A process for the preparation of donepezil

Abstract

The present invention relates to an improved process for the preparation of donepezil comprising the step of catalytic hydrogenation of a condensate of the following formula in the presence of palladium on carbon in a solvent with the addition of an additive selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, potassium bromide. The present invention has a high yield and significantly reduces the production of debenzylated impurities.

Description

Technical Field

[0001] This invention relates to an improved method for preparing donepezil, belonging to the field of organic chemical synthesis. Technical Background

[0002] Donepezil hydrochloride is a long-acting symptomatic treatment for Alzheimer's disease (AD). Its full name is 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine hydrochloride, and its structural formula is shown in Formula I.

[0003]

[0004] According to literature reports, donepezil currently has two main routes:

[0005] Synthetic Route 1: Refer to patent US 4895841:

[0006]

[0007] Synthetic Route 2: Refer to patent US5606064:

[0008]

[0009] Route 1 is the mainstream route for synthesizing donepezil. During the hydrogenation process, a debenzylated impurity of donepezil is produced. The structural formula is:

[0010]

[0011] This impurity requires column separation for removal, which is costly and generates a large amount of waste during production. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide an improved method for preparing donepezil.

[0013]

[0014] The method includes the following steps:

[0015] a) Dissolve the condensate shown in the following formula in an organic solvent, add an additive in the presence of palladium on carbon, pass hydrogen gas through the above solution, and carry out a hydrogenation reaction in the temperature range of 0℃~40℃ to obtain a hydrogenation reaction solution; the additive is selected from sodium iodide, potassium iodide, sodium bromide, and potassium bromide.

[0016]

[0017] b) The hydrogenation reaction solution obtained in step a) is distilled under reduced pressure until dry; then an organic solvent is added and recrystallized to obtain the target product donepezil.

[0018] As a preferred embodiment of the present invention:

[0019] The solvent shown in step a) is selected from tetrahydrofuran, ethanol, ethyl acetate, toluene, and more preferably tetrahydrofuran.

[0020] The amount of additive used in step a) is 0.003% to 0.03% of the mass of the condensate, more preferably 0.007%.

[0021] The preferred temperature range for step a) is 20–30°C.

[0022] Step a) The preferred hydrogen pressure is 0.0-0.6 MPa, more preferably 0.0-0.1 MPa.

[0023] The additive mentioned in step a) is sodium iodide.

[0024] The recrystallization solvents in step b) are ethanol and methanol.

[0025] Compared with the prior art, the positive technical effects achieved by the present invention are as follows:

[0026] 1. The reaction conditions are mild, the yield is high, the generation of debenzylated impurities is reduced, and the cost is lowered.

[0027] 2. The post-processing is simple. After evaporating the hydrogenated liquid, a single recrystallization can yield the target product, reducing the generation of solid waste. Detailed Implementation

[0028] The present invention will be further described in conjunction with embodiments. The following embodiments are merely illustrative of the invention and are not intended to limit the invention in any way.

[0029] Comparative Example 1:

[0030] 30g of the condensate and 250mL of tetrahydrofuran were added to a 500mL hydrogenation reactor, followed by 1.6g of 7% palladium on a dry basis. The reaction was carried out at 25℃ and a hydrogenation pressure of 0.0-0.1MPa until no hydrogen absorption occurred, and the pressure was maintained for 30min to obtain the hydrogenated reaction solution. The analytical data are shown in Table 1. The tetrahydrofuran was evaporated to dryness, and 100mL of ethanol was added. The temperature was raised to 60℃ and stirred until dissolved. Then, 100mL of methanol was added and stirred for 30min. The mixture was cooled to room temperature and stirred for 3 hours ± 30 minutes. The mixture was filtered, and the product was dried at 60℃ for 10 ± 1 hours to obtain donepezil, with a yield of 65%, a purity of 96.3%, and 2.1% debenzylated impurities.

[0031] Table 1: Data on Additive-Free Hydrogenated Liquid

[0032] 1 93.08％ 6.49％ 0.00％

[0033] Example 1:

[0034] 30g of the condensate and 250mL of tetrahydrofuran were added to a 500ml hydrogenation reactor. 1.6g of 7% palladium on carbon (dry basis) was added, followed by 2mg of additive. The reaction was carried out at 25℃ and a hydrogenation pressure of 0.0-0.1MPa until no hydrogen absorption occurred. The pressure was maintained for 30 minutes to obtain the hydrogenated reaction solution. The data obtained from analysis are as follows:

[0035] Table 2: Effect of Additives on Hydrogenation

[0036] 1 Sodium iodide 97.65％ 2.02％ 0.03％ 2 Potassium iodide 97.31％ 2.35％ 0.03％ 3 Sodium bromide 96.57％ 3.13％ 0.00％ 4 Potassium bromide 96.40％ 3.31％ 0.03％

[0037] Example 2:

[0038] Add 30g of the condensate and 250mL of tetrahydrofuran to a 500mL hydrogenation reactor, along with 1.6g of 7% palladium on carbon (dry basis) and 2mg of sodium iodide. React at 25℃ and a hydrogenation pressure of 0.0-0.1MPa until no hydrogen absorption occurs, then maintain the pressure for 30min to obtain the hydrogenation reaction solution. Evaporate the tetrahydrofuran to dryness, add 100mL of ethanol, heat to 60℃, and stir until dissolved. Add 100mL of methanol, stir for 30min, cool to room temperature, and maintain the temperature with stirring for 3 hours ± 30 minutes. Filter the solution, and dry the product at 60℃ for 10 ± 1 hours to obtain donepezil, with a yield of 73%, purity of 99.5%, and 0.1% debenzylidene impurities.

Claims

1. An improved method for preparing donepezil, Includes the following steps: a) Dissolve the condensate shown in the following formula in an organic solvent, add an additive in the presence of palladium on carbon, pass hydrogen gas through the above solution, and carry out a hydrogenation reaction in the temperature range of 0℃~40℃ to obtain a hydrogenation reaction solution; the additive is selected from sodium iodide, potassium iodide, sodium bromide, and potassium bromide. b) The hydrogenation reaction solution obtained in step a) is distilled under reduced pressure to dryness; then an organic solvent is added and recrystallized to obtain the target product donepezil. The amount of additive used in step a) is 0.003% to 0.03% of the mass of the condensate. The organic solvent shown in step a) is selected from tetrahydrofuran, ethanol, ethyl acetate, and toluene.

2. The method according to claim 1, wherein the organic solvent in step a) is tetrahydrofuran.

3. According to the method of claim 1, the amount of additive used in step a) is 0.007% of the mass of the condensate.

4. The method according to claim 1, wherein the temperature range in step a) is 20~30℃.

5. The method according to claim 1, wherein step a) hydrogen pressure is 0.0-0.6 MPa.

6. The method according to claim 5, wherein the hydrogen pressure in step a) is 0.0~0.1 MPa.

7. The method according to claim 1, wherein the additive in step a) is sodium iodide.

8. The method according to claim 1, wherein the recrystallization solvent in step b) is ethanol and methanol.

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