SYNTHESIS OF A BRUTON?S TYROSINE KINASE INHIBITOR

1 . 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 the compound of Formula (II) with a compound of Formula (III) wherein X is boronic acid, boronic ester or a halogen:

2 . The process of claim 1 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; the compound of Formula (II) with phenylboronic acid:

3 . The process of claim 2 , wherein the process comprises reacting a compound of Formula (II) with phenylboronic acid in the presence of a catalyst and a base.

4 . The process of claim 1 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; the compound of Formula (II) with a compound of Formula (III) wherein X is a halogen:

5 . The process of claim 4 , wherein the process comprises reacting the compound of Formula (II) with a compound of Formula (III) wherein X is a halogen, in the presence of copper salts.

6 . 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 (IV), wherein X is a halogen, with phenol:

7 . The process of claim 6 , wherein the process comprises reacting a compound of Formula (IV), wherein X is a halogen, with phenol in the presence of copper salts.

8 . 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 (V), wherein L is a leaving group, with ammonia:

9 . The process of claim 8 , wherein the leaving group is halogen, hydroxy, alkoxy, methanesulfonate, trifluoromethanesulfonate or —P(═O)R 6 2 wherein R 6 is independently OH, OR 7 (R 7 is alkyl) or halo.

10 . 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 reducing the compound of Formula (VI):

11 . The process of claim 10 , wherein the process comprises reducing the compound of Formula (VI) by catalytic hydrogenation.

12 . 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 reducing a compound of Formula (VII) wherein Z is halogen or trifluoromethanesulfonate:

13 . 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 reducing a compound of Formula (VIII) wherein Z is halogen or trifluoromethanesulfonate:

14 . 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 (IX) wherein X is a halogen or sulfonate, with a compound of Formula (X) wherein Y is an alkyltin, boronic acid or boronic ester:

15 . 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 (XI) wherein Y is an boronic acid or boronic ester, with a compound of Formula (XII) wherein X is a halogen or sulfonate:

16 . A process for the preparation of 1-((R)-3-(1-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-dipyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (ibrutinib), wherein ibrutinib is the compound of Formula (1), comprising reducing the compound of Formula (XIII):

17 . 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 deprotecting a compound of Formula (XIV):

18 . The process of claim 17 , wherein the protecting group is benzyl, benzyl carbamate, or t-butyl carbamate,

19 . A process for the preparation of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-dipyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (ibrutinib), wherein ibrutinib is the compound of Formula (I), comprising reacting the compound of Formula (XV) with a compound of Formula (XVI) wherein X is hydroxy, halogen, or sulfonate:

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 19 , wherein the leaving group is halogen, hydroxy, alkoxy, methanesulfonate, or trifluoromethanesulfonate.

22 . The process of claim 20 , wherein L is Cl.

23 . The process of any one of claims 20 - 22 , 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 any one of 20 - 25 , wherein an additive is also employed in the 3-elimination reaction.

27 . The process of claim 26 , wherein the additive is sodium trifluoroacetate.

28 . The process of any one of claims 20 - 27 , 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 any one of claims 20 - 29 , 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 or claim 31 , wherein the acylation is performed in the presence of a solvent.

33 . The process of claim 32 , wherein the solvent is Me-THE

34 . The process of claim 32 , wherein the solvent is ethyl acetate.

35 . The process of any of claims 30 - 34 , wherein the acylation is performed in the presence of a base.

36 . The process of claim 35 , wherein the base is NaHCO 3 .

37 . The process of any of claims 30 - 36 , wherein butylated hydroxytoluene is also added.

38 . A process for the preparation of 1-((R)-3-(4-amino-3-(4-phenoxypheny)-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 (XVIII) wherein L is a leaving group:

39 . The process of claim 38 , wherein the leaving group is halogen, hydroxy, a koxy, methanesulthnate, or trifluommethanesulfonate.

40 . 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 (1), comprising the reaction of a compound of Formula (XIX) wherein X is a halogen, with triphenylphosphine and formaldehyde:

41 . 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 reading a compound of Formula (XX) wherein X is halogen, with a compound of Formula (XXI) wherein Y is an alkyltin, boronic acid or boronic ester:

42 . 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 ibnitinib is the compound of Formula (I), comprising the hydrogenation of a compound of Formula (XXII):

wherein

reprents a compound of formula (XXIIa)-(XXIIg):

or a combination thereof.

43 . 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 condensation of the compound of Formula (XXIII) with formamide, ammonium formate, trimethyl orthoformate with ammonia, or formamidine or a salt thereof, such as hydrochloride or acetate salt:

44 . 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 reading a compound of Formula (XXIV) wherein X is a leaving group, with the compound of Formula (XXV):

45 . 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 (XXVI) wherein X is a leaving group, with acrylamide:

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:

47 . A compound according to Formula (XVII-1):

which is in a substantially isolated form.

48 . A compound according to claim 47 , which is in a substantially purified form.