DE1064070B - Process for the production of murexin chloride chlorohydrate - Google Patents

Description

Ornamental process for the production of murexin chloride chlorohydrate The invention refers to a new process for the synthesis of murexin chloride chlorohydrate.

In the patent specification 1,021,851 is the chemical nature of Murexin, its effect on neuromuscular transmission and a method of synthesizing described.

According to this process, which involves a multi-step synthesis the 2-chloro-ethyl ester of a-chloro-β-imidazolyl-4 (5) -propionic acid with trimethylamine implemented to obtain murexin chloride, which is extremely hygroscopic.

This compound provides when treated with a saturated picric acid solution Murexin dipikrat in the form of yellow-orange needles, a constant and almost in water insoluble connection.

For the extraction of murexin chloride chlorohydrate, which is used for therapeutic purposes Murexin dipikrate is added to a suitable chlorohydrate, z. B. 2,4-diguanidine phenyl lauryl ether chlorohydrate to. Through double implementation a precipitate is obtained, consisting of 2,4-diguanidine phenyl lauryl ether dipikrat, which can be easily filtered off, while from the solution murexin as murexin chloride chlorohydrate monohydrate, a microcrystalline white powder, is obtained.

It has now been found and is the subject of the new invention that Murexin chloride chlorohydrate can also be obtained in another way; these new synthesis leads to the goal much more quickly because, in contrast to the older synthesis, the isolation of the intermediates is not required and the desired product is obtained in a single stage. The inventive method is thereby characterized in that one malonyl monochloride at ordinary temperature in one anhydrous inert solvent, preferably ethyl ether, reacts with choline chloride, the residue after removal of the solvent at a slightly elevated temperature in Presence of another solvent, preferably ethanol, and hydrochloric acid with 4 (5) -Formyl-imidazole converts the water of reaction formed by means of a with water an azeotrope-forming low-boiling solvent, in particular benzene, is removed and finally cleans the remaining residue in a known manner.

The new method is described in more detail below: According to the invention Malonyl monochloride (I) is used at ordinary temperature and pressure in a suitable solvent with choline chloride (II), whereby one monomalonylcholine chloride (III) obtained as an intermediate product which does not need to be isolated. as An anhydrous liquid must be used as the solvent for this reaction stage which does not react with malonyl monochloride, d. i.e., this liquid is supposed to do not contain any chemical groups in their molecule similar to those in malonyl monochloride contained, very highly reactive C O Cl group can react.

Of the various possible organic solvents Anhydrous ethyl ether is best suited for this purpose, its use accordingly a preferred embodiment of the method according to the invention represents; other anhydrous ethers can also be used without the Is left within the scope of the invention.

The intermediate (III) is then after removal of the solvent at mild temperatures of z. B. 50 to 60 ° C with 4 (5) -formyl-imidazole or 4 (5) -imidazylcarbonylaldehyde (IV) in a suitable second solvent, in this case preferably ethyl alcohol, solved.

By splitting off 1 molecule of water from the oxygen atom the aldehyde group and the two hydrogen atoms of the malonic acid derivative a condensation bond is formed (with the formation of a new double bond), which has the structure of α-carboxyl-β-4 (5) -imidazyl-acrylcholine chloride (V). This intermediate product also does not need to be isolated for the purposes of the invention to become. However, in order to improve the course of the condensation reaction, it is required to remove the water formed during this reaction, what with The advantage is achieved by using an inert auxiliary solvent, which Able to bind water in azeotropic form. Anhydrous is suitable for this purpose Benzene. In the final stage of the process, the intermediate (V) easily at a moderate temperature in the presence of a mineral acid, e.g. B. hydrochloric acid, decarboxylated, the end product being murexin chloride chlorohydrate. This can finally be cleaned in the usual way, e.g. B. by washing with highly concentrated ethyl alcohol.

Of the starting compounds, malonyl monochloride is a very reactive and unstable substance; it was obtained by reacting thionyl chloride with malonic acid. However, the yields here are very small and the product obtained contains impurities. These impurities are very harmful, as their presence favors the decomposition of the monochloride, which tends to disproportionate to 31alonic acid and malonyl dichloride, according to the scheme It has now been found that malonyl monochloride can be obtained in good yield and good purity by carefully reacting water in well-determined quantities and under the same conditions with malonyl dichloride, which is an easily prepared substance.

The reaction was a partial hydrolysis of malonyl dichloride tried different methods, but always resulted in a mixture Malonic acid and the starting compound. However, if you have exactly what you need to implement stoichiometric amount of water in the cold in a solution of malonyl dichloride in a suitable anhydrous and inert solvent, e.g. B. an ether, in form moisture contained in a stream of an inert gas, e.g. B. carbon dioxide contain is, introduces, one obtains in good yield malonyl monochloride, which easily can be separated in crystalline form. However, this procedure is not an issue of the present invention.

The other starting compound, choline chloride, is also a known one Product and is used for the synthesis according to the invention in the crystallization, as described in the following example, used anhydrous form obtained.

4 (5) -Formyl-imidazole is also a known compound, which can be produced by synthesis.

The following reaction scheme of the synthesis process serves to explain the invention in more detail: A very important innovation of the process according to the invention consists in the first reaction stage, ie the reaction between malonyl monochloride and choline chloride, which has not been described so far. This reaction leads stoichiometrically to the formation of the intermediate product (III; chloride of monomalonylcholine), which is to be regarded as a new compound that has not been described so far and, even if not in the pure state, can be isolated.

The same also applies to the intermediate (V; a-carboxyl-ß-4 (5) -imidazyl-acrylcholine chloride), whose presence in the solution must only be presumed.

Another important advantage of the method according to the invention is based on the fact that the starting and intermediate products are completely synthetic Compounds can be used without resorting to histidine derivatives, as has been required so far.

Finally, there is another advantage of the method according to the invention on the fact that an end product is created which is directly in the crystalline state can be isolated from the reaction liquid in which it was formed, without it having to be precipitated as an insoluble salt (e.g. as a picrate), which is a would require further conversion to a water soluble product.

An example embodiment of the method according to the invention for the production of murexin chloride chlorohydrate according to the present invention given below, but is not to be construed in a limiting sense.

EXAMPLE The required malonyl monochloride is prepared as follows: After rectification, 20 g of malonyl dichloride, prepared essentially according to Chittarangian Raha (Org. Synth. 33, 20), are dissolved in 100 cc of anhydrous ethyl ether in a flask equipped with a stirrer, reflux condenser and CaC12 tube and a feed line is provided, the mouth of which is immersed in the liquid (outer diameter 8 mm, inner diameter 1.5 mm). The feed line is connected to a container with inert gas (e.g. CO,) via a Drechsel flask into which 2.55 cc of water has been introduced. Stirring is started and a vigorous stream of gas is passed through the reaction mixture, which has been loaded with moisture in the Drechsel flask. The evaporation of the ether due to the passage of gas causes sufficient cooling. The process takes several hours. If necessary, small amounts of ether are added from time to time so that the amount of liquid in the reaction vessel at the end, ie when all the water in the Drechsel flask has evaporated, is 50 to 60 cc.

50 to 60 cc of anhydrous chloroform are added with stirring, whereby a small amount of crystalline malonic acid can be separated.

The mixture is quickly passed through a well-dried porous plate filter filtered, and the filtrate is diluted with 3 to 4 parts by volume of petroleum ether. By Cooling down to - 30 ° C, the deposition of malonyl monochloride takes place in the form of white, pale yellowish needles with a melting point of 65 to 67 ° C, yield 50 to 60 ° / o. The liquid still contains significant amounts of malonyl monochloride and can be used as it is where it is not necessary, one perfect pure solution of this connection to use.

The anhydrous choline chloride required for the first reaction stage is crystallized as follows: 10 g of choline chloride dried carefully over P205 are dissolved in 120 cc warm absolute alcohol. The warm solution is taken in a thin stream poured vigorously into 500 cc of petroleum ether. A precipitate forms of very thin needles, which are filtered off without pressing, washed with petroleum ether and dried over Hz SO4 in a vacuum. The product appears to be soft (hardly compact) crystal mass.

In a small three-necked flask equipped with a stirrer and a CaCl2 tube is provided, one quickly gives 5.5 g of freshly prepared manonyl monochloride, 4.6 g choline chloride and 15 cc anhydrous ether. The mixture is stirred for 15 to 20 minutes, being a more or less fluorescent viscous homogeneous liquid, which sticks to the piston crown, and receives an ether layer saturated with H Cl, which is drained during the reaction. The ether layer is decanted, and the viscous residue is twice with stirring for 10 minutes with 15 ccm anhydrous Ether washed.

The small flask is heated on a water bath at 60 ° C and with a warm solution of 3 g of 4 (5) -formyl-imidazole (essentially prepared according to Pyman, J. Chem. Soc., 109, I, 192 [1916]) in 7 cc alcohol and 1 cc more concentrated H Cl added.

After a few minutes the mixture takes on the appearance of a homogeneous one Liquid with an orange color. Remove from the water bath and add while stirring Add 30 cc of anhydrous benzene. When you stop stirring, two layers form; the upper (benzene) layer is separated and discarded.

The remaining orange liquid becomes anhydrous after adding 30 ccm Benzene slowly distilled on a water bath until no more liquid passes over.

A viscous residue remains on the bottom of the flask, which slowly dissolves (within a few hours or more often a few days) into a crystalline magma transformed, which after careful treatment with 99% ethyl alcohol and Filter the murexin chloride chlorohydrate in the form of a white crystalline powder supplies, which melts at 231 to 233 ° C with decomposition.

Claims (1)

PATENT CLAIM: Process for the production of murexin chloride chlorohydrate, characterized in that malonyl monochloride at ordinary temperature in an anhydrous inert solvent, preferably ethyl ether, with choline chloride reacted, the residue after removal of the solvent at a slightly elevated temperature in the presence of another solvent, preferably ethanol, and hydrochloric acid reacts with 4 (5) -Formylimidazole, the water of reaction formed by means of a with Water, an azeotrope-forming low-boiling solvent, in particular benzene, removed and finally the remaining residue is cleaned in a known manner.