WO1999023123A1

WO1999023123A1 - Polymers containing aminophosphonium groups

Info

Publication number: WO1999023123A1
Application number: PCT/EP1998/006819
Authority: WO
Inventors: Adolf Heinz Linkies; Sergej Pasenok
Original assignee: Aventis Research & Technologies Gmbh & Co. Kg
Priority date: 1997-11-04
Filing date: 1998-10-28
Publication date: 1999-05-14
Also published as: ZA989983B; DE19748712A1; AU1557899A

Abstract

The polymer contains radicals of general formula (I) which are bonded to the polymer, wherein R1-R6 independently mean hydrogen, C¿1-12?-Alkyl, C2-12-alkenyl, C4-8-cycloalkyl, C6-12-aryl, C7-13-aralkyl or R?1 and R2, R3 and R4, R5 and R6¿ independent from each other and together mean C¿3-7?-alkylene which can be interrupted by -O-, -NH- or -N(C1-4-alkyl); Z = NH, N(C1-20-alkyl), CH2 or CH(C1-20-alkyl); X = a straight-chain or branched C1-30-alkylene, wherein one or more hydrogen atoms can be replaced by halogen, which can be interrupted by 1 to 3 not directly neighboring radicals -O-, -S-, -COO-, -O-CO-, -NH-, -NR?7¿-, NH-CO-, -NR7-CO-, NH-CO-NH-, -O-CO-NH-, -NH-CO-O-, -CO-NR7-, -CO-NH-, N?+R7R8-B-, -P+R7R8R9R9a- B-¿ together with R?7 to R9a¿ independently mean C1-6-alkyl, -C C- or -CH=CH-, phenylene, cyclohexylene, cyclopentylene, which can be substituted, and wherein B- is the anion of an acid._

Description

description

Polymers containing aminophosphonium groups

The invention relates to polymers containing aminophosphonium groups, processes for their production, monomers used in their production and processes for their production as well as uses of the polymers and pharmaceutical compositions containing them. The polymers are characterized by a bile acid adsorber effect.

Bile acids and their salts are natural detergents and have an important physiological function in fat digestion and fat absorption. As end products of the cholesterol metabolism, they are synthesized in the liver, stored in the gallbladder and from there released into the intestine as components of the bile, where they exert their physiological effect. The largest part (approx. 85-90%) of the secreted bile acids (approx. 16 g / day) is resorbed from the intestinal wall via the enterohepatic circulation, preferably in the terminal ileum, and transported back to the liver, i.e. recycled. Only 10-15% of the bile acids are excreted in the faeces. In the liver, a

Reduction in the amount of bile acid can be compensated to a certain extent by post-synthesis of bile acids from cholesterol. A decrease in the liver cholesterol level leads to an increase in the absorption of cholesterol from the blood serum and thus lowers the cholesterol level in the blood serum. Ultimately, the enterohepatic circulation can be interrupted and the serum cholesterol level in the blood reduced as a result by inhibiting the absorption of galienic acid in the intestine by means of suitable inhibitors or bile acid adsorbers. Too high a serum cholesterol level is considered to be of concern in medicine because it leads to atherosclerosis and thus the risk of heart attack increases.

There are many therapeutic approaches for the treatment of so-called hypercholesterolemia. One of these approaches is to interrupt the enterohepatic cycle. This approach can also be used to treat all diseases in which inhibition of bile acid reabsorption in the small intestine appears desirable. to Binding of bile acids has been used therapeutically for some time now as non-resorbable polymers. In particular, insoluble, mostly crosslinked, polymers are used for this purpose, which contain quaternized nitrogen centers. Polymers with quaternized phosphorus centers are also described. Such compounds act similarly to anion exchangers. They bind part of the bile acid anions occurring in the intestine via predominantly ionic interactions and transport them out of the intestine.

US Pat. No. 5,427,777 describes, for example, compatible polymeric phosphonium salts in which quaternized phosphorus centers are present in a polymer matrix. The phosphorus atoms are attached to four alkyl groups and neutralized by counterions. Treatment of hypercholesterolemia is suggested as an application.

JP-A 56/122 803 describes anion exchange resins based on polyvinyl chloride. Polyvinyl chloride is reacted with sodium azide and then with a phosphine so that phosphinimine structures are present in the product.

Serum cholesterol levels! Lowering copolymers of diethylenetriamine and 1-chloro-2,3-epoxypropane are sold under the name Colestipol. The chloride of a styrene-divinylbenzene copolymer containing quaternary ammonium groups, which is effective as an anion exchanger for binding bile acids in bile congestion and hypercholesterolemia, is marketed under the name cholestyramine.

The known compounds have disadvantages that make their use in therapy difficult. They have to be used in a high dosage of about 10 to 30 g per day due to the low binding rate or a partial re-release of the adsorbed bile acids in the isotonic intestinal medium. In addition, they often have a fish-like smell and a sand-like unpleasant

Taste combined with a sandy consistency. In some cases, more than 50% by weight of the drug used must be added to taste and odor-improving additives. This in turn increases the daily dose of the adsorber drug. The object of the present invention is to provide polymers which have improved properties in the treatment of hypercholesterolemia compared to the known agents and avoid the disadvantages of the known preparations.

The object is achieved according to the invention by providing a polymer containing radicals of the general formula (I) bound to the polymer

in which R ¹ to R ⁶ independently of one another are hydrogen, C ₁ -ir-alkyl, C ₂ -12-alkenyl, C-ws-cycloalkyl, Cβ- _12- aryl, C ₇ . _13- aralkyl, or R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁶ independently of one another together C ^ -alkylene, which can be interrupted by -O- NH- or -N (Cι ^ alkyl) ,

NH, N (C _1, ₂ o-alkyl), CH ₂ or CH (Cι _-20 alkyl),

straight-chain or branched d- ₃₀ -alkylene, in which one or more hydrogen atoms can be replaced by halogens, preferably fluorine, which is replaced by 1 to 3 not directly adjacent radicals -O-, -S-, - COO-, -O-CO-, NH-, -NR ⁷ -, -NH-CO-, -NR ⁷ -CO-, -NH-CO-NH-, -CO-NR ⁷ - -CO-NH-, -O-CO-NH-, - NH-CO-O-, -N ⁺ R ⁷ R ⁸ - B ^", -P ⁺ R ⁷ R ⁸ R ⁹ R ^9a - ^B" with R ⁷ to R ^9a are independently Cι _-6 alkyl, -C≡C -, or -CH = CH-, phenylene, cyclohexylene, cyclopentylene, which may be substituted, may be interrupted, mean, and

B ^'is the anion of an acid. The type of polymer is not critical within wide limits. The polymer should be physiologically acceptable and in the stomach or small intestine during normal

Dwell time cannot be changed or reduced significantly. In addition, that should

Polymer should preferably be water-insoluble or sparingly soluble, since this ensures that it is completely excreted again.

Suitable polymers are, for example, natural polymers, such as polysaccharides, for example starch, cellulose, amylose, pectins. It can also be proteins or polypeptides such as globulin, keratin, collagen, casein. The natural polymers can be chemically modified. For example, starches can be in the form of starch esters or starch ethers.

Inorganic polymers are also conceivable, such as polyphosphazenes or silica gels.

In addition, synthetic polymers can be used according to the invention. These include polymers that are accessible through polymerization, polyaddition or polycondensation. Examples of suitable classes of substances are polyesters, polyethers, polyamides, polyimides, polyureas, polyurethanes, polysulfides. The polymers can also carry functional groups, as is the case, for example, with polyalcohols and polycarboxylic acids.

Polymers derived from ethylenically unsaturated monomers are preferred. Examples include vinyl compounds such as polyvinyl acetates, polyvinyl chlorides, polyvinyl alcohols, polyvinylamines, polyvinylphosphonic acids, polyvinylsulfonic acids, polyacrylates, polymethacrylates, polyacrylamides, polymethacrylamides or polystyrenes.

Polymers based on acrylic acid, methacrylic acid, their derivatives and polymers based on styrene are particularly preferred. The polymers can be linear, branched or crosslinked. They are preferably present in such a degree of polymerisation or degree of branching or crosslinking that the polymer is insoluble or only slightly soluble in physiological salt solutions or in water. The polymers can be present as homopolymers or copolymers derived from copolymerizations, copolyadditions and copolycondensation. The radicals of the general formula (I) can function by suitable reactions. nalized compounds which have radicals of the general formula (I) into the

Polymers are introduced. In addition, the radicals of the general formula (I) can be present as a functional group of monomers which are polymerized to form the polymer. These can be homopolymers of these monomers functionalized with radicals of the general formula (I) or copolymers in which non-functionalized comonomers or other monomers are used which have a similar or lower bile acid-binding potency. The polymer preferably has a high content of bile acid-binding radicals of the general formula (I). If the comonomers also have a bile acid-binding potency, the composition of the copolymer can vary within wide limits.

The type of monomer used is preferably the same or similar, i.e. monomers derived from acrylic acid, methacrylic acid or styrene are preferably used. Comonomers, which also contain bile acid-binding groups, can have, for example, quaternary ammonium centers with hydrophobic portions as functional groups. The copolymers that can be used

Block copolymers or statistical copolymers. Graft copolymers can also be used. With ethylenic monomers, isotactic, atactic and syndiotactic polymers can result. The molecular weight of the polymers used according to the invention can vary within wide limits. For soluble polymers, the upper limit of the molecular weight (M _n ) is approximately

1,000,000, the lower limit at around 1,000. Ranges from 1,000 to 1,000,000 for M _n are preferred. These values apply to water-soluble and preferred poorly or not water-soluble polymers.

It has been found according to the invention that polymers with tetrakisdialkylaminophosphonium groups have an excellent binding behavior towards bile acids. This binding capacity makes the polymers usable for the production of drugs that are used to treat hypercholesterolemia.

The following are different manufacturing methods for the preferred ones

Polymers containing tetrakisdialkylaminophosphonium groups.

For example, as already stated above, polymers with reactive groups such as polychloromethylstyrene with tris (dialkylamino) iminophosphoranes can be added to the implement the desired products. Structures of the general form

Formula (I) by attaching group Z to a reactive group of the polymer.

The leaving group of the polymer is preferably a halogen atom, tosylate or the like attached to a methylene group. The reaction is possible with all suitable polymers that carry such a leaving group. One can also use fully-formed tetrakisdialkylaminophosphonium groups

Bind polymer if one of the alkyl groups in one of the dialkylamino residues bears a suitable functional group necessary for this. For example, such

Alkyl group carry a halide or tosylate.

The polymers according to the invention preferably contain basic building blocks which are derived from monomers of the general formula (II).

in which R ¹ to R ⁶ , Z, X and B ^"have the meaning given above,

Y is a single bond, -O-, -COO-, -O-CO-, -NR ¹² -CO-,

-NH-, -CO-NR ⁷ -, -CO-NH-, -CO-NR ¹² -, or -N (C _1-6 alkyl) -CO- and

R> 10, _D R1 ¹ 2 are hydrogen or C _1-4 alkyl.

The polymerization follows conventional methods, as described for example in Houben-Weyl. It can be initiated thermally, by free radical initiators, cationically or anionically. The polymerization is preferably carried out by free radicals. The solvents customary for polymerizations can be used as solvents. Water can also be used as a solvent if the starting materials are water-soluble. For radical polymerization, azo initiators such as 2,2'-azobis (2- (2-imidazolin-2- yl) propane) dihydrochloride, which provide water-soluble, non-toxic fragments upon cleavage.

The polymerization itself takes place at room temperature or at elevated temperatures. To ensure that the polymerization runs smoothly, it should be carried out under protective gas.

The same applies to the production of copolymers. Suitable vinyl comonomers are, for example, acrylates, methacrylates, styrene, substituted styrenes, acrylonitrile, methacrylonitrile, maleic anhydride, vinyl acetate, vinylformamide, vinylpyrrolidone, vinylimidazole, vinylpyridine, allylammonium compounds, vinylsulfonic acids, vinylphosphonic acids and other compounds, diallylammonium compounds, diallylammonamines, diallylammonium compounds. The use of crosslinking monomers which have at least two polymerizable groups is also possible. Polymers which are difficult or insoluble in water can be obtained in this way.

The polymers obtained can be worked up by filtration or, in the case of water-soluble products, by ultrafiltration. Drying is carried out using suitable methods such as freeze drying.

A large number of reactions are suitable for the preparation of the polymerizable monomers. Imino-tris-dialkylaminophosphoranes can be alkylated with alkyl halides to tetrakisdialkylaminophosphonium salts, see R. Schwesinger, J. Willaredt, H. Schlemper, M. Keller, P. Schmidt, H. Fritz, Chem. Ber. 1994, 127, 2435-2454. For example, alkylating agents with an olefinic group such as

React vinylbenzyl chlorides or allyl halides with tris (dialkylamino) iminophosphoranes:

The alkylation reaction can also be carried out with di- or polyhaloalkanes, only one halogen atom being reacted and one or more of the remaining halogen atoms being linked to a suitable olefinic partner. Such an implementation can be as follows, for example

It is also possible to introduce one or more polymerizable groups already during the preparation of the tris (dialkylamino) phosphoranes from phosphorus pentachloride and amines. A trisdialkylaminophosphorodichloride can first be prepared by reacting phosphorus pentachloride and dialkylamines. This can then be converted to the tris (dialkylamino) iminophosphoranes by reaction with a primary amine which contains a polymerizable unit in the remainder. If, instead of phosphorus pentachloride, phosphoric acid trisdialkylamides are used, the residues of the general formula (I) in which Z is a

Methylene group or CH (Cι _-20 alkyl). An example implementation is:

Suitable reactions are explained below using the radicals of the general formula (I). The synthesis can of monomer precursors of the general formula (III)

Ri R2 N

go out in which R ¹ to R ⁶ , Z and B ^"have the meaning given above and B is a leaving group, such as halogen, tosylate, mesylate, triflate, or another suitable perfluoroalkyl sulfonate, preferably halogen, in particular chlorine or

Is bromine. These monomer precursors can be prepared, in particular if ZN denotes (-C ₂ -alkyl), by reacting compounds of the general formula (IV)

-Alkyl) (IV)

with compounds of the general formula B- (-C-3o-alkylene) -B, where R ¹ to R ⁶ and B have the meaning given above. The compounds of the general formula (IV) are, as described above, by reacting Phosphorus pentachloride with the amines R ¹ R ² NH, R ³ R ⁴ NH or R ⁵ R ⁶ NH and subsequent reaction with H ₂ N (Cι. ₂ o-alkyl) accessible.

The basic building blocks of the general formula (II) can be obtained from the monomer precursors of the general formula (IV)

in which R ¹ to R ⁶ , Z, X and B have the meaning given above,

-Y- a single bond, -O-, -COO-, -O-CO-, -NH-COO-, -NH-CO-, -CO-NR ⁷ -, -CO-NH-, -NR ⁷ -CO -, -NH-CO-NH-, -O-CO-NH-, -NH, -NR ⁷ - with R ⁷ Cι- ₆ alkyl, or phenylene, cyclohexylene, cyclopentylene, which may be substituted, and

R ^{10 is} hydrogen or C ₄ alkyl, are prepared.

For this purpose, compounds of the general formula (IV) with compounds of the general formula (V)

BXY-CR ¹⁰ = CH ₂ (V)

implemented, wherein R ¹ to R ⁶ , R ¹⁰ , X, Y, B have the meaning given above.

The radicals of the general formula (I) preferably have the following features or the following meanings for the radicals:

R ¹ to R ⁶ are independently Cι _-6 alkyl radicals; Z is N (Cι _-2 o-alkyl) or NH;

X is C ₂₀ alkylene, which is independently by 1 to 3 of the radicals -NH-, -N ⁺ R ⁷ R ⁸ -B- with R ⁷ and R ⁸

is interrupted;

B ^" is halide.

The radicals of the general formula (I) preferably have all of the above features.

The alkyl and alkenyl radicals given above can be linear or branched. They are preferably linear alkyl and alkenyl radicals.

R ¹ to R ⁶ are particularly preferably the same Ci-e-alkyl radicals, in particular methyl or ethyl radicals. Z is preferably an N (Cι- ₆ alkyl) or N (Cιo-i ₅ alkyl), particularly preferably an N (Cι _-2 alkyl) or N (Cn-i ₄ alkyl).

X is preferably a C ₂₀ alkylene radical which is interrupted by a phenylene group or a radical - N ⁺ R ⁷ R ⁸ - B ^" with R ⁷ and R ⁸ independently of one another d - ₄ alkyl, particularly preferably Ci - alkyl .

Another particularly preferred radical X is (-C ₂ o-alkylene) -N ⁺ R ⁷ R ⁸ - (-C 1 -alkoalkylene) B ^" with R ⁷ = R ⁸ = methyl or ethyl. -C _{2 -2} -alkylene preferably

in particular C ₄ -ι ₂ alkylene. Ci.io-alkylene is preferably C ₅ alkylene, particularly preferably C ₃ alkylene.

B is preferably chlorine or bromine, B ^" bromide or chloride.

Y in the general formula (II) is preferably O-CO or NH-CO. R ¹⁰ is preferably methyl or ethyl, especially methyl. It is therefore with the

Basic building blocks of the general formula (II) are particularly preferably methacrylamides.

Monomers of the general formula (II), in the ZN (Cι- ₂ o-alkyl) and X (-C ₂ -alkylene) -N ⁺ R ⁷ R ⁸ - (-C-alkylene) B ^" are preferably by reacting compounds of the general formula (IV) as indicated above with

Compounds of the general formula B- (-C 2o-alkylene) -B and subsequent

Reaction with a compound of the general formula (VI)

R ⁸ R ⁷ N- (-CC-alkylene) -Y-CR ¹⁰ = CH ₂ (VI)

wherein R ¹ to R ¹⁰ , Y and B have the meaning given.

The polymers described above can be used as catalysts, in particular

Phase transfer catalysts, adsorber materials, ion exchangers, membranes, formulation auxiliaries, detergents, crop protection agents, drilling fluids, hair conditioners, film formers, preservatives, food additives or textile auxiliaries are used.

For example, they can be used in the Halex reaction, in which a moderately activated aromatic chlorine is replaced by fluorine. Such a reaction is, for example, the conversion of p-chlorobenzaldehyde to p-fluorobenzaldehyde.

In particular, however, the polymers are used for the production of pharmaceutical compositions. In addition to the above polymers, such pharmaceutical compositions generally contain customary carriers, auxiliaries and / or additives. These carriers, auxiliaries and additives are pharmaceutically acceptable substances.

In particular, the pharmaceutical compositions are used for the treatment of hypercholesterolemia and more generally for influencing the enterohepatic circulation of the bile acids. Further areas of application of the pharmaceutical composition are the influencing of lipid absorption, the influencing of

Serum cholesterol levels, the inhibition of bile acid absorption in the gastrointestinal tract and the prevention of arteriosclerotic symptoms. In particular, the polymers are used for the production of pharmaceutical compositions for the treatment of hypercholesterolemia.

The pharmaceutical compositions or medicaments can also contain other lipid-lowering agents. They can be administered in various dosage forms, preferably orally in the form of tablets, capsules or liquids or slurries.

The adsorption activity of the polymers according to the invention in relation to bile acid can be measured in an in vitro model. For this, the

Substance in an aqueous saline solution, which approximates the conditions in the small intestine, is stirred or shaken with glycoic and taurocholic acid for a certain time, and after filtration or centrifugation the amounts of bile acids remaining in the solution are determined by means of HPLC. By stirring the residue with aqueous salt solution and determining the bile acids released in the salt solution

HPLC determines the strength of the adsorption.

The invention is explained in more detail below with the aid of examples.

EXAMPLES

example 1

5.0 g (17.2 mmol) of tris (diethylamino) ethyliminophosphorane and 3.1 g (20 mmol) of vinylbenzyl chloride (mixture of the 3- and 4-isomers in the ratio 7/3) are in 20 ml

Acetonitrile dissolved and stirred at room temperature. The next day, 1 g of benzyl compound and a little hydroquinone are added. The mixture is stirred at room temperature for a further 3 days. The acetonitrile is distilled off in vacuo and the residue is stirred with ethyl acetate and a lot of hexane. The supernatant is decanted off and the oil is stirred out twice with a large amount of hexane. The dark syrup is dissolved in water and freeze-dried. Yield: 6 g (oil)

¹ H NMR: (DMSO D6) d = 7.2-7.6 (m, 4H, aromatic), 6.6-6.8 (m, 1 H, olefin), 5.8-5.9 ( m, 1 H, olefin), 5.2-5.4 (m, 1 H, olefin), 4.2-4.4 (m, 2H, CH ₂ -aromatic), 3.0-3.2 ( m, 14H, N-CH ₂ ), 1, 0-1, 2 (m, 21 H, CH ₃ ) ppm. ³¹ P NMR: (DMSO D6) = 45 ppm (bs).

6.0 g of oil from stage 1 are dissolved in 40 ml of water and stirred at 45 ° C. Then 200 mg of 2,2'-azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride are added. After 2 hours, the mixture is warmed to 50 ° C. and a further 200 mg of initiator are added. After a further 2 hours, the mixture is warmed to 60 ° C. and a further 200 mg of initiator are added. 4 hours later, the mixture is cooled and ultrafiltration is carried out until no educt can be detected in the permeate. The residue is freeze-dried. Yield: 4.4 g ³¹ P-NMR: (DMSO D6) = 45 ppm (bs).

Example 2

6.6 g (32.6 mmol) of tris (diethylamino) ethyliminophosphorane and 32.8 g (100 mmol)

Dibromo dodecane are dissolved in 10 ml acetonitrile. The mixture is stirred at 50-60 ° C. for 6 hours and then at 80 ° C. for 9 hours. The acetonitrile is distilled off and the residue is stirred with hexane. 20 ml of DMF and 6.8 g (40 mmol) of N- (3-N, N-dimethylaminopropyl) methacrylamide are added to the insoluble residue. After stirring at 60-70 ° C. for 12 hours, the DMF is distilled off in vacuo. The residue is stirred twice with ether and 6 times with ethyl acetate. After drying in vacuo, 10 g of syrup are obtained. Column chromatography gives 6 g of product. ¹ H-NMR (CDCI) d = 8.1 (m, 1H, NH), 5.4 and 5.8 (2s, 2H, olefin. H), 3.0-3.6 (3 m, 6H, CH ₂ -N), 3.2 (s, 6H, N-CH ₃ , 3.2 (m, 16H, N-CH ₂ ), 2.0 (s, 3H, CH ₃ ), 1, 2-2 , 1 (4m, 43H, aliphatic CH ₂ ) ppm

³¹ P NMR (CDCI ₃ ) d = 45 ppm (bs)

4.5 g of stage 1 are dissolved in 30 ml of H ₂ O and at 70-80 ° C. by adding 200 mg of 2,2'-azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride within portions polymerized for 4 hours. After adding 50 ml of saline, the filter is ultrafiltered until the chloride test in the eluate is negative. The residue is freeze-dried. 1.7 g.

Example 3

70 g (210 mmol) of dibromo dodecane and 13.3 g (70 mmol) of tris (dimethylamino) methyliminophosphorane are dissolved in 70 ml of acetonitrile and heated to 50 ° C. After stirring for 6 hours, the mixture is cooled and the precipitate is filtered off with suction, the filtrate is concentrated and dissolved in 150 ml of water. It is extracted 3 times with hexane. The hexane is discarded. The aqueous phase is extracted 5 times with dichloromethane. The methylene chloride is dried with sodium sulfate and concentrated. Yield: 35 g

¹ H NMR (DMSO D6) d = 3.4 (t, 2H, CH ₂ -Br), 3.0 (m, 2H, N-CH ₂ ), 3.8-3.9 (2d, 21 H) , N-CH ₃ ), 1, 2-1, 8 (4m, 20H, aliphatic, CH ₂ ) ppm.

2.0 g (3.8 mol) of the product are dissolved in 20 ml of DMF. After adding 0.65 g

(3.8 mmol) N- (3-N, N-dimethylaminopropyl) methacrylamide is heated to 80 ° C. After 8 hours of stirring, another 0.65 g (3.8 mmol) of amide are added. It will be 4th Stirred at 100 ° C and 4 hours at 120 ° C. The DMF is distilled off on the oil pump. The distillation residue is dissolved in 20 ml dichloromethane and slowly stirred into about 200 ml acetone. Another 500 ml of hexane are added. After 30 minutes of stirring, the clear supernatant is decanted and discarded, the residue is dissolved in 20 ml of dichloromethane and precipitated again. The residue is in 20 ml

Dissolved water and extracted 10 times with dichloromethane. The dichloromethane is discarded. The aqueous phase is purified by chromatography on an XAD-16 column (Rohm & Haas). Water is first used for the elution, to which increasing amounts of isopropanol are added. Yield: 1.0 g

¹ H-NMR (D ₂ O) d = 5.5 and 5.8 (2s, 2H, olefin H), 2.9-3.4 (3m, 8H, N-CH ₂ ), 3.1 (s , 6H, N-CH ₃ ), 2.7-2.8 (2d, 21 H, N-CH ₃ ), 1.9 (s, 3H, CH ₃ , 1, 3-2.1 (4m, 22H , aliphatic CH ₂ ) ppm.

The substance is polymerized and purified as described in Example 2.

Yield: 0.8 g. The product is soluble in H ₂ O.

¹ H NMR (D ₂ O) d = 3.2-3.4 3.0-3.2, 2.8-3.0 (3m, 14H, N-CH ₂ and N-CH ₃ ), 2 , 6 to 2.8 (2d, 12H, N-CH _3), 0.9-2.0 (5m, 27H, aliphatic. H) ppm.

³¹ P NMR (D ₂ 0) d = 44 ppm

Analysis values for C ₂₈ H ₆ 3 N ₆ PO Cl ₂ + 4H ₂ O

calculated C 49.9 H 10.6 N 12.5 P 4.6% found C 49.3H 9.7 N 12.3P, 9% Example 4

PCI

/ / \

17.3 g of phosphorus pentachloride are suspended in 80 ml of dichloromethane. At -30 ° C, 22.5 g of dimethylamine (liquid) are carefully added dropwise. After 2 hours, the addition is complete and the mixture becomes thin again. After stirring for 30 minutes, the mixture is allowed to come to room temperature. After 1 hour, 46.3 g of dodecylamine in 50 ml of dichloromethane are added dropwise within 30 minutes. The temperature rises to 40 ° C. After 1 hour, 57 g of 50% sodium hydroxide solution are added dropwise. After this

After cooling, the methylene chloride phase is separated off. The aqueous solution is extracted twice with dichloromethane. After concentration, 74 g of crude product are obtained. It is poured into 50 ml of 50% sodium hydroxide solution and extracted 3 times with diethyl ether. The organic phase is dried, concentrated and distilled at 0.1 mm. At approx. 148-170 ° C, 17.6 g of colorless product are obtained.

14.6 g are placed in 50 ml of acetonitrile. Then 44.3 g of dibromo dodecane are added in portions at -60 ° C. Then allowed to come to room temperature. After 24 hours at room temperature, poured into 1 l of hexane and decanted from the residue. The residue is digested several times with hexane and dried. 25 g yield.

The entire residue is dissolved in 80 ml of DMF and stirred with 6.5 g of N- (3- (dimethylamino) propyl) methacrylamide at 70 ° C. for 8 hours. The DMF is then distilled off in vacuo. The residue is dissolved in acetone and stirred in 1 l of hexane. The precipitated product is purified on an XAD-16 column (Rohm & Haas). Eluent: water that is gradually diluted with isopropanol to a ratio of 7: 3. The product fractions are concentrated and freeze-dried. Yield: 25.5 g of oil.

¹ H NMR: (CDCI ₃ d = 8.2 (t, 1 H, NH), 5.4 and 6.0 (2s, 2H, olefin. H), 3.3 (s, 6H, CH3-N) 3.0, 3.5 and 3.7 (3m, 10H, CH ₂ -N), 2.8 (2d, 18H, CH3-N), 2.0 (s, 3H, CH ₃ ), 1, 2 -2.3 (5m, 42H, aliphatic CH ₂ ), 0.9 (t, 3H, CH ₃ ) ppm.

Example 5

10 g of acrylate from Example 4 in 50 ml of water are as described in Example 2

Polymerized and worked up at 50-60 ° C with 2 portions of starter of 100 mg each. Yield: 6.4 g. The substance is water-soluble.

Analysis values for C39 Hβs N ₆ O Cl ₂ + 6H ₂ O

calculated C 54.2H 11.5 N 9.7 P 3.6% found C 54.8H 11.3 N 9.8 P 3.5% Example 6

21 g of phosphorus pentachloride are suspended in 100 ml of dichloromethane. At -25 ° C 25 g of dimethylamine hydrochloride are added in portions. 83 ml of triethylamine are then carefully added dropwise at -30 ° C. After 2 hours, the addition is complete and the mixture becomes thin again. After stirring for 30 minutes, the mixture is allowed to come to room temperature. After 1 hour, 19 g of dodecylamine and 33 ml of triethylamine dissolved in 50 ml of dichloromethane are added dropwise within 30 minutes. The temperature rises to 40 ° C. After 1 hour, 57 g of 50% sodium hydroxide solution are added dropwise. After cooling, the methylene chloride phase is separated off. The aqueous solution is extracted twice with dichloromethane. After concentration, the mixture is poured into 40% sodium hydroxide solution and extracted 3 times with diethyl ether. The organic Phase is dried, concentrated and distilled at 0.1 mm. At approx. 148-153 ° C, 26 g of colorless product are obtained.

26 g are placed in 90 ml of acetonitrile. Then 59 g at room temperature

Dibromohexane added in portions. After 8 hours at 60-70T, the acetonitrile is distilled off and the residue is stirred with hexane. Then you decant from

Residue. The residue is digested several times with hexane and dried. 40 g

Yield.

The entire residue is dissolved in 150 ml of DMF and stirred with 15 g of N- (3- (dimethylamino) propyl) methacrylamide and 1 g of hydroquinone at 70 ° C. for 8 hours. The DMF is then distilled off in vacuo. The residue is stirred with diisopropyl ether.

The precipitated product is stirred several times with diisopropyl ether until it solidifies.

Yield: 37 g.

The compound can be recrystallized from ethyl acetate / acetone.

¹ H NMR: (CDCI ₃ d = 8.2 (t, 1 H, NH), 5.4 and 6.0 (2s, 2H, olefin. H), 3.3 (s, 6H, CH ₃ -N )

3.0, 3.5 and 3.7 (3m, 10H, CH ₂ -N), 2.8 (2d, 18H, CH ₃ -N), 2.0 (s, 3H, CH ₃ ), 1, 2-2.3 (5m, 42H, aliphatic CH ₂ ), 0.9 (t, 3H, CH ₃ ) ppm.

Example 7

11 g of acrylate from Example 6 in 80 ml of water are as described in Example 2

50-60 ° C with 2 portions of starter of 150 mg polymerized and worked up.

Yield: 6 g

Analysis values for C32 H ₆₇ N ₆ OP Cl ₂ + 3H ₂ O calculated C 54.3 H 10.4 N 11.9 found C 54.7 H 10.2 N 11.5

Example e

Preparation of 4-fluorobenzaldehyde from 4-chlorobenzaldehyde

140 g of 4-chlorobenzaldehyde, 58 g of potassium fluoride and 5 g of catalyst (compound from Example 1) are placed in a 500 ml four-necked flask equipped with a thermometer, anchor stirrer and reflux condenser with a bubble counter. The mixture is then heated to 190 ° C. with stirring and left to react for 20 hours. After the reaction is allowed to cool, the reaction mixture is dissolved in chlorobenzene, insoluble constituents are filtered off and the product is purified by fractional distillation under reduced pressure.

Yield: 65% selectivity: 85%

Comparative Example V8

The procedure is as described in Example 8, but without the addition of catalyst. Yield: 48% selectivity: 55%

Example 9

Production of 4-fluomitrobenzene from 4-chloronitrobenzene In a 500 ml four-necked flask equipped with a thermometer, anchor stirrer and reflux condenser with bubble counter, 157 g of 4-chloromitrobenzcl, 58 g of potassium fluoride, 8 g of catalyst (compound from Example 1) in 30 ml of sulfolane are stirred at 180 ° C. for 20 hours. After the reaction has ended, the mixture is allowed to cool and is purified as described in Example 9. Yield: 80% selectivity: 85%

Comparative Example V9

The procedure is as described in Example 9, but without the addition of catalyst. Yield: 62% selectivity: 81%

Example 10

Et ₂ N

PCI H NEt HN (CH) CH Et ₂ N— P = N— (CH ₂ ) _{1 (I} CH 2 2 2 2 11 N Et «

20.8 g of phosphorus pentachloride are placed under nitrogen in 100 ml of dichloromethane at - 30 ° C. A mixture of 31 ml of diethylamine and 42 ml of triethylamine in 50 ml of dichloromethane is added dropwise at -30 ° C. with good cooling. After this

Drops are allowed to come to room temperature. Stirring is continued for one hour at room temperature. A solution of 53 g of dodecylamine and 14 ml of triethylamine in 50 ml of dichloromethane is then added dropwise and the mixture is boiled for 30 hours. After cooling, a solution of 140 g of KOH (85%) in 90 ml of water is added dropwise. The mixture is then stirred for 30 minutes. The organic phase is then separated off. The organic phase is concentrated and distilled.

Kp: 167-173 ° C at 0.2 mm. Yield 17.8 g = 41.3%

* H-NMR: (CDCI ₃ ) δ = 2.8-3.2 (2m, 14H, N-CH ₂ ), 1, 0-1, 8 (4 m, 38 H, aliphatic. CH ₂ and

CH ₃ ), 0.9 (t, 3H, CH ₃ ) ppm.

Example 11

8.6 g from Example 10 and 14.6 g dibromohexane are dissolved in 20 ml acetonitrile. The mixture is stirred at 60 ° C. for 2 days and the excess dibromohexane is distilled off in vacuo. The residue is washed twice with hexane to remove excess

Dibromohexane stirred. After drying, the oily residue gave 11.0 g of syrup.

The syrup is dissolved together with 5 g of N- [3- (dimethylamino) propyl] methacrylamide and 100 mg of hydroquinone in 30 ml of DMF. The mixture is stirred at 60 ° C. under nitrogen for 2 days. The DMF is drawn off in vacuo, the residue is dissolved in a little acetone and precipitated twice by adding diisopropyl ether. The oily precipitate is dried in vacuo and gives 10.8 g. 1H-NMR: (CDC) δ = 8.2 (m, 1 H, NH), 6.0 and 5.4 (2s, 2H, olefin.H), 2.9-3.8 (6m,

28H), 1, 2 to 2.2 (5m, 48H, CH ₂ ), 2.0 (s, 3H, CH ₃ ), 0.8 (t, 3H, CH ₃ ) ppm.

The 10.8 g are dissolved in 40 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. Polymer precipitates after 5 minutes. After 30 minutes, another 100 mg of starter and 20 ml of water are added and the mixture is stirred using an ultra-stirrer. The suspension is stirred at 60 ° C. for a further 4 hours. 20 ml of saturated NaCl solution are slowly added with stirring, a lump precipitating out, which dissolves when methanol is added. It is ultrafiltered until the permeate is NaCI-free

(initially MeOH / water mixture later water). The retentate is freeze-dried.

Weight = 6.5 g

Example 12

21 g of phosphorus pentachloride are placed under nitrogen in 200 ml of dichloromethane at 30 ° C. 25 g of dimethylamine hydrochloride are added at -20 ° C.

After 15 minutes, 83 ml of triethylamine are added dropwise at -30 ° C. with good cooling. After the dropping is allowed to come to room temperature. Stirring is continued for one hour at room temperature. A solution of 19 g of dodecylamine and 33 ml of triethylamine in 50 ml of dichloromethane is then added dropwise and the mixture is boiled for 2 hours. After cooling, 140 g of 60% KOH are added dropwise.

The mixture is then stirred for 15 minutes. The organic phase is then separated off. The organic phase is concentrated and stirred with hexane. The supernatant is concentrated and distilled. Kp: 152-160 ° C at 0.05mm.

Yield 31.1 g

Example 13

34.6 g of phosphorus compound from Example 12 and 122 g of dibromohexane are combined at 0 ° C. and then stirred at 10 ° C. for 4 hours. The mixture is then stirred for 5 hours at room temperature. The excess of dibromohexane is distilled off after 24 hours and the residue is stirred 3 times with hexane. The hexane phases are discarded. The residue is dried on the oil pump.

Weigh 61, 3 g.

The 61.3 g residue are mixed with 0.5 g hydroquinone and 27.3 g N- [3-

(Dimethylamino) propyl] methacrylamide stirred in 20 ml acetonitrile. The initially slightly exothermic reaction is heated to 30-35 ° C. for 18 hours after 4 days at room temperature. After concentration, the residue is stirred into diisopropyl ether. The crystalline precipitate is filtered off and washed with diisopropyl ether. It is then recrystallized from acetone.

Weight 44.3 g = 58.2% ¹ H-NMR: (CDCI3) δ = 5.6 and 6.0 (2s, 2H, olefin.H), 3.6-3.8 (m, 4H, NCH ₂ ),

3.4-3.6 (m, 2H, NCH ₃ ), 3.3 (s, 6H, NCH ₃ ), 2.9-3.1 (d, 18H, NCH ₃ ), 2.0 (s, 3H, CH ₃ ),

1.8-2.2 (ms, 30H, CH ₂ ), 0.9 (t, 3H, CH ₃ ) ppm.

Example 14

10 g of intermediate from Example 13, 2.5 g of dimethylaminoethyl acrylate and 50 mg of hydroquinone are dissolved in 40 ml of DMF. The mixture is stirred at 60-70 ° C. under nitrogen for 12 hours. The DMF is removed in vacuo, the residue is dissolved in a little acetone and precipitated twice with diisopropyl ether. The viscous residue is dissolved in a little acetone and stirred into hot ethyl acetate. After cooling, a tough precipitate is formed. This is dried in vacuo and gives 7.8 g.

¹ H-NMR: (CDCI ₃ ) δ = 5.9-6.5 (m, 3H, olefin.H), 4.7 (m, 2H, OCH ₂ ), 3.9-4.2 (2m, 4H, NCH ₂ ), 3.5 (s, 6H, NCH ₃ ), 2.9-3.1 (m, 4H, NCH ₂ ), 2.8 (d, 18H, NCH ₃ ), 1, 2- 2.0 (ms, 28H, CH ₂ ), 0.8 (t, 3H, CH ₃ ) ppm.

The compound is dissolved in 50 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 100 mg of 2,2'-azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride are added. After 30 minutes, a further 100 mg of initiator and 20 ml of water are added and the mixture is stirred using an ultra-stirrer. The suspension is stirred at 60 ° C. for a further 4 hours. 20 ml of sat. NaCI solution added. It is ultrafiltered until the permeate is NaCI-free. The retentate is freeze-dried.

Weight: 6.5 g Example 15 n = 9

PCI5 HN Me "HN - (CH CH") CH.

21 g of phosphorus pentachloride are placed under nitrogen in 200 ml of dichloromethane at - 30 ° C. 25 g of dimethylamine hydrochloride are added at -20 ° C.

After 15 minutes, 83 ml of triethylamine are added dropwise at -30 ° C. with good cooling. After the dropping is allowed to come to room temperature. Stirring is continued for one hour at room temperature. Then a solution of 18.9 g Decylamine and 33 ml of triethylamine in 50 ml of dichloromethane were added dropwise and the mixture was boiled for 2 hours. After cooling, a solution of 80 g KOH (85%) in 60 ml

Water dropped. The mixture is then stirred for 15 minutes. The organic phase is then separated off. The organic phase is concentrated and stirred with hexane. The hexane phase is concentrated and distilled.

Kp: 125-130 ° C at 0.05mm.

Yield 25.6 g = 80%.

25.6 g of iminophosphorane and 78 g of dibromohexane are combined at 0 ° C. and then stirred at 10 ° C. for 1 hour. The mixture is then stirred for a further 7 hours at room temperature and left to stand overnight. The excess of dibromohexane is distilled off and the residue is stirred twice with hexane. The hexane phases are discarded. The residue is dried on the oil pump.

Weigh 41, 8 g.

The 41.8 g residue are stirred with 0.3 g hydroquinone and 17 g N- [3- (dimethylamino) propyl] methacrylamide in 40 ml acetonitrile at 40-50 ° C. for 30 hours. After concentration, the residue is stirred into diisopropyl ether. The supernatant is discarded and the oily residue is dissolved in acetone and precipitated with ethyl acetate.

Weighing 37 g

37 g are dissolved in 120 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. Polymer precipitates after 25 minutes. After 30 minutes, another 100 mg of starter and 50 ml of water are added and the mixture is stirred using an ultra-stirrer.

The suspension is stirred at 60 ° C. for a further 4 hours. 50 ml of sat. NaCl solution added, a lump precipitating, which becomes soluble when methanol is added. It is ultrafiltered until the permeate is free of Sodium chloride is (initially MeOH / water mixture later water). The retentate is freeze-dried.

Weight = 23 g

Example 16 n = 13

PCI5 HNMe, H CH ": CH.

N 'Br

\ l +

N-P = N- • (CH) CH Br- CH) Br N-P— N- - (CH CH. N 3 2 n

\ (CH

2'6

21 g of phosphorus pentachloride are placed under nitrogen in 200 ml of dichloromethane at - 30 ° C. 25 g of dimethylamine hydrochloride are added at -20 ° C. After 15 minutes, 83 ml of triethylamine is added dropwise at -30 ° C. with good cooling. After the dropping is allowed to come to room temperature. Stirring is continued for one hour at room temperature. A solution of 25.6 g of tetradecylamine and 33 ml of triethylamine in 50 ml of dichloromethane is then added dropwise and the mixture is boiled for 2 hours. After cooling, a solution of 80 g KOH (85%) in 60 ml water is added dropwise. The mixture is then stirred for 15 minutes. The organic phase is then separated off. The organic phase is concentrated and stirred with hexane. The hexane phase is concentrated and distilled.

Kp: 190-195 ° C at 0.05mm.

Yield 26.6 g = 71%

17.6 g iminophosphorane and 61 g dibromohexane are combined at 0 ° C and then stirred at 10 ° C for 1 hour. The mixture is then stirred for a further 24 hours at room temperature. The excess of dibromohexane is distilled off and the residue is stirred 3 times with hexane. The hexane phases are discarded. The residue is dried on the oil pump.

Weighing 27.4 g.

The 27.4 g of residue are stirred with 0.3 g of hydroquinone and 12.7 g of N- [3- (dimethylamino) propyl] methacrylamide in 20 ml of acetonitrile at 40 ° C. for 3 days.

After concentration, the residue is stirred into hot diisopropyl ether. The oily residue which has precipitated is redissolved in acetone and precipitated with ethyl acetate. The fine precipitate is suctioned off.

Weigh out 14.7 g

14.7 g are dissolved in 100 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 200 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. Polymer precipitates after 3 minutes. After 10 minutes, another 200 mg of starter and 50 ml of water are added and the mixture is stirred using an ultra-stirrer. The suspension is stirred at 60 ° C. for a further 4 hours. 50 ml of saturated NaCl solution are slowly added with stirring, a flocculent precipitate being formed. It is ultrafiltered until the permeate is NaCI-free. The retentate is freeze-dried.

Weight = 12.6 g

Example 17 n = 7

N '

\ I

PCI5 HN Me, HN ^■ (CH,) CH. NP = N (CH) CH,

/

N-,

21 g of phosphorus pentachloride are placed under nitrogen in 200 ml of dichloromethane at - 30 ° C. 25 g of dimethylamine hydrochloride are added at -20 ° C. After 15 minutes, 83 ml of triethylamine are added dropwise at -30 ° C. with good cooling. After the dropping is allowed to come to room temperature. Stirring is continued for one hour at room temperature. A solution of 15.5 g of octylamine and 33 ml of triethylamine in 50 ml of dichloromethane is then added dropwise and the mixture is boiled for 2 hours. After cooling, a solution of 80 g KOH (85%) in 60 ml water is added dropwise. The mixture is then stirred for 15 minutes. Then the organic

Phase separated. The organic phase is concentrated and stirred with hexane. The

The hexane phase is concentrated and distilled.

Kp: 115-120 ° C at 0.05mm.

Yield 13.5 g = 47%

13.5 g iminophosphorane and 45.4 g dibromohexane are combined at 0 ° C. and then stirred at 10 ° C. for 1 hour. The mixture is then stirred at RT for a further 9 hours and left to stand overnight. The excess of dibromohexane is distilled off and the residue is stirred twice with hexane. The hexane phases are discarded. The residue is dried on the oil pump.

Weighing out 24 g.

The 24 g residue are stirred with 0.2 g hydroquinone and 11.5 g N- [3- (dimethylamino) propyl] methacrylamide in 25 ml acetonitrile at 40-50 ° C for 1 day. After concentration, the residue is stirred into diisopropyl ether. The insoluble oily residue is dissolved in acetone and precipitated with ethyl acetate. The fine precipitate is suctioned off.

Weighing out 16.4 g

16.4 g are dissolved in 80 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 200 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. Polymer precipitates after 24 minutes. After 30 minutes, another 200 mg of starter and 50 ml of water are added and the mixture is stirred using an ultra-stirrer. The suspension is stirred at 60 ° C. for a further 4 hours. It's getting under

Stir 50 ml sat. NaCl solution added, a tough precipitate precipitating which becomes soluble when methanol is added. It is ultrafiltered until the permeate is NaCI-free (initially MeOH / water mixture later water). The retentate is freeze-dried. Weight = 10.3 g Example 18 n = 15

N— P = N- • (CH

21 g of phosphorus pentachloride are placed under nitrogen in 200 ml of dichloromethane at - 30 ° C. 25 g of dimethylamine hydrochloride are added at -20 ° C. After 15 minutes, 83 ml of triethylamine are added dropwise at -30 ° C. with good cooling. After the dropping is allowed to come to room temperature. Stirring is continued for one hour at room temperature. Then a solution of 29 g of hexadecylamine and 33 ml of triethylamine in 50 ml of dichloromethane is added dropwise and it is cooked for 2 hours. After cooling, a solution of 80 g KOH

(85%) added dropwise in 60 ml of water. The mixture is then stirred for 15 minutes. The organic phase is then separated off. The organic phase is concentrated and with

Hexane mixed. The hexane phase is concentrated and distilled.

Kp: 187-195 ° C at 0.05mm.

Yield 26.2 g

26 g iminophosphorane and 73 g dibromohexane are combined at 0 ° C and then stirred at 10 ° C for 1 hour. The mixture is then stirred at room temperature for a further 18 hours. The excess of dibromohexane is distilled off and the residue is stirred twice with hexane. The hexane phases are discarded. The residue is dried on the oil pump.

Weighing 36.7 g.

The 36.7 g of residue are stirred with 0.3 g of hydroquinone and 15 g of N- [3- (dimethylamino) propyl] methacrylamide in 20 ml of acetonitrile at 40 ° C. for 18 hours. After concentration, the residue is stirred into hot diisopropyl ether. The oily phase which has precipitated is dissolved in acetone and precipitated with ethyl acetate.

Weight 19.8 g

19.8 g are dissolved in 120 ml of water. After nitrogen has been passed through, the

Heated at 60 ° C and 300 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride added. Polymer precipitates after 5 minutes. After 30 minutes, another 300 mg of starter and 50 ml of water are added and the mixture is stirred using an ultra-stirrer. The suspension is stirred at 60 ° C. for a further 4 hours. 50 ml of sat. NaCl solution added, a lump precipitating, which is crushed with the ultra-stirrer. It is ultrafiltered until the permeate is NaCI-free. The retentate is freeze-dried.

Weight = 17.2 g Example 19

11 g of p-dibromoxylene are dissolved in 200 ml of DMF with heating. 7.6 g of iminophosphorane from Example 12 are at 0 ° C within 10 minutes admitted. Then the mixture is stirred for a further 25 hours at room temperature. The DMF is distilled off and the residue is extracted twice with hexane and twice with methyl tert-butyl ether. The organic phases are discarded. The backlog is at

Oil pump dried.

Weighing 5 g.

The 5 g of residue are stirred with 50 mg of hydroquinone and 2 g of N- [3- (dimethylamino) propyl] methacrylamide in 25 ml of acetonitrile at RT for 24 hours. The precipitate is filtered off and the filtrate is concentrated. After this

The residue is stirred with methyl tert-butyl ether. The oily precipitate is stirred with methanol and the insolubles are separated off. The filtrate is concentrated and dried.

Weight 4.7 g.

4.7 g are dissolved in 40 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. After 15 minutes everything is polymerized. A further 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added and 4 hours at 60-

70 ° C stirred. Then MeOH is saturated until solution and then 50 ml. NaCI solution added. It is ultrafiltered until the permeate is NaCI-free. The retentate is freeze-dried.

Weight = 3.1 g

Example 20

31.2 g of phosphorus pentachloride are placed under nitrogen in 500 ml of dichloromethane at - 30 ° C. A mixture of 63 ml of pyrrolidine and 102 ml of triethylamine is added dropwise at -30 ° C with good cooling. After dropping, let it go

Room temperature come. Stirring is continued for one hour at room temperature and briefly at reflux. A solution of 27.9 g of dodecylamine in 60 ml of dichloromethane is then added dropwise and the mixture is boiled for 4 hours. After cooling, a solution of 125 g of KOH (85%) in 85 ml of water is added dropwise. After that, 15 Minutes stirred. The organic phase is then separated off. The organic phase is concentrated and distilled.

Kp: 190-200 ° C at 0.02mm.

Yield 41 g = 64%

41 g of iminophosphorane and 73.2 g of dibromohexane are combined at 0 ° C. and then stirred at 10 ° C. for 1 hour. The mixture is then stirred at RT for a further 8 hours and left to stand overnight. The excess of dibromohexane is distilled off and the residue is stirred twice with hexane. The

Hexane phases are discarded. The residue is dried on the oil pump.

Weighing 63 g.

The 63 g residue are mixed with 0.3 g hydroquinone and 24 g N- [3-

(Dimethylamino) propyl] methacryiamide in 50 ml of acetonitrile was stirred for 8 hours at 40-50 ° C. and left to stand for 60 hours. After concentration, the residue is stirred into methyl tert-butyl ether. The crystalline precipitate is filtered off and washed with methyl tert-butyl ether. It is then recrystallized from acetone.

Weight 39.5 g = 50.1%

27 g are dissolved in 250 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. Polymer precipitates after 40 minutes. After 30 minutes, a further 100 mg of starter are added and the batch is stirred using an ultra-stirrer. The suspension is stirred at 60 ° C. for a further 4 hours. 20 ml of sat. NaCl solution added, a lump precipitating, which becomes soluble when methanol is added. It is ultrafiltered until the permeate is NaCI-free

(initially MeOH / water mixture later water). The retentate is freeze-dried.

Weight = 24.3 g Example 21

6.4 g of iminophosphorane (step 1 from Example 20) and 5.4 g of allyl bromide are combined at 0 ° C. and stirred for a further 4 hours at RT and left to stand overnight. The excess of allyl bromide is distilled off and the residue with

Hexane stirred. The hexane phases are discarded. The residue is dried on the oil pump.

Weight 7.7 g.

7.7 g are dissolved in 40 ml of water. After nitrogen has been passed through, the mixture is heated to about 60 ° C. and 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride are added. After 30 minutes another 100 mg of starter are added. After 30 minutes, another 500 mg of starter are added. It will be at another 8 hours 60 ° C stirred. Then 30 ml of sat. NaCI solution added. It is ultrafiltered until the permeate is NaCI-free. The retentate is freeze-dried.

Weight = 5.0 g

Example 22

6.4 g of iminophosphorane from Example 20 (stage 1) and 6.9 g of 4-vinylbenzyl chloride are combined at 0 ° C. and stirred for a further 4 hours at RT and left to stand for 24 hours. The excess of 4-vinylbenzyl chloride is distilled off and the residue is stirred with hexane. The hexane phases are discarded. The residue is dried on the oil pump.

Weighing out 10 g. 10 g are dissolved in 50 ml of water. After nitrogen has been passed through, the

Heated at 60 ° C and 100 mg of 2,2'-azobis [2 (2-imidazolin-2-yl) propane] dihydrochloride were added. After 15 minutes everything is jelly-like. The mixture is stirred at 60 ° C for a further 4 hours. Then MeOH / water mixture is added. It is ultrafiltered until that

Permeate is NaCI-free. The retentate is freeze-dried.

Weight = 7.0 g

Bile acid adsorption

Test conditions

I. Preparation of the Salt Solution a) Stock Solution: NaCI 160 g

KCI 4 g

Na ₂ HPO ₄ , 2H ₂ O 28 g

KH ₂ PO 4 g on 1 IH ₂ O b) working solution - standard

The stock solution is diluted 1:20 with water and the

Galleic acid salts are added.

Bile acid salts: 8 mmol / l

Na glycocholate / Na taurocholate = 2/1

Na glycocholate (bCA) 2.60 g / l 5.33 mmol / l

Na taurocholate (TCA) 1.43 g / l 2.67 mmol / l

NaCI 8.00 g / l 137 mmol / l

KCI 0.20 g / l 2.7 mmol / l

Na ₂ HPO ₄ , 2H ₂ O 1.40 g / l 8.0 mmol / l

KH ₂ PO 0.20 g / l 1.45 mmol / l

:Adsorption

The polymer sample is weighed and the standard solution is added so that the concentration is 5 mg polymer / ml standard. (10 mg / 2ml)

The solutions are stirred for 2 hours at room temperature.

The solutions are then filtered (0.2 μm)

Comparison: colestyramine

The pH of the filtrate is checked. : HPLC measurement

Column: RP 18 Licrospher 5μm (250 x 4 mm)

Eluent: 900 ml acetonitrile

1100 ml H ₂ O 6.8 g tetrabutylammonium hydrogen sulfate

Flow: 1 ml / min

Detection: 210 nm

Injection volume: 5μl

Retention time: GCA4 min TCA 5 min

Standard and samples are injected 3 times.

:Calculation

Area Standard - Area Sample Ads% = * 100

Standard area

Bile acid desorption

Test conditions

: Ready-to-use solutions a: Standard solution: as for the adsorption determination b: Saline solution: standard solution without bile acids

NaCI 8.00 g / l 137.00 mmol / l

KCI 0.20 g / l 2.70 mmol / l

Na ₂ HPO ₄ , 2H ₂ O 1, 40 g / l 8.00 mmol / l

KH ₂ PO ₄ 0.20 g / l 1.45 mmol / l

:Execution

The polymer sample is weighed and the standard solution is added to give a concentration of 5 mg sample / ml standard solution. (50 mg / 10ml). This solution is stirred for 2 hours at room temperature.

Then it is filtered through membrane filtration (0.45 μm). A: filtrate: adsorption determination B: filter cake

Put the filter with filter cake in a glass jar. Add the same volumes of salt solution as the standard solution.

Stir for 2 hours at room temperature. Then filter through membrane filtration. a: Filtrate: Desorption determination b: Filter cake: Repeat the procedure as B. Some polymer samples are difficult to filter or stick to the wall. In this case the solution is centrifuged at 4500 rpm instead of filtered. 3: Bile acid determination

GCA and TCA detection via HPLC measurement (see adsorption determination)

4: Adsorption

Area standard - area filtrate A

Ads% = ^* 100

Standard area

5: Desorption

Area a ^* 100

Des% =

Area standard - area filtrate A

The following values resulted from these measurements:

GCA: Glycocholic Acid TCA: Taurocholic Acid

Claims

claims

1. Polymer containing radicals of the general formula (I) bound to the polymer

in the

R ¹ to R ⁶ independently of one another hydrogen, Ci.iralkyl, C ₂ -1 ₂ alkenyl, C4- ₈ - cycloalkyl, Cβ-12-aryl, C ₇ .i3-aralkyl, or R ¹ and R ² , R ³ and R ⁴ , R ⁵ and R ⁶ independently of one another together are Cs-yalkylene, which can be interrupted by -O-, -NH- or -N (Cι- ₄ -alkyl) -,

Z is NH, N (Cι _-20 alkyl), CH ₂ or CH (C _1-20 alkyl),

X straight-chain or branched Cι- ₃ o-alkylene, in which one or more hydrogen atoms can be replaced by halogen, which by 1 to 3 not directly adjacent residues -O-, -S-, -COO-, -O-CO-, -NH-, -NR ⁷ -, -NH-CO-, -NR ⁷ -CO-, -NH-CO-NH-, -O-CO-NH-, -NH-CO-O-, -CO-NO ⁷ -, -CO-NH-, -N ⁺ R ⁷ R ⁸ - B ^" , -P ⁺ R ⁷ R ⁸ R ⁹ R ^9a - B ^" with R ⁷ to R ^9a independently of one another Cι- ₆ alkyl, -C ≡C- or -CH = CH-, phenylene, cyclohexylene, cyclopentylene, which may be substituted, may be interrupted, mean, and

B ^"is the anion of an acid.

2. Polymer according to claim 1 with one or more of the following features:

R ¹ to R ⁶ are independently Ci-β-alkyl radicals;

- Z is N (Cι _-20 alkyl), or NH;

X is C ₂₀ alkylene, which is not adjacent by 1 to 3 radicals

-NH-, or -N ⁺ R ⁷ R ⁸ - B ^" with R ⁷ and R ⁸ independently of one another

is interrupted;

B ^" is halide;

the polymer is difficult or insoluble in water under physiological conditions.

3. Polymer containing basic building blocks which are derived from monomers of the general formula (II)

in the

R ¹ to R ⁶ , Z, X and B ^"have the meaning given in claim 1 or 2,

-Y- a single bond, -O-, -COO-, -O-CO-, -NH-CO-, -NR ⁷ -CO-,

-CO-NR ⁷ -, -CO-NH-, -NH-CO-NH, -O-CO-NH-, -NH-, -NR ⁷ - with R ⁷ Cι- ₆ - alkyl or phenylene, cyclohexylene, cyclopentylene that can be substituted and

R »1 ^ι 0 ^{υ is} hydrogen or Cι _-4 alkyl.

4. Monomer of the general formula (II) as defined in claim 3.

5. Monomer precursors of the general formula (III)

in the

R ¹ to R ⁶ , Z and B ^"have the meaning given in claim 1 or 2 and

B is a halogen atom.

6. A process for the preparation of monomer precursors of the general formula (III) according to claim 5, wherein ZN (Cι _-2 o-alkyl) means by reacting compounds of the general formula (IV)

R ⁱ R ² N _L 2 _Q alkyl) (IV)

with compounds of the general formula B- (Cι- ₃ o-alkylene) -B.

7. Process for the preparation of monomers of the general formula (II)

Claim 3, wherein ZN (Cι _-2 o-alkyl) means by reacting compounds of the general formula (IV)

R1 R ² NC.,. ₂₀ alkyl) (IV)

with compounds of the general formula (V)

BXY-CR ¹⁰ = CH ₂ (V)

where B is a halogen atom.

8. Process for the preparation of monomers of the general formula (II)

Claim 4, wherein ZN (Cι _-20 alkyl) and X (Cι _-2 o-alkylene) -N ⁺ R ⁷ R ⁸ - (Cι.ι ₀ alkylene) B ^" ,

by reacting compounds of the general formula (IV)

NR ³ R ⁴

R ¹ R2 NP = N (C _1.20 alkyl) (IV)

NR ⁵ R ⁶

with compounds of the general formula B- (Cι _-20 alkylene) -B, followed by

Reaction with a compound of the general formula (VI)

R ⁸ R ⁷ N- (-CC-alkylene) -Y-CR ¹⁰ = CH ₂ (VI)

where B is a halogen atom.

9. Use of polymers according to one of claims 1 to 3 as catalysts,

Adsorber materials, ion exchangers, membranes, formulation auxiliaries, detergents, crop protection agents, drilling fluids, hair conditioners, film formers, preservatives, food additives or textile auxiliaries.

10. Use of polymers according to one of claims 1 to 3 for the production of pharmaceutical compositions.

11. Pharmaceutical composition containing polymers according to one of claims 1 to 3 in addition to conventional carriers, auxiliaries and / or additives.

12. Use of polymers according to one of claims 1 to 3 for the preparation of pharmaceutical compositions for the treatment of hypercholesterolemia.