CN107141226A - The method that six arm initiators or eight arm initiators are synthesized based on 1,3 2 [three (methylol) methylaminos] propane - Google Patents

The method that six arm initiators or eight arm initiators are synthesized based on 1,3 2 [three (methylol) methylaminos] propane Download PDF

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Publication number
CN107141226A
CN107141226A CN201710451362.6A CN201710451362A CN107141226A CN 107141226 A CN107141226 A CN 107141226A CN 201710451362 A CN201710451362 A CN 201710451362A CN 107141226 A CN107141226 A CN 107141226A
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China
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propane
reaction
methylol
bis
aqueous solution
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CN201710451362.6A
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Chinese (zh)
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李钟玉
王禄胜
卢成洁
卢稳
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温州大学
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Priority to CN201710451362.6A priority Critical patent/CN107141226A/en
Publication of CN107141226A publication Critical patent/CN107141226A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins

Abstract

The invention discloses the invention discloses based on 1, the method that 3 two [three (methylol) methylaminos] propane synthesize six arm initiators or eight arm initiators, using BIS TRIS propane and bromoethane as raw material, add water mixing, temperature 60 C reaction 4h is controlled, reaction system is cooled to room temperature, NaOH solution is added dropwise, 60 DEG C are warming up to after dripping off, continues to react 60h.The mol ratio of BIS TRIS propane and bromoethane is 1:2.0~2.2.Mixture is boiling off water with Rotary Evaporators heating after the completion of reaction, is extracted with absolute ethyl alcohol, n-butanol recrystallization obtains the arm new initiator of product 6.Using BIS TRIS propane and bromoethanol as raw material, added water mixing, control temperature 60 C reaction 4h, and reaction system is cooled into room temperature, NaOH solution is added dropwise, 48 DEG C are warming up to after dripping off, continues to react 60h.Mixture is boiling off water with Rotary Evaporators heating after the completion of reaction, is extracted with absolute ethyl alcohol, n-butanol recrystallization obtains the arm new initiator of product 8.This method equipment requirement is simple, and raw material is saved, and cost is low, efficiency high, is adapted to industrialized production, and the yield of product is higher than 90%, purity more than 98%.

Description

Six arm initiators or eight arms are synthesized based on 1,3- bis- [three (methylol) methylaminos] propane The method of initiator

Technical field

The invention belongs to organic chemical synthesis field, specifically refer to close based on 1,3- bis- [three (methylol) methylaminos] propane Into the method for six arm initiators or eight arm initiators.

Background technology

In recent years, with pharmaceutical grade protein polyethyleneglycol modified technology development, pegylated medicament obtained extensively General application.More than ten are had at present plants polyethyleneglycol modified protein drug listing, clinical treatment excellent effect, in the market also table Good achievement is revealed.Also tens of kinds pegylated protein medicines are in the clinical or preclinical study stage simultaneously. Therefore, demand more and more higher is synthesized for polyethylene glycol, and then causes the demand of initiator for synthesizing polyethylene glycol continuous Improve.

Initiator English is initiator, also known as radical initiator, refers to a class and is easily thermally decomposed into free radical (i.e. Primary group of free radicals) compound, available for triggering alkenes, the radical polymerization of double vinyl monomers and copolymerization, it is also possible to Reacted in the crosslinking curing and high molecular crosslink of unsaturated polyester (UP).

BIS-TRIS propane (BIS-TRIS-PROPANE) is 1,3- bis- [three (methylol) methylaminos] propane, is a kind ofization Organic matter is learned, white crystalline powder state can be used in biochemical diagnosis kit and make biological buffer, molecular formula is C11H26N2O6, molecular weight is 282.33.In the prior art, BIS-TRIS propane common-use words biological buffer, and used in biochemistry In diagnostic kit, DNA/RNA extracts kits and PCR diagnostic kits.

Initiator is synthesized by BIS-TRIS propane, report is had no in the prior art.

The content of the invention

Technical problem to be solved of the embodiment of the present invention is to be based on [three (methylol) the first ammonia of 1,3- bis- there is provided one kind Base] propane synthesize six arm initiators method.

Third object of the present invention is to provide a kind of based on 1,3- bis- [three (methylol) methylaminos] propane eight arms of synthesis The method of initiator.

To realize first goal of the invention of the present invention, the technical scheme is that with [three (methylol) first of 1,3- bis- Amino] propane and bromoethane be raw material, add water mixing, and 1,3- bis- [three (methylol) methylaminos] propane and bromoethane rub You are than being 1:2.0~2.2, control temperature 60 C reaction, system after 3-5h of reacting is cooled to room temperature, and configuration concentration is 5mol/L's The NaOH aqueous solution, the cumulative volume of the NaOH aqueous solution is with NaOH therein and 1,3- bis- [three (methylol) methylaminos] propane Mol ratio is 2.0~2.2:1 is calculated, and the NaOH aqueous solution of half volume is added drop-wise in reaction system, anti-at 60 DEG C after adding Answer 3-5 hours, be cooled to room temperature, then the NaOH aqueous solution of second half volume is added dropwise, reacted 45-50 hours at 60 DEG C after adding, Mixture is boiling off water with Rotary Evaporators heating after the completion of reaction, plus absolute ethyl alcohol heating makes thick liquid all dissolving, mistake NaCl is filtered out, ethanol is removed in filtrate decompression distillation, and oily thick liquid adds n-butanol, and heating makes thick liquid all dissolvings, Solid is separated out after cooling, suction filtration is depressurized, solid is washed with ethyl acetate, then is dried in vacuo, and obtains the arm initiator of product six, reaction Equation is as follows:

To realize second object of the present invention, the technical scheme is that a kind of be based on [three (methylols) of 1,3- bis- Methylamino] the propane method that synthesizes eight arm initiators, with [three (methylol) methylaminos] propane of 1,3- bis- and bromoethanol for raw material, Add water mixing, and the mol ratio of 1,3- bis- [three (methylol) methylaminos] propane and bromoethanol is 1:2.1~2.3, control temperature System is cooled to room temperature after 60 DEG C of reactions of degree, reaction 3-5h, and configuration concentration is the 5mol/L NaOH aqueous solution, and the NaOH is water-soluble The cumulative volume of liquid is using the mol ratio of NaOH therein and 1,3- bis- [three (methylol) methylaminos] propane as 2.0~2.2:1 calculates, The NaOH aqueous solution of half volume is added drop-wise in reaction system, is reacted 3-5 hours at 60 DEG C after adding, is cooled to room temperature, then Second half the NaOH aqueous solution is added dropwise, is reacted 45-50 hours at 60 DEG C after adding, mixture steams with rotation after the completion of reaction Hair instrument heating boils off water, plus n-butanol heating makes thick liquid all dissolvings, is filtered to remove NaCl, and positive fourth is gone in filtrate decompression distillation Alcohol, solid is washed with ethyl acetate, then is dried in vacuo, and obtains the arm initiator of product eight, and reaction equation is as follows:

It is an advantage of the invention that:

This method equipment requirement is simple, and raw material is saved, and cost is low, efficiency high, is adapted to industrialized production, and the yield of product is higher than 90%, purity more than 98%.

Embodiment

To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with embodiment to this hair It is bright to be described in further detail.

Embodiment 1:

28.23g (0.1mol) is added in the three-necked bottle equipped with condenser pipeBIS-TRIS propane, 20g water, 24.6g bromines third Alkane, after temperature 60 C stirring reaction 4 hours, reaction system is down to room temperature.At room temperature, the 21gNaOH aqueous solution is slowly added dropwise (concentration is about 5mol/L), reacts 4 hours at 60 DEG C, is cooled to room temperature again after adding, and the 21gNaOH aqueous solution is slowly added dropwise (dense Degree is about 5mol/L), then reacted 48 hours at 60 DEG C.

Rotary Evaporators heating boils off water, adds 100ml ethanol, and heating makes thick liquid all dissolvings, is filtered to remove NaCl, filtrate decompression boils off ethanol, and oily thick liquid adds 100ml n-butanols, and viscous liquid all dissolvings are made under heating, It is cold go after separate out solid, depressurize suction filtration, solid is washed with ethyl acetate, then is dried in vacuo, and obtains product.N-butanol mother liquor is boiled off N-butanol is recrystallized to give product again.Product after testing, yield 90.1%, purity 98.8%.

Embodiment 2:

28.23g (0.1mol) is added in the three-necked bottle equipped with condenser pipeBIS-TRIS propane, 20g water, 27.80g bromines Propyl alcohol, after temperature 60 C stirring reaction 4 hours, reaction system is down to room temperature.At room temperature, 21gNaOH is slowly added dropwise water-soluble Liquid (concentration is about 5mol/L), reacts 4 hours at 60 DEG C, is cooled to room temperature again after adding, and the 21gNaOH aqueous solution is slowly added dropwise (concentration is about 5mol/L), then reacted 48 hours at 60 DEG C.

Rotary Evaporators heating boils off water, adds 100ml n-butanols, and heating makes thick liquid all dissolvings, is filtered to remove NaCl, filtrate is cold go after separate out solid, depressurize suction filtration, solid is washed with ethyl acetate, then is dried in vacuo, and obtains product.Positive fourth Alcohol mother liquor boils off n-butanol and is recrystallized to give product again.Product after testing, yield 90.5%, purity 99.1%.

Embodiment 3:

28.23g (0.1mol) is added in the three-necked bottle equipped with condenser pipeBIS-TRIS propane, 20g water, 27.06g bromines Propane, after temperature 60 C stirring reaction 4 hours, reaction system is down to room temperature.At room temperature, 21gNaOH is slowly added dropwise water-soluble Liquid (concentration is about 5mol/L), reacts 4 hours at 60 DEG C, is cooled to room temperature again after adding, and the 21gNaOH aqueous solution is slowly added dropwise (concentration is about 5mol/L), then reacted 48 hours at 60 DEG C.

Rotary Evaporators heating boils off water, adds 100ml ethanol, and heating makes thick liquid all dissolvings, is filtered to remove NaCl, filtrate decompression boils off ethanol, and oily thick liquid adds 100ml n-butanols, and viscous liquid all dissolvings are made under heating, It is cold go after separate out solid, depressurize suction filtration, solid is washed with ethyl acetate, then is dried in vacuo, and obtains product.N-butanol mother liquor is boiled off N-butanol is recrystallized to give product again.Product after testing, yield 91.1%, purity 99.2%.

Embodiment 4:

28.23g (0.1mol) is added in the three-necked bottle equipped with condenser pipeBIS-TRIS propane, 20g water, 30.57g bromines Propyl alcohol, after temperature 60 C stirring reaction 4 hours, reaction system is down to room temperature.At room temperature, 21gNaOH is slowly added dropwise water-soluble Liquid (concentration is about 5mol/L), reacts 4 hours at 60 DEG C, is cooled to room temperature again after adding, and the 21gNaOH aqueous solution is slowly added dropwise (concentration is about 5mol/L), then reacted 48 hours at 60 DEG C.

Rotary Evaporators heating boils off water, adds 100ml n-butanols, and heating makes thick liquid all dissolvings, is filtered to remove NaCl, filtrate is cold go after separate out solid, depressurize suction filtration, solid is washed with ethyl acetate, then is dried in vacuo, and obtains product.Positive fourth Alcohol mother liquor boils off n-butanol and is recrystallized to give product again.Product after testing, yield 90.8%, purity 98.9%.

Embodiment 5:

14.12g (0.05mol) is added in the three-necked bottle equipped with condenser pipeBIS-TRIS propane, 10g water, 12.31g bromines Propane, after temperature 60 C stirring reaction 4 hours, reaction system is down to room temperature.At room temperature, 11gNaOH is slowly added dropwise water-soluble Liquid (concentration is about 5mol/L), reacts 4 hours at 60 DEG C, is cooled to room temperature again after adding, and the 11gNaOH aqueous solution is slowly added dropwise (concentration is about 5mol/L), then reacted 48 hours at 60 DEG C.

Rotary Evaporators heating boils off water, adds 50ml ethanol, and heating makes thick liquid all dissolvings, is filtered to remove NaCl, filtrate decompression boils off ethanol, and oily thick liquid adds 50ml n-butanols, and viscous liquid all dissolvings are made under heating, It is cold go after separate out solid, depressurize suction filtration, solid is washed with ethyl acetate, then is dried in vacuo, and obtains product.N-butanol mother liquor is boiled off N-butanol is recrystallized to give product again.Product after testing, yield 90.5%, purity 98.5%.

Embodiment 6:

14.12g (0.05mol) is added in the three-necked bottle equipped with condenser pipeBIS-TRIS propane, 10g water, 13.92g bromines Propyl alcohol, after temperature 60 C stirring reaction 4 hours, reaction system is down to room temperature.At room temperature, 11gNaOH is slowly added dropwise water-soluble Liquid (concentration is about 5mol/L), reacts 4 hours at 60 DEG C, is cooled to room temperature again after adding, and the 11gNaOH aqueous solution is slowly added dropwise (concentration is about 5mol/L), then reacted 48 hours at 60 DEG C.

Rotary Evaporators heating boils off water, adds 50ml n-butanols, and heating makes thick liquid all dissolvings, is filtered to remove NaCl, filtrate is cold go after separate out solid, depressurize suction filtration, solid is washed with ethyl acetate, then is dried in vacuo, and obtains product.Positive fourth Alcohol mother liquor boils off n-butanol and is recrystallized to give product again.Product after testing, yield 90.3%, purity 99.2%.

Above disclosure is only preferred embodiment of present invention, can not limit the right model of the present invention with this certainly Enclose, therefore the equivalent variations made according to the claims in the present invention, still belong to the scope that the present invention is covered.

Claims (2)

1. the method that one kind synthesizes six arm initiators based on 1,3- bis- [three (methylol) methylaminos] propane, it is characterised in that:With 1,3- bis- [three (methylol) methylaminos] propane is raw material with bromoethane, and add water mixing, 1,3- bis- [three (methylol) first ammonia Base] mol ratio of propane and bromoethane is 1:2.0~2.2, control temperature 60 C reaction, system after 3-5h of reacting is cooled to room Temperature, configuration concentration is the 5mol/L NaOH aqueous solution, and the cumulative volume of the NaOH aqueous solution is with NaOH therein and 1,3- bis- [three (methylol) methylamino] propane mol ratio be 2.0~2.2:1 is calculated, and the NaOH aqueous solution of half volume is added drop-wise into reaction In system, reacted 3-5h hours at 60 DEG C after adding, be cooled to room temperature, then the NaOH aqueous solution of second half volume is added dropwise, added Reacted 45-50h hours at 60 DEG C afterwards, mixture is boiling off water with Rotary Evaporators heating after the completion of reaction, plus absolute ethyl alcohol adds Heat makes thick liquid all dissolvings, is filtered to remove NaCl, and ethanol is removed in filtrate decompression distillation, and oily thick liquid adds n-butanol, Heating makes thick liquid all dissolvings, and solid is separated out after cooling, suction filtration is depressurized, solid is washed with ethyl acetate, then is dried in vacuo, The arm initiator of product six is obtained, reaction equation is as follows:
2. the method that one kind synthesizes eight arm initiators based on 1,3- bis- [three (methylol) methylaminos] propane, it is characterised in that:With 1,3- bis- [three (methylol) methylaminos] propane is raw material with bromoethanol, and add water mixing, 1,3- bis- [three (methylol) first ammonia Base] mol ratio of propane and bromoethanol is 1:2.1~2.3, control temperature 60 C reaction, system after 3-5h of reacting is cooled to room Temperature, configuration concentration is the 5mol/L NaOH aqueous solution, and the cumulative volume of the NaOH aqueous solution is with NaOH therein and 1,3- bis- [three (methylol) methylamino] propane mol ratio be 2.0~2.2:1 is calculated, and the NaOH aqueous solution of half volume is added drop-wise into reaction In system, reacted 3-5 hours at 60 DEG C after adding, be cooled to room temperature, then second half the NaOH aqueous solution is added dropwise, 60 after adding DEG C reaction 45-50 hour, mixture is boiling off water with Rotary Evaporators heating after the completion of reaction, plus n-butanol is heated makes viscous fluid Body is all dissolved, and is filtered to remove NaCl, and n-butanol is removed in filtrate decompression distillation, and solid is washed with ethyl acetate, then is dried in vacuo, and is obtained To the arm initiator of product eight, reaction equation is as follows:
CN201710451362.6A 2017-06-15 2017-06-15 The method that six arm initiators or eight arm initiators are synthesized based on 1,3 2 [three (methylol) methylaminos] propane CN107141226A (en)

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Application publication date: 20170908