Malonic Acid → 3-(4-Pyridinyl)-2-propenoic acid
Reaction equation
COC1C=C2C[CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC=CC=4)[CH2:18][CH2:17]3)[C:11](=[O:12])C2=CC=1OC.C(O)(=O)CC(O)=[O:32]>>[N:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:13][C:11]([OH:12])=[O:32])=[CH:17][CH:18]=1Participants
Procedure
Patent application WO 97/22584 describes the preparation of Donepezil by reaction of pyridine-4-carboxyaldehyde with malonic acid to give 3-(pyridin-4-yl)-2-propenoic acid, followed by hydrogenation of the double bond to give 3-(piperidin-4-yl)-2-propionic acid. Reaction of this intermediate with methyl chloroformate afforded 3-[N-(methyloxycarbonyl) piperidin-4-yl]propionic acid. This was followed by reaction with oxalyl chloride to give methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate. Reaction with 1,2-dimethoxybenzene in the presence of aluminum chloride afforded methyl 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. Reaction with tetramethyldiaminomethane afforded 4-[2-(3,4-dimethoxybenzoyl)allyl] piperidin-1-carboxylate. Reaction with sulfuric acid afforded methyl 4-(5,6-dimethoxy-1-oxoindan-2-yl)methylpiperidin-1-carboxylate. This was followed by treatment with base to give 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one, then reaction with benzyl bromide afforded Donepezil (Scheme 3).
Sources & evidence
- ORD record
- ord-53e89593e1c04165a30a0ecf17f5c670
- Source dataset
- uspto-grants-2005_01
- Patent number
- US06844440B2
Reaction notes
Loading…