CA1082191A - Process for the preparation of sulfamylbenzoic acids - Google Patents

Abstract

Abstract of the disclosure:
Process for the preparation of 3-amino-5-sulfamylbonzoic acids by reducing corresponding 3-acylamino-5-sulfamyl-benzoic acids, wherein the sulfamoyl group is substituted by a protective group and subsequently splitting off said protective group.

Description

108~91 -The present invention relates to a process for the pre-paration of sulfamylbenzoic acids of the formula I

¦ .:

NH

X~

2 2 COOR
in which A represents lower alkyl, lower halogenated alkyl :
and lower cycloalkyl, X represents phenoxy which may be substituted by lower alkyl, lower alkoxy, halogen, nitro and amino, phenyl thio and N-methylpiperazino, and R means hydrogen or an alkyl or cycloalkyl radical having up to 6 carbon atoms, which comprises nitrating derivatives of sulfamoylbenzoic acids of the formula III
''.~ ~
' ', .' ' Y

~: ~ (III) '.
.
' ' ' ~ :
.
. E., -~. 2 - .. .. . . ,, . , . ~ . .. :

: , -. ~ . - . . :
-. . : . :
~. .. ..
~ - . . , : , .

~08Zl~

in which Y means a halogen atom, R is defined as above and B means a protective group of the formula 4 ~ ~ ~ 5 <

in which R4, R5 and R6 mean identical or different alkyl groups of low molecular weight, R4 meaning also possibly hydrogen and/
or two of the substituents R4, R5 and R6 being also possibly connected with one another cyclically, and esterifying the com-pounds obtained of formula IV

.
; 15 NO

(IV) X~
: BNO2S COOR
:' :, .

}~
~ ~ :

, -., ~. . .
: - .. .. : . : - : -. ,- . . .:
:, . . . . ~ ' , ,' : : ' :
. .
- : . . ~ . .

1C~8~

if R means hydrcgen, and reac~ing the eompounds obtained of for-mula IV, in which B and Y are defined as above,P~ however mea-ning an alkyl or cycloalkyl radical, with compounds of the formula XH, in which X is defined as above and reducing the eompounds obtained of the formula V

~2 B~02.5~ COOR

in whieh R' means an alkyl or cyeloalkyl radieal having up to 6 earbon atoms and B and X are defined as above and reae-ting the eompounds obtained of the formula VI
1~'12 X ~ ~ (VI) B~2S ~ ~ OOR' ' in whieh B,X and R' are defined as above with eompounds of the formula VII
O
1 1 .
:~ A - C - 1 (VII) . in whieh A is defined as above and L means a "leaving group"
or the radieal oR7 of an aetivated ester or an anhydride, R7 meaning also possibly ~ - A and reducing the compounds ob-tained of the formula VIII

.' , , . .

- - ,' :, ' ' ,~,' -' . . : . :

, . ... , : :
. . .
.
,, , ~ , .
: . - .

38'Z191 C = o 1~1 .
- X 1 (VI~I) B~2S ~ COO~ ' in which the radicals A,B,R' and X are defined as above by boron hydride optionally in the presence of Lewis acids or by complex boron hydrides in the presence of Lewis acids and hy-drolyzing the compounds obtained of the formula IX, A
CE~2 (IX) N~I

B1~025~001~ ' in which A,B,X and R' are defined as above to obtain compounds of the formuIa I, in which R means hydrogen and optionally esterifying the acids obtained(in which R is H) in usual manner.
The sulfamylbenzoic acids of the formula I are pharma-ceutical agents, especially valuable diuretics and saluretics.
A process for the preparation of these compounds is al-ready known from German Offenlegungsschrift No. 2,345,229.
The process of the invention has especial advantages as compared to the process of the former application and is more-that over surprising as it could not be expected~some reaction steps can be performed smoothly.

.. . . . : , . ,,, . :

,. . - : - . : .... : : : .. : .
. .
- - - ~ , , ' .
,, : . . .... :
.. . : , ... .
.

" 108Z~9l Ha]o~enobenzoic acids of the formula II,for example, may be nitrated surprisingly under mild conditions by incorporating the protective group B into them, which proceeding is especialiy important for their preparation on an industrial scale. ~-The benzoic acids derivatives of the formula III used according to the present invention may be obtained according to various processes.
The reaction may be carried out in an especially simple manner by using as starting compounds sulfamylbenzoic acids derivatives of the formula II

h!OzS . Co~
- ~ ,. .

which are known in the literature, by varions condensation processes, most of which are knwon in the literature.
The following references in the literature may be mentioned, by way of example:
~ J. Org.Chem. 25 (1960), 352 - 356; Zh. Org. Khim 8 (1972), 286 -` 291; Liebigs Ann. Chem. 750 (1971), 42; Zh. Org. Khim 6 (1970), 9, 1885; B. 94 (1961), 2731 - 2737; Ang. Ch. 78 (1966), 147 -148; Ang. Ch. 80 (1968), 281 - 282;
Volume 97 (1964), 483 - 489; Volume 96 (1963), 802 - 812; J.
Org. Chem. 2 (1962), 4566 - 4570; Ang. Ch. 74 (1962), 781 -782 and Doklady Akad. SSSR 145 (1962), 584.
The following derivatives, for example may be used accor-ding to the invention as compounds of the formula III.

.

.
. . .
: . - . . , : , :

~' ' " , ' ' ' .

108219~
S C NO 5~ COCH

Compound No. IR4 R5 R _ 2 CH3 CH3 CH3 Cl

3 H C2H5 C2H5 C1 C4H9 CH3 CH3 Cl , 5 H CH3 CH3 F
6 H CH3 CH3 Br ~' The compounds of the formula III are prepared according -.
~, to the processes mentioned in the above references or in analogous manner thereto. Instead of the aforesaid acids ,~ there may also be used the corresponding methyl and ethyl -ester.
The nitration of the benzoic acid derivatives of the formula III may be performed in different ways. The benzoic acids derivatives, for example may be introduced into one of the ,` . :
~ 7 ~
': ' . ` ~, .'':, ' .... ' ' ' '' . "'' ' - , 1082191 1`

conventional nitration mixtures for the nitration of inert aromatic agents ~cf. "Organikum", page 288, edition 1967).
The process may also be performed alternatively by dissolving the benzoic acid derivatives of the formula III in oleum and by controlling the nitration by adding dropwise nitric acid.
It is surprising that the benzoic acid derivatives of the formula III, may be nitrated without altering other groups in the molecule only by incorporating the protective group B
into the sulfamide radical.
The reaction temperature is in the range from about 55 to 130C, preferably in the range from 55 to 90C.
An advantageous method of carrying out the process of the invention consists in firstly introducing a nitration acid containing oleum and fuming nitric acid, in adding the sub-stance and in heating the reaction mixture to a temperature from about 60 to 80C.
The nitration may be observed by thin-layer chromatogra-phy. The final products are isolated according to processes - known in the literature, for example by pouring the reaction mixture onto ice and filtering off the precipitated crystals.
Suitable compounds for nitrating are acids or esters of the formuIa III, in which Y,B and R are de~fined as above. When nitrating esters of the formula III there are obtained, besides the esters of the formula IV, acids of the formula IV(in which R is H) in a small quantity.
The mixture may be separated in usual manner, for example by treating it with aqueous sodium carbonate.

.
.

.

.

:.

- ~0B~l9l The compcunds obtained of the formula IV, in which R
~eans hydrogen ~re then esterified in usual manner.
For esterifying the carboxyl group the carboxylic acid is converted into its acid chloride, which chloride furnishes S the corresponding esters of the formula IV when adding alcohols.
Suitable alcohols for esterifiying are especially the low molecular weight alcohols having from 1 to 6 carbon atoms, for example methanol, ethanol, propanol, butanol, pentanol, iso-propanol or hexanol or cyclohexanol and cyclopentanol.
The alcohols may be used in a stoichiometrical quantitiy, but they are preferably used in a 5 to 20 fold molar excess.
Using them simulataneously as a solvent is moreover advantage-ous .
; In the next step the compounds of the formula IV are con-verted into compounds of the formula V, by reaction with com-pounds of the formula XH optionally after having esterified the carboxyl group.
It has now b~een found surprisingly that compounds of - the formula IV, in which R means alkyl may be reacted with com-pounds of the formula XH with good results under anhydrous con- ~ -ditions.
Suitable compounds of the formula XH for example include phenol, 4-methylphenol,3-methylphenol,2-methylphenol,4-chloro-phenol,3-trifluoromethylphenol,3,5-dimethylphenol, 2,4-dimethyl-phenol, 4-methoxyphenol, 3-methoxyphenol, 4-propylphenol, thio-phe~ol and the thiophenols substituted in an analogous manner as phenol, N-methylaniline, benzenesulfinic acid~ pyrrolidine, , ..
_ g _ . .
~, .
.. .. .
.

:. .- :~, - . ' N~methylpiperazine, 5-methyl-2-mercapto-1,3,4-thiadiazole or 1-methyl-5-mercapto-1,2,3,4-tetrazole. Possibly present addi-tional functionel groups in XH such as further OH groups, ~H2 or mercapto groups are blocked by conventional protective groups, for example by acylation.
The reaction may be carried out without solvents, but is performed preferably in a solvent. Organic solvents such as ethers and tertiary carboxamides, especially diglymes, di-methylformamide or hexamethylphosphoric acid trisamide (HMPT) are especially appropriate.
The compounds X-H are used as such in the presence of bases or in the form of their alkali metal or alkaline earth metal salts. Suitable bases are alcoholates or alkali metal amides.
Compounds of the formula HOR2 and HSR2,in which R2 is de-fined as above are especially important. Especially important are the thiophenol and phenol derivatives, ~ich may be sub-stituted as mentioned above. -~
The thiophenol and phenol derivatives may be reacted in the form of their anions. There may be mentioned especially the alkali metal salts and particularly the sodium and potassium salts.
The reaction may be carried out in the presence or in the absence of a solvent. When operating without a solvent the components are heated to a temperature from 100 to 200C, pre-ferably from 140 to 180C. The products obtained may be isola-ted in usual manner, for example by dis~olving the molten pro-2~ ducts in a solvent and by precipitating subsequently by the . . .

, , ' ~ , , -, ' , ~' ' , . '~

1~8'~
addition of water or an organic nonsolvent.
Reacting ~ith phenolates or thiophenolates in solvents at a temperature rrom 100 to 200C, preferably from 120 to 160C
is especially advantageous.
Suitable solvents are organic solvents, éspecially ter-tiary carboxamides, polyethers or solvents having a high boiliny point, for example HMPT, or tetramethylenesulfone. The esters of the formula IV are reacted especially advantageously in ter-tiary carboxamides, for example dimethylformamide or dimethyl-acetamide. The reaction is terminated after 1 to 6 hours de-pending on the chosen reaction temperature.
The final products of the formula V are isolated in usual manner, for example by firstly filtering off the mineral salts and by precipitating subsequently the reaction product by the addition of a nonsolvent or by giving the reaction mixture into water or onto ice and by isolating the precipitated reaction product. 2 The compounds of the formula V, in which X means SOR or SO2R2 are obtained from the compounds of the formula V, in 20 - which X is SR2, by oxidizing according to processes known in the literature. The S oxides, for example, may be obtained by oxidizing with peracetic acid in dimethylformamide at low tem- -peratures, whereas the S dioxides are formed when adding an excess of oxidant at higher temperatures.
The nitro group may be reduced into benzoic acid deri-vatives of the formula V in various ways according to processes known in the literature, for example by catalytic hydrogenation.
28 Raney nickel is preferably used as a catalyst. Conventio-' : . ,' . .: . , ,. -.......... ~, . . . .

.. - . ,. , .. : , . . . . .

108'~91 nal noble metal catalysts such as palladium supported by car-bon or platinum oxide may also be used.
The catalytic hydrogenation is performed in a way knwon in the literature (cf.Organikum, pages 271 to 277, pages 507 to 510). The reaction is carried out in a solvent in the pre-sence of a catalyst.
Suitable solvents are preferably organic solvents such as methanol or ethanol, acetic acid ester, dioxane or other polar solvents, especially amides such as dimethylformamide, di-methylacetamide or H~PT.
Hydrogenation is performed at room temperature and under atmospheric pressure or et elevated temperature and under pres-sure above the atmospheric pressure, for example at 50C and ; under a pressure of 100 atmospheres, in an autoclave.
The 3-acylaminobenzoic acid derivatives of the formula VIII may be obtained according to various processes. They may be prepared, for example, by reacting in usual manner the amino compounds VI with carboxylic acid derivatives capable of forming amides, such as carboxylic acid anhydride or the carboxylic halides. Leaving groups in the compounds of the for-mula VII, for example may be halogen, trialkylammonium, pyri-dinium or the group O CO-A. Preferred compounds of the formula ' VII, for example, are butyric acid chloride, butyric acid an-hydride, cyclopropanecarboxylic acid chloride, cyclobutanecar-boxylic acid chloride, benzoylchloride, benzoylpyridinium chloride or ~ -chloropropionic acid chloride.
The reaction with the aforesaid compounds is performed under the conditions of the Schotten-Baumann reaction. It may be readlily observed by thin-layer chromatography, owing to 3 the fact that the compounds VI fluoresce at 366 m~ whereas the compounds VIII do not fluoresce.
; Suitable reduction agents are various boron hydrides such as diborane, optionally diborane in the presence of Lewis -acids. They may be introduced into the reaction mixture, when assuring protective measures, for example the use of nitrogen as inert gas. A simpler method consists in dissolving the bo-ron hydrides, for example diborane and in using the solution .

,, , . .

. , .. , . . : . ,: . .- . :

- , . : , , :.

108~91 obtaine~ for the reduction. Suitable solvents are especially ethers such as tetrafurhne or diethylene glycol dimethyl ether.
When allowing to act complexe boron hydrides in the pre-sence of Lewis acids there are even obtained higher yields.
The complexe boron hydrides used in the reduction method are alkali metal boronates or alkaline earth metal boronates, preferably sodium boron hydride.
Lewis acids appropriate for the present invention are especially aluminium chloride, titanium tetrachloride and boron trifluoride and its adducts such as boron trifluoride etherate. When using the latter substance diborane may be formed in situ during the reaction for example with sodium boron hydride (cf. Fieser, Fieser: Reagent for Organic Syn-thesis, John Wiley and Sons, Inc.,New York, volume 1, page 199)-For attaining an especially high yield and especially pure final products, the Lewis acids are preferably firstly introduced with the compounds of the formula VIII and boron or the complexe boron hydride are added thereafter.
The Lewis acid is preferably used in an excess and the complexe boron hydride or the boron hydrides in at least j stoichiometrical quantity calculated on the number of amide groups to be reduced.
The reduction is performed in a solvent. Suitable sol-vents are ethers such as tetrahydrofurane or diethylene glycol ~ dimethyl ether (diglyme). The solvent in which the reduction is performed may be identical with that in which the boron hydride is optionally dissolved, but it may also be a diffe-rent one.
3 The reduction can be performed in a wide temperature range.
It may be carried out at low temperature, for example of about - 10C, at room temperature or at a slightly increased tempe-rature. The time of reduction depends on the reaction com-ponent used and on the chosen temperature.
A preferred method of carrying out the process of the in-vention consists in firstly introducing the benzoic acid derivatives o the formula VII into an inert solvent together ; - , . , . , . . ......................... . . -- - .

.

::

1~8~1gl with the Lewis acids and in adding a solu~ion of boron hydride or the complexe boron hydride, optionally of a suspension of the complexe boron hydride in the same or in a different sol-vent at 0C and stirring for a short period. The cornplexe boron hydride may also be directly added in a solid state. For acce-le~ating th^ ~c-ctio.. l~ ..ay a'so bc opGlatêd Gptiv--aliy a~ a higher temperature or when h~ving terminated the addition of the reducing agent, the reaction mixture may be heated for about 1 hour up to 50C.
Another method consists in firstly introducing the sub-stance to be reduced together with the complexe boron hydride and in adding the Lewis acid at a temperature from about -10C
to room temperature. A suitable complexe boron hydride is especially the sodium boron hydride. The course of the reaction may be observed by the thin-layer chromatography, by the fact that there appears an intensive blue fluorescence (in the range of 366 nm) of the compounds formed of the formula IX. Double bonds optionally in group A may be reduced simultaneously in the reduction according to the invention.
The final prouct may be isolated in various ways. In a preferred method the solution of the reaction product is liberated of possibly present reducing agent by adding water and small quantities of an acid and the benzoic acid esters obtained are precipitated subsequently by adding a nonsolvent.
When using diethyleneglycol dimethyl ether water is especially suitable as nonsolvent. The benzoic acid esters of the formula IX formed crystallize nearly quantitatively.
The 5-sulfamylbenzoic acids of the formula I (in which R
is H) according to the invention may be obtained~ alkaline hydro-3 lysis of the compounds of the formula IX, by heating the latter compounds for several hours in sodium hydroxide solution or potassium hydroxide solution on the vapor bath. Thereby the ; ester is saponified and the protective group B and moreover possibly present further protective groups are split off.
The 5-sulfamylbenzoic acids of the formula I (in which R
is ~) may also be directly obtained by partly concentrating the reaction mixture after having de~troyed the excess of reducing - : -: . " : -:: ' ' ' ' ' ' , , 108Zl91 agent, adding a base and heating for a certain period. As base there may be used, for exa~le, sodium hydroxide solu-tion. The 5-sulfamylbenzoic acids of the formula I may be directly isolated thereby in the form of their salts. The free acids are obtained by slightly acidifying.
It is also possible to introduce the protective group B into compounds of the formulae IV,V,VI or VIII, in which B means in this case 2 hydrogen atoms, in a later reaction step for obtaining compounds of the formula IX, in which R' may also be replaced by R.
; For esterifying the corresponding esters of the formula I, in which R means an alkyl radical, the acids are ester-ified in usual manner, for example in the above-mentioned ; manner.
The free carboxylic acids may be converted into their pharmaceutically compatible salts by reacting them with the corresponding bases such as alkali metal, alkaline earth metal or aluminium hydroxides or carbonates.
An important number of highly efficient pharmaceutical agents, especially diuretics and saluretics may be prepared according to the process of the invention, some of which -:
will be mentioned hereafter:

3-cyclopro ~ methylamino-4-(4'-chlorophenoxy)-5-sulfamyl-~5 benzoic acid, - -3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-ethylaminophenoxy)-5-sulfamyl-benzoic acid, ~ - 15 -Y~ .

- , : . - : . . .

.

.

1082~91 3-cyclopropylmethylamino-4-(4'-aminophenoxy)-5-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-methoxyphenoxy)-5-sulfamyl-benzoic acid, 3-cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamyl-ben~oic acid, 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamyl-benzoic acid, .

- 15(a) -~ .

:

- ~08'hl91 3-cyclopropylmethylamino-4 (2',4'-dimethylphenoxy)--5-sulfamyl-benzoicacid, 3-cyclopropylme-chylamino-4-(3',4'-dimethylphenoxy)-5-sulfamyl~
benzoicacid, 3-cyclopropylmethylamino-4-(3'-tri.fluorophenoxy)-5-sulfamyl-hen.zoi cacid ~
3-cyclopropylmethylamino-4-phenylthio-5-sulfamylbenzoicacid, 3-cyclobutylmethylamino-4-phenoxy-5-sulfamylbenzoicacid, 3-cyclobutylmethylamino-4-phenylthio-5-sulfamylbenzoicacid, 3-benzylam.ino-4-phenoxy-5-sulfamylbenzoicacid, 3-benzylamino-4-(4'-chlorophenoxy)-5-sulfonylbenzoicacid, 3-benzylamino-4-(4'-methylphenoxy)-5-sulfamylbenzoicacid, 3-benzylamino-4-phenylthio-5-sulfamylbenzoicacid, 3-phenylethylamino-4-phenoxy-5-sulfamylbenzoicacid, 3-phenylethylamino-4-(4'-chlorophenoxy)-5-sulfamylbenzoicacid, 3-phenylethylamino-4-(4'-methylphenoxy)-5-sulfamylbenzoicacid, 3-phenylethylamino-4-(4'-methoxyphenoxy)-5-sulfamylbenzoicacid, . .
3-Phenylethylamino-4-(4'-ethylaminophenoxy)-5-sulfamylbenzoic acid, 3-phenylethylamino-4-(4'-aminophenoxy)-5-sulfamylbenzoicacid, 3-phenylethylamino-4-(2',4'-dimethylphenoxy)-5-sulfamylbenzoic-acid, 3-phenylethylamino-4-phenylthio-5-sulfamylbenzoicacid, 3-furfurylamino-4-phenoxy-5-sulfamylbenzoicacid, 3-furfurylamino-4-phenylthio-5-sulfamylbenzoicacid, 3-thenylamino-4-phenoxy-5-sulfamylbenzoicacid, 3-thenylamino-4-(4'-methylphenoxy)-5-sulfamylbenzoicacid, 3-thenylamino-4-phenylthio-5-sulfamylbenzoicacid, : 3 The following examples illustrate the invention.
E X A M P L E 1:
. . . . .. .. . .. .. ..
3-n-Butylamino-4-phenoxy-5-sulfamylbenzoic acid a~ 4-Chloro-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid Thionyl chloride was added dropwise to a solution of ' . . :

.

- ~8~

58.9 g (0.25 mole) of 4-chloro-5-sulfamoylbenzoic acid in 183 g (2.5 moles) of dimethylformamide (DMF) at -10C. The solution was then allowed to heat to room temperature, stirred for 2 hours and poured on ice. The precipiate was filtered and washed ~ith water until it was neutral. 4-Chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid was obtained in a very high yield in the form of crystals having a melting point from 266 to 267C.
b) 3-Nitro-4-chloro-S-N,N-dime,hylaminomethyleneaminosul-_nylbenzoic acid 42 ml of fuming nitric acid were added dropwise to 60 ml of 20~ oleum while cooling with ice, thereafter 34.9g (0.12 mole) of 4-chloro-5-N,N-dimethylaminomethyleneamino-sulfonylbenzoic acid was slowly introduced. After stirring at 75C for 8 hours the solution was cooled to room tempe-rature, poured on ice and the precipitate was washed with water until it was neutral. 3-Nitro-4-chloro-5-N,N-di-methylaminomethyleneaminosulfonylbenzoic acid was obtained in the form of crystals having a melting point from 274 to 276C.
c) 3-Nltro-4-chloro-5-N,N-dimethylaminomethyleneaminosul-fonylbenzoic acid methyl ester 50.4 g (0.15 mole) of 3-nitro-4-chloro-5-N,N-dimethyl- -aminomethyleneaminosulfonylbenzoic acid were refluxed in a solution of 150 ml of thionyl chloride containing 5 drops of DMF, for 1 hour. After having drawn off the excess of thionyl chloride in vacuo the solid acid chloride was suspended in 200 ml of methanol. The suspension was re-.

. :
.

."' ~ - ' :: - .' ' ' ' '.' ~ :

` ~0i 32~91 fluxed for hal an hour, cooled, filtered and washed with cold metnanol.
3--Nitro-4-chloro-5-N,N~dimethylaminomethyleneaminosul-,were obtained fonylbenzoic acid methyl ester crystal~ having a melting point from ~ b8 to i69nO. A second crystal modification ~ :
having a melting point of 155C may also occur.
d) 3-Nitro-4-phenoxy-5-N,N--dimethylaminomethyleneaminosul-fonylbenzoic acid methyl ester A solution of 105 g (0.3 mole) of 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 47.5 g (0.36 mole) of potassium phenolate in 600 ml of DMF were refluxed for two hour hours. After cooling and filtering off the potassium chloride the solu-tion was given onto ice/water and stirred for 1 hour. The precipitate was filtered, washed with water and dried.
, After having dissolved the crude product in 900 ml of ~ acetone the solution was cleared up with carbon, concen-: i trated to a volume of 500 ml and diluted with 1 l of methanol. The precipitate was filtered at 10C after having been stirred for 1 hour and washed with cold methanol.
3-Nitro-4-phenoxy-5-N,N-dimethylaminomethyleneamino-` sulfonylbenzoic acid methyl ester was obtained in the form of crystals having a melting point of from 191 to 193C.
e) 3-Amino-4-phenoxy-5-N,N-dimethylaminomethyleneamino-sul~onylbenzoic acid methyl ester 61 g (0.15 mole) of 3-nitro-4-phenoxy-5-N,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester were hydrogenated in dimethylformamide with Raney Nickel at , .
, - 18 -:-' -,.
. , ~ . , .

, ; ~

- 1~82~1 at for 8 hour~ room temperature and under atmospheric pres-sure. After having filtered off the catalyst the solution of DMF was given onto ice.
3-Amino-4-phenoxy-5-N,N-dimethylaminomethylenesulfony]-benzoic acid methyl ester was obtained in the form of crystals having a melting point from 255 to 256C
f) 3-n-Butyrylamino-4-phenoxy-5-N,N-dimethylaminomethy]ene-aminosulfonylbenzoic acid methyl ester 10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester were heated to the boil together with 2.6 ml of pyridine in 100 ml of ab-solute dioxane. A solution of 5.3 g of butyric acid chloride -- in 50 ml of absolute acetone was slowly added thereto drop-wise. The reaction was terminated after 1.5 to 2 hours.
The solution was concentrated, the remaining oil was ab-sorbed by a small quantity of methanol and the mixture was introduced dropwise into cold ice water while vigo-rously stirring. The 3-n-Butyrylamino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylhenzoic acid methyl ester precipitated and was filtered with suction.
Recrystallization from CH30H/H20, melting point from 177 to 178C
g) 3-n-Butylamino-4-phenoxy-5-N,N-dimethylaminomethylene-.. . . . . . . . . . . .
aminosulfonylbenzoic acid methyl ester 10 g of the butyryl compound prepared sub f) were sus-pended in 100 ml of absolute diglyme, 6 ml of BF3 etherate were added and a solution of 1.4 g of NaBH4 in 50 ml of absolute diglyme was added dropwise. The reaction mixture , -.- , .. , - ' ~ :
.. . : . . .. :
' - - : -: :- .
': . -- ' '- ' ' ~ . , ,', ' ~ . . .

,, :
,: ~ ' ' : :
., , : -: : -' :

. ' ~ Z~9iL
was stirred for about 1 hour and the excess OL reducing agent was destroyed by adding a small quantity of water (foaming!) Then the reaction product was filtered and the product was precipitated by adding 200 ml of water at low iemperatures.
The 3-Butylamino-4 phenoxy-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester formed~impurified by about5~ of 3-n-butylamino-4-phenoxy-5-sulfamylbenzoic acid methyl ester was recrystallized from CH30H.
Melting point from 111 to 112C.

h) 3-n-Butyl-4-phenoxy-5-sulfamylbenzoic acid The crude product obtained sub g) was refluxed with ~n NaOH until the solution was clear. Then the product ob-tained was allowed to cool and the 3-n-butylamino-4-phenoxy-5-sulfamylber.zoic ~cid precipitated with 2n HCl.
Recrystallization from ethanol/water; melting point from ` 234 to 235C.
E X A M P L E 2:

a) 3-(3'-Chloropropionylamino)-4-phenoxy-5-N,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester 10 g of 3-amino-4-phenoxy-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester were heated to the oil with 3.6 ml of pyridine in 100 ml of absolute dioxane.
A solution of 7 g of ~ -chloropropionic acid chloride in 2~ 50 ml of absolute acetone was added dropwise. After 4 hours the solution was concentrated, absorbed by a small quantity of CH30H and introduced dropwise while stirring into ice water. The 3-(3'-Chloropropionylamino)-4-phenoxy-: ~

., ~.

, . . .

- ~08~

5-N,N~dinlethylaminomethyleneaminosulfonylbenzoic acid methyl ester precipitated in this way was recrystallized from CH3OH/H2O; melting point 190C.
b) 3-(3'-Chloropropylamino)-4-phenoxy-5-N,N-dimethylamino-methyleneaminosulfon5~1benzoic acid methyl ester The process was performed as described in Example 1g).
The product was recrystallized from CH30H. Melting point from 150 to 151C.

E ~ A M P L E 3.

3-Cyclopropylmethylamino-4-phenoxy-5-sulfamylben-zol- -- acid a) 3-Cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester 9.2 ml (0.1 mole) of cyclopropanecarboxylic acid chloride in 100 ml of absolute acetone were added dropwise to a boiling solution of 19 g (0.05 mole) of 3-amino-4-phenoxy-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 100 ml absolute dioxane and 5 ml of pyridine. After having heated for 2 and a half hours while refluxing the reaction product was cooled, filtered with carbon and the solution was concentrated at the rotation -:
evaporator. The solid residue was carefully washed with acetone and dried thereafter. Melting point from 220 to - 222C.
b) 3-Cyclopropylmethylamino-4-phenoxy-5-N,N-dimethylamino-méthyleneaminosulfonylbenzoic acid methyl ester 23 g (0.052 mole) of 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-dimethylamonomethyleneaminosulfonylbenzoic acid :

.-, ,, , ,, - :, ~.. . . : . - ..
- - .. . -, . . . .
. . . : - . -: . :: .: ... .
. - :. . - . . :,: -:
.

methyl ester were suspended in a solution of 250 ml of ab-solute diglyme and 15 ml of BF3 e-therate. A solution of 3.5 g of NaBH4 in 200 ml of absolute diglyme was added dropwise at room temperature while rapidly stirring, the mixture obtained was stirred for 3 hours at room tempe-rature, the excess of sodium boron hydride was decomposed with 20 ml of water and the solution was poured on ice.
After standing over night at low temperatures the solu-tion was filtered by suction, dried and recrystallized from glacial acetic acid. Crystals having a melting point from 150 to 152C.
c) 3-Cyclopropylmethylamino-4-phenoxy-5-sulfamylbenzoic - acid The product obtained sub b) was refluxed with 2n NaOH
until the solution was clear. Then it was allowed to cool and 3-cyclopropylmethylamino-4-phenoxy-5-sulfamylbenzoic acid was precipitated with 2n HCl.
', Recrystallization from glacial acetic acid. Melting point from 234C.
E X A M P L E 4:
3-Cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamyl-benzoic acid a) 3-Nitro-~-(4'-methylphenoxy)-5-N,N-dimethylamino-methyleneaminosuifonylbenzoic acid methyl ester .. ... . _ .. . _ . _ _ A solution of 105 g (0.3 mole) of 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 53 g (0.36 mole) of potassium 4-methylpheno],ate in 600 ml of DMF was refluxed for 3 hours. After cooling - ... .', , ' ' ..... ~ - ~ ' , Z3,91 and filtering off the potassium chloride the solution was poured on ice/water and stirred for 1 hour. The pre-cipitate was filtered, washed with water and dried.
After having dissolved the crude product in 900 ml of acetone, the solution obtained was cleared with carbon, concentrated to a volume of 500 ml and diluted with 1 l of methanol. The precipitate was filtered after having been stirred for 1 hour at 10C and washed with cold methanol. 3-Nitro-4-(4-methylphenoxy)-5-N,N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester was ob-tained in the form of crystals having a melting point from 196 to 198C.
-- b) 3-amino-4(4'-methylphenoxy)-5-N!N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester A solution of 80 g of 3-nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 400 ml of DMF was hydrogenated for 8 hours at 40C and,under 50 atmospheres with about 10 g of Raney nickel. After filtration of the catalyst the DMF solution was poured on ice. The precipitate was filtered by suction, dried and recrystallized from methanol. 3-Amino-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester was obtained, in the form of ~ ~ .
crystals having a melting point of from 168 to 169C.
c) 3-Cyclopropanecarboxamido-4-(4'-methylphenoxy)-5-N,N-.
` -dimethylaminomethyienéaminosuifonylbenzoic acid methyl .. ..
ester -To a boiling solution of 49 g of 3-amino-4-(4'-methyl-~ . ' ' ,:

- .. . . . ...

.

:' ':
. , '' : ~ , :

phenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 250 ml of absolute dioxane and 12.5 ml of pyridine a solution of 26.1 g of cyclopropanecarboxylic acid chloride in 250 ml of absolute dioxane was added drop-wise. The solution was concentrated and recrystallizedfrom acetone or methanol. 3-Cyclopropanecarboxamido-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester was obtained in the form of crystals having a melting point from 201 to 203C.
d) 3-Cyclopropylmethylamino-4-(4'-methylphenoxy)-5-N,N-; dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 65 g of 3-cyclopropanecarboxamino-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester were suspended in 600 ml of absolute diglyme 40 ml of BF3 etherate were added and a solution of 9.5 g of NaBH4 in 500 ml of absolute diglyme was added dropwise at a temp-erature from 0 to 5C. The reaction solution was stirred for 4 hours at 0C and for 2 hours at room temperature, the 20 excess of reducing agent was destroyed by the addition of water and the product obtained was precipitated by further ; adding 3 liters of ice water. The 3-Cyclopropylmethylamino-

4-(4'-methylphenoxy)-5-N,N-dimethylaminomethyleneamino-sulfonylbenzoic methyl ester formed impurified by about 5%
25 of 3-cyclopropylmethylamino-4-(4'-methylphenoxy)-5-sulfamoyl-benzoic acid methyl ester was recrystallized from methanol.
Melting point from 158 to 159C.
e) 3-Cyclopropylmethylamino-4-(4-methylphenoxY)-5-sulfa-. ~ ., : . : : . .

~08Zl~l :
moylbenzoic acidThe product obtained sub d) was refluxed with 2n NaOH
until a clear solution was obtained. The product obtained was allowed cool and 3-cyclopropylmethylamino-4-(4-methyl-phenoxy)-5-sulfamoylbenzoic acid was precipitated with 2n of HCl. Recrystallization from glacial acetic acid. Melting point from 230 to 232C.
E X A M P L E 5:
3-Cyclopropylmethylamino-4-(4'-fluorophenoxy)-5-sulfa-moylbenzoic acid a) 3-Nitro-4-(4'-fluorophenoxy)-5-N,N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester A solution of 210 g (0.6 mole) of 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl 15 ester and 120 g of sodium-4-fluorophenolate in 800 ml of absolutè DMF was stirred for 3 to 4 hours at a temperature from 120 to 130C. The cold solution was slowly added dropwise while vigorously stirring in 4 to 5 liters of ice ; water. The precipitated product was filtered by suction, carefully washed with water, digested with acetone at ele-vated temperatures and recrystallized from glycol mono-methyl ether. Melting point from 224 to 225C.
b) 3-Amino-4-(4'-fluorophenoxy)-5-N,N-dimethylamino-` ' methyleneaminosulfonylbenzoic acid methyl ester 140 g of the nitro compound (18a) were dissolved in Dl~ and hydrogenated with Raney nickel for 8 hours at 50C, - under a pressure of 50 atmospheres. The Raney nickel was separated by suction-filtering and the solution obtained , '. ' .~
', , '' . ' : - : , -. . ~ ' ' - ~ , ' : -, .:, ~ -1~8~Z1'~1 was introduced dr~pwise in to ice water. The precipitated substance was separated and washed with CH30H and with ether subsequently. The practically pure subtance could be recrystallized from glycol monomethyl ether. White crystals of a melting point from 234 to 236C.
c) 3-Cyclopropanecarboxamido-4-(4'-fluorophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester ~ 9.2 ml (0.1 mole) of cyclopropanecarboxylic acid in 100 ml of absolute acetone were added dropwise to a boiling solu-tion of 20 g (0.05 mole) of 3-amino-4-(4'-fluorophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 100 ml of absolute dioxane. After having refluxed for half an hour the reaction mixture was cooled to 0C.
3-Cyclopropanecarboxamido-4-(4'-fluorophenoxy)-5-N,N-di-methylaminomethyleneaminosulfonylbenzoic acid methyl ester ~ precipiated in the form of crystals;it was filtered by - suction, firstly with a small quantity of cold acetone,thereafter with cold water, washed and dried. Melting ~ point from 201 to 202C.
d) 3-Cyclopropylmethylamino-4-(4~-fluorophenoxy)-5-N~N-dimethylaminomet_yleneaminosulfonylbenzoic acid methyl ester The example was carried out as 3b with recrystallization from methanol. Melting polnt from 165 to 166C.
e) 3-Cyclopropylmethylamino-4-(4~-fluorophenoxy)-5-sulfa moylbenzoic acid -The product obtained sub d) was refluxed with 2n NaOH
-,`

- ~ : -: - . - - - ~ . .
:' - .~ ~:; '' ' . ' ' 1C~8~
until a clear solution was obtained. The ~olution formed was allowed to cool, cleare~ with carbon and 3-cyclopropyl-methylamino-4-(4'-fluorophenoxy)-5-sulfamoylbenzoic acid was precipitated with 2n HCl.
Recrystallization from methanol. Melting point from 228 to 229C.
E X A M P L E 6:

moylbenzoic acid a) 3-Nitro-4-(4'-chlorophenoxy)-5-N,N-dimethylam _omethylene aminosulfonylbenzoic acid methyl ester A solution of 164 g of 3-nitro-4-chloro-5-N,N-dimethyl-aminomethylenesulfonylbenzoic acid methyl ester and 117 g of potassium-p-chlorophenolate in 800 ml of freshly distil-led DMF was refluxed for 2 to 3 hours. The reaction mixture was introduced dropwise while vigorously stirring into the 4-fold quantity of ice/H2O. The product precipitating there--;
by was separated and boiled out with CH30H/acetone. Melting point from 227 to 228C.
b~ 3-Amino-4-(4'-chlorophenoxy)-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester 130 g of the nitro compound t20a) were hydrogenated in 1 liter of DMF with Raney nickel for 9 hours under a pres-sure of 50 atmospheres, at a temperature of 50C. The so-lution was concentrated after Raney nickel had been filtered by suction and the residue was boiled out with CH30H.
White substance having a melting point from 207 to 208C.
c) 3-Cyclopropanecarboxamido-4-(4'-chlorophenoxy)-5-N,N--- : ~ : -.
.: . , . : . : ,, . ~
' . .` '' ~ : - , : . .

~08~
-dimet_ylamLnomethyleneaminosulfonylbenzoic acicl methyl ester The reaction was performed in an analogous manner to Example 5c). Melting point from 195 to 196C.
d) 3-Cyclopropylmethylamino-4-(4'-chlorophenoxy)-5-N,N-dimethy]aminomethyleneaminosulfonylbenzoic acid m~ yl-ester The reaction was carried out in an analogous manner to Example 3b), with recrystallization from methanol. Melting point from 186 to 187C.
e) 3-Cyclopropylmethylamino-4-(4'-chlorophenoxy)-5-sul~a-moylbenzoic acid The Example was carried out in an analogous manner to Example 5e), with recrystallization from methanol. Melting point from 247 to 248C.
E X A M P L E 7:
3-Cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)_-5-sulfa-moylbenzoic acid ; a) 3-Nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylamono-methyleneaminosulfonylbenzoic acid methyl ester 87.5 g (0.25 mole) of 3-nitro-4-chloro-5-N,N-dimethyl-- aminomethyleneaminosulfonylbenzoic acid methyl ester were dissolved in S00 ml of anhydrous dimethylformamide and 77.5 g (0.25 mole) of sodium-4-benzyloxyphenolate were added. The reaction mixture was refluxed for 3 to 4 hours while stir-ring vigorously. After cGoling, the turbid solution was introduced dropwise into 3 liters of ice/water. The pre-cipitating yellow product was filtered by suctionrcarefully .:
, .. . . .
.

: ,, . : .

washed with water and recrystallized from methanol. 94 g of 3~nitro-4-(4'--benzyloxyphenoxy)-5-N,N-dimethylamino-methylaminosulfonylbenzoic acid methyl ester were obtained as yellow crystals having a melting point of 132C.
b) 3-Amino-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylamino-methyleneaminosulfonylbenzoic acid methyl ester 94 g of 3-nitro-4-(4'-benzyloxyphenyloxy)-5-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl esters were dissolved in 1.5 liters of dimethylformamide and hydroge-nated with Raney nickel at room temperature and under atmospheric pressure for a period from 6 to 7 hours. The product obtained was filtered and the clear solution thus formed was introduced dropwise into ice/water. The pre-cipitated 3-amino-4-(4'-benzyloxyphenoxy)-5-N,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester was recrystallized from methanol. About 70 g were obtained in the form of white crystals having a melting point of 170C.
c) Cyclopropanecarboxamido-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester

- 5.5 ml of cyclopropanecarboxylic acid chloride in 50 mlof absolute acetone were added dropwise to a boiling solu-tion of 14.5 g (0.03 mole) of 3-amino-4-(4'-benzyloxy-phenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic-acid methyl ester in 150 ml of absolute dioxane and 3 ml of pyridine. After refluxing for 6 hours the mixture ob-tained was cooled to 0C. 3-Cyclopropanecarboxamido-4-(4'-108'~
benzyloxyphenoxy)-5-M,N-dimethylaminomothvleneaminosulfonyL-benzoic acid methyl ester precipitated, which was filtered by suction and washed with acetone and ether. Melting point from 210 to 211C.
d) 3-Cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)-5-sulfamoylbenzoic acid 5.6 g of the product obtained sub c) were suspended in a solution of 50 ml of absolute diglyme and 4 ml of ~F3 etherate. A solution of 1 g of NaBH4 in 50 ml of absolute diglyme was added dropwise while rapidly stirring. The reaction mixture was stirred for 2 hours at a temperature of 20C, cooled and given on ice. The crude product was filtered and refluxed with 2n NaOH for 1 hour. Thereafter - is was cooled, and precipitated with carbon and 3-cyclo-propylmethylamino-4-(4'-benzylphenoxy)-5-sulfamoylbenzoic acid with 2n HCl. Recrystallization from glacial acetic acid. Melting point from 235 to 236 C.
E X A M P L E 8:
3- Cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamoyl-benzoic acid 2 g of 3-cyclopropylmethylamino-4-(4'-benzyloxyphenoxy)-5-sulfamoylbenzoic acid were suspended in 50 ml of H20, dissolved with 5 ml of 2n NaOH and hydrogenated with ~aney nickel at 50C, under a hydrogen (H2)pressure of 50 atmos-pheres for 4 hours. After having filtered off the catalyst 3-cyclopropylmethylamino-4-(4'-hydroxyphenoxy)-5-sulfamoyl-benzoic acid was precipitated with 2n HCl. The precipitate was filtered off with suction, carefully washed with water -. . : - , - :, : .
: ...... -, , - ~ , ~
~ . - .. ... . . . .

108Z~
and dried. Melting point from 265 to 266C.
E X A M P L E 9:
3-Cyclopropylmethylamin~-4-~4'-nitrophenoxy)-5-sulfa-moylbenzoic acid a) 3-Cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosul~onylbenzoic acid methy ester 5 g of 3-cyclopropanecarboxamido-4-phenoxy-5-N,N-di-methylaminomethyleneaminosulfonylbenzoic acid methyl ester 1~ were given portionswise into 30 ml of fuming nitric acid at a temperature from -10 to -20C. The mixture was stir-red for 10 minutes and the solution was poured on ice. 3-Cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethyl--- aminomethyleneaminosulfonylbenzoic acid methyl ester pre-cipitated as crystals; it was filtered by suction and thoroughly washed with water. Melting point from 215 to 216C.
b) 3-Cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 22 g (0.045 mole) of 3-cyclopropanecarboxamido-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester were suspended in a solution of ; - 150 ml of absolute diglyme and 12.8 ml of BF3 etherate and heated to a temperature from 55 to 50C. A solution of 3 g of NaBH4 in 100 ml of absolute diglyme was added at said temperature while rapidly stirring. After having stirred for 1 hour at 50C the solution was cooled to 0C, the ex-.' ~:

.

- . . . :, '. ' -, : ., . . .~... - . .- :
, , . - : . - . . - :

. . :. , . . - - . : . - .

.
.. . . .

~8~ ~91 cess of NaBH~ was decomposed with a small quantiiy of water ~nA the product remaining was placed on ice. 3.Cyclopropyl-methylamino-4-~4'-nitrophenoxy)-5-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester crystalliæed, it was filtered with suction washed with water, dried and boiled out with methanol. Melting point from 233 to 235C.
.
c3 3-Cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoyl-benzoic acid 17 g of 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-N,N-dimethylaminomethyleneaminosl~lfonylbenzoic acid methyl ester were suspended in 400 ml of 1 n NaOH and stirred for 3 hours at 95C. The solution was allowed to cool and 3-cyclopropylmethylamino-4-(4'-nitrophenoxy)-5-sulfamoyl-benzoic acid was precipitated with concentrated HCl (pl~
Recrystallization from methanol after concentration of the solution. Melting point of 230C (decomposition).
E X A MP__E 10:
' .
benzoic acid 3 g (0.074 mole) of 3-cyclopropylmethylamino-4-(4'-nitro-- phenoxy)-5-sulfamoylbenzoic acid were hydrogenated in 50 ml of methanol with 10% of Pd/C at 20C under a hydrogen pres-sure of 10 atmospheres for 8 hours. After having filtered off the catalyst the methanolic solution was concentrated and 3-cyclopropylmethylamino-4-(4'-aminophenoxy)-5-sulfa-moylbenzoic acid was precipitated with ether. Melting point t7~C (decomposition).
E X A MP L E i-1-- ~ .: ',:
- : - . , , , , ,'~ ' ' .

1082~91 ~= methylamino~ phenylthio-5~sulfamoylben~oic .
acid a) 3-Nitro-4-phenylthio-5-N,N-dimethylaminomethyleneam no-sulfonylbenzoic acid methyl ester A solution of 210 g ~0.6 mole) of 3-nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester and 108 g (0.66 mole) of potassium thiophenolate in 800 ml of DMF was refluxed for 2.5 hours. The solution was poured on ice, the precipitate was filtered with suction, washed with water, dried and recrystallized from acetone.
3-Nitro-4-phenylthio-5-N,N-dimethylaminomethyleneamino-sulfonylbenzoic acid methyl ester was obtained as crystals having a melting point from 205 to 207C.
b) 3-Amino-4-phenylthio-5-N,N-dimethylaminomethyleneamino-sulfonylbenzoic acid methyl ester 110 g (0.26 mole) of 3-nitro-4-phenylthio-5-N,N-di-methylaminomethyleneaminosulfonylbenzoic acid methyl ester were hydrogenated for 8 hours in 400 ml of DMF with Raney nickel at 50C and under a pressure of 100 atmospheres.
After filtration of the catalyst the DMF solution was poured on ice. The precipitate was filtered with suction, washed with water~dried and recrystallized from acetone. 3-Amino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonylben-zoic acid methyl ester was obtained as crystals having a meltlng point from 214 to 215C.
c) 3 Cyclopropanecarboxamido-4-phenylthio-5-N~N-dimeth .. .. .. . . .. .. .. .. .. ..
aminomethyleneaminosulfonylbenzoic acid methyl ester To a boiling solution of 22 g ~0.056 mole) of 3-amino-.: ' .: .

, ~

. ' : ' ~, '. ' . . ' : ', , ", ,.. ".. ; . . , ~ .
; . . . . - . . :

~08~191 4-phenylthio-~-N.N-dimethylaminomethyleneaminosulfonylben-zoic acid methyl ester in 125 ml of absolute dioxane and 5.8 ml (0.11 mole) of pyridine there were added dropwise

6.1 g (0.067 mole) of cyclopropanecarboxylic acid chloride in 125 ml of abso]ute acetone. After having refluxed for 2 hours, the mixture obtained was cooled, filtered with carbon and concentrated at the rotation evaporator. The residue was suspended in acetone and filtered. The crude product was recrystallized from DMF/methanol.
3-Cyclopropanecarboxamido-4-phenylthio-5-N,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester was obtained, the crystals of which had a melting point from 245 to 247C
- d) 3-Cyclopropylmethylamino-4-phenylthio-5-sulfamoylbenæoic acid 14.4 g (0.031 mole) of 3-cyclopropanecarboxamido-4-phenyl-thio-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester were suspended in a solution of 55 ml of ab-solute diglyme and 8.1 ml of BF3 etherate. A solution of 2.36 g ~0.062 mole) of NaBH4 in 55 ml of absolute diglyme was added dropwise at room temperature while rapidly stir-ring, the solution obtained was stirred for 5 hours at a ~ temperature from 20 to 30 C and poured on ice. The crude - product was filtered and recrystallized from methanol.
8.8 g of the reduced compound were refluxed with 70 ml of 2n NaOH until a clear solution was formed. Thereafter the solution was cooled and 3-cyclopropylmethylamino-4-phenyl-- thio-5-sulfamoylbenzoic acid was precipitated with 2n HC1.

! ' 34 -:

- i : ~ , , ~
.. .
.:: , . .: - -:

10~

By recrystallization from methanol/water (3:1) there were obtained crystals having a melting point from 214 to 215C.
.
E X A ~IP I, E 12:
3-Cyclobutylamino-4-phenylthio-5-sulfamoylbenzoic acid a) 3-Cyclobutanecarboxam~ L~ ,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester To a boiling solution of 23.6 g (0.06 mole) of 3-amino-4-phenylthio-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester in 150 ml of absolute dioxane and 7.5ml of pyridine there were added dropwise 12.7 ml (0.12 mole) of cyclobutanecarboxylic acid chloride in 150 - ml of absolute acetone. After refluxing for 1 hour, the reaction mixture was concentrated at the ~otation eva-porator and the residue was suspended in 500 ml of ace-tone, filtered and washed with acetone.
3-Cyclobutanecarboxamido-4-phenylthio-5-N,N-dimethyl-aminomethyleneaminosulfonylbenzoic acid was obtained. Mel-.J' ting point from 231 to 232C.
b) 3-Cyclobutylmethylamino-4-ph_nylthio-5-N,N-dimethylamino-.
methyleneaminosulfonylbenzoic acid methyl ester i 28 g (0.062 mole) of 3-cyclobutanecarboxamido-4-phenyl-thio-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester were suspended in a solution of 280 ml of absolute diglyme and 16.5 ml of BF3 etherate. A solution of 5.5 g of NaBH4 in 250 ml of diglyme was added dropwise while rapidly stirring, the reaction mixture was stirred for half an hour at a temperature from 40 to 50C, cooled, the excess of NaBH4 was decomposed with a small quantity , ....

.
.- . - . . ... . . .
, .
. , ~ , ,, , . : .

3Z~9l of wate~ and the solution was poured on ice. After having allo~ed the solution to stand over night the precipitate was filtered with suction, dried and recrystallized from methanol/water.

3-cyciobutyirnethylamino-4-phenylthio-5-N~N-dimethyl-aminomethyleneaminosulfonylbenzoic acid methyl ester was obtained, the crystals of which had a melting point from 193 to 195C.
c) 3-Cyclobutylamino-4-phenylthio-5-sulfamoylbenzoic acid 5 g of 3-cyclobuLylmethylamino-4-phenylthio-5-N,N-di-methylaminomethyleneaminosulfonylbenzoic acid methyl ester were suspended in 100 ml of 1n NaOH and hydrolyzed for 1.5 hours at a temperature from 95 to 100C. Then the hydro-lysate was cleared up with active carbon, cooled and slightly acidified with concentrated HCl (pH of 2).
3-Cyclobutylmethylamino-4-phenylthio-5-sulfamoylbenzoic acid precipitated, was washed with water, dried and re-crystallized from glacial acetlc acid.

Crystals having a melting point from 227 to 228C.
E X A M P L E 13:
3-Cyclopropylamino-4-N-methylpiperazino-5-sulfam benzoic acid (salt of HCl) :
a) 3-Nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester 34.g g (0.1 mole) of 3-nitro-4-chloro-5-N,N-dimethyl~
aminomethyleneaminosulfonylbenzoic acid methyl ester, 11 g = 12.22 ml (0.11 mole) of N-methylpiperazine, 11,1 g= 15.2 ml (0.11 mole) of triethylamine in 150 ml of DMF were heated . , - , - : . :

. . . .

- . . , . :
-: ~ . - , , : ,', - .' . . : :
,, . . , ~ - : : . : .
., , . : -- ~: :

~0~2191 for 2.5 hours at a temperature of 85C. After cooling, the product obtained was poured in about 1 liter of ice water, the precipitate was filtered with suction,washed with water, dried and recrystallized from acetic acid ester. 3-Nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosul-fonylbenzoic acid methyl-ester was obtained, the crystals ; of which had a melting point from 181 to 182C.
b) 3-Amino-4=methylplperazino-5-N,N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester 82.6 g (0.2 mole) of 3-nitro-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester were hydrogenated in 750 ml of DMF with Raney nickel at a temperature of 50C under a pressure of 100 atmos-pheres for 12 hours. After having filtered off the catalyst the DMF solution was given on ice.
After recrystallization from methanol 3-amino-4-N-methylpiperazino-5-N~N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester was obtained as crystals having a melting point from 208 to 209C.
c) 3-Cyclopropan~carboxamido-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester .
The example was carried out as Example 3a) wiLh re-crystallization from water. Melting point from 155 to 157C.

d) 3-Cyclopropylmethylamino-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester 16 g (0.035 mole) of 3-cyclopropanecarboxamido-4-N-., .: ~ ~ . . .

': ~' -' ' ~', ' :
~ . ' methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid methyl ester were suspended in a solution of 100 ml of absolute diglyme and 18.5 ml of BF3 etherate. A
solution of 2.7 g of NaBH4 in 100 ml of absolute diglyme was added dropwise at room temperature while rapidly stir-ring, the mixture obtained was stirred for 3 hours at 55C, cooled, the excess of NaBH4 was decomposed with a small quantity of water and the solution was poured on ice. The crude product was filtered and recrystallized from methanol.
3-Cyclopropylmethylamino--4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester was obtained, the crystals of which had a melting point of 194C.
e) 3-Cyclopropylmethylamino-4-N-methylpiperazino-5-sulfa-moylbenzoic acid (salt of HCl) 5 g of 3-cyclopropylmethylamino-4-N-methylpiperazino-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester were refluxed for 2 hours in 40 ml of 2n NaOH.
The product obtained was allowed to cool, cleared up with 20 carbon and 3-cyclopropylmethylamino-4-N-methylpiperazino-5-sulfamoylbenzoic acid was precipitated with concentrated hydrochloric acid (pH of 3). The mother liquor was de-canted and the residue was separated by stirring with ace-tone. Melting point 280C (decomposition).
25 E X A M P L E 14:
.
3-Nitro-4-chloro-N,N-dimethylaminomethyleneaminosulfonyl-benzoic acid 42 ml of fuming nitric acid was added dropwise to 60 ml of - 20~ oleum while cooling with ice. The solution was . . - - ~ -:

. . . - : - , , : ~ .
.

, : . . -- -.. . . .

1~8,5~9~

heated to 90C and 34.9 g (0.12 mole) of 4-chloro-5-N,N~
dimethylaminomethyleneaminosulfonylbenzoic acid were added slowly. In this process the temperature raise to 100C.
After having stirred for 3 hours at 90C, the product ob-tained was cooled to room temperature, poured on ice, and the precipitate was washed until it was neutral. 3~Nitro-4-chloro-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid was obtained in the form of crystals having a mel-ting point from 274 to 276C.

_ 39 _ . - , .: , ~

; '- '' ~ ' ' ~ :
.

Claims (7)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a sulfamylbenzoic acid of the formula I
(I) wherein A represents lower alkyl, lower halogenated alkyl and lower cycloalkyl, X represents phenoxy which may be substituted by lower alkyl, lower alkoxy, halogen, nitro and amino, phenyl-thio and N-methylpiperazino, and R represents hydrogen or an alkyl or cyloalkyl radical having up to 6 carbon atoms, in which (a) a derivative of sulfamoylbenzoic acid of the formula III

(III) wherein Y represents a halogen atom, R is as defined above and B represents a protective group of the formula wherein R4, R5 and R6 represent identical or different alkyl groups of low molecular weight, R may also represent hydrogen and/or two of the substituents R4, R5 or R6 may be connected with one another cyclically, is nitrated, (b) the compound obtained of the formula IV

(IV) is esterified if R represents hydrogen; and the compound obtained of the formula IV wherein B and Y are as defined above and R represents an alkyl or cycloalkyl radical is reacted with a compound of the formula XH wherein X is as defined above, (c) the compound obtained of the formula V

(V) wherein R' represents an alkyl or cycloalkyl radical having up to 6 carbon atoms and B and X are as defined above is reduced, (d) the compound obtained of the formula VI

(VI) wherein B, X and R' are as defined above, is reacted with a compound of the formula VII

(VII) wherein the radical A is as defined above and L represents a leaving group or the radical OR7 of an activated ester or an anhydride, R7 may also represent , (e) the compound obtained of the formula VIII
(VIII) wherein the radicals A, B, R' and X are as defined above, is reduced by boron hydride or by a complex boron hydride in the presence of a Lewis acid and (f) the compound obtained of the formula IX

(IX) wherein A, B, X and R' are as defined above, is hydro-lyzed to obtain a compound of the formula I wherein R
represents hydrogen; or the compound obtained of formula IX wherein A, B, X and R' are as defined above, is hydrolyzed and the acid obtained is esterified to obtain a compound of formula I, wherein R represents an alkyl or cycloalkyl radical having up to six carbon atoms.

2. A process as claimed in claim 1 in which (a) is carried out at a temperature of from 60 to 80°C using a mixture of oleum and fuming nitric acid.

3. A process as claimed in claim 1 in which in (b) the compound of the formula IV wherein R represents alkyl is reacted with a compound of the formula XH under anhydrous conditions in the presence of a solvent.

4. A process as claimed in claim 1, claim 2 or claim 3 in which in (c) the reduction is carried out by catalytic hydrogenation in the presence of a solvent.

5. A process as claimed in claim 1, claim 2 or claim 3 in which in (d) L represents halogen, trialkyl-ammonium or pyridinium.

6. A process as claimed in claim 1, claim 2 or claim 3 in which in (e) the reduction is carried out in a solvent using boron hydride in the presence of a Lewis acid.

7, A process as claimed in claim 1, claim 2 or claim 3 in which in (e) the reduction is carried out in a solvent in the presence of an alkali metal or an alkaline earth metal boronate in the presence of a Lewis acid.