DE1518229C3 - Process for the preparation of N-BenzyH> T, N "-dimet hy! Guanidine - Google Patents

Description

The invention relates to processes for the preparation of N-benzyl-N ', N "-dimethylguanidine or its Acid addition salts.

From British patent specification 973 882 it is known that benzylguanidines are pharmacologically effective and particularly suitable for the treatment of high blood pressure are, such as, for example, the N-benzyl or N- (2-bromobenzyl) - or N- (2-chlorobenzyl) - or N- (3-methylbenzyl) -N ', N "-dimethylguanidine.

N-Benzyl-N ', N "-dimethylguanidine is known under the name" Bethanidine "and can be used for the process described in German Patent 1288 591 can be produced by a N-benzylisothiourea substituted on the sulfur atom is reacted with methylamine. Disadvantageous at this process is the fact that the reaction proceeds with not particularly high yields and as By-product methyl mercaptan is obtained, which is removed from the end product by careful purification must be and leads to difficulties in the destruction of the mercaptan-containing mother liquors. The hitherto customary and economically cheapest method is therefore relatively expensive because for the first stage of the process also requires an alkylating agent such as methyl iodide must generally be worked at higher temperatures, which is a not inconsiderable Energy consumption leads. However, the lengthy cleaning of the end products that is necessary is particularly disadvantageous of the mercaptans formed, thereby reducing the yields and the costs of the overall process can be greatly increased.

The invention is therefore based on the object of providing new processes for the preparation of N-benzyl-N ', N "-dimethylguanidine to develop that do not have the disadvantages described.

The invention relates to a process for the preparation of N-benzyl-N ', N "-dimethylguanidine or its acid addition salts by reacting an isocyanate dihalide with a secondary amine, which is characterized in that a benzyl isocyanate dihalide with an alcoholic solution of free methylamine base in an inert Reacts solvent at temperatures up to 25 ⁰ C to the corresponding N-benzyl-Ν ', Ν "- dimethylguanidine hydrohalide and this optionally converted into the free base or a salt of another acid.

From the German Auslegeschrift 1 089 210 it is known that Arylisocyandichloride with primary or secondary amines can be converted into trisubstituted guanidines; in H ο u b e η —W e y 1, Methods of Organic Chemistry, 4th Edition, Vol. 8, 1952, p. 188, there is a reference to the possibility to produce N, N ', N "-triphenylguanidine in this way. From German Auslegeschrift 1 170 931 a process for the preparation of substituted guanidines is also known in which alkyl,

ίο Cycloalkyl- or Arylcyandihalogenide in an aqueous alkaline medium can be reacted with primary or secondary amines. In the first paragraph However, column 1 of this German interpretative document states that this implementation with or without organic Solvent is known per se, but that long reaction times and minimal yields in Purchase must be made. From the works cited in the German Auslegeschrift 1 170 931 it turns out that so far only arylcyanedichlorides with aromatic amines, such as aniline, or with piperidine had been subjected to these reactions. In reports of the German Chemical Society 7, S. 1233 (1874), on the other hand, there is a note that the reaction of phenylisocyane dichloride with Ammonia only leads to an indefinable resin.

It was therefore completely surprising that when ammonia was replaced by the closely related methylamine the reaction with the previously unknown benzyl isocyanate dihalide under particularly mild conditions in a neutral inert solvent lead smoothly to the desired unsymmetrical guanidine it was rather to be expected that this reaction would give resinous products or under mild ones Conditions would not take place at all. Furthermore, there was a reasonable risk that the Reaction with methylamine according to the following equation:

C ₆ H ₅ -CH ₂ -N = CCl ₂ + 3H ₂ NCH ₃

- ^ C ₆ H ₅ -CH ₂ -N = C = NCH ₂ + 2H ₂ NCH ₃ -HCl

to the corresponding completely undesirable carbodiimide could lead.

The benzylisocyandihalides required as starting compounds for the process according to the invention are new compounds that can be used for numerous chemical reactions. You can use one of the various known for the production of isocyanate dihalides Procedure can be obtained. For example, they can be obtained by Benzyl isocyanide halogenated directly, conveniently in a solvent such as chloroform.

However, production from benzyl isothiocyanate with a halogen according to the equation is more advantageous (1):

C ₈ H ₅ - CH ₂ - NCS + 2HaI ₂
- + - C ₆ H ₅ - CH ₂ - NC = Hal ₂ + SHaI ₂ (1)

This process not only avoids the use of isocyanides and also avoids a high one Obtained yield, but there is practically no reaction between the phenyl nucleus and instead of the free halogen. The sulfur dihalide formed as a by-product can also be from the isocyanate dihalide can be easily separated.

This reaction is most favorable with or under- It is most advantageous to use gaseous chlorine in

half room temperature, for example between -20 metric excess in the reaction mixture

and + 30 ° C, preferably ^{carried out at about O 0} C, feed.

and most conveniently in the presence of a solvent. The implementation of the benzyl isocyanate thus prepared

solvents such as carbon tetrachloride. As halogens 5 dihalides with methylamine corresponds to the following

chlorine or bromine are preferred, these in equation:
can be in any aggregate state.

, NR ¹

RNCHaI ₂ + 2R ¹ NH ₂ - »- RNH - C 'f · HHaI + HHaI (2)

NHR ¹

Here, R is a benzyl radical, and R ^{1 is} each one

Methyl radical and Hal are each a halogen atom. 15 example

The methylamine is used as the free base and preferably in excess, specifically in a benzyl isocyanate-alcoholic medium used as the starting product, for example in methanol dichloride was produced by methods a) and b) or ethanol. The reaction medium used is a low, the latter being preferred,
boiling inert solvent such as ether or Ben-20 a) 5 g of benzyl isocyanide were zol in 50 ml of chloroform. The reaction is strongly exothermic, and the solution dissolved, whereupon the solution with dry medium contributes to the distribution and discharge of the reac-chlorine at ⁰ ° C. was saturated. The production heat at. was distilled under vacuum. The at HO ⁰ C /

The 15 torr boiling fraction obtained in the process according to the invention consisted of benzyl iso-

Products are N-benzyl-N ', N "-dimethylguanidine-25 cyandichlorid.

Acid addition salts of the corresponding halogenated water b) 40 g of benzyl isothiocyanate were dissolved in 50 ml of tetra-carbon since, according to equation (2), hydrogen halide was dissolved in chlorocarbon and formed as a by-product for about 50 minutes. The hydrohalides, in particular at 0 to 10 ⁰ C treated with chlorine. In order to remove the hydrochlorides in particular, however, the solvent and sulfur in general are very deliquescent and are therefore advantageous. heated to 100 ° C; then the added salt or a corresponding salt, ζ. B. in solution or remaining, straw-colored oil distilled, in an ion exchange column, in another salt benzyl isocyanate, boiling point 112 to 116 ° C / transferred. For example, sulfates, lactates, 16 torr, were obtained in good yield.
Citrates, tartrates, succinates, oxalates, paratoluene sulfo- 35 _ 18.8 g benzyl isocyanate dichloride in 200 ml dry nate and maleates can be prepared. Ether at 0 to 25 ° C with stirring to 200 ml

The process according to the invention can be up to a 33% ethanolic methylamine solution

be carried out under particularly mild conditions, since added dropwise, making sure that the temperature

the reactions generally did not rise above 25 ° C without heating. Solvents and

to run. In addition, almost quantitative yields 40 excess methylamine were evaporated, the

receive; in the reaction of the isothiocyanate with remaining deliquescent solid product consisted of

Halogen, for example, a yield of about substantially from a mixture of methylamine

90% and in the reaction of the isocyanate dihalide hydrochloride and N-benzyl-N ', N "-dimethylguanidine-

with the primary amine a yield between 80% hydrochloride.

and 90% achieved, which is particularly important for the technical 45 This residue was dissolved in 100 ml of water,

Implementation is of great importance. Especially the aqueous solution was washed with ether and

It is also advantageous that the second reaction is then basic with 24 g of solid sodium hydroxide

step no unpleasant mercaptans as a side effect. The yellow oil which separated out was with

products are formed and thus not extracted from the ether, and the ethereal solution was with

Product can be absorbed so that the pro-50 solid sodium hydroxide is thoroughly dried. At the

The problem of eliminating these compounds was not limited to the concentration of the dried solution.

occurs. Instead, only hydrogen halide is formed, stable base, melting point about 92 ° C, is obtained,

which in the formation of guanidine acid addition which by neutralization with dilute aqueous

half of the salt is absorbed by the product. 2η-sulfuric acid and again concentration in the N-ben-

O'.e practical advantages of the invention was transferred cyl-N ', N "-dimethyIguanidinsulfat,

Fahrens are therefore very large and represent a real melt after recrystallization from methanol / acetone

technical progress. The compound at 289 to 290 ° C with decomposition.

Claims (1)

Claim: Process for the preparation of N-benzyl-Ν ', Ν "- dimethylguanidine or its acid addition salts by reacting an isocyanic dihalide with a secondary amine, thereby characterized in that one is a benzyl isocyanate dihalide with an alcoholic solution of free methylamine base in an inert solvent at temperatures up to 25 ° C to the corresponding N-benzyl-N ', N "-dimethylguanidine hydrohalide converts and this optionally in the free base or in a salt of another Acid transferred.