WO2007149501A2 - Procédé pour préparer des polymères dendritiques à l'aide d'une synthèse assistée par micro-ondes - Google Patents

Procédé pour préparer des polymères dendritiques à l'aide d'une synthèse assistée par micro-ondes Download PDF

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WO2007149501A2
WO2007149501A2 PCT/US2007/014403 US2007014403W WO2007149501A2 WO 2007149501 A2 WO2007149501 A2 WO 2007149501A2 US 2007014403 W US2007014403 W US 2007014403W WO 2007149501 A2 WO2007149501 A2 WO 2007149501A2
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reaction
dendrimer
mixture
polymer
dendritic polymer
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PCT/US2007/014403
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WO2007149501A3 (fr
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Baohua Huang
Douglas R. Swanson
Veera Reddy Pulgam
Donald A. Tomalia
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Dendritic Nano Technologies, Inc.
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Publication of WO2007149501A3 publication Critical patent/WO2007149501A3/fr

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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
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/028—Polyamidoamines
    • 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
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/024—Polyamines containing oxygen in the form of ether bonds in the main chain
    • 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
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/10—Polyimides; Polyester-imides; Polyamide-imides; Polyamide acids or similar polyimide precursors
    • C08G73/1046—Polyimides containing oxygen in the form of ether bonds in the main chain
    • 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
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers

Definitions

  • This invention relates to the synthesis of dendritic polymers using microwave assisted synthesis.
  • Dendrimers are highly branched, often spherical molecules in which branches may terminate at charged amino groups that radiate from a central core molecule. Amine- terminated dendrimers have a high density of positively charged amine groups on the surface, such as with PAMAM dendrimers. Due to controlled chemical synthesis, dendrimers have a very precise size and defined shape.
  • Dendritic polymers have often been thought desirable to make various products because of their unique physical characteristics, such as biocompatibility when desired, interior void space for many such polymers, highly charged surface that is able to be surface modified, solubility features that can be adjusted for the purpose, to name a few.
  • the present process for preparing dendritic polymer structures of the present invention provide the advantages of faster preparation time to make the desired product, easier separations and fewer steps, resulting in greater purity of the final product.
  • MWA processes have been found to lead to products with no or little impurities, at almost stoichiometric compositions of the reactants and can be carried out often in minutes rather than days.
  • the present invention concerns a process for preparing a dendritic polymer which comprises reacting a core (C) with at least one branch cell reagent (BR) and/or an extender using MWA synthesis wherein, compared with prior processes, the amount of (BR) required is not in large excessive amounts, the time of the reaction is greatly reduced, and the purity of the final dendritic polymer is increased. Click chemistry can also be used.
  • Figure 1 shows the comparison of Sample 3 (right lane) and Sample 7 (left lane) from Table 1.
  • Figure 2 shows the TLC for Gl .0-epoxy made by the present process.
  • Figure 3 shows the TLC of the reaction of tetra-azide using stoichiometric amount of NaN3. The left lane is the tetra-azide, and the right lane is the reaction mixture. Compared with the tetra-azide made by adding large excess of NaN 3 at 55 0 C method, the new spot is the desired product.
  • Part (B) is the enlarged indicated portion of Part (A) and
  • Part (D) is the enlarged indicated portion of Part (C).
  • BR or (BR) means a branch cell
  • C or (C) means a core of a dendrimer or dendron Celite means diatomaceous earth (Fisher Scientific)
  • DAB means diaminobutane
  • DETA diethylenetriamine
  • DI water means deionized water
  • DMSO dimethylsulfoxide
  • EDA means ethylenediamine
  • EPON 1031 means l,2,2-tetrakis(4-(oxiran-2-ylmethoxy)phenyl)ethane
  • EX or (EX) means an extender
  • FF or (FF) means a focal point functionality component of a core
  • G means dendrimer generation, which is indicated by the number of concentric branch cell shells surrounding the core (usually counted sequentially from the core)
  • g means gram(s)
  • HPLC means high pressure/performance liquid chromatography
  • IF or (IF) means interior functionality
  • L liter(s)
  • MALDI-TOF matrix-assisted laser desorption ionization time of flight mass spectroscopy
  • MeOH means methanol mg means milligram(s) Mins. means minutes mL means milliliters)
  • MWA microwave assisted
  • NMR nuclear magnetic resonance
  • N-SIS means nanoscale sterically induced stoichiometry
  • PAGE means poly(acrylamide) gel electrophoresis
  • PAMAM means poly(amidoamine), including linear and branched polymers or dendrimers with primary amine terminal groups
  • PEHAM poly(etherhydroxylamine) dendrimer
  • PEI poly(ethyleneimine)
  • PETGE means pentaerythritol tetraglycidyl ether
  • Ph phenyl PIPZ means piperazine
  • POPAM means a PPI core surrounded by PAMAM dendrons
  • PPI poly(propyleneimine)
  • Rf means relative flow in TLC
  • RT ambient temperature or room temperature, about 20-25 0 C
  • SEC size exclusion chromatography
  • THF means tetrahydrofuran
  • TLC means thin layer chromatography
  • TPETGE means tetraphenylolethane tetraglycidyl ether
  • TREN means -m(2-aminoethyl)amine
  • TRIS fr ⁇ (hydroxyrnethyl)aminomethane
  • UV-vis means ultraviolet and visible spectroscopy
  • W means Watt(s)
  • This invention describes an improved synthesis of dendritic polymers. Also this invention describes the improved purity, fewer steps and separations needed to obtain these dendritic polymers.
  • the dendritic polymer structures of the present invention maybe any dendritic polymer, including without limitation, PAMAM dendrimers, PEHAM dendrimers, PEI dendrimers, POPAM dendrimers, PPI dendrimers, polyether dendrimers, dendrigrafts, random hyperbranched dendrimers, polylysine dendritic polymers, arborols, cascade polymers, avidimers or other dendritic architectures.
  • PAMAM dendrimers PEHAM dendrimers
  • PEI dendrimers PEI dendrimers
  • POPAM dendrimers PPI dendrimers
  • polyether dendrimers dendrigrafts
  • random hyperbranched dendrimers random hyperbranched dendrimers
  • polylysine dendritic polymers arborols
  • cascade polymers avidimers or other dendritic architectures.
  • avidimers or other dendritic architectures avidimers or other dendritic architectures.
  • dendritic polymers can be any physical shape, such as for example spheres, rods, tubes, or any other shape possible.
  • the interior structure may have an internal cleavable bond (such as a disulfide) or an internal functionality such as a hydroxide or other group to associate with it.
  • the Dendritic polymer can be a dendron. This dendron can have any dendritic polymer constituents desired.
  • Dendritic Polymers Most of these dendritic polymers have been taught in the literature. See Dendrimers and other Dendritic Polymers, eds. J.M.J. Fr ⁇ chet, D. A. Tomalia, pub. John Wiley and
  • MWA synthesis has exhibited unexpected and dramatic advantages compared to thermal processing. It was observed that MWA produced higher purity dendritic polymer products (i.e., dendrimers/dendrons) under more mild conditions, shorter reaction times (minutes versus days), while requiring only stoichiometric amounts or slight excess of reacting reagents.
  • the dendritic polymer as the starting material or a desired (C) is reacted with a BR or EX to obtain the desired dendritic polymer product.
  • Suitable solvents can be used, including but not limited to methylene chloride, THF, toluene, methanol, diethyl ether, DMF, DMSO, water, and hexane, if the reactant does not also serve as the solvent.
  • the mild conditions, at temperatures in the range of from about -35°C to 200 0 C, for the reaction compared to that of the prior thermal reaction leads to less by-products with fewer steps for purification of the desired dendritic polymer product.
  • the reaction times are significantly reduced compared to the prior thermal process. For example, approximately an 18 fold reduction in reaction time was noted; wherein a thermal process requiring about 3 days or 72 hours was reduced to 4 hours while producing higher quality products by using these microwave techniques. Thus this MWA synthesis is less expensive to run to make the product desired.
  • the various equipment and methods were used to run the various described tests for the results reported in the examples described below.
  • Dendrimers were analyzed qualitatively by the SEC system (Waters 1515) operated in an isocratic mode with refractive index detector (Waters 2400 and Waters 717 Plus Auto Sampler). The analysis was performed at RT on two serially aligned TSK gel columns (Supelco), G3000PW and G2500PW, particle size 10 ⁇ m, 30 cm * 7.5 mm. The mobile phase of acetate buffer (0.5M) was pumped at a flow rate of lmL/min. The elution volume of dendrimer was observed to be 11-16 mL, according to the generation of dendrimer.
  • HPLC High pressure liquid chromatography
  • a Perkin ElmerTM Series 200 apparatus equipped with refractive index and ultraviolet light detectors and a Waters Symmetry Ci 8 (5 ⁇ m) column (4.6 mm diameter, 150 mm length).
  • Thin Layer Chromatography was used to monitor the progress of chemical reactions.
  • One drop of material generally 0.05M to 0.4M solution in organic solvent, is added to a silica gel plate and placed into a solvent chamber and allowed to develop for generally 10- 15 mins. After the solvent has been eluted, the TLC plate is generally dried and then stained (as described below). Because the silica gel is a polar polymer support, less polar molecules will travel farther up the plate.
  • "Rf" value is used to identify how far material has traveled on a TLC plate. Changing solvent conditions will subsequently change the R f value. This Rf is measured by the ratio of the length the product traveled to the length the solvent traveled.
  • TLC plates used were either (1) "Thin Layer Chromatography Plates - Whatman®” PK6F Silica Gel Glass backed, size 20 x 20 cm, layer thickness: 250 ⁇ m or (2) "Thin Layer Chromatography Plate Plastic sheets - EM Science” Alumina backed, Size 20 x 20 cm, layer thickness 200 ⁇ m. Staining conditions were: (1) Ninhydrin: A solution is made with 1.5 g of ninhydrin,
  • Mass spectra were obtained on a Bruker AutoflexTM LRF MALDI-TOF mass spectrometer with Pulsed Ion Extraction. Mass ranges below 20 kDa were acquired in the reflector mode using a 19 kV sample voltage and 20 kV reflector voltage. Polyethylene oxide was used for calibration. Higher mass ranges were acquired in the linear mode using a 20 kV sample voltage. The higher mass ranges were calibrated with bovine serum albumin.
  • samples were prepared by combining a 1 ⁇ L aliquot of a 5 mg/mL solution of the analyte with 10 ⁇ L of matrix solution. Unless otherwise noted, the matrix solution was 10 mg/mL of 2,5-dihydroxybenzoic acid in 3:7 acetonitrile:water. Aliquots (2 ⁇ L) of the sample/matrix solution were spotted on the target plate and allowed to air dry at RT.
  • Dialysis Separation In a typical dialysis experiment about 500 mg of product is dialyzed through a dialysis membrane with an appropriate pore size to retain the product and not the impurities. Dialyses are done in most examples in water (other appropriate dialyzates used were acetone and methanol) for about 21 hours with two changes of dialyzate. Water (or other dialyzate) is evaporated from the retentate on a rotary evaporator and the product dried under high vacuum or lyophilized to give a solid.
  • a typical ultrafiltration separation protocol was as follows: A mixture of product and undesired compounds was dissolved in the appropriate volume of a solvent for this mixture (e.g., 125 mL of MeOH) and ultrafiltered on a tangential flow UF device containing 3K cutoff regenerated cellulose membranes at a pressure of 20 psi (137.9 kPa) at 25°C. The retentate volume as marked in the flask was maintained at 100-125 mL during the UF collection of 1500 mL permeate ( ⁇ 5 hours). The first liter of permeate was stripped of volatiles on a rotary evaporator, followed by high vacuum evacuation to give the purified product.
  • the cut-off size of the membrane e.g., 3K, 2K or IK
  • the volume of permeate and retentate varied.
  • the product is dissolved in the minimum amount of a solvent (water, PBS, or MeOH) and purified through SephadexTM LH-20 (Pharmacia) in the solvent. After eluting the void volume of the column, fractions are collected in about 2-20 mL aliquots, depending on the respective separation concerned. TLC, using an appropriate solvent as described before, is used to identify fractions containing similar product mixtures. Similar fractions are combined and solvent evaporated to give solid product.
  • a solvent water, PBS, or MeOH
  • Sample preparation To 50-100 mg of a dry sample was add 800-900 ⁇ L of a deuterated solvent to dissolve. Typical reference standards are used, i.e., trimethylsilane. Typical solvents are CDCl 3 , CD 3 OD, D 2 O, DMSO-de, and acetone-d ⁇ . The dissolved sample was transferred to an NMR tube to a height of ⁇ 5.5 cm in the tube.
  • 300MHz NMR data were obtained on a 300MHz 2-channel VarianTM Mercury Plus NMR spectrometer system using an Automation Triple Resonance Broadband (ATB) probe, WX (where X is tunable from 15 N to 31 P). Data acquisition was obtained on a Sun BladeTM 150 computer with a SolarisTM 9 operating system. The software used was VTMMR v ⁇ .lC.
  • 500MHz NMR data were obtained on a 500MHz 3-channel VarianTM Inova 500MHz NMR spectrometer system using a Switchable probe, H/X (X is tunable from 15 N to 31 P). Data acquisition was obtained on a Sun BladeTM 150 computer with a SolarisTM 9 operating system.
  • the software used was VNMR v6.1C.
  • Dendrimers that were stored in solvent are dried under vacuum and then dissolved or diluted with water to a concentration about 100 mg in 4 mL of water.
  • the water solution is frozen using dry ice and the sample dried using a lyophilizer (freeze dryer) (LABCONCO Corp. Model number is Free Zone 4.5 Liter, Freeze Dry System 77510) at about -47°C and 60 x 10 "3 mBar.
  • Freeze dried dendrimer (1-2 mg) is diluted with water to a concentration of 1 mg/mL.
  • Tracking dye is added to each dendrimer sample at 10% v/v concentration and includes (1) methylene blue dye (1% w/v) for basic compounds (2) bromophenol blue dye (0.1% w/v) for acid compounds (3) bromophenol blue dye (0.1%w/v) with 0.1% (w/v) SDS for neutral compounds.
  • Pre-cast 4-20% gradient gels were purchased from ISC BioExpress. Gel sizes were 100 mm (W) X 80 mm (H) X 1 mm (Thickness) with ten pre-numbered sample wells formed in the cassette. The volume of the sample well is 50 ⁇ L. Gels not obtained commercially were prepared as 10% homogeneous gels using 30% acrylamide (3.33 mL), 4 X TBE buffer (2.5 mL), water (4.17 mL), 10% APS (100 ⁇ L), TEMED (3.5 ⁇ L).
  • TBE buffer used for gel electrophoresis is prepared using lr/s(hydroxymethyl)aminomethane (43.2 g), boric acid (22.08 g), disodium EDTA (3.68 g) in 1 L of water to form a solution of pH 8.3. The buffer is diluted 1 :4 prior to use.
  • Electrophoresis is done using a PowerPacTM 300 165-5050 power supply and BIO- RADTM Mini Protean 3 Electrophoresis Cells. Prepared dendrimer/dye mixtures (5 ⁇ L each) are loaded into separate sample wells and the electrophoresis experiment run. Dendrimers with amine surfaces are fixed with a glutaraldehyde solutions for about one hour and then stained with Coomassie Blue R-250 (Aldrich) for about one hour. Gels are then destained for about one hour using a glacial acetic acid solution. Images are recorded using an hp ScanJetTM 5470C scanner.
  • UV/Vis Ultraviolet/Visible Spectrometry
  • UV-VIS spectral data were obtained on a Perkin ElmerTM Lambda 2 UV/VIS
  • Spectrophotometer using a light wavelength with high absorption by the respective sample for example 480 or 320 nm.
  • Microwave assisted synthesis was done using a multimode design Milestone ETHOS StartSYTH Labstation with a microwave cavity of 35 x 35 x 35 H cm.
  • the labstation is equipped with dual magnetron system using a pyramid diffuser for a homogeneous microwave distribution in the cavity.
  • the installed power is 1600 Watts
  • the unit contains a built — in ASM — 100 magnetic stirrer. Reactions were run in 12 mL or 50 mL glass tubes fitted with 15 bar pressure relief valves. Larger reactions were run in 100 mL and 250 mL capacity Teflon vessels also fitted with 20 bar pressure relief valves.
  • Propargyl triglycidyl ether ( 2 ) (60 mg, 0.165 mmol) was put in a 10 mL vial equipped with a magnetic stir bar.
  • the tri-azide compound (1) (21 mg, 0.05 mmol) was then added to the vial. Solvent was added, followed by the addition of catalyst.
  • reaction mixtures were stirred well and the reaction vial was put in a 900W domestic microwave and heated for a certain amount of time stated in Table 1 below. Reaction results were checked by TLC immediately after the heating. The TLC ratings are from 0 to 10 (10 is the best result on TLC, but is not meant to mean 100% yield).
  • Figure 1 shows the comparison of Samples 3 (right lane) and 7 (left lane).
  • the following scheme illustrates this reaction.
  • Milestone Ethos E microwave is used for all the following reactions and conditions are listed at each example. Generally, the two reaction components are mixed in the selected solvent and then the catalysts are added. The reaction mixture was stirred well for about 5 mins. The reaction tube was put in the microwave and heated for a certain amount of time as shown. The solvent was removed and the products were purified.
  • FIG. 2 shows the TLC for this product 3.
  • the solvent was then removed using rotary-evaporator and the residue was put on high vacuum for 2 hours with a periodic argon blow.
  • the product was purified with a silica gel column using DCM (10:1) as eluent.
  • the product 5 was obtained as a clear oil (155.4 mg, 55% yield).
  • Tetraglycidyl ether 360 mg, 1.0 mmol (Scheme 4) was put in a microwave tube. Then 0.5mL of DMF was added and mixed well using a magnetic stir bar. A solution of sodium azide (273 mg in 0.75 mL of water, 4.2 mmol, 1.05 equiv./epoxy) was added, followed by the addition of a solution of ammonium chloride (263 mg in 0.75 mL of water). A sticky material precipitated around the stir bar. DMF was added (4x0.5 mL) to make the mixture clear. The mixture was stirred at RT for 3 min. and then put in the microwave with the following parameters as shown in Table 4 below. Table 4
  • reaction mixture 0.25 mL was dried and 0.5 mL of DCM and 0.5 mL of water were added to the residue and shaken well. The organic layer was checked by TLC. The result showed that the reaction was completed and clean.
  • Figure 3 shows the left lane is the tetra-azide, and the right lane is the reaction mixture. Compared with the tetraazide made by adding a large excess of NaN3 at 55 0 C, the new spot is the desired product.
  • Propargyl triglycidyl ether, 2 (0.684 g, 2.0 mmol) was placed into a 15-mL screw cap vial.
  • a solution of pentaerythritol tetra-azide, 1 (0.266 g, 0.5 mmol) in 2.0 g of t- butanol was added, followed by addition of 2.0 g of water.
  • Sodium ascorbate (0.04 g, 0.2 mmol) (Acros Organics) was added to this reaction mixture, followed by CUSO45H2O powder (0.025 g, 0.1 mmol) (Acros Organics).
  • the vial was closed halfway, mixed well, placed in a microwave oven (SamsungTM, Model MW830WA), and heated for 21 seconds at 100OW.
  • the reaction mixture started to boil and turned brick-red in color.
  • the reaction progress was monitored by TLC (2: 1 acetone:toluene; iodine vapor used to visualize the spots).
  • the reaction mixture was transferred into a separatory funnel and diluted first with 30 mL of water, followed by 30 mL of DCM and 30 mL of brine solution. After thorough mixing, the organic layer was separated and the aqueous layer extracted with DCM (2x30 mL).
  • PEHAM dendrimer G1.0 3 (0.951 g, 0,5 mmol) (made from Example 3) was placed in a 50-mL microwave glass reaction vessel and 12 mL of DMF and 6.0 mL of water were added. The vessel was equipped with a stir bar, and sodium azide, NaN 3 (0.429 g, 6.6 mmol) (Aldrich) and ammonium chloride, NH 4 CI (0.35 g, 6.6 mmol) (EM Science) were added successively. The reaction vessel was closed and irradiated (7 min at 8O 0 C and 500W) using a Milestone Microwave Laboratory systems, ETHOSTM E Series.
  • TLC (2: 1 acetone:toluene) revealed that only a small amount of G1.0 epoxy dendrimer, 3 was still present after this treatment.
  • the reaction mixture was transferred into a 100-mL round bottom flask and heated at 6O 0 C for overnight.
  • the reaction mixture was allowed to cool to RT, and then 30 mL of water and 300 mL of MeOH were added.
  • Insoluble solids were filtered off through a Celite plug.
  • the filtrate was subjected to UF through a IKDa size exclusion membrane in order to remove excess NaN 3 and NH4CI and the side product NaCl.
  • a 50-mL microwave glass reaction vessel was charged with PEHAM dendrimer, G1.5, azide surface, 4 (1.2 g, 0.5 mmol) and 4.0 g of /-butanol and 4.0 g of water.
  • Propargyl triglycidyl ether, 2 (2.052 g, 6.0 mmol) was added to this solution.
  • the reaction vessel was equipped with a stir bar, and sodium ascorbate (0.119 g, 0.6 mmol) (Acros Organics) and C11SO 4 .5H 2 O (0.075 g, 0.3 mmol) were added.
  • the reaction vessel was closed, placed in a microwave oven (Milestone Microwave Laboratory systems, ETHOSTM E Series), and irradiated for 3min at 70 0 C and 500W.
  • TLC (2:1 acetonertoluene; iodine vapor used to visualize the spots) indicated a new spot with 0.11 for PEHAM dendrimer G2.0, epoxy surface, 5.
  • the absence of the azide vibration in the IR spectrum confirmed complete reaction of all azides. This epoxide was kept as starting material for future reactions without further characterization to protect the reactive epoxy groups.
  • a end of a TygonTM tube was attached to a copper coil immersed in isopropanol — dry ice at ⁇ -78°C with N 2 gently blowing through was placed next to the reaction vessel for cooling.
  • the power of the microwave instrument was set at 500W with the QP set at ⁇
  • the irradiation sequence was set at 4 mins. from RT to 100 0 C then 20 mins. at 100°C. Typical irradiation pulses were 22 seconds and summed to a total of 8 mins. per 24 min. interval for a total of 4 intervals to give 10 min. irradiation time. A total irradiation time was 40 mins. This mixture was cooled to RT and the volatiles were removed by a rotary evaporator followed by high vacuum to give 7.4 g of crude material. The reaction was monitored by TLC using 30% NH 4 OH in MeOH.
  • Fractions 1 - 19 were collected that contained material with a baseline R f only and found to be free of DEA by TLC. The volatiles of these fractions were stripped on a rotary evaporator followed by high vacuum to give 477 mg.
  • Fractions 20 - 30 contained some baseline R f material along with material ranging in Rf from 0.1 to 0.7. These fractions were collected and stripped to give 805 mg.
  • Fractions 31 -40 were found to contain only product of Rf ⁇ 0.8 - 0.9. This material was stripped of volatiles to give 530 mg.
  • Fraction 41 was collected as a volume of 250 mL and was found to contain DEA with some UV active material and was stripped to give 1.1 g.
  • the total weight of product obtained from fractions 1 - 40 was 1.81 g (79% yield based on 100% purity of EPON 1031).
  • Example 8 Preparation of Epiiodohydrin from EPI using Sodium Iodide: MWA Synthesis and Workup in Diethyl ether
  • EPON 1031 500 mg, 8.04x10-4 mol theory, ⁇ 70% TPETGE
  • This amine was dissolved in 2.5 g of MeOH and added to the reaction mixture.
  • the reaction tube was sealed and fitted with a temperature probe.
  • a end of a TygonTM tube attached to a copper coil immersed in isopropanol - dry ice at ⁇ 78°C with N 2 gently blowing through was placed next to the reaction vessel for cooling.
  • the program was set for a ramp up from RT reaction temperature to 4O 0 C for 2 mins. followed by 18 mins. where irradiation occurs until 40 0 C then shuts off until the reaction cooled to this temperature. Typical pulse times were 22 seconds.
  • the irradiation time was computed from a 10 min. irradiation sequence by adding all the pulses together and found to be 7 — 8 mins. The entire procedure took 7 hours.
  • EPON 1031 (1.0 g, 1.61 mmol theory, ⁇ 70% TPETGE) as a solution in 3.0 g of diglyme.
  • This amine was dissolved in 2.5 g of MeOH and added to the reaction mixture.
  • the reaction tube was sealed and fitted with a temperature probe.
  • a end of a TygonTM tube attached to a copper coil immersed in isopropanol — dry ice at ⁇ 78°C with N 2 gently blowing through was placed next to the reaction vessel for cooling.
  • the irradiation sequence was set at 2 mins. From RT to 100 0 C then 8 mins. at 100°C.
  • Typical irradiation pulses were 22 seconds and summed to a total of 2.5 mins. per 10 min. interval for a total of 4 intervals to give 10 min. irradiation time.
  • a total irradiation time was 40 mins. This mixture was heated at 60 0 C with 10 mL of DI for 18 hours under N 2 .
  • MALDI-TOF MS C 1 44H292N58 O 2 s; CaIc. 3284, found 3278 (perfect structure), 3222 (perfect structure + 1 loop), 3165(perfect structure + 2 loops), 3108 (perfect structure + 3 loops), 3051 (perfect structure + 4 loops), 2993 (perfect structure + 5 loops) amu.
  • TREN (7.54 g, 51.53 mmol) was put in a microwave tube equipped with a magnetic stir bar and cooled to 4°C using an ice-water bath.
  • the dendrimer container was rinsed with MeOH (2 x 1.0 mL) and the solvent added to the microwave tube.
  • the reaction mixture was irradiated in the microwave for a series of times as shown in Table 6 below. The IR spectrum of the mixture was recorded after each irradiation to monitor the reaction progress.
  • the MALDI-TOF mass spectrum of the product gave the main peak at a mass of 17,030 amu..

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Abstract

La présente invention propose un procédé amélioré pour préparer des polymères dendritiques, dans lequel un noyau est amené à réagir avec un réactif de cellule ramifiée (BR) et/ou un extendeur en utilisant un rayonnement de micro-ondes. Par comparaison avec les procédés de l'état antérieur de la technique, la quantité de (BR) nécessaire n'est pas en grandes quantités excessives, le temps de la réaction est grandement réduit et la pureté du polymère dendritique final est augmentée.
PCT/US2007/014403 2006-06-21 2007-06-20 Procédé pour préparer des polymères dendritiques à l'aide d'une synthèse assistée par micro-ondes WO2007149501A2 (fr)

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CN102010504A (zh) * 2010-11-02 2011-04-13 东南大学 一种超支化聚酯的制备方法
CN105131305A (zh) * 2015-08-18 2015-12-09 天津大学 水性超支化聚合物乳化剂及制备水性环氧树脂乳液的用途

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EP1733742A1 (fr) * 2005-06-17 2006-12-20 Universiteit Utrecht Holding B.V. Dendrimères substitués de façon multivalente par des groupes actifs
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EP1733742A1 (fr) * 2005-06-17 2006-12-20 Universiteit Utrecht Holding B.V. Dendrimères substitués de façon multivalente par des groupes actifs
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FR2926548A1 (fr) * 2008-01-21 2009-07-24 Centre Nat Rech Scient Encapsulation de la vitamine c dans des dendrimeres solubles dans l'eau
WO2009112682A1 (fr) * 2008-01-21 2009-09-17 Centre National De La Recherche Scientifique Cnrs Encapsulation de la vitamine c dans des dendrimères solubles dans l'eau
CN102010504A (zh) * 2010-11-02 2011-04-13 东南大学 一种超支化聚酯的制备方法
CN102010504B (zh) * 2010-11-02 2012-06-27 东南大学 一种超支化聚酯的制备方法
CN105131305A (zh) * 2015-08-18 2015-12-09 天津大学 水性超支化聚合物乳化剂及制备水性环氧树脂乳液的用途
CN105131305B (zh) * 2015-08-18 2018-05-11 天津大学 水性超支化聚合物乳化剂及制备水性环氧树脂乳液的用途

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