78715-23-8

Basic information

• Product Name: NORBUPRENORPHINE
• Synonyms: NORBUPRENORPHINE;(aS,5a,7a)-a-(1,1-Dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-a-methyl-6,14-ethenomorphinan-7-methanol;N-De(cyclopropylmethyl)buprenorphine;N-Dealkylbuprenorphine;N-Desalkylbuprenorphin;6,14-Ethenomorphinan-7-methanol, .alpha.-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3-hydroxy-6-methoxy-.alpha.-methyl-, (.alpha.S,5.alpha.,7.alpha.)-;N-Desalkylbuprenorphine;(αS)-α-tert-Butyl-4,5α-epoxy-3-hydroxy-6-methoxy-α-methyl-6β,14-ethanomorphinan-7α-methanol
• CAS NO: 78715-23-8
• Molecular Formula: C₂₅H₃₅NO₄
• Molecular Weight: 413.55
• EINECS: 200-659-6
• Product Categories: Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Amines;Chiral Reagents;Heterocycles
• Mol File: 78715-23-8.mol
• Article Data: 8

Chemical Properties

• Melting Point: 221-224°C
• Boiling Point: 562.7°C at 760 mmHg
• Flash Point: 9℃
• Appearance: /
• Density: 1.27g/cm³
• Vapor Pressure: 1.68E-13mmHg at 25°C
• Refractive Index: 1.627
• Storage Temp.: -20°C Freezer, Under Inert Atmosphere
• PKA: 9.14±0.60(Predicted)
• CAS DataBase Reference: NORBUPRENORPHINE(CAS DataBase Reference)
• NIST Chemistry Reference: NORBUPRENORPHINE(78715-23-8)
• EPA Substance Registry System: NORBUPRENORPHINE(78715-23-8)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 16-36/37-45-7
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 1
• Hazardous Substances Data: 78715-23-8(Hazardous Substances Data)

Usage

Description

Norbuprenorphine (CRM) (Item No. 20127) is a certified reference material categorized as an opioid. It is a major active metabolite of buprenorphine (Item Nos. 14025 | ISO60178). This product is intended for research and forensic applications.

Chemical Properties

Light Brown Solid

InChI:InChI=1/C25H35NO4/c1-21(2,3)22(4,28)16-13-23-8-9-25(16,29-5)20-24(23)10-11-26-17(23)12-14-6-7-15(27)19(30-20)18(14)24/h6-7,16-17,20,26-28H,8-13H2,1-5H3/t16-,17-,20-,22+,23-,24+,25-/m1/s1

Synthetic route

N-cyano-7α-(1--hydroxy-1,2,2-trimethylpropyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine → norbuprenorphine (78715-23-8)

Conditions	Yield
With water; potassium hydroxide In diethylene glycol at 185℃; Product distribution / selectivity; Inert atmosphere;	97.19%
With potassium hydroxide In diethylene glycol at 100 - 200℃; for 1h; Inert atmosphere;	3.2 g

(S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol (22151-78-6, 136232-87-6, 16614-59-8) → norbuprenorphine (78715-23-8)

Conditions	Yield
Stage #1: (S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol With water; potassium hydroxide In diethylene glycol at 185℃; for 5.25h; Stage #2: With sulfuric acid In water; diethylene glycol at 90℃; pH=8.6;	80%

[5α,7α]-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3,6-dimethoxy-α,17-dimethyl-6,14-ethenomorphinan-7-methanol (22152-80-3, 85080-82-6, 98301-16-7, 98301-77-0, 136232-78-5, 136314-59-5, 16196-70-6) → (S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol (22151-78-6, 136232-87-6, 16614-59-8) + norbuprenorphine (78715-23-8)

Conditions	Yield
With D-Galactose; Cunninghamella echinulata NRRL 1384 at 28 - 32℃; for 168h; Product distribution / selectivity; Microbiological reaction; Basal fermentation medium;	A 55% B 16.4%
With Maltose; Cunninghamella echinulata NRRL 1384 at 28 - 32℃; for 168h; Product distribution / selectivity; Microbiological reaction; Basal fermentation medium;	A 47.2% B 13.2%
With Sucrose; Cunninghamella echinulata NRRL 1384 at 28 - 32℃; for 168h; Product distribution / selectivity; Microbiological reaction; Basal fermentation medium;	A 42.4% B 12.1%

1-[(5α,7α)-3-methoxy-4,5-epoxy-18,19-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-ethenomorphinan-17-yl]ethanone (1352741-85-5) → [5α,7α]-17-acetyl-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanolamide (1352741-86-6) + (S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol (22151-78-6, 136232-87-6, 16614-59-8) + norbuprenorphine (78715-23-8)

Conditions	Yield
With potassium hydroxide In diethylene glycol at 170 - 180℃; for 7h; Inert atmosphere;	A 42% B 10% C 35%

1-[(5α,7α)-3-methoxy-4,5-epoxy-18,19-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-ethenomorphinan-17-yl]ethanone (1352741-85-5) → [5α,7α]-17-acetyl-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanolamide (1352741-86-6) + norbuprenorphine (78715-23-8)

Conditions	Yield
With potassium hydroxide In diethylene glycol at 170 - 180℃; for 7h; Inert atmosphere;	A 37% B 40%

C32H41NO4 → norbuprenorphine (78715-23-8)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In methanol at 60℃; under 2068.65 Torr; for 2.5h; Product distribution / selectivity;

1-[(5α,7α)-3-methoxy-4,5-epoxy-18,19-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-ethenomorphinan-17-yl]ethanone (1352741-85-5) → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide / diethylene glycol / 7 h / 170 - 180 °C / Inert atmosphere 2: potassium hydroxide / diethylene glycol / 7 h / 170 °C View Scheme
Multi-step reaction with 2 steps 1: potassium hydroxide / diethylene glycol / 7 h / 170 - 180 °C / Inert atmosphere 2: potassium hydroxide / diethylene glycol / 7 h / 170 °C View Scheme

[5α,7α]-17-acetyl-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanolamide (1352741-86-6) → norbuprenorphine (78715-23-8)

Conditions	Yield
With potassium hydroxide In diethylene glycol at 170℃; for 7h;
With Schwartz's reagent In tetrahydrofuran at 20℃; for 0.666667h; Reagent/catalyst; Inert atmosphere;

[5α,7α]-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3,6-dimethoxy-α,17-dimethyl-6,14-ethenomorphinan-7-methanol (22152-80-3, 85080-82-6, 98301-16-7, 98301-77-0, 136232-78-5, 136314-59-5, 16196-70-6) → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: copper diacetate; palladium diacetate / 1,4-dioxane / 23 h / 80 °C 2: potassium hydroxide / diethylene glycol / 7 h / 170 - 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: copper diacetate; palladium diacetate / 1,4-dioxane / 23 h / 80 °C 2: potassium hydroxide / diethylene glycol / 7 h / 170 - 180 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: copper diacetate; palladium diacetate / 1,4-dioxane / 23 h / 80 °C 2: potassium hydroxide / diethylene glycol / 7 h / 170 - 180 °C / Inert atmosphere 3: potassium hydroxide / diethylene glycol / 7 h / 170 °C View Scheme
Multi-step reaction with 3 steps 1: copper diacetate; palladium diacetate / 1,4-dioxane / 23 h / 80 °C 2: potassium hydroxide / diethylene glycol / 7 h / 170 - 180 °C / Inert atmosphere 3: potassium hydroxide / diethylene glycol / 7 h / 170 °C View Scheme
Multi-step reaction with 2 steps 1: chloroform / 12 h / Reflux 2: potassium hydroxide / diethylene glycol / 1 h / 100 - 200 °C / Inert atmosphere View Scheme

N-nororipavine (7168-66-3) → norbuprenorphine (78715-23-8)

Conditions

Yield

Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 1.5 h / 20 °C / Inert atmosphere 2: toluene / 80 h / 20 - 80 °C / Inert atmosphere 3: tetrahydrofuran; toluene / 3 h / 50 - 60 °C / Inert atmosphere 4: lithium aluminium tetrahydride / tetrahydrofuran / 21 h / 20 - 70 °C / Inert atmosphere 5: hydrogen; palladium 10% on activated carbon; acetic acid / isopropyl alcohol; water; methanol / 144 h / 60 °C / 760.05 Torr View Scheme

(12bS)-3-benzoyl-7-methoxy-2 3,4,7a-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl benzoate → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: toluene / 80 h / 20 - 80 °C / Inert atmosphere 2: tetrahydrofuran; toluene / 3 h / 50 - 60 °C / Inert atmosphere 3: lithium aluminium tetrahydride / tetrahydrofuran / 21 h / 20 - 70 °C / Inert atmosphere 4: hydrogen; palladium 10% on activated carbon; acetic acid / isopropyl alcohol; water; methanol / 144 h / 60 °C / 760.05 Torr View Scheme

(4R,4aR,7R,7aR,12bS,14S)-14-acetyl-3-benzoyl-7-methoxy-1,2,3,4,7,7a-hexahydro-7,4a-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl benzoate → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrahydrofuran; toluene / 3 h / 50 - 60 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 21 h / 20 - 70 °C / Inert atmosphere 3: hydrogen; palladium 10% on activated carbon; acetic acid / isopropyl alcohol; water; methanol / 144 h / 60 °C / 760.05 Torr View Scheme

((4R,4aR,7R,7aR,12bS,14R)-9-hydroxy-14-(2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-1,2,7,7a-tetrahydro-7,4a-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-3(4H)-yl)(phenyl)methanone → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 21 h / 20 - 70 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon; acetic acid / isopropyl alcohol; water; methanol / 144 h / 60 °C / 760.05 Torr View Scheme

(4R,4aR,7R,7aR,12bS,14R)-3-benzyl-14-(2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-1,2,3,4,7,7a-hexahydro-7,4a-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-9-ol → norbuprenorphine (78715-23-8)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol; water; isopropyl alcohol at 60℃; under 760.051 Torr; for 144h;

C25H29NO6 → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene / 3 h / 60 °C / Inert atmosphere 2: Schwartz's reagent / tetrahydrofuran / 0.67 h / 20 °C / Inert atmosphere View Scheme

C25H27NO6 → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium 10% on activated carbon; acetic acid / isopropyl alcohol; water / 72 h / 80 °C / 760.05 Torr 2: toluene / 3 h / 60 °C / Inert atmosphere 3: Schwartz's reagent / tetrahydrofuran / 0.67 h / 20 °C / Inert atmosphere View Scheme

C27H35NO5 → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; palladium 10% on activated carbon; acetic acid / isopropyl alcohol; water / 72 h / 80 °C / 760.05 Torr 2: Schwartz's reagent / tetrahydrofuran / 0.67 h / 20 °C / Inert atmosphere View Scheme

7-acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine (16196-82-0) → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium / diethyl ether; benzene 1.2: 6 h / Reflux 2.1: chloroform / 12 h / Reflux 3.1: potassium hydroxide / diethylene glycol / 1 h / 100 - 200 °C / Inert atmosphere View Scheme

thevinone (15358-22-2) → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: palladium 10% on activated carbon; hydrogen / ethanol / 50 - 60 °C / 30003 - 37503.8 Torr 2.1: magnesium / diethyl ether; benzene 2.2: 6 h / Reflux 3.1: chloroform / 12 h / Reflux 4.1: potassium hydroxide / diethylene glycol / 1 h / 100 - 200 °C / Inert atmosphere View Scheme

thebaine (115-37-7) → norbuprenorphine (78715-23-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 1 h / Reflux 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 50 - 60 °C / 30003 - 37503.8 Torr 3.1: magnesium / diethyl ether; benzene 3.2: 6 h / Reflux 4.1: chloroform / 12 h / Reflux 5.1: potassium hydroxide / diethylene glycol / 1 h / 100 - 200 °C / Inert atmosphere View Scheme

allyl bromide (106-95-6) + norbuprenorphine (78715-23-8) → 17-allyl-7α-[(2S)-3,3-dimethyl-2-hydroxybutan-2-yl]-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14α-ethanomorphinan (162333-28-0)

Conditions	Yield
With sodium hydrogencarbonate In N,N-dimethyl acetamide at 60℃; for 5h;	97.2%

cyclopropylcarbinyl bromide (7051-34-5) + norbuprenorphine (78715-23-8) → Buprenorphine (52485-79-7)

Conditions	Yield
With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 18h; Inert atmosphere;	86%
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80 - 100℃; for 4h;
With sodium hydrogencarbonate; potassium iodide In N,N-dimethyl-formamide at 85℃; for 5.5h; Product distribution / selectivity;
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 62 - 85℃; Product distribution / selectivity;

Cyclopropanecarboxaldehyde (1489-69-6) + norbuprenorphine (78715-23-8) → Buprenorphine (52485-79-7)

Conditions	Yield
With formic acid; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; triethylamine In acetonitrile at 20 - 60℃; for 1h; Inert atmosphere;	78%

norbuprenorphine (78715-23-8) + methyl iodide (74-88-4) → 17-allyl-7α-[(2S)-3,3-dimethyl-2-hydroxybutan-2-yl]-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14α-ethanomorphinan

Conditions	Yield
With sodium hydrogencarbonate In N,N-dimethyl acetamide at 20℃; for 24h;	74%

Cyclopropanecarboxaldehyde (1489-69-6) + norbuprenorphine (78715-23-8) → buprenorphine hydrochloride

Conditions	Yield
Stage #1: Cyclopropanecarboxaldehyde; norbuprenorphine With hydrogen; platinum on activated charcoal In 1-methyl-pyrrolidin-2-one; methanol at 50℃; under 2068.65 Torr; for 2h; Stage #2: With hydrogenchloride In ethanol; water

norbuprenorphine (78715-23-8) → buprenorphine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; triethylamine; formic acid / acetonitrile / 1 h / 20 - 60 °C / Inert atmosphere 2: hydrogenchloride / ethanol; water / Heating View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 13 h / 20 °C / Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3: hydrogenchloride / ethanol; diethyl ether / 20 °C / pH 2 View Scheme

norbuprenorphine (78715-23-8) → C29H39(2)H2NO4*ClH

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 13 h / 20 °C / Cooling with ice 2.1: lithium aluminium deuteride / tetrahydrofuran / 20 °C 2.2: pH 2 View Scheme

norbuprenorphine (78715-23-8) → C30H40(2)H3NO4*ClH

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 13 h / 20 °C / Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 15 h / 50 °C View Scheme

norbuprenorphine (78715-23-8) → Buprenorphine (52485-79-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 13 h / 20 °C / Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C View Scheme

norbuprenorphine (78715-23-8) → C29H39(2)H2NO4*ClH

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 13 h / 20 °C / Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3: bromine / dichloromethane / 1 h / 30 °C / Cooling with ice 4: deuterium; triethylamine; palladium 10% on activated carbon / tetrahydrofuran / 24 h / 20 °C View Scheme

norbuprenorphine (78715-23-8) → (2S)-2-[(5R,6R,7R,14S)-1,2-dibromo-N-cyclopropylmethyl-4,5-epoxy-6,14-ethylene-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutyl-2-alcohol

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 13 h / 20 °C / Cooling with ice 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3: bromine / dichloromethane / 1 h / 30 °C / Cooling with ice View Scheme

Upstream product

• 115-37-7 thebaine 
• 15358-22-2 thevinone 
• 16196-82-0 7-acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine 
• 7168-66-3 N-nororipavine 
• 22152-80-3 [5α,7α]-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-3,6-dimethoxy-α,17-dimethyl-6,14-ethenomorphinan-7-methanol 
• 1352741-86-6 [5α,7α]-17-acetyl-α-(1,1-dimethylethyl)-4,5-epoxy-18,19-dihydro-6-methoxy-α-methyl-6,14-ethenomorphinan-7-methanolamide 
• 1352741-85-5 1-[(5α,7α)-3-methoxy-4,5-epoxy-18,19-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-ethenomorphinan-17-yl]ethanone 
• 22151-78-6 (S)-2-((4R,4aS,6R,7R,7aR,12bS)-7,9-dimethoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)-3,3-dimethylbutan-2-ol 
• 467-04-9 oripavine 

Downstream Products

• 136232-95-6 buprenorphine hydrochloride 
• 52485-79-7 Buprenorphine 
• 84712-92-5 (2S)-2-[(5R,6R,7R,14S)-N-cyclopropanoyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol 

Relevant articles and documents

PROCESS FOR THE SYNTHESIS OF BUPRENORPHINE

The present invention relates to a novel route of synthesis for the opioid receptor antagonist Buprenorphine or a pharmaceutically acceptable salt thereof, starting from thebaine, wherein the route comprises the reaction of the baine with a dienophile; forming an alkylated reaction product by reaction with a Grignard-reagent; formation of an cyanamide; deprotection of the cyanamide- and the phenolic-oxygen-moiety, wherein the cleavage of one or both groups is performed in the presence of an alkali or alkaline earth sulfide; followed by derivatization with a cyclopropyl-halogen and hydrogenation to yield Buprenorphine.

DEUTERATED COMPOUND AND MEDICAL USE THEREOF

The present invention relates to a compound represented by formula I and a non-toxic pharmaceutically acceptable salt thereof. In formula (I), R1 is H, CH3 or deuterated methyl (CD3); R2 is CH3 or CH2CH3; R3, R4 and R5 are each independently H or deuterium (D); when R1 is H or CH3, at least one of R3, R4 and R5 is D.

Improved synthesis of buprenorphine from thebaine and/or oripavine via palladium-catalyzed N-demethylation/acylation and/or concomitant O-demethylation

An improved preparation of buprenorphine via palladium-catalyzed N-demethylation/acylation is reported. Three routes were investigated and compared in overall yield. The first involved N-demethylation/acylation of an advanced intermediate obtained from thebaine followed by hydrolysis of the N-acetamide and alkylation with cyclopropylmethyl bromide and/or reduction of the N-acetyl group with the Schwartz reagent followed by N-alkylation. The second route employed cyclopropylcarboxylic acid anhydride in the N-demethylation/acylation protocol and subsequent reduction of the cyclopropylcarboxamide by either lithium aluminum hydride or under hydrosilylation conditions. Both of these routes originated in thebaine and therefore required O-demethylation as a final step. The third route employed an N-demethylation/acylation sequence starting from oripavine rather than thebaine, thus avoiding the O-demethylation. The routes are compared for overall efficiency and experimental and spectral data are provided for all new compounds. Copyright