Processes and intermediates for preparing a Btk inhibitor

Patent metadata

Field	Value
Publication number	US-12459948-B2
Application number	US-202017612034-A
Country	US
Kind code	B2
Filing date	May 20, 2020
Priority date	May 21, 2019
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Disclosed is a process for the preparation of certain intermediates, e.g. process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in an enantioenriched form, which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

First claim

The invention claimed is:

1 . A process for preparing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, in an enantioenriched form, wherein:
R 1 is hydrogen or a nitrogen protecting group;
* is a chiral centre of an (R) configuration;

and the process comprises reductive hydrazination of a compound of formula (II):

or a salt thereof, with a compound of formula (III):
H 2 N—N(H)—R 2   (III)

or a salt thereof, wherein R 2 is hydrogen or a nitrogen protecting group to form a compound of formula (IV):

or a salt thereof, followed by, in any order at least one of:
optionally deprotecting R 2 (when R 2 is a nitrogen protecting group),
optionally introducing R 1 at the NH moiety of the piperidinyl ring (when R 1 is a nitrogen protecting group) to form a product, and
optionally resolving the product.

2 . The process of claim 1 , wherein the compound of formula (IV) is converted to a compound of formula (V) (wherein R 1 is a nitrogen protecting group) via intermediate compound of formula (VA) (wherein, R 1 and R 2 are, independently, nitrogen protecting groups:

3 . The process of claim 2 , further comprising resolving the compound of formula (V) to provide the compound of formula (I).

4 . The process of claim 1 , wherein the reductive hydrazination is conducted in the presence of a hydrogen source and a suitable catalyst.

5 . The process of claim 4 , wherein the suitable catalyst is a metal catalyst.

6 . The process of claim 5 , wherein the metal catalyst is a palladium, nickel or platinum catalyst.

7 . The process of claim 5 , wherein the metal catalyst is a palladium catalyst.

8 . The process of claim 7 , wherein the palladium catalyst is palladium on carbon (Pd/C).

9 . The process of claim 8 , wherein the palladium catalyst is 5-10% Pd/C.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Pye Philip James
• Horvath Andras
• Lefort Laurent
• Kaptein Bernardus
• Verzijl Gerardus Karel Maria
• Yuan Yuanyuan
• Su Jinxiong

Classifications

• C07D211/56 Primary

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title

• A61K31/519

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

• C07C59/255

  Tartaric acid · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D211/98

  Nitrogen atom · CPC title