FI58787B - FREQUENCY REFRIGERATION OF A LINE OF POLY-BASED POLYMER - Google Patents

Description

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Patent · och ragiatarstyralaan 'Arneiom utltgd och utl. * Krift «n pubik« nd 31.12.80 (32) (33) (31) Requested «uoiit ·» * - B «| ird priorities 11.06.73 19.0U.7U usa ( us) 3690U2, U62263 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (72) Nathaniel Grier, Englewood, New Jersey, Arthur Franklin Wagner,

Princeton, New Jersey, USA (7U) Oy Roister Ab (5U) Method for the production of a linear, unbranched, non-crosslinked polymer - Förfarande för framstallning av linjär, oförgrenad, icke-tvärbunden polymer

The present invention relates to a process for the preparation of a linear, unbranched, non-crosslinked polymer having repeating monomer units of formula f "V.

R, X ~ R „X ~

I I

--N - Q N —- Q— (I ·)

I I

CH-CH, where X is a halide, sulphate or sulphonate or z, which is another monovalent or polyvalent counter anion, Q is ethylene or trimethylene, and '? - represents a bond to several groups 2 58787 R1X ~ ^ 2X ~ -N —-Q-- or -N —-Q-

I I

CH 3 CH 2 wherein X and Q are as defined above, and R 1 and are the same or different and are lower alkyl; monohydroxy-substituted lower alkyl; carboxy-lower-alkyl; C ^ -C ^ alkenyl; C ^ -C ^ alkynyl; benzyl; lower-alkyl-thio-lower alkyl; ammonio-lower alkyl, lower alkyl-ammonio-lower alkyl; di-lower alkyl-ammonio-lower alkyl; a tri-lower alkyl-ammonio-lower alkyl; provided that only one of R 1 and R 2 may be lower alkyl when the ammonio cation is the counter cation of anion X.

These polymers are preferably used as antibacterial agents, flocculants, electrically conductive agents in paper coating, antistatic agents, chelating agents and bile acid sequestrants, as well as for similar applications where their high charge to weight ratio and the presence of nitrogen can be advantageously used.

In particular, they are useful as non-absorbable, gastrointestinal bile acid sequestrants, as such binding is known to lower blood cholesterol. All available evidence indicates that higher-than-normal blood cholesterol levels in humans (especially so-called type II Frederickson patients) are associated with atherosclerosis and other cholesterolemia symptoms. Arterial embrittlement disease is associated with the effects of circulatory blockages leading to coronary, cerebrovascular and other vascular diseases and is the leading cause of death in several countries.

To reduce arterial embrittlement disease, various control measures have been applied to elevated blood cholesterol levels, including a restricted specific diet, inhibition of cholesterol synthesis, acceleration of metabolism, inhibition of intestinal absorption, and binding of bile acids in the intestine. The latter is very popular because it does not require a surgical procedure or sudden and severe changes in dietary habits 3,58787 or lifestyle habits.

However, why the binding of bile acid in the intestine to lower blood cholesterol is not known; it is believed that a change in the nutritional mechanism affects the oxidation of cholesterol, which lowers blood cholesterol with the intention of restoring bile acid levels. Regardless of the uncertainty of the mechanism, the technique is fully accepted. Instead, there is a lack of a suitable, effective, non-toxic and easily tolerated binder.

Various bile acid sequestrants have been used in the past. These include iron salts which form insoluble precipitates with bile acids, organic bases which act in the same manner, and polymers which may form a salt. However, absorbable precipitants can cause acute and chronic toxicity. The use of non-absorbable polymers to avoid such toxicity problems has not provided a suitable alternative, as the average effective daily dose of such polymers for an adult has so far been up to 40 g. The mass of such a dose, especially when a water-insoluble crosslinked resin is used, can cause partial intestinal obstruction and an unpleasant heavy feeling. In addition, the smell and taste of such a large dose is difficult to disguise.

Gel-like compositions with fewer crosslinks and branch bonds, which will be defined later, swell considerably in water and, although free from wear irritation, cause pressure disturbances.

To date, the water-soluble polymers proposed as bile acid sequestrants provide very high viscosities in solution and have a significant astringent effect in the oral cavity. In addition, their dose is high in mass and they require an equal amount of water by weight. The biggest drawback, however, is that they break down in the gut.

Thus, they have had only a limited benefit, although the disease associated with hypercholesterol is very common and continues to grow alarmingly.

Several notions have been put forward to date about the inability of the proposed resins when used in cases of excess cholesterol to reconcile bile acid binding and chloride binding. According to one embodiment, the smaller inorganic anions 4,58787 can easily reach the binding sites. Thus, in order to obtain a more efficient resin, a greater separation of the bonding sites for high molecular weight acids should be provided. According to another view, the resins must be more lipoid-like to penetrate in vivo to micelle formations with fatty bile acids, with the result that reduced water solubility of the resins would be advantageous.

Unfortunately, these proposals have had little improvement in the use of polymers to treat excess cholesterol.

It has now been found that the new polymers described later are exceptionally effective in binding bile acids in the gastrointestinal tract and lowering blood cholesterol levels.

By the phrase "salt-forming nitrogen" is meant a nitrogen atom, e.g., an imino group or a substituted imino group, which is sufficiently basic to be present as either quaternary or acid addition salts or to form such with acids.

The phrase "linear polymer backbone" means a polymer having only acyclic groups, i. methylene or trimethylene groups linking nitrogen atoms in a simple continuous chain.

The term "unbranched" means a polymer that does not have repeating monomer units extending out of the polymer backbone, and the phrase "crosslinked" is used in the conventional sense to denote the bonding of two backbones.

The fact that the polymers of the invention are linear and unbranched is of paramount importance for the advantage provided by the invention. When some papers, e.g., U.S. Pat. No. 3,308,020, describe monomer units similar to the present monomer units, it should be remembered that these previously known polymers are highly branched. Furthermore, if known, Gibbs et al., Journal of the American Chemical Society, 57 (1935), 1137, and Noguchi et al., Macromolecules, 5 (1972), 261 are correct in stating that attempts to polymerize dimethylaminoethylene halides yield only cyclic dimers, which is also suitable. together with the definitions given in German patents DE 1,131,694 and DE 1,125,396.

The polymers prepared according to the invention can be represented by formula I.

OF

58787

fr · :). ML

Ti nnn / ^ - Q sihisi * n —— q τ i

l I | C

CH3 CH3 / wherein R1, R2, Q, Z and are as defined above or Z corresponds to the symbol X in formula (I1); n is an integer with an average molecular weight of 300-50,000.

and T2 are polymer end groups and T1 is

Ml Ml.

R is -N-Q and T is -N-Q-OR

I I

CH 3 CH 3 2 or a dihydro-1,3-oxazinium or Δ-oxazolinium complex with the anion of the initiator, wherein R 1, Z, m and Q are as defined above, * R 1 is the same as or CH 2, and R is a segment derived from the solvent in which the ring opening was effected, e.g. hydrogen when using water treatment or alkyl when using alcohol treatment. The exact nature or identity of T is, in fact, irrelevant to the present invention or the utility of the polymers described.

The word "lower" as used above denotes a group having 1 to 4 carbon atoms, and as regards alkyl groups, they may be straight-chain.

When m above is 1, Q is trimethylene and R 1, R 2, R 3 and R 2 are lower alkyl, the compounds described are known. However, the method for their preparation is new.

In this specification, Z represents an anion corresponding to a charge in a quaternized or protonated imino group and thus may be a monovalent anion. It is to be understood, however, that Z also includes polyvalent anions in which one anion may correspond to a charge in more than one charged imino group. Thus Z may be an anion of inorganic acids as well as an anion of organic acids such as halide, e.g. chloride, bromide or iodide, sulphate, bisulphate, phosphate, acetate, ascorbate, citrate, hydroxytitrate, carbonate, bicarbonate, nicotinate, glycine naate, taurinate, salicylate, and may be another anion derived from physiologically non-toxic acids, especially salts of physiologically active acids, such as salts derived from chlorofibrate and halogen, e.g. 2- (p-chlorophenoxy) -2-methylpropionic and 3-trifluoromethylphenoxy- (4-chlorophenyl) acetic acids. When using such anions of physiologically active compounds to neutralize quaternized or protonated imino groups, it is obvious that only a part of the charged imino groups can thus be neutralized. The amount of anion derived from the physiologically active compound is in such a proportion that the amount administered with the polymer dose is in the desired range of the physiologically active compound.

The process of the invention for preparing the polymers described above is characterized by the following steps: (1) 2R'-N-oxazoline or 2-R'-5,6-dihydro-4H-1,3-oxazine, wherein R 'is hydrogen, lower alkyl , phenyl, naphthyl or naphthylethyl, is polymerized in a manner known per se to obtain a polymer having repeating monomer units of the formula s \ L (vj,) I · k / wherein R 'and Q are as defined above; (2A) a polymer corresponding to formula VI 'is hydrolyzed to remove an acyl group with an acid or a base to give a polymer having repeating monomer units of formula fs _ (rl k H} wherein m is 0 or 1 and Q and Z are as defined above, or (2B ) a polymer of formula VI 'is reduced with diborane to a polymer having repeating monomer units with pn'; formula 7 58787 («Λ --N-Lq-- (VIII'l CH0 I 2 R '^ y where m, Q, Z and R 'is as defined above, or (2C) a polymer of formula VI' wherein R 'is hydrogen is mixed with at least one equivalent of both formaldehyde and formic acid and the resulting mixture is heated at 30-100 ° C for up to 100 hours to obtain a polymer having repeating monomer units of the formula

Or) \ + / m {ix ·> CH. » wherein m, Q and Z are as defined above; (3) methylating a polymer of formula VII 'obtained in step (2A) wherein m is 0 with at least one equivalent of both formaldehyde and formic acid and heating the resulting mixture at 30-100 ° C for up to 100 hours to obtain a polymer having repeating monomer units having formula IX 'shown in step (2C); (4). to prepare a polymer having repeating monomer units of the formula "\ (r :). (";).

--N ——- Q N - Q (X ') ch3 ch3 k) where m, Q and Z have the same meaning as above and denote a bond to several groups 8 58787 (γ;) (γ;).

_2NJv4n_Q_ or -N-Q - CH3 CH3 wherein Z, Q and m are as defined above, the polymer of formula XII 'where m = 0 is reacted with at least 1.5 equivalents of CH2X where X is a halide or a sulfonate or sulphate, in an inert solvent at a temperature of 30 to 100 ° C, to obtain a polymer of formula X 'where m = 1 and Z is X, and if desired to obtain a polymer of formula X' where m = 0, a polymer of formula X 'is treated , where m = 1, with exactly one equivalent of base; (5) a polymer of formula VIII 'obtained in step (2B), a polymer of formula IX' obtained from step (2C) or (3) or a polymer of formula X 'obtained from step (4), optionally after a polymer wherein m = 1 , is converted to a polymer where m = 0 is quaternized to incorporate the substituents defined in formula 1 'and R 2 into the polymer so that a polymer comprising repeating mononicer units of formula

s S

- N -Q —N - Q--

C »3 CH

/ wherein Q is as defined above and represents a bond of a number of size groups - N - Q - -NQ - or ch3 ch3 .VV, ·· 9 58787 is reacted (a) when R 1 and are the same as at least one equivalent of R X, wherein R and R 1 and X are a halide, sulfonate or sulfate; ib) when R 1 and R 2 are different, the polymer is first reacted with 5-95% of one equivalent of R 1 X and then reacted with at least one equivalent of R 2 X; (6) and that, if desired, anion X is converted to anion Z by means of an anion exchange resin.

Thus, the polymers are obtained by successive steps 2 in which the first polymerizes E-oxazoline of the formula: CH 2 Cl 2 -R or IV or

CH2-N

5,6-dihydro-4H-1,3-oxazine of the formula: wherein R 'is hydrogen, lower alkyl, phenyl, naphthyl or naphthylmethyl. Preferably R 'is hydrogen.

Step 1 - Polymerization 2 The polymerization of 2-R'-oxazolines is known and is described in Polymer Journal, 3 (1972), 35. However, it has been found that more reliable polymerization is obtained by using trifluoromethylsulfonic acid instead of the initiators described in that publication. In general, 0.005 to 0.1 mole of trifluoro-2-methylsulfonic acid per mole of 2-R'- & oxazoline is used, with 0.01 mole of trifluoromethylsulfonic acid per mole of 2-R'-E-oxazoline being preferred.

The polymerization of 2-R'-5,6-dihydro-4H-1,3-oxazine is also known and is described in Macromolecules, 6 (1973), 495.

58787 10

Of the known initiators, methyl iodide is the preferred initiator.

2

In general, the polymerization of 2-R'-β-oxazolines and 2-R'-5,6-dihydro-4H-1,3-oxazines is carried out in a closed system under an inert atmosphere such as nitrogen at a pressure of 1-100 atm. and heating at 30-120 ° C for 1-12 hours. By inert solvent is meant herein and elsewhere in the specification a solvent which does not react under these conditions with the reaction components and the products obtained, with dimethylformamide being the preferred solvent.

After the reaction is complete, as can be seen by the disappearance of the -C = N double bond, the polymerization reaction mixture, which now comprises polymer VI

'\ A-N-Q - -N-Q --- T-.

Il J VI

I M Jn c = o c = o

I I

R 'R' where R ', Q and n have the same meaning as above and are R' 3 | -N-n c = o: ♦; .Y-

• γ I * or JL I

N-Q-OR

R '0 R

wherein Y is an anion derived from an initiator, A is hydrogen or an initiator moiety such as methyl derived from methyl iodide, and Q and R * are as defined above, preferably treated as an anhydrous solvent with an alcohol or ether such as methanol or ethyl ether. After filtration and washing with an anhydrous solvent, the polymer is recovered and dried.

After separation, the polymer is subjected to one of three alternative second stage treatments: hydrolysis, direct reduction, or reductive methylation.

Step 2A - Hydrolysis

Hydrolysis by cleavage of the acyl group is performed by reacting polymer VI with an aqueous acid such as an aqueous mineral acid, e.g. hydrochloric acid, or a base such as an alkali metal hydroxide to give polymer VII.

11 58787 <\ (HZ ^ (ΗΖΛ '+ / m \ I + / m \ l + / m *

A-N-Q - N-Q - N-Q-OR VII

H H H

n 1) * wherein A, i, Q, Z, R and n are as defined above and Z is preferably a halide.

The alkaline hydrolysis is carried out by mixing the polymer with a saturated aqueous solution of a base, suitably alkali hydroxide and preferably sodium hydroxide, varying from 0.1N. Acid hydrolysis is performed using 1-2N mineral acid, e.g. HCl or I 2 SO 4.

The hydrolysis is performed with stirring and heating for at least 3-30 hours. Preferably, in order to achieve complete hydrolysis while sacrificing some molecular weight, the hydrolysis is performed in a closed vessel at a temperature of 40-180 ° C. The amount of hydrolysis solution is not critical if mixing is good and at least twice the theoretical amount of alkali or acid is used to effect hydrolysis.

Base hydrolysis gives polymer VII, where m is 0, and acid hydrolysis or subsequent treatment of the base-hydrolyzed polymer with acid gives polymer VII, where m is 1,

Step 2B - Direct reduction

Polymer VI is reduced directly to polymer VIII by reduction of the acyl group.

12,58787

S "N

f HZ “\ (HZ ~ \ / HZ_ \ \ + / m M \ Jm *

A-N-Q - Q N - Q N-OR

CH. CH_ CH0

I. I I

R R 'R' n

S S

ie where A, Z, Q, R ', R, Z, m and n have the same meaning as above.

Preferably, the polymer is dissolved in an inert solvent and slowly mixed with at least a molar equivalent of a chemical reducing agent such as diborane, which is also dissolved in an inert solvent. Preferred solvents are tetrahydrofuran and mixtures thereof with ethylene glycol dimethyl ether. After the addition, the reaction mixture is heated to reflux for 1-12 hours, cooled and acidified. Other reducing agents that can be used in place of diborane include aluminum hydride, lithium aluminum hydride, and lithium trimethoxyaluminum hydride.

Alternatively, the amide groups of polymer VI are converted to the iminoesters by triethyloxonium tetrafluoroborate complex in methylene chloride at 25 ° C. The iminoester units are then readily reduced to tertiary amine units using sodium borohydride in ethanol at 0-25 ° C.

Step 2C - Reductive Methylation In this process, polymer VI where R 'is hydrogen is heated with a mixture of more than one equivalent of both formaldehyde and formic acid, then treated with an aqueous acid solution and concentrated to dryness under reduced pressure to give polymer IX.

f N.

(HZ ~ \ (HZ ~ \ (ΗΖ ~ λ \ l + / m \ | + / m \ | + / m *

Rc-N-Q - N-Q - N-Q-OR IX

I I I

CH3 ch3 CH3 n \ / 13 58787 ie where R1, Q, Z, R, m and n have the same meaning as above.

The polymer to be methylated reductively is added to a mixture of 97-100% formic acid and preferably 38% aqueous formaldehyde, and the reaction mixture is heated to 30-100 ° C for 20-100 hours. Although higher reaction temperatures can be used, the increased rate of thermal decomposition of formic acid and the risk of polymer decomposition make the use of higher temperatures less advantageous. The mixture is then treated with an aqueous solution of a mineral acid, preferably hydrochloric acid, and the excess formic acid, formaldehyde and mineral acid are removed by concentration under reduced pressure.

Step 3 - Direct methylation

Polymer VII, where m is 0, is methylated directly by heating the polymer in a mixture of more than 1 equivalent of both formaldehyde and formic acid under the conditions described in Step 2C to give polymer IX, wherein R,., Q, Z, R, m and n are as defined above.

Step 4 - Addition of CH 2 substituents to polymer VII

To obtain polymers of formula X, polymer VII, where m is 0, is treated with an excess of 1.5 to 8 equivalents and preferably 4 equivalents of alkylating agent CH 2 X in an inert solvent at a temperature of 30 to 100 ° C. The reaction is carried out by dissolving the polymer in an inert solvent such as an alcohol, ketone or dimethylformamide. Preferred solvents are methanol, acetone and dimethylformamide

and preferred temperatures are 50-75 ° C. This gives the formula X

*, wherein A, Q, Z, R and n are as defined above and m is 1 and Z is X. Treatment of polymer X with exactly one equivalent of base gives polymer X, where m is 0.

14 58787 * ^ / HZ] (HZ] f HZ "] fHZ"] VJ + ^ \ | + / m V. | + / m V | + / m

A — N— Q - N - Q / UXN— Q / t'VZlN— Q-OR * X

I I I I

ch3 ch3 ch3 ch3 l in

Step $ - Quaternization - ΒΊ, addition of Rg

Polymer VIII from step 2B, polymer IX from step 2C or step 3, or polymer X from step U is usually obtained in the form of an acid addition salt (m »1) and converted to the free base (m * 0) by treatment with an equivalent amount of base. At this stage, it is preferred, although not necessary, to remove residual inorganic salts by ultrafiltration. This has the advantage that any other undesired low molecular weight material can also be removed at the same time. The aqueous polymer solution is then concentrated under reduced pressure and the product is dried before a quaternization reaction to give a polymer of formula I. The quaternization reaction is performed in an inert solvent such as an alcohol, ketone or dimethylformamide. Methanol, acetone and dimethylformamide are preferred solvents. Quaternizing agents are usually halide-containing compounds, preferably bromine compounds; other alkylating agents such as toluenesulfonate esters or trichloromethylsulfonate esters may also be used. When R 1 and denote the same, a moderate excess of alkylating agent R X is used; when and denote different groups, the polymer is first treated with a limited amount (5 to 95% equivalence array) of R 2. After the reaction is complete, the product is treated with an excess of reagent RgX. When the alkylation reaction capabilities of the reagent R 1 X and R 9 are the same, the reaction can be carried out in a mixture of R 2 and R 8X in one step. R 1 X and R 8 X may be simple alkyl halides or may have other functional groups that do not interfere with the quaternization reaction. Simple but not exhaustive list of acceptable kvaternoimisaineista comprising haloalkyl-acid ester, halogeenialkyylihappoamidit, haloketones, fluorialkyylitrikloo-rimetyylieulfonaatit, alkyylihalogeenihydridit, aralkyl, ammonioal-halides, lower-alkyl-substituted ammonio-alkyl halides, alkok-sialkyylihalogenidit, alkyylitioalkyylihalogenidit, allylic and Pro-Par gyylibromo din.

The reaction is usually carried out by heating the polymer solution and the alkylating agent in methanol, acetone or dimethylformamide at 35-100 ° C for 3-16 hours. When a particularly reactive alkylating agent is used, the reaction temperature is 50 ° C. The product is usually isolated directly by filtration, but in some cases the reaction mixture is diluted with several volumes of ether before filtration. Usually the product is partially dried, ground to a powder and then dried under reduced pressure at 25-6 ° C.

Step 6 - Ion exchange

The anions in polymer I are generally halides due to the prior art technique. Polymers in which the anion Z is other than a halide can be obtained by dissolving the polymer I having a halide anion in water, alcohol or mixtures thereof in any ratio and passing the solution through an anion exchange resin of either a synthetic or zeolite type, whereby the halide ion changes and is replaced by Z: 11a. The anion exchange method can be direct, i. the halide ion is exchanged for Z, or first the halide ion is converted to OH and then, using ion exchange or neutralization, the OH is converted to Z.

In addition, a chemical exchange technique can be used when the metal halide precipitate is less soluble than the metal salt MZ. The precipitated metal halide can then be filtered from the soluble polymer I.

In a simple example illustrating the latter technique, a solution of polymer I containing a bromide counterion is treated with an excess of freshly doped silver chloride. After the halide anion exchange has taken place, the mixture of silver chloride and silver bromide is removed by filtration, leaving a solution of polymer I containing the chloride counterion. Alternatively, polymer 1, wherein Z is sulfate, can be treated with solutions of water-soluble salts of calcium or barium. In this case, the sulphate can be replaced by nitrate and the barium sulphate precipitate removed.

Example I

poly / Tformimino) ethylene /

A solution of N, N-oxazoline and 870 mg of freshly distilled boron trifluoride etherate in 175 ml of purified dimethylformamide is placed in a glass-lined pressure reactor and the system is purged with nitrogen. The mixture is heated at 80 ° C for 5 hours and then diluted with methanol and filtered to give 30 g of poly (Formimino) ethylene 7 polymer. Using a reaction time of 5 hours at 80 ° C and a boron trifluoride etherate catalyst in a ratio of 0.01 molar to oxazoline, a solid polymer of 13.2-68% is obtained.

58787 16

Example II Poly (N-formimino) ethylene

A solution of 217 g (3.0b moles) of A.-oxazoline and U.6 g (0.03 moles) of trifluoromethylsulfonic acid in 800 ml of purified dimethylformamide in a sealed tube and under a nitrogen atmosphere is heated at 90 ° C and stirred for 5 hours. . After cooling, the mixture is diluted with 1200 ml of anhydrous methanol and the product is filtered off. The product is washed with methanol and then with ether and dried under reduced pressure. 150 g of poly (E (formimino) ethylene) are obtained.

Example III Poly (N-acetimino) ethylene 2 g of 2-methyl-γ-oxazoline are placed in a Carius incinerator with two drops of boron trifluoride etherate (U8%). The tubes are purged well with nitrogen, sealed with a flame and placed in an oven at 160 ° C for 20 hours. The poly- (acetimino) ethylene ^ 7 polymer is a glassy, almost colorless resin with a melting range of 155-175 ° C. The polymer is readily soluble in methylene chloride.

Example IV

Poly- / Ibutyrimino) ethylene In this example, the N-acetyleneimine is polymerized using a simple catalyst system which also provides rearrangement to form the intermediate oxazoline.

10 ml of N-butyrylethyleneimine and 0.05 ml of BF 3 EtOAc in an evacuated tube are heated at 60 ° C for 1+ hours. The material obtained is dissolved in 100 ml of CHCl3, precipitated by adding petroleum ether, redissolved in CHCl3 and reprecipitated with petroleum ether. The precipitate is dried to give 6.3 g of poly - ((butyrimino) ethylene) having a modified viscosity of 0.16 in 1N benzene solution and a melting point of 150 ° C.

In an analogous manner but using: N-benzoylethyleneimine, 2-'isopropyl-2'-oxazoline, 2-cyclohexyl-N'-oxazoline. 2-Naphthyl-N, N-oxazoline and 2-p-tolyl-N, N-oxazoline are obtained, respectively, O-ol / T-benzoylimino. poly - [(isobutyrimino) ethylene] poly (4-cyclohexanoylimino) ethylene] poly - [(Naphthoylamino) ethylene? poly- (toluoylamino) ethylene, 7 · 58787

Example V

Poly- (benzoylamino) ethylene, /

m, O

2-Phenyl-2-oxazoline (1.1322 g, 7.60 x 10 moles) is placed in a Carius incinerator along with 7.69 x 10 moles of boron trifluoride in the form of a dimethoxyethane solution. After the air is removed by purging with nitrogen and the tube is sealed, it is then heated at 150 ° C for 2 hours. 1 g of the pale yellow glassy polymer obtained is ground to a fine powder and dissolved in 25 ml of methylene chloride. This solution is added to 75 ml of n-hexane, which is stirred vigorously to give a thick white precipitate. The material is filtered and remixed twice in the same manner to give a fine white powder. Pure poly (benzoylimino) ethylene polymer is 80% and has a molecular weight of 7,500.

Example VI

Copolymerization of equimolar mixtures of 2-phenyl-2-oxazololine and other 2-substituted 2-oxazolines

Equimolar monomer concentrations of 2-phenyl-2-oxazoline and 2-benzyl-2-oxazoline or 2-methyl-2-oxazoline or 2-isopropyl-2-oxazoline, respectively, are heated at concentrations of 1.5 moles / liter in N, N-dimethylacetamide. At about 2 hours using 2-phenyl-2-oxazolinium perchlorate as initiator. The resulting poly (acylimino) ethylene copolymers vary widely in terms of their N-acyl group concentrations. 2-phenyl-2-oxazoline results in an N-benzoyl derivative; 2-Benzyl-2-oxazoline forms an N-phenylacetyl derivative and the 2-methyl analog forms an N-acetyl derivative. The mixed composition of the copolymers is affected by the relative reaction rates of the different monomers. Since the resulting polymers can be used to prepare linear poly (ethyleneimines), compositions containing different acyl groups are irrelevant because the acyl groups are removed during hydrolysis. They can, of course, be reduced directly as described in the following example.

Example VII Poly- (iminoethylene)

^ Tasyyli poly-imino) ethylene? the hydrolysis is performed using an acid or a base.

(a) In illustrative base hydrolysis, a solution of 3 g of poly- (Formimino) -ethylene? and 3 g of sodium hydroxide in 35 ml of water, heated with stirring at 98 ° C for 3 hours. The solution is cooled to room temperature and the precipitated white solid is filtered off, washed well with water and dried in vacuo to give 1.6 g of poly (iminoethylene).

(b) 1.29 g of poly (Tasetimino) ethylene is added to 50 ml of about 1N sodium hydroxide. The polymer is insoluble as a base at room temperature, however, after heating under reflux for 26 hours, the reaction mixture becomes homogeneous. Upon cooling to room temperature, the reaction mixture gels to a white mass. Hydrolysis occurs at approximately 65 5? Non-acylated poly (iminoethylene) is purified by re-blending, i. the solution is acidified, the partially acetylated poly (iminoethylene) is filtered off and the filtrate is neutralized.

(c) 1 g of poly (acetimino) ethylene (1) is dissolved in 50 ml of 1N sulfuric acid. A homogeneous mixture is obtained, which is heated under reflux for 3.5 hours, at which time the smell of acetic acid appears. The portion is then titrated with 1N sodium hydroxide, which indicates that the hydrolysis has taken place at 27 pounds. After heating under reflux for 21 hours, hydrolysis has taken place at 38 ° C.

In general, substantially complete hydrolysis is obtained by performing the hydrolysis as described above but in a closed tube at 120 ° C or higher.

Poly (tasylimino) ethylene is reduced to the N-alkyl and N-aralkyl derivatives without prior hydrolysis to the free base. Diborane is used as the reducing agent, as in the following example. Lithium aluminum hydride and lithium trimethoxyaluminum hydride can also be used.

Example VIII

Poly - {(ethylimino) ethylene} 1

To a solution of 200 ml (33 mmol) of 1.67 M diborane in tetrahydrofuran in a 500 ml flask equipped with a reflux condenser, a dropping funnel, a magnetic stir bar and maintained under a nitrogen atmosphere is added 17 g (200 mmol / monomer unit). ) poly - / (acetimino) ethylene / in 100 ml of tetrahydrofuran over 15 minutes. The temperature is maintained at about 0 ° C during the addition. The reaction mixture is then heated to reflux for 6 hours. The mixture is allowed to cool to room temperature and 50 ml of 6N hydrochloric acid are slowly added via addition funnel. Tetrahydrofuran is removed by distillation at atmospheric pressure as hydrogen evolves (15.5 L, 0.6 moles) in the hydrolysis of the amine-borane complex. Sodium hydroxide is added to poly (ethylimino) ethylene. to precipitate.

In an analogous manner, the polymers obtained in Example IV are reacted to give, respectively: poly - ((benzylimino) ethylene) and poly (E (isobutyl-19,58787-imino) ethylene) "; poly - (* (naphthylmethylimino)); ethylene ?.

Example IX

Poly (iminoethylene) ethylene hydrochloride 2 5/10 g of poly (iminoethylene) are slowly added to 12 g of 90% formic acid and 5.5 g of 38% formaldehyde. After heating at 100 ° C for 72 hours, the mixture is cooled and 5 to 5 ml of concentrated HCl are added. The mixture is concentrated to dryness under reduced pressure to give 5 g of poly (methylimino) ethylene hydrochloride di a).

Example X

Poly - [(dimethylimino) ethylene chloride] 500 mg (5.1 millimoles) of poly (methylimino) ethylene hydrochloride. is dissolved in 50 ml of methanol containing 291 mg (5 .mu.mol) of sodium methoxide. The solution is cooled in an acetone-dry ice bath and 10 g of methyl chloride are concentrated into solution. The mixture is heated in a sealed tube at 80 ° C for 5 hours. The mixture is then concentrated to dryness under reduced pressure and the product is taken up in 3 ml of anhydrous methanol and filtered and the solution is concentrated to dryness. The product is redissolved in methanol, filtered and then concentrated to dryness several times. The filtrate is concentrated under reduced pressure to give 100 mg of poly (dimethylimino) ethylene chloride.

Example XI

Poly / Tdimetyyli-iminoJetyleeni bromide?

A solution of 860 mg (20 milliequivalents) of poly (iminoethylene) in 30 ml of methanol is treated with 9 to 5 g (100 millimoles) of methyl bromide at 50 ° C for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure. The residue is treated with 1.08 g (20 mmol) of sodium methoxide in 10 ml of methanol and concentrated to dryness. The residue is taken up in 30 ml of anhydrous methanol and treated with 9.5 g (100 mmol) of methyl bromide; the solution is heated at 50 ° C for 3 hours. After concentration, the product is taken up in water and the solution is ultrafiltered using a VM 2 Diaflo filter. The filtrate is concentrated under reduced pressure to give 2.8 g of poly (dimethylimino) ethylene bromide.

Example XII

Poly - [(dimethylimino) ethylene methosulfate] 0.5 g of poly (methylimino) ethylene hydrochloride is dissolved in 50 ml of methanol containing 0.29 g of sodium methoxide. The solution is concentrated to a volume of about 20 ml and 0.7 g of dimethyl sulfate is added. The solution is then heated for 6 hours at 50 ° C and the product is precipitated by pouring the solution into a large volume of acetone or evaporating off the methanol and then washing with acetone.

The product is dried at ambient temperature under reduced pressure.

Example XIII

Poly (2-hydroxyethyl) methylimino) ethylene-chloro dj)

The procedure of Example X is followed, but using 15.3 g of ethylene chloride instead of 10 g of methyl chloride. The mixture is heated at 80 ° C for 5 ° T hours and then freed of solvents and excess reagents by evaporation under reduced pressure. The residue is poly ({(2-hydroxyethyl) methylimino) ethylene chloride).

In an analogous manner, using an equivalent amount of propylene chlorohydrin or sec-propylene chlorohydrin instead of ethylene chlorohydrin gives poly - ((1-methyl-2-hydroxyethyl) methylimino) ethylene chloride) and poly- (2-hydroxypropyl) methylimino) ethylene chloride.

Example XIV

Poly - [(2-hydroxyethylimino) ethylene] 0.5 g of the poly (iminoethylene) of Example VII is dissolved in 50 ml of methanol and heated with 0.35 g of ethylene oxide in a sealed tube. . · · »Wash at 60 C for 3 hours. The solvent and excess epoxide are removed by evaporation under reduced pressure. The residue is poly - [(2-hydroxyethylimino) ethylene].

Example XV

Poly ((2-hydroxybutyl) -2-hydroxyethylimino) ethylene chromium dQ

The poly - [(2-hydroxyethylimino) ethylene] obtained from the previous example is heated in 50 ml of acetone with 20 g of 2-hydroxyhutyl bromide at 80-90 ° C in a sealed tube for 6-8 hours.

The product is recovered by removing the solvent and excess reagent under reduced pressure. The residue is poly - ((2-hydroxybutyl) -2-hydroxyethylimino) ethylene bromide.

Example XVI

Our dust style -imi no) ethylene hydrochloride di)

A mixture of 25 g of poly (formiminoethylene), 50 g of 97-100 3S formic acid and 118 g of 38 5t formaldehyde (formalin) is heated at 100 ° C for 60 hours. The reaction mixture is cooled, 210 ml of concentrated hydrochloric acid are added and the mixture is concentrated to dryness under reduced pressure at 50 ° C. After washing the product 21,58787 with methanol, ether and drying, 3.6 g of poly - ((ethylethyl) ethylene hydrochloride) are obtained.

Example XVII

Poly-J (methylimino) ethyl.7

A solution containing 0.325 moles of sodium hydroxide is prepared by dissolving 17.55 g of sodium methoxide in 100 ml of water. To this solution is added 28.6 g (0.31 moles) of poly- (methylimino) ethylene hydrochloride 5 'and water is added to the solution to a total volume of 500 ml. The salts and then any product with a molecular weight below 1000 are then removed from the solution using an Amicon filter cell equipped with a UM2 Diaflo ultrafilter. The solution is then concentrated under reduced pressure at 50 ° C to give 16 g of poly - ((imino) ethylene).

Example XVIII

Poly (N-dimethylimino) ethylene bromide7 A solution of 21.7 g (0.38 moles) of poly- (methylimino) ethylene? In 130 ml of anhydrous methanol, cool and 36 g (3.8 moles) of concentrated methyl bromide are added. The mixture is heated in a glass-lined pressure reactor at 50 ° C for 5 hours. After the mixture is cooled, the product is filtered off, washed with ether and dried under reduced pressure to give 58 g of poly ((dimethylimino) ethylene bromide).

Example XIX

Poly -! / Dimethylimino) ethylene chloride)

A solution of 58 g of poly- (dimethylimino) ethylene bromide * 7 (0.38 mol) in 3 liters of water is passed slowly (10 ml / min) through a column of 770 ml packed with 200-1 * 00 mesh. in AG1-X8 with quaternary ammonium chloride resin (1078 milliequivalents of Cl). After recovering U200 ml of the flow-through, it is concentrated under reduced pressure at 50-55 [deg.] C. and dried to give 37 g of poly (N- (dimethylimino) ethylene chloride).

Example XX

Preparation of poly (dimethylimino) ethylene ascorbate (5.0 g of poly (dimethylimino) ethylene chloride) is dissolved in 75 ml of distilled water and passed through a column with an exchange capacity of 100 g (0.5 moles of Cl). ) a polystyrene resin having a benzene ring substituted with U-methoxytrimethylammonium hydroxide (Bio Rad AG 1 x 8). Collect a 6 column volume of eluate (1 x 50 ml) containing poly (N-dimethyliminoethylene ethylene hydroxide), concentrate to a volume of 150 ml, cool to 15 ° C and neutralize with 8.8 g (0.05 ml). moles) of ascorbic acid USP The clear neutralized solution is cooled and lyophilized to give a white solid which can be easily ground.

Other polymers of the invention may be converted to the ascorbate salt or, using other acids containing physiologically acceptable anions instead of ascorbic acid, other salts described previously may be obtained.

Example XXI

5,6-dihydro-l H-l, 3-okaatsiini

A mixture of 9 ** g (1.13 moles) of t-butyl isonitrile, 85 g (1.13 moles) of freshly distilled 3 "aminopropanol and 7.1 U (0.055 moles) of silver cyanide is stirred at 90 ° C. in nitrogen gas for 16 hours The product is separated from the reaction mixture by distillation at a pressure of 1 * 5 mm and purified by fractionation again, usually by two fractionations to give pure product, thus giving 1 * g of pure 5,6-dihydro-1 + H1,3-oxazine, b.p. 50 ° C / 58 mm, n ^ = 1, UU85 · The product is stored on a molecular sieve type 1 * A and under a nitrogen atmosphere.

Example XXII

Poly / fformimino) trimethylene, 7

A solution of 1 * 1 »g (0.52 moles) of 5,6-dihydro-UH-1,3-oxazine in 11 * 0 ml of purified dimethylformamide is placed in a pressure tube and 1.52 g (0.011 moles) of iodomethane are added. . The system is purged with nitrogen, sealed and heated at 80 ° C for 5 hours. The mixture is cooled and diluted with 10 volumes of ether and the product is filtered off. The product is washed with ether and dried under reduced pressure at 75 ° C to give 10 g of poly (E (formimino) trimethylene7 ', decomposing at 11-112 ° C.

Example XXIII

Poly ~ / fmetyyli-imino) trimethylene chloride hydrochloride)

A mixture of 53 g of poly (forraiminotrimethylene), 1320 g of 97 * 100 l formic acid and 308 g of 38 # formaldehyde is heated at 100 ° C for 120 hours. After cooling, 650 ml of concentrated hydrochloric acid are added and the mixture is concentrated to dryness at 50 ° C under reduced pressure. The residue is taken up in 1 * 00 ml of methanol, filtered off, washed with ether and dried under reduced pressure to give 67 g of poly- (methylimino) trimethylene hydrochloride.

23 5 8 7 8 7

Example XXIV

. Dust-/! imino-methyl) ^ trimetyleenj

A solution of 67 g (630 milliequivalents) of poly (methylimino) trimethylene hydrochloride in $ 7,600 mL of water is treated with 39 g (0.72 moles) of sodium methoxide. In this way, a solution of sodium hydroxide with exact normality can be prepared simply. An equivalent volume of standardized sodium hydroxide solution can also be used. Salts and polymer with a molecular weight of less than 1,000 are removed from the solution using an Amicon filter cell equipped with a UM2 Diaflo ultrafilter. Finally, the solution is concentrated at 50 ° C under reduced pressure to give U5 g of poly- [methylinino] triraethylene.

Example XXV

Poly (N-dimethylimino) trimethylene bromide}

A solution of 1 g (200 milliequivalents) of poly (methylimino) trimethylene and 6 g (0.8 moles) of bromomethane in 90 ml of methanol are heated at 50 ° C in a closed reactor for 5 hours. The product is filtered off, washed with methanol and then with ether and dried under reduced pressure to give 28 g of poly (N- (dimethylimino) trimethylene bromide).

Example XXVI

Poly (dimethylimino) trimethylene chloride

A solution of 28 g (170 milliequivalents) of poly (4-dimethylimino) -timethylene bromide in 1 x 10 ml of water is slowly passed through a column containing 1000 ml of Dovex 1-X2 (Cl step) resin. (0.8 moles). After the solution has passed through, water is passed through the column until a negative silver nitrate test is obtained from the effluent. The remover is concentrated to dryness and the product is dried under reduced pressure to give 17.2 g of poly (dimethylimino) trimethylene chloride.

Example XXVII

Poly / Tmetyyli- (3-hydroxypropyl) imino) trimetyleenibromidj?

A solution of 11 * 2 mg (2 milliequivalents) of dust methylmethylimino) trimethylene? and 1.12 g (8 mmol) of 3-bromopropanol in 5 ml of purified dimethylformamide are heated at 75 ° C for 2U hours. The product is filtered off, washed with acetone and dried under reduced pressure to give 330 mg of poly (methyl (3-hydroxypropyl) imino) trimethylene broride.

24 5 8 7 8 7

Example XXVIII

Poly-methyl (3-hydroxypropyl) imino) ^ trimetyleenikloridi

A solution of 315 mg (1.5 milliequivalents) of polymethyl- (3-hydroxypropyl) imino) trimethylene bromide in 16 ml of water is slowly passed through a column of 9 ml of Dowex 1-X2 ion exchange resin (7, 2 millimoles of chloride ion), and then water is passed until the scavenger gives a negative test for chloride ion. The combined removal agent is concentrated to dryness at 50 ° C under reduced pressure to give 230 mg of poly (3-methyl- (3-hydroxypropyl) imino) trimethylene chloride.

In the previous example, a polymer of formula III is synthesized wherein R 1 and are each 3-hydroxypropyl. The following 3 examples illustrate how polymers of formula III can be synthesized when R 1 is 3-hyd 3-hydroxypropyl and R 2 is CH 2. In these examples, R 1 and R 5 form 5 to 95% and 95 to 5% of the sum of R 1 and R 2, respectively, and are distributed miscellaneously along the polymer backbone.

Example XXIX

A polymer of formula III wherein = 3-hydroxypropyl and R 9 = CH 2 (mixed distributed in a ratio of 5:95).

A solution of 62 mg (6 milliequivalents) of polymethylimino) trimethylene and 0.1 mg (300 mol) of 3-bromopropanol in 12 ml of dimethylformamide is heated at 75 ° C for 2 hours. The mixture is cooled and 2.9 g (30 mmol) of methyl bromide are added. The reaction mixture is heated at 50 ° C for 3 hours. The product is separated by concentrating the reaction mixture under reduced pressure and washed with ether and dried under reduced pressure. The exchange of the bromide counterion for the chloride ion is carried out in the usual manner using the ion exchange resin described above.

Example XXX

Polymer of formula III with R 1 and 3-hydroxypropyl and R 1 = CH 2 (mixed 50:50)

A solution of 213 mg (3 milliequivalents) of polymethylimino) trimethylene and 209 mg (1.5 mmol) of 3-bromopropanol is heated at 75 ° C for 2 h. The reaction mixture is cooled and 1.5 g of methyl bromide are added. The reaction mixture is heated at 50 ° C for 3 hours and treated as described above.

Example XXXI

A polymer of formula III wherein R 1 = 3-hydroxypropyl and? ° CH ^ (mixed in a ratio of 95: 5) b ------ ........ I · —.1

A solution of 1U2 mg (2 milliequivalents) of poly (methylimino) tri-58787 methylene and 26b mg (1.9 mmol) of 3-bromopropanol is heated at 75 ° C for 16 hours. After the mixture has cooled, 1 g of methyl bromide is added and the mixture is heated at 50 ° C for 12 hours. The reaction mixture is treated as described above.

Example XXXII

Poly (methyl- (3-methoxypropyl) imino) trimethylene chloride

A solution of 28 U mg (U milliequivalents) of poly- (methylimino) trimethylene β and 2, * + 5 g (16 mmol) of 3-methoxypropyl bromide in 15 ml of dimethylformamide is heated to 75 ° C: in 16 hours. The product is filtered off, washed with ether and dried under reduced pressure. The product is dissolved in 25 ml of water and the bromide counterion is exchanged for the chloride ion by the ion exchange described above. In this way, U50 mg of poly (3-methyl- (3-methoxypropyl) -trimethylene chloride) are obtained.

To obtain polymers of formula III in which R 1 and are 3-methoxypropyl and methyl in ratios ranging from 5:95 to 95: 5, respectively, essentially the method described above is used, in which poly (N-methyloiminotri-methylene) is reacted with a limited amount of 3 -methoxypropyl bromide followed by methyl bromide in excess.

Example XXXIII

Poly / Tmetyyli- (3-methylthiopropyl) iraino) trimetyleenikloridi /

A solution of k26 mg (6 milliequivalents) of polymethylimino) trimethylene7 and * +, 06 3-methylthiopropyl bromide in 15 ml of dimethylformamide is heated at 75 ° C for 2 hours. The product is filtered off, taken up in 30 lanes of water and passed through a column of 1 + 5 »1 Dowex 1-X2 ion exchange resin (36 millimoles of chloride ion). Concentration of the aqueous eluate gives 65 mg of polymethyl- (3-methylthiopropyl) imino) trimethylene chloride.

To obtain polymers of formula III in which R 1 and are 3-methylthiopropyl and methyl, respectively, in a ratio ranging from 5:95 to 95: 5, the process is essentially the same as described above, wherein the poly (4-methylimino) trimethylene) is reacted with a limited amount of 3-methylthiopropyl bromide followed by an excess of methyl bromide.

Example XXXIV

Poly methyl (3-ammoniopropyl) imino) trimethylene dichloride

A solution of 568 mg (8 milliequivalents) of poly- (methylimino) trimethylene7 and 8.6 g (30 mmol) of 3-phthalimidopropyl bromide in 25 ml of dimethylformamide is heated at 75 ° C for 18 hours. The product is filtered off, suspended in 10 ml of methanol and treated with 1 g of anhydrous hydrazine at 50 ° C for 3 hours. The mixture is concentrated under reduced pressure, acidified with dilute HCl, stirred with ether and filtered off.

The product is taken up in water and passed through a 1 to 5 ml column containing Dovex 1-X2 ion exchange resin (36 millimoles of chloride ion). Concentration of the aqueous eluate gives poly (methyl (3-ammoniopropyl) imino) trimethylene chloride.

Alternatively, a solution of 568 mg (8 milliequivalents) of poly (Tme-methylimino) trimethylene% and 6.3 g (mill0 mmol) of 1-bromo-3-chloropropane in 20 ml of dimethylformamide is heated to 75 ° C. at 18 hours. The reaction mixture is concentrated under reduced pressure and heated with 30 ml of liquid ammonia at 50 ° C for 5 hours. The ammonia is also allowed to evaporate and the product is converted to the chloride ion-containing form by passing it through a 1 + 5 ml column with Dovex 1-X2 ion exchange resin in the chloride ion phase.

To prepare a polymer of formula III wherein R 1 and R 2 are 3-ammoniopropyl and methyl, respectively, ranging from 5:95 to 95: 5j, essentially the method described above is used, wherein the poly- (methylimino) trimethylene is reacted with a limited amount. either 3-phthalimidopropyl bromide or 1-bromo-3 'chloropropane and then with excess methyl ibomide.

Example XXXV

Poly ~ / Tmetyyli- (3-metyyliammoniopropyyli) imino) ^ -trimetyleenidikloridi

A solution of 710 mg (10 milliequivalents) of poly- (methylimino) trimethylene and 8 g of 1-bromo-3'-chloropropane in 30 ml of dimethylformamide is heated at 75 ° C for 16 hours. The mixture is concentrated under reduced pressure, suspended in 10 ml of ethanol and treated with 3 g of methylamine at 50 ° C in a sealed tube. The reaction mixture is concentrated under reduced pressure, taken up in water and passed through a 50 ml column of Dovex 1-X2 ion exchange resin to give the desired product.

For the preparation of polymers of formula III in which R 1 and R 2 are 3-methylammoniopropyl and methyl, respectively, in ratios ranging from 5:95 to 95: 5 *, the method described above is used, in which poly (N-methylimino) trimethylene with 1-bromo-3-chloropropane and then with excess methyl bromide.

1 · '"27 58787

Example XXXVI

Poly - [(methyl- (3-dimethylammoniumpropyl) imino) trimethylene dichloride /

A solution of 710 mg (10 milliequivalents) of poly (1- (methylimino) trimethylene) and 7.9 g of 1-bromo-3-chloropropane in 35 ml of dimethylformamide is heated at 75 ° C for 16 hours. The mixture is concentrated under reduced pressure, suspended in 10 ml of methanol and treated with 2.3 g (50 mmol) of dimethylamine at 50 ° C in a sealed tube. The reaction mixture is concentrated under reduced pressure, taken up in water and passed through a 50 ml column of Dowex 1-X2 ion exchange resin (40 millimoles of chloride ion) to give poly (N- (methyl- (3-dimethylammoniumpropyl) imino) trimethylene chloride).

To prepare polymers of formula III wherein and R 2 is 3-dimethylammoniopropyl and methyl, respectively, ranging from 5:95 to 95: 5, the method described above is used, wherein the poly (methylimino) trimethylene / is treated with either a limited amount of 1- bromo-3-chloropropane followed by excess methyl bromide.

Example XXXVII

Poly (methyl- (3-trimethylammoniopropyl) imino) trimethylene dibromide

A solution of 710 mg (10 milliequivalents) of poly (4-methyl- (3-trimethylene) and 10.4 g (40 mmol) of 3-bromopropyl-trimethylammonium bromide in 40 ml of purified dimethylformamide is heated at 75 ° C. 12 h The product is filtered off, washed with acetone and dried under reduced pressure to give 1.8 g of poly - ((3- (3-trimethylammoniopropyl) imino) -tri-methylene dibromide).

Example XXXVIII

Poly (1-methyl- (3-trimethylammoniopropyl) imino) trimethylene chloride

A solution of 1.66 g (5 milliequivalents) of poly - ((methyl- (3-trimethylammoniopropyl) imino) trimethylene dibromide in 85 ml of water is slowly passed through a column containing 50 ml (40 millimoles) of Dowex 1- X2 resin in the chloride ion step, water is then passed until no more chloride ion can be detected in the eluate, and the combined eluate is concentrated to dryness at 50 [deg.] C. to give 1.1 g of poly (.alpha.-methyl- (3-trimethylammoniopropyl)). Imino) trimethylene dichloride).

For the preparation of polymers of formula III in which and R is 3-trimethylammoniopropyl and methyl, respectively, ranging from 5:95 to 95: 5, the procedure described in Example XXXVII is used, in which poly (N- (methylimino) trimethylene) is reacted in a limited manner. with an amount of 3-bromopropyltrimethylammonium bromide followed by an excess of methyl bromide.

Example XXXIX

Poly ^ fmetyyli- (carboethoxymethyl) imino) ^ trimetyleenikloridi

A solution of 1 g (14 milliequivalents) of poly (4- (methylimino) trimethylene) and 8.8 g (56 mmol) of ethyl 4-bromoacetate in 20 ml of dimethylformamide is heated at 50 ° C for 12 hours. The mixture is diluted with five volumes of ether and the product is filtered off. The product is taken up in water and passed through a 75 ml column of Dowex 1-X2 ion exchange resin (60 millimoles of chloride ion) and the eluate is concentrated under reduced pressure to give poly - ((methyl- (carboethoxymethyl) imino) trimethylene chloride). .

Example XL

The polymer / 7metyyli- (karbamyylimetyyli) imino)} trimetyleenikloridi

A solution of 355 mg (5 milliequivalents) of poly- (methylimino) trimethylene and 3.5 g (25 mmol) of 2-bromoacetamide in 10 ml of dimethylformamide is heated at 60 ° C for 15 hours. The product is filtered off, taken up in water and passed through a 25 ml column of Dowex 1-X2 ion exchange resin (20 millimoles of chloride ion) to give poly (methyl (carbamylmethyl) imino) trimethylene chloride.

To obtain polymers of the formula III in which R1a3a2 is carbamylmethyl and methyl, respectively, in ratios ranging from 95: 5 to 5:95, the process described above is used essentially, in which poly - ((imino) trimethylene) is first treated with a limited amount of 2 -bromoacetamide followed by excess methyl bromide.

58787 29

Example XLI

Poly (1-methyl- (2-oxopropyl) imino) trimethylene chloride,}

A solution of 355 mg (5 milliequivalents) of poly- (methylimino) trimethylene / and 2.3 g (25 mmol) of chloropropanone-2, O 'is heated at 50 ° C for 16 hours. The product is filtered off, triturated with ether and dried under reduced pressure.

To prepare polymers of formula III in which R 1 and 1 * 2 are 2-oxopropyl and methyl, respectively, ranging from 95: 5 to 5:95, the procedure described above is followed, in which poly - ((methylimino) trimethylene) is first treated with a limited amount. chloropropanone-2 followed by excess methylene bromide. The product is treated with Dowex 1-2X resin in a chloride ion step to give the desired product containing exclusively chloride ion.

Example XLII

Poly - ^ [methyl (benzyl) imino) trimethylene chloride)

A solution of 710 mg (10 milliequivalents) of poly (dimethylimino) trimethylene} and 6.8 g (40 mmol) of benzyl bromide in 15 ml of dimethylformamide is heated at 50 ° C for 16 hours. The product is isolated by concentrating the reaction mixture under reduced pressure and extracting into water. The solution is passed through a 25 ml column of Dowex 1-X2 ion exchange resin (40 millimoles of chloride ion) to give the desired product containing the chloride counterion.

To prepare polymers of formula III in which and R 9 is benzyl and methyl, respectively, the method described above is used, in which poly / (methylimino) trimethylene / is first reacted with a limited amount of benzyl bromide and then with an excess of methyl bromide.

Example XLIII

Poly - / (methyl- (1-propeenl-3-yl) imino)} trimetyleenikloridi

A solution of 426 mg (6 milliequivalents) of poly- (methylimino) trimethylene} and 3.7 g (30 mmol) of 3-bromopropene-1 (allyl bromide) in 12 ml of dimethylformamide is heated at 50 ° C: in 16 hours. The product is filtered off and dissolved in water.

The solution is passed through a 40 ml column of Dowex 1-X2 ion exchange resin (32 millimoles of chloride ion) and the eluate is concentrated under reduced pressure to give the desired product containing the chloride counterion.

58787 30

To prepare compounds of formula III in which and R e is 1-propen-3-yl and methyl, respectively, in a ratio ranging from 95: 5 to 5:95, the method described above is used, wherein poly - (((imino) trimethylene) is reacted with a limited amount of 3-bromopropene-1 followed by an excess of methyl bromide.

Example XLIV

^ Fmetyyli- of poly (1-propyne-3-yl) imino) trimetyleenikloridi-7

A solution of 710 mg (10 milliequivalents) of poly (methylimino) trimethylene and 3.6 g (30 mmol) of 3-bromopropyn-1- (propargyl bromide) in 12 ml of dimethylformamide is heated at 50 ° C: in 16 hours. The product is filtered off, dissolved in water and passed through a 40 ml column of Dowex 1-X2 ion exchange resin (32 millimoles of chloride ion) to give the desired product containing chloride counterion. ,

As in the previous examples, polymers of formula III wherein R 1 is 1-propyn-3-yl and is CH 2 in the range 5:95 to 95: 5 can be synthesized by first treating the poly (4-methylimino) trimethylene) with a limited amount of propargyl. bromide followed by excess methyl bromide.

The methods described in Examples XXVIII-XLIV can equally be applied to the conversion of poly (4-methylimino) ethylene) to the corresponding quaternary analogs using the corresponding milli-equivalents of poly (4-methylimino) ethylene} poly (4- (methylimino) trimethylene). instead of ^ as shown in Example XLV.

Example XLV

Poly - [(methyl- (2-trimethylammonioethyl) imino) ethylene dibromide)

A solution of 570 mg (10 milliequivalents) of poly (4- (methylimino) ethylene) and 9.9 g (40 mmol) of 2-bromoethyltrimethylammonium bromide in 40 ml of dimethylformamide is heated at 75 ° C for 12 hours. After cooling, the reaction mixture is diluted with 5 volumes of ether and the product is filtered off and dried under reduced pressure.

Effective lowering of blood cholesterol levels is achieved by oral administration of significantly small doses of the polymers of the invention. This makes it possible to prepare different dosage forms, which has hitherto been impossible. The polymers 31 58787 may be finely divided powders and are suitably used as such or preferably mixed with various amounts of solid carriers such as colloidal silica, starches, sucrose, talc, lactose, cellulose or modified cellulose, powdered milk powder and protein powder, protein powder. They are preferably made into unit dosage forms such as tablets, filled gelatin capsules or film or paper bags containing a pre-measured dose, which may be supplemented with vitamins and minerals, which can be easily torn open and added to ingestible liquids such as fruit juices and other soft drinks. The unit dose may contain from 10 to 99% by weight of polymer, the remainder being carriers, flavors, additives, flow agents and the like. Such a unit dose may contain 0.1 to 10 g of active polymer in a powder package.

Also suitable are aqueous solutions or suspensions which may be prepared and preferably sweetened or perfumed. Although not entirely desirable, the polymers may be mixed with various media, such as safflower or corn oil, for oral administration as such or as an aqueous emulsion. They may also be enclosed in capsules.

As previously discussed, the total daily dose of bile acid sequestrant polymer is preferably divided and taken before each meal and before bedtime. In this way, the longest possible contact time of the resin is achieved during the highest concentrations of bile acid in the intestine.

The polymers of the invention may be used alone or, if desired, in combination with triglyceride synthesis inhibitors or other bile acid sequestrants for special treatments. In addition, as is known, the described polymers form salts with the acids clofibrate and halofenate, which salts are useful in the treatment of arterial disease.

In addition, the polymers of the invention are particularly useful throughout their molecular weight range when used as flocculants for colloidal particles in a liquid, such as fresh and wastewater. They can also be used as retention aids to be added to paper during papermaking. In addition, the polymers are useful as antibacterial and anti-static agents, and the latter can be used to treat cotton, wool, and synthetic fibers. These 32,58787 polymers can also be used as fabric softeners and dye aids, especially for binding anionic dyes. In addition, they can be used as viscosity builder agents as well as to provide antibacterial properties for nonionic and cationic detergent compositions, cosmetics, hair sprays and the like. In this case, the polymers according to the invention are used in the same amount and in an analogous manner as is customary for such purposes.

When used as a clarifying or flocculant, the polymers according to the invention are preferably dissolved or dispersed in an aqueous medium and 0.23 to 0.91 kg of polymer per 3786 liters of water to be treated are added to the water to be treated.

In general, the polymers of the invention have a molecular weight in the range of 300 to 50,000 or more. Although a polymer having a molecular weight of less than 1500 can be used as flocculants and the like, they are not suitable as a bile acid sequestrant and such polymer molecules can be separated from higher weight molecules in a manner known per se.

Claims (3)

A process for preparing a linear, unbranched, non-crosslinked polymer having repeating monomer units of the formula ^ | 1X R2X ~ --N - QN --Q-- (I ·) ch3 ch3 ^ S wherein X is halide, sulphate or sulphonate or Z, when there is no other monovalent or polyvalent counter anion, Q is ethylene or trimethylene, and denotes a bond to several groups R., x ”R2X ~ + ^ + - NQ— or —NQ- II“ 3 L 3 wherein X and Q are as defined above and R 1 and R 2 are the same or different and are lower alkyl; monohydroxy-substituted lower alkyl; carboxy-lower-alkyl; C-j-C ^ -alkenyl; C₁-C₃ alkynyl; benzyl; lower-alkyl-thio-lower alkyl; ammonio-lower alkyl, lower alkyl-ammonio-lower alkyl; di-lower alkyl-ammonio-lower alkyl; a tri-lower alkyl-ammonio-lower alkyl; provided that only one of the groups and R 2 may be lower alkyl when the ammonio cation is the countercation of the anion X, characterized by the following steps; (1) 2R '- A.2-oxazoline or 2-R'-5,6-dihydro-4H-1,3-oxazine, wherein R 'is hydrogen, lower alkyl, phenyl, naphthyl or naphthylethyl, is polymerized in a manner known per se to give a polymer having repeating monomer units of formula 34 / n 58787 --NQ-- c.0 (VI '>> »s wherein R' and Q are as defined above; (2A) the polymer of formula VI 'is hydrolyzed to remove the acyl group with an acid or base to give a polymer having repeating monomer units, of formula SN _ (d __ NQ k H> where m is 0 or 1 and Q and Z are as defined above, or {2B) a polymer of formula VI 'is reduced with diborane to a polymer of repeating monomer units of formula 7. Λ 1 --ib—— Q— (Vili ·) l "2 L * J wherein m, Q, Z and R 'are as defined above, or (2C) a polymer of formula VI' wherein R 'is hydrogen is mixed with at least one equivalent of both formaldehyde and formic acid and the resulting mixture is heated to a temperature of 30-100 ° C at least 100 hours to obtain a polymer having repeating monomer units of the formula (,,) \ + ym dx ') --- C.-Q-- 1 CH, wherein m, Q and Z are as defined above; : 35 5 8 7 8 7 (3) the polymer of formula VII 'obtained in step (2A) wherein m is 0 is methylated with at least one equivalent of both formaldehyde and formic acid and the resulting mixture is heated at 30-100 ° C for up to 100 hours to obtain the polymer, having repeating monomer units of formula IX 'shown in step (2C); (4) to prepare a polymer having repeating monomer units of the formula "" N. (r). (R :). --N— -Q ^> 2— N - Q (X ') I I CH CH k J wherein m, Q and Z are as defined above and represent a bond to several groups (r i) (r). Vm Q or -NQ-CH3 CH3 wherein Z, Q and m are as defined above, a polymer of formula XII 'wherein m = 0 is reacted with at least 1.5 equivalents of CH2X wherein X is a halide or sulphonate or sulphate , in an inert solvent at a temperature of 30 to 100 ° C, to obtain a polymer of formula X 'where m = 1 and Z is X, and if desired to obtain a polymer of formula X' where m = 0, a polymer of formula X 'wherein m = 1, with exactly one equivalent of base; (5) a polymer of formula VIII 'obtained in step (2B), a polymer of formula IX' obtained from step (2C) or (3) or a polymer of formula X 'obtained from step (4), optionally after a polymer wherein m = 1 , is converted to a polymer where m = 0 is quaternized to incorporate the substituents R1 and R2 defined in formula 1 'into the polymer so that the polymer comprising repeating monomer units of formula 58787 36 ✓' - NQ Slsis- —NQ- - CH 2 CH 2 L 3 3> wherein Q is as defined above and represents a bond to the group - NQ- -N - Q - or CH 3 CH 3 is reacted (a) when and R 2 are the same as at least one equivalent of RX where R is R 1 and X are a halide, sulfonate or sulfate; (b) when R 1 and R 2 are different, the polymer is first reacted with 5-95% of one equivalent of R 1 X and then reacted with at least one equivalent of V; (6) and that, if desired, anion X is converted to anion Z by means of an anion exchange resin. P, 58787 37 For the further preparation of a line, of which a polymer having up to the monomer content of the formula R-Ix R2X ~ NQ NQ-- (I ') CH3 CH3 ^ S is X, halogen, sulphate or sulphonate or Z, som är nägon annan envärdig eller flervärdig motanjon, Q är ethyl or tri-methylyl, och f * '-' betyder bindning account ett flertal grupper R2X "+ J - Q eller —N —-- Q- CH 3 CH3 is X and Q are selected from the group consisting of R, O and R or R or O; monohydroxy-substituted alkyl; carboxyl-alkyl; C ^ -C ^ -alkeny1; C ^ -C ^ -alkynyl; benzyl; lägre-alky1-thio-lägre-alkyl; ammonio-la-alkyl1, la-alkyl-ammonio-la-alkyl; di-lägre-alky1-ammonio-lägre-alky1; tri-lägre-alky1-ammonio-1ägre-alky1; in the case of the group consisting of R- ^ and R2 can be alkyl of the ammonium cation with an anion X moiety, which can be used as follows: (1) 2R '- ^ -oxazoline or 2-R * -5> 6, - dihydro-11H-1,3-oxazine, with R 'is an alkyl, phenyl, naphthyl or naphthylethyl, polymerized head and octane with the same value as the polymer with an upstream monomer having a formula 38 58787 S \ --NQ- - c = 0 (VI ') I · ^ sl for R * and Q betyder samma som ovan; (2A) in which the polymer of formula VI 'is hydrolyzed for the form of an acyl group with a syrup or a base for the polymer with an upstream monomer having a form of ^ N (rl --NQ-- k H> där m är 0 or 1 and Q and Z are selected from the group consisting of (2B) and a compound of formula VI 'having an optional polymer reducing agent with a diborane or polymer having an upstream monomer ester of the formula (f) --No- (VIII ·) CH0 I 2 R' S, m, Q, Z and R 'are selected from the group consisting of (2C) and a compound of formula VI' having a polymer, such as R 'and a mixture of equivalents and equivalents of formaldehyde and myrrh and a mixture of bleaching agents a temperature of 30-100 ° C is below 100 times the temperature of the polymer with up to monomer compounds of formula (f) --VIZeLq-- dx ') CH 39 58787 m, Q and Z of the same mixture as above (3) steg (2A) is obtained in the form of a polyethylene having a weight of 0, methylated with an equivalent amount of Bald formaldehyde and myrsyra o in the case of bleaching at ambient temperatures between 30 and 100 ° C, up to 100 times the temperature of the polymer with the monomer content of the monomer units (2C) to form IXf 5 (JJ) for the production of monomers with the polymer monomer form (! · :). (R). --N —-- Q N - Q (X ') I I CH3 CH3 k ^ där m, Q och Z betyder samma som ovan och betyder bindning account ett flertal grupper (“.) (R :). —Eller —N — IQ— CH3 CH3 from Z, Q and m are selected from the group consisting of XII 'in the form of a polymer, m = 0, reacting with an equivalent of 1.5 equivalents of the same CHCH X, X is a halide or a sulfonate or a sulfate having an inert solution at a temperature of 30 to 100 ° C, for which the formula is X, the polymer having a value of m = 1 and Z is a mixture of X, and the amount of the polymer the formula X 'weighs polymer, m = 0, and the formula X' weighs polymer, m = 1, exact med en equivalent to bas;