Process for the separation of racemic mixtures

Details Process for the separation of racemic mixtures Process for the separation of racemic mixtures

2002-11-29

2004-03-23

Therkorn, Ernest G. (Department: 1723)

Liquid purification or separation

Processes

Liquid/liquid solvent or colloidal extraction or diffusing...

C210S656000, C210S198200, C210S502100

Reexamination Certificate

active

06709597

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the separation of racemic mixtures comprising development of a denser molecular imprint on silica with a desired enantiomer by sol-gel protocol. More particularly, nanoporous silica with a defined shape and size is developed by molecular imprinting of the desired enantiomer for the resolution of corresponding racemic mixture. The present invention relates to the functionalized imprinted materials. More particularly, the present invention relates to amorphous silicas having discrete pores of controlled size and shape with one spatially organized functional groups formed therein.
BACKGROUND OF THE INVENTION
Reference is made to Wulf Angew,
Chem.Int.Ed
., 1812, 34, 1995, wherein separation of aminoacid derivatives and sugar compounds is carried out by using bulk polymer net work using functional monomers through covalent interactions. The major disadvantages are the amount of imprint used in the polymer preparation is only up to 3% of the total polymer and after the porogens (solvents) are removed, some of the structural integrity of the polymer is lost, leading to deformation of the sites.
Reference is made to Davis et al;
Nature
, 283, 403, 2000, wherein molecular imprinting of bulk microporous silica is carried out by covalent bonding approach using tetraethylorthosilicate as a silicon source. The major disadvantage in this process is the amount of imprint used in the sol-gel synthesis correspond to only 2 mol % of the imprint silicon relative to TEOS silicon.
Reference is made to Mosbach et al;
Biotechnology
163, 1996
; Journal of Chromatography
391, 470, 1989; wherein enantiomeric resolution of amino acid derivatives was carried out using polymerization of monomer with imprint molecule in the presence of crosslinking agent. The major drawback in this process is some of the structural integrity of the polymer is lost, leading to deformation of the sites. Reference is also made to Pinel et al.,
Advanced Materials
.1997, 9, 582, wherein (−)-menthol was used as a imprint molecule using silica. The major drawbacks in this process is poor enantioselectivity.
Reference is made to U.S. Pat. No. 5,587,273 wherein molecular imprinting method is used for organic polymers, particularly allowing the manufacture of thin films on surfaces such as silicon wafers. This method has shown that some highly selective receptor sites can be built for complex molecules such as sugars, amino acids. The major drawbacks in this process is imprinted polymers lose their affinity for substrates in aqueous solutions.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for the separation of racemic mixtures comprising development of a denser molecular imprint on silica with a desired enantiomer by sol-gel protocol.
It is another object of the invention to develop an nanoporous silica with a defined shape and size by molecular imprinting of the desired enantiomer for the resolution of corresponding racemic mixture.
It is yet another object of the invention to provide a process for the separation of racemic mixtures comprising development of a denser molecular imprint on silica with a desired enantiomer by sol-gel protocol where the selectivity is good.
It is yet another object of the invention to provide a process for the separation of racemic mixtures wherein the use of expensive chemicals for resolution is avoided.
It is yet another object of the invention to provide a process for the separation of racemic mixtures which is environmentally safe, simple and economical.
It is a further object of the invention to provide a process for the separation of racemic mixtures where imprinted silica can be used for number of cycles with consistent selectivity.
SUMMARY OF THE INVENTION
The novelty of the present invention lies in the design and development of nanoporous silica with a defined shape and size to suit the desired enantiomer for resolution of the corresponding racemic mixture with high enantiomeric purity for the first time. The nanoporous silica is developed by sol-gel protocol, involving the hydrolytic polymerization of tetraethylorthosilicate using as a monomer and amino alkylsilane as a functional monomer in presence of desired enantiomer, capping of the surface OH groups and finally desorption of the encapsulated enantiomer, for the selective adsorption of the said enantiomer from the racemic mixture to effect resolution with high optical purity.
During the hydrolytic polymerization, the monomer of the functional silica of 3-amino alkanes form strong hydrogen bonding interactions with the —COOH group of protected amino acid and also forms hydrophobic and dipole-dipole interactions between two functional monomers or functional monomer and imprint molecule. Higher enantioselectivities are obtained when silica as synthesized is used in the resolution of amino acid derivatives and mandelic acid. The nanoporous silica thus developed possess high loading capacity to enable to adsorb desired enantiomer 3-12%. Thus the nanoporous silica gives higher through put in the resolution of racemic mixture for the first time, which is not possible with polymers. Thus earlier patents fell short of expectations for commercial reality and economics of the process. Therefore, silica as synthesized is better option in particular for the resolution of racemic compounds having functional groups. Thus, this invention offers the best techno-economic route for resolution of amino acid derivatives and for mandelic acid.
Accordingly the present invention provides a process for the separation of racemic mixtures comprising developing a denser molecular imprint on silica with a desired enantiomer by sol-gel protocol, said sol-gel protocol comprising hydrolytic control polymerization of a silica source as the monomer and amino alkylsilane as a functional monomer in the presence of the desired enantiomer, capping of surface OH groups and desorption of encapsulated enantiomer from the silica, for the selective adsorption of 3-12% of the said enantiomer from the racemic mixture to effect resolution with high optical purity.
In one embodiment of the invention, the alkyl group in the amino alkyl silane is selected from the group consisting of ethyl, propyl and butyl.
In another embodiment of the invention the silica used is a nanoporous silica designed and developed with the defined shape and size to suit the desired enantiomer for resolution of the corresponding racemic mixture.
In another embodiment of the invention, the silica source used is tetraethylorthosilicate (TEOS).
In another embodiment of the invention, the functional monomer comprises 3-amino alkyl triethoxysilane.
In yet another embodiment of the invention, the alkyl is selected from the group consisting of ethyl, propyl, and butyl.
In another embodiment of the invention the imprinted silica used for resolution is recycled for number of times.
In another embodiment of the invention the ratio of imprint to the functional monomer molecule is from 1:2 to 1:5.
In an embodiment of the invention the enantiomeric imprints used comprises Cbz protected (L)-alanine, (L)-phenylalanine and (L)-glutamic acid, and 1-mandelic acid.
In another embodiment of the invention the percentage of imprint molecule to TEOS used is from 2% to 10%.
In yet another embodiment of the invention, the solvent used for controlled hydrolysis is distilled water.
In still another embodiment of the invention the capping of surface-OH group is carried out with an equimolar mixture of 1,1,1,3,3,3-hexamethyldisilazane arid chlorotrimethyl silane.
DETAILED DESCRIPTION OF THE INVENTION
The present invention applies the principles of enzyme specificity and catalysis in a non-biological context. In the most general terms, the present invention relates to the development of amorphous inorganic materials having discrete voids of controlled sized and shape that are akin to enzymatic active sites. The size and shape of the voids are readily varied and are typically complementary to the desired substrate

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