SYNTHESIS OF A BRUTON'S TYROSINE KINASE INHIBITOR
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.
1 - 19 . (canceled)
20 . 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 the β-elimination of a compound of Formula (XVII) wherein L is a leaving group:
21 . The process of claim 20 , wherein L is halogen, hydroxy, alkoxy, methanesulfonate, or trifluoromethanesulfonate.
22 . The process of claim 20 , wherein L is Cl.
23 . The process of claim 20 , wherein the β-elimination of the compound of Formula (XVII) is performed in the presence of a base and a solvent.
24 . The process of claim 23 , wherein the base is 1,8-diazabicycloundec-7-ene.
25 . The process of claim 23 , wherein the solvent is ethyl acetate.
26 . The process of claim 20 , wherein an additive is also employed in the β-elimination reaction.
27 . The process of claim 26 , wherein the additive is sodium trifluoroacetate.
28 . The process of claim 20 , wherein the compound of Formula (XVII) is purified by washing an organic solution containing that product with aqueous citric acid.
29 . The process of claim 28 , wherein the organic solution comprises an organic solvent that is ethyl acetate.
30 . The process of claim 20 , wherein the compound of Formula (XVII) is prepared by an acylation process comprising reaction of a compound of formula (XVII-A),
or a pharmaceutically acceptable salt thereof, with L 1 —C(O)—CH 2 CH 2 L or a salt thereof, wherein L 1 is a leaving group.
31 . The process of claim 30 , wherein the compound L 1 —C(O)—CH 2 CH 2 L is Cl—C(O)—CH 2 CH 2 Cl.
32 . The process of claim 30 , wherein the acylation is performed in the presence of a solvent.
33 . The process of claim 32 , wherein the solvent is Me-THF.
34 . The process of claim 32 , wherein the solvent is ethyl acetate.
35 . The process of claim 20 , wherein the acylation is performed in the presence of a base.
36 . The process of claim 35 , wherein the base is NaHO 3 .
37 - 46 . (canceled)
47 . A compound according to Formula (XVII-1):
which is in a substantially isolated form.
48 . (canceled)