Preparation method of donepezil hydrochloride impurities

A technology for donepezil hydrochloride and impurities, applied in the field of preparation of donepezil hydrochloride impurities, can solve problems such as high price

Active Publication Date: 2015-09-09
JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] It is highly selective for neuronal acetylcholinesterase, has no hepatotoxicity, and is clinically used for the treatment of Alzheimer's disease. It is in a leading position among AD therapeutic drugs and is currently expensive in the market

Method used

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  • Preparation method of donepezil hydrochloride impurities
  • Preparation method of donepezil hydrochloride impurities
  • Preparation method of donepezil hydrochloride impurities

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Preparation of donepezil hydrochloride impurity 1

[0025] The preparation of donepezil hydrochloride impurity 1 comprises the following steps:

[0026] Add 5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone (SM, 20g, 61.5mmol) into 200ml water at room temperature, cool down to 0°C, and divide at 0°C Sodium borohydride (20g, 528mmol) was added three times. After the addition was complete, it was stirred at 0°C for 0.5 hours, and the temperature was raised to 25°C-30°C within 1 hour, and kept stirring at 25-30°C for 1 hour. The system was adjusted to pH = 1 with concentrated hydrochloric acid, continued to stir at 25-30°C for 1 hour, adjusted to pH = 10 with 40% sodium hydroxide, extracted three times with ethyl acetate, combined the organic phase, washed the organic phase with saturated brine, and anhydrous sodium sulfate dry. Filtration and concentration gave a white solid (Compound I, 12.3 g, 73%).

[0027] Compound I (1.4g, 5.13mmol) was added to 15ml of m...

Embodiment 2

[0029] Example 2 Preparation of donepezil hydrochloride impurity 2

[0030] Preparation of donepezil hydrochloride impurity 2 comprises the following steps:

[0031] Compound I (800mg, 2.93mmol) was added to 5ml of formic acid at room temperature, heated to reflux with stirring, kept stirring for 2 hours, concentrated the reaction system, and the concentrate was purified by silica gel column (PE:EA volume ratio: 1:1), collected The eluent containing impurity 2 was concentrated to dryness to obtain a light red oil, which was solid at -20°C for 5 days (impurity 2, 370 mg, 41%). MS-ESI m / z:301.17[M+H] + 302.1. 1 H-NMR (400MHz, CDCl 3 )δ8.01(1H, s), 7.00(1H, s), 6.86(1H, s), 6.43(1H, s), 4.39(1H, d, J=13.2Hz), 3.89(3H, s), 3.88(3H,s), 3.60(1H,d,J=13.2Hz), 3.25(2H,s), 3.08~3.02(1H,m), 2.66~2.59(1H,m), 2.42(2H,d, J=6.4Hz), 1.81 (3H,t, J=13.2Hz), 1.19~1.08(2H,m). HPLC detection results such as figure 2 shown.

Embodiment 3

[0032] Example 3 Preparation of donepezil hydrochloride impurity 3

[0033] Preparation of donepezil hydrochloride impurity 3 comprises the following steps:

[0034] Add 15ml of methanol and 20ml of purified water to the reaction flask at room temperature, then add 5,6-dimethoxy-2-(4-piperidinylmethyl)-1-indanone (3.5g, 10.8mmol), carbonic acid Potassium (2.23 g, 16.2 mmol) was stirred at room temperature for 2 hours. Concentrate under reduced pressure to remove methanol, extract with ethyl acetate, separate the organic phase, dry over anhydrous sodium sulfate, filter and concentrate. Add 25ml of isopropyl formate to the concentrate, heat to 50°C, keep stirring for 2 hours, concentrate the reaction system under reduced pressure, purify the concentrate through a silica gel column (PE:EA volume ratio is 2:1), and collect the impurity 3 The eluent was concentrated to dryness to give a yellow solid (impurity 3, 2.9 g, 88%). MS-ESI m / z:317.16[M+H] + 318.1. 1 H-NMR (400MHz, CDC...

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Abstract

The invention provides a preparation method of three donepezil hydrochloride impurities, which comprises the following steps: 1) impurity 1: by using 5,6-dimethoxy-2-(4-piperidylmethylene)-1-indeneone (SM) as an initial raw material, generating 4-(5,6-dimethoxy-1-indene-2-methylene)piperidine (I) under the action of sodium borohydride, carrying out Pd/C reduction to generate 4-(2,3-dihydro-5,6-dimethoxy-1-indene-2-methylene)piperidine (II), and finally, carrying out formylation to generate 4-(2,3-dihydro-5,6-dimethoxy-1-indene-2-methylene)piperidine-1-formaldehyde (1); 2) impurity 2: by using the 4-(5,6-dimethoxy-1-indene-2-methylene)piperidine (I) as the raw material, carrying out formylation to generate 4-(5,6-dimethoxy-1-indene-2-methylene)piperidine-1-formaldehyde (2); and 3) impurity 3: by using the 5,6-dimethoxy-2-(4-piperidylmethylene)-1-indeneone (SM) as the initial raw material, carrying out formylation to generate 4-(2,3-dihydro-5,6-dimethoxy-1-indeneone-2-methylene)piperidine-1-formaldehyde (3). The preparation of the donepezil hydrochloride impurities has important quality monitoring meanings for industrial production of the donepezil hydrochloride active pharmaceutical ingredient.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method and application of donepezil hydrochloride impurities. Background technique [0002] Donepezil Hydrochloride is an acetylcholinesterase inhibitor developed by Japan's Eisai Pharmaceutical Co., Ltd. It was first launched in the United States in January 1997, and was launched in China under the trade name Aricept in October 1999. Its structure is as follows: [0003] [0004] It is highly selective to neuronal acetylcholinesterase, has no hepatotoxicity, and is clinically used for the treatment of Alzheimer's disease. It is in a leading position among AD therapeutic drugs, and is currently expensive in the market. The synthesis of donepezil and its derivatives has thus become a hot spot. [0005] According to the synthesis route report and reaction mechanism of donepezil, impurities 1, 2, and 3 are trace impurities generated d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32
CPCC07D211/32
Inventor 张沛王伟王庆辉牛明玉张凯黄霂胡丽娜潘晓霞
Owner JIANGSU HAICI BIOLOGICAL PHARMA CO LTD OF YANGTZE RIVER PHARMA GRP
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