CN103965463B - A kind of preparation method of mPEG2000-DSPE - Google Patents
A kind of preparation method of mPEG2000-DSPE Download PDFInfo
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- CN103965463B CN103965463B CN201410175494.7A CN201410175494A CN103965463B CN 103965463 B CN103965463 B CN 103965463B CN 201410175494 A CN201410175494 A CN 201410175494A CN 103965463 B CN103965463 B CN 103965463B
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- polyethylene glycol
- acid anhydride
- mpeg2000
- dspe
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 229920002505 N-(Carbonyl-Methoxypolyethylene Glycol 2000)-1,2-Distearoyl-Sn-Glycero-3-Phosphoethanolamine Polymers 0.000 title claims description 24
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 title claims description 24
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 71
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 69
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims abstract description 19
- 230000004913 activation Effects 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 125000003827 glycol group Chemical group 0.000 claims abstract description 3
- -1 dimethyl succinic acid acid anhydride Chemical class 0.000 claims description 19
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229940014800 succinic anhydride Drugs 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical compound [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims 1
- 229960002317 succinimide Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 238000006555 catalytic reaction Methods 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229920000151 polyglycol Polymers 0.000 description 6
- 239000010695 polyglycol Substances 0.000 description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000011574 phosphorus Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 229940031098 ethanolamine Drugs 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 229920001400 block copolymer Polymers 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229920001427 mPEG Polymers 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 150000007984 tetrahydrofuranes Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Medicinal Preparation (AREA)
- Polyethers (AREA)
Abstract
The invention discloses a kind of preparation method of polyethylene glycol phosphatidyl-ethanolamine, its concrete preparation process is as follows: polyethylene glycol is dissolved in to organic solvent, add organic acid anhydride that the hydroxyl of polyethylene glycol end group is converted into carboxyl, under the effect of catalyst, the end carboxyl of polyethylene glycol is activated with N HOSu NHS, polyethylene glycol after activation reacts 2 72 hours in 0 60 DEG C with phosphatidyl-ethanolamine, purifying in solvent, obtaining polyethylene glycol phosphatidyl-ethanolamine. described preparation method's applicability is wide, reaction condition gentleness, simple to operate, product separation purifying is easy, cost is low, be applicable to large-scale production.
Description
Technical field
The preparation method who the present invention relates to a kind of mPEG2000-DSPE, belongs to biomedical materials field.
Background technology
Nano medicament carrying system utilizes high-permeability and delay (EPR) effect of tumor tissues blood vessel make medicine passive target gather tumor tissues, can reduce the use agent of traditional cancer chemotherapeutic drug amount and number of times, thereby reducing its toxic and side effect and improve chemotherapy effect. liposome is received as one rice pharmaceutical carrier has been widely used in the research and development of nanometer anti-cancer agent, due to conventional liposome not there is the long circulatory function in body, therefore, in vivo in sanguimotor process easily in body endothelium network (RES) is removed, in order to improve liposome Nano medication following in blood the ring time, need to use long circulating liposome. an important composition composition of long circulating liposome for PEG2000-PE.
PEG2000-PE (mPEG2000-DSPE) utilizes polyethylene glycol to realize liposome and carries in vivo the long circulatory function in antineoplastic process, extend the medicine half-life in vivo, improving the bioavilability of chemotherapeutics. mPEG2000-DSPE is due to long circulatory function good in liposome, its preparation method has also been subject to paying close attention to widely. and Chinese patent (publication number CN103360590A) is taking carbonyl dimidazoles as catalyst, coupling bi-axungia acyl-phosphatidylethanolamine and poly glycol monomethyl ether, prepare methoxy poly (ethylene glycol)-bi-axungia acyl-phosphatidylethanolamine. Chinese patent (publication number CN101870767A) activates after methoxy poly (ethylene glycol)s with two succinimdyl carbonates, with 1, 2-bis-fatty acyl phosphorus The 1, 2-bi-axungia acyl-phosphatidylethanolamine of Pegylation is prepared in acyl ethanolamine reaction.In state's patent (publication number CN101015699) is between methoxy poly (ethylene glycol) and phosphatidyl choline, Being connected by connecting handle " link ", handle " link " is substituted methylene or to oxygen ether base substituted benzene methene base or oxalyl group, prepare mPEG2000-DSPE polymer. Chinese patent (publication number CN103626993A) utilizes poly glycol monomethyl ether acyl chlorides and soybean phosphorus Acyl ethanolamine is synthesized poly glycol monomethyl ether soybean phospholipid phosphatidyl ethanolamine.Above-mentioned patent is to the greatest extentPipe reports the side utilizing multiple different catalyst to prepare mPEG2000-DSPEMethod, but still it is not strong to there is such as universality, reaction condition is the gentleest, and product is not readily separated pureChange, high in cost of production defect.
Summary of the invention
The present invention is directed to the problems referred to above, it is provided that one prepares mPEG2000-DSPE
New method.
The present invention is achieved through the following technical solutions:
A kind of preparation method of mPEG2000-DSPE, its concrete preparation process is as follows:
Polyethylene Glycol is dissolved in organic solvent, adds organic acid anhydride and the hydroxyl of Polyethylene Glycol end group is converted
For carboxyl, under the effect of catalyst, with the N-hydroxy-succinamide end to Polyethylene Glycol
Carboxyl activates, and the Polyethylene Glycol after activation and PHOSPHATIDYL ETHANOLAMINE are in 0-60 DEG C of reaction
2-72 hour, purification in a solvent, i.e. obtain mPEG2000-DSPE.Described pure
Changing the solvent used is at least one in water, methanol, ethanol, propanol, ether.The present invention
Using anhydride as connecting PEG and the handle of PHOSPHATIDYL ETHANOLAMINE, reaction condition is simple, it is easy to
Realizing, each raw material is readily available, with low cost, it is simple to large-scale production and industrialization promotion.
Alternately, in above-mentioned preparation method, described dissolving Polyethylene Glycol organic molten
Agent is oxolane, dioxane, methyl pyrrolidone, acetonitrile, chloroform, dichloromethane
At least one in alkane.The concentration of gained polyglycol solution is 0.01 grams per milliliter-1 gram/in the least
Rise.
Alternately, in above-mentioned preparation method, described organic acid anhydride be succinic anhydride,
Dimethyl succinic acid acid anhydride, dimethyl succinic acid acid anhydride, anhydride maleique, methylmaleic acid acid anhydride, two
At least one in methylmaleic acid acid anhydride.Described organic acid anhydride rubs with Polyethylene Glycol terminal hydroxy group
That ratio is 1:1-10:1.
Alternately, in above-mentioned preparation method, described catalyst is that activated carboxyl is commonly used
Catalyst, specially 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC
HCl), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC), dicyclohexyl carbon two
At least one in imines (DCC).Described catalyst and the mol ratio of Polyethylene Glycol end carboxyl
For 1:1-100:1.
Alternately, in above-mentioned preparation method, N-hydroxy-succinamide and poly-second two
The mol ratio of alcohol end carboxyl is 1:1-10:1.
Alternately, in above-mentioned preparation method, described molecular weight polyethylene glycol is
500-15000
Alternately, in above-mentioned preparation method, described Polyethylene Glycol is the poly-second of monomethyl
At least one in glycol and monobenzyl Polyethylene Glycol.
Alternately, in above-mentioned preparation method, the Polyethylene Glycol after described activation and phosphorus
The mol ratio of acyl ethanolamine is 1:1-2:1.
Present invention also offers a kind of polyethylene glycol-phosphorus acyl second prepared according to above-mentioned method
Hydramine, it is characterised in that the structure of described mPEG2000-DSPE is as follows:
Wherein R1, R2For the saturated of 9-17 carbon or unsaturated alkyl chain；R3Structure be:
In
One；
R4Structure be:
CH3、In one.
Beneficial effects of the present invention:
The described preparation method suitability is wide, reaction condition is gentle, simple to operate, product separation is pure
Change easy, low cost, it is adaptable to large-scale production.
Accompanying drawing explanation
Fig. 1 is the nuclear-magnetism of the mPEG2000-DSPE prepared in the embodiment of the present invention 1
Collection of illustrative plates.
Fig. 2 is the infrared of mPEG2000-DSPE prepared in the embodiment of the present invention 1
(FTIR) collection of illustrative plates.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, it should be understood that these are real
Execute example and be only used for the purpose of illustration, be never limited in protection scope of the present invention.
Embodiment 1: the monomethyl Polyethylene Glycol 10 grams that molecular weight is 15000 is dissolved in 1000
Milliliter chloroform, with succinic anhydride (succinic anhydride is 10:1 with the mol ratio of Polyethylene Glycol terminal hydroxy group)
React with Polyethylene Glycol, EDC HCl (EDC HCl and Polyethylene Glycol end carboxyl mole
Than being 2:1) under catalysis, (N-hydroxy-succinamide is with poly-to add N-hydroxy-succinamide
The mol ratio of ethylene glycol end carboxyl is 10:1) activation, it is subsequently added PHOSPHATIDYL ETHANOLAMINE (poly-
Ethylene glycol is 1:1 with the mol ratio of PHOSPHATIDYL ETHANOLAMINE) react 72 hours in 60 DEG C, in second
Deposition and purification in alcohol, obtains mPEG2000-DSPE.
Embodiment 2: the monobenzyl Polyethylene Glycol 10 grams that molecular weight is 500 is dissolved in 10 milliliters
Dichloromethane, with anhydride maleique, (anhydride maleique with the mol ratio of Polyethylene Glycol terminal hydroxy group is
1:1) reacting with Polyethylene Glycol, at DCC, (DCC with the mol ratio of Polyethylene Glycol end carboxyl is
100:1) under catalysis, add N-hydroxy-succinamide (N-hydroxy-succinamide and poly-second
The mol ratio of glycol end carboxyl is 2:1) activation, it is subsequently added PHOSPHATIDYL ETHANOLAMINE (poly-second two
Alcohol is 2:1 with the mol ratio of PHOSPHATIDYL ETHANOLAMINE) react 48 hours in 0 DEG C, weight in methanol
Crystallization purifying, obtains mPEG2000-DSPE.
Embodiment 3: the monomethyl Polyethylene Glycol 10 grams that molecular weight is 1500 is dissolved in 100 millis
Rising dioxane, with methylmaleic acid acid anhydride, (anhydride maleique rubs with Polyethylene Glycol terminal hydroxy group
That ratio is 10:1) react with Polyethylene Glycol, at EDC, (EDC rubs with Polyethylene Glycol end carboxyl
You than be 10:1) catalysis under, add N-hydroxy-succinamide (N-hydroxy-succinamide
It is 10:1 with the mol ratio of Polyethylene Glycol end carboxyl) activation, it is subsequently added PHOSPHATIDYL ETHANOLAMINE
(Polyethylene Glycol is 1.2:1 with the mol ratio of PHOSPHATIDYL ETHANOLAMINE) reacts 24 hours in 25 DEG C,
Crystallization purifying in ethanol, obtains mPEG2000-DSPE.
Embodiment 4: the monomethyl Polyethylene Glycol 5 grams that molecular weight is 5000 is dissolved in 50 milliliters
Dichloromethane, with pyrocinchonic acid acid anhydride (pyrocinchonic acid acid anhydride and Polyethylene Glycol end hydroxyl
The mol ratio of base is 1:1) react with Polyethylene Glycol, at DCC (DCC and Polyethylene Glycol end carboxylic
The mol ratio of base is 20:1) catalysis under, add N-hydroxy-succinamide (N-hydroxysuccinimidyl
Acid imide is 5:1 with the mol ratio of Polyethylene Glycol end carboxyl) activation, it is subsequently added phosphatidyl second
Hydramine (Polyethylene Glycol and the mol ratio of PHOSPHATIDYL ETHANOLAMINE are 2:1) is little in 40 DEG C of reactions 20
Time, precipitate in water, obtain mPEG2000-DSPE.
Embodiment 5: the monomethyl Polyethylene Glycol 5 grams that molecular weight is 10000 is dissolved in 100 millis
Rise oxolane, with dimethyl succinic acid acid anhydride (dimethyl succinic acid acid anhydride and Polyethylene Glycol terminal hydroxy group
Mol ratio be 1.5:1) react with Polyethylene Glycol, at EDC (EDC and Polyethylene Glycol end carboxylic
The mol ratio of base is 5:1) catalysis under, add N-hydroxy-succinamide (N-hydroxysuccinimidyl acyl
Imines is 5:1 with the mol ratio of Polyethylene Glycol end carboxyl) activation, it is subsequently added phosphatidyl ethanol
Amine (Polyethylene Glycol and the mol ratio of PHOSPHATIDYL ETHANOLAMINE are 1.1:1) is little in 40 DEG C of reactions 20
Time, precipitate in propanol, obtain mPEG2000-DSPE.
Embodiment 6: the monobenzyl Polyethylene Glycol 5 grams that molecular weight is 8000 is dissolved in 100 milliliters
Methyl pyrrolidone, with dimethyl succinic acid acid anhydride (dimethyl succinic acid acid anhydride and Polyethylene Glycol terminal hydroxy group
Mol ratio is 3:1) react with Polyethylene Glycol, at EDC (EDC and Polyethylene Glycol end carboxyl
Mol ratio is 5:1) catalysis under, add N-hydroxy-succinamide (N-hydroxy-succinamide
It is 5:1 with the mol ratio of Polyethylene Glycol end carboxyl) activation, it is subsequently added PHOSPHATIDYL ETHANOLAMINE (poly-
Ethylene glycol is 1.1:1 with the mol ratio of PHOSPHATIDYL ETHANOLAMINE) react 60 hours in 20 DEG C,
Methanol precipitates, obtains mPEG2000-DSPE.
Embodiment 7: the monobenzyl Polyethylene Glycol 5 grams that molecular weight is 800 is dissolved in 50 milliliter four
Hydrogen furan, with succinic anhydride (succinic anhydride is 1.5:1 with the mol ratio of Polyethylene Glycol terminal hydroxy group)
React with Polyethylene Glycol, DCC (DCC is 50:1 with the mol ratio of Polyethylene Glycol end carboxyl)
Under catalysis, add N-hydroxy-succinamide (N-hydroxy-succinamide and Polyethylene Glycol end
The mol ratio of carboxyl is 3:1) activation, it is subsequently added PHOSPHATIDYL ETHANOLAMINE (Polyethylene Glycol and phosphorus
The mol ratio of acyl ethanolamine is 1.5:1) react 30 hours in 20 DEG C, heavily tie in methanol
Brilliant purification, obtains mPEG2000-DSPE.
It is respectively adopted Fourier transform infrared spectrometer, nuclear magnetic resonance, NMR to gained in above-described embodiment
Product detect and characterize, result display the various embodiments described above be all successfully prepared corresponding
MPEG2000-DSPE.The most only add as a example by the testing result in embodiment 1
With explanation, remaining embodiment is respectively provided with similar result, and therefore not to repeat here.
As it is shown in figure 1, the position at each peak and right in the nuclear magnetic spectrum of embodiment 1 products obtained therefrom
The theoretical value that the integral area answered is released with polylactic acid-polyglycol di-block copolymer structural formula
It is identical, illustrates that the product obtained by method described in embodiment 1 is polylactic acid-poly-second two
Alcohol di-block copolymer.As in figure 2 it is shown, each peak in the infared spectrum of embodiment 1 products obtained therefrom
Go out peak position and relative intensity to confirm products therefrom the most further be polylactic acid-polyglycol two
Block copolymer.
The foregoing is only the preferred embodiments of the present invention, be merely illustrative for the purpose of the present invention, and
Nonrestrictive；Those of ordinary skill in the art understand, are limited in the claims in the present invention
It can be carried out many changes, amendment, even equivalence change in spirit and scope, but all will fall
Enter protection scope of the present invention.
Claims (2)
1. the preparation method of a mPEG2000-DSPE, it is characterised in that concrete preparation process
As follows: Polyethylene Glycol is dissolved in organic solvent, with organic acid anhydride, the hydroxyl of Polyethylene Glycol end group is converted into carboxylic
Base, under the effect of catalyst, activates the end carboxyl of Polyethylene Glycol with N-hydroxy-succinamide,
Polyethylene Glycol after activation reacts 2-72 hour in 0-60 DEG C with PHOSPHATIDYL ETHANOLAMINE, purification in a solvent,
I.e. obtain mPEG2000-DSPE；Described organic acid anhydride be succinic anhydride, dimethyl succinic acid acid anhydride,
In dimethyl succinic acid acid anhydride, anhydride maleique, methylmaleic acid acid anhydride, pyrocinchonic acid acid anhydride at least
A kind of；The organic solvent of described dissolving Polyethylene Glycol be oxolane, dioxane, methyl pyrrolidone,
At least one in acetonitrile, chloroform, dichloromethane；Described organic acid anhydride and Polyethylene Glycol terminal hydroxy group
Mol ratio is 1:1-10:1；Described catalyst is 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride
Salt (EDC HCl), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC), dicyclohexyl carbon two
Imines (DCC)；Described catalyst is 1:1～100:1 with the mol ratio of Polyethylene Glycol end carboxyl；Described N-hydroxyl
Base butanimide is 1:1～10:1 with the mol ratio of Polyethylene Glycol end carboxyl；Described Polyethylene Glycol is monomethyl
At least one in Polyethylene Glycol and monobenzyl Polyethylene Glycol, molecular weight is 500-15000；After described activation
Polyethylene Glycol is 1:1-2:1 with the mol ratio of PHOSPHATIDYL ETHANOLAMINE.
2. the mPEG2000-DSPE that prepared by method according to claim 1, it is special
Levying and be, the structure of described mPEG2000-DSPE is as follows:
Wherein R1, R2For the saturated of 9-17 carbon or unsaturated alkyl chain；R3Structure be:
H2C-CH2、HC=CH,In one；
R4Structure be:
CH3、In one.
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