Tramadol N-Oxide

Cat. No.: B1240704

M. Wt: 279.37 g/mol

InChI Key: HBXKSXMNNGHBEA-ZBFHGGJFSA-N

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Overview

1. Description

6. Comparison with similar compounds

2. Preparation methods

7. Properties

3. Chemical reactions analysis

8. Synthesis routes and methods I

4. Scientific research applications

9. Synthesis routes and methods II

5. Mechanism of action

10. Disclaimer

Description

Tramadol N-oxide (TNO) is a novel analgesic agent that is believed to exert its effects following metabolic conversion to tramadol . Tramadol itself is a widely prescribed central nervous system analgesic used for the treatment of moderate to severe pain . This compound is a prodrug, meaning it is converted into the active drug (tramadol) within the body, thereby extending its analgesic effects .

Preparation Methods

Synthetic Routes and Reaction Conditions: The synthesis of Tramadol N-oxide involves the N-oxidation of tramadol. This can be achieved using various oxidizing agents such as hydrogen peroxide or peracids under controlled conditions . The reaction typically requires a solvent like methanol or ethanol and is carried out at room temperature to avoid decomposition of the product.

Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process involves the use of continuous flow reactors to ensure consistent product quality and yield. The reaction conditions are optimized to maximize the conversion rate and minimize by-products .

Chemical Reactions Analysis

Types of Reactions: Tramadol N-oxide undergoes several types of chemical reactions, including:

N-oxide reduction: This reaction converts this compound back to tramadol, which is the active analgesic form.

O-demethylation: This reaction involves the removal of a methyl group from the oxygen atom, leading to the formation of desmethyl tramadol.

N-demethylation: This reaction removes a methyl group from the nitrogen atom, producing nortramadol.

Cyclohexylhydroxylation: This reaction adds a hydroxyl group to the cyclohexyl ring.

Common Reagents and Conditions:

N-oxide reduction: Typically involves the use of reducing agents like zinc dust or catalytic hydrogenation.

O-demethylation and N-demethylation: These reactions often require strong acids or bases, such as hydrochloric acid or sodium hydroxide, under reflux conditions.

Cyclohexylhydroxylation: This reaction is usually carried out using oxidizing agents like potassium permanganate or osmium tetroxide.

Major Products:

Tramadol: The primary product of N-oxide reduction.

Desmethyl tramadol: The product of O-demethylation.

Nortramadol: The product of N-demethylation.

Hydroxylated tramadol derivatives: Products of cyclohexylhydroxylation.

Scientific Research Applications

Tramadol N-oxide has several scientific research applications, including:

Chemistry: Used as a model compound to study N-oxide reduction and other related reactions.

Biology: Investigated for its metabolic pathways and interactions with various enzymes.

Medicine: Explored for its potential as a prodrug to enhance the analgesic effects of tramadol.

Industry: Utilized in the development of new analgesic formulations and drug delivery systems.

Mechanism of Action

Tramadol N-oxide exerts its effects primarily through its conversion to tramadol. Tramadol has both opioid and non-opioid mechanisms of action. It acts as an agonist of the μ-opioid receptor and inhibits the reuptake of serotonin and norepinephrine . This dual mechanism contributes to its analgesic properties by modulating pain signals in the central nervous system .

Comparison with Similar Compounds

Tramadol: The parent compound of Tramadol N-oxide, with similar analgesic properties.

Desmethyl tramadol: A metabolite of tramadol with reduced analgesic potency.

Nortramadol: Another metabolite with distinct pharmacological properties.

Uniqueness: this compound is unique in its ability to serve as a prodrug, providing a sustained release of tramadol and potentially reducing the frequency of dosing . Its N-oxide functionality also offers distinct chemical reactivity, making it a valuable compound for research and development in medicinal chemistry .

Properties

Molecular Formula	C16H25NO3
Molecular Weight	279.37 g/mol
IUPAC Name	1-[(1R,2R)-2-hydroxy-2-(3-methoxyphenyl)cyclohexyl]-N,N-dimethylmethanamine oxide
InChI	InChI=1S/C16H25NO3/c1-17(2,19)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)20-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1
InChI Key	HBXKSXMNNGHBEA-ZBFHGGJFSA-N
Isomeric SMILES	C[N+](C)(C[C@H]1CCCC[C@@]1(C2=CC(=CC=C2)OC)O)[O-]
Canonical SMILES	C[N+](C)(CC1CCCCC1(C2=CC(=CC=C2)OC)O)[O-]
Synonyms	2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol hydrochloride RWJ 38705 tramadol N-oxide
Origin of Product	United States

Synthesis routes and methods I

Procedure details

First, tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted to its free base in basified water (pH>9) and then extracted with ether. The ether was evaporated to yield the crystalline hydrate of tramadol. The solid was then heated with steam under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 on carbon (use of Pt/C is suggested for its ease of removal) was added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered thru a filter aid. The filtrate was concentrated under vacuum while being heated to a temperature of <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45μ pore size) to yield a clear colorless filtrate. The filtrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).

Name

Tramadol hydrochloride

Quantity

0.5 mol

Type

reactant

Reaction Step One

Name

water

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

tramadol N-oxide

[Compound]

Name

hydrate

Name

tramadol

Details

Synthesis routes and methods II

Procedure details

Tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted its free base in basified water (pH>9) and then extracted with ether. The solid was then heated under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H2O2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H2O2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO2 (use of Pt/C is suggested for its ease of removal) on carbon was then added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO2 was added and the reaction mixture was stirred overnight and then filtered thru filter aid. The filtrate was concentrated under vacuum while being heated to a temperature <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45μ pore size) to yield a clear colorless filtrate. The filtrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).

Name

Tramadol hydrochloride

Quantity

0.5 mol

Type

reactant

Reaction Step One

Name

water

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

Tramadol N-oxide

[Compound]

Name

material

Details

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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.

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