CN107235848A - A kind of preparation method of amino-polyethyleneglycols propionic acid - Google Patents
A kind of preparation method of amino-polyethyleneglycols propionic acid Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
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- 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
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic
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- 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
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
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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
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
- C08G65/3344—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing oxygen in addition to sulfur
- C08G65/3346—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing oxygen in addition to sulfur having sulfur bound to carbon and oxygen
Abstract
The invention discloses a kind of amino-polyethyleneglycols propionic acid (NH2‑PEGn‑CH2CH2C00H, n=1 24) preparation method, the preparation method is using double hydroxyl polyethylene glycol of monodisperse small molecules as raw material, by sulfonylation, ammonification, and hydrolysis obtains sterling.This method is simple to operate, and reaction condition is gentle, and purifying is easy, can obtain the product of stable homogeneous.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, and in particular to a kind of preparation method of amino-polyethyleneglycols propionic acid.
Background technology
Polyethylene glycol (polyethylene glycol, PEG) is that progressively occur addition by oxirane and water or ethylene glycol
The relatively low water soluble polyether of molecule amount obtained from polymerization.The oligomeric polyethylene glycol of small-molecular-weight is that colourless, odorless has suction
Existing ether chain in moist thick liquid, molecule, there is hydroxyl again, thus with unique solubility property, can be miscible with water, alcohol, it is micro-
It is dissolved in ether.Polyethylene glycol (Polyethylene Glycol, PEG) is widely used in modified biological macromolecular and small point in recent years
The structure of sub- medicine.After PEG modified biologicals macromolecular or small-molecule drug, its water-soluble and stability can be significantly improved, is reduced
Kidney filter effect, so as to extend the circulation time of medicine in vivo.
The single dispersing longer chain polyethylene glycols degree of polymerization is certain, and molecular weight is certain, and structure is certain, in medicine, material and engineering etc.
Field has critically important application prospect.For example, in field of pharmaceutical preparations, medicine, polypeptide and the protein of Pegylation
Etc. significant impact can be produced to the stability of medicine, immunogenicity and pharmacokinetic property.
Polyethylene glycol easily causes undesirable crosslinking containing two active end groups during for chemical modification, thus how high
The monodispersed small molecule PEG of effect synthesis is still the problem that next ought be difficult to capture.It is universal in synthetic route on the market at present
There is following difficult point：
1) raw material dosage is big, and synthesis step is more, low yield；
2) difficult, purifying products hardly possible is post-processed.
Wu, Xuan；Zong, Xi；Ji, Min et al. disclose a kind of amino-PEG4Preparation method (the Journal of-carboxyl
Of Chemical Research, 2016, vol.40, p.368-370), this method is using tetraethylene glycol as raw material, by addition, right
Aminomethyl phenyl sulfonylation, Azide, reduction etc. 7 steps obtain product.This method step is more, and yield is relatively low, and has used danger
The chemicals sodium azide of danger, Raney Ni etc., it is unfavorable for production.Reaction scheme is as follows：
The content of the invention
The invention provides a kind of preparation method of amino-polyethyleneglycols carboxyl, the Optimization of preparation poly- second two of amino
The synthetic route of alcohol carboxyl, the preparation method raw material is simple and easy to get, and step is shorter, and purifying is simple, without column chromatographic isolation and purification；
Not only so that the purification of product becomes more simple, the yield and purity of amino-polyethyleneglycols carboxyl are also drastically increased.
A kind of preparation method of amino-polyethyleneglycols propionic acid, the preparation method comprises the following steps：1) double hydroxyls are gathered
Ethylene glycol and metal base are dissolved in organic solvent, instill tert-butyl acrylate, and reaction obtains hydroxyl polyethylene glycol propanoic acid tert-butyl ester；
2) by hydroxyl polyethylene glycol propanoic acid tert-butyl ester and alkali soluble in organic solvent, paratoluensulfonyl chloride is added dropwise, reaction is obtained to toluene
Sulphonic acid ester polyethylene glycol propanoic acid tert-butyl ester；3) p-methyl benzenesulfonic acid ester polyethylene glycol propanoic acid tert-butyl ester is dissolved in organic solvent, plus
Enter ammonium hydroxide and catalyst, reaction obtains amino-polyethyleneglycols propanoic acid tert-butyl ester；4) by amino-polyethyleneglycols propanoic acid tert-butyl ester
It is dissolved in organic solvent, adds acid reaction and obtain amino-polyethyleneglycols propionic acid, the structural formula of described pair of hydroxyl polyethylene glycol is：Wherein n is 1~24 integer.
Further, the step 1) in organic solvent be tetrahydrofuran, dichloromethane, dioxane in one kind.
Further, the step 1) in metal base be sodium, potassium, lithium in one kind.
Further, the step 1) in double hydroxyl polyethylene glycol, the mol ratio of tert-butyl acrylate and metal base be
1：0.72~0.8：0.02~0.03.
Further, the step 2) in alkali be triethylamine, sodium hydroxide, pyridine in one kind.
Further, the step 2) in hydroxyl polyethylene glycol propanoic acid tert-butyl ester, mole of paratoluensulfonyl chloride and alkali
Than for 1：0.72~1.11：0.86~1.3.
Further, the step 2) in p-methyl benzenesulfonic acid ester polyethylene glycol propionic acid uncle is made by hydroxyl polyethylene glycol propionic acid
It in reaction temperature is 20 DEG C~40 DEG C that the process of butyl ester, which is, and the reaction time is to carry out under conditions of 10~15h.
Further, the step 3) in catalyst be benzyltriethylammoinium chloride, TBAB, tetrabutyl chlorine
Change one kind in ammonium, 4-butyl ammonium hydrogen sulfate.
Further, the step 3) in by p-methyl benzenesulfonic acid ester polyethylene glycol propanoic acid tert-butyl ester be made amino-polyethyleneglycols
The process of propanoic acid tert-butyl ester be in reaction in temperature be 20~50 DEG C, the reaction time is to carry out under conditions of 24~48h.
Further, the step 4) in acid be one kind in hydrochloric acid or trifluoroacetic acid.
Further, the step 4) in the mistake of amino-polyethyleneglycols propionic acid is made by amino-polyethyleneglycols propanoic acid tert-butyl ester
It in the temperature of reaction is 20~80 DEG C that journey, which is, and the reaction time is to carry out under conditions of 8~16h.
The process route of the preparation method is as follows：
Compared with the existing technology, beneficial effects of the present invention are presented as：
1. raw material is simple and easy to get, step is shorter, and purifying is simple, without column chromatographic isolation and purification, greatly reduces purifying difficulty；
2. obtain the product of stable homogeneous；
3. in preparation process, not being related to poisonous reagent, environmental pollution is low, environmental protection；
4. equipment requirement is low, simple to operate, step is few, and danger coefficient is low, is adapted to industrialization large-scale production.
Brief description of the drawings
The nucleus magnetic hydrogen spectrum figure for the intermediate product that the step of Fig. 1 is embodiment 1 (3) obtains；
The nucleus magnetic hydrogen spectrum figure for the net product that the step of Fig. 2 is embodiment 1 (4) obtains.
Specific implementation step
Embodiment 1
(1) 100g tetraethylene glycols are added into 500ml tetrahydrofurans, weighs the broken metallic sodiums of 0.36g and add above-mentioned solution
In, and 1h is stirred at room temperature.Weigh 53g tert-butyl acrylates to be added drop-wise in above-mentioned reaction solution, 12h is stirred at room temperature.TLC display reactions
Terminate, plus 20ml water quenchings are gone out reaction, rotation removes solvents tetrahydrofurane, adds 300ml water, then extracts 3 with 400ml dichloromethane
It is secondary.Anhydrous sodium sulfate drying dichloromethane phase, is spin-dried for obtaining about 100g crude products；
(2) the 100g crude products for obtaining step (1), 40g triethylamines are added in 400ml dichloromethane, stirring, weigh 65g
Paratoluensulfonyl chloride is dissolved in 150ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, 20 DEG C of reactions
15h.TLC shows that reaction terminates, plus 300ml washings, and point liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, and obtains about 150g sulphonyl
The crude product of change；
(3) crude product for the 150g sulfonylations for obtaining step (2) is added in 200ml dichloromethane, adds 100g hydrogen-oxygens
Change ammonium, 10g TBABs are warming up to 40 DEG C, stir 24h.Reaction terminates, and is spin-dried for, and adds 3M hydrochloric acid, PH=3 is adjusted, with two
Chloromethanes 300ml, extraction is washed 2 times, then adjusts PH=9 with sodium hydroxide solution, then extracted 3 times with dichloromethane 400ml, anhydrous sulphur
Sour sodium is dried, and is spin-dried for, is obtained the product of 50g aminoterminals.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.724 (t,
J=6.4Hz, 2H)；3.672~3.638 (m, 14H)；3.530 (t, J=4.8Hz, 2H)；2.893 (t, J=6.8Hz, 2H)；
1.989 (s, 2H)；1.460 (s, 9H)；
(4) product for the 50g aminoterminals for obtaining step (3) is added in 100ml 3M hydrochloric acid, is warming up to 60 DEG C, stirs 8h.
Reaction terminates, and adjusts PH neutral, is then spin-dried for, suction filtration, anhydrous sodium sulfate drying filtrate is spin-dried for, and obtains 35g purified products.Nuclear-magnetism
Data are as follows：1HNMR (400MHz, CDCl3)：δ：3.775 (t, J=4.8Hz, 2H)；3.708~3.608 (m, 14H)；3.167
(t, J=4.2Hz, 2H)；2.435 (t, J=5.6Hz, 2H).
Embodiment 2
(1) glycol of 50g eight is added into 200ml dichloromethane, weighs the broken metallic sodiums of 0.09g and add above-mentioned solution
In, and 1h is stirred at room temperature.Weigh 13g tert-butyl acrylates to be added drop-wise in above-mentioned reaction solution, 12h is stirred at room temperature.TLC display reactions
Terminate, plus 20ml water quenchings are gone out reaction, rotation removes methylene chloride, adds 300ml water, then extracts 3 with 400ml dichloromethane
It is secondary.Anhydrous sodium sulfate drying dichloromethane phase, is spin-dried for obtaining about 50g crude products；
(2) the 50g crude products for obtaining step (1), 10g triethylamines are added in 150ml dichloromethane, stirring, weigh 16g pairs
Toluene sulfochloride is dissolved in 50ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, 30 DEG C of reaction 12h.
TLC shows that reaction terminates, plus 100ml washings, and point liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, and obtains about 60g sulfonylations
Crude product；
(3) crude product for the 60g sulfonylations for obtaining step (2) is added in 150ml dichloromethane, adds 50g hydroxides
Ammonium, 5g benzyltriethylammoinium chlorides are warming up to 40 DEG C, stir 24h.Reaction terminates, and is spin-dried for, and adds 3M hydrochloric acid, adjusts PH=3, uses
Dichloromethane 100ml, extraction is washed 2 times, then adjusts PH=9 with sodium hydroxide solution, then is extracted 3 times with dichloromethane 150ml, anhydrous
Sodium sulphate is dried, and is spin-dried for, is obtained the product of 30g aminoterminals.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.736
(t, J=6.4Hz, 2H)；3.662~3.630 (m, 30H)；3.535 (t, J=4.8Hz, 2H)；2.891 (t, J=6.8Hz,
2H)；1.987 (s, 2H)；1.450 (s, 9H)；
(4) product for the 30g aminoterminals for obtaining step (3) is added in 100ml 2M hydrochloric acid, is warming up to 60 DEG C, stirs 8h.
Reaction terminates, and adjusts PH neutral, is then spin-dried for, suction filtration, anhydrous sodium sulfate drying filtrate is spin-dried for, and obtains 25g purified products.Nuclear-magnetism
Data are as follows：1HNMR (400MHz, CDCl3)：δ：3.777 (t, J=4.8Hz, 2H)；3.718~3.614 (m, 30H)；3.161
(t, J=4.2Hz, 2H)；2.430 (t, J=5.6Hz, 2H).
Embodiment 3
(1) diethylene glycol (DEG)s of 50g ten are added into 200ml dioxane, weighs the broken metallic sodiums of 0.06g and add above-mentioned solution
In, and 1h is stirred at room temperature.Weigh 8.7g tert-butyl acrylates to be added drop-wise in above-mentioned reaction solution, 12h is stirred at room temperature.TLC is shown instead
It should terminate, plus 20ml water quenchings are gone out reaction, rotation removes solvent dioxane, adds 300ml water, is then extracted with 400ml dichloromethane
Take 3 times.Anhydrous sodium sulfate drying dichloromethane phase, is spin-dried for obtaining about 50g crude products；
(2) the 50g crude products for obtaining step (1), 3g sodium hydroxides are added in 150ml dichloromethane, stirring, are weighed
10.7g paratoluensulfonyl chlorides are dissolved in 50ml dichloromethane, are added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 40 DEG C anti-
Answer 10h.TLC shows that reaction terminates, plus 100ml washings, and point liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, and obtains about 60g sulphurs
Acylated crude product；
(3) crude product for the 60g sulfonylations for obtaining step (2) is added in 150ml dichloromethane, adds 50g hydroxides
Ammonium, 5g tetrabutylammonium chlorides are warming up to 40 DEG C, stir 24h.Reaction terminates, and is spin-dried for, and adds 3M hydrochloric acid, adjusts PH=3, uses dichloro
Methane 100ml, extraction is washed 2 times, then adjusts PH=9 with sodium hydroxide solution, then extracted 3 times with dichloromethane 150ml, anhydrous slufuric acid
Sodium is dried, and is spin-dried for, is obtained the product of 40g aminoterminals.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.722 (t, J
=6.4Hz, 2H)；3.671~3.635 (m, 46H)；3.528 (t, J=4.8Hz, 2H)；2.871 (t, J=6.8Hz, 2H)；
1.995 (s, 2H)；1.444 (s, 9H)；
(4) product for the 30g aminoterminals for obtaining step (3) is added in 100ml 2M hydrochloric acid, is warming up to 60 DEG C, stirs 8h.
Reaction terminates, and adjusts PH neutral, is then spin-dried for, suction filtration, anhydrous sodium sulfate drying filtrate is spin-dried for, and obtains 25g purified products.Nuclear-magnetism
Data are as follows：1HNMR (400MHz, CDCl3)：δ：3.768 (t, J=4.8Hz, 2H)；3.708~3.621 (m, 46H)；3.151
(t, J=4.2Hz, 2H)；2.411 (t, J=5.6Hz, 2H).
Embodiment 4
(1) hexaethylene glycols of 50g ten are added into 200ml tetrahydrofurans, weighs the broken metallic potassiums of 0.05g and add above-mentioned solution
In, and 1h is stirred at room temperature.Weigh 6.5g tert-butyl acrylates to be added drop-wise in above-mentioned reaction solution, 12h is stirred at room temperature.TLC is shown instead
It should terminate, plus 20ml water quenchings are gone out reaction, rotation removes solvents tetrahydrofurane, adds 300ml water, is then extracted with 400ml dichloromethane
Take 3 times.Anhydrous sodium sulfate drying dichloromethane phase, is spin-dried for obtaining 50g crude products；
(2) the 50g crude products for obtaining step (1), 5g pyridines are added in 150ml dichloromethane, stirring, weigh 8g to toluene
Sulfonic acid chloride is dissolved in 50ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, 30 DEG C of reaction 12h.TLC shows
Show that reaction terminates, plus 100ml washings, divide liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, and obtains the thick production of about 55g sulfonylations
Thing；
(3) crude product for the 55g sulfonylations for obtaining step (2) is added in 150ml methanol, adds 50g ammonium hydroxide, 5g
4-butyl ammonium hydrogen sulfate, is warming up to 40 DEG C, stirs 24h.Reaction terminates, and is spin-dried for, and adds 3M hydrochloric acid, adjusts PH=3, uses dichloromethane
100ml, extraction is washed 2 times, then adjusts PH=9 with sodium hydroxide solution, then is extracted 3 times with dichloromethane 150ml, and anhydrous sodium sulfate is done
It is dry, it is spin-dried for, obtains the product of 42g aminoterminals.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.711 (t, J=
6.4Hz, 2H)；3.681~3.629 (m, 62H)；3.525 (t, J=4.8Hz, 2H)；2.868 (t, J=6.8Hz, 2H)；2.052
(s, 2H)；1.415 (s, 9H)；
(4) product for the 42g aminoterminals for obtaining step (3) is added in 150ml 2.5M hydrochloric acid, is warming up to 60 DEG C, stirring
8h.Reaction terminates, and adjusts PH neutral, is then spin-dried for, suction filtration, anhydrous sodium sulfate drying filtrate is spin-dried for, and obtains 30g purified products.Core
Magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.760 (t, J=4.8Hz, 2H)；3.728~3.614 (m, 62H)；
3.143 (t, J=4.2Hz, 2H)；2.402 (t, J=5.6Hz, 2H).
Embodiment 5
(1) tetradecaethylene glycols of 50g bis- are added into 200ml tetrahydrofurans, weighs the broken lithium metal additions of 0.01g above-mentioned molten
In liquid, and 1h is stirred at room temperature.Weigh 4.3g tert-butyl acrylates to be added drop-wise in above-mentioned reaction solution, 12h is stirred at room temperature.TLC is shown
Reaction terminates, plus 20ml water quenchings are gone out reaction, and rotation removes solvents tetrahydrofurane, adds 300ml water, then uses 400ml dichloromethane
Extraction 3 times.Anhydrous sodium sulfate drying dichloromethane phase, is spin-dried for obtaining about 46g crude products；
(2) the 46g crude products for obtaining step (1), 3.3g triethylamines are added in 150ml dichloromethane, stirring, weigh 5.3g
Paratoluensulfonyl chloride is dissolved in 30ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, 30 DEG C of reaction 12h.
TLC shows that reaction terminates, plus 100ml washings, and point liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, and obtains about 48g sulfonylations
Crude product；
(3) crude product for the 48g sulfonylations for obtaining step (2) is added in 150ml dichloromethane, adds 50g hydroxides
Ammonium, 5g TBABs are warming up to 40 DEG C, stir 24h.Reaction terminates, and is spin-dried for, and adds 3M hydrochloric acid, adjusts PH=3, uses dichloro
Methane 100ml, extraction is washed 2 times, then adjusts PH=9 with sodium hydroxide solution, then extracted 3 times with dichloromethane 150ml, anhydrous slufuric acid
Sodium is dried, and is spin-dried for, is obtained the product of 40g aminoterminals.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.725 (t, J
=6.4Hz, 2H)；3.657~3.622 (m, 94H)；3.527 (t, J=4.8Hz, 2H)；2.886 (t, J=6.8Hz, 2H)；
1.998 (s, 2H)；1.436 (s, 9H)；
(4) product for the 40g aminoterminals for obtaining step (3) is added in 100ml 2M trifluoroacetic acids, is warming up to 60 DEG C, stirring
8h.Reaction terminates, and adjusts PH neutral, is then spin-dried for, suction filtration, anhydrous sodium sulfate drying filtrate is spin-dried for, and obtains 33g purified products.Core
Magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.766 (t, J=4.8Hz, 2H)；3.710~3.609 (m, 94H)；
3.155 (t, J=4.2Hz, 2H)；2.456 (t, J=5.6Hz, 2H).
Claims (11)
1. a kind of preparation method of amino-polyethyleneglycols propionic acid, it is characterised in that the preparation method comprises the following steps：1) will
Double hydroxyl polyethylene glycol and metal base are dissolved in organic solvent, instill tert-butyl acrylate, and reaction obtains hydroxyl polyethylene glycol third
Tert-butyl acrylate；2) by hydroxyl polyethylene glycol propanoic acid tert-butyl ester and alkali soluble in organic solvent, paratoluensulfonyl chloride is added dropwise, reacts
To p-methyl benzenesulfonic acid ester polyethylene glycol propanoic acid tert-butyl ester；3) p-methyl benzenesulfonic acid ester polyethylene glycol propanoic acid tert-butyl ester is dissolved in organic molten
In agent, ammonium hydroxide and catalyst are added, reaction obtains amino-polyethyleneglycols propanoic acid tert-butyl ester；4) by amino-polyethyleneglycols propionic acid
The tert-butyl ester is dissolved in organic solvent, is added acid reaction and is obtained amino-polyethyleneglycols propionic acid, the structure of described pair of hydroxyl polyethylene glycol
Formula is：Wherein n is 1~24 integer.
2. the preparation method of a kind of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that described organic molten
Agent is one kind in tetrahydrofuran, dichloromethane, dioxane, methanol.
3. the preparation method of a kind of amino-polyethyleneglycols carboxyl according to claim 1, it is characterised in that the step 1)
In metal base be sodium, potassium, lithium in one kind.
4. the preparation method of a kind of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step 1)
In double hydroxyl polyethylene glycol, the mol ratio of tert-butyl acrylate and metal base be 1：0.72~0.8：0.02~0.03.
5. the preparation method of a kind of amino-polyethyleneglycols carboxyl according to claim 1, it is characterised in that the step 2)
In alkali be triethylamine, sodium hydroxide, pyridine in one kind.
6. the preparation method of a kind of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step 2)
In hydroxyl polyethylene glycol propanoic acid tert-butyl ester, the mol ratio of paratoluensulfonyl chloride and alkali be 1：0.72~1.11：0.86~1.3.
7. the preparation method of a kind of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step 2)
In p-methyl benzenesulfonic acid ester polyethylene glycol propanoic acid tert-butyl ester is made by hydroxyl polyethylene glycol propionic acid process be in reaction temperature be 20
DEG C~40 DEG C, the reaction time is to carry out under conditions of 10~15h.
8. the preparation method of a kind of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step 3)
In catalyst be benzyltriethylammoinium chloride, TBAB, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate in one
Kind.
9. the preparation method of a kind of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step 3)
In the process of amino-polyethyleneglycols propanoic acid tert-butyl esters is made by p-methyl benzenesulfonic acid ester polyethylene glycol propanoic acid tert-butyl ester is to be in reaction
It it is 20~50 DEG C in temperature, the reaction time is to carry out under conditions of 24~48h.
10. a kind of preparation method of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step
4) acid in is one kind in hydrochloric acid or trifluoroacetic acid.
11. a kind of preparation method of amino-polyethyleneglycols propionic acid according to claim 1, it is characterised in that the step
4) it in the temperature of reaction is 20~80 that the process that amino-polyethyleneglycols propionic acid is made by amino-polyethyleneglycols propanoic acid tert-butyl ester in, which is,
DEG C, the reaction time is to carry out under conditions of 8~16h.
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| CN109096128A (en) * | 2018-01-12 | 2018-12-28 | 江苏金斯瑞生物科技有限公司 | A kind of preparation method of amino-polyethyleneglycols propionic acid |
| CN113646291A (en) * | 2019-03-29 | 2021-11-12 | 日油株式会社 | Preparation method of heterotype monodisperse polyethylene glycol derivative |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096128A (en) * | 2018-01-12 | 2018-12-28 | 江苏金斯瑞生物科技有限公司 | A kind of preparation method of amino-polyethyleneglycols propionic acid |
| CN109096128B (en) * | 2018-01-12 | 2021-03-09 | 江苏金斯瑞生物科技有限公司 | Preparation method of aminopolyethylene glycol propionic acid |
| CN113646291A (en) * | 2019-03-29 | 2021-11-12 | 日油株式会社 | Preparation method of heterotype monodisperse polyethylene glycol derivative |
| CN113646291B (en) * | 2019-03-29 | 2024-02-27 | 日油株式会社 | Process for preparing special-shaped monodisperse polyethylene glycol derivative |
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