WO2003026770A1

WO2003026770A1 - Method for removing metal from the products of olefin metathesis reactions

Info

Publication number: WO2003026770A1
Application number: PCT/US2002/030074
Authority: WO
Inventors: Jose J. Conde
Original assignee: Smithkline Beecham Corporation
Priority date: 2001-09-24
Filing date: 2002-09-23
Publication date: 2003-04-03

Abstract

Metal can be removed after completion of an organic synthesis reaction, particularly an olefin metathesis reaction, by contacting the reaction product mixture with alumina, such that a complex of alumina and metal is formed, then removing the complex. Purity levels of less than 20 ppm metal can be obtained by this process.

Description

METHOD FOR REMOVING METAL FROM THE PRODUCTS OF OLEFIN

METATHESIS REACTIONS

FIELD OF THE INVENTION This invention relates to methods for the removal of metal from the products of organic reactions, including small molecule and polymer synthesis reactions. In one preferred aspect, the invention relates to methods for the removal of metal from olefin metathesis reaction products, particularly the products of reactions catalyzed by ruthenium catalysts.

BACKGROUND OF THE INVENTION Metal catalysts such as ruthenium complexes and molybdenum complexes are used in olefin metathesis reactions, such as ring closure metathesis (RCM), cross metathesis, and ring-opening metathesis polymerization (ROMP). See, e.g., Grubbs, R. H. et al., Ace. Chem. Res. (1995) 28:446; Schmalz, H. -G., Angew. Chem. Int. Ed. Engl. (1995) 34(17):1833. For example, RCM reactions are used for synthesizing macrocycles, carbocycles and heterocycles. See (a) Fu, G. et al., J. Am. Chem. Soc. (1992) 114:5426; (b) Fu, G. C. et al., JAm. Chem. Soc. (1992) 114:7324; (c) Fu, G. C. et al., J. Am. Chem. Soc. (1993) 115:3800; (d) Fu, G. C. et al., J. Am. Chem. Soc. (1993) 115:9856; (e) Fujimura, O. et al., J. Org. Chem. (1994) 59:4029; (f) Kim, S. -H., J. Am. Chem. Soc. (1994) 116: 10801 ; (g) Miller, S. J. et al., J Am. Chem Soc. (1995) 117:2108; (h) Miller, S. J. et al., J. Am. Chem. Soc. (1995) 117:5855; (i) Martin, S. F. et al., Tetrahedron Lett. (1994) 35:691; (j) Borer, B. C. et al., Tetrahedron Lett. (1994) 35:3191; (k) Martin, S. F. et al., Tetrahedron Lett. (1994) 35:6005; (1) Martin, S. F. et al., Tetrahedron Lett. (1995) 36:1169; (m) Houri, A. F. et al., J. Am. Chem. Soc. (1995) 117:2943; (n) Kim, S. -H. et al., J. Org. Chem. (1996) 61 :1073; (o) Furstner, A. et al., J. Org. Chem. (1996) 61:3942; (p) Crimmins, M. T. et al., J. Org. Chem. (1996) 61:4192; (q) Zuercher, W. j. et al., J. Am. Chem. Soc. (1996) 118:6634. In particular, RCM is widely used to prepare cyclic systems, particularly those systems bearing more than six atoms. It can be difficult to remove metal after completion of an olefin metathesis reaction.

Metal is undesirable because it often causes discoloration of the final product. Another disadvantage of metal is that it may cause undesired olefin isomerization during distillation of the product, double bond migration, and decomposition of the product over time. Furthermore, residual metal may increase the toxicity of the final product. Particularly for medicinal applications, residual metal is undesirable because of the toxicity risks. For example, a drug product in the United States should contain less than 20 ppm of heavy metal in its final dosage form for approval by the regulatory agencies.

Various processes have been developed to remove metal after completion of an olefin metathesis reaction. For example, lead tetraacetate (Pb(OAc)₄) has been reported as facilitating product purification when used at very modest amounts after RCM reactions. Paquette et al., "A Convenient Method for Removing All Highly-Colored Byproducts Generated During Olefin Metathesis Reactions", Org. Letters 2000, vol. 2, pp. 1259-1261. Paquette et al. reported that colored ruthenium and phosphine impurities can be removed by using 1.5 equivalents lead tetraacetate relative to the amount of ruthenium-containing catalyst. Because lead tetraacetate is highly toxic, however, using it in a process to make an ingested compound, such as a drug product, is not preferred. Furthermore, its high toxicity raises environmental and safety concerns, particularly when it is used in a production scale process.

Strong oxidants such as hydrogen peroxide have also been used to remove residual metal byproducts, such as ruthenium byproducts. Such treatment, however, is highly exothermic and produces a large amount of gas (O₂). These two qualities make the reaction difficult to control when used on a large scale. Multiple chromatographic purifications also have been shown to reduce residual metal byproducts. Yet such steps are often time- consuming and the results may not provide reproducible yields. Tris(hydroxymethyl)phosphine has been used at high levels (ten equivalents per equivalent of catalyst) to facilitate ruthenium removal during product isolation. Maynard and Grubbs, "Purification Technique for the Removal of Ruthenium from Olefin Metathesis Reaction Products", Tet. Letters 1999, vol. 40, pp. 4137-4140. This reaction is less desirable, however, because of the high cost of the phosphine reagent and the large amount needed.

Notwithstanding these treatments developed to remove residual metal from olefin metathesis reaction products, an urgent need still exists for a method of metal removal that is simple to use, efficient, controllable on an industrial scale, and does not involve the use of highly toxic or very expensive reagents.

SUMMARY OF THE INVENTION It is has now been discovered that alumina is a very effective scavenger for metal- containing species generated in olefin metathesis reactions, particularly for ruthenium- containing species. In one embodiment of the invention, alumina is added to a solution containing the reaction products of a ruthenium-catalyzed RCM reaction and allowed to react with the solution. The resulting mixture is then filtered to remove the alumina complexes. The filtrate is concentrated by solvent removal. The resulting product shows greatly reduced levels of metal.

It is an object of the invention to provide a method for the purification of products generated during metal-catalyzed reactions. It is a further object to provide a method for the purification of products generated in ruthenium-catalyzed reactions. It is a further object to provide a method for purification of products generated in olefin metathesis reactions, such as RCM, cross metathesis, and ROMP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the removal of metal from the products of a metal-catalyzed chemical reaction. In a preferred embodiment, the process provides a means to purify products generated during olefin metathesis reactions. More particularly, the invention provides a method for the removal of metal from olefin metathesis reaction products formed in the presence of a metal catalyst comprising contacting the olefin metathesis reaction product mixture with alumina such that an alumina complex is formed between the catalytic metal and the alumina; and separating the alumina complex from the olefin metathesis reaction product mixture. In a more preferred embodiment, the catalytic metal removed is ruthenium. The invention also provides a process for the purification of cyclic products generated during olefin metathesis reactions wherein at least one olefin is reacted in the presence of a catalytic metal and a solvent such that an olefin metathesis reaction occurs, adding a second solvent, adding alumina such that an alumina complex comprising alumina and catalytic metal is produced, and removing the alumina complex. The alumina used in the present invention may be any aluminum oxide. Preferably, the alumina is activated aluminum oxide, and still more preferably is Brockmann I aluminum oxide in acidic, weakly acidic, basic, or neutral form. More preferably, the alumina is activated aluminum oxide, Brockmann I in basic form. The preferred alumina particle size is that having high surface area for maximum catalytic effect, yet also sufficiently large enough for easy removal by filtration. One preferred alumina is aluminum oxide having an average surface area of approximately 155 m²/g, a particle size of about 58 A, and isolated with a 150 mesh screen.

The alumina may be present in amounts that can be readily determined by one skilled in the art based on the specific reaction involved. Preferably, alumina is present in excess, as measured by molar equivalents, of catalytic metal. More preferably, alumina is present in an amount of greater than twofold excess, still more preferably greater than tenfold excess, yet more preferably greater than 100-fold excess, and yet more favorably greater than 300-fold excess.

As used herein, the terms "catalytic metal" and "metal catalyst" are interchangeable and are any metal-containing catalyst that catalyzes an organic reaction. Preferably, the metal catalyst includes a transition metal, and yet more preferably is a ruthenium, palladium, nickel, yttrium or molybdenum based catalyst. Still more preferably, the metal catalyst is a ruthenium based catalyst, yet more preferably a ruthenium alkylidene catalyst. Preferred metal catalysts are selected from the following compounds: (1) [Ru{η6:ηl-Ph(CH₂)₃ OH}(PCy₃)Cl]BF₄; (2) PhCH=RuCl₂(PCy₃)₂ (known as benzylidene ruthenium complex); and (3) [Ru=C=C=CR₂(L)(Cl)(arene)]PF₆ where L is PCy₃ or PPri₃. Other suitable ruthenium catalysts are known in the art. For example, the following articles teach suitable ruthenium catalysts for olefin metathesis reactions and are hereby incorporated herein in their entireties: Miyaki et al., "Co-catalyst dependent cycloisomerization or ring closing metathesis of α, ω-dienes catalyzed by arene ruthenium complex with side-arm alcohol", J. Organometallic Chem. 2000, vol. 616, pp. 135-139; Krikstolaityte et al., "Ru(H)-catalyzed RCM reactions with electrophilic diene substrates", Tetrahedron Letters 39 (1998), 7595- 7598; Adams et al., "Zr-catalyzed kinetic resolution of aliphatic cyclic allylic ethers, carbocycles to heterocycles by Ru- and Mo-catalyzed ring-opening and ring-closing metathesis", J. Organic Chem. 1999, 64, 9690-9696; Fϋrstner et al., "Cationic ruthenium allenylidene complexes as a new class of performing catalysts for ring closing metathesis", Chem. Commun. 1998, 1315-1316; Smith et al., "Assembly of (-)-cylindrocyclophanes A and F via remarkable olefin metathesis dimerizations", J. Am. Chem. Soc. 2000, 122, 4984- 4985; Schwab et al., "A series of well-defined metathesis catalysts-synthesis of [RuCl₂(= CHR') (PR₃)₂] and its reactions", Angew. Chem. Int. Ed. Engl. 1995, 34(18), 2039-2041;

Nguyen et al., "Ring-opening metathesis polymerization (ROMP) of norbornene by a Group VIII carbene complex in protic media", J. Amer. Chem. Soc. 1992, 1 14, 3975-3977.

As used herein, the removal of metal includes removal of free metal, metal ions, metal salts, or metal complexes with organic molecules. The removal of metal from the products of organic reactions includes removing metal in the form it is used as a catalyst, as well as removing metal in any other compound or complex in which it is found.

The alumina-catalytic metal complex can be removed or separated from the desired olefin metathesis reaction products by various ways, such as by filtration or centrifugation. Preferably the filtration is over charcoal, and still more preferably over celite-activated charcoal. The alumina-catalytic metal complex may also be separated from the desired olefin metathesis reaction products by attaching the alumina to a solid support and contacting the olefin metathesis reaction product mixture with the solid support under conditions such that separation is effected. For example, the alumina may be coated onto solid particles that are then stirred with the olefin metathesis reaction products. Also, alumina-coated particles may be placed in a column. The olefin metathesis reaction product mixture may be passed over the column.

By following the inventive purification process, the concentration of residual metal in the olefin metathesis reaction products can be reduced by ten fold or greater, preferably reduced by one hundred fold. Preferably the process is used to produce levels of less than about 20 ppm of metal in the olefin metathesis reaction products.

The amount of metal remaining after purification can be measured in ways known to those skilled in the art. For example, inductive-coupled plasma mass spectrometry (ICP- MS) can be used. In one embodiment, the products of an olefin metathesis reaction are added to 10 ml of high purity concentrated nitric acid and diluted with deionized water to a total of 100 ml after thorough mixing and dissolution. Calibration standards of the metal to be tested for are prepared by serial dilution of standard solutions in 10% v/v nitric acid. A blank is made from 10% v/v nitric acid. The samples are placed into an inductively coupled plasma mass spectrometer and signals are measured.

The level of ruthenium remaining after purification can also be determined qualitatively by visual inspection of a solution of olefin metathesis reaction products. A clear, colorless solution of olefin metathesis reaction products indicates that residual ruthenium is substantially removed. Similarly, when the solution of olefin metathesis reaction products is evaporated to yield solids, the solids are white when the residual ruthenium is substantially removed. In the following synthetic examples, temperature is in degrees Centrigrade (°C).

Unless otherwise indicated, all starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These Examples, are given to illustrate the invention, not to limit its scope. Reference is made to the claims for what is referred to the invention hereunder. EXAMPLE 1

To a solution of diene

in CHC1₃ was added at room temperature the catalyst shown below:

Cy₃ represents a cycloindene and CBz represents carbobenzoxy. The catalyst was obtained from Boulder Specialty Chemicals, Boulder, Colorado.

The dark solution was heated at reflux for one hour. The solvent was removed via vacuum distillation and the residue was dissolved in standard grade hexanes. Activated aluminum oxide Brockmann I basic 150 mesh, 58A from Aldrich was added to the solution at about 360 equivalents alumina per equivalent of catalyst. The resulting suspension was heated at reflux for four hours and then filtered through a pad of celite-activated charcoal. The filtrate was concentrated under vacuum distillation to afford a colorless liquid. The residual ruthenium in the concentrated filtrate was 9 ppm as measured by ICP-MS.

EXAMPLE 2

To a solution of

(20g, 0.073 mol) in CH₂C1₂ at room temperature was added the catalyst shown below (0.3 g, 0.5 mol%):

Cy₃ represents a cycloindene. The suspension becomes homogenous. The homogenous mixture was heated at reflux for 10 hours until the reaction appeared to have stopped. More catalyst was added and the mixture was stirred at reflux overnight. A GC-MS analysis showed completion of the reaction. The mixture was allowed to cool at room temperature before 50 ml of H₂O was added, followed by 50 ml of 10% NaHCO₃. H₂O₂ (30% w/w) (30 ml) was added dropwise. Foaming was observed. The mixture was stirred at room temperature for 2 hours. Celite (10 g) was then added to the mixture and the resulting mixture was stirred for 15 minutes at room temperature. The mixture was filtered and the filtrate was separated. The organic layer was washed with 10% Na₂S₂O₅, H₂O, then brine then dried over MgSO₄ and concentrated to minimize CH₂CI₂. Hexane was added followed by activated carbon DARCO (G-60) (10 g). The suspension was stirred at room temperature overnight then filtered through celite. The filtrate was concentrated by vacuum distillation to a yellow liquid. The residual ruthenium in the concentrated filtrate was greater than 300 ppm as measured by ICP-MS.

EXAMPLE 3 To a solution of N-pent-4-enyl(phenylmethoxy)-N-prop-2-enylcarboxamide (1)

(20g, 0.073 mol) in CH₂C1₂ at room temperature is added the catalyst shown below (0.32 g, 0.5 mol%):

where PCy₃ represents a tricyclohexylphosphine ligand. The homogenous mixture is heated at reflux for 4 hours. The mixture is allowed to cool at room temperature before 50 ml of H₂O is added, followed by 50 ml of 10% NaHCO₃. H₂O₂ (30% w/w) (30 ml) is added dropwise. The mixture is stirred at room temperature for 2 hours. Celite (10 g) is then added to the mixture and the resulting mixture stirred for 15 minutes at room temperature. The mixture is filtered and the filtrate separated. The organic layer is washed with 10% Na₂S₂θ₅, H₂O, brine, and dried over MgSO and concentrated to minimize CH₂CI₂. Hexane is added followed by activated carbon DARCO (G-60) (10 g). The suspension is stirred at room temperature overnight and filtered through celite. The filtrate is concentrated by vacuum distillation to give l-benzyloxycarbonyl-2H,5H,6H,7H-azepine (2) as a yellow liquid.

The above specification and examples fully disclose how to make and use the present invention. However, the present invention is not limited to the particular emdodiment described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents, and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims

What is claimed is:

1. A method for removal of metal from a reaction product mixture containing a catalytic metal, comprising:

(a) contacting the reaction product mixture with alumina such that an alumina complex is formed, wherein the alumina complex comprises the catalytic metal and alumina; and

(b) separating the alumina complex from the reaction product mixture.

2. The method of claim 1, wherein the reaction product mixture is an olefin metathesis reaction product mixture.

3. The method of claim 2, wherein the catalytic metal comprises a transition metal.

4. The method of claim 3, wherein the catalytic metal comprises ruthenium, palladium, nickel, yttrium or molybdenum.

5. The method of claim 4, wherein the alumina is activated aluminum oxide.

6. The method of claim 2, wherein the olefin metathesis reaction product mixture is formed from the reaction of a diene with a catalyst of Formula I

CL PCy₃

.Ru=r-

Ph

Cl PCy₃

The method of claim 6, wherein the diene is a compound of Formula II

8. The method of claim 6, wherein the alumina is activated aluminum oxide.