EP0325620A1

EP0325620A1 - Method for the preparation of amidino-urea derivatives

Info

Publication number: EP0325620A1
Application number: EP88903333A
Authority: EP
Inventors: Sándor TÖRÖK; Balázs NAGY; Ferenc Prib K; Sándor BALOGH
Original assignee: Reanal Finomvegyszergyar Rt
Current assignee: Reanal Finomvegyszergyar Rt
Priority date: 1987-04-10
Filing date: 1988-04-08
Publication date: 1989-08-02
Also published as: AU1598088A; FI885700A7; KR890700572A; AU605584B2; KR910008221B1; FI885700A0; WO1988007990A1

Abstract

Un procédé amélioré permet de préparer des dérivés d'amidino-urée ayant la formule générale (I), dans laquelle R1, R2 et R3 sont hydrogène, halogène, alkyl inférieur, alkoxy inférieur, trifluorométhyle, nitro ou amino éventuellement substitué, R4 est hydrogène ou alkyl inférieur, et R5 est hydrogène ou C1-10 alkyl, en mettant en réaction un carbamate d'alkyl inférieur avec un dérivé approprié de guanidine. Selon l'invention, la réaction se fait en présence d'un solvant aprotique bipolaire. En outre, un procédé permet de préparer un produit d'addition de 1-(2,6-diméthylphényle)-3-(N-méthylamidino)-urée et de sulphoxyde diméthyle, en mettant en réaction 1-(2,6-diméthylphényle)-3-(N-méthylamidino)-urée, éventuellement préparée directement dans le mélange de réaction, avec du sulphoxyde diméthyle. En décomposant ce produit d'addition avec de l'eau, on obtient 1-(2,6-diméthylphényle)-3-(N-méthylamidino)-urée à un état extrêmement pur.An improved process makes it possible to prepare amino-urea derivatives having the general formula (I), in which R1, R2 and R3 are hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro or amino optionally substituted, R4 is hydrogen or lower alkyl, and R5 is hydrogen or C1-10 alkyl, reacting a lower alkyl carbamate with an appropriate guanidine derivative. According to the invention, the reaction is carried out in the presence of a bipolar aprotic solvent. In addition, a process makes it possible to prepare an adduct of 1- (2,6-dimethylphenyl) -3- (N-methylamidino) -urea and dimethyl sulphoxide, by reacting 1- (2,6-dimethylphenyl ) -3- (N-methylamidino) -urea, optionally prepared directly in the reaction mixture, with dimethyl sulphoxide. By decomposing this adduct with water, 1- (2,6-dimethylphenyl) -3- (N-methylamidino) -urea is obtained in an extremely pure state.

Description

METHOD FOR THE PREPARATION OF AMIDINO-UREA DERIVATIVES

The invention relates to a new method for the preparation of amidino-urea derivatives.

It is known that amidino-urea derivatives possess numerous favourable physiological properties [Fortschritte der Arzneimittelforschung 28, 1435 (1978)]. Of them 1-(2,6-dimethylphenyl)-2-(N-methylamidino)-urea (lidamidine) is of 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 literature for the preparation of amidino-urea derivatives. Depending on 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 occur simultaneously during the synthesis [Fortschritte der Arzneimittelforschung 28, 1436 (1978)].

Amidino-urea derivatives can also be prepared by reacting the respective isocyanates with guanidino derivatives (US patents Nos. 4,060,635, 4,147,804, 4,203,920 and

4,283,555). The reaction proceeds generally easily and provides 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 inconveniences, since, on one hand, isocyanates are difficult to store and transport, and, on the other hand, the reaction with isocyanates frequently does not stop at the formation of the required end product but proceeds further and gets difficult or impossible to control. 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. 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 methods 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 No. 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 steps are required in order to separate the amidino-urea derivatives from the starting carbamates and phenol formed in the reaction. Considering that phenyl chloroformate, required as starting substance to prepare phenyl carbamates, is an expensive chemical, it is obvious that the above method cannot be applied for large scale production. The utilization of alkyl carbamates, which require much less expensive starting 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 conditions that no successful reaction can be expected [J. Am. Chem. Soc. 76, 4458 (1954)].

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 good yield within a relatively short period of time.

Based on the above, the invention relates to a method for the preparation of an amidino-urea derivative of the general formula (I),

wherein

R¹, R² and R ³ each stand for hydrogen, halogen, lower alkyl, lower alkoxy , trifluoromethyl, nitro or optionally substituted amino , R⁴ is hydrogen or lower alkyl , and R⁵ is hydrogen or C_1-10 alkyl, by reacting an alkyl carbamate of the general formula (II) ,

wherein R¹, R² and R³ are as defined above and R⁶ is a C_1-1 alkyl group , with a guanidine derivative of the general formula (III) , wherein R⁴ and R⁵ 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, dimethyl acetamide, dimethyl sulphoxide, hexamethylphosphoric acid triamide, diethyl acetamide or any mixture of these liquids as bipolar aprotic solvent.

The alkyl carbamate of the general formula (II) is reacted with the guanidine derivative of the general formula (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 alkanol from the mixture within a short period of time. The removal of the alkanol can also be facilitated by simultaneously lowering the pressure of the reaction.

The resulting compound of the general formula (I) is separated from the reaction mixture in a manner known per se. According to a preferred method the reaction mixture is poured into water, and the amidino-urea derivative, separated as a crystalline substance, is removed e.g. by filtration. Solvents other than water can also be applied as precipitating agents. The end products obtained are generally sufficiently 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 separated end product, optionally in undried state, is directly converted into its salt, and, if necessary, the salt is purified further. Any of the mineral and organic acids applicable 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 the invention are as follows: - no poisonous and hazardous reactants (phosgene, isocyanates) are required;

- the reaction proceeds smoothly with good yields, and byproducts 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 N-methyl-guanldlne with a lower 2,6-dimethyl¬phenyl carbamate in the presence of dimethyl sulphoxide, an adduct (molecular compound) comprising lidamidine and dimethyl sulphoxide in a molar ratio of 1:1 is formed. The same adduct is obtained when reacting crude or pure lidamidine, 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 160-162ºC . This compound can be prepared in extreme ly pure state, and can be utilized for the preparation of highly pure lidamidine. The lidamidine - dimethyl sulphoxide adduct 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 directly in the reaction mixture, is reacted with dimethyl sulphoxide optionally in the presence of one or more inert organic solvent(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 also proceed in such a way that lidamidine base is dissolved or suspended first in an inert organic solvent, and the required amount of dimethyl sulphoxide, preferably at least one molar equivalent calculated for lidamidine, is added to this solution 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 a salt of lidamidine is applied as starting substance, and lidamidine base is liberated from its salt directly in dimethyl 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-dimethylphenyl-carbamate or a lower alkyl 2,6-dimethylphenyl-carbamate is reacted with N-methyl-guanidine in the presence of dimethyl sulphoxide, whereupon lidamidine, which forms in the reaction mixture, Immediately converts into the respective dimethyl sulphoxide adduct. A particular advantage of this latter method is that the resulting adduct is extremely pure, free of any contaminations originating from the starting substances applied in the preparation of lidamidine.

As mentioned above, the lidamidine - dimethyl sulphoxide adduct can be converted directly into pharmaceutical compositions, such as tablets, capsules, suspensions, etc., by routine pharmacotechnological methods utilizing conventional 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 this 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 decomposed with water generally at 0-100°C, preferably at 20-80°C. It is preferred to apply at least one molar equivalent 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 separated from the mixture by a method known per se.

The invention is elucidated in detail by the aid of the following non-limiting Examples. Example 1

A mixture of 7.17 g (0.04 mole) of methyl 2,6-dimethylphenyl-carbamate, 3.21 g (0.044 mole) of methyl-guanidine and 15 cm³ of dimethyl formamide 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 of the reaction the mixture is stirred for additional one hour, thereafter it is cooled to room temperature, poured into 160 cm³ of cold water, and the aqueous mixture is stirred at 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 crude product is dissolved in 80 cm³ of methanol, the solution is decolourized with a small amount of activated carbon, filtered, and the filtrate is acidified to pH 2 with methanolic hydrogen 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 small amount of acetone and then with ether, and dried. 1-(2,6-Dimethylphenyl)-3-(N-methylamidino)-urea hydrochloride is obtained; m.p.: 194-197°C. The IR spectrum of the product is identical with that of the authentic sample.

Example 2

One proceeds as described in Example 1 with the difference that 15 cm³ of hexamethylphosphoric acid triamide are utilized as reaction medium, and the mixture is maintained at 100°C for 2 hours. 6.87 g (78.1 %) of 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-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-dimethylpheny l-carbamate and 36.55 g (0.5 mole ) of methylguanidine 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 in Example 1 with the difference that salt formation is omitted. 86.58 g (86.5 %) of 1- (2, 6-dimethylphenyl)-3- (N-methylamidino ) -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 methylguanidine in 15 cm³ of dimethyl sulphoxide as described in

Example 3. 6.69 g (80.6 %) of 1- (2, 6-dimethylphenyl)-3-(N-methylamidino)-urea are obtained.

Example 5

One proceeds as described in Example 1 with the difference that 15 cm³ of dimethyl acetamide are applied as reaction medium and the reaction is performed for 2 hours. The mixture is processed as described in Example 1. 6.06 g (68.8 %) of 1-(2,6-dimethy1phenyl)-3-(N-methylamidino)-urea are obtained. The hydrochloride of the product is identical with the compound prepared according to Example 1. Example 6 7.36 g (0.050 mole) of 2,6-dimethylphenyl-isocyanate are added dropwise, at room temperature, to a stirred suspension of 4.04 g (0.055 mole) of N-methylguanidine in 20 cm³ of dimethyl sulphoxide. The white, crystalline lidamidine - dimethyl sulphoxide adduct separates slowly during 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 methanol and dried. 14.80 g (99 %) of lidamidine - dimethyl sulphoxide 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%, N: 18.90 %, S: 11.51 %.

Example 7

3.38 g (0.014 mole) of phenyl 2,6-dimethylphenyl- carbamate are added in portions to a stirred suspension of

1.10 g (0.015 mole) of N-methyl-guanidine in 6 cm³ of dimethyl sulphoxide. Lidamidine - dimethyl sulphoxide adduct separates immediately. The reaction mixture is stirred for additional one hour, thereafter the crystals are filtered off, washed with 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 8 A suspension of 36.55 g (0.5 mole) of N-methylguanidine and 80.5 g (0.45 mole) of methyl 2,6-dimethylphenyl-carbamate in 170 cm³ of dimethyl sulphoxide is warmed 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 temperature, the crystals are filtered off, washed with dichloromethane and dried. 131.2 g (97.7 %) of lidamidine - dimethyl sulphoxide 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 suspended in 700 cm³ 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 crystalline 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 R¹, R² and R³ each stand for hydrogen, halogen, lower alkyl , lower alkoxy, trifluoromethyl, nitro or optionally substituted amino ,

R⁴ is hydrogen or lower alkyl , and R⁵ is hydrogen or C_1-10 alkyl, by reacting an alkyl carbamate of the general formula (ll) ,

wherein R¹, R² and R³ are as defined above and R⁶ is a C_1-3 alkyl group, with a guanidine derivative of the general formula (III) ,

wherein R⁴ and R⁵ 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 sulphoxide, hexamethylphosphoric triamide, diethyl acetamide or a mixture thereof is applied as solvent.

3. A method as claimed in claim 1 or 2, characterized in that 0.8-1.25 moles of a guanidine derivative of the general formula (III) 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 temperature 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-dimethylphenyl)-3-(N-methylamidino)-urea and dimethyl sulphoxide, characterized in that 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-urea, prepared optionally directly in the reaction mixture, is reacted with dimethyl sulphoxide optionally in the presence of one or more inert organic solvent(s), preferably a lower alkanol. 6. A method as claimed in claim 5, characterized in that 2,

6-dimethylphenyl-isocyanate is reacted with N-methylguanidine 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 N-methyl-guanidine in the presence of dimethyl sulphoxide.

8. A method as claimed in claim 7, characterized in that the lower alkyl 2,6-dimethylphenyl-carbamate is methyl 2,6-dimethyIphenyl-carbamate.

9. A method for the preparation of 1-(2,6-dimethylphenyl)-3-(N-methylamidino)-urea, characterized in that an adduct of 1-(2,6-dimethyIphenyl)-3-(N-methylamidino)-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.