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 - 45 . (canceled)
46 . 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)(OR 4 ) 2 , wherein each R 4 is independently alkyl:
47 - 48 . (canceled)
49 . The process according to claim 46 , wherein X is hydroxy.
50 . The process according to claim 46 , wherein X is alkoxy.
51 . The process according to claim 46 , wherein X is trifluoromethanesulfonate or methanesulfonate.
52 . The process according to claim 46 , wherein X is P(═O)(OR 4 ) 2 .
53 . The process according to claim 52 , wherein X is P(═O)(OMe) 2 or P(═O)(OEt) 2 .
54 . 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.
55 . The compound according to claim 54 , wherein L is Br, I, hydroxy, alkoxy, methanesulfonate, or trifluoromethanesulfonate.
56 . The compound according to claim 54 , wherein L is Br or I.
57 . The compound according to claim 54 , wherein L is hydroxy.
58 . The compound according to claim 54 , wherein L is alkoxy.
59 . The compound according to claim 54 , wherein L is trifluoromethanesulfonate.
60 . 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.
61 . The process according to claim 60 , wherein the base is present at a ratio of at least 1.5 equivalents base.
62 . The process according to claim 61 , wherein the base is present at a ratio between about 2 equivalents and about 5 equivalents.
63 . The process according to claim 60 , wherein the base is an organic base or an inorganic base.
64 . The process according to claim 63 , wherein the organic base is selected from the group consisting of an alkoxide base, an amine base, an amide base, or a mixture thereof.
65 . The process according to claim 64 , wherein the amine base is 1,8-diazabicylco[5.4.0]undec-7-ene (DBU).
66 . The process according to claim 60 , wherein L is hydroxy.
67 . The process according to claim 60 , wherein L is alkoxy.
68 . The process according to claim 60 , wherein L is trifluoromethanesulfonate.
69 . The process according to claim 60 , wherein the compound with the structure of Formula (XVII) has an HPLC purity is greater than 50%.
70 . The process according to claim 69 , wherein the compound with the structure of Formula (XVII) has an HPLC purity is greater than 80%.
71 . The process according to claim 69 , wherein the compound with the structure of Formula (XVII) has an HPLC purity is greater than 90%.