US2738355A - Production of arylsulfonyl thioureas - Google Patents

Description

United States Patent PRODUCTION OF ARYLSULFONYL THIOUREAS Elmar K. Wilip, Montreal, Quebec, and Avila E. Vendette, Dorion, Quebec, Canada, assignors to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware No Drawing. Application October 6,1952, Serial No. 313,366

Claims priority, application Canada June 17, 1952 8 Claims. (Cl. 260397.7)

This invention relates to the production of arylsulfonyl thioureas and more specifically pertains to a new and improved process for preparing arylsulfonyl thioureas.

Arylsulfonyl thioureas are known compounds. One of the methods by which these compoundshave heretofore been made comprises reacting an arylsulfonyl cyanarnide with hydrogen sulfide under pressure.

It has now been discovered thatarylsulfonyl thioureas possessing the formula wherein AR is an aryl radical, can be produced efficiently and economically by reacting an arylsulfonyl cyanamide possessing the formula wherein AR is an aryl radical, and M is hydrogen, alkali metal or alkaline earth metal, with a thiolacid in the presence of an aliphatic monocarboxylic acid to form a 1-arylsulfonyl-3-acyl thiourea and hydrolyzing this product. Although the reaction can be carried out over a substantial temperature range, for example, from 25 to 100, it is preferred to carry out the reaction of the thiolacid with the arylsulfonyl cyanamide at 40 to 80 C. It is also preferred to carry out the hydrolysis step at a temperature of from 60 to 100 C.

The reactions involved in the process of this invention are believed to take place as follows: (A)

, boxylic acid. The excess of the aliphatic monocarboxylic acid can be from 1-5 moles more than that required for the reaction with the phosphorus pentasulfide. In this, the preferred process, 6-10 moles'of the acid will be employed for each mole of phosphorus penta-,

2,738,355 Patented Mar. 13, 1956 sulfide since the reaction of phosphorus pentasulfide with the acid is as follows:

Ice

amples.

As indicated in the above reaction equations, the thiolacid employed as a reactant need not be a derivative of the lower aliphatic monocarboxylic acid. In this case, R1 and R may be dilferent alkyl radicals and R can contain more than 4 carbon atoms. Furthermore, where the thiolacid is not formed in situ any organic thiolacid can be employed as a reactant. In this case, R can be an aliphatic group such as the methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl, heptadecyl, cyclohexyl, cyclopentyl, cycloheptyl groups, as well as such groups containing non-interfering substituent radicals; or

R can be an aromatic. group such as phenyl, nitrophenyl,

and valeric acids. All these acids possess the formula RiCOOH wherein R1 is an alkyl group containing from 1-4 carbon atoms. The thiolacids suitable for reactants according to the process of this invention possess the formula RCOSH wherein R is the residue of an organic acid group. As hereinbefore stated R will contain from 1-4 carbon atoms when the preferred process is utilized, however any thiolacid can be employed as a reactant where it is not formed in situ. Because they are more readily available than are the other acids and thiolacids of the groups above defined, acetic acid and thiolacetic acid are preferred for the process of this invention.

The arylsulfonyl cyanamide compounds useful according to the process of this invention as hereinbefore indicated possess the formula wherein M is hydrogen and alkali metal or alkaline earth metal and AR is an aryl radical. The aryl radical can be phenyl, tolyl, xylyl, naphthyl, biphenyl and the like as Well as nuclear substituted aryl radicals wherein the benzene nucleus is substituted with one or more alkyl, aralkyl, aryl, amino, acylamino, nitro, hydroxy, alkoxy, or aryloxy groups. The preferred arylsulfonyl cyanamide'reactants are those containing one of the enumerated groups substituted in the position para to the sulfonyl group.

The hydrolysis of the hypothetical 1-arylsu1fonyl-3- carbonyl thiourea intermediate obtained by the reaction of the thiolacid with the arylsulfonyl cyanamide can be accomplished by any of the well known methods. However, the hydrolysis is preferably carried out by adding water to the reaction mixture and heating the resulting aqueous mixture, preferably to a temperature of from to C. Crude arylsulfonyl thiourea is precipitated from this aqueous mixture. The resulting crude product can be readily purified by dissolving it in an aqueous alkaline solution, such as a dilute aqueous solution of sodium carbonate, filtering this solution, and then acidifying the filtrate to precipitate the purified arylsulfonyl thiourea. Dilute aqueous solutions of other alkaline materials such as sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide among others can also be employed.

The process of this invention is particularly applicable to the preparation of Ni-acylsulfanilyl thioureas, important intermediates in the preparation of sulfathiazole and other therapeutically useful systemic anti-infectives.

The following specific examples are illustrative of the preferred method of carrying out the reaction, but are not intended to limit the scope of the invention.

Example I Into a 2000 ml. flask equipped with a mechanical stirrer, thermometer and air condenser, the following were charged in the order given:

286 g. glacial acetic acid 250 g. calcium acetylsulfanilyl cyanamide 52 g. phosphorus pentasulfide The mixture was heated to 60-65 on a water-bath and stirred for four hours. 760 g. of water were then added to the reaction mixture to hydrolyze the '1-arylsulfonyl-3- methylcarbonyl thiourea intermediates. This aqueous mixture was heated to 8085 and stirred for two hours. The batch was then cooled to 25 C. and stirring continued for an additional 30 minutes. The crude product was recovered by filtration and washed with water until the acetic acid content of the wash water was below The crude acetylsulfanilyl thiourea was then dissolved in a solution of 20 g. soda ash in 1200 ml. water at 40-50", the mixture being stirred for 30 minutes, filtered and the precipitated impurities washed with 400 ml. water at 5060. Hydrochloric acid was added to the filtrate to a pH of 2.0, and the resulting precipitate was isolated by filtration and dried at 100. Yield 95 %--M. P. l97199 C.

Example II 50 g. of crude benzenesulfonyl cyanamide was mixed with 100 cc. of glacial acetic acid and 20 g. of phosphorus pentasulfide. An exothermic reaction ensued, the tem perature rising to 50. The mixture was stirred at 60-65 for one hour, after which 200 ml. of hot water (8090) was added to hydrolyze the intermediate and the whole heated for 30 minutes. After cooling, the white precipitate was filtered, washed with water and dissolved in 400 ml. of 4% sodium carbonate solution.

The resulting solution was treated with l g. of activated carbon, filtered and acidified with hydrochloric acid to a pH of 1.0. The product, benzenesulfonyl thiourea, was filtered and dried to constant weight at 80'-85. The yield was 25 g. (80% of theory) M. P. 1378-1388. Found: N, 12.42%; calc. for C7HsO2N2S2: N, 12.95%.

In a similar manner 4-nitrophenylsulfonyl thiourea can be prepared by reacting 4-nitrobenzenesulfonyl cyanamide with thiolacetic acid in the presence of glacial acetic acid and hydrolyzing the intermediate with water at about 80 to 90 C. Any of the other arylsulfonyl cyanamides hereinbefore set forth can be substituted for N l-acetylsulfanilyl cyanamide employed in Example I to prepare the corresponding thiourea.

What is claimed is:

1. In the preparation of an arylsulfonyl thiourea the steps comprise heating a reaction mixture containing an aliphatic monocarboxylic acid having the formula RiCOOH wherein R1 is an alkyl group containing 1 to 4 carbon atoms, an aliphatic thiolacid having the formula RCOSH wherein R is an alkyl group containing 1 to 4 carbon atoms and an arylsulfonyl cyanamide having the formula ArSOzN--CN wherein Ar is an aryl radical and M is selected from the group consisting of hydrogen, an alkali metal and an alkaline earth metal; thereafter adding water to the resulting reaction mixture and heating this mixture, wherein said process the heat steps are carried out at a temperature of from40 C. up to but not exceeding about 100 C.

2. A process for preparing an arylsulfonyl thiourea which comprises heating at a temperature not exceeding about 100 C., the reactants comprising an arylsulfonyl cyanamide having the formula wherein Ar is an aryl radical and M is a member selected from the group consisting of hydrogen, an alkali metal and an alkaline earth metal, an anhydrous aliphatic monocarboxylic acid having the formula RiCOOH wherein R1 is an alkyl group containing 1 to 4 carbon atoms, and phosphorous pentasulfide; thereafter adding water to the resulting reaction mixture, heating at a temperature of from 40 C. up to but not exceeding 100 C., cooling the resulting mixture, and recovering the precipitate formed.

3. In the process for preparing an arylsulfonyl thiourea the steps comprise heating at a temperature not exceeding about 100 C., the reactants comprising an arylsulfonyl cyanamide having the formula Ar-SOrlIT-CN wherein Ar is an aryl radical and M is a member selected from the group consisting of hydrogen, an alkali metal and an alkaline earth metal, an anhydrous aliphatic monocarboxylic acid having the formula RiCOOH wherein R1 is an alkyl group containing 1 to 4 carbon atoms, and phosphorous pentasulfide; thereafter adding water to the resulting reaction mixture and heating at a temperature of from 40 C. up to but not exceeding 100 C., cooling the resulting mixture, and recovering the precipitate formed.

4. The process of claim 3 wherein the proportions of the reactants are 0.2 mole of phosphorous .pentasulfide and 2 to 6 moles of the aliphatic monocarboxylic acid per equivalent of said cyanamide.

5. In the process for preparing N4-acetylsulfonilyl thiourea, the steps comprising heating at a temperature not exceeding 100 C., the reactants comprising calcium acetylsulfonilyl cyanamide, glacial acetic acid, and phosphorous pentasulfide; thereafter adding water to the resulting reaction product and heating this mixture at a temperature of from 40 C. up to but not exceeding 100 C.

6. The process of claim 5 wherein the proportions of the reactants are 0.2 mole of phosphorous pentasulfide, 2 to 6 moles of glacial acetic acid for each equivalent of the cyanamide.

7. The process of claim 5 wherein the proportions of the reactants are 0.2 mole of phosphorous pentasulfide, 2 to 6 moles of glacial acetic acid for each equivalent of the cyanamide, and the initial heating step is carried out at a temperature in the range of from about 40 to about C. and the second heating step is carried out at a temperature of from about 80 to about C.

8. In the process for preparing benzenesulfonyl thiourea the steps comprising heating at a temperature of from 40 to 80 C., the reactants comprising benzenesulfonyl cyanamide, glacial acetic acid and phosphorous pentas'ulfide in the proportions of 0.2 mole of said sulfide and '2 to 6 moles of said acetic acid for each equivalent of said cyanamide; thereafter adding water to the resulting FOREIGN PATENTS reaction products and heating this mixture at a tempera- 55 Denmark 6, g ture of from about 80 to about 90 C. 7 901 259 France Oct 30, 1944 5 OTHER REFERENCES References C'ted m the file of thls patent I. G. German patent application I 7525 6--Abstracted UNITED STATES PATENTS in Auszuge Deutscher Patent, Anmeldungen," No. 6,

Band I Chernie, page 222 (1947).

2,498,782 Arquet et a1. Feb. 28, 1950 Schiff: Beilstein (Handbuch, 4th ed.), vol. 2, p. 230

2,545,764 Charpentier Mar. 20, 1951 (1920).

Claims (2)

1. IN THE PREPARATION OF AN ARYLSULFONYL THIOUREA THE STEPS COMPRISE HEATING A REACTION MIXTURE CONTAINING AN ALIPHATIC MONOCARBOXYLIC ACID HAVING THE FORMULA

5. IN THE PROCESS FOR PREPARING N4-ACETYLSULFONILYL THIOUREA, THE STEPS COMPRISING HEATING AT A TEMPERATURE NOT EXCEEDING 100* C., THE REACTANTS COMPRISING CALCIUM ACETYLSULFONILYL CYANAMIDE, GLACIAL ACETIC ACID, AND PHOSPHOROUS PENTASULFIDE; THEREAFTER ADDING WATER TO THE RESULTING REACTION PRODUCT AND HEATING THIS MIXTURE AT A TEMPERATURE OF FROM 40* C. UP TO BUT NOT EXCEEDING 100* C.