Preparation of 1-benzyl-4-piperidinemethanol_Industrial additives

Background and overview[1][2]

1-Benzyl-4-piperidinemethanol, as an important intermediate of donepezil hydrochloride, is an acetylcholinesterase inhibitor. It is a long-acting Alzheimer’s disease (AD, also known as premature aging). (Alzheimer’s disease or Alzheimer’s disease) treatment drug, developed by Japan’s Eisai Co., Ltd., was first approved to be marketed in the United States in 1997, and is currently sold in more than 70 countries around the world. In 2004, the drug’s global sales reached 2 billion US dollars, and in China it was 200-300 million yuan. 1-Benzyl-4-piperidinemethanol is characterized by low dose, low side effects and good tolerance, and it occupies an important position in the treatment of Alzheimer’s disease.


Preparation of 1-benzyl-4-piperidinecarboxaldehyde

Add 1-benzyl-4-piperidinemethanol 5.1g (25mmol), 100mL TEMPO dichloromethane solution (containing TEMPO 39mg, 0.25mmol), and 60mL NaIO4 and NaBr mixed saline solution (containing NaIO4 6.4g, 30mmol, NaBr 0.3g, 3mmol), react with vigorous stirring at 20°C for 12h. After the reaction is completed, separate the layers, collect the organic layer, wash twice with 50 mL of 1mol/L Na2S2O3 solution, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain 4.7g of light yellow liquid, yield 92.1%, purity 99% ( HPLC).

Preparation of donepezil

In a 15ml Schlenk tube, add 76.88mg (0.4mmol) 5,6-dimethoxyindanone, 82.1mg (0.4mmol) 1-benzyl-4-piperidinemethanol, 1.55mg (0.5mol% ) Pincer metal ruthenium (II) compound, 11.61 mg (0.25 equiv) sodium phenolate, 0.5 ml toluene, stir magnetically under argon atmosphere, react at 120°C for 12 hours. According to TLC analysis, the raw materials have been completely reacted. After vacuum rotary evaporation and thin layer chromatography separation and purification, the mass of the product donepezil was 100.71 mg, and the yield was 66%.


Literature reports indicate that there are two routes for the synthesis of the key intermediate 1-benzyl-4-piperidinemethanol of donepezil hydrochloride. Route 1 (J. Heterocycl. Chem., 1978, 15, 675-676) uses 1-benzyl-4-piperidone as the original GE flocculant material, and mixes it with trimethylsulfonium iodide (Me3S) in the presence of sodium hydride. (O)I) Perform Corey-Chaykovsky reaction to obtain the epoxide, and then undergo ring opening with lithium aluminum tetrahydride to obtain the target product. The two-step yield is 42.3%:

Route 2 uses 4-piperidinecarboxylic acid as raw material. After esterification, it undergoes a substitution reaction with benzyl chloride as a rubber additive to prepare 1-benzyl-4-piperidinecarboxylate. It is reduced with lithium aluminum tetrahydrogen to obtain the target product. , there are many reports on this method in the literature (J. Med. Chem., 1992, 35 (23), 4344-4361; J. Med. Chem., 1996, 39 (3), 749-756; Synthesis, 2002, 7, 911-915; J. Med. Chem., 1999, 42 (26), 5359-5368; Eur. J. Med. Chem. Chim. Ther., 2000, 35 (7-8), 699-706; European Patent 449187 (1991); U.S. Patent 5252586 (1993), etc.), the reduction yield in the last step is 61 to 93%.

Both the above two routes use the expensive, flammable and explosive reagent lithium aluminum tetrahydride, which is inconvenient to operate and difficult to achieve industrial production.

Specific method:

Put 70.0g (0.507mol) potassium carbonate and 33.3g 4-piperidinecarboxylic acid (0.250mol) into 750ml water, bathe in ice water to 0~5℃, add 35.2g (0.250mol) benzoyl chloride dropwise while stirring, Complete the dripping in about 1 hour, incubate for 1 hour and then naturally rise to room temperature and stir overnight. Add 450ml of 20% dilute hydrochloric acid, extract with ethyl acetate (500ml×3), combine the organic layers, wash once with 200ml of saturated brine, and anhydrous Dry over sodium sulfate, and evaporate the solvent under reduced pressure to obtain 56.3g of white solid 1-benzoyl-4-piperidinecarboxylic acid, with a yield of 96.6%.

Dissolve 9.4g (40.3mmol) of 1-benzoyl-4-piperidinecarboxylic acid in 120ml of dimethyl sulfoxide, add 10.8g of potassium borohydride (200mmol), and add dropwise 10.0g (100mmol) of concentrated sulfuric acid. After dropping, stir at room temperature for 15 hours, add 10 ml of methanol to quench the reaction, evaporate the solvent under reduced pressure, add 100 ml of 2 mol/L sodium hydroxide aqueous solution, reflux for 2 hours, cool to room temperature, and extract with toluene (60 ml × 3). The organic layer was washed and separated with 80 ml of 10% dilute hydrochloric acid. The resulting washed aqueous layer was adjusted to 11-12 with 6 mol/L sodium hydroxide aqueous solution, and extracted with toluene (50 ml × 3). The organic layer was dried with anhydrous sodium sulfate. , the solvent was evaporated under reduced pressure to obtain 7.1 g of the target product 1-benzyl-4-piperidinemethanol, with a yield of 85.9%.

Main reference materials

[1] Zhang Fuli, Qiu Youchun, He Bingming, & Lu Yingpeng. (0). A method for preparing 1-benzyl-4-piperidinemethanol.

[2] Lu Wenchao, Li Yingqi, & Guo Chun. (2003). Improvement of the synthesis process of 1-benzyl-4-piperidone. Liaoning Chemical Industry (01), 3-4.

[3] Sun Yuesheng, Yu Hua, Xiao Wenqing, & Li An. (2006). 1-benzyl-4-(5,6-dimethoxy.1-indanone-2-methylene Synthesis of pyridine. Chemistry World.


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