Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 Accessory Publication Improved Synthesis of 14-Hydroxy Opioid Pharmaceuticals and Intermediates Gaik B. KokA and Peter J. ScammellsA,B A Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia B Corresponding author. E-mail: [email protected] 1 Figure 1 Oxycodone (1) H NMR spectrum in CDCl3 S-2 13 Figure 2 Oxycodone (1) C NMR spectrum in CDCl3 S-3 1 Figure 3 Oxycodone (1) H NMR spectrum in CDCl3 S-4 1 Figure 4 Oxycodone (1) H NMR spectrum in CDCl3 S-5 Figure 5 Oxycodone (1) IR spectrum S-6 Figure 6 Oxycodone (1) HPLC S-7 1 Figure 7 Oxymorphone (2) H NMR spectrum in CDCl3 S-8 1 Figure 8 Oxymorphone Hydrochloride (2·HCl) H NMR spectrum in DMSO-d6 S-9 1 Figure 9 Oxymorphone Hydrochloride (2·HCl) H NMR spectrum in D2O S-10 13 Figure 10 Oxymorphone (2) C NMR spectrum in DMSO-d6 S-11 Figure 11 Oxymorphone (2) IR spectrum S-12 Figure 12 Oxymorphone (2) HPLC S-13 1 Figure 13 14-Hydroxycodeinone (5) H NMR spectrum in D2O+TFA S-14 1 Figure 14 14-Hydroxycodeinone Hydrochloride (5·HCl) H NMR spectrum in D2O S-15 13 Figure 15 14-Hydroxycodeinone Hydrochloride (5·HCl) C NMR spectrum in D2O S-16 1 Figure 16 14-Hydroxymorphinone Hydrochloride (6·HCl) H NMR spectrum in D2O S-17 13 Figure 17 14-Hydroxymorphinone Hydrochloride (6·HCl) C NMR spectrum in D2O S-18 1 Figure 18 Naltrexone (7) H NMR spectrum in CDCl3 S-19 13 Figure 19 Naltrexone (7) C NMR spectrum in CDCl3 S-20 Figure 20 Naltrexone (7) IR spectrum S-21 Figure 21 Naltrexone (7) HPLC S-22 1 Figure 22 N-Noroxymorphone Hydrochloride (9·HCl) H NMR spectrum in DMSO-d6 S-23 1 Figure 23 N-Noroxymorphone Hydrochloride (9·HCl) H NMR spectrum in D2O S-24 13 Figure 24 N-Noroxymorphone (9) C NMR spectrum in DMSO-d6 S-25 Figure 25 Noroxycodone (9) IR spectrum S-26 Figure 26 Noroxymorphone (9) HPLC S-27 1 Figure 27 14-Hydroxy-N-normorphinone HCl (13·HCl) H NMR spectrum in D2O S-28 13 Figure 28 14-Hydroxy-N-normorphinone HCl (13·HCl) C NMR spectrum in D2O S-29 1 Figure 29 Oxymorphol (17) H NMR spectrum in CDCl3 S-30 1 Figure 30 Oxymorphol (17) H NMR spectrum in D2O+HCl S-31 1 Figure 31 N-Noroxymorphol Hydrochloride (18) H NMR spectrum in D2O S-32 References S-33 S1 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 reference 1. *Prepared viaoxidationofthebaineinHOAc-TFA Figure 1. 7.270 6.719 1.01 6.699 0.99 6.650 6.630 1 H NMRofCrudeOxycodone( 14-hydroxycodeinone* over5%Pd/BaSO 1.01 4.670 S2 , accordingtoreactionconditionsreportedin 1 ) inCDCl 3.01 3.916 3.187 3.141 3.071 3.059 3 3.035 reductionof (samplefrom 1.03 3.023 4 inMeOH) 1.08 2.999 0.98 2.986 2.880 2.865 2.599 1.08 2.453 5.16 2.425 1.10 2.414 1.09 2.322 2.286 2.180 2.170 1.871 1.10 1.863 1.858 1.677 2.20 1.668 1.634 1.632 1.607 1.594 1.588 1.566 1.556 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 13 Figure 2. C NMR of Crude Oxycodone (1) in CDCl3 (sample from reduction of 14-hydroxycodeinone* over 5% Pd/BaSO4 in MeOH) 208.392 144.792 142.745 129.191 124.775 119.285 114.709 90.185 77.319 77.000 76.682 70.174 64.386 56.637 50.032 45.070 42.548 35.945 31.231 30.314 21.745 *Prepared according to conditions described in reference 1 S3 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 *Prepared viaoxidationofth Figure 3. 14-hydroxycodeinone hydrochlor 7.270 1 H NMRofCrudeOxycodone( 6.721 0.98 6.701 1.00 6.652 6.631 ebaine hydrochloridewith 0.95 5.080 1.00 4.671 S4 ide* over5%Pd/BaSO 1 ) inCDCl 3.03 3.909 m -CPBA in10%HOAc 3.189 3.143 3.074 3.061 3.038 3.025 1.04 3 3.002 reductionof (samplefrom 1.13 2.989 1.01 2.877 2.863 1.15 2.452 5.37 2.425 1.06 2.415 4 1.09 2.325 inMeOH) 2.181 2.171 1.05 1.898 1.893 4.78 1.872 1.864 1.859 1.852 1.679 1.671 1.646 1.643 1.637 1.635 1.610 1.601 1.597 1.592 1.570 1.558 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 13 Figure 4. C NMR of Crude Oxycodone (1) in CDCl3 (sample from reduction of 14-hydroxycodeinone hydrochloride* over 5% Pd/BaSO4 in MeOH) 208.407 144.800 142.747 129.212 124.810 119.286 114.713 90.199 77.319 77.000 76.682 70.185 64.387 56.647 50.052 45.060 42.562 35.960 31.237 30.343 21.737 *Prepared via oxidation of thebaine hydrochloride with m-CPBA in 10% HOAc S5 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 Figure 5. Oxycodone (1) IR spectrum S6 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 Figure 6. Oxycodone (1) HPLC *Prepared via conditions in Table 1, Entry 8. S7 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 *Prepared viaoxidationofor Figure 7. 14-hydroxymorphinone Hydrochl 1 6.740 H NMRofCrudeOxymorphone( 0.97 6.720 0.98 6.626 6.606 ipavine hydrochloridewith 1.20 1.00 4.690 S8 oride* over5%Pd/BaSO 2 m 3.184 3.138 ) inCDCl -CPBA in10%HOAc 3.089 3.077 3.053 3.040 1.00 3.017 1.05 3.004 0.94 2.899 2.885 3 (sample fromreductionof (sample 2.474 6.22 2.445 1.09 2.424 1.04 2.339 2.302 2.200 1.916 1.01 1.908 4 inMeOH) 1.903 1.896 2.04 1.882 1.875 1.870 1.863 1.683 1.675 1.647 1.641 1.639 1.613 1.605 1.590 1.584 1.562 1.551 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 *Prepared viaoxidationofor Figure 8. reduction of14-hydroxymorphinoneH 1.01 9.494 0.97 9.327 1 H NMRofCrudeOxymorphoneHydrochloride( ipavine hydrochloridewith 6.816 0.93 6.703 1.02 6.683 1.02 6.654 6.634 ydrochloride* over5%Pd/BaSO S9 1.00 4.997 m -CPBA in10%HOAc 3.701 1.05 3.688 2·HCl 3.351 3.320 2.987 1.12 2.951 2.22 2.841 ) inDMSO-d 3.11 2.518 1.19 2.513 2.509 2.504 2.500 1.04 2.152 1.04 2.116 1.931 1.927 4 1.547 inMeOH) 2.02 1.519 1.511 6 1.484 from (sample 1.475 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 * (Reference 2) * 2 1 Prepared viaoxidationofor hydrochlorideformsagem-diol Oxymorphone Figure 9. reduction of14-hydroxymor 1 H NMRofCrudeOxymorphoneHydrochloride( 6.877 6.867 6.857 71.32 6.846 6.833 6.826 6.800 6.780 ipavine hydrochloridewith phinone Hydrochloride* 29.73 5.066 S10 , withacharacteristicsingletat 2.18 4.288 1.00 4.279 m -CPBA in10% HOAc 3.784 2 29.34 3.769 over5%Pd/BaSO 3.75 3.685 3.666 2·HCl 35.72 3.502 3.452 35.62 3.205 39.00 3.189 3.037 ) inD 3.024 141.84 2.987 35.92 2.969 31.37 2.926 2.844 2.727 2 O* 4.40 2.715 4 δ 2.381 1 30.86 inMeOH) 4.65 ppm, inD 4.65ppm, 2.373 (sample from (samplefrom 2.365 2.344 2.336 34.56 1.822 1.813 1.798 1.786 68.48 1.777 1.763 2.95 1.756 1.749 2 O Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 13 Figure 10. C NMR of Crude Oxymorphone (2) in DMSO-d6 (sample from reduction of 14-Hydroxymorphinone Hydrochloride over 5% Pd/BaSO4 in MeOH) 208.815 143.475 139.460 129.331 119.119 117.291 89.366 69.994 63.861 49.640 45.154 42.314 39.938 39.729 39.520 39.312 39.103 35.781 31.124 29.864 21.600 S11 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 Figure 11. Oxymorphone (2) IR spectrum S12 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 Figure 12. Oxymorphone (2) HPLC *Prepared via conditions in Table 1 Entry 11 S13 Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012 *Prepared vialiteraturemet 6.968 6.943 1.09 6.876 1.10 6.855 1.01 Figure 13.