CN104448139B - A kind of preparation method of colesevelam hydrocholoride - Google Patents
A kind of preparation method of colesevelam hydrocholoride Download PDFInfo
- Publication number
- CN104448139B CN104448139B CN201410675368.8A CN201410675368A CN104448139B CN 104448139 B CN104448139 B CN 104448139B CN 201410675368 A CN201410675368 A CN 201410675368A CN 104448139 B CN104448139 B CN 104448139B
- Authority
- CN
- China
- Prior art keywords
- monomer
- grams
- preparation
- colesevelam hydrocholoride
- allyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- WJDIFSCXJJEGKO-SNAWJCMRSA-N CC(NC/C=C/C=C)=O Chemical compound CC(NC/C=C/C=C)=O WJDIFSCXJJEGKO-SNAWJCMRSA-N 0.000 description 1
Landscapes
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
The present invention relates to the preparation method of a kind of colesevelam hydrocholoride.The method includes: in the presence of solvent and initiator, N pi-allyl acetamide, N pi-allyl n-Decylamine, 6 allyl amino n-hexyl trimethyl ammonium chloride polymerizations, obtains polymer II；Resulting polymers II is in hydrolyzed under basic conditions, then obtains colesevelam hydrocholoride with epoxychloropropane crosslinking.The present invention reacts easily operated, and the product degree of polymerization is high, polymer molecular weight favorable reproducibility, and product remains without bromine.
Description
Technical field
The present invention relates to the novel preparation method of a kind of colesevelam hydrocholoride, belong to technical field of medicine synthesis.
Background technology
High-cholesterol disease is increasingly becoming the illness that harm is healthy, in the urgent need to developing and producing evident in efficacy and have no side effect
Medicine.Wherein colesevelam hydrocholoride is a kind of non-suction researched and developed at first by U.S. Gel Tex Pharmaceuticals company
The property received polymerization species fat-reducing medicament, it is adaptable to therapeutic serum T-CHOL (TC) or triglycerides (TG) level are too high.Hydrochloric acid is examined
Dimension logical sequence is a kind of novel polymeric resin containing cationic segment and hydrophilic fractions, and it is not absorbed by the body, but can be with
In enteron aisle, the bile acid containing anion and hydrophilic radical is combined by strong chelation, and substantially reduces the re-absorption of the latter,
And reduce the cholesterol levels in blood, for motion and the complementary therapy of dietary therapy method, alone or again and with one Statins
Medicine can reduce the high-level LDL-C ((LDL-C) of primary Hypercholesterolemia patient.
Colesevelam hydrocholoride (Colesevelam Hydrochloride), chemical name is: 2-propylene-1-amine and epoxychloropropane,
N-2-acrylic-1-decyl amine and N, N, N-trimethyl-6-(2-propylene amido)-1-hexylamine copolymer salt hydrochlorate, is that one has parent
Aqueous and water-fast pale yellow powder polymer, its molecular formula is:
(C3H7N)m(C3H5ClO)n(C12H27ClN2)o(C13H27N)p·XHCl, chemical constitution is as shown in following formula I:
The synthetic route of colesevelam hydrocholoride generally comprises following steps at present: 1. with allyl amine as raw material, be first translated into
Allylamine hydrochloride；2. under radical initiator, carry out radical polymerization, form allylamine polymer；3. and crosslinking agent
Epoxychloropropane cross-links, and obtains cross-linking products；4. cross-linking products is the most respectively through 6-bromine hexyl trimethylammonium bromide and 1-bromine last of the ten Heavenly stems
Alkane is alkylated, and prepares colesevelam hydrocholoride.
When such method carries out allylamine hydrochloride polymerization, reaction system acidity is strong, is unfavorable for that free radical causes, it is difficult to pass through
Molecular weight is higher and the allylamine polymer of narrow molecular weight distribution to select other conditions such as suitable radical initiator to prepare, and
Corresponding monomer or oligomer can be absorbed by human body parts, show relevant toxic and side effect.Allylamine polymer has certain water-soluble
Property, can be partially soluble in hot water, and cross-linking products poor solubility, it is difficult to it is dissolved in water and common solvents, in subsequent alkylation process
In, show as gel-like after being heated, even if using substantial amounts of alkylating reagent (6-bromine hexyl trimethylammonium bromide and 1-bromine last of the ten Heavenly stems
Alkane), react for a long time, because of dissolubility and sterically hindered bigger, it is also difficult to be effectively alkylated, cause gained colesevelam hydrocholoride
Side chain a, b, c, d inaccuracy (see Formulas I).And it is difficult to remove the bromo-derivative of final products absorption.
Summary of the invention
For the deficiencies in the prior art, the present invention provides a kind of method of colesevelam hydrocholoride for preparation with higher molecular weight,
Prepared colesevelam hydrocholoride number-average molecular weight and weight average molecular weight smaller also has stable side chain ratio.
Technical scheme is as follows:
The preparation method of a kind of colesevelam hydrocholoride, comprises the following steps that
(1) with monomer A:N-pi-allyl acetamide, monomer B:N-pi-allyl n-Decylamine, monomer C:6-allyl amino n-hexyl three
Ammonio methacrylate is initiation material, in a solvent, radical initiator carry out polymerisation under causing, reaction temperature 40-80 DEG C,
In 10-20 hour reaction time, obtain the polymer II of following formula；
Described monomer A: monomer B: monomer C=25～28:38～42:32～35 mol ratios；
Described solvent is one of methyl alcohol, ethanol, isopropanol, normal propyl alcohol and other carbon tetrol or combination, or oxolane,
One of methyl tertiary butyl ether or combination；
Described radical initiator is benzoyl peroxide, azodiisobutyronitrile or tertbutanol peroxide；
(2) resulting polymers II reacts 3-8 hour in hydrolyzed under basic conditions, hydrolysis temperature 10-40 DEG C；Described alkali is hydroxide
Sodium, the aqueous solution of potassium hydroxide, described alkali is (1.0-1.1) with the mol ratio of monomer A: 1；It is then cooled to 10～15 DEG C,
Adding epoxychloropropane, epoxychloropropane is 5～7:11～15 with the mol ratio of monomer A, cross-linking reaction under 15-45 DEG C of stirring condition
During 10-20, add in alkali while reaction and the hydrogen chloride of crosslinking generation；Desolvation, adds isopropanol and hydrochloric acid purifies, washing,
Obtain colesevelam hydrocholoride.
According to the invention it is preferred to:
In step (1), the dosage of solvent and the mass ratio of monomer total amount are (4-12): 1, preferably (6-9): 1；Preferred solvent is
Isopropanol and oxolane.
Radical initiator dosage described in step (1) be initiating amount, preferably dosage be the 2-10% of monomer total amount, preferably 5-8%；
In step (1), described monomer A, monomer B, the ratio of monomer C need to be determined according to polymer lateral chain ratio.Enter
One step is preferred, and described monomer A, monomer B, the mol ratio of monomer C are 26:40:34.
Polymeric reaction temperature in step (1) is 50-60 DEG C, further preferred 55 DEG C；Reaction time is 12～15 hours.
In step (1), first the 15-25% of the 15-20% of solvent gross mass, radical initiator gross mass is added in reactor,
The mode using dropping adds monomer A, monomer B, monomer C and the solvent of surplus, the mixed solution of radical initiator.
After step (1) polymerisation terminates, it is cooled to 20～25 DEG C, then polymer II is carried out the hydrolysis of next step step (2).
In step (2), described NaOH, potassium hydroxide aqueous solution, mass percent concentration is 35-40%.
In step (2), hydrolysising reacting temperature is 25 DEG C-35 DEG C, and the reaction time is 4～6 hours.
In step (2), suitably adjust according to Cross-linked degree with the mol ratio of monomer A for the epoxychloropropane of crosslinking.Enter
One step is preferred, and described epoxychloropropane is 6:13 with the mol ratio of monomer A.
In step (2), Cross-linked reaction temperature is 25 DEG C-35 DEG C, and the Cross-linked reaction time is 10～15 hours.
In step (2), with in alkali and epoxychloropropane Cross-linked during produce hydrogen chloride, described alkali be NaOH,
The aqueous solution of potassium hydroxide, described alkali is (1.0-1.1) with the mol ratio of epoxychloropropane: 1.
In initiation material used by the inventive method, described monomer N-pi-allyl acetamide (monomer A), N-pi-allyl n-Decylamine
(monomer B), 6-allyl amino n-hexyl trimethyl ammonium chloride (monomer C) are the most commercially available.Can also be by prior art by alkene
Prepared by propyl group amine, reaction simplicity, yield is good.
The synthetic route of the present invention is as follows:
Step (1)
The technical characterstic of the present invention and excellent results:
Invention describes the novel preparation method of a kind of colesevelam hydrocholoride, the method be utilize the allyl amine of derivatization to be polymerized,
Cross-linked again.I.e. with a certain proportion of N-pi-allyl acetamide (monomer A), N-pi-allyl n-Decylamine (monomer B), 6-pi-allyl
Amino n-hexyl trimethyl ammonium chloride (monomer C) is initiation material, is polymerized under appropriate solvent and radical initiator cause,
Obtain polymer II.Then resulting polymers II discharges the amino of monomer A in hydrolyzed under basic conditions, uses a certain proportion of epoxy
Chloropropane cross-links, and prepares colesevelam hydrocholoride.
With the synthetic route of existing colesevelam hydrocholoride (i.e. allyl amine hydrochloric acid salt, be polymerized, cross-link, two steps alkylations) phase
Ratio, the present invention is first monomer derived, again hydrolytic crosslinking, is directly synthesized alkylating polymer.This method has the advantage that
1. the allyl amine (the monomer A of the present invention, monomer B and monomer C) utilizing derivatization replaces allylamine hydrochloride to carry out certainly
By base polymerisation, system acidity is greatly lowered, it is easy to initiated polymerization.
2. polymerisation is easily operated, it is easy to improves the degree of polymerization, is conducive to obtaining the polymer of HMW and narrow molecular weight distribution,
Monomer-free, oligomer and bromo-derivative residual.Yield is high.
3., by controlling monomer A, monomer B and the ingredient proportion of monomer C and the consumption of crosslinking agent epoxychloropropane, can accurately control
The ratio of polymer lateral chain, i.e. primary amine side chain: epoxychloropropane Cross-linked side chain: just amino side chain in the last of the ten Heavenly stems: quaternary ammonium salt side chain=M (Monomer A-epoxychloropropane): MEpoxychloropropane: MMonomer B: MMonomer C.The side chain ratio of target product is easily controllable.
4. the monomer utilizing derivatization participates in polymerization, it is to avoid the alkylated reaction of the crosslinking allylamine polymer of more difficult generation,
The colloid alkylated reaction being difficult to occur is converted into the allyl amine derivatization of high yield.
Detailed description of the invention
Embodiment described below is described in detail the present invention, but the present invention is not limited only to following example.
In embodiment, agents useful for same is market purchase.Reagent concentration % is mass percent.Monomer purity is through GC or HPLC
Detection, polymer molecular weight measures through gel permeation chrommatograph (GPC), and oxolane (THF) is flowing phase.
Raw material N-pi-allyl acetamide (monomer A), N-pi-allyl n-Decylamine (monomer B) and 6-allyl amino n-hexyl front three
Ammonium chloride (monomer C) can be bought by market.Also can prepare in accordance with the following methods.
1, the preparation of N-pi-allyl acetamide (monomer A):
Equipped with stirring, the 500mL of thermometer and addition funnel four-hole boiling flask in add 114.2 grams of (2.0 moles) allyl amines,
1.0 grams of zinc chloride, 210 grams of acetic anhydrides, heating also stirs reaction 8 hours, air-distillation recovery acetic acid, decompression distillation in 45-50 DEG C
(120-125 DEG C/15mmHg) obtains 187.1 grams of colourless transparent liquids, GC purity 99.8%, yield 94.5%.
2, the preparation of N-pi-allyl n-Decylamine (monomer B):
Adding 900 grams of methyl alcohol in the four-hole boiling flask of the 2000mL equipped with stirring, thermometer and addition funnel, 114.2 grams (2.0 rub
You) allyl amine, 150.0 grams of potassium carbonate, 1.0 grams of TBABs, heat and keep between 35-40 DEG C drip 253.0 gram (2.0
Mole) 1-chlorodecane, within about 3 hours, to drip and finish, 40-50 DEG C of stirring is reacted 8 hours, is filtered to remove potassium chloride, and methyl alcohol washs filter cake twice,
Each 250 grams of methyl alcohol, merging filtrate, air-distillation recovery methyl alcohol, decompression distillation (135-145 DEG C/15mmHg) obtains 382.4
Gram colourless transparent liquid, GC purity 99.7%, yield 97.6%.
3,6-allyl amino n-hexyl trimethyl ammonium chloride (monomer C)
Step is 1.: add 1000 gram 1 in the stainless steel pressure still of 2000mL, 6-dichloro hexane, 1.0 grams of TBABs, and 300
Gram 40% trimethylamine aqueous solution, 50 DEG C of 8 hours (pressure are about 3-4 atmospheric pressure) of reaction, are cooled to room temperature, are transferred to cucurbit
In, the 1 of decompression distillation excess, 6-dichloro hexane and water, obtain 6-chlorine n-hexyl trimethyl ammonium chloride, be directly used in step 2.；
Step is 2.: add 900 grams of isopropanols in step (1) gained 6-chlorine n-hexyl trimethyl ammonium chloride, 114.2 gram (2.0
Mole) allyl amine, 150.0 grams of potassium carbonate, 1.0 grams of TBABs, heating, 35-40 DEG C react 3 hours, 45-50 DEG C
Stirring reaction 8 hours, 45 DEG C are filtered to remove potassium chloride while hot, and 45 DEG C of hot isopropanols wash filter cake twice, each 200 grams of isopropanols,
Merging filtrate, air-distillation recovery section isopropanol (1000 grams), cooling, filter, obtain off-white color solid 404.3 grams, HPLC
Purity 99.1%, yield 86.2%.
Embodiment 1: the preparation of colesevelam hydrocholoride
Step (1): the preparation of polymer II
100 grams of tetrahydrochysene furans are added in the four-hole boiling flask of the 1000mL equipped with stirring, thermometer, nitrogen ingress pipe and addition funnel
Mutter, 1.0 grams of benzoyl peroxides, heating, drip 12.9 grams of (0.13 mole) N-pi-allyl acetamides in interior temperature 50-55 DEG C (single
Body A), 39.4 grams of (0.20 mole) N-pi-allyl n-Decylamines (monomer B), 39.9 grams of (0.17 mole) 6-allyl aminos just oneself
Base trimethyl ammonium chloride (monomer C), 5.5 grams of benzoyl peroxides and the solution of 500 grams of oxolanes, drip and finish, hereafter for about 3 hours
55 DEG C of stirrings are reacted 15 hours, are cooled to 20 DEG C, directly carry out step (2).
Step (2): the preparation of colesevelam hydrocholoride
In temperature 20 DEG C to 30 DEG C, in step (1) gained reaction liquid, it is dividedly in some parts 13.0 grams of (0.13 mole) 40% hydrogen
Aqueous solution of sodium oxide, finishes, and 25-30 DEG C is reacted 5 hours.It is subsequently cooled to 10 DEG C, adds 5.6 grams of (0.06 mole) epoxies
Chloropropane, between 25-30 DEG C, stirring reaction 5 hours, add 6.5 gram mass concentration 40% sodium hydrate aqueous solutions, then at 25-30 DEG C
Between stirring reaction 5 hours.Distillation recovery oxolane, while hot 310 grams of isopropanols of addition, 70 gram of 30% hydrochloric acid, 25-30 DEG C
Between stir 2 hours, filter, deionized water is washed 3 times, and each 50 grams, 50 grams of isopropanols wash 1 time, 50 DEG C of vacuum
It is dried to obtain white solid particle colesevelam hydrocholoride 80.2 grams, yield 90.4%.
Gained colesevelam hydrocholoride GPC molecular weight 11-15 ten thousand, the ratio of number-average molecular weight and weight average molecular weight is 1.03.
IR(v/cm-1): 1093 (C-N stretching vibration peaks)；1452 (C-H deformation vibration peaks)；1524 (N-H deformation vibration peaks)；
1652 (N-H in-plane deformation vibration peak)；3203 (O-H stretching vibration peaks)；3437 (N-H stretching vibration peaks).
Embodiment 2: the preparation of colesevelam hydrocholoride
Step (1): the preparation of polymer II
150 grams of isopropanols are added in the four-hole boiling flask of the 1000mL equipped with stirring, thermometer, nitrogen ingress pipe and addition funnel,
1.0 grams of benzoyl peroxides, heating, in interior temperature 60-65 DEG C 12.9 grams of (0.13 mole) N-pi-allyl acetamides (monomer A) of dropping,
39.4 grams of (0.20 mole) N-pi-allyl n-Decylamines (monomer B), 39.9 grams of (0.17 mole) 6-allyl amino n-hexyl front threes
Ammonium chloride (monomer C), 5.5 grams of benzoyl peroxides and the solution of 550 grams of isopropanols, drip and finish for about 3 hours, hereafter 65 DEG C of stirrings
React 15 hours, be cooled to 20 DEG C, directly carry out step (2).
Step (2): the preparation of colesevelam hydrocholoride
In step (1) gained reaction liquid, between temperature 20 to 30 DEG C, it is dividedly in some parts 13.0 grams of (0.13 moles) 40%
Sodium hydrate aqueous solution, finishes, and 25-30 DEG C is reacted 5 hours.It is subsequently cooled to 10 DEG C, adds 5.6 grams of (0.06 mole) rings
Oxygen chloropropane, between 25-30 DEG C, stirring reaction 5 hours, add 6.5 gram mass concentration 40% sodium hydrate aqueous solutions, then at
Stirring reaction 5 hours between 25-30 DEG C.150 grams of isopropanols of Distillation recovery, are cooled to 20 DEG C, add 70 gram of 30% hydrochloric acid,
Stirring 2 hours between 25-30 DEG C, filter, deionized water washs 3 times, each 50 grams, and 50 grams of isopropanols wash 1 time, 50 DEG C
Vacuum drying obtains white solid particle colesevelam hydrocholoride 73.9 grams, yield 83.3%.GPC molecular weight 11-14 ten thousand, number is all
The ratio of molecular weight and weight average molecular weight is 1.16.
Embodiment 3: the preparation of colesevelam hydrocholoride
With 1.0 grams of azodiisobutyronitriles and 5.5 grams of azodiisobutyronitriles replace respectively embodiment 1 1.0 grams of benzoyl peroxides and
5.5 grams of benzoyl peroxides, remaining is with embodiment 1, obtains white solid particle colesevelam hydrocholoride 78.3 grams, yield 88.3%.
The ratio of GPC molecular weight 10-15 ten thousand, number-average molecular weight and weight average molecular weight is 1.32.
Embodiment 4: the preparation of colesevelam hydrocholoride
With 1.0 grams of tertbutanol peroxides and 6.5 grams of tertbutanol peroxides replace respectively embodiment 1 1.0 grams of benzoyl peroxides and
5.5 grams of benzoyl peroxides, remaining is with embodiment 1, obtains white solid particle colesevelam hydrocholoride 71.6 grams, yield 80.7%.
The ratio of GPC molecular weight 9-14 ten thousand, number-average molecular weight and weight average molecular weight is 1.56.
Claims (10)
1. a preparation method for colesevelam hydrocholoride, comprises the following steps that
(1) with monomer A:N-pi-allyl acetamide, monomer B:N-pi-allyl n-Decylamine, monomer C:6-allyl amino n-hexyl trimethyl ammonium chloride as initiation material, in a solvent, radical initiator carries out polymerisation under causing, reaction temperature 40-80 DEG C, in 10-20 hour reaction time, obtain the polymer II of following formula；
Described monomer A: monomer B: monomer C=25～28:38～42:32～35 mol ratios；
Described solvent be one of methyl alcohol, ethanol, isopropanol, normal propyl alcohol and other carbon tetrol or combination, or one of oxolane, methyl tertiary butyl ether or combination；
Described radical initiator is benzoyl peroxide, azodiisobutyronitrile or tertbutanol peroxide；
In described step (1), first the 15-25% of the 15-20% of solvent gross mass, radical initiator gross mass is added in reactor, then use the mode of dropping to add monomer A, monomer B, monomer C and the solvent of surplus, the mixed solution of radical initiator；
(2) resulting polymers II reacts 3-8 hour in hydrolyzed under basic conditions, hydrolysis temperature 10-40 DEG C；Described alkali is the aqueous solution of NaOH, potassium hydroxide, and described alkali is (1.0-1.1) with the mol ratio of monomer A: 1；It is then cooled to 10 DEG C, adding epoxychloropropane, epoxychloropropane is 5～7:11～15 with the mol ratio of monomer A, cross-linking reaction 10-20 hour under 15-45 DEG C of stirring condition, adds in alkali and the hydrogen chloride of crosslinking generation while reaction；Desolvation, adds isopropanol and hydrochloric acid purifies, washing, obtain colesevelam hydrocholoride.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that in step (1), the dosage of solvent and the mass ratio of monomer total amount are (4-12): 1.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that in step (1), the dosage of solvent and the mass ratio of monomer total amount are (6-9): 1.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that in step (1), described monomer A, monomer B, the mol ratio of monomer C are 26:40:34.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that the polymeric reaction temperature in step (1) is 50-60 DEG C.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that after step (1) polymerisation terminates, is cooled to 20～25 DEG C, then is hydrolyzed by polymer II.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that in step (2), hydrolysising reacting temperature is 25 DEG C-35 DEG C, and the reaction time is 4～6 hours.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that in step (2), described epoxychloropropane is 6:13 with the mol ratio of monomer A.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that in step (2), Cross-linked reaction temperature is 25 DEG C-35 DEG C, and the Cross-linked reaction time is 10～15 hours.
The preparation method of a kind of colesevelam hydrocholoride the most as claimed in claim 1, it is characterised in that step is as follows:
(1) preparation of polymer II
100 grams of oxolanes are added in the four-hole boiling flask of the 1000mL equipped with stirring, thermometer, nitrogen ingress pipe and addition funnel, 1.0 grams of benzoyl peroxides, heating, 12.9 grams of N-pi-allyl acetamides (monomer A), 39.4 grams of N-pi-allyl n-Decylamines (monomer B), 39.9 grams of 6-allyl amino n-hexyl trimethyl ammonium chloride (monomer C), 5.5 grams of benzoyl peroxides and the solution of 500 grams of oxolanes is dripped in interior temperature 50-55 DEG C, within 3 hours, drip and finish, hereafter 55 DEG C of stirrings are reacted 15 hours, it is cooled to 20 DEG C, directly carries out next step；
(2) preparation of colesevelam hydrocholoride
In step (1) gained reaction liquid, being dividedly in some parts 13.0 gram of 40% sodium hydrate aqueous solution, finish between temperature 20 to 30 DEG C, 25-30 DEG C is reacted 5 hours；Being subsequently cooled to 10 DEG C, add 5.6 grams of epoxychloropropane, between 25-30 DEG C, stirring reaction 5 hours, add 6.5 gram mass concentration 40% sodium hydrate aqueous solutions, stirring reaction 5 hours between 25-30 DEG C；Distillation recovery oxolane, adds 310 grams of isopropanols, 70 gram of 30% hydrochloric acid while hot, stirring 2 hours between 25-30 DEG C, filter, deionized water is washed 3 times, each 50 grams, 50 grams of isopropanols wash 1 time, and 50 DEG C of vacuum drying obtain white solid particle colesevelam hydrocholoride 80.2 grams.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410675368.8A CN104448139B (en) | 2014-11-21 | 2014-11-21 | A kind of preparation method of colesevelam hydrocholoride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410675368.8A CN104448139B (en) | 2014-11-21 | 2014-11-21 | A kind of preparation method of colesevelam hydrocholoride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104448139A CN104448139A (en) | 2015-03-25 |
| CN104448139B true CN104448139B (en) | 2016-08-17 |
Family
ID=52894938
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410675368.8A Active CN104448139B (en) | 2014-11-21 | 2014-11-21 | A kind of preparation method of colesevelam hydrocholoride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104448139B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008813B (en) * | 2016-06-15 | 2017-11-14 | 新发药业有限公司 | The method that polymerisation in solution prepares colesevelam hydrocholoride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010041268A2 (en) * | 2008-09-02 | 2010-04-15 | Usv Limited | Crosslinked polymers |
| CN101743012A (en) * | 2007-07-17 | 2010-06-16 | 奇莫埃博利卡股份有限公司 | The novel one step process for preparing crosslinked poly-(allylamine) polymer |
| WO2011154977A1 (en) * | 2010-06-11 | 2011-12-15 | Ind-Swift Laboratories Limit | 'process for the preparation of colesevelam hydrochloride" |
| CN103113503A (en) * | 2011-11-14 | 2013-05-22 | 台耀化学股份有限公司 | Method for preparing poly(allylamine) hydrochloride and derivatives therefrom |
-
2014
- 2014-11-21 CN CN201410675368.8A patent/CN104448139B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101743012A (en) * | 2007-07-17 | 2010-06-16 | 奇莫埃博利卡股份有限公司 | The novel one step process for preparing crosslinked poly-(allylamine) polymer |
| WO2010041268A2 (en) * | 2008-09-02 | 2010-04-15 | Usv Limited | Crosslinked polymers |
| WO2011154977A1 (en) * | 2010-06-11 | 2011-12-15 | Ind-Swift Laboratories Limit | 'process for the preparation of colesevelam hydrochloride" |
| CN103113503A (en) * | 2011-11-14 | 2013-05-22 | 台耀化学股份有限公司 | Method for preparing poly(allylamine) hydrochloride and derivatives therefrom |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104448139A (en) | 2015-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2175866B1 (en) | Novel one step process for preparing cross-linked poly(allylamine) polymers | |
| CN106008579A (en) | Cross-linking agent of phenylboronic acid group, preparation method and multiple sensitive hydrogel preparation method | |
| CN102892811B (en) | Method for producing copolymer of diallylamine and sulfur dioxide | |
| CN108752542B (en) | Amphiphilic block polymer with hypoxia and pH dual responsiveness and using azo bond as connecting bond and preparation method thereof | |
| CN104448139B (en) | A kind of preparation method of colesevelam hydrocholoride | |
| Max et al. | Double Hydrophilic Poly (ethylene oxide)‐block‐Poly (dehydroalanine) Block Copolymers: Comparison of Two Different Synthetic Routes | |
| CN102344524B (en) | Water-soluble click-reaction hyperbranched polymer | |
| CN1239535C (en) | Method for making water-absorbent acrylate resin | |
| CN105461865B (en) | A kind of tree-like polyacrylamide and preparation method thereof and the application as thickener | |
| WO2011099038A2 (en) | Process for preparing crosslinked allylamine polymer | |
| CN106008813B (en) | The method that polymerisation in solution prepares colesevelam hydrocholoride | |
| JP4889237B2 (en) | Method for producing cationic copolymer | |
| CN102858818B (en) | Method for producing diallylamine acetate polymer | |
| JPS6160842B2 (en) | ||
| JP2734072B2 (en) | Method for producing amphoteric copolymer | |
| González et al. | Unexpected crosslinking during acetoacetoxy group protection on waterborne crosslinkable latexes | |
| Jiang et al. | Water-soluble and hydrolysis-resistant activated ester polymers: Synthesis, characterization, and application for preparing functional polymers | |
| CN106750009A (en) | The preparation method of organic amphiprotic copolymerized macromolecule interpenetrating networks gel | |
| JPH03135945A (en) | Quaternary ammonium salt and production thereof | |
| CN106749997A (en) | The preparation method of organic amphiprotic copolymerized macromolecule interpenetrating networks gel | |
| CN106749993A (en) | The preparation method of organic amphiprotic copolymerized macromolecule interpenetrating networks gel | |
| CN106750410A (en) | The preparation method of organic amphiprotic copolymerized macromolecule interpenetrating networks gel | |
| CN106699992A (en) | Preparation method of organic amphoteric copolymerization macromolecular interpenetrating network gel | |
| CN106750014A (en) | The preparation method of organic amphiprotic copolymerized macromolecule interpenetrating networks gel | |
| CN106749999A (en) | The preparation method of organic amphiprotic copolymerized macromolecule interpenetrating networks gel |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of coleveren hydrochloride Effective date of registration: 20211130 Granted publication date: 20160817 Pledgee: Zhejiang Commercial Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2021980013546 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |