Further Investigations Into The N-Demethylation of Oripavine Using Zero-Valent Iron As A Redox Catalyst

Supplementary Material (ESI) for Organic & Biomolecular Chemistry
This journal is (c) The Royal Society of Chemistry 2011
Further Investigations into the N-Demethylation of Oripavine using Zero-valent Iron as a Redox Catalyst.
Gaik B. Kok and Peter J. Scammells*
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. E-
mail: peter.scammells@monash.edu; Fax: (+61) 3 9903 9582
General Experimental S-2

Synthesis of Oripavine-N-oxide S-2
General N-Demethylation Procedure S-2
1
Figure 1 Oripavine-N-oxide Hydrochloride (6) H NMR spectrum in D2O S-3
1
Figure 1A Oripavine-N-oxide Hydrochloride (6) H NMR spectrum in D2O (Expansion) S-4
1
Figure 1B Oripavine-N-oxide Hydrochloride (6) H NMR spectrum in D2O (Expansion) S-5
1
Figure 2 N-Nororipavine (7) Hydrochloride H NMR spectrum in D2O S-6
Figure 2A N-Nororipavine (7) Hydrochloride 1H NMR spectrum in D2O (Expansion) S-7
1
Figure 2B N-Nororipavine (7) Hydrochloride H NMR spectrum in D2O (Expansion) S-8
1
Figure 3 N-Nororipavine (7) Hydrochloride H NMR spectrum in D2O+TFA S-9
1
Figure 3A N-Nororipavine (7) Hydrochloride H NMR spectrum in D2O+TFA (Expansion) S-10
1
Figure 3B N-Nororipavine (7) Hydrochloride H NMR spectrum in D2O+TFA (Expansion) S-11
Figure 4 N-Nororipavine (7) Hydrochloride 13C NMR spectrum in D2O+TFA S-12
13
Figure 4A N-Nororipavine (7) Hydrochloride C NMR spectrum in D2O+TFA (Expansion) S-13
13
Figure 4B N-Nororipavine (7) Hydrochloride C NMR spectrum in D2O+TFA (Expansion) S-14
Figure 5 N-Nororipavine (7) Hydrochloride High Resolution MS S-15
Table A Specifications for Iron Catalysts used S-16
S-1
General Experimental
Stainless steel powders 303-L and 316-L were purchased from Alfa Aesar. Iron powder was from Höganäs Sweden. m-CPBA was purchased from Sigma-Aldrich.
All reactions were conducted under an atmosphere of nitrogen. Chloroform and 2-propanol (Merck) were used as supplied. Both solvents were degassed before use:
sonicated for 10 minutes under vacuum and then back-filled with nitrogen. Reactions were monitored using thin layer chromatography (TLC) with pre-coated Merck
5554 Kieselgel 60F254 aluminum plates using CHCl3/MeOH/NH4OH (170:30:1) as the mobile phase. The spots were visualized using both UV light and molybdate
stain. 1H and 13C NMR were recorded at 400 and 100 MHz, respectively. Chemical shifts (δ ppm) were referenced using solvent residual peaks.
Synthesis of Oripavine-N-oxide hydrochloride (6)

To a stirred solution of oripavine (1.92 g, 6.47 mmol) in CHCl3 (200 mL) and MeOH (1 mL) at -20 oC was added m-CPBA (1.54 g of a max 77% reagent)
portionwise over 10 min. The solution was then left to stir for a further 20 minutes. Ice-cold H2O (100 mL) was added; the pH of the aqueous phase was adjusted to
2–3 via the addition of 10% HCl. The layers were separated; the aqueous phase was extracted with CHCl3 (20 mL x 2), saturated with NaCl, and extracted with
CHCl3/2-propanol (3:1, 50 mL x 4). The CHCl3/2-propanol (3:1) extracts were combined, dried (Na2SO4), filtered and concentrated to give 6 as an off-white solid,
2.43 g. 1H NMR of the solid was consistent with the desired product 6 with approximately 0.5 molar equivalent of 2-propanol. This material was used in the
subsequent step without further purification. 1H NMR (D2O) δ 6.80–6.70 (m, 2H), 6.08, 5.98 (each d, J = 6.7 Hz, 1H), 5.56, 5.55 (each s, 1H), 5.32, 5.29 (each d, J
= 6.7 Hz, 1H), 4.79–4.74 (m, 1H), 3.85–3.57 (m, 9H), 3.33, 3.18 (each dd, J = 7.2, 1H), 2.70–2.47 (m, 1H), 2.18–1.98 (m, 1H).
General Procedure for N-Demethylation

To a mixture of oripavine-N-oxide hydrochloride (100 mg, 0.263 mmol) and iron powder (varying amounts; see Tables 1 and 2) was added solvent (10 mL). The
reaction mixture was then stirred at the specified temperature until complete consumption of 6 (via TLC analysis). The mixture was concentrated to dryness and the
remaining residue was subjected to column chromatography on silica gel. Elution with a gradient of CHCl3/MeOH (24:1−17:3) gave oripavine followed by N-
nororipavine, both as the corresponding hydrochloride.
The above procedure was repeated substituting iron powder with stainless steel powder 303-L or 316-L (see Table 3).
N-Nororipavine Hydrochloride (7·HCl): Off-white solid, mp >200 oC dec; [α]D24 -188 (c 1.0, 10% HOAc); [lit.1 [α]D24 -194 (c 0.83, 10% HOAc)]; 1H NMR (D2O)
δ 6.79–6.73 (m, 2H), 5.90 (d, J = 6.6 Hz, 1H), 5.50 (s, 1H), 5.25 (d, J = 6.6 Hz, 1H), 4.60 (d, J = 6.0, 1H), 3.64 (s, 3 H), 3.46–3.22 (m, 4H), 2.31 (ddd, J = 6.0, 13.3
and 13.3 Hz, 1H), 2.08–2.01 (m, 1H); 13C NMR (D2O/CF3CO2D) δ 153.0, 142.8, 138.6, 132.0, 124.4, 124.2, 120.8, 117.3, 117.0, 96.1, 87.7, 55.1, 53.2, 44.6, 37.0,
33.5, 33.1; MS (ESI) m/z 284 [M+H]+; HRMS C17H18NO3 calcd for [M+H]+ 284.1281, found 284.1287.
S-2
1
Figure 1. H NMR of Oripavine-N-oxide Hydrochloride (6) in D2O
S-3
1.0
3.009
1.9977
2.0031
2.0
2.0363 1.089
2.6455 1.092
2.6602
3.2921
3.3103
3.0
3.3422
3.3605
3.5807 1.102
3.6182
3.6307
3.6491
3.6596 8.798
3.6732
3.7564
4.0
3.7658 0.629
4.0139
4.0295
4.7402 0.359
5.0
S-4
5.2862 1.025
5.3030
5.3203 0.999
5.5533
5.5656
6.0
5.9710 1.051
5.9877
6.0708
6.0876
6.7266 2.016
6.7472
6.7623
7.0
6.7800
6.8005
8.0
9.0
PPM
1.8
1.9977
2.0031
2.0363
H NMR of Oripavine-N-oxide Hydrochloride (6) in D2O (Expansion)
2.0875
2.0
2.1087
2.1104
2.1111 1.089
2.1174
2.1440
2.1456
2.1484
2.1534
2.2
2.4
2.5154
2.5290
1.092
2.6
2.6150
2.6298
2.6455
2.6491
2.6602
2.6644
2.6794
S-5
2.6947
2.8
3.0
3.1289
3.1468
3.1783
3.2
3.1966
1.102
3.2921
3.3103
3.3422
1
3.3605
3.4
Figure 1A.
3.5807
3.6
3.6182
3.6307
3.6491
3.6596 8.798
3.6732
3.7564
3.7658
PPM
1
Figure 1B. H NMR of Oripavine-N-oxide Hydrochloride (6) in D2O (Expansion)
6.8005
6.7800
6.7623
6.7472
6.7266
6.0876
6.0708
5.9877
5.9710
5.5656
5.5533
5.3203
5.3030
5.2862
4.7402
2.016
1.051
0.999
1.025
0.359
S-6
0.0
1.0
2.0149
2.0479
2.0
2.0534 1.025
2.2850
2.3011
H NMR of N-Nororipavine (6) Hydrochloride in D2O
2.3171 1.030
3.2691
3.2855
3.0
3.3018
3.3492
3.3556
3.3654 4.069
3.3875
3.3970 2.988
3.4000
3.4046
3.6358
4.0
4.5971 1.013
4.6122
4.7900
4.8161
5.0
S-7
4.8399
5.2392 1.022
5.2557
5.5025 1.000
5.8904 1.001
6.0
5.9069
1
6.7331 2.002
6.7536
6.7667
7.0
6.7872
Figure 2.
7.6652
8.0
9.0
PPM
1
Figure 2A. H NMR of N-Nororipavine (7) Hydrochloride in D2O (Expansion)
4.6122
4.5971
3.6358
3.4046
3.4000
3.3970
3.3875
3.3654
3.3556
3.3492
3.3018
3.2855
3.2691
3.2215
2.3504
2.3354
2.3171
2.3011
2.2850
2.2694
2.0534
2.0479
2.0149
1.013
2.988
4.069
1.030
1.025
PPM 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
S-8
1
Figure 2B. H NMR of N-Nororipavine (7) Hydrochloride in D2O (Expansion)
6.7872
6.7667
6.7536
6.7331
5.9069
5.8904
5.5025
5.2557
5.2392
2.070
0.998
0.999
1.027
PPM 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0
S-9
1.0
1.9540
1.9873
2.0
1.033
H NMR of N-Nororipavine (7) Hydrochloride in D2O +TFA
1.9932
2.2420
2.2579 1.021
3.2051
3.2214
3.2379
3.2949
3.0
3.3046
3.3273
3.3355 4.142
3.3411
3.5710 2.961
4.0
4.5358
4.5508 0.998
4.7712
4.7900
4.8104
4.8124
5.0
S-10
4.8151
4.8166 1.002
4.8221
4.8406 1.000
5.1717
5.1883
5.4387
5.8252 0.998
6.0
5.8419
6.6678 2.002
6.6884
6.7041
7.0
1
6.7246
Figure 3.
8.0
9.0
PPM
Figure 3A. 1H NMR of N-Nororipavine (7) Hydrochloride in D2O +TFA (Expansion)
4.5508
4.5358
3.5710
3.3411
3.3355
3.3273
3.3046
3.2949
3.2891
3.2851
3.2379
3.2214
3.2051
3.1575
2.2911
2.2761
2.2579
2.2420
2.2255
2.2100
1.9932
1.9873
1.9540
0.998
2.961
4.142
1.021
1.033
PPM 4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0
S-11
Figure 3B. 1H NMR of N-Nororipavine (7) Hydrochloride in D2O +TFA (Expansion)
6.7246
6.7041
6.6884
6.6678
5.8419
5.8252
5.4387
5.1883
5.1717
2.002
0.998
1.000
1.002
PPM 6.80 6.70 6.60 6.50 6.40 6.30 6.20 6.10 6.00 5.90 5.80 5.70 5.60 5.50 5.40 5.30 5.20 5.10 5.00
S-12
13
Figure 4. C NMR of N-Nororipavine (7) Hydrochloride in D2O + TFA
153.0419
142.7828
138.6271
131.9846
124.3895
124.2171
120.8202
117.3440
116.9749
96.0582
87.6976
55.1246
53.1965
44.5938
37.0187
33.4732
33.1104
PPM 180 160 140 120 100 80 60 40 20 0
S-13
Figure 4A. 13C NMR of N-Nororipavine (7) Hydrochloride in D2O + TFA (Expansion)
87.6976
55.1246
53.1965
44.5938
37.0187
33.4732
33.1104
PPM 84 80 76 72 68 64 60 56 52 48 44 40 36 32 28
S-14
Figure 4B. 13C NMR of N-Nororipavine (7) Hydrochloride in D2O + TFA (Expansion)
153.0419
142.7828
138.6271
131.9846
124.3895
124.2171
120.8202
117.3440
116.9749
96.0582
PPM 152 148 144 140 136 132 128 124 120 116 112 108 104 100 96
S-15
Figure 5. High Resolution MS of N-Nororipavine (7)
S-16
Table A. Specifications for Iron and Stainless Steel Catalysts
Catalyst Supplier Physical Chemical analysis (%)
properties
Fe Cr Ni Mo Mn Si Other
Iron(0) Höganäs Powder, +212 to 99 0.002 0.01 <5 ppm 0.04 0.13 Bal
Sweden -45 microns

(MnO) (SiO2)
303-L Alfa Aesar Powder, -140 70 17 13
mesh
316-L Alfa Aesar Powder, -100 67.5 17 13 2.5
mesh
S-17

Further Investigations Into The N-Demethylation of Oripavine Using Zero-Valent Iron As A Redox Catalyst

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Supplementary Material (ESI) for Organic & Biomolecular Chemistry

This journal is (c) The Royal Society of Chemistry 2011

Supplementary Material (ESI) for Organic & Biomolecular Chemistry

Gaik B. Kok and Peter J. Scammells*

General Experimental S-2

Synthesis of Oripavine-N-oxide hydrochloride (6)

General Procedure for N-Demethylation

Figure 3A. 1H NMR of N-Nororipavine (7) Hydrochloride in D2O +TFA (Expansion)

Figure 3B. 1H NMR of N-Nororipavine (7) Hydrochloride in D2O +TFA (Expansion)

Figure 5. High Resolution MS of N-Nororipavine (7)

Table A. Specifications for Iron and Stainless Steel Catalysts

Catalyst Supplier Physical Chemical analysis (%)

Sweden -45 microns

303-L Alfa Aesar Powder, -140 70 17 13

316-L Alfa Aesar Powder, -100 67.5 17 13 2.5

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