Patent Grant
7449591
This invention relates to a process of diminishing the concentration of a metal complex from a solution by adding a solubility-enhancing compound that enhances the solubility of said complex in a second solution and extracting the solution containing said complex with the second solution. The solubility-enhancing compound is a compound of formula A
wherein,
Despite the ubiquitous use of metal complexes in organic reactions, a simple process for their removal has yet to be discovered. Unfortunately, residual metals often must be removed from the reaction mixture because they can interfere with subsequent transformations and can pose problems for shelf-life and use of the final product.
Current process for removing metal complexes involve running the reactant mixture through numerous columns or other similarly rigorous purification strategies. In addition to being cumbersome, these procedures are time consuming and labour intensive. As uses for metal complexes increases, a simple and facile process for their removal is increasingly needed and desired.
U.S. Pat. No. 6,376,690 discloses a process of removing residual metals from a solution by adding a solubility-enhancing compound, where through the relative solubilities between two solutions are manipulated so as to cause the metal complex in a first solution to transfer into a second solution that is generally immiscible with the first solution. The removal of the second solution thus also removes the metal complex from the reaction mixture.
U.S. Pat. No. 6,376,690 recommend phosphines as useful solubility-enhancing compounds. However, the examples disclosed in this invention, only demonstrate that the use of a special water-soluble phosphine, i.e. trishydroxymethylphosphine (THP) in combination with triethylamine, is able to reduce the Ruthenium content of different simple ether and ester products. With respect to the large scale synthesis of more highly functionalized organic compounds, treatments with THP solutions may cause undesired side reactions. These side reactions may be due to formaldehyde present in THP solutions, which are most easily accessible for large scale operations by means of alkaline deformylation of commercially available aqueous tetrakis(hydroxymethyl)phosphonium salts (TKC).
Moreover, in view of a potential commercial use on large scale, phosphines generally exhibit the disadvantage of being very susceptible towards oxidation. This implies that special measures have to be taken to protect these air sensitive and/or pyrogenic compounds from contact to oxygen and, hence, guarantee their desired efficiency. Hence, these phosphoric compounds are released in situ in separate vessels under inert conditions, increasing the complexity of the large scale processes. In addition, phosphines are toxic and therefore not useful in food or pharmaceutical industry, since any product contamination by these compounds has to be strictly avoided.
Surprisingly it was found, that these pitfalls can be avoided by the use of compounds of formula A
wherein,
The present invention generally relates to the invention that the solubility of metal complexes may be readily manipulated by the addition of a compound of formula A
wherein,
In one embodiment of the invention, the relative solubility's between two solutions are manipulated so as to cause the metal complex in a first solution (typically the reaction mixture) to transfer into a second solution that is generally immiscible with the first solution. The removal of the second solution thus also removes the metal complex from the reaction mixture. This embodiment is particularly useful for separating the metal complex from the reaction product.
The present invention generally relates to the discovery that the solubility of metal complexes may be readily manipulated by the addition of one or more solubility-enhancing compounds. This manipulation of the solubility's allows for the preparation of suitable samples for precise quantitative analysis and for the facile purification of the desired products from the reaction mixture containing one or more metal complexes.
In the most general sense, the present invention relates to a process of enhancing the solubility of a metal complex (or a combination of metal complexes) in a solution by the addition of one or more solubility-enhancing compounds to the solution.
Used Terms and Definitions
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
As used herein, the term “metal complexes” include the metal compound itself (e.g. Cu, Mg, Ru, Os, etc), its ions, and metal containing or metal associated compounds (either through covalent bounds or through other intermolecular forces such as chelation). Illustrative examples of metal complexes whose solubility's may be manipulated through the practice of the present invention include but are not limited to complexes of: cadmium, chromium, cobalt, copper, gold, iridium, iron, magnesium, manganese, mercury, molybdenum, nickel, osmium, palladium, platinum, rhenium, rhodium, ruthenium, silver, technetium, tungsten, and zinc.
As used herein, “solubility-enhancing compounds” are compounds that interact with a metal or transition complex in a manner that enhances the solubility of the complex in the desired solution. The solubility-enhancing compound can also be activated by a second compound. For example citric acid can be activated by an organic base. Suitable organic bases are dimethylaminopyridine, pyridine, tert. amines, i.e. trimethylamine, triethylamine, diisopropylethylamine or DBU (diazabicycloundecene).
As used herein, “activated forms of solubility-enhancing compounds” are solubility-enhancing compounds that interact with a second compound added to enhance the solubility of the solubility-enhancing compounds in the desired solution. For example, if the desired solution is a polar and/or protic solution, the solubility of a compound, containing acid functions can be enhanced by addition of a base, i.e. citric acid can be activated by an organic base. Suitable organic bases are dimethylaminopyridine, pyridine, tert. amines, i.e. trimethylamine, triethylamine, diisopropylethylamine or DBU (diazabicycloundecene).
As used herein the term “protecting group” includes functional groups used for the protection of a hydroxy function. To protect the hydroxy function the protective group replaces the hydrogen atom of the hydroxy group, to unprotect the hydroxy group cleavage of the group-oxygen bond under reformation of the OH group under mild conditions is possible.
As used herein the term “suitable leaving group” includes functional groups that replace the hydrogen atom of a hydroxy group. Then the group is displaced as stable species taking with it the bonding electrons. Typically the leaving group leaves as an anion taking the oxygen of the former hydroxy group with it. The better the leaving group, the more likely it is to depart.
A leaving group can be the same as a protecting group depending on the reaction to despatch the group. Examples of suitable leaving groups or protecting groups are 2,4,6-trimethylbenzoate, 2,4-dinitrophenyl, 2,4-dinitrophenylsulfenate, 2-chlorobenzoate, 2-trifluoromethylbenzyl, 2-trimethylsilylethyl, 3,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3-phenylpropionate, 4-bromobenzoate, 4-nitrobenzoate, 9-anthryl, 9-fluorenylmethyl, □-naphthoate, acetate, allyl, allylsulfonate, benzoylformate, benzyl, benzyloxymethyl, benzylsulfonate, brosylate, chloroacetate, chlorodiphenylacetate, dichloroacetate, diethylisopropylsilyl, dimethylisopropylsilyl, diphenylacetate, diphenylmethyl, ethyl, isobutyl, isobutyrate, menthoxymethyl, methanesulfonate, methoxyacetate, methoxymethyl, methyl, monosuccinoate, nitrobenzyl, nitrophenyl, N-phenylcarbamate, p-acylaminobenzyl, p-chlorophenyl, p-cyanobenzyl, p-halobenzyl, phenoxyacetate, phenylacetate, p-methoxybenzyl, p-methoxyphenyl, p-phenylbenzoate, propargyl, t-butyl, tosylate, tribenzylsilyl, trichloroacetate, triethylsilyl, trifluoroacetate, triisopropylsilyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, tris(trimethylsilyl)silyl, vinyl.
One embodiment of the invention is a process of diminishing the concentration of a transition metal complex from a first solution containing said complex by the addition of a second solution, comprising the following steps:
wherein,
Preferred is a process, wherein a compound of formula A, is used wherein
Also preferred is a process, wherein a compound of formula A, is used wherein
Also more preferred is a process, wherein a compound of formula A, is used wherein
Also preferred is a process, wherein a compound of formula A, is used wherein
Also preferred is a process, wherein a compound of formula A, is used wherein
Also preferred is a process, wherein a compound of formula A, is used wherein
Preferred are the compounds of formula A1,
wherein Ra, Rb, Rc, Rd and n have the meaning given for A.
Most preferred is a process, wherein the solubility-enhancing compound is selected from the group consisting of dithioerytrol, 2,3-dimercapto propane-1-sulfonic acid, 2,3-dimercapto succinic acid, citric acid or citric acid in combination with an organic base, selected from the group dimethylaminopyridine, pyridine, triethylamine and diisopropylethylamine.
Preferred is the process wherein the removed transition metal is selected from a group consisting of Cu, Ru, Os, Cd, Cr, Co, Ag, Ir, Fe, Mn, Hg, Mo, Ni, Pd, Pt, Re, Rh, Ag, Te, W or Zn.
More preferred is the process wherein the removed-transition metal is selected from a group consisting of Cu, Ru, Fe, Ni, Pd, Pt, Rh or W, preferably Ru, Pd or Rh, particular preferred is Ru.
Most preferred is a process of diminishing the concentration of a Ru, Rh or Pd complex from a first solution containing said complex by the addition of an aqueous solution, comprising the following steps:
In a preferred variation of the above process, an adsorbent is added after removing of the second solution. The process further comprises steps (e) and (f):
Therefore preferred is a process of diminishing the concentration of a Ru, Rh or Pd complex from a first solution containing said complex by the addition of an aqueous solution, comprising the following steps:
Another embodiment of the invention is a process for diminishing the concentration of a transition metal complex from a reaction mixture containing said complex, comprising:
Preferred is a process wherein the molar ratio between the transition metal and the solubility enhancing compound is from 1:10 to 1:600, preferably from 1:10 to 1:300, more preferably from 1:25 to 1:100, most preferably about 1:50.
Preferred is a process wherein step b) comprises, stirring the resulting mixture for 60-600 minutes, preferably 180-480 minutes, more preferably 300-420 minutes, most preferably 320-340 minutes.
Preferred is a process wherein step c) comprises:
Therefore preferred is a process for diminishing the concentration of a Ru, Rh or Pd complex from a reaction mixture containing said complex, comprising the following steops:
Preferred is a process, wherein step b) or steps a) and b) are done at 0-100°, preferably 0-60° C., most preferably at room temperature.
Also preferred is a process, wherein the remaining concentration of transition metal after steps a-c is same or less then 1000 ppm, <900 ppm, <800 ppm, preferably <700 ppm, <600 ppm, <500 ppm, in particular <400 ppm, <300 ppm, <200 ppm, <100 ppm, <50 ppm, <10 ppm or <5 ppm.
Preferred is a process wherein step c) is followed by the steps d-g comprising,
Preferred is a process wherein the solid adsorbent is charcoal powder.
Preferred is a process wherein step e) comprises, heating the mixture to 30-80° C., preferably 35-70° C., more preferably 40-60° C., most preferably 45-55° C.
Preferred is a process wherein step f) comprises, stirring the resulting mixture for 20-200 minutes, preferably 60-180 minutes, more preferably 100-140 minutes, most preferably 110-130 minutes.
Therefore preferred is a process for diminishing the concentration of a Ru, Rh or Pd complex from a reaction mixture containing said complex, comprising:
Also preferred is a process, wherein the remaining concentration of transition metal after steps a-h is same or less then 500 ppm, <400 ppm, preferably <300 ppm, <200 ppm, in particular <100 ppm, <50 ppm, <10 ppm or <5 ppm.
Also preferred is a process, wherein the first solution is the crude product solution of a metathesis reaction containing a compound of general formula 3,
wherein
wherein R1, R2, R4 and D are defined as above and RLG is a suitable leaving group most preferred is a process, wherein product of the metathesis reaction is a compound of general formula 3b,
wherein RLG is a suitable leaving group and
Another embodiment of the invention is a process for manufacturing a compound of formula 1
wherein R6 is H or CH3 and m is 0 or 1.
comprising,
Preferred is a process for manufacturing a compound 3c comprising ring closure metathesis reaction of a compound 2 in presence of a useful ruthenium catalyst;
and removing the ruthenium content after reaction according to one of the above described procedures.
This process is particularly effective for the diminishing the concentration of ruthenium complexes, especially of ruthenium complexes containing a metalla-heterocycle, more preferably of ruthenium complexes containing a metalla-heterocycle useful for catalysing metathesis reactions, preferably ring closing metathesis reaction, ring opening metathesis reaction or cross metathesis reaction.
Preferred ruthenium complexes are compounds of formula 6 or 7
wherein
Most preferred are the ruthenium complexes of formula 6a, 6b and 6c.
As with prior embodiments, the solubility-enhancing compound may be added to the first solution or the second solution, or the combined solutions. However, it is generally preferred that the solubility-enhancing compound is added to the first solution prior to the combining of the first solution with the second solution.
Although the present invention has been described with examples and references to preferred embodiments, it should be appreciated that the above descriptions were for the purposes of illustration only and not intended in any way to limit the scope of the present invention.
Into a flask, equipped with a mechanical stirrer, a condenser, a nitrogen inlet, a dropping funnel and a heating jacket toluene (21) is added at ambient temperature. The solvent is flushed with nitrogen and heated to 80° C., a 36.3% solution of 2 in toluene (38.8 g), is added to the reactor. After 15 minutes a first portion of solid Hoveyda catalyst 6a (0.136 g) is added, and repeated twice (60 and 120 minutes later); so that the total amount of Hoveyda catalyst at the end is 0.408 g.
After HPLC-analysis indicates >97% conversion of starting material the reaction is stopped by cooling the reactor content to ambient temperature. Three metathesis batches according to Example 1 are combined and further used for metal scavenging experiments.
Into a flask, equipped with a mechanical stirrer, a condenser and a heating jacket the clear metathesis solution from Example 1 is added (500 ml, containing ca. 6.6 mmole of 3). The contents are stirred at 25° C., the appropriate metal scavenger (see table 1) is added and the resulting mixture is stirred for the time indicated in table 1. Thereafter the solution is extracted with water, wherein the extraction processes consist of 0.5N NaHCO3 solution in water (1×80 ml) and water (2×100 ml) for Exp. A,B,C, water (1×175 ml) and 5% NaHCO3 solution in water (2×90 ml) for Exp. D. The resulting organic phases are used in the further isolation processes.
The toluene solution of metathesis product 3 after watery extraction according to example 2 (ca. 100 mL) is evaporated to dryness (rotary evaporator). The residue is analyzed for its ruthenium content. The results are summarized in table 1 under V3 (B-D).
The toluene solution of metathesis product 3 after watery extraction according to example 2 (400 ml) is concentrated to dryness. The residue is dissolved in methanol (80 ml) and water (9 ml). Charcoal powder (1.0 g, Acticarbon LS) is added and the mixture is stirred for 120 minutes at 25° C. The charcoal powder is filtered off and washed with methanol (20 ml). The solvent of the combined organic phases is distilled off and the residue crystallized from a mixture ethyl acetate/methyl cyclohexane (1:25). The yield of isolated metathesis product 3 (white solid) is 2.28-2.51 g (70-77%). The ruthenium content of the metathesis products are listed in table 1 under V4.
| Number | Date | Country | Kind |
|---|---|---|---|
| 04001747 | Jan 2004 | EP | regional |
This application claims benefit from U.S. Provisional Application 60/546,130, filed Feb. 20, 2004.
| Number | Name | Date | Kind |
|---|---|---|---|
| 4853109 | Reynolds | Aug 1989 | A |
| 5078858 | Hart et al. | Jan 1992 | A |
| 6139814 | Shigapov et al. | Oct 2000 | A |
| 6376690 | Grubbs et al. | Apr 2002 | B1 |
| 6608027 | Tsantrizos et al. | Aug 2003 | B1 |
| 20050119453 | Brenner et al. | Jun 2005 | A1 |
| Number | Date | Country |
|---|---|---|
| WO 0059929 | Oct 2000 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050215423 A1 | Sep 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60546130 | Feb 2004 | US |
