52446-24-9

Basic information

• Product Name: (5alpha)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride
• Synonyms: (5alpha)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride;Naltrexone methylbromide Impurity G
• CAS NO: 52446-24-9
• Molecular Formula: C₁₆H₁₇NO₄*ClH
• Molecular Weight: 324.77936
• EINECS: 257-924-4
• Mol File: 52446-24-9.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 566.9°Cat760mmHg
• Flash Point: 296.7°C
• Appearance: /
• Density: g/cm³
• CAS DataBase Reference: (5alpha)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: (5alpha)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride(52446-24-9)
• EPA Substance Registry System: (5alpha)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride(52446-24-9)

Safety Data

• Hazardous Substances Data: 52446-24-9(Hazardous Substances Data)

Usage

General Description

"(5alpha)-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride" is a chemical compound that is a potent opioid analgesic. It is an alkaloid found in opium and is derived from the morphinan family. The hydrochloride salt form of this compound is commonly used as a prescription pain medication, usually in the treatment of severe pain. It works by binding to and activating the body's opioid receptors, which are involved in pain sensation and modulation. The compound is a controlled substance due to its potential for abuse and addiction, and should be used under the supervision of a healthcare professional.

Synthetic route

naloxone hydrochloride (357-08-4) → (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9)

Conditions	Yield
With Wilkinson's catalyst In 1,4-dioxane; water at 150℃; for 1h; Microwave irradiation; Inert atmosphere;	99%
With Wilkinson's catalyst In water at 200℃; for 1.5h; Microwave irradiation;

noroxymorphone (33522-95-1) → (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 20℃; Inert atmosphere; Reflux; Large scale;	93.2%
With hydrogenchloride In water at 90℃;

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → 6-α-noroxymorphinol hydrochloride

Conditions	Yield
With acetic acid; tetramethylammonium triacetoxyborohydride In dimethyl sulfoxide at 50℃; for 5h;	99.5%

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) + cyclopropylcarbinyl bromide (7051-34-5) → Naltrexone (16590-41-3)

Conditions	Yield
Stage #1: (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With sodium hydrogencarbonate In ISOPROPYLAMIDE at 65 - 69℃; for 0.166667h; Stage #2: cyclopropylcarbinyl bromide In ISOPROPYLAMIDE at 69℃; for 6.5h; Stage #3: With sodium hydroxide; water In ISOPROPYLAMIDE pH=8.6 - 9;	88.6%

3-maleimidopropionic acid N-hydroxysuccinimide ester (55750-62-4) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → C23H22N2O7

Conditions	Yield
Stage #1: (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 3-maleimidopropionic acid N-hydroxysuccinimide ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere;	82%

cyclobutylaldehyde (2987-17-9) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → nalbuphine (20594-83-6)

Conditions	Yield
Stage #1: cyclobutylaldehyde; (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With acetic acid; tetramethylammonium triacetoxyborohydride In dimethyl sulfoxide at 20℃; for 1h; Large scale; Stage #2: With acetic acid; tetramethylammonium triacetoxyborohydride In dimethyl sulfoxide at 60℃; Solvent; Reagent/catalyst; Large scale;	77.7%

cyclobutylaldehyde (2987-17-9) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → 6-ketonalbuphine hydrochloride (16676-34-9)

Conditions	Yield
Stage #1: cyclobutylaldehyde; (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: With acetic acid; tetramethylammonium triacetoxyborohydride In dimethyl sulfoxide at 20℃; for 1.16667h; Stage #3: With hydrogenchloride In water; isopropyl alcohol Solvent; Reagent/catalyst;	67.6%

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → 6-β-noroxymorphinol hydrochloride

Conditions	Yield
Stage #1: (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With sodium hydroxide In water Stage #2: With Aminoiminomethanesulfinic acid; sodium hydroxide In water at 85℃; for 1h; Inert atmosphere; Stage #3: With hydrogenchloride In water at 20℃; for 3.5h;	44%

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) + bromoacetylglycyne N-hydroxysuccinimide ester (93801-73-1) → C20H21BrN2O6

Conditions	Yield
Stage #1: (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: bromoacetylglycyne N-hydroxysuccinimide ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1.33333h; Inert atmosphere;	19.3%

bromoacetic acid N-hydroxusuccinimidyl ester (42014-51-7) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → noroxymorphone bromoacetamide

Conditions	Yield
Stage #1: (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: bromoacetic acid N-hydroxusuccinimidyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #3: With sodium bromide In acetone at 56℃; for 24h; Inert atmosphere;

bromoacetic acid N-hydroxusuccinimidyl ester (42014-51-7) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → noroxymorphone bromoacetamide + noroxymorphone chloroacetamide

Conditions	Yield
Stage #1: (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: bromoacetic acid N-hydroxusuccinimidyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Overall yield = 8.7 mg;

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → C21H23NO6

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 96 h / Inert atmosphere View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → C21H25NO6

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 96 h / Inert atmosphere 3: acetic acid; sodium tris(acetoxy)borohydride / 1.5 h / 10 °C / Inert atmosphere View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → C21H27NO7

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 96 h / Inert atmosphere 3: acetic acid; sodium tris(acetoxy)borohydride / 1.5 h / 10 °C / Inert atmosphere 4: lithium hydroxide; water / tetrahydrofuran / 4 h / 20 °C View Scheme

3-bromomethyl-2-butenolide (61934-55-2) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → C21H21NO6

Conditions	Yield
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 70℃; Inert atmosphere;

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → noroxymorphone (33522-95-1)

Conditions	Yield
With ammonium hydroxide In water at 50℃; pH=8;

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → noroxymorphone sulfate

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide / water / 50 °C / pH 8 2: sulfuric acid / water / 80 °C View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → Naloxone (465-65-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide / water / 50 °C / pH 8 2: potassium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 2 h / 30 °C View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → Naltrexone (16590-41-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide / water / 50 °C / pH 8 2: potassium hydrogencarbonate / 1-methyl-pyrrolidin-2-one / 5 h / 50 °C View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → N,O3-bis(cyclobutanecarbonyl)noroxymorphone (16676-35-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide / water / 50 °C / pH 8 2: triethylamine / tetrahydrofuran / 1.5 h / 15 °C View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → nalbuphine (20594-83-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ammonium hydroxide / water / 50 °C / pH 8 2.1: triethylamine / tetrahydrofuran / 1.5 h / 15 °C 3.1: borane-THF / tetrahydrofuran / 8.33 h / 5 °C / Reflux 3.2: 1 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: potassium tri-sec-butyl-borohydride / dimethyl sulfoxide; tetrahydrofuran / 60 °C View Scheme

cyclobutylaldehyde (2987-17-9) + (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → nalbuphine (20594-83-6) + (4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7(7aH)-one (16676-33-8)

Conditions	Yield
Stage #1: cyclobutylaldehyde; (-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride With acetic acid; tetramethylammonium triacetoxyborohydride In N,N-dimethyl-formamide at 20℃; Stage #2: With acetic acid; tetramethylammonium triacetoxyborohydride In N,N-dimethyl-formamide at 60℃; Solvent;	A 44.83 %Chromat. B 53.64 %Chromat.

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → nalbuphine-N-oxide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / dimethyl sulfoxide / 1 h / 20 °C / Large scale 1.2: 60 °C / Large scale 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h View Scheme
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: sodium tetrahydroborate / dimethyl sulfoxide / 60 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: potassium tri-sec-butyl-borohydride / dimethyl sulfoxide; tetrahydrofuran / 60 °C 3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 3 h View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → 2,2'-bisnalbuphine

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / dimethyl sulfoxide / 1 h / 20 °C / Large scale 1.2: 60 °C / Large scale 2.1: phosphoric acid; oxygen / 2160 h / Irradiation View Scheme
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: phosphoric acid; oxygen / 2160 h / Irradiation View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: sodium tetrahydroborate / dimethyl sulfoxide / 60 °C 3.1: phosphoric acid; oxygen / 2160 h / Irradiation View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: potassium tri-sec-butyl-borohydride / dimethyl sulfoxide; tetrahydrofuran / 60 °C 3.1: phosphoric acid; oxygen / 2160 h / Irradiation View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → 6β-hydroxy-17-cyclobutylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan (85284-04-4) + nalbuphine (20594-83-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: sodium tetrahydroborate / dimethyl sulfoxide / 60 °C View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → nalbuphine hydrochloride (23277-43-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / dimethyl sulfoxide / 1 h / 20 °C / Large scale 1.2: 60 °C / Large scale 2.1: hydrogenchloride / water / 45 - 60 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: hydrogenchloride / water / 45 - 60 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: sodium tetrahydroborate / dimethyl sulfoxide / 60 °C 3.1: hydrogenchloride / water / 45 - 60 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; tetramethylammonium triacetoxyborohydride / N,N-dimethyl-formamide / 20 °C 1.2: 60 °C 2.1: potassium tri-sec-butyl-borohydride / dimethyl sulfoxide; tetrahydrofuran / 60 °C 3.1: hydrogenchloride / water / 45 - 60 °C / Large scale View Scheme

(-)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (52446-24-9) → 6β-hydroxy-17-cyclobutylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dimethyl sulfoxide / 0.5 h / 20 °C 1.2: 1.17 h / 20 °C 2.1: sodium hydroxide / water / Cooling with ice 2.2: 1 h / 85 °C / Inert atmosphere View Scheme

Upstream product

• 357-08-4 naloxone hydrochloride 
• 33522-95-1 noroxymorphone 

Downstream Products

• 16590-41-3 Naltrexone 
• 33522-95-1 noroxymorphone 
• 465-65-6 Naloxone 
• 20594-83-6 nalbuphine 
• 23277-43-2 nalbuphine hydrochloride 
• 85284-04-4 6β-hydroxy-17-cyclobutylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan 
• 214542-42-4 2,2'-bisnalbuphine 
• 16676-33-8 (4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7(7aH)-one 

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