DK158978B - PROCEDURE FOR PREPARING HETEROCYCLIC SUBSTITUTED 5-SULFAMYLBENZOIC ACID DERIVATIVES OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS WITH BASES OR ACIDS - Google Patents

Description

DK 158978 B

The present invention relates to a chemically unique process for the preparation of heterocyclic substituted 5-sulfamylbenzoic acid derivatives of the general formula 5

Hf '2 \ CH-

10 \ X

2 XV 1

R2 (D

\ Χχ 1 ^ 'N02S ^^ S ^ N'COOR3.

15 R

Wherein the groups R1 and are the same or different and represent hydrogen or alkyl of 1-4 carbon atoms, R3 means hydrogen, straight or branched alkyl of 1-4 carbon atoms, cycloalkyl of 5 or 6 ring members, phenyl, benzyl, benzhydryl or alkanoyloxymethyl of 2 4 is halogen, CF 3, CCl 3, methyl, benzyl or one of the groups 0-R 4, S-R 4 or NR 4 R 2, wherein R 4 optionally represents halogen, OH, NH 2, alkyl or alkoxy of 1- 4 carbon atoms substituted phenyl and R 5 means hydrogen or straight or branched alkyl of 1-4 carbon atoms, A means a 30 saturated or unsaturated alkylene chain of 2 or 3 carbon atoms which may be interrupted by an O atom or substituted by halogen atoms and / or with alkyl groups, or their pharmaceutically acceptable salts with bases or acids.

The process of preparing 35 compounds of general formula I is characterized in that:

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2 in the presence of Lewis acids reduces 3-substituted sulfamylbenzoic acid derivatives of the general formula 0 10 N) II (II) Q-02S C00R3 where Q represents a group R1 /

20 -N

VR2 or a protected amino group of the general formula R8 1, ** (III) -N = C-n "j \ / 10 ·

R

Wherein R8, R9 and R10 mean the same or different lower alkyl groups, R8 may also mean hydrogen, and / or the substituents R9 and R10 may also be interconnected and the groups R1 - R3, A and X have the meaning given above. wherein hydroxy, amino or mercapto groups are optionally blocked by protecting groups and Z means two hydrogen atoms or one oxygen atom, by hydrogen borides or alkali or alkaline earth metal borohydrides,

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3, where, if Q is a group of general formula (III), hydrogenates the resulting compounds and optionally esterifies free carboxylic acids of formula (I) (R 3 - H) and / or transfers carboxylic acid esters of general formula (I) ( R3 (H) in the carboxylic acids (R3 = H) and / or liberate hydroxy, amino or mercapto groups by cleavage of a protecting group and / or transfer carboxylic acids of formula (I) (R3 = H) into their pharmaceutically acceptable salts at treatment with bases or acids.

Preferred compounds of formula (I) according to the invention are those wherein the groups R 1 and R 2 represent hydrogen, or R 2 may also mean C 1-4 alkyl if R 1 = H, R 3 means hydrogen, C 1-4 alkyl or benzyl, X means benzyl, -OR 4 or SR4, where R4 is preferably phenyl and the phenyl nucleus 15 may also be substituted once or more e.g. with the groups Cl, OH, straight or branched alkyl of 1-3 carbon atoms or alkoxy of 1-2 carbon atoms or NH 2, and A means an optionally unsaturated alkylene chain of 2 carbon atoms which may be substituted one or more times 20 by halogen atoms or alkyl.

In the present process, it is surprising that in the presence of Lewis acids, they succeed in reducing sulfamylbenzoic acid derivatives of formula (II) by hydrogen borides or alkali or alkaline earth metal borohydrides without changing the other groups in the molecule. By this method, the final products are obtained in excellent yields.

The sulfamylbenzoic acid derivatives of formula (II) used according to the invention, wherein Q represents a group -NR 2 R 2, are available by various methods. For example, the 3-imido-5-sulfamyl-benzoic acid derivatives of formula (II) (Z = O) are prepared from the literature known from the literature of formula (IV), wherein the groups R - R 3 and X have the meanings set forth above, reacting these amino compounds with 35 dicarboxylic acid derivatives of the general formula (V) capable of the formation, and wherein A has the above

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4 is capable of formation, and wherein A is as defined above, Z is O, and L is a "leaving group", preferably a halogen atom, a trialkylammonium group or the group OR 'of an activated ester. For this acylation reaction, hydroxy, amino, and / or mercapto groups must be blocked in the other positions of the molecule by conventional protecting groups.

XA \ Z = C = O NH-

X A

15 R1 f | [+ Z = cT \ = 0 -> R * To '- ^ -SS A. O I I.

N0oS ^^ XOORJ L L N09SX C00R 'R2 R2 ^ (IV) (V) (II) 20

Dicarboxylic acids which can be transferred into their dicarboxylic acid halides are e.g. succinic acid, methyl succinic acid, 2,3-dimethyl succinic acid, glutaric acid, 2-methylglutaric acid, phthalic acid, cis-cyclopropanedicarboxylic acid, cyclobutane-1,2-cis-dicarboxylic acid, cyclohexane-1, 2-cis-dicarboxylic acid . The reaction of these dicarboxylic acid derivatives with the amino compounds of formula (IV) occurs under the conditions of the known Schotten-Baumann reaction.

Anhydrides of these dicarboxylic acids can also be used. The carboxylic acid derivatives of formula (VI) present in many

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5 cases, primarily formed, under water decomposition go directly into the imido compounds (II).

5

A

0 = <

nNH

10 \ I -> (I1) fz = °) r1 \ Χλ, no2s ^^^ coor 15 (VI)

The reaction can be easily followed by thin layer chromatography.

Depending on the choice of reaction conditions, especially when heating the reaction mixture to temperatures of from 150 to 250 ° C, the cyclized products are obtained in high yields.

The anhydride is advantageously used in a larger excess, approximately in the 2- to 3-fold excess, and the reaction is carried out in the absence of a solvent. If unsaturated dicarboxylic anhydrides are used, e.g. of the maleic anhydride, in the reaction with amino compounds of formula (IV) at temperatures of from 150 to 250 ° C at the fusion, a viscous oil, which after some time under water decomposition, becomes into the unsaturated imido compounds of the formula

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6 R6 R7> r

CrsN // 50 kJ (VII)

o) n O-S ^^^ COOR3 R Z

Wherein R 1 - R 3, R 6, R 7 and X have the meaning given above. The double bond of this imido compound enables a variety of reactions, e.g. they can be hydrogenated to form the imido compounds of formula (XI) where Z is o and A is an ethylene group.

The starting compounds of formula (II) wherein Z represents two hydrogen atoms are available by various methods, e.g. from the amino compounds of formula (IV) by reaction with ω-substituted carboxylic acid derivatives of formula (V), where z represents two hydrogen atoms, under the conditions of the Schotten-Baumann reaction and subsequent cyclization of the formed amido compounds of formula ° = ( ch2-l 30 \.

x NH

VS

V JLA, (VIII) NO2S / ^^ COOr3 R ^ under the decomposition of H-L.

35

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7

The benzoic acid derivatives of formula (II) used in the process, where Q is a protected amino group of formula (III), are available by various methods. In particular, the reaction takes place when starting from the literature known in the sulfamyl group of unsubstituted sulfamylbenzoic acid derivatives of the formula below

Y

Xx10 H2NO2S ^^ COOR3 by various condensation methods widely known from the literature for compounds of formula 15 (IX).

The following literature should e.g. Mentioned: J. Org. Chem 25 (1960), 352 - 356; Zh. Org. Khim 8 (1972), 286 - 291; Liebigs Ann. Chem. 750 (1971), 42; Zh.

Org. Khim 6 (1970), 9, 1885; B. 94 (1961), 2731-2737; 20 Ang. Ch. 28 (1966), 147 - 148; Ang. Ch. 80 (1968), 281-282; B. 97 (1964), 483-489; B. 96 (1963), 802-812; J.

Org. Chem. 27 (1962), 4566-4570; Ang. Ch. 74 (1962), 781 - 782, and Doklady Akad. SSSR 145 (1962), 584.

For example, the following derivatives can be used as compounds of general formula (IX).

R9 R8 ΥΥΊ \ I (IX) 30 N-C N02S C00h R10 35

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8

Connection

No. R8 R9 R10 Y

1 H CH3 CH3 Cl 5 2 CH3 CH3 CH3 Cl 3 H C2H5 C2H5 Cl 4 C4Hg CH3 CH3 Cl

5 H "CH3 CH3 F

6 H CH3 CH3 Br 10 7 CH3 -ch2-ch2-ch2-ch2-ch2- Cl

The compounds of formula (IX) are prepared by the above methods known in the literature or by analogy with them. Instead of the acids 15 listed above, e.g. also the corresponding methyl or ethyl esters are used.

The nitration of the benzoic acid derivatives of formula (IX) can be accomplished in various ways. One can, for example. direct benzoic acid derivatives to one of the usual nitration mixtures for nitration of reaction-slow aromatics (cf. textbook "Organicum", p. 288, edition 1967). The process can also be carried out in that the benzoic acid derivatives of formula (IX) are dissolved in oleum and the nitration is regulated by dripping of the nitric acid.

Surprisingly, it is possible to nitrate the benzoic acid derivatives of the general formula (IX) solely by introducing the protecting group into the sulfonamide group without altering other groups in the molecule.

The reaction temperature is relatively low, preferably temperatures of from 55 to 70 ° C.

Advantageously, a nitric acid is started from oleum and fuming nitric acid, the compound is allowed and the reaction mixture heated to 55-60 ° C.

Further evolution of the nitration can be followed by thin-layer chromatography. The isolation of the final products is as usual, e.g. by applying the reaction mixture to ice and filtering out the crystals obtained.

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For the nitration, acids or esters of the general formula (IX) may be used, wherein the groups Y, Q and R3 have the meaning given above. By nitrating the esters of formula (IX), in addition to the esters, in addition to the esters, the acids of formula (X) are obtained, where R 3 is H and Q is different from -NR 1 R 2.

N02

Ϊ I

1 ° a-o2sAAcooR3 <X) 15

The mixture can be separated in a conventional manner, e.g. by treatment with aqueous sodium carbonate.

The resulting compounds of formula (X) wherein R 3 is hydrogen are now esterified in conventional manner.

For the esterification of the carboxyl group, e.g.

the carboxylic acid in its acid chloride which after addition of alcohols gives the corresponding esters of formula (X).

Suitable as alcohol for the esterification are in particular alkyl alcohols having 1-4 carbon atoms such as methanol, ethanol, propanol, butanol, isopropanol or isobutanol, as well as aralkyl alcohols, e.g. benzyl alcohols or benzhydrol.

It is advantageous to use them in a 5 to 20 times molar excess or to use them as a solvent simultaneously.

By other methods known in the literature, the tert.butyl esters or benzhydryl esters can be prepared.

In the next step, the esters of formula (X) wherein R 3 is different from H are converted by reaction with compounds of formula XH into the compounds of formula (XI) where Q is different from -NR 2 R 2.

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10 no2 x ί (XI) 5 Q- ° 2S COOR3

Surprisingly, it has been found that compounds of general formula (X) wherein R 3 is alkyl can, under anhydrous conditions, react with compounds of general formula XH with good results.

As compounds of formula XH, e.g. phenol, 4-methylphenol, 3-methylphenol, 2-methylphenol, 4-chlorophenol, 3-trifluoromethylphenol, 3,5-dimethylphenol, 2,4-dimethylphenol, 4-methoxyphenol, 3-methoxyphenol, 4-propylphenyl, thiophenol and those substituted thiophenols analogously to phenol, N-methylaniline, benzenesulfinic acid, pyrrolidine, N-methylpiperazine, 5-methyl-2-mercapto-1,3,4-thiadiazole or 1-methyl-5-mercapto-1,2,3, 4-tetrazole.

Any additional functional groups present in XH, such as additional OH groups, NH 2 or mercapto groups, are blocked by conventional protecting groups, e.g. acylation.

Compounds of the general formula HOR4 and HSR4, wherein the group R4 has the indicated meaning, are of great importance. Of particular importance among these are the thiophenol and phenol derivatives, which may be substituted as set forth above.

The reaction can be carried out without solvent, but more advantageously in the presence of a solvent.

Particularly suitable are organic solvents such as ethers and tert-carboxamides, especially Diglyme, dimethylformamide or hexamethylphosphoric acid tris-amide (HMPT).

The compounds X-H are used as such in the presence of bases or in the form of their alkali or alkaline earth alimetates 1-35 salts. Alcohols or alkali metal amides are used as bases.

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11

The thiophenol and phenol derivatives are reacted in the form of their anions, in particular the alkali metal salts and, among them, especially the sodium and potassium salts, have proved particularly suitable.

The reaction may take place in the presence or absence of a solvent. Without solvent, for example, one heats up. the components for temperatures of 100 to 200 ° C, preferably 140 to 180 ° C. The products thus obtained can be isolated in the usual way, e.g. by dissolving the melt products in a solvent and subsequently precipitating 10 by adding water or an organic non-solvent.

However, particularly advantageous is the reaction with phenolates or thiophenolates in solvents at temperatures of from 100 to 200 ° C, preferably 120 to 160 ° C.

Considering solvent, organic solvents, in particular tertiary carboxamides, polyethers or high boiling solvents such as HMPT or tetramethylene sulfone, come into play. Particularly advantageous is the conversion of the esters of formula (X) into tertiary carboxamides, e.g. dimethylformamide or dimethylacetamide. Depending on the choice of reaction temperature, the reaction is completed after 1-6 hours.

The isolation of the final products of formula (XI) is carried out in a conventional manner, e.g. first, the inorganic salts can be filtered off and then the reaction product precipitated by the addition of a non-solvent, or the reaction mixture can be led to water or ice and isolate the resulting reaction product.

The reduction of the nitro group in benzoic acid derivatives of formula (XI) can be carried out in a conventional manner, e.g. by catalytic hydrogenation. The catalyst is preferably used as Raney nickel or the common precious metal catalysts, such as palladium on coal or platinum oxide (cf., for example, Organic, pp. 271 - 277, pp. 507 - 510). Compounds of formula (XII) are obtained, wherein R 3 is different from hydrogen.

35 f 12

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NH2 x 1 Y) L | J (XII) 5 Q-O ^^ COOR3

As solvent for the reduction, organic solvents are preferably used, e.g. methanol or ethanol, ethyl acetate, dioxane or other polar solvents, especially amides such as dimethylformamide, dimethylacetamide or HMPT.

One is hydrogenated at room temperature and under normal pressure or at elevated temperature and pressure, e.g. 50 ° C and 100 atm in an autoclave.

3-Imidobenzoic Acid Derivatives of Formula XIV

K

Z K / = 0 * '6 AA 3 (χΐν) Q-C ^ S ^^ COOR-3 25 where R ^ is different from hydrogen and Z is O are available by various methods. For example, when reacting amino compounds of formula (XII) with dicarboxylic acid derivatives of the general formula (XIII) capable of the formation of

O. Z

c-A-cr (xiii) / \

L L

where A has the meaning given above, Z means 0, and L means a "leaving group", preferably a halogen atom, a trialkylammonium group or the group OR 'of an activated

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13 ester. For this acylation reaction, hydroxy, amino and / or mercapto groups must be blocked in the other positions of the molecule by conventional protecting groups.

Dicarboxylic acids which can be transferred into their dicarboxylic acid halides are e.g. succinic acid, methyl succinic acid, 2,3-dimethyl succinic acid, glutaric acid, 2-methylglutaric acid, phthalic acid, cis-cyclopropanedicarboxylic acid, cyclobutane-1,2-cis-dicarboxylic acid, cyclohexane-1,2-cis-dicarboxylic acid, The reaction of these dicarboxylic acid derivatives 10 with the amino compounds of formula (XII) occurs under the conditions of the known Schotten-Baumann reaction.

Anhydrides of these dicarboxylic acids can also be used. The carboxylic acid derivatives of formula (XV), which in many cases are primarily formed, undergo water decomposition directly into the imido compounds (II).

A

20 0 = /

^ NH

VI ---> (χιν) (Z = 0)

Tj Q ^ S ^^^ COOR3 25 (XV) 30 The reaction can be readily followed by thin-layer chromatography.

Depending on the choice of reaction conditions, especially when heating the reaction mixture to temperatures of from 150 to 250 ° C, the cyclized products are obtained in high yields.

The anhydride is advantageously used in a larger excess, approximately in the 2- to 3-fold excess, and the reaction is carried out in the absence of a solvent. If you

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14 * uses unsaturated dicarboxylic anhydrides, e.g. of the maleic anhydride, in the reaction with amino compounds of formula (XV) at temperatures of from 150 to 250 ° C at the fusion, a viscous oil which, after some time during water decomposition, becomes into the unsaturated imido compounds of the formula R6 R7 w 0τ "ΐΓ ^ Ο (XVI) Q-02S / ^^ JvCOOR3 wherein the groups Q, R3, R6, R7 and X have the meaning given above. This double bond of the imido compound enables a variety of reactions, e.g. they are hydrogenated, thereby forming the imido compounds of formula (II), where Z is 0 and A is an ethylene group.

The starting compounds of formula (XIV) wherein Z represents two hydrogen atoms are available by various methods, e.g. from the amino compounds of formula 25 (XII) by reaction with ω-substituted carboxylic acid derivatives of formula (XIII) / where Z represents two hydrogen atoms, under the conditions of the Schotten-Baumann reaction and subsequent cyclization of the amido compounds of formula 30 0 = {CH2 'l JLÅ, 35 O-O2S ^ - ^ COOR3 during cleavage of HL.

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15

Examples of such carboxylic acid derivatives of formula (XIII) should be mentioned:

The bases required for the cleavage of the group H-L are preferably tertiary organic bases, such as pyridine, triethylamine or Ν, Ν-dimethylaniline, used in stoichiometric amounts or in larger excess, e.g. simultaneously as a solvent.

For the purposes of this reduction, the amido or imido derivatives may be used as free acids or in the form of the salts thereof which do not prevent the reduction, e.g. the alkali metal or alkaline earth metal salts.

In order to obtain particularly pure high yield products, it is advantageous to use the 5-cyclamylbenzoic acid esters for the reduction.

The esters (R 3 = alkyl) can be prepared from the acids by methods known in the literature. In particular, as esters, alkyl esters having 1 to 5 carbon atoms, such as the methyl, ethyl, propyl, butyl or n-pentyl ester, benzyl ester or p-methoxybenzyl ester and the t-butyl ester, benzhydryl ester and acyloxymethyl ester, the group represents the rest of a lower aliphatic carboxylic acid, e.g. acetyl or tert.butyl residue.

Considering reducing agents, complex borohydrides or diborane come in the presence of Lewis acids. In the reduction of lactams of formula (II) (Z = 2 H) one can work with diborane in the presence of Lewis acids. In contrast, 30 (Z = 0), however, requires the use of complex borohydrides in the presence of Lewis acids to obtain good yields. The detergents can be introduced into the reaction mixture under similar protective conditions, e.g. using nitrogen as inert gas. Using diborane 35, it is simpler for the reaction to absorb it in solvent and use this solution for reduction. Suitable

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16 as solvents are especially ethers, e.g. tetrahydrofuran or diethylene glycol dimethyl ether.

As complex borohydrides of boron, e.g. alkali metal boronates such as lithium borohydride, sodium borohydride or potassium borohydride, or the alkaline earth metal boronates such as calcium borohydride, but also zinc borohydride or aluminum borohydride. By the addition of Lewis acids, these borohydrides reduce the amide or imide groups present in the molecules used, surprisingly without significantly affecting the carboxylic acid ester function.

As Lewis acids in the sense of the invention, aluminum chloride, titanium tetrachloride, tin tetrachloride, cobalt II chloride, iron III chloride, mercury I chloride, zinc chloride and boron trifluoride and their addition products, in particular

Boron trifluoride etherate. Thereby, it is possible that, when reacting the boron trifluoride etherate, with the sodium borohydride, diborane can be formed in situ (cf. Fieser, Fieser: Reagents for Organic Synthesis, John Wiley and Sons, Inc.,

New York, Volume 1, p 199).

To achieve a particularly high turnover And particularly pure end products, it is advantageous to begin with the Lewis acids together with the compounds of formula (II) and to afford the complex borohydride.

It is particularly advantageous to use the Lewis acids in excess and the complex borohydride in at least stoichiometric amount, based on the amide group to be reduced.

Thus, favorable results are obtained when, e.g. using titanium tetrachloride, the triple stoichiometric amount of NaBH4 is added, while using boron trifluoride etherate the complex borohydride in stoichiometric amount can be used, calculated on the number of amide groups to be reduced.

Whether the compounds to be reduced are used as 35 imido compounds of formula (II) (Z = 0) or as amidophore compounds (Z = 2 H) is not relevant to the implementation of the reduction. In a single vessel reaction, imi-

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Surprisingly directly into the sulfamylbenzoic acid derivatives of formula (I). The reduction is carried out in a solvent. Given as a solvent, e.g. ethers such as tetrahydrofuran or diethylene glycol dimethyl ether (Diglyme). The solvent in which the reduction is effected may be the same as that in which the reducing agent is dissolved, but may also be different therefrom.

The reduction can be carried out within a wide temperature range. The reduction can be carried out at room temperature or slightly elevated temperature. While secondary amides with diborane and lactams with diborane and Lewis acid preferentially react at slightly elevated temperature (40 - 60 ° C), the reduction with complex borohydrides and Lewis acids, especially 15 by imides, often already exceeds very favorably in the temperature range of 0 to 20 ° C. . If you take slightly longer reaction times in the purchase, the reduction can also be carried out in the cold. The reduction duration depends on the reduction components used and the selected temperature.

A preferred embodiment of the present process consists in starting with the 5-sulfamylbenzoic acid derivatives of formula (II) in an inert solvent with the Lewis acid and adding a solution of the complex borohydride, optionally a suspension of the complex borohydride, in same or different solvent at room temperature and stir for a short time. The complex borohydride can also be added directly in solid form. To accelerate the reaction, the reaction may also be carried out at higher temperature or heated to 40 - 70 ° C for approx. 1 hour 30 after addition of the reducing agent.

Another embodiment consists initially of the compound to be reduced together with the complex borohydride and adding the Lewis acid at room temperature. As the complex borohydride, especially the sodium borohydride is used. Also here it may be advantageous to heat to 40 - 70 ° C for approx. 1 hour after completion of adding the Lewis acid to obtain

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18 of a faster turnover. The course of the reaction can be controlled by thin layer chromatography by the appearance of the intense light blue fluorescence (in the range of 366 nm) of the compounds of formula (I) formed. In the case of this reduction, double bonds, optionally present in group A, may be reduced.

If starting from compounds of formula (II) wherein Q is a group of formula (III), 5-sulfamylbenzoic acids of formula (I) (R 3 = H) are obtained by alkaline hydrolysis of the compounds of the general formula ( XVIII) H2 <> 2

X N

Wherein R 3 is different from hydrogen, heating these compounds of formula (XVIII) on a steam bath in sodium hydroxide solution or potassium hydroxide solution for several hours. Thereby, the esters are saponified, as well as the protecting group Q as well as any additional protecting groups present.

Alternatively, the 5-sulflamylbenzoic acids of formula (I) (R3 = H) can be prepared directly from compounds of formula (II), where Q is a group of formula (III), concentrating partially the reaction mixture after destruction of the excess reducing agent. , adds base and heats for a longer time. As a base, for example. sodium hydroxide solution. Here, the 5-sulfamylbenzoic acids of formula (I) can be isolated directly in the form of their salts. Acidification gives the free acids.

35 It is also possible to introduce the protection group Q

at a later reaction step, e.g. in compounds of formula

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19 (X), (XI), (XII) or (XIV), where Q then represents an amino group and thus reaches compounds of formula (XVIII).

The isolation of the end products can be done in 5 different ways. A preferred work-up method consists in liberating the solution of the reaction product from any reducing agent present by the addition of water and low amounts of an acid, and then precipitating the resulting 5-sulphyl benzoic acid esters by adding a non-solvent. When using diethylene glycol dimethyl ether, water is especially suitable as a non-solvent. The resulting 5-sulfamylbenzoic acid esters of formula (I) crystallize almost quantitatively and mostly in high purity.

Optionally, it is then necessary to again release 15 substituents protected by protecting groups in the group X of the sulfamylbenzoic acid derivatives of the general formula (I). For example, the p-hydroxy group is obtained by addition of the corresponding acetates.

Alternatively, the 5-sulfamylbenzoic acids of formula (I) can be prepared directly by partially concentrating the reaction mixture after destruction of the excess reducing agent, adding diluted base and optionally heating for a short time. As a base, for example. sodium hydroxide solution.

Here, the 5-sulfamylbenzoic acids of formula (I) can be isolated directly in the form of their salts. Due to the smooth course of formation of the 3-imido or 3-amido-5-sulfamylbenzoic acid derivatives of formula (II), the novel 5-sulfamylbenzoic acid derivatives of formula (I) are obtained in high purity and high space time yield of process variant a).

The reduction can be carried out with the same good result with imides or amides when substituents in the C-C chain are readily cleaved to form a carbon-carbon double bond. In this way you get, for example. starting from 2-bromo succinic acid as the starting compound for the reaction component of 35

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Formula (VIII) 3-pyrrolidine derivatives of formula (I) wherein A is one

Η H

II

5 - C = C group.

The Δ-3-pyrrolidine derivatives can be chemically converted in known manner, e.g. For example, they can be catalytically hydrogenated to the 3-position heterocyclic substituted sulfamylbenzoic acid derivatives of formula (I) wherein A represents an ethylene group, or conventional addition reactions can be carried out.

In accordance with the process of the invention, optionally, in the instant compounds of the formula (I), double bonds present can be hydrogenated in the usual manner, thereby utilizing catalytic hydrogenation.

Conversely, double bonds can also be introduced later by elimination reactions, e.g. by decomposition of hydrogen halide from halogenated compounds, by water decomposition from hydroxy compounds and other common decomposition reactions.

Once free carboxylic acids of formula (I) have been obtained using similar starting compounds, these can be transferred into the esters in the usual manner. For this purpose, alcohols of formula R 30 H or functional derivatives thereof are used or the esterification is carried out in another manner known in the literature. Conversely, first obtained carboxylic acid esters of general formula (I) can be transferred into the corresponding free carboxylic acids. In particular, hydrolysis or, in appropriate cases, also hydrogenolysis or other elimination reactions. In this way, e.g.

Thirty alkyl esters are cleaved by alkaline hydrolysis, the aralkyl esters, especially the p-nitrobenzyl esters, by hydrogenolysis or the tertiary butyl esters by cleavage of the isobutylene by the treatment with trifluoroacetic acid.

The free carboxylic acids can be transferred into their pharmaceutically acceptable salts by reaction with similar bases such as alkali metal, alkaline earth metal or ammonium hydroxides or carbonates. Finally, it is possible to manufacture

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21 of the compounds of formula (I), wherein one of the common protecting groups for the hydroxy, amino or mercapto groups is released at the last reaction step, whereby e.g. acylated hydroxy groups are hydrolyzed in the usual manner.

The protecting groups for hydroxy, amino or nmercapto groups are especially necessary in the preparation of the starting materials of formula (II) to avoid acylation with carboxylic acid derivatives of formula (V) at the undesirable sites. In this case, the present reduction 10 is often carried out with the protected hydroxy, amino or mercaptogroups, and only after the reduction is the cleavage of the protecting group as described above.

The sulfamylbenzoic acid derivatives of formula (I), as well as their pharmaceutically acceptable salts, prepared by the process of the invention are highly effective diuretics and saluretics which can be used as pharmaceuticals in the human and veterinary medicine.

Example 1 3-Nitro-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 34 g (about 0.1 mol) of 3-nitro-4-phenoxy-5-sulfamyl-benzoic acid are dissolved in 150 ml of methanol and heated. for cooking. Then slowly drop 5.4 ml of wife. H2SO4 and heated under reflux for 10 hours. On cooling, the 3-nitro-4-phenoxy-5-sulfamyl-benzoic acid methyl ester crystallizes. It can be recrystallized from a mixture of methanol and acetone.

Mp: 181 - 182 ° C.

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22

Example 2 3-Amino-4-Phenoxy-5-sulfamyl-benzoic acid methyl ester 35 g (about 0.1 mole) of 3-nitro-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are suspended in 150 ml of methanol and is hydrogenated at 40 - 50 ° C and 100 ato in a Raney nickel autoclave (5-10%). The resulting amino compound is dissolved in a steam bath by the addition of acetone and filtered from Raney nickel.

Upon cooling, the 3-amino-4-phenoxy-5-10-sulfamyl-benzoic acid methyl ester crystallizes in the pure state.

Mp: 179 ° C.

Example 3 3-N-Succinimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16.1 g (0.05 mol) of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are dissolved in 150 ml abs. dioxane and heated to boiling.

Then, with good stirring, drop evenly but separately a solution of 11.6 g (0.075 mole) of succinic dichloride in 50 ml of abs. acetone and a solution of 8 ml of pyridine in 50 ml of abs. acetone and heated to reflux. After approx.

After 2 hours the reaction is complete. The mixture is concentrated and the residual oil is taken up with a small amount of methanol. After a short time, the 3-N-succinimido-25 -4-phenoxy-5-sulfamyl-benzoic acid crystallizes out the methyl ester.

By adding some water, crystallization is completed.

Recrystallization from a mixture of methanol and acetone.

Mp: 270 ° C.

Example 3a 3-Amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester was fused at 160 - 180 ° C for approx. 2 hours with the double 35 to triple amount of succinic anhydride. On cooling and

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Addition of methane bulb crystallizes the 3-N-succinimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester.

Example 4 Dissolve 3-N-Pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester Dissolve 12.3 g (0.03 mole) of 3-N-succinimido-4-phenoxy-5-sul-family benzoic acid methyl ester or suspended in 100 ml abs. Diglyme. To this is added directly 9 g of boron trifluoride etherate and then a solution of 2.4 g (about 0.063 mole) of NaBH4 in 80 ml of Diglyme is added dropwise at room temperature and good stirring. As the reaction proceeds exothermically, cool with ice water. The reaction is usually completed after the drip and shortly after stirring.

Then, the excess reducing agent 15 is destroyed with water (foaming), the solution is filtered, and ca. Add 300 ml of yand with stirring. The crystallized 3-N-pyrr o 1 i d ino-4-phenoxy-5-sulfamyl-1-benzoic acid methyl ester is recrystallized from methanol.

White crystals with m.p. 191-192 ° C.

NMR data: (CDCl3, 60 mHz, TMS in standard) δ = 1.73 (m; 4H), δ = 3.26 (m; 4H), δ = 3.91 (s; 3H), δ = 5.0 (s; 2H), δ = 6.6-8.0 (m; 7H) in ppm.

Example 5 3-N-Pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid 61 g of 3-N-pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid - methyl ester is suspended in 350 ml of 1 N NaOH and heated on a water bath 1 hour. From the clear solution, the 3-N-pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid is precipitated with 2N HCl with good stirring. The nearly pure crude product can be recrystallized from a mixture of methanol and water.

Light yellow small plates with mp: 225 - 227 ° C with decomposition.

NMR data: (D6-DMSO, 60 mHz, TMS) δ = 1.67 (quasi-s; 4H), δ = 3.21 (quasi-s; 4H), δ = 6.6-8.0 (m; 9H) in ppm.

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24

Example 6 3-N-Glutarimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16.1 g of 3-amino-4-phenoxy-5-sulfamyl-1-benzoic acid methyl 1-ester are dissolved in 150 ml of abs. dioxane and heated to boiling.

Next, with good stirring and evenly, a solution of 16.8 g of glutaric acid dichloride in 50 ml of abs is added dropwise. acetone as well as a solution of 8 ml of pyridine in 50 ml of abs. acetone and heated to reflux. After approx. After 3 hours, the reaction is complete. The mixture is concentrated and taken up with a small amount of methanol. After a short time, the 3-N-glutarimido-4-phenoxy-5-sulfamyl-benzoic acid crystallizes out the methyl ester. It can be recrystallized from glycol monomethyl ether.

White crystals, mp: 312-314 ° C, with decomposition.

15

Example 7 3-N-Piperidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 15 g of 3-N-glutarimido-4-phenoxy-5-sulfamyl-benzoic acid - methyl ester is suspended in 200 ml of Diglyme (diethylene glycol-20-dimethyl ether). and 10 ml of boron trifluoride etherate are added. Next, at room temperature, slowly, and with good stirring, a solution of 3 g of NaBH4 in 15 ml of Diglyme is added dropwise. Then, the excess reducing agent is destroyed with a small amount of water, the solution is filtered and 500 ml of water is added with stirring. The crystallized 3-N-piperidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester can be recrystallized from alcohol.

White crystals, mp 198-199 ° C.

NMR data: (D6-DMSO, 60 mHz, TMS) δ = 1.1 (quasi-s; 6H), δ = 2.86 (quasi-s; 4H), δ = 3.92 (s; 3H ), δ = 6.7-8.1 (m; 9H) in ppm.

Example 8 3-N-Piperidino-4-phenoxy-5-sulfamyl-benzoic acid 8 g of 3-N-piperidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are suspended in 50 ml of 1 N NaOH and heated to 25

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steam bath until a clear solution is obtained. The resulting 3-N-piperidino-4-phenoxy-5-sulfamyl-benzoic acid is precipitated with 2N HCl and recrystallized from a mixture of methanol and water.

5 White crystals, mp: 258-260 ° C.

NMR data: (D 6 -DMSO, 60 mHz, TMS) S = 1.08 (quasi-s; 6H), D = 2.9 (quasi-s; 4H), δ = 6.65-8.2 ( m; 9H) in ppm.

Example 9 3-N-Phthalimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are dissolved in 200 ml of abs. dioxane and heated to boiling. Then, with good stirring, a solution of 14 ml of phthalic acid dichloride in 50 ml of acetone and a solution of 15 ml of 9 ml of pyridine in 50 ml of acetone are added dropwise. After 3 hours, the reaction is complete. The solution is concentrated, taken up with a small amount of acetone and dripped with good stirring to a mixture of ice water and 2N HCl. The 3-N-Phthalimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester precipitates as a light brown precipitate.

By recrystallization from a mixture of methanol, acetone and H2O, white crystals are obtained, mp: 237-238 ° C.

Example 10 3-N-Isoindolinyl-4-phenoxy-5 "Sulfamyl-benzoic acid methyl ester is dissolved or suspended in 150 ml of Diglyme and 16 g of 3-N-phthalimido-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester. 12 ml of boron trifluoride etherate are added, then a solution of 3.6 g of NaBH4 in 100 ml of Diglyme at room temperature is added dropwise and stirred at 60 ° C for about ¼ hour, with the addition of 400 ml of water a flocculant substance is flocculated.

It is boiled with methanol, so that the 3-N-isoindolinyl-4-phenoxy-5-sulfamyl-benzoic acid methyl ester does not dissolve.

It is extracted and recrystallized from a mixture of n-butanol and DMF.

35

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26

White needles, mp: 268-272 ° C and decomposition.

NMR data: (D6-DMSO, 60 mHz, TMS) S = 3.92 (s; 3H), δ = 4.66 (s; 4H), δ = 6.6-8.1 (m; 13H) in ppm.

Example 11 3-N-Isoindolinyl-4-phenoxy-5-sulfamyl-benzoic acid 2.5 g of 3-N-isoindolinyl-4-phenoxy-5-sulfamyl-benzoic acid methyl ester is suspended in 50 ml of 1 N NaOH and heated on a steam bath until a clear solution is formed. With 2N HCl 10, the 3-N-isoindolinyl-4-phenoxy-5-sulfamyl-benzoic acid is precipitated and recrystallized from glacial acetic acid.

Light yellow crystals, mp: 259-261 ° C and decomp.

NMR data: (D6-DMSO, 60 mHz, TMS) S = 4.68 (s; 4H), S = 6.6-8.0 (m; 13H) in ppm.

Example 12 3-N-in 2,4-Dioxo-3-azabicycloro 3.2-olheptano-4-phenoxy-5-sulphamyl-benzoic acid methyl ester 8.1 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid -Methyl ester is mixed with 6.3 g of cis-cyclobutane-1,2-dicarboxylic anhydride and 5 ml of Diglyme and heated to 180 ° C. This evaporates the Diglyme used. The melt becomes solid after approx. 1 hour. Still in the heat, it gets methanol added. The 25 solid mass falls to a white crystal porridge. The crystalline powder is aspirated and recrystallized from glycol monomethyl ether.

Mp: 284-285 ° C.

Example 13 3-N- (3-Azabicycloro3,2, Olheptano) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester 7.3 g of 3-N- (2,4-dioxo-3-azabicyclo [3 , 2.0] heptano-4-phenoxy-5-sulfamyl-benzoic acid methyl ester is suspended in 70 ml of Diglyme and 6 ml of boron trifluoride etherate is added.

Next, a solution is slowly added dropwise under ice-cooling

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27 of 1.5 g NaBH4 in 70 ml Diglyme. Stir for approx. 15 minutes and the 3-N- (3-azabicyclo [3.2.0] heptano) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester is precipitated by the addition of water.

Recrystallization from methanol or acetonitrile gives white crystals, mp: 176-177 ° C.

Example 14 3-N- (3-Azabicycloro.2.2 Olheotano) -4-phenoxy-5-sulfamyl-benzoic acid 6.2 g of 3-N- (3-azabicyclo [3.2.0] heptano) - 4-Phenoxy-5-sulfamyl-benzoic acid methyl ester is suspended in 60 ml of 1 N NaOH and heated on a water bath until a clear solution is obtained. The acid is then precipitated with 2N HCl with good stirring and recrystallized from glacial acetic acid.

White-yellow small plates with mp: 254-255 ° C during decomposition.

Example 15 3-N- (cis-1,2-Cyclohexanedicarboximido) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester 8 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester were fused with 7.5 g of cis-cyclohexane-1,2-dicarboxylic anhydride with the addition of a few drops of Diglyme. The temperature is maintained at 180-200 ° C with stirring until the mass begins to solidify. Next, methanol is gently added and the crystallized white compound is suctioned off.

From glycol monomethyl ether, white crystals, mp: 268-269 ° C.

30

Example 16 3-N- (3,5-Dioxo-morpholino) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are mixed with 15 g diglycolic anhydride and 10 ml Diglyme and heated to approx. 180 ° C in an open flask. After 1-2 hours

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28, methanol is added carefully. The imide crystallizes on cooling.

Diglyme white crystals, mp: 295-297 ° C.

Example 17 3-N-Morpholino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 9.4 g of 3-N- (3,5-dioxo-morpholino) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester is suspended in 100 ml of Diglyme and 6 ml of boron trifluoride etherate are added. Then, slowly, with ice-cooling and good stirring, a solution of 1.9 g of NaBH4 in 100 ml of Diglyme is added slowly. Upon addition of water, the resulting 3-N-morphol ino-4-phenoxy-5-sulfamyl-benzoic acid - methyl ester is precipitated.

From methanol, mp: 221-222 ° C.

15

Example 18 3-N-Morpholino-4-phenoxy-5-sulfamyl-benzoic acid

The corresponding methyl ester (Example 17) is heated on a water bath with 1 N NaOH until a clear solution is formed. Upon addition of 2 N HCl, the 3-N-morpholino-4-phenoxy-5-sulfamyl-benzoic acid is precipitated and then recrystallized from methanol.

Brownish-white crystals, mp: 194-197 ° C, with decomposition.

25

Example 19 3-N- (4-Methylglutarimido) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester and 15 g of 4-methylglutaric anhydride mix to a porridge while adding some Diglyme and heat to 160-180 ° C for 2-3 hours. The 3-N- (4-methylglutarimido) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester is precipitated by the addition of methanol.

35 White crystals from glycol monomethyl ether, mp: 315 ° C.

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29

Example 20 3-N-M-Methylpiperidino) -4-phenoxy-5-sulfamic-benzoic acid methyl ester 10.3 g of 3-N- (4-methylglutarimido) -4-phenoxy-5-sulfamyl-5-benzoic acid methyl ester is suspended in 100 ml of Diglyme and 6.5 ml of BF3 etherate is added. In addition, a solution of 1.9 g NaBH4 in 100 ml Diglyme at room temperature is dripped. After the drip, stir for a further 15 minutes, and then the 3-N- (4-methylpiperidino) -4-phenoxy-5-sulfosamyl-benzoic acid meltsyl ester is precipitated with water.

Colorless crystals from methanol, mp: 143-144 ° C.

Example 21 3-N- (4-Methylpiperidino) -4-phenoxy-5-sulfamylbenzoic acid

The corresponding methyl ester (Example 20) is heated on a water bath with 1 N NaOH until a clear solution is formed. Upon addition of 2N HCl, the 3-N- (4-methyl-piperidino) -4-phenoxy-5-sulfamyl-benzoic acid is precipitated.

20 White crystals from a mixture of methanol and water, mp: 243-244 ° C.

Example 22 3-N- (3-Methylsuccinimido) -4-phenoxy-5-sulfamyl-benzoic acid 25-methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester and 15 g of 3-methyl succinic anhydride fused with some Diglyme in an open flask and held at approx. 180 ° C for approx.

2.5 hours. Upon addition of methanol, 3-N-30- (3-methylsuccinimido) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester crystallizes.

From glycol monomethyl ether, white crystals, mp: 272 ° C.

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30

Example 23 3 - [(3-MethylPyrrolidino) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester 17 g of 3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamyl-5-benzoic acid methyl ester suspended in 150 ml Diglyme. To this is added 11 ml of BF3 etherate and then a solution of 3 g of NaBH4 in 150 ml of Diglyme is added dropwise under ice-cooling. After the drip, the resulting 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester is precipitated with water.

10 White crystals from methanol, mp: 145 ° C.

Example 24 3-N- (3-Methylpyrrolidino) -4-phenoxy-5-sulfamyl-benzoic acid 9 g of 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamyl-15-benzoic acid methyl ester are heated on a water bath. 1 N NaOH until a clear solution is formed. At room temperature, the 3-N- (3-methylpyrrolidino) -4-phenoxy-5-sulfamylbenzoic acid is then precipitated with 2N HCl and recrystallized from a mixture of CH 3 OH and H 2 O.

20 White-yellow crystals with m.p. 206-208 ° C.

Example 25 3-N-Maleinimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester and 15 g of maleic anhydride are heated together with some Diglyme to ca. . 180 ° C in an open flask. After 3 hours, cool and methanol and some water are added. The 3-N-Maleinimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester precipitates upon prolonged standing.

Recrystallization from methanol, white crystals, mp: 197-198 ° C.

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31

Example 26 3- N-Pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester

Method B

Dissolve 4.1 g of 3-N-succinimido-4-phenoxy-5-sulfamyl-benzoic acid-5-methyl ester in 40 ml of Diglyme and add 2.5 ml of titanium tetrachloride. Next, a solution of 1.1 g of NaBH4 in 30 ml of Diglyme is slowly dropped at room temperature and stirred for a further approx. 1 hour.

The resulting 3-N-pyrrolidino-4-phenoxy-5-sulfamyl-10-benzoic acid methyl ester is precipitated with water and recrystallized from methanol.

Mp: 191 ° C.

Example 27 4-Chloro-3-succinimido-5-sulfamyl-benzoic acid methyl ester 25.4 g of 4-chloro-3-amino-5-sulfamyl-benzoic acid methyl ester, m.p. 195-196 ° C is well mixed with 25 g of succinic anhydride and melted at 180 ° C for 6 hours. Next, allow to cool slowly and CH3OH is gently added. The product 20 crystallizes. A slight addition of water completes the crystallization.

Recrystallization from glycol monomethyl ether, mp: 267-269 ° C.

Example 28 4- Chloro-3-pyrrolidino-5-sulfamyl-benzoic acid 20 g of imide (Example 27) is suspended in 200 ml of Diglyme and 17 ml of BFg etherate is added. To this suspension, a solution of 4 g of NaBH4 in 200 ml of Diglyme is added dropwise under ice-cooling.

After addition, stir for 1 hour and then gently hydrolyze with a small amount of water. Filter and the 4-chloro-3-pyrrolidino-5-sulfamyl-benzoic acid methyl ester is precipitated with water.

From methanol, mp: 189-191 ° C.

The ester is saponified on a steam bath in 1 N NaOH until a clear solution is formed. When acidifying to a pH

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32 out of 4 precipitates the free acid.

Light yellow crystals from a mixture of CH 3 OH and 0, mp: 259-261 ° C.

Example 29 3-N-Succinimido-4-phenylthio-5-sulfamyl-benzoic acid methyl ester 5.8 g of 3-amino-4-phenylthio-5-sulfamyl-benzoic acid methyl ester are mixed with 5.9 g of succinic anhydride and combined -10 is melted at 170 ° C. After 5 hours, CH3OH is gently added while cooling. The compound crystallizes and recrystallizes from glycol monomethyl ether.

Mp: 250-252 ° C.

Example 30 3-N-Pyrrolidino-4-phenylthio-5-sulfamyl-benzoic acid 14.7 g of imide (Example 29) is suspended in 100 ml of Di-glyme and 10 ml of BF3 etherate is added. Next, drop 2.8 g of NaBH4 dissolved in 100 ml of Diglyme slowly under ice-cooling. The mixture is stirred for an additional hour at room temperature, and then the excess reducing agent is destroyed by the addition of a small amount of water. Then the 3- N-pyrrolidino-4-phenylthio-5-sulfamyl-benzoic acid methyl ester is precipitated with water and recrystallized from methanol.

Yellow crystals, mp 139-140 ° C.

The ester is heated on a steam bath with 1 N NaOH until a clear solution is formed, and then the acid formed is precipitated with 1 N hydrochloric acid at a pH of 3-4.

From a mixture of methanol and water, yellow crystals 30, mp: 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-sulf-amino-benzoic acid are dissolved in 100 ml of 1 N NaOH and mix with 10 ml of dimethyl sulfate. The mixture is well stirred at room temperature.

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33 perature. After approx. 30 minutes precipitates a white fluffy substance. It is aspirated with a suction filter and heated on a steam bath with 2 N NaOH. After a clear solution is formed, it is allowed to cool and precipitate the 4-phenoxy-3- (1-pyrrolidinyl) -5-dimethylsulfamoyl-benzoic acid with 2N HCl. The substance can be recrystallized from a mixture of methanol and water.

Yellow fibers, mp: 214-215 ° C.

Example 32 4-Phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoyl-benzoic acid a) 4-Phenoxy-3-N-succinimido-5-methylsulfamoyl-benzoic acid methyl ester.

71 g of 3-amino-4-phenoxy-5-methylsulfamoyl-benzoic acid methyl ester (m.p .: 188 ° C) are melted at 180-190 ° C with 87 g of succinic anhydride. After 5 hours, methanol is gently added to the melt and then the same amount of water, thereby crystallizing the imide. The 4-phenoxy-3-N-succinimido-5-methylsulfamoyl-benzoic acid ester is obtained from methanol, m.p.

249-250 ° C.

B) 4-Phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoyl-benzoic acid methyl ester.

67 g of 4-phenoxy-3-N-succinimido-5-methylsulfamoylbenzoic acid methyl ester are suspended in 300 ml of abs. Diglyme and 40 ml boron trifluoride etherate are added. Next, 25 to -10 ° C is cooled and slowly, and with good stirring, a solution of 12.2 g of NaBH4 in 300 ml of Diglyme is added dropwise. The temperature should not exceed 10 ° C. After the drip, stir for a further 10 minutes and then add water gently (foaming) to the mixture. Upon further addition of water, the reaction product precipitates. Recrystallization from methanol gives 4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoyl-benzoic acid methyl ester with m.p. 138-139 ° C. c) 4-Phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoyl-benzoic acid.

54 g of the methyl ester obtained in b) is suspended in 500 ml of 1N NaOH and heated on a steam bath with stirring. After a clear solution is formed, allow to cool, 34

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and the free acid precipitates with 1N HCl. Recrystallization from a mixture of methanol and water gives 4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoyl-benzoic acid, m.p. 245-248 ° C with decomposition.

5

Example 33 4- (4 1 -Methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-Nitro-4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid.

Dissolve 124 g (0.9 mole) of potassium carbonate in 800 ml of water.

To this solution is added portionwise 1.6 moles of β-cresol and then 112 g (0.4 moles) of 2-chloro-3-nitro-5-carboxyl-benzenesulfonamide and the solution is heated to 85 ° C. Stir at this temperature for 16 hours, cool to 25-30 ° C and acidify to a pH of 1 with concentrated hydrochloric acid. The resulting oil is separated from the aqueous phase and subjected to a steam vapor distillation. Alternatively, a pH value of 8-9 can also be adjusted, the excess phenol is quenched with ethyl acetate and then acidified the aqueous phase.

After the excess β-cresol is separated in this way, the product crystallizes on cooling. Recrystallization from a mixture of acetone and H 2 O gives the 3-nitro-4- (41-methylphenoxy) -5-sulfamoyl-benzoic acid, m.p. 236 ° C.

B) 3-Nitro-4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid methyl ester.

The crude product obtained in Example 33 (a) is dissolved in methanol and heated to boiling. Then add 5-10% wife. sulfuric acid (relative to the benzoic acid used) and refluxed for 8 hours. The solution is now concentrated to one third and cooled to 5-10 ° C.

The methyl ester crystallizes: Crystals having mp: 161-162 ° C.

35

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C) 3-Amino-4- (41-methylphenoxy) -5-sulfamoyl) -benzoic acid methyl ester.

45 g of 3-nitro-4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid methyl ester are suspended in 150 ml of acetic acid ethyl ester 5 and hydrogenated for 5 hours at 50 ° C and 100 atm hydrogen with Raney nickel. After cooling, the solution is separated from Ra nickel and concentrated to dryness.

3-Amino-4- (41-methylphenoxy) -5-sulfamoyl-benzoic acid - methyl ester is recrystallized from a mixture of methanol 10 and H 2 O.

Crystals, mp: 183-185 ° C.

d) 3-N-Succinimido-4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid methyl ester.

27 g (about 0.08 mol) of 3-amino-4- (4'-methylphenoxy) -5- sulfamoyl-benzoic acid methyl ester are melted with 24 g (ca.

0.24 mol) succinic anhydride at 170-190 ° C for 4 hours. When cooling the melt, gently add methanol and some water. The imide precipitates and recrystallizes from a mixture 20 of CH 3 OH and H 2 O.

Crystals, mp: 240-241 ° 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-sulfamoyl-benzoic acid methyl ester are suspended in 150 ml of Diglyme and 16 ml of BF3 etherate are added. Next, a solution of 4.6 g of NaBH4 in 200 ml of abs is dropped. Diglyme slowly, under ice-cooling and with good stirring. As far as possible, the temperature should not exceed 20 ° C. Stir for an additional 15 minutes and the product is finally precipitated with water.

Recrystallization from CH 3 OH, crystals mp: 156-157 ° C.

F) The methyl ester prepared under e) is suspended in 1 N NaOH and heated on a steam bath until a 36

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clear solution. It is then filtered and acidified to a pH of 3. The resulting 4- (4'-methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid is recrystallized from methanol.

5 Light yellow crystals, mp: 230-233 ° C with decomposition.

Example 34 4- (4 L-Methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-Nitro-4- (4'-methoxyphenoxy) -5-sulfamoyl-benzoic acid.

The reaction is carried out analogously to Example 33 a) with p-methoxyphenol. The product is recrystallized from a mixture of acetone and water and has a mp: 233-234 ° C.

b) 3-N itro-4- (4'-methoxyphenoxy) -5-sulfamoyl-benzoic acid methyl ester.

Analogously to Example 33 (b). Recrystallization from 20 methanol, mp: 150-152 ° C.

c) 3-Amino-4- (4'-methoxyphenoxy) -5-sulfamoylbenzoic acid methyl ester Analogous to Example 33 c). Recrystallization from methanol, mp: 176-177 ° C.

d) 3-N-Succinimido-4- (4'-methoxyphenoxy) -5-sulfamoyl-ben-30zoic acid methyl ester.

Analogously to Example 33 d), mp: 226-227 ° C.

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E) 4- (4 L-Methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid methyl ester.

Analogously to Example 33 e), mp: 190-191 ° C.

f) 4- (4'-Methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is prepared analogously to Example 33 f) and recrystallized from a mixture of methanol and water.

10 Light yellow crystals, mp: 228-229 ° C.

Example 35 4 - [(1,5 '- 1-Dimethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid (a) 3-Nitro-4- (3', 5'-dimethylphenoxy) -5- sulfamoyl-benzoic acid.

The reaction is carried out analogously to Example 33 a) with 3,5-dimethylphenol. The crude product thus obtained is directly esterified.

B) 3-Nitro-4- (3 ', 5'-dimethylphenoxy) -5-sulfamoy 1-benzoic acid methyl ester.

Analogous to 33 b), recrystallization from methanol, mp: 197-198 ° C.

C) 3-Amino-4- (3 ', 5'-dimethylphenoxy) -5-sulfamoyl-benzoic acid methyl ester.

Analogous to 33c), recrystallization from methanol, mp: 195-196 ° C.

D) 3-N-Succinimido-4- (3 ', 5, -dimethylphenoxy) -5-sulfamoylbenzoic acid methyl ester.

Analogous to 33 d), recrystallization from methanol, mp: sintering temperature of 220 ° C.

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E) 4- (3 ', 5'-Dimethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester.

Analogous to 33 e), recrystallization from methanol, mp: 208-209 ° C.

5 f) Analogously to Example 33 f). The 4- (3 ', 5'-Dimethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid is recrystallized from methanol and water, mp: 246-248 ° C, with decomposition.

10

Example 36 4-141-Chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-Nitro-4- (41-chlorophenoxy) -5-sulfamoyl-benzoic acid.

Preparation analogous to Example 33 a) with p-chloro-phenol. Recrystallization from a mixture of acetone and water, mp: 248 ° C.

b) 3-Nitro-4- (4 * -chlorophenoxy) -5-sulfamoyl benzoic acid methyl ester.

Analogous to 33 b), recrystallization from methanol, mp: 171-172 ° C.

c) 3-Amino-4- (4'-chlorophenoxy) -5-sulfamoy 1-benzoic acid methyl ester.

Analogous to 33c), recrystallization from methanol, mp: 198-199 ° C.

d) 3-N-Succinimido-4- (4'-chlorophenoxy) -5-sulfamoyl-benzoic acid methyl ester.

Analogous to 33 d), recrystallization from methanol, mp: 266-267 ° C.

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

35

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39

Analogously to 33 e), recrystallization from a mixture of methanol and water, mp: 200 ° C.

F) 4- (4'-Chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid.

Analogous to 33 f), recrystallization from methanol, mp: 253-254 ° C.

Example 37 4- (3-Trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-Nitro-4- (3 '-trifluoromethylphenoxy) -5-sulfamoyl-benzoic acid.

Analogously to Example 33 a) with 3-trifluoromethylphenol.

Recrystallization from a mixture of acetone and water, mp: 210 ° C.

b) 3-Nitro- (3'-trifluoromethylphenoxy) -5-sulfamoyl-benzoic acid-2-methyl ester.

Analogous to 33 b), recrystallization from methanol, mp: 141-143 ° C.

c) 3-Amino-4- (3 * -trifluoromethylphenoxy) -5-sulfamoyl-benzoic acid methyl ester.

Analogous to 33 c), recrystallization from methanol, mp: 186-187 ° C.

d) 3-N-Succinimido-4- (3'-trifluoromethylphenoxy) -5-sulfamoyl-ΙΟ-benzoic acid methyl ester.

Analogous to 33 d), recrystallization from methanol, mp: 227-228 ° C.

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E) 4- (3'-Trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl benzoic acid methyl ester.

Analogous to 33 e), recrystallization from methanol, mp: 170-171 ° C.

F) 4- (3'-Trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl benzoic acid.

Analogously to 33 f), recrystallization from glacial acetic acid, mp: 230-234 ° C.

10

Example 38 4- (4 * -Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3N- (3-Methylsuccinimido) -4- (4'-methylphenoxy) -5-sulfamoyl-15 benzoic acid methyl ester.

20 g of 3-amino-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester [cf. Example 33 c)] is melted at 180 ° C for 3 hours with 18 g of methyl succinic anhydride.

Upon cooling the melt, the product crystallizes 20 by the addition of methanol. It is recrystallized from a mixture of acetone and water, mp: 229-230 ° C.

b) 4- (4 L-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulf-2-amino-benzoic acid methyl ester.

22 g of 3N- (3-methylsuccinimido) -4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid methyl ester are suspended in 200 ml of abs. Diglyme and 13 ml of BF3 ~ etherate are added. At -5 to 0 ° C, a solution of 3.3 g of NaBH 4 in 200 ml of 30 Diglyme is then slowly and slowly stirred. Stir for 1 hour and the resulting product precipitates with water. Recrystallization from a mixture of methanol and water, mp: 177-178 ° C.

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41 c) 4- (41-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoyl benzoic acid.

14 g of methyl ester [38 b)] are suspended in 150 ml of 1 N NaOH and heated under good stirring on a steam bath. After a clear solution is formed, stir for a further 1 hour and then acidify with ice-cooling with 2 N HCl until a pH of about 3 is reached. The resulting product is filtered off on a suction filter, washed well with water and recrystallized from a mixture of methanol and water, mp: 220-221 ° C.

Example 39 4-Phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

A solution of 7.8 g of 4-phenylmercapto-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid in 130 ml of glacial acetic acid and 20 ml of 30% H2 O2 is stirred at room temperature. The course of the reaction is followed by thin layer chromatography. After 20 hours, the solution is poured out in approx. 800 ml of ice water. The precipitate is aspirated, washed with water and dried. Recrystallization from a mixture of methanol and water gives 4-phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid.

Yellow crystals, mp: 142-144 ° C, with decomposition.

Example 40

4- (Phenoxy-3-yl-pyrrolidinyl-5-sulfamoyl-benzoic acid) Method G

a) 4-Chloro-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid.

To a solution of 58.9 g (0.25 mole) of 4-chloro-5-sulfamoyl-benzoic acid in 183 g (2.5 mole) of dimethylformamide (DMF), 90 ml (1.25 mole) of thionyl chloride is added dropwise. 10 ° C. The solution is then allowed to come to room temperature, stirred for 2 hours and poured on ice, filtered the precipitate and washed neutral with water. 4-Chloro-5- [beta] -dimethylaminomethylenaminosulfonyl benzoic acid (in particular

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42 divides good yield) as crystals, mp: 266-267 ° C.

b) 3-Nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl - benzoic acid.

To 60 ml of 20% oleum, 42 ml of smoking nitric acid are added dropwise under ice-cooling, then slowly added 34.9 g (0.12 mole) of 4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl benzoic acid. After stirring for 24 hours at 55-60 ° C, the solution is cooled to room temperature, poured onto ice and the precipitate is washed neutral with water. 3-nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid is obtained in the form of crystals having m.p. 274-276 ° C.

c) 3-Nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl-15-benzoic acid methyl ester.

50.4 g (0.15 mol) of 3-nitro-4-chloro-5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid are refluxed for 1 hour in a solution of 150 ml of thionyl chloride containing 5 drops of DMF. After removal of the excess 20 thionyl chloride in vacuo, the solid acid chloride is suspended in 200 ml of methanol. The suspension is refluxed for ¼ hour, then cooled, filtered and washed with cold methanol.

3-nitro-4-chloro-5-N, N-dimethylaminomethylene-25-aminosulfonyl-benzoic acid methyl ester is obtained in the form of crystals having m.p. 168-169 ° C.

d) 3-N itro-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

A solution of 105 g (0.3 mole) of 3-nitro-4-chloro-5- N, N-dimethylaminophenylsulfonylbenzoic acid methyl ester and 47.5 g (0.36 mole) of potassium phenolate in 600 ml The DMF is refluxed for 2 hours. After cooling and filtering the potassium chloride, the solution is poured onto a mixture of 35 ice and water and stirred for 1 hour. The precipitate is filtered, washed with water and dried.

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43

After dissolving the crude product in 900 ml of acetone, clear with charcoal which is evaporated to 500 ml and diluted with 1 liter of methanol. The precipitate is filtered after stirring at 10 ° C for 1 hour and washed with cold methanol.

5-Nitro-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester is obtained in the form of crystals having m.p. 191-193 ° C.

e) 3-Amino-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

61 g (0.15 mol) of 3-nitro-4-phenoxy-5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester is hydrogenated with Raney nickel in methanol for 8 hours at room temperature and under normal pressure. After filtration, catalyst 15 is suspended in hot DMF and filtered and the DMF filtrate is poured onto a mixture of ice and water.

3-amino-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester is obtained in the form of crystals having m.p. 255-256 ° C.

F) 3-N-Succinimido-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester.

30 g of 3-amino-4-phenoxy-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester are melted at 180 ° C with 25 g of succinic anhydride. After approx. 2 hours of reaction duration, the resulting imide is precipitated with methanol. However, when recrystallized from n-butanol, the yield is obtained in very good yield with m.p. 283-284 ° C.

G) 4-Phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester.

23 g (0.05 mol) of 3-N-succinimido-4-phenoxy-5-N, N - dimethylaminomethylenaminosulfony-1-benzoic acid methyl ester are suspended in 200 ml of diethylene glycol dimethyl ether (Diglyme), 35 and 13 ml of BF 3 etherate ( 0.1 mol) is added. Next, a solution of 3.8 g (0.1 mole) of NaBH 4 in 200 ml of Diglyme elongate is added dropwise.

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44 while cooling, and at the same time a temperature range of -10 to + 5 ° C is observed. Next, allow to warm to room temperature to form a clear solution. After 1 1/4 hour, the reaction is complete. By adding water 5, the product precipitates. Recrystallization from methanol gives 4-phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester, m.p. 189-190 ° C.

h) 4-Phenoxy-3- (1-pyrrolidinyl) -5-sulfamylbenzoic acid.

13 g (about 0.03 mole) of 4-phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester are suspended in 100 ml of 2N NaOH and saponified at 80 90 ° C with good stirring. When a clear solution is formed, stir at the same temperature for an additional 1 hour. It is then cooled to 0 ° C and 110 ml of 2N hydrochloric acid is added slowly and with good stirring. Intensely stirred after 1 hour and then the extremely fine product obtained is suctioned sharply. The substance is recrystallized from a mixture of methanol and water.

20 Light yellow small plates with mp: 226-228 ° C.

Example 41

The reaction sequence of Example 40 is repeated until step c). Next, the resulting 3-nitro-4-25 -chloro-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester with potassium phenolate is heated to 190-200 ° C for 2 hours.

The reaction mixture is cooled, taken up in acetone and worked up in the manner described in step d) after separation of the inorganic constituents. There is obtained 3-nitro-4-phenoxy-5-N, N, dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester which can be transferred analogously to the desired end product in the manner indicated in Example 40.

Example 42 a) The reaction sequence of Example 40 is repeated with the exception that the catalytic hydrogenation of 3-nitro

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The 45 -4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester is carried out at 50 ° C and 50 atm in an autoclave. After cooling, the desired 3-amino-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid ester is isolated in the manner described in Example 40 (e).

b) The reaction sequence of Example 40 is repeated with the exception that the catalytic hydrogenation of 3-nitro-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester in dimethylformamide (DMF) is carried out with Raney nickel at room temperature and under normal pressure. After filtration of the catalyst, the DMF solution is poured onto ice. There is obtained 3-amino-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester, m.p. 255-15 256 ° C.

Example 43

The reaction sequence of Example 40 is repeated with the difference that the 4-chloro-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester is used as the starting compound.

a) 4-Chloro-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

To a solution of 74.9 g (0.3 mole) of 4-chloro-5-sulfamoyl benzoic acid methyl ester in 183 g (2.5 mole) of dimethylformamide, 90 ml (1.25 mole) of thionyl chloride is added dropwise. 10 ° C and worked up as described in Example 40. This gives 4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester with m.p. 174-176 ° C.

b) 3-Nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl - benzoic acid methyl ester.

Under the same conditions as in Example 40 b), 36.5 g (0.12 mole) of 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonyl benzoic acid methyl ester is reacted. A mixture is obtained

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46 of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid and 3-nitro-4-chloro-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester. The mixture is separated by treatment with 5% aqueous sodium carbonate. There is obtained 5 3-nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl - benzoic acid methyl ester with m.p. 168-169 ° C and after acidification 3-nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl - benzoic acid, m.p. 270-272 ° C, which can also be transferred into the ester in the manner described in Example 40 c).

The further reaction is then carried out in the reaction sequence described in Example 40.

Example 44

The nitration described in Example 40 is carried out with the difference that ethyl ester is used instead of the methyl ester.

a) 4-Chloro-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid ethyl ester.

To a solution of 65 g (0.25 mol) of 4-chloro-4-sulfonamyl-benzoic acid ethyl ester in 183 g (2.5 mol) of DMF is dropped 90 ml (1.25 mol) of thionyl chloride at -10 ° C. and worked up as in Example 40. 4-Chloro-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid ethyl ester is obtained in the form of 25 crystals, m.p. 119-121 ° C.

b) 3-Nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl - benzoic acid ethyl ester.

Under the same conditions as set forth in Example 43, 38.3 g (0.12 mol) of 4-chloro-5-N, N-dimethylaminomethyleneamino sulfonyl 1-benzoic acid ethyl ester is reacted. The separation of the nitro ester and nitric acid occurs as indicated in Example 43.

3-nitro-4-chloro-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid ether ester is obtained in the form of crystals 35, m.p. 182-184 ° C and after acidification of the aqueous solution 3-nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonyl

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47 -benzoic acid in the form of crystals with m.p. 270-2729C which, according to melting point and mixture, is identical to the carboxylic acid described in Example 43 (b).

Example 45 3- Nitro-4-phenoxy-5-sulfamyl-benzoic acid

The reaction sequence described in Example 40 is repeated until the step of the 3-nitro-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid ester. Next, 100 g of 3-10-nitro-4-phenoxy-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester in 500 ml of 2N NaOH is refluxed for 2 hours. After cooling, acidify with concentrated hydrochloric acid. 3-nitro-4-phenoxy-5-sulfamyl-benzoic acid is obtained in the form of crystals having m.p. 254-255 ° C.

15

Example 46 4- Phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid ethyl ester 36.2 g of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid are dissolved in 200 ml of methanol and 7 ml of H2 SO4 and heated at reflux for 4-6 hours. Upon cooling, the ester crystallizes.

Recrystallization from methanol, mp: 19 ° C.

Example 47 4-Phenylmercapto-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid The reaction sequence set forth in Example 40 to prepare 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester is repeated.

A) 3-Nitro-4-phenylmercapto-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

A solution of 21 g (0.06 mol) of 3-nitro-4-chloro-5- N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester, 7.7 g (0.07 mol) of thiophenol and 8 2 g (0.077 mole) of sodium carbonate in 100 ml of DMF is refluxed for 2 hours

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48 hours. After cooling and filtration, the solution is poured onto a mixture of ice and water and stirred for 1 hour. The precipitate is filtered, washed with water and dried. The crude product is recrystallized from a mixture of acetone and methanol.

There are obtained 3-nitro-4-phenylmercapto-5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester in the form of crystals having m.p. 207 ° C.

b) 3-Amino-4-phenylmercapto-5-N, N-dimethylaminomethylenamino-sulfonyl-benzoic acid methyl ester.

2 g (0.0047 mol) of 3-nitro-4-phenylmercapto-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester are hydrogenated for 8 hours at room temperature and normal pressure with Raney nickel in 30 ml of DMF. The catalyst is aspirated, washed with hot DMF and the DMF filtrate is poured onto a mixture of ice and water.

3-amino-4-phenylmercapto-5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester is obtained from acetone in the form of crystals, m.p. 214-215 ° C.

C) 3-N-Succinimido-4-phenylmercapto-5-N, N-dimethylaminomethylenaminosulfonyl benzoic acid methyl ester.

35 g (0.089 mol) of 3-amino-4-phenylmercapto-5-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester is finely quenched with 26.6 g (0.2668 mol) of succinic anhydride and melted at 175 ° C for 2 hours. After cooling to 150 ° C, dilute with 100 ml of DMF and pour the solution slowly onto a mixture of ice and water. The precipitate is aspirated, dried and recrystallized from a mixture of DMF and CH 3 OH.

Mp: 261-263 ° C.

d) 4-Phenylmercapto-3- (1-pyrrolidinyl) -5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester.

To a solution of 32 g of 3-N-succinimido-4-phenylmer-35-capto-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid - methyl ester and 17.5 ml of BF3 etherate in 135 ml of absolute Diglyme

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49, a solution of 5.1 g NaBH4 in 135 ml abs is dripped. Diglyme at a temperature of 0-10 ° C with good stirring. After 2 hours, it is hydrolyzed and the product precipitates by further water addition.

E) The precipitated crude product is heated under reflux with 2 N NaOH until a clear solution is formed. 4- Phenylmercapto-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with 2N HCl and recrystallized from a mixture of 10 CH 3 OH and H 2 O.

Mp: 237-238 ° C, see also Example 33.

Example 48 4-Phenylmercapto-3- [1- (3-methylpyrrolidinyl] -5-sulfamoyl-15-benzoic acid a) 3-Amino-4-phenylmercapto-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid methyl ester.

A solution of 110 g of 3-nitro-4-phenylmercapto-5- N, N-dimethylamino-methylamino sulfonyl-benzoic acid methyl ester in 400 ml of DMF hydrogenates at 40 ° C and 100 atm for 8 hours over approx. 10 g Raney Nickel. The catalyst is filtered and the solution is poured onto ice. The precipitate is filtered, dried and recrystallized.

Mp: 214-215 ° C.

B) 3-N- (3-Methylsuccinimido) -4-phenylmercapto-5-N, N-dimethyl 1-aminomethylenaminosulfonylbenzoic acid methyl ester.

40 g (0.1 mole) of 3-amino-4-phenylmercapto-5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester are melted at 175 ° C for 2 hours with 34 g (0.3 mole) methylsuccinic acid anhydride. After cooling to 150 ° C, dilute with 100 ml of DMF and pour the solution slowly onto a mixture of ice and water. The precipitate is aspirated and recrystallized from CH 3 OH. Mp: 206-207 ° C.

50

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c) 4-Phenylmercapto-3- [1- (3-methylpyrrolidinyl)] - 5-N, N - dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

To a solution of 29.4 g of 3-N- (3-methylsuccinimido) -4-phenylmercapto-5-N, N-dimethylaminomethylenaminosulfonyl-5-benzoic acid methyl ester and 15.9 ml of BF3 etherate in 120 ml of absolute Diglyme a solution of 4.65 g of NaBH4 in 120 ml of abs. Diglyme at 0-10 ° C. After 2 hours of stirring, the reaction product is gently precipitated with water.

Recrystallization from CH 3 OH, mp: 147-148 ° C.

D) 4-Phenylmercapto-3- [1- (3-methylpyrrolidinyl)] -5-sulfamoylbenzoic acid.

4 g of the ester [Example 48 c) J is refluxed for 2 hours in 40 ml of 2 N NaOH. A clear solution is formed. After cooling and acidification with 2N HCl to a pH of 2-3, 4-phenylmercapto-3- [1- (3-methylpyrrolidinyl)] -5-sulfamoylbenzoic acid precipitates. It is recrystallized from a mixture of CH 3 OH and H 2 O.

Yellow crystals, mp: 216-217 ° C.

20

Example 49 4-Phenylsulfoxy-3- [1- (methylpyrrolidinyl)] - 5-sulfamoyl-benzoic acid

A solution of 6 g of 4-phenylmercapto-3- [1- (methylpyrrolidinyl)] -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid in 70 ml glacial acetic acid and 15 ml of 30% H2 O is stirred at 5-20 ° C. After 20 hours, the solution is poured onto "ice water". The precipitate is washed with water, dried and hydrolyzed at 100 ° C for 2 hours with 30 ml of 2 N NaOH. The hydrolyzate is filtered and acidified to a pH of 2-3 with 2N HCl with stirring in the cold. Thereby, 4-phenylsulfoxy-3- [1- (methylpyrrolidinyl)] -5-sulfamoyl benzoic acid precipitates. By recrystallization from a mixture of methanol and water, yellow crystals are obtained, mp: 143-145 ° C, with decomposition.

35 51

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Example 50 4- (41-Nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-N-Succinimido-4 (4'-nitrophenoxy) -5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester.

5 g of 3-N-succinimido-4-phenoxy-5-N, N-dimethylaminoethylenaminosulfonyl-benzoic acid methyl ester are added at -20 ° C to -10 ° C portionwise to 200 ml of fuming nitric acid.

Stir for 10 minutes, then pour the mixture into ca. 2 liters of ice / water. Stir for 1 hour and the precipitated product is suctioned off and washed well with water. 3-N-succinimido-4- (4'-nitrophenoxy) -5-N, N-dimethylaminophenyl-aminosulfonyl-benzoic acid methyl ester is obtained in extremely good yield as a white crystalline powder, mp: 260-261 ° C .

B) 4- (4'-Nitrophenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethyl-aminomethylenaminosulfonyl-benzoic acid methyl ester.

30 g of the imide (Example 50a) is suspended for approx. 250 ml of absolute Diglyme and 22 ml of BF3 etherate are added. Then, at 50-60 ° C, a solution of 3.2 g of NaBH4 in 250 ml of absolute Diglyme is added dropwise. After 1.5 hours, the excess reducing agent is hydrolyzed with a little water and 4- (4'-nitrophenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester is precipitated with ice water. Light yellow crystals from methanol, mp: 216-217 ° C.

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

24 g of the ester (Example 50b) is heated on a clear solution steam bath for approx. 1.5 hours in 200 ml of 1 N NaOH and some methanol as solvent. Then, after cooling, the free acid precipitates with 2 N HCl. 4- (4'-Nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is recrystallized from glycol monomethyl ether / water. Light brown crystals, mp: 235-238 ° C with decomposition.

35

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52

Example 51 4-141-Aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamylbenzoic acid 18.5 g of 4- (4'-nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulphamoylbenzoic acid are dissolved in dimethylformamide and hydrogenated 5 with Raney nickel at room temperature and normal pressure for 8 hours. After filtration, 4- (4 'aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with water. Brown crystals from DMF / H2O, mp: 234-240 ° C, with decomposition. The compound crystallizes with 1 mole of dimethylformamide, which does not escape even by continuous drying in vacuo at 120-150 ° C.

Example 52 4- [4- (Benzyloxyphenoxy) -3-[(pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4 * -benzyloxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

Dissolve 87.5 g (0.25 mole) of 3-nitro-4-chloro-5-N, N-dimethylamino-methylenaminosulfonyl-benzoic acid methyl ester in 500 ml of anhydrous dimethylformamide, and 77.5 g (0.35 mole) of sodium 4-Benzyl oxyphenolate is added. With vigorous stirring, the reaction mixture is heated to reflux for 3-4 hours. After cooling, the cloudy solution is dripped to 3 liters of ice / water. The precipitated yellow precipitate is removed with suction filter, washed well with water and recrystallized from methanol.

94 g of 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester are obtained as yellow crystals mp: 132 ° C.

b) 3-Amino-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethyl-3-laminaminosulfonyl-benzoic acid methyl ester.

94 g of 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester are dissolved in 1.5 liters of dimethylformamide and hydrogenated with Raney nickel at room temperature and normal pressure for 6-7 hours. . Then filter is filtered and the clear solution is dripped to ice / water. The precipitated 3-amino-4- (4'-benzyloxyphenoxy) -5-N, N-dimethyl

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S3 aminomethylenaminosulfonyl benzoic acid methyl ester is recrystallized from methanol. There are approx. 70 g as white crystals, mp: 170 ° C.

C) 3-N-Succinimido-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonyl-benzoic acid methyl ester.

48.3 g (0.1 mole) of 3-amino-4- (4'-benzyloxyphenoxy) -5 - N, N-dimethylamino-methylenaminosulfonyl-1-benzoic acid methyl ester are dissolved in 250 ml of absolute dioxane and heated to boil. -10. To the boiling solution, drop slowly and evenly a solution of 24.5 g (about 0.16 mole) of succinic dichloride in 100 ml of absolute acetone and a solution of 16 ml of pyridine (about 0.2 mole) in 100 ml of absolute acetone. After approx. 2 hours under reflux, the reaction mixture is evaporated and the residue is mixed with ethanol. The resulting imide crystallizes and can be recrystallized from methanol and a little acetone. There are approx. 45 g of white crystals, mp: 228 ° C.

d) 4- (4'-Benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethyl-1-aminomethylenaminosulfonyl-benzoic acid methyl ester.

35.5 g of imide is suspended in 200 ml of absolute Diglyme and 16.8 ml of BF3 etherate is added. Then, at room temperature, a solution of 5 g of NaBH4 in 2 O ml of absolute Diglyme is added dropwise and stirred for approx. ¾ hour. The excess reducing agent is gently destroyed (foaming) by the addition of water and slightly diluted HCl, and the product is finally precipitated with 1 liter of water. Recrystallization from methanol gives 31.6 g of 4- (4'-benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneamihosulfonyl-benzoic acid methyl ester, mp: 152 ° C.

e) 4- (4'-Benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid.

31 g of the ester (Example 52d) are suspended for approx. 300 ml of 2 N NaOH and heated on a steam bath. When a clear solution is obtained, cool and 4- (4'-benzyloxyphenoxy) -3-

DK 158978 B

54 - (1-Pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with 2N HCl (pH approx. 3). The acid is recrystallized from methanol, white-yellow crystals, mp: 226-228 ° C.

NMR data: (D6-DMSO, 60 mHz, TMS) δ = 1.73 (quasi-s; 4H), δ = 3.24 (quasi-s; 4H), δ = 5.05 (s; 2H ), δ = 6.6 - 7.9 (m; 13H).

Example 53 4- (4 L-Hydroxyphenoxy) -3- (1-pyrrolidinyl-5-sulfamoylbenzoic acid 9.5 g of 4- (4'-benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is dissolved in water by adding the equivalent amount of KOH and hydrogenating with Raney nickel at 50 ° C and 100 atmosphere in an autoclave for 5 hours, then filtering and 4- (4'-hydroxyphenoxy) -3- (1-pyrrolidinyl) - 5 - Sulfamoylbenzoic acid is precipitated with 2 N HCl (pH approx. 3). Recrystallization from CH 3 OH / H2 O gives 6.2 g of pale yellow needles, mp: 271-273 ° C.

NMR data: (D6-DMSO, 60 mHz, TMS) δ = 1.73 (quasi-s; 4H), δ = 3.24 (quasi-s; 4H), δ - 6.64 (quasi-s) ; 4H), δ = 7.24 (s; 2H), δ = 7.58 (d; 1H), δ = 7.88 (d; 1H), δ = 9.0 (s (wide); 1H) .

Example 54 4-Anilino-3- (1-pyrrolidinyl-5-sulfamoyl-benzoic acid 12.8 g of 3-amino-4-anilino-5-sulfamoyl-benzoic acid methyl ester is suspended in glacial acetic acid and heated to reflux. 5.6 ml of 2,5-dimethoxytetrahydrofuran in a little glacial acetic acid After a reaction time of about 0.5 hour the mixture is stirred in ice water and the precipitated product is separated.

4-Anilino-3-N-pyrrolo-5-sulfamoyl-benzoic acid methyl ester is dissolved as a crude product in methanol and hydrogenated for 16 hours at 100 ° C and 100 atmosphere in the presence of Pd / carbon (about 1 g). Then filter and concentrate the filtrate.

The residue is taken up with 2 N NaOH and heated to a clear solution. Upon addition of 2 N HCl to pH 4, 55 OK 15897 8 Β 4-Anilino-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid precipitates.

For purification, the product is dissolved in a little acetone, an excess of saturated ethereal HCl solution is added and the mixture is stirred in the double amount of ether. The hydrochloride of 4-anilino-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid precipitates. It is separated, washed with acetone, dissolved in 2 N NaOH and adjusted with 2 N HCl at pH 4. The precipitated 4-anilino-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid is recrystallized from CH 3 OH / H 2 O, yellow crystals, mp: 214-216 ° C.

10

Example 55 4- (4 1 -Methylanilino-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid 3-Amino-4- (4'-methylanilino) -5-sulfamoyl-benzoic acid-15-methyl ester is reacted analogously Example 54 with 2,5-dimethoxytetrahydrofuran, and then the precipitated crude product is hydrolyzed with 2N NaOH. After acidification with 2N HCl to pH 3-4, 4- (41-methylanilino) -3-N-pyrrolo-5 is obtained. -sulfamoyl-benzoic acid, mp: 226-228 ° C (from CH 3 OH / H 2 O).

This is dissolved in ethyl acetate and hydrogenated for 16 hours at 100 ° C and 150 atmosphere in the presence of rhodium / coal. The filtrate is concentrated, the residue is taken up with a little acetone (absolute) and ethereal HCl is added. Upon further ether addition, the hydrochloride of 4- (4'-methylanilino) -25 -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid precipitates. It is separated, washed with a little acetone / ethereal HCl and then dissolved in 2N NaOH. When acidified to pH 3-4, 4- (4'-methylanilino) -3 (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid precipitates. Recrystallization from CH 3 OH / H 2 O gives yellow crystals, mp: 188-190 ° C.

Claims (2)

Q Q-02S COOR3 15 where Q means a group R1 / -N \, R 2 or a protected amino group of the general formula R 8 (III) -N = CN '> wherein R 8, R 9 and R 10 mean the same or different lower alkyl groups, R 8 may also mean hydrogen, and / or the substituents R 9 and R 10 also may be interconnected and the groups R 1 - R 3, A and X are as defined above, wherein hydroxy, amino or mercapto groups are optionally blocked by protecting groups and Z represents two hydrogen atoms or one oxygen atom by hydrogen -borides or alkali or alkaline earth metal borohydrides, where, if Q is a group of general formula (III), the compounds obtained are hydrogenated and optionally ester free carboxylic acids of formula (I) (R = H) and / or transfer carboxylic acid esters of the general formula (I) (r3 ψ h) in the carboxylic acids (R3 = H) and / or liberate hydroxy, amino or mercapto groups by cleavage of a protecting group and / or transfer carboxylic acids with flour (I) (R3 = H) in their pharmaceutically acceptable salts by treatment with bases or acids. 10 15 20 25 30 35