Soluble catalyst in tablet form, its manufacture, set and method for carrying out a catalytic reaction by introducing the tablets

Abstract

tablet containing 20 wt.% or more of a transition metal compound or 20 wt.% or more of a mixture of a transition metal compound and a phosphine ligand, the metal is selected from palladium, rhodium or ruthenium and 25 wt.% to 80 wt.% saccharide, oligosaccharide or polysaccharide, the tablet formulation contains a proportion of microcrystalline cellulose in combination with mannitol or sorbitol.

Description

[0001] The invention relates to tablets containing compounds of palladium, rhodium, or ruthenium for the precise dosing of homogeneous catalysts in chemical reactions. The tablets optionally contain excipients or further catalyst components. The invention also relates to homogeneously catalyzed chemical processes using the catalyst-containing tablets.

[0002] Homogeneous metal (Pd) catalysts are used for a variety of chemical syntheses, especially cross-coupling reactions such as the Suzuki-Miyaura reaction, the Heck or Stille coupling, and the Buchwald-Hartwig coupling for the synthesis of arylamines, and are also of great industrial importance.

[0003] Homogeneous metal (Pd) catalysts have thus become established not only in specialized applications but are also a key component in the production of large-volume products in the fields of specialty chemicals and pharmaceuticals, such as liquid crystals, antibiotics, and fungicides. Efforts are made to use as little catalyst as possible, since the precious metal compounds involved are generally very expensive reagents.

[0004] Typical homogeneous catalyst systems consist of a transition metal complex and optionally additional ligands. These can be present together in complexes or are formed by a suitable combination of so-called pre-catalyst and the required ligands.

[0005] In a typical metal-catalyzed synthesis, one of the coupling partners is placed in an organic solvent, possibly with suitable excipients, under a protective gas atmosphere, and the catalyst / catalyst system is introduced as a powder. The second coupling partner is then added and the reaction is started. Well-known couplings include the Negishi cross coupling, Suzuki cross coupling, Stille cross coupling, Heck cross coupling, Sonogashira cross coupling, and Buchwald-Hartwig cross coupling (see also Negishi, E., Handbook of Organopalladium Chemistry for Organic Synthesis; John Wiley & Sons: New York, NY, 2002; Tsuji, J., Palladium Reagents and Catalysts: New Perspectives for the 21st Century; John Wiley & Sons: Chichester, West Sussex, England, 2004; Kürti, L. and Czakö, B., Strategie Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA, 2005; Li, JJ).Named Reactions for Homologations; John Wiley & Sons: Hoboken, NJ, 2009). Another useful catalytic reaction is homogeneous hydrogenation with a Wilkinson catalyst based on rhodium. Homogeneous ruthenium catalysts are known for olefinic metathesis. The present invention provides a simplification for all these transition-metal-catalyzed reactions and others.

[0006] For some large-scale industrial products, the amount of catalyst has been reduced to such an extent that it is sometimes difficult to effectively dose small quantities into large systems, such as large stirred tank reactors. The problem is that milligram or gram amounts of catalyst must be dosed into reactors with volumes of several thousand liters. When dosing dusts or powders, complete incorporation into the reaction solution cannot always be guaranteed, as dusts or powders adhere to the dosing vessel, dosing devices, agitator shafts, the upper reactor wall, or other reactor surfaces. They are then unavailable for the actual reaction. In many cases, this results in reduced conversion, longer reaction times, and thus product loss, leading to higher costs.

[0007] Some catalysts, for example, are classified as toxic or CMR substances and are therefore subject to limit values ​​or dust limits. When powders are introduced into large production plants / reactors, harmful dusts are generated. Employees handling these materials must generally wear protective clothing and respirators to protect themselves from these risks. Specialized protective clothing and respirators are often expensive and, in addition to being sometimes cumbersome to put on and take off, also result in increased physical strain for employees during their work. Furthermore, the introduction of dusts sometimes necessitates the closure of work areas to other personnel, which entails additional effort.

[0008] Some catalyst systems consist of a metal precatalyst and a ligand. Often, both components are used in small quantities but in a specific ratio. Here, both components must be effectively introduced into the reactor, which leads to the problems mentioned above.

[0009] Many homogeneous metal (Pd) catalysts are also very sensitive with regard to their stability. For example, a large number are sensitive to air and moisture. Since the catalysts usually have to be weighed out individually in the correct quantity for each reaction, a deterioration in quality is to be expected, which leads either to an increased quantity being used or to a poorer reaction.

[0010] Only a few examples of particularly stable catalysts or preformed catalyst tablets (tablets, pellets, granules, compacts and other types of shaping) are known in the literature.

[0011] Particulate support materials loaded with transition metal catalysts are known from US 2003 / 0082095 A1, WO 02 / 098556 A1 and CN 106179401 A, but they appear to be insoluble.

[0012] WO 2012 / 093271 A1 describes the catalyst Tris[tris(3,5-bis(trifluoromethyl)phenyl)phosphine]palladium(0), which has the outstanding property of high stability in air and moisture and can therefore be used advantageously in various cross-coupling reactions such as the Suzuki-Miyaura reaction or the Buchwald-Hartwig coupling. However, the use of the catalyst is described in powder form.

[0013] The publication “Superstable Palladium(0) Complex as an Air- and Thermostable Catalyst for Suzuki Coupling Reactions” (Eur. J. Org. Chem. 2015, 60-66) describes the aforementioned catalyst Tris[tris(3,5-bis(trifluoromethyl)phenyl)phosphine]palladium(0) and its application in Suzuki reactions in more detail. The main focus of this publication, however, is the catalyst system itself and its stability under various conditions, which even allows for its compression into tablets with the addition of potassium carbonate. The use of potassium carbonate is not suitable for other catalysts due to its hygroscopic properties. Furthermore, only a mass fraction of 2.5% of the catalyst per tablet is described.

[0014] WO 2006 / 000227 A1 describes the immobilization of catalysts on inorganic supports. It also highlights the ease of dosing this formulation. The catalyst must first be applied to the support, which remains unchanged as a hard tablet at the end of the reaction. However, such systems are not suitable for large-scale industrial applications because the remaining support must be removed in a complex process or is incompatible with common materials. There is also a risk of blockage of valves and lines. Furthermore, the production of the immobilized supports is uneconomical, as it typically involves air- and temperature-sensitive solutions of the catalyst system.

[0015] In T. Li et al., Chem. Asian J. 2017, 12, 190-193, tablets made of PTFE micropowder, disintegrant, and Pd catalyst are described. According to the report, the tablets consist of 5-20 wt% of a polymeric binder, which is an undesirable impurity in fine chemicals for the electronics industry and GMP-compliant production.

[0016] E. Lindner et al., Journal of Molecular Catalysis A: Chemical (2000), 157, 97-109, describe immobilized Pd complexes on polysiloxanes. The catalysts used are no longer homogeneous in solution.

[0017] Some publications, such as US 3755192 A, DE 1667239 A1, and US 1680807 A, describe catalyst tablets intended for heterogeneous catalysis. These tablets are therefore insoluble in the medium used. The catalyst adheres to the support.

[0018] L. Ondi et al., Org. Process Res. Dev., 2016, 20, 1709-1716 discloses molybdenum catalysts for olefinic metathesis formulated as paraffin tablets. These are so stable in air that they can be added without a protective gas.

[0019] However, the use of polymers and paraffin as auxiliary materials is undesirable in many applications. One object of the invention is to avoid such byproducts.

[0020] It was found that pre-formed catalyst tablets can be easily added to typical large-scale industrial systems, such as stirred tank reactors, and dissolve within them. This ensures consistent results even when using small amounts of catalyst. The invention thus allows the advantage of reducing the amount of catalyst to be realized on an industrial scale.

[0021] The invention relates to a tablet containing 20 wt.% or more of a transition metal compound. or 20 wt.% or more of a mixture of a transition metal compound and a phosphine ligand, the metal is selected from palladium, rhodium or ruthenium, based on 100% wt. tablet weight, and 25% w / w to 80% w / w of a substance selected from saccharides, oligosaccharides or polysaccharides, wherein the tablet formulation contains a proportion of microcrystalline cellulose in combination with mannitol or sorbitol.

[0022] Another object of the invention is a set for carrying out transition metal catalysis consisting of - one or more tablets according to the invention as described above and below, and - information about the amount of transition metal per tablet or per packaging unit.

[0023] Another object of the invention is a method for producing a tablet in which a mixture containing 20 wt.% or more of a transition metal compound or 20 wt.% or more of a mixture of a transition metal compound and a phosphine ligand, wherein the metal is selected from palladium, rhodium or ruthenium, and a substance selected from saccharides, oligosaccharides or polysaccharides, wherein the tablet formulation contains a proportion of microcrystalline cellulose in combination with mannitol or sorbitol, is fed to a tableting press and is compressed into individual tablets.

[0024] Another object of the invention is a method for carrying out a catalytic reaction in a fluid reaction medium with a homogeneous transition metal catalyst, characterized in that the transition metal catalyst is supplied to the method in the form of one or more tablets as described above and below according to the invention.

[0025] It has been found that pure catalysts and catalyst precursors can be formed into catalyst tablets. The tablet strength is significantly improved by the addition of 1 to 95 wt% of a saccharide. In some cases, it has been found that the tableting process is improved by the addition of a lubricant (e.g., Parteck). ®The tablet's properties can be further improved by the addition of lubricants (e.g., binders and / or flow regulators) or additives (e.g., binders and / or flow regulators). In particular, the external addition of lubricants during the manufacturing process is advantageous, as the finished tablet contains only a small proportion of these substances.

[0026] It was found that such preformed catalysts do not produce dust, as the tablets possess sufficient rigidity and are therefore suitable for safe dosing, especially of hazardous substances. Furthermore, it was surprisingly found that these tablets have a longer shelf life than the powdered catalyst. They can also be easily incorporated into large-volume reactors, and their ingredients are homogeneously distributed within a short time. The tablets decompose in all common solvents. Unlike known tablets, they contain no polymers. The ingredients of the disclosed tablets are generally GMP-qualified substances.

[0027] If catalyst systems consisting of a metal precatalyst and a ligand are to be added, these systems can be compressed together as a tablet. Alternatively, the precatalyst and ligand can be compressed separately and dosed easily.

[0028] Large quantities of preformed catalysts and catalyst systems can be conveniently produced and stored. The product can be easily packaged and transported. Customized packaging and package sizes can be provided for highly sensitive compounds, simplifying handling and reducing losses. Furthermore, catalysts in tablet form exhibit a longer shelf life than powdered catalysts due to their smaller surface area. These preformed catalysts are dust-free and therefore suitable for the safe dosing of even hazardous substances.With regard to occupational safety, especially at low workplace and dust exposure limits, the production of metal (Pd) catalyst in pre-formed tablets (tablets, pellets, granules, compacts, and other forms) at a dedicated production site is significantly more efficient and cost-effective than equipping all affected plants and reactors in production accordingly. Furthermore, the effort required from personnel regarding protective clothing, etc., is considerably reduced.

[0029] Tablet presses and methods known from the pharmaceutical industry can be used for tableting the tablet material. Suitable devices for preparing and compressing the starting materials are commercially available and familiar to those skilled in the art.

[0030] The tablet material can be used in granular or powder form. Preferably, a powdered material is directly compressed, optionally conditioned by a small addition of flow-regulating agent (flow agent) to meet the requirements of the tableting device regarding the powder's flowability. Most common molecular metal catalysts and precatalysts are in powder form and suitable for the process when formulated with a previously mentioned saccharide.

[0031] If the tablet material consists of a mixture prone to mechanical separation, prior granulation is advantageous. The production and use of granules allows for a uniform distribution of the metal catalyst on each tablet. Prior granulation using a binder can also be beneficial for low-melting, oily, or otherwise non-flowing components of the material.

[0032] The method for manufacturing the tablets is preferably carried out such that each individual tablet contains a predefined amount of metal catalyst. The tablets of a set for carrying out transition metal catalysis therefore possess a constant, defined amount of catalyst, so that precise dosing with one or more tablets is easily possible by counting them. Alternatively, the tablets are weighed, taking into account the known content of additives. A typical tablet according to the invention comprises 0.050 to 3 g of tablet material, preferably 0.2 to 2 g. The tablet shape results from the two concave dies that face each other in a cylinder and compress the free-flowing material into a solid tablet. Deviations from the classic circular outlines of the tablets are known (e.g., oval, rectangular, optionally with embossing by notches and symbols, rounded edges) and are included here.The tablet typically has a diameter of 3 to 20 mm, preferably 5 to 15 mm. The maximum thickness typically varies from 2 to 8 mm. It has a typical mass of 0.5 to 1 g. Depending on the substrate-to-catalyst ratio (from % to ppm range), approximately 1 to 50 tablets are sufficient to carry out chemical batch reactions from laboratory scale to production scale.

[0033] The tablets disclosed herein include tablets, pellets, granules, compacts, and other forms. The cylindrical tablet shape, produced with simple pressing tools, is preferred, as it allows for a relatively constant weight of individual tablets during manufacturing. The tablets are preferably beveled or rounded at the circumferential edges. Exposure to catalyst dust during tablet use has been found to be relatively low. However, some unwanted dust may still be generated when the edges are broken. This is largely avoided by chamfering right-angled edges. A suitably shaped press die with a concave chamfer on the edge produces the desired beveled or rounded tablet shape.

[0034] The transition metal compound involved is preferably a transition metal complex. Transition metal complexes within the meaning of the present invention comprise at least one metal center from the group of transition metals and one or more coordinated ligands. Ligands are generally negative ions or electrically neutral molecules grouped around the metal center. Transition metal complexes based on metals selected from palladium, rhodium, or ruthenium are preferred, particularly palladium and rhodium, and especially palladium. The transition metal complexes are used as homogeneous catalysts or their precursors. Therefore, they are compounds soluble in at least one solvent (e.g., tetrahydrofuran, toluene, water).

[0035] Transition metal compounds within the meaning of the present invention include the transition metal complexes and transition metal salts mentioned above.

[0036] Bevorzugte Palladiumkomplexe sind Bis(dibenzylideneaceton)palladium(0), Tris(dibenzylideneaceton)-dipalladium(0), Bis(triphenylphosphin)palladium(II) dichlorid, Bis(tri-o-tolylphosphin)palladium(ll) dichlorid, trans-Bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II), Tetrakis(triphenylphosphin)-palladium(0), Allylpalladium(II)chlorid Dimer, (2-Butenyl)chloropalladium Dimer , (2-Methylallyl)palladium(II) chlorid Dimer, [1,1'-Bis-(diphenylphosphino)ferrocen]dichloropalladium(II), [1,1'-Bis(di-tert-butylphosphino)ferrocen]dichloropalladium(ll), (1,3-Bis(diphenylphosphino)propan)palladium(II)chlorid, (2,2'-Bipyridine)dichloropalladium(II), (Bicyclo[2.2.1]hepta-2,5-diene)-dichloropalladium(II), Bis(tri-o-tolylphosphino)palladium(II)dichloride, Bis(tricyclohexylphosphino)palladium(II)dichloride and (Ethylenediamine)palladium(II)chloride, as well as Pd complexes with known and commercially available ligands with proper names such as PEPPSI™ IPent / IPr / SIPr, XPhos, BrettPhos, Amphos or RuPhos (see Scheme 1).

[0037] Palladium compounds that do not fall under the transition metal complexes are Pd(II) acetate, chloride, bromide and trifluoroacetate.

[0038] Preferred rhodium compounds are Wilkinson catalyst (chlorotris(triphenylphosphine)rhodium(I), chloro(1,5-cyclooctadiene)-rhodium(I) dimer, rhodium(III) acetylacetonate and rhodium(III) chloride.

[0039] Preferred ruthenium compounds are Grubbs catalyst™ 1st and 2nd generation, Hoveyda-Grubbs catalyst 1st and 2nd generation and Ru(III) chloride.

[0040] According to the invention, 20 wt.% or more of a transition metal compound or a mixture of a transition metal compound and a phosphine ligand is used.

[0041] The composition of the tablet according to the invention, used in the process, optionally comprises additives selected from binders, ligands, fillers, lubricants, mold release agents, bases, and flow regulators (superplasticizers). The tablets preferably contain 0.1 to 80% of substances selected from binders, ligands, fillers, lubricants, mold release agents, bases, and flow regulators.

[0042] Binders are used to increase the mechanical stability of the tablet and to facilitate the processing of the ingredients. In the context of this disclosure, the term "binder" preferably refers to substances known for this purpose in pharmaceutical technology, i.e., tablet binders. In the present invention, one or more saccharides are preferably used as binders. They can also be used as fillers to achieve a specific metal concentration in the tablet composition. Dry binders are preferably used so that the solid phase of the complexes is not altered. Several binders for tablet production are known from pharmaceutical technology. For use with catalysts, those that do not interfere with the catalytic reaction and product separation are preferable.

[0043] The tablets according to the invention comprise saccharides as binders, including monosaccharides, oligosaccharides, and polysaccharides and their respective derivatives (e.g., carboxymethylcellulose, sugar alcohols, etc.). The saccharides used according to the invention comprise the class of sugars, sugar alcohols, and derivatives of sugars and sugar alcohols resulting from the functionalization of the OH groups. Non-hygroscopic excipients are preferred as binders. Mannitol (e.g., Parteck) is preferred. ® M200), Sorbitol (e.g., Parteck) ® SI), glucitol, croscarmellose sodium (e.g. Parteck ® CCS), carboxymethylcellulose, microcrystalline cellulose, maltodextrin, cyclodextrin, starch, and other typical saccharide-based binders. Thus, tablets with a binder content of up to 80% by mass can be manufactured industrially in large quantities and used for large-scale applications.

[0044] Other saccharides used according to the invention are selected from hexoses (mannose, glucose, galactose, fructose, etc.) and pentoses (ribose), corresponding sugar alcohols (by reduction of the aldehyde group or the carbonyl function), and technically available derivatives. Saccharides used according to the invention are also selected from oligosaccharides (2-10 sugar units, e.g., di-, tri-, tetra-, pentasaccharides, etc., which can be either linear (unbranched) or branched, cyclodextrins) and polysaccharides, which are composed of several monosaccharides and their derivatives via glycosidic linkage. Preferred polysaccharides are carboxymethylcellulose, carboxymethylcellulose sodium (carmellose), croscarmellose sodium (cross-linked carboxymethylcellulose sodium salt), microcrystalline cellulose, and starch.Within the scope of this disclosure, the preceding compounds from the group consisting of saccharides, oligosaccharides, and polysaccharides are also referred to by the generic term "saccharide" or "saccharides". The tablet formulations according to the invention are characterized by good compressibility, combined with sufficient hardness and abrasion resistance of the resulting tablets.

[0045] In a preferred embodiment of the invention, a tablet contains up to 95 wt.% saccharide, oligosaccharide or polysaccharide, according to the invention 25 wt.% or more and preferably 50 wt.% or more.

[0046] Suitable binders also include calcium hydrogen phosphate, polyvinylpolypyrrolidone, polyvinyl alcohol, and polyglycols. Suitable binders for granulation are carboxymethylcellulose, starch (preferably corn starch), gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, polyvinyl alcohol, alginates, and polyvinylpyrrolidone.

[0047] The binder content can vary widely, as it generally has a positive effect on tablet manufacturing.

[0048] In one embodiment of the invention, the binder content is minimized so that little byproduct is introduced into the reaction. A binder content of 60 wt.% or less is preferred, 30 wt.% or less is particularly preferred, and 20 wt.% or less is most preferred. For greater hardness, 1 wt.% or more of binder is preferred, 5 wt.% or more is more preferred, and 10 wt.% or more of binder is particularly preferred.

[0049] In another embodiment of the invention, the binder content is not minimized, so that the content varies up to 95 wt.%. The binders disclosed according to the invention, which belong to the class of saccharides, are very well tolerated in chemical syntheses under transition metal catalysis and can generally be easily separated from the product. This makes it possible to form practically all solid transition metal catalysts into catalyst tablets according to the invention. Practical limitations may arise due to the low air stability of some known transition metal complexes, since tablet production under inert gas is very complex. Preferably, the tablets according to the invention contain 40 to 95 wt.% of one or more saccharides, oligosaccharides, and polysaccharides, and particularly preferably 50 to 93 wt.%.

[0050] Combinations of two, three, or more binders are particularly preferred. High-quality tablets can be obtained with a proportion of microcrystalline cellulose (MC) in combination with mannitol (MA) or sorbitol. The MC / MA ratio is preferably 1 to 4, and particularly preferably 1.5 to 3. The same applies to sorbitol replacing mannitol.

[0051] A formulation containing a proportion of croscarmellose salt, in particular croscarmellose sodium salt (trade name Parteck), is also preferred. ® CCS). The proportion of this substance is preferably 3 to 50 wt.%, more preferably 5 to 25 wt.%. Particularly preferably, a tablet according to the invention contains microcrystalline cellulose, a substance selected from mannitol and sorbitol, and a proportion of croscarmellose sodium salt, preferably in a weight ratio of approximately 4:2:1.

[0052] In the context of this disclosure, the term "lubricant" refers to substances known as lubricants for tablet manufacturing in pharmaceutical technology and suitable for aiding tablet compression. Lubricants are used to reduce friction and adhesion in the tablet press tool. Suitable lubricants are typically soaps or waxes, such as sodium stearyl fumarate (PRUV®, JRS Pharma), magnesium stearate, calcium stearate, sodium dodecyl sulfate, or other commercially available products. Other lubricants include stearic acid, talc, triglycerides, adipic acid, fumaric acid, or macrogol (PEG). The tablet composition optionally and preferably contains 0.1 to 2.5 wt.% lubricant, particularly preferably 0.5 to 2 wt.%. The lubricant is preferably supplied externally to the press tool.This eliminates the need for additives in the tablet composition and significantly reduces the proportion of lubricant in the tablet weight.

[0053] In the context of this disclosure, the term "mold release agent" refers to substances that reduce the adhesion of the tablet to the surface of the pressing tool, particularly to the dies. The mold release agent can be supplied externally or is contained within the tablet composition. Preferably, the mold release agent is supplied externally. For example, magnesium stearate is used.

[0054] Lubricants and release agents can be supplied externally or are included in the tablet composition. With external supply, the agent is applied to the tableting press's die in a preceding step, which precedes one or more compression operations. Application is carried out, for example, manually (with a brush) or by spraying or blowing with a short burst of air. Preferred tablets therefore only have a lubricant or release agent on their surface. This distinguishes them from, for example, PTFE-containing tablets, where the filler PTFE serves simultaneously as a lubricant and release agent.

[0055] In the context of this disclosure, the term "flowing agent" refers to substances that contribute to a powdery, free-flowing mixture. They thus facilitate the filling of the pressing device and result in a uniform loading. Tablets of uniform mass and strength can therefore be obtained. Silicon dioxide (SiO2), in particular highly dispersed SiO2 (e.g., Aerosil® 200, Evonik), is used as a preferred flowing agent. In a preferred embodiment, the composition optionally contains 0.5% or more, preferably 1% or more, of the flowing agent.

[0056] In this application, unless expressly stated otherwise, the plural form of a term means both the singular and the plural forms, and vice versa. Further combinations of the embodiments and variants of the invention according to the description also result from the appended claims or from combinations of several of these claims. Beispiele

[0057] Folgende Abkürzungen werden verwendet: dba Dibenzylideneaceton Pd(dba)2 Bis(dibenzylideneaceton)palladium(0) PPh3 Triphenylphosphin BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1' -biphenyl)]palladium(II)-methansulfonat tBuBrettPhos Pd G3 tert-BuBrettPhos-Pd-G3, [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)-methansulfonat RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ll) RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ll)-methansulfonat SPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) SPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II)-methansulfonat XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)-methansulfonat tBuXPhos Pd G3 [(2-Di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(ll)-methansulfonat XantPhos Pd G2 Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthen)-2-(2'-amino-1,1'-biphenyl)]palladium(II) XantPhos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II)-methansulfonat

[0058] Folgende Hilfsstoffe werden verwendet: Mikrokristalline Cellulose (VIVAPUR ® Type 102) Mannit (Parteck ® M200) Croscarmellose sodium salt (Parteck ® CCS) Sorbitol (Parteck ® SI150) Polyethylene glycol M = 3600-4400 (PEG 4000) Magnesium stearate (Parteck) ® LUB MST) Highly dispersed SiO2 (Aerosil) ® 200)

[0059] Tableting compositions: Tablet mixture 1) component wt.% Bis(dibenzylideneacetone)palladium(0) 17,5 Trisorthotolylphosphine (ligand) 52,5 VIVAPUR® Type 102 20 Parteck® CCS 10 Tablet mixture 2) component wt.% Palladium diamphos dichloride 25 VIVAPUR ® Type 102 42,5 Parteck ® M200 21,5 Parteck ® CCS 11 Tablet mixture 3) component wt.% Bis(dibenzylideneacetone)palladium(0) 50 VIVAPUR ® Type 102 48 Parteck ® CCS 2 Tablet mixture 4) component wt.% Pd(II) chloride 25 VIVAPUR ® Type 102 42,5 Parteck ® M200 21,5 Parteck ® CCS 11 Tablet mixture 5) component wt.% Pd(II) acetate 25 VIVAPUR ® Type 102 42,5 Parteck ® M200 21,5 Parteck ® CCS 11 Tablet mixture 6) (for comparison only) component wt.% Pd(II) acetate 50 Parteck ® SI150 50 Tablet mixture 7) (for comparison only) component wt.% Bis(dibenzylideneacetone)palladium(0) 17,5 Trisorthotolylphosphin 52,5 Parteck ® M200 20 Parteck® CCS 10 Tablet mixture 8) (for comparison only) component wt.% Bis(dibenzylideneacetone)palladium(0) 25 Trisorthotolylphosphin 75 Tablet mixture 9) (for comparison only) component wt.% Bis(dibenzylideneacetone)palladium(0) 20 Trisorthotolylphosphin 60 Parteck ® M200 20 Tablet mixture 10) (for comparison only) component wt.% Bis(dibenzylideneacetone)palladium(0) 20 Trisorthotolylphosphin 60 Parteck ® SI150 20 Tablet mixture 11) (for comparison only) component wt.% Pd(PPh3)4 50 Parteck ® M200 50 Tablet mixture 12) (for comparison only) component wt.% Pd(PPh3)4 50 Parteck ® SI150 50 Tablet mixture 13) (for comparison only) component wt.% (PPh3)2PdCl2 50 Parteck ® M200 50 Tablet mixture 14) (for comparison only) component wt.% (PPh3)2PdCl2 50 Parteck ® SI150 50 Tablet mixture 15) component wt.% Palladium diamphos dichloride 50 VIVAPUR ® Type 102 48 Parteck ® CCS 2 Tablet mixture 16) (for comparison only) component wt.% Rh(PPh3)3Cl 50 Parteck ® SI150 50 Tablet mixture 17) (for comparison only) component wt.% Grubbs™-Ru catalyst 2nd generation 50 Parteck ® SI150 50

[0060] The following mixtures consist of a base formulation A as follows, to which 5 to 50 wt% of a transition metal compound is added. Basic formulation A component wt.% VIVAPUR ® Type 102 56,7 Parteck ® M200 28,7 Parteck ® CCS 14,6

[0061] The following tablet mixtures are prepared using base formulation A and the specified proportion of transition metal catalyst: Tablet mixture No. . Transition metal catalyst Percentage (weight%) 18) BrettPhos Pd G3 18.1% 19) tBuBrettPhos Pd G3 17.1% 20) RuPhos Pd G2 15.5% 21) RuPhos Pd G3 16.7% 22) SPhos Pd G2 14.4% 23) SPhos Pd G3 15.6% 24) XPhos Pd G2 15.7% 25) XPhos Pd G3 16.9% 26) tBuXPhos Pd G3 15.9% 27) XantPhos Pd G2 14.6% 28) XantPhos Pd G3 19.0% General procedure for the preparation of the mixtures:

[0062] For a batch size of 300 g, the finely powdered components are combined in a 2 l screw-top jar and homogenized for 5 min on a Turbula mixer (Willy A. Bachofen AG, Switzerland) at 47 rpm. General procedure for tableting:

[0063] For 1.00 g tablets, a die with two opposing punches, each with a diameter of 15 mm, is used. The punch edge is concavely beveled, resulting in tablets with a 45° facet. Similarly, a diameter of 11 mm is used for 0.250 g tablets, 7 mm for 100 mg tablets, and 3 mm for 10 mg tablets. Device data:

[0064] Device name: Romaco Kilian Styl'One Evolution (Kilian Tableting, Cologne, Germany)

[0065] Evaluation software: AnalisTM Software Version 2.05.8 (Kilian Tableting) Machine output: 2.5 - 8.8 tablets / min

[0066] Pressing force: 10 - 18 kN

[0067] Pre-print: Tableting without pre-compression force

[0068] Filling shoe: Stirred chamber filling shoe (speed 35 - 55%) Lubrication: Manual (brushing the piston surface) or external (PKB grease spray system, blowing in for 50 - 250 ms) - with Mg stearate (Parteck) ® LUB MST)

[0069] In-process control: hardness, weight, height, diameter. Evaluation of tablet properties:

[0070] To check the tablets, a device is used to determine the hardness, mass, diameter and height (Erweka Multicheck 5.1, ERWEKA GmbH, Germany). Example 1. Tablets from tablet mixture 1)

[0071] Tableting according to the general procedure for tablets of 1.07 g with a diameter of 15 mm and a height of 5 mm with manual lubrication. Pressing force: 10 kN Result:

[0072] Weight variations are less than 2%. With an average hardness of approximately 200 N, the tablets have sufficient strength. The tablets can be stored in air at 20 °C (~70% relative humidity) for at least 3 months. Example 2. Tablets from tablet mixture 2)

[0073] Tableting according to the general procedure for tablets of 1.07 g with a diameter of 15 mm and a height of 15 mm with external lubrication by blowing (Parteck) ® LUB MST). Pressing force: 12 kN

[0074] Result: approximately 7900 tablets of intense yellow color with a matte-glossy surface.

[0075] Weight variations are less than 1% relative standard deviation (n = 10). With an average hardness of approximately 192 N, the tablets have sufficient strength. Example 3

[0076] From tablet mixtures 18) - 28), approximately 100 tablets each are pressed, weighing 250 mg, 100 mg, and 10 mg, respectively. The corresponding diameters are 11 mm, 7 mm, and 3 mm. The resulting tablets have a standardized catalyst content of 0.05 mmol, 0.02 mmol, and 0.002 mmol, respectively.

[0077] The standardized tablets allow for the preparation of homogeneous catalytic reactions with different amounts of catalyst with minimal effort. Application example 1: Dosage and dissolving process

[0078] One tablet from Example 1 or 2 is added to 4 L of toluene in a reactor with a stirrer and stirred at 50 °C. The filling area of ​​the reactor is visibly free of catalyst residue. After less than 1 min, the catalyst is dissolved in the liquid phase. 5 Tablets from Example 2 (1.25 g precatalyst, 2.2 mmol) are combined with 1-bromo-4-propylbenzene (150.0 g, 0.75 mol, 1 eq.), 4-ethoxy-2,3-difluorophenylboronic acid (164.3 g, 0.81 mol, 1.08 eq.), and tri-orthotolylphosphine (7.9 g, 0.026 mol, 0.035 eq.) in 200 mL of THF in a 1 L reactor with a stirrer. The tablets disintegrate under stirring when the mixture is heated, releasing the homogeneous catalyst. NaOH (141.2 g, 1.13 mol, 1.5 eq.) is added under reflux. After the reaction is complete, the phases are separated and the organic phase is washed with 400 ml of water.The solvent is removed under vacuum (crude yield > 95%) and the residue is purified by column chromatography (eluent: n-heptane). The desired product is obtained as a white solid in high yield (GC: 99.9% purity). Application example 3: Solubility in different solvents

[0079] One Pd(Amphos)₂Cl₂ tablet according to Example 2 (tablet mixture 2, 25% catalyst) is dissolved in 49 g each of toluene, THF, acetone, or ethanol with 6% heptane at 25°C and at 50°C. The catalyst dissolves after 1–5 min at 25°C and after 1–2 min at 50°C. The solubility of the excipients is shown in the following table. Table: Solubility of the fillers: solvents 25°C 50°C toluene moderate moderate to good THF few very good acetone moderate moderate to good Ethanol, 6% heptane moderate to good good to very good

Claims

[1] Tablet containing 20 wt.% or more of a transition metal compound or 20 wt.% or more of a mixture of a transition metal compound and a phosphine ligand, the metal is selected from palladium, rhodium or ruthenium and 25 wt.% to 80 wt.% saccharide, oligosaccharide or polysaccharide, the tablet formulation contains a proportion of microcrystalline cellulose in combination with mannitol or sorbitol. [2] Tablet according to claim 1, characterized by that it contains a proportion of 3 to 50 wt.% croscarmellose sodium salt. [3] Tablet according to claim 1 or 2, characterized by that it only has a lubricant or mold release agent on the surface. [4] Tablet according to one or more of claims 1 to 3, characterized bythat it contains a phosphorus-free Pd transition metal complex or a palladium salt, preferably the palladium complex bis(benzylideneacetone)-Pd(0), palladium(II) chloride or palladium(II) acetate. [5] Tablet according to one or more of claims 1 to 4, characterized by that it contains a predefined amount of transition metal per tablet. [6] Tablet according to one or more of claims 1 to 5, characterized by that it is packaged airtight in a tablet blister pack. [7] Tablet according to one or more of claims 1 to 6, characterized by that it is faceted or rounded at the surrounding edges. [8] Set for carrying out a transition metal catalysis consisting of - one or more tablets according to any one of claims 1 to 7, and - information about the amount of transition metal per tablet or per packaging unit. [9] Set for carrying out a transition metal catalysis according to claim 8, characterized by that the one or more tablets are in an airtight package, preferably in a tablet blister pack. [10] Method for producing a tablet in which a mixture containing 20 wt.% or more of a transition metal compound or 20 wt.% or more of a mixture of a transition metal compound and a phosphine ligand, wherein the metal is selected from palladium, rhodium or ruthenium, and 25 wt.% to 80 wt.% saccharide, oligosaccharide or polysaccharide, wherein the tablet formulation contains a proportion of microcrystalline cellulose in combination with mannitol or sorbitol, is fed into a tableting press and compressed into individual tablets. [11] Method for manufacturing a tablet according to claim 10, characterized by, that in a preceding work step, which precedes one or more pressing operations, a lubricant or mold release agent is applied to the pressing tool of the tablet press. [12] Method for carrying out a catalytic reaction in a fluid reaction medium with a homogeneous transition metal catalyst, characterized by that the transition metal catalyst is supplied to the process in the form of one or more tablets according to one of claims 1 to 7.