CN100497437C - Preparation method of polyethylene carboxylic acid and its use - Google Patents
Preparation method of polyethylene carboxylic acid and its use Download PDFInfo
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- CN100497437C CN100497437C CNB2003101133676A CN200310113367A CN100497437C CN 100497437 C CN100497437 C CN 100497437C CN B2003101133676 A CNB2003101133676 A CN B2003101133676A CN 200310113367 A CN200310113367 A CN 200310113367A CN 100497437 C CN100497437 C CN 100497437C
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- polyoxyethylene glycol
- carboxylic acid
- hydroxyl
- bromide
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Abstract
A process for preparing the glycol carboxylic acid used for modifying protein or polypeptide features that the water is used as solvent, the hypohalate is used as oxidant, and the glycol is converted to glycol carboxylic acid under existance of free N-O radicals and bromide.
Description
Technical field
The invention belongs to the protein chemistry field, relate to the preparation method and the purposes of protein modifier.
Background technology
Polyoxyethylene glycol (PEG) is a kind of synthetic macromolecule, is the polyethers of highly-hydrophilic, is soluble in organic solvent and water, has good physical chemistry and physiological property, and nontoxic, do not have antigen and cause immunogenicity, obtained the additive that FDA approval is used to enter human body.The good biocompatibility of PEG shows as the absorption of lower protein and low platelet in vivo and hangs down cell adhesion, and these characteristics make it use very extensive at biomedical sector.Polyoxyethylene glycol is linked to each other with protein, polypeptide compounds and small molecules, can change these materials pharmacokinetics, physiological characteristic in vivo, thereby some characteristics of polyoxyethylene glycol are passed to protein, polypeptide class and micromolecular compound.For example, can shield the antigenicity of polypeptide class, reduce their clearance rates in vivo, reduce the hydrolysis of immune identification and proteolytic ferment, improve the water-soluble of protein and polypeptide compounds, improve the apparent molecular weight of protein, polypeptide class and micromolecular compound simultaneously, reduce the kidney filtration and change biological the distribution
[1]
Polyoxyethylene glycol is a lot of with the method that protein and polypeptide compounds are connected, because protein and polypeptide compounds exist amino, general method commonly used is a carbonylate in peg molecule, makes itself and protein or polypeptide compounds form parahelium or acyl ammonia.Use polyoxyethylene glycol carboxylic acid the most generally at present.The method that forms the polyoxyethylene glycol carboxylic acid can be divided into two big classes: the first kind is to introduce a carboxyl by chemical reaction on the hydroxyl of polyoxyethylene glycol, and second class is that the hydroxyl with polyoxyethylene glycol is converted into carboxyl.That generally use in first kind method is polyoxyethylene glycol Succinic Acid (SS-PEG)
[2]But, contain the ester bond of a facile hydrolysis in the SS-PEG polymer chain, after protein or polypeptide compounds were connected, this ester bond is facile hydrolysis in vivo, made the Succinic Acid that is retained on the protein serve as haptens, thereby had aggravated proteinic immunity.For fear of introduce unsettled ester bond in the peg molecule chain, general normal employing second class methods promptly directly are converted into polyoxyethylene glycol the polyoxyethylene glycol carboxylic acid.The method that alcohol is changed into carboxylic acid is a lot, and the most frequently used having is following several: (1) can obtain carboxylic acid with the nitric acid oxidation polyoxyethylene glycol, but the ehter bond of PEG easily ruptures in the reaction process.Therefore, the molecular weight distribution broad of the PEG carboxylic acid that makes is unfavorable for preparing the protein modifier of homogeneous, and molecular weight has toxicity less than the PEG of 400dalton
[3](2) prepare carboxylate salt with pure and mild caustic alkali dehydrogenation in liquid phase in the presence of noble metal catalyst, this method temperature height easily makes ether bond rupture
[4](3) under alkaline condition, prepare the polyoxyethylene glycol carboxylic acid with potassium permanganate oxidation
[5], but this method equally very easily causes the fracture of PEG ehter bond.(4) use gentle oxygenant MnO
2Earlier PEG is oxidized to PEG aldehyde, under the effect of hydrogen peroxide the PEG formoxy-is turned to the PEG carboxylic acid then, though this method mild condition, yield is low
[6]
Utilize stable nitroxyl free radical that the research that alcohol is oxidized to corresponding carboxylic acid is progressively ripe in recent years
[7,8], Fried
[9-10]Deng the synthetic alkoxyalkanoic acids of human nitroxyl free radical, the advantage of this method is the productive rate height, but this method has been used nitric acid or organic solvent.In reaction process, use nitric acid, tend to make the ether bond rupture in the PEG molecule, have a large amount of by products to generate, and in product, a spot of nitric acid can residually be arranged.With an organic solvent, can cause environmental pollution, and be unfavorable for large-scale production.
The present invention has overcome the deficiency of aforesaid method,, is reflected under the condition of normal temperature and pressure and alkalescence as solvent with water, ehter bond in the peg molecule can not rupture, and, adopt oxidation step, polyoxyethylene glycol can be converted into the polyoxyethylene glycol carboxylic acid by stoichiometry.In addition, present method adopts water as solvent, can reduce environmental pollution in actual production, helps environmental protection and has improved the security of producing.
Summary of the invention
The invention provides a kind of method that in the aqueous solution, prepares the polyoxyethylene glycol carboxylic acid, described method is as follows: under the normal pressure, in the aqueous solution, in the presence of nitroxyl free radical and a certain amount of bromide, control pH value is 7-14, temperature remains on-5 ℃-50 ℃, is corresponding polyoxyethylene glycol carboxylic acid with hypohalite oxidation polyoxyethylene glycol.
At present, the oxidation mechanism of Gong Rening is:
OCl
-+Br
-→OBr
-+Cl
- (1)
OBr
-+2TEMPO·+H
2O→2TEMPO
++2OH
-+Br
- (2)
TEMPO
++OH
-+RCH
2OH→TEMPOH+RCHO+H
2O (3)
TEMPO
++OH
-+RCHO→TEMPOH+RCOOH+H
2O (4)
TEMPO
++OH
-+TEMPOH→2TEMPO·+H
2O (5)
Specific embodiments, with polyoxyethylene glycol (PEG), nitroxyl free radical (add-on be hydroxyl among the PEG amount of substance ten thousand/to one of percentage) and Potassium Bromide (among the PEG 15 5 percent of the amount of substance of hydroxyl to 1) soluble in water, ice-water bath condition lower magnetic force stirring and dissolving.It is soluble in water to get a certain amount of hypohalite (the amount of substance 2.5-4 of hydroxyl doubly among the PEG), regulates its pH value to 9-11 with the hydrochloric acid of 4N, places ice-water bath to cool off.The refrigerative hypohalite aqueous solution is poured in the aqueous solution of aforementioned polyethylene glycols.Reaction system is cooled off with ice-water bath, and along with the carrying out that reacts, the pH value of reaction system constantly descends, and needs to control the pH value of reaction system between 9-11 with the aqueous sodium hydroxide solution of 0.5N.When the pH of system value stabilization no longer reduces, at room temperature continue to stir 6 hours, add a certain amount of ethanol annihilation reaction then.Regulate after above-mentioned pH value of aqueous solution is 3 with 4N hydrochloric acid,, merge and concentrated extract with organic solvent solvent extractions such as methylene dichloride or ethyl acetate three times.Pour at last in the cold ether, obtain the polyoxyethylene glycol carboxylic acid.
Aforesaid method will further describe by following example, but the example that provides can not be as the restriction to this method.
Description of drawings:
The infrared spectrogram of the polyoxyethylene glycol carboxylic acid of Fig. 1 embodiment 1 preparation
Among the figure: a line is the infrared spectra of mPEG (750);
The b line is the infrared spectrogram of mPEG (750) carboxylic acid after the oxidation.
As we know from the figure, after the oxidation at 1739cm
-1Carbonyl peak appears in the place.
The mass spectrum of the polyoxyethylene glycol carboxylic acid of Fig. 2 embodiment 1 preparation
Among the figure: A figure is a polyoxyethylene glycol,
B figure is the polyoxyethylene glycol carboxylic acid after the oxidation.
From collection of illustrative plates, there is not the product after unoxidized raw material and the chain rupture as can be seen.
With 7.5 gram mono methoxy polyethylene glycol (mPEG, molecular weight is 750), 0.0078 restrain 2,2,6,6-tetramethyl--piperidines-1-oxygen base, 0.2 the gram Potassium Bromide is poured in the beaker that fills 50 ml waters, magnetic agitation, ice-water bath cools off, and pours chlorine bleach liquor's (1 ℃, the pH value is 10) of 40 milliliter 8% in this beaker into.Under the ice-water bath condition, in reaction process, constantly the pH value with the sodium hydroxide conditioned reaction system of 0.5N is 10.The pH value no longer changes after about 2 hours, is stabilized in about 10.Then, under the room temperature condition, continue to stir after 6 hours, add 5 milliliters of ethanol annihilation reaction.With 4N hydrochloric acid soln conditioned reaction pH value of aqueous solution is 3, uses dichloromethane extraction reaction solution three times, and combining extraction liquid also concentrates.Concentrated solution is poured in the cold diethyl ether, and the polyoxyethylene glycol carboxylic acid is separated out in cooling, with cold diethyl ether drip washing product.With the sodium hydroxide solution titration of demarcating, transformation efficiency is 100%.By infrared spectrum characterization, there is carbonyl peak to have (Fig. 1).Prove do not have chain rupture product and raw material (Fig. 2) by mass spectrum.
Embodiment 2
With 10 gram mPEG (molecular weight is 2000), 0.0048 gram 4-methoxyl group-2,2,6,6-tetramethyl--piperidines-1-oxygen base, 0.11 the gram Potassium Bromide is poured in the beaker that fills 70 ml waters, magnetic agitation, the ice-water bath cooling, in this beaker, pour chlorine bleach liquor's (1 ℃, the pH value is 10) of 24 milliliter 8% into.Under the ice-water bath condition, in reaction process, be 10 with the pH value of the sodium hydroxide conditioned reaction system of 0.5N.The pH value no longer changes after about 1.5 hours, is stabilized in about 10.Then, under the room temperature condition, continue to stir after 6 hours, add 3.5 milliliters of ethanol annihilation reaction.PH value with 4N hydrochloric acid soln conditioned reaction liquid is 3, uses dichloromethane extraction reaction solution three times, merges extraction liquids and concentrated three times.Concentrated solution is poured in the cold diethyl ether, and cooling is separated out, and uses cold diethyl ether drip washing, obtains the polyoxyethylene glycol carboxylic acid.With the sodium hydroxide solution titration of demarcating, transformation efficiency 100%.By infrared spectrum characterization, there is carbonyl peak to exist.Prove do not have chain rupture product and raw material by mass spectrum.
Embodiment 3
With 20 gram mPEG (molecular weight is 5000), 0.004 gram 2,2,6,6-tetramethyl--piperidines-1-oxygen base, 0.08 gram Sodium Bromide is poured in the beaker that fills 120 ml waters, magnetic agitation, ice-water bath cools off, and pours chlorine bleach liquor's (1 ℃, the pH value is 10) of 13 milliliter 8% in this beaker into.Under the ice-water bath condition, in reaction process, the pH value of the sodium hydroxide conditioned reaction system of usefulness 0.5N is 10.The pH value no longer changes after about 2 hours, is stabilized in about 10.Then, under the room temperature condition, continue to stir after 6 hours, add 2 milliliters of ethanol annihilation reaction.PH value with 4N hydrochloric acid soln conditioned reaction liquid is 3, uses dichloromethane extraction reaction solution three times, merges extraction liquids and concentrated three times.Concentrated solution is poured in the cold diethyl ether, and cooling is separated out, and uses cold diethyl ether drip washing, obtains the polyoxyethylene glycol carboxylic acid.With the sodium hydroxide solution titration of demarcating, transformation efficiency 100%.By infrared spectrum characterization, there is carbonyl peak to exist.Prove do not have chain rupture product and raw material by mass spectrum.
Embodiment 4
With 10 gram PEG (molecular weight is 2000), 0.0075 gram 2,2,6,6-tetramethyl--piperidines-1-oxygen base, 0.16 gram Sodium Bromide is poured in the beaker that fills 70 ml waters, magnetic agitation, ice-water bath cools off, and pours chlorine bleach liquor's (1 ℃, the pH value is 10) of 42 milliliter 8% in this beaker into.Under the ice-water bath condition, in reaction process, the pH value of the sodium hydroxide conditioned reaction system of usefulness 0.5N is 10.The pH value no longer changes after about 1 hour, is stabilized in about 10.Then, under the room temperature condition, continue to stir after 6 hours, add 3 milliliters of ethanol annihilation reaction.PH value with 4N hydrochloric acid soln conditioned reaction liquid is 3, uses dichloromethane extraction reaction solution three times, merges extraction liquids and concentrated three times.Concentrated solution is poured in the cold diethyl ether, and cooling is separated out, and uses cold diethyl ether drip washing, obtains the polyoxyethylene glycol carboxylic acid.With the sodium hydroxide solution titration of demarcating, transformation efficiency is 100%.By infrared spectrum characterization, there is carbonyl peak to exist.Prove do not have chain rupture product and raw material by mass spectrum
Embodiment 5
With 20 gram PEG (molecular weight is 8000), 0.0036 gram 2,2,6,6-tetramethyl--piperidines-1-oxygen base, 0.13 gram Potassium Bromide is poured in the beaker that fills 110 ml waters, magnetic agitation, ice-water bath cools off, and pours chlorine bleach liquor's (1 ℃, the pH value is 10) of 21 milliliter 8% in this beaker into.Under the ice-water bath condition, in reaction process, the pH value of the sodium hydroxide conditioned reaction system of usefulness 0.5N is 10.The pH value no longer changes after about 1 hour, is stabilized in about 10.Then, under the room temperature condition, continue to stir after 6 hours, add 4 milliliters of ethanol annihilation reaction.PH value with 4N hydrochloric acid soln conditioned reaction liquid is 3, uses dichloromethane extraction reaction solution three times, merges extraction liquids and concentrated three times.Concentrated solution is poured in the cold diethyl ether, and cooling is separated out, and uses cold diethyl ether drip washing, obtains the polyoxyethylene glycol carboxylic acid.With the sodium hydroxide solution titration of demarcating, transformation efficiency is 100%.By infrared spectrum characterization, there is carbonyl peak to exist.Prove do not have chain rupture product and raw material by mass spectrum
Embodiment 6
The monoalkoxy polyoxyethylene glycol carboxylic acid (molecular weight is 5000) of a certain amount of preparation by aforesaid method is dissolved in the methylene dichloride of an amount of volume, according to monoalkoxy polyoxyethylene glycol carboxyl: dicyclohexylcarbodiimide (DCC): N-hydroxy-succinamide (NHS) is the feed ratio (amount of substance than) of 1:2:2, add DCC earlier, behind the stirring reaction one hour, add NHS, then airtight stirring reaction 24 hours under the room temperature.Stopped reaction removes by filter N, N '-dicyclohexylurea (DCU) that reaction generates, and the N-hydroxy-succinamide monoalkoxy polyoxyethylene glycol carboxylicesters precipitation after will activating with 7 times of cold diethyl ethers to the reaction solution volume is then separated out, and uses cold diethyl ether drip washing, and vacuum-drying is standby.
Get the recombinant human alpha-interferon (molecular weight 19kD) of 20 milliliter of 1.6 mg/ml and put into small beaker, adjusting the pH value is 10.4, the above-mentioned N-hydroxy-succinamide monoalkoxy polyoxyethylene glycol carboxylicesters after having activated of 0.8 gram is joined in the small beaker, behind the reaction 30min, in beaker, add glycine (2ml) stopped reaction of 0.1N.Utilize the fluorescamine method to measure modification degree, modification degree is 51%.Show that the bright polyoxyethylene glycol carboxylic acid that provides of this law can be used for proteinic modification simply.
Reference
[1]M.J.Roberts，M.D.Bentley，J.M.Harris，Chemistry?for?peptide?and?protein?PEGylation，Advanced?Drug?Delivery?Reviews?54(2002)459-476
[2]A.Abuchowski，G.M.Kazo，C.R.Verhoest?et?al，Cancer?therapy?with?chemically?modifiedenzymes.I.Antitumor?properties?of?polyethylene?glycol-asparaginase?conjugates，CancerBiochem.Biophys.7(1984)175-186
[3]Richter?A?W，Akerblom?E.Antibodies?Against?Polyethylene?Glycol?Produced?in?AnimalsbyImmunization?with?Monomethoxy?Polyethylene?Glycol?Modified?proteins.Int.Arch.Allergy.Appl.Immunol.，1983，70：124-131
[4]JP?5096516?Nov.，1986
[5]Johansson?G，Hartman?A.Proc?Int?Solvent?Extract?Conf.Lyon，1974.927
[6]Iwasaki?K，Iwashita?Yoji.Hemoglobin?combined?with?a?poly(alklene?oxide)EP0206448?1986
[7]Arjan?E.J.de?Nooy，Arie?C.Besemer，Herman?van?Bekkum，Highly?selective?nitroxylradical-mediated?oxidation?of?primary?alcohol?groups?in?water-soluble?glucans?CarbohydrateResearch，269(1995)89-98
[8]Pier?Lucio?Anelli，Carlo?Biffi，Fernando?Montanari，and?Silvio?Quici.Fast?and?SekectiveOxidation?of?Primary?Alcohols?to?Aldehydes?or?to?Carboxylic?Acids?and?of?SecondaryAlcohols?to?Ketones?Mediated?by?Oxoammonium?Salts?under?Two-Phase?Conditions?J.Org.Chem.1987，52，2559-2562。
[9]US?Patent?5,162,579(1992)
[10] Chinese patent 91110929.3 (1991)
[11]US?Patent?5,608,107(1997)
Claims (4)
1, a kind of method that in the aqueous solution, prepares the polyoxyethylene glycol carboxylic acid, it is characterized in that in the presence of nitroxyl free radical, in the aqueous solution, with the hypohalite is oxygenant, add bromide, temperature of reaction is controlled at-5 ℃-50 ℃, and the pH value is controlled at 7-14, the oxidation polyoxyethylene glycol is corresponding polyoxyethylene glycol carboxylic acid, and the molecular formula of polyoxyethylene glycol carboxylic acid is RO (CH
2CH
2O)
nCH
2COOH, the R here is-CH
2COOH or-CH
3Or-C
2H
5Or-C
3H
7Group, n are integers from 5-1000;
Wherein said nitroxyl free radical is 2,2,6, a kind of in the 6-tetramethyl--piperidines-1-oxygen base, 4-hydroxyl-2,2,6,6-tetramethyl--piperidines-1-oxygen base, 4-oxo-2,2,6,6-tetramethyl--piperidines-1-oxygen base, 4-methoxyl group-2,2,6,6-tetramethyl--piperidines-1-oxygen base or their mixture, the consumption of described nitroxyl free radical be hydroxyl in the polyoxyethylene glycol amount of substance ten thousand/arrive one of percentage;
Wherein said hypohalite is meant the sodium of hypochlorous acid or hypobromous acid or the salt of potassium or calcium, and the consumption of described hypochlorite is 1.2-10 times of amount of substance of hydroxyl in the polyoxyethylene glycol;
Wherein said bromide is meant Sodium Bromide or Potassium Bromide or Calcium Bromide, the consumption of described bromide be hydroxyl in the polyoxyethylene glycol amount of substance 30 5 percent to percent.
2, the preparation method described in claim 1, the consumption of wherein said nitroxyl free radical be hydroxyl in the polyoxyethylene glycol amount of substance 2/1000ths to 5/1000ths.
3, the preparation method described in claim 1, the consumption of wherein said hypochlorite be hydroxyl in the polyoxyethylene glycol amount of substance 2.5-4 times.
4, the preparation method described in claim 1, wherein said range of reaction temperature is 0 ℃-20 ℃, and under condition of normal pressure, the pH value is controlled at 9-11.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101724142B (en) * | 2008-10-22 | 2011-12-14 | 中国科学院过程工程研究所 | Poly alkyl ether polymer using thiosulfonate as terminal group and synthesis and application thereof |
| CN101792527B (en) * | 2010-01-29 | 2011-11-09 | 辽宁奥克化学股份有限公司 | Polyoxyethylene ether-ester type monomer, synthesis thereof and application in synthesis of water reducing agent |
| CN104761716A (en) * | 2015-04-10 | 2015-07-08 | 上海炎怡生物科技有限公司 | Method for preparing terminal-carboxylated polyethylene glycol |
| CN109701030A (en) * | 2017-10-26 | 2019-05-03 | 湖南华腾制药有限公司 | The preparation method of Pegylation small-molecule drug |
| CN108299638B (en) * | 2017-12-29 | 2020-04-28 | 浙江皇马科技股份有限公司 | Synthesis method of allyl alcohol polyoxyethylene ether carboxylic glycidyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162579A (en) * | 1991-08-30 | 1992-11-10 | Shell Oil Company | Preparation of alkoxyalkanoic acids |
| US5608107A (en) * | 1995-05-31 | 1997-03-04 | Shell Oil Company | Preparation of alkoxyalkanoic acids |
| US6083524A (en) * | 1996-09-23 | 2000-07-04 | Focal, Inc. | Polymerizable biodegradable polymers including carbonate or dioxanone linkages |
-
2003
- 2003-11-17 CN CNB2003101133676A patent/CN100497437C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162579A (en) * | 1991-08-30 | 1992-11-10 | Shell Oil Company | Preparation of alkoxyalkanoic acids |
| US5608107A (en) * | 1995-05-31 | 1997-03-04 | Shell Oil Company | Preparation of alkoxyalkanoic acids |
| US6083524A (en) * | 1996-09-23 | 2000-07-04 | Focal, Inc. | Polymerizable biodegradable polymers including carbonate or dioxanone linkages |
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