CN1323104C - Polyethylamine and polyethylene glyeol and polyamino acid (ester) bielement and trielement copolymer - Google Patents
Polyethylamine and polyethylene glyeol and polyamino acid (ester) bielement and trielement copolymer Download PDFInfo
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- CN1323104C CN1323104C CNB2004100106178A CN200410010617A CN1323104C CN 1323104 C CN1323104 C CN 1323104C CN B2004100106178 A CNB2004100106178 A CN B2004100106178A CN 200410010617 A CN200410010617 A CN 200410010617A CN 1323104 C CN1323104 C CN 1323104C
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- 239000002253 acid Substances 0.000 title claims abstract description 54
- 229920001577 copolymer Polymers 0.000 title claims abstract description 32
- 150000002148 esters Chemical class 0.000 title claims abstract description 27
- -1 polyethylene Polymers 0.000 title claims description 43
- 239000004698 Polyethylene Substances 0.000 title claims description 27
- 229920000573 polyethylene Polymers 0.000 title claims description 26
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 94
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims abstract description 24
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 9
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims abstract description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 108
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 93
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 53
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 46
- 239000000047 product Substances 0.000 claims description 45
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 34
- 238000001556 precipitation Methods 0.000 claims description 34
- 239000005057 Hexamethylene diisocyanate Substances 0.000 claims description 29
- 238000001291 vacuum drying Methods 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 26
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims description 25
- 238000004062 sedimentation Methods 0.000 claims description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 23
- 229920000151 polyglycol Polymers 0.000 claims description 23
- 239000010695 polyglycol Substances 0.000 claims description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 20
- 238000010511 deprotection reaction Methods 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical compound CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003921 oil Substances 0.000 claims description 12
- 238000006116 polymerization reaction Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 10
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000000178 monomer Substances 0.000 claims description 9
- 229920001897 terpolymer Polymers 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000010189 synthetic method Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000005587 bubbling Effects 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 230000000977 initiatory effect Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims 3
- 229920002643 polyglutamic acid Polymers 0.000 abstract description 11
- VGALFAWDSNRXJK-VIFPVBQESA-N L-aspartic acid beta-benzyl ester Chemical compound OC(=O)[C@@H](N)CC(=O)OCC1=CC=CC=C1 VGALFAWDSNRXJK-VIFPVBQESA-N 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 2
- 229920002873 Polyethylenimine Polymers 0.000 abstract 6
- 229920006027 ternary co-polymer Polymers 0.000 abstract 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 229920000835 poly(gamma-benzyl-L-glutamate) polymer Polymers 0.000 description 24
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- 239000000126 substance Substances 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
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- DALDUXIBIKGWTK-UHFFFAOYSA-N benzene;toluene Chemical compound C1=CC=CC=C1.CC1=CC=CC=C1 DALDUXIBIKGWTK-UHFFFAOYSA-N 0.000 description 3
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- 239000003937 drug carrier Substances 0.000 description 2
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
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- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Polyamides (AREA)
- Polyurethanes Or Polyureas (AREA)
Abstract
The present invention relates to a synthesis method of a binary copolymer and a ternary copolymer of polyethyleneamine, polyethylene glycol and polyamino acid (ester). In order to synthesize the binary copolymer of polyethylene glycol and polyethyleneamine, polyethylene glycol monomethyl ether with an isocyanate group as a terminal group is firstly prepared; in order to prepare the ternary copolymer of polyethylene glycol, polyethyleneamine and polyamino acid, NCA ring-opening polymerization is firstly initiated by using the terminal amine group of the polyethyleneamine to generate the copolymer containing the polyethyleneamine and the polyamino acid (ester) directly connected with each other. In the copolymers, the molecular weight of each single branch of the polyethylene glycol is from 100 to 20000, and the total of the molecular weight of all the polyethylene glycol branches of the copolymers is from 500 to 100000; the molecular weight of the branched polyethyleneamine is smaller than 30000; the polyamino acid (ester) is poly-L-glutamic acid gamma-benzyl ester and poly-L-aspartic acid beta-benzyl ester or a product obtained by completely or partially eliminating benzyl groups for protecting side carboxy groups in the poly-L-glutamic acid gamma-benzyl ester and the poly-L-aspartic acid beta-benzyl ester, and the molecular weight of the polyamino acid (ester) is from 200 to 100000.
Description
Technical field
The invention belongs to the synthetic method of poly-ethyleneamines with polyoxyethylene glycol and polyamino acid ester binary and terpolymer.
Technical background
Poly-ethyleneamines is a gene transfer vector material commonly used recently.In the body fluid environment, the poly-ethyleneamines molecular surface lotus that can become positively charged, this can and electronegative cell surface produce stronger interaction, thereby make poly-ethylene amine carrier have good targeting.These characteristics make it in medicine transfer vector field good prospects for application be arranged also.
Polyoxyethylene glycol has significant biocompatibility, anticoagulant property, and therefore nontoxic and hypoimmunity is widely used in biomedicine field.With polyoxyethylene glycol poly-ethyleneamines is carried out modification, can increase the solvability of poly-ethyleneamines, improve its stablizing as pharmaceutical carrier.
Synthetic polyamino acid ester has the character similar to natural polypeptides, can be degraded by enzyme in vivo, has good biological degradability and biocompatibility, is one of ideal medical material in organizational project and the drug delivery system solid support material.Simultaneously some polyamino acid with function side group can be introduced functional group in transgenosis and drug delivery system, has great application value.At present synthetic polyamino acid causes a-amino acid-N-carboxylic acid anhydride (NCA) ring-opening polymerization by primary amine usually and obtains.
The poly-ethyleneamines of institute of the present invention synthetic with the binary of polyoxyethylene glycol and/or polyamino acid and triblock copolymer integrated the character of polyoxyethylene glycol, poly-ethyleneamines, polyamino acid.By regulating the ratio of diblock or three block each several parts, hydrophilic that can telomerized polymer, biocompatibility, biological degradability, performances such as polymkeric substance mechanical strength.Polyamino acid that the present invention adopts can obtain having the polymkeric substance that functional group is a carboxyl on the side chain after removing Side chain protective group simultaneously, has great application prospect in transgenosis and medicament slow release system.Biodegradable polymer has excellent biological compatibility, can degrade voluntarily under physiological condition, collapse and metabolism, and then be absorbed by organism or excrete, and human body is had no side effect.When being used as pharmaceutical carrier, can regulate drug release rate by control degradation speed.Therefore, institute of the present invention synthetic macromolecular material has wide practical use in that very high use value is medically arranged.
Summary of the invention
One of order of the present invention is at first to make the poly glycol monomethyl ether that end group is an isocyanate group (mPEG-NCO);
Another object of the present invention is synthesizing polyethylene glycol-poly-ethyleneamines copolymer;
The 3rd purpose of the present invention is to cause the NCA ring-opening polymerization with the end amido that gathers ethyleneamines, generates to contain poly-ethyleneamines polyamino acid ester and the directly continuous multipolymer of poly-ethyleneamines polyamino acid ester;
The 4th purpose of the present invention is to utilize foregoing method synthetic product to prepare polyethylene glycol-ethyleneamines-polyamino acid ester terpolymer.
End group is that the preparation process of poly glycol monomethyl ether of isocyanate group is as follows:
Poly glycol monomethyl ether is dissolved in the solvent, add vulcabond again, be heated under the solvent boiling situation reaction 2-48 hour, after reaction finishes mixture poured in the precipitation agent and precipitate, with sedimentation and filtration, with the precipitation agent washing for several times, precipitation is dissolved in an amount of solvent then again, uses petroleum ether precipitation again, so repeatedly for several times, with precipitate and separate, vacuum-drying obtains the poly glycol monomethyl ether that end group is an isocyanate group at last.
The preparation process of polyethylene glycol-ethyleneamines copolymer is as follows:
Poly-ethyleneamines and mPEG-NCO are dissolved in respectively in the solvent, and the drips of solution of mPEG-NCO is added in the solution that gathers ethyleneamines reacts, and is reflected under the solvent refluxing temperature and carries out, and after reaction finishes mixture is concentrated, and uses ether sedimentation, and vacuum-drying gets product then.
End amido with poly-ethyleneamines causes the NCA ring-opening polymerization, and it is as follows to generate the preparation process that contains poly-ethyleneamines polyamino acid ester and the direct multipolymer that links to each other of poly-ethyleneamines polyamino acid ester:
Under the anhydrous and oxygen-free condition, be dissolved in the solvent gathering ethyleneamines or containing the polymkeric substance and the NCA monomer that gather ethyleneamines and also remain with the end amido of poly-ethyleneamines, polymerization temperature is 25-60 ℃, polymerization time is 24-72 hour; The product dissolution with solvents; be settled out polymkeric substance with precipitation agent; after filtration; washing; vacuum-drying; weighing; obtain containing poly-ethyleneamines polyamino acid ester copolymer, contain the deprotection of polyamino acid ester section side chain in poly-ethyleneamines and the polyamino acid ester copolymer then: will gather ethyleneamines-polyamino acid ester and be dissolved in, and add 20% palladium/carbon catalyst through in the solvent of drying and dehydrating; stirring reaction under hydrogen bubbling situation; control the reaction of deprotection rate with this and finish, remove by filter palladium/carbon, filtrate is used a large amount of ether sedimentations; filter, vacuum-drying obtains the product that the polyamino acid Side chain protective group removes fully or part removes.
The preparation process of utilizing foregoing method synthetic product to prepare polyethylene glycol-ethyleneamines-polyamino acid terpolymer is as follows:
With end group is that the poly glycol monomethyl ether of isocyanic ester is dissolved in the solvent, is added drop-wise in the solution of poly-ethyleneamines-polyamino acid ester copolymer, and reacting by heating generates polyethylene glycol-ethyleneamines-polyamino acid ester copolymer, product is with ether or the sedimentation of ethanol class precipitation agent, filter washing, vacuum-drying;
Be macromole evocating agent perhaps with foregoing method synthetic polyethylene glycol-ethyleneamines multipolymer, be dissolved in the organic solvent, utilize the amino initiation of the end amino acid-carboxylic acid anhydride NCA monomer ring-opening polymerization on the poly-ethyleneamines to obtain polyethylene glycol-ethyleneamines-polyamino acid ester copolymer, product is with ether or ethanol sedimentation, filter, washing, vacuum-drying.
Then with the deprotection of polyamino acid ester section side chain in polyethylene glycol-ethyleneamines-polyamino acid: polyethylene glycol-ethyleneamines-polyamino acid ester is dissolved in through in the solvent of drying and dehydrating; the palladium/carbon catalyst of adding 20%; stirring reaction certain hour under hydrogen bubbling situation; control the deprotection rate with this; reaction finishes; remove by filter palladium/carbon; filtrate is with a large amount of ether or petroleum ether precipitation; filter, vacuum-drying obtains product polyethylene glycol-ethyleneamines-polyamino acid ester that the polyamino acid Side chain protective group removes fully or part removes.
Gather ethyleneamines polyamino acid ester copolymer in synthetic the containing that the present invention carried out, and in synthesizing polyethylene glycol-aliphatic polyester-polyamino acid triblock copolymer experiment, polyethyleneglycol ramose molecular weight is 100～20000.The summation of each branch's molecular weight polyethylene glycol of multipolymer is 500-100000.Poly-ethyleneamines molecular weight is less than 30000; Being used for polymeric NCA monomer is γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride, β-benzyl-L-aspartic acid-N-carboxylic acid anhydride; The molecular weight of polyamino acid (ester) is 200-100000; The NCA monomer is 20-100 with the mol ratio of the end amido that plays initiation: 1, regulate these processing parameters, and form the different multipolymer of different molecular weight.Used organic solvent is that chloroform, methylene dichloride, tetrahydrofuran (THF), dioxane, benzene, toluene or dimethylbenzene are wherein any or two or more; Used vulcabond is hexamethylene-diisocyanate, tolylene diisocyanate or 4,4 '-diphenyl diisocyanate.
Embodiment
Embodiment 1
Is the poly glycol monomethyl ether OCN-mPEG550 that the poly glycol monomethyl ether prepared in reaction terminal hydroxy group of 550 (mPEG550) is modified to isocyanate group with hexamethylene-diisocyanate (HDI) with molecular weight.
In the 50ml there-necked flask of spherical condenser is housed, be that 550 mPEG is dissolved in 10 milliliters of dichloromethane solutions with 4.00 gram molecular weights, add the 10ml hexamethylene-diisocyanate, back flow reaction 8 hours.The reaction end is poured reactant in the sherwood oil into and is precipitated, and the oily precipitation is washed 3 times with 100 milliliters of sherwood oils.Again precipitation is dissolved in 20 milliliters of methylene dichloride,, carries out so repeatedly 4 times with 250 milliliters of petroleum ether precipitations.With precipitate and separate, residual solvent is removed in decompression at last.Weigh to such an extent that OCN-mPEG500 product 2.8 restrains, the mPEG550 yield is 53%.
Under the identical condition of preparation manipulation, be precipitation agent with the substituted ether sherwood oil, obtain OCN-mPEG550 product 2.7 grams, the mPEG550 yield is 52%.
Use chloroform respectively, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene solvent replace methylene dichloride, under the identical condition of other preparation condition, obtain weight and the yield such as the table 1 of product.
Table 1
| Solvent | OCN-mPEG550 product weight (g) | OCN-mPEG550 yield (%) |
| Chloroform | 2.6 | 50 |
| Tetrahydrofuran (THF) | 2.4 | 46 |
| Dioxane | 2.6 | 50 |
| Benzene | 3.0 | 57 |
| Toluene | 3.2 | 61 |
| Dimethylbenzene | 3.3 | 63 |
Embodiment 2
Is the poly glycol monomethyl ether OCN-mPEG550 that the poly glycol monomethyl ether prepared in reaction terminal hydroxy group of 550 (mPEG550) is modified to isocyanate group with tolylene diisocyanate (TDI) with molecular weight.
Testing apparatus is identical with embodiment 1 with operation steps, substitutes HDI with TDI.In the 50ml there-necked flask of spherical condenser is housed, be that 550 mPEG is dissolved in 10 milliliters of dichloromethane solutions with 4.00 gram molecular weights, add 10mlTDI, back flow reaction 12 hours.Other step is with embodiment 1.Get product 3.1 grams, productive rate 59%.
Under the identical condition of preparation manipulation, be precipitation agent with the substituted ether sherwood oil, obtain OCN-mPEG550 product 2.9 grams, the mPEG550 yield is 55%.
Use chloroform respectively, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene solvent replace methylene dichloride, under the identical condition of other preparation condition, obtain weight and the yield such as the table 2 of product.
Table 2
| Solvent | OCN-mPEG550 product weight (g) | OCN-mPEG550 yield (%) |
| Chloroform | 3.2 | 61 |
| Tetrahydrofuran (THF) | 2.7 | 51 |
| Dioxane | 2.5 | 47 |
| Benzene | 3.4 | 65 |
| Toluene | 3.3 | 63 |
| Dimethylbenzene | 3.6 | 68 |
Embodiment 3
With 4,4 '-diphenyl diisocyanate (MDI) is the poly glycol monomethyl ether OCN-mPEG550 that the poly glycol monomethyl ether prepared in reaction terminal hydroxy group of 550 (mPEG550) is modified to isocyanate group with molecular weight.
Testing apparatus is identical with embodiment 1 with operation steps, substitutes HDI with MDI.In the 50ml there-necked flask of spherical condenser is housed, be that 550 mPEG is dissolved in 10 milliliters of dichloromethane solutions with 4.00 gram molecular weights, add 10mlMDI, back flow reaction 12 hours.Other step is with embodiment 1.Get product 2.5 grams, productive rate 43%.
Under the identical condition of preparation manipulation, be precipitation agent with the substituted ether sherwood oil, obtain OCN-mPEG550 product 2.5 grams, the mPEG550 yield is 43%.
Use chloroform respectively, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene solvent replace methylene dichloride, under the identical condition of other preparation condition, obtain weight and the yield such as the table 3 of product.
Table 3
| Solvent | OCN-mPEG550 product weight (g) | OCN-mPEG550 yield (%) |
| Chloroform | 2.7 | 46 |
| Tetrahydrofuran (THF) | 2.3 | 40 |
| Dioxane | 2.4 | 41 |
| Benzene | 2.9 | 50 |
| Toluene | 2.6 | 45 |
| Dimethylbenzene | 2.7 | 46 |
Embodiment 4
Is the poly glycol monomethyl ether OCN-mPEG5000 that the poly glycol monomethyl ether prepared in reaction terminal hydroxy group of 5000 (mPEG5000) is modified to isocyanate group with hexamethylene-diisocyanate (HDI) with molecular weight.
In the 100ml there-necked flask of spherical condenser is housed, be that 5000 mPEG is dissolved in the 15ml chloroform with 16 gram molecular weights, add 60ml HDI, back flow reaction 24 hours.Reaction mixture 600ml petroleum ether precipitation is used 400ml petroleum ether three times.Be dissolved in then in the 20ml chloroform, use the 500ml petroleum ether precipitation, sedimentation is 10 times so repeatedly, and at last with precipitate and separate, vacuum-drying gets product mPEG-NC05K, 8.5 grams of weighing, and the yield of mPEG5000 is 51%.
Under the identical condition of preparation manipulation, be precipitation agent with the substituted ether sherwood oil, obtain OCN-mPEG5000 product 8.7 grams, the mPEG5000 yield is 53%.
Use methylene dichloride respectively, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene solvent replace chloroform, under the identical condition of other preparation condition, obtain weight and the yield such as the table 4 of product.
Table 4
| Solvent | OCN-mPEG5000 product weight (g) | OCN-mPEG5000 yield (%) |
| Methylene dichloride | 8.1 | 49 |
| Tetrahydrofuran (THF) | 7.8 | 47 |
| Dioxane | 8.0 | 48 |
| Benzene | 9.2 | 56 |
| Toluene | 9.3 | 56 |
| Dimethylbenzene | 9.0 | 54 |
Embodiment 5
Is the poly glycol monomethyl ether OCN-mPEG5000 that the poly glycol monomethyl ether prepared in reaction terminal hydroxy group of 5000 (mPEG5000) is modified to isocyanate group with TDI with molecular weight.
In the 100ml there-necked flask of spherical condenser is housed, be that 5000 mPEG is dissolved in the 15ml chloroform with 16 gram molecular weights, add 60ml TDI, back flow reaction 24 hours.Other steps are with embodiment 4.Get product 8.1 grams, productive rate 49%.
Under the identical condition of preparation manipulation, be precipitation agent with the substituted ether sherwood oil, obtain OCN-mPEG5000 product 8.0 grams, the mPEG5000 yield is 48%.
Use methylene dichloride respectively, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene solvent replace chloroform, under the identical condition of other preparation condition, obtain weight and the yield such as the table 5 of product.
Table 5
| Solvent | OCN-mPEG5000 product weight (g) | OCN-mPEG5000 yield (%) |
| Methylene dichloride | 7.8 | 47 |
| Tetrahydrofuran (THF) | 7.4 | 45 |
| Dioxane | 7.6 | 46 |
| Benzene | 8.3 | 50 |
| Toluene | 8.7 | 53 |
| Dimethylbenzene | 8.4 | 51 |
Embodiment 6
Is the poly glycol monomethyl ether OCN-mPEG5000 that the poly glycol monomethyl ether prepared in reaction terminal hydroxy group of 5000 (mPEG5000) is modified to isocyanate group with MDI with molecular weight.
In the 100ml there-necked flask of spherical condenser is housed, be that 5000 mPEG is dissolved in the 15ml chloroform with 16 gram molecular weights, add 80 gram MDI, back flow reaction 24 hours.Other steps are with embodiment 4.Get product 7.5 grams, productive rate 45%.
Under the identical condition of preparation manipulation, be precipitation agent with the substituted ether sherwood oil, obtain OCN-mPEG5000 product 7.2 grams, the mPEG5000 yield is 43%.
Use methylene dichloride respectively, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene solvent replace chloroform, under the identical condition of other preparation condition, obtain weight and the yield such as the table 6 of product.
Table 6
| Solvent | OCN-mPEG5000 product weight (g) | OCN-mPEG5000 yield (%) |
| Methylene dichloride | 7.1 | 42 |
| Tetrahydrofuran (THF) | 6.8 | 40 |
| Dioxane | 7.0 | 42 |
| Benzene | 8.0 | 48 |
| Toluene | 7.8 | 46 |
| Dimethylbenzene | 7.6 | 45 |
Embodiment 7
PEG-PEI copolymer synthetic that approximately contains 75% (mass ratio) different molecular weight PEI.Press shown in the table 7, every group of experiment adopts the PEI of different molecular weight to react.1.5 the PEI of gram is dissolved in the 150ml chloroform, 0.5 gram end group be isocyanate group (comprising: HDI, MDI, PEG TDI) are dissolved in the 50ml chloroform, the PEG drips of solution is added in the PEI solution, back flow reaction 12 hours finishes in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 7.
Table 7:
| Sample number | Isocyanide ester | PEI content, % (mass ratio) | The PEG molecular weight | The PEI molecular weight | Productive rate, % |
| PEG(5K)-PEI(25K) 75 | HDI | 75 | 5K | 25K | 69 |
| PEG(5K)-PEI(10K) 73 | HDI | 73 | 5K | 10K | 62 |
| PEG(600)-PEI(600) 77 | HDI | 77 | 600 | 600 | 56 |
| PEG(5K)-PEI(10K) 74 | TDI | 74 | 5K | 10K | 63 |
| PEG(5K)-PEI(10K) 76 | MDI | 76 | 5K | 10K | 64 |
Productive rate is a product weight and the ratio of PEG and PEI gross weight in the last table, and table 8 is identical to table 12.
Substitute chloroform solvent with methylene chloride, tetrahydrofuran (THF), or with the mixed solvent between them, little to the molecular weight and the solvent effect of product.
Embodiment 8
PEG-PEI copolymer synthetic that contains 25% (mass ratio) different molecular weight PEG.Press shown in the table 8, every group of experiment adopts the PEG of different molecular weight to react.1.5 the PEI of gram is dissolved in the 150ml chloroform, 0.5 gram end group be isocyanate group (comprising: HDI, MDI, PEG TDI) are dissolved in the 50ml chloroform, the PEG drips of solution is added in the PEI solution, back flow reaction 24 hours finishes in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 8.
Table 8
| Sample number | Isocyanide ester | PEI content, % (mass ratio) | The PEG molecular weight | The PEI molecular weight | Productive rate, % |
| PEG(20K)-PEI(10K) 72 | HDI | 72 | 20K | 10K | 75 |
| PEG(5K)-PEI(10K) 73 | HDI | 73 | 5K | 10K | 71 |
| PEG(550)-PEI(10K) 76 | HDI | 76 | 550 | 10K | 68 |
| PEG(5K)-PEI(10K) 77 | TDI | 77 | 5K | 10K | 70 |
| PEG(5K)-PEI(10K) 74 | MDI | 74 | 5K | 10K | 73 |
Embodiment 9
PEG-PEI copolymer synthetic that contains 50% (mass ratio) different molecular weight PEI.Press shown in the table 9, every group of experiment adopts the PEI of different molecular weight to react.1.0 the PEI of gram is dissolved in the 100ml chloroform, 1.0 gram end groups be isocyanate group (comprising: HDI, MDI, PEG TDI) are dissolved in the 100ml chloroform, the PEG drips of solution is added in the PEI solution, back flow reaction 24 hours finishes in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 9.
Table 9
| Sample number | Isocyanide ester | PEI content, % (mass ratio) | The PEG molecular weight | The PEI molecular weight | Productive rate, % |
| PEG(5K)-PEI(25K) 51 | HDI | 51 | 5K | 25K | 77 |
| PEG(5K)-PEI(10K) 48 | HDI | 48 | 5K | 10K | 70 |
| PEG(600)-PEI(600) 53 | HDI | 53 | 600 | 600 | 65 |
| PEG(5K)-PEI(10K) 48 | TDI | 49 | 5K | 10K | 72 |
| PEG(5K)-PEI(10K) 48 | MDI | 52 | 5K | 10K | 68 |
Embodiment 10
PEG-PEI copolymer synthetic that contains 50% (mass ratio) different molecular weight PEG.Press shown in the table 10, every group of experiment adopts the PEG of different molecular weight to react.1.0 the PEI of gram is dissolved in the 100ml chloroform, 1.0 gram end groups are that the PEG of HDI isocyanate group is dissolved in the 100ml chloroform, and the PEG drips of solution is added in the PEI solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 10.
Table 10
| Sample number | PEI content, % (mass ratio) | The PEG molecular weight | The PEI molecular weight | Productive rate, % |
| PEG(20K)-PEI(10K) 49 | 49 | 20K | 10K | 73 |
| PEG(5K)-PEI(10K) 50 | 50 | 5K | 10K | 70 |
| PEG(550)-PEI(10K) 52 | 52 | 550 | 10K | 67 |
Embodiment 11
PEG-PEI copolymer synthetic that contains 25% (mass ratio) different molecular weight PEI.Press shown in the table 11, every group of experiment adopts the PEI of different molecular weight to react.0.5 the PEI of gram is dissolved in the 50ml chloroform, 1.5 gram end groups are that the PEG of HDI isocyanate group is dissolved in the 150ml chloroform, and the PEG drips of solution is added in the PEI solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 11.
Table 11
| Sample number | PEI content, % (mass ratio) | The PEG molecular weight | The PEI molecular weight | Productive rate, % |
| PEG(550)-PEI(25K) 25 | 25 | 550 | 25K | 66 |
| PEG(550)-PEI(10K) 23 | 23 | 550 | 10K | 60 |
| PEG(550)-PEI(600) 26 | 26 | 550 | 600 | 53 |
Embodiment 12
PEG-PEI copolymer synthetic that contains 75% (mass ratio) different molecular weight PEG.Press shown in the table 12, every group of experiment adopts the PEG of different molecular weight to react, and reacts in different solvents.0.5 the PEI of gram is dissolved in the 50ml solvent, 1.5 gram end groups are that the PEG of HDI is dissolved in the 150ml solvent, and the PEG drips of solution is added in the PEI solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 12.
Table 12
| Sample number | Solvent | PEI content, % (mass ratio) | The PEG molecular weight | The PEI molecular weight | Productive rate, % |
| PEG(20K)-PEI(10K) 24 | Chloroform | 24 | 20K | 10K | 73 |
| PEG(5K)-PEI(10K) 26 | Methylene dichloride | 26 | 5K | 10K | 72 |
| PEG(550)-PEI(10K) 23 | Tetrahydrofuran (THF) | 23 | 550 | 10K | 68 |
| PEG(550)-PEI(10K) 25 | Chloroform/methylene dichloride (1: 1) | 25 | 550 | 10K | 69 |
Embodiment 13
The preparation of poly-ethyleneamines and poly--L-glutamic acid gamma-benzyl ester copolymer.By the requirement that feeds intake of table 13, under the anhydrous and oxygen-free condition, respectively PEI and γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA) are dissolved in the chloroform solvent.25 ℃ of following stirring reactions 72 hours; Product comes out with ether sedimentation, filters, and washing, 35 ℃ of following vacuum-drying 24 hours is weighed, and obtains poly-ethyleneamines-poly--L-glutamic acid gamma-benzyl ester copolymer, and polymerization result sees Table 13.
Table 13:
| Numbering | The PEI molecular weight | The charging capacity of PEI, g | The BLG-NCA charging capacity, g | The content of PBLG in the polymkeric substance, % | Productive rate % | M n |
| 1 | 5K | 1.0 | 2.0 | 64 | 93.6 | 14300 |
| 2 | 10K | 1.0 | 2.0 | 63 | 91.3 | 28700 |
| 3 | 20K | 1.0 | 2.0 | 63 | 90.4 | 44800 |
| 4 | 5K | 2.0 | 2.0 | 47 | 95.2 | 10200 |
| 5 | 10K | 2.0 | 2.0 | 47 | 94.6 | 22400 |
| 6 | 20K | 2.0 | 2.0 | 47 | 94.3 | 37100 |
| 7 | 5K | 2.0 | 1.0 | 31 | 96.6 | 8600 |
| 8 | 10K | 2.0 | 1.0 | 30 | 95.8 | 14700 |
| 9 | 20K | 2.0 | 1.0 | 30 | 95.1 | 26200 |
Productive rate is a binary polymer output and the percentage ratio of the ratio of PEI and BLG-NCA charging capacity summation in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Substituting ether with sherwood oil, methyl alcohol, ethanol or the mixed precipitant between them influences little to the productive rate of copolymer and the composition of multipolymer.
Substitute chloroform solvent respectively with methylene dichloride, tetrahydrofuran (THF), dioxane, benzene toluene, dimethylbenzene or with the mixed solvent between them, little to the composition influence of the productive rate of copolymer and multipolymer.
Embodiment 14
The preparation of poly-ethyleneamines and poly--L-aspartic acid β-benzyl ester copolymer.By the requirement that feeds intake of table 14, under the anhydrous and oxygen-free condition, respectively PEI (molecular weight is 10K) is dissolved in the chloroform solvent with β-benzyl-L-aspartic acid-N-carboxylic acid anhydride (BLA-NCA).25 ℃ of following stirring reactions 72 hours; Product comes out with ether sedimentation, filters, and washing, 35 ℃ of following vacuum-drying 24 hours is weighed, and obtains poly-ethyleneamines-poly--L-aspartic acid β-benzyl ester copolymer, and polymerization result sees Table 14.
Table 14:
| Numbering | The PEI molecular weight | The charging capacity of PEI, g | The BLA-NCA charging capacity, g | The content of PBLA in the polymkeric substance, % | Productive rate % | M n |
| 1 | 5K | 1.0 | 2.0 | 64 | 92.2 | 12400 |
| 2 | 10K | 1.0 | 2.0 | 61 | 90.5 | 23600 |
| 3 | 20K | 1.0 | 2.0 | 62 | 90.7 | 41300 |
| 4 | 5K | 2.0 | 2.0 | 46 | 93.3 | 10400 |
| 5 | 10K | 2.0 | 2.0 | 48 | 94.1 | 21800 |
| 6 | 20K | 2.0 | 2.0 | 47 | 93.6 | 35800 |
| 7 | 5K | 2.0 | 1.0 | 32 | 95.8 | 7800 |
| 8 | 10K | 2.0 | 1.0 | 30 | 93.4 | 13200 |
| 9 | 20K | 2.0 | 1.0 | 31 | 93.8 | 26600 |
Productive rate is a binary polymer output and the percentage ratio of the ratio of PEI and BLA-NCA charging capacity summation in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Substituting ether with sherwood oil, methyl alcohol, ethanol or the mixed precipitant between them influences little to the productive rate of copolymer and the composition of multipolymer.
Substitute chloroform solvent respectively with methylene dichloride, tetrahydrofuran (THF), dioxane, benzene toluene, dimethylbenzene or with the mixed solvent between them, little to the composition influence of the productive rate of copolymer and multipolymer.
Embodiment 15
The preparation of polyethylene glycol-ethyleneamines and poly--L-glutamic acid gamma-benzyl ester terpolymer.By the requirement that feeds intake of table 15, under the anhydrous and oxygen-free condition, respectively with PEG (5K)-PEI (10K)
73Be dissolved in the chloroform solvent with γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA).25 ℃ of following stirring reactions 72 hours; Product comes out with ether sedimentation, filters, and washing, 35 ℃ of following vacuum-drying 24 hours is weighed, and obtains polyethylene glycol-ethyleneamines-poly--L-glutamic acid gamma-benzyl ester terpolymer, and polymerization result sees Table 15.
Table 15:
| Numbering | The PEG-PEI polymkeric substance | The PEG-PEI charging capacity, g | The BLG-NCA charging capacity, g | Productive rate % | PEG-PEI- PBLG M n |
| 1 | PEG(5K)-PEI(10K) 73 | 0.26 | 2.34 | 89.0 | 87300 |
| 2 | PEG(5K)-PEI(10K) 73 | 0.78 | 1.82 | 90.2 | 54200 |
| 3 | PEG(5K)-PEI(10K) 73 | 1.3 | 1.3 | 87.5 | 32100 |
| 4 | PEG(5K)-PEI(10K) 73 | 1.82 | 0.78 | 90.6 | 22700 |
| 5 | PEG(5K)-PEI(10K) 73 | 2.34 | 0.26 | 91.3 | 18500 |
| 6 | PEG(10K)-PEI(10K) 48 | 1.5 | 1.5 | 91.3 | 42300 |
| 7 | PEG(550)-PEI(600) 53 | 1.5 | 1.5 | 89.4 | 8700 |
Productive rate is the output of PEG-PEI-PBLG and the percentage ratio of the ratio of PEG-PEI and BLG-NCA charging capacity summation in the table; M
nBe the number-average molecular weight of polyethylene glycol-ethyleneamines-poly--L-glutamic acid gamma-benzyl ester, by
1HNMR measures and obtains.
Substitute chloroform solvent respectively with methylene dichloride, tetrahydrofuran (THF), dioxane, benzene toluene, dimethylbenzene or with the mixed solvent between them, little to the composition influence of the productive rate of multipolymer and multipolymer.
Embodiment 16
The preparation of polyethylene glycol-ethyleneamines-poly--L-glutamic acid gamma-benzyl ester.Press shown in the table 16, every group of experiment adopts different PEI-PBLG to react.1.0 the PEI-PBLG of gram is dissolved in the 150ml solvent, 1.0 gram end groups are that the PEG of HDI isocyanate group is dissolved in the 100ml solvent, and the PEG drips of solution is added in the PEI-PBLG solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 16.
Table 16
| Numbering | The PEI-PBLG kind | PEI-PB LG molecular weight | The PEG molecular weight | Solvent | Productive rate, % | PEI-PBL G-PEG molecular weight |
| 1 | PEI(10K)-PBLG(19K ) | 28700 | 550 | Chloroform | 86 | 52300 |
| 2 | PEI(10K)-PBLG(5K) | 14700 | 550 | Chloroform | 88 | 26900 |
| 3 | PEI(10K)-PBLG(19K ) | 28700 | 5000 | Chloroform | 84 | 46800 |
| 4 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Chloroform | 85 | 25000 |
| 5 | PEI(10K)-PBLG(19K ) | 28700 | 10000 | Chloroform | 73 | 45600 |
| 6 | PEI(10K)-PBLG(5K) | 14700 | 10000 | Chloroform | 75 | 25400 |
| 7 | PEI(20K)-PBLG(17K ) | 37100 | 5000 | Chloroform | 63 | 58200 |
| 8 | PEI(5K)-PBLG(9K) | 14300 | 5000 | Chloroform | 81 | 23900 |
| 9 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Methylene dichloride | 84 | 24600 |
| 10 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Tetrahydrofuran (THF) | 83 | 23800 |
| 11 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Dioxane | 83 | 24000 |
| 12 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Benzene | 86 | 25300 |
| 13 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Toluene | 86 | 5800 |
| 14 | PEI(10K)-PBLG(5K) | 14700 | 5000 | Dimethylbenzene | 85 | 25600 |
Productive rate is a terpolymer output and the percentage ratio of the ratio of PEI-PBLG and PEG charging capacity summation in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Embodiment 17
The preparation of polyethylene glycol-ethyleneamines-poly--L-aspartic acid β-benzyl ester.Press shown in the table 17, every group of experiment adopts different PEI-PBLA to react.1.0 the PEI-PBLA of gram is dissolved in the 150ml solvent, 1.0 gram end groups are that the PEG of HDI isocyanate group is dissolved in the 100ml solvent, and the PEG drips of solution is added in the PEI-PBLA solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 17.
Table 17
| Numbering | The PEI-PBLA kind | PEI-P BLA molecular weight | The PEG molecular weight | Solvent | Productive rate, % | PEI-PBL A-PEG molecular weight |
| 1 | PEI(10K)-PBLA(12K) | 23600 | 550 | Chloroform | 84 | 43500 |
| 2 | PEI(10K)-PBLA(3.2K) | 13200 | 550 | Chloroform | 87 | 25100 |
| 3 | PEI(10K)-PBLA(12K) | 23600 | 5000 | Chloroform | 82 | 38700 |
| 4 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Chloroform | 83 | 24700 |
| 5 | PEI(10K)-PBLA(12K) | 23600 | 10000 | Chloroform | 72 | 41400 |
| 6 | PEI(10K)-PBLA(3.2K) | 13200 | 10000 | Chloroform | 73 | 25400 |
| 7 | PEI(20K)-PBLA(16K) | 35800 | 5000 | Chloroform | 65 | 57800 |
| 8 | PEI(5K)-PBLA(7.4K) | 12400 | 550 | Chloroform | 74 | 20900 |
| 9 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Methylene dichloride | 81 | 22300 |
| 10 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Tetrahydrofuran (THF) | 80 | 21200 |
| 11 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Dioxane | 81 | 23100 |
| 12 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Benzene | 84 | 24300 |
| 13 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Toluene | 82 | 23800 |
| 14 | PEI(10K)-PBLA(3.2K) | 13200 | 5000 | Dimethylbenzene | 79 | 24000 |
Productive rate is a ter-polymers output and the percentage ratio of the ratio of PEI-PBLA and PEG charging capacity summation in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Embodiment 18
The preparation of polyethylene glycol-ethyleneamines-poly--L-glutamic acid gamma-benzyl ester.Press shown in the table 18.1.0 the PEI-PBLG of gram is dissolved in the 150ml chloroform solvent, 1.0 gram end groups are that the PEG of different isocyanate group is dissolved in the 100ml solvent, and the PEG drips of solution is added in the PEI-PBLG solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 18.
Table 18
| Numbering | The PEI-PBLG kind | PEI-PBL G molecular weight | The PEG molecular weight | Isocyanide ester | Productive rate, % | PEI-PBLG-PEG molecular weight |
| 1 | PEI(10K)-PBLG(5K ) | 14700 | 550 | HDI | 88 | 26900 |
| 2 | PEI(10K)-PBLG(5K ) | 14700 | 550 | TDI | 86 | 26200 |
| 3 | PEI(10K)-PBLG(5K ) | 14700 | 550 | MDI | 86 | 24800 |
Productive rate is a ter-polymers output and the percentage ratio of the ratio of PEI-PBLG and PEG charging capacity summation in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Embodiment 19
The preparation of polyethylene glycol-ethyleneamines-poly--L-aspartic acid β-benzyl ester.Press shown in the table 19.1.0 the PEI-PBLG of gram is dissolved in the 150ml chloroform solvent, 1.0 gram end groups are that the PEG of different isocyanate group is dissolved in the 100ml solvent, and the PEG drips of solution is added in the PEI-PBLG solution, and back flow reaction finished in 24 hours in the there-necked flask of reflux is housed.The reaction solution ether sedimentation, precipitation vacuum-drying is weighed, and calculates productive rate, the results are shown in Table 19.
Table 19
| Numbering | The PEI-PBLG kind | PEI-PBL G molecular weight | The PEG molecular weight | Isocyanide ester | Productive rate, % | PEI-PBLG-PEG molecular weight |
| 1 | PEI(10K)-PBLA(3. 2K) | 13200 | 550 | HDI | 87 | 23600 |
| 2 | PEI(10K)-PBLA(3. 2K) | 13200 | 550 | TDI | 87 | 22800 |
| 3 | PEI(10K)-PBLA(3. 2K) | 13200 | 550 | MDI | 85 | 21600 |
Productive rate is a ter-polymers output and the percentage ratio of the ratio of PEI-PBLA and PEG charging capacity summation in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Embodiment 20
The deprotection that contains poly--L-glutamic acid gamma-benzyl ester section benzylalcohol in poly-ethyleneamines and the poly--L-glutamic acid gamma-benzyl ester copolymer.By feeding intake requirement and reaction times of table 20; need the polymkeric substance of deprotection to be dissolved in 1 gram through in the dioxane of drying and dehydrating; the palladium/carbon catalyst that adds 0.2 gram 20%, under 60 ℃ under hydrogen bubbling situation stirring reaction-fix time, control the deprotection rate with this.Reaction finishes, and removes by filter palladium/carbon, and filtrate is used a large amount of ether sedimentations, filters, and vacuum-drying obtains the product that the polyamino acid Side chain protective group removes fully or part removes.
Table 20:
| Numbering | Type of polymer | The deprotection time, hour | Productive rate % | Deprotection rate % | M n |
| 1 | PEI(5K)-PBLG(11K) | 12 | 84.3 | 37 | 14600 |
| 2 | PEI(10K)-PBLG(19K) | 24 | 82.6 | 100 | 37500 |
| 3 | PEG(5K)-PEI(10K) 75-PBLG (8K) | 8 | 88.9 | 16 | 21300 |
| 4 | PEG(5K)-PEI(10K) 75-PBLG (8K) | 24 | 79.5 | 100 | 20600 |
| 5 | PEG(5K)-PEI(10K) 75-PBLG(15 K) | 12 | 85.3 | 41 | 27400 |
| 6 | PEG(5K)-PEI(10K) 75-PBLG(15 K) | 18 | 78.0 | 70 | 26700 |
Productive rate is the ratio of weight with the weight of the preceding product of reaction of deprotection after product in the last table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Embodiment 21
Contain poly-ethyleneamines and poly--L-aspartic acid β-benzyl ester and poly-ethyleneamines and gather-gather in the multipolymer that L-aspartic acid β-the benzyl ester directly links to each other-deprotection of L-aspartic acid β-benzyl ester section benzylalcohol.
By feeding intake requirement and reaction times of table 21; need the polymkeric substance of deprotection to be dissolved in 1 gram through in the dioxane of drying and dehydrating; the palladium/carbon catalyst that adds 0.2 gram 20%, under 60 ℃ under hydrogen bubbling situation the stirring reaction certain hour, control the deprotection rate with this.Reaction finishes, and removes by filter palladium/carbon, and filtrate is used a large amount of ether sedimentations, filters, and vacuum-drying obtains the product that the polyamino acid Side chain protective group removes fully or part removes.
Table 21
| Numbering | Type of polymer | The deprotection time, hour | Productive rate % | The deprotection rate | M n |
| 1 | PEI(5K)-PBLA(10K) | 12 | 90.6 | 43 | 14300 |
| 2 | PEI(10K)-PBLA(10K) | 24 | 87.6 | 100 | 17800 |
| 3 | PEG(5K)-PEI(10K) 75-PBLA (25K) | 8 | 77.3 | 13 | 25600 |
| 4 | PEG(5K)-PEI(10K) 75-PBLA (25K)PEG(5K)-PEI(10K) 75 | 24 | 87.6 | 100 | 23700 |
| 5 | PEG(10K)-PEI(10K) 75-PBLA(1 5K) | 16 | 85.3 | 62 | 24300 |
| 6 | PEG(10K)-PEI(10K) 75-PBLA(1 5K) | 12 | 88.1 | 39 | 22500 |
Productive rate is a deprotection post polymerization thing weight and the ratio of deprotection post polymerization thing weight in the table; M
nBe number-average molecular weight, by
1HNMR measures and obtains.
Claims (4)
1, a kind of poly-ethyleneamines comprises the preparation of polyethylene glycol-ethyleneamines binary polymer with the synthetic method of polyoxyethylene glycol and polyamino acid ester copolymer, adopts following steps:
(1). at first make the poly glycol monomethyl ether that end group is an isocyanic ester: poly glycol monomethyl ether is dissolved in the organic solvent, add vulcabond again, be heated under the solvent boiling situation and reacted 2-48 hour, reaction is poured mixture in precipitation agent ether or the sherwood oil into after finishing, with sedimentation and filtration, again for several times with the precipitation agent washing, precipitation is dissolved in an amount of solvent then, precipitate with precipitation agent again, so repeatedly for several times, at last with precipitate and separate, vacuum-drying, obtain the poly glycol monomethyl ether that end group is an isocyanate group, (2) will gather end group that ethyleneamines and (1) obtains is that the poly glycol monomethyl ether of isocyanate group is dissolved in respectively in the solvent, and end group is that the drips of solution of the poly glycol monomethyl ether of isocyanate group is added in the solution of poly-ethyleneamines and reacts, be reflected under the solvent refluxing temperature and carry out, after reaction finishes mixture is concentrated, use ether sedimentation, vacuum-drying gets polyethylene glycol-ethyleneamines binary polymer then; Used vulcabond is hexamethylene-diisocyanate, tolylene diisocyanate or 4,4 '-diphenyl diisocyanate; Polyethyleneglycol ramose molecular weight is 100～20000; Poly-ethyleneamines is a branching, and molecular weight is less than 30000; The solvent that reacts used is that chloroform, methylene dichloride or tetrahydrofuran (THF) are wherein any or two or more.
2 one kinds of poly-ethyleneamineses are with the synthetic method of polyoxyethylene glycol and polyamino acid ester copolymer, comprise that the end amido with poly-ethyleneamines causes a-amino acid-N-carboxylic acid anhydride monomer ring-opening polymerization, generation contains poly-ethyleneamines polyamino acid ester and the directly continuous multipolymer of the poly-amino ester of poly-ethyleneamines, adopts following steps:
(1) under the anhydrous and oxygen-free condition, in solvent, utilize the end amido of poly-ethyleneamines to cause a-amino acid-N-carboxylic acid anhydride monomer polymerization, the mol ratio of monomer and initiating group is 20-100: 1, polymerization temperature is 25～60 ℃, polymerization time is 24～72 hours; The product dissolution with solvents is used wherein one or more mixed precipitants precipitations of ether, sherwood oil, methyl alcohol or ethanol, filters, and washing, vacuum-drying must gather the multipolymer of ethyleneamines-polyamino acid ester; Used poly-ethyleneamines is a branching, and molecular weight is less than 30000; Polymerization single polymerization monomer is γ-benzyl-L-L-glutamic acid-N-carboxylic acid anhydride or β-benzyl-L-aspartic acid-N-carboxylic acid anhydride, and the molecular weight of polyamino acid (ester) is 200-100000; The solvent that reacts used is that chloroform, methylene dichloride, tetrahydrofuran (THF), dioxane, benzene, toluene or dimethylbenzene are wherein any or two or more.
3. a poly-ethyleneamines is with the synthetic method of polyoxyethylene glycol and polyamino acid ester copolymer, and following steps are adopted in the preparation of polyethylene glycol-ethyleneamines-polyamino acid ester terpolymer; It is that the poly glycol monomethyl ether of isocyanic ester is dissolved in the organic solvent that claim 1 (1) is made end group, is added drop-wise in the organic solvent of poly-ethyleneamines-polyamino acid ester copolymer that claim 2 (1) makes; Reacting by heating generates polyethylene glycol-ethyleneamines-polyamino acid ester copolymer, and product filters with ether or ethanol sedimentation, washing, vacuum-drying; Perhaps using claim 1 (1) and (2) synthetic polyethylene glycol-ethyleneamines multipolymer is macromole evocating agent, be dissolved in the organic solvent, utilize the amino initiation of the end amino acid-carboxylic acid anhydride monomer ring-opening polymerization on the poly-ethyleneamines to obtain polyethylene glycol-ethyleneamines-polyamino acid ester copolymer, product is with ether or ethanol sedimentation, filter, washing, vacuum-drying; The solvent that reacts used is that chloroform, methylene dichloride, tetrahydrofuran (THF), dioxane, benzene, toluene or dimethylbenzene are wherein any or two or more.
4. a poly-ethyleneamines is with the synthetic method of polyoxyethylene glycol and polyamino acid ester copolymer; following steps are adopted in the ester group part deprotection of the polyamino acid ester moiety of wherein poly-ethyleneamines-polyamino acid ester or the binary of whole deprotections or the preparation of terpolymer: will gather ethyleneamines-polyamino acid ester copolymer or polyethylene glycol-ethyleneamines-polyamino acid ester terpolymer and be dissolved in through in the dioxane or tetrahydrofuran solvent of drying and dehydrating; the palladium/carbon catalyst of adding 20%; stirring reaction under hydrogen bubbling situation; control the deprotection rate with this; reaction finishes; remove by filter palladium/carbon; filtrate is with a large amount of ether or petroleum ether precipitation; filter, vacuum-drying obtains the product that polyamino acid ester side chain protecting group removes fully or part removes.
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| CN1323104C true CN1323104C (en) | 2007-06-27 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56128383A (en) * | 1980-03-13 | 1981-10-07 | Nissha Printing | Resist style agent |
| DE3901281A1 (en) * | 1989-01-18 | 1990-07-19 | Ernst Prof Dr Bayer | Highly water-absorbent, crosslinked copolymers of polyethyleneimine and polyethylene glycol |
| JPH0435741A (en) * | 1990-05-29 | 1992-02-06 | Asahi Chem Ind Co Ltd | Deodorant for lower aldehyde |
| US5260613A (en) * | 1992-06-30 | 1993-11-09 | The United States Of America As Represented By The Secretary Of The Army | Real-data FFT buffer |
-
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- 2004-01-09 CN CNB2004100106178A patent/CN1323104C/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56128383A (en) * | 1980-03-13 | 1981-10-07 | Nissha Printing | Resist style agent |
| DE3901281A1 (en) * | 1989-01-18 | 1990-07-19 | Ernst Prof Dr Bayer | Highly water-absorbent, crosslinked copolymers of polyethyleneimine and polyethylene glycol |
| JPH0435741A (en) * | 1990-05-29 | 1992-02-06 | Asahi Chem Ind Co Ltd | Deodorant for lower aldehyde |
| US5260613A (en) * | 1992-06-30 | 1993-11-09 | The United States Of America As Represented By The Secretary Of The Army | Real-data FFT buffer |
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