Novel process for preparing phenylcyclopropylamine derivatives using novel intermediates
AssigneeActavis Group Ptc Ehf
InventorsAnil Shahaji Khile, Jayesh Patel, Nikhil Trivedi, Nitin Sharadchandra Pradhan
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Abstract
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.
Claims22
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.
Use of the intermediate compounds of formulae III, IV, V and VI, and their stereochemically isomeric forms, in the process for manufacture of substituted phenylcyclopropylamine derivatives of formula II or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof.
1-(3′,4′-Difluorophenyl)-3-nitro-propan-1-one of formula Va:
An optically active substituted 3-nitro-1-propanol compound of formula IV:
- or a stereochemically isomeric form 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.
An optically active substituted nitrocyclopropane compound of formula III:
- or a stereo chemically isomeric form thereof or a mixture of stereo chemically isomeric forms 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 two or more halogen atoms, wherein the halogen atom is F, Cl, Br or I.
Dependencies are inferred from the claim text.