4-[2-(1-Azepanyl)ethoxy]benzyl chloride HCl

Uses

1-[2-[4-(Chloromethyl)phenoxy]ethyl]hexahydro-1H-azepine Hydrochloride is a useful synthetic intermediate in the synthesis of Bazedoxifene (B129250); a nonsteroidal selective estrogen receptor modulator (SERM). Also used as an antiosteoporotic.

Synthesis

S4: (4-(2-(Azepan-1-yl)ethoxy)phenyl)methanol (561 g) obtained from step S3 was dissolved in 1.2 L of tetrahydrofuran and cooled to 0 °C. Thionyl chloride (320 g) was added slowly and dropwise under stirring, keeping the reaction temperature not exceeding 55 °C, and the reaction was gradually warmed up at this temperature for 6 hours. Upon completion of the reaction, about 600 mL of solvent was removed by distillation. To the residue was added 300 mL of ethyl acetate, the mixture was cooled to 0 °C and stirred for 30 minutes. It was subsequently filtered and the solid was washed with 300 mL of ethyl acetate. The resulting solid was dried to give 1-(2-(4-(chloromethyl)phenoxy)ethyl)azepane hydrochloride (619 g) in 90% yield and 99% HPLC purity.

References

[1] Patent: CN107400087, 2017, A. Location in patent: Paragraph 0045
[2] Patent: WO2011/22596, 2011, A2. Location in patent: Page/Page column 4; 24
[3] Patent: WO2011/22596, 2011, A2. Location in patent: Page/Page column 22; 23
[4] Angewandte Chemie - International Edition, 2013, vol. 52, # 22, p. 5795 - 5798
[5] Angew. Chem., 2013, p. 5999