DD272841B5 - PROCESS FOR PREPARING PURE 1-ISOPROPENYL-BENZIMIDAZOLON- (2) - Google Patents

Description

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Field of application of the invention

The present invention relates to a process for the preparation of pure 1-isopropenyl-benzimidazolone- (2) of the formula I. This compound is a valuable intermediate for the preparation of pharmaceuticals.

Characteristic of the known technical solutions

It is known that in the reaction of ethyl acetoacetate (general formula II, R = CjHe) with o-phenylenediamine 1 -lsopropenyl-benzimidazolone- (2) (I) is formed. It is further known that in this reaction product mixtures are formed which, except I, the compounds 4-methyl-1,3-dihydro-benzo [bl (1,4] diazepin-2-one (III), 2-methylbenzimidazole (IV) and the β- (o-aminoanilinol crotonic acid ester (V).

The quantitative ratios in which products I, III, IV and V are formed depend on the reaction conditions. Furthermore, the results of different agents are contradictory in terms of product composition even when working under - according to the authors - same reaction conditions.

Without solvent at room temperature, Sexton (J., soc., 1942, 303) in the presence of hydrochloric acid as catalyst in about 25% yield, the compound V.

According to Vernin (J. Heterocyclic, formerly 18.85 (1981)), the melt is to be produced uncalcalyzed within 5 minutes at 150 ° C. in addition to IV.12 Own experiments under the same reaction conditions yielded only 26 to 31% I in addition to 14 to 19% III and 23 to 27% IV. In addition, the performance of such short-term organic melting reaction on a commercial scale is problematic.

In carrying out the reaction of II with o-phenylenediamine in solvents, especially in aromatic hydrocarbons such as xylene with azeotropic distillation of the water and alcohol formed, the results are contradictory.

Thus, sexton in xylene without catalyst was given various products, but to which it was later modified by D avoll (J. Ehern. Soc.

308) and Rossi (HeIv. Chim. Ada 1960, 129b), was assigned false structures.

Davoll and Rossi found that Sexton had received I alongside III. Thus, under the same reaction conditions as sexton (xylene, without catalyst), Rossi obtained I in yields varying from 26 to 47% in addition to 35% III and 12.5% V. Davoll also obtained !, indicating no yield.

However, Rossi and Davoll failed to find a manufacturing process with reproducible yields for I. Rossi states: "As already noted by Davoll, the amounts of isolable condensation products I and III vary from experiment to experiment."

Non-reproducibility was confirmed by later publications. While Meth-Cohn (1982, J. Soc., 1982, 261) and Ajupova (Chim., 1974, 355) claimed to have isolated I, under the same reaction conditions, other processors I either did not receive at all, such as Vernin (J. Chemica Scripta 1980, 16, 177), which received only II, or mixtures existing from I, III and IV were obtained.

Thus, Scheremet (Chim, get soed, 1981, 1255) received mixtures consisting of up to 6% I and 67% III, Guidon (Sc.Pharm.Biol.Lor.

3, [2]. 50 (1975)) in addition to 45% I also III (no yield indication) or in boiling benzene 70% IV.

The Nichtoignung this process variant for the recovery of I could be confirmed by own experiments. Thus, in the case of xylene, uncatalyzed substance mixtures were obtained only from I, III and IV (yields: 24-29%, 1.35-41% III, 19-23% IV).

Also contradictory are the results in the alkaline catalyzed reaction.

While Sexton received 18.5% I in addition to 63.5% III in high dilution (o-phenylenediamine concentration 0.9 mol / l, ester concentration 1 mol / l), Rossi was able to isolate only III (yield 64%) under the same conditions , Davoll isolated with the same procedure also only III (no yield indication). Own experiments confirmed this information in principle.

We obtained 62 to 66% III and only 7 to 11% I (space-time yield: 0.007-0.012 g ml " ¹ x h" ¹ ).

In summary, therefore, it must be stated that the described modes of operation are inadequate and an economic production method for I does not exist.

Object of the invention

The invention makes it possible to produce I in a technically applicable, economically favorable method selectively, in high space-time yield and high purity.

Explanation of the essence of the invention

The object of the present invention is to selectively produce I economically in a space-time yield and high purity in a technically applicable process.

This object is achieved surprisomie-weiso that at temperatures of about 120 to 150 ⁰ C to a solution of o-phenylenediamine in an aromatic hydrocarbon, first an alkali catalyst and then a alkyl acetoacetate of the general formula II, wherein R is an alkyl radical with 1 to 4 carbon atoms, adding and distilling off the water present in the mixture or resulting water and the resulting alcohol azeotropically.

It is advantageous if the alkyl acetoacetate is fed to the reaction mixture either continuously or quasi-continuously (in portions) as the reaction progresses.

The aromatic hydrocarbon contained in the distillate may, if desired, be recycled to the reaction mixture after removal of the water and the alcohol in the circulation. The removal of the water and alcohol contained in the distillate can be carried out in a conventional manner, for example by treatment with molecular sieves, silica gel, calcium chloride or phosphorus pentoxide.

Suitable alkali metal catalysts are, for example, alkali metal alkoxides, caustic alkalis, such as KOH or NaOH, or aqueous solutions of KOH or NaOH.

Suitable aromatic hydrocarbons are mono- or di-substituted aromatic hydrocarbons, such as toluene, xylene, chlorobenzene, bromobenzene or dichlorobenzene, both by alkyl radicals or halogen atoms. A particular embodiment of the invention, however, is that the reaction is carried out in xylene or chlorobenzene.

A particular embodiment of the invention is that the reaction is carried out in an inert gas atmosphere, for example a nitrogen atmosphere. This can be done, for example, by passing a light N ₂ stream over the solution.

If it is in principle also possible to carry out the process of the present invention at any desired concentrations, a particular embodiment of the invention consists in using the reactants o-phenylenediamine and alkyl acetoacetate in a concentration of about 3 to 4 mol / l.

According to the invention, compound I is obtained in a yield of 79 to 83% of theory and a space-time yield of 0.152 to 0.160 g.ml " ¹ .h" ¹ . It can be processed further without cleaning.

The selective formation of I in high purity and over the prior art more than tenfold the space-time yield by tripling to quadrupling the amine and ester concentration in alkaline catalysis is surprising.

embodiment

108 g (1 mol) of o-phenylenediamine is dissolved in 300 ml of xylene and heated with stirring on a water to an internal temperature of about 12O ⁰ C. At this temperature, 1.5 ml of concentrated potassium hydroxide solution (47%) as a catalyst 123.7 g (1.06 mol) of methyl acetoacetate (II, R = .times.3) are then added dropwise while stirring for 5 to 10 minutes. It begins a water-methanol elimination, which is completed after about 1 hour. From the time of the beginning cleavage, the solution is heated for 3 hours at reflux and water, during which time the boiling point rises to 136 to 138 ⁰ C. Subsequently, the reaction mixture is cooled to a temperature of 40 to 50 ° C. For about 15 minutes, a mixture of 165 ml of 47% potassium hydroxide solution and 110 ml of water is added. It is cooled with cold water, the approach to 20 to 25 ° C, stirred at this temperature for 30 minutes and then separates the phases. While stirring, about 120 ml of glacial acetic acid is allowed to run to a pH of 7, whereby I separates out. The favorable precipitation temperature is 30-35 ° C, which is achieved by the heat of neutralization (initially not cool). It is then cooled to 15 to 20 ° C, stirred at this temperature 2 stalls, filtered off with suction and washed twice with 200 ml of water.

After drying, 137-144 g (79-83%) of the melting point 117-12O ⁰ C are obtained. TLC test (mobile phase: benzene / methanol 90:10): no impurities III, IV and V detectable.

Analogously, from 108 g (1 mol) of o-phenylenediamine and 174 g (1.1 mol) of n-butyl acetoacetate 141 g (81%) of M, mp 116-119 ⁰ C prepared.

C = O

CHo - "C = CHg

CHo -

0 Il C - CH.

Il

C-OR

II

CH,

N = C

CH.

N-C

i \

H 0

III

C IV

NH.

NH

CH - COOR

I.

CH,

Claims (7)

1. A process for the preparation of pure 1-isopropenyl-benzimidazolone- (2) of the formula I by reacting o-phenylenediamine with alkyl acetoacetates of the general formula II, wherein R is an alkyl radical having 1 to 4 carbon atoms, in an aromatic hydrocarbon and in the presence of an allalic catalyst with heating to 150 ⁰ C and azeotropic distillation of water and alcohol, characterized in that at temperatures of about 120 to 15O ⁰ C to a solution of o-phenylenediamine in an aromatic hydrocarbon, first an alkali catalyst and then a alkyl acetoacetate of general formula II, wherein R has the abovementioned meaning added. 2. The method according to claim 1, characterized in that the alkali catalyst used is a solution of caustic soda or caustic potash in water, alkali metal or caustic alkalis such as KOH or NaOH. 3. Process according to claims 1 and 2, characterized in that the aromatic hydrocarbon is a mono- or disubstituted by alkyl radicals or halogen atoms aromatic hydrocarbon is used. 4. Process according to claims 1 to 3, characterized in that is used as the aromatic hydrocarbon xylene or chlorobenzene. 5. Process according to claims "Ί to 4, characterized in that the reaction in an inert gas atmosphere, for example a nitrogen atmosphere, is performed. 6. Process according to claims 1 to 5, characterized in that o-phenylenediamine and alkyl acetoacetate in a molar ratio of 1: 1 to 1: 1.2 are used. 7. Process according to claims 1 to 6, characterized in that o-phenylenediamine and alkyl acetoacetate are used in a concentration of 3 to 4 mol / l.