DD298773A5 - METHOD FOR THE CATALYTIC DEHYDRATION OF 1,2-DIPHENYL ETHANTS TO 1,2-DIPHENYL ETHERS - Google Patents

Abstract

The invention relates to a process for the catalytic dehydrogenation of derivatives of 1,2-diphenylethane to corresponding 1,2-diphenylethenes, according to the invention a specific palladium traeger catalyst is used for this purpose. The obtained diphenylethenes are important pharmaceutical agents used for antidepressants, anticonvulsants, antiepileptics and antiallergic agents. {1,2-diphenylethene; 1,2-diphenylethane; Palladium Traegerkatalysator; hydrogen acceptor}

Description

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Field of application of the invention

The invention relates to a process for the catalytic dehydrogenation of 1,2-dephenylethanes to 1,2-diphenylethenes based on a palladium catalyst on alumina and in the liquid phase in the presence of a hydrogen acceptor. Derivatives of 1,2-diphenylethene are widely used for the treatment of various diseases. Thus, derivatives of stilbene serve as estrogens (B. B. 1), iminostilbenes as antidepressants, anticonvulsants (e.g., 2) and antiepileptics, and derivatives of dibenzocycloheptatrienes as antidepressants and antiallergic agents (eg, 3).

Characteristic of the known state of the art The synthesis of 1,2-Diphenylethenen usually takes place over many stages by conventional chemical methods. For example, the synthesis of 5H-dibenzo (b, f) -azepin (iminostilbene 5) - an intermediate for the production of Carbamazepine 2 - from 10,11-dihydro-5H-dibenzo (b, f) -azepin (iminodibenzyl 4) over 4 steps, the acetylation, bromination, Include dehydrobromination and deacetylation. Of great interest are those routes which involve continuous catalytic dehydrogenation of 1,2-diphenylethanes

1,2-Diphenylethenen in simple apparatus with low energy consumption and without expensive separation processes in high

Enable yields. Such a method is not yet known.

CO-NH.

Stilb α 2 titre :)!

Π a i''ha ma, 'U ¹

dew in

Although ζ. For example, the catalytic dehydrogenation of iminodibenzyl 4 to iminostilbene 5 on various catalyst systems in the gas and liquid phase in discontinuous procedure is reported several times in the literature, these processes have found no input into practice. For this purpose, on the one hand, the performance of the previously known catalysts is not sufficient, and on the other hand, the described methods require expensive equipment, a high energy consumption and cumbersome operations for the isolation and purification of formed 5.

R.HUISGEN et. al., (Chem. Ber. 93,392 [1960]) dehydrated iminodibenzyl to iminostilbene in dimethyl maleate as solvent and hydrogen acceptor in the presence of Pd-Mohr. In the presence of sulfur (catalyst and acceptor), the reaction was carried out in the absence of a solvent. The reactions are discontinuous and characterized by loss-efficient isolation and purification of iminostilbene by fractional crystallization and vacuum distillation. Yields are given as 48% to 60% molar fraction.

According to US Pat. No. 3,074,931, iminedibenzyl is sublimated at high temperatures of 350 to 62O ⁰ C through a column with a packed catalyst noble metals on supports.

The dehydrogenation can also be carried out in the liquid phase by heating pure iminodibenzyl or in admixture with a diluent such as diphenyl, diphenyl ether or Ν, Ν-dimethylaniline with one of the catalysts mentioned to a temperature of 175 to 300 ° C. The formed iminostilbene is obtained in a complicated manner by fractional crystallization or by chromatography. Yields are not indicated.

Be described according to U.S. Patent No. 3,449,224 describes a process for the preparation of iminostilbene from iminodibenzyl in gas phase, in which 117 parts Iminodibenzyldampf diluted with N ₂ or NH ₃ 200 parts of an oxidic catalyst between 300 and 500 ⁰ C passed. The yield is about one pass at about 60%; 12 to 20% iminodibenzyl remain unreacted. The crude product is contaminated with acridine and methylacridine. -

According to DE-PS 1,545,736, the dehydrogenation of iminodibenzyl is also carried out in the gas phase at temperatures of 300 to 700 ⁰ C to NichtedelmeiuiiKatalysatoren or their salts or oxides. It works with nitrogen as a drag gas in vacuo at a pressure of 0.25 to 13.5 10 ² Pa. The conversion is indicated with 60 to 95%, the yield iminostilben with 75 to 90%. M. INOUE et. al., (Chem. Pharm. Bull. 30,24 (1982)) studied the catalytic dehydrogenation of iminodibenzyl to i-indenyls on palladium on carbon and various metal oxide mixtures in a packed column at 55O ⁰ C under atmospheric pressure in the presence of nitrogen and water. The crude product contains methylacridine and acridine as an impurity. The highest reported yield of iminostilbene is 83 mole fractions in% with an iminodibenzy conversion of 94%. The abovementioned processes for the dehydrogenation of iminodibenzyl to iminostilbene are only of limited use for practical use. The performance of the catalysts is insufficient. The incomplete conversion of iminodibenzyl and the necessary high temperatures cause the formation of by-products, in particular acridine and 9-methylacridine, and make lossy separation and purification operations necessary. The reaction is not very suitable for a technical process. All of these procedures must be considered uneconomic in practice. According to EP-PS 0.237.952 or DD-A b-263.288, a part of the above-mentioned disadvantages can be eliminated. The dehydrogenation of iminodibenzyl takes place in the liquid phase in the absence or presence of a solvent such as Ν, Ν-dimethylaniline or diphenyl ether, and in the presence of a catalyst and a hydrogen acceptor, ζ. As nitrotoluene, diethyl maleate or tetrachlorobenzoquinone, between 100 and 28O ⁰ C. As catalysts, noble metals such as Pd or Pt on activated carbon or metal oxide catalysts such as Fe ₂ O ₃ are used. Iminostilbene is precipitated after separation of the catalyst with the aid of methanol, ethanol, isopropyl alcohol or hexane from the reaction mixture. The yields are around 80 mole fractions in%, Also this method has significant disadvantages. In the course of the reaction by-products are formed as one of the causes of the unsatisfactory in a catalytic process yield of 80 mole fractions in%. The used catalysts

have an insufficient life span; their multiple use or the possibility of their regeneration is not reported. Furthermore, the catalysts allow only a discontinuous process control. The isolation of the iminostilbene additionally requires solvents which have to be worked up.

Object of the invention

The aim of the present invention is the development of a process which the catalytic dehydrogenation of derivatives of 1,2-diphenylethane to corresponding 1,2-diphenylethenes such as iminodibenzyl to iminostilbene in yields of more than 95% without significant formation of by-products in a technically easy to realizing continuous process and which also allows for dehydration. heterocyclic systems should be applicable.

Explanation of the essence of the invention The object of the invention is to provide a process for the dehydrogenation of derivatives of 1,2-diphenylethane

1,2-diphenylethenes and heterocyclic systems ii. liquid phase at temperatures between 180 and 28O ⁰ C below

Use of a Wassei Stoffakzeptors in the presence of a special supported Pd catalyst, which is easily regenerated,

to develop with high yields.

The object has been achieved in that derivatives of 1,2-diphenylethane or heterocyclic compounds

using a special palladium-supported catalyst containing 1 to 8 mass% of palladium on a

Carrier molding contains in a substantially uniform distribution over the entire molded article, wherein the carrier of Active clay consists in the gamma modification and this active clay with 2 to 5 mass fractions in% of an alkaline earth oxide

is modified, and having a specific surface area of more than 13OmVg and a total pore volume of mindestens0,65cm ³ / g with a fraction of pores having radii between 100 and 500A of 10 to 15% and of pores having radii of about 500Avon least 30%, at a temperature between 180 and 280 ° C with the exclusion of oxygen in one

Solvents which contain a hydrogen acceptor in excess or act simultaneously as a hydrogen acceptor

can, is performed.

The reaction proceeds with conversions between 90 and 100% and virtually no appreciable formation of by-products,

when gein is added under the embarrassing exclusion of oxygen. The reaction temperature must not be under- bzw.280 ⁰ C does not exceed 180 ° C. An advantageous Arboitstemperatur is between 190 and 240 ⁰ C. In most cases, at a

Temperature worked between 200 and 220 ° C. The process control in the absence of oxygen is best realized by one during the dehydration

moderately strong nitrogen flow through the reaction solution and thus at the same time good conditions for a favorable

Setting reaction kinetics of the catalytic process. But it is also often enough if one before starting the reaction means Nitrogen or a noble gas makes the reaction space oxygen-free and ensures that during the reaction no Oxygen enters. The solvents used are substances in the boiling range between 180 and 28O ⁰ C such as decalin, diphenyl, diphenyl ether, Ν, Ν-dimethylaniline, Nitroaromten, maleate, fumarates or succinates suitable. Suitable hydrogen acceptors may be suitable 1,2-substituted ethene derivatives, quinones, maleates or fumarates. Cheap

is to use a solvent that can act simultaneously as a hydrogen acceptor, such as methyl or Ethylmaleatbzw. fumarate.

If the dehydrogenation is carried out in maleic acid esters, a corresponding proportion is converted into succinic acid ester. At the same time, part of the maleic acid ester is converted to fumaric acid ester. Fumaric acid ester, on the other hand, isomerizes below Reaction conditions are not. Surprisingly, a mixture of succinic acid ester and maleic and / or fumaric acid proved especially in With regard to the insulation e.g. of iminostilbene as particularly advantageous. Under these conditions, part of the

formed iminostilbene during the cooling of the reaction solution in pure form.

It has also been found that the Pd catalyst developed for the dehydrogenation according to the invention comprises maleic acid, Fumaric acid, succinate mixtures at temperatures of about 18O ⁰ C fully hydrogenated to succinate. This hydrogenation can be carried out by conventional methods or in the apparatus described below. Obtained according to the invention

the catalyst thus completely back its originally shown activity and selectivity and at the same time thus z. B. in a technical process of dehydrogenation of 1,2-diphenylethanes in such a solvent mixture ultimately

Succinic acid ester as the only, widely usable by-product. This catalyst realizes, under suitable conditions, the dehydrogenation of 1,2-substituted ethane derivatives

corresponding 1,2-substituted ethenes in yields> 95%. According to the invention, the dehydrogenation of iminodibenzyl to iminostilbene can be achieved with virtually complete conversion of imincdibenzyl in 95 to 99% yield.

The dehydrogenation can be operated in conventional, simple equipment without technical effort. FIG. 1 shows a Apparatus, as used for the dehydrogenation of 1,2-diphenylethanes or heterocyclic systems in high yields in

continuous process can be used. This apparatus can also be used according to the invention for the hydrogenation of the mother liquors, i. e.g. a maleic acid-fumaric acid-succinic acid ester mixture to succinic acid ester, be used at the same time regeneration of the catalyst.

The apparatus consists of an electrically heated tube of 25 mm diameter, in the center by means of a tube

of 5mm diameter the inert gas (nitrogen, inert gas) is introduced. The reaction tube contains the catalyst in

Stranded form. This is with a layer of inert material, for. B. fused corundum, covered. That during the reaction

evaporated solvent is condensed in the condenser and flows back to the bottom of the reaction space. At this point, too, the dosing of the dehydrogenation substrate takes place. The concentration of 1,2-diphenylethane in the solvent and the metered volume determine the residence time of the dehydrogenation substrate on the catalyst.

The process is based on the example of the catalytic! Dehydrogenation of iminodibenzyl to iminostilbene demonstrates:

Iminodibenzyl is dissolved in a mixture of maleic acid or fumaric acid ester and Bernstiensäureester and gives part of it in the reaction space, ie up to the height of the sequence. The reaction space is filled to about ² h of its volume with the Pd-supported catalyst in strand form. The catalyst is covered with a layer of corundum. The strand catalyst can be diluted in a ratio of 1: 1 to 10 with corundum of approximately the same particle size. Then pure nitrogen is passed through the solution and the desired reaction temperature is set. After a reaction time of 3h with the cock closed

by opening the tap, the continuous operation is taken up by appropriate addition of the prepared solution.

The reaction temperature is between 190 and 220 ° C. From the hot reaction solution dripping to the same extent as during the metered addition, Iminostilban crystallizes after cooling in the form of golden leaves in pure form.

In this procedure, iminodibenzyl is> 95% reacted. By-products are not on. The filtrate, after the appropriate amount of iminodibenzyl has been dissolved therein, again fed to the continuous dehydrogenation.

If after about 80 operating hours on the catalyst signs of fatigue occur, hydrogen is introduced into the apparatus instead of the nitrogen stream and in otherwise the same procedure at 19O ⁰ C, the filtrate after distillation-fully hydrogenated to succinic acid. In this process, the catalyst is regenerated according to the invention and thus completely retains its original activity and selectivity.

embodiments

example 1

1.84 g of dibenzyl (0.01 mol) are refluxed in a mixture of 1 ml of diethyl fumarate, 5 ml of succinic acid diethyl ester in the presence of 2 g of a supported Pd catalyst (strand) for 5 h while passing through N ₂ . The hot solution is separated from the catalyst. After cooling, about 50% pure stilbene (Ε-form) precipitates. Further stilbene (Ε-form) is obtained by concentrating the reaction solution.

(Mp .: 122 to 124 "C, yield: 95%)

Example 2

1.95 g of iminodibenzyl 4 (0.01 mol) are heated in a mixture of 3 ml of diethyl maleate, 7 ml of succinic acid diethyl ester according to Example 1, wherein N ₂ purge takes place only in the heating and cooling phase. The hot reaction solution is separated from the catalyst. After cooling the filtrate, about 50% by weight precipitate in% pure iminostilbene 5. The reaction solution is then concentrated in vacuo. The residue (about 45% by weight in mass) likewise consists of pure iminostilbene (mp 197 to 198 ^° C.).

Example 3

0.975 g of 4 (0.005 mol) are heated in a mixture of 5 ml of diethyl maleate, 5 ml of succinic acid diethyl ester in the presence of 0.2 g of a supported Pd catalyst and 1.8 g of precious corundum for 5 h under reflux and passing N ₂ . The reaction solution is removed from the catalyst and then concentrated in vacuo. The residue (91% by weight) contains 95% iminostilbene.

Example 4

1.95 g of 4 (0.01 mol) are heated in a mixture of 3 ml of maleic acid diester, 7 ml of diphenyl ether for 5 h in the presence of a supported Pd catalyst under reflux and passing N ₂ . The catalyst is filtered off and the solution is concentrated in vacuo. The residue left is a mixture of 4 and 5 (90% by mass) with a proportion of 5> 95%).

Example 5

A catalyst used according to Example 2 shows fatigue after about 80 hours. The same is then washed with ethyl acetate and ethanol and then annealed at 700 ⁰ C for 1 h.

0.01 mol of 4 are then reacted according to Example 2. The hot reaction solution is separated from the catalyst and the volatiles are removed in vacuo. The residue remaining 95% by weight in% pure iminostilbene.

Example 6

The distillate obtained according to Example 2 is heated to 180 ^° C. for 3 hours while slowly passing H ₂ (about 0.5 to 1 l / h) in the presence of the dehydrogenation catalyst used. Gas chromatographic control of the composition of the reaction solution shows quantitative formation of Bernstiensäurediehtylester. This catalyst used for the hydrogenation receives its full Dehydrieraktivitat after treatment according to Example 5 back.

Example 7

An apparatus according to FIG. 1 is covered with 20 g of a supported Pd catalyst (strand form, 3 to 5 mass fractions in% Pd) with a layer of noble corundum - with a 20% solution of 4 in 80 TIn. Maleic acid, 20 TIn.

Succinic acid diethyl ester filled. The mixture is heated for 3h while passing N ₂ and reflux at 190 to 220 ° C and then removes the hot reaction solution from the reactor space. After cooling, 50 to 60% by weight of pure iminostilbene 5 precipitate out of the reaction solution. After concentrating the mother liquor, a further 35 to 40 mass fractions in% mixture of 4 and 5 with a proportion of 5> 97% can be isolated.

Reactor and catalyst can then be used again.

Example 8

An apparatus according to FIG. 1 is filled in accordance with Example 7. It is also heated here for 3h under reflux at 190 to 220 ° C. Subsequently, a 20% solution of 4 in o. Solvent-hydrogen acceptor mixture (dosing rate about 14 ml / h) supplied. The volume of hot reaction solution corresponding to the metered addition drips

simultaneously from the reaction mixture. After cooling the solution precipitated, based on the total reaction time (25 to 30h) from 50 to 60 parts by mass in% of pure iminostilbene 6 from. Further 6 can from the remaining after concentration of the mother liquor

Mixture (about 30 to 40 Massenariteile in% based on 4 used) with a proportion of Ti > 80 mass fractions in% isolated

become.

However, the mother liquor can also be recycled to the reactor in the circulation principle. After a second pass

Then 10 to 15 parts by weight in% pure 5 precipitate out of the solution.

Example 9

A reaction solution obtained according to Example 8 after removal of the precipitated iminostilbene 5 is enriched with iminodibenzyl 4 (10 g per 100 ml volume of the reaction solution) and fed again to the reaction space. After this second run, 5 to 7 g of pure iminostilbene 5 precipitate out.

Example 10

2 g of a supported Pd catalyst in 10 ml of diethyl maleate and 0.005 mol of 10,11-dihydro-SH-dibenzola.dl-cyclohepten-S-on are refluxed while reading nitrogen for 5h. The solution is separated from the catalyst and the

Distilled off ester mixture in vacuo. The residue is crystallized from benzene. It is possible to isolate 60 to 65 parts by mass in% 5H-dibenzo (a, d) -cyclohepten-5-one with a melting point of 87 to 89 ° C. Example 11 (submitted on 23.03.1990) The palladium-supported catalyst can be prepared according to the following procedure:

15 kg Bohnitt type aluminum oxide hydroxide gel having a water content of 73 parts by mass is kneaded with 2 kg of a bäi120 ⁰ C and then gemü'hlenem, but otherwise the same starting material with the addition of 0.5 kg of kaolin in a kneader to a plastic Massr and in an extruder deformed into strands of 3.5mm diameter.

After drying in a belt dryer at 90 to 110 ° C and a calcination in a strip annealing furnace at 480 to 500 ° C.

the application of the alkaline earth component. For this purpose, 1.6 liters of a close to neutral calcium nitrate solution (98 g / l Ca) prepared from calcium oxide and nitric acid are diluted with water to 5.8 liters in accordance with the water absorption capacity of the carrier moldings by83 parts by mass and sprayed onto 7 kg alumina strands. The calcium-modified support dried in the belt dryer at about 100 ° C is then calcined in a rotary kiln at 850 ° C and a residence time of 3 hours. This sets the specific texture data.

For application of the palladium component, 1 kg of this catalyst support in a rotating drum within 3 to

Sprayed for 5 minutes with the solution described below.

To 550 g of a technical grade palladium nitrate solution containing 10% by mass of palladium containing 123 g / l of free nitric acid

Ammonia water is added to pH> 8 to form the palladium tetramine complex and ammonium nitrate. It is then filled with condensate to a total of 780 ml solution volume (water absorption capacity of the carrier78% by mass). After receiving this solution through the support material follows by means of hot air (9O ⁰ C within 30 min.) Androcknung in the rotating drum. A 24 hour drying at 130 ⁰ C, followed by annealing at 700 ⁰ C in a muffle, wherein the palladium nitrate is decomposed and fixed as palladium oxide on the support. A catalysed catalyst has the following characteristics:

Content of Pd = 5.2 mass fractions in% Content of CaO = 3.1 mass fractions in% Texture: pore volume 0.72 cm ³ / g

(Pores <100 Å 0.38 cmVg

Pores 100 to 500 Å 0.08 cm ³ / g

Pores> 500 Å 0.26cm ³ / g)

specific surface area: 146m ² / g abrasion resistance: 99.4%.

Example 12

0.811 g of 1-phenyl-pyrazolidone (3) (0.005 mol) are heated under reflux in a mixture of 8 ml of diethyl fumarate and 2 ml of succinic acid diethyl ester in the presence of 2 g of a supported Pd catalyst for 5 hours and N _{2 is passed} through. The reaction solution is separated from the catalyst, the catalyst washed with CHCl ₃ and the CHCl ₃ solution combined with the mother liquor. By addition of further CHCl ₃ , the volume of the organic phase is increased to 30 ml and the organic phase is added with stirring with 10% aqueous NaOH. After 4 hours, the aqueous layer of each phase is neutralized with 2N HCl and then extracted by shaking with CHCl ₃ . After drying the CHCI ₃ phase and concentration remains as a residue a brownish solid (1-phenyl-3-hydroxy-pyrazole A) having a melting point of 148 to 152 ⁰ C (Yield 70 to 75%).

Example 13

2.53 g of 3,5-dicarbethoxy-2, e-dimethyl-dihydropyridine (0.01 mol) are refluxed in a mixture of 16 ml of diethyl fumarate and 4 ml of succinic acid diethyl ester in the presence of 4 g of a supported Pd catalyst and N ₂ read through

heated. The reaction solution separated from the catalyst is then distilled at a temperature of 143 to 146 ° C in a vacuum (16 x 10 ² Pa). The distillate is 2.28 g (90%) of 3,5-dicarbethoxy-2,6-dimethyl-pyridine B having a melting point of 69 to 70 ⁰ Cer.

coo et

Example 14

1.2 g of N-acetyl-iminodibenzyl (0.005 mol) are heated under reflux in a mixture of 5 ml of diethyl maleate and 5 ml of succinic acid diethyl ester in the presence of ₂ g of a supported Pd catalyst for 5 hours and N _{2 is passed} through. The reaction solution is separated from the catalyst and then concentrated in vacuo. The residue remaining oil (0.97 g = 33%) can be crystallized from ether-hexane (N-acetyl-iminostilbene C, mp 117 to 119 ⁰ C).

Claims (9)

1. A process for the catalytic dehydrogenation of 1,2-diphenylethanes to 1,2-diphenylethenes based on a palladium catalyst on alumina and in the liquid phase in the presence of a hydrogen acceptor, characterized in that the catalytic dehydrogenation of the 1,2-Diphenylethanderivates with a palladium catalyst, containing 1 to 8 parts by mass in% palladium on a carrier blank in a substantially uniform distribution over the entire blank, wherein the carrier of active clay in the gamma modification and this active clay is modified with 2 to 5 parts by mass in% of an alkaline earth oxide, and the one specific surface area of more than 130 m ² / g and a total pore volume of at least 0.65 cm ³ / g with a proportion of pores with radii between 100 and 500A of 10 to 15% and of pores with radii above 500 A of at least 30%, at a temperature between 180 and 28O ⁰ C excluding oxygen in a solvent, which contain a hydrogen acceptor in excess or act simultaneously as a hydrogen acceptor is performed. 2. The method according to claim 1, characterized in that the catalytic dehydrogenation is operated in continuous process control. 3. The method according to claim 1 and 2, characterized in that an iminodibenzyl derivative is used as 1,2-Diphenylethanderivat, wherein derivatives of iminostilbene arise. 4. The method according to claim 1 and 2, characterized in that instead of 1,2-Diphenylethanderivat also a heterocyclic system can be used. 5. The method according to claim 1 to 4, characterized in that a mixture of maleic, fumaric and succinic acid ester is used as the solvent for the dehydrogenation. 6. The method according to claim 1 to 5, characterized in that the dehydrogenation is carried out at a temperature between 190 and 240 ⁰ C. 7. The method according to claim 1 to 6, characterized in that the dehydrogenation is carried out at a temperature between 200 and 220 ⁰ C. 8. The method according to claim 1 to 7, characterized in that the mother liquor of the dehydrogenation is hydrogenated in the presence of the palladium catalyst at 190 ⁰ C, wherein as by-product exclusively succinic acid is obtained. 9. The method according to claim 1 to 7, characterized in that the palladium catalyst in the course of the dehyration entering loss of activity after use as a hydrogenation catalyst according to claim 8, its activity and selectivity back.