120014-06-4

Basic information

• Product Name: 2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one
• Synonyms: DONEPEZIL;2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one;1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL) METHYL] PIPERIDINE;AKOS 226-23;2,3-dihydro-5,6-dimethoxy-2-((1-(phenylmethyl)-4-piperidinyl)methyl)-1h-inde;n-1-one;N-Benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl] piperidine;5,6-Dimethoxy-2,3-dihydro-1H-inden-1-one
• CAS NO: 120014-06-4
• Molecular Formula: C₂₄H₂₉NO₃
• Molecular Weight: 379.49
• EINECS: 1312995-182-4
• Product Categories: Isotope;Other APIs
• Mol File: 120014-06-4.mol
• Article Data: 68

Chemical Properties

• Melting Point: 207°C
• Boiling Point: 527.9 ºC at 760 mmHg
• Flash Point: 273.1 ºC
• Appearance: white or almost white crystal powder
• Density: 1.141 g/cm³
• Vapor Pressure: 3.11E-11mmHg at 25°C
• Refractive Index: 1.578
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Acetone (Slightly), Chloroform (Slightly)
• PKA: 8.84±0.10(Predicted)
• Water Solubility: 2.931 mg/L
• CAS DataBase Reference: 2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one(CAS DataBase Reference)
• NIST Chemistry Reference: 2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one(120014-06-4)
• EPA Substance Registry System: 2-[(1-Benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3-dihydroinden-1-one(120014-06-4)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-36/37/39
• RIDADR: UN 2811
• Hazardous Substances Data: 120014-06-4(Hazardous Substances Data)

Usage

Description

Donepezil is another “nonclassic,” centrally acting, reversible, noncompetitive AChEI that was approved in 1997 for treatment of mild-to-moderate AD and dementia. Its selectivity for AChE is 570- to 1,250-fold that for butyrylcholinesterase, and it also exhibits greater affinity for brain AChE than for AChE in the periphery.

Uses

Different sources of media describe the Uses of 120014-06-4 differently. You can refer to the following data:
1. Donepezil is a cholinesterase inhibitors.
2. Acetylcholine is a neurotransmitter involved in neural signaling throughout the body. Donepezil is a reversible acetylcholinesterase inhibitor that readily crosses the blood-brain barrier to reduce the breakdown of acetylcholine. It has a half-life in circulation of about 70 hours. As acetylcholine modulates plasticity, excitability, and arousal in the central nervous system, donepezil is commonly used in the treatment of Alzheimer’s disease to improve cognition, memory, and behavior. In this way, it is intended to prevent or reverse dementia. Studies on these effects have been equivocal, indicating that more research into the therapeutic potential of donepezil is warranted.[Cayman Chemical]

Definition

ChEBI: Donepezil 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.

General Description

Donepezil, (±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (Aricept), commonly referred to in the literature asE2020, is a reversible inhibitor of AChE. It is indicated forthe treatment of symptoms of mild-to-moderate Alzheimerdisease. Donepezil is approximately 96% bound to plasmaproteins, with an elimination half-life of 70 hours. It is metabolizedprincipally by the 2D6 and 3A4 isozymes of theP450 system.

Metabolism

When compared to tacrine, donepezil exhibits greater CNS AChE selectivity, longer elimination half-life (70–104 hours in subjects older than 55 years) and little or no potential for hepatotoxicity. Donepezil is metabolized by CYP2D6 and CYP3A4 via demethylation, debenzylation, hydroxylation, oxidation to the cis-N-oxide, and glucuronidation. The 6-O-desmethyl metabolite accounts for 11% of a dose, and it exhibits AChE inhibitory activity comparable to that of the parent compound.

InChI:InChI=1/C24H29NO3/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

Synthetic route

ethyl acetate thrice + (±)-2-[(1-benzylpyridin-1-ium-4-yl)methyl]-5,6-dimethoxy-indan-1-one bromide → donepezil (120014-06-4)

Conditions	Yield
In methanol	99%

donepezil hydrochloride → donepezil (120014-06-4)

Conditions	Yield
With sodium hydroxide In water; ethyl acetate for 0.5h; pH=11.7; Reagent/catalyst; Solvent; pH-value;	97.5%
With sodium hydrogencarbonate In water; toluene at 60 - 65℃; for 0.5h; Purification / work up;
Stage #1: donepezil hydrochloride With sodium hydrogencarbonate In water; toluene at 60 - 65℃; for 0.75h; Stage #2: In water; isopropyl alcohol at 10 - 70℃; for 10h; Product distribution / selectivity;

2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt + benzyl bromide (100-39-0) → donepezil (120014-06-4)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide Product distribution / selectivity;	96%

benzyl bromide (100-39-0) + debenzyldonepezil (120014-30-4) → donepezil (120014-06-4)

Conditions	Yield
With sodium carbonate In ethanol at 50 - 60℃; for 6h;	92.3%
With triethylamine In dichloromethane for 4h; Heating / reflux;
Stage #1: benzyl bromide; debenzyldonepezil With tetrabutylammomium bromide; potassium carbonate In dichloromethane; water at 20℃; Stage #2: With hydrogenchloride In methanol

2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid (259170-03-1) → donepezil (120014-06-4)

Conditions	Yield
With trifluorormethanesulfonic acid; trifluoroacetic anhydride In dichloromethane at 24 - 28℃; Inert atmosphere; chemoselective reaction;	90%

(E)-2-((1-benzylpiperidine-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one → donepezil (120014-06-4)

Conditions	Yield
With sodium dithionite; tetrabutylammomium bromide; sodium hydrogencarbonate In water; ethyl acetate	88%
With sodium dithionite; tetrabutylammomium bromide; water; sodium hydrogencarbonate In ethyl acetate at 65℃; for 0.5h; Solvent; Temperature; Time;	88%
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; under 760.051 Torr; for 12h;	78%
With hydrogen; palladium carbon In methanol at 20℃; under 760.051 Torr; for 2h;	31 g
With hydrogen In tetrahydrofuran; water; isopropyl alcohol at 25℃; under 760.051 Torr; for 20h; Catalytic behavior; Flow reactor; chemoselective reaction;	95 %Spectr.

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-formylpiperidine (22065-85-6) → donepezil (120014-06-4)

Conditions	Yield
With aluminum oxide; Pt/Al2O3 In tetrahydrofuran; ethanol; water; isopropyl alcohol at 45 - 55℃; for 7h; Temperature; Solvent; Reagent/catalyst; Aldol Condensation;	88%
Multi-step reaction with 2 steps 1: sodium methylate / tetrahydrofuran 2: palladium 10% on activated carbon; hydrogenchloride / ethanol; water View Scheme

1-benzyl-4-[(5,6-dimethoxy-1-indanol)-2-yl]methylpiperidine (120012-04-6) → donepezil (120014-06-4)

Conditions	Yield
With tert.-butylhydroperoxide; tetrabutylammomium bromide In decane; benzene at 40℃; for 24h; Sealed tube; chemoselective reaction;	85%

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-piperidinemethanol (67686-01-5) → donepezil (120014-06-4)

Conditions	Yield
With bis(μ-chloro)-bis[1,3-di(2-pyridyl)-4,6-dimethylbenzene-N,C(2'),N-iridium chloride]; caesium carbonate In tert-Amyl alcohol for 12h; Reflux;	85%
With [Ir(dpyx-N,C,N)Cl(i-Cl)]2; caesium carbonate In tert-Amyl alcohol at 130℃; for 2h; Reagent/catalyst;	85%
With potassium phosphate tribasic trihydrate; C39H32Cl2N5PRu In tert-Amyl alcohol at 120℃; for 4h; Inert atmosphere; Schlenk technique;	83%

1-benzyl-4-[((5,6-dimethoxy-2-ethoxycarbonylindan-1-on)-2-yl)methyl]piperidine → donepezil (120014-06-4)

Conditions	Yield
With potassium hydroxide In ethanol; water for 1h; Heating / reflux;	80%
With potassium hydroxide In ethanol; water for 1h; Heating / reflux;	80%

C24H29NO3 → donepezil (120014-06-4)

Conditions	Yield
With acetic acid; L-proline at 120℃; for 24h; Green chemistry;	77%

2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-indene-2-carbonitrile → donepezil (120014-06-4)

Conditions	Yield
With hydrogenchloride In methanol; water	76.34%

2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt + benzaldehyde (100-52-7) → donepezil (120014-06-4)

Conditions	Yield
Stage #1: 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt With hydrogen; sodium acetate; palladium 10% on activated carbon In methanol under 760.051 Torr; for 10h; Stage #2: benzaldehyde In methanol for 8h; Product distribution / selectivity;	62%

5-[(1-benzyl-4-piperidyl)methyl]-5-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (848610-96-8) → donepezil (120014-06-4)

Conditions	Yield
With trifluorormethanesulfonic acid In nitromethane at 100℃; for 0.5h; Friedel-Crafts acylation;	61%

debenzyldonepezil (120014-30-4) + benzyl alcohol (100-51-6) → donepezil (120014-06-4)

Conditions	Yield
With trifuran-2-yl-phosphane; C42H32F3N2O2PPd; lithium hydroxide In neat (no solvent) at 100℃; for 48h; Schlenk technique; Sealed tube; Inert atmosphere; Green chemistry; chemoselective reaction;	56%

(E)-1-benzyl-4-((5,6-dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)methyl)pyridin-1-ium bromide → donepezil (120014-06-4)

Conditions	Yield
With platinum(IV) oxide; hydrogen In methanol at 23℃; under 760.051 Torr; for 24h; Inert atmosphere;	50%

2-((1-benzoylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (120013-38-9) → donepezil (120014-06-4)

Conditions	Yield
With trifluoromethylsulfonic anhydride; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In dichloromethane at 20℃; for 2h;	49%

1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine (120014-07-5) → donepezil (120014-06-4)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In tetrahydrofuran at 20℃; for 16h;	37%
With hydrogen; palladium 10% on activated carbon In tetrahydrofuran at 20℃; under 760.051 Torr; for 6h;
With hydrogen; nickel In tetrahydrofuran at 8 - 38℃; under 750.075 - 9000.9 Torr; for 0.666667 - 6h; Product distribution / selectivity;

1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine hydrochloride → donepezil (120014-06-4)

Conditions	Yield
With hydrogen; palladium on activated charcoal In tetrahydrofuran under 760 Torr; for 6h; Ambient temperature;
Stage #1: 1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine hydrochloride In methanol; acetic acid at 25 - 45℃; Stage #2: With hydrogen; 5%-palladium/activated carbon In methanol; acetic acid under 1103.36 - 1471.14 Torr;
With hydrogen; palladium 10% on activated carbon In tetrahydrofuran at 20℃; for 6h;
Stage #1: 1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine hydrochloride With hydrogen; acetic acid; 5% Pd(II)/C(eggshell) In methanol at 28 - 33℃; under 1103.36 - 1471.14 Torr; Stage #2: With sodium carbonate In dichloromethane; water for 7 - 8h; Stage #3: With hydrogenchloride In isopropyl alcohol at 25 - 30℃; pH=2;

benzyl bromide (100-39-0) + debenzyldonepezil (120014-30-4) → 1,1-dibenzyl-4-(5,6-dimethoxy-1-oxo-indan-2-ylmethyl)-piperidinium; bromide + donepezil (120014-06-4)

Conditions	Yield
With sodium carbonate In methanol; isopropyl alcohol at 60 - 65℃; for 11h;

5,6-dimethoxy-1-indanone (2107-69-9) → donepezil (120014-06-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / methanol; H2O / Heating 1.2: 77 percent / methanol; H2O / 2.5 h / 75 °C 2.1: 31 g / H2 / palladium carbon / methanol / 2 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1: 95.6 percent / p-toluenesulfonic acid / toluene / 6 h / Heating 2: 90 percent / hydrogen; acetic acid / palladium on activated charcoal / methanol / 7 h / 60 - 65 °C 3: sodium carbonate / methanol; propan-2-ol / 11 h / 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / water; dichloromethane / 1.5 h / 38 °C 2: tetrabutylammomium bromide; sodium hydrogencarbonate; sodium dithionite / water; ethyl acetate View Scheme
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / dichloromethane; water / 1.5 h / 38 °C 2: tetrabutylammomium bromide; sodium hydrogencarbonate; sodium dithionite; water / ethyl acetate / 0.5 h / 65 °C View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / 24 h / Reflux 2: hydrogen / neat (no solvent) / 144 h / 50 °C / 760.05 Torr 3: sodium carbonate / isopropyl alcohol / 12 h / 50 °C View Scheme

1-benzyl-4-formylpiperidine (22065-85-6) → donepezil (120014-06-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate / methanol; H2O / Heating 1.2: 77 percent / methanol; H2O / 2.5 h / 75 °C 2.1: 31 g / H2 / palladium carbon / methanol / 2 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 3 steps 1.1: piperidinium acetate / ethanol / 0.5 h 1.2: 47 percent / NaBH3CN / ethanol / 0 - 20 °C 2.1: 44 percent / K2CO3 / dimethylformamide 3.1: 61 percent / TfOH / nitromethane / 0.5 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: tetrabutylammomium bromide; potassium hydroxide / water; dichloromethane / 1.5 h / 38 °C 2: tetrabutylammomium bromide; sodium hydrogencarbonate; sodium dithionite / water; ethyl acetate View Scheme

pyridine-4-carbaldehyde (872-85-5) + N6-protected N2-Fmoc-lysine on Wang resin → donepezil (120014-06-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95.6 percent / p-toluenesulfonic acid / toluene / 6 h / Heating 2: 90 percent / hydrogen; acetic acid / palladium on activated charcoal / methanol / 7 h / 60 - 65 °C 3: sodium carbonate / methanol; propan-2-ol / 11 h / 60 - 65 °C View Scheme

(E)-5, 6-dimethoxy-2-(pyridin-4-ylmethylene)-2, 3-dihydro-1H-inden-1-one (877606-65-0) → donepezil (120014-06-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / hydrogen; acetic acid / palladium on activated charcoal / methanol / 7 h / 60 - 65 °C 2: sodium carbonate / methanol; propan-2-ol / 11 h / 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1: acetonitrile / 24 h / Reflux 2: platinum(IV) oxide; hydrogen / methanol / 24 h / 23 °C / 760.05 Torr / Inert atmosphere View Scheme

5-(1-benzyl-piperidin-4-ylmethyl)-2,2-dimethyl-[1,3]dioxane-4,6-dione (865718-00-9) → donepezil (120014-06-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 44 percent / K2CO3 / dimethylformamide 2: 61 percent / TfOH / nitromethane / 0.5 h / 100 °C View Scheme

benzyl bromide (100-39-0) + 5,6-dimethoxy-2-(piperidine-4-ylmethyl)-2,3-dihydro-1H-inden-1-one hydrochloride → donepezil (120014-06-4)

Conditions	Yield
With tetrabutylammomium bromide; potassium carbonate In dichloromethane; water at 20 - 25℃; for 1h;
Stage #1: benzyl bromide; 5,6-dimethoxy-2-(piperidine-4-ylmethyl)-2,3-dihydro-1H-inden-1-one hydrochloride With monopotassium carbonate; tetrabutylammomium bromide In methylene chlorid; water at 20 - 25℃; for 1h; Stage #2: With hydrogenchloride In dichloromethane; water at 20 - 25℃; for 0.25h; Stage #3: With ammonia In water; ethyl acetate pH=9.5;

1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine maleate → donepezil (120014-06-4)

Conditions	Yield
With sodium hydroxide In water; toluene at 20 - 40℃; for 2h;

benzyl chloride (100-44-7) + debenzyldonepezil (120014-30-4) → donepezil (120014-06-4)

Conditions	Yield
With potassium carbonate; tetra-(n-butyl)ammonium iodide In acetone at 60℃;
With potassium carbonate; polyethylene glycol In water; ethyl acetate at 45℃;
With potassium carbonate In water; ethyl acetate at 50 - 55℃; for 14h; Inert atmosphere;
With sodium hydrogencarbonate In ethanol at 65℃; for 0.5h; Temperature;

benzaldehyde (100-52-7) → donepezil (120014-06-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen; platinum on activated charcoal / toluene / 80 °C / Flow reactor 2: diisobutylaluminium hydride / toluene; hexane / 2.5 h / -78 °C / Flow reactor 3: water / isopropyl alcohol; tetrahydrofuran / 3 h / 55 °C / Flow reactor 4: hydrogen / isopropyl alcohol; water; tetrahydrofuran / 20 h / 25 °C / 760.05 Torr / Flow reactor View Scheme

donepezil (120014-06-4) → C24H24(2)H5NO3

Conditions	Yield
With [(2)H6]acetone; tris(pentafluorophenyl)borate In toluene at 150℃; for 3h; Inert atmosphere;	98%

donepezil (120014-06-4) → debenzyldonepezil (120014-30-4)

Conditions	Yield
With ammonium formate; palladium 10% on activated carbon In methanol at 20℃; for 3h; Heating / reflux;	97%
With hydrogen In methanol at 20℃; under 760.051 Torr; for 72h;

donepezil (120014-06-4) → donepezil hydrochloride

Conditions	Yield
With hydrogenchloride In ethanol	96.2%
With hydrogenchloride In ethanol	96.5%
With hydrogenchloride In ethanol	96.4%

donepezil (120014-06-4) → donepezil-d1 (1228545-52-5)

Conditions	Yield
With tris(pentafluorophenyl)borate; water-d2 In tetrahydrofuran at 100℃; for 12h; Solvent; Inert atmosphere; regioselective reaction;	96%
With sodium methylate at 20℃; Reagent/catalyst;	50%

(2E)-but-2-enedioic acid (110-17-8) + donepezil (120014-06-4) → 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine fumarate

Conditions	Yield
In ethanol at 20 - 60℃; for 2h;	95.4%
In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;
In methanol at 25 - 30℃; for 5h;	5.1 g
In ethanol; water at 20 - 60℃; Sealed tube;

chloroformic acid ethyl ester (541-41-3) + donepezil (120014-06-4) → 4-[(5,6-dimethoxy-1-indanon)-2-yl]methyl-1-ethoxycarbonylpiperidine (120013-42-5)

Conditions	Yield
With sodium hydrogencarbonate In benzene	94%

donepezil (120014-06-4) → Donepezil sulphate (881405-91-0)

Conditions	Yield
With sulfuric acid In isopropyl alcohol at 0℃; for 2h;	92.4%
With sulfuric acid In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;

maleic acid (110-16-7) + donepezil (120014-06-4) → 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine maleate

Conditions	Yield
In isopropyl alcohol at 20 - 60℃; for 1h;	91.2%
In water; toluene at 25 - 30℃;	90%
In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;
In methanol; water at 20 - 100℃; Sealed tube;

donepezil (120014-06-4) → 1-benzyl-4-(5,6-dimethoxy-1-indanon-2-yl)methylpiperidine hydrobromide

Conditions	Yield
With hydrogen bromide In isopropyl alcohol	89.9%
With hydrogen bromide In ethanol; water at 10 - 35℃; for 12.33h;	58.9%
With hydrogen bromide In methanol; water Purification / work up;
With hydrogen bromide In methanol; water at 0 - 5℃; for 2 - 3h;

methanesulfonic acid (75-75-2) + donepezil (120014-06-4) → donepezil methanesulfonate

Conditions	Yield
In isopropyl alcohol at 20℃; Heating / reflux;	89.2%
In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;
In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;
In isopropyl alcohol for 168h;

donepezil (120014-06-4) + benzenesulfonic acid (98-11-3) → donepezil benzenenesulfonate

Conditions	Yield
In isopropyl alcohol at 20℃; Heating / reflux;	87.5%
In ethanol; ethyl acetate Product distribution / selectivity;
In ethanol; ethyl acetate Product distribution / selectivity;
In isopropyl alcohol for 168h;
In ethanol; water at 20 - 80℃; Sealed tube;

toluene-4-sulfonic acid (104-15-4) + donepezil (120014-06-4) → 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine p-toluenesulphonate

Conditions	Yield
In isopropyl alcohol at 20℃; Heating / reflux;	84.2%
In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;
In ethanol; ethyl acetate at 20℃; Product distribution / selectivity;
In ethyl acetate; acetone at 25 - 30℃; for 12h;	6.5 g
In isopropyl alcohol for 168h;

donepezil (120014-06-4) + 2-(1-bromodifluoromethyl)benzo-1,3-oxazole (186828-50-2) → C32H32F2N2O4

Conditions	Yield
With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; zinc(II) chloride; lithium diisopropyl amide at -10℃; for 12h;	83%

n-heptanoic anhydride (626-27-7) + donepezil (120014-06-4) → donepezil enanthate

Conditions	Yield
Stage #1: n-heptanoic anhydride; donepezil With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 10℃; Inert atmosphere; Stage #2: In tetrahydrofuran at -78 - 30℃;	81.7%

i-Pr2O + N-benzyl-2-(3,4-dimethoxybenzyl)-3-(4-piperidine)propionic acid + donepezil (120014-06-4) → donepezil hydrochloride

Conditions	Yield
With P2O5; MeSO3H In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane	80%

Ethyl bromodifluoroacetate (667-27-6) + donepezil (120014-06-4) → ethyl 2-(2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-2,2-difluoroacetate

Conditions	Yield
With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; zinc(II) chloride; lithium diisopropyl amide at -10℃; for 12h;	80%

palmitic anhydride (623-65-4) + donepezil (120014-06-4) → 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-1H-inden-3-ylpalmitate

Conditions	Yield
Stage #1: palmitic anhydride; donepezil With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 10℃; Inert atmosphere; Stage #2: In tetrahydrofuran at -78 - 30℃;	79.5%

donepezil (120014-06-4) → 2-((1-benzylpiperidin-4-yl)methyl)-2-bromo-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one

Conditions	Yield
With hydrogen bromide; dimethyl sulfoxide In water; ethyl acetate at 60℃;	78%

Upstream product

• 145546-80-1 (E)-2-((1-benzylpiperidine-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one 
• 2107-69-9 5,6-dimethoxy-1-indanone 
• 22065-85-6 N-benzyl-4-formylpiperidine 
• 100-39-0 benzyl bromide 
• 120014-30-4 debenzyldonepezil 
• 231283-82-2 (±)-2-[(1-benzylpyridin-1-ium-4-yl)methyl]-5,6-dimethoxy-indan-1-one bromide 
• 120013-38-9 2-((1-benzoylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one 
• 865718-00-9 5-(1-benzyl-piperidin-4-ylmethyl)-2,2-dimethyl-[1,3]dioxane-4,6-dione 
• 877606-65-0 (E)-5, 6-dimethoxy-2-(pyridin-4-ylmethylene)-2, 3-dihydro-1H-inden-1-one 
• 872-85-5 pyridine-4-carbaldehyde 
• 848610-96-8 5-[(1-benzyl-4-piperidyl)methyl]-5-(3,4-dimethoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 4657-12-9 sodium hydroxy(phenyl)methanesulfonate 
• 5392-10-9 2-bromo-4,5-dimethoxybenzaldehyde 
• 259170-03-1 2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid 

Downstream Products

• 142057-77-0 donepezil hydrochloride 
• 1210437-15-2 Donepezil nitrate 
• 881405-90-9 Donepezil phosphate 
• 20736-28-1 4,5-dimethoxy-2-methylbenzoic acid 
• 130927-83-2 2-(1-benzylpiperidin-4-yl)acetic acid 

Relevant articles and documents

Industrially scalable synthesis of anti-alzheimer drug donepezil

This paper describes a simple, efficient and industrially scalable total synthesis of donepezil hydrochloride. The article also reported the X-ray studies of the 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one, an intermediate in the synthesis of donepezil. The crystal structure analysis of 2-(1-benzylpiperidin-4-ylmethyliden)-5,6-dimethoxyindan-1-one shows that it crystallizes in monoclinic class under the space group P121/c1 with cell parameters, a = 17.2992(7) ?, b = 10.1999(4) ?, c = 11.9539(5) ?, β = 103.450(2)°, V = 2051.42(15) ?3 and Z = 4.

New synthesis of donepezil through palladium-catalyzed hydrogenation approach

A new, economical, and efficient process has been developed for large-scale synthesis of donepezil 1, an anti-Alzheimer's drug. The process involves palladium-catalyzed hydrogenation of (2E)-5,6-dimethoxy-2-(pyridin-4- ylmethylene)indan-1-one 6 to provide 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one 8 as a key step. Copyright Taylor & Francis LLC.

A metal-free method for the facile synthesis of indanonesviathe intramolecular hydroacylation of 2-vinylbenzaldehyde

A facile method for the synthesis of indanones was developed under metal- and additive-free conditions, whereinl-proline served as an efficient and environmentally benign catalyst. Compared with previously synthesized indanones, synthesis by the transition-metal-catalyzed intramolecular hydroacylation of 2-vinylbenzaldehyde provided a more green synthetic pathway to indanone scaffolds with good to excellent yields. More importantly, it could be used to synthsize the anti-AD drug donepezil.

Method for synthesizing donepezil in water

The invention discloses a method for synthesizing donepezil. The method comprises the following steps: adding 5,6-dimethoxyindanone, (1-benzyl-4-piperidyl)methanol, a metal iridium catalyst and potassium hydroxide into a reaction vessel, carrying out heating for a reaction for several hours, the carrying out cooling to room temperature, spin-drying a solvent, and carrying out column separation toobtain the target compound. According to the method, under the catalytic action of the metal iridium catalyst, 5,6-dimethoxyindanone reacts with (1-benzyl-4-piperidyl)methanol to directly synthesize donepezil; a commercialized reagent is used as a raw material for the reaction, and alcohol is an environment-friendly and low-toxicity chemical reagent; a by-product of the reaction water, so environmental pollution is avoided; the atom economy of the reaction is high; and reaction is conducted in water. Therefore, the reaction meets the requirements of green chemistry and has a wide development prospect.