HU198177B - Process for producing molecular compound of 1-(2,6-dimethylphenyl)-3-(n-methylamidino)-urea with dimethylsulfoxide - 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 process for the preparation of a compound of 1- (2,6-dimethylphenyl) -3- (N-methylamidino) urea with dinylsulfoxide.

1- (2,6-Dimethylphenyl) -3- (N-methylamidino) urea (lidamidine) is an outstanding representative of amidino-urea derivatives. The most valuable of its many beneficial therapeutic effects is the anti-diarrhea (Fortschrittq dér Arzneimittelforschung 28, 1435 (1978)), which has not been known so far.

Nos. 4,060,635, 4,147,804, 4,203,920 and 4,283,555. U.S. Patent Nos. 4,179,197 and 5,946,185, respectively. The preparation of Lidamidine by reaction of a phenyl ester of 2,6-dimethylphenylcarbamic acid with N-methylguanidine is disclosed in U.S. Patent No. 78.03152. Dutch Patent No. 1,072,962; Canadian Patent Specification No. 78/1574; According to our own measurement results, this process can be prepared in a state contaminated with lidamidine phenol and the starting 2,6-dimethylphenylcarbamic acid phenyl ester in a yield of 60-65%, and its purification requires several steps. , and yields to about 40% during purification operations.

It is known that lidamidine is always purified by salt formation, usually by forming the hydrochloride from the contaminated base and recrystallizing the resulting salt. The recrystallized hydrochloride or the pure lidamidine liberated therefrom have a purity according to the prescriptions.

In our experiments to simplify the preparation and purification of lidamidine, we have found that lidamidine forms a 1: 1 molar compound (adduct) with dimethylsulfoxide, and this adduct is a very pure drug! can be isolated from the reaction mixture in a suitable quality. The molecule compound of lidamidine with dimethyl sulfoxide can be used directly as an active ingredient in anti-diarrheal pharmaceuticals.

Thus, when lidamidine is available in its crude (contaminated) form, it is very easy to prepare a derivative that can be used directly in the preparation of pharmaceutical compositions by reacting lidamidine with dimethyl sulfoxide. When provided in the form of the acid addition salt of lidamidine, the base release may be carried out in dimethyl sulfoxide or a mixture thereof with one or more inert solvents; in this case, a derivative which can be used directly for medical purposes is again obtained and the process of recrystallization of the acid addition salt can be eliminated. When lidamidine is formulated in a manner other than base release in the adduct-forming reaction itself, for example, by 2,6-dimethylphenyl isocyanate, 2,6-dimethylphenylcarbamic acid phenyl ester or 2,6-dimethylphenyl. carbamate (lower alkyl) ester is reacted with N-methylguanidine in the presence of dimethylsulfoxide; 97-99%) as if the reaction was carried out in the absence of dimethyl sulfoxide. This additional advantage is believed to be due to the immediate formation of lidylitin in the reaction mixture with dimethyl sulfoxide. adduct, and adduct formation shifts the basic reaction toward lidamidine formation.

The present invention therefore relates to a process for the preparation of a lidamidine molecule with dimethylsulfoxide. The process of the present invention involves the reaction of lidamidine, optionally formed in the reaction mixture itself, with dimethylsulfoxide, optionally in the presence of one or more inert organic solvents.

The lidamidine dimethylsulfoxide adduct is a novel compound; stable crystalline material, m.p. 160-162 ° C. The structure and composition of the compound were confirmed by elemental analysis and UV, IR and NMR spectra.

Pharmaceutical compositions containing the lidamidine dimethylsulfoxide adduct having anti-diarrheal activity may be prepared in a known manner by conventional pharmaceutical techniques using known pharmaceutical diluents, carriers and / or other excipients.

The invention is further illustrated by the following non-limiting Examples.

Example 1 g (0.13 mol) of a contaminated lidamidine base having a thin layer chromatogram of three spots (m.p. 171-172 ° C) was dissolved in methanol (90 ml) with heating and dimethylsulfoxide (20 ml) was added. The white crystalline lidamidine dimethyl sulfoxide adduct immediately begins to precipitate. After stirring for 1 hour at room temperature, the product is filtered off, washed with a little methanol and dried to constant weight. 30.5 g (75%) of the lidamidine dimethylsulfoxide adduct is obtained, which is homogeneous by TLC, m.p. 160-162 ° C.

Example 2

To a suspension of 4.04 g (0.055 mol) of N-methylguanidine in 20 cm ^{3 of} dimethylsulfoxide was added 7.36 g (0.050 mol) of 2,6-dimethylphenyl isocyanate at room temperature. The white crystalline lidamidine-dimethylsulfoxide adduct slowly precipitates during the addition of the reagent. After stirring for one hour, the crystals are filtered off, washed with a little cold methanol and dried. 14.80 g (99%) of product are obtained; mp 160-162 ° C.

Analysis data: 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%.

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Example 3

To a suspension of N-methylguanidine (1.10 g, 0.015 mol) in dimethyl sulfoxide (6 cm ³ ) was added 2,6-dimethylphenylcarbamic acid phenyl ester (3.38 g, 0.014 mol). The lidamidine dimethylsulfoxide adduct precipitates instantaneously. After stirring for half an hour, the crystals were filtered off, washed with methylene chloride and dried. 4.26 g (97%) of the lidamidine dimethylsulfoxide adduct are obtained. The product was homogeneous by TLC with the same melting point

Example 1.

Example 4

A suspension of 36.55 g (0.5 mole) of N-methylguanidine and 80.5 g (0.45 mole) of 2,6-dimethylphenylcarbamic acid methyl ester in 170 cm ^{3 of} dimethylsulfoxide was stirred 100 Heat to C. Meanwhile, crystallization of the final product begins. After stirring for 1 hour at 100 ° C, the reaction mixture was cooled to room temperature, the crystals were filtered off, washed with dichloromethane and dried. 131.2 (97.7%) of the lidamidine dimethylsulfoxide adduct were obtained. The product has the same melting point and purity as the product obtained in Example 1.

Claims (4)

PATENT CLAIMS A process for the preparation of a molecular compound of 1- (2,6-dimethylphenyl) -3- (N-methylaminidino) urea with dimethyl sulfoxide, characterized in that 1 (2,6-dimethylphenyl) -3 (N-Methylamidino) urea, optionally formed in the reaction mixture itself, is reacted with dimethylsulfoxide and, if required, in the presence of one or more inert organic solvents, preferably lower alkanol. Process according to claim 1, characterized in that the starting material is the reaction mixture of 1- (2,6-dimethylphenyl) -3- (2-dimethylphenyl) -3- (6-dimethylphenyl) isocyanate with N-methylguanidine. N-methylamidino) urea was used. 3. The process according to claim 1, wherein the starting material is the reaction of 2,6-dimethylphenylcarbamic acid lower alkyl ester with N-methyl guanidine. 1 (2,6-dimethylphenyl) -3- (N-methylanilino) urea formed in the reaction mixture itself. The process according to claim 3, wherein the corresponding methyl ester is used as the ester of 2,6-dimethylphenylcarbamic acid.