CN104892372B - A kind of synthetic method of little molecule Polyethylene Glycol - Google Patents
A kind of synthetic method of little molecule Polyethylene Glycol Download PDFInfo
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- CN104892372B CN104892372B CN201510278342.4A CN201510278342A CN104892372B CN 104892372 B CN104892372 B CN 104892372B CN 201510278342 A CN201510278342 A CN 201510278342A CN 104892372 B CN104892372 B CN 104892372B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses the synthetic method of a kind of little molecule Polyethylene Glycol.The present invention have developed the preparation technology of a kind of new Polyethylene Glycol; use dihydropyran to make protection group and prepare bigger unimodal molecular weight pentamer, six aggressiveness, heptamer, eight aggressiveness from oligomer Polyethylene Glycol raw materials such as the dimer of unimodal molecular weight, trimer, the tetramers, so that ten dimers, 16 aggressiveness, 20 tetramers etc..Preparation method of the present invention is simple and convenient to operate, and is suitable for industrialization and batch production.
Description
Technical field
The present invention relates to the chemical synthesis process of Polyethylene Glycol link agent, be specifically related to a kind of little molecule
The synthetic method of Polyethylene Glycol.
Background technology
Along with macromole immunity class biopharmaceutical industry, the medicine directional transmissions technology of monoclonal antibody coupling
(antibody-drug conjugate/ADC), liposome formula class (liposome formulation) and small-sized poly-
The development of compound type nano granular (polymer based Micelles or Nano Particle) technology, bio-based
Because the application in anticancer toxoid drug development of the medicine directional transmissions is progressively risen and more and more flourishing.Little
Molecule polyethylene glycols (PEG) linking agent can be modified for immunity bioprotein, and can assist little
Molecular medicine transmits, thus it shows tempting market prospect.This series products is due to synthesis and separates pure
Change difficulty big, commercially show as expensive (hundreds of to thousands of dollars every gram) so that various grind
Study carefully mechanism to hope and halt.At present, the supply commercially of the bulk formulation of polyethylene glycols is the most multiple
The mixture of the repetitive of the Polyethylene Glycol of different molecular weight, and the Polyethylene Glycol of bigger unimodal molecular weight
Pentamer, six aggressiveness, heptamer, eight aggressiveness, so that ten dimers, 16 aggressiveness, 20 tetramers
Deng the most little.Therefore, the synthesis technique studying this micromolecular Polyethylene Glycol is significant.
Summary of the invention
It is an object of the invention to, it is provided that the synthetic method of a kind of little molecule Polyethylene Glycol.
The present invention solves that the technical scheme that above-mentioned technical problem is used is as follows:
A kind of synthetic method of little molecule Polyethylene Glycol, synthetic route is as follows:
Described n, m are positive integer；
Concrete synthesis step is:
Step 1, compound 1 and dihydropyran reacting generating compound 2；
Step 2, compound 2 and paratoluensulfonyl chloride reacting generating compound 3；
Step 3, compound 3 and compound 4 reacting generating compound 5 under NaH is catalyzed；In this step
Compound 4 use with compound 2 as method prepare；
Step 4, compound 5 is sloughed the blocking group at two ends and is obtained compound 6.
Dihydropyran molecular structural formula in the present invention is:
Preferably, described step 1 method particularly includes: compound 1 and dihydropyran be molten in dichloromethane
In liquid, reacting generating compound 2 under pyridinium p-toluenesulfonate is catalyzed.
Preferably, described step 2 method particularly includes: compound 2 is dissolved in dichloromethane solution, add
Entering triethylamine and be cooled to less than 5 DEG C, then drip paratoluensulfonyl chloride, room temperature reaction generates compound 3.
Preferably, described step 3 method particularly includes: compound 4 is dissolved in dry oxolane,
Adding NaH, then dropping compound 3 under condition of ice bath, room temperature reaction generates compound 5.
Preferably, described step 4 method particularly includes: compound 5 is in methanol solution, in acid catalysis
Lower reacting generating compound 6.
Preferably, in described step 1, the isolation and purification method of product is: TLC detection reaction is complete, will
Reactant liquor saturated aqueous common salt washs more than 1 time, and rotation evaporates dichloromethane；Thick product ethyl acetate/just
Hexane mixed solvent washs more than 1 time, and aqueous phase dichloromethane extracts；Merge organic facies, dry, mistake
Filter, be spin-dried for obtaining compound 2.Preferably, the ratio of described ethyl acetate/normal hexane mixed solvent is 1:3.
Present invention also offers the synthetic method of another kind of little molecule Polyethylene Glycol, the method is:
Described n, m are positive integer；
Compound a and compound b reacting generating compound c under NaH is catalyzed；Compound c sloughs two
The blocking group of end obtains compound d.Specifically step is: compound b is dissolved in dry oxolane,
Adding NaH under condition of ice bath, then drip compound a, room temperature reaction generates compound c；Compound c
In methanol solution, reacting generating compound d under acid catalysis.
The present invention also provides for the hydroxy protecting techniques of a kind of little molecule Polyethylene Glycol, and the method is: little molecule
Hydroxyl on Polyethylene Glycol and dihydropyran, under pyridinium p-toluenesulfonate is catalyzed, carry out additive reaction,
Obtain the little molecule Polyethylene Glycol of Pentamethylene oxide. group protection.
Preferably, the hydroxy protecting techniques of a kind of little molecule Polyethylene Glycol is particularly as follows: little molecule Polyethylene Glycol
It is dissolved in dichloromethane, is sequentially added into dihydropyran and pyridinium p-toluenesulfonate, room temperature reaction, TLC
Detection reaction is complete, is washed more than 1 time by reactant liquor saturated aqueous common salt, and rotation evaporates dichloromethane；Slightly
Product ethyl acetate/normal hexane mixed solvent washs more than 1 time, and aqueous phase dichloromethane extracts；Merge
Organic facies, is dried, filters, is spin-dried for obtaining target product.Preferably, described ethyl acetate/normal hexane mixes
The ratio of bonding solvent is 1:3.
Compared with prior art, beneficial effects of the present invention is as follows:
1, the present invention has designed and developed the preparation technology of a kind of new Polyethylene Glycol, uses dihydropyran to go bail for
Protect base to prepare relatively from oligomer Polyethylene Glycol raw materials such as the dimer of unimodal molecular weight, trimer, the tetramers
Big unimodal molecular weight pentamer, six aggressiveness, heptamer, eight aggressiveness, thus ten dimers, 16 aggressiveness,
20 tetramers etc..Preparation method of the present invention is simple and convenient to operate, and is suitable for industrialization and batch production.
2, in conjunction with the feature of the molecular characterization good water solubility of little molecule Polyethylene Glycol this kind of linking agent product, this
Invention uses the WATER-WASHING METHOD of separation and purification of products, makes the low dose of synthetic technology of this series products rise to rapidly
Pilot scale and batch production, due to the batch production of this series products, to have certain science and technology labour-intensive special
Point, is suitable for technology to be advanced to may conform to country or meet the repeatable production of industry standard, and then batch
Amount produces, dominates the market；Owing to it is emerging immunity class pharmacy industry and medicine directional transmissions field extensive
Application, its market and economic benefit prospect are inestimable.
Detailed description of the invention
Below by way of specific embodiment, technical scheme is described.In the present invention used former
Material and reagent are the most commercially.
During the present invention implements1H-NMR by Varian 400 at CDCl3In record.Mass spectrum VG
PLATFORM mass spectrograph, with ESI technology sample introduction.Ripple layer chromatography (TLC) is by HF254 silicon
Obtain with the drunk method of iodine or potassium permanganate solution colour developing on offset plate.Column chromatography uses silica gel 100 to 200
Purpose medium, with petroleum ether and ethyl acetate, dichloromethane and methanol mixed solvent drip washing, solution
Decompression distillation when less than 60 degrees Celsius.
Abridge about the chemical formula in the embodiment of the present invention:
DHP: dihydropyran
PPTS: pyridinium p-toluenesulfonate
DCM: dichloromethane
P-TsCl: paratoluensulfonyl chloride
Et3N: triethylamine
THF: oxolane
MeOH: methanol
Below for the present embodiment synthesizes the synthetic route of PEG5-PEG12:
The synthesis of compound 36
Compound 35 (234.5g, 2.21mol) is dissolved in the dichloromethane of 1.5L, adds successively
Entering DHP (60g, 0.713mol), PPTS (27g, 0.107mol) stirred overnight at room temperature, TLC examines
Measured reaction is complete, is washed twice (1L × 2) by reactant liquor saturated aqueous common salt, then steams instrument in rotation
On spin off dichloromethane.The thick product ethyl acetate that will obtain: the mixed solvent of normal hexane=1:3
Washing twice (800mL × 2), aqueous phase dichloromethane is extracted twice (1L × 2), merges organic facies,
It is dried with anhydrous sodium sulfate, filters, be spin-dried for obtaining 95g colourless liquid (productivity: 70%).1H-NMR
(400MHz,CDCl3):1.49(6H,m),2.02(1H,s),3.59(8H,m),3.85(2H,t,J
4.0),4.62(1H,t,J 4.0)。
The synthesis of compound 37
Compound 36 (40g, 0.21mol) is dissolved in the dichloromethane of 400mL, adds three second
Amine 46.7g, is cooled to less than 5 DEG C, is then slowly added dropwise the dichloromethane solution of paratoluensulfonyl chloride,
Within temperature control 5 DEG C, drip and finish.Being to slowly warm up to room temperature, stir 3 hours under room temperature, TLC detects,
React complete, by reacting liquid filtering, by filtrate successively with water (500mL × 2), saturated aqueous common salt
(500mL × 2) wash, and merge organic facies, are dried with anhydrous sodium sulfate, filter, are spin-dried for, then
Cross column purification, obtain the flaxen liquid of 70g (productivity: 96.4%).
The synthesis of compound 38
Compound 9 (321.3g, 2.21mol) is dissolved in the dichloromethane of 1.5L, is sequentially added into
DHP (60g, 0.713mol), PPTS (27g, 0.107mol) stirred overnight at room temperature, TLC detects
React complete, reactant liquor saturated aqueous common salt is washed twice (1L × 2), then steam in rotation and revolve on instrument
Fall dichloromethane.The thick product ethyl acetate that will obtain: the mixed solvent of normal hexane=1:3 washes two
Secondary (800mL × 2), aqueous phase dichloromethane is extracted twice (1L × 2), merges organic facies, by nothing
Aqueous sodium persulfate is dried, and filters, is spin-dried for obtaining 124g colourless liquid (productivity: 74.3%).1H-NMR
(400MHz,CDCl3):1.47(6H,m),2.75(1H,s),3.58(12H,m),3.69(2H,t,J
12.0),4.60(1H,t,J 4.0)。
The synthesis of compound 39
Taking the there-necked flask of 2L, nitrogen is replaced twice, be sequentially added into compound 38 (47.4g,
0.203mol), the oxolane (600mL) being dried, under ice bath, add NaH (10g, 0.25mol),
Temperature control 0 degree, is slowly added dropwise the tetrahydrofuran solution of compound 37 (70g, 0.203mol), drips and finishes,
It is to slowly warm up to room temperature.Being stirred overnight under room temperature, TLC detects, and reacts complete, is fallen by reactant liquor
Entering in the water of 1000mL, add the ethyl acetate extraction of 500mL, aqueous phase dichloromethane extracts two
All over (500mL × 2), merge organic facies, be dried with anhydrous sodium sulfate, filter, be spin-dried for, cross post pure
Change, obtain 71.4g colourless liquid (productivity: 86.7%).1H-NMR(400MHz,CDCl3):
1.51(12H,m),3.61(20H,m),3.85(4H,t,J 4.0),4.62(1H,t,J 4.0)。
The synthesis of PEG5
By in the methanol of compound 39 (71.44g, 0.176mol) solution 300mL, add 30mL's
Hydrochloric acid, overnight, TLC detects stirring at normal temperature, reacts complete, is spin-dried for by reactant liquor, crosses post,
To 33.8g weak yellow liquid (productivity: 83%).1H-NMR(400MHz,CDCl3):3.57(16H,
m),4.03(4H,s)。
The synthesis of compound 40
Compound 38 (43.8g, 0.187mol) is dissolved in the dichloromethane of 400mL, adds three
Ethamine (56.7g, 0.56mol) is cooled to less than 5 degree, is then slowly added dropwise paratoluensulfonyl chloride
The dichloromethane solution of (53.5g, 0.28mol), within temperature control 5 degree, drips and finishes.It is to slowly warm up to room
Temperature, stirs 3 hours under room temperature, and TLC detects, and reacts complete, by reacting liquid filtering, by filtrate
Successively with water (500mL × 2), saturated aqueous common salt (500mL × 2) washs, and merges organic facies, uses
Anhydrous sodium sulfate is dried, and filters, is spin-dried for, and then crosses column purification, obtains the flaxen liquid of 67.7g
Body (productivity: 93.04%).1H-NMR(400MHz,CDCl3):1.49(6H,m),2.44(3H,
s),3.58(12H,m),4.14(2H,t,J 4.0),4.60(1H,t,J 4.0),7.33(2H,d,J 8.0),
7.79(2H,d,J 8.0)。
The synthesis of compound 41
Taking the there-necked flask of 2L, nitrogen is replaced twice, be sequentially added into compound 38 (42.84g,
0.183mol), the oxolane (400mL) being dried, under ice bath, add NaH (10g, 0.25mol),
Temperature control 0 degree, is slowly added dropwise the tetrahydrofuran solution of compound 40 (67.75g, 0.174mol), drips
Finish, be to slowly warm up to room temperature.Being stirred overnight under room temperature, TLC detects, and reacts complete, will reaction
Liquid is poured in the water of 1000mL, adds the ethyl acetate extraction of 500mL, and aqueous phase dichloromethane extracts
Take twice (500mL × 2), merge organic facies, be dried with anhydrous sodium sulfate, filter, be spin-dried for, mistake
Column purification, obtains 55.8g colourless liquid (productivity: 71%).1H-NMR(400MHz,CDCl3):
1.47(12H,m),2.44(3H,s),3.45(24H,m),3.81(4H,t,J 8.0),4.60(2H,t,J
4.0)。
The synthesis of PEG6
Compound 41 (55.8g, 0.124mol) is dissolved in the methanol of 500mL, adds 50mL's
Hydrochloric acid, overnight, TLC detects stirring at normal temperature, reacts complete, is spin-dried for by reactant liquor, crosses post,
To 31.6g weak yellow liquid (productivity: 90.5%).
The synthesis of compound 42
Taking the there-necked flask of 1L, nitrogen is replaced twice, is sequentially added into compound 38 (48g, 0.2mol),
The oxolane (500mL) being dried, adds NaH (9.2g, 0.222mol) under ice bath, temperature control 0 degree,
It is slowly added dropwise the tetrahydrofuran solution of compound 22 (80g, 0.185mol), drips and finish, slowly heat up
To room temperature.Being stirred overnight under room temperature, TLC detects, and reacts complete, pours reactant liquor into 1000mL
Water in, add 500mL ethyl acetate extraction, aqueous phase with dichloromethane extract twice (500mL
× 2), merge organic facies, be dried with anhydrous sodium sulfate, filter, be spin-dried for, cross column purification, obtain 40g
Colourless liquid (productivity: 73%).1H-NMR(400MHz,CDCl3):1.47(12H,m),3.57
(28H,m),3.82(4H,t,J 8.0),4.60(2H,t,J 4.0)。
The synthesis of PEG7
Compound 42 (50g, 0.101mol) is dissolved in the methanol of 500mL, adds the salt of 50mL
Acid, overnight, TLC detects stirring at normal temperature, reacts complete, is spin-dried for by reactant liquor, crosses post, obtains
24g weak yellow liquid (productivity: 88%).1H-NMR(400MHz,CDCl3):3.48(28H,m)。
The synthesis of compound 43
Taking the there-necked flask of 1L, nitrogen is replaced twice, be sequentially added into compound 9 (17.4g,
0.116mol), the oxolane (400mL) being dried, under ice bath, add NaH (10g, 0.25mol),
Temperature control 0 degree, is slowly added dropwise the tetrahydrofuran solution of compound 39 (90g, 0.232mol), drips and finishes,
It is to slowly warm up to room temperature.Being stirred overnight under room temperature, TLC detects, and reacts complete, is fallen by reactant liquor
Entering in the water of 1000mL, add the ethyl acetate extraction of 500mL, aqueous phase dichloromethane extracts two
All over (500mL × 2), merge organic facies, be dried with anhydrous sodium sulfate, filter, be spin-dried for, cross post pure
Change, obtain 41g weak yellow liquid (productivity: 61%).1H-NMR(400MHz,CDCl3):
1.48(12H,m),3.59(36H,m),3.83(4H,t,J 8.0),4.61(2H,t,J 4.0)。
The synthesis of PEG9
Compound 43 (41g, 0.07mol) is dissolved in the methanol of 500mL, adds the hydrochloric acid of 50mL,
Overnight, TLC detects stirring at normal temperature, reacts complete, is spin-dried for by reactant liquor, crosses post, obtains 29.3g
Yellow liquid (productivity: 99%).1H-NMR(400MHz,CDCl3):3.00(2H,s),3.61(36H,
m)。
The synthesis of compound 44
Taking the there-necked flask of 1L, nitrogen is replaced twice, be sequentially added into compound 1 (22.48g,
0.116mol), the oxolane (400mL) being dried, under ice bath, add NaH (10g, 0.25mol),
Temperature control 0 degree, is slowly added dropwise the tetrahydrofuran solution of compound 39 (90g, 0.232mol), drips and finishes,
It is to slowly warm up to room temperature.Being stirred overnight under room temperature, TLC detects, and reacts complete, is fallen by reactant liquor
Entering in the water of 1000mL, add the ethyl acetate extraction of 500mL, aqueous phase dichloromethane extracts two
All over (500mL × 2), merge organic facies, be dried with anhydrous sodium sulfate, filter, be spin-dried for, cross post pure
Change, obtain 38g weak yellow liquid (productivity: 52%).1H-NMR(400MHz,CDCl3):
1.49(12H,m),3.60(40H,m),3.83(4H,t,J 8.0),4.61(2H,t,J 4.0)。
The synthesis of PEG10
Compound 44 (38g, 0.06mol) is dissolved in the methanol of 500mL, adds the hydrochloric acid of 50mL,
Overnight, TLC detects stirring at normal temperature, reacts complete, is spin-dried for by reactant liquor, crosses post, obtains 32g
Yellow liquid (productivity: 98%).1H-NMR(400MHz,CDCl3):3.63(36H,m),5.89
(4H,t,J 8.0),8.6(2H,s)。
The synthesis of compound 45
Taking the there-necked flask of 1L, nitrogen is replaced twice, is sequentially added into compound 1 (27g, 0.138mol),
The oxolane (500mL) being dried, adds NaH (12g, 0.3mol) under ice bath, temperature control 0 degree,
It is slowly added dropwise the tetrahydrofuran solution of compound 22 (120g, 0.2775mol), drips and finish, slowly rise
Warm to room temperature.Being stirred overnight under room temperature, TLC detects, and reacts complete, pours reactant liquor into 1000mL
Water in, add 500mL ethyl acetate extraction, aqueous phase with dichloromethane extract twice (500mL
× 2), merge organic facies, be dried with anhydrous sodium sulfate, filter, be spin-dried for, cross column purification, obtain
58g weak yellow liquid (productivity: 58%).1H-NMR(400MHz,CDCl3):1.46(12H,m),
3.59(48H,m),3.79(4H,t,J 8.0),4.58(2H,t,J 4.0)。
The synthesis of PEG12
Compound 45 (58g, 0.06mol) is dissolved in the methanol of 500mL, adds the hydrochloric acid of 50mL,
Overnight, TLC detects stirring at normal temperature, reacts complete, is spin-dried for by reactant liquor, crosses post, obtains 31.2g
Weak yellow liquid (productivity: 94.5%).1H-NMR(400MHz,CDCl3):2.88(2H,s),
3.54(48H,m)。
Above are only the part preferred embodiment of the present invention, the present invention is not limited in the interior of embodiment
Hold.To those skilled in the art, can in the concept of technical solution of the present invention
To have various change and change, any change made and change, all scope it
In.
Claims (8)
1. a synthetic method for little molecule Polyethylene Glycol, this synthetic method is:
Described n, m are positive integer；
Concrete synthesis step is:
Step 1, compound 1 and dihydropyran reacting generating compound 2；
Step 2, compound 2 and paratoluensulfonyl chloride reacting generating compound 3；
Step 3, compound 3 and compound 4 reacting generating compound 5 under NaH is catalyzed；
Step 4, compound 5 is sloughed the blocking group at two ends and is obtained compound 6；
Described compound 1, is catalyzed at pyridinium p-toluenesulfonate with dihydropyran in dichloromethane solution
Lower reacting generating compound 2.
The synthetic method of a kind of little molecule Polyethylene Glycol the most as claimed in claim 1, it is characterised in that
Described step 2 method particularly includes: compound 2 is dissolved in dichloromethane solution, add triethylamine cooling
To less than 5 DEG C, then dripping paratoluensulfonyl chloride, room temperature reaction generates compound 3.
The synthetic method of a kind of little molecule Polyethylene Glycol the most as claimed in claim 1, it is characterised in that
Described step 3 method particularly includes: compound 4 is dissolved in dry oxolane, adds under condition of ice bath
Entering NaH, then dropping compound 3, room temperature reaction generates compound 5.
The synthetic method of a kind of little molecule Polyethylene Glycol the most as claimed in claim 1, it is characterised in that
Described step 4 method particularly includes: compound 5, in methanol solution, reacts generationization under acid catalysis
Compound 6.
The synthetic method of a kind of little molecule Polyethylene Glycol the most as claimed in claim 1, it is characterised in that
In described step 1, the isolation and purification method of product is: TLC detection reaction is complete, by reactant liquor with saturated
Brine It more than 1 time, rotation evaporates dichloromethane；Thick product ethyl acetate/normal hexane mixed solvent
Washing more than 1 time, aqueous phase dichloromethane extracts；Merge organic facies, be dried, filter, be spin-dried for obtaining
Compound 2.
6. a hydroxy protecting techniques for little molecule Polyethylene Glycol, the method is: on little molecule Polyethylene Glycol
Hydroxyl and dihydropyran, pyridinium p-toluenesulfonate be catalyzed under, carry out additive reaction, obtain tetrahydrochysene
The little molecule Polyethylene Glycol of pyrans radical protection.
The hydroxy protecting techniques of a kind of little molecule Polyethylene Glycol the most as claimed in claim 6, its feature exists
In, the method particularly as follows: little molecule Polyethylene Glycol is dissolved in dichloromethane, be sequentially added into dihydropyran and
Pyridinium p-toluenesulfonate, room temperature reaction, TLC detection reaction is complete, by reactant liquor saturated aqueous common salt
Washing more than 1 time, rotation evaporates dichloromethane；Thick product ethyl acetate/normal hexane mixed solvent washing 1
More than secondary, aqueous phase dichloromethane extracts；Merge organic facies, be dried, filter, be spin-dried for obtaining target product
Thing.
The hydroxy protecting techniques of a kind of little molecule Polyethylene Glycol the most as claimed in claim 6, its feature exists
In: the ratio of described ethyl acetate/normal hexane mixed solvent is 1:3.
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|---|---|---|---|---|
| WO2004073620A2 (en) * | 2003-02-14 | 2004-09-02 | Quanta Biodesign, Ltd | The selective and specific preparation of discrete peg compounds |
| CN103642023A (en) * | 2013-12-20 | 2014-03-19 | 武汉大学 | Synthesis method for single molecular weight polyethylene glycol and derivative thereof |
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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004073620A2 (en) * | 2003-02-14 | 2004-09-02 | Quanta Biodesign, Ltd | The selective and specific preparation of discrete peg compounds |
| CN103642023A (en) * | 2013-12-20 | 2014-03-19 | 武汉大学 | Synthesis method for single molecular weight polyethylene glycol and derivative thereof |
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| Title |
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| Multigram Synthesis of Well-Defined Extended Bifunctional Polyethylene Glycol(PEG) Chains;Francois A. Loiseau et al.;《The Journal of Organic Chemistry》;20040114;第69卷(第3期);第645页右栏第22-25行 * |
| Preparation of Antituberculous Polyoxyethylene Ethers of Homogeneous Structure;J. W. Cornforth et al.;《Tetrahedron》;1973;第29卷;1659-1667 * |
| Synthesis of a Series of Oligo(ethylene glycol)-Terminated Alkanethiol Amides Designed to Address Structure and Stability of Biosensing Interfaces;Sofia Svedhem et al.;《The Journal of Organic Chemistry》;20010531;第66卷(第13期);第4501页左栏第56-64行 * |
| 单一分布聚乙二醇的合成及其应用;冯柏成等;《高分子通报》;201005(第5期);55-60 * |
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