US009777023B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,777 , 023 B2 Mehrkhodavandi et al. ( 45 ) Date of Patent : Oct . 3 , 2017 ( 54 ) DINUCLEAR INDIUM CATALYSTS AND Douglas et al ( A Highly Active Chiral Indium Catalyst for Living THEIR USE FOR (CO ) POLYMERIZATION Lactide Polymerization , Angew . Chem . Int. Ed . 2008 , 47 , 2290 2293 ) . * OF CYCLIC ESTERS International Search Report, International Application No . PCT/ (75 ) Inventors : Parisa Mehrkhodavandi, Vancouver CA2012 /050331 , entitled " Catalysts and Methods for Cyclic Ester (CA ) ; Insun Yu , Vancouver (CA ) ; J . (Co ) Polymerization , and Polymer and Copolymer Products ” , Inter national filing date : May 18 , 2012 , Date of Communication : Aug . Alberto Acosta -Ramirez , Whites Lake 20 , 2012 . (CA ) Written Opinion of the International Searching Authority , Interna tional Application No . PCT /CA2012 / 050331, entitled “ Catalysts ( 73 ) Assignee : University of British Columbia , and Methods for Cyclic Ester (Co ) Polymerization , and Polymer and Vancouver, British Columbia (CA ) Copolymer Products ” , International filing date : May 18 , 2012 , Date ( * ) Notice : Subject to any disclaimer , the term of this of Communication : Aug . 20 , 2012 . patent is extended or adjusted under 35 International Preliminary Report on Patentability, International Application No. PCT/ CA2012 /050331 , entitled " Catalysts and U . S . C . 154 ( b ) by 42 days . Methods for Cyclic Ester ( Co )Polymerization , and Polymer and (21 ) Appl . No. : 14 / 118 , 433 Copolymer Products ” , International filing date : May 18 , 2012 , Date of Communication : Oct. 2 , 2013 . (22 ) PCT Filed : May 18 , 2012 Acosta - Ramirez , A ., et al ., “ Synthesis and structural studies of chiral indium ( III ) complexes supported by tridentate ( 86 ) PCT No . : PCT/ CA2012 / 050331 diaminophenol ligands” , Inorg . Chem ., vol . 49 ( 12 ), pp . 5444 -5452 , 2010 . $ 371 ( c ) ( 1 ) , Douglas, A . F ., et al. , “ A highly active chiral indium catalyst for ( 2 ), (4 ) Date: Jul. 21 , 2014 living lactide polymerization ” , Angew . Chem . Int. Ed ., vol . 47 ( 12 ) , ( 87 ) PCT Pub . No. : WO2012 / 155275 pp . 2290 - 2293 , 2008 . Osten , K . M ., et al. , “ Effects of ligand tuning on dinuclear indium PCT Pub . Date : Nov . 22 , 2012 catalysts for lactide polymerization ” , Dalton Trans. , vol . 41 ( 26 ) , pp . 8123 - 8134 , Mar . 8 , 2012 . (65 ) Prior Publication Data Othman , N . , et al. , “ Thermoheological and mechanical behavior of polylactide and its enantiometric diblock copolymers and blends” , US 2015 /0038651 A1 Feb . 5 , 2015 Polymer , vol . 53 ( 12 ), pp . 2443 - 2452 , Apr. 18 , 2012 . Xu , C . , et al. , “ Highly Controlled immortal polymerization of Related U . S . Application Data B -butyrolactone by a dinuclear indium catalyst ” , Chem . Commun ., vol. 48 (54 ) , pp . 6806 -6808 , May 16 , 2012 (60 ) Provisional application No .61 / 487 ,626 , filed on May Campbell , E . J . and Nguyen , S . T ., “ Unsymmetrical Salen - Type 18 , 2011 . Ligands: High Yeild Synthesis of Salen - Type Schiff Bases Contain ing Two Different Benzaldehyde Moieties " , Tetrahedron Letters , Foreign Application Priority Data 42 : 1221 - 1225 ( 2001 ) . ( 30 ) Hiki, S ., et al. , “ Synthesis and Characterization of Hydroxy - Termi nated [RS ] -poly ( 3 -hydroxybutyrate ) and its Utilization to Block May 18 , 2011 ( CA ) 2740821 Coplolymerization With L - Lactide to Obtain a Biodegradable Ther (51 ) Int. Ci. moplastic Elastomer " , Polymer , 41 :7369 - 7379 (2000 ) . C08G 63 /84 (2006 .01 ) (Continued ) CO7F 5 / 00 ( 2006 .01 ) C08G 63 / 82 ( 2006 .01 ) Primary Examiner — Gregory Listvoyb B01J 31 / 22 (2006 . 01) (74 ) Attorney, Agent, or Firm — Hamilton , Brook , Smith (52 ) U . S . CI. & Reynolds, P . C . CPC . .. .. .. C07F 5 /006 (2013 . 01 ) ; C08G 63 /823 ( 2013 .01 ) ; C08G 63 / 84 ( 2013 .01 ) ; B01J (57 ) ABSTRACT 31/ 2243 (2013 .01 ) ; B01J 2531 /0216 (2013 .01 ) ; Provided are novel dinuclear indium catalysts of formula B01J 2531 / 0238 ( 2013 .01 ) ; BOIJ 2531/ 33 ( A ) that are capable of living and immortal ring opening ( 2013 .01 ) polymerization and copolymerization of cyclic ester mono ( 58 ) Field of Classification Search mers for the preparation of biodegradable polymers and CPC .. .. .. .. .. C07F 5 / 006 ; CO8G 63 / 84 copolymers , in particular polyesters . Also disclosed are See application file for complete search history . polymerization methods and polymer products . These dinuclear indium catalysts allow less costly , highly reactive References Cited living polymerization of cyclic ester monomers with pos (56 ) sible high turn over rates and /or substantial stereo -chemical FOREIGN PATENT DOCUMENTS and microstructure control. WO WO 2012/ 155275 A1 11 /2012 ( A ) OTHER PUBLICATIONS L - In In — 12 Hsieh et al ., “ Indium complexes incorporating bidentate substituted L ' In Xinh pyrrole ligand : Synthesis , characterization , and ring -opening polymerization of e -caprolactone ” , Inorg . Chim , Acta , vol. 359 , Issue 2 , pp . 497 - 504 , Jan . 2006 . * USPTO structure search , Jan . 2016 . * 12 Claims, 15 Drawing Sheets US 9 ,777 ,023 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Holbach , M . , et al. , “ A Practical One - Pot Synthesis of Enantiopure Unsymmetrical Salen Ligands” , J . Org . Chem . Note , 71: 2903 -2906 ( 2006 ) . Ovitt , T . M . and Coates, G . W ., “ Steroselective Ring -Opening Polymerization of rac -Lactide with a Single - Site , Racemic Alumi num Alkoxide Catalyst: Synthesis of Teroblock Poly ( lactic acid ) ” , J . Polym Scie A : Poly Chem , 38 : 4686 - 4692 ( 2000 ) . Mehrkhodavandi, P ., et al ., “ Highly Active Catalysts for Ring Opening Polymerization of Lactide .” Paper presented at the CSC National Conference , Hamilton , Ontario , (May 30 - Jun . 3 , 2009 ) . Mehrkhodavandi, P . , et al . , “ Dinuclear Indium Catalysts for Enatioselective Polymerization of Lactide. ” Presented at the Inor ganic Gordon Research Conference , University of British Colum bia, ( Jun . 20 -26 , 2010 ). Woo , E . M . and Chang , L . , “ Crystallization and Morphology of Sterocomplexes in Nonequimolar Mixtures of poly ( L -lactic acid ) with excess poly ( D - lactic acid ) ” , Polymer, 52 :6080 -6089 (2011 ) . Dauth , A . and Love, J. A . , “ Synthesis and Reactivity of 2 - Azametal lacyclobutanes ” , Dalton Trans. , 41: 7782 - 7791 (2012 ) . Extended European Search Report for EP12785681. 3 , “ Dinuclear Indium Catalysts and Their Use for (Co ) Polymerization of Cyclic Esters ” , dated Jul. 15 , 2015 . Mehrkhodavandi, P ., et al ., “ Chiral Indium Catalysts for Controlled Polymerization of Lactide ” , presented at the Canadian Society for Chemistry ( CSC ) National Conference , University of British Columbia , Toronto , Canada, (May 30 - Jun . 2 , 2010 ) , 22 pages . * cited by examiner U . S . Patent Oct . 3 , 2017 Sheet 1 of 15 US 9 , 777 ,023 B2 3 .000 2 .500 v = - 3 . 8095x + 7 . 7017 R = 0 . 9966 2 . 000 In([e-CL]/TMB) 1 . 500 1 . 000 #tTTTTTTTTr - * 0 .500 0 .000 0 .00 0 . 10 0 .20 0 .30 0 .40 0 . 50 0 .60 0 . 70 0 . 80 t ( h ) FIGURE 1 Patent Oct. 3 , 2017 Sheet 2 of 15 US 9 ,777 ,023 B2 Hy e 19831.55 1.51 11,46 11.5001.3148 88682 gg -26 ??? - = XXXX 0 sowe w o 0920- ABAWAPIPPY 2 . 26 2 . 15 3 .5529 912520 .41 TTTTTTTTTTT EUWT TTr amp moment per 3 . 0 2 . 5 20 1 . 5 10 Chemical Shift (ppm ) FIGURE 2 U . S . Patent Oct . 3 , 2017 Sheet 3 of 15 US 9 ,777 ,023 B2 16.5 movementsespompoms.17 18.5 5.15 nek7.27 6 26 5.22 How5.75 5.24 364 4.35 419 2515. 14.212014. 11 4.19 14.1814. 1813.77 -3.76 * 4 -2 - 978 . wwwwwwwwwwwxxww : : co . comWix. 00: 0 101 ZEO O 66 6 66067 Z 06E' 10 0900 80 A A A AAAF AF uuuuuu u 7 . 0 09 5 . 5 09 4 . 5 4 . 0 3 . 5 Chemical Shift ( ppm ) FIGURE 2 ctd . U . S . Patent Oct. 3 , 2017 Sheet 4 of 15 US 9 ,777 , 023 B2 V40 -125 127 1724 www . a 246- wwwwwwwwwwwwwwwvocou - 57.2 223 r260 W 69271 + N 242 n.-215 317 205 *~168 owwwwwwwwwwwwwwwwww bransceremo S At S wwwwwwwwwwwww w ARAWww 14 . 13 0 . 28 199 204 17 .62 wwwwwwwwwwww w A t bi dobnim meth and make to time have we . webwww € O 07 90 Chemical Shift (ppm ) FIGURE 3 U . S . Patent Oct. 3 , 2017 Sheet 5 of 15 US 9 ,777 , 023 B2 fiyatri 52452523 i www 5.01 184.96 201527.5 14.95 -7.27 5.74 77.515.76 -375 5.73 . me WW : wwwwwwwwwwwwwwwww w wwwwwwwwwwwwwwwww * * * 6 .84 203 0 .07 Blesk . cois TT TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT 7 . 5 7 . 0 6 . 5 5 . 0 4 . 5 4 . 0 3 . 5 Chemical Shift ( ppm ) FIGURE 3 ctd . U . S . Patent Oct. 3 , 2017 Sheet 6 of 15 US 9 ,777 , 023 B2 me 15 RelativeRIintensity cosessensor 10 11 12 13 14 15 16 17 18 19 20 Time of elution (min ) FIGURE 4 U . S . Patent Oct. 3 , 2017 Sheet 7 of 15 US 9 ,777 , 023 B2 FIGURE 5 U . S . Patent Oct. 3 , 2017 Sheet 8 of 15 US 9 ,777 , 023 B2 OR FEGIR 19202 H4ne N1 N30 FIGURE 6 U . S . Patent Oct. 3 , 2017 Sheet 9 of 15 US 9 ,777 , 023 B2 [ (NNO + Bu )InCl ] z ( u -OEt ) ( IL -CI ) 400000 . 350000 windowsand . 300000 download o . - 250000 o . Mngmol-1(v) . 200000 o . PDI(0) . 3 150000 .ä? . 100000 . H . .com 50000 wi O d * *p * r .. Aepoi poticnom . .. A. .. .. .. .. .. .. .. ..A .. .. .. .. .. .. A . .. .. .. .. .. A. öL O 0 500500 1000 1500 2000 LA / initiator FIGURE 7 U . S . Patent Oct . 3 , 2017 Sheet 10 of 15 US 9 ,777 ,023 B2 80000 [( NNHO )Inl ] 2 ( ll -OEt ) ( u - I ) . 70000 . 60000 . 50000 40000 . - Mn gmol- 1 30000 . 20000 . 10000 . 0 .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. L 100 200 300 400 500 Equiv . lactide ? FIGURE 8 osU . S . termoPatent Oct . 3 , 2017 conSheet 11 of 15 unUS 9 , 777 ,023 B2 80000 . w . [( NN , O )Inl ] zfu -OET ) ( -OH ) se 70000 ) . Co 60000 . 50000 . Ñ mi. N 40000 . ã 30000 . M , gmol- 1 ã PDI . 20000 . 10000 . wo A A A - . 0 . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 0 100 200 300 400 500 Equiv . lactide wwwwwwmmmm FIGURE 9 U . S . Patent Oct. 3 , 2017 Sheet 12 of 15 US 9 , 777 ,023 B2 120000 Cam [ (NNHO ) In (I ) (dL -OEt ) lz 100000 in.