CN107254043A - A kind of preparation method of end mercapto-polyglycol amino - Google Patents
A kind of preparation method of end mercapto-polyglycol amino Download PDFInfo
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Abstract
The invention discloses a kind of small molecule PEG derivatives end mercapto-polyglycol amino (NH2PEG SH) preparation method, the preparation method is using monodispersed small molecule PEG as raw material, and the hydroxyl at its two ends by series of steps is converted to sulfydryl and amino.Purification difficult present in prior art is this method solve, yield is relatively low, the problem of being unfavorable for production, Optimization of preparation small molecule PEG synthetic route so that the purification of product becomes more simple, reaction condition is gentle, purifying is easy, improves small molecule PEG yield and purity.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of preparation method of end mercapto-polyglycol amino.
Background technology
Polyethylene glycol (polyethylene glycol, PEG) is that progressively occur addition by oxirane and water or ethylene glycol
The water soluble polyether of a family macromolecule obtained from polymerization, nonirritant with non-corrosiveness, no antigen and immunogenicity,
Good biocompatibility, shows as low-protein and low platelet absorption and low cell adhesion, and obtained in vivo
FDA approvals are used.
However, unmodified PEG is not available as reagent in itself, because its terminal hydroxy group is reactive limited.Therefore, in order to
Prepare useful PEG reagents, it is necessary to opposite end hydroxyl modification, make the group with more reactivity.According to prior art
Method, first with alkyl ether or other non-reacted functional group's form envelope one terminal hydroxy groups, then turns uncapped terminal hydroxy group
It is melted into electrophilic center, the carboxylate of such as activation, so that new functional group is applied on terminal hydroxy group.Or, apply functional group
Onto a terminal hydroxy group, and separate monofunctional PEG and unmodified PEG, Bifunctionalized PEG mixture.
Difunctional PEG reagents are to contain reactive group on two ends of PEG molecules.These bi-functional reagents exist
Identical reactive group (i.e. equal difunctional PEG reagents) or different group (i.e. miscellaneous couple official can be contained on PEG two ends
PEG reagents can be rolled into a ball).Relative to equal difunctional PEG reagents, Heterobifunctional group PEG reagents are provided the advantage of, Heterobifunctional
Each functional group of group's PEG reagents can be covalently attached with the formation of the different molecular on each end group.In this reaction, two lists
Only molecule is connected by PEG polymer.However, wishing to connect different functional groups (i.e. miscellaneous pair on each end of PEG molecules
Functional group's PEG reagents) when, synthesis difunctional PEG reagents become complicated.So the easy difunctional PEG examinations of exploitation series
Agent is for domestic biological medicine, and the development in the field such as material has positive facilitation.
Yeo,Woon-Seok；Min,Dal-Hee；Et al. be referred to a kind of amino-PEG3The preparation method of-sulfydryl
(Journal of the American Chemical Society, 2001, vol.123, p.7560-7563), this method with
Triethylene glycol is raw material, by bromination, phthalic amide sylvite amination, thioacetic acid sulfhydrylation, and the step such as hydrazinolysis is produced
Product, but this method purification difficult, yield are relatively low, are unfavorable for production.Reaction scheme is as follows：
The content of the invention
The invention provides a kind of end mercapto-polyglycol amino (NH2- PEGn-SH, n=1-24) preparation method, solution
Determine purification difficult present in prior art, yield is relatively low, the problem of being unfavorable for production, Optimization of preparation small molecule
PEG synthetic route so that the purification of product becomes more simple, improves small molecule PEG yield and purity.
A kind of end mercapto-polyglycol amino, the end mercapto-polyglycol amino is small molecule PEG derivatives, its molecule
Formula is：Wherein n is 1-24 integer.
The method for preparing its end mercapto-polyglycol amino, comprises the following steps：1) by monodispersed small molecule PEG and
Then one alkali soluble is added dropwise RCl solution in the first organic solvent, and reaction obtains intermediate A：2)
By step 1) obtained intermediate A is dissolved in the second organic solvent, adds sodium azide, reaction obtains intermediate B：3) by step 2) obtained intermediate B is dissolved in the 3rd organic solvent, adds methylsufonyl chloride, instead
Intermediate C should be obtained：4) by step 3) obtained intermediate C is dissolved in the 4th organic solvent, plus
Enter thioacetic acid and the second alkali, reaction obtains intermediate D：5) by step 4) obtained intermediate
D is dissolved in the 5th organic solvent, adds sodium methoxide, and reaction obtains intermediate E：6) by step 5) obtain
Intermediate E be dissolved in the 6th organic solvent, add reducing agent, reaction completely post processing obtain finished product：Wherein PEG molecular formula is：Wherein n is 1-24 integer, and R is first
One kind in sulfonic group, p-methyl benzenesulfonic acid base, p-nitrophenyl sulfonic group.
Further, the step 1) in the first alkali be triethylamine, sodium hydroxide, pyridine in one kind.
The first alkali in further, it is characterised in that the step 1) is triethylamine.
Further, the step 1) in the first organic solvent be tetrahydrofuran, dichloromethane, dioxane in one
Kind.
Further, the step 1) in by small molecule PEG be made intermediate A course of reaction be in reaction temperature be 20
DEG C -30 DEG C, time of reaction is to carry out under conditions of 10-12h.
Further, the step 2) in the second organic solvent be DMF, ethanol in one kind.
Further, the step 3) in the 3rd organic solvent be tetrahydrofuran, dichloromethane, dioxane in one
Kind.
Further, the step 3) be in temperature be 20 DEG C -25 DEG C, time of reaction is to carry out under conditions of 10-12h
's.
Further, the step 4) in the 4th organic solvent be acetone, tetrahydrofuran, DMF in one kind.
Further, the step 4) in the second alkali be lithium carbonate, potassium carbonate, sodium carbonate in one kind.
Further, the step 4) in the second alkali be potassium carbonate.
Further, the step 5) in the 5th organic solvent be methanol, ethanol in one kind.
Further, the step 6) in the 6th organic solvent be tetrahydrofuran, dichloromethane, dioxane in one
Kind.
Further, the step 6) in reducing agent be lithium aluminium hydride reduction, sodium borohydride, triphenylphosphine in one kind.
The route of the preparation method is as follows：
PEG molecular formula are：Wherein n is 1-24 integer.
Beneficial effects of the present invention are presented as there is provided a kind of preparation method of end mercapto-polyglycol amino so that product
Purification become more simple, small molecule PEG yield and purity are improved, advantageously in production, while being also the miscellaneous couple of official
The preparation that PEG can be rolled into a ball provides some beneficial thinkings.
Embodiment
The invention provides a kind of preparation method of end mercapto-polyglycol amino, the end mercapto-polyglycol amino is
Small molecule PEG derivatives, its molecular formula is：Wherein n is 1-24 integer, prepares its end sulfydryl and gathers
The method of ethylene glycol amino, is mainly included the following steps that：1) it is 20 DEG C -30 DEG C in reaction temperature, the time of reaction is 10-12h
Under conditions of, by monodispersed small molecule PEG and the first alkali soluble in the first organic solvent, RCl solution, reaction is then added dropwise
Obtain intermediate A：First alkali is one kind in triethylamine, sodium hydroxide, pyridine；First is organic molten
Agent is one kind in tetrahydrofuran, dichloromethane, dioxane；2) by step 1) to be dissolved in second organic molten for obtained intermediate A
In agent, sodium azide is added, reaction obtains intermediate B：Second organic solvent is DMF, ethanol
In one kind；3) in temperature be 20 DEG C -25 DEG C, under conditions of time of reaction is 10-12h, by step 2) obtained intermediate B
It is dissolved in the 3rd organic solvent, adds methylsufonyl chloride, reaction obtains intermediate C：3rd is organic
Solvent is one kind in tetrahydrofuran, dichloromethane, dioxane；4) by step 3) to be dissolved in the 4th organic by obtained intermediate C
In solvent, thioacetic acid and the second alkali are added, reaction obtains intermediate D：4th organic solvent
For one kind in acetone, tetrahydrofuran, DMF；Second alkali is one kind in lithium carbonate, potassium carbonate, sodium carbonate；5) by step 4)
To intermediate D be dissolved in the 5th organic solvent, add sodium methoxide, reaction obtain intermediate E：The
Five organic solvents are one kind in methanol, ethanol；6) by step 5) obtained intermediate E is dissolved in the 6th organic solvent, adds
Reducing agent, reaction post processing completely obtains finished product：6th organic solvent is tetrahydrofuran, two
One kind in chloromethanes, dioxane；Reducing agent is one kind in lithium aluminium hydride reduction, sodium borohydride, triphenylphosphine；Wherein PEG's
Molecular formula is：Wherein n is 1-24 integer, and R is methanesulfonic acid base, p-methyl benzenesulfonic acid base, to nitro
One kind in benzene sulfonic acid base.
Embodiment 1
(1) by 50g diethylene glycol (DEG)s, 34g triethylamines are added in 500ml dichloromethane, stirring, weigh 54g tolysulfonyl
Chlorine is dissolved in 150ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 12h is reacted at a temperature of 20 DEG C.TLC
Display reaction terminates, plus 400ml washings, point liquid, and anhydrous sodium sulfate drying organic phase is spin-dried for, then pure by column chromatography for separation
Change obtains 55g intermediate As, yield：90%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.792 (d, J=
8.4Hz, 2H)；7.350 (d, J=8.4Hz, 2H)；4.158 (t, J=4.4Hz, 2H)；3.702~3.567 (m, 6H)；2.818
(s, 1H)；2.435 (s, 3H).
(2) the 55g intermediate As for obtaining step (1) are added in 300ml ethanol, are added 18g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 200ml water, is extracted with 500ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 28g intermediate Bs, yield：95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.740~3.542 (m, 6H)；3.342 (t, J=4.8Hz, 2H)；3.026 (s, 1H).
(3) the 28g intermediate Bs for obtaining step (2) are added in 300ml dichloromethane, 18g triethylamines are added, in frozen water
19g methylsufonyl chlorides are added dropwise under the conditions of bath, 12h are reacted at a temperature of 20 DEG C.Reaction terminates, plus 400ml washings, point liquid, anhydrous sulphur
Sour sodium dries organic phase, is spin-dried for, obtains 32g intermediate C, yield：90%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：4.373 (t, J=4.0Hz, 2H)；3.778~3.644 (m, 4H)；3.389 (t, J=4.8Hz, 2H)；3.098
(s, 3H).
(4) the 32g intermediates C that step (3) is obtained is added in 250mlDMF, 20g thioacetic acids is added, in ice-water bath bar
Under part, 33g potassium carbonate is added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 700ml water, is extracted with 500ml dichloromethane
Take, anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, then obtain 28g intermediate D, yield by column chromatographic isolation and purification：
92%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.683~3.585 (m, 4H)；3.396 (t, J=4.8Hz,
2H)；3.101 (t, J=4.8Hz, 2H)；2.329 (s, 3H).
(5) the 28g intermediates D that step (4) is obtained is added in 200ml methanol, adds 9.8g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 300ml water, is extracted with 400ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 20g intermediate Es, yield are obtained by column chromatographic isolation and purification：93%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.690~3.570 (m, 6H)；3.096 (t, J=4.8Hz, 2H)；1.682 (t, J=4.0Hz, 1H).
(6) the 20g intermediate Es for obtaining step (5) are added in 150ml tetrahydrofurans, under ice bath, and 4.0g hydrogen is added portionwise
Change aluminium lithium, and 3h is stirred at room temperature.Reaction terminates, and adds 2ml water, and 35% sodium hydroxide solution, suction filtration is spin-dried for filtrate, Ran Houjing
Cross column chromatographic isolation and purification and obtain 16g finished products, yield：96%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.677~3.556 (m, 4H)；2.822 (t, J=4.8Hz, 2H)；2.682 (t, J=4.0Hz, 2H)；2.112 (s, 2H)；
1.602 (t, J=4.0Hz, 1H).
Embodiment 2
(1) by 50g diethylene glycol (DEG)s, 15g sodium hydroxide solutions are added in 500ml tetrahydrofurans, stirring, weigh 40g methyl
Sulfonic acid chloride is dissolved in 150ml tetrahydrofurans, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 12h is reacted at 25 DEG C.TLC
Display reaction terminates, plus 400ml washings, point liquid, and anhydrous sodium sulfate drying organic phase is spin-dried for, then pure by column chromatography for separation
Change obtains 38g intermediate As, yield：88%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.792 (d, J=
8.4Hz, 2H)；7.350 (d, J=8.4Hz, 2H)；4.158 (t, J=4.4Hz, 2H)；3.702~3.567 (m, 6H)；2.818
(s, 1H)；2.435 (s, 3H).
(2) the 38g intermediate As for obtaining step (1) are added in 300mlDMF, are added 18g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 200ml water, is extracted with 500ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 25g intermediate Bs, yield：95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.740~3.542 (m, 6H)；3.342 (t, J=4.8Hz, 2H)；3.026 (s, 1H).
(3) the 25g intermediate Bs for obtaining step (2) are added in 300ml tetrahydrofurans, 18g triethylamines are added, in frozen water
19g methylsufonyl chlorides are added dropwise under the conditions of bath, 10h are reacted at a temperature of 25 DEG C.Reaction terminates, plus 400ml washings, point liquid, anhydrous sulphur
Sour sodium dries organic phase, is spin-dried for, obtains 32g intermediate C, yield：92%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：4.373 (t, J=4.0Hz, 2H)；3.778~3.644 (m, 4H)；3.389 (t, J=4.8Hz, 2H)；3.098
(s, 3H).
(4) the 32g intermediates C that step (3) is obtained is added in 250ml acetone, 20g thioacetic acids is added, in ice-water bath
Under the conditions of, 33g sodium carbonate is added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 700ml water, is extracted with 500ml dichloromethane
Take, anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, then obtain 20g intermediate D, yield by column chromatographic isolation and purification：
94%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.683~3.585 (m, 4H)；3.396 (t, J=4.8Hz,
2H)；3.101 (t, J=4.8Hz, 2H)；2.329 (s, 3H).
(5) the 20g intermediates D that step (4) is obtained is added in 200ml ethanol, adds 9.8g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 300ml water, is extracted with 400ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 12g intermediate Es, yield are obtained by column chromatographic isolation and purification：95%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.690~3.570 (m, 6H)；3.096 (t, J=4.8Hz, 2H)；1.682 (t, J=4.0Hz, 1H).
(6) the 12g intermediate Es for obtaining step (5) are added in 150ml dichloromethane, under ice bath, and 3.5g boron is added portionwise
Sodium hydride, and 3h is stirred at room temperature.Reaction terminates, and adds 2ml water, and 35% sodium hydroxide solution, suction filtration is spin-dried for filtrate, Ran Houjing
Cross column chromatographic isolation and purification and obtain 16g finished products, yield：92%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.677~3.556 (m, 4H)；2.822 (t, J=4.8Hz, 2H)；2.682 (t, J=4.0Hz, 2H)；2.112 (s, 2H)；
1.602 (t, J=4.0Hz, 1H).
Embodiment 3
(1) by 50g diethylene glycol (DEG)s, 34g pyridines are added in 500ml dioxane, stirring, weigh 54g paratoluensulfonyl chlorides
150ml dioxane is dissolved in, is added dropwise under the conditions of ice-water bath in reaction system, drop finishes, and 12h is reacted at 30 DEG C.TLC is shown instead
It should terminate, plus 400ml washings, divide liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, then obtained by column chromatographic isolation and purification
48g intermediate As, yield：87%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.792 (d, J=8.4Hz, 2H)；
7.350 (d, J=8.4Hz, 2H)；4.158 (t, J=4.4Hz, 2H)；3.702~3.567 (m, 6H)；2.818 (s, 1H)；
2.435 (s, 3H).
(2) the 48g intermediate As for obtaining step (1) are added in 300ml ethanol, are added 18g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 200ml water, is extracted with 500ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 34g intermediate Bs, yield：95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.740~3.542 (m, 6H)；3.342 (t, J=4.8Hz, 2H)；3.026 (s, 1H).
(3) the 34g intermediate Bs for obtaining step (2) are added in 300ml dioxane, 18g triethylamines are added, in frozen water
19g methylsufonyl chlorides are added dropwise under the conditions of bath, 11h are reacted at a temperature of 23 DEG C.Reaction terminates, plus 400ml washings, point liquid, anhydrous sulphur
Sour sodium dries organic phase, is spin-dried for, obtains 30g intermediate C, yield：90%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：4.373 (t, J=4.0Hz, 2H)；3.778~3.644 (m, 4H)；3.389 (t, J=4.8Hz, 2H)；3.098
(s, 3H).
(4) the 30g intermediates C that step (3) is obtained is added in 250ml tetrahydrofurans, 20g thioacetic acids is added, in ice
Under water bath condition, 28g lithium carbonates are added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 700ml water, uses 500ml dichloromethanes
Alkane is extracted, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, and then obtains 15g intermediate D by column chromatographic isolation and purification, is produced
Rate：92%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.683~3.585 (m, 4H)；3.396 (t, J=
4.8Hz, 2H)；3.101 (t, J=4.8Hz, 2H)；2.329 (s, 3H).
(5) the 15g intermediates D that step (4) is obtained is added in 200ml methanol, adds 9.8g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 300ml water, is extracted with 400ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 11g intermediate Es, yield are obtained by column chromatographic isolation and purification：88%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.690~3.570 (m, 6H)；3.096 (t, J=4.8Hz, 2H)；1.682 (t, J=4.0Hz, 1H).
(6) the 11g intermediate Es for obtaining step (5) are added in 150ml dioxane, under ice bath, and 25g tri- is added portionwise
Phenylphosphine, and 3h is stirred at room temperature.Reaction terminates, suction filtration, is spin-dried for filtrate, then obtains 6g productions eventually by column chromatographic isolation and purification
Product, yield：91%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.677~3.556 (m, 4H)；2.822 (t, J
=4.8Hz, 2H)；2.682 (t, J=4.0Hz, 2H)；2.112 (s, 2H)；1.602 (t, J=4.0Hz, 1H).
Embodiment 4
(1) by 50g diethylene glycol (DEG)s, 28g triethylamines are added in 500ml dichloromethane, stirring, weigh 48g tolysulfonyl
Chlorine is dissolved in 150ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 12h is reacted at a temperature of 22 DEG C.TLC
Display reaction terminates, plus 400ml washings, point liquid, and anhydrous sodium sulfate drying organic phase is spin-dried for, then pure by column chromatography for separation
Change obtains 49g intermediate As, yield：90%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.792 (d, J=
8.4Hz, 2H)；7.350 (d, J=8.4Hz, 2H)；4.158 (t, J=4.4Hz, 2H)；3.702~3.567 (m, 6H)；2.818
(s, 1H)；2.435 (s, 3H).
(2) the 49g intermediate As for obtaining step (1) are added in 300ml ethanol, are added 16g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 200ml water, is extracted with 500ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 26g intermediate Bs, yield：94%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.740~3.542 (m, 6H)；3.342 (t, J=4.8Hz, 2H)；3.026 (s, 1H).
(3) the 26g intermediate Bs for obtaining step (2) are added in 300ml dichloromethane, 16g triethylamines are added, in frozen water
18g methylsufonyl chlorides are added dropwise under the conditions of bath, 12h are reacted at a temperature of 25 DEG C.Reaction terminates, plus 400ml washings, point liquid, anhydrous sulphur
Sour sodium dries organic phase, is spin-dried for, obtains 30g intermediate C, yield：92%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：4.373 (t, J=4.0Hz, 2H)；3.778~3.644 (m, 4H)；3.389 (t, J=4.8Hz, 2H)；3.098
(s, 3H).
(4) the 30g intermediates C that step (3) is obtained is added in 250mlDMF, 20g thioacetic acids is added, in ice-water bath bar
Under part, 28g potassium carbonate is added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 700ml water, is extracted with 500ml dichloromethane
Take, anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, then obtain 27g intermediate D, yield by column chromatographic isolation and purification：
94%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.683~3.585 (m, 4H)；3.396 (t, J=4.8Hz,
2H)；3.101 (t, J=4.8Hz, 2H)；2.329 (s, 3H).
(5) the 27g intermediates D that step (4) is obtained is added in 200ml methanol, adds 9g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 300ml water, is extracted with 400ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 20g intermediate Es, yield are obtained by column chromatographic isolation and purification：98%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.690~3.570 (m, 6H)；3.096 (t, J=4.8Hz, 2H)；1.682 (t, J=4.0Hz, 1H).
(6) the 20g intermediate Es for obtaining step (5) are added in 150ml tetrahydrofurans, under ice bath, and 4.0g hydrogen is added portionwise
Change aluminium lithium, and 3h is stirred at room temperature.Reaction terminates, and adds 2ml water, and 35% sodium hydroxide solution, suction filtration is spin-dried for filtrate, Ran Houjing
Cross column chromatographic isolation and purification and obtain 18g finished products, yield：95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.677~3.556 (m, 4H)；2.822 (t, J=4.8Hz, 2H)；2.682 (t, J=4.0Hz, 2H)；2.112 (s, 2H)；
1.602 (t, J=4.0Hz, 1H).
Embodiment 5
(1) by 50g diethylene glycol (DEG)s, 36g pyridines are added in 500ml dioxane, stirring, weigh 54g paratoluensulfonyl chlorides
150ml dioxane is dissolved in, is added dropwise under the conditions of ice-water bath in reaction system, drop finishes, and 12h is reacted at 27 DEG C.TLC is shown instead
It should terminate, plus 400ml washings, divide liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, then obtained by column chromatographic isolation and purification
48g intermediate As, yield：88%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.792 (d, J=8.4Hz, 2H)；
7.350 (d, J=8.4Hz, 2H)；4.158 (t, J=4.4Hz, 2H)；3.702~3.567 (m, 6H)；2.818 (s, 1H)；
2.435 (s, 3H).
(2) the 48g intermediate As for obtaining step (1) are added in 300ml ethanol, are added 18g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 200ml water, is extracted with 500ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 36g intermediate Bs, yield：95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.740~3.542 (m, 6H)；3.342 (t, J=4.8Hz, 2H)；3.026 (s, 1H).
(3) the 36g intermediate Bs for obtaining step (2) are added in 300ml dichloromethane, 18g triethylamines are added, in frozen water
19g methylsufonyl chlorides are added dropwise under the conditions of bath, 11h are reacted at a temperature of 25 DEG C.Reaction terminates, plus 400ml washings, point liquid, anhydrous sulphur
Sour sodium dries organic phase, is spin-dried for, obtains 31g intermediate C, yield：93%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：4.373 (t, J=4.0Hz, 2H)；3.778~3.644 (m, 4H)；3.389 (t, J=4.8Hz, 2H)；3.098
(s, 3H).
(4) the 31g intermediates C that step (3) is obtained is added in 250ml tetrahydrofurans, 20g thioacetic acids is added, in ice
Under water bath condition, 28g lithium carbonates are added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 700ml water, uses 500ml dichloromethanes
Alkane is extracted, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, and then obtains 16g intermediate D by column chromatographic isolation and purification, is produced
Rate：90%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.683~3.585 (m, 4H)；3.396 (t, J=
4.8Hz, 2H)；3.101 (t, J=4.8Hz, 2H)；2.329 (s, 3H).
(5) the 16g intermediates D that step (4) is obtained is added in 200ml methanol, adds 10g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 300ml water, is extracted with 400ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 12g intermediate Es, yield are obtained by column chromatographic isolation and purification：97%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.690~3.570 (m, 6H)；3.096 (t, J=4.8Hz, 2H)；1.682 (t, J=4.0Hz, 1H).
(6) the 12g intermediate Es for obtaining step (5) are added in 150ml dioxane, under ice bath, and 25g tri- is added portionwise
Phenylphosphine, and 3h is stirred at room temperature.Reaction terminates, suction filtration, is spin-dried for filtrate, then obtains 8g productions eventually by column chromatographic isolation and purification
Product, yield：98%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.677~3.556 (m, 4H)；2.822 (t, J
=4.8Hz, 2H)；2.682 (t, J=4.0Hz, 2H)；2.112 (s, 2H)；1.602 (t, J=4.0Hz, 1H).
Embodiment 6
(1) by 50g hexaethylene glycols, 23g triethylamines are added in 400ml dichloromethane, stirring, weigh 29g tolysulfonyl
Chlorine is dissolved in 100ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 12h is reacted at 25 DEG C.TLC is shown
Reaction terminates, plus 200ml washings, and point liquid, anhydrous sodium sulfate drying organic phase is spin-dried for, then obtained by column chromatographic isolation and purification
To 52g intermediate As, yield：84%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.782 (d, J=8.4Hz,
2H)；7.332 (d, J=8.4Hz, 2H)；4.138 (t, J=4.4Hz, 2H)；3.712~3.555 (m, 22H)；2.807 (s,
1H)；2.439 (s, 3H).
(2) the 52g intermediate As for obtaining step (1) are added in 300ml ethanol, are added 11.5g sodium azide, are warming up to
80 DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 200ml water, is extracted with 300ml dichloromethane, and anhydrous sodium sulfate is done
Dry dichloromethane phase, is spin-dried for, and obtains 41g intermediate Bs, yield：93%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：
δ：3.735~3.540 (m, 22H)；3.332 (t, J=4.8Hz, 2H)；3.015 (s, 1H).
(3) the 41g intermediate Bs for obtaining step (2) are added in 200ml dichloromethane, 15g triethylamines are added, in frozen water
15g methylsufonyl chlorides are added dropwise under the conditions of bath, and in stirring 6h at 25 DEG C.Reaction terminates, plus 200ml washings, point liquid, anhydrous slufuric acid
Sodium dries organic phase, is spin-dried for, obtains 45g intermediate C, yield：89%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：
δ：4.384 (t, J=4.0Hz, 2H)；3.780~3.652 (m, 20H)；3.395 (t, J=4.8Hz, 2H)；3.099 (s, 3H).
(4) the 45g intermediates C that step (3) is obtained is added in 150mlDMF, 16.5g thioacetic acids is added, in ice-water bath
Under the conditions of, 28g potassium carbonate is added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 500ml water, is extracted with 400ml dichloromethane
Take, anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, then obtain 38g intermediate D, yield by column chromatographic isolation and purification：
92%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.680~3.581 (m, 20H)；3.390 (t, J=4.8Hz,
2H)；3.121 (t, J=4.8Hz, 2H)；2.320 (s, 3H).
(5) the 38g intermediates D that step (4) is obtained is added in 200ml methanol, adds 10g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 200ml water, is extracted with 300ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 35g intermediate Es, yield are obtained by column chromatographic isolation and purification：90%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.696~3.575 (m, 22H)；3.094 (t, J=4.8Hz, 2H)；1.680 (t, J=4.0Hz, 1H).
(6) the 35g intermediate Es for obtaining step (5) are added in 100ml tetrahydrofurans, under ice bath, and 1.0g hydrogen is added portionwise
Change aluminium lithium, and 3h is stirred at room temperature.Reaction terminates, and adds 1ml water, and 35% sodium hydroxide solution, suction filtration is spin-dried for filtrate, Ran Houjing
Cross column chromatographic isolation and purification and obtain 28g finished products, yield：97%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.687~3.550 (m, 20H)；2.802 (t, J=4.8Hz, 2H)；2.672 (t, J=4.0Hz, 2H)；2.105 (s, 2H)；
1.601 (t, J=4.0Hz, 1H).
Embodiment 7
(1) by the diethylene glycol (DEG)s of 20g ten, 4.8g triethylamines are added in 250ml dichloromethane, stirring, weigh 5.6g to toluene
Sulfonic acid chloride is dissolved in 60ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 12h is reacted at 25 DEG C.TLC
Display reaction terminates, plus 200ml washings, point liquid, and anhydrous sodium sulfate drying organic phase is spin-dried for, then pure by column chromatography for separation
Change obtains 18g intermediate As, yield：90%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.782 (d, J=
8.4Hz, 2H)；7.355 (d, J=8.4Hz, 2H)；4.150 (t, J=4.4Hz, 2H)；3.700~3.553 (m, 46H)；2.810
(s, 1H)；2.431 (s, 3H).
(2) the 18g intermediate As for obtaining step (1) are added in 200ml ethanol, are added 2.5g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 100ml water, is extracted with 150ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 15g intermediate Bs, yield：95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.740~3.542 (m, 6H)；3.342 (t, J=4.8Hz, 2H)；3.026 (s, 1H).
(3) the 15g intermediate Bs for obtaining step (2) are added in 150ml dichloromethane, 4g triethylamines are added, in ice-water bath
Under the conditions of be added dropwise 3.6g methylsufonyl chlorides, and 25 DEG C at stir 6h.Reaction terminates, plus 100ml washings, point liquid, anhydrous sodium sulfate
Organic phase is dried, is spin-dried for, obtains 16g intermediate C, yield：88%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
4.365 (t, J=4.0Hz, 2H)；3.768~3.655 (m, 44H)；3.372 (t, J=4.8Hz, 2H)；3.078 (s, 3H).
(4) the 16g intermediates C that step (3) is obtained is added in 100mlDMF, 4g thioacetic acids is added, in ice-water bath bar
Under part, 7.2g potassium carbonate is added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 300ml water, is extracted with 300ml dichloromethane
Take, anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, then obtain 13g intermediate D, yield by column chromatographic isolation and purification：
85%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.675~3.591 (m, 44H)；3.392 (t, J=4.8Hz,
2H)；3.104 (t, J=4.8Hz, 2H)；2.317 (s, 3H).
(5) the 13g intermediates D that step (4) is obtained is added in 100ml methanol, adds 2.5g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 100ml water, is extracted with 200ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 10g intermediate Es, yield are obtained by column chromatographic isolation and purification：86%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.691~3.566 (m, 46H)；3.095 (t, J=4.8Hz, 2H)；1.663 (t, J=4.0Hz, 1H).
(6) the 10g intermediate Es for obtaining step (5) are added in 100ml tetrahydrofurans, and under ice bath, 0.44g is added portionwise
Lithium aluminium hydride reduction, and 3h is stirred at room temperature.Reaction terminates, and adds 0.5ml water, and 35% sodium hydroxide solution, suction filtration is spin-dried for filtrate, so
Afterwards 8.5g finished products, yield are obtained by column chromatographic isolation and purification：92%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.667~3.536 (m, 44H)；2.802 (t, J=4.8Hz, 2H)；2.677 (t, J=4.0Hz, 2H)；2.105
(s, 2H)；1.601 (t, J=4.0Hz, 1H).
Embodiment 8
(1) by the glycol of 10g 20,1.7g triethylamines are added in 100ml dichloromethane, stirring, weigh 1.7g to toluene
Sulfonic acid chloride is dissolved in 150ml dichloromethane, is added dropwise under the conditions of ice-water bath in reaction system, and drop finishes, and 12h is reacted at 25 DEG C.TLC
Display reaction terminates, plus 100ml washings, point liquid, and anhydrous sodium sulfate drying organic phase is spin-dried for, then pure by column chromatography for separation
Change obtains 8g intermediate As, yield：92%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：7.791 (d, J=
8.4Hz, 2H)；7.340 (d, J=8.4Hz, 2H)；4.155 (t, J=4.4Hz, 2H)；3.722~3.583 (m, 78H)；2.812
(s, 1H)；2.430 (s, 3H).
(2) the 8g intermediate As for obtaining step (1) are added in 100ml ethanol, are added 0.75g sodium azide, are warming up to 80
DEG C, stir 10h.Reaction terminates, and is cooled to room temperature, adds 80ml water, is extracted with 150ml dichloromethane, anhydrous sodium sulfate drying
Dichloromethane phase, is spin-dried for, and obtains 6.3g intermediate Bs, yield：96%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：
3.715~3.522 (m, 78H)；3.323 (t, J=4.8Hz, 2H)；3.021 (s, 1H).
(3) the 6.3g intermediate Bs for obtaining step (2) are added in 100ml dichloromethane, 1.0g triethylamines are added, in ice
0.85g methylsufonyl chlorides are added dropwise under water bath condition, and in stirring 6h at 25 DEG C.Reaction terminates, plus 100ml washings, and point liquid is anhydrous
Sodium sulphate dries organic phase, is spin-dried for, obtains 6.1g intermediate C, yield：90%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：4.365 (t, J=4.0Hz, 2H)；3.759~3.635 (m, 76H)；3.385 (t, J=4.8Hz, 2H)；3.102
(s, 3H).
(4) the 6.1g intermediates C that step (3) is obtained is added in 50mlDMF, 0.9g thioacetic acids is added, in ice-water bath
Under the conditions of, 1.7g potassium carbonate is added portionwise, and 12h is stirred at room temperature.Reaction terminates, and adds 200ml water, uses 150ml dichloromethane
Extraction, anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, and then obtains 5g intermediate D, yield by column chromatographic isolation and purification：
95%.Nuclear magnetic data is as follows：1HNMR (400MHz, CDCl3)：δ：3.665~3.574 (m, 76H)；3.388 (t, J=4.8Hz,
2H)；3.112 (t, J=4.8Hz, 2H)；2.310 (s, 3H).
(5) the 5g intermediates D that step (4) is obtained is added in 50ml methanol, adds 0.55g sodium methoxides, and be stirred at room temperature
12h.Reaction terminates, and adds 30ml water, is extracted with 100ml dichloromethane, and anhydrous sodium sulfate drying dichloromethane phase is spin-dried for, so
Afterwards 4.5g intermediate Es, yield are obtained by column chromatographic isolation and purification：96%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.692~3.569 (m, 78H)；3.091 (t, J=4.8Hz, 2H)；1.665 (t, J=4.0Hz, 1H).
(6) the 4.5g intermediate Es for obtaining step (5) are added in 150ml tetrahydrofurans, and under ice bath, 0.16g is added portionwise
Lithium aluminium hydride reduction, and 3h is stirred at room temperature.Reaction terminates, and adds 0.2ml water, and 35% sodium hydroxide solution, suction filtration is spin-dried for filtrate, so
Afterwards 4.1g finished products, yield are obtained by column chromatographic isolation and purification：98%.Nuclear magnetic data is as follows：1HNMR (400MHz,
CDCl3)：δ：3.656~3.536 (m, 76H)；2.803 (t, J=4.8Hz, 2H)；2.669 (t, J=4.0Hz, 2H)；2.101
(s, 2H)；1.589 (t, J=4.0Hz, 1H).
Claims (13)
1. a kind of end mercapto-polyglycol amino, it is characterised in that the end mercapto-polyglycol amino derives for small molecule PEG
Thing, its molecular formula is：
Wherein n is 1-24 integer.
2. prepare the method for end mercapto-polyglycol amino as claimed in claim 1, it is characterised in that comprise the following steps：
1) by monodispersed small molecule PEG and the first alkali soluble in the first organic solvent, RCl solution is then added dropwise, during reaction is obtained
Mesosome A：2) by step 1) obtained intermediate A is dissolved in the second organic solvent, adds Azide
Sodium, reaction obtains intermediate B：3) by step 2) obtained intermediate B is dissolved in the 3rd organic solvent
In, methylsufonyl chloride is added, reaction obtains intermediate C：4) by step 3) obtained intermediate C is molten
In the 4th organic solvent, thioacetic acid and the second alkali are added, reaction obtains intermediate D：5) will
Step 4) obtained intermediate D is dissolved in the 5th organic solvent, adds sodium methoxide, reaction obtains intermediate E：6) by step 5) obtained intermediate E is dissolved in the 6th organic solvent, adds reducing agent, reacted
Full post processing obtains finished product：Wherein PEG molecular formula is：Its
Middle n is 1-24 integer, and R is one kind in methanesulfonic acid base, p-methyl benzenesulfonic acid base, p-nitrophenyl sulfonic group.
3. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
1) the first alkali in is one kind in triethylamine, sodium hydroxide, pyridine.
4. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
1) the first organic solvent in is one kind in tetrahydrofuran, dichloromethane, dioxane.
5. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
1) it in reaction temperature is 20 DEG C -30 DEG C to be by the small molecule PEG courses of reaction that intermediate A is made in, and time of reaction is 10-
Carried out under conditions of 12h.
6. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
2) the second organic solvent in is one kind in DMF, ethanol.
7. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
3) the 3rd organic solvent in is one kind in tetrahydrofuran, dichloromethane, dioxane.
8. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
3) it in temperature is 20 DEG C -25 DEG C to be, time of reaction is to carry out under conditions of 10-12h.
9. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
4) the 4th organic solvent in is one kind in acetone, tetrahydrofuran, DMF.
10. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
It is rapid 4) in the second alkali be lithium carbonate, potassium carbonate, sodium carbonate in one kind.
11. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
It is rapid 5) in the 5th organic solvent be methanol, ethanol in one kind.
12. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
It is rapid 6) in the 6th organic solvent be tetrahydrofuran, dichloromethane, dioxane in one kind.
13. a kind of preparation method of end mercapto-polyglycol amino according to claim 2, it is characterised in that the step
It is rapid 6) in reducing agent be lithium aluminium hydride reduction, sodium borohydride, triphenylphosphine in one kind.
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