DD159877A1 - PROCESS FOR PREPARING 4- [1-METHYL-5-BIS (2-CHLOROETHYL) AMINO-BENZIMIDAZOLYL-2] BUTTERIC ACID - Google Patents

Abstract

The invention relates to an improved process for the preparation of 4 (-1-methyl-5- (bis-2-chloroethyl) -amino-benzimidazolyl-2 -) - butyric acid by reaction v. 4- (1-methyl-5-bis (2-hydroxyethyl) benzimidazolyl-2) -butyric acid esters with thionyl chloride and subsequent saponification of the ester. The compound is known as a potent chemotherapeutic for controlling the growth of tumors.

Description

2307 45 4

Title of the invention

A process for the preparation of 4 - ^ - methyl-5 to C2-chloroethyl) amino- ^; benzimidazolyl-27'-butter acid

Field of application of the invention

The * present invention relates to an improved process for preparing 4- 1

"-Me t hyl-5- (bis-2-chloroethyl) Tamino ~

benzimidazole 1 - ^ - butyric acid. The connection is known -. as a highly effective chemotherapeutic to combat the growth of Tctmoren. -

Characteristic of the known technical solution

The preparation of the 4- / T-iiethyl-5-to - ^ - ^ chloroethyl aminobenzimidazolyl - ^ - butyric acid takes place by reaction of 4- / JE ethyl-5-bis- (2-hydroxyethyl) amino-benzimidaz0IyI- Zf buttersäureester with inorganic acid chlorides, preferably thionyl chloride (DDR-WP 54 727). The process gives very fluctuating yields, which also fall sharply even when increasing the -Ansatz. To achieve the required purity of the end product, it is necessary to remove the excess thionyl chloride by means of complicated distillation processes. Furthermore, by-products formed during the reaction must be separated off by a costly and labor-intensive oo-chromatographic purification on aluminum oxide.

230745

Object of the invention

The aim of the invention is the preparation of 4- / T-methyl-5-bis-C2-chloroethyl) amino-T3enzimidazolyl-2j7 ^k -'buttersäure by a process with independent of the batch size reproducibly good yields, on the one hand, the removal of the excess Chlorinating agent is simplified and. in which in particular the very complicated ohreomatographic cleaning can be omitted.

Explanation of the essence of the invention

The object was, on the one hand, to discover and eliminate the causes of the strongly fluctuating yields and, in addition, to modify the work-up of the reaction mixture in such a way that the removal of excess thionyl chloride and by-products was simplified · in order to eliminate the cost-intensive, oxy-chromatographic purification. Extensive examination of the prior art process surprisingly found that the reaction was only very incomplete after the reaction time indicated and only traces of the bis-chloroethyl compound in addition to about equal proportions of mono-chloroethyl compound and starting product were present in the reaction mixture at this time , Thin layer chromatography determined - contained were. A progress of the reaction was carried out by distilling off the solvent, which, depending on the distillation conditions, the reaction was sometimes led to the correct end point, frequently. However incomplete or was formed by too long reaction time, an increased proportion of by-products. Only by changing the reaction times a solution of the problem could not be achieved because with stoichiometric amounts of thionyl chloride the reaction did not give sufficient conversion and an excess of thionyl chloride caused the formation of byproducts uncontrolled when distilled off solved by it

230745 4

be that one to stop the reaction, the mixture, in aqueous. Hydrochloric acid stirred. On the one hand, the excess thionyl chloride was decomposed in a non-exothermic reaction, and at the same time the reaction product was dissolved in the aqueous hydrochloric acid. Since a well-defined termination of the reaction was achieved, the reaction with the thionyl chloride was allowed to proceed to complete conversion under thin-field chromatographic control, which showed that a minimum post-reaction time of 10 hours was required after defined times of the main reaction and 30 hours should not be exceeded In the subsequent saponification of the ester group, the solvent of the chlorination reaction is distilled off at the same time and impurities are precipitated in insoluble form, The further processing of the hydrochloric acid solution can then be carried out in a known manner,

, The following example shows the preferred embodiment of the invention.

embodiment

4.305 kg of 4- / T-methyl-5-bis- (2-hydroxyethyl) -amino-benzimidazolyl-butyric acid ethyl ester (or the corresponding amounts of methyl, propyl or butyl ester) are dissolved in 36 l of chloroform. After cooling to 0 C, 2.175 kg of thionyl chloride are added over the course of 40 min. Temperature by cooling at 0 .... + 5 ⁰ C holds ». The mixture is stirred for 1 hour at the same temperature, allowed to rise to room temperature within 2.5 to 3 hours and then allowed to stand for 15 to 16 hours at room temperature.

The solution is stirred with vigorous stirring in 37 * 5.1 conc. Hydrochloric dispersed, wherein under strong HCl and SO2 SB / twicklung the excess thionyl chloride is decomposed. The chloroform is then distilled off and then stirred at 95 C for a further 3 hours. After addition of 0.78 kg of activated carbon is stirred for a further 30 min at 95 ° C,

the solution is filtered, the reaction thin-film evaporator i. V »concentrated to" ca "8 1 and the residue with .24 1 of water and" stirred until crystallization. Further purification is carried out by recrystallization from water yield 75 "to 80 fo of theory.

Claims (2)

7 45 4 Erfindungsanspruoh 1. A process for the preparation of 4- / T-methyl - ^ - bisO? - chloroethyl) -benzimidazolyl-27-butyric acid by reaction of 4- / T-methyl- 1- bis (2-hydroxyethyl) benzimidazole 1 -Z / - butyric acid esters with thionyl chloride and subsequent saponification of the ester, characterized in that the reaction at temperatures of. -5 to 30 C, until the complete conversion of the Hydroxyäthylgruppen' leads by reacting the carried out at 0 to 5 C main reaction 10 to 30 hours after-reaction at temperatures between 20 to 25 C followed and daj3 acid for the targeted termination of the reaction, the excess thionyl chloride by stirring the reaction mixture in aqueous hydrochloric acid hydrolyzed, preferably at 15 to 25 ° C. 2. The method according to item 1, characterized in that the post-reaction preferably takes 15 to 16 hours.