HU212939B - Process for producing n-cyano-(n`-3,4-dimethoxyphenyl)-guanidine derivatives - Google Patents

Abstract

Amino derivs. of general formula (1), are prepd. from an iso-thio-carbamide of formula R1NH(CH2)nNHR2 (IV), and a disamine of formula (V) in presence of a catalyst. In formulae, R1 and R2 are H or 1-4C alkyl, or R1 and R2 together are ethylene or propylene; n= 2 or 3.

Description

The present invention relates to a novel process for the preparation of N-cyano-N '- (3,4-dimethoxyphenyl) guanidine derivatives of formula I wherein:

R ¹ is C 1-4 alkyl,

R ² is hydrogen, or

R ¹ and R ² together are ethylene or propylene, n is 2 or 3rd

The compounds of formula (I) are new, except one in which R ¹ and R ² together are ethylene, n is 2. The present invention encompasses all isomers of compounds of formula (I) and tautomeric forms of the preparation.

The compounds of formula (I) are useful as intermediates in the preparation of the known antihypertensive compounds of formula (II), wherein R ¹ , R ² and n are as defined above [J. Chem., 29, 19-25 (1986)].

To this end, the compounds of formula (I) may be acylated by reaction with a mixed anhydride, as described in Hungarian Patent Application Publication No. T / 65360, to give the corresponding N-cyanocarboxamidine derivative disclosed in U.S. Patent No. 203,342. According to the method of the Hungarian patent, cyclization to a quinazoline derivative of the formula II having antihypertensive activity can be carried out.

The preparation of the only known compound of formula (I) is described in U. S. Patent No. 191,252. Hungarian Patent Specification No. 841,360; South African patent application. According to the known procedure, Ncyano-N '- (3,4-dimethoxyphenyl) isothiourea, ΙΠ, which is readily obtainable from 3,4-dimethoxyaniline and N-cyanodiphenylimidocarbonate, is refluxed with piperazine in isopropanol.

A disadvantage of the known process is the use of N-cyanodiphenylimidocarbonate bar, which is difficult to obtain as a starting material and which is difficult to obtain only under the exclusion of moisture and under corrosive conditions, which makes the synthesis of the known compound of formula I very expensive.

Nos. 203,333 and 203,342. According to Hungarian patent applications known method the R ² is furoyl compounds of formula (I) may be prepared from the corresponding diamine and reaction of the isothiourea. The known process has the disadvantage that during the reaction, methyl mercaptan is released, which is dangerous for the environment. A further disadvantage of the known process is that the reaction results in the formation of a by-product of the compound of formula VI, which contaminates the product. Therefore, the quinazoline derivative of the formula (II) can be obtained from the product obtained by the known process only by introducing a substantial loss of material.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simple, economical process for the preparation of the amino derivatives of formula (I).

It has been found that the above object is achieved by reacting the isothiourea derivative of formula IV with a diamine of formula V in the presence of a catalyst, wherein R ¹ , R ² and n are as defined above.

This finding is surprising to those skilled in the art because the methylthio-leaving group of the isothiourea derivative of formula (IV) is less reactive. Considering this from the literature [Org. Prep. Proc. Int., 20, 465 (1988)], it is known that at high temperatures, instead of the S-alkyl leaving group, the cleavage of the cyanimino leaving group is preferred, which is a compound of formula VI wherein R ¹ , R ² and n leading to the foregoing, and given the sensitivity of the diamines of formula (V) to heat and oxidation, the skilled artisan expects a significant amount of by-product to be formed in the reaction of the isothiourea derivative (IV) with the diamine (V). This expectation is confirmed by the presence of two reactive amino groups of the compound of formula (V).

It is therefore surprising that, in the presence of a catalyst, the reaction can be carried out under much milder conditions than the usual reactivity of the methylthio leaving group without the substitution of both amino groups. or significant other by-products are formed.

Furthermore, it was not expected at all that the mercaptides formed from the heavy metal ions added as catalysts to the reaction mixture could be quantitatively removed from the reaction mixture, so that the product was not contaminated, which is particularly important for the purity of the final product.

The catalyst of the present invention is preferably a heavy metal cation in the form of the corresponding oxide or inorganic salt thereof. Preferred catalysts are mercury (II) oxide, lead (II) oxide or mercury (II) chloride.

The amount of catalyst is suitably selected so that 1 mol to 4 molar equivalents, preferably 1 to 1.5 molar equivalents, of heavy metal is added per mol of N-cyano-N '- (3,4-dimethoxyphenyl) -S-methylisothiourea of formula IV.

The reaction is generally carried out in a polar protic or aprotic organic solvent, preferably methanol, ethanol, acetonitrile, dimethylformamide or a halogenated paraffinic derivative, preferably chloroform or 1,2-dichloroethane.

The reaction temperature may be from 20 to 100 ° C, preferably from 50 to 70 ° C.

The reaction produces a heavy metal mercaptide from the catalyst which can be removed from the product solution by simple filtration.

The compound of formula (I) may be isolated in a manner known per se, preferably by evaporation of the filtrate remaining after filtration of the heavy metal mercaptide. The product then precipitates in crystalline form.

The starting compound of formula (IV) may be prepared by reaction of dimethyl N-cyanoimidodithiocarbonate with 3,4-dimethoxyaniline according to conventional procedures [Synthesis. 1972, 322]. The starting compounds of formula (V) are readily available commercially.

The process of the present invention is simple to carry out and provides compounds of formula I in a yield of over 90%.

HU 212 939 Β

The invention is illustrated in detail by the following examples.

Example 1

N-cyano-N- (3,4-dimethoxy-phenyl) amidino-l-piperazine

25.1 g (0.1 mole) of N-cyano-N '- (3,4-dimethoxyphenyl) S-methylisothiourea are suspended in 250 ml of chloroform, 9.5 g (0.11 mole) of anhydrous piperazine are added and Mercury (II) oxide (10.8 g, 0.05 mol) was heated under reflux for 2 hours. The precipitated mercury (II) mercaptide was warm filtered, washed with chloroform (2 x 30 mL), and the filtrate was concentrated in vacuo. The remaining crystalline product was recrystallized from acetonitrile to give 26.9 g (93.0%) of the title product. Mp: 180-182 ° C.

Example 2

N-Cyano-N- (3,4-dimethoxyphenyl) amidino-1-piperazine

All proceed as in Example 1, except that instead of 0.05 mole of mercury (II) oxide

Mercury (II) oxide (21.6 g, 0.1 mol) was used. This gave 27.0 g (93.5%) of the title compound. 180-182 'C.

Example 3

N-Cyano-N- (3,4-dimethoxyphenyl) amidino-1-piperazine

All proceed as in Example 1, except that 13.6 g (0.05 mol) of mercury (H) chloride is used instead of mercury (II) oxide. 26.3 g (91.0%) of the title compound are obtained. Mp 180-182'C.

Example 4

N-Cyano-N '- (3,4-dimethoxyphenyl) amidino-J-piperazine

All proceed as in Example 1, except that 11.2 g (0.025 mol) of lead (II) oxide is used instead of mercury (II) oxide. 24.0 g (83.0%) of the title compound are obtained. Mp: 180-182 ° C.

Example 5

N-Cyano-N '- (3,4-dimethoxyphenyl) amidino] piperazine

All proceed as in Example 1, except that 400 ml methanol is used as solvent instead of chloroform. 25.2 g (87.0%) of the title compound are obtained. Mp: 180182 'C.

Example 6

N-cyano-N- (3,4-dimethoxy-phenyl) amidino-l-piperazine

All proceed as in Example 1 except that 400 ml of ethanol are used as solvent instead of chloroform. 25.7 g (89.0%) of the title compound are obtained. Mp: 180-182 ° C.

Example 7

N-cyano-N '- (3,4-dimethoxy-phenyl) amidino-l-piperazine

All proceed as in Example 1 except that 400 ml of acetonitrile was used as solvent instead of chloroform. 26.3 g (91.0%) of the title compound are obtained. Mp 180-182 'C.

Example 8

N-Cyano-N '- (3,4-dimethoxyphenyl) amidino-1-piperazine

All proceed as in Example 1, except that 40 ml of 1,2-dichloroethane is used as solvent instead of chloroform. 25.2 g (87.0%) of the title compound are obtained. Mp: 180182 'C.

Example 9

N-Cyano-N- (3,4-dimethoxyphenyl) amidino-1-piperazine

All proceed as in Example 1 except that 100 ml of dimethylformamide is used as solvent instead of chloroform and the reaction mixture is stirred at 100 ° C for 1/2 hour. This way

21.1 g (73.0%) of the title compound are obtained. Mp: 180-182 ° C.

Example 10

N-cyano-N- (3,4-dimethoxy-fenir) amidino-l-piperazine

All proceed as in Example 9, except that the reaction mixture is stirred at 20 ° C for 5 hours instead of heating at 100 ° C for 1/2 hour. 17.6 g (61.0%) of the title compound are obtained. Mp: 180-182 ° C.

Example 11

N-cyano-N- (3,4-dimethoxy-phenyl) amidino-l-homopiperazine

All proceed as in Example 1 except that 11.0 g (0.11 mole) of homopiperazine was used in place of piperazine. 26.79 (88.0%) of the title compound are obtained. Mp: 151-153 ° C.

Example 12 1- (3,4-Dimethoxyphenyl) -2-cyano-3-methyl-3- (3-aminopropyl) guanidine

All proceed as in Example 1, except that 9.7 g (0.11 mole) of piperazine is replaced by

3-methylaminopropylamine was used. This way

25.1 g (86.0%) of the title compound are obtained. 127-129 'C.

Claims (2)

PATENT CLAIMS A process for the preparation of amino derivatives of the formula I wherein: R * is C 1 -C 4 alkyl, HU 212 939 Β R ² is hydrogen, or R ¹ and R ² together are ethylene or propylene, n is 2 or 3, for the preparation, wherein the i- formula (IV) 5 thiourea derivative catalyst of a diamine (V) wherein R ^1, R ² and n is as defined above. Process according to claim 1, characterized in that the catalyst is an oxide or halide of a heavy metal, preferably mercury (II) oxide or lead (II) oxide or mercury (II) chloride.