Triethyl phosphite → Donepezil

HRID 1645377Notes

Reaction equation

HRID 1645377 reaction equation
Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].P(OCC)(OCC)OCC.[CH2:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH:39]=O)[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([N-]C(C)C)(C)C.[Li+]>[Pd].O1CCCC1>[CH3:12][O:11][C:7]1[CH:8]=[C:9]2[CH2:10][CH:2]([CH2:39][CH:36]3[CH2:35][CH2:34][N:33]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:38][CH2:37]3)[C:3](=[O:15])[C:4]2=[CH:5][C:6]=1[O:13][CH3:14]

Participants

7

Reactant 4

HCID 31215Triethyl phosphiteHCID 895841-Benzylpiperidine-4-carbaldehydeHCID 2724682Lithium diisopropylamideHCID 109236312-Bromo-5,6-dimethoxy-indan-1-one

Product 1

HCID 3152DonepezilYield 50.8%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8028TetrahydrofuranSolvent

Procedure

There are many processes as disclosed in the prior arts for producing donepezil of formula 1. U.S. Pat. No. 4,895,841 wherein substituted 1-indanone-2-phosphonate prepared from 2-bromo-5,6-dimethoxyindanone and triethyl phosphite, is treated with 1-benzylpiperidine-4-carboxaldehyde in the presence of a strong base, such as lithium diisopropylamide (LDA), followed by catalytic reduction using palladium on carbon in tetrahydrofuran (40 volumes) to yield donepezil with an overall yield of 50.8%. This process however suffers with few limitations i.e. it employs triphenylphosphonium methoxymethyl chloride, which is expensive and toxic and the overall yield of this process is quite low. (scheme 1).

Sources & evidence

ORD record
ord-a91868260619440cb738a37d927b78f0
Source dataset
uspto-grants-2012_02
Patent number
US08124783B2

Reaction notes

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