Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
  • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
  • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
  • B01J20/289—Phases chemically bonded to a substrate, e.g. to silica or to polymers bonded via a spacer
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  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3204—Inorganic carriers, supports or substrates
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  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3206—Organic carriers, supports or substrates
  • B01J20/3208—Polymeric carriers, supports or substrates
  • B01J20/321—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions involving only carbon to carbon unsaturated bonds
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  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
  • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
  • B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
  • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
  • B01J20/3221—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond the chemical bond being an ionic interaction
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  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3244—Non-macromolecular compounds
  • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
  • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
  • B01J20/3251—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising at least two different types of heteroatoms selected from nitrogen, oxygen or sulphur
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3244—Non-macromolecular compounds
  • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
  • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
  • B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3268—Macromolecular compounds
  • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
  • B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/42—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having etherified hydroxy groups and at least two amino groups bound to the carbon skeleton
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
  • C07D213/20—Quaternary compounds thereof
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/50—Nitrogen atoms bound to hetero atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
  • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
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  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to multiply positively charged substances - anchors, to which it is possible to easily covalently bind almost any substance, a method for their preparation and the use of such prepared modifiers for the modification of negatively charged surfaces. Negatively charged solid surfaces can then be modified by simply immersing the solid in an aqueous solution of the modifier. In this way, many materials used in practice can be prepared in a much easier manner. This is demonstrated by the preparation of a modified silica gel phase suitable for the chromatographic separation of enantiomers.
• the prior art lacks a universal and economically advantageous arrangement which would ensure a strong ionic bond of a non-polymeric substance (compound) to a solid carrier without eluting this substance in polar solvents.
• One of the practical applications of this method is, for example, the preparation of stationary phases based on modified silica gel and their use for chromatographic separations.
• Figure 1 shows the general structure of the resulting system of the present invention, which comprises a positively charged anchor (with one to three positive charges), an optional (oligo ethylene glycol) linker and substances A (compounds A) attached thereto.
• the multiply positively charged anchor provides strong ionic bonding of substance A to the surface of the solid carrier; the linker allows to regulate the distance of substance A from the surface ( ⁇ ccording to the purpose of use); and the optional multiplier of the charged anchor allows up to seven multiple charged anchors to be bound to a single molecule, increasing the total charge from one, two or three up to 7, 14 or 21 positive charges, thus ensuring an even stronger ionic bond of the anchor to the solid carrier surface.
• Quaternary ammonium groups were chosen as the positively charged groups, but only those that do not easily undergo Hofmann elimination (Lethesh, K. C. et al. RSC Adv., 2013, 4, 4472-4477) so that they can be used over a wide pH range.
• an allyl group which can be introduced into the substances described below under very similar conditions as the propargyl group.
• the allyl group allows easy attachment of other types of compounds, most easily those containing a thiol group, via a thiol-ene reaction (Hoyle, C. E. et al. Angew. Chem. Int. Ed., 2010, 49, 1540-1573).
• the propargyl and allyl groups can be further oxidatively cleaved to the corresponding carboxyl or aldehyde derivatives, which can also be used for covalent binding of substances by amide or imine bond formation, or for reductive amination to form amine, carbamate or thiocarbamate bonds.
• the amino group obtained by reductive amination can also be used to bind a carboxyl group-containing substance A via an amide bond.
• R 1 is H, (Cl-C6)alkyl, which may be linear or branched; or (C5-C6)cykloalkyl;
• R 2 to R 6 are independently selected from the group consisting of -H, (Cl-C6)alkyl, (Cl- C6)alkoxyl, -N(R 7 )2, wherein R 7 is independently (Cl-C6)alkyl; wherein at least one R is selected from the group consisting of
• R 1 is H, methyl, ethyl, cyclopentyl or cyclohexyl.
• R 2 to R 6 are independently selected from the group consisting of -H, methyl, ethyl, methoxyl, ethoxyl and -N(R 7 )2, wherein R 7 is independently methyl or ethyl.
• R 7 is independently methyl or ethyl.
• the positive charges of the anchors of general formula (I) are compensated by anions, preferably selected from the group consisting of iodides, triflates (trifluoromethanesulpho nates), carbonates and chlorides.
• the compounds ( ⁇ nchors) of general formula (I) are compounds, the structures thereof with one, two or three positive charges are shown in Scheme 1.
• Scheme 1 Prepared positively charged anchors with one (Kl), two (K2) or three (K3) permanent charges contained in the trimethylammonio methyl (TMAM), methylimidazolio methyl (MIMM) or pyridinio methyl (PYRM) group.
• TMAM trimethylammonio methyl
• MIMM methylimidazolio methyl
• PYRM pyridinio methyl
• Any substance A containing an azide functional group can be attached to the propargyl group (Cg) of the compound of general formula (I) using Huisgen cycloaddition of azide to form a triazole bridge.
• this substance A can be attached to the propargyl group by means of a CuAAC reaction, which is regioselective.
• any thiol group-containing substance A can be attached to the allyl group (Cg) of the compound of general formula (I) by the above-mentioned thiol-ene reaction to form a sulphide bridge. It can also be readily converted, e.g. by ozonolysis, to a formylmethyl group to which amino group-containing substances A can be attached either to form an imine bond or by reductive amination to form an amine bond. The formylmethyl group can also be converted to an aminoethyl group by reductive amination and use it either directly to react with substance A containing a carboxyl (Hartman, T. et al.
• the solid support is preferably selected from the group comprising cation-exchange materials, most of which are commercially available:
• metal oxides e.g. AI 2 O 3 , ZrCO 2 , Ti O 2 (Nawrocki, J. et al. J. Chromatogr. A, 2004, 1028(1), 1-30), which are also used as chromatographic sorbents
• the two R groups are methyl and the resulting molecule has one or two positive charges; in another embodiment one R group is methyl and the resulting molecule has two, three or four positive charges; in yet another embodiment no R group is methyl and the resulting molecule has at least three positive charges.
• R is selected from -CH 3 , -CH 2 -N + (CH 3 ) 3 , In one preferred embodiment, R is selected from -CH3, -CH 2 -N + (CH3)3,
• the compound of general formula (I) is selected from the group comprising: 2-((Dimethylamino)methyl)-N 1 ,N 1 ,N 3 ,N 3 -tetramethyl-2-((prop-2-yn-1- yloxy)methyl)propan- 1 ,3-diamin; N 1 ,N 1 ,N 1 ,N 3 ,N 3 ,N 3 -Hexamethyl-2-((prop-2-yn-1-yloxy)methyl)-2-
• the present invention further relates to a method of preparation of a compound of general formula (I) which comprises the following steps:
• the fluorinated alkylsulphonic acid ester from step (ii) reacts with at least one compound selected from the group consisting of trimethylamine, dimethylamine, wherein R 1 to R 6 are as defined above, preferably the compound is selected from the group consisting of trimethylamine, dimethylamine, 1-methylimidazole and pyridine, to give a compound of general formula (I);
• Step (i) of providing a compound of formula (II) comprises providing compounds of general formula (Ila) and compounds of general formula (llp) wherein Z is as defined above.
• a further object of the present invention is a modifier of a surface of a negatively charged carrier, the modifier having the general formula (III), which comprises a substance A linked via an oligoethylene glycol linker, wherein R is as defined above and n is an integer in the range of from 0 to 20, preferably from 2 to 10, more preferably from 3 to 7.
• Substance A is preferably selected from the group comprising cyclodextrin (CD) derivatives (Crini, G. Chem. Rev., 2014, 114(21), 10940-10975) used for chiral separations due to their ability of inclusion complexation or also the ability to serve as a skeleton to which a large number of other groups can be covalently bound, e.g., phenylcarbamoyl groups (Yang, B. et al.
• CD cyclodextrin
• amino acid derivatives that can be used as chiral selectors such as N-(3,5-dinitrophenyl)amino acid derivatives used in Pirkle-type columns (Pirkle, WH et al. J. Chromatogr. A, 1986, 369, 175-177); or other modifiers hitherto used for the preparation of chiral solid phases using a covalent bond (Teixeira, J. et al. Molecules, 2019, 24, 865) based on macrocyclic compounds, proteins, carbohydrates, crown ethers or cinchonine derivatives.
• the chiral modifier is amylose or cellulose, with free hydroxyl groups or modified by reaction with phenylisocyanates (Ali, I. et al. Sep. Purif. Rev., 2009, 38, 97-147), peptides with an amino acid number of 2 to 200 or proteins used hitherto in covalently bonded form (Bocian, S. et al. J. Sep. Sci., 2016, 39, 83-92).
• the oligoethylene glycol linker serves to regulate the distance of the substance A binding site from the surface of the negatively charged carrier.
• Substance A is linked via the oligoethylene glycol linker to the compound of general formula (I) by means of the triazole bridge formed by the addition of azide (oligoethylene glycol linker end group) to the propargyl group of the compound of general formula (I) (the modifier is derived from the anchor of general formula (I), wherein Cg is propargyl).
• This reactive functional group then reacts with the oligoethylene glycol derivative containing, in addition to the end azide group, for example an amino group ( ⁇ mino -azido- oligoethylene glycol), a carboxyl group (carboxyl-azido-oligoethylene glycol), a carbonyl group (carbonyl-azido-oligoethylene glycol) or hydroxyl group ( ⁇ zido-oligoethylene glycol) at the other end, to form a covalent bond between the above functional group of substance A and the amino, carboxyl, carbonyl or hydroxyl group of the oligoethylene glycol linker, which is subsequently attached via an azide group to the propargyl group of the compound of general formula (I) by Huisgen cycloaddition to form a triazole bridge.
• an amino group ⁇ mino -azido- oligoethylene glycol
• carboxyl group carboxyl group
• carboxyl-azido-oligoethylene glycol
• substance A is ⁇ -, ⁇ -, or y-cyclodextrin.
• the oligoethylene glycol linker is attached to the cyclodextrin via position 6 of the glucose unit of cyclodextrin by converting the OH group to an amino group, to which the oligoethylene glycol linker, attached to the anchor of general formula (I) via the triazole bridge, is bound.
• Another object of the invention is a method of synthesis of modifiers of general formula (III), wherein the bound substance A is a covalently attached ⁇ -, ⁇ -, or y-cyclodextrin (hereinafter CD modifier), which comprises the following steps:
• step (ii) binding of the charged anchor of general formula (I), wherein Cg is propargyl, by azido-alkyne Huisgen cycloaddition (CuAAC) to the CD derivatives prepared in step (i) to give a modifier of general formula (III), wherein the bound substance A is ⁇ -, ⁇ -, or y-cyclodextrin.
• CuAAC azido-alkyne Huisgen cycloaddition
• substance A if it contains an -N 3 group, can be attached directly to the anchor of general formula (I), wherein Cg is propargyl, by azido-alkyne Huisgen cycloaddition (without the use of the oligoethylene glycol linker).
• An example of such substance A is a 6-azido-CD derivative (Boffa, L. et al. New J. Chem., 2010, 34, 2013.).
• a phenylcarbamoyl group is introduced, which may be further independently substituted with -Cl or methyl group, preferably in position 3 and 5, to all free hydroxyl groups and amino group of the CD intermediate prepared in step (i).
• the cyclodextrin modifier thus obtained contains phenylcarbamoyloxy groups instead of OH groups; the bound substance A is thus in this embodiment the phenylcarbamoyl derivative of cyclodextrin.
• the CD modifier may contain, in addition to the CD unit, a fluorescent group that can be used to easily monitor the binding strength of the modifier to solids. It can be prepared, for example, by introducing a naphthalimide group (Dian, J. et al. Monatshefte Fiir Chem. - Chem. Mon., 2017, 148, 1929-1935) onto the amino group of the CD intermediate prepared in step (i) instead of acetylating the free amino group, followed by CuAAC reaction with the charged anchor as in step (ii).
• a fluorescent group that can be used to easily monitor the binding strength of the modifier to solids. It can be prepared, for example, by introducing a naphthalimide group (Dian, J. et al. Monatshefte Fiir Chem. - Chem. Mon., 2017, 148, 1929-1935) onto the amino group of the CD intermediate prepared in step (i) instead of acetylating the free amino group, followed by CuAAC reaction with the charged anchor as in
• the surface modifier of the negatively charged carrier further comprises a multiplier located between the bound substance A and the anchor of general formula (I).
• the multiplier is preferably the most common and cheapest of the above-mentioned cyclodextrins - ⁇ - cyclodextrin (cyclic oligosaccharide composed of 7 glucose units), or its other commercially available analogues ⁇ - and y-cyclodextrin (containing 6 and 8 glucose units).
• the result is a substance of general formula (IV),
• m is an integer in the range of from 6 to 8, the value of which depends on the number of anchors that the given type of multiplier is able to bind to itself (in the case of ⁇ -CD modified on primary hydroxyls it is at most 7) and the anchor is the compound of general formula (I).
• the bound substance A is defined above.
• L is a bond or oligoethylene glycol linker -(CH 2 ) 2- (O- (CH 2 ) 2 ) n— NH— , covalently attached to the CD multiplier via position 6 of the cyclodextrin glucose unit whose OH group has been converted to an amino group; wherein n is an integer from 1 to 20;
• Y represents possible substituents on the secondary hydroxyls of CD.
• Y is selected from the group consisting of H, an oligoethylene glycol linker with attached substance A, wherein the oligoethylene glycol linker may be attached to the hydroxyl group of CD via ether or carbamate bond, and wherein at least one Y of the modifier of formula (IV) is not H.
• ⁇ -CD it is possible to covalently bind from one to 14 molecules of substance A, optionally using oligoethylene glycol linkers, preferably using an ether (b) or carbamate (c) bond.
• the resulting substance of general formula (IV) contains a high number of positive charges concentrated in a small volume and is thus capable of very strong ionic interaction with the surface of a negatively charged solid.
• the object of the present invention is also a method of preparation of the modifier of general formula (IV), wherein the multiplier is the cyclodextrin derivative per-(6-azido-6-deoxy)- ⁇ - cyclodextrin, which comprises the following steps:
• Substance A as defined above preferably selected from the group consisting of phenylcarbamoyl, N-(3,5-dinitrophenyl) amino acid derivatives, macrocyclic compounds, peptides and proteins, carbohydrates, crown ethers, cinchonine derivatives, is attached to free hydroxyl groups of per-6-azido ⁇ -cyclodextrin (Jicsinszky, L. et al. Beilstein J. Org. Chem., 2016, 12, 2364-2371); (iii) The compound of general formula (I) from step (i) reacts with the multiplier comprising azide groups and the attached substance A from step (ii) to form the compound of general formula (IV).
• Another object of the present invention is the use of the compound of general formula (I), (III) or (IV) for binding of substance A to the surface of a negatively charged solid (carrier), which may be selected from the group comprising catex resins, zeolites, stationary phases for ion-exchange chromatography, copolymer of perfluoro-3,6-diox ⁇ -4-methyl-7-octenesulphonic acid with tetrafluoroethylene, silica gel, glass, metal oxides, and the use of the compound of general formula (I), (III) or (IV) for chromatographic separation and purification of substances, or as a sorbent for solid-phase extraction or as a heterogeneous catalyst.
• a negatively charged solid carrier
• Type (III) and (IV) modifiers with optionally attached chromophore can be attached to negatively charged carriers selected from the group comprising catex resins and zeolites, stationary phases for ion-exchange chromatography, silica gel, glass, metal oxides, surfaces of uncharged materials modified to obtain a negative charge, e.g. by sulphonation or plasma treatment, by mixing the carrier with an aqueous solution of the modifier, preferably with a 0.1 to 1% aqueous solution of the modifier. If the modifier contains a bound chromophore, the course of the reaction can be monitored spectrophotometrically, for example until the decrease in UV absorption is stopped.
• negatively charged carriers selected from the group comprising catex resins and zeolites, stationary phases for ion-exchange chromatography, silica gel, glass, metal oxides, surfaces of uncharged materials modified to obtain a negative charge, e.g. by sulphonation or plasma treatment, by mixing the carrier with an a
• the modifier binding half-life is in the order of hours at most. Furthermore, in the case of such modified carriers, the binding strength of the modifier to the carrier was determined by eluting with eluents of different polarity and ionic strength.
• Figure 1 General scheme of modifying the surface of a negatively charged solid using a multiply positively charged modifier, which is the subject-matter of the patent.
• K1TMAM N,N,N,2,2-Pentamethyl-3-(prop-2-yn-1-yloxy)propan-1-aminium
• 2,2-Dimethyl-3-(prop-2-yn-1-yloxy)propyl trifluoromethanesulphonate 3 (2.29 g, 8.36 mmol) was mixed with freshly distilled and dried trimethylamine (60 ml) at -78 °C.
• the reaction vessel was carefully sealed, heated to 60 °C and stirred overnight.
• the reaction mixture was monitored by TLC (MeOH/HOAc/1% aqueous solution of NH 4 OAC 10/1/9 - detection with aqueous basic solution of potassium permanganate). After cooling the reaction vessel to 0 °C and opening it, the trimethylamine was evaporated at room temperature by standing in a fume hood.
• the crude product was extracted between water (60 mL) and toluene (60 mL).
• the aqueous phase was washed with toluene (60 mL) and evaporated on a rotary vacuum evaporator at 50 °C.
• the residue (1.77 g) was dissolved in water (40 mL) and purified on strong Dowex 50W catex resin (17 mL).
• the elution solutions were water, 5% aqueous solution of NH 3, concentrated aqueous solution of NH 3 , 5% aqueous solution of NH 4 HCO 3 and 20% aqueous solution of NH 4 HCO 3 .
• aqueous phase was evaporated on a rotary vacuum evaporator at 55 °C.
• the product was dried at 85 0 C using an oil rotary pump and obtained as a light brown oil in a yield of 72 % (1.93 g).
• Substances were detected by immersing the TLC plate in a mixture of ammonium sulphate tetrahydrate (0.5 g), ammonium molybdate tetrahydrate (2.5 g), sulphuric acid (5 mL) and water (45 mL) followed by heating.
• the reaction mixture was neutralized with potassium carbonate (1.5 g, 11 mmol), filtered and evaporated on a rotary vacuum evaporator at 40 °C.
• the product was purified by distillation under reduced pressure (130 °C, 1.5 mbar). The product was obtained as a colourless oil in a yield of 80 % (64.5 g).
• the reaction mixture was monitored by TLC using hexane/EtOAc 5/1 mixture. Substances were detected by immersing the TLC plate in a mixture of ammonium sulphate tetrahydrate (0.5 g), ammonium molybdate tetrahydrate (2.5 g), sulphuric acid (5 mL) and water (45 mL) followed by heating. The reaction mixture was filtered through celite and evaporated on a rotary vacuum evaporator at 40 °C. The product was purified by distillation under reduced pressure (115 °C, 1.5 mbar). The product was obtained as a colourless oil in a yield of 84 % (32,0 g).
• the reaction mixture was neutralized with 50% aqueous NaOH solution.
• the resulting NaCl precipitate was filtered off.
• the filtrate was evaporated on a rotary vacuum evaporator at 40 °C.
• the residue was dissolved in as little CHCl 3 as possible and purified by column chromatography (600 g of silica gel) with elution CHCl 3 /MeOH 30/1 mixture.
• the product was obtained as a yellowish oil in a yield of 96 % (24.5 g).
• the reaction mixture was extracted between Et 2 0 (60 ml) and 1M HC1 (40 mL). The organic phase was then extracted with saturated aqueous solutions of NaHCO 3 (40 mL) and NaCl (40 mL). The organic phase was dried over MgSO 4 (1 g), filtered and evaporated on a rotary vacuum evaporator at laboratory temperature. The product was dried on an oil rotary pump at laboratory temperature and obtained as a light brown oil in a yield of 92 % (2.55 g).
• the reaction mixture was extracted between dichloromethane (10 mL) and 5% aqueous solution of NaOH (10 mL).
• the organic phase was evaporated on a rotary vacuum evaporator at laboratory temperature.
• the residue was suspended in water (20 mL) and co-distilled at 110 °C.
• the distillate was extracted with dichloromethane (20 mL).
• the organic phase was dried over MgSO 4 (0.1 g), filtered and evaporated on a rotary vacuum evaporator at laboratory.
• the product was obtained as a colourless oil in a yield of 73 % (0.113 g).
• K2TMAM 2-Heptamethyl-2-((prop-2-yn-1-yloxy)methyl)propan-1,3-diaminium
• N 1 ,N 1 ,N 3 ,N 3 ,2-Pentamethyl-2-((prop-2-yn-1-yloxy)methyl)propan- 1,3- diamine 9 (0.38 g, 1.79 mmol) was dissolved in dry THF (10 mL) and methyl iodide (5.08 g, 35.8 mmol) was added slowly. The reaction mixture was brought to a boil and stirred for 24 hours.
• the reaction mixture was monitored by TLC (CHCl 3 /MeOH/concentrated aqueous solution of NH 3 90/10/0.5 - for substance 9, detection with aqueous basic solution of potassium permanganate, MeOH/HOAc/1% aqueous solution of NH 4 OAC 10/1/9 - for product, detection with aqueous basic solution of potassium permanganate).
• TLC CHCl 3 /MeOH/concentrated aqueous solution of NH 3 90/10/0.5 - for substance 9, detection with aqueous basic solution of potassium permanganate, MeOH/HOAc/1% aqueous solution of NH 4 OAC 10/1/9 - for product, detection with aqueous basic solution of potassium permanganate).
• a precipitate formed.
• the THL was filtered off and the precipitate was washed with THL (3 x 8 mL).
• the precipitate was dissolved in water and evaporated on a rotary vacuum evaporator at 50 °C.
• N-Methylimidazole was distilled off from the reaction mixture under reduced pressure (1-10 mbar) at 100 °C. Residual N- methylimidazole was extracted with EtOAc (2 > ⁇ 5 mL). The crude product was extracted between water (5 mL) and CHCl 3 (5 mL). The aqueous phase was extracted with additional CHCl 3 (8 x 5 mL) and evaporated on a rotary vacuum evaporator at 50 °C.
• the reaction mixture was monitored by TLC (MeOH/HOAc/1% aqueous solution of NH 4 OAc 10/1/9 - detection with aqueous basic solution of potassium permanganate). Pyridine was distilled off from the reaction mixture under reduced pressure (1-10 mbar) at 60 °C. The crude product was extracted between water (50 mL) and CHCl 3 (50 mL). The aqueous phase was extracted once more with CHCl 3 (50 mL) and evaporated on a rotary vacuum evaporator at 40 °C. The product was dried at 60 °C on an oil rotary pump and obtained as a brownish oil in a yield of 73 % (1.9 g).
• TLC MeOH/HOAc/1% aqueous solution of NH 4 OAc 10/1/9 - detection with aqueous basic solution of potassium permanganate.
• Pentaerythritol 10 (15 g, 0.11 mol) was suspended in toluene (11 mL). Triethyl orthoacetate (17.9 g, 0.11 mol) and p-toluenesulphonic acid monohydrate (55 mg,
• the reaction mixture was cooled to laboratory temperature, neutralized with 5% aqueous solution of NaOH and evaporated on a rotary vacuum evaporator at 50 °C.
• the residue was extracted between water (500 mL) and CHCl 3 (500 mL).
• the aqueous phase was further extracted with CHCl 3 (2 x 400 mL), evaporated on a rotary vacuum evaporator at 50 °C and the residue was suspended in acetone (200 mL).
• the mixture was filtered and the filtrate was evaporated on a rotary vacuum evaporator at 40 °C.
• the product was dried at 60 °C on an oil rotary pump and obtained as a yellowish oil in a yield of 60 % (6.4 g).
• the reaction mixture was monitored by TLC (CHCl 3 /McOH 15/1 - for the starting triol, detection with aqueous basic potassium permanganate solution, hexane/EtOAc 10/1 - for product, detection by immersing the TLC plate in a 1% ethanolic solution of 4-(4- nitrobenzyl) pyridine, followed by heating the plate and immersion in a concentrated aqueous ammonia solution).
• the reaction mixture was extracted between Et 2 O (60 mL) and 1M HC1 (40 mL).
• the reaction mixture was extracted between dichloromethane (12 mL) and 5% aqueous solution of NaOH (12 mL).
• the organic phase was evaporated on a rotary vacuum evaporator at laboratory temperature.
• the residue was suspended in water (30 mL) and co-distilled at 120 °C.
• the distillate was extracted with CHCl 3 (30 mL).
• the organic phase was dried over MgSO 4 (0.7 g), filtered and evaporated on a rotary vacuum evaporator at laboratory temperature.
• the product was dried at laboratory temperature on an oil rotary pump and obtained as a colourless oil in a yield of 81 % (0.13 g).
• N-methylimidazole was distilled off under reduced pressure (1-10 mbar) at 80 °C.
• the crude product was dissolved in water (100 mL) and extracted with CHCl 3 (4 x 100 mL).
• the crude product in aqueous solution was purified using weak Amberlite cation exchange resin (60 mL, NH 4 + form).
• the elution solutions were successively water, 5% aqueous solution of NH 3 , 1% aqueous solution of NH 4 HCO 3 , 5% aqueous solution of NH 4 HCO 3 and 10% aqueous solution of NH 4 HCO 3 .
• Fractions containing pure product were evaporated on a rotary vacuum evaporator at 50 °C.
• reaction mixture was monitored by TLC (MeOH/HOAc/1% aqueous solution of NH 4 OAc 10/10/9 - detection with aqueous basic solution of potassium permanganate).
• the pyridine was distilled off under reduced pressure (1-10 mbar) at 50 °C.
• the crude product was purified using weak Amberlite cation exchange resin (32 mL, NH 4 + form).
• the elution solutions were successively water, 1% aqueous solution of NH 4 HCO 3 and 10% aqueous solution of NH 4 HCO 3 . Fractions containing pure product were evaporated on a rotary vacuum evaporator at 40 °C.
• the solution was diluted with water (2 mL) and the reaction mixture was poured into acetone (200 mL). The resulting precipitate was separated by filtration, washed with acetone and dried for 3 hours at laboratory temperature using an oil rotary pump.
• the crude product (1.02 g) was dissolved in water (14 mL) and poured again into acetone (200 mL). The resulting precipitate was separated by centrifugation, dissolved in as little water as possible and purified by ion exchange column chromatography.
• the strong cation exchange resin Amberlite IR 120 (160 mL) was used in the H + cycle. The by-products were removed with water and the product was eluted with 5% aqueous solution of NH 3 . The product- containing solution was evaporated at 50 °C using a rotary vacuum evaporator. The residue (0.93 g) was dissolved in water (18 mL) and lyophilised. The product was obtained as a white solid in a yield of 94 % (0.92 g). [ ⁇ ] 25 D +121.4° ( ⁇ +0.085, 7.0 mg, H 2 O). IR(KBr): 3324 v(O-H), 2932 v(C-
• the solution was diluted with water (2 mL) and the reaction mixture was poured into acetone (200 mL). The resulting precipitate was separated by filtration, washed with acetone and dried for 2 hours at laboratory temperature using an oil rotary pump.
• the crude product (1.10 g) was dissolved in water (15 mL) and poured again into acetone (200 mL). The resulting precipitate was separated by centrifugation, dissolved in as little water as possible and purified by ion exchange column chromatography.
• the strong cation exchange resin Amberlite IR 120 160 mL was used in H + cycle. The by-products were removed with water and the product was eluted with 5% aqueous solution of NH 3 .
• N-(2-(2-azidoethoxy)eth-1-yl)-6 A -amino-6 A -deoxy- ⁇ -cyclodextrin 19 (0.40 g, 0.32 mmol) was dissolved in deionised water (9 mL) and NaOH solution (51 mg in 1 mL water) was added.
• Acetic anhydride (0.12 mL,
• the reaction mixture was neutralised with 1M HC1, and silica gel (2 g) was added to the solution.
• the suspension was evaporated on a rotary vacuum evaporator at 55 °C.
• the crude product adsorbed on silica gel was purified by column chromatography (20 g of silica gel) with elution mixture CHCl 3 /MeOH/H 2 O 5/4/1.
• the product-containing fractions were evaporated on a rotary vacuum evaporator at 50 °C.
• the product was dried at 60 °C using an oil rotary pump and obtained as a white free-flowing material in a yield of 78 % (320 mg). [ ⁇ ] 25 D +137.3° ( ⁇ +0.070, 5.1 mg, DMSO).
• N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)eth-1-yl)-6 A -amino-6 A - dco x y- ⁇ -cyclodcxtrin 20 (0.40 g, 0.30 mmol) was dissolved in deionised water (9 mL) and NaOH solution (48 mg in 0.9 mL water) was added. The acetic anhydride (0.11 mL, 1.20 mmol) was then added and the solution was stirred at laboratory temperature for 3 hours. The reaction mixture was monitored by TLC using the mixture CHCl 3 /MeOH/H 2 O 5/4/1 and the substances were detected by carbonisation in 50% aqueous sulfuric acid.
• the crude product adsorbed on silica gel was purified by column chromatography (20 g of silica gel) with elution mixture CHCl 3 /MeOH/H 2 O 5/4/1. The product was not obtained sufficiently pure.
• the product-containing fractions were evaporated on a rotary vacuum evaporator at 50 °C.
• the residue (0.49 g) was dissolved in water and purified by C18-reversed phase column chromatography (10 g of silica gel).
• the product was eluted with 10% aqueous solution of MeOH.
• the product-containing fractions were evaporated on a rotary vacuum evaporator at 50 °C.
• the residue (0.104 g) was suspended in water (15 mL) and the insoluble Cul was filtered through a layer of celite.
• the product in aqueous solution was purified by C18-reversed phase column chromatography (3.2 g of silica gel).
• the product was eluted with 5% aqueous solution of MeOH.
• the product-containing fractions were evaporated on a rotary vacuum evaporator at 50 °C and propanol was added during evaporation to give the free-flowing product.
• the product was dried at 60 °C using an oil rotary pump and obtained as a white free-flowing material in a yield of 67 % (69 mg).
• H-7 7.51 (s, 2H, H-15), 7.45 (m, 2H, H-16), 5.22 - 4.69 (m, 9H, H-1 , H- 1' H-9), 4.47 - 4.20 (m, 5H, H-13, H-5‘), 4.07 - 3.53 (m, 45H, H-2, H-2‘, H-3, H-3‘, H-4, H-4‘, H-5, H-6, H-17), 3.23 (s, 2H, H-10), 3.20 - 2.83 (m, 2H, H-6‘), 1.00 (s, 3H, H-12) ppm.
• the reaction mixture was heated to 90 °C and stirred at this temperature for 13 hours.
• the reaction mixture was monitored by TLC using the mixture toluene/MeOH 6/1 and the substances were detected by UV lamp and carbonisation in 50% aqueous sulphuric acid solution.
• the pyridine was then distilled off from the reaction mixture at 90 °C using an oil rotary pump.
• the residue (0.31 g) was dissolved in the mixture CHCl 3 /MeOH 1/1, silica gel (1.5 g) was added and the mixture was evaporated on a rotary evaporator at 50 °C.
• the crude product adsorbed on silica gel was purified by column chromatography (15 g silica gel) with elution mixture toluene/MeOH 10/1. The product was not obtained in pure form.
• the product-containing fractions were evaporated on a rotary vacuum evaporator at 50 °C.
• the residue (0.23 g) was dissolved in CHCl 3 , silica gel (1.1 g) was added and the mixture was evaporated on a rotary vacuum evaporator at 50 °C.
• the second time adsorbed product was again purified by column chromatography (5 g of silica gel) with eluting mixtures hexane/EtOAc 7/1 and hexane/EtOAc 1/1.
• the product-containing tractions were evaporated on a rotary vacuum evaporator at 40 °C.
• the product was dried at 50 °C using an oil rotary' pump and obtained as a white free-flowing material in a yield of 55 % (0.150 g).
• Scheme 7 Synthesis of a type (III) modifier containing a cyclodextrin and a fluorophore group attached via a tetraethylene glycol linker to a charged anchor. 6-((6-Isothiocyanatohexyl)amino)-2-propyl-1H-benzo[de]isochinolin-1,3(2H)-dion (30).
• 6-((6-Aminohexyl)amino)-2-propyl-1H- benzo[de]isochinolin-1,3(2H)-dion 29 (0.57 g, 1.62 mmol) was dissolved in CHCl 3 (100 mL) and K 2 CO 3 (0.67 g, 4.84 mmol) was added.
• Thiophosgene (0.28 g,
• the organic phase was diluted with Et 2 0 (150 mL), washed with water (2 x 100 mL) and dried over MgSCb (3 g). The drying agent was removed by filtration and the filtrate was evaporated at 40 °C using a rotary vacuum evaporator. The residue (0.9 g) was dissolved in CHCl 3 , silica gel (4.5 g) was added and the suspension was evaporated again at 40 °C using the rotary vacuum evaporator. The adsorbed product was purified by column chromatography (40 g of silica gel) with eluting mixture hexane/EtOAc 3/1. The pro duct- containing fractions were evaporated at 40 °C using a rotary vacuum evaporator.
• the reaction mixture was monitored by TLC using the mixture n-propanol/water/EtOAc/concentrated aqueous solution of NH 3 6/3/1/1 and the substances were detected by UV lamp and carbonisation in 50% aqueous sulphuric acid solution.
• DMF was distilled off at 80 °C using an oil vacuum pump.
• the residue (0.87 g) was dissolved in MeOH, C18-reversed phase silica gel (4.5 g) was added and the suspension was evaporated again at 40 °C using the rotary vacuum evaporator.
• the adsorbed product was purified by column chromatography with C18-reversed phase silica gel (18 g). The product was eluted with 50% aqueous solution of MeOH.
• the product-containing fractions were evaporated at 55 °C using a rotary vacuum evaporator.
• the product was dried at 60 °C with an oil vacuum pump and obtained as a yellow free-flowing substance in a yield of 64 % (0.396 g).
• the product was eluted with 20% aqueous solution of MeOH.
• the product-containing fractions were evaporated at 50 °C using the rotary vacuum evaporator; n-propanol was added to the product during evaporation for the substance to be free-flowing.
• the product was dried at 70 °C with an oil vacuum pump and obtained as a yellow free-flowing material in a yield of 65 % (0.25 g). [ ⁇ ] 25 D +67.3° ( ⁇ +0.035, 5.2 mg, DMSO).
• Scheme 8 describes the synthesis of a type IV modifier in which per(6-azido-6-deoxy)- ⁇ - cyclodextrin appears as a multiplier to which seven type I anchors - K1MIMM bind and the active groups are phenylcarbamate groups that are attached to all free hydroxyl groups of cyclodextrin.
• Scheme 8 Synthesis of a type IV modifier containing phenylcarbamoyl groups attached to the multiplier with seven bound charged anchors.
• (34) Heptakis(6-azido- 6-deoxy)- ⁇ -cyclodextrin 33 (0.05 g, 38.2 ⁇ mol) was dissolved in dry pyridine (1 mL), phenyl isocyanate (90 ⁇ L, 0.802 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 5 hours.
• the reaction mixture was monitored by TLC using the mixtures n- propanol/water/EtO Ac/concentrated aqueous solution of NH 3 6/3/1/1 and hexane/EtOAC 5/1 and the substances were detected by UV lamp and carbonisation in 50% aqueous sulphuric acid solution.
• Pyridine was distilled off from the reaction mixture at 80 °C using an oil vacuum pump.
• the distillation residue was dissolved in CHCl 3 and silica gel (0.6 g) was added.
• the mixture was evaporated at 50 °C using a rotary vacuum evaporator.
• the adsorbed crude product was purified by column chromatography using elution mixtures hexane/EtOAc 5/1 and 1/1 .
• the product- containing fractions were evaporated at 50 °C using the rotary vacuum e vaporator and the product obtained (0,070 g) was used for the next reaction.
• Example 4 Binding of modifiers to a solid carrier
• the modifiers of general formula (III) K1MIMM, K2MIMM, K3MIMM and K3TMAM with bound chromophore according to Example 3.4 were bound to negatively charged carriers selected from the group consisting of cation exchange resins and zeolites, stationary phases for ion exchange chromatography, silica gel, surfaces of uncharged materials modified to obtain a negative charge, e.g., by sulphonation or plasma treatment, by mixing the carrier with a 0.1 to 1% aqueous solution of the modifier of general formula (III) until the decrease in UV absorption is stopped. Under these conditions (depending on the carrier), the modifier binding half-life is in the order of hours at most. Furthermore, in the case of such modified carriers, the binding strength of the modifier to the carrier was determined by eluting with eluents of different polarity and ionic strength.
• the modifier (3 ⁇ mol) containing a naphthalimide group attached to the corresponding anchor bound in 0.5 ml of 0.1M NH 4 HCO 3 on 50 mg of Merck silica gel for column chromatography. Continuous elution of the modifier: o - not detected, + - was detected.
• the modifier (1.5 mg) containing a naphthalimide group attached to the K3TMAM anchor was dissolved in water and applied to a column (250 ⁇ l) of the carrier in a glass column and subsequently eluted with elution solutions having their pH adjusted to 2 with HC1. enCit - ethylenediamine citrate. Continuous elution of the modifier: o - not detected, + - was detected.
• Example 5 Binding of multiplier-containing modifiers to a solid carrier From per-6-azido-6-deoxy- ⁇ -CD (33), modifiers containing 7, 14 and 21 positive charges were prepared by reaction with K1MIMM, K2MIMM and K3MIMM anchors as described above for the preparation of substance 35. Furthermore, the strength of their bond to silica gel and aluminium oxide, i.e. the substances to which the anchors of general formula I, with one to three charges, are bound relatively weakly, was studied. The strength of the bond was determined using TLC chromatography, when it was monitored whether the modifier, applied in a 1% aqueous solution (1-2 ⁇ l), moves from the place on the TLC plate to which it was applied, using different eluents.
• Table 3 Elution of modifiers with 7, 14 and 21 positive charges on a silica gel TLC plate
• Table 4 Elution of modifiers with 7, 14 and 21 positive charges on a TLC plate with aluminium oxide

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