NEW PROCESS FOR THE SYNTHESIS OF (1S)-4,5-DIMETHOXY-1-(METHYLAMINOMETHYL)- BENZOCYCLOBUTANE AND ADDITION SALTS THEREOF, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF, WITH A PHARMACEUTICALLY ACCEPTABLE ACID

摘要

Resolving 4,5-dimethoxy-1-aminomethyl-benzocyclobutane (IV) comprises reacting (IV) with an optically active diacid (II); filtering or centrifuging to recover the salt (VII) of (S)-(IV) and treating with base to give (VIII). Resolving 4,5-dimethoxy-1-aminomethyl-benzocyclobutane of formula (IV) comprises reacting (IV) with an optically active diacid (II); filtering or centrifuging to recover the salt of formula (VII) of (S)-(IV) and treating with base to give (VIII). Independent claims are also included for: (1) preparation of (S)-4,5-dimethoxy-1-(methylaminomethyl)benzocyclobutane (I) from the corresponding -1-cyano compound (III) comprising reducing (III) to racemic (IV); resolving (IV) to give (VIII); reacting (VIII) with ethyl chloroformate to give the optically active N-ethoxycarbonyl compound (IX); and reducing (IX) to give (I). (2) preparation of ivabradine (3-{3-[{[(7S)-3,4-dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) (II) from (I). [Image] [Image].