GB2558514A — Process for the synthesis of stable amorphous ibrutinib

USPTO Abstract

Process for the production of amorphous ibrutinib 4 comprising: a) reacting compound 1 with a 3-position functionalised (X) and amino-protected (Z) piperidine, wherein X is a leaving group and Z is an amino-protecting group, to yield compound 2; b) deprotection of compound 2 to yield compound 3; c) reacting compound 3 and acryloyl chloride (2-propenoyl chloride) in a pharmaceutically acceptable solvent to yield compound 4 ibrutinib; d) filtration of the reaction mixture obtained in step c); and e) evaporation of the solvent to precipitate essentially amorphous compound 4; wherein the pharmaceutically acceptable solvent of step c) comprises an electric dipole moment μ/D of ≥ 2 and ≤ 8. Disclosed herein is a new route of synthesis and a new stable amorphous form of ibrutinib. Also disclosed are pharmaceutical compositions, oral dosage forms and the use of the amorphous ibrutinib in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia.