(R)-Rivastigmine
Overview
Description
®-Rivastigmine is a chiral carbamate derivative used as a medication for the treatment of mild to moderate dementia associated with Alzheimer’s disease and Parkinson’s disease. It functions as a cholinesterase inhibitor, enhancing cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase.
Scientific Research Applications
®-Rivastigmine has a wide range of applications in scientific research:
Chemistry: Used as a model compound to study cholinesterase inhibition and related mechanisms.
Biology: Investigated for its effects on neurotransmitter levels and neuronal function.
Medicine: Extensively studied for its therapeutic potential in neurodegenerative diseases.
Industry: Utilized in the development of new cholinesterase inhibitors and related pharmaceuticals.
Mechanism of Action
Target of Action
The primary targets of ®-Rivastigmine are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), enzymes that are crucial in the breakdown of acetylcholine, a neurotransmitter involved in memory and learning . By inhibiting these enzymes, ®-Rivastigmine increases the availability of acetylcholine in the synaptic cleft, enhancing cholinergic transmission .
Mode of Action
®-Rivastigmine acts as a pseudo-irreversible inhibitor of AChE and BuChE . It binds to the active site of these enzymes, preventing them from hydrolyzing acetylcholine . This results in an increased concentration of acetylcholine in the synaptic cleft, which can then bind to and activate postsynaptic acetylcholine receptors .
Biochemical Pathways
The action of ®-Rivastigmine primarily affects the cholinergic pathway. By inhibiting AChE and BuChE, it prevents the breakdown of acetylcholine, leading to an increase in cholinergic transmission . This can enhance cognitive function in patients with neurodegenerative disorders like Alzheimer’s disease, where cholinergic transmission is impaired .
Pharmacokinetics
The ADME properties of ®-Rivastigmine are complex and can be influenced by several factors. After oral administration, it is rapidly and completely absorbed . It undergoes extensive first-pass metabolism in the liver, resulting in a low systemic bioavailability . The drug is primarily excreted in the urine .
Result of Action
The inhibition of AChE and BuChE by ®-Rivastigmine leads to an increase in acetylcholine levels in the synaptic cleft . This enhances cholinergic transmission, which can improve cognitive function in patients with Alzheimer’s disease and other types of dementia .
Action Environment
The action, efficacy, and stability of ®-Rivastigmine can be influenced by various environmental factors. For instance, factors such as pH and temperature can affect the stability and activity of the drug . Additionally, individual patient factors, such as age, liver function, and concomitant medications, can also influence the pharmacokinetics and pharmacodynamics of ®-Rivastigmine .
Preparation Methods
Synthetic Routes and Reaction Conditions: The synthesis of ®-Rivastigmine typically involves the following steps:
Formation of the Chiral Intermediate: The chiral intermediate is synthesized through the reaction of ®-3-(1-dimethylaminoethyl)phenol with 3-bromopropylamine hydrobromide.
Carbamate Formation: The intermediate is then reacted with methyl isocyanate to form ®-Rivastigmine.
Industrial Production Methods: Industrial production of ®-Rivastigmine involves large-scale synthesis using optimized reaction conditions to ensure high yield and purity. The process includes:
Batch Processing: Utilizing batch reactors for the controlled addition of reagents.
Purification: Employing techniques such as crystallization and chromatography to purify the final product.
Types of Reactions:
Oxidation: ®-Rivastigmine can undergo oxidation reactions, typically in the presence of strong oxidizing agents.
Reduction: Reduction reactions can occur under specific conditions, although they are less common.
Substitution: The compound can participate in nucleophilic substitution reactions, particularly at the carbamate group.
Common Reagents and Conditions:
Oxidation: Reagents such as hydrogen peroxide or potassium permanganate.
Reduction: Reagents like lithium aluminum hydride.
Substitution: Nucleophiles such as amines or thiols.
Major Products:
Oxidation: Oxidized derivatives of ®-Rivastigmine.
Reduction: Reduced forms of the compound.
Substitution: Substituted carbamate derivatives.
Comparison with Similar Compounds
Donepezil: Another cholinesterase inhibitor used in Alzheimer’s disease.
Galantamine: A natural alkaloid with cholinesterase inhibitory properties.
Tacrine: An older cholinesterase inhibitor with a similar mechanism of action.
Comparison:
Uniqueness: ®-Rivastigmine is unique in its dual inhibition of both acetylcholinesterase and butyrylcholinesterase, whereas Donepezil primarily inhibits acetylcholinesterase.
Efficacy: Studies suggest that ®-Rivastigmine may offer benefits in patients who do not respond to other cholinesterase inhibitors.
Side Effects: The side effect profile of ®-Rivastigmine is comparable to other cholinesterase inhibitors, with gastrointestinal symptoms being the most common.
Properties
IUPAC Name |
[3-[(1R)-1-(dimethylamino)ethyl]phenyl] N-ethyl-N-methylcarbamate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C14H22N2O2/c1-6-16(5)14(17)18-13-9-7-8-12(10-13)11(2)15(3)4/h7-11H,6H2,1-5H3/t11-/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
XSVMFMHYUFZWBK-LLVKDONJSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCN(C)C(=O)OC1=CC=CC(=C1)C(C)N(C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CCN(C)C(=O)OC1=CC=CC(=C1)[C@@H](C)N(C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C14H22N2O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID90194422 |
Source
|
| Record name | Rivastigmine, (R)- | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID90194422 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
250.34 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
415973-05-6 |
Source
|
| Record name | Rivastigmine, (R)- | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0415973056 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Rivastigmine, (R)- | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID90194422 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | RIVASTIGMINE, (R)- | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/Z25UDQ15MV | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Synthesis routes and methods
Procedure details
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: What is unique about the synthesis method for (R)-N-ethyl-N-methyl carbamic acid-3-(1-hydroxyethyl) phenyl ester described in the research?
A1: The research highlights a novel approach to synthesizing (R)-N-ethyl-N-methyl carbamic acid-3-(1-hydroxyethyl) phenyl ester, a crucial intermediate in the production of (R)-Rivastigmine []. This method boasts high stereoselectivity, utilizing a chiral catalyst to achieve an enantiomeric excess (ee) exceeding 98% for the desired (R)-enantiomer []. Remarkably, this impressive selectivity is achieved with a remarkably low catalyst loading, requiring just 1/100,000th to 1/1,000,000th of the reactant amount []. This efficient use of the catalyst, coupled with the method's ability to achieve complete reactant conversion, underscores its potential for large-scale production of this important pharmaceutical intermediate.
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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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