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Method for producing high-purity donepezil hydrochloride anhydrous I type crystal form and product thereof

A technology of donepezil hydrochloride and its production method, which is applied in the field of drug synthesis, can solve problems such as low residual amount and unresolved water content, and achieve the effect of simple production method, few steps, and overcoming technical barriers

Active Publication Date: 2011-05-18
浙江东亚药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the residual amount of solvent methanol and isopropyl ether in the donepezil hydrochloride I crystal form obtained by this method is relatively low, the problem of water content in the product has not been solved

Method used

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  • Method for producing high-purity donepezil hydrochloride anhydrous I type crystal form and product thereof
  • Method for producing high-purity donepezil hydrochloride anhydrous I type crystal form and product thereof
  • Method for producing high-purity donepezil hydrochloride anhydrous I type crystal form and product thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] According to the prior art (publication number: CN101723878A), 35.0 g of white solid donepezil free base was prepared. Dissolve in 140.0 g of toluene, add 10 ml of concentrated hydrochloric acid, heat to reflux until the internal temperature reaches 111 °C, cool to room temperature, filter the precipitated crystals, and dry to obtain 37.0 g of crude product of donepezil hydrochloride in crystal form III, with a yield of 96.4%. Its X-ray diffraction pattern is as figure 1 shown.

[0029] According to the above preparation, 30.0 g of crude product of donepezil hydrochloride in crystal form II was obtained. Suspended in 120.0 g of methanol, 1.3 g of pure water was added. The solution was heated and stirred to make the solution clear, and then cooled to room temperature, crystals were precipitated, further cooled to -10°C, and kept at this temperature for 3 hours for crystallization.

[0030] The precipitated crystals were filtered off. Put it into a vacuum oven, mainta...

Embodiment 2

[0032] According to the prior art (publication number: CN101723878A), 35.0 g of white solid donepezil free base was prepared. Dissolve in 200.0 g of toluene, add 20 ml of concentrated hydrochloric acid, heat to reflux until the internal temperature reaches 111 °C, cool to room temperature, filter the precipitated crystals, and dry to obtain 36.4 g of crude product of donepezil hydrochloride in the form of III, with a yield of 94.8%.

[0033] According to the above preparation, 30.0 g of crude product of donepezil hydrochloride in crystal form III was obtained. Suspend in 200.0 g of methanol, and add 4.0 g of pure water. The solution was heated and stirred to make the solution clear, and then cooled to room temperature to precipitate crystals, further cooled to -5°C, and kept at this temperature for 4 hours to crystallize.

[0034] The precipitated crystals were filtered off. Put it into a vacuum oven, maintain the vacuum at -0.95MPa, and bake at 45°C for 24 hours. Under the...

Embodiment 3

[0036]According to the method of the prior art (publication number: CN1221404A), 30.0 g of donepezil hydrochloride crystal form I compound was prepared, with a water content of 5.22%. 150.0 g methanol containing 0.15 g water was added. The solution was heated and stirred to make the solution clear, and then cooled to room temperature to precipitate crystals, further cooled to -10°C, and kept at this temperature for 4 hours to crystallize. The precipitated crystals were filtered off. Put it in a vacuum oven, keep the vacuum at -0.95MPa, bake at 45°C for 4 hours; then bake at -0.80MPa, 75°C for 8 hours. Under the protection of nitrogen, the vacuum was broken and cooled to room temperature to obtain 25.5 g of anhydrous I crystal form of donepezil hydrochloride. The content is 99.80%, the single impurity is less than 0.1%, and the moisture measured by Karl Fischer is 0.19%.

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Abstract

The invention relates to a method for producing a high-purity donepezil hydrochloride anhydrous I type crystal form and a product thereof, belonging to the technical field of drug synthesis. The method comprises the following steps of: re-crystallizing a donepezil hydrochloride polycrystal type crude product or an amorphous donepezil hydrochloride crude product with a lower alcohol solvent to obtain a donepezil hydrochloride I type crystal form wet product; and drying in vacuum and cooling to the room temperature to obtain a high-purity donepezil hydrochloride anhydrous I type crystal form finished product under the protection of nitrogen, wherein KF is less than 0.5%; the purity reaches more than 99.5%; and single impurity is less than 0.1%. The invention has the advantages of simple production method and fewer steps, is suitable for industrial production, has better crystal form of the product and great significance to pharmacy, sale and storage of the product, and overcomes technology barriers.

Description

technical field [0001] The invention relates to a raw material drug and a production method thereof, in particular to a production method of high-purity donepezil hydrochloride anhydrous I crystal form and a product thereof, belonging to the technical field of drug synthesis. Background technique [0002] Donepezil Hydrochloride (Donepezil Hydrochloride), the chemical name is 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine hydrochloride, the molecular formula is C 24 h 29 NO 3 • HCl, molecular weight 415.95. Its structural formula is as follows: [0003] [0004] Donepezil hydrochloride was developed by Eisai Company of Japan and has excellent anti-acetylcholinesterase activity. It has high selectivity, small dose, long half-life, small adverse reactions, and no toxicity to the liver. It is widely used in clinical prevention, treatment and improvement of Alzheimer's disease. [0005] There are five polymorphic forms of donepezil hydrochloride, namely do...

Claims

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Application Information

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IPC IPC(8): C07D211/32
Inventor 王海平池正明驰骋
Owner 浙江东亚药业股份有限公司
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