Synthesis of a bruton?s tyrosine kinase inhibitor

Patent metadata

Field	Value
Publication number	US-2018009814-A1
Application number	US-201615542848-A
Country	US
Kind code	A1
Filing date	Jan 14, 2016
Priority date	Jan 14, 2015
Publication date	Jan 11, 2018
Grant date	—

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.

First claim

What is claimed is:

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.

Assignees

• Pharmacyclics Llc
• Janssen Pharmaceutica Nv

Inventors

• Benhaim Cyril
• Chen Wei
• Goldman Erick
• Horvath Andras
• Pye Philip
• Smyth Mark S
• Verner Erik J

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title