KR790001445B1 - 3- n -(3-haloproply)-n-methylamino -n,n,n,-trimethyl-1-propanaminium halide and acid additon salts thereof - Google Patents

Abstract

Title compd. (I; X = chloro, bromo, Y = pharmaceutically acceptable anion, chloro, bromo, iodine, a = ionic charge of Y, m = reciprocal of a polymer), useful as hypercholesterolemic agent, antistatic agent, antimicrobials, flocculating agent, and electro-conductive agent for paper were prepd. Thus, I was reacted with oxidant to give II, which was halogenized and subst. of X- with Y- to give title compd. polymer.

Description

Preparation of 3- [N '-(3-halopropyl) -N'-methylamino] -N, N, N-trimethyl-1-propanealuminum halide

The present invention relates to a process for the preparation of novel linear, non-branched, non-crosslinked polymers. In more detail, the present invention relates to 3- [N ^1- (3-halopropyl)-of the following general formula (1): A method for producing a N ¹ -methyl amino] -N, N, N-trimethyl-1-propanealuminum compound.

The present invention also includes a method for preparing acid addition salts of compounds represented by the general formula (1).

As used herein, "non-branched" refers to a polymer that does not have repeating monomer units extending from the backbone of the polymer, and "linear" refers to a polymer having a straight chain, and "non-crosslinked". "Is used in its ordinary meaning.

The present invention further relates to a polymer prepared from the monomer of general formula (1), ie, a poly [{methyl- (3-trimethylammoniopropyl) imino} trimethylene] compound of the following general formula (2).

Since the conditions of the polymerization reaction determine the degree and nature of substitution of the chloro portion of the end group, the ratio of the end group W which is 3-halopropyl, 3-hydroxy propyl or aryl is changed or determined by the conditions of the polymerization reaction. do. As the reaction time and temperature increase, the polymerization ratio of the hydroxypropyl end group or allyl end group increases compared to the halopropyl end group, whereas when the reaction time is short or the temperature is low, the polymerization rate of the substituted halo end group is increased. Decreases.

Generally about 10-80% by weight of the polymer (2) is hydroxypropyl end group, 5-90% by weight is halopropyl end group, and the remainder is allyl end group. In practical terms, the hydroxypropyl group is satisfactory, but this terminal group is not completely satisfactory since the chain growth is prematurely stopped because it can no longer be polymerized upon reaction with the monomer (1). The halopropyl end group ends up as a group that can receive chain growth more strongly, but consumes monomer (1). Allyl groups are terminal groups from which HX has been removed and which can no longer be polymerized.

The three types appear in this manner because dispersive reactions occur during the polymerization of the monomer (1).

In particular, the present invention relates to a method for producing an end group modified polymer (3) in which a 3-halopropyl end group is modified by substitution of a halo moiety by hydrogen, alkylthio, or trilower alkyl amonio function.

The polymer (3) modified with such end groups is a poly-[{methyl- (3-trimethyl ammoniopropyl) imino} trimethylene] compound which can be prepared from polymer (2) and is represented by the following general formula (3): .

The proportion of terminal group Z, which is 3-hydroxypropyl or allyl group, depends largely on the nature of the terminal group W of the polymer precursor (2).

In the case of preparing the polymer represented by the general formula (3), since n is generally 10 or more, each terminal group average molecular weight may be in the range of 600-20,000, but the average molecular weight is in the range of about 4,000-16,000.

The molecular weights of the polymers (2) and (3) are demonstrated by the worry of unique tertiary amine end groups, gel permeation chromatography and intrinsic viscosity measurements, while titration yields an average molecular weight of about 5,000, whereas gel permeation chromatography By, an average molecular weight of about 14,000 and above is obtained. Polymers (2) and (3) are useful as antistatic agents, antibacterial agents, coagulants, paper coating agents for imparting electrical conductivity to paper, and nonabsorbable gastrointestinal bile acid binders.

The properties of the polymers (2) and (3) as bile acid binders are of particular value because they are known to lower cholesterol concentrations in serum by sequestering bile acids in the human body. Polymers (2) and (3) are most effective among those that can be used as bile acid sequestrants because they have a water-soluble and linear, non-branched, non-crosslinked structure and a high charge to mass ratio. In this respect, the polymer (3) is particularly valuable because its end group Z is more pharmaceutically stable for long-term use in order to lower the cholesterol concentration in the serum.

Evidence suggests that higher serum cholesterol levels in humans than normal (especially in the case of Fredericson's disease of Form II) are signs of atherosclerosis and other hypercholesterolemia diseases. Atherosclerosis is a form of circulatory obstruction, vascular, cerebrovascular disease, and peripheral vascular disease, and is the leading cause of death. In order to reduce the incidence of atherosclerosis, the increase in serum cholesterol level is inhibited by various methods such as dietary restriction, special dietary cholesterol suppression, catabolism and bile acids in the gastrointestinal tract, as well as prevention of gastrointestinal absorption. It is important.

The patient's diet and lifestyle do not have to be severely altered and surgical interventions have been highly praised.

However, it is not known exactly why the lowering of cholesterol levels in serum when binding gastrointestinal bile acids is involved.However, the feedback mechanism affects cholesterol oxidation, which releases serum cholesterol to restore bile acid levels. It is considered to exert.

As such, this method is well used regardless of whether the regeneration mechanism is certain. Thus, as a bile acid binder, a binder that is convenient, effective, and non-toxic and has good tolerability is desired.

Conventionally, various bile acid binders have been used, and conventionally known bile acid binders include iron salts that produce bile acids and insoluble precipitates, polymers having an organic base and salt-forming ability similarly acting. However, in order to avoid such absorbent precipitations presenting a risk of acute and chronic toxicity, an effective adult daily average dose of a nonabsorbable highly crosslinked polymer is used in the range of up to 40 g, which is not a suitable method. In other words, crosslinking prevents proximity to most potential binding moieties, resulting in severely reduced efficiency resulting in the use of such large amounts.

In particular, the physical volume of such use in the case of water-insoluble crosslinked resins can lead to partial obstruction of the gastrointestinal tract, unpleasant pressure, and difficult to eliminate unpleasant odors and tastes for large doses.

As described above, the gel-like composition having less cross-linking and branching is adsorbed by water and remarkably swells, thus relatively free of friction, but often causes a feeling of pressure. The use of conventional water soluble polymers as bile acid binders results in a very high viscosity in solution and a significant convergence in the oral cavity.

Moreover, such water soluble polymers impart a large volume to consumption while retaining the same amount as water of the same weight in dry form. Most importantly, the efficacy can be reduced in the gastrointestinal tract. Although the incidence of diseases associated with hypercholesterolemia is surprisingly high and occurs without boiling, the effects obtained by treatment with conventional methods are limited.

It has been found in several theories that resins previously proposed for use in the treatment of hypercholesterolemia to satisfy bile acid absorption with the ability to capture chloride ions are ineffective.

On the one hand, it is claimed that a small amount of inorganic anions can reach the binding site more readily than bile acid anions. Therefore, in order to produce a more efficient resin, it is necessary to provide a larger bond to accommodate a large amount of acid. On the other hand, since the resin requires more lipid components to penetrate the bio-foam forming body that holds the lipid bile acid, it is proposed that a low solubility of water in the resin is preferable. Unfortunately, this concept did not make much progress when converted to polymer form to treat hypercholesterolemia.

It has been found by the inventors that the polymer produced by the present invention has an extremely important advantage as an effective treatment agent for treating hypercholesterolemia, in which the terminal groups show no potential toxicity.

The most suitable method for synthesizing the monomer (1) is the following method, i.e., 3-bromo-N, N, N-trimethyl-1-propanealuminum halide in an inert solvent at 0 ° C-30 ° C for 4-24 hours. After reacting with methyl amine (wherein inert solvent refers to alkanols such as ethanol or methanol, dimethylformamide, water or mixtures thereof, which do not react with other reactants or reaction products therefrom) Solvent), the reaction product N, N, N-trimethyl- [3- (methylamino)]-1-propaneaminium halide hydrobromide is appropriately suspended in an inert solvent such as methanol, ethanol or water and One equivalent of a base, such as an alkaline earth metal hydroxide or an alkali carbonate, was slowly added dropwise over 10 minutes-5 hours while maintaining 0 ° C.-50 ° C., and then the reaction mixture was concentrated to dryness under reduced pressure to obtain a suitable solvent such as acetonitrile. When using the extracted from the residue, N, N, N- trimethyl [3- (methylamino)] - 1-propane Amiga titanium halide is obtained.

The resulting reaction product, N, N, N-trimethyl [3- (methylamino)]-1-propanaluminum halide, was purified by recrystallization from a solvent mixture such as an alkanol-ether solvent mixture, for example isopropanol-diethyl ether. The reaction product is obtained by treating in an aqueous solution using 1.1-3 equivalents of Oxetane for 10-24 hours in a sealed container at 50 ° C.-150 ° C. or without further purification, and then concentrating and separating the reaction mixture. Dried, extracted with a suitable solvent such as acetonitrile, the solvent was evaporated to crystallization and recrystallized from acetonitrile to purify 3- [N ^1- (3-hydroxypropyl) -N ¹ -methylamino]- N, N, N-trimethyl-1-propanealuminum halide is obtained.

The intermediate compound 3- [N ^1- (3-hydroxypropyl) -N ¹ -methylamino] -N, N, N-trimethyl-1 prior to the substitution of the 3-hydroxypropyl functional group with the 3-halopropyl moiety. Propanaluminum halides can be appropriately converted to propane aluminum homologues. (At this time, the homologue is also suitable for other counter anions Ya, but the halo moiety containing the same halide moiety capable of substituting a hydroxy functional group having a hydroxypropyl moiety is most suitable. It is time to pass a specific ion exchange resin so that an aqueous solution of 1-propanealuminium halide intermediate compound acidified with acid can be made into the desired anion form).

Alternatively, the halide anion of the intermediate compound is acidified with HY to exchange with OH ^- ions or the appropriate neutral solution is passed through Ya through an ion exchange resin on the Ya cycle.

The aqueous eluate was concentrated to dryness to afford the desired intermediate compound and then treated with an appropriate hydrogenating agent, such as thionylchloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide or phosphorus pentabromide, to obtain 3- [N ^1- (3 -Halopropyl) -N ¹ -methyl amino] -N, N, N-trimethyl-1-propanealuminum halide acid addition salt is obtained.

The resulting reaction mixture is concentrated and purified, the residue is washed with a suitable ether solvent, dissolved in water, treated with activated charcoal, filtered and concentrated to dryness under reduced pressure, and then determined from a mixed solvent such as isopropanol-acetone to produce the desired reaction product. Is obtained.

In a second method, monomer (1) is a mixture of N, N, N-trimethyl- [3- (methylamino)]-1-propane aluminum halide in an inert solvent such as acetonitrile. It can be synthesized in one step of treatment with 1 equivalent of 1,3-dihalotrimethylene compound such as dopropane, 3-bromo-1-chloropropane, or 1,3-dibromopropane. The insoluble byproducts are filtered off, then the reaction mixture is dried and the concentrated product is extracted from the residue using a suitable solvent such as chloroform or methylene chloride. Crystallization from an isopropanol-ether or isopropanol-acetone mixed solvent yields the desired reaction product.

In the third method of synthesizing monomer (1), 3-aminopropanol is added to acrylonitrile to obtain 3- (2-cyanoethyl) amino propanol, and then the reaction mixture is 3- [N- (2). -Cyano ethyl) -N-formylamino) propanol. The nitrile functional group of the latter compound was subjected to catalytic reduction with a primary amine functional group and then fully alkylated with methyl halide to give the intermediate compound 3- [N ¹ -formyl-N ^1- (3-hydroxypropyl) amino] -N. , N, N-trimethyl-1-propanealuminum halide is obtained.

The obtained intermediate compound was treated with a formic acid-formalin mixture at 60 ° C.-100 ° C. for 10-24 hours to reduce the formyl moiety to a methyl functional group, acidified with a suitable water-soluble hydrogen halide, and then concentrated to dryness to obtain another intermediate compound. Phosphorus 3- [N ^1- (3-hydroxypropyl) -N ¹ -methyl amino] -N, N, N-trimethyl-1-propanealuminum halide hydride is obtained to obtain the intermediate compound 3- [ N ¹ - (3- halo-propyl) -N ¹ - methyl-amino] -N, N, N- trimethyl-1-propane aminium kimyeon when converted to halide hydro halide, obtained as a desired reaction product (where the anion Exchange is done as described above).

The polymer (2) is obtained by polymerisation of the monomer (1), preferably, the acid addition salt of the monomer (1) is treated with one equivalent of an aqueous alkali hydroxide in an oxygen-excluded atmosphere, or in an aqueous solution. It is superposing | polymerizing as a free base. Usually, the neutralized salt obtained when using the acid addition salt of monomer (1) is removed before superposing | polymerizing. The polymerization method is carried out in an aqueous medium using 3-10 moles of monomer (1).

한외여과기(UMI0 Diaflo

Ultrafilter)가 장치된 아미콘 필러셀(Amicon Filter Cell) 중의 5% 수용액을 한외여과(限外濾過)하여 염 및 저분자량 물질로 부터 제거시킨다.In more detail, the reaction medium containing the monomer (1) and water is heated for 6 to 60 hours under nitrogen or argon air excluding oxygen at 80 ° C to 110 ° C (where the temperature is increased by pressure increasing method). Temperature of 100 ° C. or more may be used). The most suitable reaction method is to react for 12-18 hours using 6-8 mol of aqueous solution of monomer (1) at 100 degreeC under nitrogen stream. Product to UMI0 diaflow at a constant volume of 60 psi

Ultrafiltration (UMI0 Diaflo)

A 5% aqueous solution in Amicon Filter Cell equipped with Ultrafilter is ultrafiltered to remove from salts and low molecular weight materials.

The filtered aqueous residue is concentrated and separated under reduced pressure at a temperature up to 50 ° C. to obtain a purified polymer which is then ground to a fine powder and dried under reduced pressure over anhydrous phosphoric acid. The residual chloro end groups of the polymer (2) are substituted according to any one of the three methods described above for obtaining the polymer (3). Such substitutions are carried out in aqueous solutions, and more suitable substitution temperatures are either at room temperature or lower than room temperature to minimize the partial degradation of the polymers that may occur in the alkaline reaction medium.

When the 3-chloropropyl end group is substituted with the 3-trimethyl ammoniopropyl halide end group, the polymer (2) is dissolved in a small amount of water and treated with an excess of 6M trimethylamine in water for 8-24 hours. The reaction medium was concentrated and dried at a temperature of 30 ° C. or lower under reduced pressure, and the separated reaction product was pulverized into powder and dried under reduced pressure or prefiltered by ultrafiltration of a 5% aqueous solution of the separated polymer, and then the residue was reduced under reduced pressure. Concentrate to dry.

Alternatively, after replacing the chloro portion of the 3-chloropropyl end group of the polymer (2) with the naphthylthio portion in the aqueous solution, the aqueous solution of this polymer was sodium salt of naphthylthiol or benzenethiol for 12-48 hours at room temperature. Treat in 2x excess. The amount of acid corresponding to sodium mercaptide is then added and the reaction medium is filtered or extracted with a suitable solvent such as diethyl ether or chloroform to remove the unreacted thiol reagent.

The aqueous solution of the obtained polymer (3) is usually purified by ultrafiltration, and the residue may be concentrated to dryness on anhydrous phosphoric acid under reduced pressure.

When the chloro end group of the polymer (2) is replaced with hydrogen, an aqueous solution of the polymer (2) and a 2 equivalent base is reduced by using a noble metal catalyst until an appropriate amount of hydrogen is absorbed at room temperature (where suitable base is Potassium acetate, a suitable catalyst is a 5% palladium catalyst on carbon, which generally requires a two day reaction time for reduction when running under hydrogen pressure of 40 psi). The reduction product is usually purified by ultrafiltration and the change in counter anion composition by the base used is controlled by passing the residue through a Doexex 1X-2 anion exchange resin column on the appropriate anion cycle. When the aqueous solution is concentrated to dryness under reduced pressure, a desired substitution product is obtained.

In the conventional method, the anions of the polymers (2) and (3) are limited to halides only by the technique of the above-described process. In all polymers, when the anion is not a halide, the polymer (2) or (3) having a halide anion is dissolved in water, alcohol or a mixture thereof in an appropriate proportion to dissolve the solution in the form of synthetic or zeolite anion exchange resin. Can be obtained by passing through (iii). This halide ion is substituted as Ya.

The anion exchange method using the ion occlusal resin method can directly exchange halide ions with Ya or first exchange halide ions with OH ⁻ and then ion exchange or simply neutralize to exchange OH ⁻ with Ya. Chemical ion exchange methods can also be used when the solubility of the metal halide precipitates is lower than the solubility of the added metal salt MY, which shows a slight solubility.

At this time, the precipitated metal halide may be filtered and separated from the soluble polymer (2) or (3).

As a latter method, for example, a solution of polymers (2) and (3) containing bromide to ions is treated with freshly precipitated excess of silver chloride to filter the mixture of silver chloride and silver bromide after the halide anion exchange is complete. There is a method of separating from a solution of polymers (2) and (3) containing counter ions. In contrast, when Ya is sulfate in the polymer (2) or (3), barium sulfate may be removed by treating the sulfate with nitrate by treating it with a water-soluble calcium salt solution or a water-soluble barium salt solution.

As described above, Ya may be a monovalent anion as an anion opposing the charge on the quaternized imino group. However, Ya can oppose the charge of one or more imino groups as a polyneumide. Ya contains anions of inorganic acids as well as organic acids, for example: Halides, ie chloride, bromide or iodide; Sulfate; Unsulfate; Phosphate; Acetate; Ascorbate; Citrate; Hydroxy citrate; Carbonate; Bicarbonate; Nicotinate; Glycinate; Taurineate; Among the other anions derived from salicylates and physiologically nontoxic acids, salts of physiologically active acids, among others, are salts of clopibrate and halophenate, namely 2- (P- Derived from chlorophenoxy) -2-methyl propionic acid and 3-trifluoromethyl phenoxy- (4-chlorophenyl) -acetic acid.

When neutralizing quaternary amino groups using anions of physiologically active compounds, only some of the charged imino groups are neutralized. The amount of anion from the physiologically active compound is distributed in an amount suitable for oral administration.

By administering extremely small oral doses of the polymers prepared by the present invention, the cholesterol concentration in the serum can be effectively reduced, and the conventional disadvantages can be eliminated. The polymer prepared according to the present invention may be used as it is, finely ground into a powder or mixed with a solid carrier, where the solid carrier is a colloidal silica, starch, glucose, talc, lactose, cellulose or Protein powders such as improved cellulose, dry milk powder, soybean meal, and the like.

The polymer treated as described above may be taken as a unit dose by making tablets, gelatin capsules, aluminum silver foils, or powdered vesicles containing desired doses supplemented with vitamins and minerals, and are easily opened. The contents can also be taken in edible juice or other beverages. The unit use composition comprises 10-99% by weight of the polymer and the remainder consists of the carrier, the flavoring agent, the excipient, the glidant and the like.

The anti-foaming agent contains 0.1-10 g of the active polymer and is prepared to be convenient for taking an aqueous solution or suspension.

Although not completely preferred, the polymer may be mixed orally administered with a medium such as safflower oil or corn oil, or may be administered as an emulsion, or may be used as a capsule.

The bile acid binding polymer is divided into three or four portions and taken before meals and before bedtime, and used in a daily dose. As such, the bile acid-binding polymer may have a maximum resin contact period while the bile acid concentration in the stomach is highest.

The polymer prepared according to the present invention may be used alone or as necessary, mixed with a triglyceride anti-synthesis agent or another bile acid conjugate to be used as a therapeutic agent for hypercholesterolemia disease with excellent efficacy.

In addition, as described above, the polymers described herein form salts with the acids of clofibrate and halophenate, which salts are very useful for treating cardiovascular diseases.

The following examples illustrate the forms of use that may be used in the practice of the present invention, where high doses may be prescribed, multiple uses such as two or three tablets or capsules at one time.

The components constituting the carrier portion of the composition of the present invention may have the pharmaceutical activity of the indicated polymers and may contain the following components as well as unsaturated fatty acids such as linoleic acid, arachidonic acid and linolenic acid.

Ie bile secretions such as tocamphyl florantyrone, hypocholesterolemia agents such as taurine, glycine, nicotinic acid, D-isomers of 3,3 ', 5-triiodotyronine, sodium L-thyroxine and sodium Thyroxine compounds such as D-thyroxine, triiodotyropropionic acid, naphoxydine hydrochloride, 5-methylpyrazole-3-carboxylic acid, 3-methyl-5-isoxazolecarboxylic acid, polo ox Analgesics such as salcol and dioctyl sodium sulfosuccinate and edible oils such as corn oil and safflower oil.

[Powder Packet (粉末 小包)]

Linear, non-branched, non-crosslinked poly-[{methyl- (3-trimethyl ammoniopropyl) imino} trimethylene dichloride] was ground finely and mixed with 1% by weight of lactose powder, followed by the mixture 0.55 g is filled in an aluminum enclosure containing a zone liner and sealed to prevent caking.

[Hard Gelatin Capsules]

As mentioned above, 250 mg of poly-[{methyl- (3-trimethylammoniopropyl) imino} trimethylene dichloride] containing 1% by weight of lactose is filled into hard gelatine capsules of suitable size.

Alternatively, dry fill capsules can be prepared from the following compositions.

300 mg poly-[{methyl-3-trimethylammonio-propyl) imino} -trimethylene dichloride]

Corn Starch 150mg

5 mg of cab-o-sil (anhydrous silica)

When a lower titer is desired as the capsule, the capsule may be reduced in size, or corn starch or another diluent may be added, and when the active ingredient is less, it is desirable to administer multiple capsules.

[Compressed tablet]

As a tablet, the dry mixture contains the following components, which are compressed directly to obtain 4,000 tablets containing 250 mg of polymer per tablet.

1 kg poly-[{(methyl)-(3-trimethyl ammoniopropyl) imino} -trimethylene dichloride

Sucrose Powder 30g

10 g of colloidal silica

Carbowax-4000 30g

Likewise, compressed tablets are prepared such that each tablet contains the following ingredients.

300 mg of poly-[{methyl- (3-trimethylammoniopropyl) imino} -trimethylene dichloride]

Corn Starch 30mg

Polyvinylpyrrolidone 10mg

Magnesium Stearate 3mg

As described above, the tablets may be coated with a plastic film to prevent moisture by methods known in the art. Occasionally, it may be coated with enteric skin, and the coating agent contains fats, fatty acid waxes and mixtures thereof, shellac, shellac treated with ammonia, cellulose acid phthalate, and the like.

Another polymer salt prepared according to the invention may also be used in place of poly-[{(methyl-3-trimethylammonopropyl) imino} trimethylene dichloride], and instead of sucrose, glucose, lactose, methyl cellulose, natural Other binders such as gums, synthetic gums can be used, and talc can be replaced with magnesium stearate and various non-toxic anti-tackifiers readily available can be used in place of colloidal silica.

Other lubricants, diluents, binders, colorants, flavors and disintegrating agents are prepared by methods known in the art, such as wet or dry granulation, direct compression and spray drying.

If desired, the following compositions may be dry granulated with polymer particles filled in microcapsules to prepare chewing tablets.

750 mg of poly-[{(methyl)-(3-trimethyl-ammoniopropyl) imino} trimethylene dichloride filled in microcapsules

Mannitol 300mg

2 mg sodium saccharin (or other sweetener)

Peppermint oil 1mg

Carbowax-4000 15mg

Microcrystalline Cellulose 100mg

The above-mentioned dosage forms are those suitable for oral administration which can exert an excellent effect as a bile acid binder. As described above, the effective dose of the general medicament is suitably used in a single or plural amount of about 0.1-5.0 g, which can effectively reduce the cholesterol concentration in serum. In some cases, the capacity may exceed 10 g.

It is also possible to eliminate the bile pruritus symptoms by taking an effective dose as described above.

The drug prepared by the present invention may be administered orally as a suspension, an aqueous chewing tablet, a coated tablet, or a capsule. In addition, when treating hypercholesterolemia using the medicament prepared by the present invention, it is recommended to continue to check the cholesterol concentration in the serum while taking the above-described initial dose daily, and to adjust the dose in an appropriate amount until the desired therapeutic purpose is achieved. desirable.

The initial dose is most preferably taken daily at 2.5-10Omg / kg of body weight. It is particularly preferred that the acid addition salts of monomers (1) and polymers (2) and (3) contain salts derived from acids H ₁ / mYa, wherein Y, m and a are the same as described above.

The present invention will be described in detail by way of examples.

Example 1

Stage 1

N, N, N-trimethyl- [3- (methylamino)]-1-propanaminium bromide hydrobromide

Into a stirred solution of 229.57 g (7.4 mol) of 40% aqueous methylamine cooled in an ice water bath, 452.66 g (1.78 mol) of 3-bromo-N, N, N-trimethyl-1-propaneaminium bromide in 400 ml of distilled water The solution was divided into 3 portions and added over 40 minutes. After removing the ice water bath, stirring the reaction mixture for 4 hours, and evaporating under reduced pressure, the obtained crystal phase residue was vacuum dried and recrystallized from anhydrous ethanol to obtain 442.62 g (87.6%) of the desired reaction product.

) ; 3.16(9H, S,

).Melting point 185-189 ° (decomposition); NMR (D ₂ O) δ: 2.76 (3H, S,

); 3.16 (9H, S,

).

Analysis of C ₇ H ₂₀ N ₂ Br ₂

Calc .: C, 28.79; H, 6.90; N, 9.59; Br, 54.72

Found: C, 28.63; H, 7.27; N, 9.47; Br, 54.49

Tier 2

N, N, N-trimethyl- [3- (methylamino)]-1-propanaminium bromide

Hydroxide in 1.0 L of anhydrous methanol in a stirred suspension of 876.Og (3.0 mol) of N, N, N-trimethyl- [3- (methyladino)]-1-propaneaminium bromide hydrobromide in 2.75 L of anhydrous ethanol at room temperature A freshly prepared solution of 120.Og (3.0 moles) of sodium was added over 1 hour.

).The solid residue obtained by evaporating the reaction mixture under reduced pressure was shaken with 750 ml of acetonitrile. The insoluble sodium bromide is filtered off, the filtrate is evaporated and the solid residue is dried in vacuo to give the hygroscopic reaction product of white crystals in quantitative yield, which can be used without further purification or recrystallized from isopropanol-ether. NMR (D ₂ O) δ: 2.28 (3H, S, -NHCH ₃ ); 3.11 (9H, S,

).

Tier 3

3- [N ^1- (3-hydroxypropyl) -N ¹ -methylamino] -N, N, N-trimethyl-1-propane aluminum bromide

A mixture of 20 g (0.34 mole) of oxetane, 32.8 g (0.156 mole) of N, N, N-trimethyl- [3- (methylamino)]-1-propaneaminium bromide, and 22 ml of water was added to a sealed tube at 100 ° C. Heated at for 15 h.

The residue obtained by vacuum evaporation of the solution was dissolved in 50 ml of acetonitrile, filtered, evaporated to crystallization and recrystallized from acetonitrile to obtain the desired reaction product.

Analysis for C ₁₀ H ₂₅ N ₂ 0Br

Calc .: C, 44.61; H, 9.36; N, 10.41; Br, 29.68

Found: C, 44.59; H, 9.02; N, 10.27; Br, 29.84

4 steps

3- [N ^1- (3-chloropropyl) -N ¹ -methyl amino] -N, N, N-trimethyl-1-propaneaminium chloride hydrochloride

44.4 g of 3- [N ^1- (3-hydroxypropyl) -N ¹ -methyl amino] -N, N, N-trimethyl-1-propaneaminium bromide, the reaction product of step 3, was dissolved in 500 ml of water. Concentrated hydrochloric acid was added to acidify to pH2. Pass the Doex 1-X2 chloride type ion exchange resin column and evaporate the eluate under reduced pressure, dry the residue viscose oil in vacuo, add 25 ml of thionyl chloride with stirring for an hour, and drop the solution. Heated at 50 ° C. for 1.5 h and evaporated under reduced pressure.

The residue was washed with ether (2 x 200 ml) and evaporated to dryness, then the crude product was dissolved in 100 ml of water and 0.5 g of activated carbon was added.

The mixture was heated to boiling and stirred for 1 hour in hot state.

After filtration through celite, the filtrate was evaporated under reduced pressure.

40 ml of isopropanol was added and evaporated to the obtained residue, and then 40 ml of isopropanol was further added and evaporated again until the isopropanol became 10 ml. At this time, 100 ml of acetone was added and crystallized, and the obtained solid was cut into fine powder, collected by suction filtration. The solid was washed with 3: 1 / acetone: isopropanol (2 × 10 ml) and acetone (90 ml) to recrystallize from 1: 2 / isopropanol: acetone to obtain 30 g of the desired reaction product. Obtained.

Analysis of C ₁₀ H ₂₅ N ₂ Cl ₂

Calc .: C, 42.95; H, 9.01; N, 10.02; Cl, 38.03

Found: C, 43.07; H, 9.30; N, 10.01; Cl, 38.15

Example 2

3- [N '-(3-chloropropyl) -N'-methylamino] -N, N, N-trimethyl-1-propane aluminum iodide

To a stirred solution of 216.2 mg (1 mmol) of N, N, N-trimethyl- [3- (methyl amino)]-1-propaneaminium bromide in 1.5 ml of acetonitrile 3-iodo-1- in 0.5 ml of acetonitrile A solution of 205 mg (1 mmol) of chloropropane was added. After the mixture was stirred at room temperature for 2.0 hours, the insoluble N, N, N-trimethyl- [3- (methylamino)]-1-propaneamide bromide hydrobromide was removed by filtration.

Evaporate and extract the solid residue with methylene chloride.

Me₃).The oily product obtained by evaporation of the methylene chloride extract was recrystallized from isopropanol-ether to give 90 ng (52%) of the desired reaction product. Melting point 93 ° (decomposition): NMRδ; 2.2 (3H, S, -NCH ₃ ); 3.46 (9H, S,

Me ₃ ).

Analysis for C ₁₀ H ₂₄ N ₂ Cll

Calc .: C, 35.89; H, 7.23; N, 8.37; Cl, 10.59

Found: C, 35.75; H, 7.39; N, 8.36; Cl, 10.20

Example 3

3- [N ^1- (3-chloropropyl) -N ¹ -methylamino] -N, N, N-trimethyl-1-propaneaminium bromide hydrobromide

2.25 g (14.3 mmol) of 3-bromo-1-chloropropane solution in 3.02 g (14.3 mmol) of N, N, N-trimethyl [3- (methylamino) -1-propaneaminium bromide in 30 ml of acetonitrile ) Was added and stirred at room temperature under a nitrogen stream for 3.5 hours. The reaction mixture was cooled in an ice water bath and the insoluble material was filtered off.

The filtrate was evaporated and dried in vacuo to extract with chloroform, then the chloroform extract was evaporated and dried to give 2.05 g (100%) of the desired oily reaction product.

).NMRδ; 2.2 (3H, S, -NCH ₃ ); 3.43 (9H, S,

).

Example 4

3- [N ^1- (3-iodopropyl) -N ¹ -methylamino-N, N, N-trimethyl-1-propaneaminium iodide

To a stirring solution of 216.2 mg (1 mmol) of N, N, N-trimethyl [3- (methylamino)]-1-propaneaminium bromide in 1.5 ml of acetonitrile, 1,3-diodopropane in 0.5 ml of acetonitrile 296 mg (1 mmol) of solution was added. The mixture was stirred at rt for 2.0 h, after which the insoluble N, N, N-trimethyl- [3- (methyl amino)]-1-propanaminium bromide hydrobromide was removed by filtration. The solid residue obtained by evaporating the filtrate was extracted with methylene chloride and the methylene chloride extract was evaporated to recrystallize the oily product from isopropanol-ether to obtain the desired reaction product.

Example 6

3- [N ^1- (3-bromopropyl) -N ¹ -methylamino-N, N, N-trimethyl-1-propaneaminium-bromide hydrobromide

2.88 g (14.3) of 1,3-dibromopropane solution in a stirring solution of 3.02 g (14.3 mmol) of N, N, N-trimethyl- [3- (methyl amino)]-1-propane aluminum bromide in 30 ml of acetonitrile Mmol) was added and stirred at room temperature under a nitrogen stream for 3.5 hours. The reaction mixture was cooled in an ice water bath and the insoluble material was filtered off.

The filtrate was evaporated and dried in vacuo to extract with chloroform, and then the chloroform extract was evaporated to dryness to afford the desired reaction product.

Example 6

Stage 1

3- (2-cyanoethyl) aminopropanol

54 g (1 mol) of acrylonitrile was added dropwise to 75 g (1 mol) of 3-aminopropanol solution. It was left at room temperature for several hours (preferably overnight), and then concentrated under reduced pressure at 50 ° C. to obtain 3- (2-cyanoethyl) aminopropanol.

Tier 2

Formate ester of 3- [N- (2-cyanoethyl) -N-formylamino] propanol

A solution of 127.7 g of 3- (2-cyanoethyl) -aminopropanol in 1 L of 99% formic acid was heated at 85 ° C. for 15 hours.

The residue obtained by concentration under reduced pressure at 80 ° C. was dissolved in 60 ml of methylene chloride-ethyl acetate (1: 1), and then purified by suction on 1,500 g of silica gel G column filled in methylene chloride ethyl acetate, followed by methylene chloride as an eluent. Elution was carried out using an ethyl acetate 1: 1 system. The combined eluates were concentrated to give a formate ester of 3- [N- (2-cyanoethyl) -N-formylamino] propanol.

Tier 3

3- [N- (2-cyanoethyl) -N-formylamino] propanol

A solution of 55.7 g of formate ester of 3- [N- (2-cyanoethyl) -N-formylamino) propanol in 300 ml of methanol was treated with 820 mg of sodium methoxide at room temperature. After 30 minutes, the residue obtained by concentrated drying under reduced pressure was dissolved in 500 ml of methylene chloride. The methylene chloride solution was filtered and the filtrate was concentrated under reduced pressure to afford 3- [N- (2-cyanoethyl) -N-formylamino] propanol.

4 steps

3- [N ¹ -formyl-N ^1- (3-hydroxypropyl) amino] -1-propaneaminium chloride

A solution of 15.6 g (100 mmol) of 3- [N- (2-cyanoethyl) -N-formylamino] -propanol in 225 ml of water was treated with 100 ml of 1N hydrochloric acid and 3.8 g of platinum at room temperature with a hydrogen pressure of 40 psi. Reduced.

The reaction mixture was filtered and concentrated under reduced pressure sikyeotdeoni 3- [N ¹ - formyl -N ¹ - (3- hydroxypropyl) amino] propan-1-aminium chloride is obtained.

5 steps

3- [N ¹ -formyl-N ^1- (3-hydroxypropyl) amino] -N, N, N-trimethyl-1-propaneaminium chloride

In a suspension of 3.6 g of 3- [N ¹ -formyl-N ^1- (3-hydroxypropyl) amino] -1-propaneaminium chloride in 25 ml of dimethylformamide, 10.7 g of anhydrous sodium carbonate and 33 g (15 ml) of iodomethane Was added. After the mixture was gently refluxed, the reaction mixture was stirred at the end of the initial reaction and heated at 50 ° C. for 18 hours.

The reaction mixture was filtered, the filter cake was washed with 3 × 10 ml of dimethyl formamide, the combined filtrates and washings were concentrated to dryness under reduced pressure, and the residue was dissolved in methanol and concentrated to dryness under reduced pressure. The obtained residue was triturated with hot isopropanol and filtered. The reaction product was converted to a chloride ion containing product by passing an aqueous solution containing 5% iodide through an AG1-X2 ion exchange resin (C1-cycle) column, and the aqueous eluate was concentrated to give the desired reaction product.

6 steps

3- [N ^1- (3-hydroxypropyl) -N ¹ -methyl amino] -N, N, N-trimethyl-1-propane aluminum chloride hydrochloride

A mixture of 2 g of 3- [N ¹ -formyl-N ^1- (3-hydroxy propyl) amino] -N, N, N-trimethyl-1-propaneaminium chloride, 4 g of 99% formic acid and 2 ml of formalin was stirred Then heated at 100 ° C. for 17 h.

11 ml of concentrated hydrochloric acid was added to the cooled mixture, and the reaction mixture was concentrated under reduced pressure. The product was dissolved in 35 ml of 1N hydrochloric acid, filtered, and concentrated to dryness under reduced pressure. 3- [N ^1- (3-hydroxypropyl) -N ¹ -methylamino] -N, N, N-trimethyl-1-propaneaminium Chloride hydrochloride was obtained.

Example 7

Poly-[{methyl- (3-trimethylammoniopropyl) imino} trimethylene dichloride]

13.92 g (47.4 mmol) of 3- [N ^1- (3-chloropropyl-N ¹ -methylamino] -N, N, N-trimethyl-1-propaneaminium chloride hydrochloride was 5.92 N under nitrogen stream upon cooling. 8.Oml (47.4 mmol) sodium hydroxide was added to adjust the pH of the mixture to 11.9 by addition of 1N hydrochloric acid and the solution was separated by centrifugation from the salt.

The supernatant was transferred to a three-necked flask equipped with a cooler, a stirrer, and an inert gas inlet tube, and stirred, and heated to 100 ° C. for 18 hours under a nitrogen stream.

When the reaction mixture is diluted to a volume of 200 ml and the chloride ion content of the ultrafiltrate can be neglected in the Amicon Filter Cell equipped with a UMI0 Diaflo Ultrafilter at 60 psi pressure. After ultrafiltration up to 1,000 ml of ultrafiltration was collected and the residue was concentrated under reduced pressure to dry the residue. Poly-[{methyl- (3-trimethyl ammoniopropyl) imino} trimethylene dichloride 9.4 g (81%) was obtained.

Example 8

Poly [{methyl- (3-trimethylammoniopropyl) imino} trimethylene dibromide]

1.689 g (4.09 mmol) of 3- [N ^1- (3-bromopropyl) -N ¹ -methyl amino] -N, N, N-trimethyl-1-propaneamide bromide hydrobromide under cooling nitrogen stream Treated with 0.67 ml 6N sodium hydroxide.

The mixture was centrifuged and the supernatant layer was transferred to a sealed tube and heated for 10 hours under a nitrogen stream at 100 ° C.

After diluting the reaction mixture to a volume of 100 ml and ultrafiltration until the test for halide (400 ml) of the ultrafiltrate in a Amicon pill was equipped with a UM diaphragm ultrafilter at a constant volume of 60 psi pressure, the residue remained after ultrafiltration. The water was concentrated to dryness under reduced pressure to give 340 mg of poly-[{methyl- (3-trimethylammoniopropyl) imino} trimethylene dibromide].

Example 9

Catalytic Conversion of Polymer Chloropropyl End Groups to Profiles

5.Og of poly-[{methyl- (3-trimethyl-ammoniopropyl) mino} trimethylene dichloride] (titration MW = 2546, 2.0 mmol) containing chloropropyl end groups, 5 supported on carbon A mixture of 0.5 g% palladium catalyst, 0.446 g (4.56 mmol) of Potassium acetate and 30 ml of water was shaken in a parr apparatus under 40 psi of hydrogen pressure at 22 ° C. for 40 hours. The reaction mixture was removed by filtration of the catalyst through a sinter funnel containing Supercel.

The filtrate was ultrafiltered with a UM2 ultrafilter to remove low molecular weight molecules and the residue was evaporated to dryness. The molecular weight (measured by the terminal titration method) of this substance was 3,042.

For analysis 1.21 g of reduction product was dissolved in 8 ml of water and acidified to pH 4 with 1% nitric acid. Excess silver nitrate solution was added and precipitated silver chloride was removed by centrifugation. The filtrate was passed through a supercell and ultrafiltration with an Amicon diaflo UM 2 through an ultrafilter, and the residue was concentrated under reduced pressure. 0.943 g of the desired reaction product was obtained. Is obtained.

Analysis of ionic and covalent Cl,

Calculated Value: Ionic Cl, 0%; Covalent Cl, 0%

Experimental Value: Ionic Cl, 0%; Covalent Cl, 0%

Example 10

Conversion of Polymer Chloropropyl Terminations to 2-Naphthyl Thiopropyl

A mixture of 154.6 mg sodium hydroxide and 650.6 mg 2-naphthylmercaptan in 3 ml of water was stirred at 22 ° C. for 30 minutes. 2.548 g of solid poly- [methyl- (3-trimethyl-ammoniopropyl) imino trimethylene dichloride] containing chloropropyl terminal portions (MW = 2,546 by terminal titration) and 7 ml of water were added and stirred for 24 hours. It was.

The mixture was filtered, water was added to the filtrate to 50 ml, and passed through an Amicon filter cell equipped with a UM 10 diaflo ultrafiltration filter to collect 600 ml of ultrafiltration, and the residue was concentrated to dryness under reduced pressure. A polymer containing methyl thiopropyl end groups was obtained.

Instead of 2-naphthyl mercaptan, similar amounts of methyl mercaptan, ethyl mercaptan, 3-propylmethcaptan, 2-propyl mercaptan and 4-butyl mircaptan may be used.

Example 11

Conversion of polymer chloropropyl end groups to benzenethio propyl

A solution of 3.8 g of poly- [methyl- (3-trimethyl-ammoniopropyl imino trimethylene dichloride) containing chloropropyl end groups in 6 ml of water was purified with nitrogen to obtain 441 mg (0.41 ml) of benzenethiol. And 4 ml of 1 N sodium hydroxide were stirred at room temperature under a stream of nitrogen for 24 hours, then treated with 5 ml of 1 N hydrochloric acid and extracted three times with 30 ml of ethet 3.7 g of the product obtained by concentrated to dryness under reduced pressure. Was dissolved in 100 ml of water and ultrafiltration through a UM2 diaflo ultrafilter under a constant volume of 60 psi pressure.

1,200 ml of the ultrafiltrate was collected and the residue was concentrated to dryness under reduced pressure to give 3.27 g of a polymer in which the 3-chloropropyl end group was converted to a 3-benzenethiopropyl end group.

Example 12

Conversion of Polymer Chloropropyl End Groups into Trimethyl Ammoniopropyl

A solution of 2.7 g of poly- [methyl- (3-trimethyl-ammoniopropyl) imino trimethylene dichloride] containing chloropropyl end groups in 5 ml of water was treated with 25 ml of 6.4 M aqueous trimethylamine at room temperature.

After 24 hours, the reaction mixture was concentrated to dryness under reduced pressure at 30 ° C., and the product obtained was pulverized into powder and dried under reduced pressure or dissolved in 50 ml of water, so that trimethylamine was no longer contained in the ultrafiltrate under a constant volume of 60 psi pressure. Until no detection, ultrafiltration through a UM 2 diaflo ultrafilter and the residue concentrated under reduced pressure yielded 2.7 g of a reaction product in which the 3-chloropropyl end group was converted to a 3-trimethylamino propyl end group.

In a similar manner, trilower amines such as triethylamine, tripropylamine and tributylamine can be used as well as mixtures of these trilower alkyl amines.

Claims (1)

As described above in the text, N, N, N-trimethyl- [3- (methylamino)]-1-propaneaminium halide is obtained by reacting with oxetane and then 3- [N- (3) in general formula (5) -Hydroxy propyl) methylamino] -N, N, N-trimethyl-propane-l-aluminum halide is reacted with a halogenating agent to yield 3- [N- (3-halopropyl) -methyl of the following general formula (6): Amino) -N, N, N-trimethyl-propane-1-aluminum compound is obtained, and then, if necessary, the anion X ⁻ of the compound of formula (6) is exchanged with ^a pharmaceutically acceptable anion Y ^a to A process for producing 3- [N- (3-halopropyl) methylamino] -N, N, N-trimethyl-propane-1-aluminum compound of formula (4).