CA1051026A - Process for the preparation of sulfonyl ureas - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
An arylene-bis-sulfonyl urea of the formula:
[R'-SO2-N-CO-NH-Ar-NH-CO-N-SO2-R']2- 2 Me+

wherein Ar is arylene, R' is amino, an aliphatic residue having 1 to 20 carbon atoms, a cycloaliphatic residue having 4 to 10 carbon atoms, an aromatic residue, an alkyl-aromatic residue, or a heterocyclic residue, and Me+ is a sodium or potassium ion, is prepared by reacting a dicarboxylic acid-N,N'-dichloramide of the formula:

CL-NH-CO-Ar-CO-NH-Cl with a sulfonic acid amide of the formula:
R'-SO2-NH2 in a mixture of dimethylformamide and water, in the presence of excess al-kali hydroxide, and at a temperature between 10° and 50°.

Description

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The present invention relates to a process for the preparation of alkali salts or arylene-bis-sulfonyl ureas and their conversion to the cor-rcsponding free sulfonyl ureas.
A number of syntheses for sulfonyl ureas are known, namely the reaction of sulfonyl-isocyanates ~Yith amines, reaction of sulfonic acid amides with cyanic acid, urea or substituted ureas, with nitrourea, urethanes~
carbamoylchlorides, with isocyanic or isothiocyanic acid esters, with acid azides and with acid amidehalides, furthermore introduction of water~ hydro-gen sulfide, alcohols or amines into sulfonylcyanamide, hydrolysis of sul~
fonyl-pseudo-ureas, the reaction of sulfonyl-urethanes with amines and the desulfuri~ing of sulfonylthiourethanes. These well-known processes have been outlined in detail by F. Kur~er in Chemical Reviews 50 ~1950) pp. 1 - 46.
Bis-sulfonyl ureas, whose urea groups are bonded by an aliphatic or cycloaliphatic residue, can be obtained according to US patent 2 962 530 by reaction of a sulfonylisocyanate, a sulfonyl-carbamic acid chloride~
sulfonyl-carbamic acid ester, sulfonyl urea~ sulfonyl acylurea or a substi-tuted nitrourea with a diamine. The above-mentioned United States Patent also discloses that bis-sulfonyl ureas can be synthesized from an acid amide and a diisocyanate or a corresponding reacting compound, e.g. a urea, nitro-urea, bis-carbamic acid ester, bis-carboxylic acid azide or bis-carboxylic acid amine-N,N~-halides. P~lrthermore, the possibility of synthesis from sulfonic acid chlorlde and a bis-iso-urea-aIkyl-ether is also mentioned.
For a large-scale synthesis of bis-sulfonyl-ureas only synthesis with sulfonyl-diisocyanate and sulfonic acid amide was considered in the past; other syntheses~ because of their low selectivity or the difficult access to starting materials made no inroads in the art. Sulfonyl-ureas are, however, relatively expensive compounds and there was a need to develop a new process for the preparation of bis-sulfonyl-ureas using more readily available and cheaper compounds. We now have for this the readily available -1- $~ .'`
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dicarbox~Jic acid ~id~-N,N'-dichloride as initial material, Howe~er, when reacting dicarboxylic acid diamide-N,N'-dichloride according to United States patent 2 962 530 in the presence of a proton acceptor in an inert solvent like benzene, acetone or dioxane, one does not obtain sulfonyl ureas. Experi-ments have shown that even with a dipolar reaction medium like e.g. dimethyl formamide, dimethyl acetamide, N-N-ethyl-pyrrolidone, dimathyl-sulfoxide, sulfolane or tetramethylene urea at temperature of 10 to 40& , there is no ;~
or only a minor reaction, while at higher -temperatures various exothermic redox processes take place, yielding dicarboxylic acid diamine and depending on the reaction medium - different oxidation products.
Also the process described in British patent 604 259, Example 13, for the preparation of mono-sulfonylureas from a mono-carboxylic acid amide-N-halide and a sulfonic acid amide, in which an aqueous reaction medium is being used, with the corresponding synthesis of bis~sulfonyl ureas does not reach the objective, since surprisingly N,N'-dichloramides of aromatic dicarboxylic acids do not react in aqueous-alkaline medium to form sulfonyl ;
ureas, not even when sulfonamide is used as alkali salt in anionic form.
There is rather under these conditions a reaction between the intermediate isocyanates formed from the N,N'-dichloramides and the unreacted N,N'- `~
dichloramide according to equation (1) with formation of acyl-urea compounds:
~' OeC=N=Aryl-N=C-O + 2 CR-CO-N-Cl] 2 Na ~ (1) R-CO-~ICO-NH-Aryl-NHlCO-~-CO-R + 2 NaOH ~ -Cl Cl The present invention relates to a process for the preparation of aIkali salts of arylene-bis-s~lfonyl ureas of the general formula:
~- [R'-S02-N-CO-NH-Ar-NH-CO-N-S02-R']2~ 2 Me+
wherein R' is an amino group~ a branched or unbranohed saturated or unsatur-ated aliphatic residue with 1 to 20 C atoms, a substituted or unsubstituted

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cycloaliphatic residue with 4 to 10 C atoms, a substituted or unsubstituted aromatic, an alkyl aromatic or heterocyclic resldue, Ar is a substituted or unsubstituted aromatic residue and Me a sodium/potassium ion.
It has now been found surprisingly that by using a special mixture of solvents, N-haloamides of aromatic dicarboxylic acids can also be success- : .
fully reacted to the corresponding bis~sulfonyl ureas.
In accordance with the invention an alkali metal salt of an arylene-bis-sulfonyl urea of the formula given above is prepared by reacting ; ~;
a dicarboxylic acid-N,N'-dichloramide of the general formula :

Cl-N}I-CO-Ar-C0-NH-Cl with a sulfonic acid amide of the general formula wherein R' and Ar assume the above significance, in a mixture of dimethyl - formamide and water, in the presence o an at least stoichiometric amount of an alkali metal hydroxide, and at a te~perature between about 10 and : about 50C. :~
When using the mixture of dimethyl formamide and water according to the invention, the aromatic diisocyanate obtained from N,N'-dichloramide reacts according to equation 2 to bis-sulfonyl-urea:

O=C=N--Ar=N=C=O ~ 2 ~R-SO -NH~ 2 Me MP/H2 ~ (2) R-S02-N-C0-NH-Ar-NH-C0-N-SOZ-R~2 2 Me According to the process o the invention there may be employed ;
as starting dicarboxylic acid-N,N'-dichloramides, for example, the N,N'-. dichloramide of terephthalic acid or a isophthalic acid, as well as N,N'- :;
dichloramide of mono-, di-, tri- and tetra-alkyl substituted terephthalic acids and isophthalic acids, whose individual substituents each contain 1 ~ to 4 C atoms. Examples of alkyl-substituted compounds are methylterephthalic ;~`' ~ ~ ~ _3-. ', ^ " ' .

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acld and 4-methyl-isophthalic acid. Other suitable N,N'-dichloramides are for example diphenyl-0ther-4J4'-dicarboxylic acid-bis-N-chloramideJ diphenyl-thioether-4,4'-dicarboxylic acid-bis-N-c}lloramide, diphenyl-sulfone-4,4'-dicarboxylic acid-bis-N-chloramide, diphenyl-alkylene-4,4'-dicarboxylic acid-bis-N-chloramide with 1 to 4 C atoms in the alkylene group, for example '~

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ethylene-1,2~bis phenyl-4,4' carboxylic acid-bis-N-chloramQde, also naptha-lene-~,6-dicarboxylic acid-bis-N-chloramide.
As regards the sulfonic acid amide the process according to the ~
invention is also remarkable in its broad range of applications. ~uitable ~ -are, in principle, all primary sulfonamides, namely both inorganic, e.g.
sulfamide, and organic sulfonamides. EXamples of organic compounds are ali-phatic, cycloaliphatic and aromatic sulfonamides, which may also be substituted. Considered can be such substituents which in the presence of isocyanates are inert or react more slowly than sulfonamides, hence alkyl, nitro, halo, sulfo, alkoxy, nitrilo, phosphanato, sulfamido and phenyl substituents. Examples of such sulfonamides are methane sulfonamide and its higher alkyl homologs with 2 to 20 ¢ atoms, benzene sulfonamide, p-toluene sulfonamide, p-fluorobenzene sulfonamide, p-chlorobenzene sulfonamide, o-bromobenzene sulfonamide, p-iodobenzene sulfonamide, 2,4,S-trichlorobenzene sulfonamide, 3-sulfamido-benzene sulfonamide, 2-naphthyl sulfonamide and cyclohexyl sulfonamide.
The composition of the reaction medium according to the invention ~'' is determined by the solubility of alkali hydroxide in the dimethylformamide/
water mixture, by the solubility of the sulfonamide salts in dimethyl for-mamide and by the basicity of sulfonamide. Water is used on the one hand in `
an amount that will allow as much as possible total solubility of alkali hydroxide in the reaction medium. On the other hand, the amount of water should not exceed a certain limit, beyond which the reaction progresses not only to sulfonyl urea but to acyl urea. There is a specific limit for each sulfonamide which depends upon the basicity and solubility of said sulfona-mide. Dimethyl formamide should be added in such amount allowing at least partial dissolution of the sulfonamide salt in the reaction medium.
Suitable ratios can be readily determined in simple preliminary experiments Good results are obtained with a dimethyl formamide/water ratio of 5 to 150 ' _4 :

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The quantity of solvent n~x~ure to be used ~ill be selected so that with relatively readily soluble sulfonamide salts the reaction can take place in ~ just homogeneous phase. With scarcely soluble sulfonamide salts, the quantity is selected so that the reaction suspension can be just readily stirred. In the latter case, 3 to 15 wt.% sulfonamide salt is usually dissolved in the reaction medium.
The process according to the invention is carried out under ;
relatively gentle conditions at temperatures ranging from 10 to 50 C.
: : -Higher reaction temperatures should be avoided to inhibit the formation of undesirable by-products. Once most of the reaction has taken place, the reaction temperature can be briefly raised to about 60 - 70 C to complete the reaction.
Reaction times are determined by the type of ~N'-dichloramide and sulfonamide being used, ranging as a rule from 10 min. to 24 hours.
Generally, a post-reaction time ~f about 30 min. at elevated temperature is enough to complete the reaction. ~ ~-For reasons of cost, alkali hydroxide in the form of sodium ;~ hydroxide is used, but all other alkali hydroxides such as potassium or lithium hydroxide, are just as suitableO At least stoichiometric amoun~s of the aIkali hydroxide must be used. Four (4) moles of hydroxide for each mole of dicarboxylic acid-N,N~ dichloramide are required since only in its anionic form will sulfonamide react as alkali salt as desired. In many cases, using excess alkali hydroxide pro~ed advantageous~ Preferably, up to 2 moles excess alkali hydroxide per mole of dicarbox~lic acid N,N'~dichlora~
1 mide is usedO
Dicarboxylic acid-N,N'-dichloramide and sulfonamide can be used in stoichiometric amounts3 ln other words in a mole ratio of 1 : 2. Exped- `-iently~ sulfonamide - being as a rule the cheaper reagent - is used in an excess of max~ 2 molesO

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~ t is advantageous in carrying out the process according to the invention to dissolve the alkali hydroxide first in the calculated amount of water~ followed by mixing with dimethyl foI~Iamide~ the finely divided sulfon-amide being subsequently stirred-in under cooling, whereby in most cases the alkali salt of sulfonamide will precipitate. The suspension is cooled and reacted with N~N'-dichloramide~ whereby in some cases there is initially complete dissolution prior to the precipitation of the salt of bis-sulfonyl urea. In other cases, the reaction takes place in a heterogeneous phase The reaction product is readily filtered off. However, since the salts of bis-sulfonyl ureas are more or less readily soluble in water/dimethyl forma-mide~ working up of the filtrate is advisable.
According to the invention, the resulting alkali salts of bis-sulfonyl ureas can be converted to free bis-sulfonyl ureas by a known treat-ment with dilute inorganic acid~ e.g. H~lo Bis-sulfonyl ureas obtained by the process of the invention are va]uable compounds, e.g. since their chemotherapeutic effect is of great interest. They can also be used for the preparation of diisocyanates, highly sought af~er in polymer chemistry: bis-sulfonyl ureas decompose under thermal treatment in a dilsocyanate and a sulfonamide~ the latter being reusable in the process according to the invention.
The following examples illustrate the invention, but are not to be regarded as limiting:
Example 1 32 g 10.80 mole) sodium hydroxide was dissolved in 40 g water ; and reacted at 25a with 550 ml dimethyl formamide (DMF). 68.5 g (0.40 mole) finely pulverized p-toluene sulfonamide was rapidly and vigorously stirred into the clear solution. This caused spontaneous precipitation of the ~ ;
sodium salt of tosyl amide as a w~ite deposit. The suspension was cooled to 5 to 10C and within 5 minutes it was mixed portion by portion with 46.6 g ~

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(0.20 mo:Le) N, N'-terephthalic acid dichloramide. In spite of strong, external cooling, the temperature of the reaction mix rose to 44 C. The suspension became gradually more thinly liquid, practically evelything was dissolved after 7 min., after 8 min. the sodium salt of p-phenylene-bis~
(p-toluylsulfonyl-urea) had already precipitated as white deposit. After 10 min. the exothermic Hofmann rearrangemen~ was nearly complete. Cooling was discontinued, and the reaction mix was kept anotber 45 min. at 40 to 45 C. To complete the reaction, the mix was subsequently heated an additional 30 min. at 60 C, then cooled and finally filtered over glass frit at room temperature. The light brown, dimethyl formamide, moist, salt-like filter residue was dissolved in 1.6 1 water. After filtering off scant undissolved substance, the clear, colorless solution was mixed with enough dilute hydro-chloric acid to obtain a pH level of 2, whereby a fine, colorless precipitate formed. To keep the suspension stirrable, it was diluted with 500 ml water.
Subsequently, the pure white precipitate was siphoned off using D4 glass frit, washed with water till the wash water reacted neutral, then suspended in methanol, siphoned off once more, followed by washing 3 times with metha-nol and finally dried under vacuum at 110 C to constant weight. The yield was 75.3 g (74O9% of the theory) p-phenylene-bis-(p-toluyl-sulfonyl urea).
Additional 9.02 g sulfonyl urea was obtained by condensation and ;
acidification of the aqueous and methanol phases. 1.67 g unreacted N,N~
terephthalic acid-dichloramide was recovered from the dimethyl formamide phase. This amounts to a total reaction of 95% and a total yield of p-phenylene-bis-(p-toluyl-sulfonyl urea) of 84%. Hence, selectivity was 88.4%.
` Examples 2 to 15 N,N'-terephthalic acid dichloramide was reacted as described in Example 1 with numerous other sulfonic acid amides. The sulfonamides were reacted as 5 to 15 wt.% solutions in a DMF/water mixture. The enclosed tables contain a list of the sulfonic acid amide~ the mole ratio of N~NI-.:

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terephthalic acid dichloramlde (TDClA): sodium hydroxide: sul~onic acid amide,the weight ratio dimethyl for~amide: water; the reaction temperature reaction time, the arylene-bis-sulfonyl urea and the corresponding yields, regardless of the fraction contained in the filtrates. :

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-11- ' Example 15 32 g (0.80 mole) sodiw~ hydroxide w~s dissolved in 80 ml ~ater, cooled to 20 C and diluted with 550 ml DMF. 68.5 g (0.40 mole) p-tosylamide was stirred in v~gorously, portion by portion, resulting immediately in the formation of a white precipitate ~sodium salt of tosylamide). The suspension ~as cooled to 5C and 46.6 g (0.20 mole) isophthalic acid-bis-N-chloramide was added portion by portion within 10 minutes. In spite of vigorous stir-ring and cooling ~rith a mixture of ice and common salt, the temperature rose to 40C. The powerfully oxidizing suspension was thinly li~uid within 4 min. assuming a yellowish orange tint. After additional S min., the sus-pension increased visibl~r in thickness~ while oxidizing properties declined.
The exothermic reaction was completed after a total of 15 min. The system was kept for 30 min. at 35 C and the reaction was completed by re-heating for 60 min. to 65C. After cooling, the white suspension was siphoned off, washed three times with 2S ml DMF, dissolved in 1.5 1 water ~clear solution pH 8) and acidified with dilute HCl, siphoned off and washed to neutral.
After drying, 65.2 g of the desired sulfonyl urea was obtained. The yellow colored DMr filtrate, after condensation to about l/lOth of its volume and cooling, yielded 6705 g of a brownish crystall:ine mass, from which an additional 31 g sulfonyl urea was obtained by dissolving in water and pre-cipitating with dilute HCl as previously described. Thus, the yield of m-phenylene-bis-3~3~-p-toluylsulfonyl urea was 95.7% of the theory ~xample 16 ~ suspension of p-tosylamide-sodium salt was prepared as described in Example 15 from 3.2 g (80 mole) sodium hydroxide~ 8 ml water, 55 ml DMF
and 6.85 g (40 mmole~ tosylamide. Within 1 minute 5~66 g (20 mmole) 2,6-naphthalene-dicarboxylic acid-bis-N-chloramide was added to this suspension.
The temperature rose to 25 C in spite of cooling with ice, and a clear, yellow solution was obtained. After an additional 2 minutes, a fine precip~

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.. . . . . ~ ., ~5~1L()Z6 itate began to form. The reaction was continued for 5 hours at room temper-ature during which the precipitate increased and the solution assumed a light brown coloration. As the solution was still moderately oxidative7 stirring continued overnight at 20C. ComFletion of the reaction by post-heating was omitted as an exploratory experiment had resulted in decomposi-tion attended by dark brohn discoloration.
The precipitate was isolated from the DMF/~dter mix, then as ~ -described in Example 15, it was dissolved in water and precipitated, yielding 5.53 g white powder. Additional 4.0 g substance was furthermore isolated from the DMF filtrate as outlined in EXample 5.
" The total yield of 2,6-naphthalino-bis-3,3'-p toluyl-sulfonyl urea ~-was thus 9.53 g + 86.2~ of the theory.
Ex~m~le 17 : `
A suspension of p-tosylamide-potassium salt was prepared, as described in Example 147 from 3.96 g potassium hydroxide (86%) (60 mmole),

3 ml water, 55 ml DMF and 6.85 g (40 mmole) p-tosylamide. Subsequently, ! 3.37 g ~10 mmole) 4,4'-diphenyl-ethanodicarboxylic acid-bis-N-chloramide ~ `
was added under vigorous stirring to this suspension ~ithin 2 min. at lo&. ~:
. . ...
After an additional S min. at 10 C7 a clear yellow solution had formed from which a fine, white precipitate began to settle after some 10 min. at 20 C.
Stirring continued for 10 hours at room temperature followed by heating for ~
30 min. at 50 C. There was a faint brown discoloration with increasing ;;
sedimentation. After competed reaction, the system was filtered7 the DMF ` ;`~
filtrate yielded after removal of the solvent, dissolution in water and acidification with dilute7 aqueous hydrochloric acid, 5.71 g p-diphenyl-ethane-bis-3,3~ p-toluyl-sulfonyl urea. Yield = 5.71 g or 94% of the theory.

A solution of p-tosylamide-potassium salt, obtained similarly to Example 17 from 13.6 g (79.6 mmole) p-tosylamide and 9.3 g potassium hydrox-~:

~5il~Z6 ide (86%) ~159.2 mmole) in a mixture of 40 ml water and 280 ml DMF, wasreacted with 12 g (39 mmole) 4,4~-diphenyl-ether-dicarboxylic acid-bis-N-chloramide added at 15-20 C ~ithin 10 m:in. in the presence of cooling. Sub-sequently, the clear, yellow solution was vigorously stirred for 3 hours at 25C and for 5 hours at 40C, wntil oxidation characteristics had disap-peared. The precipitated potassi~ chloride was filtered off. After re-moval of the solvent mixture under vacuum, dissolving in water and acidifi-; cation with dilute inorganic acid the yield was 17.3 g (29 n~ole = 7$% of the theory) p-diphenyl-ether-bis-3,3'-p-toluyl sulfonyl urea as white p~wder.

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Claims (8)

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 an alkali salt of an arylene-bis-sulfonyl urea of the formula:
2Me+

wherein Ar is arylene; R' is a member of the group consisting of amino, an aliphatic residue having 1 to 20 carbon atoms, a cycloaliphatic residue having 4 to 10 carbon atoms, an aromatic residue or an alkyl-aromatic residue;
and Me+ is a member of the group consisting of a sodium ion and a potassium ion, comprising reacting a dicarboxylic acid-N,N'-dichloramide of the for-mula:
Cl-NH-CO-Ar-CO-NH-Cl with a sulfonic acid amide of the formula:
R'-SO2-NH2 wherein Ar and R' have the foregoing meanings, in a mixture of dimethylfor-mamide and water, in the presence of an at least stoichiometric amount of an alkali metal hydroxide, and at a temperature between about 10° and about 50°C.

2. The process of claim 1 wherein in the starting materials R' is amino, alkyl of 1 to 20 carbon atoms, phenyl optionally substituted by halogen, methyl, or sufamoyl, naphthyl or cyclohexyl; and Ar is phenylene optionally substituted by alkyl groups each having 1 to 4 carbon atoms, naphthylene, or a radical of the formula -Ph-R-Ph-wherein Ph is phenylene and R is -O-, -S-, SO2 or -CnH2n, n being an integer of 1 to 4.

3. The process of claim 1 wherein in the starting materials R' is p-tolyl, amino, methyl, phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophe-nyl, p-iodophenyl, 2,4,5-trichlorophenyl, 3-sulfamidophenyl, 2-naphthyl or cyclohexyl, and Ar is p-phenylene, m-phenylene, 2,6-naphthylene, or

4. The process of claim 1, 2 or 3 in which the weight ratio of di-methylformamide to water is in the range of from 1:5 to 1:15.

5. The process of claim 1, 2 or 3 in which the alkali hydroxide is present in an amount ranging from stoichiometric to an excess of 2 moles per mole of dicarboxylic acid-N,N'-dichloramide.

6. The process of claim 1, 2 or 3 in which the molar ratio of the sulfonic acid amide ranges from stoichiometric up to a molar excess of 2 moles of sulfonic acid amide per mole of dicarboxylic acid-N,N'-dichloramide.

7. The process of claim 1, 2 or 3 in which the alkali salt of the arylene-bis-sulfonyl urea thus obtained is further reacted with an inorganic acid to obtain the free arylene-bis-sulfonyl urea.

8. The process of claim 1 in which the dicarboxylic acid -N,N'-dichloramide is the dichloramide of an acid selected from the group con-sisting of terephthalic, methylterephthalic, 4-methylisophthalic, diphenyl-ether-4,4'-dicarboxylic, diphenyl-ethane-4,4'-dicarboxylic, and naphthalene-2,6-dicarboxylic acids.