FI69071C - SOM MELLANPRODUKTER ANVAENDA FOERENINGAR VID FRAMSTAELLNING AVETEROCYKLISKT SUBSTITUERADE 5-SULFAMOYLBENSOESYRADERIVAT - Google Patents

Description

1 69071 Compounds used in the preparation of heterocyclic-substituted 5-sulfamoylbenzoic acid derivatives as intermediates 5 Separated from patent application 751213

The invention relates to intermediates used in the preparation of heterocyclic-substituted 5-sulfamoylbenzoic acid derivatives of the formula I.

A__ E2Gn ^

N IT

15 X- I

E \ X j no2s ^ \ coor ^ R1 20

The compounds of the invention have the general formula

A

25 Z = C X = Z

\ /

OF

R 2 NO 2 S 2 -C 3 R 3 wherein A is a single bond or a C 1 -C 4 hydrocarbon chain which may also contain an S, O or N atom as a chain member and may be substituted by halogen, alkyl, aralkyl, aryl or with a heteroaromatic group, 35 or A is o-phenylene or formula 2,69071

A

- a group according to C 1 -C 5 R 8 R 7, wherein Y is a single bond or a C 1 -C 6 alkylene, R 1 and R 8 are the same or different and represent hydrogen, halogen or C 1 -C 4 alkyl, R 1 and R 2 are the same or different and represent hydrogen, -C 1-4 alkyl or, when R 1 is hydrogen, R 2 may also be C 1 -C 4 alkoxymethyl, phenoxymethyl or phenylthiomethyl, or R 1 and R 2 together represent a protecting group of formula - c - A5 15 R4 Rb 4 5 6 wherein R, R, R are the same or different lower alkyl groups, or one of them is hydrogen, and the other two together with the nitrogen atom form 3 a ring, R is hydrogen, -C 1-4 alkyl, C8-C8-cycloalkyl, in which one member of the ring may be ear-substituted with O or S, phenyl, benzyl, benzhydryl or alkanoyl optionally substituted on the phenyl ring by nitro, -C1-6alkyl or -C1-4alkoxy groups or halogen -oxymethyl having 2 to 4 carbon atoms in the alkyl group, X is benzyl, phenoxy, phenylthio, phenylsulfoxy, phenylsulfonyl or anilino, wherein the phenyl ring may be substituted by halogen, OH, C 1-4, C 1-4 alkyl, -C 1-4 alkoxy, alkylamino or dialkylamino, and each Z separately represents two hydrogen atoms or one oxygen atom, each Z in which two hydrogen atoms R 1 and R 2 mer-30 have a group / * 5 = C - N 14 R R 36 The compounds of general formula I are prepared as follows:

(a) of the general formula II

3-Substituted sulfamyvlbenzoic acid derivatives according to the formula N, 3 R 6, R, R, A and X have the same meaning as defined above, wherein the hydroxy, amino or the mercapto groups are optionally protected with conventional protecting groups, and Z represents two hydrogen atoms or oxygen atoms, reduced in the presence of Lewis acids with hydrogen borohydrides or complex boron-15 hydrides, or

(b) nitration of general formula VIII

I | vm 2 0 BNO S 3

BINU2 COOR

wherein Y is a halogen atom, R 3 is as defined above, and B is a protecting group of the general formula wherein R, R 5 and R 6 are identical to the above, or various alkyl groups, where R can also be 4 5 6

30 hydrogen, and / or in each case two of the substituents R, R or R

may also be cyclically linked, and the resulting formula IX

? ° 2

Yx A

3 |) IX

35 bno2s "^ A: oor3 4 3 69071 in which R is hydrogen are esterified, and the resulting compounds of formula IX in which B and Y are 3

above, but R is an alkyl residue, is reacted with compounds of formula XH, wherein X 5 is as defined above, and the resulting compounds of formula X

BN02S · ^^ / ^ coor1 2 3 4 5 10 3

wherein R 'is an optionally substituted alkyl residue having 1 to 4 carbon atoms, and B and X are as defined above, are reduced, and the compounds of general formula XI thus obtained are reduced.

15 νΛ2

T il 3 · XI

ΒΝΟ, Β ^^ 0011 3

Compounds of formula 20 wherein B, X and R 'are as defined above are reacted with a compound of general formula XII

X "C - A - XII

25 L 7 L

in which the radicals A and Z have the same meaning as above and L is a "leaving group", or both Ls together denote an oxygen atom, and the resulting compounds of general formula XIII / '' Ά'Λ 30 Z = C / C = 0 nn y xm HL 3 »

BN02S / ^ \ / COOR

Compounds of formula 35 wherein the residues A, B and R ', X and 3 Z have the same meaning as above are reduced in the presence of Lewis acids 4 with hydrogen boron or complex borohydrides,

and obtained from general formula XIV

5 69071 H «C CH„

XIV

Compounds of formula BNO 2 S 2 X 2 COOR 3 '3, wherein A, B, X and R' are as defined above, are hydrolysed, and in the compounds of formula I obtained according to a) to b) optionally double bonds are introduced or introduced into them. in elimination reactions double bonds, and / or the free carboxylic acids of formula I (R = H) are esterified and / or the carboxylic acid esters of general formula I (R = R) are converted into carboxylic acids by hydrolysis or elimination reactions ( R = H), and / or by deprotection of the carboxylic acids, the hydroxy, amino or mercapto groups are liberated, and / or the carboxylic acids of the formula I (R = H) are converted into pharmaceutically acceptable salts by treatment with bases or acids.

In the process according to a) it is surprising that it is possible to reduce the sulfamylbenzoic acid derivatives of the formula II with hydrogen borons or complex borohydrides in the presence of Lewis acids without changing the other groups in the molecule. This procedure gives 25 compounds of formula I in excellent yields.

The sulfamylbenzoic acid derivatives of formula II can be prepared by a variety of methods. For example, 3-imido-5-sulfamylbenzoic acid derivatives of the formula II (Z = O) are obtained from 3-amino-5-sulfimylbenzoic acid derivatives of the formula XV known in the literature, in which the radicals R -R and X in the formula have the same meanings as above. amino compounds with dicarboxylic acid derivatives of general formula XVI capable of reacting with an imide, wherein A is as defined above, Z is O and L is a leaving group, preferably halogen, a trialkylammonium group or an activated ester residue OR '.

6 69071 In these acylation reactions, the hydroxy, amino and / or mercapto groups at other positions in the molecule must be protected with conventional protecting groups.

, rαλ o T2 / V z'Cx / kV / "£ V °“ r X "fAl ^ NO2S ^^^^ COOR3 L L R1 \ ^ Nxo 3

10 R2 // XV XVI / NO2S II

R2 X

Such dicarboxylic acids which can be converted into dicarboxylic acid halides include, for example, succinic acid, methylsuccinic acid, 2,3-dimethylsuccinic acid, glutaric acid, 2-methylglutaric acid, phthalic acid, phthalic acid, cis-cycloproxy-p-cyclopropo-p-isopropyl acid, cyclohexane-1,2-cis-dicarboxylic acid, bromomeric resin acid or diglycolic acid. The reaction of these dicarboxylic acid-20 derivatives with the amino compounds of formula XV takes place under the conditions of the known Schotten-Baumann reaction.

Anhydrides of these dicarboxylic acids can also be used. In many cases, the primary carboxylic acid derivatives of formula XVII formed directly convert to the imido compounds (II) upon cleavage of water.

/ A - COOH ° - = \

NH _. II (Z = O

x A

30 ^

^ NO 2 S VOOR

K2 / XVI1

The reaction can be easily monitored by thin layer chromatography. Depending on the reaction conditions, especially when the reaction mixture is heated to 150-250 ° C, ring closure products are obtained in high yields.

69071 7

Preferably, the reaction uses anhydride in a large excess, about 2-3 times the excess, and the reaction is carried out without a solvent. When unsaturated dicarboxylic anhydrides are used, such as, for example, maleic acid-5 hydride, the reaction with the amino compounds of the formula XV at 150-250 ° C on melting together produces a viscous oil which, after some time, changes as water cleaves the formula XVIII.

R6 ^ ^ R7 10 | = η

Xx Js. XVIII

r1 to give an unsaturated imido compound according to 15 r2 / N ° 2S C °° r3, in which the radicals R -R, R, R and X have the same meanings as above. The double bond of this imido compound allows many different reactions, e.g. the compound can be hydrogenated to give compounds of formula II wherein Z is O and A is an ethylene group.

Compounds of formula II in which Z represents two hydrogen atoms may be prepared by various methods, e.g. from amino compounds of formula XV in the reaction of formula XVI

With the <o-substituted carboxylic acid derivatives of formula 25, wherein Z represents two hydrogen atoms, under the conditions of the Schotten-Baumann reaction, and then by cleavage of the resulting amido compounds of formula XIX by cleavage of H-L.

30

° ^ CH2-L

NH XIX

X I

r1 \ NOj S '^ COOR3 69071 8

Examples of such carboxylic acid derivatives of formula XVI are: N-chloropropionic acid chloride, N-chloropropionic acid bromide, N-chlorobutyric acid chloride, N-bromobutyric acid chloride, N-bromo-5-butyric acid phenyl ester, trimethylacid mono.

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

In the reduction according to the invention, the amido or imido derivatives, respectively, can be reacted as free acids or as salts which do not prevent their reduction, such as, for example, alkali or alkaline earth metal salts.

In order to obtain particularly pure reaction products in high yield, it is preferable to use 5-sulfamylbenzoic acid esters for the reduction reaction.

Esters can be prepared by acidic methods known in the literature. Suitable esters are, in particular, lower alkyl esters having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl or n-pentyl ester, benzyl ester or p-methoxybenzyl ester, and t-butyl ester, benzhydryl ester and acyloxymethyl ester, which an acyl ester having an acyl residue of a lower aliphatic carboxylic acid residue, e.g. an acetyl or tert-butyryl residue.

Suitable reducing agents are complex boron-30 hydrides or diborane in the presence of Lewis acids. When reducing lactams of formula II (Z = 2H), the reduction can be performed with diborane in the presence of Lewis acids. Imides (Z = 0), on the other hand, require the use of complex borohydrides in the presence of Lewis acids to obtain good yields. The reducing agents can be introduced into the reaction mixture using suitable protective measures, such as sim. nitrogen as an inert gas. When diborane is used, it is simpler to dissolve diborane in the solvent for the reaction performance, and to use this solution for the reduction. Suitable solvents are, in particular, ethers, e.g. tetrahydrofuran or diethylene glycol dimethyl ether.

As the boron complex borohydrides, for example, alkali boronates such as lithium borohydride, sodium borohydride or potassium borohydride, or alkaline earth boronates such as calcium borohydride, but also zinc-10 boron hydride or aluminum borohydride are used. These borohydrides surprisingly reduce the amide or imide groups in the reacted molecules upon addition of Lewis acids without substantially affecting the carboxylic acid ester function.

Suitable Lewis acids for the invention are, in particular, aluminum chloride, titanium tetrachloride, tin tetrachloride, cobalt II chloride, iron III chloride, mercury I chloride, zinc chloride and boron trifluoride or its derivatives, such as boron trifluoride. In this case, there is also the possibility that in the reaction between boron trifluoride etherate and e.g. sodium borohydride, diborane may be formed in situ (cf. Fieser, Fieser: Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, vol. 1, page 199).

In order to obtain a particularly high yield and particularly pure end products, it is advantageous to first mix the Lewis acid with the compounds of the formula II and then to add the complex borohydride.

It is particularly preferred to use an excess of 30 Lewis acid and complex borohydride in at least a stoichiometric amount relative to the amide group to be reduced.

Advantageous results are thus obtained, for example, in the case of titanium chloride by adding three times the stoichiometric amount of NaBH4, whereas when boron trifluoride etherate is used, the complex borohydride can be used as a stoichiometric amount with respect to the amide groups to be reduced in each case.

69071 10

It is irrelevant in the performance of the reduction whether the compounds to be reduced are imido compounds of the formula II (Z = 0) or amido compounds (Z = 2H). Surprisingly, the imido compounds are converted directly to the sulfamylbenzoic acid derivatives of the formula I in a one-pot reaction. The reduction is performed in a solvent. Suitable solvents are ethers, such as tetrahydrofuran or diethylene glycol dimethyl ether (diglyme). The solvent in which the reduction is performed may be the same as the solvent in which the reducing agent is dissolved, but may also be another solvent.

The reduction can be performed over a wide temperature range. The reduction can be performed at room temperature or at a slightly elevated temperature. When secondary amides are reacted with diborane and lactams with diborane and Lewis acid, preferably at a slightly elevated temperature (40-60 ° C), the reduction with complex borohydrides and Lewis acids, especially with imides, often already very preferably in the temperature range 0-20 ° C . If the reaction time is allowed to be somewhat longer, the reduction can also be carried out in the cold. The reduction time depends on the reaction components used and the temperature selected.

In a preferred embodiment, the 5-sulfamylbenzoic acid derivatives of formula II are dissolved together with Lewis acid in an inert solvent, and a solution of the complex borohydride or optionally a suspension of the complex borohydride in the same or different solvent is added to the solution at room temperature, followed by stirring for some time. The complex borohydride can also be added directly as a solid. To facilitate the reaction, it may optionally be carried out at an elevated temperature, or the reaction mixture may be heated at 40-70 ° C for about one hour after the addition of the reducing agent.

In another embodiment, Lewis acid is added to the substance to be reduced and the complex borohydride at room temperature. As the complex borohydride, sodium borohydride is particularly suitable. Also in this case, it may be advantageous to heat the reaction mixture at 40-70 ° C for about an hour in order to obtain a faster reaction after the addition of the addition of Lewis acid. The progress of the reaction can be monitored by thin layer chromatography to show the strong light blue fluorescence 5 (in the range of 366 nm) of the resulting compound of formula I. In the reduction, any double bonds in group A can be reduced at the same time.

The isolation of the final products can take place in different ways. In a preferred isolation method, water and small amounts of acid are added to the reaction product solution to remove any reducing agent still present, and then the resulting 5-sulfamylbenzoic acid ester is precipitated by the addition of a non-solvent. When diethylene glycol dimethyl ether is used, water is particularly suitable as the non-solvent. The resulting 5-sulfamylbenzoic acid esters of formula I generally crystallize in high purity almost quantitatively.

It may then be necessary to re-release the present protected substituents on residue X of the sulfamylbenzoic acid derivatives of the general formula I. For example, the p-hydroxy group is obtained by soap-20 treatment with the corresponding acetate.

The 5-sulfamylbenzoic acids of the formula I can also be obtained directly by partially evaporating the reaction mixture after decomposition of the excess reducing agent, adding a dilute base and optionally heating for some time.

Suitable bases are, for example, sodium hydroxide. The 5-sulfamylbenzoic acids of the formula I can then be isolated directly as their salts. Acidification gives free acids. The easy formation of the 3-imido or 3-amido-5-sulfamylbenzoic acid derivatives of the formula II makes it possible to obtain new 5-sulfamylbenzoic acid derivatives of the formula I by process a) in very pure and high space-time yield.

Reduction of imides or amides can be performed with equal success when the C-C chain has substituents 35 which are easily cleaved to form a carbon-carbon-carbon double bond. Thus, for example, 2-bromosuccinic acid derivative of the formula I in which A is a starting material is obtained using 2-bromosuccinic acid as the reaction component of the formula VIII.

H H

I I

5 -C = C group.

The 3-pyrroline derivatives can be chemically converted in a manner known per se, e.g. by catalytic hydrogenation to 3-position heterocyclic-substituted sulfamylbenzoic acid derivatives of the formula I in which A is an ethylene group, or can be subjected to conventional rearrangement reactions.

The compounds of the formula I can also be prepared from the 3-amino compounds of the formulas XV or XI, respectively, by reacting them with the compounds of the formula L-CH2-A-15 CH2-L, in which case both leaving groups are cyclized with the 3-amino group of the formula XV or XI I or XIV, respectively, and 2 moles of HL are cleaved.

In this case, the compounds XV or XI, respectively, are reacted in an organic solvent, such as, for example, acetone, dimethylformamide, ethanol or mixtures of such solvents, with an excess of the compound of the formula L-CH2-A-CH2-L, it being expedient to boil the reaction mixture. returning over a period of several hours to more than 25 days. When L groups denote bromine or chlorine atoms, it is preferable to add an excess of alkali iodide to the reaction mixture. In some cases, the reaction is also promoted by an auxiliary base such as, for example, pyridine, triethylamine, NaHCO 3 or Na acetate.

The benzoic acid derivatives of formula VIII used in process b) are obtained by various methods. In a particularly simple manner, the reaction takes place from known sulfamylbenzoic acid derivatives of the following formula known from the literature.

69071 π π H2N02S coor3 5 by different condensation methods well known in the literature.

References to the literature include, for example, J. Org. Chem. 25 (1960), 352-356; Zh. Org. Khim 8 10 (1972), 286-291; Liebigs Ann. Chem. 750 (1971), 42;

Zh. Org. Khim 6 (1970), 9, 1885; B. 94 (1961), 2731-2737; Ang. Ch. 78 (1966), 147 * -148; Ang. Ch. 80 (1968), 281-282; B. 97 (1964), 483-489; B. 96 (1963), 802-812; J. Org.

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

According to the invention, for example, the following derivatives can be used as compounds of the general formula VIII: «Ψ«

A

* «R A ·

"C

14 69071

I — li — I r-1 I — I J-l rH I — I

cj cj o cj 2 to υ cj m id m co 2 oo m co ro 04 2 2 m 2 2 2 2 cj cj cj cj u a cj

CM

2 cj

CM

2 u

2 I

CJ (N

o 2 u a / = <f \\ // P4 mnsromroffi V _y 2 2 in k s s y

> -cj cj cj cj cj cj I

C/O--

0 2 II

(¾-CJ

1 ™ 2 ® / \>

if) 'ID CJ

04 04 04 I

σ \ cm m frj en 2 2 τ 2 a

2 CJ K CJ 2 2 CJ I

a)

-P

cn Ή τ30 iHCNfn ^ invor ^ oo s: -

> H C

It c i 15 <, 69071

The compounds of formula VIII are prepared by the methods known from the literature described above or by analogous methods thereof. Instead of the acids used above, for example, the corresponding methyl or ethyl esters can also be used.

The nitration of the benzoic acid derivatives of the formula VIII can take place by various methods. The benzoic acid derivative can, for example, be introduced into one of the usual nitration mixtures used for the nitration of aromatics which are difficult to nitrate (cf. Lehrbuch "Organicum", page 288, 1967 edition). The process can also be carried out by dissolving the benzoic acid derivative of the formula VIII in fuming sulfuric acid and carrying out the nitration by dropwise addition of nitric acid.

It is surprising that a benzoic acid derivative of the general formula VIII can be nitrated, albeit by introducing a protecting group B into a sulfonamide source without changing the other groups in the molecule. The reaction temperature is relatively low, preferably maintained at 55-70 ° C.

Preferably, a mixture of fuming sulfuric acid and fuming nitric acid to which the substance is added is used as the nitric acid, and the reaction mixture is heated to 55-60 ° C.

The progress of the nitration can be monitored by thin-layer chromatography. Isolation of the final products takes place in the usual way, e.g. by pouring the reaction mixture onto ice and filtering off the separated crystals.

Acids or esters of general formula VIII can be used for the nitration, in which the residues 3, Y, B and R have the same meaning as above. Nitration of esters of formula VIII gives, in addition to the esters, small amounts of acids of formula IX (where R3 = H).

The mixture can be separated in the usual way, e.g.

35 by treatment with aqueous sodium carbonate solution. The resulting 16 69071 3 compounds of formula IX in which R is hydrogen are now esterified in the usual manner.

In order to esterify the carboxyl group, the carboxylic acid is converted, for example, into an acid chloride, from which the addition of 5 alcohols gives the corresponding esters of the formula IX.

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

They are preferably used in a 5 to 20-fold molar excess, at the same time acting as solvents.

According to other methods known from the literature, tert-butyl ester or benzhydryl ester can be prepared.

In the next reaction step, esters of formula IX are converted to compounds of formula X by reaction with compounds of formula XH.

Surprisingly, it has been found that compounds of general formula IX in which R is alkyl can be reacted with compounds of general formula XH with good results under anhydrous conditions.

Examples of compounds of formula XH which may be used are: phenol, 4-methylphenol, 3-methylphenol, 2-methylphenol, 4-chlorophenol, 3-trifluoromethylphenol, 3,5-dimethylphenol, 2,4-dimethylphenol, 4-methoxyphenol, 3-methoxyphenol, 4-propylphenol, thiophenol and thiophenols substituted analogously to phenol, N-methylaniline, benzenesulphonic acid, pyrrolidine, N-methylpiperazine, 5-methyl-2-mercapto-1,3,4-thiadiazole or 1-methyl-5-mercapto-1,2,3,4-35 tetrazole. Other functional groups which may be present in XH, such as other OH groups, NHj or merl 17 69071

M

capto groups, are protected by conventional protecting group groups, e.g. by acylation.

....., 4 4

An important importance is the general formula HOR and HSR

A

wherein R is as defined above. Of particular importance among these are thiophenol and phenol derivatives, which may be substituted as described above.

The reaction can be carried out without a solvent, but more preferably it is carried out 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 reacted as such in the presence of 15 bases or also as their alkali and alkaline earth metal salts. Alcoholates or alkali amides can be used as bases.

Thiophenol and phenol derivatives are reacted in the form of their anions, with particular alkali salts and in particular sodium and potassium salts proving to be advantageous.

The reaction can take place in the presence or absence of a solvent. Without solvent, the components are heated to e.g. temperatures of 100-200 ° C, preferably 140-180 ° C. The products thus obtained can be isolated in a conventional manner, e.g. by dissolving the molten product in a solvent, and then precipitating the product by adding water or an organic non-solvent.

«

However, it is particularly preferred to react the phenolates or thiophenolates in solvents at temperatures of 100 to 200 ° C, preferably 120 to 160 ° C.

Suitable solvents are organic solvents, in particular tertiary carboxamides, polyethers or high-boiling solvents, such as HMPT or tetramethylenesulphone. It is particularly preferred to carry out the reaction of the ester of formula IX in tertiary carboxamides, such as, for example, dimethylformamide or dimethylacetamide. Depending on the selected reaction temperature, the reaction time is 1 to 6 hours.

The final products of formula I are isolated in the usual manner, e.g. first the inorganic salts can be filtered off and then the reaction product can be precipitated by adding a non-solvent, or the reaction mixture can be poured into water or ice and the precipitated reaction product 10 isolated.

Compounds of formula X in which the 4-position 4 is SOR or SO 2 R are obtained from the corresponding compounds of formula X having the group SR by oxidation by methods known from the literature. S-oxides 15 are obtained, for example, by oxidation with peracetic acid in dimethylformamide at low temperatures, while S-dioxides are formed by adding an excess of oxidizing agent at higher temperatures.

The reduction of the nitro group of the benzoic acid derivatives of the formula X can take place in the customary manner, e.g. by catalytic hydrogenation. The catalyst used is preferably Raney nickel, or ordinary noble metal catalysts, such as, for example, a palladium / carbon or platinum oxide catalyst (e.g. Organikum 25, pages 271-277, pages 507-510).

The solvents used in the reduction are preferably organic solvents, such as, for example, methanol or ethanol, ethyl acetate, dioxane or other polar solvents, in particular amides, such as dimethylformamide, dimethylacetamide or HMPT.

The hydrogenation is carried out at room temperature and normal pressure or at elevated temperature and elevated pressure, e.g. at 50 ° C at 100 atm in an autoclave.

The 3-imidobenzoic acid 69071 * derivatives of general formula XIII (Z = δ) can be prepared by a variety of methods. They are obtained, for example, by reacting amino compounds of the formula XI in the dicarboxyl-5-silicic acid derivatives of the general formula XII which are capable of imide formation. The reaction is carried out as described above for the reaction of compounds XV and XVI in process a) to form compounds of formula II.

The progress of the reaction can be easily monitored by thin layer chromatography, since amino compounds XI fluoresce at 366 mU, while the obtained compounds do not fluoresce.

K

Amido compounds of formula XIII in which Z represents 2 hydrogen atoms are prepared analogously to compounds of formula II in which Z represents 2 hydrogen atoms as described in process a).

The carboxylic acid derivatives of the formula XII correspond to the compounds of the formula XVI described above.

Reduction of compounds of formula XIII gives 3-position heterocyclic substituted b / benzoic acid derivatives of general formula XIV. In order to obtain particularly pure reaction products in high yield, it is also advantageous here to carry out the reduction on the benzoic acid esters of the formula XIII.

25 The reduction takes place as described in method a).

The 5-sulfamylbenzoic acids 3 of the formula I (R = H) are obtained by alkaline hydrolysis of the compounds of the general formula XIV by heating these compounds of the formula XIV in a steam bath for several hours with a solution of sodium hydroxide or potassium hydroxide. In this case, the ester is saponified and the protecting group B and any other protecting groups present are cleaved. The 5-sulfamylbenzoic acids of formula I (R 2 = H) can also be obtained directly by decomposing the excess reducing agent, partially evaporating the reaction mixture, adding base and heating for a relatively long time. Sodium hydroxide, for example, can be used as the base. The 5-sulfamylbenzoic acids of the formula I can then be isolated directly in the form of their salts. Addition of acid gives free acids.

It is also possible to introduce protecting groups B in a later reaction step, e.g. to compounds of the formulas IX, X, XI or XIII in which B represents 2 hydrogen atoms, and thus to give compounds of formula XIV in which R 'may also be replaced by R.

Example 1 3-Nitro-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 34 g (^ 0.1 mol) of 3-nitro-4-phenoxy-5-sulfamyl-benzoic acid are dissolved in 150 ml of methanol and the solution is heated to boiling. 5.4 ml of concentrated sulfuric acid are then slowly added dropwise and the mixture is refluxed for 10 hours. On cooling, 3-nitro-4-phenoxy-5-20 sulfamylbenzoic acid methyl ester crystallizes. It can be recrystallized from methanol / acetone.

Sp. 181-182 ° C.

Example 2 3-Amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 35 g (^ 0.1 mol) of 3-nitro-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are suspended in 150 ml of methanol, and the suspension is hydrogenated in an autoclave. At -50 ° C at 100 aty with Raney nickel (5-10%).

The precipitated amino compound is dissolved in a steam bath with additional acetone and the Raney nickel is filtered off. As the solution cools, pure 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester crystallizes from it.

Sp. 179 ° C.

it 35 21 * 69071

Example 3 3-N-Succinimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester * 16.1 (0.05 mol) of 3-amino-4-phenoxy-5-sulfamyl-benzo-5-acidic acid methyl ester are dissolved in 150 ml of abs. and the solution is heated to boiling. 11.6 g (0.075 moles) of succinic acid dissolved in 50 ml of abs are then added dropwise to the solution with good stirring. acetone and 8 ml of pyridine in 50 ml of abs. acetone, 10 and the mixture is refluxed. After about 2 hours, the reaction is complete. The mixture is evaporated and the residual oil is dissolved in a small amount of methanol. After some time, 3-N-succinimido-4-phenoxy-5-sulfamylbenzoic acid methyl ester crystallizes out of solution. Adding a little 15 water makes the crystallization more complete. Recrystallization from methanol / acetone.

Sp. 270 ° C.

Example 4 3-Amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester is melted with 2-3 times the molar amount of succinic anhydride and heated at 160-180 ° C for about 2 hours. After cooling, methanol is added, whereupon 3-N-succinimido-4-phenoxy-5-sulfamylbenzoic acid methyl ester crystallizes.

Example 5 3-N-Pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 12.3 g (0.03 mol) of 3-N-succinimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are dissolved or suspended. 100 no abs.diglyme. To this is added directly 9 g of boron trifluoride etherate and then a solution of 2.4 g (~ 0.063 mol) of NaBH4 in 80 ml of diglyme is added dropwise at room temperature with good stirring. Since the reaction is exothermic, it must be cooled with ice water. Reaction 35 is generally complete after dropwise addition and brief post-stirring.

09071 22

The excess reducing agent is then decomposed with a small amount of water (effervescent), the solution is filtered and about 300 ml of water are added with stirring. The crystalline 3-N-pyrrolidino-4-phenoxy-5-sulfamylbenzoic acid methyl-5 ester is recrystallized from methanol to give white crystals, m.p. 191-192 ° C.

NMR numbers: (CDCl 3, 60 MHz, TMS standard) = 1.73 (m; 4H), δ - 3.26 (m; 4H), cf = 3.91 (s; 3H), cT = 5.0 (s; 2H), ¢ / = 6.6-8.0 (m; 7H) ppm.

Example 6 3-N-Pyrrolidino-4-phenoxy-5-sulfamylbenzoic acid 61 g of 3-N-pyrrolidino-4-phenoxy-5-sulfamylbenzoic acid methyl ester are suspended in 350 ml of 1N NaOH and the suspensions are heated on a water bath for one hour. I drive.

3-N-Pyrrolidino-4-phenoxy-5-sulfamylbenzoic acid is precipitated from a clear solution with 2-n HCl with good stirring. The almost pure crude product can be recrystallized from methanol / water. Pale yellow tiles are obtained, m.p. 225-227 ° (dec.).

NMR numbers: (D, -DMSO, 60 MHz, TMS) δ = 1.67 (quasi-s; 4H),

O

= 3.21 (quasi-s; 4H), </ = 6.6-8.0 (m; 9H) ppm.

Example 7 3-N-Glutarimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 16.1 g of 3-amino-3-phenoxy-5-sulfamyl-benzoic acid methyl ester are dissolved in 150 ml of abs. dioxane, and the solution is heated to boiling. 16.8 g of glutaric acid chloride dissolved in 50 ml of abs. Acetone and 8 ml of pyridine in 50 ml of 30 abs. Acetone are then added dropwise with uniform stirring, and the mixture is refluxed. After about 3 hours, the reaction is complete. The mixture is evaporated to dryness, the residue is dissolved in methanol. After some time, 3-N-glutarimido-4-phenoxy-5-sulfamylbenzoic acid methyl ester crystallizes out of solution. It can be recrystallized from glucol monomethyl ether. White crystals are obtained, m.p. 312-314 ° C (dec.).

Il 23 69071

Example 8 * 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 are suspended in 200 ml of diglyme (diethylene glycol dimethyl ether) and suspended. 10 ml of boron trifluoride etherate are added. 3 g of NaBH4 in 150 ml of diglyme are then slowly added dropwise to the mixture at room temperature with good stirring. The excess reducing agent is then decomposed with a small amount of water, the solution is filtered and 500 ml of water are added with stirring. The crystalline separated 3-N-piperidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester can be recrystallized from alcohol. White crystals are obtained, m.p. 198-199 ° C.

NMR numbers: (D 6 -DMSO, 60 MHz, TMS) = 1.1 (quasi-s; 6H), cf = 2.86 (quasi-s? 4H), </ = 3.92 (s; 3H) ), ei = 6.7-8.1 (m; 9H) ppm.

Example 9 3-N-Piperidino-4-phenoxy-5-sulfamylbenzoic acid 20 g of 3-N-piperidino-4-phenoxy-5-sulfamylbenzoic acid methyl ester are suspended in 50 ml of 1N NaOH and the suspension is heated on a steam bath. until a clear solution is obtained. The resulting 3-N-piperidino-4-phenoxy-5-sulfamylbenzoic acid is precipitated with 2N HCl and recrystallized from methanol / water. White crystals are obtained, m.p. 258-260 ° C. NMR numbers: (D 6 -DMSO, 60 MHz, TMS) of = 1.08 (quasi-s; 6H), </ = 2.9 (quasi-s; 4H), </ = 6.65-8, 2 (m? 9H) ppm.

Example 10 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 the solution is heated to boiling. 14 ml of phthalic acid dichloride dissolved in 50 ml of acetone and 9 ml of pyridine dissolved in 50 ml of acetone are then added dropwise with uniform stirring. After 3 hours the reaction is complete with 69071 24. The solution is evaporated, the residue is dissolved in a small amount of acetone and the solution is added dropwise with stirring to a mixture of ice water and 2N HCl. 3-N-Phthalimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester precipitates as a light brown precipitate. Recrystallization from methanol / acetone / water gives white crystals, m.p. 237-238 ° C. Example 11 3-N-Ioindolinyl-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 10 g of 3-N-phthalimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester are dissolved or suspended in 150 ml of diglyme, and 12 ml are added. booritrifluoridieteraat-acetate. 3.6 g of NaBH4 dissolved in 100 ml of diglyme are then added dropwise to the mixture at room temperature and the mixture is stirred for a further 1/2 hour at 60 [deg.] C. Upon addition of 400 ml of water, a web-like mixture of substances precipitates. It is boiled with methanol so that 3-N-isoindolinyl-4-phenoxy-5-sulfamyl-benzoic acid methyl ester is insoluble. It is filtered off with suction and crystallized from n-butanol / DMF. White needles are obtained, m.p. 268-272 ° C (dec.). NMR numbers: (D 6 -DMSO, 60 MHz, TMS) of = 3.92 (s; 3H), c = 4.66 (s; 4H), c = 6.6-8.1 (m; 13H) ppm.

Example 12 3-N-Isoindolinyl-4-phenoxy-5-sulfamylbenzoic acid 2.4 g of 3-N-isoindolinyl-4-phenoxy-5-sulfamylbenzoic acid methyl ester are suspended in 50 ml of 1N NaOH and the suspension is heated. on a steam bath until a clear solution is obtained. 2-HCl precipitates 3-N-isoindolinyl-4-30 phenoxy-5-sulfamylbenzoic acid, which is recrystallized from glacial acetic acid. Pale yellow crystals are obtained, m.p. 259-261 ° C (dec.). NMR numbers: (D 6 -DMSO, 60 MHz ^ MSjc / δ 4.68 (s; 4H), d = 6.6-8.0 (m; 13H) ppm.

Example 13 35 3-N- (2,4-Dioxo-3-azabicyclo [3.2.2] heptano) -4-phenoxy-5-sulfamylbenzoic acid methyl ester 8.1 g of 3-amino-4-phenoxy-5- sulfamylbenzoic acid methyl ester is mixed with cis-cyclobutane-1,2-dicarboxylic anhydride (6.3 g) and diglyme (5 ml), and the mixture is heated at 180 ° C. In this case, the diglyme evaporates. The melt solidifies after about 1 hour. To this is added methanol while still warm. The solid mass decomposes into a white crystal bran. The crystalline powder is filtered off with suction and recrystallized from glycol monomethyl ether. Sp. 284-285 ° C, Example 14 3-N- (3-Azabicyclo- / 3,2.07-heptano) -4-phenoxy-5-10 sulfamylbenzoic acid methyl ester 7.3 g of 3-N- (2,4-dioxo- 3-Azabicyclo (3.27-heptano) -4-phenoxy-5-sulfamylbenzoic acid methyl ester is suspended in 70 of any diglyme, and 6 ml of boron trifluoride etherate are added to the suspension. Hi-15 is again added dropwise to the mixture under ice-cooling, 1.5 g of NaBH 4 dissolved in 70 diglyme. After stirring for a further 15 minutes, 3-N- (3-azabicyclo [3.2.0] heptano-4-phenoxy-5-sulfamyl-benzoic acid methyl ester is precipitated by the addition of water and recrystallized from methanol or acetonitrile to give white crystals, m.p. 176-177 ° C.

Example 15 3-N- (3-Azabicyclo [3.2.2] heptano) -4-phenoxy-5-sulfamylbenzoic acid 6.2 g of 3-N- (3-azabicyclo [3.2.07 heptano]) 4-Phenoxy-2,5-sulfamyl-benzoic acid methyl ester is suspended in 60 1N NaOH, and the suspension is 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. Yellowish-white plate-like crystals are obtained, m.p. 254-255 ° C (dec.).

69071 26

Example 16 3-N- (3,5-Dioxoraorpholino) -4-phenoxy-5-sulfamyl-benzoic acid methyl 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid 5-methyl ester are mixed with diglycolic anhydride (15 g) and together with diglyme (10 ml) and heat the mixture in an open flask to about 180 ° C. After 1-2 hours, carefully add methanol. Upon cooling, the imide crystallizes. Crystallization from diglyme yields white crystals, m.p. 295-297 ° C.

Example 17 3-N-Morpholino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 9.4 g of 3-N- (3,5-dioxomorpholino) -4-phenoxy-5-sulphenyl-benzoic acid methyl ester are suspended in 100 ml of diglyme, and 6 ml of boron trifluoride dietherate are added to the suspension. A solution of 1.9 g of NaBH 4 in 100 ml of s-diglyme is then slowly added dropwise under ice-cooling and with good stirring. Addition of water gives the resulting 3-N-morpholino-4-phenoxy-5-sulfamylbenzoic acid methyl ester to precipitate, m.p. 221-222 ° C methanol list.

Example 18 3-N-Morpholino-4-phenoxy-5-sulfamylbenzoic acid The corresponding methyl ester (Example 17) is heated with 1N NaOH in a water bath until a clear solution is formed. Addition of 2-n HCl precipitates 3-N-morpholino-4-phenoxy-5-sulfamylbenzoic acid, which is recrystallized from methanol. Obtained as brownish-30 white crystals, m.p. 194-197 ° C (dec.).

Example 19 3-N- (4-Methylglutarimido) -4-phenoxy-5-sulfamylbenzoic acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamylbenzoic acid 35 methyl ester and 15 g of 4-methylglutaric anhydride and a little diglyme are mixed into a gel. and the moon is passed for 2-3 hours at 160-180 ° C. 3-N- (4-methylglutarimido) -4-phenoxy-5-sulfamylbenzoic acid methyl ester is precipitated by the addition of methanol to give white crystals, m.p. 315 ° C from glycol monomethyl ether.

Example 20 3-N- (4-Methylpiperidino) -4-phenoxy-5-sulfamylbenzoic acid methyl ester 10.3 g of 3-N- (4-methylglutarimido) -4-phenoxy-5-sulfamylbenzoic acid methyl ester are suspended in 100 10 ml of diglyme. , and 6.5 ml of BF 4 etherate are added to the suspension. A solution of 1.9 g of NaBH 4 in 100 ml of diglyme is added dropwise at room temperature. After dropwise addition, stirring is continued for 15 minutes, and then 3-N- (4-methylpiperidino) -4-phenoxy ± -5-sulfamylbenzoic acid p-methyl ester is precipitated with water to give colorless crystals, m.p. 143-144 ° C from methanol.

Example 21 3-N- (4-Methylpiperidino) -4-phenoxy-5-sulfamylbenzoic acid The corresponding methyl ester (Example 20) is heated on a water bath with 1N NaOH until a clear solution is formed. Addition of 2-HCl precipitates 3-N- (4-methylpiperidino) -4-phenoxy-5-sulfamylbenzoic acid to give white crystals, m.p. 243-344 ° C from a methanol-25 L / water mixture.

Example 22 3-N- (3-Methylsuccinimido) -4-phenoxy-5-sulfamylbenzoic acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamylbenzoic acid 30-pomethyl ester and 15 g of 3-methylsuccinic anhydride and some diglyme are fused together in an open flask, and the melt is maintained at about 180 ° C for about 2.5 hours. Addition of methanol gives crystalline 3-N- (3-methylsuccinimido) -4-phenoxy-5-sulfamylbenzoic acid 35-methyl ester, which crystallizes from glycol monomethyl ether to give white crystals, m.p. 272 ° C.

28 69071

Example 23 3-N- (3-Methyl-pyrrolidino) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester 17 g of 3-N- (3-methyl-succinimido) -4-phenoxy-5-5-sulfamyl-benzoic acid methyl ester are suspended in 150 ml of diglyme. 11 ml of BF 4 etherate are added to the suspension and then 3 g of NaBH 4 dissolved in 150 ml of diglyme are added dropwise under ice-cooling. The 3-N- (3-methylpyrrolidino) -4-phenoxy-10-sulfamylbenzoic acid methyl ester formed after dropwise precipitation with water gives white crystals, m.p. 145 ° C from methanol.

Example 24 3-N- (3-Methylpyrrolidino) -4-phenoxy-5-sulfamyl-15-benzoic acid 9 g of 3-N- (3-methyl-pyrrolidino) -4-phenoxy-5-sulfamyl-benzoic acid methyl ester are heated in 1N NaOH. in a water bath until a clear solution is obtained. 3-N- (3-methyl-pyrrolidino) -4-phenoxy-5-sulfamylbenzoic acid is then precipitated at room temperature with 2-n HCl. Recrystallization from CH 2 OH / H-O gives pale yellow crystals, m.p. 206-208 ° C.

Example 25 3-N-Maleimimido-4-phenoxy-5-sulfamyl-benzo-25-acid methyl ester 16 g of 3-amino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester and 15 g of maleic anhydride and some diglyme are heated in one open flask at about 180 ° C. . After about 3 hours, the mixture is allowed to cool and methanol and a little water are added. 3-N-Maleimimido-4-phenoxy-5-sulfamyl-benzoic acid methyl ester precipitates after prolonged standing. Recrystallization from methanol gives white crystals, m.p. 19 7-198 ° C.

69071 29

Example 26 3- N-Pyrrolidino-4-phenoxy-5-sulfamyl-benzoic acid methyl ester 4.1 g of 3-N-succinimido-4-phenoxy-5-sulfamyl-benzo-5-acid methyl ester are dissolved in 40 ml of diglyme, and 2 g is added to the solution. , 5 ml of titanium tetrachloride. A solution of 1.1 g of NaBH 4 in 30 ml of diglyme is then slowly added dropwise at room temperature and the mixture is stirred for a further hour. The resulting 3-N-pyrrolidino-4-phenoxy-10S-5-sulfamylbenzoic acid methyl ester is precipitated with water and crystallized from methanol, m.p. 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, mixed well with succinic anhydride (25 g), and the mixture is heated as a melt at 180 ° C for 6 hours. The mixture is then allowed to cool slowly and CH 2 OH is carefully added. Product 20 crystallizes. Adding a little water makes the crystallization more complete. Recrystallization from glycol monomethyl ether, m.p. 267-269 ° C.

Example 28 4-Chloro-3-pyrrolidino-5-sulfamylbenzoic acid 25 g of imide (Example 30) are suspended in 200 of any diglyme, and 17 ml of BF 4 etherate are added to the suspension. A solution of 4 g of NaBH 4 in 200 ml of diglyme is added dropwise to this suspension under ice-cooling. After the addition is complete, stir for 1/2 hour, then hydrolyze carefully with a small amount of water. Filter and precipitate 4-chloro-3-pyrrolidino-5-sulfamyl-benzoic acid methyl ester with water. Sp. 189-191 ° C from methanol.

The ester is saponified with 1 N NaOH in a steam bath until a clear solution is obtained. Upon acidification to pH 4, free acid precipitates. Pale yellow crystals are obtained from CH 3 OH / H 2 O, m.p. 259-261 ° C.

69071 30

Example 29 3-N-Succinimido-4-phenylthio-5-sulfamyl-benzoic acid methyl ester 5.8 g of 3-amino-4-phenyl-thio-5-sulfamyl-benzoic acid-5-methyl ester are mixed with succinic anhydride (5.9 g) and the mixture is melted together at 170 °. C. After 5 hours, CH 2 OH is carefully added to the mixture as it cools. The substance separates as crystals and is recrystallized from glycol monomethyl ether, m.p. 250-251 ° C.

Example 30 3-N-Pyrrolidino-4-phenylthio-5-sulfamylbenzoic acid 14.7 g of imide (Example 29) are suspended in 100 ml of diglyme, and 10 ml of BF 4 etherate are added to the suspension. 2.9 g of NaBH4 dissolved in 100 ml of diglyme are then slowly added dropwise under ice-cooling. Stirring is continued for a further 1/2 hour at room temperature, then the excess reducing agent is decomposed by adding a little water. 3-N-Pyrrolidino-4-phenylthio-5-sulfamyl-benzoic acid methyl ester is then precipitated with water and crystallized from methanol. Yellow crystals are obtained, m.p. 139-140 ° C.

The ester is heated on a steam bath with 1 N NaOH until a clear solution is obtained, then the resulting acid is precipitated with 1 N hydrochloric acid at pH 3-4. Yellow crystals are obtained, m.p. 238-239 ° C from methanol.

Example 31 4-Phenoxy-3- (1-pyrrolidinyl) -5-dimethylsulfamoylbenzoic acid 7.2 g (0.02 mol) of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid are dissolved in 100 ml. 1N NaOH, 30 and 10 ml of dimethyl sulfate are added to the solution. The mixture is stirred well at room temperature. After about 30 minutes, a white vaporous substance precipitates. It is filtered off with suction and heated with 2-n NaOH on a steam bath. When a clear solution is formed, it is allowed to cool and 4-phenoxy-35- (1-pyrrolidinyl) -5-dimethylsulfamoylbenzoic acid is precipitated with 2N HCl. The substance can be recrystallized from methanol / water. Yellow fibers are obtained, m.p. 214-215 ° C.

69071 31

Example 32 4-Phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid a) 4-Phenoxy-3-N-succinimido-5-methylsulfamoylbenzoic acid methyl ester 71 g 3-Amino-4-phenoxy-5-methylsulfate - moylbenzoic acid methyl ester (m.p. 188 ° C) is melted with succinic anhydride (87 g) at 180-190 ° C.

After 5 hours, methanol and then an equal volume of water are carefully added to the melt, whereupon the imide separates as a crystal. 4-Phenoxy-3-N-succinimido-5-methylsulfamoyl-benzoic acid methyl ester is obtained, m.p. 1249-250 ° C from methanol.

b) 4-Phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoyl-benzoic acid methyl ester 67 g of 4-phenoxy-3-N-succinimido-5-methylsulfamoyl-benzoic acid methyl ester are suspended in 300 ml of absiglyme and 40 ml of abs. ml of boron trifluoride etherate. The mixture is then cooled to -10 [deg.] C. and 12.2 g of NaBH4 dissolved in 300 ml of diglyme are slowly added dropwise with good stirring. In this case, the temperature must not exceed 10 ° C.

After the dropwise addition, the mixture is stirred for a further 10 minutes and then (foam) water is then carefully added to the mixture. As more water is added, the reaction product precipitates. Recrystallization from methanol gives 4-phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid methyl ester, m.p. 138-139 ° C.

C) 4-Phenoxy-3- (1-pyrrolidinyl) -5-methylsulfamoylbenzoic acid 54 g of the methyl ester obtained in b) are suspended in 500 ml of 1N NaOH and the suspension is heated with stirring on a steam bath. After a clear solution is obtained, the mixture is cooled and the free acid is precipitated with 1N HCl. Recrystallization from methanol / water gives 4-phenoxy-3- (pyrrolidinyl) -5-methylsulfamoylbenzoic acid, m.p. 245-248 ° C (decomposes).

Example 33 4- (4'-Methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-35-benzoic acid a) 3-Nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid 124 g (0.9 moles) potassium carbonate is dissolved in 800 ml of water. To this solution is added portionwise 1.6 32 69071 moles of p-cresol and then 112 q (0.4 moles) of 2-chloro-3-nitro-5-carboxybenzenesulfonamide, and the solution is heated to 85 ° C. Stir for 16 hours at this temperature, cool to 25-30 ° C and then acidify the solution to pH 1 with concentrated hydrochloric acid. In this case, the oil which separates is separated from the aqueous phase and subjected to steam distillation. Alternatively, the pH can also be adjusted to 8-9, the excess phenol is shaken off with ethyl acetate and then the aqueous phase is acidified. Thus, when the excess β-cresol is separated, the product separates as crystals on cooling. Recrystallization from acetone / N, gives 3-nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid, m.p. 236 ° C.

B) 3-Nitro-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester The crude product obtained in Example 33 a) is dissolved in methanol and the solution is heated to boiling. 5-10% concentrated sulfuric acid (relative to the starting benzoic acid) is then added and the mixture is refluxed for 8 hours. The solution is now evaporated to 1/3 volume and cooled to 5-10 ° C. The methyl ester separates as crystals, m.p. 161-162 ° C.

c) 3-Amino-4- (4'-methylphenoxy) -5-sulfamoyl-25-benzoic acid methyl ester 45 g of 3-nitro-4- (4'-methylphenoxy) -5-sulfamoyl-benzoic acid methyl ester are suspended in 150 ml of ethyl acetate, then hydrogenated by Raney. using a nickel gel for 5 hours at 50 ° C under a hydrogen pressure of 100 atm. After cooling, the Raney nickel is separated off and the solution is evaporated to dryness. 3-Amino-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester is recrystallized from methanol / O to give crystals melting at 183-185 ° C.

li 69071 d) 3-N-Succinimido-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester 27 g ('-' - Ο, ΟΒ moles) 3-amino-4- (4'-methylphenoxy) -5 -sifamoylbenzoic acid methyl ester is melted with succinic anhydride (24 g, 0.24 moles) and kept molten at 170-190 ° C for 4 hours. After the melt has cooled, methanol and a little water are carefully added. The imide then precipitates and is recrystallized from CH 2 OH / i 2 O. Crystals are obtained which melt at 240-241 ° C.

e) 4- (4'-Methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester 25.6 g of 3-N-succinimido-4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester are suspended in 150 ml. to a solution of abs. diglyme, and 16 ml of BF-β-etherate are then added to the suspension. A solution of 4.6 g of NaBH 4 in 200 ml of abs. diglyme is then added slowly with ice-cooling. The temperature should not rise above 20 ° C. Stirring is continued for a further 15 minutes, then the product is precipitated with water. Recrystallization from CH 2 OH gives crystals with a melting point of 156-157 ° C.

f) The methyl ester obtained in e) is suspended in 1N NaOH and the suspension is heated on a steam bath until a clear solution is obtained. It is then filtered and acidified to pH 3. The precipitated 4- (4 * -methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid is recrystallized from methanol to give pale yellow crystals, m.p. 230-233 ° C (dec.).

Example 34 4- (4'-Methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (41-methoxyphenoxy) -5-sulfamoylbenzoic acid 35 The reaction is carried out analogously to Example 33a) 69071 34 using p-methoxyphenol. The product is crystallized from acetone / water, m.p. 233-234 ° C.

b) 3-Nitro-4- (4'-methoxy-phenoxy) -5-sulfamoyl-benzoic acid methyl ether In analogy to Example 33b). Crystallization from methanol, m.p. 150-152 ° C.

c) 3-Amino-4- (4'-methoxyphenoxy) -5-sulfamoyl-benzoic acid methyl ester in analogy to Example 33c). Crystallization from methanol, m.p. 176-177 ° C.

D) 3-N-Succinimido-4- (4'-methoxy-phenoxy) -5-sulfamoyl-benzoic acid methyl ester; analogously to Example 33 d), m.p. 226-227 ° C.

e) 4- (4'-methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester; analogously to Example 33c), m.p. 190-191 ° C.

f) 4- (4'-Methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is prepared analogously to Example 3 3 f) and crystallized from methanol / water. Pale yellow crystals are obtained, m.p. 228-229 ° 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 analogously to Example 3 3 a) using 3,5-dimethylphenol. The crude product thus obtained is directly esterified.

b) 3-Nitro-4- (3 ', 5'-dimethyl-phenoxy) -5-sulfamoyl-benzoic acid methyl ester; analogously to Example 30 3 3 b). Crystallization from methanol, m.p. 197-198 ° C.

c) 3-Amino-4- (3 ', 5'-dimethyl-phenoxy) -5-sulfamoyl-benzoic acid methyl ester; analogously to Example 3 3 c). Crystallization from methanol, m.p. 195-196 ° C.

d) 3-N-succinimido-4- (3,5-dimethylphenoxy) -5,5-sulfamoylbenzoic acid methyl ester; by analogy

with Example 3 3 d). Crystallization from methanol. Sp. sint- N

69071 35 iron from 220 ° C.

e) 4- (3 ', 5'-dimethylphenoxy) -3- (1-pyrrolidinylbenzoic acid methyl ester, analogously to Example 33 a). Crystallization from methanol, m.p. 208-209 ° C.

5 f) In analogy to Example 33 f).

4- (3 ', 5'-Dimethylphenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is crystallized from methanol / water, mp 246-248 ° C (dec).

Example 36 4- (4'-Chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4'-chlorophenoxy) -5-sulfamoylbenzoic acid

Preparation analogous to Example 33a) using p-chlorophenol. Crystallization from acetone / water, m.p. 248 ° C.

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

Analogously to Example 33b). Crystallization from 20 methanol, m.p. 171-172 ° C.

c) 3-Amino-4- (4-chloro-phenoxy) -5-sulfamoyl-benzoic acid methyl ester

Analogously to Example 33c). Crystallization from methanol, m.p. 198-199 ° C.

D) 3-N-succinimido-4- (4'-chlorophenoxy) -5-sulfamoylbenzoic acid methyl ester; analogously to Example 33 d). Crystallization from methanol, m.p. 266-267 ° C.

e) 4- (4'-chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester; analogously to Example 33 e). Crystallization from methanol / water, m.p. 200 ° C.

f) 4- (4'-chlorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid; analogously to Example 3 3 f) 35. Crystallization from methanol, m.p. 253-254 ° C.

36

Example 37 69071 4- (31-Trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (3'-trifluoromethylphenoxy) -5-sulfamoylbenzoic acid; analogously to Example 33 a) using 3-trifluoromethylphenol · Crystallization from acetone / water, m.p. 210 ° C.

b) 3-Nitro- (3'-trifluoromethyl-phenoxy) -5-sulfamoyl-benzoic acid methyl ester; analogously to Example 33 a).

10 Crystallization from methanol, m.p. 141-143 ° C.

c) 3-Amino-4- (4'-trifluoromethyl-phenoxy) -5-sulfamoyl-benzoic acid methyl ester; analogously to Example 33 c). Crystallization from methanol, m.p. 186-187 ° C.

d) 3-N-succinimido-4- (3'-trifluoromethylphenoxy) -5-sulfamoylbenzoic acid methyl ester; by analogy with 33 d).

Crystallization from methanol m.p. 227-228 ° C.

e) 4- (3'-trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester; analogously to Example 33 e). Crystallization from methanol, m.p. 170-171 ° C.

F) 4- (3'-trifluoromethylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid; analogously to Example 33 f). Crystallization from glacial acetic acid, m.p. 230-234 ° C.

Example 38 4- (4'-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-25 sulfamoylbenzoic acid a) 3N- (3-Methylsuccinimido) -4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester 20 g 3-amino 4- (4'-Methyl-phenoxy) -5-sulfamoyl-benzoic acid methyl ester (see Example 33c) is melted with 30 succinic anhydride (18 g) and the melt is heated at 180 ° C for 3 hours. After cooling the melt, the product is crystallized by adding methanol. Recrystallization from acetone / water, m.p. 229-230 ° C.

li 69071 b) 4- (4'-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester 22 g of 3N- (3-methylsuccinimido) -4- (4'-methylphenoxy) -5-sulfamoylbenzoic acid methyl ester are suspended in 5 is added to 200 ml of abs. diglyme, and 13 ml of BF 3 etherate are added to the suspension. 3.3 g of NaBH 4 dissolved in 200 ml of diglyme are then slowly added dropwise at -5 to 0 ° C with good stirring. Stirring is continued for a further 1 h and the resulting product is precipitated with water. Crystallization from methanol / 10 aqueous mixture, m.p. 177-178 ° C.

c) 4- (4'-Methylphenoxy) -3N- (3-methylpyrrolidinyl) -5-sulfamoylbenzoic acid 14 g of methyl ester (35b) are suspended in 150 ml of 1N NaOH and the suspension is heated on a steam bath. with good stirring. After a clear solution is obtained, stirring is continued for a further hour, then the mixture is acidified to about pH 3 with 2N HCl under ice-cooling. The precipitated product is filtered off with suction, washed well with water and crystallized from a methanol / water mixture, 20 m.p. 220-221 ° C.

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

Method B

25 a) 4-Chloro-4-N, N-dimethylaminomethyleneaminomethyleneaminesulfonylbenzoic acid

To a solution of 58.9 g (0.25 moles) of 4-chloro-5-sulfamoylbenzoic acid in 183 g (2.5 moles) of dimethylformamide (DMF); 90 ml of 183 g (2.5 mol) of dimethylformamide (DMF) are added dropwise at -10 [deg.] C., 90 ml (1.25 mol) of thionyl chloride are added dropwise at -10 [deg.] C. The solution is then allowed to warm to room temperature, stirred for 2 hours, then poured onto ice, filtered and the precipitate is washed neutral with water. Crystalline 35 4-chloro-5-N, N-dimethylaminomethyleneaminesulfonyl-38,69071 benzoic acid is obtained (in very good yield), m.p. 266-267 ° C.

b) 3-Nitro-4-chloro-5-N, N-dimethylaminomethylene aminosulfonylbenzoic acid 60 ml of 20% sulfuric acid are added dropwise under ice-cooling to 42 ml of fuming nitric acid, then 34.9 g (0.12 moles) of 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid. After stirring for 24 hours at 55-60 ° C, the solution is cooled to room temperature, poured onto ice, washed and the precipitate is washed neutral with water. Crystalline 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid is obtained, m.p. 274-276 ° C.

c) 3-Nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 50.4 g (0.15 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid are boiled for one hour. recovering in a solution of 150 ml of thionyl chloride and 5 drops of DMF. The excess thionyl chloride is evaporated in vacuo and the solid acid chloride is suspended in 200 ml of methanol. The suspension is refluxed for 1/2 hour, then cooled, filtered and washed with cold methanol. Crystalline 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is obtained, m.p. 168-169 ° C. 25 d) 3-Nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

A solution of 105 g (0.3 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester and 47.5 g (0.36 mol) of potassium phenolate in 600 ml of DMF, boil under reflux for 2 hours. After cooling and filtration of the potassium chloride, the solution is poured into ice water, then stirred for a further hour. The precipitate is filtered off, washed with water and dried. The crude product is dissolved in 900 ml of acetone, clarified with charcoal, evaporated to 500 ml and diluted with 1 liter of methanol. After stirring for 1 hour at 39 ° C, the precipitate is filtered off and washed with cold methanol. Crystalline 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester is obtained, m.p. 191-193 ° C.

5 e) 3-Amino-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 61 g (0.15 mol) of 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester are hydrogenated Rane with nickel in methanol at 10 room temperature under normal pressure for 8 hours. After filtration, the catalyst is suspended in warm DMF, filtered and the DMF filtrate is poured into ice water. Crystalline 3-amino-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is obtained, m.p. 255-256 ° C.

f) 3-N-Succinimido-4-phenoxy-5-N, N-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester 30 g of 3-amino-4-phenoxy-5-N, N-dimethylamino-20-ethyleneaminesulfonylbenzoic acid methyl ester are melted At 180 ° C with succinic anhydride (26 g). The reaction imide formed after a reaction time of about 2 hours is mixed with methanol. Recrystallization from n-butanol gives the imide precipitated with methanol. Recrystallization from n-butanol gives the imide in very good yield, m.p. 283-284 ° C.

g) 3-Phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid ester 23 g (0.05 mol) of 3-N-succinimido-4-phenoxy-5-N, N -Dimethylaminomethyleneaminesulfonylbenzoic acid ethyl ester is suspended in 200 ml of diethylene glycol dimethyl ether (diglyme), and 13 ml (0.1 mol) of BF3-etherate are added to the suspension. The solution is then slowly added dropwise to the mixture, while cooling, if the solution contains 3.8 g (0.1 mol) of NaBH 4 in 200 ml of diglyme, the temperature is maintained at -10 to + 5 ° C during the addition. The mixture is then allowed to warm to room temperature to give a clear solution. After 1.25 hours the reaction is complete. Addition of water causes the product to precipitate.

Crystallization from methanol gives 4-phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid ester, m.p. 189-190 ° C.

h) 4-Phenoxy-3- (1-pyrrolidinyl) -5-sulfamyl-10-benzoic acid 13 g (0.03 mol) of 4-phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminesulfonyl- the benzoic acid methyl ester is suspended in 100 ml of 2N NaOH and saponified at 80-90 ° C with good stirring.

After a clear solution is obtained, continue stirring at the same temperature for another hour. It is then cooled to 0 [deg.] C. and 110 ml of 2N hydrochloric acid are added slowly and with good stirring to the solution. Stir vigorously for a further 1/2 hour, then the very finely precipitated product is filtered off with suction immediately. It is recrystallized from methanol / water to give pale yellow plate-like crystals, m.p. 226-228 ° C.

Example 4.0

The reaction sequence shown in Example 1 is repeated until step c). The resulting 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is then heated with potassium phenolate for 2 hours at 190-200 ° C. The reaction mixture is cooled, dissolved in acetone and, after separation of the inorganic constituents, the reaction mixture is treated as described in step d). 3-Nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is obtained, which can be converted analogously according to the method described in Example 1 to the desired final product.

69071 41

Example 41 a) The reaction sequence set forth in Example 1 is repeated except that the catalytic hydrogenation of 3-nitro-4-phenoxy-5-N, N-dimethylaminomethylenesulfonyl-benzoic acid methyl-5 ester is performed in an autoclave at 50 ° C and 50 atm. pressure. After cooling the reaction mixture, the desired 3-amino-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid ester is isolated as described in Example 1 e).

B) The reaction sequence of Example 1 is repeated, except that the catalytic hydrogenation of 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is carried out in dimethylformamide (DMF) with Raney nickel at room temperature and at normal pressure. After filtration of the catalyst, the DMF solution is poured onto ice. 3-Amino-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester is obtained, m.p. 255-256 ° C.

Example 42 The reaction sequence set forth in Example 1 is repeated except that 4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is used as the starting material.

a) 4-Chloro-5-N, N-dimethylaminomethyleneamino-2-sulfonylbenzoic acid methyl ester

To a solution of 74.9 g (0.3 moles) of 4-chloro-5-sulfamoyl-benzoic acid methyl ester in 183 g (2.5 moles) of dimethylformamide is added dropwise at -10 ° C 90 ml (1.25 moles) of thionyl chloride, and further work-up of the reaction mixture is carried out according to Example 1. 4-Chloro-η 5 -N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is obtained, m.p. 174-176 ° C.

b) 3-Nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester Under the conditions described in Example 1 b), 36.5 g (0.12 mol) of 4-chloro-5-N, N -dimethylamino-methyleneaminesulfonylbenzoic acid methyl ester for the reaction. A mixture of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid and 3-nitro-4-chloro-5R-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester is obtained. The mixture is separated by treatment with 5% aqueous sodium carbonate solution. 3-Nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is obtained, m.p. 168-169 ° C and acidified by making 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid having a m.p. 270-272 ° C, and which can also be converted into an ester as described in Example 1 c). The reaction is then continued according to the reaction sequence described in Example 1.

15 Example 43

The nitration described in Example 1 is carried out with the difference that ethyl ester is used instead of methyl ester.

a) 4-Chloro-5-N, N-dimethylaminomethyleneamino-sulfonyl-benzoic acid ethyl ester

To a solution of 65 g (0.25 moles) of 4-chloro-4-sulfamyl-benzoic acid ethyl ester in 183 g (2.5 moles) of DMF at -10 ° C is added dropwise 90 ml (1.25 moles) of thionyl chloride, and the reaction mixture is stirred. further processing is performed according to Example 1. Crystalline 4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid poethyl ester is obtained, m.p. 119-121 ° C.

b) 3-Nitro-4-chloro-5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid ethyl ester Under the conditions described in Example 5, 38.3 g (0.12 mol) of 4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid ethyl ester are obtained. . The separation of the nitroester and nitro acid takes place as described in Example 6. Crystalline

"M

35 3-Nitro-4-chloro-5-N, N-dimethylaminomethyleneamino 09071 43 sulfonylbenzoic acid ethyl ester, m.p. 182-184 ° C, and acidification of the aqueous solution gives crystalline 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid, m.p. 270-272 ° C, which is identical according to the melting point and mixed with the carboxylic acid of Example 1 b).

Example 44 3-Nitro-4-phenoxy-5-sulfamylbenzoic acid

The reaction sequence described in Example 1 is repeated to step 10 to 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid ester. 100 g of 3-nitro-4-phenoxy-5-N, N-dimethylaminomethyl-aminosulfonyl-benzoic acid methyl ester are then boiled under reflux in 500 ml of 2-n NaOH for 2 hours. After cooling, the mixture is acidified with concentrated hydrochloric acid.

Crystalline 3-nitro-4-phenoxy-5-sulfamylbenzoic acid is obtained, m.p. 254-255 ° C.

Example 45 4-Phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid methyl 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 to concentrated sulfuric acid and boil for 4-6 hours at reflux. On cooling, the ester crystallizes. Recrystallization of -25 from methanol, m.p. 191 ° C.

Example 46 4-Phenylmercapto-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid

The reaction sequence set forth in Example 1 is repeated to prepare 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.

a) 3-Nitro-4-phenylmercapto-5-N, N-dimethylaminomethyleneamosulfonylbenzoic acid methyl ester 35 A solution of 21 g (0.06 moles) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonyl-44 69071 benzoic acid methyl ester, 7.7 g (0.07 mol) of thiophenol and 8.2 g (0.077 mol) of sodium carbonate in 100 ml of DMF are refluxed for 2 hours. After cooling, the solution is filtered and poured into ice water, then stirred for 5 hours. The precipitate is filtered off, washed with water and dried. The crude product is crystallized from acetone / methanol. Crystalline 3-nitro-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is obtained, m.p. 207 ° C.

10 b) 3-Amino-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 2 g (0.0047 mol) of 3-nitro-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminosulfonylbenzoate-15-acid methyl ester with nickel in 30 ml of DMF at room temperature and normal pressure for 8 hours. The catalyst is filtered off with suction, washed with warm DMF and the DMF filtrate is poured into ice water. 3-Amino-4-phenylmercapto-5-N, N-dimethylamino-20-methyleneaminesulfonylbenzoic acid methyl ester is obtained as crystals from acetone, m.p. 214-215 ° C.

c) 3-N-Succinimido-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 35 35 g (0.089 mol) of 3-amino-4-phenylmercapto-5-dimethylaminomethyleneaminosulfonic acid mernetanoate , 6 g, 0.2668 mol) and then heated at 175 ° C for 2 hours. After cooling to 150 ° C, the melt is diluted with 100 mL of DMF and the solution is slowly poured into ice water. The precipitate is filtered off with suction, dried and crystallized from DMF / CH-OH, m.p. 261-263 ° C.

d) 4-Phenylmercapto-3- (1-pyrrolidinyl) -5-35 N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 69071 45

To a solution of 32 g of 3-N-succinimido-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester and 17.5 ml of BF 4 -etherate in 135 ml of absolute diglyme is added dropwise with good stirring 0-10 At 5.1 ° C a solution of 5.1 g

NaBH 4 in 135 ml of absolute diglyme. After 2 hours, hydrolyze and the product precipitates by adding more water.

e) The precipitated crude product is refluxed with 2N NaOH until a clear solution is obtained.

4-Phenylmercapto-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid is precipitated with 2N HCl and crystallized from CH 2 OH / CH 2 Cl 2. Sp. 237-238 ° C, see also Example 33.

Example 47 4-Phenylmercapto-3- [1- (3-methylpyrrolidinyl)] - 5-sulfamoylbenzoic acid a) 3-Amino-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester A solution of 110 g 3-Nitro-4-phenylmercapto-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester in 400 mL of DMF is hydrogenated with Raney nickel (about 10 g) at 40 ° C at 100 atm. under pressure for 8 hours. The catalyst is filtered off and the solution 25 is poured onto ice. The precipitate is filtered off, dried and crystallized from acetone, m.p. 214-215 ° C.

b) 3N- (3-Methylsuccinimido) -4-phenylmercapto-5-N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester 40 g (0,10.1 mol) of 3-amino-4-phenylmercapto-5-N, N-dimethylaminomethyleneamino-benzoethylbenzenesulfonylbenzenesulfonylbenzenesulfonyl melted with methyl succinic anhydride (34 g, 0.3 mol) and kept at 175 ° C for 2.5 hours. After cooling to 150 ° C, the melt is diluted with 100 mL of DMF and the solution is slowly poured into ice water. The precipitate is filtered off with suction and crystallized from CH3OH, m.p. 206-207 ° C.

c) 4-Phenylmercapto-3- [1- (3-methylpyrrolidinyl] -5-N, N-dimethylaminomethyleneamino] phenylbenzo-5-acid methyl ester

To a solution of 29.4 g of 3-N- (3-methylsuccinimido) -4-phenylmercapto-5-N, N-dimethylaminomethylenesulfonyl] benzoic acid methyl ester and 15.9 ml of BF 4 ether in 120 ml of abs. At 0-10 ° C, a solution of 4.65 g of NaBH 4 in 120 ml of absiglyme. After stirring for 2 hours, the reaction product is carefully precipitated with water. Recrystallization from CH 2 OH, m.p. 147-148 ° C.

d) 4-Phenylmercapto-3- [1- (3-methylpyrrolidinyl] -5-sulfamoylbenzoic acid 15 g of the ester (Example 47c) are boiled under reflux in 40 ml of 2N NaOH for 2 hours to give a clear solution. then acidified with 2N HCl to pH 2-3 to precipitate 4-phenylmercapto-3- [1- (3-methylpyrrolidinyl)] -5-sulfamoylbenzoic acid. It is crystallized from CH 2 OH to give yellow crystals. , mp 216-217 ° C.

Example 48 4-Phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid

A solution of 7.8 g of 4-phenylmercapto-3- (1-pyrrolidin-25-yl) -5-sulfamoylbenzoic acid in 130 ml of glacial acetic acid and 20 ml of 30% Η3θ2 is stirred at room temperature. The progress of the reaction is monitored by thin layer chromatography. After 20 hours, the solution is poured into 800 ml of ice water. The precipitate is filtered off with suction, washed with water and dried. Crystallization from methanol / water gives 4-phenylsulfoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid as yellow crystals, m.p. 142-144 ° C (decomp.).

69071 47

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

A solution of 6 g of 4-phenylmercapto-3- [1- (methyl-5-pyrrolidinyl)] - 5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid in 70 ml of glacial acetic acid and 15 ml of 30% The mixture is stirred at 5-20 ° C. After 20 hours, the solution is poured into ice water. The precipitate is washed with water, dried and hydrolysed with 30 ml of 2N NaOH for 2 hours at 100 ° C. The hydrolyzate is filtered and acidified with 2N HCl to pH 2-3 with cold stirring. This precipitates 4-phenylsulfoxy-3- [1- (methylpyrrolidinyl)] - 5-sulfamoylbenzoic acid. Crystallization from methanol / water gives yellow crystals, m.p. 143-145 ° C (decomposes).

Example 50 4- (4'-Nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-N-Succinimido-4- (4'-nitrophenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid Acid methyl ester To 35 g of 3-N-succinimido-4-phenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is added portionwise at -20 ° to 10 ° C 200 ml of fuming nitric acid. After stirring for 10 minutes, the mixture is poured into about 2 liters of ice water. After stirring for 1 hour, the separated product is filtered and washed well with water to give 3-N-succinimido-4- (4'-nitrophenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester in very good yield as a white crystalline powder, m.p. 260-261 ° C.

b) 4- (4'-Nitrophenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 35 30 g of the imide obtained above (Example 50 a) are suspended in about 250 ml of absolute diglyme, and 22 ml of BF 3 etherate are added to the suspension, followed by dropwise addition of a solution of NaBH 4 (3.2 g) in 250 ml of diglyme at 50 to 60 ° C. After 1.5 hours, the excess reducing agent is hydrolyzed by adding a little water, and 4- (4-nitrophenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is precipitated with ice water to give pale yellow crystals, mp 216-217 ° C (from methanol).

C) 4- (4'-Nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 24 g of the ester obtained above (Example 50b) are heated for 1.5 hours on a steam bath in 200 ml of 1N sodium hydroxide, to which a little methanol has been added as a dissolution medium to give a clear solution. After cooling the solution, the free acid is precipitated with 2N hydrochloric acid. Obtained as light brown crystals, 4- (4'-nitrophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid, m.p. 235-238 ° C (dec.) (Crystallization from glycol monomer-20 ethyl ether / water).

Example 51 4- (4'-Aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 4- (4'-nitrophenoxy) -3- (1-pyrrolidinyl) -5-25 sulfamoylbenzoic acid (18.5 g) dissolved in dimethylformamide, hydrogenated in the presence of Raney nickel at room temperature under normal pressure for 8 hours. The reaction mixture is filtered and 4- (4'-aminophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with water. Brown crystals are obtained, m.p. 234-240 ° C (dec.) (Crystallization from DMF / H 2 O). The compound crystallizes with 1/2 mole of dimethylformamide, which cannot be removed even by prolonged heating at 120-150 ° C under vacuum.

69071 49

Example 5? 4- (4'-Benzyloxy-phenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-Nitro-4- (4'-benzyl-phenoxy) -5 - N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 87.5 g (0.25 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is dissolved in 500 ml of anhydrous dimethylform-10-amide and 77.5 g (9.35 mol) of sodium 4 are added. -bentsyylioksifenolaattia. The reaction mixture is heated to reflux with good stirring for 3-4 hours. After cooling the mixture, the cloudy solution is added dropwise to 3 l of ice water. The precipitated yellow precipitate is filtered off with suction, washed well with water and crystallized from methanol. 94 g of 3-nitro-4- (4-benzyloxyphenoxy) -5-Ν, Ν-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester are obtained in the form of yellow crystals, m.p. 132 ° C.

b) 3-Amino-4- (4'-benzyloxy-phenoxy) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 94 g of 3-nitro-4- (4'-benzyloxy-phenoxy) -5-N, N-dimethylamino-methyleneaminesulfonyl-benzoic acid methyl ester is dissolved in 1.5 liters of dimethylformamide and hydrogenated in the presence of Raney nickel at room temperature under normal pressure for 6-7 hours. The mixture is filtered and the clear solution is added dropwise to ice water. The precipitated 3-amino-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is crystallized from methanol. 70 g of white crystals are obtained, m.p. 170 ° C.

c) 3-N-Succinimido-4- (4'-benzyloxy-phenoxy) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 35 48.3 g (0.1 mol) of 3-amino-4- (41-benzyloxy-No. 50) 69071 Phenoxy) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester is dissolved in 250 ml of absolute dioxane. The solution is heated to boiling and a solution of succinic acid chloride (24.5 g, about 0.16 mol) in 100 ml of absolute acetone and a solution of pyridine (16 ml, about 0.2 mol) in 100 ml are slowly added dropwise at the same rate. in absolute acetone. After refluxing for about 2 hours, the reaction mixture is evaporated and methanol is added to the residue. The resulting imide crystallizes and can be recrystallized from methanol containing some acetone. 45 g of white crystals are obtained, m.p. 228 ° C.

d) 4- (4'-Benzyloxy-phenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester

The imide obtained above (25.5 g) is suspended in 200 ml of absolute diglyme, and 16.8 ml of BF 4 etherate are added to the suspension and then a solution of NaBH 4 (5 g) in 200 ml of absolute solution is added dropwise at room temperature. diglyme. After stirring for 1/2 hour, the excess reducing agent is decomposed by the careful addition of water and slightly dilute hydrochloric acid (foam), and finally the product is precipitated with water (11). Recrystallization from methanol gives 31.6 g of 4- (4'-benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester, m.p. 152 ° C.

e) 4- (4'-Benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 31 g of the ester obtained above (Example 52 <j) are suspended in 300 ml of 2N sodium hydroxide and the suspension is heated on a steam bath until a clear solution is obtained. It is cooled and 4- (4'-benzyloxyphenoxy-3S) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated by the addition of 2-hydrochloric acid (pH about 3).

69071 51

The acid is recrystallized from methanol. Kellan-white crystals are obtained, m.p. 226-228 ° C. NMR (D 6 -DMSO, 60 MHz, TMS) 1.73 (quasi-s, 4H), 3.24 (quasi-s, 4H), 5.05 (s, 2H), 6.6-7.9 ( m. 13H).

Example s3 4- (4'-Hydroxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 9.5 g of 4- (4'-benzyloxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid are dissolved in water. to which an equivalent amount of potassium hydroxide has been added, and hydrogenated in the presence of Raney nickel at 50 ° C under 100 atm in an autoclave for 5 hours. The mixture is filtered and 4- (4'-hydroxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated with 2N chloro-15 hydrochloric acid (pH about 3). Crystallization from CH 2 OH / O 2 gives the product as pale yellow crystals, m.p. 271-273 ° C. NMR (D 6 -DMSO, 60 MHz, TMS) δ: 1.73 (quasi-s, 4H), 3.24 (quasi-s, 4H), 6.64 (quasi-s, 4H), 7.24 (s, 2H), 7.58 (d, 1H), 7.88 (d, 1H), 9.0 (s, broad, 1H).

Example 4 4-Phenoxy-3- (3-chloro-1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-N- (3-Chlorosuccinimido) -4-phenoxy-5-sulfamoylbenzoic acid methyl ester 51.4 g 3- amino-4-phenoxy-5-sulfamoyl-1-benzoic acid methyl ester and 62.5 g of chlorosuccinic anhydride are stirred and heated together as a melt at 180 ° C for 1-2 hours. After about an hour, the melt is frozen. Upon addition of methanol, the product crystallizes. The crystalline mass is filtered off with suction and washed well with methanol. The resulting imide can be crystallized from acetone / DMF / O 2.

White crystals are obtained, m.p. 247-249 ° C (dec.).

b) 4-Phenoxy-3- (3-chloro-1-pyrrolidinyl) -5-35 sulfamoylbenzoic acid methyl ester 33 g (0.075 mol) of the imide obtained above are suspended in 200 ml of diglyme and 22.7 g ( 0.16 mol) of BF3-etherate. A solution of NaBH 4 (5.9 g, 0.155 mol) in 250 ml of diglyme is then added dropwise under ice-cooling, and the mixture is then stirred for 1/2 hour at room temperature, and finally the reduction is hydrolyzed with 2N hydrochloric acid. Addition of water precipitates the product as an oil. It is separated and dissolved in a small amount of hot methanol. Upon cooling, the solution crystallizes from 4-phenoxy-3- (3-chloro-1-pyrrolidinyl) -5-sulfamoyl-10-benzoic acid methyl ester, m.p. 170-171 ° C.

c) 4-Phenoxy-3- (3-chloro-1-pyrrolidinyl) -5-sulfamoylbenzoic acid

The ester obtained above is suspended in 1N sodium hydroxide and the suspension is heated on a steam bath until a solution is obtained. After cooling, the product is precipitated by adding 2N hydrochloric acid (pH 3-4), the product is recrystallized from CH 2 OH / O 2. If the product is reddish, then the red color is caused by filtering the acetone solution through a pad of silica gel. Yellowish-white crystals are obtained, m.p. 231-232 ° C.

Example 55 4-Phenoxy-3- (3-pyrrolidin-1-yl) -5-sulfamoylbenzoic acid 4-Phenoxy-3- (3-chloro-1-pyrrolidinyl) -5-sulfamoyl-benzoic acid is dissolved in d-methylsulfoxide. and 5 times the molar amount of potassium tert-butylate is added to the solution. The mixture is heated for 2-3 hours at 120 ° C, the mixture is acidified with 2N hydrochloric acid and the product is precipitated with water. Crystallization from a small amount of acetone or methanol gives off-white crystals, m.p. 275-277 ° C.

11 69071 53

Example 56 4- (4'-Methylphenoxy) -3- (3-pyrrolin-1-yl) -5-sulfamoylbenzoic acid a) 3-N- (3-chlorosuccinimide) -4- (4'-methylphenoxy) -5- N, N-Dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 25 g of 3-amino-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 25.9 g of chlorosuccinic anhydride are melted together at 180 DEG C. After about 2.5 hours, the reaction is complete and the resulting imide is precipitated with methanol. White crystals are obtained, m.p. 294-295 ° C (at 215-216 ° C the product sintered).

b) 20 g of the imide obtained above are suspended in diglyme-15, and 10.3 ml of BF 4 etherate are added to the suspension. A diglyme solution of NaBH 4 (3.1 g) is then added dropwise at room temperature and the mixture is stirred for 2-3 hours. the oily product precipitates on addition of a little 2N hydrochloric acid and a lot of water. The product is separated and immediately saponified with 2N sodium hydroxide in a water bath. From the resulting clear solution, the product is precipitated with 2-hydrochloric acid to give 4- (4'-methylphenoxy) -3-pyrrolin-1-yl) -5-sulfamoylbenzoic acid and 4- (4'-methylphenoxy) -3- (3-chloro-1- pyrrolidinyl) -5-25 sulfamoylbenzoic acid. The mixture is dried, dissolved in dimethyl sulfoxide, and a 5-fold molar amount of potassium tert-butylate is added to the solution. The mixture is heated for 2-3 hours at 120 ° C, then the mixture is acidified with 2N hydrochloric acid at room temperature and the product is precipitated with water. 4- (4'-methylphenoxy) -3- (3-pyrrolin-1-yl) -5-sulfamoylbenzoic acid is obtained, which is recrystallized from CH 3 OH / H 2 O or acetone to give off-white crystals, m.p. 270-272 ° C.

69071 54

Example 5J

4-Phenoxy-3- (3-phenyl-1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-N- (3-phenylsuccinimido) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester 20 g 3-amino-4 -phenoxy-5-sulfamoylbenzoic acid methyl ester and 32.2 g of phenylsuccinic anhydride are melted and heated at 200-210 ° C for 3 hours. The cooled mass is dissolved in methanol and added dropwise to ice water with vigorous stirring. The precipitated imide is dried and recrystallized from glycol monomethyl ether to give white crystals, m.p. 187-188 ° C.

b) 4-Phenoxy-3- (3-phenyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid methyl ester 14.4 g (0.03 mol) of the imide obtained above are dissolved in 150 ml of absolute diglyme, and 16 ml of BF 4 etherate (0.1 mol), and then a solution of NaBH 4 (3 g, about 0.08 20 mol) in 150 ml of absolute diglyme is added dropwise to the solution at 50 ° C, and the mixture is stirred after the addition for about 1/2 hours at 50 ° C. The reducing agent is hydrolyzed with a small amount of hydrochloric acid, and the product is precipitated with water. Recrystallization from CH 2 OH / acetone gives white crystals, m.p. 175-176 ° C.

c) The ester obtained above is heated with 1N NaOH in a steam bath until a clear solution is obtained. 2-N hydrochloric acid is added to pH 3, whereupon 4-phenoxy-3- (3-phenyl-1-pyrrolidinyl) -5-sulfamoyl-benzoic acid precipitates. It is crystallized from CHOH / H 2 O or acetonitrile, m.p. 216-217 ° C.

Example 58 4- (4'-Methylphenoxy) -3- (3-phenyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid 35 a) 3-Nitro-4- (4 * -methylphenoxy-5-N, N-dimethyl-69071 55 Aminomethyleneaminesulfonylbenzoic acid methyl ester A solution of 3-nitro-4-chloro-5-N, N-dimethylaminomethylene aminosulfonylbenzoic acid methyl ester (235 g, 0.67 mol) and potassium 4-methylphenolate (140 g, ca. 0.96 mol) in 1 liter. absolute dimethyl sulfoxide is heated with stirring at 90-100 ° C for 2 hours The cooled solution is slowly added dropwise with vigorous stirring to 4-5 liters of ice water The precipitated product is filtered off with suction, washed with water and recrystallized from methanol to give yellow crystals, m.p. ° C.

b) 3-Amino-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 171 g of 3-nitro-4- (4'-methylphenoxy) -5-N, N-di- methylaminomethyleneaminesulfonylbenzoic acid methyl ester is hydrogenated in the presence of Raney nickel in CH 2 OH / ethyl acetate / DMF at 50 ° C under 100 atm for 8 hours. The mixture is filtered, the precipitate is washed with dimethyl-formamide and the filtrate is evaporated. The residue is crystallized from methanol to give white crystals, m.p. 172-173 ° C.

c) 3-N- (3-Phenylsuccinimido) -4- (4 * -methylphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 25 g of the amino compound obtained above (Example 5b) and 20 g of phenylsuccinic anhydride are heated together 2 hours at 180-190 ° C. The imide is doped by adding methanol. It is crystallized from ethanol to give white crystals, 249-250 ° C.

D) 4- (4'-methylphenoxy) -3- (3-phenyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid 24.5 g of the imide obtained above (Example 58 c) are suspended in 225 ml of absolute diglyme. and 24 ml of BF 4 etherate are added to the suspension. A solution of NaBH 4 sn (4.5 g) 69071 56 in 200 ml of absolute diglyme is then added dropwise to the mixture at room temperature, and the mixture is heated and stirred at 60-80 ° C for one hour.

The product is precipitated with ice water, separated and immediately saponified with 2N sodium hydroxide. From the resulting Kirk-5 solution, the free acid is precipitated with 2N hydrochloric acid. Crystallization from glacial acetic acid / H 2 O or CH 2 OH / H 2 O gives the product, m.p. 204-206 ° C.

Example 59 4- (4'-Methoxyphenyl) -3- (3-methyl-1-pyrrolidin-10-yl) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4'-methoxyphenoxy) -5-N, N-dimethyl -liaminometyleeniaminosulfonyylibentsoehappo-methyl ester

The reaction is carried out analogously to Example 5¾ a 15 using potassium 4-methoxyphenolate. The crude product is hydrogenated directly.

b) 3-Amino-4- (4'-methoxyphenoxy-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester) The crude 3-nitro compound obtained above is hydrogenated in dimethylformamide in the presence of Raney nickel at 50 ° C and 50 atm. The nickel is filtered off and the product is precipitated from the filtrate with water by crystallization from a methanol strip to give white crystals, mp 141-143 ° C.

C) 3-N- (3-Methylsuccinimido) -4- (4'-methoxyphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 16 g (about 0.045 mol) of the amino compound obtained above are melted together with methyl succinic anhydride. din (14 g) at 180 ° C. After about 2 hours, methanol is added to the cooled, still flowing mixture. The imide crystallizes slowly and is recrystallized from CH 2 OH / acetone. White crystals are obtained, m.p. 207-208 ° C.

69071 57 d) 4- (4'-methoxyphenoxy) -3- (3-methyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid 16.5 (0.033 mol) of the imide obtained above are suspended in 150 ml of absolute diglyme, and 9 ml of BF 4 etherate are added to the suspension. A solution of NaBH 4 (2.7 g) in 150 ml of diglyme is then added dropwise with stirring at 0-10 ° C, and the mixture is stirred at room temperature for a further 15 minutes. The crude product is obtained by precipitation with a small amount of hydrochloric acid and a large amount of water, suspended in 2N sodium hydroxide, and the suspension is heated until a solution is obtained. Addition of acid to pH 3 gives the free acid, which is crystallized from CH 2 OH / 1 O 2. Pale yellow crystals are obtained, m.p. 190 ° C.

Example fifl 4-Phenylsulfonyl-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid

A solution of 11.8 g (0.3 mol) of 4-phenylsulfinyl-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid in a mixture of 20 glacial acetic acid (130 ml) and 30% hydrogen peroxide (20 ml), stirred at room temperature for about 30 hours. The reaction is monitored by thin layer chromatography (toluene / glacial acetic acid 4: 1). After completion of the reaction, the solution is added dropwise to ice water, the precipitate formed is filtered off with suction, washed with water and crystallized from CH 2 Cl 2 / CH 2 O 2.

Yellow crystals are obtained, m.p. 170-172 ° C, (dec.).

Example 61 4- (4'-Fluoro-phenoxy) -3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid 30 a) 3-Nitro-4- (4'-fluoro-phenoxy) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester

A solution of 210 g (0.6 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoate-35-acid methyl ester and 120 g of sodium 4-fluorophenolate-69071 58 in 800 ml of absolute dimethylformamide is stirred. 3-4 hours at 120-130 ° C. The cold solution is then added dropwise slowly and vigorously with stirring to 4-5 liters of ice water. The precipitated product is filtered off with suction, washed well with water, digested with acetone, heated and then crystallized from glycol monomethyl ether. Pale yellow crystals are obtained, m.p. 224-225 ° C.

b) 3-Amino-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 140 g of the nitro compound obtained above (Example fi1a) are dissolved in dimethylformamide and hydrogenated in the presence of Raney nickel at 50 ° C: at 50 atm for 15 8 hours. The Raney nickel is filtered off and the filtrate is added dropwise to ice water. The precipitate is separated off, washed with methanol and then with ether. The substantially pure product can be recrystallized from glycol monomethyl ether. White crystals are obtained, m.p. 234-236 ° C.

c) 3-N-Succinimido-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 31.6 g of the amino compound obtained above (Example 61 b) and 20 g of succinic anhydride are melted together in 180- 200 ° C. After 1.5-2 hours, methanol and a little water are added to the melt. The precipitated product is separated and crystallized from glycol monomethyl ether. White crystals are obtained, m.p. 291-293 ° C.

D) 4- (4'-Fluorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 34 g of the imide obtained above (Example 51 c) are suspended in 300 ml of absolute diglyme and 19 ml of BF- are added to the suspension. j etherate. A solution of NaBH 4 (9) in 200 ml of 69071 59 absolute diglyme is then added dropwise to the mixture at 0-15 ° C. The mixture is stirred for about an hour at 30-40 ° C, i.e. until a clear solution is obtained. The product is mixed with ice water and immediately saponified with 2N NaOH. From the clear solution, 5 free acid is precipitated in the cold with 2N hydrochloric acid.

Crystallization from CH 2 OH / 1 O 2 gives pale yellow crystals, m.p. 250-252 ° C.

Example 62 4- (4'-Fluorophenoxy) -3- (3'-methyl-1-pyrrolidin-10-yl) -5-sulfamoylbenzoic acid a) 3-N- (3'-methylsuccinimido) -4- (4'-fluorophenoxy) -5-n, n-dimetyyliaminometyleeniaminosulfo nyylibentsoehappometyyliesteri

The reaction with methyl succinic anhydride is carried out as in Example 61c. The precipitated imide is filtered and washed with methanol and ether. White crystals are obtained, m.p. 228-229 ° C.

b) 4- (4'-Fluorophenoxy) -3- (3'-methyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid The title compound is prepared in analogy to Example 61d. Crystallization from CH 2 OH / 1 O 2 60:40 or acetonitrile. Pale yellow crystals are obtained, m.p. 242-243 ° C.

Example 63 4- (4'-Chlorophenoxy) -3- (3'-methyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4'-chlorophenoxy) -5-N, N -Dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester A solution of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester (164 g) and potassium p-chlorophenolate (117 g) in refluxing (800 g) was refluxed in 800 ml of dimethylformamide. cooling for 2-3 hours. The reaction mixture is added dropwise with vigorous stirring to 4 times the amount of ice water.

69071 60

The precipitated product is separated and purified by boiling in CH 2 OH / acetone. Sp. 227-228 ° C.

b) 3-Amino-4- (4'-chlorophenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 130 g of the nitro compound obtained above (Example S3 a) are hydrogenated in the presence of Raney nickel in 1 liter of dimethylformamide at 50 ° C at 50 atm for 9 hours. The Raney nickel is filtered off and the filtrate is evaporated and the residue is purified by boiling in methanol. A white product is obtained, m.p. 207-208 ° C.

c) 3-N- (31-Methylsuccinimido) -4- (4'-chlorophenoxy) -5-N, N-dimethylaminomethylenesulfonyl-benzoic acid methyl ester 30 g of the amino compound obtained above (Example 63 b) and 27.4 g of methyl succinic anhydride are heated as a melt. At 190-200 ° C for 2 hours. The imide is precipitated by the addition of methanol and a little water. Crystallization from methanol gives white crystals, m.p. 162-164 ° C (kor-20 kea viscous oil, which only becomes flowable at 197-198 ° C).

d) 4- (4'-chlorophenoxy) -3- (3'-methyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid 15.3 g of the imide 25 obtained above (Example 63 c) are suspended in 150 ml of absolute diglyme, and 8 ml of BF 4 etherate are added to the suspension. A solution of NaBH 4 (2.35 g) in 100 ml of absolute diglyme is then added dropwise to the mixture at 0-10 ° C. The mixture is stirred for 1/2 hour at room temperature, then the product is precipitated with water. The crude product obtained is immediately saponified by refluxing with 2N NaOH. From the cooled clear solution an acid is obtained with 2N hydrochloric acid. It is crystallized from Cl 2 OH / H 2 O or acetonitrile. Pale yellow crystals 35 are obtained, m.p. 257-258 ° C.

69071 61

Example 64 3- (1'-Pyrrolidinyl) -4- (4'-methylpiperazino) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4'-methylpiperazino) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 34 .9 g (0.1 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester, 11 g (12.22 ml, 0.11 mol) of N-methylpiperazine-10, , 1 g (15.2 ml, 0.11 mol) of triethylamine and 150 ml of dimethylformamide are boiled together for 2.5 hours at 85 ° C. The mixture is cooled and poured into 1 liter of ice water. The precipitate is filtered off with suction, dried and crystallized from ethyl acetate. Yellow crystals are obtained, 15 m.p. 181-182 ° C.

b) 3-Amino-4- (4'-methylpiperazino) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 78 g of the nitro compound obtained above (Example 64 20a) are dissolved in 700 ml of dimethylformamide and hydrogenated for 12 hours at 50 ° C: at 100 atm in the presence of Raney nickel. The catalyst is filtered off and the filtrate is evaporated. The residue is digested in ether. Crystallization from methanol gives the product as pale yellow crystals, m.p. 208-209 ° C.

c) 3-Succinylamino-4- (4'-methyl-piperazino) -5-N, N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester

A solution of the amino compound obtained above (Example 64 b) 30 (9.6 g, 0.25 mol) and succinic anhydride (20 g, 0.2 mol) in 150 ml of acetonitrile is refluxed for 24 hours. After cooling, the precipitate formed is filtered off, washed with ether and crystallized from methanol / glacial acetic acid. Crystals are obtained, m.p. 225-227 ° C.

62 69071 d) 3-Succinimido-4- (4'-methylpiperazino) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid ester 5 g of 3-succinylamino-4- (4'-methylpiperazino) -5,5-N, N-dimethylaminomethyleneaminosulfonylsulfonyl The methyl ester is stirred for 1 hour at 70 [deg.] C. in 20 ml of 100% H2O. The mixture is poured into ice water, the pH of the solution is adjusted to 7 with 5N sodium hydroxide and the mixture is extracted with methylene chloride (3 x about 50 ml).

The combined extracts are washed once with about 50 ml of water, dried over sodium sulfate and evaporated. The residue is crystallized from DMF / methanol to give a crystalline product, m.p. 257 ° C.

e) 3- (1'-Pyrrolidinyl) -4- (4'-methylpiperazino) -5-sulfamoylbenzoic acid 3-Succinimido-4- (4'-methylpiperazino) -5-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester (12.6 g) ) to a suspension in 60 ml of diglyme is added 14 ml of BF 4 etherate, and then 2 g of NaBH 4 in 50 ml of diglyme are added dropwise at room temperature.

After stirring for 1.5 hours, the solution is poured into ice water, the precipitate is filtered off and hydrolysed in 50 ml of 1N NaOH solution for 2 hours. The aqueous solution is treated with activated carbon, the carbon is filtered and the filtrate is acidified to pH 3 in the cold. The precipitate is filtered off, washed with water and dried to give crystals which decompose at 314 ° C.

Example 65 4-Phenoxy-3- (3 ', 3'-dimethyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid a) 3-N- (3', 3'-dimethylsuccinimido) -4-phenoxy-5-N, N-Dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester 47 g of 3-amino-4-phenoxy-5-N, N-dimethylamino-35-ethyleneaminesulfonylbenzoic acid methyl ester li 63 69071 and 47.9 g of 3,3-dimethyl succinic anhydride are heated together in 180 ° C about 1-2 hours. The imide is precipitated with methanol and a small amount of water and crystallized from methanol. White crystals are obtained, m.p. 217-218 ° C.

b) 4-Phenoxy-3- (3,3,3'-dimethyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid 43 g of the imide obtained above (Example 65 a) are suspended in 500 ml of absolute digestion, and the suspension is suspended in 35 ml of BF 2 etherate are added and then a solution of NaBH 4 sn (7 g) in 400 ml of absolute diglyme is added dropwise at room temperature. The mixture is stirred for about 2 hours at 50-60 ° C, then the product is precipitated with water and immediately saponified with 2N NaOH solution. The free acid is precipitated in the cold from a clear solution by the addition of 2N hydrochloric acid. The product is crystallized from CH 2 OH / O 2 or acetonitrile. Pale yellow crystals are obtained, m.p. 244-246 ° C (dec.).

Example 66 4-Phenoxy-3-N-pyrrolidino-5-sulfamoyl-benzoic acid 10 g of 3-N- (N-chlorobutylamino) -4-phenoxy-5-sulfamoyl-benzoic acid methyl ester are added with stirring to 2-n sodium hydroxide. After a few minutes, a clear solution is obtained, from which 4-phenoxy-3- (2-oxo-1-pyrrolidinyl) -5-sulfamoylbenzoic acid is precipitated by adding 2-n hydrochloric acid. Crystallization of the n-butano list gives white crystals, m.p. 285-287 ° C (dec.). The acid can be converted to the corresponding methyl ester by adding an equivalent amount of diazomethane in dimethoxyethane or diglyme, and the resulting methyl ester can be converted by reduction to 3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester.

69071 64

Example 67 4-Benzyl-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid a) 3-N-Succinimido-4-benzyl-5-sulfamoyl-5-benzoic acid methyl ester 3.9 g of 3-amino-4-benzyl-5 -sulfamoylbenzoic acid methyl ester (m.p. 194-196 ° C) and 3.8 g of succinic anhydride are heated together at 180 ° C for 1 hour. After the melt has cooled, methanol and a little water are carefully added to it, whereupon the imide precipitates. It is crystallized from glycol monomethyl ether, m.p. 262-265 ° C (dec.).

b) 4-Benzyl-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid methyl ester 2.5 g of 3-N-succinimido-4-benzyl-5-sulfamoyl-benzoic acid methyl ester are suspended in 25 ml of absolute diglyme and added to the suspension. 1.9 ml of BF 2 etherate. A solution of NaBH 4 (0.5 g) in absolute 20 ml diglyme (25 ml) is then added dropwise to the mixture with good stirring at 0-5 ° C. Stirring is continued at room temperature for another 20 minutes, then the product is precipitated with water. Crystallization from CH 3 OH or CH 2 OH gives the product, m.p. is 107-109 ° C.

c) 4-Benzyl-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 1.7 g of the ester obtained above are dissolved in a mixture of 2N NaOH solution (20 ml) and methanol (10 ml) and the solution is heated on a steam bath. 2 hours. The solution is filtered and the filtrate is acidified (pH 3).

The separated acid is filtered off and recrystallized from acetonitrile or nitromethane. Pale yellow needles are obtained, m.p. 236-238 ° C. NMR (D 6 -DMSO), 60 MHz, TMS) δ: 1.72 (m, 4H), 2.92 (m, 4H), 4.53 (s, 2H), 7.1 (m, 5H), 7.57 (s, 2 H), 7.85 (d, 1 H), 8.3 (d, 1 H).

69071 65

Example 68 4-Phenoxy-3- (1-pyrrolidinyl) -5-benzyloxymethylsulfamoylbenzoic acid 11 g of 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoyl-5-ylbenzoic acid, 30 ml of a 40% formaldehyde solution and 100 ml of ml of benzyl alcohol are heated together at 100 ° C for 5 hours. The mixture is evaporated to dryness in vacuo and the residue is dissolved by heating with a small amount of acetonitrile. A crystalline product is obtained, m.p. 148-149 ° C.

Example 69 3- (1-Pyrrolidinyl) -4- (4'-cyclopentylphenoxy) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4'-cyclopentylphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 63 g (0.18 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester and 0.2 mol of sodium 4-cyclopentylphenolate (32.4 g of 4-cyclopentylphenol and 11 g of NaOCH 2) is dissolved or suspended in 300 ml of absolute dimethylformamide and the mixture is refluxed for 5 hours. The cooled cloudy solution is added dropwise to 2 liters of ice water, the pale yellow precipitate is separated and crystallized from methanol, m.p. 198-200 ° C.

B) 3-Amino-4- (4'-cyclopentylphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 25 g of the nitro compound obtained above (Example 69a) are hydrogenated with shaking in 200 ml of absolute 30 dimethylformamide in the presence of Raney nickel at room temperature . After about 3 hours, the calculated amount of hydrogen is bound, the reaction mixture is filtered and the filtrate is added dropwise to ice water. The precipitated, substantially pure amine can be crystallized from methanol, m.p. 211 ° C.

69071 66 c) 3-N-Succinimido-4- (4'-cyclopentylphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 19 g of the amine obtained above (Example 69 b) 5 and 10.7 g of succinic anhydride are heated to melt 170-200 ° C for one hour. Methanol is added to the cooled melt, the separated imide is crystallized from glycol monomethyl ether, m.p. 245 ° C.

d) 3- (1-Pyrrolidinyl) -4- (4'-cyclopentyl-phenoxy) -5-sulfamoylbenzoic acid 14 g of the imide obtained above (Example 69 c) are suspended in 150 ml of absolute diglyme and 8.4 g are added to the suspension. (.75 ml) of BF 4 etherate and then dropwise under ice-cooling a solution of NaBH 4 (2.1 g) in 100 ml of absolute diglyme. The mixture is stirred for 1 hour at room temperature, then the product is precipitated with water, separated and immediately dissolved in 2N NaOH solution at reflux temperature. The alkaline solution is filtered, acidified (pH 3-4), and the resulting acid is crystallized from acetonitrile, m.p. 241-243 ° C.

Example 70 3- (1-Pyrrolidinyl) -4- (3 ', 4'-methylenedioxyphenoxy) -5-sulfamoylbenzoic acid 25 a) 3-Nitro-4- (3', 4'-methylenedioxyphenoxy) -5-N, N-Dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 96 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester and 58 g of sodium 3,4-methylenedioxyphenolate are stirred in 500 ml of 120 ml of absolute dimethylformamide. The mixture is poured into 4 liters of ice water while stirring. The separated pale yellow product is crystallized from n-butanol or CH 2 OH / acetone, m.p. 216-217 C.

69071 67 b) 3-Amino-4- (3 ', 4'-methylenedioxyphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 76 g of the nitro compound obtained above (Example 70 5a) are dissolved in about 500 ml of absolute dimethylformamide. and hydrogenated in the presence of Raney nickel at room temperature at 50 atm for 8 hours. The filtered solution is added dropwise to ice water, the precipitated product is separated and crystallized from methanol. A colorless kilogram of tea is obtained, m.p. 19Q-191 ° C.

c) 3-N-Succinimido-4- (3 ', 41-methylenedioxyphenoxy) -5-N, N-dimethylaminosulfonylbenzoic acid methyl ester 44 g of the amine obtained above (Example 70 b) 15 and 30 g of succinic anhydride are melted together at 180 ° C . After heating for about 2.5 hours, the imide is precipitated by the addition of methanol. Crystallization from methanol / acetone, m.p. 256-257 ° C.

d) 3- (1-Pyrrolidinyl) -4- (3 ', 4'-methylenedioxy) -5-sulfamoylbenzoic acid 40 g of imide (Example 70 c) are suspended in 300 ml of diglyme. The suspension is cooled to 0-10 ° C and 21.5 ml of BF 3 etherate are added and then a solution of NaBH 4 (6.2 g) in 200 ml of absolute diglyme is added dropwise with good stirring. The temperature may then rise to room temperature. An almost clear solution is obtained, from which a white precipitate soon begins to precipitate. After 1.5 hours, 50-100 ml of water are carefully added (foaming) to the mixture, and the initially precipitated product is filtered off. Further addition of water gives a second fraction of the mother liquor. The product is suspended in 2N sodium hydroxide and the suspension is heated to reflux until a clear solution is obtained. Addition of 4N hydrochloric acid to pH 3-4 in a cold solution gives 35 free acids. It is crystallized from acetonitrile or 68 69071 CH 3 OH / H 2 O, m.p. 237-238 ° C. NMR (D 6 -DMSO, 60 MHz, TMS) 1.8 (quasi-s, 4H, 3.3 (quasi-s, 4H), 6.04 (s, 2H), 6.14 (q, 1H) , 6.52 (d, 1H), 6.78 (d, 1H), 7.3 (s, 2H), 7.58 (d, 1H), 8.2 (d, 1H).

Example 71 3- (1-Pyrrolidinyl) -4- (31-methoxyphenoxy) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (3'-methoxyphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid 10 methyl ester This the compound is prepared analogously to Example 81a using sodium 3-methoxyphenolate and a reaction time of 3 hours. Pale yellow crystals are obtained, m.p. 201 ° C (from glycol monomethyl ether).

15 b) 3-Amino-4- (3'-methoxyphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

In analogy to Example 70b, colorless crystals are obtained, m.p. 176-178 ° C (from glycol monomethyl ether).

c) 3-N-Succinimido-4- (3'-methoxyphenoxy) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 10 g of the amine obtained above (from Example 71b) 25 and 6.8 g of succinic anhydride are melted at 180-200 ° C: in. After 3 hours, methanol is added to the melt to give the title imide, m.p. 211-213 ° C.

d) 3- (1-Pyrrolidinyl) -4- (3'-methoxyphenoxy) -5-sulfamoylbenzoic acid 30 g of the imide obtained above (Example 71 b) are suspended in 80 ml of absolute diglyme, and at 0 ° C: To this cooled suspension is added 5.4 ml of BF 4 etherate and then slowly a solution of NaBH 4 (1.5 g) in 50 ml of absolute diglyme. The temperature is allowed to rise to room temperature 35 and the resulting product is precipitated with water (foam)

It 69 6 9 0 71 rooms). The product is suspended still in moist 100 ml of 2N NaOH and the mixture is heated to reflux until a clear solution is obtained. Addition of 2-N hydrochloric acid to pH 3-4 gives the free acid, m.p. 218 ° C 5 (from methanol / water).

Example, 72 3-N-Piperidino-4- (4'-methyl-phenoxy) -5-sulfamoyl-benzoic acid a) 3-N-Glutaramide-4- (4'-methyl-phenoxy) -5-N, N-10-dimethylaminomethyleneaminesulfonyl-benzoic acid methyl ester 0 .0.05 mol of 3-amino-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethylenesulfonylbenzoic acid methyl ester and 0.2 mol of glutaric anhydride are melted together at 180-220 ° C. After about 2 hours, the imide is purchased by adding methanol. Crystallization from dimethylformamide, m.p. 288-289 ° C.

b) 3-N-Piperidino-4- (4'-methylphenoxy) -5-sulphamylbenzoic acid 20.5.5 g of the imide obtained above (Example 72a) are suspended in 100 ml of absolute diglyme and 5.15 ml of BF are added to the suspension. β-etherate and then dropwise at room temperature a solution of NaBH 4 (1.5 g) in 50 ml of absolute diglyme. The solution warms up somewhat, after 1.5 hours the reaction mixture is poured into water, whereupon the product precipitates. The still moist product is heated to reflux in 2N NaOH solution until a clear solution is obtained. The title compound is obtained by adding 2N hydrochloric acid to pH 3-4 and crystallizing from a methanol / water mixture or glacial acetic acid, m.p. 222-223 ° C.

Example 73 3- (1-Pyrrolidinyl) -4- (4'-methylphenylthio) -5-sulfamoylbenzoic acid a) 3-Nitro-4- (4'-methylphenylthio) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 69071 70 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester are suspended in 450 ml of absolute dimethylformamide. The suspension is heated to 80 ° C, and 40 g of potassium p-thiocresolate in 400 ml of absolute dimethylformamide are added dropwise, and the mixture is stirred for 2 hours at 80 ° C. The mixture is poured into 4 liters of ice water, the precipitated product is filtered off, washed well with water and crystallized from glacial acetic acid. Yellow crystals are obtained, m.p. 163-164 ° C.

b) 3-Amino-4- (4'-methylphenylthio) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 67.7 g of 3-nitro-4- (4'-methylphenylthio) -5-N, N-15 dmethylaminomethyleneaminesulfonylbenzoic acid methyl ester is dissolved in 800 ml of absolute dimethylformamide and hydrogenated in the presence of Raney nickel at 50 ° C and 50 atm for 8 hours. The catalyst is filtered off and the filtrate is stirred in 2 liters of ice-20 water. The precipitated product is isolated and crystallized from methanol (activated carbon is added). Colorless crystals are obtained, m.p. 179 ° C.

c) 3-N-Succinimido-4- (4'-methylphenylthio) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester 18 g of the amine obtained above (Example 73 b) and 12 g of succinic anhydride are melted together at 180-200 ° C . After heating for 90 minutes, the imide is precipitated by adding methanol to the cooled melt.

30 Colorless crystals are obtained, m.p. 291-293 ° C.

d) 3- (1-Pyrrolidinyl) -4- (4'-methylphenylthio) -5-sulfamoylbenzoic acid 12.5 g of the imide obtained above (Example 73 c) are suspended in 110 ml of absolute diglyme. To a suspension cooled to 0 ° C is added 7 ml of BF 4 etherate 69071 71 and a dropwise solution of NaBH 4 (2 g) in 70 ml of absolute diglyme. The mixture is stirred for a further 30 minutes at room temperature, then the product is precipitated with water. Crystallization from methanol gives an almost pure product, m.p. 196-198 ° C. The resulting 3- (1-pyrrolidinyl) -4- (4'-methylphenylthio) -5-N, N-dimethylaminomethyleneaminesulfonylbenzoic acid methyl ester is saponified with 2N NaOH solution until a clear solution is obtained. Precipitation with 4N HCl gives the free acid. It is crystallized from a methanol-10 L / water mixture, glacial acetic acid or CH 2 Cl 2 to give yellow crystals, m.p. 202-204 ° C.

Example 74 4-Anilino-3- (1-pyrrolidinyl) -5-sulfamoyl-benzoic acid 15.8 g of 3-amino-4-anilino-5-sulfamoyl-benzoic acid methyl ester are suspended in glacial acetic acid. 5.6 ml of 2,5-dimethoxytetrahydrofuran dissolved in a small amount of glacial acetic acid are added dropwise to the refluxing suspension. After a reaction time of about 0.5 hours, the mixture is stirred in ice water and the precipitated product is separated.

The crude 4-anilino-3-N-pyrrolo-5-sulfamoyl-benzoic acid methyl ester obtained is dissolved in methanol and hydrogenated in the presence of a Pd / C catalyst (about 1 g) for 16 hours at 100 ° C and 100 atm. The mixture is filtered and the filtrate is evaporated. The residue is dissolved in 2N sodium hydroxide with heating until a clear solution is obtained. Addition of 2-n hydrochloric acid to pH 4 precipitates 4-anilino-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid.

To purify the product, it is dissolved in a small amount of acetone, an excess of saturated HCl-ether solution is added to the solution and the mixture is added to twice the amount of ether. 4-Anilino-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid hydrochloride precipitates, is separated, washed with acetone, dissolved in 2N sodium 72-79071 hydroxide and mixed by adding 2N hydrochloric acid to pH 4. Precipitated 4 -anilino-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid is crystallized from methanol / water to give yellow crystals, m.p. 214-216 ° C.

Example 75 4- (4'-Methylanilino) -3- (1-pyrrolicinyl) -5-sulfamoylbenzoic acid 3-Amino-4- (4'-methylanilino) -5-sulfamoylbenzoic acid methyl ester is reacted with 2,5-dimethoxytetrahydrofuran as described in Example 74, and the crude product obtained is saponified with 2N NaOH solution. The solution is acidified to pH 3-4

2-n Hel to give 4- (4'-methylanilino) -3-15 N-pyrrolo-5-sulfamoylbenzoic acid, m.p. 226-228 ° C

(Methanol-water).

The obtained compound is dissolved in ethyl acetate and hydrogenated in the presence of a Rh / C catalyst at 100 ° C and 150 atm for 16 hours. The filtrate is evaporated, the residue is dissolved in a small amount of anhydrous acetone and HCl-ether solution is added to the solution. Upon addition of ether, 4- (4'-methylanilino) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid hydrochloride precipitates. It is separated and washed with a small amount of acetone / HCl-ether-25 and then dissolved in 2N NaOH solution.

The solution is acidified to pH 3-4 to precipitate 4- (4'-methylanilino-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid, recrystallized from methanol / water to give yellow crystals, mp 188-191 ° C. .

Example 76 4-Phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid 3.5 g of 4-phenoxy-3- (4-pyrrolidinyl) -5-sulfamoyl-3-ylbenzyl alcohol are suspended in 50 ml of water and

1 g of sodium hydroxide is added to the suspension of It 69071 73. 8 g of nickel peroxide are added portionwise to the resulting solution with stirring, and the mixture is stirred for a further 3 hours at 60 ° C after the addition is complete. The mixture is filtered and the filtrate is acidified to pH 3-4 with 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid precipitating. It is crystallized from a methanol / water mixture. Yield 65%.

The following compounds are prepared analogously from the corresponding benzyl alcohols: 4-Phenoxy-3- (3'-methyl-1-pyrrolidinyl) -5-sulfamoylbenzoic acid, m.p. 207 ° C, 4- (4'-methylphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid, m.p. 233-235 ° C, 4- (4'-methylphenoxy) -3- (3 * -methyl-1-pyrrolidinyl) -5-sulphamoylbenzoic acid, m.p. 220-221 ° C.

4- (3'-methoxyphenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid, m.p. 218 ° C, 4- (4'-fluorophenoxy) -3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid, m.p. 250-252 ° C.

Claims (2)

69071 74 Claim: As intermediates of formula I Η2 <Ν / Η2 x | Compounds used in the preparation of heterocyclic-substituted 5-sulfamoylbenzoic acid derivatives of X1> NO2S / ^ ACOOR3 R2, characterized in that they have the formula Z = ζ ^ Ν: = Z v Y1 ^ NO2S r2 in which A is a single bond or C A C 1-4 hydrocarbon chain which may also contain an S, O or N atom as a chain member or which may be substituted by halogen, an alkyl, aralkyl, aryl or heteroaromatic group, or A is o-phenylene or a formula of Y 7. \. R 8 is a group according to R 7, wherein Y is a single bond or C 1 -C 4 alkylene, R 1 and R 8 are the same or different and represent hydrogen, halogen or C 1 -C 4 alkyl, R 1 and R 2 are the same or different and represent hydrogen, C 1 -C 4 alkyl or, when R 1 is hydrogen, R 2 may also be C 1 -C 4 alkoxymethyl, phenoxymethyl or phenylthiomethyl, or R 1 and R 2 together represent a protecting group of formula s 69071 75. R = C - N 2, R 6 4 5 6 wherein R, R, R are the same or different lower alkyl groups, or one of them is hydrogen, and the other two together with the nitrogen atom form a ring, R is hydrogen, C 1 -C 6 N-alkyl, C5-C6-cycloalkyl, in which one member of the ring may be replaced by O or S, phenyl, optionally in the phenyl ring by nitro, C1-C3-alkyl or -C1-alkoxy groups or halogen-substituted benzyl, benzhydryl or alkanoyloxymethyl having 2-4 carbon atoms in the alkyl group, X is benzyl, phenoxy, phenylthio, phenylsulfoxy, phenylsulfonyl or anilino, wherein the phenyl ring may be substituted by halogen, OH-, CF 2 -, C C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, alkylamino or dialkylamino, and each Z separately represents two hydrogen atoms or one oxygen atom, each R 2 denoting two hydrogen atoms R 1 and R 2 represent a group R c / ^ = C - N l4 \ R R- O 76 69071 For use as an intermediate product within the framework of heterocyclic substituents of the 5-sulfamoylbenz-5 salt derivative with Formula I, transformed into the form A / \ z = c c = z V 10. Vi NOtS ^^^ COOR3 R2 color A Å en engel bindning eller en C ^ -Cg-kolvätekedja, 15 vilken som kedjekomponent även kan innehälla en S-, O- or N-Atom eller kan var substituted with halogen or med en alkyl-, aralkyl-, aryl- or heteroaromatic groups, or A and o-phenyl or groups of the formula 20 8 - C - c - R8 R7 color Y is engel bindning or C 1 -C 4 -alkyl, and 25 Rg is a residue or a substituent, halogen or a C 1 -C 4 alkyl, R 1 and R 2 is a residue or a substituent, a C 1 -C 4 alkyl or a substituent, which is a C 2 -C 4 - alkoxymethyl, phenoxymethyl or phenylthiomethyl or R ^ och r2 betyder tillsammans en skyddsgrupp med formuleln 30 R5 '= C - N 35 4 5 6 color R, R, R is identical to that of the alkyl group, or to the face of the eye and to the other bildar en ring n