WO2006036825A1 - Polyethylene glycol compounds and process for making - Google Patents
Polyethylene glycol compounds and process for making Download PDFInfo
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- WO2006036825A1 WO2006036825A1 PCT/US2005/034251 US2005034251W WO2006036825A1 WO 2006036825 A1 WO2006036825 A1 WO 2006036825A1 US 2005034251 W US2005034251 W US 2005034251W WO 2006036825 A1 WO2006036825 A1 WO 2006036825A1
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- polyethylene glycol
- reaction mixture
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/30—Post-polymerisation treatment, e.g. recovery, purification, drying
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
Definitions
- the instant invention relates to polyethylene glycol compounds and a process for 5 making such compounds. More particularly, the instant invention relates to high molecular weight polyethylene glycol compounds having narrow molecular weight distribution and a process for making such compounds.
- the polyethylene glycol compounds of the instant invention are useful for chemical modification of physiologically active materials, which modified materials are applicable, for example, in drug delivery systems. o Biologically active compounds conjugated with polyoxyalkylenes can provide enhanced biocompatibility for the compound, See, for example, USP 5,366,735 and USP 6,280,745.
- polyethylene glycol as one of the best biocompatible polymers to conjugate with a biologically active compound (such as a drug, a protein, a peptide or an enzyme) to 5 produce a conjugate having improved properties such as compatible solubility characteristics, reduced toxicity, improved surface compatibility, increased circulation time and reduced immunogenicity.
- a biologically active compound such as a drug, a protein, a peptide or an enzyme
- Polyethylene glycol (PEG) is a linear polyoxyalkylene terminated at the ends thereof with hydroxyl groups and generally represented by the formula: HO(CH 2 CH 2 O) n H.
- monomethoxy polyethylene glycol (mPEG) generally represented by the formula: CH 3 O(CH 2 CH 2 O) n H, is usually used to prepare a polyethylene glycol conjugate with a biologically active compound typically by way of a coupling reaction between an amine group of the biologically active compound and an amine receptive derivative (such as trichloro-s-triazine activated mPEG) 5 formed via the remaining terminal hydroxyl group of the monomethoxy polyethylene glycol.
- the instant invention is a substituted polyethylene glycol compound having higher molecular weight than has previously been obtained (for example, mPEG molecular weights 5 in excess of 40,000) together with narrow molecular weight dispersion and low diol impurity contamination.
- the instant invention is also a process for making such materials. More specifically, the instant invention is a substituted polyethylene glycol compound having the formula
- RO(C 2 H 4 O) n H 0 wherein R represents a C 1-7 hydrocarbon group and n represents the average number of moles Of C 2 H 4 O groups, ranging from 500 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to a number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being 5 determined by gel permeation chromatography.
- the instant invention is a mixture comprising a substituted polyethylene glycol compound and polyethylene glycol, the substituted polyethylene glycol compound having the formula
- the instant invention is a process for the preparation of a substituted polyethylene glycol compound having the formula
- RO(C 2 H 4 O) n Y wherein R represents a C 1-7 hydrocarbon group, n represents the average number of moles of C 2 H 4 O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH2CH2)0-20OH, where R represents a C 1-7 hydrocarbon group, an alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range
- RO(C 2 H 4 O) n Y wherein R represents a C 1-7 hydrocarbon group, n represents the average number of moles of C 2 H 4 O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH 2 CH 2 ) O-20 OH, where R represents a C ⁇ 7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the alcohol being in the range
- the instant invention is a substituted polyethylene glycol compound having the formula
- the instant invention is a mixture comprising a substituted polyethylene glycol compound and polyethylene glycol, the substituted polyethylene glycol compound having the formula
- RO(C 2 H 4 O) n H wherein R represents a C 1-7 hydrocarbon group; and n represents the average number of o moles of C 2 H 4 O groups added, ranging from 500 to 2000, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight as determined by gel permeation chromatography in the range of from 1 to 1.1, the amount of polyethylene glycol being less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound, the concentration of 5 the polyethylene glycol being determined by liquid chromatography under critical conditions.
- the above weight and number average molecular weights are determined based on the entire chromatogram and not a selected portion thereof.
- n is in the range of from 600 to 2000. More preferably, n is in the range of from 700 to 1000. o Preferably, the amount of polyethylene glycol is less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. More preferably, the amount of polyethylene glycol being less than two and one half mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound.
- a specific critical condition liquid chromatography method for the determination of polyethylene glycol is outlined below.
- the process of the instant invention in one embodiment is a process for the 5 preparation of a substituted polyethylene glycol compound having the formula
- RO(C 2 H 4 O) n Y wherein R represents a C 1-7 hydrocarbon group, n represents the average number of moles of C 2 H 4 O groups, ranging from 500 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular 0 weight to number average molecular weight in the range of from 1 to 1.1 , the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH 2 CH 2 ) 0-2 oOH, where R represents a C 1-7 hydrocarbon group, an 5 alkoxide of the alcohol and an aprotic polar solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of
- RO(C 2 H 4 O) n Y wherein R represents a C 1-7 hydrocarbon group, n represents the average number of moles of 5 C 2 H 4 O groups, ranging from 100 to 2000 and Y represents hydrogen or an alkali metal, the substituted polyethylene glycol compound having a ratio of weight average molecular weight to number average molecular weight in the range of from 1 to 1.1, the weight average molecular weight and the number average molecular weight of the substituted polyethylene glycol compound being determined by gel permeation chromatography, o comprising the steps of: (a) forming a reaction mixture comprising an alcohol represented by the formula R(OCH 2 CH 2 )o- 2 oOH, where R represents a C 1-7 hydrocarbon group, an alkoxide of the alcohol and a polyether solvent, the reaction mixture being at a temperature in the range of from about 80 to about 140 degrees Celsius, the water concentration of the reaction mixture being less than ten parts per million by weight, the mole ratio of the alkoxide of the alcohol to the
- an aprotic polar solvent is an aprotic solvent having a dielectric constant of greater than about 8.
- the aprotic polar solvent is a polyether solvent such as bis(2-methoxyethyl)ether.
- the alcohol is a methyl ether of an ethylene glycol.
- a particularly suitable alcohol in the instant invention is diethyleneglycol methyl o ether.
- the temperature of reaction in the instant invention is in the range of from about 90 to about 110 degrees Celsius (and more preferably about 100 degrees Celsius).
- the ethylene oxide is contacted with the reaction mixture as a gas under pressure in the range of from about two to about ten atmospheres.
- the concentration of the substituted polyethylene glycol compound in the reaction mixture at the end of step (b) 5 is in the range of from about 20 to about 80 weight percent of the reaction mixture. More preferably the concentration of the substituted polyethylene glycol compound in the reaction mixture at the end of step (b), in the range of from about 40 to about 60 weight percent of the reaction mixture.
- the reaction mixture at the end of step (b) is likely to contain polyethylene glycol. o
- the reaction mixture at the end of step (b) contain polyethylene glycol at a concentration of less than ten mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound. More preferably, such concentration of polyethylene glycol is less than five mole percent of the total moles of polyethylene glycol and the substituted polyethylene 5 glycol compound. Most preferably, such concentration of polyethylene glycol is less than two and one half mole percent of the total moles of polyethylene glycol and the substituted polyethylene glycol compound.
- the polyethylene glycol concentration is determined by liquid chromatography under critical conditions.
- the o substituted polyethylene glycol compound has the formula RO(C 2 H 4 O) n Y where Y is hydrogen or an alkali metal. It should be understood that RO(C 2 H 4 O) n Y is an empirical formula, that Y can be a mixture of hydrogen and an alkali metal and that when Y is an alkali metal the compound may be dissociated.
- a polyether solvent and a polyether alcohol in the process of the instant invention is theorized to increase the rate of initiation with respect to the rate of propagation and thus promote a narrower molecular weight distribution of the substituted polyethylene glycol o compound.
- a narrow molecular weight distribution of the substituted polyethylene glycol compound is desired for the above discussed PEGylation applications.
- water initiates ethylene oxide polymerization to form polyethylene glycol ("diol") and since diol is u ⁇ desired in the substituted polyethylene glycol compound of the instant invention, it is beneficial to minimize the water concentration of the reaction mixture 5 during step (b) of the process of the instant invention.
- the molecular weight of the PEG will be about two times greater than the molecular weight of the substituted polyethylene compound.
- water in the solvent, alcohol and ethylene oxide water entering the reactor from outside the reactor, hydroxide in the base
- water generated by o dehydration of a polyethylene glycol alcohol are several potential sources of water, including water in the solvent, alcohol and ethylene oxide; water entering the reactor from outside the reactor, hydroxide in the base; and water generated by o dehydration of a polyethylene glycol alcohol.
- the polymerization solvent may be dried by, for example, addition of activated molecular sieves.
- the sieves are removed by filtration before the solvent is added to the polymerization reactor.
- the polymerization solvent may be passed through a column of activated alumina to remove water and other protic impurities.
- An additional column of activated molecular sieves may also be used.
- the number of moles of akoxide used is the same as the number of moles of base (such as alkali metal or alkali metal hydride) used to produce the alkoxide.
- the use of potassium 5 hydride to generate the alkoxide is preferred.
- Ethylene oxide is commercially available having a water content of less than 5 ppm by weight. Any nitrogen directed to the reactor is preferably dried to a dew point of less than -100 2 C using, for example, a Drierite gas drying system. Additions to the reactor should be made in a manner that excludes contamination by atmospheric moisture. The o reactor system is best dried by carrying out a reaction and discarding the first batch.
- the reactor system is sealed in preparation for the next batch.
- the temperature during step (b) is in the range of from about 80 to about 140 9 C, and preferably from about 90 to about 110 Q C.
- the alkali metal of the alkoxide is preferably 5 potassium.
- Reactor pressure is chosen to suit the pressure rating of the reactor, but is generally from about 15 to less than 100 psia.
- the molar ratio of ethylene oxide to alkali metal alkoxide is chosen to produce a polymer of the desired molecular weight.
- the specific alcohol is chosen to provide the desired terminal group, which is typically a monomethyl group.
- the ( alcohol preferably contains ethylene glycol units, such as o diethyleneglycol methyl ether (Dowanol DM Trade Name from The Dow Chemical
- the polymerization solvent is chosen from inert aprotic polar solvents that are preferably easily purified. Glycol ether solvents such as diglyme (bis(2-methoxyethyl)ether) are preferred.
- the amount of solvent used is adjusted to control the polymerization 5 viscosity, and may be in the range to provide a substituted polyethylene glycol compound containing 20 to 80 wt% solvent, but typically 40 to 60 wt% solvent.
- Higher molecular weight substituted polyethylene glycol compounds of the instant invention generally produce a higher viscosity solution for any given concentration in the solvent.
- the reaction mixture is mixed with, for example, a precipitating o solvent such as a heptane or hexane to precipitate the product in a solid form and remove the polymerization solvent.
- a precipitating o solvent such as a heptane or hexane
- An acid such as acetic acid is preferably also added to precipitate a neutral product.
- Liquid chromatography under critical conditions has been used to determine polyethylene glycol in mPEG (see, for example, Kazanskii et al., Polymer Science, Series A, VoI 42, No. 6 (2000), ⁇ 585-595.
- the degree of resolution of the polyethylene glycol and mPEG peaks is usually poor (see Fig. 2 of the Kazanskii et al. reference).
- the 5 degree of resolution of the polyethylene glycol and mPEG peaks in liquid chromatography under critical conditions can be significantly improved by derivatizing the polyethylene glycol and mPEG with, for example
- the amount of polyethylene glycol in the instant invention is determined by the following procedure: (a) 0.1 gram of the compound is mixed with one milliliter of dry 0 acetonitrile containing 150 microequivalents of 4-dimethylaminopyridine and one milliliter of dry acetonitrile containing 150 microequivalents of dinitrobenzoyol chloride, which mixture is heated at 100 degrees Celsius for 15 minutes, and then quenched with three milliliters of water to produce a sample for injection; (b) 5 microliters of the sample for injection is injected into a moblile phase of 52%A and 48%B (where A is 47% acetonitrile 5 in water and B is 43% acetonitrile in water) at a mobile phase flow rate of 0.75 milliliters per minute and flowed through a 5 micrometer packing diameter Zorbax Brand SB300 Cl 8 reverse phase column at a column temperature of 32 degrees Celsius, the column having an internal diameter of 4.6 millimeters and a
- the mole percent amount of polyethylene glycol of the total moles of polyethylene glycol and the substituted polyethylene glycol compound of 5 the instant invention is defined herein as: one half the area of the derivatized polyethylene glycol peak divided by the sum of one half the area of the derivatized polyethylene glycol peak and the area of the peak for the derivatized substituted polyethylene compound of the instant invention, multiplied by 100.
- a 5-gallon stainless steel reactor rinsed twice with 10 Kg of diglyme following the previous batch, is loaded with 28.02 g (0.233 mol) of anhydrous di(ethylene glycol)methyl ether (Dowanol DM, stored over 4 A molecular sieves), 3.21 g (0.024 mol) of 30% potassium hydride, and 7.32 Kg of diglyme.
- the diglyme is transferred to the reactor through a 2" x 36" column of activated alumina followed by a 2" x 36" column of 8-12 o mesh 3 angstrom activated molecular sieves at a rate of about 0.08 Kg/min.
- the reactor is heated to 100 2 C.
- the water concentration of the reaction mixture is determined to be 6.3 ppm.
- the DF tank is loaded with 7.480 Kg (170 mol) of EO (water content ⁇ 5 ppm).
- the 5-gallon reactor is vented to less than about 35 psia, and the EO addition is started.
- the EO is added 5 at a rate to maintain a pressure of less than 100 psia at a temperature of 100 9 C, and continues for seven hours.
- the reactor is cooled to 70 2 C and a vacuum is applied.
- the pressure is adjusted to 1-2 psia by addition of nitrogen through a dip pipe.
- the purge is continued for one hour and then the vacuum valve is closed.
- the reactor is pressurized to about 35 psia, and the product emptied through the o bottom valve into a 5-gallon stainless steel can.
- the reactor is rinsed twice with 10 Kg portions of diglyme. After the second rinse, the empty reactor is heated to 140 s C with a nitrogen purge out of the bottom valve and the vent valve on the top of the reactor for approximately 15 minutes.
- the reactor is sealed and cooled for a subsequent reaction.
- a 5.0 Kg portion of the mPEG reactor product is loaded into a 12-L jacketed 5 bottom-drain glass vessel positioned above a 50-L glass bottom-drain round-bottom flask.
- the temperature in the 12-L flask is maintained at 65 0 C using a recirculating water bath.
- the transfer line to the 50-L vessel is heated to approximately 70 °C using heat tape.
- the 50-L vessel is loaded with 17.3 Kg of heptane and 1.3 g of acetic acid.
- the warm mPEG solution is transferred to the 50-L flask over 63 minutes, forming a white precipitate.
- the o temperature in the 50-L vessel increases from ambient to 36 0 C during the addition.
- the slurry is stirred overnight, then the solid is isolated by vacuum filtration.
- the filtercake is collected in 3-L fritted funnels and rinsed with 8.5 Kg of fresh heptane.
- the wetcake is transferred to drying trays, and dried at 30 0 C under vacuum to a constant weight over 44 hours.
- the resulting mPEG product is characterized by GPC analysis to determine the polymer characteristics such as molecular weight and polydispersity (D).
- the peak molecular weight (Mp) is 28,613.
- the number average molecular weight (Mn) is 28,176.
- the weight average molecular weight (Mw) is 28,910.
- the molecular weight dispersion (Mw/Mn) is 1.026.
- PEG diol content is determined by liquid chromatography under critical conditions.
- Table 1 lists various reaction recipies using the system outlined in the above example (Batch 4046 is the above example).
- Table 2 lists the analysis results for the various batches of Table 1.
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- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Polyethers (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05798703A EP1797131B1 (en) | 2004-09-28 | 2005-09-27 | Process for making polyethylene glycol compounds |
AT05798703T ATE552286T1 (en) | 2004-09-28 | 2005-09-27 | METHOD FOR PRODUCING POLYETHYLENE GLYCOL COMPOUNDS |
KR1020077006984A KR101279664B1 (en) | 2004-09-28 | 2005-09-27 | Polyethylene glycol compounds and process for making |
CN2005800328299A CN101031604B (en) | 2004-09-28 | 2005-09-27 | Polyethylene glycol compounds and process for making same |
ES05798703T ES2384979T3 (en) | 2004-09-28 | 2005-09-27 | Procedure for preparing polyethylene glycol compounds |
JP2007533676A JP4987719B2 (en) | 2004-09-28 | 2005-09-27 | Polyethylene glycol compound and production method |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/952,198 US7199193B2 (en) | 2004-09-28 | 2004-09-28 | Polyethylene glycol compounds and process of making |
US10/952,198 | 2004-09-28 |
Publications (1)
Publication Number | Publication Date |
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WO2006036825A1 true WO2006036825A1 (en) | 2006-04-06 |
Family
ID=35432615
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2005/034251 WO2006036825A1 (en) | 2004-09-28 | 2005-09-27 | Polyethylene glycol compounds and process for making |
Country Status (8)
Country | Link |
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US (2) | US7199193B2 (en) |
EP (1) | EP1797131B1 (en) |
JP (1) | JP4987719B2 (en) |
KR (1) | KR101279664B1 (en) |
CN (1) | CN101031604B (en) |
AT (1) | ATE552286T1 (en) |
ES (1) | ES2384979T3 (en) |
WO (1) | WO2006036825A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2010528172A (en) * | 2007-05-29 | 2010-08-19 | ヨウル チョン ケミカル カンパニー, リミテッド | Chain end functionalized methoxypolyethylene glycol and metal nanoparticles using the same |
WO2010146082A1 (en) * | 2009-06-18 | 2010-12-23 | Basf Se | Method for producing monohydroxypolyalkylene oxides |
EP2476430A1 (en) | 2008-06-13 | 2012-07-18 | Eli Lilly and Company | Pegylated insulin lispro compounds |
EP1824901B2 (en) † | 2004-12-10 | 2013-08-07 | Clariant Produkte (Deutschland) GmbH | Method for producing pure alpha-alkoxy-omega-hydroxy-polyalkylene glycols |
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---|---|---|---|---|
JP5652691B2 (en) * | 2008-11-11 | 2015-01-14 | 日油株式会社 | Polyalkylene glycol derivative and method for producing the same |
JP5569787B2 (en) * | 2009-03-31 | 2014-08-13 | 日油株式会社 | Purification method of high molecular weight polyethylene glycol compound |
JP5713274B2 (en) * | 2009-03-31 | 2015-05-07 | 日油株式会社 | Method for purifying high molecular weight polyoxyalkylene derivatives |
WO2013157486A1 (en) * | 2012-04-18 | 2013-10-24 | 旭硝子株式会社 | Method for producing polyether |
JP2016513082A (en) | 2013-01-28 | 2016-05-12 | ニューヨーク・ユニバーシティ | Treatment methods using non-toxic neurotoxin derivatives |
JP6106104B2 (en) | 2014-01-16 | 2017-03-29 | 信越化学工業株式会社 | Method for producing narrowly dispersed polyalkylene glycol derivative having amino group at terminal |
US10377775B2 (en) | 2014-12-04 | 2019-08-13 | Shin-Etsu Chemical Co., Ltd. | Method for producing polyalkylene glycol derivative having amino group at end |
US9708350B2 (en) | 2014-12-04 | 2017-07-18 | Shin-Etsu Chemical Co., Ltd. | Method for producing polyalkylene glycol derivative having amino group at end, polymerization initiator for use in the same, and alcohol compound as raw material for the polymerization initiator |
JP6460937B2 (en) | 2014-12-04 | 2019-01-30 | 信越化学工業株式会社 | Method for producing polyalkylene glycol derivative having amino group at terminal |
EP3230457B1 (en) | 2014-12-09 | 2021-06-30 | New York University | Clostridial neurotoxin fusion proteins, propeptide fusions, their expression, and use |
WO2019035090A1 (en) * | 2017-08-17 | 2019-02-21 | Sabic Global Technologies B.V. | Method of preparing fatty acid monoester of polyoxyethylene, ester made therewith, and uses thereof |
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-
2004
- 2004-09-28 US US10/952,198 patent/US7199193B2/en not_active Expired - Fee Related
-
2005
- 2005-09-27 EP EP05798703A patent/EP1797131B1/en not_active Not-in-force
- 2005-09-27 CN CN2005800328299A patent/CN101031604B/en not_active Expired - Fee Related
- 2005-09-27 AT AT05798703T patent/ATE552286T1/en active
- 2005-09-27 KR KR1020077006984A patent/KR101279664B1/en active IP Right Grant
- 2005-09-27 JP JP2007533676A patent/JP4987719B2/en not_active Expired - Fee Related
- 2005-09-27 ES ES05798703T patent/ES2384979T3/en active Active
- 2005-09-27 WO PCT/US2005/034251 patent/WO2006036825A1/en active Application Filing
-
2007
- 2007-02-28 US US11/712,574 patent/US20070213479A1/en not_active Abandoned
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WO2005010075A2 (en) * | 2003-07-22 | 2005-02-03 | Nektar Therapeutics Al, Corporation | Method for preparing functionalized polymers from polymer alcohols |
Non-Patent Citations (1)
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Cited By (7)
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EP1824901B2 (en) † | 2004-12-10 | 2013-08-07 | Clariant Produkte (Deutschland) GmbH | Method for producing pure alpha-alkoxy-omega-hydroxy-polyalkylene glycols |
JP2010528172A (en) * | 2007-05-29 | 2010-08-19 | ヨウル チョン ケミカル カンパニー, リミテッド | Chain end functionalized methoxypolyethylene glycol and metal nanoparticles using the same |
JP2013155384A (en) * | 2007-05-29 | 2013-08-15 | Youl Chon Chemical Co Ltd | Chain-end functionalized methoxy polyethylene glycol and metal nano-particle using the same |
EP2476430A1 (en) | 2008-06-13 | 2012-07-18 | Eli Lilly and Company | Pegylated insulin lispro compounds |
WO2010146082A1 (en) * | 2009-06-18 | 2010-12-23 | Basf Se | Method for producing monohydroxypolyalkylene oxides |
EP2275470A1 (en) * | 2009-06-18 | 2011-01-19 | Basf Se | Method for manufacturing monohydroxypolyalkylene oxides |
US9920164B2 (en) | 2009-06-18 | 2018-03-20 | Basf Se | Method for producing monohydroxypolyalkylene oxides |
Also Published As
Publication number | Publication date |
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CN101031604A (en) | 2007-09-05 |
KR20070058534A (en) | 2007-06-08 |
US7199193B2 (en) | 2007-04-03 |
KR101279664B1 (en) | 2013-06-27 |
ATE552286T1 (en) | 2012-04-15 |
EP1797131A1 (en) | 2007-06-20 |
EP1797131B1 (en) | 2012-04-04 |
US20060074200A1 (en) | 2006-04-06 |
JP2008514763A (en) | 2008-05-08 |
JP4987719B2 (en) | 2012-07-25 |
US20070213479A1 (en) | 2007-09-13 |
ES2384979T3 (en) | 2012-07-16 |
CN101031604B (en) | 2010-08-11 |
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