Donepezil Hydrochloride Chemical Properties

Melting point:

220-222°C

storage temp. 

room temp

Water Solubility 

Soluble in water

solubility 

insoluble in EtOH; insoluble in DMSO; ≥10.4 mg/mL in H2O

form 

powder

color 

white to off-white

Merck 

14,3419

Stability:

Hygroscopic

InChI

InChI=1S/C24H29NO3.ClH/c1-27-22-14-19-13-20(24(26)21(19)15-23(22)28-2)12-17-8-10-25(11-9-17)16-18-6-4-3-5-7-18;/h3-7,14-15,17,20H,8-13,16H2,1-2H3;1H

InChIKey

XWAIAVWHZJNZQQ-UHFFFAOYSA-N

SMILES

C1(=O)C2=C(C=C(OC)C(OC)=C2)CC1CC1CCN(CC2=CC=CC=C2)CC1.[H]Cl

CAS DataBase Reference

120011-70-3(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26-36

RIDADR 

UN 2811

WGK Germany 

1

RTECS 

NK8927885

HS Code 

2933.39.9200

HazardClass 

6.1

PackingGroup 

II

Donepezil Hydrochloride Usage And Synthesis

Chemical Properties

Donepezil hydrochloride (E2020) alongside with galantamine and rivastigmine is a piperidine-based drug developed specifically for Alzheimer’s disease (AD) by Eisai Pharmaceuticals (Aricept). Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in n-hexane.

Originator

Eisai (Japan)

Uses

Donepezil hydrochloride is an inhibitor of acetylcholinesterase with a labelled nootropic. It has been used in dose-response experiment to study its efficacy in ameliorating nicotine withdrawal-induced deficits in contextual conditioning in mice. It has also been intraperitoneally injected into rats to study its ability to improve social behavioral deficits, repetitive behavior and hyperactivity. Labeled Donepezil, intended for use as an internal standard for the quantification of Donepezilby GC- or LC-mass spectrometry.

Definition

ChEBI: Donepezil hydrochloride is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine.

Application

Donepezil hydrochloride is a reversible，non-competitiveChEl with highly selective central action,approved for thetreatment of mild, moderate and advanced AD. Donepezil is unrelated to other ChEIs and has greaterselectivity for cerebral acetylcholinesterase (AChE) than forbutirylcholinesterase (BuChE).

Preparation

Donepezil Hydrochloride is being synthesized from alkylidene or arylidene-2-indanone formed by Aldol condensation chemistry as key intermediates (Sugimoto and co-workers)) followed by catalytic reduction affording donepezil hydrochloride with an overall yield of 27%.

Benzyl chloride (1.92 g, 0.0156 mol), potassium carbonate (2.28 g, 0.0165 mol) and PEG-200 (80 mg, 2% by weight) were added to a clear biphasic solution of 2-[(4-piperidyl)methyl]-5,6-dimethoxyindan-1-one 6 (4 g, 0.0138 mol) in 9 : 1 EtOAc–H2O (40 ml). The reaction mixture was heated to 50—55 °C and monitored on TLC. After completion of reaction (14 h), the solid was filtered and the filtrate was washed with water (4 ml). The EtOAc layer was separated, added water (8 ml) and acidified with conc. HCl till a pH 2. EtOAc layer was discarded and the acidic aqueous layer was extracted with CH2Cl2 (2*16 ml). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and evaporated under vacuum to yield the crude salt as a residue. The residue was dissolved in methanol (20 ml) followed by the addition of isopropyl ether (40 ml) and stirred for a further 1 h. The precipitated solid was filtered and dried under vacuum to yield pure donepezil hydrochloride.
A New Commercially Viable Synthetic Route for Donepezil Hydrochloride

brand name

Aricept (Eisai Medical Research).

Therapeutic Function

Anti-Alzheimer's disease

General Description

Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Donepezil Hydrochloride is known as a selective, reversible inhibitor of acetylcholinesterase enzyme. It exhibits therapeutic effect by raising the acetylcholine concentrations and improving the cholinergic function. It can be used in the treatment of mild to moderate dementia of the Alzheimer′s type.

Biological Activity

donepezil hydrochloride (donepezil hcl) is a novel, potent and selective inhibitor of acetylcholinesterase (ache), an enzyme possibly involved in cognitive dysfunction of patients suffering alzheimer’s disease (ad), with the half maximal inhibition concentration ic50 value of 6.7 nm [1].donepezil hcl is a piperidine-class ache inhibitor containing an n-benzylpiperdine and an indanone moiety, which confers it a longer and more selective action against ache as compared to buche (ic50: 7.4 μm) [1].donepezil hcl has been approved by fda for the treatment of ad, in which it has improved cognitive function of mild to severe moderate ad patients and exhibited excellent tolerability without hepatotoxicity [1].

Biochem/physiol Actions

Donepezil hydrochloride is a piperidine containing an organic compound and a non-competitive inhibitor. It is useful in treating Alzheimer′s disease, in which dementia is a prominent symptom. Donepezil is shown to induce cognitive ability and overall body function. It has a half-life of 70 hours.

Pharmacology

Donepezil hydrochloride is a second-generation highly selective acetylcholinesterase inhibitor developed by the Japanese company Eisai Pharmaceutical Company. It was first marketed in the United States in 1997 for the treatment of Alzheimer's disease. Donepezil is the second drug approved by the FDA for the treatment of Alzheimer's disease. It is a highly selective, long-acting, reversible acetylcholinesterase inhibitor with a piperidine group. Compared with tacrine, donepezil hydrochloride is more selective for neuronal acetylcholinease, has better pharmacodynamics, pharmacokinetics and safety indicators, and is well tolerated. It is an alternative drug to tacrine.
Donepezil hydrochloride is a cholinesterase inhibitor. After taking it, patients mainly increase the content of acetylcholine in the synapses that are directly involved in nerve transmission by inhibiting the activity of acetylcholine lipase. Donepezil hydrochloride can Effectively improve patients 'brain function and improve patients' cognitive ability. Currently, donepezil hydrochloride is a commonly used drug in the treatment of mild to moderate senile dementia. Donepezil hydrochloride tablets are suitable for the treatment of memory degeneration of dementia caused by various reasons. Donepezil hydrochloride has the effect of nourishing brain neurons, repairing damaged brain nerves, and can rapidly improve patients' cognitive function and memory.

Clinical Use

Treatment of dementia in mild to moderate Alzheimer’s disease

Side effects

Donepezil was generally well tolerated, although more adverse effects were reported in the 10 mg/day group than assessed as mild to moderate and transient, and were typi-cally diarrhoea，nausea，arthralgia，leg cramps，anorexia and headache. Donepezil (5-10 mg/day) had no effecton V-ADAS-cog but had significant effect on two measuresof executive function: EXIT25 and TMT-B. These subjectswere younger than most VaD patients and most (75%) hadno clinically significant memory dysfunction. The positive effect of donepezil on executive function, however, indicatessome cholinergic deficit in executive dysfunction.

Metabolism

Donepezil hydrochloride is both excreted in the urine intact and metabolised by the cytochrome P450 system to multiple metabolites, not all of which have been identified. Following administration of a single 5 mg dose of [14C]-labelled donepezil hydrochloride, plasma radioactivity, expressed as a percentage of the administered dose, was present primarily as intact donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11% - only metabolite that exhibits activity similar to donepezil hydrochloride), donepezil-cis-N-oxide (9%), 5-O-desmethyl donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl donepezil (3%).
Approximately 57% of the total administered radioactivity was recovered from the urine, and 14.5% was recovered from the faeces, suggesting biotransformation and urinary excretion as the primary routes of elimination. There is no evidence to suggest enterohepatic

storage

Room Temperature

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• XWAIAVWHZJNZQQ-RPXFAUAJSA-N