Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides

A process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amides comprising

• (a) reducing the nitrile moiety of a compound of formula (I) to an aldehyde
• wherein A is selected from aryl, heteroaryl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl, which aryl, heteroaryl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl;
• wherein the reduction of the nitrile moiety of the compound of formula (I) is carried out via partial hydrogenation to the corresponding intermediate imine applying H2 and a metal hydrogenation catalyst, followed by subsequent hydrolysis to the compound of formula (II)
• then
• (b) reacting the compound of formula (II) in the presence of a suitable Lewis acid to obtain a compound of formula (III)
• wherein * indicates a stereocentre, then
• (c) reacting a compound of formula (III) with an ammonium salt and H2 in presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV)
• wherein * indicates a stereocentre, and then
• further reacting the amine of formula (IV) with a compound of formula (X)
• wherein Y is a suitable leaving group selected from OH, OR or halogen, R is C1-C6-alkyl, and E is selected from aryl, heteroaryl, hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl which aryl, heteroaryl, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl and C3-C7-cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkylsulfanyl, C1-C6-haloalkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-haloalkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-haloalkylsulfonyl, C2-C6-haloalkenyl and C2-C6-haloalkynyl;
• so as to form the enantiomerically and diastereomerically enriched amide of formula (VII)