Method of preparation of cyclic tertiary amoebas.

The invention relates to acid derivatives 5 a-year average famoyl-benzoic-substituted heterocyclic having the general formula I

12 -

in which the radicals R and R are the same or different, and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and, in the case where R¹ represents hydrogen, R is also a radical having from 1 to 4 alcoxymêthyle carbon atoms in the alkyl radical, a radical phenoxymethyl or phenylthiomethyl, R represents a hydrogen atom, an alkyl radical straight or branched chain having from 1 to 4 carbon atoms, a cycloalkyl radical having 5 to 6 membered cycle which one of them may be replaced by an oxygen or sulfur atom, a radical phênyle, a benzyl radical optionally substituted on the phenyl ring by nitro groups, alkyl groups having 1 to 3 carbon atoms, alkoxy groups having from 1 s to 5 carbon atoms or a halogen, or a benzyhydryl radical having from 2 to 4 alkanoyloxymethyl carbon atoms in the alkyl portion, X represents a halogen, CF of ^, CCL is ^, alkyl straight or branched chain, saturated or having from 1 to 6 insaturê carbon atoms, a benzyl radical optionally substituted over-the core phênyle with halogens hydroxy groups, amino groups, of

lower alkyl or lower alkoxy radicals, or one of the groups 4, 4 4, 4 4 ς &

O R, S-R flip, OS-R., a SC - ^ the R and NR R, wherein R is a radical optionally substituted with halogens phênyle of OH, the NH₂ , alkyl radicals or alkoxy having 1 to 4 carbon atoms or so2nh2, alkyl or straight-chain or branched, having

die 1 to 4 carbon atoms, substituted, optionally by a

5

grouoephênyle, pyridyl, furyl or thienyl, and R represents

hydrogen, a radical alcoyie straight-chain or branched

4, 5

having from 1 to 4 carbon atoms, the group NR R may also be a saturated heterocyclic ring of 5 to 6 membered or optionally interrupted by oxygen, nitrogen or sulfur, a is a single bond or EMI chained alkylene optional ' ard unsaturated, having from 1 to 3 carbon atoms, which may be interrupted by oxygen nitrogen or sulfur, or may be substituted by one atom of halogen-and/or radically alcoyie, aralkyl, aryl optionally branched or heteroaromatic cydes by single-ring, or a is a radical-ortho-phenylene or the group

wherein Y is a single bond or an alkylene group

6, 7

of 1 to 4 carbon atoms, and R and R are the same or different and represent hydrogêne, halogen or a radical having from 1 to 4 alcoyie carbon atoms, as well as their pharmaceutically acceptable salts with bases or acids.

The invention further relates to a process for preparing compounds of general formula I

(I-)

wherein R¹ to R ^, a and X have the meanings indicated, characterized in that:

a) is reduced by hydrogen boronated or boranes or by complex borohydrides, in the presence of Lewis acids, derivatives of 1' sulfamoyl benzoic acid 3-substituted of formula II which -

1, 3

in which the radicals R to R, a and X have the meanings given above, wherein hydroxy, amino and mercapto groups are blocked with protective groups optionally customary, and Z represents two hydrogen atoms or an oxygen atom, or

b) derivatives of the acid 5 a-halogêno-to-year average " fonyl benzoic acid having the general formula III

(III)

wherein R " *, a and X have the meanings indicated, above and hal represents a halogen atom, with amines of the formula

THE HN

R

^XR²

1, 2

Where R and R are as defined above, or

c) converted by hydrolysis or oxidation moderate

sulfamoyl compounds having the general formula IV

(IV)

in which the radicals R and R, a and X have the meanings indicated above is 1, 2 and d represents a radical convertible into carboxylic acid, acids 5 a-sulphamoyl substituted benzoic hêtérocycle in position 3, of formula I (r=h), 3 or

d) treating the sulfamoyl benzoic acid derivatives having the general formula V

in which the radicals R to R, a and X have the meanings indicated above and 1, 3 L is easily separable, by acids or bases to remove said HL, or

e) is cyclized to the sulfamoyl benzoic acid derivatives having the general formula VI

(VI)

in which the radicals R to R and X being un - 1, 3 diquées above, Hal and Hal represent halogens iden - 1, 2 ticks or different, preferably chlorine and/or bromine, and n can be a number of 0 to 2, by reaction with metals under the conditions of the synthesis a Wurtz-to-Fittig and or by reaction with primary amines, the NH ^ or HjS, to obtain compounds of general formula I, or

f) are reduced 3 n-cyclic compounds having the general formula VII

or

g) the nitrated sulfamoyl benzoic acid derivatives having the general formula VIII

Y

(VIII)

BN0₂ E COCR '

3

wherein, Y represents a halogen atom, R has the meaning. indicated above and b is a protective group of the general formula

R

I

=C.

4

NR

vBE1 R.⁶ '

4, 5 6

wherein R, R and R are lower alkyl groups iden -

4

ticks or different, R may also be a hydrogen and/or

4, 5 6

two of the substituents R, R or R may be also linked together to form a ring, and then esterified the obtained compounds having the formula IX

(IX)

3

in the case where R is hydrogen, and the compounds thus obtained is reacted with the formula IX in which b and Y have the meanings given above, but the R ^ represents alkyl, with compounds of formula xH in which X has the meaning indicated above, are then reduced obtained compounds having the formula X

3'

wherein R represents an alkyl radical, optionally substituted, having from 1 confectioneries 4 carbon atoms and b and X have the meanings given above, and then reacting the resulting compounds of the formula XI

(XI) BN0₂ E COOR3 "

wherein B, X and R are defined the same - 3' above, with compounds of the general formula XII

(XIII) A SC-VBE1

wherein the radical A and Z have the meanings given above and L is a group easily separable or both L together represent an oxygen atom, and then reduced by hydrogen boron complex borohydrides or, in the presence of Lewis acid, the obtained compounds of the general formula XIII.

Z=c c=0 (XIII.)/VBE1

wherein the radicals a, b and R, X and Z are isolations - 3' ing indicated above, and hydrolyzing the obtained compounds having the general formula XIV

(XIV)

3¹

wherein ' has, b., X and R have the meanings given above,

hydrogen and optionally the double bonds in the Compohandler sés of formula I obtained according. a) to g), or passed into double bonds per-reactions¹ elimination and/or esterified the free carboxylic acids of the formula I (r=h) and/or converted by hydrolysis or reactions - eliminated

except of carboxylic acid esters of the formula I

3, 3' 3

(R=r) to carboxylic acids and/or (r=h) by. separation of a protective group is set free hydroxy groups, amino or mercapto and/or by treatment with bases or acids are converted into carboxylic acids of formula I

(R=h) into pharmaceutically acceptable salts thereof.

The compounds of formula I, according to 1' inven -

except, preferred are those in which the radicals R¹ and

2, 12

R represent a hydrogen atom, or Si. R=h, R may also be a lower alkyl radical of R ^ represents a hydrogen atom, a lower alkyl radical or. a benzyl radical optionally substituted; X is a benzyl radical, a

group - gold, the SR -, - OS-R where the radical phenyl. is a be focused

4

this particular as R group; wherein phenyl ring may be substituted at the n.' imports what position, one or more times, for example by the groups of Cl, OH-, FS ^ R is straight or branched chain alkyl having from 1 to 3 carbon atoms, alkylamino, dialkylamino or alkoxy having 1 to 2 carbon atoms or; and a is a single. link or chain alkylene optionally unsaturated, having from 1 to 2 carbon atoms, which may be substituted one or more times by halogen atoms, lower alkyl or phenyl radicals.

In the method has) according to the invention, it is surprising that attained reduce sulfamoyl benzoic acid derivatives of formula II by hydrogen boronated borohydrides complex in the presence of Lewis acids without modifying other groups in the molecule. This process provides the desired products with remarkable efficiency.

The sulfamoyl benzoic acid derivatives of formula II, used according to the invention, can be obtained by various methods. For example, gave acid derivatives 3 a-imido 5 a-sulfamoyl benzoic of formula II (z=0) from acid derivatives 3-amino 5 a-sulfamoyl benzoic, well known in the literature of the formula XV, in

1, 3

which the radicals R to R and X are as defined above, by reacting the compounds with amino dicarboxylic acid derivatives, capable of forming an imide, having the general formula XVI where a has the meaning indicated above, Z is oxygen and L is a group easily separable, preferably halogen, a group or the radical trialcoylammonium gold ' of an activated ester. In the acylation reaction, hydroxy, amino and/or mercapto at other positions of the molecule are blocked with protective groups customary.

(XV) (XIV) (ID.

The dicarboxylic acids which can be converted into

- halides are for example succinic acid, methyl succinic acid, acid 2.3-dimethyl-succinic, glutaric acid, acid 2-methyl glutaric, phthalic acid, cis cyclopropane dicarboxylic, the cyclobutane-1.2 cis-dicarboxylic acid, acid cylcohexane L, 2 cis-dicarboxylic, bromosuccinic acid or diglycolic acid. The reaction of these dicarboxylic acid derivatives with amine compounds having the formula XV is effected under the conditions of the reaction well known Schotten-Baumann.

May also be used dicarboxylic anhydrides thereof. The derivatives of carboxylic acid of formula XVII, which form first in many cases, merge directly into compounds (III) imido ester by water elimination.

The course of the reaction can be followed easily by thin layer chromatography. According to the conditions chosen for the reaction, particularly by heating the reaction mixture at temperatures of from 150 to 250 °c, cyclisës products are obtained in good yields.

It has interest to use a high excess anhydride, for example twice or three times the amount required, and to carry out the reaction in the absence of solvent. Whether to employ anhydrides of unsaturated dicarboxylic acids, such as for example maleic anhydride, is reacted with amine compounds having the formula XV, at temperatures of 150 to 250 °c, the assembly being melt, there is obtained a visgueuse oil which after a period of time is converted by removing water in unsaturated imido ester compounds having the general formula XVIII

(XVIII)

THE X 3, 6 7

in which the radicals R to R, where R, the R ' - and X have the meanings given above. The double bond of these compounds imido ester allows a large number of reactions, for example by hydrogenation are obtainable imido ester compounds of formula II, wherein Z represents oxygen and has an ethylene group.

The starting materials of formula II, wherein Z represents two hydrogen atoms, can be obtained by different methods, for example by reaction of the amino compounds of formula XV with carboxylic acid derivatives substituted m having the formula XVI, wherein Z represents two hydrogen atoms, in the reaction conditions Schotten-Baumann, and then final cyclization amido compounds formed having the formula XIX

(XIX)

with removal of H-I.

Examples of such derivatives of carboxylic acid of formula XVI, include: chloride Oj is-chloropropionic acid, bromide m-chloropropionic, acid chloride Û)~chlorobutyric, U-acid chloride) - bromobutyric, phenylic acid ester to head bromobutyric, chloride acid chloride trimethylammonium-butyric acid.

The bases necessary for the removal of the H-L are preferably tertiary organic bases such as pyridine, triethylamine or n, n dimêthylaniline used in stoichiometric amount or in excess, for example at the same time as the solvent.

For the reduction according to the invention, the derivatives may be used amido or imido as free acids or salts thereof not impairing the reduction, such as for example alkali metal salts or alkaline earth metal.

To obtain highly pure for high yield, it is advantageous to use for the reduction of esters of 5 a-sulfamoyl benzoic acid.

The esters can be prepared from acids, according to methods well known in the literature. Preferred esters are esters of lower alkyl having from 1.

to 5 carbon atoms, such as methyl esters, . ethyl, propyl, butyl or n-pentylic, benzyl esters or P-methoxybenzyl alcohol and tertiary butyl ester, the ester and the ester benzhydrylic acyloxymethylic where. the acyl radical is the radical of a lower aliphatic carboxylic acid, for example the acetyl radical or tertiobutyryle.

As a reducing agent are used complex borohydride or diborane in the presence of Lewis acids. For the reduction of lactams of formula II (Z-=2:00), worked with diborane in the presence of Lewis acids. In contrast,

to obtain imides (z=o) with good yields, and that can be used borohydrides, complex, in. with Lewis acid. The reducing agents may be introduced into, the reaction mixture by taking special precautions, such as by using nitrogen as inert gas. If used, diborane, it is simpler to put up in a solvent and employing this solution for the reduction. Among the suitable solvents, there may be mentioned ethers such as tetrahydrofuran or glycol dimethyl ether diéthylèhe-glycol.

As complex borohydrides, used e.g. alkali borohydrides such as lithium borohydride, sodium borohydride or potassium borohydride borohydrides or alkaline-.terreux such as calcium borohydride, but also zinc borohydride or aluminum borohydride.

These boron hydrides, in the presence of Lewis acids, reducing surprisingly amide or imide groups present in the molecules used, without interfering carboxylic ester is substantially etched.

As Lewis acids according to the invention, it is preferable to use aluminum chloride, titanium tetrachloride, tin tetrachloride, cobalt chloride (ll), ferric chloride, mercurous chloride, zinc chloride and boron trifluoride and its adduct, such as for example boron trifluoride etherate. In the latter case, it is then possible, by reacting the boron trifluoride etherate with sodium borohydride, diborane obtained in situ (see Fieser, Fieser: TSARs another evaluation constraint, by John Wiley & sounds, Inc. or, York, v. 1, P 199).

To achieve high efficiency and highly pure, it is advantageous to prepare the Lewis acid with compounds of formula II and adding the borohydride complex.

It is particularly desirable to use an excess of Lewis acid and at least a stoichiometric amount of borohydride complex, with respect to the amide group to reduce.

Very good results are obtained if, for example, with titanium tetrachloride is added three times the stoichiometric amount of NaBH₄ , while with the êthérate boron trifluoride complex borohydride may be used in stoichiometric amount relative to the number of amide groups to reduce.

To effect the reduction, regardless of whether the substances to reduce are imido ester as compounds of formula II (z=o) or in the form of amido compounds (=Z-2:00).

The imido ester compounds become surprisingly in total response, directly sulfamoyl benzoic acid derivatives. The reduction is carried out in a solvent; are preferred ethers such as tetrahydrofuran or ether glycol of the diéthylëne dimethylic (of diglyme). The solvent in which the reduction takes place may be the same as that in which is dissolved the reducing agent, but it can also be different.

The reduction may be carried out in a wide range of temperatures. It may occur at room temperature or at a somewhat higher temperature. While the secondary amide with diborane and lactams with diborane and Lewis acid preferably react at low temperature (40 to 60 °c) high, the reduction with borohydride complex and Lewis acids, especially for imides, occurs often already very favorably in a temperature range of 0 to 20 °c. If accepts have reaction times a little longer, the reduction can also occur when cold. The duration of the reduction depends on the constituents in presence and the selected temperature.

One preferred implementation of the method according to the invention comprises first mixing acid derivatives or 5 a-sulfamoyl benzoic of formula II in an inert solvent with the Lewis acid and adding a solution of the borohydride complex, optionally a suspension of the borohydride complex, in the same solvent, or in a different solvent, at room temperature, followed by stirring for a short period. The borohydride complex can also be added directly as a solid.

To accelerate the reaction, can be possibly performing the reaction at higher temperature or, after adding the reducing agent, from about 1 hour to heating during 40 and 70 degrees Celsius.

Another embodiment includes preparing the substance to reduce with the borohydride complex and adding the Lewis acid at room temperature. As borohydride complex, used primarily sodium borohydride. It is. also advantageous here, to obtain a conversion fast upon the end of the addition of the Lewis acid, about 1 hour to heat up 40 and 70 degrees Celsius. The course of the reaction is followed by thin-layer chromatography by the appearance of fluorescence light blue intense 366 nm due to the formed compounds of formula I by reduction according to the invention, can also be possibly reduce the double bonds present in the group a,

The final product may be isolated in different ways.

A procedures preferred comprises releasing the solution of the product of reaction of the reducing agent optionally still present, by adding water and small amounts of acid, and then to precipitate the acid ester 5 a-sulfamoyl benzoic obtained by adding a non-solvent. If the solvent is dimethyl ether of diethylene-glycol, water was found to be a particularly suitable non-solvent. The esters of 5 a-sulfamoyl benzoic formed, of formula I crystallize most often nearly quantitatively to the very pure state.

It may be necessary, if appropriate, also releasing the substituents protected by protecting groups in the radical X of sulfamoyl benzoic acid derivatives of the formula I is obtained for example p-hydroxy by saponification of the corresponding acetate.

May also be achieved directly 5 a-sulfamoyl benzoic acids of formula T by concentrating the reaction mixture after partially destroying excess reducing agent, by adding dilute base and optionally by heating a little. As the base, used for example caustic soda. Can be directly acids isolation 5 a-sulphamoyl benzoic acids of formula I in the form of their salts. Acids are obtained free by acidification. Easy formation of acid derivatives 3 herbicides - or 3 a-amido 5 a-sulfamoyl benzoic of formula II provides the derivatives of 5 a-sulfamoyl benzoic acid of the formula I according to the method has) state purity and yield very high space/time.

With appropriate reduction imides or amides with the same result, if in the chain of OC are present substituents that are easily separated with forming a c-c double bond. For example starting from 2 to-bromosuccinic acid, as a reaction component having the formula VIII, gave 3 a-pyrrolidino radical derivatives of formula I, wherein a is a group

ABOUT H

I-ii

C=C - -

Derivatives-3 a-pyrrolidino groups may be converted chemically in a conventional manner, for example they may be hydrogenated catalytically, in sulfamoyl benzoic acid derivatives substituted with a heterocycle 3, having the formula I wherein a is an ethylene group, or undergo addition reactions are usual.

We obtain the acid derivatives 5 a-halogëno-to-sulfonvl benzoic meeting the formula III confectioneries, required to process b), in different ways, for example from aminobenzoic acid derivatives having the formula XX

THE N (REDUNDANTABLE)

in accordance with the following reactions indicated by propynoic, according to the method described in J Pr/2/ 152, 251 (1939) or in German patent no. 859,461.

Add derivatives halo sulfonyl benzoic react in a known manner with amines of formula MST¹

by giving the end products of formula I are obtained aminobenzoic acid derivatives having the formula XX in different ways, for example from acid derivatives amino nitrobenzoic acid are well known in the literature of the formula XXI, according to the following reaction scheme:

(XXI) (XXI) (XXIII PADDLE)

by reacting the compounds with the derivatives of the carboxylic acid of formula XVI as décritdécrit.ci above, followed by a reduction in acid esters nitrobenzo 'anhydride of formula XXIII, formed compounds, of formula XXII, with boranes or complex borohydride in the presence of acids of leva, ' ls. Is

•finally reduces the nitro group, preferably by catalytic hydrogenation in the presence of Raney nickel, O.D. VBE1 by other conventional methods of reduction.

It is particularly advantageous to prepare as follows, the compound redundantable

To reduce the compounds 3 amido-or 3 herbicides of formulas XXIII and XXIV is, you can use the. the conditions already described in the switched-operative). It is to be noted herein that the reduction is very specific, even in the presence of a nitro group.

The compounds of the general formula IV, used in operation mode and c) can be obtained in various ways.

In this example the compounds in which d in the formula IV represents the ^ of OH, from derivatives of the carboxylic acid, of formula I, with an excess of reducing agent.

This reaction can even be observed as a side reaction when processing the amido or imido derivatives of formula II according to the procedure has), with an excess of reducing agent at high temperature for a relatively long time. According to the procedure of c), this achieves reduced too toto recouvertir compounds of formula IV in desired compounds of formula I, by treatment with an oxidizing agent.

The conversion products of the general formula IV into end products responding S the formula I depends on the type of the substituent d if d is a group - OH₂ halogen -, a group - HC₂ -OCOCH₂ or - ch=0, we obtain the final products by oxidation. If d is a nitrile group, by alkaline hydrolysis gave amides which can then be converted into free carboxylic acids by hydrolysis thrust, for example. Or obtained, by reacting the nitrile with hydrochloric acid in alcoholic solution, the imino esters that can be converted by hydrolysis into esters, or as applicable also in corresponding free carboxylic acids.

The sulfamoyl benzoic acid derivatives of formula V, used in operation mode and d) can be obtained in different ways, for example from the sulfamoyl benzoic acid derivatives of the formula XIX

0498, 7

even reduction of the amide group by boranes or borohydrides complex in the presence of Lewis acids, as previously described. Note that in this reduction, the amide group is reduced, without the group easily separable L be influenced. As group readily separable from the L, origins prefers: a halogen, the OH, active ester groups such as O-tosyl, trialcoylammonium or pyridinium groups.

The cyclization of compounds of formula V, by eliminating transduction can occur in basic or acidic medium.

If L is for example a halogen atom, preferably chlorine or bromine, the cyclization takes place for example by alkali treatment. In acid medium, the cyclization is carried out as indicated in " cradle. dtsch. mal. GHG. 42 _, 3427 (1907) " (Uberblick mal. Rev. 63, 55 (1963). Under these conditions, there is obtained the salts of

3

carboxylic acids of formula I (r=h). As bases usable for the removal, can be used for example triethylamine, an alkali hydroxide, N, N-dimethylaniline or also an alkali metal acetate.

For preparing compounds according to the invention, can be from 3 amino compounds of formulas XV or Xl, reacted with compounds of the formula I a-c ^ --CHj L, where both easily separable L are cyclized with group 3 a-aminô of Xv frames or XI, with elimination of 2 moles of said HL, to give the compounds of formulas I or XIV.

Which comprises reacting the compounds XV or XI in organic solvents such as e.g..1 ' acetone, dimethylformamide, ethanol or mixtures thereof, with an excess of the compounds of the formula L-CHj-a-c ^ - L-, by heating under reflux in the case of several hours to several days. It is advantageous, if L is bromine or chlorine, adding to the reaction mixture an excess' alkali iodide. In some cases, the reaction can also be accelerated by a base such as for example pyridine, triethylamine, ^ NaHCO or sodium acetate.

The sulphamoyl carboxylic acid derivatives according to formula VI, used in operation mode I) can be obtained in various ways, for example from compounds of formula V, wherein a is in this case a single bond or a methylene or ethylene group optionally substituted, and L is a halogen, preferably chlorine or bromine, which is reacted with formaldehyde and acids alaninium or in a novel manner with carboxylic acids üj-halogenated with formation of a compound of formula xxv-amidp is reduced according to the mode-operative already described (see formula below),

The subsequent ring closure takes place according to a procedure well known in the literature, for example according to the method of a Wurtz by reaction of the compounds of formula VI with metallic sodium or by action of the zinc in alcoholic solution to boiling, as described in " the j. prakt. Chem./2 /, 36./ 30, 0 (1887). This method is particularly suited to the preparation of 4 cycles at 3 and 5 links which are compounds of formula I can also be reacting the compounds of formula VI with nucleophilic agents such as primary amines, the NH ^ ^ or H O, by closing the ring position 3 by introducing another heteroatom N or S.

The compounds are obtained according to formula VII used in the 'operative F.) .' from acid derivatives 3 a-araino-to-sulfamoyl benzoic having the formula XV, the ISPs in heterozygous react conventionally with the 2, .5-to-diméthoxytêtrahydrofurannes of formula.

6, 7,

wherein R, R have the meanings de] to indicated. The reduction of the compounds VII are substituted pyrrolo, formed, preferably takes place by catalytic hydrogenation catalysts which are normally used in this case.

The benzoic acid derivatives of the formula VIII, used according to the procedure grams) can be obtained by different methods. A reaction particularly simple consists from sulfamoyl benzoic acid derivatives in the unsubstituted sulfamoyl group, well known in the literature and corresponding to the following formula:

by applying different methods of condensation described in the literature.

See for example:

J 92. Mal. 25 ^ (1960), 352 - 356; To ZH. 92. Khim. 8 ^ (1972), 286 - 291} Liebigs Αηη·. Mal. 750 (1971), 42; To ZH. 92.

Khim. 6 (1970), 9, 1885); _ (1961) 94 B, 2731 - 2737; AngII. Ch (1966) 78, 147 - 148; AngII. (1968)_ ch 80, 281 - 282; B (1964) 97, 483 - 489; B (1963) 96, 802 - 812; J 92. Mal. 27. (1962), 4566 - 4570;

AngII. Ch (1962) 74, 781 - 782 and DokladyAkad. (1962) 145 SSSR CONFIGURATIONS, 584.

As compounds of the general formula VIII, can be used according to the invention the following derivatives:

The compounds of formula VIII are prepared by methods disclosed in the above literature, or by analogy with them. The acids listed previously can be replaced for example by methylic esters or ethyl esters thereof.

The nitration, benzoic acid derivatives having the formula VIII can be done in different ways. For example it incorporate the benzoic acid derivatives in one mixture customary nitrating used for the nitration of aromatic non-responders (see the work "Organicum", 288 P, editing 1967). The method may also include dissolving in the oleum the benzoic acid derivatives of the formula VIII and nitration of by dropwise addition of nitric acid.

Must be noternoter.qu'is surprisingly been achieved simply by introducing the protecting group b in the sulfonamide group, nitrating the benzoic acid derivatives having the general formula VIII, without changing any other group in the molecule. . The reaction temperature must be relatively low, preferably between 55 and 70 °c.

It '. is advantageous in preparing a nitrating acid from oleum and fuming nitric acid, add the substance and heating the reaction mixture to 55 and 60°.

The unrolling of the nitration is followed by thin layer chromatography. The end product is isolated conventionally, for example by adding ice to the reaction mixture and the precipitated crystals are filtered.

For the nitration•, you can use the acids or esters having the general formula VIII, in which the radicals Y, b and R are as already defined. In nitrating esters having the formula VIII, ester in addition,

in this case also is obtained having the acids

3

formula IX (with r=h).

The mixture can be separated in a conventional manner, by

such as by treatment with aqueous sodium carbonate. The

-3 obtained compounds having the formula IX, wherein R represents a hydrogen atom, are then esterified in a conventional manner.

For estërifier the carboxylic group, is converted for example the carboxylic acid to acid chloride which is then transformed to the corresponding esters by addition of alcohols.

Alcohols are preferred for the esterification are lower alkanols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, butanol, 1 'isopropanol or 1' butanol, as well as alcohols aralalcoyliqnes, e.g. benzyl alcohols or benzhydrol.

It has been found advantageous to use a 5 to 20 fold molar excess alcohol, or to be available at the same time as the solvent.

In other methods described in the literature, the esters may be prepared benzhydrylic or tertiary-butyl.

In a subsequent operation, is reacted esters of formula IX with compounds of formula Xh-, to give compounds having the formula X.

It has been surprisingly compounds of the workout -

3

matches the general formula IX, wherein R represents an alkyl, can be reacted in anhydrous conditions with compounds of general formula XH, with good yields.

. As Xh-compounds of formula, can be UIC-to-wear for example phenol, the 4 a-methylphenol, the 3 a-methylphenol, the 2 a-methylphenol, the 4-chlorophenol, the 3 a-triflurométhylphénol, the 3.5 to-dimethylphenol, the 2.4 a-dimethylphenol, the 4 a-méthoxméthox.yphénol, the 3 a-méthoxyphënol, the 4 a-propylphenol, thiophenol and the thiophenols substituted as the phenol, n-methyl aniline, benzene suifinic, pyrrolidine, n-methyl piperazine, the 5-methyl 2 mercapto-L., 3.4 to-thiadiazole or L-methyl-5 mercapto-1, 2, 3, 4-tetrazole. Some additional functional groups present in Xh-, such as other OH groups, the NH₂ or mercapto, are blocked, with protective groups customary, for example

by acylation.

4

The compounds of the general formula Hor and

4, 4^

HSR STIELL where the radical R has the meaning already indicated is of value. Derivatives thiophenols and phenols which may be substituted as has been already indicated, are of particular importance here.

The reaction may be carried out without a solvent, but it is preferable to work in the presence of a solvent. The most appropriate solvents are organic solvents tsls that ethers and tertiary carboxamide, particularly diglyme, dimethyl formamide or hexaméthylphosphorotriamide (cleavage).

The compounds X-H are used as such in the presence of bases, but also in the form of their alkali metal salts or alkaline earth metal. The bases usable are alkoxides or alkali amides.

The derivatives of thiophenols and phenols are converted in the form of anions, particularly preferred for this purpose alkali salts and particularly the sodium and potassium.

The reaction can be carried out in the presence or absence

solvent. Without solvent, heated for example components at temperatures of 100 to 200 °c, preferably from 140 to 180 °c.

The products obtained are isolated conventionally, for example by dissolution of the melted products in a solvent, and then precipitation by adding water or an organic non-solvent.

But it is particularly advantageous to conduct the reaction with phenolates or thiophenoxides in solvents at temperatures of from 100 to 200 °c, preferably 120 to 160 °c.

As a solvent may be used organic solvents, preferably tertiary amides, polyethers or high boiling solvents such as the cleavage or tetramethylene sulfone. It is particularly advantageous to treat the esters of formula IX in tertiary amides, such as dimethylformamide or dimethylacetamide. According to the temperature selected for the reaction, the reaction time of 6 hours with 1.

The isolation of the end products of the formula X is done as usual; for example can be initially filtering out the mineral salts, precipitating the reaction product by adding a non-solvent, or pouring the reaction mixture into water or on ice, then isolating the reaction product precipitated.

Compounds are prepared having the formula X,

4 D.

group at position 4 or the sor s02r ' in oxidizer in accordance

methods known in the literature the corresponding compounds

4

having the formula X having a group SR. For example, s-oxides are obtained by oxidation using peracetic acid in dimethylformamide at low temperatures, whereas during the s-dioxides by adding an excess of a reducing agent to higher temperatures.

Reducing the nitro group in the benzoic acid derivatives having the formula X can be carried out conventionally, for example, by catalytic hydrogenation. Preferred as catalyst nickel ' or Raney conventional catalysts of noble metals such as palladium on charcoal or platinum oxide, (see e.g. Organikum e. 271 - 277, pp 507 - 510).

Preferred solvents for the reduction are organic solvents such as for example methanol or ethanol, ethyl acetate, dioxane or other polar solvents, particularly amides such as dimêthylformamide, the dimêthylacétamide or HMPT.

The hydrogenation is carried out at room temperature and under atmospheric pressure or higher temperature and pressure, for example 50 °c and 100 atm in an autoclave.

The dériyés acid 3 a-imidobenzoïgue of formula XIII is géhérale (z=o) are obtained by different methods. They are prepared for example by reacting the amino compounds XI with dicarboxylic acid derivatives having the general formula XII, capable of forms imides. The reaction is analogous to the conversion of compounds XV and XVI in compounds of formula II, described previously in operation mode has).

It follows the course of the reaction by chromatography

thin film, because the amino compounds XI in the mu fluoresce at 366, while the obtained compounds are not.

The compounds of the formula XIII, wherein Z represents 2 hydrogen atoms, the compounds II are prepared as, in which Z represents two hydrogen muted, as described in operation mode has).

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

By deduction to compounds of formula XIII, derivatives are obtained benzoic acid Heterocyclic substituted 3, having the general formula XIV.

To obtain pure products with high efficiency, it is also advantageous to use for the reduction of esters of benzoic acid having the formula XIII. The reduction is carried out according to the procedure has) already described.

Acids are obtained having 5 a-sulphamoyl benzoic

3

the formula I (the R ≈ hr) according to the invention, by alkaline hydrolysis of the compounds of the general formula XIV, by heating them at steam bath for several hours in a caustic soda or potash. Thus the ester is saponified and separating the protective group b and the other protecting groups may be present.

Obtainable also directly the 5 a-sulphamoyl

3

benzoic acids of formula I (r=h), by concentrating the reaction mixture after partially destroying the excess reducing agent, by adding a base and heating for a relatively long time. Base used is, for example, caustic soda. Thus isolated directly the 5 a-sulphamoyl benzoic acids of formula I in the form of their salts. Acids are obtained free by acidification.

It is also possible to introduce the protecting group b in a later stage of reaction, for example in compounds of formulas IX., the X, XI or XIII in which b is then 2 hydrogen atoms, and arrive in this way to the compounds having the formula XIV or R ' can also be substituted by R.

Upon completion methods disclosed in has) to g),

optionally conventionally hydrogenating the double bonds present in the compounds of formula I, thus using a catalytic hydrogenation process. Conversely, it is also possible to introduce additional double bonds by - elimination reactions, for example, by removing acids alaninium from halogenated compounds, by removing water hydroxyls compounds and by other conventional stripping reactions.

If first obtains the free carboxylic acids of formula I by using the corresponding starting compounds, can be conventionally converted to esters. The method involves using alcohols of the formula R^J OH or their functional derivatives, or esterification of otherwise known in the literature. Conversely, can be converted carboxylic esters having the general formula I initially obtained, corresponding free carboxylic acids. To this end, recourse is made to a hydrolysis or in particular cases to hydrogenolysis or other eliminating reactions.

For example, alkyl esters are separated by alkaline hydrolysis, aralkyl esters, in particular the P-nitrobenzyl ester, by hydrogenolysis or tertiary-butyl ester by removing 1¹ polyisobutylene by treatment with trifluoroacetic acid.

The free carboxylic acids can be converted into their pharmaceutically acceptable salts, by means of corresponding bases such as hydroxides or carbonates of alkali, alkaline earth or ammonium. It is also possible to obtain the compounds of formula I by releasing in the last stage the reaction a conventional protective groups for hydroxy, amino or mercapto, for example by hydrolysis of hydroxyl groups acylated, under conventional conditions. The protective groups of hydroxy, amino or mercapto are needed, in particular during the preparation of the starting materials of formula II, to avoid acylation with ' derivatives of the carboxylic acid of formula XII, in unwanted positions. In this case, the reduction according to the invention is conducted according to the procedure has) often with the hydroxy compound, amino or mercapto is protected and only separates the protective group at the end of the reduction, as described above. However in other procedures, it may also be advantageous to block the reactive substituents which are separated at the final point of reaction.

The method according to the invention makes it possible to prepare a large number of highly active pharmaceuticals, particularly diuretics and saluretic some of which are listed below.

Acid 3 n-acétidino-to-4-phenoxy-5 a-sulfamoyl benzoic

Acid 3 n-Aziridino anthracyclines and 4-phenoxy-5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 chloro-5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 P-chlorophenoxy-a 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 - (4'-methoxyphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 - (3¹ - methylphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 - (2 '-methoxyphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 - (2, 4' - diméthylphênoxy) - 5 a-SuIf amoylbenzoïçi, acid 3 n-pyrrolidino 4 - (3 ', 5' a-dimethylphenoxy) - 5 a-sulphamoyl benzoïçu acid 3 n-pyrrolidino 4 - (4 'a-hydroxyphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 - (4' a-methoxy-phenoxy) - 5 a-sulfamoyl benzoic-acid 3 n-pyrrolidino 4 - (4' a-trifluoromëthyl-phenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 - (3'-trifluoromethyl-phenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 - (4' a-propyl phenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 n-butoxy 5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 n-pentoxy group-a 5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 a-phenylthio-5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 - (4' a-diméthylaminophënoxy) - 5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 - (4'-aminophenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 a-phénylsulfoxy-a 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4-phenylsulfonyl-a 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 a-trichlorméthy1-a 5 a-suifamoyl benzoic acid 3 n-pyrrolidino 4 a-trifluorométhy1-a 5 a-suifamoyl benzoic acid 3 n-pyrrolidino 4 - (n-methyl-n-phenyl) - amino 5 a-sulfamoylbenzoïque

Acid 3 n-pyrrolidino 4 benzyl-5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 - (4 'a-mëthylbenzyl) - 5 a-sulfamoyl benzoic acid 3 - amino-pyrrolidino 4 - (4'-methoxybenzyl) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino 4 - (4'-chIorobenzyI) - 5 a-sulfamoyl benzoic acid 3 n-pyrrolidino~4-methyl 5 a-sulfamoyl benzoic

Acid 3 n-pyrrolidino 4 n-butyl 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 chloro-5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 P-chlorophenoxy-a 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4'-methoxyphenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (3'-methoxyphenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (2'-methoxyphenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (2', 4'- dimethylphenoxy) - 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (3 ', 5 'a-dimethylphenoxy) - 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4' a-hydroxyphenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4' a-mêthoxyphënoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-mëthylpyrrolidino) - 4 - (4 'a-IFFT luor-to-ométhyl-phenoxy) - 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (3'-trifluoromethyl-phenoxy) - 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4' a-propylphênoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 n-butoxy 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 n-pentoxy group-a 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 a-phenylthio-5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4 '-dimethylaminophenoxy) - 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4' a-aminophénoxÿ) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 a-phénylsulfoxy-a 5 a-sulphamoyl benzoï■that

Acid 3 n - (3 a-méthylpyrrolidino) - 4 a-phenylsulfonyl-5 a-sulphamoyl - Bas, zoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 a-trichloromethyl-a 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyroolidino) - 4 trifluoro-methyl-5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (n-methyl-n-phenyl) - amino 5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 benzyl-5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4¹ - methylbenzyl) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4'-methoxybenzyl) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 - (4'-chIorobenzyI) - 5 a-sulfamoyl benzoic

Acid 3 n - (3 a-méthylpyrrolidino) - 4 methyl-5 a-sulfamoyl benzoic acid 3 n - (3 a-méthylpyrrolidino) - 4 n-butyl 5 a-sulfamoyl benzoic acid 3 n - (3.3 to-diméthylpyrrolidino) - ~phénoxy 4 and 5 a-sulfamoyl benzoic acid 3 n - (3.3 to-diméthylpyrrolidino) - 4 - (4' a-mëthylphénoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3.3 to-diméthylpyrrolidino) - 4 benzyl-5 a-sulfamoyl benzoic acid 3 n - (3.4 to-diméthylpyrrolidino) - 4-phenoxy-5 a-sulfamoyl benzoic acid 3 n - (3.4 to-diméthylpyrrolidino) - 4 - (4¹ - - methylphenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n - (3.4 to-diméthylpyrrolidino) - 4 benzyl-5 a-sulfamoyl benzoic acid 3 n-has 3 a-pyrrolino-a 4 a-phënoxy-a 5 a-sulfamoyl benzoic

Acid 3 n-has 3 a-pyrrolino-a 4 - (4'-methoxyphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-has 3 a-pyrrolino-a 4 - (4¹ - chlorophenoxy) - 5 a-sulfamoyl benzoic acid 3 n-has 3 a-pyrrolino-to-4 benzyl-5 a-sulfamoyl benzoic

3 - ^~L-acid - (3 a-phénylpyrrolidinyl)_ 7 and 4-phenoxy-5" benzoic acid 3 - sylfamoyl ^ 1 - (3 a-phénylpyrrolidinyl)_ 7 - 4 - (4' - methylphenoxy) - 5 a-sulfaitDv I-benzoic

Acid 3 n - (3 a-chloropyrrolidino) - 4-phenoxy s-sulfamoyl benzoic acid 3 n - (3 a-bromopyrrolidino) - 4-phenoxy-5 a-sulfamoyl benzoic acid 3 n-pyperidino - 4 chloro-5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 P-chlorophenoxy-a 5 a-sulfamoyl benzoic acid 3 n-piperidino-4 - (4¹ - methylphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-piperidino-4 - (3 '-methoxyphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-piperidino-4 - (2'-methoxyphenoxy) - 5 a-sulfamoyl benzoic acid 3 n-piperidino-4 - (2 ', 4' a-dimethylphenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 - (3 ', 5' a-dimethylphénoxy) - 5 a-suifamoyl benzoic

Acid 3 n-pipêridino-a 4 - (4¹ - hydroxyphênoxy) - benzoic acid 5 a-suifamoyl 3 n-pipêrLdino-a 4 - (4'-trifluoromethyl-phenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 - (4' a-propyl phenoxy) - 5 a-sulfamoyl benzoic acid 3 n-piperidino-4 n-butoxy 5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 n-pentoxy group-a 5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 a-phenylthio-5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 - (4'-dimethylaminophenoxy) - 5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 - (4¹ - aminophenoxy) - 5 a-sulfamoyl benzoic acid 3 n-pipêridino-a 4 a-phénylsulfoxy - 5 a-sulfamoyl benzoic acid 3 n-piperidino-4-phenylsulfonyl-a 5 a-sulfamoyl benzoic acid 3 n-piperidino-4-trifluoromethyl-5 a-sulfamoyl benzoic acid 3 n-piperidino-4 - (n-methyl-n-phenyl) - amino 5 a-sulfamoyl benzoic

Acid 3 n-piperidino-4 - (4¹ - mëthoxyphénoxy) - 5 a-sulfamoyl benzoic acid 3 n-piperidino-4 benzyl-5 a-sulfamoyl benzoic

In the enumeration above compounds according to 1' a, it is possible for example replace also the term "5 a-sulphamoyl" by any of the following terms:

5 N-méthylsulfamoyl

5 N-êthylsulfamoyl

5 N-méthoxyméthylsulfamoyl, and

5 N-butoxyméthylsulfamoyl.

The earlier listing contains the substituted benzoic acids of the general formula I may also consider all products according to the invention, mentioned, in which replaces the term "benzoic acid" by following terms:

- benzoate

- ethyl benzoate

- benzyl benzoate

tert-butyl - benzoate.

The sulfamoyl benzoic acid derivatives according to the invention having the formula I confectioneries as well as their pharmaceutically acceptable salts are diuretic and saluretic very active which can be used, as pharmaceuticals in human or veterinary medicine.

The compounds of the invention are administered at doses of 0.5 to 100 mg in capsules, dragees, tablets or solutions, with various additions, enterally, e.g. orally with a probe or the like, or parenteral administration (injection into the vasculature, for example intravenous injection, or also intramuscular injection or beneath the skin and the like). Are suitable for treatment of edema especially of edema of cardiac, renal or hepatic, and other phenomena of same type caused by defective electrolytic balance. The compounds may be administered alone or in combination with other substances salidiuretic active having another type of action, or separately, alternatively or in combination with other drugs. It should be mentioned in particular the spiro NOLACTONE, the TRIAMTERENE, 1 'amiloride and other' compounds retaining potassium, alternately with saluretics slow acting type chlorthalidone and other, or separately with the compounds containing potassium to compensate for the loss of potassium observed with the salidiurèse (salts or the like),

The following examples illustrate the invention.

EXAMPLE 1

3-nitrate 4 a-phënoxy-a 5 a-sulphamoyl benzoate

34 Grams is dissolved Κ 0, 1 mol) acid 3-nitrate 4-phenoxy-5 a-sulfamoyl benzoic in 150 ml of methanol and heated to boiling. Then added slowly 5.4 ml of H₂ S0₄ concentrate is heated and 10 hours under reflux. The 3-nitrate 4-phenoxy-5 a-sulphamoyl benzoate crystallized by cooling. Can be recrystallized in a mixture mêthanol/acetone.

Melting point: 181 and 182 degrees Celsius.

EXAMPLE 2

3-amino 4-phenoxy-5 a-sulphamoyl benzoate. methyl

Suspended is 35 grams (^ 0, 1 moles) of 3-nitrate 4-phenoxy-5 a-sulphamoyl benzoate in 150 ml of methanol and hydrogenated with Raney nickel (5 to 10%) in an autoclave at 40 and 50 °C and 1û0 atms. Is dissolved in acetone on steam bath, the compound airiino precipitate is separated by filtration and the Raney nickel. Web 3-nitrate 4-phenoxy-5 a-sulphamoyl benzoate crystallizes in the pure state by cooling.

Melting point: 179 °c.

EXAMPLE 3

3 a-îh-to-succinimide-to-4-phenoxy-5 a-sulphamoyl-benzoic acid methyl ester

Is dissolved 16.1 grams (0.05 moles) of 3-amino 4-phenoxy-5 a-sulphamoyl benzoate in 150' ml of absolute dioxane is heated and boiled.

Then added dropwise regularly, stirring well and one after the other, a solution of 11.6 grams (0,075 moles) of succinic acid dichloride in 50 ml of acetone and a solution of 8 ml absolute pyridine in 50 ml of absolute acetone, followed by heating under reflux. The reaction is complete after 2 hours. The mixture is concentrated and the residual oil is taken up by a little methanol. The 3 n-succinimide-to-4-phenoxy-5 a-SuIf arnoyl benzoate crystallizes rapidly shortly thereafter.

The crystallization is completed by the addition of water.

Is recrystallized in methanol/acetone.

Melting point: 270 °c.

Example 3a

Melted to 160 and 180c in 2 hours about the 3-amino 4-phenoxy-5 a-sulphamoyl methyl benzoate with a 2 to 3 times the molar amount of succinic anhydride. Cooled and methanol is added to crystallize the 3 n-succiniraido-to-4-phenoxy-5 a-sulphamoyl benzoic acid methyl ester.

EXAMPLE 4

3 N-pyrrolidino ~phënoxy 4 and 5 a-sulphamoyl benzoate

Dissolving or suspending 12.3 grams (0.03 moles) of 3 n-succinimide-to-4-phenoxy-5 a-sulfamoyl~benzoate methyl in 100 ml absolute diglyme. Added directly 9 g of boron trifluoride etherate and dropwise at room temperature, stirring well, a solution of 2.4 g of {0 ^, 063 mol) in 80 ml of diglyme NaBH ^. As the reaction is exothermic, must be cool with ice water. The reaction is completed the dropwise addition and after a brief further stirring.

Destroyed excess reducing agent with a little water (foam), the solution is filtered and is added with stirring about 300 ml of water. Is recrystallized in methanol the 3 n-pyrrolidino 4-phenoxy-5 a-sulphamoyl benzoic acid methyl ester. White crystals having a melting point of 19l-to-192 degrees Celsius.

NMR data: (CDCl ^, 60 MHz band, the TMS etalon)<5=1.73 (m-: 4:00),

6=3.26 (m-: 4:00), 6=3.91 (O: 3 Η), δ=5.0 (O: 2:00), 6=6.6 - 8.0 (m-: 7:00) in ppm.

EXAMPLE 5

Acid 3 a-N~pyrrolidino-to-4-phenoxy-4 a-sulfamoyl benzoic

Suspending 61 g of 3 n-pyrrolidino~4-phenoxy-5 a-sulphamoyl benzoic acid methyl ester in 350 ml of NaOH 1 n and is heated in a water bath at 1 hour. From the clear solution, precipitated acid 3 n-pyrrolidino 4-phenoxy-5 a-ss.ulfamoyl benzoic acid by adding HCl 2 d, by stirring well. Can be almost pure recrystallizing the crude product in methanol/water.

Light yellow plates having a melting point of 225 and 227 °C with decomposition.

NMR data: (D, methacrylate-DMSO, 60 MHz band, the TMS)=1.67 than1 (quasi e; 4:00),

b.

<5=3.21 (quasi e; 4:00), 5=6,6 - 8,0<(m-: 9:00) in ppm.

EXAMPLE 6

3 N-glutarimido-to-4-phenoxy-5~sulfamoyl benzoate

16.1 G of dissolved 3-amino 4-phenoxy-5 a-sulphamoyl-benzoate in 150 ml absolute dioxane and door to éhullition. Then added regularly added dropwise.

stirring a solution of 16.8 g of glutaric acid dichloride in 50 ml of acetone and a solution of 8 ml absolute pyridine in 50 ml of absolute acetone under reflux and heating. The reaction is terminated after 3 hours. The mixture is concentrated and is taken up by a little methanol. The 3 n-glutarimido-to-4~phenoxy-5 a-sulphamoyl benzoate crystallizes shortly after. It can be recrystallized in glycol monomethyl ether.

White crystals having a melting point of 312 and 314 °C with decomposition.

EXAMPLE 7

3 N-piperidino-4-phenoxy-5 a-sulphamoyl benzoate. methyl

Suspended is 15 g of 3 n-glutarimido-to-4-phenoxy-5 a-sulphamoyl benzoate in 200 ml diglyme (dimethyl ether of 1' ethylene glycol)" and added 10 ml of boron trifluoride etherate. Then added dropwise with stirring a solution of 3 g of diglyme NaBH ^ in 150 ml at room temperature. Destroyed excess reducing agent by a little water, the solution is filtered and added 500 ml of water with stirring.

The 3 n-piperidino-4-phenoxy-5 a-sulphamoyl benzoate crystallized can be recrystallized in alcohol.

White crystals having a melting point of 198 and 199 degrees Celsius.

NMR data; (dg of methacrylate-DMSO, 60 MHz band, the TMS) d=1.1 (quasi e; 6:00),

6=2.86 (near-e, 4:00), 6=3.92 (O: 3:00), 6=6,7 - 8,1 (m-: 9:00) in ppm.

EXAMPLE 8

Acid 3 n-piperidino-4-phenoxy-5 a-sulfamoyi benzoic

Wherein suppension 8 g of 3 n-piperidino-4 a-phënoxy-a 5 a-sulphamoyl in 50 ml of methyl benzoate. In and NaOH solution is heated at steam bath until a solution. clear. Precipitated acid 3 n-piperidino-4-phenoxy-5 a-sulfamoyl benzoic formed by adding HCl 2n and allowed to recrystallize in a mixture of methanol/water "

White crystals having a melting point of 258 and 260 degrees Celsius.

NMR data: (dg of methacrylate-DMSO, 60 MHz band, the TMS)=.5 1.08 (quasi e: 6:00),

δ=2.9 (near-O; 4 Η), δ=6, 65 - 8, 2 (m-; 9:00) in ppm.

EXAMPLE 9

3 N-phthalimido-4-phenoxy-5 a-sulfsulf.amoyl methyl benzoate

16 G of dissolved 3 n-amino 4-phenoxy-5 a-sulphamoyl benzoate in 200 ml of absolute dioxane and heated to boiling. Regularly is then added dropwise, stirring well, 14 ml of a solution of phthalic acid dichloride in 50 mi of acetone and a solution of 9 ml of pyridine in 50 ml of acetone.. The reaction is completed in three hours.

The solution is concentrated, is taken up by a little acetone and stirring well is added dropwise in an ice-water mixture and HCl 2 n the 3 a-N~phtalimido-to-4-phenoxy-5 a-sulfamôyl benzoate separates into a light brown precipitate. By recrystallization from a mixture of methanol/acëtone / ^ O-, white crystals having a melting point of 237 and 238°.

EXAMPLE 10

3-n-to-isoindolinyl~4-to-phênoxy~5-to-sulphamoyl benzoate

Dissolving or suspending 16 g of 3 n-phtali-to-mido-to-4-phenoxy-5 a-sulfamoyi in 150 ml of methyl benzoate digly added 12 ml of me and êthêrate boron trifluoride. Then added dropwise at room temperature a solution of 3.6 g of NaBH ^ in 100 ml diglyme was stirred and 1/2 hour to 60^I C. The addition of 400 ml of water, a mixture, of substances separates into flakes. Is boiled in methanol wherein the 3 n-isoindolinyl-to-4-phenoxy-5~sulfamoyl benzoate remains insoluble. Is drained and allowed to recrystallize in a mixture of n-butanol/(diméthylformàmide) of DMF.

White needles having a melting point of 268 and 272 °C with decomposition.

NMR data ii (dg of methacrylate-DMSO, 60 MHz band, the TMS) 6=3.92 (O: 3:00), 5=4.66 (O: 4:00) 6=6,6 - 8,1 (m-: 13:00) in ppm.

EXAMPLE 11

Acid 3 n-iso.indolinyl~4-to-phënoxy-a 5 a-ss.ulfamo.y.l benzoic

Suspended is 2.5 g of 3 n-isoindolinyl-to-4-phenoxy-5 a-sulphamoyl benzoic acid methyl ester in 50 ml of NaOH 1 n and is heated at steam bath until the solution becomes clear is precipitated acid * 3 n-isoindolinyl-to-4-phenoxy-5 a-sulfamoyl benzoic by adding HCl 2 n and allowed to recrystallize in acetic acid.

Light yellow crystals having a melting point of 259 and 261 °C with decomposition.

NMR data: (dg of methacrylate-DMSO, 60 MHz band, the TMS) - δ=4.68 (e; 4 Η), δ ≈ 6.6 - 8.0 (m-; 13:00) in ppm.

EXAMPLE 12

3 N - c2, 4 a-dioxo 3 azabicyclo - 3, 2, 0 ^ /" heptano) - 4 a-phênoxy-a 5 a-sulphamoyl benzoic acid, methyl

8.1 G of mixed 3-amino 4-phenoxy-5 a-sulfâmoyl methyl benzoate with 6.3 g of acid anhydride L-cis-cyclobutane, 2 a-'-dicarboxylic and 5 ml diglyme and heated to 180 °c. Diglyme evaporates. The melted mixture is solidified in about one hour. Is then pours in hot methanol and the solid mass white crystalline precipitates into a slurry. The crystal powder is drained and allowed to recrystallize in ether monoraethylic glycol.

Melting point: 284 and 285 degrees Celsius.

EXAMPLE 13

3 N - (3 azabicyclo - ^ " 3.2, (Cycle-to-heptano) - 4-phenoxy-5 a-sulphamoyl-benzoic acid methyl ester

Suspended is 7.3 g of 3 n - (2.4 a-dioxo azabicy-to-CIO - ^ " 3, 2, 07 and heptaho) - 4 a-phënoxy-a 5 a-sulphamoyl benzoate in 70 ml diglyme and added 6 ml of boron trifluoride ëthérate. While cooling in ice, then high growth is poured dropwise a solution of 1.5 g of NaBH ^ in 70 ml diglyme. It is stirred for a further 15 minutes and in precipitating the 3 n - (3 azabicyclo - ^ 3.2, o7 " heptano) - 4-phenoxy-5 a-sulphamoyl benzoate by adding water.

Is recrystallized in methanol or acëtonitrile

and white crystals having a melting point of 176 -177 °C.

EXAMPLE 14

Acid 3 n - (aza - ^ / heptano - 3, 2, 0) - 4-phenoxy-5 a-sulfamoyl benzoic

" "! "_ I-suspended is 6.2 g of 3 n - (3 azabicyclo - ^ 3, 2, o7heptano) - 4-phenoxy-5 a-sulphamoyl benzoate in 60 ml of 1 NâQH clean is heated in a water bath until the solution becomes clear. By HCl acid is precipitated by stirring 2 n-well and allowed to recrystallize in acetic acid. Obtained are boards yellow-white having a melting point of 254 and 255 °C with decomposition.

. EXAMPLE 15

3 N - (cis î, 2-cyclohexane dicarboximido) - 4-phenoxy-5 a-sul£amoyl benzoate

Melted together 8.3 g of 3-amino 4-phenoxy-5 a-sulphamoyl methyl benzoate with 7.5 g of anhydride of cis-cyclohexane 1.2-dicarboxylic with few drops diglyme. The temperature is held between 180 and 200 °c, with stirring, until the mass starts to solidify. Methanol is then added carefully and is drained crystallized white matter.

Allowed to recrystallize in ether monornéthyligue glycol and white crystals having a melting point of 168 and 169°.

EXAMPLE 16

3 N - (3.5 to-dioxo-morpholino) - 4 a-phénoxy~5-to-sulfamoysulfamoy.l methyl benzoate

16 G of mixed 3-amino 4-phenoxy-5 a-sulphamoyl methyl benzoate with 15 g of diglycolic anhydride in 10 ml and diglyme and is heated in a flask open to about 180 °c. After 1 hour or 2, methanol is added carefully due. The imide crystallizes upon cooling.

White crystals by recrystallization from diglyme, melting point 295 and 297 degrees Celsius.

EXAMPLE 17

3 N-morpholino 4-phenoxy-5 a-sulfsulf.amoyl methyl benzoate

::;

Suspended is 9.4 g of the n - 3 * - (3.5 to-dioxo-morpholino) - 4-phenoxy-5 a-sulphamoyl benzoate in 100. ml diglyme and added 6 ml of boron trifluoride etherate. Then slowly poured dropwise, while cooling in ice, a solution of 1.9 g of NaBH ^ in 100 ml diglyme. In precipitating the 3 n-morpholino 4 a-phënoxy-a 5 a-sulphamoyl formed methyl benzoate, by addition of water. Is recrystallized in methanol; melting point 221 and 222°.

04987 18 G.

Acid. 3 n-morpholino~. 4-phenoxy-5 a-ss.ulf.amoyl benzoic

-⁵ Heated water bath at corresponding methyl ester (example 17) with NaOH 1 d, until the solution is clear. Precipitated acid 3 n-morpholino 4-phenoxy-5 a-sulfamoyl benzoic by adding HCl 2 n and allowed to recrystallize in methanol; brownish white crystals having a melting point of 194 and 197 ° (with decomposition).

EXAMPLE 19

3 N - (4 a-méthylglutarimido) - 4-phenoxy-5 a-sulphamoyl méthy benzoate

16 G of mixed 3-amino 4-phenoxy-5 a-sulphamoyl benzoate and 15 g of 4-methyl glutaric anhydride in by adding a little diglyme, and obtaining a slurry is heated during 2 to 3 hours at 160 and 180 degrees Celsius. In precipitating the 3 n - (4 methyl-20 glutarimido) - 4-phenoxy-5 a-sulphamoyl benzoate by addition of methanol. By recrystallization from monomethyl ether glycol, crystals melts at 315 °c.

EXAMPLE 20

25' 3 N - {4 a-mêthylpinéridino) - 4-phenoxy-5 a-suifamoyl benzoate

- - - - I-■- - - - - - - - - -

Suspended is 10.3 g of 3 n - (4 a-méthylglutarimido)

- 4 a-phënoxy-a 5 a-suifamoyl benzoate in .100 ml of diglyme and added 6.5 ml etherate LF ^. Then added dropwise at room temperature a solution of 1.9 g of NaBH ^ in 100 ml diglyme. When the addition is complete is stirred for a further 15 minutes and in precipitating the 3 n - (4 a-methylpiperidino) - 4-phenoxy-5 a-suifamoyl benzoate ' methyl by adding water; 35 by recristallisation in methanol, colorless crystals having a melting point of 143 and 144°.

EXAMPLE 21

Acid 3 n - (4 a-mêthylpipéridino) - 4-phenoxy-5 a-suifamoyl benzoic

4Ô aü heated water bath corresponding methyl ester (example 20) with NaOH-I " - up ' to Become does the solution clear. Precipitated acid 3 n - (4 a-methylpiperidino). - 4 a-phênoxy-a 5 a-sulfamoyl benzoic by adding HCl 2 n-; by recrystallization in a mixture mëthanol/water, white crystals, having a melting point of 243 and 244 degrees Celsius.

EXAMPLE 22

3 N - (3 a-méthylsuccinimidD} - 4 a-phênoxy-a 5 a-sulphamoyl benzoate

In a balloon open, melted 16 g of 3-amino 4 a-phênoxy-a 5 a-sulphamoyl benzoate and 15 g of anhydride in 3 a-second housing with some diglyme and maintained for about 2.5 hours at 180 °c. Is crystallized from 3 n - (3 a-méthylsuccinimido) - 4-phenoxy-5 a-sulphamoyl benzoate by addition of methanol and recrystallized in glycol monomethyl ether; white crystals having a melting point of 272 °c.

EXAMPLE 23

Acid 3 n - (3 a-méthylpyrrolidiho) - 4-phenoxy-5 a-sulphamoyl benzoate

Is. 17.3 g of suspension 3 n - (3 a-méthylsuccinimido)

- 4-phenoxy-5 a-sulphamoyl benzoate in 150 ml diglyme.

Is added 11 ml etherate LF ^, and then dropwise while cooling in ice a solution of 3 g of NaBH ^ in 150 ml diglyme.

Then precipitated the 3 n - (3 a-méthylpyrrolidino) - 4 a-phênoxy-a 5 a-sulphamoyl benzoate formed by adding water; is recrystallized in methanol and white crystals having a melting point of 145 °c.

•24 G.

Acid 3 n - (3 a-méthylpyrrolidino-to-4-phenoxy-5 a-sulfamoyl benzoic

Heated water bath at 9 g of 3 n - (3 a-méthylpyrrolidino) - 4 a-phênoxy-a 5 a-sulphamoyl benzoate in the NaOH 1 n until the solution becomes clear. And then precipitated at room temperature acid 3 n - (3 a-méthylpyrrolidino) - 4-phenoxy-5 a-sulphamoyl. benzoic by HCl 2 n and allowed to recrystallize in the O ^ / CHgOH; white yellow crystals having a melting point of

. EXAMPLE .25

3 N-maleinimido-a 4 a-phéhoxy-a 5 a-ss.ulf the benzoate amoamo.yl. die methyl

- - - -■:

In a balloon open, is heated up to 180 °c 16 g of 3-amino 4-phenoxy-5 a-sulphamoyl benzoate and 15 g of maleic anhydride with a little diglyme. After three hours, cooled and methanol is added and some water. The 3 n-maléi-to-nimido-to-4-phenoxy-5 a-sulphamoyl benzoate precipitates slowly. Is recrystallized in methanol and white crystals having a melting point of 197 - 198®C..

EXAMPLE 26

3 N-pyrrolidino 4-phenoxy-5 a-sulphamoyl benzoate process b

4.1 G of dissolved 3 n-succinimide-to-4-phenoxy-5 a-sulphamoyl benzoic acid methyl ester in 40 ml of diglyme and added 2.5 ml of titanium tetrachloride. Then added dropwise slowly dripped at room temperature a solution of 1.1 g of NaBH ^ in 30 ml diglyme and stirred for a further 1 hour is.

In precipitating the 3 n-pyrrolidino 4 a-phênoxy-a 5 a-sulphamoyl formed methyl benzoate, by adding water, and is recrystallized in methanol, melting point 191 * 0.

EXAMPLE 27

3 N - (m-chloro butyrylamino) - 4-phenoxy-5 a-sulphamoyl benzoate

: ^:

24 g of 3-amino 4 a-phénûxy-a 5 a-sulphamoyl benzoate and 7.5 ml of pyridine in 100 ml of absolute dioxane and 21.2 g of acid chloride in 100 ml of OA-to-chlorobutyric absolute acetone are added slowly dropwise and most regularly possible in 100 ml of dioxane boiling, in about 2 hours. It is stirred for a further 1 hour and the solution is concentrated. The residual oil is taken up by a little acetone and is added dropwise with stirring in ice water.

The 3 n - (lo-chloro bütyrylamino) - 4-phenoxy-5 a-sulphamoyl benzoate precipitates and allowed to recrystallize in methanol. Melting point 15l and 153^Q C..

. EXAMPLE 28'

3 N - (m-chloro-butylamino) - 4-phenoxy-5 a-sulphamoyl benzoate

Suspended is 12 grams of 3 n - (W-chloro-butyrylamino)

- 4-phenoxy-5 a-sulphamoyl benzoate in 150 ml diglyme. Added 7 ml of boron trifluoride etherate. Also added slowly, dropwise, at room temperature a solution of 2.2 g of NaBH ^ in 150 ml diglyme. Still stirred a few minutes and in precipitating the product by adding water carefully. Is recrystallized in methanol and a processed product obtained melting at 125 °c.

EXAMPLE 29

Acid 3 n-pyrrolidino 4-phenoxy-5 a-sulfamoyl benzoic

Process c

Suspending the 3 n - (Û) - chloro-butylamino) - 4-phenoxy-5 a-sulphamoyl benzoate in the NaOH 1 n and is heated at steam bath until the solution becomes clear.

Precipitated acid 3 n-pyrrolidino 4-phenoxy-5 a-sulfamoyl benzoic in cool solution (see example 5) by adding HCl 1 n-.

EXAMPLE 30

4 chloro-3 a-succinimide-a 5 a-sulphamoyl benzoate

Intimately mixed 25.4 g of 4 chloro-3-amino 5 a-sulphamoyl benzoate having a melting point of 195 and 196 °C with 25 g of succinic anhydride and melting during 6 hours at 180 °c. Allowed to cool slowly, then methanol is added carefully the crystallized product. Crystallization of the product is completed by the addition of a small amount of water. Is recrystallized in glycol monomethyl ether.

Melting point 267 - 269 °c.

EXAMPLE 31

Acid 4 chloro-3 a-pyrrolidino 5 a-sulfamoyl benzoic

On. cMET suspended 20 g of imide the example 30 in 200 ml diglyme and added 17 ml etherate LF ^. In this slurry. cooled in ice, is added dropwise a solution of 4 g of NaBH ^ in ' 200 ml diglyme. When the addition is completed, it is stirred for a further hour and is 1/2. hydrolysis carefully with a small amount of water.' Filtered and in precipitating the 4 chloro-3 a-pyrrolidino 5 a-sulphamoyl•methyl benzoate with a little water. Is recrystallized in methanol.

Melting point 189 - 19 l °C.

•saponifying the ester at steam bath NaOH 1 n-juice that that the solution becomes clear. Precipitated by acidifying acid, pH 4. Light yellow crystals by-recrystallization in methanol/water. Melting point 259 - 261 °c.

EXAMPLE 32

3 N-succinimide-to-4.-to-phenylthio-5 a-sulfamôyl methyl benzoate

5.8 G of mixed 3-amino 4 a-phenylthio-5 a-sulfamoysulfamoy.l methyl benzoate with 5.9 g of succinic anhydride and melted to 170 °c. 5 hours after, is added carefully by cooling, methanol, the material crystallizes and allowed to recrystallize in glycol monomethyl ether. Melting point 250 - 251^I C..

EXAMPLE 33

Acid 3 n-pyrrolidino 4 a-phenylthio-5" sulfamoyl benzoic

14.7 G of slurry is metmet.en imid (example 32) in 100 ml of diglyme and added 10 ml etherate LF ^. By cooling, then added slowly dropwise 2.8 g of NaBH ^ dissolved in 100 ml diglyme. Still agitated 1/2 hour at room temperature and is destroyed excess reducing agent by a little water. In precipitating the 3 n-pyrrolidino 4 a-phenylthio-5 a-sulphamoyl benzoate by a small quantity of water and allowed to recrystallize in methanol. Yellow crystals having a melting point of 139 - 140 °c.

The ester is heated at steam bath with NaOH 1 n until the solution becomes clear and in precipitating the acid by adding HCl to pH 3 - 4 n 1.

Is, recrystallized in - a mixture mëthanol/water and yellow crystals having a melting point of 238,239 °c.

EXAMPLE 34

Acid. 3 - (Dl-pyrroüdinyl) - 4-phenoxy-5 a-sui£amoy1 benzbenz.oïque D

has} 3 N-snccinimido-to-4-phenoxy-5-nitrate benzoate methyl.'

105 G of mixed 3-amino 4-phenoxy-5-nitrobenzoate methyl with 210 g of succinic anhydride and heating under stirring for 2 hours at 180 °c, the reaction mixture is poured in 3, 1 of water and after some time is extracted with methylene chloride. The organic phase is isolated, dried and concentrated. By recrystallization in methanol, is obtained from the residue the desired compound having a melting point of 152 - 154^I C., to high efficiency.

b) 3 - (1 a-pvrrolidinvl) - 4-phenoxy-5-nitrobenzoate mth thvle.

Is reacted under nitrogen atmosphere, with stirring and to 0 °c, a solution of 44.4 g of the ester obtained in a) in 300 ml diglyme with 34 g of trifluoride etherate. boron, and then with a solution of 9.2 g of NaBH₄ in 200 ml diglyme, by maintaining the temperature below de + 15^I C. other time, water is added dropwise. And then at the end die the exothermic reaction, 500 ml of water is added. The desired compound precipitates as orange needles having a melting point of 118,120 °c, with high work efficiency,

c) - 3 (L Pvrrolidinviy-to-4 ^ phénoxv-to-5-amino benzdatë&meq of a HY-Ig.

Catalytically hydrogenated with Raney nickel a solution of 30 g of the methyl nitrobenzoate obtained in b) in 500 ml of dioxane. At the end of the hydrogen absorption, is filtered and the filtrate is concentrated. Allowed to recrystallize the residue in methanol and obtained in high yields the desired compound, in the form of colorless crystals having a melting point of 153 - 156 °c imposition.

d). 3 - (l pyrrolidinyl) - 4-phenoxy-5 a-chlorosùlfonyl-benzoic acid methyl ester.

Is cooled to a solution of Gd 24.3 -5 °c¹aminéestet obtained in c) in 150 ml of concentrated hydrochloric acid and diazotizing with a solution of 5.46 g of nanû2 in 40 ml of water, while maintaining the temperature below de + 5 °c.

After 15 min, the solution is poured light brown of the diazonium salt in a mixture of 7.8 g of copper chloride dihydrate it, 24 ml of concentrated hydrochloric acid and 200 ml of a saturated solution of OS ^ in acetic acid at 0 °c. When the off-gas is completed, stirred still a little, and then water is added in the reaction mixture and the precipitated sulfochloride is extracted with methylene chloride. Washed twice with water the organic phase, dried and concentrated. Treated oil résiduellé by diisopropyl ether and is obtained in good yield the desired compound, having a melting point of 108 - 112 °c.

e) 3 - (L pyrrolidinyl 4-phenoxy-5 a-sulphamoyl benzoate methyl.

Gradually introduced, with stirring, 25.0 g of 5 a-chlorosulfonyl benzoate prepared in d), temperature ' room, in a mixture of 150 ml of methylene chloride and 75 ml 25% aqueous ammonia, the mixture was stirred further for one hour, the organic phase is separated, washed with water, dried over sodium sulfate and concentrated. Allowed to recrystallize the residual oil in the mëthanol and obtained with the 5 a-sulphamoyl benzoate with a melting point of 186 l88^I C..

Saponifying the ester acid 3 - (1 a-pyrrolidinylj-a 4 a-Phe-to-noxy-a 5 a-sulfamoyl benzoic, see example 5, melting point 227,228^I C..'

EXAMPLE 35

3 - Acid (1 a-pyrrolidinyl) - 4 a-phénoxy.-to-.5-to-sulfamoyl benzoic e

A) acid 3 - (1 a-pvrrolidinvl) degrees 4 a-phénoxV " 5 a-nitrobenzoïgue.

50 G of 3 is saponified - (1 a-pyrrolidinyl) - 4-phenoxy-5-nitrobenzoate methyl (for preparation, see example 34 b.)) hot by diluted sodium hydroxide solution.

The solution is extracted twice by red-orange

then the aqueous phase is acidified with concentrated hydrochloric acid. Desired acid is preferably isolated as crystals light yellow with a melting point of 228 - 230 °c.

b.) 3 - Acid (1 a-pyrrolidinyl) - 4 a-phënoxy-a 5 a-aroino-to-benben.zoiquth. 32.8 G of dissolved nitrobenzoic acid prepared has) in a solution of 8 g NaOH in 200 ml of water, cooled to 0 °c and is decomposed by a solution of 90 g of sodium dithionite in 380 ml of water, while maintaining the temperature below 10 °c. The solution orange-red originally hauler at light yellow. The solution is stirred 1 hour without cooling during, and then acidified to pH 1 with concentrated hydrochloric acid and concentrated until crystallization starts. Obtained the desired amino benzoic acid hydrochloride, as crystals having a melting point of 245 - 247 °c.

If the dithionite contains a sulfate, obtained already sulfate corresponding, before concentrating the aqueous solution, in the form of colorless crystals having a melting point of 175 - 176 °c.

From the two products, the free amine is obtained having a melting point of 100 - 103 °c by neutralizing the aqueous solution at pH 4 - 4, 5.

c) acid 3 - (1 a-pyrrolidinyl) - 4 a-phënoxy-a 5 a-chl6rosulfonvlbenzoïqui♦

Diazotizing a solution de.8, 35 g of the hydrochloride of amino benzoic acid prepared in b) in 25 ml of hydrochloric acid at 0 °c with a solution of 1.75 g of sodium nitrite in 15 ml of water, while maintaining the temperature below de + 5 °c. After 15 min, introduced with stirring the solution of the diazonium salt in a mixture cooled to 0 °c, consisting of 2 g of Cu dichloride dihydrate, 2 ml of concentrated hydrochloric acid and 15 ml of a saturated solution of s0₂ in acetic acid.

When longer foam, is stirred for a further 30 min, then the reaction mixture is treated with 150 ml of water and extracted several times with ethyl acetate. Water washed the organic phase, dried, then concentrated and by adding ether and hexane, to give the sulfochloride crystallized, melting point 163 - 165 °c.

If it is assumed aminobenzoic acid sulfate, this provides the same sulfochloride yield a little shorter.

d) acid 3 - (1 a-pyrrolidinyl) - 4-phenoxy-5 a-suifamoyl benzoic.

7.6 G of the is-introduced chlorosulfonyl derivative prepared in c) in 15 ml of liquid ammonia. Ammonia is knocked by evaporation at ambient temperature and the residue is taken up by a little water. The solution is filtered and is acidified to pH 1 with concentrated hydrochloric acid. The desired benzoic acid suifamoyl crystallises as brownish crystals is isolated in the form of straw yellow crystals by recrystallization from a mixture mêthanol/water. melting point 225 °c.

EXAMPLE 36

Acid 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-dimédimé.thylsulf amoyl benzoic

Is dissolved 7.2 grams (0.02 moles) acid 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic in 100 ml of NaOH 1 n and is treated by 10 ml dimëthyle sulfate. Well-stirred the mixture at ambient temperature. After 30 min, a substance flaky precipitates. It wrings and heating at steam bath with NaOH 2 n when the solution has become clear, is cooled and precipitated acid 4 a-phénoxy~3~(1 a-pyrrolidinyl) - 5 a-dimêthyl-to-sulfamoyl benzoic with HCl 2 d, may also be recrystallize the substance in a mixture of methanol/water. Yellow fibers are obtained having a melting point of 214 - 215 °c.

EXAMPLE 37

Acid 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-méthylsulfamoyl benzoic

a) 4-phenoxy " 3 n-succinimide-a 5 a-méthylsulfamoyl glycol benzoate methyl.

Melted 71 g of 3-amino 4-phenoxy-5 a-méthylsulfamôyl benzoate (melting point 188 °c) with 87 g of succinic anhydride to 180 - 190 °c. After 5 hours, the mëthanol added carefully, then the same amount of water used to crystallize the imide. The obtained 4-phenoxy-3 n-suceinimido-to-5-methylsulfonyl methyl benzoate, after recrystallization in the mëthanol, has a melting point of 249 - 250 °c.

b.) 4 phenoxy 3 - (1 a-pyrrolidinyl) - 5 a-méthvlsulf'méthvlsulf' amoyl benzoate.

Suspending 67 g of 4-phenoxy-3 n-succinimide-a 5 a-mêthylsuifamoyl benzoate in 300 ml diglyme absolute and is treated by 40 ml of boron trifluoride etherate. Is cooled to -10 °c and slowly added dropwise with stirring a solution of 12.2 g of NaBH ^ in 300 ml diglyme. The temperature must not exceed 10 °c. When the dropwise addition is complete, the mixture is treated carefully (foam) by water. The addition of water with another, in precipitating the reaction product. By recrystallization in methanol, to give the 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-mëthylsulfamoyle benzoate having a melting point del38 and 139 degrees Celsius.

. c.) Acid 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-méthylsulfamoyl-benzoic acid.

Suspending 54 g of the methyl ester obtained in b) in 500 ml of NaOH 1 n and is heated at steam bath with stirring. As soon as the solution has become clear, is cooled and in precipitating the free acid by HCl 1 n by recrystallization in a mixture of methanol/water, obtained acid 4 a-phênoxy and 3 - (1 a-pyrrolidinyl) - 5 a-méthylsulfamoyl benzoic acid having a melting point of 245 - 248 °c with decomposition.

EXAMPLE 3.8

4 Acid - (4'-methoxyphenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic

a) acid 3-nitrate 4 - (4'-methoxyphenoxy) - 5 a-sulphamoyl - Bas

zoîque.

- λ

Is dissolved 124 grams (0.9 moles) of potassium carbonate - 800 ml of water. With this solution, stirred gradually 1.6 moles of P-cresol and then 112 grams (0.4 moles) of 2-chloro 3 Ni-rev © a-5 carboxy-benzene sulfonamide and the solution is heated to 85 °c. The mixture is stirred 16 hours at this temperature, is cooled to 25 - 30 °c followed by acidification to pH 1 with concentrated hydrochloric acid. Separating the oil which precipitates from the aqueous phase and is subjected " to a drive to water vapor. It is also possible to adjust the pH to 8 - 9, agitating the excess phenol with ethyl acetate, then acidifying the aqueous phase. After having thus separated

the P-cresol in excess, product is crystallized by cooling. By recrystallization in a mixture acëtone/water, obtained acid 3-nitrate 4 '- (4'-methoxyphenoxy) - 5 a-sulfamoyl benzoic with a melting point of 236 °c.

b.) 3-nitrate 4? - (4' - methylphenoxy) - 5 a-year average F. amovl benzoate methyl.

Dissolving the crude product in methanol obtained

in the example 38a and is boiled. 5 To 10% is then added concentrated sulfuric acid (relative confectioneries the amount of benzoic acid used) and 8 hr under reflux by heating. The solution is concentrated to one third and is cooled to 5 and 10°. The methyl ester crystallizes crystals having a melting point of 161,162 °c.

c) 3-amino 4 degrees (4 * - méthylBhénoxv) - 5 a-sulfamovl glycol benzoate

Suspended is 45 g of 3-nitrate 4 - (4 - methylphenoxy *) - 5 a-sulphamoyl benzoate in 150 ml of ethyl acetate and hydrogenated with Raney nickel during 5 hours at 50 °c and under a hydrogen pressure of 100 atmospheres. After cooling, the solution is separated and Raney nickel is concentrated to dry.

Allowed to recrystallize the 3-amino 4 - (4^{the R} - methylphenoxy) - 5 a-sulphamoyl benzoic acid methyl ester in methanol/water and crystals having a melting point of 183 - 185 °c.

d.) 3 N-succinimide-a 4 - (4' a-méthvlphénoxv) - 5 a-sulphamoyl benzoate.

Melted 27 grams (Μ), 08 moles) of 3-amino 4 - (4'-methoxyphenoxy) - 5 a-sulphamoyl methyl benzoate with 24 grams (^ 0, 24 moles) of succinic anhydride during 4 hours at 170 - 190 °c. By cooling the mixture, is added carefully methanol and a little water. The imide precipitates and allowed to recrystallize in a mixture of methanol/water. Crystals having a melting point of 240 - 241^I C..

e) 4 - (4 '- méthvlphénoxv) - 3 - (L pvrrolid'pvrrolid' invi) - 5 a-SuIf amovlof méthvle benzoate.

Suspended is 25.6 g of 3 n-succinimide-a 4 - (4¹ - mêthylphénoxy) - 5 a-sulphamoyl benzoate in 150 ml absolute diglyme and added 16 ml etherate LF ^. While cooling in ice, is then slowly added dropwise to a solution of 4.6 g of NâBH ^ in 200 ml absolute diglyme properly by stirring. The temperature should not exceed 20 °c. It is stirred for a further^- 15 minutes and finally the product is precipitated by water. FARs recrystallization in methanol, crystals having a melting point of 156 - 157 °c.

f) suspending the ester raethylic obtained in e) in HaOH 1 - n and is heated at steam bath until the solution becomes clear. Filtered followed by acidification to pH 3. Is recrystallized in methanol acid 4 - (4'-methoxyphenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic precipitate. Light yellow crystals having a melting point of 230 - 233 °c with decomposition.

EXAMPLE 39

4 Acid - (4' a-methoxy-phenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulphamoyl benzoï -

that

;;^::

has) Acid 3-nitrate 4 - (4' a-methoxy-phenoxy) - 5 a-sulfamoyl benzoic .

The reaction is carried out with P-methoxyphenol as in the example 38a. After recrystallization from a mixture CEA -.

tone service/water, the product has a melting point of 233 - 234 °c.

b) 3-nitrate 4 - (4' a-methoxy-phenoxy) - 5 a-sulphamoyl benzoic acid methyl.

Operation is carried out as in example 38 b.. Recrystallization in methanol. Melting point 150 - 152 °c.

c.) 3-amino 4 - (4' a-methoxy-phenoxy) - 5 a-sulphamoyl benzoate.

Operation is carried out as to the example 38c. Recrystallization in methanol. Melting point 176 and l77 degrees Celsius.

d.) 3 N-succinimide-a 4 - (4' a-methoxy-phenoxy) - 5 a-sulphamoyl benzoate.

Operation is carried out as in example 38d confectioneries. Melting point 226,227 °c.

e) 4 - (4' a-methoxy-phenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulphamoyl methyl benzoate.

Operation is carried out as in example 38th confectioneries. Melting point 190,191 °c.

f) acid is prepared 4 - (4' a-methoxy-phenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic as illustrated 38f and allowed to recrystallize in a mixture of methanol/water. Light yellow crystals having a melting point of 228 - 229 °c.

EXAMPLE 4, 0.

4 - Acid (3 ', 5' a-dimethylphenoxy) - 3 - (2 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic

04987 has), 3 A-nitro~4 acid - (3¹ , 5¹ - dimethylphenoxy) - 5 a-sulfamoyl benzoic.

The ' reaction is carried in the example 38a with comae

the 3.5-dimethyl phenol. The crude product is directly estêrifie resulting..

b.) 3-nitrate 4~(3', 5¹ - dimethylphenoxy) - 5 a-sulfamovi benzoate.

Operation is carried out as to the example 38b, recrystallization in methanol. Melting point 197 - 198 °c.

c.)3 amino - (3⁸ , 5¹ - dimethylphenoxy) sulphamoyl -5~benzoate.

Operation is carried out as to the example 38c, recrystallization in methanol. Melting point 195 - 196 °c.

d) 3 n-succinimido~4~(3¹ , 5' a-dimethylphenoxy) - 5-sulphatedmoyl benzoate.

Operation is carried out as to the example 38d, recrystallization in methanol. Fusion with an unsintered; of 220 °c.

i) 4 - (3 *, 5¹ - dimethylphenoxy) - 3 - (L-~pyrroiidinyl)" 5 a-sulphamoyl benzoate.

Operation is carried out as to the example 38th, recrystallization in methanol. Melting point 208 - 209 °c<,

f) operation is carried out as to the example 38f. Allowed to recrystallize the acid 4 - (3 ', 5' a-dimethylphenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulfai&oyl benzoic acid in methanol/water. Melting point 246,248 °c with decomposition.

EXAMPLE 41

4 Acid - (4 - chlorophenoxy *) - 3 -. (1 a-pyrrolidinyl) - 57suifamoyl benzoic

3^ifl6 " - nitro 4 - (4'-chlorophenoxy) - 5 a-sulphamoyl Baszolque.

Operation is carried out as to the example 38a with P-chlorophenol.

Recrystallization from acetone/water. Melting point 248 °c.

the K) 3 a-nitro°4~(4 - chlorophenoxy *) - s eulfamoyl - fluorobenzoate

methyl.

Is worked at the example 38b; ^ recrystallization in methanol. melting point 171 - 172 °c.

c)' 3-amino 4" (4^has - chlorophenoxy) - 5 a-sulfamoyi glycol benzoate

ofe methyl.

On. operates as illustrated 38c; recrystallization in the mëthanol. Melting point 198 - 199 °c.

d.) 3 N-succinlroidO and 4 -<4¹ - chlorophenoxy) - 5 methyl ammonium benzoate amoyl.

Operation is carried out as to the example 38d; recrystallization in methanol; melting point 266 - 267^I C..

i) 4 - (4'-chlorophenoxy) - 3 - (1 a-pyrrolidinyl) - 5 a-sulphamoyl benzoate.

Operation is carried out as to the example 38th, recrystallization in methanol/water; melting point 200 °c.

f.) 4 Acid - (4'-chlorophenoxy)~-3 (1 a-pyrrolidinyl) -5-sulfamoyl benzoic.

Operation is carried out as to the example 38f; recrystallization in methanol. Melting point 253 - 254 °c.

EXAMPLE 42

4 - Acid (3' - trifluoromethylphenoxy) - 3~(1 a-pyrrolidinyl) - 5 a-SuIf amoyl benzoic

a) 3-nitrate 4 - (3'-trifluoromethylphenoxy) r5-to-sulphamoyl

-

benzoic.

Operation is carried out as to the example 38a, with the trifluorométhylphénôl. Recrystallization from acetone/water. Melting point 2lo^I C..

b.) 3 a-nltro - (3'-trifluoromethylphenoxy) - 5 a-SuIf araoylbenzoate methyl.

Operation is carried out as to the example 38b; recrystallization in methanol. Melting point 141 - 143 °c.

c.) 3-amino 4 - (3'-trifluoromethylphenoxy) - 5 a-sulphamoyl benzoate.

Operation is carried out as to the example 38c; recrystallization in methanol. Melting point 186 - 187 °c.

d.) 3 N-succinimide-a 4 - (3¹ - trifluoromethylphenoxy) - 5 a-sulphamoyl benzoic acid methyl ester.

Operation is carried out as to the example 38d, recrystallization

in the mëthanol. Melting point 227 - 228 °c.

e) 4 - (3'-trifluoromethylphenoxy) - 3 - (1 a-pyrrolidinyl) - 5 -sulphamoyl benzoic acid methyl ester.

Operation is carried out as to the example 38th, recrystallization

in methanol. Melting point 170 - 171 °c.

f) 4 - acid (3¹ - iFFT luorométhylphénoxy.) - 3 - (1 a-pyrrdlidinyl) - 5-sulfamoyl benzoic.

Operation is carried out as to the example 38f, recrystallization from acetic acid. fusicn point 230 - 234 °c.

EXAMPLE 43

3 - Acid (1 a-pyrrolidinyl) - 4-phenoxy-5 a-sulfamoyl benzoic method F.

has) 3.5 above dinitrobenzoic 4-phenoxy-benzoate méthvle.

30 G of treated dinitrobenzoic acid 4-phenoxy benzoic acid in 200 ml of methanol per 3 ml of concentrated sulfuric acid and heated to reflux for 3 hours. After removal of solvent, the residue is taken up in ethyl acetate and is. separates the traces of unreacted acid by a dilute sodium bicarbonate solution. After drying of the ethyl acetate solution, the solvent is removed by evaporation, and allowed to recrystallize the residue in an ethyl acetate/methanol. Obtained the ester sought a melting point of 171 - 173 °c, to high efficiency *

b.) 3.5-to-diamino 4-phenoxy-benzoic acid methylated.

25 G of dissolved 3.5-to-dinitrobenzoic 4-phenoxy-benzoic acid methyl ester in 250 ml of ethyl acetate, is treated hydrogen per 10 g Ni Rahey.. after securing the calculated amount of hydrogen, the catalyst is separated by filtration, the solvent is removed and crystallized out residual oil. Can be•directly converting the raw product or cause it to recrystallize in a mixture mêthanol/water, to obtain a yield remarkable diamino ester as colorless crystals having a melting point of 140 - 142 °c. The hydrogenation may also be carried out in an autoclave at 50 °c and with a pressure of 100 includes ATMS. The reaction lasts from 3 to 5 hours, according to the activity of the Raney nickel.

c) 3 a-succinylamino-to-4-phenoxy-5-amino benzoate méthvthe.

30 G of introduced 3.5-to-diamino 4-phenoxy-benzoic acid methyl chloroform with stirring in 300 ml of methylene chloride with or 12.8 g of succinic anhydride at room temperature, and the stirring is continued for 8 hours, the benzoate mth thyle sought separate while in the form of a colorless precipitate are isolated-crystals, washing them at chloroform and allowed to recrystallize. in methanol. The obtained 3 a-succinylamino-to-4-phenoxy-5-amino methyl benzoate as colorless crystals having a point, melting of 190 and 192 degrees Celsius.

d) 3 - (1 a-succinimide)~4-phenoxy-5-amino benzoate methyl.

30 G of introduced 3 a-succinylamino-a 4 a-phênoxy-a 5 amino-benzoic acid methyl ester in a mixture of 260 ml acid orthophosphorigue and 60 g of^P 2⁰ 5'^{is C.} ^^at the FF^I 2 hours to 5q °C, is cooled and is poured in 740 ml of water. Isolating the 3 - (succinimide) - 4-phenoxy-5-amino methyl benzoate as colorless crystals having a melting point of 200 - 201 °c, near quantitative yield.

e) 3 - (1 a-pyrrolidinyl) - 4-phenoxy-5-amino benzoate mththyle.

Is treated a solution of 24 g of 3 - (1 a-succinimide) - 4-phenoxy-5-amino benzoate in 180 ml diglyme by 20 g of boron trifluoride etherate and is cooled to 10 °c.

By cooling, is added dropwise to the reaction mixture a solution of 5.7 g of NaBH ^ in 125 ml of diglyme façGn that the temperature does not exceed 15 °c. When the addition is completed, it is stirred for a further 1 hour, the reaction mixture is then added 300 ml of water with caution. Isolating the solid precipitated and recrystallized in methanol. Isolating the 3 - (dl-pyrrolidinyl) - 4-phenoxy-5-amino benzoate of melting point 154 - 156 °c, with remarkable efficiency.

f) acid 3 - (1 a-pyrrolidinyl) - 4 a-phénoxv-a 5 a-sulfamovl Baszoic.

Repeating the procedure described in example 34. By reacting the 3 - (1 a-pyrrolidinyl) - dl-phenoxy s-chlorosulfonyl-benzoic acid methyl ester with ammonia concentrate, the obtained 3 - (1 pyrrolidinyl) - 4-phenoxy-5 a-sulphamoyl benzoate sought, having a melting point of 186 - 188 °c which can be converted, by heating with sodium hydroxide solution, and then acidifying, in acid 3 - (1 a-pyrrolidinyl) - 4-phenoxy-5 a-sulfamoyl benzoic melting point 226 - 228 °c.

EXAMPLE 44

3 - Acid (1 a-pyrrolidinyl.) - 4-phenoxy-5 a-sulfamo :-yl benzoic

Repeating the procedure of the example 43 to the acid 3 to-succinylamino-to-4-phenoxy-aminobenzoïqueaminobenzoïque..puis was stirred during 2 hours at 200 °c 10 g of the 3 a-succinylamino-to-4-phenoxy-5-amino benzoate. The reaction mixture is crystallized in methanol, after cooling, and is obtained in good yield the 3 a-succinimide-a 4 a-phênoxy-to-5-amino benzoate having a melting point of 199 - 200 °c.

Converted, by applying the method described in the example 43, in acid 3 - (1 a-pyrrolidinyl) - 4-phenoxy 5 a-sulfamoyl benzoic having a melting point of 227 - 228 °c.

EXAMPLE 45

3 - Acid (1 a-pypy.rrolidinyl) - 4 a-phénoxy~5-to-.sulfamoy.l benzoic

Repeating the procedure in example 43 step e is up.

Heated to boiling during 2 hours 51 g of 3 - (L pyrrolidinyl) - 4-phenoxy-5-amino benzoate in 780 ml 1 n-sodium hydroxide solution, it is possible to obtain a clear solution. And then cooled, adjusted the pH of the reaction mixture to 4 and the precipitated product is dissolved in 60 ml of HCl 2 n hydrochloride acid 3 - (1 a-pyrrolidinyl) - 4 a-phênoxy-to-5-amino benzoic acid precipitates quite rapidly in beautiful crystals having a melting point of 254 - 257 °c. Melting point mixed with the product from preparation 35 (step b): 252 - 254 °c.

Reacting the hydrochloride acid 3 - (1 a-pyrrolidinyl) - 4-phenoxy-5-amino benzoic acid 3 - (1 a-pyrrolidinyl) - 4-phenoxy-5 a-sulfamoyl benzoic sought having a melting point of 225 of "¹¹ - 226 °c, according to the method described in the example 35 through acid 3 - (1 a-pyrrolidinyl) - 4-phenoxy-5 a-chlorosulfonyl benzoic.

EXAMPLE 46

4 Acid - (4'-methoxyphenoxy) - 3n - (3 a-methylpyrrolidinyl) - 5 a-sulfamoylbenzoïque

a) 3n - (3 a-méthylsuccinimido) - 4 - (4'-methoxyphenoxy) - 5 a-sulphamoyl benzoate

Melted during 3 hours at 180 °c 20 g of 3 amino 4 - (4'-methoxyphenoxy) - 5 a-sulphamoyl-benzoic acid methyl ester (see exempie 38c) with 18 g of methyl anhydride succinic. Upon cooling of the molten mixture, is crystallized produi ' by addition of methanol. Is recrystallized in a mixture acéUne/water. Melting point 229 - 230 °c.

b.) 4 - (4¹ - methylphenoxy) - 311 - (3 a-méthylpvrrolidiny]) -5-tallowamoyl-benzoic acid methyl ester.

Suspending 22 g of 3n - (3 a-méthylsuccinimido) - 4 - (4¹ - methylphenoxy) - 5 a-sulphamoyl benzoate in 200 ml absolute and diglyme is treated by 13 ml etherate LF ^. WITH

- 5 - 0 °c, then slowly added dropwise, with stirring well, a solution of 3.3 g of NaBH ^ in 200 ml diglyme. It is stirred for a further 1 hour and in precipitating the formed product by water. Is recrystallized in a mixture of methanol/water. Melting point ill-- 178 °C.

c) acid 4 - (4'-methoxyphenoxy) - 3n - (3 a-methylpyrrolidinyl) - 5 - sulfamoyl benzoic.

Suspended is 14 g of methyl ester (46b)

in 150 ml of NaOH 1 n and is heated at steam bath with stirring properly. When this has resulted in a clear solution, was stirred 1 hour and still is acidified with HCl 2 K to a pH around 3, by cooling by ice. Is drained under vacuum the product precipitated, washed thoroughly with water and recrystallized in a mixture or methanol/water. Melting point 220 and 221°.

EXAMPLE 47

Acid 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic process G

a) acid 4 chloro-5 N, N-dimethylamino-méthvlëne aminobenzoic sulphonyl,

To a solution of 58.9 grams (0.25 moles) acid 4 chloro-5 a-sulfamoyl benzoic 183 in the g (2.5 mole) of dimethylformamide (Vilsmeier) is added dropwise to -10 °c 90 ml (1.25 mol) of thionyl chloride. The solution is allowed to return to room temperature, the mixture is stirred 2 hours is cooled on ice, the precipitate is separated by filtration and washed with water until neutrality. Obtained acid 4 chloro-5 n, n-dimethylamino-méthy-to-lène-to-aminosulphonyl benzoic (high efficiency) as crystals having a melting point of 166 - 167 °c.

b), acid 3-nitrate 4 chloro-5 n, n diméthylaminométhylëneaminosulphonly benzoic

60 Ml of oleum to 20% has, is added dropwise while cooling dansdans.la. ice 42 ml fuming nitric acid, and then slowly 34.9 grams (0.12 moles) acid 4 chloro-5 n, n i.d.-to-méihylamino-methylene-aminosulphonyl benzoic. After stirring for 24 hours at 55 - 60 °c, the solution is cooled to room temperature, poured on ice and the precipitate obtained is washed, with water until neutral pH. Obtained acid 3-nitrate 4 a-chlpro-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoic as crystals melts at 274 - 276 °c.

c) 3-nitrate 4 chloro-5 N, N-dimethylamino-methylene amine sulphonyl benzoate.

Heated to boiling under reflux during 1 hour•50.4 grams (0.15 moles) acid 3-nitrate 4~chloro-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoic acid in a solution of 150 ml of thionyl chloride which contains 5 drops of DMF. After vacuum removal of excess thionyl chloride, suspending the acid chloride solid in ' 200 ml of methanol. The suspension is heated under reflux for 1/2 hour, then cooled, filtered and washed with cold methanol.

The obtained 3-nitrate 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate as crystals having a melting point of 168 - 169 °c.

By heating under reflux for 2 hours a solution of 105 grams (0.3 moles) of^, 3-nitrate 4 chloro-5 n, n-dimethyl-amino méthylêne-to-aminosulfonylphenyl benzoate and 47.5 grams (0.36 moles) of sulfonic acid in 600 ml of DMF. After cooling and filtration of the potassium chloride, the solution is poured onto a mixture of water and ice and stirred for a further 1 hour is.

The precipitate is separated by filtration, washed with water and dried.

The raw product is dissolved in 900 ml of acetone, followed by purification on coal, is evaporated and is diluted to 500 ml with i 1 methanol. After one hour of stirring, the precipitate is filtered and washed to 10 °c cold methanol.

The obtained 3-nitrate 4-phenoxy-5 n, n diméthylaminomêthylêne-to-aminosulfonylphenyl benzoate as crystals melts at 191 - 193 °c.

θ) 3-amino 4-phenoxy-5 n, n diméthylaminométhylëne-friendnosulfonyl benzoate.

In room temperature and pressurized ' normal, is hydrogen during 8 . 61 hours (0.15 mole) of g to 3-nitrate 4-phenoxy-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate with Raney nickel in methanol. After filtration, suspending the catalyst in the DMP hot, is filtered and the filtrate is poured DMF on a mixture of water and ice.

The obtained 3-amino 4-phenoxy-5 n, n diméthylaminométhy * lène-to-aminosulfonylphenyl benzoate as crystals melts at 255 - 256 °c.

f.) 3 N-succinimide-to-4-phenoxy-5 n, n dimëthylaminométa HYlëne-to-aminosulfonylphenyl benzoate

Melted to 180 °c 30 g of. 3-amino 4-phenoxy-5 ~N, -n-dimethylaminomethylene-to-aminosulfonylphenyl methyl benzoate with 26 g of succinic anhydride. After 2 hours of reaction, the imide formed is precipitated in methanol. By recrystallization in n~a butanol, the imide is obtained in high yields. Melting point 283 - 284 °c.

9) 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 n, n dimëthylaminomethylene-aminosulfonylphenyl benzoate.

Suspended is 23 grams (0.05 moles) of 3 n-succinimide-a 4 a-phënoxy-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate in 200 ml of ethylene glycol dimethyl ether (diglyme and) and added 13 ml etherate (0.1 moles) ^ LF. Then added slowly dropwise, by cooling, a solution of 3.8 grams (0.1 mole) of NaBH₄ in 200 ml diglyme and is maintained at a temperature of + 5 °c to -10. Then allowed at room temperature and the solution becomes clear. The reaction is completed in 1 hour 1/4. In precipitating the product by addition of water. By recrystallization in methanol, to give the 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate. Melting point 189 - 190 °c.

h) acid 4-phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-suifamoyl Baszoic .

Suspending 13 grams (-0.03 moles) of 4-phenoxy-3 -

(1 a-pyrrolidinyl) - 5 n, n diméthylaminométhylènê-to-aminosulfonylphenyl benzoate in 100 ml of NaOH 2 n and stirring well is saponified to 80 - 90 °c. ' When the solution has become clear, stirred 1 hour further at the same temperature. Is then cooled to 0 °c and slowly added by stirring well. 110 ml of 2 n hydrochloric acid was stirred intensively during 1/2 hour and still liquid is removed from the product very finely precipitate. Allowed to recrystallize the substance in a mixture of methanol/water. Obtained are boards yellow-clear having a melting point of 226 - 228 °c.

EXAMPLE 48

Repeating the process of example 47 up step c.

And then heated the 3-nitrate 4 chloro-5 n, n diméthylaminométhylèneaminosulfonyl methyl benzoate with with potassium phenolate to 190 - 200 °c for two hours. The reaction mixture is cooled, is taken up by acetone and separating mineral components according to the procedure described in step d. The obtained 3-nitrate 4-phenoxy-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate which can be converted into desired end product according to the method in example 47.

EXAMPLE 49

a) repeating the following reactions indicated in the example 47, except that catalytic hydrogenation is carried dü 3-nitrate 4-phenoxy-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate in an autoclave at 50 °c and under a pressure of 50 atmospheres. After cooling, then isolating the 3 a-araino-to-4-phenoxy-5 n, n diraethylaminomethylene-to-aminosulfonylphenyl benzoate sought according to the procedure described in the example 47th.

b) repeating the following reactions indicated in the example 47 if the n? is carried out catalytic hydrogenation of 3-nitrate 4-phenoxy-5 n, n-dimethyl-aminomethylene-to-aminosulfonylphenyl benzoate in dimethylformamide (Vilsmeier) with Raney nickel, at room temperature and under normal pressure.

•after separation or filtration of the catalyst, the DMF solution of is poured onto ice. The obtained 3-amino 4-phenoxy-5 n, n aimethylaminomethylene-to-arninosulfonyl benzoate. Melting point 255 - 256 °c.

EXAMPLE 50

Repeating the following reactions indicated in 1' example 47? except that is used as the initial compound 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl mëthyle benzoate *'

a)•4 chloro-5" N._F. N dlmethylaminomethylene-to-aminosulphonyl methyl benzoate

To a solution of 74.9 grams (0.3 moles) of 4 chloro-5 a-sulphamoyl benzoate in 183 grams (2.5 mole) of dimëthylformamide, added dropwise to -10 °c 90 ml (1.25 mol) of thionyl chloride, and operation is carried out as described in example 47.

This gives the 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate having a melting point of 17, 4 176 °c.

b) 3~nitro~4-to-chloro~5~N, n diméthylaminométhylëne aminosulphonyl benzoate

Under the conditions stated in the example 47b, is treated 36.5 grams (0.12 moles) of 4 chloro-5 n, n dimëthylaminométhylèneaminosulfonyl benzoate. This creates a mixture of acid 3-nitrate 4 chloro-5 ~N, -n-dimethylaminomethylene-to-aminosulfonylphenyl benzoic acid and 3-nitrate 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosülfonyl benzoate. Mixture is worked by a 5% aqueous solution of sodium carbonate. The obtained 3-nitrate 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate having a melting point of 168 - 169 °c. then after acidifying acid 3-nitrate 4 chloro-5 n, n dimëthylaminométhylèneaminosulfonyl benzoic acid having a melting point of 270 - 272 °c, which can be optionally converted into ester according to the procedure described in the example 47c.

The further processing takes place as described in example 47.

EXAMPLE 51

The nitration is performed according to the method in example 47, except that ethyl ester is used instead of the methyl ester.

a) 4~chloro-a 5 n, n dimethylaminoethylene-to-aminosulphonyl ethyl benzoate.•

To a solution of 65 grams (0.25 moles) of 4 chloro-4~sulfamoyl ethyl benzoate in 183 grams (2.5 mole) of DMF, are added dropwise to -10 °c 90 ml (1.25 mol) of thionyl chloride and proceeds as in the example 47. The obtained 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl ethyl benzoate whose crystals have a melting point of 119 - 121 °c.

b), 3-nitrate 4 chloro-5 n, n diméthylaminométhylëne-to-a-àminosulphonyl ethyl benzoate.

Under the conditions stated in the example 47, is treated 38.3 grams (0.12 moles)' of 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl ethyl benzoate. Nitro acid is separated and the nitrated ester as indicated in the example 50b. The obtained 3-nitrate 4 chloro-5 n, n diméthylaminométhylëne-to-aminosulfonylphenyl ethyl benzoate whose crystals have a melting point of 182 - 184⁶ C., and after acidification of the aqueous solution, obtained acid 3-nitrate 4 chloro-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoic whose crystals have a melting point of: 270 - 272 °c, ' identical after melting and mixing to the carboxylic acid in example 47b.

EXAMPLE 52

•

Acid 3-nitrate 4-phenoxy-5 a-sulfamoyl benzoic

Repeating the sequence of reactions described in example 47 until the stage of the 3-nitrate 4-phenoxy-5 n, the n-dimethylaminomethylene-to-aminosulfonÿl glycol benzoate. Followed by heating under reflux for 2 hours 100 g of 3-nitrate 4-phenoxy-5 n, n diméthyldiméthyl.aminométhylèneaminosulfonyl benzoic acid methyl ester in 500 ml of NaOH 2 n after cooling, is acidified by concentrated hydrochloric acid.

Obtained acid 3-nitrate 4-phenoxy-5 a-sulfamoyl benzoic whose crystals have a melting point of 254 - 255 °c.

EXAMPLE 53

4 - phenoxy-3 - (1 a-pyrrolidinyl) - 5 a-sulphamoyl benzoate

36 Is dissolved, ' 2 g acid 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 - sulfamoyl benzoic in 200 ml of methanol and 7 ml of^H 2^S °4 concentrate, and by heating under reflux for 6 hours. The ester crystallizes upon cooling. In the recrystallization mëthanol. Melting point 191 °c.

EXAMPLE 54

Acid 4 a-phenylmercapto and 3 - (, 1 a-pyrrpyrr.ol.idinyl) - 5 a-ss.ul.f.amôÿl... benzoic

Repeating the following reactions indicated in the example 47 for the preparation of the 3-nitrate 4 chloro-5 n, n diméthylami -.

nomethylene-to-aminosulfonylphenyl benzoate.

has) 3-nitrate 4 a-phënylmercapto-a 5 n, n diméthylaminonsthy-lène-to-aminosulfonylphenyl benzoate

By heating under reflux for 2 hours 21 grams (0.06 moles) of 3-nitrate 4 chloro-5 n_F. The n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate, 7.7 grams (0.07 moles) of thiophenol and 8.2 grams (0,077 moles) of sodium carbonate in 100 ml of DMF. After cooling and filtration, the solution is poured onto a mixture of water and ice and stirred for a further 1 hour is. The precipitate is filtered, washed with water and dried. The crude product is recrystallized in a mixture of methanol/acétona. The obtained 3-nitrate 4 a-phenylmercapto-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate whose crystals have a melting point of 207 °c.

b) 3-amino 4 a-phenylmercapto-a 5 n, n diinéthylaminorai3thy -lène-to-aminosulfonylphenyl benzoate

Is hydrogen during 8 hours 2 grams (0.0047 moles) of 3-nitrate 4 a-phenylmercapto-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate with Raney nickel in 30 ml DMF at room temperature and under normal pressure. The catalyst is separated by filtration at the pump, washed with DMF hot and the filtrate is poured onto a mixture of DMF/water ice.

The obtained 3-amino 4 a-phénylimercapto-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate which was recrystallized in acetone. Melting point 214 - 215 °c.

c.) 3 N-succinimide-a 4 a-phenylmercapto-a 5 n_{the R} N diméthylaminthe O -methylene-to-aminosulfonylphenyl benzoate.

Mixed by comminuting 35 grams (0,089 moles) of 3-amino 4 a-phenylmercapto-a 5 a-dimethylaminomethylene-to-aminosulfonylphenyl methyl benzoate with 26.6 grams (0.2688 moles) of succinic anhydride and melting 2 hours at 175 °c. After cooling to 150 °c, is diluted with 100 ml of DMF and is poured slowly the solution on a water/ice mixture. The precipitate is drained, dried and allowed to recrystallize in DMF/methanol. Melting point 261,263 °c.

d.) 4 a-phenylmercapto-a 3 - (1 a-pyrrolidinyl) - 5 n, n diméthylain Minomethylene-to-aminosulfonylphenyl benzoate

To a solution of 32 g of 3 n-succinimide-a 4 a-phenylmercapto-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate and 17.5 ml of êthérate LF ^ in 135' ml of diglyme and absolute, is added dropwise with stirring a solution of 5.1 g of NaBH^135 in the MR diglyme absolute at a temperature of 0 - 10^P C..

After two hours is hydrolyzed and in precipitating the product of Ajou as yet - water.•

e) heating under ôn ' refluxing the crude product precipitated with NaOH 2 n until the solution becomes clear. Precipitated acid - 4 a-phenylmercapto-to-3. (the L-pyrrolidinyl) - 5 a-sulfamoyl benzoic by HCl 2 n and allowed to recrystallize in a mixture of OH/hr ^ ^ ch-O-. Melting point 237 - 238 °c, see also example 33.

EXAMPLE 55

.

Acid 4 a-phenylmercapto-a 3/1 - (3 a-mëthylpyrrolidinyl) - 5 - Cycle? - sulfamoyl benzoic

a) 3-amino 4 a-phenylmercapto-a 5 n_F. N diméthylaminométhy -lene-to-aminosulfonylphenyl methyl benzoateI

Hydrogen is a solution of 110 g of 3-nitrate 4 a-phênylmercapto-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate in 400 ml DMF by about 10' g of Raney nickel, during 8 hours at 40 °c and under 100 atms. The catalyst is filtered off and the solution is poured on ice. Is separated by filtering. the precipitate, is dried and allowed to recrystallize in acetone. Melting point 214 - 215 °g.

b) 3n - (3 a-méthylsuccinimido) - 4 a-phenylmercapto-a 5 n, n dimëthylaminométhylëne-to-aminosulfonylphenyl benzoate

Is: 2 1/2 hours melts during to 175 °c 40 - g (0.1 moles) of 3-amino 4 a-phënylmercapto-a 5 n, n diméthylaminométhylèneaminosulfonyl methyl benzoate with 34 grams (0.3 moles) -'d ' mëthyl-succinic acid anhydride. After; cooling to 15c °C, is diluted with 100 ml of DMF and is poured slowly the solution on ice/water mixture. Liquid is removed from the precipitate and in recristaliise in ch-OH-^.

Melting point 206 - 207 °c.

c) 4 a-phenylmercapto-a 3/1 (méthylpyrrolidiny3) - 7 a-5 n, n dimethylamlnomethylene-to-amlnosulfonyl glycol benzoate. methyl

Has a solution.de 29.4 g of 3 n (3 a-mêthylsuccinimido) - 4 a-phenylmercapto-a 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate and LF éthërate 15.9 ml of diglyme ^ in 120 ml absolute, is added dropwise to a solution of 0 - 10 °c 4.65 g of NaBH ^ in 120 ml absolute diglyme. After 2 hours of stirring, the reaction product is precipitated by adding water carefully. Is recrystallized in methanol. Melting point 147'd) acid 4 a-phénylmercapfco and 3/1 - (3 a-methylpyrrolidinyl)/-5 a-sulfamoyl benzoic

By heating under reflux for 2 hours 4 g of the ester of example 55c in 40 ml of NaOH 2 n is obtained a clear solution. After cooling and by acidifying with HCl to pH 2 - 3 2 n, precipitated acid 4 a-phenylmercapto-a 3/1 - (3 a-methylpyrrolidinyl)_ / - 5 - tallow amoyl benzoic. By recrystallization from CH-OH-/ ^ ^ 0, yellow crystals having a melting point 216 - 217 °c - OD.

EXAMPLE 56

Method of H

Acid 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic

a) acid 3 n-pyrrolo-4-phenoxy-5 a-sulfamoyl benzoic is heated under reflux 8 g of 3-amino 4-phenoxy-5 a-sulphamoyl methyl benzoate with 5 g of 2.5-dimethoxy-tetrahydrofuran in 100 ml of acetic acid. 1 1/2 To 2 hours after, the mixture is poured with stirring in ice water. Heating at steam bath the crude product precipitated with NaOH 1 N to obtain a clear solution. Precipitated acid 3 n-pyrrolo-4-phenoxy-5 a-sulfamoyl benzoic by acidification with HCl 2 n can be recrystallized in methanol or an acetic acid/water. Crystals gray-white melting 2l4 °C.

b) 8.8 g of dissolved 3 n-pyrrolo-4-phenoxy-5 a-sulphamoyl benzoic acid methyl ester (crude product) in acetic acid and hydrogen under normal pressure with 1 g of Pd on carbon.

The reaction time is about 30 hours. If hydrogen retort to 40 - 50 °c under 100 atms, the reaction is completed in 5 hours.

The solution is filtered, concentrated and saponifying

the solid residue at steam bath with NaOH 1 n is cooled and the clear solution is acidified with HCl 2 n are allowed to recrystallize in HM₃ 0:00/HR₂ 0 acid 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic precipitate. Melting point 226 - 227 °c.

EXAMPLE 57

Method i

Acid 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic

a) by heating under reflux for several days 10 g of 3-amino 4-phenoxy-5 a-sulphamoyl ' methyl benzoate with 25 g of 1.4 to-dibromobuatne and 10 grams of NAL/acetone in a mixture of DMF.

It follows the course of the reaction by thin layer chromatography. When the reaction is complete, is concentrated to dry, excess dibromobuatne is extracted with ether, decanted and saponifying the residue with NaOH 1 n in the clear solution, precipitated acid 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic by-add n-HCl 2.

' β) is heated under reflux for 5 hours 10 g of 3-amino 4-phenoxy-5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl methyl benzoate with 25 g of 1.4 to-dibromobuatne in the dimëthylfor. * mamide is concentrated to dry, excess dibromobuatne is extracted with ether, decanted and the residual red oil is taken up by a little methanol. The 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoate crystallizes at rest. It is saponified by caustic soda solution as described above and is precipitated acid 4-phenoxy-3 (1 a-pyrrolidinyl) - 5 a-suifamoyl benzoic by HCl.

EXAMPLE 58

3 - Alcohol (1 a-pyrrolidinyl) - 4-phenoxy-5 a-suifamoyl benzyl

Has. a solution of 38.7 g of 3 - (1 a-pyrrolïdinyl) - 4 a-pheno, an XY-a 5 a-sulphamoyl benzoic acid methyl ester in 500 ml diglyme

added, at 20 °c, ëthérate 35.2 g of boron trifluoride, and then 10 g of borohydride ' Na.

The reaction mixture was stirred during 2 hours at 75 °c, then cooled and added 200 ml water carefully.

When the gas evolution has ceased, 2, 1 additionally added water and isolated ' the precipitated crystals, is' washed with water and dried.

24.4 G of alcohol obtained 3 - (1 a-pyrrolidinyl) - 4 a-phênoxy-a 5 a-sulphamoyl benzyl having a melting point of 155 °c.

, 59 G.

Acid 4 a-phénylsulfoxy and 3 - (1 a-pyrrolidinyl) - 5 a-sûlfsûlf.amoyl benzoic

Confectioneries was stirred at room temperature a solution of 7.8 grams.

acid 4 a-phenylmercapto-a 3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic in 13q ml of acetic acid and 20 ml of 2 ^ ^ 2 ^⁰ⁿ

in the reaction by thin-layer chromatography. 20 hours after, the solution is poured over about 800 ml of ice water.

Liquid is removed from the precipitate, water washed and dried. Is recrystallized in a mixture of methanol/water and crystals yellow acid 4 a-phénylsulfoxy and 3 - (1 a-pyrrolidinyl) - 5 a-sulfamoyl benzoic, having a melting point of 142 and 144 °, with decomposition.

EXAMPLE 60

;

Acid 4 a-phénylsulfoxy-a 3 - / 1 - (methylpyrrolidinyl)_ 7 and 5 a-sulfamoyl benzoic

Stirred -20 °c 6 g of a solution of 4 a-phënylmercapto-a 3 - / 1 - (mêthylpyrrolidinyl)_ 7 and 5 n, the n-dimethylaminomethylene-to-aminosulfonylphenyl benzoic acid in 70 ml of acetic acid and 15 ml of 30% ^. After 20 hours, the solution is poured onto ice water.

The precipitate is washed with water, dried and hydrolysis with 30 ml of NaOH 2 n during 2 hours at 100 °c. The hydrolyzate is filtered followed by acidification to cool, with stirring, with HCl to pH 2 - 3 with n 2 so as to precipitate the acid 4 a-phénylsulfoxy-a 3 - / I - 7 (methylpyrrolidinyl)_ " 5 a-sulfamoyl benzoic. By recrystallization from a mixture of methanol/water, yellow crystals having a melting point of 143 - 145^I C with decomposition.