IMPROVED PROCESS FOR THE PREPARATION OF CHIRAL 3-AMINO-PIPERIDINS, USEFUL INTERMEDIATES FOR THE PREPARATION OF TOFACITINIB

• Main Authors: MIREIA PASTO AGUILA, SARA PRECIADO GALLEGO, EMANUELE MISERAZZI
• Format: Patent
• Language: Chinese; English
• Published: 15.01.2019
• Subjects: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOIDCHEMISTRY; CHEMISTRY; HETEROCYCLIC COMPOUNDS; METALLURGY; ORGANIC CHEMISTRY; PERFORMING OPERATIONS; PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL; THEIR RELEVANT APPARATUS; TRANSPORTING

The invention discloses an improved process for the preparation of chiral 3-amino-piperidins, useful intermediates for the preparation of tofacitinib. The present invention provides a process for thepreparation of a compound of formula (II) or a salt thereof. The process comprising the asymmetrical hydrogenation of the compound of formula (III) or a salt thereof, wherein the asymmetrical hydrogenation is performed in the presence of a Rh(I) complex and of an optically active ferrocenyl phosphine in a solvent. The solvent is 2,2,2-trifluoroethanol (TFE) or methanol, and the compound of formula(II) or a salt thereof has, at the asymmetric carbons marked with the symbol *, 3-R and 4-R optical configuration or 3-S and 4-S optical configuration or a mixture thereof, with the exclusion of theracemic mixture. 本发明公开了用于托法替尼制备的有用中间体手性3-氨基哌啶的改进制备方法。本发明具体涉及用于制备式(II)化合物或其盐的方法，所述方法通过式(III)化合物或其盐的不对称氢化进行，其中所述不对称氢化在溶剂中并在Rh(I)络合物和光学活性二茂铁基膦存在下进行；其中所述溶剂是2,2,2-三氟乙醇或甲醇，式(II)中用符号*标记的不对称碳具有3-R和4-R光学构型或3-S和4-S光学构型或其混合物，不包括外消旋混合物。