DE19541262A1 - Production of 1,4-cyclohexane:di:one compounds - Google Patents

Abstract

Production of a 1,4-cyclohexanedione of formula (I) comprises hydrogenation of a hydroquinone of formula (II) in the presence of a Group VIIIB metal catalyst (optionally supported) and an ether solvent, optionally in the presence of one or more additives selected from alkaline alkali or alkaline earth metal or ammonium compounds. R1-R4 = H, 1-4C alkyl, 1-4C alkoxy, 3-8C cycloalkyl, 3-8C cycloalkoxy (both optionally substituted by 1-4C alkyl), halo, COOR5 or CH2OR5; and R5 = H or 1-4C alkyl.

Description

The present invention relates to an improved method for producing optionally substituted 1,4-cyclohexanediones by heterogeneously catalyzed Hydrogenation of the underlying hydroquinones.

Optionally substituted 1,4-cyclohexanediones are as intermediates for the production of dyes, active pharmaceutical ingredients and plants protective agents, for a number of applications in polymer chemistry and as Tissue starch important. For example, certain Prepare epoxy resins from 1,4-cyclohexanedione (see JP-OS 60-158 216 and C.A. 104, 69702 p). Tissues can be treated with 1,4-cyclo Strengthen hexanedione (see JP-OS 60-224 866 and C.A. 104, 170083 n). As out raw material for the production of precursors for the synthesis of plants Protective agents are described in EP-OS 122 202 1,4-cyclohexanedione. The 4,4-ethylenedioxy-cyclo obtainable from 1,4-cyclohexanedione and ethylene glycol hexanone (= monoacetal of 1,4-cyclohexanedione) can according to WO 92/21647 as a starting material for the production of protease inhibitors used for treatment the immune deficiency disease AIDS can be used. In the US PS 4,294,761 is the preparation of 1,4-cyclohexanedione and 1,4-butanediol accessible monoacetals. Such monoacetals are valuable Precursors for the synthesis of active pharmaceutical ingredients.

1,4-Cyclohexanedione has so far been obtained by condensation of succinic acid diethyl ester to 1,4-cyclohexanedione-2,5-dicarboxylic acid diethyl ester followed by a ver soaping and decarboxylation. This process is multi-stage, therefore particularly complex and associated with a high use of materials.

In JP-OS 03-109 346 and C.A. 115, 207572b the production of 1,4- Cyclohexanedione by hydrogenation of hydroquinone in a high-boiling Hydrocarbon described. It must be in a very high dilution works (0.05 to 1 g hydroquinone per ml solvent), what with a great effort to separate the solvent is connected. Furthermore, for the implementation of this process on an industrial scale is the required long reaction time very disadvantageous, because for the 50% conversion of 4 g  Hydroquinone are used for 3 hours, which in the best case of a room Time yield of 20 g / l · h corresponds.

There is therefore still a need for a method with which to give optionally substituted 1,4-cyclohexanediones in good yields and good selectivities can produce at the same time favorable space-time yields.

A process for the preparation of optionally substituted 1,4- Cyclohexanediones of the formula (I) found

in the
R¹, R², R³ and R⁴ independently of one another for hydrogen, optionally C₁-C₄-alkyl linked via oxygen, for optionally linked via oxygen, optionally substituted with C₁-C₄-alkyl substituted C₃-C₈-cycloalkyl, for halogen, for the group COOR⁵ (with R⁵ = hydrogen or C₁-C₄-alkyl) or for the group CH₂-Q (with Q = hydroxy or C₁-C₄-alkyl linked via oxygen), by heterogeneously catalyzed hydrogenation of substituted hydroquinones of the formula (II)

in the
R¹, R², R³ and R⁴ have the meaning given for formula (I),
which is characterized in that the hydrogenation in the presence of an optionally supported catalyst from the group of metals from Group VIII B of the Periodic Table of the Elements (Mendeleev) and optionally in the presence of one or more additives from the series of alkali-reacting alkali -, Erdkali- or ammonium compounds is carried out in an ether as a solvent.

The finding that, with the aid of the method according to the invention, the aforementioned optionally substituted 1,4-cyclohexanediones in an uncomplicated manner and in good yields and selectivities with a favorable space-time-out booty was extremely surprising and could not be derived from the state of the art.

In formulas (I) and (II), halogen can be, for example, fluorine, chlorine or Bromine stand. Fluorine and chlorine are preferred, and chlorine is particularly preferred.

C₁-C₄-alkyl is, for example, straight-chain or branched alkyl having up to to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- Butyl or t-butyl, preferably for methyl or ethyl, particularly preferably for Methyl.

C₃-C₈-cycloalkyl is, for example, optionally C₁-C₄-alkyl-substituted Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably for unsubstituted, mono-, di-, tri- or tetramethyl-substituted Cycloalkyl of the type mentioned or for appropriately ethyl-substituted cycloalkyl. Cyclobutyl, cyclopentyl, cyclohexyl and methyl and ethyl-substituted derivatives thereof and particularly preferred are cyclobutyl, Cyclopentyl and cyclohexyl.

Hydroquinone are particularly preferred in the process according to the invention, Monomethyl hydroquinone, dimethyl hydroquinone, tetramethyl hydroquinone, ethyl hydroquinone, diethyl hydroquinone and tetraethyl hydroquinone used.

To carry out the process according to the invention, this can be used as the starting point material used, optionally substituted hydroquinone of formula (II) in an ether, e.g. B. in a weight ratio of 2: 1 to 1:10, optionally at elevated temperature, dissolve with an optionally on a solid support  applied catalyst from the group of metals of group VIII B of the Periodic Table of the Elements (Mendeleev) in a weight ratio of e.g. B. 10,000: 1 to 10: 1 (optionally substituted hydroquinone: carrier catalyst) and optionally with one or more additives, for. B. in a weight ratio of 20,000: 1 to 20: 1 (optionally substituted Hydroquinone: total amount of additives) and then hydrogenate.

As Group VIII B metals of the Periodic Table of the Elements (Mendeleev) Palladium, ruthenium, rhodium, platinum and nickel come in Question. Palladium is preferred.

For example, activated carbon, silica gel, silicon dioxide, Silicas, aluminum oxide, oxides and phosphates of rare earth metals, Zeo lithe, aluminosilicates, solid heteropolyacids, e.g. B. niobium, and ceramic Body in question. On the substrate z. B. 0.1 to 10 wt .-% of respective metal have been applied.

If one uses metal catalysts without support material, one can, based on optionally substituted hydroquinone, the same amount of metal or up to Use 5 times more than before for the use of supported catalysts is described.

The catalyst preparation can be carried out using those known to those skilled in the art Procedure.

Palladium is preferably supported as a catalyst, especially before moves on activated carbon, used.

As ether come e.g. B. dialkylene glycol dialkyl ether, alkylene glycol dialkyl ether, Dioxanes and tetrahydrofuran in question. Diethylene glycol dimethyl is preferred ether, ethylene glycol dimethyl ether and 1,4-dioxane.

It is preferably alkaline in the presence of additives from the series reacting alkali metal, alkaline earth metal and ammonium compounds works. Examples include: carbonates, hydrogen carbonates, sulfites, Sulphides, phosphates, hydrogen phosphates and borates of alkali metals, alkaline earths metals and ammonium as well as hydroxides, hydrides and boranates of alkali and  Alkaline earth metals. Also the alkali metal, alkaline earth metal, ammonium, mono alkyl, dialkyl, trialkyl and tetraalkylammonium salts of aliphatic C₁-C₆- Carboxylic acids are suitable. The carbonates, bicarbonates, Borates, formates and acetates of sodium, potassium, magnesium and calcium.

Sodium carbonate and borax are particularly preferred.

The heterogeneously catalyzed hydrogenation according to the invention can be carried out with stirring and at temperatures for example 30 to 250 ° C, preferably 40 to 240 ° C, particularly preferably from 69 to 230 ° C. and at a hydrogen pressure of 1 to 200 bar, preferably 2 to 150 bar, particularly preferably 3 to 100 bar. In order to achieve optimal selectivity, it is advantageous to use the Measure amount of hydrogen, and when reaching the pre-calculated hydrogen quantity to cancel the hydrogenation. This can be done by lowering the stirrer speed, lowering the temperature and / or interrupting the hydrogen supply can be achieved.

When determining the optimal amount of hydrogen, it should be taken into account that the desired cyclohexanedione can react further with hydrogen, e.g. B. to corresponding hydroxycyclohexanone and the corresponding cyclohexanediol. Each Depending on the reaction conditions used, optimal results can be achieved Obviously cyclohexanediones can also be obtained when the further reaction to hydrocyclohexanone or cyclohexanediol. So there are also consider amounts of hydrogen greater than 1 mole per mole Hydroquinone used.

After the hydrogenation according to the invention has ended, the catalyst can be separated in the usual way, for example by filtration.

The process can also be in a cascade or in a continuous manner for example in a tubular reactor.

In these cases, the dwell can be stopped by carefully setting the dwell times Optimum yield of 1,4-cyclohexanedione can be achieved. The dwell times can e.g. B. in the range 1 to 360 minutes, preferably in the range 5 to 120 minutes lie.  

The ether used to carry out the process according to the invention can separated using conventional techniques, for example by distillation, and if necessary be returned. The crude obtained as a reaction product optionally substituted 1,4-cyclohexanedione can in a known manner, for example by distillation or crystallization. It is beneficial that Neutralize crude product before distillation, e.g. B. by adding sulfur acid, hydrochloric acid or sodium hydrogen sulfate, only small amounts of such Additives are required.

In principle, it is also possible and can be advantageous if necessary after completion of the hydrogenation according to the invention and separation of the kata lysator's present solution directly, i.e. H. without further processing, for after the following reactions, for example acetalization or oximation put.

In addition to the advantages stated above, it should be emphasized that the Process according to the invention in a more concentrated solution than the process of JP OS 03-109346 can perform and then the effort for the separation of the Solvent is lower. For example, in the process of JP-OS 03-109346 25 ml of hydrocarbon solvent added to 4 g of hydroquinone sets what corresponds to 0.16 g of hydroquinone per ml of hydrocarbon solvent. According to the invention, good results are obtained if, for example, 1 g Hydroquinone uses 1 g ether solvent.

Examples example 1

In a stainless steel (V4A) equipped with internal cooling 0.7 l autoclave became a mixture of 150 g hydroquinone, 150 g diethylene glycol dimethyl ether, 0.5 g borax and 6.6 g catalyst (5% by weight palladium on active coal, moisture content 54% by weight).

After purging the autoclave with nitrogen, stirring was carried out at an agitator speed heated from 1,000 rpm to 180 ° C and 10 bar of hydrogen injected. During the reaction that started now the temperature of the reaction mixture by regulating the internal cooling and the internal pressure of the reaction vessel by continuously supplying hydrogen from a supply container kept constant.

After 8 minutes a total of 46 Nl of hydrogen had been taken up, and the reaction was stopped by cooling the autoclave to 20 ° C. The catalyst was separated off by filtration and the filter material was removed several times Washed a total of 50 ml of diethylene glycol dimethyl ether.

The filtrate and washing solution were combined. The gas chromatographic analysis showed the following composition (without considering the solvent):
13.5 wt% hydroquinone
39.9% by weight 1,4-cyclohexanedione
45.4% by weight 4-hydroxy-cyclohexanone
0.3% by weight 1,4-cyclohexanediol
0.9% by weight of other components.

The crude product mixtures from three hydrogenation batches carried out in this way were combined and mixed with 0.3 g of sodium bisulfate. The solution thus obtained was over a 50 cm silver jacket column, filled with 4 × 4 mm RASCHIG- Wrestle, distilled at a reflux ratio of 1:20.

At a pressure of 15 mbar and a head temperature between 121 and 123 ° C 151.2 g of a product were obtained, which according to gas chromatography  Analysis contained 98.8% by weight 1,4-cyclohexanedione. This corresponds to an isolated one Yield of 33% of theory, based on the hydroquinone used.

These figures give a space-time for 1,4-cyclohexanedione Yield 540 g / l · h.

The by-product 4-hydroxy, which is not insignificant Cyclohexanone can e.g. B. hydrogenated and the hydrogenation product thus obtainable with a Phenylhydrazine are implemented. A phenylhydrazone is obtained, which after intramolecular cyclization gives a tetrahydrocarbazole. Tetrahydrocarbazole are important intermediates for the production of pharmaceutically active Connections (see, for example, US Pat. No. 4,988,820 and DE-OS 36 31 824).

Claims (10)

1. Process for the preparation of optionally substituted 1,4-cyclohexanediones of the formula (I) in the
R¹, R², R³ and R⁴ independently of one another for hydrogen, optionally C₁-C₄-alkyl linked via oxygen, for optionally linked via oxygen, optionally substituted with C₁-C₄-alkyl C₃-C₈-cycloalkyl, for halogen, for the group COOR⁵ (with R⁵ = hydrogen or C₁-C₄-alkyl) or for the group CH₂-Q (with Q = hydroxy or C₁-C₄-alkyl linked via oxygen), by heterogeneously catalyzed hydrogenation of substituted hydroquinones of the formula (II) in the
R¹, R², R³ and R⁴ have the meaning given for formula (I),
which is characterized in that the hydrogenation in the presence of an optionally supported catalyst from the group of metals from group VIII B of the Periodic Table of the Elements (Mendeleev) and optionally in the presence of one or more further additives from the series of alkali-reacting alkali , Erdkali- or ammonium compounds and an ether is carried out as a solvent. 2. The method according to claim 1, characterized in that in the formulas (I) and (II) halogen for fluorine, chlorine or bromine, C₁-C₄-alkyl for straight chain or branched alkyl with up to 4 carbon atoms and C₃-C₈-cycloalkyl for cyclopropyl optionally substituted by C₁-C₄-alkyl, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are available. 3. Process according to claims 1 and 2, characterized in that Hydroquinone, monomethyl hydroquinone, dimethyl hydroquinone, tetra methylhydroquinone, monoethylhydroquinone, diethylhydroquinone or Tetraethyl hydroquinone as an optionally substituted hydroquinone puts. 4. Process according to Claims 1 to 3, characterized in that as Solvent dialkylene glycol dialkyl ether, alkylene glycol dialkyl ether, Dioxane or tetrahydrofuran is used. 5. The method according to claims 1 to 4, characterized in that the Catalyst as metal of group VIII B of the periodic table of the Elements (Mendeleev) palladium, ruthenium, rhodium, or platinum Contains nickel. 6. The method according to claims 1 to 5, characterized in that the Catalyst is applied to a support, which is active coal, silica gel, silicon dioxide, silica, aluminum oxide, oxides and Phosphates of rare earth metals, zeolites, aluminosilicates, solid hetero polyacids or ceramic bodies. 7. The method according to claims 1 to 6, characterized in that as a kata Palladium on activated carbon analyzer is used. 8. The method according to claims 1 to 7, characterized in that as Additives carbonates, hydrogen carbonates, sulfites, sulfides, phosphates, Hydrogen phosphates or borates of alkali metals, alkaline earth metals and Ammonium or hydroxides, hydrides or boranates of alkali and  Alkaline earth metals or ammonium salts, monoalkyl, dialkyl, trialkyl or tetraalkylammonium salts of aliphatic C₁-C₆ carboxylic acids. 9. The method according to claims 1 to 8, characterized in that it at temperatures in the range of 30 to 250 ° C and hydrogen pressure in Performs range 1 to 200 bar. 10. The method according to claims 1 to 9, characterized in that the Weight ratio of optionally substituted hydroquinone to Catalyst is in the range of 10,000 to 10: 1.