CN100494223C - Synthesis of quaternary ammonium salt modified nucleophilic NO donor - Google Patents
Synthesis of quaternary ammonium salt modified nucleophilic NO donor Download PDFInfo
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- CN100494223C CN100494223C CNB2007100417170A CN200710041717A CN100494223C CN 100494223 C CN100494223 C CN 100494223C CN B2007100417170 A CNB2007100417170 A CN B2007100417170A CN 200710041717 A CN200710041717 A CN 200710041717A CN 100494223 C CN100494223 C CN 100494223C
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Abstract
The present invention is synthesis of quaternary ammonium salt modified nucleophilic chitosan NO donor, and belongs to the field of medicine engineering technology. The synthesis includes the following steps: 1. reacting chitosan to quaternary aminate its NH2 radical and obtain ammonium salt modified chitosan molecule; and 2. reacting the ammonium salt modified chitosan molecule with NO gas molecule at high pressure in methanol solution of sodium methoxide to produce [N(O)NO] radical; washing the product with methanol and ether for several times, separating to purify, re-crystallizing, vacuum drying at room temperature and storing in a drier at -20 deg.c. The quaternary ammonium salt modified nucleophilic chitosan NO donor of the present invention has stable chemical property and relatively long release half life, and may be applied widely in treating cardiac vascular diseases and hypertensive lung, promoting wound healing, etc.
Description
Technical field
The present invention relates to a kind of method of pharmaceutical engineering technical field, specifically is a kind of synthetic method of quaternary ammonium salt-modified chitin nucleophic NO donor.
Background technology
As the natural macromolecular material that includes bioinformation, chitosan and derivative thereof have biocompatibility and biodegradability concurrently, can be by the decomposition of the N,O-Diacetylmuramidase in biological, and its security is more reliable than other synthetic materials during the field of medicaments that is applied to be correlated with.Chitosan derives from positively charged ion feature and the high charge density in solution as the potentiality of bio-medical material.The derivative reaction of chitosan is for the biological activity of strongthener and improve mechanical property new approach is provided.Hydroxyl in the chitosan molecule and amino carry out chemically modified easily, can be made into materials such as various types of films, gel, polyelectrolyte then.By introducing functional group at the chitosan side chain, destroy the crystallizing field structure, increase the noncrystalline domain part, not only its solvability can be changed, and physico-chemical property can be changed.For example: the N-alkylated chitosan has reduced solvability and can form the micella cluster when alkyl chain is greater than 5 carbon, and sulfating reaction is then given chitosan anion characteristic and water-soluble, obtains anticoagulant property simultaneously; Soluble in water through the glycosylation modified derivative that forms chitosan, show high-hygroscopicity and moisture retention, to the susceptibility of enzyme liberating also along with the increase of the substitution value of derivative and reduce.
Chitosan and derivative thereof can make the enzyme of active substance degraded inhibited to some by influencing the permeability that epithelial passage improves cell.Because its bioadhesive is strong, can strengthen hydrophilic compounds penetration in vivo again, improve the transmembrane transport ability, therefore can be used as the promotion absorption factor of biologically active substance.The quaternary ammonium salt of chitosan is a kind of Amphiphatic high polymer, and substitution value is at 25% above quaternary ammonium salinization chitosan water soluble generally speaking.The quaternary ammonium salt of chitosan also can divide two types: a class is to utilize the amino reaction of chitosan to make, concrete grammar is to obtain the halogenation chitosan quaternary ammonium salt with excessive haloalkane and chitosan reaction, because the reactive behavior of idoalkane is higher, is the halo reagent of using always.Another kind of is with the quaternary ammonium salt and the chitosan reaction that contain epoxy alkane, obtains containing the chitosan quaternary ammonium salt of hydroxyl.Human epoxypropyl trimethylammonium chloride ammonium and chitosan reactions such as Xu Chen, synthesized HACC, its water-soluble increase with substitution value increases, and 10% solution of water-soluble products can not precipitate than mixing arbitrarily with ethanol, ethylene glycol, glycerine fully.Contain [N (O) NO]
-The compound of functional group is a kind of most important NO donor medicine that grew up in recent years.It both can be under physiological condition spontaneous release NO molecule; Through O
2Can in target organ and target cell, be broken away from again after the replacement, have the function of target by certain enzyme; It also has good Modulatory character; It can be prepared into various forms in addition, is applied to different medical fields as required.A large amount of in vitro testss is verified, and it can effectively prevent the moulding postoperative restenosis, improves the antithrombotic property of medical treatment device, alleviates purposes such as lung's high pressure and vasospasm.
Find through literature search prior art, people such as Smith in 2002 at United States Patent (USP): USP6451337, title: " Chitosan-based nitric oxide donor compositions " (" based on the nitric oxide donors synthetics of chitosan "), proposed modified chitosan to synthesize serial chitosan-NO affixture as nucleophilic NO carrier.But to improving the homogeneous reaction of chitin modified product with NO, again can be without O
2The poor effect that replaces the chitosan-NO affixture that just can reach the target effect.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of synthetic method of quaternary ammonium salt-modified chitin nucleophic NO donor is provided.Quaternised modified by chitosan is carried out, produce NH nucleophilic site, after the NO reaction, obtaining a series of is contain [N (O) NO] of carrier with the chitosan
-The novel NO donor of functional group.This type of nucleophic NO donor directly target and problem that can not homogeneous reaction have been solved.
The present invention is achieved by the following technical solutions, and concrete steps of the present invention comprise as follows:
(1) gets chitosan as reactant, to the NH on the chitosan
2Group carries out quaternised modified processing, obtains quaternary ammonium salt-modified chitosan molecule;
(2) quaternary ammonium salt-modified chitosan molecule is carried out reaction under high pressure with the NO gas molecule in the methanol solution of sodium methylate, produces [N (O) NO]
-Group; Synthetic product is cleaned respectively repeatedly with the methyl alcohol ether, separate to purify, recrystallization, room temperature vacuum-drying is stored in-20 ℃ the moisture eliminator.
Described to the NH on the chitosan
2Group carries out quaternised modified processing, is undertaken by following two kinds of methods:
Its method one: adopt epoxypropyl trimethylammonium chloride ammonium (GTMAC) with the NH in the chitosan
2Group carries out addition reaction, dissolves again with methyl alcohol behind the ice acetone precipitation, uses acetone methyl alcohol (volume ratio 4:1) solution precipitation again.
Described method one, specifically: chitosan is dissolved in the deionized water, divide three minor ticks to join in the reaction soln in two hours GTMAC under 85 ℃ of temperature of reaction, react after 10-24 hours, the yellow transparent reaction solution is joined in the ice acetone soln, stirring is placed on refrigerator overnight, discard acetone in second day, add dissolve with ethanol, use 4:1 volume ratio acetone ethanol solution precipitation again, the pumping rate washing, final product is dried in 60 ℃ of vacuum drying ovens again.Reaction formula is as follows:
Or its method two: to C
2-NH
2Group carries out carboxymethylation, and successively with methyl-sulfate, 3-dimethyl propylamine and 2, the reaction of 3-epoxypropyl trimethylammonium chloride ammonium obtains at last at C
2-NH
2Introduce the modified chitosan of two quaternary ammonium salts on the group.
Described method two, concrete steps are as follows:
1) get chitosan and be dissolved in the dilute acetic acid, the equivalent oxoethanoic acid divides and adds for three times wherein, carries out reduction reaction with the sodium borohydride of 5% percentage concentration, adds the ethanol sedimentation separation, dry product N-cm-chitosan (N-CMC) (a).
2) get N-cm-chitosan (a) and methyl-sulfate in being dissolved in dimethyl sulfoxide solution, reaction 24h after reaction finishes, separates with methanol hydrochloride solution, and vacuum drying gets N-carboxymethyl methyl esters chitosan (b).
3) get N-carboxymethyl methyl esters chitosan (b) and 3-dimethyl propylamine, be dissolved in the methanol solution, 0 ℃ was reacted 4 hours down, was warming up to 25 ℃ of reaction 24h down, used acetone precipitation, and vacuum drying gets N-N, N-dimethyl propylamine carbamyl chitosan (c).
4) with above-mentioned N-N, N-dimethyl propylamine carbamyl chitosan (c) and 2,3-epoxypropyl trimethylammonium chloride ammonium, behind the room temperature reaction 4h, 25 ℃ of isothermal reaction 24h use methanol extraction at last, place 60 ℃ of oven dry of vacuum drying oven, obtain the bi-quaternary ammonium salt chitosan.Reaction formula is as follows:
Described quaternary ammonium salt-modified chitosan molecule is carried out reaction under high pressure with the NO gas molecule in the methanol solution of sodium methylate, its reactional equation is:
Described reaction under high pressure, condition is: Na
+/ NH=1-3, pressure are 3atm-9atm, room temperature reaction 3 days-7 days.
Described separation is purified, and specifically: the anhydrous methanol ether cleans respectively 3 times.
Described quaternary ammonium salt-modified chitin nucleophic NO donor: adopt the positively charged one or more amino group (NR of quaternary ammonium salt-modified generation
3 +Group), with the secondary amine nucleophilic site (NH group) of quaternised modified generation, produce [N (O) NO] with the NO reaction
-Functional group, its molecular structural formula is:
N[N (O) NO wherein]
-Group is that the NH group forms with the NO reaction.And the NH group comes from quaternary ammonium salt-modified chitosan; R is one or more quaternary ammonium salts, comprises one or more epoxypropyl trimethylammonium chloride ammoniums, and it comes from NH on epoxypropyl trimethylammonium chloride ammonium (GTMAC) and the chitosan
2The opening of group.
Described quaternary ammonium salt-modified chitin nucleophic NO donor: be yellow or pearl opal pulverulent solids, be stored in-20 ℃ the moisture eliminator; At room temperature can stable existence, in acidity or neutral aqueous solution, can spontaneous decomposition discharge NO and quaternary ammonium salt-modified chitosan.
The present invention on the chitosan-C
2-NH
2Group carries out quaternised modified, makes the stable amino group that its generation can positively charged, comprises a quaternary ammonium group or a plurality of quaternary ammonium group.Release NO molecule that can be spontaneous in acid and neutral aqueous solution, the number of quaternary ammonium salt has determined their target and their release transformation period and rate of release.
Water-soluble chitosan of the present invention has stable electropositivity in the pH of broad value scope.These characteristics can interact it with electronegative polymkeric substance, macromole even some polyanions in liquid medium; From the biological agent angle, positively charged chitosan particle can be attached to the surface of mucous membrane, and can open and epithelially be tightly linked.The secondary amine NH group that quaternary ammonium salt-modified chitosan molecule produces is with the generation [N (O) NO] of NO gas molecule
-Group aspect targeted NO, has important clinical application value and application prospect.The quaternary ammonium salt-modified chitin nucleophic NO donor of the present invention's preparation, have stable chemical property and long release transformation period, can be widely used in the treatment cardiovascular system diseases, lung's high pressure, promote wound healing, effectively prevent the moulding postoperative restenosis, improve the antithrombotic property of medical treatment device.
Embodiment
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Present embodiment 1 is implemented under following implementation condition and technical requirements condition:
(1) synthetic (HTCC) of N-mono-quaternaries chitosan: (6g 37.0mmol) is dissolved in (60ml) in the deionized water, and (7.1ml 111mmol) divides three minor ticks to join in the above-mentioned reaction soln in two hours with GTMAC under 85 ℃ of temperature of reaction with chitosan.React after 10 hours, the yellow transparent reaction solution is joined in ice acetone (200ml) solution, stir and be placed on refrigerator overnight.Discarded acetone in second day and add dissolve with ethanol, use 4:1 acetone ethanol solution precipitation again, the pumping rate washing, final product in 60 ℃ of vacuum drying ovens, dry again pale yellow powder 10.23g.
(2) quaternary ammonium salt-modified chitosan/NO donor is synthetic: quaternary ammonium salt-modified chitosan 1.2g (0.004mol) is joined in the 100ml absolute methanol solution that contains 0.43g (0.004mol) sodium methylate, in autoclave, react with NO, keep pressure 3atm, reacted 3 days, after finishing, reaction washs with anhydrous methanol and ether respectively, room temperature vacuum-drying obtains the about 1g of yellow powder.
[N (O) NO]
-Functional group the most directly perceived and effectively characterizing method be ultraviolet characteristic absorbance at the 230-280 place, in the synthetic product N-mono-quaternaries chitosan nitric oxide donors (HTCC/NO) [N (O) NO]
-The characteristic absorbance of functional group is at 262nm, measured in phosphate buffer soln (PBS) damping fluid its light absorption ratio over time, and obtaining its transformation period by the function match of release profiles is 31h.
Embodiment 2
Present embodiment 2 is implemented under following implementation condition and technical requirements condition:
(1) synthetic (HTCC) of N-mono-quaternaries chitosan: (6g 37.0mmol) is dissolved in (60ml) in the deionized water, and (7.1ml 111mmol) divides three minor ticks to join in the above-mentioned reaction soln in two hours with GTMAC under 85 ℃ of temperature of reaction with chitosan.React after 17 hours, the yellow transparent reaction solution is joined in ice acetone (200ml) solution, stir and be placed on refrigerator overnight.Discarded acetone in second day and add dissolve with ethanol, use 4:1 acetone ethanol solution precipitation again, the pumping rate washing, final product in 60 ℃ of vacuum drying ovens, dry again light yellow powder 10.72g.
(2) quaternary ammonium salt-modified chitosan/NO donor is synthetic: quaternary ammonium salt-modified chitosan 1.2g (0.004mol) is joined in the 100ml absolute methanol solution that contains 0.86g (0.008mol) sodium methylate, in autoclave, react with NO, keep pressure 6atm, reacted 5 days, after finishing, reaction washs with anhydrous methanol and ether respectively, room temperature vacuum-drying obtains the about 1.03g of yellow powder.
Ultraviolet spectroscopy [N (O) NO]
-The specific absorption of functional group is at 260nm.Discharging the transformation period in the PBS damping fluid is 33h.
Embodiment 3
Present embodiment 3 is implemented under following implementation condition and technical requirements condition:
(1) synthetic (HTCC) of N-mono-quaternaries chitosan: (6g 37.0mmol) is dissolved in (60ml) in the deionized water, and (7.1ml 111mmol) divides three minor ticks to join in the above-mentioned reaction soln in two hours with GTMAC under 85 ℃ of temperature of reaction with chitosan.React after 24 hours, the yellow transparent reaction solution is joined in ice acetone (200ml) solution, stir and be placed on refrigerator overnight.Discarded acetone in second day and add dissolve with ethanol, use 4:1 acetone ethanol solution precipitation again, the pumping rate washing, final product in 60 ℃ of vacuum drying ovens, dry again yellow powder 11.02g.
(2) quaternary ammonium salt-modified chitosan/NO donor is synthetic: quaternary ammonium salt-modified chitosan 1.2g (0.004mol) is joined in the 100ml absolute methanol solution that contains 1.29g (0.012mol) sodium methylate, in autoclave, react with NO, keep pressure 9atm, reacted 7 days, after finishing, reaction washs with anhydrous methanol and ether respectively, room temperature vacuum-drying obtains the about 1.12g of yellow powder.
Ultraviolet spectroscopy [N (O) NO]
-The specific absorption of functional group is at 260nm.Discharging the transformation period in the PBS damping fluid is 37h.
Embodiment 4:
Present embodiment 4 is implemented under following implementation condition and technical requirements condition:
(1) N-bi-quaternary ammonium salt chitosan is synthetic:
1) synthetic (N-CMC) of N-cm-chitosan (a): the dilute acetic acid (0.7%v/v that the chitosan of certain mass is dissolved in certain volume; PH=3) in and place 500ml flask (under the room temperature) magnetic agitation, the equivalent oxoethanoic acid is divided add (25min at interval) in the flask for three times, stir 1h under the room temperature.With diluted sodium hydroxide solution reaction solution pH is modulated 4.5 then.Rare sodium borohydride (5%) solution is dropwise joined in the above-mentioned reaction solution, continue to stir 1h, add ethanol sedimentation then and separate.Dry in 60 ℃ of constant temperature ovens, get product N-cm-chitosan (a).
2) in the 300ml round-bottomed flask, add 5.0g N-cm-chitosan (N-CMC), add 100ml methyl-sulphoxide and 20.0ml methyl-sulfate again, 45 ℃ are heated 24h down, after reaction finishes, separate with methanol hydrochloride solution, and vacuum drying gets N-carboxymethyl methyl esters chitosan (b).
3) 3-dimethyl propylamine is placed 150ml round-bottomed flask (0 ℃) methanol solution of 30mlN-carboxymethyl methyl esters chitosan is added round-bottomed flask, 0 ℃ was reacted four hours down, be warming up to 25 ℃ of reaction 24h down, use acetone precipitation, vacuum drying gets N-N, N-dimethyl propylamine carbamyl chitosan (c).
4) earlier with 4.0mmolN-N, N-dimethyl propylamine carbamyl chitosan (c) places the 150ml round-bottomed flask, then to wherein adding 3.0g 2,3-epoxypropyl trimethylammonium chloride ammonium, stir and add NaOH and other 2.0g2,3-epoxypropyl trimethylammonium chloride ammonium, reaction 4h down, be warming up to 25 ℃ of reaction 24h again, use methanol extraction at last, place 60 ℃ of oven dry of vacuum drying oven, obtain C
2-NH
2On with the modified chitosan white powder of two quaternary ammonium salts.
(2) synthetic method of quaternary ammonium salt-modified chitosan/NO donor gets the about 1.22g of pearl opal powder with embodiment 3.
Ultraviolet spectroscopy [N (O) NO]
-The specific absorption of functional group is at 260nm.Discharging the transformation period in the PBS damping fluid is 45h.
Claims (5)
1. the synthetic method of a quaternary ammonium salt-modified chitin nucleophic NO donor is characterized in that, concrete steps comprise as follows:
(1) gets chitosan as reactant, to the NH on the chitosan
2Group carries out quaternised modified processing, obtains quaternary ammonium salt-modified chitosan molecule;
Described to the NH on the chitosan
2Group carries out quaternised modified processing, carries out by the following method:
Its method one: adopt the epoxypropyl trimethylammonium chloride ammonium with the NH in the chitosan
2Group carries out addition reaction, dissolves again with methyl alcohol behind the ice acetone precipitation, and the acetone methanol solution in order to the 4:1 volume ratio precipitates again;
Or its method two: to C
2-NH
2Group carries out carboxymethylation, and successively with methyl-sulfate, 3-dimethyl propylamine and 2, the reaction of 3-epoxypropyl trimethylammonium chloride ammonium obtains at last at C
2-NH
2Introduce the modified chitosan of two quaternary ammonium salts on the group;
(2) quaternary ammonium salt-modified chitosan molecule is carried out reaction under high pressure with the NO gas molecule in the methanol solution of sodium methylate, produces [N (O) NO]
-Group; Synthetic product is cleaned respectively repeatedly with the methyl alcohol ether, separate to purify, recrystallization, room temperature vacuum-drying is stored in-20 ℃ the moisture eliminator;
Described reaction under high pressure, condition is: Na
+/ NH=I-3, pressure are 3atm-9atm, room temperature reaction 3 days-7 days.
2. the synthetic method of quaternary ammonium salt-modified chitin nucleophic NO donor as claimed in claim 1, it is characterized in that, described method one, specifically: chitosan is dissolved in the deionized water, divide three minor ticks to join in the reaction soln in two hours the epoxypropyl trimethylammonium chloride ammonium under 85 ℃ of temperature of reaction, react after 10-24 hours, the yellow transparent reaction solution is joined in the ice acetone soln, stirring is placed on refrigerator overnight, discard acetone in second day, add dissolve with ethanol, use 4:1 volume ratio acetone ethanol solution precipitation again, the pumping rate washing, final product is dried in 60 ℃ of vacuum drying ovens again.
3. the synthetic method of quaternary ammonium salt-modified chitin nucleophic NO donor as claimed in claim 1 is characterized in that, described method two, and concrete steps are as follows:
1) get chitosan and be dissolved in the dilute acetic acid, the equivalent oxoethanoic acid divides and adds for three times wherein, carries out reduction reaction with the sodium borohydride of 5% percentage concentration, adds the ethanol sedimentation separation, dry product N-cm-chitosan;
2) get N-cm-chitosan and methyl-sulfate in being dissolved in dimethyl sulfoxide solution, reaction 24h after reaction finishes, separates with methanol hydrochloride solution, and vacuum drying gets N-carboxymethyl methyl esters chitosan;
3) get N-carboxymethyl methyl esters chitosan and 3-dimethyl propylamine, be dissolved in the methanol solution, 0 ℃ was reacted 4 hours down, was warming up to 25 ℃ of reaction 24h down, used acetone precipitation, and vacuum drying gets N-N, N-dimethyl propylamine carbamyl chitosan;
4) with above-mentioned N-N, N-dimethyl propylamine carbamyl chitosan and 2,3-epoxypropyl trimethylammonium chloride ammonium, behind the room temperature reaction 4h, 25 ℃ of isothermal reaction 24h use methanol extraction at last, place 60 ℃ of oven dry of vacuum drying oven, obtain the bi-quaternary ammonium salt chitosan.
4. the synthetic method of quaternary ammonium salt-modified chitin nucleophic NO donor as claimed in claim 1 is characterized in that described quaternary ammonium salt-modified chitosan molecule is carried out reaction under high pressure with the NO gas molecule in the methanol solution of sodium methylate, and its reactional equation is:
5. the synthetic method of quaternary ammonium salt-modified chitin nucleophic NO donor as claimed in claim 1 is characterized in that, described separation is purified, and specifically: the anhydrous methanol ether cleans respectively 3 times.
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| CN104514158B (en) * | 2013-09-26 | 2018-04-17 | 五邑大学 | A kind of application of chitosan quaternary ammonium salt in reactive dye salt-free dyeing |
| CN104891618B (en) * | 2015-06-05 | 2017-02-22 | 于波 | Compound water treatment flocculant as well as preparation method and application thereof |
| CN106496358A (en) * | 2016-11-09 | 2017-03-15 | 深圳大学 | Amphiphilic chitosan quaternary ammonium salt derivatives and its preparation and application |
| CN107982277B (en) * | 2017-11-30 | 2020-11-10 | 青岛九远医疗科技有限公司 | Composite antibacterial aerosol and preparation method and application thereof |
| CN110372914B (en) * | 2019-06-27 | 2020-12-15 | 浙江中财管道科技股份有限公司 | Calcium-zinc stabilizer for PVC (polyvinyl chloride) pipe and preparation method thereof |
| CN112773930A (en) * | 2021-02-02 | 2021-05-11 | 福州大学 | Injectable temperature-controllable antibacterial hydrogel |
| CN113476340B (en) * | 2021-08-11 | 2022-09-20 | 广州市巧美化妆品有限公司 | Grafted chitosan derivative modified whitening co-delivery nano composition and preparation method and application thereof |
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| 新型两亲性N-烷基-季胺化壳聚糖衍生物的制备与表征. 张灿，丁娅，平其能.高分子材料科学与工程，第22卷第4期. 2006 |
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