CN100543063C - Polyethyleneglycol of end group of amino acid and preparation method thereof - Google Patents
Polyethyleneglycol of end group of amino acid and preparation method thereof Download PDFInfo
- Publication number
- CN100543063C CN100543063C CNB2006100117167A CN200610011716A CN100543063C CN 100543063 C CN100543063 C CN 100543063C CN B2006100117167 A CNB2006100117167 A CN B2006100117167A CN 200610011716 A CN200610011716 A CN 200610011716A CN 100543063 C CN100543063 C CN 100543063C
- Authority
- CN
- China
- Prior art keywords
- proline
- pro
- end group
- polyethyleneglycol
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention discloses a kind of polyethyleneglycol of end group of amino acid and preparation method thereof, with common organic solvent as reaction medium, adopt the reaction of highly basic and amino acid to make initiator system, cause list/double-chain polyethylene glycol that epoxyethane ring-expansion polymerization prepares end group of amino acid.The advantage of this method is simple to operate, the transformation efficiency height, and can prepare end group is amino acid whose strand or double-chain polyethylene glycol, the controlled and narrow molecular weight distribution of molecular weight.
Description
Technical field
The present invention relates to a kind of polyoxyethylene glycol, in particular, relate to a kind of proline(Pro) polyethyleneglycol of end group and preparation method thereof.
Background technology
Polyoxyethylene glycol (polyethylene glycol, PEG) be a kind of be the polymer that polymerizable raw material obtains with oxyethane, the polyethers that to be a kind of while for example all have the excellent dissolution performance in methyl alcohol, methylene dichloride, chloroform etc. and the water at most of organic solvents, non-corrosiveness, nonirritant, no antigen and immunogenicity, good biocompatibility, show as the absorption of lower protein and low platelet in vivo and hang down cell adhesion, and obtained FDA approval use
Because polyoxyethylene glycol has above these good character, therefore for example makeup, water-based paint, paper coating, tackiness agent, printing-ink, tensio-active agent etc. have all obtained using widely in a lot of fields as additive.Simultaneously, at biomedicine field, polyoxyethylene glycol and protein, after polypeptide or small-molecule drug link to each other by chemical process, some characteristics of polyoxyethylene glycol are passed to the protein that is attached thereto, polypeptide or micromolecular compound, thereby change these materials pharmacokinetics and physiologic character in vivo, for example, the antigenicity of shielding polypeptide, reduce clearance rate in the body, reduce the hydrolysis degree of proteolytic ferment, improve the water-soluble of protein and polypeptide compounds, increase protein, the apparent molecular weight of polypeptide or micromolecular compound, reduce the kidney clearance rate, prolong the transformation period in vivo.
In biomedicine field, be generally used for the monoalkoxy polyoxyethylene glycol (polyethylene monoalkyl ether) that protein, polypeptide or small molecules compounds are modified, in application process, inactive terminal hydroxy group must be carried out derivatize, be translated into the polyethyleneglycol derivative class modifier that has amino, aldehyde radical, carboxyl isoreactivity functional group, just can carry out next step reaction then.Whole process reaction step is various, and overall conversion is low, and the product that obtains at last is the mixture of monoalkoxy polyoxyethylene glycol and target polyoxyethylene glycol, and target product be separated purification also is a very thing of difficulty.Therefore, directly obtaining end group by polymerization is that the polyoxyethylene glycol of active function groups is a kind of relatively suitable method.
End group is that the polymerization process commonly used of the polyoxyethylene glycol of active function groups has two kinds; a kind of is to adopt suitable electrophilic reagent or chain-transfer agent to end active end in polymerization process, and another kind is to make initiator with the active anion compound that has protected active function groups to cause ethylene oxide polymerization.Wherein, first kind of mode has a bigger defective, and promptly suspended active end can not react with electrophilic reagent again in polymerization process, has reduced the degree of reactive polymer terminal functionalityization thus.Adopting the compound have active function groups is that the polymerization that initiator causes oxyethane does not then exist such problem substantially, in preparation process, in case be initiated promptly and can obtain required polymerisate, cause the part that lost efficacy also owing to being that micromolecular compound compares and is easier to remove even have.Therefore, take all factors into consideration, it is to select relatively preferably that the initiator system that employing has an active function groups causes the method that method that oxyethane carries out active anionic polymerization prepares the active function groups polyethyleneglycol of end group, and molecular weight and molecular weight distribution that this method can also the required product of better controlled.
In above-mentioned anionoid polymerization process; use the micromolecular compound that many initiators that contains active function groups normally contain hydroxyl and aldehyde radical, amino isoreactivity functional group simultaneously; at first aldehyde radical, amino isoreactivity functional group are protected by protective reaction; then; adopt the hydroxyl of highly basic and initiator molecule to carry out the active initiation of prepared in reaction center, and then the polymerization of initiation oxyethane obtain polyoxyethylene glycol.After polymerization was finished, the protected end group with product carried out deprotection reaction more again, allowed end group revert to aldehyde radical or amino isoreactivity functional group, obtained the required polyoxyethylene glycol that has the active function groups end group thus.
But above-mentioned traditional method substantially all is to cause by the hydroxyl in two/polyfunctional group small molecules; required active function groups will be protected with deprotection in the front and back of polyreaction and handle; the entire reaction course step is more; and the transformation efficiency that reacts total is not high, also exists simultaneously as the expensive problem of the polyfunctional compound price of initiator.Therefore, in actual applications, this polymerization methods is restricted to a certain extent.
Present method has overcome above-mentioned defective; adopt proline(Pro) and alkali reaction to prepare initiator system; utilize its amino open loop anionoid polymerization that causes oxyethane; and the carboxylate radical negative ion that carboxyl and alkali form can stable existence in this system; after polymerization is finished; promptly can be in sour stopped reaction with carboxylate radical negative ion reduction becoming carboxylic acid; therefore; this preparation process has been omitted protection and the deprotection reaction of common necessary polymerization front and back to active function groups; avoided the not high defective of transformation efficiency; guaranteed the purity of polymerisate; also therefore avoided complicated separation purification operations; a kind of simple and effective preparation method of polyoxyethylene glycol also is provided simultaneously, changed common needed polystep reaction and the transformation efficiency that brings not high score from the defective of difficulty.
Summary of the invention
The object of the present invention is to provide a kind of proline(Pro) polyethyleneglycol of end group, as shown below:
In the formula, n=5～1000, R ' is for being selected among Na, K, the H any one.
The present invention also aims to provide a kind of preparation method who prepares the proline(Pro) polyethyleneglycol of end group.
The method that the present invention prepares the proline(Pro) polyethyleneglycol of end group may further comprise the steps:
1. select suitable highly basic, in the effective organic solvent system, carry out prepared in reaction and obtain active initiator system (elicitation procedure is as reacting shown in 1) with proline(Pro);
2. under the protection of inert gas condition, in above-mentioned initiator system, add quantitative oxyethane and carry out anionoid polymerization (polymerization process is respectively as reacting shown in 1);
3. end polymerization with pure water or suitable acid.
Reaction 1
In the reaction 1, M is selected among Na or the K any one, is decided by selected alkali.
Above-mentioned preparation method can be used for preparing the proline(Pro) polyethyleneglycol of end group.Selected proline(Pro) source is without any specific restriction, and the proline(Pro) of any commercialization all can be used as raw material, and rank is also unrestricted.Because the stringent condition that anionoid polymerization requires, proline(Pro) will carry out the purifying drying treatment before use.Purification process for example can adopt pure water to carry out recrystallization without any specific restriction, filters, and pulverizes the method for final vacuum drying for standby.
The solvent that uses in above-mentioned preparation method's step 1 is to be selected from a kind of in tetrahydrofuran (THF), toluene or the dimethyl sulfoxide (DMSO), its source without any restriction, the above-mentioned solvent of any commercialization all can be used as raw material, rank is also unrestricted.The operation with deoxygenation because the stringent condition that anionoid polymerization requires, solvent must dewater before use.Solvent dewater with the deoxygenation operating method without any specific limited, for example can adopt in the following method: add a certain amount of sodium Metal 99.5 and benzophenone in above-mentioned solvent, after a few hours of refluxing, middle runnings is got in distillation.
The highly basic that uses in above-mentioned preparation method's step 1 is selected from a kind of of naphthalene potassium, naphthalene sodium, sodium hydride, potassium hydride KH, and its mole dosage equates with proline(Pro) active function groups integral molar quantity.Wherein said active function groups is carboxyl and amino.
The reactor that uses in above-mentioned preparation method's step 1 is without any specific restriction, but necessary sealing and connection vacuum system and gas protection system, and convenient solvent, reaction raw materials and the initiator of adding.For example can use to connect vacuum system and gas protection system, and by plug sealed glass reaction flask.Above-mentioned used shielding gas does not have specific restriction yet, for example nitrogen and argon gas.
The source of the raw material oxyethane that uses in above-mentioned preparation method's step 2 is without any specific restriction, and the oxyethane of any commercialization all can be used as raw material, and rank is also unrestricted.Because the stringent condition that anionoid polymerization requires, oxyethane must carry out the separation and purification operation before use.The method of separation and purification for example can be adopted in the following method without any specific restriction: in commodity oxyethane, add a certain amount of hydrolith, soak a couple of days after, middle runnings is got in distillation.
The terminator that uses in above-mentioned preparation method's step 3 can make active hydrogen compoundss such as water or acetate stop obtaining hydroxyl end groups without any specific restriction.
Can use crown ether compound as carry out of catalysts among the above-mentioned preparation method to promote to react.The crown ether-like catalyzer is to be selected from 18-crown ether-6, dibenzo-18-crown ether-6, and a kind of in the dicyclohexyl-18-crown ether-6, its molar weight is 0.5～1.5 times of molar weight of described proline(Pro) active function groups.
The invention has the advantages that: by simple operation, the employing proline(Pro) is an initiator, and it is suitable that high conversion ground obtains molecular weight, the proline(Pro) polyethyleneglycol of end group (I) of narrowly distributing.
Set forth embodiments of the present invention with the form of specializing below, but the present invention is not restricted in this embodiment.
Embodiment
(1) in commodity oxyethane, add a certain amount of hydrolith, soak a couple of days after, distillation, it is stand-by to get middle runnings;
(2) the commodity proline(Pro) is carried out recrystallization with pure water, filter, pulverize the final vacuum drying for standby;
(3) in tetrahydrofuran (THF), add a certain amount of sodium Metal 99.5 and benzophenone, after a few hours of refluxing, distillation, it is stand-by to get middle runnings;
(4) add quantitative naphthalene crystal and fresh potassium metal in reaction flask, the inflated with nitrogen of bleeding after the sealing is handled;
(5) stir on one side, in reaction flask to step (4) handle after add fresh tetrahydrofuran (THF) on one side, react to solution and be blackish green, set aside for use;
(6) under heating condition, the reaction flask of another sealing inflated with nitrogen of bleeding is handled, repeat repeatedly;
(7) add quantitative proline(Pro) in the reaction flask after step (6) is handled, the inflation of bleeding is once more handled, and repeats repeatedly, last inflated with nitrogen;
(8) make solvent by adding fresh tetrahydrofuran (THF) in the reaction flask of syringe after step (7) is handled;
(9) start magnetic agitation on one side, on one side adding is by the tetrahydrofuran solution of the naphthalene potassium of step (5) preparation in the tetrahydrofuran solution of the proline(Pro) that step (8) forms by syringe, naphthalene potassium mole dosage equates with proline(Pro) active function groups molar weight;
(10) after a few hours, in the reaction solution that step (9) obtains, add the oxyethane of 5～1000 times of proline(Pro) molar weights by frozen syringe;
(11) behind the stoichiometric number hour, in the reaction solution that step (10) obtains, add the hydrochloric acid stopped reaction of the 1mol/L of 5～50 times of proline(Pro) molar weights by syringe;
(12) stir on one side, on one side in the chilled ethyl ether of 5～20 times of volumes of reaction solution impouring reaction solution that step (11) is obtained, stirred for several minute continued;
(13) diethyl ether solution of the product that step (12) is obtained filters and obtains white precipitate;
(14) the precipitation drying that step (13) is obtained obtains the white powder product.
Embodiment 1
The 100mL reaction flask inflated with nitrogen of bleeding is handled, after the repeated multiple times, add 0.1152g (1mmol) proline(Pro) in the reaction flask after handling, the inflation of bleeding is once more handled, repeat repeatedly, add 50 milliliters of fresh distillatory tetrahydrofuran solvents by syringe, while the tetrahydrofuran solution 5.0ml (1.0mmol) of the naphthalene potassium that stirs the 0.2mol/L that adds prepared beforehand, after a few hours, add oxyethane 1.0ml (about 20mmol then by frozen syringe, 0.8g), behind the stoichiometric number hour, add 0.5ml acetic acid,diluted stopped reaction, then, in the cold diethyl ether with 12 times of reaction product impouring liquor capacities, obtain the white precipitate product, filter vacuum-drying, obtain fluffy powder shape polymerisate proline(Pro) polyethyleneglycol of end group 0.6g, productive rate 75%.
Claims (4)
1. preparation method with proline(Pro) polyethyleneglycol of end group of following structure (I),
Above-mentioned method comprises the steps:
(1) selects suitable highly basic, in organic solvent system, carry out prepared in reaction and obtain the active initiator system with proline(Pro);
(2) under the protection of inert gas condition, in (2) described initiator system, add quantitative oxyethane and carry out anionoid polymerization;
(3) end polymerization with pure water or suitable acid, can obtain proline(Pro) polyethyleneglycol of end group (I);
Wherein said suitable highly basic is to be selected from a kind of in naphthalene potassium, naphthalene sodium, sodium hydride or the potassium hydride KH, and described alkaline molar weight equates with the molar weight of proline(Pro) active function groups;
The mole dosage of described oxyethane is 5～1000 times of proline(Pro), and the molecular weight ranges that gained has the proline(Pro) polyethyleneglycol of end group is 500～40000;
2. the preparation method of proline(Pro) polyethyleneglycol of end group as claimed in claim 1, described organic solution are selected from a kind of in tetrahydrofuran (THF), toluene or the dimethyl sulfoxide (DMSO).
3. the preparation method of proline(Pro) polyethyleneglycol of end group as claimed in claim 1, the consumption of described proline(Pro) is 0.001～1mol/L.
4. the preparation method of proline(Pro) polyethyleneglycol of end group as claimed in claim 1 can also add the crown ether-like catalyzer to promote the carrying out of reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100117167A CN100543063C (en) | 2006-04-03 | 2006-04-03 | Polyethyleneglycol of end group of amino acid and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100117167A CN100543063C (en) | 2006-04-03 | 2006-04-03 | Polyethyleneglycol of end group of amino acid and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101050276A CN101050276A (en) | 2007-10-10 |
| CN100543063C true CN100543063C (en) | 2009-09-23 |
Family
ID=38781890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100117167A Expired - Fee Related CN100543063C (en) | 2006-04-03 | 2006-04-03 | Polyethyleneglycol of end group of amino acid and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100543063C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101176791B (en) * | 2006-11-07 | 2013-01-09 | 中国药科大学 | Amino acid communicating with polyglycol as well as manufacturing method and usage thereof |
| CN102964588A (en) * | 2012-11-09 | 2013-03-13 | 河南工业大学 | Preparation method and application of acid or active ester of polyethylene glycol with tail end connected with aminophenyl propionic acid |
| CN104944602B (en) * | 2015-06-05 | 2017-01-11 | 东南大学 | Environment-friendly polyether water treatment agent for sea water desalination film and preparation method for environment-friendly polyether water treatment agent |
| US20200206350A1 (en) * | 2017-09-05 | 2020-07-02 | Merck Sharp & Dohme Corp. | Compounds for reducing the viscosity of biological formulations |
| CN110156971A (en) * | 2018-02-13 | 2019-08-23 | 上海时莱生物技术有限公司 | A kind of amphipathic nature block polymer and preparation method thereof and nano-micelle drug-loading system |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1343494A2 (en) * | 2000-12-01 | 2003-09-17 | Enzon, Inc. | Tetrapartate prodrugs |
| CN1461762A (en) * | 2002-05-30 | 2003-12-17 | 中国科学院过程工程研究所 | Method of preparing branched polyethylene glycol |
| WO2004060406A2 (en) * | 2002-12-31 | 2004-07-22 | Nektar Therapeutics Al, Corporation | Polymeric reagents comprising a ketone or a related functional group |
-
2006
- 2006-04-03 CN CNB2006100117167A patent/CN100543063C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1343494A2 (en) * | 2000-12-01 | 2003-09-17 | Enzon, Inc. | Tetrapartate prodrugs |
| CN1461762A (en) * | 2002-05-30 | 2003-12-17 | 中国科学院过程工程研究所 | Method of preparing branched polyethylene glycol |
| WO2004060406A2 (en) * | 2002-12-31 | 2004-07-22 | Nektar Therapeutics Al, Corporation | Polymeric reagents comprising a ketone or a related functional group |
Non-Patent Citations (1)
| Title |
|---|
| 合成分枝型聚乙二醇的简便新方法. 何明磊，苏志国.高等学校化学学报，第24卷第8期. 2003 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101050276A (en) | 2007-10-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100543063C (en) | Polyethyleneglycol of end group of amino acid and preparation method thereof | |
| Montoya et al. | Cyclic carbonate synthesis from CO2 and epoxides using zinc (II) complexes of arylhydrazones of β-diketones | |
| CN109627429A (en) | A kind of preparation method of high-molecular-weight poly (gamma-butyrolacton) | |
| CN106633087B (en) | Miscellaneous arm star polymer of a kind of eight arms and preparation method thereof | |
| CN108554415A (en) | A kind of cobalt zinc bimetallic catalyst and preparation method for Catalysts of Preparing Methyl Ethyl Carbonate | |
| CN105399942B (en) | Double tail APEOs of a kind of polycarboxylic acid water reducer macromer end alkenyl ester structure and preparation method thereof | |
| CN101213017A (en) | Method for the production of double metal cyanide complex catalysts | |
| CN100435945C (en) | Method for preparing nickel catalyst carried in ion liquid | |
| CN108772100A (en) | A kind of heteropolyacid salt solid catalyst and its preparation method and application | |
| CN103897170A (en) | Amino-terminated polyether, and preparation method and applications thereof | |
| Sharma et al. | FTIR and absorption edge studies on tungsten oxide based precursor materials synthesized by sol–gel technique | |
| CN103372437A (en) | Preparation method of copper-zinc series catalyst | |
| CN111905834B (en) | BiOBr x I 1-x Preparation method of ZIF-8 composite photocatalyst | |
| CN101914200B (en) | Method for preparing allyl polyoxyethylene ether | |
| CN102634007A (en) | Polyethylene glycol polymer containing dopamine, preparation method for same and application thereof | |
| CN105542183B (en) | A kind of preparation method of polyvinyl alcohol polycaprolactone polytrimethylene carbonate dual graft copolymer micelle | |
| Sheng et al. | Synthesis and molecular structure of new heterometal alkoxide clusters Ln2Na8 (OCH2CF3) 14 (THF) 6 (Ln= Sm, Y, Yb): highly active catalysts for polymerization of ε-caprolactone and trimethylene carbonate | |
| CN109503827A (en) | A method of the catalyst of polypeptide is prepared for amino acid ring inner-acid anhydride ring-opening polymerisation and utilizes the catalyst preparation polypeptide | |
| CN104557970B (en) | A kind of preparation method of ticlopidine hydrochloride | |
| CN102180865B (en) | Synthesis method of lansoprazole | |
| CN111704713A (en) | Titanium catalyst for polyester synthesis and preparation method thereof | |
| CN100554310C (en) | Monoalkoxy polyoxyethylene glycol and preparation method thereof | |
| CN109111566A (en) | A kind of preparation method of high-purity polydioxanone | |
| CN100465196C (en) | Method for preparing high molecular compound adopting novel ion liquid polymerization initiation system | |
| CN112898326A (en) | Preparation method and application of organic boron compound, and preparation method and application of beta-hydroxy compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090923 Termination date: 20190403 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |