Intermediate compounds and processes for the preparation of tapentadol and related compounds

A process for the preparation of a compound of formula (A):

• or stereoisomers, pharmaceutically acceptable salts, or combination thereof, comprising steps (a), (b1), (c1), (d) and (e);
• or (a), (b2), (c2), (d) and (e):
• a) a Horner-Wadsworth-Emmons (HWE) reaction between 1-(3-methoxy-phenyl)-propan-1-one and a phosphonate compound of formula (I) to obtain a compound of formula (II):
• wherein each R is independently alkyl or aryl which is optionally substituted with an electron withdrawing group;
• R′ is (i) —NR1R2 wherein R1 and R2 are each alkyl;
• (ii) —OR3 wherein R3 is alkyl, aryl or alkylaryl;
• or (iii) a functional group which can be converted to an amine group;
• and
• R″ is H, alkyl, aryl, heteroalkyl, heteroaryl, alkylaryl or cycloalkyl;
• b1) and c1):
• hydrogenating compound (II) to obtain the compound of formula (III):
• and
• optionally, when R′ is other than NMe2, converting the compound of formula (III) to a compound of formula (IV):
• or
• b2) and c2) optionally, when R′ is other than NMe2, converting the compound of formula (II) to a compound of formula (V):
• and
• hydrogenating compound (V) to obtain the compound of formula (IV):
• d) reducing the resultant compound of formula (IV) obtained in steps (c1) or (c2) to a compound of formula (VI):
• and
• e) converting the compound of formula (VI) to a compound of formula (A):