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Advances in-polymer-chemistry-and-methods-reported-in-recent-us-patents

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The objective of this review have been to provide the reader with explicit laboratory methods for preparing agents/ intermediates of interest, testing methods used to assay material efficacy, and …

The objective of this review have been to provide the reader with explicit laboratory methods for preparing agents/ intermediates of interest, testing methods used to assay material efficacy, and analytical data for structural conformation.
The text format has been designed to be used as a reference and synthetic guide

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  • 1. ADVANCES IN POLYMER CHEMISTRY AND METHODS REPORTED IN RECENT US PATENTS
  • 2. ADVANCES IN POLYMER CHEMISTRY AND METHODS REPORTED IN RECENT US PATENTS THOMAS F. DEROSA
  • 3. Copyright 2008 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data DeRosa, Thomas F. Advances in polymer chemistry and methods reported in recent US patents / Thomas F. DeRosa. p. cm. Includes index. ISBN 978-0-470-31286-5 (cloth) 1. Polymers. 2. Polymerization. I. Title. QD381.D47 2009 668.9–dc22 2008009439 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1
  • 4. Dedicated in Loving Memory to My Father, John G. DeRosa November 27, 1921 – January 6, 1980
  • 5. CONTENTS Preface ................................................................................................ xix I. ADDITIVES Controlled Radical Acrylic Copolymer Thickeners ............................... 1 Polymer-Filler Coupling Additives ..................................................... 5 II. ADHESIVES (Meth)acrylate Block Copolymer Pressure Sensitive Adhesives ............. 11 Absorbable a-Cyanoacrylate Compositions......................................... 15 Use of Polybenzoxazoles (PBOS) for Adhesion................................... 20 III. BIOACTIVE A. Bioabsorbables Segmented Urea and Siloxane Copolymers and Their Preparation Methods ............................................................... 25 Functionalized Polymers for Medical Applications ......................... 28 Degradable Polyacetal Polymers .................................................. 31 Lactone Bearing Absorbable Polymers.......................................... 35 B. Contact Lenses Low Polydispersity Poly-HEMA Compositions .............................. 40 C. Drug Delivery Amphiphilic Block Copolymers and Nanoparticles Comprising the Same .............................................................. 44 Heterofunctional Copolymers of Glycerol and Polyethylene Glycol, Their Conjugates and Compositions ............................... 48 Polyalkylene Glycol Acid Additives ............................................. 51 Thermosensitive Biodegradable Copolymer ................................... 55 Polyamide Graft Copolymers....................................................... 58 Bioerodible Poly(Ortho Esters) from Dioxane-Based Di(Ketene Acetals) and Block Copolymers Containing Them ....... 61 Water-Soluble Polymer Alkanals .................................................. 65 vii
  • 6. Biodegradable Aliphatic Polyester Grafted with Poly(Ethylene Glycol) Having Reactive Groups and Preparation Method Thereof............................................... 69 Coumarin End-Capped Absorbable Polymers ................................. 72 Block Copolymers for Multifunctional Self-assembled Systems........ 76 Methods of Making Functional Biodegradable Polymers ................. 80 Monofunctional Polyethylene Glycol Aldehydes ............................ 84 IV. COATINGS A. Anionic Glycopolymers and Free Radical Polymerization Methods ............... 89 B. Aqueous Method of Making Novel Water-Soluble and Self-doped Polyaniline Graft Copolymers ............................ 93 Oxyfluorination ......................................................................... 97 Aqueous Dispersions of Crystalline Polymers and Uses................... 99 C. Fluorine Multifunctional (Meth)Acrylate Compound, Photocurable Resin Composition and Article ............................ 102 D. Hydrophilic Polyoxyalkylene Phosphonates and Improved Process for Their Synthesis .................................................... 105 E. Hydrophobic Polymers and Polymer Coatings ................................................. 108 Photochemical Crosslinkers for Polymer Coatings and Substrate Tie-Layer............................................ 112 Use of Poly(Dimethyl Ketone) to Manufacture Articles in Direct Contact with a Humid or Aqueous Medium................. 116 F. Thermally Stable Polyaryleneetherketone Phosphine Oxide Compositions Incorporating Cycloaliphatic Units for Use as Polymeric Binders in Thermal Control Coatings and Method for Synthesizing Same........................................................... 118 G. Vapor Deposition of Polymers Functionalization of Porous Materials by Vacuum Deposition of Polymers ......................................................... 121 viii Contents
  • 7. H. Succinic Anhydride Derivatives Light Absorbent Agent Polymer for Organic Anti-reflective Coating and Preparation Method and Organic Anti-reflective Coating Composition Comprising the Same ........ 124 V. COSMETICS Water-Soluble or Water-Dispersible Graft Polymers, Their Preparation and Use........................................................... 129 VI. DENTAL A. Cement (Meth)Acrylate-Substituted Iminooxidiazine Dione Derivatives ................................................................. 133 B. Dental Composites (Meth)Acrylic Ester Compound and Use Thereof ......................... 138 VII. ELECTROACTIVE A. Charge Transport Materials Hole Transport Polymers and Devices Made with Such Polymers ... 143 Acrylic Polymer and Charge Transport Material ........................... 147 B. Dielectric Materials Thermosetting Aromatic Dielectric Material ................................ 150 C. Donor-Acceptor Complexes Polyester Having p-Conjugated Group in Side Chain and Charge Transporting Material Using the Same .................... 155 D. Electroconductive Halogenated Thiophene Monomer for the Preparation of Regioregular Polythiophenes .............................................. 158 Electrically Conductive Polymeric Biomaterials, the Process for Their Preparation and Use in Biomedical and Health Care Fields ................................................................ 161 Dibenzodiazocine Polymers....................................................... 164 Redox-Active Polymer and Electrode Comprising the Same ............................................................ 168 Contents ix
  • 8. Use of Sulphonic, Phosphonic and Phosphoric Acids as Dopants for Polyaniline and for Conductive Polyaniline-Based Composite Materials ................................ 172 3,4-Alkylenedioxy-Thiophene Copolymers ............................... 177 E. Electroluminescence Electroactive Polymer, Device Made Therefrom and Method ...... 180 Polymers and Oligomers, Their Synthesis, and Electronic Devices Incorporating the Same........................................... 185 Process for Preparing Poly(Arylene Ethers) with Pendant Crosslinkable Groups ......................................................... 190 F. Semiconductors Mono-, Oligo-, and Polythieno[2,3-b]Thiophenes ...................... 196 Poly(Arylene Ether) Dielectrics............................................... 201 Polythiophenes and Devices ................................................... 205 Mono-, Oligo- and Polymers Comprising Fluorene and Aryl Groups................................................................ 211 VIII. ENERGETIC POLYMERS Glycidyl Dinitropropyl Formal, Poly(Glycidyl Dinitropropyl Formal), and Preparation Method Thereof .................................. 217 Synthesis of Energetic Thermoplastic Elastomers Containing Both Polyoxirane and Polyoxetane Blocks ................. 220 IX. FIBERS Rigid-Rod Benzobisazole Polymers Incorporating Naphthalene-1,5-Diyl Structure Units ........................................ 223 Polybenzazole Fiber and Use Thereof ........................................... 227 X. FLUORINE A. Critical Polymerization Process for Producing Fluoropolymer ...................................... 231 B. High Strength Fluorinated Terpolymer.......................................................... 234 C. Low Molecular Weight Directly Polymerized Low Molecular Weight Granular Polytetrafluoroethylene....................................................... 237 x Contents
  • 9. Fluoroelastomers Containing Copolymerized Units of Vinyl Esters ............................................................... 241 D. Low Surface Energy Amorphous Polyether Glycols Based on bis-Substituted Oxetane and Tetrahydrofuran Monomers............................... 244 E. Silicon Fluids Cyclic Siloxane Compounds and Making Method...................... 247 F. Surfactants Fluorinated Organosilicon Compounds and Fluorochemical Surfactants ........................................... 251 XI. GELS A. Gelling Agent Ferrocene-Containing, Organic Gelling Compound, and Gel and Cast Film Using the Same................................. 255 B. Hydrogels Random Block Copolymers .................................................... 259 (Meth)Acrylic Esters of Polyalkoxylated Trimethylolpropane...... 262 Prepolymers for Improved Surface Modification of Contact Lenses .................................................................. 265 Preparation of High Molecular Weight Polysuccinimides ............ 269 Degradable Crosslinkers and Degradable Crosslinked Hydrogels Comprising Them............................................... 272 C. Sol-gel Thermosensitive Poly(Organophosphazenes), Preparation Method Thereof and Injectable Thermosensitive Polyphosphazene Hydrogels Using the Same ......................... 278 XII. IMAGING AGENT Polymerization Method for the Synthesis of Polypeptide Imaging Agents ...................................................................... 283 XIII. INK Process for Preparing Chain Extended Thermoplastic Guanidinium Polymers ............................................................ 289 Contents xi
  • 10. XIV. LIQUID CRYSTALS A. Liquid Crystal Aligner Diamines, Polyimide Precursors, and Polyimides Produced by Using the Diamines and Liquid Crystal Aligning Agents .... 293 Photosensitive Polyimides for Optical Alignment of Liquid Crystals .............................................................. 298 B. Liquid Crystal Materials Homopolymers That Exhibit a High Level of Photo-inducable Birefringence .................................................................... 303 Liquid Crystalline Compound, Liquid Crystalline Composition, and Retardation Film ...................................... 307 Perfluoroallyloxy Compound and Liquid Crystal Composition Containing the Same ....................................... 315 Liquid Crystal Polymers......................................................... 318 XV. NANOPARTICLES A. Carbon Nanotubes Method of Coating a Substrate with a Polymer Having a Combination of Crown Ether and Carbon Nanotubes Having Guanidine Groups................................................... 325 Process for Derivatizing Carbon Nanotubes with Diazonium Species ..................................................... 329 Carbon Nanotube Adducts and Methods of Making the Same...... 333 Modification of Nanotubes by Oxidation with Peroxygen Compounds................................................ 336 Arylcarbonylated Vapor-Grown Carbon Nanofibers.................... 339 B. Inorganic Nanotubes Polymeric and Carbon Compositions with Metal Nanoparticles ... 343 Metal Oxide Nanotube and Process for Production Thereof......... 347 C. Nanotube Dispersant Methods for the Synthesis of Modular Poly(Phenyleneethynlenes) and Fine-Tuning the Electronic Properties Thereof for the Functionalization of Nanomaterials ............................................................... 351 XVI. NEW SYNTHETIC METHODS A. Compounds Solid-Phase Preparation of [18 F] Fluorohaloalkanes ................... 357 xii Contents
  • 11. Vinyl Sulphone Modified Polymer.......................................... 362 Ketone Peroxide Derivatives, Their Preparation and Use............ 367 B. Polymers Simplified Method of Producing Biodegradable Aliphatic Polyesters .......................................................... 371 Hydroaminomethylation of Olefins ......................................... 373 Perdeuterated Polyiimides, Their Process of Preparation, and Their Use as Materials Which Are Transparent within the Region from 2500 to 3500 cmÀ1 .................................... 376 Polybutadiene (Meth)Acrylate Composition and Method ........... 379 Soluble Aniline-Thiophene Copolymers .................................. 381 Process for the Preparation of Di- and Polyamines of the Diphenylmethane Series ........................................... 384 Method for Preparing Polymer Maleimides.............................. 386 Method for Preparing Polymers Containing Cyclopentanone Structures................................................. 389 Polypropylene Having a High Maleic Anhydride Content .......... 392 Polyamide Graft Copolymers................................................. 395 Guerbet Polymers................................................................. 398 Polymerization Method......................................................... 401 Process for Producing Polymerizable Polybranched Polyester..... 406 N-Vinylformamide Derivatives, Polymers Formed Therefrom and Synthesis Thereof ....................................................... 409 Polymers............................................................................. 413 Star-Shaped Polymer, Multiple Star Polymer, and Their Preparation Methods ......................................................... 417 XVII. OPTICAL MATERIALS Second-Order Nonlinear Optical Materials Polymers Having Pendant Nonlinear Optical Chromophores and Electrooptic Devices Therefrom.................................... 419 XVIII. PHOTOACTIVE POLYMERS A. Photoluminscence Polymeric Compound and Organic Luminescence Device.......... 427 Electroactive Fluorene Copolymers and Devices Made with Such Polymers .......................................................... 432 Light-Emitting Polymers ....................................................... 437 Modified Suzuki-Method for Polymerization of Aromatic Monomers ..................................................... 444 Contents xiii
  • 12. Block Copolymer and Polymeric Luminescent Element ............ 448 Soluble Poly(Aryl-Oxadiazole) Conjugated Polymers ............... 453 B. Photorefraction Fullerene-Containing Polymer, Producing Method Thereof, and Photorefractive Composition ........................................ 458 XIX. POLYMERIZATION METHODS A. Anionic Method for Anionic Polymerization of Oxiranes ...................... 463 Amido-Organoborate Initiator Systems ................................... 465 Process for Manufacturing Vinyl-rich Polybutadiene Rubber ............................................................................ 467 Catalyst for Synthesizing High Transpolymers......................... 469 Method for the Preparation of Poly(a)-Methylstyrene ............... 472 Use of Sulfur Containing Initiators for Anionic Polymerization of Monomers ................................................................... 474 Production Method of Polyisocyanate by End-Capping with Acyl Chloride ........................................................... 478 B. Catalytic Agents Methods for Making Functionalized Polymers ......................... 481 C. Cationic Polymerization of i-Butene in Hydrocarbon Media Using bis(Borane) Co-Initiators .......................................... 486 Copolymers of Tetrahydrofuran, Ethylene Oxide, and an Additional Cyclic Ether ........................................... 489 D. Chain Transfer Agents Dithiocarbamic Esters .......................................................... 492 E. Emulsifing Agents Amphiphilic Copolymers Useful Especially as Emulsifiers........ 497 Anionic Copolymers Prepared in an Inverse Emulsion Matrix and Their Use in Preparing Cellulosic Fiber Compositions ............................................ 501 F. Free Radical Polymerization Perfluorodiacylperoxides as Polymerization Initiators ............... 504 G. Macroinitators Polymeric Photoinitiators...................................................... 507 xiv Contents
  • 13. Radical Polymerization Method Performed in the Presence of Disulfide Compounds .............................. 511 Copolymers of Maleic Anhydride by Stable Free Radical Polymerization...................................................... 514 H. Macromolecular Depolymerization Catalysts Catalysts and Methods for Polymerizing Macrocyclic Oligomers........................................................................ 517 Catalytic Systems................................................................ 520 I. Metallocene Catalysts Metallocene Catalysts Containing a Cyclopentadienyl Ligand Substituted by a Siloxy or Germiloxy Group Containing an Olefinic Residue........................................................... 523 J. Ring-Opening Metathesis Catalyst Photochromic Polymers and Methods of Synthesizing Same...... 528 Synthesis of A,B-Alternating Copolymers by Olefin Metathesis Reactions of Cyclic Olefins or Olefinic Polymers with an Acyclic Diene .................................................................. 533 K. Ziegler–Natta High 1,4-cis Polybutadiene-Polyurethane Copolymer and Preparation Method Thereof......................................... 539 Process for Producing Polymer ............................................. 542 Polymerization Catalyst Composition .................................... 546 Synthetic Polyisoprenes and a Process for Their Preparation ..... 550 Polymerization Catalyst ....................................................... 552 Use of Stannylenes and Germylenes as Polymerization Catalysts for Heterocycles.................................................. 557 Process for Producing Polar Olefin Copolymer and Polar Olefin Copolymer Obtained Thereby ................................... 560 Carborane Trianion-Based Catalyst........................................ 565 Catalyst for Polymerization of Norbornene ............................. 569 XX. REGULATORS A. Chain Transfer Agents Method for the Production of Homo-, Co-, and Block Copolymers ...................................................... 575 Method for Radical Polymerization in the Presence of a Chain Transfer Agent.................................................. 577 Use of C4-C6-Polymercaptopolyols as Regulators in Solution or Precipitation Polymerization .......................... 581 Contents xv
  • 14. S-(a,a0 -Disubstituted-a00 -Acetic Acid) Substituted Dithiocarbonate Derivatives for Controlled Radical Polymerizations, Process, and Polymers Made Therefrom ...... 584 B. Chain Transfer Processes Chain Transfer Agents for RAFT Polymerization in Aqueous Media............................................................. 588 Hindered Spiro-Ketal Nitroxides............................................ 592 Controlled Polymerization .................................................... 595 N-Alkoxy-4,4-Dioxy-Polyalkyl-Piperidines as Radical Polymerization Inhibitors................................................... 600 C. Photolytic Regulating Agents Method for Producing Polymers with Controlled Molecular Weight and End-Group Functionality Using Photopolymerization in Microemulsions .............................. 604 Ring-Opened Azlactone Photoiniferters for Radical Polymerization ................................................................. 606 XXI. PHOTORESISTS A. Fluorine Containing Monomer Having Fluorine-Containing Acetal or Ketal Structure, Polymer Thereof, and Chemical-Amplification-Type Resist Composition as Well as Process for Formation of Pattern with Use of the Same ........................................ 611 Polymers, Resist Compositions, and Patterning Process ............ 616 Fluorine-Containing Polymerizable Cyclic Olefin Compound .... 623 Photoresist Composition ....................................................... 627 B. Norbornene Norbornene-Type Monomers and Polymers Containing Pendent Lactone or Sultone Groups .................................... 632 Photoresists Containing Sulfonamide Component..................... 636 C. Adamantane Tertiary (Meth)Acrylates Having Lactone Structure, Polymers, Resist Compositions, and Patterning Process ........................ 642 Chemical Amplification Type Positive Resist Composition........ 647 D. Diamantane Acrylate Positive Photosensitive Composition and Pattern-Forming Method Using the Same .................................................... 651 xvi Contents
  • 15. XXII. SEPARATIONS A. Gases Dithiolene Functionalized Polymer Membrane for Olefin/Paraffin Separation ............................................. 657 B. Solutions Tethered Polymer Ligands .................................................... 662 Isolatable, Water-Soluble, and Hydrolytically Stable Active Sulfones of Poly(Ethylene Glycol) and Related Polymers for Modification of Surfaces and Molecules ..................................................... 665 Optically Active Maleimide Derivatives, Optically Active Polymaleimide Derivatives, Process for Their Production, Separating Media Comprising the Optically Active Polymaleimide Derivatives, and Method of Separating Optically Active Compounds Using Them............................ 669 Polymeric Membranes and Uses Thereof ................................ 674 Separating Agent Including a Polysaccharide Derivative Having a Polycyclic Structure............................................. 678 Functionalized Polymers for Binding to Solutes in Aqueous Solutions ........................................................ 683 XXIII. THERMOSETS A. Poly(Ethyl a-Acetoxyacrylate) Acrylic Copolymer ............................................................. 687 B. Polyethersulfone High-Heat Polyethersulfone Compositions .............................. 689 C. Polynorborene Novel (Co)polymer, Process for Producing the Same, and Process for Producing Carboxylated (Co)polymer ........... 692 D. Polyformals Polyformals and Copolyformals with Reduced Water Absorption, Production, and Use Thereof.................... 695 E. Styrene and Zinc Diacrylate Ionomers Branched Ionomers.............................................................. 699 F. Polycyclodiene Copolymer of Conjugated Cyclodiene .................................... 702 Contents xvii
  • 16. G. a-Aromatic Ketones Poly(Aralkyl Ketone)s and Methods of Preparing the Same ....... 705 H. Polyimide Sulfones Polyimide Sulfones, Method and Articles Made Therefrom ....... 708 I. Benzoxazine Resins Method for Producing Benzoxazine Resin............................... 712 J. Acrylonitrile Block Copolymer ................................................................. 714 K. Polycarbonates Aliphatic Diol Polycarbonates and Their Preparation ................ 717 L. Poly(Silarylene-Siloxane-Acetylene) High-Temperature Elastomers from Linear Poly(Silarylene-Siloxane-Acetylene) ................................... 721 Contributors Academic Contributors ....................................................................... 725 Government Contributors.................................................................... 725 Industrial Contributors........................................................................ 726 Index ................................................................................................ 729 xviii Contents
  • 17. PREFACE Much has changed in polymer chemistry since the first resin/polymer patent issued. US Patent 125 (February 10, 1817) describes a method of waterproofing boots and shoes reported by inventor Patrick G. Nagel. The method entailed: Taking two pounds of balsam-copiba, five pounds of the essence of the myrtle- tree, one pound of gum-copal, two pounds of rosin, and three pounds of rendered suet. The objective of this investigation has been to provide readers with current polymer chemistry research trends from academic, governmental, and industrial sources reported in US patents for the years 2006 to 2007. Twenty-three broad subject areas were reviewed as provided below: Additives Fibers Optical materials Adhesives Fluorine Photoactive polymers Bioactive Gels Polymerization methods Coatings Imaging agents Regulators Cosmetics Ink Photoresists Dental Liquid crystals Separations Electroactive Nanoparticles Thermosets Energetic polymers New synthetic methods Another objective of this review have been to provide the reader with explicit laboratory methods for preparing agents/intermediates of interest, testing methods used to assay material efficacy, and analytical data for structural conformation. The text format has been designed to be used as a reference and synthetic guide for polymer and organic chemists as well as graduate students. The text, however, is not restricted to polymer chemistry. In many instances—and with only marginal mod- ifications—intermediates and products are readily convertible into other agents in related or dissimilar research concentrations. To underscore this point, structural depictions of reagents, intermediates, and products are provided to allow the researcher to more easily visualize other/future material applications. Finally I thoroughly enjoyed compiling this review and trust the reader will find it useful. THOMAS F. DEROSA December, 2007 xix
  • 18. I. ADDITIVES Title: Controlled Radical Acrylic Copolymer Thickeners Author: S. C. Schmidt et al., US Patent Application 2007-0082827 (April 12, 2007) Assignee: Arkema, Inc. (Philadelphia, PA) SIGNIFICANCE Di- and triblock polymers have been prepared by nitric oxide mediated polymer- ization using t-butyl 1-diethylphosphono-2,2-dimethylpropyl nitroxide. Materials prepared from this process are useful as paint thickeners and viscosity index improvers in paint. REACTION c OCH3O OCH3O O OC12H25 OCH3O a b Note 1 i EXPERIMENTAL Preparation of Poly(Methacrylate-b-(Dodecyl Methacrylate- co-Methacrylate)) A steel resin kettle was charged with t-butyl 1-diethylphosphono-2,2-dimethylpropyl nitroxide (30.0 mmol) and methyl acrylate (6.97 mol) and then heated to 110 C for 3 hours, at which point the reaction had reached 50% conversion. The reaction mixture was cooled to ambient temperature and the Mw determined to be 12,600 daltons. In a Advances in Polymer Chemistry and Methods Reported in Recent US Patents, by Thomas F. DeRosa Copyright Ó 2008 by John Wiley Sons, Inc. 1
  • 19. glassreactordodecylmethacrylate(159.4 mmol)washeatedto100 Candtreatedwith the previously prepared polymer mixture (25.3 g) and methyl acrylate (25.3 mmol). This mixture was then treated with polymethacrylate (12.65 g) and methyl acrylate (4.83 g) and heated to 100 C to 105 C for several hours. The resultant viscous liquid was diluted with an equal volume of THF and precipitated into cold stirring methanol; the product was isolated having a Mw of 56,500 daltons and Mn of 39,600 daltons. DERIVATIVES NOTES 1. The nitric oxide mediated polymerization agent t-butyl 1-diethylphosphono- 2,2-dimethylpropyl nitroxide, (I), was prepared according to the method of Gillet [1] as illustrated below: t-C4H9 H O N H t-C4H9 P t-C4H9 OC2H5 O OC2H5 N t-C4H9 P t-C4H9 OC2H5 O OC2H5 O i ii (I) i: t-Butylamine, diethyl phosphate ii: 3-Chloroperbenzoic acid 2. Random copolymers effective as paint viscosity index improvers were prepared by Shoaf as provided in Table 2. TABLE 1. Selected di- and triblock polymers prepared by controlled free radical polymerization using t-butyl 1-diethylphosphono-2,2-dimethylpropyl nitroxide. Entry Polymer*1 Mn PDI Notes 1C PDDMA-b-PS 28,000 1.6 PS ¼ 16% 1D PDDMA-b-PS-b-PDDMA 31,600 1.7 PS ¼ 35% 1E (PDDMA-co-PS)-b-PS-b-(PS-co-PDDMA) 31,600 1.7 PS ¼ 48% 1F PDDMA-b-PMA-b-PDDMA 23,000 1.5 PMA ¼ 48% 1I PDDMA-b-PMA-b-PDDMA 76,000 2.0 PMA ¼ 60% Note: All materials were used as viscosity index improvers in paint. *1 PDDMA ¼ Polydodecyl methacrylate PMA ¼ Polymethacrylate 2 Controlled Radical Acrylic Copolymer Thickeners
  • 20. 3. Blankenship [3] prepared polyethylene glycol carbamate, (II), as paint thick- eners containing poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) and either 1,6-hexamethylene diisocyanate or 4,40 -methylene bis-(isocyanatocy- clohexane). Polycarbamates were also prepared by Bauer [4] using a block polymer initiated by stearyl alcohol and consisting of poly(ethylene oxide-b- propylene oxide-b-butylene oxide-b-dodecene oxide-b-tetradecene oxide) coupled with the diisocyanate, Desmodur NÒ . a O O H N O 6 265 (II) 4. Polycarbamates, (III), prepared by Martin [5] consisting of toluene diisocya- nate, methoxypolyethylene glycol, polypropylene glycol, and dihydroxy- methyl propanoic acid were also effective as paint thickeners and viscosity index modifiers. c H N NH O OO O O H N O OO H3CO a b (III) TABLE 2. Random copolymers used as viscosity index improvers and thickeners in paints. Entry Polymer*1 Monomer Ratio*2 (wt%) 1 PS-co-PEHA-co-PAAEM-co-PMAA 51.8/22.7/8.0/2.5 5 PS-co-PEHA-co-PAAEM-co-PMAA-co-PAA 45.9/21.1/8.0/1.25/3.75 7 PS-co-PEHA-co-PMAA 63.7/18.9/2.5 *1 AA ¼ Acrylic acid AAEM ¼ Acetoacetoxy ethyl methacrylate EHA ¼ 2-Hydroxylethyl acrylate MMA ¼ Methylmethacrylate *2 The remainder of the composition consisted of alkyd. Notes 3
  • 21. References 1. J.-P. Gillet et al., US Patent 6,624,322 (September 23, 2003) 2. G.L. Shoaf et al., US Patent Application 2006-0270769 (November 30, 2006) 3. R.M. Blankenship et al., US Patent Application 2006-0106153 (May 18, 2006) 4. S. Bauer et al., US Patent 7,189,772 (March 13, 2007) 5. E. Martin et al., US Patent 7,144,945 (December 5, 2006) 4 Controlled Radical Acrylic Copolymer Thickeners
  • 22. Title: Polymer-Filler Coupling Additives Author: A. Fukushima et al., US Patent 7,186,845 (March 6, 2007) Assignee: Bridgestone Corporation (Tokyo, JP) SIGNIFICANCE A method for preparing and covalently bonding either 4-(2-oxazolyl)-phenyl- or methyl-N-phenylnitrone to natural rubber in automotive tires is described. The effect has been a 40% overall reduction in tire hysteresis and superior performance over existing polyamine formulations. REACTION O Cl O H O HO N N HO N O i ii iii Model reaction product O NH O H HO iv N O O N Notes 1,2 i: 2-Aminoethanol, CCl3H ii: Sulfuric acid, sodium hydroxide, CCl3H iii: N-Phenyl-hydroxyamine, ethanol iv: Cyclododecene 5
  • 23. EXPERIMENTAL 1. Preparation of 4-Formyl-N-(2-Hydroxyethyl)-Benzamide Asolutionof4-formyl-benzoylchloride(1eq)in300 mlofCCl3Hwasaddeddropwise at À10 C to a solution of 2-aminoethanol (2 eq), dissolved in 200 ml of CCl3H, and then stirred at 25 C for 2 hours. The mixturewas filtered, dried, and concentrated, and 17.4 g of product were isolated as a yellow liquid. 2. Preparation of 4-(2-Oxazolyl)-Benzaldehyde The Step 1 product (17.4 g) was treated dropwise with 50 ml of 18 M H2SO4 and then heated to 100 C for 60 minutes. The mixture was added dropwise with stirring to 500 ml 20% sodium hydroxide and 500 ml of CCl3H while the solution temperature was kept below 15 C. The organic phase was separated and dried, and 6.3 g of product were isolated. 3. Preparation of 4-(2-Oxazolyl)-Phenyl-N-Phenylnitrone AmixtureoftheStep2product(1eq)andN-phenyl-hydroxyamine(1eq)wasrefluxed in 100 ml of ethanol for 30 minutes and then concentrated to 50 ml. The concentrate was treated with 50 ml of water and cooled in a refrigerator to 5 C overnight. White crystals were obtained; these were isolated by filtration, dried, and 6.7 g of product were isolated. 4. Model Reaction: Reactivity of 4-(2-Oxazolyl)-Phenyl-N-Phenylnitrone with Cyclododecene In selected amounts the Step 3 product was mixed with 1 ml cyclododecene and then heated to 171 C. The amount of recoverable Step 3 compound at various timeperiodsduringthereactionwithcyclododecenewasanindicationofthereactivity of this product with unsaturated carbon–carbon bonds. Scoping results are provided in Table 1. DERIVATIVES 4-(2-Oxazolyl)-phenyl-N-methylnitrone, (I), was also prepared: N HO N O (I) 6 Polymer-Filler Coupling Additives
  • 24. TESTING 1. Reactivities Reactivities of the Step 3 product and 4-(2-oxazolyl)-phenyl-N-methylnitrone, (I), with cyclododecene at 170 C are provided in Table 1. N HO N R O 2. Tan d The effect of the experimental agents on natural rubber hysteresis was determined by measuring tan d at 5% strain using an ARES-A Rheometer at 50 C and 15 Hz. Testing results are provided in Table 2. TABLE 1. Percent incorporation of the Step 3 product and derivative into cyclododecene at 170 C. Entry R Heating Time @ 170 C (min) Nitrone Amount (mg) Amount of Incorporated Experimental Nitrone (%) 2 Phenyl 5 5.52 97 4 Phenyl 15 5.65 100 5 Phenyl 30 5.60 100 7 Methyl 5 4.09 39 9 Methyl 15 3.83 78 10 Methyl 30 4.05 98 Note: No characterization data for either experimental agents or cyclododecene addition products were provided by author. Testing 7
  • 25. NOTES 1. In a subsequent investigation by the author [1] styrene butadiene rubber functionalized with the Step 3 product was prepared and was effective in lowering tire hysteresis. 2. Bis-[2-2-thiazolyl-phenyl]disulfide, (I), derivatives were also prepared by the author [2] in a subsequent investigation and were effective in reducing tire hysteresis. S N S S S N (I) TABLE 2. Effect of experimental additives on tan d of natural rubber at various treatment levels. N HO N R O R Nitrone Dosage (mmol) Tan d Unadditized — 0.21 Reference*1 0.16 0.20 Phenyl 0.2 0.18 Phenyl 0.4 0.16 Phenyl 0.8 0.14 Phenyl 1.6 0.13 Methyl 0.2 0.2 Methyl 0.4 0.19 Methyl 0.8 0.16 Methyl 1.6 0.20 Note: Lower tan d values are preferred. *1 SumifineÒ 1162 ¼ (N,N0 -di(2-nitro-2-methyl-propyl)-hexamethylenediamine 8 Polymer-Filler Coupling Additives
  • 26. 3. Polymer nanostrings consisting of block terpolymers of butadiene, styrene, and divinyl-benzene having a Mn of 46,744 daltons were prepared Wang [3] and used as additives in natural and synthetic automotive tires. The nano strings were then postmodified to enhance tire surface and bulk performance. 4. Parker [4] end-group functionalized poly(1,3-butadiene) polymers with iso- propyl hydroxyl-amines to improve the affinity and interaction with carbon black and silica fillers to extend tire lifetime. References 1. A. Fukushima et al., US Patent Application 2006-0084730 (August 20, 2006) 2. S. C. Schmidt et al., US Patent Application (2007-0161756 (July 12, 2007) 3. X. Wang et al., US Patent 7,179,864 (February 20, 2007) 4. D.K. Parker,US Patent Application 2007-0004869 (January 4, 2007) Notes 9
  • 27. II. ADHESIVES Title: (Meth)acrylate Block Copolymer Pressure Sensitive Adhesives Author: A. I. Everaerts et al., US Patent 7,255,920 (August 14, 2007) Assignee: 3M Innovative Properties Company (St. Paul, MN) SIGNIFICANCE Block terpolymers consisting of butyl acrylate with either methylmethacrylate or methyl acrylate have been prepared where the end segments are at least 10,000 daltons and the center segment is at least 60,000 daltons. These materials were coated onto a polycarbonate surface and used to prepare an optical film and an optically clear pressure–sensitive adhesive layer that resists bubble formation when adhered to an outgassing substrate. REACTION O O n-C4H9 OO n-C4H9 O O n-C4H9 OCH3 O OCH3 O 60K10K 60K 10K i ii i: Copper (I) bromide, 1,4-dibromoadipate, n-butyl acrylate, anisole, hexadecane, tris[2-(dimethyl-amino)ethyl]amine ii: Copper (I) chloride, n-butyl acetate, 1,1,4,7,10,10-hexamethyl-triethylenetetra- mine), methylethylketone, methylmethacrylate Advances in Polymer Chemistry and Methods Reported in Recent US Patents, by Thomas F. DeRosa Copyright Ó 2008 by John Wiley Sons, Inc. 11
  • 28. EXPERIMENTAL 1. Preparation of a 60K Poly(Butyl Acrylate) Midblock Macroinitiator A reactor was charged with a mixture consisting of CuBr (0.00478 g), 1,4-dibromoa- dipate (0.06 g), n-butyl acrylate (10.0 g), anisole (0.5 g), 0.5 ml of hexadecane, and 9.0 ml of tris[2-(dimethylamino)ethyl]amine. The mixture was heated to 60 C for 20 hours, and the product was isolated having a molecular weight of 60,000 daltons. 2. Preparation Poly[(Methylmethacrylate)-b-Poly(Butyl Acrylate)-b- Poly(Methyl Methacrylate)] The Step 1 product was dissolved in roughly 10 ml of n-butyl acetate and then treated with CuCl (0.0396 g) complexed with 108.8 ml of 1,1,4,7,10,10-hexamethyl-triethy- lenetetramine), 2 ml of methylethylketone, and 4 ml of methylmethacrylate. The mixture was then heated to 60 C for 24 hours, cooled, dissolved in THF to 20% solids, and filtered through alumina to remove residual catalyst. The product poly(methyl- methacrylate)-b-poly(butyl acrylate)-b-poly(methylmethacrylate) was isolated hav- ing molecular weight segments of 10,000/60,000/10,000 daltons, respectively. DERIVATIVES TESTING Accelerated aging testing and dynamic mechanical analysis were used to evaluate the stability of coated laminates. Testing results are provided in Table 2. TABLE 1. Selected block terpolymers and corresponding segmented molecular weights. Entry Polymer*1 Segment Molecular Weights (daltons) 1 PolyMMA-b-polyBA-b-polyMMA 10K–60K–10K 3 PolyMMA-b-polyBA-b-polyMMA 14K–120K–14K 6 PolyMMA-b-polyBA-b-polyMMA 14K–60K–14 7 pMMA-b-p(BA/MA)-b-pMMA 10K–60K–10 10 (pBA-b-pMMA)3 (30K–10K)3 Note: Entry 10 is a tri-arm block copolymer. *1 MMA ¼ Methylmethacrylate BA ¼ n-Butyl acrylate MA ¼ Methyl acrylate 12 (Meth)acrylate Block Copolymer Pressure Sensitive Adhesives
  • 29. NOTES 1. In an earlier investigation by Yang [1] triblock urethane acrylate oligomers terminated with acrylic acid were prepared and used in curable pressure sensitive adhesive compositions. 2. Additional block terpolymers containing propyl acrylate and star block terpo- lymers containing styrene were previously prepared by the author [2] and used in hot-melt pressure-sensitive and heat-activatable adhesives. 3. Random terpolymers consisting of ethyl, butyl, and behenyl acrylate were prepared by the author [3] and used as heat-activatable adhesives. Randon terpolymers consisting of iso-octyl/acrylic acid/styrene macromonomer, 92/4/ 4 mol%, respectively, were prepared by Joseph [4] and used as a reinforced pressure sensitive adhesive. 4. Linear and star diblock polymers consisting of methyl and n-butyl acrylates were prepared by Paul [5] and used as high performance, low viscosity hot-melt adhesives. A single star block terpolymer containing 2-ethylhexyl acrylate was also prepared. 5. Husemann [6] prepared UV-transparent adhesives consisting of acrylic acid, acrylamide, and 2-ethylhexyl acrylate that were effective as pressure-sensitive adhesives. TABLE 2. Thermal aging stability and storage modulus analysis of laminates coated with selected experimental agents using PMMA or PC as the coating substrate. Entry Substrate 90 C Aging Test Results 80 C with 90% Humidity Test Results Log (G0 ) at 25 C (Pascals) Log (G0 ) at 150 C (Pascals) 1 PC*1 Pass Marginal 5.34 4.84 1 PMMA Pass Pass — — 3 PC Bubbles Bubbles 4.63 4.22 3 PMMA Bubbles Bubbles — — 6 PC Pass Pass — — 6 PMMA Pass Pass 7 PC Pass Bubbles — — 7 PMMA Marginal Pass — — 10 PC Bubbles Pass 5.60 4.83 10 PMMA Pass Pass — — *1 PC ¼ Polycarbonate Notes 13
  • 30. References 1. J. Yang et al., US Patent 6,887,917 (May 3, 2005) 2. A.I. Everaerts et al., US Patent 7,084,209 (August 1, 2006) and US Patent 6,806,320 (October 19, 2004) 3. A.I. Everaerts et al., US Patent 7,008,680 (March 7, 2006) 4. E.G. Joseph et al., US Patent 6,994,904 (February 7, 2006) 5. C.W. Paul et al., US Patent Application 2004-0122161 (June 24, 2004) 6. M. Husemann et al., US Patent 7,144,928 (December 5, 2006) 14 (Meth)acrylate Block Copolymer Pressure Sensitive Adhesives
  • 31. Title: Absorbable a-Cyanoacrylate Compositions Author: H. Liu, US Patent 7,238,828 (July 3, 2007) Assignee: Ethicon, Inc. (Somerville, NJ) SIGNIFICANCE Polymerizable3-(2-cyano-acryloyloxy)-butyricacidethylesterhasbeenpreparedina two-stepprocessusing3-hydroxybutyrateand cyanoaceticacid followedbytreatment with formaldehyde. This and related alkyl ester a-cyanoacrylate monomers are useful as tissue adhesives/sealants in surgical and related medical applications. REACTION OH O O NC O O O O i ii O O O O CN CN O O O O Note 1 a Oligomeric intermediate i: Cyanoacetic acid, 4-dimethylaminopyridine, CH2Cl2, DMF, dicyclo- hexylcarbodiimide ii: Paraformaldehyde, piperidine, benzene, phosphorous pentoxide 15
  • 32. EXPERIMENTAL 1. Preparation of 3-(2-Cyano-Acetoxy)-Butyric Acid Ethyl Ester A reactor was charged with ethyl-3-hydroxybutyrate (194.0 g), cyanoacetic acid (149.83 g), 4-dimethylaminopyridine (10.76 g), and 1500 ml of CH2Cl2 and then treated with 75 ml of DMF. The solution was chilled in an ice-water bath and treated with dicyclohexylcarbodiimide (363.45 g) dissolved in 600 ml of CH2Cl2. A white precipitate formed within five minutes after the start of the addition, and the mixture was stirred overnight. The precipitate was then removed by filtration and the filtrate concentrated. The product was isolated in 73% yield after being distilled twice under vacuum, bp ¼ 100–109 C/0.20–0.27 mmHg. 2. Preparation of 3-(2-Cyano-Acryloyloxy)-Butyric Acid Ethyl Ester A mixture consisting of the Step 1 product (39.84 g), paraformaldehyde (6.6 g), 0.06 ml of piperidine, and 150 ml of benzene was stirred in a 250 ml round bottomed flask containing a Dean–Stark trap and refluxed overnight. The solution was then concentrated, and aviscous residue that turned into a solid gel after cooling to ambient temperature was isolated. The solid oligomer was de-polymerized by treating with hydroquinone (0.20 g)andphosphorouspentoxideand byheating to160 C.Thecrude monomerwasdistilledundervacuumandtheproductisolatedin20%yield,bp ¼ 114– 115 C/0.17 mmHg A very small amount of this monomer product was placed between two moist fingertips and bonded the fingertips strongly within one minute. TESTING 1. General Procedure for Lap Shear Testing Using Pig Skin Fresh pigskin was harvestedfrom the backofa pigwithin 5hourspostsacrifice and the fat attached to the inside skin surface trimmed away. The skin was cut into 2 00 Â 1 00 coupons and covered by saline moist paper towels before use. The external surface of the skin was used as the bonding surface to prepare the lap shear joint samples. The coupons were dried prior to forming a lap shear joint. About 100 ml of the experimental adhesive was deposited to one coupon and smoothed to cover a 1=2 00 Â 1 00 area. Another coupon was placed over the area of the initial coupon and a l lb weight placed on top. It was cured for 20 to 30 min and the strength of the joint 1 H NMR (CDCl3) d: 7.03(s, 1H), 6.60(s, 1H), 5.43(m, 1H), 4.15(q, 2H), 2.65(m, 2H), 1.40(d, 3H), 1.23(t, 3H) GC-MS: 98.3% 1 H NMR (CDCl3) d 5.39(m, 1H), 4.16(q, 2H), 3.42(s, 2H), 2.62(m, 2H), 1.37(d, 3H), 1.27(t, 3H) GC-MS: 99.4% 16 Absorbable a-Cyanoacrylate Compositions
  • 33. evaluated using an Instron (Model 5544) with a pulling rate of 5 mm/min. A summary of testing results is provided in Table 1. 2. In vitro Degradation Testing of Polymeric Films A 1 Â 1 inch Prolene mesh was rinsed with 0.5 wt% of NaHCO3 and dried. The mesh was then placed on a freshly prepared Agar plate in a petri dish and roughly 100 mg of a selected experimental adhesive applied across the mesh. The selected adhesive was cured overnight then sealed with parafilm; the film thickness was about 0.6 mm. The film was then placed into a hydrolysis chamber with 100 ml of water while the temperature of the solution was maintained at 75 C. The pH of the solution was maintained at 7.27 with addition of 0.05 M of a NaOH solution throughout the degradationofthepolymerfilm.Thedegradationtimewasdefinedasthetimerequired for the medium to consume 90% of the total consumed NaOH solution. The degradation and glass transition temperatures of each polymer are summarized in Table 2. TABLE 1. Instron lap shear testing results for selected a-cyanoacrylate monomeric derivatives. Entry Source Structure Load Strength (lb) 1B Invention O CN O O O 4.09 2B Invention O CN O O O 4.49 Et-e-CPL-CA Comparison O O CN O O 3.68 Et-a-CPL-CA Comparison O O CN O O 1.29 Testing 17
  • 34. NOTES 1. The polymerization was conducted accorded to the method of Leung [1]. 2. Bioabsorbable adhesive compounds and compositions containing a polyalk- ylene oxide backbone having branched or multi-arm structure derived from reacting with two or more isocyanate substituents were prepared by Roby [2] and used as surgical adhesives and sealants. 3. Photochemical tissue bonding comprising a skin graft and Rose Bengal to form a skin tissue-RB complex with fibrin or a fibrinogen adhesive were prepared by Redmond [3]. The material was crosslinked by the application of electromag- netic energy having a wavelength of at least 488 nm and was used as an adhesive for repairing musculoskeletal tissue damaged by a laceration or rupture in humans. TABLE 2. In vitro degradation and glass transition temperatures of selected a-cyanoacrylate polymeric derivatives. Entry Source Precursor Monomer Polymer Degradation Time (h) Tg ( C) 1B Invention O CN O O O 54.6 32 2B Invention O CN O O O 39.4 À11 Bu-Lac-CA Comparison O CN O O O 49.4 52 Note: Polymers formed from compositions having Tg’s lower than body temperature (37 C) are particularly preferred for medical applications. 18 Absorbable a-Cyanoacrylate Compositions
  • 35. 4. An absorbable a-cyanoacrylate adhesive composition, (I), was prepared by Jonn [4] and used as a soft tissue adhesive. CN O O O O C4H9 (I) References 1. J.C. Leung et al., US Patent 5,928,611 (July 12, 1994) 2. M.S. Roby,US Patent 7,241,846 (July 10, 2007) and US Patent 7,129,300 (October 31, 2006) 3. R.W. Redmond et al., US Patent 7,073,510 (July 11, 2006) 4. J.Y. Jonn et al., US Patent 6,620,846 (September 16, 2003) Notes 19
  • 36. Title: Use of Polybenzoxazoles (PBOS) for Adhesion Author: A. Walter et al., US Patent 7,052,936 (May 30, 2006) Assignee: Infineon Technologies AG (Munich, DE) SIGNIFICANCE A single-step method for preparing polybenzoxazole adhesives is described. These agents are particularly useful in the semiconductor industry for chip and wafer stack applications. REACTION O O HO H2N OH NH2 O O O N N O O i O O HO H2N N O O O O N N O O O O OH NH N O Not isolated O Notes 1,2 a a i: Phosphorus (V) oxide, methane sulfonic acid, 4,40 -hydroxycarbonyl dipheny- lether, methacrylic acid 20
  • 37. EXPERIMENTAL Preparation of Polybenzoxazole End-capped with Methacrylic Acid A reaction vessel was charged with 9,9-diphenyl-(4-amino-3-hydroxyl)dipheny- lether)fluorene (0.3 mol) and 800 ml of methane sulfonic acid and then treated with the dropwise addition of 4,40 -hydroxycarbonyl diphenylether (0.24) dissolved in 400 ml of methane sulfonic acid. The solution was heated for 5 hours at 80 C. After cooling to 40 C, the mixture was treated with the dropwise addition of methacrylic acid (0.12 mol) dissolved in 100 ml of methane sulfonic acid and heated an additional 6 hours at 100 C. The reaction product was isolated by filtering through a glass frit and the filtrate added dropwise to a mixture of 2 liter of water, 2 kg of ice, and 200 ml of this 12 M NH4OH; additional NH4OH was added during the filtration to ensure that the pH did not fall below 8. During the neutralization procedure the rate was such that the temperature did not exceed 30 C. The precipitated polymer was isolated by filtration and washed with 3 liter of cold water. Thereafter the solid was stirred in 3 liter 3% NH4OH at ambient temperature for 1 hour and then suspended repeatedly in water. After filtration and drying, 219 g of product were isolated. DERIVATIVES TABLE 1. Polybenzoxazole derivatives prepared using aminophenols and dicarboxylic acids with selected endcapping agents. Entry Aminophenol Reagent Diacid Reagent End-capping Agents 3 F3C CF3 H2N HO NH2 OH O2 S HO2C CO2H — 4 H2N NH2 HO OH NHO2C CO2H HO2C 5 O2 S H2N HO NH2 OH HO2C CO2H — (continued) Derivatives 21
  • 38. TESTING A 4-inch silicon wafer was sputtered with a titanium nitride layer 50 nm thick and then a selected polybenzoxazole adhesive applied by spin-coating. Following a short softbake at 120 C for 1 minute and at 200 C for 2 minutes on a hotplate, a second 50 nm titanium nitride was sputtered onto the surface. A force of 2 N was then applied to the polybenzoxazole film at 340 C. The sample was further heated to 400 C in an oven under a nitrogen atmosphere for 60 minutes. After cooling to ambient temperature the adhesion test was carried out by means of a shear tester using a Dage Series 400. Testing results are provided in Tables 2 through 4. Entry Aminophenol Reagent Diacid Reagent End-capping Agents 6 F3C CF3 H2N HO NH2 OH HO2C CO2H O O O 8 O O HO H2N OH NH2 NHO2C CO2H O — 10 F3C CF3 H2N HO NH2 OH O2 S HO2C CO2H O OH TABLE 2. Average shear force of polybenzoxazole bonded to a titanium nitride surface. Polybenzoxazole Adhesive Shear Force (N/mm2 ) Coating Type 3 17.94 Spray 4 20.67 Spin coat 5 18.69 Spray TABLE 1. (Continued) 22 Use of Polybenzoxazoles (PBOS) for Adhesion
  • 39. NOTES 1. In an earlier investigation by the author [1] phenyl-linked polyoxazole deri- vatives, (I), were prepared and converted into cyanates by reacting with isocyanate derivates. Cyanate derivatives were used as dielectrics because of their good adhesive and filling properties. O O O N N O O O HO H2N N O O O O N N O (I) a b 2. Polyhydroxyamides, (II), prepared by Halik [2] were converted into polybenzoxazole-based adhesives by curing at 300 C to 350 C. Polyhydroxy- amides, (III), were also prepared and converted into the corresponding TABLE 3. Average shear force of polybenzoxazole bonded to a tantalum nitride surface. Polybenzoxazole Adhesive Shear Force (N/mm2 ) Coating Type 6 17.03 Spray 8 18.47 Spray 10 17.26 Spin coat TABLE 4. Average shear force of polybenzoxazole bonded to a copper surface. Polybenzoxazole Adhesive Shear Force (N/mm2 ) Coating Type Step 1 product 21.28 Brushing 3 20.06 Powder melting Notes 23
  • 40. polybenzoxazoles by curing 60 minutes at 425 C. a a CO O N H CH OH H N OH O (II) OH H N OH N H O O N H O (III) 3. Hall [4] prepared crossliked polymers that were effective as adhesives by UV curing of the neutralization product of diallylamine with selected carboxylic acids, (IV). Additional UV curable diallyl amine adhesives, (V), were prepared by Milne [5]. NH2 O2C CO2H (IV) O O N N (V) References 1. A. Walter et al., US Patent 6,824,642 (November 30, 2004) 2. M. Halik et al., US Patent 7,064,176 (June 20, 2006) 3. R. Sezi et al., US Patent 7,108,807 (September 19, 2006) 4. A.W. Hall, US Patent 7,112, 639 (September 26, 2006) 5. P.E. Milne et al., US Patent 7,026,419 (April 11, 2006) 24 Use of Polybenzoxazoles (PBOS) for Adhesion
  • 41. III. BIOACTIVE A. Bioabsorbables Title: Segmented Urea and Siloxane Copolymers and Their Preparation Methods Author: I. Yilgor et al., US Patent 7,262,260 (August 28, 2007) Assignee: Virginia Tech Intellectual Properties, Inc. (Blacksburg, VA) SIGNIFICANCE Copolymersandterpolymerscontainingsiloxane-ureasegmentshavebeenpreparedby condensing a,o-N-methylaminopropyl terminated polydimethyl-siloxane with bis(4- isocyanatocyclohexyl) methane then postreacting with a,o-N-methylaminopropyl terminated polypropylene oxide. Polymeric biocompatible materials including mem- branes and adhesives obtained in this process had controlled modulus, high ultimate tensile strength, and favorable refractive index properties. REACTION b a aO Si O N H N H O Si O N H N H N H O N H N H O H N N H H NPPO O O PPO i i: a,oÀN-Methylaminopropyl terminated polydimethylsiloxane, isopropylamine, bis (4-isocyanatocyclohexyl) methane, a,oÀN-methylaminopropyl terminated poly- propylene oxide Advances in Polymer Chemistry and Methods Reported in Recent US Patents, by Thomas F. DeRosa Copyright Ó 2008 by John Wiley Sons, Inc. 25
  • 42. EXPERIMENTAL Preparation of Poly(Dimethylsiloxane-Urea-Propylene Oxide) A mixture consisting of a,o-N-methylaminopropyl terminated polydimethylsiloxane (80 mol%) having a Mn of 2500 daltons dissolved in isopropylamine and bis(4- isocyanatocyclohexyl)-methane (20 mol%) were mixed at ambient temperature then posttreated with a,o-N-methylaminopropyl terminated polypropylene oxide. The reaction extent was determined by FTIR spectroscopy by monitoring the disappear- ance of the isocyanate peak at 2270 cmÀ1 . Reaction mixtures were always homoge- neous and usually clear throughout the reactions. No precipitation was observed. DERIVATIVES AND TESTING TABLE 1. Comparison of tensile properties of bis(4-isocyanatocyclohexyl) methane- basedpolydimethylsiloxane-urea and polyether/polydimethylsiloxane-urea segmented copolymers. Entry Polyether Polyether Mn (daltons) Polymer Urea Content (wt%) [Z] (dL/g) Modulus (MPa) Tensile Strength (MPa) Elongation (%) 1 PDMS*1 2500 20 0.48 20.6 7.90 205 3 PDMS 2500 19 0.54 21.3 8.30 180 4 PEO 2000 20 0.81 4.30 25.4 1320 6 PEO 2000 19 0.72 4.50 26.5 1450 *1 Polydimethylsiloxane NOTES 1. High purity and high molecular weight siloxane-urea/urethane copolymers, (I), were prepared by Kuepfer [1] at ambient temperature using dibutyl tin diacetate as catalyst under anhydrous conditions. Additional siloxane-urea/urethane copolymer derivatives were prepared by Schafer [2]. Si O Si N H O H N O N H O O N H O H N O O a (I) 26 Segmented Urea and Siloxane Copolymers and Their Preparation Methods
  • 43. 2. Mixed urea block copolymers consisting of amine-terminated polydimethyl- siloxane were prepared by Sherman [3] and used as pressure sensitive adhe- sives. Other urea-based pressure sensitive adhesives containing polydimethyl- siloxanes are described by Zhou [4]. 3. Brandt [5] prepared a nontacky spray on bandage—“patch in a bottle”— consisting of the reaction product of isophorone diisocyanate, polydimethyl- siloxane diamine having a Mn of 5400 daltons, and polypropylene oxide diamine having a Mn of 2000 daltons. References 1. J. Kuepfer et al., US Patent 7,153,924 (December 26, 2006) 2. O. Schafer et al., US Patent 7,026,424 (April 11, 2006) 3. A.A. Sherman et al., US Patent 7,012,110 (March 14, 2006) 4. Z. Zhou et al., US Patent 7,090,922 (August 15, 2006) 5. A. Brandt et al., US Patent 6,958,154 (October 25, 2005) Notes 27
  • 44. Title: Functionalized Polymers for Medical Applications Author: A. Nathan, US Patent 7,253,248 (August 7, 2007) Assignee: Ethicon, Inc. (Somerville, NJ) SIGNIFICANCE Biodegradable and biocompatible a,b-unsaturated polyesters have been prepared by condensing maleic anhydride with monoleoyl glycerol alone or in combination with monoleoyl glycerol polyethylene glycol. Mercaptoethylamine was then free radically incorporated into the a,b-unsaturated site using azobisisobutyronitrile. These poly- meric agents were used to prepare medical devices including sutures, staples, surgical tacks, clips, and plates. REACTION O OHOH C17H30 O O OO C17H30 O O O O O O O O OO C17H30 O O O O O O O S S H2N NH2 i ii aa i: Monoleoyl glycerol, maleic anhydride ii: DMF, 2,20 -azobisisobutyronitrile, mercaptoethylamine EXPERIMENTAL 1. Preparation of Poly(Monooleoyl Glyceride-co-Maleic Anhydride) Areactorwaschargedwithmonoleoylglycerol(142.6 g)andthenheatedto140 Cand treated with maleic anhydride (39.2 g). The reaction mixture was further heated to 28
  • 45. 190 C for 3 hours and cooled to ambient temperature. The product was isolated as a pale yellow viscous liquid having a Mn of 1383 daltons and a Mw of 6435 daltons. 2. Addition of Mercaptoethylamine to Poly(Monooleoyl Glyceride-co-Maleic Anhydride) A mixture consisting of the Step 1 product (5.0 g), 0.85 ml of mercaptoethylamine, 11 mlofDMF,and2,20 -azobisisobutyronitrile(54 mg)washeatedto60 Cfor24hours and then cooled to ambient temperature. The polymer was diluted with 10 ml of EtOAc, washed once with 0.01 M of NaOH, twice with brine, dried with MgSO4, and filtered. The solution was concentrated, and the product was isolated as a yellow, transparent viscous liquid. DERIVATIVES NOTES 1. Poly(monostearoyl glycerol-co-succinate) containing upto 5% polyethylene glycol, (I), was prepared by Arnold [1] and Nathan [2] and used as a bioabsorbable and biocompatible polymeric wax. Poly(monostearoyl- glyceride-co-succinate) containing 5% N-methyl diethanoamine, (II), was prepared by the author [3] in an earlier investigation. OO O O C17H35 O O O O 5 mol% (I) 95 mol% TABLE 1. Co-components used in reacting with maleic anhydride forming the corresponding a,b-unsaturated polyester and corresponding physical properties. Entry Co-component – 1 Co-Component – 2 Mn (daltons) Mw (daltons) 2 Monooleoyl glycerol 5 mol% PEG-400 1122 5647 3 Monooleoyl glycerol 25 mol% PEG-400 1230 4481 1 HNMR (CD3Cl, ppm): d 0.86 triplet (3H), 1.26 multiplet (22H), 1.61 multiplet (2H), 2.00 multiplet (4H), 2.30 multiplet (2H), 2.80 multiplet (2H), 3.60 multiplet (2H), 4.20 multiplet (3H), 5.38 multiplet (2H); no a,b-unsaturated ester remaining in the polymer FTIR (ZnS, cmÀ1 ): 3346, 2920, 2860, 1745, 1660, 1456, 1168 Notes 29
  • 46. 95 mol% OO O O C17H35 O O O N H O (II) 5 mol% 2. The biodegradable and biocompatible polymer poly(monostearoyl glyceride- co-succinate-co-caprolactone), (III), was prepared by Nathan [4] and used in medical devices. O N H O O O O C17H35 O O (III) a 3. Block copolymers, (IV), consisting of succinic acid coupled with propylene glycol and then capped with hexamethylene diisocyanate and reacted with polylactic acid were prepared by Imamura [5] and used as biodegradable containers. O OO O O O H N O H N O O O O O a c (IV) b References 1. S. Arnold et al., US Patent 7,034,037 (April 25, 2006) 2. A. Nathan et al., US Patent 7,030,127 (April 18, 2006) 3. A. Nathan et al., US Patent 6,866,860 (March 15, 2005) 4. A. Nathan et al., US Patent 6,967,234 (November 22, 2005) 5. S. Imamura et al., US Patent 7,223,815 (May 29, 2007) 30 Functionalized Polymers for Medical Applications
  • 47. Title: Degradable Polyacetal Polymers Author: S. J. Brocchini et al., US Patent 7,220,414 (May 22, 2007) Assignee: A. P. Pharma, Inc. (Redwood City, CA) SIGNIFICANCE Polyacetal polymers containing polyethylene glycol have been prepared which are stable at physiological pH but which readily degrade at lower pH’s. Bolton Hunter reagent conjugates prepared from these materials showed a favorable bio- distribution profile of the 125 I product. REACTION a a a HO OH NH2 HO OH HN O O O HN O O OO OO OO 3 360 O NH2 OO OO OO 3 360 O HN OO OO OO 3 360 O I HO I i ii iiiiv 125 125 i: Sodium hydroxide, N-(9-fluorenylmethoxycarbonyl)chloride, CH2Cl2 ii: Polyethylene glycol, p-toluene sulfonic acid, divinyl tri(ethylene glycol),THF, triethylamine 31
  • 48. iii: Piperidine, CH2Cl2 iv: N-Succinimidyl 3-(4-hydroxy 5-[125 I]iodophenyl) propionate), benzene, DMF, sodium hydroxide EXPERIMENTAL 1. Preparation of N-(9-Fluorenylmethoxycarbonyl) Intermediate A reactor containing 2-amino-1,3-propanediol (10.0 mmol) and 25 ml of 1M NaOH was cooled to 0.2 C and treated with N-(9-fluorenylmethoxycarbonyl)chloride (13.1 mmol) dissolved in 10 ml of CH2Cl2 over a 1 hour period. The solution was stirred for 1 hour at 0 C and 4 hours at ambient temperature. The organic solvent was evaporated and the aqueous residue poured into 70 ml of EtOAc. The organic phase was isolated, washed with 5% aqueous HCl, dilute NaHCO3, brine, and dried. The mixture was concentrated, the residue re-crystallized in chloroform, and the product was isolated. 2. Preparation of Polyether N-(9-Fluorenylmethoxycarbonyl) Intermediate Polyethylene glycol having a Mn of 3400 daltons (1.47 mmol) and p-toluene sulfonic acid (0.012 g) were added to a 100-ml flask and heated to 80 C to 90 C for 3 hours at 0.5to 1.0 torr.The mixturewas cooled and treated with the Step 1product (1.47 mmol) and 10.0 ml of THF; it was further treated with divinyl tri(ethylene glycol) (2.94 mmol) in 10 ml of THF. This reaction mixture was stirred for 2 hours at ambient temperature and then treated with 0.3 ml triethylamine. The reaction mixturewasprecipitatedin100 mlofhexane,andtheproductwasisolatedhavingaMn of 25,000 daltons. 3. Preparation of Polyether Acetal Amine Intermediate A solution of the Step 2 product (2.050 g) in 20% piperidine containing 10 ml of CH2Cl2 was stirred at ambient temperature and monitored by thin layer chromatog- raphy. The amino functionalized polyacetal was then isolated by partitioning the piperidine into hexane and next CH2Cl2. The residue was dissolved in THF, and the polymer was precipitated by pouring into 100 ml of hexane. The product was isolated having a Mn of 23,000 daltons. 4. Preparation of 125 I Polyether Acetal The Step 3 product (50 mg) was dissolved in 10 mg/ml of 0.1M borate with a pH 8.5 bufferbytheadditionofasmallamountofNaOHandthentreatedwithN-succinimidyl 3-(4-hydroxy5-[125 I]iodophenyl)propionate),500 mCi,dissolvedinbenzenecontain- ing DMF, and stirred for 15 minutes at ambient temperature. The mixture was diluted 32 Degradable Polyacetal Polymers
  • 49. with phosphate buffer solution to 10 ml, transferred to dialysis tubing, and dialyzed against water until no radioactivity was found in the dialysate, and the product was isolated. DERIVATIVES Three additional divinyl ether derivatives were prepared as illustrated below. O N H H N O N H O O O N H O N H O O O N H O N H O O NH2 NOTES 1. Bleach resistant polyacetals consisting of 98% trioxane and 2% dioxolane was prepared by Notorgiacomo [1] and used in molding compositions. 2. Branched polyformals and copolyformals, (I), were prepared Heuer [2] and used in the production of molded articles. O O O Oa b c (I) 3. Polyvinyl butyral resins, (II), were prepared by Miyake [3] and used in heat- developable photosensitive material film. O O (II) a b Notes 33
  • 50. 4. Polyacetal resin compositions having excellent wear resistance were pre- pared by Kim [4]. These resins consisted of polyoxymethylene polymer, ethylene vinylacetate, melamine, triethyleneglycol-bis-3-(3-t-butyl-4-hydroxy- 5-methylphenyl)-propionate, and hydroxyl pentaerythritol fatty acid ester. References 1. V.J. Notorgiacomo et al., US Patent 7,223,809 (May 29, 2007) 2. H.-W. Heuer et al., US Patent 7,208,564 (April 24, 2007) and US Patent 7,199,208 (April 3, 2007) 3. Y. Miyake, US Patent 7,176,257 (February 13, 2007) 4. T.-K. Kim et al., US Patent 7,098,262 (August 29, 2006) 34 Degradable Polyacetal Polymers
  • 51. Title: Lactone Bearing Absorbable Polymers Author: F. X Ingnatious, US Patent 7,205,378 (April 17, 2007) Assignee: Societe de Conseils de Recherches et d’Applications Scientifiques (Paris, FR) SIGNIFICANCE A procedure for the slow and sustained release of the growth hormone inhibitor LanreotideÒ is described. The method entails incorporating LanreotideÒ to the isocitric acid lactone component on the backbone of a polyester block copolymer using sodium hydroxide as the saponification agent. REACTION a O HO2C CO2H O O O O O O OHO O H O O O O O OHO O O O O O H R R O O O O O OHO O O O O O H R R Lanreotide(R) a b a b i ii iii R = H or CH3 NH3 O Na Note 1 i: Propanediol, benzene ii: dl-Lactide, glycolide, stannous octanoate, toluene iii: Sodium hydroxide, acetone, LanreotideÒ 35
  • 52. EXPERIMENTAL 1. Preparation of Poly(isocitric Acid Lactone-co-Propanediol) A reactor containing a Dean–Stark trap was charged with isocitric acid lactone (14.3 mmol), propanediol (15.7 mmol), and benzene was then refluxed at 90 C overnight. The mixture was concentrated and a viscous liquid isolated that solidified on cooling. 2. Preparation of Poly[(Isocitric Acid Lactone-co-Propanediol)- block-(Glycolide-co-Lactide)] The reaction vessel containing the Step 1 product was transferred to a dry box and treated with dl-lactide (25.2 g), glycolide (7.25 g), and 0.2 ml of stannous octanoate solution in toluene. The polymerization reaction was performed at 160 C for 8 hours and then quenched in liquid nitrogen. The polymer was isolated, dissolved in acetone, and precipitated in cold water, with the product isolated having a Mn of 3790 daltons and Mw of 7040 daltons. 3. Preparation of Poly[(Isocitric Acid Lactone-co-Propanediol)- block-(Glycolide-co-Lactide)] Ionically Complexed with LanreotideR The Step 2 product (1 g) was dissolved in acetone and treated with 0.45 ml of 1M NaOH, then stirred for 20 minutes, and further treated with LanreotideÒ (0.29 g) dissolved in 2 ml of 1:1 acetone/water. The polymer solution was left stirring for 2 hours and then precipitated in cold water. The product was filtered and dried; the product isolated had a 17.6% nitrogen content. DERIVATIVES No additional derivatives were prepared. TESTING In vivo Testing The Step 3 product was ground and sieved with a mortar and pestle and passed through a 125 m sieve. Rats were administered 6.75 mg of the experimental agent by injection in a medium consisting of 2% carboxymethylcellulose, 1% Tween 20Ò , and saline. Blood samples were collected at various time intervals, and the plasma levels of LanreotideÒ was determined by radioimmuno assay. Test results for are provided in Table 1. 36 Lactone Bearing Absorbable Polymers
  • 53. NOTES 1. LanreotideÒ has the formula H-b-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr- NH2, where, the two Cys are bonded by a disulfide bond. LanreotideÒ is a somatostatin analogue that inhibits the release of growth hormones. 2. In a subsequent investigation by the author [1] biodegradable microparticles such as poly(l-lactic-co-glycolic-co-d,l-malic acid), (I), were prepared and used as a drug delivery agent for the acetate salt of LanreotideÒ . baO O O O R O R O O O Lanreotide NH3 R = H or CH3 (I) OAc 3. Shalaby [2] prepared ionic molecular conjugates of the hydrolyzed drug delivery agent chitosan and SomatulineÒ , (II), in the treatment of acromegaly. TABLE 1. In vivo test results for LanreotideÒ in plasma levels using radioimmuno assay. Sample LanreotideÒ Levels after 6 Hours (ng/ml) LanreotideÒ Levels after 8 Days (ng/ml) LanreotideÒ Levels after 22 Days (ng/ml) Step 3 product 21 – 4.5 30.2 – 7.5 0.05 – 0.02 Entry 4*1 24.4 – 5.2 20.8 – 7.2 0.141 – 0.09 *1 Entry 4 was obtained by replacing NaOH with an equivalent amount of NaHCO3 in Step 3. Notes 37
  • 54. a O OO O HO NH3 OH OH NH3 CO2 OH HO O HO CO2 NH3 OH CO2 CO2 CO2 CO2 Somatuline NH3 NH3 NH3Somatuline Somatuline (II) 4. Li [3] prepared ionic complexes of aminated polyrotaxanes with bulky bio- cleavable end caps as a method for delivering nucleic acids. 5. Polyfunctional monomers, (III), prepared by Li [4] were used to synthesize cationic polymers having degradable crosslinks for therapy involving the delivery of nucleic acids into cells. O O O OO O O O O O O O (III) 6. Leong [5] and Dang [6] used cyclic phosphate monomers, (IV), and either lactide or caprolactone monomers to prepared phosphate based biodegradable polymers, (V), illustrated below, that were then converted into microspheres and used as drug deliver agents for anti-neoplastic medicaments. O P O H3CO O O O P O O O O O OCH3 (IV) (V) i a b i: d,l-Lactide, benzene, methanol 38 Lactone Bearing Absorbable Polymers
  • 55. References 1. F.X Ingnatious et al., US Patent Application 2006-0121120 (June 8, 2006) 2. S.W. Shalaby et al., US Patent 7,005,420 (February 28, 2006) 3. J. Li et al., US Patent Application 2006-0211643 (September 21, 2006) 4. S. Li et al., US Patent 7,163,677 (January 16, 2007) 5. K.W. Leong et al., US Patent 6,805,876 (October 19, 2004) 6. W. Dang et al., US Patent 6,800,672 (October 5, 2004) Notes 39
  • 56. B. Contact Lenses Title: Low Polydispersity Poly-HEMA Compositions Author: T. Kindt-Larsen et al., US Patent 7,256,246 (August 14, 2007) Assignee: Johnson Johnson Vision Care, Inc (Jacksonville, FL) SIGNIFICANCE Cross-linked pre-polymers having fractionalized molecular weights between 35,000 and 70,000 daltons with polydispersity indexes of less than 3.4 have been prepared by the free radical addition of 2-hydroxethyl methacrylate, HEMA, with 2% methacrylic acidorglycerolmethacrylate.Oncecrosslinked,thesematerialsareparticularlyuseful as contact lenses because of their limited shrinkage and expansion. REACTION O O OH O O OO OH O O O OH i ii Fractionalization a b c d Note 2 Note 1 i: Ethanol, dodecyl mercaptan, methacrylic acid, 2,20 -azobis (2-methylbutyronitrile) ii: Ethanol, hexane EXPERIMENTAL 1. Preparation of Poly(2-Hydroxethyl Methacrylate-co-Methacrylic Acid) (poly-HEMA) A 5-liter stainless steel reactor was charged with ethanol (1911.6 g), 2-hydroxethyl methacrylate (1056.6 g), dodecyl mercaptan (3.00 g), and methacrylic acid (21.00 g) 40
  • 57. at 25 C. The temperature was raised to 68 C and then the mixture treated with 2,20 -azobis(2-methylbutyronitrile) (7.50 g). After heating for 18 hours at 68 C the mixture was heated to 80 C an additional 22 hours then cooled. The product was isolated with a solid content of 37.2% with a Mn of 68,000 daltons and a PDI of 3.75. 2. Fractionalization of Poly(2-Hydroxethyl Methacrylate-co-Methacrylic Acid) Step 1 Fractionalization Process The Step 1 product was initially diluted with ethanol to give a 10% solution of poly- HEMA in ethanol. The solution initially became turbid at 24 C and clear and homogeneous at 40 C. The solution was cooled to 21 C; the solution then separated into two clear phases after three days. The bottom fraction had a molecular weight of 144,000 daltons with a polydispersity of 3.34 and was discarded. The top soluble layer had a molecular weight of 64,000 daltons with a polydispersity of 2.28 and was further fractionated at 8 C. After 24 hours the solution was again separated into two phases. The bottom phase constituted 15 vol% of the total solution and contained 35.7 wt% of poly-HEMAhavingamolecularweightof83,800daltonswithapolydispersityof2.18 that was further fractionated. Step 2 Fractionalization Process After addition of 2% hexane to the lower layer, the solution had a cloud point at 31 C. The mixture was heated to 40 C to make it homogeneous, and then it stood at 28 C for five days before it separated into two clear phases. The top phase contained 77.1% of the polymer and was siphoned off, and the bottom phase was discarded. Step 3 Fractionalization Process The amount of hexane in the top phase was adjusted to 7%, which resulted in a cloud point of 54 C. The solution was re-heated to 57 C to make it homogeneous, and after four days at 29 C the solution separated into two clear phases. The top phase containing the low molecular weight fraction of the polymer was siphoned off, and the bottom phase was given a third fractionation. Step 4 Fractionalization Process In this procedure the hexane concentration was adjusted to 8%, and the solution stood for four days at 30 C. The top phase containing the low molecular weight fraction of the polymer was siphoned off, and the lower retained as the Step 1 fractionalized product. Experimental 41
  • 58. FRACTIONALIZATION PROFILE DERIVATIVES Poly(2-hydroxethyl methacrylate-co-glycerol methacrylate) was also prepared hav- ing a molecular weight of 41,000 daltons with a PDI of 2.80. NOTES 1. The preparation of molded contact lenses using the polymers of the current invention are described by the author [1] in an earlier investigation. 2. Ford [2] determined that isopropanol, dipropylene glycol dimethyl ether, dipropylene glycol methyl ether acetate, dipropylene glycol methyl ether, and tripropylene glycol methyl ether were also effective in fractionating analogues of the current invention. 3. Wettable polymer silicon hydrogels were prepared by Laredo, (I), [3] and Zanini, (II), [4], respectively, and used in contact lenses. O O N H O O O Si O O N H O NH O O CH2CF2(OCF2)aCF3 26 (I) Si O O Si OSi(CH3)3 (H3C)3SiO OH O OH (H3C)3SiO OSi(CH3)3 (II) TABLE 1. Fractionalization effectiveness for poly(2-hydroxethyl methacrylate- co-methacrylic acid) using selected extraction solvents. Entry Fractionalization Temperature ( C) Fractionalization Solvent Molecular Weight (daltons) PDI 5 82 2-Propanol 35,000 3.4 6 78 2-Propanol 40,000 3.4 7 74 Ethanol 50,000 2.6 8 72 Ethanol 60,000 3.6 9 68 Ethanol 70,000 3.3 42 Low Polydispersity Poly-HEMA Compositions
  • 59. 4. Biocompatible contact lenses having high oxygen and water permeability were prepared by Nicolson [5] by reacting the polysiloxane macromonomer, (III), with ethylene glycol, and 2% 2-hydroxyethyl methacrylate. O Si OOHN O OCN O H N O NCO (III) a b References 1. T. Kindt-Larsen et al., US Patent 6,846,892 (January 25, 2005) 2. J.D. Ford et al., US Patent 7,112,652 (September 26, 2006) 3. W.R. Laredo et al., US Patent 7,249,848 (July 31, 2007) 4. D. Zanini et al., US Patent 7,214,809 (May 8, 2007) 5. P.C. Nicolson et al., US Patent 7,045,248 (October 4, 2005) Notes 43
  • 60. C. Drug Delivery Title: Amphiphilic Block Copolymers and Nanoparticles Comprising the Same Author: M.-F. Hsieh et al., US Patent Application 2007-0104654 (May 10, 2007) Assignee: Industrial Technology Research Institute (Hsinchu, TW) SIGNIFICANCE A biocompatible and biodegradable amphiphilic block copolymer consisting of hydrophobic and hydrophilic segments containing zwitterions has been prepared. This agent is useful as a drug delivery agent for water-insoluble drugs, including growth factors and genes, and in cosmetic formulations. REACTION O O H3CO O O H H3CO O O P O O O H3CO O O P O O O N(CH3)3a b aa b iii iii O O O ivNanoparticles i: Poly(ethylene glycol), stannous 2-ethylhexanoate ii: Triethylamine, 2-chloro-2-oxo-1,3,2-dioxaphospholane, CH2Cl2 iii: Acetonitrile, trimethylamine, CH2Cl2 EXPERIMENTAL 1. Preparation of Poly(Ethylene Glycol-b-Valerolactone) A glass reactor was charged with poly(ethylene glycol) (60g; 5000 daltons) and d-valerolactone (12g), which was gradually heated until dissolved. This mixture was 44
  • 61. then treated with 0.38ml of stannous 2-ethylhexanoate and heated for 8 hours at 160 C. ThereafterthemixturewasdissolvedinCH2Cl2 andprecipitatedbyaddingdiethylether. The white precipitate was washed and dried, and the block copolymer was isolated. 2. Preparation of Poly(Ethylene Glycol-b-Valerolactone)-2-oxo-1,3,2- Dioxaphospholane The Step 1 product (5 g) and triethylamine (0.43 g) were dissolved in 70 ml of CH2Cl2 at 0 C, then added dropwise to 2-chloro-2-oxo-1,3,2-dioxaphospholane (3.5 g) dis- solved in 30 ml of CH2Cl2 and stirred at 0 C for 6 hours. The resulting solution was warmed to ambient temperature, filtered through 0.45 mm filter paper, and concen- trated, and the product was isolated. 3. Preparation of Poly(Ethylene Glycol-b-Valerolactone)- Trimethylammonium Phosphate The Step 2 product was dissolved in 70 ml of acetonitrile at ambient temperature and then treated with 10 ml of 33% trimethylamine in ethanol and heated for 24 hours at 60 C. The solution was next concentrated and extracted three times with CH2Cl2/ water. After re-concentrating and drying, the product was isolated as a white solid. 4. Preparation of Polymeric Nanoparticles Ten milligrams of the Step 3 product were dissolved in 1 ml of dimethyl sulfoxide and then removed by freeze-drying. Thereafter 1 ml of 10% sucrose was added to the hydrate, and the freeze-dried solids were re-dissolved to form a suspension. After ultra-sonicating for 10 minutes, polymer nanoparticles were formed. DERIVATIVES Two additional derivatives were prepared as illustrated below. H3CO O O O a b NHR H2C N SO3 O O HC CO2H N N R________________ Derivatives 45
  • 62. TESTING Micelle Formation A solution of 10 mg of a selected polymer dissolved in 1 ml THF was gradually added to 30 ml deionized water and stirred. The solution was placed in a dialysis membrane for 24 hours to form a micelle solution. Then the 3 to 5 ml micelle of the solution was placed in an acrylic cuvette to measure micelle sizes and their distribution by photon correlation spectroscopy. Testing results are provided in Table 1. NOTES 1. Amphiphilic block copolymers consisting of polyethylene glycol and poly- lactide, (I), were prepared by Seo [1] and used as drug delivery agents for PaclitaxelÒ . H3CO O O O O O O 44 24 (I) 2. Block cationomers, (II), consisting of polyisobutylene and poly(2-dimethyl- amino)ethyl methacrylate) were prepared by Kennedy [2] and used as timed release agents for pharmaceuticals. O Br OO N(CH3)3 I(II) a Polyisobutylene TABLE 1. Effect of terminus and block segment composition in poly(ethylene-glycol-b-valerolactone) on CMC formation. Polymer Terminus PEO Block (daltons) Lactone Block (daltons) CMC (10À2 wt%) Trimethylammonium phosphate 5000 1900 3.26 5000 1100 17.92 Dimethylammonium sulfate 2000 1000 1.46 2000 2000 4.47 5000 2500 3.95 5000 3700 7.76 46 Amphiphilic Block Copolymers and Nanoparticles Comprising the Same
  • 63. 3. Wang [3] prepared the amphiphilic biocompatible cyclodextrin graft polymer, poly(ethylene glycol-g-cyclodextrin), (III), containing modified cyclodextrin which was used as a bioactive drug delivery agent. O O NHO S S HN Cyclodextrin a b (III) 4. Dai [4] modified oxidized carbon nanotubes, (IV), and these were subsequently used as transporters for the delivery of biologically active agents into cells. aN H O O N H O S NH HN O H H Oxidized nanotube (IV) References 1. M.-H. Seo et al., US Patent 7,217,770 (May 15, 2007) 2. J.P. Kennedy et al., US Patent 7,196,142 (March 27, 2007) 3. L. Wang et al., US Patent 7,141,540 (November 28, 2006) 4. H. Dai et al., US Patent Application 2006-0275371 (December 7, 2006) Notes 47
  • 64. Title: Heterofunctional Copolymers of Glycerol and Polyethylene Glycol, Their Conjugates and Compositions Author: F. Ignatious, US Patent 7,196,145 (March 27, 2007) Assignee: SmithKline Beecham Corporation (Philadephia, PA) SIGNIFICANCE Block- and copolymers consisting of ethylene oxide and glycidol were prepared anionically containing an d-hydroxy butyric acid terminus. The acidic terminus was then converted into a-succinimidyl and conjugated with the protein, Grob-t, and the lipid, di-stearoyl phosphatidyl-ethanolamine. REACTION O O O O O OH OH O HO O O O O O O OH OH O O N O O O O O O O OH OH H N O O O O O O OH OH t-Grob-HN O Di-stearoyl phosphatidyl O i ii iii iv b aa b a b a b Note 1 i: 4-Hydroxy butyric acid-sodium salt, potassium, glycidol, THF ii: N,N0 -Dicyclohexyl carbodiimide, N-hydroxysuccinimide, CH2Cl2 iii: Grob-t, Dulbeccu’s phosphate, hydrochloric acid iv: Di-stearoyl phosphatidyl-ethanolamine, triethylamine, CCl3H 48
  • 65. EXPERIMENTAL 1. Preparation of a-Carboxyl-d-Hydroxyl Poly(Ethylene Oxide-block- Polyglycidol) A reactor was charged with 4-hydroxy butyric acid-sodium salt (0.045 mol) and potassium (0.046 mol) in 400 ml of THF, refluxed 12 hours, and transferred to a high-pressure reactor. The reactor temperature was lowered to À10 C and treated with 95 ml of ethylene oxide using a stainless steel capillary and the solution stirred at 50 C for 24 hours. Glycidol previously dissolved in THF was slowly added through a stainless steel capillary, and the solution was stirred at 50 C for 12 hours. The reactor was cooled, and the contents were poured into 5 ml 35% hydrochloric acid whereupon KCl precipitated. The solution was filtered. Then the filtrate, was precipitated in cold 2-propanol containing 20% hexanes and a light yellow precipitate was isolated. The dried residue was dissolved in 500 ml distilled water and extracted with CH2Cl2 to remove the unreacted initiator. After removal of the solvent, the product was washed twice with water and isolated. 2. Preparation of d-Hydroxy-a-Succinimidyl Poly(Ethylene Oxide-block-Polyglycidol) A reactor was charged with the Step 1 product (0.011 mol), N,N0 -dicyclohexylcarbo- diimide(0.0176 mol),and N-hydroxysuccinimide (0.0176 mol)dissolvedin150 ml of CH2Cl2 and then stirred overnight at ambient temperature. A cloudy heterogeneous white formed, which was removed by filtration and the filtrate concentrated. The residue was precipitated in cold diethyl ether and the product isolated after re- crystallization with ethanol. 3. Conjugation of d-Hydroxy-a-Succinimidyl Poly(Ethylene Oxide-block-Glycidol) to Grob-t The Step 2 product was added to a 2.5 mg/ml solution of Grob-t in Dulbeccu’s phosphate buffered at pH 7.0 at a molar ratio of the Step 2 product/protein 2:1, 4:1, or 10:1, respectively. The reaction was stirred for 3 hours at 40 C and quenched with 0.5 M glycine, and then the pH was lowered to 4.5 with 3 M of hydrochloric acid. The conjugate was isolated after purification by diafiltration. 4. Conjugation of d-Hydroxy-a-Succinimidyl Poly(Ethylene Oxide-block-Polyglycidol) to a Lipid The Step 2 product (0.8 mmol) dissolved in CCl3H was treated with di-stearoyl phosphatidyl-ethanolamine (0.70 mmol) containing triethylamine (1.4 mmol) and heated to 40 C to 45 C for 2 hours. The conjugate was isolated after purification by diafiltration. Experimental 49
  • 66. DERIVATIVES Poly(ethylene oxide-co-glycidol) was also prepared. NOTES 1. In a subsequent investigation by the author [1], the aldehyde-terminated Step 1 analogue was prepared and used as a conjugate with selected biomolecules. O O O O O OH OH H O ba OH (I) 2. Miyanaga [2] prepared moderate molecular weight polyglycidol ethers, (II), by polymerizing the corresponding glycidol ether with samarium triisopropoxide, samarium tris(tetramethyl heptanedionate), and yttrium tris(tetramethyl hep- tanedionate) with methyl aluminoxane. O O R a R a OH 760 CH3 700 Steryl 820 CH2C8F17 250 (II) 3. Polyglycidol containing cyanoethyl, (III), trimethylsilylacetyl, and cyanoben- zoyl termini were prepared by Sata [3] and used as a component in ion- conductive polymer electrolyte compositions. O ONC O CN (III) CN a References 1. F. Ignatious et al., US Patent Application 2005-0048650 (March 3, 2005) 2. S. Miyanaga et al., US Patent 6,906,167 (June 14, 2005) and US Patent 6,800,723 (October 5, 2004) 3. T. Sato, US Patent 6,472,106 (October 29, 2002) and US Patent 6,469,107 (October 22, 2002) 50 Heterofunctional Copolymers of Glycerol and Polyethylene Glycol
  • 67. Title: Polyalkylene Glycol Acid Additives Author: P. S. Bailon et al., US Patent 7,193,031 (March 20, 2007) Assignee: Hoffmann-La Roche, Inc. (Nutley, NJ) SIGNIFICANCE A new class of activated biological conjugates has been prepared. Methoxy polyeth- ylene glycol having a molecular weight of 2000 daltons was converted into the corresponding valeric acid succinimidyl ester then conjugated with AZT, T-20 polypeptide, and human erythropoietin. These conjugates materials produced biolog- ically active agents useful in pharmaceutical applications. REACTION H3CO O O OH H3CO O O O OC2H5 O H3CO O O O OH O H3CO O O O O O N O O H3CO O O O O O NO HN O i ii iiiiv 20 20 20 20 20 Note 1 i: Toluene, ethyl-5-bromovalerate ii: Sodium hydroxide iii: N-hydroxy-succinimide, dicyclohexylcarbodiimide iv: 30 -Azido-30 -deoxy-thymidine, 1-hydroxybenzotriazole, (4-dimethylamino)pyr- idine, dicyclohexylcarbodiimide 51
  • 68. EXPERIMENTAL 1. Preparation of Methoxy-Polyethylene Glycol Valeric Ethyl Ester Areactorwaschargedwithpolyethyleneglycol(0.5 mol;Mn 10,000),andtreatedwith 50 ml of toluene, and azeotropically dried by refluxing for 2 hours. The resulting mixture was dissolved in 30 ml of THF and treated dropwise with sodium hydride (5 mmol) dissolved in 20 ml of THF and refluxed overnight. This mixture was then treated with ethyl-5-bromovalerate (5 mmol) and refluxed overnight and concentrat- ed. The residue was precipitated by the addition of 2-propanol/diethyl ether, 1:1, and then filtered to yield 4.5 g of isolated product. 2. Preparation of Methoxy-Polyethylene Glycol Valeric Acid The Step 1 product (4 g) was dissolved in 100 ml of 1 M NaOH and stirred at ambient temperature overnight. The pH of the mixture was adjusted to 2.5 using 6 M hydrochloric acid; the mixture extracted using 50 ml, 40 ml, and 30 ml of CH2Cl2, dried with Na2SO4, and concentrated. The concentrate was precipitated in diethyl ether, and 3 g of product were isolated. 3. Preparation of Methoxy-Polyethylene Glycol Valeric Acid Succinimidyl Ester The Step 2 product (0.2 mmol) was dissolved in 10 ml of CH2Cl2 and treated with N-hydroxy-succinimide (0.41 mmol) and dicyclohexylcarbodiimide (0.42 mmol). The mixture was stirred overnight at ambient temperature and then filtered and con- centrated. The residue was precipitated in 2-propanol/diethyl ether, 1:1, and filtered to yield 1.6 g of isolated product. 4. Preparation of PEG-AZT Conjugate TheStep3product(0.02 mmol)wasdissolvedin2 mlofDMFandtreatedwith30 -azido- 30 -deoxy-thymidine (0.04mmol), 1-hydroxybenzotriazole (0.04 mmol), 4-dimethyla- minopyridine (0.042mmol), and dicyclohexylcarbodiimide (0.046mmol) and stirred overnightatambienttemperature.Themixturewasfiltered,concentrated,precipitatedin 2-propanol/diethyl ether, 1:1, and 0.17g product was isolated. 1 H-NMR (d6-DMSO) d 1.18 ppm (m, 3H, H1); 1.51 ppm (m, 2H, H9); 2.23 ppm (m, 1H, H4); 2.37 ppm (t, 2H, H8); 3.21 ppm (s, H12); 3.5 ppm (s, H11). 4.2 ppm (m, 1H, H5); 6.12 ppm (m, H3, H6); 7.45 ppm (s, 1H, H2); 11.35 ppm (br, 1H, H10) 1 H-NMR (d6-DMSO) d 1.50 ppm (q, 2H, –CH2CH2–COOH); 2.21 ppm (t, 2H, –CH2CH2–COOH); 3.21 ppm (s, –OCH3); 3.5 ppm (s, –O–CH2CH2–O–). 1 H-NMR (d6-DMSO) d 1.58 1.67 ppm (m, 4H, –CH2CH2CH2–COO–); 2.69 ppm (t, 2H, –CH2CH2CH2– COO–); 2.81 ppm (s, 4H, NHS); 3.21 ppm (s, –OCH3); 3.5 ppm (s, –O–CH2CH2–O–). 52 Polyalkylene Glycol Acid Additives
  • 69. DERIVATIVES Two linear derivatives were prepared using the Step 4 product: H3CO O O O G O 20 G = T-20 polypeptide, human erythropoietin One branched derivative was also prepared. H3CO O O H N O NH O O H3CO O N O O 20 20 NOTES 1. In subsequent investigations by the author [1] and Ley [2] the Step 4 product was used as a conjugate for the granulocyte colony stimulating factor and Kunitz domain polypeptides, respectively. 2. In other investigations by the author [3–5] an aldehyde terminated Step 4 analogue (I) was prepared and used as conjugates for T-20 polypeptide, human erythropoietin, and T1249 polypeptide, respectively. H3CO O O O CHO 20 (I) 3. A blended composition for facilitating delivery of a biologically active conju- gated material was prepared by Kabanov [6] and consisted of a block copolymer of ethylene oxide and acrylic acid salt of cetylpyridinium bromide, (II). O OO N176 186 14 (II) 4. Oh [7] prepared biodegradable lactide derivatives, (III), for conjugation with biologically active agents for use as drug delivery agents. Notes 53
  • 70. aHO O O O O O O O O O NO2 (III) 5. Roberts [8] prepared polyethylene glycol 2-pyridylthioester derivatives, (IV) for conjugating with a-amine polypeptides. H3CO O O S O Na (IV) References 1. P.S. Bailon, US Patent Application 2005-0196378 (September 8, 2005) 2. A.C. Ley, US Patent Application 2007-0041959 (February 22, 2007) 3. P.S. Bailon et al., US Patent 7,049,415 (May 23, 2006) 4. P.S. Bailon et al., US Patent 6,583,272 (June 24, 2003) 5. P.S. Bailon et al., US Patent Application 2004-0171542 (September 2, 2004) 6. A.V. Kabanov et al., US Patent 7,169,411 (January 30, 2007) 7. J.E. Oh et al., US Patent 7,163,698 (January 16, 2007) 8. J.H. Roberts et al., US Patent 7,078,496 (July 18, 2006) 54 Polyalkylene Glycol Acid Additives
  • 71. Title: Thermosensitive Biodegradable Copolymer Author: K.-Y. Chang et al., US Patent 7,179,867 (February 20, 2007) Assignee: Industrial Technology Research Institute (Hsinchu, TW) SIGNIFICANCE A method for increasingthe biodegradability of low cytotoxic poly(ethyleneglycol-b- (lactide-co-glycolide)) derivatives is described. The block copolymers are thermo- sensitive and can be easily implanted into the human body through injection for timed release of biologically active agents. REACTION H3CO O O OH O O O O O O H3CO O O O O O O a b c a b c 11 i ii i: Lactide, methoxypolyethylene glycol, tin octanate ii: Lauric acid, dicyclohexylcarbodiimide, CH2Cl2, CHCl3 EXPERIMENTAL 1. Preparation of Poly(Ethylene Glycol-b-(Lactide-co-Glycolide)) A reaction vessel was heated under nitrogen until the temperature reached 110 C and then treated with lactide (50.0 g), glycolide (11.36 g), and methoxypolyethylene glycol (24.02 g). After the monomers had melted, the contents were treated with 0.05% tin octanate while the temperature slowly increased to 160 C for 9 hours; the vessel was then cooled to ambient temperature. The solid was dissolved in 80 ml of CH2Cl2,thenpouredinton-hexane/ether,9:1,respectively,andstirredfor3hours.The solution was next separated into two phases. The upper liquid was discarded, the bottom liquid was washed three times with n-hexane/diethyl ether, dried, and the product was isolated. 55
  • 72. 2. Preparation of Poly(Ethylene Glycol-b-(Lactide-co-Glycolide)) Lauric Ester Separate solutions of lauric acid (1.53 g) and dicyclohexylcarbodiimide (1.58 g) were prepared by dissolving each into 30 ml and 20 ml of CH2Cl2, respectively. The two solutions were mixed and stirred for 30 minutes and then added to the Step 1 product (10 g)dissolvedin50 mlof CHCl3.Thismixturewastreatedwithtriethylamine(1.5 g) and stirred for 24 hours. The mixture was filtered and washed with n-hexane/diethyl ether, and the product was isolated after drying. DERIVATIVES The cholic acid analogue of the Step 1 product was also prepared. H3CO O O O O O a b c OHHO OH O TESTING Gel Formation Data collection were correlated with viscosity, time, thermocouple temperature, and rheometer torque. The rotation speed of the rheometer was adjusted so that torque value fell between 80% to 100%. The gel formation time was defined as the time needed for a sample to increase its viscosity up to 10000 cP from its starting viscosity. Viscosity testing results are provided in Table 1. 1 H-NMR(CCl3D)d1.58(d,J ¼ 6.5 Hz,H-4),3.39(s,–OCH3),4.29(m,H-1,2),4.80(m,H-5),5.14(m,H-3) 1 H-NMR(CCl3D)d0.86(t,J ¼ 6.8 Hz,H-8),1.23(m,H-7),1.58(d,J ¼ 6.5 Hz,H-4),2.38(m,H-6),3.39(s, –OCH3), 4.29 (m, H-1,2), 4.80 (m, H-5), 5.14 (m, H-3) TABLE 1. Gel formation for the Step 2 product at varying times and temperatures. Time (s) Temperature ( C) 15 wt% Solution Viscosity (cp) 25 wt% Solution Viscosity (cp) 33 wt% Solution Viscosity (cp) 8 5 Fluid Fluid Fluid 9 10 7,500 Fluid Fluid 10 13 17,000 Fluid Fluid 11 15 — Fluid Fluid 12 18 — 7,500 5,000 13 20 — 25,000 25,000 56 Thermosensitive Biodegradable Copolymer
  • 73. NOTES 1. Amphiphilic block copolymers consisting of polylactic acid or poly(lactic acid- b-glycolic acid) terminated with tocopherol or cholesterol were prepared by Seo [1] and used as drug delivery agents for PaclitaxelÒ . 2. Negatively charged amphiphilic block copolymers, (I), prepared by Seo [2] were effective as cationic drug carriers and provided the advantages of increased blood concentration and improved drug stability. Stable polymeric micelle-type drug compositions were prepared by Seo [3]. H3CO O O O O O a b c X X = PO3 - Na+ = SO3 - Na+ (I) 3. Thermosensitive block terpolymers consisting of poly(ethylene oxide-b-gly- colide-b-dl-lactide) were prepared by Piao [4] and used as drug delivery agents for insulin. 4. Block terpolymers prepared by Cheng [5] consisting of poly(N-isopropyl acrylamide-b-polyethyleneoxide-b-N-isopropyl acrylamide), (II), were effec- tive as thermally reversible gels and used as subcutaneous implants, joint or tissue spacers, and biological filler for wrinkles or cosmetic implants. Metha- crylamide analogues were prepared by Gutowska [6]. aa O OHN O NH 113 (II) References 1. M.H. Seo et al., US Patent Application 2005-0201972 (September 15, 2005) 2. M.H. Seo et al., US Patent 6,890,560 (May 10, 2005) 3. M.H. Seo et al., US Patent 7,217,770 (May 15, 2007) 4. A-Z. Piao et al., US Patent 7,135,190 (November 14, 2006) 5. Y.-L. Cheng et al., US Patent 7,160,931 (January 9, 2007) 6. A. Gutowska, US Patent 6,979,464 (December 27, 2005) Notes 57
  • 74. Title: Polyamide Graft Copolymers Author: A. B. Brennan et al., US Patent 7,169,853 (January 30, 2007) Assignee: University of Florida Research Foundation, Inc. (Gainesville, FL) SIGNIFICANCE Polyamide copolymers containing a macromolecular graft substituent were prepared by condensing 4-amino-benzoic acid or a mixture of 1,4-phenylene diamine and adipic acid with 33%, 66%, and 90% S-(poly(n-butylacrylate)cysteine macromonomer. A second macromolecular monomer, S-(poly(methyl methacrylate)-cysteine, was also prepared and free radically copolymerized with perfluoromethyl methacrylate. REACTION O O n-C4H9 H2N OH S O Poly(butyl acrylate) N H N H S OO Poly(butyl acrylate) i ii a i: 2,20 -Azobisisobutyronitrile, cysteine, THF, hydrochloric acid ii: Triphenylphosphite, lithium chloride, pyridine, N-methyl-pyrrolidinone EXPERIMENTAL 1. Preparation of S-(Poly(n-Butyl Acrylate)-Cysteine Macromonomer The synthesis of poly(butyl acrylate) in the presence of cysteine was carried out using THF, ethyl alcohol, and water where the molar ratio of butyl acrylate monomer/ cysteine/azobisisobutyronitrile was 1000:30:1, respectively. The mixture was then refluxed for 6 hours at 65 C while under constant stirring. After cooling the cysteine- modified product consisted of a white precipitate dispersed within poly(butyl acry- late). The precipitate was isolated from the polymer by dissolving the poly(butyl acrylate) in THF and filtering. 58
  • 75. 2. Preparation of Poly(4-Amino-Benzoic Acid-co-(Cysteine-g-Poly (n-Butyl Acrylate)) The Step 1 product (1.37 g; Mn 26,000 daltons), 4-aminobenzoic acid (2.24 mmol), triphenylphosphite (5 mmol), and LiCl (0.09 g) were dissolved in 30 ml N-methyl- pyrrolidinone/pyridine solution, 80:20, and heated to 100 C for 4 hours. The reaction mixturewasthenprecipitatedinanexcessofwater/methanol,1:1,filtered,andwashed with methanol. The material was dried overnight under vacuum at 40 C, and the product was quantitatively isolated. DERIVATIVES TABLE 1. Selected comonomers reacted with cysteine macromolecular comonomer and corresponding macromolecular content. Cysteine Macromolecular Component Comonomer(s) Macromolecule Content In Copolymer (wt%) Poly(butyl acrylate) 4-Amino-benzoic acid 33 Poly(butyl acrylate) 4-Amino-benzoic acid 66 Poly(butyl acrylate) 1,4-Phenylene diamine and adipic acid 66 Poly(butyl acrylate) 1,4-Phenylene diamine/adipic acid 90 Poly(methyl methacrylate) Perfluoromethyl methacrylate 65 Note: Polymers derived from 4-amino-benzoic acid were insoluble in all solvents except concentrated sulfuric acid. Elemental analysis for all experimental agents supplied by author. NOTES 1. Polylysine-g-histidine derivatives, (I), prepared by Pack [1] were effective as biocompatible endosomolytic delivery agents. H N NH2 O HN O NH2 N N H a b (I) b = 10%–100% Notes 59
  • 76. 2. Kaneko [2] prepared compatibilizing agents consisting of methacrylate, (II), and styryl, (III), macromolecules. These materials were polymerized using titanium-based Ziegler–Natta catalysts. O O R R = Polyethylene Polypropylene Poly(ethylene-co-propylene) O R (II) (III) 3. TEMPO-modified poly(ethylene-co-propylene-g-maleic anhydride), (IV), and poly((ethylene-co-1-decene)-g-alkylacrylates), (V), were prepared by Matsugi [3] and used as polymer blend compatibilizing agents. O O R R = CH3 CH(CH3)CH2CH3 O O O O N O O N (V) (IV) 7 a b a b c References 1. D.W. Pack et al., US Patent Application 2001-0006817 (July 5, 2001) 2. H. Kaneko et al., US Patent 7,067,587 (June 27, 2006) 3. T. Matsugi et al., US Patent 7,022,763 (April 4, 2006) 60 Polyamide Graft Copolymers
  • 77. Title: Bioerodible Poly(Ortho Esters) from Dioxane-Based Di(Ketene Acetals) and Block Copolymers Containing Them Author: J. Heller et al., US Patent 7,163,694 (January 16, 2007) Assignee: A.P. Pharma, Inc. (Redwood City, CA) SIGNIFICANCE Bioerodible poly(ortho ester) copolymers containing hydrophilic and hydrophobic blocks have been prepared from di(ketene acetals) and oligomeric diols. These materials form micelles in aqueous solution making them useful as hydrophobic encapsulation agents or as bioerodible matrices for the sustained release of medicaments. REACTION HO HO O C2H5C2H5 OH OH O O O C2H5C2H5 O O O O O C2H5 C2H5 O O iii iii O O O C2H5C2H5 O O O C2H5 O O C2H5 O O a3 3 i: Toluene, di(trimethylolpropane), acrolein diethyl acetal, pyridinium p-toluene- sulfonate, potassium t-butoxide ii: Pentane, iron pentacarbonyl, triethylamine iii: Triethylene glycol, triethylene glycol monoglycolide, THF, salicylic acid, triethylamine 61
  • 78. EXPERIMENTAL 1. Preparation of Di[(5-Ethyl-2-Vinyl-[1,3]Dioxan-5-yl)Methyl]Ether A reactor containing 300 ml of toluene was charged with di(trimethylolpropane) (120 mmol), 45.6 ml of acrolein diethyl acetal, and pyridinium p-toluenesulfonate (6 mmol), and then refluxed for 4 hours and cooled to ambient temperature. The mixture was further treated with potassium t-butoxide (6 mmol), and then concen- trated under reduced pressure; the residue was distilled in a Kugelrohr apparatus to give 91% yield of the two crude isomers. The crude product was purified by chromatography using Silica Gel 60 and eluting with EtOAc/heptane, 20:80, and 71% yield of di[(5-ethyl-2-vinyl-[1,3]dioxan-5-yl)methyl]ether isolated as a light yellow oil. This material was re-purified by a second chromatographic separation using Silica Gel 60 while eluting with EtOAc/heptane, 10:90, and the product was isolated in 42% yield. 2. Preparation of Di[(5-Ethyl-2-Ethylidene-[1,3]Dioxan-5-yl)Methyl]Ether The Step 1 product (43.9 mmol) was added to a photochemical reactor containing 220 ml pentane and degassed by refluxing vigorously for 20 minutes and then treating with iron pentacarbonyl (0.87 mmol). The mixture was further refluxed and irradiated for 1 hour until no evidence of vinyl signals were detected using 1 H-NMR. It was cooledtoambienttemperature,treatedwith0.5 mltriethylamine,andspargedwithdry air for 4 hours. This mixture was concentrated under reduced pressure, distilled in a Kugelrohr apparatus, and a 63% yield of product was isolated as a colorless oil. 3. Preparation of Poly(Ortho Esters) Containing Triethylene Glycol A reactor was charged with the Step 2 product (3.5 mmol), triethylene glycol (4.95 mmol), triethylene glycol monoglycolide (0.05 mmol), and 5 ml of THF. The mixturewasthenpolymerizedusingsalicylicacidsolutioninTHFascatalyst.After30 minutes 0.1 ml of triethylamine was added, and the product was isolated in 99% yield after the mixture was concentrated. MS (observed): 363, 345 for C18H35O7 and C18H33O6 MS (calculated) 345 for C18H33O6 DERIVATIVES O O O C2H5C2H5 O O O C2H5 O O C2H5 A a3 62 Bioerodible Poly(Ortho Esters) from Dioxane-Based Di(Ketene Acetals)
  • 79. NOTES 1. In other investigations by the author [1] bioerodible block copoly(ortho esters), (I), consisting of the Step 2 produce and polyethylene oxide were prepared and used as controlled drug release agents. O O O C2H5C2H5 O O O C2H5C2H5 O 45 45 (I) a 2. Ng [2,3] prepared bioerodible copoly(ortho esters) consisting of the Step 2 product with monomethyl polyethylene glycol ether termini and 1,4-cyclohex- anedimethanol and either an a-hydroxy carboxylic acid, (II), or N-methyl-di- ethanol amine (III), for use as bioerodible matrices for the sustained release of biologically active agents. Other dioxalane bioerodible analogues were pre- pared by Ng [4] in an earlier investigation. O O O C2H5 C2H5 O O O C2H5 O O O C2H5 OH3CO 3 45 O a (II) TABLE 1. Selected poly(ortho ester) copolymers having bioerodible matrices used for the sustained release of medicaments. Entry A Mn (daltons) Viscosity (poise) 3 O–(CH2)10–O 5,700 78,000 4 (OCH2CH2)3 4,700 32,000 6 O O 11,400 — 7 (OCH2CH2)45 — — Note: Only limited characterization data supplied by author. Notes 63
  • 80. O O O C2H5 C2H5 O O O C2H5 N O C2H5 OH3CO 45 O a (III) 3. Biocompatible ortho aromatic polyanhydrides, (IV), prepared by Uhrich [5] were used in drug delivery systems and as scaffolding implants for tissue reconstruction. a = 6, 8 (IV) b a O O O O O O O O References 1. J. Heller et al., US Patent 7,045,589 (May 16, 2006) and US Patent Application 2006-0155101 (July 13, 2006) 2. S.Y. Ng et al., US Patent Application 2003-0152630 (August 14, 2003) 3. S.Y.Nget al.,US PatentApplication2003-0138474(July24,2003)andUSPatent 6,946,145(September 20, 2005) 4. S.Y. Ng et al., US Patent 6,822,000 (November 23, 2004) 5. K.E. Uhrich,US Patent 7,122,615 (October 17, 2006) and US Patent Application 2004-0096476 (March 20, 2004) 64 Bioerodible Poly(Ortho Esters) from Dioxane-Based Di(Ketene Acetals)
  • 81. Title: Water-Soluble Polymer Alkanals Author: A. Kozlowski US Patent 7,157,546 (January 2, 2007) Assignee: Nektar Therapeutics AL Corporation (Hunstville, AL) SIGNIFICANCE A high yielding method for preparing methoxypolyethylene glycol alkylald