Immobilization of phenolic compounds

Abstract

This disclosure relates to M w The present disclosure also relates to a method for immobilizing a phenolic compound having a molecular weight of ≥ 500 g / mol, the method comprising: ionizing the phenolic compound by subjecting the phenolic compound to a base; and contacting the ionized phenolic compound with a crosslinked resin containing a functional group represented by -C(=O)-CHXCHR, where X is selected from the group consisting of Br, Cl, I, CN, OMs, OTs, or OTf, and R is H, CH, or a branched or unbranched alkyl having 1 to 8 carbon atoms, while stirring. The present disclosure also relates to a method for immobilizing a phenolic compound having a molecular weight of ≥ 500 g / mol from a composition comprising a compound having at least one alkoxysilane group. w The present disclosure also relates to a method for removing phenolic compounds having a concentration of ≧500 g / mol. w It also relates to a product in which at least one phenolic compound having ≧500 g / mol has been removed by a method according to the present disclosure.

Description

[Technical field]

[0001] The present disclosure relates to a method for immobilizing phenolic compounds having a molecular weight of 500 g / mol or more. [Background technology]

[0002] Many phenolic compounds have a slightly yellow to brown color due to the presence of small amounts of oxidation products. Therefore, when a phenolic compound is produced as a by-product, for example, in the synthesis of a pharmaceutical compound, the reaction mixture will have a slightly yellow to brown color due to the oxidation products of the phenolic compound.

[0003] Phenolic compounds can often be removed from the reaction mixture by standard purification techniques such as extraction, reverse phase chromatography, normal phase silica chromatography, distillation or fractional crystallization.

[0004] However, depending on the nature of the phenolic compounds and / or the nature of other compounds in the mixture, the choice of purification method may be limited.

[0005] If the compound being purified is moisture sensitive, purification methods such as extraction or reverse phase chromatography that proceed under hydrolytic conditions cannot be used to remove the phenolic compounds from the mixture because the moisture sensitive compounds would hydrolyze. Normal phase silica chromatography is inappropriate if the compound being purified contains groups such as ethoxysilyl groups that react with the surface silanols of silica.

[0006] Phenols with high molecular weights, such as ≧500 g / mol, cannot be removed by distillation, even under reduced pressure. Furthermore, if the reaction mixture contains products with a molecular weight distribution, such as polymer-based products, fractional crystallization cannot be used for purification.

[0007] Mixtures containing phenols of low to medium molecular weight, i.e., ≦500 g / mol, can be purified by immobilization of the phenols on various activated resins, for example in J. Comb. Chem., 2000, 2(1), 48-65, where the attachment of the phenolic functional groups of an estradiol (Mw 282.38 g / mol) derivative to a polystyrene resin is described.

[0008] However, as the molecular weight of the phenol(s) to be removed increases, attachment of the phenol to the activated resin becomes more difficult. It is well known that to immobilize larger molecules such as enzymes, dedicated macroporous resins are required, for which only the simplest surface functional groups are available (e.g. www.sigma.aldrich.com product no. 564095-(aminomethyl)polystyrene).

[0009] The aim of the present disclosure is to overcome these problems. Summary of the Invention

[0010] According to a first aspect, the above and other objects are achieved in whole or at least in part by a method as defined in claim 1. According to this claim, the above objects are achieved by a process for the preparation of a phenolic compound having a molecular weight (M) comprising the steps of ionizing a phenolic compound by subjecting it to a base and contacting, under agitation, the ionized phenolic compound with a crosslinked resin comprising a functional group of the formula -C(=O)-CHXCH2R, where X is selected from the group consisting of Br, Cl, I, CN, OMs, OTs, or OTf, and R is H, CH3, or a branched or unbranched alkyl having 1 to 8 carbon atoms. w This is achieved by a method for immobilizing a phenolic compound having a molecular weight of ≧500 g / mol.

[0011] The phenolic compound may be a phenolic compound that has a specific molecular structure and therefore a specific molecular weight, i.e., does not have a molecular weight distribution. Alternatively, the phenolic compound may be a phenolic compound that includes a polymeric portion, i.e., a portion that includes multiple monomers. The number of monomers in the polymeric portion may vary between different individual molecules. Thus, a phenolic compound that includes a polymeric portion may have molecular weight portions and not have a specific molecular weight.

[0012] As will be appreciated by those skilled in the art, the molecular weight of a phenolic compound having a specific molecular structure is the molecular weight as calculated based on the number and nature of the atoms of the phenolic compound, which may be measured, for example, by mass spectrometry (MS).

[0013] According to one embodiment, the molecular weight of a phenolic compound containing a polymeric portion as used herein refers to the weight average molecular weight (also referred to as the mass average molar mass or weight average molar mass). As will be appreciated by those skilled in the art, the weight average molecular weight may be determined, for example, by gel filtration or size exclusion chromatography (SEC).

[0014] According to one embodiment, the weight average molecular weight is determined in accordance with ISO 16014-1:2019 and ISO 16014-5:2019 ("Determination of average molecular weight and molecular weight distribution of polymers by means of size exclusion chromatography").

[0015] According to another embodiment, the weight average molecular weight is determined according to ISO 16014-1:2019 in combination with any of ISO 16014-2:2019 to ISO 16014-4:2019.

[0016] According to a further embodiment, the weight average molecular weight is determined by SEC and verified using liquid chromatography-mass spectrometry (LC-MS) or high performance liquid chromatography (HPLC), preferably the HPLC method is as described herein.

[0017] Such methods can be used to remove phenolic compounds that cannot be removed from a mixture by traditional methods such as extraction, reverse phase chromatography, normal phase silica chromatography, distillation, or fractional crystallization. Moreover, such methods can be used even in the presence of moisture sensitive compounds. Importantly, phenolic compounds having high molecular weights of up to 5,000 g / mol, such as ≧500 g / mol, ≧1,000 g / mol, ≧1,500 g / mol, ≧2,000 g / mol, ≧2,500 g / mol, ≧3,000 g / mol, ≧3,500 g / mol, ≧4,000 g / mol, ≧4,500 g / mol, can be scavenged from the resin and thus removed from the mixture.

[0018] The method comprises the steps of: w It may be used to remove phenolic compounds having a molecular weight of ≧500 g / mol.

[0019] The method comprises the steps of: obtaining M from a mixture containing compounds containing at least one alkoxysilane group, so-called alkoxysilanes; w It may be used to remove phenolic compounds having a molecular weight of ≧500 g / mol. The alkoxysilane group may be an ethoxysilyl group.

[0020] An additional advantage of the method is that masked phenols, such as phenols protected by hydrolysis sensitive silanes, may be hydrolyzed and removed from the mixture.

[0021] Agitation may be achieved in a number of ways, for example, by shaking, mechanical agitation, mechanical stirring, or agitation by bubbling inert gas or flowing liquid through the resin bed. Resins are generally very fragile after swelling in organic solvents, so non-abrasive agitation is essential. Thus, shaking at medium speed (320 rpm) with a shaker is useful, especially on a small scale. Gentle mechanical agitation with blunt impellers is also useful, especially on a large scale. Agitation by nitrogen bubbling can also be used.

[0022] According to one embodiment, the phenolic compound is M w ≧750 g / mol, preferably M w ≧1,000 g / mol.

[0023] The phenolic compounds are w It may have a molecular weight of ≦5,000 g / mol.

[0024] The phenolic compounds are w It may have a molecular weight of ≦4,000 g / mol.

[0025] The phenolic compounds are w It may have a molecular weight of ≦3,000 g / mol.

[0026] According to one embodiment, the phenolic compound is M w ≦2,000 g / mol.

[0027] The cross-linked resin may be a cross-linked polymer resin.

[0028] The crosslinked polymer resin may be any polymer that is compatible with the desired solvent, such as polystyrene resin, polyamide resin, or acrylamide-Peg copolymer.

[0029] In the functional group represented by -C(=O)-CHXCH2R, R is preferably a branched or unbranched alkyl having 1 to 8 carbon atoms, such as methyl or ethyl, etc. Even more preferably, R is methyl.

[0030] According to one embodiment, the functional group represented by -C(=O)-CHXCH2R is an α-haloketo group.

[0031] Preferably in the α-haloketo group, X is Br or Cl. Even more preferably, X is Br.

[0032] Preferably, in the α-haloketo group, R is a branched or unbranched alkyl having 1 to 8 carbon atoms, such as methyl or ethyl, and even more preferably R is methyl.

[0033] The α-haloketo group is

[0034] It may also be an α-bromo-ketone such as TIFF0007675445000001.tif40170.

[0035] Preferably the α-haloketo group is

[0036] The file is TIFF0007675445000002.tif28170.

[0037] According to one embodiment, the crosslinked resin is

[0038] It is a crosslinked polymer resin containing the functional group represented by TIFF0007675445000003.tif27170.

[0039] This resin is also called Brominated Wang.

[0040] The base may be soluble in the solvent.

[0041] The base may be insoluble in the solvent.

[0042] The base may be the corresponding base of the solvent.

[0043] According to another embodiment, the base is selected from the group consisting of alkali metal hydrides, alkaline earth metal hydrides, sterically hindered alkoxides, strong amidine bases, amide bases and phosphazene bases.

[0044] The alkali metal hydride may be sodium hydride, lithium hydride, and potassium hydride.

[0045] The alkaline earth metal hydride may be calcium hydride.

[0046] The sterically hindered alkoxide may be t-butoxide.

[0047] The strong amidine base may be tetramethylguanidine, DBU or DBN.

[0048] The amide base may be LDA, LiTMP, LiHMDS or KHMDS.

[0049] The phosphazene base may be tert-butylimino-tris(dimethylamino)phospholene. Highly non-nucleophilic bases such as phosphazene bases may be used directly in the presence of the resin.

[0050] If the net effect of nucleophilic substitution on electrophilic functional groups in compounds such as ethoxysilanes in mixtures containing phenolic compounds is zero, e.g., ethoxide is replaced by ethoxide, or methoxide is replaced by methoxide, then a nucleophilic base such as NaOEt, NaOMe, or NaOiPr can be used.

[0051] Specifically, the base is selected from the group consisting of sterically hindered alkoxides, NaOEt, NaOMe, NaOiPr, NaH, LiH, KH, and CaH2.

[0052] The sterically hindered alkoxide may be present as t-butoxy or another sterically hindered alkoxide having up to 8 carbon atoms.

[0053] The alkoxy base may be NaOEt, NaOMe, or NaOiPr.

[0054] Preferably the base is selected from NaOEt or NaH.

[0055] The base may be present in an amount of 1 to 10 equivalents, or 1 to 7 equivalents, or 1 to 3 equivalents, or 1 to 1.2 equivalents relative to the amount of phenolic compound.

[0056] The -C(=O)-CHXCH2R group may be present in an amount of 1 to 10 equivalents, or 1 to 7 equivalents, or 1 to 3 equivalents, or 1 to 1.2 equivalents in terms of the amount of phenolic compound relative to the amount of phenolic compound.

[0057] In one embodiment, the linker is

[0058] TIFF0007675445000004.tif27170,

[0059] The base is NaOEt.

[0060] In another embodiment, the linker is

[0061] TIFF0007675445000005.tif28170,

[0062] The base is NaH.

[0063] According to another aspect, the contacting step is carried out in the presence of a base and a solvent.

[0064] According to yet another embodiment, the solvent is selected from the group consisting of THF, MTBE, dioxane, cyclopentyl methyl ether, dibutyl ether, toluene, dichloromethane, DMF, NMP, and MeCN.

[0065] The solvent may be a mixture of two or more solvents.

[0066] The solvent may be THF, toluene, dichloromethane or MTBE.

[0067] The solvent may be THF or toluene.

[0068] In one embodiment, the α-haloketo group is

[0069] TIFF0007675445000006.tif25170,

[0070] The base is NaOEt and the solvent is toluene.

[0071] In another embodiment, the α-haloketo group is

[0072] TIFF0007675445000007.tif28170,

[0073] The base is NaH and the solvent is toluene.

[0074] In one embodiment, the α-haloketo group is

[0075] TIFF0007675445000008.tif28170,

[0076] The base is NaOEt and the solvent is THF.

[0077] In another embodiment, the α-haloketo group is

[0078] TIFF0007675445000009.tif27170,

[0079] The base is NaH and the solvent is THF.

[0080] In another embodiment, the α-haloketo group is

[0081] TIFF0007675445000010.tif28170,

[0082] The base is NaOEt and the solvent is MTBE.

[0083] According to one embodiment, the crosslinked resin has a swelling factor of 1 to 5.5 in a given solvent. A high swelling factor gives the phenolic compound better access to the (=O)-CHXCH2R group and therefore a shorter time is required for immobilization.

[0084] The solvent may be suitable for large-scale solid phase synthesis. Examples of such solvents are THF, MTBE, dioxane, cyclopentyl methyl ether, dibutyl ether, toluene, dichloromethane, DMF, NMP, and MeCN.

[0085] The size of the resin bed may be 100-400 mesh, such as 100-200 mesh or 200-400 mesh, such as 170 mesh, 120 mesh, etc. Preferably the bead size is 100-200 mesh or 200-400 mesh.

[0086] Before the resin is used for the first time, it may be washed to remove potentially toxic compounds. The step of washing the resin should be performed without deactivating or physically destroying the resin. The resin generally becomes very fragile after swelling in the organic solvent, so non-abrasive agitation is essential. This can be achieved as described above. Shaking at medium speed (320 rpm) on a shaker is useful for small scale. For large scale, gentle mechanical agitation with blunt impellers is useful. Agitation by nitrogen bubbling may also be useful.

[0087] The solvent used to wash the resin may be selected from the group consisting of THF, toluene, dibutyl ether, cyclopentyl methyl ether, dioxane, DMF, NMP, DCM, MeCN. Such solvents do not appreciably degrade the resin. Specific examples of solvents suitable for washing the resin are ethers, such as methoxy t-butyl ether.

[0088] Effective washing of the resin may be achieved by repeatedly soaking the resin with fresh solvent several times, or more efficiently by subjecting the resin to successive extractions in a Soxhlet apparatus.

[0089] Thus, in one embodiment of the invention, the resin is subjected to Soxhlet extraction prior to use.

[0090] Elution of the scavenged phenolic compounds may be achieved by photolysis, preferably at 350 nm.

[0091] According to the second form, M w There is provided the use of the method according to the present disclosure for removing phenolic compounds having ≧500 g / mol.

[0092] According to a third aspect, a composition comprising a compound having at least one alkoxysilane group is prepared by the method of claim 1, w A method for removing phenolic compounds having a molecular weight of ≧500 g / mol is provided, wherein the alkoxysilane group is —SiR 1 R 2 R 3 where R 1 is -O(CH2)x-CH3, where x = 0 to 7; R 2 is R 1 or OH; R 3 is R 1 or is OH; the method comprises the steps of ionizing the phenolic compound by subjecting it to a base, and contacting the ionized phenolic compound with a crosslinked resin containing a functional group represented by -C(=O)-CHXCH2R, where X is selected from the group consisting of Br, Cl, I, CN, OMs, OTs, or OTf, and R is H, CH3, or a branched or unbranched alkyl having 1 to 8 carbon atoms, while stirring. The nature of the resin and the base may be as described above.

[0093] The resin may contain α-haloketo groups as described above.

[0094] The contacting step may be carried out in the presence of a base and a solvent, the nature of which may be as described above.

[0095] The base may be an alkoxy base.

[0096] According to one embodiment, the base is CH3-(CH2) y -OY, where y=0-7 and y=x; Y is Na, K, Li.

[0097] In one embodiment, x is 1, i.e. R 1 is -O-CH2-CH3, R 2 is R 1 or OH; R 3 is R 1 or is OH.

[0098] An additional advantage of utilizing the above method to remove phenolic compounds from a mixture containing compounds having at least one alkoxysilane group is that silane hydrolysis products that affect the purity of the final product, possibly formed from moisture exposure during work-up of a prior hydrosilylation reaction, are also removed, resulting in a significantly purer product, which is advantageous when producing materials for pharmaceutical use.

[0099] According to a fourth aspect, there is provided the use of the method according to the present disclosure for removing phenolic compounds having a Mw≧500 g / mol from a composition comprising a compound having at least one alkoxysilane group.

[0100] According to a fifth aspect there is provided a product in which at least one phenolic compound having Mw≧500 g / mol has been removed by the process according to the present disclosure.

[0101] Other objects, features and advantages of the present invention will become apparent from the following detailed disclosure, from the appended claims, and from the drawings. It is to be noted that the present invention relates to all possible combinations of features.

[0102] In general, all terms used in the claims should be interpreted according to their ordinary meaning in the art, unless expressly defined otherwise herein. All references to "a / an / the [solvent, base, step, etc.]" should be interpreted straightforwardly as a reference to at least one example of said solvent, base, step, etc., unless expressly stated otherwise. The steps of any method disclosed herein do not have to be performed in the exact order disclosed, unless expressly stated otherwise.

[0103] As used herein, the term "comprising" and variations of this term are not intended to exclude other additives, components, integers or steps.

[0104] Definitions and Abbreviations As used herein, the term "alkoxy" refers to a group of the formula -OR, where R is C 1~8 Alkoxy refers to alkoxy groups, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amyloxy, iso-amyloxy, and the like. Alkoxy groups according to the present invention may be optionally substituted.

[0105] As used herein, the term "gel" refers to a cross-linked polymer in which a network of covalent bonds extends throughout the mass. Network polymer is a synonym of gel.

[0106] As used herein, the term "lower alkyl" refers to an alkyl having 1 to 8 carbon atoms.

[0107] Phenol (or phenolic compound) is the trivial name for hydroxybenzene, or more broadly, any compound containing a hydroxy-substituted aromatic ring.

[0108] As used herein, the term "molecular weight" refers to the molecular weight of a compound having a specific molecular structure, or the weight average molecular weight, also referred to as the mass average molar mass or weight average molar mass, of a compound containing a polymeric portion that varies between individual molecules with different numbers of monomers in the polymeric portion. Thus, the molecular weight of a phenolic compound having a specific molecular structure is the molecular weight calculated based on the number and nature of the atoms of the phenolic compound, or the molecular weight measured, for example, by mass spectrometry. The molecular weight of a phenolic compound containing a polymeric portion refers to the weight average molecular weight, also referred to as the mass average molar mass or weight average molar mass, and may be determined, for example, by gel filtration or size exclusion chromatography (SEC). More specifically, the weight average molecular weight may be determined according to ISO 16014-1:2019 and ISO 16014-5:2019 ("Determination of the average molecular weight and molecular weight distribution of polymers using size exclusion chromatography"), or according to ISO 16014-1:2019 in combination with any of ISO 16014-2:2019 to ISO 16014-4:2019. Alternatively, the weight average molecular weight may be determined by SEC and verified using liquid chromatography-mass spectrometry (LC-MS) or high performance liquid chromatography (HPLC), preferably the HPLC method is as described herein.

[0109] As used herein, the term "resin" is defined as an insoluble organic material.

[0110] Brominated Wang Resin: Brominated α-methylphenylacyl polystyrene resin.

[0111] DBU is an acronym for diazabicycloundecene (1,8-diazabicyclo[5.4.0]undec-7-ene).

[0112] DCM is an acronym for dichloromethane.

[0113] DMF is the acronym for dimethylformamide.

[0114] DVB is an acronym for divinylbenzene.

[0115] EtOH is an acronym for ethanol.

[0116] Karstedt's catalyst is an organoplatinum catalyst derived from a divinyl-containing disiloxane and is widely used among hydrosilylation catalysts (US Pat. No. 3,775,452).

[0117] KHMDS is an acronym for potassium hexamethyldisilazide.

[0118] LDA is an acronym for lithium diisopropylamide.

[0119] LiHMDS is an acronym for lithium hexamethyldisilazide.

[0120] LiTMP is an acronym for lithium 2,2,6,6-tetramethylpiperidine.

[0121] Functional groups: To attach reactive substrates, such as phenols, to the polymer support.

[0122] MeCN is the acronym for acetonitrile.

[0123] MeOH is the acronym for methanol.

[0124] MTBE is an acronym for methyl tert-butyl ether.

[0125] NMP is an acronym for 1-methyl-2-pyrrolidinone.

[0126] OMs is an acronym for methylsulfonatooxy.

[0127] OTs is an acronym for para-toluenesulfonatooxy.

[0128] OTf is an acronym for trifluoromethylsulfonatooxy.

[0129] PEGylation: Alkylation with polymeric ethylene oxide.

[0130] PEG is an acronym for polyethylene glycol.

[0131] PPOA is an acronym for (4-propionylphenoxy)acetic acid.

[0132] Scavenging: The removal of unwanted impurities from a reaction mixture.

[0133] THF is the acronym for tetrahydrofuran.

[0134] "% a / a" is calculated as the area of ​​the peak representing a specific compound divided by the total area of ​​all peaks in the chromatogram. In this disclosure, chromatograms were obtained at a wavelength of 220 nm.

[0135] Further objects, features and advantages will become apparent from the following detailed description when taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0136] [Figure 1] Shown is a chromatogram (Scheme 1, HPLC method 1) of the impurity profile of the crude material containing compound 1 and phenol 2. The numbers under the peaks correspond to the numbers in Schemes 1-4. [Diagram 2] FIG. 2 shows a chromatogram (HPLC Method 1) of the material from FIG. 1 when all of the hidden phenol (4) has been liberated from the ethoxide by nucleophilic attack (i.e., converted to phenol 2) during the process according to the present disclosure. The numbers under the peaks correspond to the numbers in Schemes 1-4 below. [Diagram 3]FIG. 2 shows a chromatogram (HPLC Method 1) of the material from FIG. 1 after the phenol present in the material has been removed according to the present disclosure. The numbers under the peaks correspond to the numbers in Schemes 1-4 below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0137] WO 2018 / 130713 A1 discloses several compounds for use in coating nanomaterials for use as pharmaceutical products. One example of such a coating material is compound 1. 1 is produced from methoxy PEG with a distribution of molecular weights averaging around 750 g / mol. The most common degree of polymerization is 16, and analogs with degrees of polymerization from 9 to 25 can be found in 1. Thus, in the present disclosure, compound 1 is taken to have 9 to 25 (-CH2-CH2-O-) units, such as 10 to 22, such as 12 to 20, such as 14 to 18, such as 15 to 17. The same applies to compounds 2, 3, 4, 5, 6, 7 and 13. The molecular weights of these compounds (1, 2, 3, 4, 5, 6, 7 and 13) containing a polymeric portion, i.e. a PEG portion, are weight-average molecular weights, also referred to as mass-average molar mass or weight-average molar mass.

[0138] When producing the coating material 1 (Scheme 1, Mw=1267.7 g / mol) on a large scale, brown coloration of the product is sometimes encountered. The brown coloration may be due to the presence of phenolic impurities (2), which are sometimes found in rather large amounts in the product. The chromatogram in FIG. 1 shows the impurity profile of the crude material with structure assignment. Hydrosilylation reactions in the presence of platinum catalysts such as Karstedt's catalyst always give a mixture of the desired hydroxylation and reduction to an alkane. The case where the double bond can rearrange is also usually encountered to some extent (J.Polym.Sci.,Part A:Polym.Chem.,2018,56,527-536). In the present case, rearrangement of the double bond gives vinyl ethers (3, Scheme 1) that are sensitive to hydrolysis, with subsequent liberation of phenol, which in turn gives a dark brown coloration of the product. This is undesirable for a formulated product. It is well known that phenols can form dark, high molecular weight polymers in a reaction called phenol coupling under oxidative conditions (e.g., J.Org.Chem.,1973,(5)97-134, J.Org.Chem.,2019,84(4),1677-1686). The sensitivity of 1 precludes the use of standard purification methods such as extraction or reversed-phase chromatography, which proceed under hydrolytic conditions. Normal-phase silica chromatography is also inappropriate, since the ethoxysilyl groups of 1 react with the surface silanols of silica. Furthermore, the high molecular weight precludes distillation, even under reduced pressure, and for mixtures containing compounds with polymeric moieties, the spread in molecular weight precludes the use of fractional crystallization for purification.

[0139] TIFF0007675445000011.tif234170

[0140] A large number of reactive resins are available for the large and developing field of solid-phase peptide synthesis. However, compound 2, with a molecular weight of 1063.4 g / mol, is already large enough to prevent or substantially slow down diffusion in network polymers (gels / resins). The general consensus in the literature is that compounds with molecular weights above 500 g / mol start to become difficult to immobilize on resins. Despite this commonly accepted conventional wisdom, the inventors have performed an initial screening of commercially available resins (Table 1). This initial screening of commercially available resins (Table 2) shows that some of these resins have M w ≧500g / molM w For immobilizing phenolic compounds having a molecular weight of ≧500 g / mol and / or from a composition comprising a compound having at least one alkoxysilane group, w It has been shown that it could potentially be useful for removing phenolic compounds with a molecular weight of ≧500 g / mol.

[0141] TIFF0007675445000012.tif112170TIFF0007675445000013.tif217170TIFF0007675445000014.tif209170

[0142] The initial amount of phenolic compounds in the mixture was 5.4% a / a (220 nm) and the ratio between compounds 1 and 5 (% a / a (220 nm):% a / a (220 nm)) was 3.66. Upon agitating the crude 1 mixture (Figure 1) in a solvent in the presence of base, the amount of phenol 2 was found to increase to 17% a / a (220 nm) via hydrolysis of hidden phenol 4 (Figure 1) (Figure 2). % a / a is calculated as the area of ​​the peak representing a specific compound divided by the total area of ​​all peaks in the chromatogram. In this case, the chromatogram was obtained at a wavelength of 220 nm.

[0143] We have shown that the resins Merrifield peptide resin (Experiment 1, Table 2), Wang bromide (Experiment 3, Table 2), Tentagel R Br (Experiment 4, Table 2), Tentagel S Br (Experiment 5, Table 2) and sulfonyl chloride resin (Experiment 2, Table 2) reduced the concentration of phenol 2, but also led to substantial degradation of 1, as indicated by the decrease in the 1 / 5 ratio (Table 2). The degradation of 1 indicates that the resins used are unsuitable as phenol scavenger resins in hydrolysis-sensitive reaction mixtures.

[0144] This experiment revealed that brominated PPOA (brominated [4-propionylphenoxy] acetic acid) resin (Experiment 6, Table 2) and brominated Wang (Experiment 7, Table 2) could be used to immobilize phenolic compounds with molecular weights of ≥ 500 g / mol, since the ratio of compounds 1 to 5 at the end of the experiment was greater than 2.0.

[0145] The functional groups in brominated PPOA resin and brominated Wang share the same electrophilic functional group (methyl-substituted α-bromoketone, Table 1), but the attachment of the linker to the polymeric support is different (CC vs. amide / ether bond). The secondary amide functional group is susceptible to deprotonation / nucleophilic attack, and the ether bond modifies the electron density on the α-bromoketone. Surprisingly, brominated Wang resin (run 7, Table 2) removed phenol 2 from the dipod mixture in just 2 hours without any decomposition of 1, while brominated PPOA (run 6, Table 2) reduced the total concentration of phenol 2, but also led to substantial decomposition of 1. Surprisingly, the above results indicate that the resin solid named brominated Wang, having the structure shown in Table 1, was able to remove M in the reaction mixture consisting of hydrolysis-sensitive substrates. w The results indicate that the resin can be used for scavenging phenols of > 500. Therefore, this resin was selected for further evaluation (Table 3).

[0146] Table 2. Resins for immobilization of phenol 2. The experiment was carried out on the same batch of crude material containing 1 and phenolic compounds. The solvent was THF. The experiment was carried out at room temperature (RT). The results in column FI are reported after the time indicated in column E (time 2). The amount of resin and base is expressed as %a / a (220 nm) with respect to phenol 2 (Scheme 1). The phenol content after removal of phenol (expressed as %a / a (220 nm) with respect to the total mixture) is shown. The left and right shoulders correspond to 4 (Figure 1). The ratio of compounds 1 and 5 (%a / a (220 nm):%a / a (220 nm)) is also shown. TIFF0007675445000015.tif175170

[0147] In particular, immobilization of phenols having molecular weights above 500 g / mol is relevant to the present invention. If the molecular weight is 5,000 g / mol or more, the reaction time becomes prohibitively long (Example 5 below) and falls outside the scope of the present invention. For molecular weights between 500 g / mol and 2,000 g / mol, inclusive, the method of the present invention is particularly useful.

[0148] Two other high molecular weight phenols were synthesized and investigated (compounds 10 and 12 in Schemes 2 and 3, respectively).

[0149] TIFF0007675445000016.tif59170

[0150] TIFF0007675445000017.tif59170

[0151] As a result, phenol 10, having a molecular weight (weight average molecular weight, also called mass average molar mass or weight average molar mass) of about 2,000 g / mol (2 kDa), was immobilized and removed from the solution in less than 24 hours (Example 1c below) and deemed useful, whereas phenol 12, having a molecular weight (weight average molecular weight, also called mass average molar mass or weight average molar mass) of about 5,000 g / mol (5 kDa), was unaffected after one week (sodium ethoxide (NaOEt) and brominated Wang in THF at room temperature). Thus, the method of the present invention is useful for immobilizing and removing phenols having a molecular weight less than 5,000 g / mol (5 kDa).

[0152] The choice of base used is important because the ethoxy group in compound 1 is sensitive to nucleophilic attack by the base used in the method according to the present disclosure. All reasonable resins are reactive towards nucleophiles, and most bases are also nucleophilic. This creates two problems: I, possible decomposition of the activated resin by direct reaction with the base, and II, decomposition of compounds 1 and / or 5 by reaction with the nucleophile alkoxysilane, which is the most sensitive group. To avoid the first problem, it is important to use a strong enough base so that essentially all of the phenol can be deprotonated by contacting it with the base in a first step prior to the addition of the reactive resin.

[0153] TIFF0007675445000018.tif102170

[0154] It was found that the best choice for the present example (where the composition includes ethoxysilane) was to use sodium ethoxide, which has several advantages: I, it is cheap and available in high quality, II, it can react with the silane but only with the same group exchange, resulting in zero net effect (Scheme 4), and III, it is strong enough to essentially completely deprotonate the phenol so that the resin can be added thereafter, thereby minimizing the risk of resin degradation.

[0155] The most practical base for the purification of 1 from phenol 2 on a large scale was sodium ethoxide (Table 3), but many other bases are also suitable. Bases such as alkali metal hydrides such as sodium hydride, lithium hydride, and potassium hydride are useful. It is also conceivable to use alkaline earth metal hydrides such as calcium hydride. Sterically hindered alkoxides such as t-butoxide are also contemplated. Strong amidine bases such as tetramethylguanidine, DBU, or DBN, amide bases such as LDA, LiHMDS, or KHMDS, phosphazene bases such as tert-butylimino-tris(dimethylamino)phosphorane, may also be useful. It is also conceivable to use very non-nucleophilic bases such as phosphazene bases directly in the presence of the resin.

[0156] Table 3. Investigation of the effect of phenol dilution, solvent, base, number of equivalents of base, number of equivalents of resin and reaction time. The experiment was carried out on the same batch of crude material containing 1 and phenolic compounds. Results in columns H-K are reported after the time indicated in column 6 (time 2). The amount of resin (brominated Wang) and base are expressed as molecular equivalents with respect to phenol 2. The phenol content after removal of phenol (expressed as %a / a (220 nm) of the total mixture) is shown. The left and right shoulders correspond to hidden phenol 4 (Figure 2). The ratio of compounds 1 and 5 (%a / a (220 nm):%a / a (220 nm)) is also shown. TIFF0007675445000019.tif168170TIFF0007675445000020.tif137170

[0157] It has been found that the base can be present in amounts as low as 1.2 equivalents (Experiment 13) and as high as 5.9 equivalents (Experiment 7) relative to the amount of phenolic compound.

[0158] Resin, i.e.

[0159] The functional group shown in TIFF0007675445000021.tif27170 is

[0160] It has also been found that the amount of phenolic compound relative to the amount of phenolic compound can be present in amounts as low as 1.5 equivalents (Run 13) and as high as 7.6 equivalents (Run 7).

[0161] The pKa values ​​of phenols are typically in the range of 8-11 (in water) to deprotonate the phenol to over 99%, and a difference of 2 or more pKa units is appropriate for a given phenol. For example, 1,3,5-trihydroxybenzene has a pKa value of 8.45, so a suitable base in this case would have a pKa value of 10.45 or greater. Although pKa values ​​will vary in different solvents, this simple rule should be useful to one of skill in the art in selecting a base.

[0162] We have also found that during purification of the reaction mixture shown in Figure 1, more phenol is gradually liberated from some of the products identified by mass spectrometry as dimers or trimers. Presumably the phenol is masked by a silyl group and gradually released by nucleophilic attack from a nucleophile, e.g., ethoxide. When sodium ethoxide is added to the reaction mixture and then stirred for any period of time, such as 1, 2, 6, 12, 24, 48 hours, the masked phenol impurity is liberated and becomes accessible for removal by the resin (Figure 2). This is seen in Figure 2 as an increase in the peak designated 2 (phenol) and a decrease in the peak designated 4 (masked phenol) compared to the corresponding peaks in Figure 1.

[0163] Example 4 below shows how the initial phenol concentration is 5% and increases to 17% after liberation of the masked phenol fraction with sodium ethoxide. After treatment with brominated Wang resin, the phenol content drops to 1% (Figure 3). This is seen in Figure 3 as a decrease in the peak designated 2 (phenol) compared to the corresponding peaks in Figures 1 and 2.

[0164] In order to utilize the resin to purify compounds for clinical use, it must be carefully washed to remove potentially toxic compounds without inactivating or physically destroying the compound. Resins generally become very fragile after swelling in organic solvents, so non-abrasive agitation is essential. This can be achieved in several ways. We have found that shaking at medium speed (320 rpm) in a shaker is useful on a small scale. On a large scale, gentle mechanical agitation with a blunt impeller is useful. Agitation by nitrogen bubbling can also be useful. We have found that the best solvents for washing are ethers such as methoxy t-butyl ether, which are effective but do not appreciably degrade the resin. Efficient washing of the resin can be achieved by repeated immersion several times with fresh solvent (Example 5) or, more efficiently, by subjecting it to successive extractions in a Soxhlet apparatus (Example 4). Other solvents suitable for washing the resin are toluene, dibutyl ether, cyclopentyl methyl ether, dioxane, DMF, DCM, MeCN.

[0165] List of Aspects In one aspect of the present invention,

[0166] TIFF0007675445000022.tif27170

[0167] A brominated Wang resin containing the functional group represented by is used to immobilize phenol 2 in a reaction mixture containing compound 1.

[0168] In one embodiment of the invention, brominated Wang resin is used to immobilize phenol 2 in a reaction mixture containing compound 1, such that the concentration of 2 in solution is less than 5% of the concentration of 1.

[0169] In one embodiment of the invention, brominated Wang resin is used to immobilize phenol 2 in a reaction mixture containing compound 1, such that the concentration of 2 in solution is less than 2% of the concentration of 1.

[0170] In one embodiment of the invention, brominated Wang resin is used to immobilize phenol 2 in a reaction mixture containing compound 1, such that the concentration of 2 in solution is less than 1% of the concentration of 1.

[0171] In one embodiment of the invention, brominated Wang resin is used to immobilize phenol 2 in a reaction mixture containing compound 1, such that the concentration of 2 in solution is less than 0.1% of the concentration of 1.

[0172] In one embodiment of the invention, brominated Wang resin is used to immobilize and / or remove as much as 90%, or as much as 99%, or close to 100% of phenol with a molecular weight of 2,000 g / mol (2 kDa) from solution.

[0173] In one embodiment of the invention, brominated Wang resin is used to immobilize and / or remove phenols of molecular weight between 500 g / mol (0.5 kDa) and 4,000 g / mol (4 kDa) from solution, then further modify it by chemical reaction while it is bound to the resin, and finally release the product from the resin by chemical reaction, such as photochemical reaction.

[0174] In one embodiment of the invention, a soluble strong base is used to deprotonate a phenol having a molecular weight between 500 g / mol (0.5 kDa) and 4,000 g / mol (4 kDa), which is then contacted with brominated Wang resin to immobilize phenol 2 in a reaction mixture or composition containing 1.

[0175] In one embodiment of the invention, a soluble strong base is used to deprotonate phenol 2, which is then contacted with brominated Wang resin to immobilize phenol 2 in a reaction mixture or composition containing 1.

[0176] In one embodiment of the invention, sodium ethoxide is used to deprotonate phenol 2, which is then contacted with brominated Wang resin to immobilize phenol 2 in a reaction mixture or composition containing 1.

[0177] In one embodiment of the invention, sodium hydride is used to deprotonate phenol 2, which is then contacted with brominated Wang resin to immobilize phenol 2 in a reaction mixture or composition containing 1.

[0178] In one embodiment of the present invention, brominated Wang resin was washed with methoxy t-butyl ether in a Soxhlet extractor for 48 hours prior to use.

[0179] In one embodiment of the invention, brominated Wang resin was washed with several portions of methoxy t-butyl ether prior to use.

[0180] experiment General information Unless otherwise stated, materials, reagents and solvents were obtained from commercial sources and used without further purification. NMR spectra (CDCl3) were recorded on a Varian Unity INOVA 400 MHz and chemical shifts are reported relative to the residual solvent peak of the deuterated solvent. HPLC was performed on a Hewlett Packard Series 1100 equipped with an Agilent Poroshell 120 EC-C18 4.6 x 50 mm column eluting at 1 ml / min with an oven temperature of 40°C, a DAD detector recording at 220 nm, and an ELSD detector.

[0181] TIFF0007675445000023.tif76170

[0182] TIFF0007675445000024.tif77170

[0183] Example 1: Phenols with high molecular weight Example 1a: Synthesis of 9 (Scheme 2) mPeg2000OTs (1.64 g, 0.75 mmol) was heated under vacuum at 55° C. overnight. To a solution of 8 (302 mg, 1.5 mmol) in THF (4 ml) at 0° C., NaH (44 mg, 1.6 mmol) was added and the mixture was stirred at 0° C. After 35 min, the mixture was allowed to reach room temperature, the above mPeg2000-OTs dissolved in THF (2 ml) was added and the mixture was heated to 50° C. After 4 days, the reaction was quenched by the addition of MeOH (2 ml) at room temperature. The mixture was stirred for 4 h, after which the volatiles were evaporated. The crude material was taken up in CHCl3 (100 ml), MgSO4 (6.4 g) was added and the mixture was stirred at room temperature. After 2 h, the solvent was filtered off and the volatiles were evaporated. The crude material was dissolved in a minimum amount of CH2Cl2 and precipitated by slow addition of Et2O at 0 °C, centrifuged (3200 rpm) for 10 min, and decanted. The solid was washed with Et2O, centrifuged, and decanted, which was repeated three times. The product was dried in vacuum to give 9 (1.399 g, 0.65 mmol, 86%).

[0184] 1 H-NMR (400MHz, CDCl3) δ = 7.45-7.29 (m, 5H), 6.93-6.82 (m, 4H), 5.02 (s, 2H), 4.08 (t, J = 4.6 Hz, 2H), 3.82 (t, 4.6 Hz, 3H), 3.65 (bs, 208 H), 3.57-3.52 (m, 1H), 3.49-3.45 (m, 1H), 3.39 (s, 3H). Caution! mPEG2000-OH as an impurity.

[0185] Example 1b: Synthesis of 10 (Scheme 2) To the benzyl protected phenol 9 (1.399 g, 0.65 mmol) in THF (20 ml, N2 bubbling for 5 min) was added 10% Pd / C (0.073 g). Three cycles of vacuum / N2 were performed followed by three cycles of vacuum / H2. The mixture was stirred under an atmosphere of H2 (balloon) at room temperature. After 16 h, three cycles of vacuum / N2 were performed, the solid was filtered off, and the volatiles were evaporated. The crude was dissolved in a minimum amount of CH2Cl2, precipitated by slow addition of Et2O, centrifuged for 10 min (3200 rpm, 5 °C), and decanted. The solid was washed with Et2O, centrifuged, and decanted twice. The product was dried in vacuum to give 10 (1.112 g, 0.53 mmol, 81%). HPLC / NMR analysis indicates that the product is contaminated with mPeg-OH.

[0186] 1 H-NMR (400 MHz, CDCl3) δ = 6.83-6.73 (m, 4H), 6.08 (bs, 1H), 4.08 (t, J = 4.6 Hz, 2H), 3.83 (t, 4.6 Hz, 3H), 3.65 (bs, 287 H), 3.58-3.52 (m, 2H), 3.49-3.45 (m, 1H), 3.38 (s, 3H). Caution! mPEG2000-OH as an impurity.

[0187] Example 1c: Loading of 10 onto brominated Wang resin (Scheme 2) Brominated Wang resin (0.663 g, 0.73 mmol) was swollen / washed 3 times for 20 min with 4 ml MTBE, followed by swollen / washed 3 times for 20 min with 4 ml THF. To phenol 10 (486 mg, 0.24 mmol) in THF (4 ml) was added NaOEt (41 mg, 0.56 mmol) and the mixture was stirred at room temperature under a blanket of N2. After 1 h, the above swollen / washed resin was added in one portion and the mixture was stirred in the dark under a blanket of N2. The progress of the reaction was monitored by HPLC (Method 2). After 22 h, 10 (in solution) could not be detected by HPLC. After an additional day of stirring, the resin was filtered off, washed three times for 5 min with THF (5 ml), and the pooled fractions were evaporated to yield 0.1 g of non-UV active material (unreacted mPeg2000-OH).

[0188] Example 1d: Synthesis of 11 (Scheme 3) mPeg5000OTs (5 g, 0.97 mmol) was dissolved in toluene (50 ml) and heated to reflux in a Dean-Stark apparatus. After 3 h, the solution was cooled to room temperature and the volatiles were evaporated. To a solution of 8 (391 mg, 1.9 mmol) in THF (10 ml) at room temperature, NaH (60 mg, 1 mmol) was added and the mixture was stirred at room temperature. After 35 min, the above mPeg5000OTs dissolved in THF (15 ml) was added and the mixture was heated at 50 °C. After 7 days, the reaction was quenched by the addition of MeOH (10 ml) at room temperature. The mixture was stirred for 4 h and then the volatiles were evaporated. The crude material was taken up in CHCl3 (100 ml), MgSO4 (6.5 g) was added and the mixture was stirred at room temperature. After 1 h 45 min the solid was filtered off and the volatiles were evaporated. The crude was taken up in CH2Cl2 (100 ml), MgSO4 (6.3 g) was added and the mixture was stirred at room temperature. After 3.5 h the solid was filtered off and the volatiles were evaporated. The crude was dissolved in a minimum amount of CH2Cl2 and precipitated by slow addition of Et2O, centrifuged (3200 rpm) for 10 min and decanted. The solid was washed with Et2O, centrifuged and decanted three times. The product was dried in vacuum to give 11 (3.873 g, 0.74 mmol, 76%).

[0189] 1 H-NMR (400 MHz, CDCl3) δ = 7.45-7.29 (m, 5H), 6.93-6.80 (m, 4H), 5.01 (s, 2H), 4.08 (t, J = 4.6 Hz, 2H), 3.82 (m, 4H), 3.74-3.52 (bs, 513 H), 3.49-3.44 (m, 2H), 3.39 (s, 3H). Caution! mPEG5000-OH as an impurity.

[0190] Example 1e: Synthesis of 12 (Scheme 3) To the benzyl protected phenol 11 (1.020 g, 0.19 mmol) in formic acid (10 ml) and dioxane (6 ml) was added 10% Pd / C (0.115 g). The mixture was heated to reflux. After 21.5 h, the mixture was cooled to room temperature, filtered through a double glass microfiber filter and a pad of MgSO4, and the volatiles were evaporated. The crude was dissolved in toluene (10 ml) and evaporated. The crude was dissolved in a minimum amount of CH2Cl2, precipitated by slow addition of Et2O, and centrifuged for 10 min (3200 rpm, 5 °C). The solid was washed with Et2O, centrifuged, and decanted, which was repeated three times. The solid was vacuum dried and evaporated from toluene for three cycles to give 12 (669 mg, 0.13 mmol, 68%).

[0191] 1 H-NMR (400 MHz, CDCl3) δ = 6.82-6.72 (m, 4H), 6.12 (bs, 1H), 4.08 (t, J = 4.6 Hz, 2H), 3.81 (t, 4.6 Hz, 2H), 3.77-3.55 (bs, 598 H), 3.49-3.44 (m, 3H), 3.39 (s, 3H). mPEG5000-OH as an impurity.

[0192] Example 1f: Loading of 12 onto brominated Wang resin (Scheme 3) Brominated Wang resin (0.214 g, 0.235 mmol) was swollen / washed with 4 ml THF three times for 20 min each. To phenol 12 (0.398 g, 0.078 mmol) in THF (5 ml) was added NaOEt (0.014 g, 0.180 mmol) and the mixture was stirred at room temperature under a blanket of N2. After 1.5 h, the above swollen / washed resin was added in one portion and the mixture was stirred in the dark under a blanket of N2. The progress of the reaction was monitored by HPLC (Method 2). After 7 days, no reduction in the UV-active phenol peak could be detected by HPLC, indicating that 12 was not loaded onto the brominated Wang resin.

[0193] Example 2: General procedure, Table 2: Resins for immobilization of phenols To the reaction mixture containing 2 in the indicated solvent was added the indicated base. The mixture was purged with N2 and stirred at room temperature. After the indicated time (Time 1), the electrophilic resin was added in one portion, purged with N2, and stirred protected from light. The reaction was monitored by HPLC (Method 1) and the results are reported after the indicated time (Time 2).

[0194] Note! Equivalent numbers are based on 17 mol% phenol in a mixture.

[0195] Example 3: General procedure, Table 3: Investigation of dilution, solvent, base, equivalents of base, equivalents of resin and reaction time NOTE! In runs 7 and 10, the resin was not swollen / washed. In run 20, the resin was Soxhlet extracted, dried and reswelled. In run 21, the resin was Soxhlet extracted and added to the reaction mixture without any further additional swelling / washing. The resin was swelled / washed 3 times for 20 min with the indicated solvent. To the reaction mixture containing 2 in the indicated solvent, the indicated base was added, purged with N2 and agitated / stirred. After the indicated time (time 1), the swollen / washed / Soxhlet extracted resin was added all at once, purged with N2 and agitated / stirred protected from light. The reaction was monitored by HPLC (method 1) and the results after the indicated time (time 2) are reported in Table 3.

[0196] Example 4: Small scale scavenging (Experiment 21, Table 3) Brominated Wang resin (1.283 g, 1.17 mmol) was swollen / washed in a Soxhlet apparatus using MTBE (60 ml) as the solvent for 48 h.

[0197] A mixture containing 1 (5.001 g, 0.8 mmol total phenol (2)) was dissolved in MTBE (33 ml) in a three-neck round bottom flask equipped with mechanical stirring. NaOEt (77 mg, 1.08 mmol) was added and the mixture was stirred under N2 atmosphere. After 70 min, all of the masked phenol was converted to phenol (2) (17%, Figure 2) and the above swollen / washed brominated Wang resin was added in one portion. The mixture was gently stirred and protected from light under N2 atmosphere. After 22 h, the phenol (2) content was 1% (Figure 3), the resin was allowed to settle and the liquid was removed using a filter stick. The resin was washed three times with MTBE (24 ml) and the filtrates were combined, filtered through a glass fiber filter and evaporated to give the purified dipod mixture (3.6 g, 86% yield calculated with 94% of phenol (2) removed).

[0198] Example 5: Large-scale scavenging (Experiment 23, Table 3) Brominated Wang resin (351 g, 386 mmol) was swollen / washed batchwise with MTBE (2.7 L) in a 5 L flask equipped with mechanical stirring (Teflon-coated double moon-blade stirrer, 100 rpm) and protected from light under N2 atmosphere until no extractable / leachable resin could be detected by HPLC / gravimetric analysis and no oligostyrene could be detected by NMR. 32 g of swollen / washed resin was removed and not used in the following scavenging step. Note! Solvent from the wash was distilled and reused in the following wash. The reaction mixture described in Scheme 1 (1048 g, 165 mmol impurity) was dissolved in MTBE (6.5 L) in a 10 L Duran bottle equipped with mechanical stirring (Teflon-coated double moon-blade stirrer, 100 rpm). After three vacuum / nitrogen cycles, NaOEt (18.8 g, 271 mmol) was added and the mixture was stirred (175 rpm) under N2 atmosphere at room temperature for 65 min, after which the phenol (2) content was 19%. The above swollen / washed resin was added to the mixture in one portion via cannula vacuum transfer. The mixture was protected from light and gently stirred (100 rpm) under N2 atmosphere. After 17.5 h, the phenol content was 1%, the liquid was removed using a filter stick, and the resin was washed twice with MTBE (1.8 L per cycle, 30 min). The fractions were combined, filtered through a double glass fiber filter, and evaporated to yield the purified dipod mixture (788 g, 89% yield calculated with 94% phenol (2) removed).

Claims

1. M ｗ 1. A method for immobilizing a phenolic compound having a molecular weight of ≧500 g / mol, comprising the steps of: - ionizing said phenolic compound by subjecting said phenolic compound to a base; - adding the ionized phenolic compound with stirring, with a crosslinked resin comprising a functional group represented by A method comprising:

2. The phenolic compound is ｗ ≧750 g / mol.

3. The phenolic compound is ｗ 3. The method of claim 1 or 2, wherein the molecular weight of the polymer is ≧1,000 g / mol.

4. The phenolic compound is ｗ 4. The method of claim 1, wherein the molecular weight of the polymer is ≦2,000 g / mol.

5. 5. The process according to any one of claims 1 to 4, wherein the base is selected from the group consisting of alkali metal hydrides, alkaline earth metal hydrides, sterically hindered alkoxides, strong amidine bases, amide bases and phosphazene bases.

6. The method of any one of claims 1 to 5, wherein the contacting step is carried out in the presence of the base and a solvent.

7. 7. The method of claim 6, wherein the solvent is selected from the group consisting of THF, MTBE, dioxane, cyclopentyl methyl ether, dibutyl ether, toluene, dichloromethane, DMF, NMP, and MeCN.

8. The method of any one of claims 1 to 7, wherein the crosslinked resin has a swelling factor of 1 to 5.5 in the given solvent.

9. Mixture of M ｗ Use of the method according to any one of claims 1 to 8 for removing phenolic compounds having a molecular weight of ≧500 g / mol.

10. From a composition comprising a compound having at least one alkoxysilane group, M ｗ ≧500 g / mol, wherein the alkoxysilane group is —SiR １ R ２ R ３ and where R １ But -O(CH ２ ) ｘ -CH ３ where x=0 to 7; R ２ But, R １ or is OH; R ３ But, R １ or is OH; The method further comprising: - ionizing said phenolic compound by subjecting said phenolic compound to a base; - adding the ionized phenolic compound with stirring, with a crosslinked resin comprising a functional group represented by A method comprising:

11. The base is CH ３ - (CH ２ ) ｙ 11. The method of claim 10, wherein the compound is -O-Y, where y=0-7, where y=x; Y is Na, K, Li.

12. From a mixture containing a compound having at least one alkoxysilane group, M ｗ 11. Use of the method according to claim 10 for removing phenolic compounds having a molecular weight of ≧500 g / mol.

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