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, also known as norbuprenorphine (CRM), is a certified reference material classified as an opioid. It is a major active metabolite of buprenorphine, a semi-synthetic opioid derived from thebaine. Norbuprenorphine is a light brown solid and is primarily used for research and forensic applications.

Uses

Used in Pharmaceutical Research:
Norbuprenorphine is used as a research compound for studying the pharmacological properties and mechanisms of action of opioids. It helps in understanding the effects of buprenorphine and its metabolites on the body, which can contribute to the development of new opioid therapies and treatments.
Used in Forensic Analysis:
Norbuprenorphine is used as a certified reference material in forensic analysis to ensure the accuracy and reliability of analytical methods used for detecting and quantifying buprenorphine and its metabolites in biological samples. This is crucial for legal and medical purposes, such as drug testing and monitoring patients on buprenorphine treatment.
Used in Drug Development:
Norbuprenorphine is used in the development of new drugs and therapies targeting the opioid receptors. By studying its interactions with these receptors, researchers can gain insights into the design of more effective and safer opioid medications.
Used in Quality Control:
Norbuprenorphine serves as a quality control standard for the manufacturing and testing of buprenorphine-containing products. It helps ensure that the active pharmaceutical ingredients meet the required specifications and maintain consistent quality throughout the production process.

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

• 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 
• 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 
• 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 
• 16196-82-0 7-acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine 
• 15358-22-2 thevinone 
• 115-37-7 thebaine 
• 467-04-9 oripavine 
• 7168-66-3 N-nororipavine 
• 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 

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

Demethylation of Reticuline and Derivatives Thereof with Fungal Cytochrome P450

The invention relates to recombinant host cells that expresses one or more genes encoding a cytochrome P450 enzyme capable of N-demethylating and/O-demethylating reticuline and/or derivatives thereof, and also methods of producing a N-demethylated and/or O-demethylated reticuline and/or derivatives thereof, comprising cultivating the recombinant host of the invention in a culture medium under conditions in which the one or more genes encoding the cytochrome P450 enzymes is/are expressed. The reticuline and derivatives thereof are useful for providing access to naturally unavailable and chemically difficult-to-produce starting materials for opioids.

DEUTERATED COMPOUND AND MEDICAL USE THEREOF

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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