| 摘要 |
Provided herein is a novel process for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein is a novel, commercially viable and industrially advantageous process for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. The intermediate is useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity. |
| 主权项 |
1. A process for preparing substituted phenylcyclopropylamine derivatives of formula II: or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, or an acid addition salt thereof; wherein R1, R2, R3, R4 and R5 are, each independently, selected from hydrogen and a halogen atom, with the proviso that the benzene ring is substituted with at least one or more halogen atoms, wherein the halogen atom is F, Cl, Br or I; comprising: a) reacting a halogen substituted phenyl compound of formula VII: wherein R1, R2, R3, R4 and R5 are as defined in formula II; with a 3-chloropropionyl halide compound of formula VIII: wherein ‘X’ is a leaving group, selected from the group consisting of hydroxy, Cl, Br and I; in the presence of a Lewis acid in a first solvent to produce an acylated compound of formula VI: wherein R1, R2, R3, R4 and R5 are as defined above; b) nitrating the compound of formula VI with a nitrating agent, in the presence or absence of a metal iodide and an ester suppressant, in a second solvent to produce a substituted 3-nitro-1-propanone compound of formula V: c) subjecting the compound of formula V to asymmetric reduction with a reducing agent in the presence of a chiral auxiliary in a third solvent to produce an optically active substituted 3-nitro-1-propanol compound of formula IV: or a stereochemically isomeric form thereof; d) subjecting the compound of formula IV to intramolecular cyclization in the presence of an azodicarboxylate, optionally in the presence of a phosphine ligand, in a fourth solvent to produce an optically active substituted nitrocyclopropane compound of formula III: or a stereochemically isomeric form thereof or a mixture of stereochemically isomeric forms thereof; and e) reducing the substituted nitrocyclopropane compound of formula III with a reducing agent, optionally in the presence of an acid, in a fifth solvent to produce the substituted phenylcyclopropylamine derivatives of formula II or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof, and optionally converting the compound of formula II obtained into an acid addition salt thereof. |
