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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]
Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20 Figure 21 Figure 22 Figure 23 Figure 24 Figure 25 Figure 26 Figure 27 Figure 28 Figure 29 Figure 30 Figure 31 References
Oxycodone (1) 1H NMR spectrum in CDCl3 Oxycodone (1) 13C NMR spectrum in CDCl3 Oxycodone (1) 1H NMR spectrum in CDCl3 Oxycodone (1) 1H NMR spectrum in CDCl3 Oxycodone (1) IR spectrum Oxycodone (1) HPLC Oxymorphone (2) 1H NMR spectrum in CDCl3 Oxymorphone Hydrochloride (2·HCl) 1H NMR spectrum in DMSO-d6 Oxymorphone Hydrochloride (2·HCl) 1H NMR spectrum in D2O Oxymorphone (2) 13C NMR spectrum in DMSO-d6 Oxymorphone (2) IR spectrum Oxymorphone (2) HPLC 14-Hydroxycodeinone (5) 1H NMR spectrum in D2O+TFA 14-Hydroxycodeinone Hydrochloride (5·HCl) 1H NMR spectrum in D2O 14-Hydroxycodeinone Hydrochloride (5·HCl) 13C NMR spectrum in D2O 14-Hydroxymorphinone Hydrochloride (6·HCl) 1H NMR spectrum in D2O 14-Hydroxymorphinone Hydrochloride (6·HCl) 13C NMR spectrum in D2O Naltrexone (7) 1H NMR spectrum in CDCl3 Naltrexone (7) 13C NMR spectrum in CDCl3 Naltrexone (7) IR spectrum Naltrexone (7) HPLC N-Noroxymorphone Hydrochloride (9·HCl) 1H NMR spectrum in DMSO-d6 N-Noroxymorphone Hydrochloride (9·HCl) 1H NMR spectrum in D2O N-Noroxymorphone (9) 13C NMR spectrum in DMSO-d6 Noroxycodone (9) IR spectrum Noroxymorphone (9) HPLC 14-Hydroxy-N-normorphinone HCl (13·HCl) 1H NMR spectrum in D2O 14-Hydroxy-N-normorphinone HCl (13·HCl) 13C NMR spectrum in D2O Oxymorphol (17) 1H NMR spectrum in CDCl3 Oxymorphol (17) 1H NMR spectrum in D2O+HCl N-Noroxymorphol Hydrochloride (18) 1H NMR spectrum in D2O
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S-2 S-3 S-4 S-5 S-6 S-7 S-8 S-9 S-10 S-11 S-12 S-13 S-14 S-15 S-16 S-17 S-18 S-19 S-20 S-21 S-22 S-23 S-24 S-25 S-26 S-27 S-28 S-29 S-30 S-31 S-32 S-33
Electronic Supplementary Material (ESI) for RSC Advances This journal is © The Royal Society of Chemistry 2012
1
2.20
1.10
2.599 2.453 2.425 2.414 2.322 2.286 2.180 2.170 1.871 1.863 1.858 1.677 1.668 1.634 1.632 1.607 1.594 1.588 1.566 1.556 1.08 5.16 1.10 1.09
1.03 1.08 0.98
3.187 3.141 3.071 3.059 3.035 3.023 2.999 2.986 2.880 2.865
3.916
4.670 1.01
3.01
6.719 6.699 6.650 6.630
H NMR of Crude Oxycodone (1) in CDCl3 (sample from reduction of 14-hydroxycodeinone* over 5% Pd/BaSO4 in MeOH)
1.01 0.99
7.270
Figure 1.
*Prepared via oxidation of thebaine in HOAc-TFA, according to reaction conditions reported in reference 1.
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*Prepared according to conditions described in reference 1
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21.745
35.945 31.231 30.314
50.032 45.070 42.548
56.637
64.386
70.174
77.319 77.000 76.682
90.185
114.709
119.285
124.775
C NMR of Crude Oxycodone (1) in CDCl3 (sample from reduction of 14-hydroxycodeinone* over 5% Pd/BaSO4 in MeOH) 129.191
13
144.792 142.745
208.392
Figure 2.
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1.898 1.893 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 4.78
1.05
2.452 2.425 2.415 2.325 2.181 2.171 1.15 5.37 1.06 1.09
1.04 1.13 1.01
3.189 3.143 3.074 3.061 3.038 3.025 3.002 2.989 2.877 2.863
4.671 1.00
3.909
5.080 0.95
3.03
6.721 6.701 6.652 6.631 0.98 1.00
7.270
Figure 3. 1H NMR of Crude Oxycodone (1) in CDCl3 (sample from reduction of 14-hydroxycodeinone hydrochloride* over 5% Pd/BaSO4 in MeOH)
*Prepared via oxidation of thebaine hydrochloride with m-CPBA in 10% HOAc
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21.737
35.960 31.237 30.343
50.052 45.060 42.562
56.647
64.387
70.185
77.319 77.000 76.682
90.199
129.212 124.810 119.286 114.713
144.800 142.747
208.407
Figure 4. 13C NMR of Crude Oxycodone (1) in CDCl3 (sample from reduction of 14-hydroxycodeinone hydrochloride* over 5% Pd/BaSO4 in MeOH)
*Prepared via oxidation of thebaine hydrochloride with m-CPBA in 10% HOAc
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Figure 5. Oxycodone (1) IR spectrum
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Figure 6. Oxycodone (1) HPLC
*Prepared via conditions in Table 1, Entry 8.
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2.04
1.01
2.474 2.445 2.424 2.339 2.302 2.200 1.916 1.908 1.903 1.896 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 6.22 1.09 1.04
1.00 1.05 0.94
3.184 3.138 3.089 3.077 3.053 3.040 3.017 3.004 2.899 2.885
4.690 1.00
1.20
0.97 0.98
6.740 6.720 6.626 6.606
Figure 7. 1H NMR of Crude Oxymorphone (2) in CDCl3 (sample from reduction of 14-hydroxymorphinone Hydrochloride* over 5% Pd/BaSO4 in MeOH)
*Prepared via oxidation of oripavine hydrochloride with m-CPBA in 10% HOAc
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*Prepared via oxidation of oripavine hydrochloride with m-CPBA in 10% HOAc
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2.02
1.12 2.22 3.11 1.19
2.152 2.116 1.931 1.927 1.547 1.519 1.511 1.484 1.475
3.351 3.320 2.987 2.951 2.841 2.518 2.513 2.509 2.504 2.500
1.04
3.701 3.688 1.05
1.04
4.997 1.00
6.816 6.703 6.683 6.654 6.634 0.93 1.02 1.02
9.327
1.01 0.97
9.494
Figure 8. 1H NMR of Crude Oxymorphone Hydrochloride (2·HCl) in DMSO-d6 (sample from reduction of 14-hydroxymorphinone Hydrochloride* over 5% Pd/BaSO4 in MeOH)
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2.95
68.48
34.56
2.381 2.373 2.365 2.344 2.336 1.822 1.813 1.798 1.786 1.777 1.763 1.756 1.749 30.86
4.40
141.84 35.92 31.37
39.00
3.502 3.452 3.205 3.189 3.037 3.024 2.987 2.969 2.926 2.844 2.727 2.715 35.62
35.72
3.784 3.769 3.685 3.666 29.34 3.75
4.288 4.279
29.73
1.00
5.066
71.32
2.18
6.877 6.867 6.857 6.846 6.833 6.826 6.800 6.780
Figure 9. 1H NMR of Crude Oxymorphone Hydrochloride (2·HCl) in D2O*1 (sample from reduction of 14-hydroxymorphinone Hydrochloride*2 over 5% Pd/BaSO4 in MeOH)
*1Oxymorphone hydrochloride forms a gem-diol, with a characteristic singlet at δ 4.65 ppm, in D2O (Reference 2) *2Prepared via oxidation of oripavine hydrochloride with m-CPBA in 10% HOAc
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21.600
49.640 45.154 42.314 39.938 39.729 39.520 39.312 39.103 35.781 31.124 29.864
63.861
69.994
89.366
119.119 117.291
129.331
139.460
143.475
208.815
Figure 10. 13C NMR of Crude Oxymorphone (2) in DMSO-d6 (sample from reduction of 14-Hydroxymorphinone Hydrochloride over 5% Pd/BaSO4 in MeOH)
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Figure 11. Oxymorphone (2) IR spectrum
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Figure 12. Oxymorphone (2) HPLC
*Prepared via conditions in Table 1 Entry 11
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4.981
1.05
*Prepared via literature methods reported in reference 1
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1.16
4.35
1.13
1.11
1.03
3.19
3.294 3.282 3.261 3.249 3.096 3.081 3.046 3.031 2.932 2.866 2.856 2.834 2.824 2.732 2.720 2.698 2.686 2.664 1.882 1.874 1.847 1.839
3.517 3.466
3.914 3.899 3.748
6.177 6.152
1.00
1.06
6.968 6.943 6.876 6.855 6.811 6.790
1.09 1.10 1.01
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Figure 13. 1H NMR of 14-Hydroxycodeinone (5)* in D2O + TFA
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1.984 1.976 1.950 1.942
*Prepared via oxidation of thebaine hydrochloride with m-CPBA in 10% HOAc
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1.08
0.03
1.13
4.49
3.008 2.993 2.982 2.960 2.949 2.927 2.917 2.811 2.799 2.777 2.764 2.744 2.731 1.16
1.15
3.602 3.551 1.11
5.074 1.00
3.997 3.982 3.848
6.278 6.253 0.99
1.05
7.055 7.029 6.993 6.972 6.913 6.892 1.12 1.10 1.04
Figure 14. 1H NMR of Crude 14-Hydroxycodeinone Hydrochloride (5·HCl)* in D2O
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26.170 22.961
47.217 45.506 40.848
56.502
67.361 65.001
85.920
115.549
122.804 121.146
128.332
C NMR of Crude 14-Hydroxycodeinone Hydrochloride (5·HCl)* in D2O 133.118
13
147.257 143.357 142.529
196.311
Figure 15.
*Prepared via oxidation of thebaine hydrochloride with m-CPBA in 10% HOAc
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*Prepared via oxidation of oripavine hydrochloride with m-CPBA in 10% HOAc
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1.04
1.09
4.27
1.12
1.08
1.07
3.983 3.968 3.570 3.520 3.369 3.357 3.336 3.325 3.162 3.146 3.111 3.096 3.004 2.986 2.963 2.953 2.930 2.920 2.801 2.789 2.767 2.755 2.734 1.978 1.969 1.943 1.935 1.03
5.046 1.00
4.790
6.269 6.243 0.99
2.09
1.05
7.049 7.024 6.848 6.827 6.817 6.796
Figure 16. 1H NMR of Crude 14-Hydroxymorphinone Hydrochloride (6·HCl)* in D2O
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26.105 22.955
47.250 45.535 40.826
67.399 65.001
85.722
121.969 121.121 118.777
128.505
C NMR of Crude 14-Hydroxymorphinone Hydrochloride (6·HCl)* in D2O 132.993
13
147.286 142.509 138.629
196.707
Figure 17.
*Prepared via oxidation of oripavine hydrochloride with m-CPBA in 10% HOAc
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0.581 0.578 0.561 0.558 0.166 0.154 0.152 2.02
2.607 2.592 2.450 2.437 2.425 2.408 2.349 2.313 2.177 2.167 2.095 1.889 1.881 1.876 1.681 1.656 1.653 1.647 1.645 0.880
3.202 3.187 3.083 3.059 3.046 3.037 3.023 2.953
4.696
5.309
6.730 6.710 6.606 6.586
2.07
1.18
2.21
1.90
1.11 1.13 3.17 1.12 1.14
2.35
1.09
1.00
2.36
1.03
1.00
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Figure 18. 1H NMR of Naltrexone (7) in CDCl3
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9.324 3.946 3.722
22.554
36.106 31.254 30.537
43.542
50.965
61.915 59.129
70.376
77.318 77.000 76.683
C NMR of Naltrexone (7) in CDCl3 90.452
13
129.001 124.041 119.763 117.913
138.829
143.522
209.951
Figure 19.
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Figure 20. Naltrexone (7) IR spectrum
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Figure 21. Naltrexone (7) HPLC
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1.94
1.03
1.00
1.44 0.47
2.932 2.919 2.895 2.569 2.557 2.536 2.528 2.500 2.130 2.122 2.100 2.093 1.937 1.914 1.906
3.676 3.662 1.06
1.02 2.05 1.08
4.914 1.00
1.04
6.676 6.656 6.636 6.616 6.384
8.532 0.94
2.05
9.452 9.301 1.91
Figure 22. 1H NMR of Crude N-Noroxymorphone Hydrochloride (9·HCl) in DMSO-d6 (sample from reduction of 14-hydroxy-N-normorphinone Hydrochloride over 5% Pd/BaSO4 in MeOH)
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0.10
2.24
2.080 2.057 2.049 2.044 1.798 1.790 1.783 1.764 1.754 1.746 1.718 1.13
1.03
0.17
1.06
1.16
1.21
3.39
3.296 3.283 3.270 3.256 3.243 3.037 3.024 3.000 2.904 2.893 2.728 2.715 2.694 2.682 2.372 2.335
4.631 0.07
3.916 3.905 3.818 3.805
5.053 1.00
0.97 0.11
6.884 6.863 6.845 6.824 6.796 6.776 2.20
Figure 23. 1H NMR of Crude N-Noroxymorphone Hydrochloride (9·HCl) in D2O* (sample from reduction of 14-hydroxy-N-normorphinone Hydrochloride over 5% Pd/BaSO4 in MeOH)
*The hydrochloride salt of 6-keto-morphinans such as oxycodone and oxymorphone are known to form gem-diols in D2O (Reference 2); in the case of N-noroxymorphone, the singlet at δ 4.63 ppm is characteristic of the chemical shift due to H-6 of the gem-diol.
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50.209 40.123 39.915 39.708 39.500 39.291 39.082 38.875 37.265 35.724 31.251 30.857 29.109
56.804
69.508
89.436
123.485 119.089 117.340
129.299
C NMR of Crude N-Noroxymorphone (9) in DMSO-d6 (sample from reduction of 14-Hydroxy-N-normorphinone Hydrochloride over 5% Pd/BaSO4 in MeOH) 139.499
13
143.516
208.659
Figure 24.
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Figure 25. Noroxymorphone (9) IR spectrum
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Figure 26. Noroxymorphone (9) HPLC
*Prepared via conditions in Table 2, Entry 3
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2.005 1.994 1.970 1.960 1.06
1.08
3.049 3.038 3.015 2.798 2.785 2.764 2.751 2.730 2.718 1.12
3.19
3.374 3.363 3.341 3.326 3.314 3.300 3.264 3.250
4.126 4.114 1.00
5.059 1.00
4.790
6.301 6.276 0.98
2.00
1.03
7.078 7.052 6.886 6.865 6.845 6.824
Figure 27. 1H NMR of Crude 14-Hydroxy-N-normorphinone Hydrochloride (13·HCl)* in D2O
*Prepared via oxidation of N-nororipavine hydrochloride with m-CPBA in 10% HOAc
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27.413 24.980
37.082
46.123
56.366
66.382
85.963
122.323 121.115 118.727
128.787
C NMR of Crude 14-Hydroxy-N-normorphinone Hydrochloride (13·HCl)* in D2O 132.853
13
147.753 142.571 138.579
196.728
Figure 28.
*Prepared via oxidation of N-nororipavine hydrochloride with m-CPBA in 10% HOAc
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*Ratio of 6-epimers: α:ß ~ 5:1
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3.156 3.110
1.09
1.66
8.55
0.58
6.84
1.27
1.705 1.670 1.650 1.629 1.579 1.552 1.262 1.228 1.213 1.167 1.136 1.107
2.787 2.771 2.609 2.419 2.371 2.363 2.285 2.279 2.266 2.258 2.249
3.582 3.567 3.555
0.23
1.11
4.262 4.234
4.672 4.661 4.512 4.497
6.726 6.705 6.574 6.554
0.96
0.20
1.00
1.02
1.00
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Figure 29. 1H NMR of Crude Oxymorphol (17)* in CDCl3
*Ratio of 6-epimers: α:ß ~ 5:1
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4.81
1.21
0.31
4.15
2.35
1.50
1.13
1.00
0.20
1.23
2.15
1.673 1.666 1.640 1.629 1.592 1.543 1.293 1.272 1.258 1.237
2.451 2.438 2.416 2.403 2.383 2.370
3.579 3.563 3.374 3.324 3.142 3.122 3.107 3.072 3.056 2.838 2.828
4.481 4.464 4.210 4.200 4.188 4.176 4.166
4.790 4.701 4.688
6.779 6.758 6.693 6.672
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Figure 30. 1H NMR of Crude Oxymorphol (17)* in D2O+HCl
*Ratio of 6-epimers: α:ß ~ 14:1
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3.68
1.14
1.16
0.19
1.02
3.47
0.17
1.14
1.00
0.16
1.41
2.28
1.752 1.742 1.718 1.706 1.650 1.608 1.590 1.387 1.366 1.352 1.331
3.345 3.296 3.280 3.238 3.228 3.205 3.191 3.012 2.990 2.979 2.507 2.494 2.473 2.460 2.439 2.426
3.798 3.783
4.790 4.773 4.760 4.555 4.538 4.295 4.285 4.273 4.264 4.261 4.251
6.872 6.852 6.775 6.755
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Figure 31. 1H NMR of Crude N-Noroxymorphol Hydrochloride (18)* in D2O
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References [1]
Hauser, F. M.; Chen, T.-K.; Carroll, F. I. J. Med. Chem. 1974, 17, 1117.
[2]
Caldwell, G. W.; Gauthier, A. D.; Villani, F. J.; Maryanoff, C. A.; Leo, G. Tetrahedron Lett. 1991, 32, 3763.
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