Preparation of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine_Kain Industrial Additive

Background and overview^[1]

2-[(4-Chlorophenyl)(4-piperidinyloxy)methyl]pyridine is the key intermediate in the synthesis of bepotastine, 2-[(4-chlorophenyl)(4- Piperidinyloxy)methyl]pyridine is then separated, reacted with ethyl bromobutyrate, and hydrolyzed in three steps to obtain the final product bepotastine.

Bepotastine besylate is a drug jointly developed by Japan’s Tanabe Pharmaceuticals and Ube Industries. It is mainly used to treat allergic rhinitis, urticaria, itching, etc. It was applied for marketing in Japan in 1998 under the trade name Talion. , it has rapid action, strong selectivity, and no sedative side effects that other anti-allergic drugs have, and has very good curative effect.

Preparation^[1]

The preparation method of 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine, the detailed steps are:

(1) Add N-ethoxycarbonyl-4-piperidinol into a four-neck bottle, add toluene, 98% concentrated sulfuric acid, and then add α-(4-chlorophenyl ring)-2-pyridinemethanol. Heat the reaction system to reflux, react at the reflux temperature for 7 hours, and then lower to room temperature. The organic phase is washed with water, and the organic phase is concentrated under reduced pressure to obtain 2-[(4-chlorophenyl)(4-piperidinyloxy) Methyl]pyridine-1-carboxylic acid ethyl ester was used directly in the next step without purification;

(2) Dissolve the 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine-1-carboxylic acid ethyl ester prepared in step (1) in isopropyl alcohol, Place the solution in a reaction bottle and stir, add sodium hydroxide solid, heat to reflux and react under reflux conditions for 6 hours. After TLC detects that the reaction is complete, stop heating, cool the reaction system, distill under reduced pressure, remove and recover the solvent. After the recovery is completed, ethyl acetate is added to the residue to dissolve. The organic phase is washed with water and saturated brine. The organic phase is dried and concentrated at room temperature to recover ethyl acetate. After concentration, 2-[(4-chlorophenyl)( The crude product of 4-piperidinyloxy)methyl]pyridine was used directly in the next step without further treatment;

(3) Add ethanol and fumaric acid to crude 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine, heat the reaction system to 55-60°C, and Stir for 1 hour at room temperature, then cool to room temperature and continue stirring overnight. When solids precipitate, place the system in an ice water bath and continue stirring for 5 hours. Filter, wash the filter cake with cold ethanol, and dry to obtain 2-[(4 -Chlorophenyl)(4-piperidinyloxy)methyl]pyridine fumarate crude product;

(4) Add 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine fumarate to dichloromethane, add water and sodium hydroxide solid, and stir until The solids are all dissolved to form a clear two-phase solution. The organic phase is separated and extracted with methylene chloride from the aqueous phase. The organic phases are combined. The organic phase is washed with water and saturated sodium chloride aqueous solution in sequence. The organic phase is concentrated to recover the methylene chloride. After concentration, the product is obtained The brown oily substance is 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine.

Main reference materials

[1] CN201610448052.4 A preparation method of 4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine