CN115197093A - Synthesis method of dendritic monodisperse poly (ethylene glycol) amine derivative - Google Patents
Synthesis method of dendritic monodisperse poly (ethylene glycol) amine derivative Download PDFInfo
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- CN115197093A CN115197093A CN202211052233.7A CN202211052233A CN115197093A CN 115197093 A CN115197093 A CN 115197093A CN 202211052233 A CN202211052233 A CN 202211052233A CN 115197093 A CN115197093 A CN 115197093A
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Abstract
The invention discloses a synthesis method of a dendritic monodisperse poly (ethylene glycol) amine derivative, which takes water as a solvent and ammonium iodide as an additive, and the poly (ethylene glycol) amine and unilaterally substituted poly (ethylene glycol) are added into dichloro (pentamethylcyclopentadienyl) iridium (III) dimer ([ Cp. IrCl) 2 ] 2 ) The dendritic monodisperse poly (ethylene glycol) amine derivative is prepared by a one-pot method through hydrogen-assisted reaction under the catalytic action of the catalyst, hectogram preparation is realized, the reaction route is short, three wastes are less, the catalyst can be recycled, the purification process is simple, the synthesis cost is greatly reduced, and the method is an economic, efficient and environment-friendly synthesis method.
Description
Technical Field
The invention belongs to the technical field of synthesis of dendritic polyethylene glycol, and particularly relates to a method for synthesizing dendritic monodisperse polyethylene glycol.
Background
Polyethylene glycol (PEG), as an inert, non-carcinogenic polymer, is one of the first polymers to modify the surface of bioactive molecules and nanoparticles. Dendritic monodisperse polyethylene glycols (dendritic PEGs) are a class of multi-branched polyethylene glycol reagents, typically having 2 to 4 branches. The nano-particle modified nano-particle can enhance the solubility of hydrophobic drugs, proteins, nucleic acids and liposomes, improve the stability and prolong the circulation time, is widely applied to the fields of connection of macromolecules and surfaces, targeting of drugs and liposomes, functionalization of nano-particles and the like, and is a more and more important connecting agent. One end of the dendritic monodisperse polyethylene glycol is connected with the target gene, and the other end of the dendritic monodisperse polyethylene glycol is connected with the therapeutic agent, so that the circulation time of the drug in vivo can be prolonged, the administration frequency can be reduced, the target treatment of the drug can be realized, and the potential for improving the drug effect can be realized. The main advantages of this dendritic monodisperse polyethylene glycol are: (1) Compared with natural polyethylene glycol main chains, the dendritic monodisperse polyethylene glycol has minimal structural disturbance and can be used for material science, nanochemistry or biological coupling. (2) The dendritic monodisperse polyethylene glycol is beneficial to molecular cutting and can selectively carry out coupling reaction, so that the biomedical material with clear and controllable structure can be obtained, and some special application requirements are met. (3) The dendritic monodisperse polyethylene glycol can prolong the internal circulation, reduce the administration frequency of patients and attach the medicine to a target part.
The existing reports prove that the dendritic monodisperse poly (ethylene glycol) amine can be simultaneously connected with a targeted drug to realize the effect of targeted therapy, so that the dendritic monodisperse poly (ethylene glycol) amine as a polymer with scientific research value and practical value has a wide application prospect in the aspects of organic synthesis, polymer synthesis, polypeptide synthesis, sustained and controlled release of drugs, targeted drug release and the like, and a variety of derivatives, which are collectively called dendritic monodisperse poly (ethylene glycol) amine derivatives, have been generated in the research and exploration of the structure and the applicability of the polymer. Common commercially valuable dendritic monodisperse polyglycolylamine derivatives are the following:
in recent years, researchers have focused on attaching different biologically active moieties to a single dendritic monodisperse poly (ethylene glycol amine) such that the targeting group and therapeutic agent are simultaneously attached to the dendritic monodisperse poly (ethylene glycol amine). For example, the modification of both ends of the dendritic monodisperse poly (ethyleneglycolamine) with an azido (N) 3 -PEG-NH-PEG-N 3 ) And an active group such as a tert-butoxycarbonyl group (COOtBu), an amino group, and a carboxyl group. Azides not only have important physiological activities such as Azidonucleoside (AZT) which is the first choice drug for the treatment of AIDS, but also have a broad range of reactivity such as reduced amino groups,With alkynes 1,3-dipolar cycloaddition reactions can take place. The terminal nitrogen-based polymer obtained by reduction of terminal azido groups plays an important role in polypeptide liquid phase synthesis as a high molecular carrier; active groups such as carboxyl, amino and the like can be connected with protein and polypeptide, so that the molecular size of the polypeptide is improved, the water solubility is increased, the characteristics of the polypeptide are optimized, and the main biological activity of the polypeptide can be retained.
The general synthetic route for obtaining dendritic monodisperse polyethylene glycol amine derivatives is shown below:
route 1:
route 2:
route 3:
route 4:
route 5:
route 6:
as indicated above, the literature methods for synthesizing dendrimeric monodisperse poly (ethylene glycol amine) derivatives require conversion of the hydroxyl group to an aldehyde followed by reductive amination, or to a suitable leaving group such as-Br, or-OTs, followed by nucleophilic substitution with an amino group. The reaction steps are long, and each step of reaction needs stoichiometric reagents, so the cost is high, liquid and solid wastes are more, and the environmental pollution is large. Therefore, the development of a new synthesis process of the dendritic monodisperse poly (ethylene glycol) amine derivative, which has the advantages of low cost, short route, single reaction product, simple purification method, high yield and purity meeting the requirements of commercial products, has potential commercial value.
Disclosure of Invention
The invention aims to provide an economical, environment-friendly and efficient method for synthesizing dendritic monodisperse poly (ethylene glycol) amine derivatives.
Aiming at the purposes, the technical scheme adopted by the invention is as follows: using water as solvent and dichloro (pentamethylcyclopentadienyl) iridium (III) dimer ([ Cp IrCl) 2 ] 2 ) Taking ammonium iodide as an additive as a catalyst, carrying out a hydrogen-assisted reaction on the compound 1 and the compound 2 at a temperature of between 80 and 100 ℃, and separating and purifying after the reaction is finished to obtain a compound 3 or a compound 4, namely the dendritic monodisperse poly (ethylene glycol) amine derivative; the reaction equation is as follows:
in the formula, R 1 、R 2 Each independently represents N 3 M and n are independent integers of 1-50.
In the synthesis method, when the molar ratio of the compound 1 to the compound 2 is 1:1-1.2, the compound 3 can be prepared; when the molar ratio of the compound 1 to the compound 2 is 1:2-2.4, the compound 4 can be prepared.
In the above synthesis method, the molar ratio of the compound 1 to ammonium iodide is preferably 1.
In the above synthesis method, the molar ratio of the compound 1 to dichloro (pentamethylcyclopentadienyl) iridium (III) dimer is preferably 1.
In the above synthesis method, the reaction time with hydrogen is more preferably 20 to 24 hours.
The invention has the following beneficial effects:
the invention uses dichloro (pentamethylcyclopentadienyl) iridium (III) dimer ([ Cp IrCl) 2 ] 2 ) The method is characterized in that ammonium iodide is used as an additive, polyethylene glycol amine and unilaterally substituted polyethylene glycol are used as raw materials, and a one-pot method is adopted to prepare the dendritic monodisperse secondary polyethylene glycol amine or tertiary polyethylene glycol amine derivative through a hydrogen-assisted reaction. The metallic iridium (Ir) in the catalyst is used for obtaining hydrogen from the hydroxyl of the raw material to form [ IrH]Or [ IrH2 ]]An intermediate, while converting the substrate with hydroxyl group into an active substrate; then, the active substrate is condensed by dehydration to form an active intermediate, and finally, [ IrH ]]Or [ IrH2 ]]And returning one molecule of hydrogen to the active intermediate, and reducing the active intermediate to generate the target product.
The invention realizes hectogram preparation, has short reaction route, uses ammonium iodide as an additive, effectively improves the catalytic efficiency, has the product yield of over 80 percent, can recycle the catalyst, has low price of raw materials, greatly reduces the synthesis cost of the dendritic monodisperse poly (ethylene glycol) amine derivative, can purify the waste water generated by the reaction through distillation, does not need complicated separation process of the product after the reaction, has environment-friendly reaction and low cost, is an atom-economic and environment-friendly synthesis method, and is suitable for industrial production. The reaction has the advantages of mild reaction conditions, low requirements on equipment and the like, and more importantly, a hydrogen catalysis system relates to a metal complex or stable metal particles, wherein the dissociation and recombination of hydrogen are extremely simple and do not need strict reaction conditions, so the reaction has wide application prospects in scientific research and industrial production.
Drawings
FIG. 1 is a scheme for synthesizing Compound 3-1 of example 1 1 H NMR nuclear magnetic spectrum.
FIG. 2 is a diagram of Compound 3-2 synthesized in example 2 1 H NMR nuclear magnetic spectrum.
FIG. 3 is the compound synthesized in example 33-3 of 1 H NMR nuclear magnetic spectrum.
FIG. 4 is a scheme for synthesizing Compound 3-2 of example 4 1 H NMR nuclear magnetic spectrum.
FIG. 5 is a scheme showing the synthesis of Compound 4-1 of example 5 1 H NMR nuclear magnetic spectrum.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
1.00g (4.60 mmol) of Compound 1-1 was dissolved in 50mL of water, and 1.21g (5.50 mmol) of Compound 2-1, 0.07g (0.46 mmol) of ammonium iodide and 0.04g (0.05 mmol) of catalyst [ Cp. Multidot.IrCl ] were added 2 ] 2 The reaction was stirred at 100 ℃ for 24h. After the reaction is finished, adding 25mL of ethyl acetate into the reaction liquid for extraction, combining organic phases, decompressing and evaporating the ethyl acetate to obtain a light yellow oily liquid compound 3-1, wherein the yield is 85%, and the structural characterization data is as follows: 1 H NMR(600MHz,CDCl 3 δ ppm): 3.62-3.52 (m, 24H), 3.32 (t, J =6.0,4H), 2.75 (t, J =12.0,4H), see fig. 1.
Example 2
3.00g (10.82 mmol) of Compound 1-2 was dissolved in 50mL of water, and 2.85g (12.98 mmol) of Compound 2-1, 0.16g (1.08 mmol) of ammonium iodide and 0.09g (0.11 mmol) of catalyst [ Cp. Multidot.IrCl ] were added 2 ] 2 The reaction was stirred at 100 ℃ for 24h. After the reaction is finished, adding 25mL of ethyl acetate into the reaction liquid for extraction, combining organic phases, and evaporating the ethyl acetate under reduced pressure to obtain a light yellow oily liquid compound 3-2, wherein the yield is 86%, and the structural characterization data are as follows: 1 HNMR(600MHz,CDCl 3 ,δppm)：3.71-3.61(m,24H),3.39(t,J＝12.0,2H),2.84(t,J＝12.0,4H),2.50(t,J＝12.0,2H),144 (s, 9H), see FIG. 2.
Example 3
3.00g (17.22 mmol) of Compound 1-3 was dissolved in 50mL of water, and 4.53g (20.67 mmol) of Compound 2-1, 0.25g (1.72 mmol) of ammonium iodide and 0.14g (0.17 mmol) of catalyst [ Cp. Multidot. IrCl ] were added 2 ] 2 The reaction was stirred at 100 ℃ for 24h. After the reaction is finished, adding 25mL of ethyl acetate into the reaction liquid for extraction, combining organic phases, decompressing and evaporating the ethyl acetate to obtain a light yellow oily liquid compound 3-3, wherein the yield is 83%, and the structural characterization data is as follows: 1 H NMR(400MHz,CDCl 3 δ ppm): 3.68-3.57 (m, 20H), 3.38 (t, J =12.0,4H), 2.81 (m, J =12.0,4H), see fig. 3.
Example 4
100.00g (0.36 mol) of Compound 1-2 was dissolved in 300mL of water, and 94.85g (0.43 mol) of Compound 2-1, 5.22g (0.04 mol) of ammonium iodide and 2.87g (0.004 mol) of catalyst [ Cp IrCl ] were added 2 ] 2 The reaction was stirred at 100 ℃ for 24h. After the reaction is finished, adding 100mL of ethyl acetate into the reaction liquid for extraction, combining organic phases, and evaporating the ethyl acetate under reduced pressure to obtain a light yellow oily liquid compound 3-2, wherein the yield is 82%, and the structural characterization data is as follows: 1 H NMR(600MHz,CDCl 3 δ ppm): 3.71-3.61 (m, 24H), 3.39 (t, J =12.0,2H), 2.84 (t, J =12.0,4H), 2.50 (t, J =12.0,2H), 1.44 (s, 9H), see fig. 4.
Example 5
3.00g (13.75 mmol) of the compound 1-4 was dissolved in 50mL of water, and 8.42g (30.24 mmol) of the compound 2-2, 0.20g (1.37 mmol) of ammonium iodide and 0.11g (0.14 mmol) of the catalyst were addedAgent [ Cp IrCl 2 ] 2 The reaction was stirred at 100 ℃ for 24h. After the reaction is finished, adding 25mL of ethyl acetate into the reaction liquid for extraction, combining organic phases, decompressing and evaporating the ethyl acetate to obtain a light yellow oily liquid compound 4-1, wherein the yield is 80%, and the structural characterization data is as follows: 1 H NMR(600MHz,CDCl 3 δ ppm): 3.45-3.32 (m, 30H), 3.46 (s, 6H), 3.32 (s, 2H), 2.70 (s, 6H), 2.43-2.42 (t, J =6.0,4H), 1.38 (s, 18H), see fig. 5.
Claims (5)
1. A method for synthesizing a dendritic monodisperse poly (ethylene glycol) amine derivative is characterized in that: taking water as a solvent, dichloro (pentamethylcyclopentadienyl) iridium (III) dimer as a catalyst and ammonium iodide as an additive, carrying out a hydrogen-assisted reaction on a compound 1 and a compound 2 at a temperature of between 80 and 100 ℃, and separating and purifying after the reaction is finished to obtain a compound 3 or a compound 4, namely a dendritic monodisperse polyethylene glycol amine derivative;
in the formula, R 1 、R 2 Each independently represents N 3 M and n are independent integers of 1-50.
2. The method of synthesizing a dendritic monodisperse poly (ethylene glycol amine) derivative of claim 1, wherein: when the molar ratio of the compound 1 to the compound 2 is 1:1-1.2, the compound 3 is obtained; when the molar ratio of the compound 1 to the compound 2 is 1:2-2.4, the compound 4 is obtained.
3. The method of synthesizing a dendritic monodisperse poly (ethylene glycol amine) derivative of claim 1, wherein: the molar ratio of the compound 1 to dichloro (pentamethylcyclopentadienyl) iridium (III) dimer is 1.
4. The method of synthesizing a dendritic monodisperse poly (ethylene glycol amine) derivative of claim 1, wherein: the molar ratio of the compound 1 to the ammonium iodide is 1.
5. The method of synthesizing a dendritic monodisperse poly (ethylene glycol amine) derivative of claim 1, wherein: the reaction time by hydrogen is 20 to 24 hours.
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