4803-74-1

Basic information

• Product Name: 5,6-Dimethoxy-2-(pyridine-4-yl)methylene-indan-1-one
• Synonyms: 2,3-dihydro-5,6-dimethoxy-2-(4-pyridinylmethylene)-1h-inden-1-one;5,6-DIMETHOXY-2-(PYRIDINE-4-YL)METHYLENE-INDAN-1-ONE;5,6-dimethoxyl-2-(piperidin-4-y)methylene-indan-1-one;5,6-DIMETHOXY-2-(4-PYRIDYLMETHYLENE)-1-INDANONE,98.0+%;5,6-Dimethoxy-2-(4-pyridylmethylene)-1-indanone (Donepezil Impurity);5,6-DiMethoxy-2-(pyridin-4-ylMethylene)-2,3-dihydro-1H-inden-1-one;1H-Inden-1-one,2,3-dihydro-5,6-diMethoxy-2-(4-pyridinylMethylene)-;5,6-Dimethoxy-2-(pyridine-4-yl)methylene-indan-1-one 2,3-Dihydro-5,6-dimethoxy-2-(4-pyridinylmethylene)-1H-inden-1-one
• CAS NO: 4803-74-1
• Molecular Formula: C₁₇H₁₅NO₃
• Molecular Weight: 281.31
• EINECS: 1312995-182-4
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles;Impurities;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 4803-74-1.mol
• Article Data: 10

Chemical Properties

• Melting Point: 210-211°C
• Boiling Point: 499.9 °C at 760 mmHg
• Flash Point: 256.1 °C
• Appearance: /
• Density: 1.255
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.639
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Methanol (Slightly, Heated)
• PKA: 5.10±0.10(Predicted)
• CAS DataBase Reference: 5,6-Dimethoxy-2-(pyridine-4-yl)methylene-indan-1-one(CAS DataBase Reference)
• NIST Chemistry Reference: 5,6-Dimethoxy-2-(pyridine-4-yl)methylene-indan-1-one(4803-74-1)
• EPA Substance Registry System: 5,6-Dimethoxy-2-(pyridine-4-yl)methylene-indan-1-one(4803-74-1)

Safety Data

• Hazardous Substances Data: 4803-74-1(Hazardous Substances Data)

Usage

Chemical Properties

Yellow Solid

Uses

An impurity of Donepezil.

InChI:InChI=1/C17H15NO3/c1-20-15-9-12-8-13(7-11-3-5-18-6-4-11)17(19)14(12)10-16(15)21-2/h3-7,9-10H,8H2,1-2H3/b13-7+

Synthetic route

pyridine-4-carbaldehyde (872-85-5) + 5,6-dimethoxy-1-indanone (2107-69-9) → 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1)

Conditions	Yield
With potassium hydroxide In water at 25 - 30℃; for 3h; Product distribution / selectivity;	98%
Stage #1: pyridine-4-carbaldehyde; 5,6-dimethoxy-1-indanone With toluene-4-sulfonic acid In toluene for 6h; Heating / reflux; Stage #2: With sodium carbonate In water for 0.5 - 1h;	95.8%
With potassium iodide; calcium chloride In acetone at 40 - 50℃; for 4h; Reagent/catalyst; Time;	92.2%

pyridine-4-carbaldehyde (872-85-5) + 2-bromo-5,6-dimethoxy-1-indanone (2747-08-2) → 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 5,6-dimethoxy-3-(pyridine-4-yl)spiro[indene-2,2'-oxiran]-1(3H)-one

Conditions	Yield
With n-butyllithium In tetrahydrofuran at -78℃; Darzens condensation; Inert atmosphere;

pyridine-4-carbaldehyde (872-85-5) + 2-bromo-5,6-dimethoxy-1-indanone (2747-08-2) → 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1)

Conditions	Yield
With potassium tert-butylate In dimethyl sulfoxide at 15 - 20℃; Darzens condensation; Inert atmosphere;

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane hydrochloride (1034439-43-4)

Conditions	Yield
With hydrogenchloride; 5%-palladium/activated carbon; hydrogen In methanol at 65℃; under 22801.5 Torr; for 480h;	97%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 5,6-dimethoxy-2-(piperidine-4-ylmethyl)-2,3-dihydro-1H-inden-1-one hydrochloride

Conditions	Yield
Stage #1: 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone With palladium 10% on activated carbon; ammonium formate In ethanol at 40 - 50℃; for 1.5h; Stage #2: With hydrogenchloride In dichloromethane; water for 2h; pH=4.5; pH-value; Reagent/catalyst;	90.1%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + benzyl chloride (100-44-7) → 1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h; Temperature; Time;	90%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + γ-chlorobutyric acid (627-00-9) → 1-(3-carboxypropyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	86%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + acetic acid (64-19-7) → C17H17NO3*C2H4O2

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In methanol at 55 - 60℃; under 6000.6 - 7500.75 Torr; Pressure; Temperature; Large scale;	83.8%

chloropropionic acid (107-94-8) + 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 1-(2-carboxyethyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	81%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + methyl iodide (74-88-4) → 1-methyl-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium iodide

Conditions	Yield
In acetone for 48h; Reflux;	81%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 5-(chloromethyl)-2-hydroxy-4H-pyran-4-one → 1-[(2-hydroxy-4H-pyran-4-one-5-yl)methyl]-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	77%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 3-chloroprop-1-ene (107-05-1) → 1-(2-propenyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	74%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + p-chlorophenylsemicarbazide (69194-89-4) → 3-(4-chlorophenyl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (1346911-17-8)

Conditions	Yield
With acetic acid for 12h; Reflux;	72%
With acetic acid for 12h; Reflux;	72%
With acetic acid

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + hydrazine carboxamide (4426-72-6, 51433-48-8) → C18H18N4O3 (1346911-48-5)

Conditions	Yield
With acetic acid for 12h; Reflux;	72%
With acetic acid

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + N-(4-fluorophenyl)hydrazinecarboxamide (153885-60-0) → 3-(pyridin-4-yl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (1321920-29-9)

Conditions	Yield
With acetic acid for 12h; Reflux;	72%
With acetic acid

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + C7H7ClFN3O (1094769-79-5) → 3-(pyridin-4-yl)-N-(3-chloro-4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (1321920-42-6)

Conditions	Yield
With acetic acid for 12h; Reflux;	72%
With acetic acid

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + chloroacetic acid (79-11-8) → 1-(carboxymethyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	71%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 1-Bromo-2-bromomethyl-benzene (3433-80-5) → 1-(2-bromobenzyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium bromide

Conditions	Yield
In acetonitrile at 80℃; for 48h;	66%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 1-bromomethyl-4-bromobenzene (589-15-1) → 1-(4-bromobenzyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium bromide

Conditions	Yield
In acetonitrile at 80℃; for 48h;	66%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + meta-bromobenzyl bromide (823-78-9) → 1-(3-bromobenzyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium bromide

Conditions	Yield
In acetonitrile at 80℃; for 48h;	64%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 4-(4-nitrophenyl)semicarbazide (17433-93-1) → 3-(pyridin-4-yl)-N-(4-nitrophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (1346911-31-6)

Conditions	Yield
With acetic acid for 12h; Reflux;	62%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 1-chloro-2-(chloromethyl)benzene (611-19-8) → 1-(2-chlorobenzyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	60%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 1-bromo-hexane (111-25-1) → 1-hexyl-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium bromide

Conditions	Yield
In acetonitrile at 80℃; for 48h;	57%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + 2-chloro-ethanol (107-07-3) → 1-(2-hydroxyethyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	56%

5-chloro-2-pentanone (5891-21-4) + 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 1-(4-oxopentyl)-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride

Conditions	Yield
In acetonitrile at 80℃; for 48h;	56%

N-(2-bromoethyl)pyrrolidine (54035-94-8) + 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 1-[2-(pyrrolidin-1-yl)ethyl]-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium bromide

Conditions	Yield
In acetonitrile at 80℃; for 48h;	50%

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 2-(pyridin-4-yl)methyl-5,6-dimethoxy-1-indanone (4803-57-0)

Conditions	Yield
With hydrogen; platinum(IV) oxide In acetic acid at 80℃; under 760.051 Torr; for 6h;	35%
With hydrogen; 5%-palladium/activated carbon In methanol; dichloromethane under 1500.15 Torr; for 3h;
With hydrogen; palladium 10% on activated carbon In methanol; dichloromethane under 760.051 Torr; for 5h;

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) → 5,6-dimethoxy-2-(4-piperidinylmethyl)-indan-1-one acetate (861675-47-0)

Conditions	Yield
With hydrogen; acetic acid; 5%-palladium/activated carbon In methanol at 60 - 65℃; under 2280.15 - 3040.2 Torr; for 8h;

5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone (4803-74-1) + benzyl bromide (100-39-0) → 1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium bromide (178551-26-3)

Conditions	Yield
In butanone at 115 - 117℃; for 3h; Product distribution / selectivity; Reflux;

Upstream product

• 872-85-5 pyridine-4-carbaldehyde 
• 2747-08-2 2-bromo-5,6-dimethoxy-1-indanone 
• 2107-69-9 5,6-dimethoxy-1-indanone 

Downstream Products

• 1034439-43-4 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane hydrochloride 
• 1346911-31-6 3-(pyridin-4-yl)-N-(4-nitrophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide 
• 1346911-17-8 3-(4-chlorophenyl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide 
• 178551-26-3 1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium bromide 
• 1321920-29-9 3-(pyridin-4-yl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide 
• 1321920-36-8 C₂₄H₂₁BrN₄O₃ 
• 1321920-42-6 3-(pyridin-4-yl)-N-(3-chloro-4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide 
• 1333385-51-5 C₂₆H₂₆N₄O₃ 
• 1188913-39-4 1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-ylidene)methyl]pyridinium chloride 

Relevant articles and documents

Synthesis, characterization and investigation of AChE and BuChE inhibitory activity of 1-alkyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium halide derivatives

Abstract: The design, synthesis and characterization of a series of 1-alkyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium halide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors for the treatment of Alzheimer’s disease were reported. The strategy for this synthesis was based on aldol condensation reaction between 4-pyridinecarboxaldehyde with 5,6-dimethoxy-1-indanone in the presence of NaOH in EtOH-H2O solution as the first step and N-alkylation reaction of the produced 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone with various alkyl halides (R–X) in the second step. This reaction was carried out under reflux temperature in polar aprotic solvents such as acetone or acetonitrile. 1H and 13C NMR and FTIR spectroscopy along with CHN analysis were used to confirm the structure of our synthesized compounds. Biological activities including acetylcholinesterase and butyrylcholinesterase (BuChE) inhibitions for synthesized compounds were tested using the Ellman method. The results were compared with donepezil and galantamine, and among the synthesized compounds, the highest inhibitory activity with BuChE IC50 = 0.55?μM was observed. Graphic abstract: [Figure not available: see fulltext.]

Synthesis and anticonvulsant activity of 3a,4-dihydro-3Hindeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues

A series of fourteen 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues were synthesized and evaluated for anticonvulsant activity according to the Antiepileptic Drug Development Programme (ADD) protocol. Some of the synthesized compounds showed significant activity in minimal clonic seizure model (6 Hz psychomotor seizure test). 3-(4-Fluorophenyl)-N-(4-bromophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c] pyrazole-2-carboxamide (4c) was found to be the most active compound of the series showing 75% (3/4, 0.25-2.0 h) and 50% (2/4, 4.0 h) protection against minimal clonic seizure at 100 mg/kg without any toxicity. 3-(Pyridin-4-yl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4f) showed protection in maximal electroshock (MES) seizure and subcutaneous metrazol (scMET) seizure at 300 mg/kg.

A PROCESS FOR PREPARATION OF INTERMEDIATES OF DONEPEZIL HYDROCHLORIDE

The present invention provides a process for the preparation of key intermediate for the synthesis 5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1-indanone hydrochloride (donepezil hydrochloride). The present invention particularly provides a process for the preparation of 5,6-dimethoxy-2-(4-pyridylmethylene)-1-indanone comprising condensation of 5,6-dimethoxy-1-indanone with 4- pyridinecarboxaldehyde using an alkali metal hydroxide as a mild base in the presence of demineralized water as a solvent at a temperature in the range of 15°C to 45°C to yield 5,6-dimethoxy-2-(4-pyridylmethylene)-1-indanone, which is subsequently benzylated using benzyl bromide in the presence of solvent at a reflux temperature to yield 1-benzyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium bromide.