Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
1999-12-30
2001-05-29
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S137000, C210S688000, C210S735000
Reexamination Certificate
active
06239301
ABSTRACT:
The present invention relates to a process for the removal of heavy metals from organic compounds by treatment with cysteine or N-acylcysteine and, more particularly, it relates to a process for the removal of heavy metals from solutions of organic compounds in solvents immiscible with water,
The heavy metals, more commonly palladium and nickel, are widely used in industrial synthetic processes for the preparation of compounds useful in different fields.
Because of the easy formation of complexes, a very common drawback bound to the use of these heavy metals is that they often remain present in relevant amounts in the organic compounds.
This results in a decrease of the compound purity and in the consequent need of removing the heavy metals from the compound.
The need of removing the heavy metals has a particular importance when the compound containing the high amount of metals is a pharmacologically active compound or an intermediate for the preparation of a pharmacologically active compound.
In fact for pharmaceutically useful compounds the content of heavy metals must be particularly low not only for reasons of purity of the compound but also for obvious reasons of therapeutical safety.
The relevance of the problem of the impurity of heavy metals, in particular of palladium, in the chemical-pharmaceutical industry is well underlined by Maryanoff C. A. et al. in chapter 18 entitled “Catalysis from the Perspective of an Organic Chemist: Common Problems and Possible Solutions” published in the book Chemistrv & Industry (Dekker) 1988, 33(Catal. Org. React.) 359-79.
For example, by citing the synthesis of the compound known as McN-5691. the Authors report several attempts carried out in order to remove the high content of palladium (table III on page 374). The results were negative and the problem was resolved only with a complete change of the synthetic scheme (FIG. 14 on page 376).
We have now found that also relevant amounts of heavy metals can be simply and efficiently removed from organic compounds by treating solutions of these organic compounds with cysteine or with a N-acylcysteine.
Therefore, object of the present invention is a process for the removal of heavy metals from organic compounds characterised in that a solution of the organic compound in a solvent immiscible with water is treated with a cysteine derivative of formula
wherein
R is a hydrogen atom, a linear or branched C
1-C
6
acyl group or a benzoyl group.
The process object of the present invention is of easy industrial applicability and allows to efficiently remove the heavy metals and in particular palladium.
The compounds of formula I are known or they can be easy prepared by known methods, specific examples including cysteine N-acetylcysteine, N-benzoylcysteine, N-pivaloylcysteine and N-propionylcysteine.
Preferably, cysteine or N-acetylcysteine (NAC), still more preferably N-acetylcysteine, are used in the process of the present invention.
The amount of cysteine derivative of formula I to be used depends on the amount of heavy metal to be removed but it is at least equimolar with respect to the heavy metal.
In general a molar amount of compound I from 1:1 to 100:1 with respect to the content of heavy metal is used.
Preferably a molar ratio compound I:heavy metal from 5:1 to 15:1 is used.
The organic compound containing the impurity of the heavy metal must be dissolved in a solvent immiscible with water or in a mixture of solvents of which at least one is immiscible with water.
The selection of the suitable organic solvent or of the mixture of solvents depends exclusively on the solubility characteristics of the compound to be purified.
Examples of these solvents are toluene, xylene, methylene chloride, chlorobenzene, 1.2-dichlorobenzene and aliphatic hydrocarbons such as hexane, optionally in admixture with aprotic dipolar solvents such as dimethylsulphoxide, tetrahydrofuran and acetonitrile.
The compound of formula I can be used as such, that is as a powder, or more preferably dissolved in water, that is as an aqueous solution.
When used as a powder, the removal of the heavy metals is carried out by filtration.
When used as an aqueous solution, the concentration of the aqueous solution of the compound of formula I is generally between 5% and 70% w/w.
From a practical viewpoint, the use of concentrated solutions, preferably with concentrations between 20% and 60% w/w. is preferred.
The aqueous solution of the compound of formula I can be prepared separately so carrying out the treatment for the removal of the heavy metals by washing the solution containing the organic compound with the aqueous solution of compound I.
Alternatively, the suitable amount of compound of formula I and the necessary amount of water can be added separately to the solution of the organic compound to be purified.
When the organic compound is dissolved in a mixture of solvents including water, the removal treatment can be simply carried out by adding the suitable amount of compound of formula I directly to the solution of the organic compound.
By separation of the phases, the heavy metal remains in the aqueous phase, likely in the form of a complex with the compound of formula I, while tie organic compound remains in solution in the organic phase.
The treatment time can be variable but generally an increase of the amount of removed heavy metal is observed when the treatment time is increased.
In the same manner, the treatment time and the molar ratio of compound I remaining the same, an increase of the amount of removed heavy metal is observed when the treatment temperature is increased.
In general, the process for the removal of the heavy metals according to the present invention is carried out at a temperature between the room value and the reflux temperature of the mixture, preferably between 20° C. and 60° C.
Depending on their initial content, the desired low values of the heavy metals can be reached after one treatment or after more treatments according to the process object of the present invention.
Furthermore, we have found that the efficacy of the treatment for the removal of the heavy metals according to the process object of the present invention can be further increased by carrying out a final washing with an aqueous basic solution.
Suitable basic solutions are aqueous solutions of ammonia, aqueous solutions of amines, such as triethylamine, and aqueous solutions of inorganic bases such as sodium or potassium carbonates, bicarbonates and hydroxides.
Preferably an aqueous 30% ammonia solution, which is directly added at the end of the treatment with the aqueous solution of compound I, that is before the separation of the phases, is used.
As already underlined, the process object of the present invention is useful for the removal of several heavy metals which are commonly used as reagents such as tin, palladium and other metals which can be retained as impurities in the form of complexes with organic compounds.
A preferred embodiment of the process object of the present invention is the removal of palladium.
In fact palladium is widely used in the organic synthesis processes especially as catalyst.
For a general reference to the use of palladium see, for example, Jiro Tsuji. Palladium Reagents and Catalysts, John Wiley & Sons (1995).
As already underlined, palladium is also the heavy metal which more frequently remains as impurity of difficult removal in the organic compounds.
The preferred method for the removal of palladium by treatment with an aqueous solution of N-acetylcysteine is extremely versatile and applicable to several organic compounds.
For example, the method object of the present invention proved to be particularly efficient in the removal of high amounts of palladium present in heteroarylphenylalanines prepared by, coupling a phenylalanine derivative with a heteroaryl-zinc halide in the presence of a palladium(0)based catalyst (international patent applications no. PCT/EP97/07024 and no. PCT/EP98/00126 in the name of the present Applicant, filed on Dec. 12. 1997 and on Jan. 12, 1998 respectively).
Th
Allegrini Pietro
Cannata Vincenzo
Rosi Alessandro
Villa Marco
Arent Fox Kintner & Plotkin & Kahn, PLLC
Nazario-Gonzalez Porfirio
Zambon Group S.p.A.
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