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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

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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

S3

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

S14 1.04

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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