IP Library › Patent Application 18209939
Patent Application
App. No. 18/209,939

SYNTHESIS OF A BRUTON'S TYROSINE KINASE INHIBITOR

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Quick Facts
Patent No.
US None
App. No.
18/209,939
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.

Claims (23)

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 the 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 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 31 , 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 any of claims 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)