HU198178B - Process for producing 1-(2,6-dimethylphenyl)-3-(n-methylamidino)-urea - Google Patents

Abstract

An amidino-urea cpd. of the formula (I) is prepd. by reacting an alkyl carbamate of the formula (II) with a guanidine cpd. of the formula (III) in the presence of a bipolar aprotic solvent. R1, R2 and R3 are each H, halogen, lower alkyl, lower alkoxy, CF3, NO2 or opt. substd. amino; R4 is H or lower alkyl; R5 is H or 1-10C alkyl; and R6 is 1-3C alkyl. - An adduct of 1-(2,6-dimethylphenyl) -3-(N-methylamidino) -urea (Ia) and DMSO is prepd. by reaction of these two cpds., opt. in the presence of an inert solvent or solvents, pref. a lower alkanol. Cpd. (Ia) is prepd. by decomposing its adduct with DMSO. The adduct is described as new but is not claimed per se.

Description

The present invention relates to a novel process for the preparation of 1- (2,6-dimethylphenyl) 3- (N-methylamidino) urea (lidamidine).

Lidamidine is an outstanding representative of amidino-urea derivatives. The most valuable of its many beneficial therapeutic effects is the anti-diarrhea effect (Fortschritte dér Arzneimittelforschung 28, 1435 (1978)).

The most obvious way of preparing the compound is to react 2,6-dimethylphenyl isocyanate and N-methylguanidine in tetrahydrofuran (U.S. Pat. Nos. 4,060,635 and 4,020,920). One variant of this method is the preparation of 2,6-dinethylphenyl isocyanate in the reaction mixture itself (Spanish Patent Nos. 546,126 and 548,902). The product is obtained in a yield of about 80%.

According to another known method, lidamidine is prepared by reacting phenyl (N- (2,6-dimethylphenyl) carbamate and N-methyl guanidine in an alcoholic or toluene medium with a yield of about 60%, which is purified at 40 ° C. Decreases to C (South African Publication No. 78/1574). As described herein, low-carbon alkyl carbamates could be used as reagents, but no exemplary embodiment or specific teaching of alkyl carbamates is provided.

Other processes for the preparation of lidamidine (e.g. acid hydrolysis of the corresponding biguanide) are also known, but their industrial applicability with the former method is also not significant.

The disadvantage of the process starting from the isocyanate derivative is that the extremely toxic phosgene is required for the preparation of the starting isocyanate, and the isocyanate compound itself is a dangerous size. In addition, the high reactivity of 2,6-dimethylphenyl isocyanate is detrimental, which on the one hand makes it difficult to store and transport the compound and on the other hand often leads to the reaction going beyond the intended extent and becoming uncontrollable. To prevent this, 100% excess N-methyl guanidine is used, which greatly increases the cost of the process.

The use of 2,6-dimethylphenyl isocyanate produced in situ can eliminate the use of toxic phosgene and the storage and transport difficulties of the isocyanate, but the reaction is much more time consuming, complicated and expensive than the phosgene-requiring method. This process is essentially for laboratory use only but not for industrial production.

Reaction of phenyl (N- (2,6-dimethylphenyl) carbamate and N-methylguanidine) yields substantially less than isocyanate yields. Further difficulties arise in the isolation of the final product: the separation of lidamidine from the phenol formed or the starting carbamate can only be accomplished by complex purification steps. Also considering that the chloro formic acid phenyl ester required for the preparation of the starting phenylcarbamate dehydrogen is a costly material, it is obvious that this method is not commercially feasible.

According to the present invention, lidamidine is prepared from a 1: 1 molar compound of lidamidine dimethyl sulfoxide by reacting the lidamidine dimethyl sulfoxide adduct with water. By this procedure, very high purity lidamidine is obtained.

The decomposition of the lidamidine dimethylsulfoxide adduct is carried out at 0-100 ° C, preferably at 20-80 ° C. Preferably, at least 1 molar equivalent of water is used for the reaction. The upper limit for the amount of water is determined primarily by considerations of economy and expediency. The lidamidine formed in the reaction is isolated in a manner known per se.

The lidamidine dimethylsulfoxide adduct used as starting material in the process of the present invention is a novel compound which can be prepared, for example, by reacting methylguanidine in dimethylsulfoxide with 2,6-dimethylphenylcarbamic acid ester or 2,6-dimethylphenylisocyanate or crude or reacting contaminated lidamidine with dimethyl sulfoxide. The lidamidine dimethylsulfoxide adduct is a white crystalline solid, m.p. 160-162 ° C.

The novel process according to the invention has the following advantages:

- lidamidine can be obtained by this process in a purity higher than the final product of any known process;

reaction time is shorter than known processes;

- yield is practically quantitative;

- the procedure is cheap and harmless.

The following Examples illustrate the process of the invention in more detail.

. example

100 g of lidamidine dimethylsulfoxide are suspended in 700 cm ^{3 of} deionized water and the suspension is stirred for half an hour at 50 ° C. The slurry is then cooled to room temperature, the excess crystalline material is filtered off, washed with deionized water and dried. 71.8 g (97.2%) of lidamidine are obtained; mp 178.4-179.5 ° C.

EXAMPLE 2 Lidamidine dimethylsulfoxide molculae compound (g) is sprayed into 50 cm ^{3 of} deionized water with stirring and the crystal suspension is stirred for 2 hours at 20 ° C. The crystalline material was filtered through a G3 sintered glass filter, washed twice with 10 cm ^{3 of} water and dried to constant weight. 3.54 g (96.0%) of lidamidine are obtained; m.p. 177.5-178.2 ° C. The product was homogeneous by TLC.

Example 3

The procedure described in Example 2 was followed except that the suspension was stirred for 10 minutes at 80-90 ° C. The slurry is then cooled to room temperature and the product is filtered off. 3.43 g (92.6%) of lidamidine are obtained; mp 178.5-179.5 ° C.

Claims (1)

Patent Claim Point A process for the preparation of 1- (2,6-dimethyl-phenyl) -3- (N-methyl-amidino) -urea, characterized in that the 1- (2,6-dimethyl-phenyl) -3- (N-methyl-anidino) ) urea with dimethyl sulfoxide is decomposed at 0-100 ° C, preferably at 20-80 ° C, with water.