Process for the preparation of 2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl-methanol and (R)-feso-deacyl

摘要

The present invention regards an improved and industrially advantageous process for the preparation of the 2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl-methanol intermediates, also called “feso chromenyl” and (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol, also called “(R)-feso deacyl”, which are in turn used in the synthesis of fesoterodine and in particular of fesoterodine fumarate. This process utilises reagents which are non-toxic and manageable at industrial level and enables obtaining a new stable and non-hygroscopic crystalline form of the key intermediate “(R)-feso deacyl”, called form B.

主权项

1. Process for the preparation of 2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl-methanol of formula (I), comprising: a. silylating 4-hydroxymethylphenol of formula (A) with a silylating agent to obtain a bis-silylated compound of formula (B) wherein PG is a silylated protective group; b. selectively deprotecting the phenolic hydroxyl of the bis-silylated compound of formula (B) to obtain a mono-silylated compound of formula (C) c. reacting the compound of formula (C) with trans-cinnamaldehyde and a cyclic secondary amine of formula (F) wherein R4 and R5 are equal or different from each other and are hydrogen, C1-C6 alkyl or aryl and n varies between 1 and 4; W is (CH2)m with m varying between 0 and 1, NR6 (with R6=C1-C6 alkyl or aryl), O or S; to obtain a compound of formula (D) d. deprotecting the compound of formula (D), to obtain a compound of formula (E) and e. hydrolyzing the compound of formula (E) to provide the compound of formula (I).