CN1189168A - Hydrophobic heteroatom-containing sequestrant for cholesterol depletion - Google Patents
Hydrophobic heteroatom-containing sequestrant for cholesterol depletion Download PDFInfo
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Abstract
The present invention relates to a poly(allylamine) polymer and, more generally, a hydrocarbon amine polymer. Preferably, these polymers are crosslinked. The present invention also relates to methods of forming these polymers and methods for their use. Further, the present invention relates to alkylating agents that can be employed to form the polymers and to methods for forming the alkylating agents. Generally, the polymer sequestrant includes a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety having one, two or three terminal hydrophobic substituents. A method of preparing quaternary amine-containing alkylating agents includes reacting an unsymmetrical dihalide with a tertiary amine having at least one hydrophobic substituent. A method for binding bile salts of bile acids in a mammal includes orally administering to the mammal a therapeutically-effective amount of the polymer sequestrant.
Description
Related application of the present invention
The application is a U. S. application number 08/469,659 (the applyings date: the application that continues of part June 6 nineteen ninety-five), and the latter is a U. S. application number 08/258, on June 10th, 1994) and U. S. application number 08/,332 431 (application orders:, 096 (applying date: the application that continues of part on October 31st, 1994), these documents all are hereby incorporated by reference.
Background technology of the present invention
Bile salt as stain remover with the dissolving so that the food that helps digest in fat.Bile acide results from cholesterol, therefore, removes bile acide and can cause cholesterol to reduce.Bile acide is absorbed by (passive) in jejunum after the digestion, or is absorbed by the active transport in the ilium again.Just do not lost by resorbent bile acide.
Heavily absorb bile acide from enteron aisle and preserved the lipoprotein cholesterol the blood flow.On the contrary, blood cholesterol concentration can reduce because of the absorption again that has reduced bile acide.
Reduce bile acide more a kind of method of absorbed dose be oral can the conjugation bile acide and himself non-absorbent compound.The bile acide of these chelatings is drained at last.
But, many bile acid chelating agents and the elementary bile acide of debond conjugated, for example, can not be well in conjunction with the conjugated bile acide to prevent that major portion from being absorbed again.In addition, the volume of the sequestrant that can be digested also is limited.As a result, the efficient of many sequestrants reduction blood cholesterol content also is restricted.
And many sequestrants synthetic also may be subjected to preparing the restriction of the reaction yield and the expense of suitable precursor.For example, the alkylating agent that is used for carrying out polymer modification may be difficult to preparation.In addition, the ability of alkylating agent and polymer reaction also may limit the efficient of gained sequestrant.
Therefore, need a kind of sequestrant and a kind ofly overcome or make the minimized method of above-mentioned difficulties.
The present invention's general introduction
The present invention relates to gather (allylamine) polymkeric substance, more generally, relate to hydrocarbon amine polymer.These polymkeric substance are preferably crosslinked.The invention still further relates to the method for preparing and use these polymkeric substance.In addition, the invention still further relates to the method that can be used for preparing the alkylating agent of these polymkeric substance and prepare alkylating agent.
On the one hand, poly-(allylamine) polymkeric substance is crosslinked, and contains the substituting group on the amine that is connected to polymkeric substance.Substituting group comprises and contains the quaternary amine part, wherein the nitrogen on this part quaternary amine is connected on the amine of polymkeric substance by the alkylidene group that 3 or more a plurality of carbon atoms are arranged, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
The method for preparing crosslinked poly-(allylamine) polymkeric substance comprises reacts crosslinked poly-(allylamine) and the quaternary ammonium compound that contains with following formula structure,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
On the other hand, the present invention relates to a substituting group and be connected to hydrocarbon amine polymer on the polymeric amine, this substituting group comprises and contains the quaternary amine part, nitrogen on the wherein said quaternary ammonium part links to each other with the amine of polymkeric substance by the alkylidene group that 3 or more a plurality of carbon atoms are arranged, and, have at least two to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is the alkyl that about 5 carbon atoms of 1-are arranged.
The method for preparing the crosslinked hydrocarbon amine polymer of the present invention comprises the step that crosslinked hydrocarbon amine polymer and the quaternary ammonium compound with following formula structure are reacted,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
The application method of poly-(allylamine) polymkeric substance of the present invention and hydrocarbon amine polymer comprises that these polymkeric substance to Mammals oral administration amount are with conjugated bile acid, reduce blood cholesterol levels, treat atherosis, treatment hypercholesterolemia or reduce mammiferous lipids contents.On the other hand, the present invention relates to have the quaternary ammonium compound of following formula structure,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
The method for preparing quaternary ammonium compound comprises will the tertiary amine of following formula structure being arranged:
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
With the step of the asymmetric dihalide reaction that the following formula structure is arranged,
X
1--(CH
2)
n--X
2
Wherein,
X
1Be chlorine,
X
2Be bromine, and
N is 〉=3 integer.
The present invention has many advantages.For example, the present invention's poly-(allylamine) and hydrocarbon amine polymer sequestrant combine with the conjugated bile acide, comprise elementary bile acide, otherwise these bile acides can be absorbed again by active transport.To aspect the conjugated bile acid, a possible explanation of polymeric chelant improvement in performance of the present invention is the ability that they and bile acide form hydrogen bond and ionic linkage.Hydrogen bond can partly be formed by the secondary amine of polymkeric substance, and ionic linkage can be formed by the quaternary amine substituting group.And, with the outside or terminal efficient that distributes to the sequestrant of remarkable each given dose of increase of the main chain of polymkeric substance and the polymeric chelant hydrophobic part relevant with the quaternary amine part contribution is arranged with the secondary amine of polymkeric substance.In addition, two or more hydrophobic alkyls are as the substituent existence of end, for the hydrophobic combination of biliary salts provides more multi-section position.
The preparation method of polymeric chelant of the present invention also comprises several advantages.For example, hydrocarbon amine polymer can adopt and will realize that described leavings group is removed three carbon atoms at least from the quaternary amine center with the amine moiety reaction on the leavings group of carbon-bearing atom with the quaternary amine alkylation as the amine moiety of poly-(allylamine) polymkeric substance.What also be sure of in addition, is with having at least the alkylidene group of three carbon atoms that quaternary amine is attached to hydrocarbon amine polymer, especially gather (allylamine) polymkeric substance, the performance of the sequestrant of generation being improved.
When containing the quaternary amine alkylating agent, preparation the present invention use asymmetric dihalide can increase the productive rate and the purity of required product.Because the halogen in the asymmetric dihalide is not of equal value aspect reactive, have more that the reaction of the carbon atom of multiple reactionness halogen almost is single-minded, therefore, it is with the good pure relatively compound of productive rate preparation.Then, the available this pure relatively amine nitrogen atom alkylation that the quaternary amine alkylating agent carries out the hydrocarbon amine polymer main chain that contains.Detailed description of the present invention
Now, we will more specifically describe characteristic of the present invention and other content, and claimed in claims.Should be appreciated that, be used for illustrating that specific examples of the present invention does not limit the present invention.Main characteristic of the present invention can be used for not deviating from the various situations of the scope of the invention.
Here used term " hydrocarbon amine polymer " refers to mainly by carbon, the polymkeric substance that hydrogen and nitrogen are formed.Preferred hydrocarbon amine polymer is crosslinked.Preferred hydrocarbon amine polymer is poly-(allylamine) polymkeric substance.Most preferred hydrocarbon amine polymer is crosslinked poly-(allylamine) polymkeric substance.Other hydrocarbon amine polymer example that is fit to comprises poly-(vinyl amine) and poly-(ethylene imine) polymkeric substance.
Hydrocarbon amine polymer sequestrant of the present invention contains a substituting group on the amine that is connected to polymkeric substance.This substituting group comprises the quaternary amine part, and the alkylidene group of the nitrogen on the wherein said quaternary ammonium part by 3 or more a plurality of carbon atoms are arranged links to each other with amine on the main polymer chain.And, have at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine with about 24 carbon atoms of 6-, remaining terminal substituting group is respectively the alkyl that about 5 carbon atoms of 1-are arranged.
" the terminal substituting group " of used here term quaternary amine refers to any one in three substituting groups on the quaternary amine nitrogen-atoms, and is not the carbochain between the amine at amine on the main polymer chain and quaternary ammonium center.
Here used term " hydrophobic alkyl " refers to have about 24 carbon atoms of 6-and end is the alkyl of hydrophobic part.For example, hydrophobic alkyl can be a fat, fragrance, side chain or ring-type carbochain.Hydrophobic substituent does not comprise the alkylidene group between the nitrogen at nitrogen on the amine polymer main chain and quaternary ammonium center.
In a specific examples, hydrocarbon amine polymer is crosslinked poly-(allylamine) polymkeric substance, and contains the substituting group on the amine that is connected to polymkeric substance.This substituting group comprises and contains the quaternary amine part, nitrogen on the wherein said quaternary ammonium part links to each other with the amine of polymkeric substance by the alkylidene group that 3 or more a plurality of carbon atoms are arranged, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl that about 5 carbon atoms of 1-are arranged.
Preferred embodiment comprises crosslinked poly-(allylamine) polymkeric substance, and wherein alkylidene group has three carbon length, has at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, and this alkyl can be an octyl group, decyl or dodecyl, and remaining terminal substituting group is a methyl.
Other preferred embodiment comprises crosslinked poly-(allylamine) polymkeric substance, and wherein alkylidene group has four carbon length, has at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, and this alkyl can be an octyl group, decyl or dodecyl, and remaining terminal substituting group is a methyl.
Other preferred embodiments comprise crosslinked poly-(allylamine) polymkeric substance, wherein alkylidene group has five carbon length, has at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, and this alkyl can be an octyl group, decyl or dodecyl, remaining terminal substituting group is a methyl.
Also have some preferred embodiments to comprise crosslinked poly-(allylamine) polymkeric substance, wherein alkylidene group has six carbon length, has at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, and this alkyl can be an octyl group, decyl or dodecyl, remaining terminal substituting group is a methyl.
On the one hand, poly-(allylamine) polymkeric substance of the present invention has following formula,
Wherein,
N is 〉=3 integer, and
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom.
The method for preparing crosslinked poly-(allylamine) polymkeric substance comprises reacts crosslinked poly-(allylamine) and the quaternary ammonium compound that contains with following formula structure,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
The preferred embodiment of crosslinked poly-(allylamine) of preparation comprises crosslinked poly-(allylamine) polymkeric substance in this way, wherein alkylidene group has three carbon length, have at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, this alkyl can be an octyl group, decyl or dodecyl, remaining terminal substituting group is a methyl.
Other preferred embodiment of crosslinked poly-(allylamine) of preparation comprises crosslinked poly-(allylamine) polymkeric substance in this way, wherein alkylidene group has four carbon length, have at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, this alkyl can be an octyl group, decyl or dodecyl, remaining terminal substituting group is a methyl.
Other preferred embodiments of crosslinked poly-(allylamine) of preparation comprise crosslinked poly-(allylamine) polymkeric substance in this way, wherein alkylidene group has five carbon length, have at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, this alkyl can be an octyl group, decyl or dodecyl, remaining terminal substituting group is a methyl.
Some other preferred embodiment of crosslinked poly-(allylamine) of preparation comprises crosslinked poly-(allylamine) polymkeric substance in this way, wherein alkylidene group has six carbon length, have at least one to be hydrophobic alkyl in three terminal substituting groups of quaternary amine, this alkyl can be an octyl group, decyl or dodecyl, remaining terminal substituting group is a methyl.
On the other hand, the present invention relates to contain a substituent hydrocarbon amine polymer on the amine that is connected to polymkeric substance.This substituting group comprises the quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or a plurality of carbon atoms to link to each other with amine on the main polymer chain by one, and having two or all three in three terminal substituting groups of quaternary amine at least is respectively the hydrophobic alkyl with about 24 carbon atoms of 6-.Two or three terminal substituting groups at quaternary amine are respectively under the situation of hydrophobic alkyl, and remaining terminal substituting group is the alkyl that about 5 carbon atoms of 1-are arranged.Hydrocarbon amine polymer is crosslinked in preferred embodiment.
The method for preparing the crosslinked hydrocarbon amine polymer of the present invention comprises the step that crosslinked hydrocarbon amine polymer and the quaternary ammonium compound with following formula structure are reacted,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
The preferred embodiment of Zhi Bei crosslinked hydrocarbon amine polymer comprises poly-(vinyl amine) in this way, poly-(allylamine) and poly-(ethylene imine) polymkeric substance.
The application method of poly-(allylamine) polymkeric substance of the present invention and hydrocarbon amine polymer comprises these polymkeric substance to Mammals oral administration amount, be used for conjugated bile acid, reduce blood cholesterol levels, treat atherosisly, treat hypercholesterolemia or reduce mammiferous lipids contents.Generally, the therapeutic dose of hydrocarbon amine polymer and poly-(allylamine) polymkeric substance is about 0.1-20 gram/sky.
On the one hand, the inventive method is the method in conjunction with the Mammals biliary salts, comprises the step to the hydrocarbon amine polymer of the present invention of Mammals oral administration amount.On the other hand, the inventive method is the method in conjunction with the Mammals biliary salts, comprises the step to poly-(allylamine) polymkeric substance of the present invention of Mammals oral administration amount.
On the other hand, the inventive method is to reduce the method for mammalian cholesterol, comprises the hydrocarbon amine polymer of the present invention of taking therapeutic dose to Mammals, the step of preferred crosslinked poly-(allylamine) polymkeric substance.Another aspect the present invention includes the atherosis method of treatment Mammals, comprises the hydrocarbon amine polymer of the present invention of taking therapeutic dose to Mammals, the step of preferred crosslinked poly-(allylamine) polymkeric substance.Another aspect, the inventive method are the methods of treatment Mammals hypercholesterolemia, comprise the hydrocarbon amine polymer of the present invention of taking therapeutic dose to Mammals, the step of preferred crosslinked poly-(allylamine) polymkeric substance.
The present invention is the method that reduces Mammals blood fat content on the other hand, comprise to the oral polymkeric substance of the present invention of Mammals with chelating tightly by Mammals excretory conjugation bile acide, therefore, the major portion of conjugation bile acide is drained by Mammals, thereby quickened the metabolism of lipid, and then reduced mammiferous serum lipid concentrations.In preferred embodiment, the elementary bile acide of chelating comprises the elementary bile acide of conjugated, as conjugated cholic acid and conjugated chenocholic acid.
Hydrocarbon amine polymer of the present invention and poly-(allylamine) polymkeric substance are particularly suitable for by oral polymkeric substance in conjunction with the elementary bile acide of the conjugated in the mammalian body such as glycocholic acid and sweet ammonia chenocholic acid.The form that is particularly suitable for hydrocarbon amine polymer and poly-(allylamine) polymkeric substance oral administration is to form gelationus form in patient's stomach.
Can prepare preferred amines polymkeric substance of the present invention with proper method, the example of these methods is as follows:
1. a method is to prepare homopolymer by the polymeric amine monomer.The example of this method comprises the polymerizable alkenyl propylamine, ethylene imine, and vinyl amine, 1, the 2-diamino-vinyl, aminopropyl acrylate or the cinnamic polymerization of right-amino methyl prepare their homopolymer separately.
2. another kind of method is with amine monomers and one or more other monomer copolymerizable.Described other monomer comprises amine monomers, as top listed those, and non-amine monomers such as acrylamide, vinylbenzene, Vinylstyrene, vinyl alcohol or vinylchlorid.Example comprises copolymerization (allylamine/acrylamide), copolymerization (vinyl amine/allylamine) and copolymerization (allylamine/Vinylstyrene).
3. another kind of method is that the non-amine monomers of polymerization prepares homopolymer, forms amine polymer through chemical modification then.The example of this method comprises the polymerization of vinyl methane amide, vinyl acetamide, and vinylchlorid, bromine ethene, chlorallylene, allyl bromide 98, acrylamide or vinyl cyanide form their homopolymer separately.By hydrolysis, nucleophilic substitution reaction or reduction reaction form amine polymer with each homopolymer chemical modification then.Like this, above-listed preceding four kinds of homopolymer become poly-(vinyl amine), and back four kinds become poly-(allylamine).Should be appreciated that not all initial non-amine monomers need carry out chemical modification, also can obtain containing the amine polymer of the initial non-amine monomers of some non-amine states.
4. the 4th kind of method is with non-amine monomers and one or more other monomer copolymerizable.Described other monomer comprises amine monomers, as listed those in the first method, and non-amine monomers, as listed those in the third method.Then with gained multipolymer chemical modification, to prepare amine polymer listed in the third method.Example comprises acrylamide and styrene copolymerisation, then prepares copolymerization (allylamine/vinylbenzene) by reduction reaction; With vinyl cyanide and vinyl formamide copolymerization, then reduce and hydrolysis reaction, form copolymerization (allylamine/vinyl amine); And, then carry out reduction reaction with vinyl cyanide and allylamine copolymerization, form poly-(allylamine).Should be appreciated that not all initial non-amine monomers need carry out chemical modification, also can obtain containing the amine polymer of the initial non-amine monomers of some non-amine states.
5. the 5th kind of method comprises by condensation mechanism and prepares amine polymer.The example of this method comprises diethylenetriamine and Epicholorohydrin, 1, and 3-dibromopropane and quadrol, spermine and 1,4-butanediol diglycidyl ether, or three (2-amino-ethyl) amine and 1, the reaction of 10-dibromo-decane.
These amine polymers molecular weight separately is generally all greater than about 2,000.The example of the suitable hydrocarbon amine polymer of gained comprises poly-(vinyl amine), poly-(allylamine) and poly-(ethylene imine) polymkeric substance.Preferred hydrocarbon amine polymer is poly-(allylamine) polymkeric substance.
Preferred hydrocarbon amine polymer is crosslinked, for example by polymkeric substance and suitable linking agent reaction generation.The example of suitable linking agent comprises acrylate chloride, Epicholorohydrin, butyleneglycol glycidyl ether, diglycidyl ether of ethylene glycol, Succinic acid dimethylester etc.Epicholorohydrin is a preferred cross-linking agents.Generally, be used for the amount of the linking agent of hydrocarbon amine polymer reaction want foot can make can with about 0.5-20% reaction generation in the site of linking agent reaction.The amine groups of about 0.5-6% and linking agent reaction in the hydrocarbon amine polymer in preferred embodiment.Amine groups in another preferred embodiment in about 2-12% hydrocarbon amine polymer and linking agent reaction.
The crosslinked of polymkeric substance can react realization in 18 hours by polymkeric substance and suitable linking agent in about 25 ℃ of aqueous solution, prepare a kind of colloid.Then this colloid is combined with water, or be dried to granular solids.Then this particulate solid is washed with water, dry under proper condition, as under about 50 ℃ of temperature dry about 18 hours.
Hydrocarbon amine polymer can be alkylated into sequestrant of the present invention.Here used term " alkylating agent " refers to can make when reacting with hydrocarbon amine polymer the nitrogen-atoms that contains the quaternary amine part by one the alkylidene group of three or more carbon atoms and the covalently bound reagent of main chain amine on one or more hydrocarbon amine polymer to be arranged.The suitable alkylating agent of the present invention can be a quaternary ammonium compound.Therefore, the present invention includes the quaternary ammonium of following formula on the other hand,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
On the other hand, X is a halogenide.The preferred value of n is 3-6.On the other hand, one or two in the described alkyl is a methyl.
The specific examples that is suitable as the quaternary ammonium compound of alkylating agent comprises:
(4-brombutyl) dioctyl methyl brometo de amonio;
(3-bromopropyl) dodecyl dimethyl brometo de amonio;
(3-chloropropyl) dodecyl dimethyl brometo de amonio;
(3-bromopropyl) octyldimethyl brometo de amonio;
(3-chloropropyl) octyldimethyl brometo de amonio;
(3-iodine butyl) dioctyl methyl brometo de amonio;
(2, the 3-epoxypropyl) decyl dimethyl brometo de amonio;
(3-chloropropyl) decyl dimethyl brometo de amonio;
(5-tosyl group amyl group) dodecyl dimethyl brometo de amonio;
(6-bromine hexyl) octyldimethyl brometo de amonio;
(12-bromine dodecyl) decyl dimethyl brometo de amonio;
(3-bromopropyl) tridecyl brometo de amonio;
(3-bromopropyl) docosyl dimethyl brometo de amonio;
(6-bromine hexyl) docosyl dimethyl brometo de amonio;
(4-chlorobutyl) dodecyl dimethyl brometo de amonio;
(3-chloropropyl) octadecyl dimethyl brometo de amonio;
(3-chloropropyl) hexyl dimethyl brometo de amonio;
(3-chloropropyl) methyl dioctyl brometo de amonio;
(3-chloropropyl) methyl didecyl brometo de amonio;
(3-chloropropyl) cyclohexyl dimethyl brometo de amonio;
(3-chloropropyl) tetradecyl dimethyl brometo de amonio; Deng.
Should be appreciated that, can halogenated form use above-claimed cpd, comprise bromide, muriate and iodide, and other negatively charged ions, as acetate, nitrate, vitriol and tosilate.
A kind of preparation comprises the tertiary amine with following formula as the example of the proper method of alkylating agent of the present invention (preferred quaternary ammonium compound),
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
With the step of the asymmetric dihalide reaction that the following formula structure is arranged,
X
1--(CH
2)
n--X
2
Wherein,
X
1Be chlorine,
X
2Be bromine, and
N is 〉=3 integer.
On the other hand, tertiary amine can have two or all three that the alkyl or the substituted alkyl of about 24 carbon atoms of 6-are arranged.Under the situation that two alkyl are arranged, that remaining alkyl has about 5 carbon atoms of 1-.Generally, alkylated reaction is that the tertiary amine that will replace combines in organic solvent with suitable dihalide.The example of suitable symmetrical dihalide is a dichloride.The example of suitable dichloride is 1, the 3-propylene dichloride.
Preferred dihalide of the present invention also comprises asymmetric dihalide.Here Ding Yi " asymmetric dihalide " is meant the different dihalide of halogen in the dihalide, therefore has different reactivities as alkylating agent.The suitable example of asymmetric dihalide comprises 1-bromo-3-chloropropane and 1-bromo-4-chlorobutane.Generally, when dihalide is a bromine/chlorine when mixing, the molecule of the terminal band of the molecular ratio chlorine of terminal band bromine has more reactivity.Therefore, the reaction of asymmetric dihalide will make exclusive reaction almost all occur in an end of band bromine, and an end of band chlorine reacts hardly.Then, available this pure relatively compound is by the nitrogen on the reaction alkylated hydrocarbons amine polymer that occurs in the chlorine end.The unwanted side reaction that usually occurs when using asymmetric dihalide to avoid using symmetrical dihalide had both increased the productive rate that contains the quaternary amine alkylating agent, had increased purity again.The example of appropriate organic solvent comprises methyl alcohol, ether etc.Preferred organic is a methyl alcohol.
The chien shih tertiary amine can react with asymmetric dihalide when keeping being reflected at certain temperature and sufficiently long.These parameters generally depend on the character of reactant, and can be by those of ordinary skills with approach is definite by experiment.
Finish reaction by removing with proper method to desolvate.Prepare the thick quaternary amine alkylating agent that contains with the known method of those of ordinary skills and be used for further reaction.
Hydrocarbon amine polymer generally by with this polymkeric substance with contain the quaternary amine alkylating agent and in organic solvent or water, combine and make its alkylation.Be used for to be enough to usually cause that with the consumption of hydrocarbon amine polymer bonded alkylating agent the reaction nitrogen-atoms greater than about 5% reacts on alkylating agent and the hydrocarbon amine polymer.The example of appropriate solvent comprises methyl alcohol, ethanol, acetonitrile, water etc.Preferred solvent is water and methyl alcohol.
The particularly preferred situation of the present invention is that hydrocarbon amine polymer is crosslinked poly-(allylamine), and wherein substituting group comprises (3-propyl group) dodecyl alkyl dimethyl ammonium chloride.Perhaps, hydrocarbon amine polymer is crosslinked poly-(allylamine), and wherein substituting group comprises butyl dioctyl ammonio methacrylate.In addition, particularly preferred crosslinked poly-(allylamine) and epichlorohydrin cross-linked, Epicholorohydrin accounts for about 0.5-6% of amine in the polymkeric substance.
Then, can prepare and be used for the hydrocarbon amine polymer liquid preparations for oral administration with other material processing hydrocarbon amine polymer of the present invention.
Pharmaceutical composition of the present invention generally prepares by currently known methods with known and composition that be easy to obtain.Can use hydrocarbon amine polymer separately when the preparation present composition, also can mix with carrier, or dilute with carrier, or wrap in capsule, sachet uses in the carrier of paper bag or other vessel form together.When carrier was used as thinner, it can be that polymkeric substance is played carrier, solid, semisolid or the fluent material of vehicle or medium effect.Therefore, said composition can be following form: tablet, pill, pulvis, lozenge, sachet, cachet, elixir, suspension agent, syrup, colloidal sol, (solid or in liquid medium), soft or hard-gelatin capsules, pulvis of sterile packed or the like.Be suitable as carrier, the example of vehicle and thinner comprises food, beverage, lactose, glucose, sucrose, Sorbitol Powder, mannitol, starch, Sudan Gum-arabic, alginate, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, methylcellulose gum, methyl hydroxybenzoate, nipasol, and talcum.
The negative charge counter ion of pharmaceutical composition can comprise organic ion, mineral ion, or their binding substances.Be applicable to that mineral ion of the present invention comprises halogenide (especially muriate), carbonate and supercarbonate.The organic ion that is fit to comprises acetate and benzoate.
The following example will further and specify the present invention.All shares and per-cent are weight except as otherwise noted.Most preferred embodiment of the present invention
Embodiment 1
The preparation that gathers (allylamine) hydrochloride with epichlorohydrin cross-linked
In one 5 gallon container, add poly-(allylamine) hydrochloride (1kg) and the water (4L) that are obtained from Nitto Boseki.Stirring the mixture makes this hydrochloride dissolving, and adds solid NaOH (284g) adjusting pH.With gained solution cool to room temperature, when stirring, once add whole epichlorohydrin cross-linked agent (50mL) then.Leniently stirring the gained mixture makes it to become glue after about 35 minutes.This crosslinking reaction is continued to carry out 18 hours in room temperature, then it is put into blending machine with 10L water altogether in batches.Each batch all slowly stirs and formed in about 3 minutes coarse particles, last restir 1 hour.Solid collected by filtration successively is suspended in 10L with solid, and rinsing is three times in 15L and the 20L water, and each stirred suspension 1 hour is solid collected by filtration then.With solid suspension once, stirred the mixture 1 hour, then solid collected by filtration again in Virahol (17L) rinsing.With solid in 50 ℃ of vacuum ovens dry 18 hours, obtain the crisp crosslinked polymkeric substance of white solid of about 677g particulate state.
Embodiment 2
With the alkylation of (3-bromopropyl) dodecyl dimethyl brometo de amonio crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described.In flask, put into crosslinked poly-(allylamine) (12.5g; 6% is crosslinked; Be ground to less than 30 orders), (3-bromopropyl) dodecyl dimethyl brometo de amonio (17.5g; By 1,3-dibromopropane and N, the reaction of the amino dodecane of N-dimethyl-1-in diethyl etherate made) and methyl alcohol (334mL).With mixture heating up to 65 ℃, to wherein adding aqueous sodium hydroxide solution (1.14g 50% solution), and continue to stir 2 hours when reaching 65 ℃ when stirring in 65 ℃.Successively add aqueous sodium hydroxide solution (1.14g 50% solution) twice, at every turn all in 65 ℃ of continuously stirring 2 hours.Add aqueous sodium hydroxide solution (1.14g 50% solution) again, and continue to stir 12 hours at 65 ℃.Then mixture is cooled to room temperature.
Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1. 459mL 2M NaCl (aqueous solution)
2. 459mL 2M NaCl (aqueous solution)
3. 2L deionized water
4. 2L deionized water
5. 2L deionized water
6. 2L deionized water
Then that the gained solid is dry in 60 ℃ of blast furnaces (forced-air oven), obtain 17.4g rice white solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 3 usefulness (3-bromopropyl) dodecyl dimethyl brometo de amonio alkylation crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described.In flask, put into crosslinked poly-(allylamine) (12.5g; 6% is crosslinked; Be ground to less than 30 orders), (3-bromopropyl) dodecyl dimethyl brometo de amonio (35g; By 1,3-dibromopropane and N, the reaction of the amino dodecane of N-dimethyl-1-in diethyl etherate made) and methyl alcohol (334mL).With mixture heating up to 65 ℃, to wherein adding aqueous sodium hydroxide solution (1.99g 50% solution), and continue to stir 2 hours when reaching 65 ℃ when stirring in 65 ℃.Successively add aqueous sodium hydroxide solution (1.99g 50% solution) twice, at every turn all in 65 ℃ of continuously stirring 2 hours.Add aqueous sodium hydroxide solution (1.99g 50% solution) again, and continue to stir 12 hours at 65 ℃.Then mixture is cooled to room temperature.
Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1. 459mL 2M NaCl (aqueous solution)
2. 459mL 2M NaCl (aqueous solution)
3. 2L deionized water
4. 2L deionized water
5. 2L deionized water
6. 2L deionized water
Then that the gained solid is dry in 60 ℃ of blast furnaces, obtain 25.6g rice white solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 4
With the alkylation of (3-bromopropyl) dodecyl dimethyl brometo de amonio crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described, but used Epicholorohydrin not 50mL, but 16.7mL.In flask, put into crosslinked poly-(allylamine) (12.5g; 2% is crosslinked; Be ground to less than 30 orders), (3-bromopropyl) dodecyl dimethyl brometo de amonio (140.8g; By 1,3-dibromopropane and N, the reaction of the amino dodecane of N-dimethyl-1-in diethyl etherate made) and methyl alcohol (334mL).With mixture heating up to 65 ℃, to wherein adding aqueous sodium hydroxide solution (7.1g 50% solution), and continue to stir 2 hours when reaching 65 ℃ when stirring in 65 ℃.Successively add aqueous sodium hydroxide solution (7.1g 50% solution) twice, at every turn all in 65 ℃ of continuously stirring 2 hours.Add aqueous sodium hydroxide solution (1.99g 50% solution) again, and continue to stir 12 hours at 65 ℃.Then mixture is cooled to room temperature.
Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1.7L 2M NaCl (aqueous solution)
2. 1.7L 2M NaCl (aqueous solution)
3. 8L deionized water
4. 8L deionized water
5. 8L deionized water
6. 8L deionized water
7. 4L deionized water
Then that the gained solid is dry in 60 ℃ of blast furnaces, obtain 39.8g rice white solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 5
With the alkylation of (3-bromopropyl) dodecyl dimethyl brometo de amonio crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described.In flask, put into crosslinked poly-(allylamine) (12.5g; 6% is crosslinked; Be ground to less than 30 orders), (3-bromopropyl) dodecyl dimethyl brometo de amonio (30.2g; By 1,3-dibromopropane and N, the reaction of the amino dodecane of N-dimethyl-1-in diethyl etherate made) and methyl alcohol (334mL).With mixture heating up to 65 ℃, to wherein adding aqueous sodium hydroxide solution (2.0g 50% solution), and continue to stir 2 hours when reaching 65 ℃ when stirring in 65 ℃.Successively add aqueous sodium hydroxide solution (2.0g 50% solution) twice, at every turn all in 65 ℃ of continuously stirring 2 hours.Add aqueous sodium hydroxide solution (2.0g 50% solution) again, and continue to stir 12 hours at 65 ℃.Then mixture is cooled to room temperature.
Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1. 800mL 2M NaCl (aqueous solution)
2. 800mL 2M NaCl (aqueous solution)
3. 2L deionized water
4. 2L deionized water
5. 1L deionized water
Then that the gained solid is dry in 60 ℃ of blast furnaces, obtain 16.8g rice white solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 6
With (6-bromine hexyl) octyldimethyl brometo de amonio alkylation crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described.In flask, put into crosslinked poly-(allylamine) (12.5g; 6% is crosslinked; Be ground to less than 30 orders), (6-bromine hexyl) octyldimethyl brometo de amonio (33.7g; By 1,6-dibromo-hexane and N, the N-dimethyl-reaction of 1-amino-octane in diethyl etherate made) and methyl alcohol (334mL).With mixture heating up to 65 ℃, to wherein adding aqueous sodium hydroxide solution (1.68g 50% solution), and continue to stir 2 hours when reaching 65 ℃ when stirring in 65 ℃.Successively add aqueous sodium hydroxide solution (1.68g 50% solution) twice, at every turn all in 65 ℃ of continuously stirring 2 hours.Add aqueous sodium hydroxide solution (1.68g 50% solution) again, and continue to stir 12 hours at 65 ℃.Then mixture is cooled to room temperature.
Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1. 1L 2M NaCl (aqueous solution)
2. 1L 2M NaCl (aqueous solution)
3. repeat to use the 1L deionized water, up to the specific conductivity of solution less than 1mS/cm
Then that the gained solid is dry in 60 ℃ of blast furnaces, obtain .15.7g rice white solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 7
With the alkylation of (4-butyl) dioctyl methyl brometo de amonio crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described, but used epichlorohydrin cross-linked agent not 50mL, but 25mL.In flask, put into crosslinked poly-(allylamine) (12.5g; 3% is crosslinked; Be ground to less than 30 orders), (4-brombutyl) dioctyl methyl brometo de amonio (65.8g crude product; By 1,4-dibromobutane and N, the reaction of N-dioctyl methylamine in methyl alcohol made) and methyl alcohol (334mL).With mixture heating up to 65 ℃, to wherein adding aqueous sodium hydroxide solution (3.28g 50% solution), and continue to stir 2 hours when reaching 65 ℃ when stirring in 65 ℃.Successively add aqueous sodium hydroxide solution (3.28g 50% solution) twice, at every turn all in 65 ℃ of continuously stirring 2 hours.Add aqueous sodium hydroxide solution (3.28g 50% solution) again, and continue to stir 12 hours at 65 ℃.Then mixture is cooled to room temperature.
Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1. 800mL methyl alcohol
2. 1000mL methyl alcohol
3. 890mL 2M NaCl (aqueous solution)
4. 890mL 2M NaCl (aqueous solution)
5. 2L deionized water
6. 2L deionized water
Then that the gained solid is dry in 60 ℃ of blast furnaces, obtain 27.1g rice white solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 8
The preparation of (3-chloropropyl) dodecyl diethyl brometo de amonio
In the 2L three neck round-bottomed flasks that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl amino dodecane (297.24g, 1.40mol), 1-bromo-3-chloropropane (220.44g, 1.40mol) and methyl alcohol (250mL).Keeping being reflected at 65 ℃ carried out 24 hours.Remove methyl alcohol by the decompression rotary evaporation, obtain brown sediment.In sediment, add methyl-uncle's butyl ether (2L), produce white solid.Mixture was stirred 2 hours, and the hemicrystalline white particle that produces is collected in vacuum filtration.With these particles in 35 ℃ of vacuum ovens dry 24 hours, obtain 228.2g (0.61mol, 44%) title compound.
Embodiment 9
With the alkylation of (3-chloropropyl) dodecyl dimethyl brometo de amonio crosslinked poly-(allylamine)
Make crosslinked poly-(allylamine) by embodiment 1 is described, be final crosslinked be 3 moles of %.In a 2L three-necked flask that thermometer and condenser be housed, put into crosslinked poly-(allylamine) (25g; 3% is crosslinked; Be ground to 10 orders), (3-chloropropyl) dodecyl dimethyl brometo de amonio (280g, 0.755mol; As preparation as described in the embodiment 8) and water (750mL).When stirring with mixture heating up to 100 ℃, reach 100 ℃ after in 8 hours by uniformly-spaced the time adds 10 aqueous sodium hydroxide solutions (6.1g 50% solution).Continuation was stirred 16 hours at 100 ℃.Then mixture is cooled to room temperature.
Add concentrated hydrochloric acid (50mL), stirred the mixture 10 minutes, then solid collected by filtration.Solid is used the 1.5L methanol rinse on funnel.Leach solid product and with suspension washing, stirred simultaneously 30 minutes, and from following liquid, filter:
1. 1L methyl alcohol
2. 3.3L 2M NaCl (aqueous solution)
3.3L 2M NaCl (aqueous solution)
4. 3.3L 2M NaCl (aqueous solution)
5. 8L deionized water
Solid is suspended in deionized water (4L) again, and regulates pH to 2.2 with HCl.Solid collected by filtration (178.6g), dry in 60 ℃ of blast furnaces then, obtain the 111g solid.Abrasive solid, and through the screening of 80 mesh sieves.
Embodiment 10
With (3-chlorine) propyl group-dimethyl hexyl brometo de amonio alkylation crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio, obtain the 85.6g product with (3-chlorine) propyl group-dimethyl hexyl brometo de amonio (216.4g).
Embodiment 11
With (3-propyl group) Dimethylcyclohexyl brometo de amonio alkylation crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio, obtain the 86.4g product with (3-chloropropyl) Dimethylcyclohexyl brometo de amonio (213.2g).
Embodiment 12
With the alkylation of (3-chloropropyl) dimethyl octyl group brometo de amonio crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio, obtain the 104.6g product with (3-chloropropyl) dimethyl octyl group brometo de amonio (237.7g).
Embodiment 13
With (3-chloropropyl) dimethyl decyl brometo de amonio alkylation crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio, obtain the 101.7g product with (3-chloropropyl) dimethyl decyl brometo de amonio (269.4g).
Embodiment 14
With the alkylation of (3-chloropropyl) dimethyl tetradecyl brometo de amonio crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio, obtain the 112.3g product with (3-chloropropyl) dimethyl tetradecyl brometo de amonio (301.2g).
Embodiment 15
With the alkylation of (3-chloropropyl) methyl dioctyl brometo de amonio crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio with (3-chloropropyl) methyl dioctyl brometo de amonio (272g), and add the 5.5g NaOH aqueous solution at every turn, obtain the 96.8g product.
Embodiment 16
With the alkylation of (4-chlorobutyl) methyl dioctyl brometo de amonio crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio with (4-chlorobutyl) methyl dioctyl brometo de amonio (241.6g), and add the 4.4gNaOH aqueous solution at every turn, obtain the 80.0g product.
Embodiment 17
With the alkylation of (4-chlorobutyl) dimethyl dodecyl brometo de amonio crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio, obtain the 93.9g product with (4-chlorobutyl) dimethyl dodecyl brometo de amonio (290.5g).
Embodiment 18
With (5-chlorine amyl group) methyl dodecyl brometo de amonio alkylation crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio with (5-chlorine amyl group) methyl dodecyl brometo de amonio (150.6g), and add the 3.0g NaOH aqueous solution at every turn, obtain the 46.2g product.
Embodiment 19
With (10-bromine decyl) trimethylammonium bromide alkylation crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio with (10-bromine decyl) trimethylammonium bromide (271.0g).Add water (100mL) after 4 hours, add water (100mL) after 8 hours again, obtain the 101.8g product.
Embodiment 20 usefulness (6-chlorine hexyl) dimethyl decyl brometo de amonio alkylation crosslinked poly-(allylamine)
Repeat embodiment 9, replace (3-chloropropyl) dodecyl dimethyl brometo de amonio with (6-chlorine hexyl) dimethyl decyl brometo de amonio (145.2g), and add the 3.0gNaOH aqueous solution at every turn, obtain the 46.2g product.
Embodiment 21
The preparation of (4-chlorobutyl) dimethyl dodecyl brometo de amonio
In a 1000mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl amino dodecane (308.8g, 1.45mol), 1-bromo-4-chlorobutane (249.98g, 1.45mol) and 300mL methyl alcohol.Keeping being reflected at 65 ℃ carried out 48 hours.Except that desolvating, obtain brown oil by the decompression rotary evaporation.In this oil, add the 100mL butanols.Mixture is stopped to collect up to distillment 30-50 ℃ of vacuum distilling, obtain 384.47g (0.99mol, 69%) title compound.
Embodiment 22
The preparation of (2-chloroethyl) dimethyl dodecyl brometo de amonio
In a 1000mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl amino dodecane (186.46g, 0.875mol), 1-bromo-2-monochloroethane (125.60g, 0.875mol) and methyl alcohol (150mL).Keeping being reflected at 65 ℃ carried out 48 hours.Except that desolvating, obtain brown oil by the decompression rotary evaporation.Put into beaker at this oil and stir, form brown white precipitate with t-butyl methyl ether (2L).Solid is collected in vacuum filtration.With solid dried overnight in 30 ℃ of vacuum ovens, obtain 197.0g (0.55mol, 63%) title compound.
Embodiment 23
Comparison to the quaternary ammonium alkylation reactions
Press embodiment 21,8 and 22 described alkylating agent (4-chlorobutyl) the dodecyl dimethyl brometo de amonios that prepare respectively, (3-chloropropyl) dodecyl dimethyl brometo de amonio and (2-chloroethyl) dodecyl dimethyl brometo de amonio.Under identical condition, each alkylating agent is reacted with poly-(allylamine) that embodiment 9 prepares respectively.Estimate and compare the reactivity of the amine of each alkylating agent and poly-(allylamine) main chain, obtain following result:
| Alkylating agent | Starting polymer | Alkylating polymkeric substance | Alkylation (%) |
| (4-chlorobutyl) dodecyl dimethyl brometo de amonio n=4 | ????25g | ??????94g | ????109 |
| (3-chloropropyl) dodecyl dimethyl brometo de amonio n=3 | ????25g | ?????111g | ????124 |
| (2-chloroethyl) dodecyl dimethyl brometo de amonio n=2 | ????25g | ??????28g | ?????15 |
Obtain alkylating per-cent with ultimate analysis.The alkylation of one times of amount of every kind of amine is corresponding to 100% alkylation; The alkylation of every kind of amine doubling dose is corresponding to 200% alkylation; The alkylation of every kind of amine triplication is corresponding to 300% alkylation.Obtain the N/C ratio of polymkeric substance from ultimate analysis.Because alkylating agent has the N/C ratio different with basic polymkeric substance, so, can directly measure how many institutes and be bound to be attached to the N/C ratio of polymkeric substance with improvement starting raw material and final product to alkylating agent.This result is represented as in whole amine of polymkeric substance by the shared per-cent of alkylating amine, numeral greater than the single amine of 100% expression by many times of alkylations.For example, the N/C of starting raw material ratio is 0.313, and after using the alkylating agent alkylation of n=3, the N/C ratio becomes 0.0922, and expression has 124% by alkylation.Calculation formula is as follows:
Alkylation %=(3.2
*(N/C)-1)/(1-N/C
*17) 3.2 are C/N ratios of starting raw material wherein, the 17th, the C/N of alkylating agent is than (for the alkylating agent of n=2 and 4, this value is respectively 16 and 18).
Can be clear that by these results the alkylating agent of n=2 effect aspect the amine of alkylated amines polymkeric substance is more much smaller than the alkylating agent of n=3 and n=4.We suppose that this effect is owing to the reactive influence of quaternary amine to alkyl halide.Therefore can reach a conclusion, use alkylating agent (wherein quaternary amine is greater than 2 carbon atoms removing from the carbon atom of the alkyl halide of band halogen) can cause not reckoning with improvement with the alkylating agent of 2 following carbon atoms.
Embodiment 24
The preparation of (3-chloropropyl) cyclohexyl dimethyl brometo de amonio
In the 1L three neck Morton flasks that atmospheric condenser and magnetic stirrer be housed, add N, and the N-dimethylcyclohexylamine (210.46g, 1.65mol), 1-bromo-3-chloropropane (259.99g, 1.65mol) and methyl alcohol (250mL).Keeping being reflected at 65 ℃ carried out 24 hours.Remove methyl alcohol by the decompression rotary evaporation, obtain brown sediment.In this sediment, add t-butyl methyl ether (600mL), form a kind of oil.Go out liquid from oily decantation, and add second batch of methyl tert-butyl ether (600mL).Stir the mixture, decantation goes out liquid from thick sediment again.In sediment, add diethyl etherate (600mL), generate the semi-solid layer of white.Stir the mixture and remove liquid.White solid is put into 35 ℃ of vacuum ovens 24 hours, obtain 404.9g (1.42mol, 85%) title compound.
Embodiment 25
The preparation of (3-chloropropyl) tetradecyl dimethyl brometo de amonio
In the 1L three neck round-bottomed flasks that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl tetradecy lamine (311.59g, 1.29mol), 1-bromo-3-chloropropane (203.09g, 1.29mol) and methyl alcohol (250mL).Keeping being reflected at 65 ℃ carried out 24 hours.Remove methyl alcohol by the decompression rotary evaporation, obtain sediment.In this sediment, add methyl tert-butyl ether (500mL), slowly form white solid.Mixture was stirred 1.5 hours, collect white pasty state piece by vacuum filtration.Solid is put into 35 ℃ of vacuum ovens 24 hours, obtain 420g (1.05mol, 82%) title compound.
Embodiment 26
The preparation of (3-chloropropyl) hexyl dimethyl brometo de amonio
In the 500mL three neck round-bottomed flasks that atmospheric condenser and magnetic stirrer be housed, add N, and the N-dimethylhexylamine (199.46g, 1.54mol), 1-bromo-3-chloropropane (243.00g, 1.54mol) and methyl alcohol (250mL).Keeping being reflected at 65 ℃ carried out 24 hours.Except that desolvating, obtain the brown sticking oil of 445.8g (1.55mol, 100%) by the decompression rotary evaporation.
Embodiment 27
The preparation of (3-chloropropyl) octyldimethyl brometo de amonio
In the 500mL three neck round-bottomed flasks that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl octylame (110.02g, 0.70mol), 1-bromo-3-chloropropane (110.2g, 0.70mol) and methyl alcohol (150mL).Keeping being reflected at 65 ℃ carried out 24 hours.Except that desolvating, obtain brown oil by the decompression rotary evaporation.Extract this oil by in a Large Crusher, mixing, and decantation goes out excessive solvent with methyl-uncle's butyl ether (600mL).So repeat 3 times.At last, extract this oil with diethyl etherate (600mL) and decantation goes out excessive solvent.To glue oil dried overnight in 35 ℃ of vacuum ovens, obtain 174.14g (0.55mol, 79%) title compound.
Embodiment 28
The preparation of (3-chloropropyl) octadecyl dimethyl brometo de amonio
In a 1000mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add N, and N dimethyl stearylamine (301.0g, 1.01mol), 1-bromo-3-chloropropane (170.0g, 1.08mol) and methyl alcohol (200mL).Keeping being reflected at 65 ℃ carried out 18 hours.Except that desolvating, obtain limpid oil by the decompression rotary evaporation.Pour the beaker that methylethylketone (250mL) is housed at this oil, form white precipitate.Solid is collected in vacuum filtration, is suspended in methylethylketone (250mL) then again.So repeat twice, last, the vacuum collection solid.Solid is placed in 30 ℃ of vacuum ovens spends the night, obtain 274.9g (0.59mol, 58%) title compound.
Embodiment 29
The preparation of (3-chloropropyl) decyl dimethyl brometo de amonio
In a 1000mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl decyl amine (200.0g, 1.08mol), 1-bromo-3-chloropropane (170g, 1.08mol) and methyl alcohol (200mL).Keeping being reflected at 65 ℃ carried out 18 hours.Remove by the decompression rotary evaporation and to desolvate, and use molecular distillation, obtain brown oil.Put into a beaker at this oil, with the stirring of 1: 1 solution (400mL) of hexane/t-butyl methyl ether, form white precipitate then.Solid is collected in vacuum filtration, with solid dried overnight in 30 ℃ of vacuum ovens, obtains 305.0g (0.089mol, 82%) title compound.
Embodiment 30
The preparation of (3-chloropropyl) dioctyl methyl brometo de amonio
In the 1L three neck round-bottomed flasks that atmospheric condenser and magnetic stirrer be housed, add N, and N-dioctyl methylamine (202.48g, 0.79mol), 1-bromo-3-chloropropane (124.8g, 0.79mol) and methyl alcohol (250mL).Keeping being reflected at 65 ℃ carried out 2 days.Remove methyl alcohol by the decompression rotary evaporation, obtain a kind of oil.In this oil, add methylethylketone (50mL) and hexane (200mL), slowly form white solid.Decantation goes out solvent from mixture.Remaining solid hexane (50mL) washed twice.Solid is put into 35 ℃ of vacuum ovens 24 hours, obtain 259g (0.625mol, 79%) waxy solid.
Embodiment 31
The preparation of (3-chloropropyl) didecyl methyl brometo de amonio
In the 2L three neck round-bottomed flasks that atmospheric condenser and magnetic stirrer be housed, add N, and N-didecyl methylamine (65.49g, 0.21mol), 1-bromo-3-chloropropane (33.06g, 0.21mol) and methyl alcohol (250mL).Keeping being reflected at 65 ℃ carried out 6 days.Remove methyl alcohol by the decompression rotary evaporation, obtain a kind of oil.In this oil, add hexane (200mL), slowly form white solid.Decantation goes out solvent from mixture.Remaining solid vacuum-drying is spent the night, obtain 81.67g (0.17mol, 82%) title compound.
Embodiment 32
The preparation of (6-chlorine hexyl) dodecyl dimethyl brometo de amonio
In a 500mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add N, and N-dioctyl methylamine (95.13g, 0.513mol), 1-bromo-3-chloropropane (102.40g, 0.513mol) and t-butyl methyl ether (200mL).Keep being reflected at 58 ℃ and carried out 14 hours, form white precipitate during this period.Reaction is cooled to room temperature, and adds t-butyl methyl ether (350mL).Solid is collected in vacuum filtration.Mother liquor continues reaction at 60 ℃, and collects solid with similar mode.Merge the solid that obtains for twice, in 35 ℃ of vacuum ovens dry 24 hours, obtain the 127.36g title compound.
Embodiment 33
The preparation of (4-chlorobutyl) dioctyl methyl brometo de amonio
In a 500mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add the N-MDOA methyldioctylamine (201.83g, 0.790mol), 1-bromo-4-chlorobutane (135.517g, 0.790mol) and methyl alcohol (250mL).Keeping being reflected at 68 ℃ carried out 48 hours.To react cool to room temperature, and remove by rotary evaporation and desolvate, up to obtaining heavy-gravity oil.Continuation removes 50 ℃ of high vacuum and desolvates, and obtains the thick brown oil of 333.53g.
Embodiment 34
The preparation of (5-chlorine amyl group) dodecyl dimethyl brometo de amonio
In a 500mL round-bottomed flask that atmospheric condenser and magnetic stirrer be housed, add N, and N-dimethyl amino dodecane (230.17g, 1.078mol), 1-bromo-5-chloropentane (199.77g, 1.076mol) and t-butyl methyl ether (250mL).Become and have sedimentary white dope at 2 hours afterreactions of 60 ℃ of heating.Add t-butyl methyl ether (250mL) again.Being reflected at 60 ℃ kept 24 hours.To react cool to room temperature, solid is collected in vacuum filtration.With solid in 35 ℃ of vacuum ovens dry 24 hours, obtain the 207.40g title compound.
Embodiment 35
The preparation of crosslinked poly-(vinyl amine); With (3-chloropropyl) diformazan
Base dodecyl brometo de amonio alkylation crosslinked poly-(vinyl amine)
To gather (vinyl amine) free alkali (mw=40,000; The product of Air Products company; 62.5g) be dissolved in water (188mL) and methyl alcohol (250mL).Add Epicholorohydrin (2.8g), stir the mixture up to being gluey.This peptization is separated and is suspended in the water (13L).Solid collected by filtration, and dry in 60 ℃ of blast furnaces, obtain the 75.2g solid.Abrasive solid is also sieved with 10 mesh sieves.
The solid (14.8g) that ground is reacted in embodiment 9 similar modes, use the reaction of 140g (3-chloropropyl) dimethyl dodecyl brometo de amonio and 30g alkali aqueous solution, obtain the 57.7g product.Embodiment 10,12, and 13 and 19 efficiency ratio
Embodiment 10,12, and 13 and 19 are made by the alkylating agent of following form:
Wherein,
| Embodiment | ????n | ????m | The longest hydrophobic alkyl | Whole carbon atoms |
| ????10 ????12 ????13 ????19 | ????3 ????3 ????3 ???10 | ????6 ????8 ???10 ????0 | ????????6 ????????8 ???????10 ???????10 | ??????11 ??????13 ??????15 ??????13 |
Embodiment 10,12 and 13 is examples that the present invention contains terminal hydrophobic alkyl.The chain length of hydrophobic alkyl is 6 among the embodiment 10, is respectively 8 and 10 among the embodiment 12 and 13.But do not consider the end among the embodiment 19 is connected quaternary amine and the other end connects the hydrocarbon chain (n=10) of the amine on the main polymer chain as terminal hydrophobic grouping.
These embodiment are considered to efficient poor of those hydrophobic groupings of the nothing of alkylating agent or terminal hydrophobic grouping and alkylating agent inside, and the suitable contrast of quaternary amine and amine polymer difference.These embodiment of comparative example 19 (example of hydrophobic materials between quaternary amine and the amine polymer) are selected identical the total number of carbon atoms (embodiment 12), or identical single hydrophobic materials length (embodiment 13) is arranged, or identical carbonatoms (11 is arranged at non-segment; Embodiment 10).In addition, serve as that the alkylating agent quantity that is connected on the main polymer chain in these polymkeric substance of basis is similar with the productive rate of alkylated reaction.
Hamster is carried out embodiment 10,12, the live test of the sequestrant of 13 and 19 preparations.Give the bile acide (cholic acid and chenocholic acid) of animal subcutaneous injection with 14C solution mark.The bile acide of mark with ratio same in gall bladder bile (3: 1; Cholic acid: chenocholic acid) exist.They enter gall-bladder and with self bile of animal.Be fed with the feed 36 hours of medicine then to animal, and collected ight soil in the end 29 hours.Faecal samples is handled and radioactivity is counted.The movement that the result crosses with radio-labeled is represented with the excremental per-cent or the ratio of feeding to the animal of sequestrant.
The embodiment activity
*
10?????????184％
12?????????200％
13?????????184％
19?????????143％
* the excretory radioactive intensity is with respect to the per-cent of the control group of no sequestrant in every gram ight soil.
These digital proofs, for the sequestrant with equivalence " hydrophobic materials " chain length, hydrophobic alkyl sequestrant endways has more significant advantage than the sequestrant of hydrophobic alkyl in inside.Equivalent
Those skilled in the art will be familiar with, or more normal experiment just can be affirmed, the Equivalent of many specifically described specific exampless of the present invention here.These Equivalents will be included in the scope of following claims.
Claims (68)
1. crosslinked poly-(allylamine) polymkeric substance, contain a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
2. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 3 carbon atoms, and hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
3. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 3 carbon atoms, and hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
4. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 3 carbon atoms, and hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
5. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 4 carbon atoms, and hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
6. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 4 carbon atoms, and hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
7. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 4 carbon atoms, and hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
8. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 5 carbon atoms, and hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
9. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 5 carbon atoms, and hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
10. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 5 carbon atoms, and hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
11. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 6 carbon atoms, and hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
12. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 6 carbon atoms, and hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
13. crosslinked poly-(allylamine) polymkeric substance according to claim 1, wherein said alkylidene group has 6 carbon atoms, and hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
14. prepare described crosslinked poly-(allylamine) polymkeric substance in order to the below method, this method comprises reacts crosslinked poly-(allylamine) and the quaternary ammonium compound that contains with following formula structure,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
15. crosslinked poly-(allylamine) polymkeric substance according to claim 14, wherein n from 3 to about 6.
16. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 3, and having an alkyl at least is octyl group, and remaining alkyl is a methyl.
17. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 3, and having an alkyl at least is decyl, and remaining alkyl is a methyl.
18. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 3, and having an alkyl at least is dodecyl, and remaining alkyl is a methyl.
19. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 4, and having an alkyl at least is octyl group, and remaining alkyl is a methyl.
20. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 4, and having an alkyl at least is decyl, and remaining alkyl is a methyl.
21. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 4, and having an alkyl at least is dodecyl, and remaining alkyl is a methyl.
22. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 5, and having an alkyl at least is octyl group, and remaining alkyl is a methyl.
23. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 5, and having an alkyl at least is decyl, and remaining alkyl is a methyl.
24. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 5, and having an alkyl at least is dodecyl, and remaining alkyl is a methyl.
25. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 6, and having an alkyl at least is octyl group, and remaining alkyl is a methyl.
26. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 6, and having an alkyl at least is decyl, and remaining alkyl is a methyl.
27. crosslinked poly-(allylamine) polymkeric substance according to claim 15, wherein n is 6, and having an alkyl at least is dodecyl, and remaining alkyl is a methyl.
28. hydrocarbon amine polymer, contain a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least two to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, another terminal substituting group is the alkyl that about 5 carbon atoms of 1-are arranged.
29. hydrocarbon amine polymer according to claim 28, wherein polymkeric substance is crosslinked.
30. hydrocarbon amine polymer, contain a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and three terminal substituting groups of quaternary amine are the hydrophobic alkyls with about 24 carbon atoms of 6-.
31. hydrocarbon amine polymer according to claim 30, wherein polymkeric substance is crosslinked.
32. in order to the crosslinked hydrocarbon amine polymer of below method preparation, this method comprises reacts crosslinked hydrocarbon amine polymer and the quaternary ammonium compound that contains with following formula structure,
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
33. crosslinked hydrocarbon amine polymer according to claim 32, wherein polymkeric substance is poly-(vinyl amine) polymkeric substance.
34. crosslinked hydrocarbon amine polymer according to claim 32, wherein polymkeric substance is poly-(allylamine) polymkeric substance.
35. crosslinked hydrocarbon amine polymer according to claim 32, wherein polymkeric substance is poly-(ethylene imine) polymkeric substance.
36. method in conjunction with the Mammals biliary salts, comprise crosslinked poly-(allylamine) polymkeric substance to Mammals oral administration amount, this polymkeric substance contains a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
37. method in conjunction with the Mammals biliary salts, comprise hydrocarbon amine polymer to Mammals oral administration amount, this polymkeric substance contains a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least two to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, another terminal substituting group is the alkyl that about 5 carbon atoms of 1-are arranged.
38. method that reduces the Mammals blood cholesterol, comprise crosslinked poly-(allylamine) polymkeric substance to Mammals oral administration amount, this polymkeric substance contains a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
39. atherosclerotic method of treatment Mammals, comprise crosslinked poly-(allylamine) polymkeric substance to Mammals oral administration amount, this polymkeric substance contains a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
40. method for the treatment of the Mammals hypercholesterolemia, comprise crosslinked poly-(allylamine) polymkeric substance to Mammals oral administration amount, this polymkeric substance contains a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
41. method that reduces Mammals blood fat content, comprise crosslinked poly-(allylamine) polymkeric substance to Mammals oral administration amount, this polymkeric substance contains a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
42. a quaternary ammonium compound contains
Wherein,
R represents alkyl, and one of them has 6 one about 24 carbon atoms at least, and remaining respectively has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
43. according to the described compound of claim 42, one of wherein said alkyl or two are methyl.
44. according to the described compound of claim 43, wherein n from 3 to about 8.
45. according to the described compound of claim 44, wherein X is a halogenide.
46. a quaternary ammonium compound contains
Wherein,
R represents alkyl, and wherein at least two have about 24 carbon atoms of 6-, and remaining one has 1-5 carbon atom,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
47. according to the described compound of claim 46, one of them alkyl is a methyl.
48. according to the described compound of claim 47, wherein n from 3 to about 8.
49. according to the described compound of claim 48, wherein X is a halogenide.
50. a quaternary ammonium compound contains
Wherein,
R represents alkyl, and about 24 carbon atoms of 6-are respectively arranged,
N is 〉=3 integer,
X is a leavings group, and
Y is the negative charge counter ion.
51. according to the described compound of claim 50, wherein n from 3 to about 8.
52. according to the described compound of claim 51, wherein X is a halogenide.
53. a method for preparing the quaternary ammonium compound of following formula structure,
Comprise the following formula tertiary amine
Wherein,
R represents alkyl, and one of them has about 24 carbon atoms of 6-at least, remaining
1-5 carbon atom respectively arranged,
With the asymmetric dihalide reaction that the following formula structure is arranged,
X
1--(CH
2)
n--X
2
Wherein,
X
1Be chlorine,
X
2Be bromine, and
N is 〉=3 integer.
54. a method for preparing the quaternary ammonium compound of following formula structure,
Comprise the following formula tertiary amine
Wherein,
R represents alkyl, and wherein at least two have about 24 carbon atoms of 6-, remaining
One has 1-5 carbon atom,
With the asymmetric dihalide reaction that the following formula structure is arranged,
X
1--(CH
2)
n--X
2
Wherein
X
1Be chlorine,
X
2Be bromine, and
N is 〉=3 integer.
55. a method for preparing the quaternary ammonium compound of following formula structure,
Comprise the following formula tertiary amine
Wherein,
R represents alkyl, and wherein whole three respectively have about 24 carbon atoms of 6-, with the asymmetric dihalide reaction that the following formula structure is arranged,
X
1--(CH
2)
n--X
2Wherein,
X
1Be chlorine,
X
2Be bromine, and
N is 〉=3 integer.
56. poly-(allylamine) polymkeric substance, contain a substituting group that is connected to the amine of described polymkeric substance, this substituting group comprises that contains a quaternary amine part, wherein said quaternary ammonium part nitrogen-atoms has the alkylidene group of 3 or more a plurality of carbon atoms to be connected on the amine of polymkeric substance by one, and, have at least one to be the hydrophobic alkyl with about 24 carbon atoms of 6-in three terminal substituting groups of quaternary amine, remaining terminal substituting group is respectively the alkyl of about 5 carbon atoms of 1-.
57. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 3 carbon atoms, hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
58. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 3 carbon atoms, hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
59. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 3 carbon atoms, hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
60. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 4 carbon atoms, hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
61. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 4 carbon atoms, hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
62. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 4 carbon atoms, hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
63. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 5 carbon atoms, hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
64. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 5 carbon atoms, hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
65. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 5 carbon atoms, hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
66. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 6 carbon atoms, hydrophobic alkyl is an octyl group, and remaining terminal substituting group is a methyl.
67. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 6 carbon atoms, hydrophobic alkyl is a decyl, and remaining terminal substituting group is a methyl.
68. according to described poly-(allylamine) polymkeric substance of claim 56, wherein said alkylidene group has 6 carbon atoms, hydrophobic alkyl is a dodecyl, and remaining terminal substituting group is a methyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96194613A CN1189168A (en) | 1995-06-06 | 1996-06-06 | Hydrophobic heteroatom-containing sequestrant for cholesterol depletion |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/469,659 | 1995-06-06 | ||
| CN96194613A CN1189168A (en) | 1995-06-06 | 1996-06-06 | Hydrophobic heteroatom-containing sequestrant for cholesterol depletion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1189168A true CN1189168A (en) | 1998-07-29 |
Family
ID=5128740
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96194613A Pending CN1189168A (en) | 1995-06-06 | 1996-06-06 | Hydrophobic heteroatom-containing sequestrant for cholesterol depletion |
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| Country | Link |
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| CN (1) | CN1189168A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858347A (en) * | 2010-02-24 | 2013-01-02 | 瑞立普萨公司 | Polyimidazoles for use as bile acid sequestrants |
| CN110396149A (en) * | 2014-02-11 | 2019-11-01 | 塞特工业公司 | As the useful polymer containing primary amine of scale inhibitor |
-
1996
- 1996-06-06 CN CN96194613A patent/CN1189168A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858347A (en) * | 2010-02-24 | 2013-01-02 | 瑞立普萨公司 | Polyimidazoles for use as bile acid sequestrants |
| GB2490853B (en) * | 2010-02-24 | 2018-08-08 | Relypsa Inc | Polyimidazoles for use as bile acid sequestrants |
| CN110396149A (en) * | 2014-02-11 | 2019-11-01 | 塞特工业公司 | As the useful polymer containing primary amine of scale inhibitor |
| CN110396149B (en) * | 2014-02-11 | 2023-09-05 | 塞特工业公司 | Primary amine-containing polymers useful as scale inhibitors |
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