CN102525926B - Propylene glycol amine derivate cationic liposome nano particles and preparation method thereof - Google Patents
Propylene glycol amine derivate cationic liposome nano particles and preparation method thereof Download PDFInfo
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Abstract
The invention discloses propylene glycol amine derivate cationic liposome nano particles and a preparation method thereof. The nano particles are iodated 2,3-dialkoxy-1-(N,N,N-trimethyl)propanaminium or bromized 2,3-dialkoxy-1-(N,N-dimethyl-N-(2-hydroxyethyl))propanaminium, wherein the alkoxy includes n-octyloxy, n-dodecyloxy, n-myristyloxy, n-hexadecyloxy and n-octadecyloxy. The propylene glycol amine derivatecationic liposome nano particles have the advantages of good structural stability, moderate particle size, narrow particle size distribution, moderate surface charges, low preparation cost and the like, can meet the basic requirements of a DNA (deoxyribonucleic acid) transfer carrier, and have potential in combining and transferring gene medicines through electrostatic effect.
Description
Technical field
The present invention relates to a kind of propylene glycol amine derivate cationic liposome nano particles and preparation method thereof.
Background technology
Along with progress and the bionic development of Life Sci-Tech, nucleic acid and nucleic acid derivative are widely used in the treatment of some large disorders such as cancers, cardiovascular diseases, leukemia, acquired immune deficiency syndrome (AIDS) etc. with its unique pharmacological action.The core of nucleic acid drug treatment is that nucleic acid drug is imported in the specific cell, and can stably keep its function, but because the obstruct of cell membrane, the nucleic acid drug molecule is difficult to directly be shifted transfered cell.Even nucleic acid drug is transferred transfered cell, also there are virus restructuring, many-sided problem such as carcinogenic, immune, its safety can not be guaranteed; The nucleic acid drugs such as antisensenucleic acids, ribozyme, RNA interference cause medicine unstable in vivo easily by the nucleic acid in vivo enzymatic degradation simultaneously, and the half-life is short.Therefore, Development of Novel, efficient, safe nucleic acid drug transfer vector become the key of nucleic acid drug treatment.
At present, the carrier that adopts in gene therapy has two types: viral vector and non-virus carrier, wherein viral vector efficiently but easily cause immunoreation, safety is relatively poor, non-virus carrier toxicity is low, efficient is relatively low, thereby studies the research direction that efficient how to improve non-virus carrier has become current gene therapy vector.Liposome has become the most widely non-virus carrier of research, and it has wide spectrum, toxicity is lower and the more high spy of efficient.The chemical constitution of liposome, size, charge ratio etc. are the key factors that affects its efficiency gene transfection.
Take epoxychloropropane as raw material, by acid catalysis ring-opening reaction, reactive tertiary amine, etherificate and quaternary ammonium salinization reaction, the propylene glycol amine derivative cation lipid of hydrophobic synthetic chain length different, hydrophilic ends difference and different physical arrangements, utilize its positively charged quaternary ammonium salt head can pass through electrostatic interaction bind nucleic acid medicine, the feature that utilization can be combined with cell wall phosphine lipid bilayer with the hydrophobic side of long-chain is expected to realize nucleic acid drug transhipment in the born of the same parents outside born of the same parents by merging endocytosis.
Summary of the invention
The object of the invention is to provide a kind of propylene glycol amine derivate cationic liposome nano particles and preparation method thereof, can realize nucleic acid drug transhipment in the born of the same parents outside born of the same parents in the hope of this propylene glycol amine derivate cationic liposome nano particles.
Propylene glycol amine derivate cationic liposome nano particles of the present invention, be iodate 2,3-dialkoxy-1-(N, N, the N-trimethyl) the third ammonium or bromination 2,3-dialkoxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium, the nano-particle mean diameter is 60-220nm, the PDI Distribution Value is 0.277-0.456, the Zeta surface potential is 40-60mv, and pH value is 5.4-5.8, and described alkoxyl is normal octane oxygen base, n-dodecane oxygen base, n-tetradecane oxygen base, hexadecane oxygen base, n-octadecane oxygen base.
The preparation method of described propylene glycol amine derivate cationic liposome nano particles comprises the steps:
(1) take epoxychloropropane as raw material, take a hydration p-methyl benzenesulfonic acid as catalyst, water is solvent and reactant, and the back hydrolysis open loop obtains colourless liquid 3-chlorine-1,2-propylene glycol through column chromatographic isolation and purification;
(2) in the presence of sodium hydroxide, colourless liquid 3-chlorine-1,2-propylene glycol and N that step (1) obtains, the N dimethylamine hydrochlorate carries out the tertiary amine reaction, obtain yellow liquid 3-(N, N-dimethyl amido)-1,2-PD through the column chromatographic isolation and purification processing;
(3) take oxolane as solvent, take sodium hydride as catalyst, 3-(N, N-dimethyl amido)-1,2-PD and alkyl bromide back flow reaction obtains 2,3-dialkoxy-1-(N, N-dimethyl) propylamine through the column chromatographic isolation and purification processing;
(4) step (3) obtain 2,3-dialkoxy-1-(N, the N-dimethyl) propylamine and iodomethane carry out quaternary ammonium salinization reaction, get white solid through the re-crystallizing in ethyl acetate purification process, after the supersonic oscillations aqueous dispersion, obtain corresponding propylene glycol amine derivative cationic-liposome TMA-Apd nano-particle.
The preparation method of described propylene glycol amine derivate cationic liposome nano particles is characterized in that this preparation method comprises the steps:
(1) take epoxychloropropane as raw material, take a hydration p-methyl benzenesulfonic acid as catalyst, water is solvent and reactant, and the back hydrolysis open loop obtains colourless liquid 3-chlorine-1,2-propylene glycol through column chromatographic isolation and purification;
(2) in the presence of sodium hydroxide, colourless liquid 3-chlorine-1,2-propylene glycol and N that step (1) obtains, the N dimethylamine hydrochlorate carries out the tertiary amine reaction, obtain yellow liquid 3-(N, N-dimethyl amido)-1,2-PD through the column chromatographic isolation and purification processing;
(3) take oxolane as solvent, take sodium hydride as catalyst, 3-(N, N-dimethyl amido)-1,2-PD and alkyl bromide back flow reaction obtains 2,3-dialkoxy-1-(N, N-dimethyl) propylamine through the column chromatographic isolation and purification processing;
(4) step (3) obtain 2,3-dialkoxy-1-(N, the N-dimethyl) propylamine and 1-bromoethanol carry out quaternary ammonium salinization reaction, get white solid through the re-crystallizing in ethyl acetate purification process, after the supersonic oscillations aqueous dispersion, obtain propylene glycol amine derivative cationic-liposome HEDMA-Apd nano-particle.
The rate of charge of described step (1) is the epoxychloropropane of mol ratio 1:0.002:4.3: a hydration p-methyl benzenesulfonic acid: water; 100 ℃ of back flow reaction 6h, concentrated, the column chromatography for separation eluant is the petroleum ether of volume ratio 2:1: ethyl acetate makes the 3-chlorine-1,2-propylene glycol.
The rate of charge of described step (2) is the 3-chlorine-1,2-propylene glycol of mol ratio 1:5.5:5.5: N, N dimethylamine hydrochlorate: sodium hydroxide; Stirring at normal temperature reaction 12h, the column chromatography for separation eluant is the ethyl acetate of volume ratio 10:1: methanol, purification obtain yellow liquid 3-(N, N-dimethyl amido)-1,2-PD.
The rate of charge of described step (3) is the 3-(N, N-dimethyl amido)-1,2-PD of mol ratio 1:2:4: sodium hydride: alkyl bromide; Take oxolane as solvent, 65 ° of C backflow 24h, the column chromatography for separation eluant is the ethyl acetate of volume ratio 1:1: petroleum ether, get yellow liquid 2,3-dialkoxy-1-(N, the N-dimethyl) propylamine, described alkyl bromide are n-Octyl Bromide, dodecyl bromide, n-tetradecane base bromine, n-hexadecyl bromine, n-octadecane base bromine.
The rate of charge of described step (4) is 2 of mol ratio 1:10,3-dialkoxy-1-(N, N-dimethyl) propylamine: iodomethane; Take acetonitrile as solvent, 81 ℃ of backflow 15h get white solid iodate 2 through re-crystallizing in ethyl acetate, and 3-dialkoxy-1-(N, N, N-trimethyl) the third ammonium obtains cationic-liposome TMA-Apd nano-particle after the supersonic oscillations aqueous dispersion.
The rate of charge of described step (4) is 2 of mol ratio 1:5,3-dialkoxy-1-(N, N-dimethyl) propylamine: 1-bromoethanol; Take acetonitrile as solvent, 81 ℃ of backflow 12h get white solid bromination 2 through re-crystallizing in ethyl acetate, 3-dialkoxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium obtains cationic-liposome HEDMA-Apd nano-particle after the supersonic oscillations aqueous dispersion.
Described acetonitrile consumption is: 1g2, and 3-dialkoxy-1-(N, N-dimethyl) propylamine uses the 20ml acetonitrile, and not enough 1g is by 1g.
Major advantage propylene glycol amine derivate cationic liposome nano particles of the present invention has the advantages such as structural stability is good, size is moderate, narrow diameter distribution, surface charge is moderate, preparation cost is cheap, can satisfy the basic demand that the DNA transport vehicle should possess.And cost of material is cheap, synthetic operation is simple and easy, can efficiently prepare the propylene glycol amine derivative cationic-liposome of different structure.Various cationic-liposomes are behind the water ultra-sonic dispersion, and the mean diameter of gained cationic-liposome nano-particle, PDI distribution, Zeta surface potential and pH value see Table 1.Data show in the table, and the mean diameter of gained cationic-liposome nano-particle is 60-220nm; The PDI value is little, and particle size distribution is relatively concentrated; Most cationic-liposome nano-particle have higher surface potential (40-60mv) and moderate pH value.Above-mentioned each physical parameter shows that the cationic liposome nanoparticles of amino acid of gained has the potentiality by electrostatic interaction combination and transporter gene class medicine.
The mean diameter of cationic-liposome, PDI distribution, Zeta surface potential and pH value after table 1 aqueous dispersion
Description of drawings
Fig. 1 is synthetic route sketch map of the present invention.
The specific embodiment
Further set forth content of the present invention below in conjunction with embodiment, the code name of each propylene glycol amine derivative cationic-liposome is listed in table 2 respectively with corresponding chemical constitution.The mean diameter of cationic-liposome, PDI distribution, Zeta surface potential and pH value are listed in table 2 after each propylene glycol amine derivative cationic-liposome aqueous dispersion.
The preparation of embodiment 1. propylene glycol amine derivative cationic-liposome TMA-Apd-C12 nano-particle:
In the 100mL round-bottomed flask, add successively epoxychloropropane (23.6g, 260.0mmol), a hydration p-methyl benzenesulfonic acid (0.10g, 0.58mmol) and water (20mL), back flow reaction.TLC (petroleum ether: ethyl acetate=1:1) detect, behind the reaction 6h, reaction is without significant change, and stopped reaction is cooled to room temperature, and reactant liquor becomes glassy yellow, and is concentrated.(eluant: petroleum ether: ethyl acetate=2:1) separate gets colourless liquid 3-chlorine-1,2-propylene glycol through column chromatography
(22.6g，210.0mmol，80.8%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：4.04(br，2H，2-OH)，3.91-3.89(m，1H，-CHOH)，3.71(dd，1H，J=3.5Hz，J=11.5Hz，-CHHOH)，3.64-3.55(m，3H，-CH
2Cl?and-CHHOH);
13C?NMR(125MHz，CDCl
3)，(ppm)：71.7(1C，-CHOH)，63.6(1C，-CH
2OH)，45.7(1C，-CH
2Cl)。
In the 50mL round-bottomed flask, add 3-chlorine-1,2-propylene glycol (2.6g, 24.0mmol) and water (15mL).Reaction mixture is cooled to 0 ° of C with ice-water bath, stirs the lower sodium hydroxide (5.0g, 120.0mmol) that slowly adds.After finishing, after the question response mixeding liquid temperature rises to room temperature, remove ice-water bath.Add N, N dimethylamine hydrochlorate (10.0g, 123.4mmol) is used rubber stopper seal, stirring at normal temperature 12h.(ethyl acetate: methanol=5:1) detect, the raw material fundamental reaction is complete for TLC.Add water (10mL) in reaction system, with chloroform (40mL/ time) extraction 3 times, merge organic facies, the organic facies anhydrous sodium sulfate drying filters, and is concentrated.(eluant: ethyl acetate: methanol=10:1) separate gets yellow liquid 3-(N, N-dimethyl amido)-1,2-PD to residue through column chromatography
(1.1g，9.7mmol，40.4%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：4.37(br，2H，2-OH)，3.71-3.68(m，1H，-CHOH)，3.55-3.65(m，2H，-CH
2OH)，2.42-2.15(m，8H，-CH
2N(CH
3)
2and?N(CH
3)
2);
13C?NMR(125MHz，CDCl
3)：68.3(1C，-CHOH)，65.1(1C，-CH
2OH)，62.1(1C，-CH
2N(CH
3)
2)，45.6(2C，-N(CH
3)
2).
In the 50mL round-bottomed flask, add N, N-dimethyl amido-1,2-PD (2.0g, 17.0mmol) and oxolane (20mL).Reaction mixture is cooled to 0 ° of C with ice-water bath, slowly adds sodium hydride (1.6g, 68.0mmol) under stirring in batches, and after finishing, the question response mixeding liquid temperature rises to room temperature, removes ice-water bath.Slowly drip dodecyl bromide (8.5g, 34.0mmol), backflow 24h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, water and ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying filters, and is concentrated.(eluant: petroleum ether: ethyl acetate=1:1) separate gets glassy yellow liquid 2,3-two n-dodecane Oxy-1s-(N, N-dimethyl) propylamine to residue through column chromatography
(2.6g，5.7mmol，33.5%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：3.57-3.40(m，7H，-CHCH
2N(CH
3)
2)，2-OCH
2CH
2(CH
2)
9CH
3and-CH
2CHCH
2N(CH
3)
2)，2.40-2.37(m，2H，-CH
2N(CH
3)
2)，2.25(s，6H，-CH
2N(CH
3)
2)，1.55-1.50(m，4H，2-OCH
2CH
2(CH
2)
9CH
3)，1.25-1.20(m，36H，2-OCH
2CH
2(CH
2)
9CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
9CH
3);
13C?NMR(125MHz，CDCl
3)：82.73(1C，-CHCH
2N(CH
3)
2)，72.4(1C，-CH
2CHCH
2N(CH
3)
2)，71.8，70.5(2C，2-OCH
2CH
2(CH
2)
9CH
3)，61.4(1C，-CH
2CHCH
2N(CH
3)
2)，46.6(2C，-CH
2CHCH
2N(CH
3)
2)，32.2，30.5，30.0，29.9，29.8，29.6，26.4(18C，some?signals?were?overlapped，2-OCH
2CH
2(CH
2)
9CH
3)，22.9(2C，2-OCH
2CH
2(CH
2)
9CH
3)，14.4(2C，2-OCH
2CH
2(CH
2)
9CH
3).
In the 50mL round-bottomed flask, add 2,3-, two n-dodecane Oxy-1s-(N, N-dimethyl) propylamine (1.0g, 2.2mmol) and acetonitrile (20mL).Stir lower drip iodomethane (3.1g, 21.8mmol), backflow 15h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid iodate 2,3-two n-dodecane Oxy-1s-(N, N, N-trimethyl) third ammonium
(0.6g，1.0mmol，45.0%)。
1H?NMR(500MHz，CDCl
3).(ppm)：4.08-4.00(m，2H，-CHCH
2N
+(CH
3)
3and-CHCHHN
+(CH
3)
3)，3.69-3.39(m，7H，-CHCHHN
+(CH
3)
3，and2-OCH
2CH
2(CH
2)
9CH
3)，3.56(s，9H，-CH
2CHCH
2N
+(CH
3)
3)，1.56-1.52(m，4H，2-OCH
2CH
2(CH
2)
9CH
3)，1.25-1.18(m，36H，2-OCH
2CH
2(CH
2)
9CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
9CH
3);
13C?NMR(125MHz，CDCl
3)：73.7(1C，-CHCH
2N
+(CH
3)
3)，72.2(1C，-CH
2CHCH
2N
+(CH
3)
3)，69.4，68.2(2C，2-OCH
2CH
2(CH
2)
9CH
3)，61.2(1C，-CH
2N
+(CH
3)
3)，55.4(3C，-N
+(CH
3)
3)，32.1，30.1，29.8，29.7，29.6，29.5，26.4，26.2(18C，some?signals?were?overlapped，2-OCH
2(CH
2)
9CH
2CH
3)，22.8，22.8(2C，2-OCH
2(CH
2)
9CH
2CH
3)，14.3(2C，2-OCH
2CH
2(CH
2)
9CH
3)。
Get iodate 2,3-two n-dodecane Oxy-1-(N, N, the N-trimethyl) the third ammonium (6.0mg, 0.01mmol) disperses to get cationic-liposome TMA-Apd-C12 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 60.64nm with Zetasizer Nano ZS instrument, PDI distributes 0.426, surface potential+53.4mv, pH=5.8.
The preparation of embodiment 2. propylene glycol amine derivative cationic-liposome HEDMA-Apd-C12 nano-particle:
In the 50mL round-bottomed flask, add 2,3-, two n-dodecane Oxy-1s-(N, N-dimethyl) propylamine (0.3g, 0.7mmol) and acetonitrile (20mL), stir lower drip bromoethanol (0.4g, 3.5mmol), backflow 12h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid bromination 2,3-two n-dodecane Oxy-1s-(N, N-dimethyl-N-(2-ethoxy)) third ammonium
(0.2g，0.34mmol，48.6%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：5.01(br，1H，-CH
2CH
2OH)，4.17-4.16(m，2H，-CH
2CH
2OH)，4.08-4.06(m，1H，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.91-3.87(m，2H，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.80-3.69(m，2H，-CH
2N
+(CH
3)
2CH
2CH
2OH)，3.56-3.53(m，2H，-CH
2CH
2OH)，3.50-3.33(m，10H，-N
+(CH
3)
2CH
2CH
2OH，2-OCH
2CH
2(CH
2)
9CH
3)，1.55-1.53(m，4H，2-OCH
2CH
2(CH
2)
9CH
3)，1.25-1.24(m，36H，2-OCH
2CH
2(CH
2)
9CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2(CH
2)
9CH
2CH
3);
13C?NMR(125MHz，CDCl
3)：73.6(1C，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，72.3(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，69.6(1C，-CH
2N
+(CH
3)
2CH
2CH
2OH)，68.9(1C，-CH
2CH
2OH)，67.6(1C，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，67.3，67.3(2C，2-OCH
2CH
2(CH
2)
9CH
3)，56.2(1C，-CH
2CH
2OH)，54.0，53.5(2C，-N
+(CH
3)
2CH
2CH
2OH)，32.1，30.2，29.9，29.8，29.7，29.6，26.4，26.3(18C，some?signals?were?overlapped，2-OCH
2(CH
2)
9CH
2CH
3)，22.9，(2C，2-OCH
2(CH
2)
9CH
2CH
3)，14.3(2C，2-OCH
2(CH
2)
9CH
2CH
3).
Get bromination 2,3-two n-dodecane Oxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium (5.8mg, 0.01mmol), disperse to get cationic-liposome HEDMA-Apd-C12 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 97.88nm with Zetasizer Nano ZS instrument, PDI distributes 0.360, surface potential+49.9mv, pH=5.4.
The preparation of embodiment 3. propylene glycol amine derivative cationic-liposome TMA-Apd-C8 nano-particle:
In the 50mL round-bottomed flask, add N, N-dimethyl amido-1,2-PD (2.3g, 20.4mmol) and oxolane (40mL).Reaction mixture is cooled to 0 ° of C with ice-water bath, slowly adds sodium hydride (2.0g, 81.6mmol) under stirring in batches, and after finishing, the question response mixeding liquid temperature rises to room temperature, removes ice-water bath.Slowly drip normal octane base bromine (7.9g, 40.8mmol), backflow 24h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, water and ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying filters, and is concentrated.(eluant: petroleum ether: ethyl acetate=1:1) separate gets glassy yellow liquid 2,3-two normal octane Oxy-1s-(N, N-dimethyl) propylamine to residue through column chromatography
(1.8g，5.2mmol，25.5%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：3.57-3.40(m，7H，-CHCH
2N(CH
3)
2)，2-OCH
2CH
2(CH
2)
5CH
3and-CH
2CHCH
2N(CH
3)
2)，2.40-2.32(m，2H，-CH
2N(CH
3)
2)，2.24(s，6H，-CH
2N(CH
3)
2)，1.55-1.53(m，4H，2-OCH
2CH
2(CH
2)
5CH
3)，1.34-1.17(m，20H，2-OCH
2CH
2(CH
2)
5CH
3)，0.86(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
5CH
3);
13C?NMR(125MHz，CDCl
3)：82.73(1C，-CHCH
2N(CH
3)
2)，72.1(1C，-CH
2CHCH
2N(CH
3)
2)，71.6，71.5(2C，2-OCH
2CH
2(CH
2)
5CH
3)，61.1(1C，-CH
2CHCH
2N(CH
3)
2)，46.3(2C，-CH
2CHCH
2N(CH
3)
2)，31.8，30.1，29.6，29.4，29.3，26.1(10C，some?signals?were?overlapped，2-OCH
2(CH
2)
5CH
2CH
3)，22.6(2C，2-OCH
2(CH
2)
5CH
2CH
3)，14.0(2C，2-OCH
2CH
2(CH
2)
5CH
3).
In the 50mL round-bottomed flask, add 2,3-, two normal octane Oxy-1s-(N, N-dimethyl) propylamine (1.1g, 3.2mmol) and acetonitrile (20mL).Stir lower drip iodomethane (4.5g, 32.0mmol), backflow 15h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get crocus liquid.(eluant: ethyl acetate: methanol=5:1) separate gets white solid iodate 2,3-two normal octane Oxy-1s-(N, N, N-trimethyl) the third ammonium (0.8g, 1.6mmol, 50.0%) through column chromatography.
1H?NMR(500MHz，CDCl
3)，(ppm)：4.08-3.97(m，2H，-CHCH
2N
+(CH
3)
3and-CHCHHN
+(CH
3)
3)，3.67-3.39(m，16H，-CHCHHN
+(CH
3)
3，-CH
2CHCH
2N
+(CH
3)
3)，-CH
2CHCH
2N
+(CH
3)
3)and2-OCH
2CH
2(CH
2)
5CH
3)，1.54-1.50(m，4H，2-OCH
2CH
2(CH
2)
5CH
3)，1.25-1.23(m，20H，2-OCH
2CH
2(CH
2)
5CH
3)，0.84(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
5CH
3);
13C?NMR(125MHz，CDCl
3)：73.6(1C，-CHCH
2N
+(C?H
3)
3)，72.2(1C，-CH
2CHCH
2N
+(CH
3)
3)，69.4，68.2(2C，2-OCH
2CH
2(CH
2)
5CH
3)，61.2(1C，-CH
2N
+(CH
3)
3)，55.3(3C，-N
+(CH
3)
3)，31.9，31.8，30.1，29.5，29.4，29.3，29.2，26.2，26.1(10C，some?signals?were?overlapped，2-OCH
2(CH
2)
5CH
2CH
3)，22.8，22.7(2C，2-OCH
2(CH
2)
5CH
2CH
3)，14.2，14.2(2C，2-OCH
2(CH
2)
5CH
2CH
3)。
Get iodate 2,3-two normal octane Oxy-1-(N, N, the N-trimethyl) the third ammonium (4.9mg, 0.01mmol) disperses to get cationic-liposome TMA-Apd-C8 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 105.1nm with Zetasizer Nano ZS instrument, PDI distributes 0.416, surface potential+51.3mv, pH=5.4.
The preparation of embodiment 4. propylene glycol amine derivative cationic-liposome HEDMA-Apd-C8 nano-particle:
In the 50mL round-bottomed flask, add 2,3-, two normal octane Oxy-1s-(N, N-dimethyl) propylamine (1.1g, 3.2mmol) and acetonitrile (20mL), stir lower drip bromoethanol (2.0g, 16.0mmol), backflow 12h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellowish-brown liquid.(eluant: ethyl acetate: methanol=2:1) separate gets white solid bromination 2,3-two normal octane Oxy-1s-(N, N-dimethyl-N-(2-ethoxy)) third ammonium (0.7g, 1.5mmol, 46.9%) through column chromatography.
1H?NMR(500MHz，CDCl
3)，(ppm)：5.03(br，1H，-CH
2CH
2OH)，4.17-4.16(m，2H，-CH
2CH
2OH)，4.08-4.06(m，1H，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.91-3.87(m，2H，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.80-3.69(m，2H，-CH
2N
+(CH
3)
2CH
2CH
2OH)，3.56-3.53(m，2H，-CH
2CH
2OH)，3.50-3.33(m，10H，-N
+(CH
3)
2CH
2CH
2OH，2-OCH
2CH
2(CH
2)
5CH
3)，1.55-1.53(m，4H，2-OCH
2CH
2(CH
2)
5CH
3)，1.25-1.24(m，20H，2-OCH
2CH
2(CH
2)
5CH
3)，0.87(t，6H，J=2.5Hz，2-OCH
2(CH
2)
6CH
3);
13C?NMR(125MHz，CDCl
3)：73.6(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，69.6(1C，-CH
2N
+(CH
3)
2CH
2CH
2OH)，72.3(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，68.9(1C，-CH
2CH
2OH)，67.6(1C，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，67.3，67.3(2C，2-OCH
2(CH
2)
6CH
3)，56.2(1C，-CH
2CH
2OH)，54.0，53.5(2C，-N
+(CH
3)
2CH
2CH
2OH)，32.1，30.2，29.9，29.8，29.7，29.6，26.4，26.3，22.9(12C，2-OCH
2(CH
2)
6CH
3)，14.1，14.1(2C，2-OCH
2(CH
2)
6CH
3).
Get bromination 2,3-two normal octane Oxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium (4.7mg, 0.01mmol), disperse to get cationic-liposome HEDMA-Apd-C8 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 162.6nm with Zetasizer Nano ZS instrument, PDI distributes 0.456, surface potential+57.4mv, pH=5.4.
The preparation of embodiment 5. propylene glycol amine derivative cationic-liposome TMA-Apd-C14 nano-particle:
In the 50mL round-bottomed flask, add N, N-dimethyl amido-1,2-PD (1.8g, 15.9mmol) and oxolane (20mL).Reaction mixture is cooled to 0 ° of C with ice-water bath, slowly adds sodium hydride (1.5g, 63.6mmol) under stirring in batches, and after finishing, the question response mixeding liquid temperature rises to room temperature, removes ice-water bath.Slowly drip n-tetradecane base bromine (8.8g, 31.8mmol), backflow 24h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, water and ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying filters, and is concentrated.(eluant: petroleum ether: ethyl acetate=1:1) separate gets faint yellow solid 2,3-two n-tetradecane Oxy-1s-(N, N-dimethyl) propylamine (1.9g, 3.7mmol, 23.3%) to residue through column chromatography.
1H?NMR(500MHz，CDCl
3)，(ppm):3.57-3.40(m，7H，-CHCH
2N(CH
3)
2)，2-OCH
2CH
2(CH
2)
11CH
3and-CH
2CHCH
2N(CH
3)
2)，2.40-2.31(m，2H，-CH
2N(CH
3)
2)，2.23(s，6H，-CH
2N(CH
3)
2)，1.55-1.50(m，4H，2-OCH
2CH
2(CH
2)
11CH
3)，1.37-1.16(m，44H，2-OCH
2CH
2(CH
2)
11CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
11CH
3);
13C?NMR(125MHz，CDCl
3)：72.3，72.3(2C，2-OCH
2CH
2(CH
2)
11CH
3)，71.7(1C，-CH
2CHCH
2N(CH
3)
2)，70.4(1C，-CHCH
2N(CH
3)
2)，61.3(1C，-CH
2CHCH
2N(CH
3)
2)，46.5(2C，-CH
2CHCH
2N(CH
3)
2)，32.1，30.4，29.9，29.8，29.7，29.6，26.3，(22C，some?signals?were?overlapped，2-OCH
2(CH
2)
11CH
2CH
3)，22.9(2C，2-OCH
2(CH
2)
11CH
2CH
3)，14.3，14.3(2C，2-OCH
2CH
2(CH
2)
11CH
3).
In the 50mL round-bottomed flask, add 2,3-, two n-tetradecane Oxy-1s-(N, N-dimethyl) propylamine (0.8g, 1.7mmol) and acetonitrile (20mL).Stir lower drip iodomethane (2.4g, 17.0mmol), backflow 15h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid iodate 2,3-two n-tetradecane Oxy-1s-(N, N, N-trimethyl) third ammonium
(0.4g，0.6mmol，35.3%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：4.06-4.00(m，2H，-CHCH
2N
+(CH
3)
3and-CHCHHN
+(CH
3)
3)，3.67-3.38(m，16H，-CHCHHN
+(CH
3)
3，-CH
2CHCH
2N
+(CH
3)
3)，-CH
2CHCH
2N
+(CH
3)
3)and2-OCH
2CH
2(CH
2)
11CH
3)，1.57-1.54(m，4H，2-OCH
2CH
2(CH
2)
11CH
3)，1.34-1.13(m，44H，2-OCH
2CH
2(CH
2)
11CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
11CH
3);
13C?NMR(125MHz，CDCl
3)：73.6(1C，-CHCH
2N
+(CH
3)
3)，72.2(1C，-CH
2CHCH
2N
+(CH
3)
3)，69.4，68.2(2C，2-OCH
2CH
2(CH
2)
11CH
3)，61.2(1C，-CHHN
+(CH
3)
3)，55.4(3C，-N
+(CH
3)
3)，32.1，30.1，29.8，29.6，29.5，26.4，26.2(22C，some?signals?were?overlapped，2-OCH
2(CH
2)
11CH
2CH
3)，22.8，22.8(2C，2-OCH
2(CH
2)
11CH
2CH
3)，14.3，14.3(2C，2-OCH
2CH
2(CH
2)
11CH
3)。
Get iodate 2,3-two n-tetradecane Oxy-1-(N, N, the N-trimethyl) the third ammonium (6.5mg, 0.01mmol) disperses to get cationic-liposome TMA-Apd-C14 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 82.26nm with Zetasizer Nano ZS instrument, PDI distributes 0.392, surface potential+46.7mv, pH=5.4.
The preparation of embodiment 6. propylene glycol amine derivative cationic-liposome HEDMA-Apd-C14 nano-particle:
In the 50mL round-bottomed flask, add 2,3-, two n-tetradecane Oxy-1s-(N, N-dimethyl) propylamine (1.0g, 1.9mmol) and acetonitrile (20mL), stir lower drip bromoethanol (1.2g, 9.5mmol), backflow 12h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid bromination 2,3-two n-tetradecane Oxy-1s-(N, N-dimethyl-N-(2-ethoxy)) third ammonium
(0.8g，1.3mmol，68.4%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：5.00(br，1H，-CH
2CH
2OH)，4.21-4.06(m，2H，-CH
2CH
2OH)，4.20-4.07(m，1H，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.93-3.85(m，2H，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.85-3.78(m，2H，-CH
2N
+(CH
3)
2CH
2CH
2OH)，3.61-3.51(m，2H，-CH
2CH
2OH)，3.51-3.49(m，10H，-N
+(CH
3)
2CH
2CH
2OH，2-OCH
2CH
2(CH
2)
11CH
3)，1.56-1.54(m，4H，2-OCH
2CH
2(CH
2)
11CH
3)，1.32-1.16(m，44H，2-OCH
2CH
2(CH
2)
11CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2(CH
2)
11CH
2CH
3);
13C?NMR(125MHz，CDCl
3)：73.5(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，72.2(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，69.5(1C，-CH
2N
+(CH
3)
2CH
2CH
2OH)，68.7(1C，-CH
2CH
2OH)，67.5(1C，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，67.5，67.2(2C，2-OCH
2CH
2(CH
2)
11CH
3)，56.1(1C，-CH
2CH
2OH)，53.9，53.4(2C，-N
+(CH
3)
2CH
2CH
2OH)，32.1，30.2，29.9，29.8，29.7，29.6，26.4，26.3，22.9，(22C，some?signals?were?overlapped，2-OCH
2(CH
2)
11CH
2CH
3)，22.8，21.1(2C，2-OCH
2(CH
2)
11CH
2CH
3)，14.1，14.1(2C，2-OCH
2(CH
2)
12CH
3).
Get bromination 2,3-two n-tetradecane Oxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium (6.4mg, 0.01mmol), disperse to get cationic-liposome HEDMA-Apd-C14 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 137.4nm with Zetasizer Nano ZS instrument, PDI distributes 0.397, surface potential+44.6mv, pH=5.8.
The preparation of embodiment 7. propylene glycol amine derivative cationic-liposome TMA-Apd-C16 nano-particle:
In the 50mL round-bottomed flask, add N, N-dimethyl amido-1,2-PD (1.9g, 16.8mmol) and oxolane (20mL).Reaction mixture is cooled to 0 ° of C with ice-water bath, slowly adds sodium hydride (1.6g, 67.2mmol) under stirring in batches, and after finishing, the question response mixeding liquid temperature rises to room temperature, removes ice-water bath.Slowly drip n-hexadecyl bromine (10.3g, 33.6mmol), backflow 24h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, water and ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying filters, and is concentrated.(eluant: petroleum ether: ethyl acetate=1:1) separate gets white solid 2,3-two hexadecane Oxy-1s-(N, N-dimethyl) propylamine to residue through column chromatography
(2.4g，4.2mmol，25.0%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：3.57-3.40(m，7H，-CHCH
2N(CH
3)
2)，2-OCH
2CH
2(CH
2)
13CH
3and-CH
2CHCH
2N(CH
3)
2)，2.42-2.34(m，2H，-CH
2N(CH
3)
2)，2.25(s，6H，-CH
2N(CH
3)
2)，1.55-1.50(m，4H，2-OCH
2CH
2(CH
2)
13CH
3)，1.31-1.20(m，52H，2-OCH
2CH
2(CH
2)
13CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
13CH
3);
13CNMR(125MHz，CDCl
3)：85.9(1C，-CHCH
2N(CH
3)
2)，72.3(1C，-CH
2CHCH
2N(CH
3)
2)，71.8，70.4(2C，2-OCH
2CH
2(CH
2)
13CH
3)，61.3(1C，-CH
2CHCH
2N(CH
3)
2)，46.5，46.5(2C，-CH
2CHCH
2N(CH
3)
2)，32.1，30.4，30.2，29.9，29.7，29.6，26.3，26.2，(26C，some?signals?were?overlapped，2-OCH
2(CH
2)
14CH
3)，22.9(2C，2-OCH
2(CH
2)
13CH
2CH
3)，14.3，14.3，(2C，2-OCH
2(CH
2)
14CH
3).
In the 50mL round-bottomed flask, add 2,3-, two hexadecane Oxy-1s-(N, N-dimethyl) propylamine (0.7g, 1.2mmol) and acetonitrile (20mL).Stir lower drip iodomethane (1.7g, 12mmol), backflow 15h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid iodate 2,3-two hexadecane Oxy-1s-(N, N, N-trimethyl) the third ammonium (0.7g, 1.0mmol, 83.3%).
1H?NMR(500MHz，CDCl
3)，(ppm)：4.09-4.04(m，2H，-CHCH
2N
+(CH
3)
3and-CHCHHN
+(CH
3)
3)，3.68-3.38(m，16H，-CHCHHN
+(CH
3)
3，-CH
2CHCH
2N
+(CH
3)
3)，-CH
2CHCH
2N
+(CH
3)
3)and2-OCH
2CH
2(CH
2)
13CH
3)，1.57-1.52(m，4H，2-OCH
2CH
2(CH
2)
13CH
3)，1.33-1.21(m，52H，2-OCH
2CH
2(CH
2)
13CH
3)，0.86(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
13CH
3);
13C?NMR(125MHz，CDCl
3)：73.6(1C，-CHCH
2N
+(CH
3)
3)，72.1，72.2，69.3(3C，-CH
2CHCH
2N
+(CH
3)
3and2-OCH
2CH
2(CH
2)
13CH
3)，68.2(1C，-CHHN
+(CH
3)
3)，55.4(3C，-N
+(CH
3)
3)，32.1，30.1，29.9，29.8，29.7，29.6，29.5，26.4，26.2(26C，some?signals?were?overlapped，2-OCH
2(CH
2)
13CH
2CH
3)，22.8(2C，2-OCH
2(CH
2)
13CH
2CH
3)，14.3，14.3(2C，2-OCH
2(CH
2)
13CH
2CH
3)。
Get iodate 2,3-two hexadecane Oxy-1-(N, N, the N-trimethyl) the third ammonium (7.1mg, 0.01mmol) disperses to get cationic-liposome TMA-Apd-C16 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 227.1nm with Zetasizer Nano ZS instrument, PDI distributes 0.277, surface potential+42.4mv, pH=5.8.
The preparation of embodiment 8. propylene glycol amine derivative cationic-liposome HEDMA-Apd-C16 nano-particle:
In the 50mL round-bottomed flask, add 2,3-, two hexadecane Oxy-1s-(N, N-dimethyl) propylamine (0.9g, 1.6mmol) and acetonitrile (20mL), stir lower drip bromoethanol (1.0g, 8.0mmol), backflow 12h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid bromination 2,3-two hexadecane Oxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium (0.8g, 1.2mmol, 75.0%).
1H?NMR(500MHz，CDCl
3)，(ppm)：5.00(br，1H，-CH
2CH
2OH)，4.13-4.09(m，2H，-CH
2CH
2OH)，4.09-4.03(m，1H，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.92-3.82(m，2H，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.82-3.74(m，2H，-CH
2N
+(CH
3)
2CH
2CH
2OH)，3.56-3.53(m，2H，-CH
2CH
2OH)，3.49-3.35(m，10H，-N
+(CH
3)
2CH
2CH
2OH，2-OCH
2CH
2(CH
2)
13CH
3)，1.58-1.42(m，4H，2-OCH
2CH
2(CH
2)
13CH
3)，1.31-1.12(m，52H，2-OCH
2CH
2(CH
2)
13CH
3)，0.85(t，6H，J=7.0Hz，2-OCH
2(CH
2)
13CH
2CH
3);
13C?NMR(125MHz，CDCl
3)：73.5(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，72.2(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，69.5(1C，-CH
2N
+(CH
3)
2CH
2CH
2OH)，68.8(1C，-CH
2CH
2OH)，67.5(1C，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，67.3，67.2(2C，2-OCH
2CH
2(CH
2)
13CH
3)，56.2(1C，-CH
2CH
2OH)，53.9，53.5(2C，-N
+(CH
3)
2CH
2CH
2OH)，32.1，30.1，29.9，29.8，29.7，29.6，26.4，26.3，22.9，(26C，some?signals?were?overlapped，2-OCH
2(CH
2)
13CH
2CH
3)，22.8(2C，2-OCH
2(CH
2)
13CH
2CH
3)，14.2，14.2(2C，2-OCH
2(CH
2)
10CH
3).
Get bromination 2,3-two hexadecane Oxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium (6.9mg, 0.01mmol), disperse to get cationic-liposome HEDMA-Apd-C16 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 203.5nm with Zetasizer Nano ZS instrument, PDI distributes 0.411, surface potential+51.8mv, pH=5.4.
The preparation of embodiment 9. propylene glycol amine derivative cationic-liposome TMA-Apd-C18 nano-particle:
In the 50mL round-bottomed flask, add N, N-dimethyl amido-1,2-PD (2.8g, 24.8mmol) and oxolane (50mL).Reaction mixture is cooled to 0 ° of C with ice-water bath, slowly adds sodium hydride (2.4g, 99.2mmol) under stirring in batches, and after finishing, the question response mixeding liquid temperature rises to room temperature, removes ice-water bath.Slowly drip n-octadecane base bromine (16.5g, 49.6mmol), backflow 24h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, water and ethyl acetate extraction, the organic facies anhydrous sodium sulfate drying filters, and is concentrated.(eluant: petroleum ether: ethyl acetate=1:1) separate gets white solid 2,3-two n-octadecane Oxy-1s-(N, N-dimethyl) propylamine (2.9g, 4.6mmol, 18.5%) to residue through column chromatography.
1H?NMR(500MHz，CDCl
3)，(ppm)：3.60-3.41(m，7H，-CHCH
2N(CH
3)
2)，2-OCH
2CH
2(CH
2)
15CH
3and-CH
2CHCH
2N(CH
3)
2)，2.42-2.33(m，2H，-CH
2N(CH
3)
2)，2.25(s，6H，-CH
2N(CH
3)
2)，1.57-1.53(m，4H，2-OCH
2CH
2(CH
2)
15CH
3)，1.35-1.11(m，60H，2-OCH
2CH
2(CH
2)
15CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
15CH
3);
13C?NMR(125MHz，CDCl
3)：72.4，71.8，71.8，70.4(4C，-CH
2CHCH
2N(CH
3)
2)，-CH
2CHCH
2N(CH
3)
2)and2-OCH
2CH
2(CH
2)
15CH
3)，61.3(1C，-CH
2CHCH
2N(CH
3)
2)，46.6(2C，-CH
2CHCH
2N(CH
3)
2)，32.1，30.4，29.9，29.8，29.7，29.6，29.5，27.1，26.3，(30C，some?signals?were?overlapped，2-OCH
2(CH
2)
15CH
2CH
3)，22.9(2C，2-OCH
2(CH
2)
15CH
2CH
3)，14.3，14.3(2C，2-OCH
2CH
2(CH
2)
15CH
3).
In the 50mL round-bottomed flask, add 2,3-, two n-octadecane Oxy-1s-(N, N-dimethyl) propylamine (0.9g, 1.4mmol) and acetonitrile (20mL).Stir lower drip iodomethane (2.0g, 14mmol), backflow 15h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid iodate 2,3-two n-octadecane Oxy-1s-(N, N, N-trimethyl) third ammonium
(0.8g，1.0mmol，71.4%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：4.12-4.04(m，2H，-CHCH
2N
+(CH
3)
3and-CHCHHN
+(CH
3)
3)，3.72-3.38(m，16H，-CHCHHN
+(CH
3)
3，-CH
2CHCH
2N
+(CH
3)
3)，-CH
2CHCH
2N
+(CH
3)
3)and2-OCH
2CH
2(CH
2)
15CH
3)，1.56-1.52(m，4H，2-OCH
2CH
2(CH
2)
15CH
3)，1.32-1.20(m，60H，2-OCH
2CH
2(CH
2)
15CH
3)，0.87(t，6H，J=7.0Hz，2-OCH
2CH
2(CH
2)
15CH
3);
13C?NMR(125MHz，CDCl
3)：73.6(1C，-CHCH
2N
+(CH
3)
3)，72.2，72.2，69.4(3C，-CH
2CHCH
2N
+(CH
3)
3and2-OCH
2CH
2(CH
2)
15CH
3)，68.2(1C，-CHHN
+(CH
3)
3)，55.4(3C，-N
+(CH
3)
3)，32.1，30.1，29.9，29.8，29.7，29.6，29.5，26.4，26.2(30C，some?signals?were?overlapped，2-OCH
2(CH
2)
15CH
2CH
3)，22.8，(2C，2-OCH
2(CH
2)
15CH
2CH
3)，14.3，14.3(2C，2-OCH
2(CH
2)
15CH
2CH
3)。
Get iodate 2,3-two n-octadecane Oxy-1-(N, N, the N-trimethyl) the third ammonium (7.7mg, 0.01mmol) disperses to get cationic-liposome TMA-Apd-C18 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 170.6nm with Zetasizer Nano ZS instrument, PDI distributes 0.398, surface potential+57.5mv, pH=5.4.
The preparation of embodiment 10. propylene glycol amine derivative cationic-liposome HEDMA-Apd-C18 nano-particle:
In the 50mL round-bottomed flask, add 2,3-, two n-octadecane Oxy-1s-(N, N-dimethyl) propylamine (0.8g, 1.3mmol) and acetonitrile (20mL), stir lower drip bromoethanol (0.8g, 6.5mmol), backflow 12h.TLC (ethyl acetate) detects, and the raw material fundamental reaction is complete.Concentrated, get yellow solid, use acetic acid ethyl dissolution, be cooled to room temperature, the adularescent solid is separated out, and filters, and gets white solid bromination 2,3-two n-octadecane Oxy-1s-(N, N-dimethyl-N-(2-ethoxy)) third ammonium
(0.8g，1.1mmol，84，.6%)。
1H?NMR(500MHz，CDCl
3)，(ppm)：4.98(br，1H，-CH
2CH
2OH)，4.20-4.15(m，2H，-CH
2CH
2OH)，4.08-4.06(m，1H，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.92-3.84(m，2H，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，3.80-3.69(m，2H，-CH
2N
+(CH
3)
2CH
2CH
2OH)，3.69-3.48(m，2H，-CH
2CH
2OH)，3.46-3.39(m，10H，-N
+(CH
3)
2CH
2CH
2OH，2-OCH
2CH
2(CH
2)
15CH
3)，1.58-1.45(m，4H，2-OCH
2CH
2(CH
2)
15CH
3)，1.30-1.09(m，36H，2-OCH
2CH
2(CH
2)
15CH
3)，0.86(t，6H，J=7.0Hz，2-OCH
2(CH
2)
15CH
2CH
3);
13C?NMR(125MHz，CDCl
3)：73.5(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，72.2(1C，-CHCH
2N
+(CH
3)
2CH
2CH
2OH)，69.6(1C，-CH
2N
+(CH
3)
2CH
2CH
2OH)，68.7(1C，-CH
2CH
2OH)，67.6(1C，-CH
2CHCH
2N
+(CH
3)
2CH
2CH
2OH)，67.3，60.5(2C，2-OCH
2CH
2(CH
2)
15CH
3)，56.2(1C，-CH
2CH
2OH)，54.0，53.5(2C，-N
+(CH
3)
2CH
2CH
2OH)，32.1，30.1，29.9，29.8，29.7，29.6，29.5，26.4，26.3，26.2(30C，some?signals?were?overlapped，2-OCH
2(CH
2)
15CH
2CH
3)，22.8，21.2(2C，2-OCH
2(CH
2)
15CH
2CH
3)，14.3，14.2(2C，2-OCH
2(CH
2)
15CH
3).
Get bromination 2,3-two n-octadecane Oxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium (7.5mg, 0.01mmol), disperse to get cationic-liposome HEDMA-Apd-C18 nano-particle with redistilled water (10mL) through ultrasound wave, record mean diameter 215.9nm with Zetasizer Nano ZS instrument, PDI distributes 0.320, surface potential+40.1mv, pH=5.4.
The chemical constitution of the various cationic-liposomes of table 2
Claims (9)
1. propylene glycol amine derivate cationic liposome nano particles, it is characterized in that this nano-particle is iodate 2,3-dialkoxy-1-(N, N, the N-trimethyl) the third ammonium or bromination 2,3-dialkoxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium, the nano-particle mean diameter is 60-220nm, the PDI Distribution Value is 0.277-0.456, the Zeta surface potential is 40-60mv, and pH value is 5.4-5.8, and described alkoxyl is normal octane oxygen base, n-dodecane oxygen base, n-tetradecane oxygen base, hexadecane oxygen base, n-octadecane oxygen base.
2. the preparation method of described propylene glycol amine derivate cationic liposome nano particles according to claim 1 is characterized in that this preparation method comprises the steps:
(1) take epoxychloropropane as raw material, take a hydration p-methyl benzenesulfonic acid as catalyst, water is solvent and reactant, and the back hydrolysis open loop obtains colourless liquid 3-chlorine-1,2-propylene glycol through column chromatographic isolation and purification;
(2) in the presence of sodium hydroxide, colourless liquid 3-chlorine-1,2-propylene glycol and N that step (1) obtains, the N dimethylamine hydrochlorate carries out the tertiary amine reaction, obtain yellow liquid 3-(N, N-dimethyl amido)-1,2-PD through the column chromatographic isolation and purification processing;
(3) take oxolane as solvent, take sodium hydride as catalyst, 3-(N, N-dimethyl amido)-1,2-PD and alkyl bromide back flow reaction obtains 2,3-dialkoxy-1-(N, N-dimethyl) propylamine through the column chromatographic isolation and purification processing;
(4) step (3) obtain 2,3-dialkoxy-1-(N, the N-dimethyl) propylamine and iodomethane carry out quaternary ammonium salinization reaction, get white solid through the re-crystallizing in ethyl acetate purification process, after the supersonic oscillations aqueous dispersion, obtain corresponding propylene glycol amine derivative cationic-liposome TMA-Apd nano-particle.
3. the preparation method of described propylene glycol amine derivate cationic liposome nano particles according to claim 1 is characterized in that this preparation method comprises the steps:
(1) take epoxychloropropane as raw material, take a hydration p-methyl benzenesulfonic acid as catalyst, water is solvent and reactant, and the back hydrolysis open loop obtains colourless liquid 3-chlorine-1,2-propylene glycol through column chromatographic isolation and purification;
(2) in the presence of sodium hydroxide, colourless liquid 3-chlorine-1,2-propylene glycol and N that step (1) obtains, the N dimethylamine hydrochlorate carries out the tertiary amine reaction, obtain yellow liquid 3-(N, N-dimethyl amido)-1,2-PD through the column chromatographic isolation and purification processing;
(3) take oxolane as solvent, take sodium hydride as catalyst, 3-(N, N-dimethyl amido)-1,2-PD and alkyl bromide back flow reaction obtains 2,3-dialkoxy-1-(N, N-dimethyl) propylamine through the column chromatographic isolation and purification processing;
(4) step (3) obtain 2,3-dialkoxy-1-(N, the N-dimethyl) propylamine and 1-bromoethanol carry out quaternary ammonium salinization reaction, get white solid through the re-crystallizing in ethyl acetate purification process, after the supersonic oscillations aqueous dispersion, obtain propylene glycol amine derivative cationic-liposome HEDMA-Apd nano-particle.
4. according to claim 2 or the preparation method of 3 described propylene glycol amine derivate cationic liposome nano particles, it is characterized in that: the rate of charge of described step (1) is the epoxychloropropane of mol ratio 1:0.002:4.3: a hydration p-methyl benzenesulfonic acid: water; 100 ℃ of back flow reaction 6h, concentrated, the column chromatography for separation eluant is the petroleum ether of volume ratio 2:1: ethyl acetate makes the 3-chlorine-1,2-propylene glycol.
5. according to claim 2 or the preparation method of 3 described propylene glycol amine derivate cationic liposome nano particles, it is characterized in that: the rate of charge of described step (2) is the 3-chloro-1 of mol ratio 1:5.5:5.5,2-propylene glycol: N, N dimethylamine hydrochlorate: sodium hydroxide; Stirring at normal temperature reaction 12h, the column chromatography for separation eluant is the ethyl acetate of volume ratio 10:1: methanol, purification obtain yellow liquid 3-(N, N-dimethyl amido)-1,2-PD.
6. according to claim 2 or the preparation method of 3 described propylene glycol amine derivate cationic liposome nano particles, it is characterized in that: the rate of charge of described step (3) is the 3-(N of mol ratio 1:2:4, the N-dimethyl amido)-and 1,2-PD: sodium hydride: alkyl bromide; Take oxolane as solvent, 65 ° of C backflow 24h, the column chromatography for separation eluant is the ethyl acetate of volume ratio 1:1: petroleum ether, get yellow liquid 2,3-dialkoxy-1-(N, the N-dimethyl) propylamine, described alkyl bromide are n-Octyl Bromide, dodecyl bromide, n-tetradecane base bromine, n-hexadecyl bromine, n-octadecane base bromine.
7. the preparation method of described propylene glycol amine derivate cationic liposome nano particles according to claim 2, it is characterized in that: the rate of charge of described step (4) is 2 of mol ratio 1:10,3-dialkoxy-1-(N, N-dimethyl) propylamine: iodomethane; Take acetonitrile as solvent, 81 ℃ of backflow 15h get white solid iodate 2 through re-crystallizing in ethyl acetate, and 3-dialkoxy-1-(N, N, N-trimethyl) the third ammonium obtains cationic-liposome TMA-Apd nano-particle after the supersonic oscillations aqueous dispersion.
8. the preparation method of described propylene glycol amine derivate cationic liposome nano particles according to claim 3, it is characterized in that: the rate of charge of described step (4) is 2 of mol ratio 1:5,3-dialkoxy-1-(N, N-dimethyl) propylamine: 1-bromoethanol; Take acetonitrile as solvent, 81 ℃ of backflow 12h get white solid bromination 2 through re-crystallizing in ethyl acetate, 3-dialkoxy-1-(N, N-dimethyl-N-(2-ethoxy)) the third ammonium obtains cationic-liposome HEDMA-Apd nano-particle after the supersonic oscillations aqueous dispersion.
9. according to claim 7 or the preparation method of 8 described propylene glycol amine derivate cationic liposome nano particles, it is characterized in that described acetonitrile consumption is: 1g2,3-dialkoxy-1-(N, N-dimethyl) propylamine uses the 20ml acetonitrile, and not enough 1g is by 1g.
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