N-demethylation

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Supplementary Material (ESI) for Organic & Biomolecular Chemistry

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: [email protected]; Fax: (+61) 3 9903 9582

General Experimental S-2

Synthesis of Oripavine-N-oxide S-2

General N-Demethylation Procedure S-2

Figure 1 Oripavine-N-oxide Hydrochloride (6)1H NMR spectrum in D2O S-3

Figure 1A Oripavine-N-oxide Hydrochloride (6)1H NMR spectrum in D2O (Expansion) S-4

Figure 1B Oripavine-N-oxide Hydrochloride (6)1H NMR spectrum in D

2O (Expansion) S-5

Figure 2 N-Nororipavine (7) Hydrochloride1H NMR spectrum in D2O S-6

Figure 2A N-Nororipavine (7) Hydrochloride1H NMR spectrum in D2O (Expansion) S-7

Figure 2B N-Nororipavine (7) Hydrochloride1H NMR spectrum in D2O (Expansion) S-8

Figure 3 N-Nororipavine (7) Hydrochloride1H NMR spectrum in D2O+TFA S-9

Figure 3A N-Nororipavine (7) Hydrochloride1H NMR spectrum in D2O+TFA (Expansion) S-10

Figure 3B N-Nororipavine (7) Hydrochloride

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H NMR spectrum in D2O+TFA (Expansion) S-11Figure 4 N-Nororipavine (7) Hydrochloride

13C NMR spectrum in D2O+TFA S-12

Figure 4A N-Nororipavine (7) Hydrochloride13

C NMR spectrum in D2O+TFA (Expansion) S-13

Figure 4B N-Nororipavine (7) Hydrochloride13C 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

Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is (c) The Royal Society of Chemistry 2011


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Figure 1.1

H NMR of Oripavine-N-oxide Hydrochloride (6) in D2O



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0.999

1.025

1.051

2.016

0.629

8.798

1.102

1.092

1.089

3.009

0.359

PPM 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0

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

4.0295

4.0139

3.7658

3.7564

3.6732

3.6596

3.6491

3.6307

3.6182

3.5807

3.3605

3.3422

3.3103

3.2921

2.6602

2.6455

2.0363

2.0031

1.9977



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Figure 1A.1H NMR of Oripavine-N-oxide Hydrochloride (6) in D2O (Expansion)

8.798

1.102

1.092

1.089

PPM 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8

3.7658

3.7564

3.6732

3.6596

3.6491

3.6307

3.6182

3.5807

3.3605

3.3422

3.3103

3.2921

3.1966

3.1783

3.1468

3.1289

2.6947

2.6794

2.6644

2.6602

2.6491

2.6455

2.6298

2.6150

2.5290

2.5154

2.1534

2.1484

2.1456

2.1440

2.1174

2.1111

2.1104

2.1087

2.0875

2.0363

2.0031

1.9977



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Figure 1B.1H NMR of Oripavine-N-oxide Hydrochloride (6) in D2O (Expansion)

0.999

1.025

1.051

2.016

0.359

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



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Figure 2.1H NMR ofN-Nororipavine (6) Hydrochloride in D2O

1.000

1.022

1.001

2.002

1.013

2.988

4.069

1.030

1.025

PPM 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.6652

6.7872

6.7667

6.7536

6.7331

5.9069

5.8904

5.5025

5.2557

5.2392

4.8399

4.8161

4.7900

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

2.3171

2.3011

2.2850

2.0534

2.0479

2.0149



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Figure 2A.1H NMR ofN-Nororipavine (7) Hydrochloride in D2O (Expansion)

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

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



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Figure 2B.1H NMR ofN-Nororipavine (7) Hydrochloride in D2O (Expansion)

0.999

1.027

0.998

2.070

PPM 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0

6.7872

6.7667

6.7536

6.7331

5.9069

5.8904

5.5025

5.2557

5.2392



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Figure 3.1H NMR ofN-Nororipavine (7) Hydrochloride in D2O +TFA

1.000

1.002

0.998

2.002

0.998

2.961

4.142

1.021

1.033

PPM 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0

6.7246

6.7041

6.6884

6.6678

5.8419

5.8252

5.4387

5.1883

5.1717

4.8406

4.8221

4.8166

4.8151

4.8124

4.8104

4.7900

4.7712

4.5508

4.5358

3.5710

3.3411

3.3355

3.3273

3.3046

3.2949

3.2379

3.2214

3.2051

2.2579

2.2420

1.9932

1.9873

1.9540



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Figure 3A.1

H NMR ofN-Nororipavine (7) Hydrochloride in D2O +TFA (Expansion)

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

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



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

1.000

1.002

0.998

2.002

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

6.7246

6.7041

6.6884

6.6678

5.8419

5.8252

5.4387

5.1883

5.1717



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Figure 4.13

C NMR ofN-Nororipavine (7) Hydrochloride in D2O + TFA

PPM 180 160 140 120 100 80 60 40 20 0

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



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Figure 4A.13

C NMR ofN-Nororipavine (7) Hydrochloride in D2O + TFA (Expansion)

PPM 84 80 76 72 68 64 60 56 52 48 44 40 36 32 28

87.6976

55.1246

53.1965

44.5938

37.0187

33.4732

33.1104



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Figure 4B.13

C NMR ofN-Nororipavine (7) Hydrochloride in D2O + TFA (Expansion)

PPM 152 148 144 140 136 132 128 124 120 116 112 108 104 100 96

153.0419

142.7828

138.6271

131.9846

124.3895

124.2171

120.8202

117.3440

116.9749

96.0582



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Figure 5. High Resolution MS ofN-Nororipavine (7)



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Table A. Specifications for Iron and Stainless Steel Catalysts

Chemical analysis (%)Catalyst Supplier Physical

propertiesFe Cr Ni Mo Mn Si Other

Iron(0) Hgans

Sweden

Powder, +212 to

-45 microns

99 0.002 0.01

N-demethylation

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