventional protecting groups,

Z is two hydrogen atoms or one oxygen atom.

In the compound of formula (I) obtained above, a double bond is introduced by hydrogenation or a elimination reaction if necessary and / or esterified free carboxylic acid of structure (I) wherein R ³ is hydrogen. R ³ is by a carboxylic acid ester of the formula (ⅰ) a R ³ above hydrolysis or elimination carboxylic acid (R ³ is hydrogen) as a switch, and / or removing the protective group of hydroxy, amino or mercapto group, And / or the carboxylic acid of formula (I), wherein R ³ is hydrogen, is treated with a base or an acid to transform it into a physiologically toxic salt thereof.

In the production process according to the invention, it is surprising that the sulfamoylbenzoic acid derivative of formula (II) can be reduced in the presence of Lewis acid without affecting other groups in the molecule and the final product can be obtained in excellent yield. have.

The sulfamoylbenzoic acid derivatives of formula (II) can be prepared by various methods. For example, the 3-imido-5-sulfamoylbenzoic acid derivative of the structural formula (II) (Z = oxygen) is a structural formula (XV) known from the literature and known (wherein R ¹ , R ² , R ³ and X have been described above). 3-amino-5-sulfamoylbenzoic acid derivative of the formula (VVI) capable of forming an imide, wherein A is as described above, Z is oxygen, and L is a leaving group, preferably a halogen atom, a tree Or an alkylammonium group or an OR 'group of an activated ester). For these acylation reactions hydroxyl, amino and / or mercapto groups in other positions of the molecule must be protected by conventional protecting groups.

Examples of dicarboxylic acids that can be converted to dicarboxylic acid halides include succinic acid, methyl succinic acid, 2,3-dimethylsuccinic acid, glutaric acid, 2-methylglutaric acid, phthalic acid, cis-cyclopropanedicarboxylic acid, cyclobutane 1,2-cis-dicarboxylic acid, cyclohexane-1,2-cis-dicarboxylic acid, bromosuccinic acid or diglycolic acid. The reaction of these dicarboxylic acid derivatives with the amino compounds of the formula (XV) is carried out under the well-known Schötten-Baumann reaction conditions.

It is also possible to use anhydrides of dicarboxylic acids. In many cases, the carboxylic acid derivatives of formula (VIII), which are preferentially formed, are converted directly to the imido compounds of formula (II) by removing water.

After the reaction can be easily thin layer chromatography, depending on the reaction conditions selected, especially when the reaction mixture is heated to a temperature of 150 to 250 ℃ cyclic products are obtained in high yield.

Anhydrides are preferably used in excess, for example about 2 to 3 times, and the reaction is carried out without the presence of a solvent. In the case of using an unsaturated dicarboxylic acid anhydride, for example maleic anhydride, when it is reacted with an amino compound of formula (VV) at a temperature of 150 to 200 ° C., a viscous oil is formed in a molten state. (Iii) to unsaturated imido compounds.

In the above structural formula

R ¹ , R ² , R ³ , R ⁶ , R ⁷ and X are as described above. The double bond of this imido compound allows many reactions to take place, for example when hydrogenated, an imido compound of formula (II) wherein Z is oxygen and A is an ethylene group is produced.

The starting material of the formula (III) wherein Z is two hydrogen atoms can be prepared by various methods, for example, the amino compound of formula (XV) under the reaction conditions of Schotten-Bauman, and the ω- of the formula (XVI) wherein Z is two hydrogen atoms. After reacting with a substituted carboxylic acid derivative, it can be prepared by ring closure by removing HL from the resulting amido compound of formula (VII).

Examples of carboxylic acid derivatives of the structural formula (VI) include ω-chloropropionic acid chloride, ω-chloropropionic acid bromide, ω-chlorobutyric acid chloride, ω-bromobutyric acid chloride, ω-bromobutyric acid phenylester and trimethylammonium butyric acid chloride, and the like. .

The base required for removing H-L is preferably a tertiary organic base such as pyridine, triethylamine, or N, N-dimethylaniline, uses a stoichiometric or substantial excess, and is also used as a solvent at the same time.

Amido or imido derivatives are used in the form of salts which do not interfere with free acid or reduction in the reduction reaction according to the invention, for example alkali metal salts or alkaline earth metal salts.

It is particularly advantageous to use 5-sulfamoylbenzoic acid esters for reduction in order to obtain pure reaction products in high yield.

This ester is prepared from an acid according to methods known in the literature. Suitable esters include lower alkyl esters, benzyl esters or p-methoxybenzyl esters and t-butyl esters, benzhydryl esters and acyloxymethyl esters, such as methyl, ethyl, propyl, butyl or n-pentyl esters. Wherein the acyl group is a lower aliphatic carboxylic acid such as acetyl or tert-butyryl group.

Suitable reducing agents are complexes of hydrogen boride or diborane in the presence of Lewis acids.

In the reduction reaction of the lactam of the structural formula (II) (Z = 2H), it is possible to perform diborane in the presence of Lewis acid, whereas imide (Z = oxygen) is present in the presence of Lewis acid in order to obtain high yield. It may also be necessary to apply a complex of hydrogen boride. The reducing agent may be introduced into the reaction mixture by an appropriate protection method such as using nitrogen as an inert gas. When using diborane, it is simpler to carry out the reaction in a solvent and use it in solution for the reduction reaction. Suitable solvents are in particular ethers such as tetrahydrofuran or diethylene glycol dimethyl ether and the like.

The complex compounds of hydrogen boride used in this reduction reaction include alkali metal borates such as lithium borohydride, sodium borohydride or potassium borohydride or alkaline earth metal borates such as calcium borohydride, zinc borohydride or aluminum borohydride. have. When Lewis acids are added, these hydrogen borides surprisingly reduce the amide or imide groups present in the compounds used without attacking the functional groups of the carboxylic acid esters.

Suitable Lewis acids for use in the process of the invention include in particular aluminum chloride, titanium tetrachloride, tin tetrachloride, ferric chloride, boron trifluoride and adducts thereof, such as boron trifluoride etherate and the like. In this case, the reaction of boron trifluoride etherate with sodium borohydride may lead to the formation of diborane in situ. See also: P.E., P. ″ Reagents for organic Syntheris ″, John Wally and Sons. , Inc. New York, Vol 1, p. 199].

In particular, in order to obtain a high yield and particularly pure final product, it is advantageous to first introduce leunic acid together with the compound of formula (II), and then add a complex of hydrogen boride, which is used in excess of the amide to be reduced and the complex of hydrogen boride It is advantageous to use at least chemical flavors.

Therefore, for example, in the case of titanium tetrachloride, the amount of NaBH ₄ is added at three times the chemical amount according to the number of amide groups to be reduced, and in the case of using boron trifluoride etherate, a chemical compound of hydrogen boride can be used to obtain an advantageous result.

In carrying out the reduction reaction, it is not important that the substance to be reduced is introduced as an imido compound of structural formula (II) (Z = 0) or as an amido compound (Z = 2H). Surprisingly, the imido compounds are converted directly into sulfamoylbenzoic acid derivatives of formula (I) in one reaction vessel. The reduction reaction is carried out in a solvent and suitable solvents are ethers such as tetrahydrofuran or diethylene glycol dimethyl ether (diglyme). The reaction solvent is the same as the solvent in which the borohydride can be dissolved but may be different.

The temperature range of the reduction reaction is wide and is carried out at room temperature or slightly elevated temperature. While the reaction of secondary amines with diborane and the reaction of lactams with diborane and Lewis acids are preferably carried out at slightly elevated temperatures (40 to 60 ° C.), the complexes of hydrogen boride and the use of leuiso acids, in particular imides, The reducing reaction proceeds very advantageously at temperatures between 0 and 20 ° C. If a slightly longer reaction time is required, the reduction reaction may be carried out in a cooled state. The time required for reduction depends on the reactive component used and the temperature selected.

In a preferred production method of the present invention, the 5-sulfamoylbenzoic acid derivative of formula (II) is first introduced together with Lewis acid in an inert solvent, followed by suspending a complex solution of hydrogen boride or a complex compound of hydrogen boride in the same or different solvent as described above. The resulting solution is added at room temperature and stirred for a while. The complex of hydrogen boride can also be added directly in solid form. In order to promote the reaction, a reducing agent is added, and then the reaction temperature is slightly raised or the reaction mixture is heated to 50 to 80 ° C. for about 1 hour.

In another production method, a substance to be reduced is first introduced together with a complex of hydrogen boride and then Lewis acid is added at room temperature. Especially suitable as a complex compound of hydrogen boride is sodium borohydride. It may also be a macro advantage to heat to 40-70 ° C. for about 1 hour after the addition of Lewis acid to allow the reaction to proceed faster. The progress of the reaction can be seen by thin layer chromatography which emits a strong light blue fluorescence of the final product of formula (I) at 366 nm. In the reduction reaction according to the present invention it is possible to simultaneously reduce the double bonds present in the A group.

The final product can be separated in several ways. A preferred treatment is to add water and a small amount of acid to liberate the solution of the reaction product from the reducing agent that may still be present and add a non-solvent to precipitate the 5-sulfamoylbenzoic acid ester. Water is particularly suitable as nonsolvent when diethylene glycol dimethyl ether is used. The resulting 5-sulfamoylbenzoic acid ester of formula (I) is generally crystallized almost quantitatively with high purity.

Optionally, it is sometimes necessary to liberate the substituents present on the groups of the sulfamoylbenzoic acid derivatives of formula (I) and protected by the protecting groups. For example, p-hydroxyl groups are obtained by saponifying the corresponding acetates.

인 구조식(Ⅰ)의 3-피롤린 유도체는 출발물질로서 2-브로모 석신산을 사용하여 제조한다.In addition, after decomposing the excess reducing agent, the reaction mixture can be partially concentrated, diluted base is added, and then heated for a while to obtain 5-sulfamoylbenzoic acid derivative of formula (I). Sodium hydroxide solution may be used as the base, and in this case, 5-sulfamoylbenzoic acid of formula (I) may be directly separated in the form of a salt thereof. Free acid is obtained by acidification. As for the 5-sulfamoylbenzoic acid derivative of the structural formula (I), since the process of producing 3-imido or 3-amido-5-sulfamoylbenzoic acid derivative of the structural formula (II) proceeds smoothly, high purity and high yield You can get If the CC chain contains a substituent which is easily removed when a carbon-carbon double bond is formed, the reduction reaction can be carried out successfully using imides or amides. So for example A

3-pyrroline derivatives of the phosphorus structural formula (I) are prepared using 2-bromo succinic acid as starting material.

3-pyrroline derivatives can be chemically modified according to known methods. For example, it may be catalytically hydrogenated to produce sulfamoylbenzoic acid derivatives of formula (I) having A as an ethylene group and having a heterocyclic substituent at the 3-position, or may be subjected to a conventional addition reaction.

After the above reaction, the double bond present in the compound of formula (I) of the present invention can be catalytically hydrogenated and saturated by a conventional method, and on the contrary, the removal reaction, for example, separates the hydrogen halide from the halogenated compound. The double bond may be introduced by, for example, separating water from a hydroxide, or other conventional removal reaction. When the free carboxylic acid of formula (I) is preferentially obtained using an appropriate starting material, it can be converted to esters by conventional means, for which alcohols or reactive derivatives of formula (I) R ³ OH are used or literature It is esterified according to a method known in the art. In contrast, when the carboxylic acid esters of formula (I) are initially obtained, they can be converted to the corresponding free carboxylic acids, for which hydrolysis or, where appropriate, hydrocracking or other removal reactions are used. Thus, the tertiary butyl ester can be removed by treating isobutylene by treating alkyl esters by alkaline hydrolysis, aralkyl esters by hydrolysis, in particular p-nitrobenzyl esters, or trifluluic acid with acetic acid. have.

The free carboxylic acid can be converted into a physiologically toxic salt thereof by reaction with an alkaline earth metal, or an appropriate base such as ammonium hydroxide or ammonium carbonate. A compound of formula (I) can be obtained by separating one of the usual protecting groups such as hydroxyl, amino, mercapto group in the final reaction step by a reaction such as hydrolyzing the acylated hydroxyl group in a conventional manner. have. These protecting groups are necessary to prevent acylation at undesired positions by the carboxylic acid derivatives of formula (XII), particularly in preparing starting materials of formula (II). In this case the reduction reaction according to the invention is carried out using a protected hydroxy, amino or mercapto compound and the protecting group is separated only after reduction as described above. However, for other methods, it may be appropriate to protect reactive substituents removed in the final reaction step.

Many highly active pharmaceutical preparations, in particular the diuretics and doublings, which will be specified later, can be prepared according to the methods of the invention.

Pharmaceutically effective compounds prepared according to the process of the present invention include commercially available benzoic acid methyl-, ethyl-, benzene- and tert-butylesters as well as the corresponding 5-N-methyl, 5-N-methoxymethyl- and 5-N-butoxymethyl sulfamoylbenzoic acid and the like.

Sulfamoylbenzoic acid derivatives of the formula (I) and physiologically toxic salts thereof according to the present invention are highly active diuretics and beating agents used as pharmaceuticals for humans and animals. The compounds according to the invention can be administered in an intestinal, oral or parenteral (for example, intravenous injection, intramuscular injection or in the form of capsules, dragees, tablets or liquids) in a dosage of 0.5 to 100 mg with various additives. Subcutaneous injection). These preparations are suitable for the treatment of edema, including edema from abnormal heart, kidney, and liver, and similar symptoms from imbalances in water and electrolyte metabolism. The average daily dose administered to the patient is 2 to 10 mg, i.e. 0.025 to 0.15 mg / kg body weight. The compounds are particularly administered to the human body, either alone or in admixture with substances having a gastroenteritis and diuretic or other action, or separately from these agents, in combination with various other agents, alternately or in combination. These include spylonolactone, triamterene, abeliolide, and other fats and oils, and are supplemented with chloritaliden or other forms of long-acting peptic diuretics or the loss of K ⁺ observed during peptic diuresis. It can be used together with or separated from potassium-containing compounds (salts, etc.).

Example 1

3-nitro-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

34 g (about 0.1 mole) of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid are dissolved in 150 ml of methanol and heated to boiling. 5.4 ml of concentrated sulfuric acid is slowly added dropwise and the mixture is heated at reflux for 10 hours. Cool to drop 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid methyl ester into the crystals. It can be recrystallized from methanol / acetone. Condensation: 181 to 182 ℃

Example 2

3-Amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

35 g (about 0.1 mole) of 3-nitro-4-phenoxy-5-sulfamoylbenzoic acid methyl ester are suspended in 150 ml of methanol and ranickel (5 to 10%) in an autoclave at 40 to 50 ° C. and 100 atm. Hydrogenated with The amino compound dropped into the precipitate is dissolved by adding acetone in a steam bath and filtered to remove ranickel. Cool to drop 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester into clean crystals. Melting Point: 179 ℃

Example 3

3-N-succinimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

Dissolve 16.1 g (0.05 mole) of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester in 150 ml of anhydrous dioxane and heat the solution to boil. A solution of 11.6 g (0.075 mol) of succinic acid dichloride in 50 ml of anhydrous acetone and 8 ml of pyridine in 50 ml of anhydrous acetone were added dropwise at the same rate while stirring, and the mixture was heated to reflux. After about 2 hours the reaction is complete and the mixture is concentrated and the oily residue is taken up in a small amount of methanol. After a while 3-N-succinimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester precipitates as crystals. Recrystallize from methanol / acetone. Melting Point: 270 ℃

Example 3

3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is melted for about 2 hours with 2-3 moles of succinic anhydride at a temperature of 160-180 ° C. After cooling and adding methanol, 3-N-succinimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester precipitates as crystals.

Example 4

3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

Dissolve or suspend 12.3 g (0.03 mole) of 3-N-succinimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester in 100 ml of anhydrous diglyme. 9 g of boron trifluoride etherate was added directly to this solution, and a solution of 2.4 g (about 0.063 mol) of NaBH ₄ dissolved in 80 ml of diglyme was added dropwise while stirring well at room temperature. Since this reaction is exothermic, cooling with ice water is necessary. The reaction is usually added dropwise, stirred for a while and then terminated. The excess reducing agent is then decomposed by adding a small amount of water (foaming), then the solution is filtered and about 300 ml of water are added with stirring. The precipitated 3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is recrystallized from methanol. Colorless Crystal, Melting Point 191 ~ 192 ℃

NMR data (ppm): (CoCl ₃ , 60MHZ, internal standard solution TMS)

δ = 1.7 (m; 4H), δ = 3.26 (m; 4H), δ = 3.91 (S; 3H), δ = 5.0 (S; 2H), δ = 6.6 to 8.0 (m; 7H)

Example 5

3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid

61 g of 3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is suspended in 350 ml of 1N sodium hydroxide and the suspension is heated on a water bath for 1 hour. To the clear solution is added 2N-hydrochloric acid with good stirring to drop 3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid to precipitate. Nearly pure crude product is recrystallized from methanol / water to give pale yellow plate crystals. Melting Point: 225-227 ℃ (Decomposition)

NMR data (ppm): (D ₆ -OMSO, 60MHZ, TMS)

delta = 1.67 (quasi-S: 4H), delta = 3.21 (quasi-S; 4H), delta = 6.6 to 8.0 (m; 9H).

Example 6

3-N-glutarimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

Dissolve 16.1 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester in 150 ml of anhydrous dioxane and heat the solution to boil. A solution of 16.8 g of glutaric acid dichloride in 50 ml of anhydrous acetone and 8 ml of pyridine in 50 ml of anhydrous acetone was added dropwise at the same rate and stirred, and the mixture was heated to reflux. After 3 hours, the reaction is terminated, the mixture is concentrated, and the residue is dissolved in a small amount of methanol. After a while, 3-N-glutarimido-4-phenoxy-5-sulfamoyl benzoic acid methyl ester is precipitated. Recrystallization with glycol monomethyl ether gives colorless crystals having a melting point of 312 to 314 ° C. (decomposition).

Example 7

3-N-piperidone-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

15 g of 3-N-glutarimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is suspended in 200 ml of diglyme (diethylene glycol dimethyl ether) and 10 ml of boron trifluoride etherate is added. A solution of 3 g of NaBH ₄ dissolved in 150 ml of diglyme is added slowly at room temperature with good stirring. Excess reducing agent is decomposed into a small amount of water, the solution is filtered and stirred and 500 ml of water is added. The precipitated 3-N-piperidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester can be recrystallized with alcohol.

White crystal, melting point 198-199 ℃

NMR data (ppm): (D ₆ -DMSO, 60MHZ, TMS)

δ = 1.1 (quasi-S; 6H), δ = 2.86 (quasi-S; 4H), δ = 3.92 (S; 3H), δ = 6.7 to 8.1 (m; 9H)

Example 8

3-N-piperidino-4-phenoxy-5-sulfamoylbenzoic acid

8 g of 3-N-piperidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is suspended in 50 ml of 1N sodium hydroxide and heated in a steam bath until a clear solution is obtained. The resulting 3-N-piperidino-4-phenoxy-5-sulfamoylbenzoic acid is precipitated with 2N-hydrochloric acid and recrystallized from methanol / water.

White Crystal, Melting Point 258 ~ 260 ℃

NMR data (ppm); (D ₆ -DMSO, 60MHZ, TMS)

δ = 1.08 (quasi-S; 6H) δ = 2.9 (quasi-S; 4H), δ = 6.65 to 8.2 (m; 9H)

Example 9

3-N-phthalimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

16 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is dissolved in 200 ml of dioxane anhydride and the solution is heated to boiling. 14 ml of phthalic acid dichloride was added to 50 ml of acetone and 9 ml of pyridine to 50 ml of acetone. After 3 hours, the reaction was terminated, the solution was concentrated, the residue was dissolved in a small amount of acetone, stirred well, and added dropwise to a mixture of 2N hydrochloric acid and ice water, and then 3-N-phthalimido-4-phenoxy-5- as a light brown precipitate. Obtain sulfamoylbenzoic acid methyl ester.

Recrystallization from methanol / acetone / water gives colorless crystals with melting points of 237 to 238 ° C.

Example 10

3-N-isoindolinyl-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

16 g of 3-N-phthalimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is dissolved or suspended in 150 ml of diglyme and then 12 ml of boron trifluoride etherate is added. A solution of 3.6 g of NaBH ₄ dissolved in 100 ml of diglyme was added dropwise at room temperature and the mixture was further stirred at 60 ° C. for half an hour. 400 ml of water is added to separate the fleecy mixture and then methanol is added to boil. Meanwhile, 3-N-isoindolinyl-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is not dissolved and is filtered and then recrystallized with n-butanol / DMF. White needle crystal, melting point 268 to 272 ° C (decomposition)

NMR data (ppm); (D ₆ -DMSO, 60MHZ, TMS)

δ = 3.92 (S; 3H), δ = 4.66 (S; 4H) δ = 6.6 to 8.1 (m; 13H)

Example 11

3-N-isoindolinyl-4-phenoxy-5-sulfamoylbenzoic acid

2.5 g of 3-N-isoindolinyl-4-phenoxy-5-sulfamoyl benzoic acid methyl ester is suspended in 50 ml of 1N sodium hydroxide and then heated in an increasing bath until a clear solution is obtained. Treatment with 2N hydrochloric acid precipitates 3-N-isoindolinyl-4-phenoxy-5-sulfamoyl benzoic acid and recrystallizes with glacial acetic acid.

Pale yellow crystals, melting point 259-261 ° C (decomposition)

NMR data (ppm); (D ₆ -DMSO, 60MHZ, TMS)

δ = 4.68 (S; 4H), δ = 6.6 to 8.0 (m; 13H)

Example 12

3-N- (2,4-dioxo-3-azabicyclo- [3.2.0] -heptano) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester

8.1 g 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is mixed with 6. g cis-cyclobutane-1,2-dicarboxylic anhydride and 5 ml diglyme and then heated to 180 ° C. . During this time, the diglyme evaporates and the melt becomes a solid after 1 hour. When warm, methanol is added to break up the solid mass into colorless crystals. The crystalline powder is filtered and recrystallized with glycol monomethyl ether. Melting Point: 284 ~ 285 ℃

Example 13

3-N- (3-azabicyclo- [3.2.0] -heptano) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester

7.3 g of 3-N- (2,4-dioxo-3-azabicyclo- [3.2.0] -heptano) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester was suspended in 70 ml of diglyme 6 ml of boron trifluoride etherate is then added. A solution of 1.5 g of NaOH ₄ dissolved in 70 ml of diglyme is slowly added dropwise with ice-cooling. The mixture is stirred for at least 15 minutes and water is added to precipitate 3-N- (3-azabicyclo- [3.2.0] -heptano) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester. Recrystallize from methanol or acetonitrile. White Crystal, Melting Point 176 ~ 177 ℃

Example 14

3-N- (3-Azabicyclo- [3.2.0) -heptano) -4-phenoxy-5-sulfamoylbenzoic acid

6.2 g of 3-N (3-azadcyclo- [3.2.0] -heptano) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester are suspended in 60 ml of 1N-sodium hydroxide to give a clear solution. Heat in water bath until Stir well, add 2N hydrochloric acid to precipitate, and recrystallize with glacial acetic acid. Pale yellow plate crystal, melting point 254 ~ 255 ℃ (decomposition)

Example 15

3-N- (cis-1,2-cyclohexanedicarboximido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester

8 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methylester is melted with 7.5 g of cis-cyclohexane-1,2-dicarboxylic acid anhydride while adding a few diglyme. The temperature is maintained between 180 and 200 ° C. and stirred until the mass becomes solid. Methanol is added carefully and the precipitated colorless material is filtered off. Recrystallization with glycol mono methyl ether gives white crystals with a melting point of 268 to 269 ° C.

Example 16

3-N- (3,5-dioxo-morpholino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

16 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methylester are mixed with 15 g of diglycolic anhydride and 10 ml of diglyme and the mixture is heated to 180 ° C. in an open flask. After 1-2 hours, methanol is added carefully and cooled to precipitate imide. White crystals are obtained from diglyme. Melting Point 295-297 ℃

Example 17

3-N-morpholino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

9.4 g of 3-N- (3,5-dioxo-morpholino) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester is suspended in 100 ml of diglyme and 6 ml of boron trifluoride etherate is added. do. A solution of 1.9 g of NaBH ₄ dissolved in 100 ml of diglyme was stirred well under ice-cooling and slowly added dropwise, followed by addition of water to precipitate 3-N-morpholino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester. Let's do it. Recrystallization with methanol gives a crystal having a melting point of 221 to 222 캜.

Example 18

3-N-morpholino-4-phenoxy-5-sulfamoylbenzoic acid

The corresponding methyl ester (Example 17) was heated with 1N sodium hydroxide in a water bath until a clear solution and then 2N hydrochloric acid was added to 3-N-morpholino-4-phenoxy-5-sulfamoyl benzoic acid. Precipitated and recrystallized with methanol to give brownish white crystals having a melting point of 194 to 197 ° C. (decomposition).

Example 19

3-N- (4-methylglutarimido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester

16 g of 3-amido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester and 15 g of 4-methyl glutaric anhydride are mixed with a small amount of diglyme and heated at 160 to 180 ° C. for 2 to 3 hours. Make a slurry. Methanol is added thereto to precipitate 3-N- (4-methyl-glutarimido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester. Crystallization in glycol monomethyl ether gives white crystals with a melting point of 315 ° C.

Example 20

3-N- (4-methylpiperidino) -4-phenoxy-5-sulfamoylbenzoic acid methyl ether

10.3 g of 3-N- (4-methylgurutarimido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester is suspended in 100 ml of diglyme and 6.5 ml of boron trifluoride is added. A solution of 1.9 g of NaBH ₄ dissolved in 100 ml of diglyme was added dropwise at room temperature. After completion of the dropwise reaction, the mixture was further stirred for 15 minutes and water was added to precipitate 3-N- (4-methylpiperidino))-4-phenoxy-5-sulfamoylbenzoic acid methyl ester.

Recrystallization from methanol yields colorless crystals with melting points of 143 to 144 ° C.

Example 21

3-N- (4-methylpiperidino) -4-phenoxy-5-sulfamoylbenzoic acid

The corresponding methyl isoether (Example 20) was heated with 1N sodium hydroxide on a water bath until the solution became clear and then 2N hydrochloric acid was added to 3-N- (4-methylpiperidino) -4-phenoxy- 5-Sulfamoyl benzoic acid is precipitated and recrystallized in methanol / water to give white crystals. Melting Point 243 ~ 244 ℃

Example 22

3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester

16 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester and 15 g of 3-methylsuccinic anhydride were melted together with a small amount of diglyme in a stoppered flask and then heated at about 180 ° C. for 2.5 hours. Keep it. To this was added methanol to precipitate 3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester as crystals and recrystallized in glycol monomethyl ether to give white crystals. Melting point 272 ℃

Example 23

3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester

Suspend 17 g of 3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamoyl benzoic acid methyl ester in 150 ml of diglyme, add 11 ml of boron trifluoride etherate and 150 ml with cooling on ice. To the diglyme of 3g NaBH ₄ dissolved in a solution is added dropwise. Water is added to precipitate 3-N- (3-methylpyrrolidino) -4-pinoxy-5-sulfamoylbenzoic acid methyl ester and crystallized in methanol to give white crystals having a melting point of 145 ° C.

Example 24

3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoylbenzoic acid

9 g of 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester is heated with 1N sodium hydroxide on a water bath until the solution becomes clear. 2N hydrochloric acid is added at room temperature to precipitate 3-N- (3-methylpiperidino) -4-phenoxy-5-sulfamoylbenzoic acid and recrystallized from methanol / water to give an off-white crystal.

Melting point 206-208 degreeC

Example 25

3-N-maleimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

16 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester and 15 g maleic anhydride were heated to about 180 ° C. with a small amount of diglyme in a stoppered flask and after 3 hours the mixture was cooled Methanol and a small amount of water are added.

After standing for a while, 3-N-maleimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is precipitated and recrystallized with methanol to give white crystals. Melting Point 197-198 ° C

Example 26

3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester

Method B

Dissolve 4.1 g of 3-N-succinimido-4-phenoxy-5-sulfamoylbenzoic acid methyl ester in 40 ml of diglyme, add 2.5 ml of titanium tetrachloride, and add 1.1 g of NaBH ₄ to 30 ml of diglyme. The solution was dissolved slowly dropwise at room temperature and stirred for about 1 hour. Water is added to precipitate 3-N-pyrrolidino-4-phenoxy-5-sulfamoyl benzoic acid methyl ester and recrystallize from water and methanol. Melting Point 191 ℃

Example 27

4-Chloro-3-succinimido-5-sulfamoylbenzoic acid methyl ester

25.4 g of 4-chloro-3-amino-5-sulfamoylbenzoic acid methyl ester (melting point: 195-196 ° C.) are thoroughly mixed with 25 g of succinic anhydride, dissolved at 180 ° C. for 6 hours, then cooled slowly and careful with methanol. The product is precipitated out as crystals. A small amount of water is added to complete the crystal product and recrystallized from glycol monomethyl ether. Melting Point 267-269 ° C

Example 28

4-Chloro-3-pyrrolidino-5-sulfamoylbenzoic acid

20 g of imide (Example 27) is suspended in 200 ml of diglyme and 17 ml of boron trifluoride etherate is added.

A solution of ₄ g of NaBH ₄ dissolved in 200 ml of diglyme was added dropwise to the suspension while cooling with ice and stirring continued for 30 minutes, followed by careful hydrolysis by addition of a small amount of water. The solution is filtered and then 4-chloro-3-pyrrolidino-5-sulfamoylbenzoic acid methyl ester is precipitated using water and recrystallized from methanol.

Melting Point 189-191 ° C

The esters are saponified with 1N-sodium hydroxide in a vapor bath until a clear solution is formed and acidified at pH 4 to precipitate free acid. Recrystallization from methanol / water gives pale yellow crystals. Melting Point 259 ~ 261 ℃

Example 29

3-N-succinimido-4-phenylthio-5-sulfamoylbenzoic acid methyl ester

5.8 g of 3-amino-4-phenylthio-5-sulfamoylbenzoic acid methyl ester is mixed with 5.9 g of succinic anhydride and dissolved at 170 ° C. After 5 hours, methanol was added carefully while cooling to precipitate crystals, which were then recrystallized from glycol monomethyl ether. Melting Point 250-251 ° C

Example 30

3-N-pyrrolidino-4-phenylthio-5-sulfamoylbenzoic acid

14.7 g of imide (Example 29) is suspended in 100 ml of diglyme and 10 ml of boron trifluoride etherate is added. A solution of 2.8 g of NaBH ₄ dissolved in 100 ml of diglyme was slowly added dropwise while cooling with ice, and stirring was continued at room temperature for 30 minutes, and then a small amount of water was added to decompose the excess reducing agent. Water is added to precipitate 3-N-pyrrolidino-4-phenylthio-5-sulfamoylbenzoic acid methyl ester and recrystallized in methanol to give yellow crystals having a melting point of 139 to 140 ° C. This ester is heated with 1N sodium hydroxide in a steam bath until the liquid is clear and then the acid produced at pH 3-4 is precipitated using 1N hydrochloric acid.

Recrystallization with methanol / water gives yellow crystals. Melting Point 238-239 ° C

Example 31

4-phenoxy-3- (1-pyrrolidinyl) -5-dimethylsulfamoyl benzoic acid

7.2 g (0.02 mole) of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is dissolved in 100 ml of 1N sodium hydroxide and mixed with 10 ml of dimethylsulfate. The mixture is stirred well at room temperature and after about 30 minutes a woolly white material precipitates out. The solution was filtered by suction, heated with 2N sodium hydroxide in a steam bath, and when the clear solution was formed, the total reaction solution was cooled and 4-phenoxy-3- (1-pyrrolidinyl)-was added to 2N hydrochloric acid. Precipitate 5-dimethylsulfamoylbenzoic acid. This material is recrystallized in methanol / water to give a yellow fibrous material having a melting point of 214 to 215 ° C.

Example 32

4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid

a. 4-phenoxy-3-N-succinimido-5-methylsulfamoylbenzoic acid methyl ester

71 g of 3-amino-4-phenoxy-5-methyl-sulfamoylbenzoic acid methyl ester (melting point 188 ° C.) are melted together with 87 g of succinic anhydride at a temperature of 180-190 ° C. After 5 hours, the melt is carefully mixed with methanol and again mixed with the same amount of water to precipitate an imide. 4-phenoxy-3-N-succinimido-5-methylsulfamoylbenzoic acid methyl ester is obtained under recrystallization in methanol. Melting Point 249 ~ 250 ℃

b. 4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid methyl ester

67 g of 4-phenoxy-3-N-succinimido-5-methylsulfamoyl benzoic acid methyl ester are suspended in 300 ml of anhydrous diglyme and mixed with 40 ml of boron trifluoride etherate. After cooling the mixture to -10 ° C, a solution of 12.2 g of NaBH ₄ dissolved in 300 ml of diglyme was added dropwise with good stirring. In the meantime, the temperature should not be higher than 10 ℃. After dropping, the total liquid is further stirred for 10 minutes and the mixture is carefully mixed with water (foaming).

Further water is added to precipitate the reaction product and recrystallized from methanol to give 4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid methyl ester having a melting point of 138 to 139 ° C.

c. 4-phenoxy-3- (1-pyrrolidinyl) -5-methyl sulfamoyl benzoic acid

54 g of methyl ester (obtained according to b) are stirred in a steam bath, suspended in 50 ml of 1N sodium hydroxide and heated. When a clear solution is formed, the total liquid is cooled and 1N hydrochloric acid is added to precipitate free acid.

Recrystallize from methanol / water to afford 4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid having a melting point of 245 to 248 ° C. (decomposition).

Example 33

4- (4'-Methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

a. 3-Nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid

124 g (0.9 mole) of potassium carbonate was dissolved in 800 ml of water, followed by 1.6 mole of P-cresol followed by 112 g (0.4 mole) of 2-chloro-3-nitro-5-carboxy-benzenesulfonamide in small portions at 85 ° C. Heated to. The reaction mixture is stirred at this temperature for 16 hours and then cooled to 25-30 ° C., concentrated hydrochloric acid and acidified to pH 1. The separated oil is separated from the aqueous phase and then steam distilled. Alternatively, it is also possible to acidify the aqueous phase after setting the pH value to 8-9 and extracting excess phenol with ethyl acetate. In this way excess ρ-cresol is separated and cooled to precipitate the product. Recrystallization from acetone / water gives 3-nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid having a melting point of 236 ° C.

b. 3-nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester

The crude product obtained according to a is dissolved in methanol and heated to boiling. To this solution is added 5-10% concentrated sulfuric acid (relative to the benzoic acid used) and the total is refluxed for 8 hours and boiled. The solution is concentrated to 1/3 and cooled to 5 to 10 ° C. to precipitate a methyl ester having a melting point of 161 to 162 ° C.

d. 3-Amino-4- (4′-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester

45 g of 3-nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester was suspended in 150 ml of ethyl acetate and hydrogenated with ranickel for 5 hours under hydrogen pressure of 50 DEG C and 100 atm. do. After cooling, Raney nickel is separated and the solution is concentrated to dryness. Recrystallization from methanol / H ₂ O affords 3-amino-4- (4′-methylphenoxy) -4-sulfamoylbenzoic acid methyl ester having a melting point of 183 to 185 ° C.

d. 3-N-succinimido-4- (4′-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester

27 g (about 0.08 mole) of 3-amino-4- (4′-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester at 170-190 ° C. with 24 g (about 0.24 mole) of succinic anhydride for 4 hours Melt. After cooling the melt, carefully add methanol and a small amount of water. The amide is precipitated and recrystallized in CH ₃ OH / H ₂ O to give crystals having a melting point of 240 to 241 ° C.

e. 4- (4'-Methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl benzoic acid methyl ester

25.6 g of 3-N-succinimido-4- (4′-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester is suspended in 150 ml of anhydrous diglyme, followed by 16 ml of boron trifluoride. . A solution of 4.6 g of NaBH ₄ dissolved in 200 ml of some diglyme is slowly added dropwise while cooling with ice and stirring well. In the meantime, the temperature should not be higher than 20 ℃. After further stirring for 15 minutes, water is added to gradually precipitate the product. Recrystallization from methanol gives a crystal having a melting point of 156 to 157 ° C.

f. The methyl ester obtained according to e is suspended in 1N sodium hydroxide and then heated in a steam bath until the liquid is clear. The total solution was filtered and acidified to pH 3, and the precipitated 4- (4′-methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid was recrystallized from methanol to have a melting point of 230 to 233 ° C ( To give pale yellow crystals.

Example 34

4- (4'-Methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

a. 3-nitro-4- (4'-methoxymethoxy) -5-sulfamoyl benzoic acid

The reaction is carried out according to a method analogous to that described in Example 33a using p-methoxyphenol.

The product is recrystallized in acetone / water to give crystals having a melting point of 233 to 234 ° C.

b. 3-nitro-4- (4'-methoxyphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33b. Melting Point 150-152 ℃

c. 3-Amino-4- (4′-methoxyphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33c. Melting Point 176-177 ° C

d. 3-N-succinamino-4- (4′-methoxyphenoxy) -5-sulfamoylbenzoic acid methyl ester

A method similar to Example 33d is used. Melting Point 226-227 ° C

e. 4- (4′-methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester

A method similar to Example 33e is used. Melting Point 190 ~ 191 ℃

f. 4- (4′-methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

Recrystallize from methanol / water using a method similar to Example 33f.

Pale yellow crystals, melting point 228 to 229 ° C

Example 35

4- (3'.5'-dimethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

a. 3-Nitro-4- (3 ', 5'-dimethylphenoxy) -5-sulfamoylbenzoic acid

The reaction is carried out according to a method analogous to Example 33a using 3,5-dimethylphenol. The resulting crude product is directly esterified.

b. 3-nitro-4- (3 ', 5'-dimethylphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33b. Melting Point 197-198 ° C

c. 3-Amino-4- (3 ′, 5′-dimethylphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33c. Melting Point 195-196 ℃

d. 3-N-succinimido-4- (3 ', 5'-dimethylphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33d. Melting point 220 ℃ (semi-melting state)

e. 4- (3 ', 5'-dimethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33e. Melting Point 208-209 ° C

f. 4- (3 ', 5'-dimethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

Recrystallize from methanol / water using a method similar to Example 33f. Melting Point 246-248 ° C (Decomposition)

Example 36

4- (4'-Chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

a. 3-Nitro-4- (4'-chlorophenoxy) -5-sulfamoylbenzoic acid

Prepared by recrystallization from acetone / water using p-chlorophenol according to a similar method as in Example 33a. Melting point 248 ℃

b. 3-nitro-4- (4'-chlorophenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33b. Melting point 171 to 172 ° C

c. 3-Amino-4- (4′-chlorophenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33C. Melting Point 198 ~ 199 ℃

d. 3-N-succinimido-4- (4′-chlorophenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol / water using methods similar to those of Example 33d. Melting Point 266-267 ℃

e. 4- (4'-Chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol / water using a method similar to Example 33e. Melting point 200 ℃

f. 4- (4'-Chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

Recrystallize from methanol using a method similar to Example 33f. Melting Point 253 ~ 254 ℃

Example 37

4- (3'-Trifluorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

a. 3-Nitro-4- (3'-trifluoromethylphenoxy) -5-sulfamoylbenzoic acid

Recrystallize from acetone / water using 3-trifluoromethylphenol following the method analogous to Example 33a. Melting Point 210 ℃

b. 3-nitro- (3'-trifluoromethylphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33b. Melting Point 141-143 ℃

c. 3-Amino-4- (3′-trifluoromethylphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33C. Melting point 186 to 187 ° C

d. 3-N-succinimido-4- (3′-trifluoromethylphenoxy) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33d. Melting point 227-228 ° C

e. 4- (3'-Trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester

Recrystallize from methanol using a method similar to Example 33e. Melting Point 170-171 ° C

f. 4- (3'-Trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

Recrystallize from glacial acetic acid in a similar manner to Example 33f. Melting Point 230-234 ° C

Example 38

4- (4'-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoylbenzoic acid

a. 3N- (3-methylsuccinimido) -4- (4'methylphenoxy) -5-sulfamoylbenzoic acid methyl ester

20 g of 3-amino-4- (4′-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester (Example 33c) are melted with 18 g of methylsuccinic anhydride at 180 ° C. for 3 hours. Methanol is added while cooling the melt to precipitate the product and recrystallize from acetone / water. Melting Point 229-230 ° C

b. 4- (4'-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester

22 g of 3N- (3-metalsuccinimido) -4- (4′-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester was suspended in 200 ml of anhydrous diglyme and mixed with 13 ml of boron trifluoride etherate do. A solution of 3.3 g of NaBH ₄ dissolved in 200 ml of diglyme was slowly added dropwise while stirring well at -5 to 0 ° C, stirred for another hour, and then water was added to add the product. Recrystallize from methanol / water. Melting point 177 to 178 ° C

c. 4- (4'-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoyl benzoic acid

14 g of methyl ester (46b) is suspended in 150 ml of 1N sodium hydroxide and then heated in a steam bath with good stirring. After 1 hour of stirring when a clear solution is formed, the mixture is acidified to pH 3 with 2N hydrochloric acid while cooling with ice. The charged product is suction filtered and washed thoroughly with water and then recrystallized from methanol / water. Melting Point 220 ~ 221 ℃

Example 39

4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid methyl ester

36.2 g of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is dissolved in 200 ml of methanol and 7 ml of concentrated sulfuric acid and heated to reflux for 4 to 6 hours. After cooling, the ester is precipitated and recrystallized from methanol. Melting Point 191 ℃

Example 40

4-Phenoxysulfoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

A solution of 7.8 g of 4-phenylmercapto-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid dissolved in 130 ml of glacial acetic acid and 20 ml of 30% hydrogen peroxide was stirred at room temperature and then passed through thin layer chromatography. After 20 hours, the solution is poured into 800 ml of ice water, suction filtered, and dried. Recrystallization in methanol / water affords the yellow crystalline product 4-phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid having a melting point of 142 to 144 ° C. (decomposition).

Example 41

4- (4'-Aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

18.5 g of 4- (4'-nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is dissolved in dimethylformamide and hydrogenated with Raney nickel for 8 hours at room temperature and atmospheric pressure. After filtration, 4- (4′-aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl benzoic acid was charged with water and crystallized in a mixture of DMF and H ₂ O to give a melting point of 234-240 ° C. ( After obtaining a brown crystal which is decomposed), it is crystallized again with 1/2 mole of dimethylformamide (dimethylformamide cannot be removed by drying for a long time under reduced pressure of 120 to 150 ° C).

Claims (1)

The 3-substituted sulfamoylbenzoic acid derivative of the following formula (II) is reduced using a complex of a borohydride or hydrogen boride in the presence of Lewis acid to obtain a compound of formula (I), and if necessary, the compound is hydrogenated at a double bond. is added to or introduced into the double bond by an elimination reaction and / or R ³ is a carboxylic acid ester of the hydrogen in the structural formula the following structural formula (ⅰ) esterification of the free carboxylic acid of (ⅰ) and / or R ³ is a R ³ above By hydrolysis or elimination to convert carboxylic acids wherein R ³ is hydrogen and / or to separate the protecting groups to liberate hydroxy, amino or mercapto groups and / or to carboxylic acids of formula (I) wherein R ³ is hydrogen The following structural formula (I) and the physiologically toxic salts thereof are prepared by treating with a base or an acid and transforming them into physiologically toxic salts thereof. Law.

Wherein R ¹ and R ² are the same or differently hydrogen or alkyl having 1 to 4 carbon atoms, and when R ¹ is hydrogen, R ² is alkoxymethyl, phenoxymethyl, or phenylthiomethyl having 2 to 5 carbon atoms in the alkyl group. R ³ is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 6 carbon atoms (one of which carbon may be substituted by oxygen or sulfur), phenyl or benzyl, wherein the phenyl nucleus is a nitro group, 1 to C May be substituted with an alkyl group of 3, alkoxy or halogen of 1 to 3 carbon atoms, benzhydryl or alkanoyloxymethyl of 3 to 5 carbon atoms, and X is halogen, CF ₃ , CCl ₃ , straight chain having 6 or less carbon atoms, or Branched saturated or unsaturated alkyl or alkoxy, benzyl, where benzyl may be substituted by hydroxy, amino, lower alkyl or lower alkoxy or OR ₄ , SR ⁴ , SO-R ⁴ , SO ₂ -R ⁴ , and NR ⁴ R ⁵ (where R ⁴ is Hal, OH, NH ₂ , CF ₃ , NO ₂ , alkyl or alkoxy having 1 to 4 carbon atoms, or phenyl substituted with SO ₂ NH ₂ group, or 1 carbon atom substituted with phenyl, pyridyl, furyl or thienyl Straight or branched chain alkyl of 4 to 4, R ⁵ is hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, and NR ⁴ R ⁵ is a saturated compound of 5 to 6 atoms blocked by 0-, N- or S-atoms And A is a single bond or A 3 or less alkyl, interrupted by O-, N- or S-atoms or substituted with a halogen atom and / or an alkyl, aralkyl, branched aryl group or mononuclear heteroaromatic ring And ortho-phenylene group or

Where Y is a single bond / or alkylene group having 1 to 4 carbon atoms and R ⁶ and R ⁷ are the same or differently hydrogen, halogen or alkyl having 1 to 4 carbon atoms, wherein the hydroxyamino or mercapto group is Protected by a common protecting group and Z is two hydrogen atoms or one oxygen atom.