NEW PROCESS FOR THE PREPARATION OF PHENYL-GUANIDINE DERIVATIVES

Abstract: The invention relates to a process for the preparation of guanidine-derivatives of general formula (I), wherein R means a C1-4 alkyl group, M means a hydrogenatom, sodium-, potassium-, or calcium ion, A means an -S-, -SO-, or -SO2-group; in a way, that thiocarbamide derivatives of general formula (II) are oxidized optionally in the presence of an inorganic or organic solvent and the sulfonic acid derivative of general formula (III) obtained is reacted with an aniline derivative of general formula (IV) optionally in the presence of an inorganic or organic solvent.

Description: New process for the preparation of pheπyl-guanidine derivatives The invention relates to a new process for the preparation of known phenyl-guanidine derivatives. 5 Due to their anthel intic activity some guanidine derivatives are applied primarily in the veterinary therapy /European Pat. Spec. 50286/. The present invention relates to the preparation of these active ingredients of the general formula (I) 10 15 The meaning of the variable substitueπts in this specifi¬ cation is always as follows: R is a C_ι_4 alkyl group, M is a hydrogenatom or sodium-, potassium- or calcium- ion, A is an -S-, -SO- or -SO2- group. 20 The most simple method to prepare guanidines is to react S-alkyl-isothiuronium salts with ammonia or with amines. /Org. Synth. Coll. Vol. Ill : 440; J. Am. Soc. 55 : 1280; 3. Am. Soc. 78: 6144: 3. Am. Soc. 1946 : 1063; USP 4.211.867/. In the practice generally the S-methyl-isothiuronium salts are applied, 5 their great disadvantage is, that as side product methyl- -mercaptaπ is formed which is of a very disagreeable smell and very toxic too. Their further disadvantage is, that the reacti¬ vity of the S-methyl group is very scanty and the reaction period can take several days too. Guaπidiπes can be prepared by reacting ammonia or ammonium-compounds with cyaπamide /Org. Synth. ]_ 46; Ber J]_ : 1681: Ber. 50 : 1620/, with carbodii ide /USP No. 4.414.211, 5 Tetrahedron 37.: 233/, with chloro-formamidine /Ber. jH: 2278; Ber. 97_ : 1232/ or with dichloro-isocyanide /USP No. 4.211.867/. The enlisted reactaπts are generally corrosive and toxic and/or sensitive to humidity. The patents protecting the preparation of phenyl- 0 -guanidiπes of the general formula (I) are describing the reaction of N-methoxy-carbonyl-N'-/2-nitro-4-propyl-thiophenyl/ -S-methyl-isothiocarbamide and N>-/2-amino ethyl/-N>-cyano-N' " >- -methyl-guanidine with a reaction period of 24 hours, applying 2 molar equivalents of amiπe in acetonitrile /European Pat. 5 Spec. No. 50286/. This process can be reproduced for target compounds of the general formula (I) even with a reaction period of several days • only with a yield of 45%. The presumably reason is that the S- -methyl group is reacting very slowly with nucleophyl-substitu- 0 tioπ, the reaction leads to side-products respectively /USP No. 4.406.983/. The present invention relates to the preparation of guaπidine- -derivatives of the general formula (I) 5 (I) C3H "A N,SC *"NH ~ C00R k ls, NH - C 2 - C - SO * M 0 2 * 3 in a way, that a thiocarbamide-derivative of the general formula (II) R -O - C - NH - C - NH - CH 2 - CH 2 - SO3M (II) 5 w 0 SH is optionally oxidized in the presence of an inorganic or organic solvent and the new sulfonic-acid derivative of the general formula (III) R-O-C -NH-C « N-CH 2 -CH 2 -SO3M (III) thus obtained is reacted with an aniline derivative of the general formula (IV) (IV) optionally in the presence of an inorganic or organic solvent. The present invention is based on the recognition, that the new compound of the general formula (III) containing an -S03~group is reacting essentially more quickly with derivatives of aniline of the general formula (IV), as the suitable derivatives containing an -SH-group /the reaction speed is about 15 fold greater/. A further recognition is, that the new compounds of the general formula (III) can be prepared in a very simple way oxidizing the suitable -SH-derivative of the general formula (II). The oxidation is carried out advantageously with oxygen, hydrogen peroxide, sodium-metaperiodate, potassium per angate, with chlorates or with some peracids,optionally in the presence of water and/or an organic solvent. Carrying out the oxidation with hydrogen peroxide at 0-45 °C, as a solvent water can be applied. To this reaction advantageously a catalyst is applied, e.g. sodium- olybdate in catalytic quantity. The oxidation according to the invention can be realized in a way too, that as an organic peracid per-acetic-acid, per- -benzoic-acid, m-chloro-per-benzoic-acid or per-phtalic-acid is used. The sulfonic acid derivative of the general formula (III) can be reacted in the presence of acetonitrile, dimethyl-forma ide, dimethyl-acetamide, dioxane and/or dimethyl-sulfoxide with the aniline-derivative of the general formula (IV) at temperatures between 0°C and the boiling point of the reaction mixture. The amine of the general formula (IV) is advantageously applied in an excess of 5-30%. Advantage of the method according to the invention is, that it is simple and leads not to smelling or toxic side- -products and the isolated intermediates are stable at room temperature. The process has generally a short reaction period and results a good yield /above 70%/. Compounds of general formula (II) and (IV) are known in the art and may be prepared by methods well-known to those skilled in the art. The process according to the invention is illustrated in detail by the following non limiting Examples. Example 1 31,33 g of N-/methoxy-carboπyl/-N'-/2-ethyl-sulfonic acid/-thio-carbamide are suspended in 100ml of water, 3 g of sodium chloride and 0,5 g of sodium-molybdate are added and cooled to 0°C. Thereafter dropwise 43 ml of a 33% hydrogen peroxide solution is added, in a way that 28 ml are added below 20°C and the other quantity below 40°C. Duration of the addition is about 1 hour. The mixture is cooled to 10°C, fil¬ tered and the remainder is washed with cold, saturated sodium chloride solution and dried. The product obtained is added to 32 g of 2-nitro-4-propylthio- aniline in 100 ml of acetoπitrile and the mixture is refluxed until the starting sulfonic acid is disappeared, /thin layer chro .: solid phase : Polygram Sil G/UV254; running mixture: metanol, acetic acid, chloroform 95:5:5/. The solvent is distilled in vacuo. To the residue 10 g of sodium hidroxide dissolved in 100 ml of water are added, the solution is filtered with a small quantity of charcoal and the pH value of the filtrate is adjusted to 1,5. The filtered crystals are washed with acetone. 42,6 g of N-/methoxy-carbonyl/-N>-/(2- -nitro-5-propyl-sulfenyl)phenyl/-N' >-/2-ethyl-sulfonic acid, guanidine are obtained. Mp.: 214-215 °C. Example 2 2,41 g of N-/methoxy-carbonyl/-N»-/-2-ethyl-sulfonic- -acid/-thiocarbamide are suspended in 30 ml of ether. At a temperature of 20°C 5,5 g of m-chloro-per-benzoic-acid dissolved in 20 ml of ether are added. After 10 minutes the solution obtained is admixed with 3x50 ml of a 5% sodium hidrogen carbonate solution, it is dried on magnesium sulfate and evaporated. 2,5 g of N-(methoxy-carbonyl)-N>-(2-ethyl- sulfonic acid) amiπo-imiπo-methanesulfoπic acid are obtained. Mp.: 211-216 °C. Example 3 5 g of N-/methoxy-carbonyl/-N'-/2-ethyl-sulfonic-acid/- -thiocarbamide are suspended in 100 ml of acetic acid and at 10°C 6 ml of a 30% hydrogen peroxide solution are dropwise added. The mixture is stirred for 6 hours at 20°C. Thereafter it is evaporated to dryness. The remainder is suspensed in acetone and filtered and dried. 5,lg of N-/methoxy-carbonyl/-N>-/2-ethyl- -sulfoπic acid/-amiπo-imino-methansulfoπic acid are obtained. Mp.: 213-214 °C. To the product above 5,5 g of 2-nitro-4-propylsulfinyl-aniline and 50 ml of dimethdylformamide are added. The solution is stirred until the starting sulfonic acid can not be detected by thin layer chromatography. Thereafter the solution is evaporated to dryness in vacuo and to the remainder 50 ml of acetone are added. After further stirring the crystals are filtered. 6,8 g /81%/ of N-/methoxy-carbαnyl/-N>-/2-nitro-5-propyl- -sulfinyl/phenyl-N"-/2-ethyl-sulfonic acid/-guaπidiπe are obtained. Mp.: 227-231 °C. Example 4 2,4 g of N-/methoxy-carbonyl/-N'-/2-ethyl-sulfonic acid/- -thiocarbamide are suspended in 50 ml of acetic acid. At 0°C 2,3 g of peracetic acid dissolved in 20 ml of acetic acid are added. The mixture is stirred for 2 hours at room temperature and thereafter it is evaporated in vacuo to dryness. To the residue 50 ml of dimethyl-acetamide and 3,2 g of 2-nitro-4- -propyl-sulfoπyl-aniline are added. The mixture is refluxed until sulfonic acid can not be detected by thin layer chroma- tography. Then it is evaporated in vacuo to dryness, the residue is stirred in 50 ml of acetone, filtered and the crystals obtained are washed with acetone. 3,75 g of N-/methoxy-carbonyl/-N>-/2-nitro-5-propyl- -sulfoπyl/pheπyl-N"-/2-ethylsulfonic acid/-guanidine are obtained. Mp.: 240-245 °C. Example 5 4,2 g of N-/methoxy-carbonyl/-N'-/(2-nitro-5-propyl-sulfe- nyl)/pheπyl/-N"-/2-ethyl-sulfoπic acid/-guaπidine are dissolved in the solution of 0,42 g of sodium hydroxide in 80 ml of water. The solution of 2,7 g of potassium peroxide-sulfate in 10 ml of water is added. The reaction mixture is stirred for 3 hours, thereafter it is evaporated to dryness in vacuo. The residue is suspended in 100 ml of hot methyl alcohol and then cooled to 20 °C. The precipitated crystals are filtered and washed with methyl alcohol. 3,96 g of N-/methoxy-carbonyl/-N>-/2-nitro-5- -prσpyl-sulfinyl/-phenyl-N> '-/2-ethyl-sul onic acid/-guanidine sodium salt are obtained. Mp.: 147-150 °C. Example 6 4,2 g of N-/methoxy-carbonyl/-N"-/2-nitro-5-propyl-sul- fenyl/-phenyl/-N"-/2-ethyl-sulfonic acid/-guaπidiπe are dissol¬ ved in the solution of 0,42 g of sodium hydroxide in 80 ml of water. To the solution at 20 °C 6 ml of a 33% hydrogen peroxide solution is dropwise added. After stirring for 8 hours to the reaction mixture the solution of 2,2 g of calcium-chloride in 10 ml of water is added. After stirring for 20 minutes the crystals obtained are filtered, washed with cold water and dried. 3,97 g of N-/methoxy-carbonyl/-N"-/(2-nitro-5-propyl-sulfonyl)- -phenyl/-N"-/2-ethyl-sulfonic acid/-guanidine calcium salt are obtained. Mp.: 330 °C. Example 7 To 1 g of N-/methoxy-carbonyl/-N>-/2-ethyl-sulfonic acid/- amino-imiπo-methane sulfonic acid prepared according to example 2, 1 g of 2-πitro-5-propyl-sulfinyl-aniliπe and 5 ml of aceto- nitrile are added. The mixture is refluxed until the starting sulfonic acid can not be detected by thin layer chromatorgraphy. Thereafter it is evaporated to dryness and to the residue 20 ml of a 1 N sodium hidroxide solution are added. The solution is clarified with charcoal and the pH value of the filtered solution is adjusted with hydrochloric acid to 1.5. 1,62 g of N-/methoxy-carbonyl/-N»-/2-πitro-5-propyl-sulfiπyl/phenyl-N» >- -/2-ethyl sulfonic acid guanidine are obtained. Mp.: 146-148 °C. Example 8 To 1 g of N-/methoxy-carboπyl/-N»-/2-ethyl-sulfonic acid/- -amino-imino-methane sulfonic acid 1 g of 2-nitro-5-propyl-sul- fonyl-aniline and 10 ml of acetoπitrile are added. The mixture is refluxed until the starting sulfonic acid can not be detected by thin layer chromatography. Thereafter it is evaporated to dryness and the residue is taken up in 10 ml of a 1 N sodium hidroxide solution. The solution is clarified with charcoal and the pH value of the filtrate is adjusted to 1.5. The precipitate thus obtained is filtered. 1,39 g of N-/methoxy-carbonyl/-N»-/2-nitro-4-propyl- -sulfonyl/phenyl-N"-/2-ethyl-sulfonic acid/-guanidine are obtained. Mp.: 241-244 °C.

Claims: What we claim is: 1. Process for the preparation of new guanidine derivatives of the general formula (I), wherein R is a C^_ alkyl group, M is a hydrogenatom, sodium-, potassium- or calcium ion, A means an -S-, -SO-, or -SO2- group- characterized by, that an thiocarbamide derivative of the general formula (II), R-O-C-NH-C-NH-CH 2 -CH 2 -S0 M - ~ \\ (ID R-O-C -NH-C=N-CH 2 -CH 2 -S0 M 0 SH wherein R is a C^_ alkyl group, M has the same meaning as mentioned above; is oxidized optionally in the presence of an inorganic or organic solvent, and a sulfonic acid derivative of the general formula (III) Ft-O-C 1 -NH-Ci -N-CH -<•-CH ? -SO * M (Iπ 0 S0 3 H wherein the meaning of R and M is the same as mentioned above; is reacted with an aniline derivative of the general formula (IV) - the meaning of A is the same as mentioned above - optionally in the presence of an inorganic or organic solvent. 2. Process according to claim 1, characterized by, that the oxidation is carried out with hydrogen peroxide, sodium-meta- -periodate or with any organic peracid, optionally in the presence of water and of a catalytic quantity of sodium-molyb- date. 3. Process according to claim 2, characterized by, that the oxidation is carried out with hydrogen peroxide in the presence of water and of a catalytic quantity of sodium-molybdate. 4. Process according to claim 2, characterized by, that as organic peracid per-acetic acid, per-beπzoic acid, m-chloro-per- benzoic acid or perphtalic acid are used. 5. Process according to any of claims 1-4, characterized by, that the sulfonic acid derivative of the general formula (III) - wherein R and M have the same meaning as mentioned in claim 1- is reacted in the presence of dimethyl-formamide, dimethyl- -aceta ide, dioxaπe and/or dimethyl-sulfoxide with an aniline derivative of the general formula (IV), wherein - A has the same meaning as mentioned in claim 1 - at temperatures between 0°C and the boiling point of the reaction mixture. 6. New sulfonic acid derivatives of the general formula (III) R-O-C-NH-C-N-CH 2 -CH 2 -S03M 0 S0 H (III) wherein R is a C 1 _4 alkyl group, M is a hydrogeπatom, sodium-, potassium-j or calcium ion.

Inventors: HUSZAR CSABA, NEMETH ATTILA, PALI LAJOSNE, SARKOEZI PETER, SOMFAI EVA, SPERBER FERENC, HUSZAR, CSABA, NEMETH, ATTILA, PALI, LAJOSNE, SARKOEZI, PETER, SOMFAI, EVA, SPERBER, FERENC
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT
Application year: 1990
Main classification: C07C323
IPC codes: A61K31, A61P33, C07C309, C07C315, C07C317, C07C319, C07C323, C07C381