Synthesis of a bruton's tyrosine kinase inhibitor
AssigneesPharmacyclics, Inc., Janssen Pharmaceutica NV
InventorsCyril Ben Haim, Wei Chen, Erick Goldman, Andras Horvath, Philip Pye, Mark S. Smyth, Erik J. Verner
Life of this patent
Estimating the term…
Abstract
Described herein is the synthesis of Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one.
Claims26
1-45. (canceled)
A process for the preparation of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (ibrutinib), wherein ibrutinib is the compound of Formula (I), comprising reacting a compound of Formula (XXVII) with a compound of Formula (XXVIII), wherein X is a leaving group selected from the group consisting of hydroxy, alkoxy, sulfonate, and P(═O)(OR4)2, wherein each R4 is independently alkyl:
47-48. (canceled)
A compound according to Formula (XVII):
- wherein L is selected from the group consisting of Br, I, hydroxy, alkoxy, sulfonate, phosphate, substituted phosphate or dialkoxyphosphoryl.
A process for the preparation of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (ibrutinib), wherein ibrutinib is the compound of Formula (I), comprising a beta-elimination of a compound with the structure of Formula (XVII), wherein L is a leaving group selected from the group consisting of hydroxy, alkoxy, methanesulfonate, and trifluoromethanesulfonate:
- wherein the beta-elimination is carried out at a reaction temperature between about 0° C. and about 60° C. and in the presence of at least one equivalent of base, for a period between about 1 hour and about 24 hours.
Dependencies are inferred from the claim text.