DE19604102C1 - Preparation of N,N'-di:benzyl-ethylene-di:amino-di:acetate - Google Patents

Abstract

Preparation of N,N'-dibenzylethylenediaminodiacetate (I) comprises: (1) reacting benzaldehyde with ethylenediamine; (2) catalytic hydrogenation of the resulting dibenzalethylenediamine; and (3) filtering off the catalyst and reacting the resulting N,N'-dibenzylethylenediamine (II) in the presence of an inert solvent with acetic acid and recovering (I) by crystallisation. In the catalytic hydrogenation, the side product 1,3-dibenzyl-2-phenyltetrahydroimidazole (III) is present in an amount of less than 1.5% w.r.t. (I). Once the catalyst has been filtered off, (II) is reacted directly with acetic acid without being first purified.

Description

The invention relates to a process for the preparation of N, N'-Di benzylethylenediamine diacetate. This substance is used e.g. B. at the Manufacture of antibiotics used.

It is known to N, N'-dibenzylethylenediamine by hydrogenation of To produce N, N'-dibenzalethylenediamine; for example BP 753500. In this process, the by-product formed 1,3-dibenzyl-2-phenyltetrahydroimidazole in a separate Synthesis step can be hydrolyzed using sulfuric acid.

This synthesis step is very complex and extremely Waste-intensive: The hydrogenation solution first becomes Solvent distilled off methanol. Then the entire N, N'-Di benzylethylenediamine with 10% sulfuric acid to pH 2 and cooked for 30 minutes. Now the N, N'-Di benzylethylenediamine sulfate solution with 20% sodium hydroxide solution Set pH 10 and released benzaldehyde Vacuum distillation can be removed. Now the N, N'-Di Benzylethylenediamine obtained by extraction with butyl acetate. The amine solution in butyl acetate is clarified with activated carbon, dried and with acetic acid to precipitate the N, N'-di benzylethylenediaminediacetate added.

This process delivers large amounts of dilute Sodium sulfate solution, which is not disposed of in wastewater can, since there are concrete pipes in sewer systems, for example corroded; therefore wastewater limit values for sulfate are general common.

The literature describes other processes for the preparation of N, N′-dibenzylethylenediamine diacetate, but they are all still less suitable for economical and environmentally friendly industrial production:
For example USP 2876236: Large quantities of the very expensive Adams ′ platinum catalyst are used. The N, N'-di benzylethylenediamine is fractionated in a high vacuum (99.99 Pa / 160 ° C). Despite this complex cleaning, the diacetate obtained has only a melting point of 110-112 ° C, so it must be heavily contaminated.

The N, N'-Di produced by the process according to the invention In contrast, benzylethylenediamine diacetate has a melting point from 117-119 ° C.

Emilia Menziani et al (Boll. Chim. Farm. 93, 359-65 (1954)) and Ilona Gruda (Przemyst Chem. 38, 162E-4 (1959)) the synthesis of N, N'-dibenzylethylenediamine by reaction of Benzylamine with 1,2-dibromoethane. This substance is carcinogenic.  

The TRGS 900 is a technical one for 1,2-dibromoethane Guideline concentration (TRK value) of 0.1 ppm fixed at the workplace placed. The high technical effort that is necessary to achieve the To enable handling of this substance, the comparatively high Price of benzylamine and 1,2-dibromoethane and the onset of Sodium bromide solution as waste make this synthetic route for an industrial production uninteresting.

The same applies to that disclosed in US Patent 2,784,231 Manufacturing process. Here is ethylenediamine with the carcinogenic and highly tearful benzyl chloride and Sodium hydroxide solution implemented. Large amounts of toluene, waste water containing amine and salt. For cleaning it will Dibenzylethylenediamine extracted with aqueous acetic acid and released with caustic soda, again large quantities waste water containing toluene, amine and sodium acetate.

The invention was based on the object of a method for Preparation of N, N'-dibenzylethylenediamine diacetate that meet the following requirements:

• - simplicity
• - high purity
• - Avoidance of waste salts
• - Avoid toxic or carcinogenic Solvents or starting materials
• - Use of only one recyclable solution medium for the entire synthesis.

The invention solves these problems or these objects.

According to the invention, a process for the preparation of N, N'-Di benzylethylenediamine diacetate provided that

• - the reaction of benzaldehyde with ethylenediamine,
• - The catalytic hydrogenation of the obtained Dibenzalethylene diamines,
• - The implementation of the N, N'-dibenzylethylenediamine obtained in Presence of an inert solvent with acetic acid and the Obtaining N, N'-dibenzylethylenediamine diacetate by Crystallization comprises and is characterized in that the Catalytic hydrogenation is carried out so that the Catalytic hydrogenation as a by-product 1,3-di less than 1.5% benzyl-2-phenyltetrahydroimidazole is present and that after filtering off the catalyst the hydrogenation mixture without purification directly with acetic acid Reaction is brought.

The reaction of ethylenediamine with the benzaldehyde can either in the same solvent in which the hydrogenation and the acetate formation is carried out or without addition of solvent. If you work without solvents, so it may be advantageous to separate the water of reaction. This can by phase separation or preferably by stripping respectively. The dibenzalethylene diamine melt is used in the Hydrogenation and diacetate formation provided solvents solved. The hydrogenation itself can also be carried out without a solvent or with little solvent added.

Come from the inert organic solvents that can be used preferably lower alcohols such as. B. methanol, ethanol, Isopropanol, especially ethanol, is used.

For the subsequent hydrogenation, the crude Dibenzalethylenediamine as a melt or solution with a Hydrogenation catalyst added. Precious metal can be used as a catalyst catalysts (e.g. Pt, Pd, Rh) or nickel. Preferably supported palladium catalysts, especially palladium Alumina used. A special embodiment is the Use of a mixture of fresh and used Catalyst.

The hydrogenation is carried out in a manner known per se. This forms what is described in the literature, unwanted 1,3-dibenzyl-2-phenyltetrahydroimidazole (see e.g. A. W. Archer, J. Pharm. Pharmacol. 17 (6), 376-8 (1965)).

According to the invention, a method has now been found with which this undesirable substance in N, N'-dibenzylethylenediamine can convert. For this, the above tetrahydroimidazole with Monobenzylethylenediamine and hydrogen according to the following Reaction equation implemented:

According to the invention this hydrogenation is up to a content of less than 1.5%, preferably less than 0.5%, in particular less 0.1% 1,3-dibenzyl-2-phenyltetrahydroimidazole driven.

Compared to the hydrogenation of Dibenzalethylenediamine needs this reaction more intensely Conditions (increase in temperature and / or reaction time and / or pressure, optionally adding further Hydrogenation catalyst).

Instead of monobenzylethylenediamine, ethylenediamine can also be used following reaction equation are used:

Usually need ethylenediamine or monobenzylethylenediamine not be added afterwards, as they are for conversion of tetrahydroimidazole required amount of monobenzylethylenediamine according to the following reaction equation, provided that the synthesis of dibenzalethylenediamine ethylenediamine and Benzaldehyde was used at least in a molar ratio of 1: 2:

If the molar ratio of ethylenediamine to benzaldehyde is <1: 2, then can be used for the conversion of tetrahydroimidazole required amount of monobenzylethylenediamine also according to the following Reaction equation by hydrogenolysis of N, N'-Di Form benzylethylenediamine:

This reaction in turn requires an intensification Reaction conditions (more active catalyst or / and higher Response time, temperature, pressure).

As can be seen from example No. 3, the implementation is such a hydrogenation extremely easy. For example, you hydrogenate raw stripped dibenzalethylene diamine made from stoichiometric amounts of benzaldehyde and ethylenediamine in ethanol with a mixture of fresh and used catalyst under 4.4 · 10⁵ Pa hydrogen, the reaction temperature within can rise from 4 hours to 96 ° C. You get one Hydrogenation solution with only 0.04% 1,3-dibenzyl-2-phenyl tetrahydroimidazole.

According to the invention, one can be one of those described above Process variants prepared hydrogenation after separation the catalyst directly with acetic acid to pure N, N'-di be implemented benzylethylenediamine diacetate.

To this end, the hydrogenation solution can be further mixed with a solvent be diluted. Preferably the same solvent as used in the hydrogenation. In particular, with mother liquor diluted.

2 to 3 moles, preferably, are used per mole of dibenzylethylenediamine 2.1 to 2.4 moles of acetic acid are used. In practice, with Acetic acid adjusted to a pH of about 6.2. Then the approach is solved or almost solved by heating.  

A particularly pure product is obtained when the temperature is slowly lowered at the start of crystallization, for example by 1-2 ° C / h and the cooling rate only after approx. 2 h is increased.

The crystallization mother liquor is largely recycled. Out the mother liquor removed becomes the solvent recovered and used again in the hydrogenation stage.

The advantages of the method according to the invention lie especially in its simplicity. Starting from the substances used will become the target compound in a few Received steps. Elaborate and waste-intensive Cleaning operations as they are known in the art are necessary.

The invention is explained in more detail in the following examples.

example 1

454.8 kg (7.567 kmol) of ethylenediamine were stirred and Cool at 57 to 60 ° C with 1600 kg (15.08 kmol) benzaldehyde transferred. At 57-60 ° C the water of reaction in a vacuum distilled off. The remaining melt was 2350 l Ethanol as well as 3 kg fresh and 7 kg water-moist (= approx. 3 kg Dry weight) used palladium catalyst (5% Pd on Alumina) and at 4 · 10⁵ Pa hydrogen pressure hydrated. The temperature was allowed to rise to 70 ° C and then hydrogenated further at this temperature until the Hydrogen uptake had largely stopped. This was the case after 7 hours. The 1,3-dibenzyl-2-phenyl content tetrahydroimidazole was in a sample of the hydrogenation solution certainly. It was 7% (based on dibenzylethylenediamine). The Hydrogenation was continued after a further 35 h of hydrogenation were finally only 0.1% of the tetrahydroimidazole present and the hydrogenation was ended.

The catalyst was filtered off and the hydrogenation solution with 2400 l ethanolic N, N'-dibenzylethylenediamine diacetate mother liquor of a previous approach. It was made with 925 l (16.17 kmol) acetic acid to pH 6.2. The reaction mixture was dissolved by heating, cooled to 52 ° C, inoculated and without for 1 h Cooling stirred. The mixture is then cooled by 2 ° C./h for 2 h. Then on Cooled to 12 ° C and centrifuged. The crystals are on the Centrifuge washed with ethanol and then dried in vacuo. 2454 kg were obtained (90.3% of theory, based on benzaldehyde) N, N'-dibenzylethylenediamine diacetate with a melting point of 117-118 ° C and a purity of 99.8%.  

Example 2

1000 kg (9.42 kmol) of benzaldehyde in 1470 l of recovered 94 % ethanol are stirred at 20 ° C with 287.8 kg (4.79 kmol) added ethylenediamine. After adding 3 kg of fresh and 3 kg of water-moist used palladium catalyst (5% Pd on Alumina) was hydrogenated at 4 · 10⁵ Pa hydrogen pressure. Man let the temperature rise to 65 ° C and hydrogenated at this Temperature continues until the hydrogen uptake largely Had come to a standstill. This was the case after 7 hours. The salary 1,3-dibenzyl-2-phenyltetrahydroimidazole was 2.6% (based on dibenzylethylenediamine). The hydrogenation was continued, after a further 14 h of hydrogenation were finally only 0.05% of the tetrahydroimidazole and the Hydrogenation has ended.

Further workup is carried out as described in Example 1. 1220 kg were obtained (72% of theory based on benzaldehyde) N, N'-dibenzylethylenediamine diacetate with a melting point of 117-119 ° C and a purity of 99.9%.

Example 3

45.1 g (0.75 mol) of ethylenediamine at 57-60 ° C with 159.2 g (1.5 mol) of benzaldehyde were added. The water of reaction was in Vacuum distilled off. The remaining melt was 185 g Ethanol as well as 0.48 g fresh and used Palladium catalyst (5% Pd on alumina) added and at 4.4 · 10⁵ Pa hydrogen pressure hydrogenated. They were left Reaction temperature from 18 ° C to 70 ° C and in within 1 h rise to 90 ° C for another hour. Then was 2 hours hydrogenated at 96 ° C. It was cooled and the reaction mixture examined. The 1,3-dibenzyl-2-phenyltetrahydro content imidazole was only 0.04% (based on dibenzylethylenediamine). At the same time, 3% (based on dibenzylethylenediamine) N-monobenzylethylenediamine and the corresponding amount of toluene Debenzylation formed.

The filtered hydrogenation solution was diluted with 108 g of ethanol and mixed with 91 g (1.51 mol) of acetic acid. Then was through Warm to 58 ° C and slowly cool. After filtration and drying gave 224 g (83% of theory based on Benzaldehyde) N, N'-dibenzylethylenediamine diacetate.

Claims (10)

1. A process for the preparation of N, N'-dibenzylethylenediamine diacetate comprising

• - the reaction of benzaldehyde with ethylenediamine,
• the catalytic hydrogenation of the dibenzalethylenediamine obtained,
• the reaction of the N, N'-dibenzylethylenediamine obtained in the presence of an inert solvent with acetic acid and the recovery of N, N'-dibenzylethylenediamine diacetate by crystallization,

characterized in that the catalytic hydrogenation is carried out in such a way that less than 1.5% of the 1,3-dibenzyl-2-phenyl tetrahydroimidazole obtained as a by-product in the catalytic hydrogenation is present and that after filtering off the catalyst, the hydrogenation mixture is present without purification is reacted directly with acetic acid. 2. The method according to claim 1, characterized in that the catalytic hydrogenation in such a way it is stated that the 1,3-di obtained as a by-product in the catalytic hydrogenation benzyl-2-phenyltetrahydroimidazole up to a content of less than 0.5% Dibenzylethylenediamine diacetate is implemented. 3. The method according to claim 1, characterized in that the catalytic hydrogenation in such a way it is stated that the 1,3-di obtained as a by-product in the catalytic hydrogenation benzyl-2-phenyltetrahydroimidazole up to a content of less than 0.1% Dibenzylethylenediamine diacetate is implemented. 4. The method according to any one of claims 1 to 3, characterized in that the at Reaction of benzaldehyde and ethylenediamine reaction mixture obtained before the hydrogenation is freed from the water of reaction. 5. The method according to any one of claims 1 to 4, characterized in that a lower Alcohol is used as a solvent. 6. The method according to claim 4, characterized in that ethanol as a solvent is used. 7. The method according to any one of claims 1 to 6, characterized in that in the hydrogenation a solvent is used that the solvent used in the precipitation corresponds. 8. The method according to any one of claims 1 to 7, characterized in that the Catalytic hydrogenation palladium on alumina is used as a catalyst. 9. The method according to claim 8, characterized in that a mixture in the hydrogenation from fresh and used catalyst is used.