Preparation of N-Boc-4-piperidinemethanol_Industrial additives

Background and overview^[1]

Piperidine is a very important six-membered nitrogen heterocyclic compound, and many natural products contain piperidine structural units. Piperidine ring is the most common heterocyclic ring in drugs. Piperidine can be used to synthesize agricultural chemicals and rubber additives. Piperidine can also synthesize a variety of important fine chemical intermediates. Piperidine is introduced into the molecules of fine chemicals. The pyridine structural unit has become one of the important means for developing new products. Piperidine derivatives have important research value in the pharmaceutical field as drug intermediates. N-Boc-copper antioxidant 4-piperidinemethanol is also an important drug intermediate for piperidine derivatives and is mainly used in the synthesis of drugs for various neurological diseases, such as convulsions, anti-epilepsy, sedation, etc.

Preparation^[1-2]

Report 1,

Dissolve 4-hydroxymethylpiperidine (5.0g, 43.41mmol) in 50ml dichloromethane, add 9ml triethylamine (65.12mmol) and place in an ice bath. Dissolve 10.5g Boc acid anhydride in 50ml methylene chloride, and add it dropwise into the reaction bottle under ice bath conditions. After completion, stir at room temperature overnight. Afterwards, 50 ml of water was added to the reaction solution to quench the reaction, and the DCM was washed twice with saturated sodium bicarbonate water (50 ml), twice with water (50 ml), and twice with brine (50 ml). The solvent DCM was then evaporated under reduced pressure to obtain a colorless waxy substance. Add 50 ml petroleum ether to the reaction bottle and stir for 2 hours to obtain white powder. The powder was filtered with suction and washed twice with diethyl ether (20 ml). After drying, the white powder is 8.0g. The yield is 85.6%. ¹H-NMR (300MHz, CDCl₃)4.14 (br, 2H), 3.51 (br, 1H), 2.71 (br,), 1.74 (br, 1H) , 1.71 (br, 1H), 1.69-1.64 (m, 1H), 1.61 (d, J=2.3Hz, 1H), 1.47 (s, 9H), 1.20-1.11 (m, 2H).

Report 2,

(1) Dissolve palladium chloride in deionized water to prepare a palladium chloride solution with a mass concentration of 5-20%; then add tartaric acid and continue stirring evenly to prepare a mixed solution; add ethylene glycol to the mixed solution , raise the temperature to 65°C, stir and mix for 1.2 hours to prepare a colloid; wherein, the mass ratio of palladium chloride, tartaric acid, and ethylene glycol is 3.5:0.1:0.5;

(2) Mix titanium tetrachloride and octyl ether, then add hexadecylamine and stir evenly, add it to a three-necked flask, raise the temperature to 160°C, stir for 30 minutes under an inert gas atmosphere, then add carbon disulfide dropwise, and continue stirring. The reaction lasted for 1.2 hours. After the reaction was completed, it was cooled to room temperature to obtain a reaction solution; among which, the molar ratio of titanium tetrachloride, hexadecylamine, and carbon disulfide was 1:0.3:1.2;

(3) Add the reaction liquid prepared in step (2) dropwise to the colloid prepared in step (1). After the dropwise addition is completed, add ammonia water dropwise and stir for 15 minutes to precipitate. Filter and remove the precipitate. Wash with ionized water and dry to prepare a catalyst; wherein the catalyst includes 40% nanopalladium and 60% titanium disulfide;

(4) Use 4-pyridinecarboxylic acid as the raw material and water as the reaction solvent. Add it to the reaction kettle, then add the catalyst prepared above, mix evenly, and then add nitrogen for 5 minutes in advance, then add hydrogen, and raise the temperature to 80-95°C, react for 1.5 hours. After the reaction is completed, cool to room temperature, remove the catalyst and water, add methanol crystallization to the liquid, and centrifuge to prepare 4-piperidinecarboxylic acid; among them, the mass ratio of 4-picolinic acid to catalyst is 1 :0.005;

(5 Dow reverse osmosis membrane) Dissolve the 4-piperidinecarboxylic acid prepared above in deionized water, then add potassium hydroxide and ethanol, stir until the solid is dissolved, and prepare a reaction liquid; and transfer the reaction liquid into the three-necked flask, add the ethanol solution of (Boc)O, and stir the reaction after the dropwise addition. After the reaction is completed, cool and crystallize, and the precipitate is washed with petroleum ether and dried to obtain N-Boc-4-piperidinecarboxylic acid;

(6) Use N-Boc-4-piperidinecarboxylic acid as the reaction raw material, tetrahydrofuran as the solvent, and under the reduction of sodium borohydride, add organic iodine at -5~0°C and react for 3.5 hours. After completion, deionized water is added dropwise at room temperature, stirring while dropping. After the dropwise addition is completed, filter, the filtrate is allowed to stand and separate into layers. The solid obtained by removing the solvent from the organic phase is added to the water phase, stirred and mixed, and extracted with ethyl acetate. , the organic phase was dried with anhydrous copper sulfate, and the ethyl acetate was evaporated to remove the product N-Boc-4 piperidinemethanol;

References

[1] Efficient synthesis method of CN201810625680.44-piperidine acetate methyl ester

[2]CN201910847790.X donepezil-oxadiazole fusion compound and its preparation method and application