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Chiral deuterated donepezil compound as well as preparation method and application thereof

A technology of donepezil and compounds, which is applied in the field of chiral deuterated donepezil compounds or pharmaceutically acceptable salts thereof, can solve the problems of increasing degradation half-life and undisclosed compounds, and achieve simple operation, high purity, excellent chemical stability and Effects on Metabolic Stability

Active Publication Date: 2020-04-24
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] US20100143505A1 discloses the structures of various deuterated donepezil compounds and states that certain isotopically enriched compounds show increased liver microsomal stability assays and recombinant CYP isoform stability tests compared to non-isotopically enriched drugs half-life of degradation, but did not disclose which specific compounds

Method used

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  • Chiral deuterated donepezil compound as well as preparation method and application thereof
  • Chiral deuterated donepezil compound as well as preparation method and application thereof
  • Chiral deuterated donepezil compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: preparation formula I compound

[0049] Take 10 g of free donepezil, dissolve it in 50 mL of methanol (deuterium rate 99%), add 2 g of sodium methoxide, stir at room temperature overnight, quench with 10 mL (deuterium rate 99.5%) of heavy water, concentrate, extract with 100 mL of DCM, and treat in the usual way. Pass through the column, elute with a 50% mixed solvent of EA and DCM, and concentrate to obtain 5 g of the target product. Yield 50%.

[0050] The structural identification data are as follows:

[0051] HNMR: 1 H NMR (400MHz, CDCl 3)δ7.32-7.27(m,4H),7.27-7.22(m,1H),7.17(s,1H),6.85(s,1H),3.96(s,3H),3.90(s,3H),3.50 (s,2H),3.22(d,1H),2.92-2.87(m,2H),2.69(d,1H),2.01-1.95(m,2H),1.94-1.88(m,1H),1.74-1.64 (m,2H),1.52-1.45(m,1H),1.41-1.36(m,1H),1.36-1.27(m,2H).MS calculated value: 380.2, MS measured value: 381.2([M+H] + ).

Embodiment 2

[0052] Embodiment 2: preparation formula I compound

[0053] Take 5g of free donepezil, dissolve it in 50mL of DMF, add 2g of sodium methoxide, stir overnight at room temperature, quench with 10mL (deuterium rate 99.5%) deuterium water, concentrate, extract with 100mL DCM, treat in the usual way, pass through the column, use 50% The mixed solvent of EA and DCM was eluted to obtain 2 g of the target product. Yield 40%.

[0054] The structural identification data are the same as in Example 1.

Embodiment 3

[0055] Embodiment 3: preparation formula I compound

[0056] Take 2 g of free donepezil, dissolve and suspend in 10 mL of heavy water and deuterated methanol, add 0.1 g of sodium hydroxide, stir at room temperature for 5 h, extract with 100 mL of DCM, treat with the usual method, pass through the column, and elute with 50% mixed solvent of EA and DCM , after concentration, 1 g of the target product was obtained. Yield 50%.

[0057] The structural identification data are the same as in Example 1.

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Abstract

The invention discloses a chiral deuterated donepezil compound shown as a formula I-a or a formula I-b or pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The chiral deuterated donepezil compound or the pharmaceutically acceptable salt of the chiral deuterated donepezil compound has excellent chemical stability and metabolic stability. The preparation method disclosed by the invention is simple to operate, and the obtained chiral deuterated donepezil compound is high in purity.

Description

technical field [0001] The invention relates to a chiral deuterated donepezil compound or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. Background technique [0002] Donepezil hydrochloride (donepezil hydrochloride), the chemical name is 1-benzyl-4-[(5,6-dimethoxyindanon-2-yl)methyl]piperidine hydrochloride, which is produced by Japan Eisai Pharmaceutical Co., Ltd. The second-generation highly selective acetylcholinesterase inhibitor (AchEI) developed by the company was approved by the US FDA in 1997. This product has no hepatotoxicity, the patient's cognitive function is obviously improved after administration, the action time is long, the tolerance is good and the dosage is small, it is the first choice drug for the treatment of Alzheimer's disease. [0003] Donepezil is a hexahydropyridine derivative with a chiral carbon atom in the molecule, and it is clinically administered in the form of a racemate. It has been shown in the...

Claims

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Application Information

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IPC IPC(8): C07D211/32A61K31/445A61P25/28
CPCC07D211/32A61P25/28
Inventor 吴茂江张守菲徐苗焕
Owner ZHEJIANG JINGXIN PHARMA
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