FR2781232A1 - Reactive polymer used in material for separation and absorption of various organic substances comprising acid chloride, chloroformiate or anhydride functions - Google Patents

Abstract

Reactive polymer used in material for separation and absorption of various organic substances comprises acid chloride, chloroformiate or anhydride functions. Reactive polymer used in material for separation and absorption of various organic substances comprising acid chloride, chloroformiate or anhydride functions comprises group represented by formulae (I) or (II): Where R = H or 1-4C alky; and m,n = 0 or 1. Independent claims are also included for material containing said polymer; and method for preparing said material.

Description

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 The present invention relates to novel materials comprising a polymer covalently bonded to a mineral carrier and a ligand, a process for their preparation from reactive polymers, and their use for the separation and adsorption of various organic substances.

 Various materials based on cyclodextrin immobilized on porous supports, such as silicas, are known that can be used for the chromatographic separation of various substances. In general, the materials are prepared by reacting, in a first step, the SiOH groups of the silica with reactive silanes of formula A - R '- Si - (OR) 3 where R is an alkyl group, R is a linking group, for example a hydrocarbon chain, and A is a reactive group allowing the attachment of the cyclodextrin in a second step. It is thus possible to prepare adsorbent materials or chromatographic supports capable of fixing various molecules.

 Thus, US-A-4,539,399 describes a material obtained by reacting a silica gel with a silane comprising a reactive end group such as an epoxy group and then with a cyclodextrin. Such a material can be used in chromatography for the separation of certain isomers.

 Patent EP-A-445 604 describes a chromatography-usable material consisting of a silica-based support comprising free amino groups for the attachment of cyclodextrin by a covalent bond of the carbamic acid type.

 These various materials are obtained by processes involving very restrictive silica grafting conditions, in particular purified reagents, a very high dehydration of the silica, a high grafting temperature for a relatively long period of time.

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 long; the reproducibility of the processes is difficult to control due to the formation of polymerized silanes. In addition, the stability of the grafting is very variable depending on the nature of the reactive group used. On the other hand, the silanes used are high-priced compounds whose purification and preservation are difficult.

 Polymers based on cyclodextrin and epichlorohydrin, obtained by adding an epoxy-ammonium salt to a cyclodextrin-epichlorohydrin polycondensate, are described in FR-A-2,671,087. These polymers are immobilized on a silica support by adsorption resulting from non-covalent bonds, and can be used in chromatography for the separation of isomers. This technique avoids the disadvantages described above, but the control of the reaction must be very rigorous because of the risk of formation of insoluble gels, and, in addition, it is generally necessary to provide an additional step of crosslinking the polymer to improve stability.

 It is therefore desirable to have a polymer which can be prepared simply under easily reproducible conditions, not involving a high temperature reaction and using low cost commercially available products.

 Accordingly, the present invention relates to a novel polymer, or copolymer, reagent capable of covalently bonding to both a mineral carrier and a ligand, as well as its application to the preparation of materials for separation. and the adsorption of various organic substances.

 The reactive polymer used in the present invention is a polymer, or copolymer, capable of binding with

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 covalent bond of ester type, both to a mineral carrier and to a ligand acting as a chiral selector, such as a cyclodextrin.

où R est un atome d'hydrogène ou un groupe alkyle inférieur linéaire ou ramifié de 1 à 4 atomes de carbone, et de préférence un groupe mêthyle, et m et n, identiques ou différents, sont égaux à 0 ou 1. More particularly, the reactive polymer used in the invention, which can be used for the separation and adsorption of organic substances, has functions of acid chloride, chloroformate or anhydride, and comprises the unit represented by one or other of the formulas (I) and (II):

where R is a hydrogen atom or a linear or branched lower alkyl group of 1 to 4 carbon atoms, and preferably a methyl group, and m and n, which are identical or different, are equal to 0 or 1.

 The reactive polymer of general formula (I) or (II) above is preferably an acryl polychloride, a methacryl polychloride, a polychloroformate or an acryl polyanhydride.

 The inorganic support may be a metal oxide having a suitable porosity and particle size, and having at its surface groups-MOH, where M is a metal atom, such as aluminum, silicon, titanium or zirconium, which give the material a high polarity.

 In particular, it is possible to use a silica, a titanium oxide, a zirconia or an alumina of a commercially available type, for example a Lichrospher silica gel, or

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 Spherisorb whose particle size may be chosen according to the intended application, and may be for example between 5 and 100 m, these values not being limiting.

 According to the present invention, the reactive polymer is attached to the inorganic support by covalent bonding, by forming an ester bond -MO-CO-, where M is a metal atom such as aluminum, silicon, titanium or zirconium, then in a second step the polymer thus supported is reacted with a ligand acting as a chiral selector, where appropriate in the presence of a catalyst and in a suitable solvent.

 According to the method of the invention, the first step, consisting of fixing the polymer on the support, can be carried out simply by suspending the support in a solution of the polymer in dichloroethane.

 The reaction of the polymer with the ligand in the second step can be carried out in a solvent in the presence of a catalyst, or, alternatively, in a solution of the deprotonated ligand by the action of an alkali metal hydride.

 The ligand is preferably a cyclodextrin. When the chosen ligand is a cyclodextrin, one may choose one of those well known in the art for their ability to form inclusion complexes. For example, an a-, ss- or γ-cyclodextrin may be used which are cyclic oligosaccharides comprising 6.7 or 8 glucopyranose units, respectively, or else cyclodextrin derivatives such as amine, sulphated or hydroxypropylated derivatives. According to the present invention, a -cyclodextrin, or a hydroxypropyl p-cyclodextrin is preferably used.

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 Studies by infrared spectroscopy (diffuse reflection) have shown that the fixing of the reactive polymer on the mineral support such as silica was done by covalent bonding to the surface of the support, evidenced by the presence of a characteristic absorption band at 1725 cm-1, while leaving sufficient reactive functions available to allow the reaction with the cyclodextrin. This reaction can be carried out from a solution of native cyclodextrin in a solvent such as pyridine or dimethylformamide, in the presence of a catalyst, for example 4-dimethylaminopyridine, or from a solution of deprotonated cyclodextrin. by the action of an alkali metal hydride in a solvent such as pyridine or dimethylformamide.

 The reactive polymer, such as acrylonitrile polychloride (PCLA) or methacryl, can be obtained by radical polymerization of acryl or methacryl chloride in dioxane, according to the Schulz method [R. C. Schulz, P. Elzer and W. Kern, "Polyacrylic acid chloride and its reactions with amines" Chimia (1959) vol. 13 p.235-237]. Alternatively, the acryl chloride may be polymerized in another solvent such as dichloroethane, according to a similar procedure.

 Thus, according to one method, freshly distilled acryl chloride can be polymerized in anhydrous dichloroethane in the presence of 2,2'-azobisisobutyronitrile (AIBN), by heating to a temperature of the order of 50 C for about 48 hours under a nitrogen atmosphere. The esterification of the polymer to methyl polyacrylate can be done by reaction with methanol in the presence of triethylamine, to determine its molecular weight by chromatography.

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 Size exclusion plasmid in tetrahydrofuran on a PL-gel column of appropriate porosities ranging from 10 to 100 nm. It is thus possible to obtain weight average molecular weights Mw = 31,000 and Mn = 20,000, measured by comparison with polystyrene samples.

 It is preferable to carry out the polymerization of acryl or methacryl chloride in dichloroethane in order to obtain a polymer solution directly usable in the adsorption step on the inorganic support, for example porous silica beads.

 The fixing of the polychloride on the inorganic support can be carried out, for example in the case of silica, by suspending the silica (for example Lichrospher Si-100 Merck) previously dehydrated, in a solution of polyacrylate of acryl in the dichloroethane, obtained as indicated above. The suspension is degassed and kept stirring, and the silica is recovered by filtration under nitrogen, for example on a regenerated cellulose membrane.

 The study of the support thus obtained by infrared spectroscopy shows two intense bands (1805 and 1762 cm -1) characteristic of the anhydride functions formed by reaction of the polymer with the residual water adsorbed on the silica. The carbonyl groups of the intact acid chloride functions, attached by hydrogen bonding to the silanol groups of the silica, are also evidenced (1762 cm -1). Another band (1725 cm -1) characteristic of the ester functions -Si-O-CO- resulting from the covalent grafting of the polymer by reaction with silica is observed.

 The amount of polymer immobilized on the support can be easily adjusted by varying the initial amounts.

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 The polymers prepared according to the present invention can be used to bind ligands (eg cyclodextrin) with an alcohol or amine function, and the materials thus obtained can serve as chromatographic supports for the separation of various substances, for example for the separation of enantiomers or for analytical chiral separations, or as adsorbent materials for retaining pollutants present in low concentration in waste waters.

Example 1 a) Polymerization of Acryl Chloride
30 cm3 of freshly distilled acryl chloride are polymerized in 30 cm3 of anhydrous dichloroethane, in the presence of 600 mg of 2,2'-azobisisobutyronitrile (AIBN), by heating at a temperature of 50 ° C. for about 48 hours in an atmosphere nitrogen. The polymer obtained is characterized by infrared spectroscopy from a sample precipitated in ether and dried under vacuum (intense band at 1788 cm -1 corresponding to the carbonyl group of the acid chloride functions).

 An esterification of the PCLA polymer in methyl polyacrylate is then carried out by reaction with methanol in the presence of triethylamine, making it possible to determine its molecular mass by steric exclusion chromatography in tetrahydrofuran on PL-gel columns of appropriate porosities ranging from 10 to 100. nm. Thus, weight average molecular weights Mw = 31,000 and Mn = 20,000, measured by comparison with polystyrene samples, are obtained.

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b) Fixing the polychloride on the support
Fixing the acrylonitrile chloride (PCLA) on the inorganic support is carried out by suspending 5 g of silica (Lichrospher Si-100-Merck) previously dehydrated in a solution of polyacrylate chloride (PCLA) in 20 ml. cm3 of dichloroethane, obtained as indicated above. The suspension is degassed with ultrasound and kept stirring for 24 h, then the silica is recovered by filtration under nitrogen on a regenerated cellulose membrane, then washed three times with a solution of 100 cm3 of dichloroethane, and dried under vacuum.

 The support obtained is characterized by infrared spectroscopy, as indicated above (characteristic intense bands at 1805 cm -1 and 1762 cm -1).

 Elemental analysis of the obtained material gives C = 14% and Cl = 2%, corresponding to about 300 mg of polymer per gram of support.

Example 2
Immobilization of cyclodextrin (1)
6 g of p-cyclodextrin (-CD) (5.25 mmol), previously dehydrated at 110 ° C. under vacuum, are added to a suspension of sodium hydride (72.5 mmol) in 30 ml of anhydrous DMF. The mixture is stirred at ambient temperature for 1 to 2 hours, at which time a gel appears. The excess of hydride remaining in suspension is separated rapidly by filtration under nitrogen on a Teflon membrane. 2.5 g of the silica-based reactive support obtained as indicated in Example 1 (silica + PCLA) are then added to the filtrate. This suspension, after degassing with ultrasound, is stirred, under a nitrogen atmosphere, at ambient temperature for 10 hours. The

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 silica, recovered by filtration, is washed three times with 50 cm3 of DMF, then dichloroethane and dried under vacuum. It is then characterized by IR spectroscopy which shows an almost total disappearance of the reactive functions (anhydride and acid chloride), in favor of ester functions, R-CO-O-ss-CD, appearing around 1728 cm-1. An increase in the percentage of carbon is also observed, from 14% to 17%, resulting from the grafting of P-cyclodextrin.

Example 3
Immobilization of cyclodextrin (2)
In a variant, to a saturated solution of 6 g of P-CD in 170 ml of pyridine, 300 mg of 4-dimethylaminopyridine (DMAP) and 2.5 g of the reactive support (silica + PCLA) obtained as indicated in FIG. EXAMPLE 1 The suspension is then stirred, after degassing with ultrasound, under a nitrogen atmosphere, at room temperature for 48 hours. The silica, recovered by filtration, is washed several times with pyridine and then with alcohol and dried under vacuum. There is an almost complete disappearance of the reactive functions of the initial support in favor of the appearance of the 0 = COp-CD ester band at 1725 cm -1. An increase in the percentage of carbon was found, similar to that observed in the case of Example 1.

 Similar experiments were performed by varying the amount of cyclodextrin, and using a hydroxypropyl derivative of cyclodextrin. They gave rise to the following Examples 4 to 7.

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Example 4
To a saturated solution of 4 g of ss-CD in 113 cm3 of pyridine, 300 mg of DMAP and 2.5 g of the reactive support (silica + PCLA) are added. The suspension obtained is treated as indicated in Example 3.

Example 5
To a saturated solution of 2 g of ss-CD in 56 cm3 of pyridine, 300 mg of DMAP and 2.5 g of the reactive support (silica + PCLA) are added. The suspension is treated as indicated in Example 3.

Example 6
6 g of hydroxypropylated ss-CD (DS = 0.8, Aldrich), dehydrated at 80 ° C., are added to a suspension of sodium hydride in 30 ml of anhydrous DMF in dioxane. The mixture is stirred at ambient temperature for 1 to 2 hours, at which time a gel appears. The excess of hydride remaining in suspension is separated rapidly by filtration under nitrogen on a Teflon membrane.

 2.5 g of the silica-based reactive support obtained previously (silica + PCLA) are then added to the filtrate, and the suspension is treated as in Example 2. Infrared spectroscopy shows the total disappearance of the reactive functions (anhydride and acid chloride) of the initial support in favor of the characteristic band of the ester functions.

Example 7
6 g of hydroxypropylated ss-CD (D.sub.S = 0.8, Aldrich), dried at 80.degree. C., are dissolved in 60 ml of pyridine, and

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 add 300 mg of DMAP and 2.5 g of the reactive support. The suspension is treated as in Example 3.

 IR spectroscopy shows a total disappearance of the reactive functions of the initial support (silica + PCLA), in favor of the characteristic band of the ester functions.

Example 8
Preparation of a chromatographic column
HPLC columns (15cm x 4.6mm) were prepared using the materials obtained in the examples described above. They have been shown to be able to separate many organic substances, especially enantiomers.

 Some results of chiral separations obtained on the material of Example 3 are presented in Table I.

Table I
Separation of enantiomers on an HPLC column
The separation is carried out on an HPLC column (15 cm × 4.6 mm) obtained from the material of Example 2.

<Tb>
<tb> k '<SEP> [alpha] Rs <SEP> eluent <SEP> (v / v)
<tb> MeOH / buffer
<tb> Aminogluthetimide <SEP> 6.16 <SEP> 1.26 <SEP> 1.33 <SEP> 50/50
<tb> Lorazepam <SEP> 3.79 <SEP> 1.24 <SEP> 1.21 <SEP> 30/70
<tb> Secobarbital <SEP> 5.53 <SEP> 1.18 <SEP> 1.05 <SEP> 30/70
<tb> Pentobarbital <SEP> 4.74 <SEP> 1.18 <SEP> 1.03 <SEP> 30/70
<tb> Thiamyal <SEP> 5.79 <SEP> 1.19 <SEP> 1.13 <SEP> 30/70
<tb> Thiopental <SEP> 4.80 <SEP> 1.19 <SEP> 1.08 <SEP> 30/70
<tb> Chlorthalidone <SEP> 5.0 <SEP> 1.24 <SEP> 1.37 <SEP> 10/90
<tb> Oxazepam <SEP> 3.79 <SEP> 2.04 <SEP> 4.11 <SEP> 30/70
<tb> Hexobarbital <SEP> 4.74 <SEP> 1.22 <SEP> 1.19 <SEP> 30/70
<tb> Mephenytoine <SEP> 5.3 <SEQ> 1.79 <SEP> 2.80 <SEP> 30/70
<Tb>

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<Tb>
<tb> MTH-tyrosine <SEP> 6.70 <SEP> 1.64 <SEP> 2.60 <SEP> 30/70
<tb> MTH-Leucine <SEP> 2.0 <SEP> 1.23 <SEP> 0.9 <SEP> 30/70
<tb> MTH-Phenylalanine <SEP> 10.3 <SEP> 1.43 <SEP> 1.95 <SEP> 30/70
<tb> PTH-leucine <SEP> 5.63 <SEP> 1.09 <SEP> 0.4 <SEP> 10/90
<tb> PTH-phenylalanine <SEP> 5.74 <SEP> 1.22 <SEP> 1.23 <SEP> 10/90
<tb> 5-MPPH <SEP> 8.05 <SEP> 1.24 <SEP> 1.20 <SEP> 30/70
<Tb>

In the table above, k 'is the retention, a is the separation factor and Rs is the resolution.

 The eluent is a mixture of methanol and 0.15 M aqueous sodium phosphate solution at pH 4.

 On the other hand, the properties of the chromatographic supports obtained in Examples 3,4 and 5 were compared.

Thus, Table II below summarizes the results obtained for the separation of the enantiomers of the methylthiohydantoin derivative of tyrosine. It can be observed that the best results are obtained using 6 g of (3-CD for 2.5 g of reactive support (silica + PCLA).

Table II
Separation of the enantiomers of the methylthiohydantoin derivative of tyrosine

Separation is performed on HPLC columns (15 cm x 4.6 mm) obtained from the materials of Examples 3.4, 5 above.

<Tb>
<Tb>

Quantity <SEP> of <SEP> ss-CD <SEP> Example <SEP> k '<SEP> [alpha] Rs
<tb> (g)
<tb> 6 <SEP> Ex. <SEP> 3 <SEP> 6.7 <SEP> 1.64 <SEP> 2.60
<tb> 4 <SEP> Ex. <SEP> 4 <SEP> 6.5 <SEP> 1.52 <SEP> 1.80
<tb> 2 <SEP> Ex. <SEP> 5 <SEP> 5.4 <SEP> 1.32 <SEP> 1.43
<Tb>

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The experimental conditions are described in Table I.

Table III
Enantiomers are separated on an HPLC column (15 cm x 4.6 mm) obtained from the material of Example 7). The results are shown below.

<Tb>
<tb> k '<SEP> [alpha] Rs <SEP> eluent <SEP> (v / v)
<tb> MeOH / buffer
<tb> Aminogluthetimide <SEP> 3.43 <SEP> 1.15 <SEP> 0.5 <SEP> 50/50
<tb> Lorazepam <SEP> 5.0 <SEP> 1.16 <SEP> 0.9 <SEP> 30/70
<tb> Temazepam <SEP> 4.0 <SEP> 1.10 <SEP> 0.6 <SEP> 30/70
<tb> Chlorthalidone <SEP> 3.0 <SEP> 1.30 <SEP> 1.4 <SEP> 0/100
<tb> Oxazepam <SEP> 4.2 <SEP> 1.76 <SEP> 3.0 <SEP> 30/70
<tb> Hexobarbital <SEP> 5.43 <SEP> 1.08 <SEP> 0.40 <SEP> 30/70
<tb> Mephenytoin <SEP> 4.86 <SEP> 1.50 <SEP> 1.94 <SEP> 30/70
<tb> MTH-tyrosine <SEP> 4.25 <SEP> 1.46 <SEP> 1.60 <SEP> 30/70
<tb> MTH-leucine <SEP> 2.25 <SEP> 1.22 <SEP> 1.10 <SEP> 30/70
<tb> MTH-phenylalanine <SEP> 7.4 <SEP> 1.30 <SEP> 1.50 <SEP> 30/70
<tb> 5-MPPH <SEP> 8.32 <SEP> 1.0- <SEP> 30/70
<Tb>

The eluent used is identical to that of the previous example.

Example 9
Extraction of vanillin
The materials described above can be used to extract any compound capable of giving an association with ss-CD from an aqueous solution of this compound.

 By way of example, it has been possible to extract vanillin from aqueous solutions using

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 porous silica of high granulometry (Lichrospher Si-100, particle size 200 microns).

 The amount fixed on the material, after equilibrium achieved by contacting it with vanillin solutions of different concentrations, was measured. This measurement was carried out, after filtration of the material, by HPLC assay of the vanillin contained in the supernatant. It is observed that the isotherm is practically linear and that it is not possible to obtain saturation of the material due to the limited solubility of vanillin in water.

Under conditions of saturation of the water with vanillin, the fixing capacity of the material is 60 mg / g.

Claims (14)

1. A reactive polymer of the type comprising acid chloride, chloroformate or anhydride functions that can be used for the separation and adsorption of organic substances, characterized in that it comprises the unit represented by one or the other of the formulas ( I) and (II):

 where R is a hydrogen atom or a linear or branched lower alkyl group of 1 to 4 carbon atoms, and m and n, same or different, are 0 or 1.  2. Polymer according to claim 1, characterized in that R is a hydrogen atom or a methyl group.  3. Polymer according to any one of claims 1 and 2, characterized in that it is selected from an acryl polychloride, a methacryl polychloride, a polychloroformate or an acryl polyanhydride.  4. Material for the separation and adsorption of organic substances, characterized in that it comprises a polymer according to any preceding claim, covalently bonded to a mineral carrier and a ligand.  5. Material according to claim 4, characterized in that the inorganic support is a metal oxide having at its <Desc / Clms Page number 16>  surface of the groups-MOH, where M is a metal atom, such as aluminum, silicon, titanium or zirconium.  6. Material according to claim 5, characterized in that the inorganic support is a silica, a titanium oxide, a zirconia or an alumina particle size between 5 and 100 m.  7. Material according to any one of claims 4 to 6, characterized in that the ligand is an α-, γ- or γ-cyclodextrin, or a hydroxypropylated cyclodextrin.  8. Material according to any one of claims 4 to 7, characterized in that the bond between the inorganic support and the polymer is provided by ester bonds -MO-CO- where M is a metal atom such as aluminum , silicon, titanium or zirconium.  9. Process for the preparation of a material according to any one of claims 4 to 8, characterized in that, in a first step, the reactive polymer is fixed on the inorganic support by formation of ester bonds -MO-CO- where M is a metal atom such as aluminum, silicon, titanium or zirconium, then in a second step the polymer fixed on the support is reacted with the ligand.  10. The method of claim 9, characterized in that the fixing of the polymer on the support is carried out by suspending the support in a solution of the polymer in dichloroethane.  11. The method of claim 9, characterized in that the reaction of the polymer with the ligand is carried out in a solvent in the presence of a catalyst.  12. The method of claim 9, characterized in that the reaction is carried out in a solution of the deprotonated ligand by action of an alkali metal hydride. <Desc / Clms Page number 17>  13. Method according to any one of claims 11 and 12, characterized in that the solvent is selected from pyridine and dimethylformamide.  14. Process according to claim 11, characterized in that the catalyst is 4-dimethylaminopyridine.