Processes and intermediates for preparing a Btk inhibitor

Patent metadata

Field	Value
Publication number	US-12358917-B2
Application number	US-202217719607-A
Country	US
Kind code	B2
Filing date	Apr 13, 2022
Priority date	Oct 6, 2016
Publication date	Jul 15, 2025
Grant date	Jul 15, 2025

Abstract

Disclosed is a process for the preparation of certain intermediates, e.g. the following compound:

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):

in an enantio enriched form, wherein:
R 1 is hydrogen,
R 2 is tert-butyloxycarbonyl (BOC);
* is a chiral centre of an(S) configuration;

the process comprising Savinase enzymatic kinetic resolution of a compound of formula (II):

in the presence of (i) an acyl donor that is vinyl butyrate or o-cresol methoxy acetate, (ii) a solvent that is toluene, methyl-tetrahydrofuran, or tert-amyl alcohol, and (ii) an inorganic base that is sodium carbonate (Na 2 CO 3 ), triethylamine (Et 3 N), or N,N-diisopropylethylamine (DIPEA).

2. The process of claim 1 , wherein the acyl donor is vinyl butyrate.

3. The process of claim 1 , wherein at least one equivalent of acyl donor is used compared to the compound of formula (II).

4. The process of claim 3 , where two equivalents of acyl donor are employed compared to the compound of formula (II).

5. The process of claim 1 , wherein the Savinase is AH24, AH06, AH09, AH 17, AH 19, AH24, and/or Subtilisin.

6. The process of claim 1 , wherein the process is performed at a temperature of between 25 and 40° C.

7. The process of claim 1 , wherein the resolution is a dynamic kinetic resolution, performed in the presence of a racemisation catalyst.

8. The process of claim 7 , wherein the racemisation catalyst is selected from the group consisting of compound I, compound II, compound III, and compound IV:

9. The process of claim 1 , further comprising:
separation/isolation of the compound of formula (I); and
conversion of the compound of formula (I) to ibrutinib.

10. The process of claim 9 , comprising converting the compound of formula (I) to ibrutinib using the following steps:

11. The process of claim 1 , wherein the inorganic base is sodium carbonate.

12. The process of claim 1 , wherein the solvent is toluene.

13. The process of claim 6 , wherein the temperature is between 25 and 35° C.

14. The process of claim 13 , wherein the temperature is 30° C.

15. The process of claim 1 , wherein the solvent is methyl-tetrahydrofuran.

16. The process of claim 1 , wherein the solvent is tert-amyl alcohol.

17. The process of claim 1 , wherein the inorganic base is triethylamine.

18. The process of claim 1 , wherein the organic base is N-diisopropylethylamine.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ben Haim Cyril
• Michiels Thomas Joost Martti
• Medina Florian Damien
• Wagschal Simon Albert
• Depré Dominique Paul M

Classifications

• C07B55/00

  Racemisation; Complete or partial inversion · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D473/32 Primary

  Nitrogen atom · CPC title

• C07D211/42 Primary

  attached in position 3 or 5 · CPC title