CS261400B1 - Process for producing benzamidine - Google Patents

Abstract

The solution ae relates to the production of benzamidine by the reaction of benzonitrile and methanol or ethanol in dioxane or tetrahydrofuran under hydrogen chloride catalysis and then ae carries out ammonolysis of the resulting iminoether salt with excess ammonia while boiling the reaction mixture in methanol or ethanol. The obtained benzamidine hydrochloride is zoela pure, is formed in high yield and is directly usable as an important reversible inhibitor of protease enzymes, especially trypsin.

Description

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Method of producing benzamidine

The present invention relates to the preparation of benzamidine by reaction of benzonitrile with methanol or ethanol in dioxane or tetrahydrofuran under catalysis with hydrogen chloride, followed by ammonolysis of the resulting imino ether salt with excess ammonia while boiling the reaction mixture in methanol or ethanol. The benzamidine hydrochloride obtained is pure, produced in high yield and is directly useful as an important reversible inhibitor of protease enzymes, especially trypsin.

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The invention relates to a process for the preparation of benzamidine, an important reversible inhibitor of protease enzymes (EC3.4), some of which have considerable practical significance. ^V ery important protease trypsin, which has applications in clinical medicine, in the production of detergents, the leather industry is indispensable when working with cell cultures and in transpeptidated at which the human insulin obtained from animal insulin. Benzamidine is used in the isolation of high-purity trypsin and in all operations in which it is necessary to protect tryptic activity by preventing autolysis of trypsin. For the same reason, benzamidine also has bactericidal activity.

Benzamidine is obtained by general processes for the preparation of amidines, only some of which are of practical interest and are usually based on ammonolysis of a suitable functional grouping of the starting substrate. A common and practically significant process involves the addition of an alcohol to benzonitrile under acid (Pinner and Klein, Ber. 11, 6, 1878 > Knorr, ibid. 50, 229, 1917) or basic catalysis (Schaefer and Peters, J. Org. Chem. 26, 412, 1961 (Richter et al., Pharmazie 28, 585, 1973) in an anhydrous medium to give the imino ether (Res. salts thereof, which are then subjected to ammonolysis with ammonia or an ammonium salt. This two-step preparation of benzamidine from readily available benzonitrile is simple and inexpensive, but its drawbacks are the lengthy process, the difficult dosing of ammonia during ammonolysis or the laborious drying of the used ammonium salt, the difficult isolation and purification of the product, and in particular unrepeatable yields.

Also, the newer processes for the preparation of benzamidine mentioned in the paper (Beilstein, Handbuch der Organischen Chemie, Band IX) and the original literature have disadvantages. Procedures based, for example, on iminothioesters (Reynaud et al., Compt. Send. 253 *

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2540, 1961), diaziridines (Peak, J. Chem. Soc. 1952, 215), arylhydrazine complexes with organometallic reagents (Hullin et al., Ibid. 1947, 394), aromatic sulfo acids (Oxley and Short, ibid. 1946, 147). ), the addition of ammonium thiocyanate to benzonitrile (Partridge and Short, ibid · 1947, 390) and a modern method based on the reduction of the N-O bond of the oximes of the N-alkyl- or N-arylbenzamides with P-pentacarbonyl (Dondoni and Barbaco, Chem. Commun · 1975, 761) require mostly difficult starting materials and special reagents, or demanding reaction conditions (high temperatures »elevated pressures, etc.)

These disadvantages are overcome by a two-step process for the preparation of benzaraidin, i.e. by the addition of a lower aliphatic alcohol to benzonitrile under acid catalysis to form the iminoether salt and subsequent ammonolysis with ammonia according to the invention, which comprises adding an anhydrous aliphatic alcohol of 1 to 2 atoms. The carbon to benzonitrile catalysis with anhydrous hydrogen chloride is carried out in a mixture with an anhydrous cyclic ether of the dioxane or tetrahydrofuran type at a temperature of from 0 to 5 ° C, the relative weight ratio of benzonitrile to the mixture being: 1.2 to 1: 2.2 of the alcohol and the cyclic ether is 2: 3, whereupon the imino ether salt is isolated, which is then reacted while boiling the reaction mixture with a 1 to 2-fold excess of ammonia in an anhydrous C 1 -C 2 aliphatic alcohol and the pure benzamidine obtained is isolated as the hydrochloride.

Methanol or ethanol in the mixture and anhydrous cyclic ether, preferably dioxane or tetrahydrofuran, in an optimum ratio of parts of alcohol to 3 parts of cyclic ether, serve as the lower aliphatic alcohol when added to the benzonitrile. Anhydrous hydrogen chloride, which is introduced into the reaction mixture while cooling with ice, serves as the acid catalyst. The addition of a cyclic ether, sometimes used in the preparation of more complex amidines, is necessary in this case to facilitate the isolation of the pure iminoether salt. Addition of an alcohol to benzonitrile without the addition of a cyclic ether forms the iminoether salt rapidly as a hard crystalline product, which must then be carefully crushed, aspirated and thoroughly washed to remove unreacted benzonitrile. With the addition of the cyclic ether, the crystalline product is formed more slowly, in an easily isolated form and in higher yield and quality, because slower crystallization allows more thorough reaction of the components of the reaction mixture and more effectively shifts the reaction equilibrium in the direction of the iminoether salt formed. 26i 400

The recovered iminoether salt is then heated with a solution of excess ammonia in anhydrous lower aliphatic alcohol such as methanol or ethanol for at least 5 hours to the boiling point of the reaction mixture. This procedure replaces the earlier several-day ammonolysis with a slight excess of ammonia at room temperature.

After completion of the ammonolysis, the solution is concentrated to a small volume and a major portion of the title compound hydrochloride crystallizes from the reaction mixture, while the second is isolated by adding diethyl ether to the mother liquors.

As a rule, benzonitrile is mixed with an anhydrous ethanol / dioxane (2: 3) mixture and dry hydrogen chloride is introduced into the solution while cooling the reaction mixture with ice, and then left to stand at reduced temperature for 3 days. The imino ether salt is dissolved in an excess of anhydrous ammonia methanol (about 23% solution) and heated to boiling for 5 hours. After concentrating the reaction mixture, the crystallized major portion is filtered off with suction and the mother liquors are diluted with diethyl ether to give an additional crop.

The process according to the invention makes it easier to isolate the iminoether, the preparation of the amidine is considerably accelerated, and the ammonia dosing does not need to be measured precisely, which is advantageous for the manufacturing process. The reaction proceeds with high yields, which saves on raw materials, reaction time and energy. The process according to the invention yields a pure product for direct further use in twice the yield that was previously common.

The following examples illustrate the method according to the invention but do not limit it.

Example!

135 g of freshly distilled benzonitrile are mixed with 65 ml of absolute ethanol and 100 ml of absolute dioxane and dry hydrogen chloride is introduced into the mixture with stirring and ice-cooling to a total weight gain of 48 g. The mixture is left to stand for 3 days. 0 to 5 ° C. The crystallized product is filtered off with suction, washed with diethyl ether and dried to constant weight. 116.9 g of the major portion of the imino ether salt are obtained. Concentrate mother liquors to a small volume with

I still obtains 40.1 g of another suitable product. 2βι 400

Dissolve 100 g of the imino ether salt in 150 ml of absolute methanol and add 72 ml of a 25% solution of absolute methanol to the solution. The reaction mixture was refluxed for 5 hours, then concentrated to a third volume and allowed to crystallize. 65.2 g of a first crop of the title compound are collected, m.p. Mp 80-82 ° C. The mother liquors are concentrated to half volume and diluted with an equal volume of diethyl ether. 18 g of an additional crop are obtained, m.p. Mp 79-81 ° C. A total of 83.2 g of the corresponding benzamidine hydrochloride is obtained. Example 2 g of benzonitrile is mixed with 84 ml of absolute methanol and 126 ml of absolute tetrahydrofuran and the reaction mixture is worked up as in Example 1. 95 g of the imino ether salt are obtained which are ammonolized with 110 ml of a 25% solution of ammonia in absolute ethanol by boiling for 5 hours. hours. Working up in analogy to Example 1 gives a total of 78.5 g of the title compound, m.p. 79 to 81

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of benzamidine by a two-step synthesis comprising the addition of a lower aliphatic alcohol to benzonitrile under acid catalysis to form an iminoether salt followed by ammonia ammonolysis, characterized in that the addition of anhydrous C 1 -C 2 aliphatic alcohol to benzonitrile is catalysed with anhydrous hydrogen chloride mixtures with an anhydrous cyclic ether of the dioxane or tetrahydrofuran type, the ratio by weight of benzonitrile to the mixture being 1 to 1.2 to 1 · 2.2 and the ratio of alcohol to cyclic ether by volume to 2: 3, whereupon the imino ether salt is isolated, it is then reacted while boiling the reaction mixture with a 1 to 2-fold excess of ammonia in anhydrous C 1 -C 2 aliphatic alcohol and the pure benzamidine obtained is isolated as the hydrochloride.