123441-03-2

Usage

Uses

Used in Pharmaceutical Industry:
Rivastigmine is used as an antidepressant for the treatment of mild-to-moderate Alzheimer's disease and mild-to-moderate dementia associated with Parkinson's disease. It works by inhibiting acetylcholinesterase, an enzyme responsible for breaking down acetylcholine, a neurotransmitter involved in memory and cognitive function. By increasing the levels of acetylcholine in the brain, Rivastigmine helps improve cognitive function and slow down the progression of these neurodegenerative disorders.

Pharmacokinetics

Rivastigmine is a centrally selective, arylcarbamate AChEI that was approved in 2000 for oral administration in the treatment of AD. It has an elimination half-life of 1.4 to 1.7 hours but is able to inhibit AChE for up to 10 hours. Because of the slow dissociation of the carbamylated enzyme, it has been referred to as a pseudo-irreversible AChEI. Like donepezil, rivastigmine exhibits a low level of hepatotoxicity. It is rapidly and extensively hydrolyzed in the CNS by cholinesterase with minimal involvement of CYP450. The phenolic metabolite is excreted primarily via the kidneys.

Clinical Use

Mild-moderate dementia in Alzheimer’s disease Idiopathic Parkinson’s disease

Drug interactions

Potentially hazardous interactions with other drugs Muscle relaxants: enhances effect of suxamethonium; antagonises effect of non-depolarising muscle relaxants.

Metabolism

Rivastigmine is the tertiary amines that are rapidly absorbed from the gastrointestinal tract, as are tacrine, donepezil, and galanthamine, whereas quaternary ammonium compounds are poorly absorbed after oral administration. Nevertheless, quaternary ammonium compounds like neostigmine and pyridostigmine are orally active if larger doses are employed. Only the quaternary ammonium inhibitors do not readily enter the CNS. Because of their high lipid solubility and low molecular weight, most of the organophosphates are absorbed by all routes of administration; even percutaneous exposure can result in the absorption of sufficient drug to permit the accumulation of toxic levels of these compounds.

InChI:InChI=1/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-/m0/s1

Upstream product

• 58105-38-7 O-benzoyl N,N-dimethylhydroxylamine 
• 218900-56-2 (S)-[1-(3-methoxyphenyl)ethyl]carbamic acid tert-butyl ester 
• 1016225-06-1 C₁₇H₁₈N₂O₅ 
• 624-78-2 N-Ethylmethylamine 
• 586-37-8 1-(3-Methoxyphenyl)ethanone 
• 23308-82-9 (R)-(+)-1-(3-methoxyphenyl)-1-ethanol 
• 89691-63-4 1-(3-methoxy)-phenylethanol 
• 855300-09-3 1-(N-ethyl-N-methylaminocarbonyloxy)-3-acetylbenzene 
• 1257519-35-9 (S)-1-(N-ethyl-N-methylaminocarbonyloxy)-3-(1-hydroxyethyl)benzene 
• 105601-04-5 (+/-)-3-<1-(Dimethylamino)ethyl>phenol 
• 1412902-99-8 (S)-1-(3-methoxyphenyl)-N,N-dimethyl-N-((S)-1-phenylethyl)ethanaminium iodide 
• 1412902-91-0 (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N-((S)-1-phenylethyl)ethanaminium iodide 
• 1162673-62-2 (S)-1-(3-methoxyphenyl)-N-methyl-N-[(S)-1-phenylethyl]ethanamine 
• 121-71-1 3-Hydroxyacetophenone 

Downstream Products

• 123441-03-2 rivastigmin 
• 1346602-84-3 3-vinylphenyl N-ethyl-N-methylcarbamate 
• 1392101-35-7 3-ethylphenyl N-ethyl-N-methylcarbamate 
• 855300-09-3 1-(N-ethyl-N-methylaminocarbonyloxy)-3-acetylbenzene 
• 1222073-98-4 rac-1-(N-ethyl-N-methylaminocarbonyloxy)-3-(1-hydroxyethyl)benzene 
• 1416014-88-4 3-(1-methoxyethyl)phenyl N-ethyl-N-methylcarbamate 
• 624-78-2 N-Ethylmethylamine 
• 124-38-9 carbon dioxide 
• 139306-10-8 (S)-3-(1-dimethylaminoethyl)phenol 

Related news

Controlled delivery of Rivastigmine (cas 123441-03-2) using transdermal patch for effective management of alzheimer's disease07/24/2019

Alzheimer's disease is a chronic neurodegenerative disease. Preparation of transdermal patches is a useful strategy for management of the disease. The transdermal patches bearing Rivastigmine tartarate were prepared using solvent casting method to provide good drug content uniformity. Trans...detailed

Paroxetine and Rivastigmine (cas 123441-03-2) mitigates adjuvant-induced rheumatoid arthritis in rats: Impact on oxidative stress, apoptosis and RANKL/OPG signals07/23/2019

Rheumatoid arthritis (RA) is considered a form of inflammatory autoimmune disease with unknown etiology, but environmental and genetic causes are sharing. T-cells, B-cells, synovial cells, osteoclast, and chondrocytes are the main cell types in RA pathophysiology. The present study aimed to inve...detailed

Enhancement of oral bioavailability of Rivastigmine (cas 123441-03-2) with quercetin nanoparticles by inhibiting CYP3A4 and esterases07/22/2019

BackgroundQuercetin is a well-known flavonoid, has pharmacokinetic interaction with ester drugs due to its capability of esterase inhibition in the gut and liver. However, the interaction between quercetin nanoparticles (NQC) and rivastigmine has not been reported. Hence, the present study was p...detailed

Spectrodensitometric determination of Rivastigmine (cas 123441-03-2) after vortex assisted magnetic solid phase extraction07/20/2019

A highly sensitive and cost-effective HPTLC method was developed for the determination of rivastigmine hydrogen tartarate (RIV) in bulk and capsules. Moreover, magnetic solid phase extraction procedure (MSPE) was performed for analysis of RIV in human plasma to preconcentrate RIV and decrease in...detailed

Persistence and adherence to Rivastigmine (cas 123441-03-2) in patients with dementia: Results from a noninterventional, retrospective study using the National Health Insurance research database of Taiwan07/21/2019

IntroductionThe objective of the study was to assess adherence and persistence of patients treated with rivastigmine versus donepezil.detailed

Relevant academic research and scientific papers

Kinetic Modeling of the Blood Oxygenation Level Dependent (BOLD) Signals and Biocatalytic Reactions Observed in the Human Brain Using MRI: An Analysis of Normal and Pathological Conditions

A kinetic model describing the pulse of increased oxygen concentrations and the subsequent changes in the concentration of N-acetylaspartate in the excited nervous tissue of the human brain in response to an external signal is presented. The model is based on biochemical data, a multistage and nonlinear dynamic process the BOLD signal and N-acetylaspartate. The existence of multiple steady states explains the triggering effect of the system. The inhibitory effect of the substrate is a necessary factor for the autostabilization of N-acetylaspartate. The kinetic model allows the dynamic behavior of previously unmeasurable metabolites, namely, products of the hydrolysis of N-acetylaspartate, such as acetic and aspartic acid, and glutamic acid to be predicted. Kinetic modeling of the BOLD signal and the subsequent hydrolysis of N-acetylaspartate provides information about the biochemical and dynamic characteristics of some pathological conditions (schizophrenia, Canavan disease, and the superexcitation of the neural network).

Preparation, Optimization, and Evaluation of Methoxy Poly(ethylene glycol)- co-Poly(?-caprolactone) Nanoparticles Loaded by Rivastigmine for Brain Delivery

The objective of this study was to formulate and investigate the neuropharmacokinetics and pharmacodynamics of rivastigmine (Riv) loaded methoxy poly(ethylene glycol)-co-poly(?-caprolactone) (MPEG-PCL) nanoparticles (Riv-NPs) in rats after IV administration. The MPEG-PCL was synthesized via ring-opening polymerization of ?-caprolactone by MPEG and used to prepare Riv-NPs by the nanoprecipitation method. Response surface D-optimal design was applied to optimize Riv-NPs drug delivery system. The optimized formulation showed a particle size (PS) of 98.5 ± 2.1 nm, drug loading (DL) of 19.2 ± 1.1%, and sustained release behavior of the drug. Moreover, the optimized Riv-NPs were characterized by AFM and DSC analyses. A simple and sensitive HPLC-DAD method for bioanalysis was developed and successfully applied to the pharmacokinetic study. The neuropharmacokinetic study in rats indicated that the integration plot was linear, and the brain uptake clearance of the drug-loaded in MPEG-PCL NPs was significantly higher than the free drug. Furthermore, results of pharmacodynamic studies using the Morris water maze test demonstrated faster regain of memory loss with Riv-NPs when compared to the free drug solution. The results revealed that the mentioned biodegradable nanoparticle holds promise as a suitable drug carrier for brain drug delivery.

Group-assisted Purification (GAP) Chemistry/Technology in synthesizing the chiral intermediate of rivastigmine and its ?-Alkyl benzylamine analogues

Introduction of (S)-configuration is the key step in the synthesis of the anti-dementia drug Rivastigmine. Twenty-one alkylation products were obtained through simple washing with hexane/ethyl acetate (v/v: 10/1) in good yields (>85%) and high diastereoselectivity (up to >99:1 dr). Moreover, the chiral auxiliary could be easily dissociated and readily regenerated. That is, the synthesis was proved to follow group-assisted purification (GAP) chemistry/technology. In addition, the chiral amine produced by this asymmetric alkylation reaction was effectively used in the synthesis of Rivastigmine.

Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines

α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.

SYNTHESIS OF NOVEL INTERMEDIATE(S) FOR PREPARING RIVASTIGMINE

The present invention relates to novel intermediate(s), which are useful for the preparation of Rivastigmine compound of formula (I) and its pharmaceutically acceptable salts. The present invention further relates to the processes for the preparation of such novel intermediate(s) and preparation of Rivastigmine using such novel intermediate(s).

Biaryl diphosphine ligands and their ruthenium complexes: Preparation and use for catalytic hydrogenation of ketones

Procedures for the preparation of the nucleophilic diphosphine ligands (R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((R)-Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((S)-Ph-Garphos, 2b) were described. The ligands were used to prepare the ruthenium(II) Ph-Garphos complexes, chloro(p-cymene)(R)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Ph-Garphos]Cl (3)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Ph-Garphos]Cl (4)). In the presence of the chiral diamine co-ligands (1R,2R)-1,2-diphenylethane-1,2-diamine (R,R-DPEN) and (1S,2S)-1,2-diphenylethane-1,2-diamine (S,S-DPEN), complexes 3 and 4 were found to be catalyst precursors for the enantioselective reduction of aryl ketones under mild conditions (room temperature and 3–4 atm of H2). The chiral alcohols were isolated in moderate to good yields and with enantioselectivities of up to 93percent. The ruthenium complexes chloro(p-cymene)(R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Xyl-Garphos]Cl (6)) were also prepared and used as catalyst precursors for the hydrogenation of aryl ketones in the presence of (R,R)-DPEN and (S,S)-DPEN. Significant improvements in the enantioselectivities of the alcohols (up to 98percent ee.) were afforded. A combination of 6 and (S,S)-DPEN afforded (R)-1-(3-methoxyphenyl)ethanol in 89percent yield and with 95percent ee which was shown to be a suitable precursor for the preparation of (S)-rivastigmine.

Iridium-catalyzed diastereoselective amination of alcohols with chiral: Tert-butanesulfinamide by the use of a borrowing hydrogen methodology

An iridium-catalyzed diastereoselective amination of alcohols with chiral tert-butanesulfinamide was developed under basic conditions, affording the optically active secondary sulfinamides in high yields and diastereoselectivities. The removal of the sulfinyl group from sulfonamides allowed a facile access to a wide range of α-chiral primary amines. This synthetic strategy was further applied in the synthesis of the marketed pharmaceuticals (S)-rivastigmine and NPS R-568.

Direct asymmetric reductive amination for the synthesis of (S)-rivastigmine

In this article we demonstrate how asymmetric total synthesis of (S)-rivastigmine has been achieved using direct asymmetric reductive amination as the key transformation in four steps. The route started with readily available and cheap m-hydroxyacetophenone, through esterification, asymmetric reductive amination, N-diphenylmethyl deprotection and reductive amination, to provide the final (S)-rivastigmine in 82% overall yield and 96% enantioselectivity. In the asymmetric reductive amination, catalysed by the iridium–phosphoramidite ligand complex and helped by some additives, the readily prepared 3-acetylphenyl ethyl(methyl)carbamate directly reductively coupled with diphenylmethanamine to yield the chiral amine product in 96% ee and 93% yield.

ASYMMETRIC SYNTHESIS OF (S)-3-(1-(DIMETHYLAMINO) ETHYL) PHENYLETHYL(METHYL)CARBAMATE AND ITS SALTS

The present invention is in relation to a process of preparation of asymmetric synthesis of Rivastigmine and its salts in high yield and purity.

A General Catalytic Method for Highly Cost- and Atom-Efficient Nucleophilic Substitutions

A general formamide-catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT-mediated dihydroxychlorination of an OH-containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E-factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional-group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one-pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN2 inversion, which demonstrates the high practical value of the presented method.