The present invention is concerned stable formulations containing olefin metathesis catalysts, methods of forming same, and the use of said formulations in olefin metathesis reactions.

Olefin metathesis is a field of synthetic organic chemistry and specifically entails the redistribution of fragments of alkenes by the scission and regeneration of carbon-carbon double bonds.

Catalysts for this reaction have evolved rapidly for the past few decades.

Typically, the reaction is catalysed by metal complexes such as well-defined molybdenumfVI)- and tungsten(VT)-based organometallic compounds. .

Whereas these complexes are highly effective catalysts, they are somewhat unstable in air and moisture, and the chemist must take necessary precautions when handling them.

Of course, moisture and air sensitive reagents are well known in the art. For example, butyl lithium and lithium aluminium hydride are sensitive to moisture and air but can be handled easily in air. Indeed, the skilled person will

understand that the term moisture and/or air sensitive is relative and can describe many reagents that are on the one hand nevertheless easy to handle, and on the other extremely unstable.

Taber et al in US 2005/0288257 describes methods and compositions for handling moisture and/ or air sensitive compounds. Taber is concerned in particular with Ruthenium complexes and methods and formulations for stabilising same. Said formulations are prepared by simply mixing the ruthenium complexes with an inert material, such as paraffin having a melting point range of 20 to 250 degrees centigrade. Formulations are prepared by immersing the unstable compound in molten inert material to create a homogenous or heterogenous mixture. Thereafter, once solidified, the mixture may be cut into useful pieces.

Molybdenum (VI)- and tungsten(VI)-based catalysts useful in olefin metathesis reactions are particularly unstable reagents, even compared with ruthenium complexes. In particular, it is necessary to handle these materials under an inert atmosphere. This would normally require the chemist to handle the materials in an inert atmosphere in a glove box. Furthermore, having regard to the high activity of these reagents, they are employed in very low concentrations in metathesis reactions, and so even very small amounts of degradation can have a marked negative effect, causing poor conversion, poor yields and low turn-over numbers (TON). Accordingly, there remains a need to provide formulations of olefin metathesis catalysts based on molybdenumfVI)- and tungsten(VT) complexes that are stable in air and therefore easy to handle by a chemist, which nevertheless can catalyze olefin metathesis reactions with good conversion, selectivity, yield and turn-over number.

The present application addresses the deficiencies in the prior art and provides in a first aspect a composition comprising a molybdenum (VI)- based or

tungsten(VI)-based organometallic complex dissolved or dispersed in an inert material having a melting point of about 50 to about 70 degrees centigrade.

The melting point range, narrow in comparison with what is mentioned elsewhere in the art, is critically important with respect to the use of

molybdenum (VI)- based or tungsten(VI)-based organometallic complexes. It is essential that the inert compound have a melting point that is neither so low that it melts during handling or storage, nor so high that the complexes thermally degrade during formulation. This is a particular problem with molybdenum (VI)- based or tungsten(VI)-based organometallic complexes, which are particularly heat-sensitive. The choice of this range allows, for the first time, the proper utilisation of molybdenum (VI)- based and tungsten(VI)-based organometallic complexes. In a particular embodiment, the inert material has a melting point of between 50°C and 6o°C. In a particular embodiment of the present invention, the inert material employed in the composition is a paraffin compound.

In addition to the foregoing considerations, the choice of inert material, in particular paraffin, maybe chosen to ensure that sufficient concentration of catalyst is dissolved therein. In particular, catalyst may be dissolved in amounts to provide a l to 10 % w/w solution.

When the inert material which forms the matrix in which the complex is dissolved or dispersed is paraffin, it may consist of mixtures of alkanes or it may be in the form of a single pure alkane. However, as pure alkanes might be more likely to solidify in the form of plate-like crystalline domains, it may be more advantageous to use a paraffin that consists of a mixture of alkanes. Should the paraffin solidify to form plate-like crystals there is a heightened risk that moisture and/or oxygen could penetrate the matrix between the plate boundaries and thereby interact with the dispersed organometallic complexes and degrade them. With a mixture of alkanes, this danger is at least substantially reduced, or even eliminated completely.

In another embodiment of the present invention the molybdenum (VI)- based or tungsten(VI)-based organometallic complexes are dissolved in the inert matrix. Whether the complex is dissolved or dispersed in the matrix will depend on the nature of the complex, but the skilled person will readily be able to determine this and to select appropriate materials for any desired end-use.

By dissolving the complex in the inert matrix material, it may be substantially uniformly distributed throughout the matrix. In this manner, aliquots of molten composition of precisely defined volume may be drawn in order to form droplets containing precisely controlled amounts of complex, as is more fully described below. Presenting the composition of the present invention in the form of a solution is particularly advantageous if it is desired to divide the composition into multiple unit dosage forms, each containing a constant weight of organometallic complex.

The provision of a solution may be verified by any techniques known in the art. In particular, the presence of a catalyst in solution can be determined using differential scanning calorimetry techniques by measuring heat-flow curves indicative of a solid-liquid transition. DSC measurements may be made on any suitable thermal analyzer apparatus, for example a SETARAM Labsys Evo TG- DSC thermal analyzer. Measurements may be carried out under an inert gas atmosphere such as a helium atmosphere. Any suitable heating rate can be selected. Typically heating rates can be set at between 1 to 10 K/min.

The concentration of catalyst dissolved in a matrix material, e.g. paraffin wax, may be selected in order to ensure that the thermal properties of the matrix material, as measured by DSC, are not altered. In a particular embodiment of the present invention, the concentration of catalyst in the matrix may be up to 20 % by weight, more particularly 1 to 10 % by weight.

The invention provides in another of its aspects a composition as hereinabove defined in the form of a multi-particulate composition, each particle containing the organometallic complex in a constant weight.

In a particular embodiment of the present invention, the multi-particulate particles may be contained in a blister pack. In a more particular embodiment, each blister may contain one particle.

In another particular embodiment of the present invention, the multi-particulate dosage form may be contained in a sachet.

In another particular embodiment, the blisters or the sachet may be inflated to some extent with an inert gas. The advantage of this construct resides not only in the additional protection afforded by the inert atmosphere surrounding the particles, but any sign of deflation of the sachet or blister would act as a visual cue of any potential damage to the contents. The invention provides in another of its aspects a method of forming

compositions as defined herein.

In a particular embodiment of the present invention the method of forming a composition defined herein comprises the steps of i) dissolving a molybdenum (Vl)-based or tungsten(VI)-based organometallic complex in a molten matrix material at a temperature of about 50 to 70 degrees centigrade under a dry, inert atmosphere to form a molten solution, and ii) cooling the molten solution to provide a solidified composition.

In a particular embodiment of the present invention, there is provided a method of forming a composition as defined herein comprising the steps of i) drawing a measured volume from the molten solution and dispensing said measured volume of the molten solution onto a surface in the form of a droplet, and ii) cooling said droplet to form a solid droplet.

The skilled person will appreciate that a multi-particulate composition can be formed by drawing multiple measured volumes of molten solution and dispensing and cooling the droplets in a manner described above.

The matrix material employed in a method according to the invention advantageously is pretreated before use. Pre-treatment is carried out to remove oxygen and/or moisture trapped in commercial grade materials.

The skilled person will be fully aware of the techniques known in the art for drying and removing oxygen from reagents. Purging solvents of oxygen and moisture can be affected by heating a matrix material, e.g. paraffin, to 130-140 °C under 1.0 - 0.1 Torr dynamic vacuum for at least 4 hours while it is continuously stirred. When no water and oxygen can be detected the matrix material, e.g. paraffin has to be cooled back to a temperature between 50 and 70 °C. Thereafter, the catalyst can be added and dissolved in the solvent in manner described above under stirring. As described above, when it is desired to prepare the composition in a multiparticulate form, the molten solution prepared according to the method described above, is dispensed in a molten state onto a surface. In a preferred embodiment, the surface is an apolar surface. This will promote the formation of substantially spherical droplets. Suitable apolar surfaces may be metal surfaces, more particularly a highly polished metal surface. The surface is advantageously a metal surface as metals are particularly effective at conducting heat and this is conducive to the rapid formation of solid, substantially spherical or pearl-shaped particles. In turn, this will promote the ease of removal of the solid particles from the surface without leaving residues on the surface. Particularly suitable surfaces can be prepared from aluminium or stainless steel.

In order to obtain accurate volumetric metering of the molten droplets, the droplets may be dispensed from a graded pipette. The volume of the pipette will be determined by the desired volume of the droplets, but typically may range from 100 to 250 microlitres, although the skilled addressee will appreciate that larger or smaller volumes may be employed according to particular needs.

In the manner described above, the present invention teaches the preparation of multiple unit dosage forms of catalyst-containing composition by a volumetric technique from a molten stock solution of said composition, each dosage form, which may be in the form of a substantially spherical, pearl-shaped droplet, containing precisely defined amounts of catalyst. The advantage to the

preparative chemist is clear: By means of the present invention, the chemist can handle very sensitive catalysts without the usual precautions of using a glove box and an inert atmosphere. Furthermore, the chemist can meter very precise amounts of such catalyst materials into a reaction mixture with a high level of confidence.

The molten solution is preferably cooled rapidly to form a solid composition or solid droplet in order to reduce the likelihood of crystal formation. As stated above, boundaries between crystal domains may provide means for ingress of oxygen and/or moisture into the matrix, which could affect the stability of the catalysts. The molten solution should be cooled to a solid form preferably within a time scale of one to two seconds. Applicant has found that dropping molten droplets onto a metal surface provides for appropriate rapid cooling and solidifying of droplets.

Compositions according to the invention may be used as a catalyst in the metathesis reactions of a variety of substrates with substrate to catalyst ratio of up to 1000:1 or even greater. Conversions of above 90 % may also be obtained. As such, compositions according to the present invention may perform as catalysts substantially in the same way in which the pure isolated tungsten and/or molybedenum can perform, but without the added precaution of handling the catalysts under an inert atmosphere in a glove box.

Modification of the pure catalysts into catalyst compositions of the present invention had no effect on the scope of substrates that could be reacted or the scope of the metathesis reactions in which the compositions could be applied. For example, said catalyst compositions may be employed in cross metathesis, homometathesis, ethenolysis, as well as ring-closing metathesis and ring opening metathesis polymerizations.

In order to further illustrate the invention there is provided hereinbelow a series of examples.

Example 1

Preparation of the droplets:

In 2.7 g of adequately pre-treated (oxygen and moisture-free) macro waxes (DWC5759; CAS: 64742-43-4; MOL Pic; m.p.: 57-59 °C) at 70-75 °C 300 mg of catalyst (Mo(N'Pr ₂ Ph)(CHCMe ₂ Ph)(2,5-Me ₂ Pyrr)(0-3,3'-Br ₂ -BitetOTBS) was dissolved in the course of 10-15 mm. Then the obtained clear burgundy red solution was pipetted onto the polished surface of an aluminium block in 111 ih portions in such a manner that it provided approximately constant weight pearllike droplets. Using an appropriate pipetting rate the droplets obtained separated readily from the surface. The weight of the droplets varied in the range of 102 - 105 mg.

Test reaction in which the stability of the droplets was studied:

In the Glove-box a pellet (ca.100 mg) of the catalyst (iowt%) in macro waxes, which had spent 6 hours under normal air prior to use was charged into a 10 mL vial and dissolved in anhydr. toluene (1.5 mL) at. r.t. Then allylbenzene (1335 μί; subst. /cat. = 1000) was added and the reaction mixture was stirred in a vented vial at r.t. for 4 h before it was quenched with wet heptane.

Work-up:

Internal standards 1.0 mL pentadecane in EtOAc (c = 59.72 mg/mL) and 1.0 mL mesitylene in EtOAc (c= 60.32 mg/mL) were added. Then the reaction was completed to 10 mL with heptane from which 1.0 mL was poured onto the top of a silica column (1.0 mL) and eluted with ethyl acetate (10 mL). From the collected elute 100 μΐ. was diluted to 1.0 mL form which 1.0 μΐ. was injected and analyzed by GCMS-GCFID. Column: Phenomenex ZB 35HT (30 m; I.D. 0.25mm; film thickness 0.25 μπι). Method: 35 °C, 5 min; 25 °C/min; 340 °C, 12 min.

Result: Pilot study, no isolation: according to GC-MS-FID the conversion of the reaction was 90%, and the reaction mixture contained only the expected product and some unreacted starting material (TON: 448). E/Z isomers of the 1,4- diphenylbut-2-ene was obtained in a 63 to 37 ratio.

Test reaction in which the applicability of the droplets on the bench were studied:

On the bench allyl benzene (125 μί; 0.94 mmole) in anhydrous toluene (2.0 mL) was charged into a 30 mL vial, dried at 140 °C for 2 hours prior to use, in a dry, argon-filled AtmosBag™. A pellet (100 mg) which contained 10 mg catalyst according to Example 1 (9.4 μπιοΐβ; substrate/catalyst =100/1; catalyst loading 1.0 mole%) was added, the vial was closed with a screw cap and the reaction mixture was stirred at 25 °C for 4 hours. Work-up:

Internal standards 1.0 mL pentadecane in EtOAc (c = 60.20 mg/mL) and 1.0 mL mesitylene in EtOAc (c= 60.12 mg/mL) were added. Then the reaction was completed to 10 mL with heptane from which 1.0 mL was poured onto the top of a silica column (1.0 mL) and eluted with ethyl acetate (10 mL). From the collected elute 100 μί, was diluted to 1.0 mL form which l^L was injected and analyzed by GCMS-GCFID. Column: Phenomenex ZB 35HT (30 m; I.D. 0.25mm; film thickness 0.25 μπι). Method: 35 °C, 5 min; 25 °C/min; 340 °C, 12 min.

Result: Pilot study, no isolation: according to GC-MS-FID the conversion of the reation was 81%, and the reaction mixture contained only the expected product and some unreacted starting material (TON: 40). E/Z isomers of the 1,4- diphenylbut-2-ene was obtained in a 78 to 22 ratio

Example 2

Demonstration of the efficacy of the catalysts of the invention.

The catalyst composition prepared according to Example 1 was used to convert diethyl diallyl malonate

into diethyl cyclopent-3-ene,i,i-dicarboxylate

Diethyl dially malonate (227 μί; 0.94 mmole) in anhydrous toluene (2.0 mL) was charged into a 30 mL vial, dried at 140 °C for 2 hours prior to use, in a dry, argon-filled AtmosBag™. A pellet (100 mg) which contained 10 mg catalyst according to Example 1 (9.4 μπιοΐε; substrate/catalyst =100/1; catalyst loading 1.0 mole%) was added, the vial was closed with a screw cap and the reaction mixture was stirred at 25 °C for 4 hours. Work-up: Internal standards 1.0 mL pentadecane in EtOAc (c = 60.02 mg/mL) and 1.0 mL mesitylene in EtOAc (c= 60.03 mg/mL) were added. Then the reaction was completed to 10 mL with heptane from which 1.0 mL was poured onto the top of a silica column (1.0 mL) and eluted with ethyl acetate (10 mL). From the collected elute 100 μL was diluted to 1.0 mL form which ι.ομί was injected and analyzed by GCMS-GCFID. According to GC analysis of the elute a complete conversion, yield GC: >99% was achieved. Column: Phenomenex ZB 5HT (30 m; I.D. 0.25mm; film thickness 0.25 μπι). Method: 50 °C, 5 min; 25 °C/min; 340 °C, 12 min.

Ή-NMR (CDCI3, 200MHz): 5.60 (s, 2H, CH), 4.19 (q, 4H, 0CH ₂ ), 3-01 (s, 4H, CH ₂ -ring), 1.25 (t, 6H, CH ₃ ) ppm.

The process was repeated with catalyst loadings of 0.5 and 0.25 mole% which gave the targeted product in >99 and 72% GC yield respectively. The TONs were 200 and 288. The TON (turnover number) indicates the efficacy of the catalyst: it shows the number of product molecules made by a single catalyst molecule. In general it is calculated as the product of the catalyst loading and the yield.

This is contrasted with the same process described in the JOC Note in J. Org. Chem. 2003, 68, 6047-6048, in which Taber and Frankowski use a Grubbs' catalyst (see third example in the experimental section).

It should be noted that Taber used a catalyst loading of 1.2 mol% and achieved a yield of 84%. With the catalysts of the present invention, even a catalyst loading of 0.25 mol% achieved a yield of 72%. Moreover, whereas the process of Taber took 11 hours, the processes of the present invention took only 4 hours. There is thus a considerable improvement in efficacy.