Oxalyl chloride → HCID 10105410, compound
Reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:19])=O>>[Cl:19][C:13]([CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:15]Participants
Procedure
PCT Publication No WO 97/22584 reports preparation of Donepezil HCl by reacting pyridine-4-aldehyde with malonic acid. The resulting 3-(pyridin-4-yl)-2-propenoic acid was reduced with rodium on carbon under hydrogen atmosphere to give 3-(piperidin-4-yl)-2-propionic acid which on reaction with methyl chlorocarbonate gave 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid. On reacting 3-[N-(methoxycarbonyl)piperidin-4-yl]propionic acid with oxalyl chloride, methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate is obtained which on reaction with 1,2-dimethoxy benzene in the presence of aluminium chloride afforded 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate. On reacting 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1-carboxylate with tetramethyl diamino methane, 4-[2-(3,4-dimethoxy benzoyl)allyl]piperidin-1-carboxylate is obtained which on treatment with sulphuric acid gave methyl 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate. On decarboxylating 4-(5,6-dimethoxy-1-indanon-2-yl methyl)piperidin-1-carboxylate, 5,6-dimethoxy-2-(piperidin-4-yl methyl)-1-indanone is obtained which on treatment with benzyl bromide afforded Donepezil HCl (Example 1 to 6). Overall yield of Donepezil HCl 19.3% (70%×84%×100%×68%×79%×61%).
Sources & evidence
- ORD record
- ord-6a8cf966e3754a42868e873743f3d1f6
- Source dataset
- uspto-grants-2003_11
- Patent number
- US06649765B1
Reaction notes
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