METHOD FOR THE PREPARATION OF AMIDINO-UREA DERIVATIVES

Abstract: The invention relates to an improved method for the preparation of an amidino-urea derivative of general formula (I), wherein R<1>, R<2> and R<3> each stand for hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro or optionally substituted amino, R<4> is hydrogen or lower alkyl, and R<5> is hydrogen or C1-10 alkyl, by reacting a lower alkyl carbamate with an appropriate guanidine derivative. According to the invention the reaction is performed in the presence of a bipolar aprotic solvent. The invention also relates to a method for preparing an adduct of 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-urea and dimethyl sulphoxide, in which 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-urea, prepared optionally directly in the reaction mixture, is reacted with dimethyl sulphoxide. When decomposing this aduct with water, 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-urea is obtained in extremely pure state.

Description: METHOD FOR THE PREPARATION OP AMIDIUO-UREA DERIVATIVES The invention relates to a new method for the pre paration of amidino-urea derivatives. It is known that amidino-urea derivatives possess numerous favourable physiological properties /JFor schrit e der Arzneimit el orschu-ng 28, 1435 (1978V7. Of them l-(2,6 dl_methylphen^l)-2-(]S-me hyla_iiidino)*-L_rea (lidamidine) is o particular interest. The hydrochloride of this compound is an excellent antidiarrhoeal agent with a still unknown mechanism, of effect, which exerts much less undesired side effects than the commonly applied antidiarrhoeal substances. Several methods have been described in the literatur for the preparation of amidino-urea derivatives. Depending o the nature and position of the substituents present, certain amidino-urea derivatives can be prepared by subjecting the respective biguanide compounds to acidic hydrolysis. The large scale applicability of this method is, however, rather restricted, since numerous undesired side reactions may occu simultaneously during the synthesis /Fortschritte der Arznei ittelforschung 28, H3 β (197817. Ajnidino-urea derivatives can also be prepared by reacting the respective isocyanates with guanidino derivativ (US patents tfos. 4,060,635, 4,147,804, 4,203,920 and 4,283,555)- The reaction proceeds generally easily and pro¬ vides the aimed compounds with good yields. It is, however, a disadvantage that phosgene, an extremely hazardous poison, is required for the preparation of the starting isocyanates, and the isocyanates themselves are also hazardous poisons. The high reactivity of isocyanates also leads to inconvenien since, on one hand, isocyanates are difficult to store and transport, and, on the other hand, the reaction with iso¬ cyanates frequently does not stop at the formation of the re quired end product but proceeds further and gets difficult or impossible to controls To avoid this latter problem the guanidine derivative is applied generally in a 100% excess, which increases the costs of production to a great extent 0 It is also known that isocyanates can be prepared from reactants other than phosgene and can be converted directly into the desired amidino-urea derivatives (Spanish patents Nos. 546,126 and 548,902). Although the use of poisonous phosgene and the difficulties in the storage and transport of isocyanates can be avoided by these methods, both of them are much more sophisticated and expensive than those utilizing phosgene as starting substance. These metho can be applied essentially for laboratory purposes but not for large scale production. Amidino-urea derivatives can also be prepared by reacting the appropriately substituted aromatic carbamates with guanidine derivatives (published South African patent application ^ HO. 78/1574), the yield is, however, very poor even when applying phenyl esters as starting substances. Several difficulties emerge at the isolation of the end products, too: difficult and sophisticated purification ste are required in order to separate the amidino-urea derivat¬ ives from the starting carbamates and phenol formed in the reaction. Considering that phenyl chloro ormate, required as starting substance to prepare phenyl carbamates, is an expensive chemical, it is obvious that the above method can¬ not be applied for large scale production. The utilization of alkyl carbamates, which require much less expensive start ing substances, is not even mentioned as an example in the cited reference. It is known, however, from other references dealing with related reactions of alkyl carbamates that the reactivity of the alkyl esters is so poor under such condi¬ tions that no successful reaction can be expected 7. Am. Che . Soc. J6, 4*458 (19517- Summing up, no method has been disclosed in the literature which could fit for all the requirements of the large scale production of amidino-urea derivatives. How it has been found, unexpectedly, that when an alkyl ester of an aromatic carbaminic acid is reacted with the appropriate guanidine derivative in the presence of a dipolar aprotic solvent, the reaction proceeds easily, and the required amidino-urea derivative is obtained with a goo yield within a relatively short period of time. Based on the above, the invention relates to a meth for the preparation of an amidino-urea derivative of the general ormula (i) , wherein R 1 , R2 and R-^ each stand for hydrogen, halogen, lower alkyl, lower alkoxy , trifluorome hyl, nitro or optionally substituted amino , R^ is hydrogen or lower alkyl , and R is hydrogen or C , , Q a l*^yi» by reacting an alkyl carbamate of the general formula (il) , R 1 ■ ' ■ *— HH - - CC -- O0RR 1 ° (II) 1 ? 3 fi wherein R , R and R-' are as defined above and R Is a c τ__3 alkyl group , with a guanidine derivative of the general formula (III) , ΉE ΈΓ R-TS ■ - _ - 2 -/ (III) Λ wherein and are as defined above. According to the invention the reaction is performed in the presence of a bipolar aprotic solvent. It is preferred to apply dimethyl formamide, dimet acetamide, dimethyl sulphoxide, hexa e h 1phosphoric acid triamide, diethyl acetamide or any mixture of these liquid as bipolar aprotic solvent. The alkyl carbamate of the general formula (II) is reacted with the guanidine derivative of the general formu (III) generally in a molar ratio near to the equimolar value, preferably in a molar ratio of 1 : (0.8-1.25). The reaction is performed preferably under heating the reaction mixture. Since a lower alkanol splits off in the reaction, it is preferred to perform the reaction at a temperature which enables one to remove the thus formed al¬ kanol from the mixture within a short period of time. The removal of the alkanol can also be facilitated ' by simul¬ taneously lowering the pressure of the reaction. The resulting compound of the general formula (i) i separated from the reaction mixture in a manner known per s According to a preferred method the reaction mixture is pou into water, and the amidino-urea derivative, separated as a crystalline substance, is removed e.g. by filtration. Sol¬ vents other than water can also be applied as precipitating agents. The end products obtained are generally sufficientl pure, however, if desired, they can be purified by standard methods, e.g. by recrystallization, chromatography or salt formation. One can also proceed in such a way that the separat ed end product, optionally in undried state, is directly converted into its salt, and, if necessary, the salt is pur fied further. Any of the mineral and organic acids applic¬ able for pharmaceutical purposes can be used in the salt formation step, of which hydrochloric acid is preferred. The main advantages resulting from the method of th invention are as follows: - no poisonous and hazardous reactants (phosgene, isocyanat are required; - the reaction proceeds smoothly with good yields, and by¬ products are formed only in insignificant amounts; - there is no need for utilizing the guanidine derivative in large excess; - the starting substances are less expensive than those applied before, thus the new method is more economical than the known ones. It has also been found that when applying the method of the invention for the preparation of lidamidine and reacting JST-methy1-guanldlne with a lower 2,6-dimethyl- phenyl carbamate in the presence of dimethyl sulphoxide, an adduct (molecular compound) comprising lidamidine and di¬ methyl sulphoxide in a molar ratio of 1:1 is formed. The same adduct is obtained when reacting crude or pure lidamid ine produced optionally directly in the reaction medium, with dimethyl sulphoxide. The lidamidine - dimethyl sulphoxide adduct is a new compound, a stable, crystalline substance melting at 160-162 G. This compound can be prepared in extremely D ure state, and can be utilized for the preparation of highly pure lidamidine. The lidamidine - dimethyl sulphoxide addu can be utilized, however, even as such for the preparation of pharmaceutical compositions, since the small amount of dimethyl sulphoxide present is physiologically tolerable. Based on the above, the invention also relates to a method for the preparation of a lidamidine - dimethyl sulphoxide adduct. According to the invention one proceeds in such a way that lidamidine, prepared optionally directl in the reaction mixture, is reacted with dimethyl sulphoxi optionally in the presence of one or more inert organic solven (s) . The reaction can be performed most simply in such a way that lidamidine • is suspended in dimethyl sulphoxide under stirring, and the resulting adduct is separated from the reaction mixture preferably by filtration. One can als proceed in such a way that lidamidine base is dissolved or suspended first in an inert organic solvent, and the requi amount of dimethyl sulphoxide, preferably at least one mol equivalent calculated for lidamidine, is added to this sol tion or suspension in one or more portions. Lidamidine can also be prepared directly in the . reaction mixture. One can proceed e.g. in such a way that salt of lidamidine is applied as starting substance, and lidamidine base is liberated from its salt directly in di¬ methyl sulphoxide or in a mixture of dimethyl sulphoxide with one or more inert solvent (s). According to another method 2,6-dimethylphenyl-isocyanate, phenyl 2, 6-dimethyl- phenyl-carbamate or a lower alkyl 2, 6-dimethylphenyl-carb- amate is reacted with H-meth l-guanidine in the presence of dimethyl sulphoxide, whereupon lidamidine, which forms in the reaction mixture, Immediately converts into the respect ive dimethyl sulphoxide adduct. A particular advantage of this latter method is that the resulting adduct is extremel 5; pure, free of any contaminations originating from the start ing substances applied in the preparation of lidamidine. As mentioned above, the lidamidine - dimethyl sulph oxide adduct can be converted directly into pharmaceutical compositions, such as tablets, capsules, suspensions, etc., ICX by routine pharmacotechnological methods utilizing conven¬ tional pharmaceutical additives (e.g. carriers, diluents or other auxiliary agents) . The lidamidine - dimethyl sulphoxide adduct can be converted into lidamidine by reacting it with water. In thi 15 operation lidamidine is obtained in particularly pure state This method is also embraced by the scope of the invention. The lidamidine - dimethyl sulphoxide adduct is de¬ composed with water generally at 0-100°C, preferably at 20-80 C. It is preferred to apply at least one molar equi- 20 " valent of water for the reaction. The upper limit of water to be added is not decisive and is determined essentially by economical factors. The resulting lidamidine is separate from the mixture by a method known per se. The invention is elucidated in detail by the aid 25 of the following non-limiting Examples. Example 1 A mixture of 7.17 g (0.04 mole) of methyl 2,6-dl- methylphenyl-carbamate, 3-21 g (0.044 mole) of methyl-guan idine and 15 cur of dimethyl forma ide is warmed to 100 C with stirring. Methanol which forms in the reaction is re moved continuously at a pressure of 100 mmHg. At the end o the reaction the mixture is stirred for additional one hou thereafter it is cooled to room temperature, poured into 160 cm of cold water, and the aqueous mixture is stirred 10-15°C for 2 hours. The separated precipitate is filtered off, auctioned, and then washed with deionized water and finally with a small amount of acetone. The resulting crud 3 product is dissolved in 80 cur of methanol, the solution i decolourized with a small amount of activated carbon, filt and the filtrate is acidified to pH 2 with methanolic hydr chloride solution. The solvent is removed under reduced pressure, and the residue is triturated with acetone. The precipitate is filtered off, suctioned, washed with a smal amount of acetone and then with ether, and dried. l-(2,6-D methy1phenyl)-3-(H-methyla idino)-urea hydrochloride is obtained; .p.: 194-197°C. The IR spectrum of the product identical with that of the authentic sample. Example 2 One proceeds as described in Example 1 with the 3 difference that 15 cm of hexamethyl hosphoric acid triamid are utilized as reaction medium, and the mixture is main¬ tained at 100°C for 2 hours. 6.87 g (78.1 %) of l-(2,6-di- methylphenyl)-3- (iT-meth lamidino)-urea are obtained. The hydrochloride of the product is identical with the compound obtained according to Example 1. Example 3 A suspension of 80.5 g (0.45 mole ) of methyl 2, 6-di- e thy 1 pheny l- carbamate and 36.55 g (0.5 mole ) of methyl- guanidine in 170 cur of dimethyl sulphoxide is heated to 100°C with stirring, and stirred at this temperature for one hour. The reaction mixture is processed as described i Example 1 with the difference that salt formation is omitte 86.58 g (86.5 %) of 1- (2, 6-dimethylphenyl)-3~ (H-meth lami¬ dino ) -urea are obtained. - Example 4 7.28 g (0.037 mole ) of ethyl 2, 6-dimethylphenyl- carbamate are reacted with 3.21 g (0.044 mole ) of me th 1- 3 guanidine in 15 cur of dimethyl sulphoxide as described in Example 3. 6.69 g (80.6 %) of l- (2, 6~dimethylphenyl)-3-(H- methylamidino)-urea are obtained. Example 5 One proceeds as described in Example 1 with the 3 difference that 15 cm of dimethyl acetamide are applied as reaction medium and the reaction is performed for 2 hou The mixture is processed as described in Example 1« 6.06 g (68.8 %) of 1-(2,6-dimethy1phenyl)-3-(ϊtf-methylamidino)-ure are obtained. The hydrochloride of the product is identica with the compound prepared according to Example 1. Example 6 7.36 g (0.050 mole) of 2,6-dimethylphenyl-isocyanat are added dropwise, at room temperature, to a stirred suspension of 4.O4 g (0.055 mole) of U-methy1guanidine in 3 20 cm of dimethyl sulphoxide. The white, crystalline lida midine - dimethyl sulphoxide adduct separates slowly durin the addition of the reactant. The reaction mixture is stirred for additional one hour, thereafter the crystals are filtered off, washed with a small amount of cold metha and dried. 14.80 g (99 ) of lidamidine - dimethyl sulph¬ oxide adduct are obtained; m.p.: 160-162 C. Analysis: calculated: C: 52.30%, H: 7.37%, N: 18.77 %■ S: 10.73 found: C: 52.00%, H: 7-53%, U: 18.90 %, S: 11.51 Example .7 3.38 g (0.014 mole) of phenyl 2,6-dimeth lphenyl- carbamate are added in portions to a stirred suspension of 1.10 g (0.015 mole) of N-methyl-guanidine in 6 cur of di¬ methyl sulphoxide. Lidamidine - dimethyl sulphoxide adduct separates immediately. The reaction mixture is stirred for additional one hour, thereafter the crystals are filtered off, washed wit methylene chloride and-dried. 4.26 g (97 of lidamidine - dimethyl sulphoxide adduct are obtained. The product is homogeneous when examined by thin layer chr matography and melts at 160-162 C. Example ? A suspension of 36.55 g (0.5 mole) of ϊϊ-methy 1- guanidine and 80.5 g (0.45 mole) of methyl 2,6-dimethyl- p-^e-yl- carbamate in 170 cr_r of dimethyl sulphoxide is warme to 100°C with stirring. The crystalline product starts to separate during the warming period. The mixture is stirred at 100°C for one hour, thereafter cooled to room temperatur the crystals are filtered off, washed with die hloro e thane and dried. 131.2 g (97.7 %) of lidamidine - dimethyl sulph¬ oxide adduct, melting at 160-162°C, are obtained. The purity grade of the product is identical with that obtained according to Example 6. Example 9 100 g of lidamidine - dimethyl sulphoxide adduct are 3 suspended in 700 cur of deionized water, and the suspension Is stirred at 50°C for 0.5 hour. Thereafter the suspension is cooled to room temperature, the separated white crystall ine substance is filtered off, washed with deionized water and dried. 71.8 g (97.2 %) of lidamidine are obtained.

Claims: What we claim is : 1 , A method for the preparation of an amidino-urea derivat ive of the general formula (I) , wherein R 1 , R2 and R^ each stand for hydrogen, halogen, lower alkyl , lower alkoxy, tri luorometh l, nitro or optionally substituted amino , R is hydrogen or lower alkyl , and _5 R is hydrogen or C, , Q alkyl, by reacting an alkyl carbamate of the general formula (ll) l * -t C. wherein R , R and Br are as defined above and R is a 0, - 2 alkyl group, with a guanidine derivative of the general formula (ill) , A ς wherein ^ " and are as defined above, characterized in that the reaction is performed in the presence of a bipolar aprotic solvent. 2. A method as claimed in claim 1, characterized in that dimethyl formamide, dimethyl acetamide, dimethyl sulp oxide, he amethylphosphoric triamide, diethyl acetamide or a mixture thereof is applied as solvent. 3. A method as claimed in claim 1 or 2, characterize in that 0.8-1.25 moles of a guanidine derivative of the general formula (ill) are applied for 1 mole of a carbamate of the general formula (ll) . 4. A method as claimed in any of claims 1 to 3, characterized in that the reaction is performed at a tempe ture between room temperature and the temperature required to remove the alcohol formed in the reaction. 5. A method for preparing an adduct of 1-(2,6-dimeth phenyl)-3-(U-methylamidino)-urea and dimethyl sulphoxide, characterized in that l-(2,6-dimeth lphenyl)-3-(H " -methyl- amidino)-urea, prepared optionally directly in the reactio mixture, is reacted with dimethyl sulphoxide optionally in the presence of one or more inert organic solvent(s), prefe ably a lower alkanol. 6« A method as claimed in claim 5, characterized in that 2,6-dimethylphenyl-isocyanate is reacted with U-methyl guanidine in the presence of dimethyl sulphoxide. 7- A method as claimed in claim 5, characterized in that a lower alkyl 2,6-dimethylphenyl-carbamate is reacted with H-m thyl-guanidine in the presence of dimethyl sulph- oxide. 8o A method as claimed in claim 7, characterized in that the lower alkyl 2,6-dimethylphenyl-carbamate is methy 2,6-dimethyIphenyl-carbamate. _. _ e A method for the preparation of 1-(2,6-dimethy1- phenyl)-3-(U-methylamidino)-urea, characterized in that an adduct of 1-(2,6-dimeth Iphenyl)-3-(N-me h lamidino)-urea and dimethyl sulphoxide is decomposed. 10, A method as claimed in claim 9, characterized in that the adduct is decomposed in the presence of water at a temperature exceeding room temperature.

Inventors: BALOGH SANDOR, NAGY BALAZS, PRIBEK FERENC, TOEROEK SANDOR, BALOGH, SANDOR, NAGY, BALAZS, PRIBEK, FERENC, TOEROEK, SANDOR
Applicants: REANAL FINOMVEGYSZERGYAR
Application year: 1988
Main classification: C07C129
IPC codes: C07C279